CN112119060A - 作为RORγ调节剂的三环砜化合物 - Google Patents
作为RORγ调节剂的三环砜化合物 Download PDFInfo
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- CN112119060A CN112119060A CN201980032870.8A CN201980032870A CN112119060A CN 112119060 A CN112119060 A CN 112119060A CN 201980032870 A CN201980032870 A CN 201980032870A CN 112119060 A CN112119060 A CN 112119060A
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
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Abstract
本申请描述了式(I)或其立体异构体、药学上可接受的盐、溶剂合物或前药的RORγ调节剂。还提供了包含该调节剂的药物组合物。本发明的化合物可以用于调节细胞中RORγ活性的方法和用于治疗患有疾病或障碍的受试者的方法中是有用的,其中该受试者可从RORγ活性例如自身免疫障碍和/或炎性障碍的调节中获得治疗益处。
Description
相关申请的交叉引用
本申请要求于2018年5月17日提交的美国临时申请号62/672802的权益,将其公开内容通过引用以其全文并入本文。
技术领域
本发明涉及类视黄醇相关的孤儿受体RORγ的调节剂和使用所述调节剂的方法。本文所述的化合物可特别用于治疗人和动物中的多种疾病和障碍。示例性障碍包括但不限于银屑病、类风湿性关节炎、炎性肠病、克罗恩病、溃疡性结肠炎、急性移植物抗宿主病、银屑病性关节炎、强直性脊柱炎、系统性红斑狼疮(SLE)、狼疮性肾炎(LN)、肖格伦综合征(syndrome)和多发性硬化。
背景技术
类视黄醇相关的孤儿受体RORα、RORβ、和RORγ在许多生物学过程中起重要作用,这些生物学过程包括器官发育、免疫、代谢和昼夜节律。参见例如Dussault等人在Mech.Dev.(1998)中第70卷,147-153;Andre等人在EMBO J.(1998)中第17卷,3867-3877;Sun等人在Science(2000)中第288卷,2369-2373;和Jetten在Nucl.Recept.Signal.(2009)中第7卷,1-32。
RORγ在若干组织中表达,这些组织包括胸腺、肾、肝和肌肉。已经确定了RORγ的两种同种型:RORγ1和RORγ2(也分别称为RORγ和RORγt)。参见例如Hirose等人在Biochem.Biophys.Res.Commun.(1994)中第205卷,1976-1983;Oritz等人在Mol.Endocrinol.(1995)中第9卷,1679-1691;和He等人在Immunity(1998)中第9卷,797-806。RORγt的表达局限于淋巴细胞类型,包括CD4+CD8+胸腺细胞、产生IL-17的T辅助细胞(Th17)、淋巴组织诱导细胞(LTi)、和γδ细胞。RORγt对于淋巴结和派尔集合淋巴结的发育以及对于Th17、γδ和LTi细胞的正常分化至关重要。参见例如Sun等人在Science(2000)中第288卷,2369-2373;Ivanov等人在Cell(2006)中第126卷,1121-1133;Eberl等人在Nat.Immunol.(2004)中第5卷,64-73;Ivanov等人在Semin.Immunol.(2007)中第19卷,409-417;和Cua和Tato在Nat.Rev.Immunol.(2010)中第10卷,479-489。
由Th17细胞和其他RORγ+淋巴细胞产生的促炎细胞因子诸如IL-17A(也称为IL-17)、IL-17F、和IL-22激活并且指导对细胞外病原体的免疫应答。参见例如Ivanov等人在Semin.Immunol.(2007)中第19卷:409-417;和Marks和Craft在Semin.Immunol.(2009)中第21卷,164-171。RORγ直接调节IL-17转录,并且小鼠中RORγ的破坏会减弱IL-17的产生。参见例如Ivanov等人在Cell(2006)中第126卷,1121-1133。
