CN109415340B - N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2h-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺的多晶型物 - Google Patents
N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2h-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺的多晶型物 Download PDFInfo
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
本发明涉及N‑{6‑(2‑羟基丙‑2‑基)‑2‑[2‑(甲基磺酰基)乙基]‑2H‑吲唑‑5‑基}‑6‑(三氟甲基)吡啶‑2‑甲酰胺的结晶形式、其制备方法、包含其的药物组合物及其在疾病防治中的用途。
Description
本发明涉及N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺的结晶形式、其制备方法、包含其的药物组合物、中间体化合物及其在疾病防治中的用途。
N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺对应于式(I)的化合物:
式(I)的化合物或式(I)化合物的B型多晶型物抑制白细胞介素-1受体相关激酶4(IRAK4)。
人IRAK4(白细胞介素-1受体相关激酶4)在免疫系统激活中起关键作用。因此,该激酶是用于开发炎症抑制物质的重要的治疗靶分子。IRAK4由许多细胞表达,并介导除TLR3外的Toll样受体(TLR)和由1L-1R(受体)、1L-18R、1L-33R和1L-36R组成的白细胞介素(1L)-1β家族的受体的信号转导(Janeway and Medzhitov,Annu.Rev.Immunol.,2002;Dinarello,Annu.Rev.Immunol.,2009;Flannery and Bowie,Biochemical Pharmacology,2010)。
IRAK4敲除小鼠或缺失IRAK4的患者的人细胞都不会对TLR(TLR3除外)和1L-1β家族的刺激起反应(Suzuki,Suzuki等人,Nature,2002;Davidson,Currie等人,The Journalof Immunology,2006;Ku,von Bernuth等人,JEM,2007;Kim,Staschke等人,JEM,2007)。
TLR配体或1L-1β家族的配体与各自受体的结合导致MyD88[髓样分化因子初次应答基因(88)]募集并与受体结合。从而,MyD88与IRAK4相互作用,导致形成活性复合物,所述活性复合物与激酶IRAK1或IRAK2相互作用并将其激活(Kollewe,Mackensen等人,Journalof Biological Chemistry,2004;Precious等人,J.Biol.Chem.,2009)。因此,NF(核因子)-kB信号途径和MAPK(促分裂原活化蛋白激酶)信号途径被激活(Wang,Deng等人,Nature,2001)。NF-kB信号途径和MAPK信号途径的激活导致与不同的免疫过程相关的过程。例如,各种炎症信号分子和酶如细胞因子、趋化因子和COX-2(环氧化酶-2)的表达增加,且炎症相关基因如COX-2、IL-6、IL-8的mRNA稳定性增加(Holtmann,Enninga等人,Journal ofBiological Chemistry,2001;Datta,Novotny等人,The Journal of Immunology,2004)。此外,这些过程可能与特定细胞类型如单核细胞、巨噬细胞、树突细胞、T细胞和B细胞的增殖和分化有关(Wan,Chi等人,Nat Immunol,2006;McGettrick and J.O′Neill,BritishJournal of Haematology,2007)。
IRAK4在各种炎症性疾病的病理学中的核心作用已经通过野生型(WT)小鼠与具有激酶失活形式的IRAK4(IRAK4 KDKI)的遗传修饰动物的直接比较而显示出来。IRAK4 KDKI动物在多发性硬化、动脉粥样硬化、心肌梗塞和阿尔茨海默病的动物模型中具有改善的临床表现(Rekhter,Staschke等人,Biochemical and Biophysical ResearchCommunication,2008;Maekawa,Mizue等人,Circulation,2009;Staschke,Dong等人,TheJournal of Immunology,2009;Kim,Febbraio等人,The Journal of Immunology,2011;Cameron,Tse等人,The Journal of Neuroscience,2012)。此外,发现在动物模型中IRAK4的缺失通过改善抗病毒反应并同时减少全身性炎症而防止病毒诱导的心肌炎(Valaperti,Nishii等人,Circulation,2013)。还已表明IRAK4的表达与伏格特-小柳-原田综合征(Vogt-Koyanagi-Harada syndrome)的程度有关(Sun,Yang等人,PLoS ONE,2014)。
除IRAK4在先天性免疫中的重要作用外,还存在这样的提示:IRAK4影响所谓的Th17 T细胞(适应性免疫的成员)的分化。在缺失IRAK4激酶活性的情况下,相比于WT小鼠,有更少的产生1L-17的T细胞(Th17 T细胞)生成。因此,IRAK4的抑制适用于预防和/或治疗动脉粥样硬化、1型糖尿病、类风湿性关节炎、脊椎关节炎、红斑狼疮、银屑病、白癜风、慢性炎症性肠病和病毒性疾病,例如HIV(人免疫缺陷病毒)、肝炎病毒(Staschke等人,TheJournal of Immunology,2009;Zambrano-Zaragoza等人,International Journal ofInflammation,2014)。
由于IRAK4在TLR(TLR3除外)和1L-1受体家族的MyD88介导的信号级联中的核心作用,IRAK4的抑制可用于预防和/或治疗由所述受体介导的疾病。TLR以及1L-1受体家族的成员与类风湿性关节炎、代谢综合症、糖尿病、骨关节炎、合格伦综合症(syndrome)和败血症的发病机理相关(Scanzello,Plaas等人,Curr Opin Rheumatol,2008;Roger,Froidevaux等人,PNAS,2009;Gambuzza,Licata,等人,Journal of Neuroimmunology,2011;Fresno,Archives Of Physiology And Biochemistry,2011;Volin and Koch,JInterferon Cytokine Res,2011;Akash,Shen等人,Journal of PharmaceuticalSciences,2012;Goh and Midwood,Rheumatology,2012;Dasu,Ramirez等人,ClinicalScience,2012;Ramirez and Dasu,Curr Diabetes Rev,2012;Li,Wang等人,Pharmacology&Therapeutics,2013;Sedimbi,Hagglof等人,Cell Mol Life Sci,2013;Talabot-Aye等人,Cytokine,2014)。皮肤病如银屑病、特应性皮炎、Kindler′s综合症、变应性接触性皮炎、反常性痤疮和寻常性痤疮与IRAK4介导的TLR信号途径有关(Gilliet,Conrad等人,Archives of Dermatology,2004;Niebuhr,Langnickel等人,Allergy,2008;Miller,Adv Dermatol,2008;Terhorst,Kalali等人,Am J Clin Dermatol,2010;Viguier,Guigue等人,Annals of Internal Medicine,2010;Cevikbas,Steinhoff,J InvestDermatol,2012;Minkis,Aksentijevich等人,Archives of Dermatology,2012;Dispenza,Wolpert等人,J Invest Dermatol,2012;Minkis,Aksentijevich等人,Archives ofDermatology,2012;Gresnigt and van de Veerdonk,Seminars in Immunology,2013;Selway,Kurczab等人,BMC Dermatology,2013;Sedimbi,Hagglof等人,Cell Mol LifeSci,2013;Wollina,Koch等人,Indian Dermatol Online,2013;Foster,Baliwag等人,TheJournal of Immunology,2014)。
肺部疾病如肺纤维化、阻塞性肺病(COPD)、急性呼吸窘迫综合症(ARDS)、急性肺损伤(ALI)、间质性肺病(ILD)、结节病和肺动脉高压也显示与各种TLR介导的信号途径有关。肺部疾病的发病机理可能是感染介导的过程或非感染介导的过程(Ramirez Cruz,Maldonado Bernal等人,Rev Alerg Mex,2004;Jeyaseelan,Chu等人,Infection andImmunity,2005;Seki,Tasaka等人,Inflammation Research,2010;Xiang,Fan等人,Mediators of Inflammation,2010;Margaritopoulos,Antoniou等人,Fibrogenesis&Tissue Repair,2010;Hilberath,Carlo等人,The FASEB Journal,2011;Nadigel,Prefontaine等人,Respiratory Research,2011;Kovach and Standiford,InternationalImmunopharmacology,2011;Bauer,Shapiro等人,Mol Med,2012;Deng,Yang等人,PLoSOne,2013;Freeman,Martinez等人,Respiratory Research,2013;Dubaniewicz,A.,HumanImmunology,2013)。TLR以及1L-1R家族成员还参与其他炎症性疾病如贝切特氏病(Behcet′s disease)、痛风、红斑狼疮、成人斯蒂尔氏病(adult-onset Still′s disease)和慢性炎症性肠病(例如溃疡性结肠炎和克罗恩氏病(Crohn′s disease))以及移植排斥的发病机理,因此,此处,IRAK4的抑制是一种合适的治疗方法(Liu-Bryan,Scott等人,Arthritis&Rheumatism,2005;Christensen,Shupe等人,Immunity,2006;Cario,Inflammatory BowelDiseases,2010;Nickerson,Christensen等人,The Journal of Immunology,2010;Rakoff-Nahoum,Hao等人,Immunity,2006;Heimesaat,Fischer等人,PLoS ONE,2007;Kobori,Yagi等人,J Gastroenterol,2010;Shi,Mucsi等人,Immunological Reviews,2010;Leventhal and Schroppel,Kidney Int,2012;Chen,Lin等人,Arthritis Res Ther,2013;Hao,Liu等人,Curr Opin Gastroenterol,2013;Kreisel and Goldstein,Transplant International,2013;Li,Wang等人,Pharmacology&Therapeutics,2013;Walsh,Carthy等人,Cytokine&Growth Factor Reviews,2013;Zhu,Jiang等人,Autoimmunity,2013;Yap and Lai,Nephrology,2013)。由于式(I)化合物的作用机理,其还适用于TLR和1L-1R家族介导的紊乱子宫内膜异位症和动脉粥样硬化的预防和/或治疗用途(Akoum,Lawson等人,Human Reproduction,2007;Allhorn,Boing等人,ReproductiveBiology and Endocrinology,2008;Lawson,Bourcier等人,Journal of ReproductiveImmunology,2008;Seneviratne,Sivagurunathan等人,Clinica Chimica Acta,2012;Sikora,Mielczarek-Palacz等人,American Journal of Reproductive Immunology,2012;Falck-Hansen,Kassiteridi等人,International Journal of MolecularSciences,2013;Khan,Kitajima等人,Journal of Obstetrics and GynaecologyResearch,2013;Santulli,Borghese等人,Human Reproduction,2013;Sedimbi,Hagglof等人,Cell Mol Life Sci,2013)。
除已经提到的疾病外,IRAK4介导的TLR过程已记载在眼部疾病如视网膜缺血、角膜炎、变应性结膜炎、干燥性角膜结膜炎、黄斑变性和葡萄膜炎的发病机理中(Kaarnirantaand Salminen,J Mol Med(Berl),2009;Sun and Pearlman,InvestigativeOphthalmology&Visual Science,2009;Redfern and McDermott,Experimental EyeResearch,2010;Kezic,Taylor等人,J Leukoc Biol,2011;Chang,McCluskey等人,Clinical&Experimental Ophthalmology,2012;Guo,Gao等人,Immunol Cell Biol,2012;Lee,Hattori等人,Investigative Ophthalmology&Visual Science,2012;Qi,Zhao等人,Investigative Ophthalmology&Visual Science,2014)。
