CN106924264A - 用于预防和/或治疗术后疼痛的σ配体 - Google Patents
用于预防和/或治疗术后疼痛的σ配体 Download PDFInfo
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- CN106924264A CN106924264A CN201710099661.8A CN201710099661A CN106924264A CN 106924264 A CN106924264 A CN 106924264A CN 201710099661 A CN201710099661 A CN 201710099661A CN 106924264 A CN106924264 A CN 106924264A
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- substitution
- unsubstituted
- pain
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- alkyl
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- 125000005936 piperidyl group Chemical group 0.000 description 1
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- 125000003367 polycyclic group Chemical group 0.000 description 1
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- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
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- 230000000750 progressive effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000005588 protonation Effects 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
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- 230000002441 reversible effect Effects 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 230000020341 sensory perception of pain Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
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- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
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- 125000001424 substituent group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 229960005137 succinic acid Drugs 0.000 description 1
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
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- 238000003786 synthesis reaction Methods 0.000 description 1
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- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000004867 thiadiazoles Chemical class 0.000 description 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明涉及σ配体的用途,特别是式(I)、(II)或(III)的σ配体,用于预防和/或治疗手术产生的急性和慢性疼痛,尤其是手术组织损伤的继发的表面和/或深部疼痛,及手术过程的继发的周围神经痛、神经痛、异常性疼痛、灼痛、痛觉过敏、感觉过敏、痛觉过度、神经炎或神经病变。
Description
技术领域
本发明涉及σ受体配体在预防和/或治疗外科手术产生的疼痛中的用途。
背景技术
疼痛症状的治疗在医学上有着重要的意义。目前在世界范围内需要另外的疼痛疗法。对疼痛症状的特异疗法的迫切需要在镇痛剂应用领域最近出现的大量科研作品中有所记载。
国际疼痛研究协会(IASP)将疼痛定义为“与实际或潜在的组织损伤有关或描述这种损伤的使人不舒服的感觉和情绪体验”(IASP,Classification of chronic pain,2ndEdition,IASP Press(2002),210)。虽然疼痛是受生理和心理因素影响的复杂的过程而且始终具有主观性,但是其起因或综合症状是可以分类的。疼痛能够基于时间、病原学或生理学标准分类。当疼痛按时间分类时,其可以是急性或慢性的。疼痛按病原学分类,其可以是恶性或非恶性的。第三种分类是生理学的,其包括伤害性疼痛(源于通过与A-三角形和C-纤维连接的组织中特定传感器的检测),其能够分为躯体型疼痛和内脏型疼痛,以及神经性疼痛(源于对神经***的刺激或损伤),其能够分为外周和中枢神经性疼痛。疼痛是躯体感觉***对伤害性刺激的正常生理反应,其使个体对实际或潜在的组织损伤警觉,它具有通知我们伤害或疾病的保护性功能,并且通常在治疗完成或病症治愈时缓解症状。然而,疼痛可能源于病理学状态,其特征在于以下一种或多种情况:不存在伤害性刺激的疼痛(自发性疼痛)、对简单刺激延长的持续性反应(持续性疼痛或痛觉过度)、降低的疼痛阈值(异常性疼痛)、对阈上刺激增强的反应性(痛觉过敏)、对未受伤组织的蔓延性疼痛和痛觉过敏(涉及疼痛和继发性痛觉过敏)以及异常感觉(例如,感觉迟钝、感觉异常)。
每年有超过2000万病人接受外科手术。术后疼痛(可互换地称为,切口后疼痛),或手术或外伤后发生的疼痛是一种严重的且通常棘手的医疗问题。疼痛通常集中在手术部位的附近。外科术后疼痛具有两个重要的临床方面,即静息痛,或患者无运动时发生的疼痛,与由于运动(咳嗽/打喷嚏、起床、物理疗法等)加重的机械疼痛。对于重大手术术后疼痛管理的主要问题是,目前使用的药物具有多种显著的副作用:延迟恢复、延长住院治疗及使某些易受伤害的患者群体遭遇严重并发症的风险。
用于治疗外科术后疼痛的药物的三个主要类型为类***镇痛剂、局部麻醉剂和非甾体抗炎药(NSAID)。通常,其中两类药物,类***镇痛剂和非甾体抗炎药在手术中全身性施用,而局部麻醉剂(例如通道阻滞剂)在手术中非全身性施用。
全身性施用药物以减轻术后疼痛往往是不恰当的。例如,外科术后全身施用类***可能会导致恶心、肠功能抑制、尿滞留、肺功能抑制、心血管影响及镇静作用。
“外科手术后疼痛”(可互换地称为“外科手术后疼痛”、“切口后疼痛”或“外伤后疼痛”)是指由外部创伤或损伤产生或引起的疼痛(包括所有手术过程中出现的疼痛,无论侵入性或非侵入性的),所述创伤或损伤如个体组织的破口、刺伤、切口、撕裂或伤口。如本文中所使用的,“外科手术后疼痛”不包括没有外部物理创伤时产生的疼痛。在一些实施方案中,外科术后疼痛是内部或外部的疼痛,且伤口、切割口、创伤、裂口或切口可能偶然地(如创伤伤口)或必然地(如手术切口)发生。影响伤口区的感染和/或物理或化学损伤可以加重或延长术后疼痛。如本文中所使用的,“疼痛”包括伤害感受和痛感,且可使用疼痛评分及其它方法,例如本领域众所周知的方案,客观并主观地评估疼痛。如本文中所使用的,外科手术后疼痛包括静息痛(也称为自发性、持续性或进行性疼痛)与诱发痛(通过刺激诱发的疼痛)。诱发痛可分为异常性疼痛(即,由通常不会引起疼痛的刺激产生的疼痛)和痛觉过敏(即,对通常产生疼痛的刺激增强的反应)。本质上刺激可以是热的或机械的(触觉的)。机械和/或热异常性疼痛和/或痛觉过敏可发生在主要伤口区(即,原发性异常性疼痛或痛觉过敏)或扩大到激活的相邻及周边区域(即,继发性异常性疼痛或痛觉过敏)。因此,疼痛的特点是热过敏性、机械过敏性和/或静息痛(例如在没有外部刺激情况下的疼痛)。痛觉过度,特点是对刺激的异常疼痛反应,所述刺激尤其是重复性刺激及增加的阈值。痛觉过度可与异常性疼痛、感觉过敏、痛觉过敏或感觉迟钝一起发生,且可能存在刺激的错误识别及定位、延迟、放射感以及后感觉,且疼痛通常是爆发性的。疼痛可以是原发性的(例如,由引起疼痛的事件直接导致的)或继发性的(例如,与引起疼痛的事件相关但不由其直接产生的疼痛)。此外,疼痛可以急性或慢性的。急性疼痛由外部创伤(切割口、刺伤、切口、裂口或伤口)引起,包括所有外科手术过程中产生的疼痛,其可以是轻微的并持续几秒、几分钟或几小时,或其可以是严重的并持续几周或几个月。在大多数情况下,急性疼痛的持续时间不超过三个月,且当疼痛的根本原因(例如伤口)已治愈或已痊愈时急性疼痛消失。然而,未缓解的急性疼痛可能导致慢性疼痛。慢性疼痛(也称为持续性疼痛)通常持续时间超过3个月,超出组织损伤的愈合周期。慢性疼痛通常起源于最初的创伤/损伤,尽管伤势已经痊愈且没有新的组织损伤发生,但其仍然存在。在神经***中疼痛信号维持活性几周、几个月或几年。身体影响包括肌肉紧张、活动受限、睡眠障碍及食欲改变。情绪影响包括抑郁、愤怒、焦虑及害怕再受伤。这种情绪影响,可能阻碍人恢复正常工作或休闲活动的能力。外科手术后疼痛还可分为“浅表的”和“深部的”,且深部疼痛分为“深躯体的”和“内脏的”。浅表疼痛来自受损的皮肤或表面组织,且其是明显的、明确的及明显定位的。深躯体疼痛来自受伤的韧带、肌腱、骨骼、血管、筋膜和肌肉,其为迟钝的、疼痛的、不易确定位置的。内脏疼痛源自受伤的内脏(器官)且通常比躯体疼痛更疼痛或绞痛。内脏疼痛可以是容易定位的,但其经常是极其难定位的,且当受伤时几个内脏区域产生“所谓的”疼痛,区域内的知觉与损伤部位完全无关。随着神经***损伤,外科手术后疼痛在本质上可以是神经性的(即,神经性疼痛)。当损伤影响周围神经***(例如,周围神经、神经根和/或神经节)时产生周围神经痛,因此发生周围神经病变。外科手术产生的神经损伤还可导致神经炎症(神经炎)与神经痛(神经分布疼痛)。当损伤影响中枢神经***(例如,大脑、小脑、脊髓)时产生中枢神经痛。疼痛可起因于神经瘤(也称为“假神经瘤”)的形成(例如,外科手术产生的神经损伤后的创伤性神经瘤),其通常以无效的、无节制的神经再生形式发生在损伤的神经纤维末端,一般在伤痕附近,浅表的(皮肤、皮下脂肪)或深部的(例如,胆囊切除术后)。如果受损或视神经轴索裂断的神经纤维退化还可发生传入神经阻滞疼痛,因此完全或部分地中断传入神经冲动。灼痛,即创伤性神经损伤后的持续性烧灼痛、异常性疼痛和痛觉过度的综合症,经常伴有血管舒缩神经和分泌汗运动神经的功能障碍,且随后还可发生营养改变。事实上,疼痛可源于任何发生外部创伤或损伤的组织或身体的部分,外部创伤或损伤如个体组织的切割口、刺伤、切口、裂口或伤口((包括所有外科手术中出现的,不论侵入性或非侵入性的))。最后,疼痛可以具有量(例如,轻度、中度和重度)和质(例如,疼痛、灼痛、刺痛、触电、刺伤)的区别,其可以包括异常的感觉(例如,感觉迟钝、感觉异常),且疼痛的强度可以是连续的、间歇性的或振荡的。
