CN103157111A - 新组合以及含有其的药物组合物 - Google Patents
新组合以及含有其的药物组合物 Download PDFInfo
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- CN103157111A CN103157111A CN2012105301129A CN201210530112A CN103157111A CN 103157111 A CN103157111 A CN 103157111A CN 2012105301129 A CN2012105301129 A CN 2012105301129A CN 201210530112 A CN201210530112 A CN 201210530112A CN 103157111 A CN103157111 A CN 103157111A
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- cis
- pyrroles
- benzoylamide
- propoxyl group
- memantine
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Images
Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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Abstract
式(I)的4-{3-[顺式-六氢环戊二烯并[c]吡咯-2(1H)-基]丙氧基}苯甲酰胺或其与可药用酸或碱的加成盐与NMDA谷氨酸能受体拮抗剂的组合产品以及含有其的药剂。
Description
技术领域
本发明涉及式(I)的4-{3-[顺式-六氢环戊二烯并[c]吡咯-2(1H)-基]丙氧基}苯甲酰胺或其与可药用酸或碱的加成盐与NMDA(N-甲基-D-门冬氨酸)谷氨酸能受体拮抗剂的新的组合产品：
用于获得用于治疗与脑衰老(cerebral ageing)和与神经变性疾病有关的认知障碍的药物组合物。
背景技术
4-{3-[顺式-六氢环戊二烯并[c]吡咯-2(1H)-基]丙氧基}苯甲酰胺具有与体内中枢组胺能系统相互作用的特征。这些特性使其在中枢神经系统中和更尤其是在治疗与脑衰老和与神经变性疾病有关的认知缺陷中具有活性。
4-{3-[顺式-六氢环戊二烯并[c]吡咯-2(1H)-基]丙氧基}苯甲酰胺、其制备及其治疗用途已经描述在专利申请W02005/089747中。
发明内容
申请人现在已经发现：与NMDA谷氨酸能受体拮抗剂组合使用的式(I)的4-{3-[顺式-六氢环戊二烯并[c]吡咯-2(1H)-基]丙氧基}苯甲酰胺或其与可药用酸或碱的加成盐对于治疗与脑衰老和与神经变性疾病有关的认知障碍具有有价值的性质。
与脑衰老相关的神经变性疾病如阿尔茨海默病的特征是记忆障碍和认知功能障碍。认知障碍通常与神经元合成和释放某些神经递质的能力下降有关。此外，还观察到突触可塑性和神经元过程的渐进性缺陷，这种神经元缺陷在脑内某些特定区域中加速。在各种神经递质中，中枢组胺和乙酰胆碱在认知功能的控制中起着关键作用(Witkin和Nelson，Pharmacol.&Therap.，2004，103，1-20)，已经证明它们在阿尔茨海默病患者的脑中的水平与在健康老年人群中观察到的那些相比显著降低(Panula等人，Neuroscience，1998，82(4)，993-997)。
在中枢神经系统中特别丰富的H3型组胺能受体主要是神经传递的突触前调节剂，它们存在于与认知有关的各种神经元回路中(Blandina等人，Learn Mem.，2004，11(1)：1-8)。它们通过负向调节神经递质如组胺、乙酰胆碱、血清素、去甲肾上腺素和多巴胺的释放而起作用。鉴于组胺能神经元显示在阿尔茨海默病中极其贫乏，因而作为H3受体的拮抗剂或反向激动剂的化合物能够给与脑衰老有关的认知障碍的新治疗开辟道路。
相反，在阿尔茨海默病的过程中观察到胆碱能神经元的渐进性退化和谷氨酸能神经传递的功能障碍。靶向于谷氨酸能系统、特别是NMDA受体提供了仅仅靶向于胆碱能系统的那些药物(即乙酰胆碱酯酶抑制剂)的一种供选治疗方法。美金刚是NMDA受体、烟碱性受体和5HT3血清素能受体的非竞争性拮抗剂，并且还具有多巴胺能成分(Lipton，Nat Rev DrugDiscov.，2006，5(2)：160-70；Aracava等人，J Pharmacol Exp Ther.，2005，312(3)：1195-205；Rammes等人，Neurosci Lett.，2001，306：81-84)。美金刚目前用于中度至严重形式的阿尔茨海默病的症状治疗。确实，已经证明美金刚象H3受体的拮抗剂/反向激动剂那样能够在情景记忆和工作记忆的各种动物模型中改善认知性能(Yuede等人，Behav.Pharmacol.，2007，18(5-6)：347-363)。因此，改善认知功能可以基于数种类型的靶向于尤其是组胺或谷氨酸能系统的策略。
