Synthesis of 3-(2-pyridylethyl)benzoxazolinone derivatives: potent analgesic and antiinflammatory compounds inhibiting prostaglandin E2.

Fourteen new 3-[2-(2- and/or 4-pyridyl)ethyl]benzoxazolinone derivatives have been synthesized by reacting 2- and/or 4-vinylpyridine and appropriate benzoxazolinones. Their chemical structures have been proven by IR, 1H-NMR, and elemental analysis. Analgesic activities of these compounds were investigated by a "Modified Koster's Test". Except for compounds 10 and 11, all the new derivatives showed higher analgesic activities than aspirin. Therefore the compounds were screened for their antiinflammatory activities using the carrageenan hind paw edema test. The compounds (6, 7, 8, 9, 14, and 17) that showed high antiinflammatory activity were then further screened for their ability to inhibit prostaglandin E2 (PGE2) induced paw edema. Although all the benzoxazolinone derivatives synthesized in this study showed higher antiinflammatory activity compared to indomethacin, those without a substituent at the 6-position of the ring were significantly more active than the rest of the group, and their ulcerogenic activities and ED50 values indicate them as promising derivatives for further study.     

吡咯类新衍生物在大鼠胸主动脉的钙拮抗作用

目的　观察 4个吡咯类新化合物是否具有钙拮抗作用。方法　采用4 5Ca跨膜内流动测定技术 ,考查 4个新化合物对大鼠主动脉电压依赖性钙通道的钙拮抗活性。化合物分别为化合物 1:3,5 二甲基 4 (4 甲基 1 甲酰基哌嗪基 ) 1H 吡咯 2 甲酸乙酯 ;化合物 2 :3,5 二甲基 4 [4 (4 硝基苯基 ) 1 甲酰基哌嗪基 ] 1H 吡咯 2 甲酸乙酯 ;化合物 3:3,5 二甲基 4 [4 (3 对甲基苯基丙烯酰基 ) 1 甲酰基哌嗪基 ] 1H 吡咯 2 甲酸乙酯 ;化合物 4 :4 [4 [3 (2 氯苯基 )丙烯酰基 ] 1 甲酰基哌嗪基 ] 3,5 二甲基 1H 吡咯 2 甲酸乙酯。结果　 4个化合物均不同程度降低4 5Ca跨膜内流 ,化合物 1和化合物 2的活性强于阳性对照药硝苯地平。结论　 4个吡咯类化合物有一定的钙拮抗活性     

Synthesis of thiazolyl and thieno cholestane derivatives: a novel class of potent antiinflammatory steroids

The reactivity of 5alpha-cholestan-3-one (1) towards the formation of thiazolyl derivatives of potential antiinflammatory activity was studied. Also starting with the aminothieno[2',3': 2,3]cholestane derivative 8 several thiazolylthieno[2',3':2,3]cholestane derivatives were synthesized. The structures of the new compounds were established based on the analytical and spectral data and the in vivo antiinflammatory activities of some of these compounds were investigated.     

Synthesis and screening of some substituted 3.5-dioxopyrazolidines.

Seven new 3.5-dioxopyrazolidine derivatives, incorporating in their molecule a p-substituted benzoyl grouping, were synthesized. The preliminary screening of four selected compounds showed that 1-phenyl-2-[p-nitrobenzoyl]-4.4-diethyl-3.5-dioxopyrazolidine possesses a low order of antiinflammatory activity.     

Chemotherapeutic agents with an imidazole moiety. II. Synthesis and biological activities of new 1,4-diarylimidazoles

The synthesis, antifungal and pharmacological activities of new 1,4-diarylimidazoles are reported. Antimicrobial data in comparison with antifungal antibiotic pyrrolnitrin pointed out that the 1,4-diaryl-2-mercaptoimidazole derivatives were inactive and all 1,4-diarylimidazoles exhibited a weak antifungal activity. Some compounds showed a selective activity against strains of Candida sp. Instead pharmacological data did not evidence any significant antiinflammatory activity. The tested compounds were prepared by reacting appropriate phenacylanilines with potassium thiocyanate in acidic medium to afford 1,4-diaryl-2-mercapto imidazoles which were then transformed into title compounds by treatment with nitric acid.     

Research on heterocyclic compounds. XIX--2-Methylimidazo[1,2-a]pyridine-3-acetic acids

A group of methyl substituted imidazo[1,2-a]pyridine-3-acetic acids was synthesized by reaction of some methyl derivatives of 2-aminopyridine with ethyl 3-bromolevulinate and subsequent hydrolysis. These new acidic compounds were tested for their antiinflammatory, analgesic, antipyretic and ulcerogenic activities in order to compare the results with those previously obtained with similar compounds.     

