可逆性胆碱酯酶抑制剂:二甲氨基甲酸-[3-烷基-4-(烷氨基)烷氧基]苯酯的合成

前文报道的一系列二甲氨基甲酸间-(烷氨基)烷氧(烷硫)基苯酯类化合物(I,X=O,S)中,多数具有较强的抑酶作用,有的对实验动物的中麻催醒效果较好,且毒性和副作用小。其中二甲氨基甲酸间-(2-二甲氨基)-乙氧基苯酯(I,X=O,n=2,R=CH_3)已命名为“催醒     

可逆性胆碱酯酶抑制剂:二甲氨基甲酸-[2-(2-二甲氨基)乙氧基-4(或5)-特丁基]苯酯的合成

前报报道在“催醒安”的对位异构体的苯环上引入烷基,可以增强对胆碱酯酶的抑制作用。为了探索在邻位异构体(Ⅰ)的苯环上引入烷基对生理活性的影响,合成了二甲氨基甲酸-[2-(2-二甲氨基)乙氧基-4(或5)-特丁基]苯酯(Ⅱ)。     

可逆性胆碱酯酶抑制剂:二甲氨基甲酸-5-(1,3,3-三甲基-6-取代基)吲哚满酯的合成

催醒宁(I,R=H,R′X=HCl)对胆碱酯酶的抑制作用较强,但稳定性较差,作用时间较短。推测可能与其酯基易于水解有关。鉴于催醒宁结构中的氨基甲酸酯是抑酶作用的药效基团,酯基被水解后,抑酶活性即消失,我们设想,如果在催醒宁结构中的酯基邻位上引入取代基,利用其空间效应的影响,使酯基增加对水解的稳定性,或有可能达到延长作用时间的目的。因此,我们合成了二甲氨基甲酸-5-(1,3,3-三甲基-6-取代基)吲哚满酯盐酸盐和季铵盐(Ⅰ_(1～14),表1),以探索取代基对抑酶强度和作用时间的影响。     

中麻催醒剂——Ⅰ.二甲氨基甲酸间-(烷氨基)烷氧基苯酯的合成

合成了一系列二甲氨基甲酸间-(烷氨基)烷氧基苯酯,并进行了实验动物的毒性和中麻催醒试验。初步临床观察表明,化合物Ⅱ_4(现命名为催醒安)比毒扁豆碱的催醒效果好,而毒性小。简要地讨论了结构和生物活性之间的关系。     

中麻催醒剂——Ⅰ.二甲氨基甲酸间-(烷氨基)烷氧基苯酯的合成

合成了一系列二甲氨基甲酸间-(烷氨基)烷氧基苯酯,并进行了实验动物的毒性和中麻催醒试验。初步临床观察表明,化合物Ⅱ₄(现命名为催醒安)比毒扁豆碱的催醒效果好,而毒性小。简要地讨论了结构和生物活性之间的关系。     

可逆性胆碱酯酶抑制剂二甲氨基甲酸-[3-(烷氨基)烷氧基-4(5)-叔丁基]苯酯的合成

在催醒安的邻位和对位异构体及其同系物的苯坏上引入烷基后,可以增强抑制胆碱酯酶的活性,我们乃进一步在催醒安及其同系物的苯环不同位置上引入叔丁基,合成了一系列二甲氨基甲酸-[3-(烷氨基)烷氧基-4(5)-叔丁基]苯酯(Ⅰ_(1～13)和Ⅱ_(1～5))(表2),以探索对活性的影响。     

可逆性胆碱酯酶抑制剂 Ⅱ.二甲氨基甲酸间-(烷氨基)烷硫基苯酯的合成

前文报道了一系列二甲氨基甲酸间-(烷氨基)烷氧基苯酯(I,X=O)的合成,发现催醒安(I,X=O,n=2,R=CH_3)对临床中麻催醒有较好的效果,是一个结构简单、易于合成、具有中枢作用的可逆性胆碱酯酶抑制剂。但催醒安对中枢胆碱酯酶的抑制作用不够强,为此,我们合成了相应的硫代衍生物(Ⅱ,X=S)(表2)以期能增强对中枢胆碱酯酶的抑制作用。     

支气管扩张新药Bambuterol

Bambuterol(KWD-2183)是瑞典Astra 公司研制的新的支气管扩张剂。合成在热吡啶中,3,5-二羟基乙酰苯(Ⅰ)与N,N-二甲基氨甲酰氯反应生应3,5-双(N,N-二甲基氨甲酸基)乙酰苯(Ⅲ)。Ⅲ在二氧六环中溴化得3,5-双(N,N二甲基氨甲酸基)苯甲酰溴甲烷(Ⅳ),Ⅳ与N-苄基特     

青光明(催醒安)

【化学名】N,N-二甲氨基甲酸-间(2-二甲氨基乙氧基)苯酯盐酸盐【结构式】【作用特点】本品为一新的抗青光眼药物,系氨基甲酸酯类可逆性胆碱酯酶抑制剂。药理毒理作用与毒扁豆碱类似。动物实验表明,本品具有降眼压和缩瞳作用,其降眼压作用与毛果芸香碱近似,缩瞳作用及对视力的影响均弱于     

