CN104817559A - 氘代喹唑啉酮化合物以及包含该化合物的药物组合物 - Google Patents
氘代喹唑啉酮化合物以及包含该化合物的药物组合物 Download PDFInfo
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- CN104817559A CN104817559A CN201410058184.7A CN201410058184A CN104817559A CN 104817559 A CN104817559 A CN 104817559A CN 201410058184 A CN201410058184 A CN 201410058184A CN 104817559 A CN104817559 A CN 104817559A
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- 159000000000 sodium salts Chemical class 0.000 description 1
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Abstract
本发明涉及氘代的喹唑啉酮化合物以及包含该化合物的药物组合物。具体地，本发明公开了式(I)所示的氘代的喹唑啉酮化合物以及含有该化合物、或其晶型、药学上可接受的盐、水合物或溶剂合物的药物组合物。本发明的化合物可用于治疗和/或预防磷脂酰肌醇3-激酶(PI3K)相关性疾病，例如癌症、细胞增殖性疾病等。
Description
技术领域
本发明属于医药领域。具体地，本发明涉及新型的氘代喹唑啉酮化合物以及含该化合物的药物组合物。
背景技术
磷脂酰肌醇-3-激酶(phosphoinositide3-kinases,PI3Ks)是一类特异性催化磷脂酰肌醇(phosphatidylinositol，PI)及其衍生物的3位羟基磷酸化并产生具有第二信使作用的磷脂酰肌醇-3-磷酸(phosphatidylinositol-3，4，5-triphosphate，PI3P)的酶。PI3Ks介导的信号传导参与细胞***、分化、凋亡、代谢以及血管生成等多种细胞功能的调节，对多种细胞生物功能的活化起到重要作用。近年来研究表明，PI3Ks和下游分子蛋白激酶B(protein kinase B,PKB或Akt)所组成的信号通路与肿瘤的发生、发展密切相关，调节肿瘤细胞的增殖、凋亡，促进肿瘤血管形成等。
喹唑啉酮化合物及衍生物是一类磷脂酰肌醇3-激酶的抑制剂。在专利WO03035075和WO2005113556中公开了系列喹唑啉酮衍生物，其中，化合物GS-1101是选择性的PI3K抑制剂，化学名为(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-5-氟-3-苯基喹唑啉-4(3H)-酮，具有治疗癌症和细胞增殖性疾病以及其它相关疾病中的用途，目前该化合物正处于治疗慢性淋巴白血病(chroniclymphocytic leukemia)和非霍奇金淋巴瘤(non-Hodgkin lymphomas)的临床三期研究中。
虽然磷脂酰肌醇-3-激酶(PI3K)是抗肿瘤新药研发的重要靶点之一，然而除了雷帕霉素(rapamycin)及同系物以外，抑制PI3K信号传导通路的研究进展相对缓慢，特别是特异性抑制PI3K亚型(如I型PI3K包括p110α，p110β，p110δ等)的抑制剂的开发还具有很大的挑战性。
因此，本领域仍需要开发具有对磷脂酰肌醇3-激酶具有很好抑制活性或更好药效学/药代动力学性能的化合物。
发明内容
本发明的目的是提供一类新型的具有磷脂酰肌醇3-激酶抑制活性和更好药效学/药代动力学性能的化合物及其用途。
在本发明的第一方面中，提供了一种式(I)所示的氘代的喹唑啉酮化合物、或其晶型、药学上可接受的盐、水合物或溶剂合物：
式中：
R1、R2各自独立地为氢、氘或卤素；
R3选自氢、氘、CH3、CH2D、CHD2、CD3、CH2CH3、CD2CH3、CH2CD3和CD2CD3；
R4、R5、R6、R7、R8、R9、R10、R11、R12和R13各自独立地为氢或氘；
附加条件是R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12或R13中至少一个是氘代的或氘。
在另一优选例中，氘在氘取代位置的氘同位素含量至少是大于天然氘同位素含量(0.015%)，较佳地大于30%，更佳地大于50%，更佳地大于75%，更佳地大于95%，更佳地大于99%。
在另一优选例中，式(I)化合物至少含有1个氘原子,更佳地3个氘原子，更佳地4个氘原子，更佳地6个氘原子。
在另一优选例中，式(I)化合物的对映体过量值(e.e.值)大于95%，更佳地大于98%，更佳地大于99%。
在另一优选例中，R1为氟和/或R2为氢。
在另一优选例中，R4为氢或氘。
在另一优选例中，R5、R6、R7、R8、R9、R10、R11、R12和R13各自独立地为氢或氘。
在另一优选例中，R1为卤素，如氟、氯、溴、碘。
在另一优选例中，R1是氟。
在另一优选例中，R3是CH3、CH2D、CHD2、CD3、CH2CH3、CD2CH3、CH2CD3或CD2CD3。
在另一优选例中，R4是氘。
在另一优选例中，R12为氘和/或R13为氘。
在另一优选例中，R12是氘。
在另一优选例中，R13是氘。
在另一优选例中，所述化合物是选自下组的化合物或其药学上可接受的盐：
