CN100448449C - 用于治疗疼痛的[[2-(氨基-3,4-二氧代-1-环丁烯-1-基)氨基]烷基]-酸衍生物 - Google Patents
用于治疗疼痛的[[2-(氨基-3,4-二氧代-1-环丁烯-1-基)氨基]烷基]-酸衍生物 Download PDFInfo
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- CN100448449C CN100448449C CNB028202430A CN02820243A CN100448449C CN 100448449 C CN100448449 C CN 100448449C CN B028202430 A CNB028202430 A CN B028202430A CN 02820243 A CN02820243 A CN 02820243A CN 100448449 C CN100448449 C CN 100448449C
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及一种治疗哺乳动物疼痛的方法,其包括给需要这种治疗的哺乳动物施用疼痛治疗有效量的式(I)的化合物:其中R1是H,烷基或苯基烷基;R2是H,烷基,链烯基或苯基烷基;或R1和R2一个构成Z是-CH2CH2-,-CH2C(R6)(R7)CH2-或-CH2C(R8)(R9)-C(R9)(R9)CH2-,其中R6,R8和R10独立地是H,烷基或羟基并且R7,R9和R11独立地是H或烷基;A是亚烷基或亚烯基;X是CO2R3,P(O)(OR4)(OR5),3,5-二氧代-1,2,4-氧杂二氮杂环戊烷-2-基或5-四唑基,其中R3,R4和R5独立地是H或烷基,或含有疼痛治疗有效量的式(I)的化合物的用于治疗疼痛的药物组合物。
Description
发明背景
文献中业已以不同方式特征化和描述了疼痛。例如,疼痛本质上可以是强烈,局部,急剧或刺痛的,和/或是迟钝,令人痛苦,弥散或灼烧的。疼痛也可以是集中的,发生在脊髓的后角、脑干和脑或外周,发生在损伤部位和外周组织。长时间出现的疼痛(即,持续的)一般称作慢性疼痛。慢性疼痛的实例包括神经病性疼痛、炎性疼痛和癌症疼痛。这些疼痛可以与痛觉过敏和/或异常性疼痛有关,其中痛觉过敏是指对典型有害刺激的敏感性增高且异常性疼痛是指对典型非有害刺激的敏感性增高。
一类目前缺乏适当药学治疗的慢性疼痛是神经病性疼痛。神经病性疼痛一般被认为是由外周或中枢神经系统被损害或病变引起的慢性疼痛。与神经病性疼痛有关的病变的实例包括长期外周或中枢神经元致敏、与神经系统抑制和/或兴奋功能受到损害有关的中枢敏化和副交感神经和交感神经神经系统之间的异常相互作用。许多临床症状与神经病性疼痛有关或构成神经病性疼痛的基础,包括例如糖尿病,切断术的术后疼痛,背下部疼痛,癌症,化学损伤或毒素,其他严重手术,由创伤性损害压迫引起的外周神经损害,营养缺乏,或感染例如带状疱疹或HIV。
目前有许多种类的药物用于治疗疼痛例如,非镇静性镇痛药例如阿斯匹林,对乙酰氨基酚或布洛芬;非甾族抗炎药(NSAID);镇静止痛药例如吗啡,氢吗啡酮,芬太尼,可待因或度冷丁;甾族化合物例如强的松或地塞米松;三环抗抑郁药例如阿米替林,去甲丙咪嗪,或丙咪嗪;抗癫痫药例如加巴喷丁,卡马西平,托吡酯,丙戊酸钠或苯妥英;或这些药物的联合形式。
然而,这些药物通常无法令人满意地治疗慢性的疼痛,并且可能存在副作用例如倦睡,头晕,口干,体重增加,记忆力损伤,和/或直立性低血压。
最新的令人感兴趣的是N-甲基-D-天冬氨酸(″NMDA″)受体的抑制剂在治疗疼痛中的应用(此后称作″NMDA受体拮抗剂″)。已经证明NMDA受体参与许多过程包括,局部缺血后神经元死亡,与记忆形成有关的突触可塑性和持续疼痛过程中的中枢敏化。可以相信调节NMDA受体的谷氨酸在疼痛和尤其是慢性疼痛中起关键作用。
NMDA受体局限在中枢神经系统。NMDA受体是配体门控阳离子通道,当它们被谷氨酸与甘氨酸合用激活时调控钠、钾和钙离子的通量。
结构上,NMDA受体被认为包括含有两种被称作NR1和NR2的主要亚基的异源多体通道。这些亚基包含甘氨酸结合位点,谷氨酸结合位点和多胺结合位点。对于NR1亚基,已经鉴定出复合剪接变体,而对于NR2亚基,已经鉴定出四种独立亚基型(NR2A,NR2B,NR2C,和NR2D)。NMDA受体还包含Mg++结合位点,该位点定位在NMDA受体的离子载体/通道复合物的内部,它阻断了离子的流出。苯环己哌啶,以及其他化合物,似乎与这个Mg++位点结合。PCP为了接近PCP受体,该通道必须首先由谷氨酸和甘氨酸打开(即,使用依赖性)。
已经开发了不同的NMDA拮抗剂来与NMDA受体的这些位点相互作用。例如,NMDA受体谷氨酸位点拮抗剂是指那些与NR2亚基的谷氨酸结合位点相互作用的拮抗剂。
已经在临床前模型中证实抑制疼痛的NMDA受体谷氨酸位点拮抗剂的实例包括CGS-19755(Selfotel;顺式-4-磷酰甲基-2-哌啶羧酸),CPP(3-(2-羧基哌嗪基-4-基)丙基-1-磷酸)和AP5(D-2氨基5-膦酰基戊酸)。参见例如,Karlsten和Gordh,药物and Aging 11:398-412,(1997)。已经确定其他NMDA受体拮抗剂在番木鳖叶硷-非敏感性甘氨酸位点(甘氨酸β)例如L701324(7-氯-4-羟基-3-(3-苯氧基)苯基-2(1H)-喹啉)和在多胺位点例如苄哌芬醇相互作用。已经发现有效抑制疼痛的非竞争性NMDA受体通道阻滞拮抗剂包括右美沙芬,氯胺酮,二甲金刚胺,和金刚烷胺.参见例如Hao等,Pain 66:279-285(1996);Chaplan等,J.Pharmacol.Exper.Ther.280:829-838(1997);Suzuki等,Pain 91:101-109,(2000);Bennett,J.Pain Symptom Management 19:S2(2000);Sang,J.Pain Symp.Manag.19(1):S21,(2000)。
NMDA受体拮抗剂已经被应用在临床上来治疗疼痛。例如,氯胺酮已经被用于治疗疱疹后神经痛,幻觉性肢体疼痛,神经损伤后疼痛,术后疼痛,和灼伤疼痛。另外,例如右美沙芬业已用来治疗糖尿病性神经病疼痛,和术后疼痛;和金刚烷胺已经用于治疗癌症患者的疼痛。
