CN117510405A - 苯基-2-羟基-乙酰氨基-2-甲基-苯基化合物 - Google Patents
苯基-2-羟基-乙酰氨基-2-甲基-苯基化合物 Download PDFInfo
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- CN117510405A CN117510405A CN202310753648.5A CN202310753648A CN117510405A CN 117510405 A CN117510405 A CN 117510405A CN 202310753648 A CN202310753648 A CN 202310753648A CN 117510405 A CN117510405 A CN 117510405A
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- methyl
- compound
- amino
- phenyl
- pharmaceutically acceptable
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- -1 Phenyl-2-hydroxy-acetamido-2-methyl-phenyl compounds Chemical class 0.000 title abstract description 16
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Abstract
本发明提供苯基‑2‑羟基‑乙酰氨基‑2‑甲基‑苯基化合物,包含所述化合物的药物组合物,以及所述化合物用于治疗生理疾病如癌症的方法。
Description
本申请是中国发明专利申请(申请日:2018年4月11日;申请号:201880033126.5(国际申请号:PCT/US2018/027005);发明名称:苯基-2-羟基-乙酰氨基-2-甲基-苯基化合物)的分案申请。
本发明涉及新型苯基-2-羟基-乙酰氨基-2-甲基-苯基化合物,包含所述化合物的药物组合物,所述化合物用于治疗生理疾病的方法,以及用于合成化合物的中间体和方法。
本发明属于癌症治疗以及包括蛋白激酶R(PKR)样内质网激酶(PERK)的其它疾病和病症在内的治疗的领域。PERK,一种在未折叠蛋白质反应(UPR)中涉及的eIF2激酶,其调节蛋白质合成,协助细胞减轻内质网应激的影响,并与肿瘤发生和癌细胞存活有关。
肿瘤细胞在敌对的微环境中茁壮成长,所述微环境主要是由于养分和氧气的限制、代谢的高需求和氧化应激引起的。已知这些应激会破坏内质网(ER)的蛋白质折叠能力,从而引发被称为未折叠蛋白质反应(UPR)的细胞修复反应。ER应激有助于增强癌细胞的致癌潜力、肿瘤转移、肿瘤耐药性以及癌细胞避免有效免疫反应的能力。
UPR有三种主要的ER跨膜感受器:1)肌醇需求酶(IRE1α/IRE1β,分别由ERN1和ERN2编码);2)PKR样ER激酶(PERK,也被称为PEK,由EIF2AK3编码);和3)活性转录因子6α(由ATF6编码)。通过结合ER腔的伴侣蛋白GRP78或BiP(由HSPA5编码)来相似地调节三个感受器中的每一个。当ER的蛋白质折叠需求超出能力时,减少的BiP结合会导致这些ER感受器蛋白质激活,从而诱导协调的信号通路以增加ER的折叠能力并减轻潜在的应激。有效的反应导致细胞适应和存活,而不可逆的ER应激触发细胞死亡和凋亡。
PERK是一种I型跨膜丝氨酸/苏氨酸激酶,且为激酶家族的一个成员,其磷酸化真核翻译起始因子2α(eIF2-α)并调节翻译起始。其它家族成员包括HRI(EIF2AK1),PKR(EIF2AK2)和GCN2(EIF2AK4)。每个eIF2激酶均响应不同的细胞应激信号,以调节一般翻译和基因特异性翻译控制。eIF2的磷酸化导致一般翻译的启动减少,这是由于eIF2B交换因子活性的降低,从而减少了进入ER的蛋白质数量(且由此减少了蛋白质折叠负担)和对ATP的翻译需求。eIF2的磷酸化还以基因特异性方式增加了某些mRNA的翻译,包括转录因子ATF4。ATF4转录靶标包括许多与细胞适应和存活有关的基因,包括与蛋白质折叠、营养吸收、氨基酸代谢、氧化还原稳态及自噬(4)有关的几个基因。预期对UPR的PERK臂的选择性抑制深刻影响肿瘤细胞的生长和存活。因此,据信抑制PERK的化合物可用于治疗癌症。
在目前的医学治疗状态下,即使在早期发现胰腺癌,胰腺癌患者的预后也往往很差。因此,对治疗胰腺癌的新的有效疗法的需求依然十分迫切。本发明的化合物是PERK的抑制剂,并且据信可用于治疗癌症,特别是胰腺癌。
WO 2015/136463公开了一些具有PERK抑制活性的吡咯烷酮衍生物,并进一步公开了化合物,其用于治疗癌症和与活化的未折叠蛋白反应有关的疾病,包括胰腺癌。
因此,本发明提供了式I的化合物:
其中
R选自:
X为CH或N;
