CN116137815A - 嘧啶并嘧啶酮化合物及包含其的药物组合物 - Google Patents
嘧啶并嘧啶酮化合物及包含其的药物组合物 Download PDFInfo
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- CN116137815A CN116137815A CN202180063334.1A CN202180063334A CN116137815A CN 116137815 A CN116137815 A CN 116137815A CN 202180063334 A CN202180063334 A CN 202180063334A CN 116137815 A CN116137815 A CN 116137815A
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- Prior art keywords
- methyl
- compound
- benzamide
- pyrimidin
- pyridin
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 17
- RLJCWYYOGHGGBV-UHFFFAOYSA-N 1h-pyrimido[5,4-d]pyrimidin-2-one Chemical class C1=NC=C2NC(=O)N=CC2=N1 RLJCWYYOGHGGBV-UHFFFAOYSA-N 0.000 title abstract description 5
- -1 pyrimidopyrimidinone compound Chemical class 0.000 claims abstract description 79
- 108010074708 B7-H1 Antigen Proteins 0.000 claims abstract description 60
- 102000008096 B7-H1 Antigen Human genes 0.000 claims abstract description 59
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 18
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 18
- 201000011510 cancer Diseases 0.000 claims abstract description 11
- 230000002265 prevention Effects 0.000 claims abstract description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 30
- 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 claims description 15
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000002971 oxazolyl group Chemical group 0.000 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
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- 206010006187 Breast cancer Diseases 0.000 claims description 2
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- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 2
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- 125000004464 hydroxyphenyl group Chemical group 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- GJVFBWCTGUSGDD-UHFFFAOYSA-L pentamethonium bromide Chemical compound [Br-].[Br-].C[N+](C)(C)CCCCC[N+](C)(C)C GJVFBWCTGUSGDD-UHFFFAOYSA-L 0.000 claims description 2
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
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- BBTGWRLIETYEJO-UHFFFAOYSA-N n-pyridin-3-ylbenzamide Chemical compound C=1C=CC=CC=1C(=O)NC1=CC=CN=C1 BBTGWRLIETYEJO-UHFFFAOYSA-N 0.000 description 12
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 11
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- 230000005764 inhibitory process Effects 0.000 description 11
- CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 239000007810 chemical reaction solvent Substances 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- GYLMOVQXUVCWLK-UHFFFAOYSA-N 3-tert-butylbenzoyl chloride Chemical compound CC(C)(C)C1=CC=CC(C(Cl)=O)=C1 GYLMOVQXUVCWLK-UHFFFAOYSA-N 0.000 description 8
- RZPSBEGGSZWYAN-UHFFFAOYSA-N 6-methyl-5-nitropyridin-3-amine Chemical compound CC1=NC=C(N)C=C1[N+]([O-])=O RZPSBEGGSZWYAN-UHFFFAOYSA-N 0.000 description 8
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- RUJYJCANMOTJMO-UHFFFAOYSA-N 3-(trifluoromethyl)benzoyl chloride Chemical compound FC(F)(F)C1=CC=CC(C(Cl)=O)=C1 RUJYJCANMOTJMO-UHFFFAOYSA-N 0.000 description 6
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Abstract
本发明涉及一种具有抑制PD‑L1表达的作用的嘧啶并嘧啶酮化合物和包含该化合物作为活性成分的药物组合物。本发明的嘧啶并嘧啶酮化合物可有效用于治疗或预防癌症。
Description
技术领域
本发明涉及一种嘧啶并嘧啶酮化合物和包含该嘧啶并嘧啶酮化合物的药物组合物,更具体地,涉及一种具有抑制PD-L1表达的作用的嘧啶并嘧啶酮化合物和包含其作为活性成分的药物组合物。
背景技术
PD-1(程序性死亡-1,CD279)是T细胞上的一种受体蛋白,已知PD-1当与其配体PD-L1(程序性死亡-配体1,CD274)或PD-L2(程序性死亡-配体2,CD273)结合时会抑制来自T细胞受体的激活信号。即,当T细胞的PD-1受体蛋白与配体PD-L1/2结合时,T细胞的功能活性(包括T细胞增殖、细胞因子分泌和细胞溶解活性)降低,从而保护正常细胞。PD-1和PD-L1/2相互作用下调了感染、肿瘤或自身免疫疾病中的免疫应答(Keir Me,Butte MJ,Freeman GJ等人,PD-1and its ligands in tolerance and immunity.Annu.Rev.Immunol.2008;26)。
使用抗PD-1和PD-L1的抗体阻断PD-1/PD-L1相互作用已显示在许多体系中恢复和增强T细胞活化。在诸如黑素瘤、非小细胞肺癌和肾癌的癌症患者中,已知使用单克隆抗体的PD-1/PD-L1组合抑制治疗等。
在一项关于通过靶向αvβ3-整合素调节癌症细胞中的PD-L1表达和免疫抗癌反应的研究中,已发现移植缺乏β3-整合素的肿瘤细胞会显著降低原发性肿瘤的生长,此结果归因于PD-L1的表达降低。因此,抑制β3-整合素可以提高免疫抗癌药物对黑素瘤的疗效(ProcNatl Acad Sci USA.,2019年10月1日,116(40),20141-20150)。已知,视网膜母细胞瘤蛋白质RB作为一种肿瘤抑制剂,通过经抑制NF-kB活性而抑制PD-L1表达而显示出抗癌功效。此外,在黑素瘤模型中,姜黄素和芹黄素显示出黑素瘤细胞生长抑制作用,并且特别地,发现芹黄素显著抑制由IFN-γ诱导的PD-L1表达。此外,已知在经EGCG和绿茶提取物(GTE)预处理的肺癌细胞系A549中,对由IFN-γ诱导的PD-L1表达降低了40%至80%。同时,在能够增强对黑素瘤的免疫抗癌作用的激酶抑制剂库筛选研究中,瑞戈非尼被确定为约20种降低细胞表面PD-L1表达水平超过50%的药物之中最强效的药物。该药物当在细胞和体内与IFN-γ或免疫检查点阻滞剂(ICB)联合使用时,可强力促进抗肿瘤疗效,强烈抑制JAK1/2-STAT1和MAPK信号发送,然后降低IFN-γ诱导的PD-L1和IDO1表达(Clin Cancer Res.,2019年7月15日,25(14),4530-4541)。
作为蛋白激酶抑制剂,3,4-二氢嘧啶并[4,5-d]嘧啶-2-酮衍生物已知为Abl、BCR-Abl、Bmx、c-Raf、Csk、Fes、FGFR、Flt3、Ikk、IR、JNK、Lck、Mkk、PKC、PKD、Rsk、SAPK、Syk、Trk、RTK、Src、EGFR、IGF、Mek、Ros、Tie2激酶活性抑制剂,但未提及这些衍生物对PD-L1的作用。还已知3-苯基-二氢嘧啶并[4,5-d]嘧啶酮衍生物对Src激酶表现出1至5nM(IC50)的抑制活性,但它们对PD-L1的作用也未被提及(国际专利公开No.WO 2005/011597)。
因此,需要开发具有PD-L1表达抑制活性以获得抗肿瘤功效的化合物。
发明内容
【技术问题】
本发明的目的是提供一种具有抑制PD-L1表达的作用的式(I)化合物或其药学上可接受的盐。
本发明的另一目的是提供一种包含式(I)化合物或其药学上可接受的盐的药物组合物。
【技术方案】
本发明的一个方面涉及下式(I)的嘧啶并嘧啶酮化合物或其药学上可接受的盐。
其中,
R1是C5-C15芳基、C5-C15杂芳基、C3-C10环烷基或C3-C10杂环烷基;
R2是氢、C1-C4烷基或C1-C4烷氧基;
R3是氢、卤素、C1-C4烷基或C1-C4烷氧基;并且
R4是未取代的C5-C15芳基或C5-C15杂芳基或被C1-C4烷基、C1-C4卤代烷基或C5-C15杂芳基取代的C5-C15芳基或C5-C15杂芳基.
