Synthesis and in vitro antitumor activity of new quinoline, pyrimido[4,5-b]quinoline, [1,2,3]triazino[4,5-b]quinoline, and [1,2,4]triazolo[2′,3′:3,4]pyrimido[6,5-b]quinoline analogs

New series of quinoline, pyrimido[4,5-b]quinoline, [1,2,3]triazino[4,5-b]quinoline, and [1,2,4]triazolo[2′,3′:3,4]pyrimido[6,5-b]quinoline analogs have been synthesized and characterized by analytical and spectrometrical methods (IR, ¹H NMR, ¹³C NMR, MS). Fifteen of the newly synthesized compounds; namely, 3a, b, 4b, 6a, b, 10a–f, and 14a–d were evaluated for their in vitro antitumor activity at the National Cancer Institute (NCI) 60 cell lines panel assay. Compounds 4b and 10f are the most active members in this study, demonstrating significant broad spectrum antitumor activity against most of the tested sub-panel tumor cell lines. The detailed synthesis, spectroscopic, and biological data are described.     

Uterotrophic assay,Hershberger assay,and subacute oral toxicity study of 4,4´-[1-[4-[1-(4-hydroxyphenyl)-1-methylethyl]phenyl]ethylidene]bis[phenol] based on the OECD draft protocols

We performed an uterotrophic assay, the Hershberger assay, and a 28-day repeated-dose toxicity study (enhanced OECD test guideline No. 407) of 4,4′-[1-[4-[1-(4-hydroxyphenyl)-1-methylethyl]phenyl]ethylidene]bis[phenol] based on the OECD draft protocols. In the uterotrophic assay, female SD rats were subcutaneously injected with the chemical at doses of 0, 100, 300, and 1,000 mg/kg on each of 3 days from postnatal day 20 to day 22, and the uterine weight of rats given the 1,000 mg/kg dose of the test chemical plus ethinyl estradiol decreased. In the Hershberger assay, the test chemical was orally administered at doses of 0, 100, 300, and 1,000 mg/kg day to castrated male SD rats for ten consecutive days beginning on postnatal day 56, and no changes were observed. On the other hand, when the test chemical was orally administered at doses 0, 100, 300, and 1,000 mg/kg day for at least 28 days, a decrease in LH values in rats of both sexes and a decrease in FSH and estradiol values in female rats were detected in the 1,000 mg/kg group, and abnormal estrous cycles, uterine glandular atrophy, persistence of ovarian corpora lutea, vaginal epithelial mucification, and mammary glandular hyperplasia were also observed in one female rat in the 1,000 mg/kg group. Therefore, the uterotrophic assay used in this study showed that the chemical has the estrogen–antagonist properties, and some potentially endocrine-mediated effects were detected in growing rats based on the results of the enhanced OECD test guideline No. 407. However, the changes were observed in rats given a high dose of the chemical, 1,000 mg/kg day.     

Synthesis,Analysis, and Acute Toxicity of 9-(2-diethylaminoethyl)-2-phenylimidazo[1,2-α]benzimidazole Dinitrate

Pharmaceutical Chemistry Journal - The key synthetic stage (cyclization) of 9-(2-diethylaminoethyl)-2-phenylimidazo[1,2-α]benzimidazole dinitrate, which possesses antiulcer activity, was...     

Ebselen类似物合成研究I:2-烷基-噻吩并[2,3-d]异硒唑-3[2H]-酮的合成

合成新的Ｅｂｓｅｌｅｎ类似物２－烷基－噻吩并「２,３－ｄ」异硒唑－３「２Ｈ」－酮（２．烷基＝ｔｅｒｔ－Ｂｕ,Ｍｅ、ｉｓｏ－Ｐｒｏ）方法：以２－噻吩甲酸为起始原料,经酰氯化、胺解、锂代、插硒和氧化反应产生３,３’－二硒双（Ｎ－烷基－２－噻吩甲酰胺）（６）,最后,通过过氧化苯甲酰诱发化合物（６）的环闭合反应得到（２）。结果：化合物（２）的结构用＾１ＨＮＭＲ、＾１３ＣＮＭＲ、＾７７ＳｅＮＭＲ、元素分析和     

