ABSTRACT
Some 2-aryl-5-hydrazino-1,3,4-thiadiazoles have been synthesized and screened for antihypertensive activity. In general, compounds with a 2-substituted phenyl ring had higher activity than their 3- or 4-substituted counterparts or those containing heteroaryl groups. The 2-methylphenyl and 2-ethylphenyl derivatives 7 and 18 were the most potent members of the series. Preliminary studies indicated that the hypotensive action of these compounds was due to a direct relaxant effect on vascular smooth muscle.
Subject(s)
Antihypertensive Agents/chemical synthesis , Hydrazines/chemical synthesis , Thiadiazoles/chemical synthesis , Animals , Blood Pressure/drug effects , Decerebrate State , Hydrazines/pharmacology , Hypertension/physiopathology , Male , Muscle, Smooth, Vascular/drug effects , Rats , Rats, Inbred Strains , Structure-Activity Relationship , Thiadiazoles/pharmacologyABSTRACT
Some 2-aryl-5-guanidino-(or N-substituted guanidino)-1,3,4-thiadiazoles and closely related analogues were found to lower blood pressure in metacorticoid (DOCA) hypertensive rats. In the unsubstituted guanidines that exhibited low toxicity, optimum activity resulted when the aryl group was a 2-methylphenyl ring (11). Modifications to the guanidine group did not increase antihypertensive activity, but, in the 2-methylphenyl series, the N-n-butyl- and N-(2-methoxyethyl)guanidines (63 and 78) and the related iminoimidazolidine 93 were of comparable activity to that of the unsubstituted guanidine 11. The iminoimidazolidine 93 showed a somewhat longer duration of action than the guanidine derivatives. Preliminary studies in a pithed rat preparation indicated that these thiadiazole derivatives (11, 63, and 93) lowered blood pressure by a direct relaxant effect on vascular smooth muscle.
Subject(s)
Antihypertensive Agents/chemical synthesis , Blood Pressure/drug effects , Guanidines/pharmacology , Thiadiazoles/pharmacology , Animals , Chemical Phenomena , Chemistry , Decerebrate State , Guanidines/chemical synthesis , Male , Muscle, Smooth, Vascular/drug effects , Rats , Structure-Activity Relationship , Thiadiazoles/chemical synthesisABSTRACT
The synthesis and anticonvulsant activity of a series of 2-aryl-5-hydrazino-1,3,4-thiadiazoles are described. The combination of preferred aromatic substituents in the 2-position coupled with alkyl substitution on the hydrazine moiety led to a number of potent compounds lacking sedation, ataxia, or lethality. 5-(2-Biphenylyl)-2-(1-methylhydrazino)-1,3,4-thiadiazole (4m) represents a new class of anticonvulsant agent and compares favorably with the standard drugs phenytoin, phenobarbital, and carbamazepine.
Subject(s)
Anticonvulsants/chemical synthesis , Hydrazines/chemical synthesis , Animals , Anticonvulsants/pharmacology , Anticonvulsants/toxicity , Hydrazines/pharmacology , Hydrazines/toxicity , Male , Rats , Rats, Inbred Strains , Structure-Activity RelationshipABSTRACT
The synthesis and antiinflammatory activity of a series of substituted (2-phenoxyphenyl)acetic acids are described. Initial screening in the adjuvant arthritis test showed that halogen substitution in the phenoxy ring enhanced activity considerably. Ulcerogenic potential, as measured by the minimum ulcerogenic dose (MUD), was low in almost all the acids tested. [2-(2,4-Dichlorophenoxy)phenyl]acetic acid possessed the most favorable combination of potency with low toxicity, including ulcerogenicity, and this compound is now in therapeutic use.
