AP459A

AP459A - Substituted 6-azaandrostenones.

Info

Publication number: AP459A
Application number: APAP/P/1993/000599A
Authority: AP
Inventors: Robert Carl Andrews; Cynthia Markert Cribbs; Stephen Vernon Frye; Curt Dale Haffner; Patrick Reed Maloney
Original assignee: Glaxo Wellcome Inc
Priority date: 1992-12-18
Filing date: 1993-12-13
Publication date: 1996-02-14
Also published as: LV10958A; IS4106A; AU6015094A; ATE172738T1; SI9300665A; FI953009A0; NO952402L; LV10958B; IL108073A0; MX9308015A; BG99729A; CZ157695A3; EP0674651A1; HUT72083A; JPH08504825A; DE69321849D1; FI953009A; AU673899B2; TW293824B; NZ261415A

Abstract

The present invention felates to certain substituted 17 substituted carbonyl-6-azaandrost-4-en-ones of formula (1): wherein r1 and r2 1)are independently hydrogen or lower alkyl and the bond between the carbons bearing r1 and r2 is a single or a double bond, or ii)taken together are a -ch2- group forming a cycloprane ring, and the bond between the carbons bearing r1 and r2 is a single bond; r3 is preferably hydrogen, halogen or lower alkyl, r4 is preferably hydrogen of lower alkyl, x is preferably ch2, y is preferably hydrogen and z is preferably c0nr14r15 and r15 are a variety of organics groups, and pharmaceutically acceptable salts thereof, preparation, medical use and pharmaceutical formulations.

Description

SUBSTITUTED 6-AZAANDROSTENONES

The present invention relates to certain substituted 17p-substituted -6azaandrost-4-en-3-ones and their use as 5a-testosterone reductase inhibitors.

BACKGROUND OF THE INVENTION

Androgens are responsible for many physiological functions in both males and females. Androgen action is mediated by specific intracellular hormone receptors expressed in androgen responsive cells. Testosterone, the major circulating androgen, is secreted by Leydig cells of the testes under the stimulation of pituitary-derived luteinizing hormone (LH). However, reduction of the 4,5 double bond of testosterone to dihydrotestosterone (DHT) is required in some target tissues, such as prostate and skin, for androgen action. Steroid

5a-reductases in target tissues catalyze conversion of testosterone to DHT in an NADPH dependent fashion as shown in Scheme A.

SCHEME A

The requirement for DHT to act as an agonist in these target tissues has been highlighted by studies of steroid 5a-reductase deficient individuals who have vestigial prostate glands and do not suffer from acne vulgaris or male pattern baldness (see McGinley, J. et al., The New England J. of Medicine, 300, 1233 (1979)). Thus, inhibition of the conversion of testosterone to DHT in these target tissues is anticipated to be useful in the treatment of a variety of

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-2androgen responsive diseases, e.g., benign prostatic hyperplasia, prostate cancer, acne, male pattern baldness, and hirsutism.

Additionally, it has recently been discovered that two isozymes of 5a-reductase exist in humans which differ in their tissue distribution, affinity for testosterone, pH profile and sensitivity to inhibitors (see Russell, D.W. et al., J. Clin. Invest., 89, 293 (1992); Russell, D.W. et al., Nature, 354, 159 (1991)). The steroid 5areductase deficient individuals studied by Imperato-McGinley are deficient in the type 2, 5a-reductase enzyme (Russell, D.W. et al., J. Clin. Invest., 90, 799 (1992); Russell, D.W. et al., New England J. Med., 327, 1216 (1992)), which is the predominant isozyme present in the prostate, while the type 1 isozyme is predominant in the skin. The relative value of isozyme specific and dual inhibitors of the two isozymes of 5a-reductase will depend upon the type of disease treated (benign prostatic hyperplasia, prostate cancer, acne, male pattern baldness, or hirsutism) as well as the stage of the disease (prevention versus treatment) and the anticipated side-effects in the intended patients (for example treatment of acne vulgaris in pubescent males).

Because of their valuable therapeutic potential, testosterone 5a-reductase inhibitors [hereinafter 5a-reductase inhibitors] have been the subject of active research worldwide. For example, see: Hsia, S. and Voight, W., J. Invest. Derm., 62, 224 (1973); Robaire, B. et al., J. Steroid Biochem., 8, 307 (1977); Petrow, V. et al., Steroids, 38, 121 (1981); Liang, T. et al., J. Steroid Biochem., 19, 385 (1983); Holt, D. et al., J. Med. Chem., 33, 937 (1990); U.S. Patent No.

4,377,584, U.S. Patent No. 4,760,071 and U.S. Patent No. 5,017,568. Two particularly promising 5a-reductase inhibitors are MK-906 (Merck), known by the generic name, finasteride, and marketed under the trademark, Proscar; and SKF-105657 (SmithKline Beecham), shown in Scheme B.

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finasteride

SKF105657

SCHEME Β

The potent inhibition of bovine adrenal and porcine granulosa cell 3p-hydroxy5 A⁵-steroid dehydrogenase / 3-keto-A⁵-steroid isomerase (3pHSD) by the 4azasteroid derivative, 4-MA, shown in Scheme C and not by the drug finasteride (Tan, C.H.; Fong, C.Y.; Chan, W.K. Biochem. Biophys. Res. Comm., 144, 166 (1987) and Brandt, M.; Levy, M.A. Biochemistry, 28,140 (1989)) along with the critical role of 3PHSD in steroid biosynthesis (Potts, G.O. et al., Steroids, 32,

257 (1978)), suggests that optimal inhibitors of type 1 and 2 5a-reductase should also be selective versus human adrenal 33HSD.

SCHEMEC

The importance of selectivity in 5a-reductase inhibitors has been emphasized by reports of hepatotoxicity in certain 4-azasteroids such as 4-MA (McConnell, J.D. The Prostate Suppl., 3, 49 (1990) and Rasmusson, G.H. et al. J. Med. Chem. ,27, 1690(1984)).

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-4SUMMARY OF THE INVENTION

One aspect of the present invention are the compounds of formula (I),

wherein

R¹ and R²

i) are independently hydrogen or lower alkyl and the bond between the carbons bearing R¹ and R² is a single or a double bond, or ii) taken together are a -CH2- group forming a cyclopropane ring, and the bond between the carbons bearing R¹ and R² is a single bond;

r3 is, hydrogen, -Alk¹-H (optionally substituted with one or more halogens), lower cycloalkyl, lower cycloalkyl-lower alkyl), halogen, -(Alk¹)n-CO2H, -(Alk¹)n-CO₂R⁷, -(Alk¹)n-Ar¹, -(Alk¹)n-CONR8R9, -(Alk¹)n-NR8R9, -(Alk¹)n-S(O)_rR⁷, -(Alk¹)n-CN, -(Alk¹)-OH, -(Alk¹)n-COR⁷; or -(Alk¹)_n-OR⁷;

wherein

Aik¹ is lower alkylene, lower alkenylene or lower alkynylene, n is 0 or 1, r is 0, 1 or 2,

R⁷ is -Alk¹-H, -(Aik¹ )_n-Ar¹ or lower cycloalkyl,

R⁸ and R⁹ are independently hydrogen, -Alk¹-H or lower cycloalkyl,

Ar¹ is a homocyclic aryl group of 6 to 14 carbons;

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-5R⁴ is, hydrogen, -Alk¹-H, lower cycloalkyl, lower cycloalkyl-lower alkyl, -(Alk¹)n-S(O)rR⁷, -(Aik¹ )n-phthalimidyl, -(Alk¹)-CO2H, -(Alk¹)n-CC>2R⁷, -(Alk¹)n-COR⁷> -(Alk¹)n-Ar¹, -(Alk¹)n-CONR³R³, -(Alk¹)n-NR8R9, -(Alk¹)n-OH or -(Alk¹)_n-OR⁷;

Xis,

JCR^,2R¹³)_q wherein

R¹ R¹¹, R¹² and R¹³ are independently hydrogen or lower alkyl, p and q are independently either 0 or 1;

and,

i) Y is hydrogen or hydroxy and Z is -(Alk²)n-COR⁵, -(Alk²)n-CO₂R⁵, -(Alk²)_n-COSR⁵,

-(Alk²)_n-CONR¹⁴R¹5,-(Alk²)-OCO2R⁵,-(Alk²)-OCOR5,

-(Alk²)-OCONR¹⁴R¹³, -(Alk²)-OR⁵, -(Alk²)-NR⁵’COR⁵, -(Alk²)-NR5'CO2R⁵, -(Alk²)-NR⁵CONR¹⁴R¹⁵, -(Alk²)n-CONR⁵NR¹⁴R¹⁵, -(Alk²)n-CONR⁵CONR¹⁴R¹5, -(Alk²)-NR⁵CSNR¹⁴R¹⁵ or -(Alk²)n-CONR5CSNR¹⁴R¹5;

wherein

Aik² is (C-j-12) alkylene, (C2-12) alkenylene or (C2-12) alkynylene,

R5 and R⁵’ are independently hydrogen, -Alk¹-H (optionally substituted independently with one or more CO2H, CO2R⁷, Ar², Ar³ or cyano groups) -(Alk¹)_n-(lower cycloalkyl (optionally substituted independently with one or more -Alk¹-H groups)), adamantyl, norbornyl, Ar², Ar³, (lower cycloalkyl)-Ar² or (lower cycloalkyl)-Ar³;

wherein

Ar² is a homocyclic aromatic group of 6 to 14 carbon ring atoms (optionally substituted independently with one or more -Alk²-H (optionally substituted independently with one or more halogens), -(Alk¹)nCOR⁷- -(Alk¹)n-OH,

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-6-(Alk¹)n-0R¹6, -(Aik*· )n-Ar³, -(Alk¹)n-CO2H, -(Alk¹)n-CO₂R⁷, S(O)rR⁷, NR⁸S(O)rR¹⁶, NR8r9, CONR³r9, lower cycloalkyl, lower alkoxy, -(Alk¹)_n-Ar¹(optionally substituted with one or more -Alk¹-H or halogen), methylenedioxy, ethylenedioxy, morpholino, thiomorpholino, cyano, nitro or halogens); wherein

R¹⁶ is -Alk¹-H (optionally substituted independently with one or more halogens), lower cycloalkyl (optionally substituted independently with one or more halogens, or -Alk¹-H (optionally substituted independently with one or more halogens)) or -(Alk¹)_n-Ar¹ (wherein Ar¹ is optionally substituted independently with one or more, lower alkoxy, cyano groups, halogens or -Alk¹-H (optionally substituted independently with one or more halogens));

Ar³ is an aromatic group of 5 to 14 ring atoms, at least one of which is Ο, N or S, (optionally substituted independently with one or more -Alk¹-H (optionally substituted independently with one or more halogens), lower cycloaikyl, lower alkoxy, CO2H, CO2R⁷, -(Alk¹)_n-Ar¹, cyano or halogen);

R¹⁴ and R¹⁵ are,

a) independently, hydroxy, hydrogen, -Aik²- H, lower alkoxy,

-(Alk¹)n-adamantyl, -(Alk¹)n-myrantyl, -(Alk¹)n-norbornyl, -(Alk¹)n-fluorenyl, -(Alk¹)n-fluorenonyl, -(Alk¹)n-indanyl (optionally substituted with one or more -Aik¹- H), -Aik¹- H (optionally substituted independently with one or more, halogens, cyano, cycloalkyl, SR5, COr5, CONR³R⁷, NRS'CORS, NR⁵'CO₂R5, NRS'CONHR³, COgRS, OR5, Ar² or Ar³), Ar² or Ar³ or a saturated C4-18 bicyclic ring or C3.11 saturated ring, optionally containing an oxygen or sulfur atom (said rings optionally substituted independently with one or more cyano, R¹⁶, Ar², Ar³);

b) alkylene groups (optionally substituted with one or more R⁷ groups, taken together with the linking nitrogen to form a 4 to 8 atom heterocyclic group)

wherein;

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-7Het represents -Ο-, -CH2-, -S(0)_r, -(NH)- or -(N(Alk¹-H))-;

with the proviso that when Z is

-(Alk²)n-COR⁵, -(Alk²)n-CO2R⁵ or -(Alk²)_n-CO-thiopyridyl and

R⁵ is hydrogen, -Alk¹-H, lower cycloalkyl, or adamantyl or when Z is

-(Alk²)_n-CONR¹⁴R¹⁵ and

R¹⁴ and R¹⁵ are

a) independently hydrogen, -Alk²-H, lower cycloalkyl, lower alkoxy, adamantyl, Ar¹, benzyl, diphenylmethyl, triphenylmethyl or -(Aik¹ )_n-norbornyl;

or

b) carbon atoms, optionally substituted with one or more lower alkyl groups, taken together with the linking nitrogen to form a 4 to 8 atom heterocylic ring as herein before defined,

Y is hydroxy; or ii) Y is hydrogen and Z is

OR⁵, OCOR⁵, OCONR¹⁴R¹⁵, NR⁵'COR⁵, NR⁵'CO2R⁵, NR⁵CONR¹⁴R¹⁵ or NR⁵CSR¹⁴R¹⁵; and iii) Y and Z taken together are =0, =CH-(Alk¹)n-COR⁵, =CH-(Alk¹)n-CO₂R⁵ or =CH-(Alk¹)_n-CONR¹⁴R¹⁵;

R⁶ is, hydrogen or methyl;

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-8and pharmaceutically acceptable salts thereof.

Other aspects of the invention are:

1. A method of inhibiting testosterone-5a-reductases comprising contacting testosterone-5a-reductases with a compound of formula (I).

2. A method of treatment of androgen responsive or mediated disease comprising administering an effective amount of a compound of formula (I) to a patient in need of such treatment.

3. Pharmaceutical formulations containing a compound of formula (I) as an active ingredient. Novel chemical intermediates used in the synthesis, as taught herein, of the compounds of formula (I) are also within the scope of the present invention.

4. A method of treatment of androgen responsive or mediated disease comprising administering an effective amount of a compound of formula (I) to a patient in need of such treatment in combination with an antiandrogen such as flutamide.

5. A method of treatment of benign prostatic hyperplasia comprising administering an effective amount of a compound of formula (I) to a patient in need of such treatment in combination with an alpha 1 adrenergic receptor blocker (e.g. terazosin).

6. A method of treatment of benign prostatic hyperplasia comprising administering an effective amount of a compound of formula (I) to a patient in need of such treatment in combination with an anti-estrogen.

DETAILED DESCRIPTION OF THE INVENTION

As used herein the term lower in reference to alkyl and alkoxy means 1-6 carbons, straight or branched chain, e.g., methyl, ethyl, propyl, butyl, pentyl and hexyl; and methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy respectively.

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-9In reference to alkenyl or alkynyl lower means 2-7 carbons, straight or branched chain e.g., ethenyl, propenyl, butenyl, pentenyl and hexenyl; and ethynyl, propynyl, butynyl, pentynyl and hexynyl respectively. In reference to cycloalkyl lower means 3-7 carbons, i.e., cyclopropyl, cyclobutyl, cyciopentyl, cyclohexyl, and cycloheptyl, preferably 3-6 carbons. The term lower cycloalkyl-lower alkyl means a lower alkyl bearing a lower cycloalkyl, e.g., cyclopropylmethyl which may also be named methylene-cyclopropyl. Preferably -Alk^- is the same as -Aik¹

The term alkanoyl of 2-6 carbons refers to alkyl, straight or branched, carboxylic acid groups with a total of 2-6 carbons attached to the structure of formula (I) at a carbon of the alkyl portion of the group, e.g., -CH2COOH, (CH₂)2COOH, -(CH₂)3COOH, -(CH^COOH and -(CH₂)5COOH. The term halogen means fluoro, chloro, bromo and iodo moieties. Where -(Alk¹)-H is optionally substituted with one or more halogens, the fluoro moiety is preferable, e.g., trifluoromethyl.

The term aromatic group includes, but is not limited to, phenyl, napthyl, anthryl, thiophenyl, isothiazolyl, pyrrolyl, imidazolyl, oxazolyl, isoxaolyl, quinolyl, isoquinolyl, indanyl, pyridyl and furyl. The term aryl means homocylic aromatic groups having 6 to 14 carbons, e.g., phenyl, naphthyl and anthryl.

Where R^1A and R¹^ are carbon atoms, optionally substituted with one or more lower alkyl groups, taken together with the linking nitrogen form a 4 to 8 atom heterocyclic group, such groups which may be formed include, but are not limited to, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl each optionally substituted with one or more lower alkyl groups.

Examples of C3-11 saturated rings containing an oxygen or sulfur atom include, but are not limited to tetrahydropyran and tetrahydrothiopyran. An example of a saturated C4-18 bicyclic ring is bicyclononyl.

Unless specified otherwise, attachment of heteroaromatic or non-aromatic heterocyclic groups containing nitrogen and/or sulfur may be through any

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-10carbon or nitrogen. However, if the heterocyclic group is non-aromatic, the preferred position of attachment is through the nitrogen. Further, if the group is a six member, hetero-aromatic ring, attachment through a carbon atom is preferred.

Preferably R³ is hydrogen, halogen, lower alkyl, lower cycloalkyl or lower cycloalkyl-lower alkyl, especially hydrogen, halogen or lower alkyl.

R⁴ is preferably hydrogen, lower alkyl, lower cycloalkyl or lower cycloalkyl-lower alkyl, especially hydrogen or lower alkyl.

X is preferably -CH2-.

Preferably Y is hydrogen and Z is -(Alk²)n-COR³, -(Alk²)n-CONR¹⁴R¹³, (Alk2)-OCO2R⁵, - (Alk²)-OCOR5, -(Alk²)-NR5'COR⁵, -(Alk²)nCONR5nr1⁴r15, -(A^-NRScONR^rIS, Or -(Alk²)n-CONR5CONR1⁴R15, especially -COR5, -CONR¹⁴R¹5 -CH2OCO2R⁵, -CH2OCOR5, -CH2NR5'COR⁵, -CONR⁵NR¹⁴R¹5 -CH2NR5CONR1⁴R15 _or-CONR5cONR¹⁴R¹5.

Compounds wherein Y is hydrogen and Z is -CONR¹⁴R¹5 are particularly of interest.

Ar¹ is preferably a phenyl group, and Ar² is preferably a phenyl group optionally substituted independently with one or more -Alk²-H (optionally substituted independently with one or more halogens), -OR¹³, -S(O)rR⁷, Ar¹, methylenedioxy, ethylenedioxy, morpholino, thiomorpholino, cyano, nitro or halogen groups.

Preferably R^-*⁴ is hydrogen or hydroxy, and R¹® is hydrogen, lower cycloalkyl (optionally substituted independently with one or more R⁷ or Ar² groups), (Alk¹)-adamantyl, -(Alk¹)n-myrantyl, -(Alk¹)n-norbomyl, -(Alk¹)n-fluorenyl, (Alkl)n-indanyl, -Alk¹-H (optionally substituted independently with one or more

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-11R¹⁴ and R¹² are carbon atoms, optionally substituted with one or more R⁷groups, taken together with the linking nitrogen to form a 5 to 7 atom heterocyclic group

wherein Het represents -CH2-.

Preferably Ar² is an aromatic group of five or six ring atoms, at least one of which is Ο, N or S, optionally substituted independently with one or more Aik¹ H groups, especially optionally substituted pyrrolyl, thienyl, furyl and pyridyl groups.

r5 is preferably hydrogen, lower alkyl optionally substituted independently with one or more Ar² groups, (lower alkyl)n-lower cycloalkyl, menthyl, adamantyl, norbornyl or Ar².

A particular group of the compounds of formula (I) are the compounds wherein:

R¹ and R²

R² is, hydrogen, -Alk¹-H (optionally substituted with one or more halogens), lower cycloalkyl, lower cycloalkyl-lower alkyl), halogen, -(Alk¹)n-CO2H, -(Alk¹)n-CO₂R⁷, -(Alk¹)n-Ar¹, -(Alk¹)n-CONR²R², -(Alk¹)n-NR8R9, -(Alk¹)n-S(O)_rR⁷, -(Alk¹)n-CN, -(Alk¹)-OH, -(Alk¹)n-COR⁷; or -(Alk¹)_n-OR⁷; wherein

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-12R⁷ is -Alk¹-H, -(Alk¹)_n-Ar¹ or lower cycloalkyl,

R⁸ and R⁹ are independently hydrogen, -Alk¹-H or lower cycloalkyl,

Ar¹ is a homocyclic aryl group of 6 to 14 carbons:

R⁴ is, hydrogen, -Alk¹-H, lower cycloalkyl, lower cycloalkyl-lower alkyl, -(Alk¹)n-S(O)rR⁷, -(Aik¹ )n-phthalimidyl, -(Alk¹)-CO2H, -(Alk¹)n-CO₂R⁷-(Alk¹)n-COR⁷- -(Alk¹)n-Ar¹, -(Alk¹)n-CONR⁸R⁹, -(Alk¹)n-NR⁸R⁹, -(Alk¹)n-OH or -(Alk¹)n-OR⁷;

X is,

JCR ¹² R'³)_q wherein

R¹⁹, R¹¹, R¹²and R¹⁸ are independently hydrogen or lower alkyl, p and q are independently either 0 or 1;

and,

i) Y is hydrogen or hydroxy and

Z is -(Alk²)n-COR5, -(Alk²)n-CO₂R⁵, -(Alk²)_n-COSR⁸,

-(Alk²)_n-CONR¹⁴R¹⁵,-(Alk²)-OCO2R⁵,-(Alk²)-OCOR⁵,

-(Alk²)-OCONR¹⁴R¹⁸, -(Alk²)-OR⁸, -(Alk²)-NR5'COR⁸, -(Alk^-NRS'CC^R⁵, -(Alk²)-NR⁵CONR¹⁴R¹⁵, -(Alk²)n-CONR⁸NR¹⁴R¹⁸, -(Alk²)n-CONR⁵CONR¹⁴R¹⁵, -(Alk²)-NR⁸CSNR¹⁴R¹⁵ or -(Alk²)_n-CONR⁸CSNR¹⁴R¹⁸;

wherein

Aik² is (C-, _i 2) alkylene, (C₂-12) alkenylene or (C2-12) alkynylene,

R⁵ and R⁵' are independently hydrogen, -Alk¹-H (optionally substituted independently with one or more CO2H, CO2R⁷, Ar², Ar⁸ or cyano groups) -(Alk¹)n-(lower cycloalkyl (optionally substituted independently with one or more -Alk¹-H groups)), adamantyl, norbornyl, Ar², Ar⁸, (lower cycloalkyl)-Ar² or (lower cycloalkyl)-Ar⁸;

wherein

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-13Ar² is a homocyclic aromatic group of 6 to 14 carbon ring atoms (optionally substituted independently with one or more -Alk²-H (optionally substituted independently with one or more halogens), -(Alk¹)n-OH, -(Alk¹)n-OR¹⁶,

-(Aik¹ )_n-Ar³, -(Alk¹)n-CO2H, -(Alk¹)n-CO₂R⁷, S(O)_rR⁷, NR8S(O)rR¹⁶, NR8r9, CONR8r9, lower cycloalkyl, lower alkoxy, -(Alk¹)n-Ar¹, methylenedioxy, ethylenedioxy, morpholino.thiomorpholino, cyano, nitro or halogens); wherein

Ar³ is an aromatic group of 5 to 14 ring atoms, at least one of which is Ο, N or S, (optionally substituted independently with one or more -Alk¹-H (optionally substituted independently with one or more halogens), lower cycloalkyl, lower alkoxy, CO2H, CO2R⁷, -(Alk¹)_n-Ar¹, cyano or halogen);

R¹⁴ and R¹⁵ are,

a) independently, hydroxy, hydrogen, -Aik²- H, lower cycloalkyl (optionally substituted independently with one or more cyano, R¹⁵, Ar², Ar³), lower alkoxy, -(Alk¹)n-adamantyl, -(Alk¹)n-myrantyl, -(Alk¹)n-norbornyl, -(Alk¹)n-fluorenyl, -(Alk¹)n-indanyl, -Aik¹- H (optionally substituted independently with one or more, halogens, cyano, cycloalkyl, SR⁵, COR⁵, CONR⁵R⁷, NR⁵'COR⁵, NR⁵'CO2R⁵, NRS'CONHR⁵, CO₂R⁵, OR⁵, Ar² or Ar³), Ar² or Ar³!

wherein;

Het represents -0-, -CH₂-, -S(0)_r-, -(NH)- or

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-14-(N(Alk¹-H))-;

with the proviso that when Z is

-(Alk2)_n-COR⁵, -(Alk2)n-CO2R⁵ or -(Alk²)n-CO-thiopyridyl and

R⁵ is hydrogen, -Alk¹-H, lower cycloalkyl, -(Alk¹)_n-Ar¹, adamantyl or when Z is

-(Alk2)_n-CONR¹⁴R15 and

R¹⁴ and R¹5 are

a) independently hydrogen, -Alk2-H, lower cycloalkyl, lower alkoxy, adamantyl, Ar¹, benzyl, diphenylmethyl, triphenylmethyl or -(Alk¹)_n-norbornyl;

or

Y is hydroxy; or ii) Y is hydrogen and Z is

OR5, OCOR5, OCONR¹⁴R¹5 nr5'C0R⁵, NR5'CO₂R⁵, NR5CONR¹⁴R¹⁵ or NR5cSR¹⁴R¹⁵; and iii) Y and Z taken together are =O, =CH-(Alk¹ )n-COR⁵, =CH-(Alk¹ )n-CO₂R⁵ or =CH-(Alk¹)_n-CONR¹⁴R¹5;

R⁶ is, hydrogen or methyl;

and pharmaceutically acceptable salts thereof.