灵芝生物碱甲和乙的合成

灵芝为担子菌类多孔菌科灵芝属植物的子实体。人工培养的有赤芝、紫芝、薄盖灵芝和树舌等。灵芝是我国广泛流传的珍贵药物之一。近年来,对于灵芝的临床疗效和药理作用做了多方面的研究,证明对慢性气管炎、慢性肝炎、冠心病、白细胞减少症、慢性克山病和神经衰弱等都有一定的疗效,特别是对神经系统和肝脏功能具有调节作用。深层培养的薄     

Research on heterocyclic compounds. XVIII. Imidazo[2,1-b]-1,3,4-thiadiazole derivatives

The synthesis of a series of 6-carbethoxy-, 6-carbethoxy-methyl-, and 5-carbethoxy-6-methylimidazo[2,1-b]-1,3,4-thiadiazoles was accomplished by reacting some 2-amino-1,3,4-thiadiazoles with ethyl bromopyruvate, 4-chloroacetoacetate, and 2-chloroacetoacetate, respectively; such carbethoxy derivatives afforded the corresponding carboxylic acids by hydrolysis. The antiinflammatory, analgesic, antipyretic and ulcerogenic activities were studied on three of the new acidic compounds.     

Antibacterial and antifungal compounds. VIII. Synthesis and antifungal activity of pyrrol derivatives similar to trichostatin A

Some p-methylbenzolpyrrole acrylic acids and related compounds were synthesized. The new pyrrole derivatives have structural features in common with trichostatin A, an antifungal antibiotic. The above acids and derivatives were tested against Candida albicans and Candida sp in comparison with miconazole, pyrrolnitrin and amphotericin B and showed very weak antifungal activities. Occasionally some activity was found against a few strains of Candida albicans and against Candida pseudotropicalis.     

Synthesis and quantitative structure-activity relationship analysis of N-triiodoallyl- and N-iodopropargylazoles. New antifungal agents

New series of N-(2,3,3-triiodoallyl) and N-(3-iodopropargyl) azole derivatives (100 compounds) involving pyrrole, pyrazole, imidazole, triazole, and tetrazole nuclei were synthesized successively with the aid of quantitative structure-activity relationship (QSAR) analysis to obtain potent antifungal agents. Starting from the derivatives of nitropyrrole-containing antibiotics, the QSAR analysis of the pyrrole derivatives against Candida albicans and Trichophyton mentagrophytes strains indicated the positive contribution of the nitro group and negative effect of the size of molecule. Further application of the QSAR analysis on the multi-azole derivatives revealed the importance of hydrophobicity and electronegativity as well as steric effect to the activities and led to the synthesis of one of the most potent iodo compounds, 2-(2,3,3-triiodoallyl)tetrazole (67, ME1401).     

5,6-二芳基-2,3-二氢-1-吡咯里嗪酮类化合物的合成及抗炎镇痛活性

目的寻找高效低毒、有抗炎镇痛活性的新的吡咯里嗪酮类化合物。方法以二芳基取代杂环类COX-2选择性抑制剂为模板,以吡里酮为母体,设计并合成了5,6-二芳基-2,3-二氢-1-吡咯里嗪酮类化合物。用IR,¹HNMR和MS确定其结构。用二甲苯致小鼠耳肿胀法和小鼠醋酸扭体法测定这些化合物的(po 200mg·kg^-1)抗炎及镇痛活性。结果合成了17个新化合物(1-17)。生物实验结果显示,多数化合物有一定的抗炎和(或)镇痛活性。结论化合物3,8,11,14和15抗炎活性优于对照药布洛芬;化合物9,10和11镇痛活性接近于对照药布洛芬,值得进一步研究。     

Synthesis and antiinflammatory properties of 2-aminobenzimidazole derivatives.

Several 1-alkyl or 1-aralkyl substituted 2-aminobenzimidazole derivatives, bearing an acetic or acetohydroxamic group at 3-position, were synthesized. Some of these products were tested for their antiinflammatory and analgesic properties. These compounds exhibited an antiinflammatory activity lower than that of reference drug Indomethacin. Compound 2e showed the highest efficacy, but not in a dose-related manner. Only compounds 3a and 16 exhibited some analgesic activity, but at a very high dose.     

4-芳杂环单/双氨甲基酚衍生物的合成和量化计算

本文在前报的基础上,设计和合成了4-芳杂环取代的氨甲基酚衍生物28个。初步药理试验表明,多数显示不同程度的抗炎活性。用CNDO/2法计算所得数据提示,该类化合物分子中的氨甲基氮和酚羟基氧与受体正电荷中心的结合,可能对抗炎活性起着重要作用。     

3,3'-bi-1,3-thiazolidine]-4,4'-dione system. I. Synthesis, conformational analysis and pharmacological activities of 2,2'-diaryl derivatives

The two configurational isomers, d1, and meso, of some 2,2'-diaryl-[3,3'-bi-1,3-thiazolidine]-4,4'-dione derivatives have been obtained and characterized. The 1H-N.M.R. spectra of both stereoisomers in DMSO-d6 solution are temperature-dependent and their dynamic behaviour has been related to the hindered rotation of the N--N bond. Evidence for an orthogonal disposition of the two heterocyclic rings, in the ground state, is presented. These new bicyclic compounds possess interesting antiinflammatory, analgesic and antipyretic activities as well as low acute toxicity and ulcerogenicity. The antiinflammatory effect, which in some compounds is higher than that of indomethacin and phenylbutazone, appears to be a function of the relative disposition of the substituents at position 2 and 2': generally the meso isomers are more active than the d1 ones. The lipophilicity of the tested compounds was determined by reversed-phase thin-layer chromatography.     