IL-17产生失调涉及若干种人自身免疫和炎性疾病,包括多发性硬化、类风湿性关节炎、银屑病、炎性肠病(IBD)、系统性红斑狼疮(SLE)和狼疮性肾炎(LN)、肖格伦综合征、和哮喘。参见例如Lock等人在Nat.Med.(2002)中第8卷,500-508;Tzartos等人在Am.J.Pathol.(2008)中第172卷,146-155;Kotake等人在J.Clin.Invest.(1999)中第103卷,1345-1352;Kirkham等人在Arthritis Rheum.(2006)中第54卷,1122-1131;Lowes等人在J.Invest.Dermatol.(2008)中第128卷,1207-1211;Leonardi等人在N.Engl.J.Med.(2012)中第366卷,1190-1199;Fujino等人在Gut(2003)中第52卷,65-70;Seiderer等人在Inflamm.Bowel Dis.(2008)中第14卷,437-445;Wong等人在Clin.Exp.Immunol.(2001)中第125卷,177-183;Duo Li等人在Autoimmunity(2015)中第48卷,353–361;M.Tahara等人在Clinical and Experimental Immunology(2016)中第187卷,213–224;和Agache等人在Respir.Med.(2010)中104:1131-1137。在这些疾病的鼠模型中,通过中和抗体或IL-17或IL-17受体的遗传破坏来抑制IL-17功能可减轻疾病进程或临床症状。参见例如Hu等人在Ann.N.Y.Acad.Sci.(2011)中第1217卷,60-76。
小鼠中RORγ的破坏还会减弱自身免疫和炎症的动物模型中的疾病进展或严重性,这些自身免疫和炎症包括实验性自身免疫性脑脊髓炎(EAE)、咪喹莫特诱导的银屑病、结肠炎、系统性红斑狼疮(SLE)和狼疮性肾炎(LN)、肖格伦综合征、和过敏性气道疾病。参见例如Ivanov等人在Cell(2006)中第126卷,1121-1133;Yang等人在Immunity(2008)中第28卷,29-39;Pantelyushin等人在J.Clin.Invest.(2012)中第122卷,2252-2256;Leppkes等人在Gastroenterology(2009)中第136卷,257-267;A.Gaweco等人在Annals of theRheumatic Diseases(2015)中,74,120;M.Tahara等人在Clinical and ExperimentalImmunology(2016)中第187卷,213–224;和Tilley等人在J.Immunol.(2007)中第178卷,3208-3218。
出于所有目的,将此背景技术部分中的各参考文献通过引用以其全文并入本文。
存在治疗多种炎性疾病和自身免疫疾病的治疗剂,但是在这些治疗领域中仍然存在显著的未满足的医学需求。考虑到IL-17在人类疾病中的作用以及IL-17和RORγ作为鼠疾病模型中靶标的验证,预期能够调节RORγt活性的化合物以在治疗多种免疫障碍和炎性障碍中提供治疗益处。
已经发现,基于体外实验,本发明的化合物能够调节RORγt活性而不会形成GSH加合物。由于代谢物的潜在形成,GSH加合物的形成可能不是所需的特征。
发明内容
在一方面,本发明包括式(I)的化合物,
或其药学上可接受的盐。本发明包括其立体异构体、溶剂合物、或前药。
在一方面,本发明包括式(I)的化合物,
在另一方面,本发明包括药物组合物,其包含如本文所述的根据式(I)的化合物、立体异构形式或药学上可接受的盐,以及药学上可接受的载体、赋形剂或稀释剂。
在另一方面,本发明包括用于调节细胞中RORγ的方法,其包括使该细胞与有效量的如本文所述的式(I)的化合物、立体异构形式或药学上可接受的盐接触。此方面可以在体外或体内进行。
在另一方面,本发明包括用于治疗患有由RORγ调节的疾病或障碍的受试者的方法,该方法包括向该受试者给予治疗有效量的如本文所述的式(I)的化合物、或立体异构形式、药学上可接受的盐或药物组合物。
在另一方面,本发明包括一种用于治疗受试者中的疾病或障碍的方法,该疾病或障碍选自炎性疾病或障碍、自身免疫疾病或障碍、过敏性疾病或障碍、代谢疾病或障碍、和/或癌症,该方法包括向该受试者给予治疗有效量的如本文所述的根据式(I)的化合物,或立体异构形式、药学上可接受的盐或药物组合物。
具体实施方式
在一方面,本发明包括式(I)的化合物,
或其立体异构体或药学上可接受的盐。
在一个实施方案中,本发明提供了一种药物组合物,其包含药学上可接受的载体和治疗有效量的本发明化合物或其立体异构体、药学上可接受的盐或溶剂合物。
在另一个实施方案中,本发明提供了一种用于制造本发明化合物或其立体异构体、药学上可接受的盐或溶剂合物的方法。
在另一个实施方案中,本发明提供了一种本发明化合物,其用于疗法。
在另一个实施方案中,本发明提供了一种本发明化合物和一种或多种另外的治疗剂的组合制剂,其用于在疗法中同时、分开或顺序使用。
在另一个实施方案中,本发明提供了一种本发明化合物,其用于治疗疾病(或治疗疾病的方法),其中炎症是包括但不限于诸如银屑病、类风湿性关节炎、炎性肠病、克罗恩病、溃疡性结肠炎、急性移植物抗宿主病、银屑病性关节炎、强直性脊柱炎和多发性硬化的疾病的一部分。
以下是本说明书和所附权利要求中使用的术语的定义。除非另有指出,否则本文提供的组或术语的初始定义适用于在整个说明书和权利要求中的所述组或术语,单独地或作为另一个组的一部分。
