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In the reaction of 2-cyano-6-alkylaminopyrazines with sec. amines in the presence of anhyd. AlCl3 amidines 1-13 were obtained. From pyrazine-2-imidoesters, 2-cyano-pyrazines and pyrazine-2-carbothioamides and hydroxylamine, amidoximes 14-49 were easily prepared. These new compounds were, however, of little tuberculostatic activity (MIC between 31.5-2000 mug/cm3).
The synthesis and pharmacological activity of a series of 2-aryl or alkyl substituted 7-methyl-1,5,6,7,8,8a-hexahydroimidaso[1,5-a]pyrazin-3(2H)-ones, are reported. The 2-aryl derivatives (VI) have been prepared by reaction of 3-(arylaminomethyl)-1-methylpiperazines (IV) have been prepared by reaction of 3-(arylaminomethyl)-1-methylpiperazines (IV) with N,N'-carbonyldiimidazole. Reaction of various anilines with 3-carbomethoxy-1-methylpiperazine (II) and subsequent reduction of the amides (III) afforded the bases (IV). The synthesis of the unsubstituted compound (XII) has been accomplished either by cyclization with sodium methoxide of methyl (1-me-thylpiperazin-3-yl)methylcarbamate (XI) or by reaction of 3-aminomethyl-1-methylpiperazine (XV) with N,N'-carbonyldiimidazole. Reduction of 1-benzyl-2-cyano-4-methylpiperazine (VII) followed by reaction with methyl chloroformate and debenzylation afforded the urethane (XI). The 2-alkyl and 2-alkenyl derivatives (XIII) have been prepared by alkylation of the sodium salt of (XII) in DMF. The compounds of these series have been tested for antiinflammatory, coronary dilator and C.N.S. depressant activities.
In the reaction of 2-cyano-6-chloropyrazine with sodium beta-aminoethanolates a mixture of nitriles 1 and imidoesters 2 is formed in relation depending on the reaction conditions. Compounds 1 and 2 with H2S and triethylamine give thioamides 3, which were converted into amides 4 and amidoximes 5. Alkaline hydrolysis of the derivatives of 6-(beta-aminoethoxy)-pyrazine-2-carboxylic acid of type 1,2,3 and 5 gave 6-ethoxypyrazine-2-carboxylic acid. The highest antituberculous activity (62-5-125 mug/cm3) showed thioamides 3a and 3b.
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1. The metabolism of several alkyl- and alkoxy-substituted pyrazines in the rat has been investigated. 2. Alkyl substituted compounds were oxidized to the corresponding acids which were excreted in the urine as such or as their glycine cojugates. The extent of oxidation was reduced when two adjacent alkyl groups were present. In the latter case ring hydroxylation also occurred. Methoxy-substituted pyrazines underwent O-demethylation and ring hydroxylation. 3. Little or no biliary excretion of the pyrazines or their metabolites occurred. 4. Some preliminary results on the metabolism of 2-isobutyl-3-methoxy-pyrazine (the major characteristic flavour component of bell pepper) have been obtained. 5. For comparative purposes the metabolism of some similarly substituted pyridines was investigated.
The 2,3-dihydroxy-6-bromo-pyrazino-[2,3-beta]-pyrazine is a substance selected during the antiviral screening of pyrazino-pyrazine derivatives. The compound shows antiviral activity in vitro against measles, NDV, some influenza viruses and against herpes simplex and zoster, infectious canine hepatitis and vaccinia viruses. It had no effect on ECHO 9 virus. Therapeutic trials showed activity also on herpetic keratoconjunctivitis experimentally induced in rabbits.
A highly specific and sensitive gas chromatographic method for the determination of 6-chloro-2-(1-piperazinyl)pyrazine (MK-212), a central serotonin-like agent, in biological fluids is described. MK-212 and a related internal standard are extracted into benzene from an alkaline solution, back-extracted into acid and then re-extracted into benzene at an alkaline pH. The amines are converted to the trifluoroacetyl derivatives (characterized by gas-liquid chromatography-mass spectrometry), chromatographed and detected with a 63Ni electron capture detector. The sensitivity of the method is such that 10 ng of drug can be measured per aliquot of biological fluid. The precision and accuracy of the method are well within acceptable limits. Specificity of analysis was established by gas-liquid chromatography-mass spectrometry techniques.
