CN1222510C - 苯甲酰基胍盐 - Google Patents

苯甲酰基胍盐 Download PDF

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CN1222510C
CN1222510C CNB028049926A CN02804992A CN1222510C CN 1222510 C CN1222510 C CN 1222510C CN B028049926 A CNB028049926 A CN B028049926A CN 02804992 A CN02804992 A CN 02804992A CN 1222510 C CN1222510 C CN 1222510C
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benzoylguanidines
heart
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克里斯琴·艾克迈耶
彼得·西格
沃尔克马·科纳
罗尔夫·赫脱
沃纳·拉尔
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Abstract

本发明关于4-[4-(2-吡咯羰基)-1-哌嗪基]-3-三氟甲基-苯甲酰基胍的盐酸盐，其制造的方法和其在制备药物组合物中的应用。

Description

苯甲酰基胍盐
本发明是关于4-[4-(2-吡咯羰基)-1-哌嗪基]-3-三氟甲基-苯甲酰基胍的盐酸盐，其制备方法和其在制备药物组合物中的应用。
发明背景
现有技术中已知有很多苯甲酰基胍的衍生物。例如，国际专利申请WO00/17176中公开的苯甲酰基胍的衍生物。其特征是具有有价值的药物学特性。这些化合物对因缺氧发生的心律不齐症特别有效，例如，它们也可用于与局部缺血有关的疾病(如心脏的、大脑的、胃肠的-诸如，肠系膜的血栓形成/栓塞-、肺或肾的局部缺血、肝的局部缺血、骨骼肌肉的局部缺血)。相应的病征包括；例如，冠状心脏疾病、心脏梗塞、心绞痛、稳定型心绞痛、室性心律不齐，室下性心律不齐，心机能不全-并有助于旁路手术、有助于开心脏外科、有助于需要中断向心脏供血的手术，并有助于心脏移植-在肺循环中的栓塞、急性或慢性的肾衰竭、慢性肾机能不全、脑梗塞、在血管堵塞破裂后，恢复向大脑区供血中再灌注的危险，和大脑的急性和慢性的循环紊乱。上述提到的化合物在这种情况下也可以与血栓溶解剂，诸如，t-PA、链激酶和尿激酶结合使用。
在向局部缺血心脏重新灌注期间(例如，心胶痛或心肌梗塞发病后)有可能对影响的心肌细胞造成不可逆转的危害。此外在这种情况下，该化合物具有保持心脏的作用。
局部缺血的类型也包括防止对移植物的危害(例如，移植器官的保护-诸如肝、肾、心脏或肺-在移植之前、期间和之后，和移植器官的存贮期间)，这种危害都可能伴随着移植而发生。在WO 00/17176中公开的化合物也是一种药物组合物，在对心脏和对周围血管进行成血管细胞外科干预中，具有保护的作用。
在主要是高血压病和糖尿病性肾病变中，可提高细胞的钠-质子交换。因此，对这些病症的预防治疗中，这些化合物适宜作这种交换的抑制剂。
该化合物的再一个特征体现在对细胞增殖的有力抑制作用。因此，在细胞增殖起主要或次要作用的疾病中，该化合物可用作药剂，并可以用作对癌、良性瘤，或者，例如，前列腺肥大、动脉粥样硬化、器官肥大和超常增生、纤维变性疾病和糖尿病的后期并发症的药剂。
现有技术中公开的苯甲酰基胍衍生物的上述药物价值特性是对作为药物组合物的有效利用化合物的重要先决条件。然而，一种活性物质为了可以用作药剂，必须满足更多的要求。这些参数与活性物质的物理化学性质有极大的关系。
