CN117106011A - 一类肽基磺胺类衍生物及其应用 - Google Patents
一类肽基磺胺类衍生物及其应用 Download PDFInfo
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- CN117106011A CN117106011A CN202310522695.9A CN202310522695A CN117106011A CN 117106011 A CN117106011 A CN 117106011A CN 202310522695 A CN202310522695 A CN 202310522695A CN 117106011 A CN117106011 A CN 117106011A
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Abstract
本发明涉及一类肽基磺胺类衍生物、其制备方法以及用途，具体涉及式Ⅰ所示化合物，其异构体、药学上可接受的盐或化学保护的形式，其制备方法及在制备治疗与COX‑2相关疾病或药物中的用途。本发明的化合物具有消炎、解热、镇痛效果，并对肿瘤等恶性疾病有较好的活性。
Description
技术领域
本发明涉及医药领域，具体涉及肽基磺胺类衍生物、其制备方法及其用途。
背景技术
炎症是具有血管系统的活体组织对损伤因子所发生的防御反应，是一种常见病、多发病，常表现为红、肿、热、痛。由炎症引起的各种疾病的发病率较高，如类风湿性关节炎在全球的发病率约为20％-40％；而由炎症所引起的发热数量之多更是无法统计。由于炎症在日常生活中普遍存在，并会导致各种疾病，因此对抗炎药物的研究是十分有必要的。
磺胺类药物塞来昔布是由美国辉瑞公司开发的一种非甾体抗炎药，临床上被用于治疗骨关节炎、类风湿关节炎和成人急性疼痛等疾病。塞来昔布还可以促进肺部肿瘤细胞的“细胞粘附分子－1”的表达，使更多的肺部肿瘤细胞被摧毁，用于肿瘤的治疗。
塞来昔布在临床用于因炎症引起的疾病以及癌症的治疗时，长期大量用药会造成强烈的胃肠道刺激，增加严重的胃肠道出血、溃疡、穿孔的风险，其风险可能是致命的，并且同时对肝肾造成不良影响。因此，本领域对以磺胺类药物塞来昔布为先导，进行衍生物设计，寻求活性更好，更低剂量，更安全的药物。
发明内容
本发明需要解决的技术问题之一是公开一类磺胺类衍生物，其作为塞来昔布的衍生物具有抗炎和抑制肿瘤的活性，有利于增强塞来昔布对COX-2的抑制作用，有利于缓解或降低塞来昔布在用于治疗因炎症引起疾病的副作用，可增强抗肿瘤活性，具有更好的用药安全性。
本发明需要解决的技术问题之二是在于公开所述的磺胺类衍生物在解热镇痛、抗炎及抗癌等相关疾病药物中的用途。
具体的，本发明的第一方面提供一种一类磺胺类衍生物(式I)、其异构体、药学上可接受的盐或化学保护的形式，
本发明涉及以下的化合物，其异构体、药学上可接受的盐或化学保护的形式：
本发明还提供所述化合物的制备方法，其中，所述式I化合物可通过如下反应路线制备得到：
上述各反应步骤的具体条件为本领域公知，对此本发明不作具体限定。根据本发明的教导结合本领域公知常识，本领域技术人员可以对通式中的各取代基进行选择替换以制备得到不同的化合物，这些选择和替换均在本发明的保护范围之内。
本发明还提供一种药物组合物，其包含本发明第一方面任一项所述化合物、其异构体、药学上可接受的盐或化学保护的形式，以及任选地，一种或多种药学上可接受的载体或赋形剂。
所述药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
这里所述的载体包括但不限于：离子交换剂，氧化铝，硬脂酸铝，卵磷脂，血清蛋白如人血白蛋白，缓冲物质如磷酸盐，甘油，山梨酸，山梨酸钾，饱和植物脂肪酸的部分甘油酯混合物，水，盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐，胶态氧化硅，三硅酸镁，聚乙烯吡咯烷酮，纤维素物质，聚乙二醇，羧甲基纤维素钠，聚丙烯酸酯，蜂蜡，羊毛脂。
所述赋形剂是指在药物制剂中除主药以外的附加物。其性质稳定，与主药无配伍禁忌，不产生副作用，不影响疗效，在常温下不易变形、干裂、霉变、虫蛀、对人体无害、无生理作用，不与主药产生化学或物理作用，不影响主药的含量测定等。如片剂中的黏合剂、填充剂、崩解剂、润滑剂；中药丸剂中的酒、醋、药汁等；半固体制剂软膏剂、霜剂中的基质部分；液体制剂中的防腐剂、抗氧剂、矫味剂、芳香剂、助溶剂、乳化剂、增溶剂、渗透压调节剂、着色剂等均可称为赋形剂。
