CN103313709B - σ配体在骨癌疼痛中的用途 - Google Patents
σ配体在骨癌疼痛中的用途 Download PDFInfo
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- CN103313709B CN103313709B CN201180065232.XA CN201180065232A CN103313709B CN 103313709 B CN103313709 B CN 103313709B CN 201180065232 A CN201180065232 A CN 201180065232A CN 103313709 B CN103313709 B CN 103313709B
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- Prior art keywords
- pain
- pyrazole
- dichlorophenyl
- compound
- sigma ligands
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/18—One oxygen or sulfur atom
- C07D231/20—One oxygen atom attached in position 3 or 5
- C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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Abstract
本发明涉及σ配体(特别是式(I)的σ配体)在预防和/或治疗与骨癌相关之疼痛中的用途。
Description
技术领域
本发明涉及σ受体配体,更特别地涉及一些吲唑衍生物,以及包含它们的药物组合物,其用于治疗和/或预防与骨癌相关的疼痛。
背景技术
骨癌疼痛是转移性癌症的破坏性表现。遗憾的是,现有疗法可以是无效的,并且当它们有效时,患者存活的持续时间通常超过疼痛缓解的持续时间。迫切需要新的、基于机械(mechanistically based)的疗法。
恶性肿瘤已转移到骨的患者常常面临不良的生活质量。作为转移性疾病后遗症的骨骼并发症在约70%的患有晚期乳腺癌或前列腺癌的患者中表现出其本身。骨骼转移发现于>90%的死于乳腺癌或前列腺癌的患者中。骨癌疼痛是由患有癌症的患者表现出的最常见的症状之一。转移性乳腺癌和前列腺癌是癌症诱导之骨疼痛盛行的主要因素。因此,来自骨癌的疼痛也代表患有晚期癌症的人患者中最常见的疼痛,这是因为最常见的肿瘤(包括乳腺癌、前列腺癌和肺癌)具有显著的向骨转移的倾向。
处于疾病晚期阶段的人癌症患者(特别是有骨转移的那些)报告,他们经受显著的疼痛并且疼痛强度似乎与骨破坏的程度相关。
牵涉骨骼的癌症患者常常遭受骨折、高钙血症、脊髓压迫和严重的疼痛,所有如上所提到的这些都促成发病率升高和生活质量下降。
源自骨骼转移的疼痛通常在疾病演化过程中以数量级增强,并且通常分为两类:持续性疼痛(ongoing pain)和爆发性或诱发性疼痛(breakthrough or incident pain)。
通常为骨癌之第一症状的持续性疼痛以不剧烈的(dull)、持续的搏动性疼痛(throbbing pain)开始,该搏动性疼痛的强度随时间增加并且通过使用相关部分的骨骼而加重。
随着骨破坏的增加和时间的延长,疼痛加剧,然后极端疼痛的间歇发作可在受影响肢体的承重或移动的同时(或者更通常地,在其之后)发生。将该疼痛称为“爆发性或诱发性疼痛”。
在这两种类型的疼痛中,爆发性疼痛更难以控制,这是因为例如,控制该疼痛所需的阿片样物质(opioid)的剂量常常高于控制持续性疼痛所需的剂量,并且因此伴随如在下文中评论的显著不期望的副作用。
机械异常性疼痛是并非通常感知为有害的机械刺激的疼痛感知。至于骨癌疼痛,该急性形式的移动诱发的疼痛可通过适度肢体使用、咳嗽或在床上转身而产生,并且具有减弱的对常规疗法的应答性。
癌症患者中疼痛强度不同并且取决于患者的疼痛敏感度、癌症的类型和肿瘤部位。由世界卫生组织(WHO)提供的癌症治疗指南已在肿瘤和疼痛治疗诊所中使用。人癌症患者的治疗包括单独或组合使用阿片样物质、非甾类抗炎药物(NSAID)、皮质类固醇、局部麻醉剂(local anhestetics)、抗抑郁剂和抗惊厥剂。
对抗炎性药剂、化疗、放疗、手术和/或二膦酸盐/酯(bisphosphonate)无响应的慢性疼痛通常用强止痛药治疗。晚期骨癌疼痛的阿片样物质疗法是常见的并且有效用于疼痛缓解。遗憾的是,减轻骨疼痛所需的阿片样物质剂量(120mg/kg/天)可产生不期望的副作用,例如精神错乱(confusion)、呼吸抑制、嗜睡和便秘。这些副作用可严重地降低总体生活质量。在接受阿片样物质治疗的晚期疾病患者见他们的医师后四周之内,73%的所述患者报告了中度至严重的疼痛,并且40%的有严重疼痛的那些患者要求增加阿片样物质治疗。
控制疼痛所需之阿片样物质的逐步增加的剂量可反映进化的阿片样物质耐受或疼痛严重性的增加。虽然两种机制都可能与该疼痛所需的吗啡之逐步增加的剂量相关,但是通过使用姑息疗法显著地降低阿片样物质需要的能力表明,高阿片样物质剂量至少部分地反映了与骨癌疼痛状态相关的强度。
因为阿片样物质并不直接靶向疼痛的来源,而是通过中枢神经系统全身性地起作用,所以对器官系统的负影响可显著地引起不良生活质量(Clin.Cancer Res.,2006,12(20Supplm.,6231s-6235s;Compar.Med.,2008,58(3),220-233;J.Pain and Symp.Manag.,2005,29(55),S32-S46)。
