US 5,998,464 AGranted

4-Oxa and 4-thia steroids

AssigneeMerck & Co., Inc.

InventorsRaman K. Bakshi, Gool F. Patel, Gary H. Rasmusson, Richard L. Tolman

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Abstract

The compounds of the present invention are those of structural formula (I) ##STR1## wherein X is oxygen or sulfur. Pharmaceutical compositions and methods of use of the compounds in the treatment of hyperandrogenic conditions are disclosed. In addition, the combination of the compounds with other active agents such as finasteride, minoxidil and retinoic acid or a derivative thereof is disclosed.

Claims14

Dependent claims

A compound of structural formula (I):

##STR28## or a pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein:
the C5-C6 bond designated with a dotted line independently represents a single or double bond, provided that when the C5-C6 is a double bond, H.sub.a is absent and when the C5-C6 bond is a single bond H.sub.a is present and represents hydrogen;
X is sulfur;
R.sup.1 is selected from hydrogen and C.sub.1-5 alkyl;
R.sup.2 is selected from CH.sub.3, CH.sub.2 OR.sup.3, and H;
R.sup.3 is selected from:
C.sub.1-5 alkyl;
Z is ##STR29## A.sup.1 is selected from:
(1) --H,
(2) keto,
(6) carboxy,
(7) protected amino,
(8) amino,
(9) substituted or unsubstituted C.sub.2-10 alkenyl,
(10) aryl-substituted C.sub.1-10 alkyl,
(11) aryl or heteroaryl,
(12) substituted aryl or heteroaryl,
(13) aryl or heteroaryl carbamoyl-substituted C.sub.1-10 alkyl,
(14) aryl or heteroaryl carbonyl,
(15) ether-substituted C.sub.1-10 alkyl,
(16) thioether-substituted C.sub.1-10 alkyl,
(17) keto-substituted C.sub.1-10 alkyl,
(18) heteroaryl-substituted C.sub.1-10 alkyl,
(19) carboxylic ester,
(20) carboxamide, including substituted and unsubstituted anilide derivatives,
(21) urea,
(22) C.sub.1-10 alkylureido C.sub.0-5 alkyl,
(23) substituted or unsubstituted heteroaryl or arylureidoC.sub.0-5 alkyl,
(24) C.sub.1-10 alkanoyloxyC.sub.1-2 alkyl,
(25) C.sub.1-10 alkylcarbonylamino,
(26) alkanoylamidoalkyl
(28) ether,
(29) thio ether, and
(30) substituted and unsubstituted aryl or heteroaryl ether;
A.sup.2 is selected from:
(1) --H,
(2) keto,
(3) protected hydroxy,
(4) acetate,
(5) hydroxy,
(6) carboxy,
(7) protected amino,
(8) amino,
(9) C.sub.1-10 alkyl,
(10) substituted or unsubstituted C.sub.2-10 alkenyl,
(11) aryl-substituted C.sub.1-10 alkyl,
(12) aryl or heteroaryl,
(13) substituted aryl or heteroaryl,
(14) aryl or heteroaryl carbamoyl-substituted C.sub.1-10 alkyl,
(15) C.sub.1-10 alkylcarbonyl,
(16) aryl or heteroaryl carbonyl,
(17) ether-substituted C.sub.1-10 alkyl,
(18) thioether-substituted C.sub.1-10 alkyl,
(19) keto-substituted C.sub.1-10 alkyl,
(20) heteroaryl-substituted C.sub.1-10 alkyl,
21) carboxylic ester,
(22) carboxamide, including substituted and unsubstituted anilide derivatives,
(23) urea,
(24) C.sub.1-10 alkylureido C.sub.0-5 alkyl,
(25) substituted or unsubstituted arylureidoC.sub.0-5 alkyl,
(26) C.sub.1-10 alkanoyloxyC.sub.1-2 alkyl,
(27) C.sub.1-10 alkylcarbonylamino,
(28) alkanoylamidoalkyl,
(29) ether,
(30) thio ether, and
(31) substituted and unsubstituted aryl- or heteroaryl-ether;
and heteroaryl is selected from:
piperidinyl, piperizinyl, pyrrolidinyl, pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, indolyl and benzofuranyl.

