HK1124337A

HK1124337A - Nuclear receptor binding agents

Info

Publication number: HK1124337A
Application number: HK09103854.0A
Authority: HK
Inventors: J‧T‧多尔顿; C‧巴雷特; 何雅丽; S-S‧洪; D‧D‧米勒; M‧L‧莫勒; R‧纳拉亚南; Z‧吴
Original assignee: Gtx公司
Priority date: 2005-11-28
Filing date: 2006-11-28
Publication date: 2009-07-10

Description

Nuclear receptor binding agents

Technical Field

The present invention relates to a novel class of Nuclear Receptor Binding Agents (NRBAs). The NRBA compounds are useful in the prevention and/or treatment of a variety of diseases and disorders, particularly hormone-related diseases, cancer, inflammation, osteoporosis, peripheral vascular disease, neurological disorders, ocular diseases, cardiovascular diseases and obesity.

Background

The nuclear hormone receptor superfamily of ligand-activated transcription factors is present in a variety of tissues and is responsible for many effects in these tissues.

The Nuclear Receptor (NR) superfamily currently comprises approximately 48 different proteins, most of which are thought to function as ligand-activated transcription factors that produce many different biological responses by regulating gene expression. Members of this family include receptors for endogenous small lipophilic molecules, such as steroid hormones, retinoids, vitamin D, and thyroid hormones.

The Nuclear Receptor (NR) superfamily includes a subfamily of steroid nuclear receptors such as Mineralocorticoid Receptor (MR) (or aldosterone receptor), Estrogen Receptor (ER), era and ER β, Androgen Receptor (AR), Progesterone Receptor (PR), Glucocorticoid Receptor (GR), and the like. Also structurally closely related are the Estrogen Related Receptors (ERRs), ERR- α, ERR- β and ERR- γ. Steroid nuclear receptors perform important functions in the body, some of which are associated with electrolyte transcriptional homeostasis and water balance, growth, development and wound healing, fertility, stress response, immune function, and cognitive function. These effects may be mediated by either cytosolic or nuclear events. Thus, compounds that modulate (i.e., antagonize, agonize, partially antagonize, partially agonize) steroid nuclear receptor activity are important agents with clear utility in a number of ways, as well as for the treatment and prevention of a variety of diseases and conditions modulated by steroid nuclear receptor activity.

Members of the steroid nuclear receptor subfamily exhibit significant homology to each other and have closely related DNA and ligand binding domains.

Due to the close similarity in the ligand binding domains of steroid nuclear receptors, it is not surprising that many naturally occurring and synthetic molecules have the ability to modulate the activity of more than one steroid nuclear receptor.

Summary of The Invention

In one embodiment, the present invention provides a Nuclear Receptor Binding Agent (NRBA), which in one embodiment is a Selective Estrogen Receptor Modulator (SERM) compound or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof, represented by the structure of formula I:

wherein

X is CO, CS, (CH)₂)_qBranched alkyl, branched alkyl having a haloalkyl side chain, haloalkyl, C (O) (CH)₂)_qSO or SO₂；

R₁、R₂And R₃Independently hydrogen, halogen, aldehyde, COOH, CHNOH, CH ═ CHCO₂H. Hydroxyalkyl, hydroxy, alkoxy, cyano, nitro, CF₃、NH₂、NHR、NHCOR、N(R)₂Sulfonamide, SO₂R, alkyl, aryl, protected hydroxy, OCH₂CH₂NR₄R₅、Z-Alk-Q、Z-Alk-NR₄R₅Z-Alk-heterocycles or OCH₂CH₂-a heterocycle, wherein the heterocycle is a 3-7 membered substituted or unsubstituted heterocycle, optionally aromatic,

Or R₁、R₂Or R₃To the R groupThe linked benzene rings together form a fused ring system represented by structure A

Wherein

R₆And R₇Independently is R₁、R₂Or R₃；

R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F、CHF₂、CF₃、CF₂CF₃Aryl, phenyl, halogen, alkenyl, CN, NO₂Or OH;

R₄and R₅Independently hydrogen, phenyl, alkyl of 1 to 6 carbon atoms, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered heteroaryl;

z is O, NH, CH₂Or

Q is SO₃H、CO₂H、CO₂R、NO₂Tetrazole, SO₂NH₂Or SO₂NHR；

j. k, l are independently 1-5;

q is 1 to 5;

alk is a C1-7 straight-chain alkyl group, a C1-7 branched-chain alkyl group, or a C3-8 cycloalkyl group; and is

X is (CH) if k is 1₂)_qCO or C (O) (CH)₂)_qAnd R is₂Is OCH₂CH₂NR₄R₅Or OCH₂CH₂-heterocyclic ring, then R₁Or R₃Not hydrogen, lower alkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogenAn element, nitro or amino group;

x is (CH) if l is 1₂)_qCO or C (O) (CH)₂)_qAnd R is₃Is OCH₂CH₂NR₄R₅Or OCH₂CH₂-heterocyclic ring, then R₁Or R₂Other than hydrogen, lower alkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro or amino.

In one embodiment, the present invention provides NRBA, which in one embodiment is a SERM compound or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof, represented by the structure of formula I:

Wherein

X is CS, branched alkyl with halogenated alkyl side chain, halogenated alkyl, SO or SO₂；

R₁、R₂And R₃Independently hydrogen, halogen, aldehyde, COOH, CHNOH, CH ═ CHCO₂H. Hydroxyalkyl, hydroxy, alkoxy, cyano, nitro, CF₃、NH₂、NHR、NHCOR、N(R)₂Sulfonamide, SO₂R, alkyl, aryl, protected hydroxy, OCH₂CH₂NR₄R₅、Z(CH₂)_qQ、Z-Alk-NR₄R₅Z-Alk-heterocycles or OCH₂CH₂-a heterocycle, wherein the heterocycle is a 3-7 membered substituted or unsubstituted heterocycle, optionally aromatic;

or R₁、R₂Or R₃Together with the benzene ring to which the R group is attached form a fused ring system represented by structure A

Wherein R is₆And R₇Independently is R₁、R₂Or R₃；

z is O, NH, CH₂Or

Q is SO₃H、CO₂H、CO₂R、NO₂Tetrazole, SO₂NH₂Or SO₂NHR；

j. k, l are independently 1-5;

q is 1 to 5;

alk is a straight chain alkyl of 1-7 carbons, a branched alkyl of 1-7 carbons, or a cycloalkyl of 3-8 carbons.

In one embodiment the present invention provides NRBA, which in one embodiment is a SERM compound or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof, represented by the structure of formula II:

Wherein

R₆And R₇Independently is R₁、R₂Or R₃；

z is O, NH, CH₂Or

Q is SO₃H、CO₂H、CO₂R、NO₂Tetrazole, SO₂NH₂Or SO₂NHR; q is 1 to 5;

X is (CH) if k is 1₂)_qCO or C (O) (CH)₂)_qAnd R is₂Is OCH₂CH₂NR₄R₅Or OCH₂CH₂-heterocyclic ring, then R₁Or R₃Is not hydrogen, lower alkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro or amino;

wherein

X is CS,Branched alkyl, branched alkyl with haloalkyl side chains, haloalkyl, SO or SO₂；

R₁、R₂And R₃Independently hydrogen, halogen, aldehyde, COOH, CHNOH, CH ═ CHCO₂H. Hydroxyalkyl, hydroxy, alkoxy, cyano, nitro, CF₃、NH₂、NHR、NHCOR、N(R)₂Sulfonamide, SO₂R, alkyl, aryl, protected hydroxy, OCH₂CH₂NR₄R₅、Z-Alk-Q、Z-Alk-NR₄R₅Z-Alk-heterocycles or OCH₂CH₂-a heterocycle, wherein the heterocycle is a 3-7 membered substituted or unsubstituted heterocycle, optionally aromatic;

Wherein R is₆Or R₇Independently is R₁、R₂Or R₃；

R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH ₂F、CHF₂、CF₃、CF₂CF₃Aryl, phenyl, halogen, alkenyl, CN, NO₂Or OH;

z is O, NH, CH₂Or

Q is SO₃H、CO₂H、CO₂R、NO₂Tetrazole, SO₂NH₂Or SO₂NHR；

In another embodiment, the present invention provides NRBA, which in one embodiment is a SERM compound or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof, represented by the structure of formula III:

wherein

A is a ring selected from:

b is a ring selected from:

c is a ring selected from:

W₁And W₂Independently hydrogen, halogen, aldehyde, COOH, CHNOH, CH ═ CHCO₂H. Hydroxyalkyl, hydroxy, alkoxy, cyano, nitro, CF₃、NH₂、NHR、NHCOR、N(R)₂Sulfonamide, SO₂R, alkyl, aryl, protected hydroxy, OCH₂CH₂NR₄R₅、Z-Alk-Q、Z-Alk-NR₄R₅Z-Alk-heterocycles or OCH₂CH₂-a heterocycle, wherein the heterocycle is a 3-7 membered substituted or unsubstituted heterocycle, optionally aromatic;

z is O, NH, CH₂Or

n is 0 to 5;

alk is a C1-7 straight-chain alkyl group, a C1-7 branched-chain alkyl group, or a C3-8 cycloalkyl group;

A. b and C cannot be benzene rings at the same time; and is

If X is (CH)₂)_qCO or C (O) (CH)₂)_qA is a pyridine ring, B and C are benzene rings, and C is OCH₂CH₂NR₄R₅Or OCH₂CH₂-heterocycle substituted, then a or B is not substituted with hydrogen, lower alkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro or amino;

if X is (CH)₂)_qCO or C (O) (CH)₂)_qA is a pyridine ring, B and C are benzene rings, and B is OCH₂CH₂NR₄R₅Or OCH₂CH₂-heterocycle substituted, then a or C are not substituted by hydrogen, lower alkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro or amino.

In another embodiment, the present invention provides NRBA, which in one embodiment is a SERM compound or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof, represented by the structure of formula IV:

Wherein

or R₁、R₂And R₃Together with the benzene ring to which the R group is attached form a fused ring system represented by structure A

Wherein

R₆And R₇Independently is R₁、R₂Or R₃；

z is O, NH, CH₂Or

Q is SO₃H、CO₂H、CO₂R、NO₂Tetrazole, SO₂NH₂Or SO₂NHR；

j. k, l are independently 1-5;

q is 1 to 5;

In another embodiment, the present invention provides NRBA, which in one embodiment is a SERM compound or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof, represented by the structure of formula V:

Wherein

R₆And R₇Independently is R₁、R₂Or R₃；

R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F、CHF₂、CF₃、CF₂CF₃Aryl, phenyl, halogen, CN, NO₂Alkenyl or OH;

z is O, NH, CH₂Or

In another embodiment, the present invention provides NRBA, which in one embodiment is a SERM compound or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof, represented by the structure of formula VI:

Wherein

R₁、R₂、R₃、R₈、R₉And R₁₀Independently hydrogen, halogen, aldehyde, COOH, CHNOH, CH ═ CHCO₂H. Hydroxyalkyl, hydroxy, alkoxy, cyano, nitro, CF₃、NH₂、NHR、NHCOR、N(R)₂Sulfonamide, SO₂R, alkyl, aryl, protected hydroxy, OCH₂CH₂NR₄R₅、Z-Alk-Q、Z-Alk-NR₄R₅Z-Alk-heterocycles or OCH₂CH₂-a heterocycle, wherein the heterocycle is a 3-7 membered substituted or unsubstituted heterocycle, optionally aromatic;

Wherein

R₆And R₇Independently is R₁、R₂Or R₃；

z is O, NH, CH₂Or

Q is SO₃H、CO₂H、CO₂R、NO₂Tetrazole, SO₂NH₂Or SO₂NHR；

j. k, l are independently 1-4;

q is 1 to 5;

X is (CH) if k is 1₂)_qCO or C (O) (CH)₂)_qAnd R is₂Is OCH₂CH₂NR₄R₅Or OCH₂CH₂-heterocycle, and R ₉Is hydrogen, lower alkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro or amino, then R₁Or R₃Is not hydrogen, lower alkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro or amino;

x is (CH) if l is 1₂)_qCO or C (O) (CH)₂)_qAnd R is₃Is OCH₂CH₂NR₄R₅Or OCH₂CH₂-heterocycle, and R₁₀Is hydrogen, lower alkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro or amino; then R₁Or R₂Is not hydrogen, lower alkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro or amino.

In another embodiment, the 3-7 membered substituted or unsubstituted heterocyclic ring, optionally aromatic, is represented by the structure of formula B:

wherein Y is CH₂CH, a bond, O, S, NH, N or NR;

if B is aryl, then z is 1; and if B is cycloalkyl, then z is 2;

m is 0 to 4;

n is 0 to 4;

where m and n cannot both be 0.

In one embodiment, B is a substituted or unsubstituted piperidine; in another embodiment, B is substituted or unsubstituted pyrrolidine; in another embodiment, B is substituted or unsubstituted morpholine; in another embodiment, B is a substituted or unsubstituted piperazine.

In one embodiment, the present invention provides NRBA, which in one embodiment is a SERM compound or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof, represented by the structure of formula VII:

wherein X is CS, (CH)₂)_qBranched alkyl, branched alkyl having a haloalkyl side chain, haloalkyl, C (O) (CH)₂)_qSO or SO₂；

Or X is CO and OH is in the meta or ortho position.

In another embodiment, the present invention provides NRBA, which in one embodiment is a SERM compound or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof, represented by the structure of formula VIII:

wherein XIs CS, (CH)₂)_qBranched alkyl, branched alkyl having a haloalkyl side chain, haloalkyl, C (O) (CH)₂)_qSO or SO₂；

Or X is CO and OH is in the meta or ortho position.

In another embodiment, the present invention provides NRBA, which in one embodiment is a SERM compound or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof, represented by the structure of formula IX:

Wherein X is CO, CS, (CH)₂)_qBranched alkyl, branched alkyl having a haloalkyl side chain, haloalkyl, C (O) (CH)₂)_qSO or SO₂；

R₄And R₅Independently hydrogen, phenyl, alkyl of 1 to 6 carbon atoms, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, 3-7 membered heteroaryl; or R₄And R₅Together with the nitrogen atom, form a 3-7 heterocyclic ring, optionally aromatic, represented by the structure of formula B:

wherein Y is CH₂CH, a bond, O, S, NH, N or NR;

if B is aryl, then z is 1; and if B is cycloalkyl, then z is 2;

m is 0 to 4;

n is 0 to 4;

wherein m and n cannot both be 0;

q is 1 to 5;

p is 1 to 4;

r is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F、CHF₂、CF₃、CF₂CF₃Aryl, phenyl, halogen, alkenyl, CN, NO₂Or OH.

In another embodiment, the present invention provides NRBA, which in one embodiment is a SERM compound or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof, represented by the structure of formula X:

wherein

X is CO, CS, (CH)₂)_qBranched alkyl, branched alkyl having a haloalkyl side chain, haloalkyl, C (O) (CH) ₂)_qSO or SO₂；

R₁、R₂、R₃、R₈、R₉、R₁₀、R₁₁、R₁₂And R₁₃Independently hydrogen, halogen, aldehyde, COOH, CHNOH, CH ═ CHCO₂H. Hydroxyalkyl, hydroxy, alkoxy, cyano, nitro, CF₃、NH₂、NHR、NHCOR、N(R)₂Sulfonamide, SO₂R, alkyl, aryl, protected hydroxy, OCH₂CH₂NR₄R₅、Z-Alk-Q、Z-Alk-NR₄R₅Z-Alk-heterocycles or OCH₂CH₂-a heterocycle, wherein the heterocycle is a 3-7 membered substituted or unsubstituted heterocycle, optionally aromatic(ii) of a family;

Wherein

R₆And R₇Independently is R₁、R₂Or R₃；

R₄and R₅Independently hydrogen, phenyl, alkyl of 1 to 6 carbon atoms, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered heteroaryl; or R₄And R₅Together with the nitrogen atom, form a 3-7 heterocyclic ring, optionally aromatic, represented by the structure of formula B:

wherein Y is CH₂CH, a bond, O, S, NH, N or NR;

if B is aryl, then z is 1; and if B is cycloalkyl, then z is 2;

m is 0 to 4;

n is 0 to 4;

wherein m and n cannot both be 0;

q is 1 to 5;

p is 1 to 4;

r is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH ₂F、CHF₂、CF₃、CF₂CF₃Aryl, phenyl, halogen, alkenyl, CN, NO₂Or OH.

Z is O, NH, CH₂Or

Q is SO₃H、CO₂H、CO₂R、NO₂Tetrazole, SO₂NH₂Or SO₂NHR；

j. k, l are independently 1-3;

q is 1 to 5;

X is (CH) if k is 1₂)_qCO or C (O) (CH)₂)_qAnd R is₂Is OCH₂CH₂NR₄R₅Or OCH₂CH₂-heterocycle, and R₉And R₁₂Is hydrogen, lower alkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro or amino,

then R₁Or R₃Is not hydrogen, lower alkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro or amino;

x is (CH) if l is 1₂)_qCO or C (O) (CH)₂)_qAnd R is₃Is OCH₂CH₂NR₄R₅Or OCH₂CH₂-heterocycle, and R₁₀And R₁₃Is hydrogen, lower alkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro or amino,

then R₁Or R₂Is not hydrogen, lower alkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro or amino.

In one embodiment, the present invention provides a method of reducing circulating lipid levels in a male subject with prostate cancer who has undergone androgen blockade therapy (ADT), comprising administering to the subject a composition comprising a Nuclear Receptor Binding Agent (NRBA) compound or a pharmaceutically acceptable salt, hydrate, N-oxide, or any combination thereof.

In one embodiment, the present invention provides a method of treating atherosclerosis and its related diseases including cardiovascular disorders, cerebrovascular disorders, peripheral vascular disorders, and intestinal vascular disorders in an individual having prostate cancer who has undergone androgen blockade therapy (ADT), comprising administering to the individual a composition comprising a Nuclear Receptor Binding Agent (NRBA) compound or a pharmaceutically acceptable salt, hydrate, N-oxide, or any combination thereof.

In one embodiment, the present invention provides a method of treating ischemia in a tissue of an individual having prostate cancer who has undergone androgen blockade therapy (ADT), comprising administering to the individual a composition comprising a Nuclear Receptor Binding Agent (NRBA) compound or a pharmaceutically acceptable salt, hydrate, N-oxide, or any combination thereof.

In another embodiment, the present invention provides the following method: the use of the Nuclear Receptor Binding Agents (NRBAs) of the invention, which in one embodiment are SERM compounds, for (i) the treatment and prevention of osteoporosis; (ii) treating, preventing or reducing the risk of death from cardiovascular disease in an individual; (iii) improving lipid profile; (iv) inhibiting, suppressing, treating or reducing the incidence of androgen-blockade induced osteoporosis, bone fracture and/or Bone Mineral Density (BMD) in men with prostate cancer; (v) ameliorating symptoms and/or clinical complications associated with menopause in a female subject; (vi) treating, preventing or lessening the severity of alzheimer's disease in an individual; (vii) treating, preventing, suppressing, inhibiting or reducing the incidence of hot flashes, male breast development and/or hair loss in a male individual; (viii) treating, suppressing, inhibiting or reducing the risk of developing prostate cancer in a subject; (ix) treating, suppressing, inhibiting or reducing the amount of a pre-cancerous precursor damaged by prostate cancer; (x) Treating, preventing, inhibiting or reducing the risk of developing breast cancer in an individual; (xi) Treating, suppressing, inhibiting or reducing the risk of colon cancer in an individual; (xii) Treating, suppressing, inhibiting or reducing the risk of developing leukemia in an individual; (xiii) Treating, suppressing, inhibiting or reducing the risk of developing bladder cancer in an individual; (xiv) Treating, suppressing, inhibiting or reducing the incidence of inflammation in a subject; (xv) Treating, suppressing, inhibiting or reducing the incidence of a neurological disorder in an individual; (xvi) Treating, suppressing, inhibiting or reducing the incidence of ocular diseases; (xvii) Reducing lipid profiles in a male subject with prostate cancer who has experienced ADT; (xviii) Treating, suppressing, inhibiting or reducing the risk of atherosclerosis in a male individual with prostate cancer who has experienced ADT; (xix) Treating, suppressing, inhibiting or reducing the risk of ischemia of a tissue in a male subject with prostate cancer who has experienced ADT.

Brief Description of Drawings

The subject matter regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of the specification. The invention, however, both as to organization and method of operation, together with objects, features, and advantages thereof, may best be understood by reference to the following description, taken in conjunction with the accompanying drawings in which:

FIG. 1: effect of the compounds shown on ER- α transactivation. COS or 293 cells plated at 90000 cells per well in 24-well plates with 10% charcoal-treated fetal bovine serum (csFBS) in phenol red-free DME were transfected by cationic liposomes (lipofectamine) with 0.25. mu.g ERE-LUC, 0.02. mu.g CMV-LUC (flower worm type) and 25 ngER-alpha. At 24 hours post-transfection, cells were treated as indicated, and at 48 hours post-transfection, cells were harvested and assayed for firefly-type and anthlemna-type luciferases.

FIG. 2: effect of the compounds shown on ER- β transactivation. COS or 293 cells plated at 90000 cells per well in 24-well plates in 10% csFBS-containing phenol-free DME were transfected by cationic liposomes with 0.25. mu.g ERE-LUC, 0.02. mu.g CMV-LUC (flower worm type) and 50ng ER-beta. At 24 hours post-transfection, cells were treated as indicated, and at 48 hours post-transfection, cells were harvested and assayed for firefly-type and anthlemna-type luciferases.

FIG. 3: effect of the compounds shown on AR transactivation. COS cells plated at 90000 cells per well in a 24-well plate with 10% csFBS in phenol red-free DME were transfected by cationic liposomes with 0.25. mu.g ARE-LUC, 0.02. mu.g CMV-LUC (flower worm type) and 12.5ng AR. At 24 hours post-transfection, cells were treated as indicated, and at 48 hours post-transfection, cells were harvested and assayed for firefly-type and anthlemna-type luciferases.

FIG. 4: compound 4a acts as a partial agonist of ER function in MCF-7 cells. MCF-7 cells were plated at a density of 500000 cells per well in 6-well plates. The cells were serum starved (serum static) for 3 days, followed by treatment or no treatment for 16 hours as indicated. RNA was isolated, message hierarchy of pS2 (a gene encoding trefoil peptide) was determined by real-time polymerase chain reaction (rtPCR) and normalized to 18S ribosomal RNA.

FIG. 5: effect of the compounds shown on ER- α transactivation. COS or 293 cells plated at 90000 cells per well in 24-well plates in 10% csFBS-containing phenol-free DME were transfected by cationic liposomes with 0.25. mu.g ERE-LUC, 0.02. mu.g CMV-LUC (flower worm type) and 5ng ER-alpha. At 24 hours post-transfection, cells were treated as indicated, and at 48 hours post-transfection, cells were harvested and assayed for firefly-type and anthlemna-type luciferases.

FIG. 6: effect of the compounds shown on ER- β transactivation. COS or 293 cells plated at 90000 cells per well in 24-well plates in 10% csFBS-containing phenol-free DME were transfected by cationic liposomes with 0.25. mu.g ERE-LUC, 0.02. mu.g CMV-LUC (flower worm type) and 50ng ER-beta. At 24 hours post-transfection, cells were treated as indicated, and at 48 hours post-transfection, cells were harvested and assayed for firefly-type and anthlemna-type luciferases.

FIG. 7: effect of the indicated compounds on TRAP-positive multinucleated osteoclasts. Bone marrow cells of rat femurs were cultured in phenol red free α MEM + 10% csFBS in the presence or absence of 30ng/mL RANKL and 10ng/mL GMCSF. Cells were treated for 12 days, stained for tartrate-resistant acid phosphatase activity (TRAP) and multinucleated osteoclasts were counted.

FIG. 8: some embodiments of the invention include inhibiting androgen-independent prostate cancer cell growth by a compound of the invention. PC-3 cells were plated in RPMI + 10% csFBS at 6000 cells per well of a 96-well plate. The medium was changed to phenol red free RPMI + 1% csFBS and then treated with increasing concentrations of SERMs for 72 hours.

FIG. 9: effect of the compounds shown on ER- α transactivation. COS or 293 cells plated at 90000 cells per well in 24-well plates in 10% csFBS-containing phenol-free DME were transfected by cationic liposomes with 0.25. mu.g ERE-LUC, 0.02. mu.g CMV-LUC (flower worm type) and 25ng ER-alpha. At 24 hours post-transfection, cells were treated as indicated, and at 48 hours post-transfection, cells were harvested and assayed for firefly-type and anthlemna-type luciferases.

FIG. 10: effect of the compounds shown on ER- β transactivation. COS or 293 cells plated at 90000 cells per well in 24-well plates in 10% csFBS-containing phenol-free DME were transfected by cationic liposomes with 0.25. mu.g ERE-LUC, 0.02. mu.g CMV-LUC (flower worm type) and 50ng ER-beta. At 24 hours post-transfection, cells were treated as indicated, and at 48 hours post-transfection, cells were harvested and assayed for firefly-type and anthlemna-type luciferases.

FIG. 11: agonistic activity of the indicated compounds in MCF-7 cells. MCF-7 cells were plated at a density of 500000 cells per well in 6-well plates. The cells were starved for 3 days, followed by treatment or no treatment for 16 hours as indicated. RNA was isolated, message-level of pS2 was determined by real-time polymerase chain reaction (rtPCR) and normalized to 18S ribosomal RNA.

FIG. 12: estrogenic activity of compound 3d as determined by increased uterine tissue weight (mg) in vivo, compared to toremifene (Tor) and estradiol (E2).

FIG. 13: estrogenic activity of compounds 4a and 4h as determined by increased uterine tissue weight (mg) in vivo compared to toremifene (Tor) and estradiol (E2).

FIG. 14: effect of the indicated compounds on TARP positive multinucleated osteoclasts.

FIG. 15: circulating lipid levels in prostate cancer patients undergoing ADT following treatment with toremifene are described.

Detailed Description

In some embodiments, the present invention provides novel NRBAs (which in some embodiments are SERM compounds) and compositions comprising the compounds.

In some embodiments, the present invention provides NRBAs, which in one embodiment are SERMs. In one embodiment, the phrase "selective estrogen receptor modulator" or "SERM" refers to a compound that affects the activity of the estrogen receptor. In one embodiment, the SERM exhibits activity as an agonist, or, in another embodiment, as an antagonist, or, in another embodiment, as a partial agonist, or, in another embodiment, as a partial antagonist of the estrogen receptor. In one embodiment, the SERM acts on estrogen receptors (e.g., ER α, ER β, or ERRs) in a tissue-dependent manner. In some embodiments, the SERMs of the present invention can act as estrogen receptor agonists in some tissues (e.g., bone, brain, and/or heart) and as antagonists in other tissue types, such as breast and/or endometrium.

In one embodiment, the SERMs of the invention will have up to about 10 μ Μ for era and/or ER β, as determined using art-known ER α and/or ER β transactivation assays or in other embodiments as described herein (examples 1, 2)IC of₅₀Or EC₅₀. In some embodiments, the SERMs exhibit an IC of no more than about 5 μ M₅₀Or EC₅₀Values (as agonists or antagonists). Representative compounds of the invention have been found to exhibit agonist or antagonist activity at the estrogen receptor. In some embodiments the compounds of the invention exhibit an antagonist or agonist IC of no more than about 5 μ M for ER α and/or ER β as measured in an ER α and/or ER β transactivation assay₅₀Or EC₅₀Or in some embodiments, no more than about 500nM, or in other embodiments, no more than about 1 nM. In some embodiments, the term "IC₅₀"refers to a concentration of SERM that reduces the activity of a target (e.g., ER α or ER β) to half of the maximum level. In some embodiments, the term "EC₅₀"refers to the concentration of SERM that produces half of the maximal effect.

In some embodiments of the invention, the compounds of the invention are characterized by a structure that contains a phenyl group added to a bisphenol agonist, thereby forming a triphenyl-based agent. In some embodiments, the triphenyl group is rigidly immobilized by an amide bond. In some embodiments, in addition to the triphenyl group, the SERMs may be characterized by a structure that contains a basic side chain (tertiary amine), which in some embodiments is present as an N-substituted ethanolamine side chain attached to one or two phenolic ether groups.

SERMs：

In one embodiment, the present invention provides a SERM compound, or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof, represented by the structure of formula I:

wherein

X is CO, CS, (CH)₂)_qBranched alkyl, branched alkyl having a haloalkyl side chain, haloalkyl, (C) O (CH)₂)_qSO or SO₂；

Wherein

R₆And R₇Independently is R₁、R₂Or R₃；

Z is O, NH, CH₂Or

Q is SO₃H、CO₂H、CO₂R、NO₂Tetrazole, SO₂NH₂Or SO₂NHR；

j. k, l are independently 1-5;

q is 1 to 5;

x is (CH) if l is 1₂)_qCO or C (O) (CH)₂)_qAnd R is₃Is OCH₂CH₂NR₄R₅Or OCH₂CH₂-heterocyclic ring, then R₁Or R₂Is not hydrogen, lower alkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro or amino.

In another embodiment, the present invention provides a SERM compound, or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof, represented by the structure of formula I:

wherein

R₁、R₂And R₃Independently hydrogen, halogen, aldehyde, COOH, CHNOH, CH ═ CHCO₂H. Hydroxyalkyl, hydroxy, alkoxy, cyano, nitro, CF₃、NH₂、NHR、NHCOR、N(R)₂Sulfonamide, SO ₂R, alkyl, aryl, protected hydroxy, OCH₂CH₂NR₄R₅、Z(CH₂)_qQ、Z-Alk-NR₄R₅Z-Alk-heterocycles or OCH₂CH₂-a heterocycle, wherein the heterocycle is a 3-7 membered substituted or unsubstituted heterocycle, optionally aromatic,

Wherein R is₆And R₇Independently is R₁、R₂Or R₃；

z is O, NH, CH₂Or

Q is SO₃H、CO₂H、CO₂R、NO₂Tetrazole, SO₂NH₂Or SO₂NHR；

j. k, l are independently 1-5;

q is 1 to 5;

In another embodiment, the present invention provides a SERM compound, or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof, represented by the structure of formula II:

Wherein:

R₆and R₇Independently is R₁、R₂Or R₃；

z is O, NH, CH₂Or

Q is SO₃H、CO₂H、CO₂R、NO₂Tetrazole, SO₂NH₂Or SO₂NHR；

q is 1 to 5;

x is (CH) if l is 1 ₂)_qCO or C (O))(CH₂)_qAnd R is₃Is OCH₂CH₂NR₄R₅Or OCH₂CH₂-heterocyclic ring, then R₁Or R₂Is not hydrogen, lower alkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro or amino.

In another embodiment, according to this aspect of the invention, X is CO and R₁、R₂And R₃Is OH, or in another embodiment, X is CO, R₁Is OCH₂CH₂Piperidine HCl salt, R₂Is H, and R₃Is OH.

wherein

Wherein R is₆And R₇Independently is R₁、R₂Or R₃；

z is O, NH, CH₂Or

Q is SO₃H、CO₂H、CO₂R、NO₂Tetrazole, SO₂NH₂Or SO₂NHR；

In another embodiment, the present invention provides a SERM compound, or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof, represented by the structure of formula III:

wherein

A is a ring selected from:

b is a ring selected from:

c is a ring selected from:

W₁And W₂Independently hydrogen, halogen, hydroxyl, aldehyde, COOH, CHNOH, CH ═ CHCO₂H. Hydroxyalkyl, alkoxy, cyano, nitro, CF₃、NH₂、NHR、NHCOR、N(R)₂Sulfonamide, SO₂R, alkyl, aryl, protected hydroxy, OCH ₂CH₂NR₄R₅、Z-Alk-Q、Z-Alk-NR₄R₅Z-Alk-heterocycles or OCH₂CH₂-a heterocycle, wherein the heterocycle is a 3-7 membered substituted or unsubstituted heterocycle, optionally aromatic;

r is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F，CHF₂、CF₃、CF₂CF₃Aryl, phenyl, halogen, alkenyl, CN, NO₂Or OH;

z is O, NH, CH₂Or

Q is SO₃H、CO₂H、CO₂R、NO₂Tetrazole, SO₂NH₂Or SO₂NHR；

q is 1 to 5;

n is 0 to 5;

and A, B and C cannot be both benzene rings; and is

In another embodiment, the present invention provides a SERM compound, or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof, represented by the structure of formula IV:

Wherein

R₁、R₂And R₃Independently hydrogen, halogen, hydroxyl, aldehyde, COOH, CHNOH, CH ═ CHCO₂H. Hydroxyalkyl, alkoxy, cyano, nitro, CF₃、NH₂、NHR、NHCOR、N(R)₂Sulfonamide, SO₂R, alkyl, aryl, protected hydroxy, OCH₂CH₂NR₄R₅、Z-Alk-Q、Z-Alk-NR₄R₅Z-Alk-heterocycles or OCH₂CH₂-a heterocycle, wherein the heterocycle is a 3-7 membered substituted or unsubstituted heterocycle, optionally aromatic;

Wherein

R₆And R₇Independently is R₁、R₂Or R₃；

z is O, NH, CH₂Or

Q is SO₃H、CO₂H、CO₂R、NO₂Tetrazole, SO₂NH₂Or SO₂NHR；

j. k, l are independently 1-5;

q is 1 to 5;

In another embodiment, the present invention provides a SERM compound, or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof, represented by the structure of formula V:

R₁、R₂And R₃Independently hydrogen, aldehyde, COOH, CHNOH, CH ═ CHCO₂H. Hydroxyalkyl, halogen, hydroxy, alkoxy, cyano, nitro, CF₃、NH₂、NHR、NHCOR、N(R)₂Sulfonamide, SO₂R, alkyl, aryl, protected hydroxy, OCH₂CH₂NR₄R₅、Z-Alk-Q、Z-Alk-NR₄R₅Z-Alk-heterocycles or OCH₂CH₂-a heterocycle, wherein the heterocycle is a 3-7 membered substituted or unsubstituted heterocycle, optionally aromatic;

Wherein

R₆And R₇Independently is R₁、R₂Or R₃；

z is O, NH, CH₂Or

Q is SO₃H、CO₂H、CO₂R、NO₂Tetrazole, SO₂NH₂Or SO₂NHR；

q is 1 to 5;

In another embodiment, the present invention provides a SERM compound, or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof, represented by the structure of formula VI:

Wherein

R₆And R₇Independently is R₁、R₂Or R₃；

z is O, NH, CH₂Or

Q is SO₃H、CO₂H、CO₂R、NO₂Tetrazole, SO₂NH₂Or SO₂NHR；

j. k, l are independently 1-4;

q is 1 to 5;

alk is a straight-chain alkyl of 1 to 7 carbons, a branched-chain alkyl of 1 to 7 carbons, or a cycloalkyl of 3 to 8 carbons, and

x is (CH) if l is 1₂)_qCO or C (O) (CH)₂)_qAnd R is₃Is OCH₂CH₂NR₄R₅Or OCH₂CH₂-heterocycle, and R₁₀Is hydrogen, lower alkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro or amino, then R₁Or R₂Is not hydrogen, lower alkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro or amino.

In one embodiment of the invention, the 3-7 membered substituted or unsubstituted heterocyclic ring, optionally aromatic, is represented by the structure of formula B:

wherein Y is CH₂CH, a bond, O, S, NH, N or NR;

if B is aryl, then z is 1; and if B is cycloalkyl, then z is 2;

m is 0 to 4;

n is 0 to 4;

where m and n cannot both be 0.

In one embodiment, the present invention provides a SERM compound, or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof, represented by the structure of formula VII:

Or X is CO and OH is in the meta or ortho position.

In another embodiment, the present invention provides a Selective Estrogen Receptor Modulator (SERM) compound, or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof, represented by the structure of formula VIII:

wherein X is CS, (CH)₂)_qBranched alkyl, branched alkyl having a haloalkyl side chain, haloalkyl, C (O) (CH)₂) q, SO or SO₂；

Or X is CO and OH is in the meta or ortho position.

In another embodiment, the present invention provides a SERM compound, or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof, represented by the structure of formula IX:

wherein Y is CH₂CH, a bond, O, S, NH, N or NR;

if B is aryl, then z is 1; and if B is cycloalkyl, then z is 2;

m is 0 to 4;

n is 0 to 4;

wherein m and n cannot both be 0;

q is 1 to 5;

p is 1 to 4;

In another embodiment, the present invention provides a SERM compound, or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof, represented by the structure of formula X:

Wherein

R₁、R₂、R₃、R₈、R₉、R₁₀、R₁₁、R₁₂And R₁₃Independently hydrogen, halogen, aldehyde, COOH, CHNOH, CH ═ CHCO₂H. Hydroxyalkyl, hydroxy, alkoxy, cyano, nitro, CF₃、NH₂、NHR、NHCOR、N(R)₂Sulfonamide, SO₂R, alkyl, aryl, protected hydroxy, OCH₂CH₂NR₄R₅、Z-Alk-Q、Z-Alk-NR₄R₅Z-Alk-heterocycles or OCH₂CH₂-a heterocycle, wherein the heterocycle is a 3-7 membered substituted or unsubstituted heterocycle, optionally aromatic;

Wherein

R₆And R₇Independently of each otherIs R₁、R₂Or R₃；

wherein Y is CH₂CH, a bond, O, S, NH, N or NR;

if B is aryl, then z is 1; and if B is cycloalkyl, then z is 2;

m is 0 to 4;

n is 0 to 4;

Wherein m and n cannot both be 0;

q is 1 to 5;

p is 1 to 4;

r is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F、CHF₂、CF₃、CF₂CF₃Aryl, phenyl, halogen, alkenyl, CN, NO₂Or OH. Z is O, NH, CH₂Or

Q is SO₃H、CO₂H、CO₂R、NO₂Tetrazole, SO₂NH₂Or SO₂NHR；

j. k, l are independently 1-3;

q is 1 to 5;

X is (CH) if k is 1₂)_qCO or C (O) (CH)₂)_qAnd R is₂Is OCH₂CH₂NR₄R₅Or OCH₂CH₂-heterocycle, and R₉And R₁₂Is hydrogen, lower alkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro or amino, then

R₁Or R₃Is not hydrogen, lower alkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro or amino;

x is (CH) if l is 1₂)_qCO or C (O) (CH)₂)_qAnd R is₃Is OCH₂CH₂NR₄R₅Or OCH₂CH₂-heterocycle, and R₁₀And R₁₃Is hydrogen, lower alkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro or amino;