癌症疼痛的动物模型可分为如下5类:骨癌疼痛模型、非骨癌疼痛模型、癌症侵袭疼痛模型、癌症化疗诱导的外周神经病变模型和自发癌症疼痛模型(spontaneousoccurring cancer pain model)。具体地,其中,已使用大鼠乳腺癌模型(MRMT-1)、鼠纤维肉瘤(2472)、鼠乳腺癌(4T1)、肝细胞癌(HCa-1)和鼠黑色素瘤(B16)研究了骨癌疼痛。
这些模型的使用揭示了与疼痛相关行为有关的许多特征,并且提供了对作为癌症疼痛之基础的神经化学和神经生理学机制的见解。在这些动物模型中观察到的许多特征由遭受肿瘤疼痛的人癌症患者所共有,所述肿瘤疼痛包括骨破坏、初级传入神经元敏化和脊髓内中枢敏化的重组和发展。
如之前所提到的,处理晚期骨癌疼痛中的主要问题是,虽然阿片样物质可能能够控制持续性疼痛,但是这些相同剂量常常不足以阻断移动诱发的爆发性疼痛。
如本领域中示出的数据表明,骨癌疼痛可具有炎性组分和神经性组分二者,并且虽然近来在检查潜在新疗法的实验模型中取得了显著进步,但是还需要用于骨癌疼痛的相比于炎性组分和神经性组分具有更大效力的明显更有效的治疗,这是由于疼痛疗法的目的并不只是缓解疼痛,还有保持患者的生理和心理健康。
发明简述
本发明涉及σ配体作为佐剂在治疗骨癌疼痛中的用途。当σ配体特别地为σ-1受体拮抗剂(优选地为(中性)拮抗剂、反向激动剂或部分拮抗剂时),本发明的该益处更明显。
因此,本发明的一个方面涉及用于预防和/或治疗与骨癌相关的疼痛的σ配体。
在一个优选实施方案中,所述σ配体具有通式(I):
其中
R1选自:氢、经取代的或未经取代的烷基、经取代的或未经取代的环烷基、经取代的或未经取代的烯基、经取代的或未经取代的芳基、经取代的或未经取代的芳基烷基、经取代的或未经取代的非芳族杂环基、经取代的或未经取代的芳族杂环基、经取代的或未经取代的杂环基烷基、-COR8、-C(O)OR8、-C(O)NR8R9、-CH=NR8、-CN、-OR8、-OC(O)R8、-S(O)t-R8、-NR8R9、-NR8C(O)R9、-NO2、-N=CR8R9和卤素;
R2选自:氢、经取代的或未经取代的烷基、经取代的或未经取代的环烷基、经取代的或未经取代的烯基、经取代的或未经取代的芳基、经取代的或未经取代的芳基烷基、经取代的或未经取代的芳族或非芳族杂环基、经取代的或未经取代的杂环基烷基、-COR8、-C(O)OR8、-C(O)NR8R9、-CH=NR8、-CN、-OR8、-OC(O)R8、-S(O)t-R8、-NR8R9、-NR8C(O)R9、-NO2、-N=CR8R9和卤素;
R3和R4独立地选自:氢、经取代的或未经取代的烷基、经取代的或未经取代的环烷基、经取代的或未经取代的烯基、经取代的或未经取代的芳基、经取代的或未经取代的芳基烷基、经取代的或未经取代的芳族或非芳族杂环基、经取代的或未经取代的杂环基烷基、-COR8、-C(O)OR8、-C(O)NR8R9、-CH=NR8、-CN、-OR8、-OC(O)R8、-S(O)t-R8、-NR8R9、-NR8C(O)R9、-NO2、-N=CR8R9和卤素,或者它们一起形成任选地取代的稠合环系统;
R5和R6独立地选自:氢、经取代的或未经取代的烷基、经取代的或未经取代的环烷基、经取代的或未经取代的烯基、经取代的或未经取代的芳基、经取代的或未经取代的芳基烷基、经取代的或未经取代的芳族或非芳族杂环基、经取代的或未经取代的杂环基烷基、-COR8、-C(O)OR8、-C(O)NR8R9、-CH=NR8、-CN、-OR8、-OC(O)R8、-S(O)t-R8、-NR8R9、-NR8C(O)R9、-NO2、-N=CR8R9和卤素,或者与它们所连接的氮原子一起形成经取代的或未经取代的芳族或非芳族杂环基;
n选自:1、2、3、4、5、6、7和8;
t是1、2或3;
R8和R9各自独立地选自:氢、经取代的或未经取代的烷基、经取代的或未经取代的环烷基、经取代的或未经取代的烯基、经取代的或未经取代的芳基、经取代的或未经取代的芳族或非芳族杂环基、经取代的或未经取代的烷氧基、经取代的或未经取代的芳基氧基和卤素;
或其可药用盐、异构体、前药或溶剂合物。
本发明的另一方面涉及如上所定义的σ配体在制备用于预防和/或治疗与骨癌相关之疼痛的药物中的用途。
本发明的另一方面是治疗遭受与骨癌相关之疼痛或者可能遭受由骨癌引起之疼痛的患者的方法,其包括向有这样的治疗或预防之需要的患者施用治疗有效量的如上所定义的σ配体。
本发明的另一方面涉及用于同时、分开或依次施用的至少一种如上所定义的σ配体与至少一种阿片样物质或阿片剂(0piate)化合物的组合,其用于预防和/或治疗与骨癌相关的疼痛。
这些方面及其优选实施方案还另外在权利要求中定义。
附图说明
图1:冯·弗莱测试(Von Frey test):用于第二阶段(阶段2)的吗啡的最佳剂量水平的确定。
图2:冯·弗莱测试:在阶段2中,吗啡(1.25mg/kg)与实施例1(40mg/kg)的协同作用。
图3:冯·弗莱测试:在阶段2中,吗啡(1.25mg/kg)与实施例1(80mg/kg)的协同作用。
发明详述
在本发明的上下文中,下列术语具有下文详述的意义。
“烷基”指由1至12个碳原子组成的直链或支链烃链基团,其不包含不饱和度,并且其通过单键与分子的其余部分相连,例如甲基、乙基、正丙基、异丙基、正丁基、叔丁基、正戊基等。烷基基团可任选地被一个或更多个取代基取代,所述取代基例如芳基、卤素、羟基、烷氧基、羧基、氰基、羰基、酰基、烷氧基羰基、氨基、硝基、巯基、烷基硫基等。优选的烷基基团具有1至6个碳原子。如果被芳基取代,则其对应于“芳基烷基”基团,例如苄基或苯乙基。如果被杂环基取代,则其对应于“杂环基烷基”基团。
