ABSTRACT
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. Although their ineffectiveness on clotting times, PT and APTT, allows the involvement of coagulation pathways to be ruled out, the mechanisms underlying the favourable benefit risk ratio for these two compounds remain to be further clarified.
Subject(s)
Hemostasis/drug effects , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation/drug effects , Pulmonary Embolism/drug therapy , Pyrimidines/pharmacology , Animals , Mice , Paralysis/drug therapy , Peptic Ulcer/drug therapy , Platelet Aggregation Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Rats , Rats, WistarABSTRACT
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.
Subject(s)
Blood-Brain Barrier/drug effects , gamma-Aminobutyric Acid/analogs & derivatives , gamma-Aminobutyric Acid/pharmacokinetics , Animals , Atropine/pharmacology , Binding, Competitive , Biotransformation , Dose-Response Relationship, Drug , Female , Hydrolysis , Hypnotics and Sedatives/pharmacology , Injections, Intraperitoneal , Injections, Intravenous , Injections, Intraventricular , Magnetic Resonance Spectroscopy , Muscarinic Antagonists/pharmacology , Oxidation-Reduction , Pentobarbital/pharmacology , Rats , Rats, Wistar , Receptors, GABA-A/drug effects , Receptors, GABA-A/metabolism , Receptors, GABA-B/drug effects , Receptors, GABA-B/metabolism , Sleep/drug effects , gamma-Aminobutyric Acid/metabolismABSTRACT
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.p. for 5 days), compounds 6 and 7 protected mice from collagen/epinephrine induced pulmonary thromboembolism at about 20-fold lower doses than acetylsalicylic acid and they prolonged bleeding time like the most part of the other derivatives. The potent antithrombotic activity was coupled with the absence of any lethal and ulcerogenic effect up to 200mgkg(-1) os.
Subject(s)
Muscle Contraction/drug effects , Parasympatholytics/pharmacology , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation/drug effects , Pulmonary Embolism/prevention & control , Thiazoles/pharmacology , Administration, Oral , Animals , Bleeding Time , Guinea Pigs , Ileum/physiology , In Vitro Techniques , Injections, Intraperitoneal , Lethal Dose 50 , Male , Mice , Muscle, Smooth/physiology , Parasympatholytics/chemistry , Parasympatholytics/toxicity , Peptic Ulcer/chemically induced , Platelet Aggregation Inhibitors/chemistry , Platelet Aggregation Inhibitors/toxicity , Thiazoles/chemistry , Thiazoles/toxicityABSTRACT
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. Almost all the compounds 3, 4 and 5 did not show acute toxicity in mice up to 800 mg kg(-1) os dose.
