CN111386264A - 用于治疗t-细胞急性淋巴细胞白血病的化合物、组合物和方法 - Google Patents
用于治疗t-细胞急性淋巴细胞白血病的化合物、组合物和方法 Download PDFInfo
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- CN111386264A CN111386264A CN201880057217.2A CN201880057217A CN111386264A CN 111386264 A CN111386264 A CN 111386264A CN 201880057217 A CN201880057217 A CN 201880057217A CN 111386264 A CN111386264 A CN 111386264A
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Abstract
在一个方面,本公开提供了化合物(II)、组合物和向有此需要的患者施用所述化合物和组合物的方法。在另一个方面,本发明涉及用于治疗癌症例如淋巴白血病的化合物和组合物。本公开进一步提供了抑制两种磷酸肌醇3‑激酶(PI3K)同工型γ和δ的化合物、包含所述化合物的药物组合物和使用所述化合物和药物组合物治疗、改善和/或预防非霍奇金淋巴瘤的方法。
Description
领域
在一个方面,本公开提供了化合物、组合物和将所述化合物和组合物施用于有此需要的患者的方法。在另一个方面,本公开涉及用于治疗癌症、例如淋巴细胞白血病或淋巴瘤的化合物和组合物。本公开还提供了抑制两种磷酸肌醇3-激酶(PI3K)同工型γ和δ的化合物、包含此类化合物的药物组合物和使用所述化合物和/或药物组合物来治疗、改善和/或预防因PI3K过度活性导致的疾病例如非霍奇金淋巴瘤的方法。
背景
PI3K信号传导途径是人类癌症中突变程度最高的系统之一。PI3K信号传导也是人类许多其它疾病的关键因素。PI3K信号传导涉及多种疾病,包括变应性接触性皮炎、类风湿性关节炎、骨关节炎、炎性肠疾病、慢性阻塞性肺病症、银屑病、多发性硬化、哮喘、糖尿病并发症相关的障碍和心血管系统的炎症并发症例如急性冠状动脉综合征。PI3K/Akt信号传导途径促进多种类型肿瘤的生长、增殖和存活。
PI3K作为杂二聚体复合物形式存在,包括p110催化(分类为α、β、γ或δ)和p50、p55、p85或p101调节亚单位。PI3K可以分为2个亚类,即Ia和Ib,由活化机制定义。
Ia类PI3K包括p110α、p110β和p110δ催化结构域,每个催化结构域均与调节蛋白结合,并在包括TCR在内的几种细胞表面受体参与时被直接或间接活化。
Ib类PI3K仅由与p101衔接子分子结合的p110γ组成,并且主要受G蛋白偶联受体刺激。
该途径的初始激活、例如通过生长因子与细胞表面受体的相互作用导致质膜内层所含特定脂质的磷酸化,从而产生第二种信使磷脂酰肌醇(3,4,5)-三磷酸(PIP3)。然后,PIP3激活关键的下游效应物例如PDK-1和Akt,后者对于促进与I类PI3K有关的生物活性至关重要。
一旦激活,则Akt会通过一定范围的胞内蛋白的磷酸化来介导下游反应—包括细胞存活、生长、增殖、迁移和血管生成。该途径存在于所有高等真核生物细胞中,并且高度保守。
PTEN为非冗余的质膜磷酸酶,其负责通过限制响应于这些脂质激酶的激活而产生的PIP3的水平来抵消PI3K的潜在促癌活性。PTEN肿瘤抑制基因的突变在多种类型的人类癌症中很常见。这些突变导致PI3K/Akt信号转导过度活跃和对化疗剂的耐药性。据报道,在约40%的原代T-ALL样品中观察到由于突变引起的PTEN功能丧失。这种相关性启示,PI3K/Akt信号传导途径的过度激活为这种血液恶性肿瘤的共同特征。
PTEN为通常抵消PI3K活性的促生存效应的肿瘤抑制基因,并且T-细胞先祖细胞中PTEN的功能丧失突变常与T-ALL相关。
在上述讨论的四个PI3K同工型中,两个同工型γ(γ)和δ(δ)足以在没有PTEN功能的存在下驱动T-细胞先祖细胞中的白血病生成。
I类PI3K的δ(δ)同工型特别涉及许多疾病和生物学过程。Ρ13K-δ(p110δ)主要在造血细胞,例如T-细胞、树突细胞、中性白细胞、肥大细胞、B-细胞和巨噬细胞中表达。Ρ13K-δ整体上牵涉哺乳动物免疫系统功能,例如T-细胞功能、B-细胞活化、肥大细胞活化、树突状细胞功能和中性白细胞活性。由于其在免疫系统功能中的重要作用,Ρ13K-δ也牵涉许多与不期望的免疫应答有关的疾病,例如过敏反应、炎症性疾病、炎症介导的血管生成、类风湿性关节炎和自身免疫病例如狼疮、哮喘、肺气肿和其它呼吸系统疾病。
Ρ13K-γ(p110γ)主要在造血细胞中表达,并且也牵涉炎症、先天性和适应性免疫应答、髓样细胞分化、免疫细胞运输和肥大细胞功能。ΡΙ3K-γ在白细胞信号传导中也起作用,并牵涉炎症、类风湿关节炎和自身免疫性疾病,例如狼疮。因此,有充分的证据表明I类PI3K同工型p110γ和p110δ具有相似的生物学作用,这可能部分取决于它们的联合激活。这通过如下观察结果得以证实:任一同工型的遗传缺失对胸腺中的整体T细胞发育的影响有限,而p110γ和p110δ二者的缺失导致T细胞发育的严重发育缺陷。
另外,已经证实,通过对PI3K-γ和PI3K-δ二者的遗传缺失和双重抑制,能够在动物模型中防止T-细胞急性淋巴细胞白血病(T-ALL)发生以及疾病进展和肿瘤细胞存活。
T-ALL为侵袭性血液恶性肿瘤,约占儿科的15%,并且约占成人ALL病例的25%。患者经常表现出高循环爆炸性计数(blast counts)和CNS浸润。尽管进行了强化治疗,但仍有25%的儿童和青少年以及50%的成年人无法使用传统疗法。令人遗憾地,患有原发性耐药性疾病或复发性T-ALL的患者预后不良。对于儿童而言,另外一个令人担忧的问题在于当前治疗方法的后期效果,包括永久性器官损伤、生殖功能障碍和第二种癌症。因此,迫切需要开发选择性靶向T-ALL中有助于肿瘤维持的关键途径、但与归一化疗相比毒性较小的药物。
PI3K-AKT信号传导途径是控制正常T-细胞发育(包括IL7和前-TCR信号传导)的多种存活和增殖因子的重要介体。PTEN缺陷小鼠中PI3K-AKT途径的异常激活将胸腺细胞转化为侵袭性T-细胞淋巴母细胞白血病。此外,约70%的人类T-ALL细胞系中存在PTEN的突变丢失和随后的PI3K-AKT信号传导途径的激活;值得注意的是,据报道,>40%的原发性T-ALL病例包含在PTEN/PI3K/Akt途径中的突变,由于控制该关键致癌枢纽的许多上游因素(即通过CK2和RAS),这一数字可能被低估。
PI3K抑制剂作为一个类别尚未在侵袭性淋巴瘤如弥漫性大B细胞淋巴瘤(DLBCL)和外周T细胞淋巴瘤(PTCL)中证明为具有富有希望的临床活性。即使对于已批准的滤泡性淋巴瘤适应症,PI3K抑制剂艾代拉里斯(idelalisib)和库潘尼西(copanlisib)也因原发性(所有患者中有40%完全没有反应)和获得性耐药(所有患者最终都会发生疾病进展)受到限制。在美国,PCTL每年影响7,000多名新患者。然而,PTCL患者的预后仍然很差,其中长期生存率低于15%。
需要开发治疗T-ALL和其它由PI3K过度活性引起的疾病的另外的PI3K抑制剂。特别地,需要用于治疗PTCL的PI3K抑制剂。
概述
在一个实施方案中,本公开提供了式(I)的化合物:
其中
A表示稠合的5-或6-元芳族或杂芳族基团;
X表示N或CY;
Y表示氢或卤素;
R1、R2、R3、R4和R5独立地表示氢、氘、C1-C6烷基、芳基、杂芳基、卤素、NO2或OCF3;
R6表示C1-C6烷基或C1-C6环烷基;
R7表示氢、烷基或卤素;或
R6和R7与R7所连接的N一起形成任选取代的5-或6-元环;
R8表示杂芳族基团(例如吡啶)或稠合系统(例如嘌呤);
Q表示直接键、羰基或亚烷基。
在一个实施方案中,本公开提供了式(II)的化合物
其中
X表示N、O或CY;
Y表示氢或卤素;
R1、R2、R3、R4和R5独立地表示氢、氘、C1-C6烷基、芳基、杂芳基、卤素、NO2或OCF3;
R6表示C1-C6烷基或C1-C6环烷基;
R7表示氢、烷基或卤素;或
R6和R7与R7所连接的N一起形成任选取代的5-或6-元环;
R8表示杂芳族基团(例如吡啶)或稠合系统(例如嘌呤);
R9、R10、R11和R12独立地表示氢、C1-C6烷基或卤素;
Q表示直接键、羰基或亚烷基。
本公开提供了式(IIa)或(IIb)的化合物
其中R1-R6和R9-R12如式(II)中所定义。在一些实施方案中,R1、R2、R3、R4和R5独立地为氢、氘、C1-C6烷基或卤素;R6为甲基、乙基或环丙基;R9为卤素或甲基;且R10、R11和R12各自为氢、C1-C6烷基或卤素。例如,在一些实施方案中,R1、R2、R3、R4和R5独立地为氢、甲基、F或氘;R9为Cl、F或甲基;且R10、R11和R12各自为氢。在一些实例中,键合至R6的手性碳具有式(IIa')或(IIb’)中所示的立体化学,即S-对映体。
在一个实施方案中,本公开提供了式(III)的化合物
其中
X表示N、O或CY;
Y表示氢或卤素;
R1、R2、R3、R4和R5独立地表示氢、氘、C1-C6烷基、芳基、杂芳基、卤素、NO2或OCF3;
R8表示杂芳族基团(例如吡啶)或稠合系统(例如嘌呤);
R9、R10、R11和R12独立地表示氢、C1-C6烷基或卤素;
Q表示直接键、羰基或亚烷基。
在一个实施方案中,本公开提供了式(IV)的化合物:
其中
X表示N、O或CY;
Y表示氢或卤素;
R1、R2、R3、R4和R5独立地表示氢、氘、C1-C6烷基、芳基、杂芳基、卤素、NO2或OCF3;
R9、R10、R11和R12独立地表示氢、C1-C6烷基或卤素;且
R13表示H、N或O;且
R14表示NH2或甲基。
在一个实施方案中,本公开提供了向有此需要的患者施用本文所述的化合物的方法。在另一个方面,本公开提供了通过向有此需要的患者或个体施用有效量的本文所述的化合物来治疗、预防或改善癌症例如淋巴白血病的方法。
在一个实施方案中,本公开涉及治疗、预防或改善淋巴恶性肿瘤的作用的方法,所述方法包括向有此需要的受试者施用有效量的本文所述的化合物。在一个方面,所述化合物为磷酸肌醇3-激酶-δ(PI3Kδ)抑制剂和磷酸肌醇3-激酶-γ(PI3Kγ)抑制剂。
在一个实施方案中,磷酸肌醇3-激酶-δ(PI3Kδ)抑制剂为本公开任意的式(I)、(II)、(III)、(IV)、表I、表II、表III、化合物实施例1-1至1-50、化合物实施例2-1至2-4和化合物实施例3-1至3-34的化合物。
本公开涉及治疗淋巴癌症、例如淋巴瘤和白血病的方法,所述方法包括向有此需要的受试者施用有效量的本文公开的化合物。在特定的实施方案中,所施用的化合物为式(I)、(II)、(IIa)、(IIa')、(IIb)或(IIb')的化合物。淋巴癌症可以是任意的淋巴瘤或白血病,例如本文公开的急性淋巴细胞白血病(ALL)、T细胞急性淋巴细胞白血病(T-ALL)、B细胞急性淋巴细胞白血病(B-ALL)、T细胞淋巴瘤、外周T细胞淋巴瘤(PTCL)、皮肤T细胞淋巴瘤(CTCL)、B细胞淋巴瘤、滤泡性淋巴瘤、皮肤B细胞淋巴瘤、慢性淋巴细胞白血病(CLL)等。在特定的方面,本公开提供了用于治疗PTCL的方法,所述方法包括向有此需要的受试者施用有效量的本文公开的化合物。在特定的实施方案中,所施用的化合物为式(I)、(II)、(IIa)、(IIa')、(IIb)或(IIb')的化合物。
