Piperazine derivatives as FASN inhibitors

#The present invention relates to novel piperazine derivatives which inhibit the activity of fatty acid synthase (FASN; also abbreviated as FAS), to pharmaceutical compositions comprising them, to processes for their preparation, and to their use in therapy for the treatment of cancers.

#Fatty Acid Synthase (FAS) is a critical enzyme for endogenous lipogenesis and plays an important role in the modulation of key intermediates of lipid and carbohydrate cellular metabolism. FAS is highly expressed in the tissues with high metabolic activity (for example liver, adipose tissue and brain) and there are good reasons to believe that a FAS inhibitor would cause beneficial metabolic effects in peripheral tissues. In addition, inhibition of FAS in the hypothalamus may result in reduced food intake. The non-specific irreversible FAS inhibitors cerulenin and C-75 have been reported in the literature to decrease brain levels of orexigenic neuropeptides and to decrease food intake.

#FAS is also highly expressed in human sebocytes, the lipid producing cells of the sebaceous glands. Acne is the most common disorder involving the sebaceous gland. The pathogenesis of acne involves lipid (over)production by the sebaceous gland and it has been reported that inhibitors of mammalian FAS inhibit the production of sebum in sebocytes (US 2005/0053631). Acne cannot occur without sebum lipids. There is an unmet medical need in the treatment of acne for agents that reduce sebum production.

#1.1 Tert-butyl 1-piperazinecarboxylate (0.5 g; 2.69 mmol) was dissolved in 10 ml of dichloromethane (DCM). N-ethyldiisopropylamine for synthesis (1.37 ml; 8.06 mmol) was added and the mixture cooled down to 0° C. Now 4-bromobenzoyl chloride for synthesis (0.66 g; 2.95 mmol) was dissolved in 10 ml of DCM and added dropwise to the reaction, followed by stirring at RT overnight. Regarding to LC-MS the reaction was complete. The reaction mixture was extracted with 50 mL of water. The organic layer was dried over MgSO4, filtered off and then reduced to dryness under vacuo to afford 1.0 g (100%) 4-(4-bromo-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester 1 as beige solid.

#1.2 4-(4-Bromo-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester 1 (0.5 g; 1.35 mmol) was dissolved in 15 ml of HCl/isopropanol (5-6N) and then stirred at 55° C. for 2 hrs. The reaction mixture was reduced to dryness under vacuo to yield quantitatively (4-bromo-phenyl)-piperazin-1-yl-methanone hydrochloride 2 as beige solid.

#1.3 (4-Bromo-phenyl)-piperazin-1-yl-methanone hydrochloride 2 (200 mg; 0.66 mmol) was dissolved in 5 ml of DCM, N-ethyldiisopropylamine for synthesis (0.34 ml; 2.0 mmol) was added and then cooled to 0° C. Propionyl chloride for synthesis (0.063 ml; 0.73 mmol) was added dropwise followed by stirring at RT for 14 h. The reaction mixture was separated between DCM and water. The organic layer was separated, dried over MgSO4, filtered off and then reduced to dryness under vacuo to afford 213 mg (99.3%) 1-[4-(4-bromo-benzoyl)-piperazin-1-yl]-propan-1-one 3 as a brown oil.