CN115417870A - Pd-l1&nampt双靶点抑制剂和用途 - Google Patents
Pd-l1&nampt双靶点抑制剂和用途 Download PDFInfo
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- CN115417870A CN115417870A CN202211148055.8A CN202211148055A CN115417870A CN 115417870 A CN115417870 A CN 115417870A CN 202211148055 A CN202211148055 A CN 202211148055A CN 115417870 A CN115417870 A CN 115417870A
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- target inhibitor
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
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- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 description 2
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Abstract
本发明公开了一种PD‑L1&NAMPT双靶点抑制剂和用途,所述抑制剂为结构通式如式Ⅰ所示的化合物或其药学上可接受的盐、消旋体、旋光异构体或溶剂化合物。本发明所述的双靶点抑制剂,可同时抑制PD‑L1和NAMPT活性并用于制备抗肿瘤药物,能有效克服单一型PD‑L1抑制剂效果差和单一型NAMPT抑制剂活性弱等缺点,有较好的应用前景。
Description
技术领域
本发明涉及一种双靶点抑制剂和用途,具体涉及一种PD-1&NAMPT双靶点抑制剂和用途。
背景技术
程序性细胞死亡蛋白配体1(PD-L1)是一种在造血和非造血细胞,如T细胞和B细胞以及各种类型的肿瘤细胞表达的免疫抑制受体配体。编码蛋白是一种I型跨膜蛋白,具有免疫球蛋白V样和C样结构域。该配体与其受体的相互作用抑制T细胞活化和细胞因子产生。在正常组织的感染或炎症期间,这种相互作用对于通过维持免疫反应的稳态来预防自身免疫很重要。在肿瘤微环境中,这种相互作用通过细胞毒性T细胞失活为肿瘤细胞提供免疫逃逸。
烟酰胺腺嘌呤二核苷酸(NAD)是许多酶促反应的辅助因子,也是许多消耗NAD的酶的底物。烟酰胺磷酸核糖基转移酶(NAMPT)属于烟酸磷酸核糖基转移酶(NAPRTase)家族,被认为参与许多重要的生物过程,包括代谢,应激反应和衰老。NAMPT催化烟酰胺单核苷酸(NMN)从烟酰胺(NAM)和PRPP(在ATP存在下)合成烟酰胺单核苷酸(NMN)。然后NMN通过烟酰胺单核苷酸腺苷酸转移酶(NMNAT)转化为NAD。癌细胞对ATP的较高需求,以及它们的代谢重编程,导致对NAD(P)的需求增加。因此,NAMPT抑制剂具有抗肿瘤的潜力。
现有技术中现有技术中尚存在PD-L1抑制剂单用效果差和单一型NAMPT抑制剂活性弱等问题,亟待解决。
发明内容
发明目的:本发明旨在提供一种能有效解决单一型PD-L1抑制剂效果差和单一型NAMPT抑制剂活性弱等缺点的双靶向化合物;本发明的另一目的在于提供一种所述双靶向抑制剂在抑制PD-L1和NAMPT活性中的应用。
技术方案:本发明所述的双靶点抑制剂为结构通式如式Ⅰ所示的化合物或其药学上可接受的盐、消旋体、旋光异构体或溶剂化合物:
其中,环A选自取代或非取代的5-6元杂环、苯环并3-6元杂环或5-6元杂环并3-6元杂环;所述5-6元杂环的取代基为卤素、氨基、羟基、羧基、氰基、烯烃或酰胺中的至少一种;
X选自氮原子或氧原子;
L1是连接基团,选自直链或支链的亚烷基链、亚螺环基、1,4-哌嗪亚基或者1,3二炔亚基,L1可被以下基团中的一个、多个或任意组合中断一或多次:-O-、-CONH-、NHCO-、-NHCONH-、-NH-、-S-、亚磺酰基、磺酰基、氨基磺酰基氨基、亚炔基、亚烯基、亚环烷基、亚芳基、6元亚杂环基或6元亚杂芳基;所述L1可被以下一个或多个基团取代:卤素、氨基、羟基、羧基、酰胺、氰基、烯烃、炔烃、C1-6烷氧基、C1-10烷基;