附图简述
图1A显示PI3Kγ/δ活性的阻滞逆转了转录因子癌基因LMO2的过表达诱导的T-ALL的致癌标记(signature),转录因子癌基因LMO2的过表达最终通过允许PTEN中功能突变丢失和NOTCH1中功能突变增加的积累而最终导致T-ALL。为了比较,显示了阻断NOTCH1活性的γ分泌酶抑制剂化合物E(“CompE”)的作用。图1B比较了度维利塞(Duvelisib)与CAL-130对癌性小鼠的作用。
图2A-2B显示对PI3Kγ/δ双重抑制剂的生物学评价(CAL-130与IPI-145)。图2A显示向野生型小鼠(B6背景)施用单次口服剂量后CAL-130与IPI-145(如本文所述的实施例1-11)的血浆浓度。图2A显示在用CAL-130与IPI-145(如本文所述的实施例1-11)治疗之前和治疗4天之后即刻的具有T-ALL的Lck/Ptenfl/fl/Luc的生物发光图像。显示了药物治疗前/后的爆炸性计数。
图3A显示化合物DWL-PI3K-3和DWL-PI3K-4(分别如本文所述的实施例编号1-3和1-4)对鼠PTEN裸(null)/NOTCH 1活化的T-ALL细胞系的影响。图3B显示本公开的化合物DWL-PI3K-4(本文所述的实施例编号1-4)对同时缺乏p110γ和p110δ催化结构域的鼠PTEN裸(null)T-ALL细胞系的有限杀伤作用。
图4A显示本公开化合物的化学结构。图4B显示与CAL-130相比化合物DWL-PI3K-3和DWL-PI3K-4(分别如本文所述的实施例编号1-3和1-4)对T-ALL细胞系存活率的影响。图4C显示化合物DWL-PI3K-7(本文所述的实施例编号1-50)对缺乏p110γ和p110δ的T-ALL细胞系的有限杀伤作用。
图5A显示CAL-130的结构分析和修饰。
图5B描述PI3Kδ和PI3Kγ双重抑制剂的合成的实例。
图6显示NOD.Cg-Prkdcscid Il2rgtm1Wjl/Sz小鼠中植入的原代T-ALL异种移植物。通过流式细胞术分析人CD45来监测肿瘤的发育。该异种移植模型通过对原代人T-ALL细胞的药物反应进行详细分析,通过将它们植入NOD.Cg-Prkdcscid Il2rgtm1Wjl/Sz小鼠中,从而对小鼠肿瘤研究进行补充。
图7为比较用DWL-PI3K-1、DWL-PI3K-2、DWL-PI3K-3、DWL-PI3K-4和其它PI3K抑制剂处理T-ALL细胞系72小时后的结果(PI细胞死亡)的示意图。
图8为显示用DWL-PI3K-1、DWL-PI3K-2、DWL-PI3K-3、DWL-PI3K-4和CAL-130处理T-ALL细胞系72小时后的结果(PI阳性细胞)的示意图。
图9为显示用DWL-PI3K-5处理T-ALL细胞系后的结果(PI阳性细胞)的示意图。
图10为显示用DWL-PI3K-6处理T-ALL细胞系后的结果(PI阳性细胞)的示意图。
图11为显示用DWL-PI3K-7处理T-ALL细胞系后的结果(PI阳性细胞)的示意图。
图12显示用CAL130和不同浓度的DWL-PI3K-5处理LM0-2-007细胞的结果。
图13显示用CAL130和不同浓度的DWL-PI3K-6处理LM0-2-007细胞的结果。
图14显示用CAL130和不同浓度的DWL-PI3K-7处理LM0-2-007细胞的结果。
图15(治疗前)和图16(治疗后)显示用DWL-PI3K-3治疗小鼠的体内结果。
图17包含在使用侵袭性B细胞淋巴瘤细胞(OCI-LY-10)进行的PI3Kγ/δ抑制剂(CellTiter-Glo)的细胞存活率测定中比较DWL-PI3K-7与tenalisib的示意图。
图18包含在使用CTCL品系(HH和H9)或T-ALL品系(PF382和CCRF-CEM)进行的PI3Kγ/δ抑制剂(CellTiter-Glo)的细胞存活率测定中比较DWL-PI3K-7与度维利塞的示意图。
图19比较DWL-PI3K-6、DWL-PI3K-7、度维利塞和tenalisib在T-ALL CCRF-CEM细胞系(CellTiter-Glo)中的存活率测定结果。
图20比较DWL-PI3K-6、DWL-PI3K-7、度维利塞和tenalisib在T-ALL PF-382细胞系(CellTiter-Glo)中的存活率测定结果。
详细描述
本公开提供了本文所述的化合物、组合物和向有此需要的患者施用本文所述的化合物或组合物的方法。在另一个方面,本公开提供了通过向有此需要的患者或个体施用有效量的本文所述的化合物或组合物来治疗、预防或改善癌症例如淋巴白血病的方法。
在另一个实施方案中,本公开涉及用于治疗、预防或改善淋巴恶性肿瘤的作用的方法,所述方法包括向有此需要的受试者施用有效量的本文所述的化合物或组合物。在一个方面,所述化合物为磷酸肌醇3-激酶-δ(PI3Kδ)抑制剂和磷酸肌醇3-激酶-γ(PI3Kγ)抑制剂。在一个实施方案中,淋巴恶性肿瘤为T-细胞急性淋巴细胞白血病(T-ALL)或T-细胞急性淋巴细胞淋巴瘤。在一个实施方案中,淋巴恶性肿瘤为T-细胞急性淋巴细胞白血病(T-ALL)。
在一个实施方案中,能够在本文所述的组合物或方法中使用的本文所述的化合物包括式(I)、(II)、(III)、(IV)、表I、表II、表III和化合物实施例1-1至1-50、化合物实施例2-1至2-4和化合物实施例3-1至3-34的化合物及其组合、由它们组成或主要由它们组成。在一个方面,将所述组合物配制成药物组合物或形式。本公开包括本文公开的和本文公开的通式涵盖的化合物的所有形式,包括药学或生理学上可接受的盐形式(例如,酸加成盐、碱加成盐、半盐)、溶剂合物(例如,水合物)、互变异构体(例如,酮-烯醇互变异构体)、所有异构形式(例如,R-和S-对映异构体)和外消旋混合物、和其中一个或多个氢原子为氘的化合物。
在一个实施方案中,本公开提供了式(I)的化合物:
其中
A表示稠合的5-或6-元芳族或杂芳族基团;
X表示N、O或CY;
Y表示氢或卤素;
R1、R2、R3、R4和R5独立地表示氢、氘、C1-C6烷基、芳基、杂芳基、卤素、NO2或OCF3;
R6表示C1-C6烷基或C1-C6环烷基;
R7表示氢、烷基或卤素;或
R6和R7与R7所连接的N一起形成任选取代的5-或6-元环;
R8表示杂芳族基团(例如吡啶)或稠合系统(例如嘌呤);
Q表示直接键、羰基或亚烷基。
在一个实施方案中,A表示任选取代的苯基、芳基和杂芳基。在另一个实施方案中,A选自任选取代的苯基、吡啶、嘧啶、噻吩。在另一个实施方案中,A表示任选取代的苯基。
在一个实施方案中,本公开提供了式(II)的化合物:
其中
X表示N、O或CY;
Y表示氢或卤素;
R1、R2、R3、R4和R5独立地表示氢、氘、C1-C6烷基、芳基、杂芳基、卤素、NO2或OCF3;
R6表示C1-C6烷基或C1-C6环烷基;
R7表示氢、烷基或卤素;或
R6和R7与R7所连接的N一起形成任选取代的5-或6-元环;
R8表示杂芳族基团(例如吡啶)或稠合系统(例如嘌呤);
R9、R10、R11和R12独立地表示氢、C1-C6烷基或卤素;
Q表示直接键、羰基或亚烷基。
在一个实施方案中,本公开提供了式(III)的化合物:
其中
X表示N、O或CY;
Y表示氢或卤素;
R1、R2、R3、R4和R5独立地表示氢、氘、C1-C6烷基、芳基、杂芳基、卤素、NO2或OCF3;
R8表示杂芳族基团(例如吡啶)或稠合系统(例如嘌呤);
R9、R10、R11和R12独立地表示氢、C1-C6烷基或卤素;
Q表示直接键、羰基或亚烷基。
在一个实施方案中,本公开提供了式(IV)的化合物:
其中
X表示N、O或CY;
Y表示氢或卤素;
R1、R2、R3、R4和R5独立地表示氢、氘、C1-C6烷基、芳基、杂芳基、卤素、NO2或OCF3;
R9、R10、R11和R12独立地表示氢、C1-C6烷基或卤素;且
R13表示H、N或O;且(请证实R13)
R14表示NH2或甲基。
在一个实施方案中,Y表示氢。
在一个实施方案中,R1、R2、R3、R4和R5独立地表示氢、氘、C1-C6烷基或卤素。在另一个实施方案中,R1、R2、R3、R4和R5独立地表示氢、氘、甲基、氟或氯。
在一个实施方案中,R6表示C1-C6烷基。在另一个实施方案中,R6表示甲基。
在一个实施方案中,R7表示氢。
在一个实施方案中,R6和R7与R7所连接的N一起形成任选取代的5-元环。
在一个实施方案中,R8表示如下之一:
在一个实施方案中,式(I)、(II)或(III)的化合物不表示CAL-130。
在一个实施方案中,本公开的PI3Kδ和PI3Kγ抑制剂包含式(I)的化合物、由其组成或主要由其组成。
在另一个实施方案中,本公开的PI3Kδ和PI3Kγ抑制剂包含式(II)的化合物、由其组成或主要由其组成。
在另一个实施方案中,本公开的PI3Kδ和PI3Kγ抑制剂包含式(III)的化合物、由其组成或主要由其组成。
在另一个实施方案中,本公开的PI3Kδ和PI3Kγ抑制剂包含式(IV)的化合物、由其组成或主要由其组成。
表1列出了另外的式(II)的示例性化合物,
其中R7、R10、R11和R12各自为氢:
表1:
表2列出了另外的式(III)的示例性化合物,
其中X为N;R9为F;且R1-R5和R10-R12各自为氢。
表2:
表3列出了另外的式(IV)的示例性化合物,
其中R1-R5和R10-R12各自为氢。
表3:
对于例如在式(I)中R6所连接的手性碳而言,以上通过式(I)、(II)、(III)或(IV)或表1、2和3列出或显示为具体化合物的任意化合物可以是(S)或(R)立体异构体。或者,上述化合物中的任意一种可以是(S)或(R)异构体的非外消旋混合物,或者所述化合物可以是单独的(S)异构体或单独的(R)异构体。
CAL101、CAL-130和度维利塞(duvelisib)为已知的PI3K抑制剂的实例,而CU-17037表示本发明的某些实施方案:
如本文所用,“Me”为甲基、“Et”为乙基、“D”为氘。
在一个方面,本公开提供了用于治疗淋巴恶性肿瘤的药物组合物,其包含药学上可接受的载体和有效量的磷酸肌醇3-激酶-δ(PI3Kδ)抑制剂和磷酸肌醇3-激酶-γ(PI3Kγ)抑制剂。
在一个实施方案中,药物组合物为单位剂型形式。在另一个实施方案中,药物组合物还包含有效量的地塞米松。
在一个实施方案中,本文所述的方法或组合物还包括向受试者共同施用至少一种化疗剂。在一个实施方案中,所述化疗剂选自放线菌素,安吖啶,蒽环类抗生素,白消安,顺铂,环磷酰胺,表柔比星,六甲蜜胺奥沙利铂(hexamethylmelamineoxaliplatin),异环磷酰胺(iphosphamide),米托蒽醌,泰索帝,替尼泊苷,三亚乙基硫代磷酰胺,氢化可的松,可的松,甲泼尼龙,泼尼松龙,地塞米松,泼尼松,倍他米松,曲安西龙,倍氯米松,氟氢可的松,脱氧皮质酮,醛固酮,奥沙利铂,唑来膦酸,伊班膦酸盐,维拉帕米,鬼臼毒素,卡铂,丙卡巴肼,氮芥,环磷酰胺,喜树碱,异环磷酰胺(ifosfamide),美法仑,苯丁酸氮芥,bisulfan,亚硝基脲,更生霉素,柔红霉素,多柔比星,博来霉素,普卡霉素(plicomycin),丝裂霉素,依托泊苷(VP16),他莫昔芬,反铂(transplatinum),5-氟尿嘧啶,长春新碱,长春碱,甲氨蝶呤,L-天冬酰胺酶,雷帕霉素,二苯并氮卓(DBZ),乌拉莫司汀,卡莫司汀,洛莫司汀,链佐星,替莫唑胺,奥沙利铂,伊达比星,托泊替康,培美曲塞(premetrexed),6-巯基嘌呤,达卡巴嗪(darcarbazine),氟达拉滨(fludarabine),5-氟尿嘧啶,阿拉伯糖胞嘧啶(arabinosycytosine),5-氟尿嘧啶,阿糖胞苷(arabinosylcytosine),卡培他滨,吉西他滨,地西他滨,长春花生物碱,紫杉醇多西他赛伊沙匹隆及其组合。
