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WO1997015564A1 - Steroides 4-oxa et 4-thia - Google Patents

Steroides 4-oxa et 4-thia Download PDF

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Publication number
WO1997015564A1
WO1997015564A1 PCT/US1996/016883 US9616883W WO9715564A1 WO 1997015564 A1 WO1997015564 A1 WO 1997015564A1 US 9616883 W US9616883 W US 9616883W WO 9715564 A1 WO9715564 A1 WO 9715564A1
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WO
WIPO (PCT)
Prior art keywords
androst
methyl
oxa
thia
carboxamide
Prior art date
Application number
PCT/US1996/016883
Other languages
English (en)
Inventor
Raman K. Bakshi
Gool F. Patel
Gary H. Rasmusson
Richard L. Tolman
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9602905.3A external-priority patent/GB9602905D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to JP9516711A priority Critical patent/JPH11513981A/ja
Priority to EP96936811A priority patent/EP0858455A4/fr
Priority to AU74644/96A priority patent/AU713582B2/en
Priority to US09/065,112 priority patent/US5998464A/en
Publication of WO1997015564A1 publication Critical patent/WO1997015564A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
    • C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
    • C07J73/006—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by sulfur as hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/28—Antiandrogens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
    • C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
    • C07J73/003—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by oxygen as hetero atom