在另一优选例中，所述化合物是选自下组的化合物或其药学上可接受的盐：
(S)-2-(1-(9H-嘌呤-6-基氨基)-(1-d-丙基))-5-氟-3-苯基喹唑啉-4(3H)-酮；
(S)-2-(1-(9H-嘌呤-6-基氨基)-(1,2,2-d3-丙基))-5-氟-3-苯基喹唑啉-4(3H)-酮；
(S)-2-(1-(9H-嘌呤-6-基氨基)-(1,2,2,3,3,3-d6-丙基))-5-氟-3-苯基喹唑啉-4(3H)-酮；
(S)-2-(1-(9H-嘌呤-6-基氨基)-(1,3,3,3-d4-丙基))-5-氟-3-苯基喹唑啉-4(3H)-酮；
(S)-2-(1-(9H-嘌呤-6-基氨基)-(2,2,3,3,3-d5-丙基))-5-氟-3-苯基喹唑啉-4(3H)-酮；
(S)-2-(1-(9H-嘌呤-6-基氨基)-(3,3,3-d3-丙基))-5-氟-3-苯基喹唑啉-4(3H)-酮；
(S)-2-(1-(9H-嘌呤-6-基氨基)-(2,2-d2-丙基))-5-氟-3-苯基喹唑啉-4(3H)-酮；
(S)-2-(1-(9H-嘌呤-6-基氨基)-(1-d-乙基))-6-氟-3-苯基喹唑啉-4(3H)-酮；
(S)-2-(1-(9H-嘌呤-6-基氨基)-(1,2,2,2-d4-乙基))-6-氟-3-苯基喹唑啉-4(3H)-酮；
(S)-2-(1-(9H-嘌呤-6-基氨基)-(2,2,2-d3-乙基))-6-氟-3-苯基喹唑啉-4(3H)-酮；
(S)-2-(1-(9H-嘌呤-8-d-6-基氨基)-(1-d-丙基))-5-氟-3-苯基喹唑啉-4(3H)-酮
(S)-2-(1-(9H-嘌呤-2,8-d2-6-基氨基)-(1-d-丙基))-5-氟-3-苯基喹唑啉-4(3H)-酮
在另一优选例中，所述的化合物为其具有如下特征：MS计算值:416；MS测量值:417(M+H)+，439(M+Na)+。
在另一优选例中，所述的化合物为其具有如下特征：MS计算值:421；MS测量值:422(M+H)+，444(M+Na)+。
在另一优选例中，所述的化合物为其具有如下特征：MS计算值:419；MS测量值:420(M+H)+，442(M+Na)+。
在另一优选例中，所述的化合物为其具有如下特征：MS计算值:405；MS测量值:406(M+H)+，428(M+Na)+。
在另一优选例中，所述的化合物为其具有如下特征：MS计算值:417；MS测量值:418(M+H)+，440(M+Na)+。
在另一优选例中，所述的化合物为其具有如下特征：MS计算值:418；MS测量值:419(M+H)+，441(M+Na)+。
在另一优选例中，所述的化合物不包括非氘代的化合物。
在另一优选例中，所述的非氘代的化合物为(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-5-氟-3-苯基喹唑啉-4(3H)-酮。
在另一优选例中，所述的化合物由实施例1-12所述的方法制备的。
在本发明的第二方面中，提供了一种制备药物组合物的方法，包括步骤：将药学上可接受的载体与本发明第一方面中所述的化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物进行混合，从而形成药物组合物。
在本发明的第三方面中，提供了一种药物组合物，它含有药学上可接受的载体和本发明第一方面中所述的化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物。
在另一优选例中，所述的药物组合物为注射剂、囊剂、片剂、丸剂、散剂或颗粒剂。
在另一优选例中，所述的药物组合物还含有另外的治疗药物，所述的另外的治疗药物为癌症、心血管疾病、炎症、感染、免疫性疾病、细胞增殖性疾病、病毒性疾病、代谢性疾病、或器官移植的药物。
更佳地，所述的另外的治疗药物包括(但并不限于)：5-氟尿嘧啶、FOLFOX、阿瓦斯丁TM(avastin，bevacizumab)、贝沙罗汀(bexarotene)、硼替佐米(bortezomib)、骨化三醇(calcitriol)、卡奈替尼(canertinib)、卡培他滨(capecitabine)、吉西他滨(gemcitabine)、碳铂(carboplatin)、塞来考昔(celecoxib)、西妥昔单抗(cetuximab)、顺铂(cisplatin)、达沙替尼(dasatinib)、地高辛(digoxin)、enzastaurin、埃罗替尼(Erlotinib)、依托泊甙(etoposide)、依维莫司(everolimus)、氟维司群(fulvestrant)、吉非替尼(gefitinib)、金雀异黄素(genistein)、伊马替尼(imatinib)、依立替康(irinotecan)、拉帕替尼(lapatinib)、来那度胺(lenalidomide)、来曲唑(letrozole)、亚叶酸(leucovorin)、马妥珠单抗(matuzumab)、奥沙利铂(oxaliplatin)、紫杉醇(paclitaxel)、多西他赛(doxetaxel)、帕尼单抗(panitumumab)、PEG化的粒细胞集落刺激因子(pegfilgrastin)、PEG化的α-干扰素(peglated alfa-interferon)、培美曲塞(pemetrexed)、E、沙铂(satraplatin)、西罗莫司(sirolimus)、舒尼替尼(sutent，sunitinib)、舒林酸(sulindac)、泰索帝(taxotere)、替莫唑胺(temodar、temozomolomide)、驮瑞塞尔(Torisel)、替西罗莫司(temsirolimus)、替吡法尼(tipifarnib)、曲妥单抗(trastuzumab)、丙戊酸(valproic