CN100591689C - 苯并氮杂环庚三烯化合物的固体盐及其在制备药物化合物中的应用 - Google Patents
苯并氮杂环庚三烯化合物的固体盐及其在制备药物化合物中的应用 Download PDFInfo
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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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
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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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Cardiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明涉及如下通式的化合物的药物可接受的金属盐:其中:R1是选自可以被(C1-C6)烷氧基取代的(C1-C6)烷氧基(C1-C6)烷基,其中苯基可以被(C1-C6)烷基、(C1-C6)烷氧基或卤素取代的苯基-(C1-C6)-烷基和苯基氧-(C1-C6)-烷基,和萘基-(C1-C6)-烷基的基团,R2和R3独立地为氢或卤素,R4是形成生物不稳定酯的基团,其特征在于,所述盐选自锂盐和二价金属离子盐如镁、钙和锌盐。本发明还涉及上述盐的制备方法,包含本发明盐的药物组合物,这些盐在治疗心脏病症或高血压,改善肠胃血流或者治疗和预防由阿霉素及类似抗癌药物所引起的心脏损害方面的应用,并涉及在上述盐的制备过程中可用作中间体的式(I)化合物的结晶S-α-甲基苄基胺盐。
Description
本发明涉及一组下式化合物的新型盐,
及它们在制备药物化合物中的应用。
具有上式的苯并氮杂环庚三烯已公开于EP 0733642,EP 0830863,WO00/48601和WO01/03699。EP 0733642涉及式(I)的化合物及它们的生理学可接受的盐,并涉及所述化合物在心脏机能不全方面的应用。EP 0830863,WO00/48601和WO01/03699分别涉及上述化合物在改善胃肠血流、在治疗高血压和在治疗和预防由阿霉素及类似抗癌药物所引起的心脏损害方面的应用。
优选的苯并氮杂环庚三烯是其中R1是苯乙基或1-萘基乙基,R2和R3都是氢,R4是生物不稳定的酯基的化合物。形成生物不稳定的酯的合适基团包括(C1-C6)-烷基、在苯环上被(C1-C6)-烷基或者被连接在两个相邻碳原子上的(C2-C6)-亚烷基链任选取代的苯基或苯基-(C1-C6)-烷基、在二氧戊环上被(C1-C6)-烷基任选取代的二氧戊环甲基、或在氧甲基上被(C1-C6)-烷基任选取代的(C2-C6)-烷酰氧甲基。当R4基团是(C1-C6)-烷基时,它优选是非支化的(C1-C4)-烷基。在最优选的化合物中,R4是乙基。
在进一步的药物和临床开发过程中,已发现最优选的化合物有严重的缺点,即该化合物是固体泡沫体。为了确保来自固体药剂形式的活性组分具有可重现的、恒定的生物利用率,使用活性化合物的均匀和可重现的变体是重要的。因此,对于源自通常不均匀的材料,例如固体泡沫体的化合物的可重现性和恒定的生物利用率,总是存在着疑问。
同样显而易见的是,在工业规模上分离固体泡沫体是非常困难的。另外,所述化合物几乎不溶于水,因此制备能够用于静脉注射(IV)的所述化合物的制剂是非常困难的。在本发明之前,只能由相应的二酸制备IV制剂(见EP0733642的实施例II)。这意味着用于IV制剂的化合物必须不同于用于口服制剂的化合物,而这对于一个药物化合物来说是不希望的。在进一步的开发过程中,已发现单酸的钠盐和钾盐在水中的溶解性要好得多,但是这些盐也只能以固体泡沫体的形式分离。
本发明的目的是提供一种通式(I)化合物的盐,该化合物的盐应当满足如下要求:
a)工业生产规模上易通过结晶或沉淀分离纯固体化合物,
b)在生理流体中有足够高的溶解性以便制成IV制剂,
c)具有允许用标准辅助化合物和标准设备制备成药物制剂的固态性质,
d)优选制备过程不会显著损失手性和化学纯度。
