Substituted 6-azaandrostenones

A compound which is:

• 17.beta.-(1-Oxo-2-cyclohexylethyl)-6-azaandrost-4-en-3-one;
• 17.beta.-(1-Oxo-1-(2,4-difluorophenyl)methyl)-6-azaandrost-4-en-3-one;
• 17.beta.-(1-Oxo-1-(4-isopropoxyphenyl)methyl)-6-azaandrost-4-en-3-one;
• 1.beta. -(1-Oxo-3,3-diphenylpropyl)-6-azaandrost-4-en-3-one;
• or
• 17.beta.-(1-Oxo-1-(2-norbornyl)methyl)-6-azaandrost-4-en-3-one or
• a pharmaceutically acceptable salt or solvate thereof.

A compound of formula (I) ##STR27## wherein R.sup.1 and R.sup.2 are,

• i) independently hydrogen or lower alkyl and the bond between the carbons bearing R.sup.1 and R.sup.2 is a single or a double bond, or
• ii) taken together are a --CH.sub.2 -- group to form a cyclopropane ring, and the bond between the carbons bearing R.sup.1 and R.sup.2 is a single bond;
• R.sup.3 is hydrogen or lower alkyl;
• R.sup.4 is hydrogen or lower alkyl'
• X is, ##STR28## wherein R.sup.10, R.sup.11, R.sup.12 and R.sup.13 are independently hydrogen or lower alkyl, p and q are independently either 0 or 1;
• Y is hydrogen;
• and
• Z is --COR.sup.5, CONR.sup.14 R.sup.15, --CH.sub.2 OCO.sub.2 R.sup.5, --CH.sub.2 OCOR.sup.5, --CH.sub.2 NR.sup.5 'COR.sup.5, --CONR.sup.5 NR.sup.14 R.sup.15, --CH.sub.2 NR.sup.5 CONR.sup.14 R.sup.5, or --CON.sup.5 CONR.sup.14 R.sup.15 wherein R.sup.5 and R.sup.5 ' are independently hydrogen, lower alkyl optionally substituted independently with one or more Ar.sup.2 groups (lower alkyl)n-lower cycloalkyl, menthyl, adamantyl, norbornyl or Ar.sup.2 ;
• Ar.sup.2 is phenyl group optionally substituted independently with one or more --Alk-H (optionally substituted independently with one or more halogens), --OR.sup.16, --S(O).sub.r R.sup.7, phenyl, methylenedioxy, ethylenedioxy, morpholino, thiomorpholino, cyano, nitro or halogen groups;
• Alk is lower alkylene, lower alkenylene or lower alkynylene;
• n is 0 or 1;
• r is 0, 1 or 2;
• R.sup.7 is --Alk-H, --(Alk).sub.n -phenyl or lower cycloalkyl;
• R.sup.6 is --Alk-H (optionally substituted independently with one or more halogens), lower cycloalkyl (optionally substituted independently with one or more halogens, or --Alk-H (optionally substituted independently with one or more halogens)) or --(Alk)n-phenyl (wherein phenyl is optionally substituted independently with one or more lower alko, cyano, halogen or --Alk-H groups (optionally substituted independently with one or more halogens));
• R.sup.14 is hydrogen or hydroxy, and R.sup.5 is hydrogen, lower cycloalkyl, (optionally substituted independently with one or more R.sup.7 or Ar.sup.2 groups), --(Alk)-adamantyl, --(Alk).sub.n -myrantyl, --(Alk).sub.n -norbornyl, --(Alk).sub.n -fluorenyl, --(Alk).sub.n -indanyl, --Alk-H (optionally substituted independently with one or more lower cycloalkyl, SR.sup.5, OR.sup.5, Ar.sup.2 or Ar.sup.3 groups), Ar.sup.2 or Ar.sup.3, or R.sup.14 and R.sup.15 taken together with the linking nitrogen form a pyrrolidinyl, piperidinyl or perhydroazepinyl ring optionally substituted with one or more R.sup.7 groups;
• Ar.sup.3 is a pyrrolyl, thienyl, furyl or pyridyl group optionally substituted independently with one or more Alk-H groups;
• with the provisos that
• when Z is COR.sup.5, R.sup.5 is substituted lower alkyl, lower alkyl lower cycloalkyl, menthyl, norbornyl or Ar.sup.2 ;
• when Z is CONR.sup.14 R.sup.15 and R.sup.15 is hydrogen, --Alk-H, lower cycloalkyl, lower lakoxy, adamantyl, phenyl, benzyl, diphenylmethyl, triphenylmethyl or --(Alk).sub.n -norbornyl, R.sup.14 is hydroxy;
• and
• when Z is CONR.sup.14 R.sup.15 and R.sup.14 andR.sup.15 taken together with the linking nitrogen form a pyrrolidinyl, piperidinyl or pergydroazepinyl ring, said ring is substituted with one or more lower alkenyl, lower alkynyl, --(Alk).sub.n -phenyl or lower cycloalkyl groups;
• or a pharmaceutically acceptable salt or solvate thereof.