In one embodiment the NRBA or SERM compound of the invention is 4-methoxy-N, N-bis- (4-methoxyphenyl) -benzamide (2 a). In one embodiment the NRBA or SERM compound of the invention is 3-methoxy-N, N-bis- (4-methoxyphenyl) -benzamide (2 b). In one embodiment the NRBA or SERM compound of the invention is 4-methoxy-N- (4-methoxyphenyl) -N- (3-methoxyphenyl) -benzamide (2 c). In one embodiment the NRBA or SERM compound of the invention is N, N-bis- (4-methoxyphenyl) -benzamide (2 d). In one embodiment the NRBA or SERM compound of the invention is 4-methoxy-N, N-diphenyl-benzamide (2 e). In one embodiment the NRBA or SERM compound of the invention is 3-methoxy-N, N-diphenyl-benzamide (2 f). In one embodiment the NRBA or SERM compound of the invention is N, N-diphenyl-benzamide (2 g). In one embodiment the NRBA or SERM compound of the invention is N- (4-methoxyphenyl) -N-phenyl-benzamide (2 h). In one embodiment the NRBA or SERM compound of the invention is N- (3-methoxyphenyl) -N-phenyl-benzamide (2 i). In one embodiment the NRBA or SERM compound of the invention is 4-methoxy-N- (4-methoxyphenyl) -N-phenyl-benzamide (2 j). In one embodiment the NRBA or SERM compound of the invention is 4-methoxy-N- (3-methoxyphenyl) -N-phenyl-benzamide (2 k). In one embodiment the NRBA or SERM compound of the invention is N, N-bis (4-methoxyphenyl) -4-fluorobenzamide (2 l). In one embodiment the NRBA or SERM compound of the invention is 4-methoxy-N, N-diphenyl-sulfonamide (2 m). In one embodiment the NRBA or SERM compound of the invention is 4-methoxy-N- (4-methoxyphenyl) -N- (4-fluorophenyl) -benzamide (2N). In one embodiment the NRBA or SERM compound of the invention is 4-methoxy-N- (4-methoxyphenyl) -N- (1-naphthyl) -benzamide (2 o). In one embodiment the NRBA or SERM compound of the invention is N- (4-methoxyphenyl) -N- (4-benzyloxyphenyl) -1-naphthamide (2 p). In one embodiment the NRBA or SERM compound of the invention is 4-chloro-N- (4-methoxyphenyl) -N- (4-benzyloxyphenyl) -benzamide (2 q). In one embodiment the NRBA or SERM compound of the invention is 4-cyano-N- (4-methoxyphenyl) -N- (4-benzyloxyphenyl) -benzamide (2 r). In one embodiment the NRBA or SERM compound of the invention is N- (4-methoxyphenyl) -N- (4-benzyloxyphenyl) -2-naphthamide (2 s). In one embodiment the NRBA or SERM compound of the invention is 4- (benzyloxy) -N- [4- (benzyloxy) phenyl ] -N- (4-methoxyphenyl) benzamide (2 t). In one embodiment the NRBA or SERM compound of the invention is N- [4- (benzyloxy) phenyl ] -4-methoxy-N- (4-methoxyphenyl) benzamide (2 u). In one embodiment the NRBA or SERM compound of the invention is N- [4- (benzyloxy) phenyl ] -N-biphenyl-4-yl-4-methoxybenzamide (2 v). In one embodiment the NRBA or SERM compound of the invention is 4-cyano-N- (4-methoxyphenyl) -N-phenylbenzamide (2 w). In one embodiment the NRBA or SERM compound of the invention is 3-methoxy-N- (4-methoxyphenyl) -N-phenylbenzamide (2 ×). In one embodiment the NRBA or SERM compound of the invention is 4-cyano-N- (3-methoxyphenyl) -N-phenylbenzamide (2 y). In one embodiment the NRBA or SERM compound of the invention is 4-cyano-N, N-biphenylbenzamide (2 z). In one embodiment the NRBA or SERM compound of the invention is 4-hydroxy-N, N-bis- (4-hydroxyphenyl) -benzamide (3 a). In one embodiment the NRBA or SERM compound of the invention is 3-hydroxy-N-bis- (4-hydroxyphenyl) -benzamide (3 b). In one embodiment the NRBA or SERM compound of the invention is 4-hydroxy-N- (4-hydroxyphenyl) -N- (3-hydroxyphenyl) -benzamide (3 c). In one embodiment the NRBA or SERM compound of the invention is N, N-bis- (4-hydroxyphenyl) -benzamide (3 d). In one embodiment the NRBA or SERM compound of the invention is 4-hydroxy-N, N-diphenyl-benzamide (3 e). In one embodiment the NRBA or SERM compound of the invention is 3-hydroxy-N, N-diphenyl-benzamide (3 f). In one embodiment the NRBA or SERM compound of the invention is N- (4-hydroxyphenyl) -N-phenyl-benzamide (3 g). In one embodiment the NRBA or SERM compound of the invention is N- (3-hydroxyphenyl) -N-phenyl-benzamide (3 h). In one embodiment the NRBA or SERM compound of the invention is 4-hydroxy-N- (4-hydroxyphenyl) -N-phenyl-benzamide (3 i). In one embodiment the NRBA or SERM compound of the invention is 4-hydroxy-N- (3-hydroxyphenyl) -N-phenyl-benzamide (3 j). In one embodiment the NRBA or SERM compound of the invention is N, N-bis (4-hydroxyphenyl) -4-fluoro-benzamide (3 k). In one embodiment the NRBA or SERM compound of the invention is 4-hydroxy-N, N-diphenyl-phenyl-sulfonamide (3 l). In another embodiment, the NRBA or SERM compound of the invention is 4-hydroxy-N- (4-hydroxyphenyl) -N- (fluorophenyl) -benzamide (3 m). In another embodiment, the NRBA or SERM compound of the present invention is N, N-bis (4-hydroxyphenyl) -1-naphthamide (3N). In one embodiment the NRBA or SERM compound of the invention is 4-hydroxy-N- (1-naphthyl) -N- (4-hydroxyphenyl) -benzamide (3 o). In one embodiment the NRBA or SERM compound of the invention is 4-cyano-N, N-bis (4-hydroxyphenyl) -benzamide (3 p). In one embodiment the NRBA or SERM compound of the invention is 3-cyano-N, N-bis (4-hydroxyphenyl) -benzamide (3 q). In another embodiment, the NRBA or SERM compound of the present invention is N, N-bis (4-hydroxyphenyl) -2-naphthamide (3 r). In one embodiment the NRBA or SERM compound of the invention is 4-cyano-N- [4- (2-piperidin-1-ylethoxy) -phenyl ] -N- (4-hydroxyphenyl) -benzamide (3 s). In another embodiment, the NRBA or SERM compound of the invention is 3-chloro-N- [4- (2-piperidin-1-ylethoxy) -phenyl ] -N- (4-hydroxyphenyl) -benzamide (3 t). In one embodiment the NRBA or SERM compound of the invention is N-biphenyl-4-yl-N- (4-hydroxyphenyl) -4-methoxybenzamide (3 u). In one embodiment the NRBA or SERM compound of the invention is N-biphenyl-4-yl-4-hydroxy-N- (4-hydroxyphenyl) -benzamide (3 v). In one embodiment the NRBA or SERM compound of the invention is 4-hydroxy-N- (4-hydroxyphenyl) -N- [4- (2-piperidin-1-ylethoxy) phenyl ] -benzamide (3 w). In another embodiment, the NRBA or SERM compound of the present invention is 3-hydroxy-N- (4-hydroxyphenyl) -N-phenyl-benzamide (3 x). In one embodiment the NRBA or SERM compound of the invention is N-biphenyl-4-yl-4-hydroxy-N- [4- (2-piperidin-1-ylethoxy) phenyl ] -benzamide (3 y). In another embodiment, the NRBA or SERM compound of the invention is N- (4-hydroxyphenyl) -N- [4- (2-piperidin-1-ylethoxy) -phenyl ] -benzamide (4 a). In another embodiment, the NRBA or SERM compound of the invention is N- (phenyl) -N- [4- (2-piperidin-1-ylethoxy) -phenyl ] -benzamide (4 b). In another embodiment, the NRBA or SERM compound of the invention is N, N-diphenyl- [3- (2-piperidinylethoxy) ] -benzamide hydrochloride (4 c). In another embodiment, the NRBA or SERM compound of the invention is N, N-diphenyl- [3- (2-piperidinylethoxy) ] -benzamide hydrochloride (4 d). In another embodiment, the NRBA or SERM compound of the present invention is N- (4-hydroxyphenyl) -N-phenyl- [4- (2-piperidin-1-ylethoxy) ] -benzamide hydrochloride (4 e). In one embodiment the NRBA or SERM compound of the invention is N, N-diphenyl-bis [4- (2-piperidin-1-ylethoxy) -phenyl ] -sulfonamide hydrochloride (4 f). In another embodiment, the NRBA or SERM compound of the present invention is N- (4-fluorophenyl) -N- [ 4-hydroxyphenyl ] - [4- (2-piperidin-1-ylethoxy) ] -benzamide (4 g). In another embodiment, the NRBA or SERM compound of the invention is N- (4-hydroxyphenyl) -N- [4- (2-piperidin-1-ylethoxy) -phenyl ] -4-fluoro-benzamide hydrochloride (4 h). In one embodiment the NRBA or SERM compound of the invention is 3- (2-piperidin-1-ylethoxy) -N, N-bis (4-hydroxyphenyl) -benzamide (4 i). In another embodiment, the NRBA or SERM compound of the invention is 4-cyano-N- [4- (2-piperidin-1-ylethoxy) -phenyl ] -N- (4-methoxyphenyl) -benzamide (4 j). In another embodiment, the NRBA or SERM compound of the invention is 4-chloro-N- [4- (2-piperidin-1-ylethoxy) -phenyl ] -N- (4-methoxyphenyl) -benzamide (4 k). In one embodiment the NRBA or SERM compound of the invention is 4-cyano-N- [4- (2-piperidin-1-ylethoxy) -phenyl ] -N- (4-methoxyphenyl) -benzamide (4 l). In another embodiment, the NRBA or SERM compound of the invention is 3-chloro-N- [4- (2-piperidin-1-ylethoxy) -phenyl ] -N- (4-methoxyphenyl) -benzamide (4 m). In another embodiment, the NRBA or SERM compound of the invention is 4-methoxy-N- (4-methoxyphenyl) -N- [4- (2-piperidin-1-ylethoxy) phenyl ] -benzamide (4N). In one embodiment the NRBA or SERM compound of the invention is N-biphenyl-4-yl-N- (4-hydroxyphenyl) -4- (2-piperidin-1-ylethoxy) -benzamide (4 o). In another embodiment, the NRBA or SERM compound of the invention is 4-methoxy-N-phenyl-N- [4- (2-piperidin-1-ylethoxy) phenyl ] -benzamide (4 p). In another embodiment, the NRBA or SERM compound of the invention is N- (4-hydroxyphenyl) -N-phenyl-3- (2-piperidin-1-ylethoxy) -benzamide (4 q). In another embodiment, the NRBA or SERM compound of the present invention is N- (4-fluorophenyl) -N- [4- (2-piperidin-1-ylethoxy) -phenyl ] - [4- (2-piperidin-1-yl-ethoxy) ] -benzamide dihydrochloride (4 r). In another embodiment, the NRBA or SERM compound of the invention is N, N-bis [4- (2-piperidin-1-ylethoxy) -phenyl ] -4-fluoro-benzamide dihydrochloride (4 s). In another embodiment, the NRBA or SERM compound of the present invention is N, N-bis [4- (2-piperidin-1-ylethoxy) -phenyl ] -benzamide dihydrochloride (4 t). In one embodiment the NRBA or SERM compound of the invention is N- [4- (2-piperidin-1-ylethoxy) -phenyl ] -N-phenyl- [4- (2-piperidin-1-ylethoxy) ] -benzamide dihydrochloride (4 u). In one embodiment the NRBA or SERM compound of the invention is 4-chloro-N- [ 4-hydroxyphenyl ] -N- (4-methoxyphenyl) -benzamide (5 a). In one embodiment the NRBA or SERM compound of the invention is 4-cyano-N- [ 4-hydroxyphenyl ] -N- (4-methoxyphenyl) -benzamide (5 b). In one embodiment the NRBA or SERM compound of the invention is 3-chloro-N- [ 4-hydroxyphenyl ] -N- (4-methoxyphenyl) -benzamide (5 c). In one embodiment the NRBA or SERM compound of the invention is 4-hydroxy-N- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -benzamide (5 d). In one embodiment the NRBA or SERM compound of the invention is N- (4-hydroxyphenyl) -4-methoxy-N- (4-methoxyphenyl) -benzamide (5 e). In one embodiment the NRBA or SERM compound of the invention is 2- (N- (4-methoxyphenyl) -4-methylphenylsulfonylamino) ethyl 4-methylbenzenesulfonate (6 a). In one embodiment the NRBA or SERM compound of the invention is (R) -3-bromo-2-hydroxy-N- (4-methoxyphenyl) -2-methylpropanamide (6 b). In one embodiment the NRBA or SERM compound of the invention is (S) -2-hydroxy-N, 3-bis (4-methoxyphenyl) -2-methylpropanamide (6 c). In one embodiment the NRBA or SERM compound of the invention is (S) -2-hydroxy-3- (4-methoxyphenoxy) -N- (4-methoxyphenyl) -2-methylpropanamide (6 d). In one embodiment the NRBA or SERM compound of the invention is (R) -3-bromo-2-hydroxy-N- (4-hydroxyphenyl) -2-methylpropanamide (6 e). In one embodiment the NRBA or SERM compound of the invention is (S) -2-hydroxy-3- (4-hydroxyphenoxy) -N- (4-hydroxyphenyl) -2-methylpropanamide (6 f). In one embodiment the NRBA or SERM compound of the invention is (S) -2-hydroxy-N, 3-bis (4-hydroxyphenyl) -2-methylpropanamide (6 g). In another embodiment, the NRBA or SERM compound of the invention is 5- [ 4-methoxy-phenyl ] -5H-phenanthridin-6-one (7 a). In another embodiment, the NRBA or SERM compound of the invention is 5- [ 4-hydroxy-phenyl ] -5H-phenanthridin-6-one (7 b). In one embodiment the NRBA or SERM compound of the invention is 5- [4- (2-piperidin-1-ylethoxy) -phenyl ] -5H-phenanthridin-6-one (7 c). In another embodiment, the NRBA or SERM compound of the present invention is cyclohexane-carboxylic acid bis (4-hydroxyphenyl) -amide (8 b). In another embodiment, the NRBA or SERM compound of the present invention is 4-cyano-N- (4-hydroxyphenyl) -N-phenylbenzamide (10 a). In another embodiment, the NRBA or SERM compound of the invention is N- (biphenyl-4-yl) -4-cyano-N- (4-methoxyphenyl) -benzamide (10 b). In another embodiment, the NRBA or SERM compound of the present invention is N, N-bis (4-hydroxyphenyl) biphenyl-4-carboxamide (10 c). In another embodiment, the NRBA or SERM compound of the present invention is N, N-bis (4-hydroxyphenyl) -3, 4-dimethylbenzamide (10 d). In another embodiment, the NRBA or SERM compound of the invention is N- (biphenyl-4-yl) -4-cyano-N- (4-hydroxyphenyl) -benzamide (10 e). In another embodiment, the NRBA or SERM compound of the present invention is 3-fluoro-4-hydroxy-N- (4-hydroxyphenyl) -N-phenylbenzamide (10 f). In another embodiment, the NRBA or SERM compound of the present invention is 4-fluoro-3-hydroxy-N, N-bis (4-hydroxyphenyl) -benzamide (10 g). In another embodiment, the NRBA or SERM compound of the present invention is 4-hydroxy-N, N-bis (4-hydroxyphenyl) -3, 5-dimethylbenzamide (10 i). In another embodiment, the NRBA or SERM compound of the present invention is N, N-bis (4-hydroxyphenyl) -2, 3-dimethylbenzamide (10 j). In another embodiment, the NRBA or SERM compound of the present invention is 3-fluoro-4-hydroxy-N, N-bis (4-hydroxyphenyl) -benzamide (10 k). In another embodiment, the NRBA or SERM compound of the invention is N, N-bis (4-hydroxyphenyl) -4-propylbenzamide (10 l). In another embodiment, the NRBA or SERM compound of the present invention is 3, 4-dihydroxy-N, N-bis (4-hydroxyphenyl) -benzamide (10 m). In another embodiment, the NRBA or SERM compound of the present invention is 4-hydroxy-N, N-bis (4-hydroxyphenyl) -3-methylbenzamide (10N). In another embodiment, the NRBA or SERM compound of the invention is N- (4-hydroxyphenyl) -N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) -4-propylbenzamide (10 o). In another embodiment, the NRBA or SERM compound of the invention is N- (4-hydroxyphenyl) -2, 3-dimethyl-N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) -benzamide (10 p). In another embodiment, the NRBA or SERM compound of the present invention is N, N-bis (4-hydroxyphenyl) -2, 4-dimethylbenzamide (10 q). In another embodiment, the NRBA or SERM compound of the present invention is N, N-bis (4-hydroxyphenyl) -3, 5-dimethylbenzamide (10 r). In another embodiment, the NRBA or SERM compound of the invention is N, N-bis (4-hydroxyphenyl) -4-methylbenzamide (10 s). In another embodiment, the NRBA or SERM compound of the present invention is 4, 4' - (2, 3-dimethyl-benzylazalidinyl) diphenol (10 t). In another embodiment, the NRBA or SERM compound of the present invention is 4-formyl-N, N-bis (4-hydroxyphenyl) -benzamide (10 u). In another embodiment, the NRBA or SERM compound of the present invention is N-cyclohexyl-4-hydroxy-N- (4-hydroxyphenyl) benzamide (10 w). In another embodiment, the NRBA or SERM compound of the invention is 4- ((4-fluorophenyl) (4-hydroxybenzyl) amino) phenol (10 ×). In another embodiment, the NRBA or SERM compound of the invention is N- (4- (2- (dimethylamino) ethoxy) phenyl) -N- (4-hydroxy-phenyl) -benzamide (10 y). In another embodiment, the NRBA or SERM compound of the invention is 3-cyano-N- (4-hydroxyphenyl) -N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) -benzamide (10 z). In another embodiment, the NRBA or SERM compound of the invention is N- (4-hydroxyphenyl) -N- (4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) benzamide (11 a). In another embodiment, the NRBA or SERM compound of the invention is N, N-bis (4-hydroxyphenyl) -4- (trifluoromethyl) -benzamide (11 b). In another embodiment, the NRBA or SERM compound of the invention is N- (4-hydroxyphenyl) -N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) -4- (trifluoromethyl) -benzamide (11 c). In another embodiment, the NRBA or SERM compound of the invention is N, N-bis (4-hydroxyphenyl) -4-nitro-benzamide (11 d). In another embodiment, the NRBA or SERM compound of the invention is 3-fluoro-N, N-bis (4-hydroxyphenyl) -benzamide (11 e). In another embodiment, the NRBA or SERM compound of the invention is N- (4-hydroxyphenyl) -N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) -1-naphthamide (11 f). In another embodiment, the NRBA or SERM compound of the present invention is 3-fluoro-N- (4-hydroxyphenyl) -N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) benzamide (11 g). In another embodiment, the NRBA or SERM compound of the invention is N- (4-hydroxyphenyl) -4-nitro-N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) benzamide (11 h). In another embodiment, the NRBA or SERM compound of the invention is N, N-bis (4-hydroxyphenyl) -4-methoxy-1-naphthamide (11 i). In another embodiment, the NRBA or SERM compound of the invention is N- (4-hydroxyphenyl) -N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) -2-naphthamide (11 j). In another embodiment, the NRBA or SERM compound of the invention is 2-hydroxy-N, 2-tris (4-hydroxyphenyl) -propionamide (11 k). In another embodiment, the NRBA or SERM compound of the invention is 4- ((hydroxyimino) methyl) -N, N-bis (4-hydroxyphenyl) benzamide (11 l). In another embodiment, the NRBA or SERM compound of the invention is N- (4-hydroxyphenyl) -2, 4-dimethyl-N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) benzamide (11 m). In another embodiment the NRBA or SERM compound of the invention is N- (4-hydroxyphenyl) -3, 5-dimethyl-N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) benzamide (11N). In another embodiment, the NRBA or SERM compound of the invention is 4- ((2, 3-dimethylbenzyl) (4- (2- (piperidin-1-yl) ethoxy) phenyl) amino) phenol (11 o). In another embodiment, the NRBA or SERM compound of the invention is N, N-bis (4-hydroxyphenyl) -4-pentylbenzamide (11 p). In another embodiment the NRBA or SERM compound of the invention is N- (4-hydroxyphenyl) -4-pentyl-N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) benzamide (11 q). In another embodiment, the NRBA or SERM compound of the present invention is 4-tert-butyl-N, N-bis (4-hydroxyphenyl) benzamide (11 r). In another embodiment the NRBA or SERM compound of the invention is 4-tert-butyl-N- (4-hydroxyphenyl) -N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) benzamide (11 s). In another embodiment, the NRBA or SERM compound of the present invention is 3- {4- [ bis- (4-hydroxy-phenyl) -carbamoyl ] -phenyl } -acrylic acid (11 t). In another embodiment, the NRBA or SERM compound of the present invention is 3- {4- [ bis- (4-hydroxy-phenyl) -carbamoyl ] -phenyl } -propionic acid (11 u). In another embodiment, the NRBA or SERM compound of the invention is N, N-bis- (4-hydroxy-phenyl) -4- (3-hydroxy-propyl) -benzamide (11 v). In another embodiment, the NRBA or SERM compound of the invention is N- (4-hydroxyphenyl) -4- (3-hydroxypropyl) -N- (4-methoxyphenyl) -benzamide (11 w). In another embodiment, the NRBA or SERM compound of the invention is 4-fluoro-N, N-bis (4-hydroxyphenyl) -2- (trifluoromethyl) -benzamide (11 x). In another embodiment, the NRBA or SERM compound of the present invention is 3-fluoro-N- (4-fluorophenyl) -4-hydroxy-N- (4-hydroxyphenyl) benzamide (11 y). In another embodiment, the NRBA or SERM compound of the invention is N- (4-hydroxyphenyl) -4-methyl-N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) benzamide (11 z). In another embodiment, the NRBA or SERM compound of the invention is N, N-bis (4-hydroxyphenyl) -isonicotinamide (11 aa). In another embodiment, the NRBA or SERM compound of the invention is N- (4-hydroxyphenyl) -N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) -isonicotinamide (11 ab). In another embodiment, the present invention provides a composition comprising an NRBA or SERM compound described herein, or any combination thereof.

In another embodiment, the SERM compound used in the methods of the present invention can be represented by the structure of formula XI:

wherein R is₁And R₂May be the same or different and is H or OH, R₃Is OCH₂CH₂OH or OCH₂CH₂NR₄R₅Wherein R is₄And R₅And may be the same or different and is H, alkyl of 1 to about 4 carbon atoms, or taken together with the nitrogen forms a cyclic 5-8 membered ring; and their pharmaceutically acceptable carriers, diluents, salts, esters or N-oxides and mixtures thereof.

In another embodiment, the SERM compound is toremifene.

In one embodiment, the term "alkyl" refers to saturated aliphatic hydrocarbons, including straight chain, branched chain, and cyclic alkyl. In one embodiment, the alkyl group has 1 to 12 carbons. In another embodiment, the alkyl group has 1 to 7 carbons. In another embodiment, the alkyl group has 1 to 6 carbons. In another embodiment, the alkyl group has 1 to 4 carbons. In another embodiment, the cycloalkyl group has 3 to 8 carbons. In another embodiment, the cycloalkyl group has 3 to 12 carbons. In another embodiment, the branched alkyl is an alkyl substituted with an alkyl side chain of 1 to 5 carbons. In another embodiment, the branched alkyl is an alkyl substituted with a haloalkyl side chain of 1 to 5 carbons. The alkyl group may be unsubstituted or substituted by halogen, haloalkyl, hydroxy, alkoxy, carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxy, thio and/or thioalkyl.

In another embodiment, "alkenyl" refers to unsaturated hydrocarbons, including straight, branched, and cyclic groups having one or more double bonds. The alkenyl group may have 1 double bond, 2 double bonds, 3 double bonds, and the like. In another embodiment, the alkenyl group has 2 to 12 carbons. In another embodiment, the alkenyl group has 2 to 6 carbons. In another embodiment, the alkenyl group has 2 to 4 carbons. Examples of alkenyl groups are ethenyl, propenyl, butenyl, cyclohexenyl and the like. Alkenyl groups may be unsubstituted or substituted by halogen, hydroxy, alkoxycarbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxy, thio and/or thioalkyl.

In another embodiment, "haloalkyl" refers to an alkyl group, as defined above, substituted with one or more halogen atoms (e.g., with F, Cl, Br, or I).

In another embodiment, "aryl" refers to an aromatic group having at least 1 carbocyclic or heterocyclic aryl group, which may be unsubstituted or substituted with one or more groups selected from halo, haloalkyl, hydroxy, alkoxycarbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxy, or thio or thioalkyl. Non-limiting examples of aromatic rings are phenyl, naphthyl, pyranyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridyl, furanyl, thienyl, thiazolyl, imidazolyl, isoxazolyl and the like.

In another embodiment, "hydroxy" refers to an OH group. It is understood by those skilled in the art that R in the compounds of the present invention₁、R₂Or R₃When OR, then R is not OH.

In one embodiment, the term "halogen" refers to a halogen, such as F, Cl, Br, or I.

In another embodiment, the phrase "phenol" refers to an alcohol (OH) derivative of benzene.

In one embodiment, a "heterocyclic" group refers to a ring structure that, in addition to carbon atoms, also contains sulfur, oxygen, nitrogen, or any combination thereof as part of the ring. In another embodiment, the heterocycle is a 3-12 membered ring. In another embodiment, the heterocycle is a 6 membered ring. In another embodiment, the heterocycle is a 5-7 membered ring. In another embodiment, the heterocycle is a 4-8 membered ring. In another embodiment, the heterocycle may be unsubstituted or substituted with halogen, haloalkyl, hydroxy, alkoxy, carbonyl, amido, alkylamido, dialkylamido, cyano, nitro, CO₂H. Amino, alkylamino, dialkylamino, carboxyl, thio and/or thioalkyl substituted. In another embodiment, the heterocyclic ring may be fused with another saturated or unsaturated cycloalkyl or 3-8 membered heterocyclic ring. In another embodiment, the heterocyclic ring is a saturated ring. In another embodiment, the heterocyclic ring is an unsaturated ring.

In some embodiments, reference to protected hydroxyl includes the introduction of a substituent bonded to an oxygen group of the benzene ring, wherein the substituent is readily removed. In some embodiments, the protecting group of the phenol may include: methyl ether, methoxymethyl (MOM) ether, Benzoyloxymethyl (BOM) ether, methoxyethoxymethyl (MEM) ether, 2- (trimethylsilyl) ethoxymethyl (SEM) ether, methylthiomethyl (MTM) ether, Phenylthiomethyl (PTM) ether, azidomethyl ether, cyanomethyl ether, 2-dichloro-1, 1-difluoroethyl ether, 2-chloroethyl ether, 2-bromoethyl ether, Tetrahydropyranyl (THP) ether, 1-ethoxyethyl (EE) ether, phenacyl ether, 4-bromobenzoyl methyl ether, cyclopropylmethyl ether, allyl ether, propargyl ether, isopropyl ether, cyclohexyl ether, t-butyl ether, benzyl ether, 2, 6-dimethylbenzyl ether, 4-methoxybenzyl ether, o-nitrobenzyl ether, 2, 6-dichlorobenzyl ether, 3, 4-dichlorobenzyl ether, 4- (dimethylamino) carbonylbenzyl ether, 4-methylsulfinylbenzyl ether, 4-anthracenylmethyl ether, 4-pyridylmethyl ether, heptafluoro-p-tolyl, tetrafluoro-4-pyridylether, Trimethylsilyl (TMS) ether, t-butyldimethylsilyl (TBDMS) ether, t-butyldiphenylsilyl (TBDPS) ether, Triisopropylsilyl (TIPS) ether, arylformate ester, arylacetate ester, aryllevulinate ester, arylpivalate ester, arylbenzoate ester, aryl 9-fluorenylcarboxylate ester, arylmethyl carbonate, 1-adamantyl carbonate, t-butyl carbonate, 4-methylsulfinylbenzyl carbonate, 2, 4-dimethylpent-3-ylcarbonate, aryl 2, 2, 2-trichloroethyl carbonate, Aryl benzyl carbonates, aryl carbamates, dimethylphosphinyl esters (Dmp-OAr), dimethylphosphinylthiolidene esters (Mpt-OAr), diphenylphosphinylthiolidene esters (Dpt-OAr), aryl mesylates, aryl tosylates or aryl 2-formylbenzenesulfonates.

In one embodiment, the present invention provides NRBA or SERM compounds and/or analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, drugs, hydrates, N-oxides, prodrugs, esters, polymorphs, impurities or crystals thereof or combinations thereof. In one embodiment, the present invention provides analogs of the NRBA or SERM compounds. In another embodiment, the present invention provides derivatives of NRBA or SERM compounds. In another embodiment, the present invention provides isomers of the NRBA or SERM compounds. In another embodiment, the present invention provides a metabolite of an NRBA or SERM compound. In another embodiment, the present invention provides a pharmaceutically acceptable salt of an NRBA or SERM compound. In another embodiment, the present invention provides a pharmaceutical product of an NRBA or SERM compound. In another embodiment, the present invention provides a hydrate of the NRBA or SERM compound. In another embodiment, the present invention provides N-oxides of NRBA or SERM compounds. In another embodiment, the present invention provides prodrugs of NRBA or SERM compounds. In another embodiment, the invention provides esters of NRBA or SERM compounds. In another embodiment, the present invention provides a polymorph of an NRBA or SERM compound. In another embodiment, the present invention provides crystals of the NRBA or SERM compound. In another embodiment, the invention provides an impurity of an NRBA or SERM compound. In another embodiment, the present invention provides a composition comprising an NRBA or SERM compound as described herein, or in another embodiment, the present invention provides a composition comprising a combination of an analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, ester, impurity or crystal of an NRBA or SERM compound of the present invention.

In one embodiment, the term "isomer" includes, but is not limited to: optical isomers and analogs, structural isomers and analogs, conformational isomers and analogs, and the like.

In one embodiment, the term "isomer" is intended to include optical isomers of NRBA or SERM compounds. It will be understood by those skilled in the art that the NRBA or SERMs of the present invention contain at least 1 chiral center. Thus, the NRBA or SERMs used in the process of the present invention may exist in optically active or racemic form and be isolated. Some compounds may also exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, and their use for any application is deemed to be within the scope of the present invention.

In one embodiment, the NRBAs or SERMs are pure (R) -isomers. In another embodiment, the NRBAs or SERMs are pure (S) -isomers. In another embodiment, the NRBAs or SERMs are a mixture of (R) and (S) -isomers. In another embodiment, the NRBAs or SERMs are racemic mixtures comprising equal amounts of the (R) and (S) -isomers. It is well known in the art how to prepare optically active forms (e.g., by resolution of racemic forms by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase), and such methods are considered to be part of this invention. In some embodiments, the synthesis of such racemic forms can be achieved by the methods described and exemplified herein, or appropriately modified therefrom, as would be understood by one of skill in the art.

In one embodiment, the NRBAs or SERMs are pure (E) -isomers. In another embodiment, the NRBAs or SERMs are pure (Z) -isomers. In another embodiment, the NRBAs or SERMs are a mixture of (E) and (Z) isomers.

The present invention includes "pharmaceutically acceptable salts" of the NRBAs or SERMs of the invention, which in one embodiment may be produced using amino substituted NRBAs or SERMs and organic and inorganic acids such as citric acid and hydrochloric acid. In one embodiment, the pharmaceutically acceptable salt of the NRBA compound comprising a piperidine ring is the hydrochloride salt. In another embodiment, the pharmaceutically acceptable salt of the NRBA compound comprising a pyrrole ring is the hydrochloride salt. In another embodiment, the pharmaceutically acceptable salt of the NRBA compound comprising a morpholine ring is the hydrochloride salt. In another embodiment, the pharmaceutically acceptable salt of the NRBA compound comprising a piperazine ring is the hydrochloride salt.

In other embodiments, pharmaceutically acceptable salts can be prepared from phenolic compounds by treatment with an inorganic base such as sodium hydroxide. In another embodiment, esters of the phenolic compounds (e.g., acetic acid and benzoic acid esters) may be prepared with aliphatic and aromatic carboxylic acids.

In some embodiments, the present invention provides derivatives of NRBA or SERM compounds. In one embodiment, the term "derivative" refers to ether derivatives, acid derivatives, amide derivatives, ester derivatives, and the like, as known in the art. In another embodiment, the present invention also includes hydrates of the NRBA or SERM compounds. In one embodiment, the term "hydrate" refers to hemihydrate, monohydrate, dihydrate, trihydrate, and the like, as is known in the art.

In some embodiments, the present invention provides metabolites of NRBA or SERM compounds. In one embodiment, the term "metabolite" refers to any substance produced by another substance by a metabolic or metabolic process.

In some embodiments, the NRBA or SERM of the present invention will comprise a compound listed in table 1. In some embodiments, the NRBAs or SERMs of the invention will have an affinity for nuclear hormone receptors, which may vary. In some embodiments of the invention, the activity of the NRBAs or SERMs of the invention may be altered, e.g., some NRBAs or SERMs have higher anabolic activity, some exhibit higher activity antiestrogenic activity, etc. It is to be understood that all such NRBAs or SERMs are considered part of the present invention.

In some embodiments, the NRBAs or SERMs of the invention may exhibit affinity for or bind to a nuclear receptor, which in some embodiments is an estrogen receptor alpha and/or estrogen receptor beta molecule. In some embodiments, the NRBAs or SERMs of the invention may exhibit agonist activity. In some embodiments, the NRBAs or SERMs of the invention may exhibit antagonist activity. Representative agonist and antagonist activities of NRBAs are exemplified in the examples herein, wherein such agonist and/or antagonist activities under specific experimental conditions are provided, which are merely representative of some embodiments of the present invention. It is to be understood that while the compounds shown may exhibit a particular activity under the experimental conditions employed (e.g., compound 3v is an agonist), in some embodiments such compounds may have variable, varying, or partial activity under different experimental settings as a function of the particular cell or the like employed. In some embodiments, the NRBAs or SERMs of the invention may exhibit agonist activity at a particular receptor and antagonist activity at a different receptor, or vice versa, or in some embodiments, the NRBAs or SERMs of the invention may exhibit agonist activity at a particular receptor under certain experimental conditions and antagonist activity at the same receptor under different experimental conditions, or vice versa, or in some embodiments, the NRBAs or SERMs of the invention may exhibit agonist activity at a particular receptor in a particular tissue and antagonist activity at the same receptor in a different tissue, or vice versa, or the like.

Steroid nuclear hormone receptors are known to have rapid, tissue-specific effects mediated through protein-protein interactions or kinase phosphorylation by cell surface and cytosolic receptors, which are known as non-genomic effects. For example, SERMs are known to have different rapid effects in the cardiovascular and central nervous systems, which may be mediated through different receptors. These non-genomic effect-recognized receptors include many G-protein coupled receptors (GPCRs), such as GPR130 for SERMs, and cell membrane-associated or cytosolic nuclear receptors. The NRBAs and SERMs of the present invention can also bind to receptors involved in these non-genomic effects, enabling a diverse pharmacological exploitation that provides genomic, non-genomic and tissue selective steroid receptor activity. These NRBAs and SERMs may have many specific and targeted steroid responses, broadening the potential for their beneficial pharmaceutical properties.

In some embodiments, the NRBAs of the invention are non-genomic agonists, or in some embodiments, non-genomic antagonists, or in some embodiments, non-genomic partial agonists of nuclear receptors. In some embodiments, the NRBAs of the invention are tissue-selective non-genomic nuclear receptors, such as estrogen or androgen receptor agonists, or in some embodiments, tissue-selective non-genomic nuclear receptor antagonists, or in some embodiments, tissue-selective non-genomic nuclear receptor partial agonists. In some embodiments, the NRBAs of the invention are non-selective non-genomic nuclear receptors, such as, for example, estrogen or androgen receptor agonists, or in some embodiments, non-selective non-genomic nuclear receptor antagonists, or in some embodiments, non-selective non-genomic nuclear receptor partial agonists. In some embodiments, the NRBAs of the invention are non-selective genomic nuclear receptors, such as, for example, estrogen or androgen receptor agonists, or in some embodiments, antagonists, or in some embodiments, partial agonists. In some embodiments, the NRBAs of the invention are tissue-selective genomic nuclear receptor modulators, such as, for example, estrogen or androgen receptor agonists, or in some embodiments, antagonists, or in some embodiments, partial agonists. In some embodiments, the NRBAs of the invention are genomic agents that selectively transactivate nuclear receptor-regulated genes. In some embodiments, selective transactivation is in a tissue-selective manner. In some embodiments, the NRBAs of the invention are genomic agents that selectively trans-inhibit (transless) nuclear receptor regulated genes. In some embodiments, the selective trans-inhibition is performed in a tissue-selective manner.

In other embodiments, the invention provides pharmaceutical products of NRBA or SERM compounds. In other embodiments, the term "pharmaceutical product" refers to a composition suitable for pharmaceutical use (pharmaceutical composition), e.g., as described herein.

In one embodiment, the present invention provides a method of binding an NRBA or SERM compound of the present invention to an estrogen receptor or an estrogen-related receptor comprising the step of contacting the estrogen receptor with said NRBA or SERM. In another embodiment, the invention provides a method of binding any of the NRBA or SERM compounds of the invention to a nuclear hormone receptor or a receptor associated therewith.

Composition (A):

in some embodiments, any of the compositions of the present invention will comprise an NRBA or SERM compound in any form or embodiment as described herein. In some embodiments, any of the compositions of the present invention will consist of an NRBA or SERM compound in any form or embodiment described herein. In some embodiments, the compositions of the present invention will consist essentially of the NRBA or SERM compound in any form or embodiment described herein. In some embodiments, the term "comprising" refers to the incorporation of the indicated active agent, e.g., NRBA or SERM compound, as well as the incorporation of other active agents and pharmaceutically acceptable carriers, excipients, lubricants, stabilizers, and the like, as known in the pharmaceutical industry. In some embodiments, the term "consisting essentially of … …" refers to a composition whose only active ingredient is the indicated active ingredient, however it may contain other compounds for stabilization, preservation, etc., but the formulation is not directly related to the efficacy of the indicated active ingredient. In some embodiments, the term "consisting essentially of … …" refers to an ingredient that promotes the release of an active ingredient or other active ingredient, however the primary compound that mediates a therapeutic effect is the active ingredient that is indicated. In some embodiments, the term "consisting of … …" refers to a composition that contains an active ingredient and a pharmaceutically acceptable carrier or excipient.

In other embodiments, the present invention provides compositions comprising NRBA or SERM, or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof, as described herein, together with a suitable carrier or diluent.

The active ingredient may be formulated into the composition as a neutral pharmaceutically acceptable salt form. Pharmaceutically acceptable salts include acid addition salts formed by reaction with inorganic acids such as, for example, hydrochloric or phosphoric acids, or organic acids such as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as sodium, potassium, ammonium, calcium, or ferric hydroxides, as well as such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine and the like.

In one embodiment, the compositions of the present invention are formulated for oral administration wherein the active compound may be combined with excipients and used in the form of ingestible tablets, buccal tablets (buccal tables), troches (troche), capsules, elixirs, suspensions, syrups, wafers, and the like. The tablets, dragees, pills, capsules and the like may also contain the following: binders, such as gum tragacanth, acacia, corn starch or gelatin; excipients, such as dicalcium phosphate; disintegrating agents such as corn starch, potato starch, alginic acid, and the like; lubricants, such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added, or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example: the tablets, pills or capsules may be coated with shellac, sugar or both. Syrups for elixirs may contain the active compound, sucrose as a sweetening agent and methyl and propylparabens as preservatives, a dye and flavoring, for example cherry or orange flavor. In addition, the active compounds can be incorporated into sustained-release, pulsed-release, controlled-release or delayed-release preparations and formulations.

In another embodiment, the compositions of the present invention comprise one or more pharmaceutically acceptable carrier materials.

In one embodiment, the carrier used in such compositions is biocompatible, and in another embodiment, biodegradable. In other embodiments, the formulation may provide a relatively constant level of release of the active ingredient. However, in other embodiments, a faster rate of release may be desired immediately after administration. In other embodiments, the release of the active compound may be event-triggered. The event-triggered release of the active compound may be the same in one embodiment, or may be different in another embodiment. The event-triggered release of the active ingredient may be exposure to humidity in one embodiment, low pH in another embodiment, or a temperature threshold in another embodiment. The formulation of such compositions is well within the level of ordinary skill in the art using known techniques. Illustrative carriers useful herein include microparticles of poly (lactide-co-glycolide), polyacrylates, latex, starch, cellulose, dextran, and the like. Other illustrative delayed release carriers include supramolecular biovectors comprising a non-liquid hydrophilic core (e.g. cross-linked polysaccharides or oligosaccharides) and optionally an outer layer comprising amphiphilic compounds, e.g. phospholipids. In one embodiment, the amount of active compound contained in a sustained release formulation depends on the site of administration, the rate and expected time of release, and the nature of the condition to be treated, suppressed or inhibited.

In one embodiment it may be desirable to deliver the compositions disclosed herein parenterally, intravenously, intramuscularly, or even intraperitoneally. Such methods are known to those skilled in the art, some of which are also described in, for example, U.S. Pat. nos. 5,543,158; U.S. Pat. No. 5,641,515 and U.S. Pat. No. 5,399,363, all of which are incorporated by reference in their entirety. In certain embodiments, solutions of the active compound as a free base or a pharmaceutically acceptable salt may be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof, and in oils. It must be stable under the conditions of preparation and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.

In another embodiment, it is preferred to include isotonic agents, for example, sugars or sodium chloride. In other embodiments, prolonged absorption of the injectable composition may be desirable. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

In certain embodiments, parenteral carriers include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, and fixed oils. Intravenous carriers include liquid and nutritional supplements, electrolyte supplements such as those based on ringer's dextrose, and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, antioxidants, finishing agents (gelling agents), inert gases and the like.

In some embodiments, the NRBAs or SERMs of the invention may be administered to a subject, which in one embodiment is a human subject, at varying doses. In one embodiment, the NRBA or SERM is administered at a dose of 0.1 to 200mg per day. In one embodiment, the NRBA or SERM is administered at a dose of 0.1 to 10mg per day, or in another embodiment, 0.1 to 25mg, or in another embodiment, 0.1 to 50mg, or in another embodiment, 0.3 to 15mg, or in another embodiment, 0.3 to 30mg, or in another embodiment, 0.5 to 25mg, or in another embodiment, 0.5 to 50mg, or in another embodiment, 0.75 to 15mg, or in another embodiment, 0.75 to 60mg, or in another embodiment, 1 to 5mg, or in another embodiment, 1 to 20mg, or in another embodiment, 3 to 15mg, or in another embodiment, 1 to 30mg, or in another embodiment, from 30 to 50mg, or in another embodiment, from 30 to 75mg, or in another embodiment, 100 to 2000 mg. In some embodiments, the NRBAs or SERMs may be administered at different doses as a function of time, or disease/symptom/disorder severity, or age, or other factors, as will be appreciated by those skilled in the art.

The NRBAs or SERMs of the present invention may be administered in different doses. In one embodiment, the NRBA or SERM is administered at a dose of 1 mg. In another embodiment, the NRBA or SERM is administered at a dose of 5mg, or in another embodiment 3mg, or in another embodiment 10mg, or in another embodiment 15mg, or in another embodiment 20mg, or in another embodiment 25mg, or in another embodiment 30mg, or in another embodiment 35mg, or in another embodiment 40mg, or in another embodiment 45mg, or in another embodiment 50mg, or in another embodiment 55mg, or in another embodiment 60mg, or in another embodiment 65mg, or in another embodiment 70mg, or in another embodiment 75mg, or in another embodiment 80mg, or in another embodiment 85mg, or in another embodiment 90mg, or in another embodiment 95mg, or in another embodiment 100 mg.

In one embodiment, the methods of the invention utilize the NRBA or SERM for oral administration at a dosage of 1 time per day as described herein.

While the compounds of the present invention may be administered as the sole active pharmaceutical ingredient, they may also be used in combination with one or more other compounds described herein, and/or with other agents used in the treatment and/or prevention of the diseases, conditions and/or disorders described herein, as will be understood by those skilled in the art. In another embodiment, a compound of the invention may be administered sequentially with one or more such agents to provide sustained therapeutic and prophylactic effects. In another embodiment, the compounds or combinations thereof may be administered via different routes, at different times. It is to be understood that any form of administered combination therapy comprising the NRBAs or SERMs of the invention in one embodiment thereof is considered to be part of the invention.

Suitable agents include, but are not limited to: other SERMs, and traditional estrogen agonists and antagonists. Representative agents useful in combination with the compounds of the invention include, for example, tamoxifen, 4-hydroxyttamoxifen, idoxifene, toremifene, 4-hydroxyteremifene, oxifeneMifene, droloxifene, raloxifene, arzoxifene, bazedoxifene, PPT (1, 3, 5-tris (4-hydroxyphenyl) -4-propyl-1H-pyrazole), DPN [2, 3-bis (4-hydroxyphenyl) propionitrile ]Lasofoxifene, pentoxifene (pipindoxifene), EM-800, EM-652, nafoxidine, indoxifene, timifene, mirtaifene phosphate, RU58,688, EM 139, ICI 164,384, ICI 182,780, clomiphene, MER-25, stilbestrol, coumestrol, genistein, GW5638, LY353581, trans-clomiphene, enrofloxacin, demegestone acetate, tibolone, DPPE, (N, N-diethyl-2- {4- (phenylmethyl) -phenoxy } ethylamine), E-424, WAY-070, WAY-292, WAY-818, Prinobeter (prinaberry), ERB-041, WAY-397, WAY-244, ERB-196, WAY-169122, MF-101, ERb-002, ERB-037, ERB-017, BE-380, BE-381, BE-380, and mey-2- {4- (phenylmethyl) -phenoxy } ethylamine, WAY-358 [ alpha ], [ alpha¹⁸F]FEDNP, LSN-500307, AA-102, CT-101, CT-102, VG-101, etc.

In some embodiments, other agents that may be combined with one or more compounds of the invention include aromatase inhibitors, such as, but not limited to, letrozole, anastrozole (anastrozole), atamestan, fadrozole, milametan, exemestane, prolimetan, liazole, NKS-01, vorozole, YM-511, fenrozole, 4-hydroxyandrostenedione, aminoglutethimide (aminoglutethimide), and luodimine.

In some embodiments, other agents for combination with the compounds of the invention include, but are not limited to: antineoplastic agents, such as alkylating agents. In some embodiments, the NRBAs or SERMs of the present invention may be administered in combination with an antibiotic, a hormonal antineoplastics and/or an antimetabolite. Examples of useful alkylating agents include alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodizepa, carboquone, mettupipa and uredepa; ethyleneimines and methylmelamines, such as hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; nitrogen mustards such as chlorambucil, chloromaphazine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine hydrochloride, melphalan, neomustard (novembichine), cholesterol carmustine p-phenylacetate, prednimustine, trofosfamide and uramustine; nitrosoureas such as carmustine, pyridylnitrosurea, fotemustine, lomustine, nimustine, ranimustine, dacarbazine, mannomustine, mitobronitol, mitolactol and pipobroman. Further such agents will be known to those skilled in the art of medicinal chemistry and oncology.

