STUDIES ON THE SYNTHESIS OF SOME HETEROCYCLIC SYSTEMS OF MEDICINAL IMPORTANCE

Abstract

Heterocyclic compounds have evinced considerable interest as they play a vital role in several important biological processes as well as due to their economic importance and their wide use as pharmaceuticals, solvents, dyes, plastics, herbicides and a host of other industrial applications. Most of the important drugs and chemotherapeutic agents are hetero cyclic compounds. Amongst several types of heterocyclic compounds used in chemotherapy, pyrazoles, acylpyrazoles, arylazapyrazoles and pyrazolones, thiazoles, pyrimidines, and thiobarbituric acids are of particular interest as they have been employed effectively as potential antitumour, antitubercu lar, antibacterial, insecticidal, trypanocidal, anticonvulsant, antifungal, antidiabetic, anesthetic, antirheumatic, antitrichinella, antimicrobial, CITS depressant, antidiuretic, analgesic, antipyretic, cardiovascular and herbicidal agents. Since earliest times, continued efforts have been made for designing and developing new drugs through molecular modifications brought about by combining different biologically active units and functional groups. The incorporation of these moieties in a single molecule may result in affording hetero cyclic systems of proven medicinal significance and the impact of such changes on their biological efficacy appears attractive. With this aim in view, author's attempts have 11 mainly been directed towards the development of potential chemotherapeutic agents and drugs which could be used safely and effectively. The present dissertation is an outcome of the workdone in a research programme going on in this laboratory on the synthesis and screening of biologically active heterocyclic compounds. The dissertation opens with the first chapter as 'General Introduction* in which a review of the relevant literature on the research methodology employed in the syntheses, structural elucidation and pharmacological importance of heterocyclic compounds has been given. The second chapter concerns with the synthesis and studies of hydrazono compounds obtained by the coupling reaction of various substituted anilines, sulphanilamide and sulphonamides, and substituted 2-aminobenzothiazole derivatives with pentane-2,4-dione, 1,3-diphenylpropane-1,3- dione, 1-phenylbutane-l,3-dione and ethyl-3-oxohutanoate. The synthesis and characteristics of substituted phenylhydrazono pen-teane-2,4-diones, substituted sulphanilamidobenzenehydrazono Pentane-2,4-diones, substituted benzothiozolylhydrazono pentone-2,4-diones, substituted phenylhydrazono-1, 3-diphenylpropone-1,3-diones, substituted sulphanilamidobenzenehydrazono- 1,3-di phenyl pro pane-1,3-dione s, substi tut ed benzothi azolylhydrazono-1,3-di phenylpro pane-1,3-diones, iii substituted Pb.enylhyarazono-l-phenylbutane-l,3-aiones, .ub.«t„t.a •ulPH«UaoHob,n«m.lVte,Bono-l-ph.ayiboiaB.-l, 3-diones, substituted benzothiazolylhydrazono-1-phenylbutane- 1,3-diones, substituted phenylhydrazono ethyl-3-oxobutanoates, substituted sulphanilamidobenzenehydrazono ethyl-3-oxobutanoates and substituted benzothiazolylhydrazono ethyl-3-oxobutaoates are reported. The structural assignments of these compounds were made on the basis of mieroanalytical, IB and «H spectral data. The purity and homogenity of the compounds were checked by thin layer chromatography. As these compounds gave coloured spots, no visualiser was, therefore, needed. However, i„ . few 0aS9s> spots were ^Blliei by iodine vapours. The synthesis of a few series of alkyl ani aryl Pyrasole derivatives containing arylazo, sulphanilamidobenzeneazo, benzothiazolylazo, picolinoyl and isonicotinoyl groupings have been described in the third chapter. Detailed studies of ^-Picolinoyl-3,5-aimethyl-4-( substituted Phenylazo), >-Piooli„oyl-3,5-dimethyl-4-(substituted sulphanilamidobenzeneazo), Jr1-i»aioottnoyi-3,5-aiBethyi^_( su,stltuted benzothiazolylazo), ^-picolinoyl-S.S-diphenyl^-Csubstituted Phenylazo), ^-Picolinoyl^s-aiphenyl-M substitutes sulphanilamiaobenzeneazo),^ lsonioottnoyl_3j5_alptienyi_4_(substi_ tuted benzothiazolylazo), ^-Picolinoyl^-methyl-g-phenvl^- (substituted Phenylazo), ^-Picolinoyl-s-^thyl-S-phenyliv 4-(substituted sulphanilamidobenzeneazo) and ^-isonicotinoyl- 3-methyl-5-phenyl-4-(substituted benzothiazolylazo)pyrazoles have been carried out. The syntheses and characteristics of more than one hundred hitherto unknown pyrazoles have been included in this chapter. The compounds have been synthesised through the reaction of appropriate acid hydrazides with hydrazono derivatives of