A compound of formula (I) ##STR29## wherein:

• R.sup.1 and R.sup.2 are,
• i) independently hydrogen or lower alkyl and the bond between the carbons bearing R.sup.1 and R.sup.2 is a single or a double bond, or
• ii) taken together are a --C H.sub.2 -- group to form a cyclopropane ring, and the bond between the carbons bearing R.sup.1 and R.sup.2 is a single bond;
• R.sup.3 is hydrogen, --Alk.sup.1 --H , --Alk.sup.1 --H substituted with one or more halogens, lower cycloalkyl, lower cycloalkyl-lower alkyl, halogen, --(Alk.sup.1).sub.n --CO.sub.2 H, --(Alk.sup.1).sub.n --CO.sub.2 R.sup.7, --(Alk.sup.1).sub.n --Ar.sup.1, --(Alk.sup.1).sub.n --CONR.sup.8 R.sup.9, --(Alk.sup.1).sub.n --NR.sup.8 R.sup.9, --(Alk.sup.1).sub.n --S(O).sub.r R.sup.7, --(Alk.sup.1).sub.n --CN, --(Alk.sup.1)--OH or --(Alk.sup.1).sub.n --OR.sup.7 ;
• wherein
• Alk.sup.1 is lower alkylene, lower alkenylene or lower alkynylene,
• n is 0or 1,
• r is0,1or 2,
• R.sup.7 is --Alk.sup.1 --H, --(Alk.sup.1).sub.n --Ar.sup.1 or lower cycloalkyl,
• R.sup.8 and R.sup.9 are independently hydrogen, --Alk.sup.1 --H or lower cycloalkyl,
• Ar.sup.1 is a homocyclic aryl group of 6 to 14 carbons;
• R.sup.4 is hydrogen, --Alk.sup.1 --H, lower cycloalkyl, lower cycloalkyl-lower alkyl, --(Alk.sup.1).sub.n --S(O).sub.r R.sup.7, --(Alk.sup.1).sub.n -phthalimidyl, (--Alk.sup.1)--CO.sub.2 H, --(Alk.sup.1).sub.n --CO.sub.2 R.sup.7, --(Alk.sup.1).sub.n --Ar.sup.1, --(Alk.sup.1).sub.n --CONR.sup.8 R.sup.9, --(Alk.sup.1).sub.n --NR.sup.8 R.sup.9, --(Alk.sup.1).sub.n --OH or --(Alk.sup.1).sub.n --OR.sup.7 ;
• X is, ##STR30## wherein R.sup.10, R.sup.11, R.sup.12 and R.sup.13 are independently hydrogen or lower alkyl, p and q are independently either 0or 1;
• Y and Z are,
• i) Y is hydrogen or hydroxy and
• Z is --(Alk.sup.2).sub.n --COR.sup.5, --(Alk.sup.2).sub.n --CO.sub.2 R.sup.5, --(Alk.sup.2).sub.n --COSR.sup.5, --(Alk.sup.2).sub.n --CONR.sup.14 R.sup.15, --(Alk.sup.2)--OCOR.sup.5, --(Alk.sup.2)--OCONR.sup.14 R.sup.15, --(Alk.sup.2)--OR.sup.5, --(Alk.sup.2)--NR.sup.5 COR.sup.5, --(Alk.sup.2)--NR.sup.5 CO.sub.2 R.sup.5, --(Alk.sup.2)--NR.sup.5 CONR.sup.14 R.sup.15, --(Alk.sup.2)--.sub.n CONR.sup.5 NR.sup.14 R.sup.15, --(Alk.sup.2).sub.n --CONR.sup.5 CONR.sup.14 R.sup.15, (--Alk.sup.2 -)NR.sup.5 CSNR.sup.14 R.sup.15 or --(Alk.sup.2).sub.n --CONR.sup.5 CSNR.sup.14 R.sup.15 ;
• wherein
