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WO1999067221A1 - COMPOSES D'INHIBITION DE LA LIBERATION DU PEPTIDE β-AMYLOIDE ET/OU DE SA SYNTHESE - Google Patents

COMPOSES D'INHIBITION DE LA LIBERATION DU PEPTIDE β-AMYLOIDE ET/OU DE SA SYNTHESE Download PDF

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Publication number
WO1999067221A1
WO1999067221A1 PCT/US1999/014193 US9914193W WO9967221A1 WO 1999067221 A1 WO1999067221 A1 WO 1999067221A1 US 9914193 W US9914193 W US 9914193W WO 9967221 A1 WO9967221 A1 WO 9967221A1
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WIPO (PCT)
Prior art keywords
substimted
methyl
amino
group
dihydro
Prior art date
Application number
PCT/US1999/014193
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English (en)
Inventor
Richard C. Thompson
Stephen Wilkie
Douglas R. Stack
Eldon E. Vanmeter
Qing Shi
Thomas C. Britton
James E. Audia
Jon K. Reel
Thomas E. Mabry
Bruce A. Dressman
Cynthia L. Cwi
Steven S. Henry
Stacey L. Mcdaniel
Russell D. Stucky
Warren J. Porter
Original Assignee
Elan Pharmaceuticals, Inc.
Eli Lilly And Company
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Publication date
Application filed by Elan Pharmaceuticals, Inc., Eli Lilly And Company filed Critical Elan Pharmaceuticals, Inc.
Priority to AU47101/99A priority Critical patent/AU4710199A/en
Priority to JP2000555875A priority patent/JP2002518483A/ja
Priority to CA002325389A priority patent/CA2325389A1/fr
Priority to EP99930594A priority patent/EP1089980A1/fr
Publication of WO1999067221A1 publication Critical patent/WO1999067221A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/12—1,5-Benzodiazepines; Hydrogenated 1,5-benzodiazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D267/14—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D269/00—Heterocyclic compounds containing rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms according to more than one of groups C07D261/00 - C07D267/00
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to compounds which inhibit ⁇ -amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease.
  • AD Alzheimer's Disease
  • AD is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability that gradually leads to profound mental deterioration and ultimately death.
  • AD is a very common cause of progressive mental failure (dementia) in aged humans and is believed to represent the fourth most common medical cause of death in the United States.
  • AD has been observed in races and ethnic groups worldwide and presents a major present and future public health problem. The disease is currently estimated to affect about two to three million individuals in the United States alone. AD is at present incurable. No treatment that effectively prevents AD or reverses its symptoms and course is currently known.
  • the brains of individuals with AD exhibit characteristic lesions termed senile (or amyloid) plaques, amyloid angiopathy (amyloid deposits in blood vessels) and neurofibrillary tangles.
  • senile or amyloid
  • amyloid angiopathy amyloid deposits in blood vessels
  • neurofibrillary tangles Large numbers of these lesions, particularly amyloid plaques and neurofibrillary tangles, are generally found in several areas of the human brain important for memory and cognitive function in patients with AD. Smaller numbers of these lesions in a more restrictive anatomical distribution are also found in the brains of most aged humans who do not have clinical AD.
  • Amyloid plaques and amyloid angiopathy also characterize the brains of individuals with Trisomy 21 (Down's Syndrome) and Hereditary Cerebral
  • HCVWA-D Hemorrhage with Amyloidosis of the Dutch Type
  • amyloid angiopathy amyloid angiopathy characteristic of AD and the other disorders mentioned above is an approximately 4.2 kilodalton (kD) protein of about 39-43 amino acids designated the ⁇ -amyloid peptide (AP) or sometimes A , A P or /A4.
  • AP ⁇ -amyloid peptide
  • B-Amyloid peptide was first purified and a partial amino acid sequence was provided by Glenner, et al. The isolation procedure and the sequence data for the first 28 amino acids are described in U.S. Patent No. 4,666,829' .
  • ⁇ - amyloid peptide is a small fragment of a much larger precursor protein termed the amyloid precursor protein (APP), that is normally produced by cells in many tissues of various animals, including humans.
  • APP amyloid precursor protein
  • Knowledge of the structure of the gene encoding APP has demonstrated that ⁇ -amyloid peptide arises as a peptide fragment that is cleaved from APP by protease enzyme(s).
  • protease enzyme(s) The precise biochemical mechanism by which the ⁇ -amyloid peptide fragment is cleaved from APP and subsequently deposited as amyloid plaques in the cerebral tissue and in the walls of the cerebral and meningeal blood vessels is currently unknown.
  • AD (familial) form of AD (Goate, et al. ; Chartier Harlan, et al. ; and Murrell, et al. ) and is referred to as the Swedish variant.
  • APP in genetically based cases of AD prove that alteration of APP and subsequent deposition of its ⁇ -amyloid peptide fragment can cause AD.
  • the treatment methods would advantageously be based on drugs that are capable of inhibiting ⁇ -amyloid peptide release and/or its synthesis in vivo.
  • This invention is directed to the discovery of a class of compounds which inhibit ⁇ -amyloid peptide release and/or its synthesis and, therefore, are useful in the prevention of AD in patients susceptible to AD and/or in the treatment of patients with AD in order to inhibit further deterioration in their condition.
  • the class of compounds having the described properties are defined by Formulas I- VI below:
  • R is selected from the group consisting of aryl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl. substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic;
  • Q is S or O
  • R 15 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, heterocyclic and heteroaryl;
  • R 15 ' is selected from the group consisting of hydrogen, hydroxyl, alkyl, substituted alkyl, aryl, heterocyclic and heteroaryl;
  • each R 4 is independently selected from the group consisting of alkyl, substituted alkyl, aryl and heteroaryl;
  • Y is represented by the formula:
  • each R is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;
  • Z is represented by the formula -T-C(X')(X")C(O)- where T is selected from the group consisting of a bond covalently linking R to -C(X')(X")-, oxygen, sulfur, and -NR where R is hydrogen, acyl, alkyl, substituted alkyl, aryl, heterocyclic or heteroaryl group;
  • R is hydrogen, alkyl, substituted alkyl, aryl, heterocyclic or heteroaryl group
  • X' and X" are independently selected from the group consisting of hydrogen, fluoro, alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic, -OR ' , -
  • this invention is directed to a method for inhibiting ⁇ -amyloid peptide release and/or its synthesis in a cell which method comprises administering to such a cell an amount of a compound or a mixture of compounds as described herein effective in inhibiting the cellular release and/or synthesis of ⁇ -amyloid peptide.
  • this invention is directed to a prophylactic method for preventing the onset of AD in a patient at risk for developing AD by administering to the patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of one or more of the compounds described herein.
  • this invention is directed to a therapeutic method for treating a patient with AD in order to inhibit further deterioration in the condition of that patient which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds as described herein.
  • R' groups include, by way of example, all of the aryl (including substituted aryl), cycloalkyl, and substituted cycloalkyl groups defined for R' above as well as the following additional groups: thiophene-2-yl, 2-furanyl, cyclopropyl, cyclobutyl, 1-phenylcyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-benzofuranyl, 5-chloro-benzofuran-2-yl, 5,5-dimethyl-butyrolactone-4-yl, 4-methylsulfonyl-phenyl, cis-2-phenyl- cyclopropyl, 5-methylsulfonylthiophen-2-yl, 1 ,8 dimethyl-6-hydroxy- bicyclo[2.2.2]oct-2-yl, l ,4-benzodioxan-2-yl, tetrahydrofuran-2-yl
  • R groups include unsubstituted aryl groups such as phenyl, 1- naphthyl, 2-naphthyl, etc. ; substituted aryl groups such as monosubstituted phenyls (preferably substituents at 3 or 5 positions); disubstituted phenyls (preferably substituents at 3 and 5 positions); and trisubstituted phenyls (preferably substituents at the 3,4,5 positions).
  • the substimted phenyl groups do not include more than 3 substituents.
  • substituted phenyls include, for instance, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2- nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl, 2- trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4- nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4- ethoxyphenyl, 4-butoxy phenyl, 4-wo-propylphenyl, 4-phenoxyphenyl, 4- trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl, 3- hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3- phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-triflu
  • R groups include, by way of example, adamantyl, benzyl, 2-phenylethyl, 3-phenyl-n-propyl, 4-phenyl-n-butyl, methyl, ethyl, n-propyl, isopropyl, iso-butyl, 5ec-butyl, tert-butyl, ⁇ -pentyl, / 0-valeryl, n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl.
  • Still other preferred R groups include those set forth in the Tables below.
  • R substituents include, by way of example, methyl, ethyl, ⁇ -propyl, z ' s ⁇ -propyl, n-butyl, w ⁇ -butyl, sec-butyl, tert-butyl, -CH 2 CH(CH 2 CH 3 ) 2 , 2-methyl-rc-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, wo-but-2-enyl, 3-methylpentyl, -CH 2 -cyclopropyl, -CH 2 -cyclohexyl, -CH 2 CH 2 -cyclopropyl, -CH 2 CH 2 - cyclohexyl, -CH 2 -indol-3-yl, /?-(phenyl)phenyl, o-fluorophenyl,
  • T is selected from the group consisting of alkylene and substimted alkylene.