Definitions

  • the present invention provides novel compounds, novel compositions, methods of their use and methods of their manufacture, where such compounds are generally pharmacologically useful as agents in therapies whose mechanism of action rely on the inhibition of 5 ⁇ - reductase.
  • Certain undesirable physiological manifestations such as acne vulgaris, seborrhea, female hirsutism, androgenic alopecia which includes female and male pattern baldness, and benign prostatic hype ⁇ lasia, are the result of hyperandrogenic stimulation caused by excessive accumulation of testosterone ("T") or similar androgenic hormones in the metabolic system. Androgenic alopecia is also known as androgenetic alopecia.
  • T testosterone
  • Androgenic alopecia is also known as androgenetic alopecia.
  • Early attempts to provide a chemotherapeutic agent to counter the undesirable results of hyperandrogenicity resulted in the discovery of several steroidal antiandrogens having undesirable hormonal activities of their own.
  • the estrogens for example, not only counteract the effect of the androgens but have a feminizing effect as well.
  • Non-steroidal antiandrogens have also been developed, for example, 4'-nitro-3'-trifluoromethyl-isobutyranilide. See Neri, et al., Endocrinol. 1972, 91 (2).
  • these products though devoid of hormonal effects, compete with all natural androgens for receptor sites, and hence have a tendency to feminize a male host or the male fetus of a female host and/or initiate feed-back effects which would cause hyperstimulation of the testes.
  • the principal mediator of androgenic activity in some target organs e.g.
  • DHT 5 ⁇ -dihydrotestosterone
  • Inhibitors of testosterone-5 ⁇ -reductase will serve to prevent or lessen symptoms of hyperandrogenic stimulation in these organs. See especially United States Patent Nos. 4,377,584, issued March 22, 1983, and 4,760,071, issued July 26, 1988, both assigned to Merck & Co., Inc.
  • the enzyme 5 ⁇ -reductase catalyzes the reduction of testosterone to the more potent androgen, dihydrotestosterone, as shown below:
  • Finasteride ( 17 ⁇ -(N-tert-buty lcarbamoyl)-3-oxo-4-aza-5 ⁇ - androst-l-ene-3-one) as shown below, is a potent inhibitor of the human prostate enzyme.
  • finasteride is known to be useful in the treatment of hyperandrogenic conditions; see eg. U.S. 4,760,071. Finasteride is currently prescribed for the treatment of benign prostatic hype ⁇ lasia (BPH), a condition afflicting to some degree the majority of men over age 55. Finasteride's utility in the treatment of androgenic alopecia and prostatic carcinoma is also disclosed in the following documents: EP 0 285,382, published 5 October 1988; EP 0 285,383, published 5 October 1988; Canadian Patent no. 1 ,302,277; and Canadian Patent no. 1,302,276.
  • BPH benign prostatic hype ⁇ lasia
  • Finasteride's utility in the treatment of androgenic alopecia and prostatic carcinoma is also disclosed in the following documents: EP 0 285,382, published 5 October 1988; EP 0 285,383, published 5 October 1988; Canadian Patent no. 1 ,302,277; and Canadian Patent no. 1,302,276.
  • isozymes of 5 ⁇ -reductase there are two isozymes of 5 ⁇ -reductase in humans.
  • One isozyme (type 1 or 5 ⁇ -reductase 1) predominates in sebaceous glands of facial and skin tissue and is relatively insensitive to finasteride (see, e.g., G. Harris, et al., Proc. Natl. Acad. Sci. USA, Vol. 89, pp. 10787-10791 (Nov. 1992)); the other (type 2 or 5 ⁇ -reductase 2) predominates in the prostate and is potently inhibited by finasteride.
  • type 1 or 5 ⁇ -reductase 1 predominates in sebaceous glands of facial and skin tissue and is relatively insensitive to finasteride (see, e.g., G. Harris, et al., Proc. Natl. Acad. Sci. USA, Vol. 89, pp. 10787-107
  • novel compounds of the present invention are those of structural formula I:
  • X is selected from O and S, or a pharmaceutically acceptable salt, ester, or stereoisomer thereof, and are inhibitors of 5 ⁇ -reductase.
  • the compounds of formula I are useful in the oral, systemic, parenteral or topical treatment of hyperandrogenic conditions such as acne vulgaris, seborrhea, androgenic alopecia which includes female and male pattem baldness, female hirsutism, benign prostatic hype ⁇ lasia, and the prevention and treatment of prostatic carcinoma, as well as in the treatment of prostatitis.
  • Another object of this invention is to provide compounds of formula I in combination with other active agents, for example with finasteride, or a potassium channel opener, such as minoxidil, or a retinoic acid or a derivative thereof, wherein such combinations would be useful in one or more of the above-mentioned methods of treatment or pharmaceutical compositions.
  • active agents for example with finasteride, or a potassium channel opener, such as minoxidil, or a retinoic acid or a derivative thereof, wherein such combinations would be useful in one or more of the above-mentioned methods of treatment or pharmaceutical compositions.
  • the C5-C6 bond designated with a dotted line independently represents a single or double bond, provided that when the C5-C6 is a double bond, H a is absent and when the C5-C6 bond is a single bond Ha is present and represents hydrogen;
  • X is selected from oxygen and sulfur;
  • Rl is selected from hydrogen and Ci-5 alkyl
  • R 2 is selected from CH3, CH2OR 3 , and H;
  • R3 is selected from: C 1-5 alkyl
  • Al is selected from: (1) -H,
  • Heteroaryl is selected from piperidinyl, piperizinyl, pyrrolidinyl, pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, indolyl and benzofuranyl.
  • (a) protected hydroxy is selected from: dimethyl-t-butyl silyloxy, trimethylsilyloxy, tri-ethylsilyloxy, tri- isopropylsilyloxy, and triphenylsilyloxy ;
  • Cl-10 alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, 1,5-dimethylhexyl, 6-methylhept-2-yl, 5- methylhexyl, and l-methyl-4-isopropylhexyl;
  • substituted or unsubstituted C2-10alkenyl is selected from: phenylmethylene, chlorophenylmethylene, ethoxycarbonylpheny lmethy lene , carboxyphenylmethylene, (((1 ,1 -dimethylethyl) amino) carbony l)pheny lmethy lene, trimethoxyphenyl methylene, methoxypheny lmethy lene, methy lsulfony lpheny lmethy lene , biphenylmethy lene , nitrophenylmethylene, aminopheny lmethy lene, acetylaminophenylmethylene, pivaloylaminophenylmethylene, phenoxyphenylmethylene,
  • aryl substituted Cl-io alkyl is selected from omega- pheny Ipropyl and l-(chlorophenoxy)ethyl;
  • aryl is selected from phenyl, and naphthyl;
  • substituted aryl or heteroaryl is selected from phenyl, pyridyl and pyrimidinyl substituted with one to three substituents independently selected from:
  • aryl or heteroaryl carbamoyl substituted Cl-10 alkyl is selected from 2-(4-pyridyl-carbamoyl)ethyl and 2-phenyl- ethyl;
  • Cl-l ⁇ alkylcarbonyl is selected from isobutylcarbonyl and isopropylcarbonyl;
  • aryl or heteroaryl carbonyl is selected from phenylcarbonyl and pyridyl carbonyl;
  • ether-substituted Ci-l oalkyl is selected from 1-methoxy- ethyl and 1-ethoxy-ethyl;
  • thioether-substituted Cl-l oalkyl is selected from 1- methylthio-ethyl, and 1-ethylthio-ethyl;
  • keto-substituted Cl-l Oalkyl is 1 -keto-ethyl, ketomethyl, 1- ketopropyl, and ketobutyl;
  • heteroaryl-substituted Cl-10 alkyl is omega-(4-pyridyl)- butyl;
  • carboxylic esters are Cl-10 alkylcarboxylic esters selected from carbomethoxy and carboethoxy;
