冠心病药物的研究——Ⅲ.若干取代氨基苯酚的Mannich碱的合成

临床验证常咯啉(Ⅰ)对短阵室性心动过速和室性早搏等症状非常有效,但存在一些副作用。为了寻找优于常咯啉的新的抗心律失常药物,我们合成了一系列芳环或芳杂环的Mannich:碱化合物37个。化合物的制备系将各类相应的氯化物分别与对氨基酚缩合,所得的中间体再与甲醛及胺反应,得到预期的Mannich碱(列于表2～表4)。药理试验结果表明。化合物9,12,13,30和33均能对抗乌头碱型实验性心律失常,其中化合物9,12和13的作用较强,安全范围较大。药理结果将另文发表。     

冠心病药物的研究——Ⅱ.抗心律失常新药常咯啉若干有关化合物的合成

在临床观察中,发现常咯啉(Ⅰ)对多种病因引起的室性早搏,房性早搏及短阵室速效果显著。惟该药尚存在一些副作用。为了寻找优于常咯啉的抗心律失常药物,我们合成了若干类似物及其有关化合物(Ⅱ～Ⅵ)。这些化合物的合成,除(Ⅴ)是以对酰胺苯酚为原料外,化合物(Ⅱ)～(Ⅳ)是以相应的氯化物与对氨基苯酚缩合,所得产物再按常法分别进行Mannich反应,便生成预期的化合物。化合物(Ⅵ)系将4-氯代喹唑啉与各种胺在适当溶液中,按不同条件反应而制备。药理试验结果表明,其中化合物1、5、7、8、14、15、17等均能对抗乌头碱引起的实验性心律失常,其中化合物14、15、17疗效显著。化合物14对抗由氯化乙酰胆碱对狗引起的房颤,其疗效可能超过常咯啉。常咯啉结构改造的进一步工作,尚在继续进行中。     

常咯啉对血浆蛋白和组织的结合率

常咯啉是一种化学结构属于新类型的抗心律失常药,它的实验药理和临床研究已有报道~[1～3],但是,它与血浆蛋白和组织的结合研究尚少。本文主要研究常咯啉与动物和人的血浆(或血清)以及动物组织的结合率,为     

介绍几种心血管药物

(一) 常咯啉常咯啉 (4-[3’,5’-双[(N-吡咯啶基)次甲基)-4-羟苯基]-氨基喹唑啉,是一个新化学结构类型的抗心律失常药物,系上海十六药厂、药物研究所将常山乙素的结构加以改造所得。合成工艺比较简单。经上海第一医院等研究证实,常咯啉能拮抗哇巴因、乌头碱所致的实验性心律失常,提高电刺激致室颤阈值。自1974年初,在上海、北京     

2－烃基－3－（3′，5′－双胺甲基－4′－羟基）－苯甲酰吲哚衍生物的合成及其心血管活性

本文以具有心血管活性的２－取代－３－对羟基苯甲酰吲哚为母核引入常咯啉双胺甲基结构合成了一系列衍生物。对部分化合物进行了抗哇巴因所致心律失常试验，受试化合物具有不同程度的抗心律失常活性，其中化合物（Ⅱ１）为常咯啉的２．４倍，并略高于慢心律，该化合物抗胆碱能的副作用较小，约为常咯啉的１／２。本文还初步探讨了构效关系。     

抗疟药咯萘啶有关化合物的合成及抗疟活性比较

合成了咯萘啶(Ⅰ)的有关化合物Ⅱ～Ⅴ,以探讨抗疟药咯萘啶化学结构中母环1位上氮杂原子及吡咯烷基Mannich碱侧链的存在,对该化合物抗疟作用的关系。经对有抗药性的疟原虫体内试验,合成的有关化合物Ⅱ～Ⅴ以及抗疟药氯喹和阿的平等的抗疟作用,均不如咯萘啶。提示上述氮杂原子及Mannich碱铡链的存在,对咯萘啶的抗疟作用,起着重要的和不可缺少的作用。     

常咯啉注射液的试制研究

常咯啉(Pyrozoline)为我国首创抗心律失常药物,系由常山乙素结构改造所得。动物实验表明,常咯啉具有明显的抗心律失常作用~[1],有较强的防乌头碱性心律失常的效果,对哇巴因所致的心律失常,在等毒性剂量条件下,效果较奎尼丁为优~[1]。常咯啉片剂已用于临床,可     

4-{3′,5′-双-[(N-吡咯烷基)甲基]-4′-羟苯胺基}喹唑啉(常咯啉)抗乌头硷诱发大鼠心律失常的作用

大鼠静注常咯啉再注射乌头硷,或同时用常咯啉和乌头硷,明显推迟乌头硷引起的心律紊乱。先静注乌头硷出现心律失常后,再注射常咯啉,抗心律失常作用较弱。剪断二侧迷走神经,或静注六烃季铵,都不影响常咯啉抗静注乌头硷所致心律失常的疗效。从静脉恒速注射乌头硷,记录室性早搏、室性心动过速和心室颤动阈值。预先静脉注射常咯啉明显提高这三种阈值。利血平化加常咯啉组,这些阀值也比对照组明显提高,与常咯啉组相比,仅显著提高心室颤动阈值。脑室内注射常咯啉后,再脑室内注射乌头硷,明显推迟心律失常出现时间。常咯啉对大鼠坐骨神经的局麻作用甚微,这与利多卡因有明显不同。     

