CA2171329C - Androstenones - Google Patents

Abstract

The present invention relates to compounds of formula (I), wherein carbons 1 and 2 are joined by either a single or a double bond;
R1 is hydrogen or methyl; R2 is hydrogen or methyl; R3 is (A) or (B) wherein X, W, Z, R4, R5, R6, R7 and R8 are various groups, and pharmaceutically acceptable solvates thereof and their use in the treatment of androgen responsive and mediated diseases.

Description

-i-ANDROSTENONES
The present invention relates to certain substituted 17~-anilide-4-aza-5a-androstan-3-ones, in particular as surprisingly potent and selective dual inhibitors of type 1 and 2 human 5a-reductase.
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. secxeted 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.
Sa.-redudases NADP'$ NADP''' ~ H
Testosterone Dihydrotestosterone 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. ef 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 androgen responsive diseases, e.g., benign prostatic hyperplasia, prostate cancer, acne, male pattern baldness and hirsutism.

- ,t.'__ ____ : G1074 ' ' ' 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. ef al., Nature, 354, 159 (1991 )). The steroid 5a-reductase 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.
CONH-t Bu CONH-t Bu H

finasteride SCHEME B
The potent inhibition of bovine adrenal and porcine granulosa cell 3(i-hydroxy-A5-steroid dehydrogenase I 3-keto-A5-steroid isomerase (3BHSD) by the 4-azasteroid derivative, 4-MA, shown in Scheme C and not by the drug finasteride . , CQNEt2 Me SCHEME C
(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 3BHSD 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 3BHSD. 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 ~ Rasrnusson, G. H. et al. .J. Med. Chem. , 27, 1690 (1984)).
SUMMARY OF THE INVENTION
One aspect of the present invention provides compounds of formula (I), O ~. R -I
R' wherein carbons 1 and 2 are joined by either a single or a double bond;
R~ is hydrogen or methyl;
R2 is hydrogen or methyl;
R3 is (A) . . , w~
z -R , X Rs (A) wherein R4 and R5 are independently hydrogen, lower alkyl, lower alkoxy, trifluoromethyl, cyano, halogen, phenyl (optionally substituted with one or more halogens), or when R4 and R5 are on adjacent carbons, taken together form a fused 5, 6 or.7 member ring optionally containing one or more oxygen or sulfur atoms;
W and Z are methylene groups which taken together with the carbon to which , .-they are attached form a saturated, 3 to 12 member ring~system optionally:
1 ) substituted independently with one or more lower alkyl groups, 2) containing an oxygen or sulfur atom, --3) two said methylene groups of said 3 to 12 member ring are joined with a (C1~) alkylene group to form a bicyclic ring system; and X is hydrogen or halogen;
or(B) X
R' Rs (B) wherein R6 is trifluoromethyl, phenyl optionally substituted with one or more halogens or branched (C4_7) alkyl groups, or branched (C4_7) alkyl;
either of R7 or R8 is trifluorori~ethyl, halogen, phenyl optionally substituted with one or more halogens or branched (C4_7)alkyl groups, or branched (C4_7) alkyl, while the other is hydrogen or halogen; and X is hydrogen or halogen, 26169-62(S) - 5 _ and pharmaceutically acceptable solvates thereof.
Other aspects of the invention are:
1. A method (in vivo or in vitro) of inhibiting testosterone-5a-reductases comprising contacting testosterone-5a-reductases with a compound of formula (I).
2. A method of treatment or prevention 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; or use of a compound of formula (I) for such treatment or prevention; or use of a compound of formula (I) for the F ~, a ~ a ed ~ r~~mor,f- for .~"v: ch treatmen t Or titaiiuiav.~.ur o1 W iv.muwu.
prevention.
3. Pharmaceutical formulations containing a compound of formula (I) as an active ingredient.
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.

26169-62(S) - 5a -7. Certain chemical intermediates used in the preparation of compounds of formula (I), i.e., (III), (IV) and (IVa) as defined below.

8. Processes for the preparation of compound of formula (I) as detailed below.

9. A commercial package comprising a compound of formula (I) and associated therewith instructions for use thereof for the treatment or prevention defined in 2. above.
DETAILED DESCRIPTION OF THE INVENTION
Compounds Those skiiied in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as -' 61074 . , _6_ °solvates". For example, a complex with water is known as a "hydrate".
Solvates of the compound of formula (I) are within the scope of the invention.
It will also be appreciated by those skilled in organic chemistry that many organic compounds can exist in more than one crystalline fomn_ For example, crystalline form may vary from solvate to solvate. Thus, all crystalline forms of the compounds of formula (I) or the pharmaceutically acceptable solvates thereof are within the scope of the present invention.
As used herein the term "lower" in relation to alkyl and alkoxy means 1 to 6 carbons, especially 1 to 4, straight or branched. As used herein the term "branched (C~7) alkyl" means 3~ carbons attached via a quaternary carbon, e.g., t-butyl, t-amyl, etc. The term "halogen" means fluoro, chloro, bromo, and iodo moieties.
- --Examples of the ring systems formed by W and Z include, but are not limited to:
- cyclopropyl, cylclobutyl, cycopentyt, cyclohexyt, cycloheptyl, cyclooctyl, cyclodo--. ~ decyl, etc.; norbomyl, bicyclo [3.3.1 J nonyl, tetrahydrofuryl, tetrahydropyranyl, or tetrahydrothiopyranyl. Ring systems of 3 to 8 members are preferred.
- - Examples of bicyclic ring systems formed when one of the W methylene groups is joined to one of the Z methylene groups by a (C1 ~) alkylene group include, but are not timited~ to:
O
\ ,l \ . il \ .,.. \
Ra Ra R4 / Ra X Rs X Rs X Rs x ~ R
Examples of fused 5, 6 or 7 member rings formed by Ra and RS include but are not limited to:
S
I \ / \ . \ o \ \ s ,- .~. / /
x x o ..- .
x ono °~.-~ x x s - ~-- -' 61074 It will be appreciated by those skilled in the art of organic chemistry that the "quaternary carbon" of -substituent (A), i.e., the carbon upon which -NH-, the phenyl group, W and Z are attached, may be asymmetric. This asymmetry about the quaternary carbon gives rise to a pair of stereoisomers (see March, J., Advanced Organic Chemistry, 3rd Ed., Chap. 4, "Stereochemistry", John Wiley and Sons, New York (1985)). Further, when W and Z are substituted with alkyl groups or are joined with an alkylene group, other asymmetric carbons may be established also resulting in other pairs of stereoisomers. Ail stereoisomers of . the novel compounds taught herein are within . the scope of the present invention.
. As used herein the rippled. lines representing single bonds connecting the quaternary carbon to W and to Z indicate that these two bonds' can.be of either an a or ~i relationship with respect to the. quaternary; .carbon. ~ The term °a' means the bond and corresponding substituent extends below the plane of the page while.the term "~' means the bond and corresponding substituent extends above the plane ef the page and is depicted herein by a solid wedge shape bond. The use of these terms is consistent with standard chemical terminology.
In a particular group of the compounds of formula (I), X is hydrogen. In another particular group of the compounds of formula (I), R2 is hydrogen. In yet another group of the compounds of formula. (I), Rs is trifluoromethyl, phenyl optionally substituted with one or more halogens, or branched (C4.7) alkyl; and either of or R8 is trifluoromethyl, halogen; phenyl optionally substituted with one or more halogens, or branched (Cø~) alkyl, while the other is hydrogen or halogen. In another particular group of the compounds of formula (I) carbons 1 and 2 are joined by a double bond.
A particular group of the compounds of formula (I) are the compounds of formula (IA) . . , , _8_ w~
Z
NH
R4 , R
(IA) R~
wherein carbons 1 and 2 are joined by either a single or a double bond;
R~ is hydrogen or methyl;

R4 and R$ are independently hydrogen, ~ lower alkyl, lower alkoxy, trifluoromethyl, cyano, halogen, phenyl (optionally substituted with one or~
more halogens), or when R4 and R5 are on adjacent carbons, taken together form a -. fused 5, 6 or 7 member ring optionally containing one or more oxygen or sulfur atoms;
W and Z are methylene groups which taken together with the carbon to which they are attached form a saturated, 3 to 12 member ring system optionally:
1 ) substituted with one or more lower alkyl groups, 2) containing an oxygen or sulfur atom, - -- - - - ~ 3).two~ said methylene groups of said 3 to 12 member ring are joined with a (C1 6) alkylene group to form a bicyclic~ ring system; and X is hydrogen or halogen.
In a particular group of the compounds of formula (IA);
R4 and R5 are independently hydrogen, lower alkyl, lower alkoxy, trifluoromethyl, cyano, halogen, or phenyl (optionally substituted with one or more halogens); and X is hydrogen.
Compounds of formula (IA) wherein at least one of X, R4 and RS is other than hydrogen are preferred. Substituents in the para (4-) position of the phenyl ring are especiaNy prefen-ed.

