CN112055706B - 取代的卤代-喹啉衍生物、其制备方法和应用 - Google Patents
取代的卤代-喹啉衍生物、其制备方法和应用 Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
- C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
Abstract
本发明涉及通式(I)的化合物:其中R1是OCH2CH2OCH3或OCH3,R’1是H或OH,R2是Cl、F、Br或I,条件是:当R1是OCH2CH2OCH3时,R’1是H,当R1是OCH3时,R’1是OH,它的药学上可接受的盐和/或其旋光异构体、互变异构体、溶剂化物或同位素变型。本发明还涉及用于治疗癌症、即实体瘤癌症、优选选自以下的那些癌症的化合物:黑素瘤、结肠癌、肺癌、胰腺癌、肾癌、梅克尔癌、鳞状细胞癌、前列腺癌、乳腺癌和膀胱癌。本发明还涉及包含所述化合物的药物组合物。
Description
发明领域:
本发明涉及新的取代的卤代-喹啉衍生物,其具有治疗癌症的活性。
发明背景:
源于黑素细胞转化的皮肤黑素瘤是成年人中最致命的癌症之一。在过去的几十年中,其发病率以惊人的速率增长。黑素瘤具有高侵袭能力并快速转移至其它器官。
靶向细胞毒性T淋巴细胞相关蛋白4(CTLA-4)以及最近靶向于程序性死亡1(PD1)和程序性死亡-配体1(PDL-1)的免疫检查点阻断是癌症疗法的最近的主要突破。最初开发用于治疗转移性黑素瘤的针对这些靶标的抗体显著性地提高患者的总体存活率,目前正在评估将其用于治疗其它实体癌,例如肾、前列腺、结肠和肺的实体癌。尽管抗-PD1抗体显示出比抗-CTLA-4抗体更好的结果,但应答率仍然低(10%-57%),取决于癌症类型和治疗组合。迄今为止,抗-PD1和抗-CTLA-4的组合治疗黑素瘤的最佳完全应答率11.5%,但与几乎70%的3级或4级副作用发生率相关。因此,几乎没有患者从这些方法中受益,并且尚未确定应答的预测因素。累积的证据提示,干扰素γ(IFN-γ)在抗-PD1治疗的应答中起关键作用(1-3)。所有基于免疫的黑素瘤治疗方法(包括抗-PD1)的元分析(meta-analysis)显示,与其它患者相比,具有白癜风样脱色素(vitiligoid depigmentation)的患者具有显著更好的无进展生存率和总生存率(4)。此外,具有白癜风的患者发生黑素瘤的风险低三倍(5)。越来越多的数据表明,白癜风样脱色素过程所涉及的IFN-γ/CXCL10途径在确定黑素瘤风险中起关键作用(6)。因此,作为有助于检查点阻断治疗方法的关键因素涉及IFN-γ应答。本申请的发明人最近证明,抑制非典型NF-kB途径以及抑制上游NF-kB诱导激酶(NIK)通过减少EZH2转录而恢复黑素瘤细胞的衰老程序,并且显著性地减少肿瘤生长(7)。越来越多的证据表明细胞衰老可触发或增强肿瘤免疫监视(8)。
本发明提供了新的NIK抑制剂,其在转录水平上降低EZH2并诱导被处理的细胞产生IFN-γ应答。这些NIK抑制剂减少皮下肿瘤尺寸,而没有显示任何特异性毒性,并且与抗-PD1治疗组合使用时,导致肿瘤尺寸大幅减小,在一些病例中完全消退。这些作用与被治疗的肿瘤内M1型巨噬细胞、树突状细胞、天然杀伤细胞和T-细胞的数量和活化的明显增加相关。
发明概述:
本发明涉及式(I)的化合物:
其中R1、R’1和R2具有下文给出的含义,并且涉及含有这类化合物的药物组合物及其用途。
发明详述:
更具体地,本发明涉及通式(I)的化合物:
其中
R1是OCH2CH2OCH3或OCH3,
R’1是H或OH,
R2是卤素基团,选自氯(Cl)、氟(F)、溴(Br)和碘(I),
条件是:
当R1是OCH2CH2OCH3时,R’1是H,
当R1是OCH3时,R’1是OH,
它的药学上可接受的盐和/或其旋光异构体、互变异构体、溶剂化物或同位素变型。
根据本发明的一个有利的实施方案,R2的卤代基团是氯(Cl)。
式(I)的化合物更具体地是如下化合物:
7-氯-N-(4-(2-甲氧基乙氧基)苯基)喹啉-4-胺(化合物42),和
7-氯-N-(3-(羟基)-4-(甲氧基)苯基)喹啉-4-胺(也称作5-((7-氯喹啉-4-基)氨基)-2-甲氧基苯酚)(化合物43)。
式(I)的化合物、它们的药学上可接受的盐和/或衍生形式(其旋光异构体、互变异构体、溶剂化物或同位素变型)是适合用于治疗和预防各种癌症的有价值的药学活性化合物。
因此,本发明还涉及如上文所定义的式(I)的化合物、如果合适以及它们的药学上可接受的盐和/或旋光异构体、互变异构体、溶剂化物或同位素变型,其用于治疗癌症,即实体瘤癌症,优选选自以下的那些癌症:黑素瘤、结肠癌、肺癌、胰腺癌、肾癌、梅克尔癌(Merkel carcinoma)、鳞状细胞癌、前列腺癌、乳腺癌、膀胱癌和淋巴瘤。
