DERIVATIVES

The present invention relates to fluorinated 17/3- substituted 4-aza-5α-androstan-3-one derivatives, to a process for their preparation, and to pharmaceutical compositions containing them. These compounds act as inhibitors of androgen action, by means of testosterone 5α reductase inhibition. In certain androgen responsive tissues the action of testosterone is mediated primarily through its 5α- reduced metabolite, dihydrotestosterone (DHT) (Bruchowsky N., Wilson J.D.; J. Biol. Chem. 243, 5953, 1968). The conversion of testosterone to dihydrotestosterone is catalyzed by the enzyme 5α-reductase and if 5α-reductaεe i inhibited, the formation of dihydroteεtosterone is reduced and its specific androgenic effect is attenuated or prevented.

The 5α-reductase inhibitors may find medical application for the treatment of hyperandrogenic conditions, e.g. certain prostatic diseases, such as benig prostatic hyperplasia and prostatic cancer, and certain skin-hair conditions, such as acne, seborrhoea, female hirsutism and male pattern baldness (Siiteri P.K., Wilson J.D., J. Clin. Invest. 4_9, 1737, 1970; Price V.H. , Arch. Dermatol. III. 1496, 1975; Sandberg A.A. , Urology 12, 34, 1981) . Also breast cancer treatment can take advantage

from use of 5α-reductase inhibitors as the said tumour is known to be aggravated by presence of androgens. Androst- 4-en-3-one-17/3-carboxylic acid and its methyl ester (Voigt and Hsia, Endocrinology, J2, 1216 (1973); Canadian Patent No. 970,692) are among the first εteroidic compounds described as 5α-reductase inhibitors.

Two 5,10-εecosteroids having a 3-keto-4,5-diene system in the expanded ring have been found to be selective inhibitors of rat epididy al 5α-reductase (Robaire et al., J. Steroid Biochem. 8 _. , 307-310 (1977)).

The (20R)-4-diazo-21-hydroxy-20-methyl-5α-pregnan- 3-one and its analogues are reported to be enzyme activated inhibitors of testosterone 5α-reductase (Blohm et al., Biochem. Biophyε. Res. Comm. 9_5, 273-80 (1980) ; United States Patent 4,317,817).

Another series of enzyme-directed irreversible inhibitors of Sα-reductase have been prepared by introducing a 6-methylene moiety into substrateε type 3- keto-Δ ⁴ -progestins and androgens (Petrow et a_l. , Steroids 38. _/ 352-53 (1981); United States Patent 4,396,615).

More recently unsaturated derivatives of 3-carboxy steroids have been reported as uncompetitive Sα-reductaεe inhibitors versus testosterone (Biorg. Chem. 12 372-376 (1989); Eur. Pat. Appln. No. 0289327). 4-Aza steroids are by far the most studied steroid

5c--reductase inhibitors. The compounds known in the art are reported in a very large number of publications and

patents. In particular the 17/3-acylamides and their metabolites are described in: J. Med. Chem. 2 _/ 1690-1701

(1984) , J. Med. Chem. H, 2298-2315 (1986) , European Patent

Application No. 0,004,949; US Patent 4,377,584; European

Patent Application No. 0,155,096; US Patent 4,845,104;

European Patent Application No. 0,462,662; European Patent

Application No. 0,484,094 A2 ; U.S. Patent 4,859,681; WO

91/12261.

The invention provides compounds of the following formula (I)

wherein: the symbols .... independently represent a single or a double bond;

B is a bond or a straight or branched Cj-C ₆ alkylene chain; R is a hydrogen atom or a C _! -C ₄ alkyl group unsubstituted or substituted by one or more fluorine atoms; R _t is a hydrogen atom, a C,-C ₆ alkyl group unsubstituted or substituted by one or more fluorine atoms, or a benzyl group; R ₂ is a) a hydrogen atom, a fluorine atom, a C _J -C _J alkyl

group unsubεtituted or substituted by one or more fluorine atoms, a C ₅ -C ₇ cycloalkyi group or a C ₆ -C ₉ cycloalkylalkyl group; or b) an aryl or C ₇ -C ₁₀ arylalkyl group, either unsubεtituted or ring substituted by one or more substituents chosen from halogen, Cι~C ₄ alkyl, C^C, alkoxy, hydroxy and trifluoromethyl; R ₃ is a) a hydrogen atom, a fluorine atom or a C,-C ₄ alkyl group unsubεtituted or εubstituted by one or more fluorine atoms; or b) an aryl or C ₇ -C _ι0 arylalkyl group, either unsubstituted or ring substituted by one or more substituents chosen from halogen, C,-C ₄ alkyl, C _! -C ₄ alkoxy, hydroxy and trifluoromethyl; R ₄ is a hydrogen atom or a fluorine atom, or is absent when Y is a double bond;

Rj is a hydrogen atom, a fluorine atom or a C,-C ₆ alkyl group unεubstituted or εubstituted by one or more fluorine atoms; and when Y is a single bond, A is hydrogen, fluorine or a

-C I ⁴ -R ₇ group wherein each of R^, R ₇ and R _g independently is

Rs hydrogen, fluorine or a C,-C ₆ alkyl group unsubεtituted or εubεtituted by one or more fluorine atoms; or

/ when Y is a double bond, A iε a =C group wherein

\ ₇ each of R^ and R ₇ iε independently hydrogen, fluorine or a

C _! -C ₆ alkyl group unsubstituted or substituted by one or more fluorine atoms; with the proviso that at least one of the groups R, R _j , R ₂ ,

R ₃ , R ₄ , R ₅ and A contains at leaεt one fluorine atom.

In the formulae of this specification the dotted line ( ^« ""'") indicates a subεtituent in the α-configuration, i,e. below the plane of the ring, and the wedged line (^^^0) indicates a subεtituent in the β-configuration, i.e. above the plane of the ring. The configuration of the chiral centreε in the side chain iε unεpecified; the invention includes both the single "R" or "S" epi ers and their "RS" mixtures. The metabolites and the metabolic precursors of the compounds of formula (I) are within the scope of the present invention.

In this specification the alkyl groups and the aliphatic portions of the cycloalkylalkyl groups may be a straight or branched chain.

A C,-C ₄ alkyl group may be, for example, methyl, ethyl, isopropyl, n-butyl or tert-butyl. The C,-C ₄ alkyl group may be unsubstituted or substituted by one or more, preferably one, two or three, fluorine atoms and may be, for example, trifluoromethyl, 2,2,2-trifluoroethyl,

fluoromethyl or difluoromethyl.

A Cj-C ₆ alkyl group may be, for example, methyl, ethyl, n-propyl, iεopropyl, n-butyl, iεo-butyl, sec-butyl, tert-butyl, n-pentyl, iεo-pentyl, neo-pentyl, n-hexyl or iso-hexyl. The Cj-Cβ alkyl group may be unsubεtituted or substituted by one or more, preferably, one to six or one, two or three, fluorine atoms and may be, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2- trifluoroethyl, 3,3,3-trifluoroprop-1-yl or 4,4,4- trifluorobut-1-yl, 1-trifluoromethyleth-1-yl, 2-trifluoro- methylprop-1-yl, 1,1,1,3,3,3-hexafluoroprop-2-yl, 4,4,5,5,5-pentafluoropentyl or 3,3,3,2,2-pentafluoroprop-1- yi.

A C ₅ -C ₇ cycloalkyi group may be, for example, cyclopentyl, cyclohexyl or cycloheptyl, preferably cyclohexyl.

A C ₆ -C ₉ cycloalkylalkyl group may be, for example, (C ₅ -C ₇ cycloalkyi) alkyl, preferably (C ₅ -C ₇ cycloalkyi) methyl or (C ₅ -C ₇ cycloalkyi) ethyl, in particular, cyclohexylmethyl, cyclohexylethyl or cycloheptylmethyl, preferably cyclohexylmethyl.

An aryl group may be, for example, phenyl unsubstituted or substituted by one or more, preferably one, chloro, bromo, fluoro, Cj-C ₄ alkyl, preferably methyl, C,-C ₄ alkoxy, preferably methoxy, hydroxy or trifluoromethyl groups, in particular, 4-methylphenyl, 4-hydroxyphenyl, 4- methoxyphenyl, 4-trifluoromethylphenyl or

4-fluorophenyl.

