US4847306A
Expired / Lapsed
US
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Antihypercholesterolemic compounds
Assignee: Merck and Co Inc
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Filing: 1988-04-11
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Granted: 1989-07-11
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Expires: 2008-04-11
Abstract
Abstract Novel 3-hydroxy-3-methylglutaryl-Coenzyme A(HMG-CoA) reductase inhibitors, which are useful as antihypercholesterolemic agents and are represented by the following general structural formulae (I) and (II) <IMAGE> (I) <IMAGE> (II) and pharmaceutically acceptable salts of the compound (II) in which Z is hydrogen are disclosed.
Inventors
- 👤 Ta J. Lee
- 👤 Clarence S. Rooney
- 👤 William F. Hoffman
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 14:21
CPC Classifications
C; C07; C07D; C07D309/00; C07D309/16; C07D309/28; C07D309/30
Claims Analysis
Total Claims: 24
Claim 1
Independent Claim
58 words
A compound represented by the following general structural formula (I'): ##STR35## wherein: n is 2 to 7; R 1 is C 1-6 alkyl; C 1-6 alkyl substituted with a group selected from halogen or hydroxy; C 1-6 alkylthio; phenylmethyl or 4-hydroxyphenylmethyl; A is ##STR36## b and d represent single bonds, or both b and d represent double bonds.
Claim 2
Dependent Claim
58 words
A compound represented by the following general structural formula (I'): ##STR35## wherein: n is 2 to 7; R 1 is C 1-6 alkyl; C 1-6 alkyl substituted with a group selected from halogen or hydroxy; C 1-6 alkylthio; phenylmethyl or 4-hydroxyphenylmethyl; A is ##STR36## b and d represent single bonds, or both b and d represent double bonds.
Claim 3
Dependent Claim
27 words
A compound of claim 1 wherein n is 2 to 5; and R 1 is C 1-6 alkyl; hydroxy-C 1-6 alkyl; C 1-6 alkylthio; phenylmethyl; or 4-hydroxyphenylmethyl.
Claim 4
Dependent Claim
9 words
A compound of claim 2 wherein n is 2.
Claim 5
Dependent Claim
8 words
A compound of claim 3 which is 6(R)-[2-[8(S)-(1-Methylcyclopropanecarbonyloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.
Claim 6
Dependent Claim
9 words
A compound of claim 2 wherein n is 3.
Claim 7
Dependent Claim
8 words
A compound of claim 5 which is 6(R)-[2-[8(S)-(1-Methylcyclobutanecarbonyloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.
Claim 8
Dependent Claim
8 words
A compound of claim 5 which is 6(R)-[2-[8(S)-(1-Methylthiocyclobutanecarbonyloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.
Claim 9
Dependent Claim
8 words
A compound of claim 5 which is 6(R)-[2-[8(S)-[1-(3-Hydroxypropyl)cyclobutanecarbonyloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.
Claim 10
Dependent Claim
8 words
A compound of claim 5 which is 6(R)-[2-[8(S)-[1-[(4-Hydroxyphenyl)methyl]cyclobutane-carbonyloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.
Claim 11
Dependent Claim
8 words
A compound of claim 5 which is 6(R)-[2-[8(S)-[(1-Hydroxymethyl)-cyclobutanecarbonyloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.
Claim 12
Dependent Claim
8 words
A compound of claim 5 which is 6(R)-[2-[8(S)-[1-(1-Phenylmethyl)-cyclobutanecarbonyloxy]-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.
Claim 13
Dependent Claim
9 words
A compound of claim 2 wherein n is 4.
Claim 14
Dependent Claim
8 words
A compound of claim 12 which is 6(R)-[2-[8(S)-(1-Methylcyclopentanecarbonyloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.
Claim 15
Dependent Claim
8 words
A compound of claim 12 which is 6(R)-[2-[8(S)-(1-Methylthiocyclopentanecarbonyloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.
Claim 16
Dependent Claim
9 words
A compound of claim 2 wherein n is 5.