  • a preferred cycloalkyl group is represented by the formula:
  • each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substimted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like; each R is independently selected from the group consisting of alkyl, substimted alkyl, alkoxy, substimted alkoxy. amino, substimted amino carboxyl, carboxyl alkyl, cyano, halo, and the like; t is an integer from 0 to 4; and w is an integer from 0 to 3.
  • t is an integer from 0 to 2 and, more preferably, is an integer equal to 0 or 1.
  • T is selected from the group consisting of alkylene, substimted alkylene, alkenylene, substituted alkenylene, -(R 21 Z) q R 21 - and -ZR 21 -, where Z is a substituent selected from the group consisting of -O-, -S- and
  • each R is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substimted alkyl, substimted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R 21 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the -O- or -S-, and q is an integer of from 1 to 3.
  • Particularly preferred alcohol or thiol substimted groups include
  • each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted amino aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like; each R is independently selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino carboxyl, carboxyl alkyl, cyano, halo, and the like; t is an integer from 0 to 4; and w is an integer from 0 to 3.
  • t is an integer from 0 to 2 and, more preferably, is an integer equal to 0 or 1.
  • T is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R 21 Z) q R 21 - and -ZR 21 -, where Z is a substituent selected from the group consisting of -O-, -S- and
  • each R is independently selected from the group consisting of alkyl, alkenyl, alkynyl. cycloalkyl, cycloalkenyl, substituted alkyl, substimted alkenyl,
  • each R is independently alkylene, substimted alkylene, alkenylene and substimted alkenylene with the proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and substimted alkenylene does not involve participation of the -O- or -S-, and q is an integer of from 1 to 3.
  • Particularly preferred cyclic ketone and thioketone groups include:
  • each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substimted alkoxy, alkenyl, substituted alkenyl, alkynyl, substimted alkynyl, amino, substituted amino aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like; each R is independently selected from the group consisting of alkyl, substimted alkyl, alkoxy, substituted alkoxy, amino, substituted amino carboxyl, carboxyl alkyl, cyano, halo, and the like; t is an integer from 0 to 4; and w is an integer from 0 to 3.
  • t is an integer from 0 to 2 and, more preferably, is an integer equal to 0 or 1.
  • T is selected from the group consisting of alkylene
  • 21 21 21 substituted alkylene, alkenylene, substimted alkenylene, -(R Z) q R - and -ZR - , where Z is a substituent selected from the group consisting of -O-, -S- and
  • each R is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,
  • each R is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the -O- or -S-, and q is an integer of from 1 to 3.
  • lactone and thiolactone groups include:
  • each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, substimted amino aminoacyl.
  • each R is independently selected from the group consisting of alkyl, substimted alkyl, alkoxy, substituted alkoxy, amino, substituted amino carboxyl, carboxyl alkyl, cyano, halo, and the like;
  • t is an integer from 0 to 4; and
  • w is an integer from 0 to 3.
  • t is an integer from 0 to 2 and, more preferably, is an integer equal to 0 or 1.
  • T is selected from the group consisting of alkylene
  • each R is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substimted alkyl, substimted alkenyl,
  • each R is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the -O- or -S-, and q is an integer of from 1 to 3.
  • t is an integer from 0 to 2 and, more preferably, is an integer equal to 0 or 1.
  • W is a cyclic group of the formula:
  • each R 6 is independently selected from the group consisting of acyl, acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkyl, substituted alkyl, alkynyl, substimted alkynyl, amino, substimted amino, aminoacyl, aryl, aryloxy, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heterocyclic, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO- aryl,
  • each R 7 is independently selected from the group consisting of acyl, acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkyl, substituted alkyl, alkynyl, substituted alkynyl, amino, substituted amino, aminoacyl, aryl, aryloxy, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl, heterocyclic, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO- aryl, -SO-heteroaryl, -SO 2 -alkyl, -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -aryl, and
  • R 8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic; p is an integer from 0 to 4; q is an integer from 0 to 4.
  • R 6 and R 7 are independently selected from the group consisting of alkoxy, substituted alkoxy, alkyl, substituted alkyl, amino, substituted amino, carboxyl, carboxyalkyl, cyano, halo, nitro, thioalkoxy and substituted thioalkoxy. More preferably, when present, R 6 and R 7 are fluoro.
  • R 8 is preferably selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, aryl, cycloalkyl and substituted cycloalkyl. More preferably, R 8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl and cycloalkyl.
  • R 8 substituents include, by way of example, hydrogen, methyl, 2-methypropyl, hexyl, methoxycarbonylmethyl, 3,3-dimethyl- 2-oxobutyl, 4-phenylbutyl, cyclopropylmethyl, 2,2,2-trifluoroethyl, cyclohexyl, and the like.
  • W is a cyclic group of the formula:
  • R 6 , R , and p are as defined herein and r is an integer from 0 to 3.
  • W is a cyclic group of the formula:
  • R 6 and p are as defined herein.
  • W is a cyclic ring of the formula:
  • R 6 and /? are as defined herein.
  • W is a cyclic ring of the formula:
  • R 6 , R 8 and p are as defined herein; and each R 9 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic; and g is an integer from 0 to 2.
  • R 9 is preferably alkyl or substimted alkyl.
  • W is a cyclic ring of the formula:
  • R 6 , R 8 , R , g and p are as defined herein.
  • W is a cyclic ring of the formula:
  • R 6 , R 8 , R y , g and p are as defined herein.
  • W is a cyclic ring of the formula:
  • R 6 , each R 8 and p are as defined herein.
  • W is a cyclic ring of the formula:
  • R 6 , each R 8 , R 9 , g and p are as defined herein.
  • W is a cyclic ring of the formula:
  • R 6 , R 8 and p are as defined herein; and R 10 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substituted amino, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heteroaryl, heterocyclic, thioalkoxy and substituted thioalkoxy.
  • W is a cyclic ring of the formula:
  • R 6 , R 10 and p are as defined herein;
  • W is a cyclic ring of the formula:
  • R 6 , R 8 , R 9 , g and p are as defined herein; and Q is oxygen, sulfur, -S(O)- or -SCO),-.
  • W is a cyclic ring of the formula:
  • R 6 , R 8 and p are as defined herein.
  • W is a cyclic ring of the formula:
  • R 8 is as defined herein.
  • T is selected from the group consisting of alkylene
  • 21 21 21 substituted alkylene, alkenylene, substimted alkenylene, -(R Z) q R - and -ZR -
  • Z is a substituent selected from the group consisting of -O-, -S- and
  • each R is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substimted alkenyl,
  • each R is independently alkylene, substituted alkylene, alkenylene and substimted alkenylene with the proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and substimted alkenylene does not involve participation of the -O- or -S-, and q is an integer of from 1 to 3.
  • T is selected from the group consisting of alkylene
  • each R is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substimted alkyl, substituted alkenyl,
  • each R is independently alkylene, substimted alkylene, alkenylene and substimted alkenylene with the proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the -O- or -S-, and q is an integer of from 1 to 3.
  • R 15 is H
  • R 1 is alkyl or aryl
  • Rb is alkyl, substituted alkyl, cycloalkyl or aryl
  • R 2 is methyl
  • the compound is a compound of Formulas I, II or VI.
  • This invention also provides for novel pharmaceutical compositions comprising a pharmaceutically inert carrier and one or more of the compounds described in Formulas I- VI above.
  • R is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic;
  • Q is S or O
  • R 15 is selected from the group consisting of hydrogen, alkyl, substimted alkyl, aryl, heterocyclic and heteroaryl;
  • R 15 ' is selected from the group consisting of hydrogen, hydroxyl, alkyl, substituted alkyl, aryl, heterocyclic and heteroaryl;
  • Y is represented by the formula:
  • each R is independently selected from the group consisting of alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;
  • Z is represented by the formula -T-C(X')(X")C(O)- where T is selected from the group consisting of a bond covalently linking R to -C(X')(X")-, oxygen, sulfur, and -NR where R is hydrogen, acyl, alkyl, substimted alkyl, aryl, heterocyclic or heteroaryl group;
  • R is hydrogen, alkyl, substimted alkyl, aryl, heterocyclic or heteroaryl group
  • X' and X" are independently selected from the group consisting of hydrogen, fluoro, alkyl, substimted alkyl, aryl, heteroaryl, heterocyclic, -OR ' , - SR , -N(R ) 2 , -N(CO)OR 15 and -N 3 , with the proviso that at least one of X' or X" is other than hydrogen, hydroxy or fluoro, and with the further proviso that both X' and X" cannot both be -OR 5 , , -SR 5 , -N(R 5 ) 2 , -N(CO)OR 15 and -N 3 ; further, neither X' and X" can be -OR 5 , -SR 5 , -N(R 5 ) 2 , -N(CO)OR 15 or -N 3 when T is other
  • compounds of the present invention exist as isomers.
  • the Cahn-Prelog-Ingold designations of (R)- and (S)- and, for amino acid derived portions of the compounds, the L- and D- designations of stereochemistry relative to the isomers of glyceraldehyde are used to refer to specific isomers where designated.
  • the specific isomers can be prepared by stereospecific synthesis or can be resolved and recovered by techniques known in the art. such as, chromatography on chiral stationary phases, and fractional recrystallization of addition salts formed by reagents used for that purpose.
