CN117643587A - 用于治疗癌症的杂二环羧酸 - Google Patents
用于治疗癌症的杂二环羧酸 Download PDFInfo
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Abstract
本申请提供了用于治疗癌症的药物组合物,其包含如下所列的化合物,或其药学上可接受的盐;本申请还提供上述化合物或其药学上可接受的盐在制备治疗癌症的药物中的应用。
Description
相关申请
本申请是中国专利申请(申请号201980011401.8、发明名称“用于治疗癌症或炎性疾病的杂二环羧酸”,申请日:2019年2月2日)的分案申请。本申请要求于2018年2月5日提交的PCT申请号PCT/CN2018/075198的优先权,其内容全部并入本文。
背景技术
前列腺素是引发疼痛,发烧和其他与炎症相关的症状的介质。特别是前列腺素E2(PGE2)是在炎症条件下检测到的主要类花生酸。此外,它还参与各种生理和/或病理症状,例如痛觉过敏,子宫收缩,消化蠕动,觉醒,胃酸分泌的抑制,血压,血小板功能,骨代谢,血管生成等等。PGE2受体四个亚型(EP1,EP2,EP3和EP4)表现出不同的药理学特性,已分别克隆出。EP4亚型,是一种G蛋白偶联受体,刺激cAMP的产生,在多种组织中分布,表明其在PGE2介导的生物学活动中起重要作用。专利申请出版物WO 96/06822,WO 96/11902,EP 752421-A1,WO03/16254,WO05/021508和WO07/121578公开了可治疗前列腺素引起的疾病的化合物。三篇综述文章描述了前列腺素受体以及最常用的选择性激动剂和拮抗剂的特征和治疗实用性:《花生酸类:从生物技术到治疗应用》,Folco,Samuelsson,Maclouf和Velo编辑,Plenum出版社,纽约,1996年,第14章,137-154页;《脂质介质和细胞信号杂志》,1996年,14卷,83-87页;《前列腺素和其他脂质介质》,2002年,69卷,557-573页。
PGE2有利于促进炎性免疫应答;无论怎样,PGE2已被认为是许多实体瘤产生的免疫抑制环境中的重要组成部分(Whiteside,Expert Opinion in Biological Therapy,2010,10,1019-1035),肿瘤微环境中的持续水平促进多种免疫抑制细胞(包括肿瘤相关巨噬细胞(TAM),Treg细胞和骨髓衍生抑制细胞(MDSCs)的积累和增强活性,从而促进肿瘤免疫逃逸。越来越多的证据表明,通过EP4升高的cAMP水平是导致免疫细胞免疫抑制的主要信号(Yokoyama U等,Pharmacol.Rev.,2013,65:1010-1052)。研究还表明,前列腺素E受体4(EP4)的拮抗剂能阻断前列腺素E2(PGE2)通过PGE2与前列腺素E受体4亚型的相互作用而进行的信号传导,从而有效诱导炎症(Chen等,British J Pharmacol,2010,160,292-310)。在APCmin突变的背景下,与野生型动物相比,小鼠中EP4的敲除显示延迟的肿瘤发生,表明宿主免疫细胞中PGE2-EP4信号传导的促肿瘤活性(Mutoh M等,Cancer Res.,2002,62:28-32)。一致地,已经显示选择性EP4受体拮抗剂在各种临床前肿瘤模型中减缓肿瘤进展和肿瘤转移而不影响体外癌细胞增殖(Yang等人,cancer Res.,2006,66:9665-9672;Mao Y等人,Clin.Canser Res.,2014,20:4096-4106)。
基于这样的研究,PGE2受体的EP4亚型的拮抗剂因此能有效治疗由EP4受体介导的疾病或病症,如癌症和炎性疾病或病症(例如急性和慢性疼痛,骨关节炎,类风湿性关节炎)。
发明内容
本发明的化合物是EP4受体的拮抗剂,因此可用于治疗前列腺素E2介导的疾病或病症。本发明中所述的EP4拮抗剂在体内生物转化后对前列腺素具有拮抗作用,因此可用于治疗,特别是用于治疗选自以下的疾病或病症:疼痛,神经性疼痛,内脏痛,炎性疼痛,伤害性疼痛,慢性疼痛,急性疼痛,风湿热、流感或其他病毒感染、普通感冒引起的发烧或发炎,腰背和颈部疼痛,骨骼疼痛,产后疼痛,痛经,头痛,偏头痛,牙痛,扭伤和拉伤,肌炎,神经痛,纤维肌痛,滑膜炎,关节炎,包括类风湿性关节炎,退行性关节疾病(骨关节炎),痛风和强直性脊柱炎,滑囊炎,烧伤,包括放射和腐蚀性化学损伤,晒伤,手术和牙科手术后的疼痛,骨折,免疫和自身免疫疾病;细胞肿瘤转化或转移性肿瘤生长;糖尿病性视网膜病变,肿瘤血管生成;前列腺素引起的平滑肌收缩,伴有痛经,早产,过敏性鼻炎,特应性皮炎,哮喘或嗜酸性粒细胞相关疾病,高免疫球蛋白血症,卡斯尔曼(Castleman)病,骨髓瘤;阿尔茨海默氏病,睡眠障碍,内分泌失调;青光眼;骨质流失;骨质疏松,促进骨形成;佩吉特氏病:消化性溃疡,胃炎,局部性肠炎,溃疡性结肠炎,憩室炎或其他胃肠道病变;胃肠道出血和正在接受化疗的患者;凝血功能异常,选自凝血酶原低,血友病,其他出血问题;肾脏疾病;血栓形成;闭塞性血管疾病;术前;和抗凝;交感神经维持性疼痛;截肢,皮肤状况(例如湿疹,牛皮癣)导致的疼痛;眼科疾病,例如青光眼,视网膜炎,视网膜病变,葡萄膜炎和眼组织急性损伤(例如结膜炎);肺部疾病(例如支气管炎,肺气肿,过敏性鼻炎,呼吸窘迫综合症,鸽友病,农民肺,COPD);胃肠道呼吸道疾病(例如口疮,克罗恩病,特应性胃炎,胃炎,胃溃疡,结肠炎,腹腔疾病,局部回肠炎,肠易激综合征,炎症性肠病,胃肠道反射性疾病);器官移植;其他具有炎症成分的疾病,例如血管疾病,偏头痛,结节性动脉炎,甲状腺炎,再生障碍性贫血,霍奇金病,巩膜瘤,重症肌无力,多发性硬化症,类瘤,肾病综合征,贝谢氏综合征,多发性肌炎,牙龈炎,心肌缺血,发热、全身性红斑狼疮,肌腱炎,滑囊炎和干燥综合征;血小板功能异常(例如闭塞性血管疾病);利尿作用;阳痿或勃起功能障碍;以骨代谢异常或吸收异常为特征的骨病,例如骨质疏松症;高钙血症,甲状旁腺功能亢进,佩吉特氏骨病,溶骨,伴有或不伴有骨转移的恶性高血钙症,类风湿性关节炎,牙周炎,骨关节炎,骨痛,骨质减少,癌性恶液质,结石,结石症(尤其是尿石症),实体癌,痛风和强直性脊柱炎,肌腱炎和滑囊炎;骨骼吸收,NSAID和COX-2抑制剂的血液动力学副作用,心血管疾病,高血压或心肌缺血;功能性或有机静脉功能不全;静脉曲张治疗;痔疮;与明显降低的动脉压有关的休克状态(例如败血性休克);神经退行性疾病和神经变性,例如痴呆,尤其是退化性痴呆(包括老年性痴呆,阿尔茨海默氏病,匹克氏病,亨廷顿舞蹈症,帕金森氏病和克雅氏病,ALS,运动神经元病);血管性痴呆(包括多发性梗塞性痴呆);以及与颅内占位性病变相关的痴呆症;外伤;感染和相关状况(包括艾滋病毒感染);代谢;毒素;缺氧和维生素缺乏症;与衰老相关的英里(mile)认知障碍,特别是与年龄相关的记忆障碍;神经保护,中风后的神经变性,心脏骤停,肺旁路,脑外伤,脊髓损伤;耳鸣,1型糖尿病并发症(例如,糖尿病微血管病,糖尿病性肾病,黄斑变性,青光眼),肾病综合征,再生障碍性贫血,葡萄膜炎,川崎病和肉瘤;肾功能不全(例如,肾炎,尤其是肾小球膜增生性肾小球肾炎,肾病综合征),肝功能不全(肝炎,肝硬化),胃肠功能不全(腹泻),酒精性肝硬化,淀粉样变性,动脉粥样硬化,心脏病,硬化,骨质疏松,器官移植后反应,糖皮质激素诱发的骨质疏松症,牙齿脱落,骨折,多发性骨髓瘤,各种水肿,高血压,经前期紧张,尿路结石,少尿,高血尿症,荨麻疹,接触型皮炎,恒河猴皮炎,尿频,学习障碍,齿龈炎,牙周炎,肺损伤,肝损伤和便秘等,在哺乳动物受试者,特别是人类体内。
本发明涉及用起EP4受体拮抗剂作用的杂环酰胺衍生物治疗炎性疾病,瘤形成和癌症的方法。用于相同治疗的药物组合物也包括在本发明的范围内。
本发明包括一种治疗对非甾体抗炎药敏感的炎性疾病的方法,该方法包括向需要这种治疗的患者施用无毒的治疗有效量的式I所示化合物。在该实施方案中包括以上方法,其中患者还处于血栓性心血管事件和/或胃肠道溃疡/出血的风险中。
本发明的另一个实施方案包括治疗前列腺素E 2介导的疾病的方法,所述疾病有利地通过选择性拮抗EP4的活性剂来治疗,而不是通过抑制COX-1/COX-2的活性剂来治疗,所述方法包括对需要这种治疗的患者施用无毒的有效量的式I所示化合物。在该实施方案中包括以上方法,其中患者也处于血栓性心血管事件的风险中。
举例来说,但不限于,本文所述的化合物可用于靶向肿瘤微环境中的宿主免疫抑制细胞的癌症免疫疗法,所述肿瘤微环境可以是髓系或淋巴系。在一个实施方案中,本文所述的化合物可用于治疗具有各种肿瘤类型的患者,包括那些具有高水平髓样浸润物的患者。可以例如基于癌症基因组图谱(TCGA)和其他来源来确定这种髓系浸润水平。还可以基于蛋白质或基因(例如,mRNA)表达分析来鉴定此类肿瘤类型。
肿瘤类型可以包括但不限于胰腺腺癌,肾透明细胞癌,头颈部鳞状细胞癌(SCCHN),非小细胞肺癌(NSCLC),结直肠癌(CRC),肝细胞癌(HCC),浆液性上皮性卵巢癌,宫颈癌,移行细胞膀胱癌,皮肤癌,成胶质细胞瘤,肾癌,前列腺癌。胰腺癌和三阴性乳腺癌(TNBC)。在本发明的更具体的方面,提供了治疗癌症和/或产生记忆免疫应答的方法,包括给予式(I)所示的化合物或其药学上可接受的盐:
其中:
R1和R2独立地选自氢,C1-6烷基,C1-6环烷基,C1-6氟环烷基,C1-6氟烷基;或R1,R2以及它们都连接的碳原子一起完成一个三元至六元碳环,该环任选被Rc取代;或R1和R2与它们都连接的碳原子一起完成一个三元至六元环,该环含有一个或两个杂原子,例如S,O或NRb,其中Rb选自氢,C1-6烷基,C1-6环烷基,C1-6氟环烷基,C1-6氟烷基,芳基,杂芳基,C(O)C1-6烷基,C(O)芳基,S(O)2烷基,和S(O)2芳基;
Y是O或S;
X是键,=CH-,CH2,O,或S;
Ar1和Ar2独立地选自C3-6环烷基,芳基,杂芳基和杂环基,或C3-6环烷基、芳基、杂芳基和杂环基的稠合类似物,其中Ar1和Ar2任选地被1-3个Rc基团取代;
Rc独立地选自卤素或R1,
Ra表示-CO2H,-CO2M,-C(O)NHS(O)2Raa,或
Raa选自C1-6烷基,C1-6卤代烷基,C1-6环烷基,C1-6环卤代烷基,芳基和杂芳基;
M是酯前药基团;和
是6,6-5,5-5,6-或6,5-双环模板。
在一实施例中,是/>其中A,B和C’各自独立地选自N,CH和C(Rc);G是–C(O),-C(S)-,或–S(O)2-;L是–CH2-,S,O或NRc。
