CN109422726A - CD47/SIRPα的阻断剂及其应用 - Google Patents
CD47/SIRPα的阻断剂及其应用 Download PDFInfo
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- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical class [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
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Abstract
本发明涉及作为CD47/SIRPα相互作用的阻断剂的化合物。具体而言，本发明涉及下式I所示化合物、含有下式I化合物的药物组合物及所述化合物在治疗CD47/SIRPα相互作用介导的疾病以及制备治疗CD47/SIRPα相互作用介导的疾病的药物中的用途。
Description
技术领域
本发明涉及药物化学领域；具体地说，本发明涉及阻断SIRPα蛋白与CD47相互作用的化合物及其应用。
背景技术
信号调节蛋白α(Signal regulatory proteinα,SIRPα)是一类广泛表达的糖蛋白分子，又称包含SHP-2结构域的蛋白酪氨酸磷酸酶底物，属于免疫球蛋白超家族的跨膜蛋白。SIRPα胞内含有免疫受体酪氨酸抑制基序(Immune-receptor tyrosin-basedinhibitory motif,ITIM)，当细胞受到生长因子刺激时，SIRPα可以通过ITIM发生磷酸化而抑制相应的生长因子的活性。SIRPα可以广泛表达于巨噬细胞和树突状细胞等髓系细胞表面。CD47又称整合素相关蛋白(Integrin-associated protein,IAP)，同属于免疫球蛋白超家族的膜蛋白，主要在各种肿瘤细胞膜上高表达。SIRPα是CD47的一种重要的表面受体，两者结合后产生的CD47-SIRPα信号在免疫系统中存在负性调节作用，在巨噬细胞吞噬过程中具有重要意义。
当SIRPα与CD47结合后，导致受体分子聚集引起酪氨酸的磷酸化和激活并且抑制巨噬细胞突触肌球蛋白的积累，在此过程中带有磷酸化ITIM的SIRPα可以募集并且激活酪氨酸磷酸酶SHP-1和SHP-2，传递抑制信号从而抑制巨噬细胞的吞噬作用，最终导致肿瘤细胞的免疫逃逸。因此阻断SIRPα与CD47结合可以恢复巨噬细胞的相关功能，最终达到治疗肿瘤的效果。
目前已有三种针对于CD47的药物进入临床试验，其中包括两种单克隆抗体(Hu5F9-G4，CC-90002)和一种融合蛋白(TTI-621)，临床效果较好。此外，还有1个处于IND申报阶段以及4个处于临床前阶段的抗体类药物。目前尚未有报道靶向于SIRPα的小分子阻断剂，而且大分子的抗体药物具有生产成本高、易产生免疫原性等缺点。因此研究生产成本低、组织渗透性好、不易产生免疫原性，具有更好的稳定性的小分子药物具有良好的应用前景。
综上所述，研究开发靶向于SIRPα的小分子阻断剂作为阻断SIRPα与CD47相互作用的候选药物具有重要的临床意义和应用前景。
发明内容
本发明的目的在于提供一种能够阻断SIRPα与CD47相互作用的小分子阻断剂。
在第一方面，本发明提供式I所示化合物或其药学上可接受的盐、前药、溶剂化物在制备阻断SIRPα蛋白与CD47相互作用的药物中的用途，
式中
X选自CH2、CHOH、C＝O、C＝S；
为单键或双键；
Y选自N或C，其中当Y为N时，R3不存在；
R1选自：氢、任选取代的C1-C10烷基、卤素、任选取代的C1-C10烷氧基、任选取代的C6-C10芳基、任选取代的苄基、硝基、CN；
R2选自：氢、C1-C10烷基或环烷基、卤素、C1-C10烷氧基、任选取代的C6-C10芳基、NRaRb、 其中Ra和Rb独立选自：氢、任选取代的C1-C6烷基；
或者，R1和R2可以相连形成其中n为1-3的整数；
R3选自：氢、卤素、任选取代的C1-C10烷氧基、任选取代的烷硫基；
R4选自：氢、任选取代的C1-C10烷基、任选取代的C3-C10环烷基、任选取代的C6-C10芳基、任选取代的苄基；
或者，R3与R4形成任选取代的六元环，或任选取代的含氧或含硫六元杂环；
R5选自：氢、任选取代的C1-C10烷基、卤素；
R6选自：H、Rc-COOH、Rc-COORd、Rc-CONR8R9、任选取代的羟基C1-C3烷基；
其中，Rc不存在或是任选取代的-(CH2)m-，m为选自1-3的整数；Rd是任选取代的C1-C3烷基；R8和R9独立选自：H、任选取代的C1-C10烷基、任选取代的C6-C10芳基；
R7选自：氢、任选取代的C1-C10烷基、卤素、氨基。
在具体的实施方式中，所述化合物如式II所示，
式中
R1选自：氢、任选取代的C1-C10烷基、卤素、任选取代的C6-C10芳基；
