Claims for Patent: 4,377,584

Summary for Patent: 4,377,584

Title:	4-Aza-17β-substituted-5α-androstan-3-one-reductase inhibitors
Abstract:	4-Aza-17 beta -substituted-5 alpha -androstan-3-ones and their A-homo analogs of the formula: where Formula (I) may also have the structure of partial Formulas (II) and/or (III); and pharmaceutically acceptable salts of the above compounds are active as testosterone 5 alpha -reductase inhibitors, and thus useful topically for treatment of acne, seborrhea, female hirsutism, and systemically in treatment of benign prostatic hypertrophy.
Inventor(s):	Gary H. Rasmusson, David B. R. Johnston, Glen E. Arth, deceased
Assignee:	Merck and Co Inc
Application Number:	US06/189,981
Patent Claims:	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) --CH2 --CH2 --; (2) --CH═CH--; (3) ##STR32## or (4) ##STR33## B is (1) ##STR34## where R1 is, (a) hydrogen; (b) methyl or ethyl; (c) ethenyl; (d) ethynyl; (e) NR2 R3 where R2 and R3 are hydrogen or methyl; or (f) cyano; or (2) ##STR35## where X.sup.⊖ is any anion and R4 is, (a) OR5 where R5 is C1-4 alkyl; or (b) NR6 R7, where R6 and R7 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 R8 is,(i) hydrogen, (ii) hydroxyl, (iii) C1-4 alkyl (iv) NR9 R10, where R9 and R10 are each independently selected from hydrogen, C1-8 straight or branched chain alkyl, C3-6 cycloalkyl, phenyl; or R9 and R10 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) OR11, where R11 is M, where M is hydrogen or alkali metal, or C1-18 straight or branched chain alkyl; benzyl; or (b) Alk-OR12, where Alk is always present and has the same meaning as above, and R12 is (i) phenyl C1-6 alkylcarbonyl, (ii) C5-10 cycloalkylcarbonyl, (iii) benzoyl, or (iv) C1-8 alkoxycarbonyl; (v) amino, or C1-8 alkyl substituted amino, carbonyl; or (vi) hydrogen, provided that Alk is a branched C3 -C8 chain; (2) ##STR37## or CH-Alk-OR12, where Alk is present or absent and has the same meaning as above, and R8 and R12 have the same meaning as above, and R12 is also hydrogen or C1-20 alkylcarbonyl; (3) ##STR38## where the dashed bond replaces the 17α hydrogen; (4) α-hydrogen and ##STR39## where R13 is, (a) C1-12 alkyl; or(b) NR9 R10 ; (5) α-hydrogen and cyano; or (6) α-hydrogen and tetrazolyl; and pharmaceutically acceptable salts of the above compounds. 2. A compound of claim 1 of the formula: ##STR40## wherein R1 is hydrogen, methyl, or amino; and T is CONHCH2 CH3, ##STR41## 3. A compound of claim 1 wherein R1 is methyl and T is CONHCH2 CH3 or CON (CH2 CH3)2. 4. A compound of claim 1 wherein the compound is 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one. 5. A compound of claim 1 wherein the compound is 17β-N,N-diethylcarbamoyl-4-aza-5α-androstan-3-one. 6. A compound of claim 1 wherein the compound is 17β-N,N-diethylcarbamoyl-4-amino-4-aza-5α-androstan-3-one. 7. A compound of claim 1 wherein the compound is 4-aza-5α-20-spiroxan-3-one. 8. A compound of claim 1 wherein the compound is 4-methyl-4-aza-5α-20-spiroxan-3-one. 9. A compound of claim 1 wherein the compound is 17β-N-ethylcarbamoyl-4-methyl-4-aza-5α-androst-3-one. 10. A compound of claim 1 wherein the compound is 4-methyl-4-aza-5α-pregnane-3,20-dione. 11. A compound of claim 1 wherein the compound is 20-hydroxymethyl-4-methyl-4-aza-5α-pregnane-3-one. 12. A compound of claim 1 wherein the compound is 17β-carbomethoxy-4-methyl-4-aza-5α-androstan-3-one. 13. A compound of claim 1 wherein the compound is 17β-N-octylcarbamoyl-4-methyl-4-aza-5α-androstane-3-one. 14. 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) --CH2 --CH2 --; (2) --CH═CH--; (3) ##STR43## or (4) ##STR44## B is (1) ##STR45## where R1 is, (a) hydrogen; (b) methyl or ethyl; (c) ethenyl; (d) ethynyl; (e) NR2 R3 where R2 and R3 are hydrogen or methyl; or (f) cyano; or (2) ##STR46## where X63 is any anion and R4 is, (a) OR5 where R5 is C1-4 alkyl; or (b) NR6 R7, where R6 and R7 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 R8 is,(i) hydrogen, (ii) hydroxyl, (iii) C1-4 alkyl (iv) NR9 R10, where R9 and R10 are each independently selected from hydrogen, C1-4 straight or branched chain alkyl, C3-6 cycloalkyl, phenyl; or R9 and R10 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) OR11, where R11 is M, where M is hydrogen or alkali metal, or C1-18 straight or branched chain alkyl; benzyl; or (b) Alk-OR12, where Alk is always present and has the same meaning as above, and R12 is (i) phenyl C1-6 alkylcarbonyl, (ii) C5-10 cycloalkylcarbonyl, (iii) benzoyl, or (iv) C1-8 alkoxycarbonyl; (v) amino, or C1-8 alkyl substituted amino, carbonyl; or (vi) hydrogen, provided that Alk is a branched C3 -C8 chain; (2) ##STR48## or CH-Alk-OR12, where Alk is present or absent and has the same meaning as above, and R8 and R12 have the same meaning as above, and R12 is also hydrogen or C1-20 alkylcarbonyl; (3) ##STR49## where the dashed bond replaces the 17α hydrogen; (4) α-hydrogen and ##STR50## where R13 is, (a) C1-12 alkyl; or(b) NR9 R10 ; (5) α-hydrogen and cyano; or (6) α-hydrogen and tetrazolyl; and pharmaceutically acceptable salts of the above compounds. 