CN101164538B - 羧胺三唑类化合物及其盐在制备治疗疼痛性疾病和/或炎症性疾病的药物中的应用 - Google Patents
羧胺三唑类化合物及其盐在制备治疗疼痛性疾病和/或炎症性疾病的药物中的应用 Download PDFInfo
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Abstract
本发明涉及羧胺三唑或其可药用的盐，类似物或衍生物及其可药用的盐的医药新用途，具体地，本发明涉及羧胺三唑或其可药用的盐，类似物或衍生物及其可药用的盐在制备治疗疼痛性疾病和/或炎症性疾病的药物中的应用。
Description
技术领域
本发明涉及羧胺三唑(carboxyamidotriazole，CAI)或其可药用的盐、类似物或衍生物的医药新用途，特别是在制备治疗疼痛性疾病和/或炎症性疾病的药物中的应用。
背景技术
本领域技术人员知道，晚期肿瘤患者往往伴有严重的疼痛，如果能找到一种药物，其既具有抗肿瘤作用，同时又具有镇痛和抗炎作用，这就会使得该药物的抗肿瘤的临床使用范围和疗效大大增加，而且还可能阐明癌症与炎症这两者病理变化之间的关系及其机理，就有可能发展以抗炎为突破口的抗癌药物。
羧胺三唑是一种新型的抗肿瘤药物，化学名为5-胺基-1-[3，5二氯-4(4-氯苯甲酰氯)苄基]-1H-1，2，3-三唑-4-苯甲酰胺，化学结构式为：
E.C.Kohn等在欧洲专利EP0644880(1995)中介绍了本化合物的抗肿瘤作用。然而，直到目前没有关于该化合物在具有抗炎和镇痛作用方面的报道。
本发明人经过长期和深入的研究，意外地发现迄今为止被认为是抗癌药物的羧胺三唑不仅具有抗癌作用，而且具有镇痛和抗炎作用。
发明内容
本发明的第一组目的在于提供羧胺三唑类化合物的医药新用途。
具体目的之一是羧胺三唑在制备镇痛和/或抗炎药物中的应用。
具体目的之二在于提供羧胺三唑可药用的盐在制备镇痛和/或抗炎药物中的应用。
具体目的之三在于提供羧胺三唑类似物或衍生物及其可药用盐在制备镇痛和/或抗炎药物中的应用。
本发明中，羧胺三唑类化合物包括：
(1)具有式一结构的化合物：
式一
其中，R1具有式二结构：
式二
这里，p为0到2的整数；m是0到4的整数；n为0到5的整数；X可以是O，S，SO，SO2，CO，CHCN，CH2或C＝NR6
其中R6可以是氢，(C1—C6)链烷基，羟基，(C1—C6)链烷氧基，氨基，(C1—C6)链烷氨基，二烷氨基或氰基；
R4和R5可以分别是卤素，氰基，三氟甲基，(C1—C6)链烷酰基，硝基，(C1—C6)链烷基，(C1—C6)链烷氧基，羰基，烷酯基，三氟甲氧基，乙酰氨基，(C1—C6)链烷硫基，(C1—C6)链烷基磺酰基，三氯乙烯基，三氟甲硫基，三氟甲基亚磺酰基，三氟甲基磺酰基；
R2是氨基，(C1—C6)链烷氨基，二烷氨基，乙酰氨基，乙酰亚胺，脲基酰基，甲酰氨基，甲酰亚胺或胍基；
R3是胺甲酰基，氰基，氨基甲酰基，亚胺基或N-羟基氨甲酰基。
(2).具体的化合物为：式二中n和m分别为0，1或2；P等于1；X是O，S，CO或CH2；
R4是氟，氯，溴，甲基，三氟甲基，氰基，甲氧羰基，三氟甲氧基，三氟甲硫基，硝基或三氯乙烯基；
R5是氯，溴，氟，甲基，三氟甲基，氰基，烷酯基，三氟乙烯基或硝基。
(3).具体的，式一化合物结构式如下：
X是CH2，S，O或CO；R4是Cl，CF3，Br或CH3；R5是Cl，Br或NO2。
(4).更具体的，式一化合物为5-胺基-1-[3，5-二氯-4(4-氯苯甲酰氯)苄基]-1H-1，2，3-三唑-4-苯甲酰胺，即羧胺三唑(carboxyamidotriazole，简称CAI)；
(5)也包括以上这些化合物可药用的盐，如盐酸盐、硫酸盐、醋酸盐等。
