Synthesis and antileukemic activity of new 3-(5-methylisoxazol-3-yl) and 3-(pyrimidin-2-yl)-2-styrylquinazolin-4(3H)-ones

3-(3-Methylisoxazol-5-yl) and 3-(pyrimidin-2-yl)-2-styrylquinazolin-4(3H)-ones 8a-l and 9a,c-e,h-l were synthesized by refluxing in acetic acid the corresponding 2-methylquinazolinones 6 and 8 with the opportune benzoic aldehyde for 12 h. The synthesized styrylquinazolinones 8a-l and 9a,c-e,h-l were tested in vitro for their antileukemic activity against L-1210 (murine leukemia), K-562 (human chronic myelogenous leukemia) and HL-60 (human leukemia) cell lines showing in some cases good activity.     

Synthesis and cytotoxicity testing of novel 2-(3-substituted-6-chloro-1,1-dioxo-1,4,2-benzodithiazin-7-yl)-3-phenyl-4(3H)-quinazolinones

A new series of thirteen 2-[3-(substituted amino)-6-chloro-1,1-dioxo-1,4,2-benzodithiazin-7-yl]-3-phenyl-4(3H)-quinazolinones 4-16 were prepared in order to evaluate their cytotoxic activity against 12 human cancer cell lines. The bioassay indicated that the quinazolinone derivatives 5, 8-12, 15, and 16 possess cancer-cell growth-inhibitory properties. Compounds 5 and 12 showed a high level of selectivity for certain cell lines. The most active compounds 9, 10, 15, and 16 showed moderate antiproliferative activity and were approximately 4-fold less potent than cisplatin.     

反相高效液相色谱法测定(E)-3-(4-((3,5,6-三甲基吡嗪-2-基)甲氧基)-3-甲氧基苯基)丙烯酸在SD大鼠血浆中的浓度

目的 建立测定SD大鼠血浆中(E)-3-(4-((3,5,6-三甲基吡嗪-2-基)甲氧基)-3-甲氧基苯基)丙烯酸浓度的反相高效液相色谱(LC-UV)方法,并用于其在SD大鼠体内的药动学研究。方法 采用Diamonsil-C₁₈(2)柱(100 mm×4.6 mm,5 μm),以乙腈:水(含5 mM的醋酸铵,用醋酸调节pH至4.0)=30:70为流动相,测定70只SD大鼠单剂量尾静脉给药15 mg/kg后不同时刻血浆中药物的浓度,并由此计算其在SD大鼠体内的药动学参数。结果 SD大鼠     

6-取代苯基哒嗪的3位γ-氨基丁酸衍生物的合成及抗惊活性

GABA的合成类似物是开发新型抗惊剂和抗癫痫药物的新领域。由芳香醛与吗啉、氰化钾反应形成的α-芳基-α-(4-吗啉)乙腈,可对α,β-不饱和腈或酯进行1,4-加成,生成1,4-酮酸型化合物。此物与肼缩合,再经芳构化即得6-芳基-3(2H)哒嗪酮。后者再经氯化后。与GABA缩合,制备3-(N-GABA)-6-芳基哒嗪类及其分子内脱水产物3-(N-丁内酰胺)-6-芳基哒嗪类化合物。本文应用此法合成了17个上述苯代哒嗪的GABA衍生物,并初步测验了它们的抗惊(MES)活性。活性最强的是3-(N-GABA)-6-(2′,4′-二氯苯基)哒嗪(ED₅₀=21.05mg/kg)。     

(3S)-3-(叔丁氧羰基氨基)-4-氧代丁酸甲酯的合成

L-门冬氨酸在氯化亚砜作用下选择性甲酯化生成L-门冬氨酸-4-甲酯盐酸盐,经二碳酸二叔丁酯保护氨基、与氯甲酸乙酯成混酐后经硼氢化钠还原得到(3S)-3-(叔丁氧羰基氨基)-4-羟基丁酸甲酯,最后经NaClO/TEMPO氧化得到西他列汀重要手性中间体(3S)-3-(叔丁氧羰基氨基)-4-氧代丁酸甲酯,总收率约41%。     

6-取代苯基-3(2H)哒嗪酮的合成、抗惊活性及其构效关系的研究

本文报道了14个6-取代苯基-4,5-二氢-3(2H)哒嗪酮和15个6-取代苯基-3(2H)哒嚎酮的合成及其抗电惊活性。其ED₅₀值表明,以2′,4′-二氯苯基-3(2H)哒嗪酮的抗惊作用为最强。构效分析表明,苯环上的取代基对化合物的抗惊活性有明显影响,吸电子取代基和疏水性参数值较大的取代基有利于提高化合物的抗惊活性。     

(2S,3R)-1-二甲氨基-3-(3-甲氧基苯基)-2-甲基戊-3-醇的合成工艺研究

目的 对(2S,3R)- 1-二甲氨基-3-(3-甲氧基苯基)-2-甲基戊-3-醇合成工艺进行研究.方法 以3-戊酮为起始原料,经Mannich反应、手性拆分、Grignard反应等步骤合成(2S,3R)-1-二甲氨基-3-(3-甲氧基苯基)-2-甲基戊-3-醇,并对化学拆分进行工艺优化.结果 合成(2S,3R)-1...     

