CN110062754B - 作为选择性Janus激酶抑制剂的氨基吡唑类化合物 - Google Patents
作为选择性Janus激酶抑制剂的氨基吡唑类化合物 Download PDFInfo
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Classifications
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
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- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Dermatology (AREA)
- Ophthalmology & Optometry (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明提供了作为选择性JAK抑制剂的式I的化合物,因此可用于治疗JAK介导的疾病,例如特应性皮炎、关节炎和癌症。
Description
发明背景
蛋白激酶是一组通过向蛋白底物添加磷酸基团来调节其靶蛋白活性的酶。激酶可以通过其靶标细分为丝氨酸/苏氨酸激酶和酪氨酸激酶,并且在包括细胞分裂、分化、细胞稳态和信号转导在内的许多生理过程中发挥至关重要的作用。
非受体酪氨酸激酶的哺乳动物Janus激酶(JAK)家族有四个成员:JAK1、JAK2、JAK3和TYK2。JAK家族参与来自> 70种不同细胞因子的细胞内信号转导。细胞因子与其细胞表面受体结合,导致受体二聚化和随后JAK酪氨酸激酶的活化/磷酸化。然后受体上的特定酪氨酸残基被活化的JAK磷酸化,并充当STAT蛋白的停靠位点。STAT被JAK磷酸化、二聚化,然后易位至细胞核,在那里它们结合特定的DNA元件并激活基因转录。JAK1以细胞因子依赖性方式与所有JAK同种型结合发出信号。
JAK对多种生理功能至关重要。使用缺乏特异性JAK的基因工程小鼠模型的研究(K. Ghoreschi, A. Laurence, J. J. O'Shea, Immunol. Rev. 228, 273 (2009)),以及与人类疾病有关的JAK酶突变的鉴定(J. J. O'Shea, M. Pesu, D. C. Borie, P. S.Changelian, Nat. Rev. Drug Discov. 3, 555 (2004)). (Y. Minegishi等人,Immunity. 25, 745 (2006))证明了这一点。
这些小鼠和人类基因数据将Jak/STAT途径与各种疾病和病症联系起来,所述疾病和病症包括但不限于过度增殖性病症和癌症(如白血病和淋巴瘤),免疫和炎性病症(如移植排斥、哮喘、慢性阻塞性肺病、过敏、类风湿性关节炎、过敏性和特应性皮炎),I型糖尿病,肌萎缩侧索硬化和多发性硬化。
WO2013/041042公开了作为Janues激酶抑制剂的吡唑甲酰胺类化合物,其可用于治疗类风湿性关节炎、哮喘、COPD和癌症。该公开的化合物具有下式
。
WO2013/040863公开了为Janus激酶1抑制剂的取代的环烷基腈吡唑甲酰胺类化合物,其可用于治疗例如,哮喘、阻塞性气道疾病、关节炎、肺气肿、癌症、重症肌无力、格雷夫斯病和阿尔茨海默病。
WO2014/146490公开了为Janus激酶抑制剂的取代的2-(3-氨基-4-氧代-4,5-二氢-吡唑并(4,3-c)吡啶-1-基)-环丁烷甲腈化合物,其用于治疗例如类风湿性关节炎、慢性哮喘、慢性阻塞性肺病、糖尿病。
利用JAK-STAT信号传导途径的细胞因子涉及特应性和过敏性皮炎的发病机制和维持。这些包括促炎IL-4和IL-6,和IL-13[Carmi-Levy等人, Clinic Rev Allerg Immunol(2011), 41:245), Ong和Leung, Curr. Allergy Asthma Rep. (2006), 6(5):384)],参与过敏反应的细胞因子,以及IL-31,其是一种参与引发瘙痒的细胞因子[Dillon等人,Nat. Immunol. (2004), 5(7): 752]。重要的是,参与特应性和过敏性皮炎的这些上述细胞因子的受体利用与JAK2、JAK3或Tyk2复合的JAK1来产生细胞内信号传导并引发生物学效应[Yamaoka K, Saharinen P, Pesu M, Holt VE 3rd, Silvennoinen O, O'Shea JJ.,Genome Biol. 2004;5(12):253]。
在患有过敏性或特应性皮炎的狗中,给予对JAK1具有适度选择性的JAK抑制剂奥拉替尼引起瘙痒的快速改善并减少损害[Cosgrove等人, Vet. Derm. (2013), 24:479;Cosgrove等人, Vet. Derm. (2013), 24:587]。在较高剂量下,奥拉替尼引起血细胞比容、血红蛋白和网织红细胞计数的减少,这可能是由于JAK2的抑制[FOI Summary NADA 141-345; Gonzales等人, J. Vet. Pharmacol. Therapeut. (2014), 37:317]。总的来说,这些数据强烈表明抑制JAK1是对狗过敏性和特应性皮炎的有效治疗,并且相比其他JAK酶对JAK1具有更高选择性的化合物将赋予改善的治疗指数。
