CN112533919B - 具有trka抑制活性的化合物和包含该化合物作为活性成分的用于预防或治疗疼痛的药物组合物 - Google Patents
具有trka抑制活性的化合物和包含该化合物作为活性成分的用于预防或治疗疼痛的药物组合物 Download PDFInfo
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- CN112533919B CN112533919B CN201980049772.5A CN201980049772A CN112533919B CN 112533919 B CN112533919 B CN 112533919B CN 201980049772 A CN201980049772 A CN 201980049772A CN 112533919 B CN112533919 B CN 112533919B
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- Prior art keywords
- pyridin
- pyrazolo
- benzamide
- methylpiperazin
- compound
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Abstract
本发明涉及具有TrkA抑制活性的化合物和包含该化合物作为活性成分的用于预防或治疗疼痛的药物组合物。由本发明的一个实施方案提供的化合物具有优异的TrkA抑制活性并且在术后疼痛的动物模型中显示优异的疼痛抑制效果，因此可以用作镇痛剂。
Description
技术领域
本发明涉及具有TrkA抑制活性的化合物和包含该化合物作为活性成分的用于预防或治疗疼痛的药物组合物。
背景技术
目前用于治疗疼痛的疗法使用几类化合物。阿片类药物(例如吗啡)具有数个缺点，包括呕吐、便秘、不利的呼吸影响以及成瘾可能性。非甾体类抗炎药(NSAID，例如COX-1型或COX-2型)也具有包括对于治疗严重疼痛功效不足的缺点。此外，COX-1抑制剂会引起黏膜溃疡。因此，一直需要新型的且更有效的用于缓解疼痛、尤其是慢性疼痛的疗法。
Trk是由称为神经营养素(NT)的可溶性生长因子群激活的高亲和力受体酪氨酸激酶。Trk受体家族具有三个成员：TrkA、TrkB和TrkC。在神经营养素中，存在(i)激活TrkA的神经生长因子(NGF)、(ii)激活TrkB的脑源性神经亲和因子(BDNF)和NT-4/5、和(iii)激活TrkC的NT3。Trk在神经组织中广泛表达并且参与神经细胞的维持、信号转导和存活(非专利文献1，Patapoutian,A.等人，Current Opinion in Neurobiology，2001，11，272-280)。已证实Trk/神经营养素通路的抑制剂在许多临床前的疼痛动物模型中是有效的。
此外，已显示由侵入肿瘤细胞和肿瘤的巨噬细胞分泌的NGF直接刺激位于外周疼痛纤维中的TrkA。在各种各样的小鼠和大鼠肿瘤模型中，已证实用单克隆抗体中和NGF抑制与癌症相关的疼痛达到与给予最高耐受剂量的吗啡类似或更好的程度。由于TrkA激酶可以起到NGF驱动的生物学响应的介导物(mediator)的作用，因此TrkA和/或其它Trk激酶的抑制剂可以为慢性疼痛病况提供有效的治疗。
发明内容
发明要解决的问题
本发明的目的在于提供具有优异的TrkA抑制活性的化合物。
本发明的另一目的在于提供用于预防或治疗疼痛的药物组合物，其包含上述化合物作为活性成分。
本发明的另一目的在于提供用于预防或减轻疼痛的保健功能性食品组合物，其包含上述化合物作为活性成分。
本发明的另一目的在于提供用于治疗疼痛的方法，其包括对有需要的受试者给予上述化合物的步骤。
本发明的另一目的在于提供用于预防或治疗疼痛的上述化合物。
本发明的另一目的在于提供上述化合物用于制备用于预防或治疗疼痛的药物的用途。
用于解决问题的方案
为了达到上述目的，在本发明的一个方面，本发明提供由式1表示的化合物、其立体异构体或其药学上可接受的盐。
在本发明的另一方面，本发明提供用于预防或治疗疼痛的药物组合物，其包含上述化合物作为活性成分。
在本发明的另一方面，本发明提供用于预防或减轻疼痛的保健功能性食品组合物，其包含上述化合物作为活性成分。
在本发明的另一方面，本发明提供用于治疗疼痛的方法，其包括对有需要的受试者给予上述化合物的步骤。
在本发明的另一方面，本发明提供用于预防或治疗疼痛的上述化合物。
在本发明的另一方面，本发明提供上述化合物用于制备用于预防或治疗疼痛的药物的用途。
发明的效果
在本发明的一个方面中提供的化合物具有优异的TrkA抑制活性并且在术后疼痛的动物模型中显示优异的疼痛抑制效果，并且因此可以有效地用作镇痛剂。
附图说明
图1为示出实施例10的化合物在各术后疼痛动物模型中的最佳药物表达时间的图。
图2为示出实施例11的化合物在各术后疼痛动物模型中的最佳药物表达时间的图。
图3为示出实施例12的化合物在各术后疼痛动物模型中的最佳药物表达时间的图。
图4为示出实施例13的化合物在各术后疼痛动物模型中的最佳药物表达时间的图。
图5为示出实施例14的化合物在各术后疼痛动物模型中的最佳药物表达时间的图。
图6为示出实施例15的化合物在各术后疼痛动物模型中的最佳药物表达时间的图。
图7为示出在各术后疼痛动物模型中实施例10的化合物在最佳药物表达时间的浓度引起的疼痛抑制效果的图。
图8为示出在各术后疼痛动物模型中实施例13的化合物在最佳药物表达时间的浓度引起的疼痛抑制效果的图。
图9为示出在各术后疼痛动物模型中实施例14的化合物在最佳药物表达时间的浓度引起的疼痛抑制效果的图。
图10为示出在各术后疼痛动物模型中实施例15的化合物在最佳药物表达时间的浓度引起的疼痛抑制效果的图。
具体实施方式
下文中，详细地描述本发明。
在本发明的一个方面，本发明提供由式1表示的化合物、其立体异构体、或其药学上可接受的盐。
[式1]
在式1中，
R1为-H，包含选自由H、N、O和S组成的组中的一个或多个杂原子的未取代或取代的5元至10元杂芳基，包含选自由N、O和S组成的组中的一个或多个杂原子的未取代或取代的6元至10元杂环烷基，未取代或取代的C6-10芳基，或-NHE1，
取代的5元至10元杂芳基、取代的6元至10元杂环烷基和取代的C6-10芳基独立地为由选自由-OH、-F、-Cl、-Br、-I、包含一个N的未取代或取代的5元至6元杂环烷基、氨基羰基和氨基羰基氨基组成的组中的一种或多种取代基取代的5元至10元杂芳基、6元至10元杂环烷基和C6-10芳基，
取代的5元至6元杂环烷基为由
取代的5元至6元杂环烷基，
E1为未取代或由一个或多个-OH取代的5元至10元环烷基；
R2为-H、未取代或取代的C6-10芳基、未取代或取代的C6-10芳基氨基、或者未取代或取代的C6-10芳基羰基氨基，
取代的C6-10芳基、取代的C6-10芳基氨基和取代的C6-10芳基羰基氨基独立地为由选自由-OH、-F、-Cl、-Br、-I和包含两个N的未取代或取代的6元杂环烷基组成的组中的一种或多种取代基取代的C6-10芳基、C6-10芳基氨基和C6-10芳基羰基氨基，
取代的6元杂环烷基为由C1-5直链或支链烷基取代的6元杂环烷基；
G1为＝CA1-或＝N-，
A1为-H、-F、-Cl、-Br、-I、未取代或取代的C6-10芳基、或者包含选自由N、O和S组成的组中的一个或多个杂原子的未取代或取代的5元至10元杂芳基，
