17-beta-hydroxysteroid dehydrogenase-II inhibitors

A method of treating a mammal having a condition of osteoporosis, osteopenia, ovarian cancer, breast cancer, endometrial cancer, endometriosis, prostate cancer, acne, androgen-dependent hair loss, non-insulin-dependent diabetes mellitus, or hypercholesterolemia comprising administering to said mammal an effective amount of a compound having the formula

• wherein
• the phenyl group labeled A and the group —C(R4)(R6)Y are oriented cis to each other;
• W represents O or S;
• R1 represents
• —H;
• or
• —(C1-C4)alkyl which is optionally substituted with up to three halogens;
• n represents 0 or an integer of 1-3;
• R2 represents
• —N(R3)2,
• —OR3,
• —SR3,
• -halogen,
• -phenyl which is optionally substituted with halogen up to perhalo, or
• —(C1-C4)alkyl which is optionally substituted with halogen, —OR3, or SR3;
• the number of said substituents being up to three for halogen, and up to two for any combination of said —OR3 and —SR3 moieties;
• and wherein
• R3 represents —H or —(C1-C4)alkyl which is optionally substituted with up to three halogens;
• R4 represents —H or a bond terminating at the ortho position of phenyl ring A;
• Y represents fluorine, —OR5, or —SR5;
• wherein
• R5 represents
• —H;
• —(C1-C4)alkyl optionally substituted with up to three halogens;
• -phenyl which is optionally substituted with halogen, —OR3A, —SR3A, or —R3A, the number of said substituents being up to perhalo for halogen, and up to two for any combination of said —OR3A, —SR3A, and —R3A moieties;
• wherein
• R3A represents —(C1-C4)alkyl optionally substituted with up to three halogens;
• and
• with the proviso that R5 may represent an optionally substituted phenyl group only if R6 represents H;
• —(C1-C4)alkyl-phenyl in which the alkyl portion is optionally substituted with up to three halogens;
• and the phenyl portion is optionally substituted with halogen, —OR3A, —SR3A, or —R3A, the number of substituents on said phenyl portion being up to perhalo for halogen, and up to two for any combination of said —OR3A, —SR3A, and —R3A moieties;
• or
• —(C1-C4)acyl optionally substituted with up to three halogens;
• R6 represents
• 1) —H;
• with the proviso that when R6 is H, then Y is OR5 wherein R5 is phenyl which is optionally substituted with halogen, —OR3A, —SR3A, or —R3A;
• the number of said substituents being up to perhalo for halogen, and up to two for any combination of said —OR3A, —SR3A, and —R3A moieties;
• 2)
• wherein
• m represents 0 or an integer of 1-3;
• X represents O or S;
• R8 represents
• a) —(C6-C10)aryl, which is optionally substituted with one or more substituents selected from
• -halogen,
• —N(R3)2;
• —OR3;
• —SR3;
• —CO2R3;
• —NO2;
• ——CN;
• —(C1-C6)alkyl optionally substituted with up to three halogens;
• -phenyl which is optionally substituted with halogen, —OR3A, —SR3A, or
• —R3A;
• the number of said substituents being up to perhalo for halogen, and up to two for any combination of said —OR3A, —SR3A, and —R3A moieties;
• -heteroaryl of 5 members and containing 1-2 heteroatoms selected from N, O, and S;
• —NHCOR9;
• in which
• R9 represents R3A or -phenyl which is optionally substituted with halogen up to perhalo;
• —NHCONHR9;
• and
• —NHSO2R9;
• the number of substituents on said (C6-C10)aryl group being up to perhalo for halogen, and up to three for any combination of said —N(R3)2, —OR3, —SR3, —CO2R3, —NO2, —CN, —(C1-C6)alkyl, -phenyl, -heteroaryl, —NHCOR9, —NHCONHR9, and —NHSO2R9 moieties;
• b) -heteroaryl of 5-10 members and containing 1-3 heteroatoms selected from
• N, O, and S;
• and being optionally substituted with halogen, —N(R3)2, —OR3A, —SR3A, —CO2R3, —NO2, —CN, or —(C1-C6)alkyl which is optionally substituted with up to three halogens;
• the number of said substituents on the heteroaryl group being up to perhalo for halogen, and up to two for any combination of said —N(R3)2, —OR3A, —SR3A, —CO2R3, —NO2, —CN, and —(C1-C6)alkyl moieties;
• c) —(C2)alkynyl-R10 wherein
• R10 represents H;
• R3A;
• or -phenyl which is optionally substituted with halogen, —OR3, —SR3, or —R3A;
• the number of said substituents being up to perhalo for halogen, and up to two for any combination of said —OR3, —SR3, and —R3A moieties;
• d) —(C1-C4)alkyl-R11 wherein
• the alkyl portion is optionally substituted with halogen, —OR3, or —SR3;
• the number of said substituents being up to three for halogen, and up to two for any combination of said —OR3 and —SR3 moieties;
• and
• R11 represents
• —H, provided that m is 2 or 3;
• or
• -phenyl optionally substituted with halogen up to perhalo;
• e) —S(O)0-2R12 wherein
• R12 represents
• —(C1-C6)alkyl optionally substituted with halogen;
• wherein