R1为氢或氟;且
R2为C1至C3烷基;
或其药学上可接受的盐。
另外,本发明提供式Ia的化合物:
其中
R选自:
X为CH或N;
R1为氢或氟;且
R2为C1至C3烷基;
或其药学上可接受的盐。
另外,本发明提供式I或Ia的化合物:
其中R为
另外,本发明提供式I或Ia的化合物:其中X为CH或N;R1为氢或氟;且R2是甲基或异丙基;或其药学上可接受的盐。
另外,本发明提供式I或Ia的化合物:其中R为
或其药学上可接受的盐。
另外,本发明提供了化合物3-氨基-6-[4-[[((2R)-2-(3,5-二氟苯基)-2-羟基-乙酰基]氨基]-2-甲基-苯基]-N-甲基-吡嗪-2-甲酰胺,其可用下式表示:
或其药学上可接受的盐。
另外,本发明提供了化合物2-氨基-5-[4-[[(2R)-2-(3,5-二氟苯基)-2-羟基-乙酰基]氨基]-2-甲基-苯基]-N-异丙基-吡啶-3-甲酰胺,其可用下式表示:
或其药学上可接受的盐。
另外,本发明提供了化合物(2R)-N-[4-(4-氨基-7-甲基-吡咯并[2,3-d]嘧啶-5-基)-3-甲基-苯基]-2-(3-氟苯基)-2-羟基-乙酰胺,其可用下式表示:
或其药学上可接受的盐。
本发明提供了一种在需要这种治疗的患者中治疗癌症的方法,所述方法包括向所述患者施用有效量的式I或Ia的化合物,或其药学上可接受的盐。本发明还提供了一种在需要这种治疗的患者中抑制PERK活性并产生抗肿瘤活性的方法,所述方法包括向所述患者施用有效量的式I或Ia的化合物,或其药学上可接受的盐。
本发明还提供一种在需要这种治疗的患者中治疗胰腺癌的方法,所述方法包括向所述患者施用有效量的式I或Ia的化合物,或其药学上可接受的盐。
另外,本发明提供了式I或Ia的化合物或其药学上可接受的盐在治疗中的用途,特别是用于胰腺癌的治疗。此外,本发明提供了用于治疗胰腺癌的式I或Ia的化合物或其药学上可接受的盐。在另一个实施方案中,本发明提供了本发明的化合物或其药学上可接受的盐在制备用于治疗胰腺癌的药物中的用途。
本发明进一步提供了一种药物组合物,其包含本发明的化合物或其药学上可接受的盐,以及一种或多种药学上可接受的载体、稀释剂或赋形剂。在另一个实施方案中,所述组合物还包含一种或多种其它治疗剂。本发明进一步提供了制备药物组合物的方法,所述方法包括将式I或Ia的化合物或其药学上可接受的盐与一种或多种药学上可接受的载体、稀释剂或赋形剂混合。本发明还包括用于合成式I和Ia的化合物的新的中间体和方法。
如本文所用,术语“治疗”包括抑制、减慢、停止或逆转现有症状或疾病的进展或严重程度。
如本文所用,术语“有效量”指本发明的化合物或其药学上可接受的盐的量或剂量,在对患者进行单剂量或多剂量给药后,其在诊断或治疗的患者中提供所需的效果。
本领域技术人员可以通过使用已知技术并通过观察在类似情况下获得的结果来容易地确定有效量。在确定患者的有效量时,要考虑许多因素,包括但不限于:患者的种类;患者的体型、年龄和总体健康状况;所涉及的特定疾病或病症;疾病或病症的程度或受累程度或严重程度;个体患者的反应;施用的特定化合物;给药方式;给药制剂的生物利用度特征;选择的剂量方案;伴随药物的使用;以及其它相关情况。
本发明的化合物通常在宽的剂量范围内有效。例如,每日剂量通常在约0.1至约50mg/kg体重的范围内。在某些情况下,低于上述范围下限的剂量水平可能都超过足够量,而在其它情况下,还可采用较大剂量并具有可接受的副作用,因此上述剂量范围无意以任何方式限制本发明的范围。应当理解,实际给药的化合物的量将由医生根据相关情况来决定,包括要治疗的病症、选择的给药途径、实际给药的化合物、患者的年龄、体重、反应以及患者症状的严重程度。
本发明的化合物优选配制成药物组合物,其通过使所述化合物具有生物利用度的任何途径给药,包括口服、静脉内和透皮途径。最优选地,所述组合物通过口服给药。这样的药物组合物及其制备方法是本领域众所周知的(参见,例如,Remington:The Science andPractice of Pharmacy,L.V.Allen编辑,第22版,Pharmaceutical Press,2012)。
可以理解,式I的化合物可以立体异构体的形式存在。本发明的实施方案包括所有对映异构体、非对映异构体及其混合物。式I的化合物的特定对映异构体由式Ia的化合物表示:
其中R和R1如上文所定义。
技术人员还将理解,所有手性中心的Cahn-Ingold-Prelog(R)或(S)指定将根据特定化合物的取代方式而变化。单一对映异构体或非对映异构体可以从手性试剂开始或通过立体选择性或立体特异性合成技术来制备。替代地,可以通过标准手性色谱法或结晶技术在合成本发明化合物的过程中的任何方便的时候从混合物中分离单一对映异构体或非对映异构体。参见,例如,J.Jacques,等人,"Enantiomers,Racemates,and Resolutions",John Wiley和Sons,Inc.,1981,及E.L.Eliel和S.H.Wilen,”Stereochemistry of OrganicCompounds”,Wiley-Interscience,1994。本发明化合物的单一对映体是本发明的一个优选实施方案。