在另一实施例中,是/>其中A,B和C’各自独立地为N,CH或C(Rc);X,L和G各自独立地为键,-CH2-,O,S或N(Rd);Rd是H,芳基,或烷基。
在另一实施例中,是/>其中Rc如先前所定义。
在另一实施例中,是/>其中A,B和C’各自独立地选自N,CH和C(Rc)。
在另一实施例中,是/>其中–K–L–M–选自:–C(R3)=C(R)–N–,–C(R4)=N–C(R)–,–C(R4)=N–N–,–N=C(R4)–N–,–N=N–N–,–C(R4)2–N=C–,–N(R4)–C(R)=C–,–N(R4)–N=C–,–O–N=C–和–S–N=C–,其中R3选自氢,卤素,C1-6烷基,C1-6氟烷基,C1-6烷氧基,C1-6氟烷氧基和乙酰基;每个R4独立地选自氢,C1-6烷基,C1-6氟烷基,C1-6烷氧基,C1-4氟烷氧基和乙酰基。
在另一实施例中,选自以下6,5-杂二环部分:
在一个实施方案中,本发明涉及式I所示的化合物,其中R1为甲基且R2为氢;或其中R1是甲基,R2是甲基;或其中R1和R2与它们都连接的碳原子一起形成三元至六元碳环。
在另一个实施方案中,本发明涉及式I所示的化合物,其中Ar1是苯基,任选地被一个至三个Rc基团取代;或式I所示的化合物,其中Ar2是苯基,Ar2任选地被1-3个Rc基团取代。
本发明还包括式I所示的前药。该前药可以是酯或酰胺或另一个合适的基团。优选的前药包括式Ia所示的酯衍生物,其中Rd代表具有1至10个碳原子的烷基或具有7至12个碳原子的芳烷基,芳基或杂芳基。
式I所示的另一种优选的前药是酯衍生物,其含有一个或多个释放一氧化氮的基团(式Ib),其中T是任何合适的连接结构。
EP4拮抗剂的释放一氧化氮的前药化合物的一个实施方案是式Ic所示的化合物或其药学上可接受的盐:
其中
Z为O,S或NRe,Re为氢,烷基或芳基;
V独立地选自O和S,并且每个V独立地连接至C1-10烷基的任何一个碳原子;和
n是1,2,3或4。
EP4拮抗剂释放一氧化氮的前药化合物的另一个实施方案是式Id所示的那些,
其中
Z为O,S或NRe;Re是氢,烷基或芳基;
V是O或S;每个V独立地连接到C1-C110烷基的一个碳原子上;
Rf选自氢,卤素,烷氧基,烷硫基,CN,CF3,烷基,烷基磺酰基,S(O)2NH2,和S(O)2NH-烷基;和
W是
优选地,EP4拮抗剂的释放一氧化氮的前药化合物是式Ie,If或Ig所示的那些:
其中n是1到10的整数;
其中n和m是1到10的整数;
其中n是1至6的整数,并且Rg是H,卤素,烷基,卤代烷基。
本发明的化合物可用于在需要这种治疗或预防的受试者中治疗或预防肿瘤形成。治疗包括部分或全部抑制肿瘤形成,扩散或转移,以及部分或全部破坏肿瘤细胞。术语“预防”包括完全预防临床上明显的瘤形成的发作或预防处于危险中的个体的临床上明显的瘤形成阶段的发作。该定义还意图包括预防恶性细胞的起始或阻止或逆转恶性前细胞向恶性细胞的发展。这包括对有发生赘生物危险的人的预防性治疗。用于治疗目的的术语“受试者”包括患有任何一种已知肿瘤的任何人类或哺乳动物受试者,并且优选是人类受试者。对于预防方法,该受试者是任何人类或动物受试者,并且优选有患上肿瘤风险的人类受试者。受试者可能由于暴露于致癌剂,遗传易患肿瘤等,而处于危险中。
EP4拮抗剂与以下药物的各种组合的抗肿瘤活性:辐射;细胞毒性t淋巴细胞抗原4的抗体(抗CTLA4);程序性死亡配体1的抗体(抗-PDL1);程序性细胞死亡蛋白1的抗体(抗PD1);并且已经检测到抗代谢物。该检查的结果表明,与单独的单药剂治疗相比,EP4拮抗剂与其他疗法的组合具有改善的和/或协同的抗肿瘤活性,在某些实施方案中,这可能导致针对肿瘤,甚至针对不同的癌症的记忆免疫反应。因此,在本发明的一个方面,提供了一种在有需要的受试者中治疗癌症的方法,该方法包括与选自放射疗法,抗体疗法和抗代谢化学疗法的疗法联合施用EP4拮抗剂。在本发明的更具体的方面,抗体治疗选自CTLA4抗体治疗,PDL1抗体治疗和PD1抗体治疗。在一些实施方案中,癌症是转移性癌症。本发明的另一方面,提供了一种在有此需要的受试者中产生记忆免疫应答的方法,该方法包括与选自放射疗法,抗体疗法和抗肿瘤药的疗法联合施用一定量的EP4拮抗剂。代谢物化学疗法。在本发明的另一个更具体的方面,抗体疗法选自CTLA4抗体疗法,PDL1抗体疗法和PD1抗体疗法。本发明还包括一种用有效量的本发明化合物治疗癌症或使用有效量的本发明化合物与有效量的下述物质组合治疗癌症的方法:放射线;抗细胞毒性t淋巴细胞抗原4的抗体(抗CTLA4);抗程序性死亡配体1的抗体(抗PDL1);抗程序性细胞死亡蛋白1的抗体(抗PD1);吲哚胺-2,3-二加氧酶(IDO)抑制剂;色氨酸-2,3-双加氧酶(TDO)抑制剂;和抗代谢物。这些抗体可以选自但不限于MDX-010(ipilimumab,Bristol-Myers Squibb),CP-675,206(tremelimumab,Pfizer),MPDL3280A(Roche),MDX-1106(nivolumab,Bristol-Myers Squibb),labrolizumab(Merck)和pembrolizumab(Merck)。
附图说明
图1显示了化合物1(INV-1121)对小鼠肿瘤生长的抑制作用;
图2显示了有或没有化合物1的不同治疗对小鼠肿瘤生长的抑制作用;
图3显示了对B16F10黑素瘤的生长的体内抑制作用的结果;
图4显示了对刘易斯肺癌生长的体内抑制作用;
图5显示了施用测试化合物的小鼠的爪的温度变化;
图6显示了施用测试化合物的小鼠的爪的肿胀减少。
具体实施方式
定义
本文所使用的缩写具有其在化学和生物学领域的常规含义。
“EP4拮抗剂”是指抑制或阻断由PGE2与EP4受体的相互作用触发的细胞信号转导的化合物。实例包括但不限于本文教导的式(1)所示的化合物,包括在PCT/US2009/0537482和WO2010/019796中描述的INV-1120和INV-1121。
术语“治疗前列腺素E2介导的疾病或病症”是指治疗或预防任何慢性疾病或病症,所述慢性疾病或病症有利地由选择性EP4拮抗剂治疗或预防。该术语包括减轻各种疾病的疼痛,发烧和炎症,所述疾病包括风湿热,与流感或其他病毒感染有关的症状,普通感冒,下背痛,颈部疼痛,痛经,头痛,偏头痛,牙痛,扭伤和拉伤,风湿性关节炎,肌炎,神经痛,滑膜炎,关节炎,包括类风湿关节炎,退行性关节疾病(骨关节炎),痛风,强直性脊柱炎,滑囊炎,烧伤,伤害,以及手术后的疼痛和炎症。另外,此类化合物可抑制细胞赘生物转化和转移性肿瘤生长,因此可用于治疗和/或预防癌症。
术语“治疗(treatment)”,“治疗(treat)”或“治疗(treating)”是指减轻,抑制和/或逆转需要其的受试者的癌症进展。术语“治疗”包括成功治疗或改善癌症的任何指标,包括任何客观或主观参数,例如减少;缓解;减轻症状或使受试者更耐受伤害、病理或病证;延缓或减缓进展速度等。治疗或改善的测量可以基于,例如,本领域已知的身体检查,病理学检查和/或诊断检查的结果。与在没有采取措施的情况下发生的情况相比,治疗还可以指减少癌症的发生或发作,或其复发(例如缓解时间的延长)。
术语“瘤形成(neoplasia)”包括良性和癌性肿瘤,增生和息肉。因此,本发明的化合物可用于治疗或预防良性肿瘤,增生和息肉,包括鳞状细胞乳头瘤,基底细胞瘤,移行细胞乳头瘤,腺瘤,胃泌素瘤,胆管细胞腺瘤,肝细胞腺瘤,肾小管腺瘤,细胞瘤,血管球瘤,黑素细胞痣,纤维瘤,粘液瘤,脂肪瘤,平滑肌瘤,横纹肌瘤,良性畸胎瘤,血管瘤,骨瘤,软骨瘤和脑膜瘤。本发明的化合物还可用于治疗或预防癌性肿瘤,增生和息肉,包括鳞状细胞癌,基底细胞癌,移行细胞癌,腺癌,恶性胃泌素瘤,胆管细胞癌,肝细胞癌,肾细胞癌,恶性黑素瘤,纤维肉瘤,肉瘤,脂肪肉瘤,平滑肌肉瘤,横纹肌肉瘤,恶性畸胎瘤,血管肉瘤,卡波济肉瘤,淋巴管肉瘤,骨肉瘤,软骨肉瘤,恶性脑膜瘤,非霍奇金淋巴瘤,霍奇金淋巴瘤和白血病。为了本说明书的目的,“赘生物(neoplasia)”包括脑癌,骨癌,上皮细胞源性瘤(上皮癌),基底细胞癌,腺癌,胃肠道癌,例如唇癌,口腔癌,食道癌,小肠癌和胃癌。癌,结肠癌,直肠癌,肝癌,膀胱癌,胰腺癌,卵巢癌,子宫颈癌,肺癌,乳腺癌和皮肤癌,例如鳞状细胞和基底细胞癌,前列腺癌,肾细胞癌等影响全身上皮,间质或血细胞的已知癌症。本发明的化合物可用于治疗或预防任何上述癌症。本发明的化合物可用于治疗或预防以下细胞类型的良性和癌性肿瘤,增生和息肉:鳞状上皮,基底细胞,过渡上皮,腺上皮,G细胞,胆管上皮,肝细胞,肾小管上皮,黑素细胞,纤维结缔组织,心脏骨骼,脂肪组织,平滑肌,骨骼肌,生殖细胞,血管,淋巴管,骨骼,软骨,脑膜,淋巴样细胞和造血细胞。所述化合物可用于治疗患有腺瘤性息肉的受试者,包括患有家族性腺瘤性息肉病(FAP)的受试者。另外,该化合物可用于防止处于FAP风险中的患者的息肉形成。优选地,本发明的化合物可用于治疗或预防以下癌症:结肠直肠癌,食道胃癌,乳腺癌,头颈癌,皮肤癌,肺癌,肝癌,胆囊癌,胰腺癌,膀胱癌,子宫颈内膜癌,前列腺癌,甲状腺癌和脑癌。
如本文所用,“癌症”可以包括基因遗传突变的结果的癌症。这类癌症的例子包括但不限于乳腺癌,与李-弗劳梅尼综合症有关的癌症,例如儿童肉瘤,白血病和脑癌,与林奇综合症有关的癌症,例如结肠癌,胆管癌,脑癌,子宫内膜癌,肾癌,卵巢癌,胰腺癌,小肠癌,胃癌和输尿管癌,肺癌,黑素瘤,前列腺癌,成视网膜细胞瘤,甲状腺癌和子宫癌。此外,癌症可以是获得性突变的结果,例如,饮食,环境和/或生活方式引起的突变或体细胞突变。此类癌症的实例可包括但不限于肾上腺癌,肾上腺皮质癌,膀胱癌,脑癌,原发性脑癌,神经胶质瘤,成胶质细胞瘤,乳腺癌,宫颈癌,结肠癌(非限制性实例包括结直肠癌如结肠腺癌和结肠癌),子宫内膜癌,表皮癌,食道癌,胆囊癌,泌尿生殖道癌,头颈癌,肾癌,肝癌,肺癌(非限制性例子包括腺癌,小细胞肺癌和非小细胞肺癌),淋巴瘤(非限制性例子包括B细胞淋巴瘤,T细胞淋巴瘤,霍奇金淋巴瘤,非霍奇金淋巴瘤),黑素瘤,恶性黑素瘤,恶性类癌,恶性胰腺胰岛素瘤,骨髓瘤,多发性骨髓瘤,卵巢癌,胰腺癌(例如外分泌胰腺癌),前列腺癌,肾细胞癌,皮肤癌,例如,除前述的其它那些之外,鳞状细胞癌,胃癌,睾丸癌,甲状腺癌,甲状腺滤泡癌,威尔姆斯氏肿瘤,绒毛膜癌,霉菌病,恶性高钙血症,子宫颈增生,白血病,急性淋巴细胞性白血病,慢性淋巴细胞性白血病,毛细胞淋巴瘤,伯克氏淋巴瘤,急性粒细胞性白血病,慢性粒细胞性白血病,骨髓增生异常综合征,早幼粒细胞性白血病,慢性粒细胞白血病,急性粒细胞白血病,纤维肉瘤,横纹肌肉瘤(habdomyosarcoma),星形细胞瘤,神经母细胞瘤,横纹肌肉瘤(rhabdomyosarcoma),神经鞘瘤,卡波济肉瘤,多发性红细胞增多症,原发性血小板增多症,霍奇金病,非霍奇金淋巴瘤,软组织肉瘤,成骨肉瘤,原发性巨球蛋白血症,精原细胞瘤,畸胎瘤,骨肉瘤,异种皮色素瘤,角化角膜瘤和视网膜母细胞瘤。