65 more elements

The compound selected from:

(1) N-t-Butyl-4-thia-5.alpha.-androst-1-en-3-one-17.beta.-carboxamide,
(2) 7.beta.-Methyl-4-thia-5.alpha.-cholest-1-en-3-one,
(3) 17.beta.-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-5.alpha.-androst -1-en-3-one,
(4) 17.beta.-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-5.alpha.-androst -1-en-3-one,
(5) 17.beta.-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-5.alpha.-androst -1-en-3-one,
(6) 17.beta.-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-5.alpha.-androst -1-en-3-one,
(7) 17.beta.-(N-tert-amylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one,
(8) 17.beta.-(N-tert-hexylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one,
(9) 17.beta.-(N-isobutylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one,
(10) 17.beta.-(N-tert-octylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one,
(11) 17.beta.-(N-1,1-diethylbutylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one,
(12) 17.beta.-(N-neopentylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one,
(13) 17.beta.-(N-2-adamantylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one,
(14) 17.beta.-(N-1-adamantylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one,
(15) 17.beta.-(N-2-norbornylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one,
(16) 17.beta.-(N-1-norbornylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one,
(17) 17.beta.-(N-phenylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one,
(18) 17.beta.-(N-benzylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one,
(19) 17.beta.-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-thia-5 .alpha.-androst-1-en-3-one,
(20) 17.beta.-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl -4-thia-5.alpha.-androst-1-en-3-one,
(21) 17.beta.-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-thia-5 .alpha.-androst-1-en-3-one,
(22) 17.beta.-(N-n-octylcarbamoyl)-4-methyl-4-thia-5.alpha.-androst-1-en-3-one,
(23) 17.beta.-(1-methoxyethyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3one
(24) 17.beta.-(isopropyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one,
(25) 17.beta.-(4-methyl -phenoxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one,
(26) 17.beta.-(1-(3-chlorophenoxy)ethyl)-7.beta.-methyl-4-thia-5.alpha.-androst -1-en-3-one,
(27) 17.beta.-(4-methylsulfonyl-phenoxy)-7.beta.-methyl-4-thia-5.alpha.-androst -1-en-3-one,
(28) 17.beta.-(4-chlorophenoxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-o ne,
(29) 17.beta.-(2-pyrimidinyloxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3- one,
(30) 17.beta.-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-thia-5 .alpha.-androst-1-en-3-one,
(31) N-t-Butyl-4-thia-5.alpha.-androst-1-en-3-one-16.beta.-carboxamide,
(32) 16.beta.-(1,5-dimethylhexyl)-7.beta.-Methyl-4-thia-5.alpha.-androst-1-en-3 -one,
(33) 16.beta.-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-androst-1-en-3-o ne,
(34) 16.beta.-(N-tert-amylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one,
(35) 16.beta.-(N-tert-hexylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one,
(36) 16.beta.-(N-isobutylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one,
(37) 16.beta.-(N-tert-octylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one,
(38) 16.beta.-(N-1,1-diethylbutylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one,
(39) 16.beta.-(N-neopentylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one,
(40) 16.beta.-(N-2-adamantylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one,
(41) 16.beta.-(N-1-adamantylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one,
(42) 16.beta.-(N-2-norbomylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one,
(43) 16.beta.-(N-1-norbomylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one,
(44) 16.beta.-(N-phenylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one,
(45) 16.beta.-(N-benzylcarbamoyl)-4-thia-5.alpha.-androst-1-en-3-one,
(46) 16.beta.-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-thia-5 .alpha.-androst-1-en-3-one,
(47) 16.beta.-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-thia-5 .alpha.-androst-1-en-3one,
(48) 16.beta.-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-thia-5 .alpha.-androst-1-en-3-one,
(49) 16.beta.-(2,3-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-androst-1-en-3-o ne,
(50) 16.beta.-(2,4-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-androst-1-en-3-o ne,
(51) 16.beta.-(2,6-bis(trifluoromethyl)phenylcarbamoyl)-4-thia-androst-1-en-3-o ne,
(52) 16.beta.-(N-n-octylcarbamoyl)-4-methyl-4-thia-5.alpha.-androst-1-en-3-one,
(53) 16.beta.-(1-methoxyethyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-on e,
(54) 16.beta.-(isopropyl)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-one,
(55) 16.beta.-(4-methyl-phenoxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3- one,
(56) 16.beta.-(1-(3-chlorophenoxy)ethyl)-7.beta.-methyl-4-thia-5.alpha.-androst -1-en-3-one,
(57) 16.beta.-(4-methylsulfonyl-phenoxy)-7.beta.-methyl-4-thia-5.alpha.-androst -1-en-3-one,
(58) 16.beta.-(4-chlorophenoxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3-o ne,
(59) 16.beta.-(2-pyrimidinyloxy)-7.beta.-methyl-4-thia-5.alpha.-androst-1-en-3- one, and
(60) 16.beta.-(2,5-bis(trifluoromethyl)phenylcarbamoyl)-7.beta.-methyl-4-thia-5 .alpha.-androst-1-en-3-one.