本发明化合物的药学上可接受的盐可以通过例如在适当的溶剂中在本领域众所周知的标准条件下,使本发明化合物的合适的游离碱与合适的药学上可接受的酸反应而形成。这种盐的形成是本领域众所周知的和所理解的。参见示例,Gould,P.L.,“Saltselection for basic drugs,”International Journal of Pharmaceutics,33:201-217(1986);Bastin,R.J.,等人“Salt Selection and Optimization Procedures forPharmaceutical New Chemical Entities,”Organic Process Research andDevelopment,4:427-435(2000);和Berge,S.M.,等人,“Pharmaceutical Salts,”Journalof Pharmaceutical Sciences,66:1-19,(1977)。
PERK酶活性的体外抑制(分离的)
获得了重组人类EIF2AK2(PKR)催化域(氨基酸252-551)、EIF2AK3(PERK)催化域(氨基酸536–1116)、GFP-eIF2α底物和铽标记的磷酸化eIF2α抗体(Invitrogen,Carlsbad,CA)。从大肠杆菌中表达并纯化HIS-SUMO-GCN2催化域(氨基酸584–1019)。在抑制剂存在或不存在的情况下,在包含50mM pH 7.5的HEPES、10mM MgCl2、1.0mM EGTA和0.01% Brij-35的反应缓冲液和100–200nM GFP-eIF2α底物中进行TR-FRET激酶测定。PKR测定包括14ng/mL酶和2.5μM ATP(Km,app~2.5μM),PERK测定包括62.5ng/mL酶和1.5μM ATP(Km,app~1.5uM),以及GCN2测定包括3nM酶和90μM ATP(Km,app~200uM)。添加测试化合物,通过添加酶引发反应,并在室温下温育45分钟。通过添加EDTA至终浓度10mM终止反应,添加终浓度为2nM的铽标记的磷酸化eIF2α抗体,并温育90分钟。在多标记读数器中监控产生的荧光(PerkinElmer,Waltham,MA)。测定TR-FRET比率并使用所示4参数非线性对数方程得出IC50值:Y=(A+((B-A)/(1+((C/x)^D)))),其中Y=%特异性抑制,A=曲线的最低点,B=曲线的最高点,C=IC50绝对值(造成50%抑制的浓度),D=坡度。
基本按照如上所述测试实施例1、5和9的化合物,所得IC50值如表1所示。这些数据证明实施例1、5和9的化合物在体外抑制分离的PERK酶活性。
表1
PERK酶活性的体外抑制(全细胞)
在384孔板中以每孔10000细胞接种表达GFP-eIF2α的Seed GripTiteTM 293细胞(Invitrogen,Carlsbad,CA),并使其附着过夜。用测试化合物预处理细胞1小时。加入衣霉素(1μM)诱导PERK活性,并将板在37℃下温育2小时。除去培养基,将细胞在缓冲液中裂解,缓冲液由20mM Tris-HCl,pH 7.5、150mM NaCl、5mM EDTA、1% NP-40、5mM NaF、蛋白酶抑制剂(Sigma,St.Louis,MO)、磷酸酶抑制剂(Sigma,St.Louis,MO)和2nM铽标记的抗磷酸化eIF2抗体(Invitrogen,Carlsbad,CA)组成。在黑暗中于室温下温育细胞裂解液2小时并用多标记读数器(PerkinElmer,Waltham,MA)监控产生的荧光。测定TR-FRET比率并从拟合抑制曲线中获得IC50值,使用未诱导(100%抑制)和诱导(0%抑制)孔作为对照。
基本按照如上所述测试实施例1、5和9的化合物,所得IC50值如表2所示。这些数据表明,实施例1、5和9的化合物在体外抑制全细胞PERK酶活性。
表2
胰腺癌的体内抑制(小鼠异种移植模型)
在雌性无胸腺裸鼠(Harlan Laboratories)右侧腹中皮下植入5x106 BxPC-3细胞,其中含有基质胶,并用卡尺监控肿瘤的生长。当肿瘤达到~250mm3时开始用化合物给药,并每天通过口服管饲法(每组8只动物)连续28天每天两次对小鼠给药。在10%阿拉伯胶中配制化合物,其含有在pH 2,25mM NaPO4缓冲液中的0.05%消泡剂或20%Captisol,分别用于实施例5和9的化合物。对对照动物只用阿拉伯胶媒介物处理。使用公式估算肿瘤体积:l×w2×(π/6),其中l是较大的测量直径,w是较小的垂直直径。使用公式计算百分比增量(delta)T/C:100×[(T-T0)/(C-C0)]并用公式计算回归百分比:100×[(T-T0)/T0],其中T和C分别是治疗组和对照组的平均肿瘤体积。T0和C0是相应的基线平均肿瘤体积。使用以下公式将T/C百分比增量转换为肿瘤生长抑制百分比增量(TGI),100-T/C百分比增量。为了进行统计分析,将肿瘤体积数据转换为log10标度,以使时间和治疗组的方差相同。使用SAS软件包(Version 9.3)中的MIXED程序,根据时间和处理方法,通过双向重复测量方差分析(空间功率相关模型)来分析log10体数据。在每个时间点将治疗组与对照组进行比较。