在一个实施方案中,所述化疗剂为糖皮质激素,其选自氢化可的松,可的松,甲泼尼龙,泼尼松龙,地塞米松,泼尼松,倍他米松,曲安西龙,倍氯米松,氟氢可的松,脱氧皮质酮,醛固酮及其组合。
在一个实施方案中,所述化疗剂为地塞米松。
在一个方面,本公开提供了用于治疗、预防或改善如可能与突变的磷酸酶和肌腱蛋白同源物(PTEN)基因一起发生或在受试者中发生的与PI3K/AKT信号传导途径的激活相关的淋巴恶性肿瘤的作用的方法,所述方法包括对所述受试者施用有效量的磷酸肌醇3-激酶。
在一个方面,本公开提供了用于治疗患有T-细胞急性淋巴细胞白血病(T-ALL)的受试者的方法,所述方法包括向该受试者施用有效量的包含磷酸肌醇3-激酶-δ(PI3Kδ)抑制剂和磷酸肌醇3-激酶-γ(PI3Kγ)抑制剂的药物组合物。在一个实施方案中,所述方法进一步包括施用有效量的糖皮质激素,其选自氢化可的松,可的松,甲泼尼龙,泼尼松龙,地塞米松,泼尼松,倍他米松,曲安西龙,倍氯米松,氟氢可的松,脱氧皮质酮,醛固酮及其组合。在一个实施方案中,糖皮质激素为地塞米松。
在一个方面,本公开提供了用于在患有T-细胞急性淋巴细胞白血病(T-ALL)的受试者中降低肿瘤负荷的方法,所述方法包括向有此需要的受试者施用有效量的包含本文所述的化合物或组合物的药物组合物。在一个方面,所述方法进一步包括施用有效量的糖皮质激素,其选自氢化可的松,可的松,甲泼尼龙,泼尼松龙,地塞米松,泼尼松,倍他米松,曲安西龙,倍氯米松,氟氢可的松,脱氧皮质酮,醛固酮及其组合。在一个实施方案中,糖皮质激素为地塞米松。
在一个方面,本公开提供了用于鉴定可以从使用磷酸肌醇3-激酶-δ(PI3Kδ)抑制剂和磷酸肌醇3-激酶-γ(PI3Kγ)抑制剂的共同治疗中受益的受试者的方法,所述方法包括从受试者的样品中确定受试者是否具有突变的PTEN基因和/或PI3K/AKT信号传导途径的激活,其中突变的PTEN基因的存在和/或PI3K/AKT信号传导途径的激活表示可能受益于使用PI3Kδ抑制剂和PI3Kγ抑制剂的共同治疗的受试者。
在一个方面,本公开提供了用于鉴定同时具有磷酸肌醇3-激酶-δ(PI3Kδ)和磷酸肌醇3-激酶-γ(PI3Kγ)抑制活性的化合物的方法,所述方法包括:
(a)使细胞与所述化合物接触;并且
(b)测定所述化合物是否调节细胞中的抗原受体-诱导的活性;
其中调节抗原受体-诱导的活性的化合物同时具有PI3Kδ和PI3Kγ抑制活性。
在一个方面,PI3Kδ抑制剂为能够降低PI3Kδ的活性水平或表达水平的活性剂。优选地,PI3Kδ抑制剂几乎没有或没有脱靶效应;除了根据本公开允许它也对PI3Kγ具有抑制作用之外。
另外的适合的PI3Kδ抑制剂包括、但不限于AMG-319(Amgen,Thousand Oaks,Calif.);PI3-δ抑制剂,Cellzome(Cellzome AG,Heidelberg,Germany);PI3-δ/γ抑制剂,Cellzome(Cellzome AG);CHR-4432(Chroma Therapeutics,Ltd.,Abingdon,UK);XL-499(Evotech,Hamburg,Germany);CAL-120(Gilead Sciences,Foster City,Calif.);CAL-129(Gilead Sciences);CAL-130(Gilead Sciences);CAL-253(Gilead Sciences);CAL-263(Gilead Sciences);GS-1101(CAL-101)(Gilead Sciences);苯并咪唑系列,Genentech(Roche Holdings Inc.,South San Francisco,Calif.);PI3激酶δ抑制剂,Genentech(Roche Holdings Inc.);PI3激酶抑制剂,Roche-4(Roche Holdings Inc.);PI3激酶抑制剂,Roche(Roche Holdings Inc.);PI3激酶抑制剂,Roche-5(Roche Holdings Inc.);pictilisib(Roche Holdings Inc.);PI3激酶δ抑制剂,Incozen(Incozen Therapeutics,Pvt.Ltd.,Hydrabad,India);PI3激酶δ抑制剂-2,Incozen(Incozen Therapeutics);PI3-δ抑制剂,Intellikine(Intellikine Inc.,La Jolla,Calif.);PI3-δ/γ抑制剂,Intellikine(Intellikine Inc.);PI3Kδ/γ抑制剂,Intellikine-1(Intellikine Inc.);KAR-4139(Karus Therapeutics,Chilworth,UK);KAR-4141(Karus Therapeutics);PI3激酶δ抑制剂,Merck KGaA(Merck&Co.,Whitehouse Station,N.J.);OXY-111A(NormOxysInc.,Brighton,Mass.);PI3-α/δ抑制剂,Pathway Therapeutics(Pathway TherapeuticsLtd.,South San Francisco,Calif.);PI3-δ抑制剂,Pathway Therapeutics-1(PathwayTherapeutics Ltd.);PI3-δ抑制剂,Pathway Therapeutics-2(Pathway TherapeuticsLtd.);PI3-δ/γ抑制剂,Pathway Therapeutics(Pathway Therapeutics Ltd.);SF-1126(Semafore Pharmaceuticals,Indianapolis,Ind.);X-339(Xcovery,West Palm Beach,Fla.);IC87114(Gilead Science);TG100-115(Targegen Inc.,San Diego,Calif.);及其组合。优选地,PI3Kδ抑制剂为CAL-130。PI3Kδ抑制剂还可以为包含shRNA或siRNA、优选shRNA的核酸。
在一个方面,PI3Kγ抑制剂为能够降低PI3Kγ的活性水平或表达水平的活性剂。优选地,PI3Kγ抑制剂几乎没有或没有脱靶效应;除了根据本公开允许它也对PI3Kδ具有抑制作用之外,如以上更详细地阐述。
另外的适合的PI3Kγ抑制剂包括、但不限于PI3-δ/γ抑制剂,Cellzome(CellzomeAG);PI3-γ抑制剂,Cellzome(Cellzome AG);PI3-γ抑制剂,Evotec(Evotec);PI3激酶抑制剂,Roche(Roche Holdings Inc.);pictilisib(Roche Holdings,Inc.);IPI-145(Intellikine Inc.);PI3-δ/γ抑制剂,Intellikine(Intellikine Inc.);PI3Kδ/γ抑制剂,Intellikine-1(Intellikine Inc.);KIN-1(Karus Therapeutics);PI3-δ/γ抑制剂,Pathway Therapeutics(Pathway Therapeutics Ltd.);PI3-γ抑制剂,PathwayTherapeutics(Pathway Therapeutics Ltd.);SC-103980(Pfizer,New York,N.Y.);SF-1126(Semafore Pharmaceuticals);AS-041164(5-苯并[1,3]间二氧杂环戊烯-5-基亚甲基-噻唑烷-2,4-二酮);AS-604850(5-(2,2-二氟-苯并[1,3]间二氧杂环戊烯-5-基亚甲基)-噻唑烷-2,4-二酮);TG100-115(Targegen Inc.,San Diego,Calif.);AS-605240(5-喹喔啉-6-亚甲基-1,3-噻唑烷-2,4-二酮);CAL-130(Gilead Sciences);及其组合。优选地,PI3Kγ抑制剂为CAL-130。PI3Kγ抑制剂还可以为包含shRNA或siRNA、优选shRNA的核酸。
在本公开中,还关注抑制PI3Kδ和PI3Kγ二者,但对其它PI3K同工型不具有或具有有限作用的单一化合物或组合物。
在本公开中,可以将一种或多种PI3Kδ和/或PI3Kγ抑制剂和/或一种或多种化疗剂在同一组合物中一起、在单独的组合物中同时或作为在不同时间施用的单独的组合物共同施用于有此需要的受试者,正如临床医师认为最适合的。
在本公开中,PI3K抑制剂的“有效量”或“治疗有效量”,无论是PI3Kγ抑制剂还是PI3Kδ抑制剂,均为当施用于受试者时足以产生有益或期望效果的这类抑制剂的量。有效的剂型、施用方式和剂量可以凭经验确定,并且可以根据本领域技术的范围做出决定。本领域技术人员应当理解,剂量将随施用途径,排泄速率,治疗持续时间,所施用的任何其它药物的种类,哺乳动物例如人体患者的年龄、大小和种类以及医学和兽医学领域众所周知的和类似因素的不同而变化。通常,本公开的PI3K抑制剂的适合剂量将是PI3K抑制剂的量,其为有效产生期望的效果而无副作用或最小副作用的最低剂量。PI3Kγ抑制剂或PI3Kδ抑制剂的有效剂量可以作为两个、三个、四个、五个、六个或更多个亚剂量施用,并在一天内以适当的间隔分别施用,但前提是PI3Kγ抑制剂或PI3Kδ抑制剂的剂量同时降低或抑制PI3Kγ和PI3Kδ的活性或表达水平。
本公开的PI3K抑制剂、特别是PI3Kγ抑制剂和/或PI3Kδ抑制剂的剂量的适合的非限制性实例在约1ng/kg至约1000mg/kg,例如约1mg/kg至约100mg/kg,包括约5mg/kg至约50mg/kg。PI3K抑制剂的另外的有代表性的剂量包括约1mg/kg、5mg/kg、10mg/kg、15mg/kg、20mg/kg、25mg/kg、30mg/kg、35mg/kg、40mg/kg、45mg/kg、50mg/kg、60mg/kg、70mg/kg、80mg/kg、90mg/kg、100mg/kg、125mg/kg、150mg/kg、175mg/kg、200mg/kg、250mg/kg、300mg/kg、400mg/kg、500mg/kg、600mg/kg、700mg/kg、800mg/kg、900mg/kg或1000mg/kg。
本公开的另一个实施方案是用于在受试者中治疗、预防或改善与突变的磷酸酶和张力蛋白同源物(PTEN)基因和/或PI3K/AKT信号传导途径的活化有关的淋巴恶性肿瘤的方法。所述方法包括向受试者施用有效量的PI3Kδ抑制剂和PI3Kγ抑制剂。
如本文所用,“突变的磷酸酶和张力蛋白同源物(PTEN)基因”是指PTEN的外显子或内含子序列具有一个或多个变异。“与突变的PTEN基因相关的”淋巴恶性肿瘤是指其中发现PTEN基因序列的一个或多个变异并导致PI3K/AKT信号传导途径活化的淋巴恶性肿瘤。此类淋巴恶性肿瘤包括例如T-ALL、淋巴细胞淋巴瘤、大B-细胞淋巴瘤、伯基特淋巴瘤、大B-细胞淋巴瘤和骨髓瘤。
