CN110997681B - 作为腺苷受体拮抗剂的噻唑并吡啶衍生物 - Google Patents
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- CN110997681B CN110997681B CN201880050465.4A CN201880050465A CN110997681B CN 110997681 B CN110997681 B CN 110997681B CN 201880050465 A CN201880050465 A CN 201880050465A CN 110997681 B CN110997681 B CN 110997681B
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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Abstract
本发明涉及通式I的噻唑并吡啶衍生物,和本发明的化合物用于治疗和/或预防哺乳动物(尤其是人)的过度增生性或感染性疾病和障碍的用途,以及包含此种化合物的药物组合物。
Description
本发明涉及通式I的噻唑并吡啶衍生物,
和本发明的化合物用于治疗和/或预防哺乳动物(尤其是人)的过度增生性或感染性疾病和障碍的用途,以及包含此类化合物的药物组合物。
发明背景
腺苷是多种生理活动的普遍存在的调节剂,特别是在心血管、神经和免疫系统内。腺苷在结构和代谢上均与生物活性核苷酸三磷酸腺苷(ATP)、二磷酸腺苷(ADP)、单磷酸腺苷(AMP)和环单磷酸腺苷(cAMP)相关,与生化甲基化剂S-腺苷基-L-甲硫氨酸(SAM)相关,并且在结构上与辅酶NAD、FAD和辅酶A相关,也与RNA相关。
腺苷通过细胞表面受体调节多种生理功能,包括镇静的诱导、血管舒张、心律和收缩力的抑制、血小板凝集力的抑制、糖异生的刺激和脂解的抑制。研究表明,腺苷能够激活腺苷酸环化酶,打开钾通道,减少通过钙通道的通量,并通过受体介导的机制抑制或刺激磷酸肌醇的周转(Muller C.E.和Stein B.,Current Pharmaceutical Design,2:501,1996;Muller C.E.,Exp.Opin.Ther.Patents,7(5):419,1997)。
腺苷受体属于G蛋白偶联受体(GPCR)的超家族。现已在药理、结构和功能上表征了腺苷受体的四种主要亚型(Fredholm等人,Pharm.Rev.,46:143-156,1994),将它们称为A1、A2A、A2B和A3。尽管相同的腺苷受体可与不同的G蛋白偶联,但腺苷A1和A3受体通常与抑制性G蛋白(称为Gi和G0)偶联,抑制性G蛋白抑制腺苷酸环化酶,并下调细胞cAMP水平。相反,腺苷A2A和A2B受体与称为GS的刺激性G蛋白偶联,刺激性G蛋白激活腺苷酸环化酶,并提高胞内cAMP水平(Linden J.,Annu.Rev.Pharmacol.Toxicol.,41:775-87 2001)。
根据本发明,“腺苷受体选择性配体”为选择性与腺苷受体的一种或多种亚型结合,从而模拟腺苷的作用(腺苷激动剂)或阻断其作用(腺苷拮抗剂)的物质。根据它们的受体选择性,可将腺苷受体选择性配体分成不同的类别,例如与A1或A2受体选择性结合的配体,在后者的情况下,例如与A2A或A2B受体选择性结合的那些配体。与多种腺苷受体亚型选择性结合的腺苷受体配体也是可能的,例如与A1和A2受体选择性结合而不与A3受体选择性结合的配体。上述受体选择性可通过物质对细胞系的作用来确定,所述细胞系在用相应的cDNA稳定转染后表达所讨论的受体亚型(Olah,M.E.等人,J.Biol.Chem.,267:10764-10770,1992)。可通过胞内信使cAMP的生化测定来监测所述物质对此类细胞系的作用(Klotz,K.N.等人,Naunyn Schmiedebergs Arch.Pharmacol.357:1-9,1998)。
已知A1受体系统包括磷脂酶C的活化以及钾和钙离子通道二者的调节。除了与腺苷酸环化酶缔合外,A3亚型还刺激磷脂酶C,因此激活钙离子通道。
从各种物种(犬、人、大鼠、狗、鸡、牛、豚鼠)克隆A1受体(326-328个氨基酸),其在哺乳动物物种中具有90-95%的序列同一性。从犬、大鼠、人、豚鼠和小鼠克隆A2A受体(409-412个氨基酸)。从人和小鼠克隆A2B受体(332个氨基酸),人A2B与人A1和A2A受体有45%的同源性。也从人、大鼠、狗、兔和绵羊克隆A3受体(317-320个氨基酸)。
有人提出A1和A2A受体亚型在腺苷的能量供应调节中起补充作用。腺苷,是ATP的一种代谢产物,它从细胞扩散,并局部作用激活腺苷受体,以降低氧需求(A1和A3),或增加氧供应(A2A),从而恢复组织内能量供应/需求的平衡。这两种亚型的作用都是增加组织的可用氧量,并保护细胞免受短期氧不平衡引起的损伤。内源性腺苷的重要功能之一是防止在创伤例如缺氧、局部缺血、低血压和癫痫发作的期间损伤。另外,已知腺苷受体激动剂与表达大鼠A3受体的肥大细胞结合导致三磷酸肌醇和胞内钙浓度增加,这增强抗原诱导的炎症介质分泌。因此,A3受体在介导哮喘发作和其它过敏反应中起作用。
这些腺苷受体由不同的基因编码,并根据它们对腺苷类似物和甲基黄嘌呤拮抗剂的亲和力分类(Klinger等人,Cell Signal.,14(2):99-108,2002)。
关于腺苷对神经系统的作用,首先观察了所有精神药物中最广泛使用的咖啡因的作用。实际上,咖啡因是一种熟知的腺苷受体拮抗剂,它能够提高哺乳动物的意识和学习能力。腺苷A2A受体途径负责这些作用(Fredholm等人,Pharmacol.Rev.,51(1):83-133,1999;Huang等人,Nat Neurosci.,8(7):858-9,2005),且咖啡因对腺苷A2A受体信号传导途径的作用激励了对高特异性和有效腺苷A2A拮抗剂的研究。
在哺乳动物中,腺苷A2A受体在脑中的分布有限,并且在纹状体、嗅结节和伏隔核中发现(Dixon等人,Br.J.Pharmacol.,118(6):1461-8,1996)。可在免疫细胞、心、肺和血管中观察到高水平和中水平的表达。在外周系统中,G3似乎是与腺苷A2A受体缔合的主要G蛋白,但在纹状体中,已显示纹状体腺苷A2A受体通过激活称为Goif的G蛋白来介导其作用(KuIl等人,MoI.Pharmacol.,58(4):772-7,2000),Goif与G3相似,并且还与腺苷酸环化酶偶联。
迄今为止,对基因修饰小鼠和药理学分析的研究表明,不仅对于治疗中枢神经系统(CNS)障碍和疾病,例如帕金森症、亨廷顿症、注意缺陷多动障碍(ADHD)、中风(缺血性脑损伤)和阿尔茨海默症(Fredholm等人,Annu.Rev.Pharmacol.Toxicol.,45:385-412,2005;Higgins等人;Behav.Brain Res.185:32-42,2007;DaIl'Igna等人,Exp.Neurol.,203(1):241-5,2007;Arendash等人,Neuroscience,142(4):941-52,2006;Trends in Neurosci.,29(11),647-654,2006;Expert Opinion Ther.Patents,17,979-991,2007;Exp.Neurol.,184(1),285-284,2003;Prog.Brain Res,183,183-208,2010;J.Alzheimer Dis.,Suppl 1,117-126,2010;J.Neurosci.,29(47),14741-14751,2009;Neuroscience,166(2),590-603,2010;J.Pharmacol.Exp.Ther.,330(1),294-303,2009;Frontiers Biosci.,13,2614-2632,2008),而且对于治疗各种器质性成因的精神病(Weiss等人,Neurology,61(11Suppl6):88-93,2003),A2A受体是有希望的治疗靶标。
腺苷A2A受体敲除小鼠的使用已表明,腺苷A2A受体失活防止由缺血(Chen等人,J.Neurosci.,19(21):9192-200,1999和Monopoli等人,Neuroreport,9(17):3955-9,1998)和线粒体毒素3-NP(Blum等人,J.Neurosci.,23(12):5361-9,2003)引起的神经元细胞死亡。那些结果为用腺苷A2A拮抗剂治疗缺血和亨廷顿症提供了基础。腺苷A2A受体的阻断也有抗抑郁效果(El Yacoubi等人,Neuropharmacology,40(3):424-32,2001)。最后,这种阻断防止记忆功能紊乱(Cunha等人,Exp.Neurol.,210(2):776-81,2008;Takahashi等人,Front.Biosci.,13:2614-32,2008),并且这可以是治疗和/或预防阿尔茨海默症的有希望的治疗途径。
关于A2A腺苷受体的综述,请参见例如Moreau等人(Brain Res.Reviews 31:65-82,1999)和Svenningsson等人(Progress in Neurobiology 59:355-396,1999)。
迄今为止,几种腺苷A2A受体拮抗剂已显示治疗帕金森症的有希望的潜力。例如,KW-6002(Istradefylline)在证明其缓解疾障碍状的功效的研究后,在美国完成了一项III期临床试验(Bara-Himenez等人,Neurology,61(3):293-6,2003和Hauser等人,Neurology,61(3):297-303,2003)。SCH420814(Preladenant),目前已在美国进行II期临床试验,并在帕金森症的动物模型(Neustadt等人,Bioorg.Med.Chem.Lett.,17(5):1376-80,2001)以及人类患者(Hunter J.C,poster Boston 2006-http://www.a2apd.org/Speakerabstracts/Hunter.pdf)中产生了运动功能的改善。
除了A2A受体拮抗剂用于治疗神经变性疾病的受欢迎实用性外,也已考虑这些化合物用于补充性症状适应症。这些是基于以下证据,即A2A受体激活可有助于一系列神经精神障碍和功能紊乱的病理生理,例如抑郁、日间过度嗜睡、不宁腿综合征、注意缺陷多动障碍和认知疲劳(Neurology,61(Suppl 6),82-87,2003;Behav.Pharmacol.,20(2),134-145,2009;CNS Drug Discov.,2(1),1-21,2007)。
一些作者建议将A2A拮抗剂用于治疗糖尿病(WO1999035147;WO2001002400)。其它研究表明A2A腺苷受体涉及伤口愈合或心房纤颤(Am.J.Path.,6,1774-1778,2007;Arthritis&Rheumatism,54(8),2632-2642,2006)。
制药公司过去发现的一些有效的腺苷A2A拮抗剂已进入临床试验,显示积极的效果,并证明这类化合物的潜力,不仅对于治疗神经变性疾病例如帕金森症、亨廷顿症或阿尔茨海默症,而且也对于其它CNS相关的疾病,例如抑郁、不宁综合征、睡眠和焦虑障碍(Clin.Neuropharmacol.,33,55-60,2010;J.Neurosci.,30(48),2010),16284-16292;Parkinson Relat.Disord.,16(6),423-426,2010;Expert Opinion Ther.Patents,20(8),987-1005,2010;Current Opinion in Drug Discovery&Development,13(4),466-480,2010及其中参考文献;Mov.Disorders,25(2),S305,2010)。
已知的A2A抑制剂为伊曲茶碱(Istradefylline)(KW-6002)、Preladenant(SCH420814)、SCH58261、CGS15943、Tozadenant、Vipadenant(V-2006)、V-81444(CPI-444、HTL-1071、PBF-509、Medi-9447、PNQ-370、ZM-241385、ASO-5854、ST-1535、ST-4206、DT1133和DT-0926,它们在大多数情况下是为帕金森症研发的。
使用标准的聚合酶链反应技术并利用设计成识别大多数G蛋白偶联受体的保守区的简并寡核苷酸引物,从大鼠下丘脑(Rivkees和Reppert,1992)、人海马体(Pierce等人,1992)和小鼠肥大细胞(Marquardt等人,1994)克隆了腺苷A2B受体。人A2B受体与大鼠和小鼠A2B受体享有86至87%的氨基酸序列同源性(Rivkees和Reppert,1992;Pierce等人,1992;Marquardt等人,1994),与人A1和A2A受体享有45%的氨基酸序列同源性。如对近缘物种预料的那样,大鼠和小鼠的A2B受体享有96%的氨基酸序列同源性。相比之下,来自不同物种的A1受体之间享有的总体氨基酸同一性为87%(Palmer和Stiles,1995)。A2A受体在物种之间享有90%的同源性(Ongini和Fredholm,1996),大多数差异发生在第二个胞外环和长C端结构域(Palmer和Stiles,1995)。对于A3受体序列,观察到物种间的同一性程度最低(72%)(Palmer和Stiles,1995)。
腺苷类似物NECA仍然是最有效的A2B激动剂(Bruns,1981;Feoktistov和Biaggioni,1993,1997;Brackett和Daly,1994),其对腺苷酸环化酶刺激产生半最大效应的浓度(EC50)为约2μM。然而,它是非选择性的,并且以在低纳摩尔(A1和A2A)或高纳摩尔(A3)范围内的EC50以甚至更大的亲和力激活其它腺苷受体。因此,A2B受体的表征经常依赖于为其它受体类型的有效和选择性激动剂的化合物的效力的缺乏。A2B受体已通过排除法表征,即,通过对其它受体特异的激动剂的效力的缺乏。例如,A2A选择性激动剂CGS-21680(Webb等人,1992)可用于区分A2A腺苷受体和A2B腺苷受体(Hide等人,1992;Chern等人,1993;Feoktistov和Biaggioni,1995;van der Ploeg等人,1996)。两种受体均与腺苷酸环化酶阳性偶联,并由非选择性激动剂NECA激活。CGS-21680实际上对A2B受体无效,但在激活A2A受体方面与NECA一样有效,对两种激动剂的EC50均在低纳摩尔范围内(Jarvis等人,1989;Nakane和Chiba,1990;Webb等人,1992;Hide等人,1992;Feoktistov和Biaggioni,1993;Alexander等人,1996)。A2B受体对A1选择性激动剂R-PIA(Feoktistov和Biaggioni,1993;Brackett和Daly,1994)以及对A3选择性激动剂N6-(3-碘苄基)-N-甲基-5′-氨基甲酰基腺苷(IB-MECA)(Feoktistov和Biaggioni,1997)的亲和力也很低。关于A2B介导的cAMP积累,测定了在人红白血病(HEL)细胞中的激动剂分布NECA>R-PIA=IB-MECA>CGS-21680。NECA与其余激动剂的EC50之间的差异约为2个数量级。因此,由NECA在低微摩尔范围(1–10μM)的浓度下引起应答,而不是由R-PIA、IB-MECA或CGS-21680,是A2B受体的特征。