这些NMDA受体拮抗剂的临床应用已受到在镇痛剂量下副作用的限制,例如头痛,运动功能的失调如共济失调,镇静和/或拟精神病作用例如头晕,幻觉,焦虑,或认知功能的障碍,参见例如,Hao等,Pain 66:279-285(1996);Chaplan等,J.Pharmacol.Exper.Ther.280:829-838(1997);Suzuki等,Pain 91:101-109,(2000);Bennett,J.Pain SymptomManagement 19:S2(2000);Sang,J.Pain Symp.Manag.19(1):S21,(2000)。例如,偶尔用于灼伤有关的头痛的高亲和性NMDA受体通道阻断剂氯胺酮据报道存在副作用,由此限制了它在患者中的应用(Pal等,Burns 23:404-412,1997).另外,NMDA受体通道阻滞拮抗剂dizocilpine(MK-801)的开发由于类似于苯环己哌啶(即,PCP)引起的那些拟精神病作用而被停止。已经建议低亲和性通道阻滞剂例如右美沙芬,金刚烷胺和二甲金刚胺可能具有比高亲和性阻滞剂更小的副作用(Rogawski,Trends Pharmacol.Sci.14:325,1998)。为了支持这个观点,右美沙芬在患有糖尿病性神经病的患者中具有镇痛作用同时副作用小于氯胺酮(Sang,J.Pain Symp.Manag.19(1):S21,2000)。同样地,金刚烷胺减轻癌症患者的手术性神经病性疼痛同时副作用较小(Hewitt,Clin.J.Pain 16:573,2000)。
然而,即使对于低亲和性非竞争性NMDA受体通道阻滞拮抗剂,如同高亲和性非竞争性拮抗剂,已经存在阻碍其开发的不良拟精神病作用。例如,在临床前模型中,亲和性不同的NMDA受体通道阻滞剂一致地在受训大鼠中对盐水和PCP之间的区别产生PCP-样辨别刺激效应。二甲金刚胺,氯胺酮和dizocilpine均在大鼠中替代PCP-样辨别刺激效应(Nicholson等,Behav.Pharmacol.9(3):231-243,1998;Mori等,Behav.Brain Res.119:33-40,2001)。此外,如同PCP般,二甲金刚胺在猴子中保持了自给药行为,这暗示可能在人体中具有滥用潜在性(Nicholson等,Behav.Pharmacol.9(3):231-243,1998)。使用依赖性NMDA受体通道阻滞剂还可以提高心律和血压,由此可能进一步限制其临床应用。
虽然NMDA受体谷氨酸拮抗剂在人体中不存在该程度的拟精神病副作用或在非人体中PCP-样辨别刺激效应(参见例如,Baron和Woods,Psychopharmacol.118(1):42-51,(1995);Mori等,Behav.Brain Res.119:33-40,(2001);France等,J.Pharmaco.Exper.Ther.257(2):727-734,(1991);France等,Eur.J.Pharmacol.159(2):133-139,(1989)),已经证实它们具有许多不良副作用。例如,已经证实NMDA谷氨酸拮抗剂CGS-19755在行为有效剂量下在小鼠和大鼠的cingulateandretrosplenial皮质的某些层中具有暂时的、可逆的空泡诱导作用(即,有效性/-空泡形成比例为1)。参见例如,Herring等,显示兴奋的AminoAcids Clinical Results with Antagnist,Academic Press出版,Chptr1(1997)。虽然空泡形成的功能意义还不清楚,已有的研究提出这种空泡形成与NMDA受体拮抗剂产生的拟精神病作用有关(参见例如,Olney等,Science,244:1630-1632,1989;Olney等,Science 254:1515-1518,1991)并且在dizocilpine的情况中可能导致有限的神经元细胞死亡(Fix等,Exp.Neurol.123:204-215,1993)。
所以,希望发现其他有效治疗疼痛的化合物。优选这些化合物具有减小的副作用和/或在治疗疼痛中更有效。
Kinney等的U.S.专利No.5,168,103(此后为″Kinney″)公开了某些[[2-(氨基-3,4-二氧代-1-环丁烯-1-基)氨基]烷基]-酸衍生物用作神经保护剂和抗惊厥药物。这些[[2-(氨基-3,4-二氧代-1-环丁烯-1-基)氨基]烷基]-酸衍生物被公开是有效治疗某些中枢神经系统疾病的竞争性NMDA拮抗剂,例如惊厥,脑细胞损伤和有关的神经变性疾病。
Kinney专利中公开的一种化合物,[2-(8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7-烯-2-基)乙基]磷酸的副作用,早已在欧洲进行的I期临床研究中在健康志愿者进行过评估。该研究涉及开发这种化合物用于治疗患者中的中风相关性局部缺血(Bradford等,Stroke and CerebralCirculationabstract,1998)。
本发明人发现Kinney中的环丁烯衍生物在多种临床前疼痛模型中有效治疗疼痛。例如,本发明人发现这些环丁烯衍生物可以在本文试验的比较物(comparitor)NMDA受体拮抗剂不起作用的条件下减轻疼痛。
而且,这些环丁烯衍生物令人惊奇地在缓解疼痛的剂量下没有已知NMDA受体拮抗剂所产生的一定程度的不良副作用。
例如,本发明人发现Kinney公开的化合物,例如[2-(8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7-烯-2-基)乙基]磷酸,与在减轻疼痛所需剂量下其他已报道的竞争性谷氨酸拮抗剂(CGS-19755)、竞争性多胺拮抗剂(苄哌芬醇)和使用依赖性通道阻滞剂(MK-801,二甲金刚胺;dizocilipine,氯胺酮)相比在临床前模型中不会导致共济失调或镇静,在下文中将作详细描述。而且,如上所述,某些NMDA受体拮抗剂,例如发现CGS-19755在小鼠和大鼠的cingulate和retrosplenial皮质的某些层中具有暂时的、可逆的空泡诱导作用。与在行为有效剂量下引起空泡形成的CGS-19755相反,环丁烯衍生物例如[2-(8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7-烯-2-基)乙基]磷酸具有的有效性/-空泡形成比大至16。而且,与上面所述的NMDA受体通道阻滞拮抗剂不同,所述的环丁烯衍生物例如[2-(8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7-烯-2-基)乙基]磷酸在大鼠中不会代替PCP,暗示了这种化合物与PCP-样拟精神病效应或含PCP-氧滥用倾向无关。此外,[2-(8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7-烯-2-基)乙基]磷酸在比局部缺血模型中有效高4-10倍的剂量下可避免多种PCP-样效应。
发明概述
本发明提供一种治疗哺乳动物中的疼痛的方法,其包括给需要这种治疗的哺乳动物施用疼痛治疗有效量的至少一种具有式(I)的化合物:
其中:
R1是氢,1-6个碳原子的烷基或7-12个碳原子的苯基烷基;
R2是氢,1-6个碳原子的烷基,2-6个碳原子的链烯基或7-12个碳原子的苯基烷基;或R1和R2一起是Z,它是-CH2CH2-,-CH2C(R6)(R7)CH2-或-CH2C(R8)(R9)-C(R10)(R11)CH2-,其中R6,R8和R10独立地是氢,1-6个碳原子的烷基或羟基并且R7,R9和R11独立地是氢或1-6个碳原子的烷基;
A是1-6个碳原子的亚烷基或2-6个碳原子的亚烯基;
X是CO2R3,P(O)(OR4)(OR5),3,5-二氧代-1,2,4-氧杂二氮杂环戊烷-2-基或5-四唑基,其中R3,R4和R5独立地是氢或1-6个碳原子的烷基;或其药学可接受盐。
