CN101024643A - 咪唑-5-羧酸类衍生物、制备方法及其应用 - Google Patents
咪唑-5-羧酸类衍生物、制备方法及其应用 Download PDFInfo
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- CN101024643A CN101024643A CNA2006100239910A CN200610023991A CN101024643A CN 101024643 A CN101024643 A CN 101024643A CN A2006100239910 A CNA2006100239910 A CN A2006100239910A CN 200610023991 A CN200610023991 A CN 200610023991A CN 101024643 A CN101024643 A CN 101024643A
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- Prior art keywords
- butyl
- methyl
- imidazole
- chloro
- xenyl
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Abstract
本发明公开了一种如通式(I)所述结构的咪唑-5-羧酸类衍生物以及它们的制备方法,其中各基团如说明书所示。本发明所述衍生物是血管紧张素II受体拮抗剂,具有强有力的血管紧张素II拮抗活性和抗高血压活性,从而可用作治疗高血压的治疗剂。
Description
技术领域
本发明涉及咪唑-5-羧酸类衍生物及其制备方法,以及这类衍生物作为抗高血压药物的应用。
发明背景
血管紧张素II是肾素-血管紧张素-醛固酮***(RAAS)的主要血管收缩激素,它在多种慢性疾病的病理生理学中起着重要的作用。它存在于多种组织中,其生成的途径主要为:血管紧张素原经肾素作用可转化为十肽的血管紧张素I(Ang I),Ang I仅有微弱的收缩血管的作用,可进一步在血管紧张素转化酶的作用下转化为八肽的血管紧张素II(Ang II),它是肾素-血管紧张素-醛固酮***(RAS)的最终生理活性物质,可与特异性的血管紧张素II(AT II)受体结合而产生血管紧缩,血压升高等生理作用。
EP0253310公开了一系列咪唑衍生物,美国杜邦公司经研究发现代号为DUP753的化合物有很好的降血压作用,并于1994年获得上市批准,成为了第一个非肽类的AngII受体拮抗剂,即氯沙坦钾,它通过选择性地阻断血管平滑肌的血管紧张素II对其I型受体的作用而抑制血管收缩,从而达到舒张血管、降低血压的作用。
随着氯沙坦钾的开发上市,各类医药研发机构和公司陆续开展了Ang II受体拮抗剂的结构学研究。US5196444公开了一系列苯并咪唑衍生物以及它们的制备方法,这类衍生物具有血管紧张素II拮抗活性和抗高血压活性,从而可用作治疗高血压。其中的坎地沙坦酯由日本武田公司于1997年开发上市,它在体内脱除酯基,水解为其活性代谢物,发挥降血压作用。
US5616599公开了与氯沙坦结构类似的一系列1-联苯甲基咪唑衍生物,结构上的最大变化就是将氯沙坦咪唑环上4位的氯原子改造为1-羟基-1-甲基乙基,5位改造为羧基、羟基以及前药结构酯或酰胺,证明具有良好的降血压作用,由此日本三共公司开发上市了奥美沙坦。
与后续上市的其他Ang II受体拮抗剂相比,氯沙坦耐受性好,副作用少,很少引起咳嗽或水肿。研究提示它还有降低血尿酸、TC、TG的作用,对高胰岛素血症患者的胰岛素敏感性、胰岛素分泌、糖耐量没有不良影响,是一种安全的抗高血压药物。然而,氯沙坦钾在体内只有14%被代谢成其活性代谢物EXP3174,尽管氯沙坦钾本身也有较强的降压性能,但仅为EXP3174降压性能的3%。EXP3174分子结构极性大,难以通过扩散等被动吸收形式穿过细胞膜,必需经过结构改造才能改善它的被动吸收。
美国专利US5298519公开了EXP3174的5位羧基酯化产物,着重研究了化合物HN-65021,并公开了口服HN-65021降低血压的试验结果,显示该化合物的降压活性类似于氯沙坦(British Journal of Clinical Pharmacology,40,1995,591-593)。表明将EXP3174分子中的咪唑环5位羧基改造成极性略小的基团,是氯沙坦结构改造的一个方向。有必要对EXP3174分子进行结构改造,获得具有更佳降压药理作用的活性化合物。
发明内容
本发明提供了一种式(I)化合物和其药学上可接受的盐或其溶剂化物,
其中,R选自直链或支链C1-C4烷基,或者R为:
或
或
或
或
其中,R1、R2、R3分别独立地选自氢、C1-C4直链或支链烷基、C3-C7环烷基。
在本发明一个优选的方案中,R选自直链或支链C1-C4烷基;优选乙基。
在本发明另一个优选的方案中,R为:
其中,R1选自氢、C1-C4直链或支链烷基、C3-C7环烷基。更优选C1-C4直链或支链烷基;最优选直链或支链丁基。
在本发明另一个优选的方案中,R为:
其中,R2选自氢、C1-C4直链或支链烷基、C3-C7环烷基;更优选C2-C4直链或支链烷基。
在本发明另一个优选的方案中,R为:
其中,R3选自氢、C1-C4直链或支链烷基、C3-C7环烷基;更优选C3-C4直链或支链烷基、C3-C7环烷基;具体地说,R3最优选为异丙基、叔丁基、环己基。
在本发明以上描述中,C1-C4直链或支链烷基是指甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基;优选甲基、乙基、丙基、异丙基、丁基或叔丁基。C3-C7环烷基是指环丙基、环丁基、环戊基、环己基、环庚基,优选环丁基、环戊基、环己基,更优选环己基。
在本发明中,具体优选的化合物为:
2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸乙酯;
2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,2-苯并[C]呋喃酮亚基酯;
2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,环2,3-碳酸酯;
