CN113786409A - 包含磷酸肌醇3-激酶抑制剂和第二抗增殖剂的组合物 - Google Patents
包含磷酸肌醇3-激酶抑制剂和第二抗增殖剂的组合物 Download PDFInfo
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Abstract
本发明涉及药物组合物,包含式(I)的化合物或其药物可接受的盐以及至少一种第二试剂的组合,所述第二试剂选自信号传导途径抑制剂、肿瘤免疫治疗剂、抑制BCL2家族蛋白的试剂、抑制Mcl‑1的试剂、蛋白酶体抑制剂、聚(ADP‑核糖)聚合酶(PARP)抑制剂、芳香化酶抑制剂、常规细胞毒性试剂或选自阿比特龙、ARN‑509和MYC抑制剂的其他试剂。
Description
发明领域
本发明涉及新型组合,该组合包含与其他特定抗肿瘤化合物组合的作为IA类磷酸肌醇3-激酶酶(PI3K-p110δ和PI3K-p110β)的抑制剂的化合物。这种组合可用于癌症的治疗。
发明背景
磷酸肌醇3-激酶(PI3K)构成了参与控制一系列细胞过程的信号转导通路网络的调节的脂质激酶家族。基于其底物的特异性,PI3K分为三个不同的亚家族,称为I类、II类和III类。IA类PI3K具有与三个调节亚基p85α、p85β或p55δ之一复合的p110α、p110β或p110δ催化亚基。IA类PI3K通过受体酪氨酸激酶、抗原受体、G-蛋白偶联受体(GPCR)和细胞因子受体激活。IA类PI3K主要产生磷脂酰肌醇-3,4,5-三磷酸盐(PI(3,4,5)P3),其是激活下游靶AKT的第二信使。AKT生物活化的结果包括肿瘤细胞进展、肿瘤细胞增殖、肿瘤细胞存活和生长,并且存在大量的证据表明在许多的人类癌症中PI3K/AKT通路被异常调节。此外,PI3K活性已涉及内分泌学、心血管疾病、免疫失调及炎症。已经确定PI3K-p110δ在免疫细胞和炎性细胞的募集和活化中起着关键性作用。PI3K-p110δ还在许多的人类肿瘤中上调并且在肿瘤细胞增殖和存活中起着关键作用。
能够调节p110β和p110δ活性的化合物在癌症及免疫失调和炎性病症中具有重要的治疗潜力。
发明概述
本发明部分涉及某些PI3K化合物和某些其他抗肿瘤化合物的组合。这些组合可以是协同的并且因此可以相对于单独的组分提供改进。例如,这些组合可以允许施用较低的剂量。本发明至少部分基于本文呈现的数据。
本文公开的某些PI3K抑制剂还公开于PCT/GB2015/050396(其至2015年8月19日止还未公开,并且其内容通过引用并入本文)。相比于WO2011/021038(其也通过引用并入本文)中描述的化合物,本文公开的某些PI3K抑制剂可以具有增大的活性和/或生物利用度。
本发明部分涉及某些PI3K抑制剂与某些抗肿瘤剂的组合。
因此,本发明是药物组合物,其包含式I的PI3K抑制剂:
或其药物可接受的盐,其中:
W为O、N-H、N-(C1-C10烷基)或S;
各个X每次出现时独立地选自CH、CR3或N;
R1为5元至7元的饱和或不饱和的、任选取代的杂环,所述杂环含有选自N或O的至少1个杂原子;
R2为L-Y;
各个L选自化学键、C1-C10亚烷基、C2-C10亚烯基和C2-C10亚炔基;
Y为任选取代的稠合、桥连或螺环的非芳香族杂环,所述非芳香族杂环含有各自独立地选自N或O的至多4个杂原子(例如,一个杂原子、两个杂原子、三个杂原子或四个杂原子),且总计包含5至12个碳原子或杂原子;以及
各个R3独立地为H、C1-C10烷基、卤素、氟代C1-C10烷基、O-C1-C10烷基、-NH-C1-C10烷基、S-C1-C10烷基、O-氟代C1-C10烷基、NH-酰基、NH-C(O)-NH-C1-C10烷基、C(O)-NH-C1-C10烷基、芳基或杂芳基;
与以下的组合
选自信号转导途径抑制剂、肿瘤免疫治疗剂、抑制BCL2家族蛋白的试剂、抑制Mcl-1的试剂、蛋白酶体抑制剂、聚(ADP-核糖)聚合酶(PARP)抑制剂、芳香化酶抑制剂、常规细胞毒性试剂或选自阿比特龙、ARN-509和MYC抑制剂的其他试剂中的至少一种试剂。
优选实施方案描述
定义
如本文所使用,“烷基”意指C1-C10烷基,其可以是直链的或支链的。优选地,其为C1-C6烷基部分。更优选地,其为C1-C4烷基部分。实例包括甲基、乙基、正丙基和叔丁基。其可以是二价的,例如亚丙基。
如本文所使用,“烯基”意指C2-C10烯基。优选地,其为C2-C6烯基。更优选地,其为C2-C4烯基。所述烯基可以是单饱和的或双饱和的,更优选为单饱和的。实例包括乙烯基、烯丙基、1-丙烯基、异丙烯基和1-丁烯基。其可以是二价的,例如亚丙烯基。
如本文所使用,“炔基”为C2-C10炔基,其可以是直链或支链的。优选地,其为C2-C4炔基或部分。其可以是二价的。
C1-C10烷基、C2-C10烯基和C2-C10炔基中的每一个可以被彼此任选取代,即,C1-C10烷基被C2-C10烯基任选取代。它们也可以被芳基、环烷基(优选为C3-C10)、芳基或杂芳基任选取代。它们也可以被卤素(例如F、Cl)、NH2、NO2或羟基取代。优选地,它们可以被至多10个卤素原子或更优选至多5个卤素原子取代。例如,它们可以被1个卤素原子、2个卤素原子、3个卤素原子、4个卤素原子或5个卤素原子取代。优选地,所述卤素为氟。例如,它们可以被CF3、CHF2、CH2CF3、CH2CHF2或CF2CF3取代。
如本文所使用,术语“氟代C1-C10烷基”意指被一个或多个氟原子取代的C1-C10烷基。优选地,一个氟原子、两个氟原子、三个氟原子、四个氟原子或五个氟原子。“氟代C1-C10烷基”的实例为CF3、CHF2、CH2F、CH2CF3、CH2CHF2或CF2CF3。
如本文所使用,“芳基”意指单环、双环或三环的一价或二价(视情况而定)的芳香族基团,例如苯基、联苯基、萘基、蒽基,其可以被优选选自以下的至多五个取代基任选取代:C1-C6烷基、羟基、C1-C3羟烷基、C1-C3烷氧基,C1-C3卤代烷氧基、氨基、C1-C3单烷基氨基,C1-C3双烷基氨基、C1-C3酰氨基,C1-C3氨基烷基、单(C1-C3烷基)氨基C1-C3烷基、双(C1-C3烷基)氨基C1-C3烷基、C1-C3-酰氨基、C1-C3烷基磺酰基氨基、卤素、硝基、氰基、三氟甲基、羧基、C1-C3烷氧基羰基、氨基羰基、单C1-C3烷基氨基羰基、双C1-C3烷基氨基羰基、-SO3H、C1-C3烷基磺酰基、氨基磺酰基、单C1-C3烷基氨基磺酰基和双C1-C3-烷基氨基磺酰基。
如本文所使用,“杂芳基”意指单环、双环或三环的一价或二价(视情况而定)的芳香族基团,其包含选自氧、氮和硫的至多四个杂原子,例如,噻唑基、异噻唑基、四唑基、咪唑基、噁唑基、异噁唑基、噻吩基、吡唑基、吡啶基、吡嗪基、嘧啶基、吲哚基、喹啉基、异喹啉基、三唑基、噻二唑基、噁二唑基,所述基团被优选选自以下的至多三个取代基任选取代:C1-C6烷基、羟基、C1-C3羟烷基、C1-C3烷氧基、C1-C3卤代烷氧基、氨基、C1-C3单烷基氨基、C1-C3双烷基氨基、C1-C3酰氨基、C1-C3氨基烷基、单(C1-C3烷基)氨基C1-C3烷基、双(C1-C3烷基)氨基C1-C3烷基、C1-C3-酰氨基、C1-C3烷基磺酰基氨基、卤素、硝基、氰基、三氟甲基、羧基、C1-C3烷氧基羰基、氨基羰基、单C1-C3烷基氨基羰基、双C1-C3烷基氨基羰基、-SO3H、C1-C3烷基磺酰基、氨基磺酰基、单C1-C3烷基氨基磺酰基和双C1-C3-烷基氨基磺酰基。
如本文所使用,术语“杂环”或“杂环烷基”为包含选自氧、氮和硫的至多4个杂原子的一价或二价的碳环基团。优选地,其包含一个或两个杂原子。优选地,杂原子中的至少一个为氮。其可以是单环或双环。其优选地是饱和的。杂环的实例为哌啶、哌嗪、硫代吗啉、吗啉、氮杂环丁烷或氧杂环丁烷。更优选地,所述杂环为吗啉。
所述杂环可以是单不饱和的或双不饱和的。所述基团可以被独立地选自以下的至多三个取代基任选取代:C1-C6烷基、羟基、C1-C3羟烷基、C1-C3烷氧基、C1-C3卤代烷氧基、氨基、C1-C3单烷基氨基、C1-C3双烷基氨基、C1-C3酰氨基、C1-C3氨基烷基、单(C1-C3烷基)氨基C1-C3烷基、双(C1-C3烷基)氨基C1-C3烷基、C1-C3-酰氨基、C1-C3烷基磺酰基氨基、卤素(例如F)、硝基、氰基、羧基、C1-C3-卤代烷基(例如CF3)、C1-C3烷氧基羰基、氨基羰基、单C1-C3烷基氨基羰基、双C1-C3烷基氨基羰基、-SO3H、C1-C3烷基磺酰基、氨基磺酰基、单C1-C3烷基氨基磺酰基和双C1-C3-烷基氨基磺酰基。
总之,上述定义的各个基团,即,烷基、烯基、炔基、芳基、杂芳基、杂环、杂环烷基,可以被优选选自以下的至多三个取代基任选取代:C1-C6烷基、羟基、C1-C3羟烷基、C1-C3烷氧基、C1-C3卤代烷氧基、氨基、C1-C3单烷基氨基、C1-C3双烷基氨基、C1-C3酰氨基、C1-C3氨基烷基、单(C1-C3烷基)氨基C1-C3烷基、双(C1-C3烷基)氨基C1-C3烷基、C1-C3-酰氨基、C1-C3烷基磺酰基氨基、酰基、卤素(例如氟)、硝基、氰基、三氟甲基、羧基、C1-C3烷氧基羰基、氨基羰基、单C1-C3烷基氨基羰基、双C1-C3烷基氨基羰基、-SO3H、C1-C3烷基磺酰基、氨基磺酰基、单C1-C3烷基氨基磺酰基和双C1-C3-烷基氨基磺酰基。
应注意,-NH-C1-C10烷基、NH-酰基、NH-C(O)-NH-C1-C10烷基和C(O)-NH-C1-C10烷基也可以写成-N-C1-C10烷基、N-酰基、N-C(O)-N-C1-C10烷基和C(O)-N-C1-C10烷基。
如本文所使用,上述基团可以加前缀“亚……”。这意指所述基团为二价,即连接基团。
如本文所使用,术语“稠合”意图采取其在有机化学领域中的通常含义。稠合体系,例如稠合双环体系,是其中两个环共用两个原子且只共用两个原子的那些。
如本文所使用,术语“桥连”意图采取其在有机化学领域中的通常含义。桥连化合物为包含联锁环的化合物。根据本发明,形成桥头的桥连非芳香族基团的原子是叔碳原子(当其余的原子为氢时)或季碳原子(当其余的原子不为氢时)。可以认为所述桥是原子链(例如,烷基)或连接两个桥头的单个原子(例如,O、S、N、C)。
如本文所使用,术语“螺环”意图采取其在有机化学领域的通常含义。例如,螺环化合物是其中环通过仅仅一个原子(被称为螺原子)连接的双环。所述环的大小可以是不同的,或者它们可以大小相同。优选地,根据本发明,经相同原子连接的两个环为非芳香族杂环,优选为杂环烷基。例如,式I的螺环非芳香族基团可以是其中两个环均为杂环烷基且通过相同的原子(优选碳原子)连接的双环。
由于不对称原子或转动限制的存在,本发明涉及的化合物可以以一种或多种立体异构形式存在,其可以以在各个手性中心处具有R或S立体化学的多种立体异构体形式存在,或者以在各个手性轴处具有R或S立体化学的旋转对映异构体形式存在。本发明包括所有此类对映异构体和非对映异构体及其混合物。
本发明的优选组-式(I)的化合物
优选地,本发明的化合物如权利要求1中所定义,但此外可以是其中至少一个R3为NH2的化合物。
优选地,R1由下列结构的任一个表示:
最优选地,R1为吗啉。
在本发明的优选实施方案中,W为氧或硫,优选为氧。
优选地,X为CH。
优选地,R3为H、C1-C10烷基、卤素或氟代C1-C10烷基。更优选地,R3为H。
优选地,式I中的6,5-环体系为吲哚。换言之,R3为氢且X为CH。
如通式I所述,可以将R2连接于芳基上的任何合适的原子。然而,优选地,将R2连接于吡啶环的间位。例如,如果将吡啶的氮原子标记为原子序数1,那么R2连接在3-位置。
R2为LY。优选地,L为C1-C10亚烷基,优选为亚甲基。
优选地,Y为任选取代的桥连杂环烷基或螺环杂环烷基,其包含选自N或O的至多4个杂原子,且总计包含5至12个原子。
优选地,Y包含一个或两个杂原子,优选地包含两个杂原子。更优选地,如在以下优选的Y基团中所述,杂原子中的至少一个为氮且Y通过所述氮原子与L连接:
其中:
