CN1384747A - 2-氨基-3,4-二氢喹啉类在生产用于治疗或预防因局部缺血情况导致的疾病的药物中的用途 - Google Patents
2-氨基-3,4-二氢喹啉类在生产用于治疗或预防因局部缺血情况导致的疾病的药物中的用途 Download PDFInfo
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Abstract
本发明涉及通式(I)的2-氨基-3,4-二氢喹唑啉类及其药物上可相容的盐在生产用于治疗和预防局部缺血性疾病的药物中的用途。R1、R2和R3具有权利要求中所述的含义。
Description
在通式I中:
R1和R2是氢、F、Cl、Br、I、直链或支链C1-C4-烷基,C1-C4-烷氧基,
R3是氢、直链或支链C1-C4-烷基或苯基,所述的苯核不被取代或带有一至三个选自F、Cl、CH3和CH3O的取代基。
优选的是通式I化合物及其盐的用途,其中:
R1和R2是氢、氟、氯、直链或支链C1-C4-烷基,C1-C4-烷氧基;
R3是氢或甲基。
如果R1、R2和R3三个取代基之一含有一个不对称中心,那么本发明包括S和R构型的化合物。这些化合物可以作为旋光异构体、非对映异构体、外消旋物或其混合物的形式存在。
从下列文献得知通式I的化合物:
EP530994,其中将它们描述为适应征AIDS中HIV逆录酶的抑制剂;
美国专利号US3,560,050,其中描述了它们的止痛、利尿和抗炎作用;和
Kosasayama等,《化学药物简报》(Chem.Pharm.Bull.)27,880(1979)和Ishikawa等,文献同上,28,1357(1980),其中能够显示2-氨基-4-苯基-3,4-二氢喹唑啉对血小板聚集的抑制作用。
目前已经令人惊奇地发现这些已知化合物的显著特征在于对Na+/H+交换的抑制作用。因此,作为其药理特性的结果,它们非常适合于生产具有用于预防梗塞和治疗梗塞以及治疗心绞痛的心脏保护成分的抗心律失常药,其中也可以以预防方式抑制或显著减少局部缺血诱发的损害形成中、特别是引起局部缺血诱发的心律失常过程中的病理生理学过程。由于本发明所用的通式I的化合物对病理性缺氧和局部缺血情况的保护作用,作为对细胞Na+/H+交换机制产生抑制作用的结果,它们可以用作治疗因局部缺血导致的所有急性或慢性损害或由此以原发或继发方式诱发的疾病的药物。这一结果与其作为用于例如器官移植形式的手术干预的药物相关,其中可以将本发明所用的化合物用于在将器官取出供体前后对其进行保护,例如在用生理浴液处理或储存过程中和在转移至受体过程中保护取出的器官。本发明所用的化合物在例如对心脏和外周血管实施血管成形的手术干预时也是具有保护作用的有价值的药物。根据所述化合物对局部缺血诱发的损害的保护作用,它们还适合作为治疗神经系统局部缺血、特别是中枢神经系统局部缺血的药物,其中它们适合于例如治疗中风或脑水肿。此外,通式I的化合物还适合于治疗各种形式的休克,例如过敏性休克、心源性休克、血容量减少性休克和细菌性休克。
此外,本发明所用的通式I化合物的显著特征在于对细胞增殖、例如成纤维细胞增殖和血管平滑肌细胞增殖的强抑制作用。本发明所用的通式I的化合物由此适合用作细胞增殖是原发或继发原因的疾病的有价值的治疗药物,并且由此可以用作抗动脉粥样硬化药、针对下列疾病的活性剂:糖尿病晚期并发症;癌性疾病;纤维化疾病,诸如肺纤维化、肝纤维化或肾纤维化;器官肥大和增生、特别是前列腺增生和前列腺肥大。
本发明所用的化合物是细胞钠/质子反向转运剂(Na+/H+交换剂)的有效抑制剂,其中所述的细胞钠/质子反向转运剂(Na+/H+交换剂)可以在许多疾病(主要是高血压、动脉粥样硬化、糖尿病等)中增多、甚至在诸如例如红细胞、血小板或白细胞这样易于测定的那些细胞中也增多。本发明所用的化合物由此适合作为既突出又简单的有专长的工具,例如将它们用作确定和区分某些形式的高血压、还有动脉粥样硬化、糖尿病、增殖性疾病等的诊断剂。此外,本发明所用的通式I的化合物适用于预防高血压、例如原发性高血压发生的预防疗法。
