CN102942562A - 一种苯并咪唑衍生物及其制备方法和应用 - Google Patents
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Abstract
本发明涉及一种苯并咪唑衍生物，所述苯并咪唑衍生物为2-间苯胺基苯并咪唑-1H-吡唑-3-甲酰胺，其结构式如下：
。本发明苯并咪唑衍生物能促进酵母菌生长，增强其代谢活性，并能显著降低长期以高脂饲料喂养的C57 BL/6J小鼠的血浆甘油三酯、总胆固醇和高密度脂蛋白，降低模型小鼠收缩压和舒张压，降低模型小鼠的空腹血糖，改善小鼠糖耐量，并影响SIRT1及相关基因（FOXO1、P53、PPARγ和PGC-1α）的表达，明显改善糖尿病模型小鼠的糖、脂代谢，因此可将其应用于制备预防及治疗糖尿病及其并发症方面的药物中。
Description
技术领域
本发明属于医药技术领域，具体涉及咪唑类衍生物，尤其是化合物2-间苯胺基苯并咪唑-1H-吡唑-3-甲酰胺及其在作为沉默信息调节因子激动剂方面的应用、在制备减轻、改善、预防和治疗II型糖尿病或因糖尿病引起的包括高血糖、糖耐量异常、脂代谢异常以及上述疾患引起的并发症的药物中的应用。
背景技术
II型糖尿病占总糖尿病的90%，其主要发病机制是胰岛素抵抗、胰岛β细胞功能衰竭和胰岛素分泌障碍。II型糖尿病病人多伴随有肥胖、高血压、高甘油三脂或高胆固醇血症，高血脂是胰岛素抵抗和胰岛β细胞功能紊乱的主要原因之一。目前常用的降糖药有：胰岛素、磺脲类药物、非磺脲类胰岛素促分泌剂、双胍类降糖药、胰岛素增敏剂等，这几类降糖药作用快、疗效好、但毒副作用强，对肝、肾等器官损害，部分糖尿病人对胰岛素表现明显的抗药性。因此，通过合成新型化合物和发现新的蛋白作用靶点寻找新的安全有效的抗糖尿病药物是目前有效的重要方法。
Sirtuin蛋白家族是一类在进化过程中非常保守的蛋白酶。该家族中首先被发现并研究的是酵母的Sir2蛋白，研究证明Sir2被视为直接连接生物代谢状态与寿命的关键分子。而且在哺乳动物中SIRT1与Sir2的同源性最高。SIRT1广泛表达于哺乳动物组织中，在限制热量摄入或脑、肝脏、脂肪组织、肾脏和肌肉处于禁食状态下，SIRT1表达增加。SIRT1通过转录调控，调节肝脏的糖脂代谢，肌肉组织的分化，脂肪组织形成等多种与代谢调节有关的生理过程。
新型SIRT1小分子激动剂（如SRT1460、SRT1720和SRT2183），其化学结构与白藜芦醇完全无关，但激活SIRT1活性的能力高于白藜芦醇1000倍。还有一些嘧啶并恶唑类化合物也被证明是SIRT1的激动剂，并且比白藜芦醇的活性更具潜力。研究结果显示，这些小分子激动剂可以产生与限制饮食和加强锻炼的同等效应，能改善胰岛素敏感性，降低葡萄糖浓度并增强线粒体功能。大鼠高胰岛素血症的血糖钳夹试验显示，小分子SIRT1激动剂能改善全身血糖的内环境平衡和脂肪组织、骨骼肌和肝脏的胰岛素敏感性。
通过酵母Sir2基因和小鼠体内测试筛选自主开发的苯并咪唑衍生物来激活SIRT1，从而寻找出高效低毒的防治糖尿病及其并发症的候选药物，至今尚未见文献报道。
发明内容
本发明的目的在于提供一种新型结构的苯并咪唑衍生物及其制备方法，该苯并咪唑衍生物可应用于制备减轻、改善、预防和治疗II型糖尿病或因糖尿病引起的包括高血糖、糖耐量异常、脂代谢异常以及上述疾患引起的并发症的候选药物。
本发明实现目的的技术方案是：
一种苯并咪唑衍生物，所述苯并咪唑衍生物为2-间苯胺基苯并咪唑-1H-吡唑-3-甲酰胺，其结构式如下：
如权上所述的苯并咪唑衍生物的制备方法，步骤如下：
⑴制备2-间苯胺基苯并咪唑；
⑵制备2-间苯胺基苯并咪唑-1H-吡唑-3-甲酰胺。
而且，所述的苯并咪唑衍生物的制备方法，其特征在于：步骤如下：
⑴制备2-间苯胺基苯并咪唑；
向反应器中通入氩气，排出空气，再分别加入间氨基苯甲酸和邻苯二胺，然后向反应器中加入多聚磷酸，间氨基苯甲酸：邻苯二胺：多聚磷酸的质量比为5：4：55，待到反应升温至200℃，持续反应5~7小时；
待反应降温至100℃，将反应液倒入冰水中，再向其中滴加质量分数为20%的氢氧化钠溶液，滴至pH为9~10；之后再滴加质量分数为5%的碳酸氢钠溶液，并伴有气泡产生，待气泡不再生成，抽滤得到淡粉色固体；再将固体使用纯二氯甲烷进行柱层析分离，得到白色固体，即为2-间苯胺基苯并咪唑-1H-吡唑-3-甲酰胺。
