CN109952291B - 与糖尿病相关的神经缺陷的改善 - Google Patents
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Abstract
用2‑氨基取代的烟酰胺或其药学上可接受的盐治疗糖尿病相关的非全身性缺陷。
Description
相关申请的交叉引用
本申请要求2016年9月12日提交的美国临时申请62/393,514的优先权。其公开内容在此完整引入以供参考。
技术领域
本发明涉及用改善与糖尿病相关的非全身性缺陷的化合物治疗糖尿病个体。更具体的，其关注2-氨基取代的烟酰胺用于该目的。
背景技术
儿童和成人中的糖尿病已经在工业化社会中日益常见。I型糖尿病在儿童中更常发生，与因为免疫系统攻击产生胰岛素的细胞使得胰脏不能提供胰岛素有关。II型糖尿病在成人中更常见，与胰岛素抗性有关，使得胰脏不能产生足够胰岛素来提供葡萄糖代谢机制。糖尿病与复杂的不良后果相关，还直接在生理上导致低血糖和提高水平的糖化血红蛋白(HbA1c)。这些糖尿病的系统性指征常伴有其他缺陷，包括热痛觉减退、小纤维病变(包括与角膜神经和真皮中的感觉纤维相关的那些)以及由于神经损伤导致的思维缺陷。
一组美国授权专利(以US8,363,262为代表)公开了能刺激神经元生长的低分子量化合物。然后，发现一些2-氨基取代的烟酰胺能用于治疗抑郁，特别是如PCT出版物WO2015/195567所述的人严重抑郁症。然而这些文献并未克服糖尿病相关的不良缺陷，尤其是与神经失常相关的缺陷。
发明内容
现已发现某些2-氨基取代的烟酰胺在预防或修复I型和II型糖尿病的不良后遗症的各个方面特别有效。
因此，在一个方面，本发明涉及一种改善糖尿病相关非全身性缺陷的方法，通过对需要这种改善的个体施用一种药学组合物，其中活性成分是2-氨基取代的烟酰胺或其药学上可接受的盐。特别是，2-氨基取代的烟酰胺是下式：
其中R1是3-8C的烷基，环A是5-或6-元饱和环，可任选地包括未取代或被额外的含氮取代基或其开环形式取代的额外的氮。
特别示范性化合物包括下述的那些：式(2)
或式(3)
其中R1是3-5C的支链烷基，或式(4)：
其中R1是含有5-或6-元环的烷基。
本发明还包括本发明化合物的药物组合物和药学上可接受的盐，尤其是其磷酸盐。
本发明的实施方式
本发明的方法涉及改善I型或II型糖尿病相关非全身性缺陷。本文所述的“糖尿病的非全身性缺陷”是那些除了初步高血糖、提高的糖化血红蛋白(HbA1c)水平和糖尿病相关的体重下降以外的症状。这些非全身性缺陷包括但不限于运动神经传导速度(MNCV)迟缓(其是大运动纤维功能的量度)，触觉异常性疼痛，与小感觉纤维相关的热反应迟缓，测定学习和记忆的巴恩斯迷宫表现差，以及目标识别测试的不佳表现。
上述列表不是穷举的，仅是非糖尿病主要指征的典型可测量缺陷。非全身性缺陷可呈现为各种症状，包括视力丧失，运动控制丧失，和其他效应以及严重综合征，例如肾损伤、中风、心脏病和高血压。其他综合征包括神经病变、胃瘫和足与皮肤的综合征。这些综合征不是糖尿病的原发性后果，而是本发明的方法设计以改善的继发性后果。
本发明方法中使用的活性药剂具有上述式(1)，其中R1是3-8C的烷基，环A是5-或6-元饱和环，可任选地包括额外的氮或其开环形式。因此，在式(1)中，R1可以是至少3个碳原子的直链或支链烷基，例如异丙基、仲丁基、正丁基、异戊基、仲戊基、己基、异己基等，或包含饱和的环。优选在式(2)或(3)中R1是3-5C支链烷基，尤其是异戊基，和在式(4)中R1包含5-或6-元饱和环。环A的优选例是哌啶或哌嗪环，或其开环形式，或吡咯烷环。通常环A被至少一个额外的含氮取代基取代，其包括额外的吡啶环，例如吡啶甲基或吡啶乙基，或是更简单的取代基例如羧酰胺。环A的优选形式如上述式(2)、(3)和4以及恰当的取代基所示。