• Alk.sup.2 is (C.sub.1-12) alkylene, (C.sub.2-12) alkenylene or (C.sub.2-12) alkynylene, R.sup.5 is hydrogen, --Alk.sup.1 --H, --(Alk.sup.1).sub.n -(lower cycloalkyl), adamantyl, --(Alk.sup.1).sub.n --Ar.sup.2, --(Alk.sup.1).sub.n --Ar.sup.3, (lower cycloalkyl).sub.n Ar.sup.2, (lower cycloalkyl).sub.n Ar.sup.3 or --Alk.sup.1 -substituted independently with one or more CO.sub.2 H, CO.sub.2 R.sup.7, Ar.sup.2 or Ar.sup.3 groups;
• wherein
• Ar.sup.2 is an aromatic group of 6 to 14 carbon ring atoms, optionally substituted with one or more Alk.sup.1, Alk.sup.1 substituted with one or more halogens, --(Alk.sup.1).sub.n -OH, --(Alk.sup.1).sub.n --OR.sup.7, --(Alk.sup.1).sub.n --CO.sub.2 H, --(Alk.sup.1).sub.n --CO.sub.2 R.sup.7, S(O).sub.r R.sup.7 or NR.sup.8 R.sup.9, lower cycloalkyl, lower alkoxy, --(Alk.sup.1).sub.n --Ar.sup.1, methylenedioxy, ethylenedioxy, morpholino, thiomorpholino, cyano or halogen groups;
• Ar.sup.3 is an aromatic group of 5 to 14 ring atoms, at least one of which is O, N or S, optionally substituted with one or more Alk.sup.1, lower cycloalkyl, lower alkoxy, CO.sub.2 H, CO.sub.2 R.sup.7, --(Alk.sup.1).sub.n --Ar.sup.1, cyano or halogen groups;
• R.sup.14 and R.sup.15 are,
• a) independently, hydrogen or --Alk.sup.2 -H, lower cycloalkyl, lower alkoxy, adamantyl, --(Alk.sup.1).sub.n -norbornyl, Ar.sup.2, Ar.sup.3, --Alk.sup.1 -substituted independently with one or more SR.sup.5, COR.sup.5, CONR.sup.5 R.sup.7, NR.sup.5 COR.sup.5, NR.sup.5 CO.sub.2 R.sup.5, NR.sup.5 CONHR.sup.5, CO.sub.2 R.sup.5, OR.sup.5, Ar.sup.2 or Ar.sup.3 groups, --(Alk.sup.1).sub.n -fluorenyl, or --(Alk.sup.1).sub.n -indanyl;
• or
• b) carbon atoms, optionally substituted with one or more lower alkyl groups, taken together with the linking nitrogen to form a 4 to 8 atom heterocyclic group ##STR31## wherein;
• Her represents --O--, --CH.sub.2 --, --S(O).sub.r --, --(NH)--or --(N(Alk.sup.1))--;
• with the proviso that
• when Z is (--Alk.sup.2 -).sub.n COR.sup.5, (--Alk.sup.2 -).sub.n CO.sub.2 R.sup.5 or --(Alk.sup.2).sub.n -CO-thiopyridyl and R.sup.5 is hydrogen, --Alk.sup.1 --H, lower cycloalkyl, --(Alk.sup.1).sub.n --Ar.sup.1, adamantyl or
• when Z is (--Alk.sup.2 -).sub.n CONR.sup.14 R.sup.15 and R.sup.14 and R.sup.15 are
• (a) independently hydrogen, --Alk.sup.2 -H, lower cycloalkyl, lower alkoxy, adamantyl, -Ar.sup.1, benzyl, diphenylmethyl, triphenylmethyl or --(Alk.sup.1).sub.n -norbornyl;
• or