4-{3′,5′-双-[(N-吡咯烷基)甲基]-4′-羟苯胺基}喹唑啉(常咯啉)抗乌头硷诱发大鼠心律失常的作用

大鼠静注常咯啉再注射乌头硷,或同时用常咯啉和乌头硷,明显推迟乌头硷引起的心律紊乱。先静注乌头硷出现心律失常后,再注射常咯啉,抗心律失常作用较弱。剪断二侧迷走神经,或静注六烃季铵,都不影响常咯啉抗静注乌头硷所致心律失常的疗效。从静脉恒速注射乌头硷,记录室性早搏、室性心动过速和心室颤动阈值。预先静脉注射常咯啉明显提高这三种阈值。利血平化加常咯啉组,这些阀值也比对照组明显提高,与常咯啉组相比,仅显著提高心室颤动阈值。脑室内注射常咯啉后,再脑室内注射乌头硷,明显推迟心律失常出现时间。常咯啉对大鼠坐骨神经的局麻作用甚微,这与利多卡因有明显不同。     

抗疟新药常咯啉类似物的合成

为寻找优于常咯啉的抗疟新药,从带有各种取代基的喹唑酮出发合成了一系列4-取代氨基喹唑啉衍生物。初步药理结果表明,2-甲基-4-{3′,5′-双[(N-吡咯烷基)甲基]4′-羟苯胺基}喹唑啉(化合物13)和6,7-甲撑二氧基-4-{3′-[(N-吡咯烷基)甲、基]-4′-羟苯胺基}喹唑啉(化合物16)对鼠疟(P.berghei)的疗效高于常咯啉。     

Antifungal activity of some mono, bis and quaternary Mannich bases derived from acetophenone

The development of resistance to current antifungal therapeutics drives search for new effective agents. Some Mannich bases have antifungal activity, but no information is available regarding the antifungal activity of acetophenone derived Mannich bases. Mono Mannich bases of acetophenone 1-3 were synthesized and converted into their corresponding bis derivatives, 5-7. Representative quaternary derivatives 4 and 8 were also synthesized. Antifungal activities of the compounds were evaluated using some yeasts and dermatophytes in vitro. Mono Mannich base 3 and quaternary compounds 4 and 8 were found to be 2-16 times more potent than the reference compound amphotericin B against dermatophytes: Trichophyton rubrum, Trichophyton mentagrophytes, and Microsporum canis. Compounds 4 and 8 were also found to be 2 times more effective compared with amphotericin B against the yeast Saccharomyces cerevisiae. Quaternization procedure improved the biological activity dramatically, whereas conversion of mono Mannich bases to corresponding bis derivatives generally did not affect antifungal activity. Our results suggest that acetophenone derived mono Mannich base 3 and quaternary derivatives 4 and 8 may serve as leading compounds for further studies to develop new antifungal agents with their highly potent antifungal activity.     

Pro-drugs as drug delivery systems XIII. Kinetics of decomposition of N-Mannich bases of salicylamide and assessment of their suitability as possible pro-drugs for amines

The kinetics of decomposition of various N-Mannich bases of salicylamide in aqueous solution at 37°C was studied to assess their suitability as pro-drugs for amino compounds. The decomposition, yielding salicylamide, amine and formaldehyde in stoichiometric amounts, showed bell-shaped pH-rate profiles which could be accounted for by assuming spontaneous decomposition of both neutral and protonated Mannich base and unreactivity of the derivatives in the anionic form. For the Mannich bases with the amines piperidine, α-alanine, methylamine and morpholine, the half-lives of decomposition at pH 7.40 and 37°C were 14, 17, 28 and 41 min, respectively, suggesting that salicylamide N-Mannich bases are possible candidates as pro-drugs for compounds containing a primary or secondary amino group. N-Amidomethylation of the amines with salicylamide resulted in a pronounced lowering of their basicity corresponding to 3–4 pK_a units which may be of potential utility for the application of N-Mannich bases as pro-drug forms for amines.     

Mannich base derivatives of theophylline and 5-fluorouracil: syntheses,properties and topical delivery characteristics

Mannich base prodrugs of theophylline and 5-fluorouracil have been prepared and tested for their ability to deliver their parent drugs through hairless mouse skin. The Mannich base derivatives were more effective than the previously described N-acyloxyalkyl derivatives. In the case of theophylline the Mannich base derivative was also found to be as effective as the previously described N-hydroxymethyl derivative. All of the Mannich bases reverted to their parent compounds in water, but some were relatively stable in aprotic solvents such as isopropyl myristate which was therefore used as a vehicle for the diffusion experiments with the prodrugs.     