式I的化合物可以游离形式(没有电离)存在或者可以形成盐,这些盐也在本发明的范围内。除非另有说明,否则提及本发明化合物应理解为包括提及游离形式及其盐。术语“盐”表示与无机和/或有机碱形成的碱式盐。药学上可接受的(即,无毒的生理学上可接受的)盐是优选的,例如像其中的阳离子对盐的毒性或生物活性没有显著贡献的可接受的金属盐和胺盐。然而,其他盐可以例如用于可在制备期间采用的分离或纯化步骤中,并且因此预期在本发明的范围内。式I的化合物的盐可以例如通过使式I的化合物与一定量(诸如当量)的碱在介质(诸如盐在其中沉淀的介质)中或在水性介质中反应,随后冻干而形成。
示例性碱式盐包括铵盐,碱金属盐,诸如钠盐、锂盐和钾盐;碱土金属盐,诸如钙盐和镁盐;钡盐、锌盐和铝盐;与有机碱(例如有机胺)诸如三烷基胺(诸如三乙胺)、普鲁卡因、二苄胺、N-苄基-β-苯乙胺、1-二苯羟甲胺、N,N′-二苄基乙二胺、脱氢枞胺、N-乙基哌啶、苄胺、二环己胺或类似的药学上可接受的胺的盐以及与氨基酸诸如精氨酸、赖氨酸等的盐。
本文采用短语“药学上可接受的”是指在合理医学判断范围内适合于与人和动物组织接触使用而没有过多的毒性、刺激、过敏反应或其他问题或并发症,与合理的效益/风险比相称的那些化合物、材料、组合物和/或剂型。
如本文所用,“药学上可接受的盐”是指所公开化合物的衍生物,其中母体化合物通过制备其碱盐而被修饰。药学上可接受的盐的例子包括但不限于羧酸的碱性盐或有机盐。药学上可接受的盐包括例如由无毒的无机碱或有机碱形成的母体化合物的常规无毒盐或季铵盐。
本发明的药学上可接受的盐可以通过常规的化学方法由含有酸性部分的母体化合物合成。通常,此类盐可以通过使得游离酸形式的化合物与化学计算量的适当的碱在水中或在有机溶剂中或者在这两者的混合物(通常优选非水性介质,如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈)中进行反应而制备。合适的盐的列表发现于Remington's PharmaceuticalSciences,第18版,Mack Publishing Company,Easton,PA(1990),将该公开通过引用特此并入。
还考虑了本发明化合物的前药和溶剂合物。术语“前药”表示这样一种化合物,该化合物在给予受试者后经受通过代谢或化学过程的化学转化,以产生式I的化合物和/或其盐和/或溶剂合物。将在体内转化以提供生物活性剂的任何化合物(即,式I)的化合物)是在本发明的范围和精神内的前药。例如,式I化合物的羧酸基团可以形成生理学上可水解的酯,其通过在体内水解而充当前药,从而产生式I的化合物本身。这些前药优选口服给予,因为在许多情况下水解主要在消化酶的影响下发生。肠胃外给药可以在酯本身具有活性的情况下使用,或者在血液中发生水解的那些情况下使用。式I的化合物的生理学上可水解的酯的例子包括C1-6烷基苄基、4-甲氧基苄基、茚满基、邻苯二甲酰基、甲氧基甲基、C1-6烷酰基氧基-C1-6烷基,例如,乙酰氧基甲基、新戊酰氧基甲基或丙酰氧基甲基、C1-6烷氧基羰基氧基-C1-6烷基,例如,甲氧基羰基氧基甲基或乙氧基羰基氧基甲基、甘氨酰基氧基甲基、苯基甘氨酰基氧基甲基、(5-甲基-2-氧代-1,3-二氧戊环烯-4-基)-甲基以及例如在青霉素和头孢菌素领域中使用的其他熟知的生理学上可水解的酯。此类酯可通过本领域已知的常规技术制备。
各种形式的前药在本领域中是熟知的。有关此类前药衍生物的例子,参见:
a)Bundgaard,H.编,Design of Prodrugs,Elsevier(1985),和Widder,K.等人编,Methods in Enzymology,112:309-396,Academic Press(1985);
b)Bundgaard,H.,第5章,“Design and Application of Prodrugs”,Krosgaard-Larsen,P.等人编,A Textbook of Drug Design and Development,第113-191页,HarwoodAcademic Publishers(1991);以及
c)Bundgaard,H.,Adv.Drug Deliv.Rev.,8:1-38(1992),
将其中每个通过引用并入本文。
本发明的另一方面是一种药物组合物,其包含如本文所述的化合物、或药用盐、或溶剂合物。本文所述的药物组合物总体上包含本文所述化合物和药学上可接受的载体、稀释剂或赋形剂的组合。此类组合物基本上不含非药学上可接受的组分,即,含有低于在提交本申请时美国法规要求所允许的量的非药学上可接受的组分。在此方面的一些实施方案中,如果该化合物溶解或悬浮于水中,则该组合物还任选地包含另外的药学上可接受的载体、稀释剂或赋形剂。在其他实施方案中,本文描述的药物组合物是固体药物组合物(例如,片剂、胶囊等)。