本发明首先提供上述化合物在制备治疗哺乳动物因任何原因引起的疼痛和/或炎症性疾病的药物中的应用。其中所述炎症为任何原因引起的急性炎症或慢性炎症；所述疾病包括但并不仅限于风湿病、类风湿关节炎、成人斯蒂尔病、干燥综合征、系统性红斑狼疮及相关综合征、脊柱关节炎、强直性关节炎、银屑病关节炎、肠性关节炎、反应性关节炎、以及分类未定的关节炎、硬皮病、混合性结缔组织病和重叠综合征、未分化结缔组织病、多发性肌炎和皮肌炎、血管炎综合征、巨细胞动脉和风湿性多肌痛、韦格纳肉芽肿、变应性肉芽肿性血管炎、结节性多动脉炎及相关综合征、显微镜下血管炎、抗中性粒细胞浆抗体相关小血管炎、大动脉炎、贝赫切特病、皮肤血管炎、晶体关节炎(其中包括痛风、焦磷酸钙沉淀病、碱性磷酸钙晶体沉淀病及其他晶体关节炎)、淀粉样变、自身免疫性肝病、结节病、纤维肌痛和慢性疲劳综合征、多中心网状组织细胞增生症、脂膜炎、莱姆病、腹膜后纤维化、骨性关节炎、弥漫性特发行骨肥厚、畸形型骨炎、ASPHO综合征、复发性多软骨炎、骨坏死、遗传性结构蛋白病、大骨节病等。为关节炎或继发性骨关节炎；所述疾病为肿瘤、风湿病、类风湿病或胶原病。
本发明的第二组目的在于提供一种具有镇痛和/或抗炎作用的联用药物组合物。
具体的，该联用药物组合物可以试剂盒的形式存在，试剂盒中还包括使用说明书。
该组合物或试剂盒中包括有效量的羧胺三唑或其可药用的盐、羧胺三唑类似物或衍生物、或羧胺三唑类似物或衍生物可药用的盐，和有效量的镇痛药或抗炎镇痛药或抗炎药等。
联用药物组合物或试剂盒中，所述镇痛药是指通过作用于中枢及/或外周神经导致镇痛作用的药物，其中包括但并不仅限于作用于阿片受体的镇痛药(阿片全碱、吗啡、哌替啶、阿法罗定、美沙酮、芬太尼、丁丙诺菲、二氢埃托啡、喷他佐辛、地佐辛、布桂嗪、苯噻啶、美普他酚、曲马朵、氟吡汀、匹米诺定等)和其他中枢镇痛药(四氢帕马丁、奈福泮、眼镜蛇毒、白曲菜碱、麦角碱、千金藤啶碱、3—乙乌头碱、高乌甲素、西马嗪等)；也包括但不仅限于解热镇痛药(阿司匹林、阿司匹林精氨酸盐、阿司匹林赖氨酸盐、三柳胆镁、水杨酸镁、双水杨酸、二氟尼柳、贝诺酯、对乙酰氨基酚、安乃近、保泰松等)。
联用药物组合物或试剂盒中，所述抗炎镇痛药是指通过影响中枢或外周于疼痛相关物质合成及代谢，同时具有抗炎和镇痛作用的药物，其中包括但不仅限于吲哚美辛、阿西美辛、苄达明、吡罗昔康、甲氯芬那酸、双氯芬酸、托美汀、酮咯酸、萘普生、布洛芬、酮洛芬、芬布芬、吡洛芬、丁苯羟酸、环氧茚酸、萘丁美酮、咪咪酯、金诺芬、卫矛醇、豆腐果甙、异丙安替比林、乙水杨酸、羟布宗、氯芬那酸、甲芬那酸、舒林酸、依匹唑、美索巴莫、强筋松、氟比洛芬、卡洛芬、非诺洛芬、非诺洛芬钙、氯索洛芬等。
联用药物组合物或试剂盒中，所述抗炎药是指通过各种机制产生抗炎作用的药物，其中包括但不仅限于肾上腺皮质激素及促肾上腺皮质激素及其类似药物(氢化可的松、泼尼松、泼尼松龙、甲泼尼松、曲按西龙、曲安奈德、地塞米松、倍他米松、氟氢可的松、氯倍他索、氟轻松、丁氯倍他松、倍氯米松、哈西奈德、可的松、氯泼尼醇、地夫可特、氟米龙、阿氯米松、卤米松、甲羟松、去羟米松、氟氢缩松、二氟可龙、莫米松、去氧皮质酮、促皮质素、美替拉酮等)；还包括通过免疫抑制作用抑制炎症的药物环孢素、硫唑嘌呤、甲氨喋呤、羟基脲、乙亚胺、乙双吗啉、环磷酰胺、苯丁酸氮芥、青霉胺、抗淋巴细胞蛋白、抗淋巴细胞血清、莫罗莫那-CD、雷公藤总甙等。
附图说明
图1：显示了福尔马林法测CAI和吗啡的镇痛作用。
图2：显示了热板法测CAI和吗啡的镇痛作用。
图3：显示了辐射热刺激法测CAI和吗啡的镇痛作用。
图4：显示了小鼠扭体法测定CAI的镇痛作用。
图5：显示了巴豆油刺激小鼠耳廓肿胀法测CAI的抗炎作用。
具体实施方式
下面通过实施例的方式进一步说明本发明。下面的实施例仅仅是为了说明的目的，而并非欲于限制本发明的范围。
实施例1CAI对吗啡所致药物依赖的影响
实验方法：
体重为18—22g昆明种小鼠160只，雌雄各半，随机分成4组，每组有动物40只。分别为：
1.溶剂对照组，PEG400/N.S.(灌胃给予聚乙二醇400(PEG400)10μl/g/天，连续给药4天)；
2.CAI处理组，CAI/N.S.(CAI溶于PEG400，浓度为2mg/ml，按照20mgCAI/kg/天灌胃给药，连续给药4天，按照表1给予吗啡的方案给予作为对照的N.S)；