本发明的化合物、其异构体、药学上可接受的盐或化学保护的形式可以通过以下途径给药：胃肠外、局部、静脉内、口服、皮下、动脉内、真皮内、经皮、直肠、颅内、腹膜内、鼻内、肌内途径或作为吸入剂。所述药物组合物可以任选地与在治疗各种疾病中至少有一定效果的其它试剂联合给药。
本发明的化合物、其异构体、药学上可接受的盐或化学保护的形式可根据给药途径配成各种适宜的剂型。
在通常情况下，足以实现预防或治疗效果的本发明组合物中含有本发明的化合物、其异构体、药学上可接受的盐或化学保护的形式的有效量为约0.001mg/千克体重/天至约10,000mg/千克体重/天。合适的情况下，剂量为约0.01mg/千克体重/天至约1000mg/千克体重/天。剂量范围可以为每天、每两天或每三天约0.01至1000mg/kg受试者体重，更通常为0.1至500mg/kg受试者体重。在预防性应用中，以相对低频率的间隔长期给予相对低的给药量。在治疗性应用中，有时需要以相对短的间隔给予相对高的给药量，直至疾病的进展被延缓或停止，并优选地直至个体表现出疾病症状的部分或完全改善，在此之后，可以给予患者预防方案。
本发明还提供本发明第一方面任一项所述化合物、其异构体、药学上可接受的盐或化学保护的形式或其药物组合物在制备COX-2抑制剂中的用途。
本发明还提供本发明第一方面任一项所述化合物、其异构体、药学上可接受的盐或化学保护的形式或其药物组合物在制备治疗与COX-2相关的疾病中的用途。
本发明还提供本发明第一方面任一项所述化合物、其异构体、药学上可接受的盐或化学保护的形式或其药物组合物，其用于治疗与COX-2相关的疾病。
本发明还提供一种治疗与COX-2相关的疾病的方法，其包括向有需要的受试者施用有效量的本发明第一方面任一项所述化合物、其异构体、药学上可接受的盐或化学保护的形式或其药物组合物。
上述所述与COX-2相关的疾病选自炎症、疼痛、发热或肿瘤。
本发明所述“药学上可接受的盐”包括与药学上可以接受的无机酸或者有机酸、或者无机碱或有机碱形成的常规盐。合适的酸加成盐的例子包括盐酸、氢溴酸、硫酸、磷酸、硝酸、高氯酸、富马酸、乙酸、丙酸、琥珀酸、三氟醋酸、羟基乙酸、甲酸、乳酸、马来酸、酒石酸、柠檬酸、扑酸、丙二酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、富马酸、甲苯磺酸、甲磺酸、萘-2-磺酸、苯磺酸、羟基萘甲酸、氢碘酸、苹果酸、鞣酸等形成的盐。合适的碱加成盐的例子包括钠、钾、镁、锂、铝、钙、锌、N,N’-二苄基乙二胺、胆碱、二乙醇胺、乙二胺、N-甲基葡糖胺等形成的盐。
本发明COX-2抑制剂肽基磺胺类化合物对由炎症引起的痛、肿具有明显的抑制，显示出较好的抗炎活性；同时对肿瘤具有明显的抑制作用。本发明化合物在用于因炎症引起的疾病以及癌症的治疗时，有利于改善降低对胃肠道刺激，减少严重的胃肠道出血、溃疡、穿孔的风险，有利于改善对肝肾的不良副作用，降低药物毒性。
具体实施方式
下面结合实例进一步阐明本发明的内容，但本发明的保护范围并不局限于这些实例。本发明所述的百分比除特别注明外，均为重量百分比。
实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
化合物的结构是通过核磁共振(1HNMR)来确定的。1HNMR的测定是用JEOL Eclipse400核磁仪，测定溶剂为，六氘代二甲基亚砜(DMSO-d6)，内标为四甲基硅烷(TMS)，化学位移是以10-6(ppm)作为单位给出；
制备高效液相使用岛津LC-8A制备液相色谱仪。
薄层色谱硅胶板(TLC)使用Merck产的铝板(20×20cm)，薄层层析分离纯化采用的规格是GF 254。
反应的监测采用薄层色谱法(TLC)或LCMS，使用的展开剂体系有：二氯甲烷和甲醇体系，正己烷和乙酸乙酯体系，石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节或者加入三乙胺等进行调节。
柱层析一般使用200～300目硅胶为载体。洗脱剂的体系包括：二氯甲烷和甲醇体系，正己烷和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺进行调节。
