CN1198619C - 苯并氮杂䓬-n-乙酸衍生物在制备治疗肺高血压的药物中的应用 - Google Patents
苯并氮杂䓬-n-乙酸衍生物在制备治疗肺高血压的药物中的应用 Download PDFInfo
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Abstract
本发明涉及苯并氮杂䓬-N-乙酸衍生物,该衍生物在相对氮原子的α位上含有氧代基团并且在3位是被1-(羧基烷基)-环戊基-羰基氨基取代的,以及这些衍生物的盐和生物不稳定的酯在大的哺乳动物和尤其人类中治疗高血压,特别是治疗某些类型的继发性高血压的应用,并涉及用于这一治疗的合适的药物的制备。需要治疗高血压的起因可以基于不同的原因。本发明特别涉及那些由各种非心脏疾病引起的继发性高血压。
Description
发明描述
本发明涉及在相对氮原子的α位上含有氧代基团并且在3-位是被1-(羧基烷基)-环戊基-羰基氨基取代的苯并氮杂-N-乙酸衍生物及其盐和生物不稳定的酯在大的哺乳动物和人类中治疗高血压,特别是治疗某些类型的继发性高血压和在制备用于这一治疗的合适的药物中的应用。在此需要治疗高血压的起固可以基于各种原因。本发明特别涉及那些可由各种非心脏疾病引起的继发性高血压。
在相对氮原子的α位上含有氧代基团并且在3-位是被1-(羧基烷基)-环戊基-羰基氨基取代的苯并氮杂-N-乙酸衍生物及其盐和生物不稳定的酯属于在德国专利申请DE 195 10 566中描述的、具有心脏NEP-抑制作用的、在相对氮原子的α位上含有氧代基团并且在3-位是被1-(羧基烷基)-环戊基-羰基氨基取代的苯并氮杂-、苯并氧氮杂(Benzoxazepin)-和苯并硫氮杂(Benzothiazepin)-N-乙酸衍生物的保护范围内。这些在本发明中使用的苯并氮杂-N-乙酸衍生物可按DE 19510 566描述的方法制备。
本发明的目的是开发新的、治疗高血压,特别是治疗某些类型的继发性高血压的药物。本发明的目的优选涉及开发治疗可由各种非心脏疾病引起的继发性高血压的新药物。
现在按发明应用通式I化合物和式I化合物的酸的生理上可接受的盐制备在较大的哺乳动物和人类中治疗高血压,特别是治疗某些类型的继发性高血压的药物。
其中
R1为苯基低级烷基,其苯环可任选被低级烷基、低级烷氧基或卤素取代,或为萘基低级烷基,
R2为氢或形成生物不稳定的酯的基团和
R3为氢或者形成生物不稳定的酯的基团。
如果式I化合物中的取代基是或者包含低级烷基-或烷氧基,这些基团可以是直链的或支链的并且尤其包含1到4个,优选1到2个碳原子并且优选代表甲基或甲氧基。如果这些取代基包含卤素,合适的为氟、氯或溴,优选为氟或氯。
在基团R1中的低级烷基可包含1到4个,优选1到2个碳原子。特别是R1表示任选取代的苯乙基,该苯乙基可任选被卤素、低级烷氧基或低级烷基一取代或多取代,或者表示萘乙基。
式I化合物表示任选酯化的二羧酸衍生物。按应用形式生物不稳定的单酯,特别是其中R2为形成生物不稳定酯的基团和R3为氢的化合物或者二羧酸为优选的,其中后者特别适合于静注用药。
作为形成生物不稳定酯的基团R2和R3合适的是低级烷基、任选在苯环上被低级烷基或被连接在两个相邻碳原子上的低级亚烷基链取代的苯基或苯基低级烷基、在二氧戊环上任选被低级烷基取代的二氧戊环甲基,优选(2,2-二甲基-1,3-二氧戊环-4-基)甲基,或者任选在氧基甲基上被低级烷基取代的C2-C6烷酰基氧基甲基。如果形成生物不稳定酯的基团R2和R3为低级烷基,这一低级烷基优选表示具有1到4,优选2个碳原子的直链烷基。如果该形成不稳定酯的基团是任选被取代的苯基低级烷基,其亚烷基链含有1-3个,优选1个碳原子。如果苯基被低级亚烷基链取代,这一低级亚烷基链优选包含3到4,特别是包含3个碳原子。作为含苯基的取代基R2和R3合适的特别是苯基、苄基或2,3-二氢化茚基。如果R2和/或R3表示任选取代的烷酰基氧基甲基,其烷酰基氧基包含2到6,优选3到5个碳原子并且优选为支链的,例如表示新戊酰基氧基甲基(=叔丁基羰基氧基甲基)。
作为生理上可接受的式I的二羧酸或单酯的盐合适的是其碱金属盐、碱土金属盐或铵盐,例如钠盐或钾盐或与生理上可接受的、药学上中性的有机胺如二乙胺或叔丁胺的盐。