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-15A subgroup of the compounds of formula (I) are the compounds wherein:

R¹ and R² are,

i) independently hydrogen or lower alkyl and the bond between the carbons bearing R¹ and R² is a single or a double bond, or ii) taken together are a -CH2- group to form a cyclopropane ring, and the bond between the carbons bearing R¹ and R² is a single bond;

R² is hydrogen, -Alk¹-H, -Alk¹-H substituted with one or more halogens, lower cycloalkyl, lower cycloalkyl-lower alkyl, halogen,-(Aik¹ )n-CO2H, -(Alk¹)n-CO2R⁷, -(Alk¹)_n-Ar¹,

-(Alk¹)_n-CONR8R9, -(Alk¹)n-NR8R9, -(Alk¹)n-S(O)_rR⁷,

-(Aik¹ )n-CN, -(Aik¹ )-OH or -(Aik¹ )n-OR⁷; wherein

R⁷ is -Alk¹-H, -(Alk¹)_n-Ar¹ or lower cycloalkyl,

R8 and R9 are independently hydrogen, -Alk¹-H or lower cycloalkyl

Ar¹ is a homocyclic aryl group of 6 to 14 carbons:

R⁴ is hydrogen, -Alk¹-H, lower cycloalkyl, lower cycloalkyl-lower alkyl,

-(Alk¹)n-S(O)rR⁷, -(Alk¹)n-phthalimidyl, {-Alk¹-)CO2H, -(Alk¹)n-CO₂R⁷,

-(Alk¹)n-Ar¹, -(Alk¹)n-CONR⁸R9, -(Alk¹)n-NR8R9 -(Alk¹)n-OH or -(Alk¹)_n-OR⁷;

X is,

wherein

R¹², R¹¹, R¹² and R¹² are independently hydrogen or lower alkyl,

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-16ρ and q are independently either 0 or 1;

Y and Z are,

i) Y is hydrogen or hydroxy and

Z is -(Alk²)n-COR³, -(Alk2)n-CO₂R⁵. -(Alk²)_n-COSR³,

-(Alk²)n-CONR¹⁴R¹³, -(Alk²)-OCOR³, -(Alk²)-OCONR¹⁴R¹³, -(Alk²)-OR³, -(Alk²)-NR³COR³, -(Alk²)-NR³CO2R³, -(Alk²)-NR⁵CONR¹⁴R¹³,-(Alk²)-nCONR³NR¹⁴R¹³, -(Alk²)n-CONR⁵CONR¹⁴R¹³, (-Alk²-)NR³CSNR¹⁴R¹5 or -(Alk²)n-CONR³CSNR¹⁴R¹³;

wherein

Aik² is (C-j _i 2) alkylene, (C₂-12) alkenylene or (C2-12 alkynylene,

R³ is hydrogen, -Alk¹-H, -(Alk¹)n-(lower cycloalkyl), adamantyl, -(Alk¹)n-Ar², -(Aik¹ )n-Ar³, (lower cycloalkyl)nAr2, (lower cycloalkyl)_nAr³ or -Aik¹- substituted independently with one or more CO2H, CO₂R⁷Ar² or Ar³ groups; wherein

Ar² is an aromatic group of 6 to 14 carbon ring atoms, optionally substituted with one or more Aik¹, Aik¹ substituted with one or more halogens, -(Alk¹)n-OH, -(Alk¹)n-OR⁷, -(Alk¹)_n-CO₂H, -(Alk¹)n-CO2R⁷, S(O)rR⁷ or NR³r9, lower cycloalkyl, lower alkoxy, -(Alk¹)_n-Ar¹, methylenedioxy, ethylenedioxy, morpholino, thiomorpholino, cyano or halogen groups;

Ar³ is an aromatic group of 5 to 14 ring atoms, at least one of which is Ο, N or S, optionally substituted with one or more Aik¹, lower cycloalkyl, lower alkoxy, CO2H, CO2R⁷, -(Alk¹)n-Ar¹, cyano or halogen groups;

R¹⁴ and R¹³ are,

a) independently, hydrogen or -Alk²-H, lower cycloalkyl, lower alkoxy, adamantyl, -(Alk¹)n-norbornyl, Ar², Ar³, -Aik¹- substituted independently with one or more, SR³, COR³, CONR³R⁷, NR³COR³, NR³CO2R³, NR³CONHR³ CO2R⁵, OR³, Ar² or Ar³ groups, -(Alk¹)n-fluorenyl, or -(Alk¹)_n-indanyl; or

b) carbon atoms, optionally substituted with one or more lower alkyl groups, taken together with the linking nitrogen to form a 4 to 8 atom heterocyclic group

BAD ORIGINAL ft

1060AC

AP Ο Ο Ο 4 5 9

wherein;

Het represents -Ο-, -CH2-, -S(O)_r-, -(NH)- or -(N(Alk¹))-:

with the proviso that when Z is (-Alk²-)nCOR⁵, (-Alk²-)nCO₂R⁵ or -(Alk²)n-CO-thiopyridyl and R⁵ is hydrogen, -Alk¹-H, lower cycloalkyl, -(Aik¹ )n-Ar¹, adamantyl or when Z is (-Alk²-)_nCONR¹⁴R¹⁵ and R¹⁴ and R¹⁵ are 10 (a) independently hydrogen, -Alk²-H, lower cycloalkyl, lower alkoxy, adamantyl, -Ar¹, benzyl, diphenylmethyl, triphenylmethyl or -(Alk¹)_n-norbornyl; or (b) carbon atoms, optionally substituted with one or more lower alkyl groups, taken together with the linking nitrogen to form a 4 to 8 atom heterocylic ring as herein before defined,

Y is hydroxy;

ii) Y is hydrogen and ( Z is OR⁵, OCOR⁵, OCONR¹⁴R¹⁵ NR⁵COR⁵, NR⁵CO₂R⁵,

NR⁵CONR¹⁴R¹⁵ or NR⁵CSR¹⁴R¹⁵;

C iii) Y and Z taken together are =0, =CH-(Alk¹)_n-COR⁵, =CH-(Alk¹ )n-CO2R⁵ or =CH-(Alk¹ )n-CONR¹⁴R¹⁵;

R⁶ is hydrogen or methyl;

and pharmaceutically acceptable salts thereof.

Particular groups of compounds of formula (I) are the compounds of formulas (IA), (IB), (IC) and (ID)

BAD ORIGINAL ft

1060AC

000459

Compounds of formula (IA) are especially of interest.

In an alternative aspect the invention provides compounds of formula (I) wherein Z is -COR⁵ including:

f 17β—(1 -Oxo-2-cyclohexylethyl)-6-azaandrost-4-en-3-one

17β—(1 -Oxo-1 -(2,4-difluorophenyl)methyl)-6-azaandrost-4-en-3-one 17β—(1 -Oxo-1 -(4-isopropoxyphenyl)methyl)-6-azaandrost-4-en-3-one

17β- (1 -Oxo-3,3-diphenylpropyl)-6-azaandrost-4-en-3-one β—(1 -Oxo-1 -(2-norbornyl)methyl)-6-azaandrost-4-en-3-one

In a particularly aspect the invention provides compounds of formula (I) wherein Z is -CONR¹⁴R¹⁵, R¹⁴ is hydrogen and R¹⁵ is Ar² or C3.11 saturated ring, optionally containing an oxygen or a sulfur atom, (optionally substituted independently with one or more R⁷ or Ar² groups). Preferably R¹⁵ is a group of formula Ar²³ bad original £

1060AC

AP 0 0 0 4 5 9

b wherein R^a and R^b are independently hydrogen, lower alkyl, trifluoromethyl, halogen or phenyl (optionally substituted with one or more halogens or branched C^alkyl) and R^c is hydrogen or one or more halogens, or R¹⁵ is a C3.11 saturated ring, optionally containing an oxygen or a sulfur atom, substituted with a group of formula Ar²³. In a particular group of compounds Ar^2a is a group of formula Ar^2aa

where R^aa is branched C^alkyl, trifluoromethyl or phenyl optionally substituted with one or more halogens; one of R^ba and R^ca is branched C4-7alkyl, trifluoromethyl, halogen or phenyl optionally substituted with one or more halogens, and the other is hydrogen or halogen; and R^da is hydrogen or halogen.

Particular compounds of the invention include :

17|3-N-((2,6-Di-/-propyl)phenyl)-carbamoyl-6-azaandrost-4-en-3-one 17p-N-(2₎4,6-trimethyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one 17p-N-(2-Chloro-5-trifluoromethyl)phenyl-carbamoyl-6-azaandrost-4-en- 3one

17(3-N-(2,6-Dimethyl-4-bromo)phenyl-carbamoyl-6-azaandrost-4-en-3-one 17f3-N-(2,6-Dimethyl-4-f-butyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one 17J3-N-(2,6-Dibromo-4-isopropyl)phenyl-carbamoyl-6-azaandrost-4-en- 3one

17(3-N-(2,5-Ditrifluoromethyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one

17p-N-(2-Phenyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one

17|3-N-(2,6-Diethyl-3,5-dichloro)phenyl-carbamoyl-6-azaandrost-4-en-3-one

17p-N-(2,6-Diethyl-3-chloro)phenyl-carbamoyl-6-azaandrost-4-en-3-one

17J3-N-(2-M3utyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one

BAD ORIGINAL A

1060AC

AP 0 0 0 4 5 9

-2017β-Ν-(2 A6-Trichloro)phenyl-carbamoyl-6-azaandrost-4-en-3-one l7p-N-(2-Bromo-5-trifluoromethyl)phenyl-carbamoyl-6-azaandrost-4-en- 3one

17p-N-(2-i-Butyl-6-methyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one

17^-N-1-(4-Chlorophenyl)cyclopentyl-carbamoyl-6-azaandrost-4-en-3-one

17(3-N-(2,6-Dibromo-4-chloro)phenyl-carbamoyl-6-azaandrost-4-en-3-one

17p-N-(2,6-Diethyl-4-bromo)phenyl-carbamoyl-6-azaandrost-4-en-3-one

17p-N-(2-Bromo-4-f-butyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one

17p-N-(2-Chloro-4-i-butyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one

17p-N-(5-Bromo-2-f-butyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one

17p-N-(5-Chloro-2-i-butyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one np-N-^.e-DiethyOphenyl-carbamoyl-e-azaandrosM-en-S-one

17(3-N-(4-Bromo-2-i-butyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one

17J3-N-(2-i-Butyl-5-cyano)phenyl-carbamoyl-6-azaandrost-4-en-3-one

173-N-(2-(0-4-Tolyl)-5-trifluoromethyl)phenyl-carbamoyl-6-azaandrost-4-en-3one

17p-N-(2-(0-4-Chlorophenyl)-5-trifluoromethyl)phenyl-carbamoyl- 6azaandrost-4-en-3-one

17[3-N-(2-Nitro-4-i-butyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one 17|3-N-(2-(O-Phenyl)-5-{1,1 -dimethyl)propyl)phenyl-carbamoyl-6-azaandrost-4en-3-one

17P-N-(2-Ethylsulfonyl-5-trifluoromethyl)phenyl-carbamoyl-6-azaandrost- 4en-3-one

17J3-N-(3,5-Di-Fbutyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one

17B-N-(2-r-Butyl-5-trifluoromethyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one 17p-N-(2-i-Butyl-5-phenyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one 17(3-N-(2,6-Di-/-propyl)phenyl-carbamoyl-6-azaandrost-1,4-dien-3-one 17p-N-(2,6-Di-Apropyl)phenyl-carbamoyl-6-azaandrost-4-methyl-1,4-dien- 3one

17p-N-1-(4-Trifluoromethylphenyl)cyclopentyl-carbamoyl-6-azaandrost-4-en-3one

17p-N-1-(4-Fluorophenyl)cyclohexyl-carbamoyl-6-azaandrost-4-en-3-one

17p-N-1-(4-Methoxyphenyl)cyclohexyl-carbamoyl-6-azaandrost-4-en-3-one

17p-N-1-(4-Methoxyphenyl)cyclopentyl-carbamoyl-6-azaandrost-4-en-3-one

1060AC

AP 0 0 0 4 5 9

-2117p-N-(2,5-bis(Trifluoromethyl))phenyl-carbamoyl-6-azaandrost-4-methyl-4-en3-one

17p-N-(2-t-Butyl-5-trifluoromethyl)phenyl-carbamoyl-6-azaandrost-4-methyl-4en-3-one

17p-N-(2,5-Di-t-butyl)phenyl-carbamoyl-6-azaandrost-4-methyl-4-en-3-one

173-N-(2-t-Butyl-5-(4-chlorophenyl))phenyl-carbamoyl-6-azaandrost-4-en-3-one

17B-N-1-(4-t-Butylphenyl)cyclopentyl-carbamoyl-6-azaandrost-4-en-3-one

17p-N-1-(4-t-Butylphenyl)cyclohexyl-carbamoyl-6-azaandrost-4-en-3-one

17p-N-1-(4-Chlorophenyl)cyclopentyl-carbamoyl-6-azaandrost-4-methyl-4-en-3one

17^-N-(2,5-bis(T rifluoromethyl))phenyl-carbamoyl-6-azaandrost-4-chloro-4-en3-one

17^-N-(2-f-Butyl-5-trifluoromethyl)phenyl-carbamoyl-6-azaandrost-4-chloro-4en-3-one

17p-N-1-(4-f-Butylphenyl)cycloheptyl-carbamoyl-6-azaandrost-4-en-3-one

17p-N-1-(4-f-Butylphenyl)cyclohexyl-carbamoyl-6-azaandrost-4-chloro-4-en-3one

173-N-(2,6-Diethyl-4-(4-chlorophenyl))phenyl-carbamoyl-6-azaandrost-4-en-3one

17p-N-4-(4-f-Butylphenyl)tetrahydrothiopyranyl-carbamoyl-6-azaandrost-4-en-3one

17p-N-9-(4-f-Butylphenyl)bicyclo[3.3.1]nonyl-carbamoyl-6-azaandrost-4-en-3one

17p-N-4-(4-i-Butylphenyl)tetrahydropyranyl-carbamoyl-6-azaandrost-4-en-3-one

17p-N-1-(4-Chlorophenyl)cyclohexyl-carbamoyl-6-azaandrost-4-en-3-one

17p-N-(2-f-Butyl-5-(4-(-butyl)phenyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one or

17β-Ν-1 -(4-Chlorophenyl)cyclopentyl-carbamoyl-6-azaandrost-4-chloro- 4en-3-one and pharmaceutically acceptable salts thereof.

A particular compound is 17(3-N-(2-f-Butyl-5-trifluoromethyl)phenyl-carbamoyl6-azaandrost-4-en-3-one and pharmaceutically acceptable salts thereof.

BAD ORIGINAL ft

AP 0 0 0 4 5 9

1060AC

-22One particular aspect of the invention provides compounds of formula (I) wherein R¹ and R² are as hereinbefore defined, R³ is hydrogen or lower alkyl; R⁴ is hydrogen or lower alkyl;

Y is hydrogen; and

Z is -COR⁵, -CONR¹⁴R¹⁵, -CH2OCO2R⁵, -CH2OCOR⁵, -CH2NR⁵'COR⁵ CONR⁵NR¹⁴R¹⁵, -CH2NR⁵CONR¹⁴R⁵, or -CON⁵CONR¹⁴R¹⁵ wherein R⁵ and R⁵’ are independently hydrogen, lower alkyl optionally substituted independently with one or more Ar² groups (lower alkyl)_n-lower cycloalkyl, menthyl, adamantyl, norbornyl or Ar²;

Ar² is a phenyl group optionally substituted independently with one or more Alk-H (optionally substituted independently with one or more halogens), -OR¹⁶, -S(O)_rR⁷, phenyl, methylenedioxy, ethylenedioxy, morpholino, thiomorpholino, cyano, nitro or halogen groups;

Aik is lower alkylene, lower alkenylene or lower alkynylene;

n is 0 or 1;

r is 0, 1 or 2;

R⁷ is -Alk-H, -(Alk)n-phenyl or lower cycloalkyl;

R¹⁶ is -Alk-H (optionally substituted independently with one or more halogens), lower cycloalkyl (optionally substituted independently with one or more halogens or -Alk-H (optionally substituted independently with one or more halogens)) or -(Alk)n-phenyl (wherein phenyl is optionally substituted independently with one or more lower alkoxy, cyano, halogen or -Alk-H groups (optionally substituted independently with one or more halogens)); R¹⁴ is hydrogen or hydroxy, and R¹⁵ is hydrogen, lower cycloalkyl (optionally substituted independently with one or more R⁷ or Ar² groups), -(Alk)-adamantyl, -(Alk)n-myrantyl, -(Alk)n-norbomyl, -(Alk)_n-fluorenyl, -(Alk)_n-indanyl, -Alk-H (optionally substituted independently with one or more lower cycloalkyl, SR⁵, OR⁵, Ar² or Ar³ groups), Ar² or Ar³, or R¹⁴ and R¹⁵ taken together with the linking nitrogen form a pyrrolidinyl, piperidinyl or perhydroazepinyl ring optionally substituted with one or more R⁷ groups; Ar³ is a pyrrolyl, thienyl, furyl or pyridyl group optionally substituted independently with one or more Alk-H groups; with the provisos that when Z is COR⁵, R⁵ is substituted lower alkyl, lower alkyl lower cycloalkyl,

1060AC

AP 0 0 0 4 5 9

-23when Ζ is CONR¹⁴R¹⁵ and R¹⁵ is hydrogen, -Alk-H, lower cycloalkyl, lower alkoxy, adamantyl, phenyl, benzyl, diphenylmethyl, triphenylmethyl or -(Alk)_nnorbornyl, R¹⁴ is hydroxy; and when Z is CONR¹⁴R¹⁵ and R¹⁴ and R¹⁵ taken together with the linking nitrogen form a pyrrolidinyl, piperidinyl or perhydroazepinyl ring, said ring is substituted with one or more lower alkenyl, lower alkynyl, -(Alk)n-phenyl or lower cycloalkyl groups; and pharmaceutically acceptable salts thereof. Compounds of formula (IA) are especially of interest. In a still further aspect of the invention of partiucalr interest, Z is CONR¹⁴R¹⁵.

Some of the substituents of the compound of formula (I) may cause asymmetry about the atoms to which they are attached giving rise to either a or β stereochemical configuration. (For a detailed explanation of stereochemical configuration see March, J. Advanced Organic Chemistry, 3rd Ed., ch 4, John Wiley & Sons, New York (1985).) Unless otherwise indicated, either the a and β stereo configurations are intended for the substituents.

The compounds of formula (I) can be used in the form of an acid addition salt derived from inorganic or organic acids. Where the salt of a compound of formula (I) is to be used for a human or veterinary medicinal application the salt must be pharmaceutically acceptable. However, non-pharmaceutically acceptable salts of the compounds of formula (I) may be useful as intermediates in the preparation of a corresponding pharmaceutically acceptable salt. Pharmaceutically acceptable salts include, but are not limited to, salts with inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide and nitrate salts or salts with an organic acid such as the acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, palmitoate, salicylate and stearate salts.

Preparation^ Compounds

According to one general process (A) the compounds of the present invention may be prepared by the procedure shown in step 8 of Scheme I, wherein R¹BAD ORIGINAL ft

1060AC

AP Ο Ο Ο 4 5 9

-24R⁴, R⁶, Υ and Ζ are as defined for formula (I) and JO is a protected hydroxy group:

SCHEME I

BAD ORIGINAL

1060AC

AP 0 0 8 4 5 9

SCHEME I (continued) ί 5 (

In Step 1 of Scheme I when Z is CO2H, the acid group at the 17 position of a compound of formula (II) is converted to the corresponding ketone, ester or amide of compound (III) accompanied by deprotection of the hydroxy group at the 3 position. Alternatively a compound of formula (III) wherein Z is CO2CH3 and Y is H may be prepared from pregnenolone as described by Rasmusson, et al., J. Med. Chem., 27,1690 (1984).

This may be accomplished by activating the carboxylic acid group toward nucleophilic displacement by treatment with an activating agent such as N,Nbis(2-oxo-3-oxazolidinyl)phosphorinic chloride (BOP-CI) or conversion to the corresponding acid halide group by treatment with a halogenating agent such as oxalyl chloride or thionyl chloride in an aprotic solvent such methylene chloride or toluene at -5 to 10°C. The intermediate activated carboxylic acid, e.g., an acid chloride, may be reacted with H-NR¹4r15 _or HOR⁵ (wherein R⁵, R^{Th * * * 14} and R¹⁵ are as defined for formula (I)) at or above room temperature in an aprotic solvent. When R^ is alkyl, alkenyl, lower cycloalkyl, or adamantyl, the activated acid is treated with R⁵M (wherein M is a metal, such as magnesium or

BAD ORIGINAL ft

AP 0 0 0 4 5 9

-261060AC lithium) in a polar, aprotic solvent such as THF or diethyl ether containing catalytic Cul, at a temperature in the range of about 0 to about -78°C.

Additionally, when, H-NR¹⁴R¹5 js a hindered, nonnucleophilic aniline the corresponding metal salt may be prepared and the activated acid treated with MNr14r15 (wherein M is a metal, such as magnesium or lithium) in a polar, aprotic solvent such as THF or diethyl ether at a temperature in the range of about 0 to about -78°C.

The amines, H-NR¹⁴R¹⁵ are commercially available or conveniently prepared by methods known in the art. For example, when either R¹⁴ or R¹⁵ is an alkyl or aryl substituted aromatic residue the alkyl group may be introduced as described by Reetz, M.T. et al., Angew. Chem. Int. Ed. Engl., 19, 900 and 901 (1980) or the aryl group introduced as described by Stille, J.K. Pure Appl. Chem., 57, 1771 (1985). When either R¹⁴ or R¹⁵ is an aryl substituted cycloalkyl residue the amine may be prepared by Curtius rearrangement of the corresponding acid, where available, or by the method of He, X. et al., J. Med. Chem., 36, 1188 (1993), i.e. by reacting the corresponding cycloalkanone with the appropriate aryl Grignard reagent followed by conversion of the resulting alcohol to the amine by treatment with sodium azide and trifluoroacetic acid followed by reduction of the azide with lithium aluminum hydride. Aryl substituted cyclopropylamines are prepared by rhodium catalyzed insertion of the appropriate aryl-a-diazo-ester (prepared by the method of Baum, J.S. et al., Synthetic Comm., 17, 1709 (1987)) into the appropriate olefin (as described by Davies, H.W. et al., Tetrahedron Lett., 30, 5057 (1989)) followed by saponification of the ester and Curtius rearrangement of the acid to give the desired amine.

In Step 2, a compound of formula (III) is treated with a suitable hydroxy protecting group such as for example a silicon derivative such as a trisubstituted silyl halide, a tetrahydropyran derivative or an arylalkyl group such as a paramethoxybenzyl group. Typically the compound of formula (III) is treated with a trialkylsilyl halide, e.g., triisopropylsilyl chloride, at about 25 to 75°C in an aprotic solvent such as dimethylformamide to protect the hydroxy

BAD ORIGINAL ft

1060AC

AP 0 ο 0 4 5 9

-27group in the 3-position to yield the corresponding trisubstituted silylated compound of formula (IV).

In Step 3, a compound of formula (IV) is treated with ozone in methanol alone or as a mixture with one or more polar, protic or aprotic solvents, e.g., methylene chloride and methanol, at a temperature substantially below 0°C, e.g., from about -50 to about -80°C to yield a corresponding compound of formula (V).

In Step 4, the compound of formula (V) in methanol alone or as a mixture with one or more polar, protic or aprotic solvents, e.g,, methylene chloride and methanol, at about -20°C is treated with a reductant such as zinc and acetic acid then allowed to slowly warm to room temperature to yield the aldehyde of formula (VI). Alternatively the compound of formula (V) may be taken directly to step 5.

In Step 5, a compound of formula (V or VI) is reacted with an oxidant, such as Jones reagent (see Bowden, et al., J. Chem. Soc., 39, (1946)) at about 0°C, to yield the corresponding compound of formula (VII).

In Step 6, a compound of formula (VII) is converted to an activated carboxylate derivative such as an acid halide, e.g., chloride, by treatment with a halogenating agent, e.g., oxalyl chloride. The resulting acid halide is reacted with an alkali metal azide, e.g., sodium azide, at about 0 to 30°C in an aqueous solvent mixture, such as water and acetone, to yield the corresponding acyl azide compound of formula (VIII). Alternatively, the acid is treated with triphenyl phosphoryl azide in an aprotic solvent such as toluene to yield the acyl azide directly.

In Step 7, an acyl azide compound of formula (VIII) is rearranged with ring closure by warming to reflux in an aprotic solvent, such as toluene, to induce rearrangment to the corresponding isocyanate followed by stirring with a weak acid such as silica gel or by reaction with a strong, sterically hindered base, e.g., potassium f-butoxide, in a protic or aprotic solvent at a temperature in the range of about 90 to about 180°C to generate the corresponding compound of formula (IX).

BAD ORIGINAL ft

1060AC

AP Ο Ο Ο 4 5 9

-28Finally, in Step 8 (general process A), the hydroxy function of a compound of formula (IX) is deprotected and oxidized. Thus, in general process (A1) compounds of formula (I) wherein R⁴ is hydrogen may be prepared by converting the protected hydroxy group of a compound of formula (IX) to the corresponding hydroxy group, i.e., the hydroxy group is deprotected by conventional means. Thus, for example a trisubstituted silyl group may be removed by reaction with aqueous hydrogen fluoride in a polar solvent such as acetonitrile at about 0°C to room temperature. Next the hydroxy group is oxidized by reaction with a suitable oxidizing agent, for example, with Jones reagent with migration of the double bond to the 4,5 position to generate the corresponding compound of formula (I) where R⁴ is hydrogen.