此外,已经发现本发明所用的通式I的化合物对血清脂蛋白显示出有利作用。一般认识到就形成动脉硬化的血管改变、特别是在冠心病中动脉硬化的血管改变而言,过高的血脂值、即所谓的血脂蛋白过多是主要的危害因素。因此使升高的血清脂蛋白降低对预防动脉粥样硬化改变并使其退化而言具有特别的重要性。除降低总血清胆固醇外,降低这种总胆固醇的特异性致动脉粥样化的脂类部分、特别是低密度脂蛋白(LDL)和极低密度脂蛋白(VLDL)具有特别的重要性,因为这些脂类部分是致动脉粥样化的危害因素。然而,对冠心病的预防作用归因于高密度脂蛋白。因此,降脂血剂不仅应能够降低总胆固醇、而且特别应能够减少VLDL和LDL血清胆固醇部分。目前已经发现本发明所用的通式I的化合物就影响血清脂类水平而言表现出有价值的治疗应用特性。因此,例如,诸如所观察到的,它们可明显使因对富含胆固醇和富含脂类的膳食的饮食摄取量增加或病理代谢改变、例如一般相关的血脂过多所造成的升高的LDL和VLDL的血清浓度降低。由此可以将它们用于预防动脉粥样硬化改变并使其退化,即它们排除了一个构成因果的危害因素。这些疾病不仅包括原发性血脂过多、而且包括某些诸如例如在糖尿病中发生的继发性血脂过多。此外,本发明所用的通式I的化合物使因代谢异常诱发的梗塞明显降低,并且特别是使诱发的梗塞大小及其严重程度显著减少和降低。此外,本发明所用的通式I的化合物对抗因代谢异常诱发的内皮损害的产生有效保护作用。由于这种对抗内皮功能异常综合征的血管保护作用,所以通式I的化合物是预防和治疗冠状血管痉挛、动脉粥样化形成和动脉粥样硬化、左心室肥大和扩张性心肌病以及血栓形成疾病的有用的药物。
因此,本发明所用的化合物I可以有利地:
用于生产治疗血胆固醇过多的药物;
用于生产预防动脉粥样化形成的药物;
用于生产预防和治疗动脉粥样硬化的药物;
用于生产预防和治疗因胆固醇水平升高导致的疾病的药物;
用于生产预防和治疗因内皮功能异常导致的疾病的药物;
用于生产预防和治疗动脉粥样硬化诱发的高血压的药物;
用于生产预防和治疗动脉粥样硬化诱发的血栓形成的药物;
用于生产预防和治疗血胆固醇过多诱发的和内皮功能异常诱发的局部缺血性损害和局部缺血后再灌注损害的药物;
用于生产预防和治疗血胆固醇过多诱发的和内皮功能异常诱发的心脏肥大和心肌病的药物;
用于生产预防和治疗血胆固醇过多诱发的和内皮功能异常诱发的冠状血管痉挛和心肌梗塞的药物;
用于生产与降血压物质、优选与血管紧张素转化酶(ACE)抑制剂和血管紧张素受体拮抗剂组合的治疗上述疾病的药物。证明通式I的NHE抑制剂与降低血脂水平的活性化合物、优选与HMG-CoA还原酶抑制剂(例如洛伐他汀或普伐他汀)的联合用药是具有提高作用和减少活性化合物应用的有利的联合用药,其中HMG-CoA还原酶抑制剂可产生降血脂作用且由此提高通式I的NHE抑制剂的降血脂特性。
要求保护通式I的钠/质子交换抑制剂在生产用于降低血脂升高水平的新型药物中的用途以及钠/质子交换抑制剂与具有降血压和/或降血脂作用的药物的联合用药。
在这种情况中可以经口服、非肠道、静脉内、直肠或通过吸入给予含有化合物I的药物,优选的给药方式取决于疾病的特定过程。在这种情况中,可以将化合物I自身或与药物赋形剂一起用于兽用药和人用药。
本领域技术人员可以基于其专门知识而熟练使用适合于所需药物制剂的赋形剂。除溶剂、胶凝剂、栓剂基质、片剂赋形剂和其它活性化合物载体外,例如还能够使用抗氧化剂、分散剂、乳化剂、消泡剂、矫味剂、防腐剂、增溶剂或着色剂。
就口服给药形式而言,将本发明所用的活性化合物I与诸如载体、稳定剂或惰性稀释剂这样适合于该给药形式的添加剂混合,并通过常规方法制成合适的给药形式,诸如片剂、包衣片、硬胶囊、水溶液、醇溶液或油溶液。可以使用的惰性载体例如是阿拉伯树胶、氧化镁、碳酸镁、磷酸钾、乳糖、葡萄糖或淀粉、特别是玉米淀粉。在这种情况中,可以将制剂制成干颗粒或湿颗粒的形式。可能的油载体或溶剂例如是植物油或动物油,诸如向日葵油或鳕鱼肝油。
就皮下给药或静脉内给药而言,如果需要,将本发明所用的活性化合物与诸如增溶剂、乳化剂或其它赋形剂这样的常用物质一起制成溶液、混悬液或乳状液。合适的溶剂例如是:水;生理盐水溶液或例如乙醇、丙醇、甘油这样的醇类;此外还有糖溶液,诸如葡萄糖或甘露糖醇溶液;或上述各种溶剂的混合物。
给药用的气溶胶或喷雾剂形式的合适药物制剂例如是通式I活性化合物溶于诸如特别是乙醇或水或这类溶剂的混合物这样药物上可接受的溶剂所得到的溶液、混悬液或乳状液。如果需要,所述制剂还可以含有其它药物赋形剂,诸如表面活性剂、乳化剂和稳定剂以及推进剂。这类制剂通常含有约0.1-10%(重量)、特别是约0.3-3%(重量)浓度的活性化合物。
所给予的通式I活性化合物的剂量和给药频率取决于所用化合物的功效和作用期限、此外还取决于所治疗疾病的性质和严重性,并且取决于所治疗哺乳动物的性别、年龄、体重和个体反应性。
就体重约为75kg的患者而言,通式I化合物的每日剂量平均为至少0.001mg/kg体重、优选0.01mg/kg体重、最高达10mg/kg体重,优选1mg/kg体重。就疾病急性发作的情况而言,例如在患心肌梗塞后还可能必须立即给予甚至更高且尤其是更频繁的剂量,例如达到每天4次单个剂量。特别就静脉内给药而言,例如在使用加强护理装置(intensive care unit)的梗塞患者的情况中,剂量可能必须达到200mg/天。
