CN1507351A - Adhd的治疗 - Google Patents
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Abstract
3－[1－[2－(1－乙酰基－2，3－二氢－1H－吲哚－3－基)乙基]－1，2，3，6－四氢吡啶－4－基]－6－氯－1H－吲哚、其任何对映异构体以及其可药用的盐用于制备治疗注意力不足活动过度病症的药物组合物的应用。
Description
本发明涉及3-[1-[2-(1-乙酰基-2，3-二氢-1H-吲哚-3-基)乙基]-1，2，3，6-四氢吡啶-4-基]-6-氯-1H-吲哚、其对映异构体以及其可药用的盐用于制备治疗ADHD(注意力不足活动过多病症)的药物的应用。
背景技术
ADHD在临床上指的是相对普通的综合征(流行病学统计已经表明ADHD在总人口中的发病率为2-10％)。ADHD开始于儿童期并且到成人一般会缓解(Szatmari Child Adolesc.Psychiat.Clin.North Am.1982，1，361-371)。ADHD的临床特征为不注意(例如不能密切注意、持续注意困难、组织工作和活动困难并且易于被外来的刺激分散注意力)、活动过多(例如保持就座困难、在不适宜的情况下运动活性过度，患者好像“被马达驱动”一样)和冲动(例如在依次等待时困难、在其未完成前回答问题并常常打断或强行进入正在进行的谈话；AmericanPsychiatric Association，Diagnostic and Statistical Manual ofMental Disorders(DSM-IV)，1994)。
ADHD研究表明ADHD约80％的病因学被归咎于遗传性因素(Gjone等人，J.Am.Acad.Child Adolesc.Psychiat.1996，35，588-596)。虽然该疾病具有强遗传成分，但ADHD的病理生理学目前仍然是未知的。认识、生理学和成像研究表明ADHD可能涉及皮质下结构的皮层抑制机能障碍(Faraone and Biederman Neurobiology of MentalIllness，编辑：Charney，Nestler 和Bunney，Oxford UniversityPress，1999，60，788-801)。涉及皮层区域的试验和公认的兴奋性药物对单胺代谢的作用都表明ADHD可能与突出到皮层的单胺能途径(包括多巴胺能和血清素激活的系统)的障碍有关。
一种十分有用的ADHD动物模型是DAT破坏的(KO)小鼠(Gainetdinov等人，Science 1999，283，397-401)。这些小鼠缺乏编码多巴胺运输器(DAT)的基因并表现出显著的活动过多，其可以被精神刺激剂如哌甲酯和苯丙胺(ADHD药物治疗常用的药物)所逆转。有趣地是，还发现可增加血清素激活的神经传递的化合物如选择性血清素再吸收抑制剂氟西汀、血清素受体激动剂喹哌嗪以及血清素的前体5-羟基色氨酸和L-色氨酸可抵抗这些DAT-KO小鼠的活动过多(Gainetdinov等人，Science 1999，283，397-401)。
一些临床研究已经发现可阻断血清素运输器的三环抗抑郁药在ADHD的治疗中是有效的(Spencer等人，J.Am.Acad.ChildAdolesc.Psychiat.1996，35，409-432；Wilens等人，J.Clin.Psychopharmacol.1995，15，270-279)。此外，还表明选择性血清素再吸收抑制剂氟西汀可有效减少ADHD的症状(Barrickman等人，J.Am.Acad.Child Adolesc.Psychiat.1991，30，762-767)。
然而，精神刺激剂，特别是哌甲酯和右苯丙胺一直并继续是选择用来对患有ADHD的患者进行治疗的药物(Faraone andBiederman，In：Neurobiology of Mental Illness，编辑：Chamey，Nestler和Bunney，Oxford UniversityPress，1999，60，788-801)。虽然精神刺激剂似乎有效，但是在用其来对ADHD患者进行治疗时仍然存在很多问题。例如，一些患者对所有的治疗都没有响应或仅仅对治疗有部分响应。此外，在长期治疗后，在用精神刺激剂进行治疗的ADHD患者中较常发生不良反应如失眠、食欲下降、易怒、痉挛和抑郁症状。
所以，仍然十分需要有效和可被更好耐受的药物来治疗这种疾病。
WO 98/28293描述了一系列对多巴胺D4受体有作用的被取代的2，3-二氢化茚和二氢吲哚化合物。认为所述的化合物可有效地用于一系列精神病学和神经病学病症的治疗并可用于改善睡眠，其中所说的病症包括精神分裂症的阳性和阴性症状、其它精神病、焦虑症如泛化性焦虑症、恐慌症和强迫症、抑郁、酗酒、冲动控制病症、攻击性、由常规安定药所诱发的副作用、局部缺血的疾病状态、偏头痛、老年痴呆、心血管病症。
