CN115894452B - 一种p2x7受体抑制剂 - Google Patents
一种p2x7受体抑制剂 Download PDFInfo
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- CN115894452B CN115894452B CN202210988191.1A CN202210988191A CN115894452B CN 115894452 B CN115894452 B CN 115894452B CN 202210988191 A CN202210988191 A CN 202210988191A CN 115894452 B CN115894452 B CN 115894452B
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Abstract
本发明公开了一种P2X7受体抑制剂,属于化学药物领域。该P2X7受体抑制剂的结构如式I所示。本发明提供的化合物不仅对P2X7受体具有优异的抑制活性,同时还具有优异的代谢稳定性。与阳性对照JNJ47965567相比,本发明化合物的代谢稳定性明显提高。本发明提供的化合物可以用来制备P2X7受体抑制剂,以及制备治疗炎症及炎症相关疾病、肾损伤、呼吸系统疾病、癌症、疼痛、中枢神经系统疾病、放射性脑损伤、脑缺血、心肌损伤、糖尿病、抑郁症、红斑狼疮、动脉粥样硬化、过敏性哮喘等疾病的药物,应用前景广阔。
Description
技术领域
本发明属于化学药物领域,具体涉及一种P2X7受体抑制剂。
背景技术
Buenstock等研究发现ATP通过作用嘌呤受体P2发挥作用,并将对ATP敏感的P2受体划分为配体门控离子通道P2X型和G蛋白偶联P2Y型两类。根据P2X型受体组件以及信号转导差异性,在哺乳动物细胞中可克隆出7种亚型(P2X1-7)。
P2X型受体均由胞内氨基末端(N端)与羧基末端(C端)和胞外半胱氨酸残基环两个跨膜区组成。不同的是,P2X7受体(简称P2X7R)全长由595个氨基酸残基组成,其C端是所有家族成员中最长的(由239氨基酸构成)。这一独特的分子结构基础,决定了其不但具有离子通道功能,而且在激活状态下可由离子通道向大的细胞孔径转化,参与机体递质释放、信号转导、炎性反应等生理病理过程。大量研究表明,P2X7受体广泛表达于中枢神经系统(CNS)中,不但是神经元和胶质细胞发挥多种生理机制的基础,而且参与多种CNS疾病的发生发展。研究发现,P2X7受体在神经元和胶质细胞中均有表达,是两者多种生理病理的沟通桥梁。P2X7受体与睡眠障碍、神经退行性疾病等疾病密切相关,通过调控P2X7受体信号通路治疗CNS疾病具有广泛的应用前景。
JNJ47965567是一种市售的P2X7受体拮抗剂,对人和大鼠P2X7均具有良好的抑制效果,具有中枢通透性、高亲和力、高选择性的优点。但是,JNJ47965567的代谢稳定性不佳,降低了药物的治疗效果。
为了克服上述问题,开发出一种不仅能够有效抑制P2X7受体,同时具有优异的代谢稳定性的化合物,对治疗包括及炎症相关疾病、中枢神经系统疾病在内的多种疾病具有重要意义。
发明内容
本发明的目的在于提供一种不仅能够有效抑制P2X7受体,同时具有优异的代谢稳定性的P2X7受体抑制剂。
本发明提供了一种式I所示的化合物、或其盐、或其同位素化合物、或其立体异构体、或其水合物:
其中,
n为0、1、2或3;
R1选自被一个或多个R1a取代的以下基团:5~6元芳基、5~6元杂芳基;R1a选自氢、氰基、卤素、羟基、氨基、C1~8烷基、卤代的C1~8烷基、C1~8烷氧基、卤代的C1~8烷氧基;
R2选自氢、氰基、卤素、羟基、氨基、C1~8烷基、卤代的C1~8烷基、C1~8烷氧基、卤代的C1~8烷氧基、5~10元芳基或5~10元杂芳基;
R3选自被一个或多个R3a取代的以下基团:5~6元芳基、5~6元杂芳基;R3a选自氢、氰基、卤素、羟基、氨基、C1~8烷基、卤代的C1~8烷基、C1~8烷氧基、卤代的C1~8烷氧基、被j个Rh取代的以下基团:5~6元芳基、5~6元杂芳基、5~6元饱和环烷基、5~6元饱和杂环基、
j为0、1、2或3;
Rh各自独立的选自氢、卤素、羟基、C1~8烷基、卤代的C1~8烷基、C1~8烷氧基、卤代的C1~8烷氧基、氰基、氨基、NHR4c、NR4cR4c、NHSO2R4c、SO2R4c、MSO2R4c、MNHSO2R4c;M选自5~6元芳基、5~6元杂芳基,R4c选自C1~8烷基、3~8元饱和环烷基、3~8元饱和杂环基。
进一步地,R1选自被一个或多个R1a取代的以下基团:
和/或,R3选自被一个或多个R3a取代的以下基团:
进一步地,所述化合物的结构如式II所示:
其中,n为0、1或2;
Y6选自N、CRs6;Y7选自N、CRs7;Y8选自N、CRs8;Y9选自N、CRs9;Y10选自N、CRs10;
Rs6、Rs7、Rs8、Rs9、Rs10各自独立的选自氢、卤素、C1~5烷基、卤代的C1~5烷基、C1~5烷氧基、卤代的C1~5烷氧基;
R2选自氢、卤素、C1~5烷基、卤代的C1~5烷基、C1~5烷氧基、卤代的C1~5烷氧基;
X选自CH2、N;
a为0、1或2;
R4各自独立的选自氢、卤素、C1~5烷基、卤代的C1~5烷基、C1~5烷氧基、卤代的C1~5烷氧基、被m个R4b取代的以下基团:5~6元芳基、5~6元杂芳基、
m为0、1或2;
R4b各自独立的选自氢、卤素、C1~5烷基、卤代的C1~5烷基、C1~5烷氧基、卤代的C1~5烷氧基、氰基、氨基、NHR4c、NR4cR4c、NHSO2R4c、SO2R4c、MSO2R4c、MNHSO2R4c;M为苯环,R4c选自C1~5烷基、3~6元饱和环烷基、3~6元饱和杂环基。
进一步地,所述化合物的结构如式II-1所示:
其中,n为0或1;
Ry1选自氢、卤素、C1~4烷基、卤代的C1~4烷基、C1~4烷氧基、卤代的C1~4烷氧基;