acid)、长春氟宁(vinflunine)、Volociximab、Vorinostat、索拉非尼(Sorafenib)、克唑替尼(Crizotinib)、埃克替尼(Lcotinib)、拉帕替尼(Lapatinib)、托法替尼(Tofacitinib)、PD-0332991(Palbociclib)、安贝生坦(ambrisentan)、多柔比星、甲氨蝶呤、***、利妥昔单抗(rituximab)、CD40和/或CD154特异性抗体、融合蛋白、NF-kB抑制剂、非甾体抗炎药、凝血因子FXa抑制剂(如利伐沙班等)、抗-TNF抗体、抗生素药物如刺孢霉素(calicheamicin)、放线菌素(actinomycin)、阿霉素(doxorubicin)等。
在本发明的第四方面中，提供了本发明第一方面中所述的化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物本发明第三方面所述的药物组合物的用途，它们被用于制备抑制磷脂酰肌醇3-激酶的药物组合物。
在另一优选例中，所述的药物组合物用于制备治疗和预防以下疾病的药物：癌症、细胞增殖性疾病、炎症、感染或免疫性疾病。
在另一优选例中，所述的癌症包括(但并不限于)：肺癌、乳腺癌、***癌、食道癌、直肠癌、结肠癌、血癌（或恶性血液病）、骨癌、肾癌、胃癌、肝癌或大肠癌。
在另一优选例中，所述的血癌（或恶性血液病）为白血病、淋巴瘤。
在另一优选例中，所述的淋巴瘤是指非霍奇金淋巴瘤(non-Hodgkinlymphomas)、B细胞淋巴瘤(B-cell lymphoma)、套细胞淋巴瘤(mantle celllymphoma)。
在另一优选例中，所述的白血病是指慢性淋巴白血病(chronic lymphocyticleukemia)、急性淋巴白血病(acute lymphocytic leukemia)、急性骨髓性白血病(acute myeloid leukemia)、多发性骨髓瘤(multiple myeloma)、慢性骨髓性白血病(chronic myeloid leukemia)。
在本发明的第五方面中，提供了一种抑制磷脂酰肌醇3-激酶的方法或一种疾病(如癌症、细胞增殖性疾病、炎症、感染、免疫性疾病)的治疗方法，它包括步骤：给需要治疗的对象施用本发明第一方面中所述的化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物，或施用本发明第三方面中所述的药物组合物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过研究，意外地发现，本发明的氘代的喹唑啉酮化合物及其药学上可接受的盐与未氘代的化合物相比，具有明显更优异的药物动力学和/或药效学性能，因此更适合作为抑制磷脂酰肌醇3-激酶的化合物，进而更适用制备治疗癌症以及磷脂酰肌醇3-激酶相关疾病的药物。在此基础上完成了本发明。
定义
如本文所用，“卤素”指F、Cl、Br、和I。更佳地，卤原子选自F、Cl和Br。
如本文所用，“更优异的药物动力学和/或药效学性能”是指更长的药物半衰期(t1/2)，或者更高的药物暴露量(AUC)，或者更高的最大药物浓度(Cmax)，或者更低的药物清除率
如本文所用，“氘代”指化合物或基团中的一个或多个氢被氘所取代。氘代可以是一取代、二取代、多取代或全取代。术语“一个或多个氘代的”与“一次或多次氘代”可互换使用。
如本文所用，“非氘代的化合物”是指含氘原子比例不高于天然氘同位素含量(0.015%)的化合物。
在另一优选例中，氘在氘取代位置的氘同位素含量是大于天然氘同位素含量(0.015%)，更佳地大于50%，更佳地大于75%，更佳地大于95%，更佳地大于97%，更佳地大于99%，更佳地大于99.5%。
在另一优选例中，式(I)化合物至少含有1个氘原子,更佳地2个氘原子、3个氘原子，更佳地4个氘原子，更佳地6个氘原子。
优选地，式(I)化合物中，N为14N和/或O为16O。
在另一优选例中，所述化合物中，14N在氮原子所在位置的同位素含量≥95%，更佳地≥99%。
在另一优选例中，所述化合物中，16O在氧原子所在位置的同位素含量≥95%，更佳地≥99%。
活性成分
如本文所用，术语“本发明化合物”指式(I)所示的化合物。该术语还包括及式(I)化合物的各种晶型形式、药学上可接受的盐、水合物或溶剂合物。
其中，术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸；甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、乙磺酸、甲苯磺酸、苯磺酸、萘磺酸等有机酸；以及脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。另一类优选的盐是本发明化合物与碱形成的盐，例如碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如镁盐或钙盐)、铵盐(如低级的烷醇铵盐以及其它药学上可接受的胺盐)，例如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐，以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。