  • carboxamides are selected from N-N-diisopropy
  • Cl -l Oalkanoy loxyC l -2alkyl is selected from acetyloxymethyl, trimethylacetyloxymethyl, and (2- ethy lhexanoy loxy )methy 1 ;
  • urea is t-butylcarbony lamino urea;
  • Cl-10 alky lureido C ⁇ -5 alkyl is selected from: N-t- butylureidomethyl, N-n-propylureidomethyl, N-n- octylureidomethyl, N-isopropylureido, allylureido,
  • substituted or unsubstituted arylureidoC ⁇ -5 alkyl is selected from: N-(ethylphenyl) ureidomethyl, N-(chlorophenyl) ureidomethyl, N-phenylureidomethyl, N-(dichloroph
  • (w) ether is selected from ethylene ketal, and
  • thioether is selected from: Cl-8alkylthio, phenylthio, and Cl-8 alkylthio substituted with phenyl;
  • (y) substituted and unsubstituted aryl or heteroaryl ether is selected from thiophenoxy, biphenyloxy, acetamidophenoxy, (3-pyridyl)oxy, chlorophenyloxy, methylphenyloxy, phenoxy, hydroxyphenyloxy, methylsulfonylphenyloxy and pyrimidinyloxy.
  • Rl is hydrogen
  • R 2 is selected from H and CH3
  • Al is selected from: carboxamide, including substituted and unsubstituted anilide derivatives.
  • carboxamide is selected from: N,N-diisopropyl carboxamide, N-t-butyl carboxamide, N-t-octyl carboxamide, N-n-octyl carboxamide, N- (hydroxyphenyl) carboxamide, N-phenylcarboxamide, N-(aminophenyl) carboxamide, N-(carbomethoxy)phenyl carboxamide, N- (methoxycarboxy) phenyl carboxamide, N-acetamidophenyl-N-acetyl- carboxamide, N-acetamidophenyl-carboxamide, N-pivalamidophenyl carboxamide, N-isobutyramidophen
  • Rl is hydrogen
  • R 2 is selected from H and CH3
  • the C5-C6 bond designated with a dotted line is a single bond
  • Ha is present and represents hydrogen
  • A is selected from: carboxamide, including substituted and unsubstituted anilide derivatives.
  • carboxamide is selected from: N,N-diisopropyl carboxamide, N-t-butyl carboxamide, N-t-octyl carboxamide, N-n-octyl carboxamide, N-
  • Rl is hydrogen
  • R 2 is selected from H and CH3
  • the C5-C6 bond designated with a dotted line is a double bond
  • Ha is absent
  • A is selected from: carboxamide, including substituted and unsubstituted anilide derivatives.
  • carboxamide is selected from: N-N-diisopropyl carboxamide, N-t-butyl carboxamide, N-t-octyl carboxamide, N-n-octyl carboxamide, N- (hydroxyphenyl) carboxamide, N-phenylcarboxamide, N-(aminophenyl) carboxamide, N-(carbomethoxy)phenyl carboxamide, N- (methoxycarboxy) phenyl carboxamide, N-acetamidophenyl-N-acetyl- carboxamide, N-acetamidophenyl-carboxamide, N-pivalamidophenyl carboxamide, N-isobutyramidophenyl carboxamide, N-(methyl),N- (diphenylmethyl) carboxamide, N-(di ⁇ henylmethyl)-carboxamide, N-t- butyl carboxamide, N-is
  • Rl is CH3, R 2 is selected from H and CH3, and Al is a selected from: carboxamide, including substituted and unsubstituted anilide derivatives, and Cl-10 alkyl.
  • Rl is Cl-5 alkyl
  • R 2 is selected from hydrogen and methyl
  • a 2 is selected from: alkoxy, aryloxy, either unsubstituted or substituted, heteroaryloxy, either substituted or unsubstituted, and alkyl, either unsubstituted or substituted.
  • a 2 is selected from: substituted aryloxy, and heteroaryloxy, either substituted or unsubstituted.
  • Exemplifying compounds of this subclass are compounds wherein the C5-C6 bond designated with a dotted line is a single bond, and Ha is present and represents hydrogen.
  • Rl is H or CH3
  • R 2 is selected from H and CH3
  • a 2 is selected from: substituted and unsubstituted aryl or heteroaryl ether.
  • substituted and unsubstituted aryl or heteroaryl ether is selected from thiophenoxy, biphenyloxy, acetamidophenoxy, (3- pyridyl)oxy, chlorophenyloxy, methylphenyloxy, phenoxy, hydroxypheny loxy, methylsulfonylphenyloxy and pyrimidinyloxy.
  • substituted or unsubstituted aryl or heteroaryl ether is selected from 4-methyl-phenoxy, 4-chlorophenoxy, and 2- pyrimidinyloxy.
  • Rl is hydrogen
  • R 2 is selected from H and CH3
  • Al is selected from: carboxamide, including substimted and unsubstituted anilide derivatives.
  • carboxamide is selected from: N,N-diisopropyl carboxamide, N-t-butyl carboxamide, N-t-octyl carboxamide, N-n-octyl carboxamide, N-
  • Rl is hydrogen
  • R 2 is selected from H and CH3
  • the C5-C6 bond designated with a dotted line is a single bond
  • Ha is present and represents hydrogen
  • A is selected from: carboxamide, including substituted and unsubstituted anilide derivatives.
  • carboxamide is selected from: N,N-diisopropyl carboxamide, N-t-butyl carboxamide, N-t-octyl carboxamide, N-n-octyl carboxamide, N- (hydroxyphenyl) carboxamide, N-phenylcarboxamide, N-(aminophenyl) carboxamide, N-(carbomethoxy)phenyl carboxamide, N- (methoxycarboxy) phenyl carboxamide, N-acetamidophenyl-N-acetyl- carboxamide, N-acetamidophenyl-carboxamide, N-pivalamidophenyl carboxamide, N-isobutyramidophenyl carboxamide, N-(methyl),N- (diphenylmethyl) carboxamide, N-(diphenylmethyl)-carboxamide, N-t- butyl carboxamide, N-isopropyl carboxamide, N-(
  • Rl is hydrogen
  • R 2 is selected from H and CH3
  • the C5-C6 bond designated with a dotted line is a double bond
  • Ha is absent
  • Al is selected from: carboxamide, including substituted and unsubstituted anilide derivatives.
  • carboxamide is selected from: N,N-diisopropyl carboxamide, N-t-butyl carboxamide, N-t-octyl carboxamide, N-n-octyl carboxamide, N-
  • R is CH3, R 2 is selected from H and CH3, and Al is a selected from: carboxamide, including substituted and unsubstituted anilide derivatives, and Ci-io alkyl.
  • 16 ⁇ -(4-methyl-phenoxy)-7 ⁇ -methyl-4-thia-5 ⁇ -androst- 1 -en-3- one 16 ⁇ -(l-(3-chlorophenoxy)ethyl)-7 ⁇ -methyl-4-thia-5 ⁇ -androst-l- en-3-one
  • 16 ⁇ -(4-chlorophenoxy)-7 ⁇ -methyl-4-thia-5 ⁇ -androst-l-en-3-one 16 ⁇ -(2-pyrimidinyloxy)-7 ⁇ -methyl-4-thia-5 ⁇ -androst-l-en-3- one.
  • R is Ci-5 alkyl
  • R 2 is selected from hydrogen and methyl
  • a 2 is selected from: alkoxy, aryloxy, either unsubstituted or substituted, heteroaryloxy, either substituted or unsubstituted, and alkyl, either unsubstituted or substituted.
  • a 2 is selected from: substituted aryloxy, and heteroaryloxy, either substituted or unsubstituted.
  • Exemplifying compounds of this subclass are compounds wherein the C5-C6 bond designated with a dotted line is a single bond, and Ha is present and represents hydrogen.
  • Rl is H or CH3
  • R 2 is selected from H and CH3
  • a 2 is selected from: substituted and unsubstituted aryl or heteroaryl ether.
  • substituted and unsubstituted aryl or heteroaryl ether is selected from thiophenoxy, biphenyloxy, acetamidophenoxy, (3-pyridyl)oxy, chlorophenyloxy, methylphenyloxy, phenoxy, hydroxypheny loxy, methy lsulfonylphenyloxy and pyrimidinyloxy.
  • substituted or unsubstituted aryl or heteroaryl ether is selected from 4-methyl-phenoxy, 4-chlorophenoxy, and 2-pyrimidinyloxy.
  • Rl is Ci-5 alkyl
  • R 2 is selected from hydrogen and methyl
  • a 2 is selected from: alkoxy, aryloxy, either unsubstituted or substituted, heteroaryloxy, either substituted or unsubstituted, and alkyl, either unsubstituted or substituted.
  • a 2 is selected from: substituted aryloxy, and heteroaryloxy, either substituted or unsubstituted.
  • Exemplifying compounds of this subclass are compounds wherein the C5-C6 bond designated with a dotted line is a single bond, and Ha is present and represents hydrogen.