The mechanism of the reduction in food consumption elicited by 6-chloro-2-[1-piperazinyl]-pyrazine (MK-212) administered systemically was investigated in the rat. (+/-)-Fenfluramine and (+)-amphetamine were included in some studies for comparative purposes. 2 Pretreatment with methergoline, a 5-hydroxytryptamine (5-HT) antagonist, reduced the magnitude of the anorectic effect of 1.5 and 3 mg/kg of MK-212, while the anti-5-HT agents, cyproheptadine and cinanserin, were likewise effective against the 3 mg/kg dose. 3 Xylamidine, an antagonist of 5-HT that penetrates poorly into the central nervous system, completely blocked the decrease in food intake caused by 5-HT administered peripherally, while not antagonizing an equianorectic dose of MK-212. 4 Reduction of brain 5-HT by intraventricular injection of 5,6-dihydroxytryptamine, intraperitoneal administration of p-chloroamphetamine or placement of a lesion in the region of the median raphé nucleus diminished the anorectic response to 3 mg/kg of MK-212. The anorectic effect of amphetamine was reduced by p-chloroamphetamine or lesion in the raphé, but not by 5,6-dihydroxytryptamine. The decrease in food consumption produced by 1.5 mg/kg of MK-212 was antagonized by prior treatment with p-chloroamphetamine, but not by 5,6-dihydroxytryptamine. 5 Haloperidol, which blocks receptors for dopamine, antagonized the anorexigenic effect of amphetamine, but was ineffective in offsetting the action of MK-212, 3 mg/kg. 6 Pretreatment with chlorimipramine to inhibit the 5-hydroxytryptaminergic uptake mechanism did not affect the anorectic response to 3 mg/kg of MK-212, whereas the response to fenfluramine was diminished. 7 The results indicate that the anorectic action of MK-212 involves a 5-HT-like component which is more evident at the higher dose level of the compound. The anorexigenic property of MK-212 may depend, at least partly, upon the integrity of 5-HT-containing neurones in the central nervous system.
A method is described for the synthesis and purification of tritiated N-benzylamidino-3,5-diamino-6-chloro-pyrazine carboxamide (benzamil). The tritium was inserted at the meta position of the benzyl ring, from which it apparently does not exchange with solvent hydrogen. When stored in ethanol at -4 degrees C the radioligand remains stable for at least 15 months. The pharmacology of benzamil is very similar to that of amiloride in terms of its effects on sodium transporting epithelia except that it has a higher affinity. The affinity of benzamil for sodium channels in amphibian epithelia in the absence of sodium is approximately 10(9) M-1. The new ligand can be used to label sodium channels in epithelia, and may be useful in channel isolation procedures.
The Authors describe the synthesis of some quaternary salts of the hexahydro-1H-2,6-methanopyrrolo[1,2-a]pyrazines mono or disubstituted at carbon-4. These were obtained directly by cyclization of the corresponding diazabicyclooctanes, by formation of a substituted ethylenic bridge between the two nitrogen atoms. The compounds were pharmacologically screened; the hypothesis of enhancement of curare-like activity in comparison with the unsubstituted derivatives was not confirmed.
6-RNH- and 6-R2NNH-pyrazine-2-carbothioamides 1--3, 5, 6, 9 and 14 were obtained from 2-cyano-6-chloropyrazine. In the in vitro screening the thioamides were active against Myc. tuber. H37Rv at the conc. range of 15.6--250 microgram/cm3. The most active thioamides 1 and 8, however, do not act in experimental tuberculosis in guinea pigs.
Quantitative relationships were studied between tuberculostatic potency in vitro and structure parameters of pyrazine carbothioamides. The activity of the compounds was found to be dependent on the parameters related both to the size of the substituent and electronic properties of the molecule. An equation was obtained, statistically significant on the 99% level, which described about 71% of variance of activity data for the compounds under study as a function of molar refractivity of the substituent and the wave length at which absorption maximum occured.
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In rats allowed to eat for 2 h/day and injected i.p. 30 min before feeding, MK-212, ED50 = 1.5 mg/kg, was two times more potent as an anorexigen than fenfluramine. However, the compounds were equiactive in the rat following p.o. administration 1.5 or 3 h before the test, while fenfluramine was more potent if the interval was extended to 6 h. In cats permitted to eat for 3 h/day, the ED50 dose (mg/kg p.o.) for MK-212 determined at 0.5, 1 and 3 h after feeding was, respectively, 15, 10, and 3 times less than that of fenfluramine. Emesis and diarrhea were frequently observed ancillary effects in cats treated with fenfluramine, whereas apparent sedation and salivation were commonly detected in animals after MK-212. In rats or cats pretreated with methergoline, the decrease in food consumption elicited by MK-212 was markedly inhibited, suggesting that the mechanism of action involves a serotoninlike effect. Compared with the marked stimulant action of amphetamine, MK-212 had only a minor and inconsistent effect on motor activity in rats and mice. Similar results were obtained with fenfluramine. MK-212 was not self-administered by rats, while the self-administration of amphetamine and morphine were demonstrated using the same experimental protocol.
CPP, administered systemically, elicited four distinct responses characteristic of serotonin-receptor activation in the central nervous system. The crossed extensor reflex in the acutely spinalized rat was enhanced by treatment with CPP, 1-16 mg/kg. CPP, 1.11-10 mg/kg, elicited a dose-related increase in head twitches in mice. A complex motor syndrome in rats similar to that produced by pargyline plus tryptophan (or other treatments effecting increased activation of central serotonin receptors) was produced by 1.25-5 mg/kg of CPP. An increase in twitch frequency of the mylohyoideus muscle in the urethane anesthetized rat occured after CPP at 0.1 mg/kg or less. Complete abolition of all four effects of CPP was achieved by pretreatment with the centrally acting indoleamine antagonist methergoline. The peripherally acting serotonin antagonist xylamidine was ineffective or only weakly active, depending upon the test procedure, in preventing the serotonin-like actions of CPP. These findings indicate that CPP has a serotoninmimetic action in the central nervous system.
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