尽管与其它受体亚型相比,A2B受体通常具有对激动剂较低的亲和力,但对拮抗剂却并非如此。腺苷拮抗剂对A2B受体的结构活性关系尚未完全表征,但至少一些黄嘌呤是与其它亚型一样或比其更有效的A2B受体亚型的拮抗剂。具体地讲,DPSPX(1,3-二丙基-8-磺基苯基黄嘌呤)、DPCPX(1,3-二丙基-8-环戊基黄嘌呤)、DPX(1,3二乙基苯基黄嘌呤)、平喘药恩丙茶碱(3-正丙基黄嘌呤)和非黄嘌呤化合物2,4-二氧代苯并蝶啶(咯嗪)的亲和力在中至高nM范围内。
其它已知的A2B抑制剂为ATL801、PSB-605、PSB-1115、ISAM-140、GS6201、MRS1706和MRS1754。
在本文中公开了腺苷受体通过充当生理“STOP”(一种终止机制)而在体内炎症下调中起非冗余作用,生理“STOP”可限制免疫应答,并由此保护正常组织在不同疾病的发病机制过程中免受过度的免疫损伤。
A2A受体拮抗剂可通过降低T细胞介导的对抗原刺激的耐受性、增强记忆T细胞的诱导并提高被动抗体施用治疗癌症和感染性疾病的功效来长期增强免疫应答,而A2A受体激动剂则通过增强T细胞介导的对抗原刺激的耐受性来长期减少免疫应答,特别是在某些条件下减少免疫抑制剂的使用。
免疫调节是许多疾病和障碍治疗的关键方面。T细胞尤其在抵抗感染方面起着至关重要的作用,并具有识别和破坏癌细胞的能力。增强T细胞介导的应答是增强对治疗剂的应答的关键组成部分。然而,在免疫调节中至关重要的是,免疫应答的任何增强都必须与预防自身免疫以及慢性炎症的需求相平衡。慢性炎症和通过T细胞的自我识别是系统性疾病如类风湿性关节炎、多发性硬化和系统性红斑狼疮的发病机制的主要原因。另外,为了防止移植器官或移植物的排斥,需要长期的免疫抑制。
肿瘤诱导的免疫抑制是目前癌症治疗功效的主要障碍。由于它们对较宽范围的癌症显著的临床功效,利用免疫检查点阻断抑制剂(例如抗CTLA-4和抗PD-1/PDL1)的最近成功正在彻底改革癌症治疗。
腺苷是临床前研究中显示的新的有希望的免疫抑制靶标之一。该代谢产物由宿主抑制细胞和肿瘤细胞上表达的外酶-CD73产生。CD73表达的增加与许多癌症的患者的预后不良相关,包括结直肠癌(Liu等人,J.Surgical Oncol,2012)、胃癌(Lu等人,WorldJ.Gastroenterol.,2013)、胆囊癌(Xiong等人,Cell and Tissue Res.,2014)。临床前研究表明,腺苷介导的免疫抑制可(至少部分)驱动CD73的促瘤作用。如上所公开,腺苷与四种已知的受体A1、A2A、A2B和A3结合,并且已知A2A和A2B受体的激活抑制很多免疫细胞的效应子功能,即A2A和A2B受体诱导cAMP的腺苷酸环化酶依赖性积累,导致免疫抑制。由于拮抗A1和A3会抵消所期望的作用,并且A1和A3激动剂充当潜在的心脏保护剂,因此,需要实现对A1和A3的选择性(Antonioli等人,Nat.rev.Cancer,2013,Thiel等人,Microbes and Infection,2003)。在肿瘤的微环境中,已证明A2A和A2B受体的激活均抑制抗肿瘤免疫性,并增加CD73肿瘤的扩散。另外,用小分子拮抗剂阻断A2A或A2B可减少肿瘤转移。已发现阻断A2A受体可克服肿瘤逃逸机制,包括由肿瘤细胞引起的无反应性和调节性T细胞诱导,并且引起对治疗的长期肿瘤敏感性。Ohta等人证明,与正常小鼠中无排斥相比,在A2A受体缺陷小鼠中有已确立CL8-1黑素瘤肿瘤的约60%的排斥(Ohta,等人;PNAS 103(35):13132-7,2006)。一致的是,研究人员还表示,在用A2A受体拮抗剂治疗后,用抗肿瘤T细胞得到肿瘤生长的抑制作用的改善、转移的破坏和新血管形成的预防。
已表明,肿瘤通过抑制B7-CD28和TNF家族中的共刺激因子以及吸引调节性T细胞(其抑制抗肿瘤T细胞反应)来阻止T细胞激活而逃避免疫破坏(Wang,Cancer.Semin.Cancer.Biol.16:73-79,2006;Greenwald,等人,Ann.Rev.Immunol.23:515-48,2005;Watts,Ann.Rev.Immunol.23:23-68,2005;Sadum等人,Clin.Cane.Res.13(13):4016-4025,2007)。由于激活后淋巴细胞中的A2A受体表达增加,因此,释放淋巴细胞效应子反应的疗法(例如抗CTLA-4和抗PD-1)也可能会增强A2A介导的免疫抑制作用。与A2A拮抗剂或双重A2A/2B拮抗剂组合的免疫检查点阻断提高对肿瘤和转移的免疫应答程度。因此,在与MC38肿瘤细胞的共培养中,A2A抑制与抗PD-1疗法的组合改善由T细胞产生IFN-γ,在4T1乳腺肿瘤模型中提高小鼠存活率,并降低AT-3ovadim CD73+肿瘤的肿瘤生长(Beavis等人,Cancer Immunol.Res.,2015;Mittal等人,Cancer Res.,2014)。
另外,临床前研究表明,A2B抑制引起Lewis肺癌、MB49膀胱癌、原位4T1乳腺癌模型中小鼠的肿瘤生长减小和存活延长(Ryzhov等人,2009,Cekic等人,2012),A2B抑制与抗PD-1疗法的组合减少B16-F10黑素瘤肿瘤的肺转移,并改善4T1乳腺肿瘤模型中的小鼠存活率。
WO 03/050241描述了通过施用抑制胞外腺苷或抑制腺苷受体的药剂来增加对抗原的免疫应答,增加疫苗功效或增加对肿瘤抗原的免疫应答或免疫细胞介导的肿瘤破坏的方法。
WO 2004/089942、WO 2005/000842和WO 2006/008041公开了作为A2A抑制剂用于治疗帕金森症的苯并噻唑衍生物,包括Tozadenant。WO 2004/092171和WO 2005/028484公开了相似的噻唑并吡啶和吡唑并嘧啶衍生物,也作为A2A抑制剂用于治疗帕金森症。然而,这些化合物在大鼠(帕金森症动物模型)中没有显示显著的A2B抑制活性,而只显示良好的药物动力学特性,但在小鼠(癌症动物模型)中则不这样。另外,这些化合物未显示它们能够防止免疫抑制,和因此能够支持抗肿瘤T细胞诱导的肿瘤生长的抑制、转移的减少或破坏、以及新血管形成的预防。
因此,仍需要长期增强对特定抗原的免疫应答的疗法,特别是用于治疗和预防过度增生性和感染性疾病和障碍,因此,本发明的目的是提供允许简化治疗方案并增强针对某些抗原的免疫应答的治疗方法。本发明的一个具体目的是提供预防或治疗宿主中的过度增生性和感染性疾病和障碍的改进方法,尤其是提供用于治疗和预防此类疾病的有效A2A拮抗剂或双重A2A/2B拮抗剂。
发明概述
已令人惊讶地发现,本发明的噻唑并吡啶衍生物是A2A腺苷受体或A2A腺苷受体和A2B腺苷受体二者的高效抑制剂,同时具有超出A1腺苷受体和A3腺苷受体的高选择性,因此,本发明的化合物可用于治疗过度增生性疾病和障碍(例如癌症)和感染性疾病和障碍。
具体地讲,与已知的腺苷A2A受体拮抗剂Tozadenant和类似的苯并噻唑衍生物大不相同,本发明的化合物令人惊讶地显示A2A/A2B双重活性,这对于治疗和/或预防过度增生性和感染性疾病和障碍是优选的,如上文所公开;或者本发明的化合物至少显示高的A2A抑制活性与本文公开的其它令人惊讶的优点,从而在治疗和/或预防过度增生性和感染性疾病和障碍中产生高功效。
另外,与已知的腺苷A2A受体拮抗剂Tozadenant和类似的苯并噻唑衍生物比较,本发明的化合物令人惊讶地在作为与癌症相关的动物模型的小鼠中显示更佳的药物动力学特性,这对于治疗和/或预防过度增生性和感染性疾病和障碍是优选的,如上所公开。
另外,如上讨论,肿瘤微环境中的腺苷可通过经由A2A受体的信号传导来抑制T细胞活性,并抑制由T细胞分泌细胞因子。A2A特异性激动剂,如CGS-21680,与腺苷相似,在体外和体内均抑制T细胞分泌细胞因子。相比之下,潜在的A2A拮抗剂或A2A/A2B双重拮抗剂可拯救T细胞免于这种抑制。与已知的腺苷A2A受体拮抗剂Tozadenant大不相同,本发明的化合物显示它们能够拯救T细胞免于抑制,并且能够防止由腺苷或A2A特异性激动剂(例如CGS-2168)诱导的细胞因子分泌的抑制,这对于治疗和/或预防过度增生性和感染性疾病和障碍是优选的,如上文所公开。因此,本发明的化合物令人惊讶地能够防止免疫抑制,并因此能够支持抗肿瘤T细胞诱导的肿瘤生长的抑制、转移的减少或破坏以及新血管形成的预防。
本发明涉及通式I的噻唑并吡啶衍生物及其生理学上可接受的盐、衍生物、溶剂化物、前药和立体异构体,包括它们所有比例的混合物,
其中
R1为具有1-10个碳原子的直链或支链烷基,该基团未取代或由R5单、二或三取代,并且其中1-4个碳原子可相互独立地由O、S、SO、SO2、NH、NCH3、–OCO–、–NHCONH–、–NHCO–、–NR6SO2R7–、–COO–、–CONH–、–NCH3CO–、–CONCH3–、–C≡C–基团和/或–CH=CH–基团代替,和/或另外,1-10个氢原子可由F和/或Cl代替;或具有3-7个碳原子的单或双环环状烷基,该基团未取代或由R5单、二或三取代,其中1-4个碳原子可相互独立地由O、S、SO、SO2、NH、NCH3、–OCO–、–NHCONH–、–NHCO–、–NR6SO2R7–、–COO–、–CONH–、–NCH3CO–、–CONCH3–、–C≡C–基团和/或由–CH=CH–基团代替,和/或另外,1-10个氢原子可由F和/或Cl代替;或包含3至14个碳原子和0-4个独立选自N、O和S的杂原子的单或双环杂芳基、杂环基、芳基或环状烷基芳基,该基团未取代或由R5单、二或三取代,
R2为具有1-10个碳原子的直链或支链烷基,该基团未取代或由R5单、二或三取代,并且其中1-4个碳原子可相互独立地由O、S、SO、SO2、NH、NCH3、–OCO–、–NHCONH–、–NHCO–、–NR6SO2R7–、–COO–、–CONH–、–NCH3CO–、–CONCH3–、–C≡C–基团和/或–CH=CH–基团代替,和/或另外,1-10个氢原子可由F和/或Cl代替;或具有3-7个碳原子的环状烷基,该基团未取代或由R5单、二或三取代,并且其中1-4个碳原子可相互独立地由O、S、SO、SO2、NH、NCH3、–OCO–、–NHCONH–、–NHCO–、–NR6SO2R7–、–COO–、–CONH–、–NCH3CO–、–CONCH3–、–C≡C–基团和/或由–CH=CH–基团代替,和/或另外,1-11个氢原子可由F和/或Cl代替;或包含3至14个碳原子和0-4个独立选自N、O和S的杂原子的单或双环杂芳基、杂环基、芳基或环状烷基芳基,该基团未取代或由R5单、二或三取代,
R3为具有1-6个碳原子的直链或支链烷基或O-烷基或具有3-6个碳原子的环状烷基,该基团未取代或由H、=S、=NH、=O、OH、具有3-6个碳原子的环状烷基、COOH、Hal、NH2、SO2CH3、SO2NH2、CN、CONH2、NHCOCH3、NHCONH2或NO2单、二或三取代,
R4为H、D、具有1-6个碳原子的直链或支链烷基或Hal,
R5为H、R6、=S、=NR6、=O、OH、COOH、Hal、NH2、SO2CH3、SO2NH2、CN、CONH2、NHCOCH3、NHCONH2、NO2;或具有1-10个碳原子的直链或支链烷基,该基团未取代或由R6单、二或三取代,并且其中1-4个碳原子可相互独立地由O、S、SO、SO2、NH、NCH3、–OCO–、–NHCONH–、–NHCO–、–NR6SO2R7–、–COO–、–CONH–、–NCH3CO–、–CONCH3–、–C≡C–基团和/或–CH=CH–基团代替,和/或另外,1-10个氢原子可由F和/或Cl代替;或具有3-7个碳原子的单或双环环状烷基,该基团未取代或由R6单、二或三取代,其中1-4个碳原子可相互独立地由O、S、SO、SO2、NH、NCH3、–OCO–、–NHCONH–、–NHCO–、–NR6SO2R7–、–COO–、–CONH–、–NCH3CO–、–CONCH3–、–C≡C–基团和/或由–CH=CH–基团代替,和/或另外,1-10个氢原子可由F和/或Cl代替;或包含3至14个碳原子和0-4个独立选自N、O和S的杂原子的单或双环杂芳基、杂环基、芳基或环状烷基芳基,该基团未取代或由R6单、二或三取代,
R6、R7相互独立地选自H、=S、=NH、=O、OH、COOH、Hal、NH2、SO2CH3、SO2NH2、CN、CONH2、NHCOCH3、NHCONH2、NO2;和具有1-10个碳原子的直链或支链烷基,其中1-4个碳原子可相互独立地由O、S、SO、SO2、NH、NCH3、–OCO–、–NHCONH–、–NHCO–、–COO–、–CONH–、–NCH3CO–、–CONCH3–、–C≡C–基团和/或–CH=CH–基团代替,和/或另外,1-10个氢原子可由F和/或Cl代替,
Hal为F、Cl、Br或I,
D为氘。
本发明优选涉及式I的化合物,其中
R1为具有1-10个碳原子的直链或支链烷基,该基团未取代或由R4单、二或三取代,并且其中1-4个碳原子可相互独立地由O、S、SO、SO2、NH、NCH3、–OCO–、–NHCONH–、–NHCO–、–NR5SO2R6–、–COO–、–CONH–、–NCH3CO–、–CONCH3–、–C≡C–基团和/或–CH=CH–基团代替,和/或另外,1-10个氢原子可由F和/或Cl代替;或以下结构之一:
该基团未取代或用R5单、二或三取代
并且其中R2、R3、R4、R5、R6和R7具有如上所公开的含义。
本发明特别优选涉及式I的化合物,其中
R1为以下结构之一:
并且其中R2、R3、R4、R5、R6和R7具有如上所公开的含义。
本发明优选涉及式I的化合物,其中
R1为苯基、甲基吡唑或二氢吡喃
并且R2、R3、R4、R5、R6和R7具有如上所公开的含义。
本发明特别优选涉及式I的化合物,其中R2为以下结构之一:
该基团未取代或用R6单、二或三取代
并且其中R1、R3、R4、R5、R6和R7具有如上所公开的含义。
本发明特别优选涉及式I的化合物,其中
R2为以下结构之一:
并且其中R1、R3、R4、R5、R6和R7具有如上所公开的含义。
本发明优选涉及式I的化合物,其中
并且R1、R2、R4、R5、R6和R7具有如上所公开的含义。
本发明优选涉及式I的化合物,其中
R3为具有1-6个碳原子的O-烷基,该基团未取代或用F单、二或三取代
并且R1、R2、R4、R5、R6和R7具有如上所公开的含义。
本发明优选涉及式I的化合物,其中
R3为OMe
并且R1、R2、R4、R5、R6和R7具有如上所公开的含义。
本发明特别优选涉及式I的化合物,其中
R1为苯基、甲基吡唑或二氢吡喃,
R3为OMe
并且R2、R4、R5、R6和R7具有如上所公开的含义。
本发明优选涉及式I的化合物,其中
R4为H、D、甲基、乙基、F、Br或Cl
并且其中R1、R2、R3、R5、R6和R7具有如上所公开的含义。
本发明优选涉及式I的化合物,其中
R4为H、D、甲基、F、Br或Cl
并且其中R1、R2、R3、R5、R6和R7具有如上所公开的含义。
本发明优选涉及式I的化合物,其中
R4为H
并且其中R1、R2、R3、R5、R6和R7具有如上所公开的含义。
本发明特别优选涉及选自下列的化合物及其生理学上可接受的盐、衍生物、溶剂化物、前药和立体异构体,包括它们所有比例的混合物,
