CN106432025B - 金刚烷磺酰胺类化合物及其制备与应用 - Google Patents
金刚烷磺酰胺类化合物及其制备与应用 Download PDFInfo
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Abstract
本发明涉及下式所示的金刚烷磺酰胺类化合物及其制备与抗炎作用、免疫抑制作用及在炎症性和炎症相关性疾病方面的治疗应用如自身免疫性疾病(风湿、类风湿性关节炎，强直性脊柱炎，红斑狼疮、克罗恩病、银屑病、幼年特发性关节炎、葡萄膜炎等)、感染性疾病(脓毒症、败血症等)、神经退行性疾病(多发性硬化、老年性痴呆、帕金森病等)、痛风、移植免疫排斥反应及动脉粥样硬化和肿瘤治疗中的应用。
Description
技术领域
本发明涉及药物化学和药物治疗学领域，具体涉及单独或组合用于治疗和/或预防炎症性和炎症相关性疾病方面如自身免疫性疾病(风湿、类风湿性关节炎，强直性脊柱炎，红斑狼疮、克罗恩病、银屑病、幼年特发性关节炎、葡萄膜炎等)、感染性疾病(脓毒症、败血症等)、神经退行性疾病(多发性硬化、老年性痴呆、帕金森病等)、痛风、移植免疫排斥反应及动脉粥样硬化和肿瘤治疗中的应用。更具体涉及新的一系列下式所示的金刚烷磺酰胺类化合物及其制备方法和药物学上可接受的盐或药物学上可接受的溶剂化物。
背景技术
炎症反应是机体对各种炎性刺激引起组织损害而产生的一种基本病理过程，也是机体对损伤或感染产生的一种重要的防御反应，可帮助机体清除有害物质，将损伤局限化，启动愈合过程对组织进行修复，从而发挥保护作用。但过度和持久的炎症反应，使抗炎和促炎反应失衡，反而加重组织细胞损伤，最终可引起器官功能障碍。炎症反应是一种常见和多发的病理过程，多种疾病均与炎症反应密切相关，如感染性疾病、自身免疫性疾病、痛风、神经退行性疾病、动脉粥样硬化、肿瘤等，尤其感染性疾病导致的脓毒血症和自身免疫性疾病中的类风湿性关节炎、强直性脊柱炎等均为炎症反应的过度活化或持久存在。因此，抗炎药物也是临床治疗中仅次于抗感染药物的第二大类药物。尤其在抗类风湿药物市场，evaluate pharma公司报道抗风湿药物按销售额已排在第二大 治疗领域，全球收入在2013年即达到411亿美元，且在未来5年仍将保持强劲增长。据估计，1986年全球非甾体抗炎药处方量已达1亿张，非处方用药更为普遍，且有逐年增加趋势，仅塞来昔布2013年销售就达27亿美元。而甾体类抗炎药糖皮质激素类在我国医院门诊处方使用率虽各家报道不一，但均在12％以上；有研究也报道某医院2014年4月住院患者糖皮质激素应用病历占该月总出院病历数的21.8％。但这两类药物都有其相应的各种不良反应。甾体类抗炎药对机体作用复杂，在产生强大抗炎作用的同时会造成机体防御功能的下降，诱发或加重感染，长期使用可引起人体物质代谢和水盐代谢紊乱、诱发加重消化性溃疡、引起骨质疏松等，甚至产生严重的并发症。非甾体类抗炎药亦有胃肠道损伤出血、肝肾功能损伤、心血管不良事件发生率增加等不良反应。因此，寻找抗炎作用强、不良反应小的抗炎新药成为国内外学者研究的热点。近年推出的治疗类风湿性关节炎等炎症性疾病的生物制剂如humira(阿达木单抗)、enbrel(依那西普)等已成为全球最畅销药物，在取得显著临床疗效的同时，也获得较大的利润，如humira 2015年销售额达140亿美元，但该类药物价格昂贵(humira在美国卖1840美元/支(40mg)，国内最高零售价为7900元/支，每2周注射1支)对医保和患者均是较重的负担。而近年辉瑞推出的首个治疗类风湿关节炎的口服JAK抑制剂xeljanz(托法替尼)，在2015年的9个月中销售即达3.51亿美元，但该药在价格上也依然昂贵，在美国的价格为3374美元/月(5mg/片，每日2次)。
