CN101704792B - 具有基质金属蛋白酶抑制活性的喹喔啉酮类衍生物及其制备方法和应用 - Google Patents
具有基质金属蛋白酶抑制活性的喹喔啉酮类衍生物及其制备方法和应用 Download PDFInfo
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- CN101704792B CN101704792B CN200910229537A CN200910229537A CN101704792B CN 101704792 B CN101704792 B CN 101704792B CN 200910229537 A CN200910229537 A CN 200910229537A CN 200910229537 A CN200910229537 A CN 200910229537A CN 101704792 B CN101704792 B CN 101704792B
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- matrix metalloproteinase
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Abstract
本发明公开了一类具有基质金属蛋白酶抑制活性的喹喔啉酮类衍生物及其制备方法和应用，属药物化学技术领域。它有如通式(I)的结构，R1，R2，R3，R4，R5，R6有说明书中的含义。本发明化合物在体外抑酶活性试验中证实具有明确的MMP-2抑制活性，为有效的基质金属蛋白酶抑制剂，有望开发成为新型的抗癌药物。
Description
技术领域
本发明涉及具有抑制基质金属蛋白酶作用的喹喔啉酮类衍生物及其制备方法和应用，属于药物化学技术领域。
背景技术
恶性肿瘤是造成人类死亡的主要疾病之一，寻找高效低毒的选择性高的抗癌药物已迫在眉睫。基质金属蛋白酶(Matrix metalloproteinases，MMPs)是一类活性依赖于锌离子的肽链内切酶，其主要的生理功能是降解和重建细胞外基质，已被证明在肿瘤生长、侵袭、转移和癌组织血管生长中发挥着关键的作用。目前已发现了28种哺乳动物的MMP亚型，如此分类众多的MMPs家族成员，且因MMPs的高表达参与了人体众多生理过程，因此抑制所有MMPs家族成员显然是不合适的。人们由此意识到开发特异性MMPs抑制剂的重要性。目前对MMP抑制剂的研究集中在设计并合成对某一MMPs家族成员选择性高的特异性抑制剂，从而降低毒副作用，提高作用选择性。
已经证实MMP-2(明胶酶A)与侵袭性肿瘤的恶性表型以及癌症患者的不良预后密切相关，它参与了肿瘤细胞对基底膜、基质的侵袭以及癌细胞的转移。正常组织中不表达MMP-2，而肿瘤组织中却广泛高表达[参见Skiles，J.W.；Gonnella，N.C.；Jeng，A.Y.Curr.Med.Chem.2004，11，2911-77.Ramnath，N.；Creaven，P.J.Curr.Oncol.Rep.2004，6，96-102.]。MMP-2已成为肿瘤研究和开发抗肿瘤药物的有吸引力的靶点，以该靶点设计并寻找特异性且选择性高的抑制剂，是当前抗肿瘤血管生成药物中很有发展前景的一类。
发明内容
本发明的目的在于提供一类具有基质金属蛋白酶抑制活性的喹喔啉酮类衍生物，该类化合物可作为特异性MMP-2抑制剂，进而有可能成为治疗指数较高的可用于临床的药物。
本发明的另一目的是提供该类衍生物的制备方法和应用。
本发明采取的技术方案为：
具有基质金属蛋白酶抑制活性的喹喔啉酮类衍生物，它具有如下通式(I)的结构：
其中：(1)R1，R2，R3和R4相同或不同，各自独立地为氢、C1～8直链或支链烷基、C2-8直链或支链烯基、C2-8直链或支链炔基、杂烷基、C3-12环烷基、如下取代基，且至少一个为如下取代基：卤素、硝基、芳基、杂芳基、羟基、芳基氧基、杂芳基氧基、杂烷氧基、氨基、C1～8直链或支链氨基、二烷基氨基、芳基氨基、杂芳基氨基、C1～8烷基芳基氨基、杂烷基氨基、巯基、C1～8烷基巯基、芳基巯基、杂芳基巯基、杂烷基巯基、C1～8烷基磺酰基、芳基磺酰基、杂芳基磺酰基、C1～8烷亚砜基、芳基亚砜基、杂芳基亚砜基、氰基、C1～8烷基羰基、芳基羰基、杂芳基羰基、C1～8烷氧基或C1～8卤代烷基。