A C ₇ -C, ₀ arylalkyl group may be, for example, phenyl(C _! -C ₄ alkyl), preferably benzyl, unsubstituted or ring substituted by one or more, preferably one or two, chloro, bromo, fluoro, C,-C ₄ alkoxy preferably methoxy, hydroxy or trifluoromethyl groups, in particular 4- hydroxybenzyl, 4-methoxybenzyl, 4-hydroxy-3-methoxybenzyl, 3,4-dimethqxybenzyl, 4-trifluoromethylbenzyl, 2- fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl or 3-fluoro-4- hydroxybenzyl.

A C _! -C ₆ straight or branched alkylene chain may be, for example, a straight or branched Cj-C ₄ alkylene chain, in particular, e.g.,

CH ₃ CH ₃

I I

-CH-, -CH-CH ₂ CH ₂ -, -CH ₂ - or -CH ₂ -CH ₂ -.

When R is a Ci-C ₄ alkyl group unsubtituted or substituted by one or more fluorine atoms, it is preferably methyl or 2,2,2-trifluoroethyl; when R _j iε a C,-C ₆ alkyl group unsubstituted or substituted by one or more fluorine atoms, it is preferably methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, 2,2,2- trifluoroeth-1-yl, 1-trifluoromethyleth-l-yl, 1,1,1,3,3,3- hexafluoroprop-2-yl, 2-trifluoromethylprop-l-yl or 2,2,3,3,3-pentafluoroprop-1-yl; when R ₂ is a C,-C ₆ alkyl group unsubstituted or

εubstituted by one or more fluorine atomε, it is preferably methyl, isopropyl, isobutyl, sec-butyl, tert-butyl, fluoromethyl, trifluoromethyl, 2,2,2-trifluoroeth-l-yl, 1- trifluoromethyleth-l-yl, 3,3,3-trifluoropropyl, 1,1,1,3,3,3-hexafluoroprop-2-yl, 2-trifluoromethylprop-1-yl or 4,4,4-trifluorobutyl; when R ₂ is a C ₅ -C ₇ cycloalkyi group it is preferably cyclohexyl; when R ₂ iε a C ₆ -C ₉ cycloalkylalkyl group, it iε preferably cyclohexylmethyl; when R ₂ iε an aryl group, it is preferably phenyl; when R ₂ is an unsubstituted C ₇ -C ₁₀ arylalkyl group, it is preferably benzyl; when R ₂ is a εubstituted C ₇ -Cι ₀ arylalkyl group, it is preferably p-trifluoromethylbenzyl; when R _? iε a Cj-C ₄ alkyl group unεubεtituted or substituted by one or more fluorine atoms, it is preferably methyl, fluoromethyl or trifluoromethyl; when R ₃ iε an aryl group, it is preferably phenyl; when R ₃ is an unsubstituted C ₇ -Cj ₀ arylalkyl group it is preferably benzyl; when R ₃ is a substituted C ₇ -C ₁₀ arylalkyl group, it is preferably p-trifluoromethylbenzyl; when Rj is a C,-C ₆ alkyl group unsubstituted or substituted by one or more fluorine atoms, it is preferably methyl, n-butyl, trifluoromethyl or pentafluoroethyl;

? ^β when A is a -C-R ₇ group, it is preferably methyl,

R ₈ fluoromethyl, difluoromethyl, trifluoromethyl, ethyl or n-propyl; * H

/ / when A is a =C group it is preferably =C ,

\ \

H

H H

=C =C =C or =C

\

H CH, CH ₂ CH ₃

Preferred compounds of formula (I) are those wherein:

1) the symbol .... representε a single or a double bond; B is a bond;

R is hydrogen, methyl or 2,2,2-trifluoroethyl; i is hydrogen;

R ₂ is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 2-trifluoromethylprop-l-yl,

1-trifluoromethyleth-l-yl, fluoromethyl, benzyl or phenyl;

R ₃ is hydrogen or methyl; R ₄ is hydrogen; R is methyl, trifluoromethyl or n-butyl;

Y iε a single bond; and

A is a group - tC-R ₇ wherein R _< , is hydrogen or fluorine ₈ and R ₇ and R ₈ are both hydrogen or fluorine atoms; with the proviso that at least one of the groups R, R ₂ , R ₅ or A contains at least one fluorine atom;

2) the symbol .... represents a single or a double bond;

B is a bond;

R is hydrogen, methyl or 2,2,2-trifluoroethyl; R, is hydrogen;

R ₂ iε hydrogen, methyl, iεopropyl, iεobutyl, sec-butyl, tert-butyl, trifluoromethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 2-trifluoromethylprop-1-yl, l- trifluoromethyleth-l-yl, fluoromethyl, benzyl or phenyl;

R ₃ is hydrogen;

R ₄ is absent;

R ₅ is methyl, trifluoromethyl or n-butyl;

Y is a double bond; and

₇ / A is a group =C wherein R ₇ and R ₈ are both

\ R ₈ hydrogen atoms or fluorine atoms; with the proviso that at least one of the groups R, R ₂ , R _s or A contains at least one fluorine atom. 3) the symbol .... representε a εingle or a double bond; R iε hydrogen, methyl or 2,2,2-trifluoroethyl; R _j iε hydrogen, 2, 2,2-trifluoroethyl, 2,2,3,3,3- pentafluoroprop-1-yl, methyl, ethyl, isopropyl, isobutyl or tert-butyl; R ₂ iε hydrogen, methyl, isopropyl, fluoromethyl, trifluoromethyl, benzyl or phenyl; R ₃ is hydrogen, methyl, fluoromethyl, trifluoromethyl, benzyl or phenyl; R ₄ iε hydrogen or fluorine; R ₅ is hydrogen, fluorine or trifluoromethyl; B iε a bond; Y is a single bond; and A is hydrogen or fluorine; with the proviso that at least one of the groups R, R,, R ₂ , R ₃ , R ₄ , R ₅ or A contains at least one fluorine atom.

Examples of preferred compounds of the

invention are:

1) N-(4,4,4-trifluoro-3-methyl-but-2-yl) 4-methyl-3-oxo- 4-aza-5α-androstane-l7j3-carboxamide;

2) N-(l,l,l-trifluoro-3-methyl-but-2-yl) 4-methyl-3-oxo- 4-aza-5α-androεtane-17/3-carboxamide;

3) N-(4,4,4-trifluoro-3-methyl-but-2-yl) 3-oxo-4-aza-5α- androεtane-17S-carboxamide;

4) N-(l, 1,1-trifluoro-3-methyl-but-2-yl) 3-oxo-4-aza-5α- androεtane-17/3-carboxamide; 5) N- (5-methyl-2-difluoromethyl-hex-3-yl) 4-methyl-3-oxo- 4-aza-5α-androstane-l7/3-carboxamide;

6) N-(3-difluoromethyl-hept-2-yl) 4-methyl-3-oxo-4-aza- 5α-androεtane-17β-carboxamide;

7) N-(5-methyl-2-difluoromethyl-hex-3-yl) 3-oxo-4-aza-5α- androstane-17S-carboxamide;

8) N-(3-difluoromethyl-hept-2-yl) 3-oxo-4-aza-5α- androstane-173-carboxamide;

9) N-(4 ,4,4-trifluoro-3-methylene-but-2-yl) 4-methyl-3- oxo-4-aza-5α.-androεtane-17β-carboxamide; 10) N-(l, 1,1-trifluoro-3-methylene-but-2-yl) 4-methyl-3- oxo-4-aza-5α-androεtane-17jS-carboxamide;

11) N-(4,4 ,4-trifluoro-3-methylene-but-2-yl) 3-oxo-4-aza- 5α-androεtane-173-carboxamide;

12) N-(l, 1,1-trifluoro-3-methylene-but-2-yl) 3-oxo-4-aza- 5α-androstane-17/3-carboxamide;

13) N-(5-methyl-2-difluoromethylene-hex-3-yl) 4-methyl-3- oxo-4-aza-5α-androstane-173-carboxamide;

14) N-(3-difluoromethylene-hept-2-yl) 4-methyl-3-oxo-4- aza-5Q-androstane-17/3-carboxamide;

15) N-(5-methyl-2-difluoromethylene-hex-3-yl) 3-oxo-4-aza- 5α-androεtane-17/3-carboxamide; 16) N-(3-difluoromethylene-hept-2-yl) 3-oxo-4-aza-5α- androstane-173-carboxamide;

17) N-(2,2,2-trifluoroethyl) 3-oxo-4-aza-5α-androst-l-ene- 17/3-carboxamide;