我们研究发现金刚烷磺酰胺类化合物可以用于炎症反应，作用机制可能涉及多个靶点，我们研究显示金刚烷磺酰胺类化合物可显著抑制培养的巨噬细胞和小胶质细胞增殖和产生炎症因子；同时对内毒素诱导的小鼠肺损伤有明显保护作用使炎症反应减轻，损伤减轻；也使佛氏佐剂诱导的大鼠关节炎症状和关 节损伤减轻、大鼠棉球肉芽肿重量减轻、小鼠二甲苯致炎耳廓肿胀度减轻。而且，毒性试验显示在有效剂量40倍剂量时未见小鼠出现死亡和器官损伤。以上结果说明我们发现的金刚烷磺酰胺类化合物有显著的抗炎作用，且毒性低。
发明内容
本发明的目的是下式所示的金刚烷磺酰胺类化合物及其制备与抗炎作用、免疫抑制作用及在炎症性和炎症相关性疾病方面的治疗应用如自身免疫性疾病(风湿、类风湿性关节炎，强直性脊柱炎，红斑狼疮、克罗恩病、银屑病、幼年特发性关节炎、葡萄膜炎等)、感染性疾病(脓毒症、败血症等)、神经退行性疾病(多发性硬化、老年性痴呆、帕金森病等)、痛风、移植免疫排斥反应及动脉粥样硬化和肿瘤治疗中的应用。
在上式结构中，其中A可取代在金刚烷环的2、3、4位上，A可以为H，X(F、Cl、Br、I)，OH，OR，NH2，NHR，NR2，CHO，COR，COOH，COOR，CONH2，CONHR，CONR2，COOCOR等常用有机基团；B可以是H，R，Ar等常用有机基团；C可以是R，Ar等常用有机基团。
进一步，A具体可以是OH，NH2，COR，COOH，CONH2等，B具体可以是(CH2) nCONH2，(CH2)nCONHR，(CH2)nCONR2等(n为1，2，3，4等)，C具体可以是Me，Et，n-Pr，i-Pr，n-Bu，i-Bu，s-Bu，t-Bu，Ph，Bn等。
更进一步，A更具体是OH，NH2，COOH等，B更具体是CH2CONH2，CH2CONHR，CH2CONR2等，C更具体是Me，Et，Ph等。
一个具体的金刚烷磺酰胺类化合物实例CQMUH-011可描述为，但并不是局限 于该实例，其中A取代在金刚烷环的3位上，A是OH，B是
C是/>
关于金刚烷磺酰胺类化合物的制备方法，应该是本专业技术人员所具有的专业知识能够完成的。这里提出一个制备方法实例，但并不是局限于该实例。
以盐酸金刚烷胺为起始原料，用混酸及氢氧化钾为试剂，对金刚烷胺环的3位进行羟基化，得到金刚烷氨醇；金刚烷氨醇再与卤代B反应，制备得到氨基B取代的金刚烷氨醇，然后继续与对甲苯磺酰氯反应，制备得到目标金刚烷磺酰胺类化合物。以及本专业技术人员所具有的专业知识能够完成的其它相应的可替代的制备方法。
本发明研究发现上述的金刚烷磺酰胺类化合物可以用于炎症反应，作用机制可能涉及多个靶点，本发明研究显示金刚烷磺酰胺类化合物可显著抑制培养的巨噬细胞和小胶质细胞增殖和产生炎症因子；同时对内毒素诱导的小鼠肺损伤有明显保护作用使炎症反应减轻，损伤减轻；也使佛氏佐剂诱导的大鼠关节炎症状和关节损伤减轻、大鼠棉球肉芽肿重量减轻、小鼠二甲苯致炎耳廓肿胀度减轻。而且，毒性试验显示在有效剂量40倍剂量时未见小鼠出现死亡和器官损伤。以上结果说明我们发现的金刚烷磺酰胺类化合物有显著的抗炎作用，且毒性低。
本发明发现的金刚烷磺酰胺类化合物具有抗炎作用、免疫抑制作用及在炎症性和炎症相关性疾病方面的治疗用途如自身免疫性疾病(风湿、类风湿性关节炎，强直性脊柱炎，红斑狼疮、克罗恩病、银屑病、幼年特发性关节炎、葡萄膜炎等)、感染性疾病(脓毒症、败血症等)、神经退行性疾病(多发性硬化、老年性痴呆、帕金森病等)、痛风、移植免疫排斥反应及动脉粥样硬化和肿瘤治 疗中的应用。
本发明的再一目的，在于提供一种药物及其组合物其特征在于，含有有效量的上述金刚烷磺酰胺类化合物，以及药学上可接受的载体或赋形剂等制成的各种剂型及其组合物。
附图说明
