4-Aza-17β-substituted-5α-androstan-3-one-reductase inhibitors

Claim 1

A compound of the formula: ##STR31## where Formula (I) may also have the structure of partial Formulas (II) and/or (III); wherein, A is (1) --CH 2 --CH 2 --; (2) --CH═CH--; (3) ##STR32## or (4) ##STR33## B is (1) ##STR34## where R 1 is, (a) hydrogen; (b) methyl or ethyl; (c) ethenyl; (d) ethynyl; (e) NR 2 R 3 where R 2 and R 3 are hydrogen or methyl; or (f) cyano; or (2) ##STR35## where X.sup.⊖ is any anion and R 4 is, (a) OR 5 where R 5 is C 1-4 alkyl; or (b) NR 6 R 7 , where R 6 and R 7 are hydrogen or methyl; R' is hydrogen or methyl; R" is hydrogen or β-methyl; R"' is hydrogen, β-methyl or hydroxyl; Z is (1) α-hydrogen or α-hydroxyl and (a) ##STR36## where AlK is present or absent and is straight or branched hydrocarbon chain of 1 to 12 carbon atoms; and R 8 is, (i) hydrogen, (ii) hydroxyl, (iii) C 1-4 alkyl (iv) NR 9 R 10 , where R 9 and R 10 are each independently selected from hydrogen, C 1-8 straight or branched chain alkyl, C 3-6 cycloalkyl, phenyl; or R 9 and R 10 taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen; or (v) OR 11 , where R 11 is M, where M is hydrogen or alkali metal, or C 1-18 straight or branched chain alkyl; benzyl; or (b) Alk-OR 12 , where Alk is always present and has the same meaning as above, and R 12 is (i) phenyl C 1-6 alkylcarbonyl, (ii) C 5-10 cycloalkylcarbonyl, (iii) benzoyl, or (iv) C 1-8 alkoxycarbonyl; (v) amino, or C 1-8 alkyl substituted amino, carbonyl; or (vi) hydrogen, provided that Alk is a branched C 3 -C 8 chain; (2) ##STR37## or CH-Alk-OR 12 , where Alk is present or absent and has the same meaning as above, and R 8 and R 12 have the same meaning as above, and R 12 is also hydrogen or C 1-20 alkylcarbonyl; (3) ##STR38## where the dashed bond replaces the 17α hydrogen; (4) α-hydrogen and ##STR39## where R 13 is, (a) C 1-12 alkyl; or (b) NR 9 R 10 ; (5) α-hydrogen and cyano; or (6) α-hydrogen and tetrazolyl; and pharmaceutically acceptable salts of the above compounds.

Claim 15

A method of treating the hyperandrogenic conditions of acne vulgaris, seborrhea, female hirsutism and benign prostatic hypertrophy comprising parenteral administration to a patient in need of such treatment of a therapeutically effective amount of a compound of formula: ##STR42## where Forumla (I) may also have the structure of partial Formulas (II) and/or (III); wherein, A is (1) --CH 2 --CH 2 --; (2) --CH═CH--; (3) ##STR43## or (4) ##STR44## B is (1) ##STR45## where R 1 is, (a) hydrogen; (b) methyl or ethyl; (c) ethenyl; (d) ethynyl; (e) NR 2 R 3 where R 2 and R 3 are hydrogen or methyl; or (f) cyano; or (2) ##STR46## where X 63 is any anion and R 4 is, (a) OR 5 where R 5 is C 1-4 alkyl; or (b) NR 6 R 7 , where R 6 and R 7 are hydrogenor methyl; R' is hydrogen or methyl; R" is hydrogen or β-methyl; R"' is hydrogen, β-methyl or hydroxyl; Z is (1) α-hydrogen or α-hydroxyl and (a) ##STR47## where Alk is present or absent and is straight or branched hydrocarbon chain of 1 to 12 carbon atoms; and R 8 is, (i) hydrogen, (ii) hydroxyl, (iii) C 1-4 alkyl (iv) NR 9 R 10 , where R 9 and R 10 are each independently selected from hydrogen, C 1-4 straight or branched chain alkyl, C 3-6 cycloalkyl, phenyl; or R 9 and R 10 taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen; or (v) OR 11 , where R 11 is M, where M is hydrogen or alkali metal, or C 1-18 straight or branched chain alkyl; benzyl; or (b) Alk-OR 12 , where Alk is always present and has the same meaning as above, and R 12 is (i) phenyl C 1-6 alkylcarbonyl, (ii) C 5-10 cycloalkylcarbonyl, (iii) benzoyl, or (iv) C 1-8 alkoxycarbonyl; (v) amino, or C 1-8 alkyl substituted amino, carbonyl; or (vi) hydrogen, provided that Alk is a branched C 3 -C 8 chain; (2) ##STR48## or CH-Alk-OR 12 , where Alk is present or absent and has the same meaning as above, and R 8 and R 12 have the same meaning as above, and R 12 is also hydrogen or C 1-20 alkylcarbonyl; (3) ##STR49## where the dashed bond replaces the 17α hydrogen; (4) α-hydrogen and ##STR50## where R 13 is, (a) C 1-12 alkyl; or (b) NR 9 R 10 ; (5) α-hydrogen and cyano; or (6) α-hydrogen and tetrazolyl; and pharmaceutically acceptable salts of the above compounds.

