取代-1,3-二氢吲哚-2-酮化合物的合成

取代苯胺经酰化、环合反应制得关键中间体取代靛红衍生物4a～4k,再用三乙基硅烷/三氟乙酸体系室温还原制得取代-1,3-二氢吲哚-2-酮类化合物1a～1k,后者可用于合成舒尼替尼等酪氨酸激酶抑制剂类抗肿瘤药.     

3-取代-5-氟-1-2-二氢-3H-吲哚-2-酮类化合物的合成及抗肿瘤活性

5-溴-1H-吲哚经氰基取代、Vilsmeier-Haack反应、水解、缩合制得3-[(Z)-(5-氟-1,2-二氢-2-氧代-3H-亚吲哚基)甲基]-1H-吲哚-5-甲酸,再和相应的胺类化合物反应制得10个3-取代-5-氟-1,2-二氢-3H-吲哚-2-酮类化合物.以舒尼替尼为阳性对照,用MTT法测试目标化合物对人乳腺上皮细胞HMEC的体外抑制活性,其中1c、1f、1g和1h在浓度为10 μmol/L时,对HMEC的抑制活性优丁舒尼替尼.进一步测试1c和1e对SGC7901、A549、HL-60、SK-BR-3、HCT116肿瘤细胞株的抗增殖活性.结果表明,1c和1e对白血病细胞株HL-60的抗增殖活性优丁舒尼替尼.     

3-取代吲哚酮类化合物的合成及抗肿瘤活性

目的设计合成具有抗肿瘤活性的3-取代吲哚-2-酮类化合物,并对其抗肿瘤活性进行评价.方法以吲哚酮和苯甲醛衍生物在微波辐射条件下进行缩合反应制得目标化合物,用人肝癌HepG2细胞进行抗肿瘤活性检测.结果合成了8个化合物,其中6个未见报道.其结构均经1H-NMR、IR及ESI-MS确证.结论初步抗肿瘤活性测试结果显示化合物Ⅱe、Ⅱg有较强的活性(IC50值分别为1.4μmol·L-1和1.2μmol·L-1,小于阳性对照药5-Fu).微波辐射技术用于3-取代吲哚酮的合成,能大幅度缩短反应时间,提高收率.     

N-取代-5-羟基-1H吲哚-3-羧酸酯类衍生物的合成

目的:以阿比朵尔为先导化合物,设计并合成一系列4-取代胺甲基-5-羟基-1-烃基-2-苯硫基甲基-1H吲哚-3-羧酸乙酯盐酸盐.方法:以4-氯代乙酰乙酸乙酯为起始原料通过硫代、胺化、Nenitzescu反应、Mannich反应、成盐反应共5步反应制得目标产物.由薄层色谱(TLC)确定每步反应终点.结果:目标化合物结构经红外光谱、核磁共振光谱及质谱确证.结论:通过该合成方法合成了9个未见报道的新化合物.     

1-(5-取代糠基)吲哚啉-2-酮衍生物的合成和初步抗肿瘤活性

为了寻找具有较好抗肿瘤活性的新型吲哚啉-2-酮类化合物，本研究以5-甲酰基-2,4-二甲基-1H-吡咯-3-羧酸乙酯与5位不同取代的吲哚啉-2-酮(2a～2d)为原料，首先经缩合得3-吡咯亚甲基-吲哚啉-2-酮(3a～3d)，再经N烃化反应得到1-(5-甲酰基糠基)-3-(吡咯亚甲基)-吲哚啉-2-酮(4a～4d)，然后与吲哚啉-2-酮缩合得到以5-亚甲基糠基连接的双吲哚啉-2-酮化合物(5a～5d)。所合成的12个新型吲哚啉-2-酮类化合物的结构经核磁共振谱、质谱和元素分析确认。采用四氮唑盐(MTT)还原法测试所合成化合物的体外抗肿瘤活性，结果表明所合成的化合物均有一定的抗肿瘤作用，其中6个化合物对SPC-A1肺癌肿瘤株体外抑制活性优于舒尼替尼，特别是化合物5a～5d， IC₅₀值均小于5 μmol·L^-1，值得作为抗肿瘤药物先导化合物。     