实施例中无特殊说明，反应的温度为室温(20℃～35℃)；
本发明所使用的试剂购自上海阿拉丁生化科技股份有限公司。
在常规的合成法以及实施例、和中间体合成例中，各缩写的意思如以下所示：
Na2SO4：硫酸钠；
DMSO：二甲基亚砜；
DIPEA：N,N-二异丙基乙胺；
HATU：2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯
Leu：亮氨酸
Gly：甘氨酸
Val：缬氨酸
Ala：丙氨酸
Phe：苯丙氨酸
Thr：苏氨酸
Pro：脯氨酸
Dimethyl：二甲基
Boc：叔丁氧基羰基；
实施例1
合成通法：
将1mmol的II、1.5mmol叔丁氧羰基保护的氨基酸(或者二肽)和1.5mmol HATU加入到装有25mL二氯甲烷的100mL单口瓶中，常温搅拌下缓慢滴加3mmol DIPEA，滴加完毕继续在常温下搅拌10h。反应结束，减压除去二氯甲烷，在所得残余物中加入100mL水，10％的盐酸调节pH值到6，用二氯甲烷萃取4次，合并有机相，无水Na2SO4干燥过夜。过滤，减压除去溶剂，剩余物经硅胶柱层析纯化，得中间体化合物III。
将化合物III加入到50mL单口瓶中，加入5mL二氯甲烷和5mL三氟醋酸，搅拌2.5h。反应完后旋蒸除溶剂，所得残余物中加入30mL水，饱和碳酸钾溶液将水相调节到pH到7，二氯甲烷萃取4次，合并有机相，无水Na2SO4干燥过夜。
过滤，减压除去溶剂，剩余物经硅胶柱层析纯化，得目标产品化合物I，收率28～78％。
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试验例2：大鼠角叉菜胶足垫水肿试验
挑选SD大鼠分成两组，禁食16小时，可以饮水。一组大鼠口服1ml悬浮于含有0.5％甲基纤维素和0.025％表面活性剂的赋形剂中的本发明化合物，安慰剂组口服1ml含有0.5％甲基纤维素和0.025％表面活性剂的赋形剂。大鼠给药量为10mg/kg体重。1小时后，两组大鼠分别由足底下注射0.1ml 1％角叉菜胶/0.9％无菌生理盐水溶液，并测定注射了药物的脚的体积。注射角叉菜胶后3小时，再次测定脚的体积。将给药物处理的一组大鼠的脚肿胀平均值与安慰剂组的大鼠进行对照比较，计算水肿抑制作用百分比。所述百分抑制作用是指与安慰剂组对照，给药组脚体积相比的降低百分比。结果如表1所示。
表1大鼠足水肿抑制作用
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由表1大鼠的足水肿的抑制试验数据显示，相对于塞来昔布33％的抑制百分比，本发明化合物的抑制百分比均大于35％，显示出较优的抑制大鼠足水肿的作用。
试验例3：由角叉菜胶诱导的大鼠痛觉缺失试验
取上述鼠角叉菜胶足垫水肿试验中SD大鼠。给药量为30mg/kg体重。在注射角叉菜胶3小时，将大鼠放于带有透明底板的有机玻璃容器中，在所述底板下面位置放有一高强度电灯作为辐射热源。在最初的20分钟内，热刺激开始作用于注射了药物的脚上，或者作用于对侧未注射药物的脚上。当光线被回缩的爪子打断时，关掉电灯和计时器电源，测定大鼠回缩其爪子的时间。以秒为单位确定对照组和药物治疗组的回缩潜伏期并确定对所述痛觉过敏的脚的百分抑制作用。结果如表2所示：
表2大鼠痛觉缺失百分抑制作用
由表2大鼠的足水肿痛觉过敏抑制试验数据显示，相对于塞来昔布35％的抑制百分比，本发明化合物的抑制百分比均大于37％，显示出较优的抑制大鼠足水肿痛觉抑制作用。
综合表1和表2数据显示，相对于塞来昔布，本发明化合物对大鼠炎症引起的水肿和疼痛显示出较优的改善和抑制作用，具有较优的抗炎作用。
试验例4：肿瘤细胞增殖抑制试验
本实验选取的肿瘤细胞包括：(HCT-116)人源的结直肠腺癌细胞、(MCF-7)人源的乳腺癌细胞、(Hela)人源的宫颈癌细胞、(SGC-7901)人源的胃腺癌细胞、(SK-MEL-1)人源的恶性黑色素瘤细胞、(HepG2)人源的肝癌细胞。