R4a选自氢、卤素、C1~4烷基、卤代的C1~4烷基、C1~4烷氧基、卤代的C1~4烷氧基;
m选自0、1或2;
R4b各自独立的选自氢、卤素、C1~4烷基、卤代的C1~4烷基、C1~4烷氧基、卤代的C1~4烷氧基、氰基、氨基、NHR4c、NR4cR4c、NHSO2R4c、SO2R4c、MSO2R4c、MNHSO2R4c;M为苯环,R4c选自C1~4烷基、3~6元饱和环烷基、3~6元饱和杂环基。
进一步地,所述化合物的结构如式Ⅲ-1或式III-2所示:
其中,n为0或1;
Ry1选自氢、卤素、C1~4烷基、卤代的C1~4烷基、C1~4烷氧基、卤代的C1~4烷氧基;
R4a选自氢、卤素、C1~4烷基、卤代的C1~4烷基、C1~4烷氧基、卤代的C1~4烷氧基;
R2选自氢、C1~5烷基;
m选自0、1或2;
R4b各自独立的选自氢、卤素、C1~4烷基、卤代的C1~4烷基、C1~4烷氧基、卤代的C1~4烷氧基、氰基、氨基、NHR4c、NR4cR4c、NHSO2R4c、SO2R4c、MSO2R4c、MNHSO2R4c;M为苯环,R4c选自C1~4烷基、3~6元饱和环烷基、3~6元饱和杂环基。
进一步地,所述化合物的结构如式Ⅳ所示:
其中,n为0或1;
Ry1选自氢、卤素、C1~4烷基、卤代的C1~4烷基、C1~4烷氧基、卤代的C1~4烷氧基;
R4a选自氢、卤素、C1~4烷基、卤代的C1~4烷基、C1~4烷氧基、卤代的C1~4烷氧基;
m选自0、1或2;
R4b各自独立的选自氢、卤素、C1~4烷基、卤代的C1~4烷基、C1~4烷氧基、卤代的C1~4烷氧基、氰基、氨基、NHR4c、NR4cR4c、NHSO2R4c、SO2R4c、MSO2R4c、MNHSO2R4c;M为苯环,R4c选自C1~4烷基、3~6元饱和环烷基、3~6元饱和杂环基。
进一步地,所述化合物的结构如式Ⅴ所示:
其中,n为0、1或2;
Y6选自N、CRs6;Y7选自N、CRs7;Y8选自N、CRs8;Y9选自N、CRs9;Y10选自N、CRs10;
Rs6、Rs7、Rs8、Rs9、Rs10各自独立的选自氢、卤素、C1~5烷基、卤代的C1~5烷基、C1~5烷氧基、卤代的C1~5烷氧基;
R2选自氢、卤素、C1~5烷基、卤代的C1~5烷基、C1~5烷氧基、卤代的C1~5烷氧基;
Y1选自N、CRs1;Y2选自N、CRs2;Y3选自N、CRs3;Y4选自N、CRs4;Y5选自N、CRs5;
Rs1、Rs2、Rs3、Rs4、Rs5各自独立的选自氢、卤素、C1~5烷基、卤代的C1~5烷基、C1~5烷氧基、卤代的C1~5烷氧基、被j个Rh取代的以下基团:5~6元芳基、5~6元杂芳基、5~6元饱和环烷基、5~6元饱和杂环基、
j为0、1或2;
Rh各自独立的选自氢、卤素、C1~5烷基、卤代的C1~5烷基、C1~5烷氧基、卤代的C1~5烷氧基、氰基、氨基、NHR4c、NR4cR4c、NHSO2R4c、SO2R4c、MSO2R4c、MNHSO2R4c;M为苯环,R4c选自C1~5烷基、3~6元饱和环烷基、3~6元饱和杂环基。
进一步地,所述化合物的结构如式Ⅴ-1所示:
其中,n为0或1;
Ry2选自氢、卤素、C1~4烷基、卤代的C1~4烷基、C1~4烷氧基、卤代的C1~4烷氧基;
R5a选自氢、卤素、C1~4烷基、卤代的C1~4烷基、C1~4烷氧基、卤代的C1~4烷氧基;
p选自0、1或2;
R5b各自独立的选自氢、卤素、C1~4烷基、卤代的C1~4烷基、C1~4烷氧基、卤代的C1~4烷氧基、氰基、氨基、NHR4c、NR4cR4c、NHSO2R4c、SO2R4c、MSO2R4c、MNHSO2R4c;M为苯环,R4c选自C1~4烷基、3~6元饱和环烷基、3~6元饱和杂环基。
进一步地,所述化合物为如下化合物之一:
本发明还提供了一种药物组合物,所述药物组合物是以上述化合物、或其盐、或其同位素化合物、或其立体异构体、或其水合物为活性成分,加上药学上可接受的辅料制得的制剂。
本发明还提供了上述化合物、或其盐、或其同位素化合物、或其立体异构体、或其水合物在制备P2X7受体抑制剂中的用途;
优选地,所述P2X7受体抑制剂为治疗炎症及炎症相关疾病、肾损伤、呼吸系统疾病、癌症、疼痛、中枢神经系统疾病、放射性脑损伤、脑缺血、心肌损伤、糖尿病、抑郁症、红斑狼疮、动脉粥样硬化、过敏性哮喘的药物;
所述炎症及炎症相关疾病优选为神经性炎症、关节炎、结肠炎、胰腺炎纤维化、酒精性脂肪性肝炎、支气管炎、肺炎、腰脊椎炎、血管炎;所述呼吸系统疾病优选为气道阻塞性疾病,更优选为支气管哮喘、过敏性哮喘、内源性哮喘、外源性哮喘、运动诱发哮喘、药物诱发哮喘;所述肾损伤优选为缺血再灌注引起的急性肾损伤、原发性肾小球疾病的肾损伤、肾小管疾病的肾损伤、间质性肾炎肾损伤、自身免疫性疾病及结缔组织疾病肾损伤、代谢性疾病肾损伤、囊肿性肾病的肾损伤、遗传性与先天性肾病的肾损伤;所述癌症优选为前列腺癌、乳腺癌、肺癌、卵巢癌、胰腺癌、肠癌、结肠癌、胃癌、皮肤癌、脑肿瘤、白血病、淋巴癌;所述疼痛优选为头痛、偏头痛、三叉神经痛、不典型面痛、关节和骨痛、因癌症和肿瘤侵入引起的疼痛、神经性疼痛综合征;所述中枢神经系统疾病优选为阿尔茨海默症、帕金森综合征、癫痫、多发性硬化和其它脱髓鞘综合征、脑动脉粥样硬化、重症肌无力;所述红斑狼疮优选为全身性红斑狼疮。
关于本发明的使用术语的定义:除非另有说明,本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语;对于本文没有具体定义的术语,应该根据公开内容和上下文,给出本领域技术人员能够给予它们的含义。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示,例如,前缀Ca~b烷基表示任何含“a”至“b”个碳原子的烷基。例如,C1~8基是指包含1~8碳原子的直链或支链的烷基。