• (b) carbon atoms, optionally substituted with one or more lower alkyl groups, taken together with the linking nitrogen to form a 4 to 8 atom heterocylic ring as herein before defined,
• Y is hydroxy;
• ii) Y is hydrogen and
• Z is OR.sup.5, OCOR.sup.5, OCONR.sup.14 R.sup.15, NR.sup.5 COR.sup.5, NR.sup.5 CO.sub.2 R.sup.5, NR.sup.5 CONR.sup.14 R.sup.15 or NR.sup.5 CSR.sup.14 R.sup.15 ;
• iii) Y and Z taken together are .dbd.O, .dbd.CH--(Alk.sup.1).sub.n --COR.sup.5, .dbd.CH--(Alk.sup.1).sub.n --CO.sub.2 R.sup.5 or .dbd.CH--(Alk.sup.1).sub.n --CONR.sup.14 R.sup.15 ;
• R.sup.6 is hydrogen or methyl;
• and pharmaceutically acceptable salts thereof.

A compound of formula (I):

• ##STR32## wherein R.sup.1 and R.sup.2
• i) are independently hydrogen or lower alkyl and the bond between the carbons bearing R.sup.1 and R.sup.2 is a single or a double bond, or
• ii) taken together are a --CH.sub.2 -- group forming a cyclopropane ring, and the bond between the carbons bearing R.sup.1 and R.sup.2 is a single bond;
• R.sup.3 is, hydrogen, --Alk.sup.1 --H (optionally substituted with one or more halogens), lower cycloalkyl, lower cycloalkyl-lower alkyl), halogen, --(Alk.sup.1).sub.n --CO.sub.2 H, --(Alk.sup.1).sub.n --CO.sub.2 R.sup.7, --(Alk.sup.1).sub.n --Ar.sup.1, --(Alk.sup.1).sub.n --CONR.sup.8 R.sup.9, --(Alk.sup.1).sub.n --NR.sup.8 R.sup.9, --(Alk.sup.1).sub.n --S(O).sub.r R.sup.7, --(Alk.sup.1).sub.n --CN, --(Alk.sup.1)--OH, --(Alk.sup.1).sub.n --COR.sup.7 or --(Alk.sup.1).sub.n --OR.sup.7 ;
• wherein
• Alk.sup.1 is lower alkylene, lower alkenylene or lower alkynylene,
• n is 0 or 1,
• r is 0, 1 or 2,
• R.sup.7 is --Alk.sup.1 --H, --(Alk.sup.1).sub.n --Ar.sup.1 or lower cycloalkyl,
• R.sup.8 and R.sup.9 are independently hydrogen, --Alk.sup.1 --H or lower cycloalkyl,
• Ar.sup.1 is a homocyclic aryl group of 6 to 14 carbons;
• R.sup.4 is, hydrogen, --Alk.sup.1 --H, lower cycloalkyl, lower cycloalkyl-lower alkyl, --(Alk.sup.1).sub.n --S(O).sub.r R.sup.7, --(Alk.sup.1).sub.n -phthalimidyl, --(Alk.sup.1)--CO.sub.2 H, --(Alk.sup.1).sub.n --CO.sub.2 R.sup.7, --(Alk.sup.1).sub.n --COR.sup.7, --(Alk.sup.1).sub.n --Ar.sup.1, --(Alk.sup.1).sub.n --CONR.sup.8 R.sup.9, --(Alk.sup.1).sub.n --NR.sup.8 R.sup.9, --(Alk.sup.1).sub.n --OH or --(Alk.sup.1).sub.n --OR.sup.7 ;
• X is, ##STR33## wherein R.sup.10, R.sup.11, R.sup.12 and R.sup.13 are independently hydrogen or lower alkyl, p and q are independently either 0or 1;
