CN1105559C - 用于治疗神经病性疼痛的抗惊厥衍生物 - Google Patents
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Abstract
本发明公开了治疗神经病性疼痛的方法,该方法包括,向患有所述病症的哺乳动物施用治疗有效量的用于治疗所述病症的式(I)化合物,其中X是CH2或氧;R1是氢或烷基;R2、R3、R4和R5彼此独立地是氢或低级烷基,并且当X是CH2时,R4和R5可以是连接在一起形成苯环的烯烃基团,当X是氧时,R2和R3和/或R4和R5合在一起可以是式(II)的亚甲二氧基,其中R6和R7相同或不同,分别是氢、低级烷基,或者R6和R7均是烷基并连在一起形成环戊基或环己基环。
Description
发明背景
式I化合物是新型结构的抗癫痫化合物,该化合物在动物实验中是非常有效的抗惊厥剂(Maryanoff,B.E.,Nortey,S.O.,Gardocki,J.F.,Shank,R.P.和Dodgson,S.P.药物化学杂志(J.Med.Chem.)30,880-887;Maryanoff,B.E.,Costanzo,M.J.,Shank,R.P.,Schupsky,J.J.,Ortegon,M.E.,和Vaught H.L.生物有机和药物化学通讯(Bioorganic&Medicinal Chemistry Letters)3,2653-2656,1993)。美国专利4513006要求保护了这些化合物。其中一种称为托吡酯的化合物[2,3:4,5-二-O-(1-甲基亚乙基)-β-D-吡喃果糖氨基磺酸酯]已在人类癫痫临床实验中被证实可以在治疗单纯性和复合性局灶癫痫发作和继发性全身性癫痫发作中用作辅助治疗或单独治疗(E.FAUGHT,B.J.WILDER,RE.RAMSEY,R.A.REIFE,L.D.KRAMER,G.W.PLEDGER,R.M.KARIM等,癫痫(Epilepsia)36(S4)33,1995;S.K.SACHEDO,R.C.SACHDEO,R.A.REIFE,P.LIM和G.PLEDGER,癫痫36(S4)33,1995),该化合物目前已在英国、芬兰、瑞典和瑞士上市,用于治疗伴有或没有继发性全身性癫痫发作的单纯性和复合性局灶癫痫发作。全球的许多国家,包括但不仅限于美国,对管理部门许可的申请目前尚未获得批准。
最初发现式I化合物在传统的小鼠最大电休克癫痫发作(MES)试验中具有抗惊厥活性(SHANK,R.P.,GARDOCKI,J.F.,VAUGHT,J.L.,DAVIS,C.B.,SCHUPSKY,J.J.,RAFFA,R.B.,DODGSON,S.J.,NORTEY,S.O.和MARYANOFF,B.E.,癫痫35 450-460,1994)。随后的研究表明,式I化合物在大鼠的MES试验中也是非常有效的。最近发现,托吡酯可以在多种啮齿动物癫痫模型(J.NAKAMURA,S.TAMURA,T.KANDA,A.ISHII,K.ISHIHARA,T.SERIKAWA,J.YAMADA和M.SASA,欧洲药理学杂(Eur.J.Pharmacol.)254 83-89,1994)和引发的癫痫动物模型(A.WAUQUIER和S.ZHOU,癫痫研究(Epilepsy Res.)24 73-77,1996)中有效地阻断的癫痫发作。
最近对托吡酯进行的临床研究显示出了以前未发现的药理学特性,表明托吡酯可用于治疗某些其它疾病。其中的一种疾病是神经病性疼痛。
本发明的公开
优选实施方案的详细描述
本发明的氨基磺酸酯具有下式(I)的结构其中
X是CH2或氧;
R1是氢或烷基;
R2、R3、R4和R5彼此独立地是氢或低级烷基,并且当X是CH2时,R4和R5可以是连接在一起形成苯环的烯烃基团,当X是氧时,R2和R3和/或R4和R5合在一起可以是式(II)的亚甲二氧基,其中R6和R7相同或不同,分别是氢、低级烷基,或者R6和R7均是烷基并连在一起形成环戊基或环己基环。
R1优选是氢或1-4个碳原子的烷基,例如甲基、乙基和异丙基。在整个说明书中,烷基包括直链和支链的烷基。R2、R3、R4、R5、R6和R7的烷基是约1-3个碳的烷基,例如甲基、乙基、异丙基和正丙基。当X是CH2时,R4和R5可以合在一起形成与含有X的6元环稠合的苯环,即R4和R5是链三烯基团=C-CH=CH-CH=。
一组优选的式(I)化合物是,当X是氧时,R2和R3以及R4和R5分别是式(II)的亚甲二氧基,其中R6和R7是氢或烷基,或合在一起形成螺环戊基或环己基环,特别优选其中R6和R7均是烷基如甲基。第二组化合物是,其中X是CH2并且R4和R5连在一起形成苯环。第三组式(I)化合物是,其中R2和R3均是氢。
式(I)化合物可以通过如下方法合成:
(a)将式RCH2OH的醇与式ClSO2NH2或ClSO2NHR1的氯代氨基磺酸酯在碱如丁醇钾或氢化钠的存在下、在约-20℃至25℃下、在溶剂如甲苯、THF或二甲基甲酰胺中反应,其中R是下(III)的部分
(b)将式RCH2OH的醇与式SO2Cl2的硫酰氯在碱如三乙胺或吡啶的存在下、在约-40℃至25℃下、在溶剂如乙醚或二氯甲烷中反应生成式RCH2OSO2Cl的氯代硫酸酯。
然后可将式RCH2OSO2Cl的氯代硫酸酯与式R1NH2的胺在约40C-25℃下、在溶剂如二氯甲烷或乙腈中反应生成式(I)化合物。(b)的反应条件也可参见T.Tsuchiya等,四面体通讯(Tet.Letters),36 3365-3368(1978)。
(c)按照M.Hedayatullah在四面体通讯2455-2458(1975)中的描述,将式RCH2OSO2Cl的氯代硫酸酯与金属叠氮化物如叠氮化钠在溶剂如二氯甲烷或乙腈中反应生成式RCH2OSO2N3的叠氮基硫酸酯。然后将叠氮基硫酸酯通过催化氢化、例如用贵金属和H2或通过与金属铜在溶剂如甲醇中加热还原生成式(I)化合物。