2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,三甲基乙酰氧甲基酯;
2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,1-[(异丙氧基)羰酰基]乙氧基酯;
2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,1-[(叔丁氧基)羰酰基]乙氧基酯;
2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,1-[(环己氧基)羰酰基]乙氧基酯;
2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,1-[(异丙氧基)羰酰基]甲氧基酯;
2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,1-[(乙氧基)羰酰基]甲氧基酯;
2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,1-[(叔丁氧基)羰酰基]甲氧基酯。
本发明还提供了所述通式(I)化合物的制备方法,
当R选自C1-C4直链或支链烷基时,可以通过以下方法制备:
a、将氯沙坦钾在KMnO4条件下氧化为2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸
b、将上述氧化产物与三苯基氯甲烷反应,得到2-丁基-4-氯-1-[2`-(1-三苯甲基-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸
c、在上述b所得产物中加入有机醇和催化酸,回流反应,萃取浓缩后得到最终产物。
本发明所述其他化合物,可以通过以下方法制备:
a、将氯沙坦钾在KMnO4条件下氧化为2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸
b、将上述氧化产物与三苯基氯甲烷反应,得到2-丁基-4-氯-1-[2`-(1-三苯甲基-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸
c、在碳酸钾和N,N-二甲基乙酰胺(DME)体系条件下,将上述b所得产物与通式化合物X-R反应,得到酯化中间体。其中,X是指卤素,优选氟、氯、溴;R代表以下结构:
或
或
或
或
其中,R1、R2、R3分别独立地选自氢、C1-C4直链或支链烷基、C3-C7环烷基。
d、将c所得酯化中间体在酸催化条件下脱去三苯甲基,纯化得到最终产物。
利用本发明所得的化合物可给药于人,可以口服、直肠、肠胃外(静脉内、肌肉内或皮下)、局部给药(粉剂、软膏剂或滴剂)。所述化合物可以单独给药,或者与其他药学上可接受的化合物联合给药。需要指出,本发明的化合物可以混合给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、娇味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明中,术语“药学上可接受的盐”是指相对无毒的本发明化合物的无机酸加成盐或有机酸加成盐。这些盐可在化合物最后的分离和提纯过程中现场制备,或者是使纯化的化合物以其游离碱形式与适宜的有机或无机酸进行反应,再将形成的盐分离而制成。代表性盐包括氢溴酸盐、盐酸盐、硫酸盐、亚硫酸盐、乙酸盐、草酸盐、戊酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、苯甲酸盐、乳酸盐、磷酸盐、甲苯甲酸盐、柠檬酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、苯甲酸盐、甲磺酸盐、葡萄糖酸盐、乳糖酸盐和月桂基磺酸盐等。它们可包含基于碱金属和碱土金属的阳离子,如钠、锂、钾、钙、镁等,以及无毒胺、季胺和胺阳离子,包括但不限于:胺、四甲基胺、四乙基胺、甲胺、二甲胺、三甲胺、三乙胺、乙胺等。
本发明化合物通过动物实验证明具有降血压作用,可用于制备治疗高血压的药物。本发明化合物降血压的药效评价方法如下:
自发性雌性高血压大鼠(SHR),以***5mg/kg+盐酸氯氨酮50mg/kg腹腔注射麻醉后背位固定。将动脉导管从左侧股动脉***直至低位腹主动脉。然后进行插胃瘘管术;术后恢复20-30小时,将动脉导管经灌注三通管与压力换能器连接。每博血压信号经压力换能器转换为生物信号,由计算机实时记录每博收缩压,舒张压;SHR与计算机***连接稳定4-5小时后,记录一小时内血压和心动间期作为给药前正常对照。然后经胃瘘管给药,给药剂量为30mg/kg,给药容量为2ml/kg。给药后连续记录6小时血压,观察收缩压、舒张压的变化情况。
以下实施例用来说明本发明,但不用于限制本发明的范围。
实施例1
2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸
2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]-5-羟甲基咪唑4.57g中加10ml水溶解,冷却到-5-0℃,滴加1.58g KMnO4的130ml水溶液,滴毕,50℃反应16h。停止反应,过滤,滤液加1mol/L的NaS2O3 50ml,再用稀盐酸调节溶液pH为2-3,溶液变得浑浊,乙酸乙酯萃取后干燥,浓缩,过快速柱,以石油醚∶乙酸乙酯=1∶6为流动相,得到白色固体3.85g,收率89.1%。
1HNMR(CDC13):
δH 0.801(3H,t,J=3.6),25(2H,m,J=3.5),1.49(2H,m,J=5),2.56(2H,t,J=3.5),5.58(2H,s),6.94-7.08(4H,m,J=5),7.65-7.50(2H,m,J=8.5)
ESI(-):435.1
Mp:125.2-128.5℃
实施例2
2-丁基-4-氯-1-[2`-(1-三苯甲基-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸
在100ml单口瓶中,依次加入2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸4.36g,15ml N,N-二甲基甲酰胺,1.66g碳酸钾和2.78g三苯基氯甲烷,室温反应过夜,停止反应,加水100ml,用100ml乙酸乙酯萃取,再用饱和盐水洗涤一次,有机相干燥,浓缩后得到黄色油状物 2-丁基-4-氯-1-[2`-(1-三苯甲基-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸7.5g。
本实施例所得粗品不用纯化,作为以下实施例中所提及的原料。
实施例3
2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸乙酯
678.5mg原料中加入无水乙醇15ml和对甲苯磺酸(TsOH)312mg,回流6h.反应结束后,加水30ml,***30ml萃取,有机相干燥,浓缩后得到无色油状产物2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸乙酯274mg,收率59%。
1H-NMR(CDCl3)
δH(ppm):0.80-0.85(m,6H,J=13.6),1.26(m,2H,J=20.2),1.38(H,t,J=14.8),1.58(m,2H,J=7.5),2.69(q,2H,J=24.5),5.44(s,2H),6.94-7.50(8H),8.10(d,1H,J=6.14)
ESI(+)m/z:465.1
实施例4
(+/-)2-丁基-4-氯-1-[2`-(1 H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,2-苯并[C]呋喃酮亚基酯
678.5mg原料溶解在8ml N,N-二甲基乙酰胺(DME)中,依次加入碳酸钾0.172g和2-苯并[C]呋喃酮亚基溴263mg,40-45℃反应4h。反应结束后,加入30ml水,***25ml×2萃取两次,有机相干燥,浓缩后得到酯化中间体606.4mg,收率75%。将酯化中间体溶解于15ml二氧六环中,加入4N HCl 4ml,室温反应过夜,约16h。将反应液倒入水中,乙酸乙酯萃取,干燥浓缩后过快速柱,以乙酸乙酯∶石油醚(1∶2)为洗脱剂,得到(+/-)2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,2-苯并[C]呋喃酮亚基酯的纯品284.7mg,收率67%。
1H-NMR(DMSO-d6)
δH(ppm):0.88(t,3H,J=21.6),1.26(m,4H,J=29.6),1.58(m,2H,J=30.5),2.50(t,2H,J=15.5),5.34(s,2H),6.95-7.63(12H),8.06(d,2H,J=9.1)Ms(ESI+)m/z:569.5
Mp:120.6-124.6℃
实施例5
2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,环2,3-碳酸酯
616.4mg原料溶解在8ml N,N-二甲基乙酰胺(DME)中,依次加入碳酸钾0.169g和4-溴甲基-5-甲基-2,3-碳酸酯257mg,40-45℃反应4h。反应结束后,加入30ml水,***25ml×2萃取两次,有机相干燥,浓缩后得到酯化中间体596.8mg。将酯化中间体溶解于15ml二氧六环中,加入4N HCl 4ml,室温反应过夜,约16h。将反应液倒入水中,乙酸乙酯萃取,干燥浓缩后过快速柱,以乙酸乙酯∶石油醚(1∶2)为洗脱剂,得到无色油状物2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,环2,3-碳酸酯,收率44.2%。
1H-NMR(DMSO-d6)
δH(ppm):0.89(t,3H,J=17.5),1.27(m,2H,J=11.0),1.41(m,2H,J=9.9),1.58(t,2H,J=7.5),2.08(s,3H),2.60(t,2H,J=17.5),5.25(s,2H),6.86-7.04(8H),8.15(d,1H,J=6.64)
ESI(+)m/z:549.1
实施例6
2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,
三甲基乙酰氧甲基酯
407.1mg原料中加入N,N-二甲基乙酰胺(DME)5ml,0.124g碳酸钾,常温搅拌10min。再加入三甲基乙酰氧基氯甲烷0.18g,搅拌30min,升温至45-50℃,反应过夜约16h,TLC(石油醚∶乙酸乙酯=1∶1)监测反应进程。过滤除去不溶物,加入50ml水,有白色乳状物产生,50ml乙酸乙酯萃取,有机相用饱和盐水洗涤后,再干燥,浓缩,过快速柱得到0.273g中间产物。再加入二氧六环10ml,加入4mol/L的盐酸溶液5ml,室温反应16h。停止反应,加入碳酸氢钠水溶液调节反应液pH6-7,有混浊出现,乙酸乙酯萃取,有机相用饱和食盐水洗涤,再干燥,浓缩,得到0.242g油状物2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,三甲基乙酰氧甲基酯。
1HNMR:(CDCl3)
δH(ppm):0.89(s,12H),1.21(t,3H,J=16.9),1.32(m,2H,J=17.5),1.54(m,2H,j=8.1),4.15(s,2H),5.50(s,2H),6.82-7.43(8H),8.17(d,1H,J=6.8)
ESI(-)m/z:547.6
实施例7异丙氧基甲酸-1-氯乙酯
氯甲酸-1-氯乙酯1.43g中加入异丙醇0.66g,溶液置于冰水浴中冷至0℃,滴加吡啶0.84g的10ml***混合液,保温反应1h,室温再发应4h。停止反应,过滤。滤液用10%盐酸和水各洗涤一次,有机相干燥,快速浓缩得到淡黄色液体异丙氧基甲酸-1-氯乙酯,粗品1.461g,收率87.7%,产物不用纯化,直接用于下一步反应。
实施例8
2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,1-[(异丙氧基)羰酰基]乙氧基酯