In some embodiments, other agents suitable for combination with the compounds of the present invention include protein synthesis inhibitors such as abrin, aurintricarboxylic acid, chloramphenicol, colicin E3, cycloheximide, diphtheria toxin, ivermectin a, emidine, erythromycin, ethionine, fluoride, 5-fluorotryptophan, fusidic acid, guanylmethylene diphosphate and guanidylimine diphosphate, kanamycin, vernalicin, xanthomycin and O-methyl threonine, modeccin, neomycin, norvaline, pactamycin, paromomycin, puromycin, ricin, α -sarcina, shiga toxin, pyromycin, sapamycin, spectinomycin, streptomycin, tetracycline, thiostreptocin, and trimethoprim. Inhibitors of DNA synthesis include alkylating agents such as dimethyl sulfate, mitomycin C, nitrogen and sulfur mustards, MNNG and NMS; intercalating agents such as acridine dyes, actinomycin, doxorubicin, anthracenes, benzopyrenes, ethidium bromide, propidium diiodide-entanglement, and agents such as distamycin and fusin may also be combined with the compounds of the present invention in pharmaceutical compositions. DNA base analogs such as acyclovir, adenine, β -1-D-cytarabine, methotrexate, aminopterin, 2-aminopurine, azafrine, 8-azaguanine, azaserine, 6-azauracil, 2 '-azido-2' -deoxynucleoside, 5-bromodeoxycytidine, cytosine, β -1-D-cytarabine, diazoxynorleucine (diazacyclonorceucine), dideoxynucleosides, 5-fluorodeoxycytidine, 5-fluorodeoxyuridine, 5-fluorouracil, hydroxyurea, and 6-mercaptopurine may also be used in combination therapy with the compounds of the present invention. Topoisomerase inhibitors such as kuramycin, nalidixic acid, novobiocin and oxolinic acid, cell differentiation inhibitors including colchicine, vinblastine and vincristine; and inhibitors of RNA synthesis including actinomycin D, alpha-muscarine and other fungal fimbricides, cordycepin (3' -deoxyadenosine), dichlorofurylnitrosurea benzimidazole, rifampin, varicocetin and ledixepin may also be combined with the compounds of the present invention to provide pharmaceutical compositions. In some embodiments, the immunostimulant is co-administered with the NRBAs or SERMs of the invention.

In addition, the compounds of the invention can be used alone or in combination with other forms (modifications) described above to prevent or treat a disorder, disease or condition described herein. In some embodiments, such other forms of treatment that would be appropriate for the condition being treated may include, but are not limited to, surgery, radiation, hormone supplementation, dietary adjustments, wound debridement, and the like. These may be performed sequentially (e.g., surgery or radiation followed by treatment with a compound of the invention) or in combination (e.g., with dietary therapy).

In another embodiment, the invention encompasses compounds and compositions wherein a compound of the invention is combined with or covalently bound to a cytotoxic agent that binds a targeting agent, such as a monoclonal antibody (e.g., murine or humanized monoclonal antibody). It would be advantageous for the latter combination to allow the introduction of cytotoxic agents into cancer cells with greater specificity. Thus, the active form (i.e., free form) of the cytotoxic agent is only present in the targeted cells of the antibody. Of course, the compounds of the invention may also be combined with monoclonal antibodies having anti-cancer therapeutic activity.

The additional active agent may generally be applied in therapeutic amounts as indicated in physicicians' DESK REFERENCE (PDR) 53 th edition (1999), or such therapeutically useful amounts are known to those of ordinary skill in the art. The compounds of the invention and other therapeutically active agents may be administered at the recommended maximum clinical dose or at lower doses. The dosage level of the active compound in the compositions of the invention may be varied according to the route of administration, the severity of the disease and the response of the patient to obtain the desired therapeutic response. The combination may be administered as separate compositions or as a single dosage form containing both agents. When administered as a combination, the therapeutic agents may be formulated as separate compositions, which are administered simultaneously or at different times, or the therapeutic agents may be administered as a single composition.

In some embodiments, the pharmaceutical compositions of the present invention will comprise NRBA or SERM compounds of formulas (I) - (X) or prodrugs, analogs, isomers, esters, metabolites, derivatives, pharmaceutically acceptable salts, pharmaceutical products, polymorphs, crystals, impurities, N-oxides, hydrates, or any combination thereof.

The pharmaceutical compositions may contain the NRBA or SERM compound alone or may further contain a pharmaceutically acceptable carrier and may be in solid or liquid form such as tablets, powders, capsules, pills, solutions, suspensions, elixirs, emulsions, gels, creams or suppositories, including rectal and urethral suppositories. Pharmaceutically acceptable carriers include gums, starches, sugars, cellulosic materials and mixtures thereof. Pharmaceutical formulations containing NRBA or SERM compounds may be administered to a subject in a bolus, for example by subcutaneous implantation; in another embodiment, the pill provides controlled release of the NRBA or SERM compound over a period of time. The preparation can also be administered by intravenous, intraarterial or intramuscular injection of a liquid formulation, oral liquid or solid formulation, or by topical application. Administration can also be accomplished by use of rectal or urethral suppositories. The pharmaceutical composition may also be a parenteral formulation; in one embodiment, the formulation comprises a liposome containing a complex of NRBA or SERM compounds.

The pharmaceutical compositions of the present invention may be prepared by known dissolution, mixing, milling or tabletting methods. For oral administration, the NRBA or SERM compounds or their physiologically tolerable derivatives such as salts, esters, N-oxides, etc. are mixed with additives customary for this purpose, such as excipients, stabilizers or inert diluents, and converted by customary methods into suitable forms for administration, such as tablets, coated tablets, hard or soft gelatin capsules, aqueous solutions, alcoholic solutions or oily solutions. Examples of suitable inert excipients are common tablet bases, for example lactose, sucrose or corn starch, in combination with binders, such as acacia, corn starch, gelatin, or with disintegrants, such as corn starch, potato starch, alginic acid, or with lubricants, such as stearic acid or magnesium stearate. Examples of suitable oily vehicles or solvents are vegetable or animal oils such as sunflower oil or cod liver oil. The article can function as both dry and wet pellets. For parenteral administration (subcutaneous, intravenous, intraarterial or intramuscular injection), the chemopreventive agents or their physiologically tolerated derivatives, such as salts, esters, N-oxides, etc., are converted into solutions, suspensions or emulsions, if desired together with substances customary and suitable for this purpose, such as solubilizers or other auxiliaries. Examples are: sterilizing liquids such as water and oils, with or without the addition of surfactants and other pharmaceutically acceptable adjuvants. Illustrative oils are those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil or mineral oil. In general, water, saline, aqueous dextrose and related sugar solutions, and glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.

Preparations of pharmaceutical compositions containing active ingredients are well known in the art. Typically, such compositions are delivered to the nasopharynx as an aerosol of the polypeptide or are prepared as an injectable, or as a liquid solution or suspension, however, solid forms suitable for solutions or suspensions may also be prepared prior to injection. The product may also be emulsified. The active therapeutic ingredient is often mixed with excipients that are pharmaceutically acceptable and compatible with the active ingredient. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol, and the like, and combinations thereof. In addition, if desired, the compositions may contain minor amounts of auxiliary substances which enhance the effectiveness of the active ingredient, for example wetting or emulsifying agents, or pH buffering agents.

The active ingredients can be formulated into the composition in the form of neutral pharmaceutically acceptable salts. Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the polypeptide or antibody molecule) and with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, or ferric hydroxide, and such organic bases as isopropylamine, trimethylamine, 2-ethylaminoethanol, histidine, procaine and the like.

For topical administration on a body surface, for example, creams, gels, drops, etc., the NRBA or SERM compounds or their physiologically tolerable derivatives, such as salts, esters, N-oxides, etc., are prepared and used as solutions, suspensions or emulsions in a physiologically acceptable diluent with or without a pharmaceutical carrier.

In another embodiment, the active compound may be delivered in vesicles, particularly in the form of Liposomes (see Langer, Science 249: 1527-.

In one embodiment, the present invention also provides a method of using the above-mentioned composition.

In one embodiment, the invention provides methods of treatment using the NRBAs, SERMs or compositions of the invention. In one embodiment, the term "treatment" includes prophylactic as well as palliative treatment of the condition. The terms "reduce", "suppress" and "inhibit" have their commonly understood meaning of alleviating or reducing, or in another embodiment delaying, or in another embodiment reducing the incidence, severity or pathogenesis of a disease, disorder or condition. In embodiments, the term treating refers to delaying the progression of a disease, disorder or condition, extending remission, reducing morbidity, or alleviating the associated symptoms. In one embodiment, the terms "treat," "reduce," "suppress," or "inhibit" refer to a reduction in morbidity, mortality, or a combination thereof associated with the indicated disease, disorder, or condition. In one embodiment, the term "progression" refers to an increase in scope or severity, enhancement, growth, or worsening. In another embodiment, the term "relapse" means a return after remission of the disease. In one embodiment, the treatment methods of the invention reduce the severity of the disease, or in another embodiment, reduce the symptoms associated with the disease, or in another embodiment, reduce the number of biomarkers expressed during the disease.

In one embodiment, the term "treating" and aspects thereof included refer to administering to a subject suffering from, or, in some embodiments, susceptible to, the indicated disease, disorder, or condition. The term "predisposed" is considered to refer inter alia to a genetic feature or familial relationship that is associated with a trend or statistical increase indicative of the incidence, severity, etc., of a disease. In some embodiments, the term "predisposed" is considered to refer to, inter alia, a lifestyle associated with an increased risk indicative of a disease. In some embodiments, the term "predisposed to" is considered to refer, inter alia, to the presence of biomarkers associated with an indicated disease, e.g., in cancer, the term "predisposed to" cancer may include the presence of pre-cancerous precursors of the indicated cancer.

In another embodiment, the term "administering" refers to contacting a subject with a compound of the invention. Administration can be accomplished in vitro (i.e., in a test tube) or in vivo (i.e., in a cell or tissue of a living body (e.g., a human)). In one embodiment, the invention includes administering a compound of the invention to a subject.

Some embodiments using the NRBAs or SERMs of the invention:

prostate carcinogenesis:

prostate cancer is the most common cancer occurring in american men, with hundreds of new cases diagnosed each year. Prostate cancer is therefore the second leading cause of cancer death. Unfortunately, over 60% of newly diagnosed cases of prostate cancer are found to be pathologically worse, incurable and have a poor prognosis. One approach to this problem is to detect prostate cancer early through screening procedures and thereby reduce the number of patients with advanced prostate cancer. Yet another approach is to develop drugs that prevent prostate carcinogenesis. 1/3 men over the age of 50 suffer from a potential form of prostate cancer, which can be activated into a life-threatening clinical form of prostate cancer. The frequency of latent prostate carcinogenesis has been shown to increase significantly every decade from 50 years (5.3-14%) to 90 years (40-80%). The number of people with latent prostate cancer is the same in all cultures, races and ethnicities, however the frequency of clinically worsening cancers varies significantly. This suggests that environmental factors play a role in activating latent prostate cancer. Therefore, the development of chemopreventive regimens for the treatment of prostate cancer has the most comprehensive medical and economic impact on the treatment of prostate cancer.

Furthermore, because prostate intraepithelial neoplasia is the direct induction pathway of prostate cancer (causalpathway), which presents a specific predictor of increased risk of prostate cancer, men diagnosed with prostate intraepithelial neoplasia have significant changes in their quality of life. The only way to diagnose prostate intraepithelial neoplasia is by prostate biopsy. However, once a diagnosis of prostate intraepithelial neoplasia is made, the common medical practice is that the patient must take more frequent biopsies and visit a physician. In addition, because the diagnosis of prostate cancer is urgent, there is great concern among patients and doctors. Currently, there is no treatment available for patients with prostate intraepithelial neoplasia.

The present invention relates to the prevention and treatment of hyperplasia. In some embodiments, the present invention provides a) a method of treating, preventing, suppressing, inhibiting or reducing the incidence of Benign Prostatic Hyperplasia (BPH) in a male subject; and b) a method of treating an individual suffering from hair loss comprising administering a therapeutically effective amount of a nuclear hormone binding agent (NRBA) of the invention, as described herein, which in some embodiments is a Selective Estrogen Receptor Modulator (SERM) compound and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal or any combination thereof.

In one embodiment, the present invention provides a method of treating, preventing, suppressing, preventing prostate cancer, BPH or a pre-cancerous precursor, preventing recurrence of, reducing the incidence of, reducing the severity of, reducing or preventing metastasis of prostate cancer, BPH or a pre-cancerous precursor of prostate cancer by administering the NRBA/SERM or NRBAs/SERMs of the present invention, or a composition comprising the same.

NRBAs/SERMs and pharmaceutical compositions containing the same compounds of the invention are particularly useful for treating individuals at increased risk of developing prostate cancer. High risk individuals include, for example, those with benign prostatic hyperplasia, Prostatic Intraepithelial Neoplasia (PIN), abnormally high levels of circulating blood prostate-specific antibody (PSA), or individuals with a family history of prostate cancer.

Intermediate endpoint biomarkers are measurable biological changes in tissue that occur between the onset and progression of overt neoplasia. Biomarkers were confirmed if the final endpoint, cancer incidence, was also reduced by recognized chemopreventive agents. Direct biomarkers in cancer can be classified into the following groups: tissue, proliferative, differentiative and biochemical markers. The availability of distinguishable histology and accepted precancerous lesions constitute important starting points in any chemopreventive regimen. For the prostate, the histological marker is a precancerous precursor of prostate cancer, of which Prostate Intraepithelial Neoplasia (PIN) is an example. PIN indicates abnormal cell development and abnormal hyperplasia in the prostatic duct at the precancerous focus of the carcinoma in situ without stromal invasion. PIN and histological prostate cancers are morphologically and phenotypically similar. Thus, the exacerbation of high-grade PIN represents an important step in the exacerbation pathway whereby normal prostate develops into PIN, histological prostate cancer, invasive clinical prostate cancer and metastases.

Prostate intraepithelial neoplasia has been shown to be a precancerous lesion or precursor of prostate adenocarcinoma. Prostate intraepithelial neoplasia is an abnormal proliferation within the prostatic duct at the precancerous focus of the cancer in situ without invasion of the stroma and cellular dysplasia. Prostate intraepithelial neoplasia is the most accurate and reliable marker of prostate carcinogenesis and can be used as an acceptable endpoint for prostate chemopreventive treatment. Prostate intraepithelial neoplasia is of high predictive value as a marker of adenocarcinoma, identifying repeated biopsies from concurrent or concurrent invasive cancers. Most studies indicate that most patients with prostate intraepithelial neoplasia will develop cancer within 10 years. Interestingly, prostate intraepithelial neoplasia does not promote plasma PSA, which is not surprising, since unlike prostate cancer, prostate intraepithelial neoplasia does not invade the prostate vasculature leading to PSA leakage into the blood stream. Prostate intraepithelial neoplasia therefore precedes prostate cancer associated with elevated plasma PSA.

In some embodiments, any NRBA that may be characterized by the structures of the formulae shown herein may be used to treat, prevent, suppress or reduce the incidence, prevent latency, suppress or extend the latency of prostate cancer, benign prostate cancer or a precancerous precursor of the same cancer, and are considered to be part of the present invention. In one embodiment, NRBAs/SERMs are used to affect all aspects of prostate cancer based on their activity in receptor binding activity studies, ER transactivation studies, in vitro studies of their effects on prostate cancer cell growth, and in vivo studies.

In some embodiments, the NRBAs/SERMs are used to treat, reduce, prevent side effects associated with prostate cancer. In some embodiments, such SERMs include their activity in vitro and in vivo studies based on receptor binding studies, ER transactivation studies, their effects on prostate cancer cell growth.

In some embodiments, the ER α antagonist and the ER β agonist are used to treat, reduce, prevent, or treat side effects associated with the treatment of prostate cancer and benign prostatic hyperplasia. In another embodiment, the era antagonists of the invention include, inter alia, 10m, 4a, 11f or 11 g. In another embodiment, the ER β agonists of the present invention include, inter alia, 10d, 10f, 10l or 11p listed in table 1, or any combination thereof.

In addition, the NRBAs/SERMs may be administered in combination with other cytokines or growth factors, including but not limited to: IFN-gamma, IFN-alpha or IFN-beta; interleukin (IL)1, IL-2, IL-4, IL-6, IL-7, IL-12, Tumor Necrosis Factor (TNF) alpha, TNF-beta, granulocyte colony stimulating agent (G-CSF), granulocyte/macrophage CSF (GM-CSF); accessory molecules, including members of the integrin superfamily and members of the Ig superfamily, such as but not limited to: LFA-1, LFA-3, CD22 and B7-1, B7-2 and ICAM-1T cell co-stimulatory molecules.

In another embodiment, the NRBA/SERM may be administered in combination with other compounds which, in one embodiment, inhibit prostate carcinogenesis, e.g., 5 α -reductase inhibitors or inhibitors of other enzymes associated with the androgen biosynthetic pathway, e.g., 3 α -hydroxysteroid dehydrogenase, 17-ketoreductase, 17 β -hydroxysteroid dehydrogenase, 17 β -aldoketoreductase, 3 β -DH Δ 4, 6-isomerase, 3 β -DH Δ 4, 5-isomerase, 17, 20 carbon chain lyase, p450c17, p450ssc, 17, 20-lyase, etc., for affecting Prostate Intraepithelial Neoplasia (PIN), carcinogenesis, conditions associated with excessive androgen production, e.g., polycystic ovarian disease, infertility, hot flashes, male breast development, e.g., when such conditions are in an individual undergoing androgen blockade or other hormone-related conditions (including diabetes), some of which are described further below.

Chemopreventive agents can be administered intermittently from a few minutes to a few weeks or following DNA damaging agent treatment. Protocols and methods are known to those skilled in the art. DNA damaging agents or factors are known to those skilled in the art and refer to any compound or therapeutic method that induces DNA damage when applied to a cell. Such agents and factors include radiation and waves that induce DNA damage, such as gamma-radiation, X-rays, UV-radiation, microwaves, electron radiation, and the like. Many compounds are also described as "chemotherapeutic agents" that function to induce DNA damage, all of which are used in the combination therapy methods disclosed herein. Chemotherapeutic agents intended for use include, for example, doxorubicin, 5-fluorouracil (5FU), etoposide (VP-16), camptothecin, actinomycin-D, mitomycin C, Cisplatin (CDDP), and even hydrogen peroxide. The invention also encompasses the use of a combination of one or more DNA damaging agents, or radiation-based or actual compounds, such as the use of X-rays with cisplatin or the use of cisplatin with etoposide.

In another embodiment, a localized tumor site may be irradiated with DNA damaging radiation, such as X-rays, UV-light, gamma-rays, or even microwaves. Alternatively, tumor cells can be contacted with a DNA damaging agent by administering to the administered individual a therapeutically effective amount of a pharmaceutical composition containing a DNA damaging compound such as doxorubicin, 5-fluorouracil, etoposide, camptothecin, actinomycin-D, mitomycin C, or more preferably Cisplatin (CDDP). Agents that damage DNA also include compounds that interfere with DNA replication, mitosis, and chromosome segregation. Such chemotherapeutic compounds include doxorubicin, also known as doxorubicin, etoposide, verapamil, podophyllotoxin, and the like.

Other factors that cause DNA damage and have been widely used include gamma-rays, X-rays, and/or radioisotopes delivered directly to tumor cells, which are generally known. Other forms of DNA damaging factors are also contemplated, such as microwave and UV radiation. Most likely all of these factors affect many of the impairments to DNA, DNA precursors, DNA replication and repair, and chromosome assembly and maintenance.

In another embodiment, the invention provides the use of NRBAs/SERMs or compositions comprising the same for treating, suppressing, inhibiting pre-cancerous precursors of prostate cancer lesions in a mammalian subject.

In another embodiment, the invention provides NRBAs/SERMs, or compositions containing the same, for treating, preventing, suppressing, inhibiting or reducing the incidence of osteoporosis, hot flashes, male breast development and/or hair loss in a male subject with prostate cancer. In some embodiments, osteoporosis, hot flashes, gynecomastia, and/or hair loss in a male subject with prostate cancer results as a result of Androgen Deprivation Therapy (ADT) induction in the subject. According to this aspect, in one embodiment, the NRBA/SERM is used to treat these ADT-induced disorders while not exacerbating prostate carcinogenesis in an individual. In another embodiment, according to this aspect of the invention, the NRBAs/SERMs/compositions of the invention simultaneously treat, suppress, inhibit, etc., prostate carcinogenesis and simultaneously treat ADT-induced disorders in these subjects.

In another embodiment, the invention provides a method of treating, suppressing, inhibiting, or reducing the risk of developing prostate cancer in a subject having prostate cancer, comprising administering to the subject a pharmaceutical composition comprising a SERM compound of formulae (I) - (X).

In another embodiment, the present invention provides a method of suppressing or inhibiting prostate cancer in a mammalian subject, said method comprising administering to said subject a pharmaceutical composition comprising a SERM compound of formulae (I) - (X) or a prodrug, ester, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrate or any combination thereof.

In another embodiment, the present invention provides a method of reducing the risk of developing prostate cancer in a mammalian subject comprising administering a pharmaceutical composition comprising a SERM/NRBA compound of formulae (I) - (X) or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, ester, polymorph, crystal, impurity, N-oxide, hydrate or any combination thereof, thereby reducing the risk of developing prostate cancer in said subject.

In another embodiment, the present invention provides a method of treating a precancerous precursor of a prostate cancer lesion in a mammalian subject, comprising administering a pharmaceutical composition comprising a SERM/NRBA compound of formulae (I) - (X) or a prodrug, ester, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrate or any combination thereof, thereby treating the precancerous precursor of a prostate cancer lesion in said subject. In another embodiment, the precancerous precursor of prostate cancer is Prostate Intraepithelial Neoplasia (PIN).

In one embodiment, the method is suitable for treating, suppressing, inhibiting, reducing the risk of potential prostate carcinogenesis, and the like, according to aspects of the present invention.

Cancer of colon

Colon cancer is the second largest diagnosed malignancy in the united states and is the second leading cause of cancer death. Cholesterol-rich diets have significant epidemiological relevance to colon cancer, which in turn can be affected by administering compounds that modulate nuclear hormone binding agents, particularly compounds that modulate the receptor binding component of the steroid-producing pathway, particularly SERM compounds as described herein.

In one embodiment, the present invention provides a method of treating, preventing, inhibiting, or reducing the incidence of a colorectal cancer disorder in a subject, comprising administering to the subject a pharmaceutical composition comprising an NRBA compound of formulae (I) - (X), which in some embodiments is a SERM, or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof.

In some embodiments, the ER- β agonist is used to treat, prevent, inhibit or reduce the incidence of inflammation in an individual. In another embodiment, the ER- β agonists of the present invention include, inter alia, 10d, 10f, 10l, or 11p listed in Table 1, or any combination thereof.

In some embodiments, treatment may include administration of other agents that treat colon cancer, such as, for example, based on azetidinone cholesterol absorption inhibitors or others, as known to those skilled in the art. In some embodiments, such treatment may be performed before or after, or concurrently with, treatment with the NRBA compounds of the present invention.

ADT-induced disorders:

in one embodiment, the present invention provides the following method: 1) improving a lipid profile of a subject; 2) reducing circulating lipid levels in the subject; 3) increasing High Density Lipoprotein (HDL) cholesterol levels in an individual; 4) altering the ratio of low density lipoprotein to high density lipoprotein in a subject, wherein the subject has prostate cancer and has undergone or has undergone ADT, wherein the method comprises administering to the subject a composition comprising a SERM compound or a pharmaceutically acceptable salt, hydrate, N-oxide, or any combination thereof; in another embodiment, the SERM compound is formula (I-XI) or a prodrug, ester, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrate or any combination thereof.

In another embodiment, the subject is experiencing or has experienced ADT. In one embodiment, the terms "experienced", "experiencing", and the like, refer to an individual who has recently (within the past 6 months) or is concurrently receiving any treatment known in the art that generally reduces androgen levels or, in particular, testosterone hormone levels. In another embodiment, the term refers to an individual who has received such treatment more than 6 months ago. In one embodiment, the treatment is surgical. In another embodiment, the treatment is pharmaceutical. In another embodiment, the treatment completely removes the androgen or testosterone, or removes below detectable levels. In another embodiment, the ADT is a side effect of a treatment that is not intended to reduce androgen or testosterone levels. Each of these possibilities represents a separate embodiment of the present invention.

In another embodiment, ADT is used for treating prostate cancer, for delaying the progression of prostate cancer, and for preventing and/or treating the recurrence of prostate cancer, comprising administering LHRH analogs, reversible antiandrogens (e.g., bicalutamide or flutamide), antiestrogens, anticancer drugs, 5-alpha reductase inhibitors, aromatase inhibitors, progestins, Selective Androgen Receptor Modulators (SARMS), or agents that act through other nuclear hormone receptors. In another embodiment, ADT is administered monthly, or every 3, 4, 6, or 12 months. In another embodiment, ADT is administered every 2 weeks during the first month, followed by every 4 weeks.

In some embodiments, the invention provides methods comprising administering a SERM compound to a subject having prostate cancer and experiencing or having experienced ADT. In one embodiment, the SERM compound of the invention may be administered prior to the ADT. In another embodiment, the SERM compounds of the invention may be administered with the ADT. In another embodiment, the SERM compounds of the invention may be administered after the ADT.

In some embodiments, the methods of the invention comprise administering the SERM compounds of the invention in combination with, before, or after the ADT as a prophylaxis of all diseases in the invention. In one embodiment, the SERM is administered between 1-2 weeks prior to ADT. In another embodiment, the SERM is administered between 2-4 weeks prior to ADT. In another embodiment, the SERM is administered between 1 and 2 months prior to ADT. In another embodiment, the SERM is administered between 2 and 4 months prior to ADT. In another embodiment, the SERM is administered between 4 and 6 months prior to ADT. In another embodiment, the SERM is administered between 1-2 weeks after ADT. In another embodiment, the SERM is administered between 2-4 weeks after ADT. In another embodiment, the SERM is administered between 1 and 2 months after ADT. In another embodiment, the SERM is administered between 2 and 4 months after ADT. In another embodiment, the SERM is administered between 4 and 6 months after ADT.

In other embodiments, the invention provides methods of treating any disease, disorder or condition associated with ADT. In other embodiments, the invention provides methods of treating any disease, disorder or condition associated with androgen blockade. In other embodiments, the invention provides methods of treating any disease, disorder or condition associated with testosterone blockade. Each disease, disorder or condition represents a separate embodiment of the present invention.

Diseases of the immune system:

cross-talk has been shown to occur between endocrine disrupting compounds and cytokine signaling through estrogen receptors, suggesting a role for SERMs and/or other nuclear hormone binding agents in the immune system and/or its disease regulation.

For example, tamoxifen, clomiphene and nafoxidine cause a reduction in variability in the estrogen receptor-negative T-lymphoblastic leukemia cell line CCRF/CEM, suggesting a role for antiestrogens in the clinical treatment of leukemia.

Leukemia is a malignant tumor of the bone marrow and blood, including acute or chronic myeloid, or acute or chronic lymphocytic-type diseases.

Standard treatments for leukemia typically include chemotherapy and/or bone marrow transplantation and/or radiation therapy. Chemotherapy typically involves the combination of two or more anticancer drugs with a common composition, including cytarabine with doxorubicin or daunorubicin or mitoxantrone or thioguanine, mercaptopurine with methotrexate, mitoxantrone with etoposide, asparaginase with vincristine, daunorubicin and prednisone, cyclophosphamide with vincristine, cytarabine with prednisone, cyclophosphamide with vincristine and prednisone, daunorubicin with cytarabine and thioguanine, and daunorubicin with vincristine and prednisone.

In one embodiment, the present invention provides a method of treating, preventing, inhibiting or reducing the incidence of leukemia in a subject, comprising administering to the subject a pharmaceutical composition comprising a SERM compound of formulae (I) - (X) or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof.

In some embodiments, the ER- β agonist is used to treat, prevent, inhibit or reduce the incidence of leukemia in a subject. In another embodiment, the ER- β agonists of the invention especially comprise 10d, 10f, 10l or 11p listed in table 1 or any combination thereof.

In another embodiment, the era antagonist is used to treat, prevent, inhibit or reduce the incidence of leukemia in an individual. In some embodiments, an era antagonist of the invention includes, inter alia, 10m, 4a, 11f, or 11 g.

In some embodiments, the NRBA/SERMs of the present invention, which in one embodiment are ER- β agonists, are used to treat, prevent, inhibit or reduce the incidence of inflammatory diseases, disorders or conditions in a subject. In another embodiment, the ER- β agonists of the invention especially comprise 10d, 10f, 10l or 11p listed in table 1 or any combination thereof.

A neurological disease, disorder or condition:

estrogens can prevent brain damage, neurodegeneration and cognitive decline. In some embodiments, estrogen may also protect cortical and hippocampal neurons in ischemic injury and injury due to disease onset, and Estrogen Receptor (ER) α agonists play a more dominant role in regulating neuroprotection.

In one embodiment, the present invention provides a method of treating, preventing, inhibiting, or reducing the incidence of a neurological disease, disorder or condition in a subject, comprising administering to the subject a pharmaceutical composition comprising an NRBA or SERM compound of formulae (I) - (X) or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof.

In some embodiments, the term "neural" is understood to include or belong to the central nervous system.

In some embodiments, the ER- β and ER- α agonists of the invention are used to treat, prevent, inhibit or reduce the incidence of inflammation in an individual. In one embodiment, the ER- β agonists of the invention for use herein include, inter alia, 10d, 10f, 10l or 11p listed in table 1, or any combination thereof. In another embodiment, the ER- α agonists of the present invention for use herein include, inter alia, the 3v, 3b, 3k, or 10x listed in Table 1, or any combination thereof.

In some embodiments, the neurological disease or disorder comprises a demyelinating disease, such as multiple sclerosis, primary demyelinating polyneuropathy, chronic inflammatory demyelinating polyneuropathy, or Guillain-Barre syndrome (Guillain-Barre syndrome). In some embodiments, the neurological disease condition or disorder includes ischemia resulting from stenosis of a vessel or vessel supplying the brain, central nervous system infection, such as, for example, meningitis or encephalomyelitis, Amyotrophic Lateral Sclerosis (ALS), alzheimer's disease, pain, Huntington's Disease (HD), Myasthenia Gravis (MG), frontotemporal dementia (FTD), stroke, traumatic brain injury, age-related retinal degeneration, mood disorders or depression, hypoxia/hypoxia injury (e.g., cardiopulmonary resuscitation, drowning), spinal cord injury, local anesthesia-induced seizure activity, ischemic stroke, retinal ischemic neurodegeneration, epilepsy, duller's syndrome, obsessive-compulsive disease, drug-induced (e.g., nerve gas-induced) CNS injury, chronic pain syndrome, acute and chronic neurodegenerative disorders (e.g., lateral sclerosis, CNS injury), chronic pain syndrome, acute and chronic neurodegenerative disorders, Alzheimer's disease, AIDS dementia complex, cocaine addiction, or neurodegenerative diseases such as hypoglycemia, cerebral palsy, transient ischemic attacks, perinatal asphyxia, psychosis, Parkinson's disease, olivopontocerebellar atrophy, and pathogen-induced neurodegeneration such as virus-induced, for example, acquired immunodeficiency syndrome and its associated dementia.

It is to be understood that any neurological disease, disorder or condition that can be treated or ameliorated by administration of a compound or composition of the invention is considered to be part of the invention.

Eye diseases

The compounds of the invention are useful for treating or ameliorating a disorder affecting the neural retina. Estrogens may have neuroprotective effects on the retina (see, e.g., Invest Ophthal Vis Sci 38: 1193-.

In one embodiment, the invention provides a method of treating a condition selected from the group consisting of glaucoma, high-tension glaucoma, normal-tension glaucoma, central chorioretinopathy, age-related macular degeneration, macular hole, cataract, senile cataract, chorioretinal hemorrhage, central retinal artery or vein occlusion, retinal arteriosclerosis, dysphotopsia, diabetic retinopathy, chorioretinal atrophy, retinal and choroidal neovascular diseases, cataract due to ovariectomy, cataract due to TGF β, macular fibrosis (macular fibrosis), epiretinal macula, retinal tear, retinal detachment, proliferative retinitis, retinitis pigmentosa, keratitis, corneal haze, corneal erosion, corneal epithelial cell exfoliation, corneal ulceration, corneal endothelial degeneration and endothelial cell dystrophy or loss, corneal dystrophy or exacerbation, A method of treating epidemic keratoconjunctivitis, chalazion, iritis, uveitis, autoimmune diseases, chorioretinitis, iridocyclitis, asthenopia, visual field reduction due to various diseases, optic atrophy, optic neuritis, anterior ischemic optic neuropathy, dynamic vision reduction, abnormal color vision, ametropia, presbyopia, myopia, hypermetropia, astigmatism, central nervous disease, psychosis, hysteria, diseases caused by pituitary disorders and hormone imbalance, diseases due to genetic disorders, and diseases of the eye due to immune disorders, the method comprising administering to the subject a pharmaceutical composition comprising a NRBA or SERM compound of formulae (I) to (X) or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, pharmaceutically acceptable salt thereof, polymorph, crystal, impurity, pharmaceutically acceptable salt thereof, or solvate thereof, Ester, hydrate or any combination thereof.

In another embodiment, a method of treating an ocular disease comprises administering to the individual a composition comprising a compound of the present invention, wherein the composition is in the form of eye drops, eye washes, ointments, mustard injections, or contact lens adsorbents. In another embodiment, the method of treating ocular diseases comprises administering a composition comprising a compound of the present invention in the form of a tablet, capsule, solution, syrup, injection, hap, ointment, eye drop, suppository, and the like, and orally or parenterally, e.g., injection, topical administration such as instillation into the eye, and the like. The active ingredient can be vaporized and inhaled, for example, through the nose, mouth or trachea.

In some embodiments, the methods of treating ocular diseases comprise administering a composition comprising a compound of the present invention in combination with any other compound useful for treating the indicated condition, as is known in the art.

In some embodiments, eye drops and eye washes comprise water-dissolved compounds (I) - (X) of the present invention, which in one embodiment is dissolved in sterilized distilled water, BSS addition, and/or physiological saline. In another embodiment, the additives added include excipients, carriers, pH control agents, isotonic agents, preservatives, glutathione, glucose, various salts, stabilizers, refrigerants, antioxidants, bactericides, or any combination thereof. In another embodiment, the eye drops and eye washes comprise hydroxypropyl methylcellulose, carboxymethyl cellulose or its sodium salt, polypyrroline, polyvinylpyrrolidone (which is added and heated), or any combination thereof.

In some embodiments, the compounds of the present invention have low solubility in water. In one embodiment, the compound may be made water soluble by using cyclodextrin. In another embodiment alpha-cyclodextrin is used. In another embodiment beta-cyclodextrin is used. In another embodiment gamma-cyclodextrin is used. In another embodiment hydroxyalkylated β -cyclodextrins are employed.

Cancer of the bladder

Bladder cancer is the second most common urogenital tumor in the human population. SERMs have been shown to induce apoptosis in bladder cancer cell lines that express estrogen receptors.

In some embodiments, the present invention provides a method of treating, suppressing, or reducing the incidence or severity of bladder cancer, prolonging the remission of bladder cancer in a subject, comprising administering to the subject a pharmaceutical composition comprising an NRBA or SERM compound of formulae (I) - (X), or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof.

In some embodiments, according to this aspect of the invention, the method comprises administering an ER- β ligand, such as, but not limited to, compound 10d, 10f, 10l or 11p listed in table 1, or any combination thereof.

Existing treatments for bladder cancer may be combined with the treatments provided herein, including cystectomy with or without methotrexate, vinblastine, doxorubicin, or cisplatin (M-VAC) or other compounds known in the art.

Bone related diseases or disorders

In one embodiment, the present invention provides a method of treating, preventing or reducing the severity of a bone-related disease or disorder in a subject, comprising administering to said subject an NRBA, in some embodiments a SERM, of the present invention. In one embodiment, a subject is administered an NRBA/SERM or a composition comprising the same, wherein NRBA/SERM is a compound of formula (I) - (X) or a prodrug, ester, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrate or any combination thereof.

In one embodiment, the bone-related disease or disorder is osteoporosis, and the methods of the invention for preventing and/or treating osteoporosis reduce the incidence of, inhibit, suppress, or treat osteoporosis, or in another embodiment, treat androgen-blockade therapy-induced osteoporosis, bone fracture, and/or loss of bone density (BMD) in an individual. In one embodiment, the subject is a female, and in some embodiments, the bone-related disease or disorder occurs in a postmenopausal female. In some embodiments, the subject is a female, and the bone-related disease or disorder occurs in a female with breast cancer or other neoplastic disorder. In some embodiments, the subject is a female and has a neoplastic disorder, and the bone-related disease or disorder is a therapeutic byproduct of treating the neoplastic disorder. According to this aspect, in some embodiments, the treatment of the bone-related disease or disorder is also suppression or is involved in treating a neoplastic disorder in a subject. In another embodiment, the subject is female and the bone-related disease or disorder is the result of aging in the subject.

In one embodiment, the subject is male, and in some embodiments, the bone-related disease or disorder is due to aging of the subject or menopause in the male. In some embodiments, the subject is a male and the bone-related disease or disorder occurs in a male with prostate cancer or other neoplastic disorder. In some embodiments, the subject is male and has a neoplastic disorder, and the bone-related disease or disorder is a therapeutic byproduct of treating the neoplastic disorder. In some embodiments, according to this aspect, the treatment is androgen blockade therapy (ADT). In some embodiments, the treatment of the bone-related disease or disorder is also suppression or participation in treating a neoplastic disorder in a subject.

Bone loss due to glucocorticoid excess is diffuse, affecting the cortex and cancellous bone, and is biased toward the axial skeleton. Thus, spontaneous fracture of the vertebrae or ribs is often a manifestation of disease. Glucocorticoid-induced osteoporosis is primarily characterized by decreased bone formation. In addition, patients receiving chronic glucocorticoid therapy sometimes develop a collapse of the femoral head (osteonecrosis).

In some embodiments, the SERMs of the present invention are used to treat glucocorticoid-induced osteoporosis in a subject. In some embodiments, the SERMs are used to prevent, ameliorate, treat, suppress, delay the incidence of, or lessen the severity of bone loss in a subject associated with a glucocorticoid. In some embodiments, the glucocorticoid is any such compound known in the art, including, inter alia, hydrocortisone, cortisone acetate, prednisolone, prednisone, methylprednisolone, triamcinolone, paramethasone, betamethasone, dexamethasone, fludrocortisone, or any combination thereof.

Osteoporosis is a systemic skeletal disease characterized by low bone mass and degeneration of bone tissue, whereby bone fragility increases and fractures easily. In osteoporotic patients, the bone strength is not normal and the risk of fracture increases. Osteoporosis depletes calcium and the protein collagen normally found in bone, resulting in abnormal bone mass or decreased bone density. Bones affected by osteoporosis may be broken by a mere wrestling or injury that does not normally cause a fracture. The fracture may be in the form of a fracture (e.g., hip fracture) or a fracture (e.g., compression fracture). The spine, buttocks and wrists are common areas of osteoporotic fractures, although fractures may occur in other skeletal areas as well.

BMD is a measure of bone true mass. The absolute amount of bone as measured by Bone Mineral Density (BMD) is generally related to bone strength and its ability to bear weight. By measuring BMD, it is possible to predict fracture risk in the same way that measuring blood pressure can help predict stroke risk.

In one embodiment, BMD may be determined by known bone mineral content mapping techniques. Bone density in the hip, spine, wrist, etc. can be measured by a number of techniques. A preferred technique for BMD determination is dual energy x-ray Densitometry (DXA). BMD, anterior-posterior (AP) spine, lateral spine and wrist of the hip can be determined using this technique. While measurements at any site predict the overall risk of fracture, information from a particular site is the best predictor of fracture at that site. Quantitative Computed Tomography (QCT) has also been used to determine BMD of the spine. See, e.g., Wahner H W, Dunn W L, Thorsen H C et al, "Nuclear Medicine: "Quanttitive Procedures", Torontolite, Brown & Co. publication, 1983, (see page 107-132). An article entitled "Association of bone Mineral Part 1" is published in the Journal of Nuclear Medicine, 1984, pages 1134 and 1141. An article entitled "Bone Mineral sensitivity of The Radius" is published in Journal of Nuclear Medicine, Vol.11/11/1985, pp.13-39. Abstract of Bone Mineral content using microgram cameras is (a) S.Hoomy et al, radio, 1985, Vol.157 (P), pp.87, and (b) C.R.Wilson et al, radio, 1985, Vol.157 (P), pp.88.

The present invention provides safe and effective methods of treating, preventing, containing, inhibiting the onset of, or reducing the risk of osteoporosis and/or BMD loss. In one embodiment, the method comprises administering to a male individual under treatment who has prostate cancer and an increased risk of developing androgen-deprivation therapy-induced osteoporosis. In another embodiment, the method is for a menopausal female subject. In another embodiment, the method comprises administering to a female subject suffering from postmenopausal osteoporosis in need thereof. In another embodiment, the female subject is genetically predisposed to developing osteoporosis. In another embodiment, the female subject develops osteoporosis as a result of a drug treatment, such as, for example, Depo-Provera. In one embodiment, the subject is a mammalian subject, or in another embodiment, the subject is a human subject.

In one embodiment, the NRBAs/SERMs and/or compositions set forth herein are effective to treat, suppress or inhibit osteopenia with bone loss. In one embodiment, "osteopenia" refers to reduced calcification or bone density. In one embodiment, the term indicated encompasses all skeletal systems of such a condition.

In another embodiment, the present invention provides a method of reducing the incidence of osteoporosis, bone fractures, and/or loss of Bone Mineral Density (BMD) in a subject, a method of inhibiting, suppressing, and treating osteoporosis, bone fractures, and/or loss of Bone Mineral Density (BMD) in a subject comprising administering an NRBA/SERM compound comprising formulas (I) - (X) or a prodrug, ester, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrate or any combination thereof, thereby reducing the incidence of osteoporosis, bone fractures, and/or loss of Bone Mineral Density (BMD) in a subject, inhibiting, suppressing, and treating osteoporosis, bone fractures, and/or loss of Bone Mineral Density (BMD) in a subject.

In one embodiment, the bone-related diseases or disorders treated with NRBAs (e.g., SERMs of the invention) are the result of androgen blockade therapy, which in one embodiment is performed in a male patient suffering from prostate cancer. In another embodiment, the bone-related diseases or disorders treated with the SERMs of the invention are the result of male menopause in aging men, or in another embodiment, result in reduced androgen production in male individuals with endocrine disorders. In another embodiment, the bone-related diseases or disorders treated with the NRBAs/SERMs of the present invention are the result of menopause in women. In another embodiment, treatment of bone-related diseases or disorders with the SERMs of the present invention is the result of female endocrine disorders, or in another embodiment is a byproduct of hormonal control, contraception, and the like.