在一个具体的实施方案中,所述癌症是黑素瘤。
通式(I)的化合物可以单独施用或组合施用。也可以将它们与一种或多种另外的药物组合施用。
通常,可以将它们与一种或多种药学上可接受的赋形剂或载体结合以制剂的形式施用。
术语“赋形剂”或“载体”在本文中用于描述本发明的化合物之外的任何成分。赋形剂的选择在很大程度上取决于诸如特定的施用模式、赋形剂对溶解度和稳定性的影响和剂型的性质等因素。
适合用于递送本发明的化合物的药物组合物及其制备方法对于本领域技术人员而言是非常显而易见的。这类组合物及其制备方法可以在例如'Remington'sPharmaceutical Sciences',第19版(Mack Publishing Company,1995)中找到。
因此,本发明的另一个方面是包含上文所定义的通式(I)的化合物并任选地包含药学上可接受的载体的药物组合物。
根据本发明的另一个有利的实施方案,上文所定义的药物组合物还可以包含:
-至少一种免疫调节化合物,所述免疫调节化合物优选是免疫调节抗体,甚至更优选选自以下的抗体:抗-PD1抗体、抗-CTLA4抗体、抗-PD-L1抗体及其两种或更多种的混合物,和/或
-至少一种另外的治疗剂。
术语“免疫调节化合物”是指调节宿主免疫系统的组分(例如免疫细胞或亚细胞因子、调节免疫组分的基因、细胞因子、趋化因子或此类分子)中的一种或多种的化合物。
优选地,免疫调节化合物是免疫刺激剂。免疫调节剂可以包括、但不限于小分子、肽、多肽、融合蛋白、抗体。免疫调节抗体是一类有前景的抗癌疗法,这归因于它们促进癌症患者的广泛而持续的抗癌免疫应答。
适合的实例是:
-抗-PD1抗体的适合的实例是纳武单抗(nivolumab)、匹地利珠单抗(pidizilumab)、派姆单抗(pembrolizumab)、替雷利珠单抗(tislelizumab)和AMP-514,
-抗-CTLA4抗体的实例是伊匹木单抗(ipilimumab),
-抗PD-L1抗体的实例是阿特珠单抗(atezolizumab)、德瓦鲁单抗(durvalumab)、阿维鲁单抗(avelumab)、乌托鲁单抗(utomilumab)和MPDL3280A。
另外的治疗剂也可以是(a)式(I)的化合物或其药学上可接受的盐、衍生形式或药物组合物,或者本领域已知用于治疗上文列出的病症的一种或多种化合物。
例如,另外的治疗剂选自式(I)化合物之外的不同类别的治疗剂。
可以与式(I)的化合物或其药学上可接受的盐或衍生形式组合使用的另外的治疗剂的适合的实例包括、但绝不限于:
-用于癌症疗法的抗癌药,例如达卡巴嗪,
-亚硝基脲烷化剂,例如福莫司汀,
-BRAF抑制剂,例如威罗菲尼(vemurafenib)或达拉菲尼(dabrafenib),
-MEK抑制剂,例如曲美替尼(trametinib),
-抗PD1融合蛋白,例如AMP-224,
-其它免疫关卡阻断剂或通常为基于用于治疗癌症的免疫方法的治疗剂,即生物或化学化合物或细胞疗法,例如继承性细胞疗法(adoptive cell therapy)、治疗性癌症疫苗、T/NK细胞活化剂。
更具体地,本发明涉及上文所定义的药物组合物,其是组合制剂,用于同时、分开或依次使用用于治疗癌症,即实体瘤癌症,优选选自以下的那些癌症:黑素瘤、结肠癌、肺癌、胰腺癌、肾癌、梅克尔癌、鳞状细胞癌、前列腺癌、乳腺癌、膀胱癌和淋巴瘤。
鉴于可能需要施用活性化合物的组合,例如为了治疗特定疾病或病症的目的,在本发明的范围内,其中至少一种药物组合物包含本发明的化合物的两种或更多种药物组合物可以便利地以适合于组合物的共同施用的药盒形式组合。
因此,本发明的药剂盒包含两种或更多种分开的药物组合物,其中至少一种药物组合物含有本发明的式(I)的化合物,以及用于分开保存所述组合物的装置例如容器、分开的瓶子或分开的箔袋。这类药盒的一个实例是用于包装片剂、胶囊等的熟悉的泡罩包装。
本发明的药盒特别适合用于施用不同的剂型例如肠胃外剂型、用于以不同的给药间隔施用分开的组合物、或用于使所述分开的组合物彼此剂量递增。为了有助于依从性,所述药盒典型地包含施用说明书,并且可以具有所谓的记忆辅助物。
如上所述,式(I)的化合物或其药学上可接受的盐、衍生形式或组合物也可以以与一种或多种另外的治疗剂的组合的形式使用,以便共同施用于患者,以获得所需的治疗最终效果,例如治疗癌症,即实体瘤癌症,优选选自以下的那些癌症:黑素瘤、结肠癌、肺癌、胰腺癌、肾癌、梅克尔癌、鳞状细胞癌、前列腺癌、乳腺癌、膀胱癌和淋巴瘤。