6-苄氧基吲哚-2-甲酸糠醇酯衍生物的合成及其抗稻瘟霉菌活性

目的设计合成一系列6-苄氧基吲哚-2-甲酸糠醇酯衍生物,并测试其抗稻瘟霉菌活性。方法以4-羟基苯甲醛为原料,经O-苄基化、Knoevenagel反应、重排和水解反应得到6-苄氧基吲哚-2-甲酸（6）,6与5-氯甲基糠醛反应得到6-苄氧基吲哚-2-甲酸-（5-甲酰基糠醇）酯（1）,1分别经过还原、还原胺化和Knoevenagel反应得到相应的目标化合物。体外活性采用稻瘟霉菌筛选模型进行评价。结果与结论合成了13个新化合物,其结构经核磁共振氢谱、质谱确证,其中化合物1、8e、8f、8g的活性优于阳性对照灰黄霉素（griseofulvin）。     

一锅法合成新型吲哚-色胺酮类化合物

目的合成新型结构的吲哚-色胺酮[6-(1H-吲哚-2-基)吲哚并[2,1-b]喹唑啉-12(5H)-酮]类化合物,并初步考察其代表性化合物3a的抗肿瘤活性。方法以2-吲哚酮为起始原料,经盐酸酸化后在过量三氯氧磷的条件下与相应的取代2-氨基苯甲酸经一锅法合成新的吲哚-色胺酮类化合物。采用MTT法考察化合物3a对不同肿瘤细胞的抑制作用。结果与结论合成了3个未见报道的新化合物,目标化合物的结构经质谱、核磁共振谱确证。活性测试结果表明,化合物3a对A549肿瘤细胞株显示出一定的抑制作用。目标化合物是在色胺酮结构中引入吲哚单元后形成的新骨架结构的化合物,将为进一步研究基于吲哚-色胺酮结构的先导化合物提供一个新的方向。     

3-取代吲哚-2-酮类化合物的设计、合成及抗肿瘤活性研究

目的设计合成对微管蛋白和血管内皮细胞生长因子受体2(VEGFR-2)激酶具有双重抑制作用的3-取代吲哚-2-酮类化合物,考察其体外抑瘤活性。方法以取代的苯胺为起始原料,经缩合、环合、还原、取代等反应制得系列目标化合物,并考察该系列化合物对微管蛋白和肿瘤细胞的抑制活性。结果共合成了11个新的目标化合物。实验结果显示,化合物j9对微管蛋白和VEGFR-2激酶具有双重抑制活性。所有目标化合物对3种肿瘤细胞株均有中等强度的抑制活性。结论该类化合物是一类具有多靶点作用的抗肿瘤化合物。     

3-取代2-吲哚酮类化合物的合成与抗肿瘤活性研究

目的寻找新的具有血管内皮细胞生长因子受体酪氨酸激酶抑制活性的3-取代2-吲哚酮类化合物。方法以2-吲哚酮为原料，利用缩合反应合成目标化合物，并进行体外初步药效学评价。结果设计并合成了5种化合物，其中4种为首次发现，体外初步药效学研究表明，所合成的化合物均具有抑制S-180肿瘤细胞生长的活性，其中化合物Ⅱ活性最强。结论3-取代2-吲哚酮类化合物具有抑制S-180肿瘤细胞生长的活性，化合物中吲哚环平面与相应的芳环平面之间处于垂直状态时活性较强。     

盐酸阿比朵尔的合成

以对苯醌、3-氨基巴豆酸乙酯经Nennzescu反应、D-酰化、N-甲基化制得1H-吲哚-3-羧酸乙酯,再经溴代、缩合、Mannich反应合成目标化合物,总收率22.9%.     

Research on substances with antiviral activity. III. Structure of the monosubstituted derivatives of 1 H-benzo-[e] indene-1,3(2H)-dione]

The N.M.R. spectra of 1H-benz[e]indene-1,3(2H)-dione (I), 1H-benz[e]indene-2,3-dihydro-1-one (II), 7-methyl-3H-benz[e]indene-1,2-dihydro-3-one (III) and of their oximes, phenylhydrazones and 4-methylthiosemicarbazones show the preferential substitution at 3 position for monoderivatives of (I). This is very interesting in correlation with the structure-activity relationship of derivatives of (I) and (II), some of which have shown in vitro antiviral action in previous research.     