Claim 16

A method of treating the hyperandrogenic conditions of acne vulgaris, seborrhea, female hirsutism and benign prostatic hypertrophy comprising parenteral administration to a patient in need of such treatment of a therapeutically effective amount of a compound of formula: ##STR42## where Forumla (I) may also have the structure of partial Formulas (II) and/or (III); wherein, A is (1) --CH 2 --CH 2 --; (2) --CH═CH--; (3) ##STR43## or (4) ##STR44## B is (1) ##STR45## where R 1 is, (a) hydrogen; (b) methyl or ethyl; (c) ethenyl; (d) ethynyl; (e) NR 2 R 3 where R 2 and R 3 are hydrogen or methyl; or (f) cyano; or (2) ##STR46## where X 63 is any anion and R 4 is, (a) OR 5 where R 5 is C 1-4 alkyl; or (b) NR 6 R 7 , where R 6 and R 7 are hydrogenor methyl; R' is hydrogen or methyl; R" is hydrogen or β-methyl; R"' is hydrogen, β-methyl or hydroxyl; Z is (1) α-hydrogen or α-hydroxyl and (a) ##STR47## where Alk is present or absent and is straight or branched hydrocarbon chain of 1 to 12 carbon atoms; and R 8 is, (i) hydrogen, (ii) hydroxyl, (iii) C 1-4 alkyl (iv) NR 9 R 10 , where R 9 and R 10 are each independently selected from hydrogen, C 1-4 straight or branched chain alkyl, C 3-6 cycloalkyl, phenyl; or R 9 and R 10 taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen; or (v) OR 11 , where R 11 is M, where M is hydrogen or alkali metal, or C 1-18 straight or branched chain alkyl; benzyl; or (b) Alk-OR 12 , where Alk is always present and has the same meaning as above, and R 12 is (i) phenyl C 1-6 alkylcarbonyl, (ii) C 5-10 cycloalkylcarbonyl, (iii) benzoyl, or (iv) C 1-8 alkoxycarbonyl; (v) amino, or C 1-8 alkyl substituted amino, carbonyl; or (vi) hydrogen, provided that Alk is a branched C 3 -C 8 chain; (2) ##STR48## or CH-Alk-OR 12 , where Alk is present or absent and has the same meaning as above, and R 8 and R 12 have the same meaning as above, and R 12 is also hydrogen or C 1-20 alkylcarbonyl; (3) ##STR49## where the dashed bond replaces the 17α hydrogen; (4) α-hydrogen and ##STR50## where R 13 is, (a) C 1-12 alkyl; or (b) NR 9 R 10 ; (5) α-hydrogen and cyano; or (6) α-hydrogen and tetrazolyl; and pharmaceutically acceptable salts of the above compounds.