现在已经令人吃惊地发现，这里描述为一种有效的多巴胺D4配体的具有如下结构式的WO 98/28293的化合物，即3-[1-[2-(1-乙酰基-2，3-二氢-1H-吲哚-3-基)乙基]-1，2，3，6-四氢吡啶-4-基]-6-氯-1H-吲哚可以特别用于注意力不足活动过多病症的治疗
发明概述
因此，本发明涉及式(I)的3-[1-[2-(1-乙酰基-2，3-二氢-1H-吲哚-3-基)乙基]-1，2，3，6-四氢吡啶-4-基]-6-氯-1H-吲哚、其任何对映异构体以及其可药用的盐用于治疗注意力不足活动过多病症的应用。
特别是本发明涉及(S)-(+)-3-[1-[2-(1-乙酰基-2，3-二氢-1-H-吲哚-3-基)乙基]-1，2，3，6-四氢吡啶-4-基]-6-氯-1H-吲哚以及其可药用的盐用于治疗注意力不足活动过多病症的应用。
本发明还涉及式(I)的3-[1-[2-(1-乙酰基-2，3-二氢-1H-吲哚-3-基)乙基]-1，2，3，6-四氢吡啶-4-基]-6-氯-1H-吲哚、其任何对映异构体，特别是(S)-(+)-3-[1-[2-(1-乙酰基-2，3二氢-1H-吲哚-3-基)乙基]1，2，3，6-四氢吡啶-4-基]-6-氯-1H-吲哚、以及可药用的盐用于制备治疗注意力不足活动过多病症的药物组合物的应用。
发明详述
化合物3-[1-[2-(1-乙酰基-2，3-二氢-1H-吲哚-3-基)乙基]-1，2，3，6-四氢吡啶-4-基]-6-氯-1H-吲哚及其对映异构体在WO98/28293中第一次公开。该申请还包含表明该化合物是一种有效的多巴胺D4配体的数据。
本发明包括式(I)化合物的外消旋体和其各对映异构体用于治疗注意力不足活动过多病症的应用。
式(I)的化合物及其对映异构体和可药用的盐可以根据WO98/28293中的描述来进行制备，特别是可参见实施例20和34。
已经用DAT-KO小鼠对化合物--(S)-(+)-3-[1-[2-(1-乙酰基-2，3-二氢-1H-吲哚-3-基)乙基]-1，2，3，6-四氢吡啶-4-基]-6-氯-1H-吲哚进行了试验，其中所说的DAT-KO小鼠是一种具有许多与患有ADHD的个体一样的行为方式和对精神刺激剂的响应的动物模型(Gainetdinov等人，Science 1999，283，397-401)。发现该化合物在这种模型中有效。
药物组合物
本发明的药物组合物可以用现有技术中的常规方法来进行制备。
因此，可以通过将活性成分与普通的助剂和/或稀释剂进行混合，然后用常规压片机对该混合物进行压缩来制备片剂。助剂或稀释剂的实例包括：玉米淀粉、马铃薯淀粉、滑石粉、硬脂酸镁、明胶、乳糖、树胶等等。如果其可以与活性成分相容，则可以使用任何常用于该类目的的其它助剂或添加剂如着色剂、矫味剂、防腐剂等。
注射用溶液可以通过将活性成分和可能的添加剂溶解于一部分注射用溶剂中，将该溶液调节至所需体积，对溶液进行灭菌并将其灌装在适宜的安瓿或小瓶中来进行制备，其中所说的注射用溶剂优选无菌水。可以添加现有技术中常用的任何适宜添加剂如张力剂、防腐剂、抗氧剂等等。
Claims (6)
1.具有如下结构式的3-[1-[2-(1-乙酰基-2，3-二氢-1H-吲哚-3-基)乙基]-1，2，3，6-四氢吡啶-4-基]-6-氯-1H-吲哚、其任何对映异构体以及其可药用的盐用于制备治疗注意力不足活动过多病症的药物组合物的应用
2.如权利要求1所述的应用，其中所用的化合物是(S)-(+)-3-[1-[2-(1-乙酰基-2，3-二氢-1H吲哚-3-基)乙基]-1，2，3，6-四氢吡啶-4-基]-6-氯-1H-吲哚或其可药用的盐。
3.如权利要求1所述的应用，其中所用的化合物是(R)-(-)-3-[1-[2-(1-乙酰基-2，3-二氢-1H-吲哚-3-基)乙基]-1，2，3，6-四氢吡啶-4-基]-6-氯-1H-吲哚或其可药用的盐。
4.一种治疗注意力不足活动过多病症的方法，其包括给需要进行治疗的患者使用具有如下结构式的3-[1-[2-(1-乙酰基-2，3-二氢-1H-吲哚-3-基)乙基]-1，2，3，6-四氢吡啶-4-基]-6-氯-1H-吲哚、其任何异构体以及其可药用的盐
5.如权利要求4所述的方法，其中所用的化合物是(S)-(+)-3-[1-[2-(1-乙酰基-2，3-二氢-1H-吲哚-3-基)乙基]-1，2，3，6-四氢吡啶-4-基]-6-氯-1H-吲哚或其可药用的盐。
6.如权利要求4所述的方法，其中所说的化合物是(R)-(-)-3-[1-[2-(1-乙酰基-2，3-二氢-1H-吲哚-3-基)乙基]-1，2，3，6-四氢吡啶-4-基]-6-氯-1H-吲哚或其可药用的盐。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DKPA200100732 | 2001-05-09 | ||
| DKPA200100732 | 2001-05-09 |
