CN1104241C - 1－(2－萘－2－基乙基)－4－(3－三氟甲基苯基)－1,2,3,6－四氢吡啶用于制备治疗肌萎缩性脊髓侧索硬化的药物的用途 - Google Patents
1－(2－萘－2－基乙基)－4－(3－三氟甲基苯基)－1,2,3,6－四氢吡啶用于制备治疗肌萎缩性脊髓侧索硬化的药物的用途 Download PDFInfo
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Abstract
本发明公开了1-(2-萘-2-基乙基)-4-(3-三氟甲基苯基)-1，2，3，6-四氢吡啶或它与药物可接受的酸的加成盐用于制备治疗肌萎缩性脊髓侧索硬化(ALS)的药物的用途。
Description
本发明涉及1-(2-萘-2-基乙基)-4-(3-三氟甲基苯基)-1，2，3，6-四氢吡啶或其与药物可接受的酸的加成盐用于制备治疗肌萎缩性脊髓侧索硬化(ALS)的药物的用途。
ALS是一种严重的进行性运动神经元疾病，它引起肌萎缩，而且最经常的是在几年内发展成致命的呼吸机能不全。
对ALS只研究了很少的产品，具体的例子是如IGF-1(胰岛素样生长因子1)和BDNF(脑产生的神经营养因子)的肽化合物，它们在神经病学纪事(Annals of Neurology)，1995，
38，971和自然(Nature)，1992，
360，753-759中有叙述。
对这一疾病测定过的唯一的非肽化合物是利芦噻唑，其化学名是2-氨基-6-三氟甲氧基苯并噻唑，它表面上能在特定的患ALS的受治疗者中减缓疾病的发展(G.Bensimon等，新英格兰医学杂志(N.Engl.J.Med.)，1994，
330，585-591；Scrip，1995，No.2035：21)，但目前在药品市场上还没有任何在治疗这种疾病上有效的产品。根据上面引用的G.Bensimon等的文章，利芦噻唑延长患ALS的病人的生命，但副作用如无力、痉挛状态和转氨酶水平的增加，损害所述病人的生活质量。
EP-A-458696叙述了使用1-(2-萘-2-基乙基)-4-(3-三氟甲基苯基)-1，2，3，6-四氢吡啶，文献中称为SR 57746，用来制备对抗神经变性状态的药物。在所述的文献中，SR57746的神经营养活性表明在记忆障碍、血管性痴呆、脑炎后遗症、卒中后遗症、由于颅外伤的外伤后综合症、由大脑缺氧产生的疾病、阿尔茨海默氏病、老年性痴呆、皮质下痴呆如杭廷顿氏舞蹈病和帕金森氏病、由爱滋病引起的痴呆、由病态或交感或感觉神经损伤产生的神经病、脑疾病如大脑水肿和脊髓小脑的退化。
SR57746对神经系统的神经营养作用与NGF，神经生长因子(EP-A-458696)的这种作用相似，而且特别地，据说通过诱导NGF系统的作用提供神经保护作用(J.Fournier，神经科学(Neuroscience)，1993，
55(3)，629-641)。
现已发现给予SR57746或一种它与药物可接受的酸的加成盐显著地减缓ALS的发展，而同时改善病人的生活质量。SR57746的这种治疗作用与NGF的释放无关，因为据说后者对运动神经元并不是一种营养因子，如在Neuron，1988，
1(4)，335-43；比较神经学杂志(J.Comp.Neurol)，1982，
210/2，174-189；和Eur.J.Neurosci.，1993，
5(5)，466-474中所指出的。
因此SR57746在治疗ALS中的活性是意想不到的。
因此，根据其一个方面，本发明涉及1-(2-萘-2-基乙基)-4-(3-三氟甲基苯基)-1，2，3，6-四氢吡啶或一种它与药物可接受的酸的加成盐用于制备治疗肌萎缩性脊髓侧索硬化的药物的用途。
通过所进行的用来评价ALS的临床和机能病征的活性指数和评价在延长给予1-(2-萘-2-基乙基)-4-(3-三氟甲基苯基)-1，2，3，6-四氢吡啶盐酸盐(SR 57746A)后的耐受性的研究证实SR57746在这种疾病上的临床活性。
在这种随机双盲法临床研究中，54个病人接收了口服相当于2mg/天剂量的游离碱，为期8个月。在本说明中所指的剂量一般是指给予的或在剂量单位中含有的游离碱的量。
在评价SR57746A在治疗ALS中所述活性时考虑了几个变量，尤其是：
