Analogues of captopril, enalaprilat, and the phosphinic acid [hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-proline incorporating 4-substituted proline derivatives have been synthesized and evaluated as inhibitors of angiotensin-converting enzyme (ACE) in vitro and in vivo. The 4-substituted prolines, incorporating alkyl, aryl, alkoxy, aryloxy, alkylthio, and arylthio substituents were prepared from derivatives of 4-hydroxy- and 4-ketoproline. In general, analogues of all three classes of inhibitors with hydrophobic substituents on proline were more potent in vitro than the corresponding unsubstituted proline compounds. 4-Substituted analogues of captopril showed greater potency and duration of action than the parent compound as inhibitors of the angiotensin I induced pressor response in normotensive rats. The S-benzoyl derivative of cis-4-(phenylthio)captopril, zofenopril, was found to be one of the most potent compounds of this class and is now being evaluated clinically as an antihypertensive agent. In the phosphinic acid series, the 4-ethylenethioketal and trans-4-cyclohexyl derivatives were found to be the most potent compounds in vitro and in vivo. A prodrug of the latter compound, fosinopril, is also being evaluated in clinical trials.
The 5,5-dimethylpyrazolidin-3-one (4), prepared from ethyl 3-methylbut-2-enoate (3) and hydrazine hydrate, was treated with various substituted benzaldehydes 5a ± i to give the corresponding (1Z)-1-(arylmethylidene)-5,5-dimethyl-3-oxopyrazolidin-1-ium-2-ide azomethine imines 6a ± i. The 1,3-dipolar cycloaddition reactions of azomethine imines 6a ± h with dimethyl acetylenedicarboxylate ( dimethyl but-2ynedioate; 7) afforded the corresponding dimethyl pyrazolo[1,2-a]pyrazoledicarboxylates 8a ± h, while by cycloaddition of 6 with methyl propiolate ( methyl prop-2-ynoate; 9), regioisomeric methyl pyrazolo[1,2-a]pyrazolemonocarboxylates 10 and 11 were obtained. The regioselectivity of cycloadditions of azomethine imines 6a ± i with methyl propiolate (9) was influenced by the substituents on the aryl residue. Thus, azomethine imines 6a ± e derived from benzaldehydes 5a ± e with a single substituent or without a substituent at the orthopositions in the aryl residue, led to mixtures of regioisomers 10a ± e and 11a ± e. Azomethine imines 6f ± i derived from 2,6-disubstituted benzaldehydes 5f ± i gave single regioisomers 10f ± i.
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