Alternatively, in general process (A2) for the preparation of compounds of formula (I), wherein R⁴ is an acyl group, the compound of formula (IX) is treated with an acylating agent such as di-f-butyldicarbonate to acylate the 6-nitrogen with migration of the double bond to the 4, 5 position. The hydroxy protecting group is then removed in a conventional manner, for example, a trisubstituted silyl protecting group may be removed with a reagent such as tetrabutylammonium fluoride and treated with an oxidant such as pyridinium dichromate or manganese dioxide to generate the corresponding compound of formula (I) where R⁴ is f-butoxycarbonyl.

Alternatively, intermediate compounds of formula (IX) may be prepared from the corresponding compounds of formula (VII) according to Scheme 1 A.

BAD ORIGINAL

1060AC

AP Ο Ο Ο 4 5 9

SCHEME 1Α

In step 6a of Scheme 1A, a compound of formula (VII) is reacted sequentially with 1) (COCI)2 in a non polar solvent, e.g., toluene or methylene chloride, in ( 5 the presence of a tertiary amine, e.g., triethyl amine or pyridine, then 2) with 2mercaptopyridine N-oxide sodium salt (Na-MPNO) in BrCCl3 to yield the corresponding compound of formula (XVI). In step 7a the compound of formula (XVI) is reacted with liquid ammonia at about 50°C in the presence of an ammonium salt of a weak acid, e.g., ammonium carbonate, in a pressure vessel to yield the corresponding compound of formula (IX).

Alternatively, according to another general process (B), the compounds of formula (I) wherein X is (CR^wR¹¹)p (CR^,Z R¹³ )„

BAD ORIGINAL ft

1060AC

AP Ο Ο Ο 4 5 9

-30and both ρ and q are 1, and R¹³, R¹¹, R¹² and R¹³ are hydrogen, may be prepared by the procedure shown in Step 5 of Scheme II wherein R¹'³ are as

SCHEME II

In Step 1 of Scheme II, the enone function of compound (XI) is protected as a ketal with concomitant migration of the double bond to the 5, 6 position by refluxing with ethylene glycol in the presence of an acid, such as ptoluenesulfonic acid, in a solvent such as toluene which allows azeotropic removal of water to yield the corresponding compound of formula (XIII).

BAD ORIGINAL

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AP 0 0 0 4 5 9

-31Ιη Step 2, a compound of formula (XII) is treated with ozone in methanol alone or with one or more polar, protic or aprotic solvents mixtures, e.g., methylene chloride and methanol, at a temperature substantially below 0°C, e.g., from about -50 to about -80°C, followed by treatment at about -20°C with a reductant, such as zinc and acetic acid, then allowed to slowly warm to room temperature to yield the aldehyde of formula (XIII).

In Step 3, a compound of formula (XIII) is reduced with a selective reducing agent, such as lithium tri-t-butoxyaluminumhydride in an aprotic solvent such as THF or diethyl ether to give the corresponding alcohol of formula (XIV).

In Step 4, the alcohol functionality of a compound of formula (XIV) is converted to a leaving group, such as the corresponding methanesulfonate by treatment with methanesulfonyl chloride in an aprotic solvent such as methylene chloride in the presence of a hindered tertiary amine base such as triethylamine. Once transformed to a leaving group, the alcohol is displaced by treatment with a source of azide, such as sodium azide, in a polar, aprotic solvent, such as DMF, to give the corresponding alkyl azide of formula (XV).

In Step 5, a compound of formula (XIV) is treated with a reductant such as triphenylphosphine in THF at reflux followed by a strong protic acid such as 4M HCI to give the corresponding compound of formula (I) where X is -CH2CH2-.

Alternatively, according to another general process (C), a compound of formula (I) may be converted into another compound of formula (I) using conventional procedures. Thus for example, a double bond may then be inserted between the carbon in the 1 position and the carbon in the 2 position by conventional means such as dehydrogenation with 2,3-dichloro-5,6-dicyano-1,4benzoquinone by refluxing in an aprotic solvent such as dioxane to produce a compound of formula (I) which is unsaturated in the 1,2 position. A compound of formula (I) with a double bond in the 1,2 position may then be treated with the anion of trimethylsulfoxonium iodide, prepared by deprotonation with a base such as sodium hydride, in an aprotic, polar solvent such as DMSO to give a compound of formula (I) wherein R¹ and r2 taken together form a cyclopropane

1060AC

AP 0 0 ο 4 5 9

-32Optionally, a compound of formula (I) wherein R³ is H and R⁴ is acyl or acyloxy, such as t-butoxycarbonyl, may be treated with bromine at 0°C in an aprotic solvent such as methylene chloride to give the corresponding compound of formula (I) wherein R³ is Br, which may then be treated with an organotin species such as phenyltrimethyltin in the presence of a palladium catalyst such as PdCl2(PPh3)2 and lithium chloride in a polar aprotic solvent such as dimethylformamide to give the corresponding compound of formula (I) wherein R³ is methyl.

Additionally, a compound of formula (I) wherein R⁴ is acyl or acyloxy, such as tbutoxycarbonyl, may be treated with a strong hindered base such as lithium diisopropylamide at -78°C in an aprotic solvent such as THF followed by an electrophile, such as methyl iodide to give compounds of formula (I) wherein R⁴is methyl or lower alkyl.

Also, a compound of formula (I) wherein R³ is H may be treated with cuprous cyanide or Ν,Ν-dimethylmethyleneammonium iodide in polar, aprotic solvents such as DMF or acetonitrile to give compounds of formula (I) wherein R³ is -CN and -CH2N(CH3)2 respectively.

Additionally, a compound of formula (I) wherein R³ is H may be treated with a halogenated succinimide such as N-iodosuccinimide in a solvent such as THF to give a compound of formula (I) wherein R³ is I.

The compounds of formula (I) wherein R⁴ is hydrogen may be reacted, via a nucleophilic reaction of the corresponding sodium or potassium salt, with Llower alkyl, L-lower alkenyl, L-alkanoyl of 2 to 6 carbons, L-Alk¹, L-lower cycloalkyl, L-lower cycloalkyl-lower alkyl, cycloalkyl, L-(Alk1)nS(O)rR⁷, L-(Alk¹)n-phthalimidyl, L-(Alk1)-CO₂H, L-(Alk1)_n-CO₂R⁷ L-(Alk1)n-Ar1, L-(Alk1)n-CONR³R9 L-(Alk1 )n._Nr8r9 L-(Alk1)_n-OH or L-(Alk¹)_n-OR⁷ at a temperature of about 5 to about 100°C in a polar, aprotic solvent such as dimethylformamide, to yield the compounds of formula (I) wherein R⁴ is other than hydrogen. The groups, R⁷-R⁹, Ar¹ and n, are as defined for formula (I) and L is a leaving group, such as defined in March, J., Advanced Organic

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-33Chemistry, 3d. Ed., 179, John Wiley & Sons, New York (1985) and in Hendrickson, J, et al., Organic Chemistry, 3d. Ed., 375-377, McGraw Hill, New York (1970), e.g., a halogen atom.

Additionally, a compound of formula (I) wherein Z is CO₂R⁵, and in particular wherein R⁵ is CH3, may be treated with a strong base, such as lithium hydroxide in a solvent system such as THF or dioxane and water to give a compound of formula (I) where Z is CO2H. An acid of this formula may then be treated as described in Step 1 of Scheme 1 to yield the corresponding compounds of formula (I) wherein Z is COR⁵, CO2R⁵ or CONR¹⁴R¹⁵.

A particular step for the preparation of compounds of formula (I) wherein Z is (Alk²)nCONR¹⁴R¹⁵ involves reacting a compound of formula (I) wherein Z is (Alk²)nCO2R⁵ with an amine of formula HNR¹⁴R¹⁵, especially compounds wherein R¹⁴ is hydrogen and R¹⁵ is Ar² or lower cycloalkyl (optionally substituted independently with one or more R⁷ or Ar² groups), e.g., a group of formula Ar^2a or a cycloalkyl group substituted with a group of formula Ar^2a. Intermediates of formula HNR¹⁴R¹⁵ wherein R¹⁴ is hydrogen and R¹⁵ is Ar²³ or lower cycloalkyl substituted with a group of formula Ar 2a are novel compounds and represent a further aspect of the invention.

Optionally, a compound of formula (I) wherein Z is CO₂R⁵, and in particular wherein R⁵ is CH3, may be reduced with a reducing agent such as diisobutylaluminum hydride and then reoxidized with Collins' reagent (CrO3-2 pyridine) or another mild oxidant to produce a compound of formula (I) wherein Z is CHO, which may be treated with R⁵M (wherein M is a metal such as magnesium or lithium) and R⁵is Alk¹-H (optionally substituted independently with one or more -CO2H, CO2R⁷, Ar² or Ar³ groups), lower cycloalkyl (optionally substituted independently with one or more -Alk¹-H groups), adamantyl, Ar², Ar³, -(lower cycloalkyl)n-Ar² or -(lower cycloalkyl)_n-Ar³ to give, after oxidation with pyridinium dichromate, a compound of formula (I) wherein Z is COR⁵.

The above product of diisobutylaluminum hydride reduction may also be selectively oxidized at the 3-position by treatment with manganese (II) oxide to give a compound of formula (I) wherein the substitutent on C-17, that is, Z, is

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-34CH2-OH, i.e., a (Alk²)alkanol. This alcohol may then be converted to an amine by standard methods, e.g., conversion to a mesylate, displacement with a metal azide such as sodium azide, and reduction with hydrogen in the presence of a catalyst such as palladium on carbon. The alcohol or amine may then be reacted with acid chlorides, chloroformates, isocyanates or isothiocyanates to give compounds of formula (I) wherein Z is -(Alk²)-OCOR⁵, -(Alk²)-OCO2R⁵, -(Alk²)-NR5'COR5, -(Alk2)-NR⁵'-CO₂R⁵, -(Alk²)-NR5CONR¹⁴R¹5,

-(Alk²)-NR5CSNR1⁴R15 _Or -(Alk²)-OCO-NR¹⁴R¹5.

Further, these compounds of formula (I), wherein Z is -CHO, may be treated with a Wittig reagent, such as Et2OPOCH2COR⁵ Et2OPOCH2CO2R⁵ or Et2OPOCH2CONRl⁴Rl5 to give a compounds of formula (I) wherein Z is CH=CH-COR⁵, CH=CH-CO2R⁵ or CH=CH-CONR¹⁴R¹5 respectively.

It will be appreciated by those skilled in this art that for certain cases of R² and Z some Steps in the procedures shown in Scheme I and Scheme II are incompatible with survival of the functional groups of interest. In these cases, R² or Z is either introduced subsequent to the incompatible Step or is present in a protected form. An example of the former is the case where R² is halogen, in which case the halogen is introduced by reaction of a compound of formula (I) with a halogenated succinimide, such as N-bromosuccinimide. An example of the latter is the use of an ester or ether to protect a carboxylic acid or alcohol, respectively.

Thus, according to another general process (D), a compound of formula (I) according to the invention, or a salt thereof may be prepared by subjecting a protected derivative of formula (I) or a salt thereof to a reaction to remove the protecting group or groups.

Thus, at an earlier stage in the preparation of a compound of formula (I) or a salt thereof it may have been necessary and/or desirable to protect one or more sensitive groups in the molecule to prevent undesirable side reactions.

The protecting groups used in the preparation of compounds of formula (I) may be used in a conventional manner. See for example Protective Groups in

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-35Organic Chemistry, Ed. J.F.W. McOmie, Plenum Press, London (1973) or Protective Groups in Organic Synthesis, Theodora Green, John Wiley and Sons, New York (1981).

Conventional amino protecting groups may include, for example, arylalkyl groups, such as benzyl, diphenylmethyl or triphenylmethyl groups; and acyl groups, such as N-benzyloxycarbonyl or t-butoxycarbonyl. Thus, compounds of formula (I) when R⁴ represents hydrogen may be prepared by deprotection of a corresponding protected compound.

Hydroxy groups may be protected, for example, by benzyl, diphenylmethyl or triphenylmethyl groups, acyl groups, such as acetyl, silicon protecting groups, such as triisopropysilyl or t-butyldimethylsilyl groups, or as tetrahydropyran derivatives.

Removal of any protecting groups present may be achieved by conventional procedures. An arylalkyl group such as benzyl, may be cleaved by hydrogenolysis in the presence of a catalyst, e.g., palladium on charcoal; an acyl group such as N-benzyloxycarbonyl may be removed by hydrolysis with, for example, hydrogen bromide in acetic acid or by reduction, for example by catalytic hydrogenation; silicon protecting groups may be removed, for example, by treatment with fluoride ion or by hydrolysis under acidic conditions; tetrahydropyran groups may be cleaved by hydrolysis under acidic conditions.

As will be appreciated, in any of the general processes (A) to (C) described above it may be desirable or even necessary to protect any sensitive groups in the molecule as just described. Thus, a reaction step involving deprotection of a protected derivative of general formula (I) or a salt thereof may be carried out subsequent to any of the above described processes (A) to (C).

Thus, according to a further aspect of the invention, the following reactions may, if necessary and/or desired be carried out in any appropriate sequence subsequent to any of the processes (A) to (C):

(i) removal of any protecting groups; and

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-36(ii) conversion of a compound of formula (I) or a salt thereof into a pharmaceutical acceptable salt or solvate thereof.

Where it is desired to isolate a compound of the invention as a salt, for example as an acid addition salt, this may be achieved by treating the free base of formula (I) with an appropriate acid, particularly with an equivalent amount, or with creatinine sulfate in a polar, protic solvent, e.g., aqueous ethanol.

As well as being employed as the last main step in the preparative sequence, the general methods indicated above for the preparation of the compounds of the invention may also be used for the introduction of the desired groups at an intermediate stage in the preparation of the required compound. It should therefore be appreciated that in such multi-stage processes, the sequence of reactions should be chosen in order that the reaction conditions do not affect groups present in the molecule which are desired in the final product.

The compound of formula (I) and the intermediate compounds, (ll)-(XIV), shown in Schemes I and II may be purified by convenient methods of the art, e.g., chromatography or crystallization.

Steroid 5a-Reductases

In Vitro Assay

Enzyme activies may be determined using microsomes derived from: 1) prostate tissue from benign prostatic hyperplasia (BPH) patients; 2) recombinant baculovirus infected SF9 cells that express human type 1 5a-reductase; 3) prostate tissue from the rat; or 4) recombinant baculovirus infected SF9 cells that express human type 2 5a-reductase. Microsomes were prepared by homogenization of the tissue or cells, followed by differential centrifugation of the homogenate. Microsome extracts were incubated with varying concentrations of [1,2,6,7-3H]-testosterone, 1mM NADPH, and varying amounts of the compounds of Formula I, i.e. a test compound, in buffer containing a NADPH regenerating system capable of maintaining NADPH concentrations for a period of time within the range 0.5-240 minutes. Corresponding incubations were carried out with no test compound as a control study. For type 1 IC50

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AP Ο Ο Ο 4 5 9

-37measurements, assay components except testosterone were preincubated for 10 minutes at pH 7.0, and following the addition of 100nM testosterone the assays were allowed to proceed for 10-120 minutes.

For type 2 IC50 measurements, assay components except testosterone were preincubated for 20 minutes at pH 6.0, and following the addition of 8nM testosterone the assays were allowed to proceed for 20-40 minutes. The percentage of conversion of testosterone to DHT in the presence of test compounds compared to the corresponding conversion in the control study was estimated using high pressure liquid chromatography (HPLC) with radiochemical detection. The results of these assays appear as IC50S reported in Table 1.

TABLE 1

5-REDUCTASE In vitro INHIBITORY ACTIVITY

Compound/ Example	IC50 Human Type 1	IC50 Human Type 2	IC50 Rat Prostatic
1	+	+++	++
2	+++	+++	+++
3	++	++	+++
4	+	+++	+
5	+	++	++
6	+	++	++
7	+	+++	++
9	++	+++	+++
10	+++	+++	++
11	++	+++	+++
12	++	+++	+++
13	++	+++	+++
14	++	+++	+++
15	+	+++	+++
16	++	+++	+++
17	++	+++	+++
18	++	+++	+++
19	+	++	++
20	+	++	++
21	+	++	+
22	++	+++	+++
23	++	+++	nt
24	++	+++	+++

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Compound/ Example	IC50 Human Type 1	IC50 Human Type 2	IC50 Rat Prostatic
25	++	+++	+++
26	++	+++	nt
27	+++	+++	++
28	++	++	+++
29	+	++	++
30	++	+++	++
31	++	+++	+++
32	++	+++	+++
33	+	++	++
34	++	+++	+++
35	+	+++	+++
36	+	+++	+++
37	++	+++	nt
38	++	+++	+
39	++	+++	++
40	++	+++	++
41	++	+++	+
42	++	+++	+++
43	+++	+++	+
44	++	+++	+
45	+	+++	++
46	++	+++	+++
47	++	+++	+++
48	+++	+++	++
49	+++	+++	+++
50	+++	+++	++
51	+	++	+
52	++	+++	++
53	++	+++	+++
54	++	+++	nt
55	++	+++	nt
56	++	+++	nt
57	++	++	nt
58	++	+++	nt
59	+	++	nt
60	+	++	nt
61	++	+++	nt
62	+	+++	nt
63	+	+++	nt
64	+++	+++	nt
65	++	+++	nt
66	+	+++	nt

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Compound/ Example	IC50 Human Type 1	IC50 Human Type 2	IC50 Rat Prostatic
67	+	+++	nt
68	++	+++	nt
69	++	+++	nt
70	++	+++	nt
71	++	+++	nt
72	++	+++	nt
73	+++	+++	nt
74	+++	+++	nt
75	+++	+++	nt
76	++	+++	nt
77	+++	+++	nt
78	++	+++	nt
79	++	+++	nt
80	++	+++	nt
81	++	+++	nt
82	+++	+++	nt
83	++	+++	nt
84	++	+++	nt
85	+++	+++	nt
86	+++	+++	nt
87	+++	+++	nt
88	+++	+++	nt
89	++	+++	nt
90	+++	+++	nt
91	++	+++	++
92	++	+++	nt
93	++	+++	+
94	++	+++	nt
95	+	++	nt
96	++	+++	nt
97	+	++	nt
98	+++	+++	nt
99	+++	+++	nt
100	+++	+++	nt
101	+++	+++	nt
102	+++	+++	nt
103	++	+++	nt
104	++	+++	nt
105	+++	+++	nt
106	+++	+++	nt
107	+	+++	nt
108	++	+++	nt

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Compound/ Example	IC50 Human Type 1	IC50 Human Type 2	IC50 Rat Prostatic
109	+++	+++	nt
110	++	+++	nt
111	+++	+++	nt
112	++	+++	nt
113	++	+++	nt
114	++	+++	nt
115	+++	+++	nt
116	+++	+++	nt
117	+++	+++	nt
118	+++	+++	nt
119	++	+++	nt
120	+++	+++	nt
121	+++	+++	nt
122	+++	+++	nt
123	++	+++	nt
124	++	+++	nt
125	+++	+++	nt
126	+++	+++	nt
127	+++	+++	nt
128	+++	+++	nt
129	++	+++	nt
130	+++	+++	nt
131	+++	+++	nt
132	++	+++	nt
133	+	+++	nt
134	++	+++	nt
135	+	+++	nt
136	+++	+++	nt
137	+	+++	nt
138	++	+++	nt
139	+++	+++	nt
140	+++	+++	nt
141	+	+++	nt
142	+	+++	nt
143	+++	+++	nt
144	+++	+++	nt
145	+++	+++	nt
146	+++	+++	nt
147	+++	+++	nt
148	nt	nt	nt

1060AC

AP 0 0 0 4 5 9

-41+++ = < 10 ηΜ ++ =10-100ηΜ + =>100ηΜ nt = not tested ln..Vivo.£xaluaiiQ.n of SterQjd.5«-7fledugiaseJntiibitois

The in vivo activity of steroid 5a-reductase inhibitors may be determined in both acute and chronic rat models. The acute model utilizes castrated male rats that receive testosterone (1 mg) subcutaneously and test compound (10 mg/kg) p.o., at 0.5 hr. and 4.5 hr. prior to sacrifice, respectively. Levels of DHT in the serum and prostate indicate the ability of the test compound to inhibit steroid 5areductase in an acute rat model. Known steroid 5a-reductase inhibitors were tested in parallel to ensure consistency of the assay method.

The chronic model also utilizes castrated male rats that are dosed daily with testosterone (20 pg/rat) subcutaneously and with test compound (0.01-10 mg/kg) p.o. for 7 days. The animals are then sacrificed and their prostates weighed. Reduction in the size of testosterone-stimulated prostate weight demonstrated activity of the test compound. Known steroid 5a-reductase inhibitors were tested in parallel to ensure consistency of the assay method.

Utility

The steroid 5a-reductase inhibitors of the present invention are useful in the treatment of androgen responsive diseases, e.g., benign and malignant diseases of the prostate, especially benign prostatic hyperplasia. For correlation of in vitro, rat in vivo and human clinical data relating to an inhibitor of 5a-reductase, see Stoner, J. Steroid Biochem. Molec. Biol., 37, 375 (1990); Brooks, et al., Steroids, 47, 1 (1986) and Rasmusson, J. Med. Chem., 29, 2298 (1986)). They are also useful in the treatment of prostatitis, prostate cancer, androgen mediated diseases of the skin, such as acne, hirsutism and male pattern baldness. Other hormone related diseases, e.g., polycystic ovary disease, would be expected to respond to treatment with these inhibitors.

1060AC

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-42The amount of compound of formula (I) required to be effective as an 5a-reductase inhibitor will, of course, vary with the individual mammal being treated and is ultimately at the discretion of the medical or veterinary practitioner. The factors to be considered include the condition being treated, the route of administration, the nature of the formulation, the mammal's body weight, surface area, age and general condition, and the particular compound to be administered. However, a suitable effective 5a-reductase inhibitory dose is in the range of about 0.01 to about 5 mg/kg body weight per day, preferably in the range of about 0.05 to about 2 mg/kg per day.

The total daily dose may be given as a single dose, multiple doses, e.g., two to six times per day, or by intravenous infusion for a selected duration. Dosages above or below the range cited above are within the scope of the present invention and may be administered to the individual patient if desired and necessary. For example, for a 75 kg mammal, a dose range would be about 5 to about 150 mg per day, and a typical dose would be about 20 mg per day. If discrete multiple doses are indicated, treatment might typically be 5 mg of a compound of formula (I) given 4 times per day.

The compounds of formula (I) may also be administered in a topical formulation, e.g., ointment, cream, gel, or lotion, in cases of dermatological disorders such as acne vulgaris. An effective topical formulation contains from about 0.25% to about 10% by weight, of a compound of formula (I) which is applied at the rate of about 0.1 g to about 1.0 g per square centimeter of infected skin area. Typically a dose is about 1 gram of a 1% ointment, cream, gel, or lotion of a compound of formula (I) gently rubbed onto the square centimeter of skin in need of treatment.

Formulations

Formulations of the present invention for medical use comprise an active compound, i.e., a compound of formula (I), together with an acceptable carrier thereof and optionally other therapeutically active ingredients. The carrier must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

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-43The present invention, therefore, further provides a pharmaceutical formulation comprising a compound of formula (I) together with a pharmaceutically acceptable carrier thereof.

The formulations include those suitable for oral, rectal, topical or parenteral (including subcutaneous, intramuscular and intravenous) administration. Preferred are those suitable for oral or parenteral administration.

The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active compound into association with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active compound into association with a liquid carrier or a finely divided solid carrier and then, if necessary, shaping the product into desired unit dosage form.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of the active compound; as a powder or granules; or a suspension or solution in an aqueous liquid or non-aqueous liquid, e.g., a syrup, an elixir, an emulsion or a draught.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form, e.g., a powder or granules, optionally mixed with accessory ingredients, e.g., binders, lubricants, inert diluents, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered active compound with any suitable carrier.

A syrup or suspension may be made by adding the active compound to a concentrated, aqueous solution of a sugar, e.g., sucrose, to which may also be added any accessory ingredients. Such accessory ingredient(s) may include flavoring, an agent to retard crystallization of the sugar or an agent to increase

BAD ORIGINAL £,

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-44the solubility of any other ingredient, e.g., as a polyhydric alcohol, for example, glycerol or sorbitol.

Formulations for rectal administration may be presented as a suppository with a conventional carrier, e.g., cocoa butter or Witepsol S55 (trademark of Dynamite Nobel Chemical, Germany), for a suppository base.

Formulations suitable for parenteral administration conveniently comprise a sterile aqueous preparation of the active compound which is preferably isotonic with the blood of the recipient. Such formulations suitably comprise a solution or suspension of a pharmaceutically and pharmacologically acceptable acid addition salt of a compound of the formula (I) that is isotonic with the blood of the recipient.

Thus, such formulations may conveniently contain distilled water, 5% dextrose in distilled water or saline and a pharmaceutically and pharmacologically acceptable acid addition salt of a compound of the formula (I) that has an appropriate solubility in these solvents, for example the hydrochloride, isothionate and methanesulfonate salts, preferably the latter. Useful formulations also comprise concentrated solutions or solids containing the compound of formula (I) which upon dilution with an appropriate solvent give a solution suitable for parental administration above.

Topical formulations include ointments, creams, gels and lotions which may be prepared by conventional methods known in the art of pharmacy. In addition to the ointment, cream, gel, or lotion base and the active ingredient, such topical formulation my also contain preservatives, perfumes, and additional active pharmaceutical agents.

In addition to the aforementioned ingredients, the formulations of this invention may further include one or more optional accessory ingredient(s) utilized in the art of pharmaceutical formulations, e.g., diluents, buffers, flavoring agents, binders, surface active agents, thickeners, lubricants, suspending agents,

1060AC

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-45EXAMPLES

The following examples illustrate aspects of this invention but should not be construed as limitations. The symbols and conventions used in these examples are consistent with those used in the contemporary chemical literature, for example, the Journal of the American Chemical Society.