本发明已经令人惊奇地证明：4-{3-[顺式-六氢环戊二烯并[c]吡咯-2(1H)-基]丙氧基}苯甲酰胺或其与可药用酸或碱的加成盐的作用增强了NMDA谷氨酸能受体拮抗剂的作用。因此，共同施用这些化合物与简单施用NMDA谷氨酸能受体拮抗剂相比能够改善患者的认知性能，然而没有增加与NMDA谷氨酸能受体拮抗剂治疗有关的副作用(尤其是嗜睡、头痛、眩晕感、血压升高、呼吸困难或便秘)。换言之，现在可以因此预期将4-{3-[顺式-六氢环戊二烯并[c]吡咯-2(1H)-基]丙氧基}苯甲酰胺与比单一疗法中常用剂量低的治疗剂量的NMDA受体拮抗剂联合并且具有等同的或者甚至更好的认知性能和较少的副作用。
这种不可预见的作用使得能够预期使用4-{3-[顺式-六氢环戊二烯并[c]吡咯-2(1H)-基]丙氧基}苯甲酰胺或其加成盐与NMDA受体拮抗剂的组合来治疗与脑衰老和与神经变性疾病有关的认知障碍。尤其靶向于与阿尔茨海默病有关的认知障碍。
在本发明的上下文中，4-{3-[顺式-六氢环戊二烯并[c]吡咯-2(1H)-基]丙氧基}苯甲酰胺优选以草酸盐或盐酸盐的形式进行使用。
在本发明的NMDA受体拮抗剂中，可以提及美金刚、L-4-氯-犬尿氨酸、1-(2，2-二苯基四氢呋喃-3-基)-N，N-二甲基甲胺(ANAVEX2-73)和(5R，9R，11E)-5-氨基-11-乙叉基-7-甲基-5，6，9，10-四氢-5，9-甲撑环辛间四烯并[b]吡啶-2(1H)-酮(石杉碱甲)。美金刚是尤其优选的。美金刚优选以盐酸盐的形式进行使用。
因此，本发明涉及4-{3-[顺式-六氢环戊二烯并[c]吡咯-2(1H)-基]丙氧基}苯甲酰胺或其与可药用酸或碱的加成盐与NMDA受体拮抗剂的组合在获得意欲用于治疗与脑衰老和与神经变性疾病有关的认知障碍的药物组合物中的用途。
更特别地，使用4-{3-[顺式-六氢环戊二烯并[c]吡咯-2(1H)-基]丙氧基}苯甲酰胺与美金刚的组合来治疗与阿尔茨海默病有关的认知障碍。
本发明还涉及药物组合物，其包含与一种或多种可药用赋形剂组合的4-{3-[顺式-六氢环戊二烯并[c]吡咯-2(1H)-基]丙氧基}苯甲酰胺或其与可药用酸或碱的加成盐与NMDA受体拮抗剂的组合。
在本发明的药物组合物中，活性成分的重量比例(活性成分的重量占组合物总重量的比例)为5至50％。
在本发明的药物组合物中，可以更尤其使用适于经口服、胃肠道外和尤其是静脉内、经皮或透皮、经鼻、直肠、经舌、经眼或呼吸道途径施用的那些，更特别是片剂、糖衣片、舌下片、硬明胶胶囊剂、glossettes、胶囊剂、锭剂、注射制剂、气雾剂、滴眼剂或滴鼻剂、栓剂、霜剂、软膏剂、皮肤凝胶剂等。
除了4-{3-[顺式-六氢环戊二烯并[c]吡咯-2(1H)-基]丙氧基}苯甲酰胺和NMDA受体拮抗剂化合物之外，本发明的药物组合物还包含一种或多种选自稀释剂、润滑剂、粘合剂、崩解剂、稳定剂、防腐剂、吸收剂、着色剂、甜味剂、矫味剂等的赋形剂或载体。
以非限制性举例的方式可以提及的有：
◆稀释剂：乳糖、右旋糖、蔗糖、甘露醇、山梨醇、纤维素、甘油，
◆润滑剂：二氧化硅、滑石粉、硬脂酸及其镁和钙盐、聚乙二醇，
◆粘合剂：硅酸镁铝、淀粉、明胶、西黄蓍胶、甲基纤维素、羧甲基纤维素钠和聚乙烯吡咯烷酮，
◆崩解剂：琼脂、海藻酸及其钠盐、泡腾混合物。
所述组合的化合物可以同时或依次进行施用。施用途径优选是口服途径，相应的药物组合物可以允许立即或延迟释放活性成分。而且，所述组合的化合物可以以各自含有活性成分之一的两种单独药物组合物的形式进行施用，或者以其中活性成分被混合的单一药物组合物的形式进行施用。
优选的药物组合物为片剂。
有用的剂量方案根据患者的性别、年龄及体重、施用途径、障碍的性质以及任意相关的治疗而不同，为每24小时0.5mg至100mg的4-{3-[顺式-六氢环戊二烯并[c]吡咯-2(1H)-基]丙氧基}苯甲酰胺，更优选每天2mg、5mg或20mg(以碱等同物表示)。NMDA受体拮抗剂的剂量将与其单独施用时所用的剂量相同或更少。对美金刚而言，剂量方案为每天1mg至20mg，优选的日剂量为10和20mg(对盐酸美金刚而言)。
在本发明的优选实施方案中，4-{3-[顺式-六氢环戊二烯并[c]吡咯-2(1H)-基]丙氧基}苯甲酰胺(化合物S)与美金刚的组合以如下剂量进行施用：
附图说明
图1是实施例A中按照Tronche等人，2010修改的方法。
图2是实施例A的试验所得的背景记忆能力结果。
具体实施方式
药物组合物：