式I化合物包含两个手性中心,即在环3-位上带有酰胺侧链的碳原子和酰胺侧链上带有基团R1的碳原子。因此这些化合物以多个光学活性立体异构体或者作为外消旋形式存在。按本发明既可使用式I化合物的外消旋混合物又可以使用异构体纯的化合物。
现在已令人惊奇地发现,本发明所应用的式I化合物-特别也考虑到某些类型的继发性高血压-具有降低人类和较大哺乳动物血压的作用。因此这些式I化合物和其酸的生理可接受的盐及其生物不稳定的酯适合于治疗高血压,特别是治疗某些类型的继发性高血压,其中要治疗的高血压可以是由不同原因引起的。
在此有利的是,式I化合物,包括其酸的盐及其生物不稳定的酯适合于治疗由于各种非-心脏疾病引起的继发性高血压。
高血压应理解为血压超出通常水平,主要表现为动脉高血压。看一下高血压的形成原因将分为两种疾病类型,一种是自发的或原发性的高血压,另一种是继发性高血压类型。自发型高血压一般是由于开始时纯功能性的,后来器质性的动脉血路的狭窄引起的流动阻力升高。相反,继发性的或也是症状型的高血压是与器官有关的,即一种器官的疾病引起的高血压,这种高血压可以表现为例如内分泌的、肾的、肺的或心血管的高血压。导致继发性高血压的源发性疾病可以是各种各样的,例如慢性阻塞性肺病和呼吸道疾病或者慢性哮喘。因此在成年人的肺中正常的血液循环在低压力和小阻力下进行。但是,如在慢性阻塞性呼吸道疾病中会出现的慢性机体缺氧的存在引起肺动脉压力过高和肺小动脉的重建(Remodelling)(血管肌细胞的生长加强)和右心室的重建(Remodelling)(心肌细胞的生长加强)。
特别有利的是式I化合物,包括其酸的盐和其生物不稳定的酯可用于治疗肺高血压,特别是也在非心脏起因的情况下。在这种情况下肺高血压可以是原发性形式(原因不明)或是继发性肺高血压并可用式I化合物或其酸的生理上可接受的盐或其生物不稳定的酯治疗。
(继发性)肺高血压(小循环中的高血压)应理解为平静状态下肺动脉系统中恒定的平均血压升高超过22mmHg。这一平均血压的升高可以是例如由于心脏引起的小循环中的堵塞(例如二尖瓣病、左心机能不全)、毛细血管区域前的血管痉挛(例如由于在高原逗留的机体缺氧、阻塞性肺气肿、使肺变小的手术后)、继发性血管收缩(在肺纤维变性、破坏性肺气肿时)、超血流,即在具有伴随性空隙(Lichtung)狭窄的血管疾病的肺循环中过度循环(例如具有大的左向右分流的心脏瓣膜病)、复发性肺栓塞、在服用某些抑食欲药(如阿米雷司)中的副作用或由于原发性肺血管变窄(=自发性=原发性血管的肺高压)产生的。
为按本发明治疗高血压可口服、静脉内或也可用经皮施用式I化合物和其酸的生理可接受的盐和生物不稳定的酯的常规药物制剂。
因此式I化合物和其酸的生理可接受的盐和生物不稳定的酯可以降血压有效量与常规药物助剂和/或载体一起包含于固体或流体的药物制剂中。固体制剂例如是可口服的制剂如片剂、糖衣药丸、胶囊剂、粉剂或颗粒剂,或者栓剂或膏药(经皮治疗体系)。这些固体制剂除药物常用助剂,例如润滑剂、片剂崩解剂外可包含制药常用的无机和/或有机载体如乳糖、滑石或淀粉。流体制剂如活性物质的溶液、悬浮液或乳液可包含常用稀释剂如水、油和/或悬浮剂如聚乙二醇等。此外可加入其它助剂,如防腐剂、调味剂。
这些活性物质可与药物助剂和/或载体按本身已知的方式混合并配制。为制备固体制剂可将活性组分与例如助剂和/或载体按常规方式混合并湿或干制粒。可将颗粒或粉末直接装入胶囊中或以常规方式压成片核。片核可在需要情况下按常规方式包衣。可通过将活性组分及任选的其它助剂溶解或分散到合适的流体载体中得到溶液或悬浮液形式的流体制剂。
按发明使用的式I化合物的降血压作用可用体内药理试验在慢性缺氧的大鼠上通过测定与对此合适的药理指标相关的物质的作用,例如通过测定缺氧大鼠中肺动脉血压和右心室的重量,以及通过测量肺血管重建证明。
测试方法和结果描述
用(3S,2R’)-3-[1-(2’-(羧基-4’-苯基丁基)-环戊烷-1-羰基氨基]-2,3,4,5-四氢-2-氧代-1H-1-苯并氮杂-1-乙酸作为测试物质代表可使用的本发明式I化合物。物质的给药剂量为每天40mg/kg(足以抑制大内皮(Big Endothelin)舒张压(Druck-Rueckkopplung)。