Example 1

173-N-9-Fluorenyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 1)

A. 3p-Triisopropylsilyloxyetienic acid methyl ester

A suspension of 3β-Ι^όΓθχγθίίθηίε acid methyl ester (J. Med. Chem. 27, 1690) (516 g, 1.55 mol) in DMF (800 mL) is heated to 55°C, imidazole (264 g, 3.88 mol) added with vigorous mechanical stirring, followed by dropwise addition of triisopropylsilylchloride (360 g, 1.87 mol). The reaction becomes homogeneous after about half of the triisopropylsilylchloride is added and the reaction temperature increases to ca. 70°C. The reaction is complete by TLC (35% ethyl acetate/hexanes) after 1.5 hrs and a thick slurry forms. The reaction is cooled to 0°C, 1 L of ice water added with stirring, the solid collected by filtration and washed with water (500 mL) and methanol (500 mL). The resulting tan solid is suspended in methanol (1 L) and allowed to stir overnight to give, on filtration, 3p-triisopropylsilyloxyetienic acid methyl ester as a tan solid of sufficient purity to carry on to the following steps; yield; 667 g (88%); m. p. 116-118°C. Recrystallization from hexane gives an analytical sample as a white crystalline solid: m.p. 124-125°C. Anal. Calcd. for C30H52O3Si; C, 73.71; H, 10.72. Found: C, 73.79; H, 10.74.

B. A solution of Οβ-ΙπϊεορωργΙεϊΙγΙοχγθΙΐθηϊο acid methyl ester (166 g, 0.34 mol), from part A, in methylene chloride (2 L) and methanol (800 mL) is cooled to 78°C and treated with ozone until a blue color persists. At this stage, the peroxy compound of formula (V) may be isolated and recrystallized from hexanes to give an analytical sample; m. p. 119-121 °C. Anal. Calcd. for C₃iH56O7Si; C, 65.45; H, 9.92. Found: C, 65.37; H, 9.86. However, more conveniently, the reaction is allowed to warm to -50°C under a stream of nitrogen, zinc dust added (89 g, 1.36 mol), followed by glacial acetic acid (150 mL). The reaction is

BAD ORIGINAL ft

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AP 0 00 4 5 9

-46then allowed to warm to room temperature with stirring, filtered to remove zinc, the solution washed with water, saturated aqueous NaCl, saturated aqueous bicarbonate, dried over MgSO4 and concentrated by rotary evaporation to give crude keto-aldehyde of formula (VI) as a white foam; yield: 176 g (99%).

C. The compound prepared in part B above (176 g, 0.34 mol) is dissolved in acetone, cooled to 0°C and treated with Jones reagent (1.05 eq.) by dropwise addition over 15 min. After 10 min isopropanol is added, the reaction is allowed to stir for 10 min, is filtered, concentrated, dissolved in ethyl acetate (400 mL), washed with saturated NaCl, dried (MgSO4) and concentrated to a green oil. The oil is dissolved in methylene chloride (150 mL), silica gel added (50 g), the mixture filtered through silica gel (200 g) and eluted with hexane/methylene chloride/ethyl acetate/ methanol (8:8:4:1) to give on concentration the corresponding keto-acid of formula (VII) as an off-white solid; yield: 163 g (89%). Recrystallization from ethyl acetate/hexanes gives a white crystalline solid: m. p. 143-145°C. Anal. Calcd. for C3oH52C>6Si; C, 67.12; H, 9.76. Found: C, 67.21; H, 9.80.

D. 17£-Carbomethoxy-3p-triisopropylsilyloxy-6-azaandrost-5-ene

A portion of the keto-acid of formula (VII) prepared above (110 g, 0.205 mol) is dissolved in methylene chloride (120 mL) and pyridine (44.7 mL) and is added dropwise to a solution of oxalyl chloride (48.3 mL, 0.553 mol) in methylene chloride (770 mL) at 0°C. After stirring 30 min, the reaction is poured into a mixture of saturated aqueous NaCl and ice (700 mL), the layers separated, the methylene chloride is washed with ice-cold 0.5M HCI (2X800 mL), ice-cold saturated NaHCO3 (3X700 mL), dried (Na2SO4) and concentrated to give the acid chloride as a white foam; yield: 110 g (96%). This material is then dissolved in acetone (1 L) and pentane (55 mL), cooled to 0°C, and treated with an aqueous solution of sodium azide (53 g, 0.82 mol, 164 mL). After 30 min the reaction is poured into a mixture of saturated NaCl (300 mL), saturated NaHCO3 (300 mL) and ice (300 mL). Toluene is added (1 L), the layers separated, toluene layer washed with ice-cold saturated NaHCO3 (3X400 mL), dried (Na2SO4), filtered and heated to 110°C to distill down to one-half the original volume. The solution is cooled to 38°C and treated with silica gel (212 g). The reaction is allowed to stir overnight, the silica removed by filtration and

BAD ORIGINAL

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ΑΡΰοο

9

-47washed with 4:1 ethyl acetate/methanol (770 mL) to give 17(3-carbomethoxy-3ptriisopropylsilyloxy-6-azaandrost-5-ene (a compound of formula ((IX)) as a white foam; yield: 106 g (94%). Flash chromatography on silica gel (30% ethyl acetate/hexanes) gives an analytical sample as a white foam. Anal. Calcd. for C29H51NO3S1; C, 71.11; H, 10.49; N, 2.86. Found: C, 71.04; H, 10.51; N, 2.80.

E. 17|3-Carbomethoxy-6-i-butoxycarbonyl-6-azaandrost-4-en-3-one

A portion of the crude product from above, 17p-carbomethoxy-3ptriisopropylsilyloxy-6-azaandrost-5-ene (66 g, 0.135 mol) is dissolved in pyridine (500 mL), treated with di-f-butyldicarbonate (150 g, 0.69 mol) and allowed to stir overnight. The pyridine is removed by rotary evaporation and tetrabutylammonium fluoride (500 mL, 1M, 0.5 mol) in tetrahydrofuran (THF) added carefully and the reaction heated to reflux for 5 min. The THF is removed by rotary evaporation, the residue dissolved in ethyl acetate (500 mL), washed cautiously with water, saturated aqueous NaCl, dried with MgSO4 and concentrated. This material is dissolved in DMF (500 mL), is treated with pyridinium dichromate (153 g, 0.41 mol) and allowed to stir overnight. The reaction is poured into water (700 mL) and extracted with ethyl acetate (2X500 mL). The combined extracts are washed with water, 5% aqueous CUSO4, saturated aqueous NaCl, dried over MgSO4, concentrated and flash chromatographed (0-60%, diethyl ether/hexanes) to give 17^-carbomethoxy-6f-butoxycarbonyl-6-azaandrost-4-en-3-one as an off-white foam; yield: 37.5 g (64%); FAB mass spec. MH⁺ 432.

F. 17(3-Carboxy-6-f-butoxycarbonyl-6-azaandrost-4-en-3-one

A solution of 17fi-carbomethoxy-6-f-butoxycarbonyl-6-azaandrost-4-en-3-one (15.4 g, 36 mmol), from part E, in dioxane (150 mL) and water (100 mL) is treated with LiOH*H2O (3.31 g, 79 mmol) and stirred overnight in a water bath. The reaction is poured into saturated aqueous NaHSO4 (150 mL), extracted with methylene chloride (3X100 mL), extracts washed with saturated aqueous NaCl, dried over MgSCM and concentrated to a volume of 100 mL. At this point crystals begin to form and 2:1 hexanes/ethyl acetate (50 mL) is added, the mixture triturated, cooled to room temperature and 17£-carboxy-6-fbutoxycarbonyl-6-azaandrost-4-en-3-one collected as a fluffy white powder;

BAD ORIGINAL flj

1060AC

APOOO

-48yield: 9.44 g (63%); m. p. 215-216°C. Anal. Calcd. for C24H35NO5*¹/4H2O ; C, 68.30; H, 8.48; N, 3.32. Found: C, 68.45; H, 8.41; N, 3.28.

The mother liquor is diluted with methylene chloride (100 mL), filtered through silica gel, silica washed with 1:1 diethyl ether/hexanes and the eluant concentrated to give recovered 17p-carbomethoxy-6-f-butoxycarbonyl-6azaandrost-4-en-3-one; yield: 2.63 g (17%). The silica pad is then washed with 1:9 methanol/methylene chloride (250 mL), the eluant concentrated, the resulting solid triturated with 2:1 hexanes/ethyl acetate (50 mL), cooled to 0°C and 17p-carboxy-6-f-butoxycarbonyl-6-azaandrost-4-en-3-one collected as a white powder; yield: 2.25 g (15%). The combined yield based on recovered starting material is 94%.

G. 17|3-N-9-Fluorenyl-carbamoyl-6-azaandrost-4-en-3-one

A sample of 17p-carboxy-6-f-butoxycarbonyl-6-azaandrost-4-en-3-one (502 mg, 1.20 mmol), from part F, is suspended in toluene (15 mL), treated with pyridine (0.15 mL, 1.5 eq.), cooled to 0°C and thionyl chloride added (0.13 mL, 1.5 eq.). After 1 hr at 0°C the reaction is concentrated to a yellow solid, this crude acid chloride is dissolved in methylene chloride (15 mL) and added to a biphasic mixture of methylene chloride (5 mL) and saturated aqueous NaHCO3 (5 mL) which contains 9-fluorenyl amine hydrochloride (2.5 eq.). After stirring 45 min, ethyl acetate (50 mL) is added, the layers separated, the ethyl acetate layer washed with saturated aqueous NaHSO4, saturated aqueous NaCl, dried over MgSO4, concentrated and chromatographed on silica gel (35-50% ethyl acetate/hexanes) to give 17(3-N-9-fluorenyl-carbamoyl-6-f-butoxycarbonyl-6azaandrost-4-en-3-one as a yellow oil; yield: 558 mg (80%). This material is dissolved in methylene chloride (15 mL) and treated with trifluoroacetic acid (2 mL) at room temperature. After 3 hrs the reaction is concentrated, methylene chloride (50 mL) and saturated aqueous bicarbonate (50 mL) added, the layers separated, methylene chloride washed with saturated aqueous NaCl, dried over MgSO4, concentrated and crystallized from acetonitrile to give 17β-Ν-9fluorenyl-carbamoyl-6-azaandrost-4-en-3-one as a white crystalline solid; yield: 325 mg (56%); m. p. 227-230°C. Anal. Calcd. for C32H36N2O2^,1/2H2O ; C, 78.49; H, 7.62; N, 5.72. Found: C, 78.25; H, 7.67; N, 5.65.

BAD ORIGINAL ft

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ΑΡ ο 0 0 4 5 9

-49Ezample 2

17β-(1 -Oxo-2-cyclohexvlethyl)-6-azaandrost-4-en-3-one (Compound 2)

A solution of 17^-carboxy-6-f-butoxycarbonyl-6-azaandrost-4-en-3-one (260 mg, 0.62 mmol), example 1, part F, is dissolved in toluene (10 mL) and treated with pyridine (3 eq) and catalytic dimethylformamide, cooled to 0°C, and thionyl chloride added (80 mL, 1.10 mmol). The reaction is then allowed to warm to room temperature and stir for 1 hr. The solids are then removed by filtration, the solution concentrated, the resulting crude acid chloride dissolved in THF (6 mL), Cul added (120 mg, 0.62 mmol), cooled to -78°C and treated with methylenecyclo-hexylmagnesium bromide (2.0M in diethyl ether, 0.5 mL, 1 mmol). The reaction is allowed to warm to room temperature, stir for 30 min, is quenched with saturated NaHSO4, extracted with ethyl acetate (2X25 mL), dried over MgSO4, concentrated and chromatographed on silica gel (25% ethyl acetate/hexane) to give 17p-(1-oxo-2-(cyclohexylethyl))-64-butoxycarbonyl-6azaan-drost-4-en-3-one; yield: 302 mg (98%). This material may be deprotected as described in example 1, part G above to give, on crystallization from ether, 17fi-(1-oxo-2-(cyclohexylethyl)-6-azaandrost-4-en-3-one; yield: 121 mg (50%); m. p. 214-216°C. Anal. Calcd. for C26H39NO2*¹/2H2O : C, 76.80; H, 9.92; N, 3.44. Found: C, 76.61; H, 9.89; N, 3.49.

Example 3

Z8-HYdrQxymethvl-(trimethyIacetate)-6iazaandrQst-4-en-3-one (Compound 3)

A. 17p-Hydroxymethyl-3p-hydroxy-6-i-butoxycarbonyl-6-azaandrost-4-ene

A solution of 17p-carbomethoxy-6-f-butoxycarbonyl-6-azaandrost-4-en-3-one (2.30 g, 5.33 mmol), example 1, part E, in methylene chloride (70 mL) at -78°C is treated with diisobutylaluminum hydride (1.5M in toluene, 15 mL, 22.5 mmol). After 20 minutes the reaction is quenched with methanol (4 mL), methylene chloride added (150 mL), washed with 2N NaOH and water, dried over MgSO4 and concentrated to give crude 17J)-hydroxymethyl-3p-hydroxy-6-fbutoxycarbonyl-6-azaandrost-4-ene of sufficient purity to carry on to the following steps; yield: 2.16 g (99%).

B. 17p-Hydroxymethyl-6-f-butoxycarbonyl-6-azaandrost-4-en-3-one

A solution of 17p-Hydroxymethyl-3b-hydroxy-6-f-butoxycarbonyl-6-azaandrost4-ene (prepared as described in Example 5 above), in chloroform (250 mL) is

BAD ORIGINAL ft

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AP Ο Ο Ο 4 5 9

-50treated with activated manganese(IV) oxide. After stirring 3.5 h, the manganese salts are removed by filtration through Celite. The solution is concentrated and chromatographed on silica gel (50% ethyl acetate/hexanes) to give 17β— hydroxymethyl-6-(-butoxycarbonyl-6-azaandrost-4-en-3-one of sufficient purity to carry on to subsequent steps; yield 9.75 g (98%).

C. 17(3-Hydroxymethyl-(trimethylacetate)-6-azaandrost-4-en-3-one A solution of 17(3-hydroxymethyl-6-f-butoxycarbonyl-6-azaandrost-4-en-3-one (1.28 g, 3.17 mmol) in dichloromethane (32 mL) is cooled to 0°C and treated with triethylamine (0.67 mL, 4.8 mmol), 4-dimethylaminopyridine (58.4 mg, 0.48 mmol), and trimethylacetyl chloride (0.6 mL, 4.8 mmol). After stirring 1 h at 0°C and 3 h at room temperature, the reaction is diluted with dichloromethane, washed with saturated aqueous NaHSO4, saturated aqueous NaHCO₃, and saturated aqueous NaCl, dried over MgSO4, filtered, concentrated, and chromatographed on silica gel (25% ethyl acetate/hexanes) to give the crude ester. This material is treated with trifluoroacetic acid as described in Example 4 above to give, after recrystallization from dichloromethane/acetonitrile, 17β— Hydroxymethyl-(trimethylacetate)-6-azaandrost-4-en-3-one as a white powder; yield: 843 mg (69%); m.p. 239-241 °C. Anal. Calcd. for C24H37NO3: C, 74.38;

H, 9.62; N, 3.61. Found: C, 74.17; H, 9.64; N, 3.58.

Examples 4-86

Following the general procedure of example 1, part G, wherein the hydrochloride salt of the amine is reacted with the acid chloride in the presence of sodium bicarbonate or by reaction with the free base of metal salt of the amine, for preparation of amides as the Z substituent in compounds of formula (I); the general procedure of example 2 for preparation of ketones as the Z substituent in compounds of formula (I); and the general procedure of example 3 for preparation of compounds where Z = CH2OCOR8 and Z = CH2OCO2R5 in compounds of formula (I) the following compounds were prepared:

BAD ORIGINAL C

1060AC

AP 0 0 0 4 5 9

-51 ·

ExamplaJ

17p-N-5-lndanylcarbamoyl-6-azaandrost-4-en-3-one (Compound 4)

Melting Point: >270°C.

Anal. Calcd. for C28H36N2O2‘³/4H2O; C, 75.39: H, 8.47; N, 6.30.

Found: C, 75.29; H, 8.42; N, 6.20.

Example 5

17ft-N-Phenyl-(4-morpholino)-carbamoyl-6-azaandrost-4-en-3-one (Compound

5)

Melting Point: >250°C.

Anal. Calcd. for C29H39N3O3*¹/4H2O; C, 72.24; H, 8.26; N, 8.72.

Found: C, 72.26; H, 8.26; N, 8.73.

Example 6

17ft-N-4-Benzodioxan-carbamoyl-6-azaandrost-4-en-3-one (Compound 6)

Melting Point: >260°C.

Anal. Calcd. for C27H34N2O4; C, 71.97; H, 7.61; N, 6.22.

Found: C, 71.70; H, 7.68; N, 6.18.

Example 7

17(3-N-(3.4-MethylenediPxy)phenyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 7)

Melting Point: >264°C.

Anal. Calcd. for C26H32N2O4*H2O; C, 68.70; H, 7.54; N, 6.16.

Found: C, 68.78; H, 7.60; N, 5.96.

Example 8 tZfi-Ni2-(3Jndolyl)ethyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 8)

Melting Point: 196-202°C.

. Anal. Calcd. for C29H37N3O2*¹/2H2O; C, 74.33; H, 8.17; N, 8.97.

Found: C, 74.31; H, 8.15; N, 8.87.

BAD ORIGINAL ft

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AP 0 0 0 4 5 9

-5217fi-N-(2-Trifluoromethyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 9)

Melting Point: 249-253°C.

Anal. Calcd. for C26H31N2O2F3*¹/3H2O; C, 66.93; H, 6.84; N, 6.00.

Found; C, 67.02; H, 7.00; N, 5.71.

Example 1Q

17fi-N-(2.5-Di-f-butyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one (Compound

IQ)

Melting Point: 178-186°C.

Anal. Calcd. for C33H48N2O2*¹/4H2O; C, 77.83; H, 9.60; N, 5.50.

Found: C, 77.72; H, 9.61; N, 5.49.

Example 11

17fr-N-(4-Chlorophenyl)(phenyl)methyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 11)

Melting Point: 245-250°C (decomp.).

Anal. Calcd. for C32H37N2O2CI«³/8H2O; C,7337;H,726;N,535;O6.78.

Found; C,7324,H,723;N,538;O676

Example 1.2

17p-N-(4-Methynphenethyl-carbamoyl-6-azaandrost-4-en-3-one (Compound

12}

Melting Point: 244-246°C.

Anal. Calcd. for C28H38N202’¹/4H2O; C, 76.59; H, 8.84; N, 6.38.

Found: C, 76.97; H, 8.93; N, 6.40.

Example.,13

17p-N-(a-Methyl)phenethyl-carbamoyl-6-azaandrost-4-en-3-one_(Compound

12}

Melting Point: 188-189°C.

Anal. Calcd. for C28H38N2O2*¹/4H2O; C. 76.59; H, 8.84; N, 6.38.

1060AC

AP 0 ο 0 4 5 9

-53Example 14

17&-N-(2.6-Di-/-Dropyl)Dhenvl-carbamovl-6-azaandrost-4-en-3-one (Compound

Η)

Melting Point: 198-200°C.

Anal. Calcd. for C31H44N2O2‘¹/2H2O; C, 76.66; H, 9.33; N, 5.76.

Found: C, 76.77; H, 9.09; N, 5.77.

Example-! 5

17[3-N-l-FluorenyLcarbamoyJ-6;azaandrost-4-en-3-one (Compound 15)

Melting Point: 215-230°C (decomp.).

Anal. Calcd. for C32H36N2O2*³/4H2O; C, 77.78; H, 7.65; N, 5.67.

Found: C, 77.91; H, 7.56; N, 5.76.

Example 16 l?P-N-I3,3J3iDhenyl)i2rQDyl-carbarnoyl-6-azaandrost-4-en-3-one (Compound

Ifi)

Melting Point: 136-141 °C.

Anal. Calcd. for C34H42N2O2*1/2H2O; C, 78.57; H, 8.34; N, 5.39.

Found: C, 78.86; H, 8.29; N, 5.40.

Example 17

17B-N-(a-P.henvl)Phenethyl-carbampyl-6-azaandrost-4-en-3-one (Compound

12)

Melting Point: >250°C.

Anal. Calcd. for C33H40N2O2; C, 79.80; H, 8.12; N, 5.64.

Found: C, 79.74; H, 8.11; N, 5.60.

Example 18

17ft-N-(4-FJuorophenyl)(2-thiophene)methyl-carbamoyl-6-azaandrost-4-en-3one (Compound 18)

Melting Point: 172-180°C.

Anal. Calcd. for C30H35N2O2S»3/gH2O; C,7Q16;H7jO2;K546;S^625

Found: £7αΐ8;Η,69θ;Ν,530;8,624.

BAD ORIGINAL £

1060AC

AP 0 0 0 4 5 9

-54Example. 19

17p-N-f2-Furanyl)methyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 19)

Melting Point: 156-158°C.

Anal. Calcd. for C24H32N2C>3‘1¹/4H2O; C, 68.79; H, 8.30; N, 6.68.

Found: C, 68.59; H, 8.18; N, 6.59.

Example 2Q

17ft-N-2-(2-Pyridyl)ethyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 20)

Melting Point: 132-135°C.

Anal. Calcd. for C26H35N3O2*H2O; C, 71.04; H, 8.48; N, 9.55.

Found: C, 70.99; H, 8.46; N, 9.12.

Example^!

17fr-N-(1.1 -Dimethvl)-2-hydroxyethyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 21)

Melting Point: 170°C (decomp.).

FAB mass spec, for C23H36N2O3; 388.54

Found: 389 MH+

Example 22

17p-N-(2.2-Diphenyl)ethyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 22)

Melting Point: >250°C.

FAB mass spec, for C33H40N2O2; 496.7

Found: 497 MH+

ExampJe.23

17(3-N-2-(Phenylthio)ethvl-carbamoyl-6-azaandrost-4-en-3-one (Compound 23)

Melting Point: 130-131 °C.

Anal. Calcd. for C27H36N2O2S*H2O; C, 68.90; H, 8.13; N, 5.95.

Found: C, 68.59; H, 7.76; N, 5.94.

BAD ORIGINAL

1060AC

AP0 Ο Ο 4 5 9

-55Examp!fi24

17p-N-Bis-(4-fluorophenyl)methyl-carbamoyl-6-azaandrost-4-en-3-one {Compounded)

Melting Point: 178-184°C.

Anal. Calcd. for C32H36N2O2F2*¹/4H2O; C, 73.47; H, 7.03; N, 5.36.

Found: C, 73.55; H, 7.04; N, 5.33.

Example25

J7fi-N.-(2e-Ojohenyl)-Itydrazidyl-6-azaandrost-4-en-3-one (Compound 25)

Melting Point: 194-196°C.

Anal. Calcd. for C31 Η37Ν3θ2·¹/2Η2θ; C,7555; H, 7.78; N, 853

Found: C, 75.44; H, 7.82; N, 8.50.

Example 26 l75-£lrOxQ-1-(2..4-difluoroDhenvnmethvl)-6-azaandrost-4-en-3-one (Compound

££) Melting Point: 238°C (decomp.). Anal. Calcd. for C25H29NO2F2^,1/4H2O; Found:	C,71B3;H,7.11;N,335 C, 72.07; H, 6.97; N, 3.64.
Example 27 175-Hvdroxvmethvl-(3-methvlbutvrate)-6-azaandrost-4-en-3-one_(Compound
2Z) Melting Point: 137-138°C. Anal. Calcd. for C24H37NO3»H2O; Found:	C, 71.07; H, 9.69; N, 3.45. C, 70.82; H, 9.69; N, 3.46.
Example 28 17P-ijydroxyinethyl-i22-diphenylacetate)-6-azaandrost-4-en-3-one (Compound

2S)

Melting Point: 200-201 °C.

Anal. Calcd. for C33H39NO3«¹/4H2O; C, 78.93; H, 7.93; N, 2.79.

Found; C, 79.14; H, 7.97; N, 2.79.

BAD ORIGINAL ft

1060AC

AP0 ο Ο 4 5 9

-56Example 29

17|3-N-2-(3-N-Methylpyrrole)ethyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 29)

Melting Point: 134-136°C.

Anal. Calcd. for C26H37N3O2*¹/2H2O; C, 72.19; H, 8.85; N, 9.71.

Found: C, 71.88; H, 8.77; N, 9.60.

Example_22

17p-N-(4-Trifluoromethylphenyl)methyl-carbamoyl-6-azaandrost-4-en-3-one (CQ-mpQLtQd 2Ω)

Melting Point: 160-168°C.

Anal. Calcd. for C27H33N2O2F3*¹/4H2O; C, 67.69; H, 7.05; N, 5.85.

Found: C, 67.75; H, 7.09; N, 5.86.

Example. 21

17[3-N-methylenecyclohexyl-carbamoyl-6-azaandrost-4-en-3-one (Compound

21}

Melting Point: 172-174°C.

Anal. Calcd. for C26H40N2O2‘³/4H2O; C, 73.28; H, 9.82; N, 6.57.

Found: C, 73.03; H, 9.88; N, 6.54.

Example. 32

17β-Ν-(1.1 -Dimethyl)-2-(4-fluorophenyl)ethyl-carbamoyl-6-azaandrost-4-en-3one (Compound 32)

Melting Point: 144-148°C.

Anal. Calcd. for C29H39N2O2F; C, 74.63; H, 8.43; N, 6.01.

Found: C, 74.66; H, 8.48; N, 5.92.

Example 33

17β-(1 -Oxo-1 (4-isoproDQxyphenyl)methyl)-6-azaandrost-4-en-3-one (Compound 33)

Melting Point: >260°C.

Anal. Calcd. for C28H37NO3‘²/3H2O; C, 75.13; H, 8.63; N, 3.13.