四氢吡啶并[1,2-a]吲哚类化合物的合成及其扩张脑血管活性

本文报道了7个2-取代-6-氧代-10-[2-(N-取代)氨甲酰基]乙基-6,7,8,9-四氢吡啶并[1,2-a]吲哚类化合物的合成。初步药理试验表明,设计合成的化合物均有一定程度的扩张脑血管作用,其中化合物Ⅰ₇的作用最为明显。构效关系显示酰胺结构中二乙氨基乙胺的作用强于二甲氨基乙胺。     

Enhancement of hepatocellular genotoxicity of several mutagens from amino acid pyrolysates and broiled foods following ethanol pretreatment

The effect of subchronic ethanol ingestion on the genotoxicity and metabolism of the mutagens 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), 3-amino-1-methyl-5H-pyrido[4,5-b]indole (Trp-P-2), 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1), 2-aminodipyrido[1,2-a:3',2'-d]imidazole (Glu-P-2), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-3,4- dimethylimidazo[4,5-f]quinoline (MeIQ) was evaluated in primary cultures of rat hepatocytes. Male Sprague-Dawley rats were pair-fed, for 8 days, liquid diets containing either ethanol (8%, v/v) or an isocaloric sucrose solution. Ethanol pretreatment significantly (P less than 0.05, Student's t test) enhanced the level of DNA repair stimulated by Glu-P-1, Glu-P-2, IQ and MeIQ. Statistically significant increases in DNA-repair activity ranged from 1.9-fold for IQ to 3.4-fold for Glu-P-2. Following a 16-hr exposure, the concentration of parent mutagen in the culture medium decreased by 75-98%. Neither the rate of mutagen metabolism in hepatocyte cultures nor the extent of mutagenic activation in microsome preparations was appreciably affected by ethanol pretreatment. The results suggest that ethanol pretreatment enhances the genotoxicity of Glu-P-1, Glu-P-2, IQ and MeIQ by inducing non-microsomal activation processes.     

New Indole and Pyridazinoindole Analogs — Synthesis and Study as Inhibitors of Phosphodiesterases and as Inhibitors of Blood Platelet Aggregation

This paper presents the synthesis of new indole, pyridazino[4,5-b]indole, and pyridazino[4,5-a]indole analogs as well as a study of their “in vitro” activity as inhibitors of different phosphodiesterases isolated from dog cardiac tissue, dog aorta, and bovine platelets; the study of their activity as inhibitors of platelet aggregation in guinea pig whole blood, with ADP and arachidonic acid (AA) as pro-aggregants, is also included. The selected compounds 8-benzyloxy-3,4-dihydro-1-(3,4,5-trimethoxy)benzylideneaminopyridazino[4,5-b]indole 14g , and 8-benzyloxy-4-[(3,5-dimethyl)pyrazolyl]pyridazino[4,5-b]indole 20 present an interesting profile as potential inodilators, with a complementary, beneficial activity as inhibitors of the aggregation, activities which could possibly be related to the inhibition of the PDE's. Among the other compounds studied, 8-benzyloxy-3,4-dihydro-1-[4-(methyl)piperazino]acetamidopyridazino[4,5-b]indol-4-one 16c and 8-benzyloxy-3,4-dihydro-1-[4-(2-methoxyphenyl)piperazino]acetamidopyridazino[4,5-b]indol-4-one 16f stood out as inhibitors of platelet aggregation, with a mechanism that could possibly be related to the AA cascade.     

2-(取代苯乙烯基)吲哚类衍生物的合成及其生物活性

目的　寻找有生物活性的吲哚类化合物。方法　用还原、氧化和Witting反应设计合成了21个2-(取代苯基乙烯基)吲哚化合物,用¹HNMR,MS和元素分析确证其结构,并对其进行了体外筛选实验。结果　这些化合物均为新化合物。结论　6个化合物(3,9,11,13,18和20)对组胺1受体、多巴胺2受体和肾上腺素α-2受体有相当的抑制作用,值得进一步研究。     

Hydrogenated benzo[f]quinolines and benz[e]indoles as analgetics. 1.

