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Claims for Patent: 4,377,584

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Claims for Patent: 4,377,584

Title: 4-Aza-17.beta.-substituted-5.alpha.-androstan-3-one-reductase inhibitors
Abstract:4-Aza-17.beta.-substituted-5.alpha.-androstan-3-ones and their A-homo analogs of the formula: ##STR1## 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): Rasmusson; Gary H. (Watchung, NJ), Johnston; David B. R. (Warren, NJ), Arth, deceased; Glen E. (late of Cranford, NJ)
Assignee: Merck & Co., Inc. (Rahway, NJ)
Application Number:06/189,981
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) --CH.sub.2 --CH.sub.2 --;

(2) --CH.dbd.CH--;

(3) ##STR32## or (4) ##STR33## B is (1) ##STR34## where R.sup.1 is,

(a) hydrogen;

(b) methyl or ethyl;

(c) ethenyl;

(d) ethynyl;

(e) NR.sup.2 R.sup.3 where R.sup.2 and R.sup.3 are hydrogen or methyl; or

(f) cyano; or

(2) ##STR35## where X.sup..crclbar. is any anion and R.sup.4 is, (a) OR.sup.5 where R.sup.5 is C.sub.1-4 alkyl; or

(b) NR.sup.6 R.sup.7, where R.sup.6 and R.sup.7 are hydrogen or methyl;

R' is hydrogen or methyl;

R" is hydrogen or .beta.-methyl;

R"' is hydrogen, .beta.-methyl or hydroxyl;

Z is

(1) .alpha.-hydrogen or .alpha.-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.sup.8 is,

(i) hydrogen,

(ii) hydroxyl,

(iii) C.sub.1-4 alkyl

(iv) NR.sup.9 R.sup.10, where R.sup.9 and R.sup.10 are each independently selected from hydrogen, C.sub.1-8 straight or branched chain alkyl, C.sub.3-6 cycloalkyl, phenyl; or R.sup.9 and R.sup.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.sup.11, where R.sup.11 is M, where M is hydrogen or alkali metal, or C.sub.1-18 straight or branched chain alkyl; benzyl; or

(b) Alk-OR.sup.12, where Alk is always present and has the same meaning as above, and R.sup.12 is

(i) phenyl C.sub.1-6 alkylcarbonyl,

(ii) C.sub.5-10 cycloalkylcarbonyl,

(iii) benzoyl, or

(iv) C.sub.1-8 alkoxycarbonyl;

(v) amino, or C.sub.1-8 alkyl substituted amino, carbonyl; or

(vi) hydrogen, provided that Alk is a branched C.sub.3 -C.sub.8 chain;

(2) ##STR37## or CH-Alk-OR.sup.12, where Alk is present or absent and has the same meaning as above, and R.sup.8 and R.sup.12 have the same meaning as above, and R.sup.12 is also hydrogen or C.sub.1-20 alkylcarbonyl;

(3) ##STR38## where the dashed bond replaces the 17.alpha. hydrogen; (4) .alpha.-hydrogen and ##STR39## where R.sup.13 is, (a) C.sub.1-12 alkyl; or

(b) NR.sup.9 R.sup.10 ;

(5) .alpha.-hydrogen and cyano; or

(6) .alpha.-hydrogen and tetrazolyl; and pharmaceutically acceptable salts of the above compounds.

2. A compound of claim 1 of the formula: ##STR40## wherein R.sup.1 is hydrogen, methyl, or amino; and T is CONHCH.sub.2 CH.sub.3, ##STR41##