图1是CQMUH-011对LPS刺激小胶质细胞增殖的影响图(CQMUH-011作用48h的IC50值为：1.305×10-8mol/L-1)
图2是不同浓度CQMUH-011对LPS刺激巨噬细胞RAW264.7增值的影响图
图3是不同浓度CQMUH-011对LPS刺激巨噬细胞RAW264.7分泌TNF-α和IL-1β的影响图
图4是CQMUH011对LPS致肺损伤肺组织病理变化的影响图(HE染色，×200倍)(A：Normal组，B：LPS组，C：DXM+LPS组，D：CQMUH-011+LPS组)
图5是CQMUH-011对LPS致肺损伤小鼠肺的湿/干比重的影响图
图6是CQMUH-011对LPS致肺损伤小鼠血清中炎症因子TNF-α和IL-6的影响图
图7是CQMUH-011对LPS致肺损伤小鼠肺组织中MDA含量和MPO活力的影响图
图8是CQMUH011对弗氏佐剂致关节炎大鼠踝关节组织病理变化的影响图(HE染色，×40倍)(A：Normal组；B：AA Model组；C：DXM+Model组；D：CQMUH-011+Model组)
图9是CQMUH-011对弗氏佐剂关节炎大鼠足围肿胀度的影响图
图10是CQMUH-011对弗氏佐剂关节炎大鼠足围肿胀度的影响(14d)图(A：Normal组；B：AA Model组；C：DXM+Model组；D：CQMUH-011+Model组)
图11是CQMUH-011对弗氏佐剂关节炎大鼠血清中炎症因子TNF-α和IL-6的影响图
图12是CQMUH-011对弗氏佐剂关节炎大鼠血清中MDA含量和MPO活力的影响图
图13是CQMUH-011对大鼠棉球肉芽肿干重的影响图
图14是CQMUH-011对棉球肉芽肿大鼠血清中NO和MDA及MPO的影响图
图15是CQMUH-011对二甲苯致小鼠耳肿胀度的影响图
具体实施方式
通过下列的具体实施例可进一步理解本发明，但它们不构成对本发明内容的限制。在本发明的上述前提下对本发明属于本专业技术人员的专业知识可获得的延伸扩展内容应该都在本发明要求保护的范围中。
实施例1
金刚烷磺酰胺类化合物CQMUH-011的合成：
38ml的98％浓硫酸与4ml的65％浓硝酸在冰浴下混合冷却，向该混酸中分次加入3.75克盐酸金刚烷胺，冰浴下搅拌反应3小时；加入碎冰60克，搅拌0.5小时；再加入氢氧化钾固体，调节pH至12-13，冰浴下搅拌反应2小时；抽滤，滤液用浓盐酸调节pH至8-9，浓缩至干；加入80ml无水乙醇回流1小时，放冷，抽滤，滤液浓缩至干；再加入10ml混合液(丙酮∶乙酸乙酯＝3∶1)回流1小时，冰浴下放置，得3-氨基金刚烷醇固体3克，熔点大于256℃。
将3克3-氨基金刚烷醇、0.25克碘化钾、10克碳酸钾加入到30ml四氢呋喃中搅拌升温至40℃，保持该温度下缓慢滴加3克N-氯乙酰基-2-氰基四氢吡咯(即氯代B)溶解在30ml四氢呋喃的溶液，约1.5小时滴完。滴毕，保温40℃反应1小时后，升温至回流反应2小时。回流结束，趁热过滤，滤饼用少量四氢呋喃洗涤，合并滤液，浓缩至油状物。油状物加入适量丁酮溶解，放置析晶，过滤，干燥得氨基B取代的金刚烷氨醇固体4克，熔点147-149℃。HPLC归一化法测定纯度为98.1％，IR、NMR等结构表征符合要求的结构。
在反应瓶中加入1克上述氨基B取代的金刚烷氨醇、适量对甲苯磺酰氯、适量吡啶和20ml四氢呋喃，搅拌并且慢慢升温至回流，反应20小时。反应完后，向反应液中加入20ml5％的碳酸钠溶液，再加入40ml乙酸乙酯，倒入分液漏斗中，收集有机层。水层再用50ml的乙酸乙酯分两次萃取。合并有机层，饱和食 盐水洗涤后，无水硫酸钠干燥，干燥完后旋蒸除去有机溶剂得白色固体粗品。用柱层析纯化，再用丙酮重结晶得到金刚烷磺酰胺类化合物CQMUH-011固体，熔点192-195℃。HPLC归一化法测定纯度为95.1％，IR、NMR等结构表征符合要求的结构。
