CN1188120C - 治疗饮食紊乱的方法 - Google Patents
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Abstract
将其中R1和R2独立为H或甲基的式I化合物或其药学上可接受的盐(例如任选以一水合物形式的N，N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺盐酸盐)用于治疗饮食紊乱，如神经性食欲缺乏、神经性食欲过盛、停止抽烟、吃零食、狂食后体重增加。
Description
本发明涉及治疗饮食紊乱的方法。
本发明提供一种治疗饮食紊乱的方法，在该方法中给予有此需要的人治疗有效量的式I化合物，包括其对映体和其药学上可接受的盐，以及药学上可接受的稀释剂或载体，
其中R1和R2独立为H或甲基。
可以用式I化合物便利地治疗的饮食紊乱包括神经性食欲缺乏、神经性食欲过盛、停止抽烟、吃零食、狂吃后体重增加以及本领域技术人员已知的其它相关疾病。
式I的一个优选化合物为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。该盐酸盐的一个优选形式为它的一水合物。
式I化合物如N，N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺及其盐的制备和在治疗抑郁中的用途描述于英国专利说明书2098602中。式I化合物如N，N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺及其盐在治疗帕金森氏病中的用途描述于公开的PCT申请WO 88/06444中。N，N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺及其盐在治疗大脑功能疾病中的用途描述于美国专利4939175中。N，N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺盐酸盐在治疗肥胖中的用途描述于公开的PCT申请WO90/06110。该化合物的一个特别优选形式为N，N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺盐酸盐一水合物(西布曲明盐酸盐)，其被描述于欧洲专利号230742中。N，N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺及其盐在改善具有缺损的葡萄糖耐受性的人或非胰岛素依赖糖尿病患者的葡萄糖耐受性中的用途描述于公开的PCT申请WO95/20949中。
本领域的技术人员应该理解式I化合物含有一个手性中心。当式I化合物含有一个单一的手性中心时，它可以存在两个对映异构体形式。本发明包括使用单独的对映体或对映体的混合物。通过本领域技术人员已知的方法可解析对映体，例如形成可以分离的非对映异构盐或复合物，如通过结晶作用分离；通过形成可以分离的非对映异构衍生物，如通过结晶作用、气-液色谱法或液相色谱法分离；一种对映体与对映异构的特殊试剂的选择性反应，例如酶氧化或还原反应，随后分离修饰的或未修饰的对映体；或在手性环境中通过气-液色谱法或液相色谱法分离，如在手性载体上如带有一个结合的手性配位体的硅胶或在手性溶剂的存在下分离。应该明白，用上述的分离方法中的一种将所需要的对映体转化为另一个化学实体，下一步要求释放出所需要的对映异构形式。或者，通过不对称合成，使用任选的活性试剂、底物、催化剂或溶剂可以合成特定的对映体，或通过不对称转变将一个对映体转化为另一个对映体合成特定的对映体。
式I的优选化合物为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-甲基胺和1-[1-(4-氯苯基)环丁基]-3-甲基丁胺，包括它们的外消旋体、单独的对映体和混合物，及其药学上可接受的盐。
可以通过对映体选择性的合成方法由任选的活性前体制备单独的对映体，或通过解析可以按照以上描述制备的外消旋化合物制备单独的对映体。式I的仲胺的对映体也可以通过以下方法制备，首先制备相应的伯胺的外消旋体，将后者解析为单独的对映体，然后用描述于英国专利说明书2098602的方法将旋光纯的伯胺对映体转化为所需的仲胺。
式I化合物的具体实例为：
(+)-N-{1-[1-(4-氯苯基)环丁基]-3-甲基丁基}-N-甲基胺；
(-)-N-{1-[1-(4-氯苯基)环丁基]-3-甲基丁基}-N-甲基胺；
(+)-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-二甲基胺；
(-)-N-{1-[1-(4-氯苯基)环丁基]-3-甲基丁基}-N，N-二甲基胺。
在每种情况下皆优选盐酸盐，但游离碱和其它药学上可接受的盐也是适宜的。
可以以任何已知的药用剂型给予式I化合物。所给予的化合物的量将取决于许多因素，包括患者的年龄、疾病的严重性和患者过去的医疗史，并且所给予的化合物的量总是在主治医师的合理决定权范围内，但是一般设计所给予化合物的剂量在每天0.1到50mg，优选1到30mg的范围内，可一次或多次给药。