  • prodrugs of the compounds of Formulas I-VI described above including acylated forms of alcohols and thiols, ammals of one or more amines, and the like, as well as acid addition salts of amines
  • This invention is not intended to encompass subject matter disclosed and claimed in co-pending U S S N 08/996,422, the contents of which are hereby incorporated by reference in its entirety
  • this invention relates to compounds that inhibit ⁇ -amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease
  • this invention relates to compounds that inhibit ⁇ -amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease
  • ⁇ -amyloid peptide refers to a 39-43 amino acid peptide having a molecular weight of about 4 2 kD, which peptide is substantially homologous to the form of the protein described by Glenner, et al including mutations and post- translational modifications of the normal ⁇ -amyloid peptide In whatever form, the ⁇ -amyloid peptide is an approximate 39-43 amino acid fragment of a large membrane-spanning glycoprotein, referred to as the ⁇ -amyloid precursor protein (APP) Its 43-ammo acid sequence is
  • Alkyl refers to monovalent alkyl groups preferably having from 1 to 20 carbon atoms, more preferably 1 to 10 carbon atoms and most preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-p ⁇ opyl, ⁇ -butyl, z ' s ⁇ -butyl, ⁇ -hexyl, and the like.
  • Substimted alkyl refers to an alkyl group, preferably of from 1 to 10 carbon atoms, having from 1 to 5 substiments, and preferably 1 to 3 substiments, selected from the group consisting of alkoxy, substimted alkoxy, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, acyl, acylamino, acyloxy, amino.
  • Alkylene refers to divalent alkylene groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), the propylene isomers (e.g. , -CH 2 CH 2 CH 2 - and -CH(CH 3 )CH 2 -) and the like.
  • Substimted alkylene refers to an alkylene group, preferably of from 1 to 10 carbon atoms, having from 1 to 3 substiments selected from the group consisting of alkoxy, substimted alkoxy, acyl, acylamino, acyloxy, amino, substimted amino aminoacyl, aminoacyloxy, oxyacylamino, , cyano, halogen, hydroxyl, keto, thioketo, , carboxyl, carboxylalkyl, thiol, thioalkoxy, substimted thioalkoxy. aryl, heteroaryl, heterocyclic.
  • substimted alkylene groups include those where 2 substiments on the alkylene group are fused to form one or more cycloalkyl, aryl, heterocyclic or heteroaryl groups fused to the alkylene group.
  • fused cycloalkyl groups contain from 1 to 3 fused ring structures.
  • Substimted alkenylene refers to an alkenylene group, preferably of from 2 to 10 carbon atoms, having from 1 to 3 substiments selected from the group consisting of alkoxy, substimted alkoxy, acyl, acylamino, acyloxy, amino, substimted amino aminoacyl, aminoacyloxy, oxyacylamino.
  • substimted alkylene groups include those where 2 substiments on the alkylene group are fused to form one or more cycloalkyl, aryl, heterocyclic or heteroaryl groups fused to the alkylene group.
  • Alkaryl refers to -alkylene-aryl groups where alkylene and aryl are as defined herein. Such alkaryl groups are exemplified by benzyl, phenethyl and the like.
  • Alkoxy refers to the group “alkyl-O-" , where alkyl is as defined above.
  • Preferred alkoxy groups include, by way of example, methoxy, ethoxy, n- propoxy, z ' s ⁇ -propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, ⁇ -hexoxy, 1 ,2-dimethylbutoxy, and the like.
  • Substimted alkoxy refers to the group “substimted alkyl-O-" where substimted alkyl is as defined above.
  • Alkylalkoxy refers to the group “-alkylene-O-alkyl” where alkylene and alkyl are as defined above. Such groups include methylenemethoxy (-CH 2 OCH3), ethylenemethoxy (-CH 2 CH 2 OCH3), ⁇ -propylene-wo-propoxy (- CH 2 CH 2 CH 2 OCH(CH 3 ) 2 ), methylene-t-butoxy (-CH 2 -O-C(CH 3 ) 3 ) and the like.
  • Alkylthioalkoxy refers to the group “-alkylene-S-alkyl” where alkylene and alkyl are as defined above. Such groups include methy lenethiomethoxy (-
  • alkenyl refers to alkenyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkenyl unsamration.
  • Substimted alkenyl refers to an alkenyl group as defined above having from 1 to 3 substituents selected from the group consisting of alkoxy, substimted alkoxy, acyl. acylamino, acyloxy. amino. substimted amino aminoacyl, aminoacyloxy, oxyacylamino, , cyano. halogen, hydroxyl, keto. thioketo. , carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy. aryl, heteroaryl, heterocyclic, heterocyclooxy, nitro.
  • -SO-alkyl -SO-substimted alkyl, -SO-aryl, - SO-heteroaryl, -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -aryl, -SO 2 -heteroaryl, and mono- and di-alkylamino, mono- and di-(substituted alkyl)amino. mono- and di-arylamino, mono- and di-heteroarylamino. mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substiments selected from alkyl, substimted alkyl, aryl, heteroaryl and heterocyclic.
  • Alkynyl refers to alkynyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkynyl unsamration.
  • Substimted alkynyl refers to an alkynyl group as defined above having from 1 to 3 substiments selected from the group consisting of alkoxy, substimted alkoxy, acyl, acylamino, acyloxy, amino, substimted amino aminoacyl, aminoacyloxy, oxyacylamino, , cyano, halogen, hydroxyl, keto, thioketo, , carboxyl, carboxylalkyl, thiol, thioalkoxy, substimted thioalkoxy, aryl, heteroaryl, heterocyclic, heterocyclooxy, nitro, -SO-alkyl, -SO-substimted alkyl, -SO-aryl, - SO-heteroaryl, -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -aryl,
  • Acyl refers to the groups alkyl-C(O)-, substimted alkyl-C(O)-, cycloalkyl-C(O)-, substimted cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl-C(O)- and heterocyclic-C(O)- where alkyl, substimted alkyl, cycloalkyl, substimted cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • Acylamino refers to the group -C(O)NRR where each R is independently hydrogen, alkyl, substimted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substimted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • Substimted amino refers to the group -N(R)2, where each R is independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl. substimted alkynyl, aryl, cycloalkyl, substimted cycloalkyl, heteroaryl, heterocyclic and where both R groups are joined to form a heterocyclic group.
  • both R groups are hydrogen
  • -N(R)2 is an amino group.
  • substimted amino groups include, by way of example, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di- arylamino, mono- and diheteroarylamino, mono and di-heterocyclic amino, and unsymmetric di-substituted amines having different substiments selected from the group consisting of alkyl, substimted alkyl, aryl, heteroaryl, heterocyclic and the like.
  • Aminoacyl refers to the group -NRC(O)R where each R is independently hydrogen, alkyl. substimted alkyl. aryl, heteroaryl. or heterocyclic wherein alkyl, substimted alkyl. aryl, heteroaryl and heterocyclic are as defined herein.
  • aminoacyloxy refers to the group -NRC(O)OR where each R is independently hydrogen, alkyl, substimted alkyl. aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • Alkyloxy refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, cycloalkyl-C(O)O-. aryl-C(O)O-, heteroaryl-C(O)O-, and heterocyclic-C(O)O- wherein alkyl, substituted alkyl. cycloalkyl, aryl, heteroaryl, and heterocyclic are as defined herein.
  • Aryl refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g. , naphthyl or anthryl).
  • Preferred aryls include phenyl, naphthyl and the like.
  • such aryl groups can optionally be substimted with from 1 to 5 substiments and preferably 1 to 3 substiments selected from the group consisting of acyloxy, 1 to 5 and preferably 1 to 3 substiments selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substimted alkyl, substimted alkoxy, substimted alkenyl, substimted alkynyl, amino, substimted amino, aminoacyl, acylamino.
  • Preferred substiments include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy.
  • Aryloxy refers to the group aryl-O- wherein the aryl group is as defined above including optionally substimted aryl groups as also defined above.
  • Carboxyalkyl refers to the group “-C(O)Oalkyl” and "-C(O)O-substituted alkyl” where alkyl and substimted alkyl are as defined above.
  • Cycloalkyl refers to cyclic alkyl groups of from 3 to 12 carbon atoms having a single cyclic ring or multiple condensed rings.
  • Such cycloalkyl groups include, by way of example, single ring strucmres such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like, or multiple ring strucmres such as adamantanyl, bicyclo[2.2.1]heptyl, bicyclo(2.2.1)hept-5-ene-yl, bicyclo (3.3.1)non-6-ene-3-carboxyl) and the like.
  • “Substimted cycloalkyl” refers to cycloalkyl groups having from 1 to 5 (preferably 1 to 3) substiments selected from the group consisting of hydroxy. acyl, acyloxy, alkyl, substimted alkyl, alkoxy. substimted alkoxy, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, amino, substimted amino aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl. thioalkoxy, substimted thioalkoxy, trihalomethyl and the like.
  • Cycloalkenyl refers to cyclic alkenyl groups of from 4 to 12 carbon atoms having at least one cyclic ring and preferably no more than four rings, which rings are optionally fused, and which include at least one point of internal unsamration.
  • suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl and the like.