3. A compound of claim 1 wherein R.sup.1 is methyl and T is CONHCH.sub.2 CH.sub.3 or CON (CH.sub.2 CH.sub.3).sub.2.

4. A compound of claim 1 wherein the compound is 17.beta.-N,N-diethylcarbamoyl-4-methyl-4-aza-5.alpha.-androstan-3-one.

5. A compound of claim 1 wherein the compound is 17.beta.-N,N-diethylcarbamoyl-4-aza-5.alpha.-androstan-3-one.

6. A compound of claim 1 wherein the compound is 17.beta.-N,N-diethylcarbamoyl-4-amino-4-aza-5.alpha.-androstan-3-one.

7. A compound of claim 1 wherein the compound is 4-aza-5.alpha.-20-spiroxan-3-one.

8. A compound of claim 1 wherein the compound is 4-methyl-4-aza-5.alpha.-20-spiroxan-3-one.

9. A compound of claim 1 wherein the compound is 17.beta.-N-ethylcarbamoyl-4-methyl-4-aza-5.alpha.-androst-3-one.

10. A compound of claim 1 wherein the compound is 4-methyl-4-aza-5.alpha.-pregnane-3,20-dione.

11. A compound of claim 1 wherein the compound is 20-hydroxymethyl-4-methyl-4-aza-5.alpha.-pregnane-3-one.

12. A compound of claim 1 wherein the compound is 17.beta.-carbomethoxy-4-methyl-4-aza-5.alpha.-androstan-3-one.

13. A compound of claim 1 wherein the compound is 17.beta.-N-octylcarbamoyl-4-methyl-4-aza-5.alpha.-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) --CH.sub.2 --CH.sub.2 --;

(2) --CH.dbd.CH--;

(3) ##STR43## or (4) ##STR44## B is (1) ##STR45## where R.sup.1 is,

(a) hydrogen;

(b) methyl or ethyl;

(c) ethenyl;

(d) ethynyl;

(e) NR.sup.2 R.sup.3 where R.sup.2 and R.sup.3 are hydrogen or methyl; or

(f) cyano; or

(2) ##STR46## where X.sup.63 is any anion and R.sup.4 is, (a) OR.sup.5 where R.sup.5 is C.sub.1-4 alkyl; or

(b) NR.sup.6 R.sup.7, where R.sup.6 and R.sup.7 are hydrogenor methyl;

R' is hydrogen or methyl;

R" is hydrogen or .beta.-methyl;

R"' is hydrogen, .beta.-methyl or hydroxyl;

Z is

(1) .alpha.-hydrogen or .alpha.-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.sup.8 is,

(i) hydrogen,

(ii) hydroxyl,

(iii) C.sub.1-4 alkyl

(iv) NR.sup.9 R.sup.10, where R.sup.9 and R.sup.10 are each independently selected from hydrogen, C.sub.1-4 straight or branched chain alkyl, C.sub.3-6 cycloalkyl, phenyl; or R.sup.9 and R.sup.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.sup.11, where R.sup.11 is M, where M is hydrogen or alkali metal, or C.sub.1-18 straight or branched chain alkyl; benzyl; or

(b) Alk-OR.sup.12, where Alk is always present and has the same meaning as above, and R.sup.12 is

(i) phenyl C.sub.1-6 alkylcarbonyl,

(ii) C.sub.5-10 cycloalkylcarbonyl,

(iii) benzoyl, or

(iv) C.sub.1-8 alkoxycarbonyl;

(v) amino, or C.sub.1-8 alkyl substituted amino, carbonyl; or

(vi) hydrogen, provided that Alk is a branched C.sub.3 -C.sub.8 chain;

(2) ##STR48## or CH-Alk-OR.sup.12, where Alk is present or absent and has the same meaning as above, and R.sup.8 and R.sup.12 have the same meaning as above, and R.sup.12 is also hydrogen or C.sub.1-20 alkylcarbonyl;

(3) ##STR49## where the dashed bond replaces the 17.alpha. hydrogen; (4) .alpha.-hydrogen and ##STR50## where R.sup.13 is, (a) C.sub.1-12 alkyl; or

(b) NR.sup.9 R.sup.10 ;

(5) .alpha.-hydrogen and cyano; or

(6) .alpha.-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 R.sup.1 is hydrogen, methyl, or amino; and T is ##STR52##

16. A method of inhibiting testosterone-5.alpha.-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.sub.2 --CH.sub.2 --;

(2) --CH.dbd.CH--;

(3) ##STR54## or (4) ##STR55## B is (1) ##STR56## where R.sup.1 is,

(a) hydrogen;

(b) methyl or ethyl;

(c) ethenyl;

(d) ethynyl;

(e) NR.sup.2 R.sup.3 where R.sup.2 and R.sup.3 are hydrogen or methyl; or

(f) cyano; or

(2) ##STR57## where X.sup..crclbar. is any anion and R.sup.4 is, (a) OR.sup.5 where R.sup.5 is C.sub.1-4 alkyl; or

(b) NR.sup.6 R.sup.7, where R.sup.6 and R.sup.7 are hydrogen or methyl;

R' is hydrogen or methyl;

R" is hydrogen or .beta.-methyl;

R"' is hydrogen, .beta.-methyl or hydroxyl;

Z is

(1) .alpha.-hydrogen or .alpha.-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.sup.8 is,