实施例2
金刚烷磺酰胺类化合物CQMUH-011的体外细胞实验
在培养的原代小胶质细胞和巨噬细胞RAW264.7中加入不同浓度的CQMUH-011，观察LPS刺激后CQMUH-011对培养的小胶质细胞和巨噬细胞增殖和炎症因子产生的影响，结果显示CQMUH-011对LPS刺激引起的小胶质细胞和巨噬细胞增殖、炎症因子产生有明显抑制作用(见图1.图2.图3.表1)
表1.CQMUH-011对小胶质细胞TNF-α和IL-1β产生的影响
| TNF-α(pg/mL) | IL-1β(pg/mL) | |
| 空白组 | 93.2±3.6 | 129.5±4.1 |
| LPS组(10μg·ml-1) | 1154.32±40.8＊ | 1271.8±36.1＊ |
| 药物组(1×10-6mol/L) | 450.2±21.8# | 346.2±21.8# |
| (3×10-7mol/L) | 451.3±26.1# | 379.2±22.3# |
| (1×10-7mol/L) | 478.3±30.8# | 406.3±33.2# |
| (3×10-8mol/L) | 491.3±34.3# | 409.3±31.9# |
| (1×10-8mol/L) | 512.7±34.1# | 412.3±31.1# |
实施例3
金刚烷磺酰胺类化合物CQMUH-011的体内抗炎实验
一、CQMUH-011对脂多糖诱导的小鼠肺损伤的保护作用
目的：评价CQMUH-011对脓毒症的抑制作用。
给药方案与实验步骤：取Balb/c雄性小鼠，称重并编号。随机分为正常组、脂多糖(LPS) 组、地塞米松(DXM)+LPS组和CQMUH-011+LPS组，每组10只小鼠。LPS组小鼠腹腔注射LPS(20mg/kg)，正常组小鼠腹腔注射给予等剂量的生理盐水，各组小鼠均于建模前2小时分别给予生理盐水、生理盐水、地塞米松溶液(1.5mg/kg)、新药CQMUH-011溶液(457μg/kg)(所有溶液均含有4％1，2-丙二醇)。于建模后6小时各组选一半的小鼠摘眼球取血，分离血清(3000r，4℃，离心10min)，按试剂盒操作测TNF-α和IL-6值；剩下的小鼠12小时后摘眼球取血，并将其部分右肺切取下来用4％多聚甲醛固定，剩下的右肺进行肺湿干重检测，部分左肺用冷生理盐水匀浆用于丙二醛(MDA)和髓过氧化物酶(MPO)检测，剩下的左肺保存于-80℃备用。
1.组织观察：4％多聚甲醛固定的标本用石蜡包埋，切片，HE染色后光学显微镜下观察其形态学改变。
2.肺的W/D值测定：取小鼠剩下的右肺，用吸水纸轻轻吸干表面液体并用万分之一天平称重，记录各样本读数。然后用锡箔纸包裹，于60℃干燥箱中干燥72h，取出再次称重，并记录。计算肺组织干湿重的变化比率作为评价肺水肿程度的指标。
3.炎症因子检测：分离的血清用相应的酶联免疫吸附试剂盒(ELISA)进行TNF-α及IL-6水平测定。具体操作方法如下：
(1)从冰箱中取出试剂盒，室温平衡20min后从铝箔袋中取出所需板条，其余放回自封袋4℃保存。
(2)向标准品孔中加入不同浓度标准品50μL；样品孔中加入样品10μL及样品稀释液40μL。
(3)标准品孔及样品孔加入HRP标记的抗体100μL，封住反应孔，37℃孵育60min。
(4)弃去液体，洗板5次。
(5)加入底物A和B各50μL，37℃避光孵育15min。
(6)加入终止液50μL，15min内于450nm波长测定各孔OD值。
由OD值和标准曲线可以得到相应炎症因子浓度。
4.MDA含量测定：将10％组织匀浆离心取上清液，然后参照相应的检测试剂盒说明书操作进行测定，最后根据试剂盒计算方法算出。具体操作如下：