Synthesis and pharmacological properties of derivatives of alpha-amino-beta-(p-chlorobenzoyl)-propionic acid and alpha-amino-gamma-(p-chlorophenyl)-tetrahydrofuran-2-one.

Several new alpha-aminoderivatives of gamma-(p-chlorophenyl)-tetrahydrofuran-2-one were synthesized. alpha-Aminoderivatives of beta-(p-chlorobenzoyl)-propionic acid 2-13 were used as the substrates. After the reduction with NaBH4 at 10-12 degrees C and cyclization the compounds were converted into the appropriate derivatives of tetrahydrofuran-2-one 16-26. In pharmacological tests compounds 9 and 26 abolished the aggressiveness in isolated mice while compound 8 showed antiinflammatory activity.     

Synthesis and pharmacological activity of 4-carbamoyl-5-aryl-6-methyl-4,5-dihydropyridazin-3(2H)-ones.

A new series of 4-carbamoyl-5-aryl-6-methyl-4,5-dihydropyridazin-3(2H)-ones have been synthesized and tested for their antiinflammatory and analgesic properties. Amongst the test compounds, only 31 showed antiinflammatory activity, though of shorter duration than that of indomethacin, taken as reference drug. On the contrary, many derivatives displayed relevant analgesic activity, 4--the only 4,5-dehydroderivative--being the most potent in the writhing test. In the hot plate test 3b, 3f and 3k were found to possess the most significant analgesic properties.     

Synthesis and antitumor activity of duocarmycin derivatives: modification of segment-A of A-ring pyrrole compounds.

A series of 3-substituted A-ring pyrrole compounds of duocarmycin were synthesized and evaluated for in vitro anticellular activity against HeLa S(3) cells and in vivo antitumor activity against murine sarcoma 180 in mice. These compounds were evaluated on the peripheral blood toxicity and delayed lethal toxicity. Further, to expand our investigation of their peripheral blood toxicity, the toxicity to bone marrow cells (CFU-GM, CFU-Meg) was investigated. Among 3-substituted A-ring pyrrole compounds of duocarmycin bearing a 5',6',7'-trimethoxy-2'-indolecarboxyl group as segment-B (Seg-B), several analogues showed remarkably potent antitumor activity with low peripheral blood toxicity. The 3-formyl compound 12h, one of such analogues, showed stronger antitumor activity with lower toxicity to bone marrow cells compared to DU-86 (2a), an active metabolite of KW-2189 (2b). However, compound 12h caused delayed death. On the other hand, the 3-bromo compound 15f, one of the 3-substituted A-ring pyrrole derivatives bearing a 4'-methoxycinnamoyl group as Seg-B, showed the most potent antitumor activity among the 4'-methoxycinnamate analogues with low toxicity to bone marrow cells. Furthermore, compound 15f did not cause delayed death similarly to 2d. These results would indicate the importance of the C-3 substituents of A-ring pyrrole duocarmycin derivatives for exhibiting antitumor activity and decreasing toxicity.     

The biosynthesis of brominated pyrrolnitrin derivatives by Pseudomonas aureofaciens

The mutant strain ACN of Pseudomonas aureofaciens ATCC 15926 produces several bromo derivatives of pyrrolnitrin. Five brominated amino- and three brominated nitrophenyl pyrrole compounds could be isolated, and their structures were established by 1H NMR, UV and mass spectroscopy. The isolated amino compounds showed no biological activity; the nitro derivatives inhibited the growth of Neurospora crassa ATCC 9276, though not as effective as pyrrolnitrin itself. 2-Carboxy-4-(2-amino-3-bromophenyl)pyrrole (X) is demonstrated to be an intermediate in the biosynthesis of brominated pyrrolnitrin; the biosynthetic pathway to bromo derivatives of pyrrolnitrin is discussed.     

2-(2-Aminoethylamino)-1,2-diphenylethanol derivatives, a new class of topical antiinflammatory agents.

A number of analogues and derivatives of the title compound were synthesized and evaluated in a new test procedure used to detect topical antiinflammatory activity. Some general comments regarding observation on the structure-activity relationship of these compounds are made.     

Synthesis of pyrazole derivatives and pyrazolo[4,3-d]pyrimidines. I

Three series of pyrazole derivatives (III a-g), (IV a-g) and (V a-g) were synthesized and tested for analgesic, antipyretic and antiinflammatory activity. Many of tested compounds showed interesting analgesic and antipyretic activity, whereas no compounds exhibited any antiinflammatory activity.