⑵制备2-间苯胺基苯并咪唑-1H-吡唑-3-甲酰胺
将无水二氯甲烷、1H-吡唑-3-羧酸和EDCI·HCl按照比例ml：g：g为50：1.2：2.9混合后，室温搅拌，再分别加入2-间苯胺基苯并咪唑、4-二甲氨基吡啶和三乙胺，三者的摩尔比为2：1：4，室温反应，TLC监测反应结束，得反应液；
将反应液加入水后，用二氯甲烷萃取，合并有机相，有机相依次经水和饱和食盐水洗涤，无水硫酸钠干燥后过滤，滤液经真空旋转蒸发仪40℃旋蒸浓缩，得到的产物按甲醇与二氯甲烷的体积比为1~2：100进行柱层析分离，得到白色固体，即为2-间苯胺基苯并咪唑-1H-吡唑-3-甲酰胺。
如上所述的苯并咪唑衍生物在作为沉默信息调节因子激动剂方面的应用。
如上所述的苯并咪唑衍生物在调控SIRT1、FOXO1、P53、PPARγ和PGC-1α基因的表达方面的应用。
如上所述的苯并咪唑衍生物在制备减轻、改善、预防及治疗糖尿病的药物中的应用。
而且，所述糖尿病为II型糖尿病。
如上所述的苯并咪唑衍生物在制备糖尿病的并发症的药物中的应用。
而且，所述并发症为因糖尿病引起的高血糖、糖耐量异常和脂代谢异常。
而且，所述并发症为因糖尿病引起的高血糖、糖耐量异常、脂代谢异常而引起的并发症。
本发明的优点和有益效果为：
1、本发明苯并咪唑衍生物能促进酵母菌生长，增强其代谢活性，并能显著降低长期以高脂饲料喂养的C57 BL/6J小鼠的血浆甘油三酯、总胆固醇和高密度脂蛋白，降低模型小鼠收缩压和舒张压，降低模型小鼠的空腹血糖，改善小鼠糖耐量，并影响SIRT1及相关基因（FOXO1、P53、PPARγ和PGC-1α）的表达，明显改善糖尿病模型小鼠的糖、脂代谢，因此可将其应用于制备预防及治疗糖尿病及其并发症方面的药物中。
2、本发明苯并咪唑衍生物经体外酵母菌实验证明促进了酵母菌的生长活性，增强了其代谢生长；体内小鼠实验实验证明了苯并咪唑衍生物能改善，预防和治疗II型糖尿病或因糖尿病引起的包括高血糖、糖耐量异常、脂代谢异常以及上述疾患引起的并发症，因而可将其应用于制备预防和治疗II型糖尿病或因糖尿病引起的包括高血糖、糖耐量异常、脂代谢异常以及上述疾患引起的并发症的药物中。
附图说明
图1为本发明化合物2-间苯胺基苯并咪唑-1H-吡唑-3-甲酰胺（简称JHJ3）的合成路线示意图；
图2为本发明实施例1中2-间苯胺基苯并咪唑的核磁共振氢谱分析图；
图3为本发明实施例1中化合物JHJ3的核磁共振氢谱分析图；
图4为本发明化合物JHJ3对BY4743酵母菌生长活性的影响图；
图5为本发明化合物JHJ3对BY4743酵母菌生长曲线斜率的比较图；
图6为本发明化合物JHJ3对高脂模型小鼠血清甘油三酯（TG）、胆固醇（TC）、高密度脂蛋白（HDL-C）水平的影响图；其中，图6-1为化合物JHJ3对高脂模型小鼠血清甘油三酯（TG）水平的影响图；图6-2为化合物JHJ3对高脂模型小鼠血清胆固醇（TC）水平的影响图；图6-3为化合物JHJ3对高脂模型小鼠血清高密度脂蛋白（HDL-C）水平的影响图；
图7为本发明化合物JHJ3对高脂模型小鼠血压（SBP，DBP）的影响图；
图8为本发明化合物JHJ3对高脂模型小鼠血清葡萄糖含量的影响图；
图9为本发明化合物JHJ3对高脂模型小鼠口服葡萄糖耐量（OGTT）的影响图；
图10为本发明化合物JHJ3对模型小鼠肝脏组织中基因SIRT1、FOXO1、P53、PPARγ和PGC-1α 的mRNA相对表达量图；其中，图10-1为化合物JHJ3对模型小鼠肝脏组织中基因SIRT1 mRNA的相对表达量影响图；图10-2为化合物JHJ3对模型小鼠肝脏组织中基因FOXO1 mRNA的相对表达量影响图；图10-3为化合物JHJ3对模型小鼠肝脏组织中基因P53 mRNA的相对表达量影响图；图10-4为化合物JHJ3对模型小鼠肝脏组织中基因PPARγ mRNA的相对表达量影响图；图10-5为化合物JHJ3对模型小鼠肝脏组织中基因PGC-1α mRNA的相对表达量影响图。
其中，图6 至图10 中，* p < 0.05 ，** p < 0.01（与模型组相比）。
具体实施方式
下面通过具体实施例对本发明作进一步详述，以下实施例只是描述性的，不是限定性的，不能以此限定本发明的保护范围。