3-（3-羟基-1-甲基丙氧基）-1-丁醇和3-（3-羟基丁氧基）-1-丁醇的合成及其工艺改进

目的合成3-（3-羟基-1-甲基丙氧基）-1．丁醇（Ⅰ）和3-（3-羟基丁氧基）-1-丁醇（Ⅰ），并改进工艺提高产品纯度。方法以1，3-丁二醇为起始原料，通过硫酸催化双分子缩合、三苯甲基选择性保护、分离提纯、脱保护基4步反应得到目标化合物。结果与结论化合物Ⅰ的结构经。H．NMR13C-NMR谱确证，其含量经C-C测定，大于99．5％。化合物Ⅰ的纯度为90．0％，与文献相比纯度都有相应提高。     

3-(S)-(1-氨甲酰基-1,1-二苯甲基)吡咯烷的合成

反式-4-羟基-L-脯氨酸经脱羧、N-Boc保护和氯代反应制得N-Boc-3-(S)-氯吡咯烷,在叔丁醇钾作用下与二苯乙腈缩合得N-Boc-3-(S)-(1-氰基-1,1-二苯甲基)毗咯烷,再经水解、脱保护、经L-(+)-酒石酸处理后碱化制得氢溴酸达非那新中间体3-(S)-(1-氨甲酰基-1,1-二苯基甲基)吡咯烷,总收率约14%.     

3-氯-4-(3-氟苄氧基)苯胺的合成

目的开发一条适合产业化的3-氯-4-（3-氟苄氧基）苯胺的合成工艺路线。方法以间氟氯苄和2-氯-4-硝基苯酚为原料,依次经碳酸钾存在下的缩合反应、铁粉／氯化铵还原得到3-氯-4-（3-氟苄氧基）苯胺。结果总收率为82％。所得产物经TLC、熔点和核磁共振氢谱表征,具有高纯度。结论本方法原料价廉易得,操作简便,环境污染更小,预期适合工业化生产。     

Synthesis and antileukemic activity of novel 2-(4-(2,4-dimethoxybenzoyl)phenoxy)-1-(4-(3-(piperidin-4-yl)propyl)piperidin-1-yl)ethanone derivatives

A series of novel 2-(4-(2,4-dimethoxybenzoyl)phenoxy)-1-(4-(3-(piperidin-4-yl)propyl) piperidin-1-yl)ethanone derivatives 9(a-e) and 10(a-g) were synthesized and characterized by (1) H NMR, IR, mass spectral, and elemental analysis. These novel compounds were evaluated for their antileukemic activity against two human leukemic cell lines (K562 and CEM) by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide assay. Some of the tested compounds showed good antiproliferative activity with IC(50) values ranging from 1.6 to 8.0 μm. Compound 9c, 9e, and 10f with an electron-withdrawing halogen substituent at the para position on the phenyl ring showed excellent in vitro potency against tested human leukemia cells (K562 and CEM).     

3-(S)-(-)-(1-氨甲酰基-1,1-二苯甲基)吡咯烷酒石酸盐的制备

以L-苹果酸(2)为原料,经与苄胺缩合、还原、氢解脱苄、磺酰化、烷基化、脱保护基、水解后成盐制得氢溴酸达非那新关键中间体3-(S)-(-)-(1-氨甲酰基-1,1-二苯甲基)吡咯烷酒石酸盐,总收率约22%(以2计).     

7-酰氨基-3-(1,2,3-三唑甲基)头孢菌素衍生物的合成及其抗菌活性

本文以青霉素G扩环而得的7-苯乙酰氨基-3-甲基-3-头孢烯-4-羧酸(Ⅰ)为原料,合成了12个C₃位上有1,2,3-三唑甲基取代的新头孢菌素衍生物(Ⅷ_1～12),并经分析确证了各化合物的结构。体外抑菌试验结果表明,其中6个化合物,即Ⅶ_2～4,9～11,不仅对革兰氏阳性菌有较高的抑制作用。而且对革兰氏阴性菌也有高度敏感性。     

Synthesis and antiproliferative activity of 3-aryl-2-[1H(2H)-benzotriazol-1(2)-yl]acrylonitriles variously substituted: Part 4

A new series of variously substituted 3-aryl-2-[1H(2H)-benzotriazol-1(2)-yl]acrylonitriles was synthesized and tested for antiproliferative and antitubercular activity as part of our continuing research program in the antimicrobial and antitumor fields. The most cytotoxic derivatives (5a,g,i,j,l and 7b) (CC50 < 3.0 microM against MT-4 cells) were evaluated against a panel of human cell lines derived from hematological and solid tumors, using 6-mercaptopurine (6-MP) and etoposide as reference drugs. In particular, E-2-(5,6-dimethyl-1H-benzotriazol-1-yl)-3-(3-nitrophenyl)acrylonitrile (5g) resulted more potent than 6-MP on all cell lines, even if 2-14-fold less potent than etoposide. In the antitubercular screening, the derivatives 5i,j and 7e showed moderate activity against some resistant strains of Mycobacterium tested.     