3.吗啡处理组，PEG400/吗啡组(灌胃给予PEG40010μl/g/天，连续给药4天，并按照表1给予吗啡)；
4.吗啡和CAI联合处理组，CAI/吗啡组(按照CAI处理组给予CAI，并按照吗啡处理组给予吗啡)。
表1CAI对吗啡所致药物依赖的影响实验给药方案
第五天给吗啡后4小时，各组动物均在内腹腔注射纳络酮(NALOXONE)1mg/kg，然后立即将动物放入5000ml大烧杯中，记录30分钟内跳跃次数。实验结果用SPSS进行双因素方差分析。
实验结果：
表2CAI对吗啡所致药物依赖的影响
实验结果用SPSS进行双因素方差分析表明：
吗啡处理(PEG400/吗啡组和CAI/吗啡组)与对照组(PEG400/N.S.)比较均有极显著差异(P<0.001)，CAI单独处理组与对照组比较并无显著差异(P＝0.802)；而CAI/吗啡组与PEG400/吗啡组比较亦无差异(P＝0.938)。这表明吗啡处理使动物表现出明显的戒断症状，而且这种戒断症状不受CAI的影响。本试验表明CAI长期使用并不造成依赖作用，纳络酮Naloxone不能诱导长期给予CAI的动物出现戒断症状，这也表明CAI与吗啡可能并不通过相同的机理产生镇痛作用。
实施例2小鼠足底注射福尔马林法测CAI和吗啡的镇痛作用
实验方法：
体重为18—22g昆明种小鼠320只，雌雄各半，随机分成4组，每组有动物80只。分别为
1.溶剂(PEG400/生理盐水)对照组：动物第一次给PEG400灌胃10μl，24小时后再次灌胃给予等量PEG400，第二次给药8小时后进行测痛实验。测痛前5分钟皮下注射生理盐水200μl。
2.吗啡/PEG400组：动物第一次给PEG400灌胃10μl，24小时后再次灌胃给予等量PEG400，第二次给药8小时后进行测痛实验。测痛前5分钟皮下注射吗啡(MORPHINE，2mg/kg体重)。
3.CAI/生理盐水组：动物第一次给CAI(20mg/kg，浓度为2mg/ml)后24小时再次灌胃给予等剂量药物CAI，第二次给药8小时后进行测痛实验。测痛前5分钟皮下注射生理盐水(N.S.)200μl。
4.CAI/吗啡组：动物第一次给CAI(20mg/kg，浓度为2mg/ml)后24小时再次灌胃给予等剂量药物CAI，第二次给药8小时后进行测痛实验。测痛前5分钟皮下注射吗啡(2mg/kg体重)。
各组动物在给予吗啡或N.S.5分钟后，向其足底皮下注射2％福尔马林20μl，并将其立即置入一悬挂在铁架台上的平底大烧杯内，烧杯下方置一倾斜30°左右的镜子，从镜面观察动物足部反应。按下述方法记录动物被注射足的反应并进行疼痛分级：舔、咬或抖足3分；提足2分；轻触底面但不负重，行走时跛行1分；正常负重，走动自如0分。并记录上述行为每次持续的时间。共记录15分钟。以动物行为级数秒数乘以其持续秒数，得到乘积之和为该动物疼痛定量指标。
实验结果：
表3CAI和吗啡对福尔马林致痛的影响
图1示出了本例福尔马林法测CAI和吗啡的镇痛作用，其中，MOR表示吗啡。结果用SPSS进行双因素方差分析，在该模型上与对照组比较，CAI(P<0.001)和吗啡(P<0.001)处理的动物疼痛评分数值均大幅下降，显示其均有显著的镇痛作用，而且两者联用组数值下降更为明显，显示二者有显著协同作用(P＝0.004)。
实施例3热板法测CAI和吗啡的镇痛作用
实验方法：
体重为18—22g的昆明种雌性小鼠随机分成4组，每组有动物20只。分别为：
1.溶剂(PEG400/N.S)对照组：动物第一次给PEG400灌胃10μl，24小时后再次灌胃给予等量PEG400，第二次给药8小时后进行测痛实验。测痛前5分钟皮下注射N.S.200μl。
2.吗啡/PEG400组：动物第一次给PEG400灌胃10μl，24小时后再次灌胃给予等量PEG400，第二次给药8小时后进行测痛实验。测痛前5分钟皮下注射吗啡(2mg/kg体重)。
3.CAI/N.S.组：动物第一次给CAI(20mg/kg，浓度为2mg/ml)后24小时再次灌胃给予等剂量药物CAI，第二次给药8小时后进行测痛实验。测痛前5分钟皮下注射N.S.200μl。