L2选自以下基团:
X1,X2,X3选自碳原子或氮原子;
R1选自氢、氘、取代或未取代的C1-4烷基;所述C1-4烷基的取代基选自羧基、羟基、酰胺、氰基、卤素、C1-4烷基或C1-4烷氧基中的至少一种;
R2选自氢、氘、氰基、卤素或C1-4烷基;
R3,R4选自氢、氘、C1-4取代或未取代的羟基、C1-4取代或未取代的氨基;所述C1-4取代的羟基、C1-4取代的氨基的取代基选自以下羧基、羟基、氨基、酰胺、氰基、卤素、C1-4烷基、C1-4烷氧基、取代或未取代的芳基、取代或未取代的吡啶基;所述取代的芳基、取代的吡啶基的取代基选自以下一个或多个取代基:氰基、羟基、羧基、氨基、酰胺、卤素;
m,t为0,1或2。
优选地,所述环A选自:
L1选自:
L2选自以下基团:
X1,X3为C,X2为C或N;
R1为氢;
R2为氯、溴或甲基;
R3为氢;
优选地,所述化合物包括:
所述双靶点抑制剂可应用于同时抑制PD-L1和NAMPT活性。
所述双靶点抑制剂可应用于制备抗肿瘤药物。
含有所述双靶点抑制剂的药物组合物,以所述抑制剂作为活性成分和药学上可接受的载体。优选地,所述药物组合物是胶囊剂、散剂、片剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂或贴剂;所述药物组合物还包括羟丙甲基纤维素E、淀粉、聚维酮K30和硬脂酸镁,该组合物通过将上述物质混合,制粒,压片后制成。
有益效果:与现有技术相比,本发明具有如下显著优点:本发明所述的双靶点抑制剂,能有效克服单一型PD-L1抑制剂效果差和单一型NAMPT抑制剂活性弱等缺点,有较好的应用前景。
具体实施方式
下面结合实施例对本发明的技术方案作进一步说明。
实施例1
本实施例所述的双靶点抑制剂,结构式如下所示:
合成路线:
化合物1-A的合成:
参考Journal of Medicinal Chemistry 2021 64(11),7390-7403中化合物22a的合成,可得化合物1-A。
化合物1的合成:
将306mg化合物1-A,413mg二环己基碳二亚胺,245mg 4-二甲氨基吡啶和226mg(E)-3-(咪唑并[1,2-a]吡啶-6-基)丙烯用5mL的DMSO溶解,氮气保护,置于室温条件下搅拌反应一天。加入50mL水,用100mL的乙酸乙酯萃取两次,饱和食盐水洗一次,有机相收集,旋干溶剂经柱层析(二氯甲烷:甲醇=20:1),得303mg白色固体化合物1。1H NMR(500MHz,Chloroform-d)δ9.48(s,1H),7.90(s,1H),7.72(dd,J=7.8,1.2Hz,1H),7.64–7.48(m,4H),7.48–7.32(m,8H),7.28(t,J=7.8Hz,1H),6.38(d,J=16.5Hz,1H),5.36(d,J=12.8Hz,1H),5.23(d,J=12.8Hz,1H),3.91(s,3H),2.57(s,3H)。
实施例2
本实施例所述的双靶点抑制剂,结构式如下所示:
合成路线:
化合物2-A的合成:
参考Journal of Medicinal Chemistry 2022 65(5),3879-3893中化合物Ⅶb的合成,可得化合物2-A。
化合物2的合成:
将306mg化合物2-A,358mg二环己基碳二亚胺,245mg 4-二甲氨基吡啶和226mg(E)-3-(咪唑并[1,2-a]吡啶-6-基)丙烯用5mL的DMSO溶解,氮气保护,置于室温条件下搅拌反应一天。加入50mL水,用100mL的乙酸乙酯萃取两次,饱和食盐水洗一次,有机相收集,旋干溶剂经柱层析(二氯甲烷:甲醇=20:1),得369mg白色固体化合物2。1H NMR(500MHz,Chloroform-d)δ8.68(s,1H),8.54–8.51(m,1H),7.92(dd,J=10.3,0.7Hz,1H),7.90(dt,J=8.6,1.3Hz,1H),7.82(d,J=4.1Hz,1H),7.61(d,J=4.1Hz,1H),7.60–7.55(m,2H),7.53(d,J=0.8Hz,1H),7.51–7.31(m,9H),7.25(t,J=7.7Hz,1H),7.20(ddt,J=7.7,2.3,1.0Hz,1H),7.13(tt,J=2.1,1.1Hz,1H),6.42(d,J=15.6Hz,1H),5.19(t,J=1.2Hz,2H),2.62(s,3H)。ESI-MS m/z:528.2[M+H]+。