• and,
• i) Y is hydrogen or hydroxy and
• Z is --(Alk.sup.2).sub.n --COR.sup.5, --(Alk.sup.2).sub.n --CO.sub.2 R.sup.5, --(Alk.sup.2).sub.n --COSR.sup.5, --(Alk.sup.2).sub.n -CONR.sup.14 R.sup.15, --(Alk.sup.2)--OCO.sub.2 R.sup.5, --(Alk.sup.2)--OCOR.sup.5, --(Alk.sup.2)--OCONR.sup.14 R.sup.15, --(Alk.sup.2)--OR.sup.5, --(Alk.sup.2)--NR.sup.5 'COR.sup.5, --(Alk.sup.2)--NR.sup.5 'CO.sub.2 R.sup.5, --(Alk.sup.2)--NR.sup.5 CONR.sup.14 R.sup.15, --(Alk.sup.2).sub.n --CONR.sup.5 NR.sup.14 R.sup.15, --(Alk.sup.2).sub.n --CONR.sup.5 CONR.sup.14 R.sup.15, --(Alk.sup.2)--NR.sup.5 CSNR.sup.14 R.sup.15 or --(Alk.sup.2).sub.n --CONR.sup.5 CSNR.sup.14 R.sup.15 ;
• wherein
• Alk.sup.2 is (C.sub.1-12) alkylene, (C.sub.2-12) alkenylene or (C.sub.2-12) alkynylene, R.sup.5 and R.sup.5 ' are independently hydrogen, --Alk.sup.1 --H (optionally substituted independently with one or more CO.sub.2 H, CO.sub.2 R.sup.7, Ar.sup.2, Ar.sup.3 or cyano groups), --(Alk.sup.1).sub.n -(lower cycloalkyl (optionally substituted independently with one or more --Alk.sup.1 --H groups)), adamantyl, norbornyl, Ar.sup.2, Ar.sup.3, (lower cycloalkyl)-Ar.sup.2 or (lower cycloalkyl)-Ar.sup.3 ;
• wherein
• Ar.sup.2 is a homocyclic aromatic group of 6 to 14 carbon ring atoms (optionally substituted independently with one or more --Alk.sup.2 -H (optionally substituted independently with one or more halogens), --(Alk.sup.1).sub.n --OH, --(Alk.sup.1).sub.n --OR.sup.16, --(Alk.sup.1).sub.n --Ar.sup.3, --(Alk.sup.1).sub.n --CO.sub.2 H, --(Alk.sup.1).sub.n --CO.sub.2 R.sup.7, S(O).sub.r R.sup.7, NR.sup.8 S(O).sub.r R.sup.16, NR.sup.8 R.sup.9, CONR.sup.8 R.sup.9, lower cycloalkyl, lower alkoxy, --(Alk.sup.1).sub.n --Ar.sup.1, methylenedioxy, ethylenedioxy, morpholino, thiomorpholino, cyano, nitro or halogens);
• wherein
• R.sup.16 is --Alk.sup.1 --H (optionally substituted independently with one or more halogens), lower cycloalkyl (optionally substituted independently with one or more halogens, or --Alk.sup.1 --H (optionally substituted independently with one or more halogens)) or --(Alk.sup.1).sub.n --Ar.sup.1 (wherein Ar.sup.1 is optionally substituted independently with one or more, lower alkoxy, cyano groups, halogens or --Alk.sup.1 --H (optionally substituted independently with one or more halogens));