如本文所使用的术语“C5-C15芳基”包括芳族基团及其部分还原的衍生物两者。芳族基团是由5至15个碳原子组成的单环或稠环类型。芳基的代表性示例包括但不限于苯基、萘基、四氢萘基等。
如本文所使用的术语“C5-C15杂芳基”包括杂芳族基团及其部分还原的衍生物两者。杂芳族基团是由5至15个碳原子组成的单环或稠环类型,并且含有一个或多个氧、硫或氮。杂芳基的代表性示例包括但不限于吡啶基、呋喃基、噻吩基、吲哚基、喹啉基、咪唑啉基、唑基、二氢唑基、噻唑基等。
如本文所使用的术语“C3-C10环烷基”是指具有3至10个碳原子的简单或稠合的环状烃,示例包括但不限于环丙基、环丁基、环戊基、环己基等。
如本文所使用的术语“C3-C10杂环烷基”是指其中具有3至10个碳原子的简单或稠合的环状烃的一个或多个环碳原子被氧、硫或氮取代的官能团,并且示例包括但不限于噻唑烷基、氧杂环丙烷基等。
如本文所使用的术语“C1-C4烷基”是指具有1至4个碳原子的直链或支链单价烃,示例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基等。
如本文所使用的术语“C1-C4烷氧基”是指具有1至4个碳原子的直链或支链烷氧基,示例包括但不限于甲氧基、乙氧基、正丙氧基等。
如本文所使用的术语“C1-C4卤代烷基”是指被选自氟、氯、溴和碘的一个或多个卤素取代的具有1至4个碳原子的直链或支链烃,示例包括但不限于三氟甲基、三氯甲基、三氟乙基等。
在本发明的一个实施方式中,化合物具有式(I)
其中,
R1是未取代的苯基或被卤素或羟基取代的苯基;
R2是C1-C4烷基;
R3是氢、卤素、C1-C4烷基或C1-C4烷氧基;并且
如本文所使用的术语“烷基噻唑基”是指被一个或多个C1-C4烷基取代的噻唑基,示例包括但不限于叔丁基噻唑基等。
在本发明的一个实施方式中,化合物具有式(I)
其中,
R1是苯基、氟苯基或羟基苯基;
R2是甲基;
R3是氢、氯、溴、甲基或甲氧基;并且
本发明的药学上可接受的盐可以包括无毒的无机酸盐和有机酸盐两者,其示例包括盐酸盐、磷酸盐、硫酸盐、硝酸盐、酒石酸盐、甲磺酸盐、对甲苯磺酸盐、乙酸盐、三氟乙酸盐、柠檬酸盐、马来酸盐、琥珀酸盐、草酸盐、苯甲酸盐、富马酸盐、扁桃酸盐、丙酸盐、乳酸盐、乙醇酸盐、葡萄糖酸盐、半乳糖醛酸盐、谷氨酸盐、戊二酸盐、葡糖醛酸盐、天冬氨酸盐、抗坏血酸盐、碳酸盐、香草酸盐、氢碘酸盐、苹果酸盐、丙二酸盐等。
根据本发明的代表性化合物选自由以下组成的组。
N-(6-甲基-5-(1-甲基-2-氧代-7-(苯基氨基)-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)-3-(三氟甲基)苯甲酰胺(I-1);
3-(叔丁基)-N-(6-甲基-5-(1-甲基-2-氧代-7-(苯基氨基)-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)苯甲酰胺(I-2);
N-(6-甲氧基-5-(1-甲基-2-氧代-7-(苯基氨基)-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)-3-(三氟甲基)苯甲酰胺(I-3);
3-(叔丁基)-N-(6-甲氧基-5-(1-甲基-2-氧代-7-(苯基氨基)-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)苯甲酰胺(I-6);
N-(6-氯-5-(1-甲基-2-氧代-7-(苯基氨基)-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)-3-(三氟甲基)苯甲酰胺(I-8);
3-(叔丁基)-N-(6-氯-5-(1-甲基-2-氧代-7-(苯基氨基)-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)苯甲酰胺(I-9);
2-(叔丁基)-N-(6-氯-5-(1-甲基-2-氧代-7-(苯基氨基)-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)噻唑-4-甲酰胺(I-10);和
N-(6-氯-5-(7-((4-羟基苯基)氨基)-1-甲基-2-氧代-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)-3-(三氟甲基)苯甲酰胺(I-11)。
在以下反应方案1中描绘了一种用于制备根据本发明的式(I)化合物的方法。然而,在以下反应方案中所例示的反应方案仅代表本发明中使用的典型方法。操作顺序、试剂、反应条件等可以改变而没有限制。
[反应方案1]
在反应方案1中,R1、R2、R3和R4如上式(I)中所定义,并且R5是卤素或氧代(=O)。
在本发明的一个实施方式中,R5是氯、溴、碘或氧代(=O),特别地是氯或氧代。
反应方案1示出了使用式(II)化合物和式(III)化合物作为原料制备式(I)化合物的四个步骤的方法。
在步骤1中,使式(II)化合物与式(III)化合物反应,得到式(IV)化合物。
此时,当R5是卤素时,在有机碱存在下进行胺化反应,得到式(IV)化合物,当R5是氧代(=O)时,加入还原剂以通过还原胺化反应得到式(Ⅳ)化合物。作为有机碱,可以使用三乙胺、N,N-二异丙基乙胺(DIPEA)等,而作为还原剂,可以使用硼氢化钠(NaBH4)、氰基硼氢化钠(NaCNBH3)、三乙酰氧基硼氢化钠(Na(CH3COO)3BH)等。
在步骤2中,向式(IV)化合物中加入三光气以进行杂环脲形成反应,得到式(V)化合物。在这种情况下,可以在有机碱的存在下进行所述杂环脲形成反应。作为有机碱,可以使用三乙胺、N,N-二异丙基乙胺(DIPEA)等。
在步骤3中,将式(V)化合物的硫化物基团氧化,得到具有砜基团的式(VI)砜化合物。
可以使用单过硫酸氢钾(oxone)、间氯过氧苯甲酸(mPBA)等作为氧化剂进行氧化反应。
在步骤4中,通过使式(VI)化合物与式(VII)胺化合物进行取代反应,获得式(I)化合物。
作为反应溶剂,可以使用乙腈、四氢呋喃、1,4-二烷、氯仿、二氯甲烷、1,2-二氯乙烷、乙酸乙酯、二甲基甲酰胺、甲醇、乙醇等。在取代反应中,可以一起使用无机碱或有机碱例如三乙胺、N,N-二异丙基乙胺和吡啶,或可以一起使用有机酸例如三氟乙酸。反应温度优选地为50-150℃,更优选地为80℃-100℃。
式(II)化合物和式(III)化合物可根据已知方法制备或可作为市售产品获得。
例如,分别在以下反应方案2至4中描绘了用于制备式(II)化合物和式(III)化合物的方法。然而,以下反应方案中所示的那些方法仅代表本发明中使用的典型方法。操作顺序、试剂、反应条件等可以改变而没有限制。
[反应方案2]
在反应方案2中,R2如上文式(I)中所定义,且R5如上文反应方案1中所定义。
如反应方案2中所示,式(II)化合物可以通过如下制备:使4-氯-2-(甲硫基)嘧啶-5-羧酸乙酯与式(XIII)胺化合物反应得到式(VIII)化合物;使用还原剂例如氢化铝锂(LiAlH4)使式(VIII)化合物发生还原反应得到式(IX)化合物;以及使用亚硫酰氯(SOCl2)等卤化式(IX)化合物的醇基或使用二氧化锰(MnO2)等通过氧化形成醛。
[反应方案3]
在反应方案3中,R3和R4如上文式(I)中所定义,并且Y是卤素或羟基。
在本发明的一个实施方式中,Y是氯、溴、碘或羟基,特别地是氯或羟基。
如反应方案3中所示,式(III)化合物可通过以下制备:使式(X)化合物和式(XI)化合物在有机碱(如DIPEA或偶联剂)存在下反应,得到式(XII)化合物,并将式(XIII)化合物的硝基还原为胺基。在这种情况下,还原反应可以通过使用叔丁醇钾和双(频哪醇合)二硼的组合,或者通过在钯碳催化剂上使用氢气来进行。
[反应方案4]
在反应方案4中,R3和R4如上文式(I)中所定义,并且Y如上文反应方案3中所定义。
或者,式(III)化合物可以通过在有机碱(例如DIPEA或偶联剂)存在下使式(X’)二胺-吡啶化合物与式(XI)化合物反应来制备,如上述反应方案4所示。
根据本发明的式I化合物或其药学上可接受的盐表现出优异的PD-L1表达抑制活性(实验例1)。
本发明的一个方面涉及用于抑制程序性死亡-配体1(PD-L1)的药物组合物,其包含式(I)化合物或其医药上可接受的盐以及药学上可接受的载体,特别地,涉及一种用于预防或治疗癌症的药物组合物。
在本发明的一个实施方式中,式(I)化合物或其医药上可接受的盐通过经抑制PD-L1表达来激活免疫细胞,从而诱导抗癌作用,因此可有效用于治疗结肠癌、肺癌、乳腺癌、胃癌、宫颈癌、膀胱癌、血癌或非霍奇金淋巴瘤。
根据本发明的药物组合物可以经口服施用,例如摄入或吸入;或经肠胃外施用,例如注射、沉积、植入或栓剂。注射可以是,例如静脉内注射、皮下注射、肌肉内注射或腹膜内注射。根据施用途径,本发明的药物组合物可以被配制为片剂、胶囊剂、颗粒剂、细粒剂(fine subtilae)、散剂、舌下片剂、栓剂、软膏剂、注射溶液剂、乳剂、悬浮剂、糖浆剂、气雾剂等。本发明的药物组合物的上述各种形式可使用通常用于每种形式的药学上可接受的载体以本领域公知的方式制备。药学上可接受的载体的示例包括赋形剂、粘合剂、崩解剂、润滑剂、防腐剂、抗氧化剂、等渗剂、缓冲剂、包衣剂、甜味剂、溶剂、碱、分散剂、润湿剂、悬浮剂、稳定剂、着色剂等。
取决于其形式,根据本发明的药物组合物包含0.01重量%至95重量%的本发明的化合物或其药学上可接受的盐。