实施例3-6
采用实施例1和实施例2的合成方法,可以合成化合物3-6。
具体合成的化合物如下表所示。
实施例7
本实施例所述的双靶点抑制剂,结构式如下所示:
合成路线:
化合物3-B的合成:
将163mg化合物咪唑并[1,2-a]吡啶-6-羧酸,226mg(4-氨基丁基)氨基甲酸叔丁酯,1.54g 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和850mg1-羟基苯并三氮唑用5mL的DMSO溶解,氮气保护,置于室温条件下搅拌反应12h。加入50mL水,用100mL的乙酸乙酯萃取两次,饱和食盐水洗一次,有机相收集,浓缩得289mg化合物3-B。
化合物3-C的合成:
将333mg化合物3-B用3.5mL的二氯甲烷和1.5mL的三氟乙酸溶解,室温搅拌反应1小时,TLC监测反应完毕,旋干溶剂经柱层析(二氯甲烷:甲醇=20:1),得210mg白色固体化合物3-C。
化合物3-D的合成:
参考Journal of Medicinal Chemistry 2021 64(11),7390-7403中化合物23a的合成,可得化合物3-D。
化合物7的合成:
将318mg化合物3-D,280mg化合物3-C用5mL的甲醇溶解,氮气保护,置于室温条件下搅拌反应3h。加入314mg氰基硼氢化钠,继续反应9h。加入50mL水,用100mL的乙酸乙酯萃取两次,饱和食盐水洗一次,有机相收集,旋干溶剂经柱层析(二氯甲烷:甲醇=15:1)得374mg化合物7。1H NMR(500MHz,Chloroform-d)δ8.65–8.61(m,1H),8.06–8.00(m,2H),7.82(d,J=4.0Hz,1H),7.70(dd,J=8.6,0.7Hz,1H),7.63(d,J=4.1Hz,1H),7.61(d,J=8.7Hz,1H),7.52–7.30(m,9H),3.95–3.91(m,5H),3.40(tt,J=6.4,5.1Hz,1H),3.30(td,J=5.3,4.6Hz,2H),2.60(q,J=4.9Hz,2H),2.50(s,3H),1.61–1.52(m,4H)。ESI-MS m/z:520.3[M+H]+。
实施例8
本实施例所述的双靶点抑制剂,结构式如下所示:
合成路线:
化合物4-B的合成:
将163mg化合物咪唑并[1,2-a]吡啶-6-羧酸,226mg(4-氨基丁基)氨基甲酸叔丁酯,1.54g 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和850mg1-羟基苯并三氮唑用5mL的DMSO溶解,氮气保护,置于室温条件下搅拌反应12h。加入50mL水,用100mL的乙酸乙酯萃取两次,饱和食盐水洗一次,有机相收集,浓缩得289mg化合物4-B。
化合物4-C的合成:
将333mg化合物3-B用3.5mL的二氯甲烷和1.5mL的三氟乙酸溶解,室温搅拌反应1小时,TLC监测反应完毕,旋干溶剂经柱层析(二氯甲烷:甲醇=20:1),得210mg白色固体化合物4-C。
化合物4-D的合成:
参考Journal of Medicinal Chemistry 2022 65(5),3879-3893中化合物Ⅷb的合成,可得化合物4-D。
化合物8的合成:
将356mg化合物4-D,280mg化合物4-C用5mL的甲醇溶解,氮气保护,置于室温条件下搅拌反应3h。加入314mg氰基硼氢化钠,继续反应9h。加入50mL水,用100mL的乙酸乙酯萃取两次,饱和食盐水洗一次,有机相收集,旋干溶剂经柱层析(二氯甲烷:甲醇=15:1)得343mg化合物8。1H NMR(500MHz,Chloroform-d)δ8.80(s,1H),8.65–8.61(m,1H),8.07–8.00(m,2H),8.0–7.97(m,1H),7.84(d,J=4.0Hz,1H),7.66(d,J=4.1Hz,1H),7.60(d,J=8.7Hz,1H),7.53(dd,J=7.7,0.8Hz,1H),7.51–7.39(m,5H),7.36–7.33(m,3H),7.25(d,J=15.6Hz,1H),7.16(tt,J=2.1,1.0Hz,1H),7.09(ddq,J=7.9,2.2,1.0Hz,1H),4.70(p,J=5.4Hz,1H),3.88(dt,J=5.5,1.0Hz,2H),3.30(td,J=5.3,4.6Hz,2H),2.69(s,3H),2.53(q,J=5.1Hz,2H),1.61–1.52(m,4H)。ESI-MS m/z:572.3[M+H]+。
