New Oxadiazole Derivatives Showing partly Antiplatelet, Antithrombotic and Serotonin Antagonistic Properties

Abstract

Ten new 1, 2, 4-oxadiazole- and six new 1, 3, 4-oxadiazole-carboxamides containing different lipophilic moieties (i.e. 4-biphenyl-, 1-naphthyl, phenylpropyl- and n-hexyl substituents) and additional basic groups which are mainly alkyl- and dialkylaminoalkyl residues have been synthesized and tested for antiplatelet effects in vitro (Born-test) and antithrombotic properties in vivo (laser thrombosis model). If the platelet aggregation was induced by collagen, the inhibitory effects (IC50) were between 58 microM and 300 microM. Using serotonin (5-HT) as an inducer, compound 6a (N-(3-dimethylaminopropyl-5-(biphenyl-4-yl)-1, 3, 4-oxadiazole-2-carboxamide) had an IC50 = 1 microM (12e: (N-3-Dimethylaminopropyl)-3-(1-naphthyl)-1, 2, 4-oxadiazole-5-carboxamide, 6.7 microM). In an in vitro rat tail artery assay 6a and 12e behaved as a competitive 5-HT2A receptor antagonist (6a: pKB = 6.86 +/- 0.04; 12e: pKB = 6.66 +/- 0.05). The antithrombotic effects of some compounds were small but significant (7-10 % inhibition of thrombus formation).

The cleavage of heterocyclic compounds.1 Synthesis of 1-phenyl-5-naphthyl-6-azacytosines

“…As starting material we prepared 2-phenyl-2,3-dihydronaphto[1´,2´:4,5]furo [2,3-e] [1,2,4] triazine-3-on 1, using the straightforward synthesis described before. 6 Using this compound, all cleavage reactions with oxygen, sulfur or nitrogen nucleophiles are very easy and lead to good yields of the end products.…”

“…6 Using this compound, all cleavage reactions with oxygen, sulfur or nitrogen nucleophiles are very easy and lead to good yields of the end products. 3a R 1 = R 2 = H 3b R 1 = H; R 2 = CH 3 3c R 1 = H; R 2 = phenyl 3d R 1 = H; R 2 = cyclohexyl 3e R 1 = H; R 2 …”

“…Heterocyclic arylderivatives are mostly represented by variously substituted phenyl derivatives. Interesting heterocyclic aryl derivatives also include naphthyl derivatives, such as antiplateled active naphtyloxadiazoles 2 or naphtylmaleinimids 3 that act as inhibitors of protein kinases. Some naphtylisoquinolines are important from the perspective of atropoisomery.…”

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

“…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.…”