4-(2-溴乙酰基)-3-氟苯硼酸的制备

4-溴-2-氟苯基氰经格氏反应得到4-溴-2-氟苯乙酮,先保护羰基,再经格氏反应和二羟硼基取代、溴代制得4-(2-溴乙酰基)-3-氟苯硼酸,总收率54%.     

3-苯并咪唑-6-(3,5-二甲氧基苯基)吲唑类FGFR抑制剂的合成及活性研究

目的 寻找具有新型骨架结构的成纤维细胞生长因子受体(FGFR)抑制剂.方法 基于活性化合物1和2的结构,利用“杂交”设计原理,设计并合成了一系列3-苯并咪唑-6-(3,5-二甲氧基苯基)吲唑类衍生物.结果 目标化合物经1 HNMR和质谱确证结构,并评价了其对人胃癌细胞SNU-16的增殖抑制活性.结论 该系列化合物均对FGFR高表达的肿瘤细胞有较好的增殖抑制活性,其中,化合物3g的IC50值达到0.32 μmol·L-1.3-苯并咪唑-6-(3,5-二甲氧基苯基)吲唑是一类新型的FGFR抑制剂骨架,值得进一步结构修饰研究.     

2-（5-氨基-1，2，4-噻二唑-3-基）-2-（Z）-甲氧亚氨基乙酸S-苯并噻唑硫酯的合成

2-(5-氨基-1,2,4-噻二唑-3-基)-2-(Z)-甲氧亚氨基乙酰胺与2-巯基苯并噻唑为原料,哌啶为溶剂,在三乙胺催化下反应制得头孢菌素中间体2-(5-氨基-1,2,4-噻二唑-3-基)-2-(Z)-甲氧亚氨基乙酸S-苯并噻唑硫酯,收率约76%。     

Synthesis of 2-(4-biphenylyl)quinoline-4-carboxylate and carboxamide analogs. New human neurokinin-3 (hNK-3) receptor antagonists

The 2-phenylquinoline-4-carboxamide 1 (Chart[TH]1) has been found to possess moderate affinity for human neurokinin-3 (hNK-3) receptor. In the present work, and in a trial to investigate the effect of the lipophilic moiety at C-2 of the quinoline ring on the antagonistic activity, an enlargement of the aromatic area at this position was suggested. In this respect, two series of 2-(4-biphenylyl)quinoline-4-carboxylates and carboxamides have been synthesized with certain modifications at the quinoline-2 and 4-position in order to study their effect on the anticipated hNK-3 receptor antagonistic activity. Fifteen compounds were screened for such activity using guinea-pig isolated ileum longitudinal muscle preparation and senktide as selective hNK-3 receptor agonist. Some compounds showed considerable antagonistic effect. Compound 7b, 6-bromo-2-(4-biphenylyl)quinoline-4-carboxylic acid, was the most prominent hNK-3 receptor antagonist in this study. Unexpectedly, some compounds were agonists.     

Synthesis and Antimicrobial Activity of Some New 2-(3-(4-Aryl)-1-phenyl-1H-pyrazol-4-yl) Chroman-4-ones

Seven new 2-(3-(4-aryl)-1-phenyl-1H-pyrazol-4-yl) chroman-4-ones (4a-4g) have been synthesized by cyclization of 2-hydroxychalcone analogues of pyrazole 3a-3g using conc. HCl in acetic acid. The structures of the compounds 4a-4g were established by the combined use of (1)HNMR, IR and mass spectra. All the seven compounds were tested in vitro for their antibacterial activity against two Gram positive bacteria namely Staphylococcus aureus and Bacillus subtilis and two Gram negative bacteria Escherichia coli and Pseudomonas aeruginosa. The compounds 4b, 4c, 4e, 4f, 4g have displayed good antibacterial activity when compared with commercially available antibiotic, ciprofloxacin. These compounds also were screened for their antifungal activity against two ear pathogenic fungi, namely Aspergillus Niger and A. flavus. The compounds 4a, 4c, 4d, 4g exhibited good antifungal activity when compared with commercially available antifungal, fluconazole.     

Synthesis and antifungal activity of (+/-)-1-(5-aryl-3-pyridin-2-yl-4,5-dihydro-pyrazol-1-yl)-2-imidazol-1-yl-ethanone derivatives

(+/-)-1-(5-Aryl-3-pyridin-2-yl-4,5-dihydro-pyrazol-1-yl)-2-imidazol-1-yl-ethanone derivatives were synthesized and tested for their in vitro antifungal activity. The compounds showed a moderate activity against strains of Candida parapsilosis, Candida pseudotropicalis and Candida glabrata.