[Derivatives of pyrimidine 1,2-condensate. IV. Synthesis and pharmacological properties of the N,N-disubstituted 4-amino-2H-pyrido(1,2-a)pyrimidin- 2-ones and 2-amino-4H-pyrido(1,2-a)pyrmidin-4-ones].
The N,N-disubstituted 4-amino-2H-pyrido[1,2-a]pyrimidin-2-ones (III) and isomer 2-amino-4H-pyrido[1,2-a]pyrimidin-4-ones (IV) were obtained from the reaction of 2-aminopyridine with the N,N-disubstituted ethyl malonamate/phosphorus oxychloride reagent (II), in refluxing 1,2-dichloroethane. 2-[(N-Benzyl, N-ethyl)amino]derivative (IV b) was also prepared in excellent yield by treating 2-chloro-4H-pyrido[1,2-a]pyrimidin-4-one (V) with N-ethylbenzylamine. Finally, hydrogenation (Raney Nickel) of 4-[(N-ethyl,N-phenyl)amino]-2H-pyrido[1,2-a]pyrimidin-2-one (III e) afforded 6,7,8,9-tetrahydroderivative (VI) which in turn was treated with potassium borohydride to give 1,6,7,8,9,9a-hexahydroderivative (VII). Several compounds described in the present paper, along with some other compounds (III) and (IV) previously synthesized by us (1,2), were tested for various pharmacological activities. The antiallergic activity (PCA in the rat), even though found in several compounds examined, turned out to be submaximal in any case, in spite of the high dose administered (500 mg/kg p.o. as a rule). The most active compound (the activity being estimated at 0.42 times that of thiaramide hydrochloride) was the 4-aminoderivative (III e). The 2-aminoderivatives (IV) series, was found to have marked antiinflammatory properties (carrageenin oedema in the rat); nevertheless, this activity was related to toxic symptoms with the exception of compound (IV b), almost asymptomatic at the administered dose (200 mg/kg p.o.). Moreover the 2-aminoderivatives (IV) generally showed weak adrenolitic activity in vitro (rat seminal vesicles), which was estimated to be from 100 to 1000 times less than that of phenoxybenzamine.
Di Braccio
M
M
Istituto di Scienze Farmaceutiche, Università di Genova.
Roma
G
G
Mazzei
M
M
Balbi
A
A
Schiantarelli
P
P
Cadel
S
S
Bongrani
S
S
D000631:Aminopyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D004353:Drug Evaluation, Preclinical; D010323:Passive Cutaneous Anaphylaxis / Q000187:drug effects*; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
D000631:Aminopyridines; D011744:Pyrimidinones
Derivati di pirimidine 1,2-condensate. Nota IV--Sintesi e proprietà farmacologiche di 4-ammino-2H-pirido[1,2-a]pirimidin-2-oni e 2-ammino-4H-pirido[1,2-a]pirimidin-4-oni N,N-disostituiti.