本发明中,“芳基”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,例如苯基和萘基。所述芳基环可以稠合于其它环状基团(包括饱和和不饱和环),但不能含有杂原子如氮,氧,或硫,同时连接母体的点必须在具有共轭的π电子体系的环上的碳原子上。芳基可以是取代的或未取代的。
“杂芳基”指包含一个到多个杂原子的杂芳族基团。这里所指的杂原子包括氧、硫和氮。例如呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。
“同位素化合物”指化合物中的一个或两个以上的原子被其对应的同位素替换后得到的化合物。比如化合物中的一个或两个以上的氢(H)被氘(D)或氚(T)替换后得到的化合物;比如化合物中的一个或两个以上的碳12被碳11或碳13替换后得到的化合物。
卤素为氟、氯、溴或碘。
“卤代的C1~8烷基”指被一个或多个卤素取代的C1~8烷基,例如-CF3。
“饱和环烷基”指饱和的环状烃取代基,该环状烃的环原子中无杂原子(包括但不限于O、S或N)。
“饱和杂环基”指饱和的环状烃取代基,该环状烃携带至少一个环杂原子(包括但不限于O、S或N)。
实验结果表明,本发明提供的化合物对P2X7受体具有优异的抑制活性,其中,化合物A6、A22、A25、A27、A31、A32、A33、A36、A38、A41和A49在该1μM下的抑制活性与阳性对照JNJ47965567活性相当;化合物A22、A32、A33在低浓度(30nM)下对的抑制效果甚至优于阳性对照JNJ47965567。实验结果还表明,与阳性对照JNJ47965567相比,本发明化合物的代谢稳定性明显提高。因此,本发明提供的化合物可以用来制备P2X7受体抑制剂。
本领域技术人员公知的,P2X7受体抑制剂可以用于治疗以下疾病:炎症及炎症相关疾病(包括神经性炎症、关节炎、结肠炎、胰腺炎纤维化、酒精性脂肪性肝炎、支气管炎、肺炎、腰脊椎炎、血管炎)、肾损伤(包括缺血再灌注引起的急性肾损伤、原发性肾小球疾病的肾损伤、肾小管疾病的肾损伤、间质性肾炎肾损伤、自身免疫性疾病及结缔组织疾病肾损伤、代谢性疾病肾损伤、囊肿性肾病的肾损伤、遗传性与先天性肾病的肾损伤)、呼吸系统疾病(包括气道阻塞性疾病,例如支气管哮喘、过敏性哮喘、内源性哮喘、外源性哮喘、运动诱发哮喘、药物诱发哮喘)、癌症(包括前列腺癌、乳腺癌、肺癌、卵巢癌、胰腺癌、肠癌、结肠癌、胃癌、皮肤癌、脑肿瘤、白血病、淋巴癌)、疼痛(包括头痛、偏头痛、三叉神经痛、不典型面痛、关节和骨痛、因癌症和肿瘤侵入引起的疼痛、神经性疼痛综合征)、中枢神经系统疾病(包括阿尔茨海默症、帕金森综合征、癫痫、多发性硬化和其它脱髓鞘综合征、脑动脉粥样硬化、重症肌无力)、放射性脑损伤、脑缺血、心肌损伤、糖尿病、抑郁症、红斑狼疮(包括全身性红斑狼疮)、动脉粥样硬化、过敏性哮喘物。因此,本发明提供的化合物还能够用于制备治疗上述疾病的药物,应用前景广阔。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明所用原料与设备均为已知产品,通过购买市售产品所得。
为方便后面对实施例合成路线及方法的描述,现将实施例所用部分原料或试剂的缩写列于表1中。
表1.实施例所用部分原料或试剂的缩写
试剂 | 缩写 |
乙酸乙酯 | EtOAc |
甲醇 | MeOH |
乙醇 | EtOH |
乙醚 | Et2O |
N,N-二甲基甲酰胺 | DMF |
盐酸 | HCl |
无水硫酸钠 | Na2SO4 |
碳酸钾 | K2CO3 |
氮气 | N2 |
石油醚 | PE |
二氯甲烷 | DCM |
水 | H2O |
碳酸氢钠 | NaHCO3 |
二甲基亚砜 | DMSO |
硫酸钠 | Na2SO4 |
三氟乙酸 | TFA |
三乙胺 | Et3N |
4-二甲氨基吡啶 | DMAP |
四丁基碘化铵 | n-Bu4NI |
叔丁基过氧化氢 | TBHP |
实施例1、2-氯-N-((1-(5-氟嘧啶-2-基)-1H-1,2,3-三唑-4-基)甲基)-3-(三氟甲基)苯甲酰胺的制备
步骤1:中间体1的制备
反应瓶中加入2-氯-5-氟嘧啶(350μl,2.6mmol)、水合肼(260μl,5.2mmol)及乙醇(5ml),60℃油浴搅拌反应1.5h,期间以TCL监测反应情况。反应完成后,将反应液置于常温冷却,白色固体析出,抽滤,乙醚洗涤,干燥。白色固体不经纯化直接用1ml水稀释并加入3ml冰乙酸,常温搅拌下缓慢滴加NaNO2水溶液(318mg NaNO2溶于10ml水),滴加完毕后常温搅拌2h,期间以TCL跟踪监测反应情况。反应完成后,向反应体系中加入饱和碳酸钠溶液调节pH至中性,加入适量水,用EA:PE=1:1的混合有机溶剂体系萃取3次,合并有机相,低温减压蒸馏得白色固体(中间体1)。1H NMR(400MHz,DMSO-d6)δ8.85(s,2H).
步骤2:中间体2的制备
反应瓶中加入2-氯-3-(三氟甲基)苯甲酸(350mg,1.6mmol)、草酰氯(10g,1mmol)、和5ml DCM,滴加一滴DMF作为催化剂,常温搅拌反应4h,旋干反应液,得到2-氯-3-(三氟甲基)苯甲酰氯的中间体。另取干净的反应瓶,加入三乙胺(420μ1,3.0mmol),炔丙胺(200μ1,1mmol)和3ml DMF,制备好的苯甲酰氯中间体用2ml DMF溶解后,常温搅拌下滴加入反应体系,常温搅拌反应0.5h,期间以TCL跟踪监测反应情况。待反应结束后,加入大量水,白色固体析出,抽滤,乙醚洗涤,干燥,得白色固体(中间体2)。1H NMR(400MHz,DMSO-d6)δ9.08(t,J=5.4Hz,1H),7.93(dd,J=7.8,1.7Hz,1H),7.70(dd,J=7.8,1.7Hz,1H),7.61(t,J=7.7Hz,1H),4.06(dd,J=5.5,2.6Hz,2H),3.18(t,J=2.6Hz,1H).Exact mass calcd forC11H7ClF3NONa,284.0066;[M+Na]+:284.0067.
