Modulators of hepatic lipoprotein metabolism

摘要

The present invention relates to compounds that are useful for modulating hepatic cholesterol metabolism in an animal. The invention includes methods of making and using the compounds of the invention. The invention further provides methods of treating, preventing and/or alleviating a cholesterol related disorder, a cardiovascular disease and/or liver disease in an animal, such as a human, comprising administering compounds of the invention, or pharmaceutically acceptable salts or solvates thereof, to the animal.

主权项

1. A method of increasing the LDL uptake or the LDL receptor level in at least one cell, the method comprising contacting the at least one cell with a therapeutically effective amount of at least one agent comprising a compound of formula (XV) and at least one pharmaceutically acceptable carrier or excipient; and any pharmaceutically acceptable salts thereof wherein in the compound of formula (XV):
Q is S(O)p, C(O), bond, C(O)NR8, C(O)CH2, C(O)O, or C(O)OCH2;R12 is halogen, C1-C8 alkyl, CF3, N(C1-C8 alkyl)2 or OR13;R13 is C1-C8 alkyl or hydrogen;R4 and R5 are each independently selected from the group consisting of hydrogen, 4-6 membered heterocyclic ring, C3-C8 cycloalkyl ring and (CH2)S-aromatic ring,
further wherein the heterocyclic, cycloalkyl, or aromatic ring is unsubstituted or substituted with one or more Rx;or R4 and R5 taken together form a 4-6 membered heterocyclic ring,
optionally substituted at two adjacent carbon atoms on the heterocylic ring, which can optionally be taken together to form a fused aromatic ring;R6 is selected from the group consisting of hydrogen, O(C1-C8 alkyl), O-aromatic ring, O(C3-C8 cycloalkyl ring), and OH;Rx is selected from the group consisting of (CH2)g-aromatic ring and OR10, or two Rx on adjacent carbon atoms are taken together form a fused aromatic ring;R10 is aromatic ring;R8 and R9 are each independently selected from the group consisting of hydrogen, C1-C8 alkyl, (CH2)t-4-8 membered heterocyclic ring, and (CH2)v-aromatic ring,
further where the alkyl, aromatic ring or heterocyclic ring are unsubstituted or substituted with one or more Rz;Rz is selected from halogen, CF3, C1-C8 alkyl, and O(C1-C8 alkyl)2;
or two Rz on adjacent carbon atoms taken together form a 1,3-dioxole ring;or R8 and R9 taken together form a 4-8 membered heterocyclic ring,further wherein the heterocyclic ring is unsubstituted or substituted with one or more Rm;Rm is halogen, CF3, C1-C8 alkyl, or OR17;R17 is hydrogen or C1-C8 alkyl;s is 0, 1, 2, or 3;p is 0, 1, or 2;n is 0, 1, 2, or 3;j is 0, 1, 2, or 3;v is 0, 1, 2, or 3;t is 0, 1, 2, or 3; andg is 0, 1, 2 or 3; whereby the at least one agent increases the LDL uptake or the LDL receptor level in the at least one cell.