18) N,N-di-(2,2,2-trifluoroethyl) 3-oxo-4-aza-5α-androεt- l-ene-17/3-carboxamide;

19) N-(l,1,1,3,3,3-hexafluoroprop-2-yl) 3-oxo-4-aza-5α- androεt-l-ene-17/3-carboxamide;

20) N,N-di-(l,l,l,3,3,3-hexafluoroprop-2-yl73-oxo-4-aza- 5α-androst-l-ene-17ιS-carboxamide; 21) N-methyl-N-(2,2,2-trifluoroethyl) 3-oxo-4-aza-5α- androεt-l-ene-17/3-carboxamide;

22) N-iεobutyl-N-(2,2,2-trifluoroethyl) 3-oxo-4-aza-5α- androεt-l-ene-17/S-carboxamide;

23) N-(l-fluoro-2-methyl-prop-2-yl) 3-oxo-4-aza-5α- androεt-l-ene-17/3-carboxamide;

24) N-(l,3-difluoro-2-methyl-prop-2-yl) 3-oxo-4-aza-5α- androst-l-ene-173-carboxamide;

25) N-(l,3-difluoro-2-fluoromethyl-prop-2-yl) 3-oxo-4-aza- 5α-androst-l-ene-173-carboxamide; 26) N-(5,5,5-trifluoro-2,4-dimethylpent-3-yl) 3-oxo-4-aza- 5α-androstane-17)3-carboxamide; 27) N-(4,4,4-trifluoro-2,3-dimethylbut-2-yl) 3-oxo-4-aza-

5α-androstane-17?-carboxamide;

28) N-(4,4,4-trifluoro-3-methylbut-2-yl) 3-oxo-4-aza-5α- androst-l-ene-179-carboxamide;

29) N-(5,5,5-trifluoro-2,4-dimethylpent-3-yl) 3-oxo-4-aza- 5Q-androst-l-ene-17^-carboxamide;

30) N-(4,4,4-trifluoro-2,3-dimethylbut-2-yl) 3-oxo-4-aza- 5α.-androst-l-ene-17β-carboxamide;

31) N-(4,4,4-trifluorobut-2-yl) 3-oxo-4-aza-5α-androεt-l- ene-173-carboxamide; 32) N-(5,5,5-trifluoro-2-methylpent-3-yl) 3-oxo-4-aza-5α- androst-l-ene-173-carboxamide;

33) N-(4,4,4-trifluoro-2-methylbut-2-yl) 3-oxo-4-aza-5α- androεt-l-ene-17/3-carboxamide;

34) N-( ,4,4-trifluoro-3-methyleήe-but-2-yl) 3-oxo-4-aza- 5α-androst-l-ene-173-carboxamide;

35) N-(5,5,5-trifluoro-4-methylene-2-methylpent-3-yl) 3- oxo-4-aza-5α-androεt-l-ene-173-carboxamide;

36) N-(4,4,4-trifluoro-3-methylene-2-methylbut-2-yl) 3- oxo-4-aza-5α-androst-l-ene-170-carboxamide; 37) N-(2,2,2-trifluoroethyl) 4-methyl-3-oxo-4-aza-5α- androεtane-173-carboxamide;

38) N-isopropyl-N-(2,2,2-trifluoroethyl) 3-oxo-4-aza-5α- androst-l-ene-179-carboxamide;

39) N-isopropyl-N-(2,2,3,3,3-pentafluoropropyl) 3-oxo-4- aza-5α-androst-l-ene-170-carboxamide;

40) N-(2,2,2-trifluorophenylethyl) 3-oxo-4-aza-5α-androst- l-ene-173-carboxamide;

41) N-(l,1,1-trifluoro-2-phenylprop-2-yl) 3-oxo-4-aza-5α- androst-l-ene-17/3-carboxamide;

42) N-(2,2,2-trifluoro-l,l-diphenylethyl) 3-oxo-4-aza-5α- androεt-l-ene-17/S-carboxamide; 43) N-(l,1,1-trifluoro-2-methylprop-2-yl) 3-oxo-4-aza-5α- androεt-l-ene-17/3-carboxamide; and 44) N-(l,1,1,3,3,3-hexafluoro-2-methylpropyl) 3-oxo-4-aza- 5α-androst-l-ene-17β-carboxamide.

The εtructural formulae of the above listed compounds, according to their numbers, are tabulated below with reference to the substituents as defined in formula (I) :

The compounds of formula (I) may be obtained by a process comprising: A) reacting a compound of formula (II)

wherein the symbol R and B are as defined above and Z iε an activating group of the carboxy function with a compound of formula (III) or a salt thereof

wherein the symbol ..... R,, R ₂ , R ₃ , R ₄ , R ₅ and A are as defined above, so obtaining a compound of .formula (I) wherein the symbol ..... R, R,, R ₂ , R ₃ , R ₄ , R ₅ , B and A are as defined above; or

B) reacting a compound of formula (IV)

wherein the symbol R, R,, R ₂ , R ₃ and B are as defined above and R ₅ is a C,-C ₆ alkyl group unsubstituted or substituted by one or more fluorine atoms with a compound of formula (V) or (VI)

W(-) (VI)

wherein R^ and R ₇ are as defined above, each R, is independently methoxy, ethoxy or phenyl, and W is a halogen atom, so obtaining a compound of formula (I) wherein the symbol R, R], R ₂ , R ₃ and B are as defined above, R ₅ is a C,-C ₆ alkyl group unsubstituted or substituted by one or more fluorine atoms, Y is a double bond, R^ iε * / absent and A is a =C group

\

R ₇ wherein _f , and R ₇ are as defined above; or

C) reducing a compound of formula (VII)

^(VI1)

wherein the εymbol R, R,, R ₂ , R ₃ , R ₅ and B are aε defined above and R,, iε hydrogen, so obtaining a compound of formula (I) wherein the symbol R, R,, R ₂ , R ₃ , R ₅ and

B are as defined above, R ₄ and A are both hydrogen and Y is a single bond; and, if desired,

D) hydrogenating a compound of formula (I) wherein

R, R,, R ₂ , R ₃ and B are as defined above, R,, is absent, R ₅ is hydrogen or C,-C ₆ alkyl group unεubstituted or subεtituted by one or more fluorine atoms, Y iε a double bond e / and A iε a group =C wherein

\

R _{7 f} , and R ₇ are aε defined above so obtaining a compound of formula (I) wherein X and Y are single bonds, R, R,, R ₂ , R ₃ and B are as defined above, R,, is hydrogen, R ₅ is hydrogen or a Cj-C ₆ alkyl group unsubstituted or substituted by one or more fluorine atoms, and A is a

group -C-R ₇ wherein R ₈ is a hydrogen atom and R and

R ₈ R ₇ are as defined above; and/or

E) dehydrogenating a compound of formula (I) wherein the ..... R, R,, R ₂ , R ₃ , R ₄ , R ₅ , B and A are as defined above, and X is a single bond so obtaining a compound of formula (I) wherein Y, R R ₂ , R ₃ , R,,, R ₅ , B and A are as defined above and X is a double bond; and, if desired, separating a mixture of isomers of formula. (I) into the single iεomerε.

In the compound of formula (II) the Z group is an activating group of the carboxy function useful in the formation of amidic and peptidic linkages; it may be for inεtance one of the following groupε:

-Cl, -O-C-OCjHj,

The reaction of a compound of formula (II) with a compound of formula (III) , according to the process variant A), may be, e.g., carried out in a solvent such as, for example, methylene chloride, ethyl acetate, tetrahydrofuran, dimethylformamide, benzene, or toluene at a temperature ranging from about 0°C to about 100°C, for a time varying from about 1 hour to about 48 hours. If the compound of formula (III) is in the salt-form a stoichiometric amount of an organic base, such as, for example, pyridine or a tri-Cι-C ₆ -alkylamine, preferably triethylamine, has to be added to the reaction mixture. The reaction of a compound of formula (IV) with a

compound of formula (V) according to the proceεε variant B) , may be carried out in the uεual conditionε of the Horner-Wadεworth-Emmons reaction.

For example, the reaction may be carried out by reacting the compound of formula (V) disεolved in an anhydrouε εolvent such as, for example, ethyl ether or tetrahydrofuran, with a lithium alkylamide such as, for example, lithium diisopropylamide or an alkyl lithium derivative, such aε butyl lithium or sodium hydride, at a temperature from about -78°C to about 0°C, under an inert atmosphere of nitrogen or argon, for a time varying from half an hour to 3 hours, then the compound of formula (IV) dissolved in tetrahydrofuran is added to the reaction mixture and the reaction continued at a temperature varying from room temperature to the reflux temperature of the reaction mixture, for a time varying from some hours to 1 or 2 days.