式I化合物的以上基团的所有上述优选的、特别优选的和非常特别优选的含义应以这样一种方式理解,即这些优选的、特别优选的和非常特别优选的含义或实施方案可以任何可能的组合相互组合,得到式I的化合物,并由此同样明确地公开了优选的、特别优选的和非常特别优选的这种类型的式I的化合物。
Hal表示氟、氯、溴或碘,具体为氟、溴或氯。
D或2H表示氘。
烷基为饱和的无支链(直链)或支链烃链,并具有1、2、3、4、5、6、7、8、9或10个碳原子。烷基优选表示烯基甲基,另外表示乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基,另外还表示戊基、1-、2-或3-甲基丁基、1,1-、1,2-或2,2-二甲基丙基、1-乙基丙基、己基、1-、2-、3-或4-甲基戊基、1,1-、1,2-、1,3-、2,2-、2,3-或3,3-二甲基丁基、1-或2-乙基丁基、1-乙基-1-甲基丙基、1-乙基-2-甲基丙基、1,1,2-或1,2,2-三甲基丙基、直链或支链庚基、辛基、壬基或癸基,更优选例如三氟甲基。
环状烷基或环烷基为饱和的环状烃链,并具有3-10个、优选3-7个碳原子,并且优选表示环丙基、环丁基、环戊基、环己基或环庚基。环烷基还表示部分不饱和的环状烷基,例如环己烯基或环己炔基。
烯基表示不饱和的无支链(直链)或支链烃链,并具有1、2、3、4、5、6、7、8、9或10个碳原子。
O-烷基或OA表示具有1-6个碳原子的直链或支链烷氧基,优选为甲氧基,另外还优选例如为乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基。
烷基氧基羰基是指本发明的羧酸衍生物的直链或支链酯,即甲基氧基羰基(MeOCO-)、乙基氧基羰基或丁基氧基羰基。
烷基羰基是指直链或支链烷基和羧酸基团。
芳基、Ar或芳族环表示单环或多环芳族或完全不饱和的环状烃链,例如未取代的苯基、萘基或联苯基,还优选为苯基、萘基或联苯基,其各自被单、二或三取代,例如,由A、氟、氯、溴、碘、羟基、甲氧基、乙氧基、丙氧基、丁氧基、戊基氧基、己基氧基、硝基、氰基、甲酰基、乙酰基、丙酰基、三氟甲基、氨基、甲基氨基、乙基氨基、二甲氨基、二乙氨基、苄基氧基、磺酰氨基、甲基磺酰氨基、乙基磺酰氨基、丙基磺酰氨基、丁基磺酰氨基、二甲基磺酰氨基、苯基磺酰氨基、羧基、甲氧基羰基、乙氧基羰基、氨基羰基取代。
杂环和杂环基是指包含至少一个选自O、S和N的杂原子的饱和或不饱和的非芳族环或环系统,杂原子还包括硫的氧化形式,即SO和SO2。杂环的实例包括四氢呋喃(THF)、二氢呋喃、1,4-二噁烷、吗啉、1,4-二噻烷、哌嗪、哌啶、1,3-二氧戊环、咪唑烷、咪唑啉、吡咯啉、吡咯烷、四氢吡喃、二氢吡喃、氧硫杂环戊烷、二硫戊环、1,3-二噁烷、1,3-二噻烷、氧硫杂环己烷、硫代吗啉等。
杂芳基指包含至少一个选自O、S和N的环杂原子的芳族或部分芳族杂环。因此,杂芳基包括稠合到其它种类的环(例如芳基、环烷基和非芳族的杂环)的杂芳基。杂芳基的实例包括吡咯基、异噁唑基、异噻唑基、吡唑基、吡啶基、噁唑基、噁二唑基、噻二唑基、噻唑基、咪唑基、三唑基、四唑基、呋喃基、三嗪基、噻吩基、嘧啶基、苯并异噁唑基、苯并噁唑基、苯并噻唑基、苯并噻二唑基、二氢苯并呋喃基、二氢吲哚基、哒嗪基、吲唑基、异噁唑基、异吲哚基、二氢苯并噻吩基、吲嗪基、噌啉基、酞嗪基、喹唑啉基、萘啶基、咔唑基、苯并二噁烯基(benzdioxinyl)、苯并二噁茂基、喹喔啉基、嘌呤基、呋咱基、噻吩基、异苄基呋喃基、苯并咪唑基、苯并呋喃基、苯并噻吩基、喹啉基、吲哚基、异喹啉基、二苯并呋喃基等。对于杂环基和杂芳基,包括形成1-3个环的包含3-15个原子的环和环系统。
单环或双环饱和、不饱和或芳族杂环优选表示未取代或单、二或三取代的2-或3-呋喃基,2-或3-噻吩基,1-、2-或3-吡咯基,1-、2-、4-或5-咪唑基,1-、3-、4-或5-吡唑基,2-、4-或5-噁唑基,3-、4-或5-异噁唑基,2-、4-或5-噻唑基,3-、4-或5-异噻唑基,2-、3-或4-吡啶基,2-、4-、5-或6-嘧啶基,更优选1,2,3-三唑-1-、-4-或-5-基,1,2,4-三唑-1-、-3-或5-基,1-或5-四唑基,1,2,3-噁二唑-4-或-5-基,1,2,4-噁二唑-3-或-5-基,1,3,4-噻二唑-2-或5-基,1,2,4-噻二唑-3-或-5-基,1,2,3-噻二唑-4-或-5-基,3-或4-哒嗪基,吡嗪基,1-、2-、3-、4-、5-、6-或7-吲哚基,4-或5-异吲哚基,1-、2-、4-或5-苯并咪唑基,1-、3-、4-、5-、6-或7-苯并吡唑基,2-、4-、5-、6-或7-苯并噁唑基,3-、4-、5-、6-或7-苯并异噁唑基,2-、4-、5-、6-或7-苯并噻唑基,2-、4-、5-、6-或7-苯并异噻唑基,4-、5-、6-或7-苯并-2,1,3-噁二唑基,2-、3-、4-、5-、6-、7-或8-喹啉基,1-、3-、4-、5-、6-、7-或8-异喹啉基,3-、4-、5-、6-、7-或8-噌啉基,2-、4-、5-、6-、7-或8-喹唑啉基,5-或6-喹喔啉基,2-、3-、5-、6-、7-或8-2H-苯并-1,4-噁嗪基,进一步优选1,3-苯并二噁茂-5-基,1,4-苯并二噁烷-6-基,2,1,3-苯并噻二唑-4-或-5-基或2,1,3-苯并噁二唑-5-基。
杂环基也可部分或完全氢化,并且还表示例如2,3-二氢-2-、-3-、-4-或-5-呋喃基,2,5-二氢-2-、3-、-4-或5-呋喃基,四氢-2-或-3-呋喃基,1,3-二氧杂环戊烷-4-基,四氢-2-或-3-噻吩基,2,3-二氢-1-、-2-、-3-、-4-或-5-吡咯基,2,5-二氢-1-、-2-、-3-、4-或-5-吡咯基,1-、2-或3-吡咯烷基,四氢-1-、-2-或-4-咪唑基,2,3-二氢-1-、-2-、-3-、-4-或-5-吡唑基,四氢-1-、-3-或-4-吡唑基,1,4-二氢-1-、-2-、-3-或-4-吡啶基,1,2,3,4-四氢-1-、-2-、-3-、-4-、-5-或6-吡啶基,1-、2-、3-或4-哌啶基,2-、3-或4-吗啉基,四氢-2-、-3-或-4-吡喃基,1,4-二噁烷基,1,3-二噁烷-2-、-4-或-5-基,六氢-1-、-3-或4-哒嗪基,六氢-1-、-2-、-4-或-5-嘧啶基,1-、2-或3-哌嗪基,1,2,3,4-四氢-1-、-2-、-3-、-4-、-5-、-6-、-7-或-8-喹啉基,1,2,3,4-四氢-1-、-2-、-3-、-4-、-5-、-6、-7-或-8-异喹啉基,2-、3-、5-、6-、7-或8-3,4-二氢-2H-苯并-1,4-噁嗪基,更优选2,3-亚甲基二氧基苯基,3,4-亚甲基二氧基苯基,2,3-亚乙基二氧基苯基,3,4-亚乙基二氧基苯基,3,4-(二氟亚甲基二氧基)苯基,2,3-二氢苯并呋喃-5-或6-基,2,3-(2-氧代亚甲基二氧基)苯基或3,4-二氢-2H-1,5-苯并二噁庚英-6-或-7-基,进一步优选2,3-二氢苯并呋喃基或2,3-二氢-2-氧代呋喃基。
杂环还表示例如2-氧代哌啶-1-基、2-氧代吡咯烷-1-基、2-氧代-1H-吡啶-1-基、3-氧代吗啉-4-基、4-氧代-1H-吡啶-1-基、2,6-二氧代哌啶-1-基、2-氧代哌嗪-1-基、2,6-二氧代哌嗪-1-基、2,5-二氧代吡咯烷-1-基、2-氧代-1,3-噁唑烷-3-基、3-氧代-2H-哒嗪-2-基、2-己内酰胺-1-基(=2-氧代氮杂环庚烷-1-基)、2-羟基-6-氧代哌嗪-1-基、2-甲氧基-6-氧代哌嗪-1-基或2-氮杂双环[2.2.2]辛-3-酮-2-基。
杂环烷基在此表示完全氢化或饱和的杂环,杂环烯基(一个或多个双键)或杂环炔基(一个或多个三键)表示部分或不完全氢化或不饱和的杂环,杂芳基表示芳族或完全不饱和的杂环。
与本发明相关的环状烷基芳基是指一个或两个芳族环Ar稠合到未取代或单或二取代的环状烷基上,其中一个或两个CH2基团和/或另外1-11个氢原子可被代替,例如在以下所绘的基团中:
另外,以下缩写具有下列含义:
Boc 叔丁氧基羰基
CBZ 苄基氧基羰基
DNP 2,4-二硝基苯基
FMOC 9-芴基甲氧基羰基
imi-DNP 咪唑环1位上的2,4-二硝基苯基
OMe 甲酯
POA 苯氧基乙酰基
DCCI 二环己基碳二亚胺
HOBt 1-羟基苯并三唑
因此,本发明涉及一种药物制剂,该制剂包含本发明的化合物和/或其生理学上可接受的盐、衍生物、溶剂化物、前药和立体异构体、包括它们所有比例的混合物中的一者。
本发明也涉及包含其它赋形剂和/或辅剂的这种类型的本发明的药物制剂。
另外,本发明涉及包含至少一种其它药物活性化合物的本发明的以上药物制剂。
药学上或生理学上可接受的衍生物应认为指例如本发明的化合物的盐,以及所谓的前药化合物。前药化合物应认为指已通过例如烷基或酰基(也参见下面的氨基-和羟基-保护基)、糖或寡肽修饰,且在生物体中快速断裂或释放而生成有效分子的本发明化合物的衍生物。这些也包括本发明化合物的生物可降解聚合物衍生物,例如描述于Int.J.Pharm.115(1995),61-67。
本发明的化合物可以其最终非盐形式使用。另一方面,本发明也包括为其药学上可接受的盐形式的胃酶抑素的用途,该盐可通过在本领域已知的方法从各种有机和无机碱得到。胃酶抑素的药学上可接受的盐形式大部分通过常规方法制备。如果本发明的化合物包含羧基,则其适合的盐之一可通过本发明的化合物与适合的碱反应生成,以得到相应的碱加成盐。此类碱为例如碱金属氢氧化物,包括氢氧化钾、氢氧化钠和氢氧化锂;碱土金属氢氧化物,如氢氧化钡和氢氧化钙;碱金属醇盐,例如乙醇钾和丙醇钠;和各种有机碱,例如哌啶、二乙醇胺和N-甲基-谷氨酰胺。同样包括胃酶抑素的铝盐。
另外,本发明化合物的碱盐包括铝、铵、钙、铜、铁(III)、铁(II)、锂、镁、锰(III)、锰(II)、钾、钠和锌盐,但这不旨在表示限制。
在上述盐中,优选铵;碱金属钠和钾盐;和碱土金属钙和镁盐。从药学上可接受的有机非毒性碱得到的本发明化合物的盐包括如下碱的盐:伯、仲和叔胺、经取代胺(也包括天然存在的取代胺)、环胺和碱性离子交换树脂,例如精氨酸、甜菜碱、咖啡因、氯普鲁卡因、胆碱、Ν,Ν'-二苄基乙二胺(苄星)、二环己基胺、二乙醇胺、二乙胺、2-二乙氨基乙醇、2-二甲氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺、氨基葡萄糖、组氨酸、海巴明、异丙胺、利多卡因、赖氨酸、甲葡胺、N-甲基-D-葡糖胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤、可可碱、三乙醇胺、三乙胺、三甲胺、三丙胺和三(羟基甲基)甲基胺(氨基丁三醇),但这不旨在表示限制。
如上提到,胃酶抑素的药学上可接受的碱加成盐用金属或胺(例如碱金属和碱土金属或有机胺)生成。优选的金属为钠、钾、镁和钙。优选的有机胺为N,N’-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基-D-葡糖胺和普鲁卡因。
通过使游离酸形式与足够量的所需碱接触,促成以常规方式生成盐,来制备本发明化合物的碱加成盐。通过使盐形式与酸接触并以常规方式分离游离酸,可再生游离酸。在某些方面,该游离酸形式就某些物理性质而论有别于其相应的盐形式,例如,在极性溶剂中的溶解性;然而,出于本发明的目的,该盐在其它方面相当于其各自的游离酸形式。
鉴于上述,可以看到,在此方面术语“药学上可接受的盐”应认为指活性化合物,其包括为其盐之一的形式的本发明化合物,特别是在该盐形式相比活性化合物的游离形式或以前所用活性化合物的任何其它盐形式而言改善活性化合物的药物动力学性质的情况下。活性化合物的药学上可接受的盐形式也可第一次为这种活性化合物提供它确实以前没有的所需药物动力学性质,甚至就其在身体中的功效而言可对这种活性化合物的药效学具有积极作用。
本发明化合物的溶剂化物应认为指惰性溶剂分子胃酶抑素由于其相互吸引力而生成的加合物。溶剂化物为例如水合物,例如一水合物或二水合物,或醇化物,即与醇的加成化合物,例如与甲醇或乙醇。
这些化合物的所有生理学上可接受的盐、衍生物、溶剂化物和立体异构体,包括它们所有比例的混合物,也符合本发明。
通式I的化合物可包含一个或多个手性中心,因此,在本发明中还要求保护通式I化合物的所有立体异构体、对映异构体、非对映异构体等。
本发明也涉及这些化合物的光学活性形式(立体异构体)、对映异构体、外消旋体、非对映异构体和水合物及溶剂化物。
本发明的式I化合物由于其分子结构而可以为手性,因此可以各种对映异构形式存在。因此,它们可以为外消旋或光学活性形式。由于本发明化合物的外消旋体或立体异构体的药物功效可能不同,因此可能期望使用对映异构体。在这些情况下,通过本领域的技术人员已知或本身已在合成中采用的化学或物理方法,不仅可将最终产物、甚至可将中间体分离成对映异构化合物。
药学上或生理学上可接受的衍生物应认为指例如本发明的化合物的盐和所谓的前药化合物。前药化合物应认为指已用例如烷基或酰基(也参见下面的氨基-和羟基-保护基)、糖或寡肽修饰,且在生物体中快速断裂或释放而生成本发明的有效化合物的式I的化合物。这些也包括本发明化合物的生物可降解聚合物衍生物,例如描述于Int.J.Pharm.115(1995),61-67。
适合的酸加成盐为所有生理学上或药理学上可接受的酸的无机或有机盐,例如卤化物(特别是盐酸盐或氢溴酸盐)、乳酸盐、硫酸盐、柠檬酸盐、酒石酸盐、马来酸盐、富马酸盐、草酸盐、乙酸盐、磷酸盐、甲基磺酸盐或对甲苯磺酸盐。
非常特别优选本发明化合物的盐酸盐、三氟乙酸盐或双三氟乙酸盐。
式I化合物的溶剂化物应认为指由于其相互吸引力而生成的惰性溶剂分子在式I化合物上的加合物。溶剂化物为例如水合物,例如一水合物或二水合物,或醇化物,即与醇的加成化合物,例如与甲醇或乙醇。
式I的化合物也旨在包括其同位素标记形式。除了化合物的一个或多个原子已被原子质量或质量数与通常天然存在的原子的原子质量或质量数不同的原子代替的事实之外,式I化合物的同位素标记形式与这种化合物相同。容易购得且能够通过熟知方法结合到式I化合物中的同位素的实例包括氢、碳、氮、氧、磷、氟和氯的同位素,例如分别为2H、3H、13C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。包含一种或多种上述同位素和/或其它原子的其它同位素的式I化合物、其前药或药学上可接受的盐旨在为本发明的一部分。式I的同位素标记化合物可以多种有利方式使用。例如,其中已结合有例如放射性同位素(如,3H或14C)的式I的同位素标记化合物适用于药物和/或底物组织分布测定。由于制备简单和极佳的可检测性,这些放射性同位素(即,氚(3H)和碳-14(14C))特别优选。由于较重同位素标记化合物的较高代谢稳定性,较重同位素(例如氘(2H))结合到式I的化合物具有治疗优势。较高代谢稳定性直接转变成延长的体内半衰期或较低剂量,在大多数情况下将代表本发明的优选实施方案。通常,通过进行所呈现文本中的合成方案和相关说明、本文实施例部分和制备部分中公开的程序,用容易得到的同位素标记反应剂代替非同位素标记反应剂,可制备式I的同位素标记化合物。
