CA2233966A1 - 4-oxa and 4-thia steroids - Google Patents
4-oxa and 4-thia steroids Download PDFInfo
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- CA2233966A1 CA2233966A1 CA002233966A CA2233966A CA2233966A1 CA 2233966 A1 CA2233966 A1 CA 2233966A1 CA 002233966 A CA002233966 A CA 002233966A CA 2233966 A CA2233966 A CA 2233966A CA 2233966 A1 CA2233966 A1 CA 2233966A1
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- androst
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- 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
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- 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
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- 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
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Abstract
The compounds of the present invention are those of structural formula (I) wherein X is oxygen or sulfur. Pharmaceutical compositions and methods of use of the compounds in the treatment of hyperandrogenic conditions are disclosed. In addition, the combination of the compounds with other active agents such as finasteride, minoxidil and retinoic acid or a derivative thereof is disclosed.
Description
W O 97/15564 PCT~US96/16883 TITLE OF THE ~VENTION
~I~T n ~F THE INVENTION
The present invention provides novel compounds, novel compositions, methods of their use and methods of their manufacture, where such compounds are generally ph~rm~cologically useful as agents in therapies whose mech~ni~m of action rely on the inhibition of 5a-reductase.
BACK(:~RO~JND OF THE ~VENTION
Certain undesirable physiological manifestations, such as acne vulgaris, seborrhea, female hirsutism, androgenic alopecia which includes female and male pattern baldness, and benign prostatic hyperplasia, are the result of hyperandrogenic stim~ tion caused by excessive accllmlll~tion of testosterone ("T") or ~imil~r androgenic hormones in the metabolic system. 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 femini7in~ effect as well. Non-steroidal ~nti~ntlrogens have also been developed, for example, 4'-nitro-3'-trifluoromethyl-isobutyr~nilicle. See Neri, et al., Endocrinol. 1972, 91 (2). However, these products, though devoid of hormonal effects, compete with all natural androgens for receptor sites, and hence have a tendency to femini7e a male host or the male fetus of a female host and/or initi~te feed-back effects which would cause . hyperstim~ tion of the testes.
The principal mediator of androgenic activity in some target organs, e.g. the prostate, is Sa-dihydrotestosterone ("DHT"), formed locally in the target organ by the action of testosterone-5a-reductase. Inhibitors of testosterone-Sa-reductase will serve to prevent or lessen synl~lollls of hyperandrogenic stimulation in these organs. See W O 97/15564 PCT~US96/16883 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 5a-reductase catalyzes the reduction of testosterone to the more potent androgen, dihydrotestosterone, as shown 5 below:
OH OH
CHJ CH~
O~J NADPH ~~~J
testosterone dih~ tes~osterone Finasteride, ( 1 7,3-(N-tert-butylcarbamoyl)-3-oxo-4-aza-Sa-10 androst-1-ene-3-one) as shown below, is a potent inhibitor of the hllm~n prostate enzyme.
H
Oq~ N
t'H~
CH~
4 ~
fi nasteride Under the trade name PROSCAR(~), finasteride is known to be use~ul in the treatment of hyperandrogenic conditions; see eg. U.S. 4,760,071.
15 Finasteride is currently prescribed for the treatment of benign prostatic hyperplasia (BPH), a condition afflicting to some degree the majority of men over age 55. Finasteride's utility in the treatment of androgenic W O 97/15564 PCT~US96/16883 alopecia and prostatic carcinoma is also disclosed in the following documents: EP 0 285,382, published 5 October 1988; EP 0 285,383, published S October 1988; C~n~ n Patent no. 1,302,277; and C~n~di~n Patent no. 1,302,276.
There are two isozymes of 5a-reductase in hllm~n~. One isozyme (type 1 or Sa-reductase 1) predomin~tes 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 5a-reductase 2) predomin~tes in the prostate and is potently inhibited by finasteride.
Since Sa-reductase and its isozymes convert testosterone to DHT, inhibition of either or both of the isozymes would serve to alleviate the conditions and diseases mediated by DHT. The present invention addresses this by providing novel compounds that are active as inhibitors of Soc-reductase.
SUMMARY OF THE TNVENTION
The novel compounds of the present invention are those of structural formula I:
~\~
O~X H~R
(1) wherein X is selected from O and S, or a ph~ ceutically acceptable salt, ester, or stereoisomer thereof, and are inhibitors of Soc-reductase. The compounds of formula I are useful in the oral, systemic, parenteral or topical treatment of - 25 hyperandrogenic conditions such as acne vulgaris, seborrhea, androgenic alopecia which includes female and male pattern baldness, female hirsutism, benign prostatic hyperplasia, and the prevention and W O 97/15564 PCT~US96/16883 treatment of prostatic carcinoma, as well as in the treatment of prostatitis.
Therefore it is an object of this invention to provide compounds that have sufficient activity in the inhibition of Sa-reductase. It is an additional object of this invention to provide methods of using the compounds of formula I for the treatment of hyperandrogenic conditions such as acne vulgaris, seborrhea, androgenic alopecia, male pattern baldness, female hirsutism, benign prostatic hyperplasia, and the prevention and treatment of prostatic carcinoma, as well as the treatment of prostatitis. It is a further object of this invention to provide phzmn~ceutical compositions for the compounds of fo~nula I. 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.
DETAILED DESCRIPTION OF THE ~VENTION
The novel compounds of ~is invention have the structural formula I:
~I~T n ~F THE INVENTION
The present invention provides novel compounds, novel compositions, methods of their use and methods of their manufacture, where such compounds are generally ph~rm~cologically useful as agents in therapies whose mech~ni~m of action rely on the inhibition of 5a-reductase.
BACK(:~RO~JND OF THE ~VENTION
Certain undesirable physiological manifestations, such as acne vulgaris, seborrhea, female hirsutism, androgenic alopecia which includes female and male pattern baldness, and benign prostatic hyperplasia, are the result of hyperandrogenic stim~ tion caused by excessive accllmlll~tion of testosterone ("T") or ~imil~r androgenic hormones in the metabolic system. 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 femini7in~ effect as well. Non-steroidal ~nti~ntlrogens have also been developed, for example, 4'-nitro-3'-trifluoromethyl-isobutyr~nilicle. See Neri, et al., Endocrinol. 1972, 91 (2). However, these products, though devoid of hormonal effects, compete with all natural androgens for receptor sites, and hence have a tendency to femini7e a male host or the male fetus of a female host and/or initi~te feed-back effects which would cause . hyperstim~ tion of the testes.
The principal mediator of androgenic activity in some target organs, e.g. the prostate, is Sa-dihydrotestosterone ("DHT"), formed locally in the target organ by the action of testosterone-5a-reductase. Inhibitors of testosterone-Sa-reductase will serve to prevent or lessen synl~lollls of hyperandrogenic stimulation in these organs. See W O 97/15564 PCT~US96/16883 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 5a-reductase catalyzes the reduction of testosterone to the more potent androgen, dihydrotestosterone, as shown 5 below:
OH OH
CHJ CH~
O~J NADPH ~~~J
testosterone dih~ tes~osterone Finasteride, ( 1 7,3-(N-tert-butylcarbamoyl)-3-oxo-4-aza-Sa-10 androst-1-ene-3-one) as shown below, is a potent inhibitor of the hllm~n prostate enzyme.
H
Oq~ N
t'H~
CH~
4 ~
fi nasteride Under the trade name PROSCAR(~), finasteride is known to be use~ul in the treatment of hyperandrogenic conditions; see eg. U.S. 4,760,071.
15 Finasteride is currently prescribed for the treatment of benign prostatic hyperplasia (BPH), a condition afflicting to some degree the majority of men over age 55. Finasteride's utility in the treatment of androgenic W O 97/15564 PCT~US96/16883 alopecia and prostatic carcinoma is also disclosed in the following documents: EP 0 285,382, published 5 October 1988; EP 0 285,383, published S October 1988; C~n~ n Patent no. 1,302,277; and C~n~di~n Patent no. 1,302,276.
There are two isozymes of 5a-reductase in hllm~n~. One isozyme (type 1 or Sa-reductase 1) predomin~tes 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 5a-reductase 2) predomin~tes in the prostate and is potently inhibited by finasteride.
Since Sa-reductase and its isozymes convert testosterone to DHT, inhibition of either or both of the isozymes would serve to alleviate the conditions and diseases mediated by DHT. The present invention addresses this by providing novel compounds that are active as inhibitors of Soc-reductase.
SUMMARY OF THE TNVENTION
The novel compounds of the present invention are those of structural formula I:
~\~
O~X H~R
(1) wherein X is selected from O and S, or a ph~ ceutically acceptable salt, ester, or stereoisomer thereof, and are inhibitors of Soc-reductase. The compounds of formula I are useful in the oral, systemic, parenteral or topical treatment of - 25 hyperandrogenic conditions such as acne vulgaris, seborrhea, androgenic alopecia which includes female and male pattern baldness, female hirsutism, benign prostatic hyperplasia, and the prevention and W O 97/15564 PCT~US96/16883 treatment of prostatic carcinoma, as well as in the treatment of prostatitis.
Therefore it is an object of this invention to provide compounds that have sufficient activity in the inhibition of Sa-reductase. It is an additional object of this invention to provide methods of using the compounds of formula I for the treatment of hyperandrogenic conditions such as acne vulgaris, seborrhea, androgenic alopecia, male pattern baldness, female hirsutism, benign prostatic hyperplasia, and the prevention and treatment of prostatic carcinoma, as well as the treatment of prostatitis. It is a further object of this invention to provide phzmn~ceutical compositions for the compounds of fo~nula I. 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.
DETAILED DESCRIPTION OF THE ~VENTION
The novel compounds of ~is invention have the structural formula I:
2~ ~ 3 O~X~
(I) or a pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein:
the C5-C6 bond designated with a dotted line independently represents a single or double bond, provided that when the CS-C6 is a double bond, Ha is absent and when the C5-C6 bond is a single bond Ha is present and represents hydrogen;
~ is selected from oxygen and sulfur;
R1 is selected from hydrogen and Cl 5 aLkyl;
R2 is selected from CH3, CH20R3, and H, R3 is selected from: Cl 5 alkyl;
5 Zis ~ A
or ~
~ ;and A 1 is selected from:
(1) -H, (2) keto, (6) carboxy, (7) protected amino, (8) amino, (9) Cl lo alkyl, (10) substituted or unsubstituted C2 10alkenyl, (11) aryl-substituted Cl lo alkyl, (12) aryl or heteroaryl, (13) substituted aryl or heteroaryl, (14) aryl or heteroaryl carbamoyl-substituted C1 1oalkyl, (15) Cl loalkylcarbonyl, (16) aryl or heteroaryl carbonyl, (17) ether-substituted Cl loalkyl, (18) thioether-substituted Cl loalkyl, (19) keto-substituted Cl loaLkYl, (20) heteroaryl-substituted C1 -10 alkyl, (21) carboxylic ester, (22) carboxamide, including substituted and unsubstituted ~nilicle ~ derivatives, (23) urea, (24) Cl lo alkylureido C0 5 alkyl, W O 97/15564 PCT~US96/16883 (25) substituted or unsubstituted heteroaryl or arylureidoCo 5 alkyl, (26) Cl loalkanoyloxyC1 2alkyl, (27) Cl -10 aLkylcarbonylamino, (28) alkanoylamidoalkyl (29) ether, (30) thio ether, and (31 ) substituted and unsubstituted aryl or heteroaryl ether;
A2 is selected from:
(1) -H, (2) keto, (3) protected hydroxy, (4) acetate, (5) hydroxy, (6) carboxy, (7) protected amino, (8) amino, (9) Cl lo alkyl, (10) substituted or unsubstituted C2 loalkenyl, (11) aryl-substituted Cl lo alkyl, (12) aryl or heteroaryl, (13) substituted aryl or heteroaryl, (14) aryl or heteroaryl carbamoyl-substituted C1 1oalkyl, (15) Cl 1oalkylcarbonyl, (16) aryl or heteroaryl carbonyl, (17) ether-substituted Cl 1oalkyl, (18) thioe~er-substituted Cl loalkyl, (19) keto-substituted Cl loaLkyl, (20) heteroaryl-substituted Cl 1o alkyl, (21) carboxylic ester, (22) carboxamide, including substituted and unsubstituted anilide derivatives, (23) urea, (24) Cl-10 alkylureido C0 5 alkyl, W O 97/15564 PCT~US96/16883 (25) substituted or unsubstituted arylureidoCo 5 alkyl, (26) Cl loaL~anoyloxyCl 2alkyl, (27) Cl lo aLl~ylcarbonylamino, (28) aLlcanoylamidoaL~yl, (29) ether, (30) thio ether, and (31 ) substituted and unsubstituted aryl- or heteroaryl-ether;
Heteroaryl is selected from piperidinyl, piperizinyl, pyrrolidinyl, pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, indolyl and benzofuranyl.
Preferred are compounds wherein:
(a) protected hydroxy is selected from: dimethyl-t-butyl lS silyloxy, trimethylsilyloxy, tri-ethylsilyloxy, tri-isopropylsilyloxy, and triphenylsilyloxy;
(b) protected amino is acetyl~mino, benzoylamino, and pivaloylamino;
(c) Cl lo aL~yl is selected from methyl, ethyl, propyl, butyl, pentyl, 1,5-dimethylhexyl, 6-methylhept-2-yl, 5-methylhexyl, and l-methyl-4-isopropylhexyl;
(d) substituted or unsubstituted ~2 loalkenyl is selected from:
phenylmethylene, chlorophenylmethylene, ethoxycarbonylphenylmethylene, carboxyphenylmethylene, (((l,l-dimethylethyl) amino) carbonyl)phenylmethylene, trimethoxyphenyl methylene, methoxyphenylmethylene, methylsulfonylphenylmethylene, biphenylmethylene, nitrophenylmethylene, aminophenylmethylene, acetylaminophenylmethylene, pivaloylaminophenylmethylene, phenoxyphenylmethylene, 2-imidazolyl methylene, 2-thiazolylmethylene, (e) aryl substituted Cl lo aLkyl is selected from omega-phenylpropyl and l-(chlorophenoxy)ethyl;
(f) aryl is selected from phenyl, and naphthyl;
WO 97/15564 PCT~US96/16883 (g) substituted aryl or heteroaryl is selected from phenyl, pyridyl and pyrimidinyl substituted with one to three substituents independently selected from:
(1) -H, (2) -OH, (3) -CH3, (4) -OCH3, (5) -S(O)n-CH3, wherein n is selected from 0, 1, and 2, (6) -CF3, (7) halo, (8) -CHO, (9) CN, (10) phenyloxy, (11) ethyl, (12) t-butyl, (1 3) OCH2CH3, (14) OC(CH3)3, and (15) -NHR7, wherein R7 is selected from:
-H, -Cl 8 aL~yl, -Cl 6 alkylcarbonyl, -Cl 6 alkylsulfonyl, and -Cl 6 alkoxycarbonyl, (h) aryl or heteroaryl carbamoyl substituted Cl lo aLkyl is selected from 2-(4-pyridyl-carbamoyl)ethyl and 2-phenyl-ethyl;
(i) Cl loalkylcarbonyl is selected from isobutylcarbonyl and isopropylcarbonyl;
(j) aryl or heteroaryl carbonyl is selected from phenylcarbonyl and pyridyl carbonyl;
(k) ether-substituted Cl loalkyl is selected from 1-methoxy-ethyl and l-ethoxy-ethyl;
(1) thioether-substituted Cl loalkyl is selected from 1-methylthio-ethyl, and l-ethylthio-e~yl;
(m) keto-substituted C1 loalkyl is 1 -keto-ethyl, ketomethyl, 1-ketopropyl, and ketobutyl;
-(n) heteroaryl-substituted Cl lo alkyl is omega-(4-pyridyl)-butyl;
(o) carboxylic esters are Cl lo aLlcylcarboxylic esters selected from carbomethoxy and carboethoxy;
S (p) carboxamides are 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 carboxarnide, N-(methoxycarboxy) phenyl carboxamide, N-acetamidophenyl-N-acetyl-carboxamide, N-acetamidophenyl-carboxamide, N-piv~l~mi~lophenyl carboxamide, N-isobutyramidophenyl carboxamide, N-(methyl),N~diphenylmethyl) carboxamide, N-lS (diphenylmethyl)-carboxamide, N-t-butyl carboxamide, N-isopropyl carboxamide, l-acl~m~n~yl carboxamide, 2-m~ntyl carboxamide and N-(substituted phenyl) carboxamides wherein the phenyl may be substituted with 1 to 2 substitutents selected from ethyl, methyl, trifluoromethyl or halo (F, Cl, Br, I);
(q) Cl loaL~anoyloxyCl -2aLkyl is selected from acetyloxymethyl, trimethylacetyloxymethyl, and (2-ethylhexanoyloxy)methyl;
~(r) urea is t-butylcarbonylamino urea;
(s) Cl lo aLkylureido C0 5 aLkyl is selected from: N-t-butylureidomethyl, N-n-propylureidomethyl, N-n-octylureidomethyl, N-isopropylureido, allylureido, (t) substituted or unsubstituted arylureidoCo 5 aL~yl is selected from: N-(ethylphenyl) ureidomethyl, N-(chlorophenyl) ureidomethyl, N-phenylureidomethyl, N-(dichlorophenyl) ureidomethyl, N-naphth-2-yl)ureidomethyl, N-thiazol-2-ylureidomethyl, N-thien-2-ylmethylureidomethyl, N-(fluorophenyl)ureido, N-(methoxyphenyl)ureido, and 2-(ethoxyphenyl)ureidomethyl;
PCT~US96/16883 (u) Cl lo alkylcarbonylamino is t-butylcarbonyl~mino;
(v) aL~anoylamidoalkyl is selected from:
trimethylacetamidomethyl, carbomethoxyoctanoylamidomethyl, S (isobutylphenyl)propionamidomethyl, 8-carboxyoctanoylamidomethyl, bromohexanoylamido methyl, hydroxydodecanoyl amidomethyl, 4-nitrophenylprionamidomethyl, isopropylthioacetamidomethyl, benzyloxyacetamidomethyl, 1 0 carbomethoxyacetamidomethyl, triphenylproprionamidomethyl, cyclohexylacetamidomethyl, methylcyclohexanecarboxamidomethyl, (3-hydroxy-4,4,4-trichlorobutyramido)methyl, and phenylthio-acetamidomethyl;
(w) ether is selected from ethylene ketal, and C1 galkyl ether optionally substituted with hydroxy, halo, C1 galkoxy, C2 6alkenyl, or aryl;
(x) thioe~er is selected from: C1 galkylthio, phenylthio, and C1 8 alkylthio substituted with phenyl; and (y) substituted and unsubstituted aryl or heteroaryl ether is selected from thiophenoxy, biphenyloxy, acetamidophenoxy, (3-pyridyl)oxy, chlorophenyloxy, methylphenyloxy, phenoxy, hydroxyphenyloxy, methylsulfonylphenyloxy and pyrimidinyloxy.
In one embodiment of the instant invention are compolmds of formula I wherein X is oxygen.
In one class of the compounds of this embodiment are 30 compounds wherein Z is W O 97/15564 PCT~US96/16883 Exemplifying this class are:
(1) N-t-Butyl-4-oxa-Sa-androst- 1 -en-3-one-17,3-carboxamide, (2) 7,3-Methyl-4-oxa-5a-cholest- 1 -en-3 -one, (3) 17,1~-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-5a-androst- 1 -en-3-one, (4) 17,13-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-5a-androst- 1 -en-3-one, (5) 17,(~-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-5a-androst- 1 -en-3-one, (6) 17,13-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-5a-androst- 1 -en-3 -one, (7) 17,1~-(N-tert-amylcarbamoyl)-4-oxa-5a-androst-1-en-3-one, (8) 17,1~-(N-tert-hexylcarbamoyl)-4-oxa-Sa-androst- 1 -en-3-one, (9) 17,1~-(N-isobutylcarbamoyl)-4-oxa-5a-androst-1-en-3-one, (10) 17,1~-(N-tert-octylcarbamoyl)-4-oxa-5a-androst- 1 -en-3-one, (11) 17,13-(N- 1,1 -diethylbutylcarbamoyl)-4-oxa-5a-androst- 1 -en-3-one, (12) 17,13-(N-neopentylcarbamoyl)-4-oxa-Sa-androst-1 -en-3-one, (13) 17,B-(N-2-~ m~ntylcarbamoyl)-4-oxa-Sa-androst- 1 -en-3-one, (14) 17~-(N-1 ~ m~ntylcarbamoyl)-4-oxa-5a-androst-1-en-3-one"
(lS) 17,13-(N-2-norbornylcarbamoyl)-4-oxa-50c-androst-l-en-3-one, (16) 17,~-(N-l-norbornylcarbamoyl)-4-oxa-Sa-androst-l-en-3-one, (17) 17~-(N-phenylcarbamoyl)-4-oxa-Sa-androst-l-en-3-one, (18) 17~13-(N-benzylcarbamoyl)-4-oxa-Sa-androst-1-en-3-one, (19) 17,3-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-7,B-methyl-4-oxa-5a-androst- 1 -en-3-one, (20) 17~-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-7,~-methyl-4-oxa-5a-androst- 1 -en-3-one, (21) 17,13-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-7~-methyl-4-oxa-5a-androst- 1 -en-3-one, (22) 17~-(N-n-octylcarbarnoyl)-4-methyl-4-oxa-5a-androst- 1 -en-3-one, (23) 17,3-(1-methoxyethyl)-7,13-methyl-4-oxa-Sa-androst-l-en-3-one, (24) 17,(~-(isopropyl)-7~(~-methyl-4-oxa-5a-androst- 1 -en-3-one, (25) 1713-(4-methyl-phenoxy)-7~-methyl-4-oxa-5a-androst- 1 -en-3-one, (26) 17~-(1-(3-chlorophenoxy)ethyl)-7,13-methyl-4-oxa-Soc-androst- 1 -en-3 -one, (27) 17,13-(4-methylsulfonyl-phenoxy)-7,B-methyl-4-oxa-5a-androst- 1 -en-3-one, (28) 17,(~-(4-chlorophenoxy)-7,B-methyl-4-oxa-5a-androst- 1 -en-3-one, (29) 17,13-(2-pyrimidinyloxy)-7,1~-methyl-4-oxa-5a-androst- 1 -en-3-one, and (30) 17~-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-7,B-methyl-4-oxa-5a-androst- 1 -en-3-one.
Further exemplifying this class are:
(1) N-t-Butyl-4-oxa-5a-androst- 1 -en-3 -one- 17~-carboxamide, (2) 7,(~-Methyl-4-oxa-5a-cholest-1-en-3-one, (3) 17~-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-androst-1-en-3-one, (4) 17~-(N-phenylcarbamoyl)-4-oxa-50~-androst- 1 -en-3-one"
(5) 1713-(N-benzylcarbamoyl)-4-oxa-5a-androst-1 -en-3-one, (6) 17,1~-(1-methoxyethyl)-7,~-methyl-~-oxa-50c-androst-1-en-3-one, (7) 17,(~-(isopropyl)-7,13-methyl-4-oxa-5a-androst-1-en-3-one, (8) 17,13-(4-methylphenoxy)-7~-methyl-4-oxa-Sa-androst- 1 -en-3-one, (9) 17,3-(1-(3-chlorophenyoxy)ethyl)-7,~-methyl-4-oxa-5a-androst- 1 -en-3-one, (10) 17,1~-(4-methylsulfonyl-phenoxy)-7,13-methyl-4-oxa-50c-androst- 1 -en-3-one, (1 1) 17~-(methyl-phenoxy)-7~-methyl-4-oxa-50c-androst-l-en-3-one, (12) 17~-(4-chlorophenoxy)-7~-methyl-4-oxa-5a-androst-l-en-3-one, (13) 17,B-(2-pyrimidinyloxy)-7,1~-methyl-4-oxa-5a-androst-1-en-3-one, and ( 14) 1 7,(~-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-7,13-methyl-4-oxa-5a-androst-1 -en-3-one.
In one subclass of this class of the invention are compounds wherein Rl is hydrogen, R2 is selected from H and CH3, and Al is selected from: carboxamide, including substituted and unsubstit~lte-anilide derivatives.
Further illustrating this subclass are compounds wherein 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-20 (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, 1-~ m~n~yl 25 carboxamide, 2-~ m~n~yl carboxamide, and N-(substituted phenyl) carboxamides wherein the phenyl may be substituted with l to 2 substitutents selected from ethyl, methyl, trifluoromethyl or halo (F, Cl, Br, I).
Still further illustrating this subclass are compounds 30 wherein carboxamide is -C(=O)NH-C(CH3)3, -C(=O)NH-C6H5 or -C(=0)NH-(2 ,5 -trifluoromethylphenyl) .
In one subclass of this class of the invention are compounds wherein Rl is hydrogen, R2 is selected from H and CH3, the C5-C6 bond designated with a dotted line is a single bond, Ha is present and W O 97/15564 PCT~US96/16883 represents hydrogen, and Al is selected from: carboxamide, including substituted and unsubstituted anilide derivatives.
Further illustrating this subclass are compounds wherein carboxamide is selected from: N,N-diisopropyl carboxamide, N-t-butyl S carboxamide, N-t-octyl carboxamide, N-n-octyl carboxamide, N-(hydroxyphenyl) carboxarnide, N-phenylcarboxamide, N-(arninophenyl) 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, l-~ m~ntyl carboxamide, 2-~ m~ntyl carboxamide, and N-(substituted phenyl) carboxamides wherein the phenyl may be substituted with 1 to 2 substitutents selected from ethyl, methyl, trifluoromethyl or halo (F, Cl, Br, I).
Still further illustrating this subclass are compounds wherein carboxamide is -C(=O)NH-C(CH3)3, -C(=O)NH-C6H5 or -C(=O)NH-(2,5-trifluoromethylphenyl).