Claim 17
Dependent Claim
8 words
A compound of claim 15 which is 6(R)-[2-[8(S)-(1-Methylcyclohexanecarbonyloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.
Claim 18
Dependent Claim
22 words
A hypocholesterolemic, hypolipidemic pharmaceutical composition comprising a nontoxic therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
Claim 19
Dependent Claim
29 words
A composition according to claim 17 wherein: n is 2 to 5; and R 1 is C 1-6 alkyl; hydroxy-C 1-6 alkyl; C 1-6 alkylthio; or phenylmethyl; or 4-hydroxyphenylmethyl.
Claim 20
Dependent Claim
38 words
A composition according to claim 18 wherein the therapeutically active ingredient is selected from the group consisting of: (1) 6(R)-[2-[8(S)-(1-Methylcyclopropanecarbonyloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (2) 6(R)-[2-[8(S)-(1-Methylcyclobutanecarbonyloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (3) 6(R)-[2-[8(S)-(1-Methylthiocyclobutanecarbonyloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (4) 6(R)-[2-[8(S)-[1-(3-Hydroxypropyl)cyclobutane-carbonyloxy]-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (5) 6(R)-[2-[8(S)-[1-[(4-Hydroxyphenyl)methyl]cyclobutanecarbonyloxy]-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (6) 6(R)-[2-[8(S)-[(1-Hydroxymethyl)cyclobutanecarbonyloxy]-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (7) 6(R)-[2-[8(S)-[1-(1-Phenylmethyl)cyclobutanecarbonyloxy]-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (8) 6(R)-[2-[8(S)-(1-Methylcyclopentanecarbonyloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (9) 6(R)-[2-[8(S)-(1-Methylthiocyclopentanecarbonyloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (10) 6(R)-[2-[8(S)-(1-Methylcyclohexanecarbonyl)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.
Claim 21
Dependent Claim
44 words
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-reabsorable form in the gastrointestinal tract and a pharmaceutically acceptable carrier.
Claim 22
Dependent Claim
28 words
A method of inhibiting cholesterol biosynthesis comprising the administration to a subject in need of such treatment a nontoxic therapeutically effective amount of a compound of claim 1.
Claim 23
Dependent Claim
27 words
A method of claim 21 wherein: n is 2 to 5; and R 1 is C 1-6 alkyl; hydroxy-C 1-6 alkyl; C 1-6 alkylthio; phenylmethyl; or 4-hydroxyphenylmethyl.
Claim 24
Dependent Claim
37 words
A method of claim 22 wherein the therapeutically active ingredient is selected from the group consisting of: (1) 6(R)-[2-[8(S)-(1-Methylcyclopropanecarbonyloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (2) 6(R)-[2-[8(S)-(1-Methylcyclobutanecarbonyloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (3) 6(R)-[2-[8(S)-(1-Methylthiocyclobutanecarbonyloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (4) 6(R)-[2-[8(S)-[1-(3-Hydroxypropyl)cyclobutane-carbonyloxy]-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (5) 6(R)-[2-[8(S)-[1-[(4-Hydroxyphenyl)methyl]cyclobutanecarbonyloxy]-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (6) 6(R)-[2-[8(S)-[(1-Hydroxymethyl)cyclobutanecarbonyloxy]-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (7) 6(R)-[2-[8(S)-[1-(1-Phenylmethyl)cyclobutanecarbonyloxy]-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (8) 6(R)-[2-[8(S)-(1-Methylcyclopentanecarbonyloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (9) 6(R)-[2-[8(S)-(1-Methylthiocyclopentanecarbonyloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (10) 6(R)-[2-[8(S)-(1-Methylcyclohexanecarbonyl)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.
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USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
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| 3.5 Years (Year 4) | 1992-07-10 | 1993-01-09 | 1993-07-11 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1996-07-10 | 1997-01-09 | 1997-07-11 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2000-07-10 | 2001-01-09 | 2001-07-11 | $7700.00 | Window Closed / Lapsed |