CN117343052B - 蛋白酪氨酸磷酸酶抑制剂及其应用 - Google Patents
蛋白酪氨酸磷酸酶抑制剂及其应用 Download PDFInfo
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- 108010087686 src-Family Kinases Proteins 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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- ALJRPIAYJALVFG-UHFFFAOYSA-N tert-butyl 2,2-dioxooxathiazolidine-3-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCOS1(=O)=O ALJRPIAYJALVFG-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明公开了蛋白酪氨酸磷酸酶抑制剂及其应用,具体地,本发明公开了一种式I所示的化合物或其药学上可接受的盐,其可用于治疗癌症等。
Description
技术领域
本发明属于医药领域,具体涉及蛋白酪氨酸磷酸酶抑制剂及其应用。
背景技术
靶向免疫逃避机制的癌症免疫治疗方案,包括检查点阻断(例如PD-1/PD-L1和CTLA-4阻断抗体),已经被证明在治疗多种癌症方面有效,显著改善了一些常规疗法难治性群体中的结果。然而,不完全临床反应以及固有或获得抗性的发展将会继续限制可能受益于检查点阻断的患者群体。
2型非受体蛋白酪氨酸磷酸酶(PTPN2),也称为T细胞蛋白酪氨酸磷酸酶(TC-PTP),是通过从酪氨酸底物去除磷酸基来控制多个细胞调控过程的磷酸酪氨酸特异性磷酸酶的1类亚家族的细胞内成员。PTPN2被广泛表达,但表达在造血细胞和胎盘细胞中最高。在人类中,通过存在两种剪接变体对PTPN2表达进行转录后控制:在剪接接点上游的C末端含有核定位信号的45kDa形式和具有C末端ER保留基序的48kDa经典形式。45kDa同功型可以在某些细胞压力条件下被动地渗入胞质液。两种同功型都具有N末端磷酸酪氨酸磷酸酶催化结构域。PTPN2负调控非受体酪氨酸激酶(例如JAK1、JAK3)、受体酪氨酸激酶(例如INSR、EGFR、CSF1R、PDGFR)、转录因子(例如STAT1、STAT3、STAT5a/b)和Src家族激酶(例如Fyn、Lck)的信号传导。作为JAK-STAT途径的一个重要负调控因子,PTPN2功能是通过细胞因子受体(包括IFNγ)直接调控信号传导。PTPN2催化结构域与PTPN1(也称为PTP1B)具有74%序列同源性,并且具有类似的酶动力学。
在小鼠B16F10可移植肿瘤模型中使用CRISPR/Cas9基因组编辑进行功能丧失体内基因筛检的数据显示,肿瘤细胞中缺失PTPN2基因改善了对GM-CSF分泌疫苗(GVAX)加PD-1检查点阻断的免疫治疗方案的反应。PTPN2丧失通过增强IFNγ介导的对抗原呈递和生长抑制的作用使肿瘤对免疫治疗敏感。相同筛检还显示已知参与免疫逃避的基因(包括PD-L1和CD47)在免疫治疗选择性压力也被耗竭,而参与IFNγ信号传导途径的基因(包括IFNGR、JAK1和STAT1)被增浓。这些观测结果指向了增强IFNγ感测和信号传导的治疗策略在增强癌症免疫治疗方案的功效方面的推定作用。
发明内容
在本发明的第一方面,本发明提出了一种式I所示的化合物或其药学上可接受的盐,
式I,
其中,R1选自C1-3烷基或C1-3烷基-环丙基。
在本发明的一些方案中,R1选自甲基或乙基,其余变量如本发明所定义。
在本发明的一些方案中,R1选自或/>,其余变量如本发明所定义。
在本发明的一些方案中,式I所示的化合物的结构如下所示:
。
在本发明的一些方案中,式I所示的化合物的结构如下所示:
。
在本发明的一些方案中,式I所示的化合物的结构如下所示:
。
在本发明的一些方案中,式I所示的化合物的结构如下所示:
。
在本发明的另一方面,本发明提出了一种药物组合物,所述药物组合物包括前面所述的化合物或其药学上可接受的盐,以及,药学上可接受的载体。
在本发明的另一方面,本发明还提出了前面所述的化合物或其药学上可接受的盐或前面所述的药物组合物在制备治疗PTPN2介导的疾病药物中的应用。
在本发明的一些方案中,所述PTPN2介导的疾病选自癌症。
本发明的化合物具有如下技术效果至少之一:
1)具有较强的PTPN2的抑制水平;
2)具有较高水平的口服体内暴露量。
如本文所用,术语“药学上可接受的盐”是指在制药上可接受的并且具有母体化合物药理学活性的本发明化合物的盐。这类盐包括:与无机酸或与有机酸形成的酸加成的盐,所述的无机酸诸如硝酸,磷酸,碳酸等;所述的有机酸诸如丙酸,己酸,环戊丙酸,乙醇酸,丙酮酸,葡糖酸,硬脂酸,粘康酸等;或在母体化合物上存在的酸性质子被金属离子,例如碱金属离子或碱土金属离子取代时形成的盐;或与有机碱形成的配位化合物,所述的有机碱诸如乙醇胺,二乙醇胺,三乙醇胺,N-甲基葡糖胺等。本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下,这样的盐的制备方法是:在水或有机溶剂或两者的混合物中,经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地,优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。除了盐的形式,本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外,前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
如本文所用,术语“C1-3烷基”指具有1至3个碳原子的直链或支链烷基。具体实例包括甲基、乙基、正丙基和异丙基,及其各种支链异构体等。
本发明式I所示的化合物可使用本领域已知的合成方法或使用本领域已知的方法与本发明记载的方法组合制备得到。本发明给出的溶剂、温度和其它反应条件均为示例性的,可根据本领域熟知的方法而变化。本发明所记载的实施例化合物可根据其具体结构,使用适当的起始原料按照实施例中记载的方法合成,也可以使用与实施例中记载的类似方法合成得到。用于合成本发明实施例化合物的起始原料可通过已知合成方法或文献记载的类似方法制备得到或从商业来源获得。化合物可根据需要,进一步通过本领域熟知的方法,例如结晶、色谱法等拆分得到其立体异构体,其拆分条件是本领域技术人员通过常规手段或有限试验而容易获得的。作为进一步说明,本发明式I化合物可利用以下的方法合成,其中每个步骤中的溶剂、温度及其它反应条件可与下述实施例中记载的相同或类似,或使用本领域已知的反应条件。
具体实施方式
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式。优选的实施方式包括但不限于本发明的实施例。
下面通过实施例对本发明进行详细描述,但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明,其中也公开了其具体实施例方式,对本领域的技术人员而言,在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
实施例1
步骤1: 在氮气条件下,1-(苄氧基)-5-溴-3-氟-2-硝基苯(30.0 g,92.0 mmol)溶于四氢呋喃(300 mL)中,反应液降温至-70℃,然后缓慢滴加入二异丙基氨基锂(92.0 mL,2.0 M)。反应液在-70℃下搅拌半小时。接着在-70℃下向反应液中缓慢滴加3-Boc-1,2,3-氧杂噻唑烷2,2-二氧化物(24.6 g,110.3 mmol)的四氢呋喃(100 mL),反应液在-70℃下搅拌3小时。反应完全后,反应液倒入冰水浴的饱和氯化铵溶液中淬灭反应。混合溶液用乙酸乙酯萃取,有机相合并后水洗干燥浓缩,所得粗产品经硅胶柱层析纯化得到化合物1-2(35.0 g,收率81.1%)。LCMS (ESI) [M+Na]+ :491.0。