取代的C6-10芳基和取代的5元至10元杂芳基独立地为由选自由-F、-Cl、-Br、-I、甲基、硝基、C1-5直链或支链烷基氨基羰基氨基、和包含一个N的未取代的6元杂环烷基组成的组中的一种或多种取代基取代的C6-10芳基和5元至10元杂芳基；
G2为＝CA2-或＝N-，
A2为-H；
G3为＝CA3-或＝N-，
A3为-H；
G4为-NA4-，
A4为-H、或者未取代或取代的苄基，
取代的苄基为由C1-5直链或支链烷氧基取代的苄基；
G5为＝CA5-或＝N-，和
A5为-H。
在另一方面，
R1为-H、包含两个N的未取代或取代的5元杂芳基、包含一个N的未取代或取代的6元杂环烷基、未取代或取代的苯基、或-NHE1，
取代的5元杂芳基、取代的6元杂环烷基和取代的苯基独立地为由选自由-OH、-F、-Cl、-Br、-I、包含一个N的未取代或取代的5元至6元杂环烷基、氨基羰基和氨基羰基氨基组成的组中的一种或多种取代基取代的5元杂芳基、6元杂环烷基和苯基，
取代的5元至6元杂环烷基为由
取代的5元至6元杂环烷基，
E1为未取代或由一个或多个-OH取代的5元至6元环烷基；
R2为-H、未取代或取代的苯基、未取代或取代的苯基氨基、或者未取代或取代的苯基羰基氨基，
取代的苯基、取代的苯基氨基和取代的苯基羰基氨基独立地为由选自由-OH、-F、-Cl、-Br、-I和包含两个N的未取代或取代的6元杂环烷基组成的组中的一种或多种取代基取代的苯基、苯基氨基和苯基羰基氨基，
取代的6元杂环烷基为由甲基取代的6元杂环烷基；
G1为＝CA1-或＝N-，
A1为-F、-Cl、-Br、-I、未取代或取代的苯基、或者包含一个或两个N的未取代或取代的5元至6元杂芳基，
取代的苯基和取代的5元至6元杂芳基独立地为由选自由-F、-Cl、-Br、-I、甲基、C1-5直链或支链烷基氨基羰基氨基、和包含一个N的未取代的6元杂环烷基组成的组中的一种或多种取代基取代的苯基和5元至6元杂芳基；
G2为＝CA2-或＝N-，
A2为-H；
G3为＝CA3-或＝N-，
A3为-H；
G4为-NA4-，
A4为-H、或者未取代或取代的苄基，
取代的苄基为由C1-5直链或支链烷氧基取代的苄基；
G5为＝CA5-或＝N-，和
A5为-H。
在另一方面，
R1为-H、
R2为
G1为＝CA1-或＝N-，
A1为-Br、
G2为＝CA2-或＝N-，
A2为-H；
G3为＝CA3-或＝N-，
A3为-H；
G4为-NA4-，
A4为-H或
G5为＝CA5-或＝N-，
A5为-H。
上述化合物可以为选自由以下化合物组成的组中的任意化合物。
(1)N-(3-氯苯基)-5-(吡啶-3-基)-1H-吡唑并[3,4-c]吡啶-3-胺；
(2)N-(3,4-二氯苯基)-5-(1-(哌啶-4-基)-1H-吡唑-4-基)-1H-吡唑并[3,4-c]吡啶-3-胺；
(3)N-(3,5-二氯苯基)-5-(1-(哌啶-4-基)-1H-吡唑-4-基)-1H-吡唑并[3,4-c]吡啶-3-胺；
(4)N-(3-氯苯基)-5-(1-甲基-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶-3-胺；
(5)N-(3,4-二氯苯基)-5-(1-甲基-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶-3-胺；
(6)N-(3,5-二氯苯基)-5-(1-甲基-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶-3-胺；
(7)N-(3,5-二氯苯基)-5-(1-(哌啶-4-基)-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶-3-胺；
(8)4-(4-甲基哌嗪-1-基)-N-(5-(1-(哌啶-4-基)-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶-3-基)苯甲酰胺；
(9)N-(5-(3-(3-异丙基脲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)-4-(4-甲基哌嗪-1-基)苯甲酰胺；
(10)4-(4-甲基哌嗪-1-基)-N-(5-苯基-1H-吡唑并[3,4-b]吡啶-3-基)苯甲酰胺；
(11)N-(5-(4-氟苯基)-1H-吡唑并[3,4-b]吡啶-3-基)-4-(4-甲基哌嗪-1-基)苯甲酰胺；
(12)4-(4-甲基哌嗪-1-基)-N-(5-(吡啶-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)苯甲酰胺；
(13)4-(4-甲基哌嗪-1-基)-N-(5-(吡啶-4-基)-1H-吡唑并[3,4-b]吡啶-3-基)苯甲酰胺；
(14)N-(5-溴-1H-吡唑并[3,4-b]吡啶-3-基)-4-(4-甲基哌嗪-1-基)苯甲酰胺；
(15)2,6-二氯-4-(4-(1-(哌啶-4-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯酚；
(16)N-(7-(4-甲氧基苄基)-4-(1-(哌啶-4-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)-4-(4-甲基哌嗪-1-基)苯甲酰胺；
(17)4-(4-甲基哌嗪-1-基)-N-(4-(1-(哌啶-4-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯甲酰胺；
(18)4-(4-(5-(4-(4-甲基哌嗪-1-基)苯甲酰氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯；
(19)4-(4-甲基哌嗪-1-基)-N-(4-(4-(吡咯烷-1-基)哌啶-1-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯甲酰胺；
(20)1-(5-(4-(4-甲基哌嗪-1-基)苯甲酰氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)哌啶-4-甲酰胺；
(21)4-(4-甲基哌嗪-1-基)-N-(4-(3-脲基哌啶-1-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯甲酰胺；
(22)4-氟-N-(5-(1-(哌啶-4-基)-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶-3-基)苯甲酰胺；
(23)2,6-二氯-4-(4-((1s,4s)-4-羟基环己基氨基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯酚；和
(24)N-(4-(3,5-二氯-4-羟基苯基)-7H-吡咯并[2,3-d]嘧啶-5-基)-4-(4-甲基哌嗪-1-基)苯甲酰胺。