基本按照如上所述测试实施例1、5和9的化合物,将肿瘤生长抑制值分别列于表3和表4中。这些数据证明实施例5和9的化合物在体内抑制胰腺肿瘤的生长。
表3
a)肿瘤平均几何体积的标准误差
b)使用100x[(T-T0)/(C-C0)]计算,其中T和C分别是治疗组和对照组的平均肿瘤体积,T0和C0是相应的基线平均肿瘤体积。
c)TGI是肿瘤生长抑制值,用100-%T/C计算
d)随机分配和治疗开始日
*显著,p<0.05
表4
a)肿瘤平均几何体积的标准误差
b)使用100x[(T-T0)/(C-C0)]计算,其中T和C分别是治疗组和对照组的平均肿瘤体积,T0和C0是相应的基线平均肿瘤体积。
c)TGI是肿瘤生长抑制值,用100-%T/C计算
d)随机分配和治疗开始日
*显著,p<0.05
本发明的化合物或其盐可以通过本领域普通技术人员已知的多种方法来制备,其中一些在以下方案、制备方法和实施例中说明。本领域普通技术人员认识到,可以将所描述的每种路线的具体合成步骤以不同的方式,或与来自不同方案的步骤结合,以制备本发明的化合物或其盐。可以通过本领域所熟知的常规方法回收以下方案中每个步骤的产物,包括萃取、蒸发、沉淀、色谱、过滤、研磨和结晶。在以下方案中,除非另有说明,所有取代基均如先前所定义。试剂和起始原料对于本领域普通技术人员来说是容易获得的。在不限制本发明的范围的情况下,提供以下方案、制备方法和实施例以进一步说明本发明。另外,本领域普通技术人员应理解,式Ia的化合物可通过使用具有相应立体化学构型的起始原料来制备,所述起始原料可由本领域技术人员制备。例如,以下方案利用具有最终对应于式Ia的构型的原料。
通常,式I的化合物可以由式III的化合物制备(方案1)。更具体地,在合适的胺碱如N,N-二异丙基乙胺或三甲基胺的存在下,式III的化合物与式II的化合物和合适的偶联剂如HATU(1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐)反应。式I的化合物可通过手性色谱法分离成其异构体。
相应地,式Ia的化合物可以由式IIa的化合物制备。更具体地,在合适的胺碱如N,N-二异丙基乙胺或三甲基胺的存在下,式III的化合物与式IIa的化合物和合适的偶联剂如HATU(1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐)反应。式IIa的化合物可由式II的化合物和脂肪分解酶(如脂肪酶PS Amano SD)制备。有关此光学拆分技术的更多信息,请参见Mendiola,J.等人,Org.Process Res.Dev.2012,16,1312-1316。
方案1
通常,式III的化合物可以由式IV的化合物制备。式III的化合物可通过将式R-Br的化合物在碱(如K2CO3)和钯催化剂(如Pd(dppf)2Cl2)的存在下,用3-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺处理而获得。
方案2
式R-Br的化合物,由式VI或VII的化合物表示,其可通过化学领域已知的方法和在以下制备方法和实施例中描述的方法制备。
制备1
4-氯-7-甲基-吡咯并[2,3-d]嘧啶的合成
在15℃下向4-氯-7H-吡咯并[2,3-d]嘧啶(200g,1.29mol)的N-甲基-2-吡咯烷酮(1.20L)溶液中加入Cs2CO3(845g,2.60mol)。温热到23℃,在30分钟内滴加MeI(202g,1.43mol)并搅拌4小时。之后,倒入冰水混合物(2.00L)中并搅拌30分钟。过滤,然后在H2O(1.00L)中将材料浆化。过滤并干燥,得到标题化合物(180g,81%)。ES/MS m/z(35Cl)168.0(M+H)。
制备2
5-溴-4-氯-7-甲基-吡咯并[2,3-d]嘧啶的合成
在15℃下,向4-氯-7-甲基-吡咯并[2,3-d]嘧啶(355g,2.12mol)的二氯甲烷(3.19L)溶液中,在20分钟内分批加入N-溴琥珀酰亚胺(418g,2.35mol),然后在23℃下搅拌3小时。然后过滤,用水(5.32L)洗涤并干燥,得到作为白色固体的标题产物(448g,86%)。ES/MS m/z(35Cl,79Br)245.9(M+H)。
制备3
5-溴-7-甲基-吡咯并[2,3-d]嘧啶-4-胺的合成