用Sprague-Dawley大鼠(260-310g;每组n=6-10)作为试验动物,为造成肺高血压将动物在压力室急性缺氧的条件下饲养。为了对照将对照组在正常空气下及另一对照组在缺氧条件下饲养。
试验如下进行:
通过渗透微泵用活性物质或赋型剂治疗试验动物。在为将动物24小时后安置在压力室为期2周之前将渗透微泵植入动物的腹膜内。在那里于常压下或者在缺氧条件下(10%O2)或者在正常的空气中饲养动物。2周后进行动物的血液动力学试验的准备和测量。
血液动力学试验:
将动物麻醉,然后用常规方式经右颈静脉、心房和心室在肺动脉中插入预备的套管针。将一根导管插入左颈静脉,以能经静注给以活性物质。为测量系统的血压同样将一根套管针插在左颈动脉。在动物醒后记录肺的动脉压(PAP=肺动脉压)。然后将动物重新置于缺氧条件(10%O2)下的微室中10分钟,测量并记录肺动脉压的上升。测试物质在正常供氧和缺氧条件下对PAP的效果列于表1与对照组比较。给出的数据是平均值±标准偏差并用ANOVA进行统计处理。
抗肥大作用的测定:
在血液动力学试验之后将动物杀死并将心脏取出解剖。称量右心室和左心室的重量并与体重相比。在常氧条件下和缺氧条件下测试物质对心脏重量的作用列于表1中与对照试验比较。所给数据为平均值±标准偏差并用ANOVA进行统计处理。
对肺动脉重建作用的试验:
杀死大鼠后除取心脏外也取出肺脏。对后者进行组织学研究,即按“van Gieson”的方法在400倍放大下确定远侧肺血管肌组织化的程度。在2周的缺氧期间测试物质对肺动脉重建(即远侧肺血管肌组织化)的作用列于表2中与对照试验比较。所给数据为平均值±标准偏差并用ANOVA进行统计处理。
结果:
在所述测试方法中用测试物质治疗缺氧动物产生肺动脉压(PAP)与缺氧对照动物相比统计学上明显降低(表1)。与此同时对正常的系统血压没有影响,即没有发现低血压性能。这是一个特别的优点,因为在患肺高血压的正常血压的人中不必担心血压会降到正常值以下。
表1:
在14天的常氧和缺氧条件下本发明所用物质(40mg/kg/天,历经14天)对大鼠肺动脉压和右心重量和左心重量的作用。
参数 | 常氧 | 缺氧 | ||
对照n=9 | 测试物质n=8 | 对照n=10 | 测试物质n=9 | |
PAP(mgHg) | 19.9±2 | 22.2±1 | 42.9±1.6* | 33.2±1.2*# |
RtHWt(mg) | 178±10 | 171±10 | 269±4.5* | 242±6.4*# |
Rt/LtHWt(mg/mg) | 0.25±0.01 | 0.25±0.01 | 0.45±0.01* | 0.40±0.02* |
RtHWt/BW(mg/g) | 0.54±0.02 | 0.56±0.03 | 0.94±0.02* | 0.87±0.03* |
表注:
*与常氧下的对照相比显著不同(p<0.05)
#与缺氧下的对照相比显著不同(p<0.05)
PAP=肺动脉压
RtHWt=右心室的重量(mg)
Rt/LtHWt=右心室与左心室的重量比
RtHWt/BW=右心室与体重之比
与缺氧对照试验相比(表1)通过测试物质使肺动脉压的降低导致大鼠的右心重量(抗肥大作用)统计学上明显降低。降低右心与左心重量比及右心重与体重之比的趋势也被记录下来(表1)。
此外,测试物质统计学上明显降低大鼠远侧肺血管的肌组织化(表2)。这一肺动脉重建的降低同样是肺高血压统计学上明显降低的结果。
表2:
在14天的缺氧期间与缺氧条件下的对照相比本发明所用物质(40mg/kg/天,历经14天)对大鼠远侧肺血管肌组织化的作用。
参数 | 14天缺氧 | |
对照n=6 | 测试物质n=8 | |
肌组织化(%) | 76±4 | 52±5* |
部分肌组织化(%) | 23±4 | 39±4* |
非肌组织化(%) | 1±1 | 9±3 |
*与缺氧对照试验相比明显不同(p<0.05)
根据它们前述的作用,式I化合物及其盐和生物不稳定的酯适合用作用于较大哺乳动物和人类治疗高血压,特别是治疗某些类型的继发性高血压的药物。本发明所用的化合物尤其适合于治疗由于各种非心脏疾病引起的继发性高血压,例如优选治疗非心脏引起的肺高血压。因此本发明所用物质提供有利的配方用于治疗和/或预防特别是缺氧引起的肺高血压及其并发症,但不损害正常的系统血压。