4.CAI+吗啡组：动物第一次给CAI(20mg/kg，浓度为2mg/ml)后24小时再次灌胃给予等剂量药物CAI，第二次给药8小时后进行测痛实验。测痛前5分钟皮下注射吗啡(2mg/kg体重)。
测痛开始将小鼠放于53±0.5℃的热板上，以跳跃反应的潜伏期(秒)作为该鼠的痛阈指标。
实验结果：
表4热板实验中CAI和吗啡的镇痛作用
图2显示了热板法测CAI和吗啡的镇痛作用，结果用SPSS进行双因素方差分析，可见在该模型上吗啡极显著的延长痛反应时间(P＝0.002)，而CAI在该模型上无明显延长痛反应时间的作用(P＝0.834)，而且CAI与吗啡的交互作用不明显(P＝0.524)。表明CAI在这个动物模型中并无明显的镇痛作用，而且也不能影响吗啡的作用。
实施例4辐射热刺激法测CAI和吗啡的镇痛作用
实验方法：
使用辐射热测痛仪(Collumbus Instruments公司生产)，甩尾模式，照射强度20。以从照射开始到甩尾反应的潜伏期(TFL)作为痛阈，光照截止时间为16秒。
体重为18—22g昆明种雄性小鼠试验给药前先测定备选小鼠的基础痛阈，痛阈超过16秒者不入选。入选小鼠60只随机分成4组，每组有动物15只。分别为：
1.溶剂(PEG400/N.S)对照组：动物第一次给PEG400灌胃10μl，24小时后再次灌胃给予等量PEG400，第二次给药8小时后进行测痛实验。测痛前5分钟皮下注射N.S.200μl。
2.吗啡/PEG400组：动物第一次给PEG400灌胃10μl，24小时后再次灌胃给予等量PEG400，第二次给药8小时后进行测痛实验。测痛前5分钟皮下注射吗啡(2mg/kg体重)。
3.CAI/N.S.组：动物第一次给CAI(20mg/kg，浓度为2mg/ml)，24小时后再次灌胃给予等剂量药物CAI，第二次给药8小时后进行测痛实验。测痛前5分钟皮下注射N.S.200μl。
4.CAI/吗啡组：动物第一次给CAI(20mg/kg，浓度为2mg/ml)，24小时后再次灌胃给予等剂量药物CAI，第二次给药8小时后进行测痛实验。测痛前5分钟皮下注射吗啡(2mg/kg体重)。
注射吗啡或N.S.前先测定每只小鼠的基础痛阈。给予吗啡或N.S.后再次测各组小鼠痛阈，以给药后数值—给药前数值为痛阈的变化指标。
实验结果：
表5CAI和吗啡在热辐射致痛模型中的镇痛作用
图3显示了辐射热刺激法测CAI和吗啡的镇痛作用，结果用SPSS进行双因素方差分析。发现与对照组比较，吗啡有极显著延长小鼠痛阈的作用(P<0.001)，而CAI在该动物模型上并无明显作用(P＝0.690)。CAI在该模型上与吗啡的交互作用不明显(P＝0.820)，表明CAI在这个动物模型上，并不能产生明显的镇痛作用，并且不能影响吗啡造成的镇痛作用。
实施例5小鼠扭体法测定CAI及其类似物的镇痛作用
实验方法：
体重为18—22g昆明种雄性小鼠若干只，随机分成不同组，每组有动物20只。分别为
1.对照组：连续4天灌胃给予PEG400，0.1ml/10g。
2.给药组：连续4天灌胃(20mg/kg，浓度为2mg/ml)，各组分别给予CAI和CAI类似物(结构式为A的化合物，其中R1为Cl或H，R2为Cl、H、Br、CH3、或CF3，R3为Cl、Br、CF3、NO2或CN，X为O、S、或C＝O)，具体化合物参见表6中A1～A10。
动物均在最后一次给药8小时后进行测痛实验。每只动物腹腔注射0.6％醋酸溶液，0.1ml/10g，立即放入烧杯中，观察并记录此后5—15min内小鼠的扭体次数。
实验结果：
表6CAI及其类似物在小鼠扭体实验模型中的镇痛活性
图4显示了本实施例小鼠扭体法测定中CAI的镇痛作用，结果用SPSS进行独立样本t检验，可见CAI在这一动物模型上能产生显著镇痛作用(P<0.001)；由表6数据可见，CAI的类似物(化合物A1～A10)在该模型上也具有相似的镇痛作用。
实施例6巴豆油刺激小鼠耳廓肿胀法测定CAI及其类似物的抗炎作用
实验方法：
体重为18—22g昆明种雄性小鼠若，随机分成不同组，每组有动物20只。分别为：
1.阴性对照组：连续3天灌胃给予生理盐水，0.1ml/10g.
