CN115784991A - N-(苯磺酰基)酰胺衍生物及其制备方法和用途 - Google Patents
N-(苯磺酰基)酰胺衍生物及其制备方法和用途 Download PDFInfo
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- CN115784991A CN115784991A CN202211469064.7A CN202211469064A CN115784991A CN 115784991 A CN115784991 A CN 115784991A CN 202211469064 A CN202211469064 A CN 202211469064A CN 115784991 A CN115784991 A CN 115784991A
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- trifluoromethyl
- pyrazol
- tolyl
- sulfonyl
- phenyl
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Abstract
本发明公开了一种N‑(苯磺酰基)酰胺衍生物及其制备方法和用途。具体地，本发明公开了一种式(I)所示的化合物或其互变异构体、同位素标记物、药学上可接受的盐以及其制备方法和用途。本发明化合物具有抑制COX‑2、TRPV1、5‑LOX多靶点的生物活性，能够有效地用于抗炎和镇痛。
Description
技术领域
本发明提供了一类N-(苯磺酰基)酰胺衍生物及其制备方法和用途，本发明化合物具有抑制环氧化酶-2(COX-2)、5-脂氧合酶(5-LOX)、TRPV1多靶点的生物活性，可以用作抗炎和/或镇痛药物。
背景技术
疼痛是一种临床最常见的症状，由于病理机制复杂，已经成为临床上急需满足的需求。目前临床上常用的镇痛药包括阿片类药物和非甾体抗炎药。非甾体抗炎药主要通过抑制花生四烯酸代谢通路中的环氧化酶(COX)来达到镇痛效果。除了COX之外，花生四烯酸代谢通路还涉及脂氧合酶(LOX)和细胞色素P450酶，上述关键酶及主要代谢产物均与炎症和疼痛的发展和消退有着密切的联系。在脂氧合酶家族中，与炎症和疼痛最密切相关的是5-脂氧合酶。研究表明，COX-2和5-LOX在氨基酸代谢过程中呈现代偿机制，抑制其中的一条通路反而会引起另一条通路的激活。因此，单纯抑制COX-2或者5-LOX的活性，无法达到非常好的治疗效果。另外，非甾体抗炎药的胃肠道副作用十分明显，这已经成为限制其临床使用的主要因素。因此，开发一种多通路抑制，高效低毒的抗炎和/或镇痛药物具有很高的临床价值。
随着相关学科的发展及新技术的应用，对各种与疼痛传导相关的受体及其选择性配体的研究取得了一定进展。随着瞬时受体电位香草酸亚型1(TRPV1，又称为香草酸受体或辣椒碱受体)的成功克隆，为治疗疼痛找到了新的作用靶点。TRPV1是瞬时受体电位的非选择性阳离子通道蛋白家族成员之一，主要表达在初级传入感觉神经元伤害性感受器上，在神经炎症应答的起始和疼痛的转导过程中起到十分关键的作用。目前，TRPV1已经成为重要的新型镇痛药物靶点，TRPV1拮抗剂能直接阻断受体，抑制疼痛信号从外周神经到中枢神经的传导，阻断与受体相关联的各种病理状态，起到镇痛效果。但是，目前研发的TRPV1拮抗剂(例如ABT-102、AMG 517)在临床试验中导致受试者的体温升高，这是非常致命的副作用。目前，尚未有成功上市的TRPV1拮抗剂。
为了解决现有技术中抗炎和/或镇痛药物所存在的缺陷，亟待提供一种抗炎和/或镇痛效果好、副作用小、生物利用度高的药物。
发明内容
为了克服现有技术的缺陷，一方面，本发明提供了一种式(I)所示的化合物
或其互变异构体、同位素富集物、药学上可接受的盐，其中R1如本文所定义。
另一方面，本发明提供了一种药物组合物，其包含治疗有效量的式(I)所示的化合物或其互变异构体、同位素标记物、药学上可接受的盐，以及药学上可接受的盐。
