CN110772523A - 一种用于防治肾病的药物组合物 - Google Patents
一种用于防治肾病的药物组合物 Download PDFInfo
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
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- Engineering & Computer Science (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种用于防治肾病的药物组合物，所述药物组合物包含5‑丁基‑3‑(6‑(吡咯烷‑1‑基)己基)‑1H‑吡唑并[4,3‑d]嘧啶‑7‑胺甲磺酸盐和药学上可接受的载体。该药物组合物可以用于治疗(包括缓解和改善)各种临床表现包括蛋白尿的肾病。
Description
技术领域
本发明涉及医药技术领域，具体涉及一种用于防治肾病的药物组合物。
背景技术
肾病又称肾脏病、肾疾病，在中医上是指病邪侵犯于肾所表现的证候，以人体生长、发育和生殖机能障碍、呼吸功能减退、水液代谢失常和骨、髓、脑、发、耳等功能失常为主要病理变化的病证。现代医学认为肾病是一种发病部位为肾脏的、严重危害人类健康的常见病的统称，主要包括不同类型的肾炎、肾衰竭、肾结石、肾囊肿等等。
鉴于肾脏具有复杂的生理功能并具有特有的组织结构特点，因此使它在多种情况下易罹患损伤。肾脏疾病的主要临床表现有蛋白尿、血尿、水肿、高血压、肾功能不全等。其中，蛋白尿是多种类型的肾病，例如急性肾小球肾炎、慢性肾小球肾炎、IgA肾炎、隐匿性肾炎、糖尿病肾病、紫癜性肾炎、肾动脉硬化的典型症状，蛋白尿的形成原因与肾小球的屏障功能和肾小管的重吸收作用有着密不可分的关系。健康人由于肾小球滤过膜的滤过作用和肾小管的重吸收作用，尿中蛋白质的含量很少，当蛋白质定性检查时会呈阴性反应。当尿中蛋白质含量增加，普通尿常规检查即可测出时，称为蛋白尿。蛋白尿的出现提示肾小球滤过膜存在滤过膜孔径增大、断裂或静电屏障作用减弱等损伤，和/或肾小管重吸收能力降低或抑制。
鉴于蛋白尿是各种肾脏病的最常见表现，是反映肾脏病病情、预测肾脏病进展速度和判断预后的最重要指标之一，预期治疗蛋白尿的药物或方法能够用于改善各种肾病的肾功能并遏制肾病的进一步恶化，而这已经成为肾病科学领域亟待解决的问题。
发明内容
本发明所要解决的技术问题是克服现有技术的不足，提供一种用于防治肾病的药物组合物。
本发明的发明人通过实验意外地发现，5-丁基-3-(6-(吡咯烷-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺甲磺酸盐能够有效地治疗蛋白尿，因而可以用于治疗(包括缓解和改善)各种临床表现包括蛋白尿的肾病，例如急性肾小球肾炎、慢性肾小球肾炎、IgA肾炎、隐匿性肾炎、糖尿病肾病、紫癜性肾炎、肾动脉硬化。
为此，本发明提供一种用于防治肾病的药物组合物，所述药物组合物包含5-丁基-3-(6-(吡咯烷-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺甲磺酸盐和药学上可接受的载体。
本发明所使用的5-丁基-3-(6-(吡咯烷-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺甲磺酸盐具有以下结构式：
该化合物先前描述于专利文献WO2014/031815A1中，并可根据该专利文献的说明书实施例23描述的方法制备。专利文献WO2014/031815A1一般地涉及可用于诱导人干扰素产生的化合物，所述化合物被认为可以表现出相对于TNFα而言对IFNα的选择性。该专利文献测试了所公开的化合物的诱导干扰素-α和TNF-α的活性，并给出了pEC50值数据。但是，该专利文献并未提及所述化合物可以用于治疗蛋白尿，而这构成了本发明的意外发现。
本发明所述的用于防治肾病的药物组合物还包括药学上可接受的载体。可以采用本领域内通常使用的任何药学上可接受的载体来制备所述药物组合物。
例如，为了制备用于口服给药的固体剂型，可以使用乳糖、微晶纤维素、蔗糖、环糊精、甘露醇、阿拉伯胶、羧甲基淀粉钠、玉米淀粉、马铃薯淀粉、滑石粉、硬脂酸镁、明胶等本领域已知的固体载体。另外，还可以使用和活性成分或已使用的成分相容的任何其它通常用于着色、矫味、防腐等目的的载体。
为了制备用于口服给药的液体剂型，可以使用水、乙醇、甘油、丙二醇、聚乙二醇以及植物油如花生油、芝麻油、大豆油、橄榄油等本领域已知的液体载体。