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| CN1507351A true CN1507351A (zh) | 2004-06-23 |
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| US (1) | US7294638B2 (zh) |
| EP (1) | EP1387682A1 (zh) |
| JP (1) | JP2004528361A (zh) |
| KR (1) | KR20040007544A (zh) |
| CN (1) | CN1507351A (zh) |
| AR (1) | AR033287A1 (zh) |
| BG (1) | BG108400A (zh) |
| BR (1) | BR0209443A (zh) |
| CA (1) | CA2446652A1 (zh) |
| CO (1) | CO5540378A2 (zh) |
| CZ (1) | CZ20033197A3 (zh) |
| EA (1) | EA200301221A1 (zh) |
| HR (1) | HRP20030852A2 (zh) |
| HU (1) | HUP0400075A2 (zh) |
| IL (1) | IL158413A0 (zh) |
| IS (1) | IS6992A (zh) |
| MX (1) | MXPA03010136A (zh) |
| NO (1) | NO20034972L (zh) |
| NZ (1) | NZ528896A (zh) |
| PL (1) | PL367778A1 (zh) |
| SK (1) | SK15002003A3 (zh) |
| WO (1) | WO2002089797A1 (zh) |
| ZA (1) | ZA200307955B (zh) |
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| AU2003236207A1 (en) * | 2002-05-31 | 2003-12-19 | H. Lundbeck A/S | The hydrochloride of (s)-(+)-3-(1-(2-(1-acetyl-2,3-dihydro-1h-indol-3-yl)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)-6-chloro-1h-indole |
| EP1812390A2 (en) * | 2004-10-22 | 2007-08-01 | Mark Froimowitz | Methylphenidate analogs and methods of use thereof |
| WO2009136410A2 (en) | 2008-04-19 | 2009-11-12 | Nisarga Biotech Pvt. Ltd. | Herbal composition for reducing add/adhd and method thereof |
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| US5521197A (en) * | 1994-12-01 | 1996-05-28 | Eli Lilly And Company | 3-<1-alkylenearyl>-4-<1,2,3,6-tetrahydropyridinyl>-and 3-<1-alkylenearyl>-4-piperidinyl-1h-indoles: new 5-HT1F agonists |
| ZA9711376B (en) * | 1996-12-20 | 1998-07-21 | Lundbeck & Co As H | Indole or dihydroindole derivatives |
| WO2002046156A2 (en) * | 2000-12-06 | 2002-06-13 | Sepracor, Inc. | 4,4-disubstituted piperidines for use as dopamine, serotonin and norepinephrine ligands |
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- 2002-05-07 CZ CZ20033197A patent/CZ20033197A3/cs unknown
- 2002-05-07 EP EP02724146A patent/EP1387682A1/en not_active Withdrawn
- 2002-05-07 PL PL02367778A patent/PL367778A1/xx not_active Application Discontinuation
