Inhibitors of sex steroid biosynthesis and methods for their production and use

A method for inhibiting sex steroid formation comprising administering to a warm-blooded patient in need of such inhibition, a therapeutically effective amount of a compound of the formula:

• ##STR25## wherein the dotted lines represent optional double bonds;
• wherein the A-ring is optionally aromatic;
• wherein R.sub.1, R.sub.2 and R.sub.4 are independently selected from the group consisting of hydrogen, hyroxyl, alkylsulfonyl(lower)alkoxy, arylsulfonyl(lower)alkoxy, halogen, lower alkyl, lower alkoxy, lower alkylsilyl, amino and nitro;
• wherein R.sub.3 is selected from the group consisting of hydrogen, hydroxyl, halogen, lower alkyl, methoxy, ethoxy, propoxy, hydroxyethoxy, lower alkoxy, acetoxy, propionyloxy, butyryloxy, oenanthoyloxy, cypionoyloxy, trans-4-n-butyl-cyclohexanecarbonoyloxy, (C.sub.2 -C.sub.20)alkanoyloxy, lower alkoxy carbonyloxy, carboxy, (C.sub.3 -C.sub.20)alkenoyloxy, (C.sub.3 -C.sub.20)alkynoyloxy, (C.sub.7 -C.sub.10)aroyloxy or a divalent common species formed jointly by R.sub.3.sbsb.(.alpha.) and R.sub.3.sbsb.(.beta.), said divalent common speices being selected from the group consisting of .dbd.O, .dbd.S, .dbd.NR.sub.36 or .dbd.NOR.sub.36 wherein R.sub.36 is hydrogen or lower alkyl;
• wherein R.sub.5 and R.sub.10 are absent or selected from the group consisting of hydrogen and lower alkyl;
• wherein R.sub.6 is selected from the group consisting of hydrogen, halogen, lower alkyl, amino and nitrile;
• wherein R.sub.7 is in .alpha. position and is hydrogen, hydroxyl, halogen, lower alkyl, lower alkoxy, lower alkylsilyl, amino, nitrile, nitro, nitroso, alkylsulfonyl, arylsulfonyl, lower alkylamino, dilower alkylamino, or is represented by the formula A.sup.1 -[Y-A.sup.11 ].sub.u --X--R.sub.21, wherein:
• u is an integer from 0 to 5;
• wherein A.sup.1 and A.sup.11 may be the same or different and are selected from the group consisting of a bond, straight- or branched-chain alkylene, straight- or branched-chain alkynylene, straight- or branched-chain alkenylene, and fluoro-substituted analogs of the foregoing, wherein R.sup.1 and A.sup.1 1 together have a total of from 3 to 30 carbon atoms, and Y is selected from the group consisting of --O--, --S--, --Se--, --SO--, --SO.sub.2 --, --CO--, --NR.sub.22 --, --SiR.sub.22 R.sub.22 --, --CR.sub.22 OR.sub.22 --NR.sub.22 CO--, --NR.sub.22 CS--, --CONR.sub.22 --, --CSNR.sub.22 --, --COO--, --COS--, --SCO--, --CSS--, --SCS--, --OCO-- and phenylene (R.sub.22 being hydrogen or lower alkyl);
• R.sub.21 is selected from the group consisting of hydrogen, straight- or branched-chain lower alkyl, lower alkenyl or lower alkynyl, (C.sub.3 -C.sub.7)cycloalkyl, halogeno(lower)alkyl, carboxy(lower)alkyl, (lower)alkoxycarbonyl(lower)alkyl, (C.sub.6 -C.sub.10)aryl, (C.sub.7 -C.sub.11)arylalkyl, di(lower)alkylamino(lower)alkyl and fluoro-substituted analogs of the foregoing, and wherein X is --CONR.sub.23 --, --CSNR.sub.23 --, --NR.sub.24 CO--, --NR.sub.24 CS--, --NR.sub.24 CONR.sub.23 --, ##STR26## --SO.sub.2 NR.sub.23 --, --CSS--, --SCS--, --NR.sub.23 --, --(NO)R.sub.23 --, --(PO)R.sub.23 --, --NR.sub.24 CO--, --NR.sub.24 SO.sub.2 --, --S--, --SO-- or --SO.sub.2 --, (wherein R.sub.23 is selected from the group consisting of hydrogen, lower alkyl, and a species which, together with R.sub.21, forms a saturated or unsaturated heterocyclic ring having at least one nitrogen atom and, optionally, a second heteroatom selected from the group consisting of oxygen, sulfur, silicon, selenium, nitrogen and fluoro-substituted analogs of the foregoing, wherein R.sub.24 is hydrogen or lower alkyl and wherein R.sub.25 is hydrogen, nitrile or nitro) (XR.sub.21 may form a tetrazole ring);