由于IRAK4在TLR介导的过程中的核心作用,抑制IRAK4还还能够治疗和/或预防心血管疾病和神经障碍,例如心肌再灌注损伤、心肌梗塞、高血压(Oyama,Blais等人,Circulation,2004;Timmers,Sluijter等人,Circulation Research,2008;Fang and Hu,Med Sci Monit,2011;Bijani,International Reviews of Immunology,2012;Bomfim,DosSantos等人,Clin Sci(Lond),2012;Christia and Frangogiannis,European Journal ofClinical Investigation,2013;Thompson and Webb,Clin Sci(Lond),2013),以及阿尔茨海默病、中风、颅脑创伤和帕金森氏病(Brough,Tyrrell等人,Trends in PharmacologicalSciences,2011;Carty and Bowie,Biochemical Pharmacology,2011;Denes,Kitazawa,Cheng等人,The Journal ofImmunology,2011;Lim,Kou等人,The American Journal ofPathology,2011;Béraud and Maguire-Zeiss,Parkinsonism&Related Disorders,2012;Denes,Wilkinson等人,Disease Models&Mechanisms,2013;Noelker,Morel等人,Sci.Rep.,2013;Wang,Wang等人,Stroke,2013)。
对于瘙痒和疼痛如癌痛、术后疼痛、炎症诱发性疼痛和慢性疼痛,由于涉及经由IRAK4的TLR信号和1L-1受体家族介导的信号,因此可认为对IRAK4的抑制在所提及的适应症中具有治疗效果(Wolf,Livshits等人,Brain,Behavior,and Immunity,2008;Kim,Lee等人,Toll-like Receptors:Roles in Infection and Neuropathology,2009;del Rey,Apkarian等人,Annals of the New York Academy of Sciences,2012;Guerrero,Cunha等人,European Journal of Pharmacology,2012;Kwok,Hutchinson等人,PLoS ONE,2012;Nicotra,Loram等人,Experimental Neurology,2012;Chopra and Cooper,J NeuroimmunePharmacol,2013;David,Ratnayake等人,Neurobiology of Disease,2013;Han,Zhao等人,Neuroscience,2013;Liu and Ji,Pflugers Arch.,2013;Stokes,Cheung等人,Journal ofNeuroinflammation,2013;Zhao,Zhang等人,Neuroscience,2013;Liu,Y.Zhang等人,CellResearch,2014)。
这也适用于一些肿瘤疾病。具体的淋巴瘤,例如ABC-DLBCL(活化的B细胞弥漫性大细胞B细胞淋巴瘤)、套细胞淋巴瘤和瓦尔登斯特伦氏病(disease),以及慢性淋巴细胞性白血病、黑色素瘤和肝细胞癌的特征在于MyD88中的突变或MyD88活性的变化,其可通过IRAK4抑制剂治疗(Ngo,Young等人,Nature,2011;Puente,Pinyol等人,Nature,2011;Srivastava,Geng等人,Cancer Research,2012;Treon,Xu等人,New EnglandJournal of Medicine,2012;Choi,Kim等人,Human Pathology,2013;Liang,Chen等人,Clinical Cancer Research,2013)。此外,MyD88在fas-依赖性肿瘤中起重要作用,因此IRAK4抑制剂也适用于其治疗(Kfoury,A.,K.L.Corf等人,Journal of the NationalCancer Institute,2013)。
通过阻断1L-1信号途径来治疗炎症性疾病,例如CAPS(冷吡啉(cryopyrin)相关周期性综合症),包括FCAS(家族性寒冷型自身炎症综合症)、MWS(Muckle-Wells综合症)、NOMID(新生儿多系统炎症性疾病)和CONCA(慢性婴儿神经皮肤关节(chronic infantile,neurological,cutaneous,and articular))综合症;FMF(家族性地中海热)、HIDS(高-IgD综合症)、TRAPS(肿瘤坏死因子受体1相关周期性综合症)、幼年特发性关节炎、成人斯蒂尔氏病、亚-贝二氏综合征(disease)、类风湿性关节炎、骨关节炎、干燥性角膜结膜炎和合格伦综合症;因此,在本文中,IRAK4抑制剂也适用于治疗所提及的疾病(Narayanan,Corrales等人,Cornea,2008;Henderson and Goldbach-Mansky,Clinical Immunology,2010;Dinarello,European Journal of Immunology,2011;Gul,Tugal-Tutkun等人,Ann Rheum Dis,2012;Pettersson,Annals of MedicinePetterson,2012;Ruperto,Brunner等人,New England Journal of Medicine,2012;Knight等人,The Journal of Rheumatology,2012;Vijmasi,Chen等人,Mol Vis,2013;Yamada,Arakaki等人,Opinion on Therapeutic Targets,2013)。1L-33R的配体1L-33特别地与急性肾衰竭的发病机理相关,因此对于预防和/或治疗而言,抑制IRAK4是一种合适的治疗方法(Akcay,Nguyen等人,Journal of the American Society of Nephrology,2011)。1L-1受体家族的成员与心肌梗塞、不同的肺部疾病如哮喘、COPD、特发性间质性肺炎、变应性鼻炎、肺纤维化和急性呼吸窘迫综合症(ARDS)有关,因此,在所提及的适应症中,可预期IRAK4的抑制具有预防和/或治疗作用(Kang,Homer等人,The Journal ofImmunology,2007;Imaoka,Hoshino等人,European Respiratory Journal,2008;Couillin,Vasseur等人,The Journal of Immunology,2009;Abbate,Kontos等人,TheAmerican Journal of Cardiology,2010;Lloyd,Current Opinion in Immunology,2010;Pauwels,Bracke等人,European Respiratory Journal,2011;Haenuki,Matsushita等人,Journal of Allergy and Clinical Immunology,2012;Yin,Li等人,Clinical&Experimental Immunology,2012;Abbate,Van Tassell等人,The American Journal ofCardiology,2013;Alexander-Brett等人,The Journal of Clinical Investigation,2013;Bunting,Shadie等人,BioMed Research International,2013;Byers,Alexander-Brett等人,The Journal of Clinical Investigation,2013;Kawayama,Okamoto等人,JInterferon Cytokine Res,2013;Martínez-González,Roca等人,American Journal ofRespiratory Cell and Molecular Biology,2013;Nakanishi,Yamaguchi等人,PLoS ONE,2013;Qiu,Li等人,Immunology,2013;Li,Guabiraba等人,Journal of Allergy andClinical Immunology,2014;Saluja,Ketelaar等人,Molecular Immunology,2014)。
现有技术公开了许多IRAK4抑制剂(参见,例如,Annual Reports in MedicinalChemistry(2014),49,117-133)。
US8293923和US20130274241公开了具有3-取代的吲唑结构的IRAK4抑制剂。没有记载2-取代的吲唑。
WO2013/106254和WO2011/153588公开了2,3-二取代的吲唑衍生物。
WO2007/091107记载了用于治疗杜氏肌营养不良的2-取代的吲唑衍生物。所公开的化合物不含6-羟基烷基取代。
WO2015/091426记载了吲唑,其烷基在2位上被羧酰胺结构取代。
WO2015/104662公开了在治疗上可用作激酶抑制剂、特别是IRAK4抑制剂的式(I)的吲唑化合物,
及其用于治疗和预防疾病和病症的药学上可接受的盐或立体异构体,特别是其在由激酶、特别是IRAK酶介导的疾病或紊乱中的用途。
WO2016/083433在本申请的优先权日之后公布,记载了下式的新的取代的吲唑
其制备方法,其单独或组合用于治疗和/或预防疾病的用途,及其用于制备用于治疗和/或预防疾病、特别是用于治疗和/或预防以下疾病的药物的用途:子宫内膜异位症以及与子宫内膜异位症相关的疼痛以及与子宫内膜异位症相关的其他症状,例如痛经、交媾困难、排尿困难和排便困难,淋巴瘤,类风湿性关节炎,脊椎关节炎(特别是牛皮癣性脊椎关节炎和别赫捷列夫氏病(Bekhterev’s disease)),红斑狼疮,多发性硬化,黄斑变性,COPD,痛风,脂肪肝疾病,胰岛素抵抗,肿瘤疾病和银屑病。
因此,需要获得具有良好的生化性能的式(I)化合物的结晶形式,其可有利地用于药物加工和药物组合物中。
新的IRAK4抑制剂应尤其适用于治疗和预防以过度反应的免疫系统为特征的增殖性疾病和炎症性疾病。这里应特别提及炎症性皮肤病、心血管疾病、肺部疾病、眼部疾病、自身免疫失调、妇科疾病(尤其是子宫内膜异位症)和癌症。
将公开一种可在工业规模上制备吲唑(I)的方法,其特别关注以下要求:
·制备工艺的放大/可升级性
·在N2-烷基化反应中的高区域选择性
·避免色谱分离和纯化步骤
·通过结晶进行最终处理
·使用3类溶剂对多晶变型体进行最终调整(根据FDA指南)
值得注意的是,可公开一种满足上述所有要求的方法。
出人意料地,已经确认了式(I)化合物的以下结晶形式:A型多晶型物、B型多晶型物和假多晶型物(其为结晶的1,7-水合物)。在上下文中,变型体、多晶型物(polymorphicform)和多晶型物(polymorph)具有相同含义。此外,存在无定形形式。总之,多晶型物、假多晶型物和无定形形式是式(I)化合物的不同的固体形式。
式(I)化合物的B型多晶型物已在本专利申请的于2016年4月29日提交的优先权申请EP16167652.3中被记载为式(I)化合物的A型多晶型物。根据Joel Bernstein,Polymorphism in molecular crystals,Clarendon Press 2002,第8-9页中记载的规则,多晶型物的指定和命名通常根据其熔点顺序进行,从具有最高熔点的多晶型物开始,命名为A型多晶型物。由于在最近几个月内的实验室测试期间,明显可见在优先权申请EP16167652.3中记载的式(I)化合物的A型多晶型物相对于另一多晶型具有较低的熔点,因此,我们在此修正于2016年4月29日提交的EP16167652.3中所记载的化合物的命名,由式(I)化合物的A型多晶型物修正为式(I)化合物的B型多晶型物。
式(I)化合物的B型多晶型物是热力学上稳定的形式。出人意料地,式(I)化合物的B型多晶型物比式(I)化合物的其他固体形式显示出有利的特性,例如但不限于稳定性(例如热力学稳定性、机械稳定性、化学稳定性和/或贮存稳定性)、与其他成分的相容性、纯度、吸湿性、溶解度(热力学的和/或动力学的)、结晶特性、习性(habitus)、生物利用度、副作用、药物动力学行为、功效、化学合成期间的有利特性(例如,对于后处理或分离,其可为例如提高的可过滤性)和/或药物组合物制备期间的有利特性。
因此,B型多晶型物比式(I)化合物的其他固体形式适于且优选用于药物领域中、特别是适于制备药物组合物,例如制备含有式(I)化合物的B型多晶型物的片剂。
特别地,式(I)化合物的B型多晶型物确保了防止不想要的向式(I)化合物的另一形式的转化和如上所述的性质的相关变化。这提高了包含式(I)化合物的制剂的安全性和质量,并降低了患者的风险。
B型多晶型物形式的式(I)化合物可使用乙腈、四氢呋喃或丙酮,通过在室温下蒸发或在冷却条件(冰箱或冷柜)下蒸发而从溶液中结晶分离出来。
本发明的实施方案不仅为各个单一结晶形式的式(I)化合物,其为式(I)化合物的A型多晶型物、B型多晶型物和1,7-水合物;还为包含两种或三种结晶形式的前述化合物的混合物。
本发明的药物组合物包括选自A型多晶型物、B型多晶型物、1,7-水合物及其混合物的结晶形式的式(I)化合物和其他药学上可接受的赋形剂。
本发明的药物组合物优选主要包含仅一种选自式(I)化合物的A型多晶型物、B型多晶型物和1,7-水合物的结晶形式,并且不含显著部分的式(I)化合物的另一形式。更优选地,药物组合物包含多于85重量%、更优选多于90重量%、最优选多于95重量%的式(I)化合物的B型多晶型物,基于组合物中存在的式(I)化合物的所有形式的总量计。
优选主要包含B型多晶型物形式的式(I)化合物,并且不含显著部分的式(I)化合物的另一固体形式(例如式(I)化合物的另一多晶型物或假多晶型物)的药物组合物。药物组合物优选包含多于80重量%、优选多于90重量%、最优选多于95重量%的式(I)化合物的B型多晶型物,基于组合物中存在的式(I)化合物的所有形式的总量计。
还优选主要包含A型多晶型物形式的式(I)化合物,并且不含显著部分的式(I)化合物的另一固体形式(例如式(I)化合物的另一假多晶型物)的药物组合物。药物组合物优选包含多于80重量%、更优选多于90重量%、最优选多于95重量%的A型多晶型物形式的式(I)化合物,基于组合物中存在的式(I)化合物的所有形式的总量计。
还优选主要包含式(I)化合物的1,7-水合物,并且不含显著部分的式(I)化合物的另一固体形式(例如式(I)化合物的另一多晶型物)的药物组合物。药物组合物优选包含多于85重量%、更优选多于90重量%、更优选多于95重量%的1,7-水合物形式的式(I)化合物,基于组合物中存在的式(I)化合物的所有形式的总量计。
式(I)化合物的不同形式可通过X-射线粉末衍射、差示扫描量热法(DSC)、IR-光谱、Raman-光谱、NIR-光谱、FIR-光谱和13C-固态-NMR-光谱来区分。
已通过X-射线粉末衍射、DSC-和TGA-差示热分析图表征了式(I)化合物的不同形式:
图1:化合物(I)的B型多晶型物的X-射线粉末衍射图
图2:化合物(I)的A型多晶型物的X-射线粉末衍射图
图3:化合物(I)的1,7-水合物的X-射线粉末衍射图
图4:化合物(I)的B型多晶型物的DSC-和TGA-差示热分析图
图5:化合物(I)的A型多晶型物的DSC-和TGA-差示热分析图
图6:化合物(I)的1,7-水合物的DSC-和TGA-差示热分析图