步骤3:化合物A1的制备
干燥三颈瓶中加入中间体1(350mg,2.5mmol)、中间体2(790mg,3.0mmol)、三乙胺(1ml,3.8mmol)、碘化亚铜(480mg,2.5mmol)、氯乙酸乙酯(34μl,0.28mmol)和5ml无水THF。氮气保护下,35℃搅拌,反应过夜,以TCL监测反应情况。待反应完成后,将反应液用硅藻土过滤,以甲醇:二氯甲烷=1:1溶剂体系洗涤,收集有机相,减压浓缩去除溶剂后,通过硅胶柱层析纯化得到产物A1。1H NMR(400MHz,DMSO-d6)δ9.25(t,J=5.7Hz,1H),9.12(s,2H),8.73(s,1H),7.93(dd,J=7.9,1.6Hz,1H),7.77(dd,J=7.7,1.6Hz,1H),7.62(t,J=7.7Hz,1H),4.64(d,J=5.6Hz,2H).13C NMR(100MHz,DMSO)δ165.51,157.07(d,J=260.8Hz),149.79,147.69(d,J=23.4Hz),147.69(d,J=23.4Hz),145.31,139.39,132.79,128.38(q,J=3.9Hz),127.89,127.71,127.35,123.01(d,J=268.1Hz),121.94,34.59.Exact masscalcd for C15H9ClF4N6ONa,423.0360;[M+Na]+:423.0357.
实施例2、4-氟-N-((1-(5-氟嘧啶-2-基)-1H-1,2,3-三唑-4-基)甲基)苯甲酰胺的制备
参照实施例1的合成方法,区别仅在于合成中间体2时,原料更换为对氟苯甲酸,制备得到产物A2。1H NMR(400MHz,CDCl3)δ8.71(s,2H),8.61(s,1H),7.85–7.80(m,2H),7.13–7.07(m,2H),4.81(d,J=5.7Hz,2H).13C NMR(100MHz,CDCl3)δ166.60,165.02(d,J=252.3Hz),157.18(d,J=265.6Hz),150.33,147.18(d,J=22.8Hz),147.18(d,J=22.8Hz),145.46,130.18(d,J=3.2Hz),129.56(d,J=9.1Hz),129.56(d,J=9.1Hz),122.04,115.81(d,J=21.8Hz),115.81(d,J=21.8Hz),35.41.Exact mass calcd for C14H10F2N6ONa,339.0782;[M+Na]+:339.0780.
实施例3、6-氯-N-((1-(5-氟嘧啶-2-基)-1H-1,2,3-三唑-4-基)甲基)烟酰胺的制备
参照实施例1的合成方法,区别仅在于合成中间体2时,原料更换为6-氯烟酸,制备得到产物A3。1H NMR(400MHz,DMSO-d6)δ9.39(t,J=5.6Hz,1H),9.10(s,2H),8.88(d,J=2.5Hz,1H),8.74(s,1H),8.28(dd,J=8.3,2.5Hz,1H),7.66(d,J=8.3Hz,1H),4.65(d,J=5.6Hz,2H).13C NMR(100MHz,DMSO)δ163.87,159.79(d,J=286.4Hz),152.67,149.94,149.10,147.68(d,J=23.3Hz),147.68(d,J=23.3Hz),145.57,138.72,128.98,124.13,122.19,34.73.Exact mass calcd for C13H9ClFN7ONa,356.0439;[M+Na]+:356.0439.
实施例4、N-((1-(5-氟嘧啶-2-基)-1H-1,2,3-三唑-4-基)甲基)噻吩-2甲酰胺的制备
参照实施例1的合成方法,区别仅在于合成中间体2时,原料更换为噻吩-2-甲酸,制备得到产物A4。1H NMR(400MHz,CDCl3)δ8.71(s,2H),8.62(s,1H),7.54(dd,J=3.7,1.2Hz,1H),7.48(dd,J=5.0,1.2Hz,1H),7.07(dd,J=5.0,3.7Hz,1H),6.91(s,1H),4.79(d,J=5.9Hz,2H).13C NMR(100MHz,CDCl3)δ162.15,157.18(d,J=265.8Hz),154.10,147.18(d,J=22.8Hz),147.18(d,J=22.8Hz),146.46,142.51,130.52,128.58,127.88,122.14,35.22.Exact mass calcd for C12H9FN6OSNa,327.0440[M+Na]+:327.0442.
实施例5、4-氯-N-((1-(4-氯吡啶-2-基)-1H-1,2,3-三唑-4-基)甲基)苯甲酰胺的制备
步骤1:中间体3的制备
反应瓶中加入4-氯-2-氟吡啶(1mL,1mol)、水合肼(1.2mL,5mol)及乙醇(5ml),60℃油浴搅拌反应1.5h,期间以TCL监测反应情况。反应完成后,将反应液置于常温冷却后,减压蒸馏旋干反应液。旋干后的油状物不经纯化直接用1ml水稀释并加入3ml冰乙酸,常温搅拌下缓慢滴加NaNO2水溶液(2.6g NaNO2,5mol溶于10ml水),滴加完毕后常温搅拌2h,期间以TCL跟踪监测反应情况。反应结束时,有大量白色固体析出,向反应体系中加入饱和碳酸钠溶液调节pH至中性,加入适量水,抽滤,乙醚洗涤,干燥,得白色固体(中间体3)。1H NMR(400MHz,DMSO-d6)δ9.38(d,J=7.3Hz,1H),8.52(d,J=2.0Hz,1H),7.56(dd,J=7.3,2.1Hz,1H).
步骤2:中间体4的制备
反应瓶中加入4-氯苯甲酸(500mg,1mmol)、草酰氯(434μ1,1.6mmol)和10ml DCM,滴加一滴DMF作为催化剂,常温搅拌反应4h,旋干反应液,得到2-氯-5溴苯甲酰氯的中间体。另取干净的反应瓶,加入三乙胺(1332μ1,3.0mmol),炔丙胺(205μ1,1mmol)和3ml DMF,制备好的苯甲酰氯中间体用2ml DMF溶解后,常温搅拌下滴加入反应体系,常温搅拌反应0.5h,期间以TCL跟踪监测反应情况。待反应结束后,加入大量水,白色固体析出,抽滤,乙醚洗涤,干燥,得白色固体(中间体4)。1H NMR(400MHz,)δ9.02(t,J=5.6Hz,1H),7.89–7.85(m,2H),7.57–7.53(m,2H),4.05(dd,J=5.5,2.6Hz,2H),3.12(t,J=2.5Hz,1H).Exact mass calcdfor C10H8ClNONa,216.0192;[M+Na]+:216.0195.