Found: C, 75.24; H, 8.57; N, 3.13.

BAD ORIGINAL ft

1060AC

AP Ο Ο Ο 4 5 9

-57Example 34 .17B-N-(DicyclPhsxyl)melhyl-.caf.bamoyl-6-azaandrost-4-en-3-one (Compound

24)

Melting Point: 245-246°C.

Anal. Calcd. for C32H50N2O2; C, 77.68; H, 10.19; N, 5.66.

Found: C, 77.54; H, 10.20; N, 5.60.

Example 35

17^-ht7U.-Phenyl)gtbyl-carbamQyl-6-azaandrost-4-en-3-one (Compound 35)

Melting Point: 160-177°C.

Anal. Calcd. for C27H36N2O2’H2O; C, 73.94; H, 8.73; N, 6.39.

Found: C, 73.95; H, 8,72; N, 6.37.

Example 36

17&-N2i4--DaoyflDh.eDyl-carbamQyl.-6-azaandrost-4-en-3-one (Compound 361 Melting Point: 151-154°C.

Anal. Calcd. for C35H52N2O2‘H2O; C, 76.32; H, 9.88; N, 5.09.

Found: C, 75.99; H, 9.62; N, 5.06.

Example 37

17B-N:i4.-BgJzyl)Dipficidyl-catbamoyl-6-azaandrost-4-en-3-one (Compound 37)

Melting Point: 250-251 °C.

Anal. Calcd. for C31H42N2O2’¹/4H2O; C, 77.70; H, 8.94; N, 5.85.

Found: C, 77.39; H, 8.88; N, 6.00.

Example 38

178-HydrQxymethyl-.(1-adamantylcarboxvlate)-6-azaandrost-4-en-3-one (Compound 38)

Melting Point: >275°C.

Anal. Calcd. for C30H43NO3; C, 77.38; H, 9.31; N, 3.01.

Found: C, 77.05; H, 9.20; N, 3.07.

BAD ORIGINAL ft

1060AC

AP0 ο 04 5 9

-58Example 39 l/B-N-Myrantyl-carbamovl-e-azaandrost^-en-S-one (Compound 39)

Melting Point: 182-185°C (foams).

Anal. Calcd. for C29H44N2O2‘³/4H2O; C, 74.71; H, 9.84; N, 6.01.

Found: C, 74.69; H, 9.78; N, 6.00.

Example 40

17p-N-(2.4.6-Trimethyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one (Compound

4Ω)

Melting Point: 243-251 °C.

Anal. Calcd. for C28H38N2O2*2TFA; C, 58.00; H, 6.08; N, 4.23.

Found: C, 59.62; H, 6.73; N, 4.73.

Example 41

17B-N-Hydroxy-N-f-butyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 41)

Melting Point: 252-254°C (decomp.).

Anal. Calcd. for C23H36N2O3; C, 71.10; H, 9.34; N, 7.21.

Found: C, 71.03; H, 9.39; N, 7.20.

Example 42

17B-N-(2.4-Difluoro)benzyl-carbamoyl-6-azaandrost-4-en-3-one (Compound

42)

Melting Point: 134-137°C.

Anal. Calcd. for C26H32N2O2F2*H2O; C, 67.80; H, 7.44; N, 6.08.

Found: C, 67.70; H, 7.25; N, 6.09.

Example 43

17β-( 1 -Oxo-3.3-diphenylpropyl)-6-azaandrost-4-en-3-one (Compound 43)

Melting Point: 106°C (shrinks).

FAB mass spec, for C33H39NO2; 481.68

Found: 482 MH+

BAD ORIGINAL ft

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AP Ο Ο Ο 4 5 9

-59Example 4,4

17fi-.Nri2-ChlQfQ;5-lrifluorQmethyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 44)

Melting Point: 173-174°C.

Anal. Calcd. for C26H30N2O2CIF3: C, 63.09; H, 6.11; N, 5.66.

Found: C, 62.88; H, 6.48; N, 5.62.

Example 45 .17&-N-i2.2-DiPhenyl-1-meihyi)elhyl-carbamoyl-6-azaandrost-4-en-3-one ( 10 {Compound 45)

Melting Point: >240°C.

Anal. Calcd. for C34H42N2O2»¹/4H2O; C, 79.26; H, 8.31; N, 5.44.

Found: C, 79.17; H, 8.35; N, 5.46.

Example, 46

JZB-N-(2.6-Piroethyl-4-_bromo)phenyl-carbamoyl-6-azaandrost-4-en-3-one {Compound 46)

Melting Point: >256°C.

Anal. Calcd. for C27H35N2O2BPI/3H2O; C, 64.15; H, 7.11; N. 5.54.

Found: C, 64.30; H, 7.10; N, 5.53.

(

Example 47 ( 17&-N-Bis-J4rChlQfppheDyDmethyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 47)

Melting Point: 188-194°C.

Anal. Calcd. for C32H36N2O2Cl2’¹/4H2O; C, 69.67; H, 6.58; N, 5.08.

Found: C, 69.51; H, 6.56; N, 5.02.

Example 48

17B-N-(2.6-Di.methyL4-FbuivllQhenvl-carbamovl-6-azaandrost-4-en-3-one {Compounds

Melting Point: 203°C (shrinks).

Anal. Calcd. for C31 Η44Ν2θ2*⁵/4Η2θ; C, 74.58; H, 9.39; N, 5.61.

Found: C, 74.59; H, 9.30; N, 5.62.

BAD ORIGINAL A

1060AC

APΟΟΟ459

-60Exampie 49

17ft-N-(2.6-Dibromo-4-isopropyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 49)

Melting Point: 182°C (foams).

Anal. Calcd. for C28H36N2O2Br2*¹/3H2O; C, 56.20; H, 6.18; N, 4.68.

Found: C, 56.08; H, 6.24; N, 4.61.

ExamplP-SQ

17β-N-(2.5-Ditrifluoromethyl)phenyl·carbamQyl-6-azaarκlΓOSt-4-en-3-one 10 (Compound 50)

Melting Point: 144°C (shrinks).

Anal. Calcd. for C27H3oN202F6*2/3H20; C, 59.99; H, 5.84; N, 5.18.

Found: C, 60.06; H, 6.10; N, 5.01.

Example 51

17f3-N-(4-f-Butyl)cyclohexyl-carbamoyl-6-azaandrost-4-en-3-one (Compound

SI)

Melting Point: 229-231 °C.

Anal. Calcd. tor C29H46N2O2*¹/4H2O; C, 75.85; H, 10.21; N, 6.10.

Found: C, 75.72; H, 10.22; N, 6.08.

Example 52

17ft-N-(2-Bromo)phenyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 52)

Melting Point: >280°C.

Anal. Calcd. for C25H31 N2O2Br; C, 63.69; H, 6.63; N, 5.94.

Pound: C, 63.56; H, 6.67; N, 5.90.

Example^

17fr-N-(2-Phenyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 53) 30 Melting Point: >280°C.

Anal. Calcd. for C31 Η36Ν2θ2*2Η2θ; C, 73.78; H, 7.99; N, 5.55.

Found: C, 73.62; H, 7.17; N, 5.47.

BAD ORIGINAL

1060AC

AP Ο Ο ο 4 5 9

-61Example 54

17P-N-(2.6-Diethyl-3.5-dichloro)phenyl-carbamoyl-6-azaandrosi-4-en-3-one (Compound 54)

Melting Point: >250°C.

Anal. Calcd. for C29H38N2O2Cl2*H2O; C, 65.04; H, 7.53; N, 5.23.

Found: C, 65.38; H, 7.49; N. 5.25.

Example 55

17B-N-(2.6-Diethvl-3-chloro)Dhenyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 55)

Melting Point: 230-232°C.

Anal. Calcd. for C29H39N2O2Ch¹/4H2O; C, 71.44; H, 8.17; N, 5.75.

Found: C, 71.41; H, 8.20; N, 5.75.

Example 56

17B-N:(2-F.Butvl)phenyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 56)

Melting Point: 174-180°C.

Anal. Calcd. for C29H4oN202^>1/2H20; C, 76.11; H, 9.03; N, 6.12.

Found: C, 76.12; H, 9.02; N, 6.14.

Example 57

17p-N-.(3.5-Dit[ifluQrQmethyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one

ICompound-S?)

Melting Point: 194°C (shrinks).

Anal. Calcd. for C27H30N2O2F6*¹/3H2O; C, 60.67; H, 5.78; N, 5.24.

Found: C, 60.72; H, 5.82; N, 5.03.

Example 58

17fi-N-(2.4.6-Trichloro)Dhenvl-carbamoyl-6-azaandrost-4-en-3-one (Compound 58)

Melting Point: >250°C.

Anal. Calcd. for C25H29N2O2Cl3*¹/3H2O; C, 60.55; H, 5.89; N, 5.65.

Found: C, 60.52; H, 5.93; N, 5.65.

BAD ORIGINAL ft

1060AC

AP000459

-62Example 59

17p-N-(3.5-Tetramethyl)cyclohexyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 59)

Melting Point: 193-195°C.

Anal. Calcd. for C29H46N2O2Br2*H2O; C, 73.68; H, 10.24; N, 5.93.

Found: C, 73.72; H, 10.34; N, 5.99.

Examula-SP

17β-(1 -Oxo-1 -((2.4.6-tri-/-Drooyl)Dhenyl)methyl)-6-azaandrost-4-en-3-one (Compound 60)

Melting Point: >230°C.

Anal. Calcd. for C34H49NO2‘¹/2H2O; C, 79.64; H, 9.82; N, 2.73.

Found: C, 79.53; H, 9.57; N, 2.73.

Example 61

17ft-N-(2-Bromo-5-trifluoromethyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 61)

Melting Point: 170-190°C (decomp.).

Anal. Calcd. for C26^H30N2O2BrF3; C, 57.89; H, 5.61; N, 5.19.

Found: C, 57.83; H, 5.63; N, 5.15.

Example 62

17p-N-(2-r-Butyl-6-methyl)Dhenvl-carbamoyl-6-azaandrost-4-en-3-one (Compound 62)

Melting Point: 190-220°C (decomp.).

FAB mass spec, for C30H42N2O2; 462.68

Found: 463 MH+

Example, 63

17β-Ν-(1 -Methvl-1 -phenvl)ethyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 63)

Melting Point: 156°C (shrinks).

Anal. Calcd. for C28H38N2O2’¹/2H2O; C, 75.81; H, 8.86; N, 6.31.

Found: C, 75.90; H, 8.84; N, 6.30.

BAD ORIGINAL

1060AC

AP Ο Ο Ο 45 9

-63Example 64

17p-N-1-(4-Chlorophenyl)cyclopentyl-carbamoyl-6-azaandrost-4-en-3-one (Compound ¢4)

Melting Point: 186-189°C.

Anal. Calcd. for C30H39N2O2CI; C, 72.77; H, 7.94; N, 5.66.

Found: C, 72.54; H, 7.92; N, 5.63.

ExamplS-65 lZfl-N-_il_-I4:ChlQrophenyl)-2-methyl)propyl-carbamoyl-6-azaandrost-4-en-310 one (Compound 65)

Melting Point: 177-179°C.

Anal. Calcd. for θ29Η39Ν2θ2^¹/4Η2θ; C, 71.43; H, 8.17; N, 5.75.

Found: C, 71.43; H, 8.20; N, 5.79.

Example, 66 .17B-N-( 1.1 -Di-4-chlorQPhenvl)ethyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 66)

Melting Point: 186-194°C.

Anal. Calcd. for C33H38N2O2CI2; C, 70.00; H, 6.78; N, 4.96; Cl, 12.54.

Found: C, 69.89; H, 6.84; N, 4.92; Cl, 12.41.

Example 67 .17&-N-/1-Phenvl-1-(4-f-butyl)phenyl)methyl-carbamoyl-6-azaandrost-4-en-3one (Compound 67)

Melting Point: 188-192°C.

Anal. Calcd. for C36H46N2O2^,1/4H2O; C, 79.59; H, 8.63; N, 5.16.

Found: C, 79.52; H, 8.67; N, 5.10.

Example 68

17B-I3.-Qxo-3-(2-norbornyl)inethvl)-6-azaandrost-4-en-3-one (Compound 68)

Melting Point: 128°C (shrinks).

High res. mass spec, for C26H37NO2; 396.2903

Found: 396.2911 MH+

BAD ORIGINAL

1060AC

ΑΡ ο 0 0 4 5 9

-64Example 69

17p-N-(2.6-Dibromo-4-chloro)phenyl-carbamoyl-6-azaandrost-4-en-3-one (Compound.69}

Melting Point: 240-244°C (decomp.).

Anal. Calcd. for C25H29N2O2Br2CI*¹/2H2O; C, 50.57; H, 5.09; N, 4.72.

Found: C, 50.41; H, 4.94; N, 4.62.

Example 70

17p-N-(2.6-Diethyl-4-bromo)phenyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 70 )

Melting Point: 212-216°C.

Anal. Calcd. for C29H39N2O2Br; C, 66.01; H, 7.46; N, 5.31; Br, 15.16.

Found: C, 65.94; H, 7.46; N, 5.29; Br, 15.24.

Example 71

17ft-N-(2-Bromo-4-f-butyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 71)

Melting Point: >250°C.

Anal. Calcd. for C29H39N2O2Br; C, 66.01; H, 7.46; N, 5.31; Br, 15.16.

Found: C, 65.91; H, 7.42; N, 5.31; Br, 15.09.

Example 72

17ft-N-(2-Chloro-4-f-butvl)phenyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 72)

Melting Point: 235-246°C (decomp.).

Anal. Calcd. for C29H39N2O2CI; C, 71.44; H, 8.16; N, 5.74; Cl, 7.27.

Found; C, 71.52; H, 8.19; N, 5.75; Cl, 7.26.

Example 73

17β-Ν-(1 -f-Butvl-1 -(4-f-butylphenyl))methyl-carbamoyl-6-azaandrost-4-en-3-one (Compound Z9}

Melting Point: 198-204°C.

Anal. Calcd. for C34H5oN202Br2; C, 76.72; H, 9.75; N, 5.26.

Found: C, 76.81; H, 9.65; N, 5.26.

BAD ORIGINAL ft

1060AC

AP 0 0 0 4 5 9

-65Example 74 .1Z&-N-(S;BiQinfl:2:(-buty.l)phenyl-carbampylL6-^zaandrost-i:eo23zpne (Compound.,74}

Melting Point: 192-195°C.

Anal. Calcd. for C29H39N2O2Br«H2O; C, 63.85; H, 7.58; N, 5.14.

Found: C, 63.75; H, 7.58; N, 5.16.

Example 75

17p-N-(5-Chloro-2-f-butvl)phenyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 75)

Melting Point: 235-246°C (decomp.).

Anal. Calcd. for C29H39N2O2CFH2O; C, 69.51; H, 8.25; N, 5.59.

Found: C, 69.34; H, 8.22; N, 5.98.

Example 76

17ft-N-(2,6-Dieihyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 76)

Melting Point: 190-196°C.

Anal. Calcd. for C29H40N2O2*³/8H2O; C, 76.49; H, 9.02; N, 6.15.

Found: C, 76.59; H, 9.01; N, 6.10.

Example 77

17^N-(4-Bromp-2-f-butyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 77).

Melting Point: 162°C (foams).

Anal. Calcd. for C29H3gN2O2Br; C, 66.01; H, 7.46; N, 5.31.

Found: C, 65.94; H, 7.60; N, 5.20.

Example 76

J7fr-N-(2zf-Butyl:5-pyanolDhenvl-carbamovl-6-azaandrost-4-en-3-one (Compound 78)

Melting Point: >300°C.

Anal. Calcd. for C30H39N3O2^,3/4H2O; C, 73.96; H, 8.38; N, 8.63.

Found: C, 74.11; H, 8.48; N, 8.68.

bad ORIGINAL d

1060AC

AP Ο Ο Ο 4 5 9

-66Example 79

17(3-N-(2-(0-4-Tolyl)-5-trifluoromethyl)Dhenyl-carbamoyl-6-azaandrost-4-en-3one (CompoundZa)

Melting Point: 134-142°C.

Anal. Calcd. for C33H37N2O3F3»‘^l/3Apropanol; C,6995;H,658;N,494.

Found: C, 69.61; H, 6.86; N, 4.73.

Example 8Q

17B-N-(2-(Q-2-Methoxyphenyl)-5-trifluoromethyl))phenyl-carbamoyl-610 azaandrost-4-en-3-one (Compound 80)

Melting Point: 132-142°C.

FAB mass spec, for C33H37N2O4F3; 582.67

Found: 583 MH+

Example 81

17(3-N-(2-(Q-4-Chlorophenyl)-5-trifluoromethyl)phenyl-carbamoyl-6-azaandrost4-en-3-one (Compound 81)

Melting Point: 132-142°C.

Anal. Calcd. for C32H34N203CIF3*¹/3Apropanol*¹/3H20; C, 64.65; H, 6.14; N, 20 457.

Found: C,64.74;H,623;N,45a

Example 82

17(3-N-(2-Nitro-4-(-butyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one 25 (Compound 82)

Melting Point: >265°C.

Anal. Calcd. for C29H39N3O4; C, 70.56; H, 7.96; N, 8.51.

Found: C. 70.42; H, 7.98; N, 8.42.

BAD ORIGINAL A

1060AC

AP 0 0 0 4 5 9

-67Example 8.3

17p-N-(2-(Q-PJienyl)-5-(1Jrdimethyl)propyllphenyl-.carbamoyl-6-azaandrost-4sn-3-one-(C.Q.mpcmnd S3)

Melting Point: 147-152°C.

Anal. Calcd. for C36H46N2O3»¹/2H2O; C, 76.70; H, 8.40; N, 4.97.

Found; C, 76.55; H, 8.39; N, 4.95.

Example 84

12^-Ν·(2:£ΐΐ3/ΐ74-ΡΥ3Π.Ρ)ρή6ηνΙ·03ΓΡ3Π0χ1·6-8Ζ3αη.±Ρ2ΐ·4.τ6Ι]-3.-Ρη6· (Compound 84)

Melting Point: >250°C.

Anal. Calcd. for C28H35N3O2; C, 75.47; H, 7.92; N, 9.43.

Found: C, 75.26; H, 7.95; N, 9.35.

Example,. 85

17fr-N-(2-Ethylsulfonyl-5-trifluoroι^nethyl)phenyl-carbamoyl·6-azaandrost-4-en3-one (Compound 85)

Melting Point: >250°C.

Anal. Calcd. for C28H35N2O4F3S»H2O; C, 58.93; H, 6.54; N, 4.91.

Found: C, 58.87; H, 6.54; N, 4.89.

Example 85

17ft-N-(3.5-Di-f-butyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one (Compound fiS)

Melting Point: 212-216°C.

Anal. Calcd. for C33H48N2O2; C, 77.49; H, 9.61; N, 5.48.

Found: C, 77.59; H, 9.57; N, 5.53.

Example_8Z

17.B-N-(2-f-Butyl-5rlriiluQrQmelhyl)phenyI-carbamoyl-6-azaandrost-4-en-3-one iCpmpQund 87)

A. 4-Trifluoromethyl-a,a-dimethylbenzyl alcohol

To magnesium turnings (30.2 g, 1.24 mol) in THF (30 mL) is added 1,2dibromoethane (0.7 mL) followed by dropwise addition, over 1 h, of 4BAD ORIGINAL &

1060AC

AP 0 0 0 4 5 9

-68bromotrifluoromethylbenzene (200 g, 0.89 mol) dissolved in THF (700 mL). The reaction is heated occasionally to maintain a gentle reflux and is stirred 45 min after the addition is complete. The dark reaction mixture is then cooled in an ice bath and acetone (103 g, 1.78 mol) added dropwise. After stirring an additional 1.5 h the reaction is carefully quenched with aqueous saturated NaHSCU, ethyl acetate added, the organics dried over MgSO4, concentrated and purified by silica gel chromatography (9:1 to 3:2, hexane to ethyl acetate) to give 4trifluoromethyl-a,a-dimethylbenzyl alcohol of sufficient purity to carry to the next step; yield: 114 g (63%).

B. 4-Trifluoromethyl-a,a-dimethylbenzyl chloride

The alcohol from step A above (54 g, 0.27 mol) is treated with ethereal HCl (1.3 L, 1 M) followed by anhydrous zinc chloride (53 mL, 1 M in ether) and the reaction allowed to stir for 22 h at room temperature. The reaction is then washed with water, aqueous 2 N NaOH, dried over MgSO4, concentrated and purified by silica gel chromatography (8:1 hexane to ethyl acetate) to give 4trifluoromethyl-a,a-dimethylbenzyl chloride of sufficient purity to carry to the next step: yield: 50.5 g (85%).

C. 4-Trifluoromethyl-f-butylbenzene

To a toluene solution of dimethylzinc (150 mL, 2.0 M, 0.30 mol) at -78°C is added a CH2CI2 solution of titanium tetrachloride (150 mL, 1.0 M, 0.15 mol) and after stirring for 30 min 4-trifluoromethyl-a,a-dimethylbenzyl chloride (83.3 g, 0.373 mol) in CH2CI2 (100 mL) is added dropwise over 20 min. After the addition is complete the reaction is allowed to warm to -40°C over 1.5 h. After an additional 2 h at -40°C the brown reaction mixture is carefully poured onto crushed ice, extracted with CH2CI2 (2X500 mL), the combined extracts dried over MgSO4 and concentrated to give 4-trifluoromethyl-f-butylbenzene; yield: 60.3 g (80%). Anal. Calcd. for C11H13F3: C, 65.32; H, 6.48. Found: C, 65.11;

H.6.38.

D. 2-f-Butyl-5-trifluoromethylnitrobenzene

To a solution of 4-trifluoromethyl-f-butylbenzene (25.6 g, 126 mmol) in H2SO4 (143 mL) at 0°C is added a mixture of HNO3 (90%, 42 mL) and H2SO4 (87 mL). After 30 min the ice bath is removed and the reaction stirred for 2.5 h further.

BAD ORIGINAL SO)

1060AC

AP Ο Ο Ο 4 5 9

-69The yellow mixture is then poured onto crushed ice and extracted with ethyl acetate, the ethyl acetate washed with 2N NaOH and water, dried (MgSO4) and concentrated to a dark oil. Purification by silica gel chromatography (14:1 hexane to ethyl acetate) gives 24-butyl-5-trifluoromethylnitrobenzene of sufficient purity to carry to the next step: yield: 18.0 g (58%).

E. 2-f-Butyl-5-trifluoromethylaniline

A solution of 2-f-butyl-5-trifluoromethylnitrobenzene (26.0 g, 105 mmol) in ethanol (95%, 100 mL) is treated with 10% Pd/C (2 g) and placed under a hydrogen atmosphere (40 psi) on a Parr apparatus for 1.5 h. The mixture is filtered, concentrated and purified by silica gel chromatography (7.Ί hexane to ethyl acetate) to give 2-f-butyl-5-trifluoromethylaniline as an oil; yield: 20.2 g (89%). Anal. Calcd. for C11H14F3N: C, 60.80; H, 6.50; N, 6.45. Found: C, 60.89; H, 6.50; N, 6.51.

F. ^-N-(2-f-Butyl-5-trifluoromethyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one The aniline prepared above is reacted with the acid chloride of 17p-carboxy-6-fbutoxycarbonyl-6-azaandrost-4-en-3-one (prepared as in example 1, part G) and deprotected as in example 1, part G to give: 7p-N-(2-f-butyl-520 trifluoro)phenyl-carbamoyl-6-azaandrost-4-en-3-one.

Melting Point: 186-190°C.

Anal. Calcd. for C30H39N2O2F3:C, 69.73; H, 7.61; N, 5.42.

Found: C, 69.45; H, 7.66; N, 5.38.

Examples 88-92

Following the general procedure of example 1, part G, wherein the hydrochloride salt of the amine is reacted with the acid chloride in the presence of sodium bicarbonate or by reaction with the free base or metal salt of the amine, for preparation of amides as the Z substituent in compounds of formula (I); the general procedure of example 2 for preparation of ketones as the Z substituent in compounds of formula (I); and the general procedure of example 3 for preparation of compounds where Z = CH2OCOR⁵ and Z = CH2OCO2R⁵in compounds of formula (I) the following compounds were prepared:

' .

BAD ORIGINAL

1060AC

AP 0 0 0 4 5 9

-70Example 88

17B-N-(2-f-Butyl-5-phenyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 88)

Melting Point: 207-209°C.

Anal. Calcd. for C35H44N2O2’¹/4H2O; C, 79.43; H, 8.48; N, 5.29.

Found: C, 79.53; H, 8.54; N, 5.31.

Example 89

17B-Hydroxymethyl-(menthylcarbonate)-6-azaandrost-4-en-3-one (Compound

22)

Melting Point: 152-155°C.

Anal. Calcd. for C3oH47N04‘H20; C, 71.53; H, 9.81; N, 2.78.

Found: C, 71.63; H, 9.79; N, 2.80.

Example 90

17B-Hydroxymethvl-(Dhenylcarbonate)-6-azaandrost-4-en-3-one (Compound

20)

Melting Point: 247-249°C (decomp.).

Anal. Calcd. for C26H33NO4*¹/8CH2Cl2; C, 72.27; H, 7.72; N, 3.23.

Found: C, 71.82; H, 7.77; N, 3.25.

Example 91

17ft-N-(2-f-Butyl-5-(N-methyl)methylsulfonamide)phenvl-6-azaandrost-4-en-3one (Compound 91)

Melting Point: 290-292°C (decomp.).

Anal. Calcd. for C31H45N3O4S; C, 65.40; H, 8.23; N, 7.38.

Found: C, 65.41; H, 8.23; N, 7.42.

Example 92

17fi-N-(3-Nitro-4-f-butyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 92)

Melting Point: 214-217°C.