  • Substimted cycloalkenyl refers to cycloalkenyl groups having from 1 to 5 substiments selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substimted alkyl, alkoxy, substimted alkoxy, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, amino. substimted amino aminoacyl, alkaryl. aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substimted thioalkoxy, trihalomethyl and the like.
  • Halo or halogen refers to fluoro, chloro, bromo and iodo and preferably is either fluoro or chloro.
  • Heteroaryl refers to an aromatic carbocyclic group of from 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring (if there is more than one ring).
  • heteroaryl groups can be optionally substimted with from 1 to 5 substiments and preferably 1 to 3 substituents selected from the group consisting of acyloxy, 1 to 5 and preferably 1 to 3 substituents selected from the group consisting of hydroxy. acyl, alkyl, alkoxy, alkenyl, alkynyl. substimted alkyl, substimted alkoxy, substimted alkenyl, substimted alkynyl, amino. substimted amino, aminoacyl, acylamino. alkaryl. aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano.
  • halo nitro, heteroaryl, heteroaryloxy, heterocyclic. heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy. substimted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substimted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -aryl, -SO -heteroaryl, trihalomethyl.
  • Preferred substiments include alkyl, alkoxy, halo, cyano.
  • heteroaryl groups can have a single ring (e.g. , pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl).
  • Preferred heteroaryls include pyridyl, pyrrolyl and furyl.
  • Heteroaryloxy refers to "O-heteroaryl", where heteroaryl is as defined herein.
  • Heterocyclooxy refers to "O-heterocyclic", where heterocyclic is as defined herein.
  • Heterocycle or “heterocyclic” refers to a monovalent saturated or unsaturated group having a single ring or multiple condensed rings, from 1 to 15 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur or oxygen within the ring.
  • heterocyclic groups can be optionally substimted with 1 to 5 substiments selected from the group consisting of alkyl, substimted alkyl, alkoxy, substimted alkoxy, aryl, aryloxy, halo, nitro, heteroaryl, thiol, thioalkoxy, substimted thioalkoxy, thioaryloxy, trihalomethyl, and the like.
  • Such heterocyclic groups can have a single ring or multiple condensed rings.
  • Preferred heterocyclics include morpholino, piperidinyl, and the like.
  • nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole. indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine. naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole.
  • Oxyacylamino refers to the group -OC(O)NRR where each R is independently hydrogen, alkyl. substimted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substimted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • Thiol refers to the group -SH.
  • Thioalkoxy refers to the group -S-alkyl.
  • Substimted thioalkoxy refers to the group -S-substimted alkyl.
  • Thioaryloxy refers to the group aryl-S- wherein the aryl group is as defined above including optionally substimted aryl groups also defined above.
  • Thioheteroaryloxy refers to the group heteroaryl-S- wherein the heteroaryl group is as defined above including optionally substimted aryl groups as also defined above.
  • “Pharmaceutically acceptable salts” refers to pharmaceutically acceptable salts of a compound of Formulas I-VI which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium. and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like can be used as the pharmaceutically acceptable salt.
  • protecting group refers to any group which when bound to one or more hydroxyl, amino or carboxyl groups of the compounds (including intermediates thereof such as the aminolactams, aminolactones, etc.) prevents reactions from occurring at these groups and which protecting group can be removed by conventional chemical or enzymatic steps to reestablish the hydroxyl, amino or carboxyl group.
  • removable blocking group employed is not critical and preferred removable hydroxyl blocking groups include conventional substiments such as allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidine, phenacyl, t-butyl-diphenylsilyl and any other group that can be introduced chemically onto a hydroxyl functionality and later selectively removed either by chemical or enzymatic methods in mild conditions compatible with the nature of the product.
  • Preferred removable amino blocking groups include conventional substiments such as t-butyoxycarbonyl (t-BOC), benzyloxycarbonyl (CBZ), and the like which can be removed by conventional conditions compatible with the nature of the product.
  • Preferred carboxyl protecting groups include esters such as methyl, ethyl, propyl, t-butyl etc. which can be removed by mild hydrolysis conditions compatible with the namre of the product.
  • reaction is conventionally conducted by using at least a stoichiometric amount of carboxylic acid I and amine 2.
  • This reaction is conventionally conducted for peptide synthesis and synthetic methods used therein can also be employed to prepare compound 3 which is a compound of formula I above.
  • well known coupling reagents such as carbodiimides with or without the use of well known additives such as N-hydroxysuccinimide, 1 -hydroxy benzotriazole, etc. can be used to facilitate coupling.
  • the reaction is conventionally conducted in an inert aprotic polar diluent such as dimethylformamide.
  • the acid halide of compound I can be employed in reaction (1) and, when so employed, it is typically employed in the presence of a suitable base to scavenge the acid generated during the reaction.
  • suitable bases include, by way of example. triethylamine. diisopropylethylamine, N-methylmorpholine and the like.
  • Carboxylic acids I can be prepared by several divergent synthetic routes with the particular route selected relative to the ease of compound preparation, commercial availability of starting materials, whether n ::- one or two.
  • R group onto the amino acid NH 2 CH(R )COOH or ester thereof can be accomplished in several methods.
  • conventional coupling of a halo acetic acid with a primary amine forms an amino acid as shown in reaction (2) below:
  • R and R are as defined above and Z is a halo group such as chloro or bromo.
  • Z is a halo group such as chloro or bromo.
  • leaving groups other than halo may be employed such as triflate and the like.
  • suitable esters of 4 may be employed in this reaction.
  • reaction (2) involves coupling of a suitable haloacetic acid derivative 4 with a primary amine 5 under conditions that provide for amino acid
  • reaction employs an excess of a suitable base such as sodium bicarbonate, sodium hydroxide, etc. to scavenge the acid generated by the reaction.
  • a suitable base such as sodium bicarbonate, sodium hydroxide, etc.
  • the reaction is preferably conducted at from about 25 °C to about 100°C until reaction completion which typically occurs within 1 to about 24 hours. This reaction is further described in U.S. Patent No. 3,598,859, which is incorporated herein by reference in its entirety.
  • N-substituted amino acid 6 is recovered by conventional methods including precipitation, chromatography, filtration and the like.
  • each of the reagents (haloacetic acid 4, primary amine 5 and alcohol 6) are well known in the art with a plurality of each being commercially available.
  • the R group can be coupled to an alanine ester (or other suitable amino acid ester) by conventional N-arylation.
  • a stoichiometric equivalent or slight excess of the amino acid ester can be dissolved in a suitable diluent such as DMSO and coupled with a halo-R compound.
  • Z -R where Z is a halo group such as chloro or bromo and R is as defined above.
  • the reaction is conducted in the presence of an excess of base such as sodium hydroxide to scavenge the acid generated by the reaction.
  • the reaction typically proceeds at from 15 °C to about 250°C and is complete in about 1 to 24 hours.
  • N-substituted amino acid ester is recovered by conventional methods including chromatography, filtration and the like. This ester is then hydrolyzed by conventional methods to provide for carboxylic acid J for use in reaction (1).
  • esterified amino acids described above can be prepared by reductive amination of a suitable pyruvate ester in the manner illustrated in reaction (3) below: on 3)
  • R is typically an alkyl group and R and R are as defined above.
  • reaction (3) approximately stoichiometric equivalents of pyruvate ester 7 and amine 5 are combined in an inert diluent such as methanol, ethanol and the like and the reaction solution treated under conditions that provide for imine formation (not shown).
  • the imine formed is then reduced under conventional conditions by a suitable reducing agent such as sodium cyanoborohydride, H 2 /palladium on carbon and the like to form the
  • the reducing agent is H 2 /palladium on carbon which is incorporated into the initial reaction medium which permits imine reduction in situ in a one pot procedure to provide for the N-substimted amino acid ester 5-
  • the reaction is preferably conducted at from about 20 °C to about 80 °C at a pressure of from 1 to 10 atmospheres until the reaction is complete, which typically occurs within 1 to about 24 hours.
  • N- substituted amino acid ester 8 is recovered by conventional methods including chromatography, filtration and the like.
  • R NHCH(R )COOH provides for esters of an analogue of carboxylic acid 1 which are then conventionally de-esterified to provide for an analogue of compound 1.
  • an ester such as H 2 NCH(R 2 )C(O)NHCH(R ⁇ )COOR
  • each R is independently as defined above and R is typically an alkyl group can first be formed by conventional peptide synthetic procedures, N-substimtion can be conducted in the manner described above followed by de-esterification to provide for analogues of carboxylic acids 1 where n is two.
  • a first synthetic method involves conventional coupling of an carboxylic acid derivative with a primary amine of an esterified amino acid as shown in reaction (4) below:
  • R is typically an alkyl group and R , R , X' and X" are as defined above.
  • Reaction (4) merely involves coupling of a suitable carboxylic acid derivative 9 with the primary amine of amino acid ester JO under conditions that provide for the N-acetyl derivative 11.
  • the carboxylic acid derivative 9 is a suitable carboxylic acid derivative 9 with the primary amine of amino acid ester JO under conditions that provide for the N-acetyl derivative 11.
  • R'COOH can be used in place of compound 9 to provide intermediates useful for preparing compounds of Formula VI above.
  • This reaction is conventionally conducted for peptide synthesis and synthetic methods used therein can also be employed to prepare the N-acetyl amino acid esters U of this invention.