Apoquel®是一种动物药物,其活性成分是奥拉替尼,其被批准用于控制与特应性皮炎相关的瘙痒,并控制至少12个月龄的狗的特应性皮炎(参见NADA的FOI摘要141-345,2013年5月14日)。还参见美国专利号6,890,929;7,687,507;8,133,899和8,987,283。
Apoquel®安全性在关键的6个月、良好实验室规范(GLP)安全范围研究中进行了评价。该产品以最大暴露剂量0.6 mg/kg(推荐的临床剂量为0.4 mg/kg)的1、3和5倍对狗口服给药,每天两次,持续6周,然后每天一次,持续20周,总共26周(6个月)。虽然该产品在所有剂量下通常都耐受良好,但在所有组中都存在与药物类别的药理作用一致的测试物效应(test article effect)。这些包括:乳头状瘤(考虑与测试物有关,但与剂量无关);趾间囊肿(蹄皮炎等)(可能与剂量有关);红细胞量减少;血清白蛋白减少;肠相关淋巴样组织(GALT)、脾和宫颈/肠系膜淋巴结的细胞结构减少;胸骨和股骨骨髓的细胞结构减少。这些效应中的大多数是温和的并且似乎是非进展性的(参见APOQUEL的CVMP评估报告(EMEA/V/C/002688/0000);EMA/481054/2013)。
发明内容
本发明提供了为JAK抑制剂的新化合物。本发明还提供了使用该新化合物治疗和预防JAK介导的疾病和病症的方法,以及含有所述化合物的药物组合物。
附图简述
图1显示了在IL-31诱导的瘙痒模型中测试时化合物1的结果。
图1A显示了化合物1与安慰剂和Apoquel的比较。
图1B显示了三种不同剂量的化合物1的作用。
发明详述
本发明提供了式I的化合物或其药学上可接受的盐或立体异构体:
。
在一个实施方案中,式I的化合物是
。
在一个实施方案中,本发明化合物是相对于JAK2和JAK3的选择性JAK1抑制剂。在一个实施方案中,本发明的化合物是相对于JAK2或JAK3的选择性JAK1抑制剂。给定JAK1抑制化合物的相对选择性的确定定义为(JAK2 IC50值/JAK1 IC50值)的相对比率为至少2。此外,(JAK3 IC50值/ JAK1 IC50值)的相对比率为至少500。
在又一个实施方案中,对于给定化合物,(JAK2 IC50值/JAK1 IC50值)的相对比率为至少5或至少10。在另一个实施方案中,(JAK3 IC50值/ JAK1 IC50值)的相对比率为至少500或至少750或至少1000。
本发明的另一个实施方案是药物组合物,其包含式I化合物或其药学上可接受的盐、或其立体异构体和药学上可接受的载体。
另一个实施方案是治疗JAK-1介导的疾病的方法,包括向有此需要的哺乳动物给予治疗有效量的式I的化合物或其药学上可接受的盐或包含式I的化合物的药物组合物。
另一个实施方案是治疗方法,其中JAK-1介导的疾病是可以通过相对于JAK 2和JAK 3选择性抑制Janus激酶JAK1来改善的疾病。
在另一个实施方案中,所述疾病选自过敏性皮炎、特应性皮炎、关节炎、干燥性角膜结膜炎、自身免疫性疾病或病症和癌症。
在另一个实施方案中,该疾病是特应性皮炎。
在一个实施方案中,该疾病是自身免疫性疾病或病症。
在一个实施方案中,该疾病是关节炎。
在另一个实施方案中,哺乳动物是伴侣动物哺乳动物。
在另一个实施方案中,伴侣动物是狗、猫或马。
在一个实施方案中,该疾病是干燥性角膜结膜炎。
在进一步的实施方案中,口服、肠胃外或局部给药。
在另一个实施方案中,选择性抑制是相对于JAK 2选择性抑制Janus激酶JAK1。
在另一个实施方案中,选择性抑制是相对于JAK 3选择性抑制Janus激酶JAK1。
在进一步的实施方案中,JAK2(IC50)/JAK1(IC50)的比率为至少5、至少10、至少12。
在另一个实施方案中,JAK3(IC50)/JAK1(IC50)的比率为至少1000或至少750或至少500。
在另一个实施方案中,化合物的日剂量为约0.001 mg/kg至约100 mg/kg或约0.01mg/kg至约10 mg/kg或约0.1 mg/kg至约3.0 mg/kg或约0.2 mg/kg至约1.0 mg/kg体重。
支持JAK1抑制和选择性的证据
来自多JAK抑制剂托法替尼(JAK1/JAK2/JAK3) (Kremer等人, Arthritis andRheumatism 2009 “The safety and efficacy of a JAK inhibitor in patients withactive RA”, Fleishman等人, Arthritis and Rheumatism 2010 “Tofacitinib inpatients with active RA”, Fleishman等人, NEJM 2012 “Placebo controlled trialof Tofacitinib monotherapy in RA”)和巴瑞替尼 (JAK1/JAK2) (Greenwald等人, ACRannual meeting Nov 2010 “A randomized dose-ranmging, PBO-controlled study ofTNCB028050, a selective JAK1 and JAK2 inhibitor, in subjects with active RA”)的临床试验结果支持了通过靶向JAK抑制可以实现高水平的功效的假设。