这个目的可通过制备上述通式(I)化合物的金属盐来实现,其中金属离子是锂离子或二价金属离子。优选的二价金属盐是钙,镁和锌盐。最优选钙盐。令人惊奇地,已发现这些盐与EP0733642中提及的钠盐和钾盐相反,具有非常需要的性质,如它们能够以固体(无定形)形式分离,且在pH 7.4的等渗流体中的溶解性要比相应的酸至少高10倍。而且可以制备二价盐而不会外消旋。
在本发明的另一方面,提供了一种制备金属盐,优选Li+或二价Ca2+、Mg2+或Zn2+盐的方法。
令人惊奇地,已经发现在室温下,式I化合物的锂盐和二价金属盐在诸如环己烷、甲苯、甲基叔丁基醚和乙酸乙酯之类的弱极性非质子溶剂中的溶解性非常好。
通过将所需金属的氢氧化物或合适的盐与式I化合物在上述弱极性非质子溶剂中的溶液或浆液混合,可以容易地获得本发明的盐类。或者,当所需金属的氢氧化物或盐的溶解度不足以开始进行反应时,可以向所述有机溶剂的溶液或浆液中加入少量的水,并且所加的水可以通过共沸蒸馏除去。在这种情况下,必须选择和水形成共沸物的非极性非质子溶剂。对于氢氧化物溶解性非常不好的金属,可以将该金属以乙氧化物(例如Mg(OEt)2)或混合氢氧化物/碳酸盐(3Zn(OH)2·2ZnCO3)的形式加入。上述方法中优选的溶剂是甲基叔丁基醚或乙酸乙酯。当已经在溶液中获得了所述盐时,可以通过如下步骤进行分离:首先通过共沸蒸馏除去仍然存在的水,随后和沉淀剂混合。沉淀剂定义为第二种液体,该液体被加入到溶液中以降低溶解化合物的溶解度,引起该化合物的沉淀/结晶并使产物的产率最大化。这两种液体(原始溶剂和所加的沉淀剂)能够以任意比例彼此完全互溶是必要的。(这种方法也用于通过加入与水互溶的有机溶剂来降低无机盐在水溶液中的溶解度(ALFASSI Z.B.等,AlChE J.1984,30,874-6;MYDLARZ J.等,J.Chem.Eng.Data 1989,34,124-6;MULLIN J.W.等,Chem.Eng.Process.1989,26,93-9)。本发明范围内的沉淀剂的实例为线性烃。优选的沉淀剂是线性C4-C10烃。最优选的沉淀剂是正己烷。
因为在所有的情况下所述盐都是以非晶态沉淀物形式分离的,该沉淀物在所有情况下似乎都是均匀的,有时需要进行真正的结晶步骤以提高必须满足严格要求的活性化合物的纯度。令人惊奇的是,已经发现式I化合物的S-α-甲基苄基胺盐非常适合用于这些化合物的纯化,例如所述盐是晶体,并且可以从有机溶剂中以高产率进行重结晶,所述有机溶剂优选是醇如乙醇或异丙醇。因此,本发明还涉及式I化合物的S-α-甲基苄基胺盐。因为S-α-甲基苄基胺似乎毒性太大不能使用,因此所述盐只适合用作纯化步骤中的中间体。
可以通过向式I化合物在乙醇或异丙醇或其它合适醇中的溶液中加入S-α-甲基苄基胺来制备式I化合物的S-α-甲基苄基胺盐。该溶液静置冷却后,所述盐将从溶液中结晶出来(根据浓度)。
可以按照现有技术的配方工艺来配制本发明的药学可接受的盐。可以使用常用制剂,例如片剂、胶囊或栓剂。这些药物制剂可以用已知的方法制备,例如直接压缩、造粒、挤出、模制,采用常规的固体赋形剂,例如填充剂如纤维素、乳糖和淀粉,粘合剂如纤维素和聚乙烯基吡咯烷酮(pvp),崩解剂如淀粉和交联pvp,滑动剂(glidiants)如胶体二氧化硅,润滑剂如硬脂酸镁,或者常规的液体和半固体赋形剂,例如聚乙二醇、蓖麻油衍生物、甘油三酯和石蜡。另外可以加入防腐剂,例如对羟基苯甲酸酯类,和乳化剂如聚山梨酸酯。
本发明的药物可接受的盐适合作为大型哺乳动物,特别是人类的用药,用于治疗心力衰竭和促进特别是心力衰竭的患者的排尿和钠尿***,用于改善胃肠血流,治疗高血压以及治疗和预防由阿霉素及类似抗癌药物引起的心脏损害。为实现该目的,可以以肠胃外给药,特别是静脉注射,口服或栓剂给药的药物形式使用本发明的化合物。所用剂量可以因人而异,并根据被治疗的状况的性质、所用的特定物质以及给药方式而变化。对于大型哺乳动物,特别是人类而言,以活性物质含量为单剂1~800mg的药物形式给药一般是合适的。
下列的实施例只是为了更详细地举例说明本发明,因此这些实施例在任何方面都不构成对本发明范围的限制。
实施例
实施例1、制备式I化合物金属盐的一般程序。
将约15mmol酸形式的活性物质溶解或悬浮在40ml弱极性非质子溶剂中。加入约1.2当量的金属试剂,该试剂溶于水或与活性化合物所用溶剂相同的溶剂中。在某些情况下,必须加入水以启动反应。通过共沸蒸馏除去水。当金属试剂不是氢氧化物或乙氧化物时,将溶剂全部除去,接着重新溶解在40~160ml的原始弱极性非质子溶剂中,随后过滤以除去未反应的金属试剂和任选的所形成的其它盐。将滤液加入己烷中,当形成固体产物时,用过滤器收集产物。当形成焦油或油状物时,将大部分溶剂轻轻倾倒出去,并蒸发掉剩余溶剂以获得固体泡沫体。