  • any variable e.g., aryl, heterocycle, Rl , etc.
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • alkyl is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, e.g., methyl (Me), ethyl (Et), propyl, butyl, pentyl, hexyl, heptyl, octyl, nonanyl, decyl, undecyl, dodecyl, and the isomers thereof such as isopropyl (i-Pr), isobutyl (i-Bu), secbutyl (s-Bu), tertbutyl (t-Bu), isopentane, isohexane, etc.
  • Alkyloxy (or “alkoxy”) represents an alkyl group having the indicated number of carbon atoms attached through an oxygen bridge, e.g., methoxy, ethoxy, propyloxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and the like.
  • aryl includes phenyl and naphthyl.
  • aryl is phenyl.
  • Heteroaryl is selected from piperidinyl, piperizinyl, pyrrolidinyl, py ⁇ olyl, furanyl, thienyl, pyridyl, pyrimidinyl, indolyl and benzofuranyl.
  • Heterocyclic rings may be attached to structural formula I at any heteroatom (N, O or S) or carbon atom in the ring which results in the creation of a stable, uncharged structure.
  • Hydroxy and amino protecting groups are known to those of ordinary skill in the art, and any such groups may be used.
  • acetate, benzoate, ether and silyl protecting groups are suitable hydroxy protecting groups.
  • Standard silyl protecting groups have the general formula -Si(Xa)3, wherein each Xa group is independently an alkyl or aryl group, and include, e.g. trimethylsilyl, tri-ethylsilyl, tri-i- propylsilyl, triphenylsilyl as well as t-butyl-di-(Xb)-silyl where Xb is methyl, ethyl, i-propyl or phenyl (Ph).
  • Standard amino protecting groups have the general formula -C(0)-Xc, wherein Xc is alkyl, aryl, O-alkyl or O-aryl, and include, e.g. N-t-butoxycarbonyl. See also Protective Groups in Organic Synthesis, T. W. Green et _ ⁇ . (John Wiley and Sons, 1991) for descriptions of protecting groups.
  • the compounds of the present invention may be administered in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt is intended to include all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methy lbromide, bromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N-memylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygal
  • salts of the compounds of this invention include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide.
  • bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethan
  • esters can be employed, e.g. methyl, ethyl, butyl, acetate, maleate, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
  • the compounds of the present invention may have chiral centers other than those centers whose stereochemistry is depicted in formula I, and therefore may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers, with all such isomeric forms being included in the present invention as well as mixtures thereof.
  • crystalline forms for compounds of the present invention may exist as polymo ⁇ hs and as such are intended to be included in the present invention.
  • some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of this invention.
  • terapéuticaally effective amount is that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disorder being treated.
  • the present invention relates to a method for treating hyperandrogenic conditions in a mammal in need of such treatment comprising the administration to the mammal in need of such treatment of a therapeutically effective amount of a compound of the present invention.
  • the novel methods of treatment of this invention are for disorders known to those skilled in the art.
  • the term "mammal" includes humans.
  • the method of the present invention is for treating hyperandrogenic conditions in a human in need of such treatment.
  • Hyperandrogenic conditions treatable by the method of the present invention include benign prostatic hype ⁇ lasia, androgenic alopecia (including male pattem baldness, female pattem baldness and female hirsutism), acne vulgaris, seborrhea, prostatitis and prostatic carcinoma.
  • the present invention has the objective of providing methods of treating hyperandrogenic conditions including androgenic alopecia, male pattern baldness, acne vulgaris, seborrhea, and female hirsutism by oral, systemic, parenteral or topical administration of the novel compounds of formula I either alone or in combination with a 5 ⁇ -reductase 2 inhibitor, preferably selected from finasteride and epristeride, or a potassium channel opener, or a retinoic acid or derivative thereof.
  • a 5 ⁇ -reductase 2 inhibitor preferably selected from finasteride and epristeride, or a potassium channel opener, or a retinoic acid or derivative thereof.
  • treatment may encompass administration of a combination of a compound of formula I with a 5 ⁇ -reductase 2 inhibitor, preferably selected from finasteride and epristeride and another active agent such as a potassium channel opener, or a retinoic acid or derivative therof.
  • a 5 ⁇ -reductase 2 inhibitor preferably selected from finasteride and epristeride
  • another active agent such as a potassium channel opener, or a retinoic acid or derivative therof.
  • treating androgenic alopecia is intended to include the arresting and/or reversing of androgenic alopecia, and the promotion of hair growth.
  • the present invention has the further objective of providing methods of treating benign prostatic hype ⁇ lasia, prostatitis, and treating and/or preventing prostatic carcinoma by oral, systemic or parenteral administration of the novel compounds of formula I either alone or in combination with a 5 ⁇ -reductase 2 inhibitor, preferably selected from finasteride and epristeride.
  • treatment may encompass administration of a combination of a compound of formula I with a 5 ⁇ -reductase 2 inhibitor and/or another active agent such as an ⁇ l or an ⁇ la adrenergic receptor antagonist ( ⁇ la receptor antagonists were formerly called ⁇ lc receptor antagonists).
  • the present invention also has a further objective of providing methods of treating acne vulgaris, androgenic alopecia, seborrhea, female hirsutism, benign prostatic hype ⁇ lasia, prostatitis and the preventing and/or treating of prostatic cancer, by oral, systemic, parental or topical administration of a combined therapy of a therapeutically effective amount of a compound of formula I with a therapeutically effective amount of an anti -androgen, such as, e.g., flutamide, spironolactone or casodex.
  • an anti -androgen such as, e.g., flutamide, spironolactone or casodex.
  • the active agents can be administered concomitantly, or they each can be administered at separately staggered times.
  • the present invention also has the objective of providing suitable topical, oral, systemic and parenteral pharmaceutical formulations for use in the novel methods of treatment of the present invention.
  • the compositions containing the present compounds as the active ingredient for use in the treatment of the above-noted conditions can be administered in a wide variety of therapeutic dosage forms in conventional vehicles for systemic administration.
  • the compounds can be administered in such oral dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups and emulsions, or by injection.
  • intravenous both bolus and infusion
  • intraperitoneal subcutaneous
  • topical with or without occlusion
  • intramuscular form all using forms well known to those of ordinary skill in the pharmaceutical arts.
