Cholesterol ester transfer protein inhibitors and their use in pharmaceutical to alter plasma lipid levels by increasing HDL and lowering LDL levels

摘要

Cholesteryl ester transfer protein inhibitors of the Formula (I) wherein: R1 is Y, W-X or W-Y W is a carbonyl, thiodarbonyl, sulfinyl or sulfnyl X is O-Y, -S-Y, -N(H)-Y or -N-(Y)2. Y is Z or an optionally substituted 1 to 10 membered straight or branched carbon chain where one or two carbon atoms, other than the connecting carbon can be replaced with O, N (or N oxide) or S (or S oxide). Z is 3 to 8 membered carbocyclic or heterocyclic ring or a bicyclic ring system. R2 is an optionally substituted 1 to 6 membered straight or branched carbon chain where one or two carbon atoms other than the connecting carbon can be replaced with O, N (or N oxide) or S (or S oxide) or an optionally substituted carbocyclic or heterocyclic ring which ring ma be optionally be attached via an (C1-C4)alkyl group. Provided that R2 is not methyl. R3 is hydrogen or Q. Q is an optionally substituted 1 to 6 membered straight or branched carbon chain where one carbon atom other than the connecting carbon can be replaced by O, N (or N oxide) or S (or S oxide). In particular Q may be substituted by V. V is a 3 to 8 membered carbocyclic or heterocyclic ring or a bicyclic ring system. R4 is Q1 or V1. Q1 is an optionally substituted 1 to 6 membered straight or branched carbon chain where one carbon atom other than the connecting carbon can be replaced by O, N (or N oxide) or S (or S oxide). V1 is a carbocyclic or heterocyclic ring. Wherein R3 must contain V or R4 must contain V1. R5, R6 , R7 and R8 are each independently hydrogen, a bond, nitro or halo wherein said bond is substituted with T or a 1 to 12 membered straight or branched carbon chain where one or two carbon atoms, other than the connecting carbon can be replaced with O, N (or N oxide) or S (or S oxide). R5 and R6 , or R6 and R7 and/or R7 and R8 may also be taken together and can form at least one optionally substituted 4 to 8 membered ring that is partially saturated or fully unsaturated optionally having 1 to 3 heteroatoms independently selected from nitrogen, sulfur and oxygen. Provided that R1 is not (C1-C6)alkyl. Pharmaceutical compositions containing such inhibitors can be used to elevate certain plasma lipid levels, including high density lipoprotein-cholesterol and to lower certain other plasma lipid levels, such as LDL-cholesterol and triglycerides and in diseases which are exacerbated by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis, cardiovascular diseases, dyslipidemia and vascular complications of diabetes, obesity or endotoxemia in some mammals, including humans.