(2)R5为药学上可以接受的无机酸或有机酸，优选盐酸、氢溴酸、硝酸、硫酸、重硫酸、磷酸、醋酸、丙酸、羟基乙酸、2-羟基丙酸、2-氧代丙酸、草酸、丙二酸、富马酸、2-羟基-1，2，3-丙三酸、乳酸、酒石酸、琥珀酸、延胡索酸、葡萄糖酸、糖二酸、苯甲酸、2-羟基苯甲酸、4-氨基-2-羟基苯甲酸、甲磺酸、乙磺酸、环己基亚磺酸、苯磺酸、对甲苯磺酸、柠檬酸、马来酸、咖啡酸、没食子酸或巴莫酸。
(3)R6为C1-C8直链或支链烷基羰基、含取代基的芳基羰基、含取代基的杂芳基羰基、具有明确生物活性的天然羧酸的酰基、含取代基的脂肪族亚酰基、含取代基的芳香族亚酰基、C1～8烷基取代的磺酰基、含取代基的芳基磺酰基、杂芳基取代的磺酰基。
所述的具有明确生物活性的天然羧酸包括烷基羧酸，芳基羧酸，杂芳基羧酸，含有保护基或取代基的芳基羧酸，以及含有保护基或取代基的杂芳基羧酸；其中优选咖啡酸、没食子酸、琥珀酸、阿魏酸、肉桂酸、N-羟基肉桂酸、对羟基苯甲酸、异阿魏酸、桂皮酸、苯丙酸、硫辛酸、植酸、原儿茶酸、香英兰酸、食子酸、甘草酸、甘草次酸、迷迭香酸、白果酸、乌头酸、对羟基桂皮酸、油酸、鞣花酸、奎宁酸、香豆酸、莽草酸、芥子酸等。
本发明中上述术语含义如下：
杂烷基指饱和或不饱和的，支链或直链的，被取代的或未取代的至少含有一个杂原子的烷基。
芳基是指芳族碳环基团，优选的芳环含有6-18碳原子。
卤或者卤素包括氟、氯、溴、碘。
环烷基是饱和的或者不饱和，取代的或未取代的环状基团，该环可以是单环或者稠环，桥环或者螺环或者含有杂原子的环系。单环优选3-9个原子，多环优选7-13个原子，杂原子是指氮，硫，磷，氧等。
杂芳基是芳族杂环，可以是单环或多环，优选的杂芳基包括：噻吩基、吡咯基、呋喃基、吡啶基、吡嗪、噻唑基、喹啉基、异喹啉、嘧啶基、四氮唑基、苯并呋喃基、苯并噻唑基、吲哚基、哌嗪基、四氢哌嗪基等等。
所述的具有基质金属蛋白酶抑制活性的喹喔啉酮类衍生物优选下列化合物：
N-(2-3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰基)苯酰肼，
2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰肼，
N-(2-3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰基)苯乙酰肼，
2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)-N′-(丙酰-2-亚基)乙酰肼，
2，6-二氯-N′-(2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰基)苯乙酰肼，
(E)-N′-苯亚甲基-2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰肼，
(E)-N′-(呋喃-2-亚甲基)-2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰肼，
(E)-2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)-N′-(2-苯亚乙基)乙酰肼，
(E)-N′-(1-(4-溴苯基)亚乙基)-2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰肼，
(E)-N′-(2-羟基-3-甲氧苯亚甲基-2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰肼，
(E)-N′-(4-甲基苯亚甲基)-2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰肼，