In one embodiment, the SERMs are useful for treating, preventing, inhibiting, etc. bone-related diseases or disorders based on their pharmacological activity, as described in receptor binding studies, in vitro studies and in vivo studies of estrogen receptor transactivation, osteoblast and osteoclast activity.

In some embodiments, the ER- α ligand is used to treat, prevent, inhibit, or prevent a bone-related disease or disorder. In another embodiment, the ER- α ligands of the present invention include, inter alia, 3v, 3b, 3k or 10x listed in table 1 or any combination thereof.

Hormone related diseases

In some embodiments, the invention provides methods of treating, preventing, suppressing, delaying the onset or severity of hormone-related disorders.

In another embodiment, the present invention provides methods for treating and/or preventing post-menopausal or post-menopausal male disorders, etc.

In another embodiment, the invention provides methods of treating and/or preventing diseases, disorders or conditions, such as those caused by hormonal control or endocrine disorders, resulting in reduced or eliminated levels of circulating hormones, such as reduced or eliminated levels of estrogen or androgen.

Such diseases, disorders or conditions may include hot flashes, night sweats, loss of libido, weight gain, hair loss, hypertension, depression, anxiety, gastrointestinal distress, or any combination thereof.

In some embodiments, such a disease, disorder or condition is the result of menopause, andropause, androgen blockade therapy, or other related condition treatment, such as treatment of female breast cancer or male prostate cancer, respectively.

In some embodiments, treating a condition associated with androgen blockade therapy can include treating or ameliorating hot flashes, male breast development, osteoporosis, decreased muscle mass, depression and other mood changes, loss of libido, and erectile dysfunction in these individuals.

In some embodiments, hormone-dependent diseases or conditions that may be affected by the above-described methods and/or using the NRBAs (SERMs in some embodiments) and/or compositions of the present invention include sex hormone-dependent cancers (e.g., prostate cancer, uterine cancer, breast cancer, pituitary tumors, etc.), prostatic hypertrophy, endometriosis, uterine fibroids, precocious puberty, dysmenorrhea, amenorrhea, premenstrual syndrome, multiple atrial ovarian syndrome, polycystic ovary syndrome, post-operative recurrence of the aforementioned cancer, dwarfism, alzheimer's disease, climacteric disorders, undefined diseases, metastasis of the aforementioned cancer, sex hormone dependent diseases such as calcium/phosphorus bone metabolism disorders and the like, contraception, infertility or other diseases and/or disorders, the development of which is a consequence of the diseases/disorders/syndromes listed herein.

In one embodiment, the cancer to be treated, prevented, contained, or the like is breast cancer. This includes, but is not limited to, hormone sensitive, hormone refractory or metastatic breast cancer. In one embodiment, the breast cancer occurs in the inner wall of the mammary duct (ductal carcinoma), or in the lobules where milk is produced (lobular carcinoma). Other forms of breast cancer include inflammatory breast cancer and recurrent breast cancer. Inflammatory breast cancer is rare, but a very severe, predisposed type of breast cancer.

In one embodiment, the term "breast cancer" refers to a condition characterized by irregular rapid proliferation of abnormal cells in one or both breasts of an individual. Abnormal cells are often referred to as "neoplastic cells," which in some embodiments refer to transformed cells capable of forming tumors. In some embodiments, the term "tumor" refers to an abnormal mass or number of cells (i.e., two or more cells) caused by excessive or abnormal cell differentiation, whether malignant or benign, as well as precancerous and cancerous cells. Malignant tumors are distinguished from benign growths or tumors, which, in addition to uncontrolled cellular proliferation, can invade surrounding tissues and can metastasize.

In breast cancer, neoplastic cells may be present in only one or both breasts, but not in another tissue or organ, in one or both breasts and in one or more adjacent tissues or organs (e.g., lymph nodes), or in one breast and non-adjacent tissues or organs to which one or more of the breast cancer cells have metastasized.

In some embodiments, the term "invasion" refers to the spread of cancer cells to adjacent surrounding tissues. In some embodiments, the term "metastasis" refers to a method of metastasis of cancer cells from one organ or tissue to another non-adjacent organ or tissue. Cancer cells in the breast may spread to tissues and organs of an individual, whereas cancer cells from other organs or tissues may invade or metastasize to the breast. Cancer cells from the breast may invade or metastasize to any other organ or tissue of the body. Breast cancer cells often invade lymph node cells and/or metastasize to the liver, brain, and/or bone, and spread the cancer in these tissues and organs.

In some embodiments, the NRBAs in some embodiments of the invention are SERMs of the invention and/or compositions containing the same for use in affecting/treating/suppressing prostate, ovarian, uterine, cervical, endometrial, vaginal, or breast cancer, among others.

In one embodiment, the NRBAs in some embodiments of the invention are SERMs and/or compositions containing the same, which can be used to prevent or treat the aforementioned hormone-dependent diseases.

In another embodiment, the present invention provides a method of suppressing, inhibiting or reducing the risk of developing endometrial cancer in a subject, a method of preventing or treating a subject having endometrial cancer, the method comprising administering to the subject a composition of the present invention in an amount effective to suppress, inhibit or reduce the risk of developing endometrial cancer in the subject, prevent or treat endometrial cancer in the subject.

In some embodiments, the NRBAs in some embodiments of the invention are SERMs of the invention for use in the treatment of endometrial cancer, or in another embodiment for the treatment of breast cancer, or in another embodiment for the treatment of any hormone-related disease, disorder or condition that is due to an overproduction or a disturbance in the production of estrogen. According to this aspect of the invention, in one embodiment, such a disease, disorder or condition may be positively affected by the administration of NRBA, which in some embodiments of the invention is a SERM, which is selected based on the pharmacological activities described in receptor binding studies, estrogen receptor transactivation, in vitro studies and in vivo studies of osteoblast and osteoclast activity.

In some embodiments, the ER- α antagonist is used to treat, suppress, inhibit, or reduce breast cancer and endometrial cancer. In another embodiment, ER- β is shown to increase proliferation of mammary epithelial cells, indicating that ER- β regulates the growth of the mammary gland and that agonists of ER- β decrease the growth of the mammary gland. Furthermore, ER- β selective ligands have anti-estrogenic activity, thereby preventing estrogenic effects in breast cancer growth, and are useful for their applications and represent embodiments of the present invention.

In one embodiment, such ER- α antagonists of the invention include, inter alia, 10m, 4a, 11f or 11 g. In another embodiment, such ER β agonists include, inter alia, 10d, 10f, 10l or 11p listed in table 1 or any combination thereof.

In another embodiment, the present invention provides a method of suppressing, inhibiting or reducing the risk of developing polycystic ovarian syndrome, or preventing or treating a subject having polycystic ovarian syndrome, comprising the step of administering to the subject a compound or composition of the invention in an amount effective to suppress, inhibit or reduce the risk of developing polycystic ovarian syndrome in the subject, or to prevent or treat polycystic ovarian syndrome in the subject.

In another embodiment, the present invention provides a method of suppressing, inhibiting or preventing diabetes, breast cancer, endometrial cancer or cardiovascular disease or delaying the onset thereof in a female subject with polycystic ovary syndrome, comprising the step of administering to said subject an amount of a compound or composition of the present invention effective to suppress, inhibit, delay or prevent the onset of diabetes, breast cancer, endometrial cancer or cardiovascular disease in said subject.

In one embodiment, the NRBAs, which in one embodiment are SERMs and/or compositions, comprise the same compound that can be used for the prevention or treatment of sexual dysfunction.

In one embodiment, the sexual dysfunction treated by the method which in one embodiment is by the NRBAs being the SERMs and/or compositions of the invention is in men and in another embodiment consists essentially of erectile dysfunction, male orgasmic disorder, inhibited or hypoactive (hypoactive) sexual desire and priapism. Suppressed or hypoactive sexual desire refers to a decreased need or interest for sexual activity, which may be caused by a number of causes, including physical illness, depression, hormonal abnormalities, or medication affecting libido.

In one embodiment, the NRBAs, which in one embodiment are the SERMs of the invention and/or compositions comprising the same, are useful in preventing or treating female sexual dysfunction. In one embodiment, the female is premenstrual. In one embodiment, the female is a postmenopausal female. According to this aspect of the invention, in one embodiment, the NRBAs, which in one embodiment are the SERMs of the invention and/or compositions comprising the same, are useful in preventing or treating symptoms associated with estrogen-blockade treatment of the menopause, such as vaginal dryness/lack of lubrication and pain associated with intercourse, which in turn may be closely associated with reduced sexual desire. Other postmenopausal symptoms such as night sweat, hot flashes, insomnia, depression, nervousness, urinary incontinence, irritability and anxiety may also be associated with reduced sexual desire and may be treated with NRBAs which in one embodiment are the SERMs of the present invention and/or compositions comprising the same.

In another embodiment, the present invention provides a method of contraception that includes a composition comprising NRBA, which in one embodiment is a SERM compound of formulas (I) - (X) or a prodrug, ester, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrate or any combination thereof, and/or its use. In one embodiment, the present invention provides a method of post-coital contraception by administering a composition comprising NRBA, which in one embodiment is a SERM compound of formulas (I) - (X) or a prodrug, ester, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrate or any combination thereof.

In one embodiment, the present invention provides a method of treating a subject having a post-menopausal condition, the method comprising the step of administering to said subject an NRBA, which in one embodiment is a SERM compound and/or a pharmaceutically acceptable salt, hydrate, N-oxide or any combination thereof.

In another embodiment, the present invention provides a method of suppressing, inhibiting, or reducing the risk of a postmenopausal disorder, the method comprising the step of administering to the subject an NRBA, which in one embodiment is a SERM compound and/or a pharmaceutically acceptable salt, hydrate, N-oxide, or any combination thereof.

In another embodiment, the invention provides a method of treating, preventing, suppressing, inhibiting or reducing the incidence of hot flashes, male breast development and/or hair loss in a female subject, or in another embodiment, a male human subject. In one embodiment, the present invention provides a method of treating, preventing, suppressing, inhibiting or reducing the incidence of hot flashes, male breast development and/or hair loss in a male subject suffering from prostate cancer, comprising administering a pharmaceutical composition comprising NRBA, which in one embodiment is a SERM compound of formulae (I) - (X) or a prodrug, ester, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrate or any combination thereof, thereby treating, preventing, suppressing, inhibiting or reducing the incidence of hot flashes, male breast development and/or hair loss in said male subject.

In one embodiment, the term "hot flashes" refers to the following: sudden sensation of heat, red dizziness of the face and neck, erythema on the chest, back and arms, profuse sweating, cold tremor, etc. on the upper part of the body or throughout the body.

It is to be understood that any sex hormone dependent disease, disorder or condition can be treated by the methods of the invention using the SERMs/compositions of the invention.

In one embodiment, hot flashes may be treated with any SERM characterized by any of the molecular formulas described herein. In one embodiment, hot flashes can be treated, prevented, reduced with the following SERMs selected for their pharmacological activity demonstrated in receptor binding studies, in vitro studies of estrogen receptor transcriptional activation, in vitro studies and in vivo studies of osteoblast and osteoclast activity.

In some embodiments, ER-alpha agonists and/or ER-beta agonists are used to treat, suppress, inhibit or reduce the risk of postmenopausal disorders, such as hot flashes, hot sweats, night sweats, hot flashes, depression and/or anxiety. In another embodiment, the ER-alpha agonists of the invention include, inter alia, 3v, 3b, 3k or 10x or any combination thereof. In another embodiment, the ER- β agonists of the present invention include, inter alia, 10d, 10f, 10l or 11p listed in Table 1 or any combination thereof.

Hot flashes are regulated by ER-alpha and ER-beta. To overcome this, tissue selective agonists of both isomers may be employed. In some embodiments, side effects associated with some ER-alpha agonists, such as thromboembolism, breast carcinogenesis (mammary carcinogenesis), and uterine cancer, can be eliminated via selection of specific ER-beta agonists for this indication.

Cardiovascular diseases and obesity

Cardiovascular cells, as well as reproductive tissues, bone, liver and brain, express two known estrogen receptors, the estrogen alpha receptor (ER- α) and the estrogen beta receptor (ER- β). These receptors are important targets for endogenous estrogen, Estrogen Replacement Therapy (ERT), and pharmacological estrogen agonists. The estrogen-estrogen receptor complex functions as a transcription factor that promotes gene expression, which has a number of vascular effects, including regulation of vascular tone and response to injury, which can prevent the development of atherosclerosis and ischemic disease. Estrogen receptors in other tissues, such as the liver, may mediate beneficial effects (e.g., changes in apoprotein gene expression that improve fat characteristics) and adverse effects (e.g., increased gene expression of coagulation proteins and/or decreased fibrinolysis). Two systemic estrogen-mediated vascular effects have been recognized. Rapid transient vasodilation occurs within minutes after estrogen exposure and is independent of changes in gene expression. Long-term effects of estrogen on the vasculature, such as those associated with limiting the development of atherosclerotic lesions or vascular lesions, occur within hours to days after estrogen treatment and have changes in vascular gene expression as their hallmarks. Progesterone and other hormone receptors are also expressed in the vasculature.

In one embodiment, the present invention provides a method of treating, preventing or reducing the risk of death therefrom in a subject, comprising administering a pharmaceutical composition comprising NRBA, which in one embodiment is a SERM compound of formulae (I) - (X) or a prodrug, ester, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrate or any combination thereof.

In some embodiments, the ER- β agonist is used to treat, prevent or reduce the risk of mortality due to cardiovascular and/or cerebrovascular disease in an individual. In another embodiment the ER- β agonists of the invention especially comprise 10d, 10f, 10l or 11p listed in Table 1 or any combination thereof.

In one embodiment, cardiovascular disease includes, inter alia, coronary atherosclerosis, angina pectoris, and myocardial infarction. In one embodiment, cerebrovascular disease includes, inter alia, intracranial or extracranial atherosclerosis, stroke, syncope, and transient ischemic attack.

In one embodiment, the methods/compounds/compositions of the present invention are used to treat an individual with one or more risk factors for cardiovascular or cerebrovascular disease, such as hypercholesterolemia, hypertension, diabetes, smoking, family or past history of coronary artery disease, cerebrovascular disease, and cardiovascular disease. Hypercholesterolemia is generally defined as a plasma total cholesterol concentration above about 5.2mmol/L (about 200 mg/dL). In some embodiments, the risk factors may include hypertension (particularly systolic blood pressure greater than 160mmHg), heart disease, transient ischemic attacks, diabetes, carotid vascular noise, and sickle cell disease. Obesity, sedentary lifestyle, smoking, drinking, and elevated plasma cholesterol and lipid levels can also be risk factors for cerebrovascular disease.

In another embodiment, the present invention provides a method of improving lipid profile in a subject comprising administering a pharmaceutical composition comprising NRBA, which in one embodiment is a SERM compound of formulae (I) - (X) or a prodrug, ester, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrate or any combination thereof, thereby improving lipid profile in said subject.

In some embodiments, the phrase "improving lipid profile" may refer to reducing circulating lipid levels, reducing plaque formation in the vasculature, altering circulating HDL/LDL ratios, reducing levels of circulating cholesterol, preventing fat accumulation in the vasculature, or any combination thereof, or other related therapeutic effects, as will be appreciated by those skilled in the art.

In one embodiment, the present invention provides NRBAs/SERMs for use in reducing fat mass in a subject. In another embodiment, the compound is a prodrug, ester, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrate or any combination thereof, or a composition comprising the same, of the NRBAs/SERMs described herein.

In another embodiment, the present invention provides the use of NRBA in the treatment of obesity or diabetes associated with metabolic syndrome in an individual, which in one embodiment is a SERM compound of the present invention, or a prodrug, ester, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrate or any combination thereof, or a composition comprising the same.

In another embodiment, the individual has a hormonal imbalance, disorder or disease. In another embodiment, the subject has been menopausal, or in another embodiment, the subject has entered male menopause, or has suffered an age-related androgen decline in a male subject.

In one embodiment, the invention provides the use of NRBA (which in one embodiment is a SERM compound as described) to increase lean mass in an individual. In one embodiment, the individual has a hormonal imbalance, disorder or disease. In another embodiment, the individual suffers from a disease listed herein that is negatively affected by obesity, or the presence of greater amounts of fat, or in another embodiment, positively affected by lean body mass gain in the individual.

In another embodiment, the present invention relates to a method of preventing, suppressing, inhibiting or reducing the incidence of obesity in a subject, comprising the step of administering to said subject NRBA, which in one embodiment is an amount of a SERM and/or its analog, ester, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal or any combination thereof described herein, effective to prevent, suppress, inhibit or reduce the incidence of obesity in a subject.

In one embodiment, the NRBA, which in one embodiment is a SERM compound, alters leptin levels in the subject when administered. In another embodiment, the NRBA/SERM compound reduces leptin levels. In another embodiment, the NRBA/SERM compound increases leptin levels in a subject. In one embodiment, the NRBAs/SERMs affect circulation, or in another embodiment, tissue levels of leptin. In one embodiment, the term "leptin level" refers to the plasma level of leptin.

Since leptin is involved in controlling appetite, weight loss, food intake, and energy expenditure, modulating and/or controlling leptin levels is a useful therapeutic approach to treating, preventing, inhibiting, or reducing the incidence of obesity in individuals suffering from obesity. Modulation of leptin levels can result in loss of appetite, decreased food intake, and increased energy expenditure in an individual, which can facilitate the control and treatment of obesity.

In one embodiment, the term "obesity" refers to an increase in body weight beyond skeletal and physical demand limits, resulting in an excessive accumulation of fat in the body.

In one embodiment, the term "obesity-related metabolic disorder" refers to a disorder resulting from obesity, which is a result of obesity, is exacerbated by obesity, or is secondary to obesity. Non-limiting examples of such conditions are osteoarthritis, type II diabetes, increased blood pressure, stroke, and heart disease.

In one embodiment, the term "diabetes" refers to a relative or absolute deficiency of insulin, resulting in uncontrolled carbohydrate metabolism. Most patients are clinically classified as having insulin-dependent diabetes (IDDM or type I diabetes) or non-insulin-dependent diabetes (NIDDM or type II diabetes).

In other embodiments, the term "increased blood pressure" or "hypertension" refers to repeatedly high pressures in excess of 140/90 mmHg. Chronic blood pressure elevation can cause ocular fundus vascular changes, myocardial thickening, renal failure, and brain damage.

In other embodiments, the term "stroke" refers to nerve cell damage in the brain due to insufficient blood supply to blood vessels, often caused by bursting of blood vessels or blood clotting. In other embodiments, the term "heart disease" refers to a dysfunction of the normal function and activity of the heart, including heart failure.

In one embodiment, the NRBA/s or SERM/s described herein, which biases lean body mass relative to fat accumulation, may be administered to any condition for which the methods of the present invention are useful.

According to this aspect of the invention, in one embodiment, the NRBA/s or SERMs of the invention may be administered in combination with adrenaline, antiandrogen, antianginal, antihyperlipidemic, antihypertensive, anti-inflammatory, aldosterone antagonists, amino acids, blood glucose regulators, cardioprotective; a cardiovascular agent; cholinergic agonists and antagonists, cholinesterase inactivators or inhibitors, enzyme inhibitors, free oxygen radical scavengers, hormones, anti-hypocholesterolemic agents, hypolipidemic agents, hypotensive agents, immunological agents, immunostimulants, potassium channel openers, post-stroke and brain trauma treatments, prostaglandins, sodium and potassium channel blockers, thyroid hormones and inhibitors.

In another embodiment, the present invention relates to a method of promoting, increasing or facilitating weight loss in a subject, comprising the step of administering to said subject an amount of NRBA/s or SERM/s and/or analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, ester, prodrug, polymorph, crystal or any combination thereof described herein effective to promote, increase or facilitate weight loss in a subject.

In another embodiment, the present invention relates to a method of reducing, suppressing, inhibiting, or reducing appetite in an individual comprising the step of administering to the individual an amount of NRBA/s or SERM/s and/or analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, ester, prodrug, polymorph, crystal, or any combination thereof, described herein, effective to reduce, suppress, inhibit, or reduce the appetite of the individual.

In another embodiment, the present invention relates to a method of altering the body composition of a subject comprising the step of administering to said subject the NRBA or SERM and/or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceuticals, hydrates, N-oxides, esters, prodrugs, polymorphs, crystals, or any combination thereof, as described herein, in an amount effective to alter the body composition of said subject. In one embodiment, altering body composition comprises altering the body weight, fat free body weight, or a combination thereof of the individual.

In another embodiment, the present invention relates to a method of altering the body weight or fat loss of an individual comprising the step of administering to said individual NRBA/s or SERM/s and/or analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, esters, prodrugs, polymorphs, crystals, or any combination thereof, as described herein, in an amount effective to alter the body weight or fat loss of an individual.

In another embodiment, the present invention relates to a method of converting fat to lean muscle in a subject, comprising the step of administering to the subject the NRBA/s or SERM/s and/or analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, prodrugs, polymorphs, esters, crystals, or any combination thereof, described herein, in an amount effective to convert fat to lean muscle in a subject.

In another embodiment, the present invention relates to a method of treating an obesity-related metabolic disorder in an individual, comprising the step of administering to the individual NRBA/s or SERM/s and/or analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceuticals, hydrates, N-oxides, esters, prodrugs, polymorphs, crystals, or any combination thereof, described herein, in an amount effective to treat an obesity-related metabolic disorder in an individual.

In another embodiment, the present invention relates to a method of preventing, suppressing, inhibiting or reducing obesity-related metabolic disorders in a subject, comprising the step of administering to said subject the selective estrogen receptor modulator NRBA/s or SERM/s and/or analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceuticals, hydrates, N-oxides, esters, prodrugs, polymorphs, crystals, or any combination thereof, described herein, in an amount effective to prevent, suppress, inhibit or reduce obesity-related metabolic disorders in a subject.

In one embodiment, the obesity-related metabolic disorder is hypertension. In another embodiment, the disorder is osteoarthritis. In another embodiment, the disorder is type II diabetes or diabetes. In another embodiment, the disorder is elevated blood pressure. In another embodiment, the disorder is stroke. In another embodiment, the disorder is a heart disease.

In another embodiment, the present invention relates to a method of reducing, suppressing, inhibiting, or reducing adipogenesis in a subject, comprising the step of administering to the subject an amount of NRBA/s or SERM/s and/or analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceuticals, hydrates, N-oxides, esters, prodrugs, polymorphs, crystals, or any combination thereof, described herein, effective to inhibit or reduce adipogenesis in the subject.

In one embodiment, the NRBA or SERM is used to a) treat, prevent, suppress, inhibit or reduce obesity; b) promoting, increasing or facilitating weight loss; c) reducing, suppressing or reducing appetite; d) changing the body composition; e) changing body weight or losing fat body weight; f) converting fat into fat-free muscle; g) treating, preventing, suppressing, inhibiting or reducing an obesity-related metabolic disorder, such as hypertension, osteoarthritis, type II diabetes or diabetes, elevated blood pressure, stroke or heart disease; h) reducing, suppressing, inhibiting or reducing adipogenesis; and/or i) altering leptin levels.

In one embodiment, the NRBA/s or SERMs of the present invention are useful in treating or interrupting the progression of diabetes or treating diabetes. In one embodiment, an individual at risk for diabetes is administered the NRBA/s or SERM/s described herein, or in other embodiments, other metabolic diseases, which alter the progression of the disease, or in other embodiments, prevent the disease, or in another embodiment, reduce its severity, or in another embodiment, reduce symptoms associated with the disease. In one embodiment, treatment is initiated after the initial indication of the risk factor, or in another embodiment, after an indication of an early stage of the disease, as will be appreciated by those skilled in the art. For example, in one embodiment, treatment is initiated when the individual exhibits hyperinsulinemia, or in another embodiment, gestational diabetes, or in another embodiment, hyperglycemia, or in another embodiment, impaired glucose tolerance, and the like, as will be appreciated by those skilled in the art.

In another embodiment, the NRBA/s or SERMs described herein are used to treat diabetes-related co-morbidities. These conditions include: hypertension, cerebrovascular disease, atherosclerotic coronary artery disease, macular degeneration, diabetic retinopathy (eye disease) and blindness, cataracts, systemic inflammation (characterized by an increase in inflammatory markers, such as an increase in the rate of erythrocyte precipitation or C-reactive protein), birth defects, pregnancy-related diabetes mellitus, pre-gestational epilepsy and hypertension, kidney disease (renal insufficiency, renal failure, etc.), neurological disease (diabetic neuropathy), superficial and systemic fungal infections, congestive heart failure, gout/hyperuricemia, obesity, hypertriglyceridemia, hypercholesterolemia, fatty liver (non-alcoholic steatohepatitis or NASH), and diabetes-related skin diseases, such as diabetic progressive Necrosis (NLD), diabetic blisters (diabetic bullae), eruptive xanthomas (eruptive xanthomas), Mural sclerosis, disseminated granuloma annulare and acanthosis nigricans.

In one embodiment, the present invention provides a) a method of treating, preventing, suppressing or inhibiting atherosclerosis, b) a method of treating, preventing, suppressing or inhibiting liver damage due to fat deposition, comprising the step of administering to said individual NRBA/s or SERM/s and/or analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceuticals, hydrates, N-oxides, esters, prodrugs, polymorphs, crystals or any combination thereof, or a composition comprising the same, described herein, in an amount effective to treat, prevent, or inhibit atherosclerosis and liver damage due to fat deposition.

In one embodiment, the NRBA/s or SERM/s described herein are used to a) treat, prevent, contain, inhibit or reduce atherosclerosis; b) treating, preventing, suppressing and inhibiting liver injury caused by fat deposition.

In one embodiment, atherosclerosis refers to a complex disease in which damage to the innermost layer of an artery begins. In another embodiment, the cause of damage to the arterial wall may include a) an increase in blood cholesterol levels; b) hypertension; c) smoking; d) diabetes mellitus. In another embodiment, the condition is treatable in smokers, although smoking can substantially exacerbate atherosclerosis and accelerate its growth in coronary arteries, the lower aorta and arteries. Similarly, in another embodiment, the methods of the invention can be used to treat individuals with an elevated risk of atherosclerosis who have a family history of cardiovascular disease at an early stage.

In one embodiment, liver injury due to fat deposition refers to the accumulation of fat in hepatocytes to form fatty liver, which may be associated with or may result in inflammation of the liver. This can cause scarring and cirrhosis of the liver. When the scar becomes extensive, it is called sclerosis.

In another embodiment, fat accumulates in the liver as a result of obesity. In another embodiment, fatty liver is also associated with diabetes, high blood triglycerides and heavy use of alcohol. In another embodiment, fatty liver may occur with certain conditions such as tuberculosis and malnutrition, intestinal bypass for the treatment of obesity, vitamin a surplus in the body, or the use of certain drugs such as valproic acid (trade name: Depakene/Depakote) and corticosteroids (cortisone, prednisone). Fatty liver sometimes occurs as a complication of pregnancy. In one embodiment, NRBA/s, which in some embodiments is a SERM/s as described herein, may be used to treat any of these conditions and represents another embodiment of the present invention. In one embodiment, the use of the NRBA/s of the present invention will not result in toxic effects to the liver, even prolonged use.

In another embodiment, the present invention provides for the treatment or prevention of Peripheral Vascular Disease (PVD), which in some embodiments is the modulation of the rheological behavior of blood, thereby improving microcirculation, by using NRBA, which in some embodiments is a SERM of the present invention. In another embodiment, PVD may be caused by hypertension. In another embodiment, PVD may be caused by diabetes. In another embodiment, PVD may be caused by a vaso-occlusive event.

In one embodiment, the phrase "vaso-occlusive event" refers to a condition characterized by or causing a decrease in local or systemic vascular inner diameter to an extent that impedes blood flow and/or is a pathological feature of an individual. In one embodiment, the vaso-occlusive event comprises a pathological stenosis or stent, a vascular graft, or a vascular closure. In one embodiment, the phrase "pathological stenosis or closure" refers to abnormal and/or disease-related stenosis or closure. Vascular closure events include events that cause stenosis or closure of a blood vessel (e.g., thrombotic events, thromboembolic events, and intimal hyperplasia) as well as conditions resulting from such vessel stenosis (e.g., myocardial infarction and ischemic stroke).

Thrombotic events, including thromboembolism, can be serious medical conditions, particularly because they can cause a decrease in blood flow to vital organs, including the brain and heart muscle. Examples of thrombotic events include, but are not limited to, arterial thrombosis, including stent and graft thrombosis, heart thrombosis, coronary artery thrombosis, heart valve thrombosis, and venous thrombosis. A heart thrombus is a thrombus in the heart. An arterial thrombus is a thrombus in an artery. Coronary thrombosis is the formation of an obstructive thrombus in the coronary artery, often resulting in sudden death or myocardial infarction. Venous thrombosis is the formation of a thrombus in a vein. Heart valve thrombosis is the formation of a thrombus on a heart valve. Stent thrombosis is caused by a thrombus located near the myocardial stent. Graft thrombosis is caused by a thrombus located near an implanted graft organ, particularly a myocardial stent.

Examples of conditions or diseases caused by thrombotic events include, but are not limited to, myocardial infarction, stroke, transient ischemic attacks, amaurosis, aortic stenosis, cardiac stenosis, coronary stenosis, and pulmonary stenosis. A stenosis is a narrowing or stenosis of a duct or pipe. A coronary stenosis is a narrowing or stenosis of a coronary artery. Cardial stenosis is the narrowing or reduction of any passageway or cavity of the heart. A pulmonary valve stenosis is a stenosis at the opening between the pulmonary artery and the right ventricle. Aortic valve stenosis is the stenosis of the aortic valve of the heart or of the aorta itself.

Vasoocclusive events also include diseases in which the blood vessel is stenotic, not necessarily due to thrombosis, but more likely due to thickening of the vessel wall, such as with intimal hyperplasia. Intimal hyperplasia refers to a condition characterized by abnormal hyperplasia in the vessel wall.

Accordingly, one aspect of the present invention relates to methods/compounds/compositions for reducing the risk of thrombotic events. In one embodiment, the method reduces the risk of stroke. Stroke is a condition caused by hypoxia in the brain, resulting from one or more occlusive thrombi. Depending on the area of the brain affected, stroke can lead to many symptoms ranging from transient ischemic attack to death (e.g., coma, reversible or irreversible paralysis, language disorders, or dementia). In a preferred embodiment, the stroke itself is non-hemorrhagic.

In other embodiments the methods/compounds/compositions of the present invention are directed to reducing the risk of myocardial infarction. Myocardial infarction refers to irreversible damage to the myocardium. Myocardial infarction is typically caused by a sudden decrease in coronary blood flow following a coronary occlusive thrombus (e.g., thromboembolism). In many cases, thrombi form after rupture of atherosclerotic plaques in diseased coronary arteries. Such damage is highly correlated with factors such as smoking, hypertension and fat accumulation.

Transient ischemic attacks are transient acute neurological dysfunctions caused by thromboembolism in the cerebral circulation. Amaurosis is a temporary blindness caused by thromboembolism in renal vessels.

The methods/compounds/compositions of the invention may be used to reduce the risk of or inhibit the exacerbation of a primary or secondary vasoocclusive event, such as a thromboembolic event. A primary vasoocclusive event refers to the first known vasoocclusive event experienced by an individual. A secondary vasoocclusive event refers to a vasoocclusive event occurring in an individual who is known or diagnosed as having previously experienced a vasoocclusive event (i.e., a first vasoocclusive event).

It is to be understood that any of these conditions, causes, symptoms, by-products, etc. of the same disease can be positively influenced by administration of the compounds/compositions of the present invention and such use is considered an embodiment thereof.

In another embodiment, the present invention provides a method of preventing the development of alzheimer's disease in a subject, comprising administering to said subject a pharmaceutical composition of a SERM compound of formulae (I) - (X) or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof, thereby preventing the development of alzheimer's disease in said subject.

Anti-inflammatory effects of SERMs

Inflammation is a common and potentially debilitating condition which occurs when white blood cells and endogenous substances, which protect us from infection and foreign bodies such as bacteria and viruses, act on a wound or on the surrounding tissue. In some diseases, however, the body's defense system (immune system) also triggers an inflammatory response when there is no foreign body to fight against. In these diseases, called autoimmune diseases, the body's normally protective immune system causes damage to its own tissues. The body reacts as if normal tissue is infected or abnormal. Some, but not all types of arthritis are the result of misdirected inflammation (misdirected inflammation). Arthritis is a general term describing joint inflammation, affecting more than 2-4% of the world population. There are a number of pharmacological treatments available to reduce swelling and inflammation, with the hope of preventing or reducing exacerbations of inflammatory diseases. Drug therapies include nonsteroidal anti-inflammatory drugs (NSAIDs-such as aspirin, ibuprofen or naproxen), glucocorticoids (such as prednisone), antimalarial drug therapies (such as hydroxychloroquine), and other drug therapies including gold, methotrexate, sulfasalazine, penicillin, cyclophosphamide and cyclosporine.

The role of estrogen receptors and their ligands as a treatment of inflammation has been considered. This effect is thought to be mediated by the isoform ER- β. Treatment of rats with estradiol or SERMs such as raloxifene and tamoxifen has been shown to reduce the incidence of lipopolysaccharide (lipo-polysachraride) induced inflammatory responses. One of the pathways that modulate the inflammatory response is through the activation of the NF κ B pathway. Nuclear receptor ligands inhibit NF κ B activity through protein interactions. Recently, SERMs have been shown to suppress inflammatory responses by inhibiting NF κ B function without having an estrogenic effect on other regenerative tissues.

In another embodiment, the present invention provides a method of treating, preventing, inhibiting or reducing the incidence of inflammation in a subject, comprising administering a pharmaceutical composition comprising a SERM compound of formulae (I) - (X) or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof, thereby treating, preventing, inhibiting or reducing the incidence of inflammation in a subject.

In some embodiments, the ER- β agonist is used to treat, prevent, inhibit or reduce the incidence of inflammation in an individual. In another embodiment, the ER- β agonists of the present invention include, inter alia, 10d, 10f, 10l, or 10p listed in Table 1, or any combination thereof.

In order to more fully illustrate the preferred embodiments of the invention, the following examples are set forth. They should not be construed, however, as limiting the broad scope of the invention.

Examples

Example 1:

novel SERMs and their estrogen receptor binding affinities, agonist and antagonist activity

Materials and methods:

ER binding affinity was determined by one of the following methods:

the method comprises the following steps:

human recombinant ER was expressed in insect Sf9 cells and a radioactive competitive binding assay was performed with deuterium-labeled estradiol. If the NRBA compound tested exhibits [ gtoreq ] at a concentration of 1. mu.M (1000nM)³H]50% inhibition of estradiol binding, they were tested with 4 concentrations of compound to obtain estimated IC₅₀And K_iThe value is obtained.

The method 2 comprises the following steps:

the Estrogen Receptor (ER) binding affinity of the NRBA compound is also used³H]-estradiol ([ alpha ], ])³H]-E₂PerkinElmer) was performed on ER α and ER β high affinity ligands in vitro competitive radioligand-binding assays. [³H]-E₂Equilibrium dissociation constant (K) of_d) By increasing the concentration of [ 2 ] at 4 ℃³H]-E₂(0.01 to 10nM) was assayed by incubation with bacterially expressed ER α or β Ligand Binding Domain (LBD) for 18 hours. By adding 1000nM E to the incubation mixture₂To determine non-specific binding. Determined in the incubation mixture To saturate the binding sites of ER α and ER β³H]-E₂The minimum concentration of (c) is 1nM each. Binding affinity of NRBA compounds by increasing the concentration under the same conditions (3X 10)^-2To 1,000nM) ligand and isolated ER LBD and 1nM³H]-E₂And (4) performing incubation measurement. After incubation, bound and free are separated by vacuum filtration using a Harvester (PerkinElmer)³H]-E₂. Briefly, the incubation mixture is filtered through a high affinity protein binding filter and washed several times to remove any unbound radioactivity. The filter plate was air dried and sealed at the bottom. Scintillation cocktail was added to each well and sealed at the top of the plate. Radioactivity was counted on a TopCount NXT microplate scintillation counter.

[³H]-E₂(B) Specific binding at each concentration of SERM is determined by subtracting³H]-E₂And in the absence of a SERM (B)₀) Lower as [, ]³H]-E₂The percentage of specific binding is expressed. Decrease by 50% (IC)₅₀) The term³H]-E²By computer fitting the data to non-linear regression analysis using SigmaPlot (SPSS inc., chicago, IL) according to the following formula:

B＝B₀*[1-C/(IC₅₀+C)]

where C is the concentration of the SERM.

The equilibrium dissociation constant of the SERM was calculated by the following formula:

K_i＝K_d*IC₅₀/(K_d+L)

wherein K_dIs [ 2 ]³H]-E₂(ER. alpha. 0.65nM, ER. beta. 1.83nM) and L is [ alpha ], [ beta ] ³H]-E₂(1 nM).

Table 1 lists a series of NRBA compounds. Representative NRBAs are described below, and their activity under specific experimental conditions is provided. It is to be understood that while the compounds shown may exhibit particular activity under the experimental conditions employed (e.g., compound 3v is an agonist), as a function, such compounds may have variable or varying activity under different experimental settings in some embodiments of the particular cell or the like employed.