• Ar.sup.3 is an aromatic group of 5 to 14 ring atoms, at least one of which is O, N or S, (optionally substituted independently with one or more --Alk.sup.1 --H (optionally substituted independently with one or more halogens), lower cycloalkyl, lower alkoxy, CO.sub.2 H, CO.sub.2 R.sup.7, --(Alk.sup.1).sub.n -Ar.sup.1, cyano or halogen);
• R.sup.14 and R.sup.15 are,
• a) independently, hydroxy, hydrogen, --Alk.sup.2 - H, lower cycloalkyl (optionally substituted independently with one or more cyano, R.sup.16, Ar.sup.2, Ar.sup.3), lower alkoxy, --(Alk.sup.1).sub.n -adamantyl, --(Alk.sup.1).sub.n -myrantyl, --(Alk.sup.1).sub.n -norbornyl, --(Alk.sup.1).sub.n -fluorenyl, --(Alk.sup.1).sub.n -indanyl, --Alk.sup.1 --H (optionally substituted independently with one or more, halogens, cyano, cycloalkyl, SR.sup.5, COR.sup.5, CONR.sup.5 R.sup.7, NR.sup.5 'COR.sup.5, NR.sup.5 'CO.sub.2 R.sup.5, NR.sup.5 'CONHR.sup.5, CO.sub.2 R.sup.5, OR.sup.5, Ar.sup.2 or Ar.sup.3), Ar.sup.2 or Ar.sup.3 ;
• b) alkylene groups (optionally substituted with one or more R.sup.7 groups, taken together with the linking nitrogen to form a 4 to 8 atom heterocyclic group) ##STR34## wherein;
• Her represents --O--, --CH.sub.2 --, --S(O).sub.r --, --(NH)-- or --(N(Alk.sup.1 --H))--;
• with the proviso that
• when Z is --(Alk.sup.2).sub.n --COR.sup.5, --(Alk.sup.2).sub.n --CO.sub.2 R.sup.5 or --(Alk.sup.2).sub.n --CO-thiopyridyl and
• R.sup.5 is hydrogen, --Alk.sup.1 --H, lower cycloalkyl, --(Alk.sup.1).sub.n --Ar.sup.1, adamantyl or
• when Z is --(Alk.sup.2).sub.n --CONR.sup.14 R.sup.15 and
• R.sup.14 and R.sup.15 are
• a) independently hydrogen, --Alk.sup.2 -H, lower cycloalkyl, lower alkoxy, adamantyl, --Ar.sup.1, benzyl, diphenylmethyl, triphenylmethyl or --(Alk.sup.1).sub.n -norbornyl;
• or
• b) carbon atoms, optionally substituted with one or more lower alkyl groups, taken together with the linking nitrogen to form a 4 to 8 atom heterocylic ring as herein before defined,
• Y is hydroxy;
• or
• ii) Y is hydrogen and
• Z is OR.sup.5, OCOR.sup.5, OCONR.sup.14 R.sup.15, NR.sup.5 'COR.sup.5 'NR.sup.5 'CO.sub.2 R.sup.5, NR.sup.5 CONR.sup.14 R.sup.15 or NR.sup.5 CSR.sup.14 R.sup.15 ;
• and
• iii) Y and Z taken together are
• .dbd.O, .dbd.CH--(Alk.sup.1).sub.n --COR.sup.5, .dbd.CH--(Alk.sup.1).sub.n --CO.sub.2 R.sup.5 or
• .dbd.CH--(Alk.sup.1).sub.n --CONR.sup.14 R.sup.15 ;
• R.sup.6 is, hydrogen or methyl;
• and pharmaceutically acceptable salts thereof.