于100ml单口瓶中依次加入原料0.678g,K2CO3 0.152g,N,N-二甲基乙酰胺5ml,室温搅拌20min,室温下加入异丙氧基甲酸-1-氯乙酯0.666g,45-50℃反应16h。反应结束后,过滤,滤液中加30ml水,用乙酸乙酯30ml萃取两次,有机相干燥,浓缩后得到油状物1.831g,不用纯化,直接用于下面反应。
再加入二氧六环10ml,加入4mol/L的盐酸溶液5ml,室温反应16h。停止反应,加入碳酸氢钠水溶液调节反应液pH6-7,有混浊出现,乙酸乙酯萃取,有机相用饱和盐水洗涤,再干燥,浓缩,得到2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,1-[(异丙氧基)羰酰基]乙氧基酯0.388g。
1HNMR:(CDCl3)
δH(ppm):0.86(t,3H,J=12.4),1.21(d,6H,J=22.8),1.32(m,2H,J=38.1),1.54(m,3H,J=15.7),1.63(m,2H,J=7.9),2.26(m,1H,J=16.2),4.15(q,1H),5.50(s,2H),6.82-7.64(8H),8.01(d,1H,J=7.7)
ESI(-)m/z::556.1
实施例9
2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,1-[(叔丁氧基)羰酰基]乙氧基酯
于100ml单口瓶中依次加入原料0.625g,K2CO3 0.146g,N,N-二甲基乙酰胺5ml,室温搅拌20min,室温下加入叔丁氧基甲酸-1-氯乙酯0.624g,45-50℃反应16h。反应结束后,过滤,滤液中加30ml水,用乙酸乙酯30ml萃取两次,有机相干燥,浓缩后得到油状物1.561g,不用纯化,直接用于下面反应。
再加入二氧六环10ml,加入4mol/L的盐酸溶液5ml,室温反应16h。停止反应,加入碳酸氢钠水溶液调节反应液pH6-7,有混浊出现,乙酸乙酯萃取,有机相用饱和盐水洗涤,再干燥,浓缩,得到2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,1-[(叔丁氧基)羰酰基]乙氧基酯0.358g。
1HNMR:(CDCl3)
δH(ppm):0.87(s,9H,J=14.7),1.21(t,3H,J=22.5),1.41(m,2H,J=39.7),1.59(q,2H,J=15.6),2.04(q,1H),2.66(4,2H,J=15.7),4.15(q,3H,J=21.3),5.50(s,2H),6.82-7.64(8H),8.06(d,1H,J=8.9)
ESI(-):551.3
Mp:60.5-62℃
实施例10
(+/-)2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,1-[(环己氧基)羰酰基]乙氧基酯
于100ml单口瓶中依次加入原料0.662g,K2CO3 0.161g,N,N-二甲基乙酰胺5ml,室温搅拌20min,室温下加入环己氧基甲酸-1-氯乙酯0.584g,45-50℃反应16h。反应结束后,过滤,滤液中加30ml水,用乙酸乙酯30ml萃取两次,有机相干燥,浓缩后得到油状物1.456g,不用纯化,直接用于下面反应。
再加入二氧六环10ml,加入4mol/L的盐酸溶液5ml,室温反应16h。停止反应,加入碳酸氢钠水溶液调节反应液pH6-7,有混浊出现,乙酸乙酯萃取,有机相用饱和盐水洗涤,再干燥,浓缩,得到2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,1-[(环己氧基)羰酰基]乙氧基酯0.412g。。
1HNMR:(CDCl3)
δH(ppm):0.87(t,3H,J=14.1),1.2-1.6(m,15H),1.73(m,2H,J=7.5),2.07(s,1H),2.69(t,2H,J=13.1),4.05(q,3H,J=22.0),5.54(s,2H),6.80-7.70(8H),8.08(d,1H,J=8.6)
ESI(-)m/z::605.7
实施例11异丙氧基甲酸氯甲酯
氯甲酸氯甲酯2.63g加入异丙醇1.32g,再加20ml***,冷至0℃,再加入吡啶1.659g的10ml***溶液,保温反应1h,再在室温下反应5h。停止反应,滤液用稀盐酸和水各洗涤一次,有机相干燥,浓缩后得到产物异丙氧基甲酸氯甲酯的粗品,不用纯化,直接用于下列反应。
实施例12
2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,1-[(异丙氧基)羰酰基]甲氧基酯
于100ml单口瓶中依次加入原料0.523g,K2CO3 0.124g,N,N-二甲基乙酰胺5ml,室温搅拌20min,室温下加入异丙氧基甲酸氯甲酯0.562g,45-50℃反应16h。反应结束后,过滤,滤液中加30ml水,用乙酸乙酯30ml萃取两次,有机相干燥,浓缩后得到油状物1.724g,不用纯化,直接用于下面反应。
再加入二氧六环10ml,加入4mol/L的盐酸溶液5ml,室温反应16h.停止反应,加入碳酸氢钠水溶液调节反应液pH6-7,有混浊出现,乙酸乙酯萃取,有机相用饱和盐水洗涤,再干燥,浓缩,得到2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,1-[(异丙氧基)羰酰基]甲氧基酯0.436g。
1HNMR:(CDCl3)
δH(ppm):0.89(t,3H,J=14.6),1.24(d,6H,J=6.3),1.37(m,2H,J=22.1),1.69(m,2H,J=30.5),2.64(t,2H,J=15.5),4.81(m,1H,J=12.4),5.54(s,2H),5.86(s,2H),6.95-7.64(8H),8.08(d,1H,J=7.42)
ESI(+)m/z::552.7
Mp:134.5-136℃
实施例13
2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,1-[(乙氧基)羰酰基]甲氧基酯
于100ml单口瓶中依次加入原料0.698g,K2CO3 0.162g,N,N-二甲基乙酰胺5ml,室温搅拌20min,室温下加入乙氧基甲酸氯甲酯0.702g,45-50℃反应16h。反应结束后,过滤,滤液中加30ml水,用乙酸乙酯30ml萃取两次,有机相干燥,浓缩后得到油状物1.854g,不用纯化,直接用于下面反应。