本发明的药物组合物的具体剂量可随哺乳动物的属性而变化,所述哺乳动物的属性包括人类、体重、性别、疾病严重程度、医生的诊断等。对于口服使用,优选地每天对于每千克体重施用0.01mg至50mg的活性成分,而对于肠胃外使用,每天对于每千克体重施用0.01mg至10mg的活性成分。根据疾病的严重程度、医生的诊断等,可以通过一次或多次来施用每天的总剂量。
【有益效果】
本发明的化合物可用于治疗或预防癌症的药物组合物中,因为其具有抑制PD-L1表达的作用。
附图说明
图1是示出向患有B16F10细胞诱导的癌症的小鼠施用示例化合物后肿瘤体积随时间的变化的图表。
图2是示出向患有B16F10细胞诱导的癌症的小鼠施用示例化合物后从小鼠中切除的肿瘤的重量的图表。
图3是对患有B16F10细胞诱导的癌症的小鼠施用示例化合物后,在从小鼠切除的肿瘤中通过蛋白质免疫印迹法(Western blotting)测量PD-L1表达的抑制程度的结果。
图4是用示例化合物处理PD-L1过表达的细胞后,通过蛋白质免疫印迹法测量PD-L1表达抑制程度的结果。
具体实施方式
通过以下示例进一步说明本发明,所述示例不应被解释为限制本发明的范围。
制备例1:式(II)化合物的制备
制备例1-1:5-(氯甲基)-N-甲基-2-(甲硫基)嘧啶-4-胺(II-1)
将4-氯-2-(甲硫基)嘧啶-5-羧酸乙酯(10.00g,42.98mmol)溶解于100mL四氢呋喃中,向其中加入三乙胺(7.37mL,52.86mmol)和40%甲胺溶液(3.54g,45.55mmol),并将混合物在20-25℃搅拌16小时。反应完成后,将沉淀的盐过滤,在减压下除去溶剂,用饱和碳酸氢钠溶液和乙酸乙酯萃取浓缩的剩余物。用盐水洗涤有机层,经无水硫酸钠干燥,减压浓缩,得到4-(甲基氨基)-2-(甲硫基)嘧啶-5-羧酸乙酯(VIII-1,8.82g,90%)。
1H NMR(400MHz,CDCl3):δ1.37(t,3H),2.55(s,3H),3.09(d,3H),4.33(q,2H),8.18(bs,1H),8.61(s,1H)
将以上得到的4-(甲基氨基)-2-(甲硫基)嘧啶-5-羧酸乙酯(VIII-1)(8.80g,38.72mmol)溶解于200mL无水四氢呋喃中,并冷却至0℃。缓慢滴加1M氢化铝锂(116.16mL,116.16mmol),并在20-25℃搅拌2小时。当反应完成时,依次向反应混合物中缓慢滴加5mL水、15mL 15%氢氧化钠溶液和15mL水,然后终止反应并搅拌1小时。过滤所得白色沉淀后,将滤液用乙酸乙酯萃取两次,合并有机层并用盐水萃取。将有机层经无水硫酸镁干燥并在减压下浓缩,得到(4-(甲基氨基)-2-(甲硫基)嘧啶-5-基)甲醇(IX-1,6.00g,84%)。
1H NMR(400MHz,CDCl3):δ2.53(s,3H),3.05(d,3H),4.40(s,2H),5.22(m,1H),6.95(br,1H),7.96(s,1H)
将以上得到的(4-(甲基氨基)-2-(甲硫基)嘧啶-5-基)甲醇(IX-1)(5.72g,30.88mmol)溶解于240mL无水四氢呋喃中,并冷却至0℃。然后,缓慢滴加亚硫酰氯(5.59mL,77.19mmol),并在70℃搅拌4小时。将所得白色固体过滤,得到7.20g(100%)标题化合物。
制备例1-2:4-(甲基氨基)-2-(甲硫基)嘧啶-5-甲醛(II-2)
向(4-(甲基氨基)-2-(甲硫基)嘧啶-5-基)甲醇(IX-1)(0.74g,4.00mmol)中加入15mL二氯甲烷后,加入二氧化锰(3.47g,39.95mmol),并在20-25℃搅拌20小时。反应完成后,将反应混合物通过硅藻土过滤,减压除去溶剂,得到0.67g(92%)标题化合物。
1H NMR(400MHz,CDCl3):δ9.70(s,1H),8.56(bs,1H),8.30(s,1H),3.12(d,3H),2.57(s,3H)
ES-MS m/z:184.18[M+H]+
制备例2:式(III)化合物的制备
制备例2-1:N-(5-氨基-6-甲基吡啶-3-基)-3-(三氟甲基)苯甲酰胺(III-1)
将6-甲基-5-硝基吡啶-3-胺(X-1)(1.00g,6.53mmol)溶解于50mL二氯甲烷中后,将混合物冷却至0℃。向反应溶液中加入3-(三氟甲基)苯甲酰氯(XI-1)(0.97mL,6.52mmol)和N,N-二异丙基乙胺(3.33mL,19.59mmol),并在20-25℃搅拌1小时。反应完成后,依次使用二氯甲烷、蒸馏水和盐水进行萃取。将有机层经无水硫酸钠干燥并在减压下浓缩,并将浓缩剩余物通过柱色谱法进行纯化,得到N-(6-甲基-5-硝基吡啶-3-基)-3-(三氟甲基)苯甲酰胺(XII-1)(1.76g,83%)。
将以上得到的N-(6-甲基-5-硝基吡啶-3-基)-3-(三氟甲基)苯甲酰胺(XII-1)(1.16g,3.57mmol)溶解于50ml甲醇中,加入0.32g 10%钯碳,并在氢气气氛下搅拌3小时。反应完成后,将反应混合物通过硅藻土过滤,用甲醇洗涤,然后在减压下浓缩,得到1.04g(99%)标题化合物。
1H NMR(400MHz,CDCl3):δ2.55(m,3H),4.07(br,2H),6.71(d,1H),7.01(s,1H),7.29(d,1H),7.45(d,1H),7.65(t,1H),7.85(s,1H),8.02(d,1H)
制备例2-2:N-(5-氨基-6-甲基吡啶-3-基)-3-(叔丁基)苯甲酰胺(III-2)
将3-(叔丁基)苯甲酸(0.6g,3.37mmol)悬浮在20mL二氯甲烷中后,加入草酰氯(0.58mL,6.73mmol)和1-2滴催化量的二甲基甲酰胺,并在室温搅拌3小时。反应完成后,在减压下蒸发反应溶剂,得到3-(叔丁基)苯甲酰氯(XI-2)(0.67g,定量(Quant)),无需纯化。
将6-甲基-5-硝基吡啶-3-胺(X-1)(0.90g,5.88mmol)溶解于50mL二氯甲烷中后,加入以上得到的3-(叔丁基)苯甲酰氯(XI-2)(1.15g,5.88mmol)和N,N-二异丙基乙胺(3.07mL,17.63mmol),并在20-25℃搅拌1小时。反应完成后,依次使用二氯甲烷、蒸馏水和盐水进行萃取。将有机层经无水硫酸钠干燥并在减压下浓缩,并将浓缩剩余物通过柱色谱法进行纯化,得到3-(叔丁基)-N-(6-甲基-5-硝基吡啶-3-基)苯甲酰胺(XII-2)(1.39g,76%)。
ES-MS m/z:314.25[M+H]+
将以上得到的3-(叔丁基)-N-(6-甲基-5-硝基吡啶-3-基)苯甲酰胺(XII-2)(1.39g,4.44mmol)溶解于40ml甲醇中,加入0.32g 10%钯碳,并在氢气气氛下搅拌3小时。反应完成后,将反应混合物通过硅藻土过滤,用甲醇洗涤,然后在减压下浓缩,得到标题化合物(III-2)(1.18g,94%)。
1H NMR(400MHz,CDCl3):δ1.34(s,9H),2.55(m,3H),4.10(br,2H),6.71(s,1H),7.21(d,1H),7.32(d,1H),7.45(d,1H),7.65(t,1H),7.85(s,1H),8.02(d,1H)
ES-MS m/z:239.31[M+H]+
制备例2-3:N-(5-氨基-6-甲氧基吡啶-3-基)-3-(三氟甲基)苯甲酰胺(III-3)
将2-甲氧基-3,5-二硝基吡啶(0.55g,2.76mmol)溶解于20mL乙醇后,加入6N盐酸(4.00mL)和铁(1.30g)并回流1小时。反应完成后,将反应混合物冷却至20-25℃,用5M氢氧化钠溶液中和,并通过硅藻土过滤。将过滤后的溶液在减压下浓缩,溶解于乙酸乙酯中,用水萃取一次,并用盐水洗涤。将有机层经无水硫酸钠干燥,并在减压下浓缩,得到2-甲氧基吡啶-3,5-二胺(X’-1)(0.21g,55%)。
1H NMR(400MHz,CDCl3):δ3.23(s,3H),3.90(br,4H),6.46(s,1H),6.69(s,1H)
ES-MS m/z:140.11[M+H]+
将以上得到的2-甲氧基吡啶-3,5-二胺(X’-1)(0.21g,1.51mmol)溶解于30mL丙酮中并冷却至0℃,并加入三乙胺(0.23g,2.27mmol)和3-(三氟甲基)苯甲酰氯(XI-1)(0.25g,1.21mmol)并搅拌20分钟。反应完成后,蒸发溶剂,并并依次使用乙酸乙酯、蒸馏水和盐水进行萃取。将有机层经无水硫酸钠干燥,在减压下浓缩,并通过柱色谱法进行纯化,得到0.17g(45%)标题化合物。
1H NMR(400MHz,CDCl3):δ3.23(s,3H),3.90(br,2H),6.59(s,1H),6.78(dd,1H),7.38(d,1H),7.65(t,1H),7.68(s,1H),7.82(d,1H),8.10(s,1H)
ES-MS m/z:312.10[M+H]+
将6-甲基-5-硝基吡啶-3-胺(X-1)(1.00g,6.52mmol)溶解于50mL二氯甲烷中并冷却至0℃,并加入N,N-二异丙基乙胺(3.41mL,19.59mmol)和4-(4,4-二甲基-4,5-二氢唑-2-基)苯甲酰氯(XI-3)(1.55g,6.52mmol)并搅拌2小时。反应完成后,使用二氯甲烷、蒸馏水和盐水依次进行萃取。将有机层经无水硫酸钠干燥并在减压下浓缩,并将浓缩剩余物通过柱色谱法进行纯化,得到4-(4,4-二甲基-4,5-二氢唑-2-基)-N-(6-甲基-5-硝基吡啶-3-基)苯甲酰胺(XII-6)(1.99g,86%)。