“烯基”指由2至12个碳原子组成的直链或支链烃链基团,其包含至少一个不饱和度,并且其通过单键与分子的其余部分相连。烯基基团可任选地被一个或更多个取代基取代,所述取代基例如芳基、卤素、羟基、烷氧基、羧基、氰基、羰基、酰基、烷氧基羰基、氨基、硝基、巯基、烷基硫基等。优选的烯基基团具有2至6个碳原子。
“环烷基”指稳定的3元至10元单环或双环基团,其为饱和的或部分饱和的,并且其只由碳原子和氢原子组成,例如环己基或金刚烷基。除非在说明书中另有特别说明,否则术语“环烷基”意为包括任选地被一个或更多个取代基取代的环烷基基团,所述取代基例如烷基、卤素、羟基、氨基、氰基、硝基、烷氧基、羧基、烷氧基羰基等。
“芳基”指单个和多个芳环基团,其包括含有分开的和/或稠合之芳基的多个环基团。典型的芳基包含1至3个分开的或稠合的环以及6至约18个碳环原子,例如苯基、萘基、茚基、菲基(fenanthryl)或蒽基基团。芳基基团可任选地被一个或更多个取代基取代,所述取代基例如羟基、巯基、卤素、烷基、苯基、烷氧基、卤烷基、硝基、氰基、二烷基氨基、氨基烷基、酰基、烷氧基羰基等。
“杂环基”指稳定的3元至15元环基团,其由碳原子和选自氮、氧和硫的一至五个杂原子组成,优选为具有一个或更多个杂原子的4元至8元环,更优选为具有一个或更多个杂原子的5元或6元环。其可以是芳族的或非芳族的。出于本发明的目的,杂环可以是单环、双环或三环系统,其可包括稠合环系统;并且杂环基中的氮、碳或硫原子可任选地被氧化;氮原子可任选地被季铵化;并且杂环基可以是部分或完全饱和的或芳香性的。这样的杂环的实例包括但不限于氮杂苯并咪唑、苯并噻唑、呋喃、异噻唑、咪唑、吲哚、哌啶、哌嗪、嘌呤、喹啉、噻二唑、四氢呋喃、香豆素、吗啉;吡咯、吡唑、唑、异唑、三唑、咪唑等。
“烷氧基”指式-ORa的基团,其中Ra是如上所定义的烷基基团,例如甲氧基、乙氧基、丙氧基等。
“氨基”指式-NH2、-NHRa或-NRaRb的基团,其任选地被季铵化,例如,甲基氨基、乙基氨基、二甲基氨基、二乙基氨基、丙基氨基等。
“卤素(halogen)”、“卤素(halo)”或“卤素(hal)”是指溴、氯、碘或氟。
在本文中提及本发明化合物中经取代的基团是指在一个或更多个可得位置处可以被一个或更多个合适的基团取代的特定部分,所述合适的基团例如:卤素(例如氟、氯、溴和碘)、氰基、羟基、硝基、叠氮基、烷酰基(alkanoyl)(例如C1-6烷酰基例如酰基等)、羰酰胺基(carboxamido)、烷基(包括具有1至约12个碳原子或1至约6个碳原子并且更优选地1至3个碳原子的那些基团)、烯基和炔基(包括具有一个或更多个不饱和连接以及2至约12个碳原子或2至约6个碳原子的基团);烷氧基(其具有一个或更多个氧连接和1至约12个碳原子或1至约6个碳原子)、芳基氧基(例如苯氧基)、烷基硫基(包括具有一个或更多个硫醚连接和1至约12个碳原子或1至约6个碳原子的那些部分)、烷基亚磺酰基(包括具有一个或更多个亚磺酰基连接和1至约12个碳原子或1至约6个碳原子的那些部分)、烷基磺酰基(包括具有一个或更多个磺酰基连接和1至约12个碳原子或1至约6个碳原子的那些部分)、氨基烷基(例如具有一个或更多个N原子和1至约12个碳原子或1至约6个碳原子的基团)、碳环芳基(其具有6个或更多个碳原子,特别是苯基或萘基和芳烷基例如苄基)。除非另有说明,否则任选地取代的基团在基团的每个可取代位置处可具有取代基,并且,每个取代彼此独立。
术语“盐”必须理解为根据本发明使用的任何形式的活性化合物,其中所述的化合物是离子形式的或者是带电荷的并且与反离子(阳离子或阴离子)结合或者在溶液中。该定义还包括季铵盐以及活性分子与其他分子和离子的复合物,特别是通过离子相互作用形成的复合物。该定义特别地包括生理上可接受的盐;该术语必须理解为等同于“药理学上可接受的盐”或“可药用盐”。
在本发明的上下文中,术语“可药用盐”指在用于适当的方式进行治疗、应用或使用时(特别是在人和/或哺乳动物中)的生理耐受的任何盐(通常指其是无毒性的,特别地,是出于反离子的原因)。在本发明的上下文中,特别是当其用于人类和/或哺乳动物时,可以与阳离子或碱形成这些生理上可接受的盐,并且理解为由至少一种根据本发明使用的化合物形成的盐—通常是酸(去质子化的)—例如阴离子。在本发明的上下文中,特别是当其用于人类和/或哺乳动物时,还可以与阴离子或酸形成这些生理上可接受的盐,并理解为由根据本发明使用的至少一种化合物形成的盐—通常是质子化的,例如在氮上—例如阳离子和至少一种生理上耐受的阴离子。在本发明的上下文中,特别是当其用于人类和/或哺乳动物时,该定义特定地包括由生理上耐受的酸形成的盐,即特定的活性化合物与生理上耐受的有机或无机酸所形成的盐。这种类型的盐的实例是与以下所形成的那些盐:盐酸、氢溴酸、硫酸、甲磺酸、甲酸、乙酸、草酸、琥珀酸、苹果酸、酒石酸、扁桃酸、富马酸、乳酸或枸橼酸。
根据本发明的术语“溶剂合物”应被理解为指根据本发明的任何形式的活性化合物,其中所述化合物通过非共价键与另一分子(通常是极性溶剂)结合,所述分子尤其包括水合物和醇化物(alcoholate)(例如,甲醇化物)。优选的溶剂合物是水合物。