用于制备1000片片剂的处方，每片片剂含有5.63mg4-{3-[顺式-六氢环戊二烯并[c]吡咯-2(1H)-基]丙氧基}苯甲酰胺盐酸盐(相当于5mg碱等同物)和10mg盐酸美金刚：
4-{3-[顺式-六氢环戊二烯并[c]吡咯-2(1H)-基]丙氧基}苯甲酰胺盐酸
盐....................................................................................5.63g
盐酸美金刚..............................................................................................10g
玉米淀粉.......................................................................................................20g
麦芽糖糊精.................................................................................................7.5g
胶体二氧化硅...............................................................................................0.2g
淀粉羟乙酸钠..................................................................................................3g
硬脂酸镁.......................................................................................................1g
乳糖...............................................................................................................55g
实施例A：
情景记忆模型试验，背景序列辨别测试(contextual serial discrimination
test)：
在中年(14-15月龄)C57B16小鼠(每组n＝12)中采用背景辨别测试研究了单独或组合施用的4-{3-[顺式-六氢环戊二烯并[c]吡咯-2(1H)-基]丙氧基}苯甲酰胺和美金刚(两者均为盐酸盐形式)的作用(Célérier等人，LearnMem.，2004，11(2)，196-204；Tronche等人，Behav.Brain Res.，2010，215(2)：255-60)。在该模型中，中年小鼠与年轻小鼠相比具有特定的背景情景记忆功能障碍，但是空间记忆没有缺陷。该模型用于评价产品在阿尔茨海默病中的作用，因为患有这种形式的痴呆的患者也具有背景情景记忆障碍，这是极早期阶段的情况(Gold和Budson，Expert Rev Neurother.，2008，8(12)：1879-1891)。
将小鼠置于边缘凸起的盒子中，在具有四个洞并且其中仅有一个洞有饵的底板上学习两种类型的连续空间辨别(D1：白色底板，然后D2：黑色底板)，在D1和D2中的安排是相反的。底板颜色(黑色或白色)构成了对每种辨别而言特定的内部背景。在学习步骤之后24小时，将小鼠放回白色背景底板，测试如下参数：
-正确反应百分数(即，将头探入在白色底板上学习训练期间有饵的洞中的％)，
-干扰反应百分数(即，将头探入在黑色底板上学习训练期间有饵的洞中的％，黑色底板是最后呈现给小鼠的背景)，和
-错误百分数(即，将头探入无论是在白色底板、还是在黑色底板上学习期间均没有饵的两个洞中的％)(参见图1)。
背景记忆能力定义为正确反应百分数和干扰反应百分数之间的差。
在该模型中已经证明中年小鼠与年轻小鼠相比有背景记忆缺陷，这归于如下事实：它们获知有饵的洞的位置的最后一个背景(即黑色底板)在很大程度上干扰了在学习期间所呈现的第一个背景(即白色底板)中的有饵的孔的记忆。由于该事实，老龄小鼠的背景记忆能力为负值，因为干扰反应百分数高于正确反应百分数。相反，年轻小鼠的背景记忆能力为正值(Tronche等人，Behav.Brain Res.，2010，215(2)：255-60)。