A选自O、S、NR4、任选取代的C1-C3亚烷基、C2-C3亚烯基和C2-C3亚炔基;
B选自NR4、O和CH2;
其中R4选自H、任选取代的C1-C10烷基、C2-C10烯基、C2-C10炔基和C1-C3卤代氟烷基;
p选自0、1或2;
各个m独立地选自0、1或2;以及
各个n独立地选自1、2或3。
优选地,A为O或C1-C3亚烷基,最优选为亚甲基。
优选地,B为O或CH2,最优选为O。
当R4存在时,其优选为H、C1-C3烷基或C1-C3卤代氟烷基。更优选地,R4为H。
优选地,选择各个m及各个n以便形成5元、6元或7元的含氮的杂环烷基。优选地,p为1。具体地,当A为O、S或NR4时,p为1。
优选地,Y为双环,更优选为桥连双环或螺环双环。
甚至更优选地,Y选自以下基团中的一个:
在某些实施方案中,本文提供了由以下表示的化合物:
在另一实施方案中,本文提供了由以下表示的化合物:
R33每次出现时独立地选自H、卤素、NH-C1-3烷基、NH2、C1-6烷基和-O-C1-6烷基(其中每次出现时C1-6烷基被选自卤素和羟基中的一个、两个或三个取代基任选取代);
R34选自H或C1-3烷基;
R44和R45,当与它们所连接的氮一起时,形成7元至10元的双环的螺环杂环或桥连杂环,所述螺环杂环或桥连杂环各自含有选自O、S或NR55的另外的杂原子,其中R55为H或C1-3烷基。
例如,R44和R45,当与它们所连接的氮一起时,可以形成由以下表示的7元至8元的双环桥连杂环:
其中D为O、S或NR55;E为O或(CH2)r,其中r为1或2,且V为O或NR55,其中R55为H或C1-3烷基。
在另一示例性实施方案中,R44和R45,当与它们所连接的氮一起时,形成7元至10元螺环,其含有选自O或NR55的一个另外的杂原子,其中R55为H或C1-3烷基。可选地,R44和R45,与它们所连接的氮一起可以是如上所述的Y取代基。
体现本发明的结构的实例为:
本发明的优选组合试剂
式(I)的PI3K抑制剂可以与信号传导途径抑制剂组合。
在一些实施方案中,所述信号传导途径抑制剂选自以下列表:
a.布鲁顿氏酪氨酸激酶(BTK)抑制剂(例如依鲁替尼、CC-292、CNX-774、CGI1746、LFM-A13、RN486);
b.脾酪氨酸激酶(SYK)抑制剂(例如R788(福他替尼(Fostamatinib)、R406、GS-9973、白皮杉醇(Piceatannol)、PRT062607);
c.BMX非受体酪氨酸激酶抑制剂;BMX是Tec家族激酶的成员。抑制剂包括BMX-IN-1;
d.间变性淋巴瘤激酶(ALK)抑制剂(例如色瑞替尼、克唑替尼、TAE684、AP26113、艾乐替尼、PF-06463922、GSK1838705A、AZD3463、ASP3016;
e.酪氨酸激酶的小分子抑制剂,以及靶向酪氨酸激酶的生物试剂,所述酪氨酸激酶包括生长因子受体酪氨酸激酶,所述抑制剂和生物试剂例如:
i.表皮生长因子受体(EGFR)(例如曲妥单抗、西妥昔单抗(Cetixumab)、帕尼单抗、扎鲁木单抗(Zalutumumab)、尼妥珠单抗(Nimotuzumab)、马妥珠单抗、吉非替尼、埃罗替尼、拉帕替尼、AP26113);
ii.血小板源生长因子受体(PDGFR)(例如索拉非尼、舒尼替尼、卡博替尼(Cabozantinib)、阿西替尼、AZD2932、多韦替尼、LY2874455、福瑞替尼(Foretinib)、凡德他尼、SKLB1002、BMS-794833、Ki8751、阿帕替尼、AEE788、Tivozanib、布立尼布(Brivanib)、ENMD-2076、乐伐替尼、OSI-930、帕唑帕尼、RAF265、CYC116、PD173074、PD173074、KRN633、卡博替尼、ZM306416、戈伐替尼(Golvatinib)、ZM323881、司马沙尼(Semaxanib)、SAR131675、MGCD-265、奥安替尼(Orantinib)、Vantanalib、西地尼布(Cediranib)、瑞戈非尼(Regorafenib));
iii.成纤维细胞生长因子受体(FGFR)(例如帕纳替尼、BGJ398、尼达尼布、PD173074、CH5183284、LY2874455、AZD4547、达鲁舍替(Danusertib)、酪氨酸磷酸化抑制剂(Tyrphostin)、SSR128129E、MK-2461、布立尼布、TSU-68);
iv.血管内皮生长因子受体(VEGFR)(例如卡博替尼、PD153035)。
f.血管内皮生长因子(VEGF)抑制剂(例如贝伐珠单抗、兰尼单抗)。
g.核糖体蛋白S6激酶(p-70S6K)的小分子抑制剂(例如LY2584702、BI-D1870、PF-4708671、AT7867、AT13148)。
h.哺乳动物雷帕霉素靶标(mTOR)的抑制剂(例如雷帕霉素、依维莫司、AZD8055、西罗莫司脂化物(Temsirolimus)、MHY1485、佐他莫司(Zotarolimus)、KU-0063794、ETO-46464、GDC-0349、XL388、WYE-354、WYE-125132、WAY-600、WYE-687、PP121、AZD2014、INK128、Voxtalisib、地磷莫司(Ridaforolimus)、Torkinib、OSI-027、Palomid529)。
i.RAF激酶抑制剂(例如维罗非尼、达拉非尼、索拉非尼、PLX-4720、LY3009120、RAF265、AZ638、恩可非尼(Encorafenib)、GDC-0879、CEP-32496、TAK-632、ZM-336372、NVP-BHG712、SB590885、GW5074);
j.丝裂原活化蛋白激酶(MEK)抑制剂(例如曲美替尼、司美替尼、PD0325901、U0126、PD184352、GDC-0623、BI-847325、考比替尼(Cobimetinib)、PD98059、BIX-02189、比尼替尼(Binimetinib)、Pimasertib、CL-327、AZD8330、TAK-733、PD318088、Redametinib);
k.BCR-ABL抑制剂(例如伊马替尼、达沙替尼、塞卡替尼、尼罗替尼、帕纳替尼、PD173955、达鲁舍替、AT9283、GNF-5、GZD824、KW-2449、DCC-2036、NVP-BHG712、GNF-2、巴氟替尼(Baferinib)、Degrasyn);
l.细胞外信号调节激酶(ERK)抑制剂(例如SCH772984、XMD8-92、FR-180204、GDC-0994、ERK5-IN-1、Ulixertinib);
m.JAK-STAT信号转导抑制剂(例如帕克替尼(Pacritinib)、托法替尼、AZD1480、鲁索替尼(Ruxolitinib)、Fedratinib、AT9283、赛度替尼(Cerdulatinib)、非戈替尼(Filgotinic)、Go6976、AG-490、Momelotinib、GLPG0634、ZM039923、ZL019、莪术醇、CEP-33779、AZ-960、TG1011209、NVP-BSK805、Baricitinib、AP1066、WHI-P154、甘多替尼(Gandotinib));
n.NF-κB-诱导激酶(NIK)抑制剂。
式(I)的化合物可以与肿瘤免疫治疗剂组合。
在一些实施方案中,所述肿瘤免疫治疗剂选自以下列表:
·小分子
a.HDAC6抑制剂;
b.吲哚胺-2,3-双加氧酶(IDO)抑制剂(例如NLG919、INCB024360、吲哚莫德(Indoximod));
c.免疫调节剂(IMiD)(例如来那度胺、泊马度胺、沙利度胺);
·生物试剂
a.抗PD-1试剂:(例如派姆单抗、纳武单抗(Nivolumab)、皮地利珠单抗(Pidilizumab)、AMP-224);
b.抗PD-L1试剂(例如MSB0010718C、阿特珠单抗(Atezolizumab)、MEDI4736、MPDL3280A);
c.CTLA-4靶向试剂(例如易普利姆玛(Ipilimumab))。
式(I)的化合物可以与抑制BCL2家族蛋白(例如BCL-2、BCL-xL、BCL-w)的试剂组合。实例包括ABT-737、ABT-263、奥巴克拉(Obatoclax)、维特克拉(Venetoclax)、萨布克拉(Sabutoclax)、AT101、HA14-1、BAM7。
式(I)的化合物可以与抑制Mcl-1的试剂(例如UMI-77)组合。
式(I)的化合物可以与蛋白酶体抑制剂(例如卡非佐米、硼替佐米、MG-132、MLN9708、艾沙唑米(Ixazomib)、ONX-0914、Oprozomib、PI-1840、CEP-18770、雷公藤红素(Celastrol))组合。
式(I)的化合物可以与聚(ADP-核糖)聚合酶(PARP)抑制剂(例如奥拉帕尼、维利帕尼(Veliparib)、瑞卡帕布(Rucaparib)、Inipararib、Talazoparib、G007-LK、NU1025、AG-14361、INO-1001、UPF-1069、AZD-2461、PJ34、ME0328、A-966492)组合。
式(I)的化合物可以与芳香化酶抑制剂(例如来曲唑、阿那曲唑)组合。
式(I)的化合物可以与常规细胞毒性试剂组合,所述常规细胞毒性试剂包括:铂复合物,例如顺铂和卡铂;米托蒽醌;长春花生物碱,例如长春新碱和长春花碱;蒽环类抗生素,例如道诺菌素和阿霉素;烷基化试剂,例如瘤可宁和美法仑;紫杉烷类,例如紫杉醇;叶酸拮抗剂,例如氨甲蝶呤和雷替曲塞;表鬼臼毒素,例如依托泊苷;喜树碱类,例如伊立替康及其活性代谢物SN38;DNA甲基化抑制剂,例如在WO02/085400中公开的DNA甲基化抑制剂。
式(I)的化合物可以与选自阿比特龙、ARN-509、MYC抑制剂的其他试剂组合。
一般描述-组合物(组合)
本发明的药物组合物包含如上定义的化合物/组合以及药物可接受的载体或稀释剂。本发明的药物组合物通常包含至多85wt%的本发明的化合物。更通常地,其包含至多50wt%的本发明的化合物。优选的药物组合物为无菌的且无热原的。此外,本发明提供的药物组合物通常包含为基本上纯的光学异构体的本发明的化合物。优选地,所述药物组合物包含本发明的化合物的药物可接受的盐形式。例如,本文涵盖的是包含所公开的化合物及药物可接受的赋形剂的药物可接受的组合物。
如本文所使用,药物可接受的盐为与药物可接受的酸或碱的盐。药物可接受的酸包括:无机酸,例如盐酸、硫酸、磷酸、焦磷酸、氢溴酸或硝酸;以及有机酸,例如柠檬酸、富马酸、马来酸、苹果酸、抗坏血酸、琥珀酸、酒石酸、苯甲酸、醋酸、甲磺酸、乙磺酸、水杨酸、硬脂酸、苯磺酸或对甲苯磺酸。药物可接受的碱包括:碱金属(例如钠或钾)氢氧化物和碱土金属(例如钙或镁)氢氧化物,以及诸如烷基胺、芳基胺或杂环胺的有机碱。
为避免产生疑义,本发明还包括在体内反应以产生本发明的化合物的前药。
可以通过将对本领域技术人员而言为显而易见的合成路线(例如基于实施例)来制备本发明的化合物。
可以以多种剂型施用本发明的化合物及包含该化合物的组合物。在一个实施方案中,可以将包含本发明的化合物的药物组合物配制为适于口服施用、直肠施用、肠胃外施用、鼻内施用或经皮施用的形式,或者适于通过吸入施用或通过栓剂施用的形式。典型的施用途径为肠胃外施用、鼻内施用或经皮施用或者通过吸入施用。
可以口服施用本发明的化合物,例如以片剂、含片(troche)、锭剂、水性悬浮液或油性悬浮液、可分散的散剂或粒剂的形式。优选的本发明的药物组合物为适于口服施用(例如片剂和胶囊)的组合物。在一些实施方案中,与例如在上述R2处含有非螺环或非桥连的杂环部分的化合物相比,所公开的化合物可以具有显著更高的口服生物利用度。
还可以肠胃外施用本发明的化合物,不论是皮下、静脉内、肌内、胸骨内、经皮或通过输注技术。还可以以栓剂的形式施用化合物。
