Synthesis of azo derivatives of 4-aminosalicylic acid

For searching a better 4-aminosalicylic acid derivative with higher activity and less side effects against the inflammatory bowel disease, 4-aminosalicylic acid (4-ASA) was protected by benzyloxycarbonyl and acetyl, respectively. The resultant was hydrogenized to remove protective group of amino group, then the product was reacted with NaNO2 to give diazonium salt, which was conjugated with salicylic acid, hydroxybenzene, TV-salicyloyl glycine acid to get azo derivatives of 4-ASA. The azo derivatives were hydrolyzed under the alkaline condition to get the target products. All compounds were characterized by FT-IR, 1H NMR, 13C NMR spectra in details. New derivatives of 4-ASA were characterized. The synthetic route was reasonable and feasible.     

七元瓜环作为5-氨基水杨酸结肠给药载体可行性考察

利用荧光光谱法考察了七元瓜环(Q[7])和5-氨基水杨酸(5-ASA)在不同pH条件下的相互作用. 在pH＝2.0, 4.0时, Q[7]与5-ASA可形成1∶1(物质的量比)的包合物; 而在pH＝5.0, 6.0, 7.4 时未观察到两者之间有明显的相互作用. 利用¹H NMR 技术研究了Q[7]-5-ASA固体包合物不同pH值的存在形式. 当体系的pH＜6.0, 5-ASA以包合物的形式存在. 而当pH＞6.0, 包合物的稳定性下降, 5-ASA被释放出来以游离的药物分子形式存在, 说明5-ASA与Q[7]之间的相互作用依赖于体系的pH值, Q[7]可作为5-ASA结肠给药的一种潜在载体; 热动力学的研究表明包合作用主要受到体系焓变的影响; 红外光谱, DSC和TG的分析进一步证实了Q[7]-5-ASA固体包合物的形成.     

4-氧代-3（4H）-喹唑啉-5-羧酸的合成

以2-氨基-6-甲基苯甲酸为起始原料,通过合环反应生成两种4-氧代-3(4H)-喹唑啉-5-羧酸衍生物(1a, 1b), 1a, 1b分别经高锰酸钾氧化合成了4-氧代-3(4H)-喹唑啉-5-羧酸（2a, 2b）,其结构经¹H NMR, ¹³C NMR和MS表征。研究了投料比｛r［n(高锰酸钾) :n(5-甲基-3(4H)-喹唑啉-4-酮)］｝和反应温度等对收率的影响。结果表明：在最佳反应条件（r=7:1,中性高锰酸钾氧化,于90 ℃反应）下合成2总收率可达66%。     

Modelling the thermal behaviour of carboxylic acid derivatives with cylcodextrins in the solid-state

The application of classical QSAR and molecular modelling to the inclusion complexation of natural and modified cyclodextrins (CDs) with carboxylic acid derivatives as guest molecules was examined. Information was available on the thermal behaviour, in the solid-state of benzoic acid (BA), salicylic acid (SA), and various substituted aminosalicylic acids (3-aminosalicylic acid, 3-ASA, 4-aminosalicylic acid, 4-ASA and 5-aminosalicylic acid, 5-ASA), as well as on the thermal behaviour of 1:1 molar ratio physical and kneaded mixtures of these acids with each of three different cyclodextrins, β-, (BCD) 2-hydroxypropyl-β-, (HPBCD) and γ-cyclodextrin (GCD). The thermal behaviour of the binary (1:1 stoichiometry) mixtures was modelled using stepwise multiple regression (SMR). Two models for the prediction of the percentage mass loss and enthalpy of dehydration of the physical mixtures were established with correlation coefficients (r) of 0.79 and 0.92, respectively. Decreased correlation in the thermal behaviour of kneaded mixtures indicated significant interaction and possible formation of inclusion complexes. This revised version was published online in July 2006 with corrections to the Cover Date.     

新型杯[4]芳烃酰肼基羰基羧酸衍生物的合成

杯[4]芳烃经醚化引入酯基后再经水合肼肼解,进一步与丁二酸酐或顺丁烯二酸酐氨解开环合成了两个新型的杯[4]芳烃酰肼基羰基羧酸衍生物,产率85％和83％,其结构经1H NMR,IR和ESI-MS表征.     