R2选自：氢、C1-C3烷基、任选取代的C6-C10芳基、NRaRb，其中Ra和Rb如上所述；
R3选自：氢、卤素、任选取代的C1-C10烷氧基；
R4选自：任选取代的环丙基、任选取代的C1-C6烷基、任选取代的苯基、任选取代的苄基；
或者，R3与R4形成任选取代的六元环；
R7选自：氢、氨基；
Y选自：C或N，其中当Y为N时，R3不存在。
在具体的实施方式中，所述化合物如式III所示，
式中
R1选自：氢、任选取代的C1-C10烷基、卤素；
R2选自：氢、
R7选自：氢、氨基；
R10选自：氢、任选取代的C1-C10烷基；
Z选自：C、O、S；
R6如上所述。
在优选的实施方式中，R6是Rc-COOH或Rc-COORd；其中，Rc不存在或是任选取代的-(CH2)m-，m为选自1-3的整数，Rd是任选取代的C1-C3烷基；更优选地，R6是-COOH。
在具体的实施方式中，所述化合物选自下组：
以及
在具体的实施方式中，所述化合物选自下组：
在具体的实施方式中，所述药物用于抑制肿瘤、或预防或治疗细菌、病毒或真菌引起的感染或治疗炎性疾病。
在具体的实施方式中，所述肿瘤包括但不限于：黑色素瘤、肺癌(优选非小细胞肺癌)、肾癌、卵巢癌、前列腺癌、乳腺癌、结肠癌、骨癌、胰腺癌、皮肤癌、头颈癌、子宫癌、直肠癌、肛门癌、胃癌、睾丸癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、何杰金氏病、非何杰金淋巴瘤、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、急性髓性白血病、慢性髓性白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、小儿实体瘤、淋巴细胞性淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经系统(CNS)肿瘤、原发性CNS淋巴瘤、肿瘤血管生成、脊轴瘤、脑干神经胶质瘤、垂体腺瘤、卡波西肉瘤、表皮样癌、鳞状细胞癌、T细胞淋巴瘤；
所述病毒包括但不限于：肝炎病毒(甲型、乙型和丙型)、孢疹病毒、流感病毒、腺病毒、冠状病毒、麻疹病毒、登革热病毒、脊髓灰质炎病毒、狂犬病病毒；
所述细菌包括但不限于：衣原体、立克次氏体、分枝杆菌、葡萄球菌、肺炎球菌、霍乱弧菌、破伤风梭菌；
所述真菌包括但不限于：假丝酵母、曲霉、皮炎芽酵母；
所述炎性疾病包括但不限于：强直性脊柱炎、自身免疫性溶血性贫血、关节炎、重症肌无力、系统性红斑狼疮、类风湿性关节炎、异种移植免疫排斥反应、恶性贫血、多肌炎。
在第二方面，本发明提供下式所示化合物，或其药学上可接受的盐、前药、溶剂化物，
式中
R1选自：氢、卤素、任选取代的C1-C10烷基、硝基、任选取代的C6-C10芳基、氰基；
R2选自：任选取代的取代苯基、丁基、吗啉基、哌啶基；
R4选自：任选取代的环己基、丁基、
R6选自：COOH、COOCH3、COOCH2CH3、CONR8R9、CONHC6H5、CH2OH；
X选自CH2、CH2CH3、CHOH、C＝O、C＝S；
环中为单键或双键。
在第三方面，本发明提供选自下组的化合物：
在第四方面，本发明提供一种药物组合物，所述药物组合物含有本发明第二或第三方面所述的化合物或其药学上可接受的盐、前药、溶剂化物，以及任选的药学上可接受的载体或赋形剂。
在优选的实施方式中，所述药物组合物用于抑制肿瘤、或预防或治疗细菌、病毒或真菌引起的感染或治疗炎性疾病。
在优选的实施方式中，所述肿瘤包括但不限于：黑色素瘤、肺癌(优选非小细胞肺癌)、肾癌、卵巢癌、前列腺癌、乳腺癌、结肠癌、骨癌、胰腺癌、皮肤癌、头颈癌、子宫癌、直肠癌、肛门癌、胃癌、睾丸癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、何杰金氏病、非何杰金淋巴瘤、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、急性髓性白血病、慢性髓性白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、小儿实体瘤、淋巴细胞性淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经系统(CNS)肿瘤、原发性CNS淋巴瘤、肿瘤血管生成、脊轴瘤、脑干神经胶质瘤、垂体腺瘤、卡波西肉瘤、表皮样癌、鳞状细胞癌、T细胞淋巴瘤；
所述病毒包括但不限于：肝炎病毒(甲型、乙型和丙型)、孢疹病毒、流感病毒、腺病毒、冠状病毒、麻疹病毒、登革热病毒、脊髓灰质炎病毒、狂犬病病毒；
所述细菌包括但不限于：衣原体、立克次氏体、分枝杆菌、葡萄球菌、肺炎球菌、霍乱弧菌、破伤风梭菌；
所述真菌包括但不限于：假丝酵母、曲霉、皮炎芽酵母；
所述炎性疾病包括但不限于：强直性脊柱炎、自身免疫性溶血性贫血、关节炎、重症肌无力、系统性红斑狼疮、类风湿性关节炎、异种移植免疫排斥反应、恶性贫血、多肌炎。