(1)肺组织匀浆液蛋白含量测定，按照说明书操作，步骤如下：
将该上清液用生理盐水按1∶9稀释成1％组织匀浆，待测。
表2 肺组织蛋白测定操作流程
肺组织匀浆上清液蛋白含量的计算公式：蛋白质含量(μg/ml)＝(测定管OD值-空白管OD值)×标准品浓度(563μg/ml)×样本测试前稀释倍数/(标准管OD值-空白管OD值)
(2)肺组织匀浆液中MDA含量的检测，按照MDA检测试剂盒说明书进行操作，步骤如下：
工作液I的配置：试剂一∶试剂二应用液∶试剂三应用液＝a∶3∶1，按需配制，配好后当天使用。
工作液I的配置：试剂一∶试剂二应用液∶试剂三应用液＝a∶3∶1，按需配制，配好后当天使用。
表3.肺组织MDA测定操作流程
| 空白管 | 标准管 | 测定管 | 对照管 | |
| 10nmol/ml标准品(ml) | a | |||
| 无水乙醇(ml) | a | |||
| 测定样品(ml) | a | a | ||
| 工作液I(ml) | 4.0ml | 4.0ml | 4.0ml | |
| 工作液II(ml) | 4.0ml |
漩涡混匀器混匀，95℃水浴40分钟，取出后流水冷却，3500-4000转/分，离心10分钟，取上清液，532nm处，测各管吸光度值。
肺组织匀浆上清液MDA含量计算公式：
MDA含量(nmol/mgprot)＝(测定管OD值-对照管OD值)/(标准管OD值-标准空白管OD值)×标准品浓度(10nmol/ml)/样本蛋白含量(mg prot/ml)
5.MPO活性检测：取未离心的10％肺组织匀浆液，按1∶1的比例加入试剂二，混匀后得到5％的肺组织匀浆。将5％的肺组织匀浆液与三号试剂按9∶1比例充分混匀，37℃水浴中水浴15min，取出后按说明书操作，步骤如下：
表4.肺组织MPO测定操作流程
MPO活力(U/g组织)＝(测定管OD值-对照管OD值)/11.3×取样量(g)
实验结果：
CQMUH-011能明显减轻LPS所致的小鼠肺损伤，降低肺湿/干比重，使小鼠血清中炎症因子TNF-α和IL-6，小鼠肺组织中MDA含量和MPO活力均降低(见图4，图5，图6，图7)，新药CQMUH-O11对LPS所致(脓毒症)小鼠的急性肺损伤具有一定的保护作用。
二、CQMUH-011对弗氏完全佐剂所致大鼠关节炎的保护作用
目的：评价CQMUH-011对免疫性炎症的保护作用。
给药方案与实验方法：选用体重180±20g雄性SD大鼠，随机分组，分别为正常组、AA模型组、地塞米松+AA组及CQMUH-011(300μg/kg)+AA组，除正常组外，其他各组大鼠右后足跖皮内注射0.1ml FCA致炎。于致炎前2小时，每组给予相应药物，即正常组和AA模型组给予生理盐水，地塞米松+AA组给予地塞米松溶液，CQMUH-011+AA组给予CQMUH-011溶液(所有溶液均含有4％1，2-丙二醇)。致炎后18小时，测量各组大鼠右后足肿胀度及体重变化；致炎一周后开始给药，连续7天，观察各组大鼠右后足肿胀度及体重变化；致炎21天后再次给药，连续7天，观察各组大鼠右后足肿胀度及体重变化。致炎28天后，大鼠行摘眼球手术取血获取血清进行炎症因子检测并取下其右后足踝关节于10％多聚甲醛中固定。
1.踝关节病理切片观察：10％多聚甲醛固定的标本用8％硝酸脱钙后，经石蜡包埋，切片，HE染色后光学显微镜下观察其形态学改变。
2.大鼠右后足肿胀度测定：于致炎前、致炎后18h、7d、14d、21d及28d用皮尺测量每只大鼠右后足同一部位的围度。
3.大鼠血清中TNF-α和IL-6测定：分别用相应ELISA试剂盒检测，具体操作步骤如下