In one subclass of this class of the invention are compounds wherein R 1 is hydrogen, R2 is selected from H and CH3, the CS-C6 bond designated with a dotted line is a double bond, Ha is absent, and Al is selected ~rom: carboxamide, including substituted and unsubstituted anilide derivatives.
Further illustrating this subclass are compounds wherein carboxamide is selected from: N,N-diisopropyl carboxamide, N-t-butyl carboxamide, N-t-octyl carboxamide, N-n-octyl carbo~mi~le, N-(hydroxyphenyl) carboxamide, N-phenylcarboxamide, N-(aminophenyl) carboxamide, N-(carbomethoxy)phenyl carboxamide, N-30 (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, 1-~ m~ntyl , W O 97tl5564 PCT~US96/16883 carboxamide, 2-~d~m~ntyl carboxamide and N-(substituted phenyl) carboxamides, wherein the phenyl may be substituted with 1 to 2 substitutents selected from ethyl, methyl, trifluoromethyl or halo (F, C~l, Br, I).
S Still further illustrating this subclass are compounds wherein carboxamide is -C(=O)NH-C(CH3)3, -C(=O)NH-C6H5 or -C(=O)NH-(2 ,5 -trifluoromethylphenyl) .
In another subclass of this class of the invention are compounds wherein Rl is CH3, R2 is selected from H and CH3, and 10 Al is a selected from: carboxamide, including substituted and unsubstituted anilide derivatives, and Cl lo aL~yl. Further iIlustrating this subclass are compounds wherein carboxamide is -C(=O)NH-C6H5 or -C(=O)NH-(2,5-trifluoromethylphenyl) and Cl lo aL~cyl is selected from isopropyl, isobutyl, 1,5-dimethylhexyl, 15 and 5-methylhexyl.
In another class of the compounds of this embodiment are compounds wherein Z is ~ A
Exemplifying compounds of this class are:
( 1 ) N-t-Butyl-4-oxa-5a-androst- 1 -en-3-one- 1 6~-carboxamide, (2) 16,B-(1,5-dimethylhexyl)-713-Methyl-4-oxa-5a-androst-1-en-3-one, (3) 1 6,~-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-androst-1-en-3-one, (4) 1 6~-(N-tert-amylcarbamoyl)-4-oxa-5a-androst- 1 -en-3-one, (5) 16~-(N-tert-hexylcarbamoyl)-4-oxa-5a-androst-1-en-3-one, (6) 16~-(N-isobutylcarbamoyl)-4-oxa-Sa-androst-l-en-3-one, (7) 16,(~-(N-tert-octylcarbamoyl)-4-oxa-5a-androst-1-en-3-one, W O 97/15564 PCT~US96/16883 (8) 16,13-(N-l,l-diethylbutylcarbamoyl)-4-oxa-5a-androst-1-en-3-one, (9) 16,1~-(N-neopentylcarbamoyl)-4-oxa-Sa-androst-l-en-3-one, (10) 16,B-(N-2-~ mantylcarbamoyl)-4-oxa-Sa-androst-1-en-3-one, (11) 16,B-(N-1 -~ m~ntylcarbamoyl)-4-oxa-Sa-androst-1-en-3-one"
(12) 16,B-(N-2-norbornylcarbamoyl)-4-oxa-Sa-androst- 1 -en-3-one, (13) 16~13-(N- 1 -norbornylcarbamoyl)-4-oxa-Sa-androst- 1 -en-3-one, (14) 16,13-(N-phenylcarbamoyl)-4-oxa-Sa-androst- 1 -en-3 -one, (15) 16,13-(N-benzylcarbamoyl)-4-oxa-5a-androst-1-en-3-one, (16) 16,(~-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-7,B-~nethyl-4-oxa-5a-androst- 1 -en-3-one, (17) 16,~-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-7,B-methyl-4-oxa-5a-androst- 1 -en-3-one, (18) 16,13-(2,6-bis(trifluorome~yl)phenylcarbamoyl)-7,(~-methyl-4-oxa-5a-androst- 1 -en-3-one, (19) 16,13-(2,3-bis(triiFluoromethyl)phenylcarbamoyl)-4-oxa-androst- 1 -en-3-one, (20) 16~-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-androst- 1 -en-3-one, (21) 16~-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-androst-l -en-3-one, (22) 16,13-(N-n-octylcarbamoyl)-4-methyl-4-oxa-Sa-androst-l-en-3-one, (23) 1613-(1 -methoxyethyl)-7,~-methyl-4-oxa-5a-androst- 1 -en-3-one, (24) 16,13-(isopropyl)-7,(~-methyl-4-oxa-5a-androst- 1 -en-3-one, (25) 16,B-(4-methyl-phenoxy)-7,B-methyl-4-oxa-Sa-androst- 1 -en-3-one, W O 97/15564 PCT~US96/16883 (26) 16,B-(1-(3-chlorophenoxy)ethyl)-7~-methyl-4-oxa-So~-androst- 1 -en-3 -one, (27) 1 6~-(4-methylsulfonyl-phenoxy)-7,13-methyl-4-oxa-50~-androst- 1 -en-3-one, (28) 16,B-(4-chlorophenoxy)-7,(~-methyl-4-oxa-5cr~-androst-1-en-3-one, (29) 1 6,(~-(2-pyrimidinyloxy)-7,B-methyl-4-oxa-50~-androst- 1 -en-3-one, and (30) 1 6,B-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-7,13-methyl-4-oxa-50~-androst-l -en-3-one.
Further exemplifying the compounds of this class are:
1 6~-(4-methyl-phenoxy)-7,13-methyl-4-oxa-5a-androst-1 -en-3-one, 16,13-(1-(3-chlorophenoxy)ethyl)-7~-methyl-4-oxa-Sa-androst-l-en-3-one, 1 6,B-(4-methylsulfonyl-phenoxy)-7,13-methyl-4-oxa-50c-androst- 1-en-3-one, 1 6~-(4-chlorophenoxy)-7~-methyl-4-oxa-50c-androst- 1 -en-3-one, and 1 6,B-(2-pyrimidinyloxy)-7,~-methyl-4-oxa-Soc-androst- 1 -en-3-one.
In one subclass of this class, Rl is C1 5 alkyl, R2 is selected from hydrogen and methyl, and A2 is selected from: alkoxy, aryloxy, either unsubstituted or substituted, heteroaryloxy, either substituted or unsubstituted, and alkyl, either unsubstituted or substituted.
Further illustrating this subclass are compounds wherein, A2 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.
Further exemplifying the compounds of this subclass are compounds wherein the C5-C6 bond designated with a dotted line is a double bond, and Ha is absent.
W O 97/15564 PCT~US96/16883 In one subclass of this class, Rl is H or CH3, R2 is selected from H and CH3, and A2 is selected from: substituted and unsubstituted aryl or heteroaryl ether. Further illustrating this subclass are ~e compounds wherein substituted and unsubstituted aryl or heteroaryl 5 ether is selected from thiophenoxy, biphenyloxy, acetamidopheno~y, (3-pyridyl)oxy, chlorophenyloxy, methylphenyloxy, phenoxy, hydroxyphenyloxy, methylsulfonylphenyloxy and pyrimidinyloxy. Still further illustrating the compounds of the present invention are compounds wherein substituted or unsubstituted aryl or heteroaryl ether 10 is selected from 4-methyl-phenoxy, 4-chlorophenoxy, and 2-pyrimidinyloxy.
In another embodiment of the instant invention are compounds o~ formula I wherein X is sulfur.
In one class of the compounds of this embo-liment are 15 compounds wherein Z is A1 Exemplifying compounds of this class are:
( 1 ) N-t-Butyl-4-thia-Soc-androst- 1 -en-3-one- 1 7,(3-carboxamide, (2) 7,13-Methyl-4-thia-5a-cholest- 1 -en-3-one, (3) 1 7~-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-Soc-androst- 1 -en-3-one, (4) 1 7~-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-5~c-androst- 1 -en-3 -one, (5) 1 7,13-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-5~-androst- 1 -en-3-one, (6) 1 7~-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-Soc-androst- 1 -en-3-one, (7) 17,1~-(N-tert-amylcarbamoyl)-4-thia-5a-androst-1-en-3-one, (8) 1 7,13-(N-tert-hexylcarbamoyl)-4-thia-So~-androst- 1 -en-3-one, W O 97/15S64 PCT~US96/16883 (9) 17,13-(N-isobutylcarbamoyl)-4-thia-5a-androst- 1 -en-3-one, (10) 17,B-(N-tert-octylcarbamoyl)-4-thia-5a-androst- 1 -en-3-one, (11) 17,(~-(N- 1,1 -diethylbutylcarbamoyl)-4-thia-5a-androst- 1 -en-3-one, (12) 17~1~-(N-neopentylcarbamoyl)-4-thia-5a-androst- 1 -en-3-one, (13) 17~13-(N-2-~d~m~ntylcarbamoyl)-4-thia-50c-androst-l-en-3-one, (14) 17,B-(N- 1 -~dzlm~ntylcarbamoyl)-4-thia-5a-androst- 1 -en-3 -one, (15) 17 ~B-(N-2-norbornylcarbamoyl)-4-thia-5a-androst- 1 -en-3 -one, (16) 17,13-(N-l-norbornylcarbamoyl)-4-thia-50~-androst-l-en-3-one, (17) 17~-(N-phenylcarbamoyl)-4-thia-5a-androst-1-en-3-one, (lg) 17,13-(N-benzylcarbamoyl)-4-thia-5a-androst-1-en-3-one, (19) 17~-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-7~-methyl-4-thia-5a-androst- 1 -en-3-one, (20) 17~-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-7,~-methyl-4-thia-5a-androst-1-en-3-one, (21) 17,13-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-7,3-methyl-4-thia-5a-androst- 1 -en-3-one, (22) 17~-(N-n-octylcarbamoyl)-4-methyl-4-thia-5a-androst-1-en-3-one, (23) 17,13-(1-methoxyethyl)-7~-methyl-4-thia-5a-androst-1-en-3-one, (24) 17,1~-(isopropyl)-7,13-methyl-4-thia-Sa-androst- 1 -en-3-one, (25) 17,~-(4-methyl-phenoxy)-7,(~-methyl-4-thia-5a-androst- 1 -en-3-one, (26) 17,1~-(1-(3-chlorophenoxy)ethyl)-7,13-methyl-4-thia-5a-androst- 1 -en-3-one, (27) 17~-(4-methylsulfonyl-phenoxy)-7,13-methyl-4-thia-5a-androst-l -en-3-one, W O97/lS564 PCTAUS96/16883 (28) 17,3-(4-chlorophenoxy)-7,B-methyl-4-thia-5a-androst-1-en-3-one, (29) 17,13-(2-pyrimidinyloxy)-7,(~-methyl-4-thia-5a-androst-1-en-3-one, and (30) 17~13-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-7~-methyl-4-thia-5a-androst- 1 -en-3 -one.
Further exemplifying compounds of this class are:
(1) N-t-Butyl-4-thia-5a-androst- 1 -en-3-one- 17,13-carbox~mide, (2) 7,13-Methyl-4-thia-5a-cholest-1-en-3-one, (3) 17,B-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-androst- 1 -en-3-one, (4) 17,(~-(N-phenylcarbamoyl)-4-thia-5a-androst- 1 -en-3 -one"
(5) 1713-(N-benzylcarbamoyl)-4-thia-5a-androst- 1 -en-3 -one, (6) 17,13-(1 -methoxyethyl)-7,B-methyl-4-thia-5a-androst- 1 -en-3-one, (7) 17,13-(isopropyl)-7~3-methyl-4-thia-5a-androst-1-en-3-one, (8) 17,(~-(4-methylphenoxy)-7,1~-methyl-4-thia-50~-androst- 1 -en-3-one, (9) 17,B-(1 -(3-chlorophenyoxy)ethyl)-7,3-methyl-4-thia-5a-androst- 1 -en-3-one, (10) 17~-(4-methylsulfonyl-phenoxy)-7,(~-methyl-4-thia-50~-androst- 1 -en-3 -one, (11) 17,13-(methyl-phenoxy)-713-methyl-4-thia-5a-androst-1-en-3-one, (12) 17,3-(4-chlorophenoxy)-7,13-methyl-4-thia-5a-androst-1-en-3-one, (13) 17,B-(2-pyrimidinyloxy)-7~-methyl-4-thia-5a-androst-1 -en-3-one, and (14) 17,B-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-7,(~-methyl-4-thia-5a-androst- 1 -en-3-one.
In one subclass of this class of the invention are compounds wherein R1 is hydrogen, R2 is selected from H and CH3, and Al is , selected from: carboxamide, including substituted and unsubstituted anilide derivatives.
Further illustrating this subclass are compounds wherein carboxamide is selected from: N,N-diisopropyl carboxamide, N-t-butyl carboxamide, N-t-octyl carboxarnide, N-n-octyl carbox~mitle, N-(hydroxyphenyl) carboxamide, N-phenylcarboxamide, N-(aminophenyl) carboxarnide, N-(carbomethoxy)phenyl carboxamide, N-(methoxycarboxy) phenyl carboxamide, N-acetamidophenyl-N-acetyl-carboxamide, N-acetamidophenyl-carboxamide, N-pivalamidophenyl carboxamide, N-isobutyramidophenyl carbox~mi~le, N-(methyl),N-(diphenylmethyl) carboxamide, N-(diphenylmethyl)-carboxamide, N-t-butyl carboxamide, N-isopropyl carboxamide, 1-~ m~ntyl carboxamide, 2-~ m~ntyl carboxamide, and N-(substituted phenyl) carboxamides wherein the phenyl may be substituted with 1 to 2 substitutents selected from ethyl, methyl, trifluoromethyl or halo (F, Cl, Br, I).
Still further illustrating this subclass are compounds wherein carboxamide is -C(=O)NH-C(CH3)3, -c(=o)NH-c6H5 or -C(=O)NH-(2 ,5 -trifluoromethylphenyl) .
In one subclass of this class of the invention are compounds wherein R1 is hydrogen, R2 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, and A1 is selected from: carboxamide, including substituted and unsubstituted anilide derivatives.
Further illustrating this subclass are compounds wherein 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)-carbox~micle, N-t-butyl carboxamide, N-isopropyl carboxamide, l~ m~ntyl WO 97/1556~ PCTAUS96/16883 carboxamide, 2~ m~ntyl carboxamide, and N-(substituted phenyl) carboxamides wherein the phenyl may be substituted with 1 to 2 substitutents selected from ethyl, methyl, trifluoromethyl or halo (F, Cl, Br, I).
Still further illustrating this subclass are compounds wherein carboxamide is -C(=O)NH-C(CH3)3, -C(=O)NH-C6H5 or -C(=O)NH-(2 ,5 -trifluoromethylphenyl) .
In one subclass of this class of the invention are compounds ~ wherein R 1 is hydrogen, R2 is selected from H and CH3, the C5-C6 bond designated with a dotted line is a double bond, Ha is absent, and Al is selected from: carboxamide, including substituted and unsubstituted anilide derivatives.
Further illustrating this subclass are compounds wherein carboxamide is selected from: N,N-diisopropyl carboxamide, N-t-butyl carboxamide, N-t-octyl carboxamide, N-n-octyl carbox~micle, N-(hydroxyphenyl) carboxamide, N-phenylcarboxamide, N-(aminophenyl) carboxamide, N-(carbomethoxy)phenyl carboxamide, N-(methoxycarboxy) phenyl carboxamide, N-acetamidophenyl-N-acetyl-carboxamide, N-acetamidophenyl-carbox~mi~le, N-pivalamidophenyl carboxamide, N-isobutyramidophenyl carboxamide, N-(methyl),N-(diphenylmethyl) carboxamide, N-(diphenylmethyl)-carboxamide, N-t-butyl carboxamide, N-isopropyl carboxamide, l-a-l~m~ntyl carboxamide, 2-~ m~ntyl carboxamide and N-(substituted phenyl) carboxamides, wherein the phenyl may be substituted with 1 to 2 substitutents selected from ethyl, methyl, trifluoromethyl or halo (F, Cl, Br, I).
Still further illustrating this subclass are compounds wherein carboxamide is -C(=O)NH-C(CH3)3, -C(=O)NH-C6H5 or -C(=0)NH-(2,5-trifluoromethylphenyl).
In another subclass of this class of the invention are compounds wherein Rl is CH3, R2 is selected from H and CH3, and Al is a selected from: carboxamide, including substituted and unsubstituted anilide derivatives, and Cl lo aL~yl. Further illustrating ~is subclass are compounds wherein carboxamide is W O 97/15564 PCTrUS96/16883 -C(=O)NH-C6H5 or -C(=0)NH-(2,5-trifluoromethylphenyl) and Cl lo alkyl is selected from isopropyl, isobutyl, 1,5-dimethylhexyl, and 5-methylhexyl.
S In another class of the compounds of this embodiment are compounds wherein Z is ~A2 Exemplifying compounds of this class are:
( 1 ) N-t-Butyl-4-thia-Soc-androst- 1 -en-3-one- 1 6,3-carboxamide, (2) 16,13-(1,5-dimethylhexyl)-7,13-Methyl-4-thia-5a-androst-1-en-3-one, (3) 1 6,(~-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-androst- 1 -en-3-one, (4) 1 6,~-(N-tert-amylcarbamoyl)-4-thia-Soc-androst-1 -en-3-one, (S) 16~-(N-tert-hexylcarbamoyl)-4-thia-Sa-androst-1-en-3-one, (6) 1 6,1~-(N-isobutylcarbamoyl)-4-thia-Soc-androst- 1 -en-3 -one, (7) 1 6,3-(N-tert-octylcarbamoyl)-4-thia-Soc-androst- 1 -en-3-one, (8) 1 6,13-(N- 1,1 -diethylbutylcarbamoyl)-4-thia-Soc-androst- 1-en-3-one, (9) 1 6,B-(N-neopentylcarbamoyl)-4-thia-Sa-androst-1 -en-3-one, (10) 16,B-(N-2-~ m~ntylcarbamoyl)-4-thia-So~-androst-1-en-3-one, (11) 16,1~ m~ntylcarbamoyl)-4-thia-5oc-androst-1-en-3-- one"
( 12) 1 6,13-(N-2-norbornylcarbamoyl)-4-thia-So~-androst- 1 -en-3-- one, ( 13) 1 6,13-(N-1 -norbornylcarbamoyl)-4-thia-Soc-androst- 1 -en-3-one, (14) 16,(~-(N-phenylcarbamoyl)-4-thia-50c-androst-1-en-3-one, W O 97/15564 PCT~US96/16883 ( 15) 1 6,13-(N-benzylcarbamoyl)-4-thia-5a-androst- 1 -en-3-one, ( 16) 1 6~-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-7~-methyl-4-thia-5a-androst- 1 -en-3-one, (17) 16,(~-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-713-methyl-4-thia-5a-androst-1-en-3-one, (18) 16~-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-7~-methyl-4-thia-Sa-androst- 1 -en-3-one, (19) 16,1~-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-androst- 1 -en-3 -one, (20) 1 6,~-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-androst- 1 -en-3-one, (21 ) 1 6~-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-4-~ia-androst- 1 -en-3-one, (22) 1 6,(~-(N-n-octylcarbamoyl)-4-methyl-4-thia-Sa-androst- 1-lS en-3-one, (23) 16~-(1-methoxyethyl)-7,~-methyl-4-thia-5a-androst-1-en-3-one, (24) 1 6~-(isopropyl)-7,B-methyl-4-thia-Sa-androst- 1 -en-3-one, (25) 16,13-(4-methyl-phenoxy)-7,(~-methyl-4-thia-Sa-androst-1-en-3-one, (26) 1613-(1-(3-chlorophenoxy)ethyl)-7,B-methyl-4-thia-Sa-androst- 1 -en-3-one, (27) 1 6~-(4-methylsulfonyl-phenoxy)-7~-methyl-4-thia-Sa-- androst-l-en-3-one, (28) 16,~-(4-chlorophenoxy)-7,13-methyl-4-thia-Sa-androst-l-en-3-one, (29) 16~-(2-pyrimidinyloxy)-7,13-methyl-4-thia-5a-androst-1-en-3-one, and (30) 1 6,B-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-713-methyl- .
4-thia-Sa-androst-l-en-3-one.
Fur~er exemplifying the compounds of this class are:
1 6~-(4-methyl-phenoxy)-7~-methyl-4-thia-Sa-androst-1 -en-3-one, , W O 97/15564 PCTrUS96/16883 16,13-(1 -(3-chlorophenoxy)ethyl)-7,13-methyl-4-thia-5Oc-androst- 1-en-3-one, 1 6,(~-(4-methylsulfonyl-phenoxy)-7,13-methyl-4-thia-Sa-androst-l -en-3-one, 1 6,13-(4-chlorophenoxy)-7,13-methyl-4-thia-5~c-androst-1 -en-3-one, and 1 6,13-(2-pyrimidinyloxy)-7~-methyl-4-thia-So~-androst- 1 -en-3-one.
In one subclass of this class, Rl is C1 5 alkyl, R2 is selected from hydrogen and methyl, and A2 is selected from: aLkoxy, aryloxy, either unsubstituted or substituted, heteroaryloxy, either substituted or unsubstituted, and alkyl, either unsubstituted or substituted.
Further illustrating this subclass are compounds wherein, A2 is selected from: substituted aryloxy, and heteroaryloxy, either substituted or unsubstituted.
Exemplifying compounds of this subclass are compounds wherein the CS-C6 bond designated with a dotted line is a single bond, and Ha is present and represents hydrogen.
Further exemplifying the compounds of this subclass are 20 compounds wherein the C5-C6 bond designated with a dotted line is a double bond, and Ha is absent.
In another subclass of this class, Rl is H or CH3, R2 is selected from H and CH3, and A2 is selected from: substituted and unsubstituted aryl or heteroaryl ether. Further illustrating this subclass 25 are the compounds wherein substituted and unsubstituted aryl or heteroaryl ether is selected from thiophenoxy, biphenyloxy, acetamidophenoxy, (3-pyridyl)oxy, chlorophenyloxy, methylphenyloxy, phenoxy, hydroxyphenyloxy, methylsulfonylphenyloxy and pyrimidinyloxy. Still further illustrating the compounds of the present 30 invention are compounds wherein substituted or unsubstituted aryl or heteroaryl e~er is selected from 4-methyl-phenoxy, 4-chlorophenoxy, and 2-pyrimidinyloxy.
In one subclass of this class, R1 is Cl 5 alkyl, R2 is selected from hydrogen and methyl, and A2 is selected from: alkoxy, aryloxy, WO 97/15564 PCT~US96/16883 either unsubstituted or substituted, heteroaryloxy, either substituted or unsubstituted, and alkyl, either unsubstituted or substituted.
Further illustrating this subclass are compounds wherein, A2 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.
Further exemplifying the compounds of this subclass are compounds wherein the C5-C6 bond designated with a doKed line is a double bond, and Ha is absent.
When any variable (e.g., aryl, heterocycle, Rl, etc.) occurs more than one time in any constituent or in foImula I, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable co~npounds.
As used herein "aL~yl" 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), lelL~ulyl (t-Bu), isopentane, isohexane, etc. "AL~yloxy" (or "alkoxy") represents an aL~yl group 2~ 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.
The term "aryl" includes phenyl and naphthyl. Preferably, aryl is phenyl.
Heteroaryl is selected from piperidinyl, piperizinyl, pyrrolidinyl, pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, indolyl and benzofuranyl.
W O 97/15~64 PCTAUS96/16883 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 5 of ordinary skill in the art, and any such groups may be used. For example, 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-10 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(O)-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 al. (John Wiley 15 and Sons, 1991) for descriptions of protecting groups.
The compounds of the present invention may be ~lmini~tered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" is intended to include all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, 20 m~l~te, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clav~ n~e, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), 25 estolate, p~lmit~te, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glllt~m~te, stearate, glycollylars~nil~te, sulfate, hexylresorcinate, subacetate, hydrabamine, succinate, hydrobromide, t~nn~te, hydrochloride, tartrate, hydroxynaphthoate, teoclate, iodide, 30 tosylate, isothionate, triethiodide, lactate, panoate, valerate, and the like which can be used as a dosage form for modifying the solubility or hydrolysis characteristics or can be used in sustained release or pro-drug formulations. Depending on the particular functionality of the compound of ~e present invention, pharmaceutically acceptable salts of W O 97/15564 PCT~US96/16883 the compounds of this invention include those formed from cations such as sodium, potassium, ~lllmim-m, calcium, lill~iunl, magnesium, zinc, and from bases such as ammonia, ethylene~ mine, N-methyl-gl-lt~mine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylene~ mine, 5 chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide. These salts may be prepared by standard procedures, e.g. by reacting a free acid with a suitable organic or inorganic base.
Also, in the case of an acid (-COOH) or alcohol group being present, pharmaceutically acceptable 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 fonmll~tions.
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 20 mixtures thereof. Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are 25 encompassed within the scope of this invention.
The telm "therapeutically effective amount" is that amount of a drug or pharrnaceutical agent that will elicit the biological or medical response of a tissue, system, ~nim~l or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, 30 which includes alleviation of the symptoms of the disorder being treated.
More particularly, the present invention relates to a method for treating hyperandrogenic conditions in a m~mm~l in need of such treatment comprising the ~lmini~tration to the m~mm~l in need of such W O 97/15564 PCT~US96/16883 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 "m~mm~l"
includes humans. Preferably, the method of the present invention is for S treating hyperandrogenic conditions in a hllm~n in need of such treatment.
Hyperandrogenic conditions treatable by the method of the present invention include benign prostatic hyperplasia, androgenic alopecia (including male pattern baldness, female pattern baldness and 10 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, 15 and female hirsutism by oral, systemic, parenteral or topical ~lmini~tration of the novel compounds of formula I either alone or in combination with a Soc-reductase 2 inhibitor, preferably selected from finasteride and epristeride, or a potassium channel opener, or a retinoic acid or derivative thereof. Alternatively, treatment may 20 encompass ~lmini~tration of a combination of a compound of formula I with a 5a-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.
