SYNTHESIS OF POTENTIAL ANTIDIABETIC AGENTS

Abstract

Despite the beat tffortt put in by tht medicintl chemists tht world over towtrds tht discovery of effective drugs for tht treatment of dltbttts in human beings, very little seems to have been tchitved in this direction. A ftw compounds btlonging to biguanides tnd sulphonylurtts, however, heve been found effective in the treatment of t few ditbttics but tt tht tame time ineffective in several others. This presents tn Interesting chellenge to study the chemotherapy of potential antidiabetic agents. A programme wes, therefore, undertaken with a view to seerch for a new claes of potential antidiabetic agents end extend the existing work in the synthesis of tntiditbttics, of tht following series, viz., 3,5-di substituted- {2H)-4-arylazo-1,2,6-thladiazine 1,1- dioxides, N^benxoyl-a.S-ditubstituted^-trylasopyraxoltt, Nx- (B-hyd ro xybenzylmethyl)-4-trylhydrtiono-3-mtthyl-a« pyrazolin-5-ones and their related derlvativea, N^-phenylctrbamoyl- 4-aryltzo-3/6 mtthyl or phenylpyrtzolts and derivatives, 4«arylazo-N1«guanylnltrate-3,5-dlsubstitutedpyrazoles end pyrazolones, 4-arylazo-N1»(4-acetamidophenyl)« sulphonyl-3,5-substituted pyrazolea and related derivatives are prepared. The proof of the structures of these compounds rests on elemental analysis, supplemented by ir spectra. The extent to which these synthetic compounds are effective as antidiabetic agent e het been tvtlutted by suitable methoda. (iv) A number of retctlvt methylene compoundt, such as 2,4-pentanedione, l-phenyl-I,3-butanedlone, and l,3-diph#nyl-l,3-propanedione have been prepared via. standard claiaen condensation of tcld esters with ketones in the presence of bttlc reagents such es sodium or sodium ethoxlde. Substituted hydrazines have been obtained by the hydrazlnolysis of ethylbenzoate, styrene oxide, phenyl* urea, 4«aeetamldophenylsulphonylchlorlde and benzylsulphonylehlorlde. Tht precursors, such tt, ethyl 2,3-dioxobutyrate- 2-arylhydrazones, 2,3,4-pentanetrione-3-arylhydrazones, l-phenyl-2-arylhydrazono-l,2,3-butanetriones, 1,3* diphanyl-2-arylhydrazono*l,2,3-propanetriones, and others have been synthesised by the usutl well known methodt described in the existing literature. Tht brominttion of copper chelates of 2,3,4. pentanetrione-3-arylhydrazonea and 5,5-dimethylcyclohexane- 2-arylhydrazono-l,2,3-triones ha a been investigated. The proof of the structure of the bromo-derivatives prepared Is based on the fact that all of them liberate iodine from potassium iodldt, tnd further supported by elamenttl analysis, uv and ir spectra. Nitration of 2,3,4.pentanetrlone*3- phenylhydrazone gives 2,3,4-pentanetrione-3-N-nitrophenylhydrtzont tt tht mtjor product. Tht rttctlon of sulphamide with 2,3,4-pentanetrione- 3-arylhydrazones, l-phenyl-2-arylhydrazono-1,2,3- (v) butanetriones, and lt3-dlphenyl-2-arylhydrazono-1,2,3» propanetriones gives 3,5-diaiethyl-, 3-methyl-*-phenyl-, and 3,5-dlphenyl-(2H)-4-arylazo-i,2,o-thiaulezine 