61074 ~ 02171329 1995-03-23 . . , In a particular group of the compounds of formula (IA) at least one of R4 and is lower alkyl, lower alkoxy, trifluoromethyl, halogen or phenyl, especially branched alkyl, e.g., t-butyl, trifluoromethyl, or halogen.
In four other particular groups of the compounds of formula (IA);
1 ) W and Z are methylene groups which taken together with the carbon to which they are attached form a saturated, 3 to 12 member ring system containing only carbon atoms and which may be substituted independently with one or more lower alkyl groups; or 2) W and Z are methylene groups which taken together with the carbon to which . they are attached form a saturated, 3 to 12 member ring system containing an oxygen or sulfur atom and which may be substituted independently with one or more lower alkyl groups; or ~~ .
3). W and Z are' methylene groups which taken together with the carbon to which they are attached form a saturated, 3 to 12 member ring system containing only carbon atoms and which may be substituted independently with one or more lower alkyl groups and two said methylene groups are joined with a {C1~) alkylene group to form a bicyclic ring system; or 4) W and Z are methylene groups which taken together with the carbon to which . .. . _ . ... _ -... .. -- -~y.are attached form a saturated, 3 to 12 member ring system containing an ' oxygen or sulfur atom and which may be substituted independently with one or more lower alkyl groups and two said methylene groups are joined with a (C1..6) alkylene group to form a bicyclic ring system.
Another particular group of the compounds of formula (I) are the compounds of formula (IB);

-- - .' G1074 Rs X
NH ~ ~ R~

O .. (IB) I
R~
wherein carbons 1 and 2 are joined by either a single or a double bond;
R~ is hydrogen or methyl;
. R6 is trifluoromethyl, phenyl optionally substituted with one or more halogens, or branched (C4_7) alkyl; ~' _ _ . either of R~ or R$ is trifluoromethyl, halogen, phenyl optionally substituted with one or more halogens, or branched (C4_7) alkyl, while the other is hydrogen or halogen; and .
- X is hydrogen or halogen.
In a particular group of the compounds of formula (IB) when R7 or R8 is branched (C4_7)~alkyl and X is hydrogen, R6 is trifluoromethyl or phenyl optionally substituted with one or more halogens. ' In another particular group of the compounds of formula (IB);
R6 is trifluoromethyl or branched (C4_7) alkyl; and either of R~ or R$ is trifluoromethyl, halogen, or phenyl substituted with one or more halogens, while the other is hydrogen or halogen.
In another particular group of the compounds of formula (IB);
R6 is trifluoromethyl or brandied (C4_7) alkyl;
either of R~ or R8 is trifluoromethyl while the other is hydrogen; and X is hydrogen.
In another particular group of the compounds of formula (IB) Rs and R8 are independently trifluoromethyl or t-butyl, while R~ and X are hydrogen.
Specific compounds of formula (1) are:
Compound I Example Compound Number Name . - 1. 17~-N-1-(4-Chlorophenyl)cyclopentylcarbamoyl-4-aza-5a.-androstan-3-one 2. 17~-N-1-(4-Chlorophenyl)cyclopentylcarbamoyl-4-methyl-4.-aza-5a-androstan-3-one 15- 3. 17~-N-1-(4-Chiorophenyl)cyclopentylcarbamoyl~-aza-Sac-androst-1-en-3-one 4. 17~-N-1-(4-t Butylphenyl)cyclopentylcarbamoyl-4-aza-5a-androst-1-en-3-one 5. 17~-N-1-(4-f Butylphenyl)cyclohexylcarbamoyl-4=aza-5a-androst-1-en-3-one 6. 17~-N-1-(4-C hlorophenyl)cyclohexylcarbamoyl-4-aza-5oc-androst-1-en-3-one 7. 17~-N-1-(4-Trifiuoromethylphenyl)cyclopentylcarbamoyl-4-aza-5a-androst-1-en-3-one 8. 17~i-N-1-(4-Methoxyphenyl)cyclopentylcarbamoyl-4-aza-5a-androst-1-en-3-one 9. 17~i-N-1-(4-Fluorophenyl)cyclopentylcarbamoyl-4-aza-5oc-androst-1-en-3-one 10. 17[3-N-1-(4-Fluoropheny!)cyclohexylcarbarrioyl-4-aza-5oc-androst-1-en-3-one 11. 17(3-N-1-(4-Methoxyphenyl)cyclohexylcarbamoyl-4-aza-5a-androst-1-en-3-one 12. 17~i-N-1-(3,4-Methylenedioxyphenyl)cyclohexylcarbamoyl-4-aza-5a-androst-1-en-3-one 13. 17~-N-1-(4-f-Butylphenyl)cycloheptylcarbamoyl-4-aza-5a-androst-1-en-3-one 14. 17~-N-4-(4-t Butylphenyl)tetrahydropyranylcarbamoyl-4-aza-5a-androst-1-en-3-one " ~ 61074 15. 17~-N-1-(2,4-Dichlorophenyt)cyclopropylcarbamoyl-4-aza-5a-androst-1-en-3-one 16. 17 ji-N-1-(4-Trifluoromethylphenyl)-2,2-diethylcyclopropytcarbamoyl-4-aza-5a-androst-1-en-3-one 17. 17 ji-N-1-(4-t Butylpheny!)-4,4-dimethylcyclohexylcarbamoyh4-aza-5a-androst-1-en-3-one 18. 17 ji-N-1-(4-t-Butylphenyt)-4-t-Butylcyclohexylcarbamoyl-4-aza-5a-androst-1-en-3-one 19. 17~-N-1-(3-Trifluoromethylphenyl}cyclopentylcarbamoyl-4-aza-5a-androst-1-en-3-one 20. 17(i-N-4-(4-f Butylphenyt)tetrahydrothiopyranylcarbamoyl-4-aza-5a-androst-1-en-3-one 21. 17(i-N-1-(4-Biphenyl~2,2-diethylcyclopropylcarbamoyl-4-aza-5a-androst-1-en-3-one 22. 17 ji-N-(2,5-bis(Trifluoromethyl))phenylcarbamoyl-4-aza-5a.-androstan-3-one 23. 17p-N-(2,5-bis(Trifluoromethyl))phenylcarbamoyl-4-methyl-4-aza-5a.-androstan-3-one 24. 17(i-N-(2-f Butyl-5-trifluoromethyl)phenytcarbamoyl-4-aza-5a-androst-1-en-3-one 25. 17~i-N-(2-t Butyl-5-tr'rfluoromethyl)phenylcarbamoyl-4-aza-5a-androstan-3-one 26. 17 ji-N-(2-t Butyl-5-trifluoromethyl)phenylcarbamoyl-4-methyl-4-aza-5a-androstan-3-one 27. 17(i-N-(2,5-Di-t butyl)phenylcarbamoyl-4-aza-5a-androst-1-en-3-one 28. 17 ji-N-(2,5-Di-f-butyl)phenytcarbamoyl-4-aza-5a-androstan-3-one 29. 17(i-N-(2,5-Di-t butyl)phenylcarbamoyl-4-methyl-4-aza-5a-androstan-3-one 30. 17(i-N-(2, 5-bis(Trifluoromethyl)phenylcarbamoyl-4-aza-7p-methyl-5a-and rost-1-en-3-one 31. 17 ji-N-(2-t-Butyl-5-trifluoromethyl)phenylcarbamoyl-4-aza-7~-methyl-5a-androst-1-en-3-one 32. 17~-N-1-(4-Chlorophenyl)cyclopentylcarbamoyl-4-aza-7~-methyl-5a.-androst-i -en-3-one 33. 17~=N-9-(4-t-Butylphenyt)bicycloj3.3.1 ]nonylcarbamoyl-4-aza-5oc-androst-1-en-3-one.
A particular specific compound of formula (I) is 17 j3-N-1-(4-Chlorophenyl)cyGopentylca~amoyl-4-aza-5oc-androst-1-en-3-one.

26169-62 (S) Specific intermediate compounds of formulas (III), (IV) and (IVa) are:
17~-N-1-(4-chlorophenyl)cyclopentylcarbamoyl-androst-4-en-3-one;
17(i-N-1-(4-chlorophenyl)cyclopentylcarbamoyl-5-oxo-A-nor-3,5-secoandrostan-3-oic acid; and 17~-N-1-(4-chlorophenyl)cyclopentylcarbamoyl-4-aza-androst-5-en-3-one.
Preparation of Compounds The compounds of the present invention may be prepared by the methods taught in US Patents 4,377,584 (hereinafter, '"584") and 4,760,071 (hereinafter, '"071") . For example, compounds of formula (I) wherein carbons 1 and 2 are joined by a single bond may be prepared by the procedure shown in Scheme I.

O " O ..
'; i R ~ (IVa ) R ~
SCHEMEI
In' -Scheme t, the 4-aza-androst-5-en-3-one compound of formula (IVa) is con-verted to the corresponding 4-aza-5a-androstan-3-one of formula (I) by hydrogenation. For example, the hydrogenation may be carried out in acetic acid at 60 to 70°C and 40-60 psi hydrogen pressure in the presence of catalytic platinum oxide.
Compounds of formula (IVa) may be prepared by the procedure of Scheme IA:

~~ 61074 . ' _ -14-2H ,~ t NHR3 t) activation 2) H2NR3 (a=) (B) d-.. ') step 3 s HZNR~
HOZ( O
R ~ (~'a) (t~
SCHEME IA
In Step 1 of Scheme IA, 3-oxo-4-androstene-17(i-carboxylic acid (II) is converted to the corresponding amide of formula (III). This may be accomplished by activation of the acid and reaction with a compound of formula (Ila). For example, the reaction sequence can be.conversion of a compound of formula (II) to the corresponding acid halide by treatment with a halogenating agent such as oxalyl chloride or thionyt chloride in an aprotic solvent such as toluene, methylene chloride or tetrahydrofuran at -5 to 10°C in the presence of a base such as pyridine. The intermediate acid halide, e.g., an acid chloride, may be reacted with an amine of formula (Ila) (wherein the substituents are as defined for formula (I)), optionally in the presence of a catalyst such as 4-N,N-dimethylaminopyridine, at 25° to 70°C in an aprotic solvent such as tetrahydrofuran to give the amide of formula (III).
The compounds of formula (Ila) wherein R3 is (A) i.e., cycloalkylbenzylamines, are 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. Substituted cyciopropylbenzylamines of formula (Ila) are prepared by radium catalyzed insertion of the appropriate aryl-a-diazo-ester (prepared by the method of Baum, J.S. et al., Synthetic Comm., Q K_ 1T, 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. The compounds of formula (Ila) wherein R3 is (B), i.e., substituted anilines, are commercially available or conveniently prepared by methods known in the art (see Blakitnyi ef al., J. Org. Chem. USSR (English translation),.10, 512 (1974) abstracted in CA
80 (25): 14623f and Reetz, M.T. et ai., Angew. Chem. lot. Ed Engl., 19, 900 and 901 (1980)). , - In Step 2, the compound of formula (III) is converted to the 5-oxo-A-nor-3,5-secoandrostan-3-oic acid derivative of formula (IV) by oxidation, e.g. by treatment with aqueous sodium permanganate and sodium periodate under basic conditions at reflux in t-butanol.
In Step 3, the compound of formula (IV) is converted to the corresponding com-pound of formula (IVa) by treatment with a compound of the fonnufa NH2R~, e.g., ammonia (R~=H) or methylamine (R~=methyl), at elevated temperatures in a erotic or aprotic solvent, e.g., at reflux in ethylene glycol.
Compounds of formula (I) may also be prepared by interconversion from other compounds of formula (I). f=or example, the process of Scheme IB may be used to prepare a compound of formula '(I) where there is a double bond between carbons 1 and 2,-and where R1 is hydrogen, i.e., the compound of formula (Ib) from the corresponding compound of formula (I), i.e., the compound of formula (la).