式(I)化合物的B型多晶型物可通过X-射线粉末衍射图(在25℃下且用铜Kα1作为辐射源)明确表征,其显示了至少以下反射:9.7、10.1、15.4,优选至少以下反射:9.7、10.1、15.4、16.1、20.2,更优选至少以下反射:9.7、10.1、15.4、16.1、20.2、22.3,最优选至少以下反射:9.7、10.1、15.4、16.1、20.2、22.3、25.2,分别表示为2θ值±0.2°。B型多晶型物形式的式(I)化合物也可通过如图1所示的X-射线粉末衍射图(在25℃且用铜Kα1作为辐射源)明确表征。
式(I)化合物的A型多晶型物可通过X-射线粉末衍射图(在25℃且用铜Kα1作为辐射源)明确表征,其显示了至少以下反射:9.2、9.8、19.3,优选至少以下反射:9.2、9.8、19.3、20.4、20.7,更优选至少以下反射:9.2、9.8、19.3、20.4、20.7、21.6,最优选至少以下反射:9.2、9.8、19.3、20.4、20.7、21.6、21.7、23.1、23.2,分别表示为2θ值±0.2°。A型多晶型物形式的式(I)化合物也可通过如图2所示的X-射线粉末衍射图(在25℃且用铜Kα1作为辐射源)明确表征。
式(I)化合物的1,7-水合物可通过X-射线粉末衍射图(在25℃且用铜Kα1作为辐射源)明确表征,其显示了至少以下反射:10.6、11.8、14.5,优选至少以下反射:10.6、11.8、14.5、14.9、15.1,更优选至少以下反射:10.6、11.8、14.5、14.9、15.1、17.6、18.7,最优选至少以下反射:10.6、11.8、14.5、14.9、15.1、17.6、18.7、19.8,分别表示为2θ值±0.2°。式(I)化合物的1,7-水合物也可通过如图3所示的X-射线粉末衍射图(在25℃且用铜Kα1作为辐射源)明确表征。
制备方法:
下文描述了通过出人意料地高选择性的N2上的烷基化来制备化合物(I):
先前文献中已经记载了N2-取代的吲唑的制备。然而,这些方法具有相当大的缺点,使得它们不适合工业规模。可通过复杂的合成步骤顺序选择性地制备N2-取代的吲唑,其不涉及直接的烷基化步骤。然而,这些顺序冗长且繁琐,并且涉及相当大的损失,最终导致低的总产率。因此,可由1H-吲唑前体通过在N2处的直接和选择性的烷基化直接制备N2-取代的吲唑的合成路线是最令人感兴趣的。在尝试直接将通式(II)的1H-吲唑前体烷基化时,通常获得由N1-(IIIa)和N2-烷基化的(III)区域异构体组成的混合物。
吲唑及其衍生物是一类典型的芳族N-杂环,由于其多种生物活性而在合成化学和药物化学中引起浓厚兴趣。此外,可由吲唑衍生的N-杂环卡宾获得多种杂环结构。在吲唑中,N1/N2取代的吲唑被广泛用作抗癌药、抗炎药、抗HIV药和抗菌药。通常,N2取代的吲唑的合成涉及各种起始材料的环化过程。遗憾的是,一般方法在文献中很少见。其中,仅获得了中等产率。
关于现有技术,已知若干出版物,并将在下部分中讨论。所公开的方法均不具有这样的反应条件:使用甲基乙烯基砜作为烷基化剂而产生直接的N2-选择性烷基化。没有观察到转化,或选择性和产率低。现有技术方法的问题在于使用不含不稳定官能团的相对简单的烷基化剂。这些试剂主要通过其卤原子、甲苯磺酸根、三氟甲磺酸根或甲磺酸根的亲核取代而连接到1H-吲唑。当使用更多官能化部分时,产率和选择性显著降低。在以下部分中,说明了为何这些现有技术方法不适用于当前挑战的原因:
1.WO2011/043479:反应在THF中在回流下进行(参见方案2)。这不适用于当前情况(甲基乙烯基砜)。不可能由例如醇制备相应的三氟甲磺酸酯,这是因为其立即发生分解。此外,仅使用了侧链中没有官能团的简单底物。
2.S.R.Baddam,N.U.Kumar,A.P.Reddy,R.Bandichhor,Tetrahedron Lett.2013,54,1661:在反应中仅使用了不含官能团的简单吲唑。仅将三氯乙酰亚胺酸甲酯用作烷基化剂。将酸催化的条件转用于通过与甲基乙烯基砜反应而在吲唑核心结构的N2位选择性引入甲基乙基砜侧链的尝试失败。该方法不易扩大规模。
3.Q.Tian,Z.Cheng,H.H.Yajima,S.J.Savage,K.L.Green,T.Humphries,M.E.Reynolds,S.Babu,F.Gosselin,D.Askin,Org.Process Res.Dev.2013,17,97:提出了优选吲唑的N2位的THP-醚的制备。该反应通过不同的机理进行,并不代表一般方法,因为THP-醚产物不容易进一步转化。此外,提出了在酸性条件下使用对甲氧基苄基衍生物保护吲唑的选择性方法。将这些条件转用于通过与甲基乙烯基砜反应而在吲唑核心结构的N2位选择性引入甲基乙基砜侧链的尝试失败。
4.D.J.Slade,N.F.Pelz,W.Bodnar,J.W.Lampe,P.S.Watson,J.Org.Chem.2009,74,6331:使用酸性条件(PPTS:对甲苯磺酸吡啶鎓盐)的THP-醚和PMB-保护,参见方案2;将这些条件转用于通过与甲基乙烯基砜反应而在吲唑核心结构的N2位选择性引入甲基乙基砜侧链的尝试失败。
5.M.Cheung,A.Boloor,J.A.Stafford,J.Org.Chem.2003,68,4093:将高反应性和高致癌性的Meerwein盐用作烷基化剂(参见方案2)。该方法仅包括简单的非官能化的乙基Meerwein盐和甲基Meerwein盐。反应在环境温度下在极性乙酸乙酯中进行。不能将这些条件转用于通过与甲基乙烯基砜反应而在吲唑核心结构的N2位选择性引入甲基乙基砜侧链。
方案1:1H-吲唑的N-烷基化
方案2:由现有技术获知的吲唑的N-烷基化方法
6.M.-H.Lin,H.-J.Liu,W.-C.Lin,C.-K.Kuo,T.-H.Chuang,Org.Biomol.Chem.2015,13,11376:方法是N2选择性的;然而,在以化学计量的量使用Ga和Al金属的情况下不能扩大规模。在所述反应条件下,形成了布朗斯特酸,其与相应的金属反应产生氢气。仅使用相对简单的底物作为烷基化剂(无砜基)。当使用更高官能化的底物时,观察到产率显著降低。将这些条件转用于通过与甲基乙烯基砜反应而在吲唑核心结构的N2位选择性引入甲基乙基砜侧链的尝试失败。
7.G.Luo,L.Chen,G.Dubowchick,J.Org.Chem.2006,71,5392:将于THF中的2-(三甲基甲硅烷基)乙氧基甲基氯(SEM-Cl)用于在吲唑的N2上的取代。将这些条件转用于通过与甲基乙烯基砜反应而在吲唑核心结构的N2位选择性引入甲基乙基砜侧链的尝试失败。该出版物记载的相应产物为醚而与我们的目标分子无关。高致癌性的2-(三甲基甲硅烷基)乙氧基甲基氯(SEM-Cl)以及苄氧基甲基氯(BOM-Cl)的使用不能代表一种可供大规模地获得目标化合物的选择方案。
8.A.E.Shumeiko,A.A.Afon‘kin,N.G.Pazumova,M.L.Kostrikin,Russ.J.Org.Chem.2006,42,294:在该方法中仅使用非常简单的底物。未报导显著的选择性。观察到在吲唑上进行N1-烷基化略优选。
9.G.A.Jaffari,A.J.Nunn,J.Chem.Soc.Perkin 1 1973,2371:使用了非常简单的底物,并且仅使用了甲基化试剂。更复杂的底物(例如甲醛与质子化甲醇的组合)仅产生N1-取代的产物(醚)。
10.V.G.Tsypin等人,Russ.J.Org.Chem.2002,38,90:反应在硫酸和氯仿中进行。仅记载了用金刚烷醇作为唯一烷基化剂的简单吲唑的转化。不能将这些条件转用于通过与甲基乙烯基砜反应而在吲唑核心结构的N2位选择性引入甲基乙基砜侧链。
11.S.K.Jains等人.RSCAdvances 2012,2,8929:该出版物的特征是吲唑的N-苄基化的实施例,其中对N1-取代的选择性低。该KF-/氧化铝催化的方法不能有效地用于合成N2-取代的吲唑。将这些条件转用于通过与甲基乙烯基砜反应而在吲唑核心结构的N2-位选择性引入甲基乙基砜侧链的尝试失败。
12.L.Gavara等人.Tetrahedron 2011,67,1633:仅使用了相对简单的底物。所述酸性THP-醚的形成和在回流THF中的苄基化不适用于我们的底物。将这些条件转用于通过与甲基乙烯基砜反应而在吲唑核心结构的N2位选择性引入甲基乙基砜侧链的尝试失败。
13.M.Chakrabarty等人.Tetrahedron 2008,64,6711:观察到了N2-烷基化,但优选获得N1-烷基化的产物。所述的在THF中使用氢氧化钠水溶液和相转移催化剂的条件不适用于2-取代的吲唑。将这些条件转用于我们的体系(甲基乙烯基砜)的尝试失败。
14.M.T.Reddy等人.Der Pharma Chemica 2014,6,411:反应在作为溶剂的相应的烷基化剂中进行。仅报导了使用高反应性的溴乙酸乙酯作为烷基化剂。没有关于选择性的数据。这些条件不适用于选择性合成N2-取代的吲唑。将这些条件转用于通过与甲基乙烯基砜反应而在吲唑核心结构的N2位选择性引入甲基乙基砜侧链的尝试失败。
15.S.N.Haydar等人.J.Med.Chem.2010,53,2521:仅记载了简单的非官能化的烷基(甲基、异丙基、异丁基)。将碳酸铯用作碱,且反应形成N1-烷基化产物和N2-烷基化产物的混合物。这些条件不适用于2-吲唑类的化合物。将这些条件转用于通过与甲基乙烯基砜反应而在吲唑核心结构的N2位选择性引入甲基乙基砜侧链的尝试失败。
16.Zh.V.Chirkova等人.Russ.J.Org.Chem.2012,48,1557:在该方法中,将相对简单的底物在DMF中用碳酸钾作为碱转化。获得了N1-烷基化产物和N2-烷基化产物的混合物。所述条件不适用于选择性合成N2-取代的吲唑。将这些条件转用于通过与甲基乙烯基砜反应而在吲唑核心结构的N2位选择性引入甲基乙基砜侧链的尝试失败。
17.C.Marminon等人.Tetrahedron 2007,63,735:吲唑中7位的邻位取代基R通过屏蔽N1免受亲电攻击而将烷基化引向N2。所述条件(在THF中氢化钠作为碱)不适用于选择性合成N2-取代的吲唑,这是因为在吲唑的7位没有取代基的情况下优选导致在N1处的烷基化。将这些条件转用于通过与甲基乙烯基砜反应而在吲唑核心结构的N2位选择性引入甲基乙基砜侧链的尝试失败。
18.D.A.Nicewicz等人.Angew.Chem.Int.Ed.2014,53,6198:仅使用了简单的底物。该方法记载了一种不易于扩大规模且不适用于一般的选择性合成N2-取代的吲唑的光化学反应。在自由基反应条件下,使用了非常特殊的苯乙烯衍生物。将这些条件转用于通过与甲基乙烯基砜反应而在吲唑核心结构的N2位选择性引入甲基乙基砜侧链的尝试失败。
19.A.Togni等人.Angew.Chem.Int.Ed.2011,50,1059:该出版物仅记载了一种特殊类型的取代基(高价碘作为三氟甲基化试剂与乙腈结合)。该特殊情况不适用于一般的选择性合成N2-取代的吲唑。
20.L.Salerno等人.European J.Med.Chem.2012,49,118:该出版物记载了吲唑在α-溴酮熔体中的转化。反应条件不能转用于N2-取代的吲唑的选择性合成中。将这些条件转用于通过与甲基乙烯基砜反应而在吲唑核心结构的N2位选择性引入甲基乙基砜侧链的尝试失败。
21.K.W.Hunt,D.A.Moreno,N.Suiter,C.T.Clark,G.Kim,Org.Lett.2009,11,5054:该出版物实质上记载了加入不同的碱的N1-选择性烷基化的方法。使用了简单的底物。将这些条件转用于通过与甲基乙烯基砜反应而在吲唑核心结构的N2位选择性引入甲基乙基砜侧链的尝试失败。
22.J.Yang等人.Synthesis 2016,48,48,1139:该出版物记载了碱催化的N1-选择性的氮杂偶联加成反应(aza-Michael reaction)。未观察到在N2处的取代。将这些条件转用于通过与甲基乙烯基砜反应而在吲唑核心结构的N2位选择性引入甲基乙基砜侧链的尝试失败。
23.P.R.Kym等人.J.Med.Chem.2006,49,2339:实质上记载了N1-烷基化。将这些条件转用于通过与甲基乙烯基砜反应而在吲唑核心结构的N2位选择性引入甲基乙基砜侧链的尝试失败。
24.A.J.Souers等人.J.Med.Chem.2005,48,1318:该出版物也记载了使用碳酸钾作为碱。该方法主要优选进行在N1处的取代,因此并不适用于选择性合成N2-取代的吲唑。将这些条件转用于通过与甲基乙烯基砜反应而在吲唑核心结构的N2位选择性引入甲基乙基砜侧链的尝试失败。
25.P.Bethanamudi等人.E-Journal of Chemistry2012,9,1676:使用离子液体和碳酸钾作为碱,产生低产率的N1-烷基化吲唑和N2-烷基化吲唑的混合物。选择性显示趋于在N1处取代。离子液体的使用不能转用于我们的体系中。将这些条件转用于通过与甲基乙烯基砜反应而在吲唑核心结构的N2位选择性引入甲基乙基砜侧链的尝试失败。
26.S.Palit等人.Synthesis 2015,3371:本文中所述的反应实质上是非选择性的,在吲唑的N1处的取代略优选。仅使用了简单的、非官能化的烷基。使用了氢化钠和类似的强碱。将这些条件转用于通过与甲基乙烯基砜反应而在吲唑核心结构的N2位选择性引入甲基乙基砜侧链的尝试失败。
过去已表明,式(I)的化合物可类似于先前在文献中公开的方法,通过例如使用2-溴乙基甲基砜进行直接烷基化合成。然而,获得的是N1-和N2-烷基化产物的混合物,其中优选N1-区域异构体(N1∶N2=约2∶1)。如在本申请优先权日后公开的WO2016/083433中所述,所需的式(I)的N2-烷基化吲唑还可通过以下反应过程以非常低的产率获得:
将160mg(0.44mmol)的N-[6-(2-羟基丙-2-基)-1H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺(中间体5-1)与182mg的碳酸钾和36mg的碘化钾一起悬浮在1.0ml的DMF中,并将混合物在室温下搅拌15min。然后,加入123mg的2-溴乙基甲基砜,并将混合物在室温下搅拌过夜。加入水,将混合物用乙酸乙酯萃取两次,且萃取物用饱和氯化钠水溶液洗涤,通过疏水性过滤器过滤并浓缩。通过制备型HPLC纯化残余物,获得20mg(产率9.7%)的标题化合物。
已证明,消耗性的制备型HPLC对于有效分离N1-/N2-区域异构体是不可或缺的。本发明的新方法的目的在于通过在有利于N2处的取代的反应中实现更好的选择性然后再进行本发明的新的重结晶过程来避免HPLC分离。
本发明提供一种由通式(II)的化合物制备通式(III)的化合物的方法
其中
R1为2-(甲基磺酰基)乙基;
R4为二氟甲基、三氟甲基或甲基;并且
R5为氢或氟;
优选R4=三氟甲基且R5=H:
出乎意料地,我们发现甲基乙烯基砜(IX)在反应中可替代相应的烷基卤化物。将乙烯基砜用于吲唑在N2处的烷基化是令人惊讶地前所未有的,并因此具有高度创造性。当通式(II)的化合物与甲基乙烯基砜在甲苯中反应时,任选地加入有机碱,例如N,N-二异丙基乙胺或三乙胺,以非常高的选择性获得所需的式(III)和式(I)的N2-异构体。发现反应混合物中的选择性在8∶1至10∶1之间,有利于N2-烷基化产物(III)和(I)。在反应混合物的后处理后,不期望的N1-取代的副产物主要残留在母液中(结晶后通常<2%)。