再加入二氧六环10ml,加入4mol/L的盐酸溶液5ml,室温反应16h.停止反应,加入碳酸氢钠水溶液调节反应液pH6-7,有混浊出现,乙酸乙酯萃取,有机相用饱和盐水洗涤,再干燥,浓缩,得到2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,1-[(乙氧基)羰酰基]甲氧基酯0.420g。
1HNMR:(CDCl3)
δH(ppm):0.92(t,3H,J=17.5),1.23(t,3H,J=14.0),1.37(m,2H,J=34.2),1.73(m,2H,J=30.8),2.69(t,2H,J=15.5),4.13(q,2H,J=15.7),5.58(s,2H),5.89(s,2H),6.99-7.61(8H),8.16(d,1H,J=6.1)
ESI(-):539.1
Mp:164.5-160℃
实施例14
2-丁基-4-氯-1-[2`-(1 H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,1-[(叔丁氧基)羰酰基]甲氧基酯
于100ml单口瓶中依次加入原料0.629g,K2CO3 0.141g,N,N-二甲基乙酰胺5ml,室温搅拌20min,室温下加入叔丁氧基甲酸氯甲酯0.625g,45-50℃反应16h。反应结束后,过滤,滤液中加30ml水,用乙酸乙酯30ml萃取两次,有机相干燥,浓缩后得到油状物1.732g,不用纯化,直接用于下面反应。
再加入二氧六环10ml,加入4mol/L的盐酸溶液5ml,室温反应16h。停止反应,加入碳酸氢钠水溶液调节反应液pH6-7,有混浊出现,乙酸乙酯萃取,有机相用饱和盐水洗涤,再干燥,浓缩,得到2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,1-[(叔丁氧基)羰酰基]甲氧基酯0.349g。
1HNMR:(CDCl3)
δH(ppm):0.92(t,3H,J=17.1),1.25(s,9H),1.37(m,2H,J=32.0),1.74(m,2H,J=29.3),2.69(t,2H,J=14.9),4.13(q,2H,J=15.5),5.58(s,2H),5.88(s,2H),6.95-7.60(8H),8.17(d,1H,J=6.20)
ESI(-):565.5
本发明实施例化合物经动物药效学评价,结果如下表:
化合物 | 给药前(mmHg) | 给药后(mmHg) |
化合物1 | 166/112 | 159/103 |
化合物2 | 167/123 | 155/105 |
化合物3 | 168/114 | 158/102 |
化合物4 | 166/110 | 159/102 |
化合物5 | 166/112 | 157/101 |
化合物6 | 169/117 | 159/103 |
化合物7 | 168/115 | 157/103 |
化合物8 | 167/114 | 156/101 |
化合物9 | 170/118 | 159/104 |
化合物10 | 168/113 | 158/103 |
Claims (19)
3、如权利要求2所述的化合物和其药学上可接受的盐或其溶剂化物,其中,R选自直链或支链C1-C4烷基。
6、如权利要求5所述的化合物和其药学上可接受的盐或其溶剂化物,其中,R2为C1-C4直链或支链烷基。
8、如权利要求7所述的化合物和其药学上可接受的盐或其溶剂化物,其中,R3选自氢、异丙基、叔丁基、环己基。
9、2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸乙酯。
10、2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,2-苯并[C]呋喃酮亚基酯。
11、2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,环2,3-碳酸酯。
12、2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,三甲基乙酰氧甲基酯。
13、2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,1-[(异丙氧基)羰酰基]乙氧基酯。
14、2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,1-[(叔丁氧基)羰酰基]乙氧基酯。
15、2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,1-[(环己氧基)羰酰基]乙氧基酯。
16、2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,1-[(异丙氧基)羰酰基]甲氧基酯。
17、2-丁基-4-氯-1-[2`-(1H基-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,1-[(乙氧基)羰酰基]甲氧基酯。
18、2-丁基-4-氯-1-[2`-(1H-四唑-5-基)1,1`-联苯基-甲基]咪唑-5-羧酸,1-[(叔丁氧基)羰酰基]甲氧基酯。
19、上述任一权利要求所述化合物在制备抗高血压药物中的应用。
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US (2) | USRE44873E1 (zh) |
EP (1) | EP1988090B1 (zh) |
JP (1) | JP5250760B2 (zh) |
KR (1) | KR101179110B1 (zh) |
CN (2) | CN101024643A (zh) |
AU (1) | AU2006338796B2 (zh) |
CA (1) | CA2643005C (zh) |
DK (1) | DK1988090T3 (zh) |
ES (1) | ES2424154T3 (zh) |
PL (1) | PL1988090T3 (zh) |
