法西多曲的合成

胡椒醛与丙二酸二乙酯经缩合、催化氢化、水解、Mannich反应并脱羧得胡椒丙烯酸，与氯化亚砜反应得酰氯后，再经与L-丙氨酸苄酯对甲苯磺酸盐缩合，与硫代乙酸加成、异丙醇重结晶制得法西多曲，总收率约为21％。     

法西多曲合成工艺的改进

目的:对法西多曲合成工艺改进.方法:以胡椒丙烯酸为原料,经加成、拆分、缩合反应以及结晶分离,制得法西多曲.结果:合成目标化合物,总收率39.2%.结论:该方法操作简单,收率较高.     

苹果酸阿莫曲坦的合成

对硝基氯苄经亚硫酸钠磺化、五氯化磷氯代、四氢吡咯取代、催化氢化、重氮化和还原制得4-(吡咯烷-1-基磺酰甲基)苯肼盐酸盐(7),与4-氯-1-羟基丁烷磺酸钠反应后,再经成腙、环合和甲基化"一锅法"制得阿莫曲坦粗品,经成富马酸盐纯化,再与苹果酸成盐制得苹果酸阿莫曲坦,总收率约6%(以对硝基氯苄计).     

洛美曲索的合成

1,1,3,3-四甲氧基丙烷经水解、溴化后与2,4.二氨基-6-羟基嘧啶反应生成吡啶并[2,3-d]嘧啶环衍牛物,经氨基保护、Heck反应、脱硅后与N-(4-碘代苯甲酰基)一L-谷氨酸二乙酯再经Heck反应、氢化和水解制得抗肿瘤药洛美曲索,总收率约15%.     

群多普利的合成

六氢邻苯二甲酸酐经醇解﹑拆分﹑还原﹑环合﹑胺解﹑醇解和氨解得（1S,trans）-2-羟甲基环己基酰胺（7）,再经Hofmann降解﹑氰甲基化反应﹑苯甲酰化﹑甲磺酰化﹑环合,水解得（2S,3aR,7aS）-八氢-1H-吲哚-2-羧酸盐酸盐（12）。12与侧链N-羧基酸酐（NCA）缩合制得抗高血压药群多普利,总收率为4.6%（以六氢邻苯二甲酸酐计）。     

浅谈抗高血压药

目前,治疗高血压病的药物主要有6大类,即利尿剂、β受体阻滞剂、钙拮抗剂、血管紧张素转换酶抑制剂(ACEI)、血管紧张素Ⅰ受体拮抗剂(AT Ⅰ RA)及α肾上腺素能阻滞剂。另外,我国也使用一些复方制剂及中药制剂。1 利尿药小剂量利尿药可减少脑血管意外和缺血性心脏病的发生率。为减轻副作用,WHO/ISH(1999)推荐使用小剂量利尿药(氢氯噻嗪≤12.5～25mg/日),尤其适用于老年收缩期高血压。对心功能不全者,可将利尿药和 ACE 抑制剂一起做为早期治疗药。利尿药还可抑制老年收缩期高血压心功能不全     

盐酸多沙唑嗪的合成工艺研究

以丙烯腈为起始原料，经六步反应制得抗高血压新药盐酸多沙唑嗪（Doxzosin.CH1.1)总收率为33．62％，反应原料易得，反应条件温和，后处理方便，适合工业化生产。     

双硬脂酸纳曲酮的合成

对吗啡受体拮抗剂纳曲酮生物降解分散系的深入研究表明 ,纳曲酮的长效缓释制剂可克服病人在长达数月乃至数年的阿片成瘾治疗过程中产生的不适应。纳曲酮的结构与吗啡极为相似 [1] ,目前初步研究所得剂型为固形植入剂 ,需手术皮下埋植。因而 ,需探索可注射用的植入剂 :小颗粒混悬液供皮下注射 ,或是酯类前药 ,以油溶液供皮下或肌肉注射。将纳曲酮结构的 3位和 1 4位分别连接乙酰基和琥珀酰基后 ,其在狗体内的活性和生物利用度均比未修饰的纳曲酮高出 60 % ,并达到了一定的缓释和控释效果[2 ,3] 。本文以纳曲酮盐酸盐 (3)为原料 ,合成了 3位和…     