在本领域已报导关于术后切口疼痛的不同动物模型和研究(T.J.Brennan等,Pain1996,64,493-501;P.K.Zahn等,Regional Anesthesia and Pain Medicine 2002,Vol.27,No 5(September-October),514-516)。
最后,重要的是强调需要提供一种新形式,从而预防和/或治疗外科手术后急性和慢性疼痛、异常性疼痛、痛觉过敏和发生在外科手术中和/或外科手术后的神经(周围神经病变)与组织(表面的与深躯体的及内脏的)损伤的继发性异常感觉。
发明内容
本发明的发明者意外地发现并证明施用σ受体配体可高效预防或治疗与外科手术相关的疼痛。当σ配体具体为σ受体拮抗剂时,优选为(中性)拮抗剂、反相激动剂或部分拮抗剂的形式,本发明的优势更明显。
因此,本发明一方面涉及用于预防和/或治疗手术产生的疼痛的σ配体。
在优选的实施方案中,所述σ配体具有通式(I):
其中
R1选自由氢、取代或未被取代的烷基、取代或未被取代的环烷基、取代或未被取代的烯基、取代或未被取代的芳基、取代或未被取代的芳基烷基、取代或未被取代的非芳香族杂环基、取代或未被取代的芳香族杂环基、取代或未被取代的杂环烷基、-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和卤素所组成的组中;
R2选自由氢、取代或未被取代的烷基、取代或未被取代的环烷基、取代或未被取代的烯基、取代或未被取代的芳基、取代或未被取代的芳基烷基、取代或未被取代的芳香族或非芳香族杂环基、取代或未被取代的杂环烷基、-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和卤素所组成的组中;
R3和R4独立地选自由氢、取代或未被取代的烷基、取代或未被取代的环烷基、取代或未被取代的烯基、取代或未被取代的芳基、取代或未被取代的芳基烷基、取代或未被取代的芳香族或非芳香族杂环基、取代或未被取代的杂环烷基、-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和卤素所组成的组中,或它们共同形成任选的取代的稠环***;
R5和R6独立地选自由氢、取代或未被取代的烷基、取代或未被取代的环烷基、取代或未被取代的烯基、取代或未被取代的芳基、取代或未被取代的芳基烷基、取代或未被取代的芳香族或非芳香族杂环基、取代或未被取代的杂环烷基、-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和卤素所组成的组中,或者与它们所连接的氮原子共同形成取代或未被取代的芳香族或非芳香族杂环基;
n选自1、2、3、4、5、6、7和8;
t是1、2或3;
R8和R9各自独立地选自由氢、取代或未被取代的烷基、取代或未被取代的环烷基、取代或未被取代的烯基、取代或未被取代的芳基、取代或未被取代的芳香族或非芳香族杂环基、取代或未被取代的烷氧基、取代或未被取代的芳氧基和卤素所组成的组中;
或其药学上可接受的盐、异构体、前体药物或溶剂化物。
在另一优选的实施方案中,σ配体具有通式(II):
其中
R1、R2和R3独立地选自氢、卤素、羟基、烷氧基、取代或未被取代的烷基、氰基、NRaRb、NHCONRc、NHSO2Rd、COOH、COORe,其中Ra是氢或烷基,且Rb、Rc、Rd和Re独立地为烷基;
R4选自氢、取代或未被取代的烷基、取代或未被取代的环烷基及取代或未被取代的芳香族或非芳香族杂环基;
R5和R6独立地为取代或未被取代的烷基,或与它们所连接的氮原子共同形成取代或未被取代的芳香族或非芳香族杂环基;
X选自–S-、-SO-、-SO2-和O;及
n是选自1、2、3、4、5、6、7和8中的整数;
或其药学上可接受的盐、异构体、前体药物或溶剂化物。
在还一优选的实施方案中,σ配体具有通式(III):
其中
R1选自由氢、取代或未被取代的烷基、取代或未被取代的环烷基、取代或未被取代的芳香族或非芳香族杂环基、取代或未被取代的芳基、取代或未被取代的芳基烷基及取代或未被取代的杂环烷基所组成的组中;
R2选自由氢、取代或未被取代的烷基、取代或未被取代的环烷基、取代或未被取代的烷氧基、取代或未被取代的芳基、取代或未被取代的芳香族或非芳香族杂环基、取代或未被取代的芳基烷基以及取代或未被取代的杂环烷基所组成的组中;
R3和R4独立地选自由氢、取代或未被取代的烷基、取代或未被取代的环烷基、取代或未被取代的芳香族或非芳香族杂环基、取代或未被取代的芳基、取代或未被取代的芳基烷基及取代或未被取代的杂环烷基所组成的组中,或R3和R4共同形成3至6元取代或未被取代的元环;
R5和R6独立地选自由氢、取代或未被取代的烷基、取代或未被取代的环烷基、取代或未被取代的芳香族或非芳香族杂环基、取代或未被取代的芳基、取代或未被取代的芳基烷基及取代或未被取代的杂环烷基所组成的组中,或R5和R6共同形成取代或未被取代的芳香族或非芳香族杂环基,环具有3至7个原子;
n选自0、1和2;
m选自0、1、2、3和4;
虚线-----为单键或双键;
附带条件是当R1是苯基,R2是H时,虚线------是双键,m是1,且R5和R6形成2,5-二氧代吡咯烷或5-乙氧基,2-氧代-吡咯烷;R3和R4不能同时为H或甲基;
或其药学上可接受的盐、异构体、前体药物或溶剂化物。
本发明的另一方面涉及上述定义的σ配体在制备预防和/或治疗手术产生的疼痛的药剂中的用途。
本发明的另一方面是治疗遭受手术产生的疼痛或可能遭受手术治疗产生的疼痛的患者的方法,其包括向需要这种治疗或预防的患者施用治疗上有效量的上述定义的σ配体。
权利要求中也限定了这些方面及其优选的实施方案。
附图说明
图1:机械性异常性疼痛的治疗方法。在大鼠的同侧(手术的)后爪评估机械性异常性疼痛之前30分钟腹膜内注射已知的σ配体(BD-1063)获得的结果[0小时:外科手术;3.5小时:腹膜内注射化合物;4小时:评估机械性异常性疼痛;*:显著性差异(p<0.05);ns:非显著性差异(p>0.05);n=10]。
图2:机械性异常性疼痛的治疗方法。在大鼠的同侧(手术的)后爪评估机械性异常性疼痛之前30分钟腹膜内施用化合物63获得的结果[0小时:手术;3.5小时:腹膜内化合物;4小时:评估机械性异常性疼痛;*:显著性差异(p<0.05);ns:非显著性差异(p>0.05);n=10]。
图3:机械性异常性疼痛的治疗和预防方法。在大鼠的同侧(手术的)后爪手术之前(预防)和之后(治疗)施用通常用于术后疼痛治疗的双氯芬酸钠获得的机械性异常性疼痛的对比结果[10分钟:腹膜内施用化合物(预防);0小时:手术;3小时:腹膜内施用化合物(治疗);4小时:评估机械性异常性疼痛;*:显著性差异(p<0.05);ns:非显著性差异(p>0.05);n=10]。
图4:机械性异常性疼痛的治疗和预防方法。在大鼠的同侧(手术的)后爪手术之前(预防)和之后(治疗)施用BD-1063和化合物63的机械性异常性疼痛的对比结果[10分钟:腹膜内施用化合物(预防);0小时:手术;3.5h:腹膜内施用化合物(治疗);4小时:评估机械性异常性疼痛;*:显著性差异(p<0.05);ns:非显著性差异(p>0.05);n=10]。
图5:热痛觉过敏的治疗和预防方法。在大鼠的同侧(手术的)后爪手术之前(预防)和之后(治疗)施用通常用于术后疼痛治疗的双氯芬酸钠获得的热痛觉过敏的对比结果[10分钟:腹膜内施用化合物(预防);0小时:手术;3小时:腹膜内施用化合物(治疗);4小时:评估热痛觉过敏;*:显著性差异(p<0.05);ns:非显著性差异(p>0.05);n=10]。
图6:热痛觉过敏的治疗和预防方法。在大鼠的同侧(手术的)后爪手术之前(预防)和之后(治疗)施用化合物63的热痛觉过敏的对比结果[10分钟:腹膜内施用化合物(预防);0小时:手术;3.5小时:腹膜内施用化合物(治疗);4小时:评估热痛觉过敏;*:显著性差异(p<0.05);ns:非显著性差异(p>0.05);n=10]。
发明详述
在本发明的上下文中,以下术语的详细说明如下。
“烷基”指的是含有1至12个碳原子的不含有不饱和链的直链或支链烃链基,并通过单键与分子的其它部分连接,例如甲基、乙基、正丙基、异丙基、正丁基、叔丁基、正戊基等。烷基可以任选地被一个或多个取代基取代,诸如芳基、卤基、羟基、烷氧基、羧基、氰基、羰基、酰基、烷氧羰基、氨基、硝基、巯基、烷硫基等。优选的烷基具有1至6个碳原子。如果由芳基取代,其相当于“芳基烷基”基团,诸如苄基或苯乙基。如果由杂环基取代,其相当于“杂环烷基”基团。
“烯基”指的是含有2至12个碳原子,并包含至少一个不饱和的直链或支链烃链自由基,并且与分子中的剩余部分通过一个单键相连。烯基自由基任选地被一个或多个取代基取代,如芳基、卤基、羟基、烷氧基、羧基、氰基、羰基、酰基、烷氧羰基、氨基、硝基、巯基、烷硫基等。优选的烯基自由基含有2至6个碳原子。