(E)-N′-(4-(二甲胺基)苯亚甲基)-2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰肼，
(E)-N′-(3-硝基苯亚甲基)-2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰肼，
(E)-2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)-N′-(1-苯亚乙基)乙酰肼，
(E)-N′-(2，4-二甲氧基苯亚甲基)-2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰肼，
(E)-N′-(3，4，5-三甲氧基苯亚甲基)-2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰肼，
(E)-N′-(2-氯苯亚甲基)-2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰肼，
(E)-N′-(3，4，-二甲氧基苯亚甲基)-2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰肼，
(E)-N′-(2，5，-二甲氧基苯亚甲基)-2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰肼，
(E)-2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)-N′-(1-(4-硝基苯基)亚乙基)乙酰肼，
(E)-N′-(1-(3-氯苯基)亚乙基)-2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰肼。
所述通式(I)的制备方法，是以邻苯二胺为起始原料，先与丙酮酸甲酯反应成环，所得到的中间体再与氯乙酸乙酯(或溴乙酸乙酯)反应得到化合物3(结构如下)，再依次经过肼解、乙酰化反应并分离纯化获得最终产物。
下面以邻苯二胺为起始原料，具体说明该类化合物的制备方法。
a用的试剂为丙酮酸乙酯和反应溶剂；b用的试剂为氯乙酸乙酯和弱无机碱；c用的试剂为无水乙醇/甲醇和水合肼；d用的试剂为R1CHO和无水乙醇/甲醇；e用的试剂为R2COCl和反应溶剂。
具有基质金属蛋白酶抑制活性的喹喔啉酮类衍生物的制备方法，包括以下步骤：
(1)用2、3、4、5-位分别被R1、R2、R3、R4取代的邻苯二胺与丙酮酸甲酯在一定溶剂中加热回流反应制备喹喔啉酮母核化合物(II)；
(2)化合物(II)与溴代的或氯代的乙酸乙酯在弱碱催化剂作用下于乙醇或丙酮溶剂中加热回流反应制备化合物(III)；
(3)化合物(III)在无水乙醇或无水甲醇反应溶剂中与质量分数30％-80％的水合肼在70～80℃反应得到中间体(IV)；
(4)中间体(IV)与醛或酮在70-90℃一定溶剂中反应，或者与酰氯在碱性催化剂作用下一定溶剂中室温反应，得到最终产物(I)。
上述步骤(1)中所述的溶剂为无水乙醇、无水四氢呋喃、无水二氯甲烷或无水1，4-二氧六环；所述的溶剂的用量为每毫摩尔的2、3、4、5-位分别被R1、R2、R3、R4取代的邻苯二胺用6～7mL溶剂；所述的2、3、4、5-位被分别R1、R2、R3、R4取代的邻苯二胺与丙酮酸甲酯用量的摩尔比为1∶1.1～1.2。
步骤(2)中所述的弱碱催化剂为弱无机碱，优选碳酸钠或碳酸钾；所述的化合物(II)与溴代或氯代乙酸乙酯与弱碱催化剂用量的摩尔比为1∶1.2∶1.2；所述的乙醇或丙酮溶剂的用量为每毫摩尔的化合物(II)用8～10mL溶剂。
步骤(3)中所述的化合物(III)与水合肼摩尔比为1∶2～2.5，反应溶剂的用量为每毫摩尔的化合物(III)用2.5～5mL溶剂，优选质量分数80％的水合肼。