In the compounds of formula (VI) , W is a halogen atom, preferably iodine. The reaction of a compound of formula (IV) with a compound of formula (VI) , according to the process variant B) , may be carried out in the usual conditions of the Wittig reaction.

For example, the reaction may be carried out reacting the compound of formula (VI) with a strong base such as, for example, a lithium alkyl amide (e.g. lithium diisopropylamide) , or an alkyl lithium (e.g. butyl lithium) or an alkaline metal hydride (e.g. sodium hydride) or an

alkaline metal alkoxide (e.g. potassium tert-butoxide) in a solvent such as, for example, diglyme, dimethylsulfoxide (DMSO) , tetrahydrofuran, diethyl ether, benzene, toluene or mixture of them, at a temperature varying from about -78°C to room temperature, preferably under an inert atmosphere of nitrogen or argon.

Succesεively the ylide εo obtained is treated with the compound of formula (IV) and the reaction is continued at a temperature varying from room temperature to the reflux temperature of the mixture for a time varying from some hours to some days.

The reduction of a compound of formula (VII) , according to a process variant C) may, for example, be performed by treating a compound of formula (VII) with tri- n-butyl tin hydride, sometimes in the presence of azobis(isobutyronitrile) (AIBN) as radical initiator, in a solvent such as, for example, toluene at a temperature ranging from room temperature to the reflux temperature of the solvent, for a time varying from 1 hour to 4 hours. The hydrogenation of a compound of formula (I) according to the process variant D) , may, for example, be carried out in a solvent εuch aε, for example, methanol, ethanol, ethyl acetate, in the presence of about 10% to 30% of hydrogenation catalyst such as, for example, 5% Pd/C or 10% Pd/C, Ni-Raney, at a hydrogen pressure of 1 atmosphere at room temperature for a time varying from half an hour to 3 hours.

The dehydrogenation of a compound of formula (I) according to the process variant E) , which is preferably performed on a compound of formula (I) wherein R is hydrogen, may be carried out by treatment with a suitable dehydrogenating agent such as, e.g., chloranil, benzeneseleninic anhydride or dichlorodicyanobenzoguinone (DDQ) , operating in an anhydrous solvent, such as, for example, chlorobenzene, dioxane, xylene, toluene or benzene, and, optionally, in the presence of BSTFA [bis- (trimethylsilyl)trifluoroacetamide] . The reaction temperature may range from the room temperature to the reflux temperature of the εolvent and the reaction time may vary approximately from about 2 hourε to about 24 hours. Preferably the reaction is carried out under an inert atmosphere, e.g., a nitrogen atmosphere.

The compounds of formula (II) are known compounds or can be prepared from known compounds according to known procedure.

The compounds of formula (III) are commercially available or they can be synthesized by known methods. For example, by the reduction of the corresponding trifluoroamideε (see JOC 24. _/ 1256-59 (1959)) or from the corresponding ketones (Tetr. Lett. 3_1 (39), 5547-50 (1990)), or by reduction of the corresponding N- hydroxylamines (JOC 3_2, 3197 (1967)) or isocyanates (DE-A- 3326875 and DE-A-3611195) .

The compounds of formula (III) , wherein R ₂ , R ₃ and R ₅

have all the meanings defined above, except hydrogen, and R, is hydrogen, Y is a single bond, and A and R ₄ are fluorine atoms may be obtained by hydrolysis of a carbamate of formula (VIII)

R ₂ F

I I R ₁₀ OOC NH C C R ₅ (VIII )

R ₃ F

wherein R ₂ , R ₃ and R ₅ have all the meanings defined above, except hydrogen and R ₁₀ is a C,-C ₄ alkyl group, preferably an ethyl group, or a benzyl group.

The hydrolysis is, for example, carried out by treatment of the carbamate in a solvent such as, for example, dioxane, tetrahyrofuran or ethanol with 48% hydrobromic acid, at the reflux temperature of the reaction mixture, for a time varying from 5 hours to 24 hours. The carbamate of formula (VIII) is obtained by reacting a compound of formula (IX)

R ₂ F

I I

R ₁₀ OOC N = C C R ₅ (IX)

F

wherein R ₁ , R ₂ and R ₅ are as defined above, with an

organomagneεium compound of formula (X)

R ₃ -MgX (X)

wherein R ₃ iε aε defined above, Mg iε a magneεium atom and X iε a halogen, preferably chlorine, bromine or iodine. The reaction iε carried out in an anhydrouε εolvent εuch as, for example, diethylether or tetrahydrofuran, at a temperature ranging from -10°C to the reflux temperature of the reaction mixture for a time varying from 30 minutes to 4 hours. A compound of formula (IX) may be obtained reacting a compound of formula (XI)

R ₁₀ OOC-N=PPh ₃ (XI)

wherein R _lt , is as defined above, with a compound of formula (XII):

(XII)

wherein R ₂ and R ₅ are as defined above. The reaction between the azaphosphorane (XI) and the fluorinated ketone (XII) is carried out in the usual conditions reported in the literature for the aza-Wittig reaction.

The compounds of formulae (X) , (XI) and (XII) are known compounds or they can be synthesized according to known methods.

The compounds of formula (IV) may be obtained, for instance, by reacting a compound of formula (II) with an α- a ino ketone of formula (XIII)

wherein R,, R ₂ , R ₃ and R ₅ are as defined above. For example, the reaction is performed in an inert solvent such as, for example, methylene chloride, ethyl acetate, tetrahydrofuran, dimethylformamide, benzene or toluene at a temperature ranging from about 0°C to about 100°C optionally in the presence of an organic base such as, for example, pyridine, p-dimethylaminopyridine or triethylamine, for a time varying from half an hour to five

dayε. The compounds of formula (XIII) are often used as N- salt-derivatives (for example, aε hydrochlorideε or trifluoroacetateε) . In that event, a stoichiometric amount of an organic base such as, for example, pyridine or a tri-

Cι-C ₆ -alkylamine, preferably triethylamine, has to be added to the reaction mixture.

A compound of formula (VII) may be obtained by reaction of a compound of formula (XIV)

wherein the symbol B, R, R,, R _2; R ₃ , R ₅ are as defined above and R ₄ is hydrogen, with a compound of formula (XV)

The reaction is, for example, performed by refluxing a mixture of the alcohol of formula (XIV) and excess 1,1-thiocarbonyl diimidazole of formula (XV) in an anhydrous solvent such as, for example, 1,2-dichloroethane, methylene chloride or tetrahydrofuran for a time varying from about 1 hour to 8 hours, preferably

under an inert atmosphere of, for example, nitrogen.

The compounds of formula (XIV) may be obtained, for instance, by reaction of a compound of formula (II) wherein the symbol .... and R and B are as defined above with a compound of formula (XVI)

wherein R,, R ₂ , R ₃ and R ₅ are as defined above and R„ is hydrogen.

The reaction may be carried out, for example, in a solvent such as, for example, methylene chloride or ethyl acetate, at a temperature ranging from about 0°C to 70°C, optionally in the preεence of an organic base such as, for example, a Cj-Cβ trialkylamine, preferably triethylamine, for a time varying from 2 hours to 24 hours. The compounds of formula (XVI) are often used as salt-derivativeε, preferably hydrochlorides, and the amino group is formed in situ in the presence of an organic base such as, for example, a Cι-C ₆ -trialkylamine, preferably triethylamine. The compounds of formulae (XV) and (XVI) are commercially available compounds or may be obtained by

known procedureε.

The compounds of formulae (V) , (VI) , and (XIII) are known compoundε or they can be εyntheεized by known methods. The compounds of the present invention inhibit specifically the testosterone 5α-reductase enzyme and, therefore, are potent antiandrogens. For example, the inhibitory effect of the compounds of the invention on 5α- reductaεe waε determined in vitro and .in vivo according to the procedure reported herebelow.

