Patent US4459422A successfully refreshed from Google Patents.
US4459422A
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Substituted pyranone inhibitors of cholesterol synthesis
Assignee: Merck and Co Inc
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Filing: 1982-06-10
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Granted: 1984-07-10
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Expires: 2002-06-10
Abstract
Abstract 6-Phenyl-, phenylalkyl- and phenylethenyl-4-hydroxytetrahydropyran-2-ones in the 4(R)-trans stereoisomeric forms are potent inhibitors of cholesterol synthesis by virtue of their ability to inhibit the enzyme, 3-hydroxy-3-methylglutaryl-coenzyme A reductase.
Inventors
- 👤 Alvin K. Willard
- 👤 Frederick C. Novello
- 👤 William F. Hoffman
- 👤 Edward J. Cragoe, Jr.
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-25 19:31
CPC Classifications
C; C07; C07D; C07D309/00; C07D309/16; C07D309/28; C07D309/30
Claims Analysis
Total Claims: 19
Claim 1
Independent Claim
124 words
A compound of structural formula ##STR8## or a pharmaceutically acceptable salt, C 1-3 alkyl ester, phenyl-C 1-3 alkyl ester, dimethylamino-C 1-3 alkyl ester or acetylamino-C 1-3 alkyl ester thereof, wherein A is H or methyl; E is --CH═CH--, or --CH 2 CH 2 --; R 2 and R 3 are each selected from halogen C 1-4 alkyl, C 1-4 haloalkyl, R 1 is substituted phenyl in which the substituents are halo, C 1-4 alkyl, or C 1-4 alkoxy, or R 4 O in which R 4 is phenyl, halophenyl, or substituted phenyl-C 1-3 alkyl wherein the substituents are selected from halogen and C 1-4 haloalkyl; all of the compounds being the enantiomer having a 3(R)configuration in the dihydroxy acid moiety of the trans racemate.
Claim 2
Dependent Claim
124 words
A compound of structural formula ##STR8## or a pharmaceutically acceptable salt, C 1-3 alkyl ester, phenyl-C 1-3 alkyl ester, dimethylamino-C 1-3 alkyl ester or acetylamino-C 1-3 alkyl ester thereof, wherein A is H or methyl; E is --CH═CH--, or --CH 2 CH 2 --; R 2 and R 3 are each selected from halogen C 1-4 alkyl, C 1-4 haloalkyl, R 1 is substituted phenyl in which the substituents are halo, C 1-4 alkyl, or C 1-4 alkoxy, or R 4 O in which R 4 is phenyl, halophenyl, or substituted phenyl-C 1-3 alkyl wherein the substituents are selected from halogen and C 1-4 haloalkyl; all of the compounds being the enantiomer having a 3(R)configuration in the dihydroxy acid moiety of the trans racemate.
Claim 3
Dependent Claim
19 words
The compound of claim 1 or salts or esters thereof as defined in claim 1 wherein A is hydrogen.
Claim 4
Dependent Claim
69 words
The compound of claim 2 or its salts or esters thereof as defined in claim 2 wherein: E is --CH 2 CH 2 -- or --CH═CH--; R 1 is in the 6-position and is substituted phenyl, wherein there are 1 or 2 substituents independently selected from chloro, fluoro, methyl and methoxy; and R 2 and R 3 are independently halo, or C 1-3 alkyl in the 2- and 4-positions.
Claim 5
Dependent Claim
20 words
The compound of claim 3 or its salts or esters thereof as defined in claim 3, wherein E is --CH═CH--.
Claim 6
Dependent Claim
84 words
The compound of claim 4 of structural formula: ##STR9## or a pharmaceutically acceptable salt, C 1-3 alkyl ester, phenyl C 1-3 alkyl ester, dimethylamino-C 1-3 alkyl ester or acetylamino-C 1-3 alkyl ester thereof, wherein: R 1 is 4-fluorophenyl, and R 2 and R 3 are chloro; R 1 is 3-methyl-4-fluorophenyl, and R 2 and R 3 are methyl; R 1 is 3-methyl-4-fluorophenyl, R 2 is methyl, and R 3 is chloro; or R 1 is 3,5-dimethylphenyl and R 2 and R 3 are methyl.