H (~) SCHEME IB
In Scheme IB, a compound of formula (la) is dehydrogenated to give the corresponding 4-aza-5a-androst-1-en-3-one of formula (Ib) by treatment with a dehydrogenating system, e.g. 2,3-dichloro-5,6-dicyano-1,4-ben~oquinone (DDQ) and bis(tri-methylsilyl)trifluoroacetamide in dry dioxane at room temperature for 2-5 hrs followed by heating at reflux for 10-20 hrs (see Bhattacharya, A. et al., J. Am. Chem. Soc., 190, 3318 (1988).
step 1 H2~3 O (~) 0 R' M R 1 (n SCHEME II
Alternatively, in Scheme II compounds of formula (I) wherein carbons 1 and 2 are joined by a double bond may be prepared from 3-oxo-4-aza-5a.-androst-1-ene-17~i-carboxylic aads of formula :(~ by reaction with a compound of fomaula (Ila) as described in Scheme IA, step 1. Compounds of formula (V) wherein R2 is hydrogen may be prepared by the method of Rasmusson, G.H. et al., J. Med Chem., 29, 2298 (1986). ~ The compounds of formula (~ wherein R2 is methyl may be prepared according to Scheme tla.

_' 7 _ CO2AIk C02A1 step 1 JO. JO
v stop 2 C02Alk CO2AIk step 3 O
_ _ - C02Alk ~- ~5 H02C ~ O
Ri COZH
('L~ wherein R2 is CH3 O
Ri SCHEME Ila In Step 1, a compound of formula (VI), wherein JO is a protected hydroxy group, e.g., a triisopropylsilyloxy group, and C02Alk is carboxylic acid ester group, e.g., a methyl ester, is reacted with a strong, heavy metal oxidizing complex , e.g., chromic acid I 3,5-dimethyl pyrazole in an aprotic solvent, e.g., dichloromethane, to yield the corresponding compound of formula (Vli).
Compounds of fom~ula (VI) may be prepared from a 3(i-hydroxyetienic acid ester (J. Med. Chem. 27, 1690) by the method taught in PCT patent application W094114833. For example, 3(3-hydroxyetienic acid methyl estar may be reacted with a hydroxy group protecting reagent such as triisopropylsilylchloride in the presence of a base, e.g., imidazole in an aprotic solvent such as dimethyi formamide or dichloromethane, at moderate temperatures ranging from 25 to 55°C.
-In Step 2, the 7-oxo moiety of the compound of formula (VII) is converted to the corresponding alkyl group, e.g., methyl group, by treatment with a wittig reagent agent followed by catalytic hydrogenation and deprotection of the 3-hydroxy group to yield the corresponding compound of formula (VIII). For example, the compound of formula (VII) may be reacted with methyl triphenylphosphonium iodide and n-butyl lithium in an aprotic solvent, such as tetrahydrofuran, in the temperature range of about -5~ to 10°C, e.g., at O~C, to yield the corresponding 7-alkylidene derivative. The exocyclic double bond may then be reduced - - selectively by treatment with tris(triphenylphosphine)rhodium chloride under a hydrogen atmosphere to yield predominately the 7(i-alkylw substituted compound.
The protecting group on the 3-hydroxy is then removed to yield the compound of __ _ formula VIII. For example, if.the protecting group is triisopropylsilyl, it may be removed by treatment with tetrabutylammoni~rm fluoride ~in tetrahydrofuran.
In Step 3, the 3-hydroxy.group of the compound of formula (VIII) is oxidized to _yield the. corresponding 3-oxo moiety with migration of the double bond to yield the compound of formula (IX). For example, the oxidation may be accomplished with Jones' reagent in an alkyl ketone, such' as acetone, at about room temperature.
In Step 4, the compound of formula (IX) is oxidized in an analogous manner to that described in Step 2 of Scheme IA to yield the corresponding 5-oxo-A-nor-3,5-secoandrostan-3-oic acid derivative of formula (X).
In Step 5, the compound of formula (X) is converted to the corresponding compound of formula (XI) in an analogous manner to that described in Scheme In Step 6, the compound of formula (XI) is dehydrogenated in an analogous manner to that described in Scheme IB to yield the corresponding 4-aza-5a-androst-1-en-3-one derivative. The 17-carboxylic acid ester group is then converted by saponification to the corresponding 17-carboxylic acid group ' . ' ' -19-yielding the compound of formula (V). For example, the carboxylic acid ester group may be converted to the carboxylic group by treatment with a moderate to strong base in a erotic or aprotic solvent, e.g., treatment with a metal hydroxide, such as lithium hydroxide, in dioxane I water at about room temperature.
_ Those skilled in the art will appreciate that at an earlier stage in the preparation of a compound of formula (I) or a solvate 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 Organic 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). ~ ~ w 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.
As will be appreciated, in any of the general processes 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.
Thus, according to a further aspect of the invention, the following reactions may, if necessary andlor desired be carried out in any appropriate sequence subsequent to any of the general processes:
(i) removal of any protecting groups; and (ii) conversion of a compound of formula (I) or a solvate thereof into a pharmaceutically acceptable solvate thereof.
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 compounds of formula (I) and the intermediate compounds, (II)-(XI), shown in Schemes 1 and II may be purified by convenient methods of the art, e.g., chromatography or crystallization:
In vitro Assays Steroid 5a-Reductases Enzyme activities 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; or 3) - 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 [1,2,6,7-3HJ-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 can-led out with no test compound as a control study.
For type 1 ICSO measurements, 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-i20 minutes. For type 2 ICSO measurements, assay components except testosterone were preincubated for 20 minutes at pH 6.0, and following the addition of 8 nM 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 pertormance liquid chromatography (HPLC) with radiochemical detection. The results of these assays appear as ICSp's reported in Table 1.
3(3-Hvdroxy-OS-steroid Dehydro4enase / 3-Keto-e5-steroid Isomerase ' ~ ~ G1074 Enzyme activities are measured using micxosomes derived from human adrenal tissues. Miaosomes were prepared by homogenization of the tissue followed by differential centrifugation of the homogenate. Microsome extracts were incubated with varying concentrations of dehydroepiandrosterone (DHEA), 1 mM NAD+~ and varying arraounts of the compounds of Formula (I), i.e. a test compound, in pH 7.5 buffer for a period of time within the range of 1 to 60 minutes. Corresponding incubations were carried out with no test compound as a control study. The percentage of conversion of DHEA to androstenedione in the presence of test compounds compared to the corresponding conversion in the control study was estimated using HPLC with radiochemical detection. The results of these assays appear as K;'s reported in Table 1.

5a-REDUCTASE (5AR) AND HUMAN ADRENAL 3~-HYDROXY-AS-STEROID
DEHYDROGENASE I 3-KETO-Os-STEROID ISOMERASE (3BHSD) in vitro INHIBITORY ACTIVITY
Compound) IC5o Human iCso Human K; Human Adrenal Example Type 1 5AR Type 2 5AR 3BHSD

1 +++ ++++ +

++++ . ++++ ++

3 ++++ ++++ +

4 +++ ++++ +

_ . . . _ _ 5 .t.+.t . ++++ +

6 +++ ~ ++++ +

. 7 +++ ++++ +

+++ ++++ +

g - +++ ++++ +

10 +++ ++++ +

11 ~ +++ nt +

12 ++ nt ++

13 +++ nt +

14 +++ . ~ nt +

15 +++ nt +

16 +++ . nt +

17 ++++ nt +

18 +++ . nt +

19 +++ nt +

' , r ' ~ -22-20 ++++ nt +

21 ++++ nt +

+++ ~ ++++ +

23 ++++ ++++ ++

.24 +++ ++++ . +

25 +++ ++++ +

26 ++++ ++++ ++

27 +++ ++++ ++

28 +++ ++++ +

2g ++++ ++++ ++

30 nt nt nt 31 ~nt nt nt 32 nt nt nt . . _ . _ _ 33 +++ nt . +

~.
Y.

++++ <1 nM nt - not tested +++ 1-1 OnM
++ 10-1000nM
+ >1000nM
In vivo Evaluation of Steroid 5a-Reductase Inhibitors The in vivo activity of steroid 5a-reductase inhibitors may be determined in~
a .chronic rat model .(Brooks, J.R: et al., Steroids, 47, 1 (1986)). The chronic model utilizes castrated male rats that are dosed daily with testosterone (20 Nglrat) subcutaneously and with test compound (0.01-10 mglkg) or vehicle-orally 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 5oc--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, in a manner similar to that for other 5a-reductase inhibitors such as finasteride and SKF105657. For correlation of in vitro, rat in vivo, and human clinical data relating to an inhibitor of 5a-reductase, see Stoner, E. et al., J. Steroid - ' ~ G1074 Biochem. Moles. BioL, 37, 375 (1990); Brooks, J.R. et al., Steroids, 47, 1 (1986) and Rasmusson, G.H. et al., J. Med. Chem., 29, 2298 (1986)).
Compounds of this invention 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, may also be treated with these compounds.
The amount of compound of formula (I) required to be effective as an 5x-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 0.001 to about 2 mglkg body weight per day, preferably in the range of about 0:005 to about 1 mglkg 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 0.4mg to about 75 mg per day, and a typical dose would be about 10 mg per day. If discrete multiple doses are indicated, treatment might typically be 2.5 mg of a compound of formula~(1) given 4 times per day.
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.
The present invention, therefore, further provides a pharmaceutical formulation-comprising a compound of formula (I) together with . a pharmaceutically acceptable carrier thereof.