步骤2:将中间体1-2(25.0 g,53.2 mmol)溶于二氧六环/水(120 mL, 5/1 v/v)中,依次加入E-2-乙氧基乙烯基-1-硼酸频呐醇酯(52.8 g,266.3 mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(1.9 g,2.66 mmol)和碳酸铯(52.1 g,159.8 mmol)。在氮气氛围下,反应混合物在90℃下搅拌3小时。反应混合物冷却至室温,加入冰水淬灭反应。混合溶液用乙酸乙酯萃取,有机相合并后水洗干燥浓缩,所得粗产品经硅胶柱层析纯化得到化合物1-3(17.5 g,收率71.3%)。LCMS(ESI)[M+Na]+ :483.4。
步骤3:将中间体1-3(17.0 g,36.9 mmol)溶于二氧六环(150 mL)中,加入盐酸二氧六环溶液(50 mL,4 M)。反应液在室温下搅拌1小时。反应完全后,将反应液用碳酸氢钠水溶液中和。混合物用乙酸乙酯(300 mL × 3)萃取,有机相依次用水和饱和食盐水洗涤,无水硫酸钠干燥,过滤。滤液经减压浓缩得到粗品。粗品经过硅胶柱层析分离纯化得到中间体1-4(8.5 g,收率55.6%)。LCMS(ESI)[M+Na]+:437.4。
步骤4:室温下将中间体1-4(17.1 g,41.2 mmol)溶于四氢呋喃(100 mL)和甲醇(100 mL)的混合溶剂中,加入饱和氯化铵溶液(50 mL)和锌粉(13.5 g, 206.3 mmol)。反应液在室温下搅拌3小时。反应完全后,将反应液过滤,滤液经减压浓缩除去大部分甲醇,然后用二氯甲烷稀释,有机相用水洗涤,无水硫酸钠干燥,过滤。滤液经减压浓缩得到粗品中间体1-5(12.5 g,收率78.8%)。LCMS(ESI)[M+H]+:385.0。
步骤5:室温下将中间体1-5(12.5 g,32.5 mmol)溶于二氯甲烷(150 mL)中,加入吡啶(6.56 mL,81.2 mmol)和三氟乙酸酐(13.7 g,65.0 mmol)。反应液在室温下搅拌2小时。反应完全后,倒入冰水中,然后用乙酸乙酯(300 mL × 3)萃取,有机相用水洗涤,无水硫酸钠干燥,过滤。滤液经减压浓缩得到粗品,经过硅胶柱层析分离纯化得到中间体1-6(15.0 g,收率96.0%)。LCMS(ESI)[M+Na]+:503.0。
步骤6:在氮气氛围下,将中间体1-6(13.0 g,27.0 mmol)溶于N,N-二甲基甲酰胺(130 mL)中,依次加入碳酸钾(11.2 g,81.2 mmol)和溴乙酸甲酯(5.0 g,32.4 mmol)。反应混合物在60℃下搅拌14小时。混合物冷却至室温,将反应液倒入冰水中,然后用乙酸乙酯(300 mL × 3)萃取,有机相用水洗涤,无水硫酸钠干燥,过滤。滤液经减压浓缩得到粗品,经过硅胶柱层析分离纯化得到中间体1-7(13.8 g,收率92.3%)。LCMS(ESI)[M+Na]+:575.0。
步骤7:室温下将中间体1-7(13.8 g,25.0 mmol)溶于甲醇(120 mL)中,加入甲醇钠(9.0 mL,5.4 M)的甲醇溶液。反应液在室温下搅拌1小时。反应完全后,将反应液倒入冰水中,用饱和氯化铵中和,然后用二氯甲烷(100 mL × 3)萃取,有机相用水洗涤,无水硫酸钠干燥,过滤。滤液经减压浓缩得到粗品中间体1-8(10.4 g,收率91.6%)。LCMS(ESI)[M+H]+:457.2。
步骤8:室温下将中间体1-8(5.0 g,10.9 mmol)溶于二氯甲烷(50 mL)中,加入N,N-二异丙基乙基胺(5.4 mL,32.8 mmol),搅拌下缓慢滴加入N-(苄氧基羰基)磺酰氯(4.1g,16.4 mmol)。混合物在室温下搅拌1小时。反应混合物用冰水淬灭。用二氯甲烷(100 mL× 3)萃取水相。用饱和盐水洗涤有机相。无水硫酸钠干燥,过滤。滤液经减压浓缩得到粗品,经过硅胶柱层析分离纯化得到中间体1-9(6.1 g,收率83.2%)。LCMS(ESI)[M-Boc+H]+:570.2。