The term "treating androgenic alopecia" is intended to include the 25 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 hyperplasia, prostatitis, and treating and/or p~eventing prostatic carcinoma by 30 oral, systemic or parenteral ~rlmini~tration of the novel compounds of formula I either alone or in combination with a Soc-reductase 2 inhibitor, preferably selected from finasteride and epristeride.
Alternatively, treatment may encompass ~llmini~tration of a combination of a compound of formula I with a Soc-reductase 2 W O 97/15~64 PCT~US96/16883 .~
inhibitor and/or another active agent such as an o~1 or an O~la adrenergic receptor antagonist (ala receptor antagonists were formerly called alc receptor antagonists).
The present invention also has a further objective of S providing methods of treating acne vulgaris, androgenic alopecia, seborrhea, female hirsutism, benign prostatic hyperplasia, prostatitis and the preventing and/or treating of prostatic cancer, by oral, systemic, parental or topical ~lmini~tration of a combined therapy of a therapeutically effective amount of a compound of formula I
10 with a therapeutically effective amount of an anti-androgen, such as, e.g., flutamide, spironolactone or casodex.
For combination treatment with more than one active agent, where the active agents are in separate dosage formulations, the active agents can be arlministered concolnilal~lly~ or they each can 15 be ~lrninistered 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 treat~ent of the present invention. The compositions cont~ining the present compounds as 20 the active ingredient for use in the treatment of the above-noted conditions can be ~lministered in a wide variety of therapeutic dosage forms in conventional vehicles for systemic ~lminilstration.
For example, the compounds can be ~lmini~tered in such oral dosage forms as tablets, capsules (each including timed release and sustained 25 release formulations), pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups and emulsions, or by injection.
Likewise, they may also be ~lmini~tered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous, topical with or without occlusion, or intramuscular form, all using forms well known to 30 those of ordinary skill in the ph~ eutical arts. An effective but non-toxic amount of the compound desired can be employed as an antiandrogenic agent.
The compounds of structural formula I useful in the present invention are typically ~lmini~tered 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 ~tlmini~tration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional ph~rm~ceutical S practices may be ~-lmini~tered systemically, by oral ~lministration or by intravenous or intramuscular injection or topically.
For instance, for oral ~lmini~tration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, 10 glycerol, water and the like. Capsules cont~ining the product of this invention can be prepared by mixing an active compound of the present invention with lactose and m~gnesium stearate, calcium stearate, starch, talc, or other carriers, and placing the nli~lulc in gelatin capsules.
Tablets may be prepared by mixing the active ingredient 15 with conventional tableting ingredients such as calcium phosphate, lactose, corn starch or magnesium stearate. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-20 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 25 include, without limit~tion, starch, methyl cellulose, agar, bentonite, x~nth~n 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 30 agents which may be employed include glycerin and the like. For parenteral ~lmini~tration, sterile suspensions and solutions are desired.
Isotonic preparations which generally contain suitable preservatives are employed when intravenous ~1mini~tration is desired.
W O 97/15564 PCT~US96116883 Topical ph~ ceutical 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 5 may include about 0.001% to 0.1% of the active compound in admixture with a ph~ ceutically acceptable carrier.
Topical preparations contz-ining 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
10 and E oils, mineral oil, propylene glycol, PPG2 myristyl propionate, and the like, to fo~n, e.g., alcoholic solutions, topical cleansers, cleansing creams, skin gels, skin lotions, and shampoos in creaIn or gel formulations. See, e.g., EP 0 285 382.
The compounds of the present invention can also be 15 ~tlmini~tered in the form of liposome delivery systems, such as small 7mil~mellar vesicles, large lmil~mellar 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 20 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, 25 polyhydroxyethylaspartamide-phenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, ~e compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for e~ample, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, 30 polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
The compounds for ~e present invention can be ~lmini~tered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal W O 97/1~564 PCT~US96/16883 skin patches well known to those of ordinary skill in the art. To be ~rlmini~tered in the form of a transdermal delivery system, the dosage ~ ~clministration will, of course, be continuous rather than inte~ Lellt throughout the dosage regimen. Compounds of the present invention 5 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.
The dosage regimen utilizing the compounds of the 10 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 ~lmini~tration; the renal and hepatic function of the patient; and the particular compound thereof employed. A physician or veterinarian 15 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 20 availability to target sites. This involves a consideration of the distribution, equilibrium, and elimin~tion of a drug. Preferably, 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 hllm~n per day. Most preferably, dosages range from 0.1 to 50 25 mg/day. For oral ~lminictration, the compositions are preferably provided in the form of tablets cont~inin~ 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 30 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/l~g of body weight per day. The range is more particularly from about 0.001 mg/kg to 1 mg/kg of body weight per day.
(I) or a pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein:
the C5-C6 bond designated with a dotted line independently represents a single or double bond, provided that when the CS-C6 is a double bond, Ha is absent and when the C5-C6 bond is a single bond Ha is present and represents hydrogen;
~ is selected from oxygen and sulfur;
R1 is selected from hydrogen and Cl 5 aLkyl;
R2 is selected from CH3, CH20R3, and H, R3 is selected from: Cl 5 alkyl;
5 Zis ~ A
or ~
~ ;and A 1 is selected from:
(1) -H, (2) keto, (6) carboxy, (7) protected amino, (8) amino, (9) Cl lo alkyl, (10) substituted or unsubstituted C2 10alkenyl, (11) aryl-substituted Cl lo alkyl, (12) aryl or heteroaryl, (13) substituted aryl or heteroaryl, (14) aryl or heteroaryl carbamoyl-substituted C1 1oalkyl, (15) Cl loalkylcarbonyl, (16) aryl or heteroaryl carbonyl, (17) ether-substituted Cl loalkyl, (18) thioether-substituted Cl loalkyl, (19) keto-substituted Cl loaLkYl, (20) heteroaryl-substituted C1 -10 alkyl, (21) carboxylic ester, (22) carboxamide, including substituted and unsubstituted ~nilicle ~ derivatives, (23) urea, (24) Cl lo alkylureido C0 5 alkyl, W O 97/15564 PCT~US96/16883 (25) substituted or unsubstituted heteroaryl or arylureidoCo 5 alkyl, (26) Cl loalkanoyloxyC1 2alkyl, (27) Cl -10 aLkylcarbonylamino, (28) alkanoylamidoalkyl (29) ether, (30) thio ether, and (31 ) substituted and unsubstituted aryl or heteroaryl ether;
A2 is selected from:
(1) -H, (2) keto, (3) protected hydroxy, (4) acetate, (5) hydroxy, (6) carboxy, (7) protected amino, (8) amino, (9) Cl lo alkyl, (10) substituted or unsubstituted C2 loalkenyl, (11) aryl-substituted Cl lo alkyl, (12) aryl or heteroaryl, (13) substituted aryl or heteroaryl, (14) aryl or heteroaryl carbamoyl-substituted C1 1oalkyl, (15) Cl 1oalkylcarbonyl, (16) aryl or heteroaryl carbonyl, (17) ether-substituted Cl 1oalkyl, (18) thioe~er-substituted Cl loalkyl, (19) keto-substituted Cl loaLkyl, (20) heteroaryl-substituted Cl 1o alkyl, (21) carboxylic ester, (22) carboxamide, including substituted and unsubstituted anilide derivatives, (23) urea, (24) Cl-10 alkylureido C0 5 alkyl, W O 97/15564 PCT~US96/16883 (25) substituted or unsubstituted arylureidoCo 5 alkyl, (26) Cl loaL~anoyloxyCl 2alkyl, (27) Cl lo aLl~ylcarbonylamino, (28) aLlcanoylamidoaL~yl, (29) ether, (30) thio ether, and (31 ) substituted and unsubstituted aryl- or heteroaryl-ether;
Heteroaryl is selected from piperidinyl, piperizinyl, pyrrolidinyl, pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, indolyl and benzofuranyl.
Preferred are compounds wherein:
(a) protected hydroxy is selected from: dimethyl-t-butyl lS silyloxy, trimethylsilyloxy, tri-ethylsilyloxy, tri-isopropylsilyloxy, and triphenylsilyloxy;
(b) protected amino is acetyl~mino, benzoylamino, and pivaloylamino;
(c) Cl lo aL~yl is selected from methyl, ethyl, propyl, butyl, pentyl, 1,5-dimethylhexyl, 6-methylhept-2-yl, 5-methylhexyl, and l-methyl-4-isopropylhexyl;
(d) substituted or unsubstituted ~2 loalkenyl is selected from:
phenylmethylene, chlorophenylmethylene, ethoxycarbonylphenylmethylene, carboxyphenylmethylene, (((l,l-dimethylethyl) amino) carbonyl)phenylmethylene, trimethoxyphenyl methylene, methoxyphenylmethylene, methylsulfonylphenylmethylene, biphenylmethylene, nitrophenylmethylene, aminophenylmethylene, acetylaminophenylmethylene, pivaloylaminophenylmethylene, phenoxyphenylmethylene, 2-imidazolyl methylene, 2-thiazolylmethylene, (e) aryl substituted Cl lo aLkyl is selected from omega-phenylpropyl and l-(chlorophenoxy)ethyl;
(f) aryl is selected from phenyl, and naphthyl;
WO 97/15564 PCT~US96/16883 (g) substituted aryl or heteroaryl is selected from phenyl, pyridyl and pyrimidinyl substituted with one to three substituents independently selected from:
(1) -H, (2) -OH, (3) -CH3, (4) -OCH3, (5) -S(O)n-CH3, wherein n is selected from 0, 1, and 2, (6) -CF3, (7) halo, (8) -CHO, (9) CN, (10) phenyloxy, (11) ethyl, (12) t-butyl, (1 3) OCH2CH3, (14) OC(CH3)3, and (15) -NHR7, wherein R7 is selected from:
-H, -Cl 8 aL~yl, -Cl 6 alkylcarbonyl, -Cl 6 alkylsulfonyl, and -Cl 6 alkoxycarbonyl, (h) aryl or heteroaryl carbamoyl substituted Cl lo aLkyl is selected from 2-(4-pyridyl-carbamoyl)ethyl and 2-phenyl-ethyl;
(i) Cl loalkylcarbonyl is selected from isobutylcarbonyl and isopropylcarbonyl;
(j) aryl or heteroaryl carbonyl is selected from phenylcarbonyl and pyridyl carbonyl;
(k) ether-substituted Cl loalkyl is selected from 1-methoxy-ethyl and l-ethoxy-ethyl;
(1) thioether-substituted Cl loalkyl is selected from 1-methylthio-ethyl, and l-ethylthio-e~yl;
(m) keto-substituted C1 loalkyl is 1 -keto-ethyl, ketomethyl, 1-ketopropyl, and ketobutyl;
-(n) heteroaryl-substituted Cl lo alkyl is omega-(4-pyridyl)-butyl;
(o) carboxylic esters are Cl lo aLlcylcarboxylic esters selected from carbomethoxy and carboethoxy;
S (p) carboxamides are 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 carboxarnide, N-(methoxycarboxy) phenyl carboxamide, N-acetamidophenyl-N-acetyl-carboxamide, N-acetamidophenyl-carboxamide, N-piv~l~mi~lophenyl carboxamide, N-isobutyramidophenyl carboxamide, N-(methyl),N~diphenylmethyl) carboxamide, N-lS (diphenylmethyl)-carboxamide, N-t-butyl carboxamide, N-isopropyl carboxamide, l-acl~m~n~yl carboxamide, 2-m~ntyl carboxamide and N-(substituted phenyl) carboxamides wherein the phenyl may be substituted with 1 to 2 substitutents selected from ethyl, methyl, trifluoromethyl or halo (F, Cl, Br, I);
(q) Cl loaL~anoyloxyCl -2aLkyl is selected from acetyloxymethyl, trimethylacetyloxymethyl, and (2-ethylhexanoyloxy)methyl;
~(r) urea is t-butylcarbonylamino urea;
(s) Cl lo aLkylureido C0 5 aLkyl is selected from: N-t-butylureidomethyl, N-n-propylureidomethyl, N-n-octylureidomethyl, N-isopropylureido, allylureido, (t) substituted or unsubstituted arylureidoCo 5 aL~yl is selected from: N-(ethylphenyl) ureidomethyl, N-(chlorophenyl) ureidomethyl, N-phenylureidomethyl, N-(dichlorophenyl) ureidomethyl, N-naphth-2-yl)ureidomethyl, N-thiazol-2-ylureidomethyl, N-thien-2-ylmethylureidomethyl, N-(fluorophenyl)ureido, N-(methoxyphenyl)ureido, and 2-(ethoxyphenyl)ureidomethyl;
PCT~US96/16883 (u) Cl lo alkylcarbonylamino is t-butylcarbonyl~mino;
(v) aL~anoylamidoalkyl is selected from:
trimethylacetamidomethyl, carbomethoxyoctanoylamidomethyl, S (isobutylphenyl)propionamidomethyl, 8-carboxyoctanoylamidomethyl, bromohexanoylamido methyl, hydroxydodecanoyl amidomethyl, 4-nitrophenylprionamidomethyl, isopropylthioacetamidomethyl, benzyloxyacetamidomethyl, 1 0 carbomethoxyacetamidomethyl, triphenylproprionamidomethyl, cyclohexylacetamidomethyl, methylcyclohexanecarboxamidomethyl, (3-hydroxy-4,4,4-trichlorobutyramido)methyl, and phenylthio-acetamidomethyl;
(w) ether is selected from ethylene ketal, and C1 galkyl ether optionally substituted with hydroxy, halo, C1 galkoxy, C2 6alkenyl, or aryl;
(x) thioe~er is selected from: C1 galkylthio, phenylthio, and C1 8 alkylthio substituted with phenyl; and (y) substituted and unsubstituted aryl or heteroaryl ether is selected from thiophenoxy, biphenyloxy, acetamidophenoxy, (3-pyridyl)oxy, chlorophenyloxy, methylphenyloxy, phenoxy, hydroxyphenyloxy, methylsulfonylphenyloxy and pyrimidinyloxy.
In one embodiment of the instant invention are compolmds of formula I wherein X is oxygen.
In one class of the compounds of this embodiment are 30 compounds wherein Z is W O 97/15564 PCT~US96/16883 Exemplifying this class are:
(1) N-t-Butyl-4-oxa-Sa-androst- 1 -en-3-one-17,3-carboxamide, (2) 7,3-Methyl-4-oxa-5a-cholest- 1 -en-3 -one, (3) 17,1~-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-5a-androst- 1 -en-3-one, (4) 17,13-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-5a-androst- 1 -en-3-one, (5) 17,(~-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-5a-androst- 1 -en-3-one, (6) 17,13-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-5a-androst- 1 -en-3 -one, (7) 17,1~-(N-tert-amylcarbamoyl)-4-oxa-5a-androst-1-en-3-one, (8) 17,1~-(N-tert-hexylcarbamoyl)-4-oxa-Sa-androst- 1 -en-3-one, (9) 17,1~-(N-isobutylcarbamoyl)-4-oxa-5a-androst-1-en-3-one, (10) 17,1~-(N-tert-octylcarbamoyl)-4-oxa-5a-androst- 1 -en-3-one, (11) 17,13-(N- 1,1 -diethylbutylcarbamoyl)-4-oxa-5a-androst- 1 -en-3-one, (12) 17,13-(N-neopentylcarbamoyl)-4-oxa-Sa-androst-1 -en-3-one, (13) 17,B-(N-2-~ m~ntylcarbamoyl)-4-oxa-Sa-androst- 1 -en-3-one, (14) 17~-(N-1 ~ m~ntylcarbamoyl)-4-oxa-5a-androst-1-en-3-one"
(lS) 17,13-(N-2-norbornylcarbamoyl)-4-oxa-50c-androst-l-en-3-one, (16) 17,~-(N-l-norbornylcarbamoyl)-4-oxa-Sa-androst-l-en-3-one, (17) 17~-(N-phenylcarbamoyl)-4-oxa-Sa-androst-l-en-3-one, (18) 17~13-(N-benzylcarbamoyl)-4-oxa-Sa-androst-1-en-3-one, (19) 17,3-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-7,B-methyl-4-oxa-5a-androst- 1 -en-3-one, (20) 17~-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-7,~-methyl-4-oxa-5a-androst- 1 -en-3-one, (21) 17,13-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-7~-methyl-4-oxa-5a-androst- 1 -en-3-one, (22) 17~-(N-n-octylcarbarnoyl)-4-methyl-4-oxa-5a-androst- 1 -en-3-one, (23) 17,3-(1-methoxyethyl)-7,13-methyl-4-oxa-Sa-androst-l-en-3-one, (24) 17,(~-(isopropyl)-7~(~-methyl-4-oxa-5a-androst- 1 -en-3-one, (25) 1713-(4-methyl-phenoxy)-7~-methyl-4-oxa-5a-androst- 1 -en-3-one, (26) 17~-(1-(3-chlorophenoxy)ethyl)-7,13-methyl-4-oxa-Soc-androst- 1 -en-3 -one, (27) 17,13-(4-methylsulfonyl-phenoxy)-7,B-methyl-4-oxa-5a-androst- 1 -en-3-one, (28) 17,(~-(4-chlorophenoxy)-7,B-methyl-4-oxa-5a-androst- 1 -en-3-one, (29) 17,13-(2-pyrimidinyloxy)-7,1~-methyl-4-oxa-5a-androst- 1 -en-3-one, and (30) 17~-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-7,B-methyl-4-oxa-5a-androst- 1 -en-3-one.
Further exemplifying this class are:
(1) N-t-Butyl-4-oxa-5a-androst- 1 -en-3 -one- 17~-carboxamide, (2) 7,(~-Methyl-4-oxa-5a-cholest-1-en-3-one, (3) 17~-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-androst-1-en-3-one, (4) 17~-(N-phenylcarbamoyl)-4-oxa-50~-androst- 1 -en-3-one"
(5) 1713-(N-benzylcarbamoyl)-4-oxa-5a-androst-1 -en-3-one, (6) 17,1~-(1-methoxyethyl)-7,~-methyl-~-oxa-50c-androst-1-en-3-one, (7) 17,(~-(isopropyl)-7,13-methyl-4-oxa-5a-androst-1-en-3-one, (8) 17,13-(4-methylphenoxy)-7~-methyl-4-oxa-Sa-androst- 1 -en-3-one, (9) 17,3-(1-(3-chlorophenyoxy)ethyl)-7,~-methyl-4-oxa-5a-androst- 1 -en-3-one, (10) 17,1~-(4-methylsulfonyl-phenoxy)-7,13-methyl-4-oxa-50c-androst- 1 -en-3-one, (1 1) 17~-(methyl-phenoxy)-7~-methyl-4-oxa-50c-androst-l-en-3-one, (12) 17~-(4-chlorophenoxy)-7~-methyl-4-oxa-5a-androst-l-en-3-one, (13) 17,B-(2-pyrimidinyloxy)-7,1~-methyl-4-oxa-5a-androst-1-en-3-one, and ( 14) 1 7,(~-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-7,13-methyl-4-oxa-5a-androst-1 -en-3-one.
In one subclass of this class of the invention are compounds wherein Rl is hydrogen, R2 is selected from H and CH3, and Al is selected from: carboxamide, including substituted and unsubstit~lte-anilide derivatives.
Further illustrating this subclass are compounds wherein 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-20 (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, 1-~ m~n~yl 25 carboxamide, 2-~ m~n~yl carboxamide, and N-(substituted phenyl) carboxamides wherein the phenyl may be substituted with l to 2 substitutents selected from ethyl, methyl, trifluoromethyl or halo (F, Cl, Br, I).
Still further illustrating this subclass are compounds 30 wherein carboxamide is -C(=O)NH-C(CH3)3, -C(=O)NH-C6H5 or -C(=0)NH-(2 ,5 -trifluoromethylphenyl) .
In one subclass of this class of the invention are compounds wherein Rl is hydrogen, R2 is selected from H and CH3, the C5-C6 bond designated with a dotted line is a single bond, Ha is present and W O 97/15564 PCT~US96/16883 represents hydrogen, and Al is selected from: carboxamide, including substituted and unsubstituted anilide derivatives.
Further illustrating this subclass are compounds wherein carboxamide is selected from: N,N-diisopropyl carboxamide, N-t-butyl S carboxamide, N-t-octyl carboxamide, N-n-octyl carboxamide, N-(hydroxyphenyl) carboxarnide, N-phenylcarboxamide, N-(arninophenyl) 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, l-~ m~ntyl carboxamide, 2-~ m~ntyl carboxamide, and N-(substituted phenyl) carboxamides wherein the phenyl may be substituted with 1 to 2 substitutents selected from ethyl, methyl, trifluoromethyl or halo (F, Cl, Br, I).
Still further illustrating this subclass are compounds wherein carboxamide is -C(=O)NH-C(CH3)3, -C(=O)NH-C6H5 or -C(=O)NH-(2,5-trifluoromethylphenyl).
In one subclass of this class of the invention are compounds wherein R 1 is hydrogen, R2 is selected from H and CH3, the CS-C6 bond designated with a dotted line is a double bond, Ha is absent, and Al is selected ~rom: carboxamide, including substituted and unsubstituted anilide derivatives.
Further illustrating this subclass are compounds wherein carboxamide is selected from: N,N-diisopropyl carboxamide, N-t-butyl carboxamide, N-t-octyl carboxamide, N-n-octyl carbo~mi~le, N-(hydroxyphenyl) carboxamide, N-phenylcarboxamide, N-(aminophenyl) carboxamide, N-(carbomethoxy)phenyl carboxamide, N-30 (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, 1-~ m~ntyl , W O 97tl5564 PCT~US96/16883 carboxamide, 2-~d~m~ntyl carboxamide and N-(substituted phenyl) carboxamides, wherein the phenyl may be substituted with 1 to 2 substitutents selected from ethyl, methyl, trifluoromethyl or halo (F, C~l, Br, I).
S Still further illustrating this subclass are compounds wherein carboxamide is -C(=O)NH-C(CH3)3, -C(=O)NH-C6H5 or -C(=O)NH-(2 ,5 -trifluoromethylphenyl) .
In another subclass of this class of the invention are compounds wherein Rl is CH3, R2 is selected from H and CH3, and 10 Al is a selected from: carboxamide, including substituted and unsubstituted anilide derivatives, and Cl lo aL~yl. Further iIlustrating this subclass are compounds wherein carboxamide is -C(=O)NH-C6H5 or -C(=O)NH-(2,5-trifluoromethylphenyl) and Cl lo aL~cyl is selected from isopropyl, isobutyl, 1,5-dimethylhexyl, 15 and 5-methylhexyl.
In another class of the compounds of this embodiment are compounds wherein Z is ~ A
Exemplifying compounds of this class are:
( 1 ) N-t-Butyl-4-oxa-5a-androst- 1 -en-3-one- 1 6~-carboxamide, (2) 16,B-(1,5-dimethylhexyl)-713-Methyl-4-oxa-5a-androst-1-en-3-one, (3) 1 6,~-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-androst-1-en-3-one, (4) 1 6~-(N-tert-amylcarbamoyl)-4-oxa-5a-androst- 1 -en-3-one, (5) 16~-(N-tert-hexylcarbamoyl)-4-oxa-5a-androst-1-en-3-one, (6) 16~-(N-isobutylcarbamoyl)-4-oxa-Sa-androst-l-en-3-one, (7) 16,(~-(N-tert-octylcarbamoyl)-4-oxa-5a-androst-1-en-3-one, W O 97/15564 PCT~US96/16883 (8) 16,13-(N-l,l-diethylbutylcarbamoyl)-4-oxa-5a-androst-1-en-3-one, (9) 16,1~-(N-neopentylcarbamoyl)-4-oxa-Sa-androst-l-en-3-one, (10) 16,B-(N-2-~ mantylcarbamoyl)-4-oxa-Sa-androst-1-en-3-one, (11) 16,B-(N-1 -~ m~ntylcarbamoyl)-4-oxa-Sa-androst-1-en-3-one"
(12) 16,B-(N-2-norbornylcarbamoyl)-4-oxa-Sa-androst- 1 -en-3-one, (13) 16~13-(N- 1 -norbornylcarbamoyl)-4-oxa-Sa-androst- 1 -en-3-one, (14) 16,13-(N-phenylcarbamoyl)-4-oxa-Sa-androst- 1 -en-3 -one, (15) 16,13-(N-benzylcarbamoyl)-4-oxa-5a-androst-1-en-3-one, (16) 16,(~-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-7,B-~nethyl-4-oxa-5a-androst- 1 -en-3-one, (17) 16,~-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-7,B-methyl-4-oxa-5a-androst- 1 -en-3-one, (18) 16,13-(2,6-bis(trifluorome~yl)phenylcarbamoyl)-7,(~-methyl-4-oxa-5a-androst- 1 -en-3-one, (19) 16,13-(2,3-bis(triiFluoromethyl)phenylcarbamoyl)-4-oxa-androst- 1 -en-3-one, (20) 16~-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-androst- 1 -en-3-one, (21) 16~-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-androst-l -en-3-one, (22) 16,13-(N-n-octylcarbamoyl)-4-methyl-4-oxa-Sa-androst-l-en-3-one, (23) 1613-(1 -methoxyethyl)-7,~-methyl-4-oxa-5a-androst- 1 -en-3-one, (24) 16,13-(isopropyl)-7,(~-methyl-4-oxa-5a-androst- 1 -en-3-one, (25) 16,B-(4-methyl-phenoxy)-7,B-methyl-4-oxa-Sa-androst- 1 -en-3-one, W O 97/15564 PCT~US96/16883 (26) 16,B-(1-(3-chlorophenoxy)ethyl)-7~-methyl-4-oxa-So~-androst- 1 -en-3 -one, (27) 1 6~-(4-methylsulfonyl-phenoxy)-7,13-methyl-4-oxa-50~-androst- 1 -en-3-one, (28) 16,B-(4-chlorophenoxy)-7,(~-methyl-4-oxa-5cr~-androst-1-en-3-one, (29) 1 6,(~-(2-pyrimidinyloxy)-7,B-methyl-4-oxa-50~-androst- 1 -en-3-one, and (30) 1 6,B-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-7,13-methyl-4-oxa-50~-androst-l -en-3-one.