' ~~ 61074 ' -24-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 discxete 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 ingredients) may include flavoring, an agent to retard crystallization of the sugar or an agent to increase the 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., coda 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. Thus, such formulations may conveniently contain distilled water, 5°~ dextrose in distilled water or saline.
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, cxeam gel, or lotion base and the alive ingredient, such topical formulation may 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 ingredients) utilized in the art of pharmaceutical formulations, e.g., diluents, buffers, flavoring agents, binders, surface active agents, thickeners, lubricants, suspending agents, preservatives (inGuding antioxidants) and the like.
EXAMPLES
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 1713-N-1-(4-Chlorophenvl)cyclopentvlcarbamoyl-4-aza-5a-androstan-3-one ~Comaound 1 ) A 17a-N-1-(4-Chlorophenyl)cyclopentylcarbamoyl-androst-4-en-3-one To a suspension of 3-oxo-4-androstene-17~i-cafioxylic acid (Rasmusson, G.H.
et al., J. Med. Chem., 27, 169011984)) (10.44 g, 32.9 mmol), in toluene (330 mL) and dry pyridine (3.75 ml) at 0°C is added thionyl chloride (3.6 mL, 49 mmol). The reaction mixture is stirred at 0°C for 15 min and then stirred at room temperature for 1 h. The reaction mixture is then cooled to 0°C, treated with 4-N,N-dimethylaminopyridine (1.01 g, 8:28 mmol) and 1-amino-1-(4-chlorophenyl)-cyclopentane (12.90 g, 65.9 mmol; prepared by Curtius rear-a~gement of the ' -26-corresponding acid) and allowed to warm to ~ room temperature and stir overnight. Next the reaction is extracted sequentially with 1 N HCI, 10°~ NaOH, water and brine, dried over sodium sulfate, and filtered. The filtrate is concentrated and flash chromatographed on silica gel, eluting with a 35-50°~
ethyl _acetate - hexane gradient to give, after concentration, 17~-N-1-(4-chlorophenyl)cyclopentylcarbam-oyl-androst-4-en-3-one as an off white foam;
yield: 8.44 g (52°~).
B.173-N-1-(4-Chlorophenyl)cyclopentylcarbamoyl-5-oxo-A-nor-3,5-secoandrostan-3-oic acid To a refiuxing solution of 17(3-N-1-(4-chlorophenyi)cyclopentylcarbamoyl-androst-4-en-3-one (8.44 g, 17.1 mmol) prepared in part~A above, t butanol (130 mL), sodium carbonate (3:18 g, 25.6 mmol), and water (35 mL) is added, over 35 min, a 75°C solution of potassium permanganate (0.678, 4.3 mmol), sodium periodate (25.578 , 120 mmol) and water (190 mL). After cefuxing an additional min, the heterogeneous mixture is cooled to room temperature, filtered through a bed of celite, the solid is washed with water and the filtrate concentrated in vacuo to remove t-butanol. The resulting aqueous solution is acidified to pH 2 with 6N HC! and then extracted with CH~CIZ (4X100 mL). The 20 CH2CI2 layers are combined and washed with water, dried over sodium sulfate, filtered and concentrated in vacuo to give 7 7~-N-1-(4 chlorophenyl)cyclopentylcarbamoyl-5-oxo-A-nor-3,5-secoandros-tan-3-oic acid as a off-white solid; yield: 7.30 g (83%'crude). This material is carried .directly - ~ - - - - into step C below.
C. 17(i-N-1-(4-Chlorophenyl)cyclopentylca~bamoyl-4-aza-androst-5-en-3-one To a suspension of 17(i-N-1~(4-chlorophenyl)cyclopentylcarbamoyl-5-oxo-A-nor-3,5-secoandrostan-3-oic acid (4.78 g, 9.30 mmol), from step B, in dry ethylene glycol (20 mL) at -5°C is added ammonia (ca. 3.5 mL, 0.14 mol) and the mixture stirred at 0°C for 30 min. The resulting solution is heated to 170°C over 1 h, and after 1 h at 170°C, the reaction mixture is cooled to 30°C and water is added.
The resulting slurry is diluted with 1 N HCI, extracted with chloroform (4X100 mL), the extracts dried over sodium sulfate, filtered and concentrated to give 17~-N-1-(4-chlorophenyl)cyclopentylcarbamoyl-4-aza-androst-5-en-3-one as a tan solid; yield: 5.08 g (100°~ crude). This material is carried directly into step D
below.
D. 17(3-N-1-(4-Chlorophenyl)cyclopentylcarbameyl-4-aza-5a-androstan-3-one . . . , To a solution of 17(i-N-1-(4-chlorophenyl)cyclopentylcarbamoyl-4-aza-androst-5-en-3-one (from above, ca. 9.30 mmol) in acetic acid (120 mL) is added platinum oxide (0.32 g). The resultant mixture is charged to 56 psi with hydrogen and heated at 75°C for 5 h then allowed to cool to room temperature overnight.
After replacing the hydrogen atmosphere with nitrogen, the reaction mixture is filtered through celite and the celite pad washed with CH2C12. Toluene is added and the filtrate is concentrated ~in vacuo to an oil which is purified by flash chromatography (toluenelacetone/ethyl acetate, 6:3:1 to 1:3:1 ) to give 17~-N-(4-chlorophenyl)cyclopentylcarbamoyl-4-aza-5a-androstan-3-one as a mixture ~-with the corresponding 17~i primary amide; yield: 0.69 g, (15°~).
Subsequent pur~cation of this material by HPLC (BDS Hypersil C8 column, 50%
CH3CN/water) and trituration with hot ethyl acetate gave a pure sample: m.p.
. 261-263°C; Anal. Calcd. for C3oH4~CIN202~1/4H20: C, 71.83 ; H, 8.34 ;
N, 5.58. Found: C, 71.85; H, 8.23; N, 5.59.
~ ...
Example 2 17~-N-1-(4-Chlorophenvl )cycloaentvlcarbamoyl-4-meth~rl-4-aza-5a-androstan-3-one (Compound 2) Starting with 17~-N-1-(4-chlorophenyl)cyclopentylcarbamoyl-5-oxo-A-nor-3,5 secoandrostan-3-oic acid (i.73 g, 3.36 mmol), from example 1, step B, and following the procedures of example 1, step C and D, with the substitution of methylamine for ammonia in step C, 17a-N-1-(4-chlorophenyl)cyclopentyl carbamoyl-4-methyl-4-aza-5a-androstan-3-one is prepared, m.p. 125-130°C.
Anal. Calcd. for C31hI43C~N2Oz~1/2H2O: C, 71.37 ; H, 8.38; N, 5.31. Found: C, 71.58; H, 8.53; N, 5.39.
Example 3 17B-N-1-(4-Chlorophenvl)cyclopentytcarbamovl-4-aza-5a-androst-1-en-3-one ,Compound 3) To a suspension of 3-oxo-4-aza-5a-androst-1-ene-17~i-carboxylic acid (Rasmusson, G.H. et al., J. Med. Chem., 29, 2298 (1986)) (0.159 g, 0.50 mmol), in toluene (5 ml), dimethylformamide (0.5 mL), and pyridine (0.06 mL, 0.7 mmol) at 0°C is added thionyl chloride (0.05 mL, 0.7 mmol). After 15 min the ice bath is removed and the reaction mixture allowed to warm to room temperature. After 1 h, the reaction mixture is concentrated in vacuo. The residue is dissolved in dry CH2CI2 and 1-amino-1-(4-chlorophenyl)-cyclopentane (0.49 g, 2.5 mmol; prepared by Curtius rearrangement of the corresponding acid) is added at room temperature followed by 4-N,N-- ~ 61074 ', dimethylaminopyridine (0.061 g, 0.50 mmol). After 4 h, 1 N HCI is added, the mixture extracted with CHC13 (3X100 mL), the CHCI3 dried over MgS04, filtered and concentrated. The residue is flash chromatographed on silica gel (toluenelacetonelethyl acetate, 26:3:1 to 11:3:1 ) to give a white solid on concentration. This material is triturated with ethyl acetate to give 17~-N-1-(4-chlorophenyl)cyclopentylcarbamoyl-4-aza-5a-androst-1-en-3-one as a white solid; yield: 129 mg, (52°~); m.p. 307-309°C (decomp.). Anal.
Calcd. for C30H39CIN202= C, 72.78; H, 7.94; N, 5.66. Found: C, 72.59; H, 7.93; N, 5.54.
Examples 4-21 These compounds were prepared as outlined in example 3 above. Amines which were not commercially available were prepared as described in PCT
Application WO 94/14833.
Example 4 17 ti-N-1-(4-f-Butv~~henvl)cyclopentylcarbamoyl-4-aza-5a-androst-1-en-3-one (Compound 4) Melting Point: 282 285°C
~ Anal. Calcd. for C~H48N202~114H20: C, 78.34; H, 9.38; N, 5.37.
Found: C, 78.29; H, 9.40; N, 5.38.
Example 5 17ti-N-1-(4-t-Butylphenyl)cyclohexylcarbamoyl-4-aza-5a-androst-1-en-3-one (Compound 5) ---. - . _ Melting Point: 233-236°C
Anal. Calcd. for C35H50N202'1~2H2O: C, 77.88; H, 9.52; N, 5.19.
Found: C, 77.82; H, 9.54; N, 5.21.
Example 6 17p-N-1-(4-Chlorophenyl)cyclohexylcarbamoyl-4-aza-5a-androst-1-en-3-one (Compound 6) Melting Point: 270-272°C
Anal. Calcd. for C3~ H47CIN2O2: C, 73.13; H, 8.12; N, 5.50.
Found: . C, 73.06; H, 8.14; N, 5.47.
Example 7 17ti-N-1-(4-Trifluoromethylphenyl )cyclopentylcarbamovl-4-aza-5a-androst-1-en-3-one (Compound 7) Melting Point: 294-297°C
Anal. Calcd. for C3~ H39F3N202: C, 70.43; H, 7.44; N, 5.30.
Found: ' C, 70.34; H, 7.46; N, 5.23.
Example 8 17 Q-N-1-(4-Methoxvphenvl )cvclopentvlcarbamoyl-4-aza-Sa.-and rost-1-en-3-one (Compound 8) Melting Point: 257-260°C
Anal. Calcd. for C3~ H42NZO3: C, 75.88; H, 8.63; N, 5.71.
Found: , C, 75.86; H, 8.57; N, 5.60.
Example 9 173-N-1-(4-Fluorophenvl)cvclopentylcarbamovl-4-aza-5a-androst-1 ~n-3-one (Compound 9) Melting Point: 290°C
Anal. Calcd. for C3oH39FN2~2: C, 75.28; H, 8.2,1; N, 5.85.
Found: - C, 75.09; H, 8.26; N, 5.75.
Example 10 17B-N-1-(4-Fluorophenyl)cyclohexvlcarbamoyl-4-aza-5a-androst-1-en-3-one (Compound 10) Melting Point: 283-285°C
Anal. Calcd. for C3~ H4~ FN202: C, 75.58; H, 8.39; N, 5.69.
. _ Found: C, 75.63; H, 8.45; N, 5.67.
Example 11 17t3-N-1-(4-Methoxvphenyl)cvclohexvlcarbamovl~-aza-5a-androst-1-en-3-one (Compound 11 ) Melting Point: 238-240°C
Anal. Calcd. for C32H,~N203~114H20: C, 75.48; H, 8.81; N, 5.50.
Found: C, 75.42; H, 8.78; N, 5.51.
~ Example 12 l7Li-N-1-(3,,4-Methvlenedioxyphenyl)cyclohexvlcarbamovl-4-aza-5a-androst-1-en-3-one (Compound 12) Melting Point: 255-257°C

