STUDIES IN THE SYNTHESIS OF POTENTIAL ANTIDIABETIC COMPOUNDS

Abstract

The present investigations attempt to synthesise the potential antidiabetic compounds as exemplified by the preparation of various pyraaoles, isoxazolea and related compounds. The overall problem of diabetes h s necessitated the preparation of drugs for treating this disease which springs from pancreatic disorder. The extent to which the synthetic pyraaoles, isoxasoles and related compounds hitve been effective as hypoglycemics has been evaluated. A number of intermediate methylene compounds, such as 2,4-pentanedione, l-phenyl-l,3-butanedione, 1,3-dipheny1- 1,3-propanedione, i-(4-chlorophenyl)-3-phenyl-l,3-propanedione, l-carbaraoyl-3-methyl-?-pyrazolin-5-one, substituted phenacyl bromides, 3-nitrosubstituted phenacyl bromides and substituted phenacyl esters have been synthesized. P,4-Pentanedlone, 1-pheny1-1,3-butanedlone and 1,3-dipheny1- 1,3-propanedl ma have been synthesised as condensation products of the corresponding ketone with an ester in the presence of sodium or sodium eshoxide followed by acidifica tion. An alternative route to 1,3-dipheny1-1,3-propanediones was through benaalacetophenones which are the condensation products of aromatic aldehydes with ketones. By bromlnation of theoe benaalacetophenones followed by treatment with sodium m< thoxide and subsequent hydrolysis afforded the corresponding l,3-diphenyl-lt3-propanediones. The precursor iv semicarbazone h s been obtained as the condensation product of ethyl accetoacetate and semlcarbazide hydrochloride. Cycllsation of this semicarbazone in ammonia yielded l-carbamoyl-3-methyl-P-pyrazolin-5-one. An improved method for the synthesis of 3-nitrosubstituted phenacyl bromides has been developed by the nitration of phenacyl bromides with fuming nitric acid at 5°. Phenacyl bromides have been convertsd into ynenacyl esters by refluxing with sodium acetate in alcohol. Coupling of substituted benzenediazonium salts, obtained from a number of substituted anilines (vide chapter III) with active methylene group, such as in ethyl acetocet^te, P,4-pentanedione, l-phenyl-lt3~butunedlone, etc. yielded the corresponding arylhydrazono derivatives. The hydrazono structure h s been supported by the NMR and IR spectra of the synthesised compounds. The following potential antidiabetic agents have been synthesised; 1-0 ,4-Dinltrophenyl)-3,5-di;nethyl-4-arylazopyrazoles, 1-(P,4-dinitrophenyl)-3-raethyl-6-phenyl-4-arylazopyrazoles, l-(P,4-dinitrophenyl)-3,5-diphenyl-4-arylazopyrazoles, and l-(P,4-dinitrophenyl)-3-methyl-4-arylhydrazono-P-pyrazolin-6- ones (for details vide chapter IV). A number of pyrazole derivatives 3-phenyl-5-(4-chlorophenyl)-4-arylazopyrazoles and l-phenyl-3-rae thy1-4-arylhydrazono-P-pyrazolin-5-ones have been obtained. I.R. spectra show the characteristic band for the arylazo and arylhydrazono groups at C-4 of pyrazolea and P-pyrazolin-5-ones respectively. l-Carbanioyl-3,5-dinethy1-4-arylazopyrazoles , l-carbamoyl-3-raethyl-5-phenyl-4-arylaaopyrazoles, and l-carbaraoyl-3,B-dipheny1-4-arylazopyrazoles have been synthesioed by the condensation of P,3,4~pentanetrione- 3-arylhydrazones, i-phenyl-P-arylhydrazono-l,P,3-butanetriones, and i,3-diphenyl-P-arylhydrazono-l,P,3-propanetriones with semicarbazide hydrochloride. By coupling diazotised anilines with l-carbamoyl-3-methyl-P-pyrazolin-5-one, l-carbamoyl- 3-raethy1-4-arylhydraaono-P-pyrazolin-5-ones have been obtained.I.R. absorption band of medium intensity at 1560 cm"- for C*C-NH~N« grouping supported the 4-hydraaono formulation of the above P-pyrazolin-5-ones. S nthetic route to 4-hydroxypyrazoles has been developed by tre tment of ethyl P,3-dioxo-4-bromobutyrate- 8-arylhydrazones and i-phenyl-P-arylhydrazono-4-bromobutanel, P,3-triones with ethanolic sodium acetate. An improved procedure for the synthesis of 4-bromo derivatives of ethyl P,3-dioxobutyrate P-arylhydraaones and 1-phenyl-P-arylhydrazono- l,P,3-butanetriones has been devised in the presence of ether as solvent. l-Aryl-3-banzoyl-4-hydroxypyraaoles coupled with 4-methylphenyldiaaonium chloride to give the corresponding l-axyl-3-benzoyl-5-(4-methylphenylhydrazono)- P-pyra55°il-n",,*'"one8 • A number of 4-arylazoisoxuzoles and 4-arylhydrazono- P-isoxaaolin-5-ones, n mely; 3,5-dimethyl-4-arylazoisoxazoles, vi 3-aethyl-6-phenyl-4-arylazoisoxazoles, 3,5-diphenyl- 4-arylazoisoxazoles, and 3-raethyl-4-arylhydrasono-P-isoxazolln- 5-ones have been prepared by the reaction of hydroxylamine with ?,3,4-pentanetrione-3-arylhydrazones, 1-phenyl- P-arylhydrazono-l,P,3-butanetriones, l,3-diphenyl-P-arylhydrasono- l,P,3-propanetriones, and ethyl t,3-dioxobutyrate P-arylhydrazones respectively. The antidiabetic activity of a few of these synthesised compounds have been biologically tested at the Smith Kline and French Laboratories, Philadelphia, U.S.A., in mice, but the results have not been found to compare favourably with the activity of 3,6-dimethyl-pyrazole (parent compound), showing that the substituted pyrazolea and P-pyraaolin-6—ones synthesised as described in the thesis fell short of the desired potentiality for being used as marketable antidiabetics for patients suffering from this disease.