A number of biphenyl substituted 1,2-dihydroquinolin-2-ones were synthesized by regiospecific alkylation of the corresponding IH-derivatives.Again, these precursors were prepared in three steps by acetoacetylation of anilines, regiospecific C-alkylation of the resulting B-ketoanilides and subsequent condensation to the quinolinones.One of the target compounds, 2-[7-ethyI-4-methyl-2-0~0.-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]l,2-dihy~uinolin-3-yl]-~,~-dimethylacetamide (lOe), is a potent angiotensin I1 receptor antagonist.The tetrasubstituted imidawle losanan (DuP 753) is the prototype of potent, selective snd orally achve nonpeptide angiotensin I1 receptor antagonists.'This compound is currently in clinical vials as an agent for the treatment of hypertension.2The alkyl chain and the biphenyltetrazole attached to the imidazole ring are the key structural features within this class of drugs.The ~midawle moiety, however, can be replaced by a number of other heterocycles such as benzimdawles,3 imidaz~~yridines?1,2,4-triazoles5 or 4-aminopyridines.6As part of a survey to peplace the potential imidawle moiety with other heterocyclic groups, we synthesized 3-substituted pyridones (I)? which were found to be potent antagonists of angiotensin 11.We were also interested in mak~ng rigid analogues of 1 by forming a nng between the pyridone nucleus and the butyl chain to provide quinolinones (2) with the alkyl chain attached to the 7-position.In this paper we report the syntheses and b !! poperties of selected 3,4,7-msubstituted 1-[(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl1-l,2-dihy-Dedicated to Dr. Amold Brossi on the occasion of h ~s 70th birthday.118 HETEROCYCLES, Vol.39, No. 1,1994 droquinolin-2-ones as angiotensin I1 antagonists.DuP 753 1 2 Two methods have been established for the preparation of a wide range of 3,7-disubstimted 1.2dihydroquinolin-2-ones: Condensation of malonates w~th anibnes leading to 4-hydroxy derivatives8 and condensation of anilines with ethyl 2-alkylacetoacetates giving rise to 4-methyl derivatives.9On account of broad variations in the 3-position we sought for a reliable method for the preparation of this ring system.We utilized the previously reported Knorr cyclization of an acetoacetanilide derivative obtained from Q-anisidine and diketene.10Instead of diketene the commercially available 2,2,6-mmethyl-4H-1,3-dioxin-4-one (4) (dioxinone) was used.II The synthesis of 3.7-disubstituted 1,2-dihydmquinolin-2-one intermediates was canied out according to Scheme I. Scheme I R' Me 0.5 h.120 O C Rl 5 a-c 3 a-c DMF H+, room H 0 temperature Me 6 a-e 7 a-h Reaction of anilines (3a-c) with dioxinone (4) led smoothly to the 0-ketoanilides (5a-c).Treatment of 5a-c
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Mederski et al. (1994) studied this question.