二氢吡咯并吡嗪酮衍生物的合成和抗炎镇痛作用

目的 研究3，4，－二氢吡咯并[1,2-a]吡嗪－1－酮（Ⅱ）类化合物的抗炎镇痛作用构效关系。方法 通过2－吡咯甲酸甲酯与N－氯乙腈的烃基化反应，制得N－氢甲基吡咯－2－甲酸甲酯（Ⅳ），Ⅳ经还原，环合，Friedel-Crafts酰基化反应，生成6－芳酰基－2－甲基－3，4－二氢吡咯并[1,2-a]吡嗪－1－酮类化合物；用小鼠测试了所合成化合物的抗炎镇痛活性。结果与结论 合成了13个目标化合物；小鼠试验表明，一些所合成的化合物具有明显的抗炎和／或镇痛作用，其中，ZP163的作用活性与对照药布洛芬相似。     

二氢吡咯并噁嗪酮衍生物的合成和抗炎镇痛作用

目的研究 (1H) 3,4 二氢吡咯 [2 ,1 c][1,4 ]嗪 1 酮 (Ⅲ )类化合物抗炎镇痛作用的构效关系。方法通过 2 吡咯甲酸甲酯与 1,2 二溴乙烷N 烃基化反应 ,制得 1 (2 溴乙基 )吡咯 2 甲酸甲酯 (Ⅳ ) ,经过氧化银处理 ,得到Ⅲ ;通过Friedel Crafts酰基化反应 ,合成Ⅲ的 6 酰基衍生物Ⅴ1～Ⅴ8;用小鼠测试了所合成的化合物的抗炎镇痛活性。结果与结论合成了 8个目标化合物 ;药理实验表明 ,所合成的一些化合物具有明显的抗炎和 /或镇痛活性 ,其中Ⅴ5活性最强。     

3-芳基-2-甲基-1-吡咯并[1,2-a]吡嗪酮类衍生物的合成和抗炎镇痛作用

目的研究3-芳基-2-甲基-1-吡咯并[1,2-a]吡嗪酮(2)类化合物抗炎镇痛作用的构效关系.方法通过吡咯-2-甲酸甲酯与α-溴代芳基乙酮的烃基化反应,制得1-(2-氧代-2-芳基)乙基吡咯-2-甲酸甲酯(4),4与甲胺反应经过环合直接生成目的化合物2;用小鼠测试了所合成化合物的抗炎镇痛活性.结果与结论合成了15个目标化合物;小鼠试验表明,一些所合成的化合物具有明显的抗炎和/或镇痛作用,其中化合物2o的作用活性与阳性对照药布洛芬相似.     

二氢吡咯并(口恶)嗪酮衍生物的合成和抗炎镇痛作用

目的研究(1H)-3,4-二氢吡咯[2,1-c][1,4](口恶)嗪-1-酮(Ⅲ)类化合物抗炎镇痛作用的构效关系.方法 通过2-吡咯甲酸甲酯与1,2-二溴乙烷N-烃基化反应,制得1-(2-溴乙基)吡咯-2-甲酸甲酯(Ⅳ),经过氧化银处理,得到Ⅲ;通过Friedel-Crafts酰基化反应,合成Ⅲ的6-酰基衍生物Ⅴ1～Ⅴ8;用小鼠测试了所合成的化合物的抗炎镇痛活性.结果与结论 合成了8个目标化合物;药理实验表明,所合成的一些化合物具有明显的抗炎和/或镇痛活性,其中Ⅴ5活性最强.     

5-芳基-1,2-二氢-1-吡咯里嗪酮类化合物的合成及抗炎镇痛作用

目的 研究5-芳基-1，2-二氢-1-吡咯里嗪酮类化合物的抗炎镇痛作用构效关系，寻找高效低毒、具有抗炎镇痛活性的新型吡咯里嗪酮衍生物。方法 以吡咯里嗪酮为母体，设计并合成了5-芳基-1，2-二氢-1-吡咯里嗪酮类化合物。用二甲苯致小鼠耳肿胀法和小鼠醋酸扭体法测定了该类化合物的抗炎及镇痛活性。结果 用两条路线合成了10个目标化合物，经1H-NMR和MS确证其结构。小鼠试验表明，一些所合成的化合物具有明显的抗炎和／或镇痛作用。结论 化合物Ⅲ1及Ⅲ5的抗炎活性优于对照药布洛芬；化合物Ⅲ5的镇痛活性优于对照药布洛芬；其中化合物Ⅲ5的抗炎及镇痛活性均强于对照药布洛芬，值得进一步研究。     