实验部分
缩写表
DMSO 二甲亚砜
RT 室温
EA 乙酸乙酯(EtOAc)
m.p. 熔点
eq. 当量
实施例1:2-氨基-4-(4-甲氧基苯基)-3,4-二氢喹唑啉盐酸盐
无色固体,m.p.169℃,M++H=254。
合成路线:
在有碳酸钾存在的情况下,通过在DMSO中加热,使2-氨基苯基4-甲氧基苯基酮与1.2当量的甲脒盐酸盐反应,得到相应的喹唑啉。在形成水溶液后,使用10%Pd/C在乙醇中使粗产物氢化,并且随后进行柱层析,使用醚性氯化氢形成盐酸盐,产生固体产物。
实施例2:2-氨基-4-(3,4-二甲氧基苯基)-3,4-二氢喹唑啉鎓富马酸盐
无色固体,m.p.179℃,M++H=284。
按照与实施例1类似的方式,使用2-氨基苯基3,4-甲氧基苯基酮进行合成。为形成盐,使所述碱与1当量的富马酸的EA溶液反应。
实施例3:2-氨基-4-(3,4-二甲氧基苯基)-3-甲基-3,4-二氢喹唑啉鎓富马酸盐
无色固体,m.p.202℃,M++H=298。
合成路线:
使用甲胺/四氯化钛由原料2-氨基苯基-3,4-二甲氧基苯基酮制备相应的二苯甲基胺,并且随后使用硼氢化钠还原。使用过量的溴化氰使粗产物环化成3,4-二氢喹唑啉并进行柱层析。随后如实施例2)中所述进行盐形成。
药理学数据:
对兔子红细胞Na+/H+交换剂的抑制作用
使白色新西兰兔子(Ivanovas)接受含有2%胆固醇的标准膳食达6周以便激活Na+/H+交换,并且由此能够通过使用火焰光度法确定通过Na+/H+交换进入红细胞的Na+流量。从耳动脉取血并使用25IU的肝素钾使之不能凝固。通过离心将每份样品的部分用于一式两份测定血细胞比容。在每种情况中,将100μl的等分部分用于测定红细胞中Na+的起始含量。
为了测定阿米洛利敏感性钠流量,在37℃和pH7.4下温育在每种情况下均溶于5ml的高渗盐/蔗糖培养基(mmol/I:140NaCl、3KCl、150蔗糖、0.1乌巴因、20三-羟甲基-氨基甲烷)100μl的每份血样。然后用冰冷的MgCl2/乌巴因溶液(mmol/I:112MgCl2、0.1乌巴因)将所述的红细胞洗涤3次并使之在2.0ml蒸馏水中发生溶血。通过火焰光度法测定细胞内钠含量。
根据钠的原始值与温育后红细胞中钠含量之差来计算Na+净流量。阿米洛利可抑制的钠流量是根据与和不与3×10-4mol/I阿米洛利一起温育后红细胞中钠含量之差得出的。就本发明的化合物而言,所述步骤是相同的。
结果
对Na+/H+交换剂的抑制作用实施例IC50(mol/I)1:3.4×10-62:3.2×10-63:4.1×10-6
Claims (12)
2.权利要求1中所述的用途,其中在通式I中:
R1和R2是氢、氟、氯、直链或支链C1-C4-烷基,C1-C4-烷氧基;
R3是氢或甲基。
3.权利要求1-2中所述的化合物I在生产用于治疗或预防心肌梗塞的药物中的用途。
4.权利要求1-2中所述的化合物I在生产用于治疗或预防心绞痛的药物中的用途。
5.权利要求1-2中所述的化合物I在生产用于治疗或预防心脏局部缺血性疾病的药物中的用途。
6.如权利要求1-2中所述的化合物I在生产用于治疗或预防外周和中枢神经系统局部缺血性疾病和中风的药物中的用途。
7.权利要求1-2中所述的化合物I在生产用于治疗或预防外周器官和四肢局部缺血性疾病的药物中的用途。
8.权利要求1-2中所述的化合物I在生产用于治疗休克情况的药物中的用途。
9.权利要求1-2中所述的化合物I在生产用于手术操作和器官移植中使用的药物中的用途。
10.如权利要求1-2中所述的化合物I在生产用于手术措施的移植物的保存和储存的药物中的用途。
11.权利要求1-2中所述的化合物I在生产用于治疗细胞增殖是原发或继发原因的疾病的药物中的用途。
12.权利要求1-2中所述的化合物I在生产用于治疗或预防脂肪代谢紊乱的药物中的用途。
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DE19951702.9 | 1999-10-27 | ||
DE19951702A DE19951702A1 (de) | 1999-10-27 | 1999-10-27 | Verwendung von 2-Amino-3,4-dihydro-chinazolinen zur Herstellung eines Medikaments zur Behandlung oder Prophylaxe von durch ischämischen Zuständen bewirkten Krankheiten |