本发明的化合物以标准药物配方配制，例如载于雷明登氏药典(最新版，Mack出版公司(Mack Publishing Co.,Easton)，宾夕法尼亚州)的那些，包括口腔给药和腹膜给药的配方。通常化合物以片剂、胶囊形式或以糖浆或其他标准配方口腔施用。在一些情况下，可设计配方用于延迟释放，或可设计成更加立即递送。本领域已知各种适用于本发明化合物的配方，可由临床医师根据给药途径决定。
剂量水平也依赖于临床医师的判断，但一般在0.01mg/kg到1-2g/kg之间。
通常，治疗对象是人，虽然也可用于实验动物以及评估合适的给药剂量、途径和配方。因此，本发明的对象不仅包括人类，还包括试验研究动物，例如家兔、大鼠、小鼠等。在一些情况下，其他哺乳动物对象也是合适的，例如在兽医学中对象可以是羊、牛、或马，或对象可以是伴侣动物，例如犬或猫。
本发明的化合物可以药学上可接受的盐形式施用，例如盐酸盐、马来酸盐、琥珀酸盐、硝酸盐等。特别优选的是磷酸盐。
给药和剂量日程的频率也由临床医师决定，剂量可以是慢性的或每日、每周或更频繁，或可以是单剂。本发明的化合物还可与其他活性药剂在同一组合物中施用或依次联合施用。
下列实施例是说明性的，但不限于本发明。
实施例1，I型糖尿病模型的测试化合物效果
在该研究中使用成年雌性Swiss Webster小鼠(20-25克)。将其维持在65-82华氏度，相对湿度30-70％的房间内，用荧光灯以12小时昼夜循环照明。每笼中装2-3只动物，自由摄取干燥食物和自来水。连续两天，通过注射链脲霉素(STZ)(90mg/kg腹膜内，0.9％无菌盐水溶液)隔夜禁食诱导糖尿病。在4天后，用带式反射计进行尾部刺血获得的血样确认了高血糖。每日观察动物，在研究期间每周称重。
对于在糖尿病发生后立即处理(A部分)或糖尿病7-8周后处理(B部分)，评估测试化合物。每组从10只动物开始，以鉴定对照和糖尿病小鼠之间的神经传导、脚爪热反应迟缓和表皮内神经纤维(IENF)密度，假定在组间常规观察到20-40％差异，并且测量变异系数为10-20％。
A部分(发生)
对照+载体
糖尿病+载体
糖尿病+胰岛素(通过植入丸剂)
糖尿病+NSI-158
糖尿病+NSI-189
糖尿病+NSI-190
B部分(7-8周)
对照+载体
糖尿病+载体
糖尿病+NSI-150
糖尿病+NSI-182
糖尿病+NSI-183
糖尿病+NSI-189
根据需要通过植入每月置换的胰岛素丸剂(LinBitTM,LinShin,加拿大)提供胰岛素，口服强饲法提供测试化合物。递送测试化合物24小时后进行如下测量：
体重：从糖尿病发生开始每周；
血糖：在发生糖尿病时以及其后每月；
MNCV(大运动纤维功能):在发生糖尿病前以及其后每月；
通过人工von Frey丝测定爪子触感反应阈值(大感觉纤维功能)；从糖尿病发生开始每月；
脚爪热反应延迟(小感觉纤维)：从糖尿病发生开始每月；
角膜神经密度(小感觉纤维结构)：在发生糖尿病前以及其后每月收集图像；
巴恩斯迷宫表现(学习和记忆)：糖尿病10周后和在研究终止时；和
目标识别测试(记忆)：糖尿病10周后和在研究终止时。
在一些病例中评估脚爪皮肤组织的IENF密度。
上述各种程序是如以下文献中所述的那些：
Jolivalt,C.G.,等,Exp.Neurol.(2010)223:422-431；
Jolivalt,C.G.,等,Diabetes Obes.Metab.(2011)13:990-1000；
Jolivalt,C.G.,等,Neuroscience(2012)202:405-412；和
Chen,D.K.,等,J.Peripher.Nerv.Syst.(2013)18:306-315。
如预料的，STZ注射削弱了体重增加，诱发高血糖且提高了终末HbA1c水平，指示I型糖尿病。A部分中从开始时施用的胰岛素治疗部分地恢复了体重增加，减轻了高血糖并降低HbA1c水平。这些全身性指标均未被任何测试化合物处理所改变。