对这些参数没有限定，但这些参数的实例是在不同的环境条件下起始物效果的稳定性，在制造药物制剂时的稳定性和最终药剂组合物的稳定性。因此，用于制备药物组合物所用的药物活性物质，即使在不同的环境条件下也必须保证具有很高的稳定性。绝对需要防止使用含有活性物质的分解产物的药物组合物，例如，除活性物质本身之外，在这种情况下，存在于药物制剂中的活性物质含量可以低于规定的含量。
由于吸水而增加重量，因此，吸收湿气会降低药物活性物质的含量。具有吸收潮湿气倾向的药物组合物，贮存期间，必须预防受潮，例如，添加适宜的干燥剂或将药物组合物贮藏在能预防受潮的环境里。而且，如果药物组合物暴露在无任何防潮的环境中，加工时，吸收湿气会降低药物活性物质的含量。因此，优选是使药物活性物质仅稍有吸湿性。
由于活性物质的晶体改性可影响到药物组合物的活性，所以必须尽可能地净化存在于结晶形式中的活性物质任何已有的多晶现象。如果活性物质存在不同的多晶型的改性，必须小心以确保物质的结晶改型不改变其后的药物制剂。否则，这将对药剂的再现活性有有害的作用。本文中，优选的活性物质，其特征是有限制的多晶型。
在某些环境下尤为重要的另一判定标准，是活性物质的溶解性，这取决于制剂的选择或制造制剂方法的选择。例如，如果制备药物溶液(例如，为浸渍剂)，主要是活性物质能充分溶解在生理可接受的溶剂中。充分溶解的活性物质对于口服的药物组合物也非常重要。
本发明的基本目的是制备一种药物活性物质，其特征不仅体现在有效的药物活性，而且也尽可能地满足以上所说的物理化学的要求。
发明的详细描述
现已发现通过4-[4-(2-吡咯羰基)-1-哌嗪基]-3-三氟甲基-苯甲酰基胍-盐酸盐1化合物可获得上述目的。
式1的化合物是不吸湿性的，并易于溶解在生理可接受的溶剂中。其特征也体现在高度的稳定性。
在WO 00/17176中公开的式1′的甲磺酸盐不同于式1化合物，而且不能满足上文中提出的要求。
Figure C0280499200052
因此，本发明的一个方面是关于如式1的化合物。本发明的另一方面是关于式1化合物的水合物形式，优选是它的一水合物或半水合物的形式。
本发明的再一个方面是关于利用式1化合物作药剂。本发明还关于利用式1化合物，优选地以其水合物形式，以制备用于治疗疾病的药物组合物，其中，细胞的Na+/H+交换抑制剂可开发一种治疗效果。
本发明还关于利用式1化合物制备用于治疗心血管疾病的药物组合物。本发明还关于利用式1化合物制备用于治疗例如，诸如缺氧引起的心律不齐的药物组合物。本发明还关于利用式1化合物制备用于治疗与局部缺血相关的疾病(例如，心脏的、大脑的、胃肠的-诸如肠系膜的血栓形成/栓塞-、肺、肾局部缺血、肝的局部缺血、骨骼肌肉的局部缺血)的药物组合物。本发明还关于利用式1化合物制备用于治疗选自以下疾病的药物组合物：冠状心脏疾病、心肌梗塞、心胶痛、稳定型心绞痛、室性心律不齐、室下性的心律不齐、心机能不全-并有助于旁通手术、有助于开心脏外科、有助于需要中断向心脏供血的手术、和有助于心脏移植-在肺循环中的栓塞、急性或慢性肾衰竭、慢性肾机能不全、脑梗塞、在血管堵塞破裂后恢复向大脑区供血中再灌注的危险、和大脑的急性和慢性的循环紊乱。本发明还关于利用式1化合物制备用于治疗其中利用心脏保护性活性物质可以有治疗效果的疾病的药物组合物。本发明还关于利用式1化合物制备治疗癌症、良性肿瘤或例如，前列腺肥大、动脉粥样硬化、器官肥大和细胞增生、纤维变性疾病和糖尿病后期症状的药物。
式1化合物可用作水性可注射的溶液(例如，静脉注射、肌肉注射或皮下注射)，可用作片剂、用作栓剂、用作软膏剂，用作通过皮肤施用的贴剂，用于吸入肺中的气雾剂或用作鼻用喷射剂。
活性物质在片剂和栓剂中的含量为5-200mg、优选为10-50mg。对于吸入剂，单剂量为0.05～20mg，优选0.2～5mg，对于非经肠道的注射，单剂量为0.1～50mg，优选0.5～20mg。如果需要，上述规定剂量可一天给药几次。