步骤3:化合物A5的制备
干燥三颈瓶中加入中间体3(350mg,1mmol)、中间体4(658mg,1.5mmol)、三乙胺(945μl,3mmol)、碘化亚铜(433mg,1mmol)、氯乙酸乙酯(51μl,0.2mmol)和5ml无水THF。氮气保护下,35℃搅拌,反应过夜,以TCL监测反应情况。待反应完成后,将反应液用硅藻土过滤,以甲醇:二氯甲烷=1:1溶剂体系洗涤,收集有机相,减压浓缩去除溶剂后,通过硅胶柱层析纯化得到产物A5。1H NMR(400MHz,DMSO-d6)δ9.19(t,J=5.6Hz,1H),8.69(s,1H),8.58(d,J=5.4Hz,1H),8.20(s,1H),7.91(d,J=8.1Hz,2H),7.69(d,J=5.4Hz,1H),7.55(d,J=8.1Hz,2H),4.62(d,J=5.5Hz,2H).13C NMR(100MHz,DMSO-d6)δ165.28,150.37,149.38,146.27,145.76,136.20,132.76,129.27,129.27,128.51,128.42,124.30,120.45,113.69,34.81.Exact mass calcd for C15H11Cl2N5ONa,370.0238,[M+Na]+:370.0242.
实施例6~21、化合物A6~A21的制备
参照实施例5的合成方法,区别仅在于合成中间体4时按照表2更改苯甲酸或芳杂环甲酸的种类,制备得到产物A6~A21。
表2.制备化合物A6~A21的原料、所得化合物结构式及化合物核磁结果
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实施例22、N-((1-(4-氯吡啶-2-基)-1H-1,2,3-三唑-4-基)甲基)-2-(4-(甲磺酰基)苯基)噻唑-5-甲酰胺的制备
具体步骤如下:
将化合物A18(200mg,1mmol),4-(甲磺酰基)苯硼酸(151mg,1.5mmol),四(三苯基膦)钯(58mg,0.1mmol),碳酸铯(328mg,2mmol.)溶于5mL二氧六环1mL水的混合溶液中,N2保护下,反应混合物在85℃过夜搅拌,通过TLC监测反应。反应完成后,冷却至室温,减压浓缩去除溶剂后,通过硅胶柱层析纯化得到产物A22。1H NMR(400MHz,DMSO-d6)δ9.46(t,J=5.6Hz,1H),8.76(s,1H),8.60(s,1H),8.58(d,J=1.3Hz,1H),8.28–8.23(m,2H),8.21(d,J=1.8Hz,1H),8.08–8.04(m,2H),7.70(dd,J=5.4,1.9Hz,1H),4.65(d,J=5.6Hz,2H),3.28(s,3H).13C NMR(100MHz,DMSO)δ168.07,159.65,150.38,149.38,145.82,145.78,144.71,142.37,136.75,136.70,129.29,128.11,127.30,124.34,120.66,115.86,113.72,43.39,34.68.Exact mass calcd for C19H15ClN6O3S2Na,497.0233,[M+Na]+:497.0237.
实施例23~31、化合物A23~A31的制备
参照实施例22的合成方法,区别仅在于按照表3更改更改苯硼酸的种类,制备得到产物A23~A31。
表3.制备化合物的原料、所得化合物结构式及化合物核磁结果
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实施例32、N-((1-(4-溴吡啶-2-基)-1H-1,2,3-三唑-4-基)甲基)-2-(4-(甲磺酰基)苯基)噻唑-5-甲酰胺的制备
具体步骤如下:
步骤1:中间体5的制备
反应瓶中加入2-溴噻唑-5-羧酸(10g,1mol)、草酰氯(6.5mL,1.6mol)和5ml DCM,滴加3滴DMF作为催化剂,常温搅拌反应4h,旋干反应液,得到2-溴噻唑-5-甲酰氯的中间体。另取干净的反应瓶,加入三乙胺(20mL,3.0mol),炔丙胺(3mL,1mol)和5ml DMF,制备好的酰氯中间体用5ml DMF溶解后,常温搅拌下滴加入反应体系,常温搅拌反应0.5h,期间以TCL跟踪监测反应情况。待反应结束后,加入大量水,用EA萃取两次,收集有机相,旋干,粗品直接用于下一步(中间体5)。
步骤2:中间体6的制备
将中间体5(1g,1mol),4-(甲磺酰基)苯硼酸(1.2g,1.5mol),四(三苯基膦)钯(0.47g,0.1mol),碳酸铯(2.7g,2mol.)溶于10mL二氧六环2mL水的混合溶液中,N2保护下,反应混合物在85℃过夜搅拌,通过TLC监测反应。反应完成后,冷却至室温,减压浓缩去除溶剂后,通过硅胶柱层析纯化得到白色固体(中间体6)。1H NMR(400MHz,DMSO-d6)δ9.32(t,J=5.5Hz,1H),8.56(d,J=1.6Hz,1H),8.27–8.23(m,2H),8.06(dd,J=8.5,1.7Hz,2H),4.09(dd,J=5.7,2.7Hz,2H),3.28(d,J=1.6Hz,3H),3.21(t,J=2.4Hz,1H).Exact mass calcdfor C14H12N2O3S2Na,343.0187,[M+Na]+:343.0182.
步骤3:中间体7的制备
反应瓶中加入4-溴-2-氟吡啶(500μl,1mmol)、水合肼(458μl,5mmol)及乙醇(5ml),60℃油浴搅拌反应1.5h,期间以TCL监测反应情况。反应完成后,将反应液置于常温冷却后,减压蒸馏旋干反应液。旋干后的油状物不经纯化直接用1ml水稀释并加入3ml冰乙酸,常温搅拌下缓慢滴加NaNO2水溶液(986mg NaNO2,5mmol,溶于10ml水),滴加完毕后常温搅拌2h,期间以TCL跟踪监测反应情况。反应结束时,有大量白色固体析出,向反应体系中加入饱和碳酸钠溶液调节pH至中性,加入适量水,抽滤,乙醚洗涤,干燥,得白色固体(中间体7),粗品直接用于下一步。
步骤4:化合物A32的制备
干燥三颈瓶中加入中间体7(300mg,1.2mmol)、中间体6(404mg,1mmol)、维生素C钠(2502mg,10mmol)、五水硫酸铜(410mg,1.3mmol)、氯乙酸乙酯(34μl,0.28mmol)和5ml DMF。氮气保护下,常温搅拌过夜,以TCL监测反应情况。待反应完成后,将反应液用硅藻土过滤,以甲醇:二氯甲烷=1:1溶剂体系洗涤,收集有机相,减压浓缩去除溶剂后,通过硅胶柱层析纯化得到产物A32。1H NMR(400MHz,DMSO-d6)δ9.47(t,J=5.7Hz,1H),8.76(s,1H),8.59(s,1H),8.50(d,J=5.4Hz,1H),8.34(d,J=1.7Hz,1H),8.27–8.23(m,2H),8.08–8.04(m,2H),7.83(dd,J=5.4,1.7Hz,1H),4.65(d,J=5.6Hz,2H),3.28(s,3H).Exact mass calcd forC19H15BrN6O3S2Na,540.9728,[M+Na]+:540.9730.