反应在不使用额外的碱的情况下进行。将通式(II)或(V)的化合物置于反应容器中。加入1-2当量的甲基乙烯基砜,并将反应混合物在甲苯中加热回流(约110℃的内部温度)。反应可使用5至30体积的甲苯进行,基于起始材料(II)或(V)的量计。优选地,反应使用8至15体积、且最好使用10体积的甲苯进行。反应时间为12至100h。优选为48至72h。在某些情况下,已证明将甲基乙烯基砜分批加入反应混合物中是有利的,例如开始时加入1当量,然后在24h后加入0.3当量,在48h后再加入0.3当量。
任选地,反应使用催化量的有机辅助碱(auxiliary base)(例如N,N-二异丙基乙胺)进行。将通式(II)或(V)的化合物与溶剂(甲苯或二甲苯)和催化量的有机碱一起置于反应容器中。
可加入0.01至1当量的量的辅助有机碱,例如N,N-二异丙基乙胺、N,N-二环己胺或三乙胺。反应使用0.01至0.1当量的碱进行。
值得注意并且当然令人惊讶的是,在相同的反应温度下使用氯苯或乙苯作为溶剂或在更高的反应温度下使用二甲苯作为溶剂时,通过水的消除反应可获得更高量的烯烃(IV)。引人注目的是,当使用甲苯作为溶剂时,观察到消除反应仅以非常小的量进行。因此,必须将甲苯视为本发明的溶剂,其对于该特定反应具有独特的且完全未预料到的特性。还发现(IV)的形成取决于(V)的质量。当使用具有高于通常水含量的(V)(1重量%而不是<0.5重量%)时,在反应中获得更显著量的(IV)。值得注意的是,可通过与甲苯共沸蒸馏并且通过加入催化量的有机碱,特别是N,N-二异丙基乙胺,从(V)中除去过量的水,从而有效地抑制消除产物(VI)的形成。
分离过程:反应完成后,可将甲苯从反应混合物中部分地蒸馏出来。随后,可向反应混合物中加入第二种溶剂,例如甲基叔丁基醚(MTBE)或二异丙基醚(优选甲基叔丁基醚)。加入各溶剂后,产物几乎定量地从混合物中沉淀出来。在某些情况下,已证明有用的是将混合物用少量晶体接种以获得可重复的结晶。在冷却并长时间搅拌所得悬浮液后,通过过滤分离产物,用溶剂洗涤,并在50至60℃下真空干燥,所得产率通常为59%至67%。粗产物的纯度通常为95%至97%(面积),具有小于2%(面积)的N1-位置异构体。
必须强调的是,取代的乙烯基砜用于N2-官能化的吲唑的定向高选择性制备的反应是新的,文献中没有先例,因此是制备这种取代模式的科学上非常重要的发明。
GMP材料(也将用于临床试验)的制备需要额外的纯化步骤。此外,由于活性药物成分将被用于制备药物组合物,例如片剂,因此,需要一种可重复提供相同的晶体习性的方法。出人意料地,这可使用乙醇或异丙醇作为重结晶的溶剂而实现。乙醇是优选的溶剂。因此,首先将化合物溶解在丙酮中,且随后通过粒子过滤器(GMP过滤)。然后,通过蒸馏将溶剂从丙酮交换为乙醇。继续蒸馏,直至达到相对于输入材料的6至7体积的乙醇的最终体积。当达到乙醇沸点(约77-78℃)时,取消蒸馏,确保蒸馏出所有的丙酮。然后冷却混合物,搅拌,通过过滤分离出结晶产物,并在高温下真空干燥。结晶产率通常>90%。从该结晶过程中获得的产物具有制备药物组合物如片剂所需的期望的多晶性质。产物显示出了非常高的纯度以及非常高的含量。表1给出了常规批料的最重要的分析数据:
表1:如表7所示的批料实施例的分析数据
纯度(HPLC) | ≥99%(面积) |
含量(使用分析) | ≥97.7%(重量) |
乙醇 | <0.25%(重量) |
Pd | <1ppm |
通过上述结晶过程获得的多晶型物在贮存期间显示出良好的稳定性。其还易于在不丧失结晶特性的情况下微粉化。
在WO 2015/091426中记载了通式(II)以及(V)的化合物的制备。本发明的新方法着重于式(V)所示的化合物:
在公开的专利申请WO 2015/091426中,式(V)的化合物通过式(VI)的甲酯化合物的反应制备:
其中使用甲基溴化镁的乙醚溶液。在后处理后,将粗产物进行柱色谱纯化,从而提供式(V)的化合物,产率45%。
WO2016/083433在本申请的优先权日后公开,也记载了一种用于制备式(V)的化合物的合成路线,从式(VI)的化合物开始,通过使用合适的烷基卤化镁(例如于THF或乙醚或THF和乙醚的混合物中的甲基氯化镁或甲基溴化镁)的格氏反应进行。
由于以下缺点,该方法不适合以工业规模制备式(V)的化合物:
·乙醚由于其低燃点和潜在的高爆炸性而必须避免使用。
·使用相对昂贵的甲基溴化镁,而不是更易获得的更常见的甲基氯化镁。
·在工业规模上应当避免色谱分离,因为其通常需要不经济地消耗大量的有机溶剂。
·没有记载结晶过程。根据研究实验室的常规实践,蒸发式(V)的化合物至干燥。该操作在工业规模上不可行。
·产率不能令人满意:出于工业目的,应达到至少75%的产率。
出人意料的,发现当使用于THF中的甲基氯化镁和氯化锂(2∶1)替代时,可以以显著更高的产率制备式(V)的化合物。反应以较少的副产物进行,所述副产物使用WO 2015/091426和WO2016/083433中记载的方法也必须通过繁琐的柱色谱法除去。发现最好用THF作为溶剂进行反应。将6至10当量的甲基氯化镁(于THF中约3M)和3至5当量的氯化锂搅拌,并保持在-10至0℃。在1至3h、优选2h内,将式(VI)的化合物作为在THF中的溶液滴加到混合物中。将反应混合物在指定的温度范围(-10℃至0℃)内搅拌5至30min,随后倒入水中淬灭。剧烈搅拌所得混合物。然后通过加入无机酸或有机酸(优选柠檬酸)将混合物的pH调节至约4,并加入乙酸乙酯。分离各相,有机相用盐水(氯化钠水溶液)洗涤数次。通过蒸馏将所得有机溶液的溶剂交换成甲苯。在这个过程中,式(V)的化合物开始结晶,并可通过过滤分离。将沉淀物在高温(50-60℃)下真空干燥。通常,在此阶段的产率为80%至96%,且纯度为95面积%至99面积%(HPLC)。
为制备具有目前优良生产规范(cGMP)质量的材料,最终将该产物在异丙醇/水的混合物(1∶1;相对于输入材料2至10体积)中搅拌证明是有利的。将材料搅拌1至5h、优选3h。然后将其过滤,并用少量的1∶1的异丙醇/水的混合物洗涤两次。产物在高温(50-60℃)下真空干燥。通常,达到>90%的产率和>97面积%(HPLC)的纯度。
在以下实施例的实验部分中,还描述了一种变化方案(参见实施例#2,变化方案#3),其中在用活性炭处理后,直接将溶剂交换成异丙醇。通过加水使产物结晶。用这种方法直接获得非常高纯度的产物。
在专利申请WO 2015/091426中还记载了式(VI)的化合物的制备。因此,使用1-[双(二甲基氨基)亚甲基]-IH-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐(CAS号:148893-10-1)作为偶联剂将6-(三氟甲基)吡啶-2-甲酸(VII)(CAS号:21190-87-4)与式(VIII)的苯胺类化合物(5-氨基-1H-吲唑-6-甲酸甲酯;CAS号:1000373-79-4)偶联。以84%产率获得酰胺(VI)。
由于过程安全的原因,基于脲的偶联剂因为其潜在的爆炸性而不能扩大规模。因此,必须找到一种可替代的偶联方法。
用于制备式(VI)的酰胺类化合物的安全且可规模化的方法是基于使用T3P(2,4,6-三丙基-1,3,5,2,4,6-三氧杂三磷杂环己烷-2,4,6-三氧化物;CAS号:68957-94-8)作为偶联剂。
反应平稳进行,并以高产率提供式(VI)的酰胺类化合物。在一锅法中,将式(VII)的羧酸类化合物(最好以相对于苯胺(VIII)略有不足来使用,约0.90-0.95当量)与1.5当量的N,N-二异丙基乙胺一起置于16体积的THF中。随后,在0至5℃下缓慢加入2当量的T3P(50重量%的乙酸乙酯溶液)。将反应混合物在0至5℃下再搅拌2至4h、优选2h。
然后用水淬灭混合物,用碳酸钠水溶液将其pH调节至约7.4,并蒸馏出大部分的THF/乙酸乙酯混合物(200mbar,内部温度45-50℃)。随后,加入水和乙醇,并通过加入碳酸钠水溶液将pH调节至约7.0。将混合物在50℃下搅拌1至5h、优选1至2h,然后冷却至20至25℃,并搅拌10至30min。产物通过过滤分离,且随后用乙醇和水的混合物洗涤,并最终在45℃下真空干燥。用这种方法,通常获得95%至96%的非常高的产率。所有情况下的纯度都>98面积%(HPLC)。
在某些情况下,特别是当使用光学质量差(例如深棕色)的式(VIII)的苯胺类化合物作为起始材料时,用活性炭进行处理证明是有用的。在以下部分中描述了此过程:
将粗酰胺(VI)溶于甲醇和THF(2∶1)的混合物中,并加入活性炭。将混合物加热至60至65℃,保持1至1.5h。过滤出活性炭,并浓缩滤液(浓缩至相对于输入材料而言2体积)。加入水,产物沉淀,将产物过滤、洗涤,并在55至60℃下(真空下)干燥。
式(VII)和(VIII)的化合物的合成已在文献中记载,且二者均可大量地市售获得。
对于式(VII)的化合物:Cottet,Fabrice;Marull,Marc;Lefebvre,Olivier;Schlosser,Manfred,European Journal of Organic Chemistry,2003,8第1559-1568页;Carter,Percy H.;Cherney,Robert J.;Batt,Douglas G.;Duncia,John V.;Gardner,Daniel S.;Ko,Soo S.;Srivastava,Anurag S.;Yang,Michael G.Patent:US2005/54627A1,2005;Ashimori;Ono;Uchida;Ohtaki;Fukaya;Watanabe;YokoyamaChemical andPharmaceutical Bulletin,1990,第38卷,9第2446-2458页。
对于式(VIII)的化合物:Nissan Chemical Industries,Ltd.;CHUGAI SEIYAKUKABUSHIKI KAISHA,EP2045253 A1,2009。
对整个过程的评估:
方案2描述了由式(VIII)的苯胺类化合物合成式(I)的纯产物的整个过程。获得的式(I)的产物的纯度>99面积%(HPLC)。当以各步骤达到的最佳产率计算时,获得50%的总产率。这还包括最终结晶形式的建立。
方案2:由式(VIII)的苯胺类化合物合成式(I)的纯产物的整个过程
当将该总产率与所公布的以下现有数据比较时:
1.酰胺偶联(式(VI)的化合物的制备):产率84%;
2.格氏反应,随后进行色谱纯化:产率45%;
3.类似于文献中已知的方法用2-溴乙基甲基砜进行烷基化,随后进行色谱纯化:产率9.68%;
新方法的优点变得非常明显:
用现有技术已知的和如上所述的方法,仅可获得3.7%的总产率,其中不包括最终结晶形式的建立。
总之,与现有技术相比,本发明的新方法以>13倍的较高的总产率提供式(I)的化合物。此外,本发明的新方法包括用于制备药物组合物如片剂的目标多晶型物的定向和可重复的制备。
必须强调的是,取代的乙烯基砜用于N2-官能化的吲唑的定向高选择性制备的反应是新的,文献中没有先例,因此是用于制备这种取代模式的非常重要的发明。
因此,在第一方面,本发明涉及一种通过反应方案IA中所示的以下步骤制备式(I)的化合物的方法,参见下文:
方案IA:由式(VIII)的化合物作为起始材料制备式(I)的化合物
其中,R表示烷基如甲基、乙基或正丙基,或芳基如苯基,且芳族烃溶剂为溶剂如甲苯或二甲苯。
在第一方面的实施方案中,本发明涉及一种通过反应方案I中所示的以下步骤制备式(I)的化合物的方法,参见下文:
方案I:由式(VIII)的化合物作为起始材料制备式(I)的化合物
在第一方面的实施方案中,本发明涉及一种制备式(I)化合物的方法:
包括以下步骤(A):
其中使式(V)的化合物:
与式(IX’)的乙烯基砜化合物反应:
其中,R表示烷基如甲基、乙基或正丙基,或芳基如苯基,
所述反应任选地在芳族烃溶剂如甲苯或二甲苯中进行,优选在所述溶剂的回流温度下进行,
从而提供所述式(I)的化合物。
在第一方面的实施方案中,本发明涉及一种制备如上所述的式(I)的化合物的方法,其中所述芳族烃溶剂为甲苯。
在第一方面的实施方案中,本发明涉及一种制备如上所述的式(I)的化合物的方法,其中所述式(V)的化合物:
通过以下步骤(B)制备:
其中使式(VI)的化合物:
与还原性甲基化剂(例如甲基金属试剂,例如甲基卤化镁,例如甲基氯化镁)反应,
所述反应任选地在碱金属卤化物如氯化锂的存在下进行,
从而提供所述式(V)的化合物。
在第一方面的实施方案中,本发明涉及一种制备如上所述的式(I)的化合物的方法,其中所述式(VI)的化合物:
通过以下步骤(C)制备:
其中使式(VIII)的化合物:
与式(VII)的化合物反应:
所述反应任选地在有机碱、特别是弱有机碱(例如叔胺,例如N,N-二异丙基乙胺)的存在下进行,
所述反应任选地在偶联剂如2,4,6-三丙基-1,3,5,2,4,6-三氧杂三磷杂环己烷2,4,6-三氧化物(T3P)的存在下进行,
从而提供所述式(VI)的化合物。
在第一方面的另一实施方案中,本发明涉及一种制备如上所述的式(I)的化合物的方法,其中所述式(I)的化合物例如通过结晶纯化,特别是从溶剂如乙醇或异丙醇中结晶纯化。
在所述第一方面的另一实施方案的变化方案中,所述溶剂为乙醇。
在所述第一方面的另一实施方案的变化方案中,所述溶剂为异丙醇。
在第一方面的实施方案中,本发明涉及一种如上所述制备的式(I)的化合物的方法,其中所述式(I)的化合物为B型多晶型物的形式。
根据第二方面,本发明涉及通过如上所述的方法制备的式(I)的化合物的B型多晶型物:
根据第三方面,本发明涉及式(I)的化合物的B型多晶型物:
根据第三方面的实施方案,本发明涉及如上所述的B型多晶型物,其具有的XRPD最大峰值[°2θ](铜(Cu))如下:
表2:化合物(I)的A、B型多晶型物和1,7-水合物的XRPD
根据第四方面,本发明涉及选自以下的化合物的用途:
用于通过如上所述的方法制备式(I)的化合物:
或如上所述的式(I)化合物的B型多晶型物。
根据第五方面,本发明涉及式(IX’)的乙烯基砜化合物的用途:
其中,R表示烷基如甲基、乙基或正丙基,或芳基如苯基,
用于制备式(I)的化合物:
或如上所述的式(I)化合物的B型多晶型物。
在第五方面的实施方案中,本发明涉及用途,其中所述式(IX’)的化合物为甲基乙烯基砜。
根据第六方面,本发明涉及式(I)化合物的结晶形式、优选B型多晶型物用于制备药剂的用途。
治疗方法:
本发明式(I)的化合物的结晶形式、优选B型多晶型物可具有有用的药学性质,并可用于预防和治疗人类和动物病症。本发明式(I)的化合物的形式可开启另一种治疗替代方案,且因此可能是对药剂学的一种丰富。
本发明式(I)的化合物的结晶形式、优选B型多晶型物可适用于治疗和预防以免疫系统过度反应为特征的增殖性和炎症性病症。这里应特别提及本发明式(I)的化合物的结晶形式、优选B型多晶型物用于治疗和预防以下病症的用途:肿瘤性疾病、皮肤病、妇科疾病、心血管疾病、肺部疾病、眼科疾病、神经障碍、代谢紊乱、肝脏疾病、肾病、炎症性疾病、自身免疫疾病和疼痛。特别地,这里应特别提及本发明式(I)的化合物的结晶形式用于治疗和预防以下病症的用途:淋巴瘤、黄斑变性、银屑病、红斑狼疮、多发性硬化症、COPD(慢性阻塞性肺病)、痛风、NASH(非酒精性脂肪性肝炎)、肝纤维化、胰岛素抵抗、代谢综合症、慢性肾病、肾病(nephropathy)、脊柱关节炎和类风湿性关节炎、子宫内膜异位症和与子宫内膜异位症相关的疼痛和其他与子宫内膜异位症相关的症状,例如痛经、交媾困难、排尿困难和大便困难。