优选地,单独或组合使用的本发明的化合物被施用于患有黑素瘤、结肠癌、肺癌、胰腺癌、肾癌、梅克尔癌、鳞状细胞癌、前列腺癌、乳腺癌、膀胱癌和淋巴瘤的在转移阶段的患者。
涉及式(I)的化合物与一种或多种另外的治疗剂的本文所用的术语“共同施用”、“联合施用”和“与……组合”旨在意指并且确实是指并包括以下情形:将所述的式(I)化合物与治疗剂的组合同时施用于需要治疗的患者,此时所述组分被一起配制成单一剂型,该剂型在基本上相同的时间释放所述组分给所述患者;将所述的式(I)化合物与治疗剂的组合基本上同时施用于需要治疗的患者,此时所述组分被彼此分开配制到分开的剂型中,所述剂型被所述患者在基本上相同的时间摄入,藉此所述组分在基本上相同的时间被释放给所述患者;将所述的式(I)化合物与治疗剂的组合依次施用于需要治疗的患者,此时所述组分被彼此分开配制成分开的剂型,所述分开的剂型被所述患者在连续时间摄入,其中在每次施用之间存在明显的时间间隔,藉此所述组分在基本上不同的时间被释放给所述患者;和将所述的式(I)化合物与治疗剂的组合依次施用于需要治疗的患者,此时所述组分被一起配制成单一剂型,所述单一剂型以控制方式释放所述组分,藉此它们被所述患者同时、连续和/或在相同和/或不同的时间施用,其中每个部分可以通过相同或不同途径施用。
本发明的化合物可以以结晶或无定形产品的形式施用。它们可以通过例如沉淀、结晶、冷冻干燥、喷雾干燥或蒸发干燥等方法以实心塞(solid plug)、粉末或薄膜的形式获得。微波或射频干燥可用于此目的。
可以通过任意适合的途径施用本发明的化合物。
因此,可以将本发明的化合物配制成用于口服、口含、鼻内、肠胃外(例如静脉内、肌内或皮下)、局部或直肠施用的药物组合物或者适合通过吸入或吹入施用的形式的药物组合物。
对于口服施用,药物组合物可以采用例如通过常规方法用药学上可接受的赋形剂制备的片剂或胶囊的形式,所述赋形剂例如粘合剂(例如预胶化玉米淀粉、聚乙烯吡咯烷酮或羟丙基甲基纤维素);填充剂(例如乳糖、微晶纤维素或磷酸钙);润滑剂(例如硬脂酸镁、滑石粉或二氧化硅);崩解剂(例如马铃薯淀粉或羟乙酸淀粉钠);或润湿剂(例如月桂基硫酸钠)。
可以通过本领域众所周知的方法将片剂包衣。用于口服施用的液体制剂可以采取例如溶液、糖浆或混悬剂的形式,或者它们可以以干燥产品的形式存在,用于在使用前用水或其它适合的媒介物配制。此类液体制剂可通过常规方法用药学上可接受的添加剂制备,所述添加剂例如助悬剂(例如山梨醇糖浆、甲基纤维素或氢化的可食用脂肪);乳化剂(例如卵磷脂或阿拉伯胶);非水性媒介物(例如杏仁油、油性酯或乙醇);和防腐剂(例如对羟基苯甲酸甲酯或丙酯或山梨酸)。
对于口含施用,组合物可以采取以常规方式配制的片剂或锭剂(lozenge)的形式。还可以根据本领域普通技术人员众所周知的方法将本发明的化合物配制用于持续递送。此类制剂的实例可以在美国专利3,538,214、4,060,598、4,173,626、3,119,742和3,492,397中找到,通过引用将其整体合并入本文。
可以将本发明的化合物配制用于通过注射肠胃外施用,包括使用常规的插管技术或输注。用于注射的制剂可以以单位剂型存在,例如在安瓿中或在具有防腐剂的多剂量容器中。组合物可以是诸如在油性或水性媒介物中的混悬剂、溶液或乳剂的形式,可以含有配制剂例如助悬剂、稳定剂和/或分散剂。或者,活性成分可以是用于在使用前用适合的媒介物例如无菌无热原的水重构的粉末形式,肠胃外制剂典型地是水溶液,其可以含有赋形剂例如盐、碳水化合物和缓冲剂(优选缓冲至pH 3-9),但对于一些应用而言,它们可以更合适地配制成无菌非水溶液或与适合的媒介物例如无菌无热原的水联用的干燥形式。
对于施用于人患者而言,本发明的化合物的总日剂量典型地在0.001mg至5000mg范围内或在0.001mg至10000mgmg范围内,这当然取决于施用模式。例如,静脉内日剂量可能仅需要0.001mg至40mg。所述总日剂量可以以单剂量或分次多剂量施用,并且可以由临床医师酌情决定超出本文给出的典型范围。
这些剂量基于体重约65kg-70kg的普通人个体。临床医师将很容易能确定用于体重在此范围之外的个体例如婴儿和老年人的剂量。
应当理解,本文对“治疗”的所有提及均包括治愈性治疗、姑息性治疗和预防性治疗。
下面的描述涉及式(I)化合物可用于的治疗应用。
本发明的另一个方面还涉及式(I)化合物或其药学上可接受的盐、衍生形式或组合物在制备具有抗癌活性的药物中的用途。
特别地,本发明涉及式(I)化合物或其药学上可接受的盐、衍生形式或组合物在制备用于治疗癌症的药物中的用途,所述癌症即实体瘤癌症,优选选自以下的那些癌症:黑素瘤、结肠癌、肺癌、胰腺癌、肾癌、梅克尔癌、鳞状细胞癌、前列腺癌、乳腺癌、膀胱癌和淋巴瘤。