为了通过一级动力学同位素效应控制化合物的氧化代谢,也可使氘(2H)结合到式I的化合物中。一级动力学同位素效应是由同位素核交换引起,继而由这种同位素交换后共价键形成所必需的基态能量变化导致的化学反应速率变化。较重同位素的交换通常引起化学键的基态能量降低,并因此导致速率限制性键断裂的速率降低。如果沿着多产物反应的坐标在鞍点区域中或附近发生键断裂,则可实质上改变产物分布比例。例如,如果氘在不可交换位置结合到碳原子,则kM/kD=2-7速率差是典型的。如果该速率差成功用于对氧化敏感的式I的化合物,则该化合物的体内分布可由此显著改变,并改善药物动力学性质。
在发现和研发治疗剂时,本领域的技术人员试图优化药物动力学参数,同时保持合乎需要的体外性质。合理的是设想具有不良药物动力学特性的很多化合物容易氧化代谢。目前可利用的体外肝微粒体测定提供关于此类型氧化代谢过程的有价值信息,这继而允许合理设计通过抗此氧化代谢具有改善稳定性的式I的氘代化合物。式I化合物的药物动力学特性由此获得显著改善,并可在体内半衰期(T/2)、最大治疗效果下的浓度(Cmax)、在剂量反应曲线下的面积(AUC)和F的增加以及清除率、剂量和原料成本的减小的方面定量表达。
以下旨在说明上述内容:作为一系列类似物制备式I的化合物,该化合物具有对于氧化代谢的多个潜在攻击位点,例如,苄基氢原子和结合到氮原子的氢原子,其中氢原子的各种组合由氘原子代替,因此这些氢原子的一些、大多数或全部已由氘原子代替。半衰期测定能够有利和精确地确定改善抗氧化代谢的程度。以此方式确定,母体化合物的半衰期可由于此类型的氘-氢交换延长达100%。
为了减少或消除不合需要的毒性代谢物,也可用在式I化合物中由氘代替氢有利地改变起始化合物的代谢物谱。例如,如果毒性代谢物通过氧化性碳-氢(C-H)键断裂出现,则可合理地设想,氘代类似物将极大减少或消除该不合需要代谢物的产生,即使特定氧化不是速率决定性步骤。关于氘-氢交换的技术水平的其它信息例如在Hanzlik等人,J.Org.Chem.55,3992-3997,1990、Reider等人,J.Org.Chem.52,3326-3334,1987、Foster,Adv.Drug Res.14,1-40,1985、Gillette et al,BioChemistry 33(10)2927-2937,1994和Jarman等人,Carcinogenesis16(4),683-688,1993中给出。
本发明也涉及本发明的式I化合物的混合物,例如,1:1、1:2、1:3、1:4、1:5、1:10、1:100或1:1000的比例的两种非对映异构体的混合物。这些是特别优选的两种立体异构化合物的混合物。然而,也优选两种或更多种式I化合物的混合物。
另外,本发明涉及一种制备式I化合物的方法,其特征在于
a)式II的化合物经历还原,得到式III的化合物,使式III的化合物与式IV的化合物在升高的温度下反应,得到式V的化合物,利用催化剂和碱的使用使式V的化合物转化成式VI的化合物,通过溴化使式VI的化合物转化成式VII的化合物,在本质上碱性的条件下使式VII的化合物转化成式VIII的化合物,并且在标准酰胺化或脲生成条件下使式VIII的化合物与式IX的化合物反应,得到式I的化合物,
b)在Suzuki型反应条件下使式V的化合物与式X的化合物反应,得到式VI的化合物,通过溴化使式VI的化合物转化成式VII的化合物,在本质上碱性的条件下使式VII的化合物转化成式VIII的化合物,并且在标准酰胺化或脲生成条件下使式VIII的化合物与式IX的化合物反应,得到式I的化合物,
c)碘化式XII的化合物,得到式XIII的化合物,通过用碱和亲电试剂处理使式XIII的化合物转化成式XIV的化合物,通过还原使式XIV的化合物转化成式XV的化合物,使式XV的化合物与式IV的化合物在升高的温度下反应,得到式XVI的化合物,在催化条件下使式XVI的化合物转化成式XVII的化合物,在碱性条件下使式XVII的化合物转化成式VIII的化合物,并在标准酰胺化或脲生成条件下使式VIII的化合物与式IX的化合物反应,得到式I的化合物,
d)通过用酸处理使式I的化合物的碱转化成其盐之一,或
e)通过用碱处理使式I的化合物的酸转化成其盐之一。
也可在每种情况下逐步进行这些反应,并通过修改保护基的概念来改变结构单元的连接反应序列。
原料或起始化合物一般已知。如果它们是新的,则可通过本身已知的方法制备。
如果需要,也可通过不从反应混合物分离,而是立即使它们进一步转化成式I的化合物,来就地生成原料。
式I的化合物优选通过溶剂解从它们的官能衍生物释放来获得,具体地讲,通过水解,或者通过氢解。用于溶剂解或氢解的优选原料为那些包含相应受保护氨基、羧基和/或羟基基团而不是一个或多个游离氨基、羧基和/或羟基的原料,优选那些带有氨基保护基而不是与氮原子连接的氢原子的原料。另外,优选带有羟基保护基而不是羟基的氢原子的原料。也优选带有受保护羧基而不是游离羧基的原料。在原料分子中也可存在多个相同或不同的受保护氨基、羧基和/或羟基基团。如果存在的保护基相互不同,则可在很多情况下选择性地断开它们。
术语“氨基保护基”一般已知,并且涉及如下的基团,该基团适用于保护(阻断)氨基免于化学反应,但在所需的化学反应已在分子的其它地方进行后可容易地去除。此类基团的典型特别为未取代或经取代酰基,另外为未取代或经取代芳基(例如2,4-二硝基苯基)或芳烷基(例如苄基、4-硝基苄基、三苯基甲基)。另外,由于氨基保护基在所需的反应或反应序列后去除,因此,它们的类型和大小不关键,但优选具有1-20个、特别是1-8个碳原子的那些。术语“酰基”应在与本发明方法相关的最广意义上理解。它包括衍生自脂族、芳脂族、芳族或杂环羧酸或磺酸的酰基,具体地讲,烷氧基羰基、芳基氧基羰基,尤其是芳烷氧基羰基。这样的酰基的实例为烷酰基,例如乙酰基、丙酰基、丁酰基;芳烷酰基,例如苯基乙酰基、芳甲酰基(例如苯甲酰基或甲苯甲酰基);芳氧基烷酰基,例如苯氧基乙酰基;烷氧基羰基,例如甲氧基羰基、乙氧基羰基、2,2,2-三氯乙氧基羰基、BOC、2-碘乙氧基羰基;芳烷氧基羰基,例如CBZ、4-甲氧基苄基氧基羰基或FMOC。优选的酰基为CBZ、FMOC、苄基和乙酰基。
术语“酸保护基”或“羧基保护基”同样通常已知的,并且涉及如下的基团,该基团适用于保护-COOH基团免于化学反应,但在所需的化学反应已在分子的其它地方进行后可容易地去除。通常用酯代替游离酸,例如经取代和未取代的烷基酯(例如甲基、乙基、叔丁基及其经取代的衍生物)、经取代和未取代的苄基酯或甲硅烷基酯。酸保护基的类型和大小不关键,但优选具有1-20个、特别是1-10个碳原子的那些。
术语“羟基保护基”同样一般已知,并且涉及如下的基团,该基团适用于保护羟基免于化学反应,但在所需的化学反应已在分子的其它地方进行后可容易地去除。此类基团的典型为上述未取代或经取代的芳基、芳烷基或酰基,另外还有烷基。羟基保护基的类型和大小不关键,但优选具有1-20个、特别是1-10个碳原子的那些。羟基保护基的实例尤其为苄基、对硝基苯甲酰基、对甲苯磺酰基和乙酰基,其中苄基和乙酰基是优选的。
氨基-、酸-和羟基-保护基的其它典型实例例如发现于“Greene’s ProtectiveGroups in Organic Synthesis”(有机合成中的格林保护基),第四版,Wiley-Interscience,2007。
要用作原料的式I化合物的官能衍生物可通过氨基酸和肽合成的已知方法制备,例如描述于所述标准著作和专利申请中。
根据所用的保护基,式I的化合物从其官能衍生物释放,例如在强酸的帮助下,有利使用三氟乙酸或高氯酸,但也可使用其它强无机酸(例如盐酸或硫酸)、强有机酸(例如三氯乙酸,或磺酸(例如苯甲酰基磺酸或对甲苯磺酸))。可存在另外的惰性溶剂和/或催化剂,但不总是必要的。
根据各自的合成路线,原料可任选在惰性溶剂存在下反应。
适合的惰性溶剂为例如庚烷、己烷、石油醚、DMSO、苯、甲苯、二甲苯、三氯乙烯-、1,2-二氯乙烷、四氯化碳、氯仿或二氯甲烷;醇,例如甲醇、乙醇、异丙醇、正丙醇、正丁醇或叔丁醇;醚,例如乙醚、异丙醚(优选用于吲哚氮上的取代)、四氢呋喃(THF)或二噁烷;二醇醚,例如乙二醇单甲醚或单乙醚、乙二醇二甲醚(二甘醇二甲醚);酮,例如丙酮或丁酮;酰胺,例如乙酰胺、二甲基乙酰胺、N-甲基吡咯烷酮(NMP)或二甲基甲酰胺(DMF);腈,例如乙腈;酯,例如乙酸乙酯;羧酸或酸酐,例如,乙酸或乙酸酐;硝基化合物,例如硝基甲烷或硝基苯,任选还包括所述溶剂相互的混合物或与水的混合物。
溶剂的量不是关键的;每g要反应的式I化合物可优选加入10g至500g溶剂。
可能有利的是加入酸结合剂,例如碱金属或碱土金属氢氧化物、碳酸盐或碳酸氢盐或其它弱酸的碱金属或碱土金属盐(优选钾盐、钠盐或钙盐),或加入有机碱,例如三乙胺、二甲胺、吡啶或喹啉,或过量的胺组分。
本发明的所得化合物可从其中制备它们的相应溶液分离(例如通过离心和洗涤),并且可在分离后储存在另一组合物中,或者它们可直接保留在制备溶液中。对于特定用途,本发明的所得化合物也可吸收在所需溶剂中。
反应持续时间取决于选择的反应条件。通常,反应持续时间为0.5小时至10天,优选1至24小时。在使用微波时,反应时间可缩短到1至60分钟的值。
另外,式I的化合物及其制备原料通过已知的方法制备,如文献中所述(例如,标准著作,如Houben-Weyl,Methoden der organischen Chemie(有机化学方法),Georg-Thieme-Verlag,Stuttgart),例如,在已知且适用于所述反应的反应条件下。在此也可利用本身已知的变体,这里不再更详细地描述。
常规的后处理步骤,例如向反应混合物加水和萃取,使得能够在去除溶剂后获得化合物。为了进一步纯化产物,在此之后利用蒸馏或结晶或进行层析纯化可能是有利的。
可用碱使式I的酸转化成相关联的加成盐,例如,通过使相等量的酸和碱在惰性溶剂(如乙醇)中反应,并包括蒸发。用于此反应的适合碱特别为得到生理学上可接受的盐的那些碱。因此,可用碱(例如氢氧化钠、氢氧化钾、碳酸钠或碳酸钾)使式I的酸转化成相应的金属盐,特别是碱金属或碱土金属盐,或转化成相应的铵盐。得到生理学上可接受的盐的有机碱,例如乙醇胺,也适用于此反应。
另一方面,可用酸使式I的碱转化成相关联的酸加成盐,例如通过使相等量的碱和酸在惰性溶剂(如乙醇)中反应,随后蒸发。用于此反应的适合酸特别为得到生理学上可接受的盐的那些酸。因此,可使用无机酸,例如硫酸、硝酸、氢卤酸(例如盐酸或氢溴酸)、磷酸(例如正磷酸)、氨基磺酸,另外可使用有机酸,特别是脂族、脂环族、芳脂族、芳族或杂环、一元或多元羧酸、磺酸或硫酸,例如甲酸、乙酸、丙酸、新戊酸、二乙基乙酸、丙二酸、琥珀酸、庚二酸、富马酸、马来酸、乳酸、酒石酸、苹果酸、柠檬酸、葡糖酸、抗坏血酸、烟酸、异烟酸、甲或乙磺酸、乙二磺酸、2-羟基磺酸、苯磺酸、对甲苯磺酸、萘单和二磺酸或月桂基硫酸。具有生理学上不可接受的酸的盐,例如苦味酸盐,可用于分离和/或纯化式I的化合物。
已发现,式I的化合物有良好的耐受性,并且具有有价值的药理学性质。
由于腺苷受体(例如A2A和A2B)显示在炎症过程中下调免疫应答,并保护组织免受免疫损伤,因此,抑制通过腺苷受体的信号传导可用于增强和延长免疫应答。
本文提供了提高免疫应答的方法。在一个实例中,该方法增加了期望的和靶向的组织损伤,如肿瘤(例如癌)的损伤。本文公开了抑制一种或多种有助于通过腺苷受体产生胞外腺苷和腺苷触发的信号传导的过程的方法。例如,可通过以下来改善免疫应答、局部组织炎症和靶向组织破坏:抑制或减轻产生腺苷的局部组织缺氧;降解积累的胞外腺苷(或使之失活);预防或减少免疫细胞上腺苷受体的表达;和/或抑制/拮抗由腺苷配体通过腺苷受体的信号传导。本文公开的结果证明,在患有各种疾病(例如癌症和败血症)的受试者中,通过体内施用破坏“缺氧->腺苷蓄积->免疫抑制性腺苷受体传导信号至免疫细胞”途径的药剂,可体内治疗肿瘤或改善免疫力。
在一个实例中,方法包括施用一种或多种胞外腺苷抑制剂和/或腺苷受体抑制剂,例如腺苷受体拮抗剂。为了提高疫苗的功效,一种或多种腺苷受体抑制剂和/或胞外腺苷抑制剂可与疫苗联合施用。在一个实例中,施用一种或多种腺苷受体抑制剂或胞外腺苷抑制剂,以增加免疫应答/炎症。在另一个实例中提供一种方法,以实现靶向组织损伤,例如用于肿瘤破坏。
因此,本发明还涉及本发明的化合物制备用于治疗和/或预防由腺苷或其它A2A和/或A2B受体激动剂引起、促进和/或传播的疾病的药物的用途。
因此,本发明还特别涉及用于治疗和/或预防生理和/或病理生理状况的药物,该药物包含至少一种本发明的化合物和/或其生理学上可接受的盐、衍生物、溶剂化物、前药和立体异构体、包括它们所有比例的混合物中的一者。
特别优选与腺苷A2A和/或A2B受体关连的生理和/或病理生理状况。
生理和/或病理生理状况应认为指医学相关的生理和/或病理生理状况,例如疾病或病和医学障碍、病痛、症状或并发症等,特别是疾病。
本发明还涉及用于治疗和/或预防选自过度增生性和感染性疾病和障碍的生理和/或病理生理状况的药物,该药物包含至少一种本发明的化合物和/或其生理学上可接受的盐、衍生物、溶剂化物、前药和立体异构体、包括它们所有比例的混合物中的一者。
本发明还涉及用于治疗和/或预防选自过度增生性和感染性疾病和障碍的生理和/或病理生理状况的药物,该药物包含至少一种本发明的化合物和/或其生理学上可接受的盐、衍生物、溶剂化物、前药和立体异构体、包括它们所有比例的混合物中的一者,其中过度增生性疾病或障碍为癌症。
因此,本发明特别优选涉及一种药物,该药物包含至少一种本发明的化合物和/或其生理学上可接受的盐、衍生物、溶剂化物、前药和立体异构体、包括它们所有比例的混合物中的一者,其中癌症选自急性和慢性淋巴细胞性白血病、急性粒细胞性白血病、肾上腺皮质癌、膀胱癌、脑癌、乳腺癌、宫颈癌、宫颈增生、宫颈癌、绒毛膜癌、慢性粒细胞性白血病、慢性淋巴细胞性白血病、结肠癌、子宫内膜癌、食道癌、原发性血小板增多症、泌尿生殖器癌、神经胶质瘤、成胶质细胞瘤、毛细胞白血病、头颈癌、霍奇金病、卡波西肉瘤、肺癌、淋巴瘤、恶性类癌、恶性高钙血症、恶性黑素瘤、恶性胰腺胰岛素瘤、甲状腺髓质癌、黑素瘤、多发性骨髓瘤、蕈样肉芽肿、髓性和淋巴细胞性白血病、成神经细胞瘤、非霍奇金淋巴瘤、非小细胞肺癌、成骨肉瘤、卵巢癌、胰腺癌、真性红细胞增多症、原发性脑癌、原发性巨球蛋白血症、前列腺癌、肾细胞癌、横纹肌肉瘤、皮肤癌、小细胞肺癌、软组织肉瘤、鳞状细胞癌、胃癌、睾丸癌、甲状腺癌和威尔姆斯瘤。
本发明还优选涉及用于治疗和/或预防选自过度增生性和感染性疾病和障碍的生理和/或病理生理状况的药物,该药物包含至少一种本发明的化合物和/或其生理学上可接受的盐、衍生物、溶剂化物、前药和立体异构体、包括它们所有比例的混合物中的一者,其中过度增生性疾病或障碍选自年龄相关性黄斑变性、克罗恩氏病、肝硬化、慢性炎症相关性障碍、增生性糖尿病视网膜病变、增生性玻璃体视网膜病变、早产儿视网膜病变、肉芽肿病、与器官或组织移植相关的免疫过度增生以及选自炎性肠病、牛皮癣、类风湿性关节炎、系统性红斑狼疮(SLE)、继发于视网膜缺氧的脉管过度增生和脉管炎的免疫增生性疾病或障碍。
本发明还优选涉及用于治疗和/或预防选自过度增生性和感染性疾病和障碍的生理和/或病理生理状况的药物,该药物包含至少一种本发明的化合物和/或其生理学上可接受的盐、衍生物、溶剂化物、前药和立体异构体、包括它们所有比例的混合物中的一者,其中感染性疾病或障碍选自:
a)由逆转录病毒、嗜肝DNA病毒、疱疹病毒、黄病毒科和/或腺病毒引起的病毒诱导的感染性疾病,其中逆转录病毒选自慢病毒或致癌逆转录病毒,其中慢病毒选自HIV-1、HIV-2、FIV、BIV、SIVs、SHIV、CAEV、VMV和EIAV,并且致癌逆转录病毒选自HTLV-I、HTLV-II和BLV,嗜肝DNA病毒选自HBV、GSHV和WHV,疱疹病毒选自HSV I、HSV II、EBV、VZV、HCMV或HHV8,且黄病毒科选自HCV、西尼罗病毒和黄热病毒,