“烷基”本身或作为另一种成分的基团,指的是,除非另有说明,直链(即无支链)或支链,或环状碳氢化合物自由基,或两者兼而有之,这些可能是完全饱和、单不饱和或多不饱和,可以包括双价和多价自由基。含有指定的碳原子数,例如,C1-10或C1-6,指一至十或一至六个碳原子。饱和烃自由基的例子包括,但不限于,如下基团,甲基、乙基、丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、环己基、(环己基)甲基、环丙基甲基,以及正戊基、正己基、正庚基、正辛基等同族体和异构体,等等。不饱和烷基基团含有一个或多个双键,或三键。不饱和烷基的示例包括,但不限于,乙烯基、2-丙烯基、巴豆基、2-异戊烯、2-(丁二烯)、2,4-戊二烯、3-(1,4-戊二烯)、乙炔基、1-和3–丙炔、3-丁炔基,以及较高级的同族体和异构体。仅限于碳氢化合物基团的烷基基团被称为“同族烷基”。
“氟烷基”是指上述定义的烷基,其中一个或多个氢原子被氟原子取代。
“亚烃基”本身或作为另一替代物的基团是指烷基衍生出来的二价基团,例子有但不限于-CH2CH2CH2CH2-、-CH2CH=CHCH2-、-CH2C≡CCH2-、-CH2CH2CH(CH2CH2CH3)CH2-。通常情况下,烷基(或亚烃基)基团含有1至24个碳原子,而那些含有10个或更少碳原子的基团是本发明的首选原子团。“低级烷基”或“低级亚烃基”是指短链烷基或亚烃基基团,一般有八个或更少的碳原子。
“炔基”是指含有至少一个碳碳三键的碳链,并且可以是直链或支链或其组合。炔基的实例包括乙炔基,炔丙基,3-甲基-1-戊炔基,2-庚炔基等等。
“环烷基”是指单环或双环饱和碳环,每个环具有3至10个碳原子。环烷基的一个“稠合类似物”是指与芳基或杂芳基基团稠合的单环,其中连接点在非芳族部分上。环烷基及其稠合类似物的实例包括环丙基,环丁基,环戊基,环己基,环庚基,四氢萘基,十氢萘基,茚满基等等。
“烷氧基”是指具有指定碳原子数的直链或支链的烷氧基。C1-6烷氧基,例如,包括甲氧基,乙氧基,丙氧基,异丙氧基等等。
除非另有说明,否则“杂烷基”本身或结合另一术语是指由至少一个碳原子和至少一个杂原子组成的稳定的直链或支链或环状碳氢基团或其组合,所述杂原子选自O,N,P,Si和S,其中氮,磷和硫原子可随意被氧化,而氮杂原子可随意被季铵化。杂原子O,N,P和S和Si可位于杂烷基基团内部的任何位置,或烷基与分子的其它部分连接的位置。实例包括但不限于-CH2-CH2-O-CH3,-CH2-CH2-NH-CH3,-CH2-CH2-N(CH3)-CH3,-CH2-S-CH2-CH3,-CH2-CH3,-S(O)-CH3,-CH2-CH2-S(O)2-CH3,-CH=CH-O-CH3,-Si(CH3)3、-CH2-CH=N-OCH3、-CH=CH-N(CH3)-CH3、-O-CH3、-O-CH2-CH3,和-CN。可以有两个或三个连续杂原子,例如-CH2-NH-OCH3和-CH2-O-Si(CH3)3。同样地,术语“杂亚烷基”本身或作为另一取代基的一部分是指衍生自杂烷基的二价基团,例如但不限于CH2-CH2-S-CH2-CH2-和-CH2-S-CH2-CH2-NH-CH2-。对于杂亚烷基,杂原子也可以占据一个或两个链末端(例如,单氧亚烃基,双氧亚烃基,单氨基亚烃基,双氨基亚烃基等等)。更进一步,对于亚烷基和杂亚烷基连接基团,该连接基团的分子式的写出方向没有暗示该连接基团的方向。例如,式-C(O)OR'-代表-C(O)OR'-和-R'OC(O)-。如上所述,本文所用的杂烷基基团,包括通过杂原子连接至分子其余部分的那些基团,例如-C(O)R',-C(O)NR',-NR'R”-OR',-SR'和/或-SO2R'。首先列举“杂烷基”,随后列举特定的杂烷基,例如-NR'R”或同类物,可以理解的是,杂烷基和-NR'R”并非多余或互相排斥。相反,列举特定的杂烷基基团以增加清晰性。因此,术语“异烷基”不应该被解释为不包含特定的杂烷基基团,如-NR'R"或同类物。
“环烷氧基”是指与氧原子键合的如上定义的环烷基,例如环丙氧基。
“氟烷氧基”是指上述定义的烷氧基,其中一个或多个氢原子被氟原子取代。
“芳基”是指仅包含碳原子的单环或双环芳香环。芳基的“稠合类似物”是指与单环环烷基或单环杂环基稠合的芳基,其中连接点位于芳香基团上。芳基及其稠合类似物的实例包括苯基,萘基,茚满基,茚基,四氢萘基,2,3-二氢苯并呋喃基,二氢苯并吡喃基,1,4-苯并二氧杂环等等。
“杂芳基”是指含有至少一个选自N,O和S的杂原子的单环或双环芳香环,每个环含有5至6个原子。杂芳基的“稠合类似物”是指与单环环烷基或单环杂环基稠合的杂芳基,其中连接点位于芳香基团上。杂芳基的实例包括吡咯基,异恶唑基,异噻唑基,吡唑基,吡啶基,恶唑基,恶二唑基,噻二唑基,噻唑基,咪唑基,三唑基,四唑基,呋喃基,三嗪基、噻吩、嘧啶、哒嗪基、吡嗪基、苯并恶唑、苯并噻唑、苯并咪唑、苯并呋喃、苯并硫基、呋喃(2,3-b)吡啶、喹啉、吲哚、异喹啉基等等。
在Ar1和Ar2的定义中人提及的所述芳基和所述杂芳基是无取代基的或含有至少一个取代基α;所述的取代基α选自卤素原子,具有1-4个碳原子的烷基,具有1-4个碳原子的烷氧基,具有1-4个碳原子的卤代烷基,含1至4个碳原子的卤烷氧基、氰基,含2至6个碳原子的炔基,含1至5个碳原子的烷酰基,含3至7个环原子的环烷基,杂环芳香基,芳香基,含7至10个碳原子的烷氧基,芳香碳酰基,两个相邻-X基团随意结合形成一个含3个或4个碳原子的亚烃基或亚烯基,氨基碳酰基,含2至5个碳原子的烯基,含1至4个碳原子的硫烷基,氨基亚硫酰基,氨基磺酰基,羟基,含1至4个碳原子的羟烷基,硝基,氨基,羧基,含2至5个碳原子烷氧碳酰基,含1至4个碳原子的烷氧基,含1至4个碳原子的烷基磺酰,含1至4个碳原子的烷酰氨基,含1至6个碳原子的烷酰基(烷基)氨基,在烷酰基和烷基均含1至6个碳原子的烷酰基氨基烷基,在烷酰基和每一烷基均含1至6个碳原子的烷酰基(烷基)氨基烷基,含1至4个碳原子的烷基磺酰氨基,含1至6个碳原子的单或双烷基氨基碳酰基,含1至6个碳原子的单或双烷基氨基亚硫酰基,含1至6个碳原子的单或双烷基氨基磺酰基,含1至4个碳原子的氨基烷基,含1至6个碳原子的单或双烷基氨基,每一烷基均含1至6个碳原子的单或双烷基氨基烷基,含7至10个碳原子的芳烷基,在烷基含1至4个碳原子的杂芳烷基,在烷氧基含1至4个碳原子的杂芳烷氧基,和含1至4个碳原子的烷基磺酰氨基。
“杂环基”是指含有至少一个选自N,S和O的杂原子的单环或双环饱和环,每个所述环具有3至10个原子,其中连接点可以是碳或氮。杂环基的“稠合类似物”是指单环杂环稠合到芳基或杂芳基,其中连接点在非芳香基团上。“杂环基”及其稠合类似物的实例包括吡咯烷基,哌啶基,哌嗪基,咪唑烷基,2,3-二氢呋喃(2,3-b)吡啶基,苯并恶嗪基,四氢对苯二酚、四氢异喹啉基、四氢吲哚等等。该术语也包括部分不饱和非芳香单环,例如通过氮或N-取代的-(1H,3H)-嘧啶-2,4-二酮(N-取代的尿嘧啶)连接的2-或4-吡啶酮。
除非另外说明,否则“卤”或“卤素”本身或作为另一取代基的一部分是指氟,氯,溴或碘原子。另外,诸如“卤代烷基”的术语是指包括单卤代烷基和多卤代烷基。例如,术语“卤代(C1-4)烷基”是指包括但不限于三氟甲基,2,2,2-三氟乙基,4-氯丁基,3-溴丙基等等。
“前药”是指一种可以在体内被转换为母体药物的药剂。前药往往是有用的,因为在某些情况下,它们可能会比母体药物更容易给药。例如,通过口服给药,它们可有生物利用度,而母体药物则不能。在药物成分方面,前药也可比母体药物具有更好的溶解度。前体药物的一个例子,但不限于此,是结构式I所示的成分,它作为酯类化合物(“前药”)给药,以促进跨细胞膜传输,水溶性对其移动性不利,但是,当它代谢水解为羧酸时,活性成分一旦进入细胞,水溶性是有益的。前药的又一个例子,同样不是为了限制术语的范围,可能是一种结合到酸基团的短肽,最终在细胞内转换为活性成分。
所治疗的癌症选自乳腺癌,宫颈癌,结肠直肠癌,子宫内膜癌,成胶质细胞瘤,头颈癌,肾癌,肝癌,肺癌,髓母细胞瘤,卵巢癌,胰腺癌,前列腺癌,皮肤癌和尿路癌。
在本发明的更具体的方面,提供了治疗癌症和/或产生记忆免疫反应的方法。这样的方法包括将式(I)所示化合物或其药学上可接受的盐给予需要治疗的受试者:
其中:
R1,R2各自独立地选自氢,C1-6烷基,C1-6环烷基,C1-6氟环烷基,C1-6氟烷基;或R1,R2以及它们都连接的碳原子一起完成一个三元至六元碳环,该环任选地被Rc取代;或R1,R2与它们都连接的碳原子一起完成一个三元至六元环,该环含有一个或两个杂原子,例如S,O或NRb,其中Rb选自氢,C1-6烷基,C1-6环烷基,C1-6氟环烷基,C1-6氟烷基,芳基,杂芳基,C(O)C1-6烷基,C(O)芳基,S(O)2烷基,S(O)2芳基;
Y是O或S;
X是键,=CH-,CH2,O,或S;
Ar1和Ar2各自独立地选自C3-6环烷基,芳基,杂芳基和杂环基,或C3-6环烷基,芳基,杂芳基和杂环基的稠合类似物,其中Ar1和Ar2任选地被1-3个Rc基团取代;
Rc独立地选自卤素或R1,
Ra表示-CO2H,-CO2M,-C(O)NHS(O)2Raa,或/>
Raa选自C1-6烷基,C1-6卤代烷基,C1-6环烷基,C1-6环卤代烷基,芳基和杂芳基;
M是酯前药基团;并且是6,6-5,5-5,6或6,5-二环模板。
在一个实施例中,是/>其中A,B和C’各自独立为N,CH,或C(Rc);G是-C(O)-,-C(S)-或-S(O)2-;L选自-CH2-,S,O和NRc。
在另一个实施例中,是/>其中A,B和C’各自独立地选自N,CH或C(Rc);X,L和G独立地选自键,-CH2-,O,S或N(Rd);Rd是H,芳基或烷基。
在另一个实施例中,is/>其中,Rc如前面所定义。
在另一个实施例中,是/>其中,A,B和C’各自独立地选自N,CH和C(Rc)。
