BMS 201038-04

Description

Lomitapide is an orally active microsomal triglyceride transfer protein (MTP) inhibitor for the treatment of hypercholesterolemia. The drug was developed by Aegerion Pharmaceuticals Inc. and licensed to Bristol–Myers Squibb Co. and the University of Pennsylvania. Lomitapide effectively lowered LDL–cholesterol, both as a single agent and in combination with commonly prescribed lipid-lowering therapies. Sold under the trade name Juxtapid, the drug offers a new treatment option to patients who cannot tolerate statin therapy or who experience insufficient LDL–cholesterol reduction with the currently available therapies, such as patients with homozygous familial hypercholesterolemia caused by mutations in the LDLR gene.

Definition

ChEBI: A methanesulfonate (mesylate) salt prepared from equimolar amounts of lomitapide and methanesulfonic acid. Used as a complement to a low-fat diet and other lipid-lowering treatments in patients with homozygous familial hypercholesterolemia.

Synthesis

Commercial 9H-fluorene-9-carboxylic acid (105) was alkylated with 1,4-dibromobutane in the presence of n-butyl lithium in THF to give 9-(4-bromobutyl)-9H-fluorene-9-carboxylic acid (106) in 85% yield. Next, activation of the acid as the acid chloride followed by coupling with (2,2,2-trifluoroethylamine) provided amide 107 in 71% yield for the two-step sequence. Displacement of the terminal bromide with the appropriate 4-carbamoyl piperidine followed by removal of the Boc group furnished piperidinyl fluorine 108 in high yield. Amine 108 was then reacted with the acid chloride derived from acid 109 (derived from the Suzuki coupling of boronic acid 110 and o-iodobenzoic acid 111) to give lomitapide, and this was followed by salt formation with methanesulfonic acid to afford lomitapide mesylate (XIV).