测试的药剂如下：
结果如下所示：
MNCV:在该非系统性指标中，糖尿病小鼠发生进展性MNCV迟缓，如A和B部分中均显示的，其中MNCV迟缓在A部分中通过施用胰岛素防止。在A部分，试剂NSI-158,NSI-189和NSI-190在研究期的终点对MNCV迟缓有轻度弱化，但测试试剂NSI-150、NSI-182和NSI-183并没有。在B部分，NSI-189部分逆转了MNCV迟缓。
脚爪触觉异常性疼痛：糖尿病小鼠如预期在糖尿病发生4周内产生触觉异常性疼痛，其由胰岛素治疗减弱。在最后一次处理24小时后测量时，A部分中测试药剂NSI-158、NSI-189和NSI-190减弱了触觉异常性疼痛，但B部分的测试药剂NSI-150、NSI-182和NSI-183没有。在B部分，NSI-189部分逆转了脚爪触觉异常性疼痛。
脚爪对热的反应：糖尿病发生8-12周后，糖尿病小鼠发生脚爪热痛觉减退，而胰岛素如预期地防止了这种情况。在A部分，测试药剂NSI-158,NSI-189和NSI-190防止了脚爪热痛觉减退，而在B部分，测试药剂NSI-150,NSI-182和NSI-183没有。在B部分，NSI-189阻止了脚爪热痛觉减退的进展。
小纤维病理学：研究了小纤维病理学的许多方面，包括鲍曼层和基质中的角膜神经密度，其在糖尿病小鼠中显著减少，而胰岛素防止了三叉神经衍生的小感觉纤维远端区域的损失和更近端区域中的这种损失。在A部分，仅NSI-189减弱鲍曼层中的损失，而NSI-189和NSI-190减弱基质中的这种损失。然而，A部分中NSI-158和NSI-190对于鲍曼层并无保护效果。在B部分，鲍曼层和基质中NSI-189都有保护作用，而在B部分中NSI-150、NSI-182或NSI-183在基质中都没有保护作用。然而，B部分中NSI-182和NSI-183在鲍曼层有保护作用。
皮下神经丛中的神经密度：糖尿病小鼠中该密度减少，而胰岛素治疗防止其减少。A部分中，NSI-158、NSI-189和NSI-190能使其减弱，而B部分中仅NSI-189有保护性。
分离组织中的IENF密度：胰岛素治疗防止了糖尿病小鼠中该密度的降低，在A部分仅NSI-189和NSI-158对其有减弱，而在B部分中仅NSI-189对其有逆转。
目标识别：在10周和16周时，糖尿病小鼠显示短期记忆受损，但全身性胰岛素对其没有防止作用。在A部分，仅NSI-190防止该记忆丧失，而B部分的所有药剂都失败了。
巴恩斯迷宫测试：糖尿病小鼠显示初始采集受损，但增强学习和短期维持正常，然而长期维持也受损。胰岛素治疗对这些均有防止。A部分中的所有测试药剂NSI-158,NSI-189和NSI-190均改善了长期维持但不改变其他参数，而B部分中的药剂均不成功。
实施例2，II型糖尿病
用db/db(BKS.Cg-Dock7m+/+Leprdb/J)小鼠作为II型糖尿病模型。这些小鼠以实施例1中所列出的类似模式维持。17-22周处理后，NSI-189显著逆转了MNCV迟缓、触觉异常性疼痛和热痛觉减退的逐渐进展。
Claims (5)
1.2-氨基取代的烟酰胺或其药学上可接受的盐的用途，用于制备改善与I型和/或II型糖尿病相关的非全身性缺陷的药物，其中2-氨基取代的烟酰胺是下式：
其中R1是异戊基。
2.如权利要求1所述的用途，其中所述非全身性缺陷是MNCV迟缓、触觉异常性疼痛、热痛觉减退、小纤维病变、或短期或长期记忆丧失。
3.如权利要求1或2所述的用途，其中2-氨基取代的烟酰胺是下式：
4.如权利要求1-3任一所述的用途，其中2-氨基取代的烟酰胺是磷酸盐形式。
5.如权利要求1-4任一所述的用途，其中所述用途还包括在对所述对象施用药物后随后测试所述对象中所述缺陷的改善。
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