  • An effective but non-toxic amount of the compound desired can be employed as an antiandrogenic agent.
  • compositions of structural formula I useful in the present invention are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices may be administered systemically, by oral administration or by intravenous or intramuscular injection or topically.
  • carrier suitable pharmaceutical diluents, excipients or carriers
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • Capsules containing the product of this invention can be prepared by mixing an active compound of the present invention with lactose and magnesium stearate, calcium stearate, starch, talc, or other carriers, and placing the mixture in gelatin capsules.
  • Tablets may be prepared by mixing the active ingredient with conventional tableting ingredients such as calcium phosphate, lactose, corn starch or magnesium stearate.
  • suitable binders, lubricants, disintegrating agents and coloring agents can also be inco ⁇ orated into the mixture.
  • suitable binders include starch, gelatin, natural sugars such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • the liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
  • Other dispersing agents which may be employed include glycerin and the like.
  • sterile suspensions and solutions are desired.
  • Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
  • Topical pharmaceutical compositions may be, e.g., in the form of a solution, cream, ointment, gel, lotion, shampoo or aerosol formulation adapted for application to the skin.
  • Topical pharmaceutical compositions useful in the method of treatment of the present invention may include about 0.001 % to 0.1 % of the active compound in admixture with a pharmaceutically acceptable carrier.
  • Topical preparations containing the active drug component can be admixed with a variety of carrier materials well known in the art, such as, e.g., alcohols, aloe vera gel, allantoin, glycerine, vitamin A and E oils, mineral oil, propylene glycol, PPG2 myristyl propionate, and the like, to form, e.g., alcoholic solutions, topical cleansers, cleansing creams, skin gels, skin lotions, and shampoos in cream or gel formulations. See, e.g., EP 0 285 382.
  • the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamide-phenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • the compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • Compounds of the present invention may also be delivered as a suppository employing bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound thereof employed.
  • a physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter, arrest or reverse the progress of the condition.
  • Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.
  • doses of the compound of structural formula I useful in the method of the present invention range from 0.01 to 1000 mg per adult human per day. Most preferably, dosages range from 0.1 to 50 mg/day.
  • the compositions are preferably provided in the form of tablets containing 0.01 to 1000 milligrams of the active ingredient, particularly 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, and 50.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0002 mg/kg to about 50 mg/kg of body weight per day.
  • the active agent of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in dividend doses of two, three or four times daily.
  • the compounds of the present invention may be used in the preparation of a medicament useful for the treatment of hyperandrogenic disorders including: acne vulgaris, androgenic alopecia, male pattern baldness, seborrhea, female hirsutism, benign prostatic hype ⁇ lasia, prostatitis and prostatic cancer.
  • the compounds of the instant invention can be combined with a therapeutically effective amount of another 5 ⁇ - reductase inhibitor, such as finasteride or epristeride, or other 5 ⁇ - reductase inhibitor compounds having type 2 activity, type 1 activity or dual activity for both isozymes, in a single oral, systemic, or parenteral pharmaceutical dosage formulation.
  • another 5 ⁇ - reductase inhibitor such as finasteride or epristeride, or other 5 ⁇ - reductase inhibitor compounds having type 2 activity, type 1 activity or dual activity for both isozymes
  • a combined therapy can be employed wherein the compound of formula I and the other 5 ⁇ -reductase inhibitor are administered in separate oral, systemic, or parenteral dosage formulations.
  • the compounds of the instant invention and another 5 ⁇ -reductase inhibitor such as finasteride or epristeride can be formulated for topical administration.
  • a compound of formula I and finasteride can be administered in a single oral or topical dosage formulation, or each active agent can be administered in a separate dosage formulation, e.g., in separate oral dosage formulations, or an oral dosage formulation of finasteride in combination with a topical dosage formulation of a compound of formula I.
  • each active agent can be administered in a separate dosage formulation, e.g., in separate oral dosage formulations, or an oral dosage formulation of finasteride in combination with a topical dosage formulation of a compound of formula I.
  • See, e.g., U.S. Patent No.'s 4,377,584 and 4,760,071 which describe dosages and formulations for 5 ⁇ -reductase inhibitors.
  • a compound of the present invention in combination with a therapeutically effective amount of a potassium channel opener, such as minoxidil, cromakalin, pinacidil, a compound selected from the classes of S- triazine, thiane-1 -oxide, benzopyran, and pyridinopyran derivatives or a pharmaceutically acceptable salt thereof, may be used for the treatment of androgenic alopecia including male pattern baldness.
  • a potassium channel opener such as minoxidil, cromakalin, pinacidil, a compound selected from the classes of S- triazine, thiane-1 -oxide, benzopyran, and pyridinopyran derivatives or a pharmaceutically acceptable salt thereof, may be used for the treatment of androgenic alopecia including male pattern baldness.
  • Therapy may further comprise the administration of a 5 ⁇ -reductase type 2 inhibitor such as finasteride or epristeride, or a 5 ⁇ -reductase type 1 inhibitor, or a type 1 and type 2 dual inhibitor, in combination with a compound of the present invention and a potassium channel opener such as minoxidil.
  • a 5 ⁇ -reductase type 2 inhibitor such as finasteride or epristeride
  • a 5 ⁇ -reductase type 1 inhibitor such as a type 1 and type 2 dual inhibitor
  • a potassium channel opener such as minoxidil.
  • the active agents can be administered in a single topical dosage formulation, or each active agent can be administered in a separate dosage formulation, e.g., in separate topical dosage formulations, or an oral dosage formulation of a compound of formula I in combination with a topical dosage formulation of, e.g., minoxidil, or a single oral dosage formulation of a compound of formula I and another 5 ⁇ -reductase inhibitor, in combination with a topical dosage formulation of, e.g., minoxidil. See, e.g., U.S. Patent No.'s 4,596,812, 4,139,619 and WO 92/02225, published 20 February 1992, for dosages and formulations of calcium channel openers.
  • a combined therapy can be used by administering a therapeutically effective amount of a compound of formula I in combination with a therapeutically effective amount of retinoic acid or a derivative thereof, e.g. an ester or amide derivative thereof, such as e.g., tretinoin or isotretinoin.
