The design and synthesis of the Angiotensin Converting Enzyme inhibitor Cilazapril and related bicyclic compounds

Abstract

The postulated binding functions for the active site of Angiotensin Converting Enzyme (A.C.E.), derived in an earlier study, have made possible the design of improved inhibitors. Consequently, (1 S,9S)-9-azepine-1 -carboxylic acid (Cilazapril), and related compounds, have been synthesized. They are very active inhibitors of A.C.E. and are highly potent antihypertensives in vivo. Modulation of the renin-angiotensin system, in particular through inhibition of angiotensin converting enzyme (A.C.E., E.C.3.4.15. l.), has assumed increasing importance in the therapy of hypertension and of congestive heart failure. Clinical investigations, initially with nonapeptide SQ2088 1 * and later with Captopril (1)3 and Enalapril (2)> have established that these potent A.C.E. inhibitors are effective antihypertensives in man.

Chemo-enzymatic synthesis of ethyl (R)-2-hydroxy-4-phenylbutyrate

“…1): classical racemate resolution of the 2-hydroxy-4-phenylbutyric acid or ester 3, enantioselective reduction of the ethyl 2-keto-4-phenyl-3-butenoate 4, and enantioselective hydrogenation of the ethyl 2-keto-4-phenylbutyrate 5. [10][11][12][13][14] All of those methodologies have been considered as non-optimal solutions particularly given the current status of the patent situation, which requires more economical strategies for the obtainment of these compounds. 15 The use of 2,4-dioxophenylbutanoic acid 6 as a starting material or the corresponding ester 7 has been considered as a valuable alternative method to produce (R)-2-HPBA 1.…”

Asymmetric organocatalytic Strecker-type reactions of aliphatic N,N-dialkylhydrazones

“…After 15 minutes, a solution of triphosgene (178 mg, 0.6 mmol) in anhydrous CH 2 Cl 2 (2 mL) was added dropwise and the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was diluted with CH 2 Cl 2 (2 mL), washed with water (5 mL), brine (5 mL), dried over Na 2 SO 4 Determination of absolute configuration (Scheme 4): synthesis of (S)-4-bromo-N-(1-cyano-2-methylpropyl)-N-(1,3-diphenylpropan-2-yl)benzamide (8) Et 3 N (0.7 mL, 5 mmol) and 4-bromobenzoyl chloride (1 g, 5 mmol) were sequentially added to a solution of 2b (150 mg, 0.5 mmol) in anhydrous CH 2 Cl 2 (2.5 mL). The reaction was stirred at reflux for 48 h, neutralized with a saturated solution of NaHCO 3 , and extracted with dichloromethane (3 × 10 mL).…”

“…until pH ∼ 8, and extracted with CH 2 Cl 2 (2 × 10 mL) and Et 2 O (2 × 10 mL). The organic extracts were dried over Na 2 SO 4 …”

“…Combined organic extracts were washed with 10% aqueous solution of sodium bicarbonate (2 × 10 mL) and brine (10 mL). The organic extracts were dried over Na 2 SO 4 General procedure for the transformation of 4 into acids 5…”

“…2 Additionally, cyclic α-hydrazino acids are present in a variety of natural peptides with remarkable biological properties (antibacterial, antitumour or even anti-HIV therapeutics). 3 The L-enantiomer of hexahydropyridazine-3-carboxylic acid ( piperazic acid) also resides within the bicyclic ring system of many bioactive synthetic products such as cilazapril, 4 a drug widely used in the treatment of hypertension. Furthermore, α-hydrazino acids have attracted a great deal of interest in recent years as valuable precursors of conformationally restricted, 5 protease-resistant peptidomimetics.…”