在另一个实施例中,是/>其中,–K–L–M–选自:–C(R3)=C(R)–N–,–C(R4)=N–C(R)–,–C(R4)=N–N–,–N=C(R4)–N–,–N=N–N–,–C(R4)2–N=C–,–N(R4)–C(R)=C–,–N(R4)–N=C–,–O–N=C–和–S–N=C–,其中R3选自氢,卤素,C1-6烷基,C1-6氟烷基,C1-6烷氧基,C1-6氟烷氧基和乙酰基;每个R4独立地选自氢,C1-6烷基,C1-6氟烷基,C1-6烷氧基,C1-4氟烷氧基和乙酰基。/>
在另一个实施例中,选自以下6,5-杂二环部分:
在一个实施方案中,本发明涉及式I所示的化合物,其中R1为甲基且R2为氢;或其中R1是甲基,R2是甲基;或,其中,R1和R2与它们都连接的碳原子一起形成三元至六元碳环。
在另一个实施例中,本发明涉及式I所示的化合物,其中Ar1是苯基,任选地被1-3个Rc基团取代;或式I所示的化合物,其中,Ar2是苯基,其任选地被1-3个Rc基团取代。
本发明还包括式I所示的前药。该前药可以是酯或酰胺或另一个合适的基团。优选的前药包括式Ia的酯衍生物,其中,Rd代表具有1至10个碳原子的烷基或具有7至12个碳原子的芳烷基,芳基或杂芳基。
式I的另一种优选的前药是一酯衍生物,含有一个或多个一氧化氮释放基团(式Ib),
其中T是任何合适的连接结构。
EP4拮抗剂的NO释放性前药的一个实施方案是式Ic所示的化合物或其药学上可接受的盐:
其中,
Z是O,S或NRe,Re为氢,烷基或芳基;
V独立地选自O和S,并且每个V独立地连接至C1-10烷基的任何一个碳原子;和
n是1,2,3或4。
EP4拮抗剂的NO释放性前药化合物的另一个实施方案是式Id所示的那些
其中,
Z是O,S或NRe,Re是氢,烷基或芳基;
V是O或S;每个V独立地连接至C1-10烷基的一个碳原子;
Rf选自氢,卤素,烷氧基,烷硫基,CN,CF3,烷基,烷基磺酰基,S(O)2NH2和S(O)2NH-烷基;和
W是
优选地,EP4拮抗剂的NO释放性前药化合物是式Ie,If或Ig所示的那些:
其中n是1到10的整数;
其中n和m为1到10的整数;
其中n是1至6的整数;Rg为H,卤素,烷基,卤代烷基。
在一些实施方案中,式(I)所示的化合物为:
或其药学上可接受的盐。
应当理解,如果分子式I的某些化合物(或盐、前药、或共轭物)有同质异构体的存在,有时它们是可以分离的,这些异构体包括互变异构体、顺式或反式异构体,以及具光学活性、外消旋、或非对映异构体。显而易见,本发明包括式I化合物的任何互变异构体或其混合物;或非对映异构体的混合物,以及单一的非对映异构体,而且,本发明包括式I化合物,其存在形式为对映结构体混合物,以及单一非对映异构体,和任何具有拮抗EP4受体的特性的混合物或结构体,行业内已经非常清楚如何制备或分离具体形式,以及如何通过包括以下所述的那些标准测试法来确定EP4受体拮抗特性。
此外,式I所示的某些化合物(或其盐、前药或共轭物)可能呈现多态性或可能与水或有机溶剂形成溶剂化物。本发明还包括任何形式的多态体、任何溶剂化物或其任何混合物。
如上所述,本发明包括式I所示化合物的药学上可接受的盐。本发明的基本化合物具有一个或多个足够碱性的功能性基团,它可与许多无机和有机酸反应,从而提供生理学可接受的抗衡离子以形成药学上可接受的盐。本发明还包括式I的前药的其他可接受形式,该可接受形式是以传统方式与化合物的官能团例如与氨基,羟基或羧基形成。
本发明还涉及通过施用有效量的式I所示化合物来拮抗EP4受体的方法。
本发明还包括治疗人类或动物受试者的方法,该受试者患有由PGE 2作用于EP4受体所引起的疾病,该方法包括向所述受试者施用有效量的式I所示化合物。
本发明还包括式I所示化合物在制备用于治疗由PGE2作用于EP4受体所引起的疾病或病症的药物中的用途。
光学异构体-非对映异构体-几何异构体-互变异构体
式I的化合物包含一个或多个不对称中心,因此可以产生外消旋物和外消旋混合物,单一对映结构体,非对映异构体混合物和单一非对映异构体。本发明旨在还包括式I至式Ig所示化合物的所有此类异构体。
本文所述的一些化合物含有烯烃双键,并且除非另有说明,指包括E和Z几何异构体。
本文描述的化合物可能存在不同的氢连接点,这称为互变异构体。例如,酮及其烯醇形式被称为酮-烯醇互变异构体。式I至式Ig所示化合物涵盖各个互变异构体及其混合物。
式I所示的化合物可以分离为对映异构体的非对映异构体;通过例如从合适的溶剂例如MeOH或EtOAc或其混合物中分步结晶而分离。由此获得的对映异构体可以通过常规手段分离为单独的立体异构体,例如通过使用光学活性胺作为拆分剂,或在手性HPLC柱上过柱。
另外,式I所示化合物的任何一个对映异构体,可以通过利用光学纯的原料或已知结构的试剂立体合成而获得。
盐
术语“药学上可接受的盐”是指从药学上可接受的无毒碱或酸制备的盐,包括无机或有机碱和无机或有机酸。从无机碱衍生的盐包括铝、铵、钙、铜、铁、亚铁、锂、镁、锰盐、锰、钾、钠、锌等等。特别优选的是铵、钙、镁、钾和钠盐。从药学上可接受的有机无毒碱衍生的盐包括一级、二级和三级胺盐,取代胺包括天然取代胺、环胺、阴离子交换树脂,如精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苄基乙二胺,二乙胺、2-二乙基乙醇胺、2-二甲基乙醇胺、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺、葡萄糖胺、组氨酸、海巴明、异丙醇胺、赖氨酸、甲基葡糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等等。
如果本发明的化合物是碱,可从药学上可接受的无毒酸来制备盐,包括无机和有机酸。这些酸包括醋酸、苯磺酸、苯甲酸、樟脑、柠檬酸、乙磺酸、富马酸、葡糖酸、谷氨酸、氢溴酸、盐酸、已酰基乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、磺酸、粘酸、硝酸、帕莫酸、泛酸、磷酸、琥珀酸、硫酸、酒石酸、对甲苯磺酸等等。特别优选的是柠檬酸、氢溴酸、盐酸、马来酸、磷酸、硫酸和酒石酸。
应当指出,分子式I所示化合物也包括药学上可接受的盐。
术语“晶体多晶型物”,“多晶型物”或“晶型”是指其中化合物(或其盐或溶剂化物)可以以不同的晶体堆积排列而结晶的晶体结构,所有这些晶体具有相同的元素成份。不同的晶体形式通常具有不同的X射线衍射图,红外光谱,熔点,密度,硬度,晶体形状,光学和电学性质,稳定性和溶解度;重结晶溶剂,结晶速率,储存温度和其他因素可能导致一种晶体的形成。化合物的晶体多晶型物可以通过在不同条件下结晶来制备,可以理解的是,本发明公开的化合物可以以晶体形式,晶体混合物,或其酸酐或水合物存在。
式I所示化合物也可以结合一种或多种化疗药物使用,例如芳香酶抑制剂,抗雌激素,抗雄激素(特别是针对前列腺癌)或促性腺激素激动剂,拓扑异构酶I抑制剂或拓扑异构酶II抑制剂,微管活性剂,烷化剂,抗肿瘤代谢药或铂化合物,靶向/降低蛋白质或脂质激酶活性或蛋白质或脂质磷酸酶活性的化合物,其他抗血管生成化合物或可诱导细胞分化过程的化合物,缓激肽I受体或血管紧张素II拮抗剂,环加氧酶抑制剂,双膦酸酯,雷帕霉素衍生物,例如依维莫司,乙酰肝素酶抑制剂(防止硫酸乙酰肝素降解),例如Pl88,一种生物反应调节剂,优选淋巴因子或干扰素,如II型干扰素,一种泛素化抑制剂,或一种阻止抗凋亡通路的抑制剂,Ras肿瘤异构体的抑制剂,如H-ras、K-ras和N-ras,或法尼基转移酶抑制剂,如L-744832或DK8G557,一种端粒酶抑制剂,例如端粒抑制剂,蛋白酶抑制剂,基质金属蛋白酶抑制剂,蛋氨酸氨基肽酶抑制剂,例如苯甲酰胺或其衍生物,或蛋白体抑制剂,例如PS 341,组蛋白乙酰转移酶抑制剂,例如伏立诺他,MG0103或MS275。
PTP 1B抑制剂
应当理解,除非另有明确指出,治疗不仅指已确定症状的治疗,也包括预防性治疗。
术语“有效治疗剂量”是指一种药物或药品的剂量,该剂量可由研究员、兽医或医生或其他临床医生根据组织、系统、动物或人类的生物或药物反应来决定。这个术语也包含一种药品的剂量,它可防止或减少研究人员、兽医、医生或其他临床医生用药时医疗事件发生的风险。EP4拮抗剂给药剂量水平可以达到常规剂量水平。适宜的剂量水平将取决于所选择EP4拮抗剂的作用,但通常适宜剂量约为每天,最好是/> 每天,尤其是/>每天。该化合物可每天给药一次、两次或三次。
配方
本发明还提供一种用于上述治疗方法的药物组合物。本发明的组合物包括式I所示的化合物,它可作为一活性成分或药学上可接受的盐,其中含有足以拮抗EP4受体的剂量,可能还包含药学上可接受的载体以及其它可选的治疗成分。术语“药学上可接受的盐”是指从药学上可接受的无毒碱(包括无机和有机碱)制备的盐。无机碱的衍生盐包括铝、铵、钙、铜、铁、亚铁、锂、镁、锰盐、锰、钾、钠、锌等等。特别优选的是铵、钙、镁、钾和钠盐。从药学上可接受的有机无毒碱衍生的盐包括,一级、二级和三级胺盐,包括天然取代胺的取代胺、环胺、阴离子交换树脂,如精氨酸、甜菜碱、咖啡因、胆碱、N,N-双苄基乙二胺、二乙基乙胺、2-二乙基氨基乙醇、2-二甲基乙醇胺、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺、葡萄糖胺、组氨酸、哈胺、异丙胺、赖氨酸、甲基葡糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等等。
显而易见,在本文的治疗方法的讨论中,提及的式I化合物还意指包括药学上可接受的盐。
含有活性成分的药物(即式I所示化合物)可以是适宜的口服剂型,例如片剂,药片,含片,水溶性或油性悬液,分散乳胶粉或颗粒,乳剂,硬或软胶囊或糖浆或酏剂。口服使用的药物可根据药物成分制造商的已知工艺方法来制备,这些组合物可包括下述一种或多种药剂,例如甜味剂,调味剂,着色剂和保护剂,以便提供优雅和美味的药品制剂。药片含有与非毒性药学上可接受的赋形剂混合的活性成分,这些赋形剂适合于生产片剂。这些赋形剂的例子有,惰性稀释剂,例如碳酸钙、碳酸钠、乳糖、钙磷酸盐或磷酸钠;制粒,崩解剂,例如,玉米淀粉或褐藻酸;结合剂,例如如淀粉、明胶或阿拉伯胶,以及润滑剂,例如硬脂酸镁、硬脂酸或滑石粉。该药片可无涂层,也可有涂层,以延迟在胃肠道的降解和吸收,从而在较长时期内维持活性。例如,可以使用延时材料如甘油单硬脂酸或甘油双硬脂酸酯。也可采用美国专利号4256108、4166452和4265874中(本文引用了这些专利的内容)描述的技术进行涂层,形成释放可控的渗透性治疗片剂。
联合疗法