这些组合物可以按制药领域中熟知的方式制备,并且可以通过多种途径给予,取决于希望局部治疗还是全身性治疗并且取决于有待治疗的部位。给予可以是局部的(包括眼的和至粘膜,包括鼻内、阴道和直肠递送)、肺部的(例如,通过吸入或吹入粉末或气溶胶,包括通过喷雾器;气管内、鼻内、表皮和经皮肤)、眼部的、口腔的或肠胃外的。用于眼部递送的方法可以包括局部给予(滴眼剂),结膜下、眼周或玻璃体内注射或者通过用手术方法放置在结膜囊中的气囊式导管或眼科插入件引入。肠胃外给予包括静脉内、动脉内、皮下、腹膜内或肌内注射或输注;或颅内(例如,鞘内或脑室内)给予。肠胃外给予可以是单次推注剂量的形式的,或者可以例如通过连续灌注泵。用于局部给予的药物组合物和配制品可以包括透皮贴剂、软膏、洗剂、乳膏、凝胶、滴剂、栓剂、喷雾剂、液体以及粉剂。常规的药物载体,水性、粉末或油性基质,增稠剂等可以是必要的或希望的。
此外,药物组合物可以含有与一种或多种药学上可接受的载体组合的上文所述的化合物作为活性成分。在制造本文所述的组合物中,典型地将活性成分与赋形剂混合,用赋形剂稀释或封装在这样一种载体内,该载体呈例如胶囊、小药囊(sachet)、纸或其他容器的形式。当该赋形剂用作稀释剂时,它可以是固体的、半固体的或液体的材料,该材料可充当用于活性成分的媒介物、载体或介质。因此,这些组合物可以呈片剂、丸剂、粉剂、锭剂、小药囊、扁囊剂、酏剂、悬浮液、乳液、溶液、糖浆、气溶胶(作为固体或在液体介质中)、含有例如按重量计高达10%的活性化合物的软膏、软和硬明胶胶囊、栓剂、无菌可注射溶液、以及无菌包装粉剂的形式。
在制备配制品中,在与其他成分组合之前,可以将活性化合物研磨以便提供适当的粒径。如果活性化合物是基本上不可溶的,可以将它研磨至小于200目的粒径。如果活性化合物是基本上水可溶的,可以通过研磨调整粒径,以便在配制品中提供基本上均匀的分布,例如约40目。
合适的赋形剂的一些例子包括乳糖、右旋糖、蔗糖、山梨糖醇、甘露醇、淀粉、阿拉伯胶、磷酸钙、海藻酸盐、黄芪胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、以及甲基纤维素。配制品可另外包含:润滑剂,诸如滑石、硬脂酸镁和矿物油;润湿剂;乳化剂和悬浮剂;防腐剂,诸如甲基-和丙基羟基-苯甲酸酯;甜味剂;以及调味剂。可以通过采用应用本领域中已知的程序来配制本文所述的组合物,以便在给予受试者之后提供活性成分的迅速、持续或延迟释放。
活性化合物可以是在宽剂量范围内有效的并且通常以药学上有效的量给予。然而应理解,实际给予的化合物的量通常将由医师根据相关情况(包括有待治疗的病症,所选择的给予途径,所给予的实际化合物,个体受试者的年龄、体重和应答,受试者的症状的严重性等)来确定。
对于制备固体组合物(诸如片剂)而言,将主要的活性成分与药物赋形剂混合,以形成包含本文所述的化合物的均匀混合物的固体预配制组合物。当提及这些预配制组合物为均匀的时,活性成分典型地均匀分散于整个组合物中,使得该组合物可以容易地被细分成同样有效的单位剂型,诸如片剂、丸剂和胶囊。然后此固体预配制品被细分成上述类型的单位剂型,其含有例如从0.1mg至约500mg的本文所述化合物的活性成分。
可以将片剂或丸剂包衣或者以其他方式被混合,以得到提供延长作用优势的剂型。例如,片剂或丸剂可以包含内剂量组分和外剂量组分,后者呈在前者上的包膜的形式。这两种组分可以被肠溶层分开,该肠溶层用来抵抗在胃中的崩解并且允许内组分完整地传递到十二指肠中或被延迟释放。多种材料可以用于此类肠溶层或包衣,此类材料包括许多聚合酸以及聚合酸与诸如虫胶、鲸蜡醇和乙酸纤维素的材料的混合物。
这些化合物和组合物可掺入其中以用于口服给予或通过注射给予的液体形式包括水溶液、适当调味的糖浆、水性或油悬浮液、以及用食用油(诸如棉籽油、芝麻油、椰子油或花生油)调味的乳液,以及酏剂和类似的药物媒介物。
用于吸入或吹入的组合物包括在药学上可接受的水性或有机溶剂或其混合物中的溶液和悬浮液,以及粉剂。这些液体或固体组合物可含有如上文所述的合适的药学上可接受的赋形剂。在一些实施方案中,这些组合物通过口或鼻的呼吸途径给予,以得到局部或全身性作用。可以通过使用惰性气体来雾化组合物。雾化溶液可以从雾化装置直接呼吸,或者可以将该雾化装置附接于面罩帷罩(face masks tent)、或者间歇性正压呼吸机。溶液、悬浮液或粉末组合物可以从以适当的方式从递送配制品的装置口服或经鼻给予。
给予受试者的化合物或组合物的量将取决于所给予的药物、给予的目的(诸如预防或疗法)、受试者的状态、给予方式等而变化。在治疗性应用中,可以足以治愈或至少部分地抑制疾病的症状及其并发症的量将组合物给予已患有该疾病的受试者。有效剂量将取决于正在治疗的疾病病状并且通过主治临床医师根据诸如疾病的严重性,受试者的年龄、体重和一般状况等因素的判断。
给予患者的组合物可以呈上述药物组合物的形式。这些组合物可以通过常规灭菌技术灭菌,或者可以是经无菌过滤的。水溶液可以按原样包装使用,或者被冻干,在给予前将该冻干制剂与无菌水性载体组合。化合物制剂的pH典型地将在3与11之间、更优选从5至9、并且最优选从7至8。应理解,某些前述赋形剂、载体或稳定剂的使用将导致形成药学上可接受的盐。