为了制备胃肠外给药的剂型，可以使用注射用水、注射用油如大豆油、花生油、蓖麻油、其它注射用溶剂如乙醇、丙二醇、甘油、聚乙二醇、二甲基乙酰胺等本领域已知的无菌载体。如果需要，还可以使用如润湿剂、增溶剂、助悬剂、乳化剂、缓冲剂、抑菌剂、抗氧剂、等渗调节剂等各种添加剂。为了制备注射用无菌粉末，还可以使用如乳糖、海藻糖、甘露醇、甘氨酸和人血清白蛋白等填充剂与保护剂。
可根据本领域的常规制剂技术将本发明所述的药物组合物制成各种药学上可接受的剂型，如片剂、粉末剂、颗粒剂、丸剂、胶囊剂、溶液剂、乳剂、混悬剂、可注射溶液、注射用无菌粉末等。
本发明所述的药物组合物可以通过口服、腹腔内和胃肠外等任何适当的给药途径给药。优选地，本发明所述的药物组合物通过口服途径给药。应理解，优选的给药途径取决于待治疗的患者的年龄、性别、体重、一般医学状况、待治疗疾病的严重程度等因素，并由主治医师根据经验判断。
本发明所述的药物组合物还可以包含其它用于防治肾病(例如，治疗蛋白尿)的药物，所述药物包括但不限于血管紧张素转化酶抑制剂如卡托普利、依那普利、贝那普利；激素类药物如泼尼松、甲泼尼松、倍他米松、泼尼松龙；和血管紧张素Ⅱ受体拮抗剂如氯沙坦、缬沙坦、厄贝沙坦、坎地沙坦酯、他索沙坦、替米沙坦。
本发明还提供了一种本发明的药物组合物在制备用于防治肾病的药物中的用途。优选的，所述肾病为临床表现包括蛋白尿的肾病，例如急性肾小球肾炎、慢性肾小球肾炎、IgA肾炎、隐匿性肾炎、糖尿病肾病、紫癜性肾炎和肾动脉硬化。
为了使本发明的实质和精神得到进一步理解，下面结合具体实施例对本发明的优选实施方案及其效果进行描述。但是，应当理解，这些描述只是用于进一步说明本发明的特征和优点，而绝非对本发明的权利要求构成任何限制。
具体实施方式
实验例5-丁基-3-(6-(吡咯烷-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺甲磺酸盐对糖尿病肾病大鼠的蛋白尿的保护作用
本实验采用以链脲佐菌素(Streptozotocin，STZ)所致的糖尿病肾病大鼠为模型来验证用5-丁基-3-(6-(吡咯烷-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺甲磺酸盐降低蛋白尿水平从而治疗肾病的效力。
1、实验动物
采用健康雄性Sprague-Dawley(SD)大鼠，体重225±25g。将动物在22℃、50％相对湿度和12小时光照-12小时黑暗条件下适应两天。动物可自由进食和饮水。
2、实验方法
(1)链脲佐菌素溶液的配制：
取2.1g柠檬酸，加入100mL双蒸水中配成A液。另取2.94g柠檬酸钠，加入100mL双蒸水中配成B液。将A、B液按1：1.32的比例混合，调节pH值至4.2-4.5，得到用于配制链脲佐菌素的柠檬酸缓冲液。临用前，用柠檬酸缓冲液以1％的浓度溶解链脲佐菌素，即得用于建立糖尿病肾病大鼠模型的链脲佐菌素溶液。
(2)糖尿病肾病大鼠模型的建立：
通过单次静脉注射链脲佐菌素(剂量：45mg/kg体重)的方法使大鼠产生糖尿病肾病状态。具体而言，对于糖尿病肾病模型组动物，以45mg/kg体重的剂量针对每只大鼠静脉内给予一剂链脲佐菌素。对于正常对照组动物，给大鼠静脉内注射不含链脲佐菌素的柠檬酸缓冲液。于链脲佐菌素注射2天后，测定大鼠血浆葡萄糖的浓度。将链脲佐菌素注射4周后血浆葡萄糖的浓度超过250mg/dL的大鼠视为造模成功的糖尿病肾病大鼠，并用于实验研究。
(3)给药：
给药从注射链脲佐菌素后第4周开始，并持续到第8周。将造模成功的糖尿病肾病大鼠随机分为4组，每组10只。另取未经造模的SD大鼠10只作为正常对照。各实验组的给药方案总结如下：
正常对照组：选用未经造模(注射不含链脲佐菌素的柠檬酸缓冲液)的SD大鼠，给予正常食物和饮用水，持续4周。
模型对照组：选用造模成功的糖尿病肾病大鼠，给予正常食物和饮用水，持续4周。
化合物低剂量组：除给予正常食物和饮用水外，还灌胃给予大鼠5-丁基-3-(6-(吡咯烷-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺甲磺酸盐，剂量为50mg/kg/日，每日一次，持续4周。
化合物中剂量组：除给予正常食物和饮用水外，还灌胃给予大鼠5-丁基-3-(6-(吡咯烷-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺甲磺酸盐，剂量为100mg/kg/日，每日一次，持续4周。