Gedatolisib的合成工艺改进

目的研究gedatolisib的合成工艺。方法以三聚氯氰为起始原料,依次经取代、Suzuki偶联、异氰酸酯成脲、水解、缩合等5步反应得到目标化合物。结果与结论该合成路线总收率达43.6%(以三聚氯氰计),各步反应条件温和,操作简便,生产成本降低,为中试放大奠定基础。     

氟曲马唑的合成

邻氟苯甲酰氯与苯经付-克反应、与对溴氟苯发生格氏反应、甲磺酰氯磺酰化，最后与咪唑发生取代反应制得抗真菌药氟曲马唑，总收率59％。     

盐酸喹那普利的合成

以苯乙酮和乙醛酸为原料制得3-苯甲酰内烯酸乙酯,与L-丙氨酸苄酯对甲苯磺酸盐经加成、酮基还原制得N-[(IS)-乙氧羰基-3-苯基内基]-L-丙氨酸(5).5经三光气活化后,与1,2,3,4-四氢异喹啉-3-羧酸苄酯对甲苯磺酸盐缩合,最后脱苄制得抗高血压药盐酸喹那普利,总收率约22%.     

Bioavailability of repeated oral administration of MDL 100,240, a dual inhibitor of angiotensin-converting enzyme and neutral endopeptidase in healthy volunteers

Background: MDL 100,240 (pyrido[2,1-a] [2]benzazepine-4-carboxylic acid,7-[[2-(acetylthio)-1-oxo-3-phenylpropyl]amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo, [4S-[4α,7α(R^*),12bβ]]-) is a molecule possessing an inhibiting ability on both angiotensin converting enzyme (ACE) and neutral endopeptidase, the enzyme responsible for atrial natriuretic peptide (ANP) degradation. Such a dual mechanism of action presents a potential clinical interest for the treatment of hypertension and congestive heart failure. Objectives: To evaluate the bioavailability of MDL 100,240 and its accumulation over repeated oral administration, using ACE inhibition as a surrogate for plasma drug level and determining its profile after oral and i.v. administration. Methods: First, in an open, one-period, single-dose study, the ACE inhibition profile was characterised following a 12.5 mg MDL 100,240 i.v. infusion. Second, in a three-group, parallel, randomised, double-blind study, each group of four subjects received q.d., over 8 days, 2.5, 10 or 20 mg of MDL 100,240 orally. The ACE inhibition profile was determined on day 1 and day 8. Trough plasma ACE was measured on days 2, 3 and 4. The recovery of ACE activity was monitored up to 72 h after the last dose of MDL 100,240. Results: ACE inhibition profile was similar on day 1 and day 8, and trough inhibition remained unchanged after the 8 days of treatment with 10 mg or 20 mg. Following repeated 2.5-mg ingestion, trough inhibition increased from 33% to 44% after the eighth dose. The oral bioavailability of MDL 100,240 was estimated at 85%, not statistically different from 100%. The accumulation ratio at steady state was estimated at 112%. Expressing the accumulation ratio in terms of half-life, a t_1/2 of 0.31 days or 7.5 h was estimated. Conclusion: MDL 100,240 (oral solution) has a good bioavailability, as estimated by ACE inhibition, and no drug accumulation seems to occur over 8 days with the 10-mg and 20-mg doses, but a slight rise in the trough level is observed with the 2.5-mg dose. Received: 30 July 1999 / Accepted: 19 October 1999     

Studies of the antihypertensive effects of CL 242,817, a new angiotensin-I converting enzyme inhibitor [S−(R*, s*)]-1-[(3-acetylthio)-3-benzoyl-2-methyl propionyl-L-proline]