In vitro assay of 5a-reductase inhibition

Inhibition of 5α-reductase waε evaluated using the particulate fraction from homogenates of hyperplastic human proεtateε aε the enzyme source. The particulate fraction waε prepared centrif ging proεtate homogenate at 140,000 x g. The resulting pellet, washed several times, was resuεpended in buffer and stored at -80°C in aliquots containing » 10 mg protein/ml. The aεsay for 5α-reductaεe waε done in a final volume of 0.5 ml, in 40 mM TRIS-HCl buffer pH 5.5, containing 1 mM dithiothreitol, 5 mM NADPH, 1 μM [ ^I4 C] testosterone, an aliquot of the enzyme preparation and various of the inhibitors. After 30 min incubation at 37°c the reaction waε terminated by addition of 2 ml cold diethyl ether and the organic phase waε εeparated, evaporated under N ₂ and reεuspended in ethyl acetate. Testosterone metabolites in

thiε extract were εeparated in TLC on silica gel F 254 plates (Merck) , using chloroform, acetone and n-hexane (2:1:2) as developing solvent system.

Radioactivity on the plate was scanned and analyzed from quantitative plots printed by a TLC-analyzer

(Berthold) . The fractional 5α-reduction of testoεterone waε calculated by relating the ^,4 C-radioactivity in the 5α- reduced metabolites (5α-dihydroteεtoεterone, 3α- and 3/3- androεtanediolε) regionε to the total radioactivity in the testosterone and 5α-reduced metabolites regions. The concentration of each compound required to reduce control 5α-reductaεe activity by 50% (IC _J0 ) waε determined by plotting % inhibition verεuε log of inhibitor concentration.

In vivo inhibition of 5α-reductase

The standard test for the antiandrogenic effect in rats was used. Prepuberal 22-day-old male ratε were castrated via εcrotal incision under light ether anaesthesia. On the seventh day after orchiectomy, androgen replacement was performed via subcutaneous implantation of 1 cm-long Silaεtic ^R tube (Dow-Corning, Model No 602-265) filled with a mixture of 25% testosterone and 75% cholesterol. The rats were then treated orally with the tested compounds (7 animals/group) , once daily for 7 conεecutive dayε. 24 hourε after the last dose the ratε were sacrificed and the ventral prostate was removed and

weighed. Control animals (testosterone controls) received the vehicle (0.5 ml/kg of 0.5 % Methocel/0.4% Tween 80). One group of castrated rats was not implanted with testosterone (castrated controls) .

The mean percentage of inhibition of the T-induced hypertrophic responεe of the prostate was calculated according to the following formula:

% inhibition = 100 x (W _τc -Wj)/(W _τc -W _cc )

where W _τc , W _cc and Wj are the mean proεtate weight of teεtosterone control, castrated control and inhibitor treated group, reεpectively.

As an example, the results obtained with some representative compounds of the invention are shown in the following Table:

Table l: In vitro and in vivo inhibition of 5o.-reductase

From the results reported in Table 1 it is evident that the new compounds are very potent 5α-reductase inhibitors, both in vitro and .in vivo. In view of the above indicated activity the compounds of the invention are

therapeutically useful in the situations in which a decrease in androgen action, by means of 5α-reductase inhibition, is desirable such as, for example, benign prostatic hyperplasia, prostatic and breast cancers and certain skin-hair conditions such as, e.g. acne, seborrhoea, female hirsutism and male pattern baldness. A mammal, e.g. a human or animal, may thus be treated by a method which comprises administering thereto a pharmaceutically effective amount of a compound of formula (I) as defined above.

The toxicity of the compounds of the invention is quite negligible so that they can be safely used in therapy. The compounds of the invention can be administered in a variety of dosage forms, e.g. orally, in the form of tablets, capsuleε, εugar or film coated tabletε, liquid solutions or suspensions; rectally, in the form of suppoεitorieε; parenterally, e.g. intramuεcularly, or by intravenouε injection or infuεion; or topically, e.g. in the form of creams. The dosage depends on the age, weight, conditions of the patient and administration route; for example the dosage adopted for oral administration to adult humans may range from about 1 to 200 mg pro dose, from 1 to 3 times daily. As already said the invention includes pharmaceutical co poεitions comprising a compound of the invention in association with a pharmaceutically acceptable

excipient (which can be carrier or diluent) .

The pharmaceutical compoεitions containing the compounds of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form.

For example, the solid oral forms may contain, together with the active compound, diluents, e.g., lactose, dextrose, εaccharose, celluloεe, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycolε; binding agentε, e.g. εtarcheε, arabic gums, gelatin, methylcellulose, carboxymethylcelluloεe or polyvinyl pyrrolidone; desegregating agents, e.g. a starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweetenerε; wetting agentε εuch aε lecithin, polyεorbateε, laurylεulphateε; and, in general, non-toxic and pharmacologically inactive substanceε uεed in pharmaceutical formulationε. Said pharmaceutical preparationε may be manufactured in known manner, for example, by meanε of mixing granulating, tabletting, sugar- coating, or film-coating processes. The liquid dispersions for oral administration may be, e.g. syrups, emulsionε and suspensions.

The syrups may contain as carrier, for example, saccharoεe or saccharose with glycerin and/or mannitol and/or εorbitol; in particular a syrup to be administered to diabetic patientε can contain aε carrierε only products

not metabolizable to glucose, or metabolizable in very small amount to glucose, for example sorbitol.

The suspenεions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.

The suspenεionε or εolutionε for intramuεcular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. εterile water, olive oil, ethyl oleate, glycol, e.g. propylene glycol and if deεired, a εuitable amount of lidocaine hydrochloride. The εolutions for intravenouε injectionε or infuεionε may contain as carrier, for example, sterile water or preferably they may be in the form of εterile, aqueous, iεotonic εaline εolutions.

The suppositories may contain together with the active compound a pharmaceutically acceptable carrier, e.g. cocoa- butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin. Conventional carriers may be used for topical formulations.

The present invention further provides a compound of formula (I) for use in a method of treatment of the human or animal body by therapy, in particular for use as a testoεterone 5α-reductaεe inhibitor.

The preεent invention further provideε the uεe of a compound of formula (I) in the manufacture of a medicament

for use as a testosterone 5α-reductase inhibitor.

The following Examples further illuεtrate the invention.

The reported NMR data are determined in deuterochloroform (CDC1 ₃ ) , unless otherwise specified, and are reported as parts per million ( δ ) downfield from tetra ethylεilane. According to the nomenclature used in the Examples the compounds are numbered as shown herebelow:

Example 1

N-(2,2,2-trifluoroethyl) 3-oxo-4-aza-5α-androεt-l-ene-17/3- carboxamide [ (I) : X = double bond; Y = single bond; B = bond; R = H; R, = H; R ₂ = H; R ₃ = H; R _< = F; R ₅ = F; A = F] .

A mixture of 2-pyridyl 3-oxo-4-aza-5α-androst-l-ene-17/3- carbothioate (102.5 mg) and 2,2,2-trifluoroethylamine (0.55 ml) in anhydrous tetrahydrofuran (2.5 ml) was refluxed for 4 hours. The solvent was removed under vacuum and the yellow solid was purified by flash chromatography (eluent: ethyl

acetate/methylene chloride 20:1) so obtaining 110 mg of the title compound as a white crystalline εolid (m.p. 220- 221°C, methylene chloride) .

NMR (CDC1 ₃ , δ ) : 6.77 (d, IH, H(l)), 5.8 (dd, IH, H(2)), 5.56 (t, IH, C0NHCH ₂ CF ₃ ) , 5.52 (bε, IH, NH) , 4.18 and 3.70 (2m, 2H, CONHCH,CF ₃ ) , 3.31 (dd, IH, H(5α)), 0.96 (ε, 3H, CH ₃ (19)), 0.78 (ε, 3H, CH ₃ (18)).

MS (m/z) : 398 M ^+*

Using the appropriate εtarting material and following an analogouε procedure the compounds listed below were alεo prepared.