本发明的由式1表示的化合物可以以药学上可接受的盐的形式使用，其中所述盐优选为由药学上可接受的游离酸形成的酸加成盐。本文中的酸加成盐可以从如下酸来获得：无机酸，例如盐酸、硝酸、磷酸、硫酸、氢溴酸、氢碘酸、亚硝酸和亚磷酸；无毒有机酸，例如脂肪族单/二羧酸酯、苯基取代的链烷酸酯、羟基链烷酸酯、链烷二酸酯、芳香族酸、和脂肪族/芳香族磺酸；或有机酸，例如乙酸、苯甲酸、柠檬酸、乳酸、马来酸、葡萄糖酸、甲烷磺酸、4-甲苯磺酸、酒石酸和富马酸。药学上无毒的盐示例为硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、硝酸盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物、氟化物、乙酸盐、丙酸盐、癸酸盐(decanoate)、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、癸酸盐(caprate)、庚酸盐、丙炔酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、丁炔-1,4-二酸盐、己烷-1,6-二酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、对苯二甲酸盐、苯磺酸盐、甲苯磺酸盐、氯苯磺酸盐、二甲苯磺酸盐、苯基乙酸盐、苯基丙酸盐、苯基丁酸盐、柠檬酸盐、乳酸盐、羟基丁酸盐、乙醇酸盐、苹果酸盐、酒石酸盐、甲磺酸盐、丙烷磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐、和扁桃酸盐。
根据本发明的酸加成盐可以通过本领域技术人员已知的常规方法来制备。例如，将由式1表示的衍生物溶解于例如甲醇、乙醇、丙酮、二氯甲烷和乙腈等有机溶剂中，向其中添加有机酸或无机酸以诱导沉淀。然后，将沉淀物过滤并且干燥以得到盐。或者将溶剂和过量的酸在减压下馏出，并且干燥以得到盐。或者使沉淀物在有机溶剂中结晶以得到盐。
可以通过使用碱来制备药学上可接受的金属盐。碱金属盐或碱土金属盐通过以下过程来获得：将化合物溶解于过量的碱金属氢氧化物溶液或碱土金属氢氧化物溶液中；过滤不溶性化合物盐；将剩余的溶液蒸发并且进行干燥。此时，优选以药学上适当形式的钠盐、钾盐或钙盐来制备金属盐。并且，通过碱金属盐或碱土金属盐与合适的银盐(例如硝酸银)的反应来制备相应的银盐。
此外，本发明不仅包括由式1表示的化合物和其药学上可接受的盐，还包括可以由其制备的溶剂化物、光学异构体、水合物等。
在本发明的另一方面，本发明提供包含上述化合物、其立体异构体或其药学上可接受的盐作为活性成分的用于预防或治疗疼痛的药物组合物。此时，所述化合物可以为抑制TrkA(原肌球蛋白受体激酶A)以显示对疼痛的预防或治疗活性的化合物。药物组合物可以为镇痛组合物。
本文中描述的疼痛包括所有类型的已知的疼痛，例如术后疼痛、由于疾病导致的疼痛、由于炎症导致的疼痛、由于创伤导致的疼痛、急性疼痛、包括神经性疼痛的慢性疼痛等。
所述疾病包括与许多病理性病况例如癌症、纤维肌痛、下背部疼痛、颈部疼痛、坐骨神经痛和骨关节炎等中的任意者相关的所有疼痛。神经性疼痛包括由受到神经损伤、神经病或其他疾病进展影响的神经引起的所有疼痛。
在临床给药期间可以以各种口服制剂和肠胃外制剂来给予由式1表示的化合物或其药学上可接受的盐。当配制由式1表示的化合物或其药学上可接受的盐时，使用通常使用的稀释剂或赋形剂，例如填充剂、增量剂、粘合剂、润湿剂、崩解剂和表面活性剂。用于口服给药的固体制剂为片剂、丸剂、散剂、颗粒剂和胶囊剂。通过将一种或多种化合物与一种或多种适当的赋形剂例如淀粉、碳酸钙、蔗糖或乳糖、明胶等混合来制备这些固体制剂。除了简单的赋形剂以外，还可以使用例如硬脂酸镁、滑石等润滑剂。用于口服给药的液体制剂为混悬剂、溶液剂、乳剂和糖浆剂，并且，除了例如水和液体石蜡等通常使用的简单稀释剂以外，上述制剂还可以包含各种赋形剂例如润湿剂、甜味剂、芳香剂和防腐剂。用于肠胃外给药的制剂为无菌水溶液剂、非水溶液剂、混悬剂和乳剂。除了活性化合物以外，非水溶液剂和混悬剂还可以包含丙二醇、聚乙二醇、如橄榄油等植物油、如油酸乙酯等可注射酯等。
包含由式1表示的化合物或其药学上可接受的盐作为活性成分的药物组合物可以肠胃外给药，并且肠胃外给药包括皮下注射、静脉内注射、肌内注射或胸腔内注射。
为了将由式1表示的化合物或其药学上可接受的盐制备为用于肠胃外给药的制剂，将由式1表示的化合物或其药学上可接受的盐与稳定剂或缓冲剂在水中混合以生产溶液剂或混悬剂，然后将其以安瓿瓶或小瓶单元来配制。本文中的组合物可以是无菌的并且额外包含防腐剂、稳定剂、可润湿性粉末或乳化剂、用于调节渗透压的盐和/或缓冲剂、和其它治疗上有用的物质，并且所述组合物可以通过常规的混合方法、制粒方法或包衣方法来配制。
用于口服给药的制剂示例为片剂、丸剂、硬/软胶囊剂、溶液剂、混悬剂、乳剂、糖浆剂、颗粒剂、酏剂和锭剂等。除了活性成分以外，这些制剂还可以包括稀释剂(例如，乳糖、右旋糖、蔗糖、甘露糖醇、山梨糖醇、纤维素和/或甘氨酸)和润滑剂(例如，二氧化硅、滑石、硬脂酸及其镁盐或钙盐、和/或聚乙二醇)。片剂可以包含粘合剂例如硅酸镁铝、淀粉糊、明胶、甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮，并且，如果需要，片剂中可以额外包含例如淀粉、琼脂糖、海藻酸或者其钠盐或共沸混合物等崩解剂和/或吸收剂、着色剂、调味剂和甜味剂。
在本发明的另一方面，本发明提供包含上述化合物、其立体异构体或其药学上可接受的盐作为活性成分的用于预防或减轻疼痛的保健功能性食品组合物。
可以使用本发明的由式1表示的化合物作为食品添加剂。在该情况下，可以根据常规方法将该化合物原样添加或者与其它食物组分混合来添加。可以根据使用目的(预防或缓解)来调节活性成分的混合比例。通常，可以以相对于总食品重量为0.1至90重量份来添加本发明的由式1表示的化合物。然而，如果为了健康和卫生或者调节健康状况而需要长期给药，则含量可以低于上述含量，但是，由于已证实该化合物非常安全，因此更高的含量也是可以接受的。
与其它饮料一样，除了该化合物以外，本发明的保健功能性饮料组合物还可以额外包含各种香料或天然碳水化合物等。上述天然碳水化合物可以为以下中的一种：单糖，例如葡萄糖和果糖；二糖，例如麦芽糖和蔗糖；多糖，例如糊精和环糊精；和糖醇，例如木糖醇、山梨糖醇和赤藓糖醇。此外，可以包含天然甜味剂(奇甜蛋白、甜叶菊提取物例如莱鲍迪甙A、甘草甜素等)和合成甜味剂(糖精、阿斯巴甜等)作为甜味剂。在100g本发明的组合物中，天然碳水化合物的含量优选为1-20g并且更优选5-12g。
除了上述成分以外，本发明的由式1表示的化合物可以包含各种各样的营养素、维生素、矿物质(电解质)、包括天然调味剂和合成调味剂的调味剂、着色剂、增量剂(乳酪、巧克力等)、果胶酸及其盐、海藻酸及其盐、有机酸、保护性胶体增粘剂(protectivecolloidal viscosifier)、pH调节剂、稳定剂、防腐剂、甘油、醇类、用于添加至碳酸饮料中的碳酸盐等。本发明的由式1表示的化合物还可以包含天然果汁、水果饮料和可添加至蔬菜饮料中的果肉。
在本发明的另一方面，本发明提供用于治疗疼痛的方法，其包括对有需要的受试者给予上述化合物的步骤。在本发明的另一方面，本发明提供用于预防或治疗疼痛的上述化合物。在本发明的另一方面，本发明提供上述化合物用于制备用于预防或治疗疼痛的药物的用途。
在本发明的另一方面，本发明提供用于预防或治疗疼痛的药剂盒，其包含：含有上述化合物、其立体异构体或其药学上可接受的盐作为活性成分的第一组分；和含有镇痛剂作为活性成分的第二组分。
此时，如果镇痛剂是已知的镇痛剂，则可以使用而没有限制。镇痛剂可以为抗炎镇痛剂(例如COX抑制剂等NSAID)或基于阿片样物质的镇痛剂。镇痛剂的一些具体实例包括对乙酰氨基酚、阿司匹林、布洛芬、酮洛芬、美洛昔康、双氯芬酸钾、依托度酸、舒林酸、吲哚美辛、塞来昔布、伐地昔布、罗非昔布、塞来昔布、氢可酮、羟吗啡酮、丁丙诺啡、芬太尼、氢化吗啡酮、曲马多或其组合。