式I所示化合物与其他药物结合有助于治疗/预防/抑制/式I化合物可发挥作用的癌症或疾病。因此,按照通常给药途径和剂量,其他药物也可与式I所示化合物同时或先后给药。当式I所示化合物与一种或多种其他药物同时给药时,最好是药剂成分中同时含有其他药物和式I所示化合物。因此,除式I所示化合物外,本发明的药物成分还包括一种或多种其他活性成分。当本发明化合物与其他治疗药物联合使用时,可通过任何方便的途径同时或先后给药。
在另一方面,本发明提供了一种联合给药方式,包括式I化合物或其药学上可接受的衍生物或盐以及其他治疗药物或药剂。
上文提到的联合用药可以方便地使用药剂配方提供,因此包括上文定义的联合用药方式与药学上可接受的载体或赋形剂的药剂配方构成了本发明的另一方面。这种联合用药的个体成分可以单独或以联合药物制剂形式先后或同时给药。
在本发明的一些实施方案中,提供了一种抑制肿瘤生长或治疗癌症的方法,其中,将EP4拮抗剂与其它疗法或药剂联合施用,可用于抑制肿瘤生长和/或治疗癌症,即,联合疗法。如本文所用,两种或多种药剂/疗法(包括EP4拮抗剂,放射疗法,抗体疗法,抗代谢化学疗法或其任何组合)的给药“组合”是指所述疗法在时间上足够紧密地给药,以使得一种药物的施用或存在会改变另一种药物的生物学效应。所述疗法可以同时或先后施用。同时给药可以,例如,通过在给药前混合两种或更多种药剂来进行,或者通过在相同的时间但在不同的解剖部位来进行,或通过使用不同的给药途径来进行,或通过在足够短的时间内给药来进行,以至于得到的结果与在同一时间点施用药剂/疗法所获得的结果没有区别。例如,同时施用一种或多种药剂与放射线,可以通过在施用放射线的同一时间点施用一种或多种药剂,或在足够短的时间内给药,以至于得到的结果与药剂和放射线疗法在同一时间施用得到的结果没有区别。可以先后给药,通过在不同的时间点施用药剂/疗法来进行,例如,在施用一种或多种其他药剂/疗法之前或之后的某个时间点施用药剂,使得药剂/联合疗法可增强癌症治疗的疗效。在一些实施方案中,在最初施用放射疗法,抗体疗法和/或抗代谢物化学疗法之前的某个时间点施用EP4拮抗剂。或者,可以在施用EP4拮抗剂之前的某个时间点施用放射疗法,抗体疗法和/或抗代谢化学疗法,并且任选地,在施用EP4拮抗剂之后的某个时间点再次施用放射疗法,抗体疗法和/或抗代谢化学疗法。在一些实施方案中,与放射疗法,抗体疗法和/或抗代谢化学疗法联合施用EP4拮抗剂导致所述放射疗法,抗体疗法和/或抗代谢化学疗法的效果增强,使得,例如,较小的放射剂量,抗体治疗和/或抗代谢化学疗法可能对治疗有效。在本发明的一些实施方案中,癌症的治疗可以包括远位效应和/或提供记忆免疫反应。“远位”效应是转移性癌症治疗中的一个现象,其中,通过例如放射疗法对特定肿瘤或癌症进行局部治疗,导致非局部的,例如,转移引起的远离局部治疗部位的那些疾病、肿瘤或癌症的缩小和消失,从而导致受试者或患者的全身疾病、肿瘤或癌症的消失。远端效应不同于可能在与局部治疗相邻的组织上发生的效应,例如可能由放射疗法引起的旁观者效应。当所提供的癌症治疗促进免疫系统的适应,并且受试者或患者的免疫反应能够减慢,减少或防止复发,即延长受试者或患者正在治疗的疾病、肿瘤或癌症的缓解时间时,就会产生“记忆免疫反应”。在一些实施方案中,记忆免疫反应可以,例如通过表位扩散来减慢,减少或预防与所治疗的癌症不同的肿瘤或癌症的发展。如本文使用的EP4拮抗剂,抗体和/或抗代谢物可以根据已知技术配制以在药物载体中施用。参见,例如,雷明顿,《药物科学与实践》(1995年第9版)。在制造根据本发明的药物制剂中,通常将活性化合物(包括其生理学上可接受的盐)与可接受的载体混合。在与制剂中的任何其他成分相容的意义上,载体必须是可接受的,并且必须对患者无害。载体可以是固体或液体,或两者兼有,并且优选与化合物一起配制为单位剂量制剂,例如片剂,其可以包含0.01%或0.5%至95%或99%重量的活性化合物。可将一种或多种活性化合物掺入本发明的制剂中,所述制剂可通过任何众所周知的药学技术制备,所述技术包括混合各组分,任选地包括一种或多种辅助成分和/或赋形剂。在一些实施方案中,本发明的任何组合物,载体,辅助成分赋形剂和/或本发明的制剂均包含来自天然或非天然来源的成分。在其他实施方案中,本发明的组合物,载体,辅助成分,赋形剂和/或制剂的任何组分可以无菌形式提供。无菌载体的非限制性实例包括无内毒素水或无热原水。EP4拮抗剂,抗体和/或抗代谢物可以通过任何合适的途径向受试者给药,包括口服(包括通过口腔给药,还包括通过胃饲管给药),腹膜内,肠胃外,吸入喷雾,局部(即皮肤和粘膜表面,包括气道表面),经皮,直肠,鼻(包括鼻胃饲管),舌下,颊,阴道或通过植入的储库。本文所用的术语“肠胃外”包括皮下,肌内,真皮内,静脉内,关节内,滑膜内,骨内,鞘内,肝内,病变内和颅内注射或输注技术。在一个具体的实施方案中,EP4拮抗剂,抗体和/或抗代谢物经口服施用。在另一个具体的实施方案中,EP4拮抗剂,抗体和/或抗代谢物静脉内施用。在一些实施方案中,可以与赋形剂材料组合以产生单一剂型的组合物的EP4拮抗剂,抗体和/或抗代谢物的量将根据所治疗的宿主和特定的给药途径而变化。在一些实施方案中,将EP4拮抗剂,抗体和/或抗代谢物作为无菌组合物/制剂的一部分提供,所述无菌组合物/制剂包含EP4拮抗剂,抗体和/或抗代谢物以及可接受的载体和/或赋形剂。在一些实施方案中,给受试者施用有效量的EP4拮抗剂。有效量通常为每天0.01mg/kg至500mg/kg体重。在一些实施方案中,可以配制药学上可接受的组合物,从而可以将每天0.01mg/kg至200mg/kg或0.01mg/kg至100mg/kg体重的化合物的剂量施用给接受这些组合物的患者(例如,基于75kg的人,剂量为0.75mg至7.5g或15g)。在某些实施方案中,配制本发明的组合物以提供0.01mg/kg至70mg/kg的剂量(例如,基于75kg的人,剂量为0.75mg至5.25g)。在一些实施方案中,EP4拮抗剂的有效剂量为约0.5至约250mg/kg,1至约250mg/kg,约2至约200mg/kg,约3至约120mg/kg,约5-约250mg/kg,约10-约200mg/kg或约20-约120mg/kg。在一些实施方案中,有效剂量包括约0.5mg/kg,1mg/kg,2mg/kg,3mg/kg,4mg/kg,5mg/kg,6mg/kg,8mg/kg,10mg/kg,20mg/kg,25mg/kg,40mg/kg,50mg/kg,60mg/kg,75mg/kg,100mg/kg,120mg/kg,150mg/kg,175mg/kg,200mg/kg,225mg/kg,250mg/kg和300mg/kg。剂型可以是例如片剂或胶囊剂的形式,并且有效剂量可以以一种或多种片剂,胶囊剂等形式提供,并且每天一次或全天以例如4、8或12个小时间隔提供。例如,片剂或胶囊剂可以包含10、25、50、75、100、150、200、250、300、350、400、450、500、600、700、800、900、1000、1100,或1250毫克化合物。例如,在一些实施方案中,向人类受试者施用EP4拮抗剂,可以包括100-1250、150-1000、200-800或250-750mg范围内的EP4拮抗剂的日剂量,日剂量可以每天一次全部施用,或分批间隔施用。还可以制备液体制剂,使得可以容易且方便地分配任何剂量。抗体,例如抗CTLA4,抗PDL1或抗PD1,通常会在给药前,与无毒的药学上可接受的载体物质(例如生理盐水或磷酸盐缓冲盐水)混合,并且可以使用任何医学上合适的方法进行给药,例如,包括但不限于静脉内或动脉内,及注射到脑脊髓液中给药。在某些情况下,施用于腹膜内,皮内,腔内,鞘内或直接施用于肿瘤或供给肿瘤的动脉可能是有利的。在一些实施方案中,抗体的有效剂量为约5至约250mg/kg,约10至约200mg/kg,或约20至约120mg/kg。在一些实施方案中,有效剂量包括5mg/kg,10mg/kg,20mg/kg,25mg/kg,40mg/kg,50mg/kg,60mg/kg,75mg/kg,100mg/kg,120mg/kg,150mg/kg,175mg/kg,200mg/kg,225mg/kg,250mg/kg和300mg/kg。剂型可以是例如片剂或胶囊剂的形式,并且有效剂量可以以一种或多种片剂,胶囊剂等形式提供,并且每天一次给药或全天以一定间隔,例如4、8或12个小时的间隔给药。片剂或胶囊剂可以包含例如10、25、50、75、100、150、200、250、300、350、400、450、500、600、700、800、900或1000mg抗体。还可以制备液体制剂,使得可以容易且方便地分配任何剂量。在一些实施方案中,向受试者施用有效量的抗体。有效量通常为每天0.01mg/kg至500mg/kg体重。在一些实施方案中,可以配制药学上可接受的组合物,从而可以将每天0.01mg/kg至200mg/kg或0.01mg/kg至100mg/kg体重的化合物的剂量给予接受这些组合物的患者(例如,基于75千克的人,剂量为0.75毫克至7.5克或15克)。在某些实施方案中,本发明的组合物被预先配制以提供0.01mg/kg至70mg/kg的剂量(例如,基于75kg人,剂量为0.75mg至5.25g)。抗体的有效量可以是例如0.05mg/kg,0.1mg/kg,1mg/kg,2mg/kg,3mg/kg,4mg/kg,5mg/kg,6mg/kg,7mg/kg或8mg/kg每剂量(例如,基于75千克的人,剂量为3.75毫克至600毫克)。在治疗过程中,抗体的剂量可以每周一次,两次,三次,四次,五次或更多,每周一次,每两周一次,甚至每三周一次施用。给药时间可以是每天一次,每两天一次,每三天一次,每四天一次,每五天一次,每周一次,每两周一次或每三周一次。可以制备包含抗体的制剂,以便可以容易、方便地分配任何剂量。
术语“同时施用”是指基本上同时给予一种或多种治疗剂。术语“同时施用”不仅包括以单一药物剂型施用两种药剂,而且包括以各自的单独药物剂型施用每种活性剂。在使用单独的剂量制剂的情况下,所述试剂可以基本上在同一时间,即同时施用。
术语“先后施用”是指在分开的交错时间施用药剂。因此,例如,可以依次施用药剂,以使患者基本上同时实现阿司匹林和本发明化合物的有益药物作用。因此,例如,如果本发明的化合物和阿司匹林两者均每天一次施用,则两种药物的先后施用的时间可以相隔最多十二小时。