实施例9-30
采用实施例7和实施例8的合成方法,可以合成化合物9-30。
具体合成的化合物如下表所示。
实施例31
本实施例所述的双靶点抑制剂,结构式如下所示:
合成路线:
化合物5-B的合成:
将148mg化合物咪唑并[1,2-a]吡啶-6-基甲胺、888mg三光气用5mL的甲苯溶解,氮气保护,置于110℃条件下搅拌回流12h。反应完毕,浓缩反应液,直接用于下一步合成。
化合物5-C的合成:
参考Journal of Medicinal Chemistry 2021 64(11),7390-7403中化合物22a的合成,可得化合物5-C。
化合物31的合成:
将上述所得化合物5-B,304mg 5-C用5mL的甲醇溶解,加入0.15mL三乙胺,置于室温条件下搅拌反应4h。加入50mL水,用100mL的乙酸乙酯萃取两次,饱和食盐水洗一次,有机相收集,浓缩得430mg化合物31。1H NMR(500MHz,Chloroform-d)δ8.92–8.88(m,1H),7.77(d,J=4.1Hz,1H),7.70(dd,J=8.5,0.7Hz,1H),7.62(d,J=4.0Hz,1H),7.49(dd,J=7.7,0.7Hz,1H),7.47–7.30(m,9H),5.85(t,J=5.1Hz,1H),4.88(d,J=4.2Hz,2H),4.21(d,J=5.0Hz,2H),4.06(d,J=7.2Hz,2H),3.95(s,3H),3.08(tt,J=7.1,4.0Hz,1H)。ESI-MS m/z:508.2[M+H]+。
实施例32
本实施例所述的双靶点抑制剂,结构式如下所示:
合成路线:
化合物6-B的合成:
将148mg化合物咪唑并[1,2-a]吡啶-6-基甲胺、888mg三光气用5mL的甲苯溶解,氮气保护,置于110℃条件下搅拌回流12h。反应完毕,浓缩反应液,得化合物6-B,直接用于下一步合成。
化合物6-C的合成:
参考Journal of Medicinal Chemistry 2021 64(11),7390-7403中化合物22a的合成,可得化合物6-C。
化合物32的合成:
将上述所得化合物6-B,358mg 6-C用5mL的甲醇溶解,加入0.15mL三乙胺,置于室温条件下搅拌反应4h。加入50mL水,用100mL的乙酸乙酯萃取两次,饱和食盐水洗一次,有机相收集,浓缩得398mg化合物32。1H NMR(500MHz,Chloroform-d)δ8.92–8.87(m,1H),8.78(s,1H),7.97(dd,J=10.2,0.7Hz,1H),7.74(d,J=4.0Hz,1H),7.62(d,J=4.0Hz,1H),7.54(dd,J=7.9,0.8Hz,1H),7.51–7.33(m,8H),7.30–7.21(m,3H),7.13(tt,J=2.1,1.1Hz,1H),5.80(t,J=5.2Hz,1H),5.08(t,J=1.0Hz,2H),4.21(d,J=5.3Hz,2H),2.67(s,3H)。ESI-MS m/z:531.2[M+H]+。
实施例33-36
采用实施例27和施例28的合成方法,可以合成化合物33-36:
具体合成的化合物如下表所示。
实施例37
所述含有双靶点抑制剂的药物组合物片剂的制备方法如下:
将实施例1中制得的化合物1(50g)、羟丙甲基纤维素E(150g)、淀粉(200g)、聚维酮K30适量和硬脂酸镁(1g)混合,制粒,压片。
此外,可以根据药典2020版常规制剂法,将实施例1-36制得的化合物赋予不同的药物辅料制成胶囊剂、散剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂或贴剂等。
应用实施例
药理试验证明,本发明的PD-L1抑制活性,可用于制备抗肿瘤药物。下面是本发明部分化合物的药理实验结果:
一、化合物对PD-1/PD-L1相互作用抑制效果的测定
(一)实验设备及试剂
1、离心机Eppendorf 5430