“环烷基”是指稳定的3至10元的单环或双环自由基,其是饱和或部分饱和的,并且其只由碳和氢原子组成,诸如环己基或金刚烷基。除非在说明书中另作具体说明,术语“环烷基”指的是包括环烷基自由基,其任选地由一个或多个取代基取代,诸如烷基、卤基、羟基、氨基、氰基、硝基、烷氧基、羧基、烷氧羰基等。
“芳基”是指单个或多个芳香环自由基,其包括含有单独和/或稠芳基的多环自由基。典型的芳基含有1至3个单独环或稠环和6至大约18个碳环原子,诸如苯基、萘基、茚基、菲基或蒽基。芳基自由基可以任选地由一个或多个取代基取代,诸如羟基、巯基、卤基、烷基、苯基、烷氧基、卤代烷基、硝基、氰基、二烷氨基、氨烷基、酰基、烷氧羰基等。
“杂环基”是指稳定的3至15元环自由基,其由碳原子和1至5个杂原子组成,该杂原子选自由氮、氧和硫组成的组中,优选地具有一个或多个杂原子的4至8元环,更优选的具有一个或多个杂原子的5或6元环,其可以是芳香族或非芳香族的。为了达到本发明的目的,杂环可以是单环、双环或三环环***,其可以包括稠环***;而且杂环基自由基中的氮、碳或硫原子可以任选地氧化;氮原子可以任选地季铵化;而且杂环基自由基可以部分或全部饱和的或是芳香族的。此类杂环的例子包括但不限于吖庚因、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、恶唑、异恶唑、***、咪唑等。
“烷氧基”是指式-ORa的基团,其中Ra是如上定义的烷基自由基,例如甲氧基、乙氧基、丙氧基等。
“氨基”是指式-NH2、-NHRa或-NRaRb的基团,任选地季铵化,例如甲氨基、乙氨基、二甲氨基、二乙氨基、丙氨基等。
“卤素(halogen)”、“卤基(halo)”或“卤素(hal)”是指溴基、氯基、碘基或氟基。
本文涉及的本发明化合物中的取代基团是指特定的基团,其可以在一个或多个可用位置由一个或多个合适基团取代,例如卤素,诸如氟、氯、溴和碘;氰基;羟基;硝基;叠氮基;烷酰基,如C1-6链烷酰基,诸如酰基等等;甲酰胺基;烷基,包括具有1至大约12个碳原子,或1至约6个碳原子,且更优选地1至3个碳原子的基团;烯基和炔基,包括具有一个或多个不饱和键和2至约12个碳或2至约6个碳原子的基团;烷氧基,具有一个或多个氧键和1至约12个碳原子,或1至大约6个碳原子的基团;芳氧基,诸如苯氧基;烷硫基,包括具有一个或多个硫醚键和1至大约12个碳原子或1至大约6个碳原子的部分;烷基亚磺酰基,包括具有一个或多个亚磺酰基键和1至约12个碳原子,或1至约6个碳原子的部分;烷硫基,包括具有一个或多个硫醚键和1至约12个碳原子或1至约6个碳原子的部分;氨烷基,诸如具有一个或多个氮原子和1至约12个碳原子或1至约6个碳原子的基团;羧基芳基,具有6个或更多碳,特别是苯基或萘基和诸如苄基的芳烷基。除非另有说明,任选地取代基可以在基团的每个可取代位置上具有取代基,并且每个取代基是相互独立的。
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,其中所述化合物是离子形式或是带电荷的,并与抗衡离子(阳离子或阴离子)结合或在溶液中。该定义还包括季胺盐以及活性分子与其它分子和离子的复合物,特别地,通过离子相互作用形成的复合物。特别地,该定义包括生理上接受的盐;该术语必须理解为等同于“药学上可接受的盐”。
在本发明的上下文中术语“药学上可接受的盐”意思是当以适当的方式进行治疗、应用或使用时,特别是在人类和/或哺乳动物中应用时,生理学上耐受的任何盐(通常是指无毒的,特别地,是因为含有抗衡离子)。在本发明的上下文中,特别是当用于人类和/或哺乳动物时,这些生理上可接受的盐可以由阳离子或碱形成,并理解为通过根据本发明使用的至少一种化合物形成的盐-通常是酸(去质子化的)-诸如阴离子和至少一个生理上耐受的阳离子,优选无机盐形成。特别优选的是具有碱和碱土金属的盐,以及用铵离子(NH4 +)形成的盐。优选的盐是用(单)或(双)钠、(单)或(双)钾、镁或钙形成的盐。在本发明的上下文中,特别是当用于人类和/或哺乳动物时,这些生理上可接受的盐还可以由阴离子或酸形成,并理解为通过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,例如在氮中-诸如阳离子和至少一个生理上耐受的阴离子。在本发明的上下文中,特别是当用于人类和/或哺乳动物时,这种限定特别包括通过生理上耐受的酸形成的盐,也就是用生理上耐受的有机或无机酸的特异性活性化合物的盐。这种类型的盐的例子用以下物质形成: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、乳酸或柠檬酸。
根据本发明,术语“溶剂化物”应该理解为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个分子(通常是极性溶剂)结合,特别包括水化物和醇化物,诸如甲醇化物。优选的溶剂化物是水化物。
σ配体的前体药物的任何化合物,特别是式(I)、(II)或(III)化合物的前体药物,也在本发明的范围内。术语“前体药物”使用其广义含义,并包含在体内转化成本发明的化合物的那些衍生物。前体药物的例子包括但不限于式I的化合物的衍生物和代谢物,其包括可生物水解部分,诸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、可生物水解的碳酸盐、可生物水解的酰脲和可生物水解的磷酸盐类似物。优选地,具有羧基官能团的化合物的前体药物是羧酸的低烷基酯。羧酸酯通过酯化存在于分子上的任意羧酸部分而容易地形成。前体药物能够典型地使用众所周知的方法制备,诸如由Burger“Medicinal Chemistry and Drug Discovery 6th ed.(Donald J.Abraham ed.,2001,Wiley)和“Design and Applications of Prodrugs”(H.Bundgaard ed.,1985,HarwoodAcademic Publishers)所描述的方法。
本文涉及的任何化合物旨在代表这种特定化合物以及某些变体或形式。特别是,本文涉及的化合物可能具有非对称中心且因此存在不同对映体或非对映体形式。因此,本文涉及的任何给定的化合物旨在代表任一消旋体,一个或多个对映体形式,一个或多个非对映体形式,及其混合物。同样,关于双键的立体异构体或几何异构体也是可能的,因此在一些情况下,分子可存在(E)-异构体或(Z)-异构体(反式和顺式异构体)。如果分子含有多个双键,每个双键可具有独有的立体异构体,其可与分子的其它双键的立体异构体相同或不同。此外,本文中涉及的化合物可存在阿托异构体。本文涉及的化合物的所有立体异构体,包括对映体、非对映异构体、几何异构体和阿托异构体,及其混合物,都在本发明的范围内。
此外,本文所涉及的任何化合物都以互变异构体形式存在。特别地,术语互变异构体是指化合物的两个或多个结构异构体中的一个,这些异构体平衡存在,并且可以相互转换。常见的互变异构体对是胺-亚胺、酰胺-亚胺酸、酮-烯醇、内酰胺-内酰亚胺等。
除非另有说明,本发明的化合物也包括同位素标记的形式,即区别仅在于含有同位素标记的一个或多个原子的化合物。例如,结构相同,但至少一个氢原子被氘或氚取代的化合物,或至少有一个碳原子被13C-或14C-取代,或至少一个氮原子被15N取代,这些化合物同样在本发明的范围内。
σ配体,尤其是式(I)、(II)或(III)的化合物或其盐或其溶剂化物,优选地以药学上可接受的或基本上纯的形式存在。药学上可接受的形式尤其是指具有药学上可接受的纯度水平,不包括常见的药物添加剂,如稀释剂和载体,并且在正常剂量水平上不具有毒性的原料。药物的纯度水平优选高于50%,更优选高于70%,最优选高于90%。在优选的实施方案中,式(I)中的化合物,或其盐或其溶剂化物或其前体药物的纯度高于95%。
如本文所使用的,术语“治疗(treat)”、“治疗(treating)”和“治疗(treatment)”包括在由外科手术引起的疼痛发病后,消除、除去、逆转、缓和、减轻或控制这种疼痛。
如本文所使用的,术语“预防(prevention)”、“预防(preventing)”、“预防性(preventive)”、“预防(prevent)”和预防(prophylaxis)指的是在疾病发作之前,治疗以避免、使减少到最小或阻碍疾病或症状的发作或发展的能力,在本文中,疼痛是由外科手术引起的。
因此,总的来说,“治疗(treating)”或“治疗(treatment)”和“预防(preventing)”或“预防(prevention)”,是指至少与使患者痛苦的病况相关的症状的抑制或改善,其中抑制或改善具有广义含义,是指至少参数的量有所减少,例如,与接受治疗的病况相关的症状,诸如疼痛。因此,本发明的方法还包括完全抑制病况的情况,例如,防止发生或停止,例如终止,患者不再遭受所述疾病。因此,目前的方法包括预防和控制由手术治疗导致的急性和慢性疼痛,包括手术组织损伤的继发的表面和/或深部疼痛,及手术神经损伤继发的周围神经痛、神经痛、异常性疼痛、灼痛、痛觉过敏、感觉过敏、痛觉过度、感觉迟钝、感觉异常、神经炎或神经病变。
本文所使用的术语“σ配体”或“σ受体配体”是指结合σ受体的任何化合物。如前所述,σ配体优选为以(中性的)拮抗剂、反相激动剂或部分拮抗剂形式存在的σ受体拮抗剂。
“激动剂”定义为与受体结合且具有内在影响的化合物,因此,当其与受体接触时增加受体的基础活性。“拮抗剂”定义为与激动剂或反相激动剂竞争结合受体的化合物,因此,阻碍激动剂或反相激动剂对受体的作用。然而,拮抗剂(也称为“中性”拮抗剂)对组成型受体活性无作用。拮抗剂通过结合受体的活性位点或别构位点介导其效应,或其可能与通常不参与受体活性生物调节的独特的结合位点相互作用。拮抗剂活性取决于拮抗剂-受体复合物的寿命是可逆的还是不可逆的,其反之取决于拮抗剂受体结合的性质。“部分拮抗剂”定义为与受体结合且产生拮抗剂反应的化合物,然而,部分拮抗剂不能产生完全的拮抗剂反应。部分拮抗剂是弱的拮抗剂,因此部分地阻止激动剂或反相激动剂对受体的作用。
“反相激动剂”被定义为占据与激动剂相同的受体但却产生与之相反作用的化合物,因此,它也降低了受体的基础活性(也就是,受体介导的信号传导)。此类化合物通常被认为是负拮抗剂。反相激动剂是受体的配体,相对于没有其它任何配体的基础状态,能够使受体适应非活性状态。因此,虽然拮抗剂能够抑制激动剂的活性,但反相激动剂是在没有激动剂的情况下能够改变受体的构象的配体。