“有效量”或“治疗有效量”是指有效治疗癌症的量,例好通过临床测试和评估,患者观察等所指出。“有效量”可以进一步指引起生物学或化学活性的可检测变化的量。对于相关的机制或过程,本领域技术人员可以检测和/或进一步量化所述可检测变化。而且,“有效量”可以指维持期望的生理状态,即减少或防止状况显着下降和/或促进状况改善的量。“有效量”可以进一步指治疗有效量。如本文所用,“受试者”是指哺乳动物受试者,特别是人类受试者,包括男性或女性受试者,并且包括新生儿,婴儿,少年,青少年,成人或老年受试者,并且进一步包括各种种族和种群。
本文所用的术语“抗体”和“抗体们”包括可能适用于本文所公开的医疗用途的所有类型的免疫球蛋白,包括IgG,IgM,IgA,IgD和IgE或其片段。抗体可以是单克隆的或多克隆的,并且可以来源任何的物种,包括,例如小鼠,大鼠,兔,马或人。“抗体”还包括保留与蛋白质或表位特异性结合的抗体片段,例如,与本发明中使用的抗体结合的CTLA4,PDL1或PD1。这样的片段可以通过已知技术产生。抗体可以是嵌合的或人源化的,特别是当它们用于治疗目的时。可以使用本领域已知的方法获得或制备抗体。“抗体疗法”是指抗体的医疗用途,抗体与靶细胞或蛋白质结合,以治疗受试者的癌症和/或刺激免疫反应,从而导致受试者中癌细胞的识别,攻击和/或破坏,并且在本发明的一些实施方案中,在受试者中激活或刺激记忆免疫反应,从而导致受试者中癌细胞的随后识别,攻击和/或破坏。“CTLA4抗体疗法”是指抗细胞毒性t淋巴细胞抗原4的抗体(抗CTLA4)在调节受试者的免疫反应中的用途。在一些实施方案中,CTLA4抗体抑制或阻断CTLA4信号传导的作用,该作用导致在癌细胞的攻击和破坏中抑制T细胞活化。适用于此用途的抗体包括但不限于是CTLA4拮抗剂的抗体或美国专利号8,685,394和8,709,417中所述的CTLA4抗体。抗体的一些实施方案包括MDX-010(ipilimumab,Bristol-Myers Squibb)和CP-675,206(tremelimumab,Pfizer)。在一个特定的实施方案中,该抗体是依匹莫单抗。“PDL1抗体疗法”是指抗程序性死亡配体1的抗体(抗PDL1)在调节受试者的免疫反应中的用途。在一些实施方案中,PDL1抗体抑制或阻断PDL1与程序性细胞死亡蛋白1(PD1)的相互作用,其中,PDL1和PD1之间的相互作用的阻断抑制了PD1对T细胞活化的负调控,以攻击和破坏癌细胞。适用于此用途的抗体包括但不限于美国专利号8,217,149、8,383,796、8,552,154和8,617,546中列出的抗体。在一个特定的实施方案中,该抗体是MPDL3280A(Roche)。“PD 1抗体疗法”是指抗程序化细胞死亡蛋白1PD1(抗PD1)的抗体在调节受试者的免疫反应中的用途。在一些实施方案中,PD1抗体抑制或阻断了PD1与PDL1的相互作用,其中,PDL1与PD1之间的相互作用的抑制或阻断抑制了PD 1对T细胞活化的负调控,以攻击和破坏癌细胞。适用于此用途的抗体包括但不限于美国专利号7,029,674、7,488,802、7,521,051、8,008,449、8,354,509、8,617,546和8,709,417中列出的抗体。抗体的具体实施方案包括尼泊单抗(Bristol-Myers Squibb),拉巴利珠单抗(Merck)和百能珠单抗(KEYTRUDA,默克)。
“抗代谢化学疗法”是指抗代谢化学疗法在治疗受试者中的用途。“抗代谢物”是指阻碍DNA和RNA合成的一组分子。抗代谢物的实例包括但不限于抗叶酸剂,氟嘧啶,脱氧核苷类似物和硫嘌呤。抗叶酸剂包括甲氨蝶呤和培美曲塞。氟嘧啶包括氟尿嘧啶和卡培他滨。脱氧核苷类似物包括阿糖胞苷,吉西他滨,地西他滨,5'-氮杂胞苷(VIDAZA),氟达拉滨,奈拉拉滨,克拉屈滨,氯法拉滨和喷他汀。硫嘌呤包括硫鸟嘌呤和巯基嘌呤。在一个实施方案中,抗代谢物是吉西他滨。在另一个实施方案中,抗代谢物是卡培西汀。为了可以更充分地理解本文所述的发明,阐述了以下实施例。应当理解,这些实施例仅用于说明目的,而不应以任何方式解释为限制本发明。
例子
例1.结肠癌CT26移植瘤在小鼠体内生长的药效学测试
1.1细胞培养
CT26肿瘤细胞系在补充有10%热灭活胎牛血清的RPMI-1640培养基中,在空气中5%CO2的气氛下于37℃进行体外单层培养。通过胰蛋白酶-EDTA处理,每周将肿瘤细胞常规传代培养两次,不超过4-5代。收获在指数生长期生长的细胞并计数以接种肿瘤。
1.2肿瘤接种方法
每只小鼠的右下腹皮下接种0.1ml无血清RPMI 1640培养基中的95%存活肿瘤细胞(3×105)的单细胞悬液,用于肿瘤发展。当平均肿瘤大小达到约100mm3时,给每只小鼠施用本发明的测试化合物。每组由6只小鼠组成。将小鼠随机分为不同的治疗组,如“组和治疗”下面的表中所示。植入前将小鼠轻轻麻醉。注意用无菌镊子提起皮肤并注射细胞,以确保皮下递送细胞。不使用任何完全或部分在皮内(ID)或肌内(IM)生长的肿瘤。
1.3体内抗肿瘤药理学
CT26细胞在37℃和5%CO2气氛下维持在补充有10%FBS的RPMI 1640培养基中。使用标准胰蛋白酶消化方法获得细胞脱离,使用NC-200自动细胞计数器对细胞数量和活力信息进行定量。将化合物1(INV-1121)通过在4℃超声处理15分钟,彻底悬浮在0.5%甲基纤维素(MC)中,然后向动物口服(p.o.)给药。给BALB/c小鼠皮下(s.c.)注射活的1×105 4T1细胞。小鼠在5天内出现了约36mm3的肿瘤。将携带CT26的荷瘤小鼠随机分为5组,每组10只。A组接受媒介物(0.5%MC);B组接受0.1mg/kg的化合物1;C组接受1mg/kg的化合物1,D组接受25mg/kg的化合物1;和,E组接受150mg/kg的化合物1。所有处理均每天口服给予化合物1,连续21天。每周两次测量肿瘤体积和体重。肿瘤细胞注射后27天终止研究。肿瘤体积表示为平均值:t SEM。在第27天,通过单因素方差分析和Tukey检验分析了治疗小鼠组之间的肿瘤体积差异。P<0.05值被认为是显著的。
1.4测量参数
为了进行常规监测,不仅监测了所有研究动物的肿瘤生长,而且还监测了行为,例如活动性,食物和水的消耗(仅通过笼侧检查),体重(BW),眼/头发消光以及任何其他异常作用。记录所有死亡率和/或异常临床体征。
1.4.1体重
在整个研究中,每周测量两次所有动物的体重。测量数据将指定为研究设计。使用以下公式计算体重变化(以%表示):
体重变化(%)=((第X天体重-第0天体重)/第0天体重)×100
1.4.2肿瘤测量
使用卡尺每周两次测量肿瘤大小,并使用以下公式估算肿瘤体积(mm3):TV=a×b2/2,其中“a”和“b”分别是肿瘤的长径和短径。所述TV用于计算肿瘤生长抑制的值(TGI,抗肿瘤效果的指标),使用公式为:TGI=(1-T/C)×100%,其中“T”和“C”分别是治疗组和对照组的肿瘤的平均相对体积(肿瘤生长百分比)。当平均肿瘤体积超过2000mm3或体重严重减轻时,终止实验。
1.5体内抗肿瘤活性
如上所述,使用小鼠结肠CT26同系肿瘤模型检查化合物1(INV-1121)在肿瘤生长中的活性。每天口服该化合物抑制肿瘤生长,以剂量效应方式,通常在0.1mg/kg-150mg/kg的范围内(图1)。在两种较低剂量(0.1和1.0mg/kg)下检测,均观察到一定抑制作用,但无统计学意义。另一方面,在25和150mg/kg的剂量下检测到显著且可比的抗肿瘤活性,表明在体内实验环境中,25mg/kg达到最佳有效剂量。测试的剂量均未显示出根据动物体重和总体动物行为判断的总毒性(图1),表明,在体内测试的动物物种具有优异的耐受性。化合物1对肿瘤生长的抑制作用如图1所示。
例2:皮下鼠结肠腺癌(MC38)的结肠癌生长的体内药效学测试
所有动物研究均由马萨诸塞州波士顿的贝斯以色列女执事医学中心动物护理和使用委员会审查并批准。在无病原体的设施中,每笼最多可容纳5只动物,无限制地使用无菌水和食物。根据委员会的指导原则进行了每日福利评估和动物牺牲。在补充有10%FBS,1%GPS,0.1mM非必需氨基酸(MilliporeSigma),1mM丙酮酸钠(MilliporeSigma),10mMHepes,和50mg/mL硫酸庆大霉素(MilliporeSigma)的DMEM中培养MC38小鼠结肠腺癌细胞(Kerafast,Boston,MA,USA)(MilliporeSigma)。用胰蛋白酶消化贴壁细胞,沉淀,通过血细胞计数器计数,并以1×106细胞/mL的PBS溶液注入小鼠。
将细胞经皮下注射到6周龄的雄性C57BL/6小鼠(杰克逊实验室,Bar Harbor,ME)的背部的中部,按照100ul/小鼠的剂量。对小鼠进行系统治疗,用化合物1(INV-1120,60mg/kg/天),抗PD1(200ug Q 3天),INV-1120(60mg/kg/天)和抗PD1(200ug Q3天),或媒介物(0.45%甲基纤维素),总量100ul,通过管经口给药。在肿瘤细胞注射后第10天开始治疗,这时肿瘤达到约2004mm3至224mm3。用卡尺测量肿瘤大小(宽度2×长度×0.52=mm3)。
治疗15天后,相对于对照组(n=5只小鼠),60mg/kg/天INV-1120(n=5只小鼠)抑制了原发性MC38鼠结肠腺癌(p<0.0001)。
治疗21天后,相对于对照组(n=5小鼠),抗PD1(200ug Q 3天)(n=5小鼠)抑制了原发性MC38鼠结肠腺癌(p<0.01)。
治疗21天后,与对照组(n=5只小鼠)相比,60mg/kg/天INV-1120和抗PD1(200ug Q3天)(n=5小鼠)抑制了MC38原发性鼠结肠腺癌(p<0.00001)。
图2显示了有或没有化合物1的不同治疗对肿瘤生长的抑制作用
例3:B16F10黑色素瘤(B16F10)生长的体内药效学测试
将B16F10(1×106细胞)皮下注射至6周龄雄性C57BL/6只小鼠(杰克逊实验室,巴港,ME)的背部的中部,按照100ul/小鼠。对小鼠进行系统治疗,用化合物1(INV-1120,90mg/kg/天),抗PD1(200ug Q 3天),INV-1120(90mg/kg/天)和抗PD1(200ug Q 3天),或媒介物(0.45%甲基纤维素),总量100ul,通过管经口给药。在肿瘤细胞注射后第10天开始治疗,这时肿瘤达到约100mm3至116mm3。用卡尺测量肿瘤大小(宽度2×长度×0.52=mm3)。
治疗8天后,相对于对照组(n=5只小鼠),90mg/kg/天INV-1120(n=5只小鼠)抑制了原发性16F10黑色素瘤的生长(p<0.001)。