Further exemplifying the compounds of this class are:
1 6~-(4-methyl-phenoxy)-7,13-methyl-4-oxa-5a-androst-1 -en-3-one, 16,13-(1-(3-chlorophenoxy)ethyl)-7~-methyl-4-oxa-Sa-androst-l-en-3-one, 1 6,B-(4-methylsulfonyl-phenoxy)-7,13-methyl-4-oxa-50c-androst- 1-en-3-one, 1 6~-(4-chlorophenoxy)-7~-methyl-4-oxa-50c-androst- 1 -en-3-one, and 1 6,B-(2-pyrimidinyloxy)-7,~-methyl-4-oxa-Soc-androst- 1 -en-3-one.
In one subclass of this class, Rl is C1 5 alkyl, R2 is selected from hydrogen and methyl, and A2 is selected from: alkoxy, aryloxy, either unsubstituted or substituted, heteroaryloxy, either substituted or unsubstituted, and alkyl, either unsubstituted or substituted.
Further illustrating this subclass are compounds wherein, A2 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.
Further exemplifying the compounds of this subclass are compounds wherein the C5-C6 bond designated with a dotted line is a double bond, and Ha is absent.
W O 97/15564 PCT~US96/16883 In one subclass of this class, Rl is H or CH3, R2 is selected from H and CH3, and A2 is selected from: substituted and unsubstituted aryl or heteroaryl ether. Further illustrating this subclass are ~e compounds wherein substituted and unsubstituted aryl or heteroaryl 5 ether is selected from thiophenoxy, biphenyloxy, acetamidopheno~y, (3-pyridyl)oxy, chlorophenyloxy, methylphenyloxy, phenoxy, hydroxyphenyloxy, methylsulfonylphenyloxy and pyrimidinyloxy. Still further illustrating the compounds of the present invention are compounds wherein substituted or unsubstituted aryl or heteroaryl ether 10 is selected from 4-methyl-phenoxy, 4-chlorophenoxy, and 2-pyrimidinyloxy.
In another embodiment of the instant invention are compounds o~ formula I wherein X is sulfur.
In one class of the compounds of this embo-liment are 15 compounds wherein Z is A1 Exemplifying compounds of this class are:
( 1 ) N-t-Butyl-4-thia-Soc-androst- 1 -en-3-one- 1 7,(3-carboxamide, (2) 7,13-Methyl-4-thia-5a-cholest- 1 -en-3-one, (3) 1 7~-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-Soc-androst- 1 -en-3-one, (4) 1 7~-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-5~c-androst- 1 -en-3 -one, (5) 1 7,13-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-5~-androst- 1 -en-3-one, (6) 1 7~-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-Soc-androst- 1 -en-3-one, (7) 17,1~-(N-tert-amylcarbamoyl)-4-thia-5a-androst-1-en-3-one, (8) 1 7,13-(N-tert-hexylcarbamoyl)-4-thia-So~-androst- 1 -en-3-one, W O 97/15S64 PCT~US96/16883 (9) 17,13-(N-isobutylcarbamoyl)-4-thia-5a-androst- 1 -en-3-one, (10) 17,B-(N-tert-octylcarbamoyl)-4-thia-5a-androst- 1 -en-3-one, (11) 17,(~-(N- 1,1 -diethylbutylcarbamoyl)-4-thia-5a-androst- 1 -en-3-one, (12) 17~1~-(N-neopentylcarbamoyl)-4-thia-5a-androst- 1 -en-3-one, (13) 17~13-(N-2-~d~m~ntylcarbamoyl)-4-thia-50c-androst-l-en-3-one, (14) 17,B-(N- 1 -~dzlm~ntylcarbamoyl)-4-thia-5a-androst- 1 -en-3 -one, (15) 17 ~B-(N-2-norbornylcarbamoyl)-4-thia-5a-androst- 1 -en-3 -one, (16) 17,13-(N-l-norbornylcarbamoyl)-4-thia-50~-androst-l-en-3-one, (17) 17~-(N-phenylcarbamoyl)-4-thia-5a-androst-1-en-3-one, (lg) 17,13-(N-benzylcarbamoyl)-4-thia-5a-androst-1-en-3-one, (19) 17~-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-7~-methyl-4-thia-5a-androst- 1 -en-3-one, (20) 17~-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-7,~-methyl-4-thia-5a-androst-1-en-3-one, (21) 17,13-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-7,3-methyl-4-thia-5a-androst- 1 -en-3-one, (22) 17~-(N-n-octylcarbamoyl)-4-methyl-4-thia-5a-androst-1-en-3-one, (23) 17,13-(1-methoxyethyl)-7~-methyl-4-thia-5a-androst-1-en-3-one, (24) 17,1~-(isopropyl)-7,13-methyl-4-thia-Sa-androst- 1 -en-3-one, (25) 17,~-(4-methyl-phenoxy)-7,(~-methyl-4-thia-5a-androst- 1 -en-3-one, (26) 17,1~-(1-(3-chlorophenoxy)ethyl)-7,13-methyl-4-thia-5a-androst- 1 -en-3-one, (27) 17~-(4-methylsulfonyl-phenoxy)-7,13-methyl-4-thia-5a-androst-l -en-3-one, W O97/lS564 PCTAUS96/16883 (28) 17,3-(4-chlorophenoxy)-7,B-methyl-4-thia-5a-androst-1-en-3-one, (29) 17,13-(2-pyrimidinyloxy)-7,(~-methyl-4-thia-5a-androst-1-en-3-one, and (30) 17~13-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-7~-methyl-4-thia-5a-androst- 1 -en-3 -one.
Further exemplifying compounds of this class are:
(1) N-t-Butyl-4-thia-5a-androst- 1 -en-3-one- 17,13-carbox~mide, (2) 7,13-Methyl-4-thia-5a-cholest-1-en-3-one, (3) 17,B-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-androst- 1 -en-3-one, (4) 17,(~-(N-phenylcarbamoyl)-4-thia-5a-androst- 1 -en-3 -one"
(5) 1713-(N-benzylcarbamoyl)-4-thia-5a-androst- 1 -en-3 -one, (6) 17,13-(1 -methoxyethyl)-7,B-methyl-4-thia-5a-androst- 1 -en-3-one, (7) 17,13-(isopropyl)-7~3-methyl-4-thia-5a-androst-1-en-3-one, (8) 17,(~-(4-methylphenoxy)-7,1~-methyl-4-thia-50~-androst- 1 -en-3-one, (9) 17,B-(1 -(3-chlorophenyoxy)ethyl)-7,3-methyl-4-thia-5a-androst- 1 -en-3-one, (10) 17~-(4-methylsulfonyl-phenoxy)-7,(~-methyl-4-thia-50~-androst- 1 -en-3 -one, (11) 17,13-(methyl-phenoxy)-713-methyl-4-thia-5a-androst-1-en-3-one, (12) 17,3-(4-chlorophenoxy)-7,13-methyl-4-thia-5a-androst-1-en-3-one, (13) 17,B-(2-pyrimidinyloxy)-7~-methyl-4-thia-5a-androst-1 -en-3-one, and (14) 17,B-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-7,(~-methyl-4-thia-5a-androst- 1 -en-3-one.
In one subclass of this class of the invention are compounds wherein R1 is hydrogen, R2 is selected from H and CH3, and Al is , selected from: carboxamide, including substituted and unsubstituted anilide derivatives.
Further illustrating this subclass are compounds wherein carboxamide is selected from: N,N-diisopropyl carboxamide, N-t-butyl carboxamide, N-t-octyl carboxarnide, N-n-octyl carbox~mitle, N-(hydroxyphenyl) carboxamide, N-phenylcarboxamide, N-(aminophenyl) carboxarnide, N-(carbomethoxy)phenyl carboxamide, N-(methoxycarboxy) phenyl carboxamide, N-acetamidophenyl-N-acetyl-carboxamide, N-acetamidophenyl-carboxamide, N-pivalamidophenyl carboxamide, N-isobutyramidophenyl carbox~mi~le, N-(methyl),N-(diphenylmethyl) carboxamide, N-(diphenylmethyl)-carboxamide, N-t-butyl carboxamide, N-isopropyl carboxamide, 1-~ m~ntyl carboxamide, 2-~ m~ntyl carboxamide, and N-(substituted phenyl) carboxamides wherein the phenyl may be substituted with 1 to 2 substitutents selected from ethyl, methyl, trifluoromethyl or halo (F, Cl, Br, I).
Still further illustrating this subclass are compounds wherein carboxamide is -C(=O)NH-C(CH3)3, -c(=o)NH-c6H5 or -C(=O)NH-(2 ,5 -trifluoromethylphenyl) .
In one subclass of this class of the invention are compounds wherein R1 is hydrogen, R2 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, and A1 is selected from: carboxamide, including substituted and unsubstituted anilide derivatives.
Further illustrating this subclass are compounds wherein 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)-carbox~micle, N-t-butyl carboxamide, N-isopropyl carboxamide, l~ m~ntyl WO 97/1556~ PCTAUS96/16883 carboxamide, 2~ m~ntyl carboxamide, and N-(substituted phenyl) carboxamides wherein the phenyl may be substituted with 1 to 2 substitutents selected from ethyl, methyl, trifluoromethyl or halo (F, Cl, Br, I).
Still further illustrating this subclass are compounds wherein carboxamide is -C(=O)NH-C(CH3)3, -C(=O)NH-C6H5 or -C(=O)NH-(2 ,5 -trifluoromethylphenyl) .
In one subclass of this class of the invention are compounds ~ wherein R 1 is hydrogen, R2 is selected from H and CH3, the C5-C6 bond designated with a dotted line is a double bond, Ha is absent, and Al is selected from: carboxamide, including substituted and unsubstituted anilide derivatives.
Further illustrating this subclass are compounds wherein carboxamide is selected from: N,N-diisopropyl carboxamide, N-t-butyl carboxamide, N-t-octyl carboxamide, N-n-octyl carbox~micle, N-(hydroxyphenyl) carboxamide, N-phenylcarboxamide, N-(aminophenyl) carboxamide, N-(carbomethoxy)phenyl carboxamide, N-(methoxycarboxy) phenyl carboxamide, N-acetamidophenyl-N-acetyl-carboxamide, N-acetamidophenyl-carbox~mi~le, N-pivalamidophenyl carboxamide, N-isobutyramidophenyl carboxamide, N-(methyl),N-(diphenylmethyl) carboxamide, N-(diphenylmethyl)-carboxamide, N-t-butyl carboxamide, N-isopropyl carboxamide, l-a-l~m~ntyl carboxamide, 2-~ m~ntyl carboxamide and N-(substituted phenyl) carboxamides, wherein the phenyl may be substituted with 1 to 2 substitutents selected from ethyl, methyl, trifluoromethyl or halo (F, Cl, Br, I).
Still further illustrating this subclass are compounds wherein carboxamide is -C(=O)NH-C(CH3)3, -C(=O)NH-C6H5 or -C(=0)NH-(2,5-trifluoromethylphenyl).
In another subclass of this class of the invention are compounds wherein Rl is CH3, R2 is selected from H and CH3, and Al is a selected from: carboxamide, including substituted and unsubstituted anilide derivatives, and Cl lo aL~yl. Further illustrating ~is subclass are compounds wherein carboxamide is W O 97/15564 PCTrUS96/16883 -C(=O)NH-C6H5 or -C(=0)NH-(2,5-trifluoromethylphenyl) and Cl lo alkyl is selected from isopropyl, isobutyl, 1,5-dimethylhexyl, and 5-methylhexyl.
S In another class of the compounds of this embodiment are compounds wherein Z is ~A2 Exemplifying compounds of this class are:
( 1 ) N-t-Butyl-4-thia-Soc-androst- 1 -en-3-one- 1 6,3-carboxamide, (2) 16,13-(1,5-dimethylhexyl)-7,13-Methyl-4-thia-5a-androst-1-en-3-one, (3) 1 6,(~-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-androst- 1 -en-3-one, (4) 1 6,~-(N-tert-amylcarbamoyl)-4-thia-Soc-androst-1 -en-3-one, (S) 16~-(N-tert-hexylcarbamoyl)-4-thia-Sa-androst-1-en-3-one, (6) 1 6,1~-(N-isobutylcarbamoyl)-4-thia-Soc-androst- 1 -en-3 -one, (7) 1 6,3-(N-tert-octylcarbamoyl)-4-thia-Soc-androst- 1 -en-3-one, (8) 1 6,13-(N- 1,1 -diethylbutylcarbamoyl)-4-thia-Soc-androst- 1-en-3-one, (9) 1 6,B-(N-neopentylcarbamoyl)-4-thia-Sa-androst-1 -en-3-one, (10) 16,B-(N-2-~ m~ntylcarbamoyl)-4-thia-So~-androst-1-en-3-one, (11) 16,1~ m~ntylcarbamoyl)-4-thia-5oc-androst-1-en-3-- one"
( 12) 1 6,13-(N-2-norbornylcarbamoyl)-4-thia-So~-androst- 1 -en-3-- one, ( 13) 1 6,13-(N-1 -norbornylcarbamoyl)-4-thia-Soc-androst- 1 -en-3-one, (14) 16,(~-(N-phenylcarbamoyl)-4-thia-50c-androst-1-en-3-one, W O 97/15564 PCT~US96/16883 ( 15) 1 6,13-(N-benzylcarbamoyl)-4-thia-5a-androst- 1 -en-3-one, ( 16) 1 6~-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-7~-methyl-4-thia-5a-androst- 1 -en-3-one, (17) 16,(~-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-713-methyl-4-thia-5a-androst-1-en-3-one, (18) 16~-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-7~-methyl-4-thia-Sa-androst- 1 -en-3-one, (19) 16,1~-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-androst- 1 -en-3 -one, (20) 1 6,~-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-androst- 1 -en-3-one, (21 ) 1 6~-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-4-~ia-androst- 1 -en-3-one, (22) 1 6,(~-(N-n-octylcarbamoyl)-4-methyl-4-thia-Sa-androst- 1-lS en-3-one, (23) 16~-(1-methoxyethyl)-7,~-methyl-4-thia-5a-androst-1-en-3-one, (24) 1 6~-(isopropyl)-7,B-methyl-4-thia-Sa-androst- 1 -en-3-one, (25) 16,13-(4-methyl-phenoxy)-7,(~-methyl-4-thia-Sa-androst-1-en-3-one, (26) 1613-(1-(3-chlorophenoxy)ethyl)-7,B-methyl-4-thia-Sa-androst- 1 -en-3-one, (27) 1 6~-(4-methylsulfonyl-phenoxy)-7~-methyl-4-thia-Sa-- androst-l-en-3-one, (28) 16,~-(4-chlorophenoxy)-7,13-methyl-4-thia-Sa-androst-l-en-3-one, (29) 16~-(2-pyrimidinyloxy)-7,13-methyl-4-thia-5a-androst-1-en-3-one, and (30) 1 6,B-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-713-methyl- .
4-thia-Sa-androst-l-en-3-one.
Fur~er exemplifying the compounds of this class are:
1 6~-(4-methyl-phenoxy)-7~-methyl-4-thia-Sa-androst-1 -en-3-one, , W O 97/15564 PCTrUS96/16883 16,13-(1 -(3-chlorophenoxy)ethyl)-7,13-methyl-4-thia-5Oc-androst- 1-en-3-one, 1 6,(~-(4-methylsulfonyl-phenoxy)-7,13-methyl-4-thia-Sa-androst-l -en-3-one, 1 6,13-(4-chlorophenoxy)-7,13-methyl-4-thia-5~c-androst-1 -en-3-one, and 1 6,13-(2-pyrimidinyloxy)-7~-methyl-4-thia-So~-androst- 1 -en-3-one.
In one subclass of this class, Rl is C1 5 alkyl, R2 is selected from hydrogen and methyl, and A2 is selected from: aLkoxy, aryloxy, either unsubstituted or substituted, heteroaryloxy, either substituted or unsubstituted, and alkyl, either unsubstituted or substituted.
Further illustrating this subclass are compounds wherein, A2 is selected from: substituted aryloxy, and heteroaryloxy, either substituted or unsubstituted.
Exemplifying compounds of this subclass are compounds wherein the CS-C6 bond designated with a dotted line is a single bond, and Ha is present and represents hydrogen.
Further exemplifying the compounds of this subclass are 20 compounds wherein the C5-C6 bond designated with a dotted line is a double bond, and Ha is absent.
In another subclass of this class, Rl is H or CH3, R2 is selected from H and CH3, and A2 is selected from: substituted and unsubstituted aryl or heteroaryl ether. Further illustrating this subclass 25 are the compounds wherein substituted and unsubstituted aryl or heteroaryl ether is selected from thiophenoxy, biphenyloxy, acetamidophenoxy, (3-pyridyl)oxy, chlorophenyloxy, methylphenyloxy, phenoxy, hydroxyphenyloxy, methylsulfonylphenyloxy and pyrimidinyloxy. Still further illustrating the compounds of the present 30 invention are compounds wherein substituted or unsubstituted aryl or heteroaryl e~er is selected from 4-methyl-phenoxy, 4-chlorophenoxy, and 2-pyrimidinyloxy.
In one subclass of this class, R1 is Cl 5 alkyl, R2 is selected from hydrogen and methyl, and A2 is selected from: alkoxy, aryloxy, WO 97/15564 PCT~US96/16883 either unsubstituted or substituted, heteroaryloxy, either substituted or unsubstituted, and alkyl, either unsubstituted or substituted.
Further illustrating this subclass are compounds wherein, A2 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.
Further exemplifying the compounds of this subclass are compounds wherein the C5-C6 bond designated with a doKed line is a double bond, and Ha is absent.
When any variable (e.g., aryl, heterocycle, Rl, etc.) occurs more than one time in any constituent or in foImula I, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable co~npounds.
As used herein "aL~yl" 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), lelL~ulyl (t-Bu), isopentane, isohexane, etc. "AL~yloxy" (or "alkoxy") represents an aL~yl group 2~ 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.
The term "aryl" includes phenyl and naphthyl. Preferably, aryl is phenyl.
Heteroaryl is selected from piperidinyl, piperizinyl, pyrrolidinyl, pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, indolyl and benzofuranyl.
W O 97/15~64 PCTAUS96/16883 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 5 of ordinary skill in the art, and any such groups may be used. For example, 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-10 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(O)-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 al. (John Wiley 15 and Sons, 1991) for descriptions of protecting groups.
The compounds of the present invention may be ~lmini~tered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" is intended to include all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, 20 m~l~te, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clav~ n~e, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), 25 estolate, p~lmit~te, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glllt~m~te, stearate, glycollylars~nil~te, sulfate, hexylresorcinate, subacetate, hydrabamine, succinate, hydrobromide, t~nn~te, hydrochloride, tartrate, hydroxynaphthoate, teoclate, iodide, 30 tosylate, isothionate, triethiodide, lactate, panoate, valerate, and the like which can be used as a dosage form for modifying the solubility or hydrolysis characteristics or can be used in sustained release or pro-drug formulations. Depending on the particular functionality of the compound of ~e present invention, pharmaceutically acceptable salts of W O 97/15564 PCT~US96/16883 the compounds of this invention include those formed from cations such as sodium, potassium, ~lllmim-m, calcium, lill~iunl, magnesium, zinc, and from bases such as ammonia, ethylene~ mine, N-methyl-gl-lt~mine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylene~ mine, 5 chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide. These salts may be prepared by standard procedures, e.g. by reacting a free acid with a suitable organic or inorganic base.
Also, in the case of an acid (-COOH) or alcohol group being present, pharmaceutically acceptable 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 fonmll~tions.
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 20 mixtures thereof. Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are 25 encompassed within the scope of this invention.
The telm "therapeutically effective amount" is that amount of a drug or pharrnaceutical agent that will elicit the biological or medical response of a tissue, system, ~nim~l or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, 30 which includes alleviation of the symptoms of the disorder being treated.
More particularly, the present invention relates to a method for treating hyperandrogenic conditions in a m~mm~l in need of such treatment comprising the ~lmini~tration to the m~mm~l in need of such W O 97/15564 PCT~US96/16883 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 "m~mm~l"
includes humans. Preferably, the method of the present invention is for S treating hyperandrogenic conditions in a hllm~n in need of such treatment.
Hyperandrogenic conditions treatable by the method of the present invention include benign prostatic hyperplasia, androgenic alopecia (including male pattern baldness, female pattern baldness and 10 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, 15 and female hirsutism by oral, systemic, parenteral or topical ~lmini~tration of the novel compounds of formula I either alone or in combination with a Soc-reductase 2 inhibitor, preferably selected from finasteride and epristeride, or a potassium channel opener, or a retinoic acid or derivative thereof. Alternatively, treatment may 20 encompass ~lmini~tration of a combination of a compound of formula I with a 5a-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.
The term "treating androgenic alopecia" is intended to include the 25 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 hyperplasia, prostatitis, and treating and/or p~eventing prostatic carcinoma by 30 oral, systemic or parenteral ~rlmini~tration of the novel compounds of formula I either alone or in combination with a Soc-reductase 2 inhibitor, preferably selected from finasteride and epristeride.
Alternatively, treatment may encompass ~llmini~tration of a combination of a compound of formula I with a Soc-reductase 2 W O 97/15~64 PCT~US96/16883 .~
inhibitor and/or another active agent such as an o~1 or an O~la adrenergic receptor antagonist (ala receptor antagonists were formerly called alc receptor antagonists).
The present invention also has a further objective of S providing methods of treating acne vulgaris, androgenic alopecia, seborrhea, female hirsutism, benign prostatic hyperplasia, prostatitis and the preventing and/or treating of prostatic cancer, by oral, systemic, parental or topical ~lmini~tration of a combined therapy of a therapeutically effective amount of a compound of formula I
10 with a therapeutically effective amount of an anti-androgen, such as, e.g., flutamide, spironolactone or casodex.
For combination treatment with more than one active agent, where the active agents are in separate dosage formulations, the active agents can be arlministered concolnilal~lly~ or they each can 15 be ~lrninistered 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 treat~ent of the present invention. The compositions cont~ining the present compounds as 20 the active ingredient for use in the treatment of the above-noted conditions can be ~lministered in a wide variety of therapeutic dosage forms in conventional vehicles for systemic ~lminilstration.
For example, the compounds can be ~lmini~tered in such oral dosage forms as tablets, capsules (each including timed release and sustained 25 release formulations), pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups and emulsions, or by injection.
Likewise, they may also be ~lmini~tered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous, topical with or without occlusion, or intramuscular form, all using forms well known to 30 those of ordinary skill in the ph~ eutical arts. An effective but non-toxic amount of the compound desired can be employed as an antiandrogenic agent.
The compounds of structural formula I useful in the present invention are typically ~lmini~tered 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 ~tlmini~tration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional ph~rm~ceutical S practices may be ~-lmini~tered systemically, by oral ~lministration or by intravenous or intramuscular injection or topically.
For instance, for oral ~lmini~tration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, 10 glycerol, water and the like. Capsules cont~ining the product of this invention can be prepared by mixing an active compound of the present invention with lactose and m~gnesium stearate, calcium stearate, starch, talc, or other carriers, and placing the nli~lulc in gelatin capsules.
Tablets may be prepared by mixing the active ingredient 15 with conventional tableting ingredients such as calcium phosphate, lactose, corn starch or magnesium stearate. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-20 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 25 include, without limit~tion, starch, methyl cellulose, agar, bentonite, x~nth~n 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 30 agents which may be employed include glycerin and the like. For parenteral ~lmini~tration, sterile suspensions and solutions are desired.
Isotonic preparations which generally contain suitable preservatives are employed when intravenous ~1mini~tration is desired.
W O 97/15564 PCT~US96116883 Topical ph~ ceutical 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 5 may include about 0.001% to 0.1% of the active compound in admixture with a ph~ ceutically acceptable carrier.
Topical preparations contz-ining 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
10 and E oils, mineral oil, propylene glycol, PPG2 myristyl propionate, and the like, to fo~n, e.g., alcoholic solutions, topical cleansers, cleansing creams, skin gels, skin lotions, and shampoos in creaIn or gel formulations. See, e.g., EP 0 285 382.
The compounds of the present invention can also be 15 ~tlmini~tered in the form of liposome delivery systems, such as small 7mil~mellar vesicles, large lmil~mellar 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 20 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, 25 polyhydroxyethylaspartamide-phenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, ~e compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for e~ample, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, 30 polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
The compounds for ~e present invention can be ~lmini~tered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal W O 97/1~564 PCT~US96/16883 skin patches well known to those of ordinary skill in the art. To be ~rlmini~tered in the form of a transdermal delivery system, the dosage ~ ~clministration will, of course, be continuous rather than inte~ Lellt throughout the dosage regimen. Compounds of the present invention 5 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.
The dosage regimen utilizing the compounds of the 10 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 ~lmini~tration; the renal and hepatic function of the patient; and the particular compound thereof employed. A physician or veterinarian 15 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 20 availability to target sites. This involves a consideration of the distribution, equilibrium, and elimin~tion of a drug. Preferably, 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 hllm~n per day. Most preferably, dosages range from 0.1 to 50 25 mg/day. For oral ~lminictration, the compositions are preferably provided in the form of tablets cont~inin~ 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 30 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/l~g of body weight per day. The range is more particularly from about 0.001 mg/kg to 1 mg/kg of body weight per day.
Advantageously, the active agent of the present invention may be ~lmini~tered in a single daily dose, or the total daily dosage may be ~lministered in dividend doses of two, three or four times daily.
S 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 hyperplasia, prostatitis and prostatic cancer.