作为结果,本发明提供了一种特别有意义的用有效量的式(I)化合物或其药学上可接受的盐、其衍生形式或组合物治疗包括人在内的哺乳动物的方法。
更准确地,本发明提供了一种特别有意义的治疗包括人在内的哺乳动物的癌症疾病、特别是上文列举的疾病和/或病症的方法,所述方法包括给所述哺乳动物施用有效量的式(I)化合物、其药学上可接受的盐和/或衍生形式。
式(I)化合物可以使用常规方法例如通过下面的示例性方法制备,其中各个取代基如上文针对式(I)化合物所定义,另有说明的除外。
因此,可以通过用适宜的胺进行芳族亲核取代以相应的4-氯-7-卤代喹啉为原料制备式(I)的化合物:
可以根据以前报道的方法(参见例如:Bioorg.Med.Chem.2013,21(11),3147-3153;J.Med.Chem.,2015,58(14),5522–5537),以相应的4-氯-7-卤代喹啉为原料制备式(I)的化合,其中R2=氟或溴。
式(I)化合物的药学上可接受的盐包括其酸加成盐和碱加成盐。
适合的酸加成盐由形成无毒性盐的酸形成。
实例包括乙酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟磺酸盐、柠檬酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、海苯酸盐、盐酸盐/氯化物、氢溴酸盐/溴化物、氢碘化物/碘化物、羟乙磺酸盐、乳酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐(naphthylate)、2-萘磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、糖二酸盐、硬脂酸盐、琥珀酸盐、酒石酸盐、甲苯磺酸盐、三氟乙酸盐和昔萘酸盐。
适合的碱盐由形成无毒性盐的碱形成。
实例包括铝盐、精氨酸盐、苄星(benzathine)盐、钙盐、胆碱盐、二乙胺盐、二醇胺盐、甘氨酸盐、赖氨酸盐、镁盐、葡甲胺盐、醇胺盐、钾盐、钠盐、氨丁三醇盐和锌盐。还可形成酸和碱的半盐,例如半硫酸盐和半钙盐。
有关适合的盐的综述,参见Stahl和Wermuth的"Handbook of PharmaceuticalSalts:Properties,Selection,and Use"(Wiley-VCH,Weinheim,德国,2002)。
可以通过以下三种方法中的一种或多种制备式(I)化合物的药学上可接受的盐:
(i)使式(I)化合物与所需的酸或碱反应;
(ii)从式(I)化合物的适合的前体中除去对酸或碱不稳定的保护基或者使用所需的酸或碱使适合的环状前体例如内酯或内酰胺开环;
(iii)通过与适宜的酸或碱反应或借助适合的离子交换柱将式(I)化合物的一种盐转化成另一种盐。
所有这三个反应均典型地在溶液中进行。所得的盐可以沉淀出来并通过过滤被收集或者可以通过蒸发溶剂进行回收。所得的盐中的电离度可以在从完全电离到几乎未电离之间改变。
本发明的化合物可以以未溶剂化形式和溶剂化形式存在。
术语“溶剂化物”在本文中用于描述包含本发明化合物和化学计量的一种或多种药学上可接受的溶剂分子例如乙醇的分子配合物(complex)。
当所述溶剂是水时,使用术语“水合物”。
在本发明的范围内包括配合物例如笼形配合物、药物-宿主包合配合物,其中,与上述溶剂化物相反,药物和宿主以化学计量或非化学计量的量存在。还包括含有两种或更多种有机和/或无机组分的药物的配合物,所述药物可以是化学计量或非化学计量的量。所得的配合物可以是电离的、部分电离的或未电离的。有关此类配合物的综述,参见Haleblian的J Pharm Sci,64(8),1269-1288(1975年8月)。
下文所有对式(I)化合物的提及均包括对其盐、溶剂化物和配合物的提及以及对其盐的溶剂化物和配合物的提及。
本发明的化合物包括上文所定义的式(I)化合物,包括上文所定义的其多晶型物和晶癖、其前药和异构体(包括旋光异构体、几何异构体和互变异构体)以及同位素标记的式(I)化合物。
如所示的,所谓的式(I)化合物的“前药”也在本发明的范围内。因此,式(I)化合物的某些衍生物(其本身可以几乎没有或无药理学活性)在施用于身体内或身体上时可以转化成具有所需活性的式(I)化合物,例如通过水解裂解转化。这类衍生物称作“前药”。有关前药的用途的进一步信息可以在'Pro-drugs as Novel Delivery Systems,第14卷,ACSSymposium Series(T.Higuchi和W.Stella)和'Bioreversible Carriers in DrugDesign',Pergamon Press,1987(编辑E.B Roche,American PharmaceuticalAssociation)中找到。