还可以通过吸入施用本发明的化合物。与经口服途径摄取的许多药物相比,吸入药物的优势为其直接递送至血液供给丰富的区域。因此,由于肺泡具有巨大的表面积和丰富的血液供给且避免了首过代谢,因此吸收是非常快的。另一个优势可以是治疗肺部系统的疾病,使得通过吸入递送的药物将药物递送至需要治疗的细胞附近。
本发明还提供了包含此类药物组合物的吸入装置。通常,所述装置为定量吸入器(MDI),其包含药物可接受的化学推进剂以将药物推出吸入器。
还可以通过鼻内施用来施用本发明的化合物。鼻腔的高渗透性组织非常易于接受药物并对其进行快速且有效地吸收,这胜过片剂形式的药物。与注射相比,鼻部药物递送的疼痛较少且侵入性较少,在患者中产生较少的焦虑。通过该方法,吸入是非常快的且通常避免了首过代谢,因此降低了患者与患者之间的可变性。此外,本发明还提供包含此类药物组合物的鼻内装置。
还可以通过经皮施用来施用本发明的化合物。因此,本发明也提供包含本发明的化合物的经皮贴剂。
还可以通过舌下施用来施用本发明的化合物。因此,本发明还提供包含本发明的化合物的舌下片剂。
还可以将本发明的化合物与降低物质降解(通过除了患者的正常代谢之外的过程)的试剂一起配制,所述试剂例如为抗菌剂或者蛋白酶抑制剂,所述蛋白酶可能存在于患者中或存在于患者体表或患者体内的共生生物或寄生生物中,并且能够降解化合物。
用于口服施用的液体分散剂可以是糖浆、乳剂和悬浮剂。
悬浮剂和乳剂可以包含作为载体的例如天然胶、琼脂、海藻酸钠、果胶、甲基纤维素、羧甲基纤维素或聚乙烯醇。用于肌内注射的悬浮剂或溶液可以包含与活性化合物一起的药物可接受的载体,例如无菌水、橄榄油、油酸乙酯、二醇(例如丙二醇),并且若需要,包含适量的盐酸利多卡因。
用于注射或输注的溶液可以包含作为载体的例如无菌水,或优选地,它们可以是无菌盐水溶液、水性盐水溶液、等渗盐水溶液的形式。
在本发明的试剂盒和/或方法提供多于一种药物的施用的情况下,所述药物可以同时、顺序或单独施用。不必将它们包装在一起(但这是本发明的一个实施方案)。也不必将它们同时施用或者它们不必是相同剂型。如本文所使用,“单独”施用意指药物作为相同的整体给药方案的一部分(其可以包括多天)来施用,但是优选在同一天施用。如本文所使用,“同时”意指一起摄取药物或将药物配制成单一组合物。如本文所使用,“顺序”意指以约相同的时间施用药物,并且优选彼此在约1小时内。
在一些实施方案中,当与某些抗肿瘤化合物(例如本文所公开的那些)组合时,可以以某些剂量(例如,低于单一治疗的剂量)施用所公开的PI3K抑制剂,但是可以是治疗有效的。例如,式I的PI3K抑制剂和本文公开的某些抗肿瘤化合物的组合可以在治疗有需要的对象中实现协同效应,其中所述组合以这样的剂量进行施用,即当单独施用一种或两种化合物时该剂量是无效的,但是当组合时该量是有效的。
一般公开内容-使用方法
本发明的组合物可以用于治疗和预防癌症并且可以用于本发明的组合治疗或其他组合中。当用于其他组合治疗时,通常将本发明的化合物与诸如铂复合物的小化学化合物、抗代谢物、DNA拓扑异构酶抑制剂、放疗、基于抗体的治疗(例如赫赛汀和利妥昔单抗)、抗癌疫苗、基因治疗、细胞治疗、激素治疗或细胞因子治疗一起使用。
在本发明的一个实施方案中,在癌症治疗中将本发明的组合物与另外的化学治疗剂或抗肿瘤剂进一步组合使用。此类其他化学治疗剂或抗肿瘤剂的实例包括:包括顺铂和卡铂的铂复合物、米托蒽醌、诸如长春新碱和长春花碱的长春花生物碱、诸如道诺菌素和阿霉素的蒽环类抗生素、诸如瘤可宁和美法仑的烷基化试剂、诸如紫杉醇的紫杉烷类、诸如氨甲蝶呤和雷替曲塞的叶酸拮抗剂、诸如依托泊苷的表鬼臼毒素、诸如伊立替康及其活性代谢物SN38的喜树碱类、以及诸如在WO02/085400中公开的DNA甲基化抑制剂的DNA甲基化抑制剂。
因此,根据本发明,提供了产品,其包含本发明的组合物和另外的化学治疗剂或抗肿瘤剂,作为同时、单独或依次用于缓解癌症的组合制剂。根据本发明,还提供了本发明的化合物在制备用于通过与另外的化学治疗剂或抗肿瘤剂共施用来缓解癌症的药物中的用途。可以以任何顺序施用本发明的化合物和所述其他试剂。在这些情况下,本发明的化合物与其他试剂可以一起施用,或者如果单独施用,则以由医师确定的任何顺序施用。
还可以将本发明的组合用来治疗由于在人类患者的手术过程中对身体组织的损害而引起的异常细胞增殖。这些损害可以由于诸如关节手术、肠道手术和瘢痕疙瘩(cheloid scarring)的各种手术程序引起出现。产生可以使用本发明的组合来治疗的纤维化组织的疾病包括肺气肿。可以使用本发明治疗的重复性运动障碍包括腕管综合征。可以使用本发明治疗的细胞增殖病症的实例是骨肿瘤。
可以使用本发明的组合来治疗的与器官移植相关的增殖反应包括引起潜在器官排斥或相关并发症的增殖反应。具体而言,这些增殖反应可以在心脏、肺、肝、肾和其他身体器官或器官系统的移植过程中发生。
可以使用本发明治疗的异常血管生成包括伴随有以下的那些异常血管生成:类风湿性关节炎、与缺血性再灌注相关的脑水肿和脑损伤、皮质缺血、卵巢增生和血管增多、多囊卵巢综合征、子宫内膜异位、银屑病、糖尿病视网膜病变和诸如早产儿视网膜病变(晶状体后纤维形成)的其他眼部血管生成疾病、黄斑变性、角膜移植排斥、新生血管性青光眼和Osler-Weber-Rendu综合征。
可以根据本发明治疗的与失控的血管生成相关的疾病的实例包括但不限于,视网膜/脉络膜新生血管和角膜新生血管形成。包括视网膜/脉络膜新生血管形成的一些组分的疾病的实例包括但不限于,Best氏疾病、近视、视盘小凹(optic pits)、Stargart氏疾病、Paget氏疾病、静脉阻塞、动脉阻塞、镰状细胞性贫血、肉样瘤、梅毒、假性弹性黄色瘤颈动脉阻塞病(pseudoxanthoma elasticum carotid apo structive diseases)、慢性葡萄膜炎/玻璃体炎、分枝杆菌感染、莱姆病、系统性红斑狼疮、早产儿视网膜病变、Eale氏疾病、糖尿病视网膜病变、黄斑变性、Bechet氏疾病、引起视网膜炎或脉络膜炎的感染、拟眼组织胞浆菌病、睫状体扁平部炎(pars planitis)、慢性视网膜脱落、高粘稠性综合征、弓形体病、损伤并发症和激光术后并发症(trauma and post-laser complications)、与发红相关的疾病(角度的新生血管)、以及由纤维血管组织或纤维组织的异常增生引起的疾病(包括所有形式的增生性玻璃体视网膜病变)。角膜新生血管形成的实例包括但不限于:流行性角膜结膜炎、维生素A缺陷、隐形眼镜过度疲劳、异位性角膜炎、上缘角膜炎(superior limbickeratitis)、翼状胬肉干燥性角膜炎(pterygium keratitis sicca)、干燥综合征(Sjogrens)、酒糟鼻(acne rosacea)、phylectenulosis、糖尿病视网膜病变、早产儿视网膜病变、角膜移植排斥、蚕蚀性角膜炎(Mooren ulcer)、Terrien氏角膜边缘变性、边缘性角质层分离(marginal keratolysis)、多动脉炎、Wegener结节病、巩膜炎、类天疱疮的放射状角膜切开术(periphigoid radial keratotomy)、新生血管性青光眼及晶体后纤维增生症、梅毒、分枝杆菌感染、脂质变性、化学灼伤、细菌性溃疡、真菌性溃疡、单纯性疱疹感染、带状疱疹感染、原虫感染和卡波西肉瘤。
还可以使用本发明的组合来治疗与失控的血管生成相关的慢性炎性疾病。慢性炎症依赖毛细血管肉芽的持续形成以维持炎性细胞的流入。炎性细胞的流入和存在产生肉芽肿并因此维持所述慢性炎性状态。单独地或与其他抗炎剂组合地使用PI3K抑制剂的血管生成抑制可以阻止肉芽肿的形成并因此缓解疾病。慢性炎性疾病的实例包括但不限于:诸如克罗恩氏病和溃疡性结肠炎的炎性肠道疾病、银屑病、结节病和类风湿性关节炎。
诸如克罗恩氏病和溃疡性结肠炎的炎性肠道疾病是以胃肠道中多个位点的慢性炎症和血管生成为特征。例如,克罗恩氏病出现为慢性透壁性炎性疾病,其最常影响回肠末端和结肠,但也可能出现在从口腔至肛门的胃肠道的任何部分及肛周区域。患有克罗恩氏病的患者通常患有与腹痛、发烧、厌食症、体重减轻和腹部肿胀相关的慢性腹泻。溃疡性结肠炎也是出现在结肠粘膜中的慢性、非特异性的炎症和溃疡性疾病,且其特征为存在带血腹泻。这些炎性肠道疾病通常是由贯穿胃肠道的慢性肉芽肿性炎症引起的,其包括由炎性细胞圆柱包围的新毛细血管芽。通过这些抑制剂抑制血管生成可抑制肉芽的形成并阻止肉芽肿的形成。炎性肠道疾病还显示出另外的肠道临床表现,例如皮肤病灶。此类病灶的特征为炎症和血管生成,且可以发生在除胃肠道以外的许多位点。通过本发明的组合抑制血管生成可以减少炎性细胞的流入并预防病灶形成。
结节病是特征为多系统性肉芽肿性病症的另一种慢性炎性疾病。该疾病的肉芽肿可以在身体的任何地方形成。因此,其症状取决于肉芽肿的位点以及所述疾病是否是活性的。肉芽肿是由提供恒定的炎性细胞供应的血管生成性毛细血管出芽生成。通过使用本发明的组合来抑制血管生成,可以抑制此类肉芽肿形成。银屑病也是特征为各种尺寸的丘疹和斑块的慢性且复发性的炎性疾病。单独地或与其他抗炎剂组合地使用这些抑制剂的治疗可阻止维持特征性病变所必需的新的血管形成并为患者提供症状的缓解。
类风湿性关节炎(RA)也是以外周关节的非特异性炎症为特征的慢性炎性疾病。认为关节的滑膜内层中的血管经历了血管生成。除了形成新的血管脉络之外,内皮细胞还释放引起血管翳生长及软骨破坏的因子和活性氧物质。参与血管生成的因子可以有效地促进并帮助维持类风湿性关节炎的慢性炎症状态。单独地或与其他抗-RA试剂组合地使用本发明的组合的治疗可以阻止维持慢性炎症所必需的新的血管的形成。
优选地,所述病况为癌症、特别是包括慢性骨髓性白血病和急性骨髓性白血病的白血病、淋巴瘤、实体瘤,以及包括PTEN-阴性血癌、乳腺癌、肺癌、子宫内膜癌、皮肤癌、脑癌和前列腺癌的PTEN-阴性肿瘤和/或PTEN-有缺陷的肿瘤(其中PTEN是指“在染色体10上删除的磷酸酶和张力蛋白同系物”)。更优选地,通过施用有效量的所公开的化合物而在有需求的患者中治疗的病况是选自以下的病症:类风湿性关节炎、哮喘、慢性阻塞性肺疾病(COPD)、多发性硬化、银屑病和其他炎性皮肤病症、系统性红斑狼疮、炎性肠道疾病和器官移植排斥。例如,本文提供的是治疗患有选自以下病症的患者的方法:白血病(包括例如,慢性骨髓性白血病和急性骨髓性白血病);淋巴瘤;诸如乳腺癌、肺癌或前列腺癌的实体瘤癌症;包括PTEN-阴性血癌、乳腺癌、肺癌、子宫内膜癌、皮肤癌、脑癌和前列腺癌的PTEN-阴性肿瘤(其中PTEN是指“在染色体10上删除的磷酸酶和张力蛋白同系物”),所述方法包括施用有效量的所公开的化合物。
认为HDAC有助于几种不同疾病的病理学和/或症状学,使得通过抑制HDAC降低对象中HDAC的活性,可以用于在治疗上解决这些疾病状态。本文描述了可以使用本发明的组合来治疗的各种疾病的实例。
可以使用本发明的组合来治疗的一组适应症是涉及不期望的或失控的细胞增殖的那些。此类适应症包括良性肿瘤、诸如原发性肿瘤和肿瘤转移的各种类型的癌症、再狭窄(例如冠状动脉、颈动脉和脑损伤)、内皮细胞的异常刺激(动脉粥样硬化)、由于手术导致的身体组织损伤、异常的伤口愈合、异常的血管生成、产生组织纤维化的疾病、重复性运动失调、未高度血管化的组织的障碍以及与器官移植相关的增殖反应。组合的更具体的适应症包括但不限于,前列腺癌、肺癌、急性白血病、多发性骨髓瘤、膀胱癌、肾癌、乳腺癌、结肠直肠癌、成神经细胞瘤和黑色素瘤。
在一个实施方案中,提供了用于治疗与不期望的和失控的细胞增殖相关的疾病的方法。该方法包括向患有失控的细胞增殖的对象施用治疗有效量的本发明的HDAC抑制剂,使得所述失控的细胞增殖减少。待使用的抑制剂的具体剂量将取决于疾病状态的严重程度、施用途径和可由主治医师确定的相关因素。通常,可接受的且有效的日剂量是足以有效减缓或消除失控的细胞增殖的量。