For the treatment of acne vulgaris, androgenic alopecia, male pattern baldness, seborrhea, female hirsutism, benign prostatic hyperplasia, prostatitis and the prevention and/or treatment of prostatic cancer, the compounds of the instant invention can be combined with a therapeutically effective amount of another Sa-lS reductase inhibitor, such as finasteride or epristeride, or other 5a-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. Alternatively, a combined therapy can be employed wherein the compound of formula I and the other Sa-reductase inhibitor are ~lmini~tered in separate oral, systemic, or parenteral dosage formulations. Also, for the skin and scalp related disorders of acne vulgaris, androgenic alopecia, male pattern baldness, seborrhea, and female hirsutism, the compounds of the instant invention and another Sa-reductase inhibitor such as finasteride or epristeride can be formulated for topical ~lmini~tration. For example, a compound of formula I and finasteride can be ~lminictered in a single oral or topical dosage formulation, or each active agent can be ~lmini~tered in a separate dosage fonn~ tion, e.g., in separate oral dosage formulations, or an oral dosage formulation of finasteride in combination with a topical dosage fonmll~tion 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 Sa-reductase inhibitors.
W O 97/15564 PCT~US96/16883 Furthermore, ~lminictration of a compound of the present invention in combination with a therapeutically effective amount of a potassium channel opener, such as minoxidil, crom~k~lin, pinacidil, a compound selected from the classes of S-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 a-lministration of a Soc-reductase type 2 inhibitor such as finasteride or epristeride, or a 5a-reductase 10 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. The active agents can be ~lmini~tered in a single topical dosage formulation, or each active agent can be ~lmini~tered in a separate dosage formulation, e.g., in lS separate topical dosage formulations, or an oral dosage form~ tion 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 5a-reductase inhibitor, in combination with a topical dosage form~ tion of, e.g., minoxidil.
20 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.
Furthermore, for the treatment of acne vulgaris, a combined therapy can be used by ~lmini~tering a therapeutically 25 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. Optionally, this combined therapy for acne vulgaris may further include a Sa-reductase type 2 inhibitor such as 30 finasteride or epristeride, or a 5a-reductase type 1 inhibitor, or a dual type 1 and type 2 inhibitory compound.
Also, for the treatnlent of benign prostatic hyperplasia, a combined therapy comprising a ~lmini~tration of a compound of formula I with a 5a-reductase type 2 inhibitor, such as e.g., W O 97/15564 PCT~US96/16883 finasteride, and an alpha-l adrenergic receptor antagonist, such as e.g., terazosin, doxazosin, prazosin, bunazosin, indoramin or alfuzosin, may be employed. More particularly, the combined therapy can comprise ~-lmini~tering a compound of formula I with a 5O~-reductase type 2 inhibitor, such as e.g., finasteride, and an alpha-la adrenergic receptor antagonist (formerly called an alpha-1c 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 (W094/08040, 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.
Also, for the treatment of acne vulgaris, androgenic alopecia, seborrhea, female hirsutism, benign prostatic hypeIplasia, prostatitis and the prevention and/or treatrnent of prostatic cancer, a combined therapy can be used by ~ ni~tering 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.
For combination treatment with more than one active agent, where the active agents are in separate dosage formulations, the active agents can be ~(1mini~tered concurrently, or they each can be ~-lmini~tered 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.
, W O 97/1~564 PCTrUS96/16883 The 4-oxa compounds of this invention can be prepared as shown in Scheme 1.
Scheme 1 r~
3 Acetic anhydride ,-~,C"
O R7 NaOAc/140~ ~ --~R7 5% Rh/C/H2 ~
~ ~ ~ Benzeneselenic anhydride THF
O~O~R7 Chlorobenzene/Reflux (3) (4) 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 - 10 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 A2 substitution may be obtained. To obtain the a~lo~,iate Al substitution, the procedures of the following W O 97/1556~ PCT~US96/16883 publications are followed starting with a 3-keto-delta4-17-one precursor: for ether or thioether WO 93/23040; for anilide WO
94/07861, EP 0 663 924; for unsubstituted, monosubstituted or disubstituted amides WO 93/23038, WO 93/23051, WO 93/23420; and 5 US 4,220,775, 4,760,071, ~,845,104, 5,237,067, 5,091,380, 5,061,801, 5,215,894, for oxo U.S. 4,220,775, 4,377,584; for cyano U.S. 4,220,775; for tetrazoyl U.S. 4,220,775; for arylaL~ylcarbonlyoxy alkyl U.S. 4,377,584; for cycloalkylarylcarbonlyoxy alkyl U.S.
4,377,584; for benzoyloxyaLkyl U.S. 4,377,584; for acyl, both 10 substituted and unsubstituted, U.S. 5,049,562, U.S. 5,138,063, U.S.
5,151,429, U.S. 5,237,061, U.S. 5,120,742, U.S. 5,162,332, U.S.
5,061,802, U.S. 5,098,908, U.S. 5,196,411, U.S. 5,075,450, U.S.
5,061,803, U.S. 5,324,734; for thiobenzyl U.S. 5,151,430; for polyaroyl U.S. 5,162,322; for ester U.S. 5,091,534, WO 93/23041, WO
15 93/23040, for alkyl, either substituted or unsubstituted WO 93/23050, WO 93/23419, WO 93/23051; for urea, thiourea, carbamate or thiocarbamate W093/23048; for thioester WO 93/23041, WO
93/23040.
The a~rol~liately 7,10,16, and 17-substituted 3-keto 20 steroid is converted to the appropriately substituted seco-acid by methods known in the art, for example, the procedures described in mll~son, et al., J.Med.Chem. 1986, 29(11): 2298-2315.
The appropriate 7-~13 substitution may be obtained following the procedures for formation of a 7-,13 bond as described in U.S. Patents 25 4,220,775, and 5,237,064.
Compounds wherein R2 is H or CH20R3 may be prepared starting with the a~lo~liately C10 substituted seco-acid. These compounds may be made by procedures known in the art.
As shown in Scheme 1, ~e seco-acid (1) is treated with a 30 dehydrating agent such as acetic anhydride, methyl ortho-formate, ethyl ortho-formate, in a nonpolar aprotic 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 forrn the ~5-oxasteroid (2). Preferably, the seco-acid (1) is treated with acetic anhydride in acetic anhydride in the presence of sodium acetate at an elevated temperature, preferably at about 140~C.
~ 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, S Pd/C, etc., preferably Rh/C in a solvent such as tetrahydrofuran (THF) or ethyl acetate. This is followed by folmation of the ~1 double bond by treatment with, for example, dichloro-dicyanoquinone (DDQ), benzeneselenic anhydride in chlorobenzene, or other known methods, for example as described in U.S. 5,084,574 and 5,021,571, to form the 10 A 1 -oxasteroid (4).
The 4-thia compounds of this invention can be prepared as shown in Scheme 2.
~ Me-Ai Toluene/A
~3--N~ RS02X/Pyrilline H HO R = CF3 or CH3 or Ar lS (5) R7 X = Cl or OSO2R
~,Ni~----~ n-Bu4NI/Toluene (6) SO2R
~N~--~
H I CH3COSH/Toluene (7) I'* ~R7 CS2C~3 W O 97/15564 PCT~US96/16883 ~NJ~
(8) H S 3% HCl/MeOH
o ~X~~ (PhSeO)2~
O S R7 O~S~~R7 g) (10) Starting with the 4-oxa-androstan-3-one ~rolJriately substituted in the B and D-ring~ obtained by following the procedures of 5 Scheme 1 to obtain compound (3), 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, aprotic 10 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 15 give the corresponding alkyl- or aryl sulfonate (6). The reaction of the alkyl- or aryl sulfonate with tetrabutylammonium iodide in a polar aprotic solvent such as toluene produces the corresponding iodide (7).
The iodide is treated with thioacetic acid in a nonpolar solvent such as toluene or dichloroethane in the presence of cesium carbonate or other 20 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 treatrnent with hydrochloric acid .
W O 97/15564 PCT~US96/16883 in methanol. The thialactone (9) may be dehydrogenated to for~n the A1-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 5 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 ~ 5-oxasteroid derivative.
The corresponding 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. Furthermore, 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 15 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.
All temperatures given in the following examples are in 20 degrees Celsius. lH and 13C nuclear magnetic resonance (NMR) spectra were taken at 400 or 500 MHz at ambient temperature in the solvents indicated. Some abbreviations used herein are as follows:
"BOC" is t-butoxycarbonyl; "BOC anhydride" is di-t-butyl dicarbonate {O(C02C(CH3)3)2}; "DBU" is 1,8-diaza-bicyclo[5.4,0] undec-7-ene;
25 "DCC" is 1,3-dicyclohexylcarbodiimide; "DMS" is methyl sulfide { (CH3)2S }; "DMF" is dimethylformamide; "EtOAc" is ethyl acetate;
"HOBT" is 1-hydroxybenzotriazole; "IPA" is isopropyl acetate; "Ph" is phenyl; "Tf" is -S02CF3; "TFA" is trifluoroacetic acid; "THF" is tetrahydrofuran; "TIPS" is triisopropylsilyl; "TIPSO" is 30 triisopropylsilyloxy. Unless otherwise specified "tlc" and "TLC" refer to thin layer SiO2 chromatography.
RxAMpLE 1 Preparation of N-t-Butyl-4-oxa-5a-androst-1-en-3-one-17,B-carboxamide.
Step 1: Benzotriazol- 1 '-yl-3-oxo-androst-4-ene- 17,13-carboxamide.
O OH Oq~O~
~ ~ N~N
D~/ DCC/HOBT/THF ~/
o To a solution of steroid acid (4g, 12.65 mmol, see Rasmusson et al., J.Med.Chem. 1986, 29(11): 2298-2315 for description of synthesis) in methylene chloride was added DCC (2.75g, 13.3 mmol) and 1-hydroxybenzotriazoie (HOBT, 2.75g, 19.1 mmol). After stirring the reaction mixture for overnight, the solid was filtered, dried and 10 used as such for further reactions.
Step 2: N-t-Butyl-3-oxo-androst-4-ene- 17~-carboxamide.
0~ H
N~ O~,N~
N---N ~ 1 t-BuNH2 /CH2Ck ~--/
0~ 0~
To a solution of benzotriazol-1'-yl-3-oxo-androst-4-ene-lS 17~-carboxamide (l.Sg, 3.46 mmol) in methylene chloride was added t-butyl amine (454 ,u1,4.33 mmol). After stirring the reaction mixture for overnight, the reaction mixtllre was concentrated, purified by chromatography over silica gel (2.5% acetone/methylene chloride).
Mass spec. M+ 372(m+1, observed).
Step 3: N-t-Butyl-S-oxo-3,5-secoandrostan-3-oic-17,B-carboxamide.
W O 97/15564 PCT~US96/16883 ~; KlMnO4/NalO4 ~
Na2CO3/t-BuOH HOOC
To a solution of N-t-butyl-3-oxo-androst-4-ene-17,13-carboxamide (550 mg, 1.48 mmol) in t-butanol (10 mL) was added sodium carbonate (172 mg, 1.63 mmol, in 1 mL of H2O). The reaction 5 mixture was heated to 80~ and a solution of NaIO4 (1.58g, 7.4 mmol) and KMnO4 (11.7mg, 0.074 mmol) in H2O (10 mL) was added dropwise in ~ 10 minutes. After stirring the reaction mixture for 2 hrs, the mixture was cooled to room temperature and acidified to pH 2. The reaction mixture was concentrated, extracted with ethyl acetate, organic 10 layer was dried and concentrated to give pure product. Mass spec. M+
392(m+1, observed).
Step 4: N-t-Butyl-4-oxa-androst-5-en-3-one- 17,~-carboxamide.
H H, ~N~ N~
~~/ Ac20/NaOAC/Q ~J~
0~ 0 0 To a solution of N-t-butyl-S-oxo-3,5-secoandrostan-3-oic-17,B-carboxamide (550 mg, 1.4 mmol) in acetic anhydride (25 mL) was added sodium acetate (1.91 g, 14 mmol). After stirring the reaction mix~lre at reflux temperature for 4 hrs, the acetic anhydride was removed under vacuum and residue partitioned between ethyl acetate 20 and water. The organic layer was washed with brine, dried, concentrated and purified by prep. tlc (5% acetone/methylene chloride).
Mass spec. M+ 374(m~1, observed).
WO 97/15564 PCT~US96/16883 Step 5: N-t-Butyl-4-oxa-Sa-androstan-3 -one- 1 7,~-carboxamide.
H H
~N~ N~
f ~-- 5% Rh/C/H2/THF ~--0~ 0~ 0~0~
To a solution of N-t-butyl-4-oxa-androst-S-en-3-one-17,13-5 carboxamide (410 mg, 1.099 mmol) in THF (20 mL) was added 5%
Rh/C(410 mg). After stirring the reaction mixture under H2 atmosphere for overnight, the mixture was flushed with N2, filtered and concentrated. The residue was purified by prep. tlc (5% acetone/
CH2Cl2). Mass spec. M+ 376(m+1, observed).
Step 6: N-t-Butyl-4-oxa-5a-androst- 1 -en-3 -one- 1 7~-carboxamide .
H H
~N~ Ny ~ (PhSeO)20/PhCl/~
O 0~ 0 0 To a solution of N-t-butyl-4-oxa-5a-androstan-3-one-17,13-carbox~mide (100 mg, 0.27 mmol) in chlorobenzene was added 15 benzeneselenic anhydride (177 mg, 0.49 mmol). After stirring the reaction mixture at reflux temperature for overnight, the reaction mixtllre was diluted with ethyl acetate, washed with brine, dried and concentrated. The residue was purified by prep. tlc (5% acetone/
CH2C12). Mass spec. M+ 374(m+1, observed).
W O 97tl5564 PCT~US96/16883 Preparation of 7,B-Methyl-4-oxa-Soc-Cholest-1-en-3-one ~O/I~aOAc/A ~X~~
HOOC o o Step 1: 7~-Methyl-4-oxa-Cholest-5-en-3-one To a solution of 7,B-methyl-5-oxo-3,5-secocholestan-3-oic 5 (5g, 12.3 mmol) in acetic anhydride (250 mL) was added sodium acetate ( 16.9 g, 124 mmol). After stirring the reaction mixtllre at reflux temperature for 4 hrs, the acetic anhydride was removed under vacuum and residue partitioned between ethyl acetate and water. The organic layer was washed with brine, dried, concentrated and purified 10 by chromatography over silica gel. Mass spec. M+ 401(m+1, observed).
Step 2: 7,B-Methyl-4-oxa-Sa-Cholestan-3-one ~--/ 5%Rh/C/H2/THF
0~0~ 0 0 To a solution of 7,~-methyl-4-oxa-Cholest-S-en-3-one (6.0g) in THF
15 (50 mL) was added 5% Rh/C(6.5g). After stirring the reaction nnixture under H2 atmosphere for overnight, the mixture was flushed with N2, filtered and concentrated. The residue was purified by chromatography over silica gel (20 % ethyl acetate/hexane). Mass spec. M+ 403(m+1, observed).
Step 3: 7,B-Methyl-4-oxa-Sa-Cholest-l-en-3-one W O 97/15564 . PCT~US96/16883 ~~ (PhSeO)20/PhCl/~
O o ~ ~ H
To a solution of 7,B-methyl-4-oxa-Sa-Cholestan-3-one (lg, 2.49 mmol) in chlorobenzene (50 mL) was added benzeneseleninic anhydride (1.165g, 3.24 mmol). After stirring the reaction mixture at 5 reflux temperature for overnight, the reaction mixture was diluted with ethyl acetate, washed with brine, dried and concentrated. The residue was purified by chromatography over silica gel (10% ethyl acetate/hexane). Mass spec. M+ 401(m+1, observed).
Preparation of N-(2'.5'-Bistrifluoromethylphenyl)-4-oxa-androst-1-en-3-one- 17,B-carbox~mide Step 1: S-2'-Pyridyl-3-oxo-androst-4-ene- 1713-thiocarboxylate ~~~02H ~S ~¢~
- ~~/ Aldrithiol/PPh3/Toluene ~~
' 0~ 0~
To a solution of steroid acid (10.26 g, 30 mmol) in toluene (50 mL) was added Aldri~iol (15.97 g, 72.49 mmol) and triphenylphosphine (16.88 g, 72.49 mmol). After stirring the reaction mixture for overnight at 23~, the reaction mixture was concentrated and purified by chromatography over silica gel using methylene chloride as 20 solvent.
Step 2: N-(2',5'-Bistrifluoromethylphenyl)-3-oxo-androst-4-ene-17,B -carboxamide W O 97/15564 PCT~US96/16883 ~S '[~ N~
~ AgOTf/CH2cl2 ~ ~ CF3 ~~J F3C ~ CF3 ~
To a solution of S-2'-pyridyl-3-oxo-androst-4-ene-1713-thiocarboxylate (2.179 g, 5.19 mmol) in methylene chloride was added 2,5-bistrifluoromethyl~niline (3 g, 13 mmol) and silver triflate (1.336 5 g, 5.2 mmol). After stirring the reaction mixtllre for overnight at 23~, he mixture was filtered, concentrated and purified by chromatography over silica gel using methylene chloride as solvent to give pure product.
Step 3: N-(2',5'-Bistrifluoromethylphenyl)-5-oxo-3,5-secoandrostan-3-oic- 1 7,B-carboxamide ,H CF3 H CF3 ~N~ N~
~ CF3 m ~ CF3 o~9 KMnO4/NalO4/t-BuOH HOOC
Na2CO3 To a solution of N-(2',5'-Bistrifluoromethylphenyl)-3-oxo-androst-4-ene-17,(3-carboxamide(600 mg, 1.27 mmol) in t-butanol (10 mL) was added sodium carbonate (200 mg, 1.88 mmol, in 1 mL of 15 H2O). The reaction mixture was heated to 80~ and a solution of NaIO4 (1.81g, 8.5 mmol) and KMn04 (13.2 mg, 0.08 mmol) in H20 (10 mL) was added dropwise in ~ 10 I~ lles. After stirring the reaction ~ixl~c for 2 hrs, the mix11lre was cooled to room temperature and acidified to pH 2. The reaction mixture was concentrated, extracted with ethyl 20 acetate, organic layer was dried and concentrated to give pure product W O 97115564 PCT~US96/16883 - 4~ -Step 4: N-(2',5'-Bistrifluoromethylphenyl)-4-oxa-androst-5-en-3-one- 1 7,B-carboxamide H, CF3 H CF3 ~N ~ N
~ CF3 ~-- CF3 HOOC o~J Ac20/NaOAc/~ ~ ,~J
S To a solution of N-(2',5'-bistrifluoromethylphenyl)-5-oxo-3,5-secoandrostan-3-oic-17,B-carboxamide (600 mg, 1.19 mmol) in acetic anhydride (10 mL) was added sodium acetate ( 1.63 g, 11.9 mmol). After stirring the reaction mixture at reflux temperature for 4 hrs, the acetic anhydride was removed under vacuum and residue partitioned between ethyl acetate and water. The organic layer was washed with brine, dried, concentrated and purified by prep. tlc (5%
acetone/methylene chloride). Mass spec. M+ 530 (m+l, observed).
Step 5: N-(2',5'-Bistrifluoromethylphenyl)-4-oxa-androstan-3-one-1 7,B-carboxamide.
H CF3 H CF3.
~N~¢~ N~
~ CF3 ~ CF3 ~~o~J 5% Rh/C ~ ,J
To a solution of N-(2',5'-bistrifluoromethylphenyl)-4-oxa-androst-5-en-3-one-17~-carboxamide (230 mg, 0.433 mml, prepared according to the procedures of Example 7) in THF (5 mL) was added 20 5% Rh/C (200 mg). After stirring the reaction mixture for overnight under hydrogen atmosphere, the reaction mixture was flushed with W O 97/15564 PCTrUS96/16883 nitrogen, filtered, concentrated and purified by preparative tlc (50%
EtOAc/hexane) to give pure product. Mass spec. M+ 532 (m+l, observed).
Step 6: N-(2',5'-Bistrifluoromethylphenyl)-4-oxa-androst-1-en-3-one- 1 7~-carboxamide ~N~ N~
~ CF3 ~-- CF3 o~o~J (PhSeO)20/PhCI o~o~J
To a solution of N-(2',5'-bistrifluoromethylphenyl)-4-oxa-androstan-3-one-1713-carboxamide. (35 mg, 0.066 mmol, prepared according to the procedures of Example 8) in chlorobenzene (5 mL) was added benzeneseleninic anhydride (30 mg, 0.085 mmol). After stirring the reaction mixture at reflux temperature for overnight, the reaction mixture was diluted with ethyl acetate, washed with brine, dried and concentrated. The residue was purified by prep. tlc (50%
EtOAc/hexane). Mass spec. M+ 530(m+1, observed).
N-t-Butyl-4-thia-5a-androst- 1 -en-3-one- 1 7,B-carboxamide.
Step 1: (N-Pyrid-3-yl)-5-hydroxy-3,5-secoandrostan-3-carboxamide-17~-(N-t-butvl)carboxamide.
From 500 mg of the product of step 5 of Example 1 [N-(t-butyl)-4-oxa-androstan-3-one-1713-carboxamidel, ~e title compound is prepared by treatment with 1.25 equivalents of the dimethyl~lllmimlm complex with 3-aminopyridine by reflux in toluene for 30 min. or until the A-ring opening is shown to be complete by hplc or thin-layer chromatography. Purification is optional by column chromatography to furnish the product in good yield.
W O 97/15564 PCTrUS96/16883 Step 2: (N-Pyrid-3-yl)-5-p-toluenesulfonyloxy-3,5-secoandrostan-3 -carboxamide- 1 7,13-(N-t-butyl)carboxamide.
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- 1713-(N-t-butyl)carboxamide.
The tosyl derivative of step 2 is stirred at ambient temperature with 3 equivalents of dry tetrabutylarnmonium 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 amorphous material is chromatographed to provide the pure iodo compound.
Step 4: (N-Pyrid-3-yl)-5-acetylthio-3,5-secoandrostan-3-carboxamide- 1 7,13-(N-t-butyl)carboxamide.
~he iodo compound of step 3 is stirred at arnbient temperature with 10 equivalents of thioacetic acid in toluene for 30 min.
and then heated at reflux for another 2 hrs. The reaction Illixllli'e is cooled, solvents and volatile reactants evaporated under reduced pressure, and the residual amorphous material chromatographed.
Step 5: N-t-Butyl4-thia-So~-androstan-3 -one- 1 7,~-carboxamide.
The thioacetyl derivative of step 4 is treated at ambient temperature with methanolic HCl (3%) until the starting material is gone by ~hin-layer chromatography or hplc. Product is isolated by chromatography and recrystallized.
-W O 97/15564 PCTrUS96/16883 Step 6 N-t-Butyl-4-thia-Sa-androst- 1 -en-3-one- 1 7,13-carboxamide.Treatment of the product of step 5 with phenylseleninic anhydride by the method of step 6 of Example 1 affords the product.
ORAL COMPOSITION
As a specific embodiment of an oral composition of a compound of this invention, S mg of a compound of structural formula I is formulated with sufficient finely divided lactose to provide a total 10 amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
Biolo~ical Assays Preparation of Human prostatic and scalp 5a-reductases SaInples of hl-m~n tissue were pulverized using a freezer mill and homogenized in 40 mM potassium phosphate, pH 6.5, 5 mM
m:~gnesium sulfate, 25 mM potassium chloride, 1 mM phenylmethyl-sulfonyl fluoride, 1 mM dithiothreitol (DTT) cont~ining 0.25 M sucrose using a Potter-Elvehjem homogenizer. A crude nuclear pellet was 20 prepared by centrifugation of the homogenate at 1,500 x g for 15 min.
The crude nuclear pellet was washed two times and resuspended in two volumes of buffer. Glycerol was added to the resuspended pellet to a final concentration of 20%. The enzyme suspension was frozen in aliquots at -80~C. The prostatic and scalp reductases were stable for at 25 least 4 months when stored under these conditions.
5a-reductase assay The reaction mixture for the type 1 5a-reductase contained 40 mM potassium phosphate, pH 6.5, 5 mM [7-3H]-testosterone, 1 mM
30 dithiothreitol and 500 ,uM NADPH in a final volume of 100 ,ul. The reaction mixture for the type 2 Sa-reductase contained 40 mM sodium citrate, pH 5.5, 0.3 mM [7-3H]-testosterone, 1 mM dithiothreitol and 500 ,uM NADPH in a final volume of 100 ,ul. Typically, the assay was initi~ted by the addition of 50-100 ~g prostatic homogenate or 75-200 35 ~lg scalp homogenate and incubated at 37~C. After 10-50 min. the W O 97/15564 PCT~US96/16883 reaction was quenched by extraction with 250 ,ul of a mixture of 70%
cyclohexane: 30% ethyl acetate cont~ining 10 ,ug each DHT and T. The aqueous and organic layers were separated by centrifugation at 14,000 lpm in an Eppendorf microfuge. The organic layer was subjected to S normal phase HPLC (10 cm Wh~ n partisil S 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.). The HPLC system consisted of a Waters Model 680 Gradient System equipped with a Hitachi Model 655a autosampler, Applied 10 Biosystems Model 757 variable UV detector, and a Radiomatic Model A120 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 ~e conditions described, the production of DHT was linear for at least 25 15 min. The only steroids observed with the human prostate and scalp preparations were T, DHT and androstanediol.
Inhibition studies Compounds were dissolved in 100% ethanol. The 20 compound to be tested was pre-incubated with the enzyme (either Sa-reductase type 1 or 2) prior to initi~tion by addition of substrate testosterone. IC50 values represent the concentration of inhibitor required to decrease enzyme conversion of testosterone to dihydrotestosterone by 50% of the control. ICso values were 25 deter~nined 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 5a-reductase type 1 and type 2 inhibition.