5,6-2H-1,2,4-三唑[3,4-b][1,3,4]噻二嗪衍生物的合成及抗癌活性测定

取代苯甲醛与4-氨基-5-(3,4,5-三甲氧基苯基)-1,2,4-三唑-3-硫酮(2)缩合生成5-(3,4,5-三甲氧基苯基)-4-取代苯基亚胺基-1,2,4-三唑-3-硫酮(3),再烷基加成化为新型5,6-2H-1,2,4-三唑[3,4-b][1,3,4]噻二嗪衍生物4.化合物结构经1HNMR 13C NMR,IR以及元素分析确认.采用噻唑兰(MTT)比色法进行化合物抑制人体前列腺癌细胞(PC3)体外活性测试,结果表明所合成的化合物具有不同程度的抑制PC3活性,其中化合物4a在10μmol·L-1浓度下对PC3的抑制率为75.9%.     

Synthesis of 4＂-benzyloxyimino-4＂-deoxyavermectin B 1 a derivatives

Six new 4＂-benzyloxyimino-4＂-deoxyavermectin B la derivatives were synthesized from avermectin Bla by the selective protection of C-5-hydroxy group, oxidation of C-4＂-hydroxy group, and deprotection followed by reaction with O-substituted hydroxylamine hydrochlorides. Their structures were confirmed by IR, 1H NMR, 13C NMR and MS. Insecticidal activities of the derivatives against Phopalosiphum pseudobrassicae, Spodoptera exigua and Pluteua xylosteua were evaluated.     

N-二异丙基磷酰化氨基酸-N-4-氨基吡啶衍生物的合成及对河豚毒素(TTX)解毒生物活性的研究

通过母体化合物4-氨基吡啶(4-AP)与N-二异丙基磷酰化氨基酸(DiPP-AA)在Ph3P和C2Cl6体系下的缩合反应,将具有生物活性的氨基吡啶环引入到磷酸化氨基酸结构中,设计、合成了5个N-二异丙基磷酰化氨基酸-N-4-氨基吡啶衍生物A1～A5.所有目标化合物均经IR,1H NMR,13C NMR,31P NMR,MS的表征.初步生物活性测试结果表明:目标化合物对河豚毒素(TTX)中毒的小鼠均有一定的解毒作用,并不同程度地延长了生存时间,而且毒性比母体化合物降低了.     

High-performance liquid-chromatographic determination of 5-aminosalicylic acid and its metabolites in blood plasma

Mesalazine (5-aminosalicylic acid, 5-ASA), an anti-inflammatory agent for the treatment of inflammatory bowel diseases, is metabolized in organism to the principal biotransformation product, N-acetyl-5-ASA. Some other phase II metabolites (N-formyl-5-ASA, N-butyryl-5-ASA, N-beta-d-glucopyranosyl-5-ASA) have also been described. 5-ASA is a polar compound and besides it exhibits amphoteric properties. The extraction of this compound from biomatrices and its chromatographic analysis is complicated. In order to improve the reliability of the determination of parent 5-ASA, a derivatization of 5-ASA together with 4-ASA (added to samples as a precursor of I.S.-2) was involved into the method. More lipophilic N-propionyl-5-ASA and N-propionyl-4-ASA (I.S.-2) were obtained using propionic anhydride. These derivatives were well extractable together with N-acyl-5-ASAs (metabolites) and N-acetyl-4-ASA (I.S.-1). As the first internal standard (I.S.-1) was used for the evaluation of extracted N-acyl-metabolites, the second internal standard (I.S.-2) served for the evaluation of both derivatization and extraction steps of parent drug 5-ASA. Based on these reasonings, new HPLC bioanalytical method for the determination of 5-ASA and its metabolites in blood plasma was developed and validated. The sample preparation step consists of the deproteination of plasma by HClO(4) and the above-mentioned derivatization of ASAs followed by liquid-liquid extraction of all N-acyl-ASA-derivatives. Chromatographic analyses were performed on a 250-4 mm column containing Purospher RP-18 e, 5 microm (Merck, Darmstadt, Germany) with a precolumn (4-4 mm). The column effluent was monitored using both UV photodiode-array (lambda = 313 nm) and fluorescence detectors (lambda(exc.) = 300 nm/lambda(emiss.) = 406 nm) in tandem. The identity of individual N-acyl-ASAs in the extracts from biomatrices was verified by characteristic UV-spectra and by HPLC/MS experiments. The whole analysis lasted 23 min at the flow rate of 1 ml min(-1). LLOQ (LOD) was estimated 126 (20) pmol ml(-1) of plasma for N-acetyl-5-ASA and 318 (50) pmol ml(-1) of plasma for N-propionyl-5-ASA. The validated HPLC method was applied to pharmacokinetic studies of mesalazine in humans and animals.     