本发明的组合还可以与抑制不期望的和失控的细胞增殖的其他试剂组合使用。可以与本发明的组合组合地使用的其他抗细胞增殖试剂的实例包括但不限于,类维生素A酸及其衍生物、2-甲氧基雌二醇、AngiostatinTM蛋白、EndostatinTM蛋白、苏拉明、角鲨胺、金属蛋白酶-I的组织抑制剂、金属蛋白酶-2的组织抑制剂、纤溶酶原激活物抑制剂-1、纤溶酶原激活物抑制剂-2、软骨源抑制剂、紫杉醇、血小板因子4、硫酸鱼精蛋白(鲱精蛋白)、硫酸化甲壳质衍生物(由皇后蟹壳制备的)、硫酸化多糖肽聚糖复合物(sp-pg)、星孢菌素、基质代谢调节剂,包括例如脯氨酸类似物((1-氮杂环丁烷-2-羧酸(LACA)、顺式羟基脯氨酸、d,l-3,4-脱氢脯氨酸、硫杂脯氨酸)、β-氨基丙腈富马酸酯、4-丙基-5-(4-吡啶基)-2(3H)-噁唑酮;甲氨蝶呤、米托蒽醌、肝素、干扰素、2巨球蛋白血清、chimp-3、胰凝乳蛋白酶抑制剂、β-环糊精十四硫酸酯、eponemycin;烟曲霉素、硫代苹果酸金钠、d-青霉胺(CDPT)、β-1-抗胶原酶血清、α-2-抗纤维蛋白溶酶、比生群、氯苯扎利二钠、n-(2-羧基苯基)-4-氯代邻氨基苯甲酸二钠或“CCA”、沙利度胺;血管生成抑制性(angiostatic)胆固醇、羧基氨基咪唑;金属蛋白酶抑制剂例如BB94。其他可以使用的抗血管生成试剂包括抗体,优选针对以下这些血管生成生长因子的单克隆抗体:bFGF、aFGF、FGF-5、VEGF同种型、VEGF-C、HGF/SF和Ang-1/Ang-2。Ferrara N.和Alitalo,K.“Clinical application of angiogenic growthfactors and their inhibitors”(1999)Nature Medicine 5:1359-1364。
通常,良性肿瘤中的细胞保持其分化特征,而不以完全失控的方式分裂。良性肿瘤通常是局部的且是非转移性的。可以使用本发明的组合来治疗的特定类型的良性肿瘤包括血管瘤、肝细胞腺瘤、海绵状血管瘤、局灶性结节性增生、听神经瘤、神经纤维瘤、胆管腺瘤、胆管囊腺瘤(cystanoma)、纤维瘤、脂肪瘤、平滑肌瘤、间皮瘤、畸胎瘤、粘液瘤、结节性再生性增生、沙眼和化脓性肉芽肿。
在恶性肿瘤的情况下,细胞变成未分化的,不响应于身体的生长控制信号,并且以失控的方式繁殖。恶性肿瘤是侵入性的并且能够扩散到远端(转移)。通常将恶性肿瘤分为两类:原发性和继发性。原发性肿瘤直接发生于其所在的组织。继发性肿瘤或转移瘤是源自身体中的其他部位,但现在已扩散至远端器官的肿瘤。转移的常见途径是直接生长进入相邻结构中,通过血管系统或淋巴系统扩散,并沿着组织面和体间隙(腹膜液、脑脊髓液等)行进。
可以使用本发明的组合来治疗的特定类型的癌症或恶性肿瘤(原发性或继发性)包括但不限于,白血病、乳腺癌、皮肤癌、骨癌、前列腺癌、肝癌、肺癌、脑癌、喉癌、胆囊癌、胰腺癌、直肠癌、甲状旁腺癌、甲状腺癌、肾上腺癌、神经组织癌、头颈癌、结肠癌、胃癌、支气管癌、肾癌、基底细胞癌、溃疡型和乳头型的鳞状细胞癌、转移性皮肤癌、骨肉瘤、尤因氏肉瘤、网状细胞肉瘤(veticulum cell sarcoma)、骨髓瘤、巨细胞瘤、小细胞肺瘤、胆结石、胰岛细胞瘤、原发性脑肿瘤、急性和慢性的淋巴细胞瘤和粒细胞肿瘤、毛细胞瘤、腺瘤、增生、髓样癌、嗜铬细胞瘤、粘膜神经瘤、肠神经节瘤(intestinal ganglloneuromas)、增生性角膜神经瘤、马凡氏体型肿瘤(marfanoid habitus tumour)、Wilms氏肿瘤、精原细胞瘤、卵巢瘤、平滑肌肿瘤(leiomyomater tumour)、宫颈非典型增生和原位癌、神经母细胞瘤、视网膜母细胞瘤、软组织肉瘤、恶性类癌、局部皮肤损伤、蕈状霉菌病、横纹肌肉瘤、卡波西肉瘤、骨源性肉瘤和其他肉瘤、恶性高钙血症、肾细胞肿瘤、真性红细胞增多症、腺癌、多形性胶质母细胞瘤、白血病、淋巴瘤、恶性黑素瘤、表皮样癌和其他癌和肉瘤。
本发明的组合还可用于治疗由于在手术期间对身体组织的损伤而产生的异常细胞增殖。这些损伤可能由于诸如关节手术、肠道手术和瘢痕疙瘩的多种手术程序而出现。可使用本发明的组合来治疗的产生纤维化组织的疾病包括肺气肿。可使用本发明治疗的重复性运动障碍包括腕管综合征。可使用本发明治疗的细胞增殖病症的实例为骨肿瘤。
可使用本发明的组合来治疗的与器官移植有关的增殖反应包括促进潜在器官排斥或相关并发症的增殖反应。具体地,这些增殖反应可在心脏、肺、肝、肾和其他身体器官或器官系统的移植期间发生。
结节病是特征为多系统肉芽肿性病症的另一种慢性炎性疾病。该疾病的肉芽肿可在身体内的任何部位形成。因此,症状取决于肉芽肿的部位和疾病是否是活性的。肉芽肿是由提供炎性细胞连续供应的生成血管的毛细血管芽产生。通过使用本发明的组合抑制血管生成,可以抑制此类肉芽肿形成。银屑病也是特征为不同大小的丘疹和斑块的慢性复发性的炎性疾病。单独地或与其他抗炎剂组合使用这些抑制剂的治疗可阻止维持特征性病变所必需的新的血管形成并减轻患者症状。
类风湿性关节炎(RA)也是特征为外周关节的非特异性炎症的慢性炎性疾病。认为关节的滑膜内层中的血管经历血管生成。除了形成新血管脉络之外,内皮细胞还释放引起血管翳生长和软骨破坏的因子和活性氧物质。参与血管生成的因子可有效地促进并帮助维持类风湿性关节炎的慢性炎症状态。单独地或与其他抗-RA试剂组合使用本发明的组合的治疗可阻止维持慢性炎症所必需的新的血管形成。
本发明的化合物还可用于治疗心脏/脉管系统疾病,如肥大、高血压、心肌梗死、再灌注、缺血性心脏病、心绞痛、心律不齐、高胆固醇血症、动脉粥样硬化和卒中。所述化合物还可用于治疗神经变性病症/CNS病症,如急性和慢性神经疾病,包括中风、亨廷顿舞蹈病、肌萎缩性侧索硬化症和阿尔茨海默氏病。
本发明的化合物还可用作抗微生物剂,例如抗细菌剂。因此,本发明还提供了用于治疗细菌性感染的化合物。本发明的化合物可用作对抗病毒、细菌、真菌和寄生虫感染的抗感染化合物。感染的实例包括原虫性寄生虫感染(包括疟原虫、微小隐孢子虫、刚地弓形虫、神经肉孢子虫和艾美球虫属(Eimeria sp.))。
本发明的化合物特别适用于治疗不期望的或失控的细胞增殖,优选地适用于治疗良性肿瘤/增生和恶性肿瘤,更优选地适用于治疗恶性肿瘤且最优选地适用于治疗慢性淋巴细胞性白血病(CLL)、乳腺癌、前列腺癌、卵巢癌、间皮瘤、T-细胞淋巴瘤。
在本发明的优选实施方案中,本发明的化合物用于缓解癌症、心脏肥大、慢性心力衰竭、炎性病况、心血管疾病、血红蛋白病、地中海贫血、镰状细胞病、CNS病症、自身免疫疾病、器官移植排斥、糖尿病、骨质疏松症、MDS、良性前列腺增生症、口腔粘膜白斑、遗传相关的代谢紊乱、感染、Rubens-Taybi、脆性X综合征或α-1抗胰蛋白酶缺乏症或用于加速伤口愈合、用于保护毛囊或用作免疫抑制剂。
通常,所述炎性病况为皮肤炎性病况(例如银屑病、痤疮和湿疹)、哮喘、慢性阻塞性肺病(COPD)、类风湿性关节炎(RA)、炎性肠病(IBD)、克罗恩氏病或结肠炎。
通常,所述癌症为慢性淋巴细胞性白血病、乳腺癌、前列腺癌、卵巢癌、间皮瘤或T-细胞淋巴瘤。
通常,所述心血管疾病为高血压、心肌梗死(MI)、缺血性心脏病(IHD)(再灌注)、心绞痛、心律不齐、高胆固醇血症、高脂血症、动脉粥样硬化、卒中、心肌炎、充血性心力衰竭、原发性和继发性即扩张型(充血性)心肌病、肥厚型心肌病、限制型心肌病、外周性血管疾病、心动过速、高血压或血栓形成。
通常,所述遗传相关的代谢紊乱为囊性纤维化(CF)、过氧化物酶体生物合成紊乱或肾上腺脑白质营养不良。
通常,本发明的化合物用作器官移植后的免疫抑制剂。
通常,所述感染为病毒、细菌、真菌或寄生虫感染,特别地感染由金黄色葡萄球菌(S aureus)、痤疮丙酸杆菌(P.acne)、念珠菌(candida)或曲霉菌(aspergillus)引起。
通常,所述CNS病症为亨廷顿舞蹈病、阿尔茨海默氏病、多发性硬化症或肌萎缩性侧索硬化症。
在该实施方案中,本发明的化合物可用于缓解癌症、心脏肥大、慢性心力衰竭、炎性病况、心血管疾病、血红蛋白病、地中海贫血、镰状细胞病、CNS病症、自身免疫疾病、糖尿病或骨质疏松症,或用作免疫抑制剂。
本发明的化合物还可用于缓解慢性淋巴细胞性白血病(CLL)、乳腺癌、前列腺癌、卵巢癌、间皮瘤、T-细胞淋巴瘤、心脏肥大、慢性心力衰竭或皮肤炎性病况,特别是银屑病、痤疮或湿疹。
本发明的化合物可用于治疗动物,优选地用于治疗哺乳动物且更优选地用于治疗人。
在适当情况下,本发明的化合物可预防性地用于降低这类病况的发病率。
在使用中,向患者施用治疗有效量的本发明的化合物。根据特定化合物的活性、待治疗对象的年龄、体重和病况、疾病的类型和严重程度以及施用的频率和途径,典型剂量为约0.001mg至50mg/千克体重。
现将通过以下实施例来例示本发明。
实施例
中间物X(式I的化合物的前体)的合成
试剂和条件:1)K2CO3、乙醇酸乙酯、DMF,115℃;2)(i)氯磺酰异氰酸酯、CH2Cl2,0-10℃随后室温(ii)水,75℃(iii)NaOH,最高温度40℃;3)POCl3、N,N-二甲基苯胺,107℃;4)吗啉、MeOH,室温;5)N,N,-二甲基丙烯酰胺、PdCl2(PPh3)2、NaOAc、DMF,110℃;6)NaIO4、OsO4、THF、水,室温;7)吲哚-4-硼酸频哪醇酯、PdCl2(PPh3)2、碳酸钠、二噁烷、水,102℃。
i.乙基-3-氨基-5-溴呋喃并[2,3-b]吡啶-2-甲酸酯
在N2(g)下,向10L烧瓶中添加5-溴-2-氯吡啶-3-甲腈(435g,2.0mol,1当量)、DMF(2790mL)和碳酸钾(553g,4.0mol,2当量)。随后添加乙醇酸乙酯(208.2mL,2.2mol,1.1当量)。将反应混合物加热至115℃过夜。完成后,将反应混合物冷却至室温并添加水(13.1L),这导致沉淀物的形成。将混合物搅拌20min,随后过滤。将所得到的褐色固体在50℃下干燥,在Et2O:庚烷(9:1,2.8L)中浆化并过滤以得到405.6g。使用TBME(4.5L)经索氏萃取进行进一步纯化产生呈黄色固体的产物(186g,34%)。该程序重复两次。
1H NMR(400MHz,CDCl3)δH:8.53(d,J=2.0Hz,1H),8.07(d,J=2.0Hz,1H),5.00(br.s.,2H),4.44(q,J=7.0Hz,2H),1.44(t,J=7.0Hz,3H)。
MS(ES+)309(100%,[M+Na]+),307(100%,[M+Na]+)。
ii.12-溴-8-氧杂-3,5,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),10,12-四烯-4,6-二酮
在0-10℃下,向溶于CH2Cl2(5.5L)的乙基-3-氨基-5-溴呋喃并[2,3-b]吡啶-2-甲酸酯(239.0g,0.84mol,1当量)中逐滴添加氯磺酰异氰酸酯(87.6mL,1.0mol,1.2当量)。将所得到的反应物搅拌30min,汽提至干燥并将所得到的固体研磨至细粉末。将水(5.5L)添加至所述固体中并将悬浮液在75℃下加热1h。在冷却至室温之后,添加固体NaOH(335g,8.4mol,10当量)使得反应放热(最高温度40℃)。将反应物冷却至0-10℃并使用5M HCl(~1L)将pH调节至5-6。将反应物搅拌30min,然后过滤。用水(2.3L)洗涤固体并吸干。在40℃的真空烘箱中进一步干燥产生呈褐色固体的产物(193g,76%)。该程序重复两次。
1H NMR(400MHz,DMSO-d6)δH:12.01(br.s.,1H),11.58(br.s,1H),8.72(d,J=2.0Hz,1H),8.59(d,J=2.0Hz,1H)。
MS(ES-)282(100%,[M+H]+)。
iii.12-溴-4,6-二氯-8-氧杂-3,5,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