b)由革兰氏阳性菌引起的细菌感染性疾病,其中革兰氏阳性菌选自甲氧西林敏感性和耐甲氧西林的葡萄球菌(包括金黄色葡萄球菌、表皮葡萄球菌、溶血葡萄球菌、人葡萄球菌、腐生葡萄球菌和凝固酶阴性葡萄球菌)、糖肽类中介敏感性金黄色葡萄球菌(GISA)、青霉素敏感性和耐青霉素的链球菌(包括肺炎链球菌、化脓性链球菌、无乳链球菌、鸟链球菌、牛链球菌、乳链球菌、血链球菌和C组链球菌(GCS)、G组链球菌(GGS)和草绿色链球菌)、肠球菌(包括万古霉素敏感性和耐万古霉素的菌株,如粪肠球菌和屎肠球菌)、艰难梭菌、单核细胞增生性李斯特菌、杰氏棒杆菌、衣原体属(包括肺炎衣原体)和结核分枝杆菌,
c)由革兰氏阴性菌引起的细菌感染性疾病,其中革兰氏阴性菌选自肠杆菌科,包括埃希氏菌属(包括大肠埃希氏菌)、克雷伯菌属、肠杆菌属、柠檬酸杆菌属、沙雷氏菌属、变形杆菌属、普罗威登斯菌属、沙门氏菌属、志贺氏菌属、假单胞菌属(包括铜绿假单胞菌)、莫拉菌属(包括卡他莫拉菌)、嗜血杆菌属和奈瑟氏菌属,
d)由胞内活性寄生虫引起的感染性疾病,所述寄生虫选自顶复亚门或肉鞭毛虫亚门(包括锥虫、疟原虫、利什曼原虫、巴贝斯虫或泰勒虫)、隐孢子虫、肉孢子虫、阿米巴虫、球虫和滴虫。
以上公开的药物旨在包括本发明的化合物制备用于治疗和/或预防以上生理和/或病理生理状况的药物的相应用途。
另外,以上公开的药物旨在包括用于治疗和/或预防以上生理和/或病理生理状况的相应方法,其中将至少一种本发明的化合物施用至需要这种治疗的患者。
如实施例中所述,本发明的化合物优选显示可在酶测定和动物试验中容易得到证明的有利生物学活性。在这样的酶基测定中,本发明的化合物优选展示和引起抑制作用,这通常由在适合的范围内的IC50值证明,优选在微摩尔范围内,更优选在纳摩尔范围内。
本发明的化合物可施用至人或动物,特别是哺乳动物,例如猿、狗、猫、大鼠或小鼠,并可用于人体或动物体的治疗性治疗,也可用于对抗上述疾病。它们还可用作诊断剂或试剂。
此外,本发明的化合物可用于分离腺苷A2A和/或A2B受体和研究其活性或表达。另外,它们特别适用于与受干扰腺苷A2A和/或A2B受体活性相关的疾病的诊断方法。因此,本发明还涉及本发明的化合物用于分离腺苷A2A和/或A2B受体和研究其活性或表达或用作腺苷A2A和/或A2B受体的结合剂和抑制剂的用途。
为了诊断目的,可例如放射性标记本发明的化合物。放射性标记的实例为3H、14C、231I和125I。优选的标记方法为indogen法(Fraker等人,1978)。另外,本发明的化合物可由酶、荧光团和发色团(chemophore)标记。酶的实例为碱性磷酸酶、β-半乳糖苷酶和葡萄糖氧化酶,荧光团的实例为荧光素,发色团的实例为鲁米诺,并且例如用于例如荧光着色的自动检测系统例如描述于US 4,125,828和US 4,207,554。
本发明还涉及包含本发明的化合物的药物组合物及其用于治疗和/或预防其中腺苷A2A和/或A2B受体部分或全部失活可能有益的疾病和障碍的用途。
式I的化合物可用于制备药物制剂,特别是通过非化学方法。在这种情况下,使它们与至少一种固体、液体和/或半液体赋形剂或辅剂并任选与一种或多种其它活性化合物组合形成适合的剂型。
因此,本发明还涉及一种药物制剂,该药物制剂包含至少一种式I的化合物和/或其生理学上可接受的盐、衍生物、溶剂化物和立体异构体,包括它们所有比例的混合物。具体地讲,本发明也涉及一种包含其它赋形剂和/或辅剂的药物制剂,还涉及包含至少一种其它药物活性化合物的药物制剂。
具体地讲,本发明还涉及制备药物制剂的方法,其特征在于使式I的化合物和/或其生理学上可接受的盐、衍生物、溶剂化物和立体异构体之一(包括它们所有比例的混合物)与固体、液体或半液体赋形剂或辅剂并任选与其它药物活性化合物一起形成适合的剂型。
本发明的药物制剂可在人或兽医学中用作药物。患者或宿主可属于任何哺乳动物种类,例如灵长类,特别是人;啮齿类,包括小鼠、大鼠和仓鼠;兔;马、牛、狗、猫等。动物模型对试验研究有意义,其中它们提供治疗人疾病的模型。
适合的载体物质为有机或无机物质,它们适用于肠内(例如口服)、肠胃外或局部施用,且不与新化合物反应,例如水、植物油(如葵花油或鱼肝油)、苯甲醇、聚乙二醇、明胶、碳水化合物(例如乳糖或淀粉)、硬脂酸镁、滑石、羊毛脂或凡士林。由于有专业知识,本领域的技术人员熟悉哪种辅剂适用于所需的药物制剂。除溶剂(例如水、生理盐水溶液或醇(例如乙醇、丙醇或甘油)、糖溶液(例如葡萄糖或甘露醇溶液))或所述溶剂、成胶剂、片剂助剂和其它活性成分载体的混合物外,也可使用例如润滑剂、稳定剂和/或湿润剂、乳化剂、影响渗透压的盐、抗氧化剂、分散剂、防沫剂、缓冲物质、调味剂和/或香料或矫味剂、防腐剂、增溶剂或染料。如果需要,本发明的制剂或药物可包含一种或多种其它活性化合物,例如一种或多种维生素。
如果需要,本发明的制剂或药物可包含一种或多种其它活性化合物和/或一种或多种作用增强剂(辅剂)。
出于本发明的目的,术语“药物配方”和“药物制剂”用作同义词。
本文所用“药学上耐受”指有利于将自其得到的药物制剂施用至哺乳动物而没有不希望的生理学副作用如恶心、头晕、消化问题等的药物、沉淀试剂、赋形剂、辅剂、稳定剂、溶剂和其它试剂。
在用于肠胃外施用的药物制剂中,需要等渗性、水合正常和耐受性以及制剂(低毒性)、所用辅剂和初级包装的安全性。令人惊讶的是,本发明的化合物优选具有以下优点:可直接使用,因此,在本发明的化合物用于药物配制之前,不必用于去除毒理学上不可接受的试剂(例如高浓度有机溶剂或其它毒理学上不可接受的辅剂)的进一步纯化步骤。
本发明特别优选还涉及药物制剂,该药物制剂包含至少一种为沉淀非晶、沉淀结晶或溶解或悬浮形式的本发明的化合物,以及任选的赋形剂和/或辅剂和/或其它药物活性化合物。
本发明的化合物优选能够制备高浓度制剂,而不会发生本发明化合物的不利、不期望聚集。因此,可借助于本发明的化合物与水性溶剂或在水性介质中制备具有高活性成分含量的即用溶液。
这些化合物和/或其生理学上可接受的盐和溶剂化物也可以冻干,所得冻干物例如用于制备注射制剂。
通过使本发明的化合物溶解或悬浮于水溶液并任选加入辅剂,可制备水性制剂。为此目的,有利地将限定体积的包含限定浓度的所述其它辅剂的储备溶液加到具有限定浓度本发明化合物的溶液或悬浮液,并任选用水稀释混合物到预先计算的浓度。或者,可以固体形式加入辅剂。随后可将在每种情况下必需的一定量储备溶液和/或水加到所得水溶液或悬浮液。本发明的化合物也可有利地直接溶解或悬浮于包含所有其它辅剂的溶液。
可有利地制备包含本发明的化合物且具有4至10的pH(优选具有5至9的pH)和250至350mOsmol/kg同渗重摩的溶液或悬浮液。因此,可基本上无痛地静脉内、动脉内、关节内、皮下或经皮直接施用药物制剂。另外,还可以将制剂加到输注溶液中,例如葡萄糖溶液、等渗盐水溶液或林格氏溶液,它们也可包含其它活性化合物,因此也能够施用相对大量的活性化合物。
本发明的药物制剂也可包含多种本发明化合物的混合物。
本发明的制剂在生理学上耐受良好,易于制备,可精确分配,并且优选在整个储存和运输过程中以及在多次冷冻和解冻过程期间就测定、分解产物和聚集体而言是稳定的。它们可优选以稳定方式在冰箱温度(2-8℃)和室温(23-27℃)及60%相对大气湿度(RH)下储存至少三个月至两年的时间。
例如,本发明的化合物可通过干燥以稳定的方式储存,并且在必要时通过溶解或悬浮转化成即用型药物制剂。可能的干燥方法为例如但不限于以下这些实例:氮气干燥、真空烘箱干燥、冻干、用有机溶剂洗涤且随后空气干燥、液床干燥、流化床干燥、喷雾干燥、辊筒干燥、层干、室温空气干燥和其它方法。
术语“有效量”指引起例如研究人员或医师寻求或希望的组织、系统、动物或人的生物或医学反应的药物或药物活性化合物的量。
另外,术语“治疗有效量”指与未接受这种量的相应受试者比较,具有以下结果的量:改善治疗、治愈、预防或消除疾病、综合症、疾病状况、病痛、障碍或防止副作用或者也减缓疾病、病痛或障碍发展的。术语“治疗有效量”也包括有效提高正常生理功能的量。
在使用本发明的制剂或药物时,通常与已知、可商购的制剂或制剂类似地使用本发明的化合物和/或其生理学上可接受的盐和溶剂化物,优选以每个使用单位在0.1和500mg之间的剂量,特别是在5和300mg之间。日剂量优选在0.001和250mg/kg体重之间,特别在0.01和100mg/kg体重之间。该制剂可每天施用一次或多次,例如每天二、三或四次。然而,患者的个体剂量取决于许多个体因素,例如取决于所用特定化合物的功效、年龄、体重、总体健康状况、性别、营养、施用时间和方法、排泄速率、与其它药物的组合以及特定疾病的严重程度和持续时间。
在生物体内药物活性化合物吸收的量度为其生物利用率。如果药物活性化合物以注射溶液的形式静脉内递送到生物体,则其绝对生物利用率,即,以不变的形式达到全身血液即主要循环的药物比例,为100%。在口服施用治疗性活性化合物的情况下,活性化合物通常在制剂中为固体形式,因此必须首先溶解,以便能够克服进入屏障,例如胃肠道、口腔粘膜、鼻膜或皮肤,特别是角质层,或者可由身体吸收。可类似于J.Shaffer等人,J.Pharm.Sciences,88(1999),313-318的方法获得关于药物动力学的数据,即,生物利用率的数据。
另外,这种类型的药物可通过制药领域中通常已知的方法之一来制备。
药物可适应于通过任何所需的适合途径施用,例如,通过口服(包括颊或舌下)、直肠、肺、鼻、局部(包括颊、舌下或透皮)、阴道或肠胃外(包括皮下、肌内、静脉内、皮内,尤其是关节内)途径。这种类型的药物可通过在制药领域已知的所有方法来制备,例如,通过使活性化合物与赋形剂或辅剂组合。
肠胃外施用优选适用于本发明药物的施用。在肠胃外施用的情况下,关节内施用是特别优选的。
因此,本发明还优选涉及本发明的药物制剂用于在选自骨关节炎、创伤性软骨损伤、关节炎、疼痛、触诱发痛或痛觉过敏的生理和/或病理生理状况的治疗和/或预防中关节内施用的用途。
关节内施用的优点在于,本发明的化合物可直接施用到关节软骨附近的滑液中,并且还可以从那里扩散到软骨组织中。因此,本发明的药物制剂也可直接注入关节间隙中,从而直接在预期的作用部位发挥其作用。本发明的化合物还适用于制备要肠胃外施用的具有活性化合物的缓慢、持续和/或受控释放的药物。因此,它们也适合于制备缓释制剂,这对患者为有利的,因为只需要以相对较长的时间间隔施用。
适应于胃肠外施用的药物包括:水性和非水性无菌注射溶液,其包含抗氧化剂、缓冲剂、抑菌剂和溶质,由此给予制剂与待治疗接受者的血液或滑液等渗性;和可包含悬浮介质和增稠剂的水性和非水性无菌悬浮液。所述制剂可在单剂量或多剂量容器中递送,例如密封的安瓿和小瓶,并且可在冷冻干燥(冻干)状态储存,以便只需直接在即将使用前加入无菌载体液体,例如注射用水。根据配方制备的注射溶液和悬浮液可由无菌粉末、颗粒和片制备。
本发明的化合物也可以脂质体递送系统的形式施用,例如小单层囊泡、大单层囊泡和多层囊泡。脂质体可由各种磷脂形成,例如胆甾醇、硬脂胺或磷脂酰胆碱。
本发明的化合物也可偶联到作为靶向药物赋形剂的可溶性聚合物。此类聚合物可包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟基丙基甲基丙烯酰氨基苯酚、聚羟基乙基天冬酰氨基苯酚或由棕榈酰基取代的聚氧化乙烯聚赖氨酸。本发明的化合物还可偶联到适于实现药物缓慢释放的一类生物可降解聚合物,例如聚乳酸、聚ε-己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二羟基吡喃、聚氰基丙烯酸酯、乳酸-乙醇酸共聚物、聚合物例如右旋糖酐和甲基丙烯酸酯之间的缀合物、聚磷酸酯、各种多糖和聚胺以及聚ε-己内酯、白蛋白、脱乙酰壳多糖、胶原蛋白或改性的明胶和水凝胶的交联或两亲性嵌段共聚物。
适于肠内施用(口服或直肠)的特别为片剂、糖衣丸、胶囊剂、糖浆、果汁、滴剂或栓剂,适合局部使用的为软膏剂、乳膏剂、糊剂、洗剂、凝胶剂、喷雾剂、泡沫剂、气雾剂、溶液(例如在醇(如乙醇或异丙醇)、乙腈、DMF、二甲基乙酰胺、1,2-丙二醇或它们相互和/或与水的混合物中的溶液)或粉剂。脂质体制剂也特别适合局部使用。
在配制得到软膏剂的情况下,活性化合物可利用石蜡或水混溶性乳膏基质。或者,活性化合物可利用水包油乳膏基质或油包水基质配制为乳膏剂。
适应于透皮施用的药物可作为与接受者表皮长期紧密接触的独立硬膏剂递送。因此,例如,可通过离子电渗疗法从硬膏剂供应活性化合物,如Pharmaceutical Research,3(6),318(1986)中所概述。
当然,除了以上特别提到的成分外,本发明的药物也可包含在本领域与特定药物制剂类型相关常用的其它试剂。
本发明还涉及由下列单独包装组成的套装(试剂盒):
a)有效量的式I的化合物和/或其生理学上可接受的盐、衍生物、溶剂化物、前药和立体异构体,包括它们所有比例的混合物,和
b)有效量的其它药物活性化合物。
套装包括适合的容器,例如盒或纸板箱、单个瓶、袋或安瓿。套装可例如包括分开的安瓿,各安瓿包含溶解或冻干形式的有效量的式I的化合物和/或其药学上可接受的盐、衍生物、溶剂化物、前药和立体异构体(包括它们所有比例的混合物)和有效量的其它药物活性化合物。
另外,本发明的药物可用于在某些已知疗法中提供加和或协同作用,和/或可用于恢复某些现有疗法的功效。
除了本发明的化合物外,本发明的药物制剂还可包含其它药物活性化合物,例如用于治疗癌症的其它抗肿瘤药物。为了治疗提及的其它疾病,除了本发明的化合物外,本发明的药物制剂还可包含本领域的技术人员在其治疗中已知的其它药物活性化合物。
在一个主要的实施方案中,提供用于增强有需要的宿主的免疫应答的方法。通过减小T细胞耐受性,包括通过增加IFN-γ释放,通过减少调节性T细胞产生或激活,或通过增加宿主中的抗原特异性记忆T细胞产生,可增强免疫应答。在一个实施方案中,方法包括与抗体组合或交替施用本发明的化合物至宿主。在具体子实施方案中,抗体为治疗性抗体。在一个具体实施方案中,提供一种增强被动抗体疗法功效的方法,方法包括与一种或多种被动抗体组合或交替施用本发明的化合物。这种方法可提高用于治疗异常细胞增生性障碍(例如癌症)的抗体疗法的功效,或者可在治疗或预防感染性疾病中提高疗法的功效。本发明的化合物可与抗体例如利妥昔单抗、赫赛汀或爱必妥组合或交替施用。
在另一个主要的实施方案中,提供一种治疗或预防异常细胞增生的方法,方法包括基本在没有另一种抗癌剂的存在下施用本发明的化合物至需要其的宿主。
在另一个主要的实施方案中,提供一种治疗或预防有需要的宿主的异常细胞增生的方法,方法包括首先基本上与第一抗癌剂组合施用本发明的化合物至宿主,随后施用第二A2A和/或A2B受体拮抗剂。在一个子实施方案中,基本在没有另一种抗癌剂的存在下施用第二拮抗剂。在另一个主要的实施方案中,提供一种治疗或预防有需要的宿主的异常细胞增生的方法,方法包括基本上与第一抗癌剂组合施用本发明的化合物至宿主,随后在没有拮抗剂的存在下施用第二抗癌剂。
因此,本文公开的癌症治疗可作为利用本发明的化合物的疗法或与手术、照射或化疗的组合来进行。这种类型的化疗可包括使用以下抗肿瘤活性化合物种类的一种或多种活性化合物:
(i)用于医学肿瘤学的抗增生/抗肿瘤/破坏DNA的活性化合物及其组合,例如烷基化活性化合物(例如顺铂、parboplatin、环磷酰胺、氮芥、美法仑、苯丁酸氮芥、白消安和亚硝基脲);抗代谢药(例如抗叶酸剂,例如氟嘧啶,例如5-氟尿嘧啶和替加氟、雷替曲塞、甲氨蝶呤、胞嘧啶阿拉伯糖苷、羟基脲和吉西他滨);抗肿瘤抗生素(例如蒽环霉素,例如阿霉素、博来霉素、多柔比星、道诺霉素、表柔比星、伊达比星、丝裂霉素-C、放线菌素和光神霉素);抗有丝分裂活性化合物(例如长春花生物碱,例如长春新碱、长春碱、长春地辛和长春瑞滨,和紫杉烷类,例如紫杉醇和泰索帝);拓扑异构酶抑制剂(例如表鬼臼毒素,例如依托泊苷和替尼泊苷、安吖啶、托泊替康、伊立替康和喜树碱)和细胞分化活性化合物(例如全反式维甲酸、13-顺式-维甲酸和维甲酰酚胺);
(ii)细胞生长抑制活性化合物,例如抗雌激素剂(例如他莫昔芬、托瑞米芬、雷洛昔芬、屈洛昔芬和碘多芬(iodoxyfene))、雌激素受体调节剂(例如氟维司群)、抗雄激素剂(例如比卡鲁胺、氟他胺、尼鲁米特和醋酸环丙孕酮)、LHRH拮抗剂或LHRH激动剂(例如戈舍瑞林、亮丙瑞林和布舍瑞林)、孕酮(例如醋酸甲地孕酮)、芳香酶抑制剂(例如阿那曲唑、来曲唑、伏氯唑和依西美坦)和5α-还原酶的抑制剂(例如,如非那雄胺);
(iii)抑制癌症侵袭的活性化合物,包括例如金属蛋白酶抑制剂(如马立马司他)和尿激酶纤溶酶原激活剂受体功能抑制剂;
(iv)生长因子功能的抑制剂,例如生长因子抗体,生长因子受体抗体,例如抗erbb2抗体曲妥珠单抗[HerceptinTM]和抗erbbl抗体西妥昔单抗[C225],法呢基转移酶抑制剂,酪氨酸激酶抑制剂和丝氨酸/苏糖酸激酶抑制剂,例如表皮生长因子家族的抑制剂(例如EGFR家族酪氨酸激酶抑制剂,例如N-(3-氯-4-氟苯基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉-4-胺(吉非替尼,AZD1839),N-(3-乙炔基苯基)-6,7-双(2-甲氧基乙氧基)喹唑啉-4-胺(厄洛替尼,OSI-774)和6-丙烯酰氨基-N-(3-氯-4-氟苯基)-7-(3-吗啉代丙氧基)-喹唑啉-4-胺(CI 1033),例如血小板衍生生长因子家族的抑制剂,和例如肝细胞生长因子家族的抑制剂;
(v)抗血管生成活性化合物,例如贝伐单抗、血管抑素、内皮抑素、利诺胺、巴马司他、卡托普利、软骨衍生的抑制剂、染料木黄酮、白介素12、薰草菌素、醋酸甲羟孕酮、重组人血小板因子4、替可加兰、血小板反应蛋白、TNP-470、抗VEGF单克隆抗体、可溶性VEGF受体嵌合蛋白、抗VEGF受体抗体、抗PDGF受体、整联蛋白抑制剂、酪氨酸激酶抑制剂、丝氨酸/苏氨酸激酶抑制剂、反义寡核苷酸、反义寡脱氧核苷酸、siRNAs、抗VEGF适配体、色素上皮衍生因子和已在国际专利申请WO 97/22596、WO 97/30035、WO 97/32856和WO 98/13354中公开的化合物;
(vi)血管破坏剂,例如康普瑞汀A4和已在国际专利申请WO 99/02166、WO 00/40529、WO 00/41669、WO 01/92224、WO 02/04434和WO 02/08213中公开的化合物;
(vii)反义疗法,例如针对上述目标的那些反义疗法,例如ISIS2503,一种抗Ras反义疗法;
(viii)基因治疗方法,包括例如置换异常、修饰的基因(例如异常p53或异常BRCA1或BRCA2)的方法,GDEPT方法(基因导向酶前药治疗),例如使用胞嘧啶脱氨酶、胸苷激酶或细菌硝基还原酶的那些方法,以及提高患者对化疗或放疗耐受性的方法,例如多药耐受治疗;和
(ix)免疫治疗方法,包括例如提高患者肿瘤细胞免疫原性的离体和体内方法,例如用细胞因子如白介素2、白介素4或粒细胞巨噬细胞集落刺激因子进行转染,降低T细胞无反应性的方法,使用经转染免疫细胞例如细胞因子转染的树突状细胞的方法,使用细胞因子转染的肿瘤细胞的方法,以及使用抗独特型抗体的方法
(x)化疗药剂,包括例如阿巴瑞克、阿地白介素、阿仑珠单抗、阿利维甲酸、别嘌呤醇、六甲蜜胺、氨磷汀、阿那曲唑、三氧化二砷、天冬酰胺酶、BCG live、贝伐珠单抗、贝沙罗汀、博来霉素、硼替佐米、白消安、卡鲁睾酮、喜树碱、卡培他滨、卡铂、卡莫司汀、塞来考昔、西妥昔单抗、苯丁酸氮芥、西那卡塞特、顺铂、克拉屈滨、环磷酰胺、阿糖胞苷、达卡巴嗪、放线菌素、达贝泊汀α、柔红霉素、地尼白介素、右雷佐生、多西他赛、多柔比星、屈他雄酮、表柔比星、依伯汀α、雌莫司汀、依托泊苷、依西美坦、非格司亭、氟尿苷、氟达拉滨、氟尿嘧啶、氟维司群和吉西他滨。
来自表1的药物可优选但非排它性与式I的化合物组合。
即使没有进一步的实施方案,也设想本领域技术人员将能够在最广泛的范围内使用以上描述。因此,优选的实施方案应只被视为绝对不以任何方式限制的描述性公开。
因此,以下实施例旨在解释本发明,而不限制本发明。除非另外指明,百分数数据表示重量百分数。所有温度均以摄氏度表示。“常规后处理”:如果必要,加入水,如果必要,根据最终产物的组成将pH调节到2和10之间的值,用乙酸乙酯或二氯甲烷萃取混合物,使相分离,使有机相经硫酸钠干燥,过滤,并蒸发,并且通过在硅胶上层析和/或通过结晶来纯化产物。
硅胶上的Rf值;质谱:EI(电子碰撞电离):M+,FAB(快速原子轰击):(M+H)+,THF(四氢呋喃),NMP(N-甲基吡咯烷酮),DMSO(二甲亚砜),EA(乙酸乙酯),MeOH(甲醇),TLC(薄层层析)
缩略语列表
AUC 血浆药物浓度-时间曲线下的面积
Cmax 最大血浆浓度
CL 清除率
CV 变异系数
CYP 细胞色素P450
DMSO 二甲亚砜
F 生物利用率
fa 吸收的分数
iv 静脉内
LC-MS/MS 液相色谱串联质谱
LLOQ 定量下限
NC 未计算
ND 未测定
PEG 聚乙二醇
Pgp 渗透性糖蛋白
PK 药物动力学
po Per os(口服)
t1/2 半衰期
tmax 达到最大血浆药物浓度时的时间
UPLC 超高效液相色谱
Vss 分布体积(稳态下)
v/v 体积/体积
实施例1:本发明化合物的实例
本发明尤其涉及表2的化合物及其生理学上可接受的盐、衍生物、溶剂化物、前药和立体异构体,包括它们所有比例的混合物。
表2–本发明化合物的实例
表3–本发明化合物的NMR特性
在此叙述的编号对应于表2中公开的化合物的编号方式。
实施例2:本发明化合物的制备和分析方法
所有所用的溶剂可商购获得,不经进一步纯化即使用。反应通常在氮气惰性气氛下使用无水溶剂进行。快速柱层析通常用硅胶60(0.035-0.070mm粒径)进行。
所有的NMR实验或在配备有Bruker 400BBFO探针的Bruker Mercury Plus 400NMR谱仪上在400MHz下记录质子NMR,或在配备有Bruker 300BBFO探针的Bruker Mercury Plus300NMR谱仪上在300MHz下记录质子NMR。所有氘代溶剂通常包含0.03%至0.05%v/v的四甲基硅烷,将其用作参比信号(对于1H和13C二者,设置在δ=0.00)。
LC-MS分析在由UFLC 20-AD系统和LCMS 2020MS检测器组成的SHIMADZU LC-MS机器上进行。使用的柱为Shim-pack XR-ODS,2.2μm,3.0x 50mm。应用线性梯度,在95%A(A:水中的0.05%TFA)开始,在100%B(B:乙腈中的0.05%TFA)结束,经2.2min,总运行时间为3.6min。柱温在40℃,流速在1.0mL/min。二极管阵列检测器从200-400nm扫描。质谱仪配备有以正或负模式操作的电喷雾离子源(ES)。质谱仪在m/z 90-900之间扫描,扫描时间为0.6s。
1.N-[4-甲氧基-7-(吗啉-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]-1-(2-甲氧基乙基)-1H-吡唑-4-甲酰胺,4
a.1-(2-甲氧基乙基)-1H-吡唑-4-甲酸乙酯
在室温向N,N-二甲基甲酰胺(18ml)中1H-吡唑-4-甲酸乙酯(950mg,6.78mmol)的溶液加入1-溴-2-甲氧基乙烷(1.14g,8.20mmol)、碳酸钾(1.80g,13.8mmol)。用微波辐射在160℃照射反应混合物2h。在反应完成时,将固体滤出。然后在真空下浓缩滤液,得到1-(2-甲氧基乙基)-1H-吡唑-4-甲酸乙酯,为浅黄色液体(1.50g,粗)。MS:m/z=199.2[M+H]+.
b.1-(2-甲氧基乙基)-1H-吡唑-4-甲酸
在室温向四氢呋喃(10ml)中1-(2-甲氧基乙基)-1H-吡唑-4-甲酸乙酯(1.50g,粗)的溶液加入水性LiOH(20ml,32mmol,1.6M)。在室温搅拌所得混合物3h。在反应完成时,用H2O(10ml)猝灭反应。用二氯甲烷(100ml x 3)萃取所得混合物,合并有机相,用盐水洗涤,并经无水Na2SO4干燥。在减压下去除溶剂,通过快速层析纯化残余物,快速层析用MeOH的DCM溶液(0%至70%梯度)洗脱,得到1-(2-甲氧基乙基)-1H-吡唑-4-甲酸,为白色固体(600mg,2步52%)。MS:m/z=171.2[M+H]+.
c.5-溴-4-氯吡啶-3-胺
在室温向EtOH(500mL)中3-溴-4-氯-5-硝基吡啶(9.50g,40.01mmol)的溶液加入NH4Cl(13.27g,248mmol)、水(50ml)和Fe(22.39g,401mmol)。在80℃搅拌所得混合物2h。在反应完成时,将固体滤出。在减压下浓缩所得混合物,并通过快速层析纯化残余物,其中用0%至60%EtOAc的石油醚溶液洗脱,得到5-溴-4-氯吡啶-3-胺,为黄色油(5.94g,72%)。MS:m/z=209.2[M+H]+.
d.N-[7-溴-[1,3]噻唑并[4,5-c]吡啶-2-基]苯甲酰胺
在室温向丙酮(64mL)中5-溴-4-氯吡啶-3-胺(2.97g,14.3mmol)的溶液加入苯甲酰基异硫氰酸酯(4.47g,27.4mmol)。在50℃搅拌所得混合物16h。在反应完成时,通过过滤收集固体,得到N-[7-溴-[1,3]噻唑并[4,5-c]吡啶-2-基]苯甲酰胺,为黄色固体(3.36g,70%)。MS:m/z=333.8[M+H]+.
e.N-[7-(吗啉-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]苯甲酰胺
在室温向二噁烷(12ml)中N-[7-溴-[1,3]噻唑并[4,5-c]吡啶-2-基]苯甲酰胺(336mg,1.01mmol)的溶液加入吗啉(7ml)、第二代RuPhos预催化剂(88mg,0.11mmol)、RuPhos(104mg,0.22mmol)、t-BuOK(380mg,3.39mmol)。在真空/氮气闪蒸三个循环后,用微波辐射在160℃照射反应混合物2h。将固体滤出。在减压下浓缩滤液,通过快速层析纯化残余物,快速层析用EtOAc的石油醚溶液(0%至66%梯度)洗脱,得到N-[7-(吗啉-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]苯甲酰胺,为白色固体(99mg,29%)。MS:m/z=341.0[M+H]+。
f.N-[4-溴-7-(吗啉-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]苯甲酰胺
在70℃下,在搅拌下在4h时间内向N,N-二甲基甲酰胺(55ml)中N-[7-(吗啉-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]苯甲酰胺(653mg,1.92mmol)的溶液滴加N,N-二甲基甲酰胺(15ml)中NBS(410mg,2.30mmol)的溶液。在添加完成时,在70℃搅拌所得混合物10min。在真空下浓缩所得混合物,得到粗产物,粗产物用热EA(100ml x 3)洗涤,得到N-[4-溴-7-(吗啉-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]苯甲酰胺,为浅黄色固体(437mg,53%)。MS:m/z=418.8[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.23-8.15(m,2H),7.72(s,1H),7.60-7.46(m,3H),3.86-3.78(m,4H),3.25-3.18(m,4H).
g.4-甲氧基-7-(吗啉-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-胺
在室温向甲醇(20ml)中N-[4-溴-7-(吗啉-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]苯甲酰胺(388mg,0.94mmol)的溶液加入MeOH中的MeONa(7.9mL,42mmol,5.4M)。用微波辐射在140℃照射反应混合物2h。在反应完成后,用H2O(6ml)猝灭反应。用二氯甲烷(50ml x3)萃取所得混合物,合并有机相,用盐水洗涤,并经Na2SO4干燥。在减压下去除溶剂,通过快速层析纯化残余物,快速层析用MeOH的DCM溶液(0%至5%梯度)洗脱,得到4-甲氧基-7-(吗啉-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-胺,为浅黄色固体(150mg,60%)。MS:m/z=267.0[M+H]+.
h.N-[4-甲氧基-7-(吗啉-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]-1-(2-甲氧基乙基)-1H-吡唑-4-甲酰胺
在30mL密封管中,在N2气氛下向THF(10ml)中1-(2-甲氧基乙基)-1H-吡唑-4-甲酸(143mg,0.84mmol)的溶液加入HATU(353mg,0.93mmol)、4-甲基吗啉(170mg,1.68mmol)。在50℃搅拌反应16h,然后加入4-甲氧基-7-(吗啉-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-胺(75mg,0.28mmol)。将所得溶液在90℃下油浴中搅拌另外16h。在反应完成时,通过加入水(10ml)猝灭反应。用DCM(30ml x 3)萃取所得溶液。合并有机相,用盐水洗涤,并经Na2SO4干燥。在减压下去除溶剂,并在以下条件下通过制备型HPLC纯化残余物:柱,XBridge PrepC18 OBD柱,19x 150mm 5um;在水中的MeCN(具有10mmol/L NH4HCO3),在8min内22%至40%梯度;检测器,UV 254/220nm,得到N-[4-甲氧基-7-(吗啉-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]-1-(2-甲氧基乙基)-1H-吡唑-4-甲酰胺,为白色固体(54mg,45%)。HPLC:98.8%纯度,RT=4.216min.MS:m/z=419.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ12.87(s,1H),8.52(s,1H),8.21(s,1H),7.64(s,1H),4.35(t,J=5.1Hz,2H),3.98(s,3H),3.84-3.76(m,4H),3.71(t,J=5.1Hz,2H),3.25(s,3H),3.14-3.06(m,4H).