2.溶剂对照组：连续3天灌胃给予PEG400，0.1ml/10g。
3.阳性药物组：连续3天腹腔注射浓度为0.2mg/ml的地塞米松溶液，0.1ml/10g。
4.试验药物组：连续3天灌胃，各组分别给予浓度为2mg/ml的CAI或其类似物(CAI类似物与实施例5相同，0.1ml/10g(20mg/kg)。
动物均在最后一次给药8小时后进行试验。在每只小鼠右侧耳廓涂布2％巴豆油乙醇溶液0.02ml，左侧不涂药，作为对照。4小时后处死动物，在双侧耳廓的相同部位用打孔器取下相同面积的耳廓组织，使用万分之一天平测重，每鼠右耳片重量减去左耳片重为肿胀度。
实验结果：
表7CAI及其类似物在巴豆油刺激小鼠耳廓肿胀模型中的抗炎作用
图5显示了巴豆油刺激小鼠耳廓肿胀法测CAI的抗炎作用。结果用SPSS进行独立样本t检验，可见CAI在该模型有显著抗炎作用(P＝0.028)，另外由表7数据可见，CAI的类似物(化合物A1～A10)在该模型上也具有相似的抗炎活性。
实施例7CAI对大鼠慢性炎症肉芽肿形成的影响试验
实验方法：
体重为160g雄性大鼠33只，随机分为4组，每组有动物11只。动物乙醚浅麻醉，局部消毒后，双侧附股沟切口，每侧皮下植入一个灭菌棉球(干重50mg)。术后当天开始按照分组分别灌胃给予药物：对照组给予N.S.，阳性对照(地塞米松组)给予地塞米松0.067mg/kg/天，CAI组给予溶于PEG400的CAI20mg/天，CAI+地塞米松组给予溶于PEG400的CAI20mg/天和地塞米松0.067mg/kg/天。给药7天后，处死动物，取出棉球，在60℃烤箱中放置12小时后称重。分别减去原始棉球重量后，得到肉芽肿的重量。以此重量除以大鼠被处死时的体重，得到肉芽肿与体重的比值。求得各组均值。
实验结果：
表8CAI对大鼠慢性炎症肉芽肿形成的影响
统计学处理(student t test)表明，给予地塞米松(p＝0.049)和CAI(p＝0.037)以及CAI+地塞米松的三组动物与对照组均有显著差异。说明CAI能抑制慢性炎症造成的肉芽肿形成，并且其作用强度与地塞米松相似甚至更强，并且能增强地塞米松的作用。
实施例8CAI对大鼠佐剂性关节炎(AA)的影响
实验方法：
体重为160±10g雄性大鼠70只，随机抽取14只大鼠用生理盐水0.1ml/200g注射于右后足跖皮内。另外56只用弗氏完全佐剂(FCA)0.1ml/只注射于右后足跖皮内致炎。造模成功后，将模型动物随机分为4组，每组有动物14只。分别为：
1.阴性对照组(AA+NS)：每天灌胃给予生理盐水，0.1ml/100g.
2.阳性药物组(AA+Dex)：每天腹腔注射浓度为2mg/ml的地塞米松溶液，0.1ml/100g。
3.溶剂对照组(AA+PEG400)：每天灌胃给予PEG400，0.1ml/100g。
4.CAI组(AA+CAI)：每天灌胃给予浓度为20mg/ml的CAI，0.1ml/100g(20mg/kg)。
大鼠注射弗氏佐剂前，测量左右后足正常容积，然后分别于第2、5、8、11、14、17、20、23、26、29日测左足容积，于第14、17、20、23、26、29日测右足容积。结果如下表所示：
实验结果：
表9CAI对佐剂性关节炎大鼠原发性足跖肿胀的影响
注：与NS组比较*P<0.05，**P<0.01；与PEG400组比较#P<0.05，##P<0.01。
表10CAI对佐剂性关节炎大鼠继发性足跖肿胀的影响
注：与NS组比较*P<0.05，**P<0.01；与PEG400组比较#P<0.05
综上，本发明使用了两类证明CAI及其类似物镇痛作用的动物试验模型：中枢镇痛模型(热板法、辐射热刺激法)和与炎症和组织损伤相关的外周镇痛模型(小鼠足底注射福尔马林法、小鼠扭体法)。从实验结果可以看到，CAI能在外周镇痛模型试验中发挥镇痛作用，而在中枢镇痛试验中，CAI并不产生镇痛作用。而且，在外周镇痛模型中(小鼠足底注射福尔马林法)CAI还能增强中枢镇痛药吗啡的作用。上述试验表明CAI是一种具有外周镇痛作用的药物。
另外，本发明使用了两种抗炎模型证明CAI及其类似物的抗炎作用。一种是急性炎症模型(巴豆油刺激小鼠耳廓肿胀法)，另外一种是慢性炎症模型(大鼠慢性炎症肉芽肿形成，佐剂性关节炎)。在这两种模型中，CAI及其类似物都有明显的抗炎作用。CAI能够抑制大鼠原发性、继发性足跖肿胀，对大鼠关节炎有明显的改善作用。
本发明发现迄今为止被认为是抗癌药物的羧胺三唑不仅具有抗癌作用，而且具有镇痛和抗炎作用。这一发现具有非常重要的意义，诸如以下各方面：
