US4375475A
Expired / Lapsed
US
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Substituted pyranone inhibitors of cholesterol synthesis
Assignee: Merck and Co Inc
•
Filing: 1981-02-11
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Granted: 1983-03-01
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Expires: 2001-02-11
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
2026-10-24 01:41
CPC Classifications
C; C07; C07D; C07D309/00; C07D309/16; C07D309/28; C07D309/30
Claims Analysis
Total Claims: 24
Claim 1
Independent Claim
102 words
A compound of structural formula ##STR13## wherein A is H or methyl; E is --CH═CH--, or --CH 2 CH 2 --; R 1 , R 2 and R 3 are each selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, substituted phenyl in which the substituents are halo, C 1-4 alkyl, or C 1-4 alkoxy, and 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 4 (R) configuration in the tetrahydropyran moiety of the trans racemate.
Claim 2
Dependent Claim
102 words
A compound of structural formula ##STR13## wherein A is H or methyl; E is --CH═CH--, or --CH 2 CH 2 --; R 1 , R 2 and R 3 are each selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, substituted phenyl in which the substituents are halo, C 1-4 alkyl, or C 1-4 alkoxy, and 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 4 (R) configuration in the tetrahydropyran moiety of the trans racemate.
Claim 3
Dependent Claim
83 words
The compound of claim 1 wherein: A is H or methyl; 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 all of the compounds being the enantiomer having a 4 (R) configuration in the tetrahydropyran moiety of the trans racemate.
Claim 4
Dependent Claim
11 words
The compound of claim 1, or 2 wherein A is hydrogen.
Claim 5
Dependent Claim
9 words
The compound of claim 3, wherein E is --CH═CH--.
Claim 6
Dependent Claim
16 words
The compound of claim 4 which is the 4 (R)-trans-enantiomer of: 6-[2-(3,5-dichloro-4'-fluoro[1,1'-biphenyl]-2-yl)ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one; 6-[2-(3,3',5-trimethyl-4'-fluoro[1,1'-biphenyl]-2-yl)ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one; 6-[2-(3,3'-dimethyl-4'-fluoro-5-chloro[1,1'-biphenyl]-2-yl)ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one; or 6-[2-(3,3'5,5'-tetramethyl[1,1'-biphenyl]-2-yl)ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one.
Claim 7
Dependent Claim
118 words
A hypocholesterolemic, hypolipemic, pharmaceutical composition comprising a pharmaceutical carrier and an effective hypocholesterolemic, hypolipemic amount of a compound of structural formula: ##STR14## wherein A is H of methyl; E is --CH═CH--, or --CH 2 CH 2 --; R 1 , R 2 and R 3 are each selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, substituted phenyl in which the substituents are halo, C 1-4 alkyl, or C 1-4 alkoxy, and 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 4 (R) configuration in the tetrahydropyran moiety of the trans racemate.
Claim 8
Dependent Claim
118 words
A hypocholesterolemic, hypolipemic, pharmaceutical composition comprising a pharmaceutical carrier and an effective hypocholesterolemic, hypolipemic amount of a compound of structural formula: ##STR14## wherein A is H of methyl; E is --CH═CH--, or --CH 2 CH 2 --; R 1 , R 2 and R 3 are each selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, substituted phenyl in which the substituents are halo, C 1-4 alkyl, or C 1-4 alkoxy, and 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 4 (R) configuration in the tetrahydropyran moiety of the trans racemate.
Claim 9
Dependent Claim
84 words
The pharmaceutical composition of claim 6 wherein: A is H or methyl; 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 all of the compounds being the enantiomer having a 4 (R) configuration in the tetrahydropyran moiety of the trans racemate.
Claim 10
Dependent Claim
12 words
The pharmaceutical composition of claim 6 or 7 wherein A is hydrogen.
Claim 11
Dependent Claim
10 words
The pharmaceutical composition of claim 8, wherein E is --CH═CH--.
Claim 12
Dependent Claim
16 words
The pharmaceutical composition of claim 9 which is the 4(R)-trans-enantiomer of: 6-[2-(3,5-dichloro-4'-fluoro[1,1'-biphenyl]-2-yl)ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one; 6-[2-(3,3',5-trimethyl-4'-fluoro[1,1'-biphenyl]-2-yl)ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one; 6-[2-(3,3'-dimethyl-4'-fluoro-5-chloro[1,1'-biphenyl]-2-yl)ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one; or 6-[2-(3,3',5,5'-tetramethyl[1,1'-biphenyl]-2-yl)ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one.