在此式I的二羧酸和其盐有利地以非肠道,特别是可静注的剂型和式I的单酯或二酯有利地以可口服的剂型用药。要用药的剂量可依个体而不同并随要治疗的疾病的类型,所用的物质和用药方式变化。例如一般非肠道剂型活性物质的含量少于口服制剂。但一般适合于较大的哺乳动物,特别是人类服用的药物每单剂量含有1-200mg的活性物质。在此药物制品中的式I化合物,包括其酸的盐和其生物不稳定的酯既可以快速又可以缓释、控释和/或控释活性物质释放的形式给药。
下列实施例用于更详细说明本发明,但这些实施例不限定本发明的范围。
下列实施例1和实施例2描述本发明的含有式I的活性物质的药物制剂以及这些药物制剂的制备。为此本发明所用的式I化合物可按照在已经提到的德国专利申请DE195 10 566中描述的方法制备。实施例3提到用于本发明应用的优选的化合物。
实施例1:
含有(3S,2’R)-3-{1-[2’-(乙氧基羰基)-4’-苯基丁基]-环戊烷-1-羰基氨基}-2,3,4,5-四氢-2-氧代-1H-1-苯并氮杂-1-乙酸的片剂
按每片包含下列组分制备片剂:
(3S,2’R)-3-{1-[2’-(乙氧基羰基)-4’-苯基丁基]-环戊烷-1-羰基氨基}-2,3,4,5-四氢-2-氧代-1H-1-苯并氮杂-
1-乙酸 20mg
玉米淀粉 60mg
乳糖 135mg
明胶(10%的溶液) 6mg
用10%的明胶溶液将活性物质、玉米淀粉和乳糖变浓。将糊状物切碎并将形成的颗粒置于合适的铁片上在45℃下干燥。将干燥颗粒通过破碎机并在混合器中进一步与下列助剂混合:
滑石 5mg
硬脂酸镁 5mg
玉米淀粉 9mg
然后压成240mg的片剂。
实施例2:
含有(3S,2’R)-3-[1-(2’-羧基-4’-苯基丁基)-环戊烷-1-羰基氨基]-2,3,4,5-四氢-2-氧代-1H-1-苯并氮杂-1-乙酸的注射液
按每5ml中包含下列组分制备注射液:
(3S,2’R)-3-[1-(2’-羧基-4’-苯基丁基)-环戊烷-1-羰基氨基]-2,3,4,5-四氢-2-氧代-1H-1-苯并氮杂-1-
乙酸 10mg
Na2HPO4·7H2O 43.24mg
NaH2PO4·2H2O 7.72mg
NaCl 30.0mg
纯水 4948.0mg
将固体物质溶于水中,进行溶液灭菌并以每份各5ml装入安瓿。
实施例3:
根据本发明用于制备治疗高血压,特别是治疗如肺高血压的继发性高血压的药物优选的式I化合物是例如(包括酸的盐):
3-{1-[2’-(乙氧基羰基)-4’-苯基丁基]-环戊烷-1-羰基氨基}-2,3,4,5-四氢-2-氧代-1H-1-苯并氮杂-1-乙酸叔丁基酯。
3-{1-[2’-(乙氧基羰基)-4’-苯基丁基]-环戊烷-1-羰基氨基}-2,3,4,5-四氢-2-氧代-1H-1-苯并氮杂-1-乙酸。
(3S,2’R)-3-{1-[2’-(乙氧基羰基)-4’-苯基丁基]-环戊烷-1-羰基氨基}-2,3,4,5-四氢-2-氧代-1H-1-苯并氮杂-1-乙酸叔丁基酯。
(3S,2’R)-3-{1-[2’-(乙氧基羰基)-4’-苯基丁基]-环戊烷-1-羰基氨基}-2,3,4,5-四氢-2-氧代-1H-1-苯并氮杂-1-乙酸。
(3S,2’R)-3-{1-[2’-(羧基-4’-苯基丁基]-环戊烷-1-氨基甲酰基氨基}-2,3,4,5-四氢-2-氧代-1H-1-苯并氮杂-1-乙酸。
3-{1-[2’-(叔丁氧基羰基)-4’-苯基丁基]-环戊烷-1-羰基氨基}-2,3,4,5-四氢-2-氧代-1H-1-苯并氮杂-1-乙酸叔丁基酯。
3-[1-(2’-羧基-4’-苯基丁基)-环戊烷-1-羰基氨基]-2,3,4,5-四氢-2-氧代-1H-1-苯并氮杂-1-乙酸。
3-{1-[2’-(叔丁氧基羰基)-4’-苯基丁基]-环戊烷-1-羰基氨基}-2,3,4,5-四氢-2-氧代-1H-1-苯并氮杂-1-乙酸苄基酯。
3-[1-(2’-羧基-4’-苯基丁基)-环戊烷-1-羰基氨基]-2,3,4,5-四氢-2-氧代-1H-1-苯并氮杂-1-乙酸苄基酯。
3-{1-[2’-(叔丁基羰基氧基甲氧基羰基)-4’-苯基丁基]-环戊烷-1-羰基氨基}-2,3,4,5-四氢-2-氧代-1H-1-苯并氮杂-1-乙酸苄基酯。
3-{1-[2’-(新戊酰氧基甲氧基羰基)-4’-苯基丁基]-环戊烷-1-羰基氨基}-2,3,4,5-四氢-2-氧代-1H-1-苯并氮杂-1-乙酸。