为σ配体之前药(特别是式(I)化合物的前药)的任何化合物也在本发明的范围内。术语“前药”使用其最宽泛的含义,其涵盖在体内转化为本发明化合物的那些衍生物。前药的实例包括但不限于,式(I)化合物的衍生物和代谢产物,其包括可生物水解的部分,例如可生物水解的酰胺、可生物水解的酯、可生物水解的氨基甲酸酯、可生物水解的碳酸酯、可生物水解的酰脲和可生物水解的磷酸酯类似物。优选地,具有羧基官能团之化合物的前药是羧酸的低级烷基酯。通过将任何存在于分子上的所述羧酸部分酯化来方便地形成所述羧酸酯。前药通常可以使用公知的方法制备,例如由Burger“Medicinal Chemistry and DrugDiscovery第六版”(Donald J.Abraham编著,2001,Wiley)、“Design and Applications ofProdrugs”(H.Bundgaard编著,1985,Harwood Academic Publishers)和Krogsgaard-Larsen等“Textbook of Drug design and Discovery”Taylor&Francis(April 2002)所述的那些方法。
由上述式(I)表示的本发明化合物可以包括依赖手性中心之存在的对映异构体或依赖多键之存在的异构体(例如,Z、E)。单一异构体、对映体或非对映异构体及其混合物属于本发明的范围。
此外,本文所提及的任何化合物都可以作为互变体存在。特别地,术语互变体是指以平衡存在的化合物的两种或更多种结构异构体之一,并且其易于从一种异构形式转化为另一种。常见的互变体对是胺-亚胺、酰胺-亚胺酸(imidic acid)、酮-烯醇、内酰胺(lactam)-内酰亚胺(lactim)等。
除非另有说明,否则本发明化合物还旨在包括同位素标记的形式,即化合物的区别仅存在于一个或更多个富含同位素的原子上。例如,除了至少一个氢原子被氘或氚替换或者至少一个碳被富含13C或14C的碳替换或者至少一个氮被富含15N的氮替换以外,具有当前结构的化合物也在本发明的范围内。
σ配体(特别地是式(I)化合物)或其盐或溶剂合物优选地为可药用形式或基本上纯的形式。可药用形式尤其指除了一般的药物添加剂(例如稀释剂和载体)外具有可药用水平的纯度,并且不包括在一般剂量水平时被认为有毒的物质。药物的纯度水平优选大于50%,更优选大于70%,最优选大于90%。在一个优选实施方案中,式(I)化合物或其盐、溶剂合物或前药的纯度水平大于95%。
如前面提到的,术语“可药用盐、溶剂合物、前药”是指向接受者施用时能够提供(直接或间接)如本文所述的化合物的任何盐、溶剂合物或任何其他化合物。但是,应理解,非可药用盐、溶剂合物和前药也属于本发明的范围,因为它们可以用于制备可药用盐、溶剂合物和前药。可以通过本领域已知方法进行所述盐、溶剂合物和前药的制备。
如本文中所使用的,术语“治疗(treat)”、“治疗(treating)”和“治疗(treatment)”包括与骨癌相关之疼痛的根除、去除、逆转、缓解、改善或控制。
如本文所使用的,术语“σ配体”或“σ受体配体”指与σ受体结合的任何化合物。如之前所陈述的,σ配体优选(中性)拮抗剂、反向激动剂或部分拮抗剂形式的σ受体拮抗剂。
“激动剂”定义为与受体结合并且具有内在作用的化合物,因此在其与受体接触时提高受体的基础活性。“拮抗剂”定义为与激动剂或反向激动剂竞争与受体结合从而阻断激动剂或反向激动剂对受体之作用的化合物。但是,拮抗剂(也称为“中性”拮抗剂)对组成的(constitutive)受体活性没有作用。拮抗剂通过与受体上的活性部位或变构部位(allosteric site)结合来介导其作用,或者它们可在通常不参与受体活性之生物调节的特殊结合部位处相互作用。根据拮抗剂-受体复合物的寿命,拮抗剂活性可以是可逆的或不可逆的,这进而取决于拮抗剂受体结合的性质。
“部分拮抗剂”定义为与受体相结合并且产生拮抗剂应答的化合物;但是部分拮抗剂不产生完全拮抗剂应答。部分拮抗剂是弱拮抗剂,因此部分阻断激动剂或反向激动剂对受体的作用。
“反向激动剂”定义为通过占有相同受体产生与激动剂作用相反之作用并且因此降低受体的基础活性(即,由受体介导的信号传导)的化合物。这样的化合物也称为负性拮抗剂(negative antagonist)。反向激动剂是引起受体采用相对于基础状态(在不存在任何配体时发生)之失活状态的受体的配体。因此,拮抗剂可抑制激动剂的活性,而反向激动剂是可以在不存在激动剂时改变受体之构象的配体。
如本申请中所使用的“σ受体”是公知的并且使用如下引用来定义:“该结合部位代表与阿片样物质、NMDA、多巴胺能和其他已知的神经递质或激素受体家族不同的典型蛋白质”(G.Ronsisvalle等Pure Appl.Chem.73,1499-1509(2001))。基于配体结合研究、解剖分布和生化特征的药理数据区分出σ受体的至少两种亚型(R.Quiron等,TrendsPharmacol.Sci.13,85-86(1992);M.L.Leitner,Eur.J.Pharmacol.259,65-69(1994);S.B.Hellewell和W.D.Bowen;Brain Res.527,244-253(1990))(G.Ronsisvalle等,PureAppl.Chem.73,1499-1509(2001))。σ受体的蛋白质序列(σ1和σ2)在本领域中是公知的(例如,Prasad,P.D.等,J.Neurochem.70(2),443-451(1998))。它们显示出对多种镇痛药(例如,喷他佐辛)的非常高的亲和力。
如本申请中使用的“与σ受体结合的化合物”或“σ配体”定义为对σ受体的IC50值≤5000nM、更优选地≤1000nM、更优选地≤500nM的化合物。更优选地,IC50值≤250nM。更优选地,IC50值≤100nM。最优选地,IC50值≤50nM。半数最大抑制浓度(IC50)是化合物在抑制生物功能或生物化学功能中的有效性的测量。IC50是取代50%的放射性配体之特异性结合的竞争配体的浓度。此外,如本申请中使用的措辞“与σ受体结合的化合物”定义为使用10nM对σ受体具有特异性的放射性配体(例如,优选为[3H]-(+)喷他佐辛)具有至少≥50%的取代,因而σ受体可以是任何类型的σ受体亚型。优选地,所述化合物与σ-1受体亚型相结合。