i Anal. Calcd. for C32H42N2~4: C, 74.10; H, 8.16; N, 5.40.
Found: C, 74.07; H, 8.17; N, 5.37.
Example 13 17 f3-N-1-(4-t-Butylphenyl)cycloheptylcarbamoyl-4-aza-5a.-androst-1-en-3-one (Compound 13) Melting Point: 152-162°C
Anal. Calcd. for C~H52N202~1I2HZO: C, 78.07; H, 9.65; N, 5.06.
Found: C, 78.11; H, 9.64; N, 5.04.
Example 14 17 f3-N-4-(4-t-Butylphenyl)tetrahydropyranylcarbamoyl~-aza-5a.-androst-1-en-3-one (Compound 14) Melting Point: 240-242°C
HRMS Calcd. for C34H4gN2O3: 533.375143. . --w Found: 533.37512 (-1.5 ppm).
Example 15 l7li N-1-(2 4-Dichlorophenyl)cyclopropylcarbamoyl~-aza-5a-androst-1-en-3-one (Compound 15) Melting Point: 297 298°C
Anal. Calcd. for C28H~C12N202: C, 67.06; H, 6.83; N, 5.59. .
Found: C, 67.18; H, 6.86; N, 5.53.
Example 16 17a-N-1-(4-Trifluoromethylphenyl)-2 2-diethylcyclopropylcarbamoyl-4-aza-5a-androst-1-en-3-one (Compound 16) Melting Point: 225-228°C
Anal. Calcd. for C33H43F3N2O2: C, 71.20; H, 7.79; N, 5.03.
Found: ~ C, 70.92; H, 7.77; N, 4.99.
Example 17 17B N 1-(4-t Butylphenyl)-4 4-dimethylcyclohexylcarbamoyl-4-aza-5a-androst-1-en-3-one (Compound 17) Melting Point: 172-175°C
Anal. Calcd. for C37H~N202~113H20: C, 78.68; H, 9.76; N, 4.96.
Found: C, 78.58; H, 9.69; N, 4.74.

61074 ' Example 18 17(3-N-1-(4-t Butylphenyl)-4-t Butylcyclohexylcarbamoyr-4-aza-5a-androst-1-en-3-one (Compound 18) Melting Point: 189-194°C
Anal. Calcd. for C39HS8N2O2: C, 79.81; H, 9.96;'N, 4.77.
Found: C, 79.65; H, 9.89; N, 4.75.
Example 19 17ti-N-1-(3-Trifluoromethylphenyl)cyclopentylcarbamoyl-4-aza-5a-androst-1-en 3-one Compound 19) Melting Point: 258-260°C
Anal. Calcd. for C3~ H39F3N2O2: C, 70.43; H, 7.44; N, 5.30.
Found: C, 70.35; H, 7.39; iN, 5.30.
i _ Example 20 17fi-N-4-~4-f Butylphenyl)tetrahydrothiopyranylcarbamoyl-4-aza-5a-androst-1-en-3-one (Compound 20) Melting Point: 267-268°C
Anal. Calcd. for C34H4gN202S~H20: C, 72.04; H, 8.89; N, 4.94.
Found: C, 72.19; H, 8.54; N, 4.92.
Example 21 17a-N-1-(4-biphenyl)-2 2-diethylcyclopropylcarbamoyl-4-aza-5a-androst-1-en-3-one Compound 21 ) Melting Point: 167-174°C
Anal. Calcd. for C38H48N202~1I2H20: C, 79.54; H, 8.61; N, 4.88.
Found: C, 79.34; H, 8.43; N, 4.76.
Example 22 17Ii-N-(2 5-bis(Trifluoromethyl))phenylcarbamoyl-4-aza-5a-androstan-3-one (Compound 22) A. 17~-N-(2,5-bis(Trifluoromethyl))phenylcarbamoyl-androst-4-en-3-one To a solution of 3-oxo-4-androstene-17(3-carboxylic acid (Rasmusson, G.H. et al., J_ Med. Chem., 27, 1690 (1984)) (17.2.8, 54.4 mmol), dry THF (180 mL) and dry pyridine (7 ml) at 2°C is added thionyl chloride (5.1 mL, 70.8 mmol). The reaction mixture is stirred at 2°C for 20 min and then stirred at room temperature for 40 min. The reaction mixture is then filtered and the solid washed with toluene. The filtrate is concentrated in vacuo to an oil which is diluted with dry THF (150 mL) and dry pyridine (7 mL). To the resultant dark solution is added 2,5-bis-(trifluoromethyl)aniline (9.4 mL, 59.8 mmol) and the reaction mixture is refluxed for 5 h, diluted with methylene chloride, extracted sequentially with HCI and brine, dried over sodium sulfate, and filtered. The frltrate is concentrated and applied to a column of 500 g of silica gel and the column eluted with a 15-30°~ ethyl acetate - hexane gradient to give, after concentration, 17(i-N-(2,5-bis(trifluoromethyl))phenyl-carbamoyl-androst-4-en-one as an off-white foam; yield: 18.3 g (64%).
B.17(i-N-(2, 5-bis(Trifluoromethyl))phenylcarbamoyl-5-oxo-A-nor-3, 5-secoandrostan-3-oic acid To a refluxing solution of 17~N-(2;5-bis(trifluoromethyl))phenylcarbamoyl-androst-4-end-one (18.3 g, 34.9 mmol) prepared in part A~above, f-butanol (275 mL), sodium carbonate (6.3 g, 50.8 mmol), . and water (36 mL) is added, over 45 min, a 75°C solution of potassium permanganate (0.38g, 2.4 mmol), sodium periodate (52.28 , 245 mmol) and water (311 mL): After refuxing an additional 15 min, the heterogeneous mixture is cooled to room temperature and celite (50 g) is added. The reaction mixture is filtered through a bed of celite (50 g) and . the solid is washed with water and the filtrate concentrated ~in vacuo to remove t butanol (ca. 175 ml). The resultant aqueous solution is acidified to pH 2' with 36% HCI and the~extracted 4 times with chloroform. The chloroform Layers are combined and washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 17p-N-(2,5-bis(trifluoromethyl))phenylcarbamoyl_ 5-oxo~4-nor-3,5-secoandros-tan-3-oic acid as a off-white solid; yield: 20.5 g (100% crude). This material is carried directly into step C below.
C. 17(i-N-(2,5-bis(Trifluoromethyl))phenylcartiamoyl-4-aza-androst-5-en-3-one .
To a suspension of 17~i-N-(2,5-bis(trifluoromethyl))phenylcarbamoyl-5-oxo-A-nor-3,5-secoandrostan-3-0ic acid (20.5 g, 34.8 mmol), from step B, in dry ethylene glycol (100 mL) at room temperature is added ammonia (ca. 8 mL, 0.32 mol) over a 5 min period. The resultant solution is heated to 180°C
over 45 min, and after 12 min at 180°C, the reaction mixture is cooled to 70°C and water (116 mL) is added over a period of 5~ min. The resultant suspension is cooled to 7°C
and stirred for 10 min and filtered under vacuum. The solid is washed with water (60 mL) and then is dissolved in chloroform and washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue is dissolved in .
- 33 _ chloroform and applied to a column of 110 g of silica gel and the column eluted with a 2-5°r6 isopropanol-chloroform gradient to give 17p-N-(2,5-bis(trifluoromethyl))phenyl-carbamoyl-4-aza-androst-5-en-3-one as an off white solid; yield: 16.5 g (90°r6).
_ D. 17(3-N-(2,5-bis(Trifluoromethyl))phenylcarbamoyl-4-aza-5oc-androstan-3-one To a solution of 17~-N-(2,5-bis(trifluoromethyl))phenylcarbamoy(-4-aza-androst-5-en-3-one (8.9g, 16.7 mmol) in acetic acid (120 mL) is added platinum oxide (0.9 g). The resultant mixture is charged to 50 psi with hydrogen and heated at 60-70°C for 6 h. After replacing the hydrogen atmosphere with nitrogen, the reaction mixture is filtered through celite and the celite pad washed with acetic acid (30 mL), chloroform (60 mL) and toluene (200 mL). The filtrate is .. concentrated in vacuo to an oil, toluene (200 mL) is added and the solution concentrated to a foam in vacuo. The foam is crystallized from ethyl acetate heptane to give, after drying in vacuo at 85°C , for 1 h, 17(i-N-(2,5 bis(t~rfluoromethyl))phenylcarbamoyl-.4-aza-Sac-androstan-3-one; yield: 4.78 g, (54°~6); m.p. 245-247°C. Anal. Calcd. for C27H32F6N2G2: C, 61.12 ; H, 6.08 ;
N, 5.28. Found: C, 61.13; H, 6.12; N, 5.21.
Example 23 17a-N~2.5-bis(Trifluoromethyl))phenylcarbamoyl-4-methyl-4-aza-5a-androstan-3-one (Compound 23) A. 17(i-N-(2,5-bis(Trifluoromethyl))phenylcarbamoyl-4-methyl-4-aza-androst-5-en-3-one To a suspension of 17~-N-(2,5-bis(trifluoromethyl))phenylcarbamoyl-5-oxo-A-nor-3,5-secoandrostan-3-oic acid (1.7 g, 3.1 mmol), from example 1- step B, in dry~ethylene glycol (8.5 mL) at room temperature is added methylamine (ca. 1 mL, 22.5 mmol) and the resultant solution is heated to 180°C over 1 h.
After 15 min at 180°C, the reaction mixture is cooled to room temperature and water (10 mL) is added. The reaction mixture is stirred at 7°C for 10 min and is filtered under vacuum. The solid is washed with water (5 mL) and is subsequently dissolved in chloroform and washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue is applied to a column of 110 g of silica gel and the column eluted with a 2-5°~ methanol-methylene chloride gradient to give 17~-N-(2,5-bis(trifiuoromethyl)~phenylcarbamoyl-4-methyl-4-aza-androst-5-en-3-one as an off white foam; yield: 1.11 g (66°~).