口服剂型为本发明使用的优选组合物并且这些剂型为此类给药方式的已知药用剂型，例如片剂、胶囊剂、颗粒剂、糖浆剂和水或油悬浮液。在制备这些组合物时使用的赋形剂为药剂师领域所熟悉的赋形剂。可以从活性化合物与如磷酸钙的填充剂、如玉米淀粉的崩解剂、如硬脂酸镁的润滑剂、如微晶纤维素或聚乙烯吡咯烷酮的粘合剂以及其它本领域已知的任选成分的混合物制备片剂，如通过已知的方法将该混合物压制成片。如果需要，可以用已知的方法和赋形剂将所述片剂包衣，所述包衣可以包括例如使用苯二甲酸羟丙基甲基纤维素的肠溶包衣。可以用本领域技术人员已知的方法配制片剂以便持续地释放出本发明的化合物。如果需要，可以用已知的方法给此类片剂提供肠溶包衣，如通过使用苯二甲酸醋酸纤维素包衣。类似地，可以用已知的方法制备含有活性化合物(加有或未加有赋形剂)的胶囊剂，例如硬或软明胶胶囊并且，如果需要，可以用已知的方法提供肠溶包衣。可以用已知的方法配制胶囊的内容物以便持续地释放出活性化合物。片剂和胶囊剂每片或每粒常规含有1到50mg，优选含有10mg或15mg的活性化合物。
例如，其它口服给药的剂型包括在无毒性的悬浮剂如羧甲基纤维素钠的存在下、在含水媒介中含有活性化合物的水性悬浮液和在适宜的植物油如花生油中含有本发明化合物的油悬浮液。可以将所述活性化合物与或不与添加的赋形剂配制成颗粒剂。患者可以直接摄入该颗粒剂或在摄入前将其加入到适宜的液体载体(如水)中。所述颗粒剂可以含有崩解剂，例如由一种酸与一种碳酸盐或碳酸氢盐形成的泡腾偶合物(effervescent couple)对以便促进在液体媒介中的分散。
可以将治疗性的式I活性化合物配制成为一种患者可以保留在口腔中的组合物以便通过口腔粘膜给予该活性化合物。
适宜直肠给药的剂型为此类给药方式的已知药用剂型，如含有可可脂或聚乙二醇基质的栓剂。
适宜胃肠外给药的剂型为此类给药方式的已知药用剂型，如在适宜溶剂中的无菌悬浮液或无菌溶液。
适宜局部给药的剂型可以包含一种基质，为了透皮给予所述化合物，将本发明的药用活性化合物分散在基质中以便该化合物保持与皮肤接触。可以通过使药用活性化合物与一种局部媒介物如矿物油、凡士林和/或一种蜡如石蜡或蜂蜡混合，与一种有效的透皮促进剂如二甲基亚砜或丙二醇一起制备适宜的透皮组合物。或者，可以将该活性化合物分散在药学上可接受的乳膏、凝胶或软膏基质中。在局部制剂中含有的活性化合物的量应该是打算将该局部制剂用于皮肤期间能够传递的化合物的治疗有效量。
可以将的式I治疗活性化合物配制为一种作为气雾剂分散进入到患者口腔或鼻腔的组合物。此类气雾剂可以由一种泵压包或含有挥发性抛射剂的加压包给药。
用于本发明方法的式I治疗活性化合物也可以通过从一个外源持续输注给药，如通过静脉输注给药或从一个放置在体内的化合物源持续给药。内源包括植入含有将要输注的化合物的储库，例如该化合物可以通过渗透持续释放，并且对于输注的化合物而言，植入物可以为(a)液体如待输注化合物的一种油悬浮液，一种很难溶于水的衍生物如十二烷酸盐或亲油性酯或(b)以植入载体形式存在的固体，如合成的树脂或蜡样物质。所述载体可以为含有所有化合物的单一实体(single body)或为一系列的若干个含有部分待传递的化合物的实体。内源中存在的活性化合物的量应该能够在长时间内释放治疗有效量的化合物。
在某些制剂中，以很小的粒径的微粒形式使用本发明的化合物可能是有益的，例如使用通过流能磨获得的微粒。
在本发明的组合物中，如果需要，该活性化合物可以与其它适配的药用活性成分组合。
另外，本发明提供式I化合物在生产治疗饮食紊乱的药物中的用途，所述饮食紊乱有如神经性食欲缺乏、神经性食欲过盛、停止抽烟、吃零食、狂食后体重增加以及本领域技术人员所熟知的其它相关疾病。
另一方面，本发明进一步提供一种药用组合物以治疗神经性食欲缺乏、神经性食欲过盛、停止抽烟、吃零食、狂食后体重增加以及本领域技术人员所熟知的其它相关疾病，该组合物包含式I化合物与药学上可接受的稀释剂或载体。
式I化合物在治疗饮食紊乱中的功效可以通过在有关人群中建立的临床试验和以下列出的数据证实。
单胺再摄取抑制剂一直用于治疗本发明描述的某些疾病。可是，已经知道这些化合物有许多缺点。首先，此类化合物不是对所有的病人有效。其次，有效的化合物不能彻底的治疗疾病。第三，该类型的化合物已知有许多不利的副作用。此类副作用包括恶心、性功能障碍、轻微头痛(headedness)、嗜睡、盗汗、颤动、口干、衰弱、失眠、腹泻、头痛、呕吐、焦虑、瞌睡、头昏、发烧、皮疹或过敏反应、关节痛、肌痛、痉挛、轻度躁狂和狂躁。
西布曲明(式I，R1＝CH3，R2＝CH3)具有一个药理学分布图，在单胺再摄取抑制剂中该分布图是唯一的。它的药理学活性代谢产物，(代谢产物1，在式I中R1＝H，R2＝CH3和代谢产物2，在式I中R1＝H，R2＝H)西布曲明抑制所有三个单胺的再摄取，这3种胺不同于5-羟色胺(5-HT)选择性再摄取抑制剂如氟苯氧丙胺、去甲肾上腺素选择性再摄取抑制剂如去甲丙咪嗪、多巴胺选择性再摄取抑制剂如丁氨苯丙酮，以及5-羟色胺-去甲肾上腺素再摄取抑制剂如文拉法辛(表1)。这是值独特的药理作用的联合，该联合作用使西布曲明和其它式I化合物有效地治疗神经性食欲缺乏、神经性食欲过盛、停止抽烟、吃零食、狂食后体重增加。