在一个方面,本公开提供了治疗淋巴系统中的淋巴恶性肿瘤或身体组织或细胞异常的生长的方法。这类异常的生长可能会侵入并破坏附近的组织,并可能扩散到身体的其它部位。术语“淋巴系统”是指一起发挥作用以产生对疾病的特异性抗性的所有细胞、组织聚集物和器官,包括但不限于骨髓,胸腺,淋巴管,T-细胞及其先祖细胞以及B-细胞及其先祖细胞。
在一个方面,本公开提供了治疗和/或预防霍奇金淋巴瘤、非霍奇金淋巴瘤(NHL)和复合型霍奇金淋巴瘤和NHL的方法。霍奇金淋巴瘤包括淋巴细胞丰富型经典霍奇金淋巴瘤、混合细胞性经典霍奇金淋巴瘤、淋巴细胞消减型经典霍奇金淋巴瘤和结节性淋巴细胞为主型霍奇金淋巴瘤、B-细胞NHL、T-细胞NHL、未知谱系的NHL、B-细胞NHL、前体B细胞NHL(例如B淋巴细胞白血病和B淋巴细胞淋巴瘤)、慢性淋巴细胞白血病、小淋巴细胞淋巴瘤、幼淋巴细胞白血病、套细胞淋巴瘤、淋巴浆细胞性淋巴瘤、瓦氏巨球蛋白血症、伯基特淋巴瘤、滤泡性淋巴瘤、脾边缘区淋巴瘤、结节外边缘区淋巴瘤、结节性边缘区淋巴瘤、多毛细胞白血病、弥漫性大B-细胞淋巴瘤、血管内大B-细胞淋巴瘤、原发性渗出性淋巴瘤、纵隔大B-细胞淋巴瘤、浆细胞瘤和多发性骨髓瘤/血浆细胞白血病。T-细胞NHL包括前体T-细胞NHL(例如T-细胞急性淋巴细胞白血病(T-ALL)和T-细胞急性淋巴细胞淋巴瘤)、蕈样真菌病、塞扎里综合征、成人T-细胞白血病、成人T-细胞淋巴瘤、NK/T-细胞淋巴瘤、侵袭性NK-细胞白血病、T-细胞巨粒淋巴细胞白血病、T-细胞幼淋巴细胞白血病和外周T-细胞淋巴瘤(例如血管免疫母细胞性淋巴瘤、皮下脂膜炎样T-细胞淋巴瘤、间变性大-细胞淋巴瘤、肝脾T-细胞淋巴瘤、肠病型T-细胞淋巴瘤、皮肤T-细胞淋巴瘤、原发性皮肤间变性大-细胞淋巴瘤)。优选地,淋巴恶性肿瘤为T-ALL或T-细胞急性淋巴细胞淋巴瘤。在另一个优选的实施方案中,其中淋巴恶性肿瘤为T-ALL。
在该实施方案的一个方面,所述方法进一步包括施用有效量的如本文所公开的化疗剂,例如糖皮质激素。优选地,所述化疗剂为地塞米松。
本公开的又一个实施方案为用于治疗淋巴恶性肿瘤的作用的药物组合物。所述药物组合物包含药学上可接受的载体和有效量的本文所述的PI3Kδ抑制剂和PI3Kγ抑制剂。在一个实施方案中,PI3Kδ抑制剂和PI3Kγ抑制剂选自:IPI-145/度维利塞、RP6530、CUX-03190、CUX-03193、CUX-03198A、CUX-03198B、DWL-PI3K-1、DWL-PI3K-2、DWL-PI3K-3和DWL-PI3K-4、DWL-PI3K-5、DWL-PI3K-6和DWL-PI3K-7。
有代表性的结构如下,包括命名为CU-17037的化合物:
该实施方案的药物组合物可以是包含双重抑制剂的单一组合物,包含两种活性剂(一种为PI3Kδ抑制剂而另一种为PI3Kγ抑制剂)的单一组合物,或两种或多种组合物,每种组合物包含至少一种为PI3Kδ抑制剂或PI3Kγ抑制剂的活性剂。
在另一个方面,药物组合物还包含有效量的如本文所公开的化疗剂,例如糖皮质激素。优选地,所述化疗剂为地塞米松。
该实施方案的药物组合物可以是包含双重抑制剂的单一组合物,包含两种活性剂(一种为PI3Kδ抑制剂而另一种为PI3Kγ抑制剂)的单一组合物,或两种或多种组合物,每种组合物包含至少一种为PI3Kδ抑制剂或PI3Kγ抑制剂的活性剂。
在该实施方案的一个方面,所述方法进一步包括施用有效量的本文所公开的化疗剂,例如糖皮质激素。优选地,所述化疗剂为地塞米松。
本公开的另一个实施方案为用于降低患有T-ALL的受试者的肿瘤负荷的方法。所述方法包括向所述受试者施用有效量的药物组合物,所述药物组合物包含本文所述的PI3Kδ抑制剂和PI3Kγ抑制剂。
如本文所用,“肿瘤负荷”是指受试者体内肿瘤细胞的数量(无论是良性还是恶性)或肿瘤的大小。
在该实施方案的一个方面,所述方法还包括施用有效量的本文所公开的化疗剂,例如也如本文所定义的糖皮质激素。优选地,所述化疗剂为地塞米松。
本公开的又一个实施方案为用于鉴定可以从使用PI3Kδ抑制剂和PI3Kγ抑制剂的共同治疗中受益的受试者的方法。所述方法包括从受试者的样品中确定受试者是否具有突变的PTEN基因,其中突变的PTEN基因的存在和随后的PI3K/AKT信号传导途径的激活表示可能受益于共同治疗的受试者。
在该实施方案中,通过任何常规方式从受试者得到样品。这样的样品包含DNA,并且可以是组织样品和/或血样,例如外周血样。这样的样品也可以是来自肿瘤的活检。可以使用本领域已知的任何常规基因分型方法,或通过使用任何常规方式(包括本文所公开的方法,包括实施例)对PTEN基因产物进行测定来确定受试者是否具有突变的PTEN基因。通过蛋白质印迹分析以检测AKT的磷酸化或通过磷酸化流式测定法(Phospho-flow assay)来确定受试者是否具有PI3K/AKT途径的激活。
本公开的另一个实施方案为用于鉴定同时具有PI3Kδ和PI3Kγ抑制活性的化合物的方法。所述方法包括:(a)使细胞与所述化合物接触;并且(b)确定所述化合物是否调节细胞中抗原受体诱导的活性;其中调节抗原受体诱导的活性的化合物同时具有PI3Kδ和PI3Kγ抑制活性。
如本文所用,“抗原受体-诱导的活性”是指由T-细胞受体信号转导引起的事件,例如,CD4T细胞中的AKT、GSK3β、mTOR、p70S6K、前存活蛋白的磷酸化和钙通量。此类活性的测定如本文所公开。
本公开的药物组合物可以以任何期望和有效的方式施用:用于口服摄入或作为软膏剂或滴剂以对眼睛的局部施用或用于肠胃外或其它任何适合方式的施用,例如腹膜内,皮下,局部,皮内,吸入,肺内,直肠,阴道,舌下,肌内,静脉内,动脉内,鞘内或淋巴管内。此外,本公开的药物组合物可以与其它治疗方法联合施用。如果期望,可以将本公开的药物组合物封装,或者另外防止其受到胃或其它分泌物影响。
本公开的药物组合物是药学上可接受的并且包含一种或多种活性成分与一种或多种药学上可接受的载体以及任选地一种或多种其它化合物、药物、成分和/或材料的混合物。无论选择的施用途径如何,通过本领域技术人员已知的常规方法将本公开的活性剂/化合物配制成药学可接受的剂型。参见,例如,Remington,The Science and Practice ofPharmacy(第21版,Lippincott Williams and Wilkins,Philadelphia,Pa.)。
药学上可接受的载体是本领域众所周知的(参见,例如Remington,The Scienceand Practice of Pharmacy(第21版,Lippincott Williams and Wilkins,Philadelphia,Pa.)和The National Formulary(American Pharmaceutical Association,Washington,D.C.)),并且包括糖(例如乳糖,蔗糖,甘露糖醇和山梨醇),淀粉,纤维素制品,磷酸钙(例如磷酸二钙,磷酸三钙和磷酸氢钙),柠檬酸钠,水,水溶液(例如盐水,氯化钠)注射液,林格氏注射液,葡萄糖注射液,葡萄糖和氯化钠注射液,乳酸林格氏注射液),醇类(例如乙醇,丙醇和苄醇),多元醇(例如甘油,丙二醇和聚乙二醇),有机酯(例如油酸酯和甘油三酸酯),可生物降解的聚合物(例如聚丙交酯-聚乙交酯,聚(原酸酯)和聚(酸酐)),弹性体基质,脂质体,微球,油(例如玉米油,胚芽油,橄榄油,蓖麻油,芝麻油,棉籽油和花生油),可可脂,蜡(例如栓剂蜡),石蜡,硅酮,滑石粉,硅酸盐等。在本公开的药物组合物中使用的每种药学上可接受的载体在与制剂的其它成分相容并且对受试者无害的意义上是“可接受的”。适合于选定剂型和预期施用途径的载体在本领域是众所周知的,并且可以使用本领域普通技术确定用于选定剂型施用方法的可接受载体。
本公开的药物组合物可任选地包含通常用于此类药物组合物中的其它成分和/或材料。这些成分和材料在本领域中是众所周知的,并且包括(1)填充剂或增量剂,例如淀粉,乳糖,蔗糖,葡萄糖,甘露糖醇和硅酸;(2)粘合剂,例如羧甲基纤维素,藻酸盐,明胶,聚乙烯吡咯烷酮,羟丙基甲基纤维素,蔗糖和阿拉伯胶;(3)保湿剂,例如甘油;(4)崩解剂,例如琼脂,碳酸钙,马铃薯或木薯淀粉,藻酸,某些硅酸盐,羟乙酸淀粉钠,交联羧甲基纤维素钠和碳酸钠;(5)溶解阻滞剂,例如石蜡;(6)吸收促进剂,例如季铵化合物;(7)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(8)吸收剂,例如高岭土和膨润粘土;(9)润滑剂,例如滑石粉,硬脂酸钙,硬脂酸镁,固体聚乙二醇和月桂基硫酸钠;(10)助悬剂,乙氧基化异硬脂醇,聚氧乙烯山梨醇和山梨坦酯,微晶纤维素,偏氢氧化铝,膨润土,琼脂和西黄蓍胶;(11)缓冲剂;(12)赋形剂,例如乳糖,奶糖,聚乙二醇,动物和植物脂肪,油,蜡,石蜡,可可脂,淀粉,西黄蓍胶,纤维素衍生物,聚乙二醇,硅酮,膨润土,硅酸,滑石粉,水杨酸盐,氧化锌,氢氧化铝,硅酸钙和聚酰胺粉;(13)惰性稀释剂,例如水或其它溶剂;(14)防腐剂;(15)表面活性剂;(16)分散剂;(17)控释或吸收延迟剂,例如羟丙基甲基纤维素,其它聚合物基质,可生物降解的聚合物,脂质体,微球,单硬脂酸铝,明胶和蜡;(18)遮光剂;(19)佐剂;(20)润湿剂;(21)乳化剂和助悬剂;(22)增溶剂和乳化剂,例如乙醇,异丙醇,碳酸乙酯,苄醇,苯甲酸苄酯,丙二醇,1,3-丁二醇,油(尤其是棉籽油,花生油,玉米油,胚芽油,橄榄油,蓖麻油和芝麻油),甘油,四氢呋喃醇,聚乙二醇和脱水山梨糖醇的脂肪酸酯;(23)推进剂,例如氯氟烃和挥发性未取代的烃,例如丁烷和丙烷;(24)抗氧化剂;(25)使制剂与预期接受者的血液等渗的试剂,例如糖和氯化钠;(26)增稠剂;(27)包衣衣料,例如卵磷脂;和(28)甜味剂、矫味剂、着色剂、加香剂和防腐剂。每种这样的成分或材料在与制剂的其它成分相容并且对受试者无害的意义上必须是“可接受的”。适合于所选剂型和预期施用途径的成分和材料是本领域众所周知的,并且用于所选剂型和施用方法的可接受成分和材料可以使用本领域普通技术来确定。
用于或口服的药物组合物可以是胶囊剂,扁囊剂,丸剂,片剂,粉剂,颗粒剂,在水性或非水性液体中的溶液或悬浮液,水包油型或油包水型液体乳剂,酏剂或糖浆,锭剂,大丸剂,干糖浆或糊剂。这些制剂可以通过本领域已知的方法制备,例如通过常规的锅包衣、混合、制粒或冻干方法。
可以例如通过将一种或多种活性成分与一种或多种药学上可接受的载体以及任选地一种或多种填充剂、增量剂、粘合剂、湿润剂、崩解剂、溶解阻滞剂、吸收促进剂、润湿剂、吸收剂、润滑剂和/或着色剂药物混合来制备用于口服施用的固体剂型(胶囊,片剂,丸剂,锭剂,粉末,颗粒剂等)。可以使用适合的赋形剂将相似类型的固体组合物用作软和硬填充明胶胶囊的填充剂。片剂可以通过任选地与一种或多种辅助成分压制或模制制成。压制片可以使用适合的粘合剂、润滑剂、惰性稀释剂、防腐剂、崩解剂、表面活性剂或分散剂来制备。模制片可以通过在适合的机器中模制来制备。可以任选地给片剂和其它固体剂型刻痕,例如锭剂、胶囊、丸剂和颗粒剂,或用包衣和衣壳、例如肠溶衣和药物配制领域众所周知的其它包衣衣料制备。它们也可以被配制为提供其中的活性成分的缓慢或受控释放。例如,可以通过截留细菌的过滤器对其进行灭菌。这些组合物还可以任选地包含遮光剂,并且可以具有这样的组成,使得它们仅或优选地在胃肠道的某些部分中、任选地以延迟的方式释放活性成分。活性成分也可以是微囊形式。
用于口服施用的液体剂型包括药学上可接受的乳剂,微乳,溶液,混悬液,糖浆剂和酏剂。液体剂型可以包含本领域常用的适合的惰性稀释剂。除惰性稀释剂外,口服组合物还可以包括佐剂,例如润湿剂,乳化和悬浮剂,甜味剂,矫味剂,着色剂,加香剂和防腐剂。