本发明式(I)的化合物的结晶形式、优选B型多晶型物还可适用于治疗和预防疼痛,包括急性、慢性、炎症性和神经性疼痛,优选痛觉过敏、异常性疼痛、关节炎疼痛(例如骨关节炎、类风湿性关节炎和脊柱关节炎)、月经前疼痛、与子宫内膜异位症相关的疼痛、手术后疼痛、间质性膀胱炎疼痛、CRPS(复杂的局部疼痛综合症)、三叉神经痛、前列腺炎疼痛、脊髓损伤引起的疼痛、炎症引起的疼痛、下腰痛、癌痛、与化学疗法相关的疼痛、HIV-治疗引起的神经病变、灼伤引起的疼痛和慢性痛。
在一些实施方案中,本发明还涉及使用有效量的至少一种形式的本发明式(I)的化合物来治疗和/或预防疾病、特别是上述疾病的方法。
在一些实施方案中,本发明还涉及使用有效量的至少一种形式的本发明式(I)的化合物来治疗和/或预防以免疫系统过度反应为特征的增殖性和炎症性疾病的方法,所述增殖性和炎症性疾病特别是肿瘤性疾病、皮肤病、妇科疾病、心血管疾病、肺部疾病、眼科疾病、神经障碍、代谢紊乱、肝脏疾病、炎症性疾病、自身免疫疾病和疼痛。
本发明式(I)的化合物的形式可单独使用或如果需要与其他活性物质结合使用。本发明还涉及含有至少一种形式的本发明式(I)的化合物和一种或多种其他活性物质、特别是用于治疗和/或预防上述疾病的活性物质的医药产品。可提及以下物质作为合适的其他活性物质:
一般可提及活性成分例如抗细菌物质(例如青霉素、万古霉素(vancomycin)、环丙沙星(ciprofloxacin))、抗病毒物质(例如阿昔洛韦(aciclovir)、奥司他韦(oseltamivir))和抗真菌物质(例如萘替芳(naftifin)、制霉菌素(nystatin))以及γ-球蛋白,免疫调节和免疫抑制化合物如环孢菌素(cyclosporin)、TNF拮抗剂(例如依那西普(Etanercept)、英夫利昔(Infliximab))、IL-1抑制剂(例如阿那白滞素(Anakinra)、卡纳单抗(Canakinumab)、利纳西普(Rilonacept))、磷酸二酯酶抑制剂(例如阿普斯特(Apremilast))、Jak/STAT抑制剂(例如托法替尼(Tofacitinib)、巴瑞替尼(Baricitinib)、GLPG0634)、来氟米特(leflunomid)、环磷酰胺、利妥昔单抗(rituximab)、贝利木单抗(belimumab)、他克莫司(tacrolimus)、雷帕霉素(rapamycin)、霉酚酸酯(mycophenolate mofetil)、干扰素、皮质类固醇(例如强的松(prednisone)、强的松龙(prednisolone)、甲基强的松龙(methylprednisolone)、氢化可的松(hydrocortisone)、倍他米松(betamethasone))、环磷酰胺、咪唑硫嘌呤(azathioprine)和柳氮磺胺吡啶(sulfasalazine);扑热息痛(paracetamol)、非甾体抗炎物质(non-steroidal anti-inflammatory substance)(NSAIDS)(阿司匹林、布洛芬(ibuprofen)、萘普生(naproxen)、依托度酸(etodolac)、塞来昔布(celecoxib)、秋水仙碱(colchicine))。
应提及用于肿瘤治疗的以下物质:免疫疗法(immunotherapy)(例如阿地白介素(aldesleukin)、阿仑单抗(alemtuzumab)、巴利昔单抗(basiliximab)、卡妥索单抗(catumaxomab)、西莫白介素(celmoleukin)、地尼白介素(denileukin diftitox)、依库丽单抗(eculizumab)、依决洛单抗(edrecolomab)、吉妥单抗(gemtuzumab)、替伊莫单抗(ibritumomab tiuxetan)、咪喹莫特(imiquimod)、α干扰素(interferon-alpha)、β干扰素(interferon beta)、γ干扰素(interferon-gamma)、易普利姆玛(ipilimumab)、来那度胺(lenalidomide)、来格司亭(lenograstim)、米伐木肽(mifamurtide)、奥法木单抗(ofatumumab)、奥普瑞白介素(oprelvekin)、溶链菌(picibanil)、普乐沙福(plerixafor)、多糖-K(polysaccharide-K)、沙格司亭(sargramostim)、sipuleucel-T、他索纳明(tasonermin)、替西白介素(teceleukin)、托珠单抗(tocilizumab));抗增殖性物质,例如但非排他性地:安吖啶(amsacrine)、arglabin、三氧化二砷、天冬酰胺酶(asparaginase)、博来霉素(bleomycin)、白消安(busulfan)、更生霉素(dactinomycin)、多西他赛(docetaxel)、表阿霉素(epirubicin)、培洛霉素(peplomycin)、曲妥单抗(trastuzumab)、利妥昔单抗(rituximab)、obinutuzumab、奥法木单抗(ofatumumab)、托西莫单抗(tositumomab);芳香酶抑制剂(aromatase inhibitors)(例如依西美坦(exemestane)、法倔唑(fadrozole)、福美司坦(formestane)、来曲唑(letrozole)、阿那曲唑(anastrozole)、伏氯唑(vorozole));抗雌激素(antioestrogen)(例如氯地孕酮(chlormadinone)、氟维司群(fulvestrant)、美雄烷(mepitiostane)、他莫昔芬(tamoxifen)、托瑞米芬(toremifen));雌激素(oestrogen)(例如雌二醇(oestradiol)、聚雌二醇磷酸酯(polyoestradiol phosphate)、雷洛昔芬(raloxifen));促孕激素(gestagen)(例如甲羟孕酮(medroxyprogesterone)、甲地孕酮(megestrol));拓扑异构酶I抑制剂(topoisomeraseI inhibitor)(例如伊立替康(irinotecan)、拓扑替康(topotecan));拓扑异构酶II抑制剂(例如氨柔比星(amrubicin)、道诺霉素(daunorubicin)、依利醋铵(elliptiniumacetate)、依托泊苷(etoposide)、依达比星(idarubicin)、米托蒽醌(mitoxantrone)、替尼泊苷(teniposide));微管活性物质(microtubuli-active substance)(例如卡巴他赛(cabazitaxel)、艾瑞布林(eribulin)、紫杉醇(paclitaxel)、长春花碱(vinblastine)、长春新碱(vincristine)、长春地辛(vindesine)、长春瑞滨(vinorelbine));端粒酶抑制剂(例如伊美司他(imetelstat));烷基化物质和组蛋白去乙酰化酶抑制剂(例如苯达莫司汀(bendamustine)、卡莫司汀(carmustine)、氮芥(chlormethine)、达卡巴嗪(dacarbazine)、雌氮芥(estramustine)、异环磷酰胺(ifosfamide)、洛莫司汀(lomustine)、二溴甘露醇(mitobronitol)、二溴卫矛醇(mitolactol)、尼莫司汀(nimustine)、泼尼莫司汀(prednimustine)、甲苄肼(procarbazine)、雷莫司汀(ranimustine)、链脲佐菌素(streptozotocin)、替莫唑胺(temozolomide)、塞替派(thiotepa)、曲奥舒凡(treosulfan)、曲磷胺(trofosfamide)、伏立诺他(vorinostat)、罗咪酯肽(romidepsin)、帕比司他(panobinostat));影响细胞分化过程的物质,例如阿巴瑞克(abarelix)、氨鲁米特(aminoglutethimide)、蓓萨罗丁(bexarotene);MMP抑制剂(肽模拟物(peptidemimetic)、非肽模拟物(non-peptide mimetic)和四环素(tetracycline),例如马马司他(marimastat)、BAY 12-9566、BMS-275291、氯膦酸盐(clodronate)、普马司他(prinomastat)、强力霉素(doxycycline));mTOR抑制剂(例如西罗莫司(sirolimus)、依维莫司(everolimus)、坦罗莫司(temsirolimus)、佐他莫司(zotarolimus));抗代谢物(antimetabolite)(例如氯法拉滨(clofarabine)、去氧氟尿苷(doxifluridine)、氨甲蝶呤(methotrexate)、5-氟尿嘧啶(5-fluorouracil)、克拉屈滨(cladribine)、阿糖孢苷(cytarabine)、氟达拉滨(fludarabine)、巯嘌呤(mercaptopurine)、氨甲蝶呤、培美曲塞(pemetrexed)、雷替曲塞(raltitrexed)、喃氟啶(tegafur)、硫鸟嘌呤(tioguanine));铂化合物(例如卡铂(carboplatin)、顺氯氨铂(cisplatin)、顺铂(cisplatinum)、依铂(eptaplatin)、洛铂(lobaplatin)、米铂(miriplatin)、奈达铂(nedaplatin)、奥沙利铂(oxaliplatin));抗血管生成化合物(例如贝伐单抗(bevacizumab));抗雄激素化合物(例如贝伐单抗、恩杂鲁胺(enzalutamide)、氟他胺(flutamide)、尼鲁米特(nilutamide)、比卡鲁胺(bicalutamide)、环丙孕酮(cyproterone)、醋酸环丙孕酮(cyproterone acetate));蛋白酶体抑制剂(例如硼替佐米(bortezomib)、卡非佐米(carfilzomib)、oprozomib、ONYX0914);促性腺激素释放激素激动剂和拮抗剂(例如阿巴瑞克(abarelix)、布舍瑞林(buserelin)、地洛瑞林(deslorelin)、加尼瑞克(ganirelix)、戈舍瑞林(goserelin)、组氨瑞林(histrelin)、曲普瑞林(triptorelin)、地加瑞克(degarelix)、亮丙瑞林(leuprorelin));甲硫氨酸胺基肽酶抑制剂(methionine aminopeptidase inhibitor)(例如bengamide衍生物、TNP-470、PPI-2458);乙酰肝素酶抑制剂(heparanase inhibitor)(例如SST0001、PI-88);抗基因修饰的Ras蛋白的抑制剂(例如法尼基转移酶抑制剂(farnesyltransferase inhibitor)如洛那法尼(lonafarnib)、替吡法尼(tipifarnib));HSP90抑制剂(例如格尔霉素(geldamycin)衍生物,例如17-烯丙基氨基格尔德霉素(17-allylaminogeldanamycin)、17-去甲氧基格尔德霉素(17-demethoxygeldanamycin,17AAG)、17-DMAG、瑞他霉素盐酸盐(retaspimycin hydrochloride)、IPI-493、AUY922、BIIB028、STA-9090、KW-2478);纺锤体驱动蛋白抑制剂(kinesin spindle proteininhibitor)(例如SB715992、SB743921、戊烷脒(pentamidine)/氯丙嗪(chlorpromazine));MEK(促分裂原活化蛋白激酶激酶(mitogen-activated protein kinase kinase))抑制剂(例如曲美替尼(trametinib)、BAY 86-9766(refametinib)、AZD6244);激酶抑制剂(例如:索拉非尼(sorafenib)、瑞格拉非尼(regorafenib)、拉帕替尼片(lapatinib)、索坦达沙替尼(dasatinib)、西妥昔单抗(cetuximab)、BMS-908662、GSK2118436、AMG 706、埃罗替尼(erlotinib)、吉非替尼(gefitinib)、伊马替尼(imatinib)、尼罗替尼(nilotinib)、帕唑帕尼(pazopanib)、roniciclib、舒尼替尼(sunitinib)、凡德他尼(vandetanib)、维莫非尼(vemurafenib));hedgehog信号抑制剂(例如环巴胺(cyclopamine)、维莫德吉(vismodegib));BTK(布鲁顿氏酪氨酸激酶(Bruton′s tyrosinekinase))抑制剂(例如依鲁替尼(ibrutinib));JAK/pan-JAK(JAK激酶)抑制剂(例如SB-1578、巴瑞替尼、托法替尼、pacritinib、momelotinib、芦可替尼(ruxolitinib)、VX-509、AZD-1480、TG-101348);PI3K抑制剂(例如BAY 1082439、BAY 80-6946(copanlisib)、ATU-027、SF-1126、DS-7423、GSK-2126458、buparlisib、PF-4691502、BYL-719、XL-147、XL-765、idelalisib);SYK(脾酪氨酸激酶(spleen tyrosine kinase))抑制剂(例如fostamatinib、Excellair、PRT-062607),p53基因疗法,双膦酸盐(例如依替膦酸钠(etidronate)、氯膦酸盐(clodronate)、替鲁膦酸盐(tiludronate)、帕米膦酸二钠(pamidronate)、阿仑棒酸(alendronic acid)、伊班膦酸盐(ibandronate)、利塞膦酸盐(risedronate)、唑来膦酸(zoledronate))。