向12-溴-8-氧杂-3,5,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),10,12-四烯-4,6-二酮(387g,1.27mol,1当量)添加POCl3(6070mL)和N,N-二甲基苯胺(348mL,2.8mol,2.2当量)。将混合物在107℃下加热10h。一旦冷却至室温,在真空下与甲苯(3×3.9L)共沸去除溶剂。将所得到的残余物在CH2Cl2(12.76L)和水(3.9L)之间分配并将相分离。用水(2×3.9L)洗涤有机相。将合并的水溶液用CH2Cl2(7.7L)反萃取并将合并的有机物经MgSO4干燥,过滤并汽提以产生褐色固体的产物(429g,~定量)。
1H NMR(400MHz,CDCl3)δH:8.78(d,J=2.5Hz,1H),8.72(d,J=2.5Hz,1H)。
iv.12-溴-4-氯-6-(吗啉-4-基)-8-氧杂-3,5,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯
在室温下,向在MeOH(8588mL)中的12-溴-4,6-二氯-8-氧杂-3,5,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(419.3g,1.32mol,1当量)添加吗啉(259mL,2.90mol,2.2当量)。在搅拌2h后,添加水(0.8L)。然后将其冷却至0-5℃并再搅拌30min。将所得到的固体过滤,用水(5.2L)洗涤并吸干。通过使用CH2Cl2/EtOAc(1:0-9:1)的硅胶柱色谱法进一步纯化产生期望的产物(419g,84%)。
1H NMR(400MHz,CDCl3)δH:8.66(d,J=2.0Hz,1H),8.62(d,J=2.0Hz,1H),4.07-4.21(m,4H),3.85-3.91(m,4H)。
MS(ES+)393(100%,[M+Na]+),391(80%,[M+Na]+)。
v.(2E)-3-[4-氯-6-(吗啉-4-基)-8-氧杂-3,5,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-12-基]-N,N-二甲基丙-2-烯酰胺
向12-溴-4-氯-6-(吗啉-4-基)-8-氧杂-3,5,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯(60g,0.15mol,1当量)中添加在DMF(1.2L)中的N,N-二甲基丙烯酰胺(16.7mL,0.15mol,1当量)、PdCl2(PPh3)2(3.4g,4.5mmol,0.03当量)和NaOAc(40g,0.45mol,3当量)。将反应物在110℃下加热7h。该过程重复3次并合并所有批次。一旦冷却至室温,在真空中去除溶剂并将所得到的残余物在CH2Cl2(6.5L)和水(5.5L)之间分配。将相分离并将水相用CH2Cl2(2×4L)萃取。将合并的有机物用盐水(2×4L)洗涤,经MgSO4干燥,过滤并汽提。将所得到的固体在EtOAc/庚烷(1:1,0.8L)中浆化30min,过滤,洗涤并用EtOAc/庚烷(1:1,2×450mL)洗涤。在40℃的真空烘箱中进一步干燥产生呈橙色固体的所期望的产物(203.0g,86%)。
1H NMR(400MHz,CDCl3)δH:8.70(s,2H),7.82(d,J=15.6Hz,1H),7.07(d,J=15.6Hz,1H),4.11-4.19(m,4H),3.85-3.93(m,4H),3.22(s,3H),3.11(s,3H)。
MS(ES+)388(100%,[M+H]+)。
vi.4-氯-6-(吗啉-4-基)-8-氧杂-3,5,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-12-甲醛
在65℃下,将(2E)-3-[4-氯-6-(吗啉-4-基)-8-氧杂-3,5,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-12-基]-N,N-二甲基丙-2-烯酰胺(124.0g,0.39mol,1当量)溶于THF(12.4L)中。一旦冷却至35℃,添加水(4.1L)、NaIO4(205.4g,1.17mol,3当量)和OsO4(2.5wt%在tBuOH中,80.3mL,2%)。将反应物在室温下搅拌60h。将反应物冷却至0-5℃,搅拌30min然后过滤。将固体用水(545mL)洗涤并吸干。将粗产物与另外两个批次(2×118.3g规格)合并,并在室温下在水(6.3L)中浆化30min。将固体过滤,用水(1.6L)洗涤并吸干。在真空烘箱中进一步干燥产生呈粉色固体的所期望的产物(260g,88%)。
1H NMR(400MHz,CDCl3:MeOD,9:1)δH:10.13(s,1H),9.04(d,J=2.0Hz,1H),8.91(d,J=2.0Hz,1H),3.99-4.13(m,4H),3.73-3.84(m,4H)。
MS(ES+)351(100%,[M+MeOH+H]+)。
vii.4-(1H-吲哚-4-基)-6-(吗啉-4-基)-8-氧杂-3,5,10-三氮杂三环[7.4.0.02 ,7]十三碳-1(9),2,4,6,10,12-六烯-12-甲醛
向4-氯-6-(吗啉-4-基)-8-氧杂-3,5,10-三氮杂三环[7.4.0.02,7]十三碳-1(9),2(7),3,5,10,12-六烯-12-甲醛(164.4g,0.52mol,1当量)中添加在二噁烷(16.4L)/水(5.8L)中的吲哚-4-硼酸频哪醇酯(376.0g,1.55mol,3当量)、PdCl2(PPh3)2(72.0g,0.10mol,2当量)和碳酸钠(110.2g,1.04mol,2当量)。将反应混合物回流1h。然后将其冷却至60℃-70℃。添加水(9.8L)、盐水(4.9L)和EtOAc(9.5L)。将相分离并在60℃-65℃下将水相用EtOAc(3×9.5L)萃取。将合并的有机物经MgSO4干燥,过滤并汽提。将所得到的固体在CH2Cl2(4.75L)中浆化30min,过滤,用CH2Cl2(3×238mL)洗涤并吸干。在40℃下的真空烘箱中进一步干燥产生呈黄色固体的中间物X(135.7g,66%)。
1H NMR(300MHz,CDCl3)δH:11.27(br.s,1H),10.26(s,1H),9.16(d,J=2.3Hz,1H),9.11(d,J=2.3Hz,1H),8.18(d,J=7.5Hz,1H),7.58-7.67(m,2H),7.49(t,J=2.8Hz,1H),7.23(t,J=7.7Hz,1H),4.08-4.16(m,4H),3.83-3.90(m,4H)。
MS(ES+)432.0(100%,[M+MeOH+H]+)。
本发明的实例的合成
实例A:
4-(1H-吲哚-4-基)-6-(吗啉-4-基)-12-[(1S,4S)-2-氧杂-5-氮杂双环[2.2.1]庚-5-基甲基]-8-氧杂-3,5,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
向中间物X(7.00g,17.53mmol,1当量)、(1S,4S)-2-氧杂-5-氮杂双环[2.2.1]庚烷盐酸盐(7.13g,52.58mmol,3当量)和NaOAc(4.31g,52.58mmol,3当量)在无水CH2Cl2(150mL)中的悬浮液添加NaBH(OAc)3(7.43g,35.06mmol,2当量)。将反应混合物在室温下搅拌过夜。然后,将其用1N NaOH(100mL)分配并用CH2Cl2(3×200mL)萃取。将合并的有机萃取物用盐水(50mL)洗涤,然后经MgSO4干燥并在真空中去除溶剂。通过使用EtOAc/MeOH(1:0-7:1)的硅胶柱色谱法纯化产生呈白色固体的产物A(6.02g,71%)。
1H NMR(300MHz,CDCl3)δH:8.65(d,J=2.1Hz,1H),8.58(d,J=2.1Hz,1H),8.37(br.s.,1H),8.24(dd,J=7.5,0.9Hz,1H),7.62(td,J=2.6,0.8Hz,1H),7.53(d,J=8.1Hz,1H),7.37-7.41(m,1H),7.31-7.37(m,1H),4.47(s,1H),4.22-4.30(m,4H),4.18(d,J=8.1Hz,1H),3.98(d,J=2.3Hz,2H),3.91-3.97(m,4H),3.70(dd,J=7.9,1.7Hz,1H),3.53(s,1H),2.94(dd,J=10.0,1.5Hz,1H),2.64(d,J=10.2Hz,1H),1.97(dd,J=9.8,1.9Hz,1H),1.80(dt,J=9.8,1.1Hz,1H)。
MS(ES+)483.1(100%,[M+H]+)。
4-(1H-吲哚-4-基)-6-(吗啉-4-基)-12-[(1S,4S)-2-氧杂-5-氮杂双环[2.2.1]庚-5-基甲基]-8-氧杂-3,5,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯;甲磺酸
将A(5.98g,12.38mmol,1当量)溶于热EtOAc(1L)和THF(200mL)中。一旦冷却至室温,缓慢添加MsOH(884μL,13.6mmol,1.1当量)在EtOAc(5mL)中的溶液。立即形成黄色沉淀物。将悬浮液剧烈摇振10s,然后在室温下静置过夜。当固体沉降时,倾出过量的上清液(200mL),然后添加EtOAc(200mL)。再次摇振悬浮液并静置1h。将该操作重复两次,然后在真空中去除溶剂。获得呈黄色固体的A的盐形式(6.50g,91%)。
1H NMR(300MHz,DMSO-d6)δH:11.33(br.s.,1H),9.69-10.24(m,1H),9.05(d,J=2.1Hz,1H),8.79-8.93(m,1H),8.19(d,J=7.5Hz,1H),7.54-7.62(m,2H),7.50(t,J=2.7Hz,1H),7.24(t,J=7.7Hz,1H),4.64-4.89(m,2H),4.47-4.61(m,2H),4.14(m,4H),3.94-4.00(m,2H),3.83-3.91(m,4H),3.72-3.83(m,1H),3.29-3.46(m,2H),2.33(s,4H),2.02-2.15(m,1H)。
MS(ES+)483.1(100%,[M-MsOH+H]+)。
实例B:
4-(1H-吲哚-4-基)-6-(吗啉-4-基)-12-{2-氧杂-7-氮杂螺[3.5]壬-7-基甲基}-8-氧杂-3,5,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
向中间物X(3.108g,7.78mmol,1当量)、2-氧杂-7-氮杂螺[3.5]壬烷半草酸盐(4.02g,23.3mmol,3当量)和NaOAc(1.91g,23.3mmol,3当量)在无水CH2Cl2(280mL)中的悬浮液添加NaBH(OAc)3(3.30g,15.6mmol,2当量)。将反应混合物在室温下搅拌过夜。然后,将其用1N NaOH(150mL)分配并用CH2Cl2(2×100mL)萃取。将合并的有机萃取物用50%盐水(100mL)洗涤,然后经MgSO4干燥,并在真空中去除溶剂。通过用EtOAc/MeOH(1:0-8:1)的硅胶柱色谱法纯化产生呈灰白色固体的产物B(3.154g,79%)。
1H NMR(300MHz,CDCl3)δH:8.59(d,J=2.1Hz,1H),8.53(d,J=1.9Hz,1H),8.41(br.s.,1H),8.24(dd,J=7.4,0.8Hz,1H),7.61(t,J=2.3Hz,1H),7.53(d,J=8.1Hz,1H),7.37-7.41(m,1H),7.34(t,J=7.9Hz,1H),4.43(s,4H),4.22-4.30(m,4H),3.86-4.00(m,4H),3.68(s,2H),2.23-2.59(m,4H),1.83-2.00(m,4H)。
MS(ES+)511.1(100%,[M+H]+)。