悬浮液可以包含助悬剂。
用于直肠或阴道施用的药物组合物可以以栓剂形式存在,其可以通过将一种或多种活性成分与一种或多种适合的无刺激性载体混合制备,所述无刺激性载体在室温下为固体,但在体温下为液体,且由此可以在直肠或阴道腔内熔化并释放出活性化合物。适于阴道施用的药物组合物还包括阴道栓,棉塞,霜剂,凝胶剂,糊剂,泡沫剂或喷雾剂,其包含本领域已知适合的这样的药学上可接受的载体。
用于局部或透皮施用的剂型包括粉末,喷雾剂,软膏剂,糊剂,霜剂,洗剂,凝胶剂,溶液,贴剂,滴剂和吸入剂。可以在无菌条件下将一种或多种活性剂/化合物与适合的药物学伤可接受的载体混合。软膏剂、糊剂、霜剂和凝胶剂可以包含赋形剂。粉末和喷雾剂可以包含赋形剂和推进剂。
适合于肠胃外施用的药物组合物包含一种或多种活性剂/化合物与一种或多种药学上可接受的无菌等渗水溶液或非水溶液、分散液、混悬液或乳剂或无菌粉末的组合,其可以在使用前重构成无菌注射液或分散液,其中可以包含适合的抗氧化剂,缓冲剂,使制剂与预期接受者的血液等渗的溶质或助悬剂或增稠剂。例如,可以通过使用包衣衣料、在分散液的情况下通过维持所需的粒径以及通过使用表面活性剂来保持适当的流动性。这些组合物还可包含适合的佐剂,例如润湿剂、乳化剂和分散剂。也可能期望包括等渗剂。另外,可以通过包含延迟吸收的试剂来延长可注射药物形式的吸收。
在某些情况下,为了延长药物(例如药物制剂)的作用,期望减慢其从皮下或肌内注射的吸收。这可以通过使用具有差水溶性的结晶或无定形材料的液体悬浮液来实现。
然后,活性剂/药物的吸收速率取决于其溶出速率,而溶解速率又取决于晶体尺寸和晶体形式。或者,可以通过将活性剂/药物溶解或悬浮在油性媒介物中来实现肠胃外施用的活性剂/药物的延迟吸收。可注射储库形式可以通过在可生物降解的聚合物中形成活性成分的微胶囊基质来制备。根据活性成分与聚合物的比例和所用特定聚合物的性质的不同,可以控制活性成分的释放速率。还可以通过将药物截留在与身体组织相容的脂质体或微乳中来制备储库注射剂。例如,可以通过细菌截留过滤器过滤来对可注射材料进行灭菌。
所述制剂可以存在于单位剂量或多剂量密封容器中,例如,安瓿和小瓶,并且可以在冻干条件下储存,仅需在使用前即刻添加无菌液体载体、例如注射用水。临时注射溶液和混悬液可以由上述类型的无菌粉末、颗粒和片剂制备。
如本文所用,“核酸”或“寡核苷酸”或“多核苷酸”是指至少两个共价连接在一起的核苷酸。核酸的许多变体可以用于与给定核酸相同的目的。因此,核酸还涵盖基本上相同的核酸及其补体。
核酸可以是单链或双链的,或者可以包含双链和单链序列二者的一部分。核酸可以是DNA(基因组和cDNA二者)、RNA或杂合体,其中所述核酸可以包含脱氧核糖-和核糖-核苷酸的组合以及碱基的组合,所述碱基包括尿嘧啶,腺嘌呤,胸腺嘧啶,胞嘧啶,鸟嘌呤,肌苷,黄嘌呤次黄嘌呤,异胞嘧啶和异鸟嘌呤。可以将核酸合成为单链分子,或使用合成基因在细胞中(体外或体内)表达。核酸可以通过化学合成方法或通过重组方法获得。
核酸也可以是RNA例如mRNA,tRNA,短发夹RNA(shRNA),短干扰RNA(sRNA),双链RNA(dsRNA),转录基因沉默RNA(ptgsRNA),Piwi-相互作用RNA,pri-miRNA,前-miRNA,微小-RNA(miRNA)或抗-miRNA,例如,如美国专利申请序列号11/429,720、11/384,049、11/418,870和11/429,720以及公开的国际申请号WO2005/116250和WO2006/126040中所述。
siRNA基因靶向可通过瞬时siRNA转移到细胞中来完成,可通过经典方法如脂质介导的转染来实现(例如封装在脂质体中,与阳离子脂质、胆固醇和/或缩合聚合物配合,电穿孔或显微注射)。siRNA基因靶向也可以通过施用与抗体缀合的siRNA或与融合蛋白复合的siRNA进行,所述融合蛋白包含与和siRNA结合的双链(ds)RNA结合结构域(DRBD)缀合的细胞穿透肽(参见,例如美国专利申请公开号2009/0093026)。
shRNA分子具有两个彼此反向互补的序列区,并且可以以分子内方式彼此形成双链。可以通过使用导入细胞中的载体,例如病毒载体(例如,慢病毒载体,腺病毒载体或腺相关病毒载体)进行shRNA基因-靶向。的siRNA和shRNA分子的设计和合成是本领域已知的,并且可以购自例如Gene Link(Hawthorne,N.Y.),Invitrogen Corp.(Carlsbad,Calif.),Thermo Fisher Scientific and Dharmacon Products(Lafayette,Colo.)。
核酸也可以是适配体、intramer或spiegelmer。术语“适配体”是指与特异性分子靶标结合的核酸或寡核苷酸分子。适配体来源于体外进化过程(例如,美国专利号5,270,163中公开的SELEX(Systematic Evolution of Ligands by EXponential Enrichment)),其从大型组合文库中选择靶标特异性适配体序列。适配体组成可以是双链或单链的,并且可以包括脱氧核糖核苷酸、核糖核苷酸、核苷酸衍生物或其它核苷酸样分子。适配体的核苷酸组分可以具有修饰的糖基(例如核糖核苷酸的2'-OH基团可以被2'-F或2'-NH2替代),这可以改善期望的性质,例如,抵抗核酸酶或血液中寿命更长。适配体可以与其它分子缀合,例如高分子量载体,以减慢适配体从循环系统中的清除。适配体可以通过交联剂的光活化而特异性地交联至它们的同源配体。
术语“intramer”是指在体内表达的适配体。例如,基于牛痘病毒的RNA表达系统已经用于在白细胞的细胞质中高水平表达特异性RNA适配体。
术语“spiegelmer”是指包括L-DNA、L-RNA或其它左旋核苷酸衍生物或核苷酸样分子的适配体。包含左旋核苷酸的适配体对天然存在的酶具有抗降解性,该酶通常作用于含有右旋核苷酸的底物。
核酸通常将包含磷酸二酯键,不过,可以包括可以具有至少一个不同键的核酸类似物,例如氨基磷酸酯、硫代磷酸酯、二硫代磷酸酯或O-甲基亚磷酰胺键和肽核酸骨架和键。其它类似物核酸包括具有正主链;非离子主链和非核糖的主链的那些,包括美国专利号5,235,033和5,034,506中公开的那些。包含一个或多个非天然存在的或修饰的核苷酸的核酸也包括在核酸的定义内。修饰核苷酸类似物可以位于例如核酸分子的5'-端和/或3'-端。核苷酸类似物的代表性实例可以选自糖-或骨架-修饰的核糖核苷酸。然而,应注意,核碱基修饰的核糖核苷酸,即核糖核苷酸,也包含非天然存在的核碱基,而不是天然存在的核碱基,例如在5-位上修饰的尿苷或胞苷,例如,5-(2-氨基)丙基尿苷,5-溴尿苷;在8-位上修饰的腺苷和鸟苷,例如8-溴鸟苷;去氮杂核苷酸,例如7-脱氮腺苷;O-和N-烷基化的核苷酸,例如N6-甲基腺苷是适合的。2'-OH-基团可以被选自H或R、卤素、SH、SR、NH2、NHR、NR2或CN的基团替代,其中R为C1-C6烷基、烯基或炔基,且卤素为F、Cl、Br或I。修饰的核苷酸还包括通过例如羟基脯氨醇键与胆固醇缀合的核苷酸,如Krutzfeldt等人Nature(2005年10月30日)、Soutschek等人Nature 432:173-178(2004)和和美国专利申请公开号20050107325中所公开的。修饰的核苷酸和核酸还可以包括锁核酸(LNA),如美国专利申请公开号20020115080中所公开。另外的修饰的核苷酸和核酸如美国专利申请公开号200500152005中所公开的。出于多种原因,可以进行核糖磷酸骨架的修饰,例如,以增加这种分子在生理环境中的稳定性和半衰期,以增强跨细胞膜的扩散或作为生物芯片上的探针。可以制备天然存在的核酸和类似物的混合物;或者,可以制备不同核酸类似物的混合物和天然存在的核酸和类似物的混合物。
如本文所用,术语“肽”、“多肽”和“蛋白质”是可互换的。在本公开中,这些术语表示氨基酸的连接序列,其可以是天然的、合成的或天然的或合成的修饰或组合。该术语包括抗体、抗体模拟物、结构域抗体、脂质运载蛋白、靶向的蛋白酶和多肽模拟物。该术语还包括包含旨在产生针对该肽或肽片段的抗体的肽或肽片段的疫苗。
如本文所用,术语“多糖”是指由糖苷键彼此连接在一起的重复单元(单糖或二糖)形成的聚合碳水化合物结构。单糖或二糖的单元可以相同或不同。多糖的非限制性实例包括淀粉、糖原、纤维素和几丁质。
如本文所用,术语“小分子有机分子”或“无机小分子”包括除多糖、多肽和核酸以外的可影响生物过程的任何化学或其它部分。小分子可以包括目前已知和使用的或可以在此类分子的文库中合成目的在于筛选生物学功能的任何数量的治疗剂。小分子与大分子的大小不同。本公开的小分子通常具有小于约5,000道尔顿(Da)的分子量,优选小于约2,500Da,更优选小于1,000Da,最优选小于约500Da。
如本文所用,术语“有机化合物”是指除生物学物质以外的任何基于碳的化合物,例如核酸、多肽和多糖。除了碳以外,有机化合物还可以包含钙,氯,氟,铜,氢,铁,钾,氮,氧,硫和其它元素。有机化合物可以是芳族或脂族形式。有机化合物的非限制性实例包括丙酮,醇,苯胺,碳水化合物,单糖,二糖,氨基酸,核苷,核苷酸,脂质,类维生素A,类固醇,蛋白聚糖,酮,醛,醛,饱和、不饱和和多不饱和脂肪,油和蜡,烯烃,酯,醚,硫醇,硫化物,环状化合物,杂环化合物,咪唑(imidizole)和酚。如本文所用的有机化合物还包括硝化的有机化合物和卤代的(例如氯代的)有机化合物。根据本发明鉴定的小分子和小分子的集合通过例如加速器质谱(AMS)这样的技术表征。
优选的小分子相对较容易且较低廉地制造、配制或以其它方式制备。优选的小分子在各种储存条件下是稳定的。可将优选的小分子与大分子紧密结合以形成具有生物活性并具有改善的药物性质的分子。改善的药物特性包括有利于期望的生物学活性的循环时间,分布,代谢,修饰,排泄,分泌,消除和稳定性方面的改变。改善的药物特性包括化学实体的毒理学和功效特性的变化。
在一个方面并且如本文所述,PI3Kγ和PI3Kδ可以充当PTEN裸T-ALL中的致瘤瓶颈,因为它们的组合缺失显著损害了小鼠的肿瘤发育。该描述进一步证明,通过鉴定主要的双重PI3Kγ/δ抑制剂(CAL-130)能够利用这种PI3K“成瘾(addiction)”,其(1)可以显著降低患病小鼠的肿瘤负荷和延长生存期;和(2)在人原代T-ALL细胞中消除Akt磷酸化和活化的促凋亡途径。本公开进一步证明了PTEN裸T-ALL对PI3Kγ/δ的联合活性的依赖性。
这也可以通过产生基因表达标记来评价药物治疗的效果来实现。使用由转录因子LMO2的过表达驱动的小鼠PTEN裸/NOTCH活化的T-ALL细胞系,一式三份获得了全基因表达谱。在该模型中,肿瘤细胞的特征在于PI3K途径和NOTCH1的激活,这二者在人T-ALL中均被上调。在CAL-130(2.5μM)或γ-分泌酶抑制剂(GSI)化合物E(1μM)的存在下培养肿瘤细胞。化合物E阻断了NOTCH1的活性,NOTCH1还被认为支持T-ALL肿瘤的形成、增殖和存活。在已知会影响原癌基因cMyc表达的时间点(分别为12小时和48小时)收获药物处理的细胞,其中cMyc是细胞生长、代谢和存活的主要调节剂。创建了维恩图,以示例通过PI3Kγ/δ阻滞(红色圆圈)或GSI(绿色圆圈)改变的基因中的重叠,其中使用0.0005的错误发现率(FDR)作为截止值(图1A)。值得注意地,PI3Kγ/δ阻滞后,影响10-倍以上的基因,包括大部分(~62%)通过GSI单一疗法改变的基因,这是一个非常重要的发现(Fisher精确检验,P<2.2×10-16)。
