CN115697317A - Ep4受体拮抗剂用于治疗肝癌、黑色素瘤、淋巴瘤和白血病的应用 - Google Patents
Ep4受体拮抗剂用于治疗肝癌、黑色素瘤、淋巴瘤和白血病的应用 Download PDFInfo
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- CN115697317A CN115697317A CN202180033910.8A CN202180033910A CN115697317A CN 115697317 A CN115697317 A CN 115697317A CN 202180033910 A CN202180033910 A CN 202180033910A CN 115697317 A CN115697317 A CN 115697317A
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- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Abstract
本发明涉及用于治疗人或动物的肝癌、黑色素瘤、淋巴瘤和白血病的前列腺素E2受体4(EP4)拮抗剂。所述方法包括施用化合物A、化合物B或化合物C或其药学上可接受的盐中的一种或多种作为EP4拮抗剂。所述方法可以包括包含所述EP4拮抗剂的药物组合物,并且可以包括一种或多种用于肝癌治疗的其他活性剂和/或疗法,如抗PD‑1抗体。
Description
技术领域
本发明涉及用于治疗肝癌、黑色素瘤、淋巴瘤和白血病(下文称为“本发明的癌症”)的前列腺素E2(PGE2)受体4(EP4)拮抗剂。本发明的癌症治疗方法包括向人或动物施用化合物A、化合物B或化合物C,或其药学上可接受的盐中的任何一种作为所述EP4拮抗剂(下文称为“本发明的化合物”),或含有本发明的化合物的药物组合物。所述治疗方法包括向患有本发明的癌症的人或动物单独施用或与一种或多种其他活性剂和/或疗法组合施用本发明的化合物。化合物A、B和C为:
化合物A:4-((1S)-1-{[5-氯-2(4-氟苯氧基)苯甲酰基]氨基}乙基)苯甲酸,或其药学上可接受的盐;
化合物B:4-[(1S)-1-({[5-氯-2-(3-氟苯氧基)吡啶-3-基]羰基}氨基)乙基]-苯甲酸,或其药学上可接受的盐;以及
化合物C:3-[2-(4-{2-乙基-4,6-二甲基-1H-咪唑并[4,5-c]吡啶-1-基}苯基)乙基]-1-[(4-甲苯)磺酰基]脲,或其药学上可接受的盐。
背景技术
前列腺素是疼痛、发热和与炎症有关的其他症状的介体。PGE2是在炎症状况下表达的主要的类二十烷酸。PGE2也参与各种生理和/或病理状况,如痛觉过敏、子宫收缩、消化道蠕动、觉醒、抑制胃酸分泌、血压、血小板功能、骨代谢、血管生成以及癌细胞生长、侵袭和转移等。非专利参考文献公开了前列腺素类受体的特性、与治疗的关系,以及最常用的选择性激动剂和拮抗剂(参见例如,Konya et al.,Pharmacology&Therapeutics,2013,138:485-502;and Yokoyama et al.,Pharmacol.Rev.,2013,65:1010-1052)。
已报道PGE2在各种类型癌症的肿瘤组织中高度表达,并且还被证明PGE2与癌症的起始、生长和发展以及患者的疾病状况相关。一般认为,PGE2与癌细胞增殖和细胞死亡的激活有关,并在癌症的起始和增殖、疾病进展和癌症转移的过程中发挥重要作用(参见例如,Konya et al.,Pharmacology&Therapeutics,2013,138:485-502;and Yokoyama et al.,Pharmacol.Rev.,2013,65:1010-1052)。
有四种PGE2受体亚型,EP1、EP2、EP3和EP4,它们表现出不同的药理学特性。EP4受体亚型属于G蛋白偶联受体亚家族,被称为具有七个跨膜结构域的受体。因此,EP4通过刺激cAMP信号介导功能在生物活动中发挥重要作用。从药理学研究方面来看,已经对具有EP4受体拮抗活性的化合物进行了大量的试验,并且已知有几种EP4受体选择性拮抗剂(Konya etal.,Pharmacology&Therapeutics,2013,138:485-502)。
关于EP4受体在癌症中的作用,一些非专利参考文献(例如,Yokoyama et al.,Pharmacol.Rev.,2013,65:1010-1052;Ma et al.,OncoImmunology,2013,2(1):e22647)和专利参考文献(例如,US8,921,391B2和US9,688,674B2)证明了,使用EP4受体拮抗剂或基因EP4缺失技术在动物肿瘤模型中对结肠、乳腺、胃、肺、前列腺和其他类型癌症的肿瘤生长抑制和/或转移。专利参考文献(例如,US8,921,391B2和US9,688,674B2)描述了使用EP4拮抗剂,包括本发明的化合物,用于“PGE2涉及的癌症”的治疗,所述“PGE2涉及的癌症”包括脑瘤、骨癌和来自上皮细胞的肿瘤(上皮癌)。一些专利参考文献(例如,WO2015/179615A1,US2015/0004175A1)表明,EP4受体拮抗剂的治疗功效或EP4信号转导的抑制的结果是抑制肿瘤生长。
肝癌
EP4受体在肝癌中的作用在非专利文献中有报道。通过PKA/CREB激活的PGE2/EP4受体信号转导上调c-Myc表达,并导致在体外促进肝细胞癌(HCC)细胞中的细胞生长(Xiaet al.,Oncology Reports,2014,32:1521-1530)。Xu等人报道了PGE2通过EP4受体促进肝星状细胞诱导的髓源性抑制细胞(MDSC)积累,从而促进肝癌的发生(Xu et al.,Oncotarget,2016,7(8):8866-8878)。肿瘤微环境的主要组成部分-间充质干细胞,被表明能促进HCC的进展和转移,以及PGE2/EP4轴支持HCC进展(Liu et al.,J.Experimental&Clinical Cancer Research 2019 38:228)。这些参考文献表明,PGE2/EP4信号转导可能在肝癌的起始、促进和进展中具有作用。然而,这些参考文献并没有直接证明EP4拮抗剂在恶性HCC/肝癌动物模型中的治疗功效。
黑色素瘤
皮肤癌是产生于皮肤的恶性肿瘤,并包括一些类型的肿瘤。上皮性皮肤癌是主要的皮肤癌,包括例如基底细胞癌、鳞状细胞癌、乳腺外佩吉特病(extramammary Paget’sdisease)、默克尔细胞癌、汗腺癌、皮脂腺癌和毛囊癌。这些肿瘤起源于上皮细胞的恶变。黑色素瘤是一种皮肤癌,但它被归类为非上皮性皮肤癌,因为它产生于神经嵴细胞来源的黑色素细胞的恶性肿瘤。
Inada等人(J.Biological Chemistry 2015 290:29781-93)表明了黑色素瘤中EP4信号抑制的治疗机会,其是基于与野生型小鼠相比在EP4缺失的Ptger4-/-小鼠中B16黑色素瘤的生长显著降低的证据。然而,EP4基因敲除小鼠在肿瘤接种之前缺乏EP4受体,该参考文献并未明确提出恶性黑色素瘤形成后EP4信号抑制的治疗功效。该参考文献仅提出了肿瘤起始/促进阶段和/或黑色素瘤生长的抑制,并且该参考文献中没有直接和明确的表明EP4信号抑制导致了针对恶性肿瘤的抗肿瘤治疗功效。一些专利参考文献(例如,WO2015/179615A1、US2015/0004175A1和US8,921,391B2)描述了EP4受体拮抗剂或EP4信号转导抑制对黑色素瘤的治疗机会,但这些参考文献没有公开本发明的化合物在动物模型中的抗黑色素瘤功效的实验证据。总之,现有技术没有基于经过验证的动物肿瘤模型描述本发明的化合物在黑色素瘤中的抗肿瘤治疗功效。
淋巴瘤和白血病
一些非专利参考文献描述了EP4受体信号转导在血癌(如淋巴瘤和白血病)中的作用。血癌是非上皮性癌症,起源于血细胞的恶性肿瘤。Paul AG等人(TranslationalResearch 2013,161:447-468)表明,通过细胞培养实验,使用EP4拮抗剂GW627368X抑制EP4信号对卡波西肉瘤(Kaposi’s sarcoma)相关的疱疹病毒和爱泼斯坦-巴尔(Epstein-Barr)病毒相关的B细胞淋巴瘤细胞系具有抗增殖和细胞死亡诱导作用。类似地,Kopp KL等人(Leukemia 2010 24:1179-1185)报道称,通过细胞培养实验,PGE2信号激活剂量依赖性地增加了恶性T细胞淋巴瘤MyLa2000细胞的增殖,而EP4选择性拮抗剂L-161982降低了PGE2介导的细胞生长。
另一方面,一些参考文献表明PGE2/EP4受体信号转导的激活抑制B细胞增殖。Prijatelj等人(J Pharmacy and Pharmacology 2012 64:1090-1098)报道称,利用体外细胞培养系统,通过EP4受体激活PGE2,介导WEHI231 B细胞的细胞生长抑制作用。在WEHI231细胞培养中,PGE2抑制细胞生长,这通过在PGE2治疗前添加EP4受体特异性拮抗剂ONO-AE3-208来恢复。Murn等人(J.Exp Med 2008 205:3091-3103)表明,EP4受体是使用小鼠稳定的A20淋巴瘤细胞系传递PGE2生长抑制作用的主要分子,其中EP4受体基因表达通过转染EP4受体基因或针对含EP4基因的表达载体的miRNA进行上调或下调。将其中通过miRNA来稳定抑制EP4基因表达的A20细胞系接种到小鼠中肿瘤扩散明显加快,而稳定过表达EP4基因的A20细胞系则显示出显著的肿瘤生长抑制。
此外,在本申请的发明之前,没有通过EP4拮抗剂在动物肿瘤模型中抑制恶性肿瘤生长的直接证据,如下面的实施例所示。
发明概述
本申请提供了一种使用EP4受体拮抗剂治疗肝癌、黑色素瘤、淋巴瘤和白血病的方法。发明人已经发现,通过使用经过验证的小鼠肿瘤模型,以下三种本发明的化合物(即化合物A、B和C及其药学上可接受的盐)中的每一种都显著降低了这些癌症的生长:4-((1S)-1-{[5-氯-2(4-氟苯氧基)苯甲酰基]氨基}乙基)苯甲酸(化合物A),4-[(1S)-1-({[5-氯-2-(3-氟苯氧基)吡啶-3-基]羰基}氨基)乙基]-苯甲酸(化合物B),以及[2-(4-{2-乙基-4,6-二甲基-1H-咪唑并[4,5-c]吡啶-1-基}苯基)乙基]-1-[(4-甲苯)磺酰基]脲(化合物C)。
PGE2和EP4信号转导对抗肿瘤治疗功效的主要作用机制被描述为对宿主免疫系统的影响。基于这一理论,在体外癌细胞增殖实验、在免疫缺陷小鼠模型中的体内抗肿瘤功效实验,或在携带EP4受体表达受基因控制的癌细胞的体内小鼠模型中,都不能检测到EP4拮抗剂的内在功效,因为这三个实验没有评估EP4拮抗剂或EP4信号抑制对宿主免疫功能的影响。本发明人使用同系小鼠肿瘤模型,并在具有正常免疫功能的小鼠中测试了肿瘤生长抑制,以评估EP4拮抗剂的抗肿瘤功效和对免疫细胞的影响。
以下实施例表明,化合物B在携带小鼠H22肝细胞癌细胞的肿瘤模型中具有极其强大的抗肿瘤功效,该模型是肝癌的常用模型。与溶媒处理的小鼠相比,化合物B处理的小鼠中肿瘤体积的抑制率为78.1%。另一方面,索拉非尼(sorafenib)是目前治疗肝癌的标准疗法之一,与相同的H22小鼠模型中的溶媒相比,据报道索拉非尼对肿瘤体积的抑制率只有54.7%(Acta Biomaterialia 2019,92:229-240)。与索拉非尼相比,化合物B在肝癌模型中的抗肿瘤功效方面出乎意料地更强大。此外,以下实施例还表明,与化合物B(单独)和抗PD-1抗体(单独)相比,使用化合物B与抗PD-1抗体组合对携带H22肿瘤的小鼠的治疗显示出更高的肿瘤生长抑制。
化合物A是化合物B的类似物,与化合物B具有非常类似的化学结构。它们的药理学活性,如针对EP4受体信号转导的抑制效力,在cAMP抑制方面几乎相同。因此,化合物A预期产生与以下实施例中表明的化合物B类似的抗肿瘤功效。
类似地,如实施例中所示,在与化合物B相同的小鼠模型中,化合物C显示出61.2%的H22肿瘤生长抑制率,这也比索拉非尼更有效。当与抗PD-1抗体组合时,化合物C也显示出与化合物B类似的功效。这些结果清楚有力地证明了本发明的化合物在肝癌治疗中的潜在用途,以及与当前标准药物相比本发明化合物在肝癌治疗方面的优越功效。
如实施例中所示,本发明人进一步证明,在携带小鼠B16F10黑色素瘤的小鼠模型中,化合物C以36.4%的抑制率抑制黑色素瘤细胞的生长,这种抑制率与溶媒处理的对照组(P=0.049)相比是显著的。在相同的小鼠模型中,化合物B对B16F10黑色素瘤的抑制率为20.6%。因此,本发明人证明了EP4拮抗剂、化合物B和化合物C抑制了携带B16F10的小鼠中黑色素瘤细胞的生长,有力地证明了本发明的化合物在临床环境中的潜在用途。化合物A具有与化合物B类似的化学结构,预期也会抑制黑色素瘤细胞的生长。
如上所述,EP4信号转导对淋巴瘤和白血病生长的影响完全是有争议的,无论是促进生长还是抑制生长。本发明人推测,这种有争议的情况归因于在包括EP4拮抗剂对宿主免疫细胞的作用的同系小鼠模型中缺乏抗肿瘤的证据。在本发明的实施例之前,没有明确的证据显示EP4拮抗剂疗法在任何小鼠同系癌症模型中治疗淋巴瘤或白血病。本发明人已经证明,化合物B或化合物C的口服全身治疗抑制了携带A20 B细胞淋巴瘤细胞和携带WEHI-231白血病细胞的小鼠同系模型中的肿瘤生长,并明确显示EP4拮抗剂全身治疗具有淋巴瘤和白血病细胞的抗肿瘤机制。化合物A具有与化合物B类似的化学结构,预期也能抑制携带淋巴瘤细胞的小鼠和携带白血病细胞的小鼠的肿瘤生长。
附图说明
图1A描述了根据实施例1作为治疗肝癌的实施例,在携带H22肝细胞癌(HCC)的小鼠模型中测试的化合物B的抗肿瘤功效。图1A显示了化合物B或溶媒对照组处理后肿瘤体积的变化。
图1B描述了根据实施例2在小鼠H22模型中,测试的化合物B和抗PD-1抗体的组合疗法的抗肿瘤功效。图1B显示了单独使用化合物B、化合物B和抗PD-1抗体组合、单独使用抗PD-1抗体或溶媒对照组处理后肿瘤体积的变化。
图2A和2B分别以与图1A和1B相同的方式描述了化合物C的抗肿瘤功效,不同之处为实施例3和4使用化合物C而不是化合物B。图2A显示了根据实施例3,使用化合物C或溶媒对照组处理后肿瘤体积的变化。图2B显示了根据实施例4,单独使用化合物C、化合物C和抗PD-1抗体组合、单独使用抗PD-1抗体或溶媒对照组处理后肿瘤体积的变化。
图3A和图3B分别描述了在根据实施例5和6的小鼠B16F10黑素瘤携带小鼠模型中,化合物B和化合物C各自的抗肿瘤功效。图3A和3B显示了用化合物B、化合物C或溶媒处理的对照组处理后的肿瘤体积变化。
图4A和图4B分别描述了根据实施例7和8在小鼠A20 B细胞淋巴瘤小鼠模型作为淋巴瘤的实施例中,化合物B和化合物C各自的抗肿瘤功效。图4A和4B显示了化合物B、化合物C或溶媒处理对照组处理后肿瘤体积的变化。
图5A和图5B分别描述了在根据实施例9和10的小鼠WEHI-3白血病小鼠模型中,化合物B和化合物C各自的抗肿瘤功效。图5A和5B显示了使用化合物B、化合物C或溶媒处理的对照组处理后肿瘤体积的变化。
发明详述
用于治疗本发明癌症的本发明化合物是:4-((1S)-1-{[5-氯-2(4-氟苯氧基)苯甲酰基]氨基}乙基)苯甲酸(化合物A),4-[(1S)-1-({[5-氯-2-(3-氟苯氧基)吡啶-3-基]羰基}氨基)乙基]-苯甲酸(化合物B),以及[2-(4-{2-乙基-4,6-二甲基-1H-咪唑并[4,5-c]吡啶-1-基}苯基)乙基]-1-[(4-甲苯)磺酰基]脲(化合物C),或其药学上可接受的盐。
本发明的化合物还包括其溶剂化物、复合物、多晶型物、前药、异构体和同位素标记的化合物。本发明的化合物可以单独或组合用于治疗任何肝癌、黑色素瘤、淋巴瘤和白血病。
本发明的化合物公开于WO2005/021508、US8,921,391B2和US10,342,785B2中。
药学上可接受的盐包括但不限于其酸加成盐和碱盐。合适的酸加成盐由形成无毒盐的酸形成。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、樟脑磺酸盐、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(hibenzate)、盐酸盐/氯化物、氢溴酸盐/溴化物、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘酸盐(naphthylate)、2-萘磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸酯、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、蔗糖盐、硬脂酸盐、琥珀酸盐、酒石酸盐、甲苯磺酸盐和三氟乙酸盐。
合适的碱盐由形成无毒盐的碱形成。实例包括铝、精氨酸、苄星青霉素(benzathine)、钙、胆碱、二乙胺、二乙醇胺、甘氨酸、赖氨酸、镁、葡甲胺、乙醇胺、钾、钠、氨丁三醇和锌盐。
有关合适盐的综述,参见Stahl和Wermuth的《药用盐手册:性质、选择和使用》("Handbook of Pharmaceutical Salts:Properties,Selection,and Use";Wiley-VCH,Weinheim,Germany,2002)。
本发明化合物的药学上可接受的盐,可以通过混合本发明的化合物溶液和所需酸或碱(视情况而定)来容易地制备。所述盐可以从溶液中沉淀,并通过过滤收集或者可以通过蒸发所述溶剂回收。所述盐中的电离程度可以从完全电离到几乎不电离变化。
本发明的化合物可以以非溶剂化和溶剂化两种形式存在。术语“溶剂化物”在本文中用于描述包含本发明的化合物和一个或多个药学上可接受的溶剂分子(例如,乙醇)的分子复合物。
包括在本发明范围内的复合物,如包合物、药物-宿主包结物,其中,与上述溶剂化物相反,所述药物和宿主以化学计量或非化学计量的量存在。还包括含有两种或多种有机和/或无机成分的化合物的复合物,其可以以化学计量或非化学计量的量存在。所产生的复合物可以是离子化的、部分离子化的或非离子化的。有关此类复合物的综述,参见Haleblian的J.Pharm.Sci.,64(8):1269-1288(August 1975)。
在下文中,所有提及本发明的化合物包括提及其盐、溶剂化物和复合物,以及提及其盐的溶剂化物和复合物。
本发明的化合物包括如上文所定义的本发明的化合物、其多晶型物、前药和下文所定义的异构体(包括光学、几何和互变异构体),以及同位素标记的本发明的化合物。
如上所述,本发明包括本文定义的本发明化合物的所有多晶型物。
还在本发明范围内的,包括本发明化合物的所述“前药”。因此,本发明化合物的某些可能几乎没有药理活性或没有药理活性的衍生物,当施用到体内或体表时,可以转化为具有所需活性的任何一种本发明化合物结构式的化合物,例如,通过水解裂解。这种衍生物被称为“前药”。关于前药使用的进一步信息,可以参见“Pro-drugs as Novel DeliverySystems”,Vol.14,ACS Symposium Series,T.Higuchi and W.Stella,以及“Bioreversible Carriers in Drug Design”,Pergamon Press,1987,ed.E.B.Roche,American Pharmaceutical Association。
根据本发明的前药可以是,例如通过用本领域技术人员已知为“前-部分”的某些部分取代存在于本发明化合物的适当官能团来产生,其描述于例如,H Bundgaard的《前体药物的设计》("Design of Prodrugs";Elsevier,1985)。
根据本发明的前药的一些实例包括:
(i)当本发明的化合物含有羧酸官能团(-COOH)时,其酯,例如,用(C1-C8)烷基取代氢;
(ii)当本发明的化合物含有醇官能团(-OH)时,其醚,例如,用(C1-C6)烷酰基氧基甲基取代氢;以及
(iii)当本发明的化合物含有伯或仲氨基官能团(-NH2或-NHR,其中R≠H)时,其酰胺,例如,用(C1-C10)烷酰基取代一个或两个氢。
除上述实例之外,取代基的其他实例为本领域技术人员已知且可在前述参考文献中找到,但不限于这些实例。
最后,本发明的化合物本身也可以作为本发明的其他化合物的前药。
含有一个或多个不对称碳原子的本发明化合物可以作为两种或多种立体异构体存在。当本发明的化合物含有烯基或亚烯基时,几何顺式/反式(或Z/E)异构体是可能的。当所述化合物含有,例如酮或肟基团或芳香部分时,可以发生互变异构(“互变异构性”)。因此,单一化合物可以表现出一种以上类型的异构性。
包括在本发明范围内的是本发明的化合物的所有立体异构体、几何异构体和互变异构形式,包括表现出两种以上类型的相同异构性的化合物,以及其中一种或多种的混合物。还包括酸加成盐或碱盐,其中抗衡离子具有光学活性,例如D-乳酸盐或L-赖氨酸,或外消旋,例如DL-酒石酸盐或DL-精氨酸。
顺式/反式异构体可以通过本领域技术人员熟知的常规技术分离,例如色谱法和分步结晶法。
用于制备/分离单个对映异构体的常规技术,包括从合适的光学纯前体手性合成,或使用例如手性高压液相色谱法(HPLC)拆分外消旋体(或盐或衍生物的外消旋体)。
或者,外消旋体(或外消旋前体)可以与合适的光学活性化合物反应,例如醇,或者在本发明的化合物含有酸性或碱性部分的情况下反应,酸或碱如酒石酸或1-苯乙胺。所产生的非对映体混合物可以通过色谱法和/或分步结晶法分离,并且一种或两种非对映异构体可以通过本领域技术人员熟知的方法转化为相应的纯对映异构体。
本发明的手性化合物(及其手性前体)可以使用色谱法(通常为HPLC)在不对称树脂上以对映体富集形式获得,不对称树脂上具有由烃类(通常为庚烷或己烷)组成的流动相,含有0-50(w/w)%的异丙醇,通常为2-20(w/w)%,以及0-5(w/w)%的烷基胺,通常为0.1(w/w)%的二乙胺。洗脱液的浓缩提供了富集的混合物。
立体异构体聚集物可以通过本领域技术人员已知的常规技术进行分离(例如,参见E L Eliel的《有机化合物的立体化学》(Stereochemistry of Organic Compounds;Wiley,New York,1994)。
本发明包括所有药学上可接受的同位素标记的本发明化合物,其中一个或多个原子被具有相同原子序数但原子质量或质量数不同于自然界中通常发现的原子质量或质量数的原子取代。
适合包含在本发明化合物中的同位素的实例包括氢同位素,如2H和3H;碳同位素,如11C、13C和14C;氯同位素,如36Cl;氟同位素,如18F;碘同位素,如123I和125I;氮同位素,如13N和15N;氧同位素,如15O、17O和18O;磷同位素,如32P;以及硫同位素,如35S。
本发明的某些同位素标记的化合物,例如那些含有放射性同位素的化合物,可用于与癌症治疗相关的药物和/或基质组织分布研究,所述癌症治疗包括诊断、症状缓解、生活质量改善和预防。放射性同位素氚(即3H)和碳14(即14C)特别适用于这个目的,因为它们易于结合和检测手段准备。
用较重的同位素如氘,即2H取代,可以由于更大的代谢稳定性而提供某些治疗优势,例如,增加的体内半衰期或减少的剂量要求,因此在某些情况下可以是优选的。
用正电子发射同位素,如11C、18F、150和13N取代,可以用于正电子发射拓扑(PET)研究以检查底物受体的占有率。
本发明的同位素标记的化合物,通常可以通过本领域技术人员已知的常规技术制备,或者通过与所附实施例和制剂中描述的那些类似的方法使用合适的同位素标记的试剂代替先前的未标记的试剂制备。
根据本发明的药学上可接受的溶剂化物,包括那些其中结晶溶剂可以被同位素取代的溶剂,例如D2O(重水)、d6-丙酮、d6-DMSO(二甲基亚砜)。
拟用于药物用途的本发明化合物可以作为结晶或非结晶产品施用。它们可以,例如通过如沉淀、结晶、冷冻干燥、喷雾干燥或蒸发干燥等方法以固体栓剂、散剂或膜剂的形式获得。为此,可使用微波或射频干燥。
本发明化合物中的每一种(即化合物A、B或C)可以单独或彼此组合或与一种或多种其他药物组合(或作为其任何组合)施用。通常,它们将与一种或多种药学上可接受的添加剂组合作为制剂施用。术语“添加剂”在本文中用于描述除本发明的化合物之外的任何成分。添加剂的选择在很大程度上取决于各种因素,如特定的施用方式、添加剂对溶解度和稳定性的影响以及剂型的性质。本发明的化合物可以单独或与药学上可接受的载体或稀释剂通过如上所述任一途径施用,并且这种施用可以以单剂量或多剂量进行。更具体地,本发明的化合物可以以多种多样不同的剂型施用,即它们可以与各种在药学上可接受的惰性载体组合为以下形式:片剂、胶囊剂、含片、锭剂、硬糖剂、散剂、喷雾剂、乳膏剂、药膏、栓剂、凝胶剂(jellies)、凝胶(gels)、糊剂、洗剂、软膏剂、水性混悬剂、溶液型注射剂、酏剂(elixirs)、糖浆剂等。这种载体包括固体稀释剂或填充剂、无菌水性介质和各种无毒有机溶剂等。而且,口服药物组合物可以适当增甜和/或调味。通常,本发明的化合物以这种剂型存在,其浓度水平范围按重量计为5-95%。对于口服施用,含有各种赋形剂(如微晶纤维素、柠檬酸钠、碳酸钙、磷酸二钾和甘氨酸)的片剂可以与各种崩解剂(如淀粉优选玉米、马铃薯或木薯淀粉,海藻酸和某些复合硅酸盐),以及粒化粘合剂(如聚乙烯吡咯烷酮、蔗糖、明胶和阿拉伯胶)一起使用。此外,润滑剂如硬脂酸镁、月桂基硫酸钠和滑石粉通常对压片目的非常有用。类似类型的固体组合物也可用作明胶胶囊的填充剂;在这方面优选的材料还包括乳糖或牛奶糖以及高分子量聚乙二醇。当口服施用需要水性混悬剂和/或酏剂时,活性成分可以与各种甜味剂或调味剂、色素或染料组合,如果需要,也可以与乳化剂和/或悬浮剂,以及水、乙醇、丙二醇、甘油等稀释剂及其组合进行组合。
因此,本发明提供了本发明的化合物、其溶剂化物、其前药、其组合,以及与一种或多种其他药理学活性剂的组合。此外,本发明提供了一种包含本发明的化合物和药学上可接受的添加剂、稀释剂或载体的药物组合物,具体地用于治疗本发明的癌症。本发明还提供了一种试剂盒,其包含:包含本发明的化合物或其药学上可接受的盐的第一药物组合物;第二药物组合物;和容器。
用于治疗本发明的癌症的试剂盒也是本发明之一,所述试剂盒包含本发明的化合物或所述其药学上可接受的盐。包含本发明的化合物或所述其药学上可接受的盐的药物组合物和与此相关的书面材料的商业包装也是本发明之一,其中所述书面材料陈述所述化合物可以或应该用于治疗本发明的癌症。
本发明的其他特征和优势可以从以下详细描述和权利要求中显而易见。尽管本发明的具体实施方案已经描述了,但是本领域中的各种其他已知或通常的变化和修改落入本发明并且在权利要求范围内。本发明还包括在本发明精神内的等同物、改变、使用或变化。
本发明的化合物以能够缩小癌症、减少癌症肿瘤大小、减少癌症转移、调节免疫细胞功能和/或增强癌症治疗功效的有效量施用。这种治疗有效量根据本发明的具体化合物、待治疗的具体病症、患者的状况、施用途径、制剂、领域决策和其他因素而变化。根据本公开,取决于本领域技术人员已知的事情,由常规优化技术决定。本发明的化合物可以通过口服、肠胃外或局部途径对哺乳动物施用。通常,这些化合物最理想的施用于人的剂量范围为1-1000mg,优选为10-600mg,可以在一天内以单次剂量或分次剂量施用,尽管根据接受治疗的受试者的体重和状况、接受治疗的疾病状态和选择的特定施用途径必然会发生变化。
药物组合物可以包括本发明化合物或其药用盐并组合有药学上可接受的转运介质或载体。
如本文所用,术语“药学上可接受的转运介质”包括与药物施用兼容的溶剂、分散介质、包衣、抗菌剂和抗真菌剂、等渗剂和吸收延迟剂等。上述介质还包括其他活性或非活性成分,并基于所述组合物靶向癌症组织。
根据本公开内容,本发明化合物的治疗功效可以通过细胞培养物或实验动物中的标准治疗程序来确定,例如,用于确定ED50(在50%的群体中治疗有效的剂量)。
从细胞培养试验和动物研究中获得的数据,可用于制定用于人类的剂量范围。所述剂量可以根据制剂和施用途径而变化。对于本发明方法中使用的任何EP4受体拮抗剂(即化合物A、B或C),治疗有效剂量可以通过细胞培养试验初步估算。可以在动物模型中制定剂量,以得到包括在细胞培养中确定的IC50的循环血浆浓度范围。这些信息可用于更准确地确定人或动物的可用剂量。例如,血浆中的水平可以通过高效液相色谱法测量。
本领域技术人员众所周知,某些因素可能会影响有效治疗哺乳动物所需的剂量和时间,包括但不限于:疾病或病症的严重程度、先前的治疗、哺乳动物的一般健康状况和/或年龄,以及存在的其他疾病。此外,用治疗有效量的本发明化合物治疗哺乳动物,可以包括但不限于单次治疗、隔日治疗或一系列治疗。本发明的化合物可以通过口服、肠胃外或局部途径对哺乳动物施用。通常,这些化合物最理想地用于人类施用为,例如,一天一次,或一天分成2-4份。
给予人类患者的所述化合物的准确剂量将由主治医师特别负责。然而,使用的剂量将取决于许多因素,包括患者的年龄和性别、治疗的确切情况及其严重程度以及施用途径。例如,在口服施用的情况下,就本发明的化合物而言,每天的剂量通常为每1kg体重的哺乳动物(包括人类)约0.02-200mg,优选为约0.1-100mg,其可以一天一次或一天分成2-4份施用。更具体地,例如,对人类的施用,是每天每kg体重约0.02-20mg,更具体地,每天每kg体重约0.2-12mg。例如,对狗的施用,是每天每kg体重约0.5-25mg,更具体地,每天每kg体重约1-10mg。例如,对小鼠的施用,是每天每kg体重约1-100mg,更具体地,每天每kg体重约3-30mg。
本发明的化合物以药物组合物的形式方便地施用,用于治疗本发明的癌症。这种组合物可以方便地以常规方式与一种或多种药学上可接受的载体或赋形剂混合使用。
尽管本发明的化合物可以作为化学原料施用,但优选将其作为药物制剂形式的药物组合物呈现。所述制剂包含所述化合物连同一种或多种可接受的载体或稀释剂,以及可选的其他治疗成分。所述载体必须是“可接受的”,即与制剂的其他成分兼容并且对其接受者无害。
配制药物组合物以满足理想的施用途径。所述施用途径是,例如,肠胃外(例如,静脉内、皮肤内、皮下)、口服(例如,摄入或吸入)、经皮(局部)、粘膜和直肠,以及局部(包括经皮、口服和舌下)施用。以溶液或悬浮液形式配制的药物组合物,可以通过例如Remington'sPharmaceutical Sciences,18thed.,Gennaro,ed.,Mack Publishing Co.,Easton,PA,(1990)中描述的方法制备。
最合适的施用途径可以是不同的,这取决于,例如,接受治疗的患者的状况和疾病。所述制剂可以方便地以单位剂型呈现,并且可以通过药学领域中众所周知的任何方法制备。所有方法都包括将所述化合物(即“活性成分”)与构成一种或多种辅助成分的载体结合的步骤。通常,所述制剂的制备,是通过将所述活性成分与液体载体或细粒固体载体或这两者均匀且紧密地结合,然后如果需要,将产品成型为所需的制剂。
适合于口服施用的本发明的制剂可以呈现为离散单位,如胶囊剂、扁囊剂或片剂(例如,特别是用于儿科施用的咀嚼片剂),每一个都含有预定量的所述活性成分;作为粉末或颗粒;作为在水性液体或非水性液体中的溶液或悬浮液;或作为水包油液体乳液或油包水液体乳液。所述活性成分也可以以丸剂、冲服剂或糊剂的形式存在。
片剂可以通过压缩或模压制成,任选地含有一种或多种辅助成分。压缩片剂可以通过在合适的机器中以自由流动的形式(如粉末或颗粒)压缩所述活性成分来制备,任选地与粘合剂、润滑剂、惰性稀释剂、润滑剂、表面活性剂或分散剂混合。模压片剂可以通过在合适的机器中模压用惰性液体稀释剂润湿的所述粉末状活性成分的混合物来制备。所述片剂任选地被包衣或刻痕,并且可以被配制以提供其中所述活性成分的缓慢或受控释放。
用于肠胃外施用的制剂包括水性和非水性无菌注射溶液,其可以含有抗氧化剂、缓冲剂、抑菌剂和使制剂与预期接受者的血液等渗的溶质;以及水性和非水性无菌悬浮液,其中可以包括悬浮剂和增稠剂。所述制剂可以呈现于单位剂量或多剂量容器中,例如密封的安瓿瓶和小瓶,并且可以储存在冷冻干燥(冻干)条件下,仅需要在紧邻使用前添加无菌液体载体,例如注射用水。临时注射溶液和混悬液可以由前述种类的无菌散剂、颗粒剂和片剂制备。
直肠施用的制剂可以以栓剂呈现,含有通常的载体,如可可脂、硬脂或聚乙二醇。
用于口腔局部施用的制剂,例如含服或舌下施用,包括在诸如蔗糖和阿拉伯胶或黄芪胶的调味基础上含有所述活性成分的锭剂,以及在诸如明胶和甘油或蔗糖和阿拉伯胶的基础上含有所述活性成分的糖锭剂。
本发明的化合物也可以配制成储库型(depot)制剂。这种长效制剂可以通过植入(例如,皮下或肌肉注射)或通过肌肉注射施用。因此,例如,本发明的化合物可以与合适的聚合物或疏水材料(例如,作为可接受的油类中的乳剂)或离子交换树脂一起配制,或作为难溶性衍生物(例如,作为难溶盐)配制。
除了上面特别提到的成分之外,考虑到所讨论的制剂的类型,所述制剂可以包括本领域常规的其他试剂,例如,适合口服施用的那些制剂可以包括调味试剂。
小分子第二活性剂也可用于减轻与本发明化合物的施用相关的副作用。然而,像一些大分子一样,许多被认为当与本发明化合物一起施用时(例如,之前、之后或同时)能够提供协同作用。小分子第二活性剂的实例包括但不限于:抗癌剂、抗生素、免疫抑制剂和类固醇。
本发明还包括以试剂盒形式组合单独的药物组合物。所述试剂盒包含两种单独的药物组合物、本发明的化合物以及如本文所述的第二治疗剂。所述试剂盒包含用于容纳所述单独的组合物的容器,如分开的瓶子或分开的箔包,然而,所述单独的组合物也可以容纳在一个单独未分开的容器中。通常,所述试剂盒包含单独组分施用的说明书。当单独的组分优选以不同的剂型(例如,口服和肠胃外)施用、以不同的剂量间隔施用或者当处方医生需要对组合中的单独组分进行滴定时,所述试剂盒形式特别有利。
这种试剂盒的一个实例是所谓的泡罩包装。泡罩包装在包装行业中是众所周知的,并且被广泛用于药物单位剂型(片剂、胶囊剂等)的包装。泡罩包装通常包含相对坚硬材料的薄片,上面覆盖有优选为透明塑料材料的箔。在包装过程中,塑料箔中形成凹槽。所述凹槽具有待包装的片剂或胶囊剂的尺寸和形状。接着,将所述片剂或胶囊剂放入凹槽中,并将相对坚硬材料的薄片密封在所述箔表面的塑料箔上,其与凹槽形成的方向相反。因此,所述片剂或胶囊剂被密封在所述塑料箔和所述薄片之间的凹槽中。优选地,所述薄片的强度使得片剂或胶囊剂可以通过手动对所述凹槽施加压力,由此在所述薄片的凹槽位置形成开口,从而从泡罩包装中取出。然后,所述片剂或胶囊剂可以通过所述开口移出。
在某些实施方案中,本文提供的所述方法包括将本发明的化合物与一种或多种第二活性剂组合,和/或与放射疗法或手术组合施用。所述第二活性剂的实例包括,例如额外的EP4拮抗剂、免疫检查点抑制剂、PD-1抑制剂、PD-L1抑制剂、CTLA4抑制剂、过继免疫细胞治疗剂、癌症疫苗和其他靶向性免疫肿瘤药物,例如集落刺激因子1受体(CSF1R)、吲哚胺2,3-双加氧酶(IDO)或癌胚抗原(CEA)。此外,分子靶向抗癌药物和癌症化疗剂也包括在所述第二活性剂中。更具体地,所述第二活性剂包括,例如PD-1抗体,如纳武单抗(nivolumab)、拉博利珠单抗(labrolizumab)/派姆单抗(pembrolizumab)、REGE2810;PD-L1抗体,如阿贝鲁单抗(abelumab)、阿特珠单抗(atezolizumab)、德瓦鲁单抗(durvalumab)、派姆单抗;CTLA-4抗体,如易普利姆玛单抗(ipilimumab)和曲美木单抗(tremelimumab);分子靶向药物,如抗HER2抗体、抗VEGF抗体、抗EGFR抗体;针对EGFR受体、PDGFR受体、VEGFR受体激酶、c-kit和Bcr-Abl的酪氨酸激酶抑制剂;以及抗肿瘤化疗剂,如烷基化试剂、抗代谢物、抗肿瘤抗生素、抗感染药物、微管抑制剂、激素治疗剂、铂类药物、拓扑异构酶抑制剂;体液治疗剂,如芳香酶抑制剂、抗雌激素药物、抗雄激素药物、黄体酮、雌二醇、LH-RH激动剂;以及免疫疗法,如过继性T细胞疗法、过继性树突状细胞疗法、过继性NK细胞疗法和癌症疫苗疗法。本发明的化合物和所述第二活性剂对患者的施用,可以通过相同或不同的施用途径同时或依次进行。用于特定活性剂的特定施用途径的适用性,将取决于所述活性剂本身(例如,是否可以口服施用而在进入血液之前不分解)和正在治疗的疾病。所述第二活性剂的推荐施用途径是本领域普通技术人员已知的。例如,参见《医生桌上参考手册》(Physicians’DeskReference)。
术语定义
“EP4拮抗剂”是指抑制或阻断由PGE2与EP4受体相互作用触发的细胞信号转导的化合物。EP4拮抗剂的实例包括但不限于:ER-819762、MK-2894、MF498、ONO-AE3-208、伊瓦坦帕(Evatanepag)、ONO-AE2-227、BGC201531、ONO-AE3-240、GW627368、TPST-1495和AH23848。化合物A、B和C及其药学上可接受的盐(本发明的化合物)也是EP4拮抗剂的实例。
“抗PD-1抗体”是指靶向程序性细胞死亡1受体(PD-1)并抑制或阻断PD-1的细胞信号转导的抗体。抗PD-1抗体的实例包括但不限于:派姆单抗、纳武单抗、西米普利单抗(cemiplimab)、斯巴达珠单抗(spartalizumab)、卡瑞利珠单抗(camrelizumab)、信迪利单抗(sintilimab)和特瑞普利单抗(toripalimab)。
“免疫检查点抑制剂”是指一种药物,它可以阻断由某些类型的免疫细胞(如T细胞)和某些癌细胞产生的某些蛋白质。这些蛋白质有助于控制免疫反应,并可以防止T细胞杀死癌细胞。当这些蛋白质被阻断时,针对免疫系统的制动刹车被释放,T细胞能够更好地杀死癌细胞。免疫检查点抑制剂的实例包括但不限于:PD-1抑制剂、CTLA-4抑制剂、LAG-3抑制剂、TIM-3抑制剂、BTLA抑制剂、PD-L1抑制剂、PD-L2抑制剂、B7-1抑制剂、B7-2抑制剂、半乳糖凝集素(galectin)-9抑制剂和HVEM抑制剂。免疫检查点抑制剂可以是小分子、肽、蛋白质(如抗体)、核酸等。
“PD-1抑制剂”是指抑制程序性死亡蛋白1(PD1)功能的抗体或其他分子。示例性抑制剂/抗体包括但不限于:美国专利US7,029,674、US7,488,802、US7,521,051、US8,008,449、US8,354,509、US8,617,546和US8,709,417中所述的抗体。抗体的具体实例包括MDX-1106/纳武单抗、BMS-936558(百时美施贵宝公司)、拉博利珠单抗(默克公司)、MK-3475/派姆单抗(默克公司)、AMP-224(葛兰素史克公司)和CT-011(医好科技公司,CureTech)。
“PD-L1抑制剂”是指抑制程序性死亡配体1(PDL1)功能的抗体或其他分子。示例性抗体包括但不限于:美国专利US8,217,149、US8,383,796、US8,552,154和US8,617,546中所述的抗体。在一个具体实施方案中,所述抗体为MPDL3280A/RG7446(罗氏公司)、BMS-936559(百时美施贵宝公司)、MEDI4736(阿斯利康公司)和MSB0010718C(默克塞罗公司)。
“CTLA4抑制剂”是指抑制细胞毒性T淋巴细胞相关抗原4(CTLA4)功能的抗体或其他分子。示例性抑制剂/抗体包括但不限于:作为CTLA4拮抗剂的抗体,或美国专利US8,685,394和US8,709,417中所述的CTLA4抗体。抗体的一些实例包括MDX-010(伊普利单抗,百时美施贵宝公司)和CP-675206(曲美木单抗,阿斯利康公司)。在一个具体实施方案中,所述抗体是易普利姆玛单抗和曲美木单抗。
“过继免疫细胞治疗剂”是指使用免疫系统细胞进行癌症疗法的治疗剂,也称为细胞免疫疗法。过继免疫细胞治疗剂的实例包括但不限于:肿瘤浸润淋巴细胞疗法、工程化T细胞受体疗法、嵌合抗原受体T细胞疗法、自然杀伤细胞疗法、树突细胞疗法和干细胞疗法。
“癌症疫苗”是指使用疫苗技术进行癌症治疗的癌症免疫治疗剂。癌症疫苗的实例包括但不限于:西普鲁塞(sipuleucel)-T、DCVAC/PCa、OncoVAX和杰莫瓦图(gemogenovatucel)-T。
“免疫肿瘤治疗剂”是指调节免疫系统以促进癌症治疗的抗肿瘤药物。免疫肿瘤治疗剂的实例包括但不限于:T细胞促进剂(效应T细胞发育和功能的促进剂),其包括癌症抗原呈递、T细胞的启动和激活、T细胞运输到肿瘤、癌细胞的识别以及癌细胞杀伤的激活剂,如TNF-α、IL-1、IFN-α、CD40L/CD40、CD28/B7.1、CD137/CD137L、OX40/OX40L、CD27/CD70、HVEM、GITR、IL-2、IL-12、CX3CL1、CXCL9、CXCL10、CCL5、LFA1/CAM1、选择素、T细胞受体、IFN-γ的激活剂,以及IL-10、IL-4、IL-13、CTLA4/B7.1、PD-L1/PD-1、前列腺素、VEGF、内皮素B受体、还原的pMHC、IDO、TGF-β、BTLA、VIATA、LAG-3、精氨酸酶、MICA/MICB、B7-H4、TIM-3/磷脂的抑制剂。免疫肿瘤治疗剂还包括过继免疫细胞治疗剂和癌症疫苗。
“癌症化疗剂”是指抑制癌细胞生长和转移的药物,主要包括烷基化试剂,如芥子气衍生物、乙烯亚胺、烷基磺酸盐、肼和三嗪、亚硝基脲、金属盐;植物生物碱,如长春花生物碱、紫杉烷、鬼臼毒素、喜树碱类似物;抗肿瘤抗生素,如蒽环类、色霉素、丝裂霉素和博来霉素;抗代谢物,如叶酸拮抗剂、嘧啶类似物、嘌呤类似物、腺苷脱氨酶抑制剂;拓扑异构酶抑制剂,如拓扑异构酶I抑制剂和拓扑异构酶II抑制剂;其他抗肿瘤药物,如核糖核苷酸还原酶抑制剂、肾上腺皮质类固醇抑制剂、酶抑制剂、抗微管剂、类维生素A和分子靶向抗肿瘤药物。癌症化疗药物的实例包括但不限于:二氯甲基二乙胺、环磷酰胺、苯丁酸氮芥、美法仑、异环磷酰胺、三胺硫磷、六甲基三聚氰胺、二甲磺酸丁酯、六甲密胺、甲基苄肼、氮烯咪胺、替莫唑胺、卡莫司汀、洛莫司汀、链脲佐菌素、卡铂、顺铂、奥沙利铂、长春新碱、长春花碱、长春瑞滨、紫杉醇、多西他赛、依托泊苷、替尼泊苷、伊立替康、托泊替康、多柔比星、柔红霉素、表柔比星、米托蒽醌、伊达比星、放线菌素、普卡霉素、丝裂霉素、博来霉素、甲氨蝶呤、5-氟尿嘧啶、氟尿苷、阿糖胞苷、卡培他滨、吉西他滨、6-巯基嘌呤、6-硫鸟嘌呤、克拉屈滨、氟达拉滨、奈拉滨、喷司他丁、安吖啶、依托泊苷、磷酸依托泊苷、替尼泊苷、羟基脲、米托坦、天冬酰胺酶、培门冬酶、雌莫司汀、贝沙罗汀、异维甲酸和维甲酸(ATRA)。
“治疗(Treatment/treat/treating)”是指减轻、抑制和/或逆转有需要的受试者的癌症进展。术语“治疗”包括任何治疗或改善癌症成功的迹象,包括任何客观或主观参数,如减轻;缓解;症状减弱,或使受试者更能耐受损伤、病理或病症;延迟或减缓进展速度等。治疗或改善的测量可以基于,例如本领域已知的身体检查、病理测试和/或诊断测试的结果。所述治疗还可以指与不采取措施的情况相比,减少癌症的发病率或发生,或其复发(如延长缓解期)。如本文所用,术语“治疗”不仅包括缩小肿瘤组织,还包括减轻症状、提高生活质量(QOL)和预防(放疗、术后预防复发、辅助化疗等)。
“药学有效量”是指如通过临床测试和评估、患者观察和/或类似方式记录的对于治疗癌症有效的量。“有效量”可以进一步指定导致生物或化学活性发生可检测的变化的量。所述可检测的变化可由本领域技术人员针对相关机制或过程进行检测和/或进一步量化。此外,“有效量”可以指定维持所需生理状态的量,即减少或防止显著下降和/或促进病症改善。“有效量”可以进一步指治疗有效量。
如本文所用,术语“药学上可接受的盐”与上文提供的实例一致,是指本发明化合物的相对无毒的无机或有机酸盐。这些盐可以在化合物的最终分离和纯化过程中原位制备,或者通过将纯化的化合物以其游离形式分别与合适的有机或无机酸反应并分离由此形成的盐。代表性的酸盐包括但不限于:乙酸盐、己二酸盐、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、樟脑磺酸盐、柠檬酸盐、环磺酸盐、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、氢碘酸盐/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、萘酸盐,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、焦谷氨酸盐、蔗糖盐、硬脂酸盐、琥珀酸盐、鞣酸盐、酒石酸盐、甲苯磺酸盐、三氟乙酸盐和羟萘甲酸盐(xinafoate)。在一个实施方案中,所述药学上可接受的盐是盐酸盐/氯化物盐。
“第二活性剂”是具有药学有效活性的低分子量药物或生物制剂,包括但不限于:PGE2信号抑制剂如额外的EP4拮抗剂、微粒体前列腺素E合酶(mPGES)-1抑制剂、COX-2抑制剂、NSAID和免疫检查点抑制剂、癌症免疫治疗剂、免疫细胞治疗剂、分子靶向抗肿瘤药物、烷基化试剂、抗代谢物、抗肿瘤抗生素、抗感染药物、微管抑制剂、激素治疗剂、铂类药物、拓扑异构酶抑制剂、分子靶向癌症治疗剂、疫苗治疗剂等等。
“免疫细胞治疗剂”包括但不限于:用于抗肿瘤疫苗疗法的药物或生物制剂,以及过继性免疫细胞疗法,如过继性T细胞疗法、过继性树突状细胞疗法、过继性NK细胞疗法和CAR-T疗法。
“癌症免疫治疗剂”包括但不限于靶向免疫细胞和与免疫细胞和癌症免疫细胞相互作用相关的分子的抗肿瘤药物。免疫细胞包括但不限于:B细胞、T细胞、调节性T细胞、自然杀伤细胞、自然杀伤T细胞、树突细胞、髓源性抑制细胞、单核细胞和巨噬细胞。与免疫细胞和癌症免疫细胞相互作用相关的分子包括但不限于:PD-1、PD-L1、CTLA4、TIM3、LAG3、TIGIT、BTLA、OX-40、ICOS、CD137、GITR、CD40、CD28、CD27、IL-2、IL-7、IL-15、IL-21、GM-CSF、IL-12、IFNα、ICAM1、VCAM1、CD103、IDO、TDO、NOS1、精氨酸酶、CSF1、FOXP3、TGFβ、IL-10、BATF3、XCR1/XCL1、STING、IFNγ、CXCL9/10/11、CXCL1/13、CCL2/5。
“分子靶向抗肿瘤药物”包括但不限于靶向特定分子的小分子和生物制剂,如与癌细胞的生长相关的蛋白激酶、凋亡调节蛋白、生长因子、血管生成调节蛋白、体液受体、转录因子、细胞因子、趋化因子、受体、酶、离子通道等。“分子靶向抗肿瘤药物”包括但不限于:伊马替尼、吉非替尼、厄洛替尼、索拉非尼、舒尼替尼、达沙替尼、拉帕替尼、尼罗替尼、硼替佐米、他莫昔芬、托法替尼、克唑替尼、奥巴托克(obatoclax)、纳维托克(navitoclax)、棉酚、依尼帕利、奥拉帕利、哌立福辛(perifosine)、阿帕替尼、威罗非尼、达拉非尼、曲美替尼、PD-0332991、LEE011、长春福肽(vintafolide)、替西罗莫司、依维莫司、维罗非尼、曲美替尼、达拉非尼、派姆单抗、利妥昔单抗、曲妥珠单抗、阿仑单抗、西妥昔单抗、帕尼单抗、贝伐单抗、伊匹单抗和纳武单抗。
“肝癌”包括但不限于:肝细胞癌、胆管癌、粘液性囊性肿瘤和导管内乳头状胆管肿瘤。“肝癌”还包括但不限于与肝硬化、乙型肝炎、丙型肝炎病毒感染和饮酒相关的肝癌。
“黑色素瘤”包括但不限于发生在皮肤、口腔、眼睛、胃肠器官、肝脏、骨骼和其他器官中的黑色素瘤,并且包括原发性黑色素瘤和转移性黑色素瘤。
“淋巴瘤”包括但不限于:霍奇金(Hodgkin’s)淋巴瘤、非霍奇金淋巴瘤和爱泼斯坦-巴尔(Epstein-barr)病毒相关的淋巴组织增生性疾病。“淋巴瘤”还包括但不限于:成熟B细胞肿瘤、成熟T细胞和自然杀伤细胞肿瘤、前体淋巴肿瘤和免疫缺陷相关的淋巴组织增生性疾病。具体地,淋巴瘤包括B细胞淋巴瘤。
“白血病”包括但不限于具有急性或慢性特性的淋巴细胞白血病和髓细胞白血病。“白血病”还包括但不限于:急性淋巴细胞白血病、慢性淋巴细胞白血病、急性髓细胞白血病、慢性髓细胞白血病、毛细胞白血病、T细胞前淋巴细胞白血病、大颗粒淋巴细胞白血病、成人T细胞白血病和克隆性嗜酸性粒细胞增多症。
如本文所用,术语“EP4信号”或“EP4信号转导”是指EP4受体介导的细胞信号转导,如环AMP和磷酸肌醇3-激酶(PI3K)信号以及与EP4受体激动性刺激相关的后续信号转导。
实施例
为了阐明本发明化合物治疗本发明癌症的抗肿瘤功效,使用经过验证的小鼠肿瘤模型,并在实验期间测试了肿瘤生长抑制和小鼠体重的变化。在这些实施例描述的实验中没有观察到与药物相关的异常体重变化或异常行为。
实施例1
在小鼠肝癌模型中,化合物B显示了对H22肝细胞癌生长的几乎完全抑制。(图1A)
实验方法
将小鼠肝细胞癌H22细胞培养在含有10%胎牛血清(FBS)、100U/mL青霉素和100μg/mL链霉素的RPMI-1640培养基中。在第0天,将2×106个细胞/0.1mL的H22细胞经皮下接种到BALB/c小鼠的右侧肋骨。在第4天,将所述小鼠分组(N=8),从第5天每天开始所述药物治疗,持续14天。化合物B以45mg/kg/天,每天二次、口服(bid,p.o.)处理。通过测量肿瘤的长短直径并使用等式:0.5×(长直径)×(短直径)来评估肿瘤体积。组间肿瘤体积的统计分析,通过单向方差分析进行。在每种药物处理开始之前,进行小鼠的体重测量和行为观察。
研究结果和结论
在第19天与溶媒处理相比,以45mg/kg/天的剂量口服化合物B显示了对H22肿瘤生长的78.1%的抑制率(图1A)。这种抑制具有统计学意义。在整个实验期间,没有观察到药物介导的异常行为或平均体重变化。
实施例2
在小鼠癌症模型中,化合物B与抗PD-1抗体组合显示了在抑制H22肝细胞癌生长的组合抗肿瘤作用。(图1B)
实验方法
本实验使用与实施例1相同的小鼠模型。在第4天,将所述小鼠分组(N=13)),从第5天开始所述药物治疗,持续12天。化合物B以15mg/kg/天,每天二次、口服(bid,p.o.)处理。抗PD-1抗体(康龙化学(Kang Long Chemicals),695318J3)以2.5mg/kg/天,每周两次、腹腔注射(i.p.)处理。肿瘤体积、体重、行为的评估和肿瘤体积统计分析的进行与实施例1相同。
研究结果和结论
以15mg/kg/天的化合物B治疗,以34.5%的抑制率抑制了肿瘤生长。每周两次以2.5mg/kg的抗PD-1抗体治疗,在第17天以33.8%的抑制率抑制了肿瘤生长。化合物B和抗PD-1抗体的组合疗法显示出更高的肿瘤生长抑制率,抑制率为58.2%。所述实验表明了化合物B与抗PD-1疗法的组合疗法或EP4抑制机制与抗PD-1疗法的组合的益处。在整个实验期间没有观察到药物介导的异常行为或平均体重变化。
实施例3
在小鼠癌症模型中,化合物C显示了对H22肝细胞癌生长的有效抑制。(图2A)
实验方法
本实验使用与实施例1相同的小鼠模型。在第4天,将所述小鼠分组(N=8),从第5天每天开始所述药物治疗,持续14天。化合物C以200mg/kg/天,每天二次、口服(bid,p.o.)处理。肿瘤体积、体重、行为的评估和肿瘤体积统计分析的进行与实施例1相同。
研究结果和结论
在第19天与溶媒处理相比,以200mg/kg/天的化合物C治疗以61.2%的抑制率抑制了肿瘤生长(图2A)。这种抑制具有统计学意义。在整个实验期间没有观察到药物介导的异常行为或平均体重变化。
实施例4
在小鼠癌症模型中,化合物C与抗PD-1抗体组合显示了在抑制H22肝细胞癌生长中的组合抗肿瘤作用。(图2B)
实验方法
本实验使用与实施例1相同的小鼠模型。在第4天,将所述小鼠分组(N=13),从第5天开始所述药物治疗,持续12天。化合物C以50mg/kg/天,每天二次、口服(bid,p.o.)处理。抗PD-1抗体(康龙化学,695318J3)以2.5mg/kg/天,每周两次、腹腔注射(i.p.)处理。肿瘤体积、体重、行为的评估和肿瘤体积统计分析的进行与实施例1相同。
研究结果和结论
以50mg/kg/天的化合物C治疗,以54.2%的抑制率抑制了肿瘤生长。每周两次以2.5mg/kg的抗PD-1抗体治疗(康龙化学,695318J3),在第17天以26.6%的抑制率抑制了肿瘤生长。化合物C和抗PD-1抗体的组合疗法显示出附加的肿瘤生长抑制,抑制率为67.3%。所述实验表明了化合物C与抗PD-1疗法或EP4抑制机制与抗PD-1疗法的组合疗法的益处。在整个实验期间,没有观察到药物介导的异常行为或平均体重变化。
实施例5
在小鼠癌症模型中,化合物B显示了对B16F10黑色素瘤生长的抑制。(图3A)
实验方法
将小鼠黑色素瘤B16F10细胞培养在含有10%FBS的DMEM中。在第0天,将1×105个B16F10细胞经皮下接种到每只小鼠C57BL/6J的右侧肋骨。在第11天,将所述小鼠分组(N=8),从第12天开始所述药物治疗,持续14天。化合物B以45mg/kg/天,每天二次、口服(bid,p.o.)处理。肿瘤体积、体重、行为的评估和肿瘤体积统计分析的进行与实施例1的方法相同。
研究结果和结论
在第24天与溶媒处理组相比,以45mg/kg/天的剂量口服化合物B显示了对B16F10黑素瘤生长的20.6%抑制率(P>0.05)。在整个实验期间,没有观察到药物介导的异常行为或平均体重变化。
实施例6
在小鼠癌症模型中,化合物C显示了对B16F10黑色素瘤生长的有效抑制。(图3B)
实验方法
本实验使用与实施例5相同的小鼠模型。在第11天,将所述小鼠分组(N=8),从第12天开始所述药物治疗,持续14天。化合物C以200mg/kg/天,每天三次、口服(tid,p.o.)处理。肿瘤体积、体重、行为的评估和肿瘤体积统计分析的进行与实施例1的方法相同。
研究结果和结论
在第24天与溶媒处理组相比,以200mg/kg/天的剂量口服化合物C显示对B16F10黑素瘤生长的36.4%的抑制率,其具有统计学意义的显著抑制(P=0.049)。在整个实验期间,没有观察到药物介导的异常行为或平均体重变化。
实施例7
在小鼠癌症模型中,化合物B显示了对A20 B细胞淋巴瘤生长的有效抑制。(图4A)
实验方法
将小鼠B细胞淋巴瘤A20细胞培养在含有10% FBS、0.05mM 2-巯基乙醇的RPMI1640中。第0天,将3×105个A20细胞经皮下接种到BALB/c小鼠的右侧肋骨。在第7天,将所述小鼠分组(N=8),从第8天开始所述药物治疗,持续14天。化合物B以45mg/kg/天,每天二次、口服(bid,p.o.)处理。肿瘤体积、体重、行为的评估和肿瘤体积统计分析的进行与实施例1的方法相同。
研究结果和结论
在第22天与溶媒处理组相比,以45mg/kg/天的剂量口服化合物B显示了对A20淋巴瘤细胞生长的52.1%的抑制率,其具有统计学意义的显著抑制(P<0.001)。在整个实验期间,没有观察到药物介导的异常行为或平均体重变化。
实施例8
在小鼠癌症模型中,化合物C显示了对A20 B细胞淋巴瘤生长的有效抑制。(图4B)
实验方法
本实验使用与实施例7相同的小鼠模型。在第7天,将所述小鼠分组(N=8),从第8天开始所述药物治疗,持续14天。化合物C以200mg/kg/天,每天三次、口服(tid,p.o.)处理。肿瘤体积、体重、行为的评估和肿瘤体积统计分析的进行与实施例1的方法相同。
研究结果和结论
在第22天与溶媒处理组相比,以200mg/kg/天的剂量口服化合物C显示了对A20 B细胞淋巴瘤细胞生长的42.2%的抑制率,其具有统计学意义的显著抑制(P=0.003)。在整个实验期间,没有观察到药物介导的异常行为或平均体重变化。
实施例9
在小鼠癌症模型中,化合物B显示了对WEHI-3白血病生长的有效抑制。(图5A)
实验方法
将小鼠白血病WEHI-3细胞培养在含有10% FBS、0.05mM 2-巯基乙醇的RPM11640中。在第0天,将3×105个WEHI-3细胞经皮下接种到BALB/c小鼠的右侧肋骨。在第7天,将所述小鼠分组(N=8),从第8天开始所述药物治疗,持续8天。化合物B以45mg/kg/天,每天二次、口服(bid,p.o.)处理。肿瘤体积、体重、行为的评估和肿瘤体积统计分析的进行与实施例1的方法相同。
研究结果和结论
在第16天与溶媒处理组相比,以45mg/kg/天的剂量口服化合物B显示了对WEHI-3白血病细胞生长的48.4%的抑制率,其具有统计学意义的显著抑制(P=0.02)。在整个实验期间,没有观察到药物介导的异常行为或平均体重变化。
实施例10
在小鼠癌症模型中,化合物C显示了对WEHI-3白血病生长的有效抑制。(图5B)
实验方法
本实验使用与实施例9相同的小鼠模型。在第7天,将所述小鼠分组(N=8),从第8天开始所述药物治疗,持续8天。化合物C以200mg/kg/天,每天三次、口服(tid,p.o.)处理。肿瘤体积、体重、行为的评估和肿瘤体积统计分析的进行与实施例1的方法相同。
研究结果和结论
在第16天与溶媒处理组相比,以200mg/kg/天的剂量口服化合物C显示了对WEHI-3白血病细胞生长的61.2%的抑制率,其具有统计学意义的显著抑制(P=0.003)。在整个实验期间,没有观察到药物介导的异常行为或平均体重变化。
Claims (20)
1.一种治疗肝癌的方法,其包括向有需要的人或动物施用药学有效量的选自以下的化合物:4-((1S)-1-{[5-氯-2(4-氟苯氧基)苯甲酰基]氨基}乙基)苯甲酸(化合物A),4-[(1S)-1-({[5-氯-2-(3-氟苯氧基)吡啶-3-基]羰基}氨基)乙基]-苯甲酸(化合物B),以及3-[2-(4-{2-乙基-4,6-二甲基-1H-咪唑并[4,5-c]吡啶-1-基}苯基)乙基]-1-[(4-甲苯)磺酰基]脲(化合物C),或其药学上可接受的盐。
2.根据权利要求1所述的方法,还包括将药学有效量的所述化合物A、B或C与第二活性剂组合施用。
3.根据权利要求2所述的方法,其中所述第二活性剂是选自以下的至少一种:免疫检查点抑制剂、过继免疫细胞治疗剂、癌症疫苗、免疫肿瘤治疗剂、分子靶向抗肿瘤药物和癌症化疗剂。
4.根据权利要求1所述的方法,还包括将药学有效量的所述化合物A、B或C与抗PD-1抗体组合施用。
5.一种治疗黑色素瘤的方法,其包括向有需要的人或动物施用药学有效量的选自以下的化合物:4-((1S)-1-{[5-氯-2(4-氟苯氧基)苯甲酰基]氨基}乙基)苯甲酸(化合物A),4-[(1S)-1-({[5-氯-2-(3-氟苯氧基)吡啶-3-基]羰基}氨基)乙基]-苯甲酸(化合物B),以及3-[2-(4-{2-乙基-4,6-二甲基-1H-咪唑并[4,5-c]吡啶-1-基}苯基)乙基]-1-[(4-甲苯)磺酰基]脲(化合物C),或其药学上可接受的盐。
6.根据权利要求5所述的方法,还包括将药学有效量的所述化合物A、B或C与第二活性剂组合施用。
7.根据权利要求6所述的方法,其中所述第二活性剂是选自以下的至少一种:免疫检查点抑制剂、过继免疫细胞治疗剂、癌症疫苗、免疫肿瘤治疗剂、分子靶向抗肿瘤药物和癌症化疗剂。
8.根据权利要求5所述的方法,还包括将药学有效量的所述化合物A、B或C与抗PD-1抗体组合施用。
9.一种治疗淋巴瘤的方法,其包括向有需要的人或动物施用药学有效量的选自以下的化合物:4-((1S)-1-{[5-氯-2(4-氟苯氧基)苯甲酰基]氨基}乙基)苯甲酸(化合物A),4-[(1S)-1-({[5-氯-2-(3-氟苯氧基)吡啶-3-基]羰基}氨基)乙基]-苯甲酸(化合物B),以及3-[2-(4-{2-乙基-4,6-二甲基-1H-咪唑并[4,5-c]吡啶-1-基}苯基)乙基]-1-[(4-甲苯)磺酰基]脲(化合物C),或其药学上可接受的盐。
10.根据权利要求9所述的方法,还包括将药学有效量的所述化合物A、B或C与第二活性剂组合施用。
11.根据权利要求10所述的方法,其中所述第二活性剂是选自以下的至少一种:免疫检查点抑制剂、过继免疫细胞治疗剂、癌症疫苗、免疫肿瘤治疗剂、分子靶向抗肿瘤药物和癌症化疗剂。
12.根据权利要求9所述的方法,还包括将药学有效量的所述化合物A、B或C与抗PD-1抗体组合施用。
13.一种治疗B细胞淋巴瘤的方法,其包括向有需要的人或动物施用药学有效量的选自以下的化合物:4-((1S)-1-{[5-氯-2(4-氟苯氧基)苯甲酰基]氨基}乙基)苯甲酸(化合物A),4-[(1S)-1-({[5-氯-2-(3-氟苯氧基)吡啶-3-基]羰基}氨基)乙基]-苯甲酸(化合物B),以及3-[2-(4-{2-乙基-4,6-二甲基-1H-咪唑并[4,5-c]吡啶-1-基}苯基)乙基]-1-[(4-甲苯)磺酰基]脲(化合物C),或其药学上可接受的盐。
14.根据权利要求13所述的方法,还包括将药学有效量的所述化合物A、B或C与第二活性剂组合施用。
15.根据权利要求14所述的方法,其中所述第二活性剂是选自以下的至少一种:免疫检查点抑制剂、过继免疫细胞治疗剂、癌症疫苗、免疫肿瘤治疗剂、分子靶向抗肿瘤药物和癌症化疗剂。
16.根据权利要求13所述的方法,还包括将药学有效量的所述化合物A、B或C与抗PD-1抗体组合施用。
17.一种治疗白血病的方法,其包括向有需要的人或动物施用药学有效量的选自以下的化合物:4-((1S)-1-{[5-氯-2(4-氟苯氧基)苯甲酰基]氨基}乙基)苯甲酸(化合物A),4-[(1S)-1-({[5-氯-2-(3-氟苯氧基)吡啶-3-基]羰基}氨基)乙基]-苯甲酸(化合物B),以及3-[2-(4-{2-乙基-4,6-二甲基-1H-咪唑并[4,5-c]吡啶-1-基}苯基)乙基]-1-[(4-甲苯)磺酰基]脲(化合物C),或其药学上可接受的盐。
18.根据权利要求17所述的方法,还包括将药学有效量的所述化合物A、B或C与第二活性剂组合施用。
19.根据权利要求18所述的方法,其中所述第二活性剂是选自以下的至少一种:免疫检查点抑制剂、过继免疫细胞治疗剂、癌症疫苗、免疫肿瘤治疗剂、分子靶向抗肿瘤药物和癌症化疗剂。
20.根据权利要求17所述的方法,还包括将药学有效量的所述化合物A、B或C与抗PD-1抗体组合施用。
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