本实施例中所使用的试剂如无特殊说明，均为市售产品；所使用的方法如无特殊说明，均为常规方法；所使用的仪器如无特殊说明，均为常规仪器。
本发明的原理是基于酵母Sir2与哺乳动物SIRT1的高度同源，证明苯并咪唑衍生物，即化合物2-间苯胺基苯并咪唑-1H-吡唑-3-甲酰胺（简称JHJ3）能促进酵母菌生长，增强其代谢活性，并能显著降低长期以高脂饲料喂养的C57 BL/6J小鼠的血浆甘油三酯、总胆固醇和高密度脂蛋白，降低模型小鼠收缩压和舒张压，降低模型小鼠的空腹血糖，改善小鼠糖耐量，并影响SIRT1及相关基因（FOXO1、P53、PPARγ和PGC-1α）的表达，明显改善糖尿病模型小鼠的糖、脂代谢。
本发明通过对体外酵母菌实验证明苯并咪唑衍生物JHJ3对酵母菌生长活性的促进，增强了其代谢生长；体内动物实验证明了苯并咪唑衍生物JHJ3能改善，预防和治疗II型糖尿病或因糖尿病引起的包括高血糖、糖耐量异常、脂代谢异常以及上述疾患引起的并发症。
一种苯并咪唑衍生物及其制备步骤如下：
一、根据图1所示合成路线合成2-间苯胺基苯并咪唑-1H-吡唑-3-甲酰胺
1、制备2-间苯胺基苯并咪唑
先向250ml圆底烧瓶中通入氩气，排出空气，再分别加入间氨基苯甲酸（2g，0.015mol）和邻苯二胺（1.6g，0.015mol），然后向反应器中缓慢加入多聚磷酸（PPA）22g，待到反应升温至200℃，持续反应约5~7小时。
待反应降温至100℃，将反应液慢慢倒入装有150ml冰水的烧杯中，再待反应降温至100℃，将反应液倒入冰水中，会产生大量沉淀，再向其中滴加质量分数为20%的氢氧化钠溶液，滴至pH为9~10，之后再滴加质量分数为5%的碳酸氢钠溶液，伴有气泡产生，以防止因沉淀凝聚而影响分离提纯，待气泡不再生成，抽滤得到淡粉色固体。再将固体使用纯二氯甲烷进行柱层析分离，得到白色固体(2.3g，73.3%)。
结果分析：
经核磁分析得图2，结果如下：
1H NMR (400 MHz, DMSO): δ(ppm) 12.682 (s, br, 1H),7.555 (s, 2H), 7.434 (t, J=2.0 Hz, 1H), 7.283 (d,J=8 Hz, 1H), 7.176 (m, 3H), 6.687 (dd, J=1.6, 1.6Hz, 1H), 5.285 (s, br, 2H)。
以上结果表明，所得产物为2-间苯胺基苯并咪唑。
2、制备2-间苯胺基苯并咪唑-1H-吡唑-3-甲酰胺（JHJ 3）
100ml圆底烧瓶加入无水二氯甲烷（50ml），1H-吡唑-3-羧酸（1.2g，0.01mol）和EDCI·HCl（2.9g，0.015mol），室温搅拌10分钟，再分别缓慢加入2-间苯胺基苯并咪唑（2.1g，0.01mol）、4-二甲氨基吡啶（DMAP）（0.6g，0.005mol）和三乙胺（2g，0.02mol），室温反应，TLC监测反应结束。
将反应液缓慢倒入250ml分液漏斗中，加入100ml的水，用二氯甲烷萃取三次，合并有机相，有机相依次经水（40 ml×2）和饱和食盐水（40 ml×2）洗涤，无水硫酸钠干燥后过滤，滤液经真空旋转蒸发仪40℃旋蒸浓缩，得到的产物按甲醇与二氯甲烷的体积比为1~2：100进行柱层析分离，得到白色固体（1.3g，42.9%），即为2-间苯胺基苯并咪唑-1H-吡唑-3-甲酰胺（JHJ 3）。
结果分析：
经核磁分析分析得图3，结果如下：
1H NMR (400 MHz, DMSO): δ(ppm) 13.456 (s, br, 1H),12.905 (s, br, 1H), 10.196 (s, br, 1H), 8.729 (s,1H), 7.924 (s, 1H), 7.853 (d, J=8 Hz, 2H), 7.484-7.635 (m, 3H), 7.216 (s, 2H), 6.828 (s, 1H).
2-间苯胺基苯并咪唑-1H-吡唑-3-甲酰胺（JHJ3）的结构式如下：
二、苯并咪唑类化合物JHJ3对酵母菌生长活性的影响
利用自动微生物生长分析仪（Growth Curves USA, Piscataway,NJ）测定酵母菌的生长活性，在100孔蜂窝板中分为2组，分别为：①148μL YPD培养基、2μL YPD 菌液，作为空白对照。 ②148μL YPD培养基、2μL YPD 菌液，0.2μL 100μM/L的JHJ3 。以上均为每孔加入的量，并进行多组平行实验，保持恒温30℃，每半小时测定其OD600的值。
