May 1965
303
I M I D A Z O [I,?-Q]PYRIDISES
Derivatives of Imidazole. I. Synthesis and Reactions of Imidazo[l,2-a]pyridines with Analgesic, Antiinflammatory, Antipyretic, and Anticonvulsant Activity L U I G I A%LJIIRA?jTE, L G I G I F O L O , -&LFOSbO ~ f U G S A l S I E , K C O L l S A 1’ROVISCIALI, 1’IERLt‘IGI ,4DRIASrl BIASCOTTI, A F R O GAXBA, AS11 lY-%LTER _\IUR\lAKX’
RUGAHLI,
Research Department, Selvi e C., Laboratorio Bioterapico Milanese, Xilan, Italy Received Septt mbcr 28, 1Y64
A series of 42 derivatives of imidazo [ 1,2-a]pyridine has been prepared and examiiied for analgesic, antiiiiflammatory, antipyretic, and muscle-relaxant activity. The results have been compared with those obtained under same conditions with acet,glsalicylic acid, aminopyriiie, pheiiylbutaao~ie,aud chlortenosazirie. Several members of the series display high activities in a variety of pharmacological tests, the most iriterestiiig being 2-(p-methylsulfonylphengl)imidazo[l,2-a]pyridinehydroc.!iloride (11) and 2-(p-methyls~ilfoug-Iphellyl)-3-(dimethylaminomethy1)imidazo [ 1,2-a]pyridine dihydrochloride (22). The experimental findiiigs siiggest that further pharmacological and toxicological investigatioii- of some of these compouiids ~risyhe of interest for evaluation as therapeutic agents in man.
The aritiiriflaniniatory activity of 2-(p-nitrophenyl)iniidazo[1,2-a]pyridine (I, R” = R’ = H ; R = p-SOn)* has led us to a more thorough and systeiiiatic study of the synthesis of related compounds.
The bromination of p-niethylsulfoxyacetopheiioiie with broiiiine in benzene led to p-methylniercapto-w-dibronioacetophenone. The sulfoxy group was reduced by nascent HBr, another mole of bromine being formed. The equilSbria represented by the following equations
+ HX (It’lt”SOH)+ S - + HX 1t’R”dO
I
The study was divided into two general areas. The first involves the replacement of the p-SOz group by other groups, chiefly by pSOd.X3, to increase the solubility without changing the electronegativity, molecular volume, or ability of the niolecule to participate in p-quinoid-type systems. I n addition, the replacement by other groups such as H, o-SO?C&, p-SCHB, pSOCH3, p - S 0 2 S H n ,p-SHCOCH3, p C H 3 , p-OCH3, and 2’,5’-OCH3 was included in this area to study the influence of the substituents on the pharniacological activity. The second object was the study of the chemistry of the iniidazo [1,2-a]pyridine ring; only 3-nitrosation3 and 3-bromination3 are known. lTe tried some of the characteristic reactions of the indole ring and succeeded in preparing -\Iannich bases, bromo, riitroso and amino, formyl, cyanoniethyl, carboxymethyl, and carbaniidoiiiethyl derivatives in the %position of the ring. Substituted 2-aryliniidazo [ 1,2-a]pyridines (Table I, 1-13) were readily prepared by condensation of 2aniinopyridirie and 2-aminopicolines with w-bronioacetophenones. * Jfethods of synthesis of iniidazo [ 1,241pyridines described recently5j6by others have not beeii used in this study. The o-niethylsulfonylacetophenone, intermediate for the synthesis of conipound 8, was synthetized from 3broniot hiochronianone by hydrolysis to 2-iiiercapt oacetophenonc that was methylated and oxidized Tvith hydrogen peroxide in aretic acid. ( 1 ) T o n-horn all inqriiries concerning pharmacology should be sent. (2) U. 11. Teotino, I,. Polo Friz, .%.Gandini, and D. Della Bella, Farmnco (Pavia), Ed. sei., 17, 988 (1962). ( 3 ) V. I