本发明还提供一种药物组合物,其含有:疼痛治疗有效量的式(I)的化合物或其药学可接受盐,其中R1和R2一起构成Z,并且其余可变部分定义如上;和至少一种药学载体。在一个优选实施方式中,这种组合物还含有药学有效量的至少一种疼痛缓解剂。还提供含有疼痛治疗有效量的式(I)的化合物或其药学可接受盐和药学有效量的至少一种疼痛缓解剂的药物组合物。
本发明还提供用于治疗哺乳动物的疼痛的单位剂型的药物组合物和为单位剂型的含式(I)化合物的治疗包装。
发明详述
本发明中有效治疗疼痛的化合物包括式(I)的环丁烯衍生物
其中
R1是氢1-6个碳原子的烷基或7-12个碳原子的苯基烷基;
R2是氢,1-6个碳原子的烷基,2-6个碳原子的链烯基或7-12个碳原子的苯基烷基;或R1和R2一起构成Z,它是-CH2CH2,CH2C(R6)(R7)CH2-或-CH2C(R8)(R9)-C(R10)(R11)CH2-,其中R6,R8和R10独立地是氢,1-6个碳原子的烷基或羟基并且R7,R9和R11独立地是氢或1-6个碳原子的烷基;
A是1-6个碳原子的亚烷基或2-6个碳原子的亚烯基;
X是CO2R3,P(O)(OR4)(OR5),3,5-二氧代-1,2,4-氧杂二氮杂环戊烷-2-基或5-四唑基,其中R3,R4和R5独立地是氢或1-6个碳原子的烷基;
或其药学可接受盐。
R1-11的烷基和A的亚烷基的实例是直链或支链基团例如甲基,乙基,丙基(例如正丙基,异丙基),丁基(例如正丁基,异丁基),戊基(例如正戊基,异戊基)或己基。本发明优选的烷基具有1-4个碳原子。R2的链烯基和A的亚烯基的实例为直链或支链一-,二-,或多不饱和基团,例如乙烯基,丙-1-烯基,烯丙基,甲代烯丙基,丁-1-烯基,丁-2-烯基或丁-3-烯基。
R1和R2的苯基烷基的实例是那些其中烷基部分为含有1-6个碳原子的直链或支链碳链的基团例如苄基,苯乙基,3-苯基丙基,或4-苯基丁基。
R1的优选值为氢,甲基,乙基或苄基。R2的优选值为氢,甲基,乙基,烯丙基,甲代烯丙基或苄基。
其他优选值为当R1和R2一起构成式(II)中的部分Z:
其中Z是-CH2CH2-,-CH2C(R6)(R7)CH2-,或-CH2C(R8)(R9)-C(R10)(R11)CH2-,并优选-CH2C(R6)(R7)CH2-,其中R6,R8和R10独立地是氢,1-6个碳原子的烷基或羟基并且R7,R9和R11独立地是氢或1-6个碳原子的烷基。优选地,R6-R11是氢。
对于A,亚烷基的优选实例是具有1-4个碳原子的直链或支链基团,例如:-CH2-,-CH2CH2-,-CH(CH3)CH2-,-CH2CH(CH3)-,-(CH2)3-,或-(CH2)4-。对于A亚烯基的优选实例是适宜具有2-4个碳原子的顺式或反式基团,例如-CH2-CH=CH-,-CH=C(CH3)-,-C(CH3)=CH-,-CH=CH-CH2-,-CH2-CH=CH-CH2-或-CH2-CH=C(CH3)-。优选A为1-4个碳原子的亚烷基或反式-2-亚丁基。X的优选取代基是羧基,膦酰基或5-四唑基。
在本发明的首选实施方式中,本发明的化合物具有式(III):
其中A和X定义如上。
本发明的化合物还包括式(I)的化合物的药学可接受盐。所谓″药学可接受盐″是指通过药学可接受碱或酸和式(I)的化合物的加成形成相应盐的任何化合物。术语″药学可接受″是指在应用于药学领域中毒理学前景可接受且与活性成分没有不良相互作用的物质。优选地,药学可接受盐是式(I)的化合物的碱金属(钠,钾,锂)或碱土金属(钙,镁)盐,或式(I)的化合物与衍生自铵或碱性胺的药学可接受阳离子的盐。后者的实例包括,但不限于,铵,一-,二-,或三甲基铵,一-,二-,或三乙基-铵,一-,二-,或三丙基铵(异和正),乙基二甲基-铵,苄基二甲基铵,环己基铵,苄基铵,二苄基铵,哌啶鎓,吗啉鎓,吡咯烷鎓,哌嗪鎓,1-甲基哌啶鎓,1-异丙基吡咯烷鎓,1,4-二甲基哌嗪鎓,1-正丁基-哌啶鎓,2-甲基哌啶鎓,1-乙基-2-甲基哌啶鎓,一-,二-,或三乙醇铵,三-(羟基甲基)甲基铵,或苯基一乙醇-铵。
本发明所述的化合物可以通过1992年12月1日授权的U.S.专利No.5,168,103(Kinney等)所述的方法制备,其全文内容在此引入作为参考。本发明的化合物还可以通过U.S.专利Nos.5,240,946(Kinney等)、5,990,307(Asselin等)或6,011,168(Asselin等)所述的方法制备;这些专利的内容也全文引入作为参考。
适用于本发明的优选化合物包括下列化合物或其药学可接受盐:
N-(2-氨基-3,4,二氧代-1-环丁烯-1-基)β-丙氨酸;
2-[2-[(2-氨基-3,4-二氧代-1-环丁烯-1-基)氨基]乙基]-1,2,4-氧杂二氮杂环戊烷-3,5-二酮;
N-(2-氨基-3,4-二氧代-1-环丁烯-1-基)-N-(2-丙烯基)甘氨酸;
[2-[(2-氨基-3,4-二氧代-1-环丁烯-1-基)氨基]乙基]膦酸;
[(E)-4-[(2-氨基-3,4-二氧代-1-环丁烯-1-基)氨基]-2-丁烯基]膦酸;
[2-[(2-氨基-3,4-二氧代-1-环丁烯-1-基)甲基氨基]乙基]膦酸;
[2-(7,8-二氧代-2,5-二氮杂二环[4.2.0]辛-1(6)-烯-2-基)乙基]膦酸;
[2-(8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基)乙基]膦酸;
[2-(4-羟基-8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)烯-2-基)乙基膦酸;
8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-乙酸;
2-[(1H-四唑-5-基)甲基]-2,6-二氮杂二环[5.2.0]-壬-1-(7)-烯-8,9-二酮;或
[2-(9,10-二氧代-2,7-二氮杂二环[6.2.0]癸-1(8)-烯-2-基)乙基]膦酸。
在本发明的一个更优选实施方式中,用于治疗疼痛的化合物是[2-(8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基)乙基]膦酸,具有下式:
或其药学可接受盐形式。
不以任何方式受理论约束,确信本发明的环丁烯衍生物对于NMDA受体上的某些结合位点具有独特的亲和性和选择性。这种独特的亲和性和选择性被认为提供了在较低剂量下对疼痛的有效治疗和/或在减轻疼痛所需剂量下不引起副作用。
本发明所述的环丁烯衍生物按照本发明的方法有效治疗哺乳动物中的疼痛。此处所谓″治疗″,是指部分或完全减轻、抑制、改善和/或缓解疼痛。例如,在此使用的″治疗″包括在一段时间内部分或完全减轻、抑制或缓解疼痛。″治疗″还包括完全缓解疼痛。
本发明所用的化合物适用于治疗哺乳动物例如人中多种不同类型的疼痛。譬如,本发明的化合物有效治疗急性疼痛(短时间)或慢性疼痛(有规律反复发作或持续)。这种疼痛还可以位于中枢或外周。