这些化合物的治疗剂量可以根据例如进行治疗的具体用途、化合物的给予方式、受试者的健康和状况、以及处方医师的判断而变化。本文所述的化合物在药物组合物中的比例或浓度可以取决于许多因素(包括剂量、化学特征(例如,疏水性)和给予途径)而变化。例如,本文所述的化合物可以用于肠胃外给予的水性生理缓冲溶液来提供,该溶液含有约0.1%至约10%w/v的该化合物。一些典型的剂量范围是从约1μg/kg至约1g/kg体重/天。在一些实施方案中,剂量范围是从约0.01mg/kg至约100mg/kg体重/天。剂量很可能取决于诸如疾病或障碍的类型和进展程度、具体受试者的总体健康状况、化合物的生物学功效、赋形剂的配方、及其给予途径的变量。可由来源于体外或动物模型测试系统的剂量-反应曲线外推出有效剂量。
本发明化合物可用于预防、诊断、和治疗人或动物中的各种医学障碍。该化合物用于抑制或减少与RORγ受体相关的一种或多种活性(相对于在不存在相同化合物的情况下的RORγ受体)。因此,在本发明的一个方面,一种用于治疗受试者中的选自自身免疫疾病或障碍、哮喘、过敏性疾病或障碍、代谢疾病或障碍和癌症中的疾病或障碍的方法,包括向该受试者给予治疗有效量的如本文所述的式(I)的化合物、或药学上可接受的盐、溶剂合物或药物组合物。参见例如L.A.Solt等人,“Action of RORs and their ligands in(patho)physiology,”Trends Endocrinol.Metab.2012,23(12):619-627;M.S.Maddur等人,“Th17cells:biology,pathogenesis of autoimmune and inflammatory diseases,andtherapeutic strategies,”Am.J.Pathol.2012 Jul;181(1):8-18;and A.M.Jetten,“Retinoid-related orphan receptors(RORs):critical roles in development,immunity,circadian rhythm,and cellular metabolism,”Nucl.Recept.Signal.2009;7:e003,将其中每个通过引用以其全文特此并入本文,以及在背景技术部分中讨论的参考文献。在某些实施方案中,该自身免疫疾病或障碍选自类风湿性关节炎、强直性脊柱炎、银屑病和银屑病性关节炎、多发性硬化、炎性肠病、肖格伦综合征和狼疮。在某些实施方案中,该过敏性疾病或障碍选自过敏性鼻炎和皮炎。在某些实施方案中,该代谢疾病或障碍选自肥胖症、肥胖症诱导的胰岛素抵抗和II型糖尿病。
在某些实施方案中,该疾病或障碍是类风湿性关节炎。
在其他实施方案中,该疾病或障碍是多发性硬化。
在其他实施方案中,该疾病或障碍是强直性脊柱炎。
在其他实施方案中,该疾病或障碍是炎性肠病。
在其他实施方案中,该疾病或障碍是狼疮。
在其他实施方案中,该疾病或障碍是肖格伦综合征。
在其他实施方案中,该疾病或障碍是银屑病。
在其他实施方案中,该疾病或障碍是银屑病性关节炎。
在其他实施方案中,该疾病或障碍是移植物抗宿主病(GVHD)。
在其他实施方案中,该疾病或障碍是自身免疫性葡萄膜炎。
在其他实施方案中,该疾病或障碍是肥胖症和/或胰岛素抵抗。
在其他实施方案中,该疾病或障碍是黑素瘤。
在某些方面,通过使用本发明公开的化合物诊断、治疗或预防的医学障碍可以是例如自身免疫障碍。在其他实施方案中,通过使用本发明公开的化合物诊断、治疗或预防的障碍可以是炎性障碍。例如,在某些实施方案中,该障碍选自关节炎、糖尿病、多发性硬化、葡萄膜炎、类风湿性关节炎、银屑病、哮喘、支气管炎、过敏性鼻炎、慢性阻塞性肺病、动脉粥样硬化、幽门螺杆菌感染和炎性肠病。在其他实施方案中,该障碍选自克罗恩病、溃疡性结肠炎、口炎性过敏和食物过敏。在其他实施方案中,该障碍是自身免疫性脑脊髓炎、咪喹莫特诱导的银屑病、结肠炎或过敏性气道疾病。
如文本所用,短语“治疗有效量”是指引发研究人员、兽医、医生或其他临床医师正在组织、系统、动物、个体或人中寻求的生物学或医学反应的活性化合物或药剂的量。
在某些实施方案中,治疗有效量可以是这样的量,该量适合于(1)预防疾病;例如,对可能易患疾病、病症或障碍但尚未经历或显示该疾病的病理学或症状学的个体中的该疾病、病症或障碍进行预防;(2)抑制疾病;例如,抑制正在经历或显示疾病、病症或障碍的病理学或症状学的个体中的该疾病、病症或障碍;或者(3)减轻该疾病;例如,减轻正在经历或显示疾病、病症或障碍的病理学或症状学的个体中的该疾病、病症或障碍(即,逆转病理学和/或症状学),例如降低疾病的严重性。
如本文所用,术语“治疗”意指(i)减轻所引用的疾病状态,例如,减轻正在经历或显示疾病、病症或障碍的病理学或症状学的个体中的该疾病、病症或障碍(即,逆转或改善病理学和/或症状学),例如降低疾病的严重性;(ii)引发研究人员、兽医、医生或其他临床医师正在组织、系统、动物、个体或人中寻求的生物学或医学反应;或(iii)抑制所引用的疾病状态;例如,抑制正在经历或显示疾病、病症或障碍的病理学或症状学的个体中的该疾病、病症或障碍。
制备方法