Claim 7
Dependent Claim
33 words
The compound of claim 5 with structural formula: ##STR10## or a pharmaceutically acceptable salt, C 1-13 alkyl ester, phenyl C 1-3 alkyl ester dimethylamino-C 1-3 alkyl ester or acetylamino-C 1-3 alkyl ester thereof.
Claim 8
Dependent Claim
31 words
A hypocholesterolemic, hypolipemic, pharmaceutical composition comprising a pharmaceutical carrier and an effective hypocholesterolemic, hypolipemic amount of the compound of claim 1 or its salts or esters as defined in claim 1.
Claim 9
Dependent Claim
10 words
The pharmaceutical composition of claim 7 wherein A is hydrogen.
Claim 10
Dependent Claim
59 words
The pharmaceutical composition of claim 8 wherein: E is --CH 2 CH 2 -- or --CH═CH--; R 1 is in the 6-position and is substituted phenyl, wherein there are 1 or 2 substituents independently selected from chloro, fluoro, methyl or methoxy; and R 2 and R 3 are independently halo, or C 1-3 alkyl in the 2- and 4-positions.
Claim 11
Dependent Claim
10 words
The pharmaceutical composition of claim 9 wherein E is --CH═CH--.
Claim 12
Dependent Claim
88 words
The pharmaceutical composition of claim 10 wherein the compound has structural formula: ##STR11## or a pharmaceutically acceptable salt, C 1-3 alkyl ester, phenyl C 1-3 alkyl ester, dimethylamino-C 1-3 alkyl ester or acetylamino-C 1-3 alkyl ester thereof, wherein: R 1 is 4-fluorophenyl, and R 2 and R 3 are chloro; R 1 is 3-methyl-4-fluorophenyl, and R 2 and R 3 are methyl; R 1 is 3-methyl-4-fluorophenyl, R 2 is methyl, and R 3 is chloro; or R 1 is 3,5-dimethylphenyl and R 2 and R 3 are methyl.
Claim 13
Dependent Claim
36 words
The pharmaceutical composition of claim 11 wherein the compound has structural formula: ##STR12## or a pharmaceutically acceptable salt, C 1-3 alkyl ester, phenyl-C 1-3 alkyl ester, dimethylamino-C 1-3 alkyl ester or acetylamino-C 1-3 alkyl ester thereof.
Claim 14
Dependent Claim
40 words
A method of inhibiting cholesterol biosynthesis comprising the administration to a patient in need of such treatment of an effective cholesterol biosynthesis inhibiting amount of the compound of claim 1 or its salts or esters as defined in claim 1.
Claim 15
Dependent Claim
9 words
The method of claim 13 wherein A is hydrogen.
Claim 16
Dependent Claim
58 words
The method of claim 14 wherein: E is --CH 2 CH 2 -- or --CH═CH--; R 1 is in the 6-position and is substituted phenyl, wherein there are 1 or 2 substituents independently selected from chloro, fluoro, methyl and methoxy; and R 2 and R 3 are independently halo, or C 1-3 alkyl in the 2- and 4-positions.
Claim 17
Dependent Claim
9 words
The method of claim 15 wherein E is --CH═CH--.
Claim 18
Dependent Claim
86 words
The method of claim 16 wherein the compound has structural formula: ##STR13## or a pharmaceutically acceptable salt, C 1-3 alkyl ester, phenyl-C 1-3 alkyl ester, dimethylamino-C 1-3 alkyl ester or acetylamino-C 1-3 alkyl ester thereof, wherein: R 1 is 4-fluorophenyl, and R 2 and R 3 are chloro; R 1 is 3-methyl-4-fluorophenyl, and R 2 and R 3 are methyl; R 1 is 3-methyl-4-fluorophenyl, R 2 is methyl, and R 3 is chloro; or R 1 is 3,5-dimethylphenyl and R 2 and R 3 are methyl.
Claim 19
Dependent Claim
35 words
The method of claim 17 wherein the compound has structural formula: ##STR14## or a pharmaceutically acceptable salt, C 1-3 alkyl ester, phenyl-C 1-3 alkyl ester, dimethylamino-C 1-3 alkyl ester or acetylamino-C 1-3 alkyl ester thereof.
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USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1987-07-10 | 1988-01-09 | 1988-07-10 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1991-07-10 | 1992-01-09 | 1992-07-10 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1995-07-10 | 1996-01-09 | 1996-07-10 | $7700.00 | Window Closed / Lapsed |