与σ受体结合的化合物(一般还称为σ配体)在本领域中是公知的。它们中的许多由如上所定义的“与σ受体结合的化合物”涵盖。虽然σ配体有许多已知用途(例如抗精神病药、抗焦虑药、抗抑郁药、中风治疗、抗癫痫药和许多其他适应症(包括抗偏头痛和一般疼痛)),但是在本领域中未提到这些化合物可用于治疗与骨癌相关的疼痛。
表1列举了在本领域中已知的一些σ配体(即,IC50≤5000nM)。这些化合物中的一些可以与σ-1和/或σ-2受体结合。这些σ配体还包括它们各自的盐、碱和酸。
表1
优选地,上表还包括还原的氟哌啶醇(haloperidol)。还原的氟哌啶醇是在人产生的氟哌啶醇的活性代谢产物,其对σ-1受体示出高亲和力(在低纳摩尔范围内)并且在实验动物和人细胞二者中产生σ-1受体的不可逆的阻断。
产生给定活性化合物之前药的公知方法的实例是本领域技术人员已知的(例如,在Krogsgaard-Larsen等,Textbook of Drug design and Discovery,Taylor&Francis(April 2002)中)。
在一个优选实施方案中,本发明上下文中的σ配体具有如上所示的通式(I)。
在一个优选实施方案中,式(I)化合物中的R1选自H、-COR8、以及经取代的或未经取代的烷基。更优选地,R1选自H、甲基和乙酰基。一个更优选的实施方案是R1为H。
在另一优选实施方案中,式(I)化合物中的R2代表H或烷基,更优选为甲基。
在本发明的另一优选实施方案中,式(I)化合物中的R3和R4位于苯基的间位和对位,并且优选地,它们独立地选自卤素和经取代的或未经取代的烷基。
在本发明的一个尤其优选的实施方案中,在式(I)化合物中,R3和R4二者与苯基一起形成任选地取代的稠合环系统(例如,可以稠合经取代的或未经取代的芳基或者经取代的或未经取代的芳族或非芳族杂环基),更优选为萘环系统。
同样在式(I)的化合物中,在本发明的上下文中优选其中n选自2、3、4的实施方案,更优选n为2。
最后,在另一实施方案中,式(I)化合物中优选R5和R6各自独立地为C1-6烷基,或者与它们所连接的氮原子一起形成经取代的或未经取代的杂环基,特别地选自吗啉基、哌啶基和吡咯烷基。更优选地,R5和R6一起形成吗啉-4-基。
在本发明的一些优选变体中,式(I)的σ配体选自以下或其可药用盐、异构体、前药或溶剂合物:
[1]4-{2-(1-(3,4-二氯苯基)-5-甲基-1H吡唑-3-基氧基)乙基}吗啉
[2]2-[1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基]-N,N-二乙基乙胺
[3]1-(3,4-二氯苯基)-5-甲基-3-[2-(吡咯烷-1-基)乙氧基]-1H-吡唑
[4]1-(3,4-二氯苯基)-5-甲基-3-[3-(吡咯烷-1-基)丙氧基]-1H-吡唑
[5]1-{2-[1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基]乙基}哌啶
[6]1-{2-[1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基]乙基}-1H-咪唑
[7]3-{1-[2-(1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基)乙基]哌啶-4-基}-3H咪唑并[4,5-b]吡啶
[8]1-{2-[1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基]乙基}-4-甲基哌嗪
[9]4-{2-[1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基]乙基}哌嗪羧酸乙酯
[10]1-(4-(2-(1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基)乙基)哌嗪-1-基)乙酮
[11]4-{2-[1-(4-甲氧基苯基)-5-甲基-1H-吡唑-3-基氧基]乙基}吗啉
[12]1-(4-甲氧基苯基)-5-甲基-3-[2-(吡咯烷-1-基)乙氧基]-1H-吡唑
[13]1-(4-甲氧基苯基)-5-甲基-3-[3-(吡咯烷-1-基)丙氧基]-1H-吡唑
[14]1-[2-(1-(4-甲氧基苯基)-5-甲基-1H-吡唑-3-基氧基)乙基]哌啶
[15]1-{2-[1-(4-甲氧基苯基)-5-甲基-1H-吡唑-3-基氧基]乙基}-1H-咪唑
[16]4-{2-[1-(3,4-二氯苯基)-5-苯基-1H-吡唑-3-基氧基]乙基}吗啉
[17]1-(3,4-二氯苯基)-5-苯基-3-[2-(吡咯烷-1-基)乙氧基]-1H-吡唑
[18]1-(3,4-二氯苯基)-5-苯基-3-[3-(吡咯烷-1-基)丙氧基]-1H-吡唑
[19]1-{2-[1-(3,4-二氯苯基)-5-苯基-1H-吡唑-3-基氧基]乙基}哌啶
[20]1-{2-[1-(3,4-二氯苯基)-5-苯基-1H-吡唑-3-基氧基]乙基}-1H-咪唑
[21]2-{2-[1-(3,4-二氯苯基)-5-苯基-1H-吡唑-3-基氧基]乙基}-1,2,3,4-四氢异喹啉
[22]4-{4-[1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基]丁基}吗啉
[23]1-(3,4-二氯苯基)-5-甲基-3-[4-(吡咯烷-1-基)丁氧基]-1H-吡唑
[24]1-{4-[1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基]丁基}哌啶
