2,4-Diphenylthiazole-5-aceticAcid (8) J . H. Moon, Cancer, 25 (2),468 (1970). (9) J. N. Attie and R. A. Khafif in “Melanotic Tumors,” Charles C Thomas, Springfield, Ill., 1964,Chapter 1. (10) J. McGuire and J . Hendnie, J . lnuest. Dermatol., 57 (4), 256 (1971). (11) Y. Ogata, Y. Sawaki, and M. Isono, Tetrahedron, 26, 731 (1970). (12) S . Pickholz,J. Chem. Soc., 685 (1946). (13) H. H. Fox in “Medicinal Chemistry,” 2nd ed, A. Burger, Ed., Interscience, Kew York, N. Y., 1970. (14) W. T. Colwell, G. Chen, V. H. Brown, J . I. DeGraw, and J . H. Peters, J . Med. Chem., 17, 142 (1974). (15) H. Jackson and T. Koch, Amer. Chem. J., 2ti,31 (1901). (16) S. Senoh and B. Witkop, J . Amer. Chem. SOC.,81, 6222 (1959). (17)A. Kaiser, W. Koch, M. Scheer, and c‘. Wolcke, Helu. Chim. Acta, 53 (7), 1708 (1970). (18) R. M. Silverstein and G. C. Bassler, “Spectrometric Identifi-
cation of Organic Compounds,” Wiley, New York, N. Y., 1964.
Journal ofMedicinal Chemistry, 1974, Vol. 17, No. I 1
1177
(19) K. Nakanishi, “Infrared Absorption Spectroscopy,” HoldenDay, San Francisco, Calif., 1962. (20) G . Prota, S . Grescenzi, G. Misuraca, and R. A. Nicolaus, Experientia, 2ti (lo), 1058 (1970). (21) H. Sanada, R. Suzue, Y. Nakashima, and S. Kawada, Biochim. Biophys. Acta, 261,258 (1972). (22)M. Dixon and E. C. Webb, “Enzymes.” Academic Press, New York, N. Y ., 1958. (23) H. S.Mason and E. W. Peterson, Biochim. Biophys. Acta, 111,134 (1965). 124) , , T. Nazatsu. Y. Sudo. T. Okada. H. Umezawa, and T. Takeuchi, kxperientia, 28 (6), 634 (1972). (25)H. S . Mason, J . Bioi. Chem., 168, 433 (1947). (26)R. Hartley and J . A. Smith, Biochem. Pharmacol., 21 (15), 2007 (1972). (27) S. Smiles and C. M. Bere, “Organic Syntheses,” Collect. Vol. I, Wiley, New York, N . Y., 1941,p 7. (28) “Worthington Enzyme Manual.” Worthington Biochemical Corp., Freehold, N . J., 1972,p 39. (29) J. Cason, Org. React., 4,305 (1948).
Nonsteroidal Antiinflammatory Agents. 1.2,4-Diphenylthiazole-5-aceticAcid and Related Compounds Kevan Brown, David P. Cater, John F. Cavalla, David Green, Robert A. Newberry,* and Alan B. Wilson Wyeth Institute of Medical Research, Taplou, Maidenhead, Berkshire SL6 OPH, England. Received February 4, 1974 A variety of novel 2,4-diarylthiazole-5-aceticacids and related compounds was prepared by the Hantzsch thiazole
synthesis and evaluated as antiinflammatory agents on the carrageenin-induced edema assay in the rat. Two compounds, namely 4-(4-chlorophenyl)-2-phenylthiazole-5-acetic acid (24)and 4-(4-chlorophenyl)-2-(3-methylphenyl)thiazole-5-acetic acid (31), were found to possess activity comparable with indomethacin. Derivatives of the acidic side chain such as esters, amides, hydroxamic acid, P-propionic acids, a-propionic acids, and a tetrazole were all less active than the parent compounds. Compound 24 was five times as effective as phenylbutazone against adjuvant-induced polyarthritis. In 1963 indomethacin, l-p-chlorobenzoyl-5-methoxy-2methylindole-3-acetic acid, was reported by Shen, et to possess antiinflammatory activity against carrageenininduced edema in the r a t hind paw. This knowledge, together with the fact t h a t aspirin a n d phenylbutazone (two nonsteroidal antiinflammatory drugs of choice a t t h a t time) were both acidic compounds, induced many workers to investigate other aryl- a n d heteroarylalkanoic acids (for a review, see ref 2). This paper describes studies based upon the discovery