在第五方面，本发明提供一种阻断SIRPα与CD47结合的方法，包括利用本发明第一、第二或第三方面所述的化合物或第四方面所述的药物组合物阻断SIRPα与CD47结合的步骤。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1显示实施例1中化合物8与人SIRPα蛋白的SPR图；
图2显示实施例1中化合物9与人SIRPα蛋白的SPR图；
图3显示实施例1中化合物11与人SIRPα蛋白的SPR图；
图4显示实施例1中化合物13与人SIRPα蛋白的SPR图；
图5显示实施例1中化合物14与人SIRPα蛋白的SPR图；
图6显示实施例1中化合物15与人SIRPα蛋白的SPR图；
图7显示实施例1中化合物16与人SIRPα蛋白的SPR图；
图8显示实施例1中化合物17与人SIRPα蛋白的SPR图；
图9显示实施例1中化合物18与人SIRPα蛋白的SPR图；
图10显示实施例1中化合物19与人SIRPα蛋白的SPR图；
图11显示实施例1中化合物20与人SIRPα蛋白的SPR图。
具体实施方式
发明人经过广泛而深入的研究，出乎意料的发现了一系列具备沟通结构的化合物能够与人SIRPα蛋白结合，从而成为阻断SIRPα与CD47相互作用的小分子先导药物，进而为抗肿瘤药物的开发提供物质基础。在此基础上完成了本发明。
除非另有定义，本文中使用的所有技术和科学术语具有与所公开的发明所属领域的技术人员的普遍理解相同的含义。为便于理解本发明，对本发明涉及的相关术语作如下定义，但本发明的范围并不限于这些具体的定义。
术语定义
本文中，“SIRPα蛋白”是指信号调节蛋白α(Signal regulatory proteinα,SIRPα)，其是一类广泛表达的糖蛋白分子。CD47又称整合素相关蛋白，也是属于免疫球蛋白超家族的膜蛋白。SIRPα是CD47的一种重要的表面受体，两者结合后产生的信号在免疫系统中存在负性调节作用。
本文中，“烷基”是指碳链长度为1-10个碳原子的饱和的支链或直链烷基，优选的烷基为1-6个碳原子、更优选1-3个碳原子的烷基。烷基的例子包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、庚基、等。类似地，“环烷基”是指碳链长度为3-10个碳原子的饱和的环状烷基，优选的环烷基为3-6个碳原子的环烷基；例如(但不限于)环丙基。在具体的实施方式中，烷基或环烷基可以被取代，例如被卤素取代。在具体的实施方式中，优选卤素取代的C1-C3烷基。
本文中，“烷氧基”指被烷基取代的氧基。优选的烷氧基是1-10个碳原子，优选1-4个碳原子、更优选1-3个碳原子的烷氧基。烷氧基的例子包括但不限于甲氧基、乙氧基、丙氧基等。在具体的实施方式中，烷氧基可以被取代，例如被卤素取代。在具体的实施方式中，优选卤素取代的C1-C3烷氧基。
本文所用“杂环基”包括但不限于含有1-3个选自O、S或N的杂原子的5元或6元杂环基团，包括但不限于呋喃基、噻吩基、吡咯基、吡咯烷基、吡唑基、咪唑基、三唑基、噁唑基、吡喃基、吡啶基、嘧啶基、吡嗪基、哌啶基、吗啉基、异吲哚基等。在具体的实施方式中，杂环基可以被取代，例如被卤素取代。
本文中，“氨基”是指结构式为“NRaRb”的基团，其中，Ra和Rb可独立选自H或任选取代的C1-C6烷基，例如C1-C6卤代烷基。在具体的实施方式中，本文所述的“氨基”可以是-NH2。
本文中，“卤素”指氟、氯、溴和碘。在优选的实施方式中，卤素是氯或氟。
在本文中，“羧基”或“羧酸基”是指结构式为“Rc-COOH”的基团，其中，Rc是任选取代的C1-C3烷基。在具体的实施方式中，“羧基”或“羧酸基”是指“-COOH”。
在本文中，“酯基”或“羧酸酯基”是指结构式为“Rc-COORd”的基团，其中，Rc如上所述；Rd是任选取代的C1-C3烷基。
本文所用的术语“任选取代的”表示在语法上被该术语所修饰的基团可以具有或不具有取代基，而取代基的类型和数量只要符合被取代基团的价键规则即可。在具体的实施方式中，可用来取代其它基团的取代基包括但不限于：羟基、卤素、C1-C6烷基、C3-C6环烷基、C1-C6烷氧基、苯基、氨基、硝基。
本发明的化合物
本发明提供了一种具备共同母核的化合物，这些化合物能够结合SIRPα，从而阻断SIRPα与CD47的相互作用。这些化合物的毒性低，安全性好。
在具体的实施方式中，本发明提供式I所示化合物或其药学上可接受的盐、前药、溶剂化物，
式中
X选自CH2、CHOH、C＝O、C＝S；
为单键或双键；
Y选自N或C，其中当Y为N时，R3不存在；
R1选自：氢、任选取代的C1-C10烷基、卤素、任选取代的C1-C10烷氧基、任选取代的C6-C10芳基、任选取代的苄基、硝基、CN；
R2选自：氢、C1-C10烷基或环烷基、卤素、C1-C10烷氧基、任选取代的C6-C10芳基、NRaRb、 其中Ra和Rb独立选自：氢、任选取代的C1-C6烷基；