4-(1H-吲哚-4-基)-6-(吗啉-4-基)-12-{2-氧杂-7-氮杂螺[3.5]壬-7-基甲基}-8-氧杂-3,5,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯;甲磺酸
在室温下,向B(2.987g,5.854mmol,1当量)在EtOAc(1.2L,加热至70℃持续5min以溶解)的溶液添加MsOH(590μL,6.14mmol,1.05当量)在EtOAc(16mL)中的溶液。立即形成黄色沉淀物。将悬浮液剧烈摇振20s,然后在室温下静置过夜。倾出过量的上清液(600mL),然后添加EtOAc(500mL)。再次摇振悬浮液并静置1h,然后再倾出500mL过量的上清液。在真空中去除溶剂以得到呈黄色固体的F的盐形式(3.230g,91%)。
1H NMR(300MHz,DMSO-d6)δH:11.33(br.s.,1H),9.45(br.s.,1H),8.90(d,J=1.9Hz,1H),8.72(d,J=1.9Hz,1H),8.19(d,J=7.3Hz,1H),7.41-7.69(m,3H),7.23(t,J=7.8Hz,1H),4.58(d,J=3.8Hz,2H),4.39(s,2H),4.29(s,2H),4.03-4.22(m,4H),3.81-3.97(m,4H),3.40(d,J=12.1Hz,2H),2.88-3.13(m,2H),2.33(s,3H),2.26(d,J=13.9Hz,2H),1.69-1.91(m,2H)。
MS(ES+)511.1(100%,[M-MsOH+H]+)。
实例C:
4-(1H-吲哚-4-基)-6-(吗啉-4-基)-12-{8-氧杂-3-氮杂双环[3.2.1]辛-3-基甲基}-8-氧杂-3,5,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
向中间物X(100mg,0.25mmol,1当量)、8-氧杂-3-氮杂双环[3.2.1]辛烷盐酸盐(112mg,0.75mmol,3当量)和NaOAc(62mg,0.75mmol,3当量)在无水CH2Cl2(10mL)中的悬浮液添加NaBH(OAc)3(106mg,0.50mmol,2当量)。将反应混合物在室温下搅拌过夜。然后,将其用1N NaOH(10mL)分配,用CH2Cl2(3×10mL)萃取。将合并的有机萃取物用盐水(10mL)洗涤,然后经MgSO4干燥,并在真空中去除溶剂。通过用EtOAc/MeOH(1:0-49:1)的硅胶柱色谱法纯化产生呈灰白色固体的产物C(116mg,93%)。
1H NMR(300MHz,CDCl3)δH:8.56(d,J=3.6Hz,2H),8.35(br.s.,1H),8.24(d,J=7.5Hz,1H),7.58-7.66(m,1H),7.51-7.57(m,1H),7.31-7.44(m,2H),4.30-4.38(m,2H),4.23-4.30(m,4H),3.89-4.01(m,4H),3.68(s,2H),2.61(d,J=10.7Hz,2H),2.40-2.52(m,2H),1.96-2.09(m,2H),1.83-1.95(m,2H)。
MS(ES+)497.1(100%,[M+H]+)。
实例D:
4-(1H-吲哚-4-基)-12-({2-甲基-2,8-二氮杂螺[4.5]癸-8-基}甲基)-6-(吗啉-4-基)-8-氧杂-3,5,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
向中间物X(1.02g,2.55mmol,1当量)、2-甲基-2,8-二氮杂螺[4.5]癸烷盐酸盐(1.46g,7.66mmol,3当量)和NaOAc(628mg,7.66mmol,3当量)在无水CH2Cl2(100mL)中的悬浮液添加NaBH(OAc)3(1.08g,5.1mmol,2当量)。将反应混合物在室温下搅拌过夜。然后,将其用1N NaOH(30mL)分配并用CH2Cl2(3×50mL)萃取。将合并的有机萃取物用盐水(10mL)洗涤,然后经MgSO4干燥并在真空中去除溶剂。通过用CH2Cl2/MeOH(0:1-4:1)的硅胶柱色谱法纯化产生呈白色固体的产物D(890mg,65%)。
1H NMR(300MHz,CDCl3)δH:8.60(d,J=2.1Hz,1H),8.54(d,J=2.1Hz,1H),8.39(br.s.,1H),8.24(dd,J=7.4,0.8Hz,1H),7.62(t,J=2.3Hz,1H),7.53(d,J=8.1Hz,1H),7.38(t,J=2.8Hz,1H),7.30-7.37(m,1H),4.21-4.31(m,4H),3.89-3.99(m,4H),3.69(s,2H),2.59(t,J=6.8Hz,2H),2.38-2.50(m,5H),2.35(s,3H),1.54-1.73(m,7H)。
MS(ES+)538.2(100%,[M+H]+)。
4-(1H-吲哚-4-基)-12-({2-甲基-2,8-二氮杂螺[4.5]癸-8-基}甲基)-6-(吗啉-4-基)-8-氧杂-3,5,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯;双(甲磺酸)
将化合物D(821mg,1.52mmol,1当量)溶于热EtOAc(400mL)中。一旦冷却至室温,缓慢添加MsOH(218μL,3.36mmol,2.2当量)在EtOAc(5mL)中的溶液。立即形成黄色沉淀物。将悬浮液剧烈摇振10s,然后在室温下静置过夜。当固体沉降时,倾出过量的上清液(200mL),然后添加EtOAc(200mL)。再次摇振悬浮液并静置1h。将该操作重复两次,然后在真空中去除溶剂。获得呈黄色固体的D的盐形式(1.037g,93%)。
1H NMR(300MHz,DMSO-d6)δH:11.32(br.s.,1H),9.46-10.03(m,2H),8.93(d,J=2.1Hz,1H),8.76(d,J=1.7Hz,1H),8.19(dd,J=7.4,0.7Hz,1H),7.53-7.60(m,2H),7.50(t,J=2.6Hz,1H),7.24(t,J=7.8Hz,1H),4.63(br.s.,2H),4.10-4.20(m,4H),3.82-3.91(m,5H),3.54-3.77(m,2H),3.36-3.51(m,2H),3.05-3.25(m,3H),2.89-3.03(m,1H),2.80-2.89(m,3H),2.36(s,6H),2.02-2.17(m,1H),1.65-1.95(m,4H)。
MS(ES+)538.2(100%,[M-2MsOH+H]+)。
实例E:
4-(1H-吲哚-4-基)-12-({7-甲基-2,7-二氮杂螺[4.4]壬-2-基}甲基)-6-(吗啉-4-基)-8-氧杂-3,5,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
向中间物X(250mg,0.63mmol,1当量)、2-甲基-2,7-二氮杂螺[4,4]壬烷二盐酸盐(400mg,1.87mmol,3当量)和NaOAc(305mg,3.70mmol,6当量)在无水CH2Cl2(20mL)中的悬浮液添加NaBH(OAc)3(265mg,1.25mmol,2当量)。将反应混合物在室温下搅拌过夜。然后,将其用1N NaOH(10mL)分配,用CH2Cl2(3×10mL)和EtOAc(10mL)萃取。将合并的有机萃取物用盐水(10mL)洗涤,然后经MgSO4干燥并在真空中去除溶剂。通过用CH2Cl2/MeOH(0:1-4:1)的硅胶柱色谱法纯化产生呈白色固体的产物E(169mg,52%)。
1H NMR(300MHz,CDCl3)δH:8.58(d,J=2.1Hz,1H),8.53(d,J=2.1Hz,1H),8.48(br.s.,1H),8.23(dd,J=7.4,0.8Hz,1H),7.63(t,J=2.2Hz,1H),7.53(d,J=7.9Hz,1H),7.39(t,J=2.7Hz,1H),7.29-7.36(m,1H),4.21-4.30(m,4H),3.89-3.99(m,4H),3.72-3.85(m,2H),2.49-2.83(m,8H),2.45(s,3H),1.81-2.06(m,4H)。
MS(ES+)524.1(100%,[M+H]+)。
4-(1H-吲哚-4-基)-12-({7-甲基-2,7-二氮杂螺[4.4]壬-2-基}甲基)-6-(吗啉-4-基)-8-氧杂-3,5,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯;双(甲磺酸)
将化合物E(129mg,0.25mmol,1当量)溶于热EtOAc(50mL)中。一旦冷却至室温,缓慢添加MsOH(35μL,0.54mmol,2.2当量)在EtOAc(2mL)中的溶液。立即形成黄色沉淀物。将悬浮液剧烈摇振10s,然后在室温下静置过夜。当固体沉降时,倾出过量的上清液(20mL),然后添加EtOAc(20mL)。再次摇振悬浮液并静置1h。将该操作重复两次,然后在真空中去除溶剂。获得呈黄色固体的E的盐形式(173mg,98%)。
1H NMR(300MHz,DMSO-d6)δH:11.33(br.s.,1H),10.39(br.s.,1H),9.72-10.12(m,1H),8.73-9.09(m,2H),8.19(d,J=7.5Hz,1H),7.41-7.63(m,3H),7.24(t,J=7.8Hz,1H),4.53-4.87(m,2H),4.10-4.22(m,4H),3.79-3.93(m,4H),3.32-3.77(m,6H),2.99-3.29(m,2H),2.78-2.89(m,3H),2.36(s,6H),1.87-2.22(m,3H)。
MS(ES+)524.5(100%,[M-2MsOH+H]+)。
实例F:
4-(1H-吲哚-4-基)-6-(吗啉-4-基)-12-[(1R,4R)-2-氧杂-5-氮杂双环[2.2.1]庚-5-基甲基]-8-氧杂-3,5,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
向中间物X(200mg,0.50mmol,1当量)、(1R,4R)-2-氧杂-5-氮杂双环[2.2.1]庚烷盐酸盐(204mg,1.50mmol,3当量)和NaOAc(123mg,1.5mmol,3当量)在无水CH2Cl2(10mL)中的悬浮液添加NaBH(OAc)3(160mg,0.76mmol,2当量)。将反应混合物在室温下搅拌过夜。然后,将其用1N NaOH(20mL)分配并用CH2Cl2(3×20mL)萃取。使合并的有机萃取物通过相分离器并在真空中去除溶剂。通过用EtOAc/MeOH(1:0-9:1)的硅胶柱色谱法纯化产生呈白色固体的产物F(141.1mg,59%)。
1H NMR(400MHz,CDCl3)δH:8.64(d,J=2.1Hz,1H),8.57(d,J=2.1Hz,1H),8.35(br.s.,1H),8.23(dd,J=7.5,0.9Hz,1H),7.62(m,1H),7.53(d,J=8.1Hz,1H),7.36-7.39(m,1H),7.31-7.36(m,1H),4.46(s,1H),4.25(m,4H),4.18(d,J=8.1Hz,1H),3.97(d,J=2.3Hz,2H),3.93-3.97(m,4H),3.68(dd,J=7.9,1.7Hz,1H),3.53(s,1H),2.93(dd,J=10.0,1.5Hz,1H),2.62(d,J=10.2Hz,1H),1.95(dd,J=9.8,1.9Hz,1H),1.79(dt,J=9.8,1.1Hz,1H)。
MS(ES+)483.1(100%,[M+H]+)。
4-(1H-吲哚-4-基)-6-(吗啉-4-基)-12-[(1R,4R)-2-氧杂-5-氮杂双环[2.2.1]庚-5-基甲基]-8-氧杂-3,5,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯;甲磺酸