在本发明的一个方面中提供的化合物具有优异的TrkA抑制活性并且在术后疼痛的动物模型中显示优异的疼痛抑制效果，并且因此可以有效地用作镇痛剂。这由下文中记载的实施例和实验例支持。
下文中，将通过以下实施例和实验例来详细地描述本发明。
然而，以下实施例和实验例仅用于说明本发明，并且本发明的内容不限于此。
<实施例1>N-(3-氯苯基)-5-(吡啶-3-基)-1H-吡唑并[3,4-c]吡啶-3-胺
参考韩国专利No.10-1753652来制备实施例1的化合物。
<实施例2>N-(3,4-二氯苯基)-5-(1-(哌啶-4-基)-1H-吡唑-4-基)-1H-吡唑并[3,4-c]吡啶-3-胺
参考韩国专利No.10-1753652来制备实施例2的化合物。
<实施例3>N-(3,5-二氯苯基)-5-(1-(哌啶-4-基)-1H-吡唑-4-基)-1H-吡唑并[3,4-c]吡啶-3-胺
参考韩国专利No.10-1753652来制备实施例3的化合物。
<实施例4>N-(3-氯苯基)-5-(1-甲基-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶-3-胺
参考韩国专利No.10-1753652来制备实施例4的化合物。
<实施例5>N-(3,4-二氯苯基)-5-(1-甲基-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶-3-胺
参考韩国专利No.10-1753652来制备实施例5的化合物。
<实施例6>N-(3,5-二氯苯基)-5-(1-甲基-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶-3-胺
参考韩国专利No.10-1753652来制备实施例6的化合物。
<实施例7>N-(3,5-二氯苯基)-5-(1-(哌啶-4-基)-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶-3-胺
参考韩国专利No.10-1753652来制备实施例7的化合物。
<实施例8>4-(4-甲基哌嗪-1-基)-N-(5-(1-(哌啶-4-基)-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶-3-基)苯甲酰胺
参考韩国专利No.10-1753654来制备实施例8的化合物。
<实施例9>N-(5-(3-(3-异丙基脲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)-4-(4-甲基哌嗪-1-基)苯甲酰胺
参考韩国专利No.10-1753654来制备实施例9的化合物。
<实施例10>4-(4-甲基哌嗪-1-基)-N-(5-苯基-1H-吡唑并[3,4-b]吡啶-3-基)苯甲酰胺
参考韩国专利No.10-1753654来制备实施例10的化合物。
<实施例11>N-(5-(4-氟苯基)-1H-吡唑并[3,4-b]吡啶-3-基)-4-(4-甲基哌嗪-1-基)苯甲酰胺
参考韩国专利No.10-1753654来制备实施例11的化合物。
<实施例12>4-(4-甲基哌嗪-1-基)-N-(5-(吡啶-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)苯甲酰胺
参考韩国专利No.10-1753654来制备实施例12的化合物。
<实施例13>4-(4-甲基哌嗪-1-基)-N-(5-(吡啶-4-基)-1H-吡唑并[3,4-b]吡啶-3-基)苯甲酰胺
参考韩国专利No.10-1753654来制备实施例13的化合物。
<实施例14>N-(5-溴-1H-吡唑并[3,4-b]吡啶-3-基)-4-(4-甲基哌嗪-1-基)苯甲酰胺
参考韩国专利No.10-1753654来制备实施例14的化合物。
<实施例15>2,6-二氯-4-(4-(1-(哌啶-4-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯酚
将4-氯-7H-吡咯并[2,3-d]嘧啶(1.2g，7.84mmol)添加至DMF(15mL)中，并且在0℃下将NaH(0.36g，9.00mmol)添加至其中。将混合物在室温下搅拌20分钟，然后将对甲苯磺酰氯(1.7g，8.91mmol)添加至其中，接着在室温下搅拌2小时。在反应完成后，在高压下除去溶剂，溶解于水中，并且用二氯甲烷(50mL×3)萃取。将残余物通过色谱法(乙酸乙酯:己烷＝2:3)来纯化以得到4-氯-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶(1.88g，78％)。
1H NMR(CDCl3,300MHz):δ8.77(s,1H),8.01(d,J＝8.4Hz,2H),7.79(d,J＝4.3Hz,1H),7.32(d,J＝8.4Hz,2H),6.71(d,J＝4.1Hz,1H),2.40(s,3H).
将4-氯-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶(1.0g，3.43mmol)、4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(dioxaborolan)-2-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(1.47g，3.89mmol)、碳酸钾(1.35g，9.75mmol)和Pd(dppf)Cl2(0.19g，0.26mmol)溶解于1,4-二噁烷和水(2:1)的混合溶液中，在85℃下加热2小时。在反应完成后，在高压下除去溶剂，溶解于水中，并且用乙酸乙酯(50mL×3)萃取。将残余物通过色谱法来纯化以得到4-(4-(7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(1.24g，69％)。
1H NMR(CDCl3,300MHz):δ8.54(s,1H),8.06(d,J＝7.8Hz,2H),7.86(d,J＝1.9Hz,1H),7.76(s,1H),7.71(d,J＝3.9Hz,1H),7.65(s,1H),7.28(s,1H),6.57(d,J＝4.0Hz,1H),4.25-4.31(m,1H),3.81-3.88(m,2H),2.91(t,J＝12.6Hz,2H),2.39(s,3H),2.17(d,J＝10.5Hz,2H),1.93-1.99(m,2H),1.48(s,9H).
将4-(4-(7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(1.4g，2.67mmol)和N-溴代琥珀酰亚胺(0.52g，2.93mmol)溶解于DMF中，然后在室温下搅拌2小时。在反应完成后，在高压下除去溶剂，溶解于水中，并且用乙酸乙酯(50mL×3)萃取。将残余物通过色谱法来纯化以得到4-(4-(5-溴-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(1.53g，87％)。
1H NMR(CDCl3,300MHz):δ8.92(s,1H),8.14(d,J＝4.2Hz,2H),8.10(s,2H),7.82(d,J＝4.2Hz,1H),7.35(d,J＝8.4Hz,2H),4.10-4.38(m,3H),2.91(t,J＝12.1Hz,2H),2.40(s,3H),2.17-2.22(m,2H),1.92-1.97(m,2H),1.47(s,9H).
