CN1149087C - 内皮素拮抗剂和β-受体阻滞剂的组合制剂 - Google Patents
内皮素拮抗剂和β-受体阻滞剂的组合制剂 Download PDFInfo
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- CN1149087C CN1149087C CNB988097273A CN98809727A CN1149087C CN 1149087 C CN1149087 C CN 1149087C CN B988097273 A CNB988097273 A CN B988097273A CN 98809727 A CN98809727 A CN 98809727A CN 1149087 C CN1149087 C CN 1149087C
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- endothelin antagonist
- combination
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- blocker
- alkyl
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- Medicinal Preparation (AREA)
Abstract
本发明提供了内皮素拮抗剂和β-受体阻滞剂的组合。所述组合适于治疗疾病。
Description
技术领域
本发明涉及新的药物组合制剂，该制剂适于治疗基于血管收缩的疾病，包含β-受体阻滞剂和内皮素拮抗剂。
背景技术
适于治疗基于血管收缩的疾病的包含β-受体阻滞剂和内皮素拮抗剂的组合制剂已经公开过(WO 92/13545)。然而，这些活性化合物的组合的活性不令人满意。
现已发现了具有改进性质的组合。
发明内容
本发明提供了式I内皮素拮抗剂和β-受体阻滞剂的组合：
其中取代基的定义如下：
R1是C1-C4-烷基，C1-C4-烷氧基；
R2是C1-C4-烷基，C1-C4-烷氧基；
R3是可被苯基取代的C1-C8-烷基，其中所述苯基本身可被1个或2个C1-C4-烷氧基取代；
Z是氧或单键。
优选的内皮素拮抗剂是取代基具有如下定义的式I化合物：
R1：C1-C2-烷基，C1-C2-烷氧基；
R2：C1-C2-烷基，C1-C2-烷氧基；
R3是可被苯基取代的C1-C2-烷基，其中所述苯基本身可被1个或2个C1-C2-烷氧基取代；
Z是氧或单键。
特别合适的内皮素拮抗剂是下述化合物：
合适的β-受体阻滞剂尤其是醋丁洛尔、阿普洛尔、阿替洛尔、美多洛尔、布拉洛尔、喷布洛尔、普萘洛尔、艾司洛尔、比索洛尔、卡拉洛尔、他林洛尔、甲吲洛尔、索他洛尔、美替洛尔、吲哚洛尔、卡替洛尔、tetratolol、西利洛尔、纳多洛尔、氧烯洛尔和波吲洛尔。可特别提及的是卡维地洛和布新洛尔。
β-受体阻滞剂与ET-系统抑制剂的组合可用作治疗基于血管收缩或与病理性血管收缩有关的疾病的组合物。所述疾病的实例有：所有类型的高血压(包括肺动脉高血压)、冠心病、心肌机能不全、肾和心肌缺血、急性和慢性肾机能不全。
与血管收缩或内皮素和/或血管紧张素II的其它生理作用有关的疾病尤其是治疗和/或预防冠状动脉疾病，心血管疾病，例如高血压、心肌机能不全，局部缺血(例如心脏、脑、胃肠道、肝脏和/或肾脏的缺血)或血管痉挛。可治疗的其它疾病实例是肾和心肌缺血、肾机能不全、组织断离(dialysis)、蛛网膜下出血、雷诺综合征、门静脉高血压和肺动脉高血压，以及治疗胃溃疡和十二指肠溃疡以及与血管收缩有关的淤血性溃疡。最后，在哮喘病人中，内皮素在支气管排溢物中的浓度增加了。在偏头痛发作时，也观察到内皮素在血浆中的水平增加了。因此，本发明的组合也可用于治疗这些疾病。
当将本发明的组合给药时，与单独使用的这两种物质相比，抗高血压效果与作用时间都有显著增加，并且这种效果比简单的叠加要高。因此，可显著减少每一活性化合物的剂量。所以，给药期间不利作用的危险性降低了。
β-受体阻滞剂与内皮素拮抗剂的重量比一般是50∶1-1∶500，优选为10∶1-1∶100，特别是2∶1-1∶50。
本发明的组合一般是口服给药，例如以未包衣片剂、包衣片剂或糖包衣片剂、硬和软明胶胶囊、溶液、乳液或悬浮液的形式口服给药。然而，也可以直肠给药，例如以栓剂的形式直肠给药，或者非胃肠道给药，例如以注射液的形式非胃肠道给药。可以以含有两种活性化合物一起的产品例如片剂或胶囊的形式将活性化合物给药，或者活性化合物分别作为单一物质的特定(ad hoc)组合，可以同时或顺序给药。
为了制备未包衣片剂、包衣片剂或糖包衣片剂以及硬明胶胶囊，可将本发明的组合与药理惰性无机或有机赋形剂一起配制。可用于未包衣和糖包衣片剂以及硬明胶胶囊的这些类型的赋形剂有乳糖、玉米淀粉或其衍生物、滑石粉、硬脂酸或其盐。适用于软明胶胶囊的赋形剂有植物油、蜡、脂肪、半固体和液体多元醇。
适用于溶液和糖浆剂的赋形剂有例如水、多元醇、蔗糖、转化糖、葡萄糖等。适用于注射液的赋形剂有水、醇、多元醇、甘油、植物油。适用于栓剂的赋形剂有天然油或氢化油、蜡、脂肪、半液体或液体多元醇等。
本发明药物制剂还可以含有防腐剂、加溶剂、稳定剂、润湿剂、乳化剂、甜味剂、色素、调味剂、调节渗透压的盐、缓冲剂、包衣剂和/或抗氧化剂。
具体实施方式
通过下述实验来证实本发明的活性化合物组合的出乎意料的优点：
在交叉设计方案中，将测试物质以胶囊的形式对长期装配有仪器的雄性beagle狗(约14kg)口服给药。胶囊不含任何物质(对照N＝5)、含有化合物A(10mg/kg，N＝10)、含有布新洛尔(0.1mg/kg，N＝5)、或含有布新洛尔+化合物A组合(0.1+10mg/kg，N＝5)。在独立给药之间，观察至少1周的洗涤相。用Statham Transducer P23Db测定心脏收缩和舒张血压，由其计算平均动脉血压。记录6小时血压(MI2，Modular Instrument，USA)。
