盐酸普拉格雷的合成工艺改进

以2-氧代-N-三苯甲基-2,4,5,6,7,7-a-六氢噻吩并[3,2-c]吡啶为原料,经酰化、脱保护反应制得2-乙酰氧基-5,6,7,7-a-四氢噻吩并[3,2-c]吡啶盐酸盐(4); 4与2-溴-2-(2-氟苯基) 1-环丙基乙酮缩合得2-[2-(乙酰氧基)-6,7-二氢噻吩并[3,2-c]吡啶-5(4H)-基]-1-环丙基-2-(2-氟苯基)乙酮(5); 5再经成盐反应得到盐酸普拉格雷,总收率75.0%,其结构经¹H NMR和MS（ESI）确证。     

新型噻吩并四氢吡啶芳酸醚类化合物的合成及其抗血小板聚集活性

运用生物电子等排及拼合设计原理,设计并合成了14个新型的噻吩并四氢吡啶芳酸醚类化合物(4a~4j和8a~8d),其结构经1H NMR,13C NMR和ESI-MS表征。采用Bron比浊法测定了4a~8d对腺苷二磷酸(ADP)和花生四烯酸(AA)诱导的血小板聚集抑制活性。结果表明:4-【3-{6,7-二氢噻吩并[3,2-c]吡啶-5(4H)-基}丙氧基】-苯甲酸对AA诱导的血小板聚集和4-【3-{6,7-二氢噻吩并[3,2-c]吡啶-5(4H)-基}丙氧基】-3,5-二甲氧基苯甲酸对ADP诱导的血小板聚集均显示出较强的抑制活性,其IC50分别为0.020 mmol·L-1和0.018 mmol·L-1。     

N-取代-2-{4,5,6,7-四氢噻吩并[3,2-c]吡啶-5-基}乙酰胺的合成及其抗血小板聚集活性

以4,5,6,7-四氢噻吩并[3,2-c]吡啶盐酸盐和2-氧代-2,4,5,6,7,7a-六氢噻吩并[3,2-c]吡啶盐酸盐为起始原料,合成了9个未见文献报道的ADP受体拮抗剂——N-取代-2-{4,5,6,7-四氢噻吩并[3,2-c]吡啶-5-基}乙酰胺(1a～1e,2a～2d),收率61.4%～80.3%,其结构经1H NMR和HR-MS表征。大鼠体内抗血小板聚集活性研究表明,1和2均有一定的抗血小板聚集作用,其中1d和2d的作用较强,抑制效率分别为50.0%和58.9%,且2d的抑制作用优于阳性对照药噻氯匹定。     

新型N-(2-氧代-2-苯基乙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶酯类衍生物的合成及其抗血小板聚集活性

以5-三苯甲基-5,6,7,7a-四氢噻吩[3,2-c]吡啶-2(4H) 酮为起始原料，依次经酯化、脱保护和亲核取代反应合成了17个新型的N-(2-氧代-2-苯基乙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶酯(1a~1q)；并以2-溴-1-环丙基-2-(2-氟苯基)乙酮合成了新的普拉格雷衍生物(6)，其结构均经¹H NMR和MS(ESI)表征。并通过“ADP对大鼠血小板聚集的影响”的药效学模型初步评价了其抗血小板聚集活性。结果表明：1f， 1p， 1q和6对血小板聚集有一定的抑制作用，其中6在低剂量(3 mg·kg^-1)下的活性优于阳性对照药氯吡格雷。     

氯吡格雷类似物的合成及其抗血小板聚集活性

α-溴代邻氯苯乙酸经酯化反应后再与4,5,6,7-四氢噻吩并[3,2-c]吡啶发生取代反应合成氯吡格雷类似物(4b～4e);2-(2-氯苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5-基)乙酸(4a)经酯化反应合成4f～4k;4f与AgNO3反应制得4l;4a经酰胺化制得另外两个氯吡格雷类似物(5c和5m).4和5的其结构经1H NMR,IR和MS表征.初步生物活性测试结果表明:4和5均有一定的抗血小板聚集作用,其中4g和4b尤其突出,对大鼠血小板聚集的抑制百分率分别为46.1%和38.2%.     