基于与野生型鼠胸腺细胞相比在T-ALL样品中的差异表达,通过对所有基因进行排序,从而进一步确定了鼠T-ALL疾病标记。为了确定PI3Kγ/δ和NOTCH1对总体疾病标记的贡献,在差异表达的基因中用CAL-130或化合物E处理后,对200个转录激活和抑制程度最高的基因进行了基因集富集分析(GSEA)。尽管两种药物均显著颠倒了T-ALL疾病标记,从而强调了这些信号传导途径在维持白血病表型中的重要性(图1B),但使用CAL-130的富集作用更为显著(归一化富集评分(NES)为对于CAL-130的-5.8(P<0.0001)与对于化合物E的NES为-2.6(P=0.006)。这些结果表明PI3Kγ/δ在T-ALL中起主要作用并且比NOTCH1调节更多的控制疾病标记的基因,NOTCH1被认为是与这种白血病有关的主要致癌基因。
PI3K抑制剂度维利塞(IPI-145)不能有效降低具有T-ALL的小鼠的肿瘤负荷或延长其总生存期(参见图1B;平均生存期18天(IPI-145;30mg/kg tid)与45天(CAL-130;10mg/kg tid)。
已经发现,要求保护的化合物在测定其杀伤培养的T-ALL细胞的能力时表现出广泛的效能。一些化合物显示出甚至比CAL-130更高的活性(例如,以纳摩尔浓度而不是微摩尔浓度杀伤),并且可能具有研发成用于侵袭性或复发性T-ALL治疗的潜能。
这组不同的PI3Kγ/δ抑制剂具有被研发成治疗癌症例如T-ALL以及与PI3K活性异常有关的其它疾病的方法的潜能。这些化合物在PI3Kγ/δ信号传导研究中进一步用作抑制PI3Kγ/δ活性的工具,并在各种研究强度下诱导细胞死亡。
进一步优化了小分子PI3Kγ/δ双重抑制剂。如图5A中所示例,CAL-130的结构可细分为四个主要区:A区、B区、C区和D区。DWL-PI3K-3和DWL-PI3K-4在诱导T-ALL细胞死亡方面比CAL-130表现出更大的效能。在A区中,苯环包括不同的取代基,例如Cl、F、CF3、OCH3。
在某些类似物中,苯环可以被杂芳基,例如吡啶、嘧啶、噻吩替代。在B区中,氮(X=N)被CH基团(X=CH)替代。在C区中,类似于A区,在某些类似物中,苯环可带有多个不同的取代基或具有不同的取代模式。在D区中,引入了杂芳基,例如图5A中列出的那些。图5B提出了一种类似物的合成实例,该类似物带有在A区中的替代苯基的噻吩、在B区中的嘧啶酮环中的CH基团而不是氮、在C区中的未取代的苯环和在D区中的嘧啶环。
在本公开的一个实施方案中,为治疗、预防或改善淋巴恶性肿瘤的作用的方法。所述方法包括向有此需要的受试者施用有效量的PI3Kδ抑制剂和PI3Kγ抑制剂。
如本文所用,“受试者”为哺乳动物,优选为人类。除人类外,本公开范围内的哺乳动物类别包括例如农业动物,家畜,实验动物等。农业动物的一些实例包括牛、猪、马、山羊等。家畜动物的一些实例包括狗、猫等。实验动物的一些实例包括大鼠、小鼠、家兔、豚鼠等。
如本文所用,术语“治疗”及其语法变化形式是指使个体受试者接受其中期望该受试者、例如患者得到生理反应或结果的计划、方案、过程或疗法。特别地,本公开的方法和组合物可用于减缓疾病症状的发展或延迟疾病或病症的发作或中止疾病发展的进程。然而,因为每个接受治疗的受试者可能对特定的治疗计划、方案、过程或疗法无应答,因此,治疗不需要在每一或每个受试者(例如患者、人群)中实现期望的生理反应或结果。因此,给定的受试者、例如患者、人群可能对治疗无应答或反应不足。
如本文所用,术语“改善”及其语法变化形式是指降低受试者的疾病症状的严重性。
如本文所用,术语“预防”及其语法变化形式是指将本公开的化合物或组合物施用于在施用时未被诊断出患有疾病或病症但可预期会发生所述疾病或病症或处于所述疾病或病症的风险增加的受试者。预防还包括将至少一种本公开的化合物或本公开的组合物施用于那些由于年龄、家族史、遗传或染色体异常、由于存在所述疾病或病症的一种或多种生物标记物而易患疾病或病症况和/或由于环境因素的受试者。
如本文所用,“生物制品”是指来源于或由活的生物体产生或合成以模仿体内来源的活性剂或其衍生物或产物的物质。例如,生物制品可以是核酸、多肽或多糖。优选地,生物制品为核酸、蛋白质或其组合。更优选地,核酸包含shRNA。
如本文所用,“化学物质”是指具有确定的化学组成和特性且无生物学方面的性质的物质。化学物质的非限制性实例包括小的有机化合物和小的无机化合物。
以下实施例用于示例本公开的某些方面,而无意于限制本公开。
实施例
实施例涉及相对于其它PI3Kγ/δ抑制剂表现出改进的性能的有代表性化合物。例如,表I、II和III中描述的化合物相对于其它PI3Kγ/δ抑制剂表现出优异的生物学作用。如针对图4中的实例所述,化合物例如I-50、DWL-PI3K-1、-2、-3、-4、-5、-6和-7且特别是DWL-PI3K-5、-6和-7具有更好的药代动力学,并且相对于CAL-130,可能需要少约10倍即达到类似的肿瘤细胞存活率降低。本文所述的化合物显然还对PI3Kγ和PI3Kδ的p110催化结构域具有选择性,因为例如缺乏这两种p110同工型的T-ALL细胞系的治疗导致有限的细胞杀伤。
实施例1:DWL-PI3K-1
步骤1:2-甲基-6-硝基-N-(邻-甲苯基)苯甲酰胺的合成。将2-甲基-6-硝基苯甲酸(4.0g,22.0mmol)、甲苯(20mL)和亚硫酰氯(SOCl2)(10g,84mmol)的混合物回流加热2h。然后在45℃减压浓缩该反应体系,并将THF(30mL)添加到得到的酰氯中。使用冰/水浴冷却,并添加N,N-二异丙基乙胺(10mL)和邻甲苯胺(2.4g,22.4mmol)。将该反应混合物在室温搅拌过夜。然后减压浓缩该混合物,并将残余物溶于EtOAc(50mL)。用1N HCl(2x 20mL)和饱和NaHCO3水溶液(2x20mL)洗涤该溶液,并真空浓缩,得到2-甲基-6-硝基-N-(邻-甲苯基)苯甲酰胺,为灰白色固体(5.94g,收率:100%)。
步骤2:2-甲基-6-硝基-N-(邻-甲苯基)亚氨苄基氯的合成。将2-甲基-6-硝基-N-(邻-甲苯基)苯甲酰胺(3.0g,11mmol)、甲苯(20mL)、亚硫酰氯(6.0mL)和DMF(40μL)的混合物回流2.5h。在45℃减压浓缩得到的溶液,得到粗产物,为黄色油状物(3.08g,未经进一步纯化使用)。
步骤3:(S)-(1-(2-甲基-6-硝基-N-(邻-甲苯基苯甲酰氨基)-1-氧代丙-2-基)氨基甲酸叔丁酯的合成。在0-5℃将步骤2中制备的粗产物(2-甲基-6-硝基-N-(邻-甲苯基)亚氨苄基氯)(3.08g)溶于CH2Cl2(8.0mL),并添加到Boc-L-丙氨酸(1.9g,17.4mmol)和N,N-二异丙基乙胺(3mL)在CH2Cl2(10mL)中的溶液中。将该反应混合物在此温度下搅拌1h,然后温热至室温过夜。用10%柠檬酸水溶液(2×15mL)、然后用饱和NaHCO3水溶液(10mL)洗涤得到的溶液,并真空浓缩。通过硅胶快速色谱法纯化,用20%在己烷中的乙酸乙酯洗脱,得到期望的产物,为固体(3.22g,收率:67%)。MS:m/z=442(M+1)。
步骤4:(S)-(1-(5-甲基-4-氧代-3-(邻-甲苯基)-3,4-二氢喹唑啉-2-基)乙基)氨基甲酸叔丁酯的合成。将锌粉(4.8g)在乙酸(30mL)和(S)-(1-(2-甲基-6-硝基-N-(邻-甲苯基苯甲酰氨基)-1-氧代丙-2-基)氨基甲酸叔丁酯(3.22g,7.3mmol,步骤3中制备)中的混悬液在室温搅拌4h。真空浓缩该混合物,并将得到的残余物溶于CH2Cl2(40mL)。用饱和NaHCO3水溶液(2x 10mL)洗涤该溶液,并真空浓缩。通过硅胶色谱法纯化残余物(20%在己烷中的乙酸乙酯),得到产物,为白色固体(822mg,收率28.6%)。MS:m/z=394(M+1)。
步骤5:(S)-2-(1-氨基乙基)-5-甲基-3-(邻-甲苯基)喹唑啉-4(3H)-酮的合成。将(S)-(1-(5-甲基-4-氧代-3-(邻-甲苯基)-3,4-二氢喹唑啉-2-基)乙基)氨基甲酸叔丁酯(822mg,2.1mmol,步骤4中制备)和三氟乙酸(5mL)在CH2Cl2(20mL)中的混合物在室温搅拌过夜。真空浓缩该反应混合物,得到产物,100%收率,为TFA盐(842mg)。MS:m/z=294(M+1)。
步骤6:(S)-2,4-二氨基-6-((1-(5-甲基-4-氧代-3-(邻-甲苯基)-3,4-二氢喹唑啉-2-基)乙基)氨基)嘧啶-5-甲腈(DWL-PI3K-1)的合成。将(S)-2-(1-氨基乙基)-5-甲基-3-(邻-甲苯基)喹唑啉-4(3H)-酮(12mg,0.4mmol,步骤5中制备)、2,4-二氨基-6-氯嘧啶-5-甲腈(10mg,0.034mmol)、N,N-二异丙基乙胺(0.1mL)和氟化钾(18mg)在DMSO(1mL)中的混合物在90℃加热过夜。将该反应混合物冷却至室温,并向该混合物中添加EtOAc(20mL)。用蒸馏水(3x 5mL)、1N HCl(水溶液)和饱和NaHCO3水溶液(2x 5mL)洗涤该溶液。真空蒸发溶剂,并通过硅胶柱色谱法纯化粗产物(EtOAc/MeOH 20:1),得到期望的产物DWL-PI3K-1,为白色固体(4.8mg,收率:33%)。MS:m/z=427(M+1)。
实施例2:DWL-PI3K-2
(S)-2-氨基-4-甲基-6-((1-(5-甲基-4-氧代-3-(邻-甲苯基)-3,4-二氢喹唑啉-2-基)乙基)氨基)嘧啶-5-甲腈(DWL-PI3K-2)的合成。将(S)-2-(1-氨基乙基)-5-甲基-3-(邻-甲苯基)喹唑啉-4(3H)-酮(133mg,0.45mmol)、2-氨基-4-氯-6-甲基嘧啶-5-甲腈(86mg,0.51mmol)、N,N-二异丙基乙胺(0.2mL)和氟化钾(96mg)在DMSO(5mL)中的混合物在90℃加热过夜。将该反应混合物冷却至室温,并添加EtOAc(20mL)。用H2O(3x 5mL)、1N HCl(水溶液)和饱和NaHCO3水溶液(2x 5mL)洗涤该溶液,随后真空浓缩。通过硅胶柱色谱法纯化粗产物(EtOAc/MeOH 20:1),得到期望的产物DWL-PI3K-2,为白色固体(115mg,60%)。MS:m/z=426(M+1)。
实施例3:DWL-PI3K-3
(S)-2,4-二氨基-6-((1-(8-氯-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)氨基)嘧啶-5-甲腈(DWL-PI3K-3)的合成。将(S)-3-(1-氨基乙基)-8-氯-2-苯基异喹啉-1(2H)-酮(23mg,0.077mmol)、2,4-二氨基-6-氯嘧啶-5-甲腈(13mg,0.08mmol)、N,N-二异丙基乙胺(0.1mL)和氟化钾(21mg)在DMSO(1mL)中的混合物在90℃加热过夜。将该反应混合物冷却至室温,并添加EtOAc(20mL)。用H2O(3x 5mL)洗涤该溶液,并真空浓缩。通过硅胶柱色谱法纯化粗产物(EtOAc/MeOH 20:1),得到期望的产物DWL-PI3K-3,为白色固体(23mg,收率70%)。MS:m/z=432(M+1)。
实施例4:DWL-PI3K-4