2.N-[4-甲氧基-7-(1-甲基-1H-吡唑-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]-4-(甲氧基甲基)苯甲酰胺,14
i.N-[7-(1-甲基-1H-吡唑-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]苯甲酰胺
在室温向二噁烷(112mL)中N-[7-溴-[1,3]噻唑并[4,5-c]吡啶-2-基]苯甲酰胺(2.94g,8.80mmol)的溶液加入1-甲基-4-(四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(2.19g,10.6mmol),Pd(dppf)Cl2CH2Cl2(359mg,0.44mmol),碳酸钠(3.27g,30.8mmol),水(23ml)。在真空/氮气闪蒸三个循环后,在80℃搅拌所得混合物16h。在反应完成时,将固体滤出。在减压下浓缩滤液,通过快速层析纯化残余物,快速层析用EtOAc的石油醚溶液(0%至100%梯度)洗脱,得到N-[7-(1-甲基-1H-吡唑-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]苯甲酰胺,为灰白色固体(2.54g,86%)。MS:m/z=336.2[M+H]+.
j.N-[4-溴-7-(1-甲基-1H-吡唑-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]苯甲酰胺
在50℃,在搅拌下在1h时间内向N,N-二甲基甲酰胺(150ml)中N-[7-(1-甲基-1H-吡唑-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]苯甲酰胺(960mg,2.86mmol)的溶液滴加N,N-二甲基甲酰胺(30mL)中的NBS(662mg,3.72mmol)。然后在50℃搅拌所得溶液1h。在反应完成时,用H2O(100ml)猝灭反应。用二氯甲烷(150ml x 3)萃取所得混合物,合并有机相,用盐水洗涤,并经无水Na2SO4干燥。在减压下去除溶剂,通过快速层析纯化残余物,快速层析用EtOAc的石油醚溶液(0%至60%梯度)洗脱,得到N-[4-溴-7-(1-甲基-1H-吡唑-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]苯甲酰胺,为白色固体(675mg,57%)。MS:m/z=414.1[M+H]+.1H NMR(400MHz,氯仿-d)δ9.92(s,1H),8.41(s,1H),8.03(d,J=7.7Hz,2H),7.98(s,1H),7.92(s,1H),7.76-7.68(m,1H),7.66-7.58(m,2H),4.07(s,3H).
k.4-甲氧基-7-(1-甲基-1H-吡唑-4-基)噻唑并[4,5-c]吡啶-2-胺
在室温向甲醇(12ml)中N-[4-溴-7-(1-甲基-1H-吡唑-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]苯甲酰胺(338mg,0.81mmol)的溶液加入MeOH中的MeONa(5.5ml,29.7mmol,5.4M)。用微波辐射在140℃照射反应混合物2h。在反应完成时,用冰水(20mL)猝灭反应。用二氯甲烷(50ml x 3)萃取所得混合物,合并有机相,用盐水洗涤,并经Na2SO4干燥。在减压下去除溶剂,通过快速层析纯化残余物,快速层析用MeOH的DCM溶液(0%至9%梯度)洗脱,得到4-甲氧基-7-(1-甲基-1H-吡唑-4-基)噻唑并[4,5-c]吡啶-2-胺,为浅黄色固体(33mg,11%)。MS:m/z=382.2[M+H]+.
l.N-[4-甲氧基-7-(1-甲基-1H-吡唑-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]-4-(甲氧基甲基)苯甲酰胺,14
在室温向四氢呋喃(5ml)中4-(甲氧基甲基)苯甲酸(53mg,0.32mmol)的溶液加入4-甲基吗啉(65mg,0.64mmol),HATU(135mg,0.35mmol)。在50℃搅拌所得混合物8h。向上述反应混合物加入4-甲氧基-7-(1-甲基-1H-吡唑-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-胺(28mg,0.11mmol),并在90℃搅拌所得混合物16h。在反应完成时,通过加入水(10ml)猝灭反应。用DCM(30ml x 3)萃取所得混合物。合并有机相,用盐水洗涤,并经Na2SO4干燥。在减压下去除溶剂,并在以下条件下通过制备型HPLC纯化残余物:柱,XBridge Shield RP18 OBD柱,19x 150mm5um;在水中的MeCN(具有10mmol/l NH4HCO3+0.1%NH3.H2O),在7min内30%至52%梯度;检测器,UV 254/220nm。N-[4-甲氧基-7-(1-甲基-1H-吡唑-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]-4-(甲氧基甲基)苯甲酰胺为白色固体(18mg,40%)。HPLC:99.4%纯度,RT=5.40min.MS:m/z=410.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ13.24(s,1H),8.25-8.13(m,4H),7.94(s,1H),7.50(d,J=8.0Hz,2H),4.53(s,2H),4.05(s,3H),3.97(s,3H),3.35(s,3H).
3.N-[4-甲氧基-7-(1-甲基-1H-吡唑-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]-4-(甲氧基甲基)苯甲酰胺,30
m.4-氯-5-碘-3-硝基吡啶-2-醇
在室温向CH3CN(500ml)中4-氯-3-硝基吡啶-2-醇(40.00g,229.22mmol)的溶液加入NIS(56.72g,252.14mmol)。在80℃搅拌所得混合物12h。反应完成时,在减压下去除溶剂。通过快速层析纯化残余物,快速层析用EtOAc的PE溶液(0%至100%梯度)洗脱,得到4-氯-5-碘-3-硝基吡啶-2-醇,为黄色固体(46.43g,63%)。MS:m/z=301.0[M+H]+.
n.4-氯-5-碘-2-甲氧基-3-硝基吡啶
在室温向甲苯(700ml)中4-氯-5-碘-3-硝基吡啶-2-醇(34.00g,112.00mmol)的溶液加入Ag2CO3(30.88g,112.0mmol),CH3I(31.81g,224.2mmol)。在80℃搅拌所得混合物16h。在反应完成时,将固体滤出。在减压下浓缩滤液,通过快速层析纯化残余物,快速层析用EtOAc的PE溶液(0%至20%梯度)洗脱,得到4-氯-5-碘-2-甲氧基-3-硝基吡啶,为浅黄色固体(19.50g,91%)。1H NMR(400MHz,DMSO-d6)δ8.82(s,1H),4.00(s,3H).
o.4-氯-5-碘-2-甲氧基吡啶-3-胺
在室温向EtOH(1l)中4-氯-5-碘-2-甲氧基-3-硝基吡啶(20.00g,63.59mmol的溶液加入NH4Cl(61.26g,1145mmol),水(180ml),Fe(53.42g,953.85mmol)。在80℃搅拌所得混合物10h。在反应完成时,将固体滤出。在减压下浓缩滤液,并在H2O(1.5L)中稀释残余物。用二氯甲烷(1.5l x 3)萃取所得溶液,合并的有机层用盐水洗涤,经无水Na2SO4干燥,并过滤。在减压下浓缩滤液,通过快速层析纯化残余物,快速层析用EtOAc的PE溶液(0%至100%梯度)洗脱,得到4-氯-5-碘-2-甲氧基吡啶-3-胺,为浅黄色固体(17.36g,96%)。MS:m/z=284.8[M+H]+.
p.N-(7-碘-4-甲氧基噻唑并[4,5-c]吡啶-2-基)苯甲酰胺
向丙酮(293ml)中4-氯-5-碘-2-甲氧基吡啶-3-胺(11.13g,39.13mmol)的溶液加入苯甲酰基异硫氰酸酯(9.58g,58.70mmol)。在50℃搅拌所得混合物16h。在反应完成时,在减压下去除溶剂,通过快速层析纯化残余物,快速层析用EtOAc的PE溶液(0%至100%梯度)洗脱,得到N-(7-碘-4-甲氧基噻唑并[4,5-c]吡啶-2-基)苯甲酰胺,为浅黄色固体(16.00g,99%)。MS:m/z=412.0[M+H]+.
q.N-(7-(3,6-二氢-2H-吡喃-4-基)-4-甲氧基噻唑并[4,5-c]吡啶-2-基)苯甲酰胺
在室温向二噁烷(120ml)中N-[7-碘-4-甲氧基-[1,3]噻唑并[4,5-c]吡啶-2-基]苯甲酰胺(2.85g,6.93mmol)的溶液加入2-(3,6-二氢-2H-吡喃-4-基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(2.18g,10.40mmol)、Pd(dppf)Cl2CH2Cl2(566mg,0.69mmol)、氢氧化钠(1.05g,26.34mmol)和水(30ml)。在真空/氮气闪蒸三个循环后,在100℃搅拌所得混合物16h。在反应完成时,将固体滤出。在减压下浓缩滤液,通过快速层析纯化残余物,快速层析用MeOH的DCM溶液(0%至10%梯度)洗脱,得到N-(7-(3,6-二氢-2H-吡喃-4-基)-4-甲氧基噻唑并[4,5-c]吡啶-2-基)苯甲酰胺,为灰白色固体(702mg,28%)。MS:m/z=368.2[M+H]+.
r.N-(4-甲氧基-7-(四氢-2H-吡喃-4-基)噻唑并[4,5-c]吡啶-2-基)苯甲酰胺
在氮气气氛下,向MeOH(30ml)中N-[7-(3,6-二氢-2H-吡喃-4-基)-4-甲氧基-[1,3]噻唑并[4,5-c]吡啶-2-基]苯甲酰胺(702mg,1.91mmol)的溶液加入Pd/C(10%,500mg)。在真空/氢气闪蒸三个循环后,用氢气球在氢气气氛下在50℃氢化反应混合物16h。在反应完成时,通过硅藻土垫过滤所得混合物。在减压下浓缩滤液,通过快速层析纯化残余物,快速层析用MeOH的DCM溶液(0%至10%梯度)洗脱,得到N-(4-甲氧基-7-(四氢-2H-吡喃-4-基)噻唑并[4,5-c]吡啶-2-基)苯甲酰胺,为白色固体(330mg,47%)。MS:m/z=370.3[M+H]+.
s.4-甲氧基-7-(四氢-2H-吡喃-4-基)噻唑并[4,5-c]吡啶-2-胺
在室温向甲醇(10ml)中N-[4-甲氧基-7-(噁烷-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]苯甲酰胺(330mg,0.89mmol)的溶液加入水(10ml),氢氧化钠(357mg,8.93mmol)。在90℃搅拌所得混合物16h。反应完成时,在减压下去除甲醇。将水(30ml)加到残余物,并用二氯甲烷(30ml x 3)萃取。用盐水洗涤合并的有机相,经Na2SO4干燥,并过滤。在减压下浓缩滤液,通过快速层析纯化残余物,快速层析用MeOH的DCM溶液(0%至10%梯度)洗脱,得到4-甲氧基-7-(四氢-2H-吡喃-4-基)噻唑并[4,5-c]吡啶-2-胺,为白色固体(106mg,42%)。MS:m/z=266.0[M+H]+.
t.(4-甲氧基-7-(四氢-2H-吡喃-4-基)噻唑并[4,5-c]吡啶-2-基)氨基甲酸苯酯
在室温向THF(20ml)中4-甲氧基-7-(噁烷-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-胺(87mg,0.33mmol)的溶液加入碳酸钾(136mg,0.98mmol)、氯甲酸苯酯(308mg,1.97mmol)和吡啶(78mg,0.98mmol)。在50℃搅拌所得混合物8h。反应完成时,在减压下去除溶剂。用水(30ml)稀释所得混合物,并用二氯甲烷(30mL x 3)萃取。用盐水洗涤合并的有机相,经Na2SO4干燥,并过滤。在减压下浓缩滤液,得到(4-甲氧基-7-(四氢-2H-吡喃-4-基)噻唑并[4,5-c]吡啶-2-基)氨基甲酸苯酯,为橙色油(88mg,70%),它不经进一步纯化即用于下一步骤。MS:m/z=386.3[M+H]+.
u.N-[4-甲氧基-7-(1-甲基-1H-吡唑-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]-4-(甲氧基甲基)苯甲酰胺,30
在室温向THF(10ml)中N-[4-甲氧基-7-(噁烷-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]氨基甲酸苯酯(88mg,0.23mmol)和4-甲基哌啶-4-醇(79mg,0.68mmol)的溶液加入DIPEA(177mg,1.37mmol)。在50℃搅拌所得混合物16h。反应完成时,在减压下去除溶剂,并在以下条件下通过制备型HPLC纯化残余物:柱,XBridge Prep OBD C18柱,30x150mm 5um;流动相,水(具有10mmol/l NH4HCO3+0.1%NH3.H2O)和ACN(13.0%ACN在8min内达到40.0%);检测器,UV220nm。得到标题化合物4-羟基-N-[4-甲氧基-7-(噁烷-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]-4-甲基哌啶-1-甲酰胺,为白色固体(30mg,32%)。HPLC:99.7%纯度,RT=3.13min.MS:m/z=407.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ11.45(s,1H),7.79(s,1H),4.41(s,1H),4.02-3.92(m,5H),3.84(d,J=13.2Hz,2H),3.54-3.44(m,2H),3.29-3.21(m,2H),3.03-2.84(m,1H),1.93-1.68(m,4H),1.56-1.36(m,4H),1.14(s,3H).