本申请中使用的“σ受体”是众所周知的且使用以下定义,“结合位点代表不同于类***、NMDA、多巴胺及其它已知神经递质素或激素受体家族的典型蛋白质”(G.Ronsisvalle等,Pure Appl.Chem.73,1499-1509(2001))。基于配体结合研究的药理学数据、解剖学分布和生物化学特性区分至少两个亚型的σ受体(R.Quiron等,Trends Pharmacol.Sci.13,85-86(1992);M.L.Leitner,Eur.J.Pharmacol.259,65-69(1994);S.B.Hellewell andW.D.Bowen;Brain Res.527,244-253(1990))(G.Ronsisvalle等,Pure Appl.Chem.73,1499-1509(2001))。σ受体(西格玛1(σ1)和西格玛2(σ2))的蛋白质序列在本领域是已知的(例如Prasad,P.D.等,J.Neurochem.70(2),443-451(1998))。它们对于多种镇痛剂显示出高亲和力(例如镇痛新)。
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受体具有IC50值≤5000nM的化合物,更优选的≤1000nM,更有选的≤500nM。更优选地,IC50值≤250nM。更有选地,IC50值≤100nM。最优选地,IC50值≤50nM。此外,本申请中使用的表述“与σ受体结合的化合物”定义为,使用10nM特异于σ受体的放射性配体(例如,优选地[3H]-(+)镇痛新)具有至少≥50%的置换,其中σ受体可以是任何σ受体亚型。优选地,所述化合与σ-1受体亚型结合。
与σ受体结合的化合物,通常被称为σ配体,这在本领域是众所周知的。它们中许多包含于上述的“与σ受体结合的化合物”定义中。尽管σ配体具有许多已知用途,诸如应用在抗精神病药物、抗焦虑药物、抗抑郁药物、治疗中风的药物、抗癫痫药物中并具有许多其它应用,包括抗偏头痛及一般性疼痛,但本领域未提到这些化合物用于预防和/或治疗由外科手术产生的疼痛。
表1中列举了本领域中已知的σ配体(也就是,它们的IC50≤5000nM)。这些化合物中的一些可结合σ-1和/或σ-2受体。这些σ配体也包括它们各自的盐、碱和酸。
表1
优选地,上表中同样包括还原的氟哌啶醇。还原的氟哌啶醇是在人体内产生的氟哌啶醇的活性代谢物,表现出对σ-1受体的高亲和力(较低的纳摩尔范围内),并且在试验的动物和人类细胞中都产生了针对σ-1受体的不可逆性阻断。
制备给定的代表化合物的前体药物的众所周知的方法的例子对于本领域技术人员是已知的(如在Krogsgaard-Larsen等,Textbook of Drug design and designscovery,Taylor&Francis(April 2002))。
在优选的实施方案中,本发明上下文中的σ配体具有如前所述的通式(I)所示的结构。
在优选的实施方案中,式(I)中的化合物的R1选自H、-COR8、取代的或未取代的烷基。更优选的,R1选自H、甲基和乙酰基。更优选的实施方案是R1为H。
在另一优选的实施方案中,式(I)中的化合物的R2表示H或烷基,更优选是甲基。
在另一优选的实施方案中,式(I)中的化合物的R3和R4位于苯基的间位和对位,更优选的,它们独立地选自于卤素和取代或未被取代的烷基。
在本发明的特别优选的实施方案中,式(I)中的化合物的R3和R4与苯基共同组成任选的取代的稠环***(如,取代或未被取代的芳基或取代或未被取代的芳香族或非芳香族杂环基团可能是稠环),更优选的,萘环***。
在式(I)的化合物中,其中n选自2、3、4的实施方案是本发明中优选的,更优选n是2。
最后,在另一实施方案中,式(I)中的化合物优选R5和R6是彼此独立的C1-6烷基或与氮原子连接共同组成取代或未被取代的杂环基团,特别选自于吗啉基、哌啶基和吡咯烷基的基团。更优选的,R5和R6共同组成吗啉-4-基基团。
在本申请的优选变体中,式(I)的σ配体选自于:
[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[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]乙基4-{2-[1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基]乙基}哌嗪羧酸盐
[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-甲氧苯基)-5-甲基-1H-吡唑-3-基氧基]乙基}吗啉
[12]1-(4-甲氧苯基)-5-甲基-3-[2-(吡咯烷-1-基)乙氧基]-1H-吡唑
[13]1-(4-甲氧苯基)-5-甲基-3-[3-(吡咯烷-1-基)丙氧基]-1H-吡唑
[14]1-[2-(1-(4-甲氧苯基)-5-甲基-1H-吡唑-3-基氧基)乙基]哌啶
[15]1-{2-[1-(4-甲氧苯基)-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-吗啉代乙氧基)-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
或其药学上可接受的盐、异构体、前体药物或溶剂化物。
在本发明更优选的变体中,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指定为化合物63。
根据之前的申请WO2006/021462中所公开的内容,制备式(I)的化合物及其盐或溶剂化物。
在另一优选的实施方案中,本发明中的σ配体具有如上所述的通式(II)。
在本发明的另一实施方案中,优选地在式(II)的化合物中,R1至R3至少一个为氢。在本发明的另一实施方案中,优选地在式(II)的化合物中,R1至R3至少一个为卤素。在另一实施方案中,优选地R1至R3的两个为氢或卤素,最后一个优选为氯。
在另一实施方案中,式(II)的化合物中的R4优选为低级烷基,更优选为甲基。
在式(II)的化合物的一个实施方案中,R5和R6独立地为烷基,更优选为C1-C6烷基,甚至更优选为乙基或异丙基。
在式(II)的化合物的另一实施方案中,R5和R6与其连接的氮原子共同形成取代或未被取代的杂环基,优选地选自吡咯烷、哌啶、氮杂环庚烷和吗啉。
此外,在式(II)的化合物的优选实施方案中,n为1、2、3、4或5。
以下为优选的式(II)的化合物:
[67]4-[2-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基硫代乙基]吗啉;
[68]1-[2-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基-硫代乙基]哌啶;
[69]1-[2-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基-硫代乙基]吡咯烷;
[70]2-[2-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基-硫代]-N,N-二异丙基乙胺;
[71]2-[1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基-硫代]-N,N-二乙基乙胺;
[72]1-[2-(1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基-硫代)乙基]氮杂环庚烷;
[73]4-[3-(1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基硫代)丙基]吗啉;
[74]1-[3-(1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基-硫代)丙基]-4-吡咯烷;
[75]1-[3-(1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基硫代)丙基]-4-苯基哌啶;
[76]1-[4-(1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基-硫代)丁基]-4-苯基哌啶;
[77]4-[4-(1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基-硫代)丁基]吗啉;
[78]1-[5-(1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基硫代)戊基]哌啶;
[79]4-[5-(1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基硫代)戊基]吗啉;
[80]1-[5-(1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基硫代)戊基]吡咯烷;
[81]1-[2-(1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基-亚磺酰基)乙基]吡咯烷;
[82]4-[2-(1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基-亚磺酰基)-乙基]-吗啉;
[83]2-[2-(1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基亚磺酰基]-N,N-二异丙基乙胺;
[84]1-[4-(1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基亚磺酰基)丁基]-4-苯基哌啶;
[85]1-[2-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基磺酰基]乙基吡咯烷;
[86]2-[1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基-磺酰基]-N,N-二乙基乙胺;
[87]4-[4-(1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基-磺酰基)-丁基]吗啉;
[88]1-[2-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基氧基)乙基]哌啶;
[89]2-[1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基氧基]-N,N-二乙基乙胺;