1,7-双(N-取代氨基甲基)-2,8-二羟基-朝格尔碱的合成及其催化的Aldol-Ullmann反应（英文）

合成了新型1,7-双(N-取代氨基甲基)-2,8-二羟基-朝格尔碱(4),以4为催化剂催化了4-羟基香豆素和2-亚苄基丙二腈[或甲基(乙基)-2-氰基-3-苯基丙烯酸]的Aldol反应,获得了一系列化合物8;以4为配体与钯联合催化了串联Aldol-Ullmann反应,得到了化合物10和12.测试了所有化合物对人三阳性乳腺癌细胞(MCF-7)、人三阴性乳腺癌细胞(MDA-MB-231)、人肝癌细胞(HepG2)和人肝癌细胞(MHCC-97H)的抗癌活性以及对人肝细胞(LO2)的细胞毒性.其中,1,7-双((甲基氨基)甲基)-6H,12H-5,11-甲二苯并[b,f][1,5]二氮芳辛-2,8-二醇(4b)对MCF-7(抑制率30%)、1,7-双((((1-苯乙基)氨基)甲基)-6H,12H-5,11-甲二苯并[b,f][1,5]二氮芳辛-2,8-二醇(4d)和1,7-双(((吡啶-2-基甲基)氨基)甲基)-6H,12H-5,11-甲基二苯并[b,f][1,5]重氮-2,8-二醇(4e)对MDA-MB-231具有较高的选择性和抑制活性, 2-氨基-5-氧代-4-(3,4,5-三甲氧基苯基)-4H,5H-二氢吡喃并[3,2-c]亚甲基-3-腈(8q)对除MDA-MB-231外其他癌细胞均具有很强的抑制活性,而2-氨基-4-(4-溴苯基)-5-氧代-4H, 5H-吡喃并[3,2-c]亚甲基-3-腈(8a), 2-氨基-4-(2,4-二氯苯基)-5-氧代-4H,5H-二氢吡喃[3,2-c]亚甲基-3-腈(8e),2-氨基-4-(3-氟苯基)-5-氧代-4H,5H-吡喃[3,2-c]亚甲基-3-腈(8m)和2-氨基-4-(3-溴苯基)-5-氧代-4H,5H-二氢吡喃[3,2-c]亚甲基-3-腈(8n)对四种癌细胞均具有较高的抑制率,但所有的化合物对正常人细胞都具有细胞毒性,需要对其结构进行修饰.     

新型ADP受体拮抗剂的合成及其抗凝血活性

以5,6,7,7a-四氢噻吩并[3,2-c]吡啶-2(4H)酮盐酸盐为起始原料,设计并合成了10个新型的ADP受体拮抗剂———2-乙酰氧基-5-[2-氧代-2-(4-取代哌嗪-1-基)]乙基-4,5,6,7-四氢噻吩并[3,2-c]吡啶(4a~4j),收率51%~72%,其结构经1H NMR,IR和HR-MS表征。初步生物活性测试结果表明,4a~4j均具有一定的抗凝血活性,其中4g,4i和4j的活性明显优于阳性对照药噻氯匹定,对大鼠凝血时间增长率分别为43.5%,71.8%和58.0%。     

Synthesis of N-substituted-2-{ 4,5,6,7-tetrahydrothieno [ 3,2-c ] pyridine-5-yl } acetamides and Their Anti-platelet Aggregation Activities

以4,5,6,7-四氢噻吩并[3,2-c]毗啶盐酸盐和2-氧代-2,4,5,6,7,7a-六氢噻吩并[3,2-c]吡啶盐酸盐为起始原料,合成了9个未见文献报道的ADP受体拮抗剂——N-取代-2-14,5,6,7-四氢噻吩并[3,2-c]吡啶-5-基}乙酰胺(1a～1e,2a～2d),收率61.4％-80.3％,其结构经1H NMR和HR-MS表征.大鼠体内抗血小板聚集活性研究表明,1和2均有一定的抗血小板聚集作用,其中1d和2d的作用较强,抑制效率分别为50.0％和58.9％,且2d的抑制作用优于阳性对照药噻氯匹定.     

含噻吩并[3,2-c]吡啶α-氨基膦酸酯类衍生物的合成及生物活性的研究

以3-噻吩甲醛和氨基乙醛缩二甲醇为原料,经亲核加成、还原、取代、成环、甲酰化反应,得到2-醛基噻吩并[3,2-c]吡啶(4),然后与亚磷酸酯、芳香胺发生类Mannich反应得到一系列新型含有噻吩并[3,2-c]吡啶环的α-氨基膦酸酯类衍生物6a～6p.所有目标化合物的结构均经1H NMR,13C NMR,31P NMR,IR和MS确证.初步的生物活性测定试验表明,在50 ug/mL浓度下,大部分目标化合物对食管癌细胞(EC109)、人体肝癌细胞(HepG2)表现出较好的抑癌活性,其中化合物6k和6o对人体肝癌细胞的抑制率超过90%.     