可逆性胆碱酯酶抑制剂——N,N-二甲胺基甲酸5-(1,2-取代苯骈咪唑)酯的合成

本文报道了用还原环合法制备1,2-二取代苯骈咪唑,并应用相转移催化反应于N-(4-甲氧基2-硝基苯基酰胺的N-烷化及5-羟基苯骈咪唑的二甲胺基甲酰化,合成了一系列N,N-二甲胺基甲酸5-(1,2-取代苯骈咪唑)酯,其碘甲烷季铵盐有一定的体外抑酶作用。     

~1H核磁共振谱直接观测N，N－二甲氨基甲酸－间－（2－二甲氨基）乙氧基苯酯在原位灌流大鼠肝脏中的代谢

应用高分辨Ｈ核磁共振谱（ＨＮＭＲ）直接观测Ｎ，Ｎ－二甲氨基甲酸－间－（２－二甲氨基）乙氧基苯酪（ＤＭＤＭＣ）在原位灌流大鼠肝脏中的代谢产物和代谢动力学过程。灌流不同时间采集样本在４００ＭＨｚＮＭＲ谱仪上直接用选择自旋翻转回波ＨＮＭＲ法进行定性和定量分析．ＤＭＤＭＣ在灌流大鼠肝脏中的主要代谢产物是羟基ＤＭＤＭＣ和Ｎ－去甲基ＤＭＯＭＣ，其消除半衰期为１１２ｍｍ．羟基ＤＭＤＭＣ的生成量最大，其最高生成值ｒｍａｘ为０．４９，Ｎ－去甲基ＤＭＤＭＣ的ｒｍａｘ为０．２６当大鼠用苯巴比妥（８０ｍｇ·ｋｇ－１·ｄ－１）预处理４ｄ后，ＤＭＤＭＣ在灌流大鼠肝脏中的代谢消除加快。消除半衰期缩短为５４ｍｈ。同时代谢产物的生成和转化速度增加结果表明。ＤＭＤＭＣ在灌流大鼠肝脏中的主要代谢途径是氨基甲酸酯侧链的氧化代谢。苯巴比妥预处理可以加速ＤＭＤＭＣ在大鼠肝脏中的氧化代谢过程．     

Synthesis and evaluation of hydroxylated polyamine analogues as antiproliferatives

The synthesis of four hydroxylated polyamine analogues, (2R, 10R)-N(1),N(11)-diethyl-2,10-dihydroxynorspermine, (2S,10S)-N(1), N(11)-diethyl-2,10-dihydroxynorspermine, (3S,12S)-N(1), N(14)-diethyl-3,12-dihydroxyhomospermine, and (3R,12R)-N(1), N(14)-diethyl-3,12-dihydroxyhomospermine, is described along with their impact on the growth and polyamine metabolism of L1210 murine leukemia cells. Four different synthetic approaches are set forth, two each for the hydroxylated norspermines and for the hydroxylated homospermines. The key step in the assembly of the norspermines was the coupling of either N-[(2R)-2,3-epoxypropyl]-N-ethyl p-toluenesulfonamide or N-[(2S)-2,3-epoxypropyl]-N-ethyl trifluoromethanesulfonamide to N,N'-dibenzyl-1,3-diaminopropane. The key step with homospermines employed alkylation of putrescine with (3S)-N-(benzyloxycarbonyl)-N-ethyl-3,4-epoxybutylamine or of N, N'-bis(mesitylenesulfonyl)-1,4-butanediamine with (2R)-2-benzyloxy-4-[N-(mesitylenesulfonyl)ethylamino]-O-tosyl-1-++ +butan ol. All of the hydroxylated analogues were active against L1210 cells with 96-h IC(50) values of 相似文献   

Synthesis and bactericidal properties of pyridinium chlorides with alkylthiomethyl and alkoxymethyl hydrophobic groups

The products of a reaction between 3-ethoxymethylpyridine and chloromethylalkyl ether or sulfide were proven to be 1-[(alkylthio)-methyl]-3-[(ethoxy)methyl]pyridinium or 1-[(alkoxy)methyl]-3-[(ethoxy)-methyl]pyridinium chlorides. Bacteriostatic properties of the obtained chlorides against 13 different microbial strains representing cocci, rods, fungi, and bacilli were studied. The MICs were measured by serial dilution. All studied chlorides showed bacteriostatic properties. Particularly high activity against microbes was shown by 1-[(dodecylthio)-methyl]-3-[(ethoxy)methyl]pyridinium and 3-[(ethoxy)methyl]-1-[(tetradecylthio)methyl]pyridinium chlorides.     

Structure-activity relationships of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine analogues: effect of substitutions at the C-6 phenyl ring and at the C-5 position on anti-HIV-1 activity.

