Bisphosphonate squalene synthetase inhibitors and method
AssigneeE. R. Squibb & Sons, Inc.
InventorsScott A. Biller, David R. Magnin
Life of this patent
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Abstract
Compounds which are inhibitors of cholesterol biosynthesis (by inhibiting de novo squalene biosynthesis), and thus are useful as hypocholesterolemic agents and antiatherosclerotic agents are provided which have the structure ##STR1## and analogs thereof, wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are the same or different and are H, lower alkyl, a metal ion or a prodrug ester; R.sup.5 is H, halogen or lower alkyl; Zq is substituted alkenyl, substituted alkynyl, mixed alkenyl-alkynyl or substituted phenylalkyl or, phenylalkenyl or phenylalkynyl, or alkyl, including all stereoisomers thereof. New methods for using such compounds to inhibit cholesterol biosynthesis are also provided.
Claims24
A compound having the structure ##STR86## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are the same or different and are H, lower alkyl, a metal ion or a prodrug ester;
- R.sup.5 is H, halogen or lower alkyl;
- Z is alkenyl group contains at least 7 carbon atoms in the chain and from 1 to 4 double bonds;
- aklynyl containing 1 to 4 triple bonds;
- mixed alkenyl-alkynyl containing 1 to 3 double bonds and 1 to 3 triple bonds, and wherien alkenyl and/or alkynyl may be substituted or unsubstituted;
- and wherein alkenyl and/or alkynyl may optionally include a (CH.sub.2).sub.x group, wherein x is 1 to 15, which is linked to the carbon joining the two phosphorus moieties;
- and wherein stubsituted alkenyl and substituted alkynyl refer to such groups substituted with alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, alkenyloxy, alkynyloxy, aryl and/or cycloalkyl, provided that if Z is an alkenyl group and contains only one carbon-carbon double bond, then it must be substituted with at least one group other than an alkyl group;
- or a group of the structure ##STR87## wherein (CH.sub.2).sub.p contains from 1 to 15 carbons in the chain and may include 0, 1, 2 or 3 triple bonds in the normal chain and/or may include 0, 1, 2 or 3 substituents which are alkyl, alkenyl, alkoxy, alkynyl, hydroxy and/or halogen;
- and R.sup.6, R.sup.7 and R.sup.8 are the same or different and are H, alkyl containing 1 to 40 carbons, alkoxy containing 1 to 40 carbons, alkenyl containing 2 to 40 carbons, alkenyloxy containg 2 to 40 carbons, alkynyl containing 2 to 40 carbons, alkynyloxy, aryloxy, hydroxy, halogen, nitro, amino, thiol, alkylthio, arylthio, arylsulfinyl, alkylsulfinyl, arylsulfonyl, alkylsulfonyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyl, arylcarbonylamino or alkylcarbonylamino, at least one or R.sup.6, R.sup.7 and R.sup.8 being alkenyl, alkenyloxy, alkynyl or alkynyloxy, and wherein the total number of carbons in ##STR88## exceeds 10 carbons, wherein the prodrug ester is (1-alkanoyloxy)-alkyl, ##STR89## wherein R.sup.14 is H, CH.sub.3, C.sub.6 H.sub.5 ;
- or R.sup.1 and R.sup.2, and/or R.sup.3 and R.sup.4 can be taken together as in ##STR90## wherein R.sup.11 and R.sup.12 are H, alkyl, aryl, or arylalkyl and n is 0 to 3.
Dependencies are inferred from the claim text.