(S)-2-氨基-4-((1-(8-氯-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)氨基)-6-甲基嘧啶-5-甲腈(DWL-PI3K-4)的合成。将(S)-3-(1-氨基乙基)-8-氯-2-苯基异喹啉-1(2H)-酮(23mg,0.077mmol),2-氨基-4-氯-6-甲基嘧啶-5-甲腈(13mg,0.08mmol)、N,N-二异丙基乙胺(0.1mL)和氟化钾(21mg)在DMSO(1mL)中的混合物在90℃加热过夜。将该反应混合物冷却至室温,并添加EtOAc(20mL)。用H2O(3x 5mL)洗涤该溶液,并真空浓缩。通过硅胶柱色谱法纯化粗产物(EtOAc/MeOH 20:1),得到期望的产物DWL-PI3K-4,为白色固体(30mg,91%收率)。MS:m/z=431(M+1)。
实施例5:DWL-PI3K-5
(S)-1-(8-氯-1-氧代-1H-异色烯-3-基)乙基氨基甲酸叔丁酯的合成。向2-氯-6-甲基苯甲酸(0.8g,4.7mmol)在无水THF(10mL)中的溶液中缓慢地添加正己基锂(8.8mL,2.3M,20.2mmol),并将该混合物在-20℃搅拌20min。在单独的烧瓶中,向(S)-1-(甲氧基(甲基)氨基)-1-氧代丙-2-基氨基甲酸叔丁酯(1.4g,6.1mmol)在无水THF(10mL)中的溶液中添加iPrMgCl(6.33mL,2M),并将该混合物在-10℃搅拌20min。在-20℃将得到的混合物通过套管转入上述烧瓶。将得到的混合物缓慢地加热至室温,并在室温下保持1.5h。用水使反应猝灭,用2N HCl(水溶液)酸化,并用乙酸乙酯(3x 50mL)萃取。干燥有机层,并真空浓缩。用10%在DCM中的甲醇进行柱色谱,得到期望的产物。将产物溶于乙酐(10mL),并将DMAP(10mg)添加到该溶液中。将该混合物在70℃保持2h。真空除去溶剂,并通过使用25%在己烷中的乙酸乙酯的柱色谱法纯化粗产物,得到(S)-1-(8-氯-1-氧代-1H-异色烯-3-基)乙基氨基甲酸叔丁酯(1.3g,86%)。
(S)-(4-(3-氯-2-((3,5-二氟苯基)氨基甲酰基)苯基)-3-氧代丁-2-基)氨基甲酸叔丁酯的合成。将(S)-1-(8-氯-1-氧代-1H-异色烯-3-基)乙基氨基甲酸叔丁酯(1.17g,3.62mmol)在DCM(25mL)中的溶液缓慢地添加到3,5-二氟苯胺2.33g,18.1mmol)和三甲基铝(9.05mL,2M,18.1mmol)在DCM(25mL)中的溶液中。将得到的混合物在室温搅拌2h,缓慢地用罗谢尔盐猝灭。干燥有机相,真空浓缩,并通过使用0-10%在DCM中的甲醇的柱色谱法纯化,得到产物(1.53g,93.5%)。
(S)-2,4-二氨基-6-(1-(8-氯-2-(3,5-二氟苯基)-1-氧代-1,2-二氢异喹啉-3-基)乙基氨基)嘧啶-5-甲腈(DWL-PI3K-5)的合成。向(S)-4-(3-氯-2-(3,5-二氟苯基氨基甲酰基)苯基)-3-氧代丁-2-基氨基甲酸叔丁酯(51mg,0.11mmol)在DCM(3mL)中的溶液中添加在二噁烷中的4N HCl(3mL)。将该反应混合物在室温搅拌2h。除去溶剂,并将粗产物溶于DMSO(1.2mL)。向该溶液中添加2,4-二氨基-6-氯嘧啶-5-甲腈(23mg)和DIPEA(0.1mL)。将得到的混合物在125℃搅拌过夜。真空蒸发溶剂,并通过使用TLC与12%在DCM中的甲醇的制备型纯化粗产物,得到期望的产物(S)-2,4-二氨基-6-(1-(8-氯-2-(3,5-二氟苯基)-1-氧代-1,2-二氢异喹啉-3-基)乙基氨基)嘧啶-5-甲腈(DWL-PI3K-5)(8.7mg,16.5%)。
实施例6:DWL-PI3K-6
步骤1:2-氯-N-(3-氟苯基)-6-甲基苯甲酰胺的合成。将2-氯-6-甲基苯甲酸(7.5g,44mmol)和亚硫酰氯(30mL)的混合物在70℃加热3h,并在45℃减压浓缩。将得到的酰氯溶于CH2Cl2(30mL),并与3-氟苯胺(3-fluroaniline)(8.3g,74.8mmol)和三甲胺(7.5mL)混合。将该反应混合物在室温搅拌过夜,然后减压浓缩。将残余物溶于EtOAc(60mL)。用2NHCl(水溶液)(2x 20mL)和饱和NaHCO3水溶液(2x 20mL)洗涤该溶液,并真空浓缩。通过色谱法纯化产物,得到2-氯-N-(3-氟苯基)-6-甲基苯甲酰胺,为白色固体(10.5g,收率:100%)。
步骤2:(S)-(1-(8-氯-2-(3-氟苯基)-1-氧代-1,2-二氢异喹啉-3-基)乙基)氨基甲酸叔丁酯的合成。向在-30℃在氩气气氛中搅拌的2-氯-N-(3-氟苯基)-6-甲基苯甲酰胺(2.63g,10mmol)在无水THF(60mL)中的混合物中滴加2.5M正丁基锂的己烷溶液(2.6mL,2.5eq),历时30min。将得到的混合物在-30℃搅拌30min。
在-30℃至-10℃的温度下向在-30℃在氩气气氛中搅拌的(S)-(1-(甲氧基(甲基)氨基)-1-氧代丙-2-基)氨基甲酸叔丁酯(0.7g,1.5eq)在无水THF(30mL)中的混合物中滴加氯化异丙基镁在THF中的溶液(3.2mL,1.65eq),历时30min。将得到的混合物在-30℃搅拌30min。然后将该溶液缓慢地添加到上述反应混合物中,同时保持内部温度在-30℃至-10℃。将得到的混合物在-15℃搅拌1h,然后用水(40mL)猝灭,随后用浓HCl在-10℃至0℃酸化以调节pH至1-3。将该混合物温热至室温,并真空浓缩。将残余物溶于MeOH(50mL),然后添加浓HCl(25mL)。将得到的混合物在回流下搅拌1h。真空浓缩该反应混合物以便将体积减少至约45mL。用庚烷和乙酸乙酯的2:1混合物(2x60mL)萃取残余物。用浓氢氧化铵碱化水层,以调节pH至9-10,同时保持内部温度在-10℃至0℃。然后用CH2Cl2(3x 50mL)萃取该混合物。用盐水洗涤合并的有机萃取物。真空浓缩该溶液。通过硅胶柱色谱法纯化产物(EtOAc/MeOH5:1),得到(S)-(1-(8-氯-2-(3-氟苯基)-1-氧代-1,2-二氢异喹啉-3-基)乙基)氨基甲酸叔丁酯,为白色固体(0.56g,收率13%)。MS:m/z=417(M+1)。
步骤3:(S)-3-(1-氨基乙基)-8-氯-2-(3-氟苯基)异喹啉-1(2H)-酮的合成。将(S)-(1-(8-氯-2-(3-氟苯基)-1-氧代-1,2-二氢异喹啉-3-基)乙基)氨基甲酸叔丁酯(560mg,1.34mmol,步骤2中制备)和三氟乙酸(5mL)在CH2Cl2(20mL)中的混合物在室温搅拌过夜。真空浓缩该反应混合物,得到期望的产物(S)-3-(1-氨基乙基)-8-氯-2-(3-氟苯基)异喹啉-1(2H)-酮,为固体,定量收率。MS:m/z=317(M+1)。
步骤4:(S)-2,4-二氨基-6-((1-(8-氯-2-(3-氟苯基)-1-氧代-1,2-二氢异喹啉-3-基)乙基)氨基)嘧啶-5-甲腈(DWL-PI3K-6)的合成。将(S)-3-(1-氨基乙基)-8-氯-2-(3-氟苯基)异喹啉-1(2H)-酮(59mg,0.18mmol,步骤3中制备)、2,4-二氨基-6-氯嘧啶-5-甲腈(38mg,0.22mmol)、N,N-二异丙基乙胺(0.1mL)和氟化钾(36mg)在DMSO(3mL)中的混合物在90℃加热过夜。将该反应混合物冷却至室温,并添加EtOAc(20mL)。用H2O(3x 5mL)、1N HCl(水溶液)和饱和NaHCO3水溶液(2x 5mL)洗涤该溶液。真空浓缩有机萃取物。通过硅胶柱色谱法纯化粗产物(EtOAc/MeOH 20:1),得到期望的产物DWL-PI3K-6,为白色固体(21mg,收率:26%)。MS:m/z=450(M+1)。
实施例7:DWL-PI3K-7
步骤1:2-氯-6-甲基-N-(苯基-d5)苯甲酰胺的合成。将2-氯-6-甲基苯甲酸(4.2g,24mmol)和亚硫酰氯(30mL)的混合物在70℃加热3h,并在45℃减压浓缩。将得到的酰氯溶于CH2Cl2(30mL),并与苯胺-d5(2.0g,20mmol)和三乙胺(4mL,过量)混合。将该反应混合物在室温搅拌过夜,随后减压浓缩。将残余物溶于EtOAc(60mL),并用2N HCl(水溶液)(2x 20mL)和饱和NaHCO3水溶液(2x 20mL)洗涤。真空浓缩该溶液,得到2-氯-6-甲基-N-(苯基-d5)苯甲酰胺,为固体(5.0g,收率:100%)。MS:m/z=249(M-1)。
步骤2:(S)-(1-(8-氯-1-氧代-2-(苯基-d5)-1,2-二氢异喹啉-3-基)乙基)氨基甲酸叔丁酯的合成。向在-30℃在氩气气氛中搅拌的2-氯-6-甲基-N-(苯基-d5)苯甲酰胺(630mg,2.5mmol)在无水THF(30mL)中的混合物中滴加2.5M正丁基锂的己烷溶液(10mL,2.5eq),历时30min,同时保持温度在-30℃。然后将得到的混合物在-30℃搅拌30min。向在-30℃在氩气气氛中搅拌的(S)-(1-(甲氧基(甲基)氨基)-1-氧代丙-2-基)氨基甲酸叔丁酯(2.7g,1.5eq)在无水THF(60mL)中的搅拌混合物中滴加氯化异丙基镁在THF中的溶液(12.4mL,1.65eq),历时30min,同时保持内部温度在-30℃至-10℃。将得到的混合物在-30℃搅拌30min。然后将该溶液缓慢地添加到上述反应混合物中,同时保持内部温度在-30℃至-10℃。将得到的混合物在-15℃搅拌1h,然后用水(50mL)猝灭,并用浓HCl在-10℃至0℃酸化以调节pH至1-3。将该混合物温热至室温,并真空浓缩。将残余物溶于MeOH(50mL),然后添加浓HCl(25mL)。将得到的混合物在回流下搅拌1h。真空浓缩该反应混合物以便将体积减少至约45mL。用庚烷和乙酸乙酯的2:1混合物(2x20mL)萃取残余物。用浓氢氧化铵碱化水层,以调节pH至9-10,同时保持内部温度在-10℃至0℃。然后用CH2Cl2(3x 20mL)萃取该混合物,并用盐水洗涤。真空浓缩该溶液。通过硅胶柱色谱法纯化产物(EtOAc/MeOH 10:1),得到(S)-(1-(8-氯-1-氧代-2-(苯基-d5)-1,2-二氢异喹啉-3-基)乙基)氨基甲酸叔丁酯,为白色固体(140mg,收率:13.9%)。MS:m/z=404(M+1)。
步骤3:(S)-3-(1-氨基乙基)-8-氯-2-(苯基-d5)异喹啉-1(2H)-酮的合成。将步骤2中制备的(S)-(1-(8-氯-1-氧代-2-(苯基-d5)-1,2-二氢异喹啉-3-基)乙基)氨基甲酸叔丁酯(140mg,0.34mmol)和三氟乙酸(5mL)在CH2Cl2(20mL)中的混合物在室温搅拌过夜。真空浓缩该反应混合物,得到期望的产物,为定量收率。(S)-3-(1-氨基乙基)-8-氯-2-(苯基-d5)异喹啉-1(2H)-酮。MS:m/z=304(M+1)。
步骤4:(S)-2,4-二氨基-6-((1-(8-氯-1-氧代-2-(苯基-d5)-1,2-二氢异喹啉-3-基)乙基)氨基)嘧啶-5-甲腈(DWL-PI3K-7)的合成。将步骤3中制备的(S)-3-(1-氨基乙基)-8-氯-2-(苯基-d5)异喹啉-1(2H)-酮(45mg,0.15mmol)、2,4-二氨基-6-氯嘧啶-5-甲腈(38mg,0.22mmol)、N,N-二异丙基乙胺(0.1mL)和氟化钾(36mg)在DMSO(3mL)中的混合物在90℃加热过夜。将该反应混合物冷却至室温,并添加EtOAc(20mL)。用H2O(3x 10mL)、1N HCl(水溶液)和饱和NaHCO3水溶液(2x 5mL)洗涤该溶液。真空浓缩有机萃取物。通过硅胶柱色谱法纯化粗产物(EtOAc/MeOH 20:1),得到期望的产物DWL-PI3K-7,为白色固体(23mg,收率35%)。MS:m/z=437(M+1)。