或者，R1和R2可以相连形成其中n为1-3的整数；
R3选自：氢、卤素、任选取代的C1-C10烷氧基、任选取代的烷硫基；
R4选自：氢、任选取代的C1-C10烷基、任选取代的C3-C10环烷基、任选取代的C6-C10芳基、任选取代的苄基；
或者，R3与R4形成任选取代的六元环，或任选取代的含氧或含硫六元杂环；
R5选自：氢、任选取代的C1-C10烷基、卤素；
R6选自：H、Rc-COOH、Rc-COORd、Rc-CONR8R9、任选取代的羟基C1-C3烷基；
其中，Rc不存在或是任选取代的-(CH2)m-，m为选自1-3的整数；Rd是任选取代的C1-C3烷基；R8和R9独立选自：H、任选取代的C1-C10烷基、任选取代的C6-C10芳基；
R7选自：氢、任选取代的C1-C10烷基、卤素、氨基。
在优选的实施方式中，本发明的化合物如式II所示，
式中
R1选自：氢、任选取代的C1-C10烷基、卤素、任选取代的C6-C10芳基；
R2选自：氢、C1-C3烷基、任选取代的C6-C10芳基、NRaRb，其中Ra和Rb如上限定；
R3选自：氢、卤素、任选取代的C1-C10烷氧基；
R4选自：任选取代的环丙基、任选取代的C1-C6烷基、任选取代的苯基、任选取代的苄基；
或者，R3与R4形成任选取代的六元环；
R7选自：氢、氨基；
Y选自：C或N，其中当Y为N时，R3不存在。
在具体的实施方式中，本发明的化合物中，R3和R4可以成环，从而形成下式III所示化合物，
式中
R1选自：氢、任选取代的C1-C10烷基、卤素；
R2选自：氢、
R7选自：氢、氨基；
R10选自：氢、任选取代的C1-C10烷基；
Z选自：C、O、S；
R6如上限定。
或者，本发明的化合物是式IV所示化合物，或其药学上可接受的盐、前药、溶剂化物，
式中
R1选自：氢、卤素、任选取代的C1-C10烷基、硝基、任选取代的C6-C10芳基、氰基；
R2选自：任选取代的取代苯基、丁基、吗啉基、哌啶基；
R4选自：任选取代的环己基、丁基、
R6选自：COOH、COOCH3、COOCH2CH3、CONR8R9、CONHC6H5、CH2OH；
X选自CH2、CH2CH3、CHOH、C＝O、C＝S；
环中为单键或双键。
基于本发明的教导以及本领域的公知常识，本领域技术人员可以理解，本发明的通式还包括本发明具体公开的化合物中的具体取代基与通式中其它取代基选择构成的化合物；本领域技术人员也可以理解，这样的化合物能够获得并且能够具备与实施例具体公开的化合物相同或相似的活性。因此，在具体的实施方式中，本发明的通式中的所有取代基可以分别是本发明具体公开的任一化合物中的相应基团。
在上述化合物的基础上，本发明进一步提供一种药物组合物，该组合物含有治疗有效量的本发明化合物或其药学上可接受的盐，以及药学上可接受的载体或赋形剂。
本发明化合物的药学上可接受的盐的例子包括但不限于无机和有机酸盐，例如盐酸盐、氢溴酸盐、硫酸盐、柠檬酸盐、乳酸盐、酒石酸盐、马来酸盐、富马酸盐、扁桃酸盐和草酸盐；以及与碱例如钠羟基、三(羟基甲基)胺基甲烷(TRIS，氨基丁三醇)和N-甲基葡糖胺形成的无机和有机碱盐。虽然每个人的需求各不相同，本领域技术人员可确定本发明药物组合物中每10种活性成分的佳剂量。一般情况下，本发明的化合物或其药学上可接受的盐，对哺乳动物每天口服给药，药量按照约0.0025到50毫克/公斤体重。但好是每公斤口服给药约0.01到10毫克。例如，单位口服剂量可以包括约0.01到50毫克，好是约0.1到10毫克的本发明化合物。单位剂量可给予一次或多次，每天为一片或多片，每片含有约0.1到50毫克，合宜地约0.25到10毫克的本发明化合物或其溶剂化物。本发明的药物组合物可被配制成适合各种给药途径的制剂形式，包括但不限于被配制成用于肠外，皮下，静脉，肌肉，腹腔内，透皮，口腔，鞘内，颅内，鼻腔或外用途径给药的形式，用于治疗肿瘤和其他疾病。给药量是有效地改善或消除一个或多个病症的药量。对于特定疾病的治疗，有效量是足以改善或以某些方式减轻与疾病有关的症状的药量。这样的药量可作为单一剂量施用，或者可依据有效的治疗方案给药。给药量也许可治愈疾病，但是给药通常是为了改善疾病的症状。一般需要反复给药来实现所需的症状改善。药的剂量将根据病人的年龄，健康与体重，并行治疗的种类，治疗的频率，以及所需治疗效益来决定。本发明的药物制剂可以给予任何哺乳动物，只要他们能获得本发明化合物的治疗效果。在这些哺乳动物中重要的是人类。本发明的化合物或其药物组合物可用于治疗SIRPα与CD47相互作用介导的疾病。本文中，由SIRPα与CD47相互作用介导的疾病为各种癌症。所述癌症包括但不限于：黑色素瘤、肺癌(优选非小细胞肺癌)、肾癌、卵巢癌、前列腺癌、乳腺癌、结肠癌、骨癌、胰腺癌、皮肤癌、头颈癌、子宫癌、直肠癌、肛门癌、胃癌、睾丸癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、何杰金氏病、非何杰金淋巴瘤、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、急性髓性白血病、慢性髓性白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、小儿实体瘤、淋巴细胞性淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经系统(CNS)肿瘤、原发性CNS淋巴瘤、肿瘤血管生成、脊轴瘤、脑干神经胶质瘤、垂体腺瘤、卡波西肉瘤、表皮样癌、鳞状细胞癌和T细胞淋巴瘤。