在120℃下,于HastelloyTM压力容器中,搅拌5-溴-4-氯-7-甲基-吡咯并[2,3-d]嘧啶(454g 1.84mol)在氨(30%水溶液,3.63L)中的悬浮液18小时。冷却至20℃,过滤,用水(1.80L)和甲醇(900mL)洗涤,然后干燥,得到作为白色固体的标题化合物(351g,82%)。ES/MS m/z(79Br)227.2(M+H)。
制备4
3-氨基-6-溴-吡嗪-2-甲酸的合成
在0℃下,向N-溴琥珀酰亚胺(61.2g,377.3mmol)和二甲基甲酰胺(236.3g,3.2mole)溶液中加入3-氨基吡嗪-2-甲酸(50.0g,369.4mmol)。在室温下放置1小时后,形成橙色固体。用乙酸乙酯(500mL)洗涤固体残留物并丢弃。用硫酸钠干燥有机相,过滤然后减压浓缩,获得作为白色固体的标题产物(32.0g,146.7mmol,41%)。ES/MS m/z(79Br/81Br)217.1/219.0(M+H)。
制备5
3-氨基-6-溴-N-甲基-吡嗪-2-甲酰胺的合成
在23℃下,用盐酸甲胺(79.7g,1.18mol)和N,N-二异丙基乙胺(445g,3.44mol)处理3-氨基-6-溴-吡嗪-2-甲酸(214g,983mmol)的二甲基甲酰胺(1.07L)溶液。30分钟内向所得悬浮液中加入1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐(449g,1.18mol)。30分钟后,在2小时内加入H2O(4.29L)。在23℃下搅拌30分钟,然后在10℃下搅拌1小时。过滤,用水(2x428mL)洗涤固体,然后干燥,获得标题化合物(227g,82%)。ES/MS m/z(79Br)231.0(M+H)。
制备6
2-氨基-5-溴-N-异丙基-吡啶-3-甲酰胺的合成
在12℃下,向2-氨基-5-溴-吡啶-3-甲酸(120g,0.553mol)的四氢呋喃(1.2L)悬浮液中加入丙-2-胺(42.5g,0.719mol)、1-乙基-3-(3-二甲基氨基丙基)碳二亚胺(127g,0.664mol)和羟基苯并三唑(89.7g,0.660mol)。在23℃下搅拌混合物过夜。加入乙酸乙酯(250mL)和饱和NaHCO3水溶液(250mL),分离各相,并用乙酸乙酯(2x150mL)萃取水溶液层。用水(300mL)和饱和NaCl水溶液(300mL)洗涤合并的有机相,减压浓缩获得标题化合物(125g,88%)。ES/MS m/z(79Br)258.0(M+H)。
制备7
(2R)-2-(3,5-二氟苯基)-2-羟基-乙酸的分离。
在使用之前,通过混合200g硅藻土和200g脂肪酶PS Amano SD,以在硅藻土中支撑(support)脂肪酶PS Amano(参见Mendiola,J.等人,Org.Process Res.Dev.2012,16,1312-1316)。加入水以覆盖固体,然后将混合物混合。在4毫巴,40℃的烘箱中处理16小时以去除H2O。通过卡尔.费歇尔(Karl Fischer)滴定法测定水,以检查H2O是否低于1%。
向外消旋2-(3,5-二氟苯基)-2-羟基乙酸(125g,664mmol)的甲基叔丁基醚(2.50L)悬浮液中加入支撑的脂肪酶PS amano SD(250g)和乙酸乙烯酯(312mL,3.36mol),然后在26℃下搅拌混合物72小时。然后过滤,用甲基叔丁基醚冲洗固体(1.50L),减压浓缩合并的滤液。在23℃下将残留物在二氯甲烷(160mL)中浆化4小时。过滤,用石油醚(150mL)洗涤固体,然后干燥,获得标题化合物(47.0g,36%)。1H NMR(d6-DMSO)δ5.11(s,1H),6.20(bs,1H),7.11-7.21(M,3H),12.8(bs,1H)。绝对构型通过振动圆二色性确定(参见FreedmanT.B等人,Chirality,2003Nov.,15(9),743-758)。手性HPLC:Rt=7.39分钟(UV);柱:AD 4.6x150mm 5μm;5%的EtOH的正己烷溶液(0.05%TFA)等梯度;流速:1.5mL/min,ee>98%。
制备8
(2R)-2-(3-氟苯基)-2-羟基-乙酸的分离。
使用前,通过混合100g硅藻土和100g脂肪酶PS Amano SD,以在硅藻土中支撑脂肪酶PS Amano SD(参见Mendiola,J.等人,Org.Process Res.Dev.2012,16,1312-1316)。加入水以覆盖固体,然后将混合物混合。在4毫巴,40℃的烘箱中处理16小时以去除H2O。通过卡尔.费歇尔滴定法测定水,以检查H2O是否低于1%。