1,1- dioxides, respectively. Tha 3,5-di«ethyl-(2H)-4-arylazol,?, 6-thlediazine 1,1-dioxidee hava alto baan obtainad by coupling of tha aryldlezonium ealts with 3,5-di»ethyl- (2H)-lt2t6-thiadlazine 1,1-dioxlde, followed by treatment with acetic acid. N^-Benzoyl-S.S-dlmethyW-erylatopyrezolea, N^-benzoyl-S-methyl-S-phenyW-arylaxopyrezolea, Nbenzoyl- 3,$-diphenyl-4-arylazopyrazolesf NX»benxoyl-3- methyl-4-arylhydrazono-2-pyrazolin-5-ones, and uMp-hydroxybenzYlmethyl)- 3,»-dimethyl-4.arylezopyrazoleaj NMp-hydroxybenzyii »ethyl)-3-methyl-*-phenyl-4-arylazopyra*olee, and NA» (B-hydroxybanzylmathyl )»3-»athyl«4«arylhydrazono-2« pyrazolln-S-ones hava baan «yhthasisa<l by tha reaction of arylhydrazono derivatives of 1,3-dlketones and ethyl 3-oxobutyrate with benzoylhydraxlne and (/•(hydrazinoaethyl)- banzylalcohol, respectively. Ir spectra ihow tha characteristic bands for tho arylazo and arylhydrazono group a at C-4 of tha pyrezolee and 2-pyrazolin-5-onea, respectively. Cyclisation of 4-ph#nylse»icarbazide with 2, 3,4-pentanetrione-3- arylhydrazonoa, 1-phenyl- 2-aryl hydrazono 1,2,3-butanetriones, l,3-dlphenyl-2-arylhydrazono- l,2,3-propanetriones and ethyl-2,3-dloxobutyrate-2- (vi) aryl hydrazones hat been found to give N*-phenylcarb amoyl- 3,5-dimethyl-4-arylazopyrazol as, N^phenylcazbamoyl-S-methyl. l-phenyl-4-arylazopyrazoles, N^phenylcarbamoyl-S.S-diphenyl" 4-arylazopyrazolea, and N^phenylcarbemoyl-S-methyl^- arylhydrazono-2-pyrazolin-5-ones, respectively. A number of 4-arylazopyrazolea and 4-arylhydrazono- 2-pyrazolin-5-ones, namely; 3,fi-dlmethyl-4- arylazo-NA-guanylnltratepyrazolea, 3»methyl-5-phenyl-4- arylazo-N*-guanylnltratepyrazolee, 3,3-dlphenyl-4-arylazo- N*-guanylnltretepyrazoles, S-methyl^-erylhydrazono-N*- guanylnltrate-2-pyrazolln-5-onea have been prepared by the reaction of aminoguanldinenitrate with 2,3,4-pentanetrione- 3-arylhydrazones, i-phenyl-2-arylhydraz©no«i,2,3-butenetrlones, l,3-diphenyl-2-arylhydrazono-l,2,3*propanetriones and ethyl 2,3-dioxobutyrate-2-arylhydrazonea, respectively. Syntheses of N1-(4-acetamidophenyl) sulphonyl- 4-arylazo-3,5-dimethylpyrazolas, N1-(4-ac©tamldophenyl)- aulphonyl-4-arylazo-3-methyl-5-phenylpyrazoles, N1- (4- acetaaidoph enyl) eulphonyl-4-arylazo-3,ft-diphenylpyraaoles, and N1«(4-acetamldophonyl) sulphonyl-4-arylhydrazono-3- methyl-2-pyrazolln-5*onee have also been achieved. The reaction of benzylsulphonylhydrazIda with 2-arylhydrazono derivatives of 1,3-dlketones, however, failed to yield the expected products. K^Benzylsulphonyl- 4-arylhydrazono-3-«ethyl-2-pyrazolin-5-ones have boen synthesised by the cycll cation of benzyl sulphonylhydrazlde (vii) with ethyl 2,3-dioxobutyrate-2-arylhydrazones. The antidiabetic activity of some of the ayntheslsed compounds haa been evaluated at the Smith Kline and French Laboratories, Philadelphia, U.S.A. and Lederle Laboratories, Pearl River, New York, U.S.A. In mice and guinea pig a and quite a few showed a varying degree of antidiabetic activity.