Anal. Calcd. for C29H39N3O4; C, 69.30; H, 8.02; N, 8.36.

Found: C, 69.11; H, 8.09; N, 8.12.

BAD ORIGINAL &

1060AC

ΑΡ ο ο Ο 4 5 9

-71Example 93

17f3-N-(2.6-Di-Apropyl)phenyl-carbamoyl-6-azaandrost-1.4-dien-3-one (CQmpQund_92)

A. 17(3-Carbomethoxy-6-i-butoxycarbonyl-6-azaandrost-1,4-dien-3-one

A solution of 17p-carbomethoxy-6-f-butoxycarbonyl-6-azaandrost-4-en-3-one (2.00 g, 4.63 mmol), prepared in example 1, part E, in dioxane (50 mL) is treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 1.37 g, 6.02 mmol) and p-nitrophenol (10 mg). The reaction is heated to reflux for 2 hrs, poured into ice water (150 mL), extracted with ethyl acetate (3X100 mL), extracts washed with saturated aqueous NaHSO3, 2N NaOH, saturated aqueous NaCl, dried over MgSO4, concentrated and chromatographed on silica gel (40% ethyl acetate/hexanes) to give crude 17p-carbomethoxy-6-fbutoxycarbonyl-6-azaandrost-1,4-dien-3-one as a tan solid of sufficient purity to carry on to the following steps; yield: 1.53 g (76%).

B. 17(3-N-(2,6-Di-/-propyl)phenyl-carbamoyl-6-f-butoxycarbonyl-6-azaandrost1,4-dien-3-one

A sample of crude 17|3-carbomethoxy-6-f-butoxycarbonyl-6-azaandrost-1,4dien-3-one (0.90 g, 2.20 mmol), prepared in part A, is demethylated as in example 1, part F and then coupled via the acid chloride (described in example 1, part G) with the lithium anion of 2,6-di-/-propylaniline to give after chromatography (30-50% ethyl acetate/hexanes), 17|3-N-(2,6-di-A propyl)phenyl-carbamoyl-6-f-butoxycarbonyl-6-azaandrost-1,4-dien-3-one as a white foam; yield: 0.210 g (16%).

C. 17p-N-(2,6-Di-/-propyl)phenyl-carbamoyl-6-azaandrost-1,4-dien-3-one

A sample of 17|3-N-(2,6-di-/-propyl)phenyl-carbamoyl-6-f-butoxycarbonyl-6azaandrost-1,4-dien-3-one (188 mg, 0.320 mmol), prepared in part B above, is treated with trifluoroacetic acid as described in example 1, part G above to give, after chromatography (50% ethyl acetate/hexanes to 5% methanol/chloroform), 17p-N-(2,6-di-/-propyl)phenyl-carbamoyl-6-azaandrost-1,4-dien-3-one as a white solid; yield: 98 mg (62%); m. p. 273-276°C. Anal. Calcd. for C31Η42Ν2Ο2Ή2Ο ; C, 75.73; H, 8.81; N, 5.69. Found: C, 75.84; H, 8.95; N, 5.68.

BAD ORIGINAL ft

1060AC

AP Ο Ο Ο 4 5 9

-72Example 94

17p-NT2.6-Di-Apropyl)Dhenyl-carbamoyl-6-azaandrost-4-methyl-1.4-dien-3-one (Compound 94)

A. 17p-Carbomethoxy-6-i-butoxycarbonyl-6-azaandrost-4-methyl-1,4-dien-35 one

A solution of 17p-carbomethoxy-6-f-butoxycarbonyl-6-azaandrost-1,4-dien-3one (2.57 g, 5.98 mmol), prepared in example 93, part A in methylene chloride (60 mL) containing anhydrous K2CO3 (8.03 g, 58 mmol) at 0°C is treated with bromine (6.1 mmol) dissolved in methylene chloride (12 mL). After 30 min the mixture is filtered, washed with 10% aqueous NaHSO3, dried over Na2SO4 and concentrated to a foam. This material is dissolved in dimethylformamide (20 mL), treated with phenyltrimethyltin (2.0 mL, 11.4 mmol) and lithium chloride (180 mg, 4.3 mmol), heated to 130°C and treated with PdCl2(PPh3)2 (400 mg, 0.57 mmol). After 1.5 hr the reaction is allowed to cool to room temperature, filtered through Celite, poured into water, the water extracted with ethyl acetate (3X30 mL), extracts washed with water (3X100 mL) and 1% aqueous ammonia (2X100 mL), dried over Na2SC>4, concentrated and chromatographed (5-10% ethyl acetate/methylene chloride) to give 17|3-carbomethoxy-6-fbutoxycarbonyl-6-azaandrost-4-methyl-1,4-dien-3-one; yield: 1.25 g (47%).

B. 17(3-N-(2,6-Di-/-propyl)phenyl-carbamoyl-6-azaandrost-4-methyl-1,4-dien-3one

A sample of crude 17p-carbomethoxy-6-f-butoxycarbonyl-6-azaandrost-4methyl-1,4-dien-3-one (0.45 g, 1.01 mmol), prepared in part A, is hydrolized as in example 1, part F and then coupled with 2,6-di-/-propylaniline as described in example 93, part B, deprotected as in example 1, part G, to give after chromatography (2.5-10% methanol/methylene chloride), 17β—N-(2,6-di-A propyl)phenyl-carbamoyl-6-azaandrost-4-methyl-1,4-dien-3-one as a white powder; yield: 70 mg (14%); m. p. 181-184°C. Anal. Calcd. tor C32H44N2O2·

V4H2O ; C, 77.93; H, 9.09; N, 5.67. Found: C, 77.81; H, 9.12; N, 5.58.

BAD ORIGINAL

1060AC

AP 0 0 0 4 5 9

-73Exampts 95

17MN-APiQDvl-N-(N-ApropylcarbamQyl))2carbamoyl-6-azaandrost-4-en-3-one (Compound 95)

A solution of 17(3-carboxy-6-i-butoxycarbonyl-6-azaandrost-4-en-3-one (500 mg, 1.2 mmol), example 1, part F, is dissolved in methylene chloride (70 mL), treated with diisopropyl carbodiimide (0.21 mL, 1.3 mmol) and stirred at room temperature for 20 hrs. The reaction mixture is then concentrated, the solid dissolved in ethyl acetate (70 mL), the ethyl acetate washed with saturated aqueous NaHCO3 (2X70 mL), 1N HCI (3X70 mL), saturated aqueous NaCl (70 mL), dried over Na2SO4, and concentrated to a yellow foam. Chromatography on silica gel (50% ethyl acetate/hexanes) gives 17p-(N-Apropyl-N-(N-A propylcarbamoyl))-carbamoyl-6-(-butoxycarbonyl-6-azaandrost-4-en-3-one as a white foam; yield: 600 mg (65%). FAB mass spec, for C31H49N3O5; 543.75 Found: 544 MH⁺ This material is deprotected with TFA as in example 1, part G to give, after crystallization from acetonitrile, 17J3-(N-/-propyl-N-(N-h propylcarbamoyl))-carbamoyl-6-azaandrost-4-en-3-one as a white solid; yield: 220 mg (64%); m. p. 162°C (decomp.). Anal. Calcd. for C26H4iN3O3*H2O ; C, 67.64; H, 9.39 N, 9.10. Found; C, 67.58; H, 9.42; N, 9.09.

Example 96

17B-(N-cvclohexvl-N-_(N-cvclohexvlcarbamoyl))-carbamoyl-6-azaandrost-4-en3.-.Qne...(Cpmppu.pd-9S)

Prepared as described in example 95.

Melting Point: 186-187°C.

Anal. Calcd. for C32H49N3O3«¹/4H2O; C, 72.76; H, 9.44; N, 7.95.

Found: C, 72.74; H, 9.45; N, 7.68.

Example. 97

17p-Aminomethyl-(acetamide)-6-azaandrost-4-en-3-one (Compound 97)

A. 17|3-Azidomethyl-6-(-butoxycarbonyl-6-azaandrost-4-en-3-one A solution of 17p-hydroxymethyl-6-(-butoxycarbonyl-6-azaandrost-4-en-3one (2.03 g, 5.04 mmol) prepared in example 3, part 15, in dichloromethane (50 mL) is treated with triethylamine (0.88 mL, 6.3 mmol), DMAP (0.155 g, 1.27 mmol) and methanesulfonyl chloride (0.43 mL, 5.6 mmol). After 3 hrs, the reaction is diluted with dichloromethane (50 mL), washed with 1N HCI,

1060AC

AP 0 0 0 4 5 9

-74saturated aqueous NaCl and dried over MgSO4. Concentration gives a white foam which is dissolved in dimethylformamide (50 mL), treated with sodium azide (0.94 g, 14.5 mmol) and heated to 75°C for 16 hrs. The reaction is poured into ethyl acetate, washed with water (5X100 mL), dried over MgSO4, concentrated and chromatographed on silica gel (20% ethyl acetate/hexane) to give 17(5-azidomethyl-6-Fbutoxycarbonyl-6-azaandrost-4-en-3-one as a white foam of sufficient purity to carry on to the next step.

B. 17f3-Aminomethyl-(acetamide)-6-azaandrost-4-en-3-one

A sample of the azide from step A above (20 mg, 50 mmol) is dissolved in

1:1 ethanol/tetrahydrofuran (2 mL), treated with 10% Pd(C) (3.2 mg) and placed under a hydrogen atmosphere for 10 min. The reaction is filtered, concentrated, dissolved in dichloromethane (2 mL) and treated with pyridine (0.1 mL) and acetic anhydride (0.06 mL). After 64 hrs the reaction is diluted with dichloromethane, dried over Na2SO4, concentrated and chromatographed on silica gel (ethyl acetate) to give 17f3-aminomethyl-(acetamide)-6-fbutoxycarbonyl-6-azaandrost-4-en-3-one which is deprotected with TFA as in example 1, part G to give 17|3-aminomethyl-(acetamide)-6-azaandrost-4-en-3one as a white solid; yield: 3 mg (17%). FAB mass spec, for C21H32N2O2; 344.5. Found: 345 MH+.

Example 98

17ft-Aminomethyl-(1 -adamantylurea)-6-azaandrost-4-en-3-one (Compound 98)

A sample of the azide from example 97, part A (100 mg, 230 mmol) is dissolved in 1:2 ethanol/tetrahydrofuran (6 mL), treated with 10% Pd(C) (60 mg) and placed under a hydrogen atmosphere for 1 hr. The reaction is filtered, concentrated, dissolved in tetrahydrofuran and treated with 1adamantylisocyanate at room temperature for 6 days. The reaction is concentrated and chromatographed on silica gel (40-70% ethyl acetate/hexanes) to give 17(5-aminomethyl-(1-adamantylurea)-6-fbutoxycarbonyl-6-azaandrost-4-en-3-one which is deprotected with TFA as in example 1, part G to give 17p-aminomethyl-(1-adamantylurea)-6-azaandrost-4en-3-one as a white solid; yield: 47 mg (35%); m. p. 227-229°C (foams.). Anal. Calcd. for C3oH45N302*H20 ; C, 72.40; H, 9.52; N, 8.44. Found: C, 72.37; H, 9.42; N, 8.46.

BAD ORIGINAL $

1060AC

AR 0 0 0 4 5 9

-75£x.amptg 5..92.:148

Following the general procedure of example 1, part G, wherein the hydrochloride salt of the amine is reacted with the acid chloride in the presence of sodium bicarbonate or by reaction with the free base or metal salt of the amine, for preparation of amides as the Z substituent in compounds of formula (I); the general procedure of example 3 for preparation of compounds where Z = CH2OCONR¹⁴R¹⁵ in compounds of formula (I); the general procedure of example 8 and 11 in WO 93/13124 for preparation of compounds of formula (I), where R³ = Cl and Me respectively, the following compounds were prepared. Novel amines used to prepare compounds of formula (I) where the Z substituent is an amide were prepared as described in example 87 above or by the method of Stille, J.K. Pure Appl. Chem., 57, 1771 (1985). When either R1⁴ or R15 is an aryl substituted cycloalkyl residue the amine may be prepared by Curtius rearrangement of the corresponding acid, where available, or by the method of He, X. et al., J. Med. Chem., 36,1188 (1993), i.e. by reacting the corresponding cycloalkanone with the appropriate aryl Grignard reagent followed by conversion of the resulting alcohol to the amine by treatment with sodium azide and trifluoroacetic acid followed by reduction of the azide with lithium aluminum hydride. Aryl substituted cyclopropylamines are prepared by rodium catalyzed insertion of the appropriate aryl-a-diazo-ester (prepared by the method of Baum, J.S. et al., Synthetic Comm., 17, 1709 (1987)) into the appropriate olefin (as described by Davies, H.W. et al., Tetrahedron Lett., 30, 5057 (1989)) followed by saponification of the ester and Curtius rearrangement of the acid to give the desired amine.

Example. 93

12fr-Hydroxyniethyl-(2.6-djisopropylphenylcarbamate)-6-azaandrost-4-en-3-one (Compound 99)

Melting Point: 161-163°C.

Anal. Calcd. for C32H46N2C>3*H2O; C, 73.25; H, 9.22; N, 5.34.

Found: C, 73.08; H, 9.19; N, 5.29.

SAD ORIGINAL ft

1060AC

AP 0 0 0 4 5 9

-76Examole 100

17B-N-(4-f-Butyl-2-trifluoromethyf)phenyl-carbamoyl-6-azaandfQSt--4-en-J3-one (Compound 100)

Melting Point: 186-190°C.

Anal. Calcd. for C30H39N2C>2F3‘1/₄H2O; C, 69.14; H, 7.64; N, 5.38.

Found: C, 69.12; H, 7.65; N, 5.35.

Example. .1(21

17B-N-1-(2.4-DichloroDhenyl)cyclopropyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 101)

Melting Point: 160-180°C (decomp.).

Anal. Calcd. for C28H34N2O2Cl2‘¹/₂H2O; C, 65.86; H, 6.91: N, 5.49.

Found: C, 69.64; H, 6.89; N, 5.47.

Example 1Q2

17β-Ν-1 -(3-T rifluoromethylphenyl)cyclopentyl-carbamoyl-6-azaandrost-4-en-3one (Compound 1Q21 Melting Point: 156-159°C.

Anal. Calcd. for C31 H39N2O2F3*H2O; C, 68.11: H, 7.56; N, 5.12.

Found: C, 67.79; H, 7.48; N, 5.02.

Example 103

17β-Ν-(1 -Ethvl-1 -phenyl)propyl-carbamoyl-6-azaandrostr4-enr3-QPe (Compound 103)

Melting Point: 157-160°C.

Anal. Calcd. for C30H42N2O2’³/₄H2O; C, 75.67; H, 9.20; N, 5.88.

Found: C, 75.80; H, 9.09; N, 5.78.

Example 1Q4

173-N-1-(4-Fluorophenyl)cycloDentyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 104)

Melting Point: 220-223°C.

Anal. Calcd. for C3oH39N202F»¹/2H20; C, 73.71; H, 8.17; N, 5.75.

Found: C, 73.89; H, 8.27; N, 5.74.

BAD ORIGINAL

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AP Ο Ο Ο 4 5 9

-771 -Amino-1 -(4-fluorophenyl)cyclopentane: ¹³C NMR (CDCI3) δ 162.8,159.6,

145.2, 127.0, 126.8, 114.8, 114.5, 63.5,41.5, 23.4.

Example 105

17ft-N-(2-f-Butvl-5-N,N-diethylcarbamoyl)phenyl-carbamoyl-6-azaandrost-4-en3-one (Compound 1Q5)

Melting Point: 167-169°C.

Anal. Calcd. for C34H49N3O3*1/₂H2O; C, 73.34; H, 9.05; N, 7.55.

Found: C, 73.41; H, 9.10; N, 7.42.

Example 106

173-N-1-(4-Trifluoromethylphenyl)cyclopentyl-carbamoyl-6-azaandrost-4-en-3one (Compound 106)

Melting Point: 201-203°C.

Anal. Calcd. for C31H39N2O2F3‘¹/2H2O; C, 69.51; H, 7.55; N, 5.09.

Found: C, 69.25; H, 7.50; N, 5.21.

-Amino-1 -(4-trifluoromethylphenyl)cyclopentane: ¹³C NMR (CDCI3) δ 153.6, 153.5, 128.5, 128.1, 126.0, 125.7, 125.1, 125.1, 125.0, 125.0, 122.4, 63.8,41.7,

23.5 .

Example 1Q7

17B-N-(3-Cvano)Phenvl-carbamovl-6-azaandrost-4-en-3-one (Compound 107)

Melting Point: 202-208°C.

Anal. Calcd. for C26H31 Ν3θ2·Η2θ; C, 71.70; H, 7.64; N, 9.65.

Found: C, 71.88; H, 7.69; N, 9.48.

Example 1Q8

17B-N-(4-f-Butvl)phenvl-carbamoyl-6-azaandrost-4-en-3-one (Compound 108) 30 Melting Point: 304-307°C.

Anal. Calcd. for C29H4oN202*¹/4H20; C, 76.86; H, 9.00; N, 6.18.

Found: C, 76.83; H, 8.92; N, 6.54.

BAD ORIGINAL d

1060AC

AP 0 ο Ο 4 5 9

-78Example 1Q9

17p-N-1-(4-FluoroDhenyl)cyclohexyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 109)

Melting Point: 167-169°C.

Anal. Calcd. for C31H41 N2O2F*¹/₃H2O; C, 74.66; H, 8.42; N, 5.61.

Found: C, 74.72; H, 8.43; N, 5.53.

Example ,110

17β-Ν-1 -(2.2-Dimethyl)indanyl-carbamoyl-6-azaandrost-4-en-3-one (Compound

11Ώ)

Melting Point: 178-182°C.

Anal. Calcd. for C30H40N2O2; C, 75.99; H, 8.82; N, 5.91.

Found: C, 75.64; H, 8.84; N, 5.88.

Example 111 l7Q-N-1-(4-Methoxyphenyl)cyclohexyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 111)

Melting Point: 167-169°C.

Anal. Calcd. for C32H44N2O3*³/4H2O; C, 74.17; H, 8.85; N, 5.41.

Found: C, 73.95; H, 8.92; N, 5.38.

Example...l.l2 np-N-^-Phenyl-S-trifluoromethyOphenyl-carbamoyl-G-azaandrosM-en-S-one (Compound 112)

Melting Point: 304-306°C.

Anal. Calcd. for C32H35N2O2F3IC, 71.62; H, 6.57; N, 5.22.

Found: C, 71.56; H, 6.56; N, 5.27.

Example 113

17p-N-(2-Methoxy-5-chloro)phenyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 113)

Melting Point: 237-238°C.

Anal. Calcd. for C26H33N2O3CI‘³/4H2O; C, 66.37; H, 7.39; N, 5.95.

Found: C, 66.17; H, 7.31; N, 5.96.

BAD ORIGINAL

1060AC

AP Ο Ο Ο 4 5 9

-79fcmpte.,11.4

37B-N-(2-CarbQethoxv)phenyl-carbamoyl-6-azaandrost-4-en-3-one (Compound

114)

Melting Point: 282-286°C.

Anal. Calcd. for C28H36N2O4; C, 72.39; H, 7.81; N, 6.03.

Found: C, 72.15; H, 7.88; N, 6.10.

Example 115

1?β4^-1-(4-Methoxy phenyl)cyclopentyl-carbamoyl-6-azaandrost-4-en-3-one 10 (Compound .315)

Melting Point: 160°C.

Anal. Calcd. for C31 Η42Ν2θ3·Η2θ; C, 73.19; H, 8.72; N, 5.51.

Found: C, 73.26; H, 8.67; N, 5.46.

Example 116

17&-N42^bis(JrifiuQrQmethyl))phenyl-carbamoyl-6-azaandrost-4-methyl-4-en3d3.QS..(Campp,nndJ16)

Melting Point: 142-146°C.

Anal. Calcd. for C28H32N2O2F6;C, 61.96; H, 5.95; N, 5.16.

Found: C, 61.70; H, 5.99; N, 5.07.

c p Example 117 l?B-N:i2-f-Butvl-5-trifluorQniethvl)phenyl-carbamoyl-6-azaandrost-4-methyl-4£Ώ:5:.ορο (Compound 117)

Melting Point: 188°C.

Anal. Calcd. for C3iH4lN2O2F3*3/₄H2O; C, 68.42; H, 7.87; N, 5.15.

Found: C, 68.31; H, 7.71; N, 5.08.

Example 118 _12B-N-(2.5-Di-r-butyl)phenyl-carbamoyl-6-azaandrost-4-methvl-4-en-3-one (Compound 118)

Melting Point: 168-176°C.

1060AC

AP 0 0 0 A 5 9

-80Example 119

17B-N-(2.5-Diethoxv)Dhenvl-carbamoyl-6-azaandrost-4-en-3-one (Compound

112)

Melting Point: 277-279°C.

Anal. Calcd. for C29H4oN204’¹/4H20; C, 71.80; H, 8.41; N, 5.77.

Found: C, 71.50; H, 8.45; N, 5.74.

Example 12Q

17(3-N-(2-f-Butyl-5-(4-chlQroDhenyl))phenyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 120)

Melting Point: 214-216°C.

Anal. Calcd. for C35H43N2O2CMI/2H2O; C, 71.71; H, 7.91; N, 4.78.

Found: C, 71.46; H, 7.88; N, 4.81.

Example 121

17p-N-1-(4-f-Butylphenyl)cyclopentyl-carbamoyl-6-azaandrost-4-en-3-one (Cojp.PfiUiid..32.11

Melting Point: 222-232°C.

Anal. Calcd. for C34H48N2O2‘³/4H2O; C, 77.01; H, 9.41; N, 5.28.

Found: C, 77.05; H, 9.46; N, 5.25.

1-Amino-1-(4-f-butylphenyl)cyclopentane: ⁱ³C NMR (CDCI3) δ 148.9, 146.4, 125.1, 125.0, 124.9, 63.7, 41.2, 34.3, 31.4, 31.3, 23.6.

Example 122

17p-N-1-(4-(-Butylphenyl)cyclohexyl-carbamoyl-6-azaandrost-4-en-3-one (Compound.,122)

Melting Point: 203°C.

Anal. Calcd. for C35H50N2O2; C, 76.60; H, 9.55; N, 5.10.

Found: C, 76.43; H, 9.59; N, 5.05.

1-Amino-1-(4-f-butylphenyl)cyclohexane: 1³C NMR (CDCI3) δ 148.8, 146.8, 125.0, 124.6, 53.4, 39.2, 34.2, 31.2, 25.7, 22.4.

BAD ORIGINAL $

1060AC

AP Ο Ο Ο 4 5 9

-81Examele_122

17ft-N-(2-Benzoyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 123)

Melting Point: 290-294°C.

Anal. Calcd. for C32H36N2O3*¹/2H2O; C, 76.01; H, 7.38; N, 5.54.

Found: C, 76.19; H, 7.35; N, 5.47.

Example 124

170-N-1-(3.4-MethylenedioxyDhenyl)cyclohexyl-carbamoyl-6-azaandrost-4-en3-one (Compound 124)

Melting Point: 192°C.

Anal. Calcd. for C32H42N2O4‘³/4H2O; C, 72.22; H, 8.24; N, 5.26.

Found: C, 72.01; H, 8.25; N, 5.14.

1-Amino-1-(3,4-methylenedioxyphenyl)cyclohexane: ¹³C NMR (CDCI3) δ 147.5, 15 145.6, 144.1, 117.9, 107.6, 106.1, 100.7, 53.6, 39.5, 25.6, 22.4.

Example 125

17S:N-l_-14iCtilQCQi?henyl)cyclopentvl-carbamoyl-6-azaandrost-4-methyl-4-en-3one (Compound 125)

Melting Point: 166°C.

High res. mass spec, for C31H41N2O2CI; 509.2935.

Found: 509.2941.

Example 126

178rN42,5--btsCriiiluQromethyl))phenyl-carbamoyl-6-azaandrost-4-chloro-4-en3.-ene (Compound 126)

Melting Point: 148-154°C.

Anal. Calcd. for C27H29N2O2CIF6; C, 57.48; H, 5.19; N, 4.98.

1060AC

AP Ο Ο Ο 4 5 9

-82Example 127

17p-N-(2-FButyl-54rifluQromelhyl)phenvl-carbamoyl-6-azaandrost-4-chloro-4en-3-one (Compound 127)

Melting Point: 174-178°C.

Anal. Calcd. for C30H38N2O2CIF3; C, 65.37; H, 6.95; N, 5.08.

Found: C, 65.49; H, 7.01; N, 5.05.

Example 128

17fr-N-(2-Methoxy-5-f-butyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one 10 (Compound 128)

Melting Point: 170-175°C.

Anal. Calcd. for C30H42N2O3*H2O; C, 72.55; H, 8.93; N, 5.64.

Found: C, 72.50; H, 8.94; N, 5.69.

Example 129

17B-N-(2-Fluoro-5-trifluoromethyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 129)

Melting Point: 167-170°C.

Anal. Calcd. for C26H30N2O2F4*³/4H2O; C, 63.47; H, 6.45; N, 5.69.

Found: C, 63.46; H, 6.26; N, 5.76.

Example 130

17p-N-(1-(4-Biphenvl)-2.2-diethyl)cycloDropyl-carbamoyl-6-azaandrost-4-en-3one (Compound 130)

Melting Point: 178-182°C.

Anal. Calcd. for C38H48N2O2; C, 79.54; H, 8.61; N, 4.88.

Found: C, 79.68; H, 8.55; N, 4.86.

1-Amino-1-(1-(4-biphenyl)-2,2-diethyl)cyclopropane: ¹³C NMR (CDCI3) δ 144.6, 30 140.9, 139.1, 128.8, 128.7, 127.1, 127.0, 127.0, 46.9, 33.2, 25.6, 24.1,22.3,

11.6, 10.5.