步骤(4)中所述反应溶剂为无水乙醇、无水甲醇、无水四氢呋喃、无水二氯甲烷或无水N，N-二甲基甲酰胺，化合物(IV)与醛(或酮)的摩尔比为1∶1.2，所述的碱性催化剂为碳酸钠、碳酸钾或Et3N，化合物(IV)与酰氯与弱碱催化剂用量的摩尔比为1∶1.2∶1.2，反应溶剂的用量均为每毫摩尔的化合物(IV)用5～10mL溶剂。
本发明的喹喔啉酮类衍生物可以游离形式或以盐形式存在。药学上可接受的盐包括常规的无毒性的盐，包括喹喔啉酮类衍生物碱与无机或有机酸形成的季铵盐。
本发明具有基质金属蛋白酶抑制活性的喹喔啉酮类衍生物在制备预防或治疗与基质金属蛋白酶活性异常表达相关的哺乳动物尤其是人类疾病的药物，特别是在制备预防或治疗癌症、炎症、多发性硬化病、各种组织溃疡、各种组织溃疡性病症和牙周病的药物中的应用。本发明的这些化合物能够抑制至少一种哺乳动物基质金属蛋白酶，优选MMP-2。因此，本发明设计含有式(I)结构化合物为主要活性成分的药学上可接受的药物组合物。
一种药物组合物，除含有一种或多种药学上可接受的载体或赋形剂外，还至少包含一种含有治疗量的本发明具有基质金属蛋白酶抑制活性的喹喔啉酮类衍生物。
该种组合物可制成口服制剂和肠胃外给药制剂，可以为片剂、丸剂、胶囊或注射剂。
本发明包含含有治疗剂量的本发明化合物的药物，和一种或多种药学上可接受载体和/或赋形剂的药物组合物。使用的药物载体可以为固体或者液体。
典型的固体载体包括乳糖，石膏粉，蔗糖，滑石，凝胶，琼脂，果胶，阿拉伯胶，硬脂酸镁，硬脂酸等等。固体载体也可以包括一种或多种可能同时作为增香剂，润滑剂，增溶剂，悬浮剂，填料，助流剂，压缩助剂，粘合剂或片剂-崩解剂的物质；它还可以是包封材料。在粉末中，载体为精细粉碎的固体，它与精细粉碎的活性成分的混合。在片剂中，活性成分与具有必要的压缩性质的载体以合适的比例混合，以需要的形状和大小压缩。粉末和片剂优选包含至多99％活性成分。合适的固体载体包括，例如，磷酸钙，硬脂酸镁，滑石，糖，孔糖，糊精，淀粉，凝胶纤维素，甲基纤维素，羧甲基纤维素钠盐，聚乙烯吡咯烷酮，低熔点蜡和离子交换树脂。
典型的液体载体包括糖浆，花生油，橄榄油，水等等。液体载体用于制备溶液，悬浮液，乳剂，糖浆。活性成分可以溶解或悬浮于药学上可接受的液体载体，如水，有机溶剂，二者的混合物或药学上可接受的油类或者脂肪。液体载体可以包含其它合适的药物添加剂如增溶剂，乳化剂，缓冲剂，防腐剂，增甜剂，增香剂，悬浮剂，增稠剂，颜料，粘度调节剂或渗透压调节剂。用于口服和肠胃外给药的液体载体的合适的例子包括水(部分地包含如同上述的添加剂，例如纤维素衍生物，优选羧甲基纤维素钠盐溶液)，醇(包括一元醇和多元醇，例如乙二醇)和它们的衍生物，和油类(例如分馏椰子油和花生油)。用于肠胃外给药的载体还可以为油脂如油酸乙酯和异丙基肉豆蔻酸盐。无菌的液体载体用于胃肠外给药的无菌的液态组合物。用于加压组合物的液体载体可以为卤代烃或其他药学上可以接受的推进剂。无菌溶液或悬浮液液体药物组合物可以用来，例如静脉内，肌肉，腹膜内或皮下注射。注射时可单次推入或逐渐注入，入30分钟的静脉内灌注。该化合物还可以以液体或者固体组合物的形式口服给药。
载体或赋形剂可以包括本领域已知的时间延迟材料，如单硬脂酸甘油酯或二硬脂酸甘油酸，还可以包括蜡，乙基纤维素，羟丙基甲基纤维素，异丁烯酸甲酯等等。当制剂用于口服时，公认PHOSALPG-50(phospholipid与1，2-丙二醇浓缩，A.Nattermann&Cie.GmbH)中的0.01％吐温80用于其他化合物的可接受的口服制剂的配制，可以适应于本发明各种化合物的配制。
给予本发明化合物时可以使用各式各样的药物形式。如果使用固体载体，制剂可为片剂，被放入硬胶囊内的粉末或小药丸形式或锭剂或糖锭形式。固体载体的量在很大程度上变化，但是优选从约25mg到约1g。如果使用液体载体，制剂可为糖浆，乳剂，软胶胶囊，在安瓿或非水的液体悬浮液中的无菌注射溶液或悬浮液。