表1、两种活性物质的不同盐的制备
化合物<sup>*</sup> | 盐中的金属 | 金属试剂M | 溶剂 | M的数量(g)(mmo) | 溶剂量(ml) | 己烷量(ml) | 产率(%) | 结果 |
I | Ca<sup>2+</sup> | Ca(OH)<sub>2</sub> | MTBE | 0.67(9.0) | 40 | 80 | 95 | 固体粉末 |
I | Mg<sup>2+</sup> | Mg(OEt)<sub>2</sub> | MTBE | 1.25(10.9) | 40 | 130 | 103 | 固体粉末 |
I | Zn<sup>2+</sup> | 3Zn(OH)<sub>2</sub>·2Zn(CO<sub>3</sub>)<sub>2</sub> | MTBE | 1.05(10.9) | 115 | 235 | 95 | 固体粉末 |
I | Li<sup>+</sup> | LiOH | MTBE | 0.4(16.7) | 160 | 130 | 85 | 固体粉末 |
I | K<sup>+</sup> | KOH | MTBE | 1.02(18.3) | 95 | 235 | 98 | 固体泡沫体 |
I | Na<sup>+</sup> | NaOH | MTBE | 1.02(17.8) | 95 | 235 | 89 | 固体泡沫体 |
II | Ca<sup>2+</sup> | Ca(OH)<sub>2</sub> | EtOAc | 0.56(7.6) | 75 | 235 | 87 | 固体粉末 |
*化合物I=(3S)-3-[[[1-(2R)-2-(乙氧羰基)-4-苯基丁基]环戊基]羰基]氨基]-2,3,4,5-四氢-2-氧代-1H-1-苯并氮杂环庚三烯-1-乙酸。
*化合物II=[S-(R*,S*)]-3-[[[1-[2-(乙氧羰基)-4-(1-萘基)丁基]环戊基]羰基]氨基]-2,3,4,5-四氢-2-氧-1H-1-苯并氮杂环庚三烯-1-乙酸。
表2总结了所制备的盐的性质。化合物含量用HPLC法测定(MACHEREY-NAGEL Nucleosil 100-5C18-HD柱,使用从5%B到100%B的梯度体系,洗脱液A是pH=5.1的磷酸缓冲液,洗脱液B是和10%洗脱液A混合的乙腈)。对于钙,金属含量用乙二胺四乙酸二钠盐配位滴定法测定,对于其它金属,金属含量用原子发射光谱(AES)测定。
表2、表1制备的盐的性能
化合物<sup>*</sup> | 盐中的金属 | 化合物含量(%rel) | 金属含量(%W/W) | 理论金属含量(%W/W) | 在弱极性非质子有机溶剂中的溶解度 | 水中的溶解性 |
I | Ca<sup>2+</sup> | 99.8 | 3.8 | 3.6 | 可溶 | 可溶 |
I | Mg<sup>2+</sup> | 99.6 | 2.4 | 2.2 | 可溶 | 可溶 |
I | Zn<sup>2+</sup> | 99.9 | 7.0 | 5.8 | 可溶 | 可溶 |
I | Li<sup>+</sup> | 88.0 | 1.6 | 1.3 | 可溶 | 易溶 |
I | K<sup>+</sup> | 78.4 | 7.5 | 6.8 | 不溶 | 易溶 |
I | Na<sup>+</sup> | 84.7 | 4.3 | 4.1 | 不溶 | 易溶 |
II | Ca<sup>2+</sup> | n.d. | 3.4 | 3.3 | 可溶 | 可溶 |
*化合物I=(3S)-3-[[[1-(2R)-2-(乙氧羰基)-4-苯基丁基]环戊基]羰基]氨基]-2,3,4,5-四氢-2-氧代-1H-1-苯并氮杂环庚三烯-1-乙酸。
*化合物II=[S-(R*,S*)]-3-[[[1-[2-(乙氧羰基)-4-(1-萘基)丁基]环戊基]羰基]氨基]-2,3,4,5-四氢-2-氧代-1H-1-苯并氮杂环庚三烯-1-乙酸。
n.d.=未测定
从表2可以看到,作为固体粉末分离出来的Li、Ca、Mg和Zn盐可溶解在弱极性非质子溶剂中。这些溶剂的实例有乙酸乙酯,甲苯,环己烷和甲基叔丁基醚。这些化合物还可溶解在极性非质子溶剂中,例如THF,丙酮,乙腈,DMF和DMSO。盐中测得的金属含量稍高于理论量,但这在这些类型的后处理和分析中是正常的。在和一价强碱性氢氧化物成盐的过程中,会发生活性物质的降解,导致最终盐中的低化合物含量。