(1)准备工作：将试剂盒放置室温，多余酶标条放回冰箱。标准品溶液制备：每瓶标准品加入标准品稀释液1mL，盖好后室温静置大约10分钟，同时反复颠倒以助溶解，其浓度为200pg/mL(贮液)。先将其稀释为100pg/mL(标准曲线最高浓度)后，再准备7个稀释标准品的EP 管，每个EP管中加入500μL的标准品稀释液，依次倍比稀释成100pg/mL、50pg/mL、25pg/mL、12.5pg/mL、6.25pg/mL、3.12pg/mL、1.56pg/mL，标准品稀释液(0pg/mL)作为空白孔。备用。
(2)样本检测：
1)加样：分别设标准孔、待测样品孔、空白孔。设标准孔7孔，依次加入100μl不同浓度的标准品(如上所示)。空白孔加100μL标准品稀释液，余孔加待测样品100μL，酶标板加上覆膜，37℃温育2小时。
2)弃去液体，甩干，不用洗涤。
3)每孔加检测溶液A工作液100μL(临用前配制)，酶标板加上覆膜，37℃温育1小时。
4)弃去孔内液体，每孔用350μL的洗涤液洗涤，浸泡1-2分钟，甩干酶标板内的液体，垫上吸水纸用力拍打几下，重复洗涤3次。最后一次洗涤后要将孔内液体完全甩干。
5)每孔加检测溶液B工作液100μL(临用前配制)，酶标板加上覆膜，37℃温育30分钟。
6)弃去液体，甩干，洗板5次，方法同步骤4。
7)每孔加底物溶液90μL，酶标板加上覆膜，37℃避光显色(反应时间15-25分钟)。
8)每孔加终止溶液50μL，终止反应，用酶标仪在450nm波长测量各孔的光密度。
由OD值和标准曲线可以得到相应炎症因子浓度。
4.大鼠血清中MDA含量测定：根据该试剂盒步骤操作，具体操作同第一部分。
5.大鼠血清中MPO活力测定：根据该试剂盒步骤操作，具体操作如下
取大鼠血清按1∶1的比例加入试剂二，充分混匀。混匀后溶液与三号试剂按9∶1比例加入并充分混匀，37℃水浴中水浴15min，取出后按说明书操作，步骤如下：
表5.大鼠血清中MPO活力测定操作步骤
MPO活力(U/L)＝(测定管OD值-对照管OD值)/11.3×取样量(L)
实验结果：
CQMUH-011对弗氏佐剂所致大鼠关节炎踝关节病理损伤有保护作用，降低关节炎大鼠足围肿胀度、血清中炎症因子(TNF-α和IL-6)和MDA水平及MPO活性(见图8，图9，图10，图11)，新药CQMUH-011对免疫性关节炎具有抑制(治疗)作用。
三、CQMUH-011对大鼠棉球肉芽肿的抑制作用
目的：评价CQMUH-011对亚急性炎症的抑制作用
给药方案及实验方法：选用体重150±10g雄性SD大鼠，称重并编号，随机分组，分别为正常组、模型组、地塞米松组及CQMUH-011(300μg/kg)组。除正常组外，其他各组大鼠在麻醉状态下，在其左、右蹊部各剪一小口，以血管钳扩充皮下组织，每侧埋入一灭菌棉球(重量10±1mg)，而后缝合。于术前2小时给药，即正常组和模型组给予生理盐水，地塞米松组给予地塞米松溶液，CQMUH-011组给予该新药溶液(所有药品均含有4％1，2-丙二醇)；之后每天给药一次，连续7天，第8天处死动物，获取全血，分离血清(3000r，4℃，离心10min)，并取出棉球，剔尽脂肪组织，待用。
1.大鼠棉球肉芽肿重量测定：将取得的棉球用锡箔纸包裹，于60℃烘箱箱中干燥48h，取出干棉球称重，减去棉球本身重量，即为肉芽肿重量，并以mg/100g体重表示。
2.大鼠血清中NO测定：根据该试剂盒步骤操作，具体操作如下
(1)取出试剂盒，使Griess Reagent I和Griess Reagent II恢复至室温。
(2)不同浓度标准品制备：用生理盐水将标准品稀释成9个浓度，分别为0、1、2、5、10、20、40、60、100μM。
(3)按50μl/孔，在96孔板中加入标准品及待测样品。
(4)按50μl/孔，在各孔中加入室温Griess Reagent I。
(5)按50μl/孔，在各孔中加入室温Griess Reagent II。