• Z represents O, S(O)0-2, C(R3)2, or NR13 wherein
• R13 represents R3A;
• or -phenyl which is optionally substituted with halogen, —OR3A, SR3A, or —(C1-C2)alkyl optionally substituted with up to three halogens;
• the number of said substituents on phenyl being up to perhalo for halogen, and up to two for any combination of said —OR3A, SR3A, and —(C1-C2)alkyl moieties;
• -phenyl, optionally substituted with halogen, —OR3 or —R3A;
• the number of said substituents being up to perhalo for halogen, and up to two for any combination of said —OR3 and —R3A moieties;
• or
• -heteroaryl of 5-6 members and containing 1-3 heteroatoms selected from N, O, and S;
• f) —C(R14)═CHR14 wherein
• R14 represents H;
• -halogen;
• —OR3A;
• or phenyl optionally substituted with halogen or with —R3A;
• the number of said substituents being up to perhalo for halogen, and up to two for —R3A moieties;
• and
• with the proviso that when 2 such alkenyl groups are adjacent to each other, they may be joined, and taken together with the ring atoms to which they are attached, constitute a fused 6-membered ring;
• g)
• optionally substituted with halogen, —OR3A or
• —(C1-C6)alkyl optionally substituted with up to three halogens;
• the number of said substituents on phenyl being up to perhalo for halogen, and up to two for any combination of said —OR3A or —(C1-C6)alkyl moieties;
• h)
• wherein the phenyl ring is optionally substituted with halogen, —OR3A, or —(C1-C6)alkyl optionally substituted with up to three halogens;
• the number of said substituents on phenyl being up to perhalo for halogen, and up to two for any combination of said —OR3A and —(C1-C6)alkyl moieties;
• i)
• wherein the heteroaryl ring contains 5-6 members and up to 3 heteroatoms selected from N, O, and S, and is optionally substituted with up to 2 substitutents R3A;
• 3) —(C1-C4)alkyl-R15 wherein
• the alkyl portion is optionally substituted with up to three halogens;
• and
• R15 represents
• -phenyl optionally substituted with halogen, —R3A, —OR3A, or with -phenyl′ optionally substituted with halogen up to perhalo;
• the number of said substituents on said phenyl being up to perhalo for halogen, and up to two for any combination of said —R3A, —OR3A, or -phenyl′ moieties;
• or
• a heteroaryl ring of 5-6 members and containing up to 3 heteroatoms selected from N, O, and S, and optionally bearing up to 2 substituents selected from halogen, —R3A, —OR3A, and -phenyl optionally substituted with halogen up to perhalo;
• 4) —CH═CH—(C6-C10)aryl-(R16)s wherein
• s represents 0 or an integer of 1-4;
• R16 represents a substituent selected from halogen, —R3A, —N(R3)2, —OR3A, —SR3A, —NO2, and —CO2R3;
• 5) —CH═CH-heteroaryl wherein the heteroaryl ring contains 5-6 members and up to 3 heteroatoms selected from N, O, and S;
• and is optionally substituted with R3A;
• 6)
• optionally substituted with halogen, —R3A;
• —N(R3)2;
• —OR3A;
• —SR3A;
• —NO2;
• —CO2R3;
• phenyl′ optionally substituted with halogen up to perhalo;
• and -heteroaryl of 5-6 members and containing up to 3 heteroatoms selected from N, O, and S and optionally substituted with up to 2 substituents R3A;
• the number of said substituents on phenyl being up to perhalo for halogen, and up to two for any combination of said —R3A;
• —N(R3)2;
• —OR3A;
• —SR3A:
• —NO2;
• —CO2R3;
• and phenyl′ moieties;
• 7) —C≡C-heteroaryl wherein the heteroaryl ring contains 5-6 members and up to 3 heteroatoms selected from N, O, and S, and is optionally substituted with up to 2 substituents R3A;
• 8) —C═C—CH2—R12
• 9) phenyl, optionally substituted with halogen up to perhalo, this phenyl being also optionally substituted with up to 2 substituents selected from -phenyl′, optionally substituted with halogen, —NHCOR3, —N(R3)2, —OR3, or —NO2;
• the number of said substituents being up to perhalo for halogen, and up to two for any combination of said —NHCOR3, —N(R3)2, —OR3, and —NO2 moieties;
• -heteroaryl of 5-6 members and containing up to 3 heteroatoms selected from N, O, and S;
• —R3A;
• —OR3;
• —SR3;
• —N(R3)2;
• and
• —CF3;
• 10)
• wherein
• s′ represents 0, 1, or 2;
• and
• R17 represents halogen;
• R3A;
• —OR3;
• or —N(R3)2;
• 11)
• 12)
• and with the further provisos that:
• an aliphatic carbon atom attached to oxygen may not also bear a halogen substituent;
• when any alkyl group is attached to O, S, or N, and bears a hydroxyl substituent, then said hydroxyl substituent is separated by at least two carbon atoms from the O, S, or N to which the alkyl group is attached;
• and
• two alkyl groups located on the same N atom they may be linked by a bond, an O, an S, or NR3 to form a N-containing heterocycle of 5-7 ring atoms;
• or a pharmaceutically acceptable salt thereof or N-oxide thereof.