Claim 18

A method of inhibiting testosterone-5α-reductase in a patient in need of such inhibiting treatment, comprising administration to such a patient of a therapeutically effective amount of a compound of the formula: ##STR53## where Formula (I) may also have the structure of partial Formulas (II) and/or (III); wherein, A is (1) --CH 2 --CH 2 --; (2) --CH═CH--; (3) ##STR54## or (4) ##STR55## B is (1) ##STR56## where R 1 is, (a) hydrogen; (b) methyl or ethyl; (c) ethenyl; (d) ethynyl; (e) NR 2 R 3 where R 2 and R 3 are hydrogen or methyl; or (f) cyano; or (2) ##STR57## where X.sup.⊖ is any anion and R 4 is, (a) OR 5 where R 5 is C 1-4 alkyl; or (b) NR 6 R 7 , where R 6 and R 7 are hydrogen or methyl; R' is hydrogen or methyl; R" is hydrogen or β-methyl; R"' is hydrogen, β-methyl or hydroxyl; Z is (1) α-hydrogen or α-hydroxyl and (a) ##STR58## where Alk is present or absent and is straight or branched hydrocarbon chain of 1 to 12 carbon atoms; and R 8 is, (i) hydrogen, (ii) hydroxyl, (iii) C 1-4 alkyl (iv) NR 9 R 10 , where R 9 and R 10 are each independently selected from hydrogen, C 1-4 straight or branched chain alkyl, C 3-6 cycloalkyl, phenyl; or R 9 and R 10 taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen; or (v) OR 11 , where R 11 is M, where M is hydrogen or alkali metal, or C 1-18 straight or branched chain alkyl; benzyl; or (b) Alk-OR 12 , where Alk is always present and has the same meaning as above, and R 12 is (i) phenyl C 1-6 alkylcarbonyl, (ii) C 5-10 cycloalkylcarbonyl, (iii) benzoyl, or (iv) C 1-8 alkoxycarbonyl; (v) amino, or C 1-8 alkyl substituted amino, carbonyl; or (vi) hydrogen, provided that Alk is a branched C 3-C 8 chain; (2) ##STR59## or CH-Alk-OR 12 , where Alk is present or absent and has the same meaning as above, and R 8 and R 12 have the same meaning as above, and R 12 is also hydrogen or C 1-20 alkylcarbonyl; (3) ##STR60## where the dashed bond replaces the 17α hydrogen; (4) α-hydrogen and ##STR61## where R 13 is, (a) C 1-12 alkyl; or (b) NR 9 R 10 ; (5) α-hydrogen and cyano; or (6) α-hydrogen and tetrazolyl; and pharmaceutically acceptable salts of the above compounds.

Claim 19

A method of inhibiting testosterone-5α-reductase in a patient in need of such inhibiting treatment, comprising administration to such a patient of a therapeutically effective amount of a compound of the formula: ##STR53## where Formula (I) may also have the structure of partial Formulas (II) and/or (III); wherein, A is (1) --CH 2 --CH 2 --; (2) --CH═CH--; (3) ##STR54## or (4) ##STR55## B is (1) ##STR56## where R 1 is, (a) hydrogen; (b) methyl or ethyl; (c) ethenyl; (d) ethynyl; (e) NR 2 R 3 where R 2 and R 3 are hydrogen or methyl; or (f) cyano; or (2) ##STR57## where X.sup.⊖ is any anion and R 4 is, (a) OR 5 where R 5 is C 1-4 alkyl; or (b) NR 6 R 7 , where R 6 and R 7 are hydrogen or methyl; R' is hydrogen or methyl; R" is hydrogen or β-methyl; R"' is hydrogen, β-methyl or hydroxyl; Z is (1) α-hydrogen or α-hydroxyl and (a) ##STR58## where Alk is present or absent and is straight or branched hydrocarbon chain of 1 to 12 carbon atoms; and R 8 is, (i) hydrogen, (ii) hydroxyl, (iii) C 1-4 alkyl (iv) NR 9 R 10 , where R 9 and R 10 are each independently selected from hydrogen, C 1-4 straight or branched chain alkyl, C 3-6 cycloalkyl, phenyl; or R 9 and R 10 taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen; or (v) OR 11 , where R 11 is M, where M is hydrogen or alkali metal, or C 1-18 straight or branched chain alkyl; benzyl; or (b) Alk-OR 12 , where Alk is always present and has the same meaning as above, and R 12 is (i) phenyl C 1-6 alkylcarbonyl, (ii) C 5-10 cycloalkylcarbonyl, (iii) benzoyl, or (iv) C 1-8 alkoxycarbonyl; (v) amino, or C 1-8 alkyl substituted amino, carbonyl; or (vi) hydrogen, provided that Alk is a branched C 3-C 8 chain; (2) ##STR59## or CH-Alk-OR 12 , where Alk is present or absent and has the same meaning as above, and R 8 and R 12 have the same meaning as above, and R 12 is also hydrogen or C 1-20 alkylcarbonyl; (3) ##STR60## where the dashed bond replaces the 17α hydrogen; (4) α-hydrogen and ##STR61## where R 13 is, (a) C 1-12 alkyl; or (b) NR 9 R 10 ; (5) α-hydrogen and cyano; or (6) α-hydrogen and tetrazolyl; and pharmaceutically acceptable salts of the above compounds.