氯雷他定的合成

2-氰基-3-甲基吡啶经Ritter反应、烷基化、氰化得到2-氰基-3-[2-（3-氯苯基）乙基]吡啶，在PPA／P2O5作用下闭环后和N-乙氧羰基-4-哌啶酮偶合制得氯雷他定，总收率39％。     

抗血小板聚集药 氯匹格雷硫酸氢盐

1化学名S－（＋）－2－（2－氯苯基）－2－（4，5，6，7－四氢隆吩并［3，2－c］吡啶－5－基）乙酸甲酯硫酸氢盐2研制厂商Sanofi（法国）3合成氯匹格雷可经以下几步合成：1）（＋）－》（又氯苯基）甘氨酸甲酯〔（＋）－IVj可按下法制备：a）外消旋》（2一氯苯基）甘氨酸（I）在甲醇一盐酸条件下甲基化，得甲酯（11），再用（＋）一酒石酸拆分得活性酯化物「（＋）－IV」。b）外消族（！）用（＋）－10一樟脑磺酸拆分，得（＋）－2。（2一氯苯基）甘氨酸「（＋）－Ill」，再酯化得「（＋）－IV］。2）（＋）－｝（｝氯苯基卜＊－「》（9…     

4-(4-氯苯基)-3-甲基-2,4-二氧代丁酸乙酯的合成

对氯苯丙酮经烯胺化得4-[（Z）-1-（4-氯苯基）丙烯基]吗啉，再与草酰氯单乙酯缩合得利莫那班合成中间体4-（4-氯苯基）-3-甲基-2-4-二氧代丁酸乙酯，纯度91％，粗收率66％。     

利莫那班合成路线图解

利莫那班（rimonabant，1），化学名为5-（4-氯苯基）-1-（2，4-二氯苯基）-4-甲基-N-（哌啶-1-基）-1H-吡唑-3-甲酰胺盐酸盐，是法国Sanofi-Aventis公司研发的首个用于肥胖症治疗的大麻素1型受体（CB1）拮抗剂，2006年7月首次在英国上市，商品名Acomplia。本品能显著地降低体重、缩小腰围，减少心血管疾病等危险因素，而且还可以改善血脂和胰岛素抵抗以及代谢综合征等。1的合成主要涉及两个重要中间体：4-（4-氯苯基）-3-甲基-2，4-二氧代丁酸乙酯（3）和5-（4-氯苯基）-1-（2，4-二氯苯基）-4-甲基吡唑-3-羧酸（8）。本文对1的合成进行了综述（图1）。     

米氮平的合成

1-（3-羧基吡啶-2-基）-2-苯基-4-甲基哌嗪在由硼氢化钠/氯化氢或硼氢化钠/醚合三氟化硼制得的二硼烷作用下还原，制得的1-（3-羟甲基吡啶-2-基）-2-苯基-4-甲基哌嗪在浓硫酸中脱水环合得到米氮平，两步总收率约60％。     

抗肿瘤药物neratinib的合成

目的合成抗癌药neratinib。方法以2-氯-4-硝基苯酚和2-氯甲基吡啶为起始原料,经醚化、硝基还原得到3-氯-4-（吡啶-2-甲氧基）苯胺,3-氯-4-（吡啶-2-甲氧基）苯胺与3-氰基-6-乙酰氨基-7-乙氧基-4-氯喹啉反应得到3-氰基-6-乙酰氨基-4-[3-氯-4-（吡啶-2-甲氧基）苯氨基]-7-乙氧基喹啉,3-氰基-6-乙酰氨基-4-[3-氯-4-（吡啶-2-甲氧基）苯氨基]-7-乙氧基喹啉去乙酰保护基后,与（E）-4-二甲氨基-2-丁烯酰氯经酰化反应得到ner-atinib。结果与结论目标物neratinib的总收率为56.0%,其结构经核磁共振氢谱、质谱确证。     