A series of octahydrobenzo[f]quinolines(IIIa) and hexahydro-1H-benz[e]indoles(IIIb), rigid structures related to 3-phenylpiperidine and pyrrolidine analgetics, has been synthesized. Structure-activity relationships were investigated by varying the structural parameters including a change in the stereochemistry of the ring junction. Several of the resulting compounds had analgetic activity on the order of meperidine.     

Syntheses of two isotopically labeled CB1 receptor antagonists

Synthesis of deuterium‐labeled CB₁ receptor antagonist 2‐d₉ was accomplished in three steps by alkylation of 2‐nitrophenylacetonitrile with cyclopentyl‐d₉ bromide, reductive cyclization of the resulting secondary nitrile into the 3‐cyclopentyl indole‐d₉ and its N‐sulfonylation with corresponding p‐amidosulfonyl chloride. Another, structurally related, CB₁ receptor antagonist 1 was radiolabeled with carbon‐14 by oxidative cleavage of 3‐cyclopentyl indole followed by the ring closure of o‐acyl substituted N‐formylaniline with potassium cyanide‐[¹⁴C], in situ reduction‐elimination of the intermediate amino alcohol, and N‐sulfonylation of the resulting 3‐cyclopentyl indole‐2‐[¹⁴C].     

Research on substances with antiviral activity. VIII. Benzindanoncarboxylic acids]

New derivatives (esters, amides, nitriles, amidines, thiosemicarbazones and guanylhydrazones) of 1H-benz[e]indene-2,3-dihydro-5-methyl-1-oxo-3-carboxylic acid and 1H-benz[e]indene-2,3-dihydro-7-methyl-3-oxo-1-carboxylic acid were prepared and tested for antiviral activities in vitro against vaccinia virus, HID stock and parainfluenza type 3 virus, HA-I/CR-8 stock. Four compounds (II g), (II i), (III b), (III g), showed weak activity in vitro against vaccinia virus.     

Hypolipidemic activity of cyclic imido alkyl ethers, thioethers, sulfoxides, and sulfones

N-Substituted alkyl ethers, thioethers, sulfoxides, and sulfones of cyclic imides (e.g., phthalimide, saccharin, 1,8-naphthalimide, succinimide, and 2,3-dihydrophthalazine-1,4-dione) were shown to have potent hypolipidemic activity at doses of 10 and 20 mg/kg/d in rodents. These N-substitutions afforded no improvement over other known N-substitutions (e.g., butyl, 3-butanone, or the propionic acid derivatives of phthalimide, saccharin, and 2,3-dihydrophthalazine-1,4-dione) compared with the respective parent compounds. However, 2-(methoxyethyl)-1H-benz[de]isoquinoline-1,3-(2H)dione (3a), 2-[2-methylsulfinyl]ethyl-1H-benz[de]isoquinoline-1,3-(2H)dione (3c), 1-(2-methylsulfinyl)-2,5-pyrrolidenedione (4c), and 1-(2-methoxyethyl-2,5-pyrrolidenedione (4a) significantly improved activity compared with parent compounds, as well as previously reported N-substituted analogues, reducing serum cholesterol levels and serum triglyceride levels by 40%. The thioether of succinimide afforded a 54% reduction of serum cholesterol and a 41% reduction of serum triglyceride levels in mice after 16 d. The alkyl thioethers of 1,8-naphthalimide and succinimide significantly lowered cholesterol levels in serum VLDL and LDL, while the alkyl thioethers of succinimide elevated HDL cholesterol content. Tissue lipids were reduced in the liver and aorta by these selected derivatives. The activities of regulatory enzymes in de novo synthesis of hepatic cholesterol and triglyceride were inhibited by the selected 1,8-naphthalimide derivatives. In situ cholesterol and cholic acid reabsorption from intestines were suppressed by the presence of the agents.     

2-aryl-3-phenylamino-4,5-dihydro-2h-benz[g]indazoles with analgesic activity

A series of 2-aryl-3-phenylamino-4,5-dihydro-2H-benz[g]indazoles was synthesized and tested for antiarrhythmic, local anaesthetic and analgesic activity. The title compounds showed a good antinociceptive activity.