The effect of substitution on the pyrimidine moiety of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) and 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-2-thiothymine (HEPT-S) on anti-HIV-1 activity was investigated by synthesizing a series of 5-methyl-6-(arylthio) and 5-substituted-6-(phenylthio) derivatives. Preparation of the 5-methyl-6-(arylthio) derivatives was carried out based on either LDA lithiation of 1-[[2-(tert-butyldimethylsiloxy)ethoxy]methyl]thymine (3) and 1-[[2-(tert-butyldimethylsiloxy)ethoxy]methyl]-2-thiothymine (4) followed by reaction with diaryl disulfides or an addition-elimination reaction of 1-[[2-(tert-butyldimethylsiloxy)ethoxy]-methyl]-6- (phenylsulfinyl)thymine (31) with aromatic thiols. Preparation of the 5-substituted-6-(phenylthio) derivatives was carried out based on either C-5 lithiation of the 1-[[2-(tert-butyldimethylsiloxy)ethoxy]methyl]-6-(phenylthio)uraci l (41) with LTMP or the LDA lithiation of 5-alkyl-1-[[2-(tert-butyldimethylsiloxy)ethoxy]methyl]-2-thiouraci l derivatives 45-47. Substitution at the meta position of the C-6-(phenylthio) ring by the methyl group improved the original anti-HIV-1 activity of HEPT, and introduction of two m-methyl groups to the phenylthio ring further potentiated the activity [EC50: 6-[(3,5-dimethylphenyl)thio]-1-[(2-hydroxyethoxy)methyl]thymine (28), 0.26 microM; 6-[(3,5-dimethylphenyl)thio]-1-[(2-hydroxyethoxy)methyl]-2-thiothymin e (30), 0.22 microM]. When the 5-methyl group was replaced by an ethyl or an isopropyl group, the anti-HIV-1 activity of HEPT was also improved remarkably [EC50: 5-ethyl-1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-2-thiouracil (48), 0.11 microM; 5-isopropyl-1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)-2-thiouracil (50), 0.059 microM; 5-ethyl-1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-2-thiouracil (54), 0.12 microM; 5-isopropyl-1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-2-thiouracil (56), 0.063 microM]. 6-[(3,5-Dimethylphenyl)thio]-5-ethyl-1-[(2-hydroxyethoxy)methyl]thymine derivatives 51 and 57 and 6-[(3,5-dimethylphenyl)thio]-5-isopropyl-1-[(2- hydroxyethoxy)methyl]thymine derivatives 52 and 58 inhibited the replication of HIV-1 in the nanomolar concentration range.     

New anticancer agents: alterations of the carbamate group of ethyl (5-amino-1,2-dihydro-3-phenylpyrido[3,4-b]pyrazin-7-yl)car bamates

The ethyl (1,2-dihydropyrido[3,4-b]pyrazin-7-yl)carbamates have been reported to bind with cellular tubulin, to produce an accumulation of cells at mitosis, and to exhibit cytotoxic activity against experimental neoplasms in mice. Studies on the disposition of ethyl (5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b]pyrazin-7 -yl)carbamate (8) in mice showed that one metabolite was formed by cleavage of the ethyl carbamate moiety. Analogues with alterations in the carbamate group were prepared by transformations at the carbamate of 8, by reductive cyclization of nitropyridine intermediates, and by hydride reduction of the ring of heteroaromatic compounds. In vitro and in vivo evaluations of analogues indicated that a carbamate group was required for activity. No significant change in activity was observed when ethyl was replaced by methyl. However, activity was reduced when ethyl was replaced with bulky aliphatic groups and when ethoxy was replaced with a methylamino group. Also, the activity of 8 was decreased by acetylation of the 5-amino group and was destroyed by substitution of an amino group at the 8-position.     

Identification of novel metabolites of pioglitazone in rat and dog

1. Four new metabolites of pioglitazone were identified by liquid chromatography-mass spectrometry (LC-MS/MS) as being formed by hydroxylation (M-VII and M-VIII), opening of the thiazolidinedione ring (M-X) and by desaturation of the terminal ethyl side chain or tether ethoxy moiety (M-IX), respectively. The structure of one of the hydroxylated metabolites (M-VII) was confirmed by chemical modification using the Jones reaction. 2. Oxidative cleavage of the thiazolidinedione ring is a novel pathway not previously reported for pioglitazone. 3. The hydroxylated M-VII was detected in incubations with rat, dog and human liver and kidney microsomes, and in plasma from rats and dogs dosed orally with [(3)H]pioglitazone. 4. The carboxylic acid derivative of M-VII (M-V) and its taurine conjugate were the major radioactive components in dog bile.     

Synthesis and evaluation of antiinflammatory activity of substituted chalcone derivatives

In an effort to develop potent antiinflammatory agents, a series of substituted chalcone derivatives was synthesized and evaluated for antiinflammatory activity through monitoring of their ability to inhibit xylene-induced ear edema in mice. Some of the tested compounds exhibited significant activity, and compounds 3f [(E)-1-(2,4-dihydroxyphenyl)-3-(4-dimethylamino)phenyl)prop-2-en-1-one] and 3h [(E)-3-(4-chlorophenyl)-1-(2,4-dihydroxyphenyl)prop-2-en-1-one] showed the highest antiinflammatory activity (62 and 68% inhibition, respectively, 2 h before administration), comparable with or even slightly more potent than the reference drug ibuprofen (53%). Furthermore, the structure–activity relationship of these substituted chalcone derivatives was demonstrated.