Representative examples of NRBAs of the invention and their activity under the indicated conditions are shown below:

an era agonist: 3v (ER-alpha: K)_i＝20nM；EC₅₀＝22.4nM)，3b(ER-α：K_i＝14nM；EC₅₀＝10nM)，3k(ER-α：K_i＝129nM；EC₅₀＝12nM)，10x(ER-α：K_i＝13nM；EC₅₀＝16nM)。

An ER α antagonist: 10m (ER-alpha: K)_i＝221nM；IC₅₀＝＜10nM)，4a(ER-α：K_i＝111nM；IC₅₀＝35nM)，11f(ER-α：K_i＝60nM；IC₅₀69nM), and 11g (ER- α: k_i＝79nM；IC₅₀＝16nM)

ER β agonists: 10d (ER-beta: K)_i＝61nM；EC₅₀＝85nM)，10f(ER-β：K_i＝57nM；EC₅₀＝42nM)，10l(ER-β：K_i＝82nM；EC₅₀＝27nM)，11p(ER-β：K_i＝108nM；EC₅₀＝＜10nM)

An ER β antagonist: 10j (ER-beta: K)_i＝36nM；IC₅₀＝20nM)，10n(ER-β：K_i＝92nM；IC₅₀＝47nM)，10t(ER-β：K_i＝＜10nM；IC₅₀＝17nM)

Table 1:

compounds and IUPAC nomenclature	Physical characterization
compounds and IUPAC nomenclature	Physical characterization	Estradiol (E2)
Propyl Pyrazole Triol (PPT)		Estradiol (E2)
Propyl Pyrazole Triol (PPT)		Dipropionitrile (DPN)
ICI-182780		Dipropionitrile (DPN)
ICI-182780		5d 4-hydroxy-N- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -benzamide	A tan solid. The yield was 95%. Melting point 239-.¹H NMR(DMSO-d₆，300MHz)δ9.80(bs，1H)，9.46(bs，1H)，7.23-7.21(m，2H)，7.08-7.05(m，2H)，6.96-6.93(m，2H)，6.87-6.84(m，2H)，6.68-6.65(m，2H)，6.60-6.57(m，2H)，3.72(s，3H)。MS m/z 334(M-H)^-。
5eN- (4-hydroxyphenyl) -4-methoxy-N- (4-methoxyphenyl) -benzamide	A tan solid. The yield was 90%. Melting point 205-.¹H NMR(DMSO-d₆，300MHz)δ9.48(bs，1H)，7.35-7.32(m，2H)，6.99-6.97(m，2H)，6.87-6.85(m，2H)，6.81-6.77(m，2H)，6.68-6.66(m，2H)，3.72(s，6H)。MS m/z348(M-H)^-。
		4N 4-methoxy-N- (4-methoxyphenyl) -N- [4- (2-piperidin-1-ylethoxy) phenyl ]-benzamides	A white solid. The yield was 88%. Melting point 163-.¹H NMR(DMSO-d₆，300MHz)δ7.36(d，2H，J＝8.69Hz)，7.16-7.07(m，4H)，6.94(d，2H，J＝8.82Hz)，6.87(d，2H，J＝8.82Hz)，6.80(d，2H，J＝8.75Hz)，4.38-4.35(m，2H)，3.69(s，6H)，3.48-3.44(m，4H)，

Compounds and IUPAC nomenclature	Physical characterization
Compounds and IUPAC nomenclature	Physical characterization		2.51-2.50(m，2H)，1.78-1.66(m，4H)，1.41-1.37(m，2H)。MS m/z 461(M+H)⁺。
3 uN-Biphenyl-4-yl-N- (4-hydroxyphenyl) -4-methoxybenzamide	A tan solid. The yield was 21%. Melting point 232-.¹H NMR(DMSO-d₆，300MHz)δ9.55(s，1H).7.65-7.62(m，4H)，7.45(t，1H，J＝7.69Hz)，7.40-7.34(m，4H)，7.23(d，2H，J＝8.55Hz)，7.03-7.02(m，2H)，6.82-6.80(m，2H)，6.71-6.69(m，2H)，3.73(s，3H)，.MS m/z 418(M+Na)⁺。
3 uN-Biphenyl-4-yl-N- (4-hydroxyphenyl) -4-methoxybenzamide		3 vN-biphenyl-4-yl-4-hydroxy-N- (4-hydroxyphenyl) -benzamides	A white solid. The yield was 49%. Melting point 253-.¹H NMR(DMSO-d₆，300MHz)δ7.65-7.61(m，4H)，7.45(t，2H，J＝7.69Hz)，7.36-7.33(m，1H)，7.28-7.26(m，2H)，7.21-7.19(m，2H)，7.01-6.98(m，2H)，6.71-6.68(m，2H)，6.62-6.60(m，2H)。MS m/z 404(M+Na)⁺。
3w 4-hydroxy-N- (4-hydroxyphenyl) -N- [4- (2-piperidin-1-ylethoxy) phenyl]-benzamides	A tan solid. The yield was 46%. Melting point 233-.¹H NMR(DMSO-d₆，300MHz)δ9.81(bs，1H)，9.47(bs，1H)，7.24-7.20(m，2H)，7.05-7.03(m，2H)，6.96-6.93(m，2H)，6.87-6.84(m，2H)，6.68-6.65(m，2H)，6.60-6.57(m，2H)，4.02-3.99(m，2H)，2.63-2.60(m，2H)，2.09-2.08(m，4H)，1.48-1.36(m，6H)。MS m/z433(M+H)⁺。
		2w 4-cyano-N- (4-methoxyphenyl) -N-phenylbenzamide	Light yellow solid. The yield was 96%. Melting point 125-.¹H NMR(DMSO-d₆，300MHz)δ7.77-7.74(m，2H)，7.61-7.58(m，2H)，7.34-7.21(m，7H)，6.88(d，2H，J＝7.92Hz)，3.71(s，3H。MS m/z 351(M+Na)⁺。

Compounds and IUPAC nomenclature	Physical characterization
Compounds and IUPAC nomenclature	Physical characterization	4 oN-Biphenyl-4-Yl-N- (4-hydroxyphenyl) -4- (2-piperidin-1-ylethoxy) -benzoylAmines as pesticides	Light yellow solid. The yield was 40%. Melting point 132-.¹H NMR(DMSO-d₆，300MHz)δ7.65-7.61(m，4H)，7.47-7.45(m，2H)，7.36-7.33(m，1H)，7.28-7.26(m，2H)，7.21-7.19(m，2H)，7.01-6.98(m，2H)，6.70-6.67(m，2H)，6.62-6.61(m，2H)，4.05(bs，2H)，2.66(bs，2H)，2.50-2.45(m，4H)，1.49-1.38(m，6H)。MS m/z493(M+H)⁺。
3x 3-hydroxy-N- (4-hydroxyphenyl) -N-phenyl-benzamide	A tan solid. The yield was 78%. Melting point 221-¹H NMR((DMSO-d₆，300MHz)δ9.51(bs，2H)，7.33-7.29(m，2H)，7.19-7.15(m，3H)，7.04-6.98(m，3H)，6.82-6.66(m，5H)。MS m/z 304(M-H)^-。
3x 3-hydroxy-N- (4-hydroxyphenyl) -N-phenyl-benzamide		10a 4-cyano-N- (4-hydroxyphenyl) -N-phenylbenzamide	Yellow solid. The yield was 74%. Melting point 243-.¹H NMR(DMSO-d₆，300MHz)δ7.76-7.74(m，1H)，7.58-7.56(m，2H)，7.33-7.21(m，5H)，7.09-7.08(m，2H)，6.67(s，2H)。MS m/z 313(M-H)^-。
4p 4-methoxy-N-phenyl-N- [4- (2-piperidin-1-ylethoxy) phenyl ]-benzamides	Yellow solid. The yield was 84%. Melting point 139-.¹H NMR(DMSO-d₆，300MHz)δ7.35-7.33(m，4H)，7.26-7.22(m，5H)，7.15-7.14(m，2H)，7.12-7.11(m，2H)，6.91-6.87(m，2H)，6.83-6.80(m，2H)，4.02(t，2H，J＝5.79Hz)，3.72(s，3H)，2.63(t，2H，J＝5.79Hz)，2.41(bs，4H)，1.48-1.46(m，4H)，1.38-1.36(m，2H)。MS m/z 507(M+H)⁺。	10a 4-cyano-N- (4-hydroxyphenyl) -N-phenylbenzamide
		2y 4-cyano-N- (3-methoxyphenyl) -N-phenylbenzamide	Brown oil. The yield was 85%.¹H NMR(DMSO-d₆，300MHz)δ7.77-7.75(m，2H).7.63-7.61(m，2H)，7.35-7.30(m，4H)，7.25-7.22(m，2H)，6.91(s，1H)，6.83-6.80(m，2H)，3.67(s，3H)。MS m/z 351(M+Na)⁺。

Compounds and IUPAC nomenclature	Physical characterization
Compounds and IUPAC nomenclature	Physical characterization	10dN, N-bis (4-hydroxyphenyl) -3, 4-dimethylbenzamide	Tan solid. The yield was 68%. The melting point is more than 250 ℃.¹H NMR(DMSO-d₆，300MHz)δ9.46(s，3H)，7.20(s，1H)，7.03-6.95(m，6H)，6.68-6.65(m，4H)，2.14(s，3H)，2.12(s，4H)。MS m/z 334(M+H)⁺。
10eN- (biphenyl-4-yl) -4-cyano-N- (4-hydroxyphenyl) -benzamides	Yellow solid. The yield was 58%. Melting point 223-.¹H NMR(DMSO-d₆，300MHz)δ9.63(s，3H)，7.78-7.76(m，2H)，7.66-7.60(m，6H)，7.48-7.43(m，2H)，7.38-7.35(m，3H)，7.12(d，2H，J＝8.27Hz)，6.69(d，2H，J＝8.27Hz)。MS m/z 334(M+H)⁺。	10dN, N-bis (4-hydroxyphenyl) -3, 4-dimethylbenzamide
		10f 3-fluoro-4-hydroxy-N- (4-hydroxyphenyl) -N-phenylbenzamide	A white solid. The yield was 66%. Melting point 223-.¹H NMR(DMSO-d₆，300MHz)δ10.11(bs，1H)，9.57(bs，1H)，7.34-7.29(m，2H)，7.20-7.10(m，4H)，7.06-6.97(m，3H)，6.81-6.75(m，1H)，6.70-6.67(m，2H)。MSm/z 324(M+H)⁺。
10g 4-fluoro-3-hydroxy-N, N-bis (4-hydroxyphenyl) -benzamide	Tan solid. The yield was 71%. The melting point is more than 250 ℃.¹H NMR(DMSO-d₆，300MHz)δ9.95(bs，1H)，9.47(bs，2H)，7.02-6.95(m，6H)，6.75-6.72(m，1H)，6.68-6.66(m，4H)。MS m/z 340(M+H)⁺。
		10i 4-hydroxy-N, N-bis (4-hydroxyphenyl) -3, 5-dimethylbenzamide	Tan solid. The yield was 91%. The melting point is more than 250 ℃.¹H NMR(DMSO-d₆，300MHz)δ9.41(bs，2H)，6.96-6.92(m，6H)，6.66(d，4H，J＝8.79Hz)，2.02(s，6H)。MS m/z350(M+H)⁺。
10jN, N-bis (4-hydroxyphenyl) -2, 3-dimethylbenzamide	A pink white solid. The yield was 68%. The melting point is more than 250 ℃.¹H NMR(DMSO-d₆，300MHz)δ9.47(bs，2H)，7.18(d，2H，J＝8.30Hz)，7.06(d，1H，J＝7.08Hz)，7.00-6.92(m，4H)，6.78(d，2H，J＝8.30Hz)，6.51(d，2H，J＝8.06Hz)，2.22(s，3H)，2.15(s，3H)。MS m/z 334(M+H)⁺。

Compounds and IUPAC nomenclature	Physical characterization
Compounds and IUPAC nomenclature	Physical characterization	10k 3-fluoro-4-hydroxy-N, N-bis (4-hydroxyphenyl) -benzamide	Tan solid. The yield was 71%. The melting point is more than 250 ℃. ¹H NMR(DMSO-d₆，300MHz)δ10.25(bs，1H)，9.48(bs，2H)，7.12-6.95(m，6H)，6.80-6.65(m，5H)。MS m/z338(M-H)^-。
10lN, N-bis (4-hydroxyphenyl) -4-propylbenzamide	Tan solid. The yield was 77%. Melting point 224-.¹H NMR(DMSO-d₆，300MHz)δ9.46(s，2H)，7.27-7.26(m2H)，7.06-7.04(m，2H)，6.99-6.97(m，4H)，6.66-6.65(m，4H)，2.50(s，2H)，1.53-1.52(m，2H)，0.82(t，3H，J＝7.33Hz)。MS m/z 346(M-H)^-。
10lN, N-bis (4-hydroxyphenyl) -4-propylbenzamide		10m3, 4-dihydroxy-N, N-bis (4-hydroxyphenyl) -benzamide	Pale pink solid, 66% yield, melting point > 250 ℃.¹H NMR(DMSO-d₆，300MHz)δ9.39(bs，4H)，6.91(d，2H，J＝8.79Hz)，6.84(d，1H，J＝1.95Hz)，6.66(d，4H，J＝8.55Hz)，6.62-6.60(m，1H)，6.51(d，1H，J＝8.30Hz)。MS m/z 336(M-H)^-。
10N 4-hydroxy-N, N-bis (4-hydroxyphenyl) -3-methylbenzamide	Tan solid. Yield 78%, melting point > 250 ℃.¹H NMR(DMSO-d₆，300MHz)δ9.69(bs，1H)，9.44(bs，2H)，7.15(d，1H，J＝1.71Hz)，6.97(dd，2H，J＝1.95，8.30Hz)，6.93(d，4H，J＝8.55Hz)，6.66(d，4H，J＝8.80Hz)，6.55(d，1H，J＝8.55Hz)，2.50(s，3H)。MSm/z 334(M-H)^-	10m3, 4-dihydroxy-N, N-bis (4-hydroxyphenyl) -benzamide
10N 4-hydroxy-N, N-bis (4-hydroxyphenyl) -3-methylbenzamide		10oN- (4-hydroxyphenyl) -N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) -4-propylbenzamide	Yellow solid. Yield 39%, M.p.168-171 ℃.¹H NMR(DMSO-d₆，300MHz)δ9.49(s，1H)，7.28(d，2H，J＝7.28Hz)，7.09(d，2H，J＝8.06Hz)，7.06(d，2H，J＝8.30Hz)，6.99(d，2H，J＝8.06Hz)，6.86(d，2H，J＝7.82Hz)，6.66(d，2H，J＝7.57Hz)，4.00(bs，2H)，2.62(bs，2H)，2.51-2.50(m，2H)，2.40(bs，4H)，1.54-1.46(m，6H)，1.37-1.36(m，2H)，0.82(t，3H，J＝7.33Hz)。MS m/z 459(M+H)⁺。

Compounds and IUPAC nomenclature	Physical characterization
Compounds and IUPAC nomenclature	Physical characterization	10pN- (4-hydroxyphenyl) -2, 3-dimethyl-N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) -benzamide	Tan foam, 32% yield, melting point 93-96 ℃.¹H NMR(DMSO-d₆，300MHz)δ9.46(s，1H)，7.28(d，1H，J＝7.82Hz)，7.18(d，1H，J＝7.08Hz)，7.08(d，2H，J＝7.08Hz)，6.99-6.91(m，4H)，6.77(d，1H，J＝7.33Hz)，6.70(d，1H，J＝7.33Hz)，6.51(d，1H，J＝7.57Hz)，4.07(bs，1H)，3.91(bs，1H)，2.68-2.64(m，2H)，2.50-2.35(m，4H)，2.22(s，3H)，2.14(s，3H)，1.50-1.37(m，6H)。MS m/z 445(M+H)⁺。
10qN, N-bis (4-hydroxyphenyl) -2, 4-dimethylbenzamide	Yellow solid. Yield 80%, melting point 227-.¹H NMR(DMSO-d⁶，300MHz)δ9.45(bs，2H)，7.10-7.08(m，4H)，6.99-6.83(m，3H)，6.81-6.54(m，4H)，2.28(s，3H)，2.17(s，3H)。MS m/z 334(M+H)⁺。
10qN, N-bis (4-hydroxyphenyl) -2, 4-dimethylbenzamide		10rN, N-bis (4-hydroxyphenyl) -3, 5-dimethylbenzamide	A white solid. Yield 61%, melting point > 250 ℃.¹H NMR(DMSO-d₆，300MHz)δ9.45(bs，2H)，7.10-7.08(m，4H)，6.98-6.83(m，3H)，6.81-6.54(m，4H)，2.28(s，3H)，2.17(s，3H)。MS m/z 334(M+H)⁺。
10sN, N-bis (4-hydroxyphenyl) -4-methylbenzamide	Tan solid. Yield 32%, melting point 223-.¹H NMR(DMSO-d₆，300MHz)δ9.47(bs，2H)，7.25(d，2H，J＝8.04Hz)，7.05-6.97(m，6H)，6.66(d，4H，J＝8.33Hz)，2.23(s，3H)。MS m/z 320(M+H)⁺。	10rN, N-bis (4-hydroxyphenyl) -3, 5-dimethylbenzamide
10sN, N-bis (4-hydroxyphenyl) -4-methylbenzamide		10t4, 4' - (2, 3-dimethyl-benzylazelidinyl) biphenol	Tan foam, 41% yield, melting point 147-.¹H NMR(DMSO-d₆，300MHz)δ8.92(s，2H)，7.07(d，1H，J＝7.33Hz)，1)，7.00-6.94(m，2H)，6.76-6.72(m，4H)，6.63-6.59(m，4H)，4.72(s.2H)，2.23(s，3H)，2.16(s，3H)。MS m/z 320(M+H)⁺。

Compounds and IUPAC nomenclature	Physical characterization
Compounds and IUPAC nomenclature	Physical characterization	10u 4-formyl-N, N-bis (4-hydroxyphenyl) -benzamide	Yellow foam, 50% yield, melting point 117-.¹H NMR(DMSO-d₆，300MHz)δ9.98(s，1H)，9.52(s，2H)，7.78(d，2H，J＝8.13Hz)，7.61(d，2H，J＝8.13Hz)，7.06(bs，4H)，6.67(bs，4H)。MS m/z 332(M-H)^-。
11l4- ((hydroxyimino) methyl) -N, N-bis (4-hydroxyphenyl) benzamide	Yellow solid. Yield 67%, m.p. 146-.¹H NMR(DMSO-d₆，300MHz)δ11.36(s，1H)，9.49(s，2H)，8.07(s，1H)，7.45(d，2H，J＝8.28Hz)，7.37(d，1H，J＝8.28Hz)，7.01(d，4H，J＝7.52Hz)，6.67(d，4H，J＝6.45Hz)。MS m/z 349(M+H)⁺。	10u 4-formyl-N, N-bis (4-hydroxyphenyl) -benzamide
		11mN- (4-hydroxyphenyl) -2, 4-dimethyl-N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) benzamide	Pale yellow foam, 26% yield, mp 92-95 ℃.¹H NMR(DMSO-d₆，300MHz)δ9.48(s，1H)，7.13-6.81(m，11H)，3.33(bs，2H)，2.65(bs，2H)，2.51-2.45(m，4H)，2.29(s，3H)，2.17(s，3H)，1.49(bs，4H)，1.38(bs，2H)。MS m/z 446(M+H)⁺。
11nN- (4-hydroxyphenyl) -3, 5-dimethyl-N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) benzamide	Pale yellow foam, 26% yield, melting point 94-100 ℃.¹H NMR(DMSO-d₆，300MHz)δ9.50(s，1H)，7.11(d，2H，J＝8.67Hz)，7.02-6.98(m，3H)，6.91-6.86(m，3H)，6.67(d，2H，J＝8.46Hz)，4.03(t，2H，J＝5.10Hz)，2.67(bs，2H)，2.51-2.46(m，4H)，2.15(s，6H)，1.50-1.49(m，4H)，1.39-1.37(m，2H)。MS m/z 445。
		11o4- ((2, 3-dimethylbenzyl) (4- (2- (piperidin-1-yl) ethoxy) phenyl) amino) phenol	Purple foam, 38% yield, melting point 65-70 ℃.¹H NMR(DMSO-d₆，300MHz)δ9.08(s，1H)，7.08-6.86(m，5H)，6.78-6.65(m，6H)，4.75(s，2H)，3.96(t，2H，J＝5.83Hz)，3.34(bs，2H)，2.65(bs，2H)，2.51(bs，2H)，2.27(s，3H)，2.16(s，3H)，1.51-1.48(m，4H)，1.38-1.37(m，2H)。MS m/z 432。

Compounds and IUPAC nomenclature	Physical characterization
Compounds and IUPAC nomenclature	Physical characterization	6d (S) -2-hydroxy-3- (4-methoxyphenoxy) -N- (4-methoxyphenyl) -2-methylpropanamide	A white solid. The yield was 99%. Melting point 101.0-102.0 ℃.¹HNMR(CDCl₃，300MHz)δ8.64(s，1H)，7.49(d，2H，J＝8.9Hz)，6.89-6.79(m，6H)，4.35(d，1H，J＝8.9Hz)，3.93(d，1H，J＝8.9Hz)，3.79(s，3H)，3.76(s，3H)，1.56(s，3H)。MS m/z 254(M+Na)⁺。
6e (R) -3-bromo-2-hydroxy-N- (4-hydroxyphenyl) -2-methylpropanamide	Colorless oil, yield 98%.¹H NMR(DMSO-d₆，500MHz)δ9.33(s，1H)，9.21(s，1H)，7.47(d，2H，J＝8.9Hz)，6.68(d，2H，J＝9.0Hz)，6.08(s，1H)，3.80(d，1H，J＝10.3Hz)，3.55(d，1H，J＝10.5Hz)，1.44(s，3H)。MSm/z 297(M+Na)⁺。
		6f (S) -2-hydroxy-3- (4-hydroxyphenoxy) -N- (4-hydroxyphenyl) -2-methylpropanamide	Colorless oil, yield 67%.¹H NMR(DMSO-d₆，500MHz)δ9.35(s，1H)，9.19(s，1H)，8.90(s，1H)，7.48(d，2H，J＝8.8Hz)，6.73(d，2H，J＝9.0Hz)，6.68(d，2H，J＝9.0Hz)，6.63(d，2H，J＝9.0Hz)，5.89(s，1H)，4.06(d，1H，J＝9.5Hz)，3.81(d，1H，J＝9.3Hz)，1.36(s，3H)。MS m/z 326(M+Na)⁺。
6g of (S) -2-hydroxy-N,3-bis (4-hydroxyphenyl) -2-methylpropanamide	Colorless oil, yield 65%.¹H NMR(DMSO-d₆，300MHz)δ9.15(s，1H)，9.08(s，1H)，9.03(s，1H)，7.34(d，2H，J＝9.0Hz)，6.97(d，2H，J＝8.4Hz)，6.64(d，2H，J＝8.9Hz)，6.58(d，2H，J＝8.4Hz)，5.50(s，1H)，2.90(d，1H，J＝13.5Hz)，2.68(d，1H，J＝13.5Hz)，1.29(s，3H)。MS m/z 310(M+Na)⁺。
		2a 4-methoxy-N, N-bis- (4-methoxyphenyl) -benzamide	A white solid. The yield was 98%. Melting point 119.5-120 ℃.¹HNMR(CDCl₃，300MHz)δ7.42(d，2H，J＝8.9Hz)，7.05(d，4H，J＝8.8Hz)，6.81(d，4H，J＝8.9Hz)，6.71(d，2H，J＝8.9Hz)，3.77(s，9H)。MS m/z 364(M+H)。

Compounds and IUPAC nomenclature	Physical characterization
Compounds and IUPAC nomenclature	Physical characterization	3a 4-hydroxy-N, N-bis- (4-hydroxyphenyl) -benzamide	A white solid. The yield was 79%. Melting point 275-.¹H NMR(DMSO-d₆，300MHz)δ9.79(s，1H)，9.44(s，2H)，7.21(d，2H，J＝9.0Hz)，6.93(d，4H，J＝8.7Hz)，6.66(d，4H，J＝8.7Hz)，6.58(d，2H，J＝9.0Hz)。MS m/z 344(M+Na)⁺。
2dN, N-bis- (4-methoxyphenyl) -benzamide	A white solid. The yield was 98%. Melting point 77-77.5 ℃.¹H NMR(CDCl₃，300MHz)δ7.46-7.42(m，2H)，7.29-7.17(m，3H)，7.09-7.06(m，4H)，6.81-6.78(m，4H)，3.76(s，6H)。MS m/z 356(M+Na)⁺。	3a 4-hydroxy-N, N-bis- (4-hydroxyphenyl) -benzamide
2dN, N-bis- (4-methoxyphenyl) -benzamide		3dN, N-bis- (4-hydroxyphenyl) -benzamides	A white solid. The yield was 98%. Melting point > 265 deg.C (decomposed).¹H NMR(DMSO-d₆，300MHz)δ9.48(s，2H)，7.37-7.20(m，5H)，7.01(d，4H，J＝8.9Hz)，6.66(d，4H，J＝7.9Hz)，6.58(d，2H，J＝7.3Hz)。MS m/e 304(M-H)^-。
2gN, N-Diphenyl-benzamide	A white solid. The yield was 89%. Melting point 178.4-179.3 ℃.¹H NMR(CDCl₃，300MHz)δ7.46-7.44(m，2H)，7.28-7.23(m，5H)，7.21-7.14(m，8H)。MS m/z 296(M+Na)⁺。	3dN, N-bis- (4-hydroxyphenyl) -benzamides
2gN, N-Diphenyl-benzamide		3e 4-hydroxy-N, N-diphenyl-benzamide	A white solid. The yield was 57%. Melting point 193.7.0-194.3 ℃.¹HNMR(DMSO-d₆，300MHz)δ9.89(s，1H)，7.35-7.13(m，12H)，6.59(d，2H，J＝8.6Hz)。MS m/z312(M+Na)⁺。
2iN- (3-methoxyphenyl) -N-phenyl-benzamide	A white solid. The yield was 93%. Melting point 103-105.9 ℃.¹HNMR(CDCl₃，300MHz)δ7.49-7.45(m，2H)，7.31-7.15(m，9H)，6.75-6.70(m，3H)，3.76(s，3H)。MS m/z 326(M+Na)⁺。	3e 4-hydroxy-N, N-diphenyl-benzamide

Compounds and IUPAC nomenclature	Physical characterization
Compounds and IUPAC nomenclature	Physical characterization	3hN- (3-hydroxyphenyl) -N-phenyl-benzamides	A white solid. The yield was 56%. The melting point is 199.0-202.0 ℃.¹HNMR(DMSO-d₆，300MHz)δ9.55(s，1H)，7.44-7.06(m，12H)，6.62-6.59(m，2H)。MS m/z 312(M+Na)⁺。
2j 4-methoxy-N- (4-methoxyphenyl) -N-phenyl-benzamide	A white solid. The yield was 78%.¹H NMR(CDCl₃，300MHz)δ7.44-7.41(m，2H)，7.28-7.26(m，2H)，7.15-7.05(m，5H)，6.83-6.80(m，2H)，6.72-6.70(m，2H)，3.77(s，6H)。MS m/z 356(M+Na)⁺。	3hN- (3-hydroxyphenyl) -N-phenyl-benzamides
2j 4-methoxy-N- (4-methoxyphenyl) -N-phenyl-benzamide		3i 4-hydroxy-N- (4-hydroxyphenyl) -N-phenyl-benzamide	A white solid. The yield was 55%. Melting point 240.0-243.0 deg.C (decomposed).¹H NMR(DMSO-d₆，300MHz)δ9.84(s，1H)，9.51(s，1H)，7.33-7.11(m，7H)，6.97-6.94(m，2H)，6.69-6.67(m，2H)，6.61-6.58(m，2H)。MS m/e 304(M-H)^-。
2hN- (4-methoxyphenyl) -N-phenyl-benzamide	A white solid. Yield of95 percent. Melting point 153-154.2 ℃.¹H NMR(CDCl₃，300MHz)δ7.47-7.43(m，2H)，7.30-7.02(m，8H)，6.83-6.78(m，2H)，3.76(s，3H)。MS m/z326(M+Na)⁺。	3i 4-hydroxy-N- (4-hydroxyphenyl) -N-phenyl-benzamide
2hN- (4-methoxyphenyl) -N-phenyl-benzamide		2k 4-methoxy-N- (3-methoxyphenyl) -N-phenyl-benzamide	A white solid. The yield was 84%. Melting point 119.0-119.5 ℃.¹HNMR(CDCl₃，300MHz)δ7.47-7.43(m，2H)，7.31-7.13(m，7H)，6.75-6.68(m，4H)，3.77(s，3H)，3.71(s，3H)。MS m/z 356(M+Na)⁺。
3g of N- (4-hydroxyphenyl) -N-phenyl-benzamide;	a white solid. The yield was 70%. Melting point 255.0-256.0 ℃.¹H NMR(DMSO-d₆，300MHz)δ9.53(s，1H)，7.40-7.15(m，10H)，7.02(d，2H，J＝8.7Hz)，6.67(d，2H，J＝8.7Hz)。MS m/z 312(M+Na)⁺。	2k 4-methoxy-N- (3-methoxyphenyl) -N-phenyl-benzamide

Compounds and IUPAC nomenclature	Physical characterization
Compounds and IUPAC nomenclature	Physical characterization	3j 4-hydroxy-N- (3-hydroxyphenyl) -N-phenyl-benzamide;	a white solid. The yield was 73%. Melting point 245.0-247.5 deg.C (decomposed).¹H NMR(DMSO-d₆，300MHz)δ9.90(s，1H)，9.53(s，1H)，7.35-7.06(m，8H)，6.63-6.52(m，5H)。MS m/e 304(M-H)^-。
4aN- (4-hydroxyphenyl) -N- [4- (2-piperidin-1-ylethoxy) -phenyl]-benzamides	Yellow solid. The yield was 45%. Melting point 164.5-165.0 ℃.¹HNMR(DMSO-d₆，300MHz)δ9.49(s，1H)，7.38-7.36(m，2H)，7.26-7.24(m，3H)，7.12(d，2H，J＝8.5Hz)，7.01(d，2H，J＝8.5Hz)，6.87(d，2H，J＝8.3Hz)，6.65(d，2H，J＝8.3Hz)，4.01(t，2H，J＝5.1Hz)，2.63(br，2H)，2.50-2.43(m，4H)，1.48(br，4H)，1.38-1.36(m，2H)。MS m/z 417(M+H)⁺。	3j 4-hydroxy-N- (3-hydroxyphenyl) -N-phenyl-benzamide;
		3b 3-hydroxy-N-bis- (4-hydroxyphenyl) -benzamide	A white solid. The yield was 92%. Melting point 257.0-259.0 ℃.¹H NMR(DMSO-d₆，300MHz)δ9.49(s，1H)，9.47(s，2H)，7.02-6.98(m，5H)，6.80-6.65(m，7H)。MS m/e 320(M-H)^-。
3kN, N-bis (4-hydroxyphenyl) -4-fluoro-benzamide	A white solid. The yield was 87%. Melting point 270.0-271.0 ℃.¹H NMR(DMSO-d₆，300MHz)δ9.90(s，1H)，9.53(s，1H)，7.35-7.06(m，8H)，6.63-6.52(m，5H)。MS m/e 304(M-H)^-。	3b 3-hydroxy-N-bis- (4-hydroxyphenyl) -benzamide
3kN, N-bis (4-hydroxyphenyl) -4-fluoro-benzamide		3f 3-hydroxy-N, N-diphenyl-benzamide	A white solid. The yield was 85%. Melting point 152.5-153.2 ℃. ¹H NMR(DMSO-d₆，300MHz)δ9.89(s，1H)，7.35-7.13(m，12H)，6.59(d，2H，J＝8.6Hz)。MS m/z 312(M+Na)⁺。
3c 4-hydroxy-N- (4-hydroxyphenyl) -N- (3-hydroxyphenyl) -benzamide	A white solid. The yield was 92%. Melting point 249.1 deg.C (decomposed).¹HNMR(DMSO-d₆，300MHz)δ9.79(s，1H)，9.44(s，2H)，7.21(d，2H，J＝9.0Hz)，6.93(d，4H，J＝8.7Hz)，6.66(d，4H，J＝8.7Hz)，6.58(d，2H，J＝9.0Hz)。MS m/z 344(M+Na)。	3f 3-hydroxy-N, N-diphenyl-benzamide

Compounds and IUPAC nomenclature	Physical characterization
Compounds and IUPAC nomenclature	Physical characterization	4cN, N-diphenyl- [3- (2-piperidinyl-ethoxy)]-benzamide hydrochloride	Yellow solid. The yield was 57%. Melting point 149.5-150.0 ℃.¹HNMR(DMSO-d₆，300MHz)δ10.76(s，1H)，7.33-6.92(m，14H)，4.32(s，2H)，3.42-3.40(m，4H)，2.94-2.92(m，2H)，1.78-1.67(m，5H)，1.38(br，1H)。MS m/z 401(M+H)⁺。
4dN, N-diphenyl- [3- (2-piperidinyl-ethoxy)]-benzamide hydrochloride	Yellow solid. The yield was 50%. Melting point 148.5-149.5 ℃.¹HNMR(DMSO-d₆，300MHz)δ10.67(s，1H)，7.40-6.85(m，14H)，4.38(s，2H)，3.48-3.41(m，4H)，2.96-2.94(m，2H)，1.77-1.66(m，5H)，1.34(br，1H)。MS m/z 401(M+H)⁺。
		3l 4-hydroxy-N, N-diphenyl-phenyl-sulphonamides	A white solid. Yield 86%, m.p. 158.0-158.8 ℃.¹H NMR(CDCl₃，300MHz)δ10.61(s，1H)，7.52-7.47(m，2H)，7.39-7.25(m，10H)，6.93-6.89(m，2H)。MS m/z324(M-H)^-。
4eN- (4-hydroxyphenyl) -N-phenyl- [4- (2-piperidin-1-ylethoxy)]-benzamide hydrochloride	Yellow solid. The yield was 38%. Melting point 183.7-185.0 deg.C (decomposed).¹H NMR(DMSO-d₆，300MHz)δ10.76(s，1H)，9.66(s，1H)，7.35-6.61(m，13H)，4.37(m，2H)，3.40(m，4H)，2.94(m，2H)，1.76-1.65(m，5H)，1.34(m，1H)。MS m/z 417(M+H)⁺。	3l 4-hydroxy-N, N-diphenyl-phenyl-sulphonamides
		4uN- [4- (2-piperidin-1-ylethoxy) -phenyl]-N-phenyl- [4- (2-piperidin-1-ylethoxy)]-benzamide dihydrochloride	Yellow solid. The yield was 27%. Melting point 210.9-212.0 deg.C (decomposed).¹H NMR(DMSO-d₆，300MHz)δ11.07(s，2H)，7.35-6.84(m，13H)，4.38(m，4H)，3.40(br，8H)，2.95(m，4H)，2.05-1.65(m，10H)，1.34(m，2H)。MS m/z528(M+H)⁺。
4bN- (phenyl) -N- [4- (2-piperidin-1-ylethoxy) -phenyl]-benzamide hydrochloride	Yellow solid. The yield was 89%. Melting point 138.3-139.5 ℃.¹H NMR(DMSO-d₆，300MHz)δ9.52(s，1H)，7.42-7.39(m，2H)，7.33-7.16(m，10H)，6.89-6.91(m，2H)，4.17(s，2H)，2.76(s，2H)，2.51-2.49(m，4H)，1.61(br，4H)，1.43(br，2H)。MS m/z 401(M+H)⁺。

Compounds and IUPAC nomenclature	Physical characterization
Compounds and IUPAC nomenclature	Physical characterization	3m 4-hydroxy-N- (4-hydroxyphenyl) -N- (fluorophenyl) -benzamide	A white solid. The yield was 90%. Melting point 246.3-247.0 deg.C.¹H NMR(DMSO-d₆，300MHz)δ9.84(s，1H)，9.53(s，1H)，7.24-7.13(m，6H)，6.98-6.95(m，2H)，6.69-6.67(m，2H)，6.69-6.66(m，2H)，6.61-6.58(m，2H)。MS m/z324(M+H)⁺。
4fN, N-Diphenyl-bis [4- (2-piperidin-1-ylethoxy) -phenyl]-sulfonamide hydrochloride	Light yellow solid. The yield was 79%. Melting point 211.6-212.5 ℃.¹HNMR(DMSO-d₆，300MHz)δ10.78(s，1H)，7.65-7.17(m，14H)，4.52(m，2H)，3.36-3.47(m，4H)，3.00(br，2H)，1.67-2.50(m，5H)，1.38(m，1H)。MSm/z 437(M+H)⁺。
		4g of N- (4-fluorophenyl) -N- [ 4-hydroxyphenyl]- [4- (2-piperidin-1-ylethoxy)]-benzamides	Light yellow solid. The yield was 45%. Melting point 168.3-169.0 ℃.¹HNMR(DMSO-d₆，500MHz)δ10.61(s，1H)，9.65(s，1H)，7.38-6.69(m，12H)，4.38(m，2H)，3.46-3.36(m，4H)，2.96(m，2H)，2.04-1.66(m，5H)，1.35(br，1H)。MS m/z 435(M+H)⁺。
4rN- (4-fluorophenyl) -N- [4- (2-piperidin-1-ylethoxy) -phenyl]- [4- (2-piperidin-1-yl-ethoxy)]-benzamide dihydrochloride	Yellow solid. The yield was 95%. Melting point 253.5-254.0 deg.C (decomposed).¹HNMR(DMSO-d₆，300MHz)δ11.03(s，2H)，7.42-7.39(m，2H)，7.28-7.26(m，3H)，7.20-7.17(m，4H)，6.94-6.92(m，4H)，4.39(br，4H)，3.46-3.42(m，8H)，3.01-2.94(m，4H)，1.85-1.65(m，10H)，1.38-1.34(m，2H)。MS m/z 528(M+H)⁺。
		4hN- (4-hydroxyphenyl) -N- [4- (2-piperidin-1-ylethoxy) -phenyl]-4-fluoro-benzamide hydrochloride	Yellow solid. The yield was 42%. Melting point 234.0-235.8 deg.C (decomposed).¹HNMR(DMSO-d₆，300MHz)δ10.85(s，1H)，9.65(s，1H)，7.42-6.68(m，12H)，4.38(m，2H)，3.40(m，4H)，2.95(m，2H)，2.06-1.77(m，5H)，1.35(m，1H)。MS m/z 435(M+H)⁺。
4sN, N-bis [4- (2-piperidin-1-ylethoxy) -phenyl]-4-fluoro-benzamide dihydrochloride;	yellow solid. The yield was 20%. Melting point 204.8-205.5 deg.C (decomposed).¹H NMR(DMSO-d₆，300MHz)δ11.01(s，2H)，7.45-6.92(m，12H)，4.38(m，4H)，3.38(m，8H)，2.95(m，4H)，2.06-1.67(m，10H)，1.35(m，2H)。MS m/z

Compounds and IUPAC nomenclature	Physical characterization
Compounds and IUPAC nomenclature	Physical characterization		546(M+H)⁺。
3nN, N-bis (4-hydroxyphenyl) -1-naphthamide; (3n)	A white solid. The yield was 86%. Melting point 215.7 deg.C (decomposed).¹H NMR(DMSO-d₆，500MHz)δ9.54(s，1H)，9.35(s，1H)，8.11(d，1H，J＝9.0Hz)，8.87(d，1H，J＝8.0Hz)，7.79(d，1H，J＝8.5Hz)，7.61-7.58(m，1H)，7.53-7.48(m，2H)，7.37-7.34(m，1H)，7.30(s，2H)，7.00(s，2H)，6.83(s，2H)，6.38(s，2H)。MS m/z 356(M+H)⁺。		546(M+H)⁺。
3nN, N-bis (4-hydroxyphenyl) -1-naphthamide; (3n)		4tN, N-bis [4- (2-piperidin-1-ylethoxy) -phenyl]-benzamide dihydrochloride; (4t)	Yellow solid. The yield was 28%. Melting point 218.6-219.5 deg.C (decomposed).¹H NMR(DMSO-d₆，300MHz)δ11.09(s，2H)，7.38-6.86(m，12H)，4.40(m，4H)，3.39(m，8H)，2.96(m，4H)，2.07-1.66(m，10H)，1.35(m，2H)。MS m/z546(M+H)⁺。
3o 4-hydroxy-N- (1-naphthyl) -N- (4-hydroxyphenyl) -benzamide	A white solid. The yield was 84%. Melting point > 300 deg.C (decomposed).¹H NMR(DMSO-d₆，300MHz)δ9.84(s，1H)，9.47(s，1H)，8.07(d，1H，J＝7.8Hz)，7.97(d，1H，J＝7.8Hz)，7.86(d，1H，J＝8.1Hz)，7.58-7.45(m，3H)，7.39-7.30(m，3H)，7.02(d，2H，J＝8.1Hz)，6.66-6.56(m，4H)。MS m/e 354(M-H)^-。
		5a 4-chloro-N- [ 4-hydroxyphenyl]-N- (4-methoxyphenyl) -benzamide	A white solid. The yield was 93%. Melting point 237.5-238.9 ℃.¹H NMR(DMSO-d₆，300MHz)δ9.53(s，1H)，7.41-7.38(m，2H)，7.34-7.31(m，2H)，7.17-7.14(m，2H)，7.05-7.02(m，2H)，6.88-6.86(m，2H)，6.70-6.66(m，2H)，3.71(s，3H)。MS m/z 354(M+H)⁺。

Compounds and IUPAC nomenclature	Physical characterization
Compounds and IUPAC nomenclature	Physical characterization	5b 4-cyano-N- [ 4-hydroxyphenyl]-N- (4-methoxyphenyl) -benzamide	A white solid. The yield was 71%. Melting point 182-182.9 ℃.¹HNMR(DMSO-d₆，300MHz)δ9.56(s，1H)，7.76-7.71(m，2H)，7.56-7.55(m，2H)，7.20(br，2H)，7.07(br，2H)，6.87(br，2H)，6.67(br，2H)，3.71(s，3H)。MS m/z345(M+H)⁺。
4j 4-cyano-N- [4- (2-piperidin-1-ylethoxy) -phenyl]-N- (4-methoxyphenyl) -benzamide	Colorless oil, yield 61%. Melting point ℃.¹H NMR(DMSO-d₆，300MHz)δ7.42-7.40(m，2H)，7.34-7.31(m，2H)，7.18-7.13(m，4H)，6.88-6.86(m，4H)，4.00(tr，2H，J＝5.7Hz)，3.71(s，3H).2.60(tr，2H，J＝5.7Hz)，2.40(br，4H)，1.47-1.45(m，4H)，1.37-1.36(m，2H)。MS m/z 465(M+H)⁺。
		5c 3-chloro-N- [ 4-hydroxyphenyl]-N- (4-methoxyphenyl) -benzamide	White colour (Bai)A colored solid. The yield was 74%. Melting point C.¹H NMR(DMSO-d₆，300MHz)δ9.53(s，1H)，7.45-7.44(m，1H)，7.36-7.24(m，3H)，7.20-7.18(m，2H)，7.08-7.05(m，2H)，6.89(br，2H)，6.69(br，2H)，3.71(s，3H)。MSm/z 354(M+H)⁺。
4i3- (2-piperidin-1-ylethoxy) -N, N-bis (4-hydroxyphenyl) -benzamide	Yellow solid. The yield was 47%. Melting point 293.9-295.0 deg.C (decomposed).¹H NMR(DMSO-d₆，300MHz)δ10.51(s，2H)，8.18-7.68(m，12H)，4.00(tr，2H，J＝5.5Hz)，2.62(m，2H)，2.41(m，4H)，1.50-1.46(m，4H)，1.37-1.35(m，2H)。MS m/e 431(M-H)^-。
		4k 4-chloro-N- [4- (2-piperidin-1-ylethoxy) -phenyl]-N- (4-methoxyphenyl) -benzamide	A white solid. The yield was 45%. Melting point 285.0-287.0 deg.C (decomposed).¹HNMR(DMSO-d₆，300MHz)δ9.55(s，1H)，7.40-7.39(m，2H)，7.34-7.32(m，2H)，7.20(br，2H)，7.02(br，2H)，6.95(br，2H)，6.68-6.67(m，2H)，4.28(m，2H)，3.34(br，4H)，2.99(m，2H)，1.72(br，4H)，1.46(br，2H)。MS m/z 451(M+H)⁺。

Compounds and IUPAC nomenclature	Physical characterization
Compounds and IUPAC nomenclature	Physical characterization	4l 4-cyano-N- [4- (2-piperidin-1-ylethoxy) -phenyl]-N- (4-methoxyphenyl) -benzamide	Yellow solid. The yield was 75%. Melting point 118.1-118.5 ℃.¹H NMR(DMSO-d₆，300MHz)δ7.51(br，4H)，7.05(br，4H)，6.82(br，4H)，4.10(m，2H)，3.78(s，3H)，2.81(m，2H)，2.56(m，4H)，1.64-1.62(m，4H)，1.48-1.46(m，2H)。MS m/z 456(M+H)⁺。
4m 3-chloro-N- [4- (2-piperidin-1-ylethoxy) -phenyl]-N- (4-methoxyphenyl) -benzamide	Yellow solid. The yield was 82%. Melting point 114.9-115.5 ℃.¹H NMR(DMSO-d₆，300MHz)δ7.47-7.46(m，1H)，7.26-7.23(m，2H)，7.14-7.05(m，5H)，6.83-6.80(m，4H)，4.08(tr，2H，J＝6.0Hz)，3.77(s，3H)，2.76(tr，2H，J＝6.0Hz)，2.53-2.49(m，4H)，1.65-1.58(m，4H)，1.48-1.43(m，2H)。MS m/z 465(M+H)⁺。
		7a5- [ 4-methoxy-phenyl ]]-5H-phenanthridin-6-one	Yellow solid. The yield was 65%. Melting point 217.0-218.5 deg.C (decomposed).¹H NMR(DMSO-d₆，500MHz)δ8.61-8.59(m，1H)，8.54-8.51(m，1H)，8.36-8.34(m，1H)，7.94-7.89(m，1H)，7.71-7.66(m，1H)，7.43-7.28(m，4H)，7.19-7.16(m，2H)，6.63-6.60(m，1H)。MS m/z 302(M+H)⁺。
3p 4-cyano-N, N-bis (4-hydroxyphenyl) -benzamide	A white solid. The yield was 84%. Melting point 272.0-273.5 deg.C (decomposed).¹H NMR(DMSO-d₆，300MHz)δ9.53(s，2H)，7.74-7.73(m，2H)，7.55-7.53(m，2H)，7.12。MS m/e329(M-H)^-。	7a5- [ 4-methoxy-phenyl ]]-5H-phenanthridin-6-one
3p 4-cyano-N, N-bis (4-hydroxyphenyl) -benzamide		7b5- [ 4-hydroxy-phenyl ]]-5H-phenanthridin-6-one	Yellow solid. The yield was 78%. Melting point 325.7-327.0 deg.C (decomposed).¹HNMR(DMSO-d₆，500MHz)δ9.82(s，1H)，8.60-8.58(m，1H)，8.52-8.51(m，1H)，8.35-8.33(m，1H)，7.92-7.89(m，1H)，7.69-7.66(m，1H)，7.41-7.38(m，1H)，7.32-7.29(m，1H)，7.15-7.13(m，2H)，6.99-6.97(m，2H)，6.65-6.63(m，1H)。MS m/z310(M+Na)⁺。

