CN1352552A - 关于骨关节炎的治疗 - Google Patents
关于骨关节炎的治疗 Download PDFInfo
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Abstract
应用式I化合物或其药学上可接受的盐(例如任选为其一水合物的盐酸N,N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺)治疗骨关节炎或痛风,在所述式I中R1和R2独立为H或甲基。
Description
本发明涉及治疗骨关节炎和痛风的方法。
本发明提供一种治疗骨关节炎的方法,其中对其需要患者给予有效治疗量的式I化合物和药学上可接受的稀释剂或载体,所述式I化合物为:其中R1和R2独立为H或甲基,所述式I化合物包括其对映异构体和药学上可接受的盐。
式I化合物可有效治疗的疾病包括骨关节炎和痛风。
一种优选的式I化合物是N,N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺或其盐,例如盐酸盐。该盐酸盐的一种优选形式是其一水合物。
英国专利说明书2098602和美国专利4,522,328介绍了式I化合物及其盐的制备和用于治疗抑郁症的用途,所述式I化合物例如N,N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺、N-{1-[1-(4-氯苯基)-环丁基]-3-甲基丁基}-N-甲胺和1-[1-(4-氯苯基)-环丁基]-3-甲基丁胺。公布的PCT申请WO88/06444介绍了式I化合物及其盐用于治疗帕金森氏病的用途,所述式I化合物例如N,N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺。美国专利4,939,175介绍了N,N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺及其盐用于治疗脑功能紊乱的用途。公布的PCT申请WO90/06110介绍了盐酸N,N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺用于治疗肥胖症的用途。特别优选的该化合物为欧洲专利第230742号介绍的盐酸N,N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺一水合物(盐酸西布曲明(sibutramine))。公布的PCT申请WO95/20949介绍了N,N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺及其盐用于改善葡萄糖耐受不良或非胰岛素依赖型糖尿病患者的葡萄糖耐受的用途。
本领域技术人员知道,式I化合物含有一个手性中心。如果式I化合物包含有一个手性中心,则它可能存在两种对映异构体。本发明包括各种对映异构体以及对映异构体混合物的应用。可用本领域技术人员已知方法解析各种对映异构体,例如形成可通过例如结晶分离的非对映异构体盐或络合物;形成可通过例如结晶、气液色谱法或液相色谱法分离的非对映异构体衍生物;一种对映异构体与对映异构体特异性试剂选择性反应,例如酶性氧化或还原,然后分离改性和未改性的对映异构体;或例如在手性载体如结合手性配体的硅胶上或手性溶剂存在下在手性条件下进行气液色谱法或液相色谱法分离。人们知道,需要的对映异构体通过一种上述分离方法转化为另外一种化学体时,进一步需要释放需要的对映异构体。或者,可用旋光性试剂、底物、催化剂或溶剂通过不对称合成或者通过不对称性转化使一种对映异构体转化为另一种对映异构体而合成特定的对映异构体。
式I的优选化合物有N,N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺、N-{1-[1-(4-氯苯基)环丁基]-3-甲基丁基}-N-甲胺和1-[1-(4-氯苯基)环丁基]-3-甲基丁胺,包括它们的外消旋体、各种对映异构体及其混合物以及它们药学上可接受的盐。
可用旋光体前体通过对映异构体选择性合成或者通过解析如上所述制备的外消旋化合物而制得各种对映异构体。也可如下制备式I的仲胺对映异构体:应用英国专利说明书2098602介绍的方法,首先制备相应伯胺的外消旋体,使后者解析为各种对映异构体,然后使旋光纯的伯胺对映异构体转化为所需要的仲胺。
式I化合物的具体实例有:
(+)-N-{1-[1-(4-氯苯基)环丁基]-3-甲基丁基}-N-甲胺;
(-)-N-{1-[1-(4-氯苯基)环丁基]-3-甲基丁基}-N-甲胺;
(+)-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺;
(-)-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺;