结果分析：
实验结果如图4所示，加入JHJ3的BY4743酵母菌表现出进入对数期较早的趋势，表明JHJ3可能对BY4743酵母菌有激活的作用。图5为每一时刻生长曲线斜率的变化图，即Ln(OD/ODi)，其中JHJ 3斜率总体趋势与对照一致，相差不大，表明JHJ3不会对BY4743酵母菌的生长产生明显的抑制作用。
三、苯并咪唑类化合物JHJ3对高脂模型小鼠糖、脂代谢的影响。
1、小鼠的分组及饲养配比
所有C57 BL/6J小鼠适应性饲养1周后，随机分为2组：基础组10只、高脂模型组20只。其中高脂模型组又分为2组（每组10只），分别为：高脂组和JHJ3组。基础组与高脂组继续分别喂饲相应的基础饲料和高脂饲料，各给药组小鼠喂饲高脂饲料，并分别添加100mg/(kg·bw·d) JHJ3进行干预，干预时间为13w。实验期间，小鼠自由摄食、饮水，室内温度22士2℃，相对湿度55士5%，室内通风良好。每天观察小鼠的精神状态，活动情况，每周称量两次体重。各组小鼠饲料构成见表1。
表1 各组饲料配比（%）
| 成分 | 基础组 | 高脂组 | JHJ3组 |
| 酪蛋白 | 20 | 20 | 20 |
| DL-蛋氨酸 | 0.1 | 0.1 | 0.1 |
| 蔗糖 | 20 | 20 | 20 |
| 玉米淀粉 | 41.9 | 26.8 | 26.7 |
| 猪油 | 5 | 20 | 20 |
| 胆固醇 | - | 0.1 | 0.1 |
| 纤维素 | 5 | 5 | 5 |
| 矿物质 | 4 | 4 | 4 |
| 维生素 | 2 | 2 | 2 |
| 明胶 | 2 | 2 | 2 |
| JHJ3 | - | - | 0.1 |
2、对高脂模型小鼠脂代谢的影响
利用相应试剂盒分别测定其血清的TG、TC、HDL-C等血脂指标。从表2及图6中可见，JHJ3给药13周后模型小鼠血清的TG、TC及HDL-C显著高于正常对照组；给药组小鼠血清的TG、TC较模型组均明显降低，虽然给药组小鼠血清的HDL-C较模型组差异不大，但是给药组小鼠血清HDL-C/TC的比值较模型组明显升高。
表2 JHJ3治疗13周对高脂模型小鼠血脂的影响
| 组别 | TG (mg/dL) | TC (mg/dL) | HDL-C (mg/dL) |
| 正常对照 | 56.95±19.64** | 95.37±8.14** | 40.21±10.44** |
| 模型 | 119.70±17.75 | 220.19±30.98 | 108.89±32.78 |
| JHJ 3 | 90.39±14.43* | 187.74±38.35* | 117.71±22.28 |
* ：P ＜ 0.05vs 模型组；** ：P ＜ 0.01vs 模型组，下同。
3、对高脂模型小鼠血压的影响
在12周时，利用智能无创血压仪Softron BP-2010A对小鼠进行血压测定，对比其收缩压(SBP)和舒张压(DBP)。如图7所示，给药12周后高脂组小鼠血压明显高于正常组；相比模型组，JHJ 3能显著降低小鼠的收缩压（SBP）和舒张压（DBP）。
4、对高脂模型小鼠糖代谢的影响
⑴对高脂模型小鼠血清葡萄糖含量的影响
饲养小鼠13周后，处死小鼠。利用Glu试剂盒以葡萄糖氧化酶法测定血清葡萄糖含量。如图8所示，JHJ3给药13周后，模型组小鼠空腹血糖较正常对照组明显升高；与模型组比较，JHJ3各给药组小鼠空腹血糖明显降低。
⑵对高脂模型小鼠口服糖耐量(OGTT) 的影响
在12周时，对小鼠进行口服糖耐量试验。小鼠禁食12h，采取尾静脉取血的方式，利用血糖仪和血糖试纸（强生）测定正常组、高脂组和给药组的血糖，根据体重灌胃葡萄糖（2g/kg body weight）。灌胃前的测定记为0min，灌胃后分别测30、60、120min的血糖值。如图9所示，进过13周的高脂饲养，模型组小鼠的葡萄糖耐量明显低于正常对照组；JHJ3给药13周后，JHJ3能提高小鼠葡萄糖耐量。
5、对高脂模型小鼠肝脏组织基因表达水平的影响