例如,可以通过用本领域技术人员已知为“前-原子团”的某些原子团替代存在于式(I)化合物中的适宜的官能团来生产本发明的前药,所述的“前-原子团”如例如H.Bundgaard的"Design of Prodrugs"(Elsevier,1985)中所述。
本发明的前药的一些实例包括:例如当式(I)化合物含有醇官能团(-OH)时,其中式(I)化合物的醇官能团的氢被(C1-C6)烷酰基氧基甲基替代的化合物。
上述实例和其它前药类型的实例的替代基团的另外的实例可以在上述参考文献中找到。
在本发明的范围内还包括式(I)化合物的代谢物,即,药物施用后在体内形成的化合物。
本发明的代谢物的一些实例包括其中式(I)化合物含有酚原子团的情况。
含有一个或多个不对称碳原子的式(I)化合物可以以两种或更多种立体异构体形式存在。在本发明的范围内包括式(I)化合物的所有立体异构体、几何异构体和互变异构体形式,包括表现出一种以上异构类型的化合物及其一种或多种的混合物。
还包括其中抗衡离子是旋光的(例如D-乳酸盐或L-赖氨酸)或者是外消旋的(例如DL-酒石酸盐或DL-精氨酸)的酸加成盐或碱加成盐。
用于制备/分离各个对映体的常规技术包括用适合的旋光纯的前体进行的手性合成或使用例如手性高压液相色谱法(HPLC)进行的外消旋体(或者盐或衍生物的外消旋体)的拆分。
或者,可以使外消旋体(或外消旋前体)与适合的旋光化合物例如醇反应,或者在其中式(I)化合物含有酸性或碱性原子团的情况下,与酸或碱例如酒石酸或1-苯基乙胺反应。可以通过色谱法和/或分级结晶分离所得的非对映异构体混合物,并且通过本领域技术人员众所周知的方式将非对映异构体中的一种或两种均转化成相应的纯对映体。
可以使用色谱法、典型地HPLC(手性柱)在不对称树脂上得到对映体富集形式的本发明的手性化合物(及其手性前体),所使用的流动相的组成是:烃,典型地为庚烷或己烷,其含有0-50%、典型地为2%-20%体积的异丙醇以及0-5%体积的烷基胺、典型地为0.1%二乙胺。对于反相HPLC,用CH3CN和H2O、MeOH或iPrOH和H2O作为溶剂。浓缩洗脱液,得到所述的富集的混合物。
可以通过本领域技术人员已知的常规技术分离立体异构体聚集物,参见例如E.L.Eliel的"Stereochemistry of Organic Compounds"(Wiley,New York,1994)、G.Subramanian的"Chiral Separation Techniques".John Wiley&Sons,2008、G.B.Cox的"Preparative Enantioselective Chromatography".Wiley,2005。
本发明的药学上可接受的溶剂化物包括其中结晶溶剂可以被同位素取代例如D2O的那些。
下列实施例举例说明了式(I)的化合物的制备和它们的药理学性质。
图1:与化合物42、43(10μM)或DMSO(对照)一起温育96h的A375癌细胞中通过qPCR检测的EZH2的mRNA水平。
图2:与化合物42、43(10μM)或DMSO(对照)一起温育96h的A375癌细胞中通过qPCR检测的p21的mRNA水平。
图3:用化合物42、43(10μM)或DMSO(对照)处理96h的A375癌细胞上清液中通过ELISA检测的IFN-γ水平。
图4:使用化合物42和43的体外剂量响应研究。
图5:单独的或与抗-PD-1抗体组合的化合物42的体内作用。
实施例1:本发明化合物(I)的制备
根据如下方法制备了化合物42和43。
·7-氯-N-(4-(2-甲氧基乙氧基)苯基)喹啉-4-胺(化合物42)
将4,7-二氯喹啉(1mmol,1eq)和4-(2-甲氧基乙氧基)苯胺(1mmol,1eq)在乙醇中的混合物在80℃进行微波照射1h。将混合物冷却至室温,然后添加乙酸乙酯,收集所得沉淀物,用乙酸乙酯和乙醚洗涤,得到纯产物,无需任何进一步纯化。
7-氯-N-(4-(2-甲氧基乙氧基)苯基)喹啉-4-胺
化学式:C18H17ClN2O2
准确质量:328,0979
分子量:328,7960
1H NMR(400MHz,DMSO-d6)δ14.79(s,1H),11.13(s,1H),8.87(d,J=9.1Hz,1H),8.49(d,J=7.1Hz,1H),8.18(d,.J=2.2Hz,1H),7.86(dd,J=9.1,2.1Hz,1H),7.40(d,J=8.9Hz,2H),7.14(d,.J=8.9Hz,2H),6.65(d,.J=7.0Hz,1H),4.21-4.13(m,2H),3.75-3.67(m,2H),3.34(s,3H).