再一方面，本发明提供了式(I)所示化合物或其互变异构体、同位素富集物、药学上可接受的盐在制备用于预防和/或治疗炎症性疾病或者镇痛的药物中的用途。
有益效果：本发明化合物是一种能够抑制COX-2、5-LOX、TRPV1多靶点的N-(苯磺酰基)酰胺衍生物，具有显著优于现有技术药物的抗炎和镇痛活性，而且具有更强的水溶性和生物利用度，以及更低的副作用。
具体实施方式
定义
如在本说明书中所使用的，除非使用它们的上下文指示其它含义，否则下列词和短语通常旨在具有如下所阐述的含义。
如本文所使用的，术语“烷基”是指具有1至6个碳原子的直链或支链的饱和烃链的单价基团。该术语例示性地为基团如甲基、乙基、1-丙基(正丙基)、2-丙基(异丙基)、1-丁基(正丁基)、2-甲基-1-丙基(异丁基)、2-丁基(仲丁基)、2-甲基-2-丙基(叔丁基)、1-戊基(正戊基)、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、1-己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3-二甲基-2-丁基等。
如本文所使用的，术语“烯基”是指具有2至6个碳原子并具有碳-碳双键(例如1、2或3个碳-碳双键)的直链或支链的不饱和烃链单价基团。该术语例示性地为基团如乙烯基(即-CH＝CH2)、丙烯-1-基(即-CH＝CHCH3)、丙烯-3-基(或烯丙基，即-CH2CH＝CH2)、丙烯-2-基(即-C(CH3)＝CH2)、丁二烯基(包括1,2-丁二烯基和1,3-丁二烯基)等。
如本文中使用的，术语“炔基”是指具有2至6个碳原子并具有碳-碳三键(例如1、2或3个碳-碳三键)的直链或支链的不饱和烃链单价基团。该术语例示性地为基团如乙炔基(即-C≡CH)、炔丙基(即-CH2C≡CH)、丙炔基(即-C≡CCH3)等。
如本文所使用的，术语“卤素”是指氟、氯、溴和碘。
如本文所使用的，术语“烷氧基”是指“烷基-O-”基团，其中烷基如本文所定义。该术语例示性地为基团如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基等。
如本文所使用的，术语“卤代烷基”是指其中一个或多个氢原子被卤素取代的烷基，其中烷基如本文所定义。该术语例示性地为基团三氟甲基、二氟甲基、一氟甲基、2,2,2-三氟乙基、1,1,-二氟乙基等。
如本文所使用的，术语“环烷基”是指具有3至6个碳原子作为环原子的单基饱和基团。环烷基的实例包括环丙烷、环丁烷、环戊烷、环己烷。
如本文所使用的，术语“杂环基”是指具有在环内具有5至6个环原子的单环单基饱和基团，其中除了碳原子以外，所述环原子还包含至少一个以上选自氧、氮和/或硫的杂原子。杂环基基团的实例包括，但不限于四氢呋喃基、四氢吡咯基、四氢噻吩基、咪唑烷基、吡唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基、1,3-二氧杂环戊烷基、1,2-二氧杂环戊烷基、1,3-二硫杂环戊烷基、1,2-二硫杂环戊烷基、1,2-氧硫杂环戊烷基、1,3-氧硫杂环戊烷基、哌啶基、哌嗪基、四氢吡喃基、四氢噻喃基、二噁烷基、二噻喃基、氧硫杂环己烷基、吗啉基等。
如本文所使用的，术语“治疗有效量”是指当给予需要这种治疗的哺乳动物时，如下所限定的足以影响治疗的量。治疗有效量将随着被治疗的对象和疾病状况、受试者的重量和年龄、疾病状况的严重性、给药方式等而变化，其可以由本领域的普通技术人员容易地确定。
如本文所使用的，术语“互变异构体”指的是两种(或两种以上)化合物的共存，这些化合物之间的区别只在于一个(或一个以上)活动原子的位置和电子分布，例如酮-烯醇互变异构体。