该研究的结果证实了中年小鼠有背景记忆缺陷，采用该实验的载体处置的小鼠显示出负的背景记忆能力，为-34％。采用4-{3-[顺式-六氢环戊二烯并[c]吡咯-2(1H)-基]丙氧基}苯甲酰胺盐酸盐(口服0.1mg/kg碱，该化合物在图2中称为化合物S)长期治疗9天后，与载体相比，没有观察到背景记忆能力显著提高(-15％对比于-34％)，干扰反应％维持大于正确反应％。此外，与载体相比，用盐酸美金刚以口服1mg/kg碱的剂量长期治疗9天后背景记忆能力略微提高(-2％对比于-34％)，但是仍然为负值(干扰反应％＞正确反应％)，导致1mg/kg剂量的盐酸美金刚为亚活性剂量的可能性。相反，与单独用载体获得的值相比，施用4-{3-[顺式-六氢环戊二烯并[c]吡咯-2(1H)-基]丙氧基}苯甲酰胺(口服0.1mg/kg碱)与美金刚(口服1mg/kg碱的亚活性剂量)的组合导致背景记忆能力有很大和显著的提高，背景记忆能力则为正值(正确反应％＞干扰反应％)。这些结果清楚地证明，亚活性剂量的美金刚的作用在非活性剂量的4-{3-[顺式-六氢环戊二烯并[c]吡咯-2(1H)-基]丙氧基}苯甲酰胺的存在下增强。
当美金刚(口服1mg/kg碱)与活性剂量的4-{3-[顺式-六氢环戊二烯并[c]吡咯-2(1H)-基]丙氧基}苯甲酰胺(口服1mg/kg碱)联合时也证实了这种增强：与单独施用美金刚相比，观察到经治疗小鼠的记忆性能有很大的提高，其在统计学上是显著的(背景记忆能力为+40％：对比于单独的美金刚的负反应-2％，该组合提供了非常正的反应)。也与单独的4-{3-[顺式-六氢环戊二烯并[c]吡咯-2(1H)-基]丙氧基}苯甲酰胺(口服1mg/kg碱)相比证实了用组合治疗的小鼠的记忆性能的这种增加(组合的背景记忆能力为+40％，而4-{3-[顺式-六氢环戊二烯并[c]吡咯-2(1H)-基]丙氧基}苯甲酰胺的背景记忆能力为+14％)，其在统计学上也是显著的。对两种组合所观察到的背景记忆能力的提高不能通过简单地将化合物单独施用时的作用相加而解释，这种提高显示了当两种化合物共同施用时它们的协同活性。
该结果清楚地证明，组合地施用这两种化合物使得能够获得完全无法预期的显著的协同作用。而且，药物动力学分析已经证明：在两种治疗之间没有药物动力学类型的相互作用，这可能调整或干扰上述协同作用。
总之，上文给出的结果证实了就认知性能而言4-{3-[顺式-六氢环戊二烯并[c]吡咯-2(1H)-基]丙氧基}苯甲酰胺与美金刚之间存在协同活性，对该情况而言没有药物动力学相互作用。
Claims (13)
1.式(I)的4-{3-[顺式-六氢环戊二烯并[c]吡咯-2(1H)-基]丙氧基}苯甲酰胺或其与可药用酸或碱的加成盐与NMDA谷氨酸能受体拮抗剂的组合产品：
2.根据权利要求1的组合产品，其特征在于4-{3-[顺式-六氢环戊二烯并[c]吡咯-2(1H)-基]丙氧基}苯甲酰胺以草酸盐或盐酸盐的形式进行使
用。
3.根据权利要求1或2的组合产品，其中NMDA谷氨酸能受体拮抗剂为美金刚。
4.根据权利要求1至3之一的组合产品，其中美金刚以盐酸盐的形式进行使用。
5.用作药剂的权利要求1至4之一的组合产品，其中(i)4-{3-[顺式-六氢环戊二烯并[c]吡咯-2(1H)-基]丙氧基}苯甲酰胺以盐酸盐形式以2mg、5mg或20mg(以碱等同物表示)的日剂量进行施用，和(ii)NMDA谷氨酸能受体拮抗剂为以10mg或20mg的日剂量进行施用的盐酸美金刚。
6.药物组合物，包含与一种或多种可药用赋形剂组合的作为活性成分的与根据权利要求1-4之一的NMDA谷氨酸能受体拮抗剂组合的4-{3-[顺式-六氢环戊二烯并[c]吡咯-2(1H)-基]丙氧基}苯甲酰胺或其与可药用酸或碱的加成盐。
7.根据权利要求6的药物组合物，用于治疗与脑衰老和与神经变性疾病有关的认知障碍。
8.根据权利要求7的药物组合物，用于治疗与阿尔茨海默病有关的认知障碍。
9.根据权利要求6的药物组合物，其特征在于其包含2mg、5mg或20mg(以碱等同物表示)的盐酸盐形式的4-{3-[顺式-六氢环戊二烯并[c]吡咯-2(1H)-基]丙氧基}苯甲酰胺和10mg或20mg的作为NMDA谷氨酸能受体拮抗剂的盐酸美金刚。
10.权利要求1至5之一的组合产品在制备意欲用于治疗与脑衰老和与神经变性疾病有关的认知障碍的药剂中的用途。
11.权利要求1至5之一的组合产品在制备意欲用于治疗与阿尔茨海默病有关的认知障碍的药剂中的用途。
12.根据权利要求1至5之一的4-{3-[顺式-六氢环戊二烯并[c]吡咯-2(1H)-基]丙氧基}苯甲酰胺或其与可药用酸或碱的加成盐与美金刚的组合产品，用于治疗与阿尔茨海默病有关的认知障碍。
13.根据权利要求1至5之一的4-{3-[顺式-六氢环戊二烯并[c]吡咯-2(1H)-基]丙氧基}苯甲酰胺或其与可药用酸或碱的加成盐与美金刚的组合产品在制备意欲用于治疗与阿尔茨海默病有关的认知障碍的药剂中的用途。