N-(4,4,4-trifluoro-3-methyl-but-2-yl) 4-methyl-3-oxo-4-aza-

5α-androstane-173-carboxamide; N-(1,1,1-trifluoro-3-methyl-but-2-yl) 4-methyl-3-oxo-4-aza-

5 -androstane-17/3-carboxamide;

N-(4,4,4-trifluoro-3-methyl-but-2-yl) 3-oxo-4-aza-5α- androstane-17/3-carboxamide;

N-(1,1 ,1-trifluoro-3-methyl-but-2-yl) 3-oxo-4-aza-5α- androstane-17/3-carboxamide;

N-(5-methyl-2-difluoromethyl-hex-3-yl) 4-methyl-3-oxo-4- aza-5α-androεtane-173-carboxamide;

N-(3-difluoromethyl-hept-2-yl) 4-methyl-3-oxo-4-aza-5α- androstane-17/3-carboxamide;

N-(5-methyl-2-difluoromethyl-hex-3-yl) 3-oxo-4-aza-5α- androεtane-17/3-carboxamide ;

N- (3-dif luoromethyl-hept-2-yl) 3-oxo-4-aza-5α-androεtane-

17/3-carboxamide ; N-(4,4,4-trifluoro-3-methylene-but-2-yl) 4-methyl-3-oxo-4- aza-5α-androεtane-17/3-carboxamide;

N-(l, 1, 1-trif luoro-3-methylene-but-2-yl) 4-methyl-3-oxo-4- aza-5α-androεtane-17β-carboxamide;

N- (4 , 4 , 4-trif luoro-3-methylene-but-2-yl) 3-oxo-4-aza-5α- androεtane-17/3-carboxamide;

N-(l, 1, 1-trif luoro-3-methylene-but-2-yl) 3-oxo-4-aza-5α- androstane-17/3-carboxamide;

N-(5-methyl-2-difluoromethylene-hex-3-yl) 4-methyl-3-oxo-4- aza-5α-androstane-17j8-carboxamide; N-(3-difluoromethylene-hept-2-yl) 4-methyl-3-oxo-4-aza-5α-- androεtane-17/S-carboxamide;

N-(5-methyl-2-difluoromethylene-hex-3-yl) 3-oxo-4-aza-5α- androstane-17/S-carboxamide;

N-(3-difluoromethylene-hept-2-yl) 3-oxo-4-aza-5α- androstane-173-carboxamide;

N,N-di-(2,2,2-trifluoroethyl) 3-oxo-4-aza-5α-androstan-l- ene-17/3-carboxamide ;

N-(l, 1, l,3,3,3-hexafluoroprop-2-yl) 3-oxo-4-aza-5cι-androst- l-ene-17/3-carboxamide; N,N-di-(l,l,l,3,3,3-hexafluoroprop-2-yl) 3-oxo-4-aza-5α- androεt-l-ene-17/3-carboxamide;

N-methyl-N-(2,2,2-trifluoroethyl) 3-oxo-4-aza-5α-androεt-l-

ene-17/3-carboxamide ;

N-iεobutyl-N- ( 2 , 2 , 2-trif luoroethyl ) 3-oxo-4-aza-5α-androst- l-ene-17 S-carboxamide ;

N- ( l-f luoro-2-methyl-prop-2-yl) 3-oxo-4-aza-5α-androst-l- ene-17/3-carboxamide ;

N- ( 1 , 3-dif luoro-2-methyl-prop-2-yl ) 3-oxo-4-aza-5α-androst- l-ene-17 3-carboxamide ;

N- ( 1 , 3-dif luoro-2-f luoromethyl-prop-2-yl ) 3-oxo-4-aza-5α- androst-l-ene-17 S-carboxamide .

Example 2

N-(2,2,2-trifluoroethyl)-4-methyl-3-oxo-4-aza-5o.- androstane-17β-carboxamide [ (I) : X = single bond; Y = εingle bond; B = bond; R = CH ₃ ; R, = H; R ₂ = H; R ₃ = H; R =

To a εuεpenεion of 2,2,2-trifluoroethylamine hydrochloride (948.5 mg) in anhydrouε tetrahydrofuran (10 ml), triethylamine (0.973 ml) waε added. After εtirring for 15 min at room temperature, εolid 2-pyridyl 4-methyl-3-oxo-4- aza-5α-androεtane-17/3-carbothioate (426 mg) was added and the mixture was heated to reflux for 4 hours.

The volatiles were removed under vacuum and the crude waε purified by flaεh chromatography on silica gel (eluent: ethylacetate/ ethylene chloride 20:1) to yield 330 mg of the title compound ( .p. 242-244°C). NMR (CDC1 ₃ ) δ t 5. 65 (m, IH, NH) , 4 .5-3 .5 (m, 2H, CH ₂ CF ₃ ) ,

3.1 (dd, IH, H(5α)) , 2.9 (ε, 3H, N-CH ₃ ) , 0.87 (s, 3H, CH ₃ (19)) 0.67 (ε, 3H, CH ₃ (18)) .

Elemental analysiε Calculated for C ₂₂ H ₃₃ F ₃ N ₂ 0 ₂ C 63.75%, H 8.02%, N 6.76% found C 63.44%, H 7.78%, N 6.67%

Following an analogous procedure and uεing the appropriate εtarting materialε the compounds listed below were prepared:

N-isopropyl-N-(2,2,2-trifluoroethyl) 3-oxo-4-aza-5α- androεt-l-ene-17 _/ 3-carboxamide;

N-iεopropyl-N-(2,2,3,3,3-pentafluoropropyl) 3-oxo-4-aza-5α- androεt-l-ene-173-carboxamide.

Example 3

(22RS)-N-(2,2,2-trifluorophenylethyl) 3-oxo-4-aza-5α- androst-l-ene-17S-carboxamide [(I): X = double bond; Y = single bond; B = bond; R = H; Rj = H; R ₂ = Ph; R ₃ = H; R ₄ = F; R ₅ = F; A = F] .

To a solution of (RS)-2,2,2-trifluorophenylethylamine hydrochloride (205 mg) in anhydrous dimethylformamide (4 ml) , triethylamine (0.270 ml) waε added. After stirring at room temperature for 30 minutes, solid 2-

pyridyl 3-oxo-4-aza-5α-androεt-l-ene-173-carbothioate (200 mg) was added and the mixture was heated to 100°C for 8 hours.

The reaction mixture was diluted with water and extracted with ethylacetate; the organic extracts were washed with IN hydrochloric acid, with water until neutral, dried over sodium sulphate and the solvent was evaporated under reduced pressure.

The residue was purified by flash chromatography on silica gel (eluent: ethylacetate/methylene chloride 20:1) to yield 125 mg of the title compound (m.p. 260-265°C) .

NMR (CDC1 ₃ ) δ : 7.38 (ε, 5H, Ph) , 6.77 (d, IH, H(l)), 5.95- 5.70 (m, 3H, H(2) + NH(21) + CH(CF ₃ )Ph), 5.21 (ε, IH, NH(4)), 3.33 (dd, IH, H(5α)), 0.99 and 0.94 (2ε, 3H, CH ₃ (19)), 0.72 and 0.56 (2ε, 3H, CH ₃ (18)) MS (m/Z) : 474 M ⁺ \ 459 M- ^* CH ₃ 1 ⁺ , 454 M-HF~| ^+* .

Following an analogouε procedure N-(l,3-difluoro-2- fluoromethylprop-2-yl) 3-oxo-4-aza-5α-androst-l-ene-17/3- carboxamide was prepared.

Example 4

(RS)-1-trifluoromethyl-1-phenyleth-l-ylamine hydrochloride [(III): Y = single bond; R, = H; R ₂ = Ph; R ₃ = CH ₃ ; R ₄ = F; R ₅ = F; A=F]

A mixture of trifluoroacetophenone [(XII): R ₂ = Ph, R ₅ = F] (1.536 ml), N-carbethoxytriphenylphoεphinimine [(XI): R ₁₀ =Et] (3.494 g) in anhydrouε toluene (25 ml) waε heated to reflux for 24 hours. The volatiles were removed under vacuum and the solid residue was suspended in diethylether/petroleum ether (50:50) and filtered; the filtrate waε evaporated under vacuum to yield an oil (2.15 g) that waε purified by chromatography on silica gel (eluent: petroleum ether/diethylether 3:1) so obtaining 1.40 g of

N-carbethoxy-2,2,2-trifluoro-1-phenylethanimine [(IX): Rjo = Et; R ₂ = Ph; R ₅ = F] as a colourless oil.

NMR (CDC1 ₃ ) δ : 7.3-7.7 (m, 5H, Ph) , 4.25 (q, 2H, COOCH ₂ ) 1.2 (t, 3H, COOCHjCHj)

IR (neat): 1725, 1680 cm ^"1

A solution of N-carbethoxy-2,2,2-trifluoro-1- phenylethanimine (210 mg) in anhydrous diethylether (5.0 ml) was added dropwise at room temperature to a freshly prepared 1M solution of methyl magnesium iodide in

diethylether (8.0 ml); then the reaction mixture was refluxed for 0.5 hours and stirred at room temperature for 1 hour.