[90]1-[2-(1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基氧基)乙基]吡咯烷;
[91]4-[2-(1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基氧基)乙基]吗啉;
[92]2-(5-甲基-1-苯基-1H-1,2,4-***-3-基氧基)-N,N-二乙基乙胺;
[93]1-[2-(5-甲基-1-苯基-1H-1,2,4-***-3-基氧基)乙基]吡咯烷;
[94]4-[2-(5-甲基-1-苯基-1H-1,2,4-***-3-基氧基)乙基]吗啉;
[95]1-[2-(5-甲基-1-苯基-1H-1,2,4-***-3-基氧基)乙基]哌啶;
[96]4-[4-(5-甲基-1-苯基-1H-1,2,4-***-3-基氧基)丁基]吗啉;
[97]1-[2-(1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基硫代)乙基]-4-甲基哌啶;
[98]4-[2-(5-甲基-1-苯基-1H-1,2,4-***-3-基硫代)乙基]吗啉;
[99]4-[2-(1-(4-氯苯基)-5-甲基-1H-1,2,4-***-3-基硫代)乙基]吗啉;
[100]N-[2-(1-(3-氯苯基)-5-甲基-1H-1,2,4-***-3-基硫代)乙基]-N,N-二异丙基丙-2-胺;
[101]1-[2-(1-(3-氯苯基)-5-甲基-1H-1,2,4-***-3-基硫代)乙基]哌啶;
[102]4-[2-(1-(3-氯苯基)-5-甲基-1H-1,2,4-***-3-基硫代)乙基]吗啉;
[103]4-[2-(1-(3-氯苯基)-5-甲基-1H-1,2,4-***-3-基硫代)乙基]吡咯烷;
[104]2-[1-(3-氯苯基)-5-甲基-1H-1,2,4-***-3-基硫代]-N,N-二乙基乙胺;
[105]4-[1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基硫代]-N,N-二乙基丁-1-胺;
[106]1-[4-(1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基硫代)丁基]哌啶;
[107]1-[4-(1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基硫代)丁基]吡咯烷;
[108]2-[1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基亚磺酰基]-N,N-二乙基乙胺;
[109]1-[2-(1-(3-氯苯基)-5-甲基-1H-1,2,4-***-3-基-亚磺酰基)乙基]吡咯烷;
[110]1-[2-(1-(3-氯苯基)-5-甲基-1H-1,2,4-***-3-基-亚磺酰基)乙基]吗啉;
[111]1-[2-(1-(3-氯苯基)-5-甲基-1H-1,2,4-***-3-基-亚磺酰基)乙基]-N,N-二乙基胺;
[112]1-[2-(1-(3-氯苯基)-5-甲基-1H-1,2,4-***-3-基-磺酰基)乙基]吡咯烷;
[113]1-[2-(1-(3-氯苯基)-5-甲基-1H-1,2,4-***-3-基-磺酰基)乙基]-N,N-二异丙胺;
[114]1-[2-(1-(3-氯苯基)-5-甲基-1H-1,2,4-***-3-基-磺酰基)乙基]-N,N-二乙基胺;
或其药学上可接受的盐、异构体、前体药物或溶剂化物。
此外,在本发明的另一优选实施方案中,式(II)的化合物是其草酸盐。
以下是式(II)的化合物的优选的盐:
[115]4-[2-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基硫代乙基]吗啉草酸盐;
[116]1-[2-(3,4-二氯苯基)-5-甲基-1H-1.2.4-***-3-基-硫代乙基]哌啶草酸盐;
[117]1-[2-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基-硫代乙基]吡咯烷草酸盐;
[118]2-[2-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基-硫代]-N,N-二异丙基乙胺草酸盐;
[119]2-[1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基-硫代]-N,N-二乙基乙胺草酸盐;
[120]1-[2-(1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基-硫代)乙基]氮杂环庚烷草酸盐;
[121]4-[3-(1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基硫代)丙基]吗啉草酸盐;
[122]1-[3-(1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基-硫代)丙基]吡咯烷草酸盐;
[123]1-[3-(1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基硫代)丙基]-4-苯基哌啶草酸盐;
[124]1-[4-(1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基-硫代)丁基]-4-苯基哌啶草酸盐;
[125]4-[4-(1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基-硫代)丁基]吗啉草酸盐;
[126]1-[5-(1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基硫代)戊基]哌啶草酸盐;
[127]4-[5-(1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基硫代)戊基]吗啉草酸盐;
[128]1-[5-(1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基硫代)戊基]吡咯烷草酸盐;
[129]4-[2-(1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基氧基)乙基]吗啉草酸盐;
[130]4-[2-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基硫代)乙基]吗啉盐酸盐;
[131]1-[2-(1-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基硫代)乙基]-4-甲基哌啶草酸盐;
[132]4-[2-(5-甲基-1-苯基-1H-1,2,4-***-3-基硫代)乙基]吗啉草酸盐;
[133]4-[2-(1-(4-氯苯基)-5-甲基-1H-1,2,4-***-3-基硫代)乙基]吗啉草酸盐;
[134]N-[2-(1-(3-氯苯基)-5-甲基-1H-1,2,4-***-3-基硫代)乙基]-N,N-二异丙基丙-2-胺草酸盐;
[135]1-[2-(1-(3-氯苯基)-5-甲基-1H-1,2,4-***-3-基硫代)乙基]哌啶草酸盐;
[136]4-[2-(1-(3-氯苯基)-5-甲基-1H-1,2,4-***-3-基硫代)乙基]吗啉草酸盐;
[137]4-[2-(1-(3-氯苯基)-5-甲基-1H-1,2,4-***-3-基硫代)乙基]吡咯烷草酸盐;
[138]2-[1-(3-氯苯基)-5-甲基-1H-1,2,4-***-3-基硫代]-N,N-二乙基乙胺草酸盐。
在本发明更优选变体中,式(II)的σ配体是4-[2-(3,4-二氯苯基)-5-甲基-1H-1,2,4-***-3-基硫代乙基]吗啉草酸盐。
可根据之前的申请WO2008/055932所公开的内容制备式(II)的化合物。
在另一优选的实施方案中,本发明中的σ配体具有上述的通式(III)。
在本发明另一实施方案中,优选地在式(III)的化合物中,R2优选为氢或烷基;更优选为氢。
在式(III)的化合物中,还优选地m为1或2,且n为0或1。
而且,在式(III)的化合物中,还优选地R3和R4为氢或烷基;更有选地为氢或甲基;且最优选地均为氢。
此外,优选地在式(III)的化合物中,R1选自由取代或未被取代的烷基、取代或未被取代的环烷基、取代或未被取代的杂环基和取代或未被取代的芳基所组成的组中;更优选为取代或未被取代的烷基、未取代的环烷基、未取代的芳基及芳香族杂环基;且最优选为甲基、叔丁基、环己基和苯基。
而且,还优选地R5和R6共同形成具有3至7个原子的取代或未被取代的杂环基,特别是吗啉-4-基、2,6-二甲基吗啉-4-基、哌啶-1-基、4-苯基哌啶-1-基、3-苯基哌啶-1-基、4-苄基哌嗪-1-基、4-苯基-哌嗪-1-基、2-[螺[异苯并呋喃-1(3H),4'-哌啶]-1'-基、氮杂环庚-1-基、1,2,3,4-四氢异喹啉-2-基、吡咯烷-1-基、3-苯基-吡咯烷-1-基、异吲哚-2-基或咪唑-1-基;特别是R2是氢,m是1且n是1时;更特别的是当R3和R4都是氢时;且甚至更特别的是当R1是取代或未被取代的苯基时。当R5是苄基且R6是甲基时获得良好效果。
可将以上关于R1至R6、n、m和虚线-----的实施方案和优选选择,以结合给予更优选的化合物。
式(III)的本发明特定独有的化合物包括以下列举的化合物:
[139]4,5,6,7-四氢-4-(2-(吗啉-4-基)乙基)-1-苯基-1H-吲唑;
[140]4,5,6,7-四氢-4-(2-(吗啉-4-基)乙基)-1-苯基-1H-吲唑草酸盐;
[141]1-(3,4-二氯苯基)-4,5,6,7-四氢-4-(2-(4-苯基吡啶-1-基)乙基)-1H-吲唑;
[142]1-(3,4-二氯苯基)-4,5,6,7-四氢-4-(2-(4-苯基吡啶-1-基)乙基)-1H-吲唑草酸盐;
[143](E)-4,5,6,7-四氢-4-(2-(吗啉-4-基)亚乙基)-1-苯基-1H-吲唑;
[144]1-(3,4-二氯苯基)-4,5,6,7-四氢-4-(2-(吗啉-4-基)乙基)-1H-吲唑;
[145]1-(3,4-二氯苯基)-4,5,6,7-四氢-4-(2-(吗啉-4-基)乙基)-1H-吲唑草酸盐;