A compound referred to herein as a Sa-reductase 1 30 inhibitor is a compound ~at shows inhibition of the 50c-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 Soc-reductase 2 inhibitor is a compound that shows inhibition of the 5a-reductase 2 W O 97/15564 PCTrUS96/16883 isozyme in the above-described assay, having an ICso value of about or under 100 nM.
Human Dermal Papilla Cell Assay S 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 5a reductase activity, and it is therefore possible to test inhibitors of Sa 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., 1 10:685-689 (1984) and Itami, S. et al., "Sa-Reductase Activity In Cultured Human Dermal Papilla Cells From Beard Compared With Reticular Dermal Fibroblasts," J. Invest. Dermatol., 94:150-152 (1990). Beard dermal papilla cells and occipital scalp hair of two different individuals are used throughout the study. All experiments are performed at conf~uency after the fourth to sixth subculture.
Confluent monolayers are rinsed twice with phosphate-buffered saline, scraped from dishes by rubber policemen, and collected into a centrifuge tube. The cell suspensions are centrifuged at 1,500 rpm for 10 min. at 4~C. The pellets are resuspended in 20 mM Tris-HCl buffer, pH 7.5, at 4~C, cont~inin~ 250 mM sucrose, 1 mM MgC12, and 2 mM CaCl2, by vortexing and 10 passes through a 25-gauge needle. The crude homogenate is further homogenized by a teflon-glass homogenizer, and is used as the cell homogenate. For the study of subcellular localization of 50~-reductase, the cell homogenate is centrifuged at 800 x g for 10 min. to yield a crude nuclear pellet.
The resultant supern~t~nt is centrifuged at 10,000 x g for 15 min. to produce a crude mitochondrial pellet. The superr ~t~nt is centrifuged at 100,000 x g for 60 min. to yield a microsomal pellet and cytosol.
Each particulate ~raction is washed twice and resuspended in the buffer.
W O 97/15564 PCTrUS96/16883 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 S protein. Incubation is carried out at 37~C for 30 min. During this incubation, the reaction is proportional to the time. For the study of optimum pH, citrate buffer is used at pH 4.5-6.5, and the Tris HCl buffer at pH 7.0-9Ø The protein content is determined by the method of Lowry, et al., "Protein Measurement With The Folin 10 Phenol Reagent," J. Biol. Chem., 193:265-275 (1951).
After incubation, the reaction is stopped by adding 4 times volume of chloroform-methanol (2/1 :V/V) cont~ining 110 mg each of carrier steroids. The extracted steroids are analyzed by thin-layer chromatography as previously described by Gomez, et al., "In Vitro Metabolism Of Testosterone-4-14C and D-androstene-3, 17-dione-4-14C In Human Skin.," Biochem., 7:24-32 (1968), and ~e purity of each steroid is determined by the recryst~lli7~tion method.
The activity of 5a-reductase is expressed by the sum of dihydro-testosterone, androstanediol and androstanedione formed. [1,2-3H]-testosterone (55.2 Ci/mmol) is obtainable from New Fngl~n~l Nuclear Corporation (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.
MACROPHOTOGRAPHY AND GLOBAL PHOTOGRAPHY
PROCEDURE FOR DETECTION OF HAIR GROWTlH
A. Macrophoto~raphic Procedure Location: ID card Haircount target area _ W O 97/1~564 PCT~US96/16883 Equipment: Film: Kodak-T-max 24 exposure each of same emulsion lot number Camera: Nikon N-6000 Lens: Nikkor 60 mm ~2.8 Flashes: Nikon SB-21B Macroflash Device: registration device Photo~raphic Procedure:
In these clinical photographs, the only variable allowed is the haircount. Film emulsion, lighting, framing, exposure, and reproduction ratios are held constant.
1. 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 m~ml~lly (needle and ink). An area approximately one square inch in size, centered at the tattoo at ~he le~ling edge of the balding area, is clipped short (~2mm). Cut hairs are removed from the area to be photographed, using tape. Compressed air and/or ethanol wipes may also be used to facilitate removal of cut hairs.
2. Magnification: Each lens supplied has a fixed reproduction ratio of 1:1.2.
Aperture: Every photograph is taken at f/22.
Film: T-Max 100 (24 exposure) is used.
3. Patient's haircount target area. Three exposures (-2/3, 0, and +2/3 f-stop).
A trained technician places a transparency over the 30 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 corresponding to study site, visit number and patient allocation number W O 97/15564 ~ PCT~US96/16883 to insure blinding to time. At Month 6, baseline and Month 6 photographs are counted and data analyzed for interim analysis. At Month 12, baseline, Month 6 and 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).
B. Global Photographic Procedure Locations: Color card/patient Id Global photograph Equipment: Film: Kodachrome KR-64 24 exposure each of same emulsion lot number Camera: Nikon N-6000 Lens: Nikkor 60 mm f2.8 Flashes: Nikon SB-23 Photographic Procedure In these clinical photographs, the only variable allowed is the global area's appearance. Anything extraneous to the area (clothing, furniture, walls, etc.) is elimin~ted from the fields to be photographed.
1. Patients will have global photographs taken prior to hair clipping with the head in a fixed position (determined by the supplied stereotactic device). Hair on the patient's head is positioned consistently so as to not obscure ~e bald area.
2. Magnification: Each lens supplied has a fixed reproduction ratio of 1:6.
Aperture: Every photograph will be taken at f/l 1.
Film: Kodachrome (24 exposure) is used.
3. Patient's global photographs. Three exposures at zero compensation.
While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the W O 97/15564 PCT~US96/16883 art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of S variations in the responsiveness of the m~mm?~l being treated for any of the indications for the compounds of the invention indicated above.
Likewise, the specific pharmacological responses observed may vary according to and depending upon the particular active compound selected or whether there are present phar~naceutical carriers, as well as 10 the type of formulation and mode of ~lminictration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be hlte,~leted as broadly as is 15 reasonable.
........
S 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 hyperplasia, prostatitis and prostatic cancer.
For the treatment of acne vulgaris, androgenic alopecia, male pattern baldness, seborrhea, female hirsutism, benign prostatic hyperplasia, prostatitis and the prevention and/or treatment of prostatic cancer, the compounds of the instant invention can be combined with a therapeutically effective amount of another Sa-lS reductase inhibitor, such as finasteride or epristeride, or other 5a-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. Alternatively, a combined therapy can be employed wherein the compound of formula I and the other Sa-reductase inhibitor are ~lmini~tered in separate oral, systemic, or parenteral dosage formulations. Also, for the skin and scalp related disorders of acne vulgaris, androgenic alopecia, male pattern baldness, seborrhea, and female hirsutism, the compounds of the instant invention and another Sa-reductase inhibitor such as finasteride or epristeride can be formulated for topical ~lmini~tration. For example, a compound of formula I and finasteride can be ~lminictered in a single oral or topical dosage formulation, or each active agent can be ~lmini~tered in a separate dosage fonn~ tion, e.g., in separate oral dosage formulations, or an oral dosage formulation of finasteride in combination with a topical dosage fonmll~tion 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 Sa-reductase inhibitors.
W O 97/15564 PCT~US96/16883 Furthermore, ~lminictration of a compound of the present invention in combination with a therapeutically effective amount of a potassium channel opener, such as minoxidil, crom~k~lin, pinacidil, a compound selected from the classes of S-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 a-lministration of a Soc-reductase type 2 inhibitor such as finasteride or epristeride, or a 5a-reductase 10 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. The active agents can be ~lmini~tered in a single topical dosage formulation, or each active agent can be ~lmini~tered in a separate dosage formulation, e.g., in lS separate topical dosage formulations, or an oral dosage form~ tion 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 5a-reductase inhibitor, in combination with a topical dosage form~ tion of, e.g., minoxidil.
20 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.
Furthermore, for the treatment of acne vulgaris, a combined therapy can be used by ~lmini~tering a therapeutically 25 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. Optionally, this combined therapy for acne vulgaris may further include a Sa-reductase type 2 inhibitor such as 30 finasteride or epristeride, or a 5a-reductase type 1 inhibitor, or a dual type 1 and type 2 inhibitory compound.
Also, for the treatnlent of benign prostatic hyperplasia, a combined therapy comprising a ~lmini~tration of a compound of formula I with a 5a-reductase type 2 inhibitor, such as e.g., W O 97/15564 PCT~US96/16883 finasteride, and an alpha-l adrenergic receptor antagonist, such as e.g., terazosin, doxazosin, prazosin, bunazosin, indoramin or alfuzosin, may be employed. More particularly, the combined therapy can comprise ~-lmini~tering a compound of formula I with a 5O~-reductase type 2 inhibitor, such as e.g., finasteride, and an alpha-la adrenergic receptor antagonist (formerly called an alpha-1c 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 (W094/08040, 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.
Also, for the treatment of acne vulgaris, androgenic alopecia, seborrhea, female hirsutism, benign prostatic hypeIplasia, prostatitis and the prevention and/or treatrnent of prostatic cancer, a combined therapy can be used by ~ ni~tering 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.
For combination treatment with more than one active agent, where the active agents are in separate dosage formulations, the active agents can be ~(1mini~tered concurrently, or they each can be ~-lmini~tered 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.
, W O 97/1~564 PCTrUS96/16883 The 4-oxa compounds of this invention can be prepared as shown in Scheme 1.
Scheme 1 r~
3 Acetic anhydride ,-~,C"
O R7 NaOAc/140~ ~ --~R7 5% Rh/C/H2 ~
~ ~ ~ Benzeneselenic anhydride THF
O~O~R7 Chlorobenzene/Reflux (3) (4) 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 - 10 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 A2 substitution may be obtained. To obtain the a~lo~,iate Al substitution, the procedures of the following W O 97/1556~ PCT~US96/16883 publications are followed starting with a 3-keto-delta4-17-one precursor: for ether or thioether WO 93/23040; for anilide WO
94/07861, EP 0 663 924; for unsubstituted, monosubstituted or disubstituted amides WO 93/23038, WO 93/23051, WO 93/23420; and 5 US 4,220,775, 4,760,071, ~,845,104, 5,237,067, 5,091,380, 5,061,801, 5,215,894, for oxo U.S. 4,220,775, 4,377,584; for cyano U.S. 4,220,775; for tetrazoyl U.S. 4,220,775; for arylaL~ylcarbonlyoxy alkyl U.S. 4,377,584; for cycloalkylarylcarbonlyoxy alkyl U.S.
4,377,584; for benzoyloxyaLkyl U.S. 4,377,584; for acyl, both 10 substituted and unsubstituted, U.S. 5,049,562, U.S. 5,138,063, U.S.
5,151,429, U.S. 5,237,061, U.S. 5,120,742, U.S. 5,162,332, U.S.
5,061,802, U.S. 5,098,908, U.S. 5,196,411, U.S. 5,075,450, U.S.
5,061,803, U.S. 5,324,734; for thiobenzyl U.S. 5,151,430; for polyaroyl U.S. 5,162,322; for ester U.S. 5,091,534, WO 93/23041, WO
15 93/23040, for alkyl, either substituted or unsubstituted WO 93/23050, WO 93/23419, WO 93/23051; for urea, thiourea, carbamate or thiocarbamate W093/23048; for thioester WO 93/23041, WO
93/23040.
The a~rol~liately 7,10,16, and 17-substituted 3-keto 20 steroid is converted to the appropriately substituted seco-acid by methods known in the art, for example, the procedures described in mll~son, et al., J.Med.Chem. 1986, 29(11): 2298-2315.
The appropriate 7-~13 substitution may be obtained following the procedures for formation of a 7-,13 bond as described in U.S. Patents 25 4,220,775, and 5,237,064.
Compounds wherein R2 is H or CH20R3 may be prepared starting with the a~lo~liately C10 substituted seco-acid. These compounds may be made by procedures known in the art.
As shown in Scheme 1, ~e seco-acid (1) is treated with a 30 dehydrating agent such as acetic anhydride, methyl ortho-formate, ethyl ortho-formate, in a nonpolar aprotic 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 forrn the ~5-oxasteroid (2). Preferably, the seco-acid (1) is treated with acetic anhydride in acetic anhydride in the presence of sodium acetate at an elevated temperature, preferably at about 140~C.
~ 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, S Pd/C, etc., preferably Rh/C in a solvent such as tetrahydrofuran (THF) or ethyl acetate. This is followed by folmation of the ~1 double bond by treatment with, for example, dichloro-dicyanoquinone (DDQ), benzeneselenic anhydride in chlorobenzene, or other known methods, for example as described in U.S. 5,084,574 and 5,021,571, to form the 10 A 1 -oxasteroid (4).
The 4-thia compounds of this invention can be prepared as shown in Scheme 2.
~ Me-Ai Toluene/A
~3--N~ RS02X/Pyrilline H HO R = CF3 or CH3 or Ar lS (5) R7 X = Cl or OSO2R
~,Ni~----~ n-Bu4NI/Toluene (6) SO2R
~N~--~
H I CH3COSH/Toluene (7) I'* ~R7 CS2C~3 W O 97/15564 PCT~US96/16883 ~NJ~
(8) H S 3% HCl/MeOH
o ~X~~ (PhSeO)2~
O S R7 O~S~~R7 g) (10) Starting with the 4-oxa-androstan-3-one ~rolJriately substituted in the B and D-ring~ obtained by following the procedures of 5 Scheme 1 to obtain compound (3), 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, aprotic 10 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 15 give the corresponding alkyl- or aryl sulfonate (6). The reaction of the alkyl- or aryl sulfonate with tetrabutylammonium iodide in a polar aprotic solvent such as toluene produces the corresponding iodide (7).
The iodide is treated with thioacetic acid in a nonpolar solvent such as toluene or dichloroethane in the presence of cesium carbonate or other 20 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 treatrnent with hydrochloric acid .
W O 97/15564 PCT~US96/16883 in methanol. The thialactone (9) may be dehydrogenated to for~n the A1-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 5 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 ~ 5-oxasteroid derivative.
The corresponding 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. Furthermore, 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 15 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.
All temperatures given in the following examples are in 20 degrees Celsius. lH and 13C nuclear magnetic resonance (NMR) spectra were taken at 400 or 500 MHz at ambient temperature in the solvents indicated. Some abbreviations used herein are as follows:
"BOC" is t-butoxycarbonyl; "BOC anhydride" is di-t-butyl dicarbonate {O(C02C(CH3)3)2}; "DBU" is 1,8-diaza-bicyclo[5.4,0] undec-7-ene;
25 "DCC" is 1,3-dicyclohexylcarbodiimide; "DMS" is methyl sulfide { (CH3)2S }; "DMF" is dimethylformamide; "EtOAc" is ethyl acetate;
"HOBT" is 1-hydroxybenzotriazole; "IPA" is isopropyl acetate; "Ph" is phenyl; "Tf" is -S02CF3; "TFA" is trifluoroacetic acid; "THF" is tetrahydrofuran; "TIPS" is triisopropylsilyl; "TIPSO" is 30 triisopropylsilyloxy. Unless otherwise specified "tlc" and "TLC" refer to thin layer SiO2 chromatography.
RxAMpLE 1 Preparation of N-t-Butyl-4-oxa-5a-androst-1-en-3-one-17,B-carboxamide.
Step 1: Benzotriazol- 1 '-yl-3-oxo-androst-4-ene- 17,13-carboxamide.
O OH Oq~O~
~ ~ N~N
D~/ DCC/HOBT/THF ~/
o To a solution of steroid acid (4g, 12.65 mmol, see Rasmusson et al., J.Med.Chem. 1986, 29(11): 2298-2315 for description of synthesis) in methylene chloride was added DCC (2.75g, 13.3 mmol) and 1-hydroxybenzotriazoie (HOBT, 2.75g, 19.1 mmol). After stirring the reaction mixture for overnight, the solid was filtered, dried and 10 used as such for further reactions.
Step 2: N-t-Butyl-3-oxo-androst-4-ene- 17~-carboxamide.
0~ H
N~ O~,N~
N---N ~ 1 t-BuNH2 /CH2Ck ~--/
0~ 0~
To a solution of benzotriazol-1'-yl-3-oxo-androst-4-ene-lS 17~-carboxamide (l.Sg, 3.46 mmol) in methylene chloride was added t-butyl amine (454 ,u1,4.33 mmol). After stirring the reaction mixture for overnight, the reaction mixtllre was concentrated, purified by chromatography over silica gel (2.5% acetone/methylene chloride).
Mass spec. M+ 372(m+1, observed).
Step 3: N-t-Butyl-S-oxo-3,5-secoandrostan-3-oic-17,B-carboxamide.
W O 97/15564 PCT~US96/16883 ~; KlMnO4/NalO4 ~
Na2CO3/t-BuOH HOOC
To a solution of N-t-butyl-3-oxo-androst-4-ene-17,13-carboxamide (550 mg, 1.48 mmol) in t-butanol (10 mL) was added sodium carbonate (172 mg, 1.63 mmol, in 1 mL of H2O). The reaction 5 mixture was heated to 80~ and a solution of NaIO4 (1.58g, 7.4 mmol) and KMnO4 (11.7mg, 0.074 mmol) in H2O (10 mL) was added dropwise in ~ 10 minutes. After stirring the reaction mixture for 2 hrs, the mixture was cooled to room temperature and acidified to pH 2. The reaction mixture was concentrated, extracted with ethyl acetate, organic 10 layer was dried and concentrated to give pure product. Mass spec. M+
392(m+1, observed).
Step 4: N-t-Butyl-4-oxa-androst-5-en-3-one- 17,~-carboxamide.
H H, ~N~ N~
~~/ Ac20/NaOAC/Q ~J~
0~ 0 0 To a solution of N-t-butyl-S-oxo-3,5-secoandrostan-3-oic-17,B-carboxamide (550 mg, 1.4 mmol) in acetic anhydride (25 mL) was added sodium acetate (1.91 g, 14 mmol). After stirring the reaction mix~lre at reflux temperature for 4 hrs, the acetic anhydride was removed under vacuum and residue partitioned between ethyl acetate 20 and water. The organic layer was washed with brine, dried, concentrated and purified by prep. tlc (5% acetone/methylene chloride).
Mass spec. M+ 374(m~1, observed).
WO 97/15564 PCT~US96/16883 Step 5: N-t-Butyl-4-oxa-Sa-androstan-3 -one- 1 7,~-carboxamide.
H H
~N~ N~
f ~-- 5% Rh/C/H2/THF ~--0~ 0~ 0~0~
To a solution of N-t-butyl-4-oxa-androst-S-en-3-one-17,13-5 carboxamide (410 mg, 1.099 mmol) in THF (20 mL) was added 5%
Rh/C(410 mg). After stirring the reaction mixture under H2 atmosphere for overnight, the mixture was flushed with N2, filtered and concentrated. The residue was purified by prep. tlc (5% acetone/
CH2Cl2). Mass spec. M+ 376(m+1, observed).
Step 6: N-t-Butyl-4-oxa-5a-androst- 1 -en-3 -one- 1 7~-carboxamide .
H H
~N~ Ny ~ (PhSeO)20/PhCl/~
O 0~ 0 0 To a solution of N-t-butyl-4-oxa-5a-androstan-3-one-17,13-carbox~mide (100 mg, 0.27 mmol) in chlorobenzene was added 15 benzeneselenic anhydride (177 mg, 0.49 mmol). After stirring the reaction mixture at reflux temperature for overnight, the reaction mixtllre was diluted with ethyl acetate, washed with brine, dried and concentrated. The residue was purified by prep. tlc (5% acetone/
CH2C12). Mass spec. M+ 374(m+1, observed).
W O 97tl5564 PCT~US96/16883 Preparation of 7,B-Methyl-4-oxa-Soc-Cholest-1-en-3-one ~O/I~aOAc/A ~X~~
HOOC o o Step 1: 7~-Methyl-4-oxa-Cholest-5-en-3-one To a solution of 7,B-methyl-5-oxo-3,5-secocholestan-3-oic 5 (5g, 12.3 mmol) in acetic anhydride (250 mL) was added sodium acetate ( 16.9 g, 124 mmol). After stirring the reaction mixtllre at reflux temperature for 4 hrs, the acetic anhydride was removed under vacuum and residue partitioned between ethyl acetate and water. The organic layer was washed with brine, dried, concentrated and purified 10 by chromatography over silica gel. Mass spec. M+ 401(m+1, observed).
Step 2: 7,B-Methyl-4-oxa-Sa-Cholestan-3-one ~--/ 5%Rh/C/H2/THF
0~0~ 0 0 To a solution of 7,~-methyl-4-oxa-Cholest-S-en-3-one (6.0g) in THF
15 (50 mL) was added 5% Rh/C(6.5g). After stirring the reaction nnixture under H2 atmosphere for overnight, the mixture was flushed with N2, filtered and concentrated. The residue was purified by chromatography over silica gel (20 % ethyl acetate/hexane). Mass spec. M+ 403(m+1, observed).
Step 3: 7,B-Methyl-4-oxa-Sa-Cholest-l-en-3-one W O 97/15564 . PCT~US96/16883 ~~ (PhSeO)20/PhCl/~
O o ~ ~ H
To a solution of 7,B-methyl-4-oxa-Sa-Cholestan-3-one (lg, 2.49 mmol) in chlorobenzene (50 mL) was added benzeneseleninic anhydride (1.165g, 3.24 mmol). After stirring the reaction mixture at 5 reflux temperature for overnight, the reaction mixture was diluted with ethyl acetate, washed with brine, dried and concentrated. The residue was purified by chromatography over silica gel (10% ethyl acetate/hexane). Mass spec. M+ 401(m+1, observed).
Preparation of N-(2'.5'-Bistrifluoromethylphenyl)-4-oxa-androst-1-en-3-one- 17,B-carbox~mide Step 1: S-2'-Pyridyl-3-oxo-androst-4-ene- 1713-thiocarboxylate ~~~02H ~S ~¢~
- ~~/ Aldrithiol/PPh3/Toluene ~~
' 0~ 0~
To a solution of steroid acid (10.26 g, 30 mmol) in toluene (50 mL) was added Aldri~iol (15.97 g, 72.49 mmol) and triphenylphosphine (16.88 g, 72.49 mmol). After stirring the reaction mixture for overnight at 23~, the reaction mixture was concentrated and purified by chromatography over silica gel using methylene chloride as 20 solvent.
Step 2: N-(2',5'-Bistrifluoromethylphenyl)-3-oxo-androst-4-ene-17,B -carboxamide W O 97/15564 PCT~US96/16883 ~S '[~ N~
~ AgOTf/CH2cl2 ~ ~ CF3 ~~J F3C ~ CF3 ~
To a solution of S-2'-pyridyl-3-oxo-androst-4-ene-1713-thiocarboxylate (2.179 g, 5.19 mmol) in methylene chloride was added 2,5-bistrifluoromethyl~niline (3 g, 13 mmol) and silver triflate (1.336 5 g, 5.2 mmol). After stirring the reaction mixtllre for overnight at 23~, he mixture was filtered, concentrated and purified by chromatography over silica gel using methylene chloride as solvent to give pure product.
Step 3: N-(2',5'-Bistrifluoromethylphenyl)-5-oxo-3,5-secoandrostan-3-oic- 1 7,B-carboxamide ,H CF3 H CF3 ~N~ N~
~ CF3 m ~ CF3 o~9 KMnO4/NalO4/t-BuOH HOOC
Na2CO3 To a solution of N-(2',5'-Bistrifluoromethylphenyl)-3-oxo-androst-4-ene-17,(3-carboxamide(600 mg, 1.27 mmol) in t-butanol (10 mL) was added sodium carbonate (200 mg, 1.88 mmol, in 1 mL of 15 H2O). The reaction mixture was heated to 80~ and a solution of NaIO4 (1.81g, 8.5 mmol) and KMn04 (13.2 mg, 0.08 mmol) in H20 (10 mL) was added dropwise in ~ 10 I~ lles. After stirring the reaction ~ixl~c for 2 hrs, the mix11lre was cooled to room temperature and acidified to pH 2. The reaction mixture was concentrated, extracted with ethyl 20 acetate, organic layer was dried and concentrated to give pure product W O 97115564 PCT~US96/16883 - 4~ -Step 4: N-(2',5'-Bistrifluoromethylphenyl)-4-oxa-androst-5-en-3-one- 1 7,B-carboxamide H, CF3 H CF3 ~N ~ N
~ CF3 ~-- CF3 HOOC o~J Ac20/NaOAc/~ ~ ,~J
S To a solution of N-(2',5'-bistrifluoromethylphenyl)-5-oxo-3,5-secoandrostan-3-oic-17,B-carboxamide (600 mg, 1.19 mmol) in acetic anhydride (10 mL) was added sodium acetate ( 1.63 g, 11.9 mmol). After stirring the reaction mixture at reflux temperature for 4 hrs, the acetic anhydride was removed under vacuum and residue partitioned between ethyl acetate and water. The organic layer was washed with brine, dried, concentrated and purified by prep. tlc (5%
acetone/methylene chloride). Mass spec. M+ 530 (m+l, observed).
Step 5: N-(2',5'-Bistrifluoromethylphenyl)-4-oxa-androstan-3-one-1 7,B-carboxamide.
H CF3 H CF3.
~N~¢~ N~
~ CF3 ~ CF3 ~~o~J 5% Rh/C ~ ,J
To a solution of N-(2',5'-bistrifluoromethylphenyl)-4-oxa-androst-5-en-3-one-17~-carboxamide (230 mg, 0.433 mml, prepared according to the procedures of Example 7) in THF (5 mL) was added 20 5% Rh/C (200 mg). After stirring the reaction mixture for overnight under hydrogen atmosphere, the reaction mixture was flushed with W O 97/15564 PCTrUS96/16883 nitrogen, filtered, concentrated and purified by preparative tlc (50%
EtOAc/hexane) to give pure product. Mass spec. M+ 532 (m+l, observed).