富马酸卢帕他定的合成

以烟酸乙酯(4)和间氯苯乙腈(5)为原料,经克莱森缩合、酸水解脱羧反应,得2-(3-氯苯基)-1-(吡啶-3-基)-1-乙酮(6)。6与水合肼经黄鸣龙还原反应,得3-(3-氯苯乙基)吡啶(7),7在钨酸钠催化下经过氧化氢氧化后,再经Reissert-Henze吡啶氰基化反应,得3-(3-氯苯乙基)-2-氰基吡啶(8),水解后闭环得8-氯-10,11-二氢-4-氮杂-5H-二苯并[a,d]-5-环庚酮(3),再与1-[(5-甲基吡啶-3-基)甲基]-4-哌啶酮(12)经McMurry偶联反应,并与富马酸成盐,得到富马酸卢帕他定(1),总收率28.0%(以4计),纯度99.7%。该路线避免格氏试剂的使用,且环合反应使用“一锅法”,操作方便,适合工业化生产。     

SPECT显像剂埘131I-Nalepride的合成

5-碘-2，3-二甲氧基苯甲酸与（S）-1-烯丙基-2-氨甲基吡咯烷反应得到（S）-（-）-N-[（1-烯丙基-2-吡咯烷基）甲基]-2,3-二甲氧基-5-碘苯甲酰胺，与双三丁基锡反应得到标记前体（S）-（-）-M[（1-烯丙基-2-吡咯烷基）甲基]-2，3-二甲氧基-5-三丁基锡苯甲酰胺，总收率约70％。用双氧水法对标记前体进行碘[131↑I]标记得到SPECT显像剂131↑I-nalepride，标记率和放射化学纯度分别为95．4％和96．3％。     

奥美拉唑的合成

2,3，5-三甲基吡啶经氧代、硝化、在乙酐中重排、水解及氯代制得2-氯甲基-3，5-二甲基-4-硝幕吡啶盐酸盐，与2-巯基-5-甲氧基苯并咪唑在甲醇钠作用下同时完成缩合、甲氧基化得到5-甲氧基-2-[（4-甲氧基-3，5-二甲基吡啶-2-基）甲硫基]-1H-苯并咪唑，最后氧化得到奥美拉唑，总收率约42％。     

硫酸头孢匹罗的合成

7-氨基头孢霉烷酸（7-ACA）和2，3-环戊烯并吡啶在三甲基碘硅烷催化下进行3-位取代反应，得到1-[[（6R，7R）-7-氨基-2-羧基-8-氧代-5-硫杂-1-氮杂二环[4．2．0]辛-2-烯-3-基]甲基]-6，7-二氢-5H-环戊烷并[b]吡啶内鲻盐（7-ACP）二氢碘酸盐，转化为盐酸盐后与苯并噻唑硫醇活性酯（MAEM）在三乙胺催化下缩合得到头孢匹罗，最后用硫酸成盐得到硫酸头孢匹罗，总收率约57％。     

Synthesis and biological evaluation of some novel 2-phenyl benzimidazole-1-acetamide derivatives as potential anthelmintic agents

The present study describes synthesis of a series of 2-phenyl benzimidazole-1-acetamide derivatives and their evaluation for anthelmintic activity using Indian adult earthworms, Pheretima posthuma. The structure of the title compounds was elucidated by elemental analysis and spectral data. The compounds 4-({[2-(4-nitrophenyl)-1H-benzimidazol-1-yl]acetyl}amino) benzoic acid (3a), N-ethyl-2-[2-(4-nitrophenyl)-1H-benzimidazol-1-yl] acetamide (3c), N-benzyl-2-[2-(4-nitrophenyl)-1H-benzimidazol-1-yl] acetamide (3d), N-(4-hydroxyphenyl)-2-[2-(4-nitrophenyl)-1H-benzimidazol-1-yl] acetamide (3f), 2-[2-(4-nitrophenyl)-1H-benzimidazol-1-yl]-N-phenyl acetamide (3h), 2-[2-(4-chlorophenyl)-1H-benzimidazol-1-yl]-N'-phenylacetohydrazide (3k), 2-[2-(4-chlorophenyl)-1H-benzimidazol-1-yl]-N-(4-nitrophenyl) acetamide (3n) and 2-[2-(4-chlorophenyl)-1H-benzimidazol-1-yl]-N-phenyl acetamide (3q) were found better to paralyze worms whereas N-ethyl-2-[2-(4-nitrophenyl)-1H-benzimidazol-1-yl] acetamide (3c), N-(4-nitrophenyl)-2-[2-(4-nitrophenyl)-1H-benzimidazol-1-yl] acetamide (3e), 4-({[2-(4-chlorophenyl)-1H-benzimidazol-1-yl] acetyl}amino) benzoic acid (3j), 2-[2-(4-chlorophenyl)-1H-benzimidazol-1-yl]-N-ethyl acetamide (31) and 2-[2-(4-chlorophenyl)-1H-benzimidazol-1-yl]-N-phenyl acetamide (3q) were better to cause death of worms compared to the anthelmintic drug albendazole.     