Pentane-2,4-dione, 1,3-di phenyl pro pane- 1,3-dione and 1-Phenylbutane-l,3-dione followed by their cyclisation. The homogenity and purity of these compounds have been checked by thin layer chromatography. The structures of the compounds have been established on the basis of microanalytical data, IS, MB, and MS studies. A suitable modification of the pyrazole moiety into the Pyrazolin-5-one moiety with all the important substituents has been carried out and the resulting compounds are discussed in the fourth chapter. Detailed studies of I -picolinoyl-3-methyl-4-(substituted Phenylhydrazono), N1- picolinoyl-3-methyl-4-(substituted sulphaniland dobenzenehydrazono) and I^-isonicotinoyl-S-methyl^-C substituted benzothiazolylhydrazono)pyrazolin-5-ones have been described. The compounds have been synthesised through the condensation of picolinic and isonicotinic acid hydrazides with appropriate hydrazono derivatives of ethyl-3-oxobutanoates and their subsequent cyclisation in glacial acetic acid. The assigned structures of the given compounds have been confirmed on the basis of microanalysis, IB, MB and mass spectroscopic criteria. The homogenity and purity in each case has been checked by thin layer chromatography. Six membered heterocyclic compounds also play a very significant role in biological processes and therefore, occupy an important place in medicine. Synthesis and studies of vari ous medicinally important heterocyclic systems have been reported in the fifth chapter. A large number of 1,3-diaryl-5- (substituted sulphanilamidobenzeneazo)-2-thiobarbituric acids, l,3-diaryl-5-(substituted benzothiazolylazo)-2-thiobarbituric acids and 1,3-diaryl-5-(substituted phenylthiazolylazo)-2- thiobarbituric acids of different series have been synthesised. The compounds have been synthesised by reacting malonic acid with corresponding 1,3-diaryl thioureas followed by incorpora tion of a variety of biologically active units i.e. sulphani- 1amide* sulphonamides, derivatives of 2-ominobenzothiazoles and 2-amino-4-phenyl thiazoles. These compounds have been synthesised with a view to finding out whether the biological activity if any possessed by a particular thiobarbituric acid is modified or not. The characterization and structural assignments of these compounds have been made on the basis of elemental analysis, IB, MB and mass spectral data. VI Most of the synthesised compounds have been evaluated for their antitumour, antitubercular, herbicidal and insecticidal activities. A preliminary antitumour activity study against P-388 leukemia system in mice has been carried out. Assays were performed in accordance with the specifications of the National Cancer Institute, Maryland. Female BDF1 mice weighing 17-23 g were used. Five mice for each test group were implanted intraperitoneally with 106 cells of P-388. The test solutions were prepared by dissolving or suspending the compound under test in 0.3$ sodium carboxymethyl cellulose (CMC) and was administered orally once for 9 days, starting one day after implantation. The antitumour activity of the compounds was expressed by the ratio of the median survival time of the treated mice (T) to that of the control mice (C). Most of the compounds showed insignificant activity. However, •i it has been observed that IT -isonicotinoyl-3,5-dimethyl-4- (6-nitrobenzothiazolylazo)pyrazole, 11 -picolinoyl-3,5- diphenyl-4-(N -2-pyrimidyl sulphanilamidobenzeneazo)pyrazole, 1 1 H -Picolinoyl-3-methyl-4-(lT -2-guanyl sulphanilamidobenzenehydrazono) pyrazolin-5-one,l,3-diphenyl-5-(2-sulphanilamidobenzeneazo)- 2-thiobrabituric acid, l,3-p-dlchlorodiphenyl-5- (2-sulphanilamidobenzeneazo)-2-thiobarbituric acid and 1,3-pdichlorodiphenyl- 5-(N -2-guanyl sulphanilamidobenzeneazo)-2- thiobarbituric acid have shown good promise as potential antitumour agents and have been selected for further vii examination by the National Cancer Institute, Maryland. A few of the compounds prepared in this study were also evaluated for their antitubercular activity in Lowenstein Jensen medium against mycobacterium tuberculosis H3«Bv at the concentration of 20p. , 10a. , 4jj and 2u /ml. Fourteen compounds belonging to different series of pyrazoles, pyrazolin-5-ones and thiobarbituric acids have also been evaluated for their herbicidal and insecticidal activities. Some of the compounds under test have shown significant activity as a result of preliminary investigations. All the biological screening results have been summarized in the sixth chapter. The cumulative references in order of their appearance in the chapters have been given at the close of each.