式RCH2OH的原料可购买到或是本领域已知的。例如,其中R2和R3以及R4和R5均相同并且是式(II)基团的式RCH2OH的原料可以通过R.F.Brady在糖研究(Carbohydrate Research)Vol.14,35-40页(1970)中所述的方法制得,或通过将R6COR7酮或醛的三甲基硅烷基烯醇醚与果糖在约25℃下、在溶剂如卤代烃例如二氯甲烷中、在质子酸如盐酸或Lewis酸如氯化锌的存在下反应制得。三甲基硅烷基烯醇醚的反应参见G.L.Larson等,有机化学杂志(J.Org.Chem)Vol.38(22),3935(1973)。
此外,可以通过常规的还原方法将式RCOOH和RCHO的羧酸和醛还原成式RCH2OH的醇,例如,与氢化锂铝、硼氢化钠或硼烷-THF配合物在惰性溶剂如二甘醇二甲醚、THF或甲苯中、在约0℃-100℃下反应,参见,例如H.O.House“现代合成反应”第2版,45-144页(1972)。
式I化合物还可以通过US 5387700中公开的方法制备,该文献引入本文作为参考。
式I化合物包括各种单独的异构体及其外消旋体,例如6元环上R2、R3、R4和R5的各种α和和β连接,即,在图的平面下方或平面上方。优选亚甲二氧基(II)的氧是连接在6元环的同一侧。
式I化合物治疗神经病性疼痛的活性首先在评估托吡酯在神经病性疼痛动物模型中的效力的临床前期研究中证实。S.H.KIM和J.M.CHUNG(疼痛,50 355-363,1992)首先记载并发展了该模型,该模型被称为“Kim和Chung模型”
取体重在150-250g之间的雄性Sprague-Dawley大鼠,在其身体的一侧,在脊髓和坐骨神经(后腿内)的入口之间将L5和L6(腰椎区)脊神经紧紧结扎(用手术线系紧)。该方法可在结扎的身体同侧后爪(受影响的爪)导致异常性疼痛(对正常无害刺激的疼痛反应)和痛觉过敏(对正常疼痛刺激的过激反应),但不会使该爪丧失功能。试验对象仍可爬行并使用受影响的爪。几天内,将试验对象置于带有金属丝网底的升高的观察室内(约4”×6”×10”)。用vonFrey毛发(被调整至在一定量压力下弯曲的单丝,压力范围从0.41-45.1g)在爪底的特定区域施加逐渐增加的压力。根据S.R.CHAPLAN等(神经学方法杂志(J.Neurosci.Meth.)53 55-63,1994)的方法,通过记录受影响的爪从逐渐增加的刺激中回缩时的不同压力来测定触觉的异常疼痛。动物在其未受影响的爪对12-15g的压力产生反应,而Kim和Chung模型的动物在其受影响的爪对1-3g的压力产生反应。可用于该研究的大鼠的截止值为,在手术7天后,受影响的爪可对4g或更低的压力产生反应。
用三种剂量(3、10和30mg/kg)的托吡酯测定在Kim和Chung模型中对神经病性疼痛的口服活性;口服给药ULTRAMTM(盐酸曲马多,60mg/kg)作为阳性对照(D.BIAN等,镇痛(Analgesia)2 57-62,1996)。正如所预期的,盐酸曲马多(60mg/kg,口服)可降低Chung模型大鼠受影响爪的敏感性,开始为3g,给药后2小时达到峰值13.9g;8小时后,敏感性灰复至4.6g(n=4)。托吡酯(30mg/kg,口服)也可降低Chung模型大鼠受影响爪的敏感性,最初为3.0g,1小时达到峰值8.9g;8小时时,敏感性缓慢恢复至6.3g并在给药后24小时后仍保持在5.6g(n=4)。较小剂量的托吡酯效果较弱,敏感性改变的最大值在4小时为2.9g(3mg/kg,口服),在8小时为5.2g(10mg/kg,口服),但这些影响在该研究中被认为是不显著的(n=4)。
托吡酯在该神经病性疼痛动物模型中的长效抗异常性疼痛作用表明该药物可用于治疗人的神经病性疼痛。
在治疗神经病性疼痛时,对于普通成年人,式(I)化合物的每日口服剂量约为50-400mg,通常分两次给药。每单位剂量可含有约25-200mg活性成分。
为了制备本发明的药物组合物,可根据常规的药物混合技术将一种或多种式(I)的氨基磺酸酯化合物与药物载体紧密混合,根据给药(例如通过口服、栓剂、或胃肠外给药)所需的制剂形式,所述载体可以是各种形式的。在制备口服剂量形式的组合物时,可以使用任何常用的药物介质。因此,对于液体口服制剂例如混悬剂、酏剂和溶液剂,适宜的载体和添加剂包括水、乙二醇、油、醇、矫味剂、防腐剂、着色剂等;对于固体口服制剂如散剂、胶囊和片剂,适宜的载体和添加剂包括淀粉、糖、稀释剂、造粒剂、润滑剂、粘合剂、崩解剂等。由于易于给药,因此片剂和胶囊代表了最佳的口服剂量单位形式,在该情况下,很明显使用的是固体药物载体。如需要,可将片剂通过常规技术进行糖包衣或肠溶包衣。栓剂可使用可可脂作为载体进行制备。对于胃肠外给药,载体通常包括无菌水,但也可以包含其它成分,例如用于增加溶解度或用于防腐的成分。还可以制备可注射混悬剂,为此,可使用适宜的液体载体、悬浮剂等。
通常可将托吡酯以含有25mg、100mg或200mg活性成分的圆形片剂的形式口服给药。所述片剂含有如下惰性成分:含水乳糖、预胶化淀粉、微晶纤维素、淀粉甘醇酸钠、硬脂酸镁、纯净水、巴西棕榈蜡、羟丙甲基纤维素、二氧化钛、聚乙二醇、合成氧化铁和吐温80。
每剂量单位(例如片剂、胶囊、散剂、注射剂、一茶匙的容量、栓剂等)的本发明药物组合物可以含有约25-约200mg活性成分。
Claims (3)
1.治疗有效量的托吡酯在制备治疗神经病性疼痛的药物中的用途。
2.权利要求1的用途,其中的治疗有效量为约50-400mg。
3.权利要求1的用途,其中的量为约25-200mg。