  • well known coupling reagents such as carbodiimides with or without the use of well known additives such as N-hydroxysuccinimide, 1- hydroxybenzotriazole, etc. can be used to facilitate coupling.
  • the reaction is conventionally conducted in an inert aprotic polar diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, or tetrahydrofuran.
  • the acid halide of compound 9 can be employed in reaction (4) and, when so employed, it is typically employed in the presence of a suitable base to scavenge the acid generated during the reaction.
  • suitable bases include, by way of example, triethylamine, diisopropylethylamine, and N- methy lmorpholine .
  • Reaction (4) is preferably conducted at from about 0°C to about 60 °C until the reaction is complete, which typically occurs within 1 to about 24 hours.
  • N-acetyl amino acid ester U is recovered by conventional methods including precipitation, chromatography, and filtration or alternatively is hydrolyzed to the corresponding acid without purification and/or isolation other than conventional work-up (e.g.. aqueous extraction, etc.).
  • each of the reagents (carboxylic acid derivative 9 and amino acid ester 10) are well known in the art with a plurality of each being commercially available.
  • a further amino acid ester is coupled to the amino acid ester 11 by first de-esterifying U and then using well known peptide coupling chemistry with well known coupling reagents such as carbodiimides with or without the use of well known additives such as N-hydroxysuccinimide and 1- hydroxybenzotriazole,. which can be used to facilitate coupling.
  • the reaction is conventionally conducted in an inert aprotic polar diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, or tetrahydrofuran. De-esterification of the resulting ester provides for carboxylic acids I having n equal to 2.
  • carboxylic acids 1 having n equal to 2 can be prepared by first forming the ester, N-acetylating these esters and then de-esterifying the resulting product.
  • Carboxylic acids I having n equal to 1 or 2 can also be prepared by using polymer-supported forms of carbodiimide peptide coupling reagents.
  • PEPC and its corresponding polymer-supported forms have been discovered and are very useful for preparing such compounds.
  • Polymers suitable for use in making a polymer-supported coupling reagent are either commercially available or may be prepared by methods well known to those of skill in the polymer arts.
  • a suitable polymer must possess pendant sidechains bearing moieties reactive with the terminal amine of the carbodiimide. Such reactive moieties include chloro, bromo, iodo and methanesulfonyl. Preferably, the reactive moiety is a chloromethyl group.
  • the polymer backbone must be inert to both the carbodiimide and reaction conditions under which the ultimate polymer-bound coupling reagents will be used.
  • hydroxymethylated resins may be converted into chloromethylated resins useful for the preparation of polymer-supported coupling reagents.
  • these hydroxylated resins include the 4- hydroxymethylphenylacetamidomethyl resin (Pam Resin) and 4-benzyloxybenzyl alcohol resin (Wang Resin) available from Advanced Chemtech of Louisville, Kentucky, USA (see Advanced Chemtech 1993-1994 catalog, page 115).
  • the hydroxymethyl groups of these resins may be converted into the desired chloromethyl groups by any of a number of methods well known to the skilled artisan.
  • Preferred resins are the chloromethylated styrene/divinylbenzene resins because of their ready commercial availability. As the name suggests, these resins are already chloromethylated and require no chemical modification prior to use. These resins are commercially known as Merrifield's resins and are available from Aldrich Chemical Company of Milwaukee, Wisconsin. USA (see Aldrich 1994- 1995 catalog, page 899). Methods for the preparation of PEPC and its polymer- supported forms are outlined in the following scheme.
  • PEPC is prepared by first reacting ethyl isocyanate with l-(3- aminopropyl)pyrrolidine. The resulting urea is treated with 4-toluenesulfonyl chloride to provide PEPC. The polymer-supported form is prepared by reaction of PEPC with an appropriate resin under standard conditions to give the desired reagent.
  • the carboxylic acid coupling reactions employing these reagents are performed at about ambient temperature to about 45 °C, for from about 3 to 120 hours.
  • the product is isolated by washing the reaction mixture with CHCI3 and concentrating the remaining organics under reduced pressure. As discussed supra, isolation of products from reactions where a polymer bound reagent has been used is greatly simplified, requiring only filtration of the reaction mixture and then concentration of the filtrate under reduced pressure.
  • Sulfonamides such as those in Formula III, can be readily prepared using known sulfonamidation reactions. These typically involve the reaction of sulfonyl chlorides with primary or secondary amines in the presence of a tertiary amine or other suitable acid scavenger (See, for Example, page 923. Morrison and Boyd, Organic Chemistry, fourth edition).
  • Suitable sulfonic acids can be prepared by several divergent synthetic routes with the particular route selected relative to the ease of compound preparation, and commercial availability of starting materials.
  • Alkyl sulfonic acids can be prepared using means well known to those of skill in the art, as described, for example, in U.S. Patent Nos. 2,493,038 and 2,697,722, the contents of which are hereby incorporated by reference.
  • One method for preparing alkyl sulfonic acids is by the oxidation of disulfides, which can themselves be prepared by the oxidation of thiols.
  • Aromatic sulfonic acids can be produced by the sulfonating action of sulfuric acid, SO,, oleum or alkyl sulfonic acids on aromatic compounds using techniques well known to those of skill in the art.
  • Suitable sulfonic acid derivatives can be prepared, for example, by reacting a sulfonic acid with a chlorinating reagent such as phosphorous pentachloride or sulfonyl chloride.
  • Ureas can be prepared by any known methodology, but preferably are prepared by reacting an amine with an isocyanate, as described on page 844 of Morrison and Boyd, Organic Chemistry, Fourth Edition, Allyn and Bacon, ed., Boston (1983). Suitable isocyanates can be prepared using methods known to those of skill in the art.
  • Cyclic amino compounds 2 employed in reaction (1) above are generally aminolactams, aminolactones, aminothiolactones and aminocycloalkyl compounds which can be represented by the formula:
  • aminolactams. aminolactones and aminothiolactones of the formulas above can be prepared by use or adaptation of known chemical syntheses which syntheses are well described in the literature. See, e.g. , Ogliaruso and Wolfe. Synthesis ofLactones and Lactams. Patai, et al. Editor, J. Wiley & Sons, New York, New York, USA, pp. 1085 et seq. (1993) 15 .
  • 3-amino substimted lactams 13. with 5, 6 or 7 ring atoms may be prepared by the direct cyclization of a suitable , omega-diamino acid ester . 12 as shown in reaction (5) below: 12 (Reaction 5)
  • L is a linking group (typically an alkylene group) of from 2-4 atoms
  • Pr is a suitable protecting group such as t-butoxycarbonyl, carbobenzyloxy, or the like
  • R is an alkoxy or aryloxy group such as methoxy, ethoxy, j-nitrophenoxy, N-succinimidoxy, and the like.
  • the reaction may be carried out in a solvent such as water, methanol. ethanol, pyridine, and the like.
  • a solvent such as water, methanol. ethanol, pyridine, and the like.
  • Such reactions are exemplified by cyclization of a lysine ester to a caprolactam as described by Ugi, et al.. Tetrahedron, 52(35): 11657-11664 (1996) .
  • such a cyclization can also be conducted in the presence of dehydrating agents such as alumina or silica to form lactams as described by Blade-Font, Tetrahedron Lett.. 21 :2443 (1980) 17 .
  • reaction (7) is presented by Semple, et al. , supra. , and
  • lactams 20 can be prepared from cyclic ketones 19 using either the well known Beckmann rearrangement (e.g. , Donaruma, et al., 21 Organic Reactions, 11: 1-156 (I960)) or the well known Schmidt reaction
  • lactams especially lactams having two hydrogen atoms on the carbon to the lactam carbonyl which lactams form a preferred group of lactams in the synthesis of the compounds described above.
  • the L group can be highly variable including, for example, alkylene, substimted alkylene and hetero containing alkylene with the proviso that a heteroatom is not adjacent to the carbonyl group of compound 19.
  • the Beckmann rearrangement can be applied to bicyclic ketones as described in Krow, et al. , J. Org. Chem. , 61:5574-5580 (1996) 23 .
  • lactones can be similarly conducted using peracids in a Baeyer-Villiger reaction on ketones.
  • thiolactones can be prepared by cyclization of an omega -SH group to a carboxylic acid and thiolactams can be prepared by conversion of the oxo group to the thiooxo group by P 2 S5 or by use of the commercially available Lawesson's Reagent, Tetrahedron, 35:2433 (1979) 24 .
  • One recently reported route for lactam synthesis is a variation of the Schmidt reaction through the use of an alkyl azide, either intermolecularly or intramoiecularly, through a tethered alkylazide function that attacks a ketone under
  • R is exemplified by alkyl. substimted alkyl, alkoxy, substimted alkoxy, aryl, heteroaryl. cycloalkyl and heterocyclic.
  • ketone 21 is converted to an -(w-alkyl)ketone 22 which is cyclized to form bicyclic lactam 23.
  • Such intramolecular reactions are useful in forming bicyclic lactams having 5-7 members and the lactam ring of 6-13 members. The use of heteroatoms at non-reactive sites in these rings is feasible in preparing heterobicyclic lactams.
  • R and Pr are as defined above and R is exemplified by halo, alkyl. substimted alkyl, alkoxy, substimted alkoxy, aryl, heteroaryl, cycloalkyl and heterocyclic wherein the aryl, heteroaryl, cycloalkyl and heterocyclic group is optionally fused to the lactam ring structure.