_34_ B. 17~-N-(2,5-bis(Trifluoromethyl))phenylcarbamoyl-4-methyl-4-aza-5a-androstan-3-one To a solution of 17ø-N-(2,5-bis(trifluoromethyl))phenylcarbamoyl-4-methyl-4-aza-androst-5-en-3-one (1.0 g, 1.9 mmol) in acetic acid (10mL) is added platinum oxide (0.10 g). The resultant mixture is charged to 50 psi with hydrogen and is heated at 60-70°C for 45 min. After replacing the hydrogen atmosphere with nitrogen, the reaction mixture is filtered through celite and the celite pad washed with acetic acid (10 mL), chloroform (60 mL) and toluene (30 mL). The filtrate is concentrated in vacuo to an oil, toluene (30 mL) is added, and the solution concentrated to a foam in vacuo. This material is chromatographed twice on 93 g of silica gel by eluting with a 2 to 4% gradient of methanol-methylene chloride to give,- after drying in vacuo at 60°C for 21 h, 17(i-N-(2,5-bis(trifluoromethyl))-phenylcarbamoyl~-methyl-4-aza-5oc-androstan-3-one, m.p.
103-105°C. Anal. Calcd. for C28H34F6N202: C, 61.76 ;. H, 6.29 ; N, 5.14.
Found: C, 61.60; H, 6.32; N, 5.08. ~ w Example 24 17(i-N j2-t Butyl-5-trifluorometh~rl)phenylcarbamoyl-4-aza-5oc-androst-1-en-3-one (Compound 24) To a suspension ' of 3-oxo-4-aza-5a.-androst-.1-ene-17(i-carboxylic acid (Rasmusson, G.H. et al., J. Med. Chem., 29, 2298 (1986)) (0.021. g, 0.063 mmol), dry methylene chloride (6 ml) and dry pyridine (8.1 mL, 0.1 mmol) at 0°C
is added thionyl chloride (6.8 mL, 0.095 mmol). ~ The ice bath is removed and the reaction mixture allowed to warm to room temperature. After 1 h, toluene . (1 mL) is added and the reaction mixture is concentrated in vacuo. The residue is dissolved in dry methylene -chloride (1.5 mL) and dry pyridine (8.5 mL, 0.11 mmol) and 2-f -butyl-5-trifluoromethylaniline (0.023 g, 0.126 mmol ) is added at room temperature. After 13 h, methylene chloride (20 mL) is added and the reaction mixture is washed with 1 M sulfuric acid, saturated sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated in vacuo.
The residue is chromatographed on 7 g of silica gel by eluting with a 2.5 to 5%
methanol-methylene chloride gradient to give 0.01 g of a white foam. This material is crystallized from ethyl acetate-hexanes to give 17p-N-(2-t-Butyl-5-trifluoromethyl)phenylcarbamoyl-4-aza-5a-androst-1-en-3-one as a white solid;
m.p. 263-264°C. Mass Spectrum (mlz) =517 MH+
Example 25 ~ , 17(i-N-l2-t Butyl-5-trifluoromethyl)phenylcarbamovl-4-aza-5a-androstan-3-one ~Com~ound 25) Compound 25 is prepared as described for Example 1 using a corresponding amount of 2-t-butyl-5-trifluoromethylaniline in place of 2,5-bis(trifluoromethyl) aniline.
Melting Point: 256-259°C
Anal. Calcd. for C3pH4~ F3N2O2: C, 69.47; H, 7.97; N, 5.40.
Found: C, 69.49; H, 8_00; N, 5.41.
~ Example 26 17Q-N-(2-t Butyl-5-trifluoromethyl)phen~rlcarbamoyl-4-rnethyl-4-aza-5a-androstan-3-one (Compound 26) Compound 26 is prepared by a method analogous to that of Example 3.
Melting Point:- 229-232°C
Anal. Calcd. for C3~ H43F3N2O2: C, 69.90; H; 8.14; N, 5.26.
Found: C, 69.79; H, 8.07; N, 5.19.
Example 27 '17~-N-l2 5-Di t-butyl)nhenylcarbamoyl-4-aza-5a.-androst-1-en-3-one Compound 27) Compound 27 is prepared by a method analogous to that of Example 3.
Melting Point: 165-171 °C (dec.) Anai. Calcd. for C33H48N202~2/3H2O: C, 76.70; H, 9.62; N, 5.42.
Found: C, 76.76; H, 9.51; N, 5.43.
Example 28 17a-N-(2 5-Di-t-buty~ahenylcarbamoyl-4-aza-5a-androstan-3-one (Compound Compound 28 is prepared as described for Example 1 using a corresponding amount of 2,5-di-t butylaniline in place of 1-amino-1-(4 chlorophenyl)cyclopentane.
Melting Point: 162-164°C
Anal. Calcd. for C33H50N2~2'1~4H20: C, 77.52; H, 9.96; N, 5.48.
Found: C, 77.58; H, 9.97; N, 5.48.
Example 29 17J3-N-(2 5-Di-t-butyl)phenvlcarbamovl-4-methyl-.4-aza-5a-androstan-3-one ~Com~ound 29) _36_ Compound 29 is prepared by a method analogous to that of Example 2.
Melting Point: 150-152°C
Anal. Calcd. for C~H52N202: ~ C, 78.41; H, 10.06; N, 5.38.
Found: ~ C, 78.17; H, 10.01; N, 5.33.
_ Example 30 17t3-N-~2.5-bis(Trifluorometh~rl)phenylcarbamyl-4-aza-(7Q-methyl)-5a-androst-1-en-3-one (Compound 30) A. 3(i-Triisopropylsilyloxyetienic acid methyl ester A suspension of 3[3-hydroxyetienic acid methyl ester (J. Med. Chem. 27, 1690) (5168, 1.55 mol) in DMF (800 mL) is heated to 55°C, imidazole (264g, 3.88 mol) added with vigorous mechanical stirring, followed by dropwise addition of triisopropylsilylchloride (360g, ~ 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 acetatelhexanes) 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.
B. 3(i Triisopropylsilyloxy-7-oxo-etienic acid methyl ester .
To a suspension of chromic acid (50.7 g, 507 mmol) in . dichloromethane (175 ml) at Oo C is added 3,5-dimethyl pyrazole (48.7 g, 507 mmol) and the reaction mixture is stirred 30 min. Next 3-~ triisopropylsilyloxyetienic acid methyl ester, as prepared in Part A, (31 g, 63.4 mmol) in dichloromethane (120 ml) is added and the reaction allowed to stir at ambient temperature for 21 h. An aqueous solution of NaOH (2N, 100 ml) is then added followed by celite (ca. 200 cc), the reaction is filtered through glass wool, the solvent removed in vacuo and the resulting residue partitioned between ethyl aoetate:water. The organics are washed with 2N NaOH , water, saturated aqueous NaCI, and dried over MgS04 and the solvent is removed by rotary evaporation. The residue is flash chromatographed on silica gel (5-156 ethyl aoetatelhexane) to give 3(3-triisopropylsilyloxy-7-oxo-etienic acid methyl ester as a white solid; yield:
13.8 g, (43°~); Anal. Calcd. for C3pH5p04Si: C, 71.66; H, 10.02. Found: C, 71.43; H, 10.10.