实施例2、(3S)-3-[[[1-(2R)-2-(乙氧羰基)-4-苯基丁基]环戊基]羰基]氨基]-2,3,4,5-四氢-2-氧代-1H-1-苯并氮杂环庚三烯-1-乙酸的S-α-甲基苄基胺盐的制备
将18g(3S)-3-[[[1-(2R)-2-(乙氧羰基)-4-苯基丁基]环戊基]羰基]氨基]-2,3,4,5-四氢-2-氧代-1H-1-苯并氮杂环庚三烯-1-乙酸溶解在90ml无水乙醇中。在20~25℃下加入4.1g S-α-甲基苄基胺。将自然形成的晶体浆液加热至40℃,并搅拌1小时。待冷却至0~5℃后,再搅拌4小时,过滤收集晶体,用40ml冷无水乙醇洗涤,45℃下在真空烘箱中干燥。第一批收集到19g(3S)-3-[[[1-(2R)-2-(乙氧羰基)-4-苯基丁基]环戊基]羰基]氨基]-2,3,4,5-四氢-2-氧代-1H-1-苯并氮杂环庚三烯-1-乙酸的S-α-甲基苄基胺盐。
实施例3、(3S)-3-[[[1-(2R)-2-(乙氧羰基)-4-苯基丁基]环戊基]羰基]氨基]-2,3,4,5-四氢-2-氧代-1H-1-苯并氮杂环庚三烯-1-乙酸钙盐的制备
向30g(3S)-3-[[[1-(2R)-2-(乙氧羰基)-4-苯基丁基]环戊基]羰基]氨基]-2,3,4,5-四氢-2-氧代-1H-1-苯并氮杂环庚三烯-1-乙酸的S-α-甲基苄基胺盐在120ml甲基叔丁基醚(MTBE)中的溶液中,加入100ml 1M盐酸水溶液,搅拌所得的混合物10分钟。分离各层,并用15ml水洗涤有机层至少3次,直至pH高于5。加入2g 95%Ca(OH)2,加热回流混合物至55℃。当30分钟后悬浮液数量不明显减少时,加入0.5ml水。通过脱水器(Dean-Stark设备)回流混合物2小时。2小时后,馏出液完全澄清而反应混合物有一点浑浊。将混合物冷却至30-35℃,并通过在线过滤器在30分钟之内加到240ml己烷中。过滤分离固体产物,并用50ml己烷洗涤。干燥后获得25.6g灰白色自由流动的粉末。
1H-NMR:δ=7.29(1H,dd,J=2.2和8.1),7.28(1H,ddd,J=2.0,6.6,8.1),7.25(1H,dd,J=2.0和7.6),7.19(1H,ddd,J=2.2,6.6,7.6),7.19(2H,dddd,J=0.6,1.7,7.5,7.8),7.13(1H,dd,J=1.3和7.5),7.10(2H,ddd,J=1.3,2.1,7.8),4.39(1H,d,J=16.9),4.28(1H,dd,J=8.1和11.7),4.28(1H,d,J=16.9),4.07(1H,dd,J=7.2和10.8),4.01(1H,dd,J=7.1和10.8),3.33(1H,ddd,J=8.0,13.2,13.7),2.57(1H,ddd,J=1.2,7.1,13.7),2.52(1H,dd,J=5.9和9.6),2.49(1H,dd,J=6.7和9.4),2.31(1H,dddd,J=3.3,5.1,9.2,9.3),2.29(1H,dddd,J=7.1,8.1,13.1,13.2),2.03(1H,dddd,J=1.2,8.0,11.7,13.1),2.0(1H,dd,J=9.3和14.2),1.82(1H,dd,J=3.3和14.2),1.82(1H,ddd,J=5.9,9.4,13.6),1.70(1H,ddd,J=6.7,9.6,13.6),2.02-1.42(8H,m),1.21(3H,dd,J=7.1和7.2)。
实施例4、化合物II即[S-(R*,S*)]-3-[[[1-[2-(乙氧羰基)-4-(1-萘基)丁基]环戊基]羰基]氨基]-2,3,4,5-四氢-氧代-1H-1-苯并氮杂环庚三烯-1-乙酸的S-α-甲基苄基胺盐的制备
将21g化合物II即[S-(R*,S*)]-3-[[[1-[2-(乙氧羰基)-4-(1-萘基)丁基]环戊基]羰基]氨基]-2,3,4,5-四氢-氧代-1H-1-苯并氮杂环庚三烯-1-乙酸溶于190ml MTBE中。加入45ml乙醇和4.5g S-α-甲基苄基胺。在4℃贮存4天并每天搅拌一次后,过滤收集晶体,用80ml MTBE洗涤,在真空烘箱中于45℃干燥。第一批收集到19g化合物II即[S-(R*,S*)]-3-[[[1-[2-(乙氧羰基)-4-(1-萘基)丁基]环戊基]羰基]氨基]-2,3,4,5-四氢-氧代-1H-1-苯并氮杂环庚三烯-1-乙酸的S-α-甲基苄基胺盐。
