2-氧代-5,6,7,7a-四氢噻吩并[3,2-c]吡啶的合成

N-乙氧羰基-4-哌啶酮经Vilsmerier氯化甲酰化反应、在碳酸钾作用下与巯基乙酸乙酯环合制得6,7-二氧-4H-噻吩并[3,2-c]吡啶-2,5-二羧酸二乙酯(4),再经肼解、叠氮化、重排及脱保护反应制得2-氨基-6,7-二氢-4H-噻吩并[3,2-c]吡啶-5-羧酸乙酯盐酸盐(8),8经重氮化、水解后再由氢氧化钾碱解、成盐,制得普拉格雷的关键中间体2-氧代-5,6,7,7a-四氢噻吩并[3,2-c]毗啶,总收率约25％.     

6,7-二氢-5H-环戊烯并[b]吡啶的合成

己二酸二乙酯经缩合、氨化、闭环、水解后脱羧、氯化及脱氯等6步反应制得头孢匹罗的中间体6，7-二氢-5H-环戊烯并[b]吡啶，总收率31％。     

硫酸头孢匹罗的合成

7-氨基头孢霉烷酸（7-ACA）和2，3-环戊烯并吡啶在三甲基碘硅烷催化下进行3-位取代反应，得到1-[[（6R，7R）-7-氨基-2-羧基-8-氧代-5-硫杂-1-氮杂二环[4．2．0]辛-2-烯-3-基]甲基]-6，7-二氢-5H-环戊烷并[b]吡啶内鲻盐（7-ACP）二氢碘酸盐，转化为盐酸盐后与苯并噻唑硫醇活性酯（MAEM）在三乙胺催化下缩合得到头孢匹罗，最后用硫酸成盐得到硫酸头孢匹罗，总收率约57％。     

10,11-二氢-5H-二苯并[b,f]氮杂的合成

以邻硝基甲苯为起始原料 ,经缩合、加氢还原、磷酸成盐得 2 ,2′-二氨基联苄二磷酸盐 ,再经环合制得 10 ,11-二氢 - 5 H -二苯并 [b,f]氮杂。总收率 6 3.5 %。     

莫西沙星的合成

1-环丙基-6,7,8-三氟-1,4-二氢-4-氧代-3-喹啉羧酸乙酯(5)经水解、缩合和甲氧基化制得抗菌剂莫西沙星,总收率为71.5%(以5计).缩合剂(S,S)-八氢-6H-吡咯并[3,4-b]吡啶可由8-苄基-八氢-6H-吡咯并[3,4-b]吡啶经D-(-)-酒石酸拆分和氢解脱苄制得.     

茚并吡啶类衍生物诱导HEp-2细胞凋亡

目的:探讨1-甲基-5-(4-二甲氨基苄烯)-5H-茚[1,2b]吡啶三氟甲磺酸盐(受试物)对人喉表皮样肿瘤细胞HEp-2的增殖抑制和凋亡诱导作用。方法:采用MTT法观察受试物对HEp-2增殖的抑制作用,Hoechst 33258荧光染色观察HEp-2细胞凋亡形态学变化,流式细胞仪PI单染法检测细胞周期及凋亡率,采用Western Blot分析检测促凋亡蛋白Bid的表达。结果:1-甲基-5-(4-二甲氨基苄烯)-5H-茚[1,2b]吡啶三氟甲磺酸盐可抑制HEp-2细胞的增殖,并呈时间和剂量依赖性;用受试物(4μmol.L-1)处理细胞(24和48 h),经Hoechst 33258荧光染色,可见细胞凋亡形态学改变;流式细胞仪检测显示,HEp-2细胞周期发生改变,凋亡率增加;Western Blot分析结果显示,受试物可使促凋亡蛋白Bid表达水平上升。结论:1-甲基-5-(4-二甲氨基苄烯)-5H-茚[1,2b]吡啶三氟甲磺酸盐可抑制HEp-2细胞增殖,诱导其凋亡。     

新型强心剂2-吡啶-6,7-二氢-3H,5H-吡咯[2-3-f]苯并咪唑-6-酮

近年来在强心药领域中重视非甾体、非儿茶酚胺类强心剂的寻找,但至今尚无口服有效的慢性充血性心衰的治疗药物。作者设计并合成了2-吡啶-6,7-二氢-3H,5H-吡咯[2,3-f]苯并咪唑-6-酮系列化合物共24只,其中R_(1,2,3,4)主要为氢、烷基等,X为亚甲基、乙烯基等。     