2、酶标仪Perkin Elmer EnVision
3、PD-1-Eu、PD-L1-Biotin、Dye labeled acceptor(BPS Bioscience)
4、BMS-202(Selleckchem)
5、384well microplate(Perkin Elmer)
(二)实验方法
利用TR-FRET assay的方法检测化合物对PD-1/PD-L1相互作用的抑制效果,化合物以1000nM起始,3倍稀释,10个浓度点,单孔检测。以BMS-202作为阳性对照化合物。用酶标仪测试得到不同浓度化合物在665nm和620nm的荧光强度并计算TR-FRET ratio(665nmemission/620nm emission)。
1.实验步骤
1.1配制1×modified TR-FRET assay buffer。
1.2化合物浓度梯度的配制:受试化合物测试浓度为1000nM起始,3倍稀释,10个浓度点,单孔检测。在96孔板中用DMSO稀释成100倍终浓度的溶液,然后用1×buffer稀释至20倍终浓度,转移1uL到384反应板中备用。阴性对照孔和阳性对照孔中分别加1uL的20%DMSO。
1.3用1×modified TR-FRET assay buffer配制5倍终浓度的PD-L1-Biotin溶液。
1.4在化合物孔和阳性对照孔分别加4μL的5倍终浓度的PD-L1-Biotin溶液;在阴性对照孔中加4μL的1×modified TR-FRET assay buffer。
1.5 1000rpm离心30秒,振荡混匀后室温孵育15分钟。
1.6用1×modified TR-FRET assay buffer配制4倍终浓度的PD-1-Eu和2倍终浓度的Dye labeled acceptor混合溶液。
1.7加入15μL PD-1-Eu和Dye labeled acceptor混合溶液(其中含5μL的4倍终浓度的PD-1-Eu和10μL 2倍终浓度的Dye labeled acceptor)。
1.8 1000rpm离心30秒,振荡混匀后室温孵育90分钟。
1.9将384孔板1000rpm离心30秒,振荡混匀后用EnVision读取665nm和620nm的荧光强度,并计算TR-FRET ratio(665nm emission/620nm emission)。
(三)实验结果
下表为化合物对PD-1/PD-L1抑制活性的活性范围或IC50。范围如下:A=1-10nM;B=10.01-100nM;C=100.1-1000nM。
编号 | PD-1/PD-L1 IC<sub>50</sub>(nM) | 编号 | PD-1/PD-L1IC<sub>50</sub>(nM) |
1 | A | 19 | B |
2 | B | 20 | B |
3 | A | 21 | A |
4 | B | 22 | A |
5 | B | 23 | B |
6 | B | 24 | B |
7 | B | 25 | B |
8 | B | 26 | B |
9 | 7.2 | 27 | B |
10 | B | 28 | B |
11 | B | 29 | B |
12 | B | 30 | B |
13 | B | 31 | 3.9 |
14 | B | 32 | B |
15 | 2.6 | 33 | A |
16 | A | 34 | B |
17 | A | 35 | B |
18 | B | 36 | B |
二、化合物对NAMPT活性抑制效果的测定
(一)实验设备及仪器
1、酶标仪Molecular Devices SpectraMax i3x
2、NAMPT比色试剂盒(CycLex货号:CY-1251)
3、DMSO(国药试剂,货号:30072418)
4、96孔板(NEST,货号:701001)
(二)实验方法
NAM和PRPP在NAMPT的催化下可以生成NMN,而NMN和ATP在NAMPT1的作用下会生成NAD+,经乙醇脱氢酶(ADH)的催化变成NADH,而NADH在心肌黄酶的作用下又会变回NAD+。WST-1在NAD+/NADH的循环中变成橙黄色的甲臜,在450nm左右有最大吸收峰。所以450nm波长处吸光度变化反映化合物对NAMPT酶活性的影响。
1.实验步骤
1.1化合物溶液配制:用DMSO溶解配制浓度为10mM的母液,设置8个浓度梯度,2倍稀释,3个复孔。