Pro-drugs as drug delivery systems XIX. Bioreversiblf derivatization of aromatic amines by formation of N-Mannich bases with succinimide

The kinetics of decomposition of various N-Mannich bases derived from succinimide or 5,5-dimethylhydantoin and a series of primary aromatic amines in aqueous solution at 37°C was studied to assess their suitability as pro-drugs for such amino compounds. The pH-rate profile for each compound showed a sigmoid shape and could be accounted for by assuming spontaneous decomposition of unprotonated Mannich base. The reaction rate increased markedly with increasing amine basicity. For the succinimide Mannich bases the half-lives of decomposition at pH 7.4 and 37°C were found to range from 0.9 min for the p-toluidine derivative to 4 h for derivatives of procaine and benzocaine. The results suggested the potential utility of such N-Mannich bases as pro-drug candidates for drugs containing a primary aromatic amino group, e.g. with the aim of protecting such drugs against metabolic inactivation by N-acetylation.     

Antifungal evaluation of bis Mannich bases derived from acetophenones and their corresponding piperidinols and stability studies

The development of resistance to current antifungal therapeutics drives the search for effective new agents. The fact that some acetophenone-derived Mannich bases had shown antifungal activities in our previous studies led us to design and synthesize acetophenone-derived bis Mannich bases, B1-B5, bis(beta-aroylethyl)methylamine hydrochlorides, to evaluate their antifungal activity. These bis Mannich bases were then converted to the corresponding piperidinols, C1-C5, which are structural isomers of bis derivatives, 3-aroyl-4-aryl-1-methyl-4-piperidinol hydrochlorides, to see alterations in biological activity. A stability study of B1 and Cl was also carried out to estimate whether they alkylate the thiols. All compounds studied have shown antifungal activity, especially against dermatophytes (Trichophyton rubrum, Trichophyton mentagrophytes, Trichophyton tonsurans, and Microsporum canis), in the concentration range studied (2-128 microng/ml). The activity was especially apparent against T. tonsurans. All compounds had at least equal antifungal activity compared with the reference compound amphotericin-B against T. tonsurans. Bis Mannich bases were generally found to be more potent compounds than their structural isomer piperidinols. The results of our stability studies suggest that thiol alkylation may contribute to the antifungal activity of the Mannich bases synthesized. Even though all compounds showed antifungal activity against dermatophytes, bis Mannich bases B1, B2, B4, and B5 appear to have potential for developing novel antifungal agents against dermatophytes.     

Studies on arylfuran derivatives. Part VII. Synthesis and characterization of some Mannich bases carrying halophenylfuryl moieties as promising antibacterial agents

A series of 4-[5-(halophenyl)-2-furfurylidene)] amino-3-mercapto-5-substituted-1,2,4-triazoles (3) were synthesized. Aminomethylation of 3 with formaldehyde and a secondary amine furnished Mannich bases, 4. Both Schiff bases and Mannich bases were characterized on the basis of IR, NMR, mass spectral data and elemental analysis. All the newly synthesized compounds were tested for their antibacterial activities. Some of them carrying morpholino and N-methylpiperazino residues were found to be promising antibacterial agents.     

Effects of Mannich bases on cellular glutathione and related enzymes of Jurkat cells in culture conditions.

Jurkat cells were exposed to representative acetophenone-derived mono Mannich bases 2 and 3 and also cyclic Mannich base C1 in culture conditions to see the alterations in the most abundant cellular thiol, glutathione and also some of the enzymes in its metabolic pathway. Jurkat cells were exposed to the compounds for 24 h in cell culture medium with fetal bovine serum (1%) at 37 degrees C under a humidified atmosphere of 95% air and 5% CO2. Mannich bases generally increased total glutathione level (123-151% of control). Glutathione S-transferase (GST) activity also increased (150-363% of control), while glutathione disulfide reductase (GRD) activity was not affected. The increase in cellular glutathione level may possibly result from de novo glutathione synthesis. The consumption of the glutathione due to alkylation by Mannich bases might have stimulated the enzymes in the gamma-glutamyl cycle in our experimental design, where the cells had nutrients and time to react with their feedback mechanisms. A remarkable increase in GST activity might be a compensatory up-regulation to detoxify Mannich bases by conjugating them with cellular thiols.     

Nuclear-substituted styryl ketone analogs: effects on neoplasms, microorganisms, and mitochondrial respiration of tumorous and normal cells.

Analogs of some antineoplastic and cytotoxic Mannich bases derived from conjugated styryl ketones were prepared and evaluated for activity in the P-388 lymphocytic leukemia screen. Most of the new compounds had lower antineoplastic and murine toxicity than the parent compounds. Antimicrobial evaluation of some oximes and alcohols related to the Mannich bases revealed activity against certain Gram-positive bacteria and fungi. Primary pharmacological evaluation showed that some compounds containing a dimethylaminomethyl group displayed analgesic and antihistaminic properties. Five of the Mannich bases were evaluated as respiratory inhibitors in mitochondria derived from hepatic tumors, liver tissue from tumor-bearing animals, and normal rat liver. No statistical difference between the sensitivity of the three tissues to the compounds was obtained.