that 2,4-diphenylthiazole-5-aceticacid also inhibits carrageenin-induced edema in the rat.3 Of the 75 related compounds t h a t were synthesized and studied using this assay procedure, only two compounds were found t o possess a potency comparable with indomethacin. Chemistry. T h e bulk of the compounds were synthesized by t h e Hantzsch method, which involved reacting together the appropriate thioamide a n d a-bromo ketone in a solvent. In the course of this work three different solvent systems were investigated. Initially, we were also interested in testing esters of the acids. Therefore, in some cases, for example, 1, 10, a n d 27, the reactants were heated together in refluxing E t O H to give the esters 46, 49, a n d 48, which were then hydrolyzed to the corresponding acids. Although this route gave reasonable yields, some esters were difficult to separate from starting materials a n d unwanted side products. I t was decided to obtain t h e acids directly by heating the reactants in i-PrOH a t 60” in the presence of Na2C03 essentially according to Knott.4 Compounds 2-7, 9, a n d 13-22, for example, were prepared in this way b u t yields were usually below 50%. It was then found t h a t better
yields a n d cleaner reactions were obtained when the reactants were heated in DMF a t 70” without the presence of sodium carbonate, as illustrated for compounds 24-26 a n d 29-41. Derivatives of the acids, such as the amides 52 a n d 53 and the hydroxamic acid 54, were prepared in the usual way as indicated in the footnotes of Table 11. T h e 0-propionic acid 61 was prepared from the appropriate bromoketo acid b u t the a-propionic acid 62 was prepared via alkylation of the ester 47 with CHJI, essentially according t o Kenyon, Kaiser, a n d H a ~ s e r a, n~ d subsequent hydrolysis. The tetrazole 63 was obtained by treating the corresponding acetonitrile derivative 90, prepared by dehydration of the amide 53, with NaN3 in DMF. Structure-Activity Relationships. Analogs of 1 obtained by substitution in one or both of the phenyl rings are detailed in Table I together with the results on the carrageenin-induced edema test. Because of the variability inherent in this assay procedure, the ED40 of each compound is expressed as being within one of the six ranges detailed in the footnotes of Table I. T h e compounds were prepared essentially in the order shown. The objective was to establish the structure-activity pattern for each phenyl ring a n d from these d a t a to prepare the appropriate polysubstituted compounds. Substitution in the 2-phenyl ring resulted in a reduction of activity (compared t o 1) when the group was in the 2 position (2, 6, 9). When the group was in the 3 or 4 position activity was usually retained. In two cases, however, namely the 4-C1 (7) a n d the 4-N(CH& ( l l ) , activity was slightly increased. Substitution in the 4-phenyl ring quickly revealed t h a t the optimum group was chloro in
1178 Journal ofMedicinal Chemist?, 1974, Vol. 17, N o . 11
Newber?. c t u i
Table I
Rat paw edema,
R'
R
No.
Methoda
Yield, %
Mp, "C
Recrystn solvent C~HG C6Hs-pet. ether C &H6-pet. ether C6H6 C 6Hs-pet. ether C6Hc-pet. ether CGHG C&G AcOH-H~O CeH, CsH6 CeHs AcOH-HyO AcOH-H~O AcOH-H~O AcOH-H2O AcOH-Hy0 AcOH-HyO AcOH-H~O AcOH-HyO AcOH-H~O C ,:H6 AcOH-H2O C6H6 C6Hc Ce" C6Hs CsHs CRHG CiH6 CRHJ CeH, CGH~ C,H, CsH6 AcOH-H~O EtOH EtOH-H?O CsH, CsH, C6H6 AcOH-HzO AcOH-H.0 AcOH-HZO
1
H
2
2-CH3