(i) hydrogen,

(ii) hydroxyl,

(iii) C.sub.1-4 alkyl

(iv) NR.sup.9 R.sup.10, where R.sup.9 and R.sup.10 are each independently selected from hydrogen, C.sub.1-4 straight or branched chain alkyl, C.sub.3-6 cycloalkyl, phenyl; or R.sup.9 and R.sup.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.sup.11, where R.sup.11 is M, where M is hydrogen or alkali metal, or C.sub.1-18 straight or branched chain alkyl; benzyl; or

(b) Alk-OR.sup.12, where Alk is always present and has the same meaning as above, and R.sup.12 is

(i) phenyl C.sub.1-6 alkylcarbonyl,

(ii) C.sub.5-10 cycloalkylcarbonyl,

(iii) benzoyl, or

(iv) C.sub.1-8 alkoxycarbonyl;

(v) amino, or C.sub.1-8 alkyl substituted amino, carbonyl; or

(vi) hydrogen, provided that Alk is a branched C.sub.3-C.sub.8 chain;

(2) ##STR59## or CH-Alk-OR.sup.12, where Alk is present or absent and has the same meaning as above, and R.sup.8 and R.sup.12 have the same meaning as above, and R.sup.12 is also hydrogen or C.sub.1-20 alkylcarbonyl;

(3) ##STR60## where the dashed bond replaces the 17.alpha. hydrogen; (4) .alpha.-hydrogen and ##STR61## where R.sup.13 is, (a) C.sub.1-12 alkyl; or

(b) NR.sup.9 R.sup.10 ;

(5) .alpha.-hydrogen and cyano; or

(6) .alpha.-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 R.sup.1 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) --CH.sub.2 --CH.sub.2 --;

(2) --CH.dbd.CH--;

(3) ##STR65## or (4) ##STR66## B is (1) ##STR67## where R.sup.1 is,

(a) hydrogen;

(b) methyl or ethyl;

(c) ethenyl;

(d) ethynyl;

(e) NR.sup.2 R.sup.3 where R.sup.2 and R.sup.3 are hydrogen or methyl; or

(f) cyano; or

(2) ##STR68## where X.sup..crclbar. is any anion and R.sup.4 is, (a) OR.sup.5 where R.sup.5 is C.sub.1-4 alkyl; or

(b) NR.sup.6 R.sup.7, where R.sup.6 and R.sup.7 are hydrogen or methyl;

R' is hydrogen or methyl;

R" is hydrogen or .beta.-methyl;

R"' is hydrogen, .beta.-methyl or hydroxyl;

Z is

(1) .alpha.-hydrogen or .alpha.-hydroxyl and

(a) ##STR69## where Alk is present or absent and is straight or branched hydrocarbon chain of 1 to 12 carbon atoms; and R.sup.8 is,

(i) hydrogen,

(ii) hydroxyl,

(iii) C.sub.1-4 alkyl

(iv) NR.sup.9 R.sup.10, where R.sup.9 and R.sup.10 are each independently selected from hydrogen, C.sub.1-4 straight or branched chain alkyl, C.sub.3-6 cycloalkyl, phenyl; or R.sup.9 and R.sup.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.sup.11, where R.sup.11 is M, where M is hydrogen or alkali metal, or C.sub.1-18 straight or branched chain alkyl; benzyl; or

(b) Alk-OR.sup.12, where Alk is always present and has the same meaning as above, and

R.sup.12 is

(i) phenyl C.sub.1-6 alkylcarbonyl,

(ii) C.sub.5-10 cycloalkylcarbonyl,

(iii) benzoyl, or

(iv) C.sub.1-8 alkoxycarbonyl;

(v) amino, or C.sub.1-8 alkyl substituted amino, carbonyl; or

(vi) hydrogen, provided that Alk is a branched C.sub.3 -C.sub.8 chain;

(2) ##STR70## or CH-Alk-OR.sup.12, where Alk is present or absent and has the same meaning as above, and R.sup.8 and R.sup.12 have the same meaning as above, and R.sup.12 is also hydrogen or C.sub.1-20 alkylcarbonyl;

(3) ##STR71## where the dashed bond replaces the 17.alpha. hydrogen; (4) .alpha.-hydrogen and ##STR72## where R.sup.13 is, (a) C.sub.1-12 alkyl; or

(b) NR.sup.9 R.sup.10 ;

(5) .alpha.-hydrogen and cyano; or

(6) .alpha.-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 R.sup.1 is hydrogen, methyl, or amino; and T is ##STR74##
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