用类似于WO98/41528描述的方法进行以下分析。
表1
实施例1和2
以及各种参照的单胺再摄取抑制剂在大鼠脑组织 中的体外单胺再摄取抑制分布比较
| Ki(nM) | |||
| [3H]去甲肾上腺素 | [3H]5-HT | [3H]多巴胺 | |
| 实施例1 | 3 | 18 | 24 |
| 实施例2 | 5 | 26 | 31 |
| 丁氨苯丙酮 | 2590 | 18312 | 409 |
| 去甲丙咪嗪 | 2 | 200 | 4853 |
| 氟苯氧丙胺 | 320 | 11 | 2025 |
| 文拉法辛 | 196 | 26 | 2594 |
所述结果为≥3次单独测定的平均值。
实施例1：在式I中R1＝H，R2＝CH3
实施例2：在式I中R1＝H，R2＝H
Claims (5)
1.式I化合物，
包括其对映体和其药学上可接受的盐在生产治疗饮食紊乱的药物中的用途，其中R1和R2独立为H或甲基。
2.权利要求1的用途，其中所述饮食紊乱为神经性食欲缺乏、神经性食欲过盛或停止抽烟、吃零食、狂食后体重增加。
3.权利要求1或2的用途，其中所述式I化合物为N，N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺盐酸盐。
4.权利要求1或2的用途，其中所述式I化合物为N，N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺盐酸盐一水合物。
5.权利要求1或2的用途，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；
(-)-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，或其药学上可接受的盐。
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| PL349002A1 (en) * | 1999-01-20 | 2002-06-17 | Knoll Pharmaceutical Co | Method to aid smoking cessation |
| ES2238999T3 (es) * | 1999-02-24 | 2005-09-16 | University Of Cincinnati | Uso de derivados de sulfamato para tratar trastornos en el control de los impulsos. |
-
2000
- 2000-03-17 AT AT00918073T patent/ATE401066T1/de not_active IP Right Cessation
- 2000-03-17 SK SK1299-2001A patent/SK12992001A3/sk unknown
- 2000-03-17 BR BR0009026-3A patent/BR0009026A/pt not_active Application Discontinuation
- 2000-03-17 HU HU0200495A patent/HUP0200495A3/hu unknown
- 2000-03-17 AU AU38947/00A patent/AU773188C/en not_active Ceased
- 2000-03-17 NZ NZ514011A patent/NZ514011A/en not_active IP Right Cessation
- 2000-03-17 CN CNB008074321A patent/CN1188120C/zh not_active Expired - Fee Related
- 2000-03-17 MX MXPA01009404A patent/MXPA01009404A/es unknown
- 2000-03-17 KR KR10-2001-7011781A patent/KR100432825B1/ko not_active IP Right Cessation
- 2000-03-17 JP JP2000604841A patent/JP2003519087A/ja active Pending
- 2000-03-17 CZ CZ20013278A patent/CZ20013278A3/cs unknown
- 2000-03-17 DE DE60039508T patent/DE60039508D1/de not_active Expired - Lifetime
- 2000-03-17 EP EP00918073A patent/EP1178789B1/en not_active Expired - Lifetime