如本文中使用的，术语“药学上可接受的盐”是指保留给定化合物的生物有效性和特性的盐，并且所述盐不是在生物学上或在其他方面不期望的。药学上可接受的盐可以是酸加成盐和/或碱加成盐。酸加成盐可以从无机酸和有机酸制得。从无机酸衍生的盐包括盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐、碳酸盐、硫酸氢盐、磷酸氢盐、磷酸二氢盐、碳酸氢盐等；从有机酸衍生的盐包括甲酸盐、乙酸盐、丙酸盐、乙醇酸盐、丙酮酸盐、草酸盐、苹果酸盐、丙二酸盐、琥珀酸盐、马来酸盐、富马酸盐、酒石酸盐、柠檬酸盐、苯甲酸盐、肉桂酸盐、扁桃酸盐、甲磺酸盐、乙磺酸盐、对甲苯磺酸盐、水杨酸盐、乳酸盐、烟酸盐、月桂基硫酸盐、萘磺酸盐、樟脑磺酸盐、葡糖酸盐、葡萄糖醛酸盐、油酸盐、棕榈酸盐、硬脂酸盐、双羟萘酸盐、三氟乙酸盐等。碱加成盐可以与无机碱或有机碱形成。从无机碱衍生的盐包括钠、钾、铵、钙、镁、铁、锌、铜、锂、钡、铝盐等；从有机碱衍生的盐包括与各种伯胺、仲胺、叔胺形成的盐，例如乙胺、二乙胺、正丙胺、异丙胺、二乙醇胺、葡甲胺、赖氨酸、哌嗪、哌啶、吗啉、氨丁三醇、胆碱等盐。
如本文所使用的，术语“药学上可接受的”表示该物质或组合物与包含制剂和/或用其处理的哺乳动物的其他成分必须化学和/或毒理学上兼容。
本文中给出的任何通式或结构，包括通式I或本文公开的任何通式，还旨在表示化合物的未标记形式以及同位素标记形式。这些同位素标记形式的化合物也可以称为“同位素标记物”或者“同位素富集类似物”。同位素标记的化合物具有本文所描绘的结构，不同之处在于一个或多个原子被具有选定原子质量或质量数的原子代替。可以掺入到本发明化合物中的同位素的实例包括氢、碳、氮、氧、磷、氟、氯和碘的同位素，例如但不限于2H(氘，D)、3H(氚)、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、36Cl、123I和125I。本发明的各种同位素标记的化合物，例如其中掺入了放射性同位素(例如3H、13C和14C)的那些。通过所属领域中熟知的手段，例如通过采用一个或多个氢已经被氘置换的起始材料来合成这类化合物。
化合物
在一个实施方案中，本发明提供式(I)所示的化合物
或其互变异构体、同位素标记物、药学上可接受的盐，其中
R1选自
其中：
R2选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、卤素、C1-C6卤代烷基、C1-C6卤代烷氧基、C1-C6烷酰氧基、C1-C6烷酰胺基、羟基、氨基、氰基、硝基、羧基；
R3选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、C1-C6烷酰氧基、C1-C6烷酰胺基、羟基、氨基、氰基、羧基；
R4选自氢或C1-C6烷基；
R5选自C3-C6环烷基或5-6元杂环基；
m选自1至5的整数；
n选自0至5的整数。
在一个实施方案中，在本发明式(I)所示的化合物或其互变异构体、同位素标记物、药学上可接受的盐中，
R1选自
其中：
R2选自氢、C1-C6烷基、C1-C6烷氧基、卤素、C1-C6卤代烷基、C1-C6卤代烷氧基、羟基、氨基、氰基、硝基、羧基。
在一个实施方案中，在本发明式(I)所示的化合物或其互变异构体、同位素标记物、药学上可接受的盐中，R1选自
其中：
R3选自氢、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、羟基、氨基、氰基、羧基；
R4选自氢或C1-C6烷基；
m选自1至3的整数。
在一个实施方案中，在本发明式(I)所示的化合物或其互变异构体、同位素标记物、药学上可接受的盐中，R1选自
其中：
R5选自环丙烷基、环丁烷基、环戊烷基、环己烷基、四氢呋喃基、四氢吡咯基、四氢噻吩基、咪唑烷基、吡唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基、1,3-二氧杂环戊烷基、1,2-二氧杂环戊烷基、1,3-二硫杂环戊烷基、1,2-二硫杂环戊烷基、1,2-氧硫杂环戊烷基、1,3-氧硫杂环戊烷基、哌啶基、哌嗪基、四氢吡喃基、四氢噻喃基、二噁烷基、二噻喃基、氧硫杂环己烷基、吗啉基；
n选自1至3的整数。
在一个具体的实施方案中，本发明的式(I)所示的化合物选自：
(E)-3-(4-羟基-3-甲氧基苯基)-N-((4-(5-(对甲苯基)-3-(三氟甲基)-1H-吡唑-1-基)苯基)磺酰基)丙烯酰胺；
2-(4-异丁基苯基)-N-((4-(5-(对甲苯基)-3-(三氟甲基)-1H-吡唑-1-基)苯基)磺酰基)丙酰胺；