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US2768796P | 1996-10-08 | 1996-10-08 | |
US60/027,687 | 1996-10-08 |
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DE60015070T2 (de) * | 1999-01-19 | 2006-01-05 | Ortho-Mcneil Pharmaceutical, Inc. | Verwendung von antikonvulsiven derivaten zur behandlung der cluster headache |
AU3582600A (en) * | 1999-01-21 | 2000-08-07 | Ortho-Mcneil Pharmaceutical, Inc. | Anticonvulsant derivatives useful in treating transformed migraine |
WO2002043731A2 (en) * | 2000-11-30 | 2002-06-06 | University Of Florida | Treatments for neurogenetic disorders, impulse control disorders, and wound healing |
MY147767A (en) | 2004-06-16 | 2013-01-31 | Janssen Pharmaceutica Nv | Novel sulfamate and sulfamide derivatives useful for the treatment of epilepsy and related disorders |
US8497298B2 (en) | 2005-12-19 | 2013-07-30 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocycle sulfamide derivatives for lowering lipids and lowering blood glucose levels |
US8937096B2 (en) | 2005-12-19 | 2015-01-20 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocyle sulfamide derivatives for the treatment of mania and bipolar disorder |
US8691867B2 (en) | 2005-12-19 | 2014-04-08 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocycle sulfamide derivatives for the treatment of substance abuse and addiction |
US8716231B2 (en) | 2005-12-19 | 2014-05-06 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocycle sulfamide derivatives for the treatment of pain |
TW200812573A (en) | 2006-05-19 | 2008-03-16 | Janssen Pharmaceutica Nv | Co-therapy for the treatment of epilepsy and related disorders |
JP5912269B2 (ja) | 2011-03-11 | 2016-04-27 | ローランド株式会社 | 電子楽器 |
US8652527B1 (en) | 2013-03-13 | 2014-02-18 | Upsher-Smith Laboratories, Inc | Extended-release topiramate capsules |
US9101545B2 (en) | 2013-03-15 | 2015-08-11 | Upsher-Smith Laboratories, Inc. | Extended-release topiramate capsules |
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WO1997013510A1 (en) * | 1995-10-13 | 1997-04-17 | New England Medical Center Hospitals, Inc. | Treatment of migraine |
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1999
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4513006A (en) * | 1983-09-26 | 1985-04-23 | Mcneil Lab., Inc. | Anticonvulsant sulfamate derivatives |
WO1997013510A1 (en) * | 1995-10-13 | 1997-04-17 | New England Medical Center Hospitals, Inc. | Treatment of migraine |
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