术语“溶剂合物”指本发明化合物与溶剂分子配位形成特定比例的配合物。“水合物”是指本发明化合物与水进行配位形成的配合物。
此外，本发明化合物还包括式(I)所示的喹唑啉酮化合物的手性对映异构体、或消旋体。
此外，本发明化合物还包括式(I)所示的喹唑啉酮化合物的前药。术语“前药”包括其本身可以是具有生物学活性的或非活性的，当用适当的方法服用后，其在人体内进行代谢或化学反应而转变成式(I)的一类化合物，或式(I)的一个化合物所组成的盐或溶液。所述的前药包括(但不局限于)所述化合物的羧酸酯、碳酸酯、磷酸酯、硝酸酯、硫酸酯、砜酯、亚砜酯、氨基化合物、氨基甲酸盐、偶氮化合物、磷酰胺、葡萄糖苷、醚、乙缩醛等形式。
制备方法
下面更具体地描述本发明式(I)结构化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得，这样的组合可由本发明所属领域的技术人员容易地进行。
本发明使用的未氘代的喹唑啉酮化合物及其生理上相容的盐的制备方法是已知的。对应氘代的喹唑啉酮化合物的制备可以用相应的氘代起始化合物为原料，用同样的路线合成。例如，本发明式(I)化合物可按WO03035075中所述的制备方法制备，不同点在于在反应中用氘代的原料代替非氘代的原料。
通常，在制备流程中，各反应通常在惰性溶剂中，在室温至回流温度(如0℃～200℃，优选0℃～100℃)下进行。反应时间通常为0.1小时-60小时，较佳地为0.5-48小时。
下面的通用制备路线可以用于合成本发明式(I)结构的化合物。
其中：R2、R1选自H、D、F、Cl、Br、I；R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13的定义同前。
如合成路线一所示，取代的间硝基苯甲酸化合物II经草酰氯酰化后与取代的苯胺III在碱性条件下反应生成化合物IV；IV在氯化亚砜作用下酰胺氢被氯代，再与相关Boc保护氘代氨基酸V作用形成化合物VI，VI结构中的芳硝基经化学还原条件如锌粉/醋酸、氯化亚锡、还原铁粉或如钯、铂、雷尼镍等催化氢化条件得到芳胺，关环得到喹唑啉酮结构VII；化合物VII在三氟乙酸/二氯甲烷、盐酸/二氧六环等条件下脱Boc再经碱游离得到化合物VIII，最后与6-溴嘌呤或6-溴氘代嘌呤在碱作用下于醇(如乙醇，正丁醇，叔丁醇)或四氢呋喃等溶剂中煮沸即可得到本发明化合物I。上述反应在惰性溶剂，如二氯甲烷、二氯乙烷、乙腈、正己烷、甲苯、四氢呋喃、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜、乙酸、丁醇、丙醇等中，温度0～200℃下进行。
氘代化合物V的制备方法如下面合成路线所示：
其中R3、R4的定义同前。
如合成路线二所示，氘代氨基酸IX和二碳酸二叔丁酯(Boc2O)在碱性条件下和惰性溶剂中反应生成N-Boc保护氨基酸V。一些氘代氨基酸IX可通过常规氘代方法制得。另一些氘代氨基酸IX可以商业化购买到，如：(2S)-2-氨基-4，4，4-d3-丁酸、(2S)-2-氨基-3，3-d2-丁酸、(2S)-2-氨基-2-d-丁酸和(2S)-2-氨基-2，3，3-d3-丁酸等。
药物组合物和施用方法
由于本发明化合物具有优异的对磷脂酰肌醇3-激酶的抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解由对磷脂酰肌醇3-激酶介导的疾病。根据现有技术，本发明化合物可用于治疗以下疾病：癌症、细胞增殖性疾病、炎症、感染、免疫性疾病等。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-1000mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明的化合物与现有技术中已知的非氘代化合物相比，具有一系列优点。本发明的主要优点包括：
(1)本发明化合物对磷脂酰肌醇3-激酶(PI3K)具有优异的抑制性。
(2)通过氘化这一技术改变化合物在生物体中的代谢，使化合物具有更好的药代动力学参数特性。在这种情况下，可以改变剂量并形成长效制剂，改善适用性。
(3)用氘取代化合物中的氢原子，由于其氘同位素效应，能够提高化合物在动物体内的药物浓度，以提高药物疗效。
(4)用氘取代化合物中的氢原子,由于某些代谢产物被抑制，可能提高化合物的安全性。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则份数和百分比为重量份和重量百分比。
实施例1制备(S)-2-(1-(9H-嘌呤-6-基氨基)-(1-d-丙基))-5-氟-3-苯基喹唑啉-4(3H)-酮(化合物6)
1、制备2-氟-6-硝基-N-苯基苯甲酰胺(化合物2)
向烧瓶中加入化合物2-氟-6-硝基苯甲酸(5.0g,0.027mol)和N，N-二甲基甲酰胺(0.5ml),加入二氯甲烷(20ml)溶解，再缓慢滴加草酰氯(5.1g,0.04mol,1.5eq)。室温搅拌2小时后，浓缩。浆状物溶于二氧六环(10ml)并冷却到5℃，将该溶液缓慢滴入到苯胺(5ml,0.027mol,1eq)及碳酸氢钠(4.5g，0.054mol，2eq)的二氧六环和水(1:1,v:v,30ml)的混合体系中。滴加完后升温至室温搅拌60分钟。加入纯水，析出大量固体，抽滤，滤饼用水洗涤，抽干，50℃下高真空干燥24h,得到类白色固体目标产物(6.0g，85%)。1H NMR(300MHz,DMSO-d6)δ10.82(s,1H),8.12(d,J=7.7Hz,1H),7.91-7.77(m,2H),7.64(d,J=7.7Hz,2H),7.38(t,J=7.9Hz,2H),7.15(t,J=7.4Hz,1H)；ESI-MS m/z261(M+H)+。