实施例5、[S-(R*,S*)]-3-[[[1-[2-(乙氧羰基)-4-(1-萘基)丁基]环戊基]羰基]氨基]-2,3,4,5-四氢-氧代-1H-1-苯并氮杂环庚三烯-1-乙酸钙盐的制备
在搅拌下,在15分钟内,向10g[S-(R*,S*)]-3-[[[1-[2-(乙氧羰基)-4-(1-萘基)丁基]环戊基]羰基]氨基]-2,3,4,5-四氢-氧代-1H-1-苯并氮杂环庚三烯-1-乙酸的S-α-甲基苄基胺盐在80ml甲基叔丁基醚(MTBE)和60ml水中形成的多相混合物中加入4.4ml 36%的盐酸水溶液,在室温下搅拌所得混合物1.5小时。分离各层,有机层用50ml水洗涤两次。将有机层浓缩成油,加入15ml乙酸乙酯,将所得溶液再次浓缩成油。用80ml乙酸乙酯再次溶解该油,并加入2ml水。加入0.56g 95%Ca(OH)2,通过脱水器(Dean-Stark设备)回流混合物4小时。过滤溶液,并将溶液体积减少到40ml。将溶液冷却至30-35℃,在30分钟内加到250ml冷己烷(10℃)中,在10℃下再搅拌30分钟。过滤分离固体产物,用10ml己烷洗涤两次。真空干燥(18小时,50℃,120毫巴)后,获得7.4g自由流动的粉末。
1H-NMR:δ=7.99(1H,宽双峰,J=8),7.88(1H,dd,J=1.5和8),7.73(1H,宽双峰,J=8),7.56-7.44(2H,m),7.37(1H,t,J=8),~7.36(NH,d,J=8),7.31(1H,dd,J=1.5和8),7.29(1H,d,J=8),7.24(1H,三重双峰,J=1.5,8,8),7.21(1H,dd,J=1.5和8),7.13(1H,三重双峰,J=1.5,8,8),4.48(1H,d,J=16),4.23(1H,双三重峰,J=8,8,12),4.14-3.99(3H,m),3.56(1H,三重双峰,J=8,13,13),3.02-2.96(2H,m),2.5-2.34(2H,m),2.2-1.74(8H,m),1.6-1.24(6H,m),1.20(3H,t,J=6)。
Claims (11)
1、[S-(R*,S*)]-3-[[[1-[2-(乙氧羰基)-4-(1-萘基)丁基]环戊基]羰基]氨基]-2,3,4,5-四氢-2-氧代-1H-1-苯并氮杂环庚三烯-1-乙酸的钙盐。
2、权利要求1的盐的制备方法,该方法包括将氢氧化钙的溶液或浆液与[S-(R*,S*)]-3-[[[1-[2-(乙氧羰基)-4-(1-萘基)丁基]环戊基]羰基]氨基]-2,3,4,5-四氢-2-氧代-1H-1-苯并氮杂环庚三烯-1-乙酸在弱极性非质子溶液中的溶液或浆液混合,产生该盐在所述弱极性非质子溶剂中的均匀溶液。
3、权利要求2的方法,其中所述的弱极性非质子溶剂是甲基叔丁基醚或乙酸乙酯。
4、权利要求2的方法,还包括通过如下步骤以固体形式分离出所述盐:
i)任选地共沸脱除水,然后
ii)通过将在弱极性非质子溶剂中的所述盐的溶液与沉淀剂混合,使所述盐沉淀,其中所述沉淀剂是线性(C4-C10)-烃。
5、权利要求4的方法,其中所述沉淀剂是正己烷。
6、含权利要求1的盐和药用载体或辅助剂的药物组合物。
7、权利要求6的药物组合物,其中所述组合物是适合静脉内给药的形式。
8、权利要求1的盐在制造药物组合物中的应用,该药物组合物用于治疗通过该组合物可以治疗的心脏病症。
9、权利要求1的盐在制造用于改善肠胃血流的组合物中的应用。
10、权利要求1的盐在制造药物组合物中的应用,该药物组合物用于治疗通过该组合物可以治疗的高血压。
11、权利要求1的盐在制造用于治疗和预防由阿霉素所引起的心脏损害的组合物中的应用。
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NL1019762 | 2002-01-17 |
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CN200910141767A Division CN101654437A (zh) | 2002-01-16 | 2003-01-15 | 苯并氮杂环庚三烯化合物的固体盐及其在制备药物化合物中的应用 |
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US (1) | US6998398B2 (zh) |
EP (1) | EP1468010A1 (zh) |