H H
A B
89 34
152-153 172-173
3
3-CH3
H
B
30
123-125
4 5
4-CH3 3-CF3
H H
B
B
51 23
173-175 143--145
6
2-C1
H
B
49
169-171
H H H H H H H H H H H H H H H
B C B A C C B B B B B B B B B B A C
44
157-158 174-175 179-181 151-152 154-156 146-147 203-205 143-145 210-212 158-160 157-159 175-177 217-219 136-138 204-205 168-169 178-180 162--163 178-180 173 -174 180-181 147-149 214-215 174-175 152-153 188- 189 165--166 199- 201 202-203 173-174 205-207 267-269 206-207 194-196 192-193
7 4-C1 8 4-Br 9 2-OCH3 10 4-OCH3 11 4-N(CHS)? 12 4-CH(CH3)2 13 2,6-(CH,), 14 2,3-(CHx)s 15 2,6-C1? 16 2,4-C1y 17 2,4-(OCH3)2 18 2-CH3, 4-C1 19 2-CH3, 6-C1 20 2-CH3, 4-OCH3 21 2-OCH3, 4-C1 22 H 23 H 24 H 25 H 26 H 27 H 28 H 29 H 30 2-CH3 31 3-CH3 32 4-CH3 33 3-C1 34 4-c1 35 4-Br 36 4-OCH3 37 4-N(CH3)y 38 4-C0yH 39 4-C1 40 4-C1 41 4-Br 42 2-CH3 43 4-C1 44 4-OCH3 Phenylbutazone Indomethacin
4-CH3 2x1 4-C1 4-Br
4-F 4-OCH3 3,4-(OCH3)2 4-OH 4-C1 4-C1 4-C1 4-C1 4-C1 4-C1 4-C1 4-C1 4-C1 4-Br 4-F 4-F 4-OCHa 4-OCH3 4-OCHa
c
C A B C C C C C C C C C
c
C C C B B B
81 78 68 52 85 37 64 45 10
44 58 63 28 65 31 30 78 75 66 85 34 40 61 68 31 66 78 80 72 38 22 69 64 88 45 57 56
140-141
199-201 176-175
EDao Formula
CigHi;NO?S C igHiiNO?S
Analyses
range']
C, H, N , S C, H , N , S
4 6
C, H, N, S
4
C, H , N , S C , H , F , N, S
c; 1
C, H , C1, N , S
6
C, H, C1, N , S c , H, N C, H , N , S C, H , N , S C, H , N , S c , H, N C, H , N , S C, H , N, S C, H , C1. N , S C, H, C1, N C, H , N . S C, H , C1, N C, H , C1, N C, H , N , S C , H , C1, N , S C, H, N , S C, H , Cl, N C , H , N, S C, H , N C, H, N , S C, H , N , S C , H, N , S C, H , N C, H , N c , H, N C, H, N C, H , N C , H, C1, N C , H. N C, H , N C, H , N C , H, N c , H, N C, H , C1, N, S C. H. N C, H , N, S C , H, N , S C, H , N , S
3 3
6 1 3
4 6 5 6 6 5 1
6 '1
6 6 6 1
2 4
4 6 6 3 1 4 3 2 3 4 4
6 3 2 4 6 6 4 i 1
a T h e letters A, B, a n d C refer to general preparative procedures detailed in t h e Experimental Section. hThe numbers 1--6refer t o t h e following ED40 ranges: 1, 1-5 mg/kg; 2, 6-10 mg/kg; 3, 11-25 m g / k g ; 4, 26-50 m g / k g ; 5, 51-100 mg/kg; 6, 5.100
mg,/kg. the 4 position (24). T h i s compound was comparable in potency to indomethacin in this screen. T h e corresponding 4-Br (25) was only slightly less potent. A series of analogs with a 4-C1 group in t h e 4-phenyl ring a n d a variety of groups in t h e 2-phenyl ring were then investigated. T h e most active compound was found to he 31, which h a d a methyl group in t h e 3 position a n d was
comparable in activity with 24. In terms of activity, this compound was followed by t h e 4-C1 analog 34 which was comparable to 25. Surprisingly, t h e 4-N(CH3)2 analog 37 only possessed activity similar to 1. When t h e compound with a 4-Br group in t h e 4-phenyl ring a n d a 4-C1 in t h e Z p h e n y l ring (39) was tested, it was found to be slightly less active t h a n 3.1 as expected (compare 25 and 24). R u t
2,4-Diphenylthiazole-5-acetic Acid
Journal ofMedicinal Chemistry, 1974, Vol. 17, No. 11 1179
d
Y
qx
ws
2
2
G x h N
5
9.
0
Y
0
Y
1180 Journal ojMedicinai Chemistry. 1974. Vol. 17, N o I 1
,Veu'berp, et ai
Table I11
R'
R
R'
64 65 66 67 68 69 70 71 72 73 74
CJ& 2-CHaCsHd 4-CIC6H4 4-OCHaCsH4 CGHi CGH: 2-CHaChH4 4-OCHaCGH4 1-Naphthyl 2-Naphthyl
76
3-Pyridyl 4-Pyridyl
2-Thienyl 2-Thienyl 2-Thienyl 2-Thienyl 1-Naphthyl 2-Naphthyl 2-Naphthyl 2-Naphthyl CsHs C6Hs 4-ClCJ1, 4-CICsH4 4-ClCsHh
76
CH CO
Yield, Method