Step 6: N-(2',5'-Bistrifluoromethylphenyl)-4-oxa-androst-1-en-3-one- 1 7~-carboxamide ~N~ N~
~ CF3 ~-- CF3 o~o~J (PhSeO)20/PhCI o~o~J
To a solution of N-(2',5'-bistrifluoromethylphenyl)-4-oxa-androstan-3-one-1713-carboxamide. (35 mg, 0.066 mmol, prepared according to the procedures of Example 8) in chlorobenzene (5 mL) was added benzeneseleninic anhydride (30 mg, 0.085 mmol). After stirring the reaction mixture at reflux temperature for overnight, the reaction mixture was diluted with ethyl acetate, washed with brine, dried and concentrated. The residue was purified by prep. tlc (50%
EtOAc/hexane). Mass spec. M+ 530(m+1, observed).
N-t-Butyl-4-thia-5a-androst- 1 -en-3-one- 1 7,B-carboxamide.
Step 1: (N-Pyrid-3-yl)-5-hydroxy-3,5-secoandrostan-3-carboxamide-17~-(N-t-butvl)carboxamide.
From 500 mg of the product of step 5 of Example 1 [N-(t-butyl)-4-oxa-androstan-3-one-1713-carboxamidel, ~e title compound is prepared by treatment with 1.25 equivalents of the dimethyl~lllmimlm complex with 3-aminopyridine by reflux in toluene for 30 min. or until the A-ring opening is shown to be complete by hplc or thin-layer chromatography. Purification is optional by column chromatography to furnish the product in good yield.
W O 97/15564 PCTrUS96/16883 Step 2: (N-Pyrid-3-yl)-5-p-toluenesulfonyloxy-3,5-secoandrostan-3 -carboxamide- 1 7,13-(N-t-butyl)carboxamide.
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- 1713-(N-t-butyl)carboxamide.
The tosyl derivative of step 2 is stirred at ambient temperature with 3 equivalents of dry tetrabutylarnmonium 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 amorphous material is chromatographed to provide the pure iodo compound.
Step 4: (N-Pyrid-3-yl)-5-acetylthio-3,5-secoandrostan-3-carboxamide- 1 7,13-(N-t-butyl)carboxamide.
~he iodo compound of step 3 is stirred at arnbient temperature with 10 equivalents of thioacetic acid in toluene for 30 min.
and then heated at reflux for another 2 hrs. The reaction Illixllli'e is cooled, solvents and volatile reactants evaporated under reduced pressure, and the residual amorphous material chromatographed.
Step 5: N-t-Butyl4-thia-So~-androstan-3 -one- 1 7,~-carboxamide.
The thioacetyl derivative of step 4 is treated at ambient temperature with methanolic HCl (3%) until the starting material is gone by ~hin-layer chromatography or hplc. Product is isolated by chromatography and recrystallized.
-W O 97/15564 PCTrUS96/16883 Step 6 N-t-Butyl-4-thia-Sa-androst- 1 -en-3-one- 1 7,13-carboxamide.Treatment of the product of step 5 with phenylseleninic anhydride by the method of step 6 of Example 1 affords the product.
ORAL COMPOSITION
As a specific embodiment of an oral composition of a compound of this invention, S mg of a compound of structural formula I is formulated with sufficient finely divided lactose to provide a total 10 amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
Biolo~ical Assays Preparation of Human prostatic and scalp 5a-reductases SaInples of hl-m~n tissue were pulverized using a freezer mill and homogenized in 40 mM potassium phosphate, pH 6.5, 5 mM
m:~gnesium sulfate, 25 mM potassium chloride, 1 mM phenylmethyl-sulfonyl fluoride, 1 mM dithiothreitol (DTT) cont~ining 0.25 M sucrose using a Potter-Elvehjem homogenizer. A crude nuclear pellet was 20 prepared by centrifugation of the homogenate at 1,500 x g for 15 min.
The crude nuclear pellet was washed two times and resuspended in two volumes of buffer. Glycerol was added to the resuspended pellet to a final concentration of 20%. The enzyme suspension was frozen in aliquots at -80~C. The prostatic and scalp reductases were stable for at 25 least 4 months when stored under these conditions.
5a-reductase assay The reaction mixture for the type 1 5a-reductase contained 40 mM potassium phosphate, pH 6.5, 5 mM [7-3H]-testosterone, 1 mM
30 dithiothreitol and 500 ,uM NADPH in a final volume of 100 ,ul. The reaction mixture for the type 2 Sa-reductase contained 40 mM sodium citrate, pH 5.5, 0.3 mM [7-3H]-testosterone, 1 mM dithiothreitol and 500 ,uM NADPH in a final volume of 100 ,ul. Typically, the assay was initi~ted by the addition of 50-100 ~g prostatic homogenate or 75-200 35 ~lg scalp homogenate and incubated at 37~C. After 10-50 min. the W O 97/15564 PCT~US96/16883 reaction was quenched by extraction with 250 ,ul of a mixture of 70%
cyclohexane: 30% ethyl acetate cont~ining 10 ,ug each DHT and T. The aqueous and organic layers were separated by centrifugation at 14,000 lpm in an Eppendorf microfuge. The organic layer was subjected to S normal phase HPLC (10 cm Wh~ n partisil S 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.). The HPLC system consisted of a Waters Model 680 Gradient System equipped with a Hitachi Model 655a autosampler, Applied 10 Biosystems Model 757 variable UV detector, and a Radiomatic Model A120 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 ~e conditions described, the production of DHT was linear for at least 25 15 min. The only steroids observed with the human prostate and scalp preparations were T, DHT and androstanediol.
Inhibition studies Compounds were dissolved in 100% ethanol. The 20 compound to be tested was pre-incubated with the enzyme (either Sa-reductase type 1 or 2) prior to initi~tion by addition of substrate testosterone. IC50 values represent the concentration of inhibitor required to decrease enzyme conversion of testosterone to dihydrotestosterone by 50% of the control. ICso values were 25 deter~nined 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 5a-reductase type 1 and type 2 inhibition.
A compound referred to herein as a Sa-reductase 1 30 inhibitor is a compound ~at shows inhibition of the 50c-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 Soc-reductase 2 inhibitor is a compound that shows inhibition of the 5a-reductase 2 W O 97/15564 PCTrUS96/16883 isozyme in the above-described assay, having an ICso value of about or under 100 nM.
Human Dermal Papilla Cell Assay S 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 5a reductase activity, and it is therefore possible to test inhibitors of Sa 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., 1 10:685-689 (1984) and Itami, S. et al., "Sa-Reductase Activity In Cultured Human Dermal Papilla Cells From Beard Compared With Reticular Dermal Fibroblasts," J. Invest. Dermatol., 94:150-152 (1990). Beard dermal papilla cells and occipital scalp hair of two different individuals are used throughout the study. All experiments are performed at conf~uency after the fourth to sixth subculture.
Confluent monolayers are rinsed twice with phosphate-buffered saline, scraped from dishes by rubber policemen, and collected into a centrifuge tube. The cell suspensions are centrifuged at 1,500 rpm for 10 min. at 4~C. The pellets are resuspended in 20 mM Tris-HCl buffer, pH 7.5, at 4~C, cont~inin~ 250 mM sucrose, 1 mM MgC12, and 2 mM CaCl2, by vortexing and 10 passes through a 25-gauge needle. The crude homogenate is further homogenized by a teflon-glass homogenizer, and is used as the cell homogenate. For the study of subcellular localization of 50~-reductase, the cell homogenate is centrifuged at 800 x g for 10 min. to yield a crude nuclear pellet.
The resultant supern~t~nt is centrifuged at 10,000 x g for 15 min. to produce a crude mitochondrial pellet. The superr ~t~nt is centrifuged at 100,000 x g for 60 min. to yield a microsomal pellet and cytosol.
Each particulate ~raction is washed twice and resuspended in the buffer.
W O 97/15564 PCTrUS96/16883 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 S protein. Incubation is carried out at 37~C for 30 min. During this incubation, the reaction is proportional to the time. For the study of optimum pH, citrate buffer is used at pH 4.5-6.5, and the Tris HCl buffer at pH 7.0-9Ø The protein content is determined by the method of Lowry, et al., "Protein Measurement With The Folin 10 Phenol Reagent," J. Biol. Chem., 193:265-275 (1951).
After incubation, the reaction is stopped by adding 4 times volume of chloroform-methanol (2/1 :V/V) cont~ining 110 mg each of carrier steroids. The extracted steroids are analyzed by thin-layer chromatography as previously described by Gomez, et al., "In Vitro Metabolism Of Testosterone-4-14C and D-androstene-3, 17-dione-4-14C In Human Skin.," Biochem., 7:24-32 (1968), and ~e purity of each steroid is determined by the recryst~lli7~tion method.
The activity of 5a-reductase is expressed by the sum of dihydro-testosterone, androstanediol and androstanedione formed. [1,2-3H]-testosterone (55.2 Ci/mmol) is obtainable from New Fngl~n~l Nuclear Corporation (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.
MACROPHOTOGRAPHY AND GLOBAL PHOTOGRAPHY
PROCEDURE FOR DETECTION OF HAIR GROWTlH
A. Macrophoto~raphic Procedure Location: ID card Haircount target area _ W O 97/1~564 PCT~US96/16883 Equipment: Film: Kodak-T-max 24 exposure each of same emulsion lot number Camera: Nikon N-6000 Lens: Nikkor 60 mm ~2.8 Flashes: Nikon SB-21B Macroflash Device: registration device Photo~raphic Procedure:
In these clinical photographs, the only variable allowed is the haircount. Film emulsion, lighting, framing, exposure, and reproduction ratios are held constant.
1. 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 m~ml~lly (needle and ink). An area approximately one square inch in size, centered at the tattoo at ~he le~ling edge of the balding area, is clipped short (~2mm). Cut hairs are removed from the area to be photographed, using tape. Compressed air and/or ethanol wipes may also be used to facilitate removal of cut hairs.
2. Magnification: Each lens supplied has a fixed reproduction ratio of 1:1.2.
Aperture: Every photograph is taken at f/22.
Film: T-Max 100 (24 exposure) is used.
3. Patient's haircount target area. Three exposures (-2/3, 0, and +2/3 f-stop).
A trained technician places a transparency over the 30 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 corresponding to study site, visit number and patient allocation number W O 97/15564 ~ PCT~US96/16883 to insure blinding to time. At Month 6, baseline and Month 6 photographs are counted and data analyzed for interim analysis. At Month 12, baseline, Month 6 and 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).
B. Global Photographic Procedure Locations: Color card/patient Id Global photograph Equipment: Film: Kodachrome KR-64 24 exposure each of same emulsion lot number Camera: Nikon N-6000 Lens: Nikkor 60 mm f2.8 Flashes: Nikon SB-23 Photographic Procedure In these clinical photographs, the only variable allowed is the global area's appearance. Anything extraneous to the area (clothing, furniture, walls, etc.) is elimin~ted from the fields to be photographed.
1. Patients will have global photographs taken prior to hair clipping with the head in a fixed position (determined by the supplied stereotactic device). Hair on the patient's head is positioned consistently so as to not obscure ~e bald area.
2. Magnification: Each lens supplied has a fixed reproduction ratio of 1:6.
Aperture: Every photograph will be taken at f/l 1.
Film: Kodachrome (24 exposure) is used.
3. Patient's global photographs. Three exposures at zero compensation.
While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the W O 97/15564 PCT~US96/16883 art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of S variations in the responsiveness of the m~mm?~l being treated for any of the indications for the compounds of the invention indicated above.
Likewise, the specific pharmacological responses observed may vary according to and depending upon the particular active compound selected or whether there are present phar~naceutical carriers, as well as 10 the type of formulation and mode of ~lminictration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be hlte,~leted as broadly as is 15 reasonable.
........
Claims (26)
1. A compound of structural formula (I):
or a pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein:
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, Ha 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;
R1 is selected from hydrogen and C1-5 alkyl;
R2 is selected from CH3, CH2OR3, and H;
R3 is selected from: C1-5 alkyl;
Z is or ;
A1 is selected from:
(1) -H, (2) keto, (6) carboxy, (7) protected amino, (8) amino, (9) substituted or unsubstituted C2-10alkenyl, (10) aryl-substituted C1-10 alkyl, (11) aryl or heteroaryl, (12) substituted aryl or heteroaryl, (13) aryl or heteroaryl carbamoyl-substituted C1-10alkyl, (14) aryl or heteroaryl carbonyl, (15) ether-substituted C1-10alkyl, (16) thioether-substituted C1-10alkyl, (17) keto-substituted C1-10alkyl, (18) heteroaryl-substituted C1-10 alkyl, (19) carboxylic ester, (20) carboxamide, including substituted and unsubstituted anilide derivatives, (21) urea, (22) C1-10 alkylureido C0-5 alkyl, (23) substituted or unsubstituted heteroaryl or arylureidoC0-5 alkyl, (24) C1-10alkanoyloxyC1-2alkyl, (25) Cl-10 alkylcarbonylamino, (26) alkanoylamidoalkyl (28) ether, (29) thio ether, and (30) substituted and unsubstituted aryl or heteroaryl ether;
A2 is selected from:
(1) -H, (2) keto, (3) protected hydroxy, (4) acetate, (5) hydroxy, (6) carboxy, (7) protected amino, (8) amino, (9) C1-10 alkyl, (10) substituted or unsubstituted C2-10alkenyl, (11) aryl-substituted C1-10 alkyl, (12) aryl or heteroaryl, (13) substituted aryl or heteroaryl, (14) aryl or heteroaryl carbamoyl-substituted C1-10alkyl, (15) C1-10alkylcarbonyl, (16) aryl or heteroaryl carbonyl, (17) ether-substituted C1-10alkyl, (18) thioether-substituted C1-10alkyl, (19) keto-substituted C1-10alkyl, (20) heteroaryl-substituted C1-10 alkyl, (21) carboxylic ester, (22) carboxamide, including substituted and unsubstituted anilide derivatives, (23) urea, (24) C1-10 alkylureido C0-5 alkyl, (25) substituted or unsubstituted arylureidoC0-5 alkyl, (26) C1-10alkanoyloxyC1-2alkyl, (27) C1-10 alkylcarbonylamino, (28) alkanoylamidoalkyl, (29) ether, (30) thio ether, and (31) substituted and unsubstituted aryl- or heteroaryl-ether; and heteroaryl is selected from: piperidinyl, piperizinyl, pyrrolidinyl, pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, indolyl and benzofuranyl.
or a pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein:
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, Ha 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;
R1 is selected from hydrogen and C1-5 alkyl;
R2 is selected from CH3, CH2OR3, and H;
R3 is selected from: C1-5 alkyl;
Z is or ;
A1 is selected from:
(1) -H, (2) keto, (6) carboxy, (7) protected amino, (8) amino, (9) substituted or unsubstituted C2-10alkenyl, (10) aryl-substituted C1-10 alkyl, (11) aryl or heteroaryl, (12) substituted aryl or heteroaryl, (13) aryl or heteroaryl carbamoyl-substituted C1-10alkyl, (14) aryl or heteroaryl carbonyl, (15) ether-substituted C1-10alkyl, (16) thioether-substituted C1-10alkyl, (17) keto-substituted C1-10alkyl, (18) heteroaryl-substituted C1-10 alkyl, (19) carboxylic ester, (20) carboxamide, including substituted and unsubstituted anilide derivatives, (21) urea, (22) C1-10 alkylureido C0-5 alkyl, (23) substituted or unsubstituted heteroaryl or arylureidoC0-5 alkyl, (24) C1-10alkanoyloxyC1-2alkyl, (25) Cl-10 alkylcarbonylamino, (26) alkanoylamidoalkyl (28) ether, (29) thio ether, and (30) substituted and unsubstituted aryl or heteroaryl ether;
A2 is selected from:
(1) -H, (2) keto, (3) protected hydroxy, (4) acetate, (5) hydroxy, (6) carboxy, (7) protected amino, (8) amino, (9) C1-10 alkyl, (10) substituted or unsubstituted C2-10alkenyl, (11) aryl-substituted C1-10 alkyl, (12) aryl or heteroaryl, (13) substituted aryl or heteroaryl, (14) aryl or heteroaryl carbamoyl-substituted C1-10alkyl, (15) C1-10alkylcarbonyl, (16) aryl or heteroaryl carbonyl, (17) ether-substituted C1-10alkyl, (18) thioether-substituted C1-10alkyl, (19) keto-substituted C1-10alkyl, (20) heteroaryl-substituted C1-10 alkyl, (21) carboxylic ester, (22) carboxamide, including substituted and unsubstituted anilide derivatives, (23) urea, (24) C1-10 alkylureido C0-5 alkyl, (25) substituted or unsubstituted arylureidoC0-5 alkyl, (26) C1-10alkanoyloxyC1-2alkyl, (27) C1-10 alkylcarbonylamino, (28) alkanoylamidoalkyl, (29) ether, (30) thio ether, and (31) substituted and unsubstituted aryl- or heteroaryl-ether; and heteroaryl is selected from: piperidinyl, piperizinyl, pyrrolidinyl, pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, indolyl and benzofuranyl.
2. The compound of Claim 1 wherein:
(a) protected hydroxy is selected from: dimethyl-t-butyl silyloxy, trimethylsilyloxy, tri-ethylsilyloxy, tri-isopropylsilyloxy, and triphenylsilyloxy;
(b) protected amino is acetylamino, benzoylamino, and pivaloylamino;
(c) C1-10 alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, 1,5-dimethylhexyl, 6-methylhept-2-yl, and 1-methyl-4-isopropylhexyl;
(d) substituted or unsubstituted C2-10alkenyl is selected from:
phenylmethylene, chlorophenylmethylene, ethoxycarbonylphenylmethylene, carboxyphenylmethylene, (((1,1-dimethylethyl) amino) carbonyl)phenylmethylene, trimethoxyphenyl methylene, methoxyphenylmethylene, methylsulfonylphenylmethylene, biphenylmethylene, nitrophenylmethylene, aminophenylmethylene, acetylaminophenylmethylene, pivaloylaminophenylmethylene, phenoxyphenylmethylene, 2-imidazolyl methylene, 2-thiazolylmethylene, (e) aryl substituted C1-10 alkyl is selected from omega-phenylpropyl and 1-(chlorophenoxy)ethyl;
(f) aryl is selected from phenyl, and naphthyl;
(g) substituted aryl or heteroaryl is selected from phenyl, pyridyl and pyrimidinyl substituted with one to three substituents independently selected from:
(1) -H, (2) -OH, (3) -CH3, (4) -OCH3, (5) -S(O)n-CH3, wherein n is selected from 0, 1, and 2, (6) -CF3, (7) halo, (8) -CHO, (9) CN, (10) phenyloxy, (11) ethyl, (12) t-butyl, (13) OCH2CH3, (14) OC(CH3)3, and (15) -NHR7, wherein R7 is selected from:
-H, -C1-8 alkyl, -C1-6 alkylcarbonyl, -C1-6 alkylsulfonyl, and -C1-6 alkoxycarbonyl, (h) aryl or heteroaryl carbamoyl substituted C1-10 alkyl is selected from 2-(4-pyridyl-carbamoyl)ethyl and 2-phenyl-ethyl;
(i) C1-10alkylcarbonyl is selected from isobutylcarbonyl and isopropylcarbonyl;
(j) aryl or heteroaryl carbonyl is selected from phenylcarbonyl and pyridyl carbonyl;
(k) ether-substituted C1-10alkyl is selected from 1-methoxy-ethyl and 1-ethoxy-ethyl;
(l) thioether-substituted C1-10alkyl is selected from 1-methylthio-ethyl, and 1-ethylthio-ethyl;
(m) keto-substituted C1-10alkyl is 1-keto-ethyl, ketomethyl, 1-ketopropyl, and ketobutyl;
(n) heteroaryl-substituted C1-10 alkyl is omega-(4-pyridyl)-butyl;
(o) carboxylic esters are C1-10 alkylcarboxylic esters selected from carbomethoxy and carboethoxy;
(p) carboxamides are 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, 1-adamantyl carboxamide, 2-adamantyl carboxamide and N-(substituted phenyl) carboxamides wherein the phenyl may be substituted with 1 to 2 substitutents selected from ethyl, methyl, trifluoromethyl or halo (F, C1, Br, I);
(q) C1-10alkanoyloxyC1-2alkyl is selected from acetyloxymethyl, trimethylacetyloxymethyl, and (2-ethylhexanoyloxy)methyl;
(r) urea is t-butylcarbonylamino urea;
(s) C1-10 alkylureido C0-5 alkyl is selected from:
N-t-butylureidomethyl, N-n-propylureidomethyl, N-n-octylureidomethyl, N-isopropylureido, allylureido, (t) substituted or unsubstituted arylureidoC0-5 alkyl is selected from: N-(ethylphenyl) ureidomethyl, N-(chlorophenyl) ureidomethyl, N-phenylureidomethyl, N-(dichlorophenyl) ureidomethyl, N-naphth-2-yl)ureidomethyl, N-thiazol-2-ylureidomethyl, N-thien-2-ylmethylureidomethyl, N-(fluorophenyl)ureido, N-(methoxyphenyl)ureido, and 2-(ethoxyphenyl)ureidomethyl;
(u) C1-10 alkylcarbonylamino is t-butylcarbonylamino;
(v) alkanoylamidoalkyl is selected from:
trimethylacetamidomethyl, carbomethoxyoctanoylamidomethyl, (isobutylphenyl)propionamidomethyl, 8-carboxyoctanoylamidomethyl,bromoheaxanoylamido methyl, hydroxydodecanoyl amidomethyl, 4-nitrophenylprionamidomethyl, isopropylthioacetamidomethyl, benzyloxyacetamidomethyl, carbomethoxyacetamidomethyl, triphenylproprionamidomethyl, cyclohexylacetamiidomethyl, methylcyclohexanecarboxamidomethyl, (3-hydroxy-4,4,4-trichlorobutyramido)methyl, and phenylthio-acetamidomethyl;
(w) ether is selected from ethylene ketal, and C1-8alkyl ether optionally substituted with hydroxy, halo, C1-8alkoxy, C2-6alkenyl, or aryl;
(x) thioether is selected from: C1-8alkylthio, phenylthio, and C1-8 alkylthio substituted with phenyl; and (y) substituted and unsubstituted aryl or heteroaryl ether is selected from thiophenoxy, biphenyloxy, acetamidophenoxy, (3-pyridyl)oxy, chlorophenyloxy, methylphenyloxy, phenoxy, hydroxyphenyloxy, methylsulfonylphenyloxy and pyrimidinyloxy.
(a) protected hydroxy is selected from: dimethyl-t-butyl silyloxy, trimethylsilyloxy, tri-ethylsilyloxy, tri-isopropylsilyloxy, and triphenylsilyloxy;
(b) protected amino is acetylamino, benzoylamino, and pivaloylamino;
(c) C1-10 alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, 1,5-dimethylhexyl, 6-methylhept-2-yl, and 1-methyl-4-isopropylhexyl;
(d) substituted or unsubstituted C2-10alkenyl is selected from:
phenylmethylene, chlorophenylmethylene, ethoxycarbonylphenylmethylene, carboxyphenylmethylene, (((1,1-dimethylethyl) amino) carbonyl)phenylmethylene, trimethoxyphenyl methylene, methoxyphenylmethylene, methylsulfonylphenylmethylene, biphenylmethylene, nitrophenylmethylene, aminophenylmethylene, acetylaminophenylmethylene, pivaloylaminophenylmethylene, phenoxyphenylmethylene, 2-imidazolyl methylene, 2-thiazolylmethylene, (e) aryl substituted C1-10 alkyl is selected from omega-phenylpropyl and 1-(chlorophenoxy)ethyl;
(f) aryl is selected from phenyl, and naphthyl;
(g) substituted aryl or heteroaryl is selected from phenyl, pyridyl and pyrimidinyl substituted with one to three substituents independently selected from:
(1) -H, (2) -OH, (3) -CH3, (4) -OCH3, (5) -S(O)n-CH3, wherein n is selected from 0, 1, and 2, (6) -CF3, (7) halo, (8) -CHO, (9) CN, (10) phenyloxy, (11) ethyl, (12) t-butyl, (13) OCH2CH3, (14) OC(CH3)3, and (15) -NHR7, wherein R7 is selected from:
-H, -C1-8 alkyl, -C1-6 alkylcarbonyl, -C1-6 alkylsulfonyl, and -C1-6 alkoxycarbonyl, (h) aryl or heteroaryl carbamoyl substituted C1-10 alkyl is selected from 2-(4-pyridyl-carbamoyl)ethyl and 2-phenyl-ethyl;
(i) C1-10alkylcarbonyl is selected from isobutylcarbonyl and isopropylcarbonyl;
(j) aryl or heteroaryl carbonyl is selected from phenylcarbonyl and pyridyl carbonyl;
(k) ether-substituted C1-10alkyl is selected from 1-methoxy-ethyl and 1-ethoxy-ethyl;
(l) thioether-substituted C1-10alkyl is selected from 1-methylthio-ethyl, and 1-ethylthio-ethyl;
(m) keto-substituted C1-10alkyl is 1-keto-ethyl, ketomethyl, 1-ketopropyl, and ketobutyl;
(n) heteroaryl-substituted C1-10 alkyl is omega-(4-pyridyl)-butyl;
(o) carboxylic esters are C1-10 alkylcarboxylic esters selected from carbomethoxy and carboethoxy;
(p) carboxamides are 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, 1-adamantyl carboxamide, 2-adamantyl carboxamide and N-(substituted phenyl) carboxamides wherein the phenyl may be substituted with 1 to 2 substitutents selected from ethyl, methyl, trifluoromethyl or halo (F, C1, Br, I);
(q) C1-10alkanoyloxyC1-2alkyl is selected from acetyloxymethyl, trimethylacetyloxymethyl, and (2-ethylhexanoyloxy)methyl;
(r) urea is t-butylcarbonylamino urea;
(s) C1-10 alkylureido C0-5 alkyl is selected from:
N-t-butylureidomethyl, N-n-propylureidomethyl, N-n-octylureidomethyl, N-isopropylureido, allylureido, (t) substituted or unsubstituted arylureidoC0-5 alkyl is selected from: N-(ethylphenyl) ureidomethyl, N-(chlorophenyl) ureidomethyl, N-phenylureidomethyl, N-(dichlorophenyl) ureidomethyl, N-naphth-2-yl)ureidomethyl, N-thiazol-2-ylureidomethyl, N-thien-2-ylmethylureidomethyl, N-(fluorophenyl)ureido, N-(methoxyphenyl)ureido, and 2-(ethoxyphenyl)ureidomethyl;
(u) C1-10 alkylcarbonylamino is t-butylcarbonylamino;
(v) alkanoylamidoalkyl is selected from:
trimethylacetamidomethyl, carbomethoxyoctanoylamidomethyl, (isobutylphenyl)propionamidomethyl, 8-carboxyoctanoylamidomethyl,bromoheaxanoylamido methyl, hydroxydodecanoyl amidomethyl, 4-nitrophenylprionamidomethyl, isopropylthioacetamidomethyl, benzyloxyacetamidomethyl, carbomethoxyacetamidomethyl, triphenylproprionamidomethyl, cyclohexylacetamiidomethyl, methylcyclohexanecarboxamidomethyl, (3-hydroxy-4,4,4-trichlorobutyramido)methyl, and phenylthio-acetamidomethyl;
(w) ether is selected from ethylene ketal, and C1-8alkyl ether optionally substituted with hydroxy, halo, C1-8alkoxy, C2-6alkenyl, or aryl;
(x) thioether is selected from: C1-8alkylthio, phenylthio, and C1-8 alkylthio substituted with phenyl; and (y) substituted and unsubstituted aryl or heteroaryl ether is selected from thiophenoxy, biphenyloxy, acetamidophenoxy, (3-pyridyl)oxy, chlorophenyloxy, methylphenyloxy, phenoxy, hydroxyphenyloxy, methylsulfonylphenyloxy and pyrimidinyloxy.