Compounds and IUPAC nomenclature	Physical characterization
Compounds and IUPAC nomenclature	Physical characterization	3q 3-cyano-N, N-bis (4-hydroxyphenyl) -benzamide	A white solid. The yield was 84%. Melting Point 237.5-238.0 ℃.¹H NMR(DMSO-d₆，300MHz)δ9.53(s，2H)，7.81-7.80(m，1H)，7.75-7.74(m，1H)，7.73-7.72(m，1H)，7.69-7.68(m，1H)，7.67-7.7.66(m，1H)，7.48-7.44(m，1H)，7.07(br，4H)，6.65(br，4H)。MS m/z 353(M+Na)⁺。
7c5- [4- (2-piperidin-1-ylethoxy) -phenyl]-5H-phenanthridin-6-one	Yellow solid. The yield was 79%. Melting point 220.0-221.5 deg.C (decomposed).¹H NMR(DMSO-d₆，300MHz)δ8.56-8.53(m，1H)，8.35-8.29(m，2H)，7.84-7.79(m，1H)，7.64-7.59(m，1H)，7.36-7.24(m，4H)，7.23-7.10(m，2H)，6.76-6.73(m，1H)，4.45(tr，2H，J＝5.1Hz)，3.16(tr，2H，J＝5.1Hz)，2.94(br，4H)，1.90-1.85(m，4H)，1.61-1.59(m，2H)。MS m/z 399(M+H)⁺。	3q 3-cyano-N, N-bis (4-hydroxyphenyl) -benzamide
		8b cyclohexane-carboxylic acid bis (4-hydroxyphenyl) -amide;	a white solid. The yield was 86%. Melting point 265.1-266.2 deg.C (decomposed).¹H NMR(DMSO-d₆，500MHz)δ9.65(s，1H)，9.37(s，1H)，7.17-6.70(m，4H)，6.78-6.67(m，4H)，2.29-2.23(m，1H)，1.71-1.62(m，4H)，1.54-1.51(m，1H)，1.41-1.32(m，2H)，1.21-1.07(m，1H)，0.97-0.90(m，2H)。MS m/z 334(M+Na)⁺。
3rN, N-bis (4-hydroxyphenyl) -2-naphthamide	A white solid. The yield was 86%. Melting point 264.3-265.2 deg.C (decomposed).¹HNMR(DMSO-d₆，500MHz)δ9.46(s，2H)，7.98(s，1H)，7.85-7.75(m，2H)，7.75-7.73(m，2H)，7.54-7.48(m，2H)，7.45-7.43(m，1H)，7.05(s，4H)，6.66(s，4H)。MS m/z 356(M+H)⁺。
3rN, N-bis (4-hydroxyphenyl) -2-naphthamide		3s 4-cyano-N- [4- (2-piperidin-1-ylethoxy) -phenyl]-N- (4-hydroxyphenyl) -benzamides	A white solid. The yield was 50%. Melting point 266.7-268.0 (decomposed).¹H NMR(DMSO-d₆，300MHz)δ9.57(s，1H)，7.76-7.74(m，2H)，7.58-7.55(m，2H)，7.24-6.96(m，6H)，6.66(s，2H)，4.26-4.21(m，2H)，3.33(br，4H).2.98(br，2H)，1.70(br，4H)，1.50-1.44(m，2H)。MSm/z 442(M+H)⁺。

Compounds and IUPAC nomenclature	Physical characterization
Compounds and IUPAC nomenclature	Physical characterization	3t 3-chloro-N- [4- (2-piperidin-1-ylethoxy) -phenyl]-N- (4-hydroxyphenyl) -benzamides	A white solid. The yield was 38%. Melting point 208.9-209.5 deg.C (decomposed).¹H NMR(DMSO-d₆，300MHz)δ9.54(s，1H)，7.44(s，1H)，7.37-7.21(m，5H)，7.08-7.05(m，2H)，6.96(s，2H)，6.69-6.67(s，2H)，4.27(s，2H)，3.33(br，4H).3.02(br，2H)，1.71(br，4H)，1.50(br，2H)。MSm/z 451(M+H)⁺。
10 wN-cyclohexyl-4-hydroxy-N- (4-hydroxyphenyl) -benzamide	A white solid. The yield was 81%. Melting point 267.3-268.5 ℃.¹H NMR(DMSO-d₆，500MHz)δ9.56(s，2H)，7.03(d，2H，J＝8.7Hz)，6.83(d，2H，J＝8.8Hz)，6.60(d，2H，J＝8.5Hz)，6.50(d，2H，J＝8.3Hz)，4.43(m，1H)，1.83-1.81(m，2H)，1.72-1.69(m，2H)，1.54-1.52(m，1H)，1.35-1.28(m，2H)，1.11-1.03(m，2H)，0.93-0.89(m，1H)。MS m/z 312(M+H)⁺。
10 wN-cyclohexyl-4-hydroxy-N- (4-hydroxyphenyl) -benzamide		10x4- ((4-fluorophenyl) (4-hydroxybenzyl) -amino) phenol	A yellow oil. The yield was 92%.¹H NMR(DMSO-d₆，500MHz)δ9.29(s，1H)，9.24(s，1H)，7.09(d，2H，J＝8.3Hz)，6.98(d，2H，J＝9.0Hz)，6.94-6.91(m，2H)，6.73(d，2H，J＝9.0Hz)，6.68-6.64(m，4H)，4.70(s，2H)。MSm/z 308(M-H)^-。
10yN- (4- (2- (dimethylamino) ethoxy) phenyl) -N- (4-hydroxy-phenyl) -benzamide	A white solid. The yield was 57%. Melting point 170.0-172.0 ℃.¹H NMR(DMSO-d₆，500MHz)δ9.50(s，1H)，7.37(d，2H，J＝8.0Hz)，7.29-7.24(m，3H)，7.12(d，2H，J＝6.5Hz)，7.01(d，2H，J＝6.5Hz)，6.87(s，2H)，6.66(s，2H)，3.99(s，2H)，2.61(t，2H，J＝5.5Hz)，2.21(s，6H)。MS m/z 375(M-H)^-。	10x4- ((4-fluorophenyl) (4-hydroxybenzyl) -amino) phenol
		10z 3-cyano-N- (4-hydroxyphenyl) -N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) -benzamide;	light yellow solid. The yield was 63%. Melting point 160.7-162.3 ℃.¹HNMR(DMSO-d₆，500MHz)δ9.56(s，1H)，7.83(s，1H)，7.76-7.74(m，1H)，7.71-7.68(m，1H)，7.47(t，1H，J＝7.5Hz)，7.19(br，2H)，7.08(br，2H)，6.90(br，2H)，6.66(br，2H)，4.02(br，2H)，2.63(br，2H)，2.42(br，4H)，1.48(br，4H)，1.36(br，2H)。MS m/z442(M+H)⁺。

Compounds and IUPAC nomenclature	Physical characterization
Compounds and IUPAC nomenclature	Physical characterization	11aN- (4-hydroxyphenyl) -N- (4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -benzamide	A white solid. The yield was 64%. Melting point 163.9-165.1 ℃. ¹H NMR(DMSO-d₆，500MHz)δ9.63(s，1H)，7.39-7.38(m，2H)，7.31-7.23(m，3H)，7.13(d，2H，J＝6.0Hz)，7.02(d，2H，J＝7.0Hz)，6.88(br，2H)，4.03(br，2H)，2.82(br，2H)，2.56(br，4H)，1.69-1.68(m，4H)。MS m/z 401(M-H)^-。
11bN, N-bis (4-hydroxyphenyl) -4- (trifluoromethyl) -benzamide;	a white solid. The yield was 96%. Melting point 255.9-256.5 ℃.¹HNMR(DMSO-d₆，500MHz)δ9.52(s，2H)，7.64-7.56(m，4H)，7.06(br，4H)，6.64(br，4H)。MS m/z 374(M+H)⁺。
		11cN- (4-hydroxyphenyl) -N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) -4- (trifluoromethyl) -benzamide;	a white solid. The yield was 41%. Melting point 158.1-158.7 ℃.¹HNMR(DMSO-d₆，500MHz)δ9.55(s，1H)，7.65-7.58(m，4H)，7.18-6.65(m，8H)，4.01(br，1H)，2.63-2.61(m，2H)，2.40-2.36(m，4H)，1.47(br，4H)，1.36(br，2H)。MS m/z 485(M+H)⁺。
11dN, N-bis (4-hydroxyphenyl) -4-nitro-benzamides	A white solid. The yield was 92%. Melting point 216.0-217.0 deg.C (decomposed).¹HNMR(DMSO-d₆，500MHz)δ9.55(s，2H)，8.11-8.09(m，2H)，7.65-7.62(m，2H)，7.15-7.03(m，4H)，6.77-6.58(m，4H)。MS m/z 349(M-H)^-。
11dN, N-bis (4-hydroxyphenyl) -4-nitro-benzamides		11e 3-fluoro-N, N-bis (4-hydroxyphenyl) -benzamide	A white solid. The yield was 87%. Melting point 254.1.1-254.6 ℃.¹HNMR(DMSO-d₆，500MHz)δ9.51(s，2H)，7.31-7.26(m，1H)，7.19-7.18(m，2H)，7.13-7.09(m，1H)，7.05(br，4H)，6.68(br，4H)。MS m/z 322(M-H)^-。
11fN- (4-hydroxy)phenyl-N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) -1-naphthamide	A white solid. The yield was 71%. Melting point 198.5-199.1 ℃.¹H NMR(DMSO-d₆，500MHz)δ9.56(s，0.5H)，9.40(s，0.5H)，8.13-8.10(m，1H)，7.89-7.78(m，2H)，7.63-7.58(m，1H)，7.54-7.49(m，2H)，7.38-7.30(m，3H)，7.00(br，3H)，6.83(br，1H)，6.61(br，1H)，6.40	11e 3-fluoro-N, N-bis (4-hydroxyphenyl) -benzamide

Compounds and IUPAC nomenclature	Physical characterization
Compounds and IUPAC nomenclature	Physical characterization		(br，1H)，4.17-3.92(m，2H)，2.73-2.44(m，6H)，1.55-1.41(m，6H)。MS m/z 467(M+H)⁺。
11g 3-fluoro-N- (4-hydroxyphenyl) -N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) benzamide	A white solid. The yield was 53%. Melting point 227.3-228.0 ℃.¹H NMR(DMSO-d₆，500MHz)δ9.56(s，1H)，7.33-7.26(m，1H)，7.21-7.12(m，5H)，7.09-7.04(m，2H)，6.89(br，2H)，4.05(br，2H)，2.71(br，2H)，2.50(br，4H)，1.93(br，2H)，1.51-1.49(m，4H)，1.39-1.37(br，2H)。MSm/z 435(M+H)⁺。
		11hN- (4-hydroxyphenyl) -4-nitro-N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) benzamide	Yellow solid. The yield was 49%. Melting point 181.7-182.3 ℃.¹H NMR(DMSO-d₆，300MHz)δ9.55(s，1H)，8.07(d，2H，J＝8.7Hz)，7.62(d，2H，J＝8.7Hz)，7.18-6.90(m，4H)，6.77-6.61(m，4H)，4.01(br，2H)，2.64-2.43(m，6H)，1.46-1.35(m，6H)。MS m/z 462(M+H)⁺。
11iN, N-bis (4-hydroxyphenyl) -4-methoxy-1-naphthamide	A white solid. The yield was 48%. Melting point 305.4 deg.C (decomposed). ¹H NMR(DMSO-d₆，300MHz)δ9.45(s，2H)，8.14-8.10(m，2H)，7.65-7.60(m，1H)，7.54-7.49(m，1H)，7.44-7.41(m，1H)，7.11(br，4H)，6.84-6.81(m，1H)，6.70-6.65(m，4H)，3.93(s，3H)。MS m/z 386(M+H)⁺。
11iN, N-bis (4-hydroxyphenyl) -4-methoxy-1-naphthamide		11jN- (4-hydroxyphenyl) -N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) -2-naphthamide	A white solid. The yield was 45.0%. Melting point 195.8-196.3 ℃.¹HNMR(DMSO-d₆，300MHz)δ9.49(s，1H)，8.01(s，1H)，7.87-7.84(m，2H)，7.77-7.74(m，1H)，7.56-7.43(m，3H)，7.19-7.16(m，2H)，7.08-7.06(m，2H)，6.88-6.85(m，2H)，6.67-6.65(m，2H)，3.99(s，2H)，2.61-2.57(m，2H)，2.39(s，4H)，1.46-1.45(m，4H)，1.37-1.35(m，2H)。MS m/z 467(M+H)⁺。

Compounds and IUPAC nomenclature	Physical characterization
Compounds and IUPAC nomenclature	Physical characterization	11k 2-hydroxy-N, N, 2-tris (4-hydroxyphenyl) -propionamide	A white solid. The yield was 78%. Melting Point 292.0-294.0 ℃.¹H NMR(DMSO-d₆，300MHz)δ9.74(s，1H)，9.39(s，1H)，9.15(s，1H)，7.18(d，2H，J＝8.7Hz)，7.09(d，2H，J＝8.7Hz)，6.80(d，2H，J＝8.7Hz)，6.72(d，2H，J＝8.7Hz)，6.60(d，2H，J＝9.1Hz)，6.53(d，2H，J＝9.1Hz)，1.68(s，3H)。MS m/z 348(M-H₂O)⁺。
11WN- (4-hydroxyphenyl) -4- (3-hydroxypropyl) -N- (4-methoxyphenyl) -benzamide	Light yellow solid. Melting point 145-147 ℃.¹H NMR((DMSO-d₆，300MHz)δ9.50bs，1H)，7.28(0(d，J＝8.10Hz，2H)，7.15-7.05(m，4H)，6.99(d，J＝8.62Hz，2H)，6.86(d，J＝8.74Hz，2H)，6.66(d，J＝8.56Hz，2H)，4.44(bs，1H)，3.71(s，3H)，3.35-3.33(m，2H)，2.57-2.49(m，2H)，1.69-1.60(m，2H)。MS m/z 376.0(M-H)^-。	11k 2-hydroxy-N, N, 2-tris (4-hydroxyphenyl) -propionamide
		11x 4-fluoro-N, N-bis (4-hydroxyphenyl) -2- (trifluoromethyl) -benzamide	A colorless oil.¹H NMR((DMSO-d₆，300MHz)δ7.29(d，J＝8.13Hz，2H)，7.13-7.09(m，4H)，7.00(d，J＝8.61Hz，2H)，6.86(d，J＝8.70Hz，2H)，6.66(d，J＝8.49Hz，2H)，3.71(s，3H)，2.76(t，J＝7.43Hz，2H)，2.51-2.45(m，2H)。MS m/z 390.0(M-H)^-。
11y 3-fluoro-N- (4-fluorophenyl) -4-hydroxy-N- (4-hydroxyphenyl) benzamide	Melting point 110-^℃。MS m/z 364.1(M+Na)⁺。¹H NMR((DMSO-d₆，300MHz)δ10.14(bs，1H)，9.71(bs，1H)，7.25-7.11(m，5H)，7.05-6.99(m，3H)，6.78(t，J＝8.61Hz，2H)，6.68(d，J＝8.68Hz，2H)。
		11zN- (4-hydroxyphenyl) -4-methyl-N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) benzamide	Melting point 135-. MS M/z 431.3(M + H)⁺。¹H NMR((DMSO-d₆，300MHz)δ9.49(bs，1H)，7.26(d，J＝8.06Hz，2H)，7.11-6.98(m，6H)，6.85(d，J＝8.72Hz，2H)，6.66(d，J＝8.53Hz，2H)，4.00(t，J＝5.85Hz，2H)，2.60(t，J＝5.85Hz，2H)，2.41-2.38(m，4H)，1.51-1.44(m，4H)，1.37-1.36(m，2H)。

Compounds and IUPAC nomenclature	Physical characterization
Compounds and IUPAC nomenclature	Physical characterization	11aaN, N-bis (4-hydroxyphenyl) -isonicotinamide	The melting point is more than 240 ℃. MS M/z 304.9(M-H)^-。¹H NMR((DMSO-d₆，300MHz)δ9.54(bs，2H)，8.52-8.43(m，2H)，7.76-7.72(m，1H)，7.31-7.27(m，1H)，7.07(bs，4H)，6.68(bs，4H)。
11abN- (4-hydroxyphenyl) -N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) -isonicotinamide	MS m/z 418.4(M+H)⁺。¹H NMR((DMSO-d₆，300MHz)δ(s，1H)，8.53(d，9.56J＝1.65Hz，1H)，8.44(dd，J＝1.61，4.83Hz，1H)，7.78-7.74(m，1H)，7.31-7.27(m，1H)，6.89(bs，2H)，6.68(bs，2H)，4.02(t，J＝7.03Hz，2H)，2.64(bs，2H)，2.43(bs，4H)，1.49-1.47(m，4H)，1.38-1.36(m，2H)。	11aaN, N-bis (4-hydroxyphenyl) -isonicotinamide

Example 2

SERMs vs ER-alpha, ER-beta and ARTrans formInfluence of activation

Materials and methods:

COS or 293 cells were plated in 90000 cells per well in phenol red-free DME containing 10% csFBS in 24-well plates, transfected with 0.25. mu.g of the vector "ERE-LUC" (in which the firefly-type luciferase gene is driven by two estrogen response elements) and 0.02. mu.g of the control CMV-LUC, a florist-type (in which the luciferin gene is driven by the CMV promoter). Also, 25ng ER- α (FIGS. 1, 5 and 9), 50ng ER- β (FIGS. 2, 6 and 10) or 12.5ng AR (FIG. 3) were introduced via cationic liposomes. All receptors were cloned from rat tissues into the PCR3.1 vector backbone. 24 hours after transfection, cells were treated with 4a, toremifene, 4h, estrogen, DHT and other SERMs or combinations thereof as shown. 48 hours after transfection, cells were harvested and assayed for firefly-type and anthurium-type luciferase activity.

Results

Under the experimental conditions, treatment of cells with 4a or toremifene alone had no effect on ER- α activity. However, both compounds inhibit estradiol (E)₂) Induced ER- α activity to basal levels, suggesting that 4a may modulate ER activity or act as a SERM, acting as an ER- α antagonist in this assay.

To determine whether the compound acts as an agonist for the ER, COS or 293 cell expression under control conditions of ERE incubation with estrogen, toremifene or 4a constructed luciferase expression. Whereas addition of estrogen resulted in dose-dependent luciferase expression, no SERM alone showed any effect. Similarly, 4h was assessed for luciferase expression (FIGS. 5a, 5b and 5 c).

4a and 4h both inhibit estrogen-stimulated luciferase expression, indicating that these compounds may act as SERMs under these conditions, e.g., as estrogen receptor α antagonists. Compound 10o also inhibited estrogen-stimulated luciferase expression, and ER- α expression was similarly increased in 293 cells (fig. 5d, 5 e).

COS or 293 cells expressed ER- β (FIGS. 2 and 6) were similarly increased. Under these experimental conditions, neither 4a nor 4h stimulated LUC expression and inhibited E individually₂Stimulated LUC expression, which is shown to also act as an ER- β antagonist.

Under the conditions of this assay, compound 4a was specific for ER, as this compound had no effect on LUC expression in COS cells expressing Androgen Receptor (AR), nor did it inhibit DHT-induced AR activation (fig. 3).

Additional SERMs were similarly tested for their ability to mediate estrogen receptor signaling in indicative conditions (fig. 9). Of the SERMs tested, compounds 3e and 3i were most effective in stimulating ER- α, and compounds 3a, 3e, 3i and 3g were most effective in stimulating ER- β (FIG. 10).

Example 3

Agonist activity of the compounds of some embodiments

The material and the method are as follows:

MCF-7 cells were plated in 6-well plates at 500000 cells per well. Cells were serum-starved for 3 days and then treated as above for 16 hours. RNA was isolated and normalized to 18S ribosomal RNA before assessing gene expression levels by real-time RT-PCR.

As a result:

4a only minimally acted when estrogen increased the expression of pS2 (the gene encoding trefoil peptide) in MCF-7 cells under the conditions tested, and it inhibited estrogen-induced upregulation of pS2 gene expression, suggesting its role as a partial agonist or antagonist under these conditions (FIG. 4). Compounds 3e, 3f and 3l also increased the expression level of pS2 (fig. 11).

Example 4

Effect of Compounds on TRAP-Positive multinucleated osteoclasts

Materials and methods:

bone marrow cells isolated from rat femurs were cultured in phenol red free α MEM containing 10% sterile FBS in the presence or absence of 30ng/mL RANKL and 10ng/mL GMCSF. The cells were treated for 12 days, and positive multinucleated osteoclasts were stained with tartrate-resistant acid phosphatase activity (TRAP) and counted.

As a result:

administration of GMCSF and RANKL to pluripotent bone marrow progenitor cells (progenitors) facilitates differentiation into osteoclasts. The presence of estrogen strongly inhibited osteoclast differentiation, whereas 4a, 4h and toremifene administered under these conditions minimally but dose-dependently inhibited osteoclast differentiation (figure 7).

Compound 3e highly inhibited osteoclast activity and stimulated osteoblast activity, 3a inhibited osteoclasts, 3d stimulated osteoblasts and inhibited osteoclasts (fig. 14), and 4h highly inhibited osteoclast activity under the test conditions.

Example 5

Compounds for inhibiting growth of androgen dependent prostate cancer cells

Materials and methods:

prostate cancer cell line PC-3 was plated in RPMI + 10% csFBS at a density of 6000 cells per well in 96-well plates. The medium was changed to RPMI + phenol red free 1% csFBS and the cells were treated with increasing concentrations of SERMs for 72 hours.

As a result:

at a concentration of 10. mu.M, 4r, 4u and toremifene all inhibited PC-3 cell growth by 100%. However, compound 4h inhibited PC-3 cell growth by 75% even at a concentration of 1. mu.M under the same conditions. The compound partially inhibited by about 50% (fig. 8). PC-3 growth inhibition was quantified in vitro and expressed as a hierarchical system based on the ability of SERMs to inhibit growth. The number-4 is a compound that induces 100% growth inhibition at 1uM, -3 is a compound that inhibits growth by about 75-90%, -2 is about 50-70%, -1 is a compound that inhibits growth by less than 50%.

Toremifene and compounds 4a, 3l, 4e, 4u, 4b, 4r and 4h each inhibited growth (data not shown). Toremifene inhibited growth at a level of-2, as did compounds 3l and 4 h. Compounds 4a, 4e and 4b showed moderate inhibition (-1); 4u and 4r showed greater inhibition with quantitative ratings of-3 and-4, respectively.

Example 6

In vivo estrogenic Activity of Compounds of some embodiments

Materials and methods:

female rats were dosed with increasing doses of toremifene, estrogen and the respective SERMs and/or ICI-182, 780 and uterine weights were determined. Rats dosed with vehicle alone served as controls.

As a result:

under the test conditions, rats administered with compounds 4a, 3d and 4g showed estrogenic activity according to uterine weight gain (figures 12 and 13). When 4a, 4g and estrogen were co-administered, an increase in uterine weight was observed. Under these conditions, ICI-182, 780 reversed the effect of 4a and 4g on uterine weight gain.

Compounds 3e, 3l, 4h and 4e showed no estrogenic or antiestrogenic activity on the uterus and compounds 3a, 3f, 4g and 4a showed estrogenic activity in vivo (data not shown).

Example 7

Metabolic stability of compounds of some embodiments in human liver microsomes

Materials and methods:

to evaluate the potential of compounds to form pharmacologically inactive or unwanted potentially toxic metabolites due to phase I metabolism, human liver microsomes were used as a representative system.

Each substrate or reference control was dissolved in DMSO to form a solution with a concentration of 10mM, from which a 5. mu.M spiking solution was prepared by dilution with water. The substrate (1. mu.M) was incubated at 37 ℃ and pH 7.4 in the presence of 0.5mg/mL liver microsomes (Xenotech LLC, Kansas City MO) boosted with an NADPH regenerating system. The NADPH regeneration system was established at 0.05M K₂HPO₄Glucose-6-phosphate dehydrogenase (1 unit/mL) in (1). Two incubations were performed in 96-well polypropylene family tubes (polypropylene cluster tube) with a final volume of 250. mu.L per reaction. Stop solution (300 μ L acetonitrile) was added to aliquots of the reaction mixture at 0, 2, 4, 6, 10, 30 and 60 minutes. The precipitated protein was removed by centrifugation (3000rpm for 15 min) and the supernatant was transferred to a clean 96-well plate for analysis.

LC-MS/MS analysis:

the sample was injected into a Phenomenex lunahexylphenyl 50 x 2mm, internal diameter 5uM column equipped with a guard column. The mobile phase of equal concentration consisted of 50% acetonitrile and 0.1% aqueous formic acid at a flow rate of 0.3 mL/min. The protonated molecular ions (M + H) of the analyte were monitored by MDS/Sciex API 4000Q trap triple quadrupole mass spectrometer using electrospray cationic mode at 500 ℃, 4000V spray voltage. The total analysis time for each sample was 1.5 minutes.

And (3) data evaluation:

metabolic stability is defined by the amount of substrate metabolized by incubation with liver microsomes and is expressed as a percentage of the initial amount of substrate (remaining percentage%) based on peak area. The initial substrate concentration for each analyte was 1 μ M. The initial peak area for each substrate was determined at 0 and metabolic stability was assessed based on the change in analyte peak area from 0 minutes to a single fixed time point for each compound (2-60min, representative time points are listed in table 2 below).

As a result:

table 2 shows the percentage of substrate remaining after setting the incubation interval (0-60 min).

Table 2:

the remaining percentage%

^aHuman liver microsome slow reference control

^bHuman liver microsome intermediate reference control

Four embodiments of the test compounds showed better stability in the phase I metabolic system compared to the known substrate verapamil in human liver microsomes for cytochrome P450 mediated inactivation (see table 2). Compounds 3a and 3k are redox resistant reactions with 103% and 94% of the starting substrate remaining after 60 minutes of reaction, respectively. Moderate reactivity was shown in assays 4a and 4h, with 74% and 70% remaining after incubation for a period of time, respectively. These data indicate that the piperidine ring substitution on the 4a and 4h compounds makes them susceptible to phase I metabolic transformation moieties. In general, the compounds evaluated did not have significant phase I-mediated first pass liver extraction (first pass hepatic extraction). Since the determination of metabolic stability is an in vitro measure that describes the rate and extent of a compound's potential in vivo metabolic fate, additional studies are being conducted to identify other metabolic pathways that can contribute to the inactivation of lead, elucidate the structure of relevant metabolites and determine whether in vivo pharmacokinetic characteristics are consistent with these in vitro preliminary study data.

Example 8

General Synthesis of N, N-bisarylbenzamide derivatives

General Synthesis of diarylanilines. Arylamine (1.5 equivalent), aryl iodide (1 equivalent), and K ₂CO₃A mixture of (2 eq), CuI (0.1 eq) and L-proline (0.2 eq) was mixed together and dissolved in anhydrous DMSO at room temperature. The reaction mixture was then stirred and heated to 90 ℃ for 28 hours. The mixture was cooled to room temperature and hydrolyzed with water. The solution was partitioned with EtOAc. The EtOAc layer was separated, washed with brine and over anhydrous MgSO₄And (5) drying. The solvent was removed under reduced pressure. The solid residue was purified by flash chromatography (silica gel) using 5% EtOAc/hexanes as eluent to give the corresponding diarylaniline.

Bis- (4-methoxyphenyl) amine (1 a): light yellow solid. 73% yield. The melting point is 98.6-99.0 ℃.¹H NMR(CDCl₃，300MHz)δ6.93-6.81(m，8H)，5.37(s，br，1H)，3.78(s，6H)。MS m/z 228.4(M-H)⁺。

N- (4-methoxyphenyl) -aniline (1 b): light yellow solid. Yield 70%. Melting point 106.3-106.5 ℃.¹H NMR(CDCl₃，300MHz)δ7.24-7.18(m，3H)，7.08-7.06(m，2H)，6.92-6.84(m，4H)，5.61(s，br，1H)，3.79(s，3H)。MS m/z 200.1(M+H)⁺。

N- (4-methoxyphenyl) -N-3-methoxyaniline (1 c): light yellow solid. 54% yield. Melting point 69.7-70.0 ℃.¹H NMR(CDCl₃，300MHz)δ6.93-6.81(m，8H)，5.37(s，br，1H)，3.78(s，6H)。MS m/z 228.4(M-H)⁺。

N- (4-fluorophenyl) -N-4-methoxyaniline (1 d): light-yellow solid. 54% yield. Melting point 60.6-61.0 ℃.¹H NMR(CDCl₃，300MHz)δ7.01-6.83(m，8H)，3.78(s，3H)。MSm/z 217(M)⁺。

N- (4-methoxyphenyl) -N-1-naphthylamine (1 e): light yellow solid. 54% yield. Melting point 105.8-106.0 ℃.¹H NMR(CDCl₃，500MHz)δ8.00(d，1H，J＝8.0Hz)，7.92(d，1H，J＝8.0Hz)，7.50-7.43(m，3H)，7.33-7.30(m，1H)，7.10(d，1H，J＝7.5Hz)，7.05(d，2H，J＝8.5Hz)，6.88(d，2H，J＝8.5HZ)，3.80(s，3H)。MS m/z 249(M)⁺。

N- (4-benzyloxyphenyl) -N-4-methoxyaniline (1 f): light-yellow solid. 54% yield. Melting point 108.0-108.4 ℃. ¹H NMR(CDCl₃，300MHz)δ7.34-7.08(m，5H)，6.90-6.81(s，3H)，3.78(s，3H)。MS m/z 306(M+H)⁺。

N- [4- (benzyloxy) phenyl]Diphenyl-4-amine (1 g): tan solid. 40.2% yield. Melting point 136-.¹H NMR(CDCl₃，300MHz)δ5.04(s，2H，CH₂)，6.93-6.99(m，4H，ArH)，7.02-7.11(m，2H，ArH)，7.22-7.48(m，9H，ArH)，7.53-7.56(m，3H，ArH)。MS m/z 352.2(M+H)⁺。

N- [4- (benzyloxy) phenyl]Biphenyl-4-amine (1 h): a tan solid. 40.2% yield. Melting point 136-.¹H NMR(CDCl₃，300MHz)δ7.56-7.53(m，3H，ArH)，7.48-7.22(m，9H，ArH)，7.11-7.02(m，2H，ArH，6.99-6.93(m，4H，ArH)，5.04(s，2H，CH₂)；MS m/z 352.2(M+H)⁺。

Example 9

General Synthesis of benzamides

A mixture of the aryl aniline (1 equivalent), benzoyl chloride (1.3 equivalents), and pyridine (6 equivalents) were mixed together and dissolved in anhydrous THF at room temperature. The mixture was stirred and refluxed for 24 hours. The reaction mixture was cooled to room temperature and hydrolyzed by addition of 2N HCl solution. The solution was extracted with ethyl acetate. The organic phase was saturated NaHCO₃The aqueous solution was washed to remove excess acid, over anhydrous MgSO₄Dried, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using EtOAc/hexanes (3/7v/v) to afford the corresponding benzamide compound.

4-methoxy-N, N-bis- (4-methoxyphenyl) -benzamide (2 a): a white solid. 98% yield. Melting point 119.5-120 ℃.¹H NMR(CDCl₃，300MHz)δ7.42(d，2H，J＝8.9Hz)，7.05(d，4H，J＝8.8Hz)，6.81(d，4H，J＝8.9Hz)，6.71(d，2H，J＝8.9Hz)，3.77(s，9H)。MS m/z 364(M+H)。

3-methoxy-N, N-bis- (4-methoxyphenyl) -benzamide (2 b): a white solid. The yield was 99%. Melting point 113.5-113.6 ℃.¹H NMR(DMSO-d₆，300MHz)δ7.17-7.14(m，5H)，6.97-6.95(m，3H)，6.87-6.84(m，4H)。MS m/z 364(M+H)⁺。

4-methoxy-N- (4-methoxyphenyl) -N- (3-methoxyphenyl) -benzamide (2 c): a white solid. The yield was 79%. Melting point 154.5-154.9 ℃. ¹H NMR(CDCl₃，300MHz)δ7.47-7.43(m，2H)，7.31-7.13(m，7H)，6.75-6.68(m，4H)，3.77(s，3H)，3.71(s，3H)。MSm/z 356(M+Na)⁺。

N, N-bis- (4-methyl)Oxyphenyl) -benzamide (2 d): a white solid. The yield was 98%. Melting point 77-77.5 ℃.¹H NMR(CDCl₃，300MHz)δ7.46-7.42(m，2H)，7.29-7.17(m，3H)，7.09-7.06(m，4H)，6.81-6.78(m，4H)，3.76(s，6H)。MS m/z 356(M+Na)⁺。

4-methoxy-N, N-diphenyl-benzamide (2 e): a white solid. The yield was 99%. M.p.133.5-133.9 ℃.¹H NMR(CDCl₃，300MHz)δ7.45-7.42(m，2H)，7.29-7.24(m，4H)，7.18-7.12(m，6H)，6.71-6.68(m，2H)，3.74(s，3H)。MS m/z 326(M+Na)⁺。

3-methoxy-N, N-diphenyl-benzamide (2 f): a white solid. The yield was 98%. M.p.122-122.2 ℃.¹H NMR(CDCl₃，300MHz)δ7.45-7.42(m，2H)，7.29-7.24(m，4H)，7.18-7.12(m，6H)，6.71-6.68(m，2H)，3.74(s，3H)。MS m/z 326(M+Na)⁺。

N, N-diphenyl-benzamide (2 g): a white solid. The yield was 89%. Melting point 178.4-179.3 ℃.¹H NMR(CDCl₃，300MHz)δ7.46-7.44(m，2H)，7.28-7.23(m，5H)，7.21-7.14(m，8H)。MS m/z 296(M+Na)⁺。

N- (4-methoxyphenyl) -N-phenyl-benzamide (2 h): a white solid. The yield was 95%. M.p.153-154.2 ℃.¹H NMR(CDCl₃，300MHz)δ7.47-7.43(m，2H)，7.30-7.02(m，8H)，6.83-6.78(m，2H)，3.76(s，3H)。MS m/z 326(M+Na)⁺。

N- (3-methoxyphenyl) -N-phenyl-benzamide (2 i): a white solid. The yield was 93%. M.p.103-105.9 ℃.¹H NMR(CDCl₃，300MHz)δ7.49-7.45(m，2H)，7.31-7.15(m，9H)，6.75-6.70(m，3H)，3.76(s，3H)。MS m/z 326(M+Na)⁺。

4-methoxy-N- (4-methoxyphenyl) -N-phenyl-benzamide (2 j): a white solid. The yield was 78%.¹H NMR(CDCl₃，300MHz)δ7.44-7.41(m，2H)，7.28-7.26(m，2H)，7.15-7.05(m，5H)，6.83-6.80(m，2H)，6.72-6.70(m，2H)，3.77(s，6H)。MS m/z356(M+Na)⁺。

4-methoxy-N- (3-methoxyphenyl) -N-phenyl-benzamide (2 k): a white solid. The yield was 84%. Melting point 119.0-119.5 ℃.¹H NMR(CDCl₃，300MHz)δ7.47-7.43(m，2H)，7.31-7.13(m，7H)，6.75-6.68(m，4H)，3.77(s，3H)，3.71(s，3H)。MS m/z 356(M+Na)⁺。

N, N-bis (4-methoxyphenyl) -4-fluorobenzamide (2 l): a white solid. The yield was 98%. Melting point 122.2-122.4 ℃.¹H NMR(CDCl₃，300MHz)δ7.46-7.42(m，2H)，7.29-7.17(m，3H)，7.09-7.06(m，4H)，6.81-6.78(m，4H)，3.76(s，6H)。MS m/z 356(M+Na)⁺。

4-methoxy-N, N-diphenyl-sulfonamide (2 m): a white solid. The yield was 89%. Melting point 153.0-153.5 ℃.¹H NMR(CDCl₃，300MHz)δ7.64-7.61(m，2H)，7.34-7.22(m，10H)，6.94-6.91(m，2H)，3.86(s，3H)。MS m/z 362(M+Na)⁺。

4-methoxy-N- (4-methoxyphenyl) -N- (4-fluorophenyl) -benzamide (2N): a white solid. The yield was 97%. Melting point 133.5.0-134.5 ℃. ¹H NMR(CDCl₃，300MHz)δ8.11-6.66(m，15H)，3.74(s，3H)，3.73(s，3H)。MS m/z 384(M+H)⁺。

4-methoxy-N- (4-methoxyphenyl) -N- (1-naphthyl) -benzamide (2 o): a white solid. The yield was 65%. Melting point 144.0-144.5 ℃.¹H NMR(CDCl₃，300MHz)δ8.11-6.66(m，15H)，3.74(s，3H)，3.73(s，3H)。MS m/z 384(M+H)⁺。

N- (4-methoxyphenyl) -N- (4-benzyloxyphenyl) -1-naphthamide (2 p): a white solid. The yield was 95%. Melting point 143.5-144.0 ℃.¹H NMR(CDCl₃，300MHz)δ8.25-8.22(m，1H)，7.79-7.69(m，2H)，7.57-7.22(m，9H)，6.96-6.63(m，8H)，4.99(s，2H)，3.71(s，3H)。MS m/z 460(M+H)⁺。

4-chloro-N- (4-methoxyphenyl) -N- (4-benzyloxyphenyl) -benzamide (2 q): a white solid. The yield was 96%. Melting point 130.0-131.4 ℃.¹H NMR(DMSO-d₆，300MHz)δ。MS m/z 444(M+H)⁺。

4-cyano-N- (4-methoxyphenyl) -N- (4-benzyloxyphenyl) -benzamide (2 r): a white solid. The yield was 85%. Melting point 147.6-148.0 ℃.¹H NMR(DMSO-d₆，300MHz)δ.MS m/z 435(M+H)⁺。

N- (4-methoxyphenyl) -N- (4-benzyloxyphenyl) -2-naphthamide (2 s): a white solid. The yield was 58%. Melting point 174.9-175.5 ℃.¹H NMR(CDCl₃，300MHz)δ8.04(s，1H)，7.77-7.74(m，2H)，7.64-7.61(m，1H)，7.51-7.43(m，4H)，7.40-7.31(m，4H)，7.13-7.10m，4H)，6.88-6.78(m，4H)，4.99(s，2H)，3.74(s，3H)。MS m/z 460(M+H)⁺。

4- (benzyloxy) -N- [4- (benzyloxy) phenyl]-N- (4-methoxyphenyl) benzamide (2 t): a tan solid. The yield was 72.4%. Melting point 175-.¹H NMR(DMSO-d₆，300MHz)δ7.37-7.34(m，12H，ArH)，7.13-7.10(m，4H，ArH)，6.96-6.89(m，2H，ArH)，6.88-6.86(m，4H，ArH)，5.06(s，4H，2X CH₂)，3，72(s，3H，OCH₃)。MS m/z 516.3(M+H)⁺。

N- [4- (benzyloxy) phenyl]-4-methoxy-N- (4-methoxyphenyl) benzamide (2 u): a yellow oil. The yield was 71.3%.¹H NMR(CDCl₃，300MHz)δ7.44-7.34(m，7H，ArH)，7.07-7.04(m，4H，ArH)，6.89-6.86(m，2H，ArH)，6.82-6.79(m，2H，ArH)，6.72-6.69(m，2H，ArH)，5.01(s，2H，CH₂)，3.77(s，6H，2X OCH₃)。MS m/z 462.1(M+Na)⁺。

N- [4- (benzyloxy) phenyl]-N-biphenyl-4-yl-4-methoxybenzamide (2 v): light yellow foam. The yield was 78.6%. Melting point 70-72 ℃.¹H NMR(DMSO-d₆，300MHz)δ7.66-7.57(m，4H，ArH).7.47-7.32(m，10H，ArH，7.30-7.23(m，2H，ArH)，7.18-7.07(m，2H，ArH)，7.00-6.92(m，2H，ArH)，6.89-6.80(m，2H，ArH)，5.06(s，2H，CH₂)，3.72(s，3H，OCH₃)。MS m/z 508.3(M+Na)⁺。

4-cyano-N- (4-methoxyphenyl) -N-phenylbenzamide (2 w): light yellow solid. The yield was 96.3%. Melting point 125-. ¹H NMR(DMSO-d₆，300MHz)δ7.77-7.74(m，2H，ArH)，7.61-7.58(m，2H，ArH)，7.34-7.21(m，7H，ArH)，6.88(d，J＝7.92Hz，2H，ArH)，3.71(s，3H，OCH₃)。MS m/z 351.1(M+Na)⁺。

3-methoxy-N- (4-methoxyphenyl) -N-phenylbenzamide (2 ×): light yellow oil. The yield was 98.8%.¹H NMR(CDCl₃，300MHz)δ7.30-7.25(m，2H，ArH)，7.18-7.07(m，6H，ArH)，7.01-6.98(m，2H，ArH)，6.83-6.80(m，3H，ArH)，3.77(s，3H，OCH₃)，3.68(s，3H，OCH₃)。MS m/z 356.1(M+Na)⁺。

4-cyano-N- (3-methoxyphenyl) -N-phenylbenzamide (2 y): brown oil. The yield was 84.8%.¹H NMR(DMSO-d₆，300MHz)δ7.77-7.75(m，2H，ArH).7.63-7.61(m，2H，ArH)，7.35-7.30(m，4H，ArH)，7.25-7.22(m，2H，ArH)，6.91(s，1H，ArH)，6.83-6.80(m，2H，ArH)，3.67(s，3H，OCH₃)。MS m/z 351.1(M+Na)⁺。

4-cyano-N, N-biphenylbenzamide (2 z): a tan solid. The yield was 85.2%. Melting point 145-147 ℃.¹H NMR(DMSO-d₆，300MHz)7.76-7.74(m，2H，ArH)，7.61-7.59(m，2H，ArH)，7.34-7.22(m，10H，ArH)。MS m/z 321.0(M+Na)⁺。

Example 10

By means of BBr₃General procedure for demethylation of benzamide derivatives

Dissolving methoxybenzamide in dry CH₂Cl₂In, BBr is added dropwise at 0 DEG C₃(1.0MCH₂Cl₂A solution). The reaction solution was slowly warmed to room temperature and stirred at room temperature overnight. The mixture was cooled on ice at 0 ℃ and hydrolyzed by addition of water. The solution was partitioned with EtOAc. Separating the organic layer; the aqueous layer was extracted with EtOAc. The organic layer was washed with brine and over anhydrous MgSO₄And (5) drying. The solvent was removed under reduced pressure. By flash chromatography using CH₃OH/CH₂Cl₂(1/9v/v) purifying the residue to obtain the phenolic compound.