1.2 mixture-1的配制:20×NAMPT测试缓冲液5μl,PRPP 5μl,ATP 5μl,重组NAMPT1 5μl,双蒸水35μl和NAMPT 5μl混匀。
1.3 mixture-2的配制:WST-1 5μl,ADH 5μl,心肌黄酶5μl,乙醇5μl混匀。
1.4向96孔板依次加入10μl双蒸水、5μl NAM以及5μl待测化合物或DMSO,再加入60μl配制好的mixture-1,混匀后于30℃条件下孵育1小时。
1.5加入配制好的mixture-2,于30℃条件下孵育30分钟。
1.6用酶标仪测定450nm波长处吸光度OD值并计算NAMPT抑制率。
(三)实验结果
下表为化合物对NAMPT抑制活性的活性范围或IC50。范围如下:A=1-100nM;B=100-1000nM;C=1000-10000nM。
编号 | NAMPT IC<sub>50</sub>(nM) | 编号 | NAMPT IC<sub>50</sub>(nM) |
1 | B | 19 | C |
2 | B | 20 | B |
3 | C | 21 | B |
4 | C | 22 | C |
5 | B | 23 | B |
6 | B | 24 | B |
7 | B | 25 | C |
8 | B | 26 | B |
9 | B | 27 | C |
10 | C | 28 | C |
11 | B | 29 | B |
12 | C | 30 | B |
13 | B | 31 | C |
14 | B | 32 | B |
15 | B | 33 | C |
16 | B | 34 | C |
17 | C | 35 | B |
18 | C | 36 | B |
Claims (8)
1.一种双靶点抑制剂,其特征在于,所述抑制剂为结构通式如式Ⅰ所示的化合物或其药学上可接受的盐、消旋体、旋光异构体或溶剂化合物:
其中,环A选自取代或非取代的5-6元杂环、苯环并3-6元杂环或5-6元杂环并3-6元杂环;所述5-6元杂环的取代基为卤素、氨基、羟基、羧基、氰基、烯烃或酰胺中的至少一种;
X选自氮原子或氧原子;
L1是连接基团,选自直链或支链的亚烷基链、亚螺环基、1,4-哌嗪亚基或者1,3二炔亚基,L1可被以下基团中的一个、多个或任意组合中断一或多次:-O-、-CONH-、NHCO-、-NHCONH-、-NH-、-S-、亚磺酰基、磺酰基、氨基磺酰基氨基、亚炔基、亚烯基、亚环烷基、亚芳基、6元亚杂环基或6元亚杂芳基;所述L1可被以下一个或多个基团取代:卤素、氨基、羟基、羧基、酰胺、氰基、烯烃、炔烃、C1-6烷氧基、C1-10烷基;
L2选自以下基团:
X1,X2,X3选自碳原子或氮原子;
R1选自氢、氘、取代或未取代的C1-4烷基;所述C1-4烷基的取代基选自羧基、羟基、酰胺、氰基、卤素、C1-4烷基或C1-4烷氧基中的至少一种;
R2选自氢、氘、氰基、卤素或C1-4烷基;
R3,R4选自氢、氘、C1-4取代或未取代的羟基、C1-4取代或未取代的氨基;所述C1-4取代的羟基、C1-4取代的氨基的取代基选自以下羧基、羟基、氨基、酰胺、氰基、卤素、C1-4烷基、C1-4烷氧基、取代或未取代的芳基、取代或未取代的吡啶基;所述取代的芳基、取代的吡啶基的取代基选自以下一个或多个取代基:氰基、羟基、羧基、氨基、酰胺、卤素;
m,t为0,1或2。
4.一种权利要求1~3任一项所述的双靶点抑制剂在同时抑制PD-L1和NAMPT活性中的应用。
5.一种权利要求1~3任一项所述的双靶点抑制剂在制备抗肿瘤药物中的应用。
6.一种含有权利要求1~3任一项所述的双靶点抑制剂的药物组合物,其特征在于,以所述抑制剂作为活性成分和药学上可接受的载体。
7.根据权利要求6所述的含有双靶点抑制剂的药物组合物,其特征在于,所述药物组合物是胶囊剂、散剂、片剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂或贴剂。
8.根据权利要求6所述的含有双靶点抑制剂的药物组合物,其特征在于,所述药物组合物还包括羟丙甲基纤维素E、淀粉、聚维酮K30和硬脂酸镁,该组合物通过将上述物质混合,制粒,压片后制成。
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