[25]1-{4-[1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基]丁基}-4-甲基哌嗪
[26]1-{4-[1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基]丁基}-1H-咪唑
[27]4-[1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基]-N,N-二乙基丁-1-胺
[28]1-{4-[1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基]丁基}-4-苯基哌啶
[29]1-{4-[1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基]丁基}-6,7-二氢-1H吲哚-4(5H)-酮
[30]2-{4-[1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基]丁基}-1,2,3,4-四氢异喹啉
[31]4-{2-[1-(3,4-二氯苯基)-5-异丙基-1H-吡唑-3-基氧基]乙基}吗啉
[32]2-[1-(3,4-二氯苯基)-5-异丙基-1H-吡唑-3-基氧基]-N,N-二乙基乙胺
[33]1-(3,4-二氯苯基)-5-异丙基-3-[2-(吡咯烷-1-基)乙氧基]-1H-吡唑
[34]1-(3,4-二氯苯基)-5-异丙基-3-[3-(吡咯烷-1-基)丙氧基]-1H-吡唑
[35]1-{2-[1-(3,4-二氯苯基)-5-异丙基-1H-吡唑-3-基氧基]乙基}哌啶
[36]2-{2-[1-(3,4-二氯苯基)-5-异丙基-1H-吡唑-3-基氧基]乙基}-1,2,3,4-四氢异喹啉
[37]4-{2-[1-(3,4-二氯苯基)-1H-吡唑-3-基氧基]乙基}吗啉
[38]2-[1-(3,4-二氯苯基)-1H-吡唑-3-基氧基]N,N-二乙基乙胺
[39]1-(3,4-二氯苯基)-3-[2-(吡咯烷-1-基)乙氧基]-1H-吡唑
[40]1-{2-[1-(3,4-二氯苯基)-1H-吡唑-3-基氧基]乙基}哌啶
[41]1-(3,4-二氯苯基)-3-[3-(吡咯烷-1-基)丙氧基]-1H-吡唑
[42]1-{2-[1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基]乙基}哌嗪
[43]1-{2-[1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基]乙基}吡咯烷-3-胺
[44]4-{2-[1-(3,4-二氯苯基)-4,5-二甲基-1H-吡唑-3-基氧基]乙基}吗啉
[46]2-[1-(3,4-二氯苯基)-4,5-二甲基-1H-吡唑-3-基氧基]-N,N-二乙基乙胺
[47]1-(3,4-二氯苯基)-4,5-二甲基-3-[2-(吡咯烷-1-基)乙氧基]-1H-吡唑
[48]1-(3,4-二氯苯基)-4,5-二甲基-3-[3-(吡咯烷-1-基)丙氧基]-1H-吡唑
[49]1-{2-[1-(3,4-二氯苯基)-4,5-二甲基-1H-吡唑-3-基氧基]乙基}哌啶
[50]4-{4-[1-(3,4-二氯苯基)-1H-吡唑-3-基氧基]丁基}吗啉
[51](2S,6R)-4-{4-[1-(3,4-二氯苯基)-1H-吡唑-3-基氧基]丁基}-2,6-二甲基吗啉
[52]1-{4-[1-(3,4-二氯苯基)-1H-吡唑-3-基氧基]丁基}哌啶
[53]1-(3,4-二氯苯基)-3-[4-(吡咯烷-1-基)丁氧基]-1H-吡唑
[55]4-[1-(3,4-二氯苯基)-1H-吡唑-3-基氧基]-N,N-二乙基丁-1-胺
[56]N-苄基-4-[1-(3,4-二氯苯基)-1H-吡唑-3-基氧基]-N-甲基丁-1-胺
[57]4-[1-(3,4-二氯苯基)-1H-吡唑-3-基氧基]-N-(2-甲氧基乙基)-N-甲基丁-1-胺
[58]4-{4-[1-(3,4-二氯苯基)-1H-吡唑-3-基氧基]丁基}硫代吗啉
[59]1-[1-(3,4-二氯苯基)-5-甲基-3-(2-吗啉基乙氧基)-1H-吡唑-4-基]乙酮
[60]1-{1-(3,4-二氯苯基)-5-甲基-3-[2-(吡咯烷-1-基)乙氧基]-1H-吡唑-4-基}乙酮
[61]1-{1-(3,4-二氯苯基)-5-甲基-3-[2-(哌啶-1-基)乙氧基]-1H-吡唑-4-基}乙酮
[62]1-{1-(3,4-二氯苯基)-3-[2-(二乙基氨基)乙氧基]-5-甲基-1H-吡唑-4-基}乙酮
[63]4-{2-[5-甲基-1-(萘-2-基)-1H-吡唑-3-基氧基]乙基}吗啉
[64]N,N-二乙基-2-[5-甲基-1-(萘-2-基)-1H-吡唑-3-基氧基]乙胺
[65]1-{2-[5-甲基-1-(萘-2-基)-1H-吡唑-3-基氧基]乙基}哌啶
[66]5-甲基-1-(萘-2-基)-3-[2-(吡咯烷-1-基)乙氧基]-1H-吡唑。
在本发明的一个优选实施方案中,式(I)的σ配体是4-{2-[5-甲基-1-(萘-2-基)-1H-吡唑-3-基氧基]乙基}吗啉。该特定化合物在本发明的实施例中命名为化合物n°63。
在一个更优选的实施方案中,式(I)的σ配体是4-{2-[5-甲基-1-(萘-2-基)-1H-吡唑-3-基氧基]乙基}吗啉盐酸盐。该特定化合物在本发明的实施例中命名为实施例n°1。
可以按照之前的申请WO2006/021462中所公开的来制备式(I)化合物及其盐或溶剂合物。