5-(1,2-二硫杂环戊烷-3-基)-N-((4-(5-(对甲苯基)-3-(三氟甲基)-1H-吡唑-1-基)苯基)磺酰基)戊酰胺；
4-羟基-3-甲氧基-N-((4-(5-(对甲苯基)-3-(三氟甲基)-1H-吡唑-1-基)苯基)磺酰基)苯甲酰胺；
或其互变异构体、同位素标记物、药学上可接受的盐。
在一个具体的实施方案中，本发明的化合物选自：
苯甲酰基((4-(5-(对甲苯基)-3-(三氟甲基)-1H-吡唑-1-基)苯基)磺酰基)氨基钠；
(E)(-3-(4-羟基-3-甲氧基苯基)丙烯酰基)((4-(5-(对甲苯基)-3-(三氟甲基)-1H-吡唑-1-基)苯基)磺酰基)氨基钠；
(2-(4-异丁基苯基)丙酰基)((4-(5-(对甲苯基)-3-(三氟甲基)-1H-吡唑-1-基)苯基)磺酰基)氨基钠；
(5-(1,2-二硫杂环戊烷-3-基)戊酰基)((4-(5-(对甲苯基)-3-(三氟甲基)-1H-吡唑-1-基)苯基)磺酰基)氨基钠；
(4-羟基-3-甲氧基苯甲酰基)((4-(5-(对甲苯基)-3-(三氟甲基)-1H-吡唑-1-基)苯基)磺酰基)氨基钠；
(乙氧基羰基)((4-(5-(对甲苯基)-3-(三氟甲基)-1H-吡唑-1-基)苯基)磺酰基)氨基钠。
药物组合物和给药
本发明提供的药物组合物包含本发明的化合物或其立体异构体、互变异构体、溶剂化物、前药、同位素标记物、药学上可接受的盐，和至少一种药学上可接受的载体。药学上可接受的载体是本领域技术人员已知的，包括稀释剂、润滑剂、崩解剂、粘合剂、缓冲剂、防腐剂、稳定剂、润湿剂、助流剂、乳化剂、着色剂、调味剂、甜味剂等。根据药物的给药途径的不同，例如口服给药、胃肠外给药和直肠给药等，本发明的药物组合物可以以固体形式(包括但不限于片剂、胶囊剂、丸剂、颗粒剂、散剂、粉剂、栓剂)或者液体形式(包括但不限于溶液剂、混悬剂、乳剂、酊剂、糖浆剂)制成。当本发明的药物组合物为固体形式时，药学上可接受的载体通常包括以下中的一种或多种：a)稀释剂，例如乳糖、葡萄糖、蔗糖、甘露糖醇、山梨糖醇、纤维素等；b)润滑剂，例如二氧化硅、滑石、硬脂酸、聚乙二醇等；c)粘合剂，例如硅铝酸镁、胶化淀粉、明胶、黄芪胶、甲基纤维素、羧甲基纤维素钠、微晶纤维素、聚乙烯吡咯烷酮等；d)崩解剂，例如淀粉、海藻酸、琼脂、玉米淀粉；e)稳定剂，例如抗氧化剂如抗坏血酸；f)助流剂，例如二氧化硅；g)调味剂，例如薄荷、水杨酸甲酯；甜味剂，例如蔗糖、糖精。当本发明的药物组合物为液体形式时，药学上可接受的载体通常包括以下中的一种或多种：a)稀释剂，例如注射用水、生理盐水、林格氏溶液、聚乙二醇、甘油、丙二醇等；b)抗氧化剂，例如抗坏血酸或亚硫酸氢钠；c)缓冲剂，例如乙酸盐、磷酸盐等。
本发明化合物的有效剂量至少取决于所治疗病症的性质、程度、递送方法和药物剂型，并且将由临床医师最终确定。可以预期每天每千克体重约0.0001至约100mg；通常为每天每千克体重约0.01至约10mg；更典型地，每天每千克体重约0.01至约5mg；最典型的是每天每千克体重约0.05至约0.5mg。例如，约70kg体重的成年人的每日候选剂量将在1mg至1000mg的范围内，优选在5mg至500mg的范围内，并且可以采取单剂量或多剂量的形式给药。
适应症
本发明化合物具有显著的抗炎活性，可用于治疗或预防炎症相关疾病，包括类风湿性关节炎、痛风性关节炎、骨关节炎、脊柱炎、全身性红斑狼疮、牛皮癣、湿疹、皮下炎、产后炎症、肠炎、胃炎、炎症性头痛、动脉外膜炎、中风、缺血、精神创伤、变应性鼻炎、冠状动脉斑块炎症、细菌引起的炎症、病毒引起的炎症、手术引起的炎症、外伤导致的炎症或胃溃疡等。
本发明化合物具有显著的镇痛活性，可用于治疗或预防各种病因的疼痛疾病，包括但不限于各种急性疼痛和/或慢性疼痛，例如头痛、牙痛、偏头痛、内脏疼痛、神经痛等。
通用合成方法
本发明的化合物可以使用本文中公开的方法及其修改途径以及本领域中熟知的方法制备。根据本发明的化合物的典型实施方式可以使用以下的通用反应流程来合成。从本文中的描述显而易见的是，通过使用具有类似结构的其它材料代替反应原料可以获得相应不同的产物。反应原料典型地由商业来源获得或者使用公开的方法合成。