ES-MS m/z:355.25[M+H]+
将以上得到的4-(4,4-二甲基-4,5-二氢唑-2-基)-N-(6-甲基-5-硝基吡啶-3-基)苯甲酰胺(XII-6)(1.95g,5.50mmol)溶解于50mL甲醇中,加入0.30g 10%钯碳,并在氢气气氛下搅拌5小时。然后,以与制备例2-1相同的方式得到1.64g(92%)标题化合物。
ES-MS m/z:325.25[M+H]+
将6-甲基-5-硝基吡啶-3-胺(X-1)(1.00g,6.52mmol)溶解于60mL四氢呋喃中并冷却至0℃,并加入N,N-二异丙基乙胺(3.41mL,19.59mmol)和3-(4,4-二甲基-4,5-二氢唑-2-基)苯甲酰氯(XI-4)(1.55g,6.52mmol)并搅拌2小时。反应完成后,依次使用二氯甲烷、蒸馏水和盐水进行萃取。将有机层经无水硫酸钠干燥并在减压下浓缩,并将浓缩剩余物通过柱色谱法进行纯化,得到3-(4,4-二甲基-4,5-二氢唑-2-基)-N-(6-甲基-5-硝基吡啶-3-基)苯甲酰胺(XII-7)(1.39g,60%)。
将以上得到的3-(4,4-二甲基-4,5-二氢唑-2-基)-N-(6-甲基-5-硝基吡啶-3-基)苯甲酰胺(XII-7)(1.39g,3.92mmol)溶解于30mL甲醇中,加入0.30g 10%钯碳,并在氢气气氛下搅拌3小时。然后,以与制备例2-1相同的方式得到1.17g(92%)标题化合物。
ES-MS m/z:325.16[M+H]+
制备例2-6:N-(5-氨基-6-甲氧基吡啶-3-基)-3-(叔丁基)苯甲酰胺(III-6)
将2-甲氧基吡啶-3,5-二胺(X’-1)(0.44g,3.18mmol)溶解于40mL丙酮中并冷却至0℃后,加入三乙胺(0.48g,4.77mmol)和3-(叔丁基)苯甲酰氯(XI-2)(0.50g,2.54mmol)并搅拌2小时。反应完成后,蒸发溶剂,并依次使用乙酸乙酯、蒸馏水和盐水进行萃取。将有机层经无水硫酸钠干燥,并在减压下浓缩,得到0.34g(45%)标题化合物。
ES-MS m/z:300.28[M+H]+
将2-甲氧基吡啶-3,5-二胺(X’-1)(0.40g,2.87mmol)溶解于40ml丙酮中并冷却至0℃后,加入三乙胺(0.44g,4.31mmol)和3-(4,4-二甲基-4,5-二氢唑-2-基)苯甲酰氯(XI-4)(0.55g,2.30mmol)并搅拌2小时。反应完成后,蒸发溶剂,并依次使用乙酸乙酯、蒸馏水和盐水进行萃取。将有机层经无水硫酸钠干燥,并在减压下浓缩,得到0.34g(43%)标题化合物。
ES-MS m/z:341.36[M+H]+
制备例2-8:N-(5-氨基-6-氯吡啶-3-基)-3-(三氟甲基)苯甲酰胺三氟乙酸酯(III-8)
将(5-氨基-2-氯吡啶-3-基)氨基甲酸叔丁酯(1.20g,4.92mmol)溶解于60mL二氯甲烷中并冷却至0℃后,加入N,N-二异丙基乙胺(2.51mL,14.77mmol)和3-(三氟甲基)苯甲酰氯(XI-1)(1.13g,5.42mmol)并在20-25℃搅拌4小时。反应完成后,依次使用二氯甲烷、蒸馏水和饱和氯化钠溶液进行萃取。将有机层经无水硫酸钠干燥并在减压下浓缩,并将剩余物通过柱色谱法进行纯化,得到1.59g(2-氯-5-(3-(三氟甲基)苯甲酰胺基)吡啶-3-基氨基甲酸叔丁酯(78%)。
1H NMR(400MHz,CDCl3):δ1.53(s,9H),7.06(br,1H),7.64(m,1H),7.84(m,1H),8.10(m,3H),8.58(d,1H),8.78(d,1H)。
将1.50g(3.61mmol)上述得到的(2-氯-5-(3-(三氟甲基)苯甲酰胺基)吡啶-3-基氨基甲酸叔丁酯溶解于二氯甲烷:三氟乙酸(1:1)中,并在20-25℃搅拌5小时。反应完成后,在减压下蒸发反应溶剂,得到1.10g(71%)标题化合物三氟乙酸酯。
1H NMR(400MHz,DMSO-d6):δ5.69(br,2H),5.76(br,1H),7.73(d,1H),7.79(t,1H),7.97(m,2H),8.26(m,2H),10.53(S,1H)。
制备例2-9:N-(5-氨基-6-氯吡啶-3-基)-3-(叔丁基)苯甲酰胺三氟乙酸酯(III-9)
将(5-氨基-2-氯吡啶-3-基)氨基甲酸叔丁酯(0.84g,3.45mmol)溶解于50mL二氯甲烷中并冷却至0℃后,加入N,N-二异丙基乙胺(1.76mL,10.34mmol)和3-(叔丁基)苯甲酰氯(XI-2)(0.68g,3.45mmol)并在20-25℃搅拌5小时。然后,以与制备例2-8相同的方式得到(5-(3-(叔丁基)苯甲酰胺基)-2-氯吡啶-3-基)氨基甲酸叔丁酯(0.90g,65%)。
将以上得到的(5-(3-(叔丁基)苯甲酰胺基)-2-氯吡啶-3-基)氨基甲酸叔丁酯(0.88g,2.18mmol)溶解于二氯甲烷:三氟乙酸(1:1)中后,以与制备例2-8相同的方式定量得到0.88g标题化合物三氟乙酸酯。
1H NMR(400MHz,DMSO-d6):δ1.38(s,9H),5.69(br,2H),5.76(br,1H),7.73(d,1H),7.79(t,1H),7.97(m,2H),8.26(m,2H),10.53(S,1H)。
制备例2-10:N-(5-氨基-6-氯吡啶-3-基)-2-(叔丁基)噻唑-4-甲酰胺三氟乙酸酯(III-10)
将(5-氨基-2-氯吡啶-3-基)氨基甲酸叔丁酯(0.84g,3.45mmol)溶解于50mL二氯甲烷中并冷却至0℃后,加入N,N-二异丙基乙胺(1.76mL,10.34mmol)和2-(叔丁基)噻唑-4-碳酰氯(XI-5)(0.70g,3.45mmol)并在20-25℃搅拌5小时。以与制备例2-8相同的方式,得到(5-(2-(叔丁基)噻唑-4-甲酰胺基)-2-氯吡啶-3-基)氨基甲酸叔丁酯(0.94g,67%)。
将以上得到的(5-(2-(叔丁基)噻唑-4-甲酰胺基)-2-氯吡啶-3-基)氨基甲酸叔丁酯(0.92g,2.24mmol)溶解于二氯甲烷:三氟乙酸(1:1)后,以与制备例2-8相同的方式定量得到0.92g标题化合物三氟乙酸酯。
制备例3:式(IV)化合物的制备
制备例3-1:N-(6-甲基-5-(((4-(甲基氨基)-2-(甲硫基)嘧啶-5-基)甲基)氨基)吡啶-3-基)-3-(三氟甲基)苯甲酰胺(IV-1)
将制备例2-1中制备的化合物(III-1)(0.60g 2.03mmol)溶解于50mL乙腈中后,在0℃加入N,N-二异丙基乙胺(1.06mL,6.10mmol)。将制备例1-1中制备的化合物(II-1)(0.40g,1.63mmol)溶解于30mL乙腈中,并缓慢滴加到反应溶液中,然后在20-25℃搅拌1小时。在减压下蒸发反应溶剂,并依次使用乙酸乙酯、水和盐水进行萃取。将有机层经无水硫酸钠干燥并在减压下浓缩。将浓缩剩余物通过柱色谱法进行纯化,得到0.70g(70%)标题化合物。
1H NMR(400MHz,CDCl3):δ2.55(s,3H),3.05(d,3H),4.16(s,2H),5.57(m,1H),6.88(dd,1H),7.29(d,1H),7.43(d,1H),7.65(t,1H),7.82-7.85(m,2H),7.93(s,1H),8.06(d,1H),8.12(s,1H)
ES-MS m/z:463.03[M+H]+
制备例3-2:3-(叔丁基)-N-(6-甲基-5-(((4-(甲基氨基)-2-(甲硫基)嘧啶-5-基)甲基)氨基)吡啶-3-基)苯甲酰胺(IV-2)
使用制备例2-2中制备的化合物(III-2)(0.90g,3.18mmol)代替制备例1-1中制备的化合物(III-1)和化合物(II-1)(0.76g,3.16mmol),以与制备例3-1相同的方式得到0.80g(56%)标题化合物。
1H NMR(400MHz,CDCl3):δ1.34(s,9H),2.47(s,6H),2.55(s,3H),4.16(s,2H),4.32(m,2H),6.76(dd,1H),7.36(m,1H),7.54(m,1H),7.75(m,2H),7.98(m,1H),8.25(m,1H)
ES-MS m/z:451.14[M+H]+
制备例3-3:3-(叔丁基)-N-(6-甲基-5-(((4-(甲基氨基)-2-(甲硫基)嘧啶-5-基)甲基)氨基)吡啶-3-基)苯甲酰胺(IV-2)
代替化合物(III-1),将制备例2-2中制备的化合物(III-2)(2.08g,7.33mmol)溶解于50mL甲醇中,加入乙酸(0.88mL,15.28mmol)和制备例1-2中制得的化合物(II-2)(1.12g,6.11mmol)并搅拌15分钟。向反应溶液中加入氰基硼氢化钠(2.30g,36.68mmol)后,将温度升至45℃并搅拌18小时。反应完成后,将混合物冷却至20-25℃,在减压下蒸发反应溶剂,并使用乙酸乙酯和饱和碳酸氢钠溶液进行萃取。将有机层经无水硫酸钠干燥并在减压下浓缩。将浓缩剩余物通过柱色谱法进行纯化,得到1.10g(40%)标题化合物。
ES-MS m/z:451.14[M+H]+
制备例3-4:N-(4-甲氧基-3-(((4-(甲基氨基)-2-(甲硫基)嘧啶-5-基)甲基)氨基)吡啶-3-基)-3-(三氟甲基)苯甲酰胺(IV-3)
使用制备例2-3中制备的化合物(III-3)(0.17g,0.69mmol)代替化合物(III-1),以与制备例3-1相同的方式得到0.10g(30%)标题化合物。