将4-(4-(5-溴-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(0.24g，0.40mmol)、2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯酚(139mg，0.48mmol)、碳酸钠(127mg，1.20mmol)和PdCl2(PPh3)2(6mg，0.008mmol)溶解于1,4-二噁烷和水(2:1)的混合溶液中，并且在100℃下、在微波条件下加热20分钟。在反应完成后，在高压下除去溶剂，溶解于水中，并且用乙酸乙酯萃取。将残余物通过色谱法来纯化以得到4-(4-(5-(3,5-二氯-4-羟基苯酚)-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(123mg，45％)。
1H NMR(DMSO-d6,300MHz):δ8.92(s,1H),8.12(d,J＝4.2Hz,2H),8.10(d,J＝1.5Hz,2H),7.82(s,1H),7.42(s,2H),7.33(d,J＝8.0Hz,2H),4.21-4.37(m,1H),2.91(t,J＝12.5Hz,2H),2.12-2.22(m,2H),1.89-2.04(m,2H),1.47(s,9H),1.23-1.29(m,2H)。
将4-(4-(5-(3,5-二氯-4-羟基苯酚)-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(137mg，0.20mmol)溶解于四氢呋喃(2mL)和甲醇(1mL)中，向其中添加Cs2CO3(228mg，0.70mmol)，然后在室温下搅拌30分钟。在反应完成后，在减压下除去溶剂，溶解于水中，并且用乙酸乙酯萃取。将残余物通过色谱法来纯化以得到4-(4-(5-(3,5-二氯-4-羟基苯酚)-7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(45mg，42％)。
1H NMR(DMSO-d6,300MHz):δ12.09(br s,1H),8.65(s,2H),8.28(s,1H),7.42(s,2H),7.01(s,1H),4.22-4.38(m,1H),2.92(t,J＝12.5Hz,2H),2.12-2.23(m,2H),1.89-2.04(m,2H),1.48(s,9H),1.22-1.30(m,2H).
将4-(4-(5-(3,5-二氯-4-羟基苯酚)-7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(53mg，0.10mmol)溶解于二氯甲烷(3mL)中，向其中添加溶于1,4-二噁烷中的4M HCl(0.5mL，2.0mmol)，然后在室温下搅拌2小时。在减压下除去溶剂，并且将残余物通过色谱法来纯化以得到目标化合物(36mg，85％)。
1H NMR(DMSO-d6,300MHz):δ12.14(br s,1H),8.67(s,2H),8.01(s,1H),7.54(s,1H),7.03(s,2H),6.40(s,1H),4.32-4.40(m,1H),2.91(t,J＝12.5Hz,2H),2.19-2.23(m,2H),2.04(d,J＝12.5Hz,2H),1.46-1.58(m,2H).
<实施例16>N-(7-(4-甲氧基苄基)-4-(1-(哌啶-4-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)-4-(4-甲基哌嗪-1-基)苯甲酰胺
参考韩国专利No.10-1753654来制备实施例16的化合物。
<实施例17>4-(4-甲基哌嗪-1-基)-N-(4-(1-(哌啶-4-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯甲酰胺
参考韩国专利No.10-1753654来制备实施例17的化合物。
<实施例18>4-(4-(5-(4-(4-甲基哌嗪-1-基)苯甲酰氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯
参考韩国专利No.10-1753654来制备实施例18的化合物。
<实施例19>4-(4-甲基哌嗪-1-基)-N-(4-(4-(吡咯烷-1-基)哌啶-1-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯甲酰胺
参考韩国专利No.10-1753654来制备实施例19的化合物。
<实施例20>1-(5-(4-(4-甲基哌嗪-1-基)苯甲酰氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)哌啶-4-甲酰胺
参考韩国专利No.10-1753654来制备实施例20的化合物。
<实施例21>4-(4-甲基哌嗪-1-基)-N-(4-(3-脲基哌啶-1-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯甲酰胺
参考韩国专利No.10-1753654来制备实施例21的化合物。
<实施例22>4-氟-N-(5-(1-(哌啶-4-基)-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶-3-基)苯甲酰胺
A.4-(4-(6-氯-5-氰基吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯的制备
将溶于二噁烷(20mL)中的5-溴-2-氯烟腈(100mg，0.460mmol)、4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(174mg，0.460mmol)、K2CO3(191mg，1.380mmol)、PdCl2(dppf)(68mg，0.046mmol)和水(0.3mL，16.556mmol)的混合物用氩气处理，并且在密封管中在90℃下热处理8小时。将经热处理的溶液用盐水(100mL)稀释并且用乙酸乙酯(3×50mL)萃取。将有机层经无水Na2SO4干燥并且在真空中浓缩。将产物通过柱色谱法来纯化以得到4-(4-(6-氯-5-氰基吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(150mg，84％)。
B.4-(4-(3-氨基-1H-吡唑并[3,4-b]吡啶-5-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯的制备
将水合肼(98mg，1.934mmol)添加至溶于乙醇中的4-(4-(6-氯-5-氰基吡啶-3-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(150mg，0.387mmol)的搅拌溶液中。将反应混合物回流6小时、搅拌并且冷却，并且将所得固体过滤并且在真空中干燥以得到4-(4-(3-氨基-1H-吡唑并[3,4-b]吡啶-5-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(140mg，94％)。
C.4-(4-(3-(4-氟苯甲酰氨基)-1H-吡唑并[3,4-b]吡啶-5-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯的制备
将4-氟苯甲酰氯(44μl，0.365mmol)添加至溶于吡啶(10mL)中的4-(4-(3-氨基-1H-吡唑并[3,4-b]吡啶-5-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(140mg，0.365mmol)的溶液中。将反应混合物在室温下搅拌一天。将反应混合物浓缩并且通过柱色谱法来纯化以得到4-(4-(3-(4-氟苯甲酰氨基)-1H-吡唑并[3,4-b]吡啶-5-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(90mg，49％)。
D.4-氟-N-(5-(1-(哌啶-4-基)-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶-3-基)苯甲酰胺的制备
将溶于1,4-二噁烷(5mL)中的4.0M HCl的溶液添加至溶于乙酸乙酯(10mL)中的4-(4-(3-(4-氟苯甲酰氨基)-1H-吡唑并[3,4-b]吡啶-5-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(90mg，0.178mmol)的混合溶液中，然后搅拌12小时。将反应混合物浓缩以使体积最小，并且通过过滤器来收集残余物以得到目标化合物(70mg，89％)。
1H NMR(400MHz,DMSO-d6):δ11.08(s,1H),9.34(bs,1H),9.07(bs,1H),8.87-8.82(m,1H),8.41-8.31(m,2H),8.22-8.14(m,2H),8.01(s,1H),7.39(t,J＝8.85Hz,2H),4.58-4.46(m,1H),3.36(d,J＝12.21Hz,2H),3.07(q,J＝10.68Hz,2H),2.30-2.12(m,4H).
<实施例23>2,6-二氯-4-(4-((1s,4s)-4-羟基环己基氨基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯酚
将DMF(30mL)添加至4-氯-7H-吡咯并[2,3-d]嘧啶(2g，13.02mmol)中，在0℃下向其中添加NBS(2.52g，14.24mmol)。将混合物在室温下搅拌3小时。在反应完成后，在高压下除去溶剂，并且将所得物与水混合、过滤、用己烷洗涤并且干燥以得到5-溴-4-氯-7H-吡咯并[2,3-d]嘧啶(2.66g，88％)。
1H NMR(DMSO,300MHz):δ7.81(s,1H),8.76(s,1H),5.02(br s,1H).
将NaH(0.41g，10.3mmol)添加至溶于DMF(10mL)中的5-溴-4-氯-7H-吡咯并[2,3-d]嘧啶(1.2g，5.16mmol)中，然后在0℃下搅拌30分钟。将对甲苯磺酰氯(1.36g，7.16mmol)添加至混合物中，在室温下搅拌6小时。在反应完成后，将水添加至其中，然后搅拌10分钟。将所得物通过过滤来收集并且干燥以得到5-溴-4-氯-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶(1.79g，90％)。
1H NMR(CDCl3,300MHz):δ8.76(s,1H),8.09(d,2H,J＝8.1Hz),7.54(s,1H),7.34(d,2H,J＝8.1Hz),2.41(s,3H).