(+)-N-{1-[1-(4-氯苯基)环丁基]-3-甲基丁基}-N-N-二甲胺;
(-)-N-{1-[1-(4-氯苯基)环丁基]-3-甲基丁基}-N-N-二甲胺。
在各种情况下,均优选盐酸盐,但是游离碱和其它药学上可接受的盐也同样适用。
式I的化合物可以以任何已知药用剂型给药。所述化合物的给药量取决于多种因素,包括患者的年龄、病情的严重程度以及患者的过去病史,并且总是依赖于主管内科医生的合理判断,但是一般认为该化合物的给药量范围为0.1-50mg/天、优选1-30mg/天,以一剂或多剂给药。
口服剂型为本发明优选使用的组合物,而且它们为这种给药方法的已知药用剂型,例如片剂、胶囊剂、颗粒剂、糖浆剂以及水性或油性混悬剂。用于制备这些组合物的赋形剂是制药领域已知的赋形剂。利用已知方法由所述活性化合物与以下物质的混合物可制得片剂,所述物质为填充剂,例如磷酸钙;崩解剂,例如玉米淀粉;润滑剂,例如硬脂酸镁;粘合剂,例如微晶纤维素或聚乙烯吡咯烷酮以及其它本领域已知的可使所述混合物制片的任选成分。如果需要,所述片剂可以用已知方法和已知赋型剂包衣,包括应用例如邻苯二甲酸羟丙基甲基纤微素酯进行肠溶包衣。可用本领域技术人员已知的方法配制片剂,以达到持续释放本发明化合物。如果需要,例如使用醋酸邻苯二甲酸纤维素酯通过已知方法对这种片剂进行肠溶包衣。同样,也可用已知方法制备含所述活性化合物和加入赋形剂或没有加赋形剂的胶囊剂,例如硬明胶胶囊剂或软明胶胶囊剂,如果需要,可以用已知方法对其进行肠溶包衣。可用已知方法配制胶囊内容物,以达到持续释放活性化合物。所述片剂和胶囊剂适合每片或每粒含1-50mg的所述活性化合物。
其它口服给药的剂型包括,例如水性混悬剂,该混悬剂在无毒悬浮剂如羧甲基纤维素钠存在下在水性介质中含有所述活性化合物;以及油性混悬剂,它在合适的植物油如花生油中包含本发明的化合物。所述活性化合物可制成含有其它赋形剂或不含有其它赋形剂的颗粒剂。患者可以直接服用颗粒剂,也可以在服用前加入到合适的液体载体(例如水)中。颗粒剂可含有崩解剂,例如有利于药物分散在液体介质中的酸和碳酸盐或碳酸氢盐形成的泡腾剂组合物对。
式I的治疗活性化合物可以制成患者可将其保留在口腔中使得通过口腔粘膜给予所述化合物的组合物。
适合直肠给药的剂型为这种给药方法的已知药用剂型,例如可可酯基或聚乙二醇基的栓剂。
适合胃肠外给药的剂型为这种给药方法的已知药用剂型,例如合适溶剂的无菌混悬剂或无菌溶液剂。
局部给药剂型可包括本发明药理活性化合物分散在其中的基质,使所述化合物与皮肤保持接触,以便经皮给予所述化合物。可如下制得合适的透皮组合物:使所述药物活性化合物和局部应用的媒介物例如矿物油、凡士林和/或蜡如石蜡或蜂蜡以及潜在的透皮促进剂如二甲基亚砜或丙二醇混合。另一方面,可使所述活性化合物分散在药学上可接受的乳膏基、凝胶基或软膏基中。局部制剂中所含的活性化合物量应该是所述局部制剂预定用于皮肤期间传递有效量所述化合物的剂量。
式I的治疗活性化合物可配制成以气雾剂分散进入患者口腔或鼻腔的组合物。可用泵包装或装有挥发性抛射剂的加压包装给予这种气雾剂。
用于本发明方法的式I治疗活性化合物也可以由外部源如静脉输注连续给药,或者由置于体内的所述化合物源连续给药。内部源包括含有需要输注化合物的植入储库,它连续释放例如通过渗透释放所述化合物;内部源还包括植入物,植入物可为(a)液体植入物,例如需要输注的非常难溶于水的衍生物型化合物的油性混悬剂,所述衍生物例如为十二烷酸盐或亲脂性酯,或(b)植入载体固体,例如合成树脂或蜡质材料,以输注所述化合物。所述载体可以是含有所有所述化合物的单个载体,或为分别含有需要给予的部分所述化合物的若干个载体。内部源的活性化合物含量应该为长期释放治疗有效量所述化合物的剂量。
在部分制剂中,使用非常微小粒径颗粒的本发明化合物可能是有利的,例如通过流体能量研磨获得的微粒。
在本发明组合物中,如果需要,所述活性化合物可以与其它药理学上相兼容的活性成分一起使用。
本发明进一步提供式I化合物用于生产治疗骨关节炎或痛风的药物的用途。
另一方面,本发明进一步提供用于治疗骨关节炎或痛风的药用组合物,该组合物包含式I化合物和药学上可接受的稀释剂和载体。
肥胖症伴随发生骨关节炎和痛风,而绝经或绝经后肥胖中年妇女还出现膝盖内侧痛(关节旁痛性肥胖症(adipose dolorosajuxtarticularis))。肥胖症与骨关节炎之间的可能机理包括:与肥胖性负荷增加有关的机械应力、与脂肪增加有关的代谢变化以及与产生肥胖有关的膳食成分。肥胖性痛风风险增高可能与伴随的高尿酸血症有关,尽管也可能涉及中心脂肪分布,尤其是妇女如此。
单胺再摄取抑制剂已经用于治疗本发明介绍的某些病症。但是,已知这些化合物存在许多不足。首先,这类化合物不是对所有患者均有效。其次,虽然所述化合物有效,但是不能彻底治愈所述病症。第三,已知该类化合物存在许多不需要的副作用。这类副作用包括恶心、性功能紊乱、轻度头痛(headedness)、嗜睡、发汗、震颤、口干、衰弱、失眠、腹泻、头痛、呕吐、焦虑、倦睡、头昏、发热、皮疹或变态反应、关节痛、肌肉痛、痉挛、轻度躁狂和躁狂。