治疗8天后,相对于对照组(n=5只小鼠),抗PD1(200ug Q 3天)抑制了原发性16F10黑色素瘤的生长(n=5只小鼠)(p<0.01)。
治疗8天后,与对照组(n=5只小鼠)相比,90mg/kg/天INV-1120和抗PD1(200ug Q3天)(n=5只小鼠)抑制了原发性16F10黑色素瘤的生长(p<0.0001)。
例4:对LLC(刘易斯肺癌)生长的体内药效学测试
将LLC(1×106细胞)皮下注射到6周龄的雄性C57BL/6只小鼠(杰克逊实验室,BarHarbor,ME)的背部的中部,按照100ul/小鼠。对小鼠进行系统治疗,用INV-1120(90mg/kg/天),抗PD1(200ug Q 3天),INV-1120(90mg/kg/天)和抗PD1(200ug Q 3天),或媒介物(0.45%甲基纤维素),总量100ul,通过管经口给药。当肿瘤达到约249mm3至297mm3时开始治疗。用卡尺测量肿瘤大小(宽度2×长度×0.52=mm3)。
治疗9天后,与对照组(n=5只小鼠)相比,90mg/kg/天INV-1120(n=5只小鼠)抑制了原发性刘易斯肺癌的生长(p<0.01)。
在治疗9天后,与对照组(n=5只小鼠)相比,抗PD1(200ug Q 3天)(n=5只小鼠)抑制了原发性刘易斯肺癌的生长,p=0.056。
治疗9天后,与对照组(n=5只小鼠)相比,90mg/kg/天INV-1120和抗PD1(200ug Q3天)(n=5只小鼠)抑制了原发性刘易斯肺癌的生长(p<0.01)。
图4显示了对刘易斯肺癌生长的体内抑制作用。
以上在实施例1-4中讨论并在图1-4中示出的数据,表明本发明的杂环酰胺EP4拮抗剂在各种具有免疫能力的动物癌症模型中具有显著的抗肿瘤生长活性。与单独使用抗体治疗相比,杂环酰胺EP4拮抗剂加单克隆抗体的联合治疗显著增强了抗肿瘤活性,因此可以在临床上用于治疗癌症。
例5.体内抗炎活性
进行了动物研究以确定式(I)的盐抗关节炎的活性。
动物的准备
在20±2℃,在12小时的光照和12小时的黑暗周期,以及在45-70%的湿度条件下,向8至10周大的雄性路易斯小鼠饲喂固定量的食物和自由量的水。在测试之前,给所有小鼠调整生活三天。将56只这样的小鼠分成7组,每组8只。一组为对照组,仅接受1%CMCNa溶液;一组为模型组,也仅接受1%CMCNa溶液;一组是阳性组,接受塞来昔布,剂量为18mg/kg;另外四组分别接受剂量为1mg/kg,3mg/kg,10mg/kg和40mg/kg的受试化合物溶液。
制剂的制备
将1.00277g CMC-Na加入到100mL蒸馏水中,在60℃水浴中加热直至CMC-Na完全溶解,制得1%CMC-Na。
18mg/kg塞来昔布胶囊:将18.09mg塞来昔布放入研磨机中,向其中缓慢加入10mL1%CMC-Na溶液。研磨混合物直至塞来昔布完全溶解。
10mg/kg的C-003溶液:将10.08mg的测试化合物(4-(1-{[2-甲基-4-(4-三氟甲基-苄基)-4H-噻吩并[3,2-b]吡咯-3-羰基]-氨基}-环丙基)-苯甲酸二乙醇胺盐(以下称为INV-1120二乙醇胺盐)添加到研磨机中,向其中缓慢添加10mL 1%CMC-Na溶液,直至INV-1120二乙醇胺盐完全溶解。
30mg/kg INV-1120溶液:将30.3mg INV-1120二乙醇胺盐添加到研磨机中,向其中缓慢加入10mL 1%CMC-Na溶液,直到INV-1120二乙醇胺盐完全溶解。
将1.0mL的10mg/kg INV-1120二乙醇胺盐溶液与9mL的1%CMC-Na混合,制得1mg/kg INV-1120。
将1.0mL的30mg/kg INV-1120二乙醇胺盐溶液与9mL的1%CMC-Na混合,制得3mg/kg的INV-1120。
建立AIA模型
小鼠接受麻醉后,右脚用医用酒精清洗。对照组的小鼠被给予50uL PBS,其他组的小鼠的右脚用50uL CDA溶液处理。在建立模型的前一天,测量每只小鼠的基本大小(体积),建立模型的日期为D1,从D13开始,受试化合物每天以给药容积1mL/100g体重灌胃,持续12天(在D24结尾)。
定期检查动物
每三天检查小鼠并拍照,以了解它们的饮水量,食物摄入量和体重;每四天检查一次它们的后脚的承受重量的能力;每三天检查一次脚的肿胀体积,肿胀厚度和温度以及它们的行为。
测试结果,如图5-6所示,表明,所测试的化合物具有降低关节炎小鼠的脚的温度和肿胀(体积和厚度)的作用。另外,与不施用测试化合物的小鼠相比,施用测试化合物的小鼠显示出更大的体重增加和承受重量的能力。此外,被测动物表现出改善的行为模式(例如,平衡能力)。
例6.体内抗炎活性
4-(1-{[2-甲基-4-(4-三氟甲基-苄基)-4H-噻吩并[3,2-b]吡咯-3-羰基]-氨基}-环丙基)苯甲酸三(羟甲基)氨基甲烷盐,也用于如上所述的在治疗小鼠关节炎中的活性的研究。用这种化合物处理后,该盐导致甚至更有效地减少了小鼠关节炎足的肿胀,并且使小鼠具有更好的平衡或协调能力。
各项技术方案
1、一种治疗癌症或炎性疾病的方法,包括向有需要的受试者施用式I所示化合物或其药学上可接受的盐或前药,
其中:
R1和R2独立地选自氢,卤素,C1-6烷基,C1-6环烷基,C1-6氟环烷基,和C1-6氟烷基;或,R1和R2与它们均连接的碳原子一起形成三至六元碳环基团,该碳环任选地被Rc取代,或形成含有一个或两个杂原子的三至六元杂环基团,所述杂原子各自独立地选自S,O和NRb;每个Rb独立地选自氢,卤素,C1-6烷基,C1-6环烷基,C1-6氟环烷基,C1-6氟烷基,芳基,杂芳基,-C(O)-C1-6烷基,-C(O)-芳基,-S(O)2-烷基,和-S(O)2-芳基;
Y是O或S;
X是键,=CH-,CH2,O或S;
Ar1和Ar2各自独立地选自C3-6环烷基,芳基,杂芳基和杂环基,或C3-6环烷基、芳基、杂芳基、和杂环基的稠合类似物,并且Ar1和Ar2各自任选地被一个至三个Rc基团取代;每个Rc独立地选自卤素,C1-6烷基,C1-6环烷基,C1-6氟环烷基,和C1-6氟烷基;
Ra是–CO2H,-CO2M,-C(O)NHS(O)2Raa,或
Raa为C1-6烷基,C1-6卤代烷基,C1-6环烷基,C1-6环卤代烷基,芳基,或杂芳基;
M是药学上可接受的盐或酯前药基团;
是6,6-5,5-5,6或6,5-二环基团。
2、根据项1所述的方法,其中是结构/>其中:
A,B和C’各自独立地为N,CH或C(Rc);
G为-C(O)-,-C(S)-,或-S(O)2-;和
L选自-CH2-,S,O或NR1。
3、根据项1所述的方法,其中是结构/>其中:
A,B和C’各自独立地为N,CH,或C(Rc);
X,L和G各自独立地为键,-CH2-,O,S,或N(Rd);和
Rd是H,芳基,或烷基。
4、根据项1所述的方法,其中是结构/>其中二环基团具有三个Rc取代基。/>
5、根据项1所述的方法,其中是结构/>其中A,B和C’各自独立为N,CH,或C(Rc)。
6、根据项1所述的方法,其中是结构/>其中:
-K=L-M-is-C(R3)=C(R4)-N-,-C(R3)=N-C(R4)-,-C(R4)=N-N-,-N=C(R4)-N-,-N=N-N-,-C(R4)2-N=C-,-N(R4)-C(R3)=C-,-N(R4)-N=C-,-O-N=C-,或–S-N=C-;
R3为氢,卤素,C1-6烷基,C1-6氟烷基,C1-6烷氧基,C1-6氟烷氧基,或乙酰基;和每个R4独立地为氢,C1-6烷基,C1-6氟烷基,C1-6烷氧基,C1-4氟烷氧基,或乙酰基。
7、根据项1所述的方法,其中选自以下6,5-杂环部分:
/>
8、根据项1所述的方法,其中选自以下5,6-杂环二环部分:
9、根据项1所述的方法,其中所述化合物为式Ia所示的化合物或其药学上可接受的盐或前药,
其中Rd是C1-10烷基或C7-12芳烷基,芳基或杂芳基。
10、根据项1所述的方法,其中所述化合物是式Ib所示的一氧化氮释放性酯前药或其药学上可接受的盐或前药,
其中T是选自键和C1-6亚烷基的连接结构。
11、根据项1所述的方法,其中所述化合物是式Ic所示的一氧化氮释放性酯前药或其药学上可接受的盐或前药,
其中,
Z为O,S,或NRe,其中,Re为氢,烷基,或芳基;
每个V独立地为O或S,并连接至C1-10烷基的任何一个碳原子;和
n是1、2、3或4。
12、根据项1所述的方法,其中所述化合物是式Id所示的一氧化氮释放性酯前药或其药学上可接受的盐或前药,
其中:
Z为O,S,或NRe,其中,Re为氢,烷基,或芳基;
每个V独立地为O或S,并连接至C1-6烷基的一个碳原子;
每个Rf独立地是氢,卤素,烷氧基,烷硫基,CN,CF3,烷基,烷基磺酰基,S(O)2NH2或S(O)2NH-烷基;
W是和
m和n分别独立地是1、2、3或4。
13、根据项1所述的方法,其中所述化合物为式Ie所示的化合物或其药学上可接受的盐或前药
其中n是1到10的整数。
14、根据项1所述的方法,其中所述化合物是式If所示的化合物或其药学上可接受的盐或前药,
其中n和m均为1到10的整数。
15、根据项1所述的方法,其中所述化合物为式Ig所示的化合物或其药学上可接受的盐或前药,
其中:
n为1至6的整数;和
Rg为H,卤素,烷基,或卤代烷基。
16、根据项6所述的方法,其中,式I所示化合物中的-K-L-M-为-C(R3)=C(R4)-N-。
17、根据项6所述的方法,其中,式I所示化合物中的-K-L-M-为-C(R3)=N-N-。
18、根据项6所述的方法,其中,式I所示化合物中的-K-L-M-为-N(R4)-C(R3)=C-。
19、根据项6所述的方法,其中,式I所示化合物中的-K-L-M-为-N=C(R3)-N-。
20、根据项6所述的方法,其中,式I所示化合物中的-K-L-M-为-N=N-N-。
21、根据项1所述的方法,其中,所述化合物为式Ih所示的化合物或其药学上可接受的盐或前药,
其中:
-K=L-M-is-C(R3)=C(R4)-N-,-C(R3)=N-C(R4)-,-C(R4)=N-N-,-N=C(R4)-N-,-N=N-N-,
-C(R4)2-N=C-,-N(R4)-C(R3)=C-,-N(R4)-N=C-,-O-N=C-,或–S-N=C-;
n是1,2,3,或4;和
X是键,-CH2-,或-CHR1-。
22、根据项1所述的方法,其中,所述化合物为式Ii所示的化合物或其药学上可接受的盐或前药,
其中:
L是-CH2-,O,S,NR1;
n是1,2,或3;
X是键,-CH2-,或-CHR1-。