将化合物F(141mg,0.29mmol,1当量)溶于热EtOAc(100mL)中,然后在剧烈涡旋下用0.87ml的0.308M MsOH在EtOAc中的溶液处理。将混合物静置过夜。倾去过量的上清液(使用小的巴斯德移液管(Pasteur pipette))并添加更多的EtOAc(50ml)。将悬浮液再次剧烈摇振,然后在室温下静置过夜。再一次倾去过量的上清液,并在真空中去除溶剂。将所得到的固体在40℃的真空烘箱中干燥。获得呈黄色固体的F的盐形式(160mg,95%)。
1H NMR(400MHz,DMSO-d6)δH:11.33(br.s.,1H),9.65-10.16(m,1H),9.05(d,J=2.0Hz,1H),8.83-8.90(m,1H),8.20(d,J=7.3Hz,1H),7.58-7.61(m,1H),7.56(d,J=7.8Hz,1H),7.51(t,J=2.8Hz,1H),7.23(t,J=7.7Hz,1H),4.82(dd,J=13.1,4.5Hz,1H),4.65-4.76(m,1H),4.50-4.59(m,2H),4.11-4.19(m,4H),3.99(d,J=9.6Hz,1H),3.88(t,J=4.5Hz,4H),3.78(dd,J=9.5,1.4Hz,1H),3.31-3.38(m,2H),2.52-2.57(m,1H),2.30(s,3H),2.02-2.18(m,1H)。
MS(ES+)483.2(100%,[M-MsOH+H]+)。
实例G
4-(1H-吲哚-4-基)-6-(吗啉-4-基)-12-{6-氧杂-1-氮杂螺[3.3]庚-1-基甲基}-8-氧杂-3,5,10-三氮杂三环[7.4.0.02,7]十三碳-1(13),2(7),3,5,9,11-六烯
在室温下,将中间物X(125mg,0.31mmol)、6-氧杂-1-氮杂螺[3.3]庚烷半草酸盐(134mg,0.93mmol,3当量)和NaOAc(76mg,0.93mmol,3当量)悬浮于CH2Cl2(16mL)中。将混合物搅拌15min,然后添加NaBH(OAc)3(131mg,0.62mmol,2当量)。将所得到的悬浮液在室温下搅拌过夜。然后将反应混合物用0.5N NaOH(8mL)分配并用CH2Cl2(2×10mL)萃取。将合并的有机物用50%盐水(5mL)洗涤,然后经MgSO4干燥并在真空中去除溶剂。将残余物溶于DMSO(2mL)并通过碱性制备型LCMS纯化以产生呈白色固体的G(48mg,32%)。
1H NMR(DMSO-d6)δH:11.30(br s,1H),8.62(s,2H),8.18(d,J=7.6Hz,1H),7.51-7.58(m,2H),7.46-7.51(m,1H),7.22(t,J=7.7Hz,1H),4.89(d,J=7.6Hz,2H),4.55(d,J=7.3Hz,2H),4.08-4.17(m,4H),4.03(s,2H),3.81-3.91(m,4H),3.03(t,J=6.7Hz,2H),2.32(t,J=6.7Hz,2H)。
MS(ES+)483.3(100%,[M+H]+)。
生物学数据
以下列出如使用在Reaction Biology Corp.进行的HTRF生物化学试验所测定的对I类PI3K同种型的倍数形式的选择性抑制数据。
注解:*=≥10x≥50x;**=>50x
啮齿类动物药代动力学比较数据
所公开的化合物具有增加的生物利用度和/或减少的清除率(以下为小鼠的数据)。
实例A
使用以下方案来测定口服的生物利用度和清除率,且结果示于以下:
·物种=雄性小鼠;
·品系=CD1;
·n=3只雄性小鼠/时间点/途径;
·8个时间点(5min、10、min、0.5h、1h、3h、6h、8h和24h)的末端血液取样;
·血浆的收集、生物试验及药代动力学参数报告。
配制物:10%DMSO,90%盐水
给药:口服10mg/kg和静脉内注射5mg/kg。
血浆PK总结:
参数-口服,10mg/kg | 数值-甲磺酸盐 |
t<sub>1/2</sub>(h) | 1.3 |
T<sub>max</sub>(h) | 1.00 |
C<sub>max</sub>(ng/mL) | 1973 |
AUC<sub>last</sub>(h*ng/mL) | 5625 |
AUC<sub>all</sub>(h*ng/mL) | 5625 |
AUC<sub>inf</sub>(h*ng/mL) | 5822 |
F | 73.77% |
实例A
口服生物利用度(F)=74%
清除率=21mL/min/kg
实例B
使用以下方案来测定口服生物利用度和清除率,且结果示于以下:
·物种=雄性小鼠;
·品系=Balb/c;
·将18只雄性小鼠分成两组:组1(3mg/kg;静脉内注射),组2(10mg/kg;口服),且每组包含9只小鼠;
·在轻度异氟烷麻醉下,从眶后血管丛(retro orbital plexus)中收集血液样品(大约60μL),以便在给药前、0.08h、0.25h、0.5h、1h、2h、4h、8h和24h(静脉内注射)以及在给药前、0.25h、0.5h、1h、2h、4h、6h、8h和24h(口服)获得样品;
·在包含K2EDTA作为抗凝剂的经标记的微型离心管中,在各个时间点,从一组的三只小鼠中收集血液样品;
·将血浆样品通过离心全血进行分离并贮存在-70℃以下直至进行生物试验;
·将所有样品通过使用乙腈(ACN)的蛋白质沉淀来处理以用于分析,并经由适用性(fit for purpose)LC/MS/MS方法(LLOQ:2.02ng/mL)进行分析;
·使用Phoenix WinNonlin(Version 6.3)的非房室试验工具计算药代动力学参数。
配制物:
经尾静脉以3mg/kg的剂量,对组1中的动物静脉内施用实例B在20%丙二醇、50%PEG 400和30%的(20%HPβCD在水中)中的溶液配制物:
以10mg/kg的剂量,对组2中的动物施用实例B在20%丙二醇、50%PEG 400和30%的(20%HPβCD的水溶液)中的口服溶液配制物;
给药:口服10mg/kg和静脉内注射3mg/kg。
血浆PK总结:
参数-静脉内注射,3mg/kg | 数值-甲磺酸盐 |
t<sub>1/2</sub>(h) | 1.23 |
C<sub>max</sub>(ng/mL) | 621.42 |
AUC<sub>last</sub>(h*ng.mL) | 1512.20 |
AUC<sub>inf</sub>(h*ng/mL) | 1512.20 |
清除率(mL/h/Kg) | 1983.6 |
Vss(L/Kg) | 5.51 |
参数-口服,10mg/kg | 数值-甲磺酸盐 |
T<sub>max</sub>(h) | 1.00 |
C<sub>max</sub>(ng/mL) | 779.58 |
AUC<sub>last</sub>(h*ng/mL) | 3725.56 |
AUC<sub>inf</sub>(h*ng/mL) | 4103.86 |
F | 74% |
实例B
口服生物利用度(F)=74%
清除率=33mL/min/kg
实例G
使用以下方案来测定口服生物利用度和清除率,且结果示于以下:
·物种=雄性小鼠;
·品系=Balb/c;
·将18只雄性小鼠分成两组:组1(3mg/kg;静脉内注射),组2(10mg/kg;口服),且每组包含9只小鼠;
·在轻度异氟烷麻醉下,从眶后血管丛中收集血液样品(大约60μL),以便在给药前、0.08h、0.25h、0.5h、1h、2h、4h、8h和24h(静脉内注射)以及给药前、0.25h、0.5h、1h、2h、4h、6h、8h和24h(口服)获得样品;
·在包含K2EDTA作为抗凝剂的经标记的微型离心管中,在各个时间点,从一组的三只小鼠中收集血液样品;
·将血浆样品通过离心全血进行分离并贮存在-70℃以下直至进行生物试验;
·将所有样品通过使用乙腈(ACN)的蛋白质沉淀来处理用以分析,并经由适用性LC/MS/MS方法(LLOQ:2.47ng/mL)进行分析;
·使用Phoenix WinNonlin(Version 6.3)的非房室试验工具计算药代动力学参数。
配制物:
以3mg/kg剂量,对组1中的动物静脉内施用实例G在5%NMP、含5%solutol HS-15的90%HPβCD溶液(20%HPβCD在RO水中)中的溶液配制物。
对组2中的动物口服施用实例G在5%NMP、含5%solutol HS-15的90%HPβCD溶液(20%HPβCD在RO水中)中的10mg/kg溶液配制物。
给药:口服10mg/kg和静脉内注射3mg/kg。
血浆PK总结:
参数-静脉内注射,3mg/kg | 数值-甲磺酸盐 |
t<sub>1/2</sub>(h) | 0.59 |
C<sub>max</sub>(ng/mL) | 2205.80 |
AUC<sub>last</sub>(h*ng.mL) | 1918.37 |
AUC<sub>inf</sub>(h*ng/mL) | 1935.24 |
清除率(mL/h/Kg) | 1550.4 |
Vss(L/Kg) | 1.25 |
参数-口服,10mg/kg | 数值-甲磺酸盐 |
T<sub>max</sub>(h) | 0.25 |
C<sub>max</sub>(ng/mL) | 833.35 |
AUC<sub>last</sub>(h*ng/mL) | 1892.53 |
AUC<sub>inf</sub>(h*ng/mL) | 2144.97 |
F | 30% |
实例G
口服生物利用度(F)=30%
清除率=26mL/min/kg
比较例(在WO2011/021038中的实施例I)
使用以下方案来测定口服生物利用度和清除率,且结果示于以下:
·物种=雄性小鼠;
·品系=CD1;
·n=3只雄性小鼠/时间点/途径;
·8个时间点(5min、10min、0.5h、1h、3h、6h、8h和24h)末端血液取样;
·血浆的收集、生物试验及药代动力学参数的报告。
配制物:10%DMSO,90%盐水
给药:口服10mg/kg和静脉内注射5mg/kg。
血浆PK总结:
参数-静脉内注射,5mg/kg | 数值-甲磺酸盐 | 数值-HCl盐 |
t<sub>1/2</sub>(h) | 1.6 | 7.6 |
T<sub>max</sub>(h) | 0.08 | 0.08 |
C<sub>max</sub>(ng/mL) | 1618 | 1712 |
AUC<sub>last</sub>(h*ng.mL) | 1245 | 1479 |
AUC<sub>all</sub>(h*ng/mL) | 1245 | 1479 |
AUC<sub>inf</sub>(h*ng/mL) | 1261 | 1515 |
清除率(mL/hr/Kg) | 3966 | 3300 |
Vd(mL/Kg) | 4601 | 10063 |
参数-口服,10mg/kg | 数值-甲磺酸盐 | 数值-HCl盐 |
t<sub>1/2</sub>(h) | 1.9 | 1.8 |
T<sub>max</sub>(h) | 1.0 | 1.0 |
C<sub>max</sub>(ng/mL) | 212 | 322 |
AUC<sub>last</sub>(h*ng/mL) | 657 | 849 |
AUC<sub>all</sub>(h*ng/mL) | 657 | 849 |
AUC<sub>inf</sub>(h*ng/mL) | 700 | 896 |
F | 27.8% | 29.6% |
在WO2011/021038中的实例I(比较例)–甲磺酸盐形式
口服生物利用度(F)=28%
清除率=66mL/min/kg
总结
组合数据
引入
以下提供了体外组合研究的数据。
测试了单独的或与以下试剂组合的为本文所公开的实例A(在该实验部分中称为“化合物A”)的PI3K-p110研究的抑制剂对一组癌细胞系生长的作用:
i.PS-341(硼替佐米),蛋白酶体抑制剂
ii.LY2584702,p70S6K抑制剂
iii.PCI-32765(依鲁替尼),BTK和Tec家族抑制剂
iv.AZD6244(司美替尼),MEK1抑制剂
材料和方法
增殖试验
平行测试21个细胞系22RV1、786O、A375、DLD1、DU145、EJ28、GRANTA-519、KASUMI-1、L-363、MDA-MB-231、MDA-MB-468、MINO、PANC1、PC-3、SF268、SK-MEL-28、SU-DHL-6、U87MG、UMUC3、UO31和WSU-NHL。在96孔微量滴定板(Greiner Bio-One,德国)中进行细胞生长和处理。通过胰蛋白酶消化从指数期培养物收获细胞,并以最佳接种密度铺板于190μL的培养基中。48小时后,将细胞用含有10 μL的20×浓缩化合物(导致最终DMSO浓度为0.1%)的培养基处理。使得细胞在37℃下生长72小时。此外,在48小时后(Tz,时间零点,即处理前)分析具有细胞的对照板。使用磺酰罗丹明B(SRB)总蛋白染色试验测定细胞活力。简而言之,在处理后,吸出培养基并通过添加10%TCA将细胞固定于表面。在4℃孵育一小时后,将板用400μL去离子水洗涤两次并干燥。然后将细胞用100μL的0.04%wt/v SRB染色。将板在室温下孵育至少30min并用1%乙酸洗涤六次以去除未结合的染色剂。将板在室温下干燥,并用100μL的10mM Tris碱溶解结合的SRB。通过使用Victor-2板读取器(Perkin Elmer)在492nm、520nm和560nm下进行光密度的测量。
数据分析
从合适的对照数值(含有未加入药物的细胞)中、从表示被试剂处理的细胞的数值中以及从零时间下的含有细胞的孔的数值中,减去平均背景(源自含有不具有细胞的培养基的板和孔)光密度。使用Oncolead研发的算法和可视化工具进行非线性曲线拟合计算。计算包括具有最佳近似直线的剂量反应曲线、50%效应(IC50)的95%置信区间和产生50%的T/C数值%的测试试剂的浓度(或50%生长抑制(IC50))以及产生10%的T/C数值%的测试试剂的浓度(或90%生长抑制(IC90))。自动计算IC50、IC90、GI50、GI90和TGI数值。将所有数值进行log10转化以用于z分数分析,使用Oncolead研发的集成为数据库分析工具的专用软件进行z分数分析。该筛选旨在使用CI、Bliss和最高单一试剂(HSA)指数来鉴定出潜在的协同组合。数据绘制为Loewe相加模型(Loewe additivity)等效线图解或Bliss独立模型(Blissindependence)计算结果。
结果
化合物A-硼替佐米组合
在基质剂量反应研究中,在一组21个癌细胞系中测试单独的或与蛋白酶体抑制剂硼替佐米组合的PI3K-p110β/δ抑制剂化合物A对癌细胞生长的作用。平均Bliss独立模型(在所有测试的浓度中)表明在所测试的细胞系中显示出很少或不显示协同或潜在的拮抗作用。
化合物A-LY2584702组合
在基质剂量反应研究中,在一组21个癌细胞系中测试单独的或与p70S6K抑制剂LY2584702组合的PI3K-p110β/δ抑制剂化合物A对癌细胞生长的作用。当将化合物A和LY2584702组合时,平均Bliss独立模型(在所有测试的浓度中)表明对MINO、U87MG、UO31和SK-MEL-28细胞的生长抑制具有有限的协同作用。在所测试的其他细胞系中未观察到协同或潜在的拮抗作用。
化合物A-依鲁替尼组合
在基质剂量反应研究中,在一组21个癌细胞系中测试单独的或与BTK抑制剂依鲁替尼组合的PI3K-p110β/δ抑制剂化合物A对癌细胞生长的作用。当将化合物A和依鲁替尼组合时,平均Bliss独立模型(在所有测试的浓度中)表明对MINO、SU-DHL-6和WSU-NHL血液细胞系的生长抑制具有协同作用,并且还对786-O、DU-145、MDA-MB-468和DLD1实体瘤细胞的生长抑制具有协同作用。在所测试的其他细胞系中未观察到协同或潜在的拮抗作用。
化合物A-司美替尼组合
在基质剂量反应研究中,在一组21个癌细胞系中测试单独的或与MEK抑制剂司美替尼组合的PI3K-p110β/δ抑制剂化合物A对癌细胞生长的作用。当将化合物A和司美替尼组合时,平均Bliss独立模型(在所有测试的浓度中)表明对EJ28、DU-145、UO31、SK-MEL-28、786-O、WSU-NHL、MDA-MB-231和PANC1细胞的生长抑制具有协同作用。在所测试的其他细胞系中未观察到协同或潜在的拮抗作用。
Claims (24)
1.药物组合物,包含式(I)的化合物或其药物可接受的盐以及至少一种第二试剂的组合,所述第二试剂选自信号传导途径抑制剂、肿瘤免疫治疗剂、抑制BCL2家族蛋白的试剂、抑制Mcl-1的试剂、蛋白酶体抑制剂、聚(ADP-核糖)聚合酶(PARP)抑制剂、芳香化酶抑制剂、常规细胞毒性试剂或选自阿比特龙、ARN-509和MYC抑制剂的其他试剂;
式(I)
或其药物可接受的盐,其中:
W为O、N-H、N-(C1-C10烷基)或S;
各个X独立地为CH或N;
R1为5元至7元的饱和或不饱和的、任选取代的杂环,所述杂环含有选自N或O的至少1个杂原子;
R2为LY;
各个L为化学键、C1-C10亚烷基、C2-C10亚烯基或C2-C10亚炔基;
Y为任选取代的稠合、桥连或螺环的非芳香族5元至12元杂环,所述杂环含有选自N或O的至多4个杂原子;并且
各个R3独立地为H、C1-C10烷基、卤素、氟代C1-C10烷基、O-C1-C10烷基、NH-C1-C10烷基、S-C1-C10烷基、O-氟代C1-C10烷基、NH-酰基、NH-C(O)-NH-C1-C10烷基、C(O)-NH-C1-C10烷基、芳基或杂芳基。
2.试剂盒,包含至少一种式I的化合物或其药物可接受的盐以及选自信号传导途径抑制剂、肿瘤免疫治疗剂、抑制BCL2家族蛋白的试剂、抑制Mcl-1的试剂、蛋白酶体抑制剂、聚(ADP-核糖)聚合酶(PARP)抑制剂、芳香化酶抑制剂、常规细胞毒性试剂或选自阿比特龙、ARN-509和MYC抑制剂的其他试剂中的至少一种试剂,作为用于在治疗中同时、顺序或单独使用的组合制剂。
3.治疗或预防患者中的病况的方法,包括向所述患者施用治疗有效量的至少一种式I的化合物或其药物可接受的盐以及至少一种第二试剂,所述第二试剂选自信号传导途径抑制剂、肿瘤免疫治疗剂、抑制BCL2家族蛋白的试剂、抑制Mcl-1的试剂、蛋白酶体抑制剂、聚(ADP-核糖)聚合酶(PARP)抑制剂、芳香化酶抑制剂、常规细胞毒性试剂或选自阿比特龙、ARN-509和MYC抑制剂的其他试剂。
4.如权利要求3所述的方法,其中所述施用是单独的、顺序的或同时的。
6.如权利要求1或2所述的组合物、试剂盒或方法,其中R1为吗啉。
7.如前述权利要求中任一项所述的组合物、试剂盒或方法,其中W为O或S。
8.如前述权利要求中任一项所述的组合物、试剂盒或方法,其中W为O。
9.如前述权利要求中任一项所述的组合物、试剂盒或方法,其中X为CH。
10.如前述权利要求中任一项所述的组合物、试剂盒或方法,其中R3为H。
11.如前述权利要求中任一项所述的组合物、试剂盒或方法,其中L为C1-C10亚烷基,优选为亚甲基。
12.如前述权利要求中任一项所述的组合物、试剂盒或方法,其中Y含有一个或两个杂原子,优选含有两个杂原子。
14.如权利要求13所述的组合物、试剂盒或方法,其中A为O或C1-C3亚烷基,优选为亚甲基。
15.如权利要求13或14所述的组合物、试剂盒或方法,其中B为O或CH2,优选为O。
18.如前述权利要求中任一项所述的组合物、试剂盒或方法,其中所述第二试剂选自蛋白酶体抑制剂、p70S6K抑制剂、BTK家族抑制剂和Tec家族抑制剂以及MEK1抑制剂。
19.如前述权利要求中任一项所述的组合物、试剂盒或方法,其中所述第二试剂选自硼替佐米、LY2584702、依鲁替尼和司美替尼。
20.药物组合物,包含前述权利要求中任一项所述的组合物、试剂盒或方法,以及药物可接受的赋形剂。
21.用于治疗的前述权利要求中任一项所述的组合物或试剂盒。
22.如前述权利要求中任一项所述的组合物、试剂盒或方法,其中所述治疗针对癌症。
23.如权利要求22所述的组合物、试剂盒或方法,其中所述癌症涉及实体瘤或为血癌。
24.如权利要求20所述的组合物、试剂盒或方法,其中所述癌症是白血病或PTEN-阴性实体瘤。
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GB201514758D0 (en) * | 2015-08-19 | 2015-09-30 | Karus Therapeutics Ltd | Formulation |
GB201514760D0 (en) | 2015-08-19 | 2015-09-30 | Karus Therapeutics Ltd | Compounds and method of use |
GB201514751D0 (en) * | 2015-08-19 | 2015-09-30 | Karus Therapeutics Ltd | Compounds |
GB201514754D0 (en) * | 2015-08-19 | 2015-09-30 | Karus Therapeutics Ltd | Compounds |
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EP3337477B1 (en) | 2023-02-01 |
AU2016307885B2 (en) | 2019-07-25 |
KR20180064387A (ko) | 2018-06-14 |
US20210069200A1 (en) | 2021-03-11 |
MX2018001926A (es) | 2018-06-19 |
RS64095B1 (sr) | 2023-04-28 |
IL257499A (en) | 2018-07-31 |
FI3337477T3 (fi) | 2023-04-27 |
JP2018523689A (ja) | 2018-08-23 |
PL3337477T3 (pl) | 2023-07-03 |
SI3337477T1 (sl) | 2023-04-28 |
CN108348505B (zh) | 2021-10-12 |
US20230066999A1 (en) | 2023-03-02 |
CN113786409B (zh) | 2024-04-02 |
DK3337477T3 (en) | 2023-02-20 |
AU2016307885A1 (en) | 2018-03-08 |
PT3337477T (pt) | 2023-03-20 |
US11291669B2 (en) | 2022-04-05 |
WO2017029517A1 (en) | 2017-02-23 |
CA2995898A1 (en) | 2017-02-23 |
US20180243313A1 (en) | 2018-08-30 |
EP3337477A1 (en) | 2018-06-27 |
HRP20230376T1 (hr) | 2023-06-23 |
GB201514760D0 (en) | 2015-09-30 |
CN108348505A (zh) | 2018-07-31 |
HUE061615T2 (hu) | 2023-07-28 |
HK1251467A1 (zh) | 2019-02-01 |
US10668077B2 (en) | 2020-06-02 |
LT3337477T (lt) | 2023-03-10 |
ES2939815T3 (es) | 2023-04-27 |
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