对于组合物,还应示例性地但非排他性地提及以下活性成分:利妥昔单抗(rituximab)、环磷酰胺、阿霉素(doxorubicin)、与雌酮(oestrone)结合的阿霉素、长春新碱(vincristine)、苯丁酸氮芥(chlorambucil)、氟达拉滨(fludarabin)、地塞米松(dexamethasone)、克拉屈滨(cladribin)、强的松(prednisone)、131I-chTNT、阿比特龙(abiraterone)、阿柔比星(aclarubicin)、阿利维A酸(alitretinoin)、比生群(bisantrene)、亚叶酸钙(calcium folinate)、左亚叶酸钙(calciumlevofolinate)、卡培他滨(capecitabin)、卡莫氟(carmofur)、氯膦酸(clodronic acid)、罗米司亭(romiplostim)、crisantaspase、达贝泊汀α(darbepoetin alfa)、地西他滨(decitabine)、狄诺塞麦(denosumab)、二溴螺氯铵(dibrospidium chloride)、艾曲波帕(eltrombopag)、内皮抑素(endostatin)、环硫雄醇(epitiostanol)、阿法依伯汀(epoetin alfa)、非格司亭(filgrastim)、福莫司汀(fotemustin)、硝酸镓(gallium nitrate)、吉西他滨(gemcitabine)、glutoxim、组胺二盐酸盐(histamine dihydrochloride)、羟基尿素(hydroxycarbamide)、英丙舒凡(improsulfan)、伊沙匹隆(ixabepilone)、兰乐肽(lanreotide)、香菇多糖(lentinan)、左旋咪唑(levamisole)、麦角乙脲(lisuride)、氯尼达明(lonidamine)、马索罗酚(masoprocol)、甲基睾酮(methyltestosterone)、甲氧沙林(methoxsalen)、氨基乙酰丙酸甲酯(methyl aminolevulinate)、米替福新(miltefosine)、米托胍腙(mitoguazone)、丝裂霉素(mitomycin)、米托坦(mitotane)、奈拉滨(nelarabine)、尼妥珠单抗(nimotuzumab)、nitracrin、奥美拉唑(omeprazole)、帕利夫明(palifermin)、帕尼单抗(panitumumab)、培门冬酶(pegaspargase)、PEG倍他依泊汀(epoetin beta)(甲氧基-PEG倍他依泊汀)、聚乙二醇非格司亭(pegfilgrastim)、聚乙二醇干扰素α-2b(peg interferon alfa-2b)、镇痛新(pentazocine)、喷司他丁(pentostatin)、培磷酰胺(perfosfamide)、吡柔比星(pirarubicin)、普卡霉素(plicamycin)、聚氨葡糖(poliglusam)、卟吩姆钠(porfimer sodium)、普拉曲沙(pralatrexate)、喹高利特(quinagolide)、雷佐生(razoxane)、西佐喃(sizofirane)、索布佐生(sobuzoxan)、甘氨双唑钠(sodium glycididazole)、他米巴罗汀(tamibarotene)、喃氟啶(tegafur)和吉美嘧啶(gimeracil)以及奥替拉西(oteracil)的结合物、睾酮(testosterone)、替曲膦(tetrofosmin)、萨力多胺(thalidomide)、胸腺法新(thymalfasin)、曲贝替定(trabectedin)、维甲酸(tretinoin)、曲洛司坦(trilostane)、色氨酸(tryptophan)、乌苯美司(ubenimex)、伐普肽(vapreotide)、钇-90玻璃微球(glass microspheres)、净司他丁(zinostatin)、净司他丁斯酯(zinostatin stimalamer)。
还适用于肿瘤治疗的是非药物疗法的结合,例如化学疗法(例如阿扎胞苷(azacitidine)、贝洛替康(belotecan)、依诺他滨(enocitabine)、米尔法兰(melphalan)、戊柔比星(valrubicin)、长春氟宁(vinflunin)、佐柔比星(zorubicin));放射疗法(例如I-125粒子、钯-103粒子、镭-223氯化物);或光线疗法(phototherapy)(例如替莫卟吩(temoporfin)、他拉泊芬(talaporfin)),其伴随着利用本发明的IRAK4抑制剂的药物治疗,或在非药物肿瘤治疗如化学疗法、放射疗法或光线疗法结束后,补充有利用本发明的IRAK4抑制剂的药物治疗。
除上述那些之外,本发明的IRAK4抑制剂还可与以下活性成分结合:
用于阿尔茨海默病治疗的活性成分,例如乙酰胆碱酯酶抑制剂(例如多奈哌齐(donepezil)、卡巴拉汀(rivastigmine)、加兰他敏(galantamine)、他克林(tacrine))、NMDA(N-甲基-D-天冬氨酸盐)受体拮抗剂(例如美金刚(memantine));用于治疗帕金森病的L-DOPA/卡比多巴(carbidopa)(L-3,4-二羟基苯基丙氨酸)、COMT(儿茶酚-O-甲基转移酶)抑制剂(例如恩他卡朋(entacapone))、多巴胺激动剂(例如罗匹尼罗(ropinirole)、普拉克索(pramipexole)、溴麦角环肽(bromocriptine))、MAO-B(单胺氧化酶-B(monoaminooxidase-B))抑制剂(例如司来吉兰(selegiline))、抗胆碱能药(anticholinergic)(例如苯海索(trihexyphenidyl))和NMDA拮抗剂(例如金刚胺(amantadine));用于治疗多发性硬化症的β-干扰素(IFN-beta)(例如IFN β-1b、IFN β-1a 醋酸格拉替雷(glatiramer acetate)、免疫球蛋白(immunoglobulins)、那他珠单抗(natalizumab)、芬戈莫德(fingolimod)和免疫抑制剂,例如米托蒽醌(mitoxantrone)、咪唑硫嘌呤(azathioprine)和环磷酰胺;用于治疗肺部疾病的物质,例如β-2-拟交感神经药(sympathomimetics)(例如舒喘灵(salbutamol))、抗胆碱能药(anticholinergic)(例如格隆铵(glycopyrronium))、甲基黄嘌呤(methylxanthines)(例如茶碱(theophylline))、白三烯(leukotriene)受体拮抗剂(例如孟鲁司特(montelukast))、PDE-4(4型磷酸二酯酶)抑制剂(例如罗氟司特(roflumilast))、氨甲蝶呤、IgE抗体、咪唑硫嘌呤和环磷酰胺、含皮质醇的制剂;用于治疗骨关节炎的物质,例如非甾体抗炎物质(NSAID)。对于类风湿性疾病,例如类风湿性关节炎、脊柱关节炎和幼年特发性关节炎,除所述两种疗法外,应提及用于B-细胞和T-细胞治疗的氨甲蝶呤和生物制剂(例如利妥昔单抗(rituximab)、阿巴西普(abatacept))。神经营养物质例如乙酰胆碱酯酶抑制剂(例如多奈哌齐(donepezil))、MAO(单胺氧化酶(monoaminooxidase))抑制剂(例如司来吉兰)、干扰素和抗惊厥药(anticonvulsives)(例如加巴喷丁(gabapentin));用于治疗心血管疾病的活性成分,例如β受体阻滞剂(beta-blocker)(例如美托洛尔(metoprolol))、ACE抑制剂(例如贝那普利(benazepril))、血管紧张素受体阻滞剂(例如氯沙坦(losartan)、缬沙坦(valsartan))、利尿剂(diuretic)(例如氢氯噻嗪)、钙通道阻滞剂(例如硝苯地平(nifedipine))、他汀类(statin)(例如辛伐他汀(simvastatin)、氟伐他汀(fluvastatin));抗糖尿病药,例如二甲双胍(metformin)、格列奈类(glinide)(例如那格列奈(nateglinide))、DPP-4(二肽基肽酶-4(dipeptidyl peptidase-4))抑制剂(例如利拉利汀(linagliptin)、沙格列汀(saxagliptin)、西他列汀(sitagliptin)、维达列汀(vildagliptin))、SGLT2(钠/葡萄糖协同转运蛋白2)抑制剂/格列净(gliflozin)(例如达格列净(dapagliflozin)、依帕列净(empagliflozin))、肠降血糖素模拟物(incretinmimetics)(荷尔蒙葡萄糖依赖性促胰岛素肽(hormone glucose-dependentinsulinotropic peptide)(GIP)和胰高血糖素样肽1(glucagon-like peptid 1)(GLP-1)类似物/激动剂)(例如艾塞那肽(exenatide)、利拉鲁肽(liraglutide)、利西拉肽(lixisenatide))、α-葡萄糖苷酶抑制剂(例如阿卡波糖(acarbose)、米格列醇(miglitol)、伏格列波糖(voglibiose))和磺脲类(例如格列本脲(glibenclamide)、甲苯磺丁脲(tolbutamide))、胰岛素增敏剂(例如吡格列酮(pioglitazone))和胰岛素疗法(例如NPH胰岛素、赖脯胰岛素(insulin lispro)),用于治疗低血糖的物质,用于治疗糖尿病和代谢综合症的物质。降血脂药,例如贝特类(fibrate)(例如苯扎贝特(bezafibrate)、依托贝特(etofibrate)、非诺贝特(fenofibrate)、吉非贝齐(gemfibrozil))、烟酸衍生物(例如烟酸/拉罗皮兰(laropiprant))、依泽替米贝(ezetimib)、他汀类(例如辛伐他汀(simvastatin)、氟伐他汀(fluvastatin))、阴离子交换剂(例如考来烯胺(colestyramine)、考来替泊(colestipol)、考来维纶(colesevelam))。用于治疗慢性炎症性肠病的活性成分,例如美沙拉嗪(mesalazine)、柳氮磺胺吡啶(sulfasalazine)、咪唑硫嘌呤、6-巯基嘌呤或氨甲蝶呤、益生菌(Mutaflor、鼠李糖乳杆菌(Lactobacillus GG)、植物乳杆菌(Lactobacillus plantarum)、嗜酸乳杆菌(L.acidophilus)、干酪乳杆菌(L.casei)、婴儿双歧杆菌(Bifidobacterium infantis)35624、屎肠球菌(Enterococcus fecium)SF68、长双歧杆菌(Bifidobacterium longum)、大肠杆菌(Escherichia coli)Nissle 1917);抗生素,例如环丙沙星(ciprofloxacin)和甲硝唑(metronidazole);抗腹泻药,例如洛哌丁胺(loperamide);或轻泻药(laxative)(比沙可啶(bisacodyl))。用于治疗红斑狼疮的免疫抑制剂例如糖皮质激素(glucocorticoid)和非甾体抗炎物质(NSAID)、可的松(cortisone)、氯喹(chloroquine)、环孢霉素(cyclosporine)、咪唑硫嘌呤、贝利木单抗、利妥昔单抗、环磷酰胺。对于器官移植,示例性地但非排除性地,钙调磷酸酶(calcineurin)抑制剂(例如他克莫司(tacrolimus)和环孢素(ciclosporin))、细胞分裂抑制剂(例如咪唑硫嘌呤、霉酚酸酯(mycophenolate mofetil)、霉酚酸(mycophenolic acid)、依维莫司(everolimus)或西罗莫司(sirolimus))、雷帕霉素(rapamycin)、巴利昔单抗、达克珠单抗(daclizumab)、抗CD3抗体、抗T淋巴细胞球蛋白(anti-T-lymphocyte globulin)/抗淋巴细胞球蛋白。对于皮肤病,维他命D3类似物,例如钙泊三醇(calcipotriol)、他卡西醇(tacalcitol)或骨化三醇(calcitriol)、水杨酸、尿素、环孢素(ciclosporine)、氨甲蝶呤、依法利珠单抗(efalizumab)。
药物组合物:
式(I)的化合物的结晶形式可具有全身和/或局部的活性。为此,可以以合适的方式给药,例如通过口服、肠胃外、肺部、经鼻、舌下、经舌、口腔、直肠、阴道、皮肤、透皮、结膜、经耳途径给药或作为植入物或支架。
对于这些给药途径,式(I)化合物的结晶形式可以以合适的给药形式给药。
对于口服给药,可将式(I)化合物的结晶形式配制成本领域已知的剂型,其快速和/或以缓和方式递送本发明化合物,所述剂型为例如片剂(未包衣或包衣的片剂,例如具有延迟溶解或不溶的肠溶包衣或控释包衣)、口服-崩解片剂、薄膜/薄片(wafer)、薄膜/冻干剂(lyophylisate)、胶囊(例如硬明胶胶囊或软明胶胶囊)、糖衣片剂、颗粒剂、丸剂、粉剂、乳剂、悬浮剂、气溶胶或溶液。可将本发明的化合物以结晶形式和/或无定形形式和/或溶解形式纳入所述剂型中。
肠胃外给药可通过避免吸收步骤(例如静脉内、动脉内、心脏内、脊柱内或腰椎内的)或包括吸收步骤(例如肌肉内、皮下、皮内、经皮或腹膜内的)进行。适于肠胃外给药的给药形式尤其是溶液、悬浮剂、乳剂、冻干剂或无菌粉剂形式的注射用和输液用制剂。
适于其他给药途径的实例为用于吸入的药物形式(尤其是粉末吸入剂、喷雾剂)、滴鼻剂、鼻溶液、喷鼻剂;用于经舌、舌下或口腔给药的片剂/薄膜/薄片/胶囊;栓剂;滴眼剂、眼膏剂、洗眼杯(eye bath)、眼部插入物(ocular insert)、滴耳剂、喷耳剂(earspray)、耳粉剂(ear powder)、洗耳剂(ear-rinse)、耳填塞剂(ear tampon);阴道胶囊、水性悬浮剂(洗剂、振荡合剂(mixturae agitandae))、亲脂性悬浮剂、乳剂(emulsion)、软膏剂、乳膏剂、经皮治疗系统(例如贴剂)、乳剂(milk)、糊剂、泡沫剂(foam)、撒布剂(dustingpowder)、植入物或支架。
式(I)化合物的结晶形式可纳入所述给药形式中。这可以以本身已知的方式通过与药学上合适的赋形剂混合而实现。药学上合适的赋形剂尤其包括
·软膏剂基质(例如凡士林、石蜡、甘油三酯、蜡、羊毛蜡、羊毛蜡醇、羊毛脂、亲水软膏、聚乙二醇),
·栓剂基质(例如聚乙二醇、可可脂、硬脂),
·溶剂(例如水、乙醇、异丙醇、丙三醇、丙二醇、中等链长甘油三酯脂肪油、液体聚乙二醇、链烷烃),
·表面活性剂,乳化剂、分散剂或湿润剂(例如十二烷基硫酸钠)、卵磷脂、磷脂质、脂肪醇(例如)、失水山梨醇脂肪酸酯(例如)、聚氧乙烯失水山梨醇脂肪酸酯(例如)、聚氧乙烯脂肪酸甘油酯(例如)、聚氧乙烯脂肪酸酯、聚氧乙烯脂肪醇醚、脂肪酸甘油酯、泊洛沙姆(例如),
·缓冲液、酸和碱(例如磷酸盐、碳酸盐、柠檬酸、乙酸、盐酸、氢氧化钠溶液、碳酸铵、氨丁三醇、三乙醇胺),
·等渗剂(例如葡萄糖、氯化钠),
·吸附剂(例如高分散二氧化硅),
·包衣材料(例如糖、虫胶)和用于快速溶解或以缓和方式溶解的薄膜或扩散膜的成膜剂(例如聚乙烯吡咯烷酮(例如)、聚乙烯醇、羟丙基甲基纤维素、羟丙基纤维素、乙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯、醋酸纤维素、邻苯二甲酸乙酸纤维素、聚丙烯酸酯、聚甲基丙烯酸酯(例如)),
·胶囊材料(例如明胶、羟丙基甲基纤维素),
·增塑剂(例如聚乙二醇、丙二醇、丙三醇、三乙酸甘油酯(triacetine)、三乙酰基柠檬酸酯、邻苯二甲酸二丁酯),
·渗透促进剂,
·稳定剂(例如抗氧化剂,例如抗坏血酸、抗坏血酸棕榈酸酯、抗坏血酸钠、丁基羟基茴香醚、丁基羟基甲苯、没食子酸丙酯),
·防腐剂(例如对羟基苯甲酸酯、山梨酸、硫柳汞(thiomersal)、苯扎氯铵、乙酸氯己定、苯甲酸钠),
·着色剂(例如无机颜料如氧化铁、二氧化钛),
·调味剂、甜味剂、遮味剂和/或气味掩蔽剂。
此外,本发明还涉及一种包含至少一种式(I)化合物的结晶形式且通常还与一种或多种药学上合适的赋形剂一起的药物组合物,及其根据本发明的用途。
本发明药物组合物的剂量:
基于已知的用于评估有益于疾病治疗的化合物的实验技术,通过用于确定在哺乳动物中上述病情(condition)的治疗方案的药理学分析,并通过将这些结果与用于治疗这些病情的已知药剂的结果相比较,可以容易地确定用于治疗各种所需适应症的本发明化合物的有效剂量。在治疗这些病情中的一种时,待给予的活性成分的量可根据这样的考虑而广泛变化:如所用的具体化合物和剂量单元、给药方式、治疗周期、所治疗患者的年龄和性别以及所治疗的紊乱的性质和程度。
待给予的活性成分的总量通常为约5至2000mg/天、优选15至750mg/天、更优选15至200mg/天。单位剂量可含有约15至750mg、优选15至120mg的活性成分,且可每天给药一次或多次。