Claims (6)
2.按照权利要求1的化合物的应用,其中R2和/或R3为形成生物不稳定酯的基团。
3.按照权利要求1或2的化合物的应用,其中形成生物不稳定酯的基团为C1-C4-烷基、苯环上非必需地被C1-C4-烷基或被连在2个相邻碳原子上的C1-C4-亚烷基链取代的苯基或苯基-(C1-C4-烷基),在二氧戊环上非必需地被C1-C4-烷基取代的二氧戊环甲基,或者非必需地在氧基甲基上被C1-C4-烷基取代的C2-C6烷酰基氧基甲基。
4.按照权利要求3的化合物的应用,其中形成生物不稳定酯的基团为苯基、苄基、2,3-二氢化茚基、(2,2-二甲基-1,3-二氧戊环-4-基)甲基。
5.按照权利要求1或2的化合物的应用,其特征是R2为形成生物不稳定酯的基团和R3为氢。
6.按照权利要求5的化合物的应用,其特征是使用(3S,2′R)-3-{1-[2’-(乙氧基羰基)-4’-苯基丁基]-环戊烷-1-羰基氨基}-2,3,4,5-四氢-2-氧代-1H-1-苯并氮杂-1-乙酸或其生理上可接受的盐。
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DE19906310A DE19906310A1 (de) | 1999-02-16 | 1999-02-16 | Arzneimittel zur Behandlung von Bluthochdruck |
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EP (1) | EP1154777B1 (zh) |
JP (1) | JP2002537258A (zh) |
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DE19932555A1 (de) * | 1999-07-13 | 2001-01-18 | Solvay Pharm Gmbh | Arzneimittel mit protektiver Wirkung gegen oxidativ-toxische und insbesondere gegen kardiotoxische Substanzen |
AU784327B2 (en) * | 1999-11-19 | 2006-03-09 | Abbvie B.V. | Human enzymes of the metalloprotease family |
ATE367815T1 (de) * | 2000-10-04 | 2007-08-15 | Astellas Pharma Inc | Verwendung von einem vasopressin-antagonisten wie conivaptan zur herstellung eines medikaments für die behandlung der pulmonalen hypertension |
AR039352A1 (es) * | 2001-05-18 | 2005-02-16 | Solvay Pharm Gmbh | Uso de un compuesto que tiene actividad inhibitoria combinada y concurrente con endopeptidasa neutra y metaloproteasa igs5. |
DE60234952D1 (de) * | 2001-09-10 | 2010-02-11 | Tibotec Pharm Ltd | VERFAHREN ZUR HERSTELLUNG VON HEXAHYDROFUROc2,3-BÜFURAN-3-OL |
EP1468010A1 (en) * | 2002-01-16 | 2004-10-20 | Solvay Pharmaceuticals B.V. | Solid salts benzazepine compounds and their use in the preparation of pharmaceuticals compounds |