  • lactam 26 is formed from an appropriate unsaturated amide (e.g. , 24) through a ruthenium or molybdenum complexes catalyzed olefin metathesis reaction to form unsaturated lactam 25 which can be used herein without mrther modification.
  • unsamration in 25 permits a myriad of techniques such as hydroboration, Sharpless or Jacobsen epoxidations, Sharpless dihydroxylations, Diels-Alder additions, dipolar cycloaddition reactions and many more chemistries to provide for a wide range of substiments on the lactam ring.
  • subsequent transformations of the formed substitution leads to other additional substiments (e.g. , mesylation of an alcohol followed by nucleophilic substitution reactions). See, for example,
  • proline derivative 27 is cyclized via a tributyltin-radical cyclization to provide for lactam 28.
  • lactams described above contain the requisite amino group to the lactam carbonyl whereas others did not. However, the introduction of the required amino group can be achieved by any of several routes delineated below which merely catalogue several recent literature references for this synthesis.
  • Still another example of this first general procedure uses a Mitsunobu reaction of an alcohol and a nitrogen equivalent (either -NH 2 or a phthalimido group) in the presence of an azodicarboxylate and a triarylphosphine as described in Wada, et al. , Bull. Chem. Soc Japan, 46:2833-2835 (1973) using an open chain reagent.
  • Yet another example of this first general procedure involves reaction of ⁇ - chlorolactams with anilines or alkyl amines in a neat mixmre at 120°C to provide for 2-(N-aryl or N-alkyl)lactams as described by Gaetzi, Chem. Abs. , 66:28690m. 37
  • N-substimted lactams are first converted to the 3-alkoxycarbonyl derivatives by reaction with a dialkyl carbonate and a base such as sodium hydride. See, for example, M.L. Reupple, et al. , J. Am. Chem.
  • Pr is as defined above and R is typically hydrogen, an alkyl or an aryl group.
  • Pr H or a protecting group such as Boc.
  • (1) above include ring N-substituted lactams in addition to ring N-H lactams.
  • Some methods for preparing ring N-substimted lactams have been described above. More generally, however, the preparation of these compounds range from the direct introduction of the substituent after lactam formation to essentially introduction before lactam formation.
  • the former methods typically employ a base and an primary alkyl halide although it is contemplated that a secondary alkyl halide can also be employed although yields may suffer.
  • a first general method for preparing N-substituted lactams is achieved via reaction of the lactam with base and alkyl halide (or acrylates in some cases).
  • This reaction is quite well known and bases such as sodamide, sodium hydride, LDA, LiHMDS in appropriate solvents such as THF, DMF, etc. are employed provided that the selected base is compatible with the solvent. See for
  • a second general method employs reductive amination on an amino function that is then cyclized to an appropriate ester or other carbonyl function.
  • a third general method achieves production of the N-substimtion during lactam formation.
  • Literature citations report such production from either photolytic or thermal rearrangement of oxaziridines, particularly of N-aryl
  • lactams and appropriate corresponding lactones
  • Similar alcohol functions at the carbonyl position are derivative of either amine ring opening of cyclic epoxides, ring opening of aziridines, displacement of appropriate halides with amine or alcohol nucleophiles, or most likely reduction of appropriate ketones. These ketones are also of interest to the present invention.
  • R ⁇ and R 2 are exemplified by alkyl, aryl or alkenyl (e.g. , allyl).
  • R is exemplified by CH3- or PhCH 2 -.
  • R is exemplified by benzyl (includes both the cis and trans hydroxy lactams).
  • R is alkyl, alkenyl, alkynyl, cycloalkyl, or benzyl.
  • N-Methoxylactams prepared from cyclohexanone and dimethoxyamine are describ >eedd bbyy VVeeddeejjss,, eett aall.. ,, TTeett.. Lett. , 33:3261-3264 (1992). These strucmres are represented by the formula:
  • R j and R 2 are independently selected from alkyl, substimted alkyl, alkenyl, substimted alkenyl, aryl, heteroaryl, heterocyclic or are fused to form a cyclic group.
  • Ring substimted lactams are described by Lowe, et al., Bioorg. Med.
  • R 2 and R3 are exemplified by aryl and substimted aryl and R j is exemplified by alkyl or hydrogen.
  • R is aryl or heteroaryl and R corresponds to any substiment for which the
  • R H or CH3-;
  • R j is substimted aryl or cyclohexyl
  • X is a suitable substiment
  • R 2 can be H or alkyl.
  • X is -OH. -NH 2 or -NR R where R is as defined above.
  • the reported ketone is a versatile synthetic intermediate which can be modified by conventional methods such as reductive amination, reduction, etc.
  • saturated bicyclic ⁇ -aminolactams are also contemplated for use in the synthesis of compounds of formulas I-VI.
  • Such saturated bicyclic ⁇ -aminolactams are well known in the art. For example.
  • RI and R2 are H or -CH3
  • ring A can have from 6-13 members and ring B can have from 5 - 7 members.
  • R can be alkyl, aryl, cycloalkyl, and the like.
  • Lactams having further heteroatom(s) in the cyclic lactam structure are described by
  • X O, S and NR wherein R is, for example, alkyl, substimted alkyl, aryl, heteroaryl, heterocyclic, heterocyclooxy, and the like.
  • R is acyl, alkyl, substimted alkyl, aryl, heteroaryl or heterocyclic provided that R is not an acid labile group such as t-Boc; and R' is hydrogen, alkyl, substimted alkyl, alkoxy. substituted alkoxy, aryl. aryloxy, heteroaryl, heteroarvloxy, heterocyclic, heterocyclooxy, halo, cyano, nitro, trihalomethyl, and the like.
  • R is as defined in this reference.
  • the disclosure of Yokoo, et al. can be extended to cover R being alkyl, substimted alkyl, aryl, alkoxy, substimted alkoxy, heteroaryl, cycloalkyl, heterocyclic, heterocyclooxy, alkenyl. substimted alkenyl, and the like.
  • R' is as defined in the reference and R can be alkyl, substimted alkyl, aryl, alkoxy, substimted alkoxy, heteroaryl, cycloalkyl, heterocyclic, heterocyclooxy, alkenyl, substituted alkenyl, and the like.
  • the coupling agent is any standard reagent used in the formation of typical peptide or amide bonds, for example, carbodiimide reagents. See, also,
  • R 2 will be limited to aryl and heteroaryl groups and sterically hindered alkyl groups such as t-butyl.
  • R j can be highly variable and is limited only by subsequent reaction steps.
  • the Kametani procedure allows for a wide selection of RI and R2 groups limited primarily by stability to the reaction conditions.
  • the first synthetic route is:
  • Selective al yl;atio ⁇ R 2 can be highly variable (e.g. , alkyl, substimted alkyl, aryl, heteroaryl, heterocyclic and the like) since a number of well documented routes exist for the synthesis of nitroethylene derivatives from aldehydes and nitromethane (Henry reaction) followed by dehydration.
  • R j is limited to groups that can undergo alkylation reactions.
  • the second compound series can be prepared as follows:
  • R 2 can be highly variable.
  • the starting component required to introduce R 2 can be readily derived by the reduction of any known ⁇ - BOC-amino acid to the alcohol derivative followed by formation of the mesylate.
  • Beckmann/ Schmidt ring expansion reaction using either inter- or intramolecular approaches serves to prepare lactams of various ring sizes.
  • the intramolecular approach generates bicyclic materials with the lactam nitrogen incorporated into the ring fusion.
  • Additional approaches set forth above involve the internal cyclization of omega-amino acids/esters where the construction of the substiment pattern takes place prior to cyclization, and internal cyclization of an electrophilic center onto a nucleophilic functional group as in the Friedel Crafts type cyclization used in the Ben-Ishal procedure for making benzazepinones. This latter procedure is applicable to a wide variety of heteroaromatics as well as benzenoid rings, and may also be applied to non-aromatic double or triple bonds to generate a wide array of substiments or ring fusions.
  • the 5,7-dihydro-6H-dibenz[b,d]azepin-6-one derivatives employed in this invention can be prepared using conventional procedures and reagents.
  • an appropriately substimted N-tert-Boc-2-amino-2'- methy lbiphenyl compound can be cyclized to form the corresponding 5,7-dihydro- 6H-dibenz[b,d]azepin-6-one derivative by first treating the biphenyl compound with about 2.1 to about 2.5 equivalents of a strong base, such as sec-butyl lithium. This reaction is typically conducted at a temperature ranging from about -80°C to about -60 °C in an inert diluent such as THF.
  • the resulting dianion is then treated with dry carbon dioxide at a temperature of about -78°C to afford the 5,7-dihydro- 6H-diben[b,d]azepin-6-one.
  • This procedure is described further in R. D. Clark et al., Tetrahedron, 49(7), 1351-1356 (1993) and references cited therein.
  • the amide nitrogen can be readily alkylated by first treating the dibenazepinone with about 1.1 to about 1.5 equivalents of a strong base, such as sodium hydride, in an inert diluent, such as DMF.
  • This reaction is typically conducted at a temperamre ranging from about -10 °C to about 80° C for about 0.5 to about 6 hours.
  • the resulting anion is then contacted with an excess, preferably about 1.1 to about 3.0 equivalents, of an alkyl halide, typically an alkyl chloride, bromide or iodide.
