Effects of subacute treatment with benzopyranopyrimidines in hemostasis and experimental thrombosis in mice.

The antithrombotic activity of a series of benzopyranopyrimidine derivatives was investigated in platelet-dependent and independent pulmonary thromboembolism in mice. Intraperitoneal subacute treatment with 2-morpholino derivative 3c significantly prevented paralysis due to collagen plus epinephrine-induced pulmonary thrombosis while 2-piperidino substituted derivative 3h significantly protected mice from paralysis caused by thrombin-induced intravascular fibrin formation at dosage not affecting bleeding time. These compounds, previously proved to be effective as antiplatelet agents in vitro, were in vivo more potent as antithrombotics than lysine acetylsalicylate and possessed lower prohemorrhagic activity than the reference drug.

Synthesis and biological evaluation of GABA derivatives able to cross the blood-brain barrier in rats.

Two new GABA derivatives, 1 and 2, were synthesized and tested for their capacity to display CNS activity, which was assessed by determining the effects on the duration of pentobarbital-induced hypnosis in rats. Compound 1, peripherally injected, significantly prolonged the hypnosis time, a typical GABA-mimetic effect, while both intracerebroventricular and intravenous administration of compound 2 surprisingly shortened the hypnotic effect in an atropine-sensitive way. The study was extended also to compounds 1a, 1b and 2a, putative oxidative/hydrolytic metabolites of 1 and 2.

1,5-benzodiazepines. Part XIII. Substituted 4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-5-amines and 4H-imidazo[1,2-a][1,5]benzodiazepin-5-amines as analgesic, anti-inflammatory and/or antipyretic agents with low acute toxicity.

The reaction of proper N,N-dialkyl-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-5-amines (1) with N-chlorosuccinimide afforded their 4-chloroderivatives 3 which in turn were treated with cyclic amines to give the corresponding 4,5-diaminoderivatives 4. The N,N-dialkyl-4H-imidazo[1,2-a][1,5]benzodiazepin-5-amines (5) were prepared starting from suitable 4-(dialkylamino)-1,3-dihydro-2H-1,5-benzodiazepin-2-ones (8), through multistep synthetic routes. At the 200 mg kg(-1) os dose, some compounds 3 and 4 showed notable analgesic or anti-inflammatory activity but no antipyretic properties, whereas the 5-(dibutylamino) derivatives 5b and 5f proved to be significantly endowed with all these activities.

New insights into the pharmacological properties of potent antiplatelet 2-amino-benzo[d]isothiazol-3-one derivatives.

A series of 2-amino-benzo[d]isothiazol-3-one derivatives (1-8), previously described as in vitro potent antiaggregatory agents endowed with spasmolytic properties, was evaluated for in vitro antiplatelet activity in guinea-pig platelet rich plasma and for in vivo effects on experimental thrombosis and bleeding time in mice. All the 2-amino-benzo[d]isothiazol-3-one derivatives 1-8 were more potent antiplatelets against collagen than acetylsalicylic acid and, unlike this drug, strongly inhibited thromboxane agonist U46619-induced aggregation. Subacutely administered (5mgkg(-1) day i.