2-甲基-3-取代苯基吡咯并吡嗪酮类化合物的合成及抗癌活性研究

目的 寻找具有抗癌活性的新吡咯并吡嗪酮类化合物。方法 以吡咯、对氨基苯乙酮为原料,经Friedel-Crafts酰化、醇解、亲核取代、环合及醇解反应制得母体化合物2-甲基-3-对氨基苯基吡咯并[1,2-a]吡嗪-1(2H)-酮,再通过酰基化/磺酰基化和烷基化反应引入酰基和烷基即制得系列吡咯并吡嗪酮类化合物。结果 合成了8个未见文献报道的吡咯并吡嗪酮类化合物,其结构经¹H-NMR、MS和IR谱确证。结论 8个目标化合物的体外抗乳腺癌细胞、肝癌细胞和肺癌细胞的活性试验结果显示,化合物4、5 具有明显的抗癌活性。     

二氢吡咯并恶嗪酮衍生物的合成和抗炎镇痛作用

目的 研究（1H）－3，4－二氢吡咯[2,1-c][1,4]恶嗪－1－酮（Ⅲ）类化合物抗炎镇痛作用的构效关系。方法 通过2－吡咯甲酸甲酯与1，2－二溴乙烷N－烃基化反应，制得1－（2－溴乙基）吡咯－2－甲酸甲酯（Ⅳ），经过氧化银处理，得到Ⅲ；通过Friedel-Crafts酰基化反应，合成Ⅲ的6－酰基衍生物Ⅴ1－Ⅴ8；用小鼠测试了所合成的化合物的抗炎镇痛活性。结果与结论 合成了8个目标化合物；药理实验表明，所合成的一些化合物具有明显的抗炎和／或镇痛活性，其中Ⅴ5活性最强。     

含氟咪唑酮系列衍生物的串联合成及其初步药理学研究

目的优化以含氟乙酰丙酸乙酯衍生物为原料一锅法合成3a-三氟甲基-2,3,3a,4-四氢-1H-苯并[d]吡咯[1,2-a]咪唑-1-酮衍生物的方法,并对合成的衍生物进行初步的药理学研究。方法以含氟乙酰丙酸乙酯衍生物与二羰基酯类化合物为原料,通过Claisen酯缩合再脱羧的方法合成3a-三氟甲基-2,3,3a,4-四氢-1H-苯并[d]吡咯[1,2-a]咪唑-1-酮类衍生物。初步药理学研究采用抗戊四唑(pentylenetetrazole,PTZ)实验对大鼠测定药物的抗惊厥活性;采用旋转法测定其神经毒性。结果成功合成5个含氟乙酰丙酸乙酯衍生物,并将其与一系列胺类化合物反应,一锅法合成了22个含氟氮杂双环化合物。初步药理结果显示:2,3,3a,4-四氢-1H-苯并[d]吡咯[1,2-a]咪唑-1-酮的ED50为50μmol/kg,保护指数(protection index,PI)为10.5(PI=TD50/ED50),显示较好的抗惊厥活性。结论本研究优化了反应条件,缩短了反应时间,提高了反应收率,合成的化合物均具有抗惊厥活性和神经毒性。     

中国药物化学杂志2006年 第16卷 第1期～第6期（总69-74期）总目次

研究论文α-苯亚甲基-β-氧代苯丙酸衍生物的合成及其醛糖还原酶抑制活性…………………………………王绍杰,张智勇,吴静,等(1)(1)芳甲酰烷基哌嗪类化合物的合成及抗脑缺氧缺血活性………………………………………………李建其,黄丽瑛,夏玉叶,等(1)(6)苯并吡喃类C-4位一氧化氮供体衍生物的合成及降压活性……………………………………………许忻,张奕华,彭司勋,等(1)(1 5)Rutaecarpine衍生物的合成及体外抗血小板聚集活性…………………………………………………刘青,郑伟,桑海婴,等(1)(2 0)3,4-二氢吡咯[1,2-a]吡嗪-1-酮衍生物的合成及抗…     

3H-1,2-二氢-1-吡里酮衍生物的合成

发现3 H-1,2-二氢-1-吡咯里嗪酮具有明显的抗炎镇痛作用。用Friedel-Crafts酰化和Dieckmann缩合等反应制备了该酮的一些衍生物,其中五个未见于文献报道。药理实验证明,这些化合物均有不同程度的抗炎镇痛作用。     

Synthesis of novel 1-pyrazolylpyridin-2-ones as potential anti-inflammatory and analgesic agents

A new series of 4-alkyl/aryl-2-oxo-1-pyrazolyl-1,2-dihydropyridine-3-carbonitriles, pyrazolo[3,4-b]pyridine-5-carbonitriles and pyrido[2,3-d]pyrimidine-6-carbonitriles have been synthesized and tested for their anti-inflammatory and analgesic activities. Among the tested compounds, 3e and 8b exhibited comparable anti-inflammatory activity to the standard (indomethacin). Compounds 5, 7a, and 8b displayed potent analgesic activity. Detailed syntheses, spectroscopic and biological data are reported.     