1H NMR(400MHz,CDCl3):δ2.55(s,3H),2.87(d,3H),4.01(s,3H),4.25(s,2H),5.60(dd,2H),6.88(dd,1H),7.12(d,1H),7.42-7.89(m,4H),7.93(s,1H),8.12(s,1H)
ES-MS m/z:527.97[M+H]+
使用制备例2-4中制备的化合物(III-4)(1.00g,3.08mmol)代替化合物(III-1),以与制备例3-1相同的方式得到0.45g(30%)标题化合物。
ES-MS m/z:492.54[M+H]+
使用制备例2-5中制备的化合物(III-5)(1.00g,3.08mmol)代替化合物(III-1),以与制备例3-1相同的方式得到0.40g(30%)标题化合物。
ES-MS m/z:492.54[M+H]+
制备例3-7:3-(叔丁基)-N-(6-甲氧基-5-(((4-(甲基氨基)-2-(甲硫基)嘧啶-5-基)甲基)氨基)吡啶-3-基)苯甲酰胺(IV-6)
使用制备例2-6中制备的化合物(III-6)(0.34g,1.14mmol)代替化合物(III-1),以与制备例3-1相同的方式得到0.18g(51%)标题化合物。
ES-MS m/z:467.61[M+H]+
使用制备例2-7中制备的化合物(III-7)(0.34g,1.00mmol)代替化合物(III-1),以与制备例3-1相同的方式得到0.15g(45%)标题化合物。
ES-MS m/z:508.55[M+H]+
制备例3-9:N-(6-氯-5-(((4-(甲基氨基)-2-(甲硫基)嘧啶-5-基)甲基)氨基)吡啶-3-基)-3-(三氟甲基)苯甲酰胺(IV-8)
使用制备例2-8中制备的化合物(III-8)(1.15g 1.99mmol)代替化合物(III-1),以与制备例3-1相同的方式得到0.26g(41%)标题化合物。
制备例3-10:3-(叔丁基)-N-(6-氯-5-(((4-(甲基氨基)-2-(甲硫基)嘧啶-5-基)甲基)氨基)吡啶-3-基)苯甲酰胺(IV-9)
使用制备例2-9中制备的化合物(III-9)(1.17g 2.91mmol)代替化合物(III-1),以与制备例3-1相同的方式得到0.28g(41%)标题化合物。
制备例3-11:2-(叔丁基)-N-(6-氯-5-(((4-(甲基氨基)-2-(甲硫基)嘧啶-5-基)甲基)氨基)吡啶-3-基)噻唑-4-甲酰胺(IV-10)
使用制备例2-10中制备的化合物(III-10)(0.67g 3.33mmol)代替化合物(III-1),以与制备例3-1相同的方式得到0.32g(41%)标题化合物。
1H NMR(400MHz,CDCl3):δ9.24(s,1H),8.07(m,1H),7.95(s,1H),7.87(d,1H),5.45(br,1H),4.15-4.19(m,2H),3.07(d,2H),2.55(s,3H),1.47(s,9H)。
制备例4:式(V)化合物的制备
制备例4-1:N-(6-甲基-5-(1-甲基-7-(甲硫基)-2-氧代-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)-3-(三氟甲基)苯甲酰胺(V-1)
将制备例3-1中制备的化合物(IV-1)(0.70g,1.51mmol)溶解于60mL 1,4-二烷中后,在0℃加入N,N-二异丙基乙胺(0.78mL,4.54mmol)和三光气(0.63g,2.12mmol),并在100℃搅拌3小时。反应完成后,用饱和碳酸氢钠溶液和乙酸乙酯进行萃取,并用盐水洗涤有机层。将有机层经无水硫酸钠干燥并在减压下浓缩,并将浓缩剩余物通过柱色谱法进行纯化,得到0.37g(50%)标题化合物。
1H NMR(400MHz,CDCl3):δ2.55(s,3H),2.63(s,3H),3.65(d,3H),5.16(s,2H),6.88(dd,1H),7.29(d,1H),7.43(d,1H),7.65(t,1H),7.82-7.85(m,2H),7.93(s,1H),8.12(s,1H)
ES-MS m/z:489.50[M+H]+
制备例4-2:3-(叔丁基)-N-(6-甲基-5-(1-甲基-7-(甲硫基)-2-氧代-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)苯甲酰胺(V-2)
使用制备例3-2中制备的化合物(IV-2)(0.80g,1.78mmol)代替化合物(IV-1),以与制备例4-1相同的方式得到0.50g(60%)标题化合物。
1H NMR(400MHz,CDCl3):δ1.34(s,9H),2.47(d,3H),2.55(d,3H),2.70(d,3H),4.42(d,2H),6.76(m,1H),7.36(m,1H),7.54(m,1H),7.75(m,2H),7.98(m,1H),8.25(m,1H)
ES-MS m/z:477.60[M+H]+
制备例4-3:N-(6-甲氧基-5-(1-甲基-7-(甲硫基)-2-氧代-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)-3-(三氟甲基)苯甲酰胺(V-3)
使用制备例3-4中制备的化合物(IV-3)(0.10g,0.21mmol)代替化合物(IV-1),以与制备例4-1相同的方式得到0.10g(95%)标题化合物。
1H NMR(400MHz,CDCl3):δ2.55(s,3H),3.34(d,3H),4.25(s,3H),5.06(s,2H),6.88(dd,1H),7.31-7.42(m,2H),7.65-7.95(m,4H),8.06(d,1H),8.12(s,1H)
ES-MS m/z:505.09[M+H]+
制备例4-4:4-(4,4-二甲基-4,5-二氢唑-2-基)-N-(6-甲基-5-(1-甲基-7-(甲硫基))-2-氧代-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)苯甲酰胺(V-4)
使用制备例3-5中制备的化合物(IV-4)(0.40g,0.81mmol)代替化合物(IV-1),以与制备例4-1相同的方式得到0.32g(76%)标题化合物。
ES-MS m/z:518.09[M+H]+
制备例4-5:3-(4,4-二甲基-4,5-二氢唑-2-基)-N-(6-甲基-5-(1-甲基-7-(甲硫基)-2-氧代-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)苯甲酰胺(V-5)
使用制备例3-6中制备的化合物(IV-5)(0.40g,0.81mmol)代替化合物(IV-1),以与制备例4-1相同的方式得到0.35g(83%)标题化合物。
ES-MS m/z:518.09[M+H]+
制备例4-6:3-(叔丁基)-N-(6-甲氧基-5-(1-甲基-7-(甲硫基)-2-氧代-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)苯甲酰胺(V-6)
使用制备例3-7中制备的化合物(IV-6)(0.18g,0.39mmol)代替化合物(IV-1),以与制备例4-1相同的方式得到0.17g(90%)标题化合物。
ES-MS m/z:493.62[M+H]+
制备例4-7:3-(4,4-二甲基-4,5-二氢唑-2-基)-N-(6-甲氧基-5-(1-甲基-7-(甲硫基)-2-氧代-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)苯甲酰胺(V-7)
使用制备例3-8中制备的化合物(IV-7)(0.15g,0.30mmol)代替化合物(IV-1),以与制备例4-1相同的方式得到0.15g(93%)标题化合物。
ES-MS m/z:534.65[M+H]+
制备例4-8:N-(6-氯-5-(1-甲基-7-(甲硫基)-2-氧代-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)-3-(三氟甲基)苯甲酰胺(V-8)
使用制备例3-9中制备的化合物(IV-8)(0.27g,0.56mmol)代替化合物(IV-1),以与制备例4-1相同的方式得到0.27g(96%)标题化合物。
制备例4-9:3-(叔丁基)-N-(6-氯-5-(1-甲基-7-(甲硫基)-2-氧代-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)苯甲酰胺(V-9)
使用制备例3-10中制备的化合物(IV-9)(0.28g,0.59mmol)代替化合物(IV-1),以与制备例4-1相同的方式得到0.23g(78%)标题化合物。
制备例4-10:2-(叔丁基)-N-(6-氯-5-(1-甲基-7-(甲硫基)-2-氧代-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)噻唑-4-甲酰胺(V-10)
使用制备例3-11中制备的化合物(IV-10)(0.31g,0.65mmol)代替化合物(IV-1),以与制备例4-1相同的方式得到0.25g(77%)标题化合物。
制备例5:式(VI)化合物的制备
制备例5-1:N-(6-甲基-5-(1-甲基-7-(甲基磺酰基)-2-氧代-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)-3-(三氟甲基)苯甲酰胺(VI-1)