西布曲明(式I中R1=CH3,R2=CH3)具有单胺再摄取抑制剂独特的药理学特征。西布曲明通过其药理学活性代谢物(代谢物1,在式I中R1=H,R2=CH3,以及代谢物2,在式I中R1=H,R2=H)抑制所有三种单胺的再摄取,从而使其区别于选择性五羟色胺(5-HT)再摄取抑制剂如氟西汀、选择性去甲肾上腺素再摄取抑制剂如地昔帕明、选择性多巴胺再摄取抑制剂如安非他酮以及五羟色胺-去甲肾上腺素再摄取抑制剂如文拉法辛(表1)。就是这种独特的综合药理作用使西布曲明和式I的其它化合物能够有效治疗骨关节炎和痛风。
以类似WO98/41528介绍的方法进行以下分析。表
比较实例1和2以及不同对照单胺再摄取抑制剂对大鼠脑组织的体外单胺再摄取的抑制特性
Ki(nM) | |||
[3H]去甲肾上腺素 | [3H]5-HT | [3H]多巴胺 | |
实例1 | 3 | 18 | 24 |
实例2 | 5 | 26 | 31 |
安非他酮 | 2590 | 18312 | 409 |
地昔帕明 | 2 | 200 | 4853 |
氟西汀 | 320 | 11 | 2025 |
文拉法辛 | 196 | 26 | 2594 |
上述结果是≥3次单独测试的平均值
实例1 在式I中R1=H,R2=CH3
实例2 在式I中R1=H,R2=H
式I化合物治疗骨关节炎或痛风的疗效通过相关人群组的临床试验得到证实。
参考各种具体实施方案阐述了本发明。然而,可对本发明进行许多改变和改进而仍属于本发明范畴和精神。
Claims (20)
2.权利要求1要求保护的方法,其中治疗骨关节炎。
3.权利要求1或2要求保护的方法,其中所述式I化合物为盐酸N,N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺。
4.权利要求1或2要求保护的方法,其中所述式I化合物为盐酸N,N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺一水合物。
5.权利要求1或2要求保护的方法,其中所述式I化合物为(+)-N-{1-[1-(4-氯苯基)环丁基]-3-甲基丁基}-N-甲胺。
6.权利要求1或2要求保护的方法,其中所述式I化合物为(-)-N-{1-[1-(4-氯苯基)环丁基]-3-甲基丁基}-N-甲胺。
7.权利要求1或2要求保护的方法,其中所述式I化合物为(+)-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺。
8.权利要求1或2要求保护的方法,其中所述式I化合物为(-)-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺。
9.权利要求1或2要求保护的方法,其中所述式I化合物为(+)-N-{1-[1-(4-氯苯基)环丁基]-3-甲基丁基}-N-N-二甲胺。
10.权利要求1或2要求保护的方法,其中所述式I化合物为(-)-N-{1-[1-(4-氯苯基)环丁基]-3-甲基丁基}-N-N-二甲胺。
11.权利要求1或2要求保护的方法,其中所述式I化合物为(±)-N-{1-[1-(4-氯苯基)环丁基]-3-甲基丁基}-N-甲胺。
12.权利要求1或2要求保护的方法,其中所述式I化合物为(±)-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺。
13.权利要求1或2要求保护的方法,其中所述式I化合物为(±)-N-{1-[1-(4-氯苯基)环丁基]-3-甲基丁基}-N-N-二甲胺。
14.一种式I化合物用于制造治疗骨关节炎或痛风的药物的用途,所述式I化合物为:其中R1和R2独立为H或甲基,所述式I化合物包括其对映异构体和药学上可接受的盐。
15.权利要求14要求保护的用途,其中治疗骨关节炎。
16.权利要求14或15要求保护的用途,其中所述式I化合物为盐酸N,N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺。
17.权利要求14或15要求保护的用途,其中所述式I化合物为盐酸N,N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺一水合物。
19.权利要求18要求保护的药用组合物,其中所述式I化合物为盐酸N,N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺。
20.权利要求18要求保护的药用组合物,其中所述式I化合物为盐酸N,N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺一水合物。
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