反应流程
具体的反应过程是：
步骤1：将化合物I-a溶解于合适的溶剂中，例如甲醇/水中，然后加入碱(例如氢氧化钠)，升温至60℃反应20小时，得到化合物I-b白色固体。
步骤2：将化合物I-b溶于合适的溶剂中，例如二氯甲烷、乙酸乙酯、氯仿等中，室温下依次加入塞来昔布(I-c)、缩合剂(例如DCC/DMAP等)，在氮气保护下，于35℃反应20小时，得到化合物I。
任选地，步骤3：将化合物I溶于合适的溶剂中(包括但不限于甲醇、乙醇、已经、DMF等)，加入碱(例如氢氧化钠、氢氧化钾、碳酸钠、碳酸钾等)，在0℃至室温下反应0.5小时，过滤得化合物I’。
| 缩写 | 名称 |
| DCC | 二环己基碳二亚胺 |
| DCM | 二氯甲烷 |
| DMAP | 4-二甲基氨基吡啶 |
| EA | 乙酸乙酯 |
| g | 克 |
| MeCN | 乙腈 |
| mg | 毫克 |
| mL | 毫升 |
| mmol | 毫摩尔 |
| PE | 石油醚 |
| TLC | 薄层层析 |
实施例1化合物苯甲酰基((4-(5-(对甲苯基)-3-(三氟甲基)-1H-吡唑-1-基)苯基)磺酰基)氨基钠(HY-1)的合成
步骤1：化合物1的合成
将塞来昔布(2.29g,6.00mmol)溶于DCM(50mL)，室温下加入苯甲酸(732mg,6.00mmol)，DCC(1.85g,9.00mmol)和DMAP(732mg,6.00mmol)。氮气保护下，室温反应2小时，TLC显示反应完成。反应液用1N盐酸溶液(20mL×3)洗涤三次，无水硫酸钠干燥，过滤、浓缩柱层析纯化(SiO2,PE:EA＝5:1)得到粗品1.00g。再次通过制备板纯化(SiO2,DCM:MeOH＝20:1)得到白色固体状目标化合物1(550mg，收率19.0％)。
步骤2：化合物HY-1的合成
将化合物1(550mg,1.13mmol)溶于乙醇(5mL)，0℃下滴加氢氧化钠(45mg,1.13mmol)的乙醇溶液(5mL)，加毕后保温反应0.5小时，过滤、滤饼用***(5mL×1)洗涤，真空干燥滤饼得到黄色固体状目标化合物HY-1(350mg，收率61.0％)。1H NMR(400MHz,DMSO-d6)ppm 7.87-7.92(m,4H),7.30-7.40(m,5H),7.18-7.23(m,4H),7.15(s,1H),2.31(s,3H)。
实施例2化合物(E)(-3-(4-羟基-3-甲氧基苯基)丙烯酰基)((4-(5-(对甲苯基)-3-(三氟甲基)-1H-吡唑-1-基)苯基)磺酰基)氨基钠(HY-3)的合成
参考实施例1的合成方法，用阿魏酸替换苯甲酸，制得黄色固体状化合物HY-3(375mg，收率64.7％)。1H NMR(400MHz,DMSO-d6)δppm 7.82(d,J＝8.4Hz,2H),7.33(d,J＝8.8Hz,2H),7.18-7.23(m,4H),7.09-7.15(m,2H),6.92(s,1H),6.76(d,J＝8.4Hz,1H),6.45(d,J＝8.0Hz,1H),6.02(d,J＝15.6Hz,1H),3.73(s,3H),2.31(s,1H)。
实施例3化合物(2-(4-异丁基苯基)丙酰基)((4-(5-(对甲苯基)-3-(三氟甲基)-1H-吡唑-1-基)苯基)磺酰基)氨基钠(HY-4)的合成
参考实施例1的合成方法，用布洛芬替换苯甲酸，制得白色固体状化合物HY-4(365mg，收率70.3％)。1H NMR(400MHz,DMSO-d6)δ(ppm):7.65(d,J＝8.28Hz,2H),7.26(d,J＝8.53Hz,2H),7.13-7.22(m,5H),7.06(d,J＝7.78Hz,2H),6.95(d,J＝8.03Hz,2H),3.27-3.33(m,1H),2.36(d,J＝7.03Hz,2H),2.32(s,3H),1.71-1.81(m,1H),1.16(d,J＝7.03Hz,3H),0.84(d,J＝6.53Hz,6H).