3. The compound of Claim 1 wherein X is oxygen.
4. The compound of Claim 1 wherein X is sulfur.
5. The compound of Claim 1 wherein Z is:
Z is
Z is
6. The compound of Claim 5 wherein:
R1 is hydrogen, R2 is selected from H and CH3, and A1 is carboxamide.
R1 is hydrogen, R2 is selected from H and CH3, and A1 is carboxamide.
7. The compound of Claim 6 wherein 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, 1-adamantyl carboxamide, 2-adamantyl carboxamide, and N-(substituted phenyl) carboxamides, wherein:
the phenyl may be substituted with 1 to 2 substitutents selected from ethyl, methyl, trifluoromethyl or halo (F, C1, Br, I).
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, 1-adamantyl carboxamide, 2-adamantyl carboxamide, and N-(substituted phenyl) carboxamides, wherein:
the phenyl may be substituted with 1 to 2 substitutents selected from ethyl, methyl, trifluoromethyl or halo (F, C1, Br, I).
8. The compound of Claim 7 wherein carboxamide is selected from: -C(=O)NH-C(CH3)3, -C(=O)NH-C6H5 and -C(=O)NH-(2,5-trifluoromethylphenyl).
9. The compound of Claim 5, wherein:
R1 is CH3, R2 is selected from H and CH3, and A1 is carboxamide.
R1 is CH3, R2 is selected from H and CH3, and A1 is carboxamide.
10. The compound of Claim 9 wherein carboxamide is selected from -C(=O)NH-C6H5 and -C(=O)NH-(2,5-trifluoromethyl-phenyl).
11. The compound of Claim 1 wherein Z is
12. The compound of Claim 11 wherein R1 is H or CH3, R2 is selected from H and CH3, and A2 is selected from: aryl ether and heteroaryl ether, either unsubstituted or substituted with one to three substituents independently selected from:
(1) -H, (2) -OH, (3) -CH3, (4) -OCH3, (5) -S(O)n-CH3, wherein n is selected from 0, 1, and 2, (6) -CF3, (7) halo, (8) -CHO, (9) CN, (10) phenyloxy, (11) ethyl, (12) t-butyl, (13) OCH2CH3, (14) OC(CH3)3, and (15) -NHR7, wherein R7 is selected from:
-H, -C1-8 alkyl, -c1-6 alkylcarbonyl, -C1-6 alkylsulfonyl, and -C1-6 alkoxycarbonyl.
(1) -H, (2) -OH, (3) -CH3, (4) -OCH3, (5) -S(O)n-CH3, wherein n is selected from 0, 1, and 2, (6) -CF3, (7) halo, (8) -CHO, (9) CN, (10) phenyloxy, (11) ethyl, (12) t-butyl, (13) OCH2CH3, (14) OC(CH3)3, and (15) -NHR7, wherein R7 is selected from:
-H, -C1-8 alkyl, -c1-6 alkylcarbonyl, -C1-6 alkylsulfonyl, and -C1-6 alkoxycarbonyl.
13. The compound of Claim 12 wherein substituted and unsubstituted aryl or heteroaryl ether is selected from thiophenoxy, biphenyloxy, acetamidophenoxy, (3-pyridyl)oxy, chlorophenyloxy, methylphenyloxy, phenoxy, hydroxyphenyloxy, methylsulfonyl-phenyloxy and pyrimidinyloxy.
14. The compound selected from:
(1) N-t-Butyl-4-oxa-5.alpha.-androst-1-en-3-one-17.beta.-carboxamide, (2) 7.beta.-Methyl-4-oxa-5.alpha.-cholest-1-en-3-one, (3) 17.beta.-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (4) 17.beta.-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (5) 17.beta.-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (6) 17.beta.-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (7) 17.beta.-(N-tert-amylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one.
(8) 17.beta.-(N-tert-hexylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (9) 17.beta.-(N-isobutylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (10) 17.beta.-(N-tert-octylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (11) 17.beta.-(N-1,1-diethylbutylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (12) 17.beta.-(N-neopentylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (13) 17.beta.-(N-2-adamantylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (14) 17.beta.-(N-1-adamantylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one,, (15) 17.beta.-(N-2-norbornylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (16) 17.beta.-(N-1-norbornylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (17) 17.beta.-(N-phenylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (18) 17.beta.-(N-benzylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (19) 17.beta.-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-7,13-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (20) 17.beta.-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (21) 17.beta.-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (22) 17.beta.-(N-n-octylcarbamoyl)-4-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (23) 17.beta.-(1-methoxyethyl)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3- one, (24) 16.beta.-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one.
(25) 17.beta.-(4-methyl-phenoxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (26) 17.beta.-(1-(3-chlorophenoxy)ethyl)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (27) 17.beta.-(4-methylsulfonyl-phenoxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (28) 17.beta.-(4-chlorophenoxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (29) 17.beta.-(2-pyrimidinyloxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (30) 17.beta.-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (31) N-t-Butyl-4-oxa-5.alpha.-androst-1-en-3-one-16.beta.-carboxamide, (32) 16.beta.-(1,5-dimethylhexyl)-7.beta.-Methyl-4-oxa-5.alpha.-androst-1-en-3-one, (33) 16.beta.-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-androst-1-en-3-one, (34) 16.beta.-(N-tert-amylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (35) 16.beta.-(N-tert-hexylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (36) 16.beta.-(N-isobutylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (37) 16.beta.-(N-tert-octylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (38) 16.beta.-(N-1,1-diethylbutylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (39) 16.beta.-(N-neopentylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (41) 16.beta.-(N-2-adamantylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (41) 16.beta.-(N-1-adamantylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (42) 16.beta.-(N-2-norbornylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (43) 16.beta.-(N-1-norbornylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (44) 16.beta.-(N-phenylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (45) 16.beta.-(N-benzylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (46) 16.beta.-(2,3-bis(trifluoromethyl)phenylcarbarnoyl)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (47) 16.beta.-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (48) 16.beta.-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (49) 16.beta.-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-androst-1-en-3-one, (50) 16.beta.-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-androst-1-en-3-one, (51) 16.beta.-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-androst-1-en-3-one, (52) 16.beta.-(N-n-octylcarbamoyl)-4-methyl-4-oxa-5.alpha.-androst-1 -en-3-one, (53) 16.beta.-(1-methoxyethyl)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (54) 16.beta.-(isopropyl)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (55) 16.beta.-(4-methyl-phenoxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (56) 16.beta.-(1-(3-chlorophenoxy)ethyl)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (57) 16.beta.-(4-methylsulfonyl-phenoxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (58) 16.beta.-(4-chlorophenoxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (59) 16.beta.-(2-pyrimidinyloxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (60) 16.beta.-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (61) N-t-Butyl-4-thia-5.alpha.-androst-1-en-3-one-17.beta.-carboxamide, (62) 7.beta.-Methyl-4-thia-5.alpha.-cholest-1-en-3-one, (63) 17.beta.-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (64) 17.beta.-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (65) 17.beta.-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (66) 17.beta.-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (67) 17.beta.-(N-tert-amylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (68) 17.beta.-(N-tert-hexylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (69) 17.beta.-(N-isobutylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (70) 17.beta.-(N-tert-octylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (71) 17.beta.-(N-1,1-diethylbutylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (72) 17.beta.-(N-neopentylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (73) 17.beta.-(N-2-adamantylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (74) 17.beta.-(N-1-adamantylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (75) 17.beta.-(N-2-norbornylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (76) 17.beta.-(N-1-norbornylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (77) 17.beta.-(N-phenylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (78) 17.beta.-(N-benzylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (79) 17.beta.-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (80) 17.beta.-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (81) 17.beta.-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (82) 17.beta.-(N-n-octylcarbamoyl)-4-methyl-4-thia-5.alpha.-androst-1-en-3-one, (83) 17.beta.-(1-methoxyethyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (84) 17.beta.-(isopropyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (85) 17.beta.-(4-methyl-phenoxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (86) 17.beta.-(1-(3-chlorophenoxy)ethyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (87) 17.beta.-(4-methylsulfonyl-phenoxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (88) 17.beta.-(4-chlorophenoxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (89) 17.beta.-(2-pyrimidinyloxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (90) 17.beta.-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (91) N-t-Butyl-4-thia-5.alpha.-androst-1-en-3-one-16.beta.-carboxamide, (92) 16.beta.-(1,5 -dimethylhexyl)-7.beta.-Methyl-4-thia-5.alpha.-androst-1-en-3-one, (93) 16.beta.-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-androst-1-en-3-one, (94) 16.beta.-(N-tert-amylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (95) 16.beta.-(N-tert-hexylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (96) 16.beta.-(N-isobutylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (97) 16.beta.-(N-tert-octylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (98) 16.beta.-(N-1,1-diethylbutylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (99) 16.beta.-(N-neopentylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (101) 16.beta.-(N-2-adamantylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (101) 16.beta.-(N-1-adamantylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one,, (102) 16.beta.-(N-2-norbornylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (103) 16.beta.-(N-1-norbornylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (104) 16.beta.-(N-phenylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (105) 16.beta.-(N-benzylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (106) 16.beta.-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (107) 16.beta.-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (108) 16.beta.-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (109) 16.beta.-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-androst-1-en-3-one, (110) 16.beta.-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-androst-1-en-3-one, (111) 16.beta.-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-androst-1-en-3-one, (112) 16.beta.-(N-n-octylcarbamoyl)-4-methyl-4-thia-5.alpha.-androst-1-en-3-one, (113) 16.beta.-(1-methoxyethyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (114) 16.beta.-(isopropyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (115) 16.beta.-(4-methyl-phenoxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (116) 16.beta.-(1-(3-chlorophenoxy)ethyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (117) 16.beta.-(4-methylsulfonyl-phenoxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (118) 16.beta.-(4-chlorophenoxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (119) 16.beta.-(2-pyrimidinyloxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one.
(1) N-t-Butyl-4-oxa-5.alpha.-androst-1-en-3-one-17.beta.-carboxamide, (2) 7.beta.-Methyl-4-oxa-5.alpha.-cholest-1-en-3-one, (3) 17.beta.-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (4) 17.beta.-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (5) 17.beta.-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (6) 17.beta.-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (7) 17.beta.-(N-tert-amylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one.
(8) 17.beta.-(N-tert-hexylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (9) 17.beta.-(N-isobutylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (10) 17.beta.-(N-tert-octylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (11) 17.beta.-(N-1,1-diethylbutylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (12) 17.beta.-(N-neopentylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (13) 17.beta.-(N-2-adamantylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (14) 17.beta.-(N-1-adamantylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one,, (15) 17.beta.-(N-2-norbornylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (16) 17.beta.-(N-1-norbornylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (17) 17.beta.-(N-phenylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (18) 17.beta.-(N-benzylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (19) 17.beta.-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-7,13-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (20) 17.beta.-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (21) 17.beta.-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (22) 17.beta.-(N-n-octylcarbamoyl)-4-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (23) 17.beta.-(1-methoxyethyl)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3- one, (24) 16.beta.-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one.
(25) 17.beta.-(4-methyl-phenoxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (26) 17.beta.-(1-(3-chlorophenoxy)ethyl)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (27) 17.beta.-(4-methylsulfonyl-phenoxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (28) 17.beta.-(4-chlorophenoxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (29) 17.beta.-(2-pyrimidinyloxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (30) 17.beta.-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (31) N-t-Butyl-4-oxa-5.alpha.-androst-1-en-3-one-16.beta.-carboxamide, (32) 16.beta.-(1,5-dimethylhexyl)-7.beta.-Methyl-4-oxa-5.alpha.-androst-1-en-3-one, (33) 16.beta.-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-androst-1-en-3-one, (34) 16.beta.-(N-tert-amylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (35) 16.beta.-(N-tert-hexylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (36) 16.beta.-(N-isobutylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (37) 16.beta.-(N-tert-octylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (38) 16.beta.-(N-1,1-diethylbutylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (39) 16.beta.-(N-neopentylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (41) 16.beta.-(N-2-adamantylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (41) 16.beta.-(N-1-adamantylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (42) 16.beta.-(N-2-norbornylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (43) 16.beta.-(N-1-norbornylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (44) 16.beta.-(N-phenylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (45) 16.beta.-(N-benzylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (46) 16.beta.-(2,3-bis(trifluoromethyl)phenylcarbarnoyl)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (47) 16.beta.-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (48) 16.beta.-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (49) 16.beta.-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-androst-1-en-3-one, (50) 16.beta.-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-androst-1-en-3-one, (51) 16.beta.-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-androst-1-en-3-one, (52) 16.beta.-(N-n-octylcarbamoyl)-4-methyl-4-oxa-5.alpha.-androst-1 -en-3-one, (53) 16.beta.-(1-methoxyethyl)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (54) 16.beta.-(isopropyl)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (55) 16.beta.-(4-methyl-phenoxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (56) 16.beta.-(1-(3-chlorophenoxy)ethyl)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (57) 16.beta.-(4-methylsulfonyl-phenoxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (58) 16.beta.-(4-chlorophenoxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (59) 16.beta.-(2-pyrimidinyloxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (60) 16.beta.-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (61) N-t-Butyl-4-thia-5.alpha.-androst-1-en-3-one-17.beta.-carboxamide, (62) 7.beta.-Methyl-4-thia-5.alpha.-cholest-1-en-3-one, (63) 17.beta.-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (64) 17.beta.-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (65) 17.beta.-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (66) 17.beta.-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (67) 17.beta.-(N-tert-amylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (68) 17.beta.-(N-tert-hexylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (69) 17.beta.-(N-isobutylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (70) 17.beta.-(N-tert-octylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (71) 17.beta.-(N-1,1-diethylbutylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (72) 17.beta.-(N-neopentylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (73) 17.beta.-(N-2-adamantylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (74) 17.beta.-(N-1-adamantylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (75) 17.beta.-(N-2-norbornylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (76) 17.beta.-(N-1-norbornylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (77) 17.beta.-(N-phenylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (78) 17.beta.-(N-benzylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (79) 17.beta.-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (80) 17.beta.-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (81) 17.beta.-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (82) 17.beta.-(N-n-octylcarbamoyl)-4-methyl-4-thia-5.alpha.-androst-1-en-3-one, (83) 17.beta.-(1-methoxyethyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (84) 17.beta.-(isopropyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (85) 17.beta.-(4-methyl-phenoxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (86) 17.beta.-(1-(3-chlorophenoxy)ethyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (87) 17.beta.-(4-methylsulfonyl-phenoxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (88) 17.beta.-(4-chlorophenoxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (89) 17.beta.-(2-pyrimidinyloxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (90) 17.beta.-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (91) N-t-Butyl-4-thia-5.alpha.-androst-1-en-3-one-16.beta.-carboxamide, (92) 16.beta.-(1,5 -dimethylhexyl)-7.beta.-Methyl-4-thia-5.alpha.-androst-1-en-3-one, (93) 16.beta.-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-androst-1-en-3-one, (94) 16.beta.-(N-tert-amylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (95) 16.beta.-(N-tert-hexylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (96) 16.beta.-(N-isobutylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (97) 16.beta.-(N-tert-octylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (98) 16.beta.-(N-1,1-diethylbutylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (99) 16.beta.-(N-neopentylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (101) 16.beta.-(N-2-adamantylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (101) 16.beta.-(N-1-adamantylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one,, (102) 16.beta.-(N-2-norbornylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (103) 16.beta.-(N-1-norbornylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (104) 16.beta.-(N-phenylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (105) 16.beta.-(N-benzylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (106) 16.beta.-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (107) 16.beta.-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (108) 16.beta.-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (109) 16.beta.-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-androst-1-en-3-one, (110) 16.beta.-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-androst-1-en-3-one, (111) 16.beta.-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-androst-1-en-3-one, (112) 16.beta.-(N-n-octylcarbamoyl)-4-methyl-4-thia-5.alpha.-androst-1-en-3-one, (113) 16.beta.-(1-methoxyethyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (114) 16.beta.-(isopropyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (115) 16.beta.-(4-methyl-phenoxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (116) 16.beta.-(1-(3-chlorophenoxy)ethyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (117) 16.beta.-(4-methylsulfonyl-phenoxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (118) 16.beta.-(4-chlorophenoxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (119) 16.beta.-(2-pyrimidinyloxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one.
15. The compound of Claim 14 selected from:
(1) N-t-Butyl-4-oxa-5.alpha.-androst-1-en-3-one-17.beta.-carboxamide, (2) 16.beta.-(4-chlorophenoxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, and (3) 17.beta.(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-androst-1-en-3-one, (4) 17.beta.-(N-phenylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one,, (5) 17.beta.-(N-benzylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (6) 17.beta.-(1-methoxyethyl)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (7) 16.beta.-(2-pyrimidinyloxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one.
(8) 17.beta.-(4-methylphenoxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (9) 17.beta.-(1-(3-chlorophenyoxy)ethyl)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (10) 17.beta.-(4-methylsulfonyl-phenoxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (11) 17.beta.-(methyl-phenoxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (12) 17.beta.-(4-chlorophenoxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (13) 17.beta.-(2-pyrimidinyloxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (14) 17.beta.-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (15) 16.beta.-(4-methyl-phenoxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (16) 16.beta.-(1-(3-chlorophenoxy)ethyl)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (17) 16.beta.-(4-methylsulfonyl-phenoxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (18) 16.beta.-(4-chlorophenoxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (19) 16.beta.-(2-pyrimidinyloxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (20) N-t-Butyl-4-thia-5.alpha.-androst-1-en-3-one-17.beta.-carboxamide, (21) 7.beta.-Methyl-4-thia-5.alpha.-cholest-1-en-3-one, (22) 17.beta.-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-androst-1-en-3-one, (23) 17.beta.-(N-phenylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (24) 17.beta.-(N-benzylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (25) 17.beta.-(1-methoxyethyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (26) 17.beta.-(isopropyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (27) 17.beta.-(4-methylphenoxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (28) 17.beta.-(1-(3-chlorophenyoxy)ethyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (29) 17.beta.-(4-methylsulfonyl-phenoxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (30) 17.beta.-(methyl-phenoxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (31) 17.beta.-(4-chlorophenoxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (32) 17.beta.-(2-pyrimidinyloxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (33) 17.beta.-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (34) 16.beta.-(4-methyl-phenoxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (35) 16.beta.-(1-(3-chlorophenoxy)ethyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (36) 16.beta.-(4-methylsulfonyl-phenoxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one,
(1) N-t-Butyl-4-oxa-5.alpha.-androst-1-en-3-one-17.beta.-carboxamide, (2) 16.beta.-(4-chlorophenoxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, and (3) 17.beta.(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-oxa-androst-1-en-3-one, (4) 17.beta.-(N-phenylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one,, (5) 17.beta.-(N-benzylcarbamoyl)-4-oxa-5.alpha.-androst-1-en-3-one, (6) 17.beta.-(1-methoxyethyl)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (7) 16.beta.-(2-pyrimidinyloxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one.
(8) 17.beta.-(4-methylphenoxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (9) 17.beta.-(1-(3-chlorophenyoxy)ethyl)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (10) 17.beta.-(4-methylsulfonyl-phenoxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (11) 17.beta.-(methyl-phenoxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (12) 17.beta.-(4-chlorophenoxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (13) 17.beta.-(2-pyrimidinyloxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (14) 17.beta.-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (15) 16.beta.-(4-methyl-phenoxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (16) 16.beta.-(1-(3-chlorophenoxy)ethyl)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (17) 16.beta.-(4-methylsulfonyl-phenoxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (18) 16.beta.-(4-chlorophenoxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (19) 16.beta.-(2-pyrimidinyloxy)-7.beta.-methyl-4-oxa-5.alpha.-androst-1-en-3-one, (20) N-t-Butyl-4-thia-5.alpha.-androst-1-en-3-one-17.beta.-carboxamide, (21) 7.beta.-Methyl-4-thia-5.alpha.-cholest-1-en-3-one, (22) 17.beta.-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-androst-1-en-3-one, (23) 17.beta.-(N-phenylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (24) 17.beta.-(N-benzylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one, (25) 17.beta.-(1-methoxyethyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (26) 17.beta.-(isopropyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (27) 17.beta.-(4-methylphenoxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (28) 17.beta.-(1-(3-chlorophenyoxy)ethyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (29) 17.beta.-(4-methylsulfonyl-phenoxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (30) 17.beta.-(methyl-phenoxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (31) 17.beta.-(4-chlorophenoxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (32) 17.beta.-(2-pyrimidinyloxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (33) 17.beta.-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (34) 16.beta.-(4-methyl-phenoxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (35) 16.beta.-(1-(3-chlorophenoxy)ethyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one, (36) 16.beta.-(4-methylsulfonyl-phenoxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one,
16. A method of inhibiting 5.alpha.-reductase or the isozymes thereof, comprising the step of administering to a mammal in need of such inhibition a therapeutically effective amount of a compound of Claim 1.
17. A method for treating the hyperandrogenic conditions of acne vulgaris, androgenic alopecia, female hirsutism, benign prostatic hyperplasia, prostatitis, and the treatment and/or prevention of prostatic cancer comprising the step of administering to a human in need of such treatment a therapeutically effective amount of a compound of Claim 1.
18. The method of Claim 17 wherein the androgenic alopecia is male pattern baldness.
19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 1.
20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 1 and finasteride or a pharmaceutically acceptable salt thereof.
21. The pharmaceutical composition of Claim 20, additionally comprising an .alpha.l or an .alpha.la adrenergic receptor antagonist.
22. The pharmaceutical composition of Claim 20, additionally comprising an antiandrogen selected from flutamide, spironolactone and casodex.
23. A pharmaceutical composition comprising a pharmaceutically acceptable carrier adapted for topical application and a therapeutically effective amount of a compound of Claim 1.
24. The pharmaceutical composition of Claim 23 additionally comprising minoxidil or a pharmaceutically acceptable salt thereof.
25. The pharmaceutical composition of Claim 23 additionally comprising retinoic acid or an ester or amide derivative thereof.
26. The pharmaceutical composition of Claim 23 additionally comprising benzoyl peroxide.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US600195P | 1995-10-26 | 1995-10-26 | |
| US60/006,001 | 1995-10-26 | ||
| GB9602905.3 | 1996-02-13 | ||
| GBGB9602905.3A GB9602905D0 (en) | 1996-02-13 | 1996-02-13 | 4-oxa and 4-thia steroids |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2233966A1 true CA2233966A1 (en) | 1997-05-01 |
Family
ID=26308677
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002233966A Abandoned CA2233966A1 (en) | 1995-10-26 | 1996-10-22 | 4-oxa and 4-thia steroids |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0858455A4 (en) |
| JP (1) | JPH11513981A (en) |
| AU (1) | AU713582B2 (en) |
| CA (1) | CA2233966A1 (en) |
| WO (1) | WO1997015564A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2462456C (en) * | 2001-10-03 | 2010-05-04 | Merck & Co., Inc. | Androstane 17-beta-carboxamides as androgen receptor modulators |
| AU2004238238C1 (en) * | 2003-05-07 | 2010-01-14 | Merck Sharp & Dohme Corp. | Androgen receptor modulators and methods of use thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3644421A (en) * | 1968-12-02 | 1972-02-22 | Syntex Corp | 4-oxa-3-keto-delta**1-pregnene derivatives |
| 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 |
-
1996
- 1996-10-22 AU AU74644/96A patent/AU713582B2/en not_active Ceased
- 1996-10-22 WO PCT/US1996/016883 patent/WO1997015564A1/en not_active Application Discontinuation
- 1996-10-22 JP JP9516711A patent/JPH11513981A/en active Pending
- 1996-10-22 EP EP96936811A patent/EP0858455A4/en not_active Withdrawn
- 1996-10-22 CA CA002233966A patent/CA2233966A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| AU713582B2 (en) | 1999-12-02 |
| EP0858455A1 (en) | 1998-08-19 |
| EP0858455A4 (en) | 2000-04-12 |
| WO1997015564A1 (en) | 1997-05-01 |
| AU7464496A (en) | 1997-05-15 |
| JPH11513981A (en) | 1999-11-30 |
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