以下是含有活性物质药物制剂的几个实例。
片剂：
式1化合物                       18.0mg
硬脂酸镁                        1.2mg
玉米淀粉                        60.0mg
乳糖                            90.0mg
聚乙烯吡咯烷酮                  1.5mg
注射用溶液：
式1化合物                       0.3g
氯化钠                          0.9g
注射用水                        ad 100ml
这种溶液可利用标准方法消毒。
WO 00/17176公开一种可用于合成游离碱4-[4-(2-吡咯羰基)-1-哌嗪基]-3-三氟甲基-苯甲酰基胍的生产方法。从这种化合物开始，以实施例的方式说明以下可合成式1化合物的方法。
实施例1：4-[4-(2-吡咯羰基)-1-哌嗪基]-3-三氟甲基-苯甲酰基胍-盐酸盐
将15.1g的4-[4-(2-吡咯羰基)-1-哌嗪基]-3-三氟甲基-苯甲酰基胍溶于151ml甲醇中，将产生的悬浮液冷却到约10℃。再向该悬浮液中加入16ml饱和的醚化HCl溶液，酸化到pH1-2，继续搅拌，同时用冰冷却，直到结晶完成。抽吸过滤结晶，用冷甲醇洗涤，然后用冷乙醚洗涤。
产额：16.19g，熔点：223℃(未校准)
实施例2：4-[4-(2-吡咯羰基)-1-哌嗪基]-3-三氟甲基-苯甲酰基胍-盐酸盐 -半水合物
取15.0kg的4-[4-(2-吡咯羰基)-1-哌嗪基]-3-三氟甲基-苯甲酰基胍，与120l乙酸乙酯混合。将悬浮液加热到约45℃，再混合30l水。产生的混合物搅拌约15分钟，然后分离掉水相，将20l水中的3.62kg浓盐酸的溶液，在恒温下，加入到有机相中，在1～2小时内，使混合物冷却到25℃～20℃，再分离出获得的盐酸，用50l乙酸乙酯洗涤，在60℃的真空中干燥。
产额：78％，熔点225±5℃(DSC的加热速度为10K/min)。
实施例3：4-[4-(2-吡咯羰基)-1-哌嗪基]-3-三氟甲基-苯甲酰基胍-盐酸盐 -一水化合物
在1.5l水中悬浮109.4g的4-[4-(2-吡咯羰基)-1-哌嗪基]-3-三氟甲基-苯甲酰基胍，加热到约50℃。将26.1ml的浓盐酸用300ml水稀释，并在20分钟内滴加到预热的悬浮液中。在恒温下将混合物搅拌15分钟。在搅拌1.5小时的过程中，使温度降低到约35℃。然后冷却到5～10℃，在此温度下再搅拌1小时，分离出获得的结晶，用少量水洗涤，并在约50℃的真空中干燥。
产额：116.5g，熔点：180±5℃(DSC的加热速度为10K/min)。

Claims (7)

1.4-[4-(2-吡咯羰基)-1-哌嗪基]-3-三氟甲基-苯甲酰基胍-盐酸盐。
2.根据权利要求1的化合物，特征是，其以水合物的形式存在。
3.根据权利要求1或2的化合物，特征是，其以一水合物的形式存在。
4.根据权利要求1或2的化合物，特征是，其以半水合物的形式存在。
5.根据权利要求1或2的化合物在制备用于治疗其中细胞Na+/H+交换抑制剂可以产生疗效的疾病的药物组合物中的用途。
6.根据权利要求5的用途，其中所述的化合物以一水合物的形式存在。
7.根据权利要求5的用途，其中所述的化合物以半水合物的形式存在。
CNB028049926A 2001-02-15 2002-02-14 苯甲酰基胍盐 Expired - Fee Related CN1222510C (zh)

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