2-Acylaminopropoanol-Type Glucosylceramide Synthase Inhibitors

摘要

A compound is represented by Structural Formula (I):;;or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprises a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof. A method of treating a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof. The subject has type 2 diabetes; renal hypertrophy or hyperplasia associated with diabetic nephropathy; Tay-Sachs; Gaucher's; or Fabry's disease. Methods of decreasing plasma TNF-α, lowering blood glucose levels, decreasing glycated hemoglobin levels, inhibiting glucosylceramide synthase, and lowering glycosphingolipid concentrations in a subject in need thereof respectively comprise administering to the subject a therapeutically effective amount of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof.

主权项

1. A compound represented by the following structural formula: or a pharmaceutically acceptable salt thereof, wherein: R1 is a substituted or unsubstituted aryl group; Y is —H, a hydrolyzable group, or a substituted or unsubstituted alkyl group; R2 and R3 are each independently —H, a substituted or unsubstituted aliphatic group, or a substituted or unsubstituted aryl group, or R2 and R3 taken together with the nitrogen atom of N(R2R3) form a substituted or unsubstituted non-aromatic heterocyclic ring; and X is —(CR5R6)n-Q-; Q is —O—, —S—, —C(O)—, —C(S)—, —C(O)O—, —C(S)O—, —C(S)S—, —C(O)NR7—, —NR7—, —NR7C(O)—, —NR7C(O)NR7—, —OC(O)—, —SO3—, —SO—, —S(O)2—, —SO2NR7—, or —NR7SO2—; and R4 is —H, a substituted or unsubstituted aliphatic group, or a substituted or unsubstituted aryl group; or X is —O—, —S— or —NR7—; and R4 is a substituted or unsubstituted aliphatic group, or substituted or unsubstituted aryl group; or X is —(CR5R6)n—; and R4 is a substituted or unsubstituted cyclic alkyl group, or a substituted or unsubstituted cyclic alkenyl group, a substituted or unsubstituted aryl group, —CN, —NCS, —NO2 or a halogen; or X is a covalent bond; and R4 is a substituted or unsubstituted aryl group; and R5 and R6 are each independently —H, —OH, —SH, a halogen, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted lower alkylthio group, or a substituted or unsubstituted lower aliphatic group; n is 1, 2, 3, 4, 5 or 6; and each R7 is independently —H, a substituted or unsubstituted aliphatic group, or a substituted or unsubstituted aryl group, or R7 and R4 taken together with the nitrogen atom of NR7R4 form a substituted or unsubstituted non-aromatic heterocyclic group.