15. The method of claim 14 wherein there is employed a compound of formula: ##STR51## wherein R1 is hydrogen, methyl, or amino; and T is ##STR52## 16. 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) --CH2 --CH2 --; (2) --CH═CH--; (3) ##STR54## or (4) ##STR55## B is (1) ##STR56## where R1 is, (a) hydrogen; (b) methyl or ethyl; (c) ethenyl; (d) ethynyl; (e) NR2 R3 where R2 and R3 are hydrogen or methyl; or (f) cyano; or (2) ##STR57## where X.sup.⊖ is any anion and R4 is, (a) OR5 where R5 is C1-4 alkyl; or (b) NR6 R7, where R6 and R7 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 R8 is,(i) hydrogen, (ii) hydroxyl, (iii) C1-4 alkyl (iv) NR9 R10, where R9 and R10 are each independently selected from hydrogen, C1-4 straight or branched chain alkyl, C3-6 cycloalkyl, phenyl; or R9 and R10 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) OR11, where R11 is M, where M is hydrogen or alkali metal, or C1-18 straight or branched chain alkyl; benzyl; or (b) Alk-OR12, where Alk is always present and has the same meaning as above, and R12 is(i) phenyl C1-6 alkylcarbonyl, (ii) C5-10 cycloalkylcarbonyl, (iii) benzoyl, or (iv) C1-8 alkoxycarbonyl; (v) amino, or C1-8 alkyl substituted amino, carbonyl; or (vi) hydrogen, provided that Alk is a branched C3-C 8 chain; (2) ##STR59## or CH-Alk-OR12, where Alk is present or absent and has the same meaning as above, and R8 and R12 have the same meaning as above, and R12 is also hydrogen or C1-20 alkylcarbonyl; (3) ##STR60## where the dashed bond replaces the 17α hydrogen; (4) α-hydrogen and ##STR61## where R13 is, (a) C1-12 alkyl; or(b) NR9 R10 ; (5) α-hydrogen and cyano; or (6) α-hydrogen and tetrazolyl; and pharmaceutically acceptable salts of the above compounds. 17. The method of claim 16 wherein there is employed a compound of formula: ##STR62## wherein R1 is hydrogen, methyl, or amino; and T is ##STR63## 18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula: ##STR64## where Formula (I) may also have the structure of partial Formulas (II) and/or (III);wherein, A is(1) --CH2 --CH2 --; (2) --CH═CH--; (3) ##STR65## or (4) ##STR66## B is (1) ##STR67## where R1 is, (a) hydrogen; (b) methyl or ethyl; (c) ethenyl; (d) ethynyl; (e) NR2 R3 where R2 and R3 are hydrogen or methyl; or (f) cyano; or (2) ##STR68## where X.sup.⊖ is any anion and R4 is, (a) OR5 where R5 is C1-4 alkyl; or (b) NR6 R7, where R6 and R7 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) ##STR69## where Alk is present or absent and is straight or branched hydrocarbon chain of 1 to 12 carbon atoms; and R8 is,(i) hydrogen, (ii) hydroxyl, (iii) C1-4 alkyl (iv) NR9 R10, where R9 and R10 are each independently selected from hydrogen, C1-4 straight or branched chain alkyl, C3-6 cycloalkyl, phenyl; or R9 and R10 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) OR11, where R11 is M, where M is hydrogen or alkali metal, or C1-18 straight or branched chain alkyl; benzyl; or (b) Alk-OR12, where Alk is always present and has the same meaning as above, and R12 is (i) phenyl C1-6 alkylcarbonyl, (ii) C5-10 cycloalkylcarbonyl, (iii) benzoyl, or (iv) C1-8 alkoxycarbonyl; (v) amino, or C1-8 alkyl substituted amino, carbonyl; or (vi) hydrogen, provided that Alk is a branched C3 -C8 chain; (2) ##STR70## or CH-Alk-OR12, where Alk is present or absent and has the same meaning as above, and R8 and R12 have the same meaning as above, and R12 is also hydrogen or C1-20 alkylcarbonyl; (3) ##STR71## where the dashed bond replaces the 17α hydrogen; (4) α-hydrogen and ##STR72## where R13 is, (a) C1-12 alkyl; or(b) NR9 R10 ; (5) α-hydrogen and cyano; or (6) α-hydrogen and tetrazolyl; and pharmaceutically acceptable salts of the above compounds. 19. The composition of claim 18 wherein there is employed a compound of formula: ##STR73## wherein R1 is hydrogen, methyl, or amino; and T is ##STR74##