PT (1) | PT1988090E (zh) |
WO (1) | WO2007095789A1 (zh) |
Cited By (9)
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WO2009049495A1 (fr) | 2007-10-11 | 2009-04-23 | Shanghai Allist Pharmaceuticals, Inc. | Dérivé acide imidazol-5-carboxylique cristallin |
WO2009146608A1 (zh) * | 2008-06-05 | 2009-12-10 | 上海艾力斯医药科技有限公司 | 含有咪唑5-羧酸类衍生物的药用组合物,其制备方法及用途 |
CN102558064A (zh) * | 2012-01-29 | 2012-07-11 | 安润医药科技(苏州)有限公司 | 抗高血压化合物及其制备方法和应用,以及其在药学上可接受的盐和溶剂化物 |
CN103012377A (zh) * | 2011-09-27 | 2013-04-03 | 江苏艾力斯生物医药有限公司 | 一种咪唑-5-羧酸酯的重结晶方法 |
USRE44873E1 (en) | 2006-02-20 | 2014-04-29 | Salubris Asset Management Co., Ltd. | Imidazole-5-carboxylic acid derivatives, the preparation method therefor and the uses thereof |
CN103965171A (zh) * | 2014-04-30 | 2014-08-06 | 上海艾力斯医药科技有限公司 | 一种阿利沙坦酯的制备方法 |
CN104610232A (zh) * | 2013-11-01 | 2015-05-13 | 深圳信立泰药业股份有限公司 | 阿利沙坦酯无定形及其制备方法及含所述无定形的药物组合物 |
CN106188012A (zh) * | 2014-06-20 | 2016-12-07 | 深圳信立泰药业股份有限公司 | 一种阿利沙坦酯结晶及其制备方法及含有该结晶的药物组合物 |
US11026925B2 (en) | 2016-01-20 | 2021-06-08 | Shenzhen Salubris Pharmaceuticals Co. Ltd. | Angiotensin II receptor antagonist metabolite and NEP inhibitor composite and preparation method thereof |
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AU2006351517B8 (en) * | 2006-12-06 | 2012-01-19 | Shenzhen Salubris Pharmaceuticals Co., Ltd. | The salts of imidazol-5-carboxylic acid derivatives, preparation methods and use thereof |
CN101214242A (zh) | 2007-01-05 | 2008-07-09 | 上海艾力斯医药科技有限公司 | 新的药用组合物 |
CN101317842A (zh) * | 2007-06-07 | 2008-12-10 | 上海艾力斯医药科技有限公司 | 一种咪唑-5-羧酸衍生物的治疗用途 |
EP2291076A4 (en) * | 2008-05-15 | 2012-03-21 | Merck Sharp & Dohme | Angiotensin-II Receptor Antagonists |
JP5575783B2 (ja) * | 2008-12-12 | 2014-08-20 | ファーマコステック カンパニー リミテッド | トリフェニルメタン保護基の除去方法 |
KR101213467B1 (ko) * | 2010-04-30 | 2012-12-20 | 진양제약주식회사 | 로자탄 대사체 이엑스피-3174 이수화물의 신규한 제조 방법 |
CN105218527B (zh) * | 2015-10-10 | 2018-04-24 | 江苏宝众宝达药业有限公司 | 一种exp-3174的制备方法 |
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CA1334092C (en) * | 1986-07-11 | 1995-01-24 | David John Carini | Angiotensin ii receptor blocking imidazoles |
US5138069A (en) | 1986-07-11 | 1992-08-11 | E. I. Du Pont De Nemours And Company | Angiotensin II receptor blocking imidazoles |
US5196444A (en) | 1990-04-27 | 1993-03-23 | Takeda Chemical Industries, Ltd. | 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate and compositions and methods of pharmaceutical use thereof |
US5616599A (en) | 1991-02-21 | 1997-04-01 | Sankyo Company, Limited | Angiotensin II antagosist 1-biphenylmethylimidazole compounds and their therapeutic use |