1.本领域技术人员知晓晚期肿瘤患者往往伴有严重的疼痛，而作为一种抗肿瘤药物，同时有具有镇痛作用，这还是第一次发现。这使其抗肿瘤的临床使用范围和疗效大大增加。
2.这一发现开创了发展CAI类似物或衍生物结构的新型的抗炎镇痛药物的可能。使得CAI及其类似物或衍生物结构的药物的适应症不再仅仅局限于肿瘤的治疗，可能用于所有与抗炎镇痛相关的治疗领域，包括(但不局限于)风湿病、类风湿病、其他胶原病等。
3.深入的机理研究，可能阐明癌症与炎症这两种病理变化之间的关系，及其机理，有可能发展破口的抗癌药物。
4.实验中还确实了CAI类似物也有与CAI近似的镇痛和抗炎作用，为新的镇痛和抗炎药物选择提供了广大空间。
5.实验中还证实了CAI与已有的镇痛药(如吗啡)或抗炎药(如地塞米松)联合使用具有协同增效作用。
可以理解的是，上面的描述仅是本发明的示例，因而本发明权利要求所保护的范围并不仅仅以此处公开的特定实施方案来限定。例如，本领域人员均了解，CAI可药用的盐以及CAI类似物可药用的盐如盐酸盐、硫酸盐、醋酸盐等均具有与其化合物同样的效果，在此不一一赘述。
本领域技术人员还可以了解，联用药物中，镇痛药是指通过作用于中枢及/或外周神经导致镇痛作用的药物，其中包括但并不仅限于作用于阿片受体的镇痛药(阿片全碱、吗啡、哌替啶、阿法罗定、美沙酮、芬太尼、丁丙诺菲、二氢埃托啡、喷他佐辛、地佐辛、布桂嗪、苯噻啶、美普他酚、曲马朵、氟吡汀、匹米诺定等)和其他中枢镇痛药(四氢帕马丁、奈福泮、眼镜蛇毒、白曲菜碱、麦角碱、千金藤啶碱、3—乙乌头碱、高乌甲素、西马嗪等)；也包括但不仅限于解热镇痛药(阿司匹林、阿司匹林精氨酸盐、阿司匹林赖氨酸盐、三柳胆镁、水杨酸镁、双水杨酸、二氟尼柳、贝诺酯、对乙酰氨基酚、安乃近、保泰松等)；抗炎镇痛药是指通过影响中枢或外周于疼痛相关物质合成及代谢，同时具有抗炎和镇痛作用的药物，其中包括但不仅限于吲哚美辛、阿西美辛、苄达明、吡罗昔康、甲氯芬那酸、双氯芬酸、托美汀、酮咯酸、萘普生、布洛芬、酮洛芬、芬布芬、吡洛芬、丁苯羟酸、环氧茚酸、萘丁美酮、咪咪酯、金诺芬、卫矛醇、豆腐果甙、异丙安替比林、乙水杨酸、羟布宗、氯芬那酸、甲芬那酸、舒林酸、依匹唑、美索巴莫、强筋松、氟比洛芬、卡洛芬、非诺洛芬、非诺洛芬钙、氯索洛芬等；抗炎药是指通过各种机制产生抗炎作用的药物，其中包括但不仅限于肾上腺皮质激素及促肾上腺皮质激素及其类似药物(氢化可的松、泼尼松、泼尼松龙、甲泼尼松、曲按西龙、曲安奈德、地塞米松、倍他米松、氟氢可的松、氯倍他索、氟轻松、丁氯倍他松、倍氯米松、哈西奈德、可的松、氯泼尼醇、地夫可特、氟米龙、阿氯米松、卤米松、甲羟松、去羟米松、氟氢缩松、二氟可龙、莫米松、去氧皮质酮、促皮质素、美替拉酮等；还包括通过免疫抑制作用抑制炎症的药物环孢素、硫唑嘌呤、甲氨喋呤、羟基脲、乙亚胺、乙双吗啉、环磷酰胺、苯丁酸氮芥、青霉胺、抗淋巴细胞蛋白、抗淋巴细胞血清、莫罗莫那-CD、雷公藤总甙等。
本领域人员还应了解，本发明可应用于因任何原因引起的疼痛和/或炎症性疾病的治疗。其中所述炎症为任何原因引起的急性炎症或慢性炎症；所述疾病包括但并不仅限于风湿病、类风湿关节炎、成人斯蒂尔病、干燥综合征、系统性红斑狼疮及相关综合征、脊柱关节炎、强直性关节炎、银屑病关节炎、肠性关节炎、反应性关节炎、以及分类未定的关节炎、硬皮病、混合性结缔组织病和重叠综合征、未分化结缔组织病、多发性肌炎和皮肌炎、血管炎综合征、巨细胞动脉和风湿性多肌痛、韦格纳肉芽肿、变应性肉芽肿性血管炎、结节性多动脉炎及相关综合征、显微镜下血管炎、抗中性粒细胞浆抗体相关小血管炎、大动脉炎、贝赫切特病、皮肤血管炎、晶体关节炎(其中包括痛风、焦磷酸钙沉淀病、碱性磷酸钙晶体沉淀病及其他晶体关节炎)、淀粉样变、自身免疫性肝病、结节病、纤维肌痛和慢性疲劳综合征、多中心网状组织细胞增生症、脂膜炎、莱姆病、腹膜后纤维化、骨性关节炎、弥漫性特发行骨肥厚、畸形型骨炎、ASPHO综合征、复发性多软骨炎、骨坏死、遗传性结构蛋白病、大骨节病等。为关节炎或继发性骨关节炎；所述疾病为肿瘤、风湿病、类风湿病或胶原病。
任何等同的实施方案将被认为在本发明的范围之内。事实上，根据前面的描述，对本发明进行有关的修改和变化对于本领域技术人员来讲都将是可能的，因而，这种修改和变化也将落在本发明的范围之内。
Claims (11)