步骤9:室温下将中间体1-9(8.1 g, 12.1 mmol)溶于异丙醇(100 mL)中,加入湿钯碳(810 mg,7.61 mmol)。反应液在氢气(15 psi)氛围中40℃下搅拌3小时。将反应液过滤,滤液经减压浓缩得到粗品中间体1-10(4.7 g,收率86.8%)。LCMS (ESI) [M+Na]+:470.4。
步骤10:室温下将中间体1-10(4.1 g,9.16 mmol)溶于甲醇(40 mL)中,加入甲醇钠(10.0 mL,5.4 M)的甲醇溶液。反应液在40℃下搅拌1小时。反应完全后,将反应液倒入冰水和氯化铵溶液中,然后用乙酸乙酯(200 mL × 3)萃取,有机相用水洗涤,无水硫酸钠干燥,过滤。滤液经减压浓缩得到粗品,经过硅胶柱层析分离纯化得到中间体1-11(3.2 g,收率84.1%)。LCMS(ESI)[M+Na]+:438.0。
步骤11:冰浴下将中间体1-11(5.4 g,13.1 mmol)溶于二氯甲烷(45 mL)中,加入三氟乙酸(15 mL)。反应液缓慢回到室温,搅拌2小时,旋干溶剂得到粗产品。粗产品经过C18反相色谱制备分离纯化得到化合物1(2.1 g,收率51.2%)。LCMS(ESI)[M+H]+:316.0。1H NMR(400 MHz,DMSO-d6)δ 9.40(brs,1H),7.26(brs,2H), 6.59(s,1H),3.93(s,2H),3.23 -3.12(m,4H),3.03 - 2.91(m,4H)。
实施例2
在氮气氛围下,将化合物1(50 mg,0.16 mmol)溶于异丙醇(10 mL)中,加入多聚甲醛(143 mg,1.59 mmol)和两滴冰醋酸。反应混合物在40℃下搅拌1小时。分批加入氰基硼氢化钠(49.8 mg,0.79 mmol),反应液在40℃下继续搅拌12小时。将混合物冷却至室温,加入冰水(10 mL)淬灭反应,反应液经减压浓缩得到粗品。粗产品经反相高效液相色谱制备分离纯化得到化合物2(10.0 mg,收率19.1%)。化合物2:LCMS (ESI)[M+H]+:330.1。1H NMR(400MHz,DMSO-d6)δ 9.67(br,1H),9.36(s,1H),6.59(s,1H),3.93(s,2H),3.31 - 3.18(m,4H),3.00 - 2.90(m,4H),2.79 (s,3H)。
实施例3
本实施例化合物可应用类似于所描述的实施例2的合成方法制得。化合物3:LCMS(ESI)[M+H]+:344.1。1H NMR(400 MHz,DMSO-d6)δ 9.64 - 9.09(m,2H),6.59(s,1H),3.92(s,2H),3.70 - 3.45(m,1H),3.26 - 2.64(m,9H),1.21(t,J = 6.9 Hz,3H)。
实施例4
本实施例化合物可应用类似于所描述的实施例2的合成方法制得。化合物4:LCMS(ESI)[M+H]+:370.0。1H NMR(400 MHz,DMSO-d6)δ 8.92(s,1H),6.42(s,1H),3.85(s,2H),2.81 - 2.73(m,4H),2.67 - 2.55(s,4H),2.27(d,J = 6.0 Hz, 2H),0.89 - 0.78(m,1H),0.49 - 0.40(m,2H),0.09 - 0.01(m,2H)。
实施例5
本实施例化合物可应用类似于所描述的实施例2的合成方法制得。化合物5LCMS(ESI)[M+H]+:384.2。1H NMR(400 MHz,DMSO-d6)δ 9.37(brs,1H),6.59(s,1H),3.92(s,2H),3.62(s,2H),3.32 - 2.83(m,8H),1.60 - 1.55(m,2H),0.77 - 0.62(m,1H),0.54 - 0.41(m,2H),0.13 - 0.09(m,2H)。
实施例6