为了获得稳定的水溶性的剂型，可以将化合物或其药学上可接受的盐溶于有机或无机酸的水溶液，0.3M琥珀酸或柠檬酸溶液。选择性地，酸性的衍生物可以溶于合适的碱性溶液。如果得不到可溶形式，可将化合物溶于合适的共溶剂或他们的结合。这样的合适的共溶剂的例子包括，但是不局限于，浓度范围从0-60％总体积的乙醇，丙二醇，聚乙二醇300，聚山梨酸酯80，甘油，聚氧乙烯脂肪酸酯，脂肪醇或甘油强脂肪酸酯等等。
各种释放系统是已知的并且可用于化合物或其各种制剂的给药，这些制剂包括片剂，胶囊，可注射的溶液，脂质体中的胶囊，微粒，微胶囊等等。引入的方法包括但是不局限于皮肤的，皮内，肌肉，腹膜内的，静脉内的，皮下的，鼻腔内的，肺的，硬膜外的，眼睛的和(通常优选的)口服途径。化合物可以通过任何方便的或者其它适当的途径给药，例如通过注入或快速浓注，通过上皮的或粘膜线路(例如，口腔粘膜，直肠和肠粘膜等等)吸收或通过负载药物的支架以及可以与其生物活性剂一起给药。可以全身或局部给药。用于鼻，支气管或肺疾病的治疗或预防时，优选的给药途径为口服，鼻给药或支气管烟雾剂或喷雾器。
附图说明
图1为明胶中游离氨基测定的标准曲线图。
具体实施方式
本发明使用表1列出来的化合物进一步来说明，但是并不限定本发明。
表1
以下结合实施例来进一步说明本发明。
实施例1
2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰肼(表1中lyg-31)的制备方法
称取邻苯二胺(10.81g，0.10mol)，加入250ml无水乙醇中，常温搅拌15min至溶解，加入丙酮酸乙酯(12.77g，0.11mol)，有黄色固体生成，继续搅拌4h，反应完毕。抽滤，得浅黄色固体，乙醇重结晶得到3-甲基喹喔啉-2(1H)-酮，产率为92.7％，m.p.241-243℃；称取3-甲基喹喔啉-2(1H)-酮(8.01g，0.05mol)，无水碳酸钾(8.29g，0.06mol)和氯乙酸乙酯(7.353g，0.06mol)，加入200ml丙酮，呈混悬液，加入四丁基溴化铵(0.5g，cat.)，油浴条件下加热回流，TLC检测反应完毕，减压蒸除溶剂，加入100ml水和200ml乙酸乙酯萃取三次，乙酸乙酯旋干得固体，用乙醇重结晶得2-(3-甲基-2-氧代喹喔啉-1(2H)-基)-乙酸乙酯，产率为73.2％，m.p.120-122℃；称取2-(3-甲基-2-氧代喹喔啉-1(2H)-基)-乙酸乙酯(2.46g，0.01mol)，加入50ml无水乙醇，常温搅拌至溶解，滴加80％水合肼(5.01g，0.1mol)，滴加完毕，回流反应10h，TLC检测反应完毕，减压蒸除溶剂，加入100ml水和200ml乙酸乙酯萃取三次，旋干有机溶剂得固体，用乙酸乙酯重结晶得白色2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰肼固体，产率为86.4％，m.p.221-224℃.ESI-MS 233.1(M+H)，1H-NMR：(DMSO-d6，ppm)δ：2.45(s，3H，CH3)，4.28(d，J＝1.8Hz，2H，NH2)，4.86(s，2H，NCH2CO)，7.30(d，J＝8.4Hz，1H，ArH)，7.35(t，J＝7.8Hz，1H，ArH)，7.54(t，J＝7.2Hz，1H，ArH)，7.76(d，J＝7.8Hz，1H，ArH)，9.36(s，1H，CONH)。
实施例2
N-(2-3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰基)苯乙酰肼(表1中lyg-32)的制备方法
称取邻苯二胺(10.81g，0.10mol)，加入250ml无水乙醇中，常温搅拌15min至溶解，加入丙酮酸乙酯(12.77g，0.11mol)，有黄色固体生成，继续搅拌4h，反应完毕。抽滤，得浅黄色固体，乙醇重结晶得到3-甲基喹喔啉-2(1H)-酮，产率为92.7％，m.p.241-243℃；称取3-甲基喹喔啉-2(1H)-酮(8.01g，0.05mol)，无水碳酸钾(8.29g，0.06mol)和氯乙酸乙酯(7.353g，0.06mol)，加入200ml丙酮，呈混悬液，加入四丁基溴化铵(0.5g，cat.)