饲养小鼠13周后，处死小鼠，解剖，取肝脏组织。按TRIzol说明书操作步骤，提取30~50mg小鼠肝脏组织的总mRNA。通过计算出RNA的浓度（RNA浓度=A260×40×稀释倍数μg/μL），取1μg（20μL体系）按Takara RT 试剂盒试剂盒说明，进行反转录反应。取2μL cDNA模板，以β-肌动蛋白（β-actin）作为内参对照，利用Takara SYBR® Premix Ex TaqTM II为荧光染料的试剂盒，进行实时定量荧光PCR分析，利用BIO-RAD IQTM 5实时荧光定量PCR仪进行测定，同时做融解曲线判定引物质量。采用△△Ct法，以与内参对照β-actin的相对比值作为目的基因的相对含量，分析小鼠肝脏中SIRT1、FOXO1、P53、PPARγ和PGC-1α mRNA表达量。
如图10所示，结果显示，JHJ3组的小鼠肝脏组织基因SIRT1、FOXO1、P53、PPARγ和PGC-1α的表达量均明显高于模型组；JHJ3组的小鼠肝脏组织基因P53 mRNA的表达量明显低于模型组，这些都符合先前有关SIRT1激动剂的研究。即在分子水平进一步证实本发明化合物JHJ3能改善由长期食用高脂膳食等引起的血脂代谢紊乱等。
综上，可以看出化合物2-间苯胺基苯并咪唑-1H-吡唑-3-甲酰胺（简称JHJ3）可以应用在作为沉默信息调节因子激动剂方面，也可以应用在制备减轻、改善、预防及治疗糖尿病及其并发症方面的药物中，尤其是在制备减轻、改善、预防和治疗II型糖尿病或因糖尿病引起的包括高血糖、糖耐量异常、脂代谢异常以及上述疾患引起的并发症的药物中的应用。
Claims (10)
1.一种苯并咪唑衍生物，其特征在于：所述苯并咪唑衍生物为2-间苯胺基苯并咪唑-1H-吡唑-3-甲酰胺，其结构式如下：
2.一种如权利要求1所述的苯并咪唑衍生物的制备方法，其特征在于：步骤如下：
⑴制备2-间苯胺基苯并咪唑；
⑵制备2-间苯胺基苯并咪唑-1H-吡唑-3-甲酰胺。
3.根据权利要求2所述的苯并咪唑衍生物的制备方法，其特征在于：步骤如下：
⑴制备2-间苯胺基苯并咪唑
向反应器中通入氩气，排出空气，再分别加入间氨基苯甲酸和邻苯二胺，然后向反应器中加入多聚磷酸，间氨基苯甲酸：邻苯二胺：多聚磷酸的质量比为5：4：55，待到反应升温至200℃，持续反应5~7小时；
待反应降温至100℃，将反应液倒入冰水中，再向其中滴加质量分数为20%的氢氧化钠溶液，滴至pH为9~10；之后再滴加质量分数为5%的碳酸氢钠溶液，有气泡产生，滴至气泡不再生成，抽滤得到淡粉色固体；再将固体使用纯二氯甲烷进行柱层析分离，得到白色固体，即为2-间苯胺基苯并咪唑-1H-吡唑-3-甲酰胺。
⑵制备2-间苯胺基苯并咪唑-1H-吡唑-3-甲酰胺
将无水二氯甲烷、1H-吡唑-3-羧酸和EDCI·HCl按照比例ml：g：g为50：1.2：2.9混合后，室温搅拌，再分别加入2-间苯胺基苯并咪唑、4-二甲氨基吡啶和三乙胺，三者的摩尔比为2：1：4，室温反应，TLC监测反应结束，得反应液；
将反应液加入水后，用二氯甲烷萃取，合并有机相，有机相依次经水和饱和食盐水洗涤，无水硫酸钠干燥后过滤，滤液经真空旋转蒸发仪40℃旋蒸浓缩，得到的产物按甲醇与二氯甲烷的体积比为1~2：100进行柱层析分离，得到白色固体，即为2-间苯胺基苯并咪唑-1H-吡唑-3-甲酰胺。
4.如权利要求1所述的苯并咪唑衍生物在作为沉默信息调节因子激动剂方面的应用。
5.如权利要求1所述的苯并咪唑衍生物在调控SIRT1、FOXO1、P53、PPARγ和PGC-1α基因的表达方面的应用。
6.如权利要求1所述的苯并咪唑衍生物在制备减轻、改善、预防及治疗糖尿病的药物中的应用。
7.根据权利要求6所述的苯并咪唑衍生物在制备减轻、改善、预防及治疗糖尿病的药物中的应用，其特征在于：所述糖尿病为II型糖尿病。
8.如权利要求1所述的苯并咪唑衍生物在制备糖尿病的并发症的药物中的应用。
9.根据权利要求8所述的苯并咪唑衍生物在制备糖尿病的并发症的药物中的应用，其特征在于：所述并发症为因糖尿病引起的高血糖、糖耐量异常和脂代谢异常。
10.根据权利要求8所述的苯并咪唑衍生物在制备糖尿病的并发症的药物中的应用，其特征在于：所述并发症为因糖尿病引起的高血糖、糖耐量异常、脂代谢异常而引起的并发症。