表1表明，对照组和用布新洛尔治疗组的血压没有下降。观察到化合物A治疗组的血压有轻微下降。用布新洛尔和ET拮抗剂化合物A联合治疗(0.1+10mg/kg)使得血压显著降低。
表1：在血压正常的醒着的狗中，将不同物质口服给药后，以平均值表示的平均动脉血压的变化(mmHg，相对于初始值的改变)
| N | 初始值 | 1小时 | 2小时 | 3小时 | 4小时 | 5小时 | 6小时 | |
| 对照 | 10 | 103 | 3 | 2 | 2 | 1 | 1 | 1 |
| 化合物A10mg/kg | 10 | 99.6 | -5.9 | -8.9 | -9.0 | -9.1 | -8.4 | -8.2 |
| 布新洛尔0.1mg/kg | 5 | 100.4 | -0.8 | -3.8 | -3.4 | -3.8 | -3.8 | -1.4 |
| 化合物A+布新洛尔10+0.1mg/kg | 5 | 100.8 | -8.8 | -15.2 | -17 | -15.6 | -13.4 | -11.8 |
用下述实施例举例说明本发明。
实施例1
制备具有下述组成的包衣片剂：
化合物A 100.0mg
布新洛尔 10.0mg
无水乳糖 30.0mg
微晶纤维素 30.0mg
聚乙烯基吡咯烷酮 20.0mg
硬脂酸镁 5.0mg
聚乙二醇6000 0.8mg
氧化铁黄 1.2mg
二氧化钛 0.3mg
滑石粉 0.7mg
将化合物A、布新洛尔、乳糖、纤维素和聚乙烯基吡咯烷酮湿法制粒并干燥。将颗粒过筛，与硬脂酸镁混合，将该准备好压片的混合物压制成每片重190.0mg的椭圆形药片核。然后将药片核包衣，直到包衣片的最终重量达到200mg为止。
实施例2
制备具有下述组成的硬明胶胶囊：
化合物A 100.0mg
布新洛尔 30.0mg
乳糖晶体 18.0mg
聚乙烯基吡咯烷酮 15.0mg
微晶纤维素 17.5mg
羧甲基淀粉钠 10.0mg
滑石粉 9.0mg
硬脂酸镁 3.0mg
将前5种组分湿法制粒并干燥。将颗粒与羧甲基淀粉钠、滑石粉和硬脂酸镁混合，把所得混合物装到大小为1的硬明胶胶囊中。
Claims (4)
1.式I内皮素拮抗剂和β-受体阻滞剂以1∶10至100∶1重量比的组合：
其中取代基的定义如下：
R1是C1-C4-烷基，C1-C4-烷氧基；
R2是C1-C4-烷基，C1-C4-烷氧基；
R3是可被苯基取代的C1-C8-烷基，其中所述苯基本身可被1个或2个C1-C4-烷氧基取代；
Z是氧或单键。
2.包含如权利要求1所述的组合的药物制剂。
3.制备药物制剂的方法，包括通过将如权利要求1所述的β-受体阻滞剂和内皮素拮抗剂的组合与药物学上惰性的无机或有机赋形剂混合而将其制成药物给药形式。
4.权利要求1所述的β-受体阻滞剂和内皮素拮抗剂的组合在制备治疗基于血管收缩或与病理性血管收缩有关的疾病的药物中的应用。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19743143.7 | 1997-09-30 | ||
| DE19743143A DE19743143A1 (de) | 1997-09-30 | 1997-09-30 | Pharmazeutische Kombinationspräparate |
Publications (2)
| Publication Number | Publication Date |
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| CN1272786A CN1272786A (zh) | 2000-11-08 |
| CN1149087C true CN1149087C (zh) | 2004-05-12 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNB988097273A Expired - Fee Related CN1149087C (zh) | 1997-09-30 | 1998-09-10 | 内皮素拮抗剂和β-受体阻滞剂的组合制剂 |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US6352992B1 (zh) |
| EP (1) | EP1019055B1 (zh) |
| JP (1) | JP4608093B2 (zh) |
| KR (1) | KR100623122B1 (zh) |
| CN (1) | CN1149087C (zh) |
| AT (1) | ATE239479T1 (zh) |
| AU (1) | AU739860B2 (zh) |
| BR (1) | BR9812404A (zh) |
| CA (1) | CA2304698C (zh) |
| CZ (1) | CZ298745B6 (zh) |
| DE (2) | DE19743143A1 (zh) |
| ES (1) | ES2199461T3 (zh) |
| HK (1) | HK1032355A1 (zh) |
| HU (1) | HU226745B1 (zh) |
| NO (1) | NO319048B1 (zh) |
| RU (1) | RU2213577C2 (zh) |
| WO (1) | WO1999016444A1 (zh) |
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| DE19533023B4 (de) * | 1994-10-14 | 2007-05-16 | Basf Ag | Neue Carbonsäurederivate, ihre Herstellung und Verwendung |
| EP1243262B1 (en) | 2001-03-20 | 2006-05-31 | Schwarz Pharma Ag | Novel use of a peptide class of compound for treating non-neuropathic inflammatory pain |