  • an alkyl halide typically an alkyl chloride, bromide or iodide.
  • this reaction is conducted at a temperamre of about 0°C to about 100°C for about 1 to about 48 hours.
  • An amino group can then be introduced at the 5-position of the 7-alkyl-5,7- dihydro-6H-diben[b,d]azepin-6-one using conventional procedures and reagents.
  • a strong base such as potassium 1,1 , 1,3,3,3-hexamethyldisilazane (KHMDS)
  • KHMDS potassium 1,1 , 1,3,3,3-hexamethyldisilazane
  • benzodiazepine derivatives suitable for use in this invention can be prepared using conventional procedures and reagents.
  • a 2-aminobenzophenone can be readily coupled to ⁇ -(isopropylthio)-N- (benzyloxycarbonyl)glycine by first forming the acid chloride of the glycine derivative with oxalyl chloride, and then coupling the acid chloride with the 2- aminobenzophenone in the presence of a base, such as 4-methylmorpholine, to afford the 2-[ -(isopropylthio)-N-(benzyloxycarbonyl)glycinyl]- aminobenzophenone.
  • a base such as 4-methylmorpholine
  • 2,3-dihydro-5-phenyl-lH-l ,4-benzodiazepin-2-ones can be readily aminated at the 3 -position using conventional azide transfer reactions followed by reduction of the resulting azido group to form the corresponding amino group. The conditions for these and related reactions are described in the examples set forth below. Additionally, 2,3-dihydro-5-phenyl-lH-l ,4- benzodiazepin-2-ones are readily alkylated at the 1 -position using conventional procedures and reagents.
  • this reaction is typically conducted by first treating the benzodiazepinone with about 1.1 to about 1.5 equivalents of a base, such as sodium hydride, potassium tert-butoxide, potassium 1,1 , 1 ,3,3,3- hexamethyldisilazane. cesium carbonate, in an inert diluent, such as DMF. This reaction is typically conducted at a temperature ranging from about -78 °C to about 80 °C for about 0.5 to about 6 hours. The resulting anion is then contacted with an excess, preferably about 1.1 to about 3.0 equivalents, of an alkyl halide, typically an alkyl chloride, bromide or iodide. Generally, this reaction is conducted at a temperamre of about 0°C to about 100°C for about 1 to about 48 hours.
  • a base such as sodium hydride, potassium tert-butoxide, potassium 1,1 , 1 ,3,3,3- hexamethyldisilazane. ces
  • 3-amino-2,4-dioxo-2,3,4,5-tetrahydro-lH-l,5- benzodiazepines employed in this invention are typically prepared by first coupling malonic acid with a 1 ,2-phenylenediamine. Conditions for this reaction are well known in the art and are described, for example, in PCT Application WO 96- US8400 960603. Subsequent alkylation and amination using conventional procedures and reagents affords various 3-amino-l ,5-bis(alkyl)-2,4-dioxo-2, 3,4,5- tetrahydro-lH-l ,5-benzodiazepines. Such procedures are described in further detail in the example set forth below.
  • the starting materials can contain a chiral center (e.g. , alanine) and, when a racemic starting material is employed, the resulting product is a mixmre of R,S enantiomers.
  • a chiral isomer of the starting material can be employed and, if the reaction protocol employed does not racemize this starting material, a chiral product is obtained.
  • Such reaction protocols can involve inversion of the chiral center during synthesis.
  • the compounds described herein are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • the pharmaceutical compositions contain, as the active ingredient, one or more of the compounds described above, associated with pharmaceutically acceptable carriers.
  • the pharmaceutical compositions can be prepared, for example, by mixing the active ingredient with an excipient, diluting the active ingredient with an excipient, or enclosing the active ingredient within a carrier such as a capsule (including microparticles, nanoparticles, and liposomes), sachet, paper or other container.
  • a carrier such as a capsule (including microparticles, nanoparticles, and liposomes), sachet, paper or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, macrocrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • the compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the compound of Formulas I-VI above is employed at no more than about 20 weight percent of the pharmaceutical composition, more preferably no more- than about 15 weight percent, with the balance being pharmaceutically inert carrier(s).
  • the active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixmre of a compound of the present invention.
  • a solid preformulation composition containing a homogeneous mixmre of a compound of the present invention.
  • the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can separated by enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • aqueous solutions suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face masks tent, or intermittent positive pressure breathing machine.
  • Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
  • the following formulation examples illustrate the pharmaceutical compositions of the present invention.
  • the above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
  • a tablet formula is prepared using the ingredients below:
  • Quantity Ingredient (mg/tablet)
  • the components are blended and compressed to form tablets, each weighing 240 mg.
  • Formulation Example 3 A dry powder inhaler formulation is prepared containing the following components:
  • the active ingredient is mixed with the lactose and the mixmre is added to a dry powder inhaling appliance.
  • Formulation Example 4 Tablets, each containing 30 mg of active ingredient, are prepared as follows:
  • the active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinyl-pyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve.
  • the granules so produced are dried at 50 to 60°C and passed through a 16 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
  • the active ingredient, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
  • Suppositories each containing 25 mg of active ingredient are made as follows:
  • the active ingredient, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 560 mg quantities .
  • a subcutaneous formulation may be prepared as follows: Ingredient Quantity
  • a topical formulation may be prepared as follows:
  • the white soft paraffin is heated until molten.
  • the liquid paraffin and emulsifying wax are inco ⁇ orated and stirred until dissolved.
  • the active ingredient is added and stirring is continued until dispersed.
  • the mixmre is then cooled until solid.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g.. U.S. Patent 5,023,252, issued June 11, 1991, herein inco ⁇ orated by reference.
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Indirect techniques usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs.
  • Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier.
  • the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.
  • the compounds and pharmaceutical compositions of the invention are useful in inhibiting ⁇ -amyloid peptide release and/or its synthesis, and, accordingly, have utility in diagnosing and treating Alzheimer's disease in mammals including humans.
  • the compounds described herein are suitable for use in a variety of drug delivery systems described above. Additionally, in order to enhance the in vivo serum half-life of the administered compound, the compounds may be encapsulated, introduced into the lumen of liposomes, prepared as a colloid, or other conventional techniques may be employed which provide an extended serum half-life of the compounds.
  • a variety of methods are available for preparing liposomes, as described in, e.g., Szoka, et al. , U.S. Patent Nos. 4,235,871, 4,501 ,728 and 4,837,028, the contents of each of which is inco ⁇ orated herein by reference.
  • compositions are administered to a patient already suffering from AD in an amount sufficient to at least partially arrest further onset of the symptoms of the disease and its complications. An amount adequate to accomplish this is defined as "therapeutically effective dose. "
  • the compounds described herein are administered at dosages ranging from about 1 to about 500 mg/kg/day.
  • compositions are administered to a patient at risk of developing AD (determined for example by genetic screening or familial trait) in an amount sufficient to inhibit the onset of symptoms of the disease.
  • An amount adequate to accomplish this is defined as a "prophylactically effective dose. " Amounts effective for this use will depend on the judgment of the attending clinician depending upon factors such as the age, weight and general condition of the patient, and the like.
  • the compounds described herein are administered at dosages ranging from about 1 to about 500 mg/kg/day.
  • the compounds administered to a patient are in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered. The resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 and 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
  • the compounds described herein are also suitable for use in the administration of the compounds to a cell for diagnostic and drug discovery pu ⁇ oses. Specifically, the compounds may be used in the diagnosis of cells releasing and/or synthesizing ⁇ -amyloid peptide. In addition the compounds described herein are useful for the measurement and evaluation of the activity of other candidate drugs on the inhibition of the cellular release and/or synthesis of ⁇ -amyloid peptide.
  • HOBT 1-hydroxybenzotriazole hydrate
  • Hunig's base diisopropylethylamine

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des composés inhibant la libération du peptide β-amyloïde et/ou sa synthèse et présentant par conséquent une utilité dans le traitement de la maladie d'Alzheimer. L'invention concerne également des compositions pharmaceutiques comprenant un composé inhibant la libération du peptide β-amyloïde et/ou sa synthèse ainsi que des méthodes de traitement de la maladie d'Alzheimer à la fois de façon prophylactique et thérapeutique à l'aide de ces compositions pharmaceutiques.
