Studies on cerebral protective agents. VIII. Synthesis of 2-aminothiazoles and 2-thiazolecarboxamides with anti-anoxic activity.
Various 2-aminothiazoles (2a-s and 3a-g) and 2-thiazolecarboxamides (4a-h), possessing a nitrogenous basic moiety at the C-2 position of the thiazole ring, were prepared and tested for anti-anoxic (AA) activity in mice. Among them, N-[2-(4-morpholinyl)ethyl]-4-(3-trifluoromethylphenyl)-2- thiazolecarboxamide hydrochloride (4e, FR108143) (minimum effective doses of 3.2 mg/kg i.p. and 10 mg/kg p.o., respectively) exhibited more potent AA activity than either FK360 or compound 1, each of which has a nitrogenous basic moiety at the C-5 position. The structure-activity relationships with regard to AA activity of this series of compounds are discussed, and the three-dimensional electrostatic potentials (3D-MEP) around the basic nitrogen atom of FK360 and the thiazole derivative (4e) are compared.
Ohkubo
M
M
New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Kuno
A
A
Nakanishi
I
I
Takasugi
H
H
D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002534:Hypoxia, Brain / Q000188:drug therapy* / Q000523:psychology; D066298:In Vitro Techniques; D007928:Lethal Dose 50; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C096560:FK 360; D011743:Pyrimidines; D013844:Thiazoles