-用来测定最大呼吸量的肺活量测验；
-用来评价肌肉力量的肌测验；
-用来评价反射的神经病检查；和
-用来评价病人进行某些运动的能力的诺里斯氏实验(延髓和肢)。
进行检测的化合物的有效性的评价以分数的形式表示，它指出与健康的受治疗者相比病人中疾病的发展状况。
获得的结果显示，在8个月中两个治疗组(2mg/天的SR57746A和安慰剂)逐渐对所研究的三个主要变量表现出显著的差别：呼吸肺活量、肌力和诺里斯氏机能标准。
用SR57746A治疗8个月的病人的发展衰退的平均值比那些用安慰剂治疗的病人的低40％。
通过这一研究获得的结果表明SR57746A能显著地减缓ALS的发展。这一产品还可很好的被耐受，正如通过8个月的治疗所观察到的。
根据本发明的另一方面，本发明涉及一种治疗肌萎缩性脊髓侧索硬化的方法，它包括向受这种疾病折磨的病人给予一有效剂量的1-(2-萘-2-基乙基)-4-(3-三氟甲基苯基)-1，2，3，6-四氢吡啶或一种它与药物可接受的酸的加成盐。
根据本发明，SR57746可以其本身或与其它有效成分一起给药，尤其是与利芦噻唑联合治疗或在同一药物形式中。
更具体地说，本发明涉及1-(2-萘-2-基乙基)-4-(3-三氟甲基苯基)-1，2，3，6-四氢吡啶和2-氨基-6-三氟甲氧基苯并噻唑或它们与药物可接受的酸的加成盐用于制备治疗肌萎缩性脊髓侧索硬化的药物的用途。
含有联合的SR57746和利芦噻唑或它们的药物可接受的盐的药物组合物，以及所述的联合用于制备治疗肌萎缩性脊髓侧索硬化的药物的用途，构成本发明更进一步的方面。
因此，本发明还涉及一种药物组合物，其中1-(2-萘-2-基乙基)-4-(3-三氟甲基苯基)-1，2，3，6-四氢吡啶和2-氨基-6-三氟甲氧基苯并噻唑或它们与药物可接受的酸的加成盐是作为有效成分存在的。
其它含SR57746和蛋白质生长因子如IGF-1(胰岛素样生长因子)和BDNF(脑产生的神经营养因子)的组合物，它们在治疗ALS中是有活性的。
因此，根据它的另一方面，发明涉及1-(2-萘-2-基乙基)-4-(3-三氟甲基苯基)-1，2，3，6-四氢吡啶或一种它与药物可接受的酸的加成盐与另一种选自BDNF，IGF-1和它们的药物可接受的盐的有效成分相联合用于制备治疗肌萎缩性脊髓侧索硬化的药物的用途。
根据另一方面，本发明还涉及一种治疗ALS的方法，它包括向患这种疾病的病人给予有效剂量的1-(2-萘-2-基乙基)-4-(3-三氟甲基苯基)-1，2，3，6-四氢吡啶或一种它与药物可接受的酸的加成盐和有效剂量的2-氨基-6-三氟甲氧基苯并噻唑或一种它与药物可接受的酸的加成盐，所述的给药是同时、顺序或隔一段时间进行。
根据其另一方面，发明还涉及一种治疗ALS的方法，它包括向患这种疾病的病人给予一有效剂量的1-(2-萘-2-基乙基)-4-(3-三氟甲基苯基)-1，2，3，6-四氢吡啶或一种它与药物可接受的酸的加成盐和一有效剂量的另一种选自BDNF、IGF-1和它们的药物可接受的盐的有效成分，所述的给药是同时、顺序或隔一段时间进行。
根据另一方面，发明还涉及一种用于治疗ALS的试剂盒，它包括：
(a)一或多单位剂量的1-(2-萘-2-基乙基)-4-(3-三氟甲基苯基)-1，2，3，6-四氢吡啶或一种它的药物可接受的盐；和
(b)一或多单位剂量的2-氨基-6-三氟甲氧基苯并噻唑，BDNF、IGF-1或一种它们的药物可接受的盐，
所述的试剂盒是用于同时、顺序或隔一段时间给予成分(a)和(b)。
SR57746和它与药物可接受的酸的加成盐优选口服给药。
在用于口服给药的本发明的药物组合物中，用作有效成分的SR57746或其一种药物可接受的盐可与通常的药物载体以单位剂型对动物和人给药，以治疗上述疾病。给药的合适的单位剂型包括例如片剂它可以是可分的，明胶胶囊、粉剂、颗粒剂和口服的溶液或悬浮液。
当制备片剂形式的固体组合物时，主要活性成分是与例如明胶、淀粉、乳糖、硬脂酸镁、滑石、阿拉伯树胶诸如此类的药物载体混合。片剂可用蔗糖或其它适当物质包衣，或者处理它们以使具有持续的或延时的活性和使连续地释放预定量的有效成分。
一种明胶胶囊形式的制剂是通过把活性成分与稀释剂混合并把产生的混合物倾入软或硬的明胶胶囊中获得的。