  • this combined therapy for acne vulgaris may further include a 5 ⁇ -reductase type 2 inhibitor such as finasteride or epristeride, or a 5 ⁇ -reductase type 1 inhibitor, or a dual type 1 and type 2 inhibitory compound.
  • a combined therapy comprising a administration of a compound of formula I with a 5 -reductase type 2 inhibitor, such as e.g., finasteride, and an alpha- 1 adrenergic receptor antagonist, such as e.g., terazosin, doxazosin, prazosin, bunazosin, indoramin or alfuzosin, may be employed.
  • a 5 -reductase type 2 inhibitor such as e.g., finasteride
  • an alpha- 1 adrenergic receptor antagonist such as e.g., terazosin, doxazosin, prazosin, bunazosin, indoramin or alfuzosin
  • the combined therapy can comprise administering a compound of formula I with a 5 ⁇ -reductase type 2 inhibitor, such as e.g., finasteride, and an alpha- la adrenergic receptor antagonist (formerly called an alpha- lc adrenergic receptor antagonist).
  • a 5 ⁇ -reductase type 2 inhibitor such as e.g., finasteride
  • an alpha- la adrenergic receptor antagonist previously called an alpha- lc adrenergic receptor antagonist.
  • Compounds which are useful as alpha- la adrenergic receptor antagonists can be identified according to procedures known to those of ordinary skill in the art, for example, as described in PCT/US93/09187 (WO94/08040, published April 14, 1994); PCT/US94/03852 (WO 94/22829, published October 13, 1994); PCT/US94/10162 (WO 95/07075, published March 16, 1995), and U.S. Patent 5,403,847.
  • a combined therapy can be used by administering a therapeutically effective amount of a compound of formula I with a therapeutically effective amount of an anti-androgen, such as, e.g., flutamide, spironolactone or casodex.
  • an anti-androgen such as, e.g., flutamide, spironolactone or casodex.
  • the active agents can be administered concurrently, or they each can be administered at separately staggered times.
  • the compounds of the present invention can be prepared readily according to the following Schemes and Examples or modifications thereof using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail.
  • the 4-oxa compounds of this invention can be prepared as shown in Scheme 1.
  • Scheme 1 outlines the synthesis of the novel oxasteroids of the present invention.
  • the appropriately substituted seco-acid may be prepared by methods known in the art.
  • PCT publication WO 95/11254 describes procedures for the synthesis of compounds having various substituents at the 16-position of the azasteroid. Starting with a 3-keto- delta4-17-one precursor and following the procedures of WO 95/11254, the appropriate A 2 substitution may be obtained.
  • the appropriately 7,10,16, and 17-substituted 3-keto steroid is converted to the appropriately substituted seco-acid by methods known in the art, for example, the procedures described in Rasmusson, et al., J.Med.Chem. 1986, 29(11): 2298-2315.
  • R 2 is H or CH20R3
  • R 2 is H or CH20R3
  • the seco-acid (1) is treated with a dehydrating agent such as acetic anhydride, methyl ortho-formate, ethyl ortho-formate, in a nonpolar aprotie solvent such as toluene, xylene, dichloroethane, chlorobenzene and the like optionally in the presence of an acidic catalyst, such as PTSA (paratoluenesulfonic acid), or sodium acetate to form the ⁇ 5-oxasteroid (2).
  • a dehydrating agent such as acetic anhydride, methyl ortho-formate, ethyl ortho-formate
  • a nonpolar aprotie solvent such as toluene, xylene, dichloroethane, chlorobenzene and the like
  • an acidic catalyst such as PTSA (paratoluenesulfonic acid)
  • sodium acetate sodium acetate
  • Hydrogenation of the double bond to form the oxasteroid (3) may be carried out in the presence of an appropriate catalyst such as Rh/C, Pd/C, etc., preferably Rh C in a solvent such as tetrahydrofuran (THF) or ethyl acetate.
  • an appropriate catalyst such as Rh/C, Pd/C, etc., preferably Rh C in a solvent such as tetrahydrofuran (THF) or ethyl acetate.
  • THF tetrahydrofuran
  • ethyl acetate ethyl acetate
  • the lactone is opened to form the hydroxamide (5).
  • the lactone may be opened by various means such as treatment with dimethylalumino-3-aminopyridine (which may be prepared in situ by treating trimethyl aluminum with 3 -amino pyridine), chlorobenzene or dichloroethane in a nonpolar, aprotie solvent such as toluene.
  • the hydroxamide (5) is treated with alkyl- or aryl sulfonyl chloride in a solvent such as methylene chloride, toluene or dichloroethane in the presence of a base such as pyridine, dimethylaminopyridine (DMAP), or N-methylpyrolidine (NMP), to give the corresponding alkyl- or aryl sulfonate (6).
  • a base such as pyridine, dimethylaminopyridine (DMAP), or N-methylpyrolidine (NMP)
  • the iodide is treated with thioacetic acid in a nonpolar solvent such as toluene or dichloroethane in the presence of cesium carbonate or other base such as potassium carbonate or sodium carbonate to give the thioacetate (8).
  • the thioacetate (8) is hydrolyzed to form the thialactone (9), preferably by treatment with acid in a polar solvent such as methanol or ethanol, preferably by treatment with hydrochloric acid in methanol.
  • the thialactone (9) may be dehydrogenated to form the ⁇ 1 -thiasteroid (10) as described above, preferably by treatment with benzeneselenic anhydride in chlorobenzene at reflux.
  • the 4-oxa and 4-thia steroids of the present invention include the 1,2-5,6 diene which may be prepared by treating the compound of structural formula (2) with benzeneselenic anhydride in chlorobenzene with refluxing to obtain the ⁇ l , ⁇ 5-oxasteroid derivative.
  • the co ⁇ esponding thiasteroid derivative may be obtained by following the procedures of Scheme 2, starting with (2), the ⁇ 5 -oxasteroid.
  • the following examples are not intended to be limitations on the scope of the instant invention in any way, and they should not be so construed.
  • the compounds described in the following examples are not to be construed as forming the only genus that is considered as the invention, and any combination of the compounds or their moieties may itself form a genus. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.
  • Step 1 Benzotriazol- 1 '-yl-3-oxo-androst-4-ene- 17 ⁇ -carboxamide.
  • Step 2 N-t-Butyl-3-oxo-androst-4-ene- 17 ⁇ -carboxamide.
  • Step 3 N-t-Butyl-5-oxo-3,5-secoandrostan-3-oic-17 ⁇ - carboxamide.
  • Step 4 N-t-Butyl-4-oxa-androst-5-en-3-one- 17 ⁇ -carboxamide.
  • Step 6 N-t-Butvl-4-oxa-5 ⁇ -androst-l-en-3-one-17 ⁇ -carboxamide.
  • Step 3 7 ⁇ -Methyl-4-oxa-5 ⁇ -Cholest- 1 -en-3-one
  • Step 1 S-2'-Pyridyl-3-oxo-androst-4-ene- 17 ⁇ -thiocarboxylate
  • Step 3 N-(2 5'-Bistri luoromethylphenyl)-5-oxo-3,5- secoandrostan-3-oic- 17 ⁇ -carboxamide
  • Step 5 N-(2',5'-Bistrifluoromethylphenyl)-4-oxa-androstan-3-one- 17 ⁇ -carboxamide.
  • Step 6 N-(2',5'-Bistrifluoromethylphenyl)-4-oxa-androst-l-en-3- one- 17 ⁇ -carboxamide
  • step 1 The product of step 1 in pyridine solution (50 mL) is cooled to 5° in ice before 1.2 equivalents of p-toluenesulfonyl chloride is added. After standing 18 hours in the refrigerator, the reaction is warmed to ambient temperature, partitioned between water and dichloromethane and washed with dilute bicarbonate solution to remove residual sulfonyl chloride. The organic layer is dried and evaporated to a residue, which is immediately taken on to the iodide displacement.