2-[4-(2-甲氧基乙基)苯氧基甲基]环氧乙烷的制备

对甲氧乙基苯酚于30%碳酸钾水溶液中,在相转移催化剂PEG400参与下与氯甲基环氧乙烷于90℃反应6h,制得标题化合物,收率87%.     

5-羟基-5H-[1]-苯并吡喃[2,3-b]吡啶的制备

目的改进5-羟基-5H-[1]-苯并吡喃[2,3-b]吡啶的合成工艺。方法以2-氯烟酸为起始原料,经亲核取代、环合和还原制得目标化合物。结果总收率68.6%,产物经熔点和1HNMR确证。结论改进后的工艺具有操作简便,对环境友好,收率高等优点。     

2-[4-[(4-氯苯基)苯甲基]-1-哌嗪基]乙醇的合成

目的制备2-[4-[(4-氯苯基)苯甲基]-1-哌嗪基]乙醇。方法以氯苯和苯甲酰氯为起始原料,经付克反应、还原、氯化,再分别与哌嗪、氯乙醇、氯乙酸钠缩合,得到最终产物。结果合成目标产物的总收率为49.1%,中间体4-氯双苯酮,4-氯双苯甲醇,4-氯双苯氯甲烷,1-[(4-氯苯基)苯甲基]哌嗪为鲁南贝特制药有限公司生产确证。结论通过对合成路线的优化,使生产收率提高,降低成本,工艺更适于工业化的生产。     

Studies on the synthesis,in vitro antitumor activity of 4H-benzo[h]chromene, 7H-benzo[h]chromene[2,3-d]pyrimidine derivatives and structure–activity relationships of the 2-,3- and 2,3-positions

Some 4H-benzo[h]chromene and 7H-benzo[h]chromeno[2,3-d]pyrimidine derivatives were prepared as potential cytotoxic agents. The in vitro cytotoxic activity of the synthesized compounds was investigated in comparison with the well-known anticancer standard drugs Vinblastine, Colchicine, and Doxorubicin using MTT colorimetric assay. It was found that compounds 23, 15, 20, and 21 showed the highest anticancer activity against the three tumor cell lines MCF-7, HCT, and HepG-2, compared with Vinblastine and Colchicine, while compound 23 was the most active against HepG-2 as compared with Doxorubicin. We explored the SAR of 4H-benzo[h]chromenes with modification at the 2-,3- positions and 7H-benzo[h]chromeno[2,3-d]pyrimidine at 2,3-positions. The structure–activity relationship (SAR) study revealed that the antitumor activity on 4H-benzo[h]chromene and 7H-benzo[h]chromeno[2,3-d]pyrimidine derivatives were significantly affected by the lipophilicity (hydrophobic or hydrophilic), of the substituent at 2-,3- and 2,3-positions. Structures of these compounds were established on the basis of spectral data, IR, ¹H NMR, ¹³C NMR, ¹³C NMR-DEPT, and MS data.     

新型强心剂2-吡啶-6,7-二氢-3H,5H-吡咯[2-3-f]苯并咪唑-6-酮

近年来在强心药领域中重视非甾体、非儿茶酚胺类强心剂的寻找,但至今尚无口服有效的慢性充血性心衰的治疗药物。作者设计并合成了2-吡啶-6,7-二氢-3H,5H-吡咯[2,3-f]苯并咪唑-6-酮系列化合物共24只,其中R_(1,2,3,4)主要为氢、烷基等,X为亚甲基、乙烯基等。     