实施例33、N-((1-(4-氯吡啶-2-基)-1H-1,2,3-三唑-4-基)甲基)-2-(4-(甲磺酰基)苯基)噻唑-4-甲酰胺的制备
参照实施例22的合成方法,区别仅在于将2-溴噻唑-5-羧酸原料更改为2-溴-4-噻唑羧酸,制备得到产物A33。1H NMR(400MHz,DMSO-d6)δ9.26(t,J=6.0Hz,1H),8.69(s,1H),8.57(d,J=5.4Hz,1H),8.47(s,1H),8.33(d,J=8.4Hz,2H),8.19(d,J=1.9Hz,1H),8.08(d,J=8.4Hz,2H),7.68(dd,J=5.4,1.9Hz,1H),4.68(d,J=6.0Hz,2H),3.29(s,3H).13CNMR(100MHz,DMSO-d6)δ173.40,163.05,150.40,149.40,146.95,144.70,142.35,142.19,138.85,131.56,131.46,128.86,128.74,127.27,124.33,120.53,113.72,43.38,34.40.Exact mass calcd for C19H15ClN6O3S2Na,497.0223,[M+Na]+:497.0224.
实施例34、N-((1-(4-氯吡啶-2-基)-1H-1,2,3-三唑-4-基)甲基)-2-(3-(甲磺酰氨基)苯基)噻唑-4-甲酰胺的制备
参照实施例33的合成方法,区别仅在于将4-甲磺酰基苯硼酸原料更改为3-甲磺酰胺基苯硼酸,制备得到产物A34。1H NMR(400MHz,DMSO-d6)δ9.97(s,1H),9.07(t,J=6.0Hz,1H),8.69(s,1H),8.58(d,J=5.4Hz,1H),8.36(d,J=1.1Hz,1H),8.20(d,J=1.8Hz,1H),7.86–7.79(m,2H),7.69(dt,J=5.4,1.4Hz,1H),7.51(t,J=7.9Hz,1H),7.37(ddd,J=8.0,2.2,1.1Hz,1H),4.67(d,J=6.0Hz,2H),3.05(s,3H).13C NMR(100MHz,DMSO-d6)δ166.83,160.59,150.46,150.34,149.37,146.29,145.76,139.31,133.45,130.32,124.68,124.27,121.95,121.77,120.48,117.56,113.65,48.62,34.41.Exact mass calcd forC19H15ClN6O3S2Na,497.0223,[M+Na]+:497.0224.
实施例35、(R)-N-((1-(4-氯吡啶-2-基)-1H-1,2,3-三唑-4-基)甲基)-2-(4-(甲磺酰基)苯基)噻唑-4-甲酰胺的制备
参照实施例33的合成方法,区别仅在于将炔丙胺原料更改为(R)-丁-3-炔-2-基氨基甲酸叔丁酯,制备得到产物A35。1H NMR(400MHz,DMSO-d6)δ8.97(d,J=8.5Hz,1H),8.76(s,1H),8.58(d,J=5.4Hz,1H),8.48(s,1H),8.34(d,J=8.1Hz,2H),8.20(d,J=2.1Hz,1H),8.07(d,J=8.1Hz,2H),7.69(dd,J=5.4,2.0Hz,1H),5.46(p,J=7.2Hz,1H),3.29(s,3H),1.67(d,J=7.0Hz,3H).13C NMR(101MHz,DMSO)δ165.18,159.63,150.80,150.62,150.31,149.37,145.74,142.12,136.62,127.90,127.90,127.29,127.29,126.14,124.26,119.54,113.64,43.35,41.21,20.29.Exact mass calcd for C20H17ClN6O3S2Na,511.0390,[M+Na]+:511.0395.
实施例36、(S)-N-((1-(4-氯吡啶-2-基)-1H-1,2,3-三唑-4-基)甲基)-2-(4-(甲磺酰基)苯基)噻唑-4-甲酰胺的制备
参照实施例35的合成方法,区别仅在于将(R)-丁-3-炔-2-基氨基甲酸叔丁酯原料更改为(S)-丁-3-炔-2-基氨基甲酸叔丁酯,制备得到产物A36。1H NMR(400MHz,DMSO-d6)δ9.01–8.96(m,1H),8.76(d,J=1.7Hz,1H),8.56(dd,J=5.4,1.8Hz,1H),8.48(d,J=1.8Hz,1H),8.35–8.31(m,2H),8.18(d,J=2.0Hz,1H),8.06(dd,J=8.5,1.9Hz,2H),7.68(dd,J=4.9,2.5Hz,1H),5.47(h,J=7.2,6.5Hz,1H),3.29(s,3H),1.67(dd,J=7.1,1.8Hz,3H).13CNMR(100MHz,DMSO-d6)δ165.19,159.66,150.84,150.66,150.34,149.39,145.76,142.14,136.65,127.93,127.93,127.32,127.32,126.17,124.29,119.58,113.65,43.39,41.25,20.34.Exact mass calcd for C20H17ClN6O3S2Na,511.0390,[M+Na]+:511.0391.
实施例37、N-((1-(4-氯吡啶-2-基)-1H-1,2,3-三唑-4-基)甲基)-4-(4-(甲磺酰基)苯基)噻唑-2-甲酰胺的制备
参照实施例22的合成方法,区别仅在于将2-溴噻唑-5-羧酸原料更改为4-溴-1,3-噻唑-2-羧酸,制备得到产物A37。1H NMR(400MHz,DMSO-d6)δ9.60(t,J=5.9Hz,1H),8.75(d,J=1.3Hz,1H),8.69(d,J=1.3Hz,1H),8.58(dd,J=5.4,1.3Hz,1H),8.37–8.32(m,2H),8.20(t,J=1.6Hz,1H),8.03(dd,J=8.5,1.4Hz,2H),7.69(dt,J=5.5,1.6Hz,1H),4.69(d,J=5.9Hz,2H),3.27(d,J=1.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ163.70,159.08,153.38,150.38,149.38,145.78,145.76,140.35,137.96,127.64,127.64,126.90,126.90,124.34,122.60,120.69,113.73,43.49,34.62.Exact mass calcd for C19H15ClN6O3S2Na,497.0223,[M+Na]+:497.0226.
实施例38、N-((1-(2-氯吡啶-4-基)-1H-1,2,3-三唑-4-基)甲基)-2-(4-(甲磺酰基)苯基)噻唑-4-甲酰胺的制备
参照实施例33的合成方法,区别仅在于将制备叠氮的原料更改为2-氯-4-氟吡啶,制备得到产物A38。1H NMR(400MHz,DMSO-d6)δ9.33(t,J=6.0Hz,1H),9.11(s,1H),8.90(d,J=5.4Hz,1H),8.63(s,1H),8.48(d,J=7.6Hz,3H),8.34(d,J=8.0Hz,2H),8.06(s,1H),4.71(d,J=5.9Hz,2H),3.29(s,3H).Exact mass calcd for C19H15ClN6O3S2Na,497.0223,[M+Na]+:497.0221.