After cooling to 0°C with an ice bath, the reaction was quenched with IN hydrochloric acid (10 ml) and extracted with diethylether. The organic extractε were waεhed with water, IN εodium thiosulphate, brine and dried over sodium sulphate. After removing the solvent under vacuum, the crude was purified by flash chromatography on silica gel (eluent petroleum ether/diethylether 4:1) to yield 730 mg of (RS)-ethyl N-(1-trifluoromethyl-1-phenylethyl) carbamate [(VIII) : R ₁₀ = Et; R ₂ =Ph; R ₃ = CH ₃ ; R _s = F] as a white solid.

NMR (CDC1 ₃ ) δ : 7.3-7.6 (m, 5H, Ph) , 5.55 (bε, IH, NH) ,

4 . 05 (q , 2H , COOCH ₂ CH ₃ ) , 2 . 05 (m , 3H , PhCCH, f CF,) ) . 1. 20 (t , 3H , COOCH ₂ CH ₃ ) .

MS (m/ z ) : 261 M ^+Φ ; 192 M - ^* CF ₃ 1

The carbamate (730 mg) dissolved in dioxane (6.0 ml) was treated with 48% hydrobromic acid (2 ml) and the mixture was heated to reflux for 16 hours.

After cooling and diluting with water the solution was washed with diethylether, basified to pH 12-13 with IN

εodium hydroxide and extracted with diethylether; the organic extracts were washed with brine and dried over sodium sulphate. The anhydrifier waε filtered off, 2.2N hydrochloric acid (1 ml) was added and the solvent was removed under reduced presεure; the crude oil so obtained was crystallized from acetonitrile to afford 435 mg of the title compound.

MS (m/z) : 189 M ^+* ; 174 M - ^* CH ₃ ^~ | ⁺ ; 120 M - ^* CF ₃ ] ⁺

Example 5 (22RS)-N-(1,1,1-trifluoro-2-phenylprop-2-yl) ^~ 3-oxo-4-aza-

5 -androεt-l-ene-17/3-carboxamide [(I): X = double bond; Y = single bond; B = bond; R = H; Rj = H; R ₂ = Ph; R ₃ = CH ₃ ; R, =

2-Pyridyl-3-oxo-4-aza-5α-androst-l-ene-17/3-carbothioate (205 mg) was dissolved in methylene chloride (2.5 ml) containing methyl iodide (63 μl) . After stirring at room temperature for 15 minutes, (RS)-1-trifluoromethyl-l- phenyleth-1-yl amine (160 mg) , dissolved in 3 ml of DMF, was added and the mixture was heated at 100°C for 8 hours. The reaction mixture waε poured into water (75 ml) and extracted with methylene chloride. The organic extracts were washed with IN hydrochloric acid,

with water and anhydrified over sodium sulphate and the solvent was evaporated at reduced pressure. The solid residue waε taken up with ethyl acetate: the inεoluble solid was filtered off and the filtrate was chromatographed on silica gel (eluent: ethylacetate/methylene chloride 20:1) to yield 47 mg of the title compound, that solidified by treatment with n-pentane (m.p. 151-155°C).

NMR (CDC1 ₃ ) δ : 7.48-7.35 (m, 5H, Ph) , 6.79 (dd, IH, H(l)) 5.88 (d, IH, NH(21)), 5.81 (dd, IH, H(2)), 5.48 (ε, IH, NH(4)), 3.33 (dd, IH, H(5 )), 2.05 and 2.07 (2ε, 3H, NHCU ₃ (CF ₃ )Ph) , 0.98 and 0.97 (2s, 3H, CH ₃ (19)), 0.72 and 0.68 (2S, 3H, CH ₃ (18)).

MS(m/z) : 488 M ^+* ; 473 M - ^* CH ₃ ] ⁺ ; 173 ^* C(CF ₃ ) (CH ₃ )Ph] ⁺

Following an analogous procedure and using the appropriate starting materials the following compounds were prepared:

N-(2,2,2-trifluoro-1,1-diphenylethyl) 3-oxo-4-aza-5α- androεt-l-ene-173-carboxamide;

N-(1,1,1-trifluoro-2-methylprop-2-yl) 3-oxo-4-aza-5α- androst-l-ene-17/3-carboxamide;

N-(l,l,1,3,3,3-hexafluoro-2-methylpropyl) 3-oxo-4-aza-5α- androεt-l-ene-17/3-carboxamide.

Example 6

(22RS)-N-(4,4,4-trifluoro-3-methylene-but-2-yl) 3-oxo-4- aza-5α-androεt-l-ene-17/3-carboxamide [ (I) : X = double bond; Y = double bond; B = bond; R = H; Rj = H; R ₂ = CH ₃ ; R ₃ = H; R ₄ is absent; A = CH ₂ ; R ₅ = CF ₃ ] .

Methyltriphenylphosphonium iodide (44 mg) was added portionwise to a stirred solution of potassium tert- butylate (9 mg) in dimethylsulphoxide (0.5 ml) maintained under nitrogen at room temperature. After 10 minutes the yellow solution of the ylide so obtained was treated dropwise with a solution of (22RS)-N- (1,1,1-trifluoro-2-oxobut-3-yl) 3-oxo-4-aza-5 -androst-l- ene-170-carboxamide (30 mg) in 1.5 ml of dimethylεulphoxide. The solution became clear in a few minutes.

After diluting with ethyl acetate, the reaction mixture was washed with water, dried over εodium sulphate and the solvent was evaporated at reduced pressure. The crude oil was purified by flash chromatography (eluent methylene chloride/acetone 50:50) to yield 21 mg of the title compound.

NMR (CDC1 ₃ ) δ : 6.78 (d, IH, H(l)), 5.80 (dd, IH, H(2)),

5.75 (d, IH, NH(21)) , 5.55 (bε, IH, NH(4)), 5.60 and 5.35 (2m, 2H, C=CH ₂ ) , 4.70 (m, IH, NHCH(CH ₃ ) ) , 3.33 (dd, IH, H(5α)), 1.35 (d, 3H, NHCH CJi,)), 0.97 (s, 3H, CH ₃ (19)), 0.70 (ε, 3H, CH ₃ (18)) .

Following an analogous procedure the compounds listed below were prepared:

N-(5,5,5-trifluoro-4-methylene-2-methylpent-3-yl)

3-oxo-4-aza-5α-androst-l-ene-17/3-carboxamide;

N- (4 , 4 , 4-trif luoro-3-methylene-2-methylbut-2-yl) -3-OXO-4- aza-5α-androεt-l-ene-173-carboxamide ;

N- (4 , 4 , 4-trif luoro-3-methylene-but-2-yl) -4-methyl-3-oxo-4- aza-5α-androεtane-l70-carboxamide;

N-(1,1,1-trifluoro-3-methylene-but-2-yl)-4-methyl-3-oxo-4 - aza-5α-androεtane-17/3-carboxamide; N-(4,4,4-trifluoro-3-methylene-but-2-yl)- ^t 3-oxo-4-aza-5o:- androεtane-17/3-carboxamide;

N-(1,1,1-trifluoro-3-methylene-but-2-yl)-3-oxo-4-aza-5α- androεtane-173-carboxamide .

Example 7 (22RS-23RS)-N-(4,4,4-trifluoro-3-methylbut-2-yl) 3-oxo-4- aza-5α-androstane-17jS-carboxamide [(I): X = single bond; Y ■ = single bond; B = bond; R = H; Rj = H; R ₂ = CH ₃ ; R ₃ = H; R, = H; A = CH ₃ ; Rj = CF ₃ ] .

A solution of (22R,S)-N-(2-trifluoromethyl-but-l-en-3-yl) 3-oxo-4-aza-5α-androst-l-ene-17/3-carboxamide (21 mg) in ethyl acetate waε hydrogenated under pressure (30 psi) at room temperature for 3 hours, in the presence of 10% Pd/C (4 mg) .

The catalyst was filtered off and the solvent was evaporated under vacuum.

The residue was chromatographed on silica gel (eluent methylene chloride/acetone 50:50) to yield 16 mg of the title compound.

NMR (CDC1 ₃ ) δ : 5.67 (ε, IH, NH(4)), 5.30 (d, IH, NH(21)), 4.35 ( , IH, NHCH(CH ₃ ) ) , 3.03 (dd, IH, H(5α)"), 2.35 (m, IH, -CH(CH ₃ )CF ₃ ) , 1.23 (2d, 6H, NHCH(CH,)CH(CH,)CF,) . 0.87 (ε, 3H, CH ₃ (19)), 0.70 (s, 3H, CH ₃ (18)).