(R)-3-氨基-2,3,4,5-四氢-1H-[1]-2-氧代苯并氮杂(艹卓)的合成

3,4-二氢-2H-萘-1-酮与盐酸羟胺反应后,在PPA中经Beckmann重排、碘代得到3-碘代-2,3,4,5-四氢-1H-[1]-2-氧代苯并氮杂(5),5经氨解、D-焦谷氨酸拆分、浓氨水处理后催化氢化还原,得到(R)-3-氨基-2,3,4,5-四氢-1H[1]-2-氧代苯并氮杂(艹卓),总收率约44%,纯度98%,ee值99.5%.     

2-氨基-6-氯吡啶的制备

2-氨基-6-氯吡啶（1）是常用医药中间体，合成方法主要有以下几种：（1）2-氯吡啶-N-氧化物与4-氯-2,2-二甲基-2H-1，3-苯并噫嗪反应制得，但原料不易得；（2）2-氯吡啶在铜粉催化下与氨水反应制得2-氨基吡啶，再经氯代制得，但反应须高温高压，操作困难；（3）2-肼基-6-氯吡啶（3）在雷尼镍催化下，用100％水合肼还原制得，收率81%，高纯度水合肼不易得，易爆炸，且毒性大，     

富马酸卢帕他定的合成

氯雷他定经碱性水解、与5-甲基烟酸缩合得8-氯-6，11-二氢-11-[1-（5-甲基烟酰基）-4-哌啶亚基]-5H-苯并[5，6]环庚烷并[1，2-b]吡啶，再经POCl，／NaBH。还原后成盐制得抗过敏药富马酸卢帕他定，总收率为28％。5．甲基烟酸可由3，5．二甲基吡啶氧化得到。     

Adenosine deaminase inhibitors. Synthesis and biological evaluation of (+/-)-3,6,7,8-tetrahydro-3-[(2-hydroxyethoxy)methyl]imidazo[4,5-d] [1,3]diazepin-8-ol and some selected C-5 homologues of pentostatin

The synthesis of several analogues of (8R)-3-(2-deoxy-beta-D-erythro- pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol (pentostatin, 1a) is described. Ring closure of 2-amino-1-(5-amino-1H-imidazol-4-yl)ethanone dihydrochloride (3) with triethyl orthoacetate or triethyl orthopropionate gave the C-5 methyl and ethyl ketoaglycons, 6,7-dihydro-5-methylimidazo[4,5-d][1,3]diazepin-8(3H)-one (4b) and 5-ethyl-6,7-dihydroimidazo[4,5-d][1,3]diazepin-8(3H)-one (4c), respectively. Stannic chloride catalyzed condensation of the pertrimethylsilyl derivatives of 4b and 4c with a protected glycosyl halide afforded anomeric mixtures of ketonucleosides 3-(2-deoxy-3,5-di-O-p-toluoyl-beta- and -alpha-D-erythro-pentofuranosyl)-6,7-dihydro-5-methylimidazo[4,5-d] [1,3]diazepin-8(3H)-one (5b and 6b) and 3-(2-deoxy-3,5-di-O-p-toluoyl)-beta- and -alpha-D-erythro-pentofuranosyl)-5-ethyl-6,7-dihydroimidazo[4,5-d]- [1,3]diazepin-8(3H)-one (5c and 6c), respectively. Subsequent separation of the anomers, followed by deprotection and reduction of 5b, 6b, and 5c, afforded the respective 8R and 8S isomers. Stannic chloride catalyzed condensation of pertrimethylsilyl ketoaglycon 4a with 2-(chloromethoxy)-1-(p-toluoyloxy) ethane to give ketonucleoside 6,7-dihydro-3-[[2-(p-toluoyloxy)ethoxy] methyl]imidazo[4,5-d][1,3]diazepin-8(3H)-one (9a) was followed by deprotection to 6,7-dihydro-3[(2-hydroxyethoxy)methyl]imidazo[4,5-d][1,3] diazepin-8(3H)-one (9b) and then reduction to the racemic acyclic pentostatin analogue (+/-)-3,6,7,8-tetrahydro-3-[ (2-hydroxyethoxy)methyl]imidazo[4,5-d][1,3]diazepin-8-ol (2). Ki values for the in vitro adenosine deaminase (EC 3.5.4.4; type I; calf intestinal mucosa) inhibitory activities of 1b, 1c, and 2 were determined to be 1.6 X 10(-8), 1.5 X 10(-6), and 9.8 X 10(-8) M, respectively. When compounds 2 and 9b were tested in combination with vidarabine against herpes simplex virus, type 1, in an HEp-2 plaque reduction assay, only compound 2 was able to potentiate the antiviral activity of vidarabine.     