实施例39、4-氯-N-((1-(4-氯吡啶-2-基)-1H-1,2,3-三唑-4-基)甲基)-3'-(甲磺酰基)-[1,1'-联苯]-3-甲酰胺的制备
具体步骤:
将化合物A10(200mg,1mmol),3-(甲磺酰基)苯硼酸(141mg,1.5mmol),四(三苯基膦)钯(54mg,0.1mmol),碳酸铯(307mg,2mmol.)溶于5mL二氧六环1mL水的混合溶液中,N2保护下,反应混合物在85℃搅拌10小时,通过TLC监测反应。反应完成后,冷却至室温,减压浓缩去除溶剂后,通过硅胶柱层析纯化得到产物A39。1H NMR(400MHz,DMSO-d6)δ9.26(t,J=5.7Hz,1H),8.76(s,1H),8.59(d,J=5.4Hz,1H),8.26–8.19(m,2H),8.12–8.06(m,1H),7.96–7.93(m,1H),7.91(d,J=2.4Hz,1H),7.86(dd,J=8.4,2.4Hz,1H),7.76(t,J=7.8Hz,1H),7.70(dd,J=5.4,1.9Hz,1H),7.65(d,J=8.4Hz,1H),4.65(d,J=5.7Hz,2H),3.59(s,3H).13C NMR(100MHz,DMSO-d6)δ166.09,150.43,149.40,145.98,145.79,141.77,139.48,137.22,136.88,131.84,130.46,130.29,130.22,129.34,127.54,126.29,125.15,124.33,120.40,113.69,43.43,34.77.Exact mass calcd for C22H17Cl2N5O3SNa,524.0327,[M+Na]+:524.0331.
实施例40~50、化合物A40~A50的制备
参照实施例39的合成方法,区别仅在于按照表4更改硼酸的种类,制备得到产物A40~A50。
表4.制备化合物的原料、所得化合物结构式及化合物核磁结果
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实施例51、2-氯-N-((1-(4-氯吡啶-2-基)-1H-1,2,3-三唑-4-基)甲基)-5-(4,4-二氟哌啶-1-基)甲酰胺的制备
具体步骤:
将化合物A10(200mg,1mmol),4,4-二氟哌啶(64mg,1.2mmol),Pd2(dba)3(43mg,0.1mmol),BINAP(88mg,0.3mmol),碳酸铯(307mg,2mmol)溶于5mL 1,4-二氧六环和1Ml水中,N2保护下,反应混合物在80℃搅拌8-10小时,通过TLC监测反应。反应完成后,冷却至室温,减压浓缩去除溶剂后,通过硅胶柱层析纯化得到产物A51.1H NMR(400MHz,DMSO-d6)δ8.98(t,J=5.7Hz,1H),8.70(s,1H),8.59(d,J=5.4Hz,1H),8.21(d,J=1.9Hz,1H),7.69(dd,J=5.5,1.8Hz,1H),7.29(d,J=8.5Hz,1H),7.06(d,J=8.5Hz,2H),4.59(d,J=5.7Hz,2H),3.35(s,4H),2.07–1.97(m,4H).13C NMR(100MHz,DMSO-d6)δ166.71,150.44,149.41,148.19,146.12,145.83,136.75,130.17,124.34,122.71,120.32,119.38,118.11,116.00,113.69,45.45,45.45,34.74,32.92,32.47.Exact mass calcd for C20H18Cl2F2N6ONa,489.0785,[M+Na]+:489.0781.
以下通过具体的试验例证明本发明的有益效果。
试验例1、化合物对P2X7受体的抑制活性测试
1.实验方法
本领域技术人员公知的,P2X7受体(简称P2X7R)主要受到ATP调控,0.5~1mM及以上的高浓度ATP能够刺激P2X7R激活,导致受体孔隙的开放。开放的“大孔”能够使分子量高达900Da的亲水溶质(如溴化乙锭、YO-Pro、碘化丙啶(PI)或路西法黄)等原本不可渗透进入细胞内环境的有机染料的摄入。本次实验采用PI作为荧光染料,进行了PI染料摄取抑制实验。
根据慢病毒转染在HEK293(人胚胎肾细胞293)上构建了能够稳定表达人和小鼠P2X7R的细胞(mP2X7-HEK293、hP2X7-HEK293),并建立了一个体外基于细胞的检测方法:使用ATP诱导细胞P2X7R激活,同时加入荧光染料用于标记。测试药物对hP2X7R(人P2X7R)和mP2X7R(小鼠P2X7R)的抑制活性。
材料:PI、ATP、DMEM培养基。
测试药物:化合物A1~A51,以已知的P2X7R拮抗剂JNJ47965567作为阳性对照。
药物溶液的配制:1)用100%的DMSO将化合物配成10mmol/L的母液;2)用无菌PBS将PI配制成1mg/ml的母液;3)用无菌PBS将ATP配制成600mM的母液。
方法:将mP2X7R-HEK293和hP2X7R-HEK293细胞(2×105个/mL,100μL/孔)分别接种在96孔黑色透明平底酶标板中,置于培养箱(37℃、25%CO2)培养24小时。然后用DMEM培养基将化合物、PI、ATP稀释为作用浓度后混合加入孔板中(100μL/孔),避光培养2h,然后吸掉培养基加入预冷的PBS(100μL/孔),立即用酶标仪测荧光(Ex/Em=535/617nM)。其中PI、ATP的作用浓度分别为:0.05g/mL、3mM。读出并记录每孔的原始数据,并对原始数据进行相应的转换,计算出各化合物对hP2X7R和mP2X7R的抑制活性。
2.实验结果
结果如表5和表6所示。表5中化合物的作用浓度为1μM,表6中化合物的作用浓度为30nM。抑制率>80%表示为“+++”,50%<抑制率<80%表示为“++”,抑制率<50%表示为“+”。
表5.化合物在1μM时对hP2X7R和mP2X7R的抑制活性
由上述表5可以看出,本发明化合物在1μM下对P2X7R均有抑制活性,其中化合物A6、A22、A25、A27、A31、A32、A33、A36、A38、A41和A49在该浓度下的抑制活性与阳性对照JNJ47965567活性相当。