Benzimidazole condensed ring systems: New synthesis and antineoplastic activity of substituted 3,4-dihydro- and 1,2,3,4-tetrahydro-benzo [4,5]imidazo[1,2-a]pyrinnidine derivatives

As part of an ongoing effort to develop new antineoplastic agents, a series of substituted 3,4-dihydro- and 1,2,3,4-tetrahydro-benzo[4,5]imidazo[1,2-a]pyrimidine derivatives (5-19) were synthesized. 1,2,3,4-Tetrahydrobenzo[4,5]imidazo[1,2-a]pyrimidine-2-one derivatives (5-7) were prepared via one-pot two-component thermal cyclization reaction of 2-aminobenzimidazole 1 and P-substituted methyl cinnamates (2-4). Vilsmir-Haack formylation of these derivatives (5-7) afforded the 2-chloro-3-carboxaldehyde targets (8-10) followed by nucleophilic displacement of the chloro atom in the 3-carboxaldehyde compounds (8-10) to yield the remaining final targets (11-19). The structures of the synthesized derivatives (5-19) were confirmed by means of IR, 1H NMR, MS and elemental analyses. The synthesized derivatives (5-19) were subjected to the National Cancer Institute (NCI) in vitro disease human cell screening panel assay. 2-Chloro-4-phenyl-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carboxyaldehyde (8, NCI 722731) and 4-(4-methoxyphenyl)-2-(4-methylpiperazin-1-yl)-3,4-dihydrobenzo[4,5]imidazo [1,2-a]pyrimidine-3-carboxaldehyde (18, NCI 722739) showed a variable degree of antineoplastic activity against some of the cell lines tested. 2-Chloro-4-(4-nitrophenyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carboxyaldehyde (10, NCI 722743) exhibited good in vitro antineoplastic activity with subpanel disease selectivity against all the cell lines tested with log10 G150 (M), the concentration that inhibits 50% of cell growth, values ranging from -5.08 to < -8.00.     

4-Cyclohexyl-1-substituted-4H-[1,2,4]triazolo [4,3-a] quinazolin-5-ones: novel class of H1-antihistaminic agents

A series of novel 1-substituted-4-cyclohexyl-4H-[1,2,4]triazolo [4,3-a] quinazolin-5-ones were synthesized by the cyclization of 3-cyclohexyl-2-hydrazino-3H-quinazolin-4-one with various one carbon donors. When tested for their in vivo H1-antihistaminic activity on guinea-pigs, all the test compounds protected the animals from histamine induced bronchospasm significantly. The compound 4-cyclohexyl-1-methyl-4H-[1,2,4]triazolo[4,3-a] quinazolin-5-one (II) emerged as the most active compound of the series and it is more potent (72.96% protection) when compared to the reference standard chlorpheniramine maleate (71.00% protection). The compound II shows negligible sedation (9%) when compared to chlorpheniramine maleate (30%). Hence, it could serve as prototype molecule for further development as a new class of H1-antihistamines.     

Amide derivatives of [6-(5-methyl-3-phenylpyrazole-1-yl)-3(2H)-pyridazinone-2-yl]acetic acids as potential analgesic and anti-inflammatory compounds

In this study, amide derivatives of [6-(5-methyl-3-phenyl-pyrazole-1-yl)-3(2H)-pyridazinone-2-yl]acetic acid were synthesized and tested for their in vivo analgesic and anti-inflammatory activity by using the p-benzoquinone-induced writhing test and carrageenan-induced hind paw edema model, respectively. The analgesic and anti-inflammatory activity of the compounds 6a, 6d, 6e, 6g, 6h and 6m were more potent than that of aspirin as an analgesic and indomethacin as an anti-inflammatory drug, respectively. The other derivatives generally resulted in comparable activity to reference compounds. Inhibitor activity of the active compounds on cyclooxygenase isoforms was also investigated by using in vitro human whole blood assay and found that these derivatives did not exert their analgesic and anti-inflammatory activities through COX inhibition and other mechanisms might be involved.     

3,4-二氢喹啉-2(1H)-酮衍生物的设计合成及抗精神分裂活性研究

目的 设计合成3,4-二氢喹啉-2(1H)-酮类化合物,考察其对D2、5-HT2A、5-HT1A受体的亲和力,并对代表化合物进行体内抗精神分裂活性测试.方法 7-羟基-3,4-二氢喹啉-2(1H)-酮与二卤代烷进行O-烷基化反应,再与相应的哌啶衍生物反应得到目标产物(Ⅰ1～Ⅰ11);对目标化合物进行了D2、5-HT2A...     