本实施例化合物可应用类似于所描述的实施例1的合成方法制得。化合物6:LCMS(ESI)[M+H]+:330.2。1H NMR(400 MHz,DMSO-d6)δ 7.40 - 7.32(m,3H),6.58 (s,1H),4.00- 3.89(m,2H),3.09 - 2.96(m,3H),2.95 - 2.80(m,2H),2.56 - 2.51(m,2H),1.25(d,J =6.4 Hz,3H)。
测试例1:PTPN2 酶学抑制检测
以6,8-二氟-4-甲基伞形甲基磷酸(DiFMUP)为底物,在384孔板中,5 μL PTPN2溶液(反应缓冲液PTPN2稀释至0.2 nM:50 mM Tris-HCl, pH 7.2, 50 mM NaCl, 0.01%Triton X-100, 1 mM DTT)与化合物或DMSO(0.5% v/v)在室温下孵育10分钟。加入5 μLDiFMUP (10 μM)启动反应,室温孵育30 min后,在CLARIO Star Plusacu酶标仪(BMG)上测量反应终溶液的荧光(激发波长为360 nm,发射波长为460 nm)。实验设双复孔进行。低对照(DMSO和空白反应缓冲液)设置为100%抑制,高对照(DMSO和PTPN2酶反应溶液)设置为0%抑制。以100*(平均高对照-化合物孔)/(平均高对照-平均低对照)计算抑制率。采用XLfit拟合非线性回归方程确定IC50值。
表1:PTPN2 酶学活性(IC50)
实施例编号 | h-PTPN2 IC50(nM) |
实施例 1 | 21.6 |
实施例 2 | 4.5 |
实施例 3 | 9.3 |
实施例4 | 6.0 |
实施例5 | 4.3 |
实施例6 | 31.2 |
实施例1为对照分子(WO2023150523,实施例30)。
测试例2:本发明部分化合物的小鼠药代动力学测试
选取健康成年C57BL/6N雌性小鼠(购自上海必凯科翼生物科技有限公司),口服给药剂量为10 mg/kg。小鼠在给药前禁食至少12小时,给药2小时后恢复供食,整个实验期间自由饮水。
实验当天通过灌胃单次给与相应化合物,给药体积为10 mL/kg。给药后血浆采集时间为0.25、0.5、1、2、4、6、8、24小时采血。每个时间点采集大约200 μL全血(EDTA-K2抗凝)用于制备血浆,供高效液相色谱-串联质谱(LC-MS/MS)进行浓度测定,并采用药代学软件使用线性对数梯形法计算药动学参数。
本发明化合物的药代动力学参数如下。
表2:化合物的小鼠体内药代动力学评价结果
实施例编号 | Cmax(ng/mL) | AUC (h*ng/mL) |
实施例 1 | N.A. | N.A. |
实施例 2 | 2294 | 7978 |
实施例 3 | 4747 | 20904 |
实施例4 | 899 | 5142 |
实施例5 | 328 | 1316 |
实施例6 | 392 | 1356 |
根据表2可知,在式I所示的化合物的左侧含N原子的七元杂环基上N原子上进行适当的取代基取代,有助于改善式I所示的化合物的PK数据,提高体内暴露量。在其他位置进行取代或者R1的取代基过大,会造成这类化合物的体内暴露量降低。
尽管本发明的具体实施方式已经得到详细的描述,根据已经公开的所有教导,本领域技术人员可以对本发明技术方案的细节进行各种修改和替换,这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。
Claims (6)
1.一种式I所示的化合物或其药学上可接受的盐,
式I,
其中,R1选自甲基或乙基。
2.根据权利要求1所述的化合物或其药学上可接受的盐,其中,式I所示的化合物的结构如下所示:
。
3.根据权利要求1所述的化合物或其药学上可接受的盐,其中,式I所示的化合物的结构如下所示:
。
4.一种药物组合物,其中,所述药物组合物包括权利要求1-3任一项所述的化合物或其药学上可接受的盐,
以及,药学上可接受的载体。
5.权利要求1-3任一项所述的化合物或其药学上可接受的盐或权利要求4所述的药物组合物在制备治疗PTPN2介导的疾病药物中的应用。
6.根据权利要求5所述的应用,其中,所述PTPN2介导的疾病选自癌症。
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