The following compounds synthesized and characterized as described above and summarized in table 1 herein: 4-hydroxy-N, N-bis- (4-hydroxyphenyl) -benzamide (3 a); 3-hydroxy-N-bis- (4-hydroxyphenyl) -benzamide (3 b); 4-hydroxy-N- (4-hydroxyphenyl) -N- (3-hydroxyphenyl) -benzamide (3 c); n, N-bis- (4-hydroxyphenyl) -benzamide (3 d); 4-hydroxy-N, N-diphenyl-benzamide (3 e); 3-hydroxy-N, N-diphenyl-benzamide (3 f); n- (4-hydroxyphenyl) -N-phenyl-benzamide (3 g); n- (3-hydroxyphenyl) -N-phenyl-benzamide (3 h); 4-hydroxy-N- (4-hydroxyphenyl) -N-phenyl-benzamide (3 i); 4-hydroxy-N- (3-hydroxyphenyl) -N-phenyl-benzamide (3 j); n, N-bis (4-hydroxyphenyl) -4-fluorobenzamide (3 k); 4-hydroxy-N, N-diphenyl-phenylsulfonamide (3 l); 4-hydroxy-N- (4-hydroxyphenyl) -N- (fluorophenyl) -benzamide (3 m); n, N-bis (4-hydroxyphenyl) -1-naphthamide (3N); 4-hydroxy-N- (1-naphthyl) -N- (4-hydroxyphenyl) -benzamide (3 o); 4-cyano-N, N-bis (4-hydroxyphenyl) -benzamide (3 p); 3-cyano-N, N-bis (4-hydroxyphenyl) -benzamide (3 q); n, N-bis (4-hydroxyphenyl) -2-naphthamide (3 r); 4-cyano-N- [4- (2-piperidin-1-ylethoxy) -phenyl ] -N- (4-hydroxyphenyl) -benzamide (3 s); 3-chloro-N- [4- (2-piperidin-1-ylethoxy) -phenyl ] -N- (4-hydroxyphenyl) -benzamide (3 t); N-biphenyl-4-yl-N- (4-hydroxyphenyl) -4-methoxybenzamide (3 u); N-biphenyl-4-yl-4-hydroxy-N- (4-hydroxyphenyl) -benzamide (3 v); 4-hydroxy-N- (4-hydroxyphenyl) -N- [4- (2-piperidin-1-ylethoxy) phenyl ] -benzamide (3 w); 3-hydroxy-N- (4-hydroxyphenyl) -N-phenyl-benzamide (3 x); N-biphenyl-4-yl-4-hydroxy-N- [4- (2-piperidin-1-ylethoxy) phenyl ] -benzamide (3 y); 4-cyano-N- (4-hydroxyphenyl) -N-phenylbenzamide (10 a); n, N-bis (4-hydroxyphenyl) biphenyl-4-carboxamide (10 c); n, N-bis (4-hydroxyphenyl) -3, 4-dimethylbenzamide (10 d); n- (biphenyl-4-yl) -4-cyano-N- (4-hydroxyphenyl) -benzamide (10 e); 3-fluoro-4-hydroxy-N- (4-hydroxyphenyl) -N-phenylbenzamide (10 f); 4-hydroxy-N, N-bis (4-hydroxyphenyl) -3, 5-dimethylbenzamide (10 i); n, N-bis (4-hydroxyphenyl) -2, 3-dimethylbenzamide (10 j); 3-fluoro-4-hydroxy-N, N-bis (4-hydroxyphenyl) -benzamide (10 k); n, N-bis (4-hydroxyphenyl) -4-propylbenzamide (10 l); 3, 4-dihydroxy-N, N-bis (4-hydroxyphenyl) -benzamide (10 m); 4-hydroxy-N, N-bis (4-hydroxyphenyl) -3-methylbenzamide (10N); n, N-bis (4-hydroxyphenyl) -2, 4-dimethylbenzamide (10 q); n, N-bis (4-hydroxyphenyl) -4-methylbenzamide (10 s); 4, 4' - (2, 3-dimethylbenzylazaldi) diphenol (10 t); 4-formyl-N, N-bis (4-hydroxyphenyl) -benzamide (10 u); n, N-bis (4-hydroxyphenyl) -4- (trifluoromethyl) benzamide (11 b); n, N-bis (4-hydroxyphenyl) -4-nitrobenzamide (11 d); 3-fluoro-N, N-bis (4-hydroxyphenyl) benzamide (11 e); n, N-bis (4-hydroxyphenyl) -4-methoxy-1-naphthamide (11 i); 4- ((hydroxyimino) methyl) -N, N-bis (4-hydroxyphenyl) benzamide (11 l); n, N-bis (4-hydroxyphenyl) -4-pentylbenzamide (11 p); 4-tert-butyl-N, N-bis (4-hydroxyphenyl) benzamide (11 r); 3- {4- [ bis- (4-hydroxy-phenyl) -carbamoyl ] -phenyl } -acrylic acid (11 t); 3- {4- [ bis- (4-hydroxy-phenyl) -carbamoyl ] -phenyl } -propionic acid (11 u); n, N-bis- (4-hydroxy-phenyl) -4- (3-hydroxy-propyl) -benzamide (11 v); n- (4-hydroxyphenyl) -4- (3-hydroxypropyl) -N- (4-methoxyphenyl) -benzamide (11 w); 4-fluoro-N, N-bis (4-hydroxyphenyl) -2- (trifluoromethyl) -benzamide (11 x); 3-fluoro-N- (4-fluorophenyl) -4-hydroxy-N- (4-hydroxyphenyl) benzamide (11 y); and N, N-bis (4-hydroxyphenyl) -isonicotinamide (11 aa).

General procedure for debenzylation of benzyloxyphenyl-benzamides

The compound was dissolved in EtOH in a 250mL hydrogenation flask. Pd/C powder (5% mol) was added to the solution. The reaction vessel was mounted on a hydrogenator under 20psi hydrogen pressure. The reaction was monitored by TLC until the starting material disappeared. The solvent was then removed under reduced pressure. The residue was purified by flash column chromatography with hexane/EtOAc 3/2v/v to afford the desired compound.

The following compounds synthesized and characterized as described above and summarized in table 1 herein: 4-chloro-N- [ 4-hydroxyphenyl ] -N- (4-methoxyphenyl) -benzamide (5 a); 4-cyano-N- [ 4-hydroxyphenyl ] -N- (4-methoxyphenyl) -benzamide (5 b); 3-chloro-N- [ 4-hydroxyphenyl ] -N- (4-methoxyphenyl) -benzamide (5 c); 4-hydroxy-N- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -benzamide (5 d); n- (4-hydroxyphenyl) -4-methoxy-N- (4-methoxyphenyl) -benzamide (5 e).

Example 11

General Synthesis of O- (2-piperidin-1-ylethoxy) -benzamides and analogs

To a solution containing hydroxyphenyl (1 equivalent) of benzamide analog in acetone, K is added₂CO₃(3 equivalents) and N-chloroethyl-piperidine hydrochloride (1.2 equivalents). The solution was heated to reflux for 6 hours. The solution was evaporated to dryness. The residue was hydrolyzed by adding water, followed by extraction with ethyl acetate. The organic phase was separated and over anhydrous MgSO ₄And drying. The solvent was removed under reduced pressure. The residue was purified by flash chromatography with dichloromethyl/methanol-9/1 v/v to obtain the desired compound. By mixing with Et₂HCl in O was added to a solution of compound in methanol, followed by evaporation of the solvent to obtain the hydrochloride salt.

The following compounds synthesized and characterized as described above and summarized in table 1 herein: n- (4-hydroxyphenyl) -N- [4- (2-piperidin-1-ylethoxy) -phenyl ] -benzamide (4 a); n- (phenyl) -N- [4- (2-piperidin-1-ylethoxy) -phenyl ] -benzamide (4 b); n, N-diphenyl- [3- (2-piperidinylethoxy) ] -benzamide hydrochloride (4 c); n, N-diphenyl- [3- (2-piperidinylethoxy) ] -benzamide hydrochloride (4 d); n- (4-hydroxyphenyl) -N-phenyl- [4- (2-piperidin-1-ylethoxy) ] -benzamide hydrochloride (4 e); n, N-diphenyl-bis [4- (2-piperidin-1-ylethoxy) -phenyl ] -sulfonamide hydrochloride (4 f); n- (4-fluorophenyl) -N- [ 4-hydroxyphenyl ] - [4- (2-piperidin-1-ylethoxy) ] -benzamide (4 g); n- (4-hydroxyphenyl) -N- [4- (2-piperidin-1-ylethoxy) -phenyl ] -4-fluoro-benzamide hydrochloride (4 h); 3- (2-piperidin-1-ylethoxy) -N, N-bis (4-hydroxyphenyl) -benzamide (4 i); 4-cyano-N- [4- (2-piperidin-1-ylethoxy) -phenyl ] -N- (4-methoxyphenyl) -benzamide (4 j); 4-chloro-N- [4- (2-piperidin-1-ylethoxy) -phenyl ] -N- (4-methoxyphenyl) -benzamide (4 k); 4-cyano-N- [4- (2-piperidin-1-ylethoxy) -phenyl ] -N- (4-methoxyphenyl) -benzamide (4 l); 3-chloro-N- [4- (2-piperidin-1-ylethoxy) -phenyl ] -N- (4-methoxyphenyl) -benzamide (4 m); 4-methoxy-N- (4-methoxyphenyl) -N- [4- (2-piperidin-1-ylethoxy) phenyl ] -benzamide (4N); N-biphenyl-4-yl-N- (4-hydroxyphenyl) -4- (2-piperidin-1-ylethoxy) -benzamide (4 o); 4-methoxy-N-phenyl-N- [4- (2-piperidin-1-ylethoxy) phenyl ] -benzamide (4 p); n- (4-hydroxyphenyl) -N-phenyl-3- (2-piperidin-1-ylethoxy) -benzamide (4 q); n- (4-hydroxyphenyl) -N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) -4-propylbenzamide (10 o); n- (4-hydroxyphenyl) -2, 3-dimethyl-N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) -benzamide (10 p); n- (4-hydroxyphenyl) -N- (4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) benzamide (11 a); n- (4-hydroxyphenyl) -N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) -4- (trifluoromethyl) benzamide (11 c); n- (4-hydroxyphenyl) -N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) -1-naphthamide (11 f); 3-fluoro-N- (4-hydroxyphenyl) -N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) benzamide (11 g); n- (4-hydroxyphenyl) -4-nitro-N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) benzamide (11 h); n- (4-hydroxyphenyl) -N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) -2-naphthamide (11 j); n- (4-hydroxyphenyl) -2, 4-dimethyl-N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) benzamide (11 m); n- (4-hydroxyphenyl) -3, 5-dimethyl-N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) benzamide (11N); 4- ((2, 3-dimethylbenzyl) (4- (2- (piperidin-1-yl) ethoxy) phenyl) amino) phenol (11 o); n- (4-hydroxyphenyl) -4-pentyl-N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) benzamide (11 q); 4-tert-butyl-N- (4-hydroxyphenyl) -N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) benzamide (11 s); n- (4-hydroxyphenyl) -4-methyl-N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) benzamide (11 z); and N- (4-hydroxyphenyl) -N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) -isonicotinamide (11 ab).

Synthesis of two-tailed (two-tailed) SERMs

N- (4-fluorophenyl) -N- [4- (2-piperidin-1-ylethoxy) -phenyl ] - [4- (2-piperidin-1-yl-ethoxy) ] -benzamide dihydrochloride (4 r); n, N-bis [4- (2-piperidin-1-ylethoxy) -phenyl ] -4-fluoro-benzamide dihydrochloride (4 s); n, N-bis [4- (2-piperidin-1-ylethoxy) -phenyl ] -benzamide dihydrochloride (4 t); and N- [4- (2-piperidin-1-ylethoxy) -phenyl ] -N-phenyl- [4- (2-piperidin-1-ylethoxy) ] -benzamide dihydrochloride (4 u).

Example 12

General procedure for the Synthesis of Cyclohexanecarboxylic acid bis-arylamides

N-cyclohexyl-4-methoxyaniline. The compound was synthesized according to the literature. NMR, MS data and melting points were consistent with those reported. Reference (D.Ma, Q.Cai, H.Zhang, org.Lett.2003, 5, 2453.)

Aniline (1 eq), cyclohexylcarbonyl chloride (1.3 eq s) and pyridine (6 eq). The reaction mixture was stirred and heated to 90 ℃ for 24 hours. The reaction solution was cooled to room temperature and hydrolyzed by adding 2N HCl solution. The solution was extracted 2 times with ethyl acetate. The combined organic phases were washed with saturated NaHCO₃The aqueous solution was washed to remove excess acid, over anhydrous MgSO₄Dried, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using EtOAc/hexanes (3/7v/v) to give the corresponding cyclohexylamide compound.

Cyclohexanecarboxylic acid N- (4-methoxyphenyl) -N- (4-benzyloxyphenyl) -amide (8 a): a white solid. 92% yield. Melting point 102.7-128.0 ℃.¹H NMR(CDCl₃，300MHz)δ7.40-6.90(m，13H)，5.03(s，2H)，3.80(s，3H)，2.41-2.04(m，1H)，1.78-1.53(m，7H)，1.28-1.06(m，3H)。MS m/z 438(M+Na)⁺。

General procedure for the Synthesis of bis N-hydroxyphenyl Cyclohexanecarboxylic acids

Dissolving a methoxyphenyl cyclohexylamide compound in dry CH₂Cl₂In (1). BBr was added dropwise via syringe with stirring at 0 deg.C₃(1.0M CH₂Cl₂A solution). The reaction solution was slowly warmed to room temperature and stirred at room temperature overnight. The mixture was cooled to 0 ℃ on an ice bath and hydrolyzed by addition of water. The solution was partitioned with EtOAc. Separating the organic phase; the aqueous phase was extracted twice with EtOAc. The organic layers were combined, washed with brine and over anhydrous MgSO₄And drying. The solvent was removed under vacuum. The residue was flash chromatographed on silica gel using CH₃OH/CH₂Cl₂(1/9v/v) purification to obtain the pure desired phenolic compound.

Cyclohexanecarboxylic acid bis (4-hydroxyphenyl) -amide (8 b): a white solid. Yield 86%. Melting point 265.1-266.2 deg.C (decomposed).¹H NMR(DMSO-d₆，500MHz)δ9.65(s，1H)，9.37(s，1H)，7.17-6.70(m，4H)，6.78-6.67(m，4H)，2.29-2.23(m，1H)，1.71-1.62(m，4H)，1.54-1.51(m，1H)，1.41-1.32(m，2H)，1.21-1.07(m，1H)，0.97-0.90(m，2H)。MS m/z 334(M+Na)⁺。

Example 13

5- [ 4-methoxyphenyl]General Synthesis of-5H-phenanthridin-6-one

Mixing 6- (5H) -phenanthridinone (6- (5H) -phenathroidinone) (1.5 equiv.), 4-iodoanisole (1 equiv.), and K₂CO₃A mixture of (2 equiv.), CuI (0.1 equiv.), and L-proline (0.2 equiv.) was mixed together and dissolved in anhydrous DMSO at room temperature. The reaction mixture was then stirred and heated to 150 ℃ for 28 hours. The mixture was cooled to room temperature and hydrolyzed with water. The solution was partitioned with EtOAc. The EtOAc layer was separated, washed with brine, over anhydrous MgSO ₄And drying. The solvent was removed under reduced pressure. The residue was purified by flash chromatography (silica gel) using EtOAc/hexanes (2/3v/v) to afford the desired product.

5- [ 4-methoxyphenyl]-5H-phenanthridin-6-one (7 a): yellow solid. 65% yield. Melting point 217.0-218.5 deg.C (decomposed).¹HNMR(DMSO-d₆，500MHz)δ8.61-8.59(m，1H)，8.54-8.51(m，1H)，8.36-8.34(m，1H)，7.94-7.89(m，1H)，7.71-7.66(m，1H)，7.43-7.28(m，4H)，7.19-7.16(m，2H)，6.63-6.60(m，1H)。MS m/z 302(M+H)⁺。

General Synthesis of 5- [ 4-hydroxyphenyl ] -5H-phenanthridin-6-one

Reacting 5- [ 4-methoxyphenyl]-5H-phenanthridin-6-one in dry CH₂Cl₂In the reaction, BBr is added dropwise through a syringe under stirring at 0 DEG C₃(1.0M CH₂Cl₂A solution). The reaction solution was slowly warmed to room temperature and stirred at room temperature overnight. The mixture was cooled to 0 ℃ in an ice bath and hydrolyzed by the addition of water. The solution was partitioned with EtOAc.Separating the organic layer; the aqueous layer was extracted twice with EtOAc. The organic layers were combined, washed with brine and over anhydrous MgSO₄And (5) drying. The solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel with CH₃OH/CH₂Cl₂(1/9v/v) purification to give the pure desired phenolic compound.

5- [ 4-Hydroxyphenyl group]-5H-phenanthridin-6-one (7 b): yellow solid. 78% yield. Melting point 325.7-327.0 deg.C (decomposed).¹H NMR(DMSO-d₆，500MHz)δ9.82(s，1H)，8.60-8.58(m，1H)，8.52-8.51(m，1H)，8.35-8.33(m，1H)，7.92-7.89(m，1H)，7.69-7.66(m，1H)，7.41-7.38(m，1H)，7.32-7.29(m，1H)，7.15-7.13(m，2H)，6.99-6.97(m，2H)，6.65-6.63(m，1H)。MS m/z 310(M+Na)⁺。

General Synthesis of 5- [4- (2-piperidin-1-ylethoxy) -phenyl ] -phenanthridin-6-one derivatives

To 5- [ 4-hydroxyphenyl group in acetone]Addition of K to a solution of phenanthridin-6-one (1 eq) ₂CO₃(3 equivalents) and N-chloroethyl-piperidine hydrochloride (1.2 equivalents). The solution was heated to reflux for 6 hours. The solution was evaporated to dryness. The residue was hydrolyzed by adding water, and then extracted with ethyl acetate. The organic phase was separated and passed over anhydrous MgSO₄And (5) drying. The solvent was removed under reduced pressure. The residue was purified by flash chromatography (silica gel; dichloromethyl/methanol-9/1 v/v) to obtain the desired compound. The hydrochloride salt is reacted with Et₂HCl in O was added to a solution of compound in methanol followed by evaporation of the solvent.

5- [4- (2-piperidin-1-ylethoxy) -phenyl]-5H-phenanthridin-6-one (7 c): yellow solid. Yield 79%. Melting point 220.0-221.5 deg.C (decomposed).¹HNMR(DMSO-d₆，300MHz)δ8.56-8.53(m，1H)，8.35-8.29(m，2H)，7.84-7.79(m，1H)，7.64-7.59(m，1H)，7.36-7.24(m，4H)，7.23-7.10(m，2H)，6.76-6.73(m，1H)，4.45(tr，2H，J＝5.1Hz)，3.16(tr，2H，J＝5.1Hz)，2.94(br，4H)，1.90-1.85(m，4H)，1.61-1.59(m，2H)。MS m/z 399(M+H)⁺。

Example 14

General Synthesis of 6b, 6c, 6d, 6e, 6f and 6g

(2R) -1-methacryloylpyrrolidine-2-carboxylic acid. D-proline (14.93g, 0.13mol) was dissolved in 71mL 2N NaOH and cooled in an ice bath; the basic solution thus obtained was diluted with acetone (71 mL). To an aqueous solution of D-proline was added simultaneously acryloyl chloride (13.56g, 0.13mol) in acetone (71mL) and 2N NaOH solution (71mL) in an ice bath over 40 minutes. The mixture pH was maintained at 10-11 ℃ during the acryloyl chloride addition. After stirring (3 hours, room temperature), the mixture was evaporated in vacuo at 35-45 ℃ to remove acetone. The solution thus obtained was washed with diethyl ether and acidified to pH 2 with concentrated HCl. The acidic mixture was saturated with NaCl and extracted with EtOAc (100 mL. times.3). The combined extracts were extracted with Na ₂SO₄Dry, filter through celite, and evaporate under vacuum to give the crude product as a colorless oil. The oil was recrystallized from ether and hexane to give 16.2 (68%) of the desired compound as colorless crystals: melting point 102-]Melting point 102.5-103.5 ℃); the NMR spectrum of this compound demonstrated the presence of two rotamers of the title compound.¹H NMR(300MHz，DMSO-d₆) Delta, first rotamers 5.28(s) and 5.15(s), second rotamers 5.15(s) and 5.03(s) (total of the two rotamers 2H, vinyl CH₂) First rotamer 4.48-4.44, second rotamer 4.24-4.20(m) (total of two rotamers 1H, CH at chiral center), 3.57-3.38(m, 2H, CH)₂)，2.27-2.12(1H，CH)，1.97-1.72(m，6H，CH₂，CH，Me)；¹³C NMR(75MHz，DMSO-d₆) δ major rotamers 173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: minor rotamers 174.0, 170.0, 141.6, 115.2, 60.3, 45.9，31.0，22.3，19.7；IR(KBr)3437(OH)，1737(C＝O)，1647(CO，COOH)，1584，1508，1459，1369，1348，1178cm^-1；[α]_D ²⁶+80.8°(c＝1，MeOH)；C₉H₁₃NO₃Elemental analysis: c59.00, H7.15, N7.65. Measurement (Found): c59.13, H7.19, N7.61.

(3R, 8aR) -3-bromomethyl-3-methyl-tetrahydro-pyrrolo [2, 1-c)][1，4]Oxazine-1, 4-diones. A solution of N-bromosuccinimide (NBS) (23.5g, 0.132mol) in 100mL of DMF was added dropwise at room temperature under an argon atmosphere to a stirred solution of (meth-acryloyl) -pyrrolidine (16.1g, 88mmol) in 70mL of DMF and the resulting mixture was stirred for 3 days. The solvent was removed in vacuo and a yellow solid precipitated. The solid was suspended in water, stirred at room temperature overnight, filtered and dried to give 18.6 (81%) (light-weight when dry-34%) of the title compound as a yellow solid: melting point 152- ]Melting point 107 ℃ -);¹H NMR(300MHz，DMSO-d₆) δ 4.69(dd, J ═ 9.6Hz, J ═ 6.7Hz, 1H, CH at the chiral center), 4.02(d, J ═ 11.4Hz, 1H, CHH)_a)，3.86(d，J＝11.4Hz，1H，CHH_b)，3.53-3.24(m，4H，CH₂)，2.30-2.20(m，1H，CH)，2.04-1.72(m，3H，CH₂And CH), 1.56(s, 2H, Me);¹³C NMR(75MHz，DMSO-d₆)δ167.3，163.1，83.9，57.2，45.4，37.8，29.0，22.9，21.6；IR(KBr)3474，1745(C＝O)，1687(C＝O)，1448，1377，1360，1308，1227，1159，1062cm^-1；[α]_D ²⁶+124.5 ° (c ═ 1.3, chloroform); c₉H₁₂BrNO₃Elemental analysis: c41.24, H4.61, N5.34, found: c41.46, H4.64, N5.32.

(2R) -3-bromo-2-hydroxy-2-methylpropionic acid. A mixture of tribromophenol (18.5g, 71mmol) in 300mL of 24% HBr was heated at reflux for 1 hour. The thus-obtained solution was diluted with brine (200mL) and extracted with ethyl acetate (100 mL. times.4). The combined extracts were extracted with saturated NaHCO₃Washing (100 mL. times.4). The aqueous solution was acidified with concentrated HCl to pH 1, which was in turn extracted with ethyl acetate (100mL × 4). The combined organic solution was passed over Na₂SO₄Dried, filtered through celite, and evaporated to dryness under vacuum. Recrystallization from toluene gave 10.2g (86%) of the desired compound as colorless crystals: melting point 107-]Melting point 109-113 ℃ for the S-isomer);¹H NMR(300MHz，DMSO-d₆)δ3.63(d，J＝10.1Hz，1H，CHH_a)，3.52(d，J＝10.1Hz，1H，CHH_b)，1.35(s，3H，Me)；IR(KBr)3434(OH)，3300-2500(COOH)，1730(C＝O)，1449，1421，1380，1292，1193，1085cm^-1；[α]_D ²⁶+10.5°(c＝2.6，MeOH)；C₄H₇BrO₃elemental analysis: c26.25, H3.86. Measurement value: c26.28, H3.75.

Synthesis of (R) -3-bromo-2-hydroxy-N- (4-methoxyphenyl) -2-methylpropanamide (6b)

(R) -3-bromo-2-hydroxy-2-methylpropionic acid (8.54g, 46.7mmol) was placed in a 250mL three-necked round bottom flask equipped with a stirrer and an addition funnel and dissolved in 100mL anhydrous THF at room temperature. The solution was cooled to 0 ℃. Then SOCl was added dropwise over 3 hours ₂(7.78g, 65.4 mmol). P-anisidine (5.00g, 40.6mmol) and triethylamine (6.62g, 65.4mmol) were added to the mixture at 0 ℃. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure to obtain a yellow residue, which was dissolved in ethyl acetate and water. The organic phase was separated and washed with saturated NaHCO₃The solution was washed and dried over anhydrous MgSO₄And (5) drying. The solvent was removed and the residue was purified by flash column chromatography (silica gel, EtOAc/hexanes: 1/1v/v) to afford a white colorSolid product, 8.50g, yield 63.2%.

Synthesis of (S) -2-hydroxy-N, 3-bis (4-methoxyphenyl) -2-methylpropanamide (6c)

Mixing (R) -3-bromo-2-hydroxy-N- (4-methoxyphenyl) -2-methylpropanamide (6b) (5.80g, 20.13mmol) and K₂CO₃(5.56g, 40.26mmol) was placed in a 500mL round bottom flask equipped with a stir bar. 150mL of acetone was added at room temperature. The reaction solution was heated under reflux for 3 hours. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography (silica gel, EtOAc/hexanes 1/1v/v) to give the product, (S) -N- (4-methoxyphenyl) -2-methyloxirane-2-carboxamide, 4.00g, 96.0% yield as a white solid.

To a 500mL single-necked round-bottomed flask equipped with a stir bar, a rubber stopper and a nitrogen introduction tube were added (S) -N- (4-methoxyphenyl) -2-methyloxirane-2-carboxamide (1.00g, 4.83mmol) and anhydrous THF (50 mL). The solution was cooled to-78 ℃ in a dry ice-acetone bath. 4-Methoxyphenylmagnesium bromide solution (14.50mL of 0.5M THF solution, 7.25mmol) was added dropwise with stirring at-78 deg.C. The thus-produced solution was stirred at-78 ℃ for 30 minutes and then at room temperature for 3 hours. The reaction was carried out by adding 20mL of saturated NH at 0 deg.C ₄The reaction was stopped with Cl solution. The solution was extracted by addition of EtOAc (3X 30 mL). The organic phase was separated, washed with brine (20mL) and over anhydrous MgSO₄And (5) drying. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (silica gel, EtOAc/hexanes 1/1v/v) to give the product, (S) -2-hydroxy-N, 3-bis (4-methoxyphenyl) -2-methylpropanamide (6c), 0.60g, 39.5% yield as a white solid.

Synthesis of (S) -2-hydroxy-3- (4-methoxyphenoxy) -N- (4-methoxyphenyl) -2-methylpropanamide (6d)

(S) -N- (4-methoxyphenyl) -2-methyloxirane-2-carboxamide (0.50g, 2.41mmol), 4-methylphenol (0.39g, 3.14mmol) and K₂CO₃(0.67g, 4.82mmol) was placed in a 250mL round bottom flask equipped with a stirrer. 100mL of isopropanol was added at room temperature. The reaction solution was heated under reflux for 3 hoursThen (c) is performed. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography (silica gel, EtOAc/hexanes 2/3v/v) to give the product, (S) -2-hydroxy-3- (4-methoxyphenoxy) -N- (4-methoxyphenyl) -2-methylpropanamide (6d) as a white solid, 0.79g, 98.8% yield.

Synthesis of (R) -3-bromo-2-hydroxy-N- (4-hydroxyphenyl) -2-methylpropanamide (6e)

In a 250mL round bottom flask equipped with a stir bar, nitrogen inlet and rubber stopper, (R) -3-bromo-2-hydroxy-N- (4-methoxyphenyl) -2-methylpropanamide (6b) (0.55g, 1.91mmol) was dissolved in 25mL anhydrous dichloromethane. Adding BBr dropwise under the condition of stirring at 0 DEG C ₃Solution (16.0mL 0.5MCH₂Cl₂Solution, 8.0 mmol). The reaction solution was stirred at room temperature overnight. The reaction was quenched by the addition of 20mL of water and extracted with EtOAc (3X 30 mL). The EtOAc layer was separated and passed over anhydrous MgSO₄And (5) drying. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography (silica gel, EtOAc/hexanes 1/1v/v) to give the product, (R) -3-bromo-2-hydroxy-N- (4-hydroxyphenyl) -2-methylpropanamide (6e), 0.51g, 97.9% yield as a white solid.

Synthesis of (S) -2-hydroxy-3- (4-hydroxyphenoxy) -N- (4-hydroxyphenyl) -2-methylpropanamide (6f)

(S) -2-hydroxy-3- (4-methoxyphenoxy) -N- (4-methoxyphenyl) -2-methylpropanamide (6d) (0.20g, 0.60mmol) was dissolved in dry CH₂Cl₂(30 mL). BBr was added dropwise via syringe with stirring at room temperature₃(4mL 1.0M CH₂Cl₂A solution). The reaction solution was stirred at room temperature overnight. The mixture was cooled to 0 ℃ in an ice bath and hydrolyzed by the addition of water (25 mL). EtOAc (50mL) was added and the solution was partitioned. Separating the organic layer; the aqueous layer was extracted twice with EtOAc (2X 10 mL). The organic layers were combined, washed with brine and over anhydrous MgSO₄And drying. The solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel with hexane/EtOAc (3/7v/v) to afford the product as a white solid. (S) -2-hydroxy-3- (4-hydroxyphenoxy) -N- (4-hydroxyphenyl) -2-methylpropanamide (C) 6f) 0.13g, yield 67.2%.

Synthesis of (S) -2-hydroxy-N, 3-bis (4-hydroxyphenyl) -2-methylpropanamide (6 g).

(S) -2-hydroxy-N, 3-bis (4-methoxyphenyl) -2-methylpropanamide (6c) (0.20g, 0.63mmol) was dissolved in dry CH₂Cl₂(20 mL). BBr was added dropwise via syringe with stirring at room temperature₃(6mL，1.0M CH₂Cl₂A solution). The reaction solution was stirred at room temperature overnight. The mixture was cooled to 0 ℃ in an ice bath and hydrolyzed by the addition of water (25 mL). EtOAc (50mL) was added and the solution was partitioned. Separating the organic layer; the aqueous layer was extracted twice with EtOAc (2X 10 mL). The organic layers were combined, washed with brine and over anhydrous MgSO₄And drying. The solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel with hexane/EtOAc (3/7v/v) to give the product, (S) -2-hydroxy-N, 3-bis (4-hydroxyphenyl) -2-methylpropanamide (6g), 0.12g, 65.6% yield as a white solid.

Example 15

Synthesis of 11k

Synthesis of 2-hydroxy-N, N, 2-tris (4-hydroxyphenyl) propionamide (11k)

Pyruvic acid (1.00g, 11.34mmol) was placed in a 250mL three-necked round-bottomed flask equipped with a stir bar, reflux condenser and nitrogen inlet and dissolved in 30mL anhydrous THF at room temperature. Then SOCl was added dropwise over 3 hours with stirring at room temperature ₂(2.03g, 17.01 mmol). Bis (4-methoxyphenyl) amine (2.00g, 8.72mmol) was added under nitrogen protection. Pyridine (4.14g, 52.3mmol) was added to the mixture at 0 ℃. The reaction mixture was heated to reflux for 12 hours. The reaction was stopped by adding 30mL of 2N HCl solution. The mixture was extracted with EtOAc (3X 20 m)L). The organic phase was separated, washed with brine (20mL) and over anhydrous MgSO₄And (5) drying. The solvent was removed under reduced pressure to give a yellow residue. The solvent was removed and the residue was purified by flash column chromatography (silica gel, EtOAc/hexanes 3/7v/v) to give the product as a white solid, N-bis (4-methoxyphenyl) -2-oxopropanamide, 2.15g, 82.4% yield. MS: m/z 322[ M + Na ]]⁺。

In a 250mL three-necked round-bottomed flask equipped with a stir bar, a rubber stopper and a nitrogen introduction tube, N-bis (4-methoxyphenyl) -2-oxopropanamide (0.53g, 1.77mmol) was dissolved in 30mL anhydrous THF. The solution was cooled to-78 ℃ in a dry ice-acetone bath. 4-Methoxyphenylmagnesium bromide solution (3.89mL of 0.5M THF solution, 7.25mmol) was added dropwise with stirring at-78 deg.C under a nitrogen atmosphere. The solution thus obtained was stirred at-78 ℃ for 1 hour and then at room temperature for 1 hour. The reaction was carried out by adding 20mL of saturated NH ₄The reaction was stopped with Cl solution. The solution was extracted by addition of EtOAc (3X 30 mL). The organic phase was separated, washed with brine (20mL) and over anhydrous MgSO₄And (5) drying. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (silica gel, EtOAc/hexanes 1/1v/v) to give the product as a white solid, 2-hydroxy-N, 2-tris (4-methoxyphenyl) propionamide, 0.61g, 84.7% yield.

In a 250mL round-bottom flask equipped with a stir bar, nitrogen inlet, and rubber stopper, 2-hydroxy-N, N, 2-tris (4-methoxyphenyl) propionamide (0.60g, 1.47mmol) was dissolved in 30mL anhydrous dichloromethane. Adding BBr dropwise under the condition of stirring at 0 DEG C₃Solution (6.00mL 1M CH₂Cl₂Solution, 6.00 mmol). The reaction solution was stirred at room temperature overnight. The reaction was quenched by the addition of 20mL of water and extracted with EtOAc (3X 30 mL). The EtOAc layer was separated and passed over anhydrous MgSO₄And (5) drying. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography (silica gel, CH)₂Cl₂9/1v/v) to yield the product as a white solid, 2-hydroxy-N, 2-tri (4-hydroxyphenyl) propionamide (11k), 0.42g, 77.8% yield.

Example 16:

toremifene lowers total LDL cholesterol and triglycerides and raises HDL in prostate cancer patients undergoing Androgen Deprivation Therapy (ADT)

The method comprises the following steps:

1392 men, 50 or over 50 years old, had a history of prostate cancer and received ADT and were classified in human clinical trials as either toremifene (80mg/day) or placebo treated groups. The mid-term analysis evaluated the change in blood fat levels from baseline to 12 months in the first 197 individuals to complete their first year determination of the change in the ratio of total cholesterol, Low Density Lipoprotein (LDL) cholesterol, High Density Lipoprotein (HDL) cholesterol, triglycerides and total circulating cholesterol to HDL levels in the individual individuals.

As a result:

prostate cancer patients who received toremifene who had undergone Androgen Deprivation Therapy (ADT) were compared to placebo. Toremifene treatment resulted in lower total blood cholesterol (-7.1%; p ═ 0.001), LDL (-9.0%; p ═ 0.003), and triglyceride (-20.1%; p ═ 0.009) levels, with a reduced total cholesterol/HDL ratio (-11.7%; p < 0.001), and higher HDL levels (+ 5.4%; p ═ 0.018) (fig. 1).

Patients given concomitant statins showed further reductions in total cholesterol, however the fat changes produced by toremifene treatment were orders of magnitude greater than those patients who did not concomitantly take statins. Thus, patients treated with toremifene had a statistically significant improvement in all of the serum lipid parameters determined.

Example 17:

exemplary SERM Compounds that lower LDL Cholesterol levels

The method comprises the following steps:

other SERM compounds than toremifene can be similarly evaluated in clinical trials. The following compounds can be similarly administered as described in example 1, and their effects on altering lipid profiles in subjects with prostate cancer undergoing ADT are similarly evaluated. Some of the compounds thus evaluated include:

compound (1): n, N-bis (4-hydroxyphenyl) -3, 4-dimethylbenzamide;

compound (2): n, N-bis (4-hydroxyphenyl) -4-propylbenzamide;

compound (3): 3-fluoro-4-hydroxy-N- (4-hydroxyphenyl) -N-phenylbenzamide;

compound (4): n, N-bis (4-hydroxyphenyl) -4-pentylbenzamide; and/or

Ospemifene (Ospemifene).

While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those skilled in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.

Claims

1. A nuclear receptor binding agent or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof, represented by the structure of formula I:

wherein

Wherein

R₆And R₇Independently is R₁、R₂Or R₃；

z is O, NH, CH ₂Or

Q is SO₃H、CO₂H、CO₂R、NO₂Tetrazole, SO₂NH₂Or SO₂NHR；

j. k, l are independently 1-5;

q is 1 to 5;

and is

2. The Nuclear Receptor Binding Agent (NRBA) of claim 1, wherein said 3-7 membered substituted or unsubstituted heterocyclic ring is optionally aromatic, represented by the structure of formula B:

wherein Y is CH₂CH, a bond, O, S, NH, N or NR;

if B is aryl, then z is 1; and if B is cycloalkyl, then z is 2;

m is 0 to 4;

n is 0 to 4;

where m and n cannot both be 0.

3. The Nuclear Receptor Binding Agent (NRBA) of claim 2, wherein formula B is a substituted or unsubstituted piperidine, pyrrolidine, morpholine, or piperazine.

4. The Nuclear Receptor Binding Agent (NRBA) of claim 1, wherein said pharmaceutically acceptable salt is an HCl salt.

5. The Nuclear Receptor Binding Agent (NRBA) or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof of claim 1, represented by the structure of formula I:

wherein

R₆And R₇Independently is R₁、R₂Or R₃；

Z is O, NH, CH₂Or

Q is SO₃H、CO₂H、CO₂R、NO₂Tetrazole, SO₂NH₂Or SO₂NHR；

j. k, l are independently 1-5;

q is 1 to 5;

6. The Nuclear Receptor Binding Agent (NRBA) of claim 5, wherein said 3-7 membered substituted or unsubstituted heterocyclic ring, optionally aromatic, is represented by the structure of formula B:

wherein Y is CH₂CH, a bond, O, S, NH, N or NR;

if B is aryl, then z is 1; and if B is cycloalkyl, then z is 2;

m is 0 to 4;

n is 0 to 4;

where m and n cannot both be 0.

7. The Nuclear Receptor Binding Agent (NRBA) of claim 5, wherein formula B is a substituted or unsubstituted piperidine, pyrrolidine, morpholine, or piperazine.

8. The Nuclear Receptor Binding Agent (NRBA) of claim 5, wherein said pharmaceutically acceptable salt is the HCl salt.

9. The Nuclear Receptor Binding Agent (NRBA) or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof of claim 1, represented by the structure of formula II:

R₁、R₂And R₃Independently hydrogen, aldehyde, COOH, CHNOH, CH ═ CHCO₂H. Hydroxyalkyl, halogen, hydroxy, alkoxy, cyano, nitro, CF₃、NH₂、NHR、NHCOR、N(R)₂Sulfonamide, SO₂R, alkyl, aryl, protected hydroxy, OCH₂CH₂NR₄R₅、Z-Alk-Q、Z-Alk-NR₄R₅Z-Alk-heterocycles or OCH₂CH₂-a heterocycle, wherein the heterocycle is a 3-7 membered substituted or unsubstituted heterocycle, optionally aromatic,

or R₁、R₂Or R₃A benzene ring to which the R group is attachedTogether forming a fused ring system represented by structure A

Wherein:

R₆and R₇Independently is R₁、R₂Or R₃；

z is O, NH, CH₂Or

Q is SO₃H、CO₂H、CO₂R、NO₂Tetrazole, SO₂NH₂Or SO₂NHR；

q is 1 to 5;

and is

If X is (CH)₂)_qCO or C (O) (CH)₂)_qAnd R is₂Is OCH₂CH₂NR₄R₅Or OCH₂CH₂-heterocyclic ring, then R₁Or R₃Is not hydrogen, lower alkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro or amino;

If X is (CH)₂)_qCO or C (O) (CH)₂)_qAnd R is₃Is OCH₂CH₂NR₄R₅Or OCH₂CH₂-heterocyclic ring, then R₁Or R₂Is other than hydrogen, lower alkyl: (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro or amino.

10. The Nuclear Receptor Binding Agent (NRBA) compound of claim 8, wherein the 3-7 membered substituted or unsubstituted heterocyclic ring, optionally aromatic, is represented by the structure of formula B:

wherein Y is CH₂CH, a bond, O, S, NH, N or NR;

if B is aryl, then z is 1; and if B is cycloalkyl, then z is 2;

m is 0 to 4;

n is 0 to 4;

where m and n cannot both be 0.

11. The Nuclear Receptor Binding Agent (NRBA) of claim 10, wherein formula B is a substituted or unsubstituted piperidine, pyrrolidine, morpholine, or piperazine.

12. The Nuclear Receptor Binding Agent (NRBA) of claim 9, wherein said pharmaceutically acceptable salt is an HCl salt.

13. The Nuclear Receptor Binding Agent (NRBA) or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof of claim 1, represented by the structure of formula II:

Wherein

R₆And R₇Independently is R₁、R₂Or R₃；

z is O, NH, CH₂Or

Q is SO₃H、CO₂H、CO₂R、NO₂Tetrazole, SO₂NH₂Or SO₂NHR；

14. The Nuclear Receptor Binding Agent (NRBA) of claim 13, wherein said 3-7 membered substituted or unsubstituted heterocyclic ring, optionally aromatic, is represented by the structure of formula B:

Wherein Y is CH₂CH, a bond, O, S, NH, N or NR;

r is alkyl, hydrogen, CN, NO₂Haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F、CHF₂、CF₃、CF₂CF₃Aryl, phenyl, halogen, alkenyl or OH;

if B is aryl, then z is 1; if B is cycloalkyl, then z is 2;

m is 0 to 4;

n is 0 to 4;

where m and n cannot both be 0.

15. The Nuclear Receptor Binding Agent (NRBA) of claim 14, wherein formula B is a substituted or unsubstituted piperidine, pyrrolidine, morpholine, or piperazine.

16. The Nuclear Receptor Binding Agent (NRBA) of claim 13, wherein said pharmaceutically acceptable salt is an HCl salt.

17. The Nuclear Receptor Binding Agent (NRBA) or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof of claim 1, represented by the structure of formula VII:

Or X is CO and OH is in meta or ortho position.

18. A Selective Estrogen Receptor Modulator (SERM) compound or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof according to claim 1, represented by the structure of formula VIII:

Wherein X is CO, CS, (CH)₂)_qBranched alkyl, branched alkyl having a haloalkyl side chain, haloalkyl, C (O) (CH)₂)_qSO or SO₂(ii) a And is

If X is CO, the hydroxyl group is not in the para position.

19. The nuclear receptor binding compound of claim 1, or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof, represented by the structure of formula IX:

wherein X is CO, CS, (CH)₂)_qBranched alkyl, branched alkyl having a haloalkyl side chain, haloalkyl, C (O) (CH)₂)_q、SO or SO₂；

R₄And R₅Independently hydrogen, phenyl, alkyl of 1 to 6 carbon atoms, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, 3-7 membered heteroaryl, or R₄And R₅Together with the nitrogen atom, form a 3-7 membered heterocyclic ring, optionally aromatic, represented by the structure of formula B:

wherein Y is CH₂CH, a bond, O, S, NH, N or NR;

if B is aryl, then z is 1; and if B is cycloalkyl, then z is 2;

m is 0 to 4;

n is 0 to 4;

wherein m and n cannot both be 0;

q is 1 to 5;

p is 1 to 4;

r is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F、CHF₂、CF₃、CF₂CF₃Aryl, phenyl, halogen, alkenyl, CN, NO ₂Or OH.

20. The Nuclear Receptor Binding Agent (NRBA) of claim 19, wherein formula B is piperidine, pyrrolidine, morpholine, or piperazine.

21. The Nuclear Receptor Binding Agent (NRBA) of claim 19, wherein said pharmaceutically acceptable salt is an HCl salt.

22. The Nuclear Receptor Binding Agent (NRBA) of claim 1, wherein said compound is a Selective Estrogen Receptor Modulator (SERM).