可以按照本发明的方法治疗的急性或慢性疼痛的实例包括炎性疼痛,肌肉骨骼疼痛,多骨疼痛,腰骶疼痛,颈或背上部疼痛,内脏疼痛,躯体疼痛,神经病性疼痛,癌性疼痛,损伤或手术引起的疼痛例如灼伤疼痛,或头痛例如偏头痛或紧张性头痛,或这些疼痛的联合形式。所属领域技术人员应懂得这些疼痛可能彼此重叠。例如,炎症引起的疼痛还可以在性质上是内脏或肌肉骨骼性的。
在本发明的一个优选实施方式中,本发明所用的化合物施用给哺乳动物来治疗慢性疼痛例如神经病性疼痛,例如与外周或中枢神经系统受损或病变有关的神经病性疼痛;癌症疼痛;内脏疼痛,例如与腹部、骨盆和/或会阴区域或胰腺炎有关的内脏疼痛;肌肉骨骼疼痛,例如与被下部或上部、脊柱、fibromylagia、颞下颌关节或肌筋膜疼痛综合征有关的;多骨疼痛,例如与骨或关节变性疾病有关的疼痛,例如骨关节炎,类风湿性关节炎,或脊柱狭窄;头痛例如偏头痛或紧张性头痛;或与感染有关的疼痛,例如HIV,镰刀细胞贫血症,自身免疫性障碍,多发性硬化,或炎症,例如骨关节炎或类风湿性关节炎。
在一个优选实施方式中,本发明所用的化合物按照本发明所述的方法用于治疗慢性疼痛,它是神经病性疼痛、内脏疼痛、肌肉骨骼疼痛、多骨疼痛、头痛、癌性疼痛或炎性疼痛或其联合形式。炎性疼痛可以与多种医学病症有关,例如骨关节炎,类风湿性关节炎,手术,或损伤。神经病性疼痛可以与例如糖尿病性神经病,外周神经痛,疱疹后神经痛,三叉神经病,腰部或子宫颈神经根病,fibromyalgia,舌咽神经痛,反射性交感神经营养不良,casualgia,丘脑综合征,神经根撕脱,或外周和/或损害引起的导致外周和/或中枢敏化的神经损伤,例如幻肢疼痛,反射交感神经营养不良或胸廓切开术后疼痛,癌症,化学损伤,毒素,营养缺乏,或病毒或细菌感染例如带状疱疹或HIV,或其联合形式。本发明的化合物的应用方法进一步包括治疗,其中神经病性疼痛是由转移性浸润、肥胖性痛、灼伤或与丘脑疾病有关的中枢疼痛症所继发的病症。
如上所述,本发明的方法可以用来治疗躯体和/或内脏性疼痛。例如,可以按照本发明的方法治疗的躯体疼痛包括与在手术、牙科处理、灼伤或创伤性机体损害过程中遭受的结构或软阻滞损伤有关的疼痛。可以按照本发明的方法治疗的内脏疼痛的实例包括那些与内部器官的疾病有关或导致的疼痛,所述的疾病例如溃疡性结肠炎,应激性肠综合征,应激性膀胱,克罗恩氏病,类风湿性(关节痛),肿瘤,胃炎,胰腺炎,器官的感染,或胆道疾病,或其联合形式。所属领域技术人员还应理解按照本发明的方法治疗的疼痛还可以与痛觉过敏、异常性痛疼或两者的病症有关。而且,慢性疼痛可以存在或不存在外周或中枢敏化。
适用于本发明的化合物还可以用来治疗与女性疾病有关的急性和/或慢性疼痛,其也可以称作为女性特有的疼痛。此类疼痛包括只有或主要由女性遭受的疼痛,包括与月经、排卵、妊娠或分娩、流产、异位妊娠、退行性月经、卵泡或黄体囊肿的破裂、骨盆内酯的刺激、子宫纤维瘤、子宫内膜异位、感染和炎症、骨盆器官局部缺血、梗阻、腹内粘连、骨盆内酯的解剖学畸形、卵巢脓肿、骨盆支持的丧失、肿瘤、骨盆充血有关的疼痛或非妇科原因导致的疼痛。
适用于本发明的环丁烯衍生物可以以不同的方式给药,例如通过口服,肌肉内,腹膜内,硬膜外,鞘内,静脉内,皮下,粘膜内例如舌下或鼻内,或透皮给药。在本发明的一个优选实施方式中,本发明所用的化合物经口服、内膜内或静脉内给药。
本发明所用的化合物是以疼痛治疗有效量施用给需要治疗疼痛的哺乳动物。在此使用的″疼痛治疗有效量″至少是环丁烯衍生物或其药学可接受盐形式的最小量,其治疗所述的疼痛。为了测定疼痛治疗中所施用化合物的疼痛治疗有效量,主治医生可以,例如,通过递增剂量片剂给药的环丁烯衍生物在患者中的作用,例如口服剂量,优选约3mg/kg-约1000mg/kg直至达到所需的症状缓解水平。则可以改进连续给药方案来获得预期效果,并且口服剂量的范围优选约150mg/天-约900mg/天。类似方法随后可以基于生物利用度数据测定其他给药途径的有效剂量范围,例如通过静脉内或肌肉内途径的。例如,评价静脉内剂量应优选约3mg/天-约50mg/天。
虽然所述的环丁烯衍生物作为治疗疼痛的唯一活性成分可以按照本发明的方法测定,本发明人发现所述的环丁烯衍生物也与一种或多种其他疼痛缓解剂一起给药。所谓″疼痛缓解剂″是指任何直接或间接治疗疼痛症状的药物。间接疼痛缓解剂的实例包括例如抗炎药,例如抗类风湿药物。
一种或多种其他疼痛缓解剂可以同时给药(例如在相同时间内单独给药,或共同存在于一种药物组合物中),和/或与一种或多种本发明的环丁烯衍生物顺序给药。优选地,所述的环丁烯衍生物和一种或多种疼痛缓解剂以这样的方式给药,即使上述两者在某段时间内存在于哺乳动物机体内用于治疗疼痛。
其他疼痛缓解剂的给药方法可以与所述环丁烯衍生物所采用的给药途径相同或不同。例如,其他疼痛缓解剂可以是通过口服,肌肉内,腹膜内,硬膜外,鞘内,静脉内,粘膜内(例如通过鼻内或舌下),皮下或透皮给药。优选的给药途径应依赖于选择的特定疼痛缓解剂及其所属领域技术人员已知的推荐给药途径。例如,阿片类优选通过口服、静脉内或肌肉内给药途径施用。
所属领域技术人员应理解其他疼痛缓解剂对哺乳动物的给药剂量应依赖于所述的特定疼痛缓解剂和所需给药途径。因此,其他疼痛缓解剂可以按照所属领域技术人员已知的实践操作和给药,例如公开在参考文献中的那些,如the Physicians′Desk Reference,55版,2001,MedicalEconomics Co.,Inc.,Montvale,NJ出版。
可以与本发明的环丁烯衍生物一起给药的疼痛缓解剂的实例包括镇痛剂,例如非镇静性镇痛剂或镇静性镇痛剂;抗炎药例如非甾族抗炎药(NSAID),甾族或抗类风湿性药物;偏头痛制剂例如肾上腺素能阻滞剂,麦角衍生物,或异美汀;三环抗抑郁药例如阿米替林,去甲丙咪嗪,或丙咪嗪;抗癫痫药例如加巴喷丁,卡马西平,托吡酯,丙戊酸钠或苯妥英;α2激动剂;或选择性5-羟色胺摄取抑制剂/-选择性去甲肾上腺素摄取抑制剂,或其联合形式。所属领域技术人员应理解下面描述的一些药物发挥减轻多种病症的作用,例如疼痛和炎症,而且其他药物只可减轻一种症状例如疼痛。具有多种性质的药物的一个具体实例是阿斯匹林,而阿斯匹林在以高剂量给药时是抗炎药,但在低剂量时仅仅是镇痛剂。所述的疼痛缓解剂可以包括任何上述药物的联合,例如,所述的疼痛缓解剂可以是非镇静性镇痛剂与镇静性镇痛剂的联合。
适用于本发明的非镇静性镇痛剂包括,例如,水杨酸类例如阿斯匹林,布洛芬酮洛芬萘普生对乙酰氨基酚,吲哚美辛或其联合形式。可以与环丁烯衍生物联合使用的镇静性镇痛剂的实例包括阿片类镇痛剂例如芬太尼,舒芬太尼,吗啡,氢吗啡酮,可待因,羟考酮,丁丙诺啡或其药学可接受盐或其联合形式。可以与所述环丁烯衍生物联合使用的抗炎药的实例包括但不限于阿斯匹林;布洛芬;酮洛芬;萘普生;依托度酸COX-2抑制剂例如celecoxibrofecoxibvaldecoxibparecoxib,etoricoxib(MK663),deracoxib,2-(4-乙氧基-苯基)-3-(4-甲磺酰基-苯基)-吡唑并[1,5-b]哒嗪,4-(2-氧代-3-苯基-2,3-二氢恶唑-4-基)苯磺酰胺,darbufelone,flosulide,4-(4-环己基-2-甲基-5-恶唑基)-2-氟苯磺酰胺),meloxicam,nimesulide,1-甲基磺酰基-4-(1,1-二甲基-4-(4-氟苯基)环戊-2,4-二烯-3-基)苯,4-(1,5-二氢-6-氟-7-甲氧基-3-(三氟甲基)-(2)-苯并硫代吡喃并(4,3-c)吡唑-1-基)苯磺酰胺,4,4-二甲基-2-苯基-3-(4-甲基磺酰基)苯基)环丁烯酮,4-氨基-N-(4-(2-氟-5-三氟甲基)-噻唑-2-基)-苯磺酰胺,1-(7-叔丁基-2,3-二氢-3,3-二甲基-5-苯并呋喃基)-4-环丙基丁-1-酮,或其生理可接受盐、酯或溶剂化物;舒林酸双氯酚酸钠吡罗昔康二氟尼柳那布米酮恶丙嗪吲哚美辛或甾族化合物例如强的松龙磷酸钠口服溶液;SOLU-注射用甲基强的松龙琥珀酸钠,牌和强的松龙糖浆。