AR038681A1 (es) * | 2002-02-14 | 2005-01-26 | Solvay Pharm Bv | Formulacion oral de solucion solida de una sustancia activa pobremente soluble en agua |
WO2004062692A1 (en) * | 2003-01-13 | 2004-07-29 | Solvay Pharmaceuticals B.V. | Formulation of poorly water-soluble active substances |
US7262184B2 (en) | 2003-09-26 | 2007-08-28 | Solvay Pharmaceuticals Gmbh | Amidomethyl-substituted 1-(carboxyalkyl) cyclopentyl-carbonylamino-benzazepine-N-acetic acid compounds, process and intermediate products for their preparation and pharmaceutical compositions containing them |
SA04250283B1 (ar) * | 2003-09-26 | 2008-05-26 | سولفاي فارماسيتيكالز جي أم بي أتش | مشتقات من amidomethy1-substituted1-(carboxyalkyl)-cyclopentylcarbonylamino-benzazepine-N-acetic acid |
US7427611B2 (en) | 2003-09-26 | 2008-09-23 | Solvay Pharmaceuticals Gmbh | Amidomethyl-substituted 1-(carboxyalkyl)-cyclopentyl-carbonylamino-benzazepine-N-acetic acid compounds, process and intermediate products for their preparation and pharmaceutical compositions containing them |
US7452875B2 (en) | 2003-09-26 | 2008-11-18 | Solvay Pharmaceuticals Gmbh | Amidomethyl-substituted 1-(carboxyalkyl) cyclopentyl-carbonylamino-benzazepine-N-acetic acid compounds, process and intermediate products for their preparation and pharmaceutical compositions containing them |
WO2005049035A1 (en) | 2003-11-18 | 2005-06-02 | Solvay Pharmaceuticals Gmbh | Pharmaceutical compositions for the treatment of renal dysfunction, disease or disorder, in particular in diabetic patients |
US20050267072A1 (en) * | 2004-05-14 | 2005-12-01 | Solvay Pharmaceuticals Gmbh | Pharmaceutical compositions containing dually acting inhibitors of neutral endopeptidase for the treatment of sexual dysfunction |
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 |