6,7-二氢-5H-环戊烷并[b]吡啶的合成

以“一勺烩”方法制备中间体O 烯丙基 环戊酮肟 ,无需分离纯化化合物O 烯丙基羟胺 ,热解反应以氧气代替空气 ,制得 6 ,7 二氢 5H 环戊烷并 [b]吡啶 ,反应总收率为 35 %。     

Synthesis of new N,N-disubstituted 4-amino-5,6-dihydro-3-phenyl-2H-thieno[2,3-h]-1-benzopyran-2-ones

The synthesis of some N,N-disubstituted 4-amino-5,6-dihydro-3-phenyl-2H-thieno[2,3-h]-1-benzopyran-2-ones (4a-f), by reaction of phenylchloroketene with a series of N,N-disubstituted (E)-5-aminomethylene-6,7-dihydrobenzo[b]thiophen-4(5)-ones, followed by dehydrochlorination in situ of the primary adducts with DBN, is described. A moderate local anaesthetic activity was observed in the title compounds, particularly in 4e.     

Synthesis and photobiological activity of new N,N-disubstituted 4-amino-3-chloroangelicins

The synthesis of a series of new N,N-disubstituted 4-amino-3-chloroangelicins (4-amino-3-chloro-2H-furo[2,3-h]-1-benzopyran-2-ones) starting from N,N-disubstituted (E)-5-aminomethylene-6,7-dihydrobenzo[b]furan-4(5H)-ones is described. Their capacity of inhibiting DNA synthesis in Ehrlich ascites tumor cells by U.V.-A light irradiation as well as their phototoxic activity on guinea-pig skin have been studied and the data computed by probit analysis; the results are discussed in the light of the modifications introduced in the molecular structure.     

5-氨基-8-甲氧基-喹诺酮类的合成及其体外抗菌作用

以1-环丙基-6，7-二氟-8-甲氧基-1，4-二氢-4-氧代喹啉-3-羧酸乙酯为起始原料依次经过硝化、还原和水解三步反应制得5-氨基-1-环丙基-6，7-二氟-8-甲氧基-1，4-二氢-4-氧代喹啉-3-羧酸，然后分别与2（R）-（-）／2（S）-（＋）或2（R，S）-甲基哌嗪缩合，得到3种目标化合物（5a、5b和5c）。测定它们对20株临床分离和标准革兰阴性菌和标准革兰阳性菌的最低抑菌浓度。结果表明，5a和5b的体外抗菌活性与外消旋体5c基本相当。     

3,7-Dideazapurine nucleosides. Synthesis and antitumor activity of 1-deazatubercidin and 2-chloro-2'-deoxy-3,7-dideazaadenosine

1-Deazatubercidin (5) has been synthesized by glycosylation of the anion of 4,6-dichloro-1H-pyrrolo[3,2-c]pyridine (9) with 1-chloro-2,3-O-isopropylidene-5-O-(tert-butyldimethylsilyl)-alpha-D-r ibofuranos e (12). The reaction gave a mixture of blocked nucleosides with beta- and alpha-configuration (13a and 13b). Deprotection of 13a provided 4,6-dichloro-1-beta-D-ribofuranosylpyrrolo[3,2-c]pyridine (14), which on treatment with hydrazine, followed by reduction of the resulting 4-hydrazino compound with Raney nickel, gave 4-amino-6-chloro-1-beta-D-ribofuranosylpyrrolo[3,2-c]pyridine (15), 1-deazatubercidin, and a small quantity of 4,6-diamino-1-beta-D-ribofuranosylpyrrolo[3,2-c]pyridine (16). Dehalogenation of 15 provided another route to 5. 2-Chloro-2'-deoxy-3,7-dideazaadenosine (6) together with 2'-deoxy-3,7-dideazaadenosine (18) was obtained by hydrazinolysis of 4,6-dichloro-1-(2-deoxy-beta-D-erythro-pentofuranosyl)pyrrolo- [3,2-c]pyridine (17), followed by reduction of the resulting 4-hydrazino compound. Nucleosides 5, 6, 15, and 18 are devoid of any significant antitumor activity in vitro. Compound 16 showed significant activity against P388 leukemia in cell culture.     