23、根据项1所述的方法,其中,所述化合物为式Ij所示的化合物或其药学上可接受的盐或前药,
其中:
n是1,2,或3;
X是键,-CH2-,-CHR1-,O,S,或NR1。
24、根据项1所述的方法,其中,所述化合物为式Ik所示的化合物或其药学上可接受的盐或前药,
其中
n是1,2,或3;
X是键,-CH2-,-CHR1-,O,S,或NR1。
25、根据项1所述的方法,其中,所述化合物为式(I)所示的化合物
或其药学上可接受的盐或前药。
26、根据项1所述的方法,其中,所述化合物为式Im所示的化合物或其药学上可接受的盐或前药,
其中,L是O,S,或-CH2-。
27、根据项1所述的方法,其中,所述化合物为式In所示的化合物或其药学上可接受的盐或前药,
其中X是键,-CH2-,O,或S。
28、根据项1所述的方法,其中,所述化合物是:
4-((1S)-1-{[4-(4-氯苄基)-4H-噻吩并[3,2-b]吡咯-3-羰基]氨基}乙基)苯甲酸;
4-((1S)-1-{[4-(4-氯苄基)-2-甲基-4H-噻吩并[3,2-b]吡咯-3-羰基]氨基}乙基)苯甲酸;
4-((1S)-1-{[4-(4-三氟甲基苄基)-2-甲基-4H-噻吩并[3,2-b]吡咯-3-羰基]氨基}乙基)苯甲酸;
4-(1-{[4-(4-氯苄基)-2-甲基-4H-噻吩并[3,2-b]吡咯-3-羰基]氨基}环丙基)苯甲酸;
4-(1-{[2-甲基-4-(4-三氟甲基-苄基)-4H-噻吩并[3,2-b]吡咯-3-羰基]氨基}环丙基)苯甲酸;
4-(1-{[5-氧代-4-(4-三氟甲基苄基)-5,6-二氢-4H-噻吩并[3,2-b]吡咯-3-羰基]氨基}环丙基)苯甲酸;
4-((1S)-1-{[5-氯-1-(4-氯苄基)-2-氧代-2,3-二氢-1H-吲哚-7-羰基]氨基}乙基)苯甲酸;
4-((1S)-1-{[6-氯-3-(4-氯苄基)-2-氧代-2,3-二氢苯并恶唑-4-羰基]氨基}乙基)苯甲酸;
4-(1-{[6-氯-2-氧代-3-(4-三氟甲基苄基)-2,3-二氢苯并恶唑-4-羰基]氨基}环丙基)苯甲酸;
4-((1S)-1-{[7-氯-3-(4-三氟甲基苄基)吲哚嗪5-羰基]氨基}乙基)苯甲酸;
4-(1-{[7-氯-3-(4-三氟甲基苯氧基)吲哚嗪-5-羰基]-氨基}环丙基)苯甲酸;
4-(1-{[7-氯-3-(4-三氟甲基苯氧基)-咪唑并[1,2-a]吡啶-5-羰基]氨基}环丙基)苯甲酸;
4-((1S)-1-{[7-氯-3-(4-三氟甲基苯氧基)咪唑并[1,2-a]吡啶-5-羰基]氨基}乙基)苯甲酸;
4-((1S)-1-{[7-氯-3-(4-三氟甲基苯基硫烷基)-咪唑并[1,2-a]吡啶-5-羰基]氨基}乙基)苯甲酸;
4-(1-{[7-氯-3-(4-三氟甲基苄基)-咪唑并[1,2-a]吡啶-5-羰基]氨基}环丙基)苯甲酸;
4-(1-{[7-氟-3-(4-三氟甲基苄基)-咪唑并[1,2-a]吡啶-5-羰基]氨基}环丙基)苯甲酸;
4-(1-{[7-氟-3-(4-三氟甲基苄基)-吲哚嗪-5-羰基]氨基}-氯丙基)苯甲酸;
4-((1S)-1-{[7-氟-3-(4-三氟甲基苄基)吲哚嗪5-羰基]氨基}乙基)苯甲酸;
4-(1-{[7-氟-3-(4-三氟甲基苄基)-吲哚嗪-5-羰基]氨基}-1-甲基-乙基)苯甲酸;
4-(1-甲基-1-{[4-(4-三氟甲基苄基)-4H-噻吩并[3,2-b]吡咯-3-羰基]氨基}乙基)苯甲酸;
4-(1-{[2-氟-6-(4-三氟甲基苄基)吡咯并[1,2-a]嘧啶-4-羰基]氨基}环丙基)苯甲酸;
4-(1-{[3-氟-7-(4-三氟甲基苄基)吡咯并[1,2-c]嘧啶-1-羰基]氨基}环丙基)苯甲酸;
7-氟-5-(4-三氟甲基苄基)-吲哚嗪-3-羧酸(1-苯基环丙基)酰胺;或
7-氟-5-(4-三氟甲基苄基)-咪唑并[1,2-a]吡啶-3-羧酸(1-苯基环丙基)酰胺;或其药学上可接受的盐或前药。
29、根据项28所述的方法,其中,所述化合物是酯前药或一氧化氮释放性酯前药。
30、根据项28所述的方法,其中,所述化合物是与氨基化合物,碱金属化合物或路易斯碱形成的盐。
31、根据项30所述的方法,其中,所述化合物是二乙醇胺盐或三(羟甲基)氨基甲烷盐。
32、根据项1-31中任一项所述的方法,其中,所述癌症是乳腺癌,子宫内膜癌,子宫颈癌,卵巢癌,肺癌,头颈癌,脑癌,甲状腺癌,食道癌,胃癌,结肠癌和直肠癌,肝癌,胰腺癌,皮肤癌,肾癌,膀胱癌,前列腺癌,睾丸癌,骨癌,淋巴瘤或血液癌。
33、根据项1-31中任一项所述的方法,其中,所述炎性疾病是关节炎,寻常痤疮,哮喘,自身免疫性疾病,自身炎性疾病,腹腔疾病,慢性前列腺炎,结肠炎,憩室炎,肾小球肾炎,化脓性汗腺炎,过敏反应,炎性肠病,间质性膀胱炎,肥大细胞活化综合症,肥大细胞增多症,中耳炎,盆腔炎,再灌注损伤,风湿热,类风湿关节炎,鼻炎,结节病或血管炎。
34、根据项32或33所述的方法,其中,所述方法还包括第二治疗剂或作用,所述第二治疗剂或作用选自放射线,抗细胞毒性t-淋巴细胞抗原4的抗体(抗CTLA4),抗程序性死亡配体1的抗体(抗PDL1),抗程序性细胞死亡蛋白1的抗体(抗PD1),和已经检测到的抗代谢物。
35、一种用于治疗癌症或炎性疾病的药物组合物,其包含项1-34中任一项所述的化合物和药学上可接受的载体。
36、根据项35所述的药物组合物,其进一步包含另一种治疗剂或作用,所述治疗剂或作用选自辐射,抗细胞毒性t-淋巴细胞抗原4的抗体(抗CTLA4),抗程序性死亡配体1的抗体(抗PDL1),抗程序性细胞死亡蛋白1的抗体(抗PD1),和已检测到的抗代谢物。
Claims (8)
1.一种用于治疗癌症的药物组合物,特征在于,包含如下所列的化合物,或其药学上可接受的盐;
2.根据权利要求1所述的用于治疗癌症的药物组合物,其中,所述的药学上可接受的盐是所述化合物与二乙醇胺或三(羟甲基)氨基甲烷(Tris)形成的盐。
3.根据权利要求1所述的用于治疗癌症的药物组合物,其进一步包含第二治疗剂或作用,所述治疗剂选自抗细胞毒性t-淋巴细胞抗原4的抗体(抗CTLA4),抗程序性死亡配体1的抗体(抗PDL1),抗程序性细胞死亡蛋白1的抗体(抗PD1),和已检测到的抗代谢物;所述作用选自辐射。
4.根据权利要求3所述的用于治疗癌症的药物组合物,其中所述第二治疗剂是抗程序性细胞死亡蛋白1的抗体(抗PD1)。
5.如下所列的化合物或其药学上可接受的盐在制备治疗癌症的药物中的应用:
6.根据权利要求5所述的应用,其中,所述的药学上可接受的盐是所述化合物与二乙醇胺或三(羟甲基)氨基甲烷(Tris)形成的盐。
7.根据权利要求5或6所述的应用,其中所述化合物或其药学上可接受的盐与第二治疗剂或作用联合使用,所述第二治疗剂选自抗细胞毒性t-淋巴细胞抗原4的抗体(抗CTLA4),抗程序性死亡配体1的抗体(抗PDL1),抗程序性细胞死亡蛋白1的抗体(抗PD1),和已检测到的抗代谢物;所述作用选自辐射。
8.根据权利要求1-4任一项所述的药物组合物或权利要求5-7任一项所述的应用,其中,所述癌症选自乳腺癌,子宫内膜癌,子宫颈癌,卵巢癌,肺癌,黑色素瘤,头颈癌,脑癌,甲状腺癌,食道癌,胃癌,结肠癌和直肠癌,肝癌,胰腺癌,皮肤癌,肾癌,膀胱癌,前列腺癌,睾丸癌,骨癌,淋巴瘤或血液癌。
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JP6860559B2 (ja) * | 2015-10-16 | 2021-04-14 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Ep4アンタゴニスト |
US11065226B2 (en) * | 2016-07-07 | 2021-07-20 | Ono Pharmaceutical Co., Ltd. | Combination comprising EP4 antagonist and immune checkpoint inhibitor |
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2019
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- 2019-02-02 WO PCT/CN2019/074618 patent/WO2019149286A1/en unknown
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- 2019-02-02 US US16/967,130 patent/US20200352906A1/en active Pending
- 2019-02-02 CN CN202311816268.8A patent/CN117643587A/zh active Pending
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- 2019-02-02 KR KR1020207022656A patent/KR20200118037A/ko active Search and Examination
- 2019-02-02 CN CN201980011401.8A patent/CN111727044A/zh active Pending
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CN111727044A (zh) | 2020-09-29 |
EP3749323A4 (en) | 2021-11-03 |
JP2021513512A (ja) | 2021-05-27 |
CA3090485A1 (en) | 2019-08-08 |
US20200352906A1 (en) | 2020-11-12 |
WO2019149286A1 (en) | 2019-08-08 |
EP3749323A1 (en) | 2020-12-16 |
CA3090485C (en) | 2024-01-16 |
AU2019214193A1 (en) | 2020-08-27 |
AU2019214193B2 (en) | 2022-06-16 |
KR20200118037A (ko) | 2020-10-14 |
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