4-[2-(N-甲基,N-(2-吡啶基)氨基)-乙氧基]苯甲醛的合成方法改进

目的:改进罗格列酮的关键中间体4-[2-(N-甲基,N-(2-吡啶基)氨基)-乙氧基]苯甲醛的合成方法。方法:以2-[N-甲基,N-(2-吡啶基)氨基]乙醇为原料,分别与对氟苯甲醛发生威廉森成醚反应(以乙腈作溶剂,KOH作去酸剂)及与对羟基苯甲醛发生脱水缩合反应,合成目标化合物。结果:得到目标化合物,其结构经1HNMR和MS验证。结论:两种改进的合成方法操作简便,适于工业化生产。     

2-(咪唑并[1, 2-a]吡啶-3-基)乙酸的合成工艺改进

目的 改进抗骨质疏松药米诺膦酸的关键中间体2-(咪唑并[1, 2-a]吡啶-3-基)乙酸的制备方法。方法 以2-氧代戊二酸二乙酯为起始原料,经溴代、环合、水解和脱羧4步反应制得目标产物。结果 目标化合物的熔点与¹H-NMR 谱数据与文献报道相符,总收率为40.5%(以2-氧代戊二酸二乙酯计)。结论 与文献报道的方法相比,改进后的工艺路线后处理简单,更有利于工业化生产。     

微波辅助制备3-[2-(7-氯-2-喹啉基)乙烯基]苯甲醛

3-[2-(7-氯-2-喹啉基)乙烯基]苯甲醛(1)是白三烯受体拮抗剂LY0290154和抗过敏、平喘药孟鲁司特钠(montelukast sodium)的重要中间体~([1,2]),文献用7-氯喹哪啶(2)、间苯二甲醛(3)和乙酸酐在甲苯中回流12 h制得1,收率63%~([2]).若改在甲苯和正已烷混合溶液中回流反应13 h,未反应的3可循环套用6次,平均收率82%~([3]).     

Synthesis of 6-[1-[4-(benzoxazol-2-yl)thiobuthyl]-1,2,3-triazole-4-yl]methylenepenam as β-lactamase inhibitors

The 6,6-dibromopenam6 was treated with CH₃MgBr and carbaldehyde5 to afford the 6-bromo-6-(1-hydroxy-1-methyl)penicillanate7, which was reacted with acetic anhydride to give acetoxy compound8. The deacetobromination of8 with zinc and acetic acid gave 6-exomethylenpenams, Z-isomer9 and E-isomer10, which were oxidized to sulfones11 and12 by m-CPBA. The p-methoxybenzyl compounds were deprotected by AlCl₃ and neutralized to give the sodium salts13, 14, and15.     

催化氢转移法还原2-[β-(2-噻吩基)乙烯基]苯甲酸

2-[β-(2-噻吩基)乙烯基]苯甲酸(1)是合成镇痛药苯噻啶的主要中间体。生产中是通过催化氢化还原1,生成2-[β-(2-噻吩基)乙基]苯甲酸(2),继而合成苯噻啶。但经常会出现不吸氢或少吸氢的问题,严重影响了2的收率。     

4-[2-（2-氨基-4，7m二氢-4-氧-1H-吡咯[2，3-d]嘧啶-5-基）乙基]苯甲酸的中试生产

目的：研究培美曲塞二钠的关键中间体4-[2-（2-氨基4,7-二氢4-氧-1H-吡咯[2,3-d]嘧啶-5-基）乙基]苯甲酸的放大生产。方法：以对碘苯甲酸甲酯为起始原料,经缩合、溴代、环合、水解等反应得到制备培关曲塞二钠的关键中间体。结果：总收率约36．8％,本方法操作简单,收率稳定,适合工业化生产。     

Synthesis of novel 2-(3′-aryl-sydnon-4′-ylidene)-5′-substituted-[1,3,4]-thiadiazolylamines and [1,3,4]-thiadiazol-2′-yl-3-oxo-[1,2,4]-triazoles as antimicrobial agents

The title compounds (3g–n) and (6g–n) were synthesized using 3-arylsydnones as synthons, and the structures were confirmed by IR, ¹H NMR, FAB mass and CHN analysis. These compounds were evaluated for their antibacterial and the antifungal activities in terms of minimum inhibitory concentrations (MICs) against the bacterial strains E. coli, B. cereus, and the fungal strains A. niger, C. albicans. Some of the compounds have shown significant activities.     