[146]4,5,6,7-四氢-1-苯基-4-(2-(4-苯基吡啶-1-基)乙基)-1H-吲唑;
[147]4,5,6,7-四氢-1-苯基-4-(2-(4-苯基吡啶-1-基)乙基)-1H-吲唑草酸盐;
[148]4-(2-(4-苄基哌嗪-1-基)乙基)-4,5,6,7-四氢-1-苯基-1H-吲唑;
[149]4,5,6,7-四氢-1-苯基-4-(2-[螺[异苯并呋喃-1(3H),4'-吡啶]-1'-基]乙基)-1H-吲唑;
[150]4,5,6,7-四氢-1-苯基-4-(2-[螺[异苯并呋喃-1(3H),4'-吡啶]-1'-基]乙基)-1H-吲唑草酸盐;
[151]4,5,6,7-四氢-1-苯基-4-(2-(吡啶-1-基)乙基)-1H-吲唑;
[152]4,5,6,7-四氢-1-苯基-4-(2-(吡啶-1-基)乙基)-1H-吲唑草酸盐;
[153](E)-4-(2-(氮杂环庚-1-基)亚乙基)-4,5,6,7-四氢-1-苯基-1H-吲唑;
[154](E)-4-(2-(氮杂环庚-1-基)亚乙基)-4,5,6,7-四氢-1-苯基-1H-吲唑草酸盐;
[155](E)-4,5,6,7-四氢-1-苯基-4-(2-(4-苯基吡啶-1-基)亚乙基)-1H-吲唑;
[156](E)-4,5,6,7-四氢-1-苯基-4-(2-[螺[异苯并呋喃-1(3H),4'-吡啶]-1'-基]亚乙基)-1H-吲唑;
[157](E)-4,5,6,7-四氢-1-苯基-4-(2-[螺[异苯并呋喃-1(3H),4'-吡啶]-1'-基]亚乙基)-1H-吲唑草酸盐;
[158](E)-4,5,6,7-四氢-1-苯基-4-(2-(4-苯基哌嗪-1-基)亚乙基)-1H-吲唑;
[159]1,2,3,4-四氢-2-((E)-2-(6,7-二氢-1-苯基-1H-吲唑-4(5H)-亚)乙基)异喹啉;
[160]1,2,3,4-四氢-2-((E)-2-(6,7-二氢-1-苯基-1H-吲唑-4(5H)-亚)乙基)异喹啉草酸盐;
[161](E)-4,5,6,7-四氢-1-苯基-4-(2-(3-苯基吡啶-1-基)亚乙基)-1H-吲唑;
[162](E)-4,5,6,7-四氢-1-苯基-4-(2-(3-苯基吡咯烷-1-基)亚乙基)-1H-吲唑;
[163](E)-4,5,6,7-四氢-1-苯基-4-(2-(3-苯基吡咯烷-1-基)亚乙基)-1H-吲唑草酸盐;
[164](E)-4,5,6,7-四氢-4-(2-(异二氢吲哚-2-基)亚乙基)-1-苯基-1H-吲唑;
[165](E)-4,5,6,7-四氢-1-苯基-4-(2-(吡啶-1-基)亚乙基)-1H-吲唑;
[166]1-(3,4-二氯苯基)-4,5,6,7-四氢-4-(2-(4-苯基哌嗪-1-基)乙基)-1H-吲唑;
[167]1-(3,4-二氯苯基)-4,5,6,7-四氢-4-(2-(4-苯基哌嗪-1-基)乙基)-1H-吲唑草酸盐;
[168]1,4,5,6-四氢-4-(2-(吗啉-4-基)乙基)-1-苯基环戊二烯并[c]吡唑;
[169]1,4,5,6-四氢-4-(2-(吗啉-4-基)乙基)-1-苯基环戊二烯并[c]吡唑草酸盐;
[170]4,5,6,7-四氢-1-苯基-4-(2-(4-苯基哌嗪-1-基)乙基)-1H-吲唑;
[171]4,5,6,7-四氢-1-苯基-4-(2-(4-苯基哌嗪-1-基)乙基)-1H-吲唑草酸盐;
[172]2-(2-(1,4,5,6-四氢-1-苯基环戊二烯并[c]吡唑-4-基)乙基)异二氢吲哚;
[173]2-(2-(1,4,5,6-四氢-1-苯基环戊二烯并[c]吡唑-4-基)乙基)异二氢吲哚草酸盐;
[174]1,4,5,6-四氢-1-苯基-4-(2-(4-苯基吡啶-1-基)乙基)环戊二烯并[c]吡唑;
[175]1,4,5,6-四氢-1-苯基-4-(2-(吡啶-1-基)乙基)环戊二烯并[c]吡唑;
[176]1,4,5,6-四氢-1-苯基-4-(2-(4-苯基哌嗪-1-基)乙基)环戊二烯并[c]吡唑;
[177]1,4,5,6-四氢-1-苯基-4-(2-(吡咯烷-1-基)乙基)环戊二烯并[c]吡唑;
[178]1,4,5,6-四氢-1-苯基-4-(2-(吡咯烷-1-基)乙基)环戊二烯并[c]吡唑草酸盐;
[179]4-(2-(4-苄基哌嗪-1-基)乙基)-1,4,5,6-四氢-1-苯基环戊二烯并[c]吡唑;
[180]4-(2-(4-苄基哌嗪-1-基)乙基)-1,4,5,6-四氢-1-苯基环戊二烯并[c]吡唑二草酸盐;
[181]1,2,3,4-四氢-2-(2-(1,4,5,6-四氢-1-苯基环戊二烯并[c]吡唑-4-基)乙基)异喹啉;
[182]1,2,3,4-四氢-2-(2-(1,4,5,6-四氢-1-苯基环戊二烯并[c]吡唑-4-基)乙基)异喹啉草酸盐;
[183]4-(2-(1H-咪唑-1-基)乙基)-1,4,5,6-四氢-1-苯基环戊二烯并[c]吡唑;
[184]顺-1,4,5,6-四氢-4-(2-(2,6-二甲基吗啉-4-基)乙基)-1-苯基环戊二烯并[c]吡唑;
[185]顺-1,4,5,6-四氢-4-(2-(2,6-二甲基吗啉-4-基)乙基)-1-苯基环戊二烯并[c]吡唑草酸盐;
[186]顺-4,5,6,7-四氢-4-(2-(2,6-二甲基吗啉-4-基)乙基)-1-苯基-1H-吲唑;
[187]顺-4,5,6,7-四氢-4-(2-(2,6-二甲基吗啉-4-基)乙基)-1-苯基-1H-吲唑草酸盐;
[188]1,4,5,6-四氢-1-苯基-4-(2-[螺[异苯并呋喃-1(3H),4'-吡啶]-1'-基]-乙基)环戊二烯并[c]吡唑;
[189]1,4,5,6-四氢-1-苯基-4-(2-[螺[异苯并呋喃-1(3H),4'-吡啶]-1'-基]-乙基)环戊二烯并[c]吡唑草酸盐;
[190]N-苄基-2-(1,4,5,6-四氢-1-苯基环戊二烯并[c]吡唑-4-基)-N-甲基-乙胺;
[191]1,4,5,6-四氢-1-苯基-4-(2-(3-苯基吡啶-1-基)乙基)环戊二烯并[c]吡唑的非对映体混合物;
[192]N-苄基-2-(4,5,6,7-四氢-1-苯基-1H-吲唑-4-基)-N-甲基乙胺;
[193]4,5,6,7-四氢-4-(2-(异二氢吲哚-2-基)乙基)-1-苯基-1H-吲唑;
[194]4,5,6,7-四氢-4-(2-(异二氢吲哚-2-基)乙基)-1-苯基-1H-吲唑草酸盐;
[195]4,5,6,7-四氢-1-甲基-4-(2-(4-苯基吡啶-1-基)乙基)-1H-吲唑;
[196]4,5,6,7-四氢-1-甲基-4-(2-(4-苯基吡啶-1-基)乙基)-1H-吲唑草酸盐;
[197]4,5,6,7-四氢-4-(2-(异二氢吲哚-2-基)乙基)-1-甲基-1H-吲唑;
[198]4,5,6,7-四氢-4-(2-(异二氢吲哚-2-基)乙基)-1-甲基-1H-吲唑草酸盐;
[199]N-苄基-2-(4,5,6,7-四氢-1-甲基-1H-吲唑-4-基)-N-甲基乙胺;
[200]N-苄基-2-(4,5,6,7-四氢-1-甲基-1H-吲唑-4-基)-N-甲基乙胺草酸盐;
[201]4,5,6,7-四氢-1-甲基-4-(2-(吗啉-4-基)乙基)-1H-吲唑;
[202]4,5,6,7-四氢-1-甲基-4-(2-(吗啉-4-基)乙基)-1H-吲唑草酸盐;
[203]1-(4-氟苯基)-4,5,6,7-四氢-4-(2-(吗啉-4-基)乙基)-1H-吲唑;
[204]1-(4-氟苯基)-4,5,6,7-四氢-4-(2-(吗啉-4-基)乙基)-1H-吲唑草酸盐;
[205]顺-1-(4-氟苯基)-4,5,6,7-四氢-4-(2-(2,6-二甲基吗啉-4-基)乙基)-1H-吲唑;
[206]顺-1-(4-氟苯基)-4,5,6,7-四氢-4-(2-(2,6-二甲基吗啉-4-基)乙基)-1H-吲唑草酸盐;
[207]N-苄基-2-(1-(4-氟苯基)-4,5,6,7-四氢-1H-吲唑-4-基)-N-甲基-乙胺;
[208]1-(4-氟苯基)-4,5,6,7-四氢-4-(2-(异二氢吲哚-2-基)乙基)-1H-吲唑;
[209]1-(4-氟苯基)-4,5,6,7-四氢-4-(2-(异二氢吲哚-2-基)乙基)-1H-吲唑草酸盐;
[210]1-(4-氟苯基)-4,5,6,7-四氢-4-(2-(4-苯基吡啶-1-基)乙基)-1H-吲唑;
[211](+)-4,5,6,7-四氢-4-(2-(吗啉-4-基)乙基)-1-苯基-1H-吲唑;
[212](+)-4,5,6,7-四氢-4-(2-(吗啉-4-基)乙基)-1-苯基-1H-吲唑草酸盐;
[213](-)-4,5,6,7-四氢-4-(2-(吗啉-4-基)乙基)-1-苯基-1H-吲唑;
[214](-)-4,5,6,7-四氢-4-(2-(吗啉-4-基)乙基)-1-苯基-1H-吲唑草酸盐;
[215](E)-4,5,6,7-四氢-4-(2-(吗啉-4-基)亚乙基)-1-苯基-1H-吲唑草酸盐;
[216](E)-4,5,6,7-四氢-1-苯基-4-(2-(吡啶-1-基)亚乙基)-1H-吲唑草酸盐;
[217](E)-N-苄基-2-(6,7-二氢-1-苯基-1H-吲唑-4(5H)-基亚)-N-甲基-乙胺;
[218](E)-N-苄基-2-(6,7-二氢-1-苯基-1H-吲唑-4(5H)-基亚)-N-甲基-乙胺草酸盐;
[219](E)-4,5,6,7-四氢-4-(2-(顺-2,6-二甲基吗啉-4-基)亚乙基)-1-苯基-1H-吲唑;
[220](E)-4,5,6,7-四氢-4-(2-(顺-2,6-二甲基吗啉-4-基)亚乙基)-1-苯基-1H-吲唑草酸盐;
[221](E)-1-(3,4-二氯苯基)-4,5,6,7-四氢-4-(2-(顺-2,6-二甲基吗啉代-4-基)-亚乙基)-1H-吲唑;
[222](E)-1-(3,4-二氯苯基)-4,5,6,7-四氢-4-(2-(顺-2,6-二甲基-吗啉代-4-基)亚乙基)-1H-吲唑草酸盐;
[223](E)-1-(3,4-二氯苯基)-4,5,6,7-四氢-4-(2-(吗啉代-4-基)亚乙基)-1H-吲唑;
[224](E)-1-(3,4-二氯苯基)-4,5,6,7-四氢-4-(2-(吗啉代-4-基)-亚乙基)-1H-吲唑草酸盐;
[225](E)-1-(3,4-二氯苯基)-4,5,6,7-四氢-4-(2-(吡啶-1-基)亚乙基)-1H-吲唑;
[226](E)-1-(3,4-二氯苯基)-4,5,6,7-四氢-4-(2-(吡啶-1-基)-亚乙基)-1H-吲唑草酸盐;