本发明的药物组合物或药物制剂可用已知的方式制造。例如，由传统的混合，制粒，制锭，溶解，或冷冻干燥过程制造。制造口服制剂时，可结合固体辅料和活性化合物，选择性研磨混合物。如果需要或必要时加入适量助剂后，加工颗粒混合物，获得片剂或锭剂芯。合适的辅料特别是填料，例如糖类如乳糖或蔗糖，甘露醇或山梨醇；纤维素制剂或钙磷酸盐，例如磷酸三钙或磷酸氢钙；以及粘结剂，例如淀粉糊，包括玉米淀粉，小麦淀粉，大米淀粉，马铃薯淀粉，明胶，黄芪胶，甲基纤维素，羟丙基甲25基纤维素，羧甲基纤维素钠或聚乙烯吡咯烷酮。如果需要，可增加崩解剂，比如上面提到的淀粉，以及羧甲基淀粉，交联聚乙烯吡咯烷酮，琼脂，或褐藻酸或其盐，如海藻酸钠。辅助剂特别是流动调节剂和润滑剂，例如，硅石，滑石，硬脂酸盐类，如镁硬脂酸钙，硬脂酸或聚乙二醇。如果需要，可以給锭剂核芯提供可以抵抗胃液的合适包衣。为此，可以应用浓缩糖类溶液。这个溶液可以含有阿拉伯树胶，滑石，聚乙烯吡咯烷酮，聚乙二醇和/或二氧化钛，漆溶液和合适的有机溶剂或溶剂混合物。为了制备耐胃液的包衣，可使用适当的纤维素溶液，例如醋酸纤维素邻苯二甲酸或羟丙基甲基纤维素邻苯二甲酸。可向药片或锭剂核芯的包衣加入染料或色素。例如，用于识别或为了表征活性成分剂量的组合。本领域技术人员可以基于其专业知识以及实际需求，将本发明的药物组合物制备成任何剂型。例如，在具体的实施方式中，本发明的药物组合物是适于口服的5剂型，包括但不限于片剂、溶液剂、混悬液、胶囊剂、颗粒剂、粉剂。
基于上述化合物和药物组合物，本发明进一步提供一种治疗SIRPα与CD47相互作用介导的疾病的方法，该方法包括给予需要的对象以本发明的化合物或药物组合物。给药方法包括但不限于本领域周知的各种给药方法，可根据患者的实际情况加以确定。这些方法包括但不限于肠外、皮下、静脉、肌肉、腹腔内、透皮、口腔、鞘内、颅内、鼻腔或外用途径给药。本发明也包括本发明化合物在制备预防或治疗SIRPα与CD47相互作用介导的疾病的药物中的用途。
本发明的优点：
1.本发明首次发现了一系列化合物能够结合SIRPα，从而阻断SIRPα与CD47的相互作用；
2.本发明的化合物是高效、低毒的SIRPα阻断剂，从而具备很重要的学术价值与现实意义。
以下结合具体实施案例对本发明的技术方案进一步描述，但以下实施案例不构成对本发明的限制，所有依据本发明的原理和技术手段采用的各种施用方法，均属于本发明范围。下列实施案例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例1.1-对氟苯基-6-氟-1,4-二氢-4-氧代-7-(1-哌嗪基)-3-喹啉乙酸乙酯(D3)的合成
1.1-对氟苯基-6-氟-1,4-二氢-4-氧代-7-(1-哌嗪基)-3-喹啉乙酸乙酯(D3)的合成途径如下所示：
实验步骤：
1)2,4-二氯-5-氟苯甲酰乙酸乙酯的合成
先将NaH(466mg,24.3mmol)放入100mL干燥的三口瓶中，加无水THF和碳酸二乙酯溶解，氩气保护，在45℃下搅拌30分钟，缓慢滴加含2,4-二氯-5-氟苯乙酮(1g,4.9mmol)的碳酸二乙酯溶液，保持内温在50-55℃，滴毕，搅拌5小时，反应完成，将反应液倒入含醋酸的冰水中，乙酸乙酯萃取，过硅胶柱(PE:DCM＝15:1)，得到黄色油状物0.65g，产率为48％。投到量得到产物4.1g，产率为61％。LC-MS:m/z:279.05(M+H)+。
2)2-(2,4-二氯-5-氟苯甲酰)-3-对氟苯胺基丙烯酸乙酯的合成
向25mL反应瓶中加入上一步产物(0.3g,1.08mmol)，原甲酸三乙酯(269μL,1.62mmol)及乙酸酐10mL，搅拌下缓缓升温至125℃反应3小时，减压除去生成的乙醇，向得到的固体物中加入无水乙醇3mL，在0℃左右滴加对氟苯胺(120mg,1.08mmol)，加毕室温反应1.5小时，抽滤，烘干，得到白色固体0.278g，收率64.6％。1H NMR(400MHz,DMSO-d6)δ12.41(d,J＝11.2Hz,1H),8.54(d,J＝12.4Hz,1H),7.83(d,J＝6.8Hz,1H),7.62(s,2H),7.48(d,J＝9.2Hz,1H),7.30(t,J＝8.8Hz,2H),3.96(q,J＝7.2Hz,2H),0.98(t,J＝6Hz,3H)。LC-MS:m/z:400.10(M+H)+。