培养一段时间后，将细胞移到显微镜下观察细胞的状态和数量，用于实验，然后消化。处理步骤与上述步骤相同。细胞悬浮液混合均匀后，调整移液枪刻度至10μL吸取悬浮液，血细胞计数板进行细胞计数。调整到适当的浓度，以便在96孔板中铺设。初筛时，96孔板中每孔100μL，每100μL含5000个细胞。在放置96孔板后，将96孔板转移到培养箱中过夜，直到细胞粘附在壁上。实验分为对照组和给药组，每组6个孔。对照组在完全培养基中加入0.5％二甲基亚砜，给药组在完全培养基中不加入0.5％二甲基亚砜，药物浓度为25μL。培养箱中孵育时间为48h，到达时间后细致观察形态变化，并及时拍照记录。然后采用MTT法测定化合物的吸光度，根据对照组和实验组的吸光度的数值来计算抑制率。抑制率公式如下：
细胞抑制率＝(对照孔吸光度值-给药孔吸光度值)/对照孔吸光度值×100％(2-1)
表3 25μM下化合物作用于肿瘤细胞48h后抑制率(％)
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“―”表示未进行试验
试验例5：小鼠Lewis肺癌模型试验
将小鼠随机分为三组，正常对照组、荷瘤对照组和待测样品组。收集对数生长期的Lewis肺癌细胞，对荷瘤对照组和待测样品组的小鼠右侧腋部皮下注射细胞悬液，建立Lewis肺癌小鼠皮下接种模型。正常对照组和荷瘤对照组给予普通饲料喂养，待测组从接种之日起到试验结束每日给予含本发明化合物的待测药物1mg/g的饲料喂养。接种后35天，脱颈处死小鼠，分离皮下肿瘤称重。结果如表3所示。
表3
| 化合物 | 瘤重(g) |
| 荷瘤对照组 | 7.7 |
| T1 | 7.0 |
| T2 | 6.3 |
| T3 | 5.3 |
| T4 | 4.7 |
| T5 | 7.0 |
| T6 | 4.9 |
| T7 | 4.8 |
| T8 | 5.4 |
| T9 | 5.4 |
| T10 | 4.8 |
| T11 | 4.6 |
| T12 | 4.4 |
| T13 | 4.3 |
| T14 | 4.5 |
| T15 | 4.6 |
| T16 | 4.5 |
| T17 | 4.8 |
| T18 | 4.7 |
| T19 | 4.6 |
| T20 | 4.2 |
| T21 | 4.8 |
| T22 | 4.7 |
| T23 | 4.6 |
| T24 | 4.8 |
| T25 | 4.2 |
| T26 | 4.3 |
| T27 | 4.7 |
| T28 | 4.7 |
| T29 | 4.2 |
| T30 | 4.4 |
| T31 | 4.5 |
由表3数据可见，与荷瘤对照组相比，给予本发明化合物的小鼠的瘤重不大于7克，明显低于对照组小鼠7.7克的瘤重；表明本发明化合物对肿瘤具有明显的抑制作用。
本发明的其他化合物也具有与上述试验相类似的肿瘤抑制作用。
制剂例6
制备方法：将实施例1的化合物与蔗糖、玉米淀粉混合，加水湿润，搅拌均匀，干燥，粉碎过筛，加入硬脂酸钙，混合均匀，压片得片剂。每片重200mg，活性成分含量为10mg。
制剂例14
实施例1的化合物 20mg
注射用水 80mg
制备方法：将实施例1的化合物溶解与注射用水，混合均匀，过滤，将所获得的溶液在无菌条件下分装与安瓿瓶中，每瓶10mg，活性成分含量为2mg/瓶。
本申请活性数据经过与申请号2017107229000，一类肽基塞来昔布衍生物及其应用中化合物活性数据相比，本申请化合物T1～T31活性数据显著优于2017107229000，一类肽基塞来昔布衍生物及其应用中化合物活性数据。
Claims (5)
1.式I所示化合物,其异构体、药学上可接受的盐或化学保护的形式，
具体化合物如下表所示
2.权利要求1所述化合物的制备方法，其包括以下步骤：
化合物II与叔丁氧羰基保护的氨基酸(或二肽)用HATU进行N-酰化反应得到中间体III，III脱保护生成目标化合物I。
3.药物组合物，其包含权利要求1所述化合物、其异构体、药学上可接受的盐或化学保护的形式；以及任选地，一种或多种药学上可接受的载体或赋形剂。
4.权利要求1所述化合物、其异构体、药学上可接受的盐或化学保护的形式或权利要求3的药物组合物在制备COX-2抑制剂中的用途。
5.权利要求1所述化合物、其异构体、药学上可接受的盐或化学保护的形式或权利要求8的药物组合物在制备治疗与COX-2相关的疾病中的用途；其中所述与COX-2相关的疾病选自炎症、疼痛、发热或肿瘤。
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