23. The Nuclear Receptor Binding Agent (NRBA) of claim 1, wherein the compound is:

4-methoxy-N, N-bis- (4-methoxyphenyl) -benzamide (2 a);

3-methoxy-N, N-bis- (4-methoxyphenyl) -benzamide (2 b);

4-methoxy-N- (4-methoxyphenyl) -N- (3-methoxyphenyl) -benzamide (2 c);

n, N-bis- (4-methoxyphenyl) -benzamide (2 d);

4-methoxy-N, N-diphenyl-benzamide (2e).

3-methoxy-N, N-diphenyl-benzamide (2 f);

n, N-diphenyl-benzamide (2 g);

n- (4-methoxyphenyl) -N-phenyl-benzamide (2 h);

n- (3-methoxyphenyl) -N-phenyl-benzamide (2 i);

4-methoxy-N- (4-methoxyphenyl) -N-phenyl-benzamide (2 j);

4-methoxy-N- (3-methoxyphenyl) -N-phenyl-benzamide (2 k);

n, N-bis (4-methoxyphenyl) -4-fluorobenzamide (2l)

4-methoxy-N, N-diphenyl-sulfonamide (2 m);

4-methoxy-N- (4-methoxyphenyl) -N- (4-fluorophenyl) -benzamide (2N);

4-methoxy-N- (4-methoxyphenyl) -N- (1-naphthyl) -benzamide (2 o);

n- (4-methoxyphenyl) -N- (4-benzyloxyphenyl) -1-naphthamide (2 p);

4-chloro-N- (4-methoxyphenyl) -N- (4-benzyloxyphenyl) -benzamide (2 q);

4-cyano-N- (4-methoxyphenyl) -N- (4-benzyloxyphenyl) -benzamide (2 r);

n- (4-methoxyphenyl) -N- (4-benzyloxyphenyl) -2-naphthamide (2 s);

4- (benzyloxy) -N- [4- (benzyloxy) phenyl ] -N- (4-methoxyphenyl) benzamide (2 t);

n- [4- (benzyloxy) phenyl ] -4-methoxy-N- (4-methoxyphenyl) benzamide (2 u);

n- [4- (benzyloxy) phenyl ] -N-biphenyl-4-yl-4-methoxybenzamide (2 v);

4-cyano-N- (4-methoxyphenyl) -N-phenylbenzamide (2 w);

3-methoxy-N- (4-methoxyphenyl) -N-phenylbenzamide (2 ×);

4-cyano-N- (3-methoxyphenyl) -N-phenylbenzamide (2 y);

4-cyano-N, N-diphenylbenzamide (2 z);

n, N-bis- (4-methoxyphenyl) -benzamide (2 d);

n, N-diphenyl-benzamide (2 g);

n- (4-methoxyphenyl) -N-phenyl-benzamide (2 h);

N- (3-methoxyphenyl) -N-phenyl-benzamide (2 i);

4-methoxy-N- (4-methoxyphenyl) -N-phenyl-benzamide (2 j);

4-methoxy-N- (3-methoxyphenyl) -N-phenyl-benzamide (2 k);

4-cyano-N- (4-methoxyphenyl) -N-phenylbenzamide (2 w);

4-cyano-N- (3-methoxyphenyl) -N-phenylbenzamide (2 y);

4-cyano-N, N-diphenylbenzamide (2 z);

4-hydroxy-N, N-bis- (4-hydroxyphenyl) -benzamide (3 a);

3-hydroxy-N-bis- (4-hydroxyphenyl) -benzamide (3 b);

4-hydroxy-N- (4-hydroxyphenyl) -N- (3-hydroxyphenyl) -benzamide (3 c);

n, N-bis- (4-hydroxyphenyl) -benzamide (3 d);

4-hydroxy-N, N-diphenyl-benzamide (3 e);

3-hydroxy-N, N-diphenyl-benzamide (3 f);

n- (4-hydroxyphenyl) -N-phenyl-benzamide (3 g);

n- (3-hydroxyphenyl) -N-phenyl-benzamide (3 h);

4-hydroxy-N- (4-hydroxyphenyl) -N-phenyl-benzamide (3 i);

4-hydroxy-N- (3-hydroxyphenyl) -N-phenyl-benzamide (3 j);

n, N-bis (4-hydroxyphenyl) -4-fluorobenzamide (3 k);

4-hydroxy-N, N-diphenyl-phenyl-sulfonamide (3 l);

4-hydroxy-N- (4-hydroxyphenyl) -N- (fluorophenyl) -benzamide (3 m);

n, N-bis (4-hydroxyphenyl) -1-naphthamide (3N);

4-hydroxy-N- (1-naphthyl) -N- (4-hydroxyphenyl) -benzamide (3 o);

4-cyano-N, N-bis (4-hydroxyphenyl) -benzamide (3 p);

3-cyano-N, N-bis (4-hydroxyphenyl) -benzamide (3 q);

n, N-bis (4-hydroxyphenyl) -2-naphthamide (3 r);

4-cyano-N- [4- (2-piperidin-1-ylethoxy) -phenyl ] -N- (4-hydroxyphenyl) -benzamide (3 s);

3-chloro-N- [4- (2-piperidin-1-ylethoxy) -phenyl ] -N- (4-hydroxyphenyl) -benzamide (3 t);

N-biphenyl-4-yl-N- (4-hydroxyphenyl) -4-methoxybenzamide (3 u);

N-biphenyl-4-yl-4-hydroxy-N- (4-hydroxyphenyl) -benzamide (3 v);

4-hydroxy-N- (4-hydroxyphenyl) -N- [4- (2-piperidin-1-ylethoxy) phenyl ] -benzamide (3 w);

3-hydroxy-N- (4-hydroxyphenyl) -N-phenyl-benzamide (3 x);

N-biphenyl-4-yl-4-hydroxy-N- [4- (2-piperidin-1-ylethoxy) phenyl ] -benzamide (3 y);

n- (4-hydroxyphenyl) -N- [4- (2-piperidin-1-ylethoxy) -phenyl ] -benzamide (4 a);

n, N-diphenyl- [3- (2-piperidinylethoxy) ] -benzamide hydrochloride (4 c);

n- (4-hydroxyphenyl) -N-phenyl- [4- (2-piperidin-1-ylethoxy) ] -benzamide hydrochloride (4 e);

n, N-diphenyl-bis [4- (2-piperidin-1-ylethoxy) -phenyl ] -sulfonamide hydrochloride (4 f);

N- (4-fluorophenyl) -N- [ 4-hydroxyphenyl ] - [4- (2-piperidin-1-ylethoxy) ] -benzamide (4 g);

n- (4-hydroxyphenyl) -N- [4- (2-piperidin-1-ylethoxy) -phenyl ] -4-fluoro-benzamide hydrochloride (4 h);

3- (2-piperidin-1-ylethoxy) -N, N-bis (4-hydroxyphenyl) -benzamide (4 i);

4-cyano-N- [4- (2-piperidin-1-ylethoxy) -phenyl ] -N- (4-methoxyphenyl) -benzamide (4 j);

4-chloro-N- [4- (2-piperidin-1-ylethoxy) -phenyl ] -N- (4-methoxyphenyl) -benzamide (4 k);

4-cyano-N- [4- (2-piperidin-1-ylethoxy) -phenyl ] -N- (4-hydroxyphenyl) -benzamide (4 l);

N-biphenyl-4-yl-N- (4-hydroxyphenyl) -4- (2-piperidin-1-ylethoxy) -benzamide (4 o);

n- (4-hydroxyphenyl) -N-phenyl-3- (2-piperidin-1-ylethoxy) -benzamide (4 q);

n- (4-fluorophenyl) -N- [4- (2-piperidin-1-ylethoxy) -phenyl ] - [4- (2-piperidin-1-yl-ethoxy) ] -benzamide dihydrochloride (4 r);

n, N-bis [4- (2-piperidin-1-ylethoxy) -phenyl ] -4-fluoro-benzamide dihydrochloride (4 s);

n, N-bis [4- (2-piperidin-1-ylethoxy) -phenyl ] -benzamide dihydrochloride (4 t);

n- [4- (2-piperidin-1-ylethoxy) -phenyl ] -N-phenyl- [4- (2-piperidin-1-ylethoxy) ] -benzamide dihydrochloride (4 u);

4-chloro-N- [ 4-hydroxyphenyl ] -N- (4-methoxyphenyl) -benzamide (5 a);

4-cyano-N- [ 4-hydroxyphenyl ] -N- (4-methoxyphenyl) -benzamide (5 b);

3-chloro-N- [ 4-hydroxyphenyl ] -N- (4-methoxyphenyl) -benzamide (5 c);

4-hydroxy-N- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -benzamide (5 d);

n- (4-hydroxyphenyl) -4-methoxy-N- (4-methoxyphenyl) -benzamide (5 e);

4-cyano-N- (4-hydroxyphenyl) -N-phenylbenzamide (10 a);

n- (biphenyl-4-yl) -4-cyano-N- (4-methoxyphenyl) -benzamide (10 b);

n, N-bis (4-hydroxyphenyl) biphenyl-4-carboxamide (10 c);

n, N-bis (4-hydroxyphenyl) -3, 4-dimethylbenzamide (10 d);

n- (biphenyl-4-yl) -4-cyano-N- (4-hydroxyphenyl) -benzamide (10 e);

n, N-bis (4-hydroxyphenyl) -4-propylbenzamide (10 l);

3, 4-dihydroxy-N, N-bis (4-hydroxyphenyl) -benzamide (10 m);

n- (4-hydroxyphenyl) -N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) -4-propylbenzamide (10 o);

n- (4-hydroxyphenyl) -2, 3-dimethyl-N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) -benzamide (10 p);

n, N-bis (4-hydroxyphenyl) -2, 4-dimethylbenzamide (10 q);

n, N-bis (4-hydroxyphenyl) -3, 5-dimethylbenzamide (10 r);

N, N-bis (4-hydroxyphenyl) -4-methylbenzamide (10 s);

4, 4' - (2, 3-dimethylbenzylazaldi) diphenol (10 t);

4-formyl-N, N-bis (4-hydroxyphenyl) -benzamide (10 u);

N-cyclohexyl-4-hydroxy-N- (4-hydroxyphenyl) benzamide (10 w);

4- ((4-fluorophenyl) (4-hydroxybenzyl) amino) phenol (10 ×);

n- (4- (2- (dimethylamino) ethoxy) phenyl) -N- (4-hydroxyphenyl) benzamide (10 y);

3-cyano-N- (4-hydroxyphenyl) -N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) benzamide (10 z);

n- (4-hydroxyphenyl) -N- (4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) benzamide (11 a);

n, N-bis (4-hydroxyphenyl) -4- (trifluoromethyl) benzamide (11 b);

n- (4-hydroxyphenyl) -N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) -4- (trifluoromethyl) benzamide (11 c);

n, N-bis (4-hydroxyphenyl) -4-nitrobenzamide (11 d);

3-fluoro-N, N-bis (4-hydroxyphenyl) benzamide (11 e);

n- (4-hydroxyphenyl) -N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) -1-naphthamide (11 f);

3-fluoro-N- (4-hydroxyphenyl) -N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) benzamide (11 g);

n- (4-hydroxyphenyl) -4-nitro-N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) benzamide (11 h);

N, N-bis (4-hydroxyphenyl) -4-methoxy-1-naphthamide (11 i);

n- (4-hydroxyphenyl) -N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) -2-naphthamide (11 j);

2-hydroxy-N, 2-tris (4-hydroxyphenyl) propanamide (11 k);

4- ((hydroxyimino) methyl) -N, N-bis (4-hydroxyphenyl) benzamide (11 l);

n- (4-hydroxyphenyl) -2, 4-dimethyl-N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) benzamide (11 m);

n- (4-hydroxyphenyl) -3, 5-dimethyl-N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) benzamide (11N);

4- ((2, 3-dimethylbenzyl) (4- (2- (piperidin-1-yl) ethoxy) phenyl) amino) phenol (11 o);

n, N-bis (4-hydroxyphenyl) -4-pentylbenzamide (11 p);

n- (4-hydroxyphenyl) -4-pentyl-N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) benzamide (11 q);

4-tert-butyl-N, N-bis (4-hydroxyphenyl) benzamide (11 r);

4-tert-butyl-N- (4-hydroxyphenyl) -N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) benzamide (11 s);

3- {4- [ bis- (4-hydroxy-phenyl) -carbamoyl ] -phenyl } -acrylic acid (11 t);

3- {4- [ bis- (4-hydroxy-phenyl) -carbamoyl ] -phenyl } -propionic acid (11 u);

n, N-bis- (4-hydroxy-phenyl) -4- (3-hydroxy-propyl) -benzamide (11 v);

N- (4-hydroxyphenyl) -4- (3-hydroxypropyl) -N- (4-methoxyphenyl) -benzamide (11 w);

n- (4-hydroxyphenyl) -4-methyl-N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) benzamide (11 z); or any combination thereof.

24. The Nuclear Receptor Binding Agent (NRBA) of claim 23, wherein said compound is a Selective Estrogen Receptor Modulator (SERM).

25. A method of binding the Nuclear Receptor Binding Agent (NRBA) of claim 1 to an estrogen receptor or an estrogen-related receptor comprising the step of contacting the estrogen receptor with the SERM.

26. A composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 1 and a suitable carrier or diluent.

27. A method of treating, preventing or lessening the severity of osteoporosis in a subject, said method comprising administering to said subject a composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 1.

28. The method of claim 27, wherein the NRBA compound is an ER- α ligand.

29. A method of treating, preventing or reducing the risk of death from cardiovascular disease in a subject, comprising administering to the subject a composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 1.

30. The method of claim 29, wherein said Nuclear Receptor Binding Agent (NRBA) is an ER- β ligand.

31. A method of improving lipid profile in a subject, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 1.

32. A method of inhibiting, suppressing, treating or reducing the incidence of androgen blockade induced osteoporosis, bone fractures, and/or reduction in Bone Mineral Density (BMD) in a male with prostate cancer, the method comprising administering to a male subject in need of treatment with prostate cancer a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 1.

33. The method of claim 32, wherein said Nuclear Receptor Binding Agent (NRBA) is an ER- α ligand.

34. A method of ameliorating symptoms and/or clinical complications associated with menopause in a female subject, the method comprising administering to a female menopausal subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 1.

35. The method of claim 34, wherein said Nuclear Receptor Binding Agent (NRBA) is an ER- α ligand.

36. A method of treating, preventing or lessening the severity of alzheimer's disease in a subject, said method comprising administering to said subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 1.

37. The method of claim 36, wherein said Nuclear Receptor Binding Agent (NRBA) is an ER- α or ER- β ligand.

38. A method of treating, preventing, suppressing, inhibiting or reducing the incidence of hot flashes, male breast development and/or hair loss in a male subject suffering from prostate cancer, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 1.

39. The method of claim 38, wherein said Nuclear Receptor Binding Agent (NRBA) compound is an ER- α or ER- β ligand.

40. A method of treating, suppressing, inhibiting, or reducing the risk of developing prostate cancer in a subject, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) compound of claim 1.

41. The method of claim 40, wherein said Nuclear Receptor Binding Agent (NRBA) compound is an ER- α ligand or an ER- β ligand.

42. A method of treating, suppressing, inhibiting or reducing the amount of a pre-cancerous precursor of a prostate cancer lesion in a subject, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 1.

43. The method of claim 42, wherein said Nuclear Receptor Binding Agent (NRBA) compound is an ER- α ligand or an ER- β ligand.

44. The method of claim 42, wherein the pre-cancerous precursor of prostate cancer is Prostate Intraepithelial Neoplasia (PIN).

45. A method of treating, preventing, inhibiting or reducing the incidence of inflammation in a subject, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 1, thereby treating, preventing, inhibiting or reducing the incidence of inflammation in the subject.

46. The method of claim 45, wherein said Nuclear Receptor Binding Agent (NRBA) compound is an ER- β ligand.

47. A method of treating, preventing, inhibiting or reducing the risk of breast cancer in a subject, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 1.

48. The method of claim 47, wherein said Nuclear Receptor Binding Agent (NRBA) compound is an ER- α ligand.

49. A method of treating, preventing, inhibiting or reducing the risk of endometrial cancer in a subject, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) compound of claim 1.

50. The method of claim 49, wherein said Nuclear Receptor Binding Agent (NRBA) compound is an ER- α ligand.

51. A method of treating, preventing, inhibiting, or reducing the risk of bladder cancer in a subject, comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 1.

52. A method of treating, preventing, inhibiting or reducing the risk of colon cancer in a subject, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 1.

53. The method of claim 52, wherein said Nuclear Receptor Binding Agent (NRBA) is an ER- β ligand.

54. A method of treating, preventing, inhibiting or reducing the risk of leukemia in a subject, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 1.

55. The method of claim 54 wherein said Nuclear Receptor Binding Agent (NRBA) compound is an ER- β ligand.

56. A Nuclear Receptor Binding Agent (NRBA) or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof, represented by the structure of formula III:

wherein

A is a ring selected from:

b is a ring selected from:

c is a ring selected from:

W₁And W₂Independently hydrogen, halogen, aldehyde, COOH, CHNOH, CH ═ CHCO ₂H. Hydroxyalkyl, hydroxy, alkoxy, cyano, nitro, CF₃、NH₂、NHR、NHCOR、N(R)₂Sulfonamide, SO₂R, alkyl, aryl, protected hydroxy, OCH₂CH₂NR₄R₅、Z-Alk-Q、Z-Alk-NR₄R₅Z-Alk-heterocycles or OCH₂CH₂-a heterocycle, wherein the heterocycle is a 3-7 membered substituted or unsubstituted heterocycle, optionally aromatic;

r is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F、CHF₂，CF₃、CF₂CF₃Aryl, phenyl, halogen, alkenyl, CN, NO₂Or OH;

z is O, NH, CH₂Or

Q is SO₃H、CO₂H、CO₂R、NO₂Tetrazole, SO₂NH₂Or SO₂NHR；

n is 0 to 5;

q is 1 to 5;

and A, B and C cannot be both benzene rings; and is

57. The Nuclear Receptor Binding Agent (NRBA) of claim 56, wherein said 3-7 membered substituted or unsubstituted heterocyclic ring, optionally aromatic, is represented by the structure of formula B:

wherein Y is CH₂CH, a bond, O, S, NH, N or NR;

if B is aryl, then z is 1; and if B is cycloalkyl, then z is 2;

m is 0 to 4;

n is 0 to 4;

where m and n cannot both be 0.

58. The Nuclear Receptor Binding Agent (NRBA) of claim 57, wherein formula B is a substituted or unsubstituted piperidine, pyrrolidine, morpholine, or piperazine.

59. The Nuclear Receptor Binding Agent (NRBA) of claim 56 wherein said pharmaceutically acceptable salt is the HCl salt.

60. The Nuclear Receptor Binding Agent (NRBA) of claim 56, wherein said compound is a Selective Estrogen Receptor Modulator (SERM).

61. The Nuclear Receptor Binding Agent (NRBA) of claim 56, wherein said compound is:

cyclohexane-carboxylic acid bis (4-hydroxyphenyl) -amide (8 b);

n, N-bis (4-hydroxyphenyl) -isonicotinamide (11 aa);

n- (4-hydroxyphenyl) -N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) -isonicotinamide (11 ab);

Or any combination thereof.

62. The nuclear receptor binding agent of claim 61, wherein the compound is a Selective Estrogen Receptor Modulator (SERM).

63. A method of binding the Nuclear Receptor Binding Agent (NRBA) of claim 56 to an estrogen receptor or an estrogen-related receptor comprising the step of contacting the estrogen receptor with said SERM.

64. A composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 63 and a suitable carrier or diluent.

65. A method of treating, preventing or lessening the severity of osteoporosis in a subject, said method comprising administering to said subject a composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 56.

66. The method of claim 65, wherein the NRBA compound is an ER- α ligand.

67. A method of treating, preventing or reducing the risk of death from cardiovascular disease in a subject, comprising administering to the subject a composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 56.

68. The method of claim 67, wherein said Nuclear Receptor Binding Agent (NRBA) is an ER- β ligand.

69. A method of improving lipid profile in a subject, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 56.

70. A method of inhibiting, suppressing, treating, or reducing the incidence of androgen blockade induced osteoporosis, bone fractures, and/or Bone Mineral Density (BMD) reduction in a male with prostate cancer, comprising administering to a male subject in need of treatment with prostate cancer a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 56.

71. The method of claim 70, wherein said Nuclear Receptor Binding Agent (NRBA) is an ER- α ligand.

72. A method of ameliorating symptoms and/or clinical complications associated with menopause in a female subject, the method comprising administering to a female menopausal subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 56.

73. The method of claim 72, wherein said Nuclear Receptor Binding Agent (NRBA) is an ER- α ligand.

74. A method of treating, preventing or lessening the severity of Alzheimer's disease in a subject, said method comprising administering to said subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 56.

75. The method of claim 74, wherein said Nuclear Receptor Binding Agent (NRBA) is an ER- α or ER- β ligand.

76. A method of treating, preventing, suppressing, inhibiting or reducing the incidence of hot flashes, male breast development and/or hair loss in a male subject suffering from prostate cancer, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 56.

77. The method of claim 76, wherein said Nuclear Receptor Binding Agent (NRBA) compound is an ER- α or ER- β ligand.

78. A method of treating, suppressing, inhibiting, or reducing the risk of developing prostate cancer in a subject, comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) compound of claim 56.

79. The method of claim 78, wherein said Nuclear Receptor Binding Agent (NRBA) compound is an ER- α ligand or an ER- β ligand.

80. A method of treating, suppressing, inhibiting or reducing the amount of a pre-cancerous precursor damaged by prostate cancer in a subject, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 56.

81. The method of claim 80, wherein said Nuclear Receptor Binding Agent (NRBA) compound is an ER- α ligand or an ER- β ligand.

82. The method of claim 80, wherein the pre-cancerous precursor of prostate cancer is Prostate Intraepithelial Neoplasia (PIN).

83. A method of treating, preventing, inhibiting, or reducing the incidence of inflammation in a subject, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 56, thereby treating, preventing, inhibiting, or reducing the incidence of inflammation in the subject.

84. The method of claim 83, wherein said Nuclear Receptor Binding Agent (NRBA) compound is an ER- β ligand.

85. A method of treating, preventing, inhibiting, or reducing the risk of breast cancer in a subject, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 56.

86. The method of claim 85, wherein said Nuclear Receptor Binding Agent (NRBA) compound is an ER- α ligand.

87. A method of treating, preventing, inhibiting or reducing the risk of endometrial cancer in a subject, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) compound of claim 56.

88. The method of claim 87, wherein said Nuclear Receptor Binding Agent (NRBA) compound is an ER- α ligand.

89. A method of treating, preventing, inhibiting, or reducing the risk of bladder cancer in a subject, comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 56.

90. A method of treating, preventing, inhibiting, or reducing the risk of colon cancer in a subject, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 56.

91. The method of claim 90, wherein said Nuclear Receptor Binding Agent (NRBA) compound is an ER- β ligand.

92. A method of treating, preventing, inhibiting, or reducing the risk of leukemia in a subject, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) compound of claim 56.

93. The method of claim 92, wherein said Nuclear Receptor Binding Agent (NRBA) is an ER- β ligand.

94. A Nuclear Receptor Binding Agent (NRBA) or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof, represented by the structure of formula IV:

wherein

R₁、R₂And R₃Independently hydrogen, halogen, aldehyde, COOH, CHNOH, CH ═ CHCO₂H. Hydroxyalkyl, hydroxy, alkoxy, cyanoNitro, CF₃、NH₂、NHR、NHCOR、N(R)₂Sulfonamide, SO₂R, alkyl, aryl, protected hydroxy, OCH₂CH₂NR₄R₅、Z-Alk-Q、Z-Alk-NR₄R₅Z-Alk-heterocycles or OCH₂CH₂-a heterocycle, wherein the heterocycle is a 3-7 membered substituted or unsubstituted heterocycle, optionally aromatic,

Wherein:

R₆and R₇Independently is R₁、R₂Or R₃；

z is O, NH, CH₂Or

Q is SO₃H、CO₂H、CO₂R、NO₂Tetrazole, SO₂NH₂Or SO₂NHR；

j. k, l are independently 1-5;

q is 1 to 5;

95. The Nuclear Receptor Binding Agent (NRBA) of claim 94, wherein said 3-7 membered substituted or unsubstituted heterocyclic ring, optionally aromatic, is represented by the structure of formula B:

wherein Y is CH₂CH, a bond, O, S, NH, N or NR;

if B is aryl, then z is 1; and if B is cycloalkyl, then z is 2;

m is 0 to 4;

n is 0 to 4;

where m and n cannot both be 0.

96. The Nuclear Receptor Binding Agent (NRBA) of claim 95, wherein formula B is a substituted or unsubstituted piperidine, pyrrolidine, morpholine, or piperazine.

97. The Nuclear Receptor Binding Agent (NRBA) of claim 94, wherein said pharmaceutically acceptable salt is the HCl salt.

98. The Nuclear Receptor Binding Agent (NRBA) or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof of claim 94, represented by the structure of formula V:

x is CO, CS, (CH)₂)_qBranched alkyl, branched alkyl having a haloalkyl side chain, haloalkylRadical, C (O) (CH)₂)_qSO or SO₂；

Wherein

R₆And R₇Independently is R₁、R₂Or R₃；

Z is O, NH, CH₂Or

Q is SO₃H、CO₂H、CO₂R、NO₂Tetrazole, SO₂NH₂Or SO₂NHR；

q is 1 to 5;

99. The Nuclear Receptor Binding Agent (NRBA) of claim 98, wherein the 3-7 membered substituted or unsubstituted heterocyclic ring, optionally aromatic, is represented by the structure of formula B:

wherein Y is CH₂CH, a bond, O, S, NH, N or NR;

if B is aryl, then z is 1; and if B is cycloalkyl, then z is 2;

m is 0 to 4;

n is 0 to 4;

where m and n cannot both be 0.

100. The Nuclear Receptor Binding Agent (NRBA) of claim 99, wherein formula B is a substituted or unsubstituted piperidine, pyrrolidine, morpholine, or piperazine.

101. The Nuclear Receptor Binding Agent (NRBA) of claim 98, wherein the pharmaceutically acceptable salt is an HCl salt.

102. The Nuclear Receptor Binding Agent (NRBA) of claim 94, wherein said compound is:

5- [ 4-methoxy-phenyl ] -5H-phenanthridin-6-one (7 a);

5- [ 4-hydroxy-phenyl ] -5H-phenanthridin-6-one (7 b);

5- [4- (2-piperidin-1-ylethoxy) -phenyl ] -5H-phenanthridin-6-one (7 c);

Or any combination thereof.

103. The Nuclear Receptor Binding Agent (NRBA) compound of claim 102, wherein the compound is a Selective Estrogen Receptor Modulator (SERM).

104. A method of binding the Nuclear Receptor Binding Agent (NRBA) compound of claim 94 to an estrogen receptor or an estrogen-related receptor comprising the step of contacting the estrogen receptor with said SERM.

105. A composition comprising the Nuclear Receptor Binding Agent (NRBA) compound of claim 94 and a suitable carrier or diluent.

106. A method of treating, preventing or reducing the severity of osteoporosis in a subject, said method comprising administering to said subject a composition comprising a Nuclear Receptor Binding Agent (NRBA) compound according to claim 94.

107. The method of claim 106, wherein the NRBA is an ER- α ligand.

108. A method of treating, preventing, or reducing the risk of death from a cardiovascular disease in a subject, comprising administering to the subject a composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 94.

109. The method of claim 108, wherein said Nuclear Receptor Binding Agent (NRBA) is an ER- β ligand.

110. A method of improving lipid profile in a subject, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) compound of claim 94.

111. A method of inhibiting, suppressing, treating, or reducing the incidence of androgen blockade induced osteoporosis, bone fractures, and/or Bone Mineral Density (BMD) reduction in a male with prostate cancer, the method comprising administering to a male subject in need of treatment with prostate cancer a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) compound of claim 94.

112. The method of claim 111, wherein said Nuclear Receptor Binding Agent (NRBA) compound is an ER- α ligand.

113. A method of ameliorating symptoms and/or clinical complications associated with menopause in a female subject, said method comprising administering to a female menopausal subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 94.

114. The method of claim 113, wherein said Nuclear Receptor Binding Agent (NRBA) is an ER- α ligand.

115. A method of treating, preventing or lessening the severity of alzheimer's disease in a subject, said method comprising administering to said subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) compound of claim 94.

116. The method of claim 115, wherein said Nuclear Receptor Binding Agent (NRBA) compound is an ER- α or ER- β ligand.

117. A method of treating, preventing, suppressing, inhibiting or reducing the incidence of hot flashes, male breast development and/or hair loss in a male subject suffering from prostate cancer, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) compound of claim 94.

118. The method of claim 117, wherein said Nuclear Receptor Binding Agent (NRBA) is an ER- α or ER- β ligand.

119. A method of treating, suppressing, inhibiting, or reducing the risk of developing prostate cancer in a subject, comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) compound of claim 94.

120. The method of claim 119, wherein said Nuclear Receptor Binding Agent (NRBA) is an ER- α ligand or an ER- β ligand.

121. A method of treating, suppressing, inhibiting or reducing the amount of a pre-cancerous precursor of a prostate cancer lesion in a subject, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 94.

122. The method of claim 121, wherein said Nuclear Receptor Binding Agent (NRBA) is an ER- α ligand or an ER- β ligand.

123. The method of claim 121, wherein the pre-cancerous precursor of prostate cancer is Prostate Intraepithelial Neoplasia (PIN).

124. A method of treating, preventing, inhibiting or reducing the incidence of inflammation in a subject, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 94, thereby treating, preventing, inhibiting or reducing the incidence of inflammation in the subject.

125. The method of claim 124, wherein said Nuclear Receptor Binding Agent (NRBA) is an ER- β ligand.

126. A method of treating, preventing, inhibiting, or reducing the risk of breast cancer in a subject, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 94.

127. The method of claim 126, wherein said Nuclear Receptor Binding Agent (NRBA) is an ER- α ligand.

128. A method of treating, preventing, inhibiting or reducing the risk of endometrial cancer in a subject, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 94.

129. The method of claim 128, wherein said Nuclear Receptor Binding Agent (NRBA) is an ER- α ligand.

130. A method of treating, preventing, inhibiting, or reducing the risk of bladder cancer in a subject, comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 94.

131. A method of treating, preventing, inhibiting, or reducing the risk of colon cancer in a subject, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) compound of claim 94.

132. The method of claim 131, wherein the Nuclear Receptor Binding Agent (NRBA) is an ER- β ligand.

133. A method of treating, preventing, inhibiting, or reducing the risk of leukemia in a subject, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 94.

134. The method of claim 133, wherein the Nuclear Receptor Binding Agent (NRBA) compound is an ER- β ligand.

135. A Nuclear Receptor Binding Agent (NRBA) or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof, represented by the structure of formula X:

wherein

R₁、R₂、R₃、R₈、R₉、R₁₀、R₁₁、R₁₂And R₁₃Independently hydrogen, halogen, aldehyde, COOH, CHNOH, CH ═ CHCO₂H. Hydroxyalkyl, hydroxy, alkoxy, cyano, nitro, CF₃、NH₂、NHR、NHCOR、N(R)₂Sulfonamide, SO₂R, alkyl, aryl, protected hydroxy, OCH₂CH₂NR₄R₅、Z-Alk-Q、Z-Alk-NR₄R₅Z-Alk-heterocycles or OCH₂CH₂-a heterocycle, wherein the heterocycle is a 3-7 membered substituted or unsubstituted heterocycle, optionally aromatic,

Wherein

R₆And R₇Independently is R₁、R₂Or R₃；

R₄and R₅Independently hydrogen, phenyl, alkyl of 1 to 6 carbon atoms, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, 3-7 membered heteroaryl, or R₄And R₅With nitrogenThe atoms taken together form a 3-7 heterocyclic ring, optionally aromatic, represented by the structure of formula B:

wherein Y is CH₂CH, a bond, O, S, NH, N or NR;

if B is aryl, then z is 1; and if B is cycloalkyl, then z is 2;

m is 0 to 4;

n is 0 to 4;

wherein m and n cannot both be 0;

q is 1 to 5;

p is 1 to 4;

z is O, NH, CH₂Or

Q is SO₃H、CO₂H、CO₂R、NO₂Tetrazole, SO₂NH₂Or SO₂NHR；

J. k, l are independently 1-3;

q is 1 to 5;

and is

R₁Or R₃Not being hydrogen, lower alkyl (1-4 carbons),Lower alkoxy (1-4 carbons), halogen, nitro or amino;

136. The Nuclear Receptor Binding Agent (NRBA) compound of claim 135, wherein formula B is piperidine, pyrrolidine, morpholine, or piperazine.

137. The Nuclear Receptor Binding Agent (NRBA) of claim 135, wherein the pharmaceutically acceptable salt is an HCl salt.

138. The Nuclear Receptor Binding Agent (NRBA) or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof of claim 135, represented by the structure of formula VI:

wherein

R₁、R₂、R₃、R₈、R₉And R₁₀Independently hydrogen, halogen, aldehyde, COOH, CHNOH, CH ═ CHCO ₂H. Hydroxyalkyl, hydroxy, alkoxy, cyano, nitro,CF₃、NH₂、NHR、NHCOR、N(R)₂Sulfonamide, SO₂R, alkyl, aryl, protected hydroxy, OCH₂CH₂NR₄R₅、Z-Alk-Q、Z-Alk-NR₄R₅Z-Alk-heterocycles or OCH₂CH₂-a heterocycle, wherein the heterocycle is a 3-7 membered substituted or unsubstituted heterocycle, optionally aromatic,

Wherein

R₆And R₇Independently is R₁、R₂Or R₃；

R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F、CHE₂、CF₃、CF₂CF₃Aryl, phenyl, halogen, CN, NO₂Alkenyl or OH;

z is O, NH, CH₂Or

Q is SO₃H、CO₂H、CO₂R、NO₂Tetrazole, SO₂NH₂Or SO₂NHR；

j. k, l are independently 1-4;

q is 1 to 5;

and is

X is (CH) if k is 1₂)_qCO or C (O) (CH)₂)_qAnd R is₂Is OCH₂CH₂NR₄R₅Or OCH₂CH₂-heterocycle, and R₉Is hydrogen, lower alkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro or amino, then

X is (CH) if l is 1₂)_qCO or C (O) (CH)₂)_qAnd R is₃Is OCH₂CH₂NR₄R₅Or OCH₂CH₂-heterocycle, and R₁₀Is hydrogen, lower alkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro or amino;

139. The Nuclear Receptor Binding Agent (NRBA) compound of claim 138, wherein the 3-7 membered substituted or unsubstituted heterocyclic, optionally aromatic, is represented by the structure of formula B:

wherein Y is CH₂CH, a bond, O, S, NH, N or NR;

if B is aryl, then z is 1; and if B is cycloalkyl, then z is 2;

m is 0 to 4;

n is 0 to 4;

where m and n cannot both be 0.

140. The Nuclear Receptor Binding Agent (NRBA) of claim 139, wherein formula B is a substituted or unsubstituted piperidine, pyrrolidine, morpholine, or piperazine.

141. The Nuclear Receptor Binding Agent (NRBA) of claim 135, wherein the pharmaceutically acceptable salt is an HCl salt.

142. The Nuclear Receptor Binding Agent (NRBA) compound of claim 135, wherein the compound is:

3-fluoro-4-hydroxy-N- (4-hydroxyphenyl) -N-phenylbenzamide (10 f);

4-fluoro-3-hydroxy-N, N-bis (4-hydroxyphenyl) -benzamide (10 g);

4-hydroxy-N, N-bis (4-hydroxyphenyl) -3, 5-dimethylbenzamide (10 i);

n, N-bis (4-hydroxyphenyl) -2, 3-dimethylbenzamide (10 j);

3-fluoro-4-hydroxy-N, N-bis (4-hydroxyphenyl) -benzamide (10 k);

4-hydroxy-N, N-bis (4-hydroxyphenyl) -3-methylbenzamide (10N);

4-fluoro-N, N-bis (4-hydroxyphenyl) -2- (trifluoromethyl) -benzamide (11 x);

3-fluoro-N- (4-fluorophenyl) -4-hydroxy-N- (4-hydroxyphenyl) benzamide (11 y);

or any combination thereof.

143. The compound of claim 142, wherein the compound is a Selective Estrogen Receptor Modulator (SERM).

144. A method of binding the Nuclear Receptor Binding Agent (NRBA) of claim 135 to an estrogen receptor or an estrogen-related receptor comprising the step of contacting the estrogen receptor with said SERM.

145. A composition comprising the Nuclear Receptor Binding Agent (NRBA) compound of claim 135 and a suitable carrier or diluent.

146. A method of treating, preventing or reducing the severity of osteoporosis in a subject, said method comprising administering to said subject a composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 135.

147. The method of claim 146, wherein the NRBA compound is an ER- α ligand.

148. A method of treating, preventing, or reducing the risk of death from a cardiovascular disease in a subject, comprising administering to the subject a composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 135.

149. The method of claim 148, wherein said Nuclear Receptor Binding Agent (NRBA) is an ER- β ligand.

150. A method of improving lipid profile in a subject, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 135.

151. A method of inhibiting, suppressing, treating, or reducing the incidence of androgen blockade induced osteoporosis, bone fractures, and/or Bone Mineral Density (BMD) reduction in a male with prostate cancer, the method comprising administering to a male subject in need of treatment with prostate cancer a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 135.

152. The method of claim 151, wherein said Nuclear Receptor Binding Agent (NRBA) compound is an ER- α ligand.

153. A method of ameliorating symptoms and/or clinical complications associated with menopause in a female subject, the method comprising administering to a female menopausal subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 135.

154. The method of claim 153, wherein said Nuclear Receptor Binding Agent (NRBA) compound is an ER- α ligand.

155. A method of treating, preventing or lessening the severity of alzheimer's disease in a subject, said method comprising administering to said subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 135.

156. The method of claim 155, wherein said Nuclear Receptor Binding Agent (NRBA) compound is an ER- α or ER- β ligand.

157. A method of treating, preventing, suppressing, inhibiting or reducing the incidence of hot flashes, male breast development and/or hair loss in a male subject suffering from prostate cancer, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 135.

158. The method of claim 157, wherein said Nuclear Receptor Binding Agent (NRBA) compound is an ER- α or ER- β ligand.

159. A method of treating, suppressing, inhibiting, or reducing the risk of developing prostate cancer in a subject, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 135.

160. The method of claim 159, wherein said Nuclear Receptor Binding Agent (NRBA) compound is an ER- α ligand or an ER- β ligand.

161. A method of treating, suppressing, inhibiting or reducing the amount of a pre-cancerous precursor of a prostate cancer lesion in a subject, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 135.

162. The method of claim 161, wherein said Nuclear Receptor Binding Agent (NRBA) compound is an ER- α ligand or an ER- β ligand.

163. The method of claim 161, wherein the pre-cancerous precursor of prostate cancer is Prostate Intraepithelial Neoplasia (PIN).

164. A method of treating, preventing, inhibiting or reducing the incidence of inflammation in a subject, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 135, thereby treating, preventing, inhibiting or reducing the incidence of inflammation in the subject.

165. The method of claim 164, wherein said Nuclear Receptor Binding Agent (NRBA) compound is an ER- β ligand.

166. A method of treating, preventing, inhibiting, or reducing the risk of breast cancer in a subject, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 135.

167. The method of claim 166, wherein said Nuclear Receptor Binding Agent (NRBA) compound is an ER- α ligand.

168. A method of treating, preventing, inhibiting or reducing the risk of endometrial cancer in a subject, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 135.

169. The method of claim 168, wherein said Nuclear Receptor Binding Agent (NRBA) compound is an ER- α ligand.

170. A method of treating, preventing, inhibiting, or reducing the risk of bladder cancer in a subject, comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) compound of claim 135.

171. A method of treating, preventing, inhibiting, or reducing the risk of colon cancer in a subject, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 135.

172. The method of claim 171, wherein said Nuclear Receptor Binding Agent (NRBA) compound is an ER- β ligand.

173. A method of treating, preventing, inhibiting, or reducing the risk of leukemia in a subject, the method comprising administering to the subject a pharmaceutical composition comprising the Nuclear Receptor Binding Agent (NRBA) of claim 135.

174. The method of claim 173, wherein said Nuclear Receptor Binding Agent (NRBA) is an ER- β ligand.

175. A method of reducing circulating lipid levels in a male subject with prostate cancer who has undergone androgen blockade therapy (ADT), the method comprising administering to the subject a composition comprising a Nuclear Receptor Binding Agent (NRBA), or a pharmaceutically acceptable salt, hydrate, N-oxide, or any combination thereof.

176. The method of claim 175, wherein the lipid level that is reduced comprises triglycerides, Low Density Lipoprotein (LDL) cholesterol, or a combination thereof.

177. The method of claim 175, wherein the method comprises increasing circulating levels of High Density Lipoprotein (HDL) cholesterol in the individual.

178. The method of claim 175, wherein the method further comprises reducing the ratio of total circulating cholesterol level to High Density Lipoprotein (HDL) level in the individual.

179. The method of claim 175, wherein the subject further suffers from atherosclerosis and its associated diseases, premature aging, alzheimer's disease, stroke, toxic hepatitis, viral hepatitis, peripheral vascular insufficiency, nephropathy, hyperglycemia, or any combination thereof.

180. The method of claim 175, wherein the Nuclear Receptor Binding Agent (NRBA) is represented by the structure

Wherein R is₁And R₂May be the same or different and is H or OH, R₃Is OCH₂CH₂OH or OCH₂CH₂NR₄R₅Wherein R is₄And R₅And may be the same or different and is H, alkyl of 1 to about 4 carbon atoms, or taken together with the nitrogen atom forms a cyclic 5-8 membered ring; and their pharmaceutically acceptable carriers, diluents, salts, esters or N-oxides and mixtures thereof.

181. A method of treating atherosclerosis and its related diseases including cardiovascular disorders, cerebrovascular disorders, peripheral vascular disorders, and intestinal vascular disorders in an individual having prostate cancer who has undergone androgen blockade therapy (ADT), comprising administering to the individual a composition comprising a Nuclear Receptor Binding Agent (NRBA) or a pharmaceutically acceptable salt, hydrate, N-oxide, or any combination thereof.

182. The method of claim 181, wherein the Nuclear Receptor Binding Agent (NRBA) is represented by the structure

183. A method of treating ischemia in a tissue of an individual having prostate cancer who has undergone Androgen Deprivation Therapy (ADT), the method comprising administering to the individual a composition comprising a Nuclear Receptor Binding Agent (NRBA) or a pharmaceutically acceptable salt, hydrate, N-oxide, or any combination thereof.

184. The method of claim 183, wherein said Nuclear Receptor Binding Agent (NRBA) is represented by the structure