Claims
- 1. A compound represented by the following structural formulae (I) or (II): ##STR21## wherein: R.sub.1 is selected from:
- (1) C.sub.1-10 alkyl;
- (2) substituted C.sub.1-10 alkyl in which one or more substituent(s) is selected from
- (a) halogen,
- (b) hydroxy,
- (c) C.sub.1-10 alkoxy,
- (d) C.sub.1-5 alkoxycarbonyl,
- (e) C.sub.1-5 acyloxy,
- (f) C.sub.3-8 cycloalkyl,
- (g) phenyl,
- (h) substituted phenyl in which the substituents are X and Y,
- (i) C.sub.1-10 alkylS(0).sub.n in which n is 0 to 2,
- (j) C.sub.3-8 cycloalkylS(0).sub.n,
- (k) phenylS(0).sub.n,
- (l) substituted phenylS(0).sub.n in which the substituents are X and Y, and
- (m) oxo;
- (3) C.sub.1-10 alkoxy;
- (4) C.sub.2-10 alkenyl;
- (5) C.sub.3-8 cycloalkyl;
- (6) substituted C.sub.3-8 cycloalkyl in which one substituent is selected from
- (a) C.sub.1-10 alkyl
- (b) substituted C.sub.1-10 alkyl in which the substituent is selected from
- (i) halogen,
- (ii) hydroxy,
- (iii) C.sub.1-10 alkoxy,
- (iv) C.sub.1-5 alkoxycarbonyl,
- (v) C.sub.1-5 acyloxy,
- (vi) phenyl,
- (vii) substituted phenyl in which the substituents are X and Y
- (viii) C.sub.1-10 alkylS(0).sub.n,
- (ix) C.sub.3-8 cycloalkylS(0).sub.n,
- (x) phenylS(0).sub.n,
- (xi) substituted phenylS(0).sub.n in which the substituents are X and Y, and
- (xii) oxo,
- (c) C.sub.1-10 alkylS(0).sub.n,
- (d) C.sub.3-8 cycloalkylS(0).sub.n,
- (e) phenylS(0).sub.n,
- (f) substituted phenylS(0).sub.n in which the substituents are X and Y,
- (g) halogen,
- (h) hydroxy,
- (i) C.sub.1-10 alkoxy,
- (j) C.sub.1-5 alkoxycarbonyl,
- (k) C.sub.1-5 acyloxy,
- (l) phenyl, and
- (m) substituted phenyl in which the substituents are X and Y;
- (7) phenyl;
- (8) substituted phenyl in which the substituents are X and Y;
- (9) amino;
- (10) C.sub.1-5 alkylamino;
- (11) di(C.sub.1-5 alkyl)amino;
- (12) phenylamino;
- (13) substituted phenylamino in which the substituents are X and Y;
- (14) phenyl C.sub.1-10 alkylamino;
- (15) substituted phenyl C.sub.1-10 alkylamino in which the substituents are X and Y;
- (16) a member selected from
- (a) piperidinyl,
- (b) pyrrolidinyl,
- (c) piperazinyl,
- (d) morpholinyl, and
- (e) thiomorpholinyl; and
- (17) R.sub.3 S in which R.sub.3 is selected from
- (a) C.sub.1-10 alkyl,
- (b) phenyl, and
- (c) substituted phenyl in which the substituents are X and Y;
- R.sub.2 is H, CH.sub.3, or CH.sub.2 OH;
- X and Y are independently selected from:
- a) OH,
- b) halogen,
- c) trifluoromethyl,
- d) C.sub.1-3 alkoxy,
- e) C.sub.1-3 alkylcarbonyloxy,
- f) phenylcarbonyloxy,
- g) C.sub.1-3 alkoxycarbonyl,
- h) phenyloxycarbonyl,
- i) hydrogen;
- j) C.sub.1-5 alkyl;
- Z is selected from
- (1) hydrogen;
- (2) C.sub.1-5 alkyl;
- (3) substituted C.sub.1-5 alkyl in which the substituent is selected from
- (a) phenyl,
- (b) dimethylamino, and
- (c) acetylamino, and
- (4) 2,3-hydroxypropyl;
- halogen is C1 or F; a is a single bond or a double bond; and pharmaceutically acceptable salts of the compound (II) in which Z is hydrogen.
- 2. A compound of claim 1 wherein:
- R.sub.1 is selected from: .