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| FR3003466B1 (fr) * | 2013-03-22 | 2015-08-07 | Servier Lab | Utilisation du 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1h)-yl]propoxy}benzamide pour le traitement des douleurs neuropathiques |
| KR101484405B1 (ko) * | 2013-08-14 | 2015-01-19 | 서울대학교산학협력단 | Ｎｉｎｊｕｒｉｎ１ 결핍 유래의 강박증 예방 또는 치료용 약학적 조성물 |
| GB201509134D0 (en) * | 2015-05-28 | 2015-07-15 | Electrophoretics Ltd | Biomolecules involved in Alzheimer's disease |
| CN107708687A (zh) * | 2015-07-22 | 2018-02-16 | 阿纳韦克斯生命科学公司 | 四氢‑N,N‑二甲基‑2,2‑二苯基‑3‑呋喃甲胺的对映体（ANAVEX2‑73）及其在治疗阿尔海默氏病和其他由σ1受体调节的疾病中的用途 |
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| US20050014743A1 (en) * | 2003-05-27 | 2005-01-20 | Forest Laboratories, Inc. | Combination of an NMDA receptor antagonist and a selective serotonin reuptake inhibitor for the treatment of depression and other mood disorders |
| EP1638560A1 (en) * | 2003-06-20 | 2006-03-29 | Eli Lilly And Company | 3-aminopiperidines and 3-aminoquinuclidines as inhibitors of monoamine uptake |
| CA2551689A1 (en) * | 2004-01-05 | 2005-07-28 | Merz Pharma Gmbh & Co. Kgaa | Memantine for the treatment of mild and mild-to-moderate alzheimer's disease |
| TW200531680A (en) * | 2004-03-03 | 2005-10-01 | Merz Pharma Gmbh & Co Kgaa | Therapy using 1-aminocyclohexane derivatives for the treatment of behavioral disorders associated with alzheimer's disease |
| JP2007529556A (ja) * | 2004-03-19 | 2007-10-25 | アクソニクス インコーポレイテッド | 認知障害の処置に有用なアセチルコリンエステラーゼ阻害剤およびｎ−メチル−ｄ−アスパラギン酸拮抗剤 |
| FR2937119B1 (fr) | 2008-10-15 | 2010-12-17 | Air Liquide | Procede de production d'energie et capture de co2 |
| FR2937251B1 (fr) * | 2008-10-16 | 2011-03-18 | Servier Lab | Utilisation du 4-{3-°hexahydrocyclopenta°c!pyrrol-2(1h)-yl! propoxy}benzamide pour l'obtention de medicaments destines au traitement des troubles du sommeil |
| FR2953515B1 (fr) * | 2009-12-09 | 2011-12-23 | Servier Lab | Nouveaux derives du type hexahydrocyclopenta[b]pyrrole, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
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