向外消旋2-(3-氟苯基)-2-羟基乙酸(96g,560mmol)的甲基叔丁基醚(2.00L)悬浮液中,加入支撑的脂肪酶PS amano SD(200g)和乙酸乙烯酯(269mL,2.90mol),然后在26℃下搅拌混合物90小时。然后过滤,用甲基叔丁基醚(1.50L)冲洗固体,减压浓缩合并的滤液。在23℃下将残留物在二氯甲烷(160mL)中浆化4小时。过滤,用石油醚(150mL)洗涤固体,然后干燥,获得标题化合物(31.0g,32%)。1H NMR(d6-DMSO)δ5.07(s,1H),6.17(bs,1H),7.12(M,1H),7.23(M,1H),7.39(M,1H),12.8(bs,1H)。[α]D 20=-119°(C=2.83,丙酮)。手性HPLC:Rt=10.22min(UV);柱:AD 4.6x150 mm 5μm;5%的EtOH的正己烷溶液(0.05%TFA)等梯度;流速:1.5mL/min,ee>98%。
制备9
3-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺的合成
在95℃下加热三环己基膦(59.85g,213mmol)的1,4-二噁烷(2.98L)悬浮液10分钟,直到获得溶液。然后,加入4-溴-3-甲基苯胺(752g,2.67mol),双(频哪醇合)二硼(745.17g,2.93mol),乙酸钾(524g,5.34mol)和乙酸钯(II)(23.96g,107mmol),然后在95℃下继续加热混合物4小时。然后,冷却至23℃,用甲基叔丁基醚(2.5L)稀释,通过硅藻土过滤,然后用甲基叔丁基醚(1L)冲洗固体。将滤液合并,用水(1.5L)和饱和NaCl水溶液(1.2L)洗涤,然后减压浓缩获得标题化合物(593g,95%)。为了获得分析样品,在40℃下用己烷(1.6mL/g)浆化2小时,然后冷却至23℃,过滤然后用己烷(2x0.5 mL/g)洗涤固体。ES/MS m/z 234.1(M+H)。
制备10
2-氨基-5-(4-氨基-2-甲基-苯基)-N-异丙基-吡啶-3-甲酰胺的合成
向2-氨基-5-溴-N-异丙基-吡啶-3-甲酰胺(74.0g,0.287mol)的二噁烷(888mL)和H2O(296mL)的溶液中加入3-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(93.6g,0.401mol)、K2CO3(119g,0.860mol)和Pd(dppf)2Cl2(10.6g,140mmol),然后将混合物在55℃下加热过夜。冷却至23℃,加入乙酸乙酯(150mL),通过硅藻土过滤所得悬浮液,然后用乙酸乙酯(50mL)冲洗固体。用水(30mL)和饱和NaCl水溶液(300mL)洗涤合并的滤液,然后减压浓缩获得标题化合物(78.0g,96%)。ES/MS m/z 285.1(M+H)。
制备11
3-氨基-6-(4-氨基-2-甲基苯基)-N-甲基吡嗪-2-甲酰胺的合成
向3-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(122g,450mmol)的1,4-二噁烷(3.00L)溶液中加入3-氨基-6-溴-N-甲基吡嗪-2-甲酰胺(99.1g,429mmol)、Na2CO3(2M于H2O中,500mL,1.00mol)和1,1'-双(二苯基膦基)二茂铁)二氯化钯(II)(19g,22.8mmol),然后将混合物在85℃下加热32小时。冷却至30℃,加入乙酸乙酯(4.00L),通过硅胶垫过滤,并用乙酸乙酯(3x1.00 L)冲洗固体。用水(2x1.50 L)洗涤合并的滤液,然后减压浓缩。用色谱法纯化残留物(洗脱剂:石油醚/乙酸乙酯5:1至1:1)得到黄色固体的标题化合物(80g,72%)。ES/MS m/z 258.1(M+H)。
制备12
5-(4-氨基-2-甲基-苯基)-7-甲基-吡咯并[2,3-d]嘧啶-4-胺的合成
在23℃下,向5-溴-7-甲基-吡咯并[2,3-d]嘧啶-4-胺(21.4g,94.3mmol)和3-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(28.6g,123mmol)的2-甲基-四氢呋喃(214mL)悬浮液中,加入乙酸钯(II)(635mg,2.83mmol)、cataCXium ATM(2.03g,5.65mmol)和饱和NaHCO3水溶液(186mL,188mmol),然后在100℃,密封管中搅拌混合物3小时。冷却至23℃,通过硅藻土垫过滤,并用H2O(50mL)和乙酸乙酯(100mL)冲洗固体。分离有机层,用饱和NaCl水溶液(50mL)洗涤,然后减压浓缩。用色谱法纯化残留物(洗脱剂:己烷/丙酮0-100%)获得黄色固体的标题化合物(12.1g,51%)。ES/MS m/z 254.1(M+H)。
实施例1
2-氨基-5-[4-[[(2R)-2-(3,5-二氟苯基)-2-羟基-乙酰基]氨基]-2-甲基-苯基]-N-异丙基-吡啶-3-甲酰胺的合成