  • Step 3 (N-Pyrid-3-yl)-5-(epi)iodo-3,5-secoandrostan-3- carboxamide-17 ⁇ -(N-t-buty0carboxamide.
  • the tosyl derivative of step 2 is stined at ambient temperamre with 3 equivalents of dry tetrabutylammonium iodide in toluene for 30 min. and then heated at reflux for another 2 hrs. The reaction mixture is cooled, partitioned with dichloromethane and water, and washed to remove ammonium salts. After drying and solvent removal under reduced pressure, the residual amo ⁇ hous material is chromatographed to provide the pure iodo compound.
  • Step 4 (N-Pyrid-3-yl)-5-acetylthio-3,5-secoandrostan-3- carboxamide- 17 ⁇ -(N-t-butv0carboxamide.
  • the iodo compound of step 3 is stirred at ambient temperature with 10 equivalents of thioacetic acid in toluene for 30 min. and then heated at reflux for another 2 hrs. The reaction mixture is cooled, solvents and volatile reactants evaporated under reduced pressure, and the residual amo ⁇ hous material chromatographed.
  • Step 5 N-t-Butyl-4-thia-5 ⁇ -androstan-3-one-17 ⁇ -carboxamide.
  • the thioacetyl derivative of step 4 is treated at ambient temperature with methanolic HCl (3%) until the starting material is gone by thin-layer chromatography or hplc. Product is isolated by chromatography and recrystallized.
  • Step 6 N-t-Butyl-4-thia-5 ⁇ -androst- 1 -en-3-one- 17 ⁇ -carboxamide.
  • an oral composition of a compound of this invention 5 mg of a compound of stmctural formula
  • I is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
  • the reaction mixture for the type 1 5 ⁇ -reductase contained 40 mM potassium phosphate, pH 6.5, 5 mM [7 - ⁇ H] -testosterone, 1 mM dithiothreitol and 500 ⁇ M NADPH in a final volume of 100 ⁇ l.
  • the reaction mixture for the type 2 5 ⁇ -reductase contained 40 mM sodium citrate, pH 5.5, 0.3 mM [7- ⁇ H] -testosterone, 1 mM dithiothreitol and 500 ⁇ M NADPH in a final volume of 100 ⁇ l.
  • the assay was initiated by the addition of 50-100 ⁇ g prostatic homogenate or 75-200 ⁇ g scalp homogenate and incubated at 37°C. After 10-50 min. the reaction was quenched by extraction with 250 ⁇ l of a mixture of 70% cyclohexane: 30% ethyl acetate containing 10 ⁇ g each DHT and T. The aqueous and organic layers were separated by centrifugation at 14,000 ⁇ m in an Eppendorf microfuge.
  • the organic layer was subjected to normal phase HPLC (10 cm Whatman partisil 5 silica column equilibrated in 1 mL/min 70% cyclohexane: 30% ethyl acetate; retention times: DHT, 6.8-7.2 min.; androstanediol, 7.6-8.0 min.; T, 9.1-9.7 min.).
  • HPLC system consisted of a Waters Model 680 Gradient System equipped with a Hitachi Model 655 ⁇ autosampler, Applied Biosystems Model 757 variable UV detector, and a Radiomatic Model A 120 radioactivity analyzer.
  • the conversion of T to DHT was monitored using the radioactivity flow detector by mixing the HPLC effluent with one volume of Flo Scint 1 (Radiomatic). Under the conditions described, the production of DHT was linear for at least 25 min.
  • the only steroids observed with the human prostate and scalp preparations were T, DHT and androstanediol.
  • IC50 values represent the concentration of inhibitor required to decrease enzyme conversion of testosterone to dihydrotestosterone by 50% of the control. IC50 values were determined using a 6 point titration where the concentration of the inhibitor was varied from 0.1 to 1000 nM. Representative compounds of this invention were tested in the above described assay for 5 ⁇ - reductase type 1 and type 2 inhibition.
  • a compound refened to herein as a 5 ⁇ -reductase 1 inhibitor is a compound that shows inhibition of the 5 ⁇ -reductase 1 isozyme in the above-described assay, having an IC50 value of about or under 100 nM.
  • a compound referred to herein as a 5 ⁇ -reductase 2 inhibitor is a compound that shows inhibition of the 5 ⁇ -reductase 2 isozyme in the above-described assay, having an IC50 value of about or under 100 nM.
  • the dermal papilla is a small group of cells at the base of each hair follicle, and it is presently thought that these cells are stem cells that form the basis for hair growth. These cells have been shown to have 5 ⁇ reductase activity, and it is therefore possible to test inhibitors of 5 ⁇ reductase in these cell culture systems. Isolated and cultured dermal papilla cells are prepared according to the methods of Messenger, A.G., "The Culture of Dermal Papilla Cells From Human Hair Follicles," Br. J. Dermatol., 110:685-689 (1984) and Itami, S.
  • the pellets are resuspended in 20 mM Tris-HCl buffer, pH 7.5, at 4°C, containing 250 mM sucrose, 1 mM Mg ⁇ 2, and 2 mM CaCl2, by vortexing and 10 passes through a 25-gauge needle.
  • the cmde homogenate is further homogenized by a teflon- glass homogenizer, and is used as the cell homogenate.
  • the cell homogenate is centrifuged at 800 x g for 10 min. to yield a cmde nuclear pellet.
  • the resultant supematant is centrifuged at 10,000 x g for 15 min. to produce a cmde mitochondrial pellet.
  • the supematant is centrifuged at 100,000 x g for 60 min. to yield a microsomal pellet and cytosol. Each particulate fraction is washed twice and resuspended in the buffer.
  • a standard incubation mixture will consist of 50 nM [3H]-testosterone, 1 mM NADPH, 100 mM sodium citrate, pH 5.5 or 100 mM Tris-HCl, pH 7.5, and 50 mL of the cell homogenate, in a final volume of 100 mL. Each tube contains 50-100 mg of cellular protein. Incubation is carried out at 37°C for 30 min. During this incubation, the reaction is proportional to the time.
  • citrate buffer is used at pH 4.5-6.5
  • Tris HCl buffer at pH 7.0-9.0.
  • the protein content is determined by the method of Lowry, et al., "Protein Measurement With The Folin Phenol Reagent," J. Biol. Chem., 193:265-275 (1951).
  • Nuclear Co ⁇ oration (Boston, MA) and unlabeled steroids can be purchased from Sigma Chemical Company (St. Louis, MO). Fetal calf serum is obtainable from Hazleton (Lenaxa, Kansas). All other chemicals are of reagent grade. The following describes an example of methodology that can be used for detection of hair growth.
  • Haircount target area Equipment Film: Kodak-T-max 24 exposure each of same emulsion lot number
  • the haircount area on the patient is prepared as follows:
  • a small ( ⁇ lmm) dot tattoo is placed at the beginning of the study at the leading edge of the bald area directly anterior to the center of the vertex bald spot, using a commercial tattooing machine or manually (needle and ink).
  • a trained technician places a transparency over the photographic print and, using a felt tip pen, places a black dot over each visible hair.
  • the dot map transparency is then counted using image analysis with computer assistance.
  • Photographs are coded with a random number co ⁇ esponding to study site, visit number and patient allocation number to insure blinding to time.
  • baseline and Month 6 photographs are counted and data analyzed for interim analysis.
  • Month 12 photographs are counted and data analyzed for the primary endpoint.
  • Methodology for detection of hair growth is also described in Olsen, E.A. and DeLong, E., J. American Academy of Dermatology, Vol. 23, p. 470 (1990).
  • Each lens supplied has a fixed reproduction ratio of 1 :6.