实施例3:试验本发明化合物在重组细胞中对人腺苷受体的抑制活性
人A2A、A2B、A1和A3受体的功能活性通过cAMP定量来确定,cAMP为腺苷受体的第二信使。为此目的,加入表达人A2A或A2B受体的重组HEK293细胞(偶联的两种Gs均接种到394孔微量滴定板)、试验化合物和激动剂(NECA)。培育15min后,加入HTRF试剂(cAMP dynamic 2,Cis Bio),并用ENVISION(Perkin Elmer)读板器测定细胞cAMP水平。
对于人A1和A3受体,使用表达A1或A3受体的重组CHO细胞。由于两种受体均与Gi蛋白偶联,因此调整了测定方案:
将细胞接种到384孔板,加入毛喉素、试验化合物和激动剂(对A1-受体使用CPA,对于A3-受体使用IB-MECA)。培育30min后,加入HTRF试剂(cAMP dynamic 2,Cis Bio),并用ENVISION(Perkin Elmer)读板器测定细胞cAMP水平。将得到的原始数据对抑制剂对照和中性对照(DMSO)归一化,并用GeneData软件拟合归一化的数据。
本发明的化合物显示对腺苷A2A和A2B受体超出腺苷A1和A3受体的高选择性(见例如表4中本发明化合物的一些实例的数据)。
具体地讲,与已知的腺苷A2A受体拮抗剂Tozadenant和类似的苯并噻唑衍生物大不相同,本发明的化合物令人惊讶地显示A2A/A2B双重活性(参见表4),这对于治疗和/或预防过度增生性和感染性疾病和障碍是优选的,如上文所公开;或者本发明的化合物至少显示高的A2A抑制活性与本文公开的其它令人惊讶的优点,从而在治疗和/或预防过度增生性和感染性疾病和障碍中产生高功效。
表4
A表示IC50值<10nM,B表示IC50值<100nM,C表示IC50值<1μM,D表示IC50值>1μM。
实施例4:试验本发明化合物对内源性人A2A受体的作用
测定T细胞中Gs偶联的人A2A受体的内源功能活性,这种受体在T细胞中高度表达。通过定量cAMP测定受体活性,cAMP为腺苷受体的第二信使。
简而言之,从来源于新鲜全血的人PBMC(MACS Pan T细胞分离试剂盒,MiltenyiBiotec)分离人pan T细胞。将T细胞接种在384孔微量滴定板中,并用试验化合物处理。在室温培育10min后,加入A2A腺苷受体激动剂CGS-21680,并培育板另外45min。最后,将HTRF试剂(cAMP Femto试剂盒,CisBio)加到孔中,并在1h后用ENVISION(Perkin Elmer)读板器测定细胞cAMP水平。
将得到的原始数据对抑制剂对照和中性对照(DMSO)归一化,并用GenedataScreener软件拟合归一化的数据。
本发明的化合物显示它们能够抑制在利用A2A腺苷受体激动剂CGS-21680培育的人T细胞中表达的A2A受体(通过cAMP的定量测定),这对治疗和/或预防过度增生性和感染性疾病和障碍是优选的,如上文中所公开。因此,本发明的化合物令人惊讶地能够防止免疫抑制,并因此能够支持抗肿瘤T细胞诱导的肿瘤生长的抑制、转移的减少或破坏、以及新血管形成的预防。
实施例5:试验大鼠和小鼠中本发明化合物的药物动力学性质
该研究的目的是获得本发明化合物在单次静脉内和口服施用后的雌性Wistar大鼠/小鼠中的药物动力学性质的信息。
材料和方法
动物实验(生命阶段)
雌性Wistar大鼠/小鼠(n=6)接受试验的化合物的单次静脉内(推注)注射或口服施用(通过管饲法)。分别静脉内和口服给予0.2和10mg/kg(每一化合物)的剂量,对静脉内施用作为在DMSO(0.2%)/PEG200(40%)/水中的溶液,对口服施用作为在Methocel(0.5%)/吐温20(0.25%)水溶液中的悬浮液。在0.1(仅静脉注射)、0.25(仅口服)、0.5、1、2、4、6和24h后,每种施用途径从3只动物在异氟烷吸入下舌下获得连续血样,并进一步处理得到血浆。同样,经0-24h的时间间隔,每种施用途径收集3只大鼠的尿和粪便样品,并合并用于分析。
生物分析:
使用先前在“Institute of Drug Metabolism and Pharmacokinetics”(药物代谢和药物动力学研究所)研发的具有串联质谱检测(LC-MS/MS)的UPLC方法,对血浆、粪便中化合物的浓度进行定量。LC-MS/MS系统由偶联到AB Sciex质谱仪API 5500Q-trap的WatersAcquity UPLC组成。在反相柱(HSS T3,1.8μM,2.1×50mm)上,利用0.1%甲酸和乙腈作为洗脱液,用流动相梯度进行UPLC分离。使用多反应监测以正电离模式进行化合物的检测。对血浆样品掺加内标(20μl),并用叔丁基甲基醚(tBME)从基质提取分析物。在氮流下蒸发有机相至干。使残余物溶于乙腈/0.1%甲酸,用于LC-MS/MS分析。粪便样品用其体积4倍的乙醇/水混合物(4:1,v/v)均化。对水-乙醇提取物的等分试样掺加内标,用乙腈/水(1:1,v/v)稀释,并直接注入LC-MS/MS系统。
药物动力学评估:
从观察到的数据获取药物动力学参数Cmax和tmax。使用定制软件‘DDS-TOX’计算曲线下面积(AUC)、清除率(CL)、体积(V)、半衰期(t1/2)、F和所有剂量归一化值。评估几种化合物的“DDS-TOX”值,显示与经验证软件WinNonLin给出的值相当。使用线性上升/对数下降(linear up/log down)方法,通过非房室分析计算AUC值。平均血浆浓度和推导的药物动力学参数的数值数据四舍五入到3位有效数字来表达。口服生物利用率和排泄数据(表示为剂量的%)用2位有效数字显示。
与已知的腺苷A2A受体拮抗剂Tozadenant和类似的苯并噻唑衍生物比较,本发明的化合物令人惊讶地在作为与癌症相关的动物模型的小鼠中显示更佳的药物动力学特性(参见表6),这对于治疗和/或预防过度增生性和感染性疾病和障碍是优选的,如上所公开。
表6
实施例6:试验本发明的化合物对小鼠T细胞的作用
背景:
肿瘤微环境中的腺苷(Ado)可通过经由A2A受体的信号传导来抑制T细胞活性,并抑制由T细胞分泌细胞因子。A2A特异性激动剂,如CGS-21680,在体外和体内做抑制T细胞分泌细胞因子的类似工作。潜在的A2A拮抗剂或A2A/A2B双重拮抗剂可拯救T细胞免于这种抑制。在这里,我们描述了我们建立的体外系统,其用来自小鼠脾脏的Pan T细胞筛选其活性的潜在A2A拮抗剂或A2A/A2B双重拮抗剂。所述方法涉及用CD3/CD28预包被的珠刺激从小鼠脾细胞提纯的Pan T细胞,与潜在的A2A或A2A/A2B双重拮抗剂连同A2A激动剂的加入相组合,以评估T细胞细胞因子产生的增强。
分析说明:
简而言之,根据制造商的规程,用Pan T细胞分离试剂盒Mouse II(MACS Miltenyibiotech目录订单编号130-095-130)从BALB/c小鼠的脾脏提纯小鼠Pan T细胞。将经提纯的T细胞接种在NuncTM96孔聚苯乙烯圆底微孔板中具有10%热灭活胎牛血清的RPMI培养基中。在37℃静置细胞1h之后用CD3/CD28预包被的珠(DynabeadsTMMouse T-Activator CD3/CD28;Cat#11456D)激活。30min后,用不同剂量的试验拮抗剂处理细胞。在37℃培育细胞另外30min之后,用A2A激动剂CGS-21680(1μM)或中性对照(DMSO)处理。根据制造商的规程(R&Dsystems Cat#DY402(IL-2);DY485(IFN-γ)),通过ELISA测定在培育24h后上清液中的IL-2水平和在培育48h后上清液中的IFN-γ水平。一旦计算出浓度,就计算DMSO对照和激动剂单独对照的细胞因子浓度之差(称为Δ),并用Microsoft Excel计算各拮抗剂浓度的拯救百分数。在GraphPad Prism软件中绘制拮抗剂的剂量依赖性方式的这些细胞因子拯救百分数,并计算IC50。
与已知的腺苷A2A受体拮抗剂Tozadenant大不相同,本发明的化合物显示它们能够拯救T细胞免于抑制,并且能够防止由腺苷或A2A特异性激动剂(例如CGS-2168)诱导的细胞因子分泌的抑制(参见表7),这对于治疗和/或预防过度增生性和感染性疾病和障碍是优选的,如上文所公开。因此,本发明的化合物令人惊讶地能够防止免疫抑制,并因此能够支持抗肿瘤T细胞诱导的肿瘤生长的抑制、转移的减少或破坏、以及新血管形成的预防。
表7
实施例7:注射小瓶
用2N盐酸将3l双蒸馏水中100g本发明的化合物和5克磷酸氢二钠的溶液调节到pH6.5,在无菌条件下过滤,转入注射小瓶,在无菌条件下冻干,并在无菌条件下密封。各注射小瓶包含5mg的本发明的化合物。
实施例8:溶液
从1g本发明的化合物、9.38g NaH2PO4·2H2O、28.48g Na2HPO4·12H2O和0.1g苯扎氯铵在940ml双蒸馏水中制备溶液。将pH调节至6.8,使溶液补足到1l,并通过照射灭菌。
实施例9:安瓿
将60l双蒸馏水中1kg本发明的化合物的溶液在无菌条件下过滤,转入安瓿中,在无菌条件下冻干,并在无菌条件下密封。各安瓿包含10mg的本发明的化合物。
Claims (28)
3.根据权利要求1的化合物及其生理学上可接受的盐和立体异构体,其中
R3为OMe
并且R1、R2和R4具有权利要求1中公开的含义。
5.权利要求1的化合物及其生理学上可接受的盐和立体异构体,其中
R4为H,
并且其中R1、R2和R3具有权利要求1中公开的含义。
7.一种制备根据权利要求1的式I化合物的方法,其特征在于
a)式II的化合物经历还原,得到式III的化合物,使式III的化合物与式IV的化合物在升高的温度下反应,得到式V的化合物,利用催化剂和碱的使用使式V的化合物转化成式VI的化合物,通过溴化使式VI的化合物转化成式VII的化合物,在本质上碱性的条件下使式VII的化合物转化成式VIII的化合物,并且在标准酰胺化或脲生成条件下使式VIII的化合物与式IX的化合物反应,得到式I的化合物,
b)在Suzuki型反应条件下使式V的化合物与式X的化合物反应,得到式VI的化合物,通过溴化使式VI的化合物转化成式VII的化合物,在本质上碱性的条件下使式VII的化合物转化成式VIII的化合物,并且在标准酰胺化或脲生成条件下使式VIII的化合物与式IX的化合物反应,得到式I的化合物,
c)碘化式XII的化合物,得到式XIII的化合物,通过用碱和亲电试剂处理使式XIII的化合物转化成式XIV的化合物,通过还原使式XIV的化合物转化成式XV的化合物,使式XV的化合物与式IV的化合物在升高的温度下反应,得到式XVI的化合物,在催化条件下使式XVI的化合物转化成式XVII的化合物,在碱性条件下使式XVII的化合物转化成式VIII的化合物,并在标准酰胺化或脲生成条件下使式VIII的化合物与式IX的化合物反应,得到式I的化合物,
d)通过用酸处理使式I的化合物的碱转化成其盐之一,或
e)通过用碱处理使式I的化合物的酸转化成其盐之一。
8.一种药物制剂,所述药物制剂包含至少一种根据权利要求1至6中任一项的化合物和/或其生理学上可接受的盐和立体异构体。
9.根据权利要求8的药物制剂,所述药物制剂包含赋形剂。
10.一种药物制剂,所述药物制剂包含:至少一种根据权利要求1至6中任一项的化合物和/或其生理学上可接受的盐和立体异构体;以及至少一种其它药物活性化合物。
11.一种制备药物制剂的方法,其特征在于使以下化合物与固体、液体和/或半液体赋形剂一起形成适合的剂型:根据权利要求1至6中任一项的化合物和/或其生理学上可接受的盐和立体异构体。
12.以下化合物在制备用于治疗和/或预防选自过度增生性和感染性疾病和障碍的生理和/或病理生理状况的药物中的用途:至少一种根据权利要求1至6中任一项的化合物和/或其生理学上可接受的盐和立体异构体。
13.根据权利要求12的用途,其中过度增生性疾病或障碍为癌症。
14.根据权利要求13的用途,其中癌症选自急性和慢性淋巴细胞性白血病、急性粒细胞性白血病、肾上腺皮质癌、脑癌、乳腺癌、绒毛膜癌、慢性粒细胞性白血病、结肠癌、子宫内膜癌、食道癌、泌尿生殖器癌、毛细胞白血病、头颈癌、霍奇金病、卡波西肉瘤、肺癌、淋巴瘤、恶性胰腺胰岛素瘤、甲状腺髓质癌、黑素瘤、多发性骨髓瘤、髓性和淋巴细胞性白血病、成神经细胞瘤、成骨肉瘤、胰腺癌、肾细胞癌、横纹肌肉瘤、皮肤癌、软组织肉瘤、鳞状细胞癌、胃癌、和威尔姆斯瘤。
15.根据权利要求12的用途,其中过度增生性疾病或障碍选自膀胱癌、宫颈癌、宫颈增生、神经胶质瘤、成胶质细胞瘤、非霍奇金淋巴瘤、原发性血小板增多症、恶性类癌、恶性高钙血症、蕈样肉芽肿、卵巢癌、真性红细胞增多症、原发性巨球蛋白血症、前列腺癌、睾丸癌和甲状腺癌。
16.根据权利要求12的用途,其中过度增生性疾病或障碍选自年龄相关性黄斑变性、克罗恩氏病、肝硬化、慢性炎症相关性障碍、增生性糖尿病视网膜病变、增生性玻璃体视网膜病变、早产儿视网膜病变、肉芽肿病以及与器官或组织移植相关的免疫过度增生。
17.根据权利要求12的用途,其中过度增生性疾病或障碍选自炎性肠病、牛皮癣、类风湿性关节炎、系统性红斑狼疮(SLE)、继发于视网膜缺氧的脉管过度增生和脉管炎的免疫增生性疾病或障碍。
18.根据权利要求12的用途,其中感染性疾病或障碍选自:
a)由逆转录病毒、嗜肝DNA病毒、疱疹病毒、黄病毒科和/或腺病毒引起的病毒诱导的感染性疾病,其中逆转录病毒选自慢病毒或致癌逆转录病毒,其中慢病毒选自HIV-1、HIV-2、FIV、BIV、SIVs、SHIV、CAEV、VMV和EIAV,并且致癌逆转录病毒选自HTLV-I、HTLV-II和BLV,嗜肝DNA病毒选自HBV、GSHV和WHV,疱疹病毒选自HSV I、HSV II、EBV、VZV、HCMV或HHV 8,且黄病毒科选自HCV、西尼罗病毒和黄热病毒,
b)由革兰氏阳性菌引起的细菌感染性疾病,其中革兰氏阳性菌选自甲氧西林敏感性和耐甲氧西林的葡萄球菌、糖肽类中介敏感性金黄色葡萄球菌、青霉素敏感性和耐青霉素的链球菌、肠球菌、艰难梭菌、单核细胞增生性李斯特菌、杰氏棒杆菌、衣原体属和结核分枝杆菌,
c)由革兰氏阴性菌引起的细菌感染性疾病,其中革兰氏阴性菌选自埃希氏菌属、克雷伯菌属、肠杆菌属、柠檬酸杆菌属、沙雷氏菌属、变形杆菌属、普罗威登斯菌属、沙门氏菌属、志贺氏菌属、假单胞菌属、莫拉菌属、嗜血杆菌属和奈瑟氏菌属,
d)由胞内活性寄生虫引起的感染性疾病,所述寄生虫选自顶复亚门或肉鞭毛虫亚门、隐孢子虫、肉孢子虫、阿米巴虫、球虫和滴虫。
19.根据权利要求18的用途,其中甲氧西林敏感性和耐甲氧西林的葡萄球菌选自金黄色葡萄球菌、表皮葡萄球菌、溶血葡萄球菌、人葡萄球菌、腐生葡萄球菌和凝固酶阴性葡萄球菌。
20.根据权利要求18的用途,其中青霉素敏感性和耐青霉素的链球菌选自肺炎链球菌、化脓性链球菌、无乳链球菌、鸟链球菌、牛链球菌、乳链球菌、血链球菌、C组链球菌、G组链球菌和草绿色链球菌。
21.根据权利要求18的用途,其中肠球菌选自万古霉素敏感性和耐万古霉素的菌株。
22.根据权利要求21的用途,其中万古霉素敏感性和耐万古霉素的菌株选自粪肠球菌和屎肠球菌。
23.根据权利要求18的用途,其中衣原体属选自肺炎衣原体。
24.根据权利要求18的用途,其中埃希氏菌属选自大肠埃希氏菌。
25.根据权利要求18的用途,其中假单胞菌属选自铜绿假单胞菌。
26.根据权利要求18的用途,其中莫拉菌属选自卡他莫拉菌。
27.根据权利要求18的用途,其中肉鞭毛虫亚门选自锥虫、疟原虫、利什曼原虫、巴贝斯虫和泰勒虫。
28.一种由下列的单独包装组成的套装或试剂盒:
a)有效量的根据权利要求1至6中任一项的化合物和/或其生理学上可接受的盐和立体异构体,和
b)有效量的其它药物活性化合物。
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CN112174943A (zh) * | 2019-07-03 | 2021-01-05 | 四川大学 | 一种吲哚-2-酮类化合物在制备防治口腔细菌产品中的用途 |
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WO2024028273A1 (en) | 2022-08-02 | 2024-02-08 | Merck Patent Gmbh | Novel crystalline forms of (s)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2h-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide and co-crystal forms thereof |
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