[227](E)-4-(2-(N,N-二乙胺)亚乙基)-4,5,6,7-四氢-1-苯基-1H-吲唑;
[228](E)-4-(2-(N,N-二乙胺)亚乙基)-4,5,6,7-四氢-1-苯基-1H-吲唑草酸盐;
[229](E)-4-(2-(4-环己基哌嗪-1-基)亚乙基)-4,5,6,7-四氢-1-苯基-1H-吲唑;
[230](E)-4,5,6,7-四氢-4-(2-(4-甲基吡啶-1-基)亚乙基)-1-苯基-1H-吲唑;
[231]4,5,6,7-四氢-4-(2-(4-甲基吡啶-1-基)乙基)-1-苯基-1H-吲唑;
[232]4,5,6,7-四氢-4-(2-(4-甲基吡啶-1-基)乙基)-1-苯基-1H-吲唑草酸盐;
[233]1,4,5,6-四氢-1-苯基-4-(2-(吡啶-1-基)乙基)环戊二烯并[c]吡唑草酸盐;
[234]1,4,5,6-四氢-1-苯基-4-[2-(硫代吗啉-4-基)乙基]环戊二烯并[c]吡唑;
[235]1,4,5,6-四氢-1-苯基-4-[2-(硫代吗啉-4-基)乙基]环戊二烯并[c]吡唑草酸盐;
[236]1,4,5,6-四氢-4-(2-(4-甲基吡啶-1-基)乙基)-1-苯基环戊二烯并[c]吡唑;
[237]1,4,5,6-四氢-4-(2-(4-甲基吡啶-1-基)乙基)-1-苯基环戊二烯并[c]吡唑草酸盐;
[238]1,4,5,6-四氢-4-(2-(4-甲基哌嗪-1-基)乙基)-1-苯基环戊二烯并[c]吡唑;
[239]4-(2-(4-环己基哌嗪-1-基)乙基)-1,4,5,6-四氢-1-苯基环戊二烯并[c]吡唑;
[240]4-(2-(氮杂环庚-1-基)乙基-4,5,6,7-四氢-1-苯基-1H-吲唑;
[241]N-苄基-2-(1-叔丁基-4,5,6,7-四氢-1H-吲唑-4-基)-N-甲基乙胺;
[242]1-叔丁基-4,5,6,7-四氢-4-(2-(4-苯基吡啶-1-基)乙基)-1H-吲唑;
[243]1-叔丁基-4,5,6,7-四氢-4-(2-(4-苯基吡啶-1-基)乙基)-1H-吲唑草酸盐;
[244](-)-N-苄基-2-(4,5,6,7-四氢-1-甲基-1H-吲唑-4-基)-N-甲基乙胺;
[245](+)-N-苄基-2-(4,5,6,7-四氢-1-甲基-1H-吲唑-4-基)-N-甲基乙胺;
[246]N-(2-(4,5,6,7-四氢-1-甲基-1H-吲唑-4-基)乙基)-N-甲基环已胺;
[247]4,5,6,7-四氢-4-(2-(4-羟基-4-苯基吡啶-1-基)乙基)-1-甲基-1H-吲唑;
[248]4,5,6,7-四氢-1-甲基-4-(2-(4-苯基吡啶-1-基)乙基)-1H-吲唑;
[249]N-苄基-2-(4,5,6,7-四氢-1-甲基-1H-吲唑-4-基)-N-甲基乙胺;
[250]4,5,6,7-四氢-1-苯基-4-(2-[螺[异苯并呋喃-1(3H),4'-吡啶]-1'-基]-乙基)-1H-吲唑。
尽管列出了草酸盐,但其它药学上可接受的盐类也组成优选化合物基团的部分。
在本发明更优选的变体中,式(III)的σ配体选自:
[251]4-(2-(1-(4-氟苯基)-4,5,6,7-四氢-1H-吲唑-4-基)乙基)吗啉草酸盐;
[252]4-(1-(2-(1-甲基)-4,5,6,7-四氢-1H-吲唑-4-基)乙基)吡啶-4-基)苄腈草酸盐;以及
[253]1-(4-(7-((5-溴噻吩-2-基)甲基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-2-基氨基)苯基)乙酸乙酯。
可根据之前的申请WO2006/021463所公开的内容制备式(III)的化合物。
在本发明的特定实施方案中,由手术产生的疼痛是表面和/或深部疼痛,例如为周围神经痛、神经痛、异常性疼痛、灼痛、痛觉过敏、感觉过敏和/或痛觉过度。
在本发明的另一方面,如本文中前述定义的手术产生的疼痛伴随着神经病变和/或神经炎。更优选地,该疼痛是热痛觉过敏或机械异常性疼痛。
IASP将“神经性疼痛”定义为“神经***中由原发性损伤或机能障碍引起或导致的疼痛”(IASP,Classification of chronic pain,2nd Edition,IASP Press(2002),210)。为了本发明的目的,该术语视为“神经源性疼痛”的同义词,IASP将其定义为“周围或中枢神经***中的原发性损害、功能障碍或短暂扰动引起或导致的疼痛”。根据本发明的神经性疼痛被限定为手术引起的神经性疼痛。
IASP将“异常性疼痛”定义为“由通常不会引起疼痛的刺激产生的疼痛”(IASP,Classification of chronic pain,2nd Edition,IASP Press(2002),210)。IASP将“周围神经痛”定义为“周围神经***中的原发性损害或功能障碍引起或导致的疼痛”,且“周围神经痛”被定义为“周围神经***中由原发性损害、功能障碍或短暂扰动引起或导致的疼痛”(IASP,Classification of chronic pain,2nd Edition,IASP Press(2002),213)。
IASP将“灼痛”定义为“创伤性神经病变后的持续性灼痛、异常性疼痛和痛觉过度的综合症,经常伴有血管收缩和发汗机能障碍且随后还可发生营养改变”(IASP,Classification of chronic pain,2nd Edition,IASP Press(2002),210)。
IASP将“痛觉过敏”定义为“对通常产生疼痛的刺激的增强反应”(IASP,Classification of chronic pain,2nd Edition,IASP Press(2002),211)。
IASP将“感觉过敏”定义为“对刺激的增强的敏感性,排除意识上的”(IASP,Classification of chronic pain,2nd Edition,IASP Press(2002),211)。
IASP将“痛觉过度”定义为“特征为对刺激的异常疼痛反应的疼痛综合症,尤其是重复性刺激及增加的阈值”(IASP,Classification of chronic pain,2nd Edition,IASPPress(2002),212)。
IASP描述了“异常性疼痛”、“痛觉过敏”和“痛觉过度”之间具有以下区别(IASP,Classification of chronic pain,2nd Edition,IASP Press(2002),212):
IASP将“神经痛”定义为“神经分布的疼痛”(IASP,Classification of chronicpain,2nd Edition,IASP Press(2002),212)。
IASP将“神经炎”定义为“神经炎症”(IASP,Classification of chronic pain,2ndEdition,IASP Press(2002),212)。
IASP将“神经病/神经炎”定义为“神经的功能紊乱或病理改变:在单一神经上为单神经病,在多个神经中为多发性单神经病,如果扩散并且双向,则为多神经病”(IASP,Classification of chronic pain,2nd Edition,IASP Press(2002),212)。
如前所述,本发明一方面涉及上述σ配体在制备预防和/或治疗手术产生的疼痛的药剂中的用途。
根据本发明的药物组合物的辅料或添加剂可选自载体、赋形剂、支撑材料、润滑剂、填料、溶剂、稀释剂、着色剂、调味剂如糖、抗氧化剂、粘合剂、粘着剂、崩解剂、防粘剂、助流剂和/或胶合剂。在栓剂的情况下,其可指肠胃外应用的蜡或脂肪酸酯或防腐剂、乳化剂和/或载体。这些辅料和/或添加剂的选择及其用量将取决于药物组合物的施用形式。
包含根据本发明的σ配体的药物组合物可适应于任何施用形式,口服地或肠胃外地,例如经肺的、经鼻的、直肠的和/或静脉注射。因此,根据本发明的制剂可适应于局部或全身施用,特别是通过带有或不带泵装置的针头或导管,用于皮肤的、经过皮肤的、皮下的、肌内的、关节内的、腹膜内的、静脉内的、动脉内的、膀胱内的、骨内的、海绵体内的、肺的、颊的、舌下的、眼睛的、玻璃体内的、鼻内的、经由皮肤的、直肠的、***的、口腔的、硬膜外的、鞘内的、心室内的、大脑内的、脑室内的、脑池内的、脊柱内的、髓周的、颅内的递送或其它施用途径。
用于口腔施用的合适的制剂是片剂、丸剂、囊片、胶帽、口香糖、胶囊剂、颗粒剂、滴剂或糖浆。
用于肠胃外施用的合适的制剂是溶液、悬浮液、可复水的干燥制剂或喷雾。
本发明的组合物可制成以溶解形式或小片存储,用于经由皮肤施用。
皮肤施用包括软膏、凝胶、乳霜、乳液、悬浮液或乳化液。
直肠施用的合适形式是使用栓剂。
而且,该组合物可以适合每天、每周或每月施用一次的形式。
因此,本发明另一方面提供了治疗患有外科术后疼痛或可能患有外科手术治疗产生的疼痛的患者的方法,其包括向需要这种治疗或预防的患者,以如上所述的合适的治疗频率施用治疗上有效量的σ配体。
在一些实施方案中,外科手术后疼痛包括一种或多种:异常性疼痛、痛觉过敏、热诱导疼痛、机械引起的疼痛或静息痛。例如,术后疼痛可包括机械引起的疼痛和/或静息痛。在一些情况下,外科手术后疼痛导致静息痛。
在某些实施方案中,异常性疼痛被抑制、改善和/或预防,且在一些实施方案中,痛觉过敏被抑制、改善和/或预防。在一些情况下,疼痛是慢性痛。在另一些情况中,疼痛是位于、邻近和/或靠近一个或多个外伤、伤口或切口的位点。本实验方法的其它方面包括通过向受试者施用σ配体改善和/或预防术后疼痛的发展或恶化的方法。在某些实施方案中,可在可能产生外部创伤、伤口或切口的活动,诸如手术之前施用σ配体。例如,可在可能产生外部创伤、伤口或切口的活动之前,诸如手术之前的30分钟、1小时、2小时、5小时、10小时、15小时、24小时或更久,诸如1天、几天、或甚至1周、两周、三周或更久施用乳化剂。在其它实施方案中,可在手术或产生外部创伤、伤口或切口的活动期间和/或之后施用σ配体。在一些情况下,在手术或产生外部创伤、伤口或切口的活动之后的1小时、2小时、3小时、4小时、6小时、8小时、12小时、24小时、30小时、36小时或更久施用σ配体。
在本发明的一个实施方案中,优选地使用治疗上有效量的σ配体。医师将决定目前治疗药物的剂量,其是最合适的,且将随着不同施用形式和选择的特定化合物而改变,此外,其随着接受治疗的患者、患者年龄、治疗的疼痛类型的不同而改变。医师一般希望最开始治疗时使用实际上小于该化合物的最优剂量的小剂量,并且将剂量渐渐增加直到达到该情况下的最优效果。当口服施用组合物时,需要更多量的活性剂产生相同效果,而肠胃外施用需要较少量的活性剂。该化合物以与可比较的治疗药物相同的方式使用,且剂量水平与其它治疗药物采用相同的数量级。