优选用于治疗类风湿关节炎的抗炎药的其他实例包括萘普生,它是以Roche Labs提供的EC-缓释片、 和DS片和混悬液的形式商购,牌的celecoxi片剂,牌的rofecoxib,牌的倍他米松,牌的青霉胺胶囊,牌的滴定青霉胺片剂,DEPO-MEDROL牌的醋酸甲基强的松龙可注射混悬液,ARAVATM leflunomide片,AZULFIDLINE EN-牌的柳氮磺吡啶缓释片,牌的吡罗昔康胶囊,双氯酚酸甲片剂,双氯酚酸钠缓释片,-XR双氯酚酸钠长效释放片,或etanerecept产品。
治疗炎症、尤其是类风湿性关节炎的其他试剂的实例包括免疫抑制剂例如GENGRAFTM牌环孢菌素胶囊,牌环孢菌素胶囊或口服溶液,或牌硫唑嘌呤片剂或IV注射剂;牌吲哚美辛胶囊、口服混悬剂或栓剂;牌硫酸羟氯喹;或infliximab重组体的IV注射剂;或昂贵的化合物例如金诺芬或硫代苹果酸金钠注射剂。
适用于本发明的环丁烯衍生物还可以与一种或多种其他药学活性剂一起给药,例如那些用于治疗任何存在于哺乳动物中的与哺乳动物所受疼痛有关或无关的医学病症的药物。此类药学活性剂的实例包括抗血管生成药物、抗瘤形成药物、抗糖尿病药物、抗感染药或胃肠道药物,或其联合形式。
药学活性剂的更加全面的目录,包括疼痛减轻药,可以参见Physicians’Desk Reference,55版,2001,Medical Economics Co.,Inc.,出版,Montvale,NJ。这些药物各自可以按照该技术领域已知的药学有效剂量和方案给药,例如那些在Physicians′Desk Reference,55版,2001,Medical Economics Co.,Inc.出版,Montvale,NJ中描述的产品。
在本发明的一个优选实施方式中,至少一种环丁烯衍生物与至少一种阿片镇痛剂按照在此所述的方法一起给药。令人惊奇地发现适用于本发明的环丁烯衍生物,当与至少一种阿片镇痛剂例如吗啡一起给药时,具有协同减轻疼痛感、增加疼痛减轻的时间和/或与其他可比NMDA拮抗剂相比很大程度地减少副作用的有益效果。
适用于本发明的环丁烯衍生物可以单纯(即,本身)或以药物组合物给药。本发明的药物组合物可以是所属领域技术人员已知的任何形式例如液体或固体形式。
药物组合物,除了含有疼痛治疗有效量的一种或多种本发明的环丁烯衍生物以外,可以包括所属领域技术人员用于配制药物组合物已知的一种或多种组分。所述的组分包括例如,载体(例如,固体或液体形式),矫味剂,润滑剂,增溶剂,助悬剂,填充剂,助流剂,压缩助剂,粘合剂,片剂崩解剂,包封材料,乳化剂,缓冲剂,防腐剂,甜味剂,增稠剂,着色剂,粘度调节剂,稳定剂或嗅觉调节剂,或其联合形式。
固体药物组合物优选含有一种或多种固体载体,并且选择性地含有一种或多种其他添加剂例如矫味剂,润滑剂,助溶剂,助悬剂,填充剂,助流剂,压缩助剂,粘合剂或片剂崩解剂或包封材料。适当的固体载体包括,例如,磷酸钙,硬脂酸镁,滑石粉,蔗糖,乳糖,糊精,淀粉,明胶,纤维素,甲基纤维素,羧甲基纤维素钠,聚乙烯吡咯烷酮,低熔点蜡或离子交换树脂,或其联合形式。在散剂药物组合物中,载体优选是微粉化固体,其与微粉化活性成分混合。在片剂中,活性成分与具有必要压缩性质的载体以适当比例混合,并且选择性地与其他添加剂混合,和压缩为所需形状和大小。固体药物组合物,例如散剂和片剂,优选含有至多99%的活性成分。
液体药物组合物优选含有一种或多种环丁烯衍生物和一种或多种液体载体用于形成溶液、混悬剂、乳剂、糖浆剂、酏剂或加压组合物。
药学可接受液体载体包括例如水,有机溶剂,药学可接受油或脂肪,或其联合形式。液体载体可以含有其他适当的药学添加剂例如增溶剂,乳化剂,缓冲剂,防腐剂,甜味剂,矫味剂,助悬剂,增稠剂,着色剂,粘度调节剂,稳定剂或溴觉调节剂,或其联合形式。
适合口服或非肠道给药的液体载体的实例包括水(优选含有添加剂例如纤维素衍生物,如羧甲基纤维素钠),醇或其衍生物(包括一元醇或多元醇例如二醇类)或油(例如,分馏椰油和花生油)。为了非肠道给药所述的载体还可以是油酯,例如油酸乙酯和肉豆蔻酸异丙酯。用于加压组合物的液体载体可以是卤代烃类或其他药学可接受抛射剂。
可以是灭菌溶液或混悬剂的液体药物组合物可以经非肠道给药,例如提供肌肉内、腹膜内、硬膜外、鞘内、静脉内或皮下注射。用于口服或透内膜给药的药物组合物可以是液体或固体组合物形式。
在本发明的一个优选实施方式中,所述的药物组合物,除了含有所述的环丁烯衍生物以外还可以含有药学有效量的一种或多种上述疼痛缓解剂,和/或药学有效量的一种或多种上述其他药学活性剂。所以,本发明还提供一种治疗疼痛的药物组合物,该组合物含有疼痛治疗有效量的至少一种适用于本发明的环丁烯衍生物和药学有效量的至少一种上述疼痛缓解剂。在一个更优选实施方式中,所述的疼痛缓解剂包括阿片镇痛剂。
优选该药物组合物为单位剂型,例如片剂或胶囊。以这样的形式,所述的组合物进一步分为含有适量活性成分的单位剂量。该单位剂型可以是包装组合物,例如小包的粉,瓶,安瓿,预填装注射器或含液体的小药囊。该单位剂型可以是,例如,胶囊或片剂本身,或它可以是适当数量的此类组合物的包装形式。
所以,本发明还提供用于哺乳动物中的疼痛的单位剂型的药物组合物,其中含有疼痛治疗有效量的至少一种本发明的环丁烯衍生物。所属领域技术人员应理解,优选的疼痛治疗有效单位剂量应依赖于例如给药的方法。例如,口服给药的单位剂量优选范围在约75mg-约300mg,且更优选约100mg-约300mg的本发明的环丁烯衍生物。
本发明还提供一种将本发明的环丁烯衍生物分配给治疗疼痛的哺乳动物的药物包装。优选地,该治疗包装含有一个或多个单位剂量的环丁烯衍生物和含有该一个或多个单位剂量的容器,并且贴有指导该包装在治疗哺乳动物中疼痛的用途的标签。在一个优选实施方式中,单位剂型是片剂或胶囊形式。在一个优选实施方式中,各单位剂量为疼痛治疗有效量。
实施例
评估本发明所用的环丁烯衍生物在治疗疼痛中的有效性。也测试已知可减轻疼痛的NMDA受体拮抗剂作为比较。