• wherein R.sub.11 is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, (C.sub.6 -C.sub.10)aryl, alkylsulfonyl, arylsulfonyl, a substituted 5-to-7 member heterocyclic ring having at least one heteroatom (selected from oxygen, sulfur, silicon, selenium, nitrogen), --(CH.sub.2).sub.s W (wherein W is nitrile, hydroxyl, azido, nitroso, nitro, thionitrile, halogen, alkylsulfonyl or arylsulfonyl, and s is an integer from 1 to 6), OR.sub.26 (wherein R.sub.26 is hydrogen, lower alkyl or (C.sub.6 -C.sub.10)aryl), DR.sub.27 (wherein D is --Se--, --NR.sub.26, --S-- or --O--, and R.sub.27 is hydrogen, lower alkyl), .dbd.O, .dbd.S, .dbd.Se, .dbd.NR.sub.28 (wherein R.sub.28 is hydrogen or lower alkyl;
• wherein R.sub.12 and R.sub.13 are independently hydrogen or lower alkyl;
• wherein R.sub.14 is selected from the group consisting of hydrogen, hydroxyl, nitrile, nitro, nitroso, halogen, lower alkyl, lower alkoxy, lower alkyseleno, lower alkylamino or diloweralkylamino;
• or R.sub.14 and R.sub.15 together are --CH.sub.2 --, --CHX--, --CX.sub.2 --, (X=halogen, carboxyl or alkoxycarbonyl), --O--, --S--, --Se--, >N-CN, >NR.sub.29 and >NCO.sub.2 R.sub.29 wherein R.sub.29 is hydrogen or lower alkyl;
• wherein R.sub.15 is selected from the group consisting of hydrogen, hydroxyl, nitro, nitroso, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkylseleno, lower alkylamino, di(lower)alkylamino, nitrile, azido, arylseleno, AXR.sub.21, A.sub.1 -[Y-A.sup.11 ].sub.u -X-R.sub.21 or R.sub.15 and R.sub.16 together are --CH.sub.2 --, --CHX--, --CX.sub.2 --, (X=halogen, carboxyl or alkoxycarbonyl), --O--, --S--, --Se--, >N-CN, >NR.sub.29 and >NCO.sub.2 R.sub.29 wherein R.sub.29 is hydrogen or lower alkyl;
• wherein R.sub.16 is selected from the group consisting of hydrogen, nitroso, halogen, lower alkyl, carboxyl, lower alkoxy, lower alkylseleno, lower alkylamino, nitrile, azido, arylseleno, lower alkylseleno, di(lower)alkylamino, AXR.sub.21, or A.sup.1 -[Y-A.sup.11 ].sub.u -X-R.sub.21,
• R.sub.16.sbsb.(.alpha.) and R.sub.16.sbsb.(.beta.) together are .dbd.CG.sub.2, where G is hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, nitrile, alkoxycarbonyl, alkylcarbonyl and carboxyl;
• wherein R.sub.17.sbsb.(.alpha.) is selected from the group consisting of hydrogen, hydroxyl, lower alkyl, halogeno(lower)alkyl, AXR.sub.2, A.sup.1 -[Y-A.sup.11 ].sub.u X-R.sub.21, B.sup.1 -T-R.sub.30 wherein:
• B.sup.1 is straight- or branched-chain (C.sub.1 -C.sub.12)alkylene, (C.sub.2 -C.sub.12)alkynylene, (C.sub.2 -C.sub.12)alkenylene;
• T is --O--, --NR.sub.31, --Se--, --S-- or S-S and R.sub.30 and R.sub.31 are independently hydrogen, lower alkyl, or R.sub.30 and R.sub.31, together are (C.sub.3 -C.sub.7)cycloalkyl, (C.sub.5 -C.sub.7)cycloalkenyl, (C.sub.3 -C.sub.7)cycloalkyl or (C.sub.5 -C.sub.7)cycloalkenyl having one or more hydrogen atoms replaced by halogen atoms, --HC.dbd.CHR.sub.32 and --C.tbd.CR.sub.33 wherein:
• R.sub.32 and R.sub.33 are independently hydrogen, halogen, tri(lower)alkylsilyl, carboxyl, carbonyl, lower alkoxy, nitrile, sulfinyl lower alkyl, AXR.sub.21, A.sup.1 -[Y-A.sup.11 ].sub.u -X-R.sub.21 or a species represented by the formula:
• ##STR27## wherein n and m are independently 0 to 6 and Q is --Se--, --SiH.sub.2 --, --S--, --O-- or --NR.sub.34 -- wherein R.sub.34 is hydrogen, lower alkyl or (C.sub.1 -C.sub.7)alkanoyl;
• or a species represented by the formula:
• ##STR28## wherein q is --CH.sub.2 --, --S--, --O-- or --NR.sub.35 -- wherein R.sub.35 is hydrogen or lower alkyl;
• wherein R.sub.17.sbsb.(.beta.) is selected from the group consisting of hydrogen, hydroxyl, halogen, 1-oxo-2-propoynyl, 1-hydroxy-2-propynyl, alkoxy, (C.sub.1 -C.sub.17)alkanoyloxy, (C.sub.3 -C.sub.7)alkenyloxy, (C.sub.3 -C.sub.7)alkynoyloxy, alkenyloxy, cycloalkenyloxy, 1-alkyloxy-alkyloxy, 1-alkyloxy cycloalkyloxy, alkylsilyloxy and a divalent common species formed jointly by R.sub.17.sbsb.(.alpha.) and R.sub.17.sbsb.(.beta.), said divalent common species being selected from the group consisting of .dbd.O, .dbd.S, .dbd.NR.sub.36 or .dbd.NOR.sub.36 wherein R.sub.36 is hydrogen or lower alkyl, wherein at least one or R.sup.7, R.sup.16 or R.sup.17 is A.sup.1 -[Y-A.sup.11 -].sub.u XR.sup.21.