61074 ~ 02171329 1995-03-23 v C. 3~-Triisopropylsilyloxy-7~-methyl etienic acid methyl ester To a slurryc of methyl triphenylphosphonium iodide (14 g, 34.6 mmol) in tetrahydrofuran (THF 60 ml) at Oo C is added n-butyl lithium (21.7 ml, 1.6M in hexane, 34.7 mmol). After stirring 20 min a solution of 3~-triisopropylsilyloxy-7-oxo-etienic acid methyl ester (8.72 g, 17.3 mmol) in 25 ml THF is added and after 10 min water (120 ml) is added followed by saturated aqueous NaHS04 solution (15 ml). The product is then extracted with ethyl acetate (200 ml), dried over MgS04, concentrated to ca. 50 ml, treated with tris(triphenylphosphine)rhodium chloride (460 mg, 0.51 mmol) and stirred under a hydrogen atmosphere overnight. The catalyst is filtered through a plug of silica gel and the filtrate is condensed and flash chromatographed on silica gel (35%
ethyl acetatelhexane) to give 3(i-triisopropylsilyloxy-7[i-methyl etienic acid methyl ester as a white foam; yield: 4.29 g of a 3:1 mixture of 7~:7a epimers (86%); Anal. Calcd. for C31 H~03Si: C, 74.04; H, 10.82. Found: C, 74.15; H, 10.88. , D. 3~-Hydroxy-7[3-methyl etienic acid methyl ester To a solution of 3~-triisopropylsifyloxy-7[i-methyl etienic acid methyl ester (4.25 g, 8.45 mmol) in 25 m) THF is added tetrabutylammonium fluoride (17 ml, 1 M in THF , 17 mmol) followed by stirring 6 h at room temperature. Water (100 ml) and ethyl acetate (150 ml) are added and the organic phase is washed with water, saturated aqueous -NaCt, dried over MgS04, and concentrated. The resulting concentrate is flash chromatographed on silica gel (25-40% ethyl acetatelhexane) to give 3~-hydroxy-7~-methyl etienic acid methyl ester, yield:
2.65 g, (90%); Anal. Calcd. for C22H34O3~ 114 H20: C, 75.28; H, 9.91. Found:
C, 75.67; H, 9.98.
E. 17(3-Carbomethoxy-7[3-methyl-androst-4-en-3-one To a solution of 3[i-hydroxy-7~-methyl etienic acid methyl ester (6.6 g, 19 mmol) in 220 ml acetone is added 7.5 ml Jones' reagent (3.1 M, 23.3 mmol) the reaction stirred 1 h and concentrated to ca. 40 ml. The resulting residue is taken up in ethyl acetate, washed with 2N NaOH, water, saturated aqueous NaCI, dried over MgS04, concentrated, and flash chromatographed on silica gel (35%
ethyl acetatelhexane) to give 17ji-carbomethoxy-7(i-methyl-androst-4-en-3-one as a yellow oil; yield: 2.73 g, (42°r6); high resolution mass spectra Calcd. for [MHfJ C~H33O3: 345.2430, Found:
F. 17(i-Carbomethoxy-7(3-methyl-5-oxo-A-nor-3,5-secoandrostan-3-oic acid .-1;1074 To a solution of 17~-carbomethoxy-7[i-methyl-androst-4-en-3-one (2.9 g, 8.4 mmol) in 60 ml tert-butanol is added sodium carbonate (1.04 g, 8.4 mmol) in 6 ml water, a slung of sodium periodate (9 g, 42 mmol) and potassium permanganate (134 mg , 850 mmol) in ca. 35 ml water and the reaction heated at reflux for 48 h. After cooling to room temperature the solids are removed by filtration, washed with water and concentrated to leave an aqueous residue which is acidified with saturated aqueous NaHS04, extracted with ethyl acetate, washed with water, saturated aqueous NaCI, dried over MgS04, concentrated, and flash chromatographed on silica gel (5-10% methanolldichloromethane) to give 17[i-carbomethoxy-7(3-methyl-5-oxo-A-nor-3,5-secoandrostan-3-oic acid;
yield: 1.2 g, (39°~); high resolution mass spectra Calcd. for [MH+j C21 H3305:
365.2328, Found: 365.2328 .
G. 17~-Carbomethoxy-7~-methyl-4-aza-androst-5-en-3-one To a suspension of 17[i-carboEnethoxy-7(3-methyl-5-oxo; A=nor-3,5-secoandrost-.
an-3-oic acid. (1.2 g, 3.29 mmol) in .8 ml anhydrous ethylene glycol is added ammonia (ca. 15 ml, 4:2 mmol) at = 40o C, the mixture stirred 30 min and then heated to 170o C for 45 min. The reaction mixture is then cooled to room temperature and water is added. The resulting slurry is extracted with ethyl acetate, the extracts washed with saturated aqueous NaCt, dried over MgS04, and concentrated. The resulting concentrate is flash chromatographed on silica gel (3-5% methanoUdichloromethane) to give 17a-carbomethoxy-7~-methyl-4-aza-androst-5-en-3-one; yield: 590 mgr (52%); Anal. Calcd. for Cz,Hs,N03: C, 73.01; H, 9.04; N, 4.05; Found: C, 72.97; H, 8.98; N, 4.04.
H. 17~i-Carbomethoxy-7[i-methyl-4-aza-5a-androstan-3-one To a solution of 17[i-carbomethoxy-7p-methyl-4-aza-androst-5-en-3-one (590 mg, 1.71 mmol) in 20 mi acetic acid is added platinum oxide (60 mg, 0.26 mmol).
The resulting mixture is charged to 40 psi with hydrogen , shaken 16 h , and purged with nitrogen. The catalyst is filtered, and the filtrate condensed.
The resulting oil is flash chromatographed on silica gel (3-5%
methanolldichloromethane) to give 17~-carbomethoxy-7~-methyl-4-aza-5-a.-androstan-3-one; yield: 465 mg, (78°~); high resolution mass spectra Calcd. for [MH+j C21 H34N03: 348.2539, Found: 348.2537 .
I. 17~i-Carbomethoxy-7[i-methyl-4-aza-5a-androst-1-en-3-one To a solution of 17[i-carbomethoxy-7(i-methyl-4-aza-5a-androstan-3-one (182 mg, 0.52 rnmol) in 4 ml dioxane is added 2,3-dichloro-5,6-dicyano-26169-62(S) benzoquinone (120 mg, 0.52 mmol), bis(trimethylsilyl)trifluoroacetamide (O.Sfi ml, 2.1 mmol) and .the mixture stirred at room temperature overnight. The reaction is condensed and the resulting oii taken up in dichloromethane (75 ml) and washed with 2N NaOH, water, saturated aqueous NaCI, dried over MgS04, and concentrated. The resulting concentrate is flash chromatographed on silica gel (50°~ ethyl acetatelhexane) to give 17[i-carbomethoxy-7[i-methyl-.4-aza-5-a.-androst-1-en-3-one as a tan foam; yield: 150 mg, (83°r6); high resolution mass spectra Calcd. for [MH'] C21 H32N03: 346.2382, Found: 346_2382.
J. 3-Oxo-4-aza 7[3-methyl-5a-androst-1-en-17[i-carboxylic acid To a suspension of 17[i-carbomethoxy-7~-methyl-4-aza-5a-androst-1-en-3-one (180 mg, 0.52 mmol) in 5 ml dioxane at 55o C is added lithium hydroxide (43 mg, 1.02 mmol) in water-(2ml) and the reaction stir-ed 24 overnight. Water is added (25 ml) followed by saturated aqueous NaHS04; extraction with ethyl acetate, subsequent washing with saturated aqueous NaCI, drying over-MgS04, and concentration to a residue which is flash chromatographed on silica gel (50% ethyl acetatelhexane) to give a white solid; yield: 94 mg, (55%); high resolution mass spectra Calcd. for [MH~j C2pH30N03: 332.2226, Found:
332.2225 .
K 17(3-N-{2,5-bis(Trifluoromethyl))phenylcarbamoyl-4-aza-7[i-methyl-5a-androst-1-en-3-one T o a suspensic~:~-of 3-Oxo~-aza=7~-methyl_5~.-andro~t-'!-en-17~-carboxylic acid (50 mg, 0.15 mmol) in 1.5 ml 0.03°~ DMF in toluene at Oo C is added pyridine (0.030 ml, 0.37 mmol) and thionyl chloride (0.013 ml, 0.18 mmol). After 15 min , the reaction mixture is warmed to room temperature for 1.5 h, excess reagents are removed via azeotrope and the resulting solids slurried in 1.5 ml toluene.
The reaction mixture is treated with 4-(N,N-dimethylamino)pyridine (1 mg, cat.), heated to 100o C and 2,5-bis(trifluoromethyl)aniline {0.035 ml, 0.22 mmol) is added. After 3.5 h the reaction is condensed, partitioned with ethyl acetate/saturated aqueous NaHS04, and the organic phase is washed with 2N
NaOH, saturated aqueous NaCt, dried over MgS04, and condensed. The concentrate is purified via flash chromatography (10% ethyl TM
acetate/dichloromethane) followed by HPLC (BDS Hypersil C8 column, 40 70%CH3CNIwater), and lyophilization to give a white solid; yield: 12 mg, (15%);
high resolution mass spectra Calcd. for [MH'J C28H33F6N202: 543.2456, Found: 543.2446.

' ~~ 61074 _40_ Example 31 78-N-(2-t Buhrl-5~rifluoromethyllphenYlcarbamoyl-4-aza-7Q-methyl-5a-androst-1-en-3-one (Comt~ound 31) To a suspension of 3-axo-4-aza-7~-methyl-5a.-androst-1-en-17~-carboxylic acid, as prepared in Part J of Example 31, (38 mg, 0.12 mmol) in i.5,ml 0.03% DMF
in toluene at Oo C is added pyridine (0.023 ml, 0.29 mmol) and thionyl chloride (0.010 ml, 0.14 mmol)_ After 15 min , the reaction mixture is warmed to room temperature for 1.5 h, excess reagents are removed via azeotrope and the resulting solids dissolved in dichloromethane (1 ml), treated with pyridine (0.025 ml, 0.30 mmol), and 2-t-butyl-5-trifluoromethyfaniline (50 mg, 0.23 mmol).
After 24 h the reaction mixture is diluted with dichloromethane. (20 ml), washed with saturated aqueous NaHS04, .2N NaOH, saturated aqueous NaCi, dried over MgS04, condensed, and purified via flash chromatography on silica gel (40°~
ethyl acetatelhexane); yield: 15 mg, (25°~b); high resolution mass spectra Catcd.
for [MH~JC31H42F3N242: 531.3198, Found: 531.3206 .-~~~ ----- -- Example 32 17~i-N-1a(4-Chlorophenyl) clopentvlcarbamovl-4-aza-7Q-methyl-5a-androst-1-en-3-one f Compound 32 i This compound is prepared by the procedure of Example ~3 except a corresponding amount of 3-oxo-4-aza-7[i-methyl-5-a=androst-1-en-17J3-carboxylic acid, as prepared in Part J of Example 31, is used in place of 3-oxo-4-aza-5a-androst=1-ene-17~-carboxylic acid.
Example 33 17S-N-9-(4-t-Butvlphenvl)bicyclo[3.3.1 ~nonvlcarbamovl-4-aza-5oc-androst-1-en~
3-one.
Compound 33 is prepared by a method analogous to that of Example 3, using 9-amino-bicyclo [3.3.1] nonane in place of 1-amino-1-(4~hlorophenyl)-cyclopentane.
Melting point 277-280°C.
Examples 34-57 These compounds may be prepared as outlined in Example 3. Amines which were not commercially available were prepared as described in W094114833.