Antibacterial and antifungal agents. IV. Synthesis and antifungal activity of econazole analogs with pyrrole structure

The synthesis of analogues of antifungal econazole with a pyrrole moiety starting from 1-(4-chlorophenyl)-2-(1H-pyrrol-1-yl)ethanone and from 1-(4-chlorophenyl)-2-(1H-pyrrol-1-yl)ethanol is described. Results of antimicrobial screening of the new derivatives in comparison with econazole are also reported.     

Novel dicationic imidazo[1,2-a]pyridines and 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridines as antiprotozoal agents

2-[5-(4-Amidinophenyl)-furan-2-yl]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-6-carboxamidine acetate salt (7) was synthesized from 2-[5-(4-cyanophenyl)-furan-2-yl]-imidazo[1,2-a]pyridine-6-carbonitrile (4a), through the bis-O-acetoxyamidoxime followed by hydrogenation in glacial acetic acid. Compound 4a was obtained in four steps starting with two successive brominations of 2-acetylfuran first with N-bromosuccinimide, and second with bromine to form alpha-bromo-2-acetyl-5-bromofuran (2) in a moderate yield. The product (3a), of the condensation reaction between 6-amino-nicotinonitrile and 2, undergoes Suzuki coupling with 4-cyanophenylboronic acid to furnish 4a in good yield. Acetate salt of 2-[5-(4-amidinophenyl)-furan-2-yl]-imidazo[1,2-a]pyridine-6-carboxamidine (8a) was obtained from 4a, through the bis-O-acetoxyamidoxime followed by hydrogenation in a mixture of ethanol/ethyl acetate. N-Methoxy-2-(5-[4-(N-methoxyamidino)-phenyl]-furan-2-yl)-imidazo[1,2-a]pyridine-6-carboxamidine (6) was prepared via methylation of the respective diamidoxime 5a with dimethyl sulfate. By these approaches eight new diamidines and four potential prodrugs were prepared. All of the diamidines showed strong DNA affinities as judged by high DeltaT(m) values. Six of the eight diamidines gave in vitro IC(50) values of 63 nM or less vs T. b. rhodesiense with two exhibiting values of 6 nM and 1 nM. Also, six of the eight diamidines gave in vitro IC(50) values of 88 nM or less vs P. falciparum with two exhibiting values of 14 nM. Excellent in vivo activity in the trypanosomal STIB900 mouse model was found for five of the diamidines on ip dosage; these compounds gave 4/4 cures in this model. The oral activity of the prodrugs was modest with only one showing 2/4 cures in the same mouse model.     

Syntheses, calcium channel agonist-antagonist modulation activities, and nitric oxide release studies of nitrooxyalkyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2,1,3-benzoxadiazol-4-yl)pyridine-5-carboxylate racemates, enantiomers, and diastereomers

A novel group of hybrid calcium channel (CC) modulators was prepared where the isopropyl ester moiety of isopropyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2,1,3-benzoxadiazol-4-yl)pyridine-5-carboxylate (PN 202-791) was replaced by a variety of nitric oxide (*NO) donor nitrooxyalkyl ester substituents. Enantiomers, or diastereomers, having the (R)-configuration at the C-4 position of the 1,4-dihydropyridine ring (1,4-DHP) exhibited more potent in vitro CC antagonist activity on guinea pig ileum longitudinal smooth muscle (GPILSM) than compounds having the (4S)-configuration. None of the nitrooxyalkyl compounds exhibited a contraindicated CC agonist effect on GPILSM that would cause smooth muscle contraction. Structure-activity studies showed the enantiomers having the (S)-configuration at the C-4 position of the 1,4-DHP ring or diastereomers having the a (4S)-configuration at the C-4 position of the 1,4-DHP ring in conjunction with a (1R-)-1-methyl-2-nitrooxyethyl ester substituent exhibited the most potent cardiac CC agonist (positive inotropic) activity on guinea pig left atrium (GPLA). This class of compounds releases *NO in vitro that is enhanced by the presence of a thiol such as N-acetylcysteamine. The novel *NO donor (-)-(S,R)-1-methyl-2-nitrooxyethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2,1,3-benzoxadiazol-4-yl)pyridine-5-carboxylate [(-)-(S,R)-38], which acts as a dual cardioselective calcium channel agonist (GPLA)/smooth muscle selective calciumchannel antagonist (GPILSM), is a useful lead compound for drug discovery targeted to the treatment of congestive heart failure, and it provides a useful research probe to study the structure-function relationship of calcium channels.     