实施例4化合物(5-(1,2-二硫杂环戊烷-3-基)戊酰基)((4-(5-(对甲苯基)-3-(三氟甲基)-1H-吡唑-1-基)苯基)磺酰基)氨基钠(HY-5)的合成
参考实施例1的合成方法，用α-硫辛酸替换苯甲酸，制得黄色固体状化合物HY-5(451mg,收率51.0％)。1H-NMR(DMSO-d6,400MHz)δ(ppm):7.77(d,J＝8.4Hz,2H),7.32(d,J＝8.4Hz,2H),7.22-7.17(m,4H),7.15(s,1H),3.59-3.52(m,1H),3.20-3.06(m,2H),2.42-2.34(m,1H),2.32(s,3H),1.92(t,J＝7.2Hz,2H),1.86-1.78(m,1H),1.67-1.47(m,2H),1.44-1.37(m,2H),1.30-1.22(m,2H).
实施例5化合物(4-羟基-3-甲氧基苯甲酰基)((4-(5-(对甲苯基)-3-(三氟甲基)-1H-吡唑-1-基)苯基)磺酰基)氨基钠(HY-6)的合成
参考实施例1的合成方法，用香草酸替换苯甲酸，制得白色固体状化合物HY-6(323mg,收率99.3％)。1H NMR(400MHz,DMSO-d6)δ(ppm):7.86-7.83(m,2H),7.32-7.29(m,2H),7.26-7.23(m,1H),7.22-7.17(m,5H),7.23(s,1H),6.03(d,J＝8.4Hz,1H),3.62(s,3H),2.30(s,3H).
实施例6化合物(乙氧基羰基)((4-(5-(对甲苯基)-3-(三氟甲基)-1H-吡唑-1-基)苯基)磺酰基)氨基钠(HY-7)的合成
参考实施例1的合成方法，用碳酸氢乙酯替换苯甲酸，制得白色固体状化合物HY-7(0.44g,收率79.5％)。1H NMR(400MHz,DMSO-d6)δ(ppm):7.15(d,J＝8.4Hz,2H),7.33(d,J＝8.4Hz,2H),7.21-7.17(m,4H),7.14(s,1H),3.74-3.68(q,J＝7.2Hz,2H),2.30(s,3H),1.01(t,J＝7.2Hz,3H).
(四)生物活性测试
1.本发明化合物对TRPV1、COX-2、5-LOX的抑制活性
为了验证化合物对TRPV1、COX-2、5-LOX的抑制作用，以塞来昔布、5-LOX抑制剂齐留通和TRPV1抑制剂N-(4-叔丁基苯基)-4-(3-氯吡啶-2-基)哌嗪-1-甲酰胺(BCTC)为阳性对照药物，对最终化合物HY-1-7对TRPV1、COX-2和5-LOX的抑制活性进行测试和分析。
1.1TRPV1体外抑制试验
用添加5mM乙二胺四乙酸的Ca2+和Mg2+游离磷酸缓冲盐水的培养基培养TRPV1水母发光蛋白细胞(Perkin Elmer，Waltham，MA，美国)。1000g时细胞球团化2min；重悬于含有15mM HEPES(pH＝7.0)和0.1％BSA(测定缓冲液)的Dulbecco’s最小基本培养基F12(密度为3*105细胞/mL)，在5mM腔肠素存在下(Promega,麦迪逊，威斯康星州，美国)避光孵育4小时。上样后，用测定缓冲液稀释细胞至浓度为5*106细胞/mL。分别在384孔板上注射不同浓度(0.001,0.005,0.01,0.05,0.1,0.5,1,5μM)20uL的样品溶液，在空白对照孔中加入测定缓冲液作为参考，样品溶液和细胞温育2.5min，然后加入激动剂辣椒素(Tocris，英国)和盐酸溶液(pH＝5)，立即检测，在可变时间记录光发射。然后计算IC50。
1.2COX-2体外抑制试验
设置空白对照孔、100％酶活性对照孔、阳性对照药物(塞来昔布)对照孔和待测化合物样品孔，每个待测化合物样品设置两个平行孔。37℃孵育10分钟后检测荧光强度，激发波长为560nm，发射波长为590nm。具体操作按照COX-2抑制剂筛选试剂盒(中国博奥特生物科技有限公司)说明书进行。通过测定不同浓度(0.001,0.005,0.01,0.05,0.1,0.5,1,5μM))化合物溶液的相对荧光值(RFU)，研究药物/化合物对COX-2酶活性的抑制作用。
抑制活性计算:
抑制率(％)＝(RFU 100％酶活性-RFU样品)/(RFU 100％酶活性-RFU空白对照)×100％
1.3 5-LOX体外抑制试验