US20050288272A1 (en) * | 2004-06-23 | 2005-12-29 | Solvay Pharmaceuticals Gmbh | Pharmaceutical compositions comprising NEP-inhibitors, inhibitors of the endogenous endothelin producing system and AT1 receptor antagonists |
BRPI0519919A2 (pt) | 2004-12-15 | 2009-04-07 | Solvay Pharm Gmbh | composições farmacêuticas compreendendo inibidores da nep, inibidores do sistema de produção de endotelina endógena e inibidores da hmg coa redutase |
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 |
US20070292503A1 (en) * | 2006-06-16 | 2007-12-20 | Gorissen Henricus R | Oral pharmaceutical composition of poorly water-soluble active substance |
US20070299054A1 (en) * | 2006-06-22 | 2007-12-27 | Rajesh Jain | Oral pharmaceutical composition of a poorly water-soluble active agent |
HUE043235T2 (hu) * | 2008-01-31 | 2019-08-28 | Univ Vanderbilt | Terápiás kezelések tüdõbetegségekhez |
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US4749688A (en) * | 1986-06-20 | 1988-06-07 | Schering Corporation | Use of neutral metalloendopeptidase inhibitors in the treatment of hypertension |
EP0254032A3 (en) * | 1986-06-20 | 1990-09-05 | Schering Corporation | Neutral metalloendopeptidase inhibitors in the treatment of hypertension |
CA1337400C (en) * | 1987-06-08 | 1995-10-24 | Norma G. Delaney | Inhibitors of neutral endopeptidase |
US5362727A (en) * | 1993-07-26 | 1994-11-08 | Bristol-Myers Squibb | Substituted azepino[2,1-a]isoquinoline compounds |
DE19510566A1 (de) * | 1995-03-23 | 1996-09-26 | Kali Chemie Pharma Gmbh | Benzazepin-, Benzoxazepin- und Benzothiazepin-N-essigsäurederivate sowie Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel |
DE19638020A1 (de) * | 1996-09-18 | 1998-03-19 | Solvay Pharm Gmbh | Die gastrointestinale Durchblutung fördernde Arzneimittel |
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