AT398202B (de) * | 1991-10-04 | 1994-10-25 | Chem Pharm Forsch Gmbh | Neue imidazolderivate, verfahren zu ihrer herstellung und ihre verwendung |
ATE199548T1 (de) * | 1992-06-02 | 2001-03-15 | Sankyo Co | 4-carboxyimidazolderivate als angiotensin-ii- antagonisten und ihre therapeutische verwendung |
JPH083162A (ja) * | 1994-04-19 | 1996-01-09 | Tanabe Seiyaku Co Ltd | イミダゾピリジン誘導体及びその製法 |
JPH11507627A (ja) * | 1995-06-07 | 1999-07-06 | ジー.ディー.サール アンド カンパニー | 充血性心不全症を処置するためのエポキシ−ステロイド系アルドステロン拮抗物質とアンギオテンシンii拮抗物質との組合せ治療 |
AU2004260830B2 (en) | 2003-07-31 | 2010-04-29 | Nicox S.A. | Nitrooxy derivatives of losartan, valsatan, candesartan, telmisartan, eprosartan and olmesartan as angiotensin-II receptor blockers for the treatment of cardiovascular diseases |
JP2007504136A (ja) | 2003-08-28 | 2007-03-01 | ニトロメッド インコーポレーティッド | ニトロソ化およびニトロシル化利尿化合物、組成物、ならびに使用方法 |
JP5051897B2 (ja) | 2005-04-22 | 2012-10-17 | 第一三共株式会社 | 骨代謝性疾患の予防又は治療のための医薬 |
CN101024643A (zh) | 2006-02-20 | 2007-08-29 | 上海艾力斯医药科技有限公司 | 咪唑-5-羧酸类衍生物、制备方法及其应用 |
AU2006351517B8 (en) | 2006-12-06 | 2012-01-19 | Shenzhen Salubris Pharmaceuticals Co., Ltd. | The salts of imidazol-5-carboxylic acid derivatives, preparation methods and use thereof |
CN101214242A (zh) | 2007-01-05 | 2008-07-09 | 上海艾力斯医药科技有限公司 | 新的药用组合物 |
CN101317842A (zh) | 2007-06-07 | 2008-12-10 | 上海艾力斯医药科技有限公司 | 一种咪唑-5-羧酸衍生物的治疗用途 |
CN101407511B (zh) | 2007-10-11 | 2013-01-09 | 上海艾力斯生物医药有限公司 | 一种结晶型的咪唑-5-羧酸衍生物 |
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2006
- 2006-02-20 CN CNA2006100239910A patent/CN101024643A/zh active Pending
- 2006-07-31 US US13/727,587 patent/USRE44873E1/en active Active
- 2006-07-31 CN CNB2006800003978A patent/CN100506818C/zh active Active
- 2006-07-31 EP EP06775249.3A patent/EP1988090B1/en active Active
- 2006-07-31 WO PCT/CN2006/001914 patent/WO2007095789A1/zh active Application Filing
- 2006-07-31 PT PT67752493T patent/PT1988090E/pt unknown
- 2006-07-31 KR KR1020087022811A patent/KR101179110B1/ko active IP Right Grant
- 2006-07-31 JP JP2008555597A patent/JP5250760B2/ja active Active
- 2006-07-31 AU AU2006338796A patent/AU2006338796B2/en not_active Ceased
- 2006-07-31 US US11/576,094 patent/US7858651B2/en active Active
- 2006-07-31 CA CA2643005A patent/CA2643005C/en not_active Expired - Fee Related
- 2006-07-31 ES ES06775249T patent/ES2424154T3/es active Active
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Publication number | Priority date | Publication date | Assignee | Title |
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USRE44873E1 (en) | 2006-02-20 | 2014-04-29 | Salubris Asset Management Co., Ltd. | Imidazole-5-carboxylic acid derivatives, the preparation method therefor and the uses thereof |