13C NMR(101MHz,DMSO)δ157.2,154.8,142.6,138.5,137.76,128.9,126.7,126.6,125.6,118.6,115.2,115.12,99.5,69.8,66.7,57.7.
MS:ESI(m/z):[M+H]+C18H17ClN2O2计算值329.09测定值329.32
HPLC:纯度λ254:99.4%,tR:3.54
·7-氯-N-(3-(羟基)-4-(甲氧基)苯基)喹啉-4-胺(化合物43)(也称作5-((7-氯喹啉-4-基)氨基)-2-甲氧基苯酚)
将4,7-二氯喹啉(1mmol,1eq)和5-氨基-2-甲氧基苯酚(1mmol,1eq)在乙醇中的混合物在80℃进行微波照射1h。将混合物冷却至室温,然后添加乙酸乙酯,收集所得沉淀物,用乙酸乙酯和乙醚洗涤,得到纯产物,无需任何进一步纯化。
5-((7-氯喹啉-4-基)氨基)-2-甲氧基苯酚
化学式:C16H13ClN2O2
准确质量:300,0666
分子量:300,7420
1H NMR(400MHz,DMSO-d6)δ14.41(s,1H),10.88(s,1H),9.56(s,1H),8.76(d,J=9.2Hz,1H),8.49(d,J=7.0Hz,1H),8.10(d,J=2.1Hz,1H),7.86(dd,J=9.1,2.1Hz,1H),7.09(d,J=8.4Hz,1H),6.91-6.81(m,2H),6.72(d,J=7.0Hz,1H),3.84(s,3H).
13C NMR(101MHz,DMSO)δ154.7,147.1,146.7,142.5,138.5,137.7,129.0,126.6,125.5,118.6,115.7,115.2,112.4,112.3,99.6,55.3.
MS:ESI(m/z):[M+H]+C16H13ClN2O2计算值301.06测定值301.14
HPLC:纯度λ254:99.0%,tR:3.21
实施例2:本发明的化合物42和43的体外活性
材料和方法
癌细胞增殖试验(A375、A549、PC3、HT-29、MiaPaca-2和MCF-7)
测试的癌细胞如下:人黑素瘤细胞(A375),肺癌细胞(A549),前列腺癌细胞(PC3),结肠腺癌(HT29),胰腺癌(MiaPaca 2)和乳腺癌(MCF-7)。
使用Malassez室对细胞进行计数。由一式三份的实验计算平均值和标准偏差。通过锥虫蓝(trypan blue)排除试验评价抗增殖作用。简言之,将细胞接种到12-孔板中,并使其在补充有1或10μM的所示化合物的培养基中生长48h或96h。将细胞用PBS洗涤,通过胰蛋白酶消化分离,收集并用锥虫蓝染色。
对死细胞和活细胞进行计数,如下计算增殖率:增殖率(%)=[(处理的细胞数/未处理的细胞数)*100]。
作为比较,还测定并如下计算了细胞存活率:存活率(%)=100-[(死细胞数/总细胞数)*100]。
表1a(存活率)和表1b(增殖)中概括了得到的结果。
黑素细胞存活率试验(MHN)
通过锥虫蓝排除试验评价了细胞存活效果。简言之,将细胞接种到12-孔板中,并使其在补充了10μM的所示化合物的培养基中生长96h。将细胞用PBS洗涤,通过胰蛋白酶消化分离,并且用锥虫蓝染色。对死细胞和活细胞进行计数,并如下计算存活率:存活率(%)=100-[(死细胞数/总细胞数)*100]。
表2中概括了得到的结果。
EZH2和p21基因表达的定量RT-PCR分析
根据制造商的方法,使用RNAeasy小型试剂盒(Qiagen)从细胞中分离出总RNA。使用AMV逆转录系统(Promega)进行逆转录,按照制造商的说明书使用Power Sybr green(Applied Biosystems,Life Technologies,Grand Island,NY)进行定量PCR。使用StepOne plus Real-Time PCR系统(Applied Biosystems)进行PCR。所有分析均一式三份进行,进行熔化曲线分析以控制产品质量和特异性。用SB34作为校准剂,使用相对定量的比较方法计算表达水平。使用斯氏t-检验(Student’s t-test)分析数据的统计学显著性。将结果表示为相对于对照的平均值±SEM。