3)7-氯-6-氟-1-对氟苯基-1,4-二氢-4-氧代喹啉-3-乙酸乙酯的合成
将上述产物(150mg,0.376mmol)、无水K2CO3(78mg,0.564mmol)和DMF10mL投入25mL反应瓶中，在125℃反应2小时，减压旋干DMF，降温至室温，向固体中加水15mL，常温搅拌30分钟，抽滤，用少量水洗涤，烘干。得到浅黄色固体120mg，产率为88％。1H NMR(400MHz,DMSO-d6)δ8.47(s,1H),8.07(d,J＝9.2Hz,1H),7.78(dd,J1＝4.8Hz,J2＝4Hz,2H),7.53(t,J＝8.8Hz,2H),7.12(d,J＝6Hz,1H),4.21(q,J＝6.8Hz,2H),1.26(t,J＝6.8Hz,3H)。LC-MS:m/z:364.10(M+H)+。
4)1-对氟苯基-6-氟-1,4-二氢-4-氧代-7-(1-哌嗪基)-3-喹啉乙酸乙酯
将上一步产物(65mg,0.18mmol)，无水哌嗪(62mg,0.72mmol)加入25mL反应瓶中，加入吡啶溶解，搅拌下缓缓升温回流,反应8小时后,减压蒸除吡啶，得到的粗产品加1mL乙醇加热回流，30分钟后冷却至室温，析出固体，抽滤，少量乙醇洗涤，烘干。得到淡黄色固体20mg，产率为27％。产率较低，之后用购买的原料药酯化也可获得产物，产率66.3％。1H NMR(400MHz,DMSO-d6)δ8.37(s,1H),7.81-7.75(m,3H),7.53(t,J＝8.8Hz,2H),6.26(d,J＝7.2Hz,1H),4.19(q,J＝7.2Hz,2H),3.64-3.57(m,4H),3.02-2.86(m,4H),1.25(t,J＝7.2Hz,3H)。LC-MS:m/z:364.10(M+H)+。HRMS(ESI)(m/z):[M+H]+calcd for C22H22F2N3O3,414.1629；found,414.1633.
实施例2.1-对氟苯基-6-氟-1,4-二氢-4-氧代-7-(1-哌嗪基)-3-喹啉乙酸甲酯(D2)的合成
将上述原料药(500mg,1.2mmol)放于50mL反应瓶中，加甲醇10mL和浓硫酸1.5mL，加热回流，5小时后反应完成。在冰浴下，加NaOH中和至pH＝8～9，加DCM萃取，有机相旋干，得到白色固体360mg，产率为76.1％。1H NMR(400MHz,DMSO-d6)δ8.39(s,1H),7.80(d,J＝13.6Hz,1H),7.76(dd,J1＝4.8Hz,J2＝4Hz,2H),7.52(t,J＝8.8Hz,2H),6.26(d,J＝7.2Hz,1H),3.72(s,3H),2.88-2.86(m,4H),2.78-2.77(m,4H)。
实施例3.1-对氟苯基-6-氟-1,4-二氢-4-氧代-7-(1-哌嗪基)-3-喹啉乙酰丁胺(D4)的合成
将甲酯产物(50mg,0.13mmol)放于25mL反应瓶中，加正丁胺溶解，66℃下搅拌，6小时反应完成，旋干溶剂，得到黄色产物40mg，产率为72.7％。1H NMR(400MHz,CD3OD)δ8.63(s,1H),7.95(d,J＝13.6Hz,1H),7.64(dd,J1＝4.8Hz,J2＝4.4Hz,2H),7.45(t,J＝8.4Hz,2H),6.42(d,J＝7.2Hz,1H),3.43(t,J＝6.8Hz,2H),3.09-3.07(m,4H),3.01-2.98(m,4H),1.65-1.58(m,2H),1.50-1.41(m,2H),0.98(t,J＝7.6Hz,3H)。HRMS(ESI)(m/z):[M+H]+calcd forC24H27F2N4O2,441.2102；found,441.2100。
实施例4.1-对氟苄基-6-氟-1,4-二氢-4-氧代-7-(1-哌嗪基)-3-喹啉乙酸(D9)的合成
1)2-(2,4-二氯-5-氟苯甲酰)-3-对氟苄胺基丙烯酸乙酯的合成
得到白色固体420mg，收率56.5％。1H NMR(400MHz,DMSO-d6)δ11.13-11.08(m,1H),8.35(d,J＝14.4Hz,1H),7.76(d,J＝6.8Hz,1H),7.47-7.44(m,2H),7.38(d,J＝9.2Hz,1H),7.24(t,J＝9.2Hz,2H),4.71(d,J＝6.4Hz,2H),3.88(q,J＝6.8Hz,2H),0.92(t,J＝7.2Hz,3H)。LC-MS:m/z:414.10(M+H)+。
2)7-氯-6-氟-1-对氟苯苄基-1,4-二氢-4-氧代喹啉-3-乙酸乙酯的合成
得到白色固体0.34g，收率88.8％。1H NMR(400MHz,DMSO-d6)δ8.91(s,1H),8.05(d,J＝9.6Hz,1H),8.00(d,J＝6Hz,1H),7.36-7.33(m,2H),7.22(t,J＝8.8Hz,2H),5.70(s,2H),4.29(q,J＝7.2Hz,2H),1.29(t,J＝7.2Hz,3H)。LC-MS:m/z:378.10(M+H)+。