BAD ORIGINAL

1060AC

AP 0 0 0 4 5 9

-83Example_L31 l7p:N.:(1-(4-Trifluoromethylphenyl)-2.2-diethyl)cyclopropyl-carbamoyl-6azaandrost-4-.en-3-one (Compound 131)

Melting Point: 176-182°C.

Anal. Calcd. for C33H43N2O2F3*¹/3H2O; C, 70.44; H, 7.82; N, 4.98.

Found: C, 70.44; H, 7.83; N, 4.97.

-Amino-1 -(1 -(4-trifluoromethylphenyl)-2,2-diethyl)cyclopropane: ¹³C NMR (CDCI₃) δ 149.5, 149.5, 129.7, 128.8, 128.4, 126.1, 126.0, 125.5, 125.5, 125.4,

125.3, 122.5, 46.9, 33.4, 25.6, 24.3, 22.2, 11.5, 10.4.

Example 132

176-N-3-(2-£.arbQmethQxy-5-L-butyl)thiophenyl-carbamoyl-6-azaandrost-4-en-3one (Compound, 132)

Melting Point: 273-275°C.

Anal. Calcd. for C29H40N2O4S; C, 67.94; H, 7.86; N, 5.46.

Found: C, 67.67; H, 7.90; N, 5.42.

Example 133

J?g-Nr(2-PheP.ylsuJfQnyl)pbenvl-carbamoyl-6-azaandrost-4-en-3-one (Compound 133)

Melting Point: 175-180°C.

Anal. Calcd. for C31 H36N2O4S»¹/4H2O; C, 69.31; H, 6.84; N, 5.22.

Found: C, 69.18; H, 7.01; N, 5.15.

Example 134 lZe-Nii4:Car.bQelhPx.v)phenyl-carbamQyl-6-azaandrost-4-en-3-one (Compound

124}

Melting Point: 299-301 °C.

Anal. Calcd. for C28H36N2O4*¹/4H2O; C, 71.69; H, 7.84; N, 5.97.

Found: C, 71.74; H, 7.83; N, 5.98.

BAD ORIGINAL

1060AC

AP Ο Ο Ο 4 5 9

-84Example 135

17fi-N-(2-(4-f-Butyl)phenyl-5-trifluoromethyl)phenyl-carbamoyl-6-azaandrost-4en-3-one (Compound 135)

Melting Point: 185-189°C.

Anal. Calcd. for C36H43N2O2F3;C, 72.95; H, 7.31; N, 4.73.

Found: C, 72.84; H, 7.36; N, 4.65.

Example 136

176-N-1-(4-f-Butylphenyl)cycloheptyl-carbamoyl-6-azaandrost-4-en-3-one 10 (Compound 136)

Melting Point: 190-194°C.

Anal. Calcd. for C36H52N2O2‘³/₄H2O; C, 77.27; H, 9.65; N, 5.00.

Found; C, 77.44; H, 9.66; N, 5.01.

1-Amino-1-(4-Fbutylphenyl)cycloheptane: ¹³C NMR (CDCI3) δ 148.7, 148.2,

125.0, 124.7, 57.3, 42.9, 34.2, 31.2, 29.7, 23.1.

Example 1,37

17p-N-(3-Carboxy)phenyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 20 137)

Melting Point: 258-260°C.

Anal. Calcd. for C26H32N2O4*HCI*1¹/₄H2O; C, 63.02; H, 7.22; N, 5.65.

Found: C, 63.02; H, 7.22; N, 5.62.

ExamplelSS

17β-Ν-1 -(9-Fluorenonyl)-carbamoyl-6-azaandrost-4-en-3-one (Compound 138)

Melting Point: 260-264°C.

Anal. Calcd. for C32H34N2O3·¹¹/₄H2O;C, 74.32; H, 7.11; N, 5.42.

Found: C, 74.49; H, 7.12; N, 5.38.

BAD ORIGINAL A

1060AC

AP 0 0 0 4 5 9

-85Example 139

17p-N-1-(4-f-Butylphenyl)cyclohexyl-carbamoyl-6-azaandrost-4-chloro-4-en-3one (Compound 139)

Melting Point: 158°C.

FAB mass spec, for C35H49N2O2CI; 565.2.

Found: 565.2 M+.

Example 1.4Q

17B-N-(2.6-Oielhvl^-J4-OhlorQDhenvD)phenyl-carbamoyl-6-azaandrost-4-en-3one (Compound 140)

Melting Point: >300°C.

Anal. Calcd. for θ35Η43Ν2θ2θ·¹/₄Η2θ; C, 74.58; H, 7.78; N, 4.97.

Found: C, 74.27; H, 7.80; N, 4.97.

Example 141

17ft-N-(2-Phenyl)-hydrazidyl-carbamoyl-6-azaandrost-4-en-3-one (Compound

141)

Melting Point: 193-195°C.

Anal. Calcd. for C25H33N3O2’H2O; C, 70.56; H, 8.29; N, 9.87.

Found: C, 70.17; H, 8.26; N, 9.87.

Example, 142

17fi-N-(2-(-ButyJcarbamoyl-5-trifluoromethyl)phenyl-carbamoyl-6-azaandrost-4en.:3-J2n.a-tCampQund 1.42),

Melting Point: 198-200°C.

Anal. Calcd. for C3lH4oN3C>3F3;C, 66.53; H, 7.20; N, 7.51.

Found: C, 66.41; H, 7.32; N, 7.36.

Example..:! 43

17p-N-4-(4-fcButylphenvl)tetrahydrothiopyranyl-carbamoyl-6-azaandrost-4-en-3one (Compound 143)

Melting Point: 197°C.

Anal. Calcd. for C34H48N2O2S*³/4H2O; C, 72.62; H, 8.87; N, 4.98.

Found: C, 72.46; H, 8.97; N, 4.99.

bad original d

1060AC

AP 0 0 0 4 5 9

-864-Amino-4-(4-(-butylphenyl)tetrahydrothiopyran: ¹³C NMR (CDCI3) δ 149.3,

146.7, 125.3, 124.3, 52.6, 39.8, 34.2, 31.3, 24.3.

Example 144

17p-N-9-(4-f-Butv lphenvl)bicyclo[3.3.11nonyl-carbamoyl-6-azaandrost-4-en-3one (Compound 144)

Melting Point: >260°C.

Anal. Calcd. for C38H54N2O2*1¹/4H2O;C, 76.92; H, 9.60; N, 4.72.

Found: C, 76.82; H, 9.63; N, 4.67.

9-Amino-9-(4-f-Butylphenyl)bicyclo[3.3.1]nonane: ¹³C NMR (CDCI3) δ 148.6,

144.8, 125.4, 125.3, 124.7, 124.3, 64.1,55.4, 38.9, 35.3, 34.2, 31.7, 31.3, 31.3, 29.1,27.0, 24.4,21.1,20.5.

Example 145 l76-N-4-(4-f-Butylphenyl)tetrahydropyranyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 145)

Melting Point: 181 °C.

Anal. Calcd. for C34H48N2O3‘³/4H2O; C, 74.75; H, 9.13; N, 5.13.

Found: C, 74.72; H, 9.11; N, 5.15.

4-Amino-4-(4-(-butylphenyl)tetrahydropyran; ¹³C NMR (CDCI3) δ 149.4, 146.5,

125.3, 124.3, 64.1,51.2, 38.9, 31.3, 22.4.

Example 146

17B-N-1-(4-Chlorophenyl)cyclohexyl-carbamoyl-6-azaandrost-4-en-3-one (Compound 146)

Melting Point: 184°C.

Anal. Calcd. for C31H41N2O2CI; C, 73.13; H, 8.11; N, 5.50.

Found: C, 72.74; H, 8.39; N, 5.38.

BAD ORIGINAL ft

1060AC

AP 0 0 0 4 5 9

-87ExampJe 147.

17p-N-(2-f-Butyl-5-(4-f-butyl)phenyl)phenyl-carbamoyl-6-azaandrost-4-en-3one (CQmpQimdJ4Z)

Melting Point: >300

Anal. Calcd. for C39H52N2O2: C,78.22; H.9.09; N.4.68.

Found: C.77.98; H,8.99; N.4.65

Example 148

J7p-N--1rf4^ChlQfQphenyl)cycJQpentyl-carbamoyl-6-azaandrost-4-chloro-4-en-3one (Compound 148)

FAB mass spec, for C30H3QN2O2CI2 529.55

Found: 529.3M+

Example 149

Pharmaceutical formulations (A) Transdermal System - For 1000 Patches

Ingredients Amaant

Active compound 40 g

Silicone fluid 450 g

Colloidal silicon dioxide 25 g

The silicon fluid and active compound are mixed together and the colloidal silicon dioxide is added to increase viscosity. The material is then dosed into a subsequently heat sealed polymeric laminate comprised of the following: polyester release liner, skin contact adhesive composed of silicone or acrylic polymers, a control membrane which is a polyolefin (e.g. polyethylene, polyvinyl acetate or polyurethane), and an impermeable backing membrane made of a polyester multilaminate. The resulting laminated sheet is then cut into 10 sq. cm patches.

(B) Oral Tablet - For 1000 Tablets

Ingredients Amount

BAD ORIGINAL

1060AC

AP 0 0 0 4 5 9

-88Active compound 20 g

Starch 20 g

Magnesium Stearate 1 g

The active compound and the starch are granulated with water and dried. Magnesium stearate is added to the dried granules and the mixture is thoroughly blended. The blended mixture is compressed into tablets.

(C) Suppository - For 1000 Suppositories Amount

Active compound 25 g

Theobromine sodium salicylate 250 g

Witepsol S55 1725 g

The inactive ingredients are mixed and melted. The active compound is then distributed in the molten mixture, poured into molds and allowed to cool.

(D) Injection - For 1000 Ampules

Ingredients Amount

Active Compound 5 g

Buffering Agents q.s.

Propylene glycol 400 mg

Water for injection 600 mL

The active compound and buffering agents are dissolved in the propylene glycol at about 50°C. The water for injection is then added with stirring and the resulting solution is filtered, filled into ampules, sealed and sterilized by autoclaving.

BAD ORIGINAL

1060AC

ΑΓ Ο Ο Ο 4 5 9

-89(Ε) Capsule - For 1000 Capsules ingredients Amount

Active Compound 20 g

Lactose 450 g

Magnesium stearate 5 g

The finely ground active compound is mixed with the lactose and stearate and

Claims

Claims:

1. A compound of formula (I):

wherein R¹ and R²

i) are independently hydrogen or lower alkyl and the bond between the carbons bearing R¹ and R² is a single or a double bond, or ii) taken together are a -CHg- group forming a cyclopropane ring, and the bond between the carbons bearing R¹ and R² is a single bond;

R³ is hydrogen, -Alk¹-H (optionally substituted with one or more halogens), lower cycloalkyl, lower cycloalkyl-lower alkyl), halogen, -(Alk¹)n-CO2H, -(Alk‘*)n-CO2R⁷, -(Alk¹)n-Ar¹, -(Alk¹)n-CONR³R9, -(Aik¹ )n-NR³R9 -(Alk¹)n-S(O)rR⁷, -(Alk¹)n-CN, -(Alk¹)-OH, -(Alk¹)n-COR⁷; or-(Alk¹)n-OR⁷;

wherein

Aik¹ is lower alkylene, lower alkenylene or lower alkynylene, n is 0 or 1, r is 0, 1 or 2,

R⁷ is -Alk¹-H, -(Alk¹)_n-Ar¹ or lower cycloalkyl,

R³ and R³ are independently hydrogen, -Alk¹-H or lower cycloalkyl,

Ar¹ is a homocyclic aryl group of 6 to 14 carbons;

R⁴ is hydrogen, -Alk¹-H, lower cycloalkyl, lower cycloalkyl-lower alkyl,

-(Alk¹)n-S(O)rR⁷, -(Aik¹ )n-phthalimidyl, -(Alk¹)-CC>2H, -(Alk¹)n-CO2R⁷, -(Alk¹)n-COR⁷- -(Alk¹)n-Ar¹, -(Alk¹)n-CONR8R9, -(Alk¹)n-NR8R³, -(Alk¹)n-OH or -(Aik¹ )_n-OR⁷;

BAD ORIGINAL ft

1060AC

AP Ο Ο Ο 4 5 9

X is, (CR¹²R¹³)q /

5 wherein

R¹³, R¹¹, R¹² and R¹³ are independently hydrogen or lower alkyl, p and q are independently either 0 or 1 ;

and,

10 i) Y is hydrogen or hydroxy and

Z is -(Alk²)n-COR³, -(Alk²)n-CO₂R⁵, -(Alk²)_n-COSR⁵,

-(Alk²)n-CONR¹⁴R15i.(Alk²)-OCO2R⁵,-(Alk²)-OCOR5, -(Alk²)-OCONR¹⁴R¹5, -(Alk²)-OR⁵, -(Alk²)-NR5'COR5, -(Alk^-NRS'CC^R⁵, -(Alk²)-NR5CONR¹⁴R¹³( -(Alk²)n-CONR⁵NR¹⁴R¹5, -(Alk²)n-CONR5CONR¹⁴R¹5, -(Alk²)15 NR5cSNR¹⁴R¹³ or -(Alk²)_n-CONR⁵CSNR¹⁴R¹5; wherein

Aik² is (C-|-12) alkylene, (C2-12) alkenylene or (C2-12) alkynylene,

R³ and R³' are independently hydrogen, -Alk¹-H (optionally substituted independently with one or more CO₂H, CO2R⁷, Ar², Ar³ or cyano groups),

20 (Aik¹ )_n-(lower cycloalkyl (optionally substituted independently with one or more -Alk¹-H groups)), adamantyl, norbornyl, Ar², Ar³, (lower cycloalkyl)-Ar² or (lower cycloalkyl)-Ar³;

wherein

Ar² is a homocyclic aromatic group of 6 to 14 carbon ring atoms (optionally

25 substituted independently with one or more -Alk²-H (optionally substituted independently with one or more halogens), -(Alk¹)nCOR⁷> -(Alk¹)n-OH, -(Alk¹)n-OR¹⁸, -(Alk¹)n-Ar³, -(Alk¹)n-CO2H, -(Alk¹)n-CO₂R⁷ S(O)rR⁷, NR⁸S(O)rR¹⁶, NR⁸R⁹, CONR⁸R⁹, lower cycloalkyl, lower alkoxy, -(Alk¹)_n-Ar¹

BAD ORIGINAL

1060AC

AP 0 0 0 4 5 t (optionally substituted with one or more -Alk¹-H or halogen), methylenedioxy, ethylenedioxy, morpholino, thiomorpholino, cyano, nitro or halogens);

wherein

R¹⁶ is -Alk¹-H (optionally substituted independently with one or more halogens), lower cycloalkyl (optionally substituted independently with one or more halogens, or -Alk¹-H (optionally substituted independently with one or more halogens)) or -(Alk¹)_n-Ar¹ (wherein Ar¹ is optionally substituted independently with one or more lower alkoxy, cyano, halogen or -Alk¹-H (optionally substituted independently with one or more halogens);

Ar³ is an aromatic group of 5 to 14 ring atoms, at least one of which is Ο, N or S (optionally substituted independently with one or more -Alk¹-H (optionally substituted independently with one or more halogens), lower cycloalkyl, lower alkoxy, CO2H, CO2R⁷, -(Alk¹)_n-Ar¹, cyano or halogen);

R¹⁴ and R¹⁵ are

a) independently, hydroxy, hydrogen, -Alk²-H, lower alkoxy, -(Alk¹)n-adamantyl, -(Alk¹)n-myrantyl, -(Alk¹)n-norbornyl, -(Aik¹ )n-fluorenyl, -(Alk¹)n-fluorenonyl, -(Alk¹)n-indanyl (optionally substituted with one or more -Alk¹-H), -Alk¹-H (optionally substituted independently with one or more halogens, cyano, cycloalkyl, sr⁵, cor⁵, conr⁵r⁷, nr⁵'cor⁵, nr⁵'co2r⁵, nr⁵'conhr⁵, co2r⁵, OR⁵, Ar² or Ar³), Ar² or Ar³ or a saturated C4-18 bicyclic ring or C3.11 saturated ring, optionally containing an oxygen or sulfur atom (said rings optionally substituted independently with one or more cyano, R¹⁶, Ar² or Ar³);

b) alkylene groups (optionally substituted with one or more R⁷ groups, taken together with the linking nitrogen to form a 4 to 8 atom heterocyclic group) wherein;

Het represents -O-, -CH₂-, -S(O)_r-, -(NH)- or

1060AC

AP Ο Ο Ο 4 5 9

-(N(Alk¹-H))-;

with the proviso that when Z is -(Alk²)n-COR⁵, -(Alk²)n-CO2R⁵ or -(Alk²)n-CO-thiopyridyl and R⁵ is hydrogen, -Alk1-H, lower cycloalkyl, or adamantyl or when Z is -(Alk²)n-CONR1⁴R¹⁵ and R¹⁴ and R¹5 are

a) independently hydrogen, -Alk²-H, lower cycloalkyl, lower alkoxy, adamantyl, Ar¹, benzyl, diphenylmethyl, triphenylmethyl or -(Alk1)_n-norbornyl;

or

b) carbon atoms, optionally substituted with one or more lower alkyl groups, taken together with the linking nitrogen to form a 4 to 8 atom heterocylic ring as herein before defined,

Y is hydroxy; or ii) Y is hydrogen and

Z is OR⁵, OCOR⁵, OCONR¹⁴R15, NR⁵’COR⁵, NRS’CX^R⁵,

NR⁵CONR¹⁴R¹⁵ or NR⁵CSR¹⁴R¹⁵; and iii) Y and Z taken together are =0, =CH-(Alk¹)n-COR⁵, =CH-(Alk¹)n-CO₂R⁵ or =CH-(Alk¹)_n-CONR¹⁴R¹⁵;

r6 is hydrogen or methyl; or a pharmaceutically acceptable salt thereof.

BAD ORIGINAL $

1060AC

AP 0 0 0 4 5 9
2. A compound of Claim 1 which is a compound of formula (IA), (IB), (IC) or (ID)
3. A compound as claimed in Claim 1 or Claim 2 wherein R⁸ is hydrogen, halogen, ( lower alkyl, lower cycloalkyl or lower cycloalkyl-lower alkyl.
4. A compound as claimed in Claim 3 wherein R⁸ is hydrogen, halogen or lower 10 alkyl.
5. A compound of Claim 1 or Claim 2 wherein R³ is methyl, ethyl, cyano, iodo, bromo, chloro or dimethylaminomethyl.

15
6. A compound as claimed in any one of the preceding claims wherein R⁴ is hydrogen, lower alkyl, lower cycloalkyl or lower cycloalkyl-lower alkyl.

1060AC

AP ΟΟΟ459
7. A compound as claimed in Claim 6 wherein R⁴ is hydrogen or lower alkyl.
8. A compound as claimed in any one of claims 1 to 5 wherein R⁴ is methyl, ethyl, 5 propyl, Apropyl, butyl, Abutylhexyl, 3-hydroxypropyl, propenyl, methylenecyclopropyl, benzyl, 2-methoxyethyl, 2-acetic acid, 3-proponic acid, 5-pentanoic acid, 6-hexanoic acid, methyl-5-pentanoate, ethyl-6-hexanoate, 3phthalimidylpropyl and 4-phthalimidylpropyl.
10 9. A compound according to any one of the preceding claims wherein X is -CH2-.

10. A compound as claimed in any one of the preceding claims wherein Y is hydrogen and Z is -(Alk²)n-COR⁵, -(Alk²)n-CONR^{13 14}R¹⁵, -(Alk²)-OCO2R⁵, (Alk²)-OCOR⁵, -(Alk²)-NR⁵COR⁵, -(Alk²)n-CONR⁵NR¹⁴R¹⁵, -(Alk²)15 NR⁵CONR¹⁴R¹⁵, Or -(Alk²)_n-CONR⁵CONR¹⁴R¹⁵.
11. A compound as claimed in Claim 10 wherein Z is -COR⁵, -CONR¹⁴R¹⁵, -CH2OCO2R⁵, -CH2OCOR⁵, -CH2NR⁵'COR⁵, -CONR⁵NR1⁴R15, -CH2NR⁵CONR¹⁴R1⁵ or -CONR⁵CONR¹⁴R¹⁵.
12. A compound as claimed in Claim 11 wherein Z is -CONR¹⁴R¹⁵.
13. A compound as claimed in any one of the preceding claims wherein Ar¹ is a phenyl group.
14. A compound as claimed in any one of the preceding claims wherein Ar² is a phenyl group optionally substituted independently with one or more -Alk²-H (optionally substituted independently with one or more halogens), -OR^-*⁵, -S(O)rR⁷, Ar¹, methylenedioxy, ethylenedioxy, morpholino, thiomorpholino, cyano, nitro or

30 halogen groups.

BAD ORIGINAL

1060AG

AP 0 0 0 4 5 9
15. A compound as claimed in any one of the preceding claims wherein R¹⁴ jS hydrogen or hydroxy, and R¹⁵ is hydrogen, lower cycloalkyl (optionally substituted independently with one or more R⁷ or Ar² groups), -(Alk¹)-adamantyl, -(Alk¹)nmyrantyl, -(Alk¹)n-norbornyl, -(Aik¹ )_n-fluorenyl, -(Alk¹)n-indanyl, -Alk¹-H (optionally substituted independently with one or more lower cycloalkyl, SR⁵, OR⁵, Ar² or Ar³groups), Ar² or Ar³; or

R¹⁴ and R¹⁵ are carbon atoms, optionally substituted with one or more R⁷ groups, taken together with the linking nitrogen to form a 5 to 7 atom heterocyclic group —N Het wherein Het represents -CH2-.
16. A compound as claimed in any one of the preceding claims wherein Ar³ is an aromatic group of five or six ring atoms, at least one of which is Ο, N or S, optionally substituted independently with one or more Alk¹H groups.
17. A compound as claimed in Claim 16 wherein Ar³ is an optionally substituted pyrrolyl, thienyl, furyl or pyridyl group.
18. A compound as claimed in any one of the preceding claims wherein R⁵ is hydrogen, lower alkyl optionally substituted independently with one or more Ar²groups, (lower alkyl)n-lower cycloalkyl, menthyl, adamantyl, norbornyl or Ar².
19. A compound as claimed in any one of Claims 1 to 11 or 13 to 18 wherein Z is -COR⁵.
20. A compound as claimed in Claim 19 which is:

17(3-(1 -Oxo-2-cyclohexylethyl)-6-azaandrost-4-en-3-one;

17(3-(1 -Oxo-1 -(2,4-difluorophenyl)methyl)-6-azaandrost-4-en-3-one;

17()-(1-Oxo-1-(4-isopropoxyphenyl)methyl)-6-azaandrost-4-en-3-one;

BAD ORIGINAL ft

1060AC

AP 0 0 0 4 5 9

17β—(1 -Oxo-3,3-diphenylpropyl)-6-azaandrost-4-en-3-one; or

17β-(1 -Oxo-1 -(2-norbornyl)methyl)-6-azaandrost-4-en-3-one or a pharmaceutically acceptable salt thereof.
21. A compound as claimed in any one of Claims 1 to 18 wherein Z is CONR¹⁴R¹⁵, R¹⁴ is hydrogen and R¹⁵ is Ar² or a C3.11 saturated ring, optionally containing an oxygen or sulphur atom (optionally substituted independently with one or more R⁷ or Ar² groups).
22. A compound as claimed in any one of the preceding claims wherein R¹⁵ is a group of formula Ar²³ wherein R^a and R^b are independently hydrogen, lower alkyl, trifluoromethyl, halogen or phenyl (optionally substituted with one or more halogens or branched C4-7alkyl) and R^c is hydrogen or one or more halogens, or R¹⁵ is a C3.11 saturated ring, optionally containing an oxygen or sulphur atom substituted with a group of formula Ar^2a.
23. A compound as claimed in Claim 22 wherein Ar^2a is a group oi formula Ar^2aa where R^aa is branched C4-7alkyl, trifluoromethyl or phenyl optionally substituted with one or more halogens; one of R^ba and R⁰³ is branched C4-7alkyl, trifluoromethyl, halogen or phenyl optionally substituted with one or more halogens, and the other is hydrogen or halogen; and R^da is hydrogen or halogen.
24. A compound as claimed in Claim 1 which is:

17|S-N-((2,6-Di-Apropyl)phenyl)-carbamoyl-6-azaandrost-4-en-3-one bad original

1060AU

AP Ο Ο Ο 4 5 9

17^N-(2,4,6-trimethyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one

17^-N-(2-Chloro-5-trifluoromethyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one

17p-N-(2,6-Dimethyl-4-bromo)phenyl-carbamoyl-6-azaandrost-4-en-3-one

17p-N-(2,6-Dimethyl-4-i-butyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one

5 17(3-N-(2,6-Dibrc>mo-4-isopropyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one 17|i-N-(2,5-Ditrifluoromethyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one 17^-N-(2-Phenyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one 17p-N-(2,6-Diethyl-3,5-dichloro)phenyl-carbamoyl-6-azaandrost-4-en-3-one 17p-N-(2,6-Diethyl-3-chloro)phenyl-carbamoyl-6-azaandrost-4-en’3-one

10 17p-N-(2-FButyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one

17p-N-(2,4,6-Trichloro)phenyl-carbamoyl-6-azaandrost-4-en-3-one

17p-N-(2-Bromo-5-trifluoromethyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one

17^-N-(2-f-Butyl-6-methyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one l7p-N-1-(4-Chlorophenyl)cyclopentyl-carbamoyl-6-azaandrost-4-en-3-one