JP (1) | JP4384495B2 (zh) |
KR (1) | KR100979077B1 (zh) |
CN (1) | CN100591689C (zh) |
AU (1) | AU2003206755B2 (zh) |
BR (1) | BR0306701A (zh) |
CA (1) | CA2473447A1 (zh) |
HK (1) | HK1072946A1 (zh) |
HR (1) | HRP20040560A2 (zh) |
IL (1) | IL162645A0 (zh) |
MX (1) | MXPA04006887A (zh) |
NO (1) | NO330528B1 (zh) |
PL (1) | PL371511A1 (zh) |
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KR20050009031A (ko) * | 2003-07-15 | 2005-01-24 | 엘지전자 주식회사 | 1회 기록 가능한 광디스크 및 광디스크의 관리정보 기록방법 |
SA04250283B1 (ar) * | 2003-09-26 | 2008-05-26 | سولفاي فارماسيتيكالز جي أم بي أتش | مشتقات من amidomethy1-substituted1-(carboxyalkyl)-cyclopentylcarbonylamino-benzazepine-N-acetic acid |
AU2004290925B2 (en) * | 2003-11-18 | 2010-07-01 | Solvay Pharmaceuticals Gmbh | Pharmaceutical compositions for the treatment of renal dysfunction, disease or disorder, in particular in diabetic patients |
US20050267124A1 (en) * | 2004-05-14 | 2005-12-01 | Solvay Pharmaceuticals Gmbh | Pharmaceutical compositions comprising NEP-inhibitors, inhibitors of the endogenous producing system and PDEV inhibiitors |
CA2590278A1 (en) | 2004-12-15 | 2006-06-22 | Solvay Pharmaceuticals Gmbh | Pharmaceutical compositions comprising nep-inhibitors, inhibitors of the endogenous endothelin producing system and hmg coa reductase inhibitors |
US20060159748A1 (en) * | 2004-12-23 | 2006-07-20 | Rajesh Jain | Oral immediate release formulation of a poorly water-soluble active substance |
US20060205625A1 (en) * | 2005-02-18 | 2006-09-14 | Solvay Pharmaceuticals Gmbh | Pharmaceutical compositions comprising NEP-inhibitors, inhibitors of the endogenous endothelin producing system and diuretics |
WO2007054975A1 (en) * | 2005-11-08 | 2007-05-18 | Panacea Biotec Ltd | Pharmaceutical compositions for the treatment of cardiovascular and other associated disorders |