- (1) C.sub.1-10 alkyl;
- (2) substituted C.sub.1-10 alkyl in which one or more substituent(s) is selected from
- (a) halogen,
- (b) hydroxy,
- (c) C.sub.1-10 alkoxy,
- (d) C.sub.1-5 alkoxycarbonyl,
- (e) C.sub.1-5 acyloxy.
- (f) C.sub.3-8 cycloalkyl,
- (g) phenyl,
- (h) substituted phenyl in which the substituents are X and Y, and
- (i) oxo;
- (3) C.sub.3-8 cycloalkyl;
- (4) substituted C.sub.3-8 cycloalkyl in which one substituent is selected from
- (a) C.sub.1-10 alkyl,
- (b) substituted C.sub.1-10 alkyl in which the substituent is selected from
- (i) halogen.
- (ii) hydroxy,
- (iii) C.sub.1-10 alkoxy
- (iv) C.sub.1-5 acyloxy,
- (v) C.sub.1-5 alkoxycarbonyl,
- (vi) phenyl,
- (vii) substituted phenyl in which the substituents are X and Y, and
- (viii) oxo,
- (c) halogen,
- (d) hydroxy,
- (e) C.sub.1-10 alkoxy,
- (f) C.sub.1-5 alkoxycarbonyl,
- (g) C.sub.1-5 acyloxy,
- (h) phenyl,
- (i) substituted phenyl in which the substituents are X and Y;
- (5) phenylamino;
- (6) substituted phenylamino in which the substituents are X and Y;
- (7) phenylC.sub.1-10 alkylamino; and
- (8) substituted phenyl C.sub.1-10 alkylamino in which the substituents are X and Y;
- X and Y are independently selected from:
- (a) OH,
- (b) F,
- (c) trifluoromethyl,
- (d) C.sub.1-3 alkoxy,
- (e) hydrogen,
- (f) C.sub.1-5 alkyl.
- 3. A compound of claim 2 wherein: R.sub.1 is C.sub.1-10 alkyl.
- 4. A compound of claim 3 wherein: R.sub.1 is 2-butyl or 2-methyl-2-butyl; R.sub.2 is H or CH.sub.3.
- 5. A compound of claim 4 selected from the group consisting of:
- (1) 7-[1,2,3,7,8,8a(R)-hexahydro-2(S)-6-dimethyl-3-oxo-8(S)-(2-methylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid;
- (2) 7-[1,2,3,7,8,8a(R)-hexahydro-2(S)-6-dimethyl-3-oxo-8(S)-(2,2-dimethylbutyryloxy)-1(S)-naphthyl]-3(R), 5(R)-dihydroxyheptanoic acid;
- (3) 7-[1,2,3,7,8,8a(R)-hexahydro-2(S)-methyl-3-oxo-8(S)-(2-methylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid;
- (4) 7-[1,2,3,7,8,8a(R)-hexahydro-2(S)-methyl-3-oxo-8(S)-(2,2-dimethylbutyryloxy)-1(S)-naphthyl]-3(R), 5(R)-dihydroxyheptanoic acid;
- (5) 7-[1,2,3,5,6,7,8,8a(R)-octahydro-2(S),6(R)-dimethyl -3-oxo-8(S)-(2,2-dimethylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid;
- (6) 7-[1,2,3,5,6,7,8,8a(R)-octahydro-2(S)-methyl-3-oxo-8(S)-(2,2-dimethylbutyryloxy)-1(S)-naphthyl]-3(R), 5(R)-dihydroxyheptanoic acid;
- (7) 7-[1,2,3,5,6,7,8,8a(R)-octahydro-2(S),6(R)-dimethyl -3oxo-8(S)-(2-methylbutyryloxy)-1(S)-naphthyl]-3(R), 5(R)-dihydroxyheptanoic acid;
- (8) 7-[1,2,3,5,6,7,8,8a(R)-octahydro-2(S)-methyl-3-oxo-8(S)-(2-methylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid.
