New basic esters of 2-phenyl-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylic acid endowed with spasmolytic properties. Synthesis and pharmacological-pharmacokinetic evaluation.
In order to obtain new analogs of flavoxate endowed with higher stability and possibly higher potency, a new series of basic esters of 2-phenyl-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylic acid (MFCA) has been prepared and investigated. Derivatives in which the structure of flavoxate was modified by branching and lengthening of the estereal alkyl chain were synthesized, together with the conformationally restricted N-piperidinyl derivatives. Esters containing in their structure various alicyclic tertiary amines which are present in natural or synthetic drugs endowed with spasmolytic properties, mainly of anticholinergic nature, were also prepared. The stability in aqueous solution, acute toxicity in mouse, and in vitro spasmolytic properties of the new compounds were investigated in comparison with flavoxate. Based on the results obtained from this screening procedure, 3 compounds were selected for further investigation. In this phase, further pharmacological and stability testing as well as preliminary animal pharmacokinetic investigations were carried out. The obtained results suggested the choice of 1,1-dimethyl-2-(1-piperidinyl)ethyl 2-phenyl-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylate HCl (Rec 151 2053, terflavoxate, CAS 86433-39-8) as a candidate for preclinical development. The deeper pharmacological characterization of this compound, carried out mainly in comparison with flavoxate, terodiline, and oxybutynin confirmed its good spasmolytic activity.
Nardi
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D
Chemistry Laboratory, Recordati S.p.A., Milan, Italy.
Leonardi
A
A
Pennini
R
R
Tajana
A
A
Cazzulani
P
P
Testa
R
R
D000284:Administration, Oral; D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001646:Bile / Q000378:metabolism; D004558:Electric Stimulation; D005243:Feces / Q000737:chemistry; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D009130:Muscle, Smooth / Q000187:drug effects; D010276:Parasympatholytics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D001743:Urinary Bladder / Q000187:drug effects; D014630:Vagus Nerve / Q000502:physiology
D001578:Benzopyrans; D010276:Parasympatholytics