CN112930181A - 小分子cd-47抑制剂与其它抗癌剂的组合 - Google Patents
小分子cd-47抑制剂与其它抗癌剂的组合 Download PDFInfo
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- CN112930181A CN112930181A CN201980071532.5A CN201980071532A CN112930181A CN 112930181 A CN112930181 A CN 112930181A CN 201980071532 A CN201980071532 A CN 201980071532A CN 112930181 A CN112930181 A CN 112930181A
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Abstract
本发明涉及一种包含CD47‑SIRPα阻断剂和一种或多种抗癌剂的组合物:其中所述CD47‑SIRPα阻断剂由式(I)的化合物表示。本发明还涉及通过将治疗有效量的由式(I)表示的CD47‑SIRPα阻断剂与一种或多种抗癌剂组合施用来治疗受试者的癌症的方法。
Description
相关申请
本申请要求于2018年11月08日提交的印度临时申请号201841042108的权益,其内容以引用的方式整体并入本文。
技术领域
本发明涉及药物组合物,其包含小分子CD-47-SIRPα通路抑制剂和一种或多种能够刺激受体诸如活化Fc受体(FcR)或其它促吞噬受体的剂。
背景技术
CD47/SIRPα轴被确立为骨髓细胞活化的关键调节因子,并充当巨噬细胞介导的吞噬作用的免疫检查点。由于CD47在数种癌症中频繁上调,因此有助于免疫逃避和癌症进展。CD47主要通过与巨噬细胞上表达的SIRP1α相互作用来调节吞噬作用。SIRP1α/CD47的阻断已显示可显著增强肿瘤细胞吞噬作用和树突状细胞成熟,用于更好地呈递抗原,从而导致在癌症的临床前模型中充分改善抗肿瘤反应(M.P.Chao等人Curr Opin Immunol.2012(2):225-232)。目前,正在通过使用靶向CD47或SIRPα的单克隆抗体和工程受体诱饵来评估破坏CD47-SIRPα相互作用作为癌症的治疗策略。
CD47实际上在所有非恶性细胞上表达,并且阻断CD47或CD47表达的丧失或膜分布的变化可用作老化或受损细胞的标志物,尤其是在红细胞(RBC)上。可选地,对于还存在吞噬前信号的那些细胞,阻断SIRPα还可以吞噬正常不会被吞噬的靶标。CD47是一种广泛表达的具有单个Ig样结构域和五个跨膜区的跨膜糖蛋白,其充当SIRPα的细胞配体,通过SIRPα的NH2端V样结构域介导结合。SIRPα主要在骨髓细胞上表达,包括巨噬细胞、粒细胞、髓样树突状细胞(DC)、肥大细胞及其前体,包括造血干细胞。
CD47在许多癌症上也组成性上调,诸如非霍奇金淋巴瘤(NHL)、急性骨髓性白血病(AML)、乳腺癌、结肠癌、胶质母细胞瘤、胶质瘤、卵巢癌、膀胱癌和前列腺癌等。肿瘤细胞过度表达CD47,有效地帮助肿瘤细胞逃避免疫监视和先天免疫细胞的杀伤。但在大多数肿瘤类型中,阻断CD47-SIRPα的相互作用作为单一动因可能无法诱导显著的吞噬作用和抗肿瘤免疫,因此有必要与其它治疗剂组合。为了发挥CD-47-SIPRα通路阻断的最大潜力,可能需要活化受体诸如Fc受体(FcR)或其它促吞噬受体(统称为“吃我”信号)的同时参与。
通过抗CD47 F(ab)片段、CD-47的单链可变片段或不含Fc部分的SIRPα蛋白在阻断CD47-SIRPα相互作用中低效率地触发吞噬作用,证明了促吞噬受体的参与作用。当活化促吞噬受体参与时,如在使用含Fc部分的阻断抗CD47抗体的情况下显而易见,CD47-SIRPα阻断能够触发更有效的吞噬作用。将CD47-SIRPα阻断剂与靶向肿瘤抗原的治疗性抗体(含Fc)组合,刺激活化Fc受体(FcR),从而产生高效的吞噬作用。靶向肿瘤抗原的治疗性抗体的Fc部分还诱导抗体依赖性细胞毒性(ADCC),这也增加了治疗功效。因此,选自由以下组成的组的抗体由于其肿瘤靶向性和ADCC,可以触发更高效的吞噬作用:利妥昔单抗(rituximab)、赫赛汀(herceptin)、曲妥珠单抗(trastuzumab)、阿仑单抗(alemtuzumab)、贝伐单抗(bevacizumab)、西妥昔单抗(cetuximab)和帕尼单抗(panitumumab)、达雷木单抗(daratumumab)。
早期破坏CD47-SIRPα相互作用的方法利用靶向CD47或SIRPα的单克隆抗体和工程化受体诱饵与Fc片段融合。然而,这种方法的一个顾虑是,CD47在造血和非造血正常细胞上都高度表达。因此,连同肿瘤细胞一起,含有Fc部分的CD47-SIRPα阻断剂也可能靶向许多正常细胞,可能导致它们被巨噬细胞消除。阻断抗体与正常细胞的相互作用被认为是一个主要的安全性问题,导致贫血、血小板减少和白细胞减少。这些剂也可能影响富含巨噬细胞的实体组织,诸如肝、肺和脑。因此,可能理想的是通过不含Fc部分的剂,诸如小分子、肽、Fab片段等阻断CD47-SIRPα的相互作用,同时通过适当的组合激活肿瘤细胞中的促吞噬受体,以诱导肿瘤细胞的高效吞噬。
除Fc受体外,还报道许多其它促吞噬受体通过触发吞噬作用来响应CD47-SIRPα阻断而促进肿瘤细胞的吞噬。这些受体包括SLAMF7、Mac-1、钙网蛋白的受体和可能尚未确定的受体。B细胞肿瘤系诸如Raji和其它弥漫性大B细胞淋巴瘤表达SLAMF7,并涉及在CD47-SIRPα阻断期间触发促吞噬信号。
因此,已知激活促吞噬受体的治疗剂也是与CD47-SIRPα阻断剂组合使用以实现高效吞噬的理想伴侣。这些剂包括蛋白酶体抑制剂(硼替佐米(bortezomib)、伊沙佐米(ixazomib)和卡非佐米(carfilzomib))、蒽环类药物(多柔比星(Doxorubicin)、表柔比星(Epirubicin)、柔红霉素(Daunorubicin)、伊达比星(Idarubicin)、米托蒽醌(Mitoxantrone))奥沙利铂(Oxaliplatin)、环磷酰胺(Cyclophosphamide)、博莱霉素(Bleomycin)、伏立诺他(Vorinostat)、紫杉醇(Paclitaxel)、5-氟尿嘧啶、阿糖胞苷(Cytarabine)、BRAF抑制性药物(达拉非尼(Dabrafenib)、维罗非尼(Vemurafenib))、PI3K抑制剂、多西他赛(Docetaxel)、丝裂霉素C(Mitomycin C)、索拉非尼(Sorafenib)、他莫昔芬(Tamoxifen)和溶瘤病毒。
除了已知对‘吃我’信号有影响的特定剂外,其它剂,包括乙酸阿比特龙(Abiraterone acetate)、阿法替尼(Afatinib)、阿地白介素(Aldesleukin)、阿地白介素、阿仑单抗、阿那曲唑(Anastrozole)、阿西替尼(Axitinib)、贝利司他(Belinostat)、苯达莫司汀(Bendamustine)、比卡鲁胺(Bicalutamide)、博纳吐单抗(Blinatumomab)、伯舒替尼(Bosutinib)、本妥昔单抗(Brentuximab)、白消安(Busulfan)、卡巴他赛(Cabazitaxel)、卡培他滨(Capecitabine)、卡铂(Carboplatin)、卡非佐米(Carfilzomib)、卡莫司汀(Carmustine)、色瑞替尼(Ceritinib)、氯法拉滨(Clofarabine)、克唑替尼(Crizotinib)、达卡巴嗪(Dacarbazine)、放线菌素D(Dactinomycin)、达沙替尼(Dasatinib)、地加瑞克(Degarelix)、地尼白介素(Denileukin)、地诺单抗(Denosumab)、恩杂鲁胺(Enzalutamide)、艾日布林(Eribulin)、埃罗替尼(Erlotinib)、依维莫司(Everolimus)、依西美坦(Exemestane)、依西美坦、氟达拉滨(Fludarabine)、氟维司群(Fulvestrant)、吉非替尼(Gefitinib)、戈舍瑞林(Goserelin)、替伊莫单抗(Ibritumomab)、伊马替尼(Imatinib)、伊匹单抗(Ipilimumab)、伊立替康(Irinotecan)、伊沙匹隆(Ixabepilone)、拉帕替尼(Lapatinib)、来那度胺(Lenalidomide)、来曲唑(Letrozole)、甲酰四氢叶酸(Leucovorin)、亮丙瑞林(Leuprolide)、洛莫司汀(Lomustine)、二氯甲基二乙胺(Mechlorethamine)、甲地孕酮(Megestrol)、奈拉滨(Nelarabine)、尼罗替尼(Nilotinib)、纳武单抗(Nivolumab)、奥拉帕尼(Olaparib)、奥马西他辛(Omacetaxine)、帕博西尼(Palbociclib)、帕米膦酸盐(Pamidronate)、帕尼单抗、帕比司他(Panobinostat)、帕唑帕尼(Pazopanib)、培门冬酶(Pegaspargase)、派姆单抗(Pembrolizumab)、培美曲塞二钠(Pemetrexed Disodium)、帕妥珠单抗(Pertuzumab)、普乐沙福(Plerixafor)、泊马度胺(Pomalidomide)、普纳替尼(Ponatinib)、普拉曲沙(Pralatrexate)、丙卡巴肼(Procarbazine)、镭223、雷莫芦单抗(Ramucirumab)、瑞格非尼(Regorafenib)、rIFNa-2b、罗米地辛(Romidepsin)、舒尼替尼(Sunitinib)、替莫唑胺(Temozolomide)、替西罗莫司(Temsirolimus)、噻替派(Thiotepa)、托西莫单抗(Tositumomab)、曲美替尼(Trametinib)、长春瑞宾(Vinorelbine)、甲氨喋呤(Methotrexate)、依鲁替尼(Ibrutinib)、阿柏西普(Aflibercept)、托瑞米芬(Toremifene)、长春花碱(Vinblastine)、长春新碱(Vincristine)、艾代拉利司(Idelalisib)、巯基嘌呤及沙利度胺(Thalidomide),可能在与CD-47-SIRPα阻断剂组合时对‘吃我’信号通路具有影响。
除上述治疗剂以外,癌症疗法中使用的其它治疗方式也能激活促吞噬受体,因此可与CD47-SIRPα阻断剂组合,以实现高效吞噬。这些治疗方式包括基于金丝桃素的光动力疗法(Hyp-PDT)、放射疗法、高静压、基于光卟啉的PDT和基于乙酸孟加拉玫瑰酯的PDT。
然而,将小分子CD-47-SIRPα通路抑制剂与能够刺激活化受体诸如Fc受体(FcR)或其它促吞噬受体的剂组合,或与癌症疗法中用于激活促吞噬受体的其它治疗方式组合,以发挥CD-47-SIRPα通路阻断的最大潜力,这种需求尚未得到满足。
发明内容
本发明提供了一种组合物,其包含小分子CD-47-SIRPα通路抑制剂与刺激活化受体诸如Fc受体(FcR)或其它促吞噬受体的剂,或与癌症疗法中用于激活促吞噬受体的其它治疗方式组合,以发挥CD-47-SIRPα通路阻断的最大潜力。
在本发明的一个方面,本文提供了一种包含CD47-SIRPα阻断剂和一种或多种抗癌剂的组合物,其中所述CD-47-SIRPα阻断剂是由式(I)的化合物表示的小分子:
或其药学上可接受的盐或酰胺或酯或其立体异构体;其中,
Ra为氢;并且R1表示氢、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)3NHC(=NH)NH2、-(CH2)4NH2、-CH2CONH2、-CH2-芳基或-CH2-杂芳基;或者Ra和R1与它们所连接的原子一起形成吡咯烷环;
R2表示氢、-(CH2)3NHC(=NH)NH2、-(CH2)2CONH2、-(CH2)2COOH、-CH2-芳基或-CH2-杂芳基;
Rb为氢;并且R3表示氢、-CH2-芳基、-(CH2)3NHC(=NH)NH2、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)4NH2或-CH2-杂芳基;或者Rb和R3与它们所连接的原子一起形成吡咯烷环。
在另一个方面,本发明涉及用于治疗呈现CD47通路失调的受试者的方法,其包括向有需要的受试者施用治疗有效量的式(I)的化合物,或其药学上可接受的盐或酰胺或酯,或立体异构体与一种或多种抗癌剂的组合。
本发明的又一个方面提供了一种治疗由CD47介导的疾病或病症的方法,其包括施用式(I)的化合物或其药学上可接受的盐或酰胺或酯,或其立体异构体与一种或多种抗癌剂的组合。
在本发明的另一个方面,本文提供了一种包含CD47-SIRPα阻断剂和一种或多种抗癌剂的组合,其中小分子CD-47-SIRPα阻断剂由式(I)的化合物表示:
或其药学上可接受的盐或酰胺或酯或其立体异构体;其中,
Ra为氢;并且R1表示氢、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)3NHC(=NH)NH2、-(CH2)4NH2、-CH2CONH2、-CH2-芳基或-CH2-杂芳基;或者Ra和R1与它们所连接的原子一起形成吡咯烷环;
R2表示氢、-(CH2)3NHC(=NH)NH2、-(CH2)2CONH2、-(CH2)2COOH、-CH2-芳基或-CH2-杂芳基;
Rb为氢;并且R3表示氢、-CH2-芳基、-(CH2)3NHC(=NH)NH2、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)4NH2或-CH2-杂芳基;或者Rb和R3与它们所连接的原子一起形成吡咯烷环。
附图简述
图1:化合物3和化合物6与抗CD20抗体组合增强淋巴瘤细胞的吞噬作用
图2:化合物3和化合物6与硼替佐米组合增强多发性骨髓瘤细胞的吞噬作用
图3:化合物6单独或与抗小鼠PD-L1抗体组合对A20肿瘤携带小鼠的抗肿瘤功效
具体实施方式
每个实施方案均以解释本发明,而非限制本发明的方式提供。事实上,所属领域的技术人员容易了解,在不脱离本发明的范围或精神的前提下,可以对本文所述的化合物、组合物和方法做出不同修改和变化。例如,作为一个实施方案的一部分进行说明或描述的特征可应用于另一个实施方案,从而得到再一个实施方案。因此,意图是本发明包括此类修改和变化及其等同形式。本发明的其它目的、特征和方面在以下详细描述中公开或从以下详细描述中显而易见。本领域普通技术人员将理解,本论述仅仅是示范性实施方案的描述,并且不应被解释为限制本发明的较广泛方面。
在某些实施方案中,本发明提供了一种包含CD47-SIRPα阻断剂和一种或多种抗癌剂的组合物:其中所述CD47-SIRPα阻断剂由式(I)的化合物表示:
或其药学上可接受的盐或酰胺或酯或其立体异构体;其中,
Ra为氢;并且R1表示氢、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)3NHC(=NH)NH2、-(CH2)4NH2、-CH2CONH2、-CH2-芳基或-CH2-杂芳基;或者Ra和R1与它们所连接的原子一起形成吡咯烷环;
R2表示氢、-(CH2)3NHC(=NH)NH2、-(CH2)2CONH2、-(CH2)2COOH、-CH2-芳基或-CH2-杂芳基;
Rb为氢;并且R3表示氢、-CH2-芳基、-(CH2)3NHC(=NH)NH2、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)4NH2或-CH2-杂芳基;或者Rb和R3与它们所连接的原子一起形成吡咯烷环。
在某些实施方案中,抗癌剂是化学治疗剂或免疫调节剂。
在某些实施方案中,与CD47-SIRPα阻断剂一起使用的感兴趣的特定组合伴侣包括靶向肿瘤抗原的治疗性抗体,所述肿瘤抗原刺激活化Fc受体(FcR),从而产生高效的吞噬作用。在某些实施方案中,感兴趣的特定组合伴侣包括刺激Fc受体介导的吞噬作用的治疗性抗体。因此,选自由能够触发高效吞噬作用的剂组成的组的抗体包括抗CD20,例如利妥昔单抗、泰泽坦(tiuxetan)、托西莫单抗(tositumomab)等,其组合特别适用于治疗非霍奇金B细胞淋巴瘤和慢性淋巴细胞性白血病(CLL)。与抗CD22,例如依帕珠单抗(Epratuzumab)等的组合特别适用于治疗B细胞白血病和毛细胞白血病。与抗CD52,例如阿仑单抗等的组合特别适用于治疗B细胞和T细胞白血病,包括但不限于慢性淋巴细胞性白血病。与抗CD33,例如吉妥珠单抗奥佐米星(gemtuzumab ozogomicin)等的组合特别适用于治疗骨髓性白血病,诸如急性骨髓性白血病。与曲妥珠单抗的组合特别适用于治疗乳腺癌。与贝伐单抗的组合特别适用于治疗某些类型的脑肿瘤以及某些类型的肾癌、肺癌、结肠癌、直肠癌、子宫颈癌、卵巢癌或输卵管癌。与西妥昔单抗的组合特别适用于治疗结肠癌和头颈癌。与帕尼单抗的组合特别适用于治疗结直肠癌。与达雷木单抗的组合特别适用于治疗多发性骨髓瘤。用于治疗骨髓性白血病的其它感兴趣的组合包括但不限于抗CD96、抗CD44和抗CD123。
在某些优选实施方案中,Fc受体(FcR)包含Fcγ受体(FcγR)。
其它与CD47-SIRPα阻断剂组合的感兴趣的治疗性抗体包括但不限于用于慢性淋巴细胞性白血病的奥法木单抗(ofatumumab)、用于滤泡性淋巴瘤的奥比妥珠单抗(obinutuzumab)、用于B细胞慢性淋巴细胞性白血病的阿仑单抗、用于B细胞非霍奇金淋巴瘤的替伊莫单抗(Ibritumomab tiuxetan)、用于神经母细胞瘤的迪努妥昔单抗(dinutuximab)和用于肺癌的耐昔妥珠单抗(necitumumab)。
在某些实施方案中,抗癌剂是抗CD20抗体,诸如利妥昔单抗、泰泽坦、托西莫单抗。
在某些实施方案中,已知激活促吞噬受体的治疗剂也因此是与CD47-SIRPα阻断剂组合使用以实现高效吞噬的理想伴侣。这些剂包括蛋白酶体抑制剂(硼替佐米、伊沙佐米和卡非佐米)、蒽环类药物(多柔比星、表柔比星、柔红霉素、伊达比星、米托蒽醌)奥沙利铂、环磷酰胺、博莱霉素、伏立诺他、紫杉醇、5-氟尿嘧啶、阿糖胞苷、BRAF抑制性药物(达拉非尼、维罗非尼)、PI3K抑制剂、多西他赛、丝裂霉素C、索拉非尼和他莫昔芬;或其组合。
在某些实施方案中,抗癌剂是蛋白酶体抑制剂。
在某些实施方案中,抗癌剂是硼替佐米、伊沙佐米或卡非佐米或其类似物或其衍生物。
在某些实施方案中,除了已知对‘吃我’信号有影响的特定剂外,其它剂,包括乙酸阿比特龙、阿法替尼、阿地白介素、阿地白介素、阿仑单抗、阿那曲唑、阿西替尼、贝利司他、苯达莫司汀、比卡鲁胺、博纳吐单抗、伯舒替尼、本妥昔单抗、白消安、卡巴他赛、卡培他滨、卡铂、卡非佐米、卡莫司汀、色瑞替尼、氯法拉滨、克唑替尼、达卡巴嗪、放线菌素D、达沙替尼、地加瑞克、地尼白介素、地诺单抗、恩杂鲁胺、艾日布林、埃罗替尼、依维莫司、依西美坦、依西美坦、氟达拉滨、氟维司群、吉非替尼、戈舍瑞林、替伊莫单抗、伊马替尼、伊匹单抗、伊立替康、伊沙匹隆、拉帕替尼、来那度胺、来曲唑、甲酰四氢叶酸、亮丙瑞林、洛莫司汀、二氯甲基二乙胺、甲地孕酮、奈拉滨、尼罗替尼、纳武单抗、奥拉帕尼、奥马西他辛、帕博西尼、帕米膦酸盐、帕尼单抗、帕比司他、帕唑帕尼、培门冬酶、派姆单抗、培美曲塞二钠、帕妥珠单抗、普乐沙福、泊马度胺、普纳替尼、普拉曲沙、丙卡巴肼、镭223、雷莫芦单抗、瑞格非尼、rIFNa-2b、罗米地辛、舒尼替尼、替莫唑胺、替西罗莫司、噻替派、托西莫单抗、曲美替尼、长春瑞宾、甲氨喋呤、依鲁替尼、阿柏西普、托瑞米芬、长春花碱、长春新碱、艾代拉利司、巯基嘌呤和沙利度胺,可能在与CD-47-SIRPα阻断剂组合时对‘吃我’信号通路具有影响。
在其它实施方案中,除上述治疗剂以外,癌症疗法中使用的其它治疗方式也能激活促吞噬受体,因此可与CD47-SIRPα阻断剂组合,以实现高效吞噬。这些治疗方式包括基于金丝桃素的光动力疗法(Hyp-PDT)、放射疗法、高静压、基于光卟啉的PDT和基于乙酸孟加拉玫瑰酯的PDT。
在某些实施方案中,化学治疗剂是阿巴瑞克斯(abarelix)、阿地白介素、阿利维甲酸(alitretinoin)、别嘌呤醇(allopurinol)、六甲蜜胺(altretamine)、三氧化二砷、天冬酰胺酶、阿扎胞苷(azacitidine)、贝沙罗汀(bexarotene)、巴瑞替尼(baricitinib)、硼替佐米、静脉内白消安、口服白消安、二甲睾酮(calusterone)、西妥昔单抗、苯丁酸氮芥(chlorambucil)、顺铂(cisplatin)、克拉屈滨(cladribine)、达肝素钠(dalteparinsodium)、地西他滨(decitabine)、地氟妥昔(diftitox)、双硫仑(disulfiram)、右雷佐生(dexrazoxane)、丙酸屈他雄酮(dromostanolone propionate)、依库珠单抗(eculizumab)、雌莫司汀(estramustine)、磷酸依托泊苷(etoposide phosphate)、依托泊苷(etoposide)、柠檬酸芬太尼(fentanyl citrate)、非格司亭(filgrastim)、氟尿苷(floxuridine)、吉西他滨(gemcitabine)、乙酸组氨瑞林(histrelin acetate)、环磷酰胺(fosfamide)、干扰素α2a、二甲苯磺酸拉帕替尼(lapatinib ditosylate)、左旋咪唑(levamisole)、马瑞佐米(marizomib)、氮芥(meclorethamine)、美法仑(melphalan)、巯基嘌呤、甲氨喋呤(methotrexate)、甲氧沙林(methoxsalen)、米托坦(mitotane)、苯丙酸诺龙(nandrolonephenpropionate)、诺非单抗(nofetumomab)、奥普佐米(oprozomib)、培非格司亭(pegfilgrastim)、喷司他汀(pentostatin)、哌泊溴烷(pipobroman)、普卡霉素(plicamycin)、丙卡巴肼、奎纳克林(quinacrine)、拉布立酶(rasburicase)、芦可替尼(ruxolitinib)、卢卡帕尼(rucaparib)、链佐星(streptozocin)、替尼泊苷(teniposide)、睾内酯(testolactone)、沙利度胺、硫鸟嘌呤、拓扑替康(topotecan)、托瑞米芬(toremifene)、维甲酸(tretinoin)、尿嘧啶氮芥(uracil mustard)、戊柔比星(valrubicin)、长春花碱、长春新碱、尼拉帕尼(niraparib)、维利帕尼(veliparib)、他拉唑帕尼(talazoparib)或唑来膦酸盐(zoledronate)。
在某些实施方案中,抗癌剂为免疫调节剂。在进一步的实施方案中,免疫调节剂是共刺激或共抑制分子,诸如CTLA-4(例如伊匹单抗)、4-1BB(例如乌瑞鲁单抗(urelumab)和乌托米单抗(utomilumab))、PD-1和PD-L1的抗体(例如纳武单抗、派姆单抗、阿特珠单抗(atezolizumab)、度伐鲁单抗(Durvalumab)和卡瑞利珠单抗(Camrelizumab))、细胞因子抗体(IL-10、TGF-β)、TIM-3抗体、LAG3抗体、B7H3抗体、B7H4抗体和B7H6抗体;或其组合。
在本发明的一些实施方案中,施用两种或更多种由式(I)的化合物表示的CD47-SIRPα阻断剂。在一些实施方案中,施用CD47-SIRPα阻断剂一次以上。
在某些实施方案中,CD47-SIRPα阻断剂是阻断CD47和SIRPα之间的相互作用的剂。在某些实施方案中,阻断CD47和SIRPα之间的相互作用诱导巨噬细胞吞噬表达CD47的肿瘤细胞。
在某些实施方案中,本发明提供了一种组合物,其包含如式(I)的化合物中所述的小分子CD47-SIRPα阻断剂和蛋白酶体抑制剂。在某些实施方案中,蛋白酶体抑制剂是硼替佐米、伊沙佐米或卡非佐米或其任何类似物或其衍生物。
在某些实施方案中,本发明的组合物包含式(I)的化合物,其中R1为氢、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)3NHC(=NH)NH2、-(CH2)4NH2、-CH2-苯基或-CH2-咪唑基。
在某些实施方案中,本发明的组合物包含式(I)的化合物,其中R1为-(CH2)2CONH2、-(CH2)2COOH、-(CH2)3NHC(=NH)NH2或-(CH2)4NH2。
在某些实施方案中,本发明的组合物包含式(I)的化合物,其中R1为-(CH2)2CONH2或-(CH2)2COOH。
在某些实施方案中,本发明的组合物包含式(I)的化合物,其中R2表示氢、-(CH2)3NHC(=NH)NH2、-(CH2)2CONH2、-(CH2)2COOH、-CH2-苯基或-CH2-咪唑基。
在某些实施方案中,本发明的组合物包含式(I)的化合物,其中R2为氢、-(CH2)3NHC(=NH)NH2或-(CH2)2COOH。
在某些实施方案中,本发明的组合物包含式(I)的化合物,其中R2为氢、-(CH2)2CONH2或-(CH2)2COOH。
在某些实施方案中,本发明的组合物包含式(I)的化合物,其中R3表示氢、-CH2-苯基、-(CH2)3NHC(=NH)NH2、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)4NH2或-CH2-咪唑基。
在某些实施方案中,本发明的组合物包含式(I)的化合物,其中R3表示氢、-CH2-苯基、-(CH2)3NHC(=NH)NH2、-(CH2)2CONH2、-(CH2)2COOH或-(CH2)4NH2。
在某些实施方案中,本发明的组合物包含式(I)的化合物,其中Ra为氢;并且R1表示氢、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)3NHC(=NH)NH2、-(CH2)4NH2、-CH2CONH2、-CH2-苯基或-CH2-咪唑基;或者Ra和R1与它们所连接的原子一起形成吡咯烷环;
R2表示氢、-(CH2)3NHC(=NH)NH2、-(CH2)2CONH2、-(CH2)2COOH、-CH2-苯基或-CH2-咪唑基;
Rb为氢;并且R3表示氢、-CH2-苯基、-(CH2)3NHC(=NH)NH2、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)4NH2或-CH2-咪唑基;或者Rb和R3与它们所连接的原子一起形成吡咯烷环。
在某些实施方案中,本发明的组合物包含式(I)的化合物,其为式(IA)的化合物:
或其药学上可接受的盐或酰胺或酯或其立体异构体;其中R1,、Ra和R2如式(I)的化合物所定义。
在某些实施方案中,本发明的组合物包含式(IA)的化合物,其中R1表示氢、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)3NHC(=NH)NH2、-(CH2)4NH2、-CH2-苯基或-CH2-咪唑基。
在某些实施方案中,本发明的组合物包含式(IA)的化合物,其中R2表示氢、-(CH2)3NHC(=NH)NH2、-(CH2)2CONH2、-(CH2)2COOH、-CH2-苯基或-CH2-咪唑基。
在某些实施方案中,本发明的组合物包含式(IA)的化合物,其中Ra为氢;并且R1表示氢、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)3NHC(=NH)NH2、-(CH2)4NH2、-CH2-苯基或-CH2-咪唑基;R2表示氢、-(CH2)3NHC(=NH)NH2、-(CH2)2CONH2、-(CH2)2COOH、-CH2-苯基或-CH2-咪唑基。
在另一个实施方案中,本发明的组合物包含式(IA)的化合物:其中Ra为氢;并且R1表示-(CH2)2CONH2、-(CH2)2COOH、-(CH2)3NHC(=NH)NH2或-(CH2)4NH2。R2表示氢、-(CH2)3NHC(=NH)NH2、-(CH2)2COOH、-CH2-苯基或-CH2-咪唑基。
在某些实施方案中,本发明的组合物包含式(I)的化合物,其选自,
或其药学上可接受的盐或酰胺或酯或其立体异构体。
在某些实施方案中,本发明的组合物包含式(I)的化合物,其选自,
或其药学上可接受的盐或酰胺或酯或其立体异构体。
在某些实施方案中,本发明的组合物包含式(IA)的化合物,其也可以通过显示其绝对立体化学来书写,如
在某些实施方案中,本发明的组合物包含式(I)的化合物,其为式(IB)的化合物:
或其药学上可接受的盐或酰胺或酯或其立体异构体;其中R1、Ra、Rb和R3如式(I)的化合物所定义。
在某些实施方案中,本发明的组合物包含其中R1表示氢、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)3NHC(=NH)NH2、-(CH2)4NH2或-CH2-苯基的化合物。
在某些实施方案中,本发明的组合物包含其中R1为-(CH2)2CONH2或-(CH2)2COOH的化合物。
在某些实施方案中,本发明的组合物包含其中R3为氢、-CH2-苯基、-(CH2)2CONH2或-(CH2)2COOH的化合物。
在某些实施方案中,本发明的组合物包含其中R3为氢或-CH2-苯基的化合物。
在某些实施方案中,本发明的组合物包含式(IB)的化合物,其中Rb为氢。
在某些实施方案中,在式(IB)中,Rb和R3与它们所连接的原子一起形成吡咯烷环。
在某些实施方案中,本发明的组合物包含式(IB)的化合物,其中R1表示-(CH2)2CONH2或-(CH2)2COOH;Rb为氢;并且R3表示氢或-CH2-苯基;或者Rb和R3与它们所连接的原子一起形成吡咯烷环。
在某些实施方案中,本发明的组合物包含式(I)的化合物,其中所述化合物选自,
或其药学上可接受的盐或酰胺或酯或其立体异构体。
在某些实施方案中,本发明的组合物包含式(I)的化合物,其为式(IC)的化合物:
或其药学上可接受的盐或酰胺或酯或其立体异构体;其中R1、Ra、R3和Rb如式(I)的化合物所定义。
在某些实施方案中,本发明的组合物包含其中R1为-(CH2)2CONH2、-(CH2)3NHC(=NH)NH2或-(CH2)4NH2的化合物。
在某些实施方案中,本发明的组合物包含其中R1为-(CH2)2CONH2或-(CH2)3NHC(=NH)NH2的化合物。
在某些实施方案中,本发明的组合物包含式(IC)的化合物,其中Ra为氢。在某些实施方案中,在式(IC)中,Ra和R1与它们所连接的原子一起形成吡咯烷环。
在某些实施方案中,本发明的组合物包含其中R3为氢、-CH2-苯基、-(CH2)3NHC(=NH)NH2或-CH2-咪唑基的化合物。
在某些实施方案中,本发明的组合物包含式(IC)的化合物,其中Rb为氢。
在某些实施方案中,在式(IC)中,Rb和R3与它们所连接的原子一起形成吡咯烷环。
在另一个实施方案中,本发明的组合物包含式(IC)的化合物:其中Ra为氢;并且R1表示-(CH2)2CONH2、-(CH2)3NHC(=NH)NH2或-(CH2)4NH2;或者Ra和R1与它们所连接的原子一起形成吡咯烷环;并且Rb为氢;并且R3表示-CH2-苯基、-(CH2)3NHC(=NH)NH2或-CH2-咪唑基;或者Rb和R3与它们所连接的原子一起形成吡咯烷环。
在某些实施方案中,本发明的组合物包含式(I)的化合物,其中所述化合物选自,
或其药学上可接受的盐或酰胺或酯或其立体异构体。
在某些实施方案中,本发明的组合物包含式(I)的化合物,其为式(ID)的化合物:
或其药学上可接受的盐或酰胺或酯或其立体异构体;其中R1、Ra、R3和Rb如式(I)的化合物所定义。
在某些实施方案中,本发明的组合物包含其中R1为-(CH2)3NHC(=NH)NH2、-(CH2)4NH2或-CH2CONH2的化合物。
在某些实施方案中,本发明的组合物包含其中R3为氢、-(CH2)3NHC(=NH)NH2或-(CH2)4NH2的化合物。
在某些实施方案中,本发明的组合物包含式(ID)的化合物,其中Rb为氢。
在某些实施方案中,在式(ID)中,Rb和R3与它们所连接的原子一起形成吡咯烷环。
在另一个实施方案中,本发明的组合物包含式(ID)的化合物:其中R1表示-(CH2)3NHC(=NH)NH2、-(CH2)4NH2或-CH2CONH2;Rb为氢;并且R3表示氢、-(CH2)3NHC(=NH)NH2或-(CH2)4NH2;或者Rb和R3与它们所连接的原子一起形成吡咯烷环。
在某些实施方案中,本发明的组合物包含式(I)的化合物,其中所述化合物选自,
或其药学上可接受的盐或酰胺或酯或其立体异构体。在某些实施方案中,本发明的组合物包含式(I)的化合物,其为式(IE)的化合物:
或其药学上可接受的盐或酰胺或酯或其立体异构体;其中R2、R3和Rb如式(I)的化合物所定义。
在某些实施方案中,本发明的组合物包含其中R2为氢或-(CH2)3NHC(=NH)NH2的化合物。
在某些实施方案中,本发明的组合物包含式(IE)的化合物,其中Rb和R3与它们所连接的原子一起形成吡咯烷环。
在另一个实施方案中,本发明的组合物包含式(IE)的化合物:其中R2表示氢或-(CH2)3NHC(=NH)NH2;Rb和R3与它们所连接的原子一起形成吡咯烷环。在某些实施方案中,本发明的组合物包含式(I)的化合物,其为式(IF)的化合物:
或其药学上可接受的盐或酰胺或酯或其立体异构体;其中R2、R3和Rb如式(I)的化合物所定义。
在某些实施方案中,本发明的组合物包含其中R2为氢、-CH2-苯基、-(CH2)3NHC(=NH)NH2或-(CH2)2COOH的化合物。
在某些实施方案中,本发明的组合物包含其中R3为-CH2-苯基、-(CH2)2CONH2或-(CH2)2COOH的化合物。
在某些实施方案中,本发明的组合物包含式(IF)的化合物,其中Rb为氢。
在某些实施方案中,在式(IF)中,Rb和R3与它们所连接的原子一起形成吡咯烷环。
在特定实施方案中,本发明的组合物包含式(IF)的化合物:其中R2表示氢、-CH2-苯基、-(CH2)3NHC(=NH)NH2或-(CH2)2COOH;Rb为氢;并且R3表示-CH2-苯基、-(CH2)2CONH2或-(CH2)2COOH;或者Rb和R3与它们所连接的原子一起形成吡咯烷环。
在某些实施方案中,本发明的组合物包含式(I)的化合物,其中所述化合物选自,
或其药学上可接受的盐或酰胺或酯或其立体异构体。
在某些实施方案中,本发明的组合物包含一种化合物,其中所述化合物选自:
或其药学上可接受的盐或酰胺或酯或其立体异构体。
在某些实施方案中,本发明涉及包含CD47-SIRPα阻断剂和一种或多种抗癌剂的组合物,其用作药物,其中所述CD47-SIRPα阻断剂是式(I)的化合物或其药学上可接受的盐或酰胺或酯,或其立体异构体,如本文所述;所述抗癌剂是化学治疗剂或免疫调节剂,如本文所述。
在某些实施方案中,本发明涉及包含CD47-SIRPα阻断剂和一种或多种抗癌剂以及药学上可接受的载体的组合物,其中所述CD47-SIRPα阻断剂是式(I)的化合物或其药学上可接受的盐或酰胺或酯,或其立体异构体,如本文所述;所述抗癌剂是化学治疗剂或免疫调节剂,如本文所述。
在某些实施方案中,本发明提供了一种包含CD47-SIRPα阻断剂和一种或多种抗癌剂的组合:其中所述CD47-SIRPα阻断剂由式(I)的化合物表示:
或其药学上可接受的盐或酰胺或酯或其立体异构体;其中,
Ra为氢;并且R1表示氢、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)3NHC(=NH)NH2、-(CH2)4NH2、-CH2CONH2、-CH2-芳基或-CH2-杂芳基;或者Ra和R1与它们所连接的原子一起形成吡咯烷环;
R2表示氢、-(CH2)3NHC(=NH)NH2、-(CH2)2CONH2、-(CH2)2COOH、-CH2-芳基或-CH2-杂芳基;
Rb为氢;并且R3表示氢、-CH2-芳基、-(CH2)3NHC(=NH)NH2、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)4NH2或-CH2-杂芳基;或者Rb和R3与它们所连接的原子一起形成吡咯烷环。
在某些实施方案中,本发明的组合包含式(I)的化合物的CD47-SIRPα阻断剂和蛋白酶体抑制剂。
在某些实施方案中,本发明的组合包含式(I)的化合物的CD47-SIRPα阻断剂和抗CD-20抗体。
在某些实施方案中,本发明的组合包含式(IA)、(IB)、(IC)、(ID)、(IE)或(IF)的化合物的CD47-SIRPα阻断剂。
在某些实施方案中,本发明涉及一种治疗呈现CD47通路失调的受试者的癌症的方法,所述方法包括向所述受试者施用治疗有效量的CD47-SIRPα阻断剂与治疗有效量的一种或多种抗癌剂的组合:其中所述CD47-SIRPα阻断剂由式(I)的化合物表示:
或其药学上可接受的盐或酰胺或酯;或其立体异构体;
其中,
Ra为氢;并且R1表示氢、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)3NHC(=NH)NH2、-(CH2)4NH2、-CH2CONH2、-CH2-芳基或-CH2-杂芳基;或者Ra和R1与它们所连接的原子一起形成吡咯烷环;R2表示氢、-(CH2)3NHC(=NH)NH2、-(CH2)2CONH2、-(CH2)2COOH、-CH2-芳基或-CH2-杂芳基;Rb为氢;并且R3表示氢、-CH2-芳基、-(CH2)3NHC(=NH)NH2、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)4NH2或-CH2-杂芳基;或者Rb和R3与它们所连接的原子一起形成吡咯烷环。
在某些实施方案中,呈现CD47通路失调的受试者是呈现CD47+疾病细胞的受试者。在某些实施方案中,CD47+疾病细胞是CD47+癌细胞。
在某些实施方案中,本发明涉及一种方法,其中用一种或多种抗癌剂治疗是在用式(I)的化合物或其药学上可接受的盐治疗之前、同时或之后。
在某些实施方案中,本发明涉及一种用于治疗受试者中由CD47通路介导的疾病或病症或延缓所述疾病或病症的进展的方法,所述方法包括向有需要的受试者施用治疗有效量的阻断CD47-SIRPα通路的剂与治疗有效量的一种或多种抗癌剂的组合:其中所述阻断CD47-SIRPα通路的剂由式(I)的化合物表示:
或其药学上可接受的盐或酰胺或酯;或其立体异构体;
其中,
Ra为氢;并且R1表示氢、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)3NHC(=NH)NH2、-(CH2)4NH2、-CH2CONH2、-CH2-芳基或-CH2-杂芳基;或者Ra和R1与它们所连接的原子一起形成吡咯烷环;R2表示氢、-(CH2)3NHC(=NH)NH2、-(CH2)2CONH2、-(CH2)2COOH、-CH2-芳基或-CH2-杂芳基;Rb为氢;并且R3表示氢、-CH2-芳基、-(CH2)3NHC(=NH)NH2、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)4NH2或-CH2-杂芳基;或者Rb和R3与它们所连接的原子一起形成吡咯烷环。
在某些实施方案中,本发明涉及一种方法,其中由CD47-SIRPα通路介导的疾病或病症是癌症。
在某些实施方案中,本发明涉及一种方法,其中由CD47通路介导的疾病或病症是动脉粥样硬化。
在某些实施方案中,本发明涉及一种方法,其中由CD47通路介导的疾病或病症是多发性硬化症。
在某些实施方案中,本发明提供了一种药物组合物,其包含如本文所公开的化合物,任选地与药学上可接受的载体或稀释剂混合。
在某些实施方案中,本发明提供了如本文所述的包含CD47-SIRPα阻断剂和一种或多种抗癌剂的组合物在制造用于治疗呈现CD47通路失调的受试者的癌症的药物中的用途。
在某些实施方案中,本发明提供了一种试剂盒,其包含如本文所述的组合物和包装插页,所述包装插页包含用于治疗呈现CD47通路失调的受试者的药物施用说明。
本发明还提供了用于配制所公开的用于药物施用的化合物的方法。
本发明的组合物和方法可用于治疗有需要的个体。在某些实施方案中,个体为哺乳动物,诸如人或非人哺乳动物。当施用于动物诸如人时,所述化合物优选以药物组合物的形式施用,所述药物组合物包含例如本发明化合物和药学上可接受的载体。在一个优选实施方案中,当此类药物组合物用于人施用时,特别是用于侵入性施用途径(即规避通过上皮屏障运输或扩散的途径,诸如注射或植入)时,水溶液为无热原的或基本上无热原的。可以选择赋形剂,例如以实现剂的延迟释放或选择性靶向一种或多种细胞、组织或器官。药物组合物可以呈剂量单位形式,诸如片剂、胶囊剂(包括洒胶囊剂和明胶胶囊剂)、颗粒剂、用于重构的冻干剂、散剂、溶液剂、糖浆剂、栓剂、注射剂等。所述组合物也可以存在于透皮递送系统中,例如皮肤贴剂。所述组合物也可以存在于适合局部施用的溶液中,诸如滴眼剂。
药学上可接受的载体可以含有生理上可接受的剂,其起到例如稳定、增加溶解度或增加化合物的吸收的作用。此类生理上可接受的剂包括例如碳水化合物,诸如葡萄糖、蔗糖或葡聚糖;抗氧化剂,诸如抗坏血酸或谷胱甘肽;螯合剂;低分子量蛋白质或其它稳定剂或赋形剂。药学上可接受的载体(包括生理上可接受的剂)的选择取决于(例如)组合物的施用途径。药物组合物的制备可以是自乳化药物递送系统或自微乳化药物递送系统。药物组合物(制备剂)也可以是脂质体或其它聚合物基质,其中可以掺入例如本发明的化合物。脂质体,例如包含磷脂或其它脂质的脂质体,可以是制造和施用相对简单的无毒的、生理上可接受的和可代谢的载体。
组合物中的剂是同时施用的,即每种剂在约45天、30天、15天、7天、3天、2天、1天内施用,或相对于组合物中的其它剂基本上同时施用。如果施用时间安排使两种剂的血清水平达到治疗水平,则可认为所述剂是组合使用的。
在某些实施方案中,对于施用,CD47-SIRPα阻断剂和抗癌剂组合的每个剂量将在宿主体重的约0.0001至100mg/kg,更通常是0.01至50mg/kg的范围内。例如剂量可以是1mg/kg体重、10mg/kg体重或30mg/kg体重,或在1-50mg/kg的范围内。剂量可以根据所述CD47-SIRPα阻断剂或抗癌剂的分子量进行调整,并且可以相对于组合中任一剂的单药治疗所需的剂量而降低。示例性治疗方案需要每天、每半周、每周、每两周一次、每月一次等施用。
本文采用短语“药学上可接受的”指在合理医学判断范围内、适用于与人类和动物组织接触而没有过量毒性、刺激、过敏反应或其它问题或并发症、与合理的利益/风险比相称的那些化合物、材料、组合物和/或剂型。
如本文所用,短语“药学上可接受的载体”意指药学上可接受的材料、组合物或媒介物,诸如液体或固体填充剂、稀释剂、赋形剂、溶剂或封装材料。在与制剂的其它成分相容并且对患者无害的意义上,每种载体必须是“可接受的”。可以充当药学上可接受的载体的材料的一些实例包括:(1)糖,诸如乳糖、葡萄糖以及蔗糖;(2)淀粉,诸如玉米淀粉和马铃薯淀粉;(3)纤维素及其衍生物,诸如羧甲基纤维素钠、乙基纤维素以及乙酸纤维素;(4)黄芪胶粉;(5)麦芽;(6)明胶;(7)滑石;(8)赋形剂,诸如可可脂和栓剂蜡;(9)油,诸如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油以及大豆油;(10)二醇,诸如丙二醇;(11)多元醇,诸如甘油、山梨醇、甘露醇以及聚乙二醇;(12)酯,诸如油酸乙酯和月桂酸乙酯;(13)琼脂;(14)缓冲剂,诸如氢氧化镁和氢氧化铝;(15)褐藻酸;(16)无热原水;(17)等渗盐水;(18)林格氏溶液;(19)乙醇;(20)磷酸盐缓冲溶液;以及(21)药物组合物中采用的其它无毒相容性物质。
药物组合物(制备剂)可通过多种施用途径中的任一种施用于受试者,所述途径包括例如口服途径(例如,以水性溶液或非水性溶液或混悬液的形式的药水、片剂、胶囊剂(包括洒胶囊剂和明胶胶囊剂)、大丸剂、散剂、颗粒剂、涂敷于舌头的糊剂);通过口腔粘膜吸收途径(例如,舌下);肛门、直肠或阴道途径(例如作为阴道栓剂、乳霜或泡沫);肠胃外途径(包括肌肉内、静脉内、皮下或鞘内,例如作为无菌溶液或混悬剂);鼻腔途径;腹膜内途径;皮下途径;透皮途径(例如作为贴在皮肤上的贴剂);以及局部途径(例如,作为涂敷于皮肤上的乳霜、药膏或喷雾剂或作为滴眼剂)。所述化合物还可以被配制成用于吸入。在某些实施方案中,化合物可以简单地溶解或混悬于无菌水中。
制剂可方便地以单位剂型存在并且可通过药学领域中熟知的任何方法来制备。组合物中可与载体材料组合以产生单一剂型的每种活性成分的量将根据所治疗的宿主、特定施用方式而变化。组合物中可与载体材料组合以产生单一剂型的每种活性成分的量一般将是产生治疗效果的化合物的量。一般来说,在百分之一百中,此量将在每种活性成分的约1%至约99%之间,优选约5%至约70%,最优选约10%至约30%。
制备这些制剂或组合物的方法包括使本发明的组合物与载体和任选的一种或多种辅助成分结合的步骤。一般来说,通过将本发明的化合物与液体载体、或精细分开的固体载体、或两者均匀且密切地缔合,然后必要时使产物成形来制备制剂。
适用于口服施用的本发明的制剂可呈以下形式:胶囊剂(包括洒胶囊剂和明胶胶囊剂)、扁囊剂、丸剂、片剂、锭剂(使用经调味的基质,通常为蔗糖和阿拉伯胶或黄芪胶)、冻干剂、散剂、颗粒剂或作为水性液体或非水性液体中的溶液剂或混悬剂、或作为水包油或油包水乳剂、或作为酏剂或糖浆剂、或作为软锭剂(pastille)(使用惰性基质,诸如明胶和甘油,或蔗糖和阿拉伯胶)和/或作为漱口剂等,每种均含有预定量的本发明组合物作为治疗活性组合。组合物还可以作为大丸剂、糖饵剂(electuary)或糊剂施用。
为了制备口服施用的固体剂型(胶囊剂(包括洒胶囊剂和明胶胶囊剂)、片剂、丸剂、糖锭剂、散剂、颗粒剂等),将所述组合物与一种或多种药学上可接受的载体(诸如柠檬酸钠或磷酸二钙)和/或以下中的任何一种进行混合:(1)填充剂或增充剂,诸如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和/或硅酸;(2)粘合剂,例如像,羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和/或阿拉伯胶;(3)湿润剂,诸如甘油;(4)崩解剂,诸如琼脂、碳酸钙、马铃薯或木薯淀粉、藻酸、某些硅酸盐以及碳酸钠;(5)溶液延迟剂,诸如石蜡;(6)吸收加速剂,诸如季铵化合物;(7)润湿剂,例如像,鲸蜡醇和单硬脂酸甘油酯;(8)吸收剂,诸如高岭土和膨润土;(9)润滑剂,诸如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠及其混合物;(10)络合剂,诸如修饰和未修饰的环糊精;以及(11)着色剂。在胶囊剂(包括洒胶囊剂和明胶胶囊剂)、片剂以及丸剂的情况下,所述药物组合物还可以包含缓冲剂。在使用赋形剂(诸如乳糖(lactose)或乳糖(milk sugar))以及高分子量聚乙二醇等的软质和硬质填充的明胶胶囊中还可采用相似类型的固体组合物作为填充剂。
片剂可通过压制或模制来制备,任选地具有一种或多种辅助成分。可使用粘合剂(例如明胶或羟丙基甲基纤维素)、润滑剂、惰性稀释剂、防腐剂、崩解剂(例如羧甲基淀粉钠或交联羧甲基纤维素钠)、表面活性剂或分散剂制备压制片剂。模制片剂可以通过在合适的机器中模制用惰性液体稀释剂湿润的粉末状化合物的混合物来制备。
所述片剂和药物组合物的其它固体剂型,诸如糖锭剂、胶囊剂(包括洒胶囊剂和明胶胶囊剂)、丸剂和颗粒剂,可以任选地刻痕或用包衣和衣壳(诸如肠溶衣和药物制剂领域中众所周知的其它包衣)制备。还可以使用例如提供所需的释放曲线的不同比例的羟丙基甲基纤维素、其它聚合物基质、脂质体和/或微球来配制它们以便使其中的组合活性成分缓慢或受控释放。可通过例如过滤通过截留细菌的过滤器或通过在使用前即刻掺入为可溶于无菌水或一些其它无菌注射介质的呈无菌固体组合物形式的灭菌剂使它们灭菌。这些组合物还可任选含有遮光剂并且还可为仅在或优先在胃肠道的某一部分任选以延迟方式释放活性成分的组合物。可使用的包埋组合物的实例包括聚合物质和蜡。所述活性成分还可呈微囊化形式并且适当地具有一种或多种上述赋形剂。
可用于口服施用的液体剂型包括药学上可接受的乳剂、用于重构的冻干剂、微乳剂、溶液剂、混悬剂、糖浆剂和酏剂。除活性成分以外,液体剂型可含有通常在本领域中使用的惰性稀释剂,例如像水或其它溶剂、环糊精及其衍生物、溶解剂和乳化剂诸如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、油(具体地是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油以及芝麻油)、甘油、四氢糠醇、聚乙二醇和脱水山梨醇的脂肪酸酯及其混合物。
除了惰性稀释剂,所述口服组合物还可包含助剂,诸如润湿剂、乳化剂和助悬剂、甜味剂、矫味剂、着色剂、芳香剂和防腐剂。
除活性成分以外,混悬剂还可含有助悬剂,例如像乙氧基化异硬脂醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂和黄芪胶及其混合物。
用于直肠、阴道或尿道施用的药物组合物的制剂可作为栓剂存在,所述栓剂可通过将本发明组合物的一种或多种活性成分与一种或多种适合的无刺激性赋形剂或载体(包括,例如,可可脂、聚乙二醇、栓剂蜡或水杨酸酯)混合来制备,并且所述栓剂在室温下为固体,但在体温下为液体并且因此将会在直肠或阴道腔中融化并释放活性成分。
用于向口施用的药物组合物的制剂可以以漱口剂、口服喷雾剂或口服药膏的形式存在。
可替代地或另外地,组合物可以被配置成用于通过导管、支架、金属丝或其它腔内装置递送。通过此类装置的递送可能对于递送到膀胱、尿道、输尿管、直肠或肠特别有用。
适用于阴道施用的制剂还包括含有本领域已知的适合的此类载体的阴道栓剂、止血栓、乳霜、凝胶剂、糊剂、泡沫剂或喷雾制剂。
用于局部或经皮施用的剂型包括散剂、喷雾剂、药膏、糊剂、乳霜、洗剂、凝胶剂、溶液剂、贴剂以及吸入剂。可以在无菌条件下将活性化合物与药学上可接受的载体以及与可能需要的任何防腐剂、缓冲剂、或推进剂进行混合。
除活性化合物以外,所述药膏、糊剂、乳霜和凝胶剂可含有赋形剂,诸如动物和蔬菜脂肪、油、蜡、石蜡、淀粉、黄蓍胶、纤维素衍生物、聚乙二醇、硅酮、膨润土、硅酸、滑石和氧化锌或其混合物。
除活性化合物以外,散剂和喷雾剂可含有赋形剂诸如乳糖、滑石、硅酸、氢氧化铝、硅酸钙和聚酰胺粉末或这些物质的混合物。喷雾剂可额外地含有常规推进剂,诸如氯氟烃和挥发性未取代的烃(诸如丁烷或丙烷)。
透皮贴剂具有提供本发明化合物向身体的受控递送的附加优点。此类剂型还可通过将活性化合物溶解或分散于适当的介质中来制备。吸收促进剂也可用于增加化合物穿过皮肤的通量。这种通量的速率可通过提供速率控制膜或通过将化合物分散于聚合物基质或凝胶中来控制。
如本文所用,短语“肠胃外施用”和“肠胃外地施用”意指除了肠内施用和局部施用以外的、通常通过注射进行的施用模式,并且包括但不限于静脉内、肌肉内、动脉内、鞘内、囊内、眼眶内、心内、真皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、脊柱内以及胸骨内注射和输注。
适合于肠胃外施用的药物组合物包含一种或多种活性化合物与一种或多种药学上可接受的无菌等渗水性溶液或非水性溶液、分散液、混悬液或乳液,或可在临使用前复原成无菌可注射溶液或分散液的无菌散剂的组合,所述组合可以含有抗氧化剂、缓冲剂、抑菌剂、使制剂与预期受体的血液等渗的溶质、或助悬剂或增稠剂。
可用于本发明的药物组合物中的合适的水性和非水性载体的实例包括水、乙醇、多元醇(诸如甘油、丙二醇、聚乙二醇等)和其合适的混合物、植物油(诸如橄榄油)和可注射有机酯(诸如油酸乙酯)。适当流动性可例如通过使用包衣材料(诸如卵磷脂),在分散液的情况下通过维持所需粒径和通过使用表面活性剂来维持。
这些组合物也可含有助剂,诸如防腐剂、润湿剂、乳化剂和分散剂。可通过包含各种抗菌剂和抗真菌剂例如尼泊金、三氯叔丁醇、苯酚山梨酸等确保防止微生物的作用。还可合乎需要的是在组合物中包含等渗剂,诸如糖、氯化钠等。另外,可通过包含延迟吸收的剂(诸如单硬脂酸铝和明胶)来实现可注射药物形式的延迟吸收。
在一些情况下,为了延长药物的效果,需要减缓皮下注射或肌肉内注射的药物的吸收。这可通过使用具有低水溶性的结晶或无定形材料的液态混悬剂来实现。药物的吸收速率则取决于其溶解速率,溶解速率进而可取决于晶体大小和晶形。可替代地,通过将药物溶解或混悬于油媒介物中来实现肠胃外施用的药物形式的延迟吸收。
可注射储库式形式是通过在诸如聚乳酸交酯-聚乙交酯等可生物降解聚合物中形成主题化合物的微囊化基质来制备。根据药物与聚合物的比率和所采用的具体聚合物的性质,可控制药物释放的速率。其它可生物降解聚合物的实例包括聚(原酸酯)和聚(酸酐)。也通过将药物截留在与身体组织相容的脂质体或微乳液中来制备储库式可注射制剂。
引入的方法也可由可再充电或可生物降解装置提供。近年来,已经开发了各种缓释聚合物装置并在体内进行了测试,以控制药物的递送,包括蛋白质生物药物。包括可生物降解和不可降解的聚合物二者在内的多种生物相容性聚合物(包括水凝胶)可用于形成植入物,以在特定靶标部位缓释本发明组合物的化合物。
药物组合物中的活性成分的实际剂量水平可改变以便获得对于特定患者、组合物以及施用模式有效实现所需的治疗反应,而对患者无毒的活性成分的量。
选择的剂量水平将取决于多种因素,包括使用的特定化合物组合或其酯、盐或酰胺的活性,施用途径,施用时间,使用的特定化合物的排泄速率,治疗的持续时间,与所使用的特定化合物组合使用的其它药物、化合物和/或材料,所治疗患者的年龄、性别、体重、病状、综合的健康状态和先前的病史,以及在医学领域众所周知的类似因素。
一般来说,用于本发明的组合物和方法中的活性化合物的合适的日剂量将为化合物有效产生治疗效果的最低剂量的量。这种有效剂量将通常取决于上述因素。
接受这种治疗的患者是任何需要的动物,包括灵长类动物,特别是人,以及其它哺乳动物,诸如马、牛、猪和绵羊;以及一般的家禽和宠物。
润湿剂、乳化剂和润滑剂诸如月桂基硫酸钠和硬脂酸镁以及着色剂、释放剂、包衣剂、甜味剂、矫味剂和芳香剂、防腐剂和抗氧化剂也可存在于所述组合物中。
药学上可接受的抗氧化剂的实例包括:(1)水溶性抗氧化剂,诸如抗坏血酸、盐酸半胱氨酸、硫酸氢钠、焦亚硫酸钠、亚硫酸钠等;(2)油溶性抗氧化剂,诸如抗坏血酸棕榈酸酯、丁基化羟基茴香醚(BHA)、丁基化羟基甲苯(BHT)、卵磷脂、没食子酸丙酯、α-生育酚等;和(3)金属螯合剂,诸如柠檬酸、乙二胺四乙酸(EDTA)、山梨糖醇、酒石酸、磷酸等。
在某些实施方案中,本文所述的组合物增强了对癌细胞例如AML细胞的巨噬细胞吞噬活性。在其它实施方案中,吞噬活性相对于在不存在本文所述组合物的情况下的巨噬细胞增强了例如1%、5%、10%、20%、30%、40%、50%、60%、70%、80%或90%。
在某些实施方案中,本发明提供了本发明的组合物在制备药物中的用途。
在某些实施方案中,本发明提供了本发明的组合物在制备例如用于治疗癌症的药物中的用途。
在某些实施方案中,本发明提供了用于治疗癌症的方法,其中所述方法包括向有需要的受试者施用例如治疗有效量的本发明的组合物。
在某些实施方案中,本发明提供了通过向有需要的受试者施用例如治疗有效量的本发明的组合物来抑制肿瘤细胞生长和/或转移的方法。
代表性肿瘤细胞包括癌症的细胞,所述癌症诸如但不限于黑素瘤、肾癌、前列腺癌、乳腺癌、结肠癌和肺癌、骨癌、胰腺癌、皮肤癌、头部或颈部癌、皮肤或眼内恶性黑素瘤、子宫癌、卵巢癌、直肠癌、肛门区癌、胃癌、睾丸癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、霍奇金病、非霍奇金淋巴瘤、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、慢性或急性白血病包括(急性骨髓性白血病、急性淋巴细胞性白血病、慢性骨髓性白血病、急性成淋巴细胞性白血病、慢性淋巴细胞性白血病)、儿童期实体瘤、淋巴细胞性淋巴瘤、膀胱癌、肾脏或输尿管癌、肾盂癌、中枢神经系统(CNS)肿瘤、非小细胞肺癌(NSCLC)、原发性CNS淋巴瘤、肿瘤血管生成、脊柱肿瘤、脑干神经胶质瘤、垂体腺瘤、卡波西肉瘤(Kaposi's sarcoma)、表皮样癌、鳞状细胞癌、T细胞淋巴瘤、B细胞淋巴瘤、骨髓增生性病症/肿瘤(MPDS)、骨髓增生异常综合征、巨细胞骨髓瘤、重链骨髓瘤、轻链骨髓瘤和本-周骨髓瘤(Bence-Jones myeloma)、由环境引起的癌症包括由石棉引起的癌症(例如,间皮瘤)、以及所述癌症的组合。术语“治疗”包括预防性和/或治疗性治疗。术语“预防性或治疗性”治疗是本领域认可的,并且包括向宿主施用主题组合物中的一种或多种。如果在临床表现不希望的病状(例如,宿主动物的疾病或其它不希望的状态)之前施用,那么治疗是预防性的(即,其保护宿主免于发展不希望的病状),而如果在表现不希望的病状之后施用,那么治疗是治疗性的(即,其旨在减弱、改善或稳定现有的不希望的病状或其副作用)。
如本文所用,术语‘化合物’包括式(I)、(IA)、(IB)、(IC)、(ID)、(IE)、(IF)的化合物及其药学上可接受的盐或其立体异构体。
如本文所用的术语“芳基”包括取代或未取代的单环芳族基团,在所述基团中环的每个原子都为碳。优选地,环为5至7元环,更优选地为6元环。术语“芳基”还包括具有两个或更多个环的多环系统,其中两个或更多个碳是两个相邻环共用的,其中至少一个环是芳族的,例如,其它环可以是环烷基、环烯基、环炔基、芳基、杂芳基和/或杂环基。芳基基团包括苯、萘、菲等。优选地,术语‘芳基’包括苯基。
术语“杂芳基”包括取代或未取代的芳族单环结构,优选地5至7元环,更优选地5至6元环,其环结构包括至少一个杂原子,优选地一至四个杂原子,更优选地一个或两个杂原子。术语“杂芳基(heteroaryl)”和“杂芳基(hetaryl)”还包括具有两个或更多个环的多环系统,其中两个或更多个碳是两个相邻环共用的,其中至少一个环是杂芳族的,例如,其它环可以是环烷基、环烯基、环炔基、芳基、杂芳基和/或杂环基。杂芳基基团包括例如吡咯、呋喃、噻吩、咪唑、噁唑、噻唑、吡唑、吡啶、吡嗪、哒嗪、吲哚、1,2,4-噁二唑、1,3,4-噁二唑、1,3,4-噻二唑、苯并咪唑、嘧啶等。杂芳基基团可以在化合价允许的一个或多个位置被本文所述的任何任选的取代基取代。优选地,术语‘杂芳基’包括咪唑基和吲哚基。
如本文所用,“预防”病症或病状的治疗剂是指一种化合物,其在统计学样品中,相对于未治疗对照样品在所治疗样品中降低病症或病状的发生率,或者相对于未治疗对照样品延迟病症或病状的一种或多种症状的发作或降低其严重性。
术语“治疗”包括预防性和/或治疗性治疗。术语“预防性或治疗性”治疗是本领域认可的,并且包括向宿主施用主题组合物中的一种或多种。如果在临床表现不希望的病状(例如,宿主动物的疾病或其它不希望的状态)之前施用,那么治疗是预防性的(即,其保护宿主免于发展不希望的病状),而如果在表现不希望的病状之后施用,那么治疗是治疗性的(即,其旨在减弱、改善或稳定现有的不希望的病状或其副作用)。
如本文所用,短语“延迟进展”是指旨在及时延迟疾病或疾病的症状发展(包括及时延迟特定疾病的至少一种症状的出现或发生)的程序或应用。
术语“前药”旨在涵盖在生理条件下转化为本发明的治疗活性剂(例如,式(I)化合物)的化合物。用于制备前药的常见方法包括一个或多个选定的部分,这些部分在生理条件下水解以展现所需的分子。在其它实施方案中,前药通过宿主动物的酶促活性转化。例如,酯或碳酸盐(例如,醇或羧酸的酯或碳酸盐)是本发明优选的前药。在某些实施方案中,可以用对应的合适的前药代替上文表示的制剂中的式(I)的化合物的一些或全部,例如其中母体化合物中的羟基以酯形式存在,或母体化合物中存在的碳酸盐或羧酸以酯形式存在。
如本文所用,术语“包含(comprise或comprising)”通常的意思是包括,也就是说允许存在一种或多种附加的(未指定的)特征或组分。
如本文所用,使用术语“包括(including)”以及其它形式诸如“include”、“includes”和“included”不是限制性的。
如本文所用,术语“疾病(disease)”或“病症(disorder)”是指生物体内由病因或病状(包括但不限于感染、获得性病状、遗传病状)引起的病理学病状,并且特征在于可识别的症状。
如本文所用,待治疗的“患者”或“受试者”或“个体”包括人和/或非人动物,包括哺乳动物。哺乳动物包括灵长类动物,诸如人、黑猩猩、大猩猩和猴子;驯养的动物,诸如狗、马、猫、猪、山羊、牛;以及啮齿动物,诸如小鼠、大鼠、仓鼠和沙鼠。
术语CD47+疾病细胞是指具有CD47+表型并与疾病相关的细胞。在一个实施方案中,CD47+疾病细胞是癌细胞。
术语“CD47+”是用于指本发明CD47-SIRPα阻断剂结合所靶向的细胞的表型。可以通过使用CD47抗体作为亲和配体的流式细胞术鉴定CD47+的细胞。适当标记的CD47抗体可商购用于此用途(例如,克隆B6H12的抗体产物可购自Santa Cruz Biotechnology)。针对CD47表型检查的细胞可以包括标准的肿瘤活检样品,尤其包括从怀疑带有内源性CD47+癌细胞的受试者身上采集的血液样品。作为用本发明的药物组合治疗的靶标而特别感兴趣的CD47疾病细胞是“过表达”CD47的那些。这些CD47+细胞通常是疾病细胞,其表面上的CD47密度超过给定类型细胞的正常CD47密度。CD47过表达将在不同细胞类型之间变化,但是在本文中是指通过例如流式细胞术或通过免疫染色或通过基因表达分析等确定的任何CD47水平都大于具有该细胞类型正常的CD47表型的健康对应细胞上可测量的水平。
本发明包括包含本文所述化合物的药学上可接受的盐的组合物及其在本发明的组合物和方法中的用途。在某些实施方案中,预期盐包括但不限于烷基、二烷基、三烷基或四烷基铵盐。在某些实施方案中,本发明的预期盐包括但不限于L-精氨酸、苯乙苄胺(benenthamine)、苄星青霉素、甜菜碱、氢氧化钙、胆碱、丹醇、二乙醇胺、二乙胺、2-(二乙氨基)乙醇、乙醇胺、乙二胺、N-甲基葡糖胺、海巴明盐、1H-咪唑、锂、L-赖氨酸、镁、4-(2-羟乙基)吗啉、哌嗪、钾、1-(2-羟乙基)吡咯烷、钠、三乙醇胺、氨丁三醇和锌盐。在某些实施方案中,本发明的预期盐包括但不限于Na、Ca、K、Mg、Zn或其它金属盐。
药学上可接受的酸加成盐也可以各种溶剂化物的形式存在,诸如与水、甲醇、乙醇、二甲基甲酰胺等的溶剂化物。也可以制备此类溶剂化物剂的混合物。此类溶剂化物的来源可以来自结晶的溶剂,是制备或结晶的溶剂中固有的或者不溶于此类溶剂。
如本文所用,术语“药学上可接受的盐”旨在包括药物领域中已知和使用的所有盐。药学上可接受的盐包括但不限于胺盐,诸如但不限于氯普鲁卡因、胆碱、N,N'-二苄基-乙二胺、氨、二乙醇胺和其它羟烷基胺、乙二胺、N-甲基葡糖胺、普鲁卡因、N-苄基-苯乙胺、1-对氯-苄基-2-吡咯烷-1'-基甲基-苯并咪唑、二乙胺和其它烷基胺、哌嗪和三(羟甲基)氨基甲烷;碱金属盐,诸如但不限于锂、钾和钠;碱土金属盐,诸如但不限于钡、钙和镁;过渡金属盐,诸如但不限于锌;以及其它金属盐,诸如但不限于磷酸氢钠和磷酸二钠;并且还包括但不限于无机酸的盐,诸如但不限于盐酸盐和硫酸盐;以及有机酸的盐,诸如但不限于乙酸盐、乳酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、抗坏血酸盐、琥珀酸盐、丁酸盐、戊酸盐和富马酸盐。示例性的药学上可接受的盐包括乙酸盐、乳糖醛酸盐、苯磺酸盐、月桂酸盐、苯甲酸盐、苹果酸盐、碳酸氢盐、马来酸盐、硫酸氢盐、扁桃酸盐、酒石酸氢盐、甲磺酸盐、硼酸盐、溴甲烷、甲基硝酸盐、乙二胺四乙酸钙、甲基硫酸盐、樟磺酸盐、粘酸盐、碳酸盐、萘磺酸盐、溴化物、氯化物、硝酸盐、克拉维酸盐、N-甲基葡萄糖胺、柠檬酸盐、铵盐、二盐酸盐、油酸盐、乙二胺四乙酸盐、草酸盐、乙二磺酸盐、扑酸盐(双羟萘酸盐)、依托酸盐、棕榈酸盐、乙磺酸盐、泛酸盐、富马酸盐、磷酸盐/磷酸氢盐、葡庚糖酸盐、聚半乳糖醛酸盐、葡萄糖酸盐、水杨酸盐、谷氨酸盐、硬脂酸盐、甘苯砷盐(glycollylarsanilate)、硫酸盐、己基间苯二酚盐、碱式乙酸盐、海巴明盐、琥珀酸盐、氢溴酸盐、鞣酸盐、盐酸盐、酒石酸盐、羟基萘甲酸盐、茶氯酸盐、碘化物、甲苯磺酸盐、羟乙磺酸盐、三乙基碘化物、乳酸盐、泮酸盐和戊酸盐,其可用作改变溶解度或水解特性的剂型,或者可以用于缓释或前药制剂。上述药学上可接受的盐和其它典型的药学上可接受的盐的制备在Berg等的“Pharmaceutical Salts,”J.Pharm.Sci.66:1-19(1977)中更充分地描述。
术语“立体异构体”是指诸如本文所述化合物的任何对映体、非对映体或几何异构体。当此类化合物是手性时,它们可以外消旋或旋光形式存在。由于根据本发明的化合物的外消旋体或立体异构体的药物活性可能不同,因此可能需要使用富含一种对映体的化合物。在这些情况下,可以通过本领域技术人员已知的化学或物理措施将最终产物甚至中间体分离为对映体化合物,或者甚至就此用于合成中。在外消旋胺的情况下,通过与旋光拆分剂反应,由混合物形成非对映异构体。合适的拆分剂的实例是旋光酸,诸如R和S形式的酒石酸、二乙酰酒石酸、二苯甲酰基酒石酸、扁桃酸、苹果酸、乳酸、合适的N-保护的氨基酸(例如N-苯甲酰脯氨酸或N-苯磺酰脯氨酸)或各种旋光樟脑磺酸。同样有利的是借助旋光拆分剂(例如二硝基苯甲酰基苯基甘氨酸、三乙酸纤维素或碳水化合物的其它衍生物或固定在硅胶上的手性衍生的甲基丙烯酸酯聚合物)的色谱对映体拆分。
如本文所用,术语“酯”是指基团-C(O)OR11,其中R11表示烃基基团。
如本文所用,术语“酰胺”是指基团-C(O)NH2。
在某些实施方案中,本发明所述的化合物可为外消旋的。在某些实施方案中,本发明所述的化合物可以富含一种对映体。例如,本发明所述的化合物可具有大于30%的ee、40%的ee、50%的ee、60%的ee,70%的ee、80%的ee、90%的ee或甚至95%或更高的ee。在某些实施方案中,本发明所述的化合物可以具有一个以上的立体中心。在某些此类实施方案中,本发明所述的化合物可以富含一种或多种非对映体。例如,本发明所述的化合物可具有大于30%的de、40%的de、50%的de、60%的de,70%的de、80%的de、90%的de或甚至95%或更高的de。
术语“受试者”包括哺乳动物(特别是人)和其它动物,诸如驯养动物(例如,包括猫和狗的家庭宠物)和非驯养动物(诸如野生动物)。
在某些实施方案中,本发明提供了一种组合物,其包含小分子CD-47-SIRPα通路抑制剂与能够激活受体诸如Fc受体(FcR)或促吞噬受体的剂或癌症疗法中用于激活促吞噬受体的其它治疗方式,以发挥CD-47-SIRPα通路阻断的最大潜力。
实施例-1:制备本发明所述化合物的合成程序描述于2018年1月12日共同未决的印度临时专利申请201841001438中,所述申请转换为PCT申请PCT/IB2019/050219,其内容在此以引用的方式全部并入。
生物实施例:
试剂DPBS(Gibco)、具有HEPES和L-GLN-500ML的RPMI 1640(Lonza)、重组人M-CSF(R&D systems)、CD47单克隆抗体(B6H12)、功能级抗体(Ebioscience)、功能级小鼠IgG1κ同型对照(Ebioscience)、真空采血管(多个样品鲁尔接头)(BD)、真空采血管(肝素钠(NH)158USP单位)、采血管(BD)、Histopaque(密度1.077gm/ml)(SIGMA 1077)、台盼蓝溶液(SIGMA-T8154)、血细胞计数器(Bright line-SIGMA Z359629)、头皮静脉输液器(JMS)、细胞解离缓冲液(Gibco)、48孔无菌平底板(Corning)、表达荧光素酶的Raji细胞(通过荧光素酶基因转染Raji细胞在内部产生)光度计、潮霉素B(Invitrogen)、Bright Glo荧光素酶测定系统(Promega)、96孔板、聚苯乙烯、高谱带、白色平底孔(Sigma CLS3912)、抗人CD20抗体(Invivogen hcd20-mab1)、硼替佐米(Selleckchem,S1013)
实施例-2:基于荧光素酶的吞噬作用测定
进行体外吞噬作用测定以评估测试项目增强巨噬细胞吞噬活性的能力。从健康供体的血液中分离单核细胞,并使用10%的RPMI(Roswell Park Memorial Institute)培养基和重组人M-CSF培养6-8天,以分化为巨噬细胞。培养基每隔一天更换一次。分化后,通过轻轻刮擦收集粘附的巨噬细胞,并在10%的RPMI中以每孔10万的密度在48孔组织培养板中培养过夜。同时,将表达荧光素酶的Raji(淋巴瘤细胞系)细胞在组织培养瓶中在具有100μg/mL潮霉素B的10%RPMI培养基中培养。在吞噬的当天,使巨噬细胞血清饥饿2小时。将每孔40万个表达荧光素酶的Raji细胞在37℃下用抗人CD47抗体或小鼠IgG1 K同型对照抗体或各种浓度的本发明所选化合物单独或与抗人CD20抗体组合在无血清培养基中培育30分钟,并加入到接种有巨噬细胞的48孔板的各孔中。2小时后,将细胞用PBS洗涤两次,并向每个孔中加入100μl无血清RPMI。此外,向每个孔中加入50μl bright glow试剂,然后混合细胞,并在黑暗中培育5分钟。将每个孔的内容物转移到白板后,使用酶标仪读取发光读数。发光强度指示吞噬作用的程度。每个实验条件一式两份进行。结果在图1中示出。
图1中的结果显示,与单独使用CD47-SIRPα阻断化合物相比,用抗人CD20抗体处理肿瘤细胞致使吞噬作用显著增加。
实施例-3:人类巨噬细胞吞噬作用测定以评估与硼替佐米组合的化合物
进行体外吞噬作用测定以评估测试项目增强巨噬细胞吞噬活性的能力。从健康供体的血液中分离单核细胞,并使用补充有20ng/mL重组人M-CSF的完全RPMI(Roswell ParkMemorial Institute)培养基培养6-8天,以使其分化为巨噬细胞。培养基每隔一天更换一次。同时将H929细胞在完全RPMI培养基中培养,并用10nM硼替佐米处理48小时。使巨噬细胞中在无血清的RPMI中饥饿2小时。将CFSE染色、硼替佐米处理/未处理的H929(多发性骨髓瘤细胞系)细胞以0.2x106个细胞/孔的密度接种于96孔低附着板中,在37℃下用抗人CD47纯化的B6H12(5μg/mL)/小鼠IgG1 K同型对照抗体(5μg/mL)/不同浓度的本发明所选化合物6在无血清培养基中处理30分钟。将血清饥饿的巨噬细胞以1:4的比例(巨噬细胞:H929细胞)加入到H929细胞中,并在37℃下培育2小时。将每个孔中的细胞在黑暗中于4℃下用抗人CD11b APC染色30分钟,然后进行固定和FACS分析。FITC和APC阳性的细胞被认为是被巨噬细胞吞噬的H929细胞。使用Flow Jo软件分析使用FACS verse获取的数据。结果在图2中示出。
图2中的结果显示,与单独使用CD47-SIRPα阻断化合物相比,用蛋白酶体抑制剂(硼替佐米)处理肿瘤细胞致使吞噬作用显著增加。
实施例-4:化合物6与PD-L1抗体组合在A20同基因淋巴瘤模型中的功效研究
将内部繁殖的雌性Balb/c(BALB/cAnNTac)小鼠(6-8周大)用于A20同源淋巴瘤模型的这项功效研究。将动物分别用尾标标记并关在笼子中,笼子卡上应标明研究代码、实验日期、性别和动物数量。在实验过程中,每天对动物称重。A20细胞系(源自老BALB/cAnN小鼠的自发性网状细胞赘生物的B细胞淋巴瘤系)购自ATCC。
当平均肿瘤体积达到约75mm3时,根据肿瘤体积将动物随机分为四组(G1至G4),每组十二只动物(N=12),并给予媒介物、化合物6、抗小鼠PD-L1抗体以及化合物6与抗小鼠PD-L1抗体的组合,如下所述:
治疗持续21天,在此期间,基于治疗期间观察到的肿瘤体积和体重变化来评估总体功效和耐受性。
在整个实验期间,每天在施用化合物6之前记录各个动物的体重。在整个实验期间,每天观察一次动物的死亡率/发病率,并且在整个实验期间,每天观察一次动物的临床体征。使用数字游标卡尺每周测量三次(每2-3天一次)所有治疗组动物的肿瘤体积。作为疗效的量度,计算T(治疗)/C(对照)%和TGI(肿瘤生长抑制%)%的值。使用GraphPad版本7.0进行图形和统计分析。为了分析肿瘤体积数据,在第18天使用单向方差分析和Dunnett多重比较检验对所有组进行了统计比较。所有分析和比较均在5%(p<0.05)水平进行评估。小于0.05的“p”值被认为是显著的。结果和统计数据汇总在下表中。
单因素方差分析,Dunnett多重比较检验:*-p<0.05,***-p<0.001;TGI-肿瘤生长抑制;
化合物6在30mg/kg bid剂量下,作为单一剂以及与PD-L1抗体组合都具有良好的耐受性,而没有任何治疗相关的临床体征和死亡率,表明在施用剂量下,测试药物具有极好的耐受性。在治疗期结束时,以30mg/kg单独给药的化合物6、单独的抗小鼠PD-L1抗体以及化合物6与抗小鼠PD-L1组合显示的肿瘤生长抑制(TGI)值分别为72%、41%和90%。治疗对肿瘤生长动力学的影响以图形方式表示于图3中。
进一步观察到,当与单独的治疗相比时,化合物6与抗小鼠PD-L1抗体组合显著增强肿瘤生长抑制以及更持久的应答。用化合物6和抗小鼠PD-L1抗体组合治疗的11只动物中有5只显示出完全的肿瘤消退。用化合物6单独治疗和化合物6与抗小鼠PD-L1抗体组合治疗所观察到的肿瘤生长抑制在统计学上是显著的。
Claims (57)
1.一种包含CD47-SIRPα阻断剂和一种或多种抗癌剂的组合物:其中所述CD47-SIRPα阻断剂由式(I)的化合物表示:
或其药学上可接受的盐或酰胺或酯或其立体异构体;其中,
Ra为氢;并且R1表示氢、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)3NHC(=NH)NH2、-(CH2)4NH2、-CH2CONH2、-CH2-芳基或-CH2-杂芳基;或者Ra和R1与它们所连接的原子一起形成吡咯烷环;
R2表示氢、-(CH2)3NHC(=NH)NH2、-(CH2)2CONH2、-(CH2)2COOH、-CH2-芳基或-CH2-杂芳基;
Rb为氢;并且R3表示氢、-CH2-芳基、-(CH2)3NHC(=NH)NH2、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)4NH2或-CH2-杂芳基;或者Rb和R3与它们所连接的原子一起形成吡咯烷环。
2.根据权利要求1所述的组合物,其中所述抗癌剂是化学治疗剂或免疫调节剂。
3.根据权利要求1所述的组合物,其中所述抗癌剂是靶向刺激活化Fc受体(FcR)的肿瘤抗原的治疗性抗体。
4.根据权利要求3所述的组合物,其中所述抗体选自能够触发高效吞噬作用的组。
5.根据权利要求4所述的组合物,其中所述能够触发高效吞噬作用的组包括抗CD20(利妥昔单抗、泰泽坦、托西莫单抗),其组合特别适用于治疗非霍奇金B细胞淋巴瘤和慢性淋巴细胞性白血病(CLL);抗CD22(依帕珠单抗),其组合特别适用于治疗B细胞白血病和毛细胞白血病;抗CD52(阿仑单抗),其组合特别适用于治疗B细胞和T细胞白血病(慢性淋巴细胞性白血病);抗CD33(吉妥珠单抗奥佐米星),其组合特别适用于治疗骨髓性白血病(急性骨髓性白血病);曲妥珠单抗,其组合特别适用于治疗乳腺癌;贝伐单抗,其组合特别适用于治疗某些类型的脑肿瘤以及某些类型的肾癌、肺癌、结肠癌、直肠癌、子宫颈癌、卵巢癌或输卵管癌;西妥昔单抗,其组合特别适用于治疗结肠癌和头颈癌;帕尼单抗,其组合特别适用于治疗结直肠癌;抗CD38(达雷木单抗),其组合特别适用于治疗多发性骨髓瘤;CD96、抗CD44、抗CD123,其组合特别适用于治疗骨髓性白血病;奥法木单抗,其组合特别适用于治疗慢性淋巴细胞性白血病;奥比妥珠单抗,其组合特别适用于治疗滤泡性淋巴瘤;阿仑单抗,其组合特别适用于治疗B细胞慢性淋巴细胞性白血病;替伊莫单抗,其组合特别适用于治疗B细胞非霍奇金淋巴瘤;迪努妥昔单抗,其组合特别适用于治疗神经母细胞瘤;以及耐昔妥珠单抗,其组合特别适用于治疗肺癌。
6.根据权利要求1至5中任一项所述的组合物,其中所述抗癌剂是选自利妥昔单抗、泰泽坦和托西莫单抗的抗CD20抗体。
7.根据权利要求2所述的组合物,其中所述化学治疗剂是蛋白酶体抑制剂(硼替佐米、伊沙佐米和卡非佐米)、蒽环类药物(多柔比星、表柔比星、柔红霉素、伊达比星、米托蒽醌)奥沙利铂、环磷酰胺、博莱霉素、伏立诺他、紫杉醇、5-氟尿嘧啶、阿糖胞苷、BRAF抑制性药物(达拉非尼、维罗非尼)、PI3K抑制剂、多西他赛、丝裂霉素C、索拉非尼或他莫昔芬;或其组合。
8.根据权利要求1至2中任一项所述的组合物,其中所述抗癌剂是蛋白酶体抑制剂。
9.根据权利要求8所述的组合物,其中所述抗癌剂是硼替佐米、伊沙佐米或卡非佐米,或其衍生物。
10.根据权利要求2所述的组合物,其中所述化学治疗剂是乙酸阿比特龙、阿法替尼、阿地白介素、阿仑单抗、阿那曲唑、阿西替尼、贝利司他、苯达莫司汀、比卡鲁胺、博纳吐单抗、伯舒替尼、本妥昔单抗、白消安、卡巴他赛、卡培他滨、卡铂、卡非佐米、卡莫司汀、色瑞替尼、氯法拉滨、克唑替尼、达卡巴嗪、放线菌素D、达沙替尼、地加瑞克、地尼白介素、地诺单抗、恩杂鲁胺、艾日布林、埃罗替尼、依维莫司、依西美坦、依西美坦、氟达拉滨、氟维司群、吉非替尼、戈舍瑞林、替伊莫单抗、伊马替尼、伊匹单抗、伊立替康、伊沙匹隆、拉帕替尼、来那度胺、来曲唑、甲酰四氢叶酸、亮丙瑞林、洛莫司汀、二氯甲基二乙胺、甲地孕酮、奈拉滨、尼罗替尼、纳武单抗、奥拉帕尼、奥马西他辛、帕博西尼、帕米膦酸盐、帕尼单抗、帕比司他、帕唑帕尼、培门冬酶、派姆单抗、培美曲塞二钠、帕妥珠单抗、普乐沙福、泊马度胺、普纳替尼、普拉曲沙、丙卡巴肼、镭223、雷莫芦单抗、瑞格非尼、rIFNa-2b、罗米地辛、舒尼替尼、替莫唑胺、替西罗莫司、噻替派、托西莫单抗、曲美替尼、长春瑞宾、阿巴瑞克斯、阿地白介素、阿利维甲酸、别嘌呤醇、六甲蜜胺、三氧化二砷、天冬酰胺酶、阿扎胞苷、贝沙罗汀、巴瑞替尼、硼替佐米、静脉内白消安、口服白消安、二甲睾酮、西妥昔单抗、苯丁酸氮芥、顺铂、克拉屈滨、达肝素钠、地西他滨、地氟妥昔、双硫仑、右雷佐生、丙酸屈他雄酮、依库珠单抗、雌莫司汀、磷酸依托泊苷、依托泊苷、柠檬酸芬太尼、非格司亭、氟尿苷、吉西他滨、乙酸组氨瑞林、环磷酰胺、干扰素α2a、二甲苯磺酸拉帕替尼、左旋咪唑、马瑞佐米、氮芥、美法仑、巯基嘌呤、甲氨喋呤、甲氧沙林、米托坦、苯丙酸诺龙、诺非单抗、奥普佐米、培非格司亭、喷司他汀、哌泊溴烷、普卡霉素、丙卡巴肼、奎纳克林、拉布立酶、芦可替尼、卢卡帕尼、链佐星、替尼泊苷、睾内酯、沙利度胺、硫鸟嘌呤、拓扑替康、托瑞米芬、维甲酸、尿嘧啶氮芥、戊柔比星、长春花碱、长春新碱、尼拉帕尼、维利帕尼、他拉唑帕尼、唑来膦酸盐、依鲁替尼、阿柏西普和艾代拉利司。
11.根据权利要求2所述的组合物,其中所述免疫调节剂是共刺激或共抑制分子,包括CTLA-4(例如伊匹单抗)、4-1BB(例如乌瑞鲁单抗和乌托米单抗)、PD-1和PD-L1的抗体(例如纳武单抗、派姆单抗、阿特珠单抗、度伐鲁单抗和卡瑞利珠单抗)、细胞因子抗体(IL-10、TGF-β)、TIM-3抗体、LAG3抗体、B7H3抗体、B7H4抗体或B7H6抗体;或其组合。
12.根据权利要求1所述的组合物,其中CD47-SIRPα阻断剂是阻断CD47和SIRPα之间的相互作用的剂。
13.根据权利要求1所述的组合物,其中阻断CD47和SIRPα之间的相互作用诱导巨噬细胞吞噬表达CD47的肿瘤细胞。
14.根据权利要求1所述的组合物,其中R1表示氢、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)3NHC(=NH)NH2、-(CH2)4NH2、-CH2CONH2、-CH2-苯基或-CH2-咪唑基。
15.根据权利要求1所述的组合物,其中R2表示氢、-(CH2)3NHC(=NH)NH2、-(CH2)2CONH2、-(CH2)2COOH、-CH2-苯基或-CH2-咪唑基。
16.根据权利要求1所述的组合物,其中R3表示氢、-CH2-苯基、-(CH2)3NHC(=NH)NH2、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)4NH2或-CH2-咪唑基。
17.根据权利要求16所述的组合物,其中R3表示氢、-CH2-苯基、-(CH2)3NHC(=NH)NH2、-(CH2)2CONH2、-(CH2)2COOH或-(CH2)4NH2。
18.根据权利要求1至17中任一项所述的组合物,其中
Ra为氢;并且R1表示氢、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)3NHC(=NH)NH2、-(CH2)4NH2、-CH2CONH2、-CH2-苯基或-CH2-咪唑基;或者Ra和R1与它们所连接的原子一起形成吡咯烷环;
R2表示氢、-(CH2)3NHC(=NH)NH2、-(CH2)2CONH2、-(CH2)2COOH、-CH2-苯基或-CH2-咪唑基;
Rb为氢;并且R3表示氢、-CH2-苯基、-(CH2)3NHC(=NH)NH2、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)4NH2或-CH2-咪唑基;或者Rb和R3与它们所连接的原子一起形成吡咯烷环。
20.根据权利要求19所述的组合物,其中R1表示氢、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)3NHC(=NH)NH2、-(CH2)4NH2、-CH2-苯基或-CH2-咪唑基。
21.根据权利要求19所述的组合物,其中R2表示氢、-(CH2)3NHC(=NH)NH2、-(CH2)2CONH2、-(CH2)2COOH、-CH2-苯基或-CH2-咪唑基。
22.根据权利要求19、20或21所述的组合物,其中
Ra为氢;并且R1表示氢、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)3NHC(=NH)NH2、-(CH2)4NH2、-CH2-苯基或-CH2-咪唑基;
R2表示氢、-(CH2)3NHC(=NH)NH2、-(CH2)2COOH、-CH2-苯基或-CH2-咪唑基。
24.根据权利要求23所述的组合物,其中R1表示氢、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)3NHC(=NH)NH2、-(CH2)4NH2或-CH2-苯基。
25.根据权利要求23所述的组合物,其中R3表示氢、-CH2-苯基、-(CH2)2CONH2或-(CH2)2COOH。
26.根据权利要求23所述的组合物,其中Rb和R3与它们所连接的原子一起形成吡咯烷环。
27.根据权利要求23至26中任一项所述的组合物,其中
R1表示-(CH2)2CONH2或-(CH2)2COOH;
Rb为氢;并且R3表示氢或-CH2-苯基;或者Rb和R3与它们所连接的原子一起形成吡咯烷环。
29.根据权利要求28所述的组合物,其中R1表示-(CH2)4NH2、-(CH2)3NHC(=NH)NH2或-(CH2)2CONH2。
30.根据权利要求28所述的组合物,其中Rb为氢;R3表示氢、-CH2-苯基或-CH2-杂芳基;或者Rb和R3与它们所连接的原子一起形成吡咯烷环。
31.根据权利要求28至30中任一项所述的组合物,其中:
R1表示-(CH2)4NH2、-(CH2)3NHC(=NH)NH2或-(CH2)2CONH2;
Rb为氢;R3表示氢、-CH2-苯基或-CH2-杂芳基;或者Rb和R3与它们所连接的原子一起形成吡咯烷环。
33.根据权利要求32所述的组合物,其中R1表示-CH2CONH2、-(CH2)4NH2或(CH2)3NHC(=NH)NH2。
34.根据权利要求32至33中任一项所述的组合物,其中:
R1表示-(CH2)4NH2或(CH2)3NHC(=NH)NH2;
Rb为氢;R3表示氢、-(CH2)3NHC(=NH)NH2或-(CH2)4NH2;或者Rb和R3与它们所连接的原子一起形成吡咯烷环。
36.根据权利要求35所述的组合物,其中R2表示氢或-(CH2)3NHC(=NH)NH2。
37.根据权利要求34至35中任一项所述的组合物,其中:
R1表示氢或-(CH2)3NHC(=NH)NH2;并且Rb和R3与它们所连接的原子一起形成吡咯烷环。
39.根据权利要求38所述的组合物,其中R2表示氢、-CH2-苯基、-(CH2)2COOH或-(CH2)3NHC(=NH)NH2。
40.根据权利要求38至39中任一项所述的组合物,其中:
R2表示氢、-CH2-苯基、-(CH2)2COOH或-(CH2)3NHC(=NH)NH2;
Rb为氢;并且R3表示-CH2-苯基、-(CH2)2CONH2、-(CH2)4NH2或-(CH2)2COOH;Rb和R3与它们所连接的原子一起形成吡咯烷环。
42.根据权利要求1至41中任一项所述的包含CD47-SIRPα阻断剂和一种或多种抗癌剂的组合物,其用作药物。
43.一种治疗呈现CD47通路失调的受试者的癌症的方法,所述方法包括向所述受试者施用治疗有效量的CD47-SIRPα阻断剂与治疗有效量的一种或多种抗癌剂的组合:其中所述CD47-SIRPα阻断剂由式(I)的化合物表示:
或其药学上可接受的盐或酰胺或酯或其立体异构体;其中,
Ra为氢;并且R1表示氢、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)3NHC(=NH)NH2、-(CH2)4NH2、-CH2CONH2、-CH2-芳基或-CH2-杂芳基;或者Ra和R1与它们所连接的原子一起形成吡咯烷环;
R2表示氢、-(CH2)3NHC(=NH)NH2、-(CH2)2CONH2、-(CH2)2COOH、-CH2-芳基或-CH2-杂芳基;
Rb为氢;并且R3表示氢、-CH2-芳基、-(CH2)3NHC(=NH)NH2、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)4NH2或-CH2-杂芳基;或者Rb和R3与它们所连接的原子一起形成吡咯烷环。
44.根据权利要求43所述的方法,其中所述呈现CD47通路失调的受试者是呈现CD47+疾病细胞的受试者。
45.根据权利要求44所述的方法,其中CD47+疾病细胞是CD47+癌细胞。
46.根据权利要求43所述的方法,其中用一种或多种抗癌剂治疗是在用式(I)的化合物或其药学上可接受的盐治疗之前、同时或之后。
47.根据权利要求43所述的方法,其中所述抗癌剂是抗CD20抗体。
48.根据权利要求43所述的方法,其中所述抗癌剂是蛋白酶体抑制剂。
49.根据权利要求43所述的方法,其中所述抗癌剂是硼替佐米或其任何衍生物。
50.一种用于治疗受试者中由CD47-SIRPα通路介导的疾病或病症或延缓所述疾病或病症的进展的方法,所述方法包括向有需要的受试者施用治疗有效量的阻断CD47-SIRPα通路的剂与治疗有效量的一种或多种抗癌剂的组合:其中所述阻断CD47-SIRPα通路的剂由式(I)的化合物表示:
或其药学上可接受的盐或酰胺或酯或其立体异构体;其中,
Ra为氢;并且R1表示氢、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)3NHC(=NH)NH2、-(CH2)4NH2、-CH2CONH2、-CH2-芳基或-CH2-杂芳基;或者Ra和R1与它们所连接的原子一起形成吡咯烷环;
R2表示氢、-(CH2)3NHC(=NH)NH2、-(CH2)2CONH2、-(CH2)2COOH、-CH2-芳基或-CH2-杂芳基;
Rb为氢;并且R3表示氢、-CH2-芳基、-(CH2)3NHC(=NH)NH2、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)4NH2或-CH2-杂芳基;或者Rb和R3与它们所连接的原子一起形成吡咯烷环。
51.根据权利要求50所述的方法,其中所述由CD47-SIRPα通路介导的疾病或病症为癌症。
52.根据权利要求51所述的方法,其中所述癌症选自以下:黑素瘤、肾癌、前列腺癌、乳腺癌、结肠癌和肺癌、骨癌、胰腺癌、皮肤癌、头部或颈部癌、皮肤或眼内恶性黑素瘤、子宫癌、卵巢癌、直肠癌、肛门区癌、胃癌、睾丸癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、霍奇金病、非霍奇金淋巴瘤、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、慢性或急性白血病包括(急性骨髓性白血病、急性淋巴细胞性白血病、慢性骨髓性白血病、急性成淋巴细胞性白血病、慢性淋巴细胞性白血病)、儿童期实体瘤、淋巴细胞性淋巴瘤、膀胱癌、肾脏或输尿管癌、肾盂癌、中枢神经系统(CNS)肿瘤、非小细胞肺癌(NSCLC)、原发性CNS淋巴瘤、肿瘤血管生成、脊柱肿瘤、脑干神经胶质瘤、垂体腺瘤、卡波西肉瘤、表皮样癌、鳞状细胞癌、T细胞淋巴瘤、B细胞淋巴瘤、骨髓增生性病症/肿瘤(MPDS)、骨髓增生异常综合征、巨细胞骨髓瘤、重链骨髓瘤、轻链骨髓瘤和本-周骨髓瘤、由环境引起的癌症包括由石棉引起的癌症(例如,间皮瘤)、以及所述癌症的组合。
53.根据权利要求1至41所述的包含CD47-SIRPα阻断剂和一种或多种抗癌剂的组合物在制造用于治疗呈现CD47通路失调的受试者的癌症的药物中的用途。
54.根据权利要求53所述的用途,其中所述癌症选自以下:黑素瘤、肾癌、前列腺癌、乳腺癌、结肠癌和肺癌、骨癌、胰腺癌、皮肤癌、头部或颈部癌、皮肤或眼内恶性黑素瘤、子宫癌、卵巢癌、直肠癌、肛门区癌、胃癌、睾丸癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、霍奇金病、非霍奇金淋巴瘤、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、慢性或急性白血病(包括急性骨髓性白血病、急性淋巴细胞性白血病、慢性骨髓性白血病、急性成淋巴细胞性白血病、慢性淋巴细胞性白血病)、儿童期实体瘤、淋巴细胞性淋巴瘤、膀胱癌、肾脏或输尿管癌、肾盂癌、中枢神经系统(CNS)肿瘤、非小细胞肺癌(NSCLC)、原发性CNS淋巴瘤、肿瘤血管生成、脊柱肿瘤、脑干神经胶质瘤、垂体腺瘤、卡波西肉瘤、表皮样癌、鳞状细胞癌、T细胞淋巴瘤、B细胞淋巴瘤、由环境引起的癌症包括由石棉引起的癌症(例如,间皮瘤)、以及所述癌症的组合。
55.一种试剂盒,其包含根据权利要求1至41中任一项所述的组合物和包装插页,所述包装插页包含用于治疗呈现CD47通路失调的受试者的药物施用说明。
56.一种药物组合物,其包含如权利要求1至41中任一项所述的CD47-SIRPα阻断剂和一种或多种抗癌剂以及药学上可接受的载体。
57.一种组合,其包含CD47-SIRPα阻断剂和一种或多种抗癌剂:其中所述CD47-SIRPα阻断剂由式(I)的化合物表示:
或其药学上可接受的盐或酰胺或酯或其立体异构体;其中,
Ra为氢;并且R1表示氢、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)3NHC(=NH)NH2、-(CH2)4NH2、-CH2CONH2、-CH2-芳基或-CH2-杂芳基;或者Ra和R1与它们所连接的原子一起形成吡咯烷环;
R2表示氢、-(CH2)3NHC(=NH)NH2、-(CH2)2CONH2、-(CH2)2COOH、-CH2-芳基或-CH2-杂芳基;
Rb为氢;并且R3表示氢、-CH2-芳基、-(CH2)3NHC(=NH)NH2、-(CH2)2CONH2、-(CH2)2COOH、-(CH2)4NH2或-CH2-杂芳基;或者Rb和R3与它们所连接的原子一起形成吡咯烷环。
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JP2024508395A (ja) * | 2021-02-10 | 2024-02-27 | グレート ノベル セラピューティクス バイオテック アンド メディカルズ コーポレイション | がんに対する免疫応答を刺激する又は免疫抑制を克服するための医薬組み合わせ及び方法 |
CN113018415B (zh) * | 2021-03-17 | 2022-07-01 | 遵义医科大学 | 一种药物组合及其应用 |
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WO2018073754A1 (en) * | 2016-10-20 | 2018-04-26 | Aurigene Discovery Technologies Limited | Dual inhibitors of vista and pd-1 pathways |
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MX365218B (es) | 2013-09-06 | 2019-05-27 | Aurigene Discovery Tech Ltd | Derivados de 1,2,4-oxadiazol como inmunomoduladores. |
KR20170123317A (ko) | 2015-03-10 | 2017-11-07 | 오리진 디스커버리 테크놀로지스 리미티드 | 면역조절제로서의 3-치환된-1,2,4-옥사다이아졸 및 티아다이아졸 화합물 |
US20160304809A1 (en) | 2015-04-14 | 2016-10-20 | The Procter & Gamble Company | Consumer Product Composition |
CN104804093A (zh) | 2015-05-27 | 2015-07-29 | 江苏春申堂药业有限公司 | 一种针对cd47的单域抗体 |
NZ741324A (en) | 2015-09-21 | 2021-09-24 | Erasmus Univ Medical Center | Anti-cd47 antibodies and methods of use |
EP3454879B1 (en) | 2016-05-10 | 2021-12-22 | INSERM (Institut National de la Santé et de la Recherche Médicale) | New compounds and pharmaceutical use thereof in the treatment of cancer |
EP3243522A1 (en) | 2016-05-10 | 2017-11-15 | Université Pierre et Marie Curie (Paris 6) | Agonist agents of cd47 inducing programmed cell death and their use in the treatments of diseases associated with defects in programmed cell death |
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BR112020018555A2 (pt) * | 2018-03-14 | 2020-12-29 | Aurigene Discovery Technologies Limited | Método de modulação das vias de sinalização de tigit e pd-1 usando compostos de 1,2,4-oxadiazol |
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WO2016142833A1 (en) * | 2015-03-10 | 2016-09-15 | Aurigene Discovery Technologies Limited | 1,2,4-oxadiazole and thiadiazole compounds as immunomodulators |
WO2018047139A1 (en) * | 2016-09-12 | 2018-03-15 | Aurigene Discovery Technologies Limited | Compounds as modulators of tigit signalling pathway |
WO2018073754A1 (en) * | 2016-10-20 | 2018-04-26 | Aurigene Discovery Technologies Limited | Dual inhibitors of vista and pd-1 pathways |
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US20220241248A1 (en) | 2022-08-04 |
WO2020095256A1 (en) | 2020-05-14 |
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JP2022507025A (ja) | 2022-01-18 |
CA3118843A1 (en) | 2020-05-14 |
AU2019375193A1 (en) | 2021-05-13 |
SG11202104192TA (en) | 2021-05-28 |
KR20210088584A (ko) | 2021-07-14 |
EP3876931A1 (en) | 2021-09-15 |
US11311517B2 (en) | 2022-04-26 |
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