本文所述的试验方法已经为其他所属领域技术人员用于评价化合物的镇痛作用。参见例如,Bennett GJ和Xie TK,A peripheralmononeuropathy in rats produces disorders of Pain sensation like thoseseen in man,Pain 33:87-107(1988);Chaplan SR,Bach RW,Pogrel JW,Chung JM和Yaksh TL,Quantitative assessment of tactile allodynia inthe rats paw,J.Neurosci.Methods 53:55-63(1994);和Mosconi T和Kruger L,Fixed-diameter polyethylene cuffs applied to the rats Sciatcnerve induce a painful neuropathy:ultrastructural morphometric analysisof axonal alterations Pain 64:37-57(1996)。
对象
各个圈养的Spraque-Dawley大鼠随意接受大鼠食物和水。实施12小时光照/12小时黑暗循环(光照自6:00am至6:00pm)。动物的维持和研究是按照National Institutes of Health Committee on LaboratoryAnimal Resources提供的指南进行。这些对象用于下列试验中。
试验化合物
实施例中试验的环丁烯衍生物是:
A.[2-(8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基)乙基]膦酸(称作化合物A);和
B.2-[(1H-四唑-5-基)甲基]-2,6-二氮杂二环[5.2.0]-壬-1-(7)-烯-8,9-二酮(称作化合物B)。
化合物A和B分别按照Asselin的U.S.专利No.5,990,307和Kinney等的U.S.专利No.5,168,103所述的方法制备。
本发明的环丁烯衍生物与一种或多种减轻疼痛的下列已知NMDA拮抗剂进行比较:
二甲金刚胺,得自RBI(Natick,MA)
dizocilipine,得自RBI(Natick,MA)
氯胺酮,得自Fort Dodge(Fort Dodge,10)
苄哌芬醇,得自Sigma(St.Louis,MO)
CGS-19755,得自Tocris(Ellisville,MO)
氯胺酮和dizocilpine是高亲和性使用依赖性NMDA受体通道阻滞剂,而二甲金刚胺是中等亲和性使用依赖性NMDA受体通道阻滞剂。CGS-19755是竞争性NMDA拮抗剂和苄哌芬醇是竞争性多胺拮抗剂。
试验方法1:前列腺素E2-诱发的热超敏性。
将尾的末端10cm置于含热水的热水瓶中,该热水温热到38,42,46,50,54或58℃。动物从水中抽出尾部的以秒计的潜伏期用作感受伤害的量度。如果动物在20秒内没有抽出尾部,试验者取出尾部并记录最大潜伏期为20秒。
在评估基线热敏感性之后,通过0.1mg前列腺素E2(PGE2)的50μL注射剂注射到尾部末端1cm处来产生热超敏性。温度-效应曲线是在PGE2注射之前(基线)和之后(15,30,60,90和120分钟)得到。在其他动物(例如,猴子;Brandt等,J.Pharmacol.Exper.Ther.296:939,2001)中的已有研究和由目前研究的结果证实PGE2产生剂量-和时间-依赖性的热超敏,其在注射后15分钟时达到峰值且在2小时后消失。
单一化合物的研究.药物逆转PGE2-诱发的热超敏性的能量利用单剂量时间-过程法评估。
在这种方法下,将被测化合物的一个剂量经腹膜内(IP)、口服(PO)或鼻内(IN)在注射PGE2之前30分钟给药。在PGE2注射后30分钟评估触觉敏感性。
组合化合物的研究.进行采用NMDA受体拮抗剂与mu阿片激动剂吗啡的组合研究。将最小有效剂量的吗啡(5.6mg/kg)单独给药和与无效剂量的NMDA受体拮抗剂在热水尾部抽出热试验中一起给药。试验之前30分钟同时IP给予化合物。
在PGE2-诱发的热超敏性试验中也进行采用NMDA受体拮抗剂与mu阿片激动剂吗啡的组合研究。吗啡完全逆转热超敏性(即恢复到基线)的剂量(5.6mg/kg)单独给药和与多剂量的NMDA受体拮抗剂在PGE2-诱发的热水尾部抽出热试验中一起给药。化合物与PGE2同时IP给药,其在试验之前30分钟时施用。
试验方法1数据分析-由各温度-效应曲线计算出产生尾部抽出潜伏期半数最大增量时的温度(即,T10)。该T10是通过内推法由温度-效应曲线上10秒上下的点绘制的线。由这些研究,热超敏性定义为在温度-效应曲线中向左方的移动且T10值减小。热超敏性的逆转定义为恢复到温度-效应曲线的基线和T10值并且按照下列公式计算:
其中T10 药物+PGE2是药物与PGE2组合后的T10,T10 PGE 2是PGE2单用的T10,和T10 基线是在对照条件下的T10。100的A%MPE值是指没有PGE2注射下观察到完全恢复到基线热敏感性。大于100%的值是指该被测化合物减小热敏感性超过了没有PGE2注射时基线热敏感性。
试验方法2:慢性狭窄损伤
大鼠用在O2中的3.5%氟烷于1L/min下麻醉且在手术中用O2中1.5%氟烷维持。通过皮肤切开并经弘二头肌顿器解剖暴露于坐骨神经下来产生改进的坐骨神经狭窄损伤(Mosconi&Kruger,1996;Bennett&Xie,1988)。PE 90聚乙烯管(Intramedic,Clay Adams;BectonDickinson Co.)管头(长2mm)置于大腿中部水平的坐骨神经四周。该创伤用4-丝质缝线和创伤夹封闭为层。手术后进行6-10天的试验。
将动物置于升高的线笼内且给其45-60分钟来适应实验室。基线触觉敏感性用一系列的校准von Frey单丝(Stoelting;Wood Dale,IL)在手术前0-3天评估。Von Frey单丝以顺序上升或下降次序置于中足底后爪,如果必要,达到尽可能接近响应的阈值。该阈值是由对刺激产生强烈退回反应时的最低作用力。所以,退回反应导致下次提供更高的刺激且对退回反应的缺乏导致下次提供更强的刺激。该研究排除具有基线阈值<10g作用力的大鼠。CCI手术后约1周,再次评价触觉敏感性且下面的试验排除了那些表现出运动缺乏(即爪慢移动)或无法产生继发触觉超敏性(阈值≥10g)的动物。在累积给药的条件下,化合物经IP每30分钟给药且该累积剂量以1/2 log单位增量提高。各药物给药后20-30分钟时评价触觉超敏性。
试验方法2数据分析-计算通过Dixon非参数试验(Chaplan等,1994)评价的50%阈值(以gm作用力计)且用15g克作用力作为最大作用力。由各大鼠的试验状况得到剂量-效应曲线。求各触觉超敏性阈值的平均值(±SEM)。触觉超敏性的逆转定义为恢复到基线触觉敏感性并按照下面的公式计算:
其中50%药物+CCI是CCI手术后约1周动物中给予化合物后的50%值,50%CCI是单独CCI手术后约1周的50%值,和50%基线是CCI手术之前的50%值。100%逆转的最大效应表示在试验条件下恢复到对象的平均术前阈值。
试验方法3:预定控制响应