Synthesis, anti-inflammatory and analgesic activity of some new 4(3H)-quinazolinone derivatives

4(3H)-quinazolinone and pyrazole derivatives have been shown to have analgesic and anti-inflammatory properties. In this study, 14 new 3-methyl-4(3H)quinazolinone derivatives bearing 2-[1'-phenyl-3'-(substituted-phenyl)-2'-propenylidene]hydrazino or 2[5'-(substituted phenyl)-3'-phenyl-2'-pyrazolin-1'-yl] groups have been synthesized with the aim of obtaining new analgesic and anti-inflammatory leads. The structures were elucidated by means of UV, IR, 1H-NMR, 13C-NMR, mass spectroscopy, and elemental analysis data. The anti-inflammatory activities of the synthesized compounds were determined by carrageenan-induced hind paw edema test in mice. All the compounds showed statistically significant effects. For analgesic activity assessment, p-benzoquinone-induced writhing test was applied in mice. The results obtained were in accordance with the anti-inflammatory activity tests.     

Synthesis of 1-acyl-2-alkylthio-1,2,4-triazolobenzimidazoles with antifungal, anti-inflammatory and analgesic effects

Some new derivatives of 1,2,4-triazolo[2,3-a]benzimidazoles were synthesized through the reaction of 1,2-diaminobenzimidazole with carbon disulfide. The resulting 1,2,4-triazolo[2,3-a]benzimidazole-2-thione intermediate reacted with one equivalent of the alkyl halide to give the corresponding 2-alkylthio derivative 3a-g. The latters were acylated to afford the 1-acyl-2-alkylthio-1,2,4-triazolo[2,3-a]-benzimidazole derivatives 4-10 in good yields. Structures of the new compounds were verified on the basis of spectral and elemental methods of analyses. Fourteen of the prepared compounds were tested for their possible antifungal activities. Most of the tested compounds showed activity against Candida albicans and Fusarium oxysporum comparable to that of fluconazole as a reference drug. Compounds 8a, 9a, and 10d are the most active ones against most of the fungi used. Compounds 3e, 4d, 5d, 6d, 7d, 8c, 8d, 9d, and 10d were tested for their anti-inflammatory and analgesic effects; most of these compounds showed potent and significant results compared to indomethacin. Moreover, ulcerogenicity and the median lethal dose (LD(50)) of the most active compound 8d were determined in mice; LD(50) was found to be 275 mg kg(-1) (i.p.).     

Synthesis of some triazolophthalazine derivatives for their anti-inflammatory and antimicrobial activities

Several novel series of triazolophthalazine derivatives namely; pyrazolylethenyltriazolophthalazinones (4a-d), styryltriazolophthalazinones (5a,b), aryloxopropenyltriazolophthalazinones (7a,b), pyrazolinyl- (8a,b), (9a,b) and (10a-f), pyrazolyl- (11a-d), (1,2-oxazol-5-yl)-1,2,4-triazolo[3,4-a]phthalazin-6(5H)-ones (14a,b), triazolo[3,4-a]phthalazin-3-yl-pyridine-3-carbonitriles (12a,b), triazolo[3,4-a]phthalazin-3-yl)ethylthioacetic acids (13a,b) and 2-aryl-5-arylamino-1H,5H-pyrazolo[2″,3″-1',5']imidazo[3',4'-1,5]-1,2,4-triazolo[3,4-a]phthalazin-12(13H)-ones (15a-c) have been synthesized. The anti-inflammatory activity of representative compounds has been studied. Compounds 8b, 10c, 10f, 11b, 12a, 13b, and 15a showed anti-inflammatory activities comparable to that of the reference standard, indomethacin. They exhibit also minimal ulcerogenic effect relevant to the reference standard and were found to be non-toxic up to 120 mg/kg orally or up to 75 mg/kg through parenteral route. Concerning the antimicrobial activity; compounds 12b and 13b were found to be equipotent to ampicillin against Staphylococcus aureus, while compounds 10a and 10f were found to be as potent as ampicillin against E. coli, whereas compound 14b exhibited equipotency to clotrimazole against Candida albicans. Compounds 8b, 10f, 11b, 12a, and 13b exhibited, besides their antimicrobial activity, moderate to potent anti-inflammatory profiles. This represents a fruitful matrix for the development of a new class of dual non-acidic anti-inflammatory/antimicrobial agents.     

Synthesis and anticonvulsant properties of 2,3,3a,4-tetrahydro-1H-pyrrolo[1,2-a]benzimidazol-1-one derivatives.

A number of novel 1H-pyrrolo[1,2-a]benzimidazol-1-one derivatives were prepared and their anticonvulsant properties evaluated. The new synthesized compounds proved to possess anticonvulsant effects depending on the nature of substituents at C-6, C-2, and C-3a positions of the polycyclic system. In particular, the 6-chloro-3a-(p-tolyl)-2,3,3a,4-tetrahydro-1H-pyrrolo[1,2-a]benzimidazol-1-one derivative (22) displayed potency fivefold higher than unsubstituted compound (13).