化合物高剂量组：除给予正常食物和饮用水外，还灌胃给予大鼠5-丁基-3-(6-(吡咯烷-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺甲磺酸盐，剂量为200mg/kg/日，每日一次，持续4周。
(4)检测：
到第8周末，将各组大鼠放入代谢笼内，收集24小时尿液用于检测。肾功能采用血中的肌酸酐和尿素水平以及尿中的排出的白蛋白的量来监测。采用Bio-Rad(Bio-Rad，赫拉克勒斯，加利福尼亚州)的蛋白测定试剂定量测定尿蛋白。采用Beckman分析仪(BeckmanInstruments Inc.，贝瑞阿，加利福尼亚州)测定血中的肌酸酐和尿素水平。
3、实验结果：
本实验的结果如表1所示。
表1本发明的化合物对糖尿病肾病大鼠的肾功能的影响
注：以上数据表示为平均值±标准误(n＝10)。
**表示与模型对照组比较，p<0.05。
4、讨论
从体重和血糖两项指标来看，与正常对照组大鼠相比，经造模的糖尿病肾病大鼠表现出明显的体重下降和血糖水平的升高。5-丁基-3-(6-(吡咯烷-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺甲磺酸盐的持续4周的给药对糖尿病肾病大鼠的体重生长有一定促进作用，但对血糖水平的下降没有特别显著的改善作用。
从排尿量、尿液白蛋白排出量、血清肌酸酐含量和血液尿素含氮量四项指标来看，与正常对照组大鼠相比，经造模的糖尿病肾病大鼠表现出以上四项指标的明显的升高，提示糖尿病肾病大鼠的肾脏的结构和/或功能显著受损。然而，5-丁基-3-(6-(吡咯烷-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺甲磺酸盐的持续4周的给药明显地减少了糖尿病肾病大鼠的排尿量和尿液白蛋白排出量，提高了血液中肌酸酐和尿素的清除率，有效地改善了肾功能。这说明，5-丁基-3-(6-(吡咯烷-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺甲磺酸盐可以用于治疗(包括缓解和改善)各种临床表现包括蛋白尿的肾病。
以上所述仅是本发明的优选实施方式。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明的精神和原理的前提下，还可以做出若干改进、修饰和等同替换等，这些改进、修饰和等同替换后的技术方案也应视为落在本发明的保护范围之内。
Claims (7)
1.一种用于防治肾病的药物组合物，所述药物组合物包含5-丁基-3-(6-(吡咯烷-1-基)己基)-1H-吡唑并[4,3-d]嘧啶-7-胺甲磺酸盐和药学上可接受的载体。
2.如权利要求1所述的药物组合物，其特征在于，所述药物组合物还包含其它用于防治肾病的药物，所述药物选自血管紧张素转化酶抑制剂；激素类药物；和血管紧张素Ⅱ受体拮抗剂。
3.如权利要求1或2所述的药物组合物，其特征在于，所述药物组合物是口服给药的剂型。
4.如权利要求1或2所述的药物组合物，其特征在于，所述药物组合物是胃肠外给药的剂型。
5.权利要求1-4中任一项所述的药物组合物在制备用于防治肾病的药物中的用途。
6.如权利要求5所述的用途，其特征在于，所述肾病为临床表现包括蛋白尿的肾病。
7.如权利要求6所述的用途，其特征在于，所述临床表现包括蛋白尿的肾病选自急性肾小球肾炎、慢性肾小球肾炎、IgA肾炎、隐匿性肾炎、糖尿病肾病、紫癜性肾炎和肾动脉硬化。
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| WO2010090716A1 (en) * | 2009-01-30 | 2010-08-12 | Millennium Pharmaceuticals, Inc. | Heteroaryls and their use as pi3k inhibitors |
| WO2014031815A1 (en) * | 2012-08-24 | 2014-02-27 | Glaxosmithkline Llc | Pyrazolopyrimidine compounds |
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| WO2010090716A1 (en) * | 2009-01-30 | 2010-08-12 | Millennium Pharmaceuticals, Inc. | Heteroaryls and their use as pi3k inhibitors |
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