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US 5,506,219 AGranted
Pyridine anchors for HMG-CoA reductase inhibitors
AssigneeE. R. Squibb & Sons, Inc.
InventorJeffrey A. Robl
Life of this patent
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Abstract
Compounds which are useful as inhibitors of cholesterol biosynthesis and thus as hypocholesterolemic agents are provided which have a quinoline or a pyridine anchor attached by means of a linker to a binding domain sidechain, which compounds inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase.
Claims22
A compound of the formula ##STR61## or a pharmaceutically acceptable salt thereof wherein:
- Am is ##STR62## X is --(CH.sub.2).sub.a --, --CH.dbd.CH--, --C.tbd.C-- or --CH.sub.2 O--;
- R.sup.1 and R.sup.2 are the same or different and are each independently selected from
- (i) hydrogen,
- (ii) alkyl,
- (iii) aryl,
- (iv) cycloalkyl,
- (v) aralkyl,
- (vi) aralkoxy,
- (vii) alkenyl, and
- (viii) cycloalkenyl;
- R.sup.3 is selected from
- (i) hydrogen,
- (ii) lower alkyl,
- (iii) aryl,
- (iv) cycloalkyl,
- (v) alkoxy,
- (vi) aralkyl,
- (vii) aralkoxy,
- (viii) alkenyl,
- (ix) cycloalkenyl,
- (x) halo-substituted alkyl,
- (xi) adamantyl and
- (xii) thienyl, furyl, pyrrolyl, pyridyl, benzodioxolyl, imidazolyl, pyrrolidinyl, piperidinyl and indolyl;
- R.sup.4 is selected from
- (i) hydrogen,
- (ii) lower alkyl,
- (iii) aryl,
- (iv) cycloalkyl,
- (v) alkoxy,
- (vi) aralkyl,
- (vii) aralkoxy,
- (viii) alkenyl,
- (ix) cycloalkenyl,
- (x) adamantyl,
- (xi) halogen,
- (xii) halo-substituted alkyl and
- (xiii) thienyl, furyl, pyrrolyl, pyridyl, benzodioxolyl, imidazolyl, pyrrolidinyl, piperidinyl and indolyl;
- R.sup.5 and R.sup.7 are each independently selected form hydrogen, lower alkyl, alkali metal salt ion and alkaline earth metal salt ion;
- R.sup.6 is hydrogen or lower alkyl;
- R.sup.8 is hydrogen or lower alkyl in the free acid form or in the form of a physiologically acceptable and hydrolyzable ester or .delta.-lactone thereof, or an alkali metal salt ion or alkaline earth metal salt ion;
- n is 0 or 1;
- and
- a is 1, 2 or 3, and wherein "aryl" by itself or as part of another group is a monocyclic or bicyclic aromatic group containing 6 to 10 carbons in the ring portion;
- "alkyl" or "lower alkyl" by itself or as part of another group contains 1 to 12 carbons;
- "cycloalkyl" by itself or as part of another group contains 3 to 12 carbons;
- "cycloalkenyl" by itself or as part of another group contains 3 to 12 carbons.
43 more elements
A compound of the formula ##STR63## or a pharmaceutically acceptable salt thereof wherein:
- Am is ##STR64## X is --(CH.sub.2).sub.a --, --CH.dbd.CH--, --C.tbd.C-- or --CH.sub.2 O--;
- R.sup.1 and R.sup.2 are the same or different and are each independently selected from
- (i) hydrogen,
- (ii) alkyl,
- (iii) aryl,
- (iv) cycloalkyl and
- (v) alkenyl,
- R.sup.3 is selected from
- (i) hydrogen,
- (ii) lower alkyl,
- (iii) aryl,
- (iv) cycloalkyl,
- (v) aralkyl,
- (vi) alkenyl,
- (vii) adamantyl and
- (vii) thienyl, furyl, pyrrolyl, pyridyl, benzodioxoyl, imidazolyl, pyrrolidinyl, piperidinyl and indolyl;
- R.sup.4 is selected from
- (i) hydrogen,
- (ii) lower alkyl,
- (iii) aryl,
- (iv) cycloalkyl,
- (v) aralkyl,
- (vi) alkenyl and
- (vii) thienyl, furyl, pyrrolyl, pyridyl, benzodioxolyl, imidazolyl, pyrrolidinyl, piperidinyl and indolyl;
- R.sup.5 and R.sup.7 are each independently selected form hydrogen, lower alkyl, alkali metal salt ion and alkaline earth metal salt ion;
- R.sup.6 is hydrogen or lower alkyl;
- R.sup.8 is hydrogen or lower alkyl in the free acid form or in the form of a physiologically acceptable and hydrolyzable ester or .delta.-lactone thereof, or an alkali metal salt ion or alkaline earth metal salt ion;
- n is 0 or 1;
- and
- a is 1, 2 or 3 and wherein "aryl" by itself or as part of another group is a monocyclic or bicyclic aromatic group containing 6 to 10 carbons in the ring portion;
- "alkyl" or "lower alkyl" by itself or as part of another group contains 1 to 12 carbons;
- "cycloalkyl" by itself or as part of another group contains 3 to 12 carbons;
- "cycloalkenyl" by itself or as part of another group contains 3 to 12 carbons.
30 more elements
(S)-4-[[2-[4-(4-Fluorophenyl)-5-methyl-2-(1-methylethyl)-6- phenyl-3-pyridinyl]ethenyl]hydroxyphosphinyl]-3-hydroxybutanoic acid.
Dependencies are inferred from the claim text.