CN101407511B (zh) * | 2007-10-11 | 2013-01-09 | 上海艾力斯生物医药有限公司 | 一种结晶型的咪唑-5-羧酸衍生物 |
WO2009049495A1 (fr) | 2007-10-11 | 2009-04-23 | Shanghai Allist Pharmaceuticals, Inc. | Dérivé acide imidazol-5-carboxylique cristallin |
US8178569B2 (en) | 2007-10-11 | 2012-05-15 | Shanghai Allist Pharmaceuticals, Inc. | Crystalline imidazole-5-carboxylic acid derivative |
WO2009146608A1 (zh) * | 2008-06-05 | 2009-12-10 | 上海艾力斯医药科技有限公司 | 含有咪唑5-羧酸类衍生物的药用组合物,其制备方法及用途 |
CN102088972B (zh) * | 2008-06-05 | 2013-06-05 | 深圳市信立泰资产管理有限公司 | 含有咪唑-5-羧酸类衍生物的药用组合物,其制备方法及用途 |
CN103012377A (zh) * | 2011-09-27 | 2013-04-03 | 江苏艾力斯生物医药有限公司 | 一种咪唑-5-羧酸酯的重结晶方法 |
CN102558064A (zh) * | 2012-01-29 | 2012-07-11 | 安润医药科技(苏州)有限公司 | 抗高血压化合物及其制备方法和应用,以及其在药学上可接受的盐和溶剂化物 |
CN102558064B (zh) * | 2012-01-29 | 2014-04-16 | 安润医药科技(苏州)有限公司 | 抗高血压化合物及其制备方法和应用,以及其在药学上可接受的盐 |
CN111018841B (zh) * | 2013-11-01 | 2023-04-07 | 深圳信立泰药业股份有限公司 | 阿利沙坦酯无定形及其制备方法及含所述无定形的药物组合物 |
CN104610232A (zh) * | 2013-11-01 | 2015-05-13 | 深圳信立泰药业股份有限公司 | 阿利沙坦酯无定形及其制备方法及含所述无定形的药物组合物 |
CN109320501A (zh) * | 2013-11-01 | 2019-02-12 | 深圳信立泰药业股份有限公司 | 阿利沙坦酯无定形及其制备方法及含所述无定形的药物组合物 |
CN104610232B (zh) * | 2013-11-01 | 2019-09-20 | 深圳信立泰药业股份有限公司 | 阿利沙坦酯无定形及其制备方法及含所述无定形的药物组合物 |
CN111018841A (zh) * | 2013-11-01 | 2020-04-17 | 深圳信立泰药业股份有限公司 | 阿利沙坦酯无定形及其制备方法及含所述无定形的药物组合物 |
CN109320501B (zh) * | 2013-11-01 | 2021-06-01 | 深圳信立泰药业股份有限公司 | 阿利沙坦酯无定形及其制备方法及含所述无定形的药物组合物 |
CN103965171A (zh) * | 2014-04-30 | 2014-08-06 | 上海艾力斯医药科技有限公司 | 一种阿利沙坦酯的制备方法 |
CN106188012A (zh) * | 2014-06-20 | 2016-12-07 | 深圳信立泰药业股份有限公司 | 一种阿利沙坦酯结晶及其制备方法及含有该结晶的药物组合物 |
CN106188012B (zh) * | 2014-06-20 | 2018-11-30 | 深圳信立泰药业股份有限公司 | 一种阿利沙坦酯结晶及其制备方法及含有该结晶的药物组合物 |
US11026925B2 (en) | 2016-01-20 | 2021-06-08 | Shenzhen Salubris Pharmaceuticals Co. Ltd. | Angiotensin II receptor antagonist metabolite and NEP inhibitor composite and preparation method thereof |
Also Published As
Publication number | Publication date |
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US20090036505A1 (en) | 2009-02-05 |
ES2424154T3 (es) | 2013-09-27 |
AU2006338796B2 (en) | 2011-05-12 |
EP1988090B1 (en) | 2013-05-01 |
AU2006338796A1 (en) | 2007-08-30 |
CN101031562A (zh) | 2007-09-05 |
CA2643005A1 (en) | 2007-08-30 |
DK1988090T3 (da) | 2013-08-05 |
PL1988090T3 (pl) | 2013-10-31 |
CA2643005C (en) | 2012-05-15 |
CN100506818C (zh) | 2009-07-01 |
WO2007095789A1 (fr) | 2007-08-30 |
KR20080096707A (ko) | 2008-10-31 |
USRE44873E1 (en) | 2014-04-29 |
EP1988090A4 (en) | 2010-06-30 |
EP1988090A1 (en) | 2008-11-05 |
PT1988090E (pt) | 2013-08-05 |
US7858651B2 (en) | 2010-12-28 |
JP5250760B2 (ja) | 2013-07-31 |
KR101179110B1 (ko) | 2012-09-07 |
JP2009527509A (ja) | 2009-07-30 |
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