(6)540nm波长测定吸光度。
由吸光度和标准曲线可以得到NO浓度。
3.大鼠血清中MDA含量测定：根据该试剂盒步骤操作，具体操作同第一部分。
4.大鼠血清中MPO活力测定：根据该试剂盒步骤操作，具体操作同第二部分。
实验结果：
CQMUH-011可明显降低大鼠棉球肉芽肿干重，降低肉芽肿大鼠血清中NO和MDA水平及MPO的活性(见图12，图13)，新药CQMUH-011对亚急性炎症具有一定的抑制作用。
四、CQMUH-011对小鼠耳二甲苯致炎的保护作用
目的：评价CQMUH-011对急性炎症的抑制作用
给药方案及实验方法：取体重25g左右雄性小鼠，随机分组，分别为正常组、模型组、地塞米松组及CQMUH-011(457μg/kg)组，每组10只，除正常组外，其他各组均滴二甲苯0.03～0.05ml于鼠右耳，左耳不作处理。于致炎前2小时每组分别给予相应药物，即正常组和模型组给予生理盐水，地塞米松组给予地塞米松溶液，CQMUH-011组给予该新药溶液。致炎2小时后，将小鼠处死，沿耳廊基线剪下两耳，用直径5mm的打孔器分别在左、右耳同一部位打下圆形耳片，称重，求左、右耳片重量之差，作为肿胀度。
实验结果：
CQMUH-011可明显降低二甲苯所致的小鼠耳肿胀，使耳肿胀度降低(见图14)。新药CQMUH-011对急性炎症具有一定的抑制作用。
五、急性毒性实验
给予小鼠治疗剂量(小鼠457μg/kg)的10倍(4570μg/kg)、20倍(9142μg/kg)、40倍剂量(18284μg/kg)的CQMUH-011腹腔注射，观察2周，仅用药40倍的小鼠在用药后2小时内出现嗜睡，后恢复正常。全部小鼠2周内无死亡，精神活动正常，病理解剖各器官无异常。
Claims (5)
1.一种如下式所示的金刚烷磺酰胺类化合物，其特征在于，
A取代在金刚烷环的3位上，A是OH，B
是
C是/>
2.如权利要求1所述的金刚烷磺酰胺类化合物在制备抗炎药物中的应用；在制备预防或治疗免疫抑制药物中的应用；在制备预防或治疗自身免疫性疾病药物中的应用；在制备预防或治疗感染性疾病药物中的应用；在制备预防或治疗神经退行性疾病药物中的应用；在制备预防或治疗痛风药物中的应用；在制备预防或治疗移植免疫排斥反应药物中的应用；在制备预防或治疗肿瘤药物中的应用。
3.如权利要求2所述的应用，其特征在于，所述自身免疫性疾病选自风湿、类风湿性关节炎，强直性脊柱炎，红斑狼疮、克罗恩病、银屑病、幼年特发性关节炎或葡萄膜炎；所述感染性疾病选自脓毒症或败血症；所述神经退行性疾病选自多发性硬化、老年性痴呆或帕金森病。
4.一种药物组合物，其特征在于，含有权利要求1所述的金刚烷磺酰胺类化合物，以及药学上可接受的载体。
5.如权利要求1所述的金刚烷磺酰胺类化合物的制备方法，其特征在于，以盐酸金刚烷胺为起始原料，用混酸及氢氧化钾为试剂，对金刚烷胺环的3位进行羟基化，得到金刚烷氨醇；金刚烷氨醇再与卤代B反应，制备得到氨基B取代的金刚烷氨醇，然后继续与对甲苯磺酰氯反应，制备得到目标金刚烷磺酰胺类化合物。
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|---|---|---|---|---|
| WO2011087758A1 (en) * | 2009-12-22 | 2011-07-21 | H. Lundbeck A/S | Adamantyl amide derivatives and uses of same |
| WO2012043866A1 (en) * | 2010-09-29 | 2012-04-05 | Fujifilm Corporation | Actinic-ray- or radiation-sensitive resin composition, actinic-ray- or radiation-sensitive film and method of forming pattern |