设置空白对照孔、100％酶活性对照孔、阳性对照药物(齐留通)对照孔、塞来昔布和待测化合物样品孔，每个待测化合物样品设置两个平行孔。37℃孵育10min后，每孔分别加入10μL3,3',5,5'-四甲基联苯胺(TMB)和10μL花生四希酸(AA)激活反应，继续37℃孵育15min后，用酶标仪在450nm处检测荧光强度。通过测定不同浓度(0.001,0.005,0.01,0.05,0.1,0.5,1,5μM))化合物溶液的光密度(OD)，研究药物/化合物对5-LOX酶活性的抑制作用。
抑制活性计算:
抑制率(％)＝(OD 100％酶活性-OD样品)/(OD 100％酶活性-OD空白对照)×100％
表1本发明化合物对TRPV1、COX-2、5-LOX的抑制活性
通过上述实验结果可知，本发明化合物具有同时抑制COX-2和5-LOX双靶点的生物活性。特别地，本发明的化合物HY-3、HY-4、HY-6具有同时抑制TRPV1、COX-2和5-LOX多靶点的生物活性。
2.本发明化合物的镇痛活性
***致痛实验能较好的模拟临床慢性疼痛，是一种重要的慢性疼痛模型。小鼠***致痛实验可分为两个时相，分别是注射***后0-5min内(第I时相或I相时间)和15-30min(第II时相或II相时间)，这两个时相引起的疼痛机制不同。第Ⅰ时相，是刺激伤害性感受器引起的直接效应，能被中枢性镇痛药如***抑制。第Ⅱ时相，是由***素介导的炎症反应，能被非类固醇类抗炎剂、类固醇和中枢性镇痛药抑制。
2.1试剂和仪器
***(西陇科学股份有限公司，批号：190603 2)，电子天平(赛多利斯科学仪器有限公司，型号：京制00000246)，1mL注射器(曙光健士，批号：210617)，微量注射针头，灌胃针。
2.2实验动物及分组
雄性ICR小鼠40只，安徽医科大学提供(批号：No.SCXK 2017-001)，40只雄性ICR小鼠按体重随机分为4组，分别为模型对照组、阳性对照塞来昔布20mg/kg剂量组、化合物HY-320mg/kg剂量组、HY-6 20mg/kg剂量组，均灌胃给药，给药一次。
2.3实验方法
实验前12h小鼠禁食不禁水，正式试验时各组小鼠依次给药，给药后30min自小鼠右后爪足背皮下注射2％***0.05ml，放入玻璃罩内观察并记录0～5min内小鼠舔舐注射脚掌总时间和15～30min内小鼠舔舐注射脚掌总时间。
2.4实验结果
表2本发明化合物HY-3和HY-6的镇痛实验数据
ap<0.05，aap<0.01vs模型bp<0.05，bbp<0.01vs阳性对照
根据上表可知，与模型对照组相比，本发明化合物HY-3、HY-6均能显著性地降低Ⅱ相疼痛时间(P<0.01)和Ⅰ相疼痛时间(P<0.05)。特别地，与阳性对照药塞来昔布相比，本发明化合物HY-6降低Ⅱ相疼痛时间的效果明显更佳(P<0.01)。
3.本发明化合物的生物利用度研究
雄性SD大鼠16只，上海西普尔-必凯实验动物有限公司提供(批号：SCXK2019-0004)。16只雄性SD大鼠随机分成2组，每组8只，禁食12h但可自由饮水，单剂量静脉注射HY-6(1mg/kg)5、10、15、30、45、60、90、120、240和360min后，以及单剂量灌胃HY-6(10mg/kg)10、20、30、45、60、90、120、240、360、720min后，分别眼底静脉丛连续取血200μL于肝素处理的试管中，8000rpm离心5min后取50μl体积的血浆用于LC-MS/MS分析。将所得的血药浓度-时间数据，使用Phoenix WinNonlin 6.3软件计算药代动力学参数(使用非房室模型)。
表3本发明化合物HY-6的药代动力学参数
结果显示，化合物HY-6的口服生物利用度高达96.8％，显著优于阳性对照塞来昔布(文献报道其口服生物利用度在22-40％之间)。[Abdul Rasool BK,Khalifa A,Abu-Gharbieh E,R.,K.Employment of Alginate Floating In Situ Gel for ControlledDelivery of Celecoxib:Solubilization and Formulation Studies.Biomed ResInt.2020,1879125]。
Claims (10)
1.式(I)所示的化合物
或其互变异构体、同位素标记物、药学上可接受的盐，其中