一种糖浆或酏剂形式的制剂可包含活性成分，连同甜味剂(优选它是不含热量的)、羟苯甲酸甲酯和对羟苯甲酸丙酯作防腐剂、调味剂和适当的颜色。
可用水分散的粉剂或颗粒剂可包含与分散剂或润湿剂或与悬浮剂如聚乙烯吡咯烷酮以及甜味剂或口味校正剂混合的活性成分。
有效成分还可选择性地与一种或更多种载体或添加剂配制成微胶囊。
在根据本发明的药物组合物中，有效成分还可是在环糊精，它们的醚或它们的酯中的包合配合物的形式。
给予的有效成分的量如通常那样取决于疾病的程度和病人的年龄和体重。而且单位剂量通常包含从0.5到10mg，有益地是1到5和优选1到3mg，例如1、1.5、2、2.5、或3mg的有效成分。这些单位剂量通常一天一次或更多次给药，优选一天1到3次，对人总的剂量在每天0.5和50mg之间变化，例如每天1到20mg。
当SR57746与其它有效成分结合给药时，尤其与利芦噻唑，剂量选自根据疾病的严重程度和病人的年龄和体重给予的每种药的剂量。优选的联合给药每一剂量单位含从0.5到10mg的SR57746或一种它的药物可接受的盐和从30到100mg的利芦噻唑或一种它的药物可接受的盐，特别优选的是那些每一剂量单位含0.5mg的SR57746或一种它的药物可接受的盐和50mg的利芦噻唑或一种它的药物可接受的盐，1mg的SR57746或一种它的药物可接受的盐和50mg的利芦噻唑或一种它的药物可接受的盐，1.5mg的SR57746或一种它的药物可接受的盐和50mg的利芦噻唑或一种它的药物可接受的盐，或2mg的SR57746或一种它的药物可接受的盐和50mg的利芦噻唑或一种它的药物可接受的盐，与药物赋形剂混合。这些剂量单位可一天给药1或2次。
下面的非限制性的实施例阐述本发明。
实施例1到3
制备明胶胶囊，它含0.5mg、1mg、或2mg的SR57746(如在EP-A-0101381中叙述的制备)。
产品SR57746A经一0.200mm筛孔的筛子筛分，然后与赋形剂预混。这种混合物经一0.315mm筛孔的筛子筛分，再混合，然后再经0.315mm筛孔的筛子筛分。最后混合后，填充明胶胶囊。
SR57746A 0.548mg 1.096mg 2.192mg
改良的玉米淀粉 142.852mg 142.304mg 141.208mg
微晶纤维素 26.0mg 26.0mg 26.0mg
无水胶体二氧化硅 0.20mg 0.20mg 0.20mg
硬脂酸镁 0.40mg 0.40mg 0.40mg
Claims (6)
1. 1-(2-萘-2-基乙基)-4-(3-三氯甲基苯基)-1，2，3，6-四氢吡啶或一种它与药物可接受的酸的加成盐用于制备治疗肌萎缩性脊髓侧索硬化的药物的用途。
2.根据权利要求1的用途，其中的酸加成盐是盐酸盐。
3.根据权利要求1或2的用途，其中的药物是一种单位剂型的药物组合物。
4.根据权利要求3的用途，其中的单位剂型包括0.5到10mg的有效成分。
5.根据权利要求4的用途，其中的单位剂型包括1到5mg的有效成分。
6.根据权利要求3到5任一个的用途，其中的药物组合物是一种口服给药形式的组合物。
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| FR9512635A FR2740343B1 (fr) | 1995-10-26 | 1995-10-26 | Utilisation de la 1-(2-napht-2-yl-ethyl)-4- (3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine pour la preparation de medicaments destines au traitement de la sclerose laterale amyotrophique |
| FR9512635 | 1995-10-26 | ||
| FR9607336 | 1996-06-13 | ||
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| KR101130212B1 (ko) * | 2002-03-27 | 2012-04-13 | 파이토팜 피엘씨 | 사포게닌 및 그 유도체의 치료 방법 및 사용법 |