3)7-氯-6-氟-1-对氟苯苄基-1,4-二氢-4-氧代喹啉-3-乙酸的合成
将乙酯产物(100mg，0.26mmol)放于25mL反应瓶中，加5％NaOH溶液，100℃下回流，4小时后反应完成，调pH＝2～3，析出固体，抽滤，水洗，烘干，得到淡黄色固体55mg，产率为59.8％。1H NMR(400MHz,DMSO-d6)δ14.67(s,1H),9.26(s,1H),8.25(d,J＝6Hz,1H),8.22(d,J＝9.2Hz,1H),7.41-7.37(m,2H),7.22(t,J＝8.8Hz,2H),5.88(s,2H)。LC-MS:m/z:350.10(M+H)+。
4)1-对氟苄基-6-氟-1,4-二氢-4-氧代-7-(1-哌嗪基)-3-喹啉乙酸
1H NMR(400MHz,DMSO-d6)δ9.20(s,1H),7.90(d,J＝13.2Hz,1H),7.42-7.37(m,2H),7.22(t,J＝9.2Hz,2H),7.06(d,J＝7.2Hz,1H),5.84(s,2H),3.15-3.13(m,4H),2.92-2.89(m,4H)。HRMS(ESI)(m/z):[M+H]+calcd for C21H20F2N3O3,400.1472；found,400.1468。
实施例5.1-对氟苯基-6-氟-1,4-二氢-4-氧代-7-苯基-3-喹啉乙酸(D11)的合成
将乙酯产物(0.315mg,0.87mmol)，氟化铯(0.143mg,0.87mmol)，苯硼酸(0.184mg,1.13mmol)放于50mL三口瓶中，加甲苯溶解，除氧15分钟后加入催化量的钯催化剂，再除氧15分钟，在氩气保护下，加热回流，24小时后，大部分原料反应完成，抽滤，滤液旋干，过柱，得到粗产物100mg，HRMS(ESI)(m/z):[M+H]+calcd for C24H18F2NO3,406.1255；found,406.1248。向粗品中加入5％NaOH溶液，加热回流，反应完成后用盐酸溶液调节pH＝2～3，析出固体，抽滤，得到白色固体40mg，产率12.2％。1H NMR(400MHz,DMSO-d6)δ14.77(s,1H),8.80(s,1H),8.24(d,J＝10Hz,1H),7.85(d,J＝0.8Hz,2H),7.56-7.50(m,7H),7.15(d,J＝5.6Hz,1H)。
实施例6.6-氟-1-(4-对氟苯基)-7-(哌嗪基)-4-氧代-2,3-二氢喹啉(D21)的合成
将上述原料药的乙酸盐(80mg,0.19mmol)溶于甲醇中，滴加含有NaBH4(29mg,0.76mmol)的甲醇溶液，搅拌1小时，加入催化量的对甲苯磺酸，加热至回流，2小时后反应完成，降温，DCM萃取，过柱(DCM:MeOH＝50:1),得到黄色固体40mg，产率为61.5％。1H NMR(400MHz,DMSO-d6)δ7.42-7.39(m,2H),7.35(d,J＝11.2Hz,1H),7.33-7.29(m,2H),5.89(d,J＝7.6Hz,1H),3.81(t,J＝7.2Hz,2H),2.85-2.82(m,4H),2.75-2.73(m,4H),2.68(d,J＝6.8Hz,2H)。LC-MS:m/z:342.20(M+H)+。
实施例7.本发明化合物与SIRPα的结合常数的测定
在本实施例中，采用表面等离子体共振测定本发明化合物与SIRPα的结合常数。
本实施例中所用的以下化合物1-22购买于Aladdin公司。利用Biacore T200进行表面等离子体共振(SPR)实验，测定本发明化合物与人SIRPα蛋白之间的结合常数。具体实验步骤如下：首先将购买的SIRPα蛋白(北京义翘神州生物技术有限公司)用pH 4.5的醋酸钠稀释至50μg/ml，使用氨基偶联试剂盒将蛋白偶联在CM7芯片上，以10μl/min的流速结合600s，最终偶联量约为15000RU。偶联结束后，将CM7芯片用缓冲液(1.05×PBS，0.05％ P20)平衡至稳定状态。随后用运行缓冲液(1.05×PBS，0.05％ P20，1％ DMSO)将化合物稀释至一系列不同浓度，随运行缓冲液流经芯片表面，流速30μL/min，结合时间90s，解离时间120s。最后数据用BIAevaluation2.0软件分析，利用稳态拟合得到KD值。下表1中列出了所测化合物的KD值。
表1.本发明的小分子化合物与重组人SIRPα蛋白的结合亲和力
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (11)
1.式I所示化合物或其药学上可接受的盐、前药、溶剂化物在制备阻断SIRPα蛋白与CD47相互作用的药物中的用途，
式中
X选自CH2、CHOH、C＝O、C＝S；
为单键或双键；
Y选自N或C，其中当Y为N时，R3不存在；