新型查尔酮哌嗪衍生物的合成

以4-二甲氨基苯甲醛和2-溴-4′-氟苯乙酮为原料,经缩合和取代反应制得4-二甲氨基-4′-(1-哌嗪基)查尔酮(2); 2与卤代烃反应合成了6个新型的查尔酮哌嗪衍生物,收率71%~88%,其结构经¹H NMR,¹³C NMR和HR-MS表征。     

含三氟甲基均三唑衍生物的合成及结构表征

以3－三氟甲基－4－氨基－5－巯基－1,2,4－三唑为原料,在不同反应条件下与取代苯甲酸或芳醛缩合,得到15个含三氟甲基均三唑衍生物,利用元素分析,IR,^1H NMR和MS确定了这些化合物的组成与结构。     

含噻二唑官能基的对叔丁基硫桥杯[4]芳烃衍生物的合成及结构

以对叔丁基硫桥杯[4]芳烃(1)为原料, 在碳酸钾存在下与碘甲烷反应, 生成1,3-二取代桥杯[4]芳烃(2), 其分别与1,2-二溴乙烷, 1,3-二溴丙烷在碳酸钾的存在下进行烷基化反应, 生成硫桥杯[4]芳烃衍生物3和4. 在氢氧化钠存在下,其与过量的含不同官能团的2-巯基-1,3,4-噻二唑反应, 生成下缘含1,3,4-噻二唑基的硫桥杯[4]芳烃衍生物5a, 5b, 6a和6b, 并通过了¹H NMR, ¹³C NMR, IR, MS和元素分析的确证. 同时, X射线分析确定了硫桥杯[4]芳烃3和5a的晶体结构.     

含噻二唑基的对叔丁基杯[4]芳烃衍生物的合成及表征

以对叔丁基杯[4]芳烃(1)为原料, 分别与1,2-二溴乙烷、1,3-二溴丙烷在碳酸钾的存在下进行选择性烷基化反应, 生成杯[4]芳烃衍生物2和3. 在氢氧化钠存在下, 化合物2和3与过量的含不同官能团的2-巯基噻二唑反应, 生成下缘含噻二唑基的杯芳烃衍生物4a～4c, 5a～5c, 其结构经¹H NMR, ¹³C NMR, IR, MS和元素分析确证.     

Synthesis and characterization of tributyltin derivatives from 4‐oxo‐4‐(arylamino)butanoic acids and their in vitro biological activity against cervical cancer cell lines

Uterine (cervix and corpus) cancer is one of the major causes of mortality in women in Mexico. Organotin carboxylated derivatives have shown high cytotoxic activity against various cell lines of human origin. We describe the synthesis of three new tri‐n‐butyltin derivatives from 4‐oxo‐4‐(arylamino)butanoic acids; their structures were confirmed using spectral data (¹H NMR, ¹³C NMR, ¹¹⁹Sn NMR and infrared), elemental analyses, mass spectrometry and X‐ray diffraction. All the tri‐n‐butyltin carboxylates exhibit ¹ J (^119/117Sn–¹³C) coupling satellites in solution and lie in the range 357 to 339 Hz, suggesting a tetrahedral geometry around the tin atom. The polymeric structures of two of the derivatives and the monomeric structure of another were confirmed using X‐ray crystallography. Using succinic anhydride as raw material, five N‐substituted succinamic acid compounds were synthesized by the acylation reaction with aniline, 4‐nitroaniline, 4‐nitro‐3‐(trifluoromethyl)aniline, 2‐amino‐5‐nitrothiazole and 4‐aminoantipyrine. From these compounds, five tin derivatives were prepared and their in vitro anti‐proliferative effect on HeLa, CaSki and ViBo cell lines was screened. All of the compounds showed potency against all three strains and null or low cytotoxic activity (necrotic) as well. The most potent of our derivatives as an anti‐proliferative agent against the three cell lines was tributylstannyl 4‐oxo‐4‐[(3‐trifluoromethyl‐4‐nitrophen‐1‐yl)amino]butanoate, exhibiting an IC₅₀ value of 0.43 μM against the HeLa cell line. Copyright © 2014 John Wiley & Sons, Ltd.     