Following an analogous procedure the following compounds were prepared:

N-(5,5,5-trifluoro-2,4-dimethylpent-3-yl) 3-oxo-4-aza-5α- androεtane-170-carboxamide;

N-(4,4,4-trifluoro-2,3-dimethylbut-2-yl) 3-oxo-4-aza-5α- androεtane-17/3-carboxamide;

N-(4,4,4-trifluoro-3-methyl-but-2-yl) 4-methyl-3-oxo-4-aza- 5α-androstane-17/3-carboxamide;

N-(1,1,1-trifluoro-3-methyl-but-2-yl) 4-methyl-3-oxo-4-aza- 5 -androstane-17 _/ 9-carboxamide;

N-(1,1,1-trifluoro-3-methyl-but-2-yl) 3-oxo-4-aza-5α- androstane-17J-carboxamide; N-(5-methyl-2-difluoromethyl-hex-3-yl)4-methyl-3-oxo-4-aza- 5α-androstane-170-carboxamide;

N-(3-difluoromethyl-hept-2-yl) 4-methyl-3-oxo-4-aza-5α- androεtane-173-carboxamide;

N-(5-methyl-2-difluoromethyl-hex-3-yl) 3-oxo-4-aza-5α- androεtane-170-carboxamide;

N-(3-difluoromethyl-hept-2-yl) 3-oxo-4-aza-5 -androεtane- 17/3-carboxamide.

Example 8

N- ( 4 , 4 , 4-trif luoro-3-methylbut-2-yl ) 3-oxo-4-aza-5α- androst-l-ene-17 9-carboxamide [ (I ) : X = double bond ; Y = single bond ; B = bond ; R = H ; R, = H ; R ₂ = CH ₃ ; R ₃ = H ; R ₄ = H ; A = CH ₃ ; R ₅ = CF ₃ ] .

To N-(4,4,4-trifluoro-3-methylbut-2-yl) 3-oxo-4-aza-5α- androstane-17,9-carboxamide [(I): X = single bond; B = single bond; Y = single bond; R = H; R. - H; R ₂ = CH ₃ ; R ₃ = H; R ₄ ■ H; A = CH ₃ ; R ₅ = CF ₃ ] (55 mg) suspended in chlorobenzene (5.0 ml), benzeneseleninic acid anhydride (64 mg) was added and the mixture was refluxed for 4 hours.

The solvent was removed under vacuum and the residue was dissolved in methylene chloride; the organic solution was washed with sodium bicarbonate, with saturated sodium chloride, anhydrified over sodium sulphate and the solvent was evaporated under reduced pressure.

Purification of the brown crude by chromatography on silica gel (eluent methylene chloride/ethyl acetate/methanol 50:45:5) afforded 28 mg of the title compound.

NMR (CDC1 ₃ ) δ : 6.78 (d, IH, H(l)), 5.80 (dd, IH, H(2)), 5.67 (ε, IH, NH(21)), 5.30 (d, IH, NH(21)), 4.35 (m, IH,

NHCH(CH ₃ )-), 3.33 (dd, IH, H(5α)), 2.35 (m, IH, CH(CH ₃ )CF ₃ ), 1.23 (2d, 6H, NHCH(CH ₃ )CH(CH ₃ )CF ₃ ) , 0.97(s, 3H, CH ₃ (19)), 0.68 (ε, 3H, CH ₃ (18)).

Following an analogouε procedure the compounds listed below were prepared:

N-(5,5,5-trifluoro-2,4-dimethylpent-3-yl) 3-oxo-4-aza-5α- androεt-l-ene-17/S-carboxamide;

N-(4,4,4-trifluoro-2, 3-dimethylbut-2-yl) 3-oxo-4-aza-5α- androεt-l-ene-17/3-carboxamide.

Example 9

(22RS)-N-(4,4,4-trifluorobut-2-yl) 3-oxo-4-aza-5α-androεt-

l-ene-17/S-carboxamide [(I) : X = double bond; Y = single bond; B = bond; R = H; Rj = H; R ₂ = CH ₃ ; R ₃ = H; R - H; A =

(22RS-23RS) -N- (4 , 4 , 4-trif luoro-3-hydroxybut-2-yl) 3-oxo-4- aza-5α-androst-l-ene-17/3-carboxamide [ (XIV) : X = double bond; B = single bond; R = H; Rj = H; R ₂ = CH ₃ ; R ₃ = H; R^ = H; R ₅ = CF ₃ ] (50 mg) was dissolved in 1,2-dichloromethane (1.3 ml) at room temperature under an inert atmosphere of nitrogen; solid 90% 1, 1 '-thiocarbonyldiimidazole (45 mg) was added and the mixture was heated at 75 °C (oil bath temperature) for 3 hours.

Purification of the reaction mixture by flash chromatography on silica gel (eluent: methylene chloride/ ethylacetate/methanol 50:45:5) yielded 61 mg of (22RS- 23RS)-N-[4,4,4-trifluoro-3-{[ (imidazol-1- yl)thiocarbonyl]oxy}but-2-yl] 3-oxo-4-aza-5α-androst-l-ene- 170-carboxamide [(VII): X = double bond; B = bond; R = H; R, = H; R ₂ = CH ₃ ; R ₃ = H; R = H; R ₅ = CF ₃ ] . Tributyltin hydride (0.049 ml) in toluene (2.5 ml) was heated at reflux and a solution of N-[ ,4,4-trifluoro-3-

{[ (imidazol-l-yl)thiocarbonyl]oxy}but-2-yl] 3-oxo-4-aza-5α- androεt-l-ene-17j3-carboxamide (51 mg) in toluene (1.3 ml) was added dropwise over 15 minutes and the mixture was refluxed for 85 minutes.

The solvent waε removed under reduced preεsure and the residue was purified by flash chromatography on εilica gel (eluent methylene chloride/ethyl acetate/methanol 50:45:5) to give the title product (27 mg) .

MS(m/z) : 426 M ^+# ; 411 M - ^* CH ₃ ⁺

NMR (CDC1 ₃ ) _^ <S: 6.78 (d, IH, H(l)), 5.80 (dd, IH, H(2)), 5.67 (ε, IH, NH(4)), 5.30 (d, IH, NH(21)), 4.35 (m, IH, -NHCH(CH ₃ )-) , 3.33 (dd, IH, H(5α)), 2.42 and 2.28 (2m, 2H, -CH ₂ CF ₃ ) , 1.25 (d, 3H, -NHCH(CH ₃ )-) , 0.97 (ε, 3H, Me(19)), 0.68 (ε, 3H, Me(18) ) .

Following an analogouε procedure and using the appropriate starting materials the compounds listed below were prepared:

N-(5,5,5-trifluoro-2-methylpent-3-yl) 3-oxo-4-aza-5α- androεt-l-ene-17/3-carboxamide;

N-(4,4,4-trifluoro-2-methylbut-2-yl) 3-oxo-4-aza-5α- androεt-l-ene-17/3-carboxamide.

Example 10

Scored tablets for oral use, each containing 250 mg of the active substance, were manufactured as followε:

Composition (for 10,000 tablets)

N-(2,2,2-trifluorophenylethyl) 3-oxo-4-aza-5α-androst-l- ene-17/3-carboxamide 2500 g corn starch 275 g talc powder 187 g calcium stearate 38 g

The active substance was granulated with a 4% w/v aqueouε solution of methyl cellulose. To the dried granules a mixture of the remainder of the ingredients is added and the final mixture compressed into tablets of proper weight.

Example 11

Two-piece hard gelatin capsules for oral use, each containing 250 mg of active substance were manufactured as follows.

Composition for 10,000 capsules

N-(2,2,2-trifluorophenylethyl) 3-oxo-4-aza-5α-androst-l- ene-173-carboxamide 2500 g lactose 1000 g corn starch 300 g talc powder 65 g calcium stearate 35 g

The active substance was mixed with the starch-lactose mixture followed by the talc and calcium stearate.

Example 12

Scored tablets for oral use, each containing 250 mg of the active substance, were manufactured as follows. Composition (for 10,000 tablets)

N-(2,2,2-trifluorophenylethyl) 3-oxo-4-aza-5α-androst-l- ene-17J-carboxamide 2500 g corn starch 280 g talc powder 180 g calcium stearate 40 g

The active substance was granulated with a 4% w/v aqueous solution of methyl cellulose. To the dried granules a mixture of the remainder of the ingredients is added and the final mixture compressed into tables of proper weight.