2、制备(S)-[1-(2-氟-6-硝基-苯甲酰基)-苯基-氨甲酰基]-(1-d-丙基)-氨基甲酸叔丁酯(化合物3)
向烧瓶中一次加入2-氟-6-硝基-N-苯基苯甲酰胺(7.8g，0.03mol)、N，N-二甲基甲酰胺(0.5ml)和氯化亚砜(17.8g，0.15mol，5eq)，升温到85℃并搅拌5小时。样品浓缩得棕色稠状物。稠状物用二氯甲烷(20ml)溶解后，10℃下缓慢滴加到(S)-2-(叔丁氧羰酰胺)-2-d-丁酸(6.7g，0.033mol，1.1eq)，三乙胺(3.4g，0.033mol，1.1eq)的二氯甲烷(50ml)溶液中。室温搅拌3小时后，过滤除去固体，滤液分别用纯水、饱和碳酸氢钠、纯水、5%柠檬酸及饱和食盐水洗涤。有机相用无水硫酸镁干燥，浓缩得红色稠状物。稠状物经硅胶柱层析(10%-25%正己烷/乙酸乙酯)得到类白色的目标化合物3(8.0g，60%)。ESI-MS m/z447(M+H)+。
3、制备(S)-[1-(5-氟-4-氧-3-苯基-3,4-二羟基-喹唑啉-2-基)-(1-d-丙基)]-氨基甲酸叔丁酯(化合物4)
向烧瓶中加入(S)-[1-(2-氟-6-硝基-苯甲酰基)-苯基-氨甲酰基]-(1-d-丙基)-氨基甲酸叔丁酯(4.5g,0.01mol,1eq)和醋酸(50ml),搅拌。控制温度低于20℃,分三批加入锌粉(48.4g，740mmol，6eq)。室温下搅拌2小时。抽滤并用醋酸洗涤滤饼，滤液浓缩后溶于乙酸乙酯，依次用纯水、饱和碳酸氢钠水溶液及食盐水洗涤，无水硫酸镁干燥，浓缩得残余物。残余物经硅胶柱层析(10%-25%正己烷/乙酸乙酯)得到类白色的泡状固体(2.5g，63%)。1H NMR(400MHz,DMSO-d6)δ7.80(s,1H),7.62-7.44(m,5H),7.38(d,J=7.6Hz,1H),7.30(m,1H),7.23(d,J=7.6Hz,1H),1.76-1.68(m,1H),1.60-1.46(m,1H),1.31(s,9H),0.62(t,J=7.2Hz,3H).ESI-MS m/z399(M+H)+.
4、制备(S)-2-(1-氨基-1-d-丙基)-5-氟-3-苯基喹唑啉-4(3H)-酮(化合物5)
向烧瓶中依次加入(S)-[1-(5-氟-4-氧-3-苯基-3,4-二羟基-喹唑啉-2-基)-(1-d-丙基)]-氨基甲酸叔丁酯(1.99g，5mmol)和二氯甲烷(6ml)，搅拌，加入三氟乙酸(6ml)。室温下搅拌1小时。高真空浓缩，残留物溶于二氯甲烷，加入10%碳酸钾水溶液直至pH约为9，分层，水相再用二氯甲烷萃取，合并有机相依次用纯水及食盐水洗涤，无水硫酸镁干燥，浓缩得到类白色固体目标产物(1.4g，93%)。1H NMR(400MHz,CDCl3)δ7.74-7.66(m,1H),7.62-7.50(m,4H),7.30-7.20(m,2H),7.12-7.06(m,1H),1.88-1.72(m,1H),1.58-1.41(m,1H),0.78(t,J=7.2Hz,3H).ESI-MS m/z299.1(M+H)+。
5、制备(S)-2-(1-(9H-嘌呤-6-基氨基)-1-d-丙基)-5-氟-3-苯基喹唑啉-4(3H)-酮(化合物6)
向反应瓶中依次加入(S)-2-(1-氨基-1-d-丙基)-5-氟-3-苯基喹唑啉-4(3H)-酮(1.2g,4mmol,1eq)、6-溴嘌呤(0.88g,4.4mmol,1.1eq)和二异丙基乙胺(1.04g,8mmol,2eq)和叔丁醇(8ml)。混合物在80℃下搅拌30小时。样品浓缩得到固体粗品,经硅胶柱层析(4%甲醇/二氯甲烷)分离纯化得到淡黄色固体产物(1.0g，60%)。1H NMR(400MHz,DMSO-d6)δ12.70(s,1H),8.12(s,1H),8.02(s,1H),7.82-7.74(m,1H),7.62-7.40(m,6H),7.26-7.15(m,2H),2.03-1.75(m,2H),0.78(t,J=7.2Hz,3H).ESI-MS m/z417(M+H)+。
实施例2制备(S)-2-(1-(9H-嘌呤-6-基氨基)-1,2,2-d3-丙基)-5-氟-3-苯基喹唑啉-4(3H)-酮(化合物7)
按实施例1中所述的方法，不同点在于：用(S)-2-(叔丁氧羰酰胺)-2,3,3-d3-丁酸替换(S)-2-(叔丁氧羰酰胺)-2-d-丁酸，从而制得目标化合物7。ESI-MS m/z419(M+H)+。
实施例3制备(S)-2-(1-(9H-嘌呤-6-基氨基)-1,2,2,3,3,3-d6-丙基)-5-氟-3-苯基喹唑啉-4(3H)-酮(化合物8)
按实施例1中所述的方法，不同点在于：用(S)-2-(叔丁氧羰酰胺)-2,3,3,4,4,4-d6-丁酸替换(S)-2-(叔丁氧羰酰胺)-2-d-丁酸，从而制得目标化合物8。ESI-MS m/z422(M+H)+。
实施例4制备(S)-2-(1-(9H-嘌呤-6-基氨基)-1,3,3,3-d4-丙基)-5-氟-3-苯基喹唑啉-4(3H)-酮(化合物9)
按实施例1中所述的方法，不同点在于：用(S)-2-(叔丁氧羰酰胺)-2,4,4,4-d4-丁酸替换(S)-2-(叔丁氧羰酰胺)-2-d-丁酸，从而制得目标化合物9。ESI-MS m/z420(M+H)+。