2-氨基-6-三氟甲基嘧啶衍生物的合成及表征

近几年,含嘧啶结构单元的高效低毒农药层出不穷,如用作杀菌剂的嘧啶胺类、嘧啶腺类及嘧啶丙烯酸酯类,除草剂有嘧啶磺酰脲类、嘧啶水杨酸类、酰基(硫)脲类及三唑并嘧啶磺酰脲类。将含氟基团引入杂环结构是新药创制的一个发展方向,     

新型含1,3,4-噻二唑的硫色满酮衍生物的合成及其抗真菌活性

以取代苯硫酚和顺丁烯二酸酐为原料,经迈克尔加成反应制得2-羧基-硫色满酮衍生物（2a~2d）; 2a~2d分别与氨基硫脲反应制得2-(5-氨基-1,3,4-噻二唑-2-基)硫色满-4-酮衍生物（3a~3d）; 3a~3d与酰氯经酰化反应合成了14个新型的含1,3,4-噻二唑的硫色满酮衍生物（5a~5n）,其结构经^1H NMR, ¹³C NMR和HR-ESI-MS表征。采用微量稀释法测定了5a~5n的抗真菌活性。结果表明：部分化合物对絮状表皮癣菌和总状毛霉菌有较好的抑制活性,优于阳性对照药氟康唑。     

2-(3-芳氧甲基-4-苯基-1,2,4-三唑-5-硫基)乙酸的微波合成及生物活性研究

在微波辐射条件下, 芳氧乙酰肼经两步反应制得4-苯基-3-芳氧甲基-1,2,4-三唑-5-硫酮衍生物, 再与氯乙酸反应得到6种尚未见文献报道的2-(3-芳氧甲基-4-苯基-1,2,4-三唑-5-硫基)乙酸衍生物. 目标化合物的结构经IR, ¹H NMR和元素分析进行了确证. 生物活性试验结果表明, 该类化合物对双子叶植物油菜具有良好的生物调节活性.     

A validated HPLC method with electrochemical detection for simultaneous assay of 5-aminosalicylic acid and its metabolite in human plasma

A high-performance liquid chromatographic method was developed, validated and applied to the simultaneous determination of 5-aminosalicylic acid (5-ASA) and its acetylated metabolite (acetyl-5-ASA) in human plasma. The method involves liquid-liquid extraction with methanol followed by isocratic reversed-phase chromatography on a Kromasil KR100 C(18) column with electrochemical detection. The recovery, selectivity, linearity, precision and accuracy of the method were evaluated from spiked human plasma samples. The effects of mobile phase composition, buffer concentration, mobile phase pH and concentration of organic modifiers on retention of 5-ASA, acetyl 5-ASA and internal standard were investigated. Limits' of detection were 5 ng/mL for 5-ASA and 10 ng/mL for acetyl-5-ASA, respectively. The method can be used for supporting therapeutical drug monitoring and pharmacokinetic studies.     

含长碳烷基核苷氢亚磷酸酯衍生物的合成与表征

通过将抗病毒药物核苷(3'-叠氮-2',3'-二脱氧胸苷AZT或2',3'-二脱氢-2',3'-二脱氧胸苷d4T)与三氯化磷反应, 然后在不同的醇解试剂作用下, 一锅法合成得到6个含长链烷基的核苷氢亚磷酸二酯衍生物, 并采用³¹P NMR, ¹H NMR, ¹³C NMR和ESI-MS对其结构进行了表征.     

Aminosalicylate-based biodegradable polymers: Syntheses and in vitro characterization of poly(anhydride-ester)s and poly(anhydride-amide)s

Poly(anhydride-ester)s and poly(anhydride-amide)s derived from both 4- and 5-aminosalicylate acids (4- and 5-ASA) were synthesized and characterized by physicochemical methods. Thermal and solubility characteristics directly correlated to the polymer backbone composition; polymers based on 5-ASA had greater solubilities in organic solvents than polymers based on 4-ASA, and the poly(anhydride-ester)s thermally decomposed at temperatures nearly 100 °C higher than the corresponding poly(anhydride-amide)s. The polymers were self-contained, controlled-release systems that combine the drug and controlled-release mechanism into the polymer backbone. The erosion and degradation characteristics of the polymers were measured in physiologically relevant media. All polymer matrices fully degraded in media buffered to pH 7.4, whereas in acidic media (pH 1.2), all polymer matrices maintained greater than 50% mass over a 90-day time period. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 3667–3679, 2003