将制备例4-1中制备的化合物(V-1)(0.37g,0.76mmol)溶解于四氢呋喃:蒸馏水(2:1,30mL)中,加入单过硫酸氢钾(4.66g,7.57mmol),作为氧化剂,并将混合物在65℃搅拌5小时。反应完成后,在减压下蒸发反应溶剂,依次用乙酸乙酯、水和盐水洗涤,将有机层经无水硫酸钠干燥并在减压下浓缩。将浓缩剩余物通过柱色谱法进行纯化,得到0.17g(44%)标题化合物。
1H NMR(400MHz,CDCl3):δ2.70(s,3H),3.38(s,3H),3.40(s,3H),4.42(d,2H),6.76(m,1H),7.36(m,1H),7.48-7.99(m,4H),8.25(m,1H),9.12(s,1H)
ES-MS m/z:521.60[M+H]+
制备例5-2:3-(叔丁基)-N-(6-甲基-5-(1-甲基-7-(甲基磺酰基)-2-氧代-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)苯甲酰胺(VI-2)
使用制备例4-2中制备的化合物(V-2)(0.51g,1.07mmol)代替化合物(V-1),以与制备例5-1相同的方式得到0.22g(42%)标题化合物。
1H NMR(400MHz,CDCl3):δ1.34(s,9H),2.70(s,3H),3.38(s,3H),3.40(s,3H),4.42(d,2H),6.76(m,1H),7.36(m,1H),7.54(m,1H),7.75(m,2H),7.98(m,1H),8.25(m,1H),9.15(s,1H)
ES-MS m/z:509.72[M+H]+
制备例5-3:N-(6-甲氧基-5-(1-甲基-7-(甲基磺酰基)-2-氧代-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)-3-(三氟甲基)苯甲酰胺(VI-3)
使用制备例4-3中制备的化合物(V-3)(0.09g,0.17mmol)代替化合物(V-1),以与制备例5-1相同的方式得到90mg(97%)标题化合物。
1H NMR(400MHz,CDCl3):δ3.10(s,3H),3.45(s,3H),4.63(s,3H),5.51(s,2H),6.56(dd,1H),7.13-7.81(m,3H),8.16-8.17(m,2H),8.28(d,1H),9.10(s,1H)
ES-MS m/z:537.01[M+H]+
制备例5-4:4-(4,4-二甲基-4,5-二氢唑-2-基)-N-(6-甲基-5-(1-甲基-7-(甲基磺酰基))-2-氧代-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)苯甲酰胺(VI-4)
使用制备例4-4中制备的化合物(V-4)(0.30g,0.58mmol)代替化合物(V-1),以与制备例5-1相同的方式得到0.24g(76%)标题化合物。
ES-MS m/z:550.25[M+H]+
制备例5-5:3-(4,4-二甲基-4,5-二氢唑-2-基)-N-(6-甲基-5-(1-甲基-7-(甲基磺酰基)-2-氧代-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)苯甲酰胺(VI-5)
使用制备例4-5中制备的化合物(V-5)(0.35g,0.58mmol)代替化合物(V-1),以与制备例5-1相同的方式得到0.24g(76%)标题化合物。
ES-MS m/z:550.21[M+H]+
制备例5-6:3-(叔丁基)-N-(6-甲氧基-5-(1-甲基-7-(甲基磺酰基)-2-氧代-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)苯甲酰胺(VI-6)
使用制备例4-6中制备的化合物(V-6)(0.17g,0.35mmol)代替化合物(V-1),以与制备例5-1相同的方式得到0.17g(91%)标题化合物。
1H NMR(400MHz,CDCl3):δ1.36(s,9H),3.37(s,3H),3.90(s,3H),4.82(s,2H),7.41(t,1H),7.60(d,1H),7.66(d,1H),7.94(s,1H),8.21(dd,1H),8.24(s,1H),8.38(t,1H)
ES-MS m/z:525.61[M+H]+
制备例5-7:3-(4,4-二甲基-4,5-二氢唑-2-基)-N-(6-甲氧基-5-(1-甲基-7-(甲基磺酰基)-2-氧代-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)苯甲酰胺(VI-7)
使用制备例4-7中制备的化合物(V-7)(0.15g,0.28mmol)代替化合物(V-1),以与制备例5-1相同的方式得到0.14g(89%)标题化合物。
ES-MS m/z:566.50[M+H]+
制备例5-8:N-(6-氯-5-(1-甲基-7-(甲基磺酰基)-2-氧代-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)-3-(三氟甲基)苯甲酰胺(VI-8)
使用制备例4-8中制备的化合物(V-8)(0.26g,0.51mmol)代替化合物(V-1),以与制备例5-1相同的方式得到0.21g(77%)标题化合物。
制备例5-9:3-(叔丁基)-N-(6-氯-5-(1-甲基-7-(甲基磺酰基)-2-氧代-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)苯甲酰胺(VI-9)
使用制备例4-9中制备的化合物(V-9)(0.23g,0.46mmol)代替化合物(V-1),以与制备例5-1相同的方式得到0.21g(86%)标题化合物。
制备例5-10:2-(叔丁基)-N-(6-氯-5-(1-甲基-7-(甲基磺酰基)-2-氧代-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)噻唑-4-甲酰胺(VI-10)
使用制备例4-10中制备的化合物(V-10)(0.26g,0.52mmol)代替化合物(V-1),以与制备例5-1相同的方式得到0.19g(67%)标题化合物。
实施例:式(I)化合物的制备
实施例1:N-(6-甲基-5-(1-甲基-2-氧代-7-(苯基氨基)-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)-3-(三氟甲基)苯甲酰胺(I-1)
将制备例5-1中制备的化合物(VI-1)(0.17g,0.33mmol)溶解于10ml的1,4-二烷中,加入4ml苯胺,并在100℃搅拌3小时。反应完成后,依次用乙酸乙酯、水和盐水进行萃取,将有机层经无水硫酸钠干燥并在减压下浓缩。将浓缩剩余物通过柱色谱法进行纯化,得到87mg(50%)标题化合物。
1H NMR(400MHz,DMSO-d6):δ2.55(s,3H),3.09(s,3H),4.42(d,2H),6.46-7.54(m,6H),7.75(m,2H),8.01(m,1H),8.17(m,1H),9.60(s,1H),10.36(s,1H)
ES-MS m/z:534.62[M+H]+
实施例2:3-(叔丁基)-N-(6-甲基-5-(1-甲基-2-氧代-7-(苯基氨基)-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)苯甲酰胺(I-2)
使用制备例5-2中制备的化合物(VI-2)(0.21g,0.41mmol)代替化合物(VI-1),以与实施例1相同的方式得到86mg(40%)标题化合物。
1H NMR(400MHz,DMSO-d6):δ1.34(s,9H),2.55(s,3H),3.11(s,3H),4.42(d,2H),6.46-7.54(m,9H),7.75(m,1H),7.98(m,1H),8.25(m,1H),9.53(s,1H),10.35(s,1H)
ES-MS m/z:522.72[M+H]+
实施例3:N-(6-甲氧基-5-(1-甲基-2-氧代-7-(苯基氨基)-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)-3-(三氟甲基)苯甲酰胺(I-3)
使用制备例5-3中制备的化合物(VI-3)(90mg,0.17mmol)代替化合物(VI-1),以与实施例1相同的方式得到25mg(27%)标题化合物。
1H NMR(400MHz,DMSO-d6):3.35(s,3H),δ3.90(s,3H),4.63(s,2H),6.95(t,1H),7.29(t,1H),7.70(d,2H),7.79(t,2H),8.00(d,1H),8.16-8.17(m,2H),8.28(d,1H),8.33(s,1H),8.51(s,1H),9.60(s,1H),10.67(s,1H)
ES-MS m/z:550.07[M+H]+
实施例4:4-(4,4-二甲基-4,5-二氢唑-2-基)-N-(6-甲基-5-(1-甲基-2-氧代-7-(苯基氨基)-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)苯甲酰胺(I-4)
使用制备例5-4中制备的化合物(VI-4)(0.20g,0.36mmol)代替化合物(VI-1),以与实施例1相同的方式得到0.10g(55%)标题化合物。
