Comparative studies of antiplatelet activity of nonsteroidal antiinflammatory drugs and new pyrazine CH- and NH-acids.

Nine known nonsteroidal antiinflammatory drugs (NSAID) and three new pyrazine derivatives possessing an active methylene moiety (pyrazine CH/NH-acids) were tested with regards to their in vitro and in vivo antiplatelet activity. Concentrations of the agents were determined which caused 25% and 50% inhibition of aggregation of human blood platelets induced by fixed concentrations of ADP, collagen and epinephrine. The in vivo test consisted in determination of percent protection of mice from pulmonary microembolism caused by injection of a mixture of collagen and epinephrine. The in vitro antiaggregatory activity of the agents studied was rather low, excepting the inhibition of the collagen-induced aggregation by ketoprofen. Several NSAID and two new pyrazine CH/NH-acids appeared highly potent antithrombotic agents in vivo. Activity of NSAID expressed as percent protection against lung thromboembolism in the mouse was demonstrated to depend quantitatively on acid properties of the agents. The new chemical class of pharmacologically active agents, pyrazine CH/NH-acids, offers an original pharmacophore which is distinctive from the carboxylic or enolic functionalities typical for the established NSAID, and as such, may be devoid of some disadvantages of known antiplatelet drugs.

Synthesis and analgetic and antiinflammatory activity of derivatives of 3-(1H-benzimidazole-2)propanoic acid.

Condensation reactions of 3-(1H-benzimidazole-2)propanoic acid (procodazol) with aromatic aldehydes were carried out resulting in lactam and acid derivatives. Basing on the spectral studies (MS, NMR) it was found that in the reaction the hydrogen atoms of the 3-methylene group of procodazol take part. 3-[2'-Acetoxyphenyl)methylene]-2,3-dihydro-1 H-pyrrole[1,2-a]benzimidazol-1-one (3c) was found to possess some analgetic properties.

Synthesis and pharmacological activity of 5-substituted-s-triazole-3-thiols.

Two subgroups of 5-substituted triazoles were synthesized: derivatives of 3(3-substituted-amino-2-hydroxypropylthio)-5-substituted-4H-1,2,4- triazole and derivatives of N-substituted amides of 5-substituted-s-(1,2,4-triazole-3)thioglycolic acid. Selected members of the two subseries were tested pharmacologically. The blood pressure lowering effect in anaesthetized normotensive rats was weak to moderate. More pronounced was the inhibitory effect against adrenaline induced human blood platelet aggregation. In experiments on isolated rat heart atria and on isolated rat tail artery the activity of the agents was much weaker than in the case of known beta or alpha adrenoceptor antagonists. Generally, the chance to find a potential antihypertensive agent within the group studied seems to be low. Antiaggregatory activity of the compounds deserves further studies.

Synthesis, structure and biological activity of 1,2,4-triazolo-1,3-thiazine derivatives.

A group of condensed triazole-thiazine derivatives (2a-i, 3b, 3j) was obtained in reaction of the corresponding 5-substituted 1,2,4-triazole-3-thiones (1a-j) with epichlorohydrin in alkaline medium. The structure of the compounds synthesized was confirmed by spectral and roentgenographic methods. Tuberculostatic and circulatory activities of the compounds were also studied.

[Study of the synthesis of pyrazine derivates. Part XXVIII. Reaction of pyrazineamide with CS-2]. / Badania nad pochodnymi pirazyny. XXVIII. Reakcje pirazynoamidrazonu z disiarczkiem wegla.

The synthesis of pyrazine derivatives, e.g. 1,3,4-thiodiazole (I, III-V, XII), 1,2,4-triazole (II) and N-substituted amidrazones is reported.

[Investigations of pyrazine derivatives. Part XXVII. Synthesis and tuberculostatic activity of some 6-alkoxypyrazine-2-carbotioamids]. / Badania nad pochodnymi pirazyny. XXVII. Synteza i dzialanie tuberkulostatyczne 6-alkoksypirazyno-2-karbotioamidów.

It was found that reaction of sodium alcoholates and cyanopyrazine yields alkoxypyrazine-nitriles. In heterogenic reaction both 2-alkylimidesters-6-chloropyrazine or 2-alkylimidoesters-6-alkoxypyrazine can be obtained dependent. This is dependent on quantity of alcohol used for reaction. Final products, alkoxypyrazinethioamides were tested for tuberculostatic activity (MIC within 31-500 mcg/cm3).

[Studies on pyrazine derivatives. XXVI. Synthesis and tuberculostatic activity of N-pyrazinylthiourea]. / Badania nad pochodnymi pirazyny. XXVI. Synteza i aktywnosc tuberkulostatyczna N-pirazynylotiomoczników.