| DE602006009670D1 (de) * | 2005-08-15 | 2009-11-19 | Univ Virginia | Neurorestauration mit r(+) pramipexol |
| US8518926B2 (en) * | 2006-04-10 | 2013-08-27 | Knopp Neurosciences, Inc. | Compositions and methods of using (R)-pramipexole |
| AU2007253899A1 (en) | 2006-05-16 | 2007-11-29 | Knopp Neurosciences, Inc. | Compositions of R(+) and S(-) pramipexole and methods of using the same |
| US8524695B2 (en) | 2006-12-14 | 2013-09-03 | Knopp Neurosciences, Inc. | Modified release formulations of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine and methods of using the same |
| US8519148B2 (en) | 2007-03-14 | 2013-08-27 | Knopp Neurosciences, Inc. | Synthesis of chirally purified substituted benzothiazole diamines |
| CN102186350A (zh) | 2008-08-19 | 2011-09-14 | 诺普神经科学股份有限公司 | 使用(r)-普拉克索的组合物与方法 |
| WO2013096816A1 (en) | 2011-12-22 | 2013-06-27 | Biogen Idec Ma Inc. | Improved synthesis of amine substituted 4,5,6,7-tetrahydrobenzothiazole compounds |
| US9662313B2 (en) | 2013-02-28 | 2017-05-30 | Knopp Biosciences Llc | Compositions and methods for treating amyotrophic lateral sclerosis in responders |
| US9468630B2 (en) | 2013-07-12 | 2016-10-18 | Knopp Biosciences Llc | Compositions and methods for treating conditions related to increased eosinophils |
| CN105764507B (zh) | 2013-07-12 | 2019-07-19 | 诺普生物科学有限责任公司 | 治疗升高的嗜酸性粒细胞和/或嗜碱性粒细胞的水平 |
| ES2813674T3 (es) | 2013-08-13 | 2021-03-24 | Knopp Biosciences Llc | Composiciones y métodos para el tratamiento de trastornos de células plasmáticas y trastornos prolinfocíticos de células b |
| HUE055850T2 (hu) | 2013-08-13 | 2022-01-28 | Knopp Biosciences Llc | Készítmények és módszerek a krónikus urticaria (csalánkiütés) kezelésére |
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