将n-BuOH(10mL)、反式-4-氨基环己烷-1-醇(223mg，1.94mmol)和DIPEA(2.58mmol)添加至5-溴-4-氯-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶(500mg，1.29mmol)中。将混合物在110℃下加热3小时。在高压下除去溶剂并且将残余物通过色谱法来纯化以得到(反式)-4-((5-溴-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)环己烷-1-醇(540mg，90％)。
1H NMR(CDCl3,300MHz):δ8.37(s,1H),8.06(d,2H,J＝8.3Hz),7.45(s,1H),7.31(d,2H,J＝8.2Hz),5.87(d,1H),4.12(m,1H),3.70(m,1H),2.40(s,3H),2.16(m,2H),2.03(m,2H),1.54(m,2H),1.31(m,2H).
将(反式)-4-((5-溴-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)环己烷-1-醇(200mg，0.43mmol)、2,6-二氯-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯酚(0.86mmol)、Na2CO3(0.86mmol)、二噁烷(4mL)和水(1mL)添加至微波瓶中。将溶剂脱气15分钟，向其中添加Pd(PPh3)2Cl2(10mol％)，然后在80℃下照射微波30分钟。将溶液用硅藻土层来过滤，并且将滤液用盐水(10mL×5)洗涤。将有机层通过色谱法(10％甲醇:二氯甲烷)来浓缩以得到(反式)-2,6-二氯-4-(4-((-4-羟基环己基)氨基)-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-5-基)苯酚(40％)。
1H NMR(CDCl3,300MHz):δ8.46(s,1H),8.11(d,2H,J＝8.36Hz),7.41(s,1H),7.36(s,2H),7.31(d,2H,J＝8.13Hz),6.03(m,1H),4.71(d,1H),4.09(m,1H),3.63(m,1H),2.41(s,3H),2.05(m,2H),1.89(m,2H),1.40(m,2H),1.10(m,2H).
将1M TBAF(在THF中)添加至中间体(反式)-2,6-二氯-4-(4-((-4-羟基环己基)氨基)-7-甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-5-基)苯酚中，然后在室温下搅拌20小时。将反应物在减压下浓缩并且通过色谱法(15％甲醇:二氯甲烷+0.1％氨水)来纯化以得到目标化合物(40％)。
1H NMR(DMSO-d6,300MHz):δ11.82(br s,1H),10.16(br s,1H),8.17(s,1H),7.42(s,2H),7.29(s,1H),5.27(d,1H),4.54(m,1H),4.01(m,1H),3.43(m,1H),1.95(m,2H),1.76(m,2H),1.40(m,2H),1.20(m,4H).
<实施例24>N-(4-(3,5-二氯-4-羟基苯基)-7H-吡咯并[2,3-d]嘧啶-5-基)-4-(4-甲基哌嗪-1-基)苯甲酰胺
参考韩国专利No.10-1753654来制备实施例24的化合物。
实施例1至24中制备的化合物的结构在下表1中示出。
【表1】
<实验例1>TrkA抑制活性的评价
使用MBL International的
TrkA激酶测定/抑制剂筛选试剂盒(CatNo.CY-1091)来评价化合物的TrkA抑制活性。根据由制造商提供的分析方法来进行试验。试验方法如下。
1.通过在ddH2O中稀释10×洗涤缓冲液来制备1×洗涤缓冲液。
2.通过将1.6mL蒸馏水添加至包含溶于NA2盐中并且冷冻干燥的ATP的管来制备20×ATP溶液(1.25mM)。
3.如下表中所示，使用20×ATP溶液来制备激酶反应缓冲液(ATP plus)。
【表2】
4.制备用于评价实施例化合物的活性的工作溶液混合物和适当浓度的实施例化合物的溶液，并且如下表中所示分配至96孔板中。
【表3】
5.在将溶液分配至96孔板中之后，将板在30℃下温育30分钟。
6.在将板在30℃下温育30分钟之后，将200μL 1×洗涤缓冲液添加至板的各孔中，然后洗涤。该过程重复5次。
7.在将板进行洗涤之后，将100μL缀合有HRP的检测抗体(PY-39)添加至板的各孔中，然后在室温下反应60分钟。
8.在反应完成后，将200μL 1×洗涤缓冲液添加至板的各孔中，然后洗涤。该过程重复5次。
9.在将板进行洗涤之后，将100μL含有显色底物和四甲基联苯胺(TMB)的底物试剂添加至板的各孔中，然后在室温下温育5-15分钟。
10.在反应完成后，将100μL终止溶液(1N H2SO4)添加至板的各孔中，然后在30分钟内测量OD450。
结果在表4中示出。
【表4】
-：NT(未测定)
<实验例2>对TrkB和TrkC的抑制活性的评价
使用DiscoverX的
eXpress TrkB或TrkC功能测定试剂盒(产品代码：93-0463E3和93-0464E3)来评价实施例化合物对TrkB和TrkC的抑制活性。根据由制造商提供的分析方法来进行试验。取决于细胞的情况，在2天或3天内如下进行试验。
第1天：细胞的接种
1.在开始实验之前，将储存在-80℃下的细胞铺板试剂(cell plating(CP)reagent)在37℃水浴中溶解。
2.当CP试剂溶解时，准备用于TrkB或TrkC的细胞瓶以待解冻。
3.将储存在液氮中的两个U2OS细胞瓶(TrkB试剂盒&TrkC试剂盒)解冻。
4.将500μL CP试剂添加至解冻的细胞瓶中，并且将细胞通过吹吸(pipetting)来充分混合并且转移至其中分配有11.5mL CP试剂的锥形管中。
5.将12mL细胞(在CP试剂中的1×106个细胞)接种在96孔经组织培养处理的板(tissue culture treated plate)上(100μL/孔)，然后在37℃、5％CO2湿润的培养箱中培养24小时或48小时。
第2天或第3天：测试物质的处理
1.根据实验设计将测试物质、激动剂和拮抗剂制备为储备溶液。
-测试物质：10mM在DMSO中的储备溶液
-拮抗剂(GNF-5837)：10mM在1.8674mL DMSO中的储备溶液
-激动剂：TrkB激动剂→BDNF，TrkC激动剂→NT-3
2.根据实验设计来制备浓度比最终筛选浓度浓22倍的测试物质和拮抗剂的10mM储备溶液。
3.将含有细胞的96孔培养板的各孔用5μL浓度比最终筛选浓度(#2)浓22倍的测试物质和拮抗剂的溶液来处理，然后在37℃下温育60分钟。
4.在温育期间，为了实验的目的，使用重构缓冲液来制备TrkB和TrkC的各激动剂的10μg/mL储备溶液，并且将板的各孔用5μL所制备的溶液来处理，然后在19-25℃下温育3小时。
5.在温育期间，制备检测试剂工作溶液(4.75ml细胞测定缓冲液(Cell assaybuffer)、1.25ml底物试剂1、0.25ml底物试剂2)。在温育完成后，将55μL工作溶液添加至板的各孔中。
7.将板在暗处在室温下温育60分钟，并且用发光酶标仪(luminescence platereader)测量吸光度。
结果在表5中示出。
【表5】
-：NT(未测定)
<实验例3>在术后疼痛模型中的药理活性的评价
使用体重约150g的Sprague-Dawley雄性大鼠(Orient bio.,韩国)。在维持12小时明暗循环的环境中饲养大鼠，每个覆盖有碎木屑作为垫料的透明塑料笼中4只。自由提供食物和水。为了验证实施例化合物的镇痛作用，将所有大鼠用从吸气室(induction chamber)以3:3的比例递送的O2和异氟烷麻醉并且进行手术。在手术期间，将经麻醉的大鼠置于37℃热板(warm plate)上以防止体温过低。将实验动物的后足的同侧足底(左侧)用10％聚维酮-碘溶液消毒，并且用#11手术刀切开至长度为1cm。从距离脚后跟的近端边缘0.5cm处开始、通过同侧足底一侧的皮肤和筋膜朝向脚趾切开切口。切开后，对切口部位施加适度的压力以止血并且将皮肤缝合。将手术部位用10％聚维酮-碘溶液灭菌，并且腹腔内注射给予庆大霉素(8mg/kg)以防止感染。在手术后2天在实验动物中评价化合物对术后疼痛的镇痛作用。通过Dixon's上-下法(Dixon's up-down method)(使用von-Frey纤维丝来测定机械触摸痛的方法)来进行评价，以计算例如Dixon建议的Chaplan等缩足阈值(withdrawthreshold)。用于计算50％缩足阈值(g)的算式如下。
[数学式1]
50％缩足阈值(g)＝(10(x+kd))/104
x＝最后测试的纤维丝的值(对数单位值)。
k＝表示通过上-下法获得的正/负响应的值。
d＝作为刺激之间的平均差的固定在0.224的值。
结果在表6和图1至10中示出。
表6示出术后疼痛动物模型中各化合物的ED50值与对照药物的ED50值的比较结果。