PCT/US1999/014193 1998-06-22 1999-06-22 COMPOSES D'INHIBITION DE LA LIBERATION DU PEPTIDE β-AMYLOIDE ET/OU DE SA SYNTHESE WO1999067221A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU47101/99A AU4710199A (en) 1998-06-22 1999-06-22 Compounds for inhibiting beta-amyloid peptide release and/or its synthesis
JP2000555875A JP2002518483A (ja) 1998-06-22 1999-06-22 β−アミロイドペプチド放出を阻害するための化合物および／またはその合成
CA002325389A CA2325389A1 (fr) 1998-06-22 1999-06-22 Composes d'inhibition de la liberation du peptide .beta.-amyloide et/ou de sa synthese
EP99930594A EP1089980A1 (fr) 1998-06-22 1999-06-22 Composes d'inhibition de la liberation du peptide beta-amyloide et/ou de sa synthese

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US10250798A 1998-06-22 1998-06-22
US09/102,507 1998-06-22

Publications (1)

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WO1999067221A1 true WO1999067221A1 (fr) 1999-12-29

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JP (1) JP2002518483A (fr)
AU (1) AU4710199A (fr)
CA (1) CA2325389A1 (fr)
WO (1) WO1999067221A1 (fr)

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WO2001027108A1 (fr) * 1999-10-08 2001-04-19 Bristol-Myers Squibb Pharma Company AMINO SULFONAMIDES DE LACTAME UTILISES COMME INHIBITEURS DE LA PRODUCTION DE PROTEINE A$g(b)
WO2001072324A1 (fr) * 2000-03-28 2001-10-04 Bristol-Myers Squibb Pharma Company Lactames en tant qu'inhibiteurs de production de proteines a-beta
WO2001074783A1 (fr) * 2000-04-03 2001-10-11 Dupont Pharmaceuticals Company Lactames cycliques utilises comme inhibiteurs de la production de la proteine beta-amyloide
WO2001060826A3 (fr) * 2000-02-17 2002-01-17 Du Pont Pharm Co CARBOCYCLES ET HETEROCYCLES SUCCINOYLAMINO UTILISES EN TANT QU'INHIBITEURS DE LA PRODUCTION DE LA PROTEINE A$g(b)
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US6503902B2 (en) 1999-09-13 2003-01-07 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of a β protein production
US6509333B2 (en) 2000-06-01 2003-01-21 Bristol-Myers Squibb Pharma Company Lactams substituted by cyclic succinates as inhibitors of Aβ protein production
US6713476B2 (en) 2000-04-03 2004-03-30 Dupont Pharmaceuticals Company Substituted cycloalkyls as inhibitors of a beta protein production
US6794381B1 (en) 1998-08-07 2004-09-21 Bristol-Myers Squibb Company Succinoylamino lactams as inhibitors of aβ protein
WO2004080983A1 (fr) * 2003-03-14 2004-09-23 Astrazeneca Ab Nouveaux lactames et leurs utilisations
US6846836B2 (en) 2003-04-18 2005-01-25 Bristol-Myers Squibb Company N-substituted phenylurea inhibitors of mitochondrial F1F0 ATP hydrolase
US6878363B2 (en) 2000-05-17 2005-04-12 Bristol-Myers Squibb Pharma Company Use of small molecule radioligands to discover inhibitors of amyloid-beta peptide production and for diagnostic imaging
US6900199B2 (en) 2000-04-11 2005-05-31 Bristol-Myers Squibb Pharma Company Substituted lactams as inhibitors of Aβ protein production
WO2005055940A3 (fr) * 2003-12-03 2005-09-15 Glaxo Group Ltd Nouveaux antagonistes de recepteur d'acetylcholine muscarinique m3
US6960576B2 (en) 1999-09-13 2005-11-01 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of Aβ protein production
US7053084B1 (en) 1998-12-24 2006-05-30 Bristol-Myers Squibb Company Succinoylamino benzodiazepines as inhibitors of Aβ protein production
US7153491B2 (en) 1998-11-12 2006-12-26 Bristol-Myers Squibb Pharma Company Use of small molecule radioligands to discover inhibitors of amyloid-beta peptide production and for diagnostic imaging
US7304055B2 (en) 1998-08-07 2007-12-04 Bristol-Myers Squibb Pharma Company Succinoylamino lactams as inhibitors of Aβ protein production
US7312358B2 (en) 2000-10-17 2007-12-25 Laboratoires Serono Sa Pharmaceutically active sulfanilide derivatives
WO2008099210A2 (fr) 2007-02-12 2008-08-21 Merck & Co., Inc. Dérivés de pipérazine pour le traitement de la maladie d'alzheimer et des conditions apparentées
WO2009128057A2 (fr) 2008-04-18 2009-10-22 UNIVERSITY COLLEGE DUBLIN, NATIONAL UNIVERSITY OF IRELAND, DUBLIN et al Produits psycho-pharmaceutiques
US7858776B2 (en) 2002-10-03 2010-12-28 Astrazeneca Ab Lactams and uses thereof
EP2489656A1 (fr) 2007-12-21 2012-08-22 Ligand Pharmaceuticals Inc. Modulateurs de récepteurs androgènes sélectifs (sarm) et leurs utilisations
US8258302B2 (en) 2006-01-31 2012-09-04 Api Corporation Method for producing benzazepinone
CN103214391A (zh) * 2013-05-11 2013-07-24 罗梅 一种手性化合物
EP3613418A1 (fr) 2014-01-17 2020-02-26 Ligand Pharmaceuticals, Inc. Procédés et compositions de modulation des niveaux d'hormones
WO2023241738A3 (fr) * 2022-06-15 2024-02-15 复旦大学 Composé de 1,4-benzodiazépine et utilisation associée dans la préparation d'un médicament antitumoral
US12319651B2 (en) 2019-04-19 2025-06-03 Ligand Pharmaceuticals Incorporated Crystalline forms and methods of producing crystalline forms of a compound

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US11939302B2 (en) 2020-10-21 2024-03-26 The Governors Of The University Of Alberta Compounds for the treatment of Alzheimer's disease

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US6794381B1 (en) 1998-08-07 2004-09-21 Bristol-Myers Squibb Company Succinoylamino lactams as inhibitors of aβ protein
US7304055B2 (en) 1998-08-07 2007-12-04 Bristol-Myers Squibb Pharma Company Succinoylamino lactams as inhibitors of Aβ protein production
US7101870B2 (en) 1998-08-07 2006-09-05 Bristol-Myers Squibb Pharma Company Succinoylamino lactams as inhibitors of A-β protein production
US7304056B2 (en) 1998-08-07 2007-12-04 Bristol-Myers Squibb Pharma Company Succinoylamino lactams as inhibitors of Aβ protein production
US6962913B2 (en) 1998-08-07 2005-11-08 Bristol-Myers Squibb Company Benzo-1,4-diazepin-2-ones as inhibitors of Aβ protein production
US7507815B2 (en) 1998-08-07 2009-03-24 Bristol-Myers Squibb Pharma Company Succinoylamino lactams as inhibitors of a-β protein production
US7153491B2 (en) 1998-11-12 2006-12-26 Bristol-Myers Squibb Pharma Company Use of small molecule radioligands to discover inhibitors of amyloid-beta peptide production and for diagnostic imaging
US7053084B1 (en) 1998-12-24 2006-05-30 Bristol-Myers Squibb Company Succinoylamino benzodiazepines as inhibitors of Aβ protein production
US7718795B2 (en) 1998-12-24 2010-05-18 Bristol-Myers Squibb Pharma Company Succinoylamino benzodiazepines as inhibitors of aβ protein production
US7304049B2 (en) 1998-12-24 2007-12-04 Bristol-Myers Squibb Pharma Company Succinoylaminobenzodiazepines as inhibitors of Aβ protein production
US7456172B2 (en) 1998-12-24 2008-11-25 Bristol-Myers Squibb Pharma Company Succinoylamino benzodiazepines as inhibitors of Aβ protein production
US7423033B2 (en) 1999-09-13 2008-09-09 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of aβ protein production
US6960576B2 (en) 1999-09-13 2005-11-01 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of Aβ protein production
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US6503902B2 (en) 1999-09-13 2003-01-07 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of a β protein production
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WO2001027091A1 (fr) * 1999-10-08 2001-04-19 Du Pont Pharmaceuticals Company AMINO SULFONAMIDES DE LACTAME UTILISES COMME INHIBITEURS DE LA PRODUCTION DE PROTEINE A$g(b)
US6503901B1 (en) 1999-10-08 2003-01-07 Bristol Myers Squibb Pharma Company Amino lactam sulfonamides as inhibitors of Aβ protein production
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US6432944B1 (en) 2000-07-06 2002-08-13 Bristol-Myers Squibb Company Benzodiazepinone β-amyloid inhibitors: arylacetamidoalanyl derivatives
US7312358B2 (en) 2000-10-17 2007-12-25 Laboratoires Serono Sa Pharmaceutically active sulfanilide derivatives
US7858776B2 (en) 2002-10-03 2010-12-28 Astrazeneca Ab Lactams and uses thereof
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US6846836B2 (en) 2003-04-18 2005-01-25 Bristol-Myers Squibb Company N-substituted phenylurea inhibitors of mitochondrial F1F0 ATP hydrolase
WO2005055940A3 (fr) * 2003-12-03 2005-09-15 Glaxo Group Ltd Nouveaux antagonistes de recepteur d'acetylcholine muscarinique m3
US8258302B2 (en) 2006-01-31 2012-09-04 Api Corporation Method for producing benzazepinone
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EP3613418A1 (fr) 2014-01-17 2020-02-26 Ligand Pharmaceuticals, Inc. Procédés et compositions de modulation des niveaux d'hormones
US12319651B2 (en) 2019-04-19 2025-06-03 Ligand Pharmaceuticals Incorporated Crystalline forms and methods of producing crystalline forms of a compound
WO2023241738A3 (fr) * 2022-06-15 2024-02-15 复旦大学 Composé de 1,4-benzodiazépine et utilisation associée dans la préparation d'un médicament antitumoral

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AU4710199A (en) 2000-01-10
JP2002518483A (ja) 2002-06-25
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CA2325389A1 (fr) 1999-12-29

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