Fluorine-containing heterocycles: synthesis and some reactions of new 3-amino-2-functionalized-6-(2'-thienyl)-4-trifluoromethylthieno [2,3-b]pyridines

3-Cyano-6-(2'-thienyl)-4-trifluoromethylpyridine-2(1H)-thione (2) was prepared and reacted with chloroacetone or phenacyl bromide to yield the 2-acetyl or benzoyl-3-amino-6-(2'-thienyl)-4-trifluoromethylthieno[2,3-b]pyridines (3a, b). In contrast, the reaction of 2 with chloroacetamide or its N-aryl derivatives gave the corresponding 2-carbamoylmethyl thiopyridines 4a-c. Upon treatment of these educts with K2CO3 or C2H5ONa in ethanol, they underwent intramolecular Thorpe-Ziegler cyclization to afford 3-amino-2-carbamoyl-6-(2'-thienyl)-4-trifluoromethyl-thieno[2,3-b]pyridine (5a) and its N-aryl analogs 5b, c. Compounds 5a-c underwent some reactions to yield new pyrido[3',2':4,5]thieno[3,2-d]pyrimidines and pyrido[3',2':4,5]thieno[3,2-d][1,2,3] triazines.     

Recent developments in the synthesis of acetylcholinesterase inhibitors

The acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities of a series of pyrano[2,3-b]quinolines (2, 3), [1,8]naphthyridines (5, 6), 4-amino-2,3-diaryl-5,6,7,8-tetrahydrofuro[2,3-b]quinolines (11-13)/ 4-amino-6,7,8,9-tetrahydro-2,3-diphenyl-5H-cyclohepta[e]furo[2,3-b]pyridine (14), 4-amino-5,6,7,8-tetrahydro-2,3-diphenylthieno[2,3-b]quinoline (15)/ 4-amino-6,7,8,9-tetrahydro-2,3-diphenyl-5H-cyclohepta[e]thieno[2,3-b]pyridine (16) are described. These compounds are tacrine analogues that have been prepared from readily available polyfunctionalized ethyl [6-amino-5-cyano-4H-pyran]-3-carboxylates (9, 10), ethyl [6-amino-5-cyanopyridine]-3-carboxylates (7, 8), 2-amino-3-cyano-4,5-diarylfurans (17-19) and 2-amino-3-cyano-4,5-diphenylthiophene (20) via Friedl?nder condensation with selected ketones. These compounds are competitive and, in a few cases, non-competitive inhibitors for AChE, the most potent being compound (14), though three-fold less active than tacrine. The BuChE inhibitory activity is only significant in compounds 11 and 14, ten-fold less active than tacrine. Furthermore, the products 12 and 13 are selective and moderate AChE inhibitors.     

Antiulcer agents. 3. Structure-activity-toxicity relationships of substituted imidazo[1,2-a]pyridines and a related imidazo[1,2-a]pyrazine

Investigation of the interrelationship between structure, antiulcer activity, and toxicology screening data derived from a series of compounds selected from structure-activity studies directed toward identifying a successor to 3-(cyanomethyl)-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine, Sch 28080 (1), has identified 3-(cyanomethyl)-2,7-dimethyl-8-(phenylmethoxy)imidazo[1,2 -a]pyridine (5), 3-amino-2-methyl-8-(2-phenylethyl)imidazo[1,2-a]pyridine (6), and 3-amino-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyrazine (7). These analogues exhibit a combination of antisecretory and cytoprotective activity in animal models, while eliminating the adverse effects of the prototype 1. One of these, 3-amino-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyrazine, Sch 32651 (7), has a profile meeting all criteria.