The antihypertensive activity of CL 242, 817 and captopril were evaluated in conscious, unrestrained aorta-coarcted hypertensive rats (AHR); spontaneously hypertensive rats (SHR); and in the two-kidney, one-clip, Goldblatt renal hypertensive beagle (RH2 dog). In AHR, equimolar oral doses of CL 242,817 (5 mg/kg) and captopril (3 mg/kg) had rapid onsets of action and relatively long durations of action. CL 242,817 was significantly more potent and longer-acting than captopril. In the SHR, CL 242,817 was effective in lowering blood pressure by oral, intravenous, or intraperitoneal routes of administration, although less effectively than in AHR. In RH2 dogs, pretreated with the diuretic quinethazone, CL 242,817 (20 mg/kg, p.o.) lowered blood pressure more effectively than an equimolar dose of captopril (12 mg/kg). In RH2 dogs sodium-depleted by furosemide pretreatment and maintained on a salt-free diet to raise plasma renin activity (PRA) levels, CL 242,817 (20 mg/kg, p.o) was more effective than an equimolar oral dose of captorpril (12 mg/kg) in lowering blood pressure. In RH2 dogs, repletion of body sodium (and reduction in PRA) by maintenance on a normal sodium diet for 14 days decreased the antihypertensive effect of CL 242,817 and abolished that of captopril. The data suggest that angiotensin converting enzyme inhibitors (ACEI) are more effective in models in which PRA is elevated and the hypertension appears to be renin-dependent. The RH₂ dog that is sodium-depleted by furosemide and mainted on a sodium-free diet appears to be a suitable model for evaluating the antihypertensive effects of ACEI.     

缬沙坦的合成

N-[(2’-氰基联苯-4-基)甲基]-L-缬氨酸甲酯,与正戊酰氯在甲苯中,以DMAP作催化剂、碳酸钠作缚酸剂进行酰化反应制得N-(1-氧代戊基)-N-[(2’-氰基联苯-4-基)甲基]-L-缬氨酸甲酯,再在相转移催化剂双三甲基硅烷化聚乙二醇400(4)作用下与叠氮钠反应成四唑后,经水解制得抗高血压药缬沙坦,总收率约75%。     

阿折地平的合成

目的：合成阿折地平。方法：以二苯基甲胺为原料,经加成、酯化、酸化、氨化、缩合等反应合成阿折地平。结果：经元素分析、Ms,IR,NMR等测试确定了化学结构,总收率21％。结论：本方法原料易得,便于工业化生产。     

盐酸贝那普利的合成

以L-苹果酸为手性源,经成酐活化、傅-克反应、常压氢化和酯化反应制得(S)-2-羟基-4-苯基丁酸乙酯(8),8经甲磺酰化活化后经与丙酸钾反应和水解制得构型反转的(R)-2-羟基4-苯基丁酸乙酯(3).3经磺酰化活化后与(3S)-3-氨基-2,3,4,5-四氢-2-氧代-1H-1-苯并氮(革)-1-乙酸叔丁酯(2)反应后水解、成盐制得盐酸贝那普利,总收率约32％.     

盐酸奈必洛尔的合成

6-氟-3，4-二氢-2H-1-苯并吡喃-2-甲醛与亚硫酸氢钠和氰化钠反应制得2-羟基-2-（6-氟-3，4-二氢-2H-1-苯并吡喃-2-基）乙腈，经硅胶柱色普分离，得到未见文献报道的顺式（3A）和反式（3B）非对映异构体。分别合成顺式，2-羟基-2-（6-氟-3，4-二氧-2H-1-苯并吡喃-2-基）乙醛（S）和反式-N-[2-羟基-2-（6-氟-3，4-二氢-2H-1-苯并吡喃-2-基）乙基]苄胺（8）。5和8经催化氢化及缩合、还原脱苄基、成盐后重结晶等步骤得到抗高血压药盐酸奈必洛尔。     

乌拉地尔的合成

以氰乙酸为原料,经与Ｎ,Ｎ＾’－二甲基脲环合、与３－氨基－１－丙醇缩合脱氨、二氯亚砚氯化和Ｎ－邻甲氧基苯基哌嗪取代共４步反应合成降压药乌拉地尔,总收率５１％。其中后３步反应条件均比文献有较大改进。