- 2002-05-07 WO PCT/DK2002/000298 patent/WO2002089797A1/en not_active Application Discontinuation
- 2002-05-07 NZ NZ52889602A patent/NZ528896A/xx unknown
- 2002-05-07 CN CNA028095790A patent/CN1507351A/zh active Pending
- 2002-05-07 IL IL15841302A patent/IL158413A0/xx unknown
- 2002-05-07 CA CA002446652A patent/CA2446652A1/en not_active Abandoned
- 2002-05-07 HU HU0400075A patent/HUP0400075A2/hu unknown
- 2002-05-07 JP JP2002586932A patent/JP2004528361A/ja active Pending
- 2002-05-07 EA EA200301221A patent/EA200301221A1/ru unknown
- 2002-05-07 BR BR0209443-6A patent/BR0209443A/pt not_active IP Right Cessation
- 2002-05-07 SK SK1500-2003A patent/SK15002003A3/sk unknown
- 2002-05-07 MX MXPA03010136A patent/MXPA03010136A/es unknown
- 2002-05-07 US US10/477,382 patent/US7294638B2/en not_active Expired - Lifetime
- 2002-05-07 KR KR10-2003-7014554A patent/KR20040007544A/ko not_active Application Discontinuation
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- 2003-10-13 IS IS6992A patent/IS6992A/is unknown
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Also Published As
| Publication number | Publication date |
|---|---|
| HUP0400075A2 (hu) | 2004-04-28 |
| WO2002089797A1 (en) | 2002-11-14 |
| WO2002089797A8 (en) | 2004-03-25 |
| SK15002003A3 (sk) | 2004-05-04 |
| NO20034972D0 (no) | 2003-11-07 |
| EA200301221A1 (ru) | 2004-04-29 |
| EP1387682A1 (en) | 2004-02-11 |
| HRP20030852A2 (en) | 2005-06-30 |
| IS6992A (is) | 2003-10-13 |
| MXPA03010136A (es) | 2004-03-10 |
| BR0209443A (pt) | 2004-08-03 |
| US7294638B2 (en) | 2007-11-13 |
| NZ528896A (en) | 2004-12-24 |
| JP2004528361A (ja) | 2004-09-16 |
| US20040152737A1 (en) | 2004-08-05 |
| ZA200307955B (en) | 2004-10-13 |
| PL367778A1 (en) | 2005-03-07 |
| BG108400A (bg) | 2004-11-30 |
| CZ20033197A3 (en) | 2004-06-16 |
| IL158413A0 (en) | 2004-05-12 |
| NO20034972L (no) | 2003-11-07 |
| CA2446652A1 (en) | 2002-11-14 |
| KR20040007544A (ko) | 2004-01-24 |
| CO5540378A2 (es) | 2005-07-29 |
| AR033287A1 (es) | 2003-12-10 |
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