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Abstract

Les composés de cette invention sont représentés par la formule (I) dans laquelle X représente oxygène ou soufre. Sont également décrits des compositions pharmaceutiques et des procédés d'utilisation desdits composés dans le traitement des pathologies hyperandrogéniques, ainsi que la combinaison de ces mêmes composés avec d'autres agents actifs tels que le finastéride, le minoxidil et l'acide rétinoïque ou un dérivé de ce dernier.
PCT/US1996/016883 1995-10-26 1996-10-22 Steroides 4-oxa et 4-thia WO1997015564A1 (fr)

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JP9516711A JPH11513981A (ja) 1995-10-26 1996-10-22 ４−オキサ及び４−チアステロイド
EP96936811A EP0858455A4 (fr) 1995-10-26 1996-10-22 Steroides 4-oxa et 4-thia
AU74644/96A AU713582B2 (en) 1995-10-26 1996-10-22 4-oxa and 4-thia steroids
US09/065,112 US5998464A (en) 1995-10-26 1996-10-22 4-Oxa and 4-thia steroids

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US600195P 1995-10-26 1995-10-26
US60/006,001 1995-10-26
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GBGB9602905.3A GB9602905D0 (en) 1996-02-13 1996-02-13 4-oxa and 4-thia steroids

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EP1622567A4 (fr) * 2003-05-07 2009-04-29 Merck & Co Inc Modulateurs du recepteur d'androgenes et leur methode d'utilisation

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AU2002331916B2 (en) * 2001-10-03 2008-07-24 Merck Sharp & Dohme Corp. Androstane 17-beta-carboxamides as androgen receptor modulators

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US3644421A (en) * 1968-12-02 1972-02-22 Syntex Corp 4-oxa-3-keto-delta**1-pregnene derivatives

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NZ225100A (en) * 1987-06-29 1991-09-25 Merck & Co Inc Reaction of steroids (including 4-azasteroids) with a silylating agent in the presence of a quinone to introduce a delta' double bond and silylated intermediates

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US3644421A (en) * 1968-12-02 1972-02-22 Syntex Corp 4-oxa-3-keto-delta**1-pregnene derivatives

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Title
JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANS. I, Number 8, August 1982, BARTON et al., "Dehydrogenation of Lactones Using Benzeneseleninic Anhydride. X-Ray Crystal Structure of 3beta-Acetoxy-14alpha-hydroxy-17a-oxa-D-hom o-5alpha-androst-15-en-17-one", pages 1919-1922. *
See also references of EP0858455A4 *
TETRAHEDRON LETTERS, No. 35, August 1979, BARTON et al., "Preparation of Aldehydes and Ketones by Oxidation of Benzylic Hydrocarbons With Benzeneseleninic Anhydride", pages 3331-3334. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1622567A4 (fr) * 2003-05-07 2009-04-29 Merck & Co Inc Modulateurs du recepteur d'androgenes et leur methode d'utilisation

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