在每周进行5天的试验期间在多周期法下训练大鼠。各训练周期由10分钟的预处理期、随后10分钟的反应期组成。在预处理期中,不照射刺激光线,和反应没有预定结果。在反应期中,照射左或右刺激光(在动物中达到平衡),延长反应水平且对象可在食物供给的固定比30程序表下反应。训练期由3个连续周期组成。除在首个周期开始时给予单剂量的药物之外,试验期与训练期相同。
数据分析.将各动物在使用期中三个周期的操作反应比求平均值且转化为对照反应比的百分率(即,三个周期的平均值),用得自训练日前的平均比作为对照值。数据表示为平均(±1SEM)反应比作为对照的百分率。所以,例如,100%创伤的试验值表示被测化合物给药后的反应比与对照反应比相同且被测化合物没有副作用。
结果
试验方法1:基线热感受伤害和PGE2-诱发的热超敏性
在基线条件下,最大尾部抽出潜伏期(即,20秒)提出是在38、42和46℃的温度下得到。当水温升高到50℃时,各大鼠的尾部抽出潜伏期一般在5-15秒。54℃的最高温度在所有大鼠中产生小于10秒的尾部抽出潜伏期。平均基线T10值(10秒抽出)是在49℃-51℃之间。
产生剂量-和时间-依赖性热超敏性的0.1mgPGE2的剂量表现为在温度-效应曲线中左移且T10值降低。在给药后尾部抽出潜伏期的最大减少为15分钟,并且潜伏期在注射后120分钟恢复到基线。
下表1显示,PGE2与对比NMDA拮抗剂化合物联合时的效果。直至达到产生镇静和共济失调的可目测迹象时的剂量(即,对比实施例1-<10mg/kg,对比实施例2-<100mg/kg,对比实施例3-<0.3mg/kg,对比实施例4至6-<30mg/kg),无一对比化合物,包括二甲金刚胺(对比实施例1和2),dizocilpine(对比实施例3),氯胺酮(对比实施例4),苄哌酚胺(对比实施例5)或CGS-19755(对比实施例6),产生高于PGE2-诱导的热超敏性的25%逆转。相比之下,[2-(8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基)乙基]膦酸,本发明的环丁烯衍生物(化合物A),在以10mg/kg IP给药后产生79%逆转并且在以100mg/kg PO给药后产生87%逆转。这些剂量(高达178mg/kg)与由比较化合物可见的镇静或共济失调无关。此外,经鼻内(IN)给药的1mg或3mg的化合物A分别产生37%或79%逆转。由对象体重计算的平均剂量分别是2.6和7.5mg/kg的剂量。同样地,本发明的另一种环丁烯衍生物,2-[(1H-四唑-5-基)甲基]-2,6-二氮杂二环[5.2.0]-壬-1-(7)-烯-8,9-二酮(化合物B)导致PGE2-诱发热超敏性的完全逆转。
本发明的环丁烯衍生物在减轻疼痛中的有效性,例如化合物A和B,例如热超敏性,令人惊奇且意外。例如,所有按照试验方法1试验的化合物均是NMDA受体拮抗剂,然而化合物A和B基本上且明显优于对比化合物。尤其重要的是,注意到两种化合物A和B,如同对比化合物CGS-19755是竞争性谷氨酸NMDA受体拮抗剂,但化合物A和B明显且基本上更加良好。
表1:PGE2-诱导的热超敏性的结果
表1(续):PGE2-诱导的热超敏性的结果
*栏中表示近似值;实际平均剂量为2.6mg/kg
**栏中表示近似值;实际平均剂量为7.5mg/kg
适用于本发明的环丁烯衍生物也与阿片镇痛剂一起进行试验来测定所述的环丁烯衍生物与阿片镇痛剂吗啡合用减轻热敏感性的能力。吗啡的最小有效剂量单独施用和与被测化合物的无效剂量联合施用。下表1-2表示热水尾部抽出试验的实施例。5.6mg/kg吗啡IP(对比实施例11)的剂量与载体T10(48.9±0.1)相比产生小但有效的T10增加(51.2±0.7)。当与5.6mg/kg吗啡合用时,无效剂量的18mg/kg氯胺酮IP(对比实施例12)与吗啡单用(对比实施例13)相比使T10的增加不显著(52.8±0.5)。相反,无效剂量的10mg/kg化合物A IP(实施例14)与吗啡合用时与吗啡单用(实施例15)相比产生显著和令人惊奇的T10增加(55.8±1.3)。
表1-2:热水尾部抽出组合研究
实施例 | 被测化合物 | 剂量(mg/kg) | 距离基线的变化 |
对比实施例11 | 吗啡 | 5.6 | +2.3 |
对比实施例12 | 氯胺酮 | 18.0 | -0.3 |
对比实施例13 | 吗啡+氯胺酮 | 5.6+18.0 | +3.9 |
实施例14 | A | 10.0 | -0.3 |
实施例15 | 吗啡+A | 5.6+10.0 | +6.9 |
适用于本发明的环丁烯衍生还与阿片镇痛剂一起试验来测定环丁烯衍生物与阿片镇痛剂吗啡合用时降低PGE2-诱导的热超敏性的能力。下表1-3表示PGE2-诱导的热超敏性试验的实施例。将PGE2注射到尾部与载体T10(50.3±0.4;对比实施例16)相比明显降低T10(44.8±0.1)。5.6mg/kg吗啡(对比实施例17)的剂量有效逆转T10至类似于载体(50.6±0.5)的值。当与5.6mg/kg吗啡联合给药时,无效剂量的18mg/kg实施例3IP(对比实施例18)与吗啡单用(对比实施例19)相比使T10没有显著增加(51.7±0.2)。相反,有效剂量的10mg/kg实施例6IP(T10=48.8±0.2;实施例20)与吗啡联合与吗啡单用(实施例21)明显且令人惊奇地增高T10(55.3±0.2)。
表1-3:PGE2-诱导的热超敏性组合研究
实施例 | 被测化合物 | 剂量(mg/kg) | 距离基线的变化 |
对比实施例16 | 载体 | -5.6 | |
对比实施例17 | 吗啡 | 5.6 | +0.3 |
对比实施例18 | 氯胺酮 | 18.0 | -5.5 |
对比实施例19 | 吗啡+氯胺酮 | 5.6+18.0 | +1.4 |
实施例20 | A | 10.0 | -1.5 |
实施例21 | 吗啡+A | 5.6+10.0 | +5.0 |
试验方法2结果:慢性狭窄损伤
表2表示本发明的环丁烯衍生物逆转动物中CCI-诱导的触觉超敏性的作用,所述的动物在试验前1周接受CCI手术。NMDA受体拮抗剂二甲金刚胺(对比实施例22)和CGS-19755(对比实施例23)还进行测试用于对比。高达产生镇静和共济失调的可目测迹象的剂量时(即,对比实施例22-<10mg/kg,对比实施例23-<30mg/kg),无一对比化合物产生对CCI-诱导的触觉超敏性的逆转作用。与其相比,化合物A(实施例24)在IP给药后产生97%逆转,化合物B(实施例25)在IP给药后产生40%逆转。
化合物A和B的剂量与在对比化合物中可见的镇静或共济失调无关。
表2:慢性狭窄损伤诱导的触觉超敏性
本发明的环丁烯衍生物例如化合物A和B在减轻疼痛例如CCI-诱导的触觉超敏性中的有效性令人惊奇且意外。例如,化合物A和B比已知NMDA受体拮抗剂二甲金刚胺和CGS-19755作用更加显著和良好。
试验方法3结果
为了评估本发明的环丁烯衍生物的潜在副作用,化合物A在食物供给的时间表响应下给予动物。NMDA受体拮抗剂二甲金刚胺和dizocilpine也进行试验用于对比。表3表明二甲金刚胺(对比实施例26)和dizocilpine剂量-依赖性地降低反应的比例。这些是没有逆转PGE2-诱导的热超敏性或CCI-诱导的触觉超敏性的剂量。相反,IP(实施例28)或PO(实施例29)给药的化合物A意外地在逆转PGE2-诱导的热超敏性或CCI-诱导的触觉超敏性的剂量下没有明显改变反应的比例。