| PT1243263E (pt) | 2001-03-21 | 2003-03-31 | Sanol Arznei Schwarz Gmbh | Nova utilizacao de uma classe peptidica de composto para o tratamento de alodinia ou de outros tipos diferentes de dor cronica ou fantasma |
| CN1950101B (zh) | 2004-04-16 | 2011-03-30 | 舒沃茨药物股份公司 | 肽化合物用于预防和治疗慢性头痛的用途 |
| NZ552651A (en) | 2004-08-27 | 2010-07-30 | Sanol Arznei Schwarz Gmbh | Novel use of peptide compounds for treating bone cancer pain, chemotherapy-and nucleoside-induced pain |
| US20070196510A1 (en) * | 2006-02-17 | 2007-08-23 | Gerber Michael J | Method for treating resistant hypertension |
| AU2007260207B2 (en) | 2006-06-15 | 2012-11-08 | Ucb Pharma Gmbh | Pharmaceutical composition with synergistic anticonvulsant effect |
| JP2010536880A (ja) | 2007-08-22 | 2010-12-02 | ギリード・コロラド・インコーポレーテッド | 糖尿病の合併症のための療法 |
| CN104887645B (zh) * | 2015-06-15 | 2016-12-14 | 吉林万通药业集团梅河药业股份有限公司 | 阿莫西林胶囊及其制备方法 |
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| US4786441A (en) * | 1987-08-24 | 1988-11-22 | International Business Machines Corporation | Preparation of iodonium and sulfonium triflates |
| SE8704081D0 (sv) * | 1987-10-21 | 1987-10-21 | Haessle Ab | A new prohylactic method |
| ATE189217T1 (de) * | 1993-03-19 | 2000-02-15 | Merck & Co Inc | Phenoxyphenylessigsäurederivate |
| EP0750608A1 (en) * | 1994-01-28 | 1997-01-02 | Cal International Limited | Pharmaceutical product comprising a salicylate of an esterifiable beta-blocker |
| DE19533023B4 (de) * | 1994-10-14 | 2007-05-16 | Basf Ag | Neue Carbonsäurederivate, ihre Herstellung und Verwendung |
| MX9703988A (es) | 1994-12-12 | 1998-02-28 | Omeros Med Sys Inc | SOLUCIaN Y MÉTODO DE IRRIGACIaN PARA LA INHIBICIaN DEL DOLOR, LA INFLAMACIaN Y ES ESPASMO. |
| PL184060B1 (pl) * | 1995-01-27 | 2002-08-30 | Rhone Poulenc Rorer Ltd | Podstawione związki fenylowe do zastosowania jako środki antagonistyczne endoteliny |
| DE19636046A1 (de) | 1996-09-05 | 1998-03-12 | Basf Ag | Neue Carbonsäurederivate, ihre Herstellung und Verwendung als gemischte ET¶A¶/ET¶B¶-Rezeptorantagonisten |
| DE19652374A1 (de) * | 1996-12-04 | 1998-06-10 | Schering Ag | Verwendung von Endothelin-Konjugaten in der Therapie, neue Endothelin-Konjugate, diese enthaltende Mittel, sowie Verfahren zu deren Herstellung |
| HUP0000553A3 (en) * | 1996-12-18 | 2001-08-28 | Abbott Gmbh & Co Kg | Sixmembered nitrogencontained heteroaromatic carboxylic acid derivatives, pharmaceutical compositions containing them, and their use for producing pharmaceutical compositions |
-
1997