实施例5制备(S)-2-(1-(9H-嘌呤-6-基氨基)-2,2,3,3,3-d5-丙基)-5-氟-3-苯基喹唑啉-4(3H)-酮(化合物10)
按实施例1中所述的方法，不同点在于：用(S)-2-(叔丁氧羰酰胺)-3,3,4,4,4-d5-丁酸替换(S)-2-(叔丁氧羰酰胺)-2-d-丁酸，从而制得目标化合物10。ESI-MS m/z421(M+H)+。
实施例6制备(S)-2-(1-(9H-嘌呤-6-基氨基)-3,3,3-d3-丙基)-5-氟-3-苯基喹唑啉-4(3H)-酮(化合物11)
按实施例1中所述的方法，不同点在于：用(S)-2-(叔丁氧羰酰胺)-4,4,4-d3-丁酸替换(S)-2-(叔丁氧羰酰胺)-2-d-丁酸，从而制得目标化合物11。ESI-MS m/z419(M+H)+。
实施例7制备(S)-2-(1-(9H-嘌呤-6-基氨基)-2,2-d2-丙基)-5-氟-3-苯基喹唑啉-4(3H)-酮(化合物12)
按实施例1中所述的方法，不同点在于：用(S)-2-(叔丁氧羰酰胺)-3,3-d2-丁酸替换(S)-2-(叔丁氧羰酰胺)-2-d-丁酸，从而制得目标化合物12。ESI-MS m/z418(M+H)+。
实施例8制备(S)-2-(1-(9H-嘌呤-6-基氨基)-1-d-乙基)-6-氟-3-苯基喹唑啉-4(3H)-酮(化合物13)
按实施例1中所述的方法，不同点在于：用3-氟-6-硝基苯甲酸替换2-氟-6-硝基苯甲酸、(S)-2-(叔丁氧羰酰胺)-2-d-丙酸替换(S)-2-(叔丁氧羰酰胺)-2-d-丁酸，从而制得目标化合物13。ESI-MS m/z403(M+H)+。
实施例9制备(S)-2-(1-(9H-嘌呤-6-基氨基)-1,2,2,2-d4-乙基)-6-氟-3-苯基喹唑啉-4(3H)-酮(化合物14)
按实施例1中所述的方法，不同点在于：用3-氟-6-硝基苯甲酸替换2-氟-6-硝基苯甲酸、(S)-2-(叔丁氧羰酰胺)-2,3,3,3-d4-丙酸替换(S)-2-(叔丁氧羰酰胺)-2-d-丁酸，从而制得目标化合物14。ESI-MS m/z406(M+H)+。
实施例10制备(S)-2-(1-(9H-嘌呤-6-基氨基)-2,2,2-d3-乙基)-6-氟-3-苯基喹唑啉-4(3H)-酮(化合物15)
按实施例1中所述的方法，不同点在于：用3-氟-6-硝基苯甲酸替换2-氟-6-硝基苯甲酸、(S)-2-(叔丁氧羰酰胺)-3,3,3-d3-丙酸替换(S)-2-(叔丁氧羰酰胺)-2-d-丁酸，从而制得目标化合物15。ESI-MS m/z405(M+H)+。
实施例11制备(S)-2-(1-(9H-嘌呤-8-d-6-基氨基)-(1-d-丙基))-5-氟-3-苯基喹唑啉-4(3H)-酮(化合物16)
按实施例1中所述的方法，不同点在于：用6-溴-8-d-嘌呤替换6-溴嘌呤从而制得目标化合物16。ESI-MS m/z418(M+H)+。
实施例12制备(S)-2-(1-(9H-嘌呤-2,8-d2-6-基氨基)-(1-d-丙基))-5-氟-3-苯基喹唑啉-4(3H)-酮(化合物17)
按实施例1中所述的方法，不同点在于：用6-溴-2,8-d2-嘌呤替换6-溴嘌呤从而制得目标化合物17。ESI-MS m/z419(M+H)+。
实施例13：大鼠中的药代动力学评价
4只雄性Sprague-Dawley大鼠，7-8周龄，体重约210g，单次联合口服给予3mg/kg剂量的(a)对照组：(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-5-氟-3-苯基喹唑啉-4(3H)-酮和(b)试验组：实施例1～12制备的一些化合物，比较其药代动力学差异。
大鼠采用标准饲料饲养，给予水。试验前16小时开始禁食。药物用PEG400和二甲亚砜溶解。眼眶采血，采血的时间点为给药后0.25小时、0.5小时、1小时、2小时、4小时、6小时、8小时、12小时、24小时和36小时。
大鼠吸入***后短暂麻醉，眼眶采集300μL血样于试管。试管内有30μL1%肝素盐溶液。使用前，试管于60℃烘干过夜。在随后一个时间点血样采集完成之后，大鼠***麻醉后处死。
血样采集后，立即温和地颠倒试管至少5次，保证混合充分后放置于冰上。血样在4℃5000rpm离心5分钟，将血浆与红细胞分离。用移液器吸出100μL血浆到干净的塑料离心管中，表明化合物的名称和时间点。血浆在进行分析前保存在-80℃。用LC-MS/MS测定血浆中本发明化合物的浓度。药代动力学参数基于每只动物在不同时间点的血药浓度进行计算。
从结果看出，相对于对照化合物，本发明化合物在动物体内具有更好的药物动力学性质，因而具有更好的药效学和治疗效果。
实施例14：本发明化合物对磷脂酰肌醇3-激酶的体外药效学评价
本发明化合物的体外药效学评价试验方案参照文献J.Med.Chem.2013,56,1922?1939。
实验结果如表1所示。可见，本发明所述的化合物对磷脂酰肌醇3-激酶具有优异的抑制活性。
表1
| 化合物 | 对PI3Kδ抑制活性(IC50) |
| 实施例1 | ＜20nM |
| 实施例2 | ＜20nM |
| 实施例3 | ＜20nM |
| 实施例4 | ＜20nM |
| 实施例5 | ＜20nM |
| 实施例6 | ＜20nM |
| 实施例7 | ＜20nM |
| 实施例8 | ＜20nM |
| 实施例9 | ＜20nM |
| 实施例10 | ＜20nM |
| 实施例11 | ＜20nM |
| 实施例12 | ＜20nM |
实施例15药物组合物
化合物(实施例1-12) 100g