实施例8
(S)-2-(5-氟-4-氧代-3-苯基-3,4-二氢喹唑啉-2-基)吡咯烷-1-甲酸叔丁酯的合成。向2-氨基-6-氟苯甲酸(0.5g,3.22mmol)和(S)-1-(叔丁氧基羰基)吡咯烷-2-甲酸(0.69g,3.22mmol)在吡啶(3mL)中的溶液中添加亚磷酸三苯酯(2.11mL,8.05mmol)。将该反应混合物加热至70℃,并在该温度保持2h。向上述混合物中添加苯胺(0.35mL,3.9mmol),然后将其搅拌8h。用乙酸乙酯稀释该反应混合物,用碳酸氢钠水溶液、水和盐水洗涤,用硫酸钠干燥,并真空浓缩。使用25%在己烷中的乙酸乙酯进行柱色谱,得到产物(0.99g,75%)。
(S)-5-氟-3-苯基-2-(吡咯烷-2-基)喹唑啉-4(3H)-酮的合成。将上述产物(S)-2-(5-氟-4-氧代-3-苯基-3,4-二氢喹唑啉-2-基)吡咯烷-1-甲酸叔丁酯溶于DCM/TFA(2:1之比),并将该反应混合物在室温搅拌1h,然后浓缩,得到产物(S)-5-氟-3-苯基-2-(吡咯烷-2-基)喹唑啉-4(3H)-酮,定量收率。
(S)-2-(1-(2-氨基-7H-嘌呤-6-基)吡咯烷-2-基)-5-氟-3-苯基喹唑啉-4(3H)-酮的合成。向(S)-5-氟-3-苯基-2-(吡咯烷-2-基)喹唑啉-4(3H)-酮(0.07mmol)在DMF(0.5mL)中的溶液中添加2-氨基-6-氯嘌呤和N,N-二异丙基乙胺(0.04mL),并将该反应体系在150℃在氩气气氛中搅拌1h。除去溶剂,并通过制备型TLC用10%在二氯甲烷中的甲醇纯化粗产物,得到产物(S)-2-(1-(2-氨基-7H-嘌呤-6-基)吡咯烷-2-基)-5-氟-3-苯基喹唑啉-4(3H)-酮(18.9mg,60%)。
实施例8
(S)-2,4-二氨基-6-(2-(5-氟-4-氧代-3-苯基-3,4-二氢喹唑啉-2-基)吡咯烷-1-基)嘧啶-5-甲腈的合成。向(S)-5-氟-3-苯基-2-(吡咯烷-2-基)喹唑啉-4(3H)-酮(0.06mmol)在DMF(0.5mL)中的溶液中添加2,4-二氨基-6-氯嘧啶-5-甲腈(10.2mg)和DIPEA(0.031mL,0.18mmol),并将得到的混合物在125℃在氩气气氛中搅拌2h。然后真空除去溶剂,并通过制备型TLC用10%在二氯甲烷中的甲醇纯化粗混合物,得到产物(S)-2,4-二氨基-6-(2-(5-氟-4-氧代-3-苯基-3,4-二氢喹唑啉-2-基)吡咯烷-1-基)嘧啶-5-甲腈(20.9mg,79%)。
实施例9
(S)-2-氨基-4-(2-(5-氟-4-氧代-3-苯基-3,4-二氢喹唑啉-2-基)吡咯烷-1-基)-6-甲基嘧啶-5-甲腈的合成。向(S)-5-氟-3-苯基-2-(吡咯烷-2-基)喹唑啉-4(3H)-酮(0.06mmol)在DMF(0.5mL)中的溶液中添加2-氨基-4-氯-6-甲基嘧啶-5-甲腈(10.1mg)和DIPEA(0.031mL,0.18mmol),并将得到的混合物在125℃在氩气气氛中搅拌2h。然后除去溶剂,并通过制备型TLC用10%在二氯甲烷中的甲醇纯化粗混合物,得到产物(S)-2-氨基-4-(2-(5-氟-4-氧代-3-苯基-3,4-二氢喹唑啉-2-基)吡咯烷-1-基)-6-甲基嘧啶-5-甲腈(22.2mg,84%)。
实施例10:PI3K抑制
测试如下所示的化合物对PI3Kα、PI3Kβ、PI3Kγ和PI3Kδ的抑制:
使用KINOMEscanTM(DiscoverX)测试化合物,其基于竞争结合测定法,该竞争结合测定法定量测量化合物与固定的活性位点定向配体竞争的能力。通过合并以下三种组分进行测定:DNA标记激酶;固定化配体;和测试化合物。通过DNA标记的定量PCR测定测试化合物与固定的配体竞争的能力。
对于大部分测定,在来源于BL21菌株的大肠杆菌(E.coli)宿主中制备激酶标记的T7噬菌体菌株,使其生长至对数期,并用T7噬菌体感染,并在32℃振荡下温育直至裂解。将裂解物离心并过滤以除去细胞碎片。其余的激酶在HEK-293细胞中产生,随后用DNA标记以进行qPCR检测。在室温下,用生物素化的小分子配体处理链霉抗生物素包被的磁珠30分钟,以生成亲和树脂用于激酶测定。用过量的生物素封闭配体珠,并用封闭缓冲液(SeaBlock(Pierce),1%BSA,0.05%Tween 20,1mM DTT)洗涤,以除去未结合的配体并减少非特异性结合。通过在1x结合缓冲液(20%SeaBlock,0.17x PBS,0.05%Tween 20,6mM DTT)中合并激酶、配体亲和珠和测试化合物来组装结合反应。将测试化合物制备成在100%DMSO中的111X储备液。使用具有三个DMSO对照点的11-点3-倍化合物稀释系列确定Kd。用于Kd测量的所有化合物均通过在100%DMSO中的声学传递(非接触式分配)进行分配。然后将化合物直接稀释到测定中,以使DMSO的最终浓度为0.9%。所有反应在聚丙烯384-孔板中进行。各自为0.02mL的终体积。将测定板在室温下摇动温育1小时,并用洗涤缓冲液(1x PBS,0.05%Tween 20)洗涤亲和珠。然后将珠重悬于洗脱缓冲液(1x PBS,0.05%Tween 20,0.5μM非生物素化的亲和配体)中,并在室温下振摇温育30分钟。通过qPCR测定洗脱液中的激酶浓度。
在100%DMSO中制备100x最终测试浓度的每种测试化合物的11-点3-倍系列稀释液,然后在测定中稀释至1x(最终DMSO浓度=1%)。使用化合物最高浓度=30,000nM来测定大部分Kd。如果确定的初始Kd<0.5nM(测试的最低浓度),则以从较低的最高浓度开始的系列稀释液重复测定。报告的Kd值为40,000nM,表明将Kd测定为>30,000nM。
结合常数(Kd)使用Hill方程通过标准剂量响应曲线计算:
将Hill斜率设置为-1。使用非线性最小二乘拟合和Levenberg-Marquardt算法拟合曲线。下表4显示了对这些化合物测定的结果,其中PIK3CA为PI3Kα,PIK3CB为PI3Kβ,PIK3CD为PI3Kγ,且PIK3CG为PI3Kδ:
实施例11:细胞试验
评价化合物DWL-PI3K-1、DWL-PI3K-2、DWL-PI3K-3、DWL-PI3K-4、DWL-PI3K-5、DWL-PI3K-6和DWL-PI3K-7和参比化合物CAL-130、tenalisib、度维利塞对多种癌细胞的效能(通过测量ATP(CellTiter-Glo)或碘化丙啶(PI)摄取量来提高细胞存活率),所述多种癌细胞包括LM0-2-007、OCI-LY-10、HH、H9、PF382和CCRF-CEM。结果如图7-14和17-20中所示。
实施例12:DWL-PI3K-3处理的
每12h用10mg/kg的化合物DWL-PI3K-3处理具有表达萤光素酶的遗传诱导的T-ALL小鼠7天。结果如图16-17中所示,表明肿瘤负荷显著降低,正如通过治疗后荧光素信号的缺失和Ki67/thy1.2阳性群体减少所证实的。
贯穿本申请引用的所有参考文献、待审专利申请和公开专利的内容在此明确地通过引用并入。
上述实施方案仅以实施例的方式给出。本领域普通技术人员将理解,可以在不脱离本发明的精神和范围的情况下进行各种变型。
Claims (28)
3.权利要求2的化合物,其中:
R1、R2、R3、R4和R5独立地为氢、甲基、F或氘;
R9为Cl、F或甲基;且
R10、R11和R12各自为氢。
5.前述权利要求任一项的化合物,其中:
R1、R2、R3、R4和R5独立地为氢、F或氘;
R6为甲基;且
R9为Cl或甲基。
10.权利要求9的化合物,其中X为N且R'为氢。
12.前述权利要求任一项的化合物,其中对于R6所连接的手性碳而言,所述化合物为(S)或(R)立体异构体,或所述化合物为(S)和(R)立体异构体的非外消旋混合物,或所述化合物为单独的(S)异构体或单独的(R)异构体。
13.前述权利要求任一项的化合物,其中所述化合物为PI3Kδ抑制剂、PI3Kγ抑制剂、或PI3Kδ和PI3Kγ二者的抑制剂。
14.权利要求13的化合物,其中所述化合物为PI3Kδ和PI3Kγ二者的抑制剂。
15.药物组合物,包含前述权利要求任一项的化合物和药学上可接受的载体。
16.前述权利要求任一项的化合物,其中所述化合物为药物组合物形式,其中所述化合物为PI3Kδ和PI3Kγ的双重抑制剂,或其中所述组合物包含为PI3Kδ抑制剂的一种活性剂和为PI3Kγ抑制剂的第二种活性剂。
17.用于治疗非霍奇金淋巴瘤的方法,包括对有此需要的受试者施用有效量的前述权利要求任一项的化合物或组合物。
18.权利要求的方法17,其中所述非霍奇金淋巴瘤为T-细胞淋巴瘤。
19.权利要求的方法18,其中所述T-细胞淋巴瘤为外周T-细胞淋巴瘤。
20.治疗淋巴瘤或白血病的方法,包括对有此需要的受试者施用有效量的权利要求1-16任一项的化合物或组合物。
21.权利要求20的方法,其中所述淋巴瘤或白血病为急性淋巴细胞白血病(ALL)、T细胞急性淋巴细胞白血病(T-ALL)、B细胞急性淋巴细胞白血病(B-ALL)、T细胞淋巴瘤、外周T细胞淋巴瘤(PTCL)、皮肤T细胞淋巴瘤(CTCL)、B细胞淋巴瘤、滤泡性淋巴瘤、皮肤B细胞淋巴瘤或慢性淋巴细胞白血病(CLL)。
22.权利要求20的方法,其中所述淋巴瘤或白血病为T-ALL。
23.权利要求17-22任一项的方法,还包括对受试者共同施用至少一种化疗剂。
24.权利要求23的方法,其中所述化疗剂为放线菌素,安吖啶,蒽环类抗生素,白消安,顺铂,环磷酰胺,表柔比星,六甲蜜胺奥沙利铂,异环磷酰胺,米托蒽醌,泰索帝,替尼泊苷,三亚乙基硫代磷酰胺,氢化可的松,可的松,甲泼尼龙,泼尼松龙,地塞米松,泼尼松,倍他米松,曲安西龙,倍氯米松,氟氢可的松,脱氧皮质酮,醛固酮,奥沙利铂,唑来膦酸,伊班膦酸盐,维拉帕米,鬼臼毒素,卡铂,丙卡巴肼,氮芥,环磷酰胺,喜树碱,异环磷酰胺,美法仑,苯丁酸氮芥,bisulfan,亚硝基脲,更生霉素,柔红霉素,多柔比星,博来霉素,普卡霉素,丝裂霉素,依托泊苷(VP16),他莫昔芬,反铂,5-氟尿嘧啶,长春新碱,长春碱,甲氨蝶呤,L-天冬酰胺酶,雷帕霉素,二苯并氮卓(DBZ),乌拉莫司汀,卡莫司汀,洛莫司汀,链佐星,替莫唑胺,奥沙利铂,伊达比星,托泊替康,培美曲塞,6-巯基嘌呤,达卡巴嗪,氟达拉滨,5-氟尿嘧啶,阿拉伯糖胞嘧啶,5-氟尿嘧啶,阿糖胞苷,卡培他滨,吉西他滨,地西他滨,长春花生物碱,紫杉醇多西他赛伊沙匹隆或其组合。
25.权利要求24的方法,其中所述化疗剂为糖皮质激素,其选自氢化可的松,可的松,甲泼尼龙,泼尼松龙,地塞米松,泼尼松,倍他米松,曲安西龙,倍氯米松,氟氢可的松,脱氧皮质酮,醛固酮及其组合。
26.权利要求25的方法,其中所述化疗剂为地塞米松。
27.权利要求17-26任一项的方法,其中所述化合物为药物组合物形式,所述药物组合物包含有效量的所述化合物和药学上可接受的载体。
28.权利要求27的方法,其中所述组合物为单位剂型形式。
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US20200165211A1 (en) | 2020-05-28 |
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