1H NMR(400MHz,DMSO-d6):δ1.31(s,6H),2.89(d,3H),3.36(s,3H),4.16(s,2H),4.61(d,1H),4.73(d,1H),7.12-7.23(m,5H),7.83(t,1H),8.03(d,1H),8.29(d,1H),8.37(s,1H),8.56(d,1H),8.66(s,1H),8.77(s,1H),9.53(s,1H),10.98(s,1H)
ES-MS m/z:563.72[M+H]+
实施例5:3-(4,4-二甲基-4,5-二氢唑-2-基)-N-(6-甲基-5-(1-甲基-2-氧代-7-(苯基氨基)-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)苯甲酰胺(I-5)
使用制备例5-5中制备的化合物(VI-5)(0.23g,0.42mmol)代替化合物(VI-1),以与实施例1相同的方式得到0.14g(58%)标题化合物。
1H NMR(400MHz,DMSO-d6):δ1.41(s,6H),2.59(d,3H),3.36(s,3H),4.13(s,2H),4.61(d,1H),4.73(d,1H),7.12-7.23(m,5H),7.81(s,1H),8.03(d,1H),8.29(d,1H),8.37(s,1H),8.56(d,1H),8.66(s,1H),8.77(s,1H),9.53(s,1H),10.98(s,1H)
ES-MS m/z:563.62[M+H]+
实施例6:3-(叔丁基)-N-(6-甲氧基-5-(1-甲基-2-氧代-7-(苯基氨基)-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)苯甲酰胺(I-6)
使用制备例5-6中制备的化合物(VI-6)(0.17g,0.32mmol)代替化合物(VI-1),以与实施例1相同的方式得到83mg(47%)标题化合物。
1H NMR(400MHz,DMSO-d6):δ1.34(s,9H),3.37(s,3H),3.90(s,3H),4.63(d,2H),6.95(t,1H),7.29(t,1H),7.47(t,1H),7.64(d,1H),7.76-7.81(m,2H),7.96(t,1H),8.14(d,1H),8.16(s,1H),8.52(d,1H),9.59(s,1H),10.38(s,1H)
ES-MS m/z:538.64[M+H]+
实施例7:3-(4,4-二甲基-4,5-二氢唑-2-基)-N-(6-甲氧基-5-(1-甲基-2-氧代-7-(苯基氨基)-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)苯甲酰胺(I-7)
使用制备例5-7中制备的化合物(VI-7)(0.14g,0.25mmol)代替化合物(VI-1),以与实施例1相同的方式得到65mg(44%)标题化合物。
1H NMR(400MHz,DMSO-d6):δ1.34(s,9H),3.37(s,3H),3.90(s,3H),4.15(s,2H),4.63(d,1H),4.71(d,1H),6.95(t,1H),7.29(t,1H),7.47(t,1H),7.64(d,1H),7.78-7.85(m,2H),8.01-8.12(m,2H),8.35(t,1H),8.56(d,1H),8.66(s,1H),8.77(s,1H),9.57(s,1H),10.98(s,1H)
ES-MS m/z:579.65[M+H]+
实施例8:N-(6-氯-5-(1-甲基-2-氧代-7-(苯基氨基)-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)-3-(三氟甲基)苯甲酰胺(I-8)
使用制备例5-8中制备的化合物(VI-8)(0.20g,0.37mmol)代替化合物(VI-1),以与实施例1相同的方式得到92mg(46%)标题化合物。
1H NMR(400MHz,DMSO-d6):δ3.33(s,3H),4.59-4.74(m,2H),6.91(t,1H),7.25(t,2H),7.72-7.81(m,3H),7.99(d,1H),8.15(s,1H),8.26(m,2H),8.46(s,1H),8.73(s,1H),9.59(s,1H),10.92(s,1H)
ES-MS m/z:553.97[M+H]+
实施例9:3-(叔丁基)-N-(6-氯-5-(1-甲基-2-氧代-7-(苯基氨基)-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)苯甲酰胺(I-9)
使用制备例5-9中制备的化合物(VI-9)(0.21g,0.40mmol)代替化合物(VI-1),以与实施例1相同的方式得到98.3mg(46%)标题化合物。
1H NMR(400MHz,DMSO-d6):δ1.31(s,9H),3.33(s,3H),4.59-4.74(m,2H),6.91(t,1H),7.26(t,2H),7.46(t,1H),7.63(d,1H),7.72-7.79(m,3H),7.79(s,1H),8.15(s,1H),8.44(d,1H),8.75(d,1H),9.58(s,1H),10.65(s,1H)
ES-MS m/z:542.14[M+H]+
实施例10:2-(叔丁基)-N-(6-氯-5-(1-甲基-2-氧代-7-(苯基氨基)-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)噻唑-4-甲酰胺(I-10)
使用制备例5-10中制备的化合物(VI-10)(0.18g,0.33mmol)代替化合物(VI-1),以与实施例1相同的方式得到0.12g(64%)标题化合物。
1H NMR(400MHz,DMSO-d6):δ1.47(s,9H),3.37(s,3H),4.62-4.77(m,2H),6.95(t,1H),7.27-7.31(t,2H),7.78(d,2H),8.18(s,1H),8.39(s,1H),8.51(d,1H),8.90(d,1H),9.62(s,1H),10.43(s,1H)
ES-MS m/z:549.16[M+H]+
实施例11:N-(6-氯-5-(7-((4-羟基苯基)氨基)-1-甲基-2-氧代-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)-3-(三氟甲基)苯甲酰胺(I-11)
将制备例5-8中制备的化合物(VI-8)(1.00g,1.85mmol)代替化合物(VI-1)溶解于20ml的1,4-二烷中,并加入4-氨基苯酚(1.00g、9.24mmol)和三氟乙酸(0.71ml,9.24mmol),并在85℃搅拌7小时。反应完成后,除去反应溶剂,加入甲醇,将混合物回流2小时,得到0.63g(60%)标题化合物。
1H NMR(400MHz,DMSO-d6):δ3.33(s,3H),4.58-4.74(m,2H),6.68-6.72(m,2H),7.47-7.50(m,2H),7.81-7.85(m,1H),8.01-8.03(m,1H),8.11(s,1H),8.28-8.34(m,2H),8.47(d,1H),8.77(d,1H),9.05(s,1H),9.29(s,1H),10.95(s,1H)
ES-MS m/z:569.16[M+H]+
实验例1:PD-L1表达抑制活性的分析
将PD-L1启动子基因区以如下方式插入pGL4.14-[luc2/Hygro]载体(promega,Madison,WI)中,以制备用于测量基因转录活性的启动子报告构建体。
在PD-L1中制备包含KpnI和XhoI限制性酶位点的引物后,进行PCR(聚合酶链反应),并通过在琼脂糖凝胶上进行电泳来分离启动子区DNA。用相同的限制性酶处理含有萤火虫荧光素酶作为报告基因的pGL4.14-[luc2/Hygro]载体,并通过琼脂糖凝胶电泳和凝胶提取进行分离。使用注入DNA连接酶(Takara)使纯的分离的PD-L1启动子基因区和pGL4.14-[luc2/Hygro]载体在50℃反应1小时,然后进行大肠杆菌转化,以制备插入PCSK9启动子的启动子报告构建体(命名为pGL4.14-PD-L1)。
为了测量PD-L1基因启动子的转录活性,如下将A549细胞用PD-L1启动子报告构建体进行瞬时转染,然后测量细胞提取物的荧光素酶活性。
根据制造商的方案,使用0.1μg启动子报告构建体质粒和lipofectamine 2000试剂(Invitrogen)制备DNA-lipofectamine复合物。在DNA与Lipofectamine 2000之间形成复合物的过程中使用Opti-MEM培养基(Invitrogen)。通过在即将加入DNA之前立即检查细胞的数量而以2.5×105个细胞/孔(1ml)在12孔板中制备A549细胞。将DNA-lipofectamine复合物小心地与A549细胞混合,并在37℃在培养箱中反应6小时。此后,改变培养基以搜寻转染的细胞,并通过荧光素酶试验找到被PD-L1转染的A549细胞。这被命名为A549 pGL4.14-PD-L1细胞系,并进行了实验。使用IFNγ(50ng/ml)作为PD-L1诱导剂。