在0℃下,对(2R)-2-(3,5-二氟苯基)-2-羟基乙酸(29.0g,0.154mol)、2-氨基-5-(4-氨基-2-甲基-苯基)-N-异丙基-吡啶-3-甲酰胺(43.83g,0.154mol)和N,N-二异丙基乙胺(39.8g,0.308mol)在四氢呋喃(960mL)中的混合物用(1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐)(87.9g,0.231mol)处理30分钟,然后加热至20℃并搅拌2小时。加入乙酸乙酯(50mL),然后过滤混合物。减压浓缩滤液,并通过色谱法纯化残留物(洗脱剂:2:1石油醚/乙酸乙酯),然后通过超临界流体色谱纯化,SFC(柱:IC 30x250mm 5μm(Daicel);MeOH/CO2=30:70等梯度;流速:80g/min;背压:100巴;柱温:40℃)以得到作为白色固体的标题化合物(27.5g,39%)。ES/MS m/z 455.2(M+H)。
实施例2
2-氨基-5-[4-[[2-(3,5-二氟苯基)-2-羟基-乙酰基]氨基]-2-甲基-苯基]-N-异丙基-吡啶-3-甲酰胺的合成
向2-(3,5-二氟苯基)-2-羟基-乙酸(793mg,4.2mmol)、(1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐)(1.7g,4.6mmol)、N,N-二异丙基乙胺(909.5mg,7.0mmol)的四氢呋喃溶液(7.9g,93.6mol)中加入2-氨基-5-(4-氨基-2-甲基-苯基)-N-异丙基-吡啶-3-甲酰胺(1000.5mg,3.5mmol)。在室温下放置2小时后,加入3mL乙酸乙酯并搅拌反应10分钟。过滤掉固体然后在减压下减小有机相体积。用饱和NaHCO3水溶液(10mL)洗涤残留物,然后用DCM(2x10mL)萃取。用硫酸钠干燥有机相,过滤并减压浓缩。
用HPLC纯化残留物,Rt(保留时间)=2.036分钟(UV),LC柱:XTerra MS C18(2.1X50mm,3.5um;H2O:乙腈;梯度:5%B下为0.25分钟;5%B至100%B下为3分钟;100%B下停留0.25分钟;柱温:50℃;流速1.1mL/min,以获得标题化合物,其为白色固体形式的异构体1和2的混合物(0.97g,60%)。ES/MS(M/z):455.4(M+H)。
实施例3和4
将2-氨基-5-[4-[[2-(3,5-二氟苯基)-2-羟基-乙酰基]氨基]-2-甲基-苯基]-N-异丙基-吡啶-3-甲酰胺分离为异构体1和异构体2。
使用OD-H(4.6x100mm,5um),20% MeOH-DMEA(0.2%)于CO2中,2.5mL/min,100巴出口压力,35℃的温度分离异构体1和异构体2的混合物,获得单独的异构体1和异构体2,为白色固体。
实施例3:2-氨基-5-[4-[[2-(3,5-二氟苯基)-2-羟基-乙酰基]氨基]-2-甲基-苯基]-N-异丙基-吡啶-3-甲酰胺异构体1。Rt(保留时间)=1.131分钟(430mg,ee>98%),ES/MS m/z 455.4(M+H)。
实施例4:2-氨基-5-[4-[[2-(3,5-二氟苯基)-2-羟基-乙酰基]氨基]-2-甲基-苯基]-N-异丙基-吡啶-3-甲酰胺异构体2。Rt(保留时间)=1.823分钟(404mg,ee>98%),ES/MS m/z 455.4(M+H)。
实施例5
3-氨基-6-[4-[[(2R)-2-(3,5-二氟苯基)-2-羟基-乙酰基]氨基]-2-甲基-苯基]-N-甲基-吡嗪-2-甲酰胺的合成
向3-氨基-6-(4-氨基-2-甲基苯基)-N-甲基吡嗪-2-甲酰胺(18.0g,70.0mmol)和(2R)-2-(3,5-二氟苯基)-2-羟基-乙酸(13.2g,70.0mmol)的四氢呋喃(90.0mL)溶液中加入N,N-(15.3mL 87.5mmol)和1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐(33.2g,87.5mmol),然后在23℃下搅拌混合物5小时。然后减压浓缩混合物,将残留物在乙酸乙酯(100mL)中浆化15分钟,过滤,然后用乙酸乙酯(2x25mL)冲洗固体。减压浓缩合并的滤液,然后用色谱法纯化残留物(洗脱剂:己烷/丙酮2:1,然后己烷/乙醇4:1)。将原料溶解于(115mL)甲醇中,添加硅硫醇树脂(0.4g/g),然后在23℃下搅拌悬浮液8小时。然后过滤,用甲醇(2x12mL)冲洗固体。减压浓缩合并的滤液。用SFC纯化(柱:IC 4.6x100mm 5μm;35%甲醇(0.2% N,N-二甲基乙胺)于CO2中,等梯度;流速:2.5mL/min;背压:100巴;柱温:40℃)以获得标题化合物(19.7g,62%)。ES/MS m/z428.1(M+H)。
实施例6
3-氨基-6-[4-[[2-(3,5-二氟苯基)-2-羟基-乙酰基]氨基]-2-甲基-苯基]-N-甲基-吡嗪-2-甲酰胺的合成