Claim 13
Independent Claim
127 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 a compound having the structure: ##STR15## wherein A is H or methyl; E is --CH═CH--, or --CH 2 CH 2 --; R 1 , R 2 and R 3 are each selected from halogen; C 1-4 alkyl, C 1-4 haloalkyl, substituted phenyl in which the substituents are halo, C 1-4 alkyl, or C 1-4 alkoxy, and 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 4 (R) configuration in the tetrahydropyran moiety of the trans racemate.
Claim 14
Independent Claim
127 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 a compound having the structure: ##STR15## wherein A is H or methyl; E is --CH═CH--, or --CH 2 CH 2 --; R 1 , R 2 and R 3 are each selected from halogen; C 1-4 alkyl, C 1-4 haloalkyl, substituted phenyl in which the substituents are halo, C 1-4 alkyl, or C 1-4 alkoxy, and 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 4 (R) configuration in the tetrahydropyran moiety of the trans racemate.
Claim 15
Dependent Claim
83 words
The method of claim 11 wherein: A is H or methyl; 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 all of the compounds being the enantiomer having a 4 R configuration in the tetrahydropyran moiety of the trans racemate.
Claim 16
Dependent Claim
11 words
The compound of claim 11 or 15 wherein A is hydrogen.
Claim 17
Dependent Claim
9 words
The method of claim 13, wherein E is --CH═CH--.
Claim 18
Dependent Claim
15 words
The method of claim 14 which is the 4(R)-trans-enantiomer of: 6-[2-(3,5-dichloro-4'-fluoro[1,1'-biphenyl]-2-yl)ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one; 6-[2-(3,3',5-trimethyl-4'-fluoro[1,1'-biphenyl]-2-yl)ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one; 6-[2-(3,3'-dimethyl-4'-fluoro-5-chloro[1,1'-biphenyl]-2-yl)ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one; or 6-[2-(3,3'-5,5'-tetramethyl[1,1'-biphenyl]-2-yl)ethenyl]-3,4,5,6-tetrahydro-4-hydrox-2H-pyran-2-one.
Claim 19
Dependent Claim
11 words
The 4(R)-trans enantiomer of the compound 6-[2-(3,3',5-trimethyl-4'-fluoro-[1,1'-biphenyl]-2-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one of structural formula: ##STR16##
Claim 20
Dependent Claim
11 words
The 4(R)-trans enantiomer of the compound 6-[2-(3,3',5-trimethyl-4'-fluoro-[1,1'-biphenyl]-2-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one of structural formula: ##STR16##
Claim 21
Dependent Claim
27 words
A hypocholesterolemic, hypolipemic, pharmaceutical composition comprising a pharmaceutical carrier and an effective hypocholesterolemic, hypolipemic amount of the 4(R)-trans enantiomer of the compound 6-[2-(3,3',-5-trimethyl-4'-fluoro[1,1'-biphenyl]-2-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2one of structural formula: ##STR17##
Claim 22
Dependent Claim
27 words
A hypocholesterolemic, hypolipemic, pharmaceutical composition comprising a pharmaceutical carrier and an effective hypocholesterolemic, hypolipemic amount of the 4(R)-trans enantiomer of the compound 6-[2-(3,3',-5-trimethyl-4'-fluoro[1,1'-biphenyl]-2-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2one of structural formula: ##STR17##
Claim 23
Independent Claim
35 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 4(R)-trans enantiomer of the compound 6-[2-(3,3'-5-trimethyl-4'-fluoro[1,1'-biphenyl]-2-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one with structural formula: ##STR18##
Claim 24
Independent Claim
35 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 4(R)-trans enantiomer of the compound 6-[2-(3,3'-5-trimethyl-4'-fluoro[1,1'-biphenyl]-2-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one with structural formula: ##STR18##
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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) | 1986-02-28 | 1986-08-30 | 1987-03-01 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1990-02-28 | 1990-08-30 | 1991-03-01 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1994-02-28 | 1994-08-30 | 1995-03-01 | $7700.00 | Window Closed / Lapsed |