淀粉 130g
微晶纤维素 60g
按常规方法，将上述物质混合均匀后，装入普通明胶胶囊，得到1000颗胶囊。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (11)
1.一种式(I)所示的氘代的喹唑啉酮化合物、或其晶型、药学上可接受的盐、水合物或溶剂合物：
其中：
R1、R2各自独立地为氢、氘或卤素；
R3选自氢、氘、CH3、CH2D、CHD2、CD3、CH2CH3、CD2CH3、CH2CD3和CD2CD3；
R4、R5、R6、R7、R8、R9、R10、R11、R12和R13各自独立地为氢或氘；
附加条件是R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12或R13中至少一个是氘代的或氘。
2.如权利要求1所述的化合物，其特征在于，R1为氟和/或R2为氢。
3.如权利要求1所述的化合物，其特征在于，R3为CH3、CH2D、CHD2、CD3、CH2CH3、CD2CH3、CH2CD3或CD2CD3。
4.如权利要求1中所述的化合物，其特征在于，R4为氘或氢。
5.如权利要求1-4中任一所述的化合物，其特征在于，R12为氘和/或R13为氘。
6.如权利要求1所述的化合物，其特征在于，所述化合物是选自下组的化合物或其药学上可接受的盐：
7.如权利要求1所述的化合物，其特征在于，所述的化合物不包括非氘代的化合物。
8.一种药物组合物，其特征在于，它含有药学上可接受的载体和权利要求1所述的化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物。
9.如权利要求8所述的药物组合物，其特征在于，它还含有另外的治疗药物，所述的另外的治疗药物为癌症、细胞增殖性疾病、心血管疾病、炎症、感染、免疫性疾病、病毒性疾病、或代谢性疾病的药物。
10.一种权利要求1所述的化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物或如权利要求8所述的药物组合物的用途，其特征在于，用于制备抑制磷脂酰肌醇3-激酶(PI3K)的药物组合物。
11.如权利要求10所述的用途，其特征在于，所述的药物组合物用于制备用于治疗和预防以下疾病的药物：癌症、细胞增殖性疾病、炎症、感染或免疫性疾病。
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| CN201410058184.7A CN104817559B (zh) | 2014-01-30 | 2014-02-20 | 氘代喹唑啉酮化合物以及包含该化合物的药物组合物 |
| EP15743414.3A EP3101020B1 (en) | 2014-01-30 | 2015-01-30 | Deuterated quinazolinone compound and pharmaceutical composition comprising same |
| JP2016549229A JP6606806B2 (ja) | 2014-01-30 | 2015-01-30 | 重水素化キナゾリノン化合物及び該化合物を含む薬物組成物 |
| CA2956773A CA2956773C (en) | 2014-01-30 | 2015-01-30 | Deuterated quinazolinone compounds and pharmaceutical compositions comprising same |
| US15/115,316 US10414767B2 (en) | 2014-01-30 | 2015-01-30 | Deuterated quinazolinone compound and pharmaceutical composition comprising same |
| RU2016135192A RU2656485C2 (ru) | 2014-01-30 | 2015-01-30 | Дейтерированные соединения хиназолинона и содержащие их фармацевтические композиции |
| BR112016017628-6A BR112016017628A2 (pt) | 2014-01-30 | 2015-01-30 | compostos de quinazolinona deuterados e composições farmacêuticas que compreendem os mesmos |
| PCT/CN2015/071996 WO2015113521A1 (zh) | 2014-01-30 | 2015-01-30 | 氘代喹唑啉酮化合物以及包含该化合物的药物组合物 |
| CN201580006716.5A CN106232602B (zh) | 2014-01-30 | 2015-01-30 | 氘代喹唑啉酮化合物以及包含该化合物的药物组合物 |
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| CN201580006716.5A Active CN106232602B (zh) | 2014-01-30 | 2015-01-30 | 氘代喹唑啉酮化合物以及包含该化合物的药物组合物 |
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| EP (1) | EP3101020B1 (zh) |