- 6. A hypocholesterolemic, hypolipidemic pharmaceutical composition comprising a nontoxic therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
- 7. A composition of claim 6 wherein the therapeutically effective compound is selected from the group consisting of:
- (1) 7-[1,2,3,7,8,8a(R)-hexahydro-2(S),6-dimethyl-3-oxo-8(S)-(2-methylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid;
- (2) 7-[1,2,3,7,8,8a(R)-hexahydro-2(S),6-dimethyl-3-oxo-8(S)-(2,2-dimethylbutyryloxy)-1(S)-naphthyl]-3(R), 5(R)-dihydroxyheptanoic acid;
- (3) 7-[1,2,3,7,8,8a(R)-hexahydro-2(S)-methyl-3-oxo-8(S)-(2-methylbutyryloxy)-1(S)-naphthyl]-3(R), 5(R)-dihydroxyheptanoic acid;
- (4) 7-[1,2,3,7,8,8a(R)-hexahydro-2(S)-methyl-3-oxo-8(S)-(2,2-dimethylbutyryloxy)-1(S)-naphthyl]-3(R), 5(R)-dihydroxyheptanoic acid.
- (5) 7-[1,2,3,5,6,7,8,8a(R)-octahydro-2(S),6(R)-dimethyl -3-oxo-8(S)-(2,2-dimethylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid;
- (6) 7-[1,2,3,5,6,7,8,8a(R)-octahydro-2(S)-methyl-3-oxo-8(S)-(2,2-dimethylbutyryloxy)-1(S)-naphthyl]-3(R), 5(R)-dihydroxyheptanoic acid;
- (7) 7-[1,2,3,5,6,7,8,8a(R)-octahydro-2(S),6(R)-dimethyl -3-oxo-8(S)-(2-methylbutyryloxy)-1(S)-naphthyl]-3(R), 5(R)-dihydroxyheptanoic acid;
- (8) 7-[1,2,3,5,6,7,8,8a(R)-octahydro-2(S)-methyl-3-oxo-8(S)-(2-methylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid.
- 8. A hypocholesterolemic, hypolipidemic pharmaceutical composition comprising a nontoxic therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable nontoxic cationic polymer capable of binding bile acids in a non-reabsorbable form in the gastrointestinal tract and a pharmaceutically acceptable carrier.
- 9. A method of treating hypercholesterolemia comprising the administration to a subject in need of such treatment a nontoxic therapeutically effective amount of a compound of claim 1.
- 10. A method of claim 9 wherein the therapeutically effective compound is selected from the group consisting of:
- (1) 7-[1,2,3,7,8,8a(R)-hexahydro-2(S),6-dimethyl-3-oxo-8(S)-(2-methylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid;
- (2) 7-[1,2,3,7,8,8a(R)-hexahydro-2(S),6-dimethyl-3-oxo-8(S)-(2,2-dimethylbutyryloxy)-1(S)-naphthyl]-3(R), 5(R)-dihydroxyheptanoic acid;
- (3) 7-[1,2,3,7,8,8a(R)-hexahydro-2(S)-methyl-3-oxo-8(S)-(2-methylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid;
- (4) 7-[1,2,3,7,8,8a(R)-hexahydro-2(S)-methyl-3-oxo-8(S)-(2,2-dimethylbutyryloxy)-1(S)-naphthyl]-3(R), 5(R)-dihydroxyheptanoic acid.
- (5) 7-[1,2,3,5,6,7,8,8a(R)-octahydro-2(S),6(R)-dimethyl -3-oxo-8(S)-(2,2-dimethylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid;
- (6) 7-[1,2,3,5,6,7,8,8a(R)-octahydro-2(S)methyl-3-oxo-8(S)-(2,2-dimethylbutyryloxy)-1(S)-naphthyl]-3(R), 5(R)-dihydroxyheptanoic acid;
- (7) 7-[1,2,3,5,6,7,8,8a(R)-octahydro-2(S),6(R)-dimethyl -3-oxo-8(S)-L(2-methylbutyryloxy)-1(S)-naphthyl]-3(R), 5(R)-dihydroxyheptanoic acid;
- (8) 7-[1,2,3,5,6,7,8,8a(R)-octahydro-2(S)-methyl-3-oxo-8(S)-(2-methylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid.
Parent Case Info
This is a division of application Ser. No. 363,792 filed June 9, 1989 now U.S. Pat. No. 4,968,693, which is a CIP of Ser. No. 07/162,785 filed 3/22/88, now abandoned.
US Referenced Citations (8)
Foreign Referenced Citations (1)
Number |
Date |
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186972 |
Oct 1984 |
JPX |
Divisions (1)
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Number |
Date |
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Parent |
363792 |
Jun 1989 |
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Continuation in Parts (1)
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Number |
Date |
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162785 |
Mar 1988 |
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