- 2000-03-17 ES ES00918073T patent/ES2307501T3/es not_active Expired - Lifetime
- 2000-03-17 CA CA002367666A patent/CA2367666C/en not_active Expired - Fee Related
- 2000-03-17 PL PL00351963A patent/PL351963A1/xx not_active Application Discontinuation
- 2000-03-17 TR TR2001/02646T patent/TR200102646T2/xx unknown
- 2000-03-17 WO PCT/US2000/007115 patent/WO2000054765A1/en active IP Right Grant
- 2000-03-17 US US09/528,355 patent/US6365633B1/en not_active Expired - Fee Related
- 2000-03-17 IL IL145240A patent/IL145240A/en not_active IP Right Cessation
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2001
- 2001-09-12 ZA ZA200107533A patent/ZA200107533B/xx unknown
- 2001-09-14 NO NO20014479A patent/NO20014479L/no not_active Application Discontinuation
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2002
- 2002-07-17 HK HK02105308.4A patent/HK1045455B/zh not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| IL145240A0 (en) | 2002-06-30 |
| JP2003519087A (ja) | 2003-06-17 |
| EP1178789A4 (en) | 2004-02-18 |
| CA2367666C (en) | 2008-11-25 |
| DE60039508D1 (de) | 2008-08-28 |
| ATE401066T1 (de) | 2008-08-15 |
| EP1178789A1 (en) | 2002-02-13 |
| CZ20013278A3 (cs) | 2002-07-17 |
| WO2000054765A1 (en) | 2000-09-21 |
| NO20014479D0 (no) | 2001-09-14 |
| WO2000054765A8 (en) | 2002-05-23 |
| AU3894700A (en) | 2000-10-04 |
| IL145240A (en) | 2007-02-11 |
| AU773188B2 (en) | 2004-05-20 |
| KR100432825B1 (ko) | 2004-05-24 |
| TR200102646T2 (tr) | 2002-08-21 |
| CA2367666A1 (en) | 2000-09-21 |
| SK12992001A3 (sk) | 2002-03-05 |
| HUP0200495A3 (en) | 2004-09-28 |
| NO20014479L (no) | 2001-11-02 |
| NZ514011A (en) | 2001-09-28 |
| ZA200107533B (en) | 2002-12-12 |
| AU773188C (en) | 2006-01-05 |
| PL351963A1 (en) | 2003-07-14 |
| HUP0200495A2 (en) | 2002-08-28 |
| ES2307501T3 (es) | 2008-12-01 |
| KR20020063107A (ko) | 2002-08-01 |
| BR0009026A (pt) | 2003-03-05 |
| MXPA01009404A (es) | 2004-03-19 |
| US6365633B1 (en) | 2002-04-02 |
| HK1045455B (zh) | 2009-04-09 |
| EP1178789B1 (en) | 2008-07-16 |
| CN1365276A (zh) | 2002-08-21 |
| HK1045455A1 (en) | 2002-11-29 |
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