表6.化合物在30nM时对mP2X7R的抑制活性
化合物 | mP2X7R抑制率 |
化合物A22 | ++ |
化合物A32 | +++ |
化合物A33 | ++ |
阳性对照JNJ47965567 | + |
由上述表6可以看出,本发明化合物A22、A32、A33在低浓度(30nM)下对mP2X7R的抑制效果甚至优于阳性对照JNJ47965567。
上述结果表明,本发明提供的化合物能够有效抑制人和小鼠P2X7受体,可以用来制备P2X7受体抑制剂。
试验例2、代谢稳定性测试
1.实验方法
测试药物:化合物A22、A26、A32、A33、A36,以已知的P2X7R拮抗剂JNJ47965567作为阳性对照。
测试方法:将化合物在体外与人肝微粒体溶液在37℃下共同孵育,以孵育0min时间点时化合物的浓度为100%,其他孵育时间点的浓度与之相比得剩余百分量,再将各时间点的剩余百分量的自然对数对孵育时间作线性回归,求算得斜率k,根据以下公式可以计算得到半衰期(T1/2)和清除率(CL)。
T1/2=-0.693/k;
CL=[0.693/T1/2]*[孵育液体积(ml)/微粒体质量(mg)]。
2.实验结果
表7.化合物的代谢稳定性测试结果
从表7可以看出,与阳性对照JNJ47965567相比,本发明化合物的半衰期明显延长,清除率明显降低。说明与阳性对照JNJ47965567相比,本发明化合物的代谢稳定性明显提高。
综上,本发明提供了一种式I所示的P2X7受体抑制剂。本发明提供的化合物不仅对P2X7受体具有优异的抑制活性,同时还具有优异的代谢稳定性。与阳性对照JNJ47965567相比,本发明化合物的代谢稳定性明显提高。本发明提供的化合物可以用来制备P2X7受体抑制剂,以及制备治疗炎症及炎症相关疾病、肾损伤、呼吸系统疾病、癌症、疼痛、中枢神经系统疾病、放射性脑损伤、脑缺血、心肌损伤、糖尿病、抑郁症、红斑狼疮、动脉粥样硬化、过敏性哮喘等疾病的药物,应用前景广阔。
Claims (10)
1.一种化合物或其盐,其特征在于:所述化合物的结构如式II-1所示:
其中,n为0;
Ry1选自氢、卤素、C1~4烷基、卤代的C1~4烷基、C1~4烷氧基、卤代的C1~4烷氧基;
R4a选自氢、卤素、C1~4烷基、卤代的C1~4烷基、C1~4烷氧基、卤代的C1~4烷氧基;
m选自0、1或2;
R4b各自独立的选自氢、卤素、C1~4烷基、卤代的C1~4烷基、C1~4烷氧基、卤代的C1~4烷氧基、氰基、氨基、NHR4c、NR4cR4c、NHSO2R4c、SO2R4c;R4c选自C1~4烷基、3~6元饱和环烷基、3~6元饱和杂环基。
2.一种化合物或其盐,其特征在于:所述化合物的结构如式Ⅲ-1或式III-2所示:
其中,n为0;
Ry1选自氢、卤素、C1~4烷基、卤代的C1~4烷基、C1~4烷氧基、卤代的C1~4烷氧基;
R4a选自氢、卤素、C1~4烷基、卤代的C1~4烷基、C1~4烷氧基、卤代的C1~4烷氧基;
R2选自氢、C1~5烷基;
m选自0、1或2;
R4b各自独立的选自氢、卤素、C1~4烷基、卤代的C1~4烷基、C1~4烷氧基、卤代的C1~4烷氧基、氰基、氨基、NHR4c、NR4cR4c、NHSO2R4c、SO2R4c;R4c选自C1~4烷基、3~6元饱和环烷基、3~6元饱和杂环基。
3.一种化合物或其盐,其特征在于:所述化合物的结构如式Ⅳ所示:
其中,n为0;
Ry1选自氢、卤素、C1~4烷基、卤代的C1~4烷基、C1~4烷氧基、卤代的C1~4烷氧基;
R4a选自氢、卤素、C1~4烷基、卤代的C1~4烷基、C1~4烷氧基、卤代的C1~4烷氧基;
m选自0、1或2;
R4b各自独立的选自氢、卤素、C1~4烷基、卤代的C1~4烷基、C1~4烷氧基、卤代的C1~4烷氧基、氰基、氨基、NHR4c、NR4cR4c、NHSO2R4c、SO2R4c;R4c选自C1~4烷基、3~6元饱和环烷基、3~6元饱和杂环基。
4.一种化合物或其盐,其特征在于:所述化合物的结构如式Ⅴ-1所示:
式Ⅴ-1中,n为0;
Ry2选自氢、卤素、C1~4烷基、卤代的C1~4烷基、C1~4烷氧基、卤代的C1~4烷氧基;
R5a选自氢、卤素、C1~4烷基、卤代的C1~4烷基、C1~4烷氧基、卤代的C1~4烷氧基;
p选自0、1或2;
R5b各自独立的选自氢、卤素、C1~4烷基、卤代的C1~4烷基、C1~4烷氧基、卤代的C1~4烷氧基、氰基、氨基、NHR4c、NR4cR4c、NHSO2R4c、SO2R4c;R4c选自C1~4烷基、3~6元饱和环烷基、3~6元饱和杂环基。
5.一种化合物或其盐,其特征在于:所述化合物为如下化合物之一:
6.一种药物组合物,其特征在于:所述药物组合物是以权利要求1~5任一项所述化合物或其盐为活性成分,加上药学上可接受的辅料制得的制剂。
7.权利要求1~5任一项所述化合物或其盐在制备P2X7受体抑制剂中的用途。
8.根据权利要求7所述的用途,其特征在于:所述P2X7受体抑制剂为治疗炎症及炎症相关疾病、肾损伤、呼吸系统疾病、癌症、疼痛、中枢神经系统疾病、放射性脑损伤、脑缺血、心肌损伤、糖尿病、抑郁症、红斑狼疮、动脉粥样硬化、过敏性哮喘的药物。
9.根据权利要求8所述的用途,其特征在于:所述炎症及炎症相关疾病为神经性炎症、关节炎、结肠炎、胰腺炎纤维化、酒精性脂肪性肝炎、支气管炎、肺炎、腰脊椎炎、血管炎;所述呼吸系统疾病为气道阻塞性疾病;所述肾损伤为缺血再灌注引起的急性肾损伤、原发性肾小球疾病的肾损伤、肾小管疾病的肾损伤、间质性肾炎肾损伤、自身免疫性疾病及结缔组织疾病肾损伤、代谢性疾病肾损伤、囊肿性肾病的肾损伤、遗传性与先天性肾病的肾损伤;所述癌症为前列腺癌、乳腺癌、肺癌、卵巢癌、胰腺癌、肠癌、结肠癌、胃癌、皮肤癌、脑肿瘤、白血病、淋巴癌;所述疼痛为头痛、偏头痛、三叉神经痛、不典型面痛、关节和骨痛、因癌症和肿瘤侵入引起的疼痛、神经性疼痛综合征;所述中枢神经系统疾病为阿尔茨海默症、帕金森综合征、癫痫、多发性硬化和其它脱髓鞘综合征、脑动脉粥样硬化、重症肌无力;所述红斑狼疮为全身性红斑狼疮。
10.根据权利要求8所述的用途,其特征在于:所述呼吸系统疾病为支气管哮喘、过敏性哮喘、内源性哮喘、外源性哮喘、运动诱发哮喘、药物诱发哮喘。
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