例如,必须施用于患者的给药方案将取决于患者的体重、应用类型、疾病的状况和严重程度。优选的给药方案包含施用0.01至300mg/kg的根据本发明的化合物,更优选地0.01至100mg/kg,最优选地0.01至50mg/kg。
以下实施例只是说明本发明的某些实施方案,不能视为任何方式的限制。
具体实施例
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可以根据之前的申请WO2006/021462所公开的内容制备,根据以下步骤获得化合物63的盐酸盐:
将化合物63(6.39g)溶解于盐酸饱和的乙醇中,搅拌混合物数分钟并蒸发干燥。从异丙醇中结晶残留物。首次结晶后的母液通过浓缩进行第二次结晶。两次结晶共获得5.24g(63%)相应的盐酸盐(熔点=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%
实施例2.在大鼠中对手术后疼痛的镇痛活性的评估
使用3%的兽医用异氟醚,并应用Ohmeda蒸发器在麻醉室中进行大鼠的麻醉诱导。在外科手术过程中通过将异氟醚蒸汽对准动物鼻口的软管保持麻醉。一旦大鼠麻醉,以伏卧位使大鼠躺平,并用酒精清洁右后爪。
然后,用解剖刀在后爪上切割大约10mm的皮肤切口,从足跟开始大约5mm并沿着脚趾延伸。定位筋膜,并通过弯剪来提拔肌肉,制备大约5mm的纵向切口,从而保持原始的肌肉和***物完整。因此,表面(皮肤)和深层(肌肉)组织以及神经都损伤。使用缝合术,利用面包丝缝合爪的皮肤,用聚乙烯吡啶酮清理伤口。
在手术(足底切割)4小时后,施用所述产物30分钟或60分钟后进行评估。进行两种类型的分析:
-使用von Frey细丝测试机械性异常性疼痛;将动物置于高架表面的甲基丙烯酸酯缸中,其具有金属网孔,从而可以应用细丝。动物在大约30分钟适应缸内环境之后,刺激两个后爪(损伤的和非损伤的爪,非损伤的爪作为对照),开始使用最细的细丝(0.4g)并增加到15g丝。动物对疼痛的反应通过动物对由细丝引起的痛苦刺激所产生的爪的退缩行为来显示。记录下引起爪缩回的压力(以g为单位来计量力)阈值。
-使用Ugo Basile足底实验测试热痛觉过敏。将动物置于所述装置的甲基丙烯酸酯笼中,该装置具有透明的地板。动物在笼内的适应期大约为10分钟。热刺激来自于在透明地板下移动的灯,将其应用到两个后爪上。在两次刺激之间具有最小1分钟的间隔,从而避免学习行为。当感觉到由灯产生的热度时,大鼠能够自由缩回后爪,然后关闭灯,以秒为单位记录缩回应答的等待时间。为了避免伤害动物的后爪,32秒后自动关闭灯。
足底切割-机械性异常性疼痛
治疗:
图1:在大鼠的同侧(手术的)后爪中,评估机械性异常性疼痛之前30分钟,腹腔内施用已知的σ配体(BD-1063)获得的结果。
图2:在大鼠的同侧(手术的)后爪中,评估机械性异常性疼痛之前30分钟,腹腔内施用化合物63获得的结果。
预防/治疗比较:
图3:使用双氯芬酸钠获得的机械性异常性疼痛的比较结果,双氯芬酸钠通常用于术后疼痛的治疗,在大鼠的同侧(手术的)后爪,在手术之前(预防)和之后(治疗)施用。
图4:在大鼠的同侧(手术的)后爪,在手术之前(预防)和之后(治疗)施用BD-1063和化合物63获得的机械性异常性疼痛的比较结果。
足底切割-热痛觉过敏
预防/治疗比较:
图5:使用双氯芬酸钠获得的热痛觉过敏的比较结果,双氯芬酸钠通常用于术后疼痛的治疗,在大鼠的同侧(手术的)后爪中,在手术之前(预防)和之后(治疗)施用。
图6:在大鼠的同侧(手术的)后爪,在手术之前(预防)和之后(治疗)施用化合物63获得的热痛觉过敏的比较结果。
在热痛觉过敏中观察到的主要问题与之前描述的实验(机械性异常性疼痛)相同。
通过降低机械性异常性疼痛和热痛觉过敏,σ配体对于抵抗术后疼痛十分有效。重要的是需要注意,与双氯芬酸相比(图3和图5),当手术之前(预防)和之后(治疗)施用时,σ配体都具有活性,当在手术前施用化合物时,其效能增强(图4和图6)。
Claims (17)
1.一种用于预防和/或治疗由外科手术产生的疼痛的σ配体。
2.根据权利要求1所述的σ配体,其中所述疼痛选自由外科手术产生的急性和/或慢性疼痛,尤其是外科手术组织损伤继发的表面和/或深部疼痛,及外科手术过程继发的周围神经痛、神经痛、异常性疼痛、灼痛、痛觉过敏、感觉过敏、痛觉过度、神经炎或神经病变。
3.根据权利要求1或2所述的σ配体,其选自σ受体拮抗剂,优选地选自中性拮抗剂、反相激动剂或部分拮抗剂。
4.根据之前任何一项权利要求所述的σ配体,具有通式(I):
其中
R1选自由氢、取代或未被取代的烷基、取代或未被取代的环烷基、取代或未被取代的烯基、取代或未被取代的芳基、取代或未被取代的芳基烷基、取代或未被取代的非芳香族杂环基、取代或未被取代的芳香族杂环基、取代或未被取代的杂环烷基、-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和卤素所组成的组中;
R2选自由氢、取代或未被取代的烷基、取代或未被取代的环烷基、取代或未被取代的烯基、取代或未被取代的芳基、取代或未被取代的芳基烷基、取代或未被取代的芳香族或非芳香族杂环基、取代或未被取代的杂环烷基、-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和卤素所组成的组中;
R3和R4独立地选自由氢、取代或未被取代的烷基、取代或未被取代的环烷基、取代或未被取代的烯基、取代或未被取代的芳基、取代或未被取代的芳基烷基、取代或未被取代的芳香族或非芳香族杂环基、取代或未被取代的杂环烷基、-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和卤素所组成的组中,或者它们共同形成任选的取代的稠环***;
R5和R6独立地选自由氢、取代或未被取代的烷基、取代或未被取代的环烷基、取代或未被取代的烯基、取代或未被取代的芳基、取代或未被取代的芳基烷基、取代或未被取代的芳香族或非芳香族杂环基、取代或未被取代的杂环烷基、-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和卤素所组成的组中;或者与它们所连接的氮原子共同形成取代或未被取代的芳香族或非芳香族杂环基基团;
n选自1、2、3、4、5、6、7和8;
t是1、2或3;
R8和R9各自独立地选自由氢、取代或未被取代的烷基、取代或未被取代的环烷基、取代或未被取代的烯基、取代或未被取代的芳基、取代或未被取代的芳香族或非芳香族杂环基、取代或未被取代的烷氧基、取代或未被取代的芳氧基和卤素所组成的组中;
或其药学上可接受的盐、异构体、前体药物或溶剂化物。
5.根据权利要求4所述的σ配体,其中R1选自H、-COR8和取代或未被取代的烷基。
6.根据权利要求4或5所述的σ配体,其中R2是H或烷基。
7.根据权利要求4至6任一项所述的σ配体,其中R3和R4共同形成稠萘环***。
8.根据权利要求4至7任一项所述的σ配体,其中R5和R6共同形成吗啉-4-基基团。
9.根据权利要求4至8任一项所述的σ配体,其中σ配体是4-{2-[5-甲基-1-(萘-2-基)-1H-吡唑-3-基氧基]乙基}吗啉,或其药学上可接受的盐、异构体、前体药物或溶剂化物。
10.根据权利要求4至8任一项所述的σ配体,其中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。
11.根据权利要求1至3任一项所述的σ配体,具有通式(II):
其中
R1、R2和R3独立地选自氢、卤素、羟基、烷氧基、取代或未被取代的烷基、氰基、NRaRb、NHCONRc、NHSO2Rd、COOH、COORe,其中Ra是氢或烷基,且Rb、Rc、Rd和Re独立地为烷基;
R4选自氢、取代或未被取代的烷基、取代或未被取代的环烷基及取代或未被取代的芳香族或非芳香族杂环基;
R5和R6独立地为取代或未被取代的烷基,或与它们所连接的氮原子共同形成取代或未被取代的芳香族或非芳香族杂环基基团;
X选自–S-、-SO-、-SO2-和O;及
n是选自1、2、3、4、5、6、7和8中的整数;
或其药学上可接受的盐、异构体、前体药物或溶剂化物。
12.根据权利要求11所述的σ配体,其中R1至R3中的至少一个是氢或卤素。
13.根据权利要求11或12所述的σ配体,其中R4是烷基。
14.根据权利要求1至3任一项所述的σ配体,具有通式(III):
其中
R1选自由氢、取代或未被取代的烷基、取代或未被取代的环烷基、取代或未被取代的芳香族或非芳香族杂环基、取代或未被取代的芳基、取代或未被取代的芳基烷基及取代或未被取代的杂环烷基所组成的组中;
R2选自由氢、取代或未被取代的烷基、取代或未被取代的环烷基、取代或未被取代的烷氧基、取代或未被取代的芳基、取代或未被取代的芳香族或非芳香族杂环基、取代或未被取代的芳基烷基及取代或未被取代的杂环烷基所组成的组中;
R3和R4独立地选自由氢、取代或未被取代的烷基、取代或未被取代的环烷基、取代或未被取代的芳香族或非芳香族杂环基、取代或未被取代的芳基、取代或未被取代的芳基烷基及取代或未被取代的杂环烷基所组成的组中,或R3和R4共同形成3至6元取代或未被取代的元环;
R5和R6独立地选自由氢、取代或未被取代的烷基、取代或未被取代的环烷基、取代或未被取代的芳香族或非芳香族杂环基、取代或未被取代的芳基、取代或未被取代的芳基烷基及取代或未被取代的杂环烷基所组成的组中,或R5和R6共同形成取代或未被取代的芳香族或非芳香族杂环基,环具有3至7个原子;
n选自0、1和2;
m选自0、1、2、3和4;
虚线-----为单键或双键;
附带条件,当R1是苯基,R2是H时,虚线------是双键,m是1,且R5和R6形成2,5-吡咯烷二酮或5-乙氧基,2-氧代-吡咯烷;R3和R4不能同时为H或甲基;
或其药学上可接受的盐、异构体、前体药物或溶剂化物。
15.根据权利要求14所述的σ配体,其中R4是氢或烷基。
16.根据权利要求1至15任一项所定义的σ配体在制备预防和/或治疗手术产生的疼痛的药剂中的用途。
17.一种治疗遭受手术产生的疼痛或可能遭受手术治疗产生的疼痛的患者的方法,其包括向需要这种治疗或预防的患者施用治疗上有效量的根据权利要求1至15任一项所定义的σ配体。
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