如前面所述,本发明的一个方面涉及如上所定义的σ配体在制备用于预防和/或治疗与骨癌相关的疼痛(即,骨癌疼痛)的药物中的用途。优选地,疼痛选自由骨癌引发的急性和/或慢性疼痛,优选为神经性疼痛、神经痛(neuralgia)、异常性疼痛(allodynia)、灼痛(causalgia)、痛觉过敏(hyperalgesia)、感觉过敏(hyperesthesia)、痛觉过度(hyperpathia)、手术过程继发的神经炎或神经病。
还发现当σ配体与阿片样物质或阿片剂化合物组合时,有显著的协同作用:施用伴随实施例1处理的阈下剂量的吗啡,在施用后30分钟导致镇痛作用增强并且该作用持续至少24小时(阳性对照(5mg/kg吗啡)在施用后24小时未示出作用)。因此,本发明还涉及用于同时、分开或依次施用的至少一种如上所定义之σ配体与至少一种阿片样物质或阿片剂化合物的组合,其用于预防和/或治疗与骨癌相关的疼痛。在本发明的范围内与阿片样物质受体结合的化合物包括天然阿片剂,例如吗啡、可待因和蒂巴因;衍生自天然阿片样物质的半合成阿片剂,例如氢吗啡酮、氢可酮、羟考酮、羟吗啡酮、地索吗啡(desomorphine)、二乙酰吗啡、尼可吗啡(nicomorphine)、二丙酰基吗啡、苄基吗啡和乙基吗啡;完全合成的阿片样物质,例如芬太尼、哌替啶、美沙酮、曲马多和丙氧芬;以及体内自然地产生的内源性阿片肽(opioid peptide),例如内啡肽、脑啡肽、强啡肽和内吗啡肽及其类似物。优选地,根据本发明的组合包含吗啡或其类似物。
本发明的组合可以至少与可药用载体、添加剂、佐剂或载剂一起制剂用于其同时、分开或依次施用。这意味着两种活性化合物的组合可以如下施用:
a)作为相同药物制剂的部分的组合,那么该两种活性化合物总是同时施用。
b)作为两个单元的组合,每个单元具有一种活性化合物,导致可以同时、依次或分开施用。在一个特定实施方案中,σ配体独立于阿片样物质或阿片剂(即以两个单元)施用,但是同时施用。在另一个特定实施方案中,首先施用σ配体,然后分开或依次施用阿片样物质或阿片剂。在另一个特定实施方案中,如所定义的,首先施用阿片样物质或阿片剂,然后分开或依次施用σ配体。
根据本发明的药物组合物(即,包含至少一种σ配体的组合物或包含至少一种σ配体和至少一种阿片样物质或阿片剂化合物的组合物)的辅料或添加剂可选自:载体、赋形剂、支持材料、润滑剂、填充剂、溶剂、稀释剂、着色剂、调味剂(例如糖)、抗氧化剂、粘结剂、粘合剂、崩解剂、防粘剂、助流剂和/或凝集剂(agglutinant)。在栓剂的情况下,这可能意味着用于胃肠外施用的蜡类或脂肪酸酯或防腐剂、乳化剂和/或载体。这些辅料和/或添加剂的选择和待使用的量将取决于药物组合物的施用形式。
根据本发明的药物组合物可适于任何施用形式,其为经口或肠胃外,例如肺部、经鼻、经直肠和/或静脉内。因此,根据本发明的制剂可以适合于局部或全身应用,特别是真皮、经皮、皮下、肌内、关节内、腹膜内、静脉内、动脉内、膀胱内、骨内、海绵体内、肺部、口腔、舌下、眼部、玻璃体内、鼻内、透皮、直肠、阴道、经口、硬膜外、鞘内、心室内、大脑内、脑室内、脑池内、椎管内、髓周、颅内、通过具有或不具有泵设备的针或导管递送或其他应用途径。
用于经口应用的合适的制剂是片剂、丸剂、囊片、胶囊帽(gel cap)、口香糖、胶囊剂、颗粒剂、滴剂或糖浆剂。
用于肠胃外应用的合适的制剂是溶液剂、混悬剂、可复水的干燥制剂、气雾剂或喷雾剂。
本发明的组合物可以配制成用于透皮施用的以溶解形式或贴片的沉积物。
皮肤应用包括软膏剂、凝胶剂、乳膏剂、洗剂、混悬剂或乳剂。
直肠应用的合适形式是通过栓剂。
此外,组合物可以以适合于每天施用一次、每周施用一次或每月施用一次的形式呈现。
因此,本发明的另一方面提供了治疗遭受与骨癌相关之疼痛或者可能遭受由骨癌引起之疼痛的患者(特别是人)的方法,其包括向有这样的治疗或预防之需要的患者施用治疗有效量的如上所定义的σ配体。
在本发明的一个实施方案中,优选σ配体以治疗有效量使用。医师将确定本治疗剂的最合适的剂量,并且它会随施用形式和所选择的特定化合物而不同,此外,它将随所治疗患者、患者的年龄、所治疗的病症的类型而不同。医师一般将希望以基本上低于化合物的最佳剂量的小剂量开始治疗,并将剂量以小增量增加直至在该情况下达到最佳作用。当所述组合物经口施用时,将需要更大量的活性剂来与胃肠外施用的较小量产生相同的作用。所述化合物可以以与可对照的治疗剂相同的方式进行使用,剂量水平具有与这些其他治疗剂通常采用的数量级相同的数量级。
例如,必须施加于患者的剂量方案将取决于患者的体重、应用类型、疾病的病症和严重性。优选的剂量方案包括在0.01mg/kg至300mg/kg、更优选0.01mg/kg至100mg/kg并且最优选0.01mg/kg至50mg/kg的范围内施用根据本发明的化合物。
下面的实施例仅仅举例说明本发明的某些实施方案,不能被认为以任何方式限制本发明。
实施例
实施例1.4-{2-[5-甲基-1-(萘-2-基)-1H-吡唑-3-基氧基]乙基}吗啉(化合物63)及其盐酸盐的合成
化合物63可以按照之前的申请WO2006/021462中所公开的来制备。其盐酸盐可以根据下述过程获得:
将化合物63(6.39g)溶解于用HCl饱和的乙醇中,然后将混合物搅拌数分钟,并蒸发至干燥。从异丙醇中结晶残余物。第一次结晶的母液通过浓缩来提供第二次结晶。两次结晶一起产生5.24g(63%)的相应盐酸盐(m.p.=197-199℃)。
1H-NMR(DMSO-d6)δppm:10,85(bs,1H),7,95(m,4H),7,7(dd,J=2,2,8,8Hz,1H),7,55(m,2H),5,9(s,1H),4,55(m,2H),3,95(m,2H),3,75(m,2H),3,55-3,4(m,4H),3,2(m,2H),2,35(s,3H).