向2-(3,5-二氟苯基)-2-羟基-乙酸(701.9mg,3.4mmol),(1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐)(1.7g,4.6mmol),N,N-二异丙基乙胺(803.2mg,6.3mmol)的四氢呋喃(7.9g,93.6mol)溶液中加入3-氨基-6-(4-氨基-2-甲基-苯基)-N-甲基-吡嗪-2-甲酰胺(800.0mg,3.2mmol)。在室温下放置2小时后,加入3mL乙酸乙酯,然后搅拌反应10分钟。过滤掉固体然后减小有机相体积。用饱和NaHCO3水溶液(10mL)冲洗残留物,然后用二氯甲烷(2x10mL)萃取。用硫酸钠干燥有机相,过滤并减压浓缩。用硅胶快速色谱纯化残留物,用乙酸乙酯:己烷(30:70)洗脱以获得标题化合物,其为棕色固体形式的异构体1和异构体2的混合物(0.72g,1.6mmol)。ES/MS(M/z):428.3(M+H)。
实施例7和8
将3-氨基-6-[4-[[2-(3,5-二氟苯基)-2-羟基-乙酰基]氨基]-2-甲基-苯基]-N-甲基-吡嗪-2-甲酰胺分离为异构体1和异构体2。
用OD(4.6x50mm,5um),20%MeOH-DMEA(0.2%)于CO2中,5mL/min,100巴出口压力,35℃的温度分离异构体1和异构体2的混合物,获得单独的异构体1和异构体2。
实施例7.3-氨基-6-[4-[[2-(3,5-二氟苯基)-2-羟基-乙酰基]氨基]-2-甲基-苯基]-N-甲基-吡嗪-2-甲酰胺异构体1。Rt(保留时间)=1.610分钟(258mg,ee>98%),ES/MSm/z 428.3(M+H)。
实施例8.3-氨基-6-[4-[[2-(3,5-二氟苯基)-2-羟基-乙酰基]氨基]-2-甲基-苯基]-N-甲基-吡嗪-2-甲酰胺异构体2。Rt(保留时间)=2.410分钟(278mg,ee>98%),ES/MSm/z 428.3(M+H)。
实施例9
(2R)-N-[4-(4-氨基-7-甲基-吡咯并[2,3-d]嘧啶-5-基)-3-甲基-苯基]-2-(3-氟苯基)-2-羟基-乙酰胺的合成
在23℃下,对5-(4-氨基-2-甲基-苯基)-7-甲基-吡咯并[2,3-d]嘧啶-4-胺(15.5g,44.1mmol)和(2R)-2-(3-氟苯基)-2-羟基-乙酸(8.25g,48.5mmol)的四氢呋喃(56mL)溶液用N,N-二异丙基乙胺(9.22mL,52.9mmol)和1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐(20.1g,52.9mmol)处理3.5小时。然后减压浓缩混合物,在乙酸乙酯(100mL)中浆化15分钟。过滤,用乙酸乙酯(2x15mL)冲洗固体,减压浓缩合并的滤液。通过色谱法纯化残留物(洗脱剂:二氯甲烷/甲醇0-10%),然后用SFC纯化(柱尺寸:5um,2x25cm;固定相类型:2-乙基吡啶;流动相类型:CO2(A)/甲醇-N,N-二甲基乙胺(0.2%)(B);流动相组成(即A/B比例):等梯度72/25A/B;流速:65mL/min;负载:70mg/4.35min)以获得标题化合物(11.7g,65%)。ES/MS m/z406.1(M+H)。
Claims (12)
1.一种具有下式的化合物或其药学上可接受的盐:
其中
R选自
X为CH或N;
R1为氢或氟;且
R2为C1至C3烷基。
2.权利要求1的化合物或其药学上可接受的盐,所述化合物具有下式:
其中
R选自
X为CH或N;
R1为氢或氟;且
R2为C1至C3烷基。
3.权利要求1或2的化合物或盐,其中R为
4.权利要求1或2的化合物或盐,其中
X为CH或N;
R1为氢或氟;且
R2为甲基或异丙基。
5.权利要求1或2的化合物或盐,其中R为
6.权利要求1或2的化合物化合物或其药学上可接受的盐,所述化合物为3-氨基-6-[4-[[(2R)-2-(3,5-二氟苯基)-2-羟基-乙酰基]氨基]-2-甲基-苯基]-N-甲基-吡嗪-2-甲酰胺,其可用下式表示:
7.权利要求1或2的化合物或其药学上可接受的盐,所述化合物为2-氨基-5-[4-[[(2R)-2-(3,5-二氟苯基)-2-羟基-乙酰基]氨基]-2-甲基-苯基]-N-异丙基-吡啶-3-甲酰胺,其可用下式表示:
8.权利要求1或2的化合物或其药学上可接受的盐,所述化合物为(2R)-N-[4-(4-氨基-7-甲基-吡咯并[2,3-d]嘧啶-5-基)-3-甲基-苯基]-2-(3-氟苯基)-2-羟基-乙酰胺,其可用下式表示:
9.一种药物组合物,其包含根据权利要求1-8中任一项的化合物或其药学上可接受的盐,以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
10.一种在患者中治疗胰腺癌的方法,其包括对有需要的患者施用有效量的权利要求1-8中任一项的化合物或其药学上可接受的盐。
11.根据权利要求1-8中任一项的化合物或其药学上可接受的盐,其用于治疗。
12.根据权利要求1-8中任一项的化合物或其药学上可接受的盐,其用于治疗胰腺癌。
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