新型4-芳氧基吡啶并[3′,2′∶4,5]噻吩并[3,2-d]嘧啶衍生物的合成

2-氯-3-氰基吡啶与巯基乙酸乙酯经闭环反应制得3-氨基吡啶并[3,′2′∶4,5]噻吩-2-甲酸乙酯(1);1与甲酰胺第二次成环生成吡啶并[3,′2′∶4,5]噻吩并[3,2-d]嘧啶-4-酮(2);2经氯化后与取代苯酚反应合成了12个新型的4-芳氧基吡啶并[3,′2′∶4,5]噻吩并[3,2-d]嘧啶衍生物,其结构经1H NMR,13C NMR,IR和元素分析表征。     

Preparation,molecular structures,and characteristic properties of (E)-1-(2-furyl)- and (E)-1-(2-thienyl)-2-(3-guaiazulenyl)ethylenes and (E)-1-(3-furyl)- and (E)-1-(3-thienyl)-2-(3-guaiazulenyl)ethylenes

Wittig reactions of 2-furaldehyde (20) [and thiophene-2-carbaldehyde (21)] with (3-guaiazulenylmethyl)triphenylphosphonium bromide (19) in ethanol containing NaOEt at 25 °C for 24 h under argon give (E)-1-(2-furyl)-2-(3-guaiazulenyl)ethylene (22E) and (E)-1-(2-thienyl)-2-(3-guaiazulenyl)ethylene (23E) in 53 and 36% yields. Similarly, Wittig reactions of 3-furaldehyde (29) [and thiophene-3-carbaldehyde (30)] with 19 under the same reaction conditions as for 20 and 21 afford (E)-1-(3-furyl)-2-(3-guaiazulenyl)ethylene (31E) and (E)-1-(3-thienyl)-2-(3-guaiazulenyl)ethylene (32E) in 32 and 46% yields. Molecular structures and characteristic properties as well as preparation of the title E (i.e., one of the geometrical isomers) forms, with a view to comparative study, are reported. Moreover, reactions of those conjugated π-electron systems with TCNE (=tetracyanoethylene) in benzene [and in DMF (=N,N-dimethylformamide)] at 25 °C for 24 h under argon yield unique products, possessing interesting molecular structures, respectively, whose characteristic properties and crystal structures are documented, also.     

苯乙烯基氮氧杂芳烃间的交叉光二聚反应

用中压汞灯(λ > 300 nm)照射4-苯乙烯基吡啶、2-苯乙烯基苯并噁唑和5-苯基-2-苯乙烯基噁唑三种杂芳基乙烯单体中任意两种的硫酸水溶液，得到三种交叉二聚体.用高效液相色谱跟踪研究了交叉光二聚反应，发现每组反应生成三种光二聚体，其中二种为单体自身的光二聚体，而另外一种是两种不同单体的交叉光二聚体.交叉二聚体通过柱色谱分离得到，其顺式头对尾结构经紫外、红外、氢谱、碳谱和元素分析确定.用紫外光谱和高效液相色谱跟踪研究了交叉光二聚体的稀溶液在低压汞灯（λmax=254 nm）照射下的光解反应.研究发现交叉二聚体能够彻底发生光解，首先生成原来的反式单体，所生成的反式单体容易发生异构化而生成顺式单体，最终建立起反顺异构化平衡.     

First row transition metal complexes of (E)-2-(2-(2-hydroxybenzylidene) hydrazinyl)-2-oxo-N-phenylacetamide complexes

Manganese(II), iron(II), cobalt(II), nickel(II), copper(II), and chromium(III) complexes of (E)-2-(2-(2-hydroxybenzylidene)hydrazinyl)-2-oxo-N-phenylacetamide were synthesized and characterized by elemental and thermal (TG and DTA) analyses, IR, UV-vis and (1)H NMR spectra as well as magnetic moment. Mononuclear complexes are obtained with 1:1 molar ratio except [Mn(HOS)(2)(H(2)O)(2)] and [Co(OS)(2)](H(2)O)(2) complexes which are obtained with 1:2 molar ratios. The IR spectra of ligand and metal complexes reveal various modes of chelation. The ligand behaves as a monobasic bidentate one and coordination occurs via the enolic oxygen atom and azomethine nitrogen atom. The ligand behaves also as a monobasic tridentate one and coordination occurs through the carbonyl oxygen atom, azomethine nitrogen atom and the hydroxyl oxygen. Moreover, the ligand behaves as a dibasic tridentate and coordination occurs via the enolic oxygen, azomethine nitrogen and the hydroxyl oxygen atoms. The electronic spectra and magnetic moment measurements reveal that all complexes possess octahedral geometry except the copper complexes possesses a square planar geometry. From the modeling studies, the bond length, bond angle, HOMO, LUMO and dipole moment had been calculated to confirm the geometry of the ligands and their investigated complexes. The thermal studies showed the type of water molecules involved in metal complexes as well as the thermal decomposition of some metal complexes. The protonation constant of the ligand and the stability constant of metal complexes were determined pH-metrically in 50% (v/v) dioxane-water mixture at 298 K and found to be consistent with Irving-Williams order. Moreover, the minimal inhibitory concentration (MIC) of these compounds against Staphylococcus aureus, Escherechia coli and Candida albicans were determined.