2-Amino-3-chloropyrazine and 2-amino-6-chloropyrazine were reacted with appropriate sodium alkoxides to give 2-aminopyrazine derivatives with the methoxy, benzyloxy, chlorobenzyloxy, dichlorobenzyloxy, bromobenzyloxy or dibromobenzyloxy group at positions 3 and 6 (I-XIV). The obtained compounds were converted into N-pyrazinyl-N'-benzoylthioureas (XV-XXXI) by reacting with benzoyl isothiocyanate. Their hydrolysis yielded N-pyrazinylthioureas XXXII-XLVII. Analogical reactions of alkoxyaminopyrazines with p-chlorophenyl isothiocyanate or 2,6-dichlorophenyl isothiocyanate afforded corresponding N-pyrazinyl-N'-(p-chlorophenyl)thioureas and N-pyrazinyl-N'- (2,6-dichlorophenyl)thioureas (XLVIII-LVIII). The obtained compounds were found to display tuberculostatic in vitro activity with MIC values from 8 meg/cm3 to 1000 mu meg/cm3.

Studies on quinoxaline derivatives. Synthesis of quinoxalylamino-1,3-diazacycloalkanes with potential hypotensive activity.

A series of quinoxalylamino-1,3-diazacycloalkanes was obtained by the reaction of the corresponding substituted aminoquinoxalines with alcohols and amines. The effect of selected compounds on the blood pressure of anaesthesized normotensive rats was studied.

Comparative study of antithrombotic and antiaggregatory activity of acetylsalicylic acid, ticlopidine and a new noncarboxylic acid antiinflammatory pyrazine derivative HF90.

The action of acetylsalicylic acid, ticlopidine and a new pyrazine derivative HF90 selected in preliminary screenings (11, 18, 19) was studied by using the mouse antithrombotic assay according to DiMinno and Silver (22) and in vitro blood platelet aggregation method according to Born (23). Acute pulmonary thromboembolism was induced by injection of a mixture of collagen and epinephrine into the mouse tail vein. The effect of HF90, an acidic pyrazine derivative possessing active methylene moiety, administered at doses of 50 and 100 mg/kg, was compared to the action of the well established antithrombotic agents: ticlopidine (100 mg/kg) and acetylsalicylic acid (20 mg/kg). The compounds were administered i.p. in single doses 1 h and 24 h before the thrombotic challenge or once a day per three consecutive days before the thrombotic challenge. Ticlopidine appeared to provide the better protection against microembolism than acetylsalicylic acid although its effect has not manifested itself immediately after administration. The pyrazine derivative examined has a lower but significant antithrombotic activity. The chemical class of pyrazine derivatives with active methylene moiety (the so called pyrazine CH/NH-acids) (16) provides a new original antiinflammatory pharmacophore and HF90 may serve as the "lead compound" in the search for new agents of pharmacological interest.

Studies on pyrazine derivatives. XXX. Synthesis of pyrazinylamino-1,3-diazacycloalkanes of potential circulatory activity.

A series of pyrazinylamino-1,3-diazacycloalkanes was obtained by reaction of the corresponding substituted aminopyrazines with aliphatic amines. Selected compounds were studied with respect to their potential circulatory activity. The effect on the blood pressure, isolated rat tail artery and heart atria, and an influence on the human blood platelet aggregation were investigated.

Studies on pyrazine derivatives. XXXII. Synthesis and tuberculostatic activity of acetylpyrazine thiosemicarbazone derivatives.

Syntheses of 4-N-substituted thiosemicarbazoic acetylpyrazine derivatives have been described. The in vitro microbiological investigations of the 25 synthesized compound were carried out.

Studies on pyrazine derivatives--XXXIV. Synthesis and tuberculostatic activity of alpha-oxo ketene dithioacetals pyrazine derivatives.

The alpha-oxo ketene dithioacetalic derivatives (2a-e) were obtained by the reaction of 2-acetylpyrazine (1) with CS2 and appropriate mono- or dihalogeno-compound. An action of the primary amines and diamines upon 3,3-di(methylsulphanyl)-1-(2-pyrazinyl)-2-propen-1-one (2a) yielded 3-(alkylamino)-3-(methylsulphanyl)-1-(2-pyrazinyl)-2-propen-1-on e (3a-g), 1-(2-pyrazinyl)-2-tetrahydro-1H-2-imidazolyliden-1-ethanone (3h) and the 2-hexahydro-2-pyrimidinyliden-1-(2-pyrazinyl)-1-ethanone derivatives (3i-j), respectively. Tuberculostatic activity of the studied compounds was found to be low except the compound 2b (MIC 192-62 micrograms/cm3; MIC 210-31 micrograms/cm3).

Studies on pyrazine derivatives. XXXIII. Synthesis and tuberculostatic activity of 1-[1-(2-pyrazinyl)-ethyl]-4-N-substituted thiosemicarbazide derivatives.

Hydrogenation of 4-N-substituted thiosemicarbazonic acid acetylpyrazine derivatives with NaBH4 in dry ethanol led to seventeen new compounds. The in vitro tuberculostatic activity investigations of the 15 synthesized compound were carried out. MIC few of i.v. compounds were lower than 32 micrograms/cm3.