- 1997-09-30 DE DE19743143A patent/DE19743143A1/de not_active Withdrawn
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1998
- 1998-09-10 US US09/508,989 patent/US6352992B1/en not_active Expired - Lifetime
- 1998-09-10 CZ CZ20001081A patent/CZ298745B6/cs not_active IP Right Cessation
- 1998-09-10 WO PCT/EP1998/005772 patent/WO1999016444A1/de active IP Right Grant
- 1998-09-10 ES ES98945323T patent/ES2199461T3/es not_active Expired - Lifetime
- 1998-09-10 CA CA002304698A patent/CA2304698C/en not_active Expired - Fee Related
- 1998-09-10 RU RU2000111500/14A patent/RU2213577C2/ru not_active IP Right Cessation
- 1998-09-10 DE DE59808297T patent/DE59808297D1/de not_active Expired - Lifetime
- 1998-09-10 CN CNB988097273A patent/CN1149087C/zh not_active Expired - Fee Related
- 1998-09-10 EP EP98945323A patent/EP1019055B1/de not_active Expired - Lifetime
- 1998-09-10 HU HU0004590A patent/HU226745B1/hu not_active IP Right Cessation
- 1998-09-10 JP JP2000513580A patent/JP4608093B2/ja not_active Expired - Fee Related
- 1998-09-10 KR KR1020007003346A patent/KR100623122B1/ko not_active IP Right Cessation
- 1998-09-10 AU AU92672/98A patent/AU739860B2/en not_active Ceased
- 1998-09-10 BR BR9812404-8A patent/BR9812404A/pt active Search and Examination
- 1998-09-10 AT AT98945323T patent/ATE239479T1/de active
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2000
- 2000-03-29 NO NO20001634A patent/NO319048B1/no not_active IP Right Cessation
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Also Published As
| Publication number | Publication date |
|---|---|
| RU2213577C2 (ru) | 2003-10-10 |
| CZ20001081A3 (en) | 2001-05-16 |
| EP1019055B1 (de) | 2003-05-07 |
| NO20001634L (no) | 2000-03-29 |
| AU739860B2 (en) | 2001-10-25 |
| KR20010015650A (ko) | 2001-02-26 |
| CN1272786A (zh) | 2000-11-08 |
| HUP0004590A3 (en) | 2002-01-28 |
| CA2304698A1 (en) | 1999-04-08 |
| ES2199461T3 (es) | 2004-02-16 |
| DE59808297D1 (de) | 2003-06-12 |
| NO20001634D0 (no) | 2000-03-29 |
| DE19743143A1 (de) | 1999-04-01 |
| CA2304698C (en) | 2008-02-19 |
| HK1032355A1 (en) | 2001-07-20 |
| CZ298745B6 (cs) | 2008-01-16 |
| US6352992B1 (en) | 2002-03-05 |
| EP1019055A1 (de) | 2000-07-19 |
| AU9267298A (en) | 1999-04-23 |
| JP2001517703A (ja) | 2001-10-09 |
| NO319048B1 (no) | 2005-06-06 |
| BR9812404A (pt) | 2000-09-19 |
| ATE239479T1 (de) | 2003-05-15 |
| HU226745B1 (en) | 2009-09-28 |
| HUP0004590A2 (hu) | 2001-11-28 |
| WO1999016444A1 (de) | 1999-04-08 |
| KR100623122B1 (ko) | 2006-09-12 |
| JP4608093B2 (ja) | 2011-01-05 |
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