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103554140A (zh) * | 2013-10-28 | 2014-02-05 | 中山大学 | 蒽醌多吡啶配体及其双核钌配合物的制备方法和应用 |
| WO2015138500A1 (en) * | 2014-03-11 | 2015-09-17 | Icahn School Of Medicine At Mount Sinai | Sulfonamides derived from tricyclyl-2-aminocycloalkanols as anticancer agents |
| US9796717B2 (en) | 2013-02-19 | 2017-10-24 | Icahn School Of Medicine At Mount Sinai | Tricyclic heterocycles as anticancer agents |
| US9937180B2 (en) | 2014-03-11 | 2018-04-10 | Icahn School Of Medicine At Mount Sinai | Constrained tricyclic sulfonamides |
| US10221158B2 (en) | 2015-09-09 | 2019-03-05 | Icahn School Of Medicine At Mount Sinai | Heterocyclic constrained tricyclic sulfonamides as anti-cancer agents |
| US10759790B2 (en) | 2015-09-09 | 2020-09-01 | Ichan School Of Medicine At Mount Sinai | Heterocyclic constrained tricyclic sulfonamides as anti-cancer agents |
| CN111875545A (zh) * | 2020-07-17 | 2020-11-03 | 安阳师范学院 | 一种6-位取代苯并咪唑衍生物的定向合成方法及应用 |
Families Citing this family (1)
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|---|---|---|---|---|
| WO2015187082A1 (en) * | 2014-06-02 | 2015-12-10 | Lipigon Pharmaceuticals Ab | New plasma lipid lowering agents |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1426303A (zh) * | 2000-01-19 | 2003-06-25 | 奥尔顿有限公司 | 噻唑、咪唑和噁唑化合物以及与蛋白老化相关疾病的治疗 |
| WO2005030206A1 (en) * | 2003-09-24 | 2005-04-07 | Imclone Systems Incorporated | Aryl-1,3-azole derivatives and methods for inhibiting heparnase activity |
| WO2006094235A1 (en) * | 2005-03-03 | 2006-09-08 | Sirtris Pharmaceuticals, Inc. | Fused heterocyclic compounds and their use as sirtuin modulators |
| US20100168084A1 (en) * | 2008-05-08 | 2010-07-01 | Huber L Julie | Therapeutic compounds and related methods of use |
-
2012
