New nonsteroidal antiinflammatory agent. 2-Substituted 5- or 6

Aug 1, 1973 - 2-Substituted 5- or 6-benzothiazoleacetic acids and their derivatives. Jin Wada, Tadayuki Suzuki, Morio Iwasaki, Hiroki Miyamatsu, Shinj...
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Journal of Medicinal Chemispy, 1973, Vol. 16, No. 8

Wada, et al. (2) B. Belleau and J. Moran,Ann. N.Y. Acad. Sci., 107, 822 ( 1963). (3) C. L. Zirkle and C. Kaiser, “Psychopharmacological Agents,’‘ M. Gordon, Ed., Vol. 1, Academic Press, New York, N. Y., 1964, p 445. (4) C. L. Zirkle, C. Kaiser, D. H. Tedeschi, R. E. Tedeschi, and A. Burger, J. Med. Pharm. Chem., 5,1265 (1962). (5) C. Hansch and T. Fujita, J. Amer. Chem. SOC.,86, 1616 (~1 964). -- (6) C. Hansch, “Drug Design,” Vol. I, E. J. Ariens, Ed., Academic Press, New York, N. Y., 1971, P 271. (7) T. Fujita, J. Iwasa, and C. Hansch, J. Amer. Chem. SOC., 86, 5175 (1964). (8) A. Leo, C. Hansch, and D.Elkins, Chem. Rev., 71, 551 (1971). (9) M. S. Tute,Advan. DrugRes., 6, l(1971). (10) E. Kutter and C. Hansch, J. Med. Chem., 12,647 (1969). (11) C. Hansch, E. J. Lien, and F. Helmer,Arch. Biochem. Biophys., 128, 319 (1968). (12) H. K. Hall, Jr., J. Amer. Chem. SOC.,79, 5441 (1957). (13) B. M. Bloom, Ann. N. Y. Acad. Sci., 107, 878 (1963). (14) R. A. Abramovitch and I. D. Spencer, Advan. Heterocycl. Chem., 3,187 (1964). (15) C. Hansch, E. W. Deutsch, and N. R. Smith, J. Amer. Chem, SOC.,87,2738 (1965). (16) T. Fujita,Advan, Chem. Ser., No. 114, 1 (1972). (17) B. T. Ho,J. PhQmt. Sci., 61, 821 (1972). (18) P. R. Wells, “Linear Free Energy Relationships,” Academic Press, London, 1968, p 24. (19) E. A. Zeller,Ann. N.Y. Acad. Sci., 107, 811 (1963). (20) T. Fujita, C. Takayama, and M. Nakajima, J. Org. Chem., 38, 1623 (1973). (21) A. H. Neims, D. C. DeLuca, and L. Hellerman, Biochemistry, 5, 203 (1966). (22) J. A. Mazrimas, P. S . Song, L. L. Ingraham, and R. D. Draper, Arch. Biochem. Biophys., 100,409 (1963). (23) E. Kutter and C. Hansch, ibid., 135, 126 (1969).

vea, that the aromatic substituent effects on MA0 i r h b i tion are essentially the same in various sets of inhibitors against enzyme from the same origin. It is also suggested that the inhibition against enzymes from various origins involves similar physicochemical mechanism. Although the electronic effect of substituents does not seem to contribute significantly in some series of inhibitors, the most probable role of the aromatic moiety would be to interact as an electron acceptor with the noncatalytic electron-rich site of the enzyme surface. These findings would not have been uncovered unless the structure-activity relationships were described in the form of equations so that the various features among them could be compared quantitatively. The present work also supports the use o f E s parameters in explaining intermolecular steric interactions in biomedical systems developed by Hansch and K ~ t t e r .It~is~hoped ,~~ that the role of side chain structure in the mechanism of MA0 inhibitors could be delineated in physicochemical as well as quantitative terms so that a comprehensive structure-activity picture for MA0 inhibitors can be drawn.

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Acknowledgments. The author expresses his sincere thanks to Dr. Takashi Ban for his cooperation and Professor Minoru Nakajima for his support during the course of this work. References (1) C. Kaiser and C. L. Zikle, “Medicinal Chemistry,” 3rd ed, A. Burger, Ed., Wiley-Interscience, New York, N. Y., 1970, p 1483. -

A New Nonsteroidal Antiinflammatory Agent. 2-Substituted 5- or 6-Benzothiazoleacetic Acids and Their Derivatives Jin Wada,* Tadayuki Suzuki, Morio Iwasaki, Hiroki Miyamatsu, Shinji Ueno, and Mitsuhiro Shimizu Department of Research and Development, Tokyo Tambe Company, Ltd., Tokyo, Japan. Received February 20, 1973

Synthesis of 34 2-substituted benzothiazole compounds with an acetic acid function at the 5 or 6 position was carried out and their antiinflammatory activity was investigated. It was found that the presence of an acetic acid function was important for antiinflammatory activity and also that 2-substituted 5-benzothiazoleacetic acids (6) were better than 2-substituted 6-benzothiazoleacetic acids ( 7 ) in antiinflammatory activity Many aromatic and heteroaromatic acetic acids have been reported’-3 as nonsteroidal antiinflammatory agents. Among them, Messer, et 0 1 . , ~recently reported on 10-methyl-2-phenothiazinylacetic acid (metiazinic acid, I) and Hepworth, et d,’ R = phenyl, mono- or disubstituted phenyl, pyridyl, naphthyl, furyl, benzyl, phenetyl, styryl, and phenoxymethyl; Z = -OH, -OEt, -NH,, reported on 2-(4-chlorophenyl)thiazol-4-ylacetic acid (fen01 -NHOH clozic acid, II), both of which contain nitrogen and sulfur atoms in their skeleton. Chemistry. 3-Amino-4-mercaptoacetophenone(1 ), which was obtained by the reaction of 4-chloro-3-nitroacetophenone with sodium sulfide nonahydrate in water, was condensed with arylcarboxylic acid chlorides or aldehydes to yield the 2-substituted 5-acetylbenzothiazoles (3). fenclozic acid (11) methiazinic acid (I) 5-Acetylbenzothiazole derivatives 3 were allowed to react with sulfur and morpholine in a Willgerodt-Kindler reaction and the morpholides 5 were isolated as intermediates. These Little is known about the antiinflammatory activity of morpholides 5 were hydrolyzed with concentrated hydrothe benzothiazole ring system6 and, moreover, a compound chloric acid or 10%aqueous sodium hydroxide solution to which has an acetic acid function in such a system has not yield the 2-substituted 5-benzothiazoleacetic acids (6).In yet been reported at all. Therefore, novel 2-substituted 5- or the ring closure with aryl aldehydes, benzothiazoline deriva6-benzothiazoleaceticacids (6 and 7 ) and their derivatives tives 2 were often obtained, but these (2) were easily oxiwere synthesized and their antiinflammatory activities and LDso values were examined. dized to a benzothiazole 3 by refluxing in the presence of

Journnl of Medicinal Chemistry, 1973, Vol. 16, No.8

5- or 6-BenzothiazoleaceticAcids

Scheme 11. Another Synthetic Route to 2-PhenyI-5-benzothiazoleacetic Acid (6a)

Scheme I. General Synthetic Route to 2-Substituted 5-Benzothiazoleacetic Acids (6) Using the Willgerodt-Kindler Reaction

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