57 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound of structural formula (I):

##STR28## or a pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein:
the C5-C6 bond designated with a dotted line independently represents a single or double bond, provided that when the C5-C6 is a double bond, H.sub.a is absent and when the C5-C6 bond is a single bond H.sub.a is present and represents hydrogen;
X is sulfur;
R.sup.1 is selected from hydrogen and C.sub.1-5 alkyl;
R.sup.2 is selected from CH.sub.3, CH.sub.2 OR.sup.3, and H;
R.sup.3 is selected from:
C.sub.1-5 alkyl;
Z is ##STR29## A.sup.1 is selected from:
(1) --H,
(2) keto,
(6) carboxy,
(7) protected amino,
(8) amino,
(9) substituted or unsubstituted C.sub.2-10 alkenyl,
(10) aryl-substituted C.sub.1-10 alkyl,
(11) aryl or heteroaryl,
(12) substituted aryl or heteroaryl,
(13) aryl or heteroaryl carbamoyl-substituted C.sub.1-10 alkyl,
(14) aryl or heteroaryl carbonyl,
(15) ether-substituted C.sub.1-10 alkyl,
(16) thioether-substituted C.sub.1-10 alkyl,
(17) keto-substituted C.sub.1-10 alkyl,
(18) heteroaryl-substituted C.sub.1-10 alkyl,
(19) carboxylic ester,
(20) carboxamide, including substituted and unsubstituted anilide derivatives,
(21) urea,
(22) C.sub.1-10 alkylureido C.sub.0-5 alkyl,
(23) substituted or unsubstituted heteroaryl or arylureidoC.sub.0-5 alkyl,
(24) C.sub.1-10 alkanoyloxyC.sub.1-2 alkyl,
(25) C.sub.1-10 alkylcarbonylamino,
(26) alkanoylamidoalkyl
(28) ether,
(29) thio ether, and
(30) substituted and unsubstituted aryl or heteroaryl ether;
A.sup.2 is selected from:
(1) --H,
(2) keto,
(3) protected hydroxy,
(4) acetate,
(5) hydroxy,
(6) carboxy,
(7) protected amino,
(8) amino,
(9) C.sub.1-10 alkyl,
(10) substituted or unsubstituted C.sub.2-10 alkenyl,
(11) aryl-substituted C.sub.1-10 alkyl,
(12) aryl or heteroaryl,
(13) substituted aryl or heteroaryl,
(14) aryl or heteroaryl carbamoyl-substituted C.sub.1-10 alkyl,
(15) C.sub.1-10 alkylcarbonyl,
(16) aryl or heteroaryl carbonyl,
(17) ether-substituted C.sub.1-10 alkyl,
(18) thioether-substituted C.sub.1-10 alkyl,
(19) keto-substituted C.sub.1-10 alkyl,
(20) heteroaryl-substituted C.sub.1-10 alkyl,
21) carboxylic ester,
(22) carboxamide, including substituted and unsubstituted anilide derivatives,
(23) urea,
(24) C.sub.1-10 alkylureido C.sub.0-5 alkyl,
(25) substituted or unsubstituted arylureidoC.sub.0-5 alkyl,
(26) C.sub.1-10 alkanoyloxyC.sub.1-2 alkyl,
(27) C.sub.1-10 alkylcarbonylamino,
(28) alkanoylamidoalkyl,
(29) ether,
(30) thio ether, and
(31) substituted and unsubstituted aryl- or heteroaryl-ether;
and heteroaryl is selected from:
piperidinyl, piperizinyl, pyrrolidinyl, pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, indolyl and benzofuranyl.

65 more elements