表3:操作反应
Claims (20)
1.式(I)的化合物或其药学可接受盐在制备用于治疗哺乳动物中的疼痛的药物中的用途:
其中:
R1是氢,1-6个碳原子的烷基或7-12个碳原子的苯基烷基;
R2是氢,1-6个碳原子的烷基,2-6个碳原子的链烯基或7-12个碳原子的苯基烷基;或
R1和R2一起是Z,它是-CH2CH2-,-CH2C(R6)(R7)CH2-或-CH2C(R8)(R9)-C(R10)(R11)CH2-,其中R6,R8和R10独立地是氢,1-6个碳原子的烷基或羟基并且R7,R9和R11独立地是氢或1-6个碳原子的烷基;
A是1-6个碳原子的亚烷基或2-6个碳原子的亚烯基;
X是CO2R3,P(O)(OR4)(OR5),3,5-二氧代-1,2,4-氧杂二氮杂环戊烷-2-基或5-四唑基,其中R3,R4和R5独立地是氢或1-6个碳原子的烷基。
2.权利要求1的用途,其中:
R1是氢,甲基,乙基,或苄基,
R2是氢,甲基,乙基,烯丙基,甲代烯丙基或苄基,
或R1和R2一起构成Z,它是-CH2CH2-,-CH2C(R6)(R7)CH2-,或-CH2C(R8)(R9)-C(R10)(R11)CH2-;
A是选自-CH2-,-CH2CH2-,-CH(CH3)CH2-,-CH2CH(CH3)-,-(CH2)3-,或-(CH2)4-的直链或支链亚烷基;和
X选自羧基,膦酰基或5-四唑基;或其药学可接受盐形式。
3.权利要求1的用途,其中:
R1和R2一起构成Z,它是-CH2CH2-,-CH2C(R6)(R7)CH2-,或-CH2C(R8)(R9)-C(R10)(R11)CH2-;
A是选自-CH2-,-CH2CH2-,-CH(CH3)CH2-,-CH2CH(CH3)-,-(CH2)3-或-(CH2)4-的直链或支链亚烷基;和
X选自羧基,膦酰基或5-四唑基。
4.权利要求1的用途,其中式(I)的化合物包括至少一种的:
N-(2-氨基-3,4-二氧代-1-环丁烯-1-基)β-丙氨酸;
2-[2-[(2-氨基-3,4-二氧代-1-环丁烯-1-基)氨基]乙基]-1,2,4-氧杂二氮杂环戊烷-3,5-二酮;
N-(2-氨基-3,4-二氧代-1-环丁烯-1-基)-N-(2-丙烯基)甘氨酸;
[2-[(2-氨基-3,4-二氧代-1-环丁烯-1-基)氨基]乙基]膦酸;
[(E)-4-[(2-氨基-3,4-二氧代-1-环丁烯-1-基)氨基]-2-丁烯基]膦酸;
[2-[(2-氨基-3,4-二氧代-1-环丁烯-1-基)甲基氨基]乙基]膦酸;
[2-(7,8-二氧代-2,5-二氮杂二环[4.2.0]辛-1(6)-烯-2-基)乙基]膦酸;
[2-(8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基)乙基]膦酸;
[2-(4-羟基-8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)烯-2-基)乙基]膦酸;
8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-乙酸;
2-[(1H-四唑-5-基)甲基]-2,6-二氮杂二环[5.2.0]-壬-1-(7)-烯-8,9-二酮;或
[2-(9,10-二氧代-2,7-二氮杂二环[6.2.0]癸-1(8)-烯-2-基)乙基]膦酸;或其药学可接受盐。
5.权利要求1的用途,其中式(I)的化合物包括[2-(7,8-二氧代-2,5-二氮杂二环[4.2.0]辛-1(6)-烯-2-基)乙基]膦酸,或其药学可接受盐。
6.权利要求1的用途,其中式(I)的化合物包括[2-(8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-基)乙基]膦酸,或其药学可接受盐形式。
7.权利要求1的用途,其中式(I)的化合物包括[2-(4-羟基-8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)烯-2-基)乙基]膦酸,或其药学可接受盐形式。
8.权利要求1的用途,其中式(I)的化合物包括8,9-二氧代-2,6-二氮杂二环[5.2.0]壬-1(7)-烯-2-乙酸,或其药学可接受盐形式。
9.权利要求1的用途,其中式(I)的化合物包括2-[(1H-四唑-5-基)甲基]-2,6-二氮杂二环[5.2.0]-壬-1-(7)烯-8,9-二酮,或其药学可接受盐。
10.权利要求1的用途,其中式(I)的化合物包括[2-(9,10-二氧代-2,7-二氮杂二环[6.2.0]癸-1(8)-烯-2-基)乙基]膦酸,或其药学可接受盐形式。
11.权利要求1-10任一项的用途,其中所述的疼痛是急性疼痛或慢性疼痛。
12.权利要求11的用途,其中所述的疼痛是炎性疼痛,肌肉骨骼疼痛,多骨疼痛,腰骶疼痛,颈或背上部疼痛,内脏疼痛,躯体疼痛,神经病性疼痛,癌性疼痛,损伤或手术引起的疼痛,或头痛,或其联合形式。
13.权利要求11的用途,其中所述的疼痛是慢性头痛。
14.权利要求13的用途,其中该慢性疼痛与异常性疼痛、痛觉过敏或两者有关。
15.权利要求13的用途,其中该慢性疼痛是神经病性疼痛;癌性疼痛;内脏疼痛;肌肉骨骼疼痛;多骨疼痛;头痛;或与感染、镰刀细胞贫血、自身免疫性疾病、多发性硬化或炎症有关的疼痛,或其联合形式。
16.权利要求13的用途,其中所述的疼痛包括神经病性疼痛。
17.权利要求16的用途,其中所述的神经病性疼痛与糖尿病性神经病,外周神经病,疱疹后神经痛,三叉神经痛,腰部或子宫颈神经根病,fibromyalgia,舌咽神经痛,反射性交感神经营养不良,casualgia,丘脑综合征,神经根撕脱,幻肢疼痛,反射交感神经营养不良,胸廓切开术后疼痛,癌症,化学损伤,毒素,营养缺乏,或病毒或细菌感染,或其联合形式有关。
18.权利要求1-10任一项的用途,进一步包括施用药学有效量的至少一种疼痛缓解剂。
19.权利要求18的用途,其中该疼痛缓解剂包括一种或多种镇痛剂;抗炎药;偏头痛制剂;三环抗抑郁药;抗癫痫药;α2激动剂;或选择性5-羟色胺摄取抑制剂/选择性去甲肾上腺素摄取抑制剂;或其联合形式。
20.权利要求19的用途,其中该疼痛缓解剂包括阿片镇痛剂。
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HOW DO DRUGS RELIEVE NEUROGENIC PAIN. KARLSTEN.DRUGS AND AGING,ADIS INTERNATION LTD,Vol.11 No.5. 1997 |
HOW DO DRUGS RELIEVE NEUROGENIC PAIN. KARLSTEN.DRUGS AND AGING,ADIS INTERNATION LTD,Vol.11 No.5. 1997 * |
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