，油浴条件下加热回流，TLC检测反应完毕，减压蒸除溶剂，加入100ml水和200ml乙酸乙酯萃取三次，乙酸乙酯旋干得固体，用乙醇重结晶得2-(3-甲基-2-氧代喹喔啉-1(2H)-基)-乙酸乙酯，产率为73.2％，m.p.120-122℃；称取2-(3-甲基-2-氧代喹喔啉-1(2H)-基)-乙酸乙酯(2.46g，0.01mol)，加入50ml无水乙醇，常温搅拌至溶解，滴加80％水合肼(5.01g，0.1mol)，滴加完毕，回流反应10h，TLC检测反应完毕，减压蒸除溶剂，加入100ml水和200ml乙酸乙酯萃取三次，乙酸乙酯旋干得固体，用乙酸乙酯重结晶得白色固体2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰肼，产率为86.4％，m.p.221-224℃。称取2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰肼(0.23g，1mmol)，无水碳酸钠(0.12g，1.1mmol)，加入20ml无水四氢呋喃中，然后加入苯乙酰氯(0.154g，1mmol)，常温搅拌12h，反应完毕。减压蒸除溶剂，得到粉红色固体，加少量水洗涤，过滤；滤饼用乙醇重结晶，得到白色粉末N-(2-3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰基)苯乙酰肼，产率为47.6％，m.p.276-277℃，ESI-MS 351.2(M+H)，1H-NMR：(DMSO-d6，ppm)δ：2.45(s，3H，CH3)，3.453(s，2H，CH2CO)，4.976(s，2H，NCH2CO)，7.21-7.36(m，7H，ArH)，7.54(t，J＝7.2Hz，1H，ArH)，7.76(d，J＝7.8Hz，1H，ArH)，10.181(s，1H，CONH)，10.308(s，1H，CONH)。
实施例3
2，6-二氯-N′-(2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰基)苯乙酰肼(表1中lyg-34)的制备方法
2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰肼的制备见实施例1。称取2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰肼(0.23g，1mmol)，无水碳酸钠(0.12g，1.1mmol)，加入20ml无水四氢呋喃中，然后加入2，6-二氯苯甲酰氯(0.209g，1mmol)，常温搅拌12h，反应完毕。减压蒸除溶剂，加少量水洗涤，过滤；滤饼用乙醇重结晶，得到白色粉末2，6-二氯-N′-(2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰基)苯乙酰肼，产率为57.1％，m.p.294-296℃，ESI-MS 405.8(M+H)，1H-NMR：(DMSO-d6，ppm)δ：2.43(s，3H，CH3)，5.048(s，2H，NCH2CO)，7.355-7.38(m，2H，ArH)，7.46(d，J＝8.4Hz，1H，ArH)，7.517-7.582(m，2H，ArH)，7.72(d，J＝1.8Hz，1H，ArH)，7.78(dd，J＝1.8，8.4Hz，1H，ArH)，10.499(s，1H，CONH)，10.57(s，1H，CONH)。
实施例4
(E)-N′-苯亚甲基-2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰肼(表1中lyg-35)的制备方法
