Antihypercholesterolemic compounds and related pharmaceutical compositions and methods of use
AssigneeSRI International
InventorsWesley K. M. Chong, Wan-Ru Chao, Dennis M. Yasuda, John G. Johansson, Mitchell A. Avery, Masato Tanabe
Life of this patent
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Abstract
Novel antihypercholesterolemic agents are provided. An exemplary group of compounds has the structural formula (I) ##STR1## wherein R is a C-17 side chain, R.sup.1 is --OH, .dbd.O, or the like, and X and Y are CH, C--OH, C--OCH.sub.3 or C--Z. Methods of using the compound of formula (I) or other novel oxysterol analogs to treat hypercholesterolemia are provided, as are pharmaceutical compositions containing the compounds.
Claims17
A compound having the structural formula (III) ##STR46## wherein:
- R is selected from the group consisting of CH.sub.3, CH.sub.2 OH, CH.sub.2 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2, CH.sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2 --OH, CH.sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2 --F, and CH.dbd.CH--CH(CH.sub.3)--CH(CH.sub.3).sub.2, CH.sub.2 CH.sub.2 CH(CH.sub.2 CH.sub.3)CH(CH.sub.3).sub.2, and CH.dbd.CH--CH(CH.sub.2 CH.sub.3)CH(CH.sub.3).sub.2 ;
- R.sup.1 is selected from the group consisting of --OH, .dbd.O, --OR.sup.8, --O(CO)R.sup.9, --O(CO)--(CH.sub.2).sub.n --COOH, a sulfate group, and an Mg, Na, or K salt of a sulfate group, where R.sup.8 is lower alkyl, R.sup.9 is a C.sub.1 -C.sub.20 aliphatic group or a phenyl group, and n is an integer in the range of 2 to 6 inclusive;
- R.sup.4 and R.sup.5 are independently selected from the group consisting of H, lower alkyl, lower acyl, lower alkoxy, --NH.sub.2 and halogen;
- and
- a represents either a single bond or a double bond.
A pharmaceutical composition for lowering serum cholesterol, comprising, in combination with a pharmaceutically acceptable carrier, an effective serum cholesterol lowering amount of a compound having the structural formula (III) ##STR47## wherein:
- R is selected from the group consisting of CH.sub.3, CH.sub.2 OH, CH.sub.2 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2, CH.sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2 --OH, CH.sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2 --F, and CH.dbd.CH--CH(CH.sub.3)--CH(CH.sub.3).sub.2, CH.sub.2 CH.sub.2 CH(CH.sub.2 CH.sub.3)CH(CH.sub.3).sub.2, and CH.dbd.CH--CH(CH.sub.2 CH.sub.3)CH(CH.sub.3).sub.2 ;
- R.sup.1 is selected from the group consisting of --OH, .dbd.O, --OR.sup.8, --O(CO)R.sup.9, --O(CO)--(CH.sub.2).sub.n --COOH, a sulfate group, or an Mg, Na, or K salt of a sulfate group, where R.sup.8 is lower alkyl, R.sup.9 is a C.sub.1 -C.sub.20 aliphatic group or a phenyl group, and n is an integer in the range of 2 to 6 inclusive;
- R.sup.4 and R.sup.5 are independently selected from the group consisting of H, lower alkyl, lower acyl, lower alkoxy, --NH.sub.2 and halogen;
- and
- a represents either a single bond or a double bond.
A method for lowering serum cholesterol level in a warm-blooded mammal, comprising administering to such mammal an effective serum cholesterol lowering amount of a compound having the structural formula (III) ##STR48## wherein:
- R is selected from the group consisting of CH.sub.3, CH.sub.2 OH, CH.sub.2 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2, CH.sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2 --OH, CH.sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2 --F, and CH.dbd.CH--CH(CH.sub.3)--CH(CH.sub.3).sub.2, CH.sub.2 CH.sub.2 CH(CH.sub.2 CH.sub.3)CH(CH.sub.3).sub.2, and CH.dbd.CH--CH(CH.sub.2 CH.sub.3)CH(CH.sub.3).sub.2 ;
- R.sup.1 is selected from the group consisting of --OH, .dbd.O, --OR.sup.8, --O(CO)R.sup.9, --O(CO)--(CH.sub.2).sub.n --COOH, a sulfate group, or an Mg, Na, or K salt of a sulfate group, where R.sup.8 is lower alkyl, R.sup.9 is a C.sub.1 -C.sub.20 aliphatic group or a phenyl group, and n is an integer in the range of 2 to 6 inclusive;
- R.sup.4 and R.sup.5 are independently selected from the group consisting of H, lower alkyl, lower acyl, lower alkoxy, --NH.sub.2 and halogen, or R.sup.4 R.sup.5 may be linked together to form a 5- or 6-membered aromatic or heterocyclic ring!;
- and
- a represents either a single bond or a double bond.
Dependencies are inferred from the claim text.