微波辐射快速合成喹诺酮类药物关键中间体7-卤代-6-氟-1-甲基-4-氧代-1, 4-二氢-[1, 3]硫氮杂环丁烷并[3, 2-a]喹啉-3-羧酸乙酯

采用微波辐射法简便、快速、高效地合成喹诺酮类药物关键中间体7-卤代-6-氟-1-甲基-4-氧代-1, 4-二氢-[1, 3]硫氮杂环丁烷并[3, 2-a]喹啉-3-羧酸乙酯。中间产物及目标化合物的结构经 IR、¹H-NMR、MS谱和元素分析确证。结果表明在微波辐射下反应物分子内环合反应速度显著加快,中间产物及目标化合物的收率均有所提高。 关键词：微波辐射法;三环喹诺酮;环化     

抗疟药的研究 1,3-双[4-[2-(取代苯乙烯基)吡啶基-4-]哌嗪基-1-]丙烷的合成及其抗疟活性

2-(取代苯乙烯基)-4-氨基吡啶类化合物(Ⅰ)对感染伯氏鼠疟原虫的小鼠具有较好的治疗作用~[1]。为了提高这类化合物的抗疟作用并延长其作用时间,我们模拟长效抗疟药喹哌(Ⅱ)的结构特点,合成了双分子化合物——1,3-双[4-[2-(取代苯乙烯基)吡啶基-4-哌嗪基-1-]丙烷(Ⅲ)。     

2-氨基-2-[2-(4-正辛基苯基)乙基]-1,3-丙二醇盐酸盐的合成工艺改进

目的 合成新型免疫抑制剂2-氨基-2-[2-（4-正辛基苯基）乙基]-1，3-丙二醇盐酸盐（FTY-720）。方法 以苯和正辛酰氯为起始原料，经傅克酰基化、还原、酰化、缩合、还原羰基、还原酯基、去乙酰化和成盐反应得到目的化合物FTY-720，总收率为12．0％。结果与结论 目标化合物的结构经^1H-NMR、IR和MS确证，中间体的^1H-NMR谱和mp值与文献值相符。该合成路线成本低廉，操作简单。     

Synthesis of a radiotracer for studying nicotinic acetylcholine receptors: (+/−)-exo-2-(2-[18F]fluoro-5-pyridyl)-7-azabicyclo[2.2.1]heptane

The radiochemical synthesis of (+/−)-exo-2-(2-[¹⁸F]fluoro-5-pyridyl)-7-azabicyclo[2.2.1]heptane ([¹⁸F] (UNDERLINE)1(/UNDERLINE) ) was accomplished by Kryptofix® 222 assisted nucleophilic no-carrier-added [¹⁸F]fluorination of (+/−)-exo-2-(2-bromo-5-pyridyl)-7-azabicyclo[2.2.1] heptane ( (UNDERLINE)3a(/UNDERLINE) ). The average radiochemical yield of the final product was 10% and the average specific activity was greater than >2000 mCi/μmol, calculated at end-of-synthesis. The stable fluorine ligand ([¹⁹F] (UNDERLINE)1(/UNDERLINE) ) was prepared by Kryptofix® 222 assisted nucleophilic fluorination of (+/−)-exo-2-(2-bromo-5-pyridyl) - 7 -methoxycarbonyl - 7 - azabicyclo[2.2.1]heptane ( (UNDERLINE)3b(/UNDERLINE) ) followed by acid deprotection.