1.一种羧胺三唑类化合物在制备治疗哺乳动物治疗疼痛性疾病和/或炎症性疾病的药物中的用途，所述疾病不包括与血管增生密切关联的疼痛性疾病和炎症性疾病，所述羧胺三唑类化合物为羧胺三唑或以结构式A表示的羧胺三唑类似物化合物及其可药用的盐：
其中R1为Cl或H，R2为Cl、H、Br、CH3、或CF3，R3为Cl、Br、CF3、NO2或CN，X为O、S、或C＝O。
2.根据权利要求1中的用途，其中，结构式A表示的化合物为：
A1：5-氨基-1-(4-[4-氯苯甲酰基]-3，5-二氯苯甲基)-1，2，3-三唑-4-羧胺、
A2：5-氨基-1-(4-[4-氯苯硫基]-3-氯苯甲基)-1，2，3-三唑-4-羧胺、
A3：5-氨基-1-(4-[4-氯苯硫基]-5-三氟甲基苄基)-1，2，3-三唑-4-羧胺、
A4：5-氨基-1-(4-[4-三氟甲基苯甲酰基]-3-氯-5-甲基苄基)-1，2，3三唑-4-羧胺、
A5：5-氨基-1-(4-[4-氰基-苯甲酰基]-3，5-二氯苯甲基)-1，2，3-三唑-4-羧胺、
A6：5-氨基-1-(3-氯-4-[4-氯苯甲酰基]-5-溴-苯甲基)-1，2，3-三唑-4-羧胺、
A7：5-氨基-1-(4-[4-溴苯氧基]-3，5-二氯苯甲基)-1，2，3-三唑-4-羧胺、
A8：5-氨基-1-(4-[4-溴苯甲酰基]-3，5-二氯苯甲基)-1，2，3-三唑-4-羧胺、
A9：5-氨基-1-(4-[4-硝基-苯氧基]-3，5-二氯苯甲基)-1，2，3-三唑-4-羧胺、或
A10：5-氨基-1-(3-氯-4-[4-氯苯氧基]-5-甲基苄基)-1，2，3三唑-4羧胺。
3.根据权利要求1中的用途，其中化合物为5-胺基-1-[3，5-二氯-4(4-氯苯甲酰氯)苄基]-1H-1，2，3-三唑-4-苯甲酰胺，即羧胺三唑或其可药用的盐。
4.根据权利要求1-3中任一所述用途，所述疼痛包括肿瘤，炎症，化学刺激或损伤，物理刺激或损伤，细菌感染等导致的疼痛，但不包括与血管增生密切关联疾病引起的疼痛。
5.根据权利要求1-3中任一所述的用途，所述炎症包括风湿病、类风湿关节炎、成人斯蒂尔病、干燥综合征、系统性红斑狼疮及相关综合征、脊柱关节炎、强直性关节炎、银屑病关节炎、肠性关节炎、反应性关节炎、以及分类未定的关节炎、硬皮病、混合性结缔组织病和重叠综合征、未分化结缔组织病、多发性肌炎和皮肌炎、血管炎综合征、巨细胞动脉和风湿性多肌痛、韦格纳肉芽肿、变应性肉芽肿性血管炎、结节性多动脉炎及相关综合征、显微镜下血管炎、抗中性粒细胞浆抗体相关小血管炎、大动脉炎、贝赫切特病、皮肤血管炎、晶体关节炎、淀粉样变、自身免疫性肝病、结节病、纤维肌痛和慢性疲劳综合征、多中心网状组织细胞增生症、脂膜炎、莱姆病、腹膜后纤维化、骨性关节炎、弥漫性特发行骨肥厚、畸形型骨炎、ASPHO综合征、复发性多软骨炎、骨坏死、遗传性结构蛋白病、大骨节病等引起的急性炎症或慢性炎症，但不包括与血管增生密切关联疾病引起的炎症。
6.根据权利要求5所述的用途，其中所述晶体关节炎包括痛风、焦磷酸钙沉淀病、碱性磷酸钙晶体沉淀病引起的晶体关节炎。
7.一种联用的用于镇痛和/或抗炎的药物组合物，其包括有效量的权利要求1至3任一所述的羧胺三唑类化合物，和有效量的镇痛药或抗炎镇痛药或抗炎药；
所述镇痛药是指通过作用于中枢及/或外周神经导致镇痛作用的药物，其中包括作用于阿片受体的镇痛药和其他中枢镇痛药和解热镇痛药；
所述抗炎镇痛药是指通过影响中枢或外周于疼痛相关物质合成及代谢，同时具有抗炎和镇痛作用的药物，其中包括吲哚美辛、阿西美辛、苄达明、吡罗昔康、甲氯芬那酸、双氯芬酸、托美汀、酮咯酸、萘普生、布洛芬、酮洛芬、芬布芬、吡洛芬、丁苯羟酸、环氧茚酸、萘丁美酮、咪咪酯、金诺芬、卫矛醇、豆腐果甙、异丙安替比林、乙水杨酸、羟布宗、氯芬那酸、甲芬那酸、舒林酸、依匹唑、美索巴莫、强筋松、氟比洛芬、卡洛芬、非诺洛芬、非诺洛芬钙、氯索洛芬；
所述抗炎药是指通过各种机制产生抗炎作用的药物，包括通过免疫抑制作用抑制炎症的药物环孢素、硫唑嘌呤、甲氨喋呤、羟基脲、乙亚胺、乙双吗啉、环磷酰胺、苯丁酸氮芥、青霉胺、抗淋巴细胞蛋白、抗淋巴细胞血清、莫罗莫那-CD、雷公藤总甙。
8.根据权利要求7所述的药物组合物，其特征在于，所述阿片受体的镇痛药为阿片全碱、吗啡、哌替啶、阿法罗定、美沙酮、芬太尼、丁丙诺菲、二氢埃托啡、喷他佐辛、地佐辛、布桂嗪、苯噻啶、美普他酚、曲马朵、氟吡汀或匹米诺定。
9.根据权利要求7所述的药物组合物，其特征在于，所述中枢镇痛药为四氢帕马丁、奈福泮、眼镜蛇毒、白曲菜碱、麦角碱、千金藤啶碱、3-乙乌头碱、高乌甲素或西马嗪。