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DE10163914A1 (de) * | 2001-12-22 | 2003-07-03 | Aventis Pharma Gmbh | Substituierte 4-Phenyltetrahydroisochinolinium-Salze, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament, sowie sie enthaltendes Medikament |
DE10312963A1 (de) * | 2003-03-24 | 2004-10-07 | Aventis Pharma Deutschland Gmbh | Substituierte 4-Phenyltetrahydroisochinoline, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament, sowie sie enthaltendes Medikament |
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WO1994007498A1 (en) * | 1992-10-07 | 1994-04-14 | Sumitomo Pharmaceuticals Company, Limited | Pharmaceutical composition for inhibiting tumor necrosis factor production |
DE19713427A1 (de) * | 1997-04-01 | 1998-10-08 | Hoechst Ag | Ortho-substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
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HRP20020363A2 (en) | 2004-02-29 |
US6331546B1 (en) | 2001-12-18 |
NO20021710L (no) | 2002-04-11 |
EE200200215A (et) | 2003-06-16 |
WO2001030328A2 (de) | 2001-05-03 |
PL356399A1 (en) | 2004-06-28 |
HUP0203774A3 (en) | 2003-07-28 |
TR200201141T2 (tr) | 2002-11-21 |
HUP0203774A2 (en) | 2003-05-28 |
BR0014985A (pt) | 2003-07-22 |
ATE324111T1 (de) | 2006-05-15 |
DE19951702A1 (de) | 2001-05-03 |
NZ518588A (en) | 2004-06-25 |
CN1181822C (zh) | 2004-12-29 |
IL149160A0 (en) | 2002-11-10 |
JP2003512420A (ja) | 2003-04-02 |
CA2388965A1 (en) | 2001-05-03 |
NO20021710D0 (no) | 2002-04-11 |
TWI227135B (en) | 2005-02-01 |
WO2001030328A3 (de) | 2002-06-20 |
DE50012667D1 (de) | 2006-06-01 |
SK5582002A3 (en) | 2002-08-06 |
EP1244454A2 (de) | 2002-10-02 |
EP1244454B1 (de) | 2006-04-26 |
YU30602A (sh) | 2004-12-31 |
ZA200204057B (en) | 2003-02-26 |
RU2002113667A (ru) | 2004-01-10 |
AR026242A1 (es) | 2003-02-05 |
AU7664800A (en) | 2001-05-08 |
CZ20021414A3 (cs) | 2002-07-17 |
HK1050480A1 (en) | 2003-06-27 |
MXPA02004035A (es) | 2002-10-11 |
KR20020041831A (ko) | 2002-06-03 |
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