本发明化合物可通过有机化学领域技术人员可用的许多方法合成。制备方法的一个实例显示在以下实施例中。制备本发明化合物的不同方法将对于本领域技术人员来说是清楚的。通常,合成领域的化学技术人员可以设计出可替代的制备方法,这些制备方法基于一种或多种考量可能是期望的,所述考量例如为较短的反应时间、较便宜的起始原料、易于操作或分离、改善的收率、对催化的适用性、避免有毒试剂、专门仪器的可及性、减少数目的线性步骤等。
纯手性化合物或中间体的制备可以通过本领域技术人员已知的技术进行。例如,可以通过手性相制备型色谱分离外消旋产物或非对映异构体来制备纯手性化合物。可替代地,可通过已知的方法制备化合物,以给出对映异构体或非对映异构体富集的产物。用于制备本发明化合物的反应和技术在适合于所用试剂和材料的溶剂中进行,并且适用于所进行的转化。所有的反应条件,包括溶剂的选择、反应气氛、反应温度、实验的持续时间和后处理程序,被选择为对于所述反应为标准的条件,本领域技术人员应该容易认识到这一点。有机合成领域的技术人员应理解,分子各部分上存在的官能团必须与所提出的试剂和反应相容。对与反应条件相容的取代基的此类限制将对于本领域技术人员来说是显而易见的,并且当存在不相容的取代基时需要替代方案。有时,这将需要判断以修改合成步骤的顺序或选择一种而不是另一种特定的过程方案,以便获得所希望的本发明的化合物。还将认识到,在此领域中任何合成途径的规划中的另一个主要考虑因素是明智地选择用于保护本发明中所述化合物中存在的反应性官能团的保护基团。向训练有素的从业者描述的权威性报道是Wuts和Greene,Greene’s Protective Groups in Organic Synthesis,FourthEdition,Wiley and Sons(2007)。
实施例
以下实施例说明了本发明的具体和优选实施方案,但不限制本发明的范围。以下描述了制备本发明化合物的合成方案。该方案是说明性的且不意在限制本领域技术人员可用于制备本申请公开的化合物的可用技术。除非另有指明,否则化学缩写和符号以及科学缩写和符号具有其通常和惯常的含义。以下定义了实施例和本申请中其他地方使用的其他缩写。
通常使用自动色谱装置(Teledyne Isco)用预填充的硅胶小柱用指定的溶剂或溶剂混合物洗脱进行柱色谱法。使用适于被分离材料的量的尺寸的反相柱进行分析型高效液相色谱(HPLC),其中通常用在水中递增浓度的乙腈(还含有0.05%三氟乙酸)的梯度以适合于柱尺寸和待实现的分离的洗脱速率洗脱。使用指定的条件进行对映异构体或非对映异构体的手性超临界流体色谱(SFC)分离。通过使用电喷雾电离的液相色谱质谱(LCMS)获得质谱数据。
化学名称使用ChemBioDraw Ultra,版本14.0.0.126(PerkinElmer Inc.)确定。使用了以下缩写:
制备式I化合物(化合物1)
实施例1
(1R,3S,4R)-4-((3aR,9bR)-8-氟-7-(全氟丙烷-2-基)-9b-(苯基磺酰基)-2,3,3a,4,5,9b-六氢-1H-苯并[e]吲哚-3-羰基)-3-甲基环己烷-1-甲酸
步骤1:制备2,2,2-三氟-1-((3aR,9bR)-7-(全氟丙烷-2-基)-9b-(苯基磺酰基)-1,2,3a,4,5,9b-六氢-3H-苯并[e]吲哚-3-基)乙-1-酮
向在冰水浴中冷却的(3aR,9bR)-7-(全氟丙烷-2-基)-9b-(苯基磺酰基)-2,3,3a,4,5,9b-六氢-1H-苯并[e]吲哚盐酸盐(国际专利申请WO 2016/179460,1.78g,3.44mmol)在DCM(20mL)内的溶液中加入吡啶(1.39mL,17.2mmol),然后加入2,2,2-三氟乙酸酐(0.717mL,5.16mmol)。将混合物在室温搅拌1h。将反应混合物用DCM(40mL)稀释,依次用0.2NHCl(2x50mL)、水(2x40mL)、和盐水(50mL)洗涤,干燥并浓缩,得到作为黄色固体(1.9g,96%收率)的2,2,2-三氟-1-((3aR,9bR)-7-(全氟丙烷-2-基)-9b-(苯基磺酰基)-1,2,3a,4,5,9b-六氢-3H-苯并[e]吲哚-3-基)乙-1-酮,其无需进一步纯化即用于下一步骤。
步骤2和3:制备1-((3aR,9bR)-8-氨基-7-(全氟丙烷-2-基)-9b-(苯基磺酰基)-1,2,3a,4,5,9b-六氢-3H-苯并[e]吲哚-3-基)-2,2,2-三氟乙-1-酮
在0℃向溶解在H2SO4(95%,40mL)内的2,2,2-三氟-1-((3aR,9bR)-7-(全氟丙烷-2-基)-9b-(苯基磺酰基)-1,2,3a,4,5,9b-六氢-3H-苯并[e]吲哚-3-基)乙-1-酮(2.50g,4.33mmol)的溶液中按份加入KNO3(0.700g,6.93mmol)。将混合物缓慢升温至室温,并在室温搅拌18h。将反应混合物加入到冰水(150mL)中并用EtOAc(2x100mL)萃取。将有机层依次用水(2x80mL)和盐水(80mL)洗涤,干燥(Na2SO4)并浓缩,得到粗产物。加入乙醇(20mL),在搅拌1h之后,通过过滤收集棕色固体,其无需进一步纯化即可使用。