2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰肼的制备见实施例1。称取2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰肼(0.23g，1mmol)，无水碳酸钠(0.12g，1.1mmol)，加入20ml无水四氢呋喃中，然后加入2，6-二氯苯甲酰氯(0.106g，1mmol)，常温搅拌12h，反应完毕。减压蒸除溶剂，加少量水洗涤，过滤；滤饼用乙醇重结晶，得到白色粉末(E)N′-苯亚甲基-2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰肼，产率为43.1％，m.p.272-273℃，ESI-MS 321.1(M+H)，1H-NMR：(DMSO-d6，ppm)δ：2.47(s，3H，CH3)，5.46(s，2H，NCH2CO)，7.35-7.80(m，9H，ArH)，8.08(s，1H，ArH)，10.42(s，1H，CONH)，10.49(s，1H，CONH)。
实施例5
(E)N′-(3，4，-二甲氧基苯亚甲基)-2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰肼(表1中lyg-47)的制备方法
2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰肼的制备见实施例1。称取2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰肼(0.23g，1mmol)，无水碳酸钠(0.12g，1.1mmol)，加入20ml无水四氢呋喃中，然后加入2，6-二氯苯甲酰氯(0.18g，1mmol)，常温搅拌12h，反应完毕。减压蒸除溶剂，加少量水洗涤，过滤；滤饼用乙醇重结晶，得到白色粉末(E)-N′-(3，4，-二甲氧基苯亚甲基)-2-(3-甲基-2-氧-喹喔啉-1-(2H)-基)乙酰肼，产率为49.4％，m.p.284-285℃，ESI-MS 381.3(M+H)，1H-NMR：(DMSO-d6，ppm)δ：2.477(s，3H，CH3)，3.809(s，3H，OCH3)，3.811(s，3H，OCH3)，5.460(s，2H，NCH2CO)，7.011-7.034(m，1H，ArH)，7.202-7.580(m，5H，ArH)，7.792(d，J＝7.2Hz，1H，ArH)，8.001(s，1H，ArH)，11.744(s，1H，CH＝N)。
实施例6
抑酶试验
6.1目标化合物抑制明胶酶活性试验(In vitro)
6.1.1原理：琥珀酰明胶已被证明能被MMP-2水解，肽键水解产生的游离氨基浓度的高低与酶活性呈正相关。琥珀酸酐保护明胶中的游离氨基，水解后暴露的伯氨与2，4，6-三硝基苯磺酸(TNBS)反应显色，通过检测450nm波长处的吸收度确定氨基含量，从而确定MMP-2的活性，间接反映出化合物对MMP-2的抑制情况。
6.1.2材料与方法：MMP-2购自欣经科生物技术公司，TNBS、明胶购自sigma公司
6.1.2.1明胶中游离氨基测定：甘氨酸溶于50mmol/L硼酸钠缓冲液(5ml，pH＝8.5)中，配制成0.007mol/L溶液，取不同体积甘氨酸溶液与TNBS反应30min，测试样品见表2，做出标准曲线如图1。
表2
标准曲线为：A＝0.13485C-0.10038。明胶配制成20mg/3mL的溶液，按上述方法测定吸收度为0.142，即20mg明胶中约含有1.8μmol游离氨基。
6.1.2.2明胶琥珀酰化：200mg明胶溶于50mmol/L硼酸钠缓冲液(10ml，pH＝8.5)中，将20mg琥珀酸酐分批加入，用1mol/L NaOH调节，使溶液保持pH＝8.0～8.5，反应5h，用50mmol/L硼酸钠缓冲液(pH8.5)充分透析(48h内透析三次)，得到琥珀酰明胶溶液。
6.1.2.3明胶酶活性分析：96孔板中分别加入上述琥珀酰明胶溶液55μL(约含200μg琥珀酰明胶)，酶溶液[3mg酶溶于50mmol/L硼酸钠缓冲液(pH＝8.5)100ml中]，50mmol/L硼酸钠缓冲液(pH＝8.5)补足150μL，37℃孵化30min，加入0.03％TNBS溶液50μL，室温放置20min，于450nm波长处测定吸收度，结果如表3、表4。