图1至6为示出实施例10、11、12、13、14和15的化合物在各术后疼痛动物模型中的最佳药物表达时间的图。
图7至10为示出在各术后疼痛动物模型中实施例10、13、14和15的化合物在最佳药物表达时间的浓度的疼痛抑制效果的图。
【表6】
<制造例1>药物制剂的制备
1-1.散剂的制备
由式1表示的化合物 500mg
乳糖 100mg
滑石 10mg
通过将所有上述组分混合来制备散剂，根据用于制备散剂的常规方法将所述组分填充在密封的包装中。
1-2.片剂的制备
通过借助用于制备片剂的常规方法将所有上述组分混合来制备片剂。
1-3.胶囊剂的制备
通过将所有上述组分混合来制备胶囊剂，根据用于制备胶囊剂的常规方法将所述组分填充在明胶胶囊中。
1-4.注射用溶液的制备
由式1表示的化合物 500mg
注射用无菌蒸馏水 适量
pH调节剂 适量
通过借助用于制备注射用溶液的常规方法将所有上述组分混合、将混合物置于2mL安瓿瓶中并且将其灭菌来制备注射用溶液。
1-5.液体制剂的制备
将所有上述组分溶解于纯化水中。在添加柠檬香料之后，通过添加纯化水将总体积调整为100mL。通过借助用于制备液体制剂的常规方法将混合物置于棕色瓶中并且将其灭菌来制备液体制剂。
产业上的可利用性
在本发明的一个方面提供的化合物具有优异的TrkA抑制活性并且在术后疼痛动物模型中显示优异的疼痛抑制效果，并且因此可以有效地用作镇痛剂。
Claims (5)
1.一种化合物或其药学上可接受的盐，其中所述化合物为选自由以下化合物组成的组中的任一种化合物：
(14)N-(5-溴-1H-吡唑并[3,4-b]吡啶-3-基)-4-(4-甲基哌嗪-1-基)苯甲酰胺；
(15)2,6-二氯-4-(4-(1-(哌啶-4-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯酚；
(22)4-氟-N-(5-(1-(哌啶-4-基)-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶-3-基)苯甲酰胺；和
(23)2,6-二氯-4-(4-((1s,4s)-4-羟基环己基氨基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯酚。
2.药物组合物在制备用于预防或治疗疼痛的药物中的用途，所述药物组合物包含化合物或其药学上可接受的盐作为活性成分，
其中所述化合物为选自由以下化合物组成的组中的任一种化合物：
(8)4-(4-甲基哌嗪-1-基)-N-(5-(1-(哌啶-4-基)-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶-3-基)苯甲酰胺；
(9)N-(5-(3-(3-异丙基脲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)-4-(4-甲基哌嗪-1-基)苯甲酰胺；
(10)4-(4-甲基哌嗪-1-基)-N-(5-苯基-1H-吡唑并[3,4-b]吡啶-3-基)苯甲酰胺；
(11)N-(5-(4-氟苯基)-1H-吡唑并[3,4-b]吡啶-3-基)-4-(4-甲基哌嗪-1-基)苯甲酰胺；
(12)4-(4-甲基哌嗪-1-基)-N-(5-(吡啶-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)苯甲酰胺；
(13)4-(4-甲基哌嗪-1-基)-N-(5-(吡啶-4-基)-1H-吡唑并[3,4-b]吡啶-3-基)苯甲酰胺；
(14)N-(5-溴-1H-吡唑并[3,4-b]吡啶-3-基)-4-(4-甲基哌嗪-1-基)苯甲酰胺；
(15)2,6-二氯-4-(4-(1-(哌啶-4-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯酚；
(22)4-氟-N-(5-(1-(哌啶-4-基)-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶-3-基)苯甲酰胺；和
(23)2,6-二氯-4-(4-((1s,4s)-4-羟基环己基氨基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯酚。
3.根据权利要求2所述的用途，其中所述化合物通过抑制原肌球蛋白受体激酶A来显示预防或治疗疼痛的活性。
4.镇痛组合物在制备用于治疗或缓解疼痛的药物中的用途，所述镇痛组合物包含化合物或其药学上可接受的盐作为活性成分，
其中所述化合物为选自由以下化合物组成的组中的任一种化合物：
(8)4-(4-甲基哌嗪-1-基)-N-(5-(1-(哌啶-4-基)-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶-3-基)苯甲酰胺；
(9)N-(5-(3-(3-异丙基脲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)-4-(4-甲基哌嗪-1-基)苯甲酰胺；
(10)4-(4-甲基哌嗪-1-基)-N-(5-苯基-1H-吡唑并[3,4-b]吡啶-3-基)苯甲酰胺；
(11)N-(5-(4-氟苯基)-1H-吡唑并[3,4-b]吡啶-3-基)-4-(4-甲基哌嗪-1-基)苯甲酰胺；
(12)4-(4-甲基哌嗪-1-基)-N-(5-(吡啶-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)苯甲酰胺；
(13)4-(4-甲基哌嗪-1-基)-N-(5-(吡啶-4-基)-1H-吡唑并[3,4-b]吡啶-3-基)苯甲酰胺；
(14)N-(5-溴-1H-吡唑并[3,4-b]吡啶-3-基)-4-(4-甲基哌嗪-1-基)苯甲酰胺；
(15)2,6-二氯-4-(4-(1-(哌啶-4-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯酚；
(22)4-氟-N-(5-(1-(哌啶-4-基)-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶-3-基)苯甲酰胺；和
(23)2,6-二氯-4-(4-((1s,4s)-4-羟基环己基氨基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯酚。
5.化合物或其药学上可接受的盐在制备用于预防或治疗疼痛的药物中的用途，
其中所述化合物为选自由以下化合物组成的组中的任一种化合物：
(8)4-(4-甲基哌嗪-1-基)-N-(5-(1-(哌啶-4-基)-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶-3-基)苯甲酰胺；
(9)N-(5-(3-(3-异丙基脲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)-4-(4-甲基哌嗪-1-基)苯甲酰胺；
(10)4-(4-甲基哌嗪-1-基)-N-(5-苯基-1H-吡唑并[3,4-b]吡啶-3-基)苯甲酰胺；
(11)N-(5-(4-氟苯基)-1H-吡唑并[3,4-b]吡啶-3-基)-4-(4-甲基哌嗪-1-基)苯甲酰胺；
(12)4-(4-甲基哌嗪-1-基)-N-(5-(吡啶-3-基)-1H-吡唑并[3,4-b]吡啶-3-基)苯甲酰胺；
(13)4-(4-甲基哌嗪-1-基)-N-(5-(吡啶-4-基)-1H-吡唑并[3,4-b]吡啶-3-基)苯甲酰胺；
(14)N-(5-溴-1H-吡唑并[3,4-b]吡啶-3-基)-4-(4-甲基哌嗪-1-基)苯甲酰胺；
(15)2,6-二氯-4-(4-(1-(哌啶-4-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯酚；
(22)4-氟-N-(5-(1-(哌啶-4-基)-1H-吡唑-4-基)-1H-吡唑并[3,4-b]吡啶-3-基)苯甲酰胺；和
(23)2,6-二氯-4-(4-((1s,4s)-4-羟基环己基氨基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯酚。
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| KR10-2018-0087092 | 2018-07-26 | ||
| PCT/KR2019/006648 WO2020022636A1 (ko) | 2018-07-26 | 2019-06-03 | TrkA 저해 활성을 갖는 화합물 및 이를 유효성분으로 함유하는 통증의 예방 또는 치료용 약학적 조성물 |
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080194557A1 (en) * | 2007-01-18 | 2008-08-14 | Joseph Barbosa | Methods and compositions for the treatment of pain, inflammation and cancer |