Synthesis and evaluation of antioxidant properties of novel 2-[2-(4-chlorophenyl) benzimidazole-1-yl]-N-(2-arylmethylene amino) acetamides and 2-[2-(4-chlorophenyl) benzimidazole-1-yl]-N-(4-oxo-2-aryl-thiazolidine-3-yl) acetamides-I

Our approach was to synthesize and examine the antioxidant properties of some new 2-[2-(4-chlorophenyl)benzimidazole-1-yl]-N-(2-arylmethyleneamino) acetamide (1-18) and 2-[2-(4-chlorophenyl)benzimidazole-1-yl]-N-(4-oxo-2-aryl-thiazolidine-3-yl)acetamide (1t-18t) derivatives. Their in vitro effects on rat liver microsomal NADPH-dependent lipid peroxidation levels (LP assay) and microsomal ethoxyresorufin O-deethylase activities (EROD assay) were determined. The free radical scavenging properties of the compounds were also examined in vitro determining the interaction of 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical. The compounds showed significant effects in the above tests.     

Modulation of Cyp450, ALS1 and COX-2 signaling pathways induced by Candida albicans infection via novel antifungal agents

Although, fluconazole is widely used in clinical treatment as an antifungal drug, it recorded potential problems as resistance and intracellular accumulation. Female albino mice were injected with single ip dose of Candida albicans (1.5?×?10⁶ CFU). Three weeks post treatment with fluconazole and two novel synthesized compounds [(2-(4-(Pyridin-2-yl) aminosulfonylphenylamino)-6-(naphthalen-2-yl)-4-(pyridin-2-yl) pyridine-3carbonitrile) and (2-(4-(Pyrimidin-2-yl) aminosulfonylphenylamino)-6-(naphthalen-2-yl)-4-(pyridine-2-yl)pyridine-3-carbonitrile) (13b & 14b, respectively)] in both low and high doses (50?mg/kg & 200?mg/kg), liver function and vaginal inflammation were assessed. Candida albicans significantly elevated serum alanine aminotransferase (ALT) and butrylcholinesterase (BCHE) as well as hepatic malondialdehyde (MDA). Molecular analysis confirmed a significant up-regulation in mRNA gene expression of Agglutinin-like sequence (ALS1), hepatic cytochrome p450 (Cyp450). Vaginal COX-2 gene expression was also elevated. Nevertheless, a significant down-regulation was apparent in mice treated with the aforementioned compounds. Meanwhile, administration of 14b in a high dose noticeably down-regulated the altered parameters expression showing a significant effect in comparison to animals treated with the variable doses of the tested compounds. Histopathological finding confirmed the obtained results. The current work investigated the efficiency of new synthetic pyrimidine derivatives 14bas anti-microbial agents and recommended to be improved and evaluated as a novel antifungal drug to overcome the emergence of resistance problem.     

Synthesis and anticonvulsant properties of new N-[(4-arylpiperazin-1-yl)-methyl] derivatives of 3-aryl pyrrolidine-2,5-dione and 2-aza-spiro[4.4]nonane-1,3-dione

A series of N-[(4-arylpiperazin-1-yl)-methyl] derivatives of 3-arylpyrrolidine-2,5-dione and 2-aza-spiro[4.4]nonane-1,3-dione were synthesized and tested for anticonvulsant activity in the maximum electroshock seizure (MES) and metrazole seizure threshold (sc.MET) tests. The most potent in the series were N-[[4-(3-chlorophenyl)-piperazin-1-yl]-methyl]-3-(2-chlorophenyl)-pyrrolidine-2,5-dione (ED50=14.18 mg/kg) and N-[[4-(2-methoxyphenyl)-piperazin-1-yl]-methyl]-3-(3-bromophenyl)-pyrrolidine-2,5-dione (ED50=33.64 mg/kg). Structures of the novel compounds were confirmed by elemental and spectral analyses.     