15 17p-N-(2,6-Dibromo-4-chloro)phenyl-carbamoyl-6-azaandrost-4-en-3-one

173-N-(2,6-Diethyl-4-bromo)phenyl-carbamoyl-6-azaandrost-4-en-3-one 17p-N-(2-Bromo-4-f-butyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one 17p-N-(2-Chloro-4-f-butyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one 17p-N-(5-Bromo-2-f-butyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one

20 17p-N-(5-Chloro-2-f-butyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one 17(V-N-(2,6-Diethyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one 17^-N-(4-Bromo-2-i-butyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one 17^-N-(2-f-Butyl-5-cyano)phenyl-carbamoyl-6-azaandrost-4-en-3-one 17B-N-(2-(0-4-Tolyl)-5-trifluoromethyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one
25 l7p-N-(2-(0-4-Chlorophenyl)-5-trifluoromethyl)phenyl-carbamoyl-6-azaandrost-4en-3-one

17p-N-(2-Nitro-4-f-butyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one 17f3-N-(2-(O-Phenyl)-5-(1,1 -dimethyl)propyl)phenyl-carbamoyl-6-azaandrost-4-en3-one

30 l7p-N-(2-Ethylsulfonyl-5-trifluoromethyl)phenyl-carbamoyl-6-azaandrost-4-en-3one

17(3-N-(3,5-Di-i-butyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one

BAD ORIGINAL ft

AP Ο Ο Ο 4 5 9

1060AC ly^-N-^^Butyl-S-trifluoromethyOphenyl-carbamoyl-e-azaandrosM-en-S-one

17p-N-(2-r-Butyl-5-phenyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one

17(3-N-(2,6-Di-/-propyl)phenyl-carbamoyl-6-azaandrost-1,4-dien-3-one

17p-N-(2,6-Di-/-propyl)phenyl-carbamoyl-6-azaandrost-4-methyl-1,4-dien-3-one

5 17p-N-1-(4-Trifluoromethylphenyl)cyclopentyl-carbamoyl-6-azaandrost-4-en-3one

17p-N-1-(4-Fluorophenyl)cyclohexyl-carbamoyl-6-azaandrost-4-en-3-one

17p-N-1-(4-Methoxyphenyl)cyclohexyl-carbamoyl-6-azaandrost-4-en-3-one

17p-N-1-(4-Methoxyphenyl)cyclopentyl-carbamoyl-6-azaandrost-4-en-3-one

10 17p-N-(2,5-bis(Trifluoromethyl))phenyl-carbamoyl-6-azaandrost-4-methyl-4-en-3one

17p-N-(2-t-Butyl-5-trifluoromethyl)phenyl-carbamoyl-6-azaandrost-4-methyl-4-en-3one

17p-N-(2,5-Di-t-butyl)phenyl-carbamoyl-6-azaandrost-4-methyl-4-en-3-one 15 173-N-(2-t-Butyl-5-(4-chlorophenyl))phenyl-carbamoyl-6-azaandrost-4-en-3-one

17p-N-1-(4-t-Butylphenyl)cyclopentyl-carbamoyl-6-azaandrost-4-en-3-one

17p-N-1-(4-t-Butylphenyl)cyclohexyl-carbamoyl-6-azaandrost-4-en-3-one

17p-N-1-(4-Chlorophenyl)cyclopentyl-carbamoyl-6-azaandrost-4-methyl-4-en-3-one

17(J-N-(2,5-bis(Trifluoromethyl))phenyl-carbamoyl-6-azaandrost-4-chloro-4-en20 3-one

17^-N-(2-f-Butyl-5-trifluoromethyl)phenyl-carbamoyl-6-azaandrost-4-chloro-4-en-3one

17p-N-1-(4-f-Butylphenyl)cycloheptyl-carbamoyl-6-azaandrost-4-en-3-one

17p-N-1-(4-f-Butylphenyl)cyclohexyl-carbamoyl-6-azaandrost-4-chloro-4-en-3-one

25 17^-N-(2,6-Diethyl-4-(4-chlorophenyl))phenyl-carbamoyl-6-azaandrost-4-en-3one

17p-N-4-(4-f-Butylphenyl)tetrahydrothiopyranyl-carbamoyl-6-azaandrost-4-en-3one

17p-N-9-(4-r-Butylphenyl)bicyclo[3.3.1Jnonyl-carbamoyl-6-azaandrost-4-en-3-one 30 17p-N-4-(4-i-Butylphenyl)tetrahydropyranyl-carbamoyl-6-azaandrost-4-en-3-one

173-N-1-(4-Chlorophenyl)cyclohexyl-carbamoyl-6-azaandrost-4-en-3-one 17(3-N-(2-i-Butyl-5-(4-i-butyl)phenyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one or

BAD ORIGINAL ft

1060AC

AP 0 0 0 4 5 9

100

17p-N-1-(4-Chlorophenyl)cyclopentyl-carbamoyl-6-azaandrost-4-chloro-4-en-3-one or a pharmaceutically acceptable salt thereof.

25. 17(i-N-(2-Z-Butyl-5-trifluoromethyl)phenyl-carbamoyl-6-azaandrost-4-en-3-one or a pharmaceutically acceptable salt thereof.
26. A compound of formula (I) wherein R¹ and R² are,

i) independently hydrogen or lower alkyl and the bond between the carbons bearing R¹ and R² is a single or a double bond, or ii) taken together are a -CH2- group to form a cyclopropane ring, and the bond between the carbons bearing R¹ and R² is a single bond;

R³ is hydrogen or lower alkyl;

R⁴ is hydrogen or lower alkyl;

Y is hydrogen; and

Z is -COR⁵, -CONR¹⁴R¹⁵, -CH2OCO2R⁵, -CH2OCOR⁵, -CH2NR⁵'COR⁵, -CONR⁵NR¹⁴R¹⁵, -CH2NR⁵CONR¹⁴R⁵, or -CON⁵CONR¹⁴R¹⁵ wherein R⁵ and R⁵’ are independently hydrogen, lower alkyl optionally substituted independently with one or more Ar² groups (lower alkyl)_n-lower cycloalkyl, menthyl, adamantyl, norbornyl or Ar²;

Ar² is a phenyl group optionally substituted independently with one or more -Alk-H (optionally substituted independently with one or more halogens), -OR¹⁶, -S(O)_rR⁷, phenyl, methylenedioxy, ethylenedioxy, morpholino, thiomorpholino, cyano, nitro or halogen groups;

Aik is lower alkylene, lower alkenylene or lower alkynylene;

n is 0 or 1;

1060AC

AP Ο Ο Ο 4 5 9

101 r is Ο, 1 or 2;

R⁷ is -Alk-H, -(Alk)n-phenyl or lower cycloalkyl;

R¹⁶ is -Alk-H (optionally substituted independently with one or more halogens), lower cycloalkyl (optionally substituted independently with one or more halogens or

5 -Alk-H (optionally substituted independently with one or more halogens)) or -(Alk)_nphenyl (wherein phenyl is optionally substituted independently with one or more lower alkoxy, cyano, halogen or -Alk-H groups (optionally substituted independently with one or more halogens)); R¹⁴ is hydrogen or hydroxy, and R¹⁵ is hydrogen, lower cycloalkyl (optionally substituted independently with one or more R⁷ or Ar²

10 groups), -(Alk)-adamantyl, -(Alk)_n-myrantyl, -(Alk)_n-norbornyl, -(Alk)_n-fluorenyl, (Alk)n-indanyl, -Alk-H (optionally substituted independently with one or more lower cycloalkyl, SR⁵, OR⁵, Ar² or Ar³ groups), Ar² or Ar³, or R¹⁴ and R¹⁵ taken together with the linking nitrogen form a pyrrolidinyl, piperidinyl or perhydroazepinyl ring optionally substituted with one or more R⁷ groups; Ar³ is a pyrrolyl, thienyl, furyl or

15 pyridyl group optionally substituted independently with one or more Alk-H groups; with the provisos that when Z is COR⁵, R⁵ is substituted lower alkyl, lower alkyl lower cycloalkyl, menthyl, norbornyl or Ar²;

when Z is CONR¹⁴R¹⁵ and R¹⁵ is hydrogen, -Alk-H, lower cycloalkyl, lower alkoxy, adamantyl, phenyl, benzyl, diphenylmethyl, triphenylmethyl or -(Alk)_n-norbomyl, R¹⁴ is hydroxy; and

25 when Z is CONR¹⁴R¹⁵ and R¹⁴ and R¹⁵ taken together with the linking nitrogen form a pyrrolidinyl, piperidinyl or perhydroazepinyl ring, said ring is substituted with one or more lower alkenyl, lower alkynyl, -(Alk)n-phenyl or lower cycloalkyl groups; or a pharmaceutically acceptable salt thereof.

BAD ORIGINAL ft

1060AC

ΑΡΟΟΟ459

102
27. A compound of formula (I) wherein:

R¹ and R² are,

i) independently hydrogen or lower alkyl and the bond between the carbons bearing R¹ and R² is a single or a double bond, or ii) taken together are a -CH₂- group to form a cyclopropane ring, and the bond between the carbons bearing R¹ and R² is a single bond;

R³ is hydrogen, -Alk¹-H, -Alk¹-H substituted with one or more halogens, lower cycloalkyl, lower cycloalkyl-lower alkyl, halogen,-(Aik¹ )n-CO2H, -(Alk¹)n-CO₂R⁷, -(Alk¹)_n-Ar¹,

-(Alk¹)n-CONR⁸R⁹, -(Alk¹)n-NR⁸R⁹, -(Alk¹)_n-S(O)_rR⁷,

-(Alk¹)n-CN, -(Alk¹)-OH or -(Alk¹)n-OR⁷;

wherein

Aik¹ is lower alkylene, lower alkenylene or lower alkynylene, n is 0 or 1, r is 0,1 or 2,

R⁷ is -Alk¹-H, -(Alk¹)_n-Ar¹ or lower cycloalkyl,

R⁸ and R⁹ are independently hydrogen, -Alk¹-H or lower cycloalkyl, Ar¹ is a homocyclic aryl group of 6 to 14 carbons;

R⁴ is hydrogen, -Alk¹-H, lower cycloalkyl, lower cycloalkyl-lower alkyl, -(Alk¹)n-S(O)rR⁷, -(Aik¹ )n-phthalimidyl, (-Alk¹-)CO2H, -(Alk¹)n-CO₂R⁷, -(Alk¹)_n-Ar¹,

-(Alk¹)n-CONR⁸R⁹, -(Alk¹)n-NR⁸R⁹, -(Alk¹)n-OH or-(Alk¹)n-OR⁷;

Xis,

BAD ORIGINAL

1060AC

AP Ο Ο Ο 4 5 9

103 (CR¹⁰R¹¹)_p

JCR¹²R^,3)_q wherein

R¹ θ, R¹¹, R¹² and R¹³ are independently hydrogen or lower alkyl,

5 p and q are independently either 0 or 1 ;

Y and Z are,

ί) Y is hydrogen or hydroxy and

Z is -(Alk²)n-COR⁵, -(Alk²)n-CO2R⁵, -(Alk²)_n-COSR5,

10 -(Alk²)_n-CONR¹⁴R¹5, -(Alk²)-OCOR⁵, -(Alk²)-OCONR¹⁴R¹5,

-(Alk²)-OR5, -(Alk²)-NR³COR³, -(Alk²)-NR³CO₂R5,

-(Alk²)-NR5CONR¹⁴R¹³, -<Alk²)-nCONR⁵NR¹⁴R¹5, -(Alk²)n-CONR³CONR¹⁴R¹5, (-Alk²-)NR³CSNR¹⁴R¹5 or -(Alk²)_n-CONR³CSNR¹⁴R¹³;

15 wherein

Aik² is (Ci-12) alkylene, (C₂-1₂) alkenylene or (C₂-12) alkynylene,

R⁵ is hydrogen, -Alk¹-H, -(Alk¹)n-(lower cycloalkyl), adamantyl, -(Alk¹)n-Ar², -(Aik¹ )n-Ar³, (lower cycloalkyl)nAr², (lower cycloalkyl)nAr³ or -Aik¹- substituted independently with one or more CO2H, CO₂R⁷, Ar² or Ar³ groups;

20 wherein

Ar² is an aromatic group of 6 to 14 carbon ring atoms, optionally substituted with one or more Aik¹, Aik¹ substituted with one or more halogens, -(Alk¹)n-OH, -(Alk¹)n-OR⁷, -(AIk¹)n-CO2H, -(Alk¹)n-CO₂R⁷, S(O)rR⁷ or NR³r9, lower cycloalkyl, lower alkoxy, -(Alk¹)n-Ar¹, methylenedioxy, ethylenedioxy, morpholino,

25 thiomorpholino, cyano or halogen groups;

Ar³ is an aromatic group of 5 to 14 ring atoms, at least one of which is

Ο, N or S, optionally substituted with one or more Aik¹, lower cycloalkyl, lower alkoxy, CO2H, CO2R⁷, -(Alk¹)n-Ar¹, cyano or halogen groups;

BAD ORIGINAL

1060AC

AP 0 0 0 4 5 9

104

R¹⁴ and R¹³ are,

a) independently, hydrogen or -Alk²-H, lower cycloalkyl, lower alkoxy, adamantyl, -(Alk¹)n-norbornyl, Ar², Ar³, -Aik¹- substituted independently with one or more SR³, COR³, CONR³R⁷, NR³COR³, NR³CO2R³, NR³CONHR³, CO2R³, OR³, Ar² or Ar³ groups, -(Aik¹ )n-fluorenyl, or -(Aik¹ )n-indanyl; or

b) carbon atoms, optionally substituted with one or more lower alkyl groups, taken together with the linking nitrogen to form a 4 to 8 atom heterocyclic group —N Het wherein:

Het represents -0-, -CH₂-, -S(O)_r, -(NH)- or -(N(Alk¹))-;

with the proviso that when Z is (-Alk²-)nCOR³, (-Alk²-)nCO₂R³ or -(Alk²)n-COthiopyridyl and R³ is hydrogen, -Alk¹-H, lower cycloalkyl, -(Alk¹)n-Ar¹, adamantyl or when Z is (-Alk²-)_nCONR¹⁴R¹³ and R¹⁴ and R¹³ are (a) independently hydrogen, -Alk²-H, lower cycloalkyl, lower alkoxy, adamantyl, -Ar¹, benzyl, diphenylmethyl, triphenylmethyl or -(Aik¹ )_n-norbornyl; or (b) carbon atoms, optionally substituted with one or more lower alkyl groups, taken together with the linking nitrogen to form a 4 to 8 atom heterocylic ring as herein before defined,

Y is hydroxy:

ii) Y is hydrogen and

Z is OR³, OCOR³, OCONR¹⁴R¹³, NR³COR³, NR³CO₂R⁵,

NR³CONR¹⁴R¹³ or NR³CSR¹⁴R¹⁵;

iii) Y and Z taken together are =0, =CH-(Alk¹)n-COR³, =CH-(Alk¹)n-CO₂R⁵ or =CH-(Alk¹)_n-CONR¹⁴R¹³;

BAD ORIGINAL ft

1060AC

APΟ Ο Ο 4 5 g

105

R⁶ is hydrogen or methyl; and pharmaceutically acceptable salts thereof.

5 28. A compound of formula (I);

wherein R¹ and R²

10 i) are independently hydrogen or lower alkyl and the bond between the carbons bearing R¹ and R² is a single or a double bond, or ii) taken together are a -CH2- group forming a cyclopropane ring, and the bond between the carbons bearing R¹ and R² is a single bond;

R² is, hydrogen, -Alk¹-H (optionally substituted with one or more halogens), lower cycloalkyl, lower cycloalkyl-lower alkyl), halogen, -(Alk¹)n-CO2H, -(Alk¹)n-CO2R⁷, -(Alk¹)n-Ar¹, -(Alk¹)n-CONR²R9, -(Alk¹)n-NR²R9, -(Aik¹ )n-S(O)_rR⁷ -(Alk¹)_n-CN,

20 -(Aik¹ )-OH, -(Aik¹ )n-COR⁷ or -(Aik¹ )n-OR⁷; wherein

Aik¹ is lower alkylene, lower alkenylene or lower alkynylene, n is 0 or 1, r is 0, Ί or 2,

25 R⁷ is -Alk¹-H, -(Aik¹ )_n-Ar¹ or lower cycloalkyl, r8 and R^ are independently hydrogen, -Alk¹-H or lower cycloalkyl,

Ar¹ is a homocyclic aryl group of 6 to Ί 4 carbons;

BAD ORIGINAL ft

1060AC

ΑΡθ Ο Ο 5 g

106

R⁴ is, hydrogen, -Alk¹-H, lower cycloalkyl, lower cycloalkyl-lower alkyl, -(Alk¹)n-S(O)rR⁷, -(Alk¹)n-phthalimidyl, -(Alk¹)-CO2H, -(Alk¹)n-CO₂R⁷,

-(Aik¹ )n-COR⁷- -(Aik¹ )n-Ar¹, -(Aik¹ )n-CONR³R9, -(Aik¹ )n-NR³R9, -(Aik¹ )n-OH or -(Alk¹)n-OR⁷;

X is, wherein

R¹O, R¹¹, R¹² and R¹³ are independently hydrogen or lower alkyl, p and q are independently either 0 or 1;

and,

i) Y is hydrogen or hydroxy and

Z is -(Alk²)n-COR⁵, -(Alk²)n-CO₂R⁵, -(Alk²)_n-COSR⁵,

-(Alk²)n-CONR¹⁴R¹⁵,-(Alk²)-OCO2R⁵,-(Alk²)-OCOR⁵, -(Alk²)-OCONR¹⁴R¹5, -(Alk²)-OR⁵, -(Alk²)-NR⁵ COR⁵, -(Alk²)-NR5’CO2R⁵, -(Alk²)-NR⁵CONR¹⁴R¹5, -(Alk²)n-CONR⁵NR¹⁴R¹⁵, -(Alk²)n-CONR⁵CONR¹⁴R¹5, -(Alk²)NR⁵CSNR¹⁴R¹⁵ or -(Alk²)n-CONR⁵CSNR¹⁴R¹5;

wherein

Aik² is (C-|-12) alkylene, (C₂-12) alkenylene or (C₂-1₂) alkynylene,

R⁵ and R⁵' are independently hydrogen, -Alk¹-H (optionally substituted independently with one or more CO2H, CO2R⁷, Ar², Ar³ or cyano groups), -(Alk¹)n-(lower cycloalkyl (optionally substituted independently with one or more -Alk¹-H groups)), adamantyl, norbornyl, Ar², Ar³, (lower cycloalkyl)-Ar² or (lower cycloalky l)-Ar³;

wherein

Bad ORIGINAL

1060AC

AP 0 ο 0 4 5 S

107

Ar² is a homocyclic aromatic group of 6 to 14 carbon ring atoms (optionally substituted independently with one or more -Alk²-H (optionally substituted independently with one or more halogens), -(Alk¹)n-OH, -(Alk¹)n-OR¹⁵, -(Alk¹)_n-Ar³, -(Alk¹)n-CO2H, -(Alk¹)n-CO₂R⁷, S(O)_rR⁷, NR8S(O)rR¹⁶, NR8r9, CONR8r9, lower cycloalkyl, lower alkoxy, -(Alk¹)n-Ar¹, methylenedioxy, ethylenedioxy, morpholino, thiomorpholino, cyano, nitro or halogens);

wherein

R¹⁶ is -Alk¹-H (optionally substituted independently with one or more halogens), lower cycloalkyl (optionally substituted independently with one or more halogens, or -Alk¹-H (optionally substituted independently with one or more halogens)) or -(Aik¹ )_n-Ar¹ (wherein Ar¹ is optionally substituted independently with one or more, lower alkoxy, cyano groups, halogens or -Alk¹-H (optionally substituted independently with one or more halogens));

Ar³ is an aromatic group of 5 to 14 ring atoms, at least one of which is Ο, N or S, (optionally substituted independently with one or more -Alk¹-H (optionally substituted independently with one or more halogens), lower cycloalkyl, lower alkoxy, CO2H, CO2R⁷, -(Alk¹)_n-Ar¹, cyano or halogen);

R¹⁴ and R¹⁵ are,

a) independently, hydroxy, hydrogen, -Aik²- H, lower cycloalkyl (optionally substituted independently with one or more cyano, R¹⁵, Ar², Ar³), lower alkoxy, -(Alk¹)n-adamantyl, -(Alk¹)n-myrantyl, -(Alk¹)n-norbornyl, -(Aik¹ )n-fluorenyl, -(Alk¹)n-indanyl, -Aik¹- H (optionally substituted independently with one or more, halogens, cyano, cycloalkyl, SR⁵, COR⁵, CONR⁵R⁷, NR⁵'COR⁵, NR⁵'CO2R⁵, NR⁵’CONHR⁵, CO₂R⁵, OR⁵, Ar² or Ar³), Ar² or Ar³:

b) alkylene groups (optionally substituted with one or more R⁷ groups, taken together with the linking nitrogen to form a 4 to 8 atom heterocyclic group) —N Het

BAD ORIGINAL ft

1060AC

ΑΡΟΟΟ

108 wherein;

Het represents -Ο-, -ΟΗρ-, -S(0)_r-, -(NH)- or -(N(Alk¹-H))-;

with the proviso that when Z is

-(Alk²)n-COR⁵, -(Alk²)n-CC>2R5 or -(Alk²)_n-CO-thiopyridyl and

R⁵ is hydrogen, -Alk¹-H, lower cycloalkyl, -(Alk¹)_n-Ar¹, adamantyl or when Z is

-(Alk²)_n-CONR¹⁴R15 and

R¹⁴ and R¹⁵ are

a) independently hydrogen, -Alk²-H, lower cycloalkyl, lower alkoxy, adamantyl, Ar¹, benzyl, diphenylmethyl, triphenylmethyl or -(Alk¹)_n-norbornyl;

or

b) carbon atoms, optionally substituted with one or more lower alkyl groups, taken together with the linking nitrogen to form a 4 to 8 atom heterocylic ring as herein before defined,

Y is hydroxy; or ii) Y is hydrogen and Z is

OR⁵, OCOR⁵, OCONR¹⁴R¹⁵, NR⁵’COR⁵, NR⁵'CO2R⁵,

NR⁵CONR¹⁴R¹⁵ or NR⁵CSR¹⁴R¹⁵; and iii) Y and Z taken together are =0, =CH-(Alk1)_n-COR⁵, =CH-(Alk¹)n-CO2R⁵ or =CH-(Alk¹)n-CONR¹⁴R¹⁵;

bad original

109

R⁶ is, hydrogen or methyl;

5 and pharmaceutically acceptable salts thereof.

2¾ A pharmaceutical composition comprising a compound of formula (I) as claimed in any one of Claims 1 to 28 together with a pharmaceutically acceptable carrier.
30. A method of inhibiting testosterone-5a-reductases comprising contacting testosterone-5a-reductases with a compound of formula (I) as claimed in any one of Claims 1 to 28.

BAD ORIGINAL ¢2

1060AC

AP0 Ο π 4 5 9

110
31 - A method of treatment of androgen responsive or mediated disease comprising administering an effective amount of a compound of formula (I) as claimed in any one of Claims 1 to 28 to a patient in need thereof in combination.
32· A method of treatment of androgen responsive or mediated disease comprising administering an effective amount of a compound of formula (I) as claimed in any one of Claims 1 to 28 to a patient in need thereof in combination with an antiandrogen.
33. A method of treatment of androgen responsive or mediated disease comprising administering an effective amount of a compound of formula (I) as claimed in any one of Claims 1 to 28 to a patient in need thereof in combination with an alpha 1 adrenergic receptor blocker.
34. A method of treatment of androgen responsive or mediated disease comprising administering an effective amount of a compound of formula (I) as claimed in any one of Claims 1 to 28 to a patient in need thereof in combination with an antiestrogen.
35. A method of treatment as claimed in any one of Claims 33 to 36 wherein the androgen responsive or mediated disease is benign prostatic hyperplasia, prostatitis, prostate cancer, acne, male pattern baldness and hirsutism.
36. Use of a compound of formula (I) as claimed in any one of Claims 1 to 28 or a physiologically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of an androgen responsive or mediated disease.
37. A process for preparing a compound of formula (I) as defined in Claim 1 or a pharmaceutically acceptable salt thereof which comprises (A) reacting a compound of formula (IX)

BAD original $

1060AC

AP Ο Ο ο 4 5 9

111 wherein JO is hydroxy or a protected hydroxy group, with an oxidising agent; or

(B) for the preparation of compounds of formula (I) wherein X is -CH₂CH₂- 5 reacting a compound of formula (XV) CH₃ Z r’ ^R\ l I c Y R (XV)

with a reducing agent, and if necessary and/or desired subjecting the compound thus obtained to one or more further reactions comprising

10 (i) converting the resulting compound of formula (I) or a salt or protected derivative thereof into another compound of formula (I); and/or (ii) removing any protecting group or groups; and/or (iii) converting a compound of formula (I) or a salt thereof into a pharmaceutically acceptable salt thereof.
38. A process as claimed in Claim 39 wherein a compound of formula (IX) wherein JO is a protected hydroxy group is deprotected and then oxidised with an appropriate oxidising agent to give a compound of formula (I) where R⁴ is hydrogen.
39. A process as claimed in Claim ⁴0 wherein the oxidising agent is Jones reagent.

BAD ORIGINAL d

1060AC ^ΑΡ0Ο Ο 4 5 9

112
40. A process as claimed in Claim 39 wherein a compound of formula (IX) wherein JO is a protected hydroxy group is treated with an acylating agent, deprotected and then oxidised with an appropriate oxidising agent to give a compound of formula (I) where R⁴ is acyl.

⁴¹ · A process as claimed in Claim 42 wherein the oxidising agent is pyridinium dichromate.
42. a process as claimed in Claim 39 wherein a compound of formula (XV) is 10 reacted with triphenylphosphine to give a compound of formula (I) wherein X is CH₂CH₂-.

bad original $