Synthesis and Antiplatelet Activity of New Imidazole‐4‐Carboxylic Acid Derivatives

Abstract

1-Arylalkyl-5-phenylsulfonamino-imidazole-4-carboxylic acid esters and their carboxamides with an additional secondary amino group were synthesized and identified as antiplatelet agents in a low micromolar range (Born-test, inducer collagen). To describe the mechanism of action more precisely the Born-test was carried out as well with ADP, adrenaline or PAF, respectively. In addition, two compounds were investigated for their COX-1 inhibitory activities. Provided the essential structural criteria are met i.e. amide group or ester, sulfonylamino rest, hydrophobic moieties, and a secondary amino function, slight structural modifications are able to shift the pattern of activity among the above platelet receptors. So, the ester 5c exhibits PAF antagonistic activity at IC(50) = 1 microM and COX-1 inhibition (IC(50) = 0.4 microM). The carboxamide 6c shows ADP antagonistic properties (IC(50) = 2 microM). Compound 6g is as well PAF antagonistic (IC(50) = 4 microM) and a COX-1 inhibitor (IC(50) = 1 microM). The derivative 6i shows a strong antiadrenergic (IC(50) = 0.15 microM) and PAF antagonistic (IC(50) = 0.66 microM) effect.

New 1H‐Pyrazole‐4‐Carboxamides with Antiplatelet Activity

“…In a number of previous publications, we were able to show that the substitution of heterocycles rich in nitrogen like purines [1], indazoles [2], triazoles [3], oxadiazoles [4], imidazoles [5], pyrimidocinnolines [6], phthalazines [7], or thiazoles [8] with a carboxamide partial structure in addition to basic groups leads to a wide variety of compounds with antiplatelet activities in micromolar concentrations. In this paper, we wish to report a number of pyrazole derivatives fulfilling these structural requirements and, consequently, were promising to show remarkable antiplatelet activities.…”

New 2‐Amino‐thiazole‐4‐acetamides with Antiplatelet Activity

“…The reason for this difference is the basic substituent. Since Steege [5] moiety in the imidazole derivatives 9, the way for getting strong antiplatelet activity was opened (see 10 and 3a). The purine derivative 11, however, shows that the pyrrol moiety can substitute the cyclohexylamino rest (IC 50 = 3 lM).…”

“…1, where the N,N-dimethylaminopropyl-group (4,5,6,7,8) had been taken for the basic substituent. The (most effective) hydrophobic substituent in 6, 7, and 8 is 4,49-biphenyl.…”

“…From 2.5 g (7.26 mmol) 2a and 4.0 g N-cyclohexyl-1,3-propanediamine, procedure A2, column chromatography (CHCl 3 / CH 3 7.39 (dd,J = 8.8/8.8 Hz,2H,3,2H,2, (14), 280 (49), 262 (41), 236 (13), 139 (10), 123 (100), 112 (24), 98 (41), 95 (24), 56 (17), 30 (20). 2-[- (1, 7.38 (t,J = 7.6 Hz,1H,7.47 (t,J = 7.6 Hz,2H,39,4H,3,5,29, (44), 231 (14), 223 (15), 191 (21), 175 (23), 166 (58), 123 (100), 112 (53), 55 (19), 36 (64). 3253;3058;2935;2856;2810;2431;2364;1708 (CO);1657 (CO);1601;1551;1451;1386;1348;1334;1302;1302;1258;1212;1189;1162;1123;1077;1046;1032.…”

“…In a number of publications, we have shown that the substitution of heterocycles rich in nitrogen-like purines [1], indazoles [2], triazoles [3], oxadiazoles [4], imidazoles [5], pyrimidocinnolines [6], or phthalazines [7] with a carboxamide partial structure, a hydrophobic moiety and basic groups leads to a wide variety of compounds with antiplatelet activities in micromolar concentrations. In this paper, we wish to report a number of thiazole derivatives fulfilling these structural requirements and, consequently, were promising to show remarkable antiplatelet activities.…”