将以上固体与乙醇(30mL)和乙酸(20mL)混合,加入铁粉(1.21g,21.7mmol),将混合物在室温搅拌18h。将反应混合物过滤通过硅藻土短柱,将滤饼用EtOAc(2x20mL)洗涤。将滤液减压浓缩,用水(100mL)和EtOAc(100mL)稀释,用固体Na2CO3制成碱性。将有机层分离,将水层用EtOAc(50mL)萃取,将合并的有机层干燥(Na2SO4)并浓缩。将残余物通过在硅胶(80g)上的柱色谱纯化,用DCM洗脱,得到1-((3aR,9bR)-8-氨基-7-(全氟丙烷-2-基)-9b-(苯基磺酰基)-1,2,3a,4,5,9b-六氢-3H-苯并[e]吲哚-3-基)-2,2,2-三氟乙-1-酮(1.70g,66%收率)。1H NMR(500MHz,氯仿-d)δ7.57(tt,J=7.3,1.4Hz,1H),7.41-7.31(m,4H),7.20(s,1H),6.79(br s,1H),4.77(dd,J=11.9,5.0Hz,1H),4.42(br s,2H),4.22-4.14(m,1H),3.97-3.89(m,1H),3.61-3.53(m,1H),2.62(dt,J=14.7,9.8Hz,1H),2.55-2.47(m,1H),2.33(dt,J=16.0,3.1Hz,1H),1.68-1.60(m,1H),1.28-1.17(m,1H)。LCMS m/z(M+H)+593.2。
步骤4和5:制备(3aR,9bR)-8-氟-7-(全氟丙烷-2-基)-9b-(苯基磺酰基)-2,3,3a,4,5,9b-六氢-1H-苯并[e]吲哚
在0℃向1-((3aR,9bR)-8-氨基-7-(全氟丙烷-2-基)-9b-(苯基磺酰基)-1,2,3a,4,5,9b-六氢-3H-苯并[e]吲哚-3-基)-2,2,2-三氟乙-1-酮(2.00g,3.38mmol)在DCM(40mL)内的悬浮液中加入LiBF4(0.949g,10.1mmol)和BF4NO(0.591g,5.06mmol)。在该温度搅拌1.5h之后,将混合物在密封的压力烧瓶中加热至100℃并保持4.5h。在冷却至室温之后,将混合物过滤,将固体用DCM洗涤数次,将滤液和DCM洗涤液合并,真空浓缩,并通过在硅胶(40g)上的柱色谱纯化,用DCM洗脱,得到2,2,2-三氟-1-((3aR,9bR)-8-氟-7-(全氟丙烷-2-基)-9b-(苯基磺酰基)-1,2,3a,4,5,9b-六氢-3H-苯并[e]吲哚-3-基)乙-1-酮(1.30g)。
向该物质在THF(16mL)、水(4mL)和MeOH(4mL)内的溶液中加入LiOH水合物(0.916g,21.8mmol),将混合物在室温搅拌2h。将反应混合物真空浓缩,将残余物用水(30mL)和NaHCO3饱和水溶液(10mL)稀释,并用DCM(2x 60mL)萃取。将合并的有机相干燥(Na2SO4)并真空浓缩,得到(3aR,9bR)-8-氟-7-(全氟丙烷-2-基)-9b-(苯基磺酰基)-2,3,3a,4,5,9b-六氢-1H-苯并[e]吲哚(0.97g,历经两个步骤为58%,但是含有约20%的(3aR,9bR)-8-氯-7-(全氟丙烷-2-基)-9b-(苯基磺酰基)-2,3,3a,4,5,9b-六氢-1H-苯并[e]吲哚的杂质),其无需进一步纯化即可使用。
步骤6和7:制备(1R,3S,4R)-4-((3aR,9bR)-8-氟-7-(全氟丙烷-2-基)-9b-(苯基磺酰基)-2,3,3a,4,5,9b-六氢-1H-苯并[e]吲哚-3-羰基)-3-甲基环己烷-1-甲酸
在室温向(3aR,9bR)-8-氟-7-(全氟丙烷-2-基)-9b-(苯基磺酰基)-2,3,3a,4,5,9b-六氢-1H-苯并[e]吲哚(0.95g,1.90mmol)在N,N-二甲基甲酰胺(10mL)内的溶液中加入(1R,2S,4R)-4-(甲氧基羰基)-2-甲基环己烷-1-甲酸(国际专利申请WO 2018/071620,0.457g,2.28mmol)、HATU(0.940g,2.47mmol)和二异丙基乙基胺(0.997mL,5.71mmol)。将反应混合物在室温搅拌1.5h,用NH4Cl饱和水溶液(10mL)淬灭,用水(50mL)稀释,并用EtOAc(3x50mL)萃取。将合并的有机相依次用NH4Cl饱和水溶液(2x40mL)、NaHCO3饱和水溶液(50mL)、和盐水(50mL)洗涤,干燥(Na2SO4)并真空浓缩。将残余物通过在硅胶(40g)上的柱色谱纯化,用EtOAc/己烷洗脱(从0-60%的梯度历时25min),以得到(1R,3S,4R)-4-((3aR,9bR)-8-氟-7-(全氟丙烷-2-基)-9b-(苯基磺酰基)-2,3,3a,4,5,9b-六氢-1H-苯并[e]吲哚-3-羰基)-3-甲基环己烷-1-甲酸甲酯。