- 2012-12-05 CN CN201210517136.0A patent/CN102942562B/zh active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1426303A (zh) * | 2000-01-19 | 2003-06-25 | 奥尔顿有限公司 | 噻唑、咪唑和噁唑化合物以及与蛋白老化相关疾病的治疗 |
| WO2005030206A1 (en) * | 2003-09-24 | 2005-04-07 | Imclone Systems Incorporated | Aryl-1,3-azole derivatives and methods for inhibiting heparnase activity |
| WO2006094235A1 (en) * | 2005-03-03 | 2006-09-08 | Sirtris Pharmaceuticals, Inc. | Fused heterocyclic compounds and their use as sirtuin modulators |
| US20100168084A1 (en) * | 2008-05-08 | 2010-07-01 | Huber L Julie | Therapeutic compounds and related methods of use |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9796717B2 (en) | 2013-02-19 | 2017-10-24 | Icahn School Of Medicine At Mount Sinai | Tricyclic heterocycles as anticancer agents |
| CN103554140A (zh) * | 2013-10-28 | 2014-02-05 | 中山大学 | 蒽醌多吡啶配体及其双核钌配合物的制备方法和应用 |
| WO2015138500A1 (en) * | 2014-03-11 | 2015-09-17 | Icahn School Of Medicine At Mount Sinai | Sulfonamides derived from tricyclyl-2-aminocycloalkanols as anticancer agents |
| CN106458936A (zh) * | 2014-03-11 | 2017-02-22 | 西奈山伊坎医学院 | 作为抗癌药的三环‑2‑氨基环烷醇衍生的磺酰胺 |
| US9937186B2 (en) | 2014-03-11 | 2018-04-10 | Icahn School Of Medicine At Mount Sinai | Sulfonamides derived from tricyclyl-2-aminocycloalkanols as anticancer agents |
| US9937180B2 (en) | 2014-03-11 | 2018-04-10 | Icahn School Of Medicine At Mount Sinai | Constrained tricyclic sulfonamides |
| US10221158B2 (en) | 2015-09-09 | 2019-03-05 | Icahn School Of Medicine At Mount Sinai | Heterocyclic constrained tricyclic sulfonamides as anti-cancer agents |
| US10759790B2 (en) | 2015-09-09 | 2020-09-01 | Ichan School Of Medicine At Mount Sinai | Heterocyclic constrained tricyclic sulfonamides as anti-cancer agents |
| CN111875545A (zh) * | 2020-07-17 | 2020-11-03 | 安阳师范学院 | 一种6-位取代苯并咪唑衍生物的定向合成方法及应用 |
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