Synthesis and pharmacological activity of derivatives of 3-cyano-4(6)-methyl-6(4)-dimethylaminopyridine

Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 25, No. 9, pp. 29–33, September, 1991.     

Potential cardiotonics. 7. Synthesis and cardiovascular effects of 5-(4-pyridinyl)-, 6-methyl-4-(4-pyridinyl) and 6-methyl-5-phenyl-substituted 3-cyano-2-aminoalkylamino-pyridines

The title compounds were synthesized by treating of 2-chloro-pyridines 1-3 with the appropriate aminoalkylamines or piperazines. In isolated guinea pig atria some compounds showed greater positive inotropic activity than amrinone. Heart rate was decreased or remained unchanged. In anesthetized dogs some derivatives exerted a dose-dependent increase in myocardial contractility and, additionally, a decrease in blood pressure.     

Synthesis and anti-viral activity of N-alkyl-3-cyano-2-pyridones and 3-cyano-2-alkoxypyridines

Translated from Khimiko-farmatsevticheskii Zhurnal Vol. 24, No. 2, pp. 132–134, February, 1990.     

Synthesis of 8-methyltheobromine from 3-methyl-4-aminouracil

A new three-step method has been developed for the synthesis of 8-methyltheobromine from 3-methyl-4-aminouracil, based on its bromination, the conversion of 3-methyl-4-amino-5-bromouracil to 3-methyl-4-amino-5-dimethylaminouracil, and the reaction of the latter with acetic anhydride.Translated from Khimiko-Farmatsevticheskii Zhurnal, No. 1, pp. 23–25, January, 1967.     

Synthesis and procoagulatory activity of n-(6-methyl-3-cyano-5-ethoxycarbonyl-2-pyridyl) aminoalkanecarboxylic acids

Interaction of 6-methyl-2-chloro-3-cyano-5-ethoxycarbonylpyridine with potassium salts of amino acids was shown to form N-(6-methyl-3-cyano-5-ethoxycarbonyl-2-pyridyl)aminoalkanecarboxylic acids. Most of the resulting substances had procoagulatory activity.     

Synthesis of 3-cyano-6-methyl-4-pyridyl-2(1H)-pyridinethiones as well as 2-substituted 6-methyl-4-pyridyl-pyridine-3-carbonitriles and 3-carbonic acid amides, respectively, and testing their cardiovascular activity

By the base catalyzed reaction of our previously described 3-cyano-6-methyl-4-pyridyl-2(1H)-pyridinethiones 1 and 2, respectively, with branched and unbranched, respectively, alkyl, aralkyl-, alkinyl-, hydroxyalkyl-, ethoxycarbonyl- and carbamoylalkylhalides the new in 2-position substituted 6-methyl-4-pyridyl-pyridine-3-carbonitriles 15-30 were formed. By means of oxidation of the 2-methylthio-substituted pyridine-3-carbonitriles 3 and 4 with potassium periodate and potassium permanganate in diluted acetic acid, respectively, the sulfinyl compounds 5 and 6, respectively, and the sulfonyl compounds 7 and 8, respectively, were prepared. By heating of 3 and 4, respectively, with concentrated sulphuric acid the 2-methylthio-pyridine-3-carboxamides 9 and 10 were obtained. The oxidation of these compounds with potassium periodate and potassium permanganate, respectively, had yield the pyridines 11 and 12, respectively, as well as 13 and 14, respectively.     

4—氨基—1—甲基—3—丙基吡唑—5—甲酰胺的合成

以２－戊酮和草酸二乙酯为起始原料,经缩合,环合、甲基化、水解、硝化、氨解、还原等７步反应合成了新型磷酸二酯酶５型（ＰＤＥ５）抑制剂西地那非的关键中间体－４－氨基－１－３－丙基吡唑－５－甲酰胺。     

2-(3-氰基-4-羟基)苯基-4-甲基-5-噻唑甲酸乙酯的合成

目的优化非布司他关键中间体2-(3-氰基-4-羟基)苯基-4-甲基-5-噻唑甲酸乙酯(4)的合成方法。方法采用"一勺烩"方法,以4-羟基苯甲腈为起始原料,首先与硫氢化钠和无水氯化镁在N,N-二甲基甲酰胺中反应,所得中间体不经分离,直接加入2-氯乙酰乙酸乙酯进行环合反应,得到2-(4-羟基)苯基-4-甲基-5-噻唑甲酸乙酯(2);然后通过六亚甲基四胺/三氟乙酸进行Duff反应,得到2-(3-甲酰基-4-羟基)苯基-4-甲基-5-噻唑甲酸乙酯(3);再经盐酸羟胺/甲酸/甲酸钠体系脱水得到目标化合物。结果经四步反应合成非布司他关键中间体4,总收率为22.6%,其结构经核磁共振氢谱、质谱确证。结论改进后的工艺终产品无需柱色谱纯化,适合工业化生产。     

Synthesis and biological activities of 2,6-diaryl-3-methyl-4-piperidone derivatives

In the present study, a new series of 2,6-diaryl-3-methyl-4-piperidones was synthesized by Mannich reaction (condensation) of ethyl-methyl ketone, substituted aromatic aldehydes and ammonium acetate. Oximes and thiosemicarbazone derivatives of 2,6-diaryl-3-methyl-4-piperidones were synthesized by reaction with hydroxylamine hydrochloride and thiosemicarbazide respectively. The chemical structures were confirmed by means of IR, 1H-, 13C-NMR and mass spectral data. The compounds were screened for acute toxicity, analgesic, local anaesthetic and antifungal activity. 2-(4-Methylphenyl)-3-methyl-6-(4-chlorophenyl)-piperidin-4-one 2 exhibited the highest analgesic and local anaesthetic activity. The oximes and thiosemicarbazones were completely devoid of analgesic and local anaesthetic activity. 2-(4-Methylphenyl)-3-methyl-6-(4-hydroxyphenyl)-piperidin-4-oxime 21 and 2-(4-methoxyphenyl)-3-methyl-6-(4-chlorophenyl)-piperidin-4-oxime 17 exhibited potent antifungal activity against Aspergillus niger. Antifungal activity against Candida albicans was observed only with 2-(4-dimethylaminophenyl)-3-methyl-6-(4-chlorophenyl)-piperidin-4-oxime 20. 2,6-Diaryl-3-methyl-4-piperidones did not exhibit antifungal property.     

Potential cardiotonic agents. 6. Synthesis and cardiovascular properties of 5-(4-pyridinyl)-, 6-methyl-5-(4-pyridinyl)- and 6-methyl-5-phenyl-substituted 3-cyano-2-oxaalkyoxy-pyridines

The headline compounds were prepared by the reaction of 2-chloropyridines 1-3 with the appropriate alcohols in presence of potassium hydroxide and the sodium alkoxides, respectively. Especially some of the 3-cyano-2-hydroxyalkoxy-5-(4-pyridinyl)pyridines showed remarkable positive inotropic potency and, additionally, a vasodilator activity. In spontaneously beating isolated guinea pig atria they had a greater activity than amrinone.     

Synthesis of 4-methyl-5-ethoxycarbonyloxazole

Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 23, No. 4, pp. 452–454, April, 1989.