表3
空白组表4
1号孔中的吸收度为0.418，适于吸收度测定，所以选定酶溶液的体积为5μL。
6.1.2.4抑酶检测：96孔板中分别加入上述琥珀酰明胶溶液55μL，明胶酶溶液5μL，不同梯度浓度的化合物，50mmol/L硼酸钠缓冲液(pH＝8.5)补足150μL；100％组不含抑制剂，空白组仅加入5μL明胶酶溶液，均用硼酸钠缓冲液补足150μL。37℃孵化30min，加入0.03％TNBS溶液50μL，室温放置20min，于450nm波长处测定吸收度。按照如下公式计算抑制率：
根据化合物浓度和相应的抑制率，利用OriginPro 7.5软件处理，求出各化合物的IC50。结果如下表5：
表5
Claims (3)
1.具有基质金属蛋白酶抑制活性的喹喔啉酮类衍生物，其特征是，如下结构式化合物：
2.按照权利要求1所述的具有基质金属蛋白酶抑制活性的喹喔啉酮类衍生物在制备预防或治疗与基质金属蛋白酶活性异常表达相关的哺乳动物类疾病的药物中的应用。
3.一种药物组合物，其特征是，除含有一种或多种药学上可接受的载体或赋形剂外，还至少包含一种含有治疗量的按照权利要求1所述的具有基质金属蛋白酶抑制活性的喹喔啉酮类衍生物。
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| CN103787993B (zh) * | 2014-02-21 | 2016-04-27 | 北京工业大学 | 喹喔啉-2(1h)-酮类化合物及其制备方法和应用 |
| CN107827828B (zh) * | 2017-11-21 | 2021-03-30 | 南京华漫新材料科技有限公司 | 含苯酰肼骨架的喹喔啉衍生物及其制备方法和在制备抗肿瘤药物中的应用 |
| CN110467578A (zh) * | 2018-05-11 | 2019-11-19 | 南京大学 | 一种人半胱氨酸荧光探针及其制法和用途 |
| CN108997230B (zh) * | 2018-07-26 | 2020-08-04 | 山东大学 | 具有基质金属蛋白酶抑制活性的喹喔啉衍生物及其制备方法和应用 |
| CN109535086B (zh) * | 2019-01-29 | 2020-05-05 | 湖南科技学院 | 一种喹喔啉-2(1h)-酮c-3位羧酸酯化合物的合成方法 |
| CN109535087B (zh) * | 2019-01-29 | 2020-07-31 | 湖南科技学院 | 一种喹喔啉-2(1h)-酮c-3位芳酰基化合物的合成方法 |
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Non-Patent Citations (2)
| Title |
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| G.K. Rao, et al..Synthesis and evaluation of N"-((substituted phenyl)methylidene)-2-(3-methyl-2-oxoquinoxalin-1(2H)-yl)acetohydrazide for possible antibacterial and antifungal activities.《International journal of biological chemistry》.2009,第3卷(第2期),71-77. * |
| M. Z. A. BADR, et al..Synthesis and chemistry of some novel quinoxalinone derivatives and their antimicrobial effects.《J. Indian Chem. Soc.》.1990,第67卷216-219. * |
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