34. 17~-N-(5-Chloro-2-t butyl)phenylcarbamoyl-4-aza-Sac-androst-1-en-3-one . .

35. 17 j3-N-(4-Bromo-2-t-butyl)phenylcarbamoyl-4-aza-5a-androst-1-en-3-one 36. 17~-N-(2-t-Butyl-5-phenyl)phenylcarbamoyl-4-aza-5a-androst-1-en-3-one 37. 17/i-N-(4-f-Butyl-2 trifluoromethyl)phenylcarbamoyl-4-aza-5a-androst-1-en-3-one 38.11~-N-(2-Phenyl-5-trifluoromethyl)phenylcarbamoyl~-aza-5a-androst-1-en-3-one 39. 17~-N-(2-t Butyl-5-(4-chlorophenyl))phenylcarbamoyl-4-aza-5a-androst-1-en-3-one 40. 17(i-N-(2-(4-t-Butyl)phenyl-5-trifluoromethyl)phenylcarbamoyl-4-aza-5a-androst-1-en-3-one 41. 173-N-(2-f Butyl-5-(4-t butyl)phenyl)phenylcarbamoyl-4-aza-5a-androst-1-en-3-one 42. 17~-N-(4-Chloro-2,5-bis(triftuoromethyl))phenylcarbamoyl-4-aza-5a-androst-1-en-3-one 43.17~i-N-(2-(2,4-Dichlorophenyl)-5-trifluoromethyl)pheny(carbamoyl-4-aza-5a-androst-1-en-3-one 44. 17(i-N-(4-Bromo-2-trifluoromethyl)phenylcarbamoyl-~-aza-5oc-androst-1-en-3-one 45. 17~-N-(5-Bromo-2 trifluoromethyl)phenylcarbamoyl-4-aza-5a.-androst-1-en-3-one 46. 17~-N-(4,5-Dibromo-2-trifluoromethyl)phenylcarbamoyl-4-aza-5oc-androst-1-en-3-one 47. 17(i-N-(5-t Butyl-4-chloro-2-trifluoromethyl)phenylcarbamoyl-4-aza-5oc-androst-1-en-3-one 48.17(i-N-(5-t-Butyl-6-chloro-2-trifiuoromethyl)phenylcarbamoyl~l-aza-5a-androst-1-en-3-one ' 49. 17(3-N-(2,4-Bis(trifluoromethyl))phenylcarbamoyl-4-aza-5oc-androst-1-en-3-one 50. 17~-N-(2-t-Butyl-4-trifluoromethyl)phenylcarbamoyl-4-aza-5a-androst-1-en-3-one 51. 17(i-N-1-(4-t-Butyl-2-trifluoromethylphenyl)cyclopentylcarbamoyl-4-aza-5a-androst-1-en-3-one 52. 17(i-N-1-(4-Cyanophenyl)cyclohexylcarbamoyl-4-aza-5a-androst-1-en-3-one 53. 17~-N-1-(3-(3-Fluorophenyl)phenyl)cyclopentylcarbamoyl-4-aza-5a-androst 1-en-3-one 54. 17~-N-1-(5-indanyl)cyclohexylcarbamoyl-4-aza-5a-androst-1-en-3-one 55. 17(i-N-1-(5-Chloro-2,4-dimethylphenyl)cyciopentylcarbamoyl-4-aza-5oc-androst-1-en-3-one '~ 61074 56. 17~-N-2-(4-trifluoromethylphenyl)bicyclo[3.2.1 ]octanylcarbamoyi-4-aza-5a-androst-1-en-3-one.

57. 17[i-N-(5-Bromo-2-t-butyl)phenylcarbamoyl-4-aza-5a-androst-1-en-3-one.
_ Example 58 Pharmaceutical formulations (A) Transdermal System - For 1000 Patches In4redients Amount Active compound 40 g Silicone fluid 450 g Colloidal silicon dicxide - 25 g The silicone fluid and active compound are mixed together and the colloidal silicone .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,-poiyvinyl 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 Inctredients Amount Active compound 20 '9 Starch 20 9 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 In4redients Amount Active compound 25 g ' ~ ~ G1074 . . , ' -43-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 In4redients 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 50oC. The water for injection is then added with stirring and the resulting solution is filtered, filled into ampules, sealed and sterilized by autoclaving.
(E) Capsule - For 1000 Capsules lnctredients 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 packed into gelatin capsules.

Claims (22)

CLAIMS:

1. A compound of formula (I) wherein carbons 1 and 2 are joined by either a single or a double bond;
R1 is hydrogen or methyl;
R2 is hydrogen or methyl;
R3 is wherein R6 is trifluoromethyl, phenyl optionally substituted with one or more halogens or branched (C4-7) alkyl groups, or branched (C4-7) alkyl; either of R7 or R8 is trifluoromethyl, halogen, phenyl optionally substituted with one or more halogens or branched (C4-7) alkyl groups, or branched (C4-7) alkyl, while the other is hydrogen or halogen; and X is hydrogen or halogen, or a pharmaceutically acceptable solvate thereof.

2. A compound as claimed in claim 1 wherein X is hydrogen.

3. A compound as claimed in claim 1 or claim 2 wherein R2 is hydrogen.

4. A compound as claimed in any one of claims 1 to 3 wherein R6 is trifluoromethyl, phenyl optionally substituted with one or more halogens, or branched (C4-7) alkyl; and either of R7 or R8 is trifluoromethyl, halogen, phenyl optionally substituted with one or more halogens, or branched (C4-7) alkyl, while the other is hydrogen or halogen.

5. A compound as claimed in any one of claims 1 to 4 wherein carbons 1 and 2 are joined by a double bond.

6. A compound as claimed in claim 1 of formula (IB);

wherein carbons 1 and 2 are joined by either a single or a double bond;
R1 is hydrogen or methyl;
R6 is trifluoromethyl, phenyl optionally substituted with one or more halogens, or branched (C4-7) alkyl;
either of R7 or R8 is trifluoromethyl, halogen, phenyl optionally substituted with one or more halogens, or branched (C4-7) alkyl, while the other is hydrogen or halogen; and X is hydrogen or halogen.

7. A compound as claimed in claim 6 wherein when R7 or R8 is branched (C4-7) alkyl and X is hydrogen, R6 is trifluoromethyl or phenyl optionally substituted with one or more halogens.

8. A compound as claimed in claim 6 wherein R6 is trifluoromethyl or branched (C4-7) alkyl; and either of R7 or R8 is trifluoromethyl, halogen, or phenyl substituted with one or more halogens, while the other is hydrogen or halogen.

9. A compound as claimed in claim 8 wherein R6 is trifluoromethyl or branched (C4-7) alkyl; either of R7 or R8 is trifluoromethyl while the other is hydrogen; and X is hydrogen.

10. A compound as claimed in claim 6 wherein R6 and R8 are independently trifluoromethyl or t-butyl, while R7 and X
are hydrogen.

11. A pharmaceutical formulation comprising a compound as claimed in any one of claims 1 to 10 or a pharmaceutically acceptable solvate thereof and a pharmaceutically acceptable carrier thereof.

12. Use of a compound as claimed in any one of claims 1 to 10 or a pharmaceutically acceptable solvate thereof, or a formulation as claimed in claim 11 in the manufacture of a medicament for the treatment or prevention of an androgen responsive or mediated disease.

13. Use according to claim 12 wherein the androgen responsive or mediated disease is benign prostatic hyperplasia, prostate cancer, acne, male pattern baldness, polycystic ovary disease and hirsutism.

14. A process for preparing a compound as claimed in any one of claims 1 to 10 which comprises:
(A) for compounds of formula (I) wherein carbons 1 and 2 are joined by a single bond, hydrogenating a compound of formula (IVa) (B) for compounds of formula (I) wherein carbons 1 and 2 are joined by a double bond, reacting a compound of formula (V) with a compound of formula (IIa) H2NR3 (IIa) and if necessary and/or desired, subjecting the compound thus obtained to one or more further reactions comprising:
(i) interconversion to another compound of formula (I);
(ii) removing any protecting group or groups; and/or (iii) converting the compound of formula (I) into a pharmaceutically acceptable solvate thereof.

15. A process as claimed in claim 14 wherein in process (B) the compound of formula (V) is treated with a halogenating agent in the presence of a base prior to reaction with a compound of formula (IIa).

16. A process as claimed in claim 14 or claim 15 wherein in step (i) a compound of formula (I) wherein there is a double bond between carbons 1 and 2 and wherein R1 is hydrogen is prepared by dehydrogenating a compound of formula (Ia)

17. An in vitro method of inhibiting 5a-testosterone reductase enzyme comprising contacting said enzyme with an effective 5.alpha.-testosterone inhibitory amount of a compound as claimed in any one of claims 1 to 10.

18. A compound of formula (IVa) wherein R1 and R2 are independently hydrogen or methyl and R3 is as defined in claim 1, or a solvate thereof.

19. Use of a compound as claimed in any one of claims 1 to 10 or a pharmaceutically acceptable solvate thereof, or a formulation as claimed in claim 11 for the treatment or prevention of an androgen responsive or mediated disease.

20. Use according to claim 19 wherein the androgen responsive or mediated disease is benign prostatic hyperplasia, prostate cancer, acne, male pattern baldness, polycystic ovary disease and hirsutism.

21. A commercial package comprising a compound as claimed in any one of claims 1 to 10 or a pharmaceutically acceptable solvate thereof, or a formulation as claimed in claim 11, and associated therewith instructions for use thereof for the treatment or prevention of an androgen responsive or mediated disease.

22. A commercial package according to claim 21, wherein the androgen responsive or mediated disease is benign prostatic hyperplasia, prostate cancer, acne, male pattern baldness, polycystic ovary disease and hirsutism.