| CN105523985A (zh) * | 2015-12-18 | 2016-04-27 | 天津民祥生物医药股份有限公司 | 一种维格列汀的制备方法 |
-
2016
- 2016-09-12 CN CN202310613837.2A patent/CN116640081A/zh active Pending
- 2016-09-12 CN CN201610818842.7A patent/CN106432025B/zh active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011087758A1 (en) * | 2009-12-22 | 2011-07-21 | H. Lundbeck A/S | Adamantyl amide derivatives and uses of same |
| WO2012043866A1 (en) * | 2010-09-29 | 2012-04-05 | Fujifilm Corporation | Actinic-ray- or radiation-sensitive resin composition, actinic-ray- or radiation-sensitive film and method of forming pattern |
| CN105523985A (zh) * | 2015-12-18 | 2016-04-27 | 天津民祥生物医药股份有限公司 | 一种维格列汀的制备方法 |
Non-Patent Citations (3)
| Title |
|---|
| "Compatible validated spectrofluorimetric and spectrophotometric methods for determination of vildagliptin and saxagliptin by factorial design experiments";Omar Abdel-Aziz等;《Spectrochimica Acta Part A: Molecular & Biomolecular Spectroscopy》;20151231(第140期);第229-240页 * |
| Omar Abdel-Aziz等."Compatible validated spectrofluorimetric and spectrophotometric methods for determination of vildagliptin and saxagliptin by factorial design experiments".《Spectrochimica Acta Part A: Molecular & Biomolecular Spectroscopy》.2015,(第140期),第229-240页. * |
| 新化合物CQMUH-011对LPS诱导的小胶质细胞增殖的抑制作用及其机制研究;蔡江晖;《重庆医科大学硕士学位论文》;20160810;摘要，第17-18页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN116640081A (zh) | 2023-08-25 |
| CN106432025A (zh) | 2017-02-22 |
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