当然,每位患者的具体初始剂量和持续剂量方案将根据主治诊断医生确定的病情的性质和严重程度、所用具体化合物的活性、患者的年龄和一般状况、给药时间、给药途径、药物排泄速度、药物组合等变化。本领域技术人员使用常规治疗试验可以确定所需的治疗方式和本发明化合物或其药学上可接受的盐或酯或组合物的剂量。
除非另有说明,以下试验和实施例中的重量数据为重量百分比;份数为重量份数。在每种情况下,溶剂比、稀释比和液体/液体溶液的浓度数据基于体积计。
工作实施例
以下实施例阐明了本发明。
方法:
DSC热分析图使用来自Perkin-Elmer的差示扫描量热仪(型号DSC7、Pyris 1或Diamond)记录。使用非气密性铝盘以20K min-1的加热速率进行测量。流动气体为氮气。没有样品制备。
TGA热分析图使用来自Perkin-Elmer的热天平(型号TGA7和Pyris 1)记录。使用开口铂盘以10K min-1的加热速率进行测量。流动气体为氮气。没有样品制备。
X-射线衍射图在室温下使用XRD-衍射仪X`Pert PRO(PANalytical)和STOESTADI-P(辐射源铜K α1,波长)记录。没有样品制备。所有的X-射线反射都表示为°2θ值,分辨率为±0.2°。
拉曼光谱在室温下使用来自Bruker的FT-拉曼-分光光度计(型号RFS 100和MultiRam)记录。分辨率为2cm-1。在小玻璃瓶或铝盘中进行测量。没有样品制备。
IR-ATR-光谱在室温下使用来自Perkin-Elmer的具有通用金刚石ATR装置的FT-IR-分光光度计记录。分辨率为4cm-1。没有样品制备。
HPLC
方法A
设备:具有1290Infinity取样器的Agilent Technologie 1260Infinity和Agilent 1100系列
Zorbax SB-AQ,50*4,6mm,1,5μm
缓冲液:磷酸二氢铵pH:2.4
乙腈
0min 5%缓冲液
8.3min 80%缓冲液
11min 80%缓冲液
210nm/4nm
1.2ml/min
方法B
GC-HS
通过顶空气相色谱(GC-HS)进行残留溶剂分析。
具有分流进样和FID的Agilent 6890气相色谱仪(柱:Restek Rxi Sil MS;长度:20m;内径:0.18mm;df=1μm)。进样器温度160℃,流率1.2ml/min(H2)分流比18,箱温40℃(4.5min)-14℃/min-70℃-90℃/min-220℃(1.69min)。检测器:温度300℃,400ml/min(合成空气),40ml/min(H2),30ml/min(N2),速率20Hz。
Perkin Elmer Turbomatrix 40顶空取样器:箱温80℃,针150℃,传输线160℃,系统压力140kPa,平衡时间32min,加压4.0min,进样时间0.04min(取样器)0.05min(GC)。
样品浓度:20mg物质于2ml DMF中。
N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺(I)的制备
实施例#1
5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-1H-吲唑-6-甲酸甲酯(VI)
将2000g(10.46mol)的5-氨基-1H-吲唑-6-甲酸基酯、1899g(9.94mol)的6-(三氟甲基)吡啶-2-甲酸和2028g(15.69mol)的N,N-二异丙基乙胺于14.2kg的THF中混合。在0至5℃下,在30min内滴加13.3kg的T3P的乙酸乙酯溶液(50重量%)。在相同温度下继续搅拌2h。
后处理:
将反应混合物温热至环境温度(20℃)。在将温度保持在20至25℃的同时,加入3000g的水。继续搅拌10min。用4N的碳酸钠水溶液调节pH至约7.4(7-8)。继续搅拌10min。如果需要,再次用4N的碳酸钠水溶液调节pH至7.4。
在减压(约200mbar,内部温度45-50℃)下蒸发溶剂(THF/乙酸乙酯)直至到达搅拌极限。加入4.7kg乙醇和14.0kg水的混合物,并再次用4N的碳酸钠水溶液调节pH至7.4(7-8)。
将混合物在50℃下搅拌1h,随后冷却至20至25℃。在相同温度下继续搅拌10min。过滤出沉淀的晶体,用乙醇和水的混合物(1.3kg的乙醇与4kg的水)洗涤,并在干燥箱中在真空下干燥(45℃,N2流通,至少12h)。
根据上述过程,在技术实验室中使用2kg的起始材料(5-氨基-1H-吲唑-6-甲酸甲酯)制备了四批批料:
产率:
批料#1:3476g(95%)
批料#2:3449g(95%)
批料#3:3476g(95%)
批料#4:3494g(96%)
所有批料的纯度均测定为>98面积%(HPLC)。
HPLC(方法A):Rt=6.5min。
MS(ESI pos):m/z=365(M+H)+
1H NMR(500MHz,DMSO-d6):δ[ppm]:3.98(s,3H),8.21(d,1H),8.25(s,1H),8.31(s,1H),8.39(t,1H),8.48(d,1H),9.16(s,1H),12.57(s,1H),13.45(br s,1H)。
1H NMR(300MHz,DMSO-d6):δ[ppm]=3.97(s,3H),8.13-8.27(m,2H),8.30(s,1H),8.33-8.45(m,1H),8.45-8.51(m,1H),9.15(s,1H),12.57(s,1H),13.44(br s,1H)。
实施例#2
N-[6-(2-羟基丙-2-基)-1H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺(V)
在以下部分中,描述了反应过程和后处理的不同变化方案。根据各个技术工厂中的给定条件调试这些过程。
以下实验在使用惰性气体(N2或Ar)在除去水和空气的情况下进行。
变化方案#1
将50g(137.225mmol)的5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-1H-吲唑-6-甲酸甲酯(VI)溶于800ml的THF中。在正常压力下、在70℃下蒸馏出约300ml的THF。然后将溶液冷却至0至3℃。
将溶液保持在该温度,并在0至3℃下在120min内滴加到457.5ml(1372.6mmol)甲基氯化镁的3M THF溶液和29.1g的氯化锂(686.3mmol)的冷却混合物中。加入完成后,从混合物中取样,并进行HPLC分析,显示转化完全。在0至3℃下在25min内小心地将混合物倒入500ml的氯化钠的1/2-饱和水溶液中(注意:放热!在最初的50ml期间,观察到温度骤升至29℃!)。获得悬浮液,当加入358ml的20重量%的柠檬酸水溶液时(pH从8.08降至4.28),悬浮液溶解。在20至25℃下继续搅拌10min。加入500ml的乙酸乙酯,并继续搅拌10min。分离各相。向有机相中加入沉浮物(mulm)。向有机相中加入5g的活性炭。将混合物加热至78℃(内部温度),在该温度搅拌30min,且随后冷却至50℃(内部温度)。用硅藻土过滤温热的溶液,并用125ml的乙酸乙酯洗涤两次。将混合物在环境压力(1atm)和110℃下浓缩至约150ml。加入350ml的甲苯,并在环境压力(1atm)和110℃下蒸馏出200ml甲苯。产物沉淀。在60℃的内部温度下,经45min加入200ml的正庚烷。将混合物冷却至0至3℃,并在该温度下搅拌2h。过滤产物,并用50ml的甲苯/正庚烷(1∶1)的混合物洗涤两次。将沉淀的产物在40℃和20mbar下在干燥箱中干燥>48h。
产率:39.42g(78.83%,纯度97.84面积%HPLC)
HPLC(方法A):Rt=5.8min。
MS(ESI pos):m/z=365(M+H)+
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.63(s,6H),5.99(s,1H),7.50(s,1H),8.06(s,1H),8.17(d,1H),8.37(t,1H),8.46(d,1H),8.78(s,1H),12.33(s,1H),12.97(br s,1H)。
按照变化方案#1的方法制备13批批料。下表3总结了各自的产率。就使用5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-1H-吲唑-6-甲酸甲酯(VI)作为起始材料而言,以1kg规模进行反应。在大多数情况下,在用活性炭处理后合并两批批料:
表3:由(VI)合成(V)的批料1至13获得的产率
*)单一批料
变化方案#2
将30g(82.4mmol)的5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-1H-吲唑-6-甲酸甲酯(VI)溶于480ml的THF中。在正常压力下、在70℃下蒸馏出约180ml的THF。然后将混合物(轻微悬浮)冷却至0至3℃。
将溶液保持在该温度,并在0至3℃下在120min内滴加到274.5ml(823.5mmol)甲基氯化镁的3M THF溶液和17.5g氯化锂(411.8mmol)的冷却混合物中。在加入完成后15min,从混合物中取样,并进行HPLC分析,显示(VI)完全转化。在0至3℃下小心地将混合物经15min倒入300ml的水中(注意:放热!在最初的50ml期间,观察到温度骤升!)。加入310ml的20重量%的柠檬酸的水溶液(pH降至4.05)。在20至25℃下继续搅拌60min。加入300ml的乙酸乙酯,并继续搅拌30min。分离各相。向有机相中加入沉浮物。有机相用450ml的水洗涤两次。将有机相在65℃(内部温度)和环境压力(1atm)下浓缩至350ml。加入250ml的乙酸乙酯。向有机相中加入6g的活性炭。将混合物加热至65℃(内部温度),在该温度下搅拌120min,且随后冷却至50℃(内部温度)。用硅藻土过滤温热的溶液,并用125ml的乙酸乙酯洗涤两次。将混合物在环境压力(1atm)和110℃下浓缩至约150ml。加入300ml的甲苯,并在环境压力(1atm)和110℃下蒸馏出200ml甲苯。产物沉淀。在60℃的内部温度下,经45min加入200ml的正庚烷。将混合物冷却至0-3℃,并在该温度下搅拌2h。过滤产物,并用50ml的甲苯/正庚烷(1∶1)的混合物洗涤两次。将沉淀的产物在40℃和20mbar下在干燥箱中干燥>48h。
产率:24.0g(80%,纯度95.8面积%HPLC)。
HPLC(方法A):Rt=5.8min。
MS(ESI pos):m/z=365(M+H)+
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.63(s,6H),5.99(s,1H),7.50(s,1H),8.06(s,1H),8.17(d,1H),8.37(t,1H),8.46(d,1H),8.78(s,1H),12.33(s,1H),12.97(br s,1H)。
变化方案#3
将30g(82.4mmol)的5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-1H-吲唑-6-甲酸甲酯(VI)溶于600ml的THF中。在正常压力下、在70℃下蒸馏出约150ml的THF。然后将混合物(轻微悬浮)冷却至0至3℃。
将溶液保持在该温度,并在0至3℃下在120min内滴加到274.5ml(823.5mmol)甲基氯化镁的3M THF溶液和17.5g的氯化锂(411.8mmol)的冷却混合物中。将滴液漏斗用10ml的THF洗涤两次。在加入完成后15min,从混合物中取样,并进行HPLC分析,显示(VI)完全转化。在0至3℃下在10min内小心地将混合物倒入300ml的水中(注意:放热!在最初的50ml期间,观察到温度骤升至25℃!)。加入250ml的20重量%的柠檬酸的水溶液(pH由8降至4)。在20-25℃下继续搅拌30min。加入300ml的乙酸乙酯,并继续搅拌10min。分离各相。向有机相中加入沉浮物。有机相用200ml的1重量%的氯化钠水溶液洗涤两次。分离各相,将有机相在65℃(内部温度)和环境压力(1atm)下浓缩至250ml。向有机相中加入150ml的乙酸乙酯和6g的活性炭。将混合物加热至65℃(内部温度),在该温度下搅拌120min,且随后冷却至50℃(内部温度)。用硅藻土过滤温热的溶液,并用125ml的乙酸乙酯洗涤两次。将混合物在环境压力(1atm)和110℃下浓缩至约100ml。加入300ml的异丙醇。在环境压力(1atm)和110℃下蒸馏出300ml。再次加入300ml的异丙醇,并在110℃下蒸馏出(约355ml)。将所得悬浮液冷却至20-25℃。在45min内加入45ml的水。将混合物搅拌1h。过滤沉淀的产物,并用50ml的甲苯/异丙醇(1∶1)混合物洗涤。将沉淀的产物在50℃和20mbar下在干燥箱中干燥>48h。
产率:24.9g(83%,纯度97.84面积%HPLC)
HPLC(方法A):Rt=5.8min。
MS(ESI pos):m/z=365(M+H)+
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.63(s,6H),5.99(s,1H),7.50(s,1H),8.06(s,1H),8.17(d,1H),8.37(t,1H),8.46(d,1H),8.78(s,1H),12.33(s,1H),12.97(br s,1H)。
变化方案#4
该变化方案用于以kg规模制备工业批料(>10kg)(参见表4)。
将60g(164.7mmol)的5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-1H-吲唑-6-甲酸甲酯(VI)溶于1500ml的THF中。在正常压力下、在70℃下蒸馏出约600ml的THF。然后将混合物(黄色溶液)冷却至0至3℃。
将溶液保持在该温度,并在0-3℃下在120min内滴加到550ml(1647.1mmol)的3M甲基氯化镁THF溶液和35g的氯化锂(823.5mmol)的冷却混合物中。在加入完成后15min,从混合物中取样,并进行HPLC分析,显示(VI)完全转化。在0至3℃下小心地将混合物在15min内倒入600ml的水中(注意:放热!在最初的50ml期间,观察到温度骤升!)。加入600ml的20重量%的柠檬酸水溶液(pH降至4)。在20至25℃下继续搅拌30min。分离各相。将有机相用400ml的1重量%的氯化钠水溶液洗涤两次。向有机相中加入沉浮物。分离各相。将有机相在65℃(内部温度)和环境压力(1atm)下浓缩至700ml。向有机相中加入500ml的乙酸乙酯和12g的活性炭。将混合物加热至65℃(内部温度),在该温度下搅拌120min,且随后冷却至50℃(内部温度)。用硅藻土过滤温热的溶液,并用200ml的乙酸乙酯洗涤两次。在减压(200mbar)下继续浓缩。将溶剂交换成甲苯(剩余体积约850ml)。将所得悬浮液冷却至0-3℃。过滤沉淀的产物,并用50ml的甲苯洗涤。将沉淀的产物在50℃和20mbar下在干燥箱中干燥>48h。
产率:51.2g(85.3%,纯度96.51面积%HPLC)。
HPLC(方法A):Rt=5.8min。
MS(ESI pos):m/z=365(M+H)+
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.63(s,6H),5.99(s,1H),7.50(s,1H),8.06(s,1H),8.17(d,1H),8.37(t,1H),8.46(d,1H),8.78(s,1H),12.33(s,1H),12.97(br s,1H)。