EZH2(登录号NM004456.4)和p21(CDKN1A)(登录号NM078467.2)的PCR引物得自引物库(primer bank)或引物储库(primer depot)(http://pga.mgh.harvard.edu/primerbank/,https://primerdepot.nci.nih.gov),采用primer blast(http://www.ncbi.nlm.nih.gov/tools/primer-blast/)验证它们的特异性。
表3以及图1(EZH2)和图2(p21)中概括了得到的结果。
ELISA测定
根据制造商的说明,通过ELISA(peprotech,目录号900-k27和900-k98)试剂盒测试处理96h的细胞上清液中人或小鼠IFN-γ的含量。
表4和图3中概括了得到的结果。
定量衰老相关的β-半乳糖苷酶试验
通过测量4-甲基伞形酮基-β-D-吡喃半乳糖苷(4-methylumbelliferyl-β-D-galactopyranoside,4-MUG)的裂解来定量细胞提取物中衰老相关的β-半乳糖苷酶(SA-β-Gal)的活性,所述裂解直到被所述酶裂解产生荧光团4-甲基伞形酮后才发荧光。如所报道的,在365/460nm的发射/激发波长下监测荧光团的产生(Gary和Kindell,2005)
表5中概括了得到的结果。
微粒体稳定性(小鼠肝微粒体)
在37℃用小鼠肝微粒体(0.5mg/mL)和NAD辅因子(1mM)评价微粒体稳定性。通过测定色谱图上化合物峰下的面积用LC-MS在5min时测定残留化合物的百分比。
表6中概括了得到的结果。
结果和结论
表1a、1b、2-6中概括了得到的结果。
表1a:存活率
*用DMSO处理的对照校准的存活率
表1b:增殖
*用DMSO处理的对照校准的增殖率
表1a显示,与未处理的癌细胞相比,化合物42和43不显著影响处理的癌细胞的存活率。
另一方面,表1b显示,化合物42和43、更特别是化合物42强烈降低所有测试的癌细胞(人黑素瘤细胞(A375)、肺癌细胞(A549)、前列腺癌细胞(PC3)、结肠腺癌(HT29)、胰腺癌(MiaPaca 2)和乳腺癌(MCF-7)的增殖。
在早期时间点(直至96h)均未观察到存活率降低。这些化合物对NIK具有非竞争性抑制作用,从而导致了很强的选择性,而没有使用竞争性NIK抑制剂所观察到的脱靶效应(9)。通过对EZH2的作用,NIK的抑制导致细胞周期中牵涉的几个关键基因例如p21去甲基化,并且因此增加其表达。作为结果,到目前为止,所有测试的处理的细胞的增殖率均被强烈降低(从55%降至3.5%,因化合物和细胞系而异)。
表2:黑素细胞存活率
*用DMSO处理的对照校准的存活率
表2显示,化合物42和43不显著影响人黑素细胞的存活率。
在正常细胞中不表达或以非常低的水平表达NIK和下游靶标EZH2。因此,本发明的化合物对NIK的选择性抑制不改变正常细胞,也不改变正常细胞例如黑素细胞的存活。
表3:定量RT-PCR分析
*mRNA(相对于DMSO处理的对照的倍数)
表3显示,与和对照化合物(DMSO)一起温育相比,细胞与化合物42一起温育导致EZH2的mRNA表达急剧下降。相应地,用化合物42处理导致p21mRNA表达大幅增加(图2)。
当用化合物43处理细胞时,观察到EZH2mRNA表达的更适度的减少,以及p21mRNA表达的显著增加。
化合物42和43通过抑制NIK来发挥作用,NIK调节非典型的NF-kB途径,而该途径又通过转录方式抑制EZH2。
EZH2是中心靶标,因为它通过促进其甲基化来降低p21并通过在其启动子上直接相互作用来抑制IFN-γ的转录。
通过减少EZH2转录,本发明的化合物增加p21并促进衰老。因此其诱导处理的细胞增殖减少。免疫激活归因于处理的细胞诱导的IFN-γ分泌。
表4:Elisa测定
测试的化合物 | ELISA IFN-γ(A375)* |
DMSO对照 | 0.17 |
化合物42 | 1.73 |
化合物43 | 0.41 |
*IFN-γ浓度(ng/mL)/数百万细胞
表4显示,用化合物42和43、特别是化合物42处理的A375细胞产生并分泌IFN-γ,而在未处理的细胞中几乎检测不到IFN-γ(图3)。
EZH2通过直接干扰其启动子位点来抑制IFN-γ的产生。通过在其转录水平上减量调节EZH2,这些化合物诱导IFN-γ转录及其由处理的癌细胞的产生。表4显示,与对照相比,处理的癌细胞在培养基中的IFN-γ分泌显著增加。这种IFN-γ的局部产生对于吸引和激活将在体内参与消除癌细胞的免疫细胞而言是关键的。
表5:定量衰老相关的β-半乳糖苷酶试验
测试的化合物 | %衰老* |
化合物42 | 645.9 |
化合物43 | 1875.1 |
*转化率(相对于DMSO处理的对照的倍数)
已经证实,通过减少p21的甲基化并因此增加其表达对非典型NFkB途径的抑制降低了EZH2并恢复衰老程序(9)。表5显示,与对照相比,本发明的化合物(其通过选择性抑制NIK来抑制非典型NFkB途径)在处理的细胞中诱导衰老的明显增加。这种衰老增加与表3中所示的p21表达增加是一致的。
表6:微粒体稳定性
测试的化合物 | 微粒体稳定性,小鼠肝(5min)* |
化合物42 | 21%±3 |
化合物43 | 41%±3 |
*与微粒体一起温育5min后剩余化合物的百分比
表6显示,化合物43与化合物42相比表现出高的微粒体稳定性(41%VS21%)。微粒体稳定性用作药物的第一路径代谢的体外评价,因此是体外肝清除的代表和体内稳定性的初步指示物。
实施例3:本发明的化合物42和43的体外活性
使用阶梯浓度的化合物42和43在96h期间处理黑素瘤细胞系A375。在培养期结束时,测定了细胞浓度。
结果表明,从约5mM化合物42和43开始抑制A375增殖(参见图4)。
化合物42具有0.42μM的IC50,化合物43具有1.83μM的IC50。
实施例4:本发明的化合物42的体内活性
皮下施用B9黑素瘤细胞。
IP施用化合物42,每日1次,50mg/kg。IP施用抗-PD1化合物(BE0146-克隆RMP1-14),每日1次,10mg/kg。
当肿瘤可见时(50-100mm3),进行治疗施用。
结果如图5中所示。
参考文献:
在本申请的上下文中,各种参考文献描述了本发明所述领域的状态。通过引用在此将这些参考文献的公开内容合并入本申请中。
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Claims (14)
1.通式(I)的化合物:
其中
R1是OCH2CH2OCH3或OCH3,
R’1是H或OH,
R2是Cl、Br或I,
条件是:
当R1是OCH2CH2OCH3时,R’1是H,
当R1是OCH3时,R’1是OH,
或其药学上可接受的盐。
2.根据权利要求1所述的化合物,其中R2是Cl。
3.根据权利要求1所述的化合物,其是:
7-氯-N-(4-(2-甲氧基乙氧基)苯基)喹啉-4-胺。
4.根据权利要求1所述的化合物,其是:
7-氯-N-(3-(羟基)-4-(甲氧基)苯基)喹啉-4-胺。
5.权利要求1-4中任意一项所述的化合物在制备用于治疗癌症的药剂中的用途。
6.根据权利要求5所述的用途,其中所述癌症是实体瘤癌症。
7.根据权利要求5所述的用途,其中所述的癌症选自:黑素瘤、结肠癌、肺癌、胰腺癌、肾癌、梅克尔癌、鳞状细胞癌、前列腺癌、乳腺癌和膀胱癌。
8.药物组合物,其包含:
-权利要求1-4中任意一项中所定义的化合物,
-任选地,至少一种药学上可接受的载体。
9.根据权利要求8所述的药物组合物,其中所述化合物是7-氯-N-(4-(2-甲氧基乙氧基)苯基)喹啉-4-胺。
10.根据权利要求8所述的药物组合物,其中所述化合物是7-氯-N-(3-(羟基)-4-(甲氧基)苯基)喹啉-4-胺。
11.根据权利要求8所述的药物组合物,其还包含:
-至少一种免疫调节化合物,和/或
-至少一种另外的治疗。
12.根据权利要求11所述的药物组合物,其中所述免疫调节化合物是免疫调节抗体。
13.根据权利要求11所述的药物组合物,其中所述免疫调节化合物是选自以下的抗体:抗-PD1抗体、抗-CTLA4抗体、抗-PD-L1抗体及其两种或更多种的混合物的抗体。
14.根据权利要求11所述的药物组合物,其中所述治疗选自抗癌药、亚硝基脲烷化剂、BRAF抑制剂、MEK抑制剂、抗PD1融合蛋白、继承性细胞疗法、治疗性癌症疫苗和T/NK细胞活化剂。
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