R1选自：氢、任选取代的C1-C10烷基、卤素、任选取代的C1-C10烷氧基、任选取代的C6-C10芳基、任选取代的苄基、硝基、CN；
R2选自：氢、C1-C10烷基或环烷基、卤素、C1-C10烷氧基、任选取代的C6-C10芳基、NRaRb、 其中Ra和Rb独立选自：氢、任选取代的C1-C6烷基；
或者，R1和R2可以相连形成其中n为1-3的整数；
R3选自：氢、卤素、任选取代的C1-C10烷氧基、任选取代的烷硫基；
R4选自：氢、任选取代的C1-C10烷基、任选取代的C3-C10环烷基、任选取代的C6-C10芳基、任选取代的苄基；
或者，R3与R4形成任选取代的六元环，或任选取代的含氧或含硫六元杂环；
R5选自：氢、任选取代的C1-C10烷基、卤素；
R6选自：H、Rc-COOH、Rc-COORd、Rc-CONR8R9、任选取代的羟基C1-C3烷基；
其中，Rc不存在或是任选取代的-(CH2)m-，m为选自1-3的整数；Rd是任选取代的C1-C3烷基；R8和R9独立选自：H、任选取代的C1-C10烷基、任选取代的C6-C10芳基；
R7选自：氢、任选取代的C1-C10烷基、卤素、氨基。
2.如权利要求1所述的用途，其特征在于，所述化合物如式II所示，
式中
R1选自：氢、任选取代的C1-C10烷基、卤素、任选取代的C6-C10芳基；
R2选自：氢、C1-C3烷基、任选取代的C6-C10芳基、NRaRb，其中Ra和Rb如权利要求1所限定；
R3选自：氢、卤素、任选取代的C1-C10烷氧基；
R4选自：任选取代的环丙基、任选取代的C1-C6烷基、任选取代的苯基、任选取代的苄基；
或者，R3与R4形成任选取代的六元环；
R7选自：氢、氨基；
Y选自：C或N，其中当Y为N时，R3不存在。
3.如权利要求1所述的用途，其特征在于，所述化合物如式III所示，
式中
R1选自：氢、任选取代的C1-C10烷基、卤素；
R2选自：氢、
R7选自：氢、氨基；
R10选自：氢、任选取代的C1-C10烷基；
Z选自：C、O、S；
R6如权利要求1所述。
4.如权利要求1-3中任一项所述的用途，其特征在于，所述化合物选自下组：
以及
5.如权利要求1-3中任一项所述的用途，其特征在于，所述化合物选自下组：
6.如权利要求1-3中任一项所述的用途，其特征在于，所述药物用于抑制肿瘤、或预防或治疗细菌、病毒或真菌引起的感染或治疗炎性疾病。
7.如权利要求6所述的用途，其特征在于，所述肿瘤包括但不限于：黑色素瘤、肺癌(优选非小细胞肺癌)、肾癌、卵巢癌、前列腺癌、乳腺癌、结肠癌、骨癌、胰腺癌、皮肤癌、头颈癌、子宫癌、直肠癌、肛门癌、胃癌、睾丸癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、何杰金氏病、非何杰金淋巴瘤、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、急性髓性白血病、慢性髓性白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、小儿实体瘤、淋巴细胞性淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经系统(CNS)肿瘤、原发性CNS淋巴瘤、肿瘤血管生成、脊轴瘤、脑干神经胶质瘤、垂体腺瘤、卡波西肉瘤、表皮样癌、鳞状细胞癌、T细胞淋巴瘤；
所述病毒包括但不限于：肝炎病毒(甲型、乙型和丙型)、孢疹病毒、流感病毒、腺病毒、冠状病毒、麻疹病毒、登革热病毒、脊髓灰质炎病毒、狂犬病病毒；
所述细菌包括但不限于：衣原体、立克次氏体、分枝杆菌、葡萄球菌、肺炎球菌、霍乱弧菌、破伤风梭菌；
所述真菌包括但不限于：假丝酵母、曲霉、皮炎芽酵母；
所述炎性疾病包括但不限于：强直性脊柱炎、自身免疫性溶血性贫血、关节炎、重症肌无力、系统性红斑狼疮、类风湿性关节炎、异种移植免疫排斥反应、恶性贫血、多肌炎。
8.一种下式所示化合物，或其药学上可接受的盐、前药、溶剂化物，
式中
R1选自：氢、卤素、任选取代的C1-C10烷基、硝基、任选取代的C6-C10芳基、氰基；
R2选自：任选取代的取代苯基、丁基、吗啉基、哌啶基；
R4选自：任选取代的环己基、丁基、
R6选自：COOH、COOCH3、COOCH2CH3、CONR8R9、CONHC6H5、CH2OH；
X选自CH2、CH2CH3、CHOH、C＝O、C＝S；
环中为单键或双键。
9.选自下组的化合物：
10.一种药物组合物，所述药物组合物含有权利要求8或9所述的化合物或其药学上可接受的盐、前药、溶剂化物，以及任选的药学上可接受的载体或赋形剂。
11.一种阻断SIRPα与CD47结合的方法，包括利用权利要求1-8中任一项所述的化合物或权利要求9所述的药物组合物阻断SIRPα与CD47结合的步骤。
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