US 4,377,584 AGranted

4-Aza-17.beta.-substituted-5.alpha.-androstan-3-one-reductase inhibitors

AssigneeMerck & Co., Inc.

InventorsGary H. Rasmusson, David B. R. Johnston, Glen E. Arth, deceased

Life of this patent

Estimating the term…

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.

Claims19

Dependent claims

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.

47 more elements

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.

47 more elements

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.

47 more elements

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.

48 more elements

Dependencies are inferred from the claim text.

Facts

Application: 06/189,981Filed 23 Sep 1980 · continuation in part
Priority: 13 Apr 1978
Granted: 22 Mar 1983
Term ends: Not estimatedThe source records don’t support an estimate.

Classification11 codes

C07J 41/0066
Not covered by C07J41/0005: the 17-beta position being substituted by a carbon atom forming part of an amide group
C07J 3/005
Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom: the carbon atom being part of…
C07J 11/00
Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position
C07J 17/00
Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero

Family

Serial896,118Parent of this continuation-in-part · filed 13 Apr 1978
Serial20,371Parent of this continuation-in-part · filed 15 Mar 1979
US 4,377,584 AThis patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

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.

47 more elements

Facts

Application

06/189,981Filed 23 Sep 1980 · continuation in part

Priority

13 Apr 1978

Granted

22 Mar 1983

Term ends

Not estimatedThe source records don’t support an estimate.

Classification11 codes

C07J 41/0066
Not covered by C07J41/0005: the 17-beta position being substituted by a carbon atom forming part of an amide group
C07J 3/005
Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom: the carbon atom being part of…
C07J 11/00
Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position
C07J 17/00
Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero