CN108164474B - 作为免疫调节剂的1,2,4-二唑衍生物 - Google Patents
作为免疫调节剂的1,2,4-二唑衍生物 Download PDFInfo
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- CN108164474B CN108164474B CN201810056892.5A CN201810056892A CN108164474B CN 108164474 B CN108164474 B CN 108164474B CN 201810056892 A CN201810056892 A CN 201810056892A CN 108164474 B CN108164474 B CN 108164474B
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Abstract
本发明涉及1,2,4‑
Description
本申请是国际申请日为2014年9月5日、国际申请号为PCT/IB2014/064279、进入中国国家阶段的申请号为201480057738.X且发明名称为“作为免疫调节剂的1,2,4-二唑衍生物”的中国发明申请的分案申请。
本申请要求2013年9月6日提交的印度临时申请号4011/CHE/2013 的权益;其在此通过参考结合。
技术领域
发明背景
程序性细胞死亡-1(PD-1)是CD28超家族的成员,其与它的两种配体, PD-L1或PD-L2相互作用时递送负性信号。PD-1和其配体广泛表达并且与其他CD28成员相比,在T细胞活化和耐受方面发挥更宽范围的免疫调节作用。PD-1和其配体参与减弱感染性免疫和肿瘤免疫,并且促进慢性感染和肿瘤进展。PD-1和其配体的生物学重要性提示了PD-1通路的操作对各种人类疾病的治疗可能性(Ariel Pedoeem等人,Curr Top Microbiol Immunol.(2011);350:17-37)。
T细胞活化和功能失调依赖于直接和调节的受体。基于它们的功能结果,共信号转导分子可以分为共刺激剂和共抑制剂,其正面和负面控制T 细胞应答的启动、生长、分化和功能成熟(Li Shi,等人,Journal of Hematology&Oncology 2013,6:74)。
阻断程序性细胞死亡蛋白-1(PD-1)免疫检查点通路的治疗性抗体阻止T细胞下调并且促进针对癌症的免疫应答。多种PD-1通路抑制剂在正在进行的临床实验的各个阶段显示出强烈的活性(RD Harvey,Clinical Pharmacology&Therapeutics(2014);962,214-223)。
程序性死亡-1(PD-1)是T细胞主要表达的共受体。PD-1与其配体, PD-L1或PD-L2的结合,对于免疫系统的生理调节至关重要。PD-1信号传导通路的主要功能作用是抑制自反应性T细胞,其用于保护免于自身免疫性疾病。因此PD-1通路的消除可以导致免疫耐受的破坏,其可以最终导致发展出病理性自身免疫。相反,肿瘤细胞有时可以指定PD-1通路逃脱免疫监督机制。因此,阻断PD-1通路已经变为癌症治疗的有吸引力的靶点。目前的方法包括六种药剂,其是靶向PD-1和PD-L1的中和抗体或融合蛋白。多于四十个临床试验在进行中,以更好地定义PD-1阻断在多种肿瘤类型中的作用(Hyun-Tak Jin等人,ClinicalImmunology (Amsterdam,Netherlands)(2014),153(1),145-152)。
国际申请WO 01/14557、WO 02/079499、WO 2002/086083、WO 03/042402、WO 2004/004771、WO 2004/056875、WO2006121168、 WO2008156712、WO2010077634、WO2011066389、WO2014055897、 WO2014059173、WO2014100079和美国专利US08735553报道了PD-1或 PD-L1抑制性抗体或融合蛋白。
此外,国际申请WO2011161699、WO2012/168944、WO2013144704 和WO2013132317报道了能够压制和/或抑制程序性细胞死亡1(PD1)信号传导通路的肽或肽类化合物。
发明概述
其中,
Q是S或O;
R1是氨基酸Ser或Thr的侧链,其任选地被烷基或酰基取代;
R2是氢或-CO-Aaa;
Aaa是氨基酸残基Thr或Ser;其中其C-末端是游离末端,是被酰胺化的或是被酯化的;
R3是选自Asn,Asp,Gln或Glu的氨基酸的侧链;
-----是任选的键;
R4和R5独立地是氢或不存在;
R6选自氢,烷基或酰基;
或其药用盐或立体异构体。
在本发明的其他方面,其涉及包含式(I)的化合物或药用盐或立体异构体的药物组合物和用于制备其的方法。
发明详述
通过解释本发明的方式,并且不是通过限制本发明的方式,提供各个实施方案。实际上,对于本领域技术人员而言将显而易见的是,在本发明中,在不偏离本发明的范围和精神的情况下,可以进行各种改进和变化。例如,作为一个实施方案的部分说明或描述的特征可以用于另一实施方案以获得更进一步的实施方案。因此,意在本发明覆盖这样的改进和变化,如在所附权利要求和其对等物的范围内。本发明的其他目标、特征和方面在以下详述中公开,或从以下详述显而易见。本领域技术人员要理解,本讨论仅是示例性实施方案的描述,并且不理解为限制本发明的较宽范围。
在一个实施方案中,本发明涉及式(I)的化合物
其中,
Q是S或O;
R1是氨基酸Ser或Thr的侧链,其任选地被烷基或酰基取代;
R2是氢或-CO-Aaa;
Aaa是氨基酸残基Thr或Ser;其中其C-末端是游离末端,是被酰胺化的或是被酯化的;
R3是选自Asn,Asp,Gln或Glu的氨基酸的侧链;
-----是任选的键;
R4和R5独立地是氢或不存在;
R6选自氢,烷基或酰基;
或其药用盐或立体异构体。
在另一实施方案中,本发明提供式(IA)的化合物
或其药用盐或立体异构体;其中,
R1,R3和Aaa与式(I)中所定义的相同。
在再另一进一步的实施方案中,本发明提供式(IB)的化合物
或其药用盐或立体异构体;其中,
R1和R3与式(I)中所定义的相同。
根据再另一实施方案,本发明提供式(I)的化合物,其中
R1是Ser或Thr的侧链;
R2是-CO-Aaa;
Aaa是氨基酸残基Thr或Ser;其中C-末端游离;
R3是Asn或Glu的侧链。
在另一更进一步的实施方案中,根据式(I)的化合物,其中Q是S。
在另一更进一步的实施方案中,根据式(I)的化合物,其中R4是氢。
在另一更进一步的实施方案中,根据式(I)的化合物,其中R5是氢。
以下实施方案说明本发明并且不意在将权利要求限制于举例说明的具体实施方案。
根据一个实施方案,具体提供的是式(I)、(IA)和(IB)的化合物,其中 R1是Ser的侧链。
根据另一实施方案,具体提供的是式(I)、(IA)和(IB)的化合物,其中 R1是Thr的侧链。
根据再另一实施方案,具体提供的是式(I)的化合物,其中R2是氢。
根据再另一实施方案,具体提供的是式(I)的化合物,其中R2是 --CO-Aaa。
根据再另一实施方案,具体提供的是式(I)和(IA)的化合物,其中Aaa 是Thr。
根据再另一实施方案,具体提供的是式(I)和(IA)的化合物,其中Aaa 是Ser。
根据再另一实施方案,具体提供的是式(I)、(IA)和(IB)的化合物,其中 R3是Asn的侧链。
根据再另一实施方案,具体提供的是式(I)和(IA)的化合物,其中R3是 Asp的侧链。
根据再另一实施方案,具体提供的是式(I)和(IA)的化合物,其中R3是 Gln的侧链。
根据再另一实施方案,具体提供的是式(I)和(IA)的化合物,其中R3是 Glu的侧链。
根据再另一实施方案,具体提供的是式(I)的化合物,其中Q是O。
根据再另一实施方案,具体提供的是式(I)的化合物,其中R1是Ser的侧链,其任选地被C1-5烷基,如甲基取代。
根据再另一实施方案,具体提供的是式(I)的化合物,其中R6是氢。
根据再另一实施方案,具体提供的是式(I)的化合物,其中R6是酰基如 -C(O)CH3、-C(O)CH2CH3、-C(O)(CH2)2CH3、-C(O)(CH2)3CH3、 -C(O)(CH2)4CH3或-C(O)(CH2)5CH3。
根据再另一实施方案,具体提供的是式(I)的化合物,其中R6是丁酰基。
根据再另一实施方案,具体提供的是式(I)的化合物,其中R4和R5不存在。
根据再另一实施方案,具体提供的是式(I)的化合物,其中Aaa的C- 末端是游离的(例如-CO2H形式)。
根据再另一实施方案,具体提供的是式(I)的化合物,其中Aaa的C- 末端被酯化(例如-CO2Me形式)。
根据再另一实施方案,具体提供的是式(I)的化合物,其中Aaa的C- 末端被酰胺化(例如-CONH2形式)。
根据再另一实施方案,具体提供的是式(I)、(IA)和(IB)的化合物,其中一个、多个或全部氨基酸是D氨基酸。
在一个实施方案中,在没有任何限制的情况下,具体的式(I)的化合物列举在表(1)中:
表1
或其药用盐或立体异构体。
在一个实施方案中,本发明提供药物组合物,其包含所公开的化合物和药用载体或稀释剂。
在另一实施方案中,所述药物组合物还包含抗癌剂、化疗剂或抗增殖化合物中的至少一种。
配制本发明中公开的化合物,用于药物施用。
在一个实施方案中,本发明提供本发明中所公开的化合物,用于制备药物。
在另一实施方案中,本发明提供本发明中所公开的化合物,用于制备用于治疗癌症或感染性疾病的药物。
在一个实施方案中,本发明提供本发明中所公开的化合物,用于制备药物,所述药物用于治疗细菌感染性疾病、病毒感染性疾病或真菌感染性疾病。
在一个实施方案中,本发明提供化合物,其用于制备药物,所述药物用于治疗癌症,其中所述癌症选自由以下各项组成的组:乳腺癌、结肠癌、肺癌、黑素瘤、前列腺癌和肾癌、骨癌、头或颈癌、胰腺癌、皮肤癌、皮肤或眼内恶性黑素瘤、子宫癌、卵巢癌、直肠癌、肛门区域癌、胃癌、睾丸癌、子宫癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、霍奇金病(Hodgkin’s Desease)、非霍奇金淋巴瘤(non-Hodgkin’s Desease)、食道癌、小肠癌、内分泌系统癌症、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(包括急性髓细胞白血病、慢性髓细胞白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病)、儿童实体瘤、淋巴细胞性淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经系统(CNS)肿瘤、原发性CNS淋巴瘤、肿瘤血管生成、脊柱肿瘤、脑干胶质瘤、垂体腺瘤、卡波济氏肉瘤、表皮样癌、鳞状上皮细胞癌、T细胞淋巴瘤、环境诱发的癌症(包括石棉诱发的癌症)、和所述癌症的组合。
在一实施方案中,本发明提供本发明所公开的化合物,其用于治疗癌症。
在一实施方案中,本发明提供本发明所公开的化合物,其用于治疗细菌感染性疾病、病毒感染性疾病或真菌感染性疾病。
在一实施方案中,本发明提供治疗癌症的方法,其中所述方法包括向需要其的受治疗者施用有效量的本发明的化合物。
在另一实施方案中,本发明提供调节受治疗者中PD-1信号传导通路介导的免疫应答的方法,其包括向受治疗者施用治疗有效量的本发明的化合物,从而受治疗者中的免疫应答被调节。
在另一实施方案中,本发明提供抑制受治疗者中肿瘤细胞的生长和/ 或转移的方法,所述方法包括向受治疗者施用治疗有效量的本发明的能够抑制程序性细胞死亡1(PD1)信号传导通路的化合物。
所述肿瘤细胞包括癌症,比如但不限于骨癌、头或颈癌、胰腺癌、皮肤癌、皮肤或眼内恶性黑素瘤、子宫癌、卵巢癌、直肠癌、肛门区域癌、胃癌、睾丸癌、子宫癌、输卵管癌、子宫内膜癌、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、内分泌系统癌症、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(包括急性髓细胞白血病、慢性髓细胞白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病)、儿童实体瘤、淋巴细胞性淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经系统(CNS)肿瘤、原发性CNS淋巴瘤、肿瘤血管生成、脊柱肿瘤、脑干胶质瘤、垂体腺瘤、卡波济氏肉瘤、表皮样癌、鳞状上皮细胞癌、T细胞淋巴瘤、环境诱发的癌症(包括石棉诱发的癌症)、和所述癌症的组合。
在另一更进一步的实施方案中,本发明提供治疗受治疗者中的感染性疾病的方法,其包括向受治疗者施用治疗有效量的能够抑制程序性细胞死亡1(PD1)信号传导通路的本发明的化合物,从而对受治疗者治疗感染性疾病。
本发明的另一更进一步实施方案提供治疗受治疗者中的细菌、病毒和真菌感染的方法,其包括向受治疗者施用治疗有效量的能够抑制程序性细胞死亡1(PD1)信号传导通路的本发明的化合物,从而对受治疗者治疗细菌、病毒和真菌感染。
感染性疾病包括但不限于HIV、流感、疱疹、贾第虫、疟疾、利什曼原虫、由肝炎病毒(A、B、&C)导致的致病感染、疱疹病毒(例如、VZV、 HSV-I、HAV-6、HSV-II、和CMV、EB(EpsteinBarr)病毒)、腺病毒、流感病毒、虫媒病毒、埃可病毒、鼻病毒、柯萨奇病毒、冠状病毒、呼吸道合胞体病毒、腮腺炎病毒、轮状病毒、麻疹病毒、风疹病毒、细小病毒、牛痘病毒、HTLV病毒、登革热病毒、乳头瘤病毒、软疣病毒、脊髓灰质炎病毒、狂犬病毒、JC病毒和虫媒病毒脑炎病毒、细菌衣原体导致的致病感染、立克次体细菌、分枝杆菌、葡萄球菌、链球菌、肺炎球菌 (pneumonococci)、脑膜炎球菌和conococci、克雷白氏杆菌、变形杆菌、沙雷氏菌、假单胞菌、大肠杆菌、军团杆菌、白喉、沙门氏菌、杆菌、霍乱、破伤风、肉毒中毒、炭疽、鼠疫、细螺旋体病和莱姆病细菌,以下真菌引起的致病感染:假丝酵母(白色假丝酵母、克鲁斯假丝酵母(krusei)、光滑假丝酵母(glabrata)、热带假丝酵母(tropicalis)等)、新型隐球菌、曲霉属(烟曲霉(fumigatus)、黑曲霉(niger)等)、毛霉属(毛霉菌、腐化米霉菌、根霉(rhizophus))、申克孢子丝菌、皮炎芽生菌(Blastomyces dermatitidis)、巴西副球孢子菌(Paracoccidioides brasiliensis)、粗球孢子菌(Coccidioides immitis) 和荚膜组织胞浆菌(Histoplasma capsulatum),和由以下寄生虫导致的致病感染:痢疾内变形虫(Entamoeba histolytica)、结肠小袋虫(Balantidium coli)、福纳氏虫(Naegleriafowleri)、棘变形虫(Acanthamoeba sp.)、吸吮贾第虫 (Girdia lambia)、隐孢子虫(Cryptosporidium sp.)、卡氏肺囊虫(Pneumocystis carinii)、间日疟原虫(Plasmodium vivax)、果氏巴贝虫(Babesia microti)、布鲁斯锥虫(Trypanosomabrucei)、克鲁斯锥虫(Trypanosoma cruzi)、多氏利什曼原虫(Leishmania donovani)、鼠弓浆虫(Toxoplasma gondi)、巴西日圆线虫(Nippostrongylus brasiliensis)。
本发明的化合物可以用作单个药物或作为药物组合物,其中将所述化合物与不同药用材料混合。
药物组合物通常通过口服或吸入途径施用,但可以通过肠胃外施用途径施用。在本发明的实践中,组合物可以例如通过口服、静脉输注、外用、腹膜内、膀胱内或鞘内施用。肠胃外施用的实例包括但不限于关节内(在关节中)、静脉内、肌肉内、皮内、腹膜内、和皮下途径,包括水性和非水性的等渗无菌注射液,其可以含有抗氧化剂、缓冲剂、抑菌剂和使得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(其可以包括悬浮剂、增溶剂、增稠剂、稳定剂、和防腐剂)。口服施用、肠胃外施用、皮下施用和静脉施用是优选的施用方法。
本发明的化合物的剂量根据年龄、重量、症状、疗效、剂量给药方案和/或治疗次数而变化。通常,在成人的情况下,它们可以通过口服或吸入途径,以1mg至100mg/次的量,数天一次、3天一次、2天一次、一天一次、一天多次施用,或通过口服或吸入的途径一天连续施用1至24小时。因为剂量受各种条件影响,小于上述剂量的量有时可以足够好地起作用,或在一些情况下可以需要较高剂量。
本发明的化合物可以与其他药物联合施用,以用于(1)本发明的预防性和/或治疗性药物的预防和/或治疗功效的补充和/或增强,(2)本发明的预防性和/或治疗性药物的动力学、吸收改善、剂量减少,和/或(3)本发明的预防性和/或治疗性药物的副作用的减少。
包含本发明的化合物和其他药物的伴随药物(concomitant medicine)可以作为其中在单个制剂中含有两种成分的组合制剂施用,或以分开的制剂施用。通过分开的制剂施用包括同时施用和间隔一些时间施用。在间隔一些时间施用的情况下,可以首先施用本发明的化合物,接着施用另一药物,或可以首先施用另一药物,然后施用本发明的化合物。各个药物的施用方法可以相同或不同。
基于已经在临床使用的剂量,可以适当选择其他药物的剂量。可以根据要施用的受治疗者的年龄和体重、施用方法、施用时间、要治疗的病症、症状和其组合适当选择本发明的化合物和其他药物的复合比例。例如,基于1质量份的本发明的化合物,其他药物可以以0.01至100质量份的量使用。其他药物可以是适当比例的两种或更多种任意药物的组合。基于上述机制,补充和/或增强本发明的化合物的预防性和/或治疗性功效的其他药物不仅包括已经发现的那些,而且包括未来将要发现的那些。
该伴随使用发挥预防性和/或治疗性作用所针对的疾病不特别限制。伴随药物可以用于任何疾病,只要其补充和/或增强本发明的化合物的预防性和/或治疗性功效即可。
本发明的化合物可以与现有化疗剂同时使用或以混合形式使用。化疗剂的实例包括烷基化剂、亚硝基脲剂、抗代谢物、抗癌抗体、植物来源的生物碱、拓扑异构酶抑制剂、激素药物、激素拮抗剂、芳香酶抑制剂、P- 糖蛋白抑制剂、铂配合物衍生物、其他免疫治疗性药物和其他抗癌药物。此外,其可以与癌症治疗辅助剂,如白细胞减少症(嗜中性白血球减少症) 治疗药物、血小板减少症治疗药物、止吐和癌症疼痛干预药物,同时使用或以混合形式一起使用。
在一个实施方案中,本发明的一种或多种化合物可以与其他免疫调节剂和/或增效剂同时或以混合形式一起使用。免疫调节剂的实例包括各种细胞因子、疫苗和佐剂。刺激免疫应答的这些细胞因子、疫苗和佐剂的实例包括但不限于GM-CSF,M-CSF,G-CSF,干扰素-α、β或γ,IL-1,IL-2, IL-3,IL-12,Poly(I:C)和CpG。
在另一实施方案中,增效剂包括环磷酰胺和环磷酰胺的类似物,抗 -TGFβ和伊马替尼(Imatinib)(Gleevac),有丝分裂抑制剂,如紫杉醇,舒尼替尼(Sunitinib)(Sutent)或其他抗血管生成剂,芳香酶抑制剂,如来曲唑, A2a腺苷受体(A2AR)拮抗剂,血管生成抑制剂,蒽环类抗生素,奥沙利铂 (oxaliplatin),阿霉素(doxorubicin),TLR4拮抗剂,和IL-18拮抗剂。
除非另有限定,本文使用的所有技术和科学术语具有与本文中的主题术语的领域中的通常所理解的相同的意义。如本文中所使用的,提供以下定义以帮助理解本发明。
如本文中所使用的,术语‘一种或多种化合物’是指本发明中公开的化合物。
如本文中所使用的,术语“包含(comprise)”或“包含(comprising)”通常以包括的意义使用,即允许存在一个或多个特征或成分。
如本文中所使用的,术语“包括(including)”以及其他形式,如“包括(include)”,“包括(includes)”,和“包括(included)”不受限制。
如本文中所使用的,术语″任选地被取代″是指用指定取代基的自由基替代给定结构中的一个或多个氢自由基,所述取代基包括,但不限于:烷基、烷氧基、酰基、卤代和羟基。要理解,所述取代基可以进一步被取代。
如本文中所使用的术语″烷基″是指在骨架上仅包括碳和氢原子的烃链基,不含有不饱和性,具有一至二十个碳原子(即,C1-20烷基)或一至十个碳原子(即,C1-10烷基)或一至五个碳原子(即,C1-5烷基),并且其通过单键链接于分子的其余部分,例如,包括但不限于甲基、乙基、丙基、丁基、异丁基、仲丁基、叔丁基、异戊基或新戊基。除非有相反解释或陈述,本文描述或要求的所有烷基可以是直链或支链的、取代的或未取代的。
如本文中所使用的,术语“酰基”是指RC(O)-,其中R是如上文定义的烷基。酰基的实例包括,但不限于乙酰基、-C(O)(CH2)4CH3, -C(O)(CH2)6CH3和-C(O)(CH2)8CH3。
如本文中所使用的,术语“酰胺化的C-末端”是指氨基酸的酰胺形式的 C末端。
如本文中所使用的,术语“酰胺形式”是指伯、仲和/或叔酰胺,并且可以由式-C(O)NRxRy表示,其中Rx和Ry各自独立地表示氢或烷基。
如本文中所使用的,术语“氨基”是指-NH2基团。除非有相反解释或陈述,本文描述和要求的所有氨基可以是取代的或未取代的。
如本文中所使用的,术语“氨基酸”是指在α碳具有L或D立体化学的氨基酸。氨基酸上任选的取代基意为用指定取代基的自由基替代给定结构中的一个或多个氢自由基,在含有羟基的氨基酸如丝氨酸或苏氨酸的情况下,羟基可以被指定取代基取代。
如本文中所使用的,术语“芳基”是指含有一个或两个环的C4-C10碳环芳香族体系,其中所述环可以是稠合的。芳基的实例包括,但不限于苯基和萘基。
如本文中所使用的,术语“芳基烷基”是指与烷基直接键合的上面定义的芳基(例如,苄基等)。
如本文中所使用的,术语“羧酸”是指-COOH基团。
如本文中所使用的,术语″偶联剂″是指与羧基部分的羟基部分反应从而使其易受亲核攻击的化合物。该类型的偶联剂是本领域中已知的,并且包括但不限于,EDCI,HATU,HOBt,DIC和DCC。
如本文中所使用的术语“酯”是指(C1-C6)直链或支链烷基,(C4-C10)芳基,(C4-C10)杂芳基或芳基烷基酯。
如本文中所使用的术语“酯化的C-末端”是指氨基酸的酯形式的C末端。
如本文中所使用的术语“游离C-末端’是指氨基酸的-CO2H形式的C 末端。
如本文中所使用的,术语″卤素″或″卤代″包括氟、氯、溴或碘。
如本文中所使用的术语″羟基(Hydroxy)″或“羟基(Hydroxyl)”是指 -OH基团。
采用“药用盐”意为包括其一种盐的形式的式(I)的化合物活性成分,尤其是如果与之前使用的活性成分的游离形式或活性成分的任何其他盐形式相比,该盐形式赋予该活性成分改善的药物代谢动力学性质。活性成分药用盐形式还可以首次为该活性成分提供其之前不具有的所需的药物代谢动力学性质,并且可以甚至就其在体内的治疗功效而言对该活性成分的药物代谢动力学具有积极影响。
″药用″意为其可以用于制备通常安全、无毒的、并且既不是生物学上不希望的也不是其他方面不希望的药物组合物,并且包括其适于兽用以及人药用。
术语“立体异构体/立体异构体”是指式(I)的化合物的任何对映异构体、非对映异构体或几何异构体(不论它们在何处具有手性或它们何时带有一个或多个双键)。当式(I)的化合物和相关分子式是手性时,它们可以以外消旋或以光学活性形式存在。因为根据本发明的化合物的外消旋物或立体异构体的药学活性可能不同,可能希望使用对映异构体。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方法将终产物或甚至中间体分离为对映异构化合物或甚至以原样在合成中使用。在外消旋胺的情况下,非对映异构体通过与光学活性拆分剂反应从所述混合物形成。适当的拆分剂的实例是光学活性酸如R和S形式的酒石酸、二乙酰基酒石酸、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- 苯甲酰基脯氨酸或N-苯黄酰基脯氨酸),或各种光学活性樟脑磺酸。此外有利的是在光学活性拆分剂(例如固定在硅胶上的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他衍生物或手性衍生的甲基丙烯酸聚合物)的帮助下的色谱对映异构体拆分。
术语″受治疗者″包括哺乳动物(特别是人)和其他动物,如驯养动物(例如,家庭宠物,包括猫和狗)和非驯养动物(如野生动物)。
术语“治疗有效量”或“有效量”是指本发明的一种或多种化合物(i)治疗或预防特定疾病、病症或综合征(ii)减轻、改善或消除特定疾病、病症或综合征的一个或多个症状或(iii)阻止或延迟本文所述的特定疾病、病症或综合征的一个或多个症状的开始的足够量。在癌症的情况下,治疗有效量的药物可以减少癌细胞的数量;降低癌尺寸;抑制(即,减慢到一定程度或备选地终止)癌细胞浸润入周围器官;压制(即,减慢到一定程度或备选地终止)肿瘤转移;一定程度上抑制肿瘤生长;和/或一定程度上缓解与癌症相关的一个或多个症状。在感染性疾病状态的情况下,治疗有效量是足以降低或缓解感染性疾病(由细菌、病毒和真菌引起的感染症状)的量。
天然存在氨基酸在整个说明书中由下表2中指出的常规三字母缩写标识:
表2(氨基酸编码)
名称 | 3-字母编码 | 名称 | 3-字母编码 |
天冬酰胺 | Asn | 谷氨酰胺 | Gln |
天冬氨酸 | Asp | 丝氨酸 | Ser |
谷氨酸 | Glu | 苏氨酸 | Thr |
本文整个说明书中使用的缩写可以被总结在下文中,其具有它们的特定意义:
℃(摄氏度);δ(delta);%(百分数);盐水(NaCl溶液);CDI CH2Cl2/DCM (二氯甲烷);DMF(二甲基甲酰胺);DMSO(二甲亚砜);DCC(二环己基碳二亚胺);DIC(N,N′-二环异丙基碳二亚胺);DMSO-d6(氘化DMSO); EDC.HCl/EDCI(1-(3-二甲基氨基丙基)-3-碳二亚胺盐酸盐);Et2NH(二乙胺);EtOH(乙醇);EtOAc(乙酸乙酯);ECF(氯甲酸乙酯);Fmoc(芴基甲氧基碳酰氯);g或gr(克);H或H2(氢);H2O(水);HOBt/HOBT(1-羟基苯并三唑);HCl(盐酸);h或hr(小时);HATU(2-(1H-7-氮杂苯并三唑-1- 基)-1,1,3,3-四甲基脲六氟磷酸盐甲铵);Hz(Hertz);HPLC(高效液相色谱);K2CO3(碳酸钾);LiOH(氢氧化锂);LCMS(液相色谱质谱);mmol(毫摩);M(摩尔);μl(微升);mL(毫升);mg(毫克);m(多重峰);MHz(兆赫);MS(ES)(质谱-电喷雾);min.(分钟);Na(钠);NaHCO3(碳酸氢钠); NaOAc(乙酸钠);NMM(N-甲基吗啉);Na2SO4(硫酸钠);N2(氮);NMR(核磁共振谱);NH3(氨);NH2OH.HCl(盐酸羟胺;PD-L1(程序性死亡-配体1); PD-L2(程序性细胞死亡1配体2);制备型-HPLC/制备型HPLC(制备型高效液相色谱);S(单线肽);tBu(叔丁基);TEA/Et3N(三乙胺);TFA(三氟乙酸);TFAA(三氟乙酸酐);TLC(薄层色谱);THF(四氢呋喃);TIPS(三异丙基硅烷);TFA/CF3COOH(三氟乙酸);t(三重峰);tR=(保留时间);Trt (三苯基甲烷);等。
实验
本发明的实施方案提供使用适当材料的根据以下实施例的式(I)的化合物的制备。本领域技术人员将理解,以下制备程序的条件和方法的已知改变可以用于制备这些化合物。此外,通过详细描述的步骤,本领域技术人员可以制备本发明的其他化合物。
起始材料通常从商业来源,比如从美国或德国的Sigma-Aldrich;美国的Chem-Impex;中国的G.L.Biochem和印度的Spectrochem获得。
化合物的纯化和表征
分析型HPLC方法:使用ZIC HILIC 200A°柱(4.6mm×250mm,5μm) 进行分析型HPLC,流速:1.0mL/min。使用的洗脱条件是:缓冲液A: 5mmol乙酸氨,缓冲液B:乙腈,用90%缓冲液B平衡柱,并且在30min 期间内用90%至40%缓冲液B梯度洗脱。
制备型HPLC方法:使用SeQuant ZIC HILIC 200A°柱(10mm×250 mm,5μm),流速:5.0mL/min进行制备型HPLC。使用的洗脱条件是:缓冲液A:5mmol乙酸氨(用乙酸调节至pH-4),缓冲液B:乙腈,用90%缓冲液B平衡柱并且在20min内用90%至40%缓冲液B梯度洗脱。
利用具有G1315B DAD的Agilent 1100系列HPLC,使用Mercury MS 柱或使用具有G1315B DAD的Agilent 1100系列HPLC的Agilent LC/MSD VL单四极(single quad),使用Mercury MS柱或使用具有SPD-20A DAD 的Prominence UFLC系统的Shimadzu LCMS 2020单四极,在AP1 2000 LC/MS/MS三联四极(triple quad)(应用生物系统(Applied biosystems)) 进行LCMS。
实施例1:化合物1的合成
步骤1a:
将氯甲酸乙酯(1.5g,13.78mmol)和N-甲基吗啉(1.4g,13.78mmol) 加入至化合物1a(3g,11.48mmol)在THF(30mL)中的溶液中并且在 -20℃搅拌。20分钟后,将液态氨(0.77g,45.92mmol)加入至原位形成的活性混合酐并且在0-5℃搅拌20分钟。反应的完成通过TLC分析确认。将反应混合物在减压下蒸发并且在水和乙酸乙酯之间分开。将有机层用NaHCO3、柠檬酸、盐水溶液洗涤,经Na2SO4干燥并且在减压下蒸发,得到2.9g的化合物1b(收率:96.3%)。LCMS:261.0(M+H)+。
步骤1b:
将三氟乙酸酐(9.7g,46.0mmol)加入至化合物1b(8g,30.7mmol) 在吡啶(24.3g,307.0mmol)中的溶液中并且在室温搅拌3h。反应的完成通过TLC分析确认。将反应混合物在减压下蒸发并且在水和乙酸乙酯之间分开。将有机层用NaHCO3、柠檬酸、盐水溶液洗涤,经Na2SO4干燥并且在减压下蒸发,获得7g的化合物1c(收率:94.0%)。LCMS:187.2 (M-tBu)+。
步骤1c:
将盐酸羟胺(3g,43.37mmol)和碳酸钾(6g,43.37mmol)加入至化合物1c(7g,28.91mmol)在EtOH(70mL)中的溶液中,并且在90℃搅拌2 h。反应的完成通过TLC分析确认。将反应混合物在减压下蒸发并且在水和乙酸乙酯之间分开。将有机层用盐水溶液洗涤,经Na2SO4干燥并且在减压下蒸发。将粗制化合物用硅胶柱色谱纯化(洗脱剂:己烷中的0-5%乙酸乙酯),得到4.2g的化合物1d(收率:52.8%)。LCMS:276.4(M+H)+。
步骤1d:
将Deoxo-(1.83g,8.3mmol)加入至Fmoc-Asn(Trt)-OH(4.5g, 7.5mmol)在CH2Cl2(50mL)中的溶液中,并且在0℃搅拌3h。然后将 CH2Cl2蒸发并用己烷研磨,滗析并在真空中蒸发,得到相应酰基氟。将 THF中的NMM(1.17g,11.6mmol)和化合物1d(1.6g,5.8mmol)加入至酰基氟中并且在室温搅拌12h。然后将THF蒸发并且加入乙酸钠(0.72g,8.7mmol),然后加入EtOH(50mL)。将反应混合物在90℃搅拌2h。将反应的完成通过TLC分析确认。将反应混合物在减压下蒸发并且在水和乙酸乙酯之间分开。将有机层用NaHCO3、柠檬酸、盐水溶液洗涤,经 Na2SO4干燥并且在减压下蒸发,其进一步通过硅胶柱色谱(洗脱剂:己烷中的0-5%乙酸乙酯)纯化,获得2.8g的化合物1e(收率:44.4%)。LCMS: 836.4(M+H)+。
步骤1e:
向在CH2Cl2(10mL)中化合物1e(2.3g,2.7mmol)加入二乙胺(10mL) 并且将反应混合物在室温搅拌30分钟。将得到的溶液在真空中浓缩,得到胶质残留物。将粗制化合物通过中性铝土柱色谱(洗脱剂:己烷中的 0-50%乙酸乙酯,随后氯仿中的0-5%甲醇)纯化,得到1.4g的1f(收率: 90%)。LCMS:636.5(M+Na)+。
步骤1f:
向化合物1f(0.45g)在CH2Cl2(5mL)中的溶液中加入三氟乙酸(5mL) 和催化量的三异丙基硅烷并且在室温搅拌3h以移除酸敏感保护基团。将得到的溶液在真空中浓缩,获得0.29g的粗制化合物1,使用实验条件下描述的制备型HPLC方法将其纯化。1H NMR(DMSO-d6,400MHz):δ2.58 (m,2H),3.53(m,3H),3.91(t,1H),4.36(t,1H),6.91(s,1H),7.45(s, 1H);13C NMR(DMSO-d6,400MHz):δ20.85,45.71,50.23,65.55,171.03, 171.41,181.66。LCMS:216.2(M+H)+;HPLC:tR=13.1分钟。
实施例2:化合物2的合成
步骤2a:
在室温将THF(30mL)中的化合物1f(2.7g,4.39mmol)与化合物2b (1.67g,4.39mmol)偶联进行脲连接。偶联通过加入在THF(10mL)中的 TEA(0.9g,8.78mmol)来引发并且将得到的混合物在室温搅拌。20h完成后,将THF从反应物料中蒸发,并且在水和乙酸乙酯之间分开。将有机层用水、盐水洗涤,经Na2SO4干燥并且在减压下蒸发,得到化合物2a,将其通过硅胶柱色谱(洗脱剂:己烷中的0-50%乙酸乙酯)进一步纯化,获得3.46g的化合物2a(收率:92.10%)。LCMS 857.4(M+H)+。
步骤2b:
向化合物2a(0.22g,0.25mmol)在CH2Cl2(5mL)中的溶液中,加入三氟乙酸(5mL)和催化量的三异丙基硅烷,并且在室温搅拌3h。将得到的溶液在减压下浓缩,获得0.35g粗制化合物。将粗制固体材料使用实验条件下描述的制备型-HPLC方法纯化。LCMS:347.1(M+H)+;HPLC:tR= 12.9分钟。
化合物2b(NO2-C6H4-OCO-Thr(OtBu)-OtBu)的合成:
向CH2Cl2(20mL)中的化合物H-Ser(tBu)-OtBu(2g,9.2mmol)中加入三乙胺(1.39g,13.8mmol)并且将溶液在室温搅拌5-10分钟。向该混合物中加入氯甲酸4-硝基苯酯(2.22g,11.04mmol)在CH2Cl2中的溶液,并且将得到的混合物在室温搅拌30分钟。反应的完成通过TLC分析确认。反应完成后,将反应混合物用CH2Cl2稀释并用水和5.0M柠檬酸溶液洗涤,经Na2SO4干燥并且在减压下蒸发,得到粗制化合物2b,将其通过硅胶柱色谱(洗脱剂:己烷中的0-20%乙酸乙酯)进一步纯化,获得2.1g(58.9%) 的2b。
实施例3:化合物3的合成
使用与实施例1(化合物1)中所述类似的程序合成化合物并且以相反顺序连接D-氨基酸。使用Boc-D-Thr(tBu)-OH替代Boc-Ser(tBu)-OH(化合物1a,实施例1)并且使用Fmoc-D-Asn(trt)-OH替代Fmoc-Asn(trt)-OH,获得0.15g标题化合物3的粗制材料。LCMS:230.1(M+H)+。
实施例4:化合物4的合成
使用与对于用于合成化合物2的实施例2所述类似的程序,使用 H-Thr(tBu)-OtBu替代H-Ser(tBu)-OtBu(在化合物2b的合成中)合成化合物,获得0.35g标题化合物的粗制材料。使用实验条件下描述的制备型 HPLC纯化粗制固体材料。LCMS:361.2(M+H)+,HPLC:tR=12.19分钟。
实施例5:化合物5的合成
使用与实施例4(化合物4)中所述类似的程序合成化合物,D-氨基酸以相反顺序连接。使用Boc-D-Thr(tBu)-OH替代Boc-Ser(tBu)-OH,使用 Fmoc-D-Asn(trt)-OH替代Fmoc-Asn(trt)-OH,并且使用H-D-Ser(tBu)-OtBu 替代H-Thr(tBu)-OtBu,获得0.3g标题化合物的粗制材料。使用实验条件下描述的制备型HPLC纯化粗制固体材料。LCMS:361.3(M+H)+。HPLC: tR=13.58分钟。
实施例6:化合物6的合成
使用与实施例2中所述类似的程序,通过使用H-Thr(tBu)-OMe替代 H-Ser(tBu)-OtBu(化合物2b的合成中)来合成化合物,获得0.2g标题化合物的粗制材料。使用实验条件下描述的制备型HPLC纯化粗制固体材料。 LCMS:375.1(M+H)+,HPLC:tR=11.84分钟。
实施例7:化合物7的合成
步骤7a:
使用与对于化合物2a(实施例2,步骤2a)相似的步骤,使用 H-Thr(tBu)-OMe替代H-Ser(tBu)-OtBu,合成化合物7a,得到粗制材料,将其通过硅胶柱色谱(洗脱剂:己烷中的0-50%乙酸乙酯)进一步纯化,得到2.0g的化合物7a(收率:74%)。LCMS:829.2(M+H)+。
步骤7b:
在0℃向化合物7a(0.35g,4.0mmol)在THF(5mL)中的溶液中加入氢氧化锂(0.026g,0.63mmol)并且将混合物在室温搅拌2h。反应的完成通过TLC分析确认。从反应材料蒸发THF,并且在水和乙酸乙酯之间分开。将有机层用柠檬酸、盐水溶液洗涤,经Na2SO4干燥并且在减压下蒸发,获得7b,将其通过硅胶柱色谱(洗脱剂:DCM中的0-5%甲醇) 进一步纯化,得到0.3g产物7b(收率:86.7%).LCMS 815.2(M+H)+。
步骤7c:
使用DMF(10mL)中的HOBT(0.072g,0.54mmol)和DIC(0.068g, 0.54mmol)方法将化合物7b(0.295g,0.39mmol)固定在Rink酰胺(Rink amide)树脂(0.7g,0.55mmol/g)。将树脂在室温搅拌12h。将树脂用DCM、 DMF和DCM洗涤并干燥。使用TFA(5mL)和催化量的TIPS将目标化合物从Rink酰胺树脂裂解。让树脂在室温保持2h并偶尔搅拌。2h后,在氮气氛下蒸发TFA和TIPS,并且将得到的残基用二乙醚洗涤,获得0.1g 的标题化合物7的粗制材料。使用实验条件下描述的制备型HPLC纯化粗制固体材料。LCMS:360.0(M+H)+,HPLC:tR=13.88分钟。
实施例8:化合物8的合成
使用与实施例2(化合物2)中所述类似的程序,使用 Fmoc-Glu(OtBu)-OH替代Fmoc-Asn(Trt)-OH,合成化合物,得到0.4g标题化合物的粗制材料。使用实验条件下描述的制备型HPLC纯化粗制固体材料。LCMS:362.1(M+H)+。HPLC:tR=13.27分钟。
基于上述实验步骤制备下表3中的化合物。
表3
实施例9:在重组PD-L1/PD-L2的存在下小鼠脾细胞增殖的挽救
使用重组小鼠PD-L1(rm-PDL-1,目录号:1019-B7-100;R&D系统) 作为PD-L1的来源。
必需品:
从6-8周龄C57BL6小鼠获得的小鼠脾细胞;RPMI 1640(GIBCO, Cat#11875);高葡萄糖DMEM(GIBCO,Cat#D6429);胎牛血清[Hyclone, Cat#SH30071.03];青霉素(10000单位/mL)-链霉素(10,000μg/mL)液体 (GIBCO,Cat#15140-122);MEM丙酮酸钠溶液100mM(100x),液体 (GIBCO,Cat#11360);非必需氨基酸(GIBCO,Cat#11140);L-谷氨酰胺(GIBCO,Cat#25030);抗-CD3抗体(eBiosciences-16-0032);抗-CD28 抗体(eBiosciences-16-0281);ACK裂解缓冲液(1mL)(GIBCO,Cat# -A10492);Histopaque(密度-1.083gm/mL)(SIGMA10831);台盼蓝溶液 (SIGMA-T8154);2mL Norm Ject Luer Lock注射器-(Sigma 2014-12);40μm 尼龙细胞滤器(BD FALCON 35230);血球计(Bright line-SIGMA Z359629);FACS缓冲液(PBS/0.1%BSA):具有0.1%牛血清白蛋白(BSA)(SIGMA A7050)和叠氮化钠(SIGMA 08591)的磷酸缓冲盐水(PBS)pH 7.2(HiMedia TS1006);5mM CFSE储存溶液:CFSE储存溶液通过用180μL的二甲亚砜(DMSO C2H6SO,SIGMA-D-5879)稀释冻干的CFSE而制备并且等分到小管中用于进一步使用。将工作浓度从10μM滴定到1μM. (eBioscience-650850-85);0.05%胰蛋白酶和0.02%EDTA(SIGMA 59417C); 96-孔形式ELISA板(CorningCLS3390);BD FACS口径(E6016);重组小鼠 B7-H1/PDL1 Fc Chimera,(rm-PD-L1目录号:1019-B7-100)。
方案
脾细胞制备和培养:
将通过在40μm细胞滤器磨碎小鼠脾而获得的在50mL离心管中的脾细胞进一步在室温用1mL ACK裂解缓冲液处理5min。在用9mL RPMI 完全培养基洗涤后,将细胞重悬在15mL管中的3mL的1xPBS中。将3mL Histopaque小心加入至管底,不破坏上面覆盖的脾细胞悬浮液。在室温在 800xg离心20min后,小心收集脾细胞的不透明层,不使层破坏/混合。用冷的1xPBS洗涤脾细胞两次,然后使用台盼蓝排除方法进行总细胞计数,并且进一步用于基于细胞的测定。
将脾细胞培养在RPMI完全培养基(RPMI+10%胎牛血清+1mM丙酮酸钠+10,000单位/mL青霉素和10,000μg/mL链霉素)中,并且在37℃维持在具有5%CO2的CO2温箱中
CFSE增殖测定:
CFSE是被动散布到细胞中并且结合于细胞内蛋白的染料。将1x106个细胞/mL的所获得的脾细胞用预温热的1xPBS/0.1%BSA溶液中的5μM 的CFSE在37℃处理10min。将5体积的冰冷的培养基使用于细胞并在冰上孵育5分钟以将过量的CFSE猝灭。CFSE标记的脾细胞用冰冷的完全RPMI培养基进一步洗涤三次。将CFSE标记的1x105个脾细胞加入至含有MDA-MB231细胞(在高葡萄糖DMEM培养基中培养的1x105个细胞) 或重组人PDL-1(100ng/mL)和测试化合物的孔中。用抗-小鼠CD3和抗- 小鼠CD28抗体(各自1μg/mL)刺激脾细胞,并且将培养物进一步在37℃用5%CO2孵育72h。收获细胞并且用冰冷的FACS缓冲液洗涤三次并且通过流式细胞术用488nm激发和521nm发射滤波器分析增殖百分比。
数据搜集,加工和推断:
使用细胞寻找FACS程序分析脾细胞增殖百分数,并且在减去%背景增殖值并且相对于作为100%的%刺激的脾细胞增殖(阳性对照)标准化后,评估化合物导致的脾细胞增殖的挽救百分数。
刺激的脾细胞:脾细胞+抗-CD3/CD28刺激
背景增殖:脾细胞+抗-CD3/CD28+PD-L1
化合物增殖:脾细胞+抗-CD3/CD28+PD-L1+化合物
通过在配体(PDL-1)的存在下向抗-CD3/CD28刺激的脾细胞中加入需要浓度的化合物来检测化合物效应(表4)。
表4
Claims (44)
2.根据权利要求1所述的用途,其中R2是–CO-Aaa。
4.根据权利要求1所述的用途,其中Aaa是选自Thr和Ser的氨基酸残基;其中所述C-末端是CO2H。
6.根据权利要求1所述的用途,其中R1表示氨基酸Ser或Thr的侧链。
7.根据权利要求1所述的用途,其中R1被C1-C5烷基取代。
8.根据权利要求1所述的用途,其中R3表示氨基酸Asn或Glu的侧链。
9.根据权利要求1所述的用途,其中
R1表示氨基酸Ser或Thr的侧链;
R2是-CO-Aaa;
Aaa是选自Thr和Ser的氨基酸残基;其中所述C-末端是CO2H;
R3表示氨基酸Asn或Glu的侧链。
10.根据权利要求9所述的用途,其中R1表示氨基酸Ser的侧链。
11.根据权利要求9所述的用途,其中R1表示氨基酸Thr的侧链。
12.根据权利要求9所述的用途,其中Aaa是Ser。
13.根据权利要求9所述的用途,其中Aaa是Thr。
14.根据权利要求1所述的用途,其中R3表示氨基酸Asn的侧链。
15.根据权利要求1所述的用途,其中R3表示氨基酸Asp的侧链。
16.根据权利要求1所述的用途,其中R3表示氨基酸Gln的侧链。
17.根据权利要求1所述的用途,其中R3表示氨基酸Glu的侧链。
18.根据权利要求1所述的用途,其中R2是H。
43.根据权利要求1至42中任一项所述的用途,其中所述癌症选自乳腺癌、结肠癌、肺癌、黑素瘤、前列腺癌和肾癌。
44.根据权利要求1至42中任一项所述的用途,其中所述癌症选自骨癌、头或颈癌、胰腺癌、皮肤癌、皮肤或眼内恶性黑素瘤、子宫内膜癌、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、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、慢性白血病、急性白血病、急性髓细胞白血病、慢性髓细胞白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、淋巴细胞性淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、原发性CNS淋巴瘤、肿瘤血管生成、脊柱肿瘤、脑干胶质瘤、垂体腺瘤、卡波济氏肉瘤、表皮样癌、鳞状上皮细胞癌和T细胞淋巴瘤。
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