R1选自
其中：
R2选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、卤素、C1-C6卤代烷基、C1-C6卤代烷氧基、C1-C6烷酰氧基、C1-C6烷酰胺基、羟基、氨基、氰基、硝基、羧基；
R3选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、C1-C6烷酰氧基、C1-C6烷酰胺基、羟基、氨基、氰基、羧基；
R4选自氢或C1-C6烷基；
R5选自C3-C6环烷基或5-6元杂环基；
m选自1至5的整数；
n选自0至5的整数。
2.根据权利要求1所示的化合物或其互变异构体、同位素标记物、药学上可接受的盐，其中
R1选自
其中：
R2选自氢、C1-C6烷基、C1-C6烷氧基、卤素、C1-C6卤代烷基、C1-C6卤代烷氧基、羟基、氨基、氰基、硝基、羧基。
3.根据权利要求1所述的化合物或其互变异构体、同位素标记物、药学上可接受的盐，其中
R1选自
其中：
R3选自氢、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、羟基、氨基、氰基、羧基；
R4选自氢或C1-C6烷基；
m选自1至3的整数。
4.根据权利要求1所述的化合物或其或其互变异构体、同位素标记物、药学上可接受的盐，其中
R1选自
其中：
R5选自环丙烷基、环丁烷基、环戊烷基、环己烷基、四氢呋喃基、四氢吡咯基、四氢噻吩基、咪唑烷基、吡唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基、1,3-二氧杂环戊烷基、1,2-二氧杂环戊烷基、1,3-二硫杂环戊烷基、1,2-二硫杂环戊烷基、1,2-氧硫杂环戊烷基、1,3-氧硫杂环戊烷基、哌啶基、哌嗪基、四氢吡喃基、四氢噻喃基、二噁烷基、二噻喃基、氧硫杂环己烷基、吗啉基；
n选自1至3的整数。
5.根据权利要求1所述的化合物，选自：
(E)-3-(4-羟基-3-甲氧基苯基)-N-((4-(5-(对甲苯基)-3-(三氟甲基)-1H-吡唑-1-基)苯基)磺酰基)丙烯酰胺；
2-(4-异丁基苯基)-N-((4-(5-(对甲苯基)-3-(三氟甲基)-1H-吡唑-1-基)苯基)磺酰基)丙酰胺；
5-(1,2-二硫杂环戊烷-3-基)-N-((4-(5-(对甲苯基)-3-(三氟甲基)-1H-吡唑-1-基)苯基)磺酰基)戊酰胺；
4-羟基-3-甲氧基-N-((4-(5-(对甲苯基)-3-(三氟甲基)-1H-吡唑-1-基)苯基)磺酰基)苯甲酰胺；
或其互变异构体、同位素标记物、药学上可接受的盐。
6.化合物，选自：
(E)(-3-(4-羟基-3-甲氧基苯基)丙烯酰基)((4-(5-(对甲苯基)-3-(三氟甲基)-1H-吡唑-1-基)苯基)磺酰基)氨基钠；
(2-(4-异丁基苯基)丙酰基)((4-(5-(对甲苯基)-3-(三氟甲基)-1H-吡唑-1-基)苯基)磺酰基)氨基钠；
(5-(1,2-二硫杂环戊烷-3-基)戊酰基)((4-(5-(对甲苯基)-3-(三氟甲基)-1H-吡唑-1-基)苯基)磺酰基)氨基钠；
(4-羟基-3-甲氧基苯甲酰基)((4-(5-(对甲苯基)-3-(三氟甲基)-1H-吡唑-1-基)苯基)磺酰基)氨基钠；
(乙氧基羰基)((4-(5-(对甲苯基)-3-(三氟甲基)-1H-吡唑-1-基)苯基)磺酰基)氨基钠。
7.一种药物组合物，其包含治疗有效量的根据权利要求1至6中任一项所述的化合物或其互变异构体、同位素富集物、药学上可接受的盐，以及药学上可接受的载体。
8.根据权利要求1-6中任一项所述的化合物或者根据权利要求7所述的药物组合物在制备用于预防和/或治疗炎症性疾病的药物中的用途。
9.根据权利要求8所述的用途，其中所述炎症性疾病包括类风湿性关节炎、痛风性关节炎、骨关节炎、脊柱炎、全身性红斑狼疮、牛皮癣、湿疹、皮下炎、产后炎症、肠炎、胃炎、炎症性头痛、动脉外膜炎、中风、缺血、精神创伤、变应性鼻炎、冠状动脉斑块炎症、细菌引起的炎症、病毒引起的炎症、手术引起的炎症、外伤导致的炎症或胃溃疡。
10.根据权利要求1-6中任一项所述的化合物或者根据权利要求7所述的药物组合物在制备用于镇痛的药物中的用途。
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