| WO2008112695A2 (en) * | 2007-03-12 | 2008-09-18 | Irm Llc | Pyrazolo [3,4-d] pyrimidines and 1, 2, 5, 6-tetraaza- as- indacenes as protein kinase inhibitors for cancer treatment |
| WO2012135631A1 (en) * | 2011-03-30 | 2012-10-04 | Arrien Pharmaeuticals Llc | Substituted 5-(pyrazin-2-yl)-1h-pyrazolo [3, 4-b] pyridine and pyrazolo [3, 4-b] pyridine derivatives as protein kinase inhibitors |
| CN102947305A (zh) * | 2010-04-21 | 2013-02-27 | 普莱希科公司 | 用于激酶调节的化合物和方法及其适应症 |
| CN104684554A (zh) * | 2012-07-27 | 2015-06-03 | 皮埃尔法布雷医药公司 | 用于治疗疼痛的氮杂吲唑或二氮杂吲唑型衍生物 |
| WO2015143652A1 (en) * | 2014-03-26 | 2015-10-01 | Merck Sharp & Dohme Corp. | TrkA KINASE INHIBITORS,COMPOSITIONS AND METHODS THEREOF |
| WO2015143653A1 (en) * | 2014-03-26 | 2015-10-01 | Merck Sharp & Dohme Corp. | TrkA KINASE INHIBITORS,COMPOSITIONS AND METHODS THEREOF |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050009876A1 (en) | 2000-07-31 | 2005-01-13 | Bhagwat Shripad S. | Indazole compounds, compositions thereof and methods of treatment therewith |
| JP2004509891A (ja) | 2000-09-22 | 2004-04-02 | スミスクライン ビーチャム パブリック リミテッド カンパニー | 抗糖尿病薬としてのピラゾロピリジンおよびピラゾロピリダジン |
| JP4787150B2 (ja) | 2003-03-06 | 2011-10-05 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Ｊｎｋ阻害剤 |
| US8993756B2 (en) * | 2011-12-06 | 2015-03-31 | Merck Sharp & Dohme Corp. | Pyrrolopyrimidines as janus kinase inhibitors |
| KR102412146B1 (ko) | 2015-02-11 | 2022-06-22 | 주식회사 아이엔테라퓨틱스 | 소디움 채널 차단제 |
| KR101753654B1 (ko) * | 2015-10-21 | 2017-07-05 | 한국화학연구원 | 3-(4-(피페라진-1-일)벤즈아미도)-1h-피라졸로피리딘 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 포함하는 melk 관련 질환의 예방 또는 치료용 약학적 조성물 |
| KR101753652B1 (ko) * | 2015-10-21 | 2017-07-05 | 한국화학연구원 | N-아릴-1h-피라졸로피리딘-3-아민 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 포함하는 melk 관련 질환의 예방 또는 치료용 약학적 조성물 |
| KR102507967B1 (ko) | 2016-09-09 | 2023-03-09 | 인사이트 코포레이션 | Hpk1 조절제로서의 피라졸로피리딘 유도체 및 암을 치료하기 위한 이의 용도 |
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2018
- 2018-07-26 KR KR1020180087092A patent/KR102129114B1/ko active IP Right Grant
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2019
- 2019-06-03 EP EP19840528.4A patent/EP3819298A4/en active Pending
- 2019-06-03 JP JP2021528310A patent/JP7132471B2/ja active Active
- 2019-06-03 WO PCT/KR2019/006648 patent/WO2020022636A1/ko unknown
- 2019-06-03 CN CN201980049772.5A patent/CN112533919B/zh active Active
- 2019-06-03 US US17/261,944 patent/US20210309665A1/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080194557A1 (en) * | 2007-01-18 | 2008-08-14 | Joseph Barbosa | Methods and compositions for the treatment of pain, inflammation and cancer |
| WO2008112695A2 (en) * | 2007-03-12 | 2008-09-18 | Irm Llc | Pyrazolo [3,4-d] pyrimidines and 1, 2, 5, 6-tetraaza- as- indacenes as protein kinase inhibitors for cancer treatment |
| CN102947305A (zh) * | 2010-04-21 | 2013-02-27 | 普莱希科公司 | 用于激酶调节的化合物和方法及其适应症 |
| WO2012135631A1 (en) * | 2011-03-30 | 2012-10-04 | Arrien Pharmaeuticals Llc | Substituted 5-(pyrazin-2-yl)-1h-pyrazolo [3, 4-b] pyridine and pyrazolo [3, 4-b] pyridine derivatives as protein kinase inhibitors |
| CN104684554A (zh) * | 2012-07-27 | 2015-06-03 | 皮埃尔法布雷医药公司 | 用于治疗疼痛的氮杂吲唑或二氮杂吲唑型衍生物 |
| WO2015143652A1 (en) * | 2014-03-26 | 2015-10-01 | Merck Sharp & Dohme Corp. | TrkA KINASE INHIBITORS,COMPOSITIONS AND METHODS THEREOF |
| WO2015143653A1 (en) * | 2014-03-26 | 2015-10-01 | Merck Sharp & Dohme Corp. | TrkA KINASE INHIBITORS,COMPOSITIONS AND METHODS THEREOF |
Also Published As
| Publication number | Publication date |
|---|---|
| JP7132471B2 (ja) | 2022-09-07 |
| KR102129114B1 (ko) | 2020-07-02 |
| WO2020022636A1 (ko) | 2020-01-30 |
| CN112533919A (zh) | 2021-03-19 |
| JP2021531350A (ja) | 2021-11-18 |
| US20210309665A1 (en) | 2021-10-07 |
| EP3819298A4 (en) | 2021-07-14 |
| KR20200012168A (ko) | 2020-02-05 |
| EP3819298A1 (en) | 2021-05-12 |
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