HU227696B1 (en) * | 2006-04-13 | 2011-12-28 | Egyt Gyogyszervegyeszeti Gyar | Zinc salt of rosuvastatin, process for its preparation and pharmaceutical compositions containing it |
PL424452A1 (pl) | 2018-01-31 | 2019-08-12 | Forty-Four Pharmaceuticals Spółka Z Ograniczoną Odpowiedzialnością | Inhibitory obojętnej endopeptydazy (NEP) i ludzkiej rozpuszczalnej endopeptydazy (hSEP) do profilaktyki i leczenia chorób oczu |
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DE19906310A1 (de) * | 1999-02-16 | 2000-08-17 | Solvay Pharm Gmbh | Arzneimittel zur Behandlung von Bluthochdruck |
DE19932555A1 (de) * | 1999-07-13 | 2001-01-18 | Solvay Pharm Gmbh | Arzneimittel mit protektiver Wirkung gegen oxidativ-toxische und insbesondere gegen kardiotoxische Substanzen |
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CN1059436C (zh) * | 1995-03-23 | 2000-12-13 | 索尔瓦药物有限公司 | 苯并氮杂䓬-、苯并氧氮杂䓬-和苯并硫氮杂䓬-n-乙酸衍生物 |
US5783573A (en) * | 1996-09-18 | 1998-07-21 | Solvay Pharmaceuticals Gmbh | Pharmaceuticals which promote gastrointestinal blood circulation |
CN1217334A (zh) * | 1997-11-12 | 1999-05-26 | 索尔瓦药物有限公司 | 磷酸取代的苯并氮杂卓酮-n-醋酸衍生物、制法和药物 |
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NO20043295L (no) | 2004-08-06 |
RU2004124840A (ru) | 2006-01-20 |
EP1468010A1 (en) | 2004-10-20 |
JP2005520809A (ja) | 2005-07-14 |
CA2473447A1 (en) | 2003-07-24 |
MXPA04006887A (es) | 2004-12-06 |
US6998398B2 (en) | 2006-02-14 |
HRP20040560A2 (en) | 2004-10-31 |
BR0306701A (pt) | 2004-12-28 |
WO2003059939A1 (en) | 2003-07-24 |
CN1617883A (zh) | 2005-05-18 |
HK1072946A1 (en) | 2005-09-16 |
AU2003206755B2 (en) | 2008-07-17 |
NO330528B1 (no) | 2011-05-09 |
JP4384495B2 (ja) | 2009-12-16 |
KR20040089106A (ko) | 2004-10-20 |
IL162645A0 (en) | 2005-11-20 |
RU2303041C2 (ru) | 2007-07-20 |
AU2003206755A1 (en) | 2003-07-30 |
US20050038012A1 (en) | 2005-02-17 |
KR100979077B1 (ko) | 2010-08-31 |
PL371511A1 (en) | 2005-06-27 |
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