向以上中间体中加入THF(8mL)、水(2.5mL)、MeOH(2.5mL)和LiOH水合物(0.798g,19.0mmol),将混合物在室温搅拌2h。将反应混合物减压浓缩,用水(50mL)稀释,用1N HCl水溶液酸化至pH 1,并用EtOAc(2x50mL)萃取。将合并的有机相干燥(Na2SO4)并减压浓缩,使残余物经受SFC纯化(柱:手性IC(4.6x25cm,5微米);柱温40℃;CO2流动速率:3mL/min;助溶剂:0.1NH4OH在MeOH中,流动速率3mL/min;注射体积:10mL),得到(1R,3S,4R)-4-((3aR,9bR)-8-氟-7-(全氟丙烷-2-基)-9b-(苯基磺酰基)-2,3,3a,4,5,9b-六氢-1H-苯并[e]吲哚-3-羰基)-3-甲基环己烷-1-甲酸(730mg,58%收率,98-99%纯度)。1H NMR(500MHz,甲醇-d4)δ7.76(d,J=13.1Hz,1H),7.69-7.63(m,1H),7.48-7.21(m,5H),4.84-4.77(m,1H),4.11(s,1H),3.95-3.86(m,1H),3.62-3.49(m,1H),2.80-2.67(m,2H),2.61-2.53(m,2H),2.50-2.42(m,2H),2.09-2.01(m,1H),2.00-1.91(m,2H),1.85-1.75(m,2H),1.65-1.48(m,2H),1.35-1.27(m,1H),1.14-1.09(m,3H)。LCMS m/z(M+H)+668.3。HPLC(12min,从95:5水/MeCN到5:95水/MeCN的梯度,其中含有0.05%TFA;流动速率1mL/min)tR 10.45min,99%纯度(ACE UCore Super C18 2.5μm,3.0x125 mm),tR 9.62min,98.2%纯度(ACE UCoreSuperHexPh 2.5μm,3.0x125 mm)。化合物的绝对立体化学基于使用FLACK方法对异常色散信号的单晶X-射线分析来确定。
通用RORγGal4报告基因测定
通过在Jurkat细胞中的Gal4-荧光素酶报告基因测定中抑制发光来测量潜在配体对RORγ的反向激动剂活性。
将稳定过表达RORγ受体的Jurkat细胞(Jurkat pEx/Gal/hRORγCLBD/HYGpG5luc/blast)以10,000细胞/孔的浓度接种到384孔固体白细胞培养板(Perkin Elmer#6007899)中的含有0.1%BSA、100X HEPES(Gibco 15360-080)、100mM丙酮酸钠(Gibco11360-040)、50mg/mL潮霉素B(Invitrogen 10687-010)和10mg/mL杀稻瘟素(InvitrogenR210-01)的测定缓冲液RPMI 1640(Gibco 11875-085 1L)中。将100nL 3倍连续稀释的测试化合物(终浓度范围为从40μM至0.67nM)添加至细胞,然后将其孵育过夜。
第二天,将细胞用10μL Steady-Glo荧光素酶测定系统(Promega目录号EZ550)裂解并且立即分析。测定IC50值。IC50值被定义为将荧光素酶活性降低50%所需的测试化合物浓度,并且使用四参数逻辑斯谛方程拟合标准化数据来计算。
以下提供了在RORγGal4报告基因测定中化合物1和参考化合物A的IC50值。美国专利号9,815,859中公开并请求保护了化合物A。
实施例编号 | RORγGal4 IC<sub>50</sub>,μM |
化合物1 | 0.0036 |
化合物A | 0.0025 |
对于在大鼠或人类胞液中形成谷胱甘肽缀合物的测定
将化合物A和化合物1在10μM的浓度用在1mL磷酸钾缓冲液(50mM,pH 8.5)中的大鼠或人类肝胞液(3-5mg/mL)(雄性Sprague-Dawley大鼠肝胞液,lot BIM,n=100,购自Bioreclamation IVT,或混合性别池(mixed gender pool),lot 452115,n=150,购自Corning)中进行培养。反应(n=2,总体积=1000μL)如下引发:添加谷胱甘肽(GSH)(5mM),并在热混合器中在37℃培养。在0分钟和60分钟,收集等份(100μL)的反应混合物,通过添加两体积的乙腈来终止反应。然后使用Millipore Sigma(Massachusetts,BA)MultiscreenSolvinert滤板、通过在2000rpm离心(Eppendorf 5810 R,Hamburg,Germany)5min移除蛋白质。在96-孔板中收集滤液,将其通过高分辨Velos LTQ-Orbitrap(LC-UV/MS)系统分析。从220-600nm收集紫外吸光度。GSH缀合物鉴定基于观察到的精确质量,将MS裂解规律与在可比条件下获得的母体化合物的MS裂解规律进行比较,以计算母体化合物和GSH缀合物的峰面积。
以下显示了从两种化合物形成GSH缀合物的程度。条目表示在260-280nm相对于母体化合物计算的紫外峰面积。括号中的数据表示两个实验的平均值。
化合物结构
已发现,基于体外实验,化合物1未形成GSH加合物。
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