| JP (1) | JP6606806B2 (zh) |
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Cited By (4)
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| CN106232602A (zh) * | 2014-01-30 | 2016-12-14 | 苏州泽璟生物制药有限公司 | 氘代喹唑啉酮化合物以及包含该化合物的药物组合物 |
| CN108137592A (zh) * | 2015-11-03 | 2018-06-08 | 纽弗姆制药有限公司 | 用于治疗血癌的氘代化合物以及其组合物和方法 |
| CN108699061A (zh) * | 2015-11-16 | 2018-10-23 | 纽弗姆制药有限公司 | 用于治疗血液恶性肿瘤、炎症和自身免疫性疾病的氘代化合物 |
| CN113603713A (zh) * | 2017-12-05 | 2021-11-05 | 深圳市塔吉瑞生物医药有限公司 | 一种取代的硼酸酯化合物的制备方法及其晶型 |
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- 2015-01-30 CN CN201580006716.5A patent/CN106232602B/zh active Active
- 2015-01-30 JP JP2016549229A patent/JP6606806B2/ja active Active
- 2015-01-30 WO PCT/CN2015/071996 patent/WO2015113521A1/zh active Application Filing
- 2015-01-30 CA CA2956773A patent/CA2956773C/en active Active
- 2015-01-30 BR BR112016017628-6A patent/BR112016017628A2/pt not_active Application Discontinuation
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| CN106232602A (zh) * | 2014-01-30 | 2016-12-14 | 苏州泽璟生物制药有限公司 | 氘代喹唑啉酮化合物以及包含该化合物的药物组合物 |
| CN106232602B (zh) * | 2014-01-30 | 2021-06-18 | 苏州泽璟生物制药股份有限公司 | 氘代喹唑啉酮化合物以及包含该化合物的药物组合物 |
| CN108137592A (zh) * | 2015-11-03 | 2018-06-08 | 纽弗姆制药有限公司 | 用于治疗血癌的氘代化合物以及其组合物和方法 |
| CN108137592B (zh) * | 2015-11-03 | 2021-03-05 | 纽弗姆制药有限公司 | 用于治疗血癌的氘代化合物以及其组合物和方法 |
| CN108699061A (zh) * | 2015-11-16 | 2018-10-23 | 纽弗姆制药有限公司 | 用于治疗血液恶性肿瘤、炎症和自身免疫性疾病的氘代化合物 |
| CN108699061B (zh) * | 2015-11-16 | 2022-07-05 | 纽弗姆制药有限公司 | 用于治疗血液恶性肿瘤、炎症和自身免疫性疾病的氘代化合物 |
| CN113603713A (zh) * | 2017-12-05 | 2021-11-05 | 深圳市塔吉瑞生物医药有限公司 | 一种取代的硼酸酯化合物的制备方法及其晶型 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP3101020A1 (en) | 2016-12-07 |
| RU2656485C2 (ru) | 2018-06-06 |
| EP3101020A4 (en) | 2017-06-14 |
| RU2016135192A (ru) | 2018-03-05 |
| CA2956773C (en) | 2019-04-30 |
| US10414767B2 (en) | 2019-09-17 |
| RU2016135192A3 (zh) | 2018-03-05 |
| BR112016017628A2 (pt) | 2020-10-27 |
| CN106232602B (zh) | 2021-06-18 |
| WO2015113521A1 (zh) | 2015-08-06 |
| CN106232602A (zh) | 2016-12-14 |
| EP3101020B1 (en) | 2020-03-11 |
| CN104817559B (zh) | 2021-05-25 |
| JP6606806B2 (ja) | 2019-11-20 |
| CA2956773A1 (en) | 2015-08-06 |
| US20170305911A1 (en) | 2017-10-26 |
| JP2017504638A (ja) | 2017-02-09 |
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