HPLC纯度:99.8%。
药理数据
在该测定中,使用由癌症诱导的骨疼痛的同源大鼠模型来评价实施例1在治疗肿瘤诱导的骨疼痛中的用途。将大鼠乳腺癌细胞系MRMT-1注入胫骨近端的骨髓隙(marrowspace),并在第18天用载剂、参照化合物(吗啡)或实施例1处理动物。
使用冯·弗莱测试来测量对于阶段1的基线、第18天给药之前和第18天给药之后以及对于阶段2的基线、第18天给药之前、第18天给药之后和第19天给药之后(24小时)的触诱发痛(tactile allodynia),从而确定实施例1的效力。
该研究以两部分进行:第一阶段确定第二阶段的最佳剂量水平。第二阶段探索用吗啡和实施例1进行处理的潜在协同作用。
在第一阶段的研究中,在第18天施用多种剂量的吗啡(图1),并且只有2.5mg/kg和5mg/kg的剂量能够缓解异常性疼痛(其具有统计显著性)。基于这些结果,为阶段2的研究选择1.25mg/kg的阈下剂量以查看具有实施例1处理的潜在协同作用。在阶段2研究中,选择5mg/kg的吗啡作为阳性对照。
在第二阶段的研究中,单独的实施例1能够在以80mg/kg(类似于5mg/kg的吗啡)施用后30分钟示出异常性疼痛的统计显著性缓解,但在40mg/kg并非如此。施用阈下剂量的吗啡(1.25mg/kg)与实施例1处理(80mg/kg和40mg/kg),在施用后30分钟导致镇痛作用增强并且该作用持续了至少24小时。相反,5mg/kg的吗啡在施用后24小时未示出显著作用。
总之,实施例1与吗啡组合在骨癌疼痛模型中产生了持续至少24小时的协同镇痛作用。
Claims (5)
1.σ配体作为唯一镇痛药在制备用于预防和/或治疗骨癌疼痛的药物中的用途,其中所述σ配体是4-{2-[5-甲基-1-(萘-2-基)-1H-吡唑-3-基氧基]乙基}吗啉或其可药用盐。
2.根据权利要求1所述的σ配体的用途,其中所述疼痛选自由骨癌引发的急性和/或慢性疼痛。
3.根据权利要求2所述的σ配体的用途,其中所述疼痛选自:神经性疼痛、手术过程继发的神经炎或神经病。
4.根据权利要求2所述的σ配体的用途,其中所述疼痛选自:异常性疼痛、灼痛、痛觉过敏、感觉过敏和痛觉过度。
5.根据权利要求1所述的σ配体的用途,其中所述σ配体是4-{2-[5-甲基-1-(萘-2-基)-1H-吡唑-3-基氧基]乙基}吗啉盐酸盐。
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ATE517872T1 (de) * | 2003-06-26 | 2011-08-15 | Novartis Ag | Fünfgliedrige p38-kinaseinhibitoren auf heterocyclusbasis |
MX2007002341A (es) * | 2004-08-27 | 2007-09-25 | Esteve Labor Dr | Inhibidores del receptor sigma. |
EP1781618B1 (en) * | 2004-08-27 | 2012-10-03 | Laboratorios Del Dr. Esteve, S.A. | Sigma receptor inhibitors |
CA2641144A1 (en) * | 2006-03-01 | 2007-09-07 | Rosa Cuberes-Altisent | Pyrazole derivatives as sigma receptor inhibitors |
EP2113501A1 (en) * | 2008-04-25 | 2009-11-04 | Laboratorios Del. Dr. Esteve, S.A. | 5-Methyl-1-(naphthalen-2-YL)-1H-Pyrazoles useful as sigma receptor inhibitors |
EP2116539A1 (en) * | 2008-04-25 | 2009-11-11 | Laboratorios Del. Dr. Esteve, S.A. | 1-aryl-3-aminoalkoxy-pyrazoles as sigma ligands enhancing analgesic effects of opioids and attenuating the dependency thereof |
EP2353591A1 (en) * | 2010-02-04 | 2011-08-10 | Laboratorios Del. Dr. Esteve, S.A. | Sigma ligands for potentiating the analgesic effect of opioids and opiates in post-operative pain and attenuating the dependency thereof |
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