10.根据权利要求7所述的药物组合物，其特征在于，所述解热镇痛药为阿司匹林、阿司匹林精氨酸盐、阿司匹林赖氨酸盐、三柳胆镁、水杨酸镁、双水杨酸、二氟尼柳、贝诺酯、对乙酰氨基酚、安乃近或保泰松。
11.根据权利要求7至10任一所述的药物组合物，其特征在于，为联用的用于镇痛和/或抗炎的药物试剂盒，其中还包括有使用说明书。
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| US5359078A (en) * | 1989-05-19 | 1994-10-25 | The United States Of America As Represented By The Department Of Health And Human Services | Signal transduction inhibitor compounds |
| US5602156A (en) * | 1993-09-17 | 1997-02-11 | The United States Of America As Represented By The Department Of Health And Human Services | Method for inhibiting metalloproteinase expression |
| US6057346A (en) * | 1994-12-12 | 2000-05-02 | The United States Of America As Represented By The Department Of Health And Human Services | Inhibition of retroviral LTR promoters by calcium response modifiers |
| CN100493609C (zh) * | 2005-01-19 | 2009-06-03 | 中国医学科学院基础医学研究所 | 抗恶性肿瘤的药物组合物及其应用 |
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- 2007-07-04 KR KR1020097009858A patent/KR20090066329A/ko not_active Application Discontinuation
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| WO2006037106A2 (en) * | 2004-09-24 | 2006-04-06 | Rfe Pharma Llc | Carboxy-amido-triazoles for the localized treatment of ocular diseases |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2008046285A1 (fr) | 2008-04-24 |
| EP2085085A1 (en) | 2009-08-05 |
| RU2448704C2 (ru) | 2012-04-27 |
| RU2009117300A (ru) | 2010-11-27 |
| AU2007312840A1 (en) | 2008-04-24 |
| CN101164538A (zh) | 2008-04-23 |
| BRPI0717762A2 (pt) | 2013-05-07 |
| AU2007312840B2 (en) | 2012-07-05 |
| KR20090066329A (ko) | 2009-06-23 |
| US20100041632A1 (en) | 2010-02-18 |
| CN101553225A (zh) | 2009-10-07 |
| EP2085085A4 (en) | 2010-06-09 |
| CN101553225B (zh) | 2012-06-06 |
| EP2085085B1 (en) | 2012-10-17 |
| MX2009004017A (es) | 2009-07-24 |
| ZA200903401B (en) | 2010-08-25 |
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