使用已知在Beas-2B细胞(人正常肺上皮细胞系)中诱导PD-L1的EGF和IFNγ建立PD-L1表达条件。在RNA水平上,当以25ng/ml、50ng/ml和100ng/ml的浓度处理EGF时,未观察到PD-L1激活,只有IFNγ增加PD-L1。此外,用50ng/ml IFNγ处理后2小时,PD-L1的mRNA水平增加,最后,用50ng/ml IFNγ处理后4小时,mRNA水平增加最明显。
同样,作为确认Beas-2B细胞中PD-L1蛋白水平的结果,当处理IFNγ时,8小时前没有显著变化,但8小时后PD-L1表达量增加。因此,在用50ng/ml IFNγ处理20小时后,裂解并使用该蛋白。
分别以0.1μM和1.0μM的浓度用实施例的嘧啶并嘧啶酮衍生物处理A549pGL4.14-PD-L1细胞系,并使用光度计评价PD-L1表达抑制。为了进行比较,对已知具有PD-L1表达抑制活性的GS9973(Entospletinib)进行了相同的实验。
PD-L1表达的抑制率通过以下等式1计算。
[等式1]
PD-L1表达抑制率(%)=100-[(A/B)×100]
其中,A是当用药物处理时的值,B是不用药物处理时的值。
结果如下表1中所示。
[表1]
从表1中可以看出,与GS9973(Entospletinib)相比,根据本发明的嘧啶并嘧啶酮化合物具有优异的PD-L1表达抑制活性,并且这种PD-L1表达抑制活性以浓度依赖性的方式呈现。
实验例2:PD-L1表达抑制剂的体内疗效评价
将黑素瘤B16F10细胞以1×106个细胞/100μl的浓度皮下注射到6周龄雄性C57BL/6小鼠的颈部,以制备疾病模型。制备疾病模型后,第二天是作为施用的第一天,如下面的表2中所示,每天口服施用一次,持续14天,并在试验的第15天提取肿瘤。测量肿瘤体积和肿瘤大小的变化。
结果如图1和图2中所示。
[表2]
从图1至图2中可以看出,与对照组相比,化合物I-2、I-3、I-8和I-9具有22%至59%的肿瘤生长抑制能力。
实验例3:蛋白质免疫印迹法分析
实验例3-1:
在使用实验例2的化合物I-8进行体内肿瘤抑制试验后,通过蛋白质免疫印迹法分析证实了在从小鼠提取的肿瘤细胞中的PD-L1表达抑制作用。为了进行比较,还通过蛋白质免疫印迹法分析证实了在从对照小鼠提取的肿瘤细胞中抑制PD-L1表达的疗效。
使用化学发光(ECL)试剂盒(elpis biotec,EBP-1073)用ChemiDocTM成像系统(Bio-rad)鉴定蛋白质。结果如图3中所示。
从图3中可以看出,与对照组相比,当施用化合物I-8时,降低了PD-L1的表达。
实验例3-2:
在用实施例化合物处理PD-L1过表达的细胞后,通过蛋白质免疫印迹法分析证实PD-L1表达抑制作用。
为了考察PD-L1蛋白水平的变化,以6×105个细胞/ml接种NCI-H358(NSCLC)细胞系。24小时后,用IFN-γ(20ng/ml)处理NCI-H358(NSCLC)细胞系以过度表达PD-L1,24小时后分别以1μM和10μM另外处理该化合物。24小时后,使用化学发光(ECL)试剂盒(elpisbiotec,EBP-1073)用ChemiDoc TM的成像系统(Bio-rad)鉴定蛋白质。蛋白质免疫印迹法分析结果在图4中示出。
从图4中可以证实,与未用药物处理的对照组相比,实施例化合物以浓度依赖的方式表现出对PD-L1表达的抑制作用。
Claims (7)
4.根据权利要求1所述的嘧啶并嘧啶酮化合物或其药学上可接受的盐,选自由以下化合物组成的组:
N-(6-甲基-5-(1-甲基-2-氧代-7-(苯基氨基)-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)-3-(三氟甲基)苯甲酰胺(I-1);
3-(叔丁基)-N-(6-甲基-5-(1-甲基-2-氧代-7-(苯基氨基)-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)苯甲酰胺(I-2);
N-(6-甲氧基-5-(1-甲基-2-氧代-7-(苯基氨基)-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)-3-(三氟甲基)苯甲酰胺(I-3);
3-(叔丁基)-N-(6-甲氧基-5-(1-甲基-2-氧代-7-(苯基氨基)-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)苯甲酰胺(I-6);
N-(6-氯-5-(1-甲基-2-氧代-7-(苯基氨基)-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)-3-(三氟甲基)苯甲酰胺(I-8);
3-(叔丁基)-N-(6-氯-5-(1-甲基-2-氧代-7-(苯基氨基)-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)苯甲酰胺(I-9);
2-(叔丁基)-N-(6-氯-5-(1-甲基-2-氧代-7-(苯基氨基)-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)噻唑-4-甲酰胺(I-10);和
N-(6-氯-5-(7-((4-羟基苯基)氨基)-1-甲基-2-氧代-1,2-二氢嘧啶并[4,5-d]嘧啶-3(4H)-基)吡啶-3-基)-3-(三氟甲基)苯甲酰胺(I-11)。
5.一种用于抑制程序性死亡-配体1(PD-L1)的药物组合物,包含根据权利要求1至4中任一项所述的嘧啶并嘧啶酮化合物或其药学上可接受的盐以及药学上可的载体。
6.根据权利要求5所述的药物组合物,用于治疗或预防癌症。
7.根据权利要求6所述的药物组合物,用于治疗或预防结肠癌、肺癌、乳腺癌、胃癌、宫颈癌、膀胱癌、血癌或非霍奇金淋巴瘤。
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US (1) | US20230348474A1 (zh) |
EP (1) | EP4215533A1 (zh) |
JP (1) | JP2023541052A (zh) |
KR (1) | KR102673031B1 (zh) |
CN (1) | CN116137815A (zh) |
AU (1) | AU2021344164A1 (zh) |
BR (1) | BR112023004179A2 (zh) |
CA (1) | CA3190461A1 (zh) |
IL (1) | IL300920A (zh) |
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WO2005011597A2 (en) | 2003-07-29 | 2005-02-10 | Irm Llc | Compounds and compositions as protein kinase inhibitors |
CA2576818A1 (en) | 2004-08-31 | 2006-03-09 | F. Hoffmann-La Roche Ag | Amide derivatives of 3-phenyl dihydropyrimido[4,5-d]pyrimidinones, their manufacture and use as pharmaceutical agents |
SI2348023T1 (sl) | 2005-12-13 | 2015-10-30 | Incyte Corporation | S heteroarilom substituirani pirolo (2,3-b)piridini in pirolo (2,3-b)pirimidini kot zaviralci janus kinaze |
GB201315072D0 (en) * | 2013-08-23 | 2013-10-02 | Galapagos Nv | Novel compounds and pharmaceutical compositions thereoffor the treatment of proliferative disorders |
ES2920823T3 (es) | 2016-07-05 | 2022-08-10 | Broad Inst Inc | Inhibidores bicíclicos de la urea quinasa y usos de los mismos |
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US20230348474A1 (en) | 2023-11-02 |
IL300920A (en) | 2023-04-01 |
KR102673031B1 (ko) | 2024-06-07 |
CA3190461A1 (en) | 2022-03-24 |
BR112023004179A2 (pt) | 2023-04-11 |
AU2021344164A1 (en) | 2023-05-04 |
WO2022060094A1 (ko) | 2022-03-24 |
JP2023541052A (ja) | 2023-09-27 |
EP4215533A1 (en) | 2023-07-26 |
AU2021344164A9 (en) | 2024-03-21 |
MX2023003087A (es) | 2023-04-14 |
KR20220036895A (ko) | 2022-03-23 |
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