Rapid and sensitive LC/MS/MS analysis of the novel tyrosine kinase inhibitor ZD6474 in mouse plasma and tissues

ZD6474 (N-(4-Bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy] quinazolin-4-amine) is a tyrosine kinase inhibitor with anti-angiogenic and anti-tumor activity that is currently undergoing human trials for cancer treatment. Pharmacokinetic studies in animal models are an important component in clinical development of this agent to relate pre-clinical models to patient treatment. A liquid chromatography tandem mass spectrometry method was developed for the determination of ZD6474 levels in mouse plasma and tissues. Plasma (0.05 mL) and tissue homogenates (0.1 mL of 10 mg/mL) were extracted under alkaline conditions with ethyl acetate:pentane (1:1, v/v) after addition of the internal standard (trazodone, 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-1,2,4-triazolo[4,3-a]pyridine-3(2H)-one). Separation was achieved on a C18, 50 mm x 2 mm column with quantitation by internal standard reference and multiple reaction monitoring of the ion transitions m/z 475-->112 (ZD6474) and m/z 372-->176 (trazodone). The calibration curve was linear from a range spanning 20-20,000 ng/mL in plasma and 10-320 ng/mg in tissue homogenates. Mean recoveries from plasma and tissue homogenates were 88 and 90%, respectively. The accuracy in plasma was 88% at the lower limit of quantitation (20 ng/mL with a 50 microL plasma sample) with high precision (R.S.D.%<10%). Assay performance in liver and other tissue homogenates is also reported. The assay was applied to a pharmacokinetic study in mice to determine dosing schedules that would approximate therapeutic ZD6474 levels determined in humans.     

新型6,7-二甲氧基-4-(2-氟苯氧基)喹啉类c-Met抑制剂的设计、合成及生物活性研究

基于卡博替尼(cabozantinib)和foretinib的化学结构,通过改变中间链,设计合成了一系列含有哌嗪酰胺的6,7-二甲氧基-4-(2-氟苯氧基)喹啉类c-Met抑制剂。这些化合物未见文献报道,其结构通过MS和NMR确证。采用酶联免疫吸附测定(ELISA)法和MTT法测定了目标化合物对c-Met的抑制活性和对人结肠癌细胞(HT-29)、人肺癌细胞(H460)、人非小细胞肺癌细胞(A549)和人胃癌细胞(MKN-45)的细胞毒性。结果表明,4-(4-氯苯基)-N-[4-[(6,7-二甲氧基-4-喹啉)氧基]-3-氟苯基]哌嗪-1-甲酰胺(1b)、4-(3-氯苯基)-N-[4-[(6,7-二甲氧基-4-喹啉)氧基]-3-氟苯基]哌嗪-1-甲酰胺(1h)和4-(2-氯苯基)-N-[4-[(6,7-二甲氧基-4-喹啉)氧基]-3-氟苯基]哌嗪-1-甲酰胺(1j)对HT-29、H460、A549和MKN-45细胞的抑制活性明显优于对照药卡博替尼。其中,化合物1h和1j对c-Met具有较强的抑制活性,其IC50值分别为0.007 2和0.009 8 μmol/L。     

Discovery of aminobenzyloxyarylamides as κ opioid receptor selective antagonists: application to preclinical development of a κ opioid receptor antagonist receptor occupancy tracer

Arylphenylpyrrolidinylmethylphenoxybenzamides were found to have high affinity and selectivity for κ opioid receptors. On the basis of receptor binding assays in Chinese hamster ovary (CHO) cells expressing cloned human opioid receptors, (S)-3-fluoro-4-(4-((2-(3-fluorophenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide (25) had a K(i) = 0.565 nM for κ opioid receptor binding while having a K(i) = 35.8 nM for μ opioid receptors and a K(i) = 211 nM for δ opioid receptor binding. Compound 25 was also a potent antagonist of κ opioid receptors when tested in vitro using a [(35)S]-guanosine 5'O-[3-thiotriphosphate] ([(35)S]GTP-γ-S) functional assay in CHO cells expressing cloned human opioid receptors. Compounds were also evaluated for potential use as receptor occupancy tracers. Tracer evaluation was done in vivo, using liquid chromatography-tandem mass spectrometry (LC/MS/MS) methods, precluding the need for radiolabeling. (S)-3-Chloro-4-(4-((2-(pyridine-3-yl)pyrrolidin-1-yl)methyl)phenoxy)benzamide (18) was found to have favorable properties for a tracer for receptor occupancy, including good specific versus nonspecific binding and good brain uptake.