变化方案#5
通过在异丙醇/水中搅拌纯化。
根据粗产物的纯度,可通过在异丙醇和水(优选1∶1)的混合物中搅拌而进行额外的纯化步骤。根据粗产物的纯度,在相对于粗起始材料2-10体积内进行搅拌。以下实施例描述了在3体积的异丙醇/水中搅拌:
在20℃下将7.5g的纯度为95面积%(HPLC)的N-[6-(2-羟基丙-2-基)-1H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺(V)在22.5ml的水和异丙醇的1∶1(体积)混合物中搅拌2h。然后过滤悬浮液,并用4ml的相同的溶剂混合物洗涤产物。将产物在50℃的干燥箱中在真空(<100mbar)下干燥。
产率:6.8g(90.7%,纯度>98面积%HPLC)。
HPLC(方法A):Rt=5.8min。
MS(ESIpos):m/z=365(M+H)+
1H-NMR(400MHz,DMSO-4):δ[ppm]=1.63(s,6H),5.99(s,1H),7.50(s,1H),8.06(s,1H),8.17(d,1H),8.37(t,1H),8.46(d,1H),8.78(s,1H),12.33(s,1H),12.97(br s,1H)。
变化方案#4和#5的结合以44kg的规模进行(参见下表4)。
表4:按照变化方案#4和#5的方案制备式(V)的化合物
实施例#3
N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺(I)
变化方案#1
该变化方案用于以kg规模制备工业批料,并遵循WO2016/083433中记载的方案。
将2.5kg(6.86mol)的N-[6-(2-羟基丙-2-基)-1H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺(I)悬浮在33L(28.6kg)的甲苯中。将混合物加热至回流,并从混合物中蒸馏出约8L的甲苯。将混合物冷却至90℃,并向混合物中加入44g(0.34mol)的N,N-二异丙基乙胺。将混合物在90℃下再搅拌15min,然后加入1.17kg(10.98mmol)的甲基乙烯基砜。将反应混合物保持在112℃(回流甲苯),并搅拌至少72h。将混合物冷却至20℃。然后将混合物加热至回流,并从混合物中蒸馏出8L的甲苯。然后将混合物冷却至70℃,并在30min内加入12.6kg的甲基叔丁基醚(MTBE)。在2h内将混合物冷却至20℃,并在20℃搅拌过夜。然后将其冷却至0℃并搅拌1h。过滤出沉淀并用3L的冷MTBE洗涤两次。将结晶产物在烘箱中在50℃下真空干燥。
产率:2.39kg(73.9%,纯度:97.8面积%HPLC)。
HPLC(方法B):Rt=3.07min。
MS(ESI pos):m/z=471(M+H)+
1H NMR(400MHz,DMSO-d6):δ[ppm]=1.63(s,6H),2.90(s,3H),3.85(t,2H),4.86(t,2H),5.97(s,1H),7.59(s,1H),8.13-8.19(m,1H),8.37(s,1H),8.41-8.48(m,2H),8.74(s,1H),12.37(s,1H)。
表5:由(V)至(I)的三批批料获得的产率和纯度(HPLC后以%计)
*方法B
为获得具有非常高的纯度且具有所定义的结晶形式(B型多晶型物)的材料,引入额外的纯化步骤。
在环境温度下将1.85kg的粗N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺(I)溶于36.6kg(46.3L)的丙酮中。将所得溶液在2.5h内加入到回流的乙醇中。在加入过程中,蒸馏出54L的溶剂,并达到63℃的内部温度。加入额外的20.8L乙醇,并从混合物中蒸馏出27L的溶剂。另外,加入额外的10.2L乙醇,并从混合物中蒸馏出9.3L。最后,另加入10.2L额外的乙醇,并从混合物中蒸馏出10.2L的溶剂。将混合物在3h内冷却至20℃并搅拌过夜。将混合物在1.5h内冷却至0-2℃并在该温度下再搅拌3h。过滤悬浮液,并用2x0.93L的冷乙醇洗涤沉淀。将产物在干燥箱中在50℃下真空干燥。
产率:1.59kg(85.7%,纯度:99.0面积%HPLC)。
HPLC(方法B):Rt=3.07min。
MS(ESI pos):m/z=471(M+H)+
1H NMR(400MHz,DMSO-d6):δ[ppm]=1.63(s,6H),2.90(s,3H),3.85(t,2H),4.86(t,2H),5.97(s,1H),7.59(s,1H),8.16(d,1H),8.37(t,1H),8.41-8.48(m,2H),8.74(s,1H),12.37(s,1H)。
表6:由(V)合成的(I)的合成获得的产率和纯度以及在HPLC之后的纯度(%)
变化方案#2
该变化方案用于以kg规模制备工业批料。
将10g(27.448mmol)的N-[6-(2-羟基丙-2-基)-1H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺(V)悬浮在100ml的甲苯中。加入3.496g(32.937mmol)的甲基乙烯基砜。将反应混合物加热至110℃(回流甲苯),并搅拌至少15h。加入额外部分的583mg(5.49mmol)的甲基乙烯基砜,并将反应混合物在回流下搅拌7h。另加入583mg(5.49mmol)的甲基乙烯基砜,并将反应混合物搅拌>15h。根据HPLC分析,2.5%的起始材料(V)仍存在于反应混合物中。N1/N2的选择性已达到1:8。蒸馏出30ml的甲苯。将混合物冷却至70℃。在该温度下,在5min内向混合物中滴加70ml的MTBE,形成悬浮液。将混合物冷却至20℃过夜。然后将其冷却至0℃并搅拌2h。过滤出沉淀,并用10ml的冷MTBE洗涤两次。将结晶产物在50℃和<100mbar下在干燥箱中干燥至少48h。
产率:8.6g(66.6%,纯度:94.7面积%HPLC)。
HPLC(方法B):Rt=3.07min。
MS(ESI pos):m/z=471(M+H)+
1H NMR(400MHz,DMSO-d6):δ[ppm]=1.63(s,6H),2.90(s,3H),3.85(t,2H),4.86(t,2H),5.97(s,1H),7.59(s,1H),8.16(d,1H),8.37(t,1H),8.41-8.48(m,2H),8.74(s,1H),12.37(s,1H)。
工业规模的批料:
按照如变化方案#2所述的方法,以起始材料(V)为3.396kg和1.699kg的规模制备的批料:
表7:由化合物(V)合成的化合物(I)的产率
N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2H-吲唑-5-基}-6-(三氟甲
基)吡啶-2-甲酰胺(I)的多晶型物的制备
N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺(I)的B型多晶型物的制备
当在以下合成方案中使用术语“室温”时,意指约20至25℃的温度。
实施例0
为制备cGMP-级的材料,并且为调节用于片剂制备的结晶形式,引入了额外的纯化步骤。
将1500kg的粗N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺(I)溶于45kg的丙酮中,并进行澄清过滤(滤筒:3.0μm→GMP-过滤)。将滤液浓缩,并将溶剂交换为乙醇。因此,在蒸馏的过程中同时加入乙醇,直至达到77℃的内部温度。将溶液浓缩至相对于乙醇起始体积的6-7体积。将混合物冷却至20℃,并在该温度下搅拌12h。然后冷却至0℃,并另外搅拌3h。过滤出产物,并用1kg的冷乙醇洗涤两次。将产物在60℃下的干燥箱中真空(<100mbar)干燥。
产率:1370g(91.33%)。类似于所述方法,以工业规模获得三批批料,参见表7。
表8:由粗产物(I)通过上述纯化获得的纯化合物(I)的产率
表9:合并的如表8中所示的三批批料的分析数据
*方法B:**GC-HS
实施例1
N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺(I)的A型多晶型物的制备
A)在回流下将400mg的N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺溶于40ml的THF中。过滤溶液。通过在室温下或在冰箱中或在冷柜中储存将澄清溶液蒸发至干燥。
B)在回流下将400mg的N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺溶于40ml的丙酮中。过滤溶液。通过在室温下或在冰箱中储存将澄清溶液蒸发至干燥。
C)在回流下将400mg的N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺溶于40mL的丙酮中。向溶液中加入20ml的水。通过在室温下储存将澄清溶液蒸发至干燥。
实施例2
N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺的B型多晶型物的制备
A)在回流下将400mg的N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺溶于40ml的乙腈中。过滤溶液,并通过在室温下储存将澄清溶液蒸发至干燥。
B)在回流下将400mg的N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺溶于40ml的丙酮中。过滤溶液,并通过在冷柜中储存将澄清溶液蒸发至干燥。
C)在回流下将400mg的N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺溶于40ml的四氢呋喃中。向溶液中加入20ml的正庚烷,且之后通过在室温下储存将其蒸发至干燥。
实施例3
N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺的假多晶型物(1,7-水合物)的制备
将100mg的N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺悬浮于1ml的乙醇/水1∶1的混合物中,并在室温下搅拌2周。过滤出固体,并通过在室温下储存干燥。
在表2和图1、2和3中给出了式(I)化合物的A型多晶型物、B型多晶型物和1,7-水合物的XRPD数据。
X-射线粉末衍射;测量条件:
实施例4
含有N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺的A型多晶型物或B型多晶型物或假多晶型物(1,7-水合物)中的一种的药物组合物
通过混合微粒化形式的式(I)化合物、十二烷基硫酸钠(sodium laurilsulfate)、羟丙甲纤维素3cP和大量的纯水来制备造粒液体。将甘露醇、微晶纤维素和交联羧甲基纤维素钠混合。用造粒液体将该混合物在流化床造粒机中造粒。将颗粒干燥并过筛。
将颗粒与过筛的硬脂酸镁在混合器中混合,形成即压型混合物。将即压型混合物压制成片剂。测试未包衣片剂的质量、厚度、抗破碎性、崩解性和易碎性的均匀性。将羟丙甲纤维素5cP、聚乙二醇(macrogol)3350、滑石、二氧化钛和氧化铁红与大量的纯水结合以形成均匀的包衣悬浮液,在合适的包衣装置(例如穿孔鼓式涂布机)中将其喷涂到片剂上。
表10:片剂的组成
按照在实施例4中给出的方案制备分别含有15和120mg的N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺的B型多晶型物的片剂。
含有N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺的A型多晶型物或B型多晶型物或假多晶型物(1,7-水合物)中的一种的药物组合物的稳定性分析
将含有15mg或120mg的N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺的B型多晶型物(药物)的包衣片剂包装在带有防儿童的白色聚丙烯/聚乙烯螺帽盖的HDPE(高密度聚乙烯)瓶中。该包装结构提供了足够的保护,避免光照和湿度损坏。
稳定性研究通过定期测试稳定性指示参数(药物的外观、溶出度(dissolution)、降解产物和含量)而进行,以确定含有15mg或120mg的药物的包衣片剂在建议的研究期内的稳定性。
将包装在HDPE瓶内的包衣片剂(15mg或120mg)的样品储存在25℃/60%相对湿度、30℃/75%相对湿度和40℃/75%相对湿度以及2-8℃的条件下。定期进行稳定性研究实验。
含有15mg或120mg的N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺的B型多晶型物(药物)的包衣片剂在所有的研究条件下都是稳定的。在该储存期间,未观察到降解产物增加,且未观察到药物含量减少。
Claims (6)
2.一种药物组合物,其包含权利要求1所定义的式(I)化合物的结晶形式,和其他药学上可接受的赋形剂,其中所述式(I)化合物的结晶形式大于85重量%,基于存在于组合物中的式(I)化合物的所有形式的总量计。
3.根据权利要求2所述的药物组合物,其包含大于90重量%的权利要求1所定义的式(I)化合物的结晶形式,基于存在于组合物中的式(I)化合物的所有形式的总量计。
4.如权利要求1所定义的式(I)化合物的结晶形式用于制备用于治疗或预防以下疾病的药物组合物的用途:肿瘤疾病、皮肤病、妇科疾病、心血管疾病、肺部疾病、眼科疾病、神经障碍、代谢紊乱、肝脏疾病、炎症性疾病、自身免疫疾病和疼痛。
5.如权利要求1所定义的式(I)化合物的结晶形式用于制备用于治疗或预防以下疾病的药物组合物的用途:淋巴瘤、黄斑变性、银屑病、红斑狼疮、多发性硬化症、COPD、痛风、NASH、肝纤维化、胰岛素抵抗、代谢综合症、脊柱关节炎和类风湿性关节炎、子宫内膜异位和子宫内膜异位相关的疼痛和其他与子宫内膜异位关联的症状,选自痛经、交媾困难、排尿困难和大便困难。
6.如权利要求1所定义的式(I)化合物的结晶形式用于制备稳定的药物组合物的用途。
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WO2015091426A1 (de) * | 2013-12-19 | 2015-06-25 | Bayer Pharma Aktiengesellschaft | Neue indazolcarboxamide, verfahren zu ihrer herstellung, pharmazeutische präparate die diese enthalten, sowie deren verwendung zur herstellung von arzneimitteln |
WO2015104662A1 (en) * | 2014-01-10 | 2015-07-16 | Aurigene Discovery Technologies Limited | Indazole compounds as irak4 inhibitors |
TW201629037A (zh) * | 2014-11-26 | 2016-08-16 | 拜耳製藥公司 | 新穎經取代吲唑、其製法、包含其之醫藥製劑及其製備藥劑之用途 |
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