然而,剂量限制性不良事件限制了这些药剂的功效和用途。服用托法替尼和巴瑞替尼的患者均观察到显著的造血不良事件,特别是贫血,在较高剂量时发生率和严重程度较高。预计这是由于EPO信号传导的抑制,EPO是通过JAK2发出信号的红细胞发育的关键生长因子。EPO的抑制也导致无法从慢性疾病的贫血中恢复。大约40%的RA患者患有慢性疾病的贫血(Masson. JointBone Spine 2011 “Rheumatopid Anemia”, Han等人, J Rheumatology 2007“Association of anemia and physical disability among patients with RA”)。目前的治疗范例是治疗引起这种贫血的炎症,然而用也抑制EPO信号传导的多JAK抑制剂治疗抵消了治疗炎症对血红蛋白水平的益处。特异性JAK1抑制剂不会影响EPO信号传导,不会受到贫血性不良事件的限制,并且在炎症逆转后会使血红蛋白水平反弹。
支持JAK1假设的其他临床证据来自托珠单抗,一种靶向IL-6受体的抗体(IL-6通过JAK1和JAK2发信号)。使用这种生物药剂可以实现高水平的功效而不会诱发贫血,并且成功地逆转了炎症的贫血(Emery等人, Ann Rheum Dis 2008 “IL-6 receptor inhibitionwith tocilizumab improves treatment outcomes in patients with RA refractoryto anti-TNF biologicals: results of a 24-week multicenter randomized placebo-controlled trial”, Mashizume 等人, Rheumatol Int. 2010 “Tocilizumab, ahumanized anti-IL-6 receptor antibody, improved anemia in monkey arthritis bysuppressing IL-6 induced hepcidin production”)。
如本文所用的“患者”是指已成为治疗、观察或实验对象的哺乳动物。
“哺乳动物”是指哺乳的动物。哺乳动物可以是雄性或雌性。哺乳动物可以是选自人、牛科动物(例如牛)、猪类动物(porcine)(例如猪)、绵羊类动物(ovine)(例如绵羊)、山羊属动物(例如山羊)、马科动物(例如马)、犬科动物(例如家犬)、猫科动物(例如家猫)、兔形目动物(兔)、啮齿动物(例如大鼠或小鼠)、浣熊属动物(Procyon lotor)(例如浣熊)中的一种或多种。在特定的实施方案中,哺乳动物是伴侣动物(例如犬科动物、猫科动物或马科动物)。
“治疗有效量”是指将引起研究人员、兽医、医师或其他临床医生正在寻求的组织、系统、动物或人的生物或医学反应的药物或药剂的量。
术语“治疗(treatment)”或“治疗(treating)”包括减轻、改善、缓解或以其他方式减少与疾病或病症相关的体征和症状。
如在药物组合物中的术语“组合物”旨在包括包含活性成分和构成载体的惰性成分(药学上可接受的赋形剂)的产物,以及直接或间接地产生自任何两种或更多种成分的组合、络合或聚集、或一种或多种成分的解离、或一种或多种成分的其他类型的反应或相互作用的任何产物。因此,本发明的药物组合物包括通过混合式I的化合物和药学上可接受的赋形剂制备的任何组合物。
光学异构体-非对映异构体-几何异构体-互变异构体
式I的化合物含有一个或多个不对称中心,因此可以外消旋体和外消旋混合物、单一对映异构体、非对映异构体混合物和单独的非对映异构体形式存在。本发明旨在包括作为单一物类或其混合物的式I的化合物的所有这种异构形式。
本文所述的一些化合物含有烯属双键,除非另有说明,否则意味着包括E和Z几何异构体二者。
本发明的具体实施方案包括选自本文实施例的主题化合物或其药学上可接受的盐的化合物。
本发明的化合物可以含有一个或多个不对称中心,因此可以作为“立体异构体”出现,包括外消旋体和外消旋混合物、对映异构体混合物、单一对映异构体、非对映异构体混合物和单独的非对映异构体。每个这样的不对称中心将独立地产生两种光学异构体,并且意图是以混合物形式以及作为纯的或部分纯化的化合物的所有可能的光学异构体和非对映异构体都包括在本发明的范围内。本发明旨在包含这些化合物的所有这些异构形式。当在本发明的式中与手性碳的键描绘为直线时,应理解手性碳的(R)和(S)构型以及因此两种对映异构体及其混合物都包含在该式中。例如,式I显示了没有特定立体化学的化合物类的结构。当本发明化合物含有一个手性中心时,术语“立体异构体”包括对映异构体和对映异构体的混合物,例如称为外消旋混合物的特定50:50混合物。
非对映异构体混合物可以通过本领域技术人员熟知的方法,例如通过色谱法和/或分级结晶,基于它们的物理化学差异分离成它们各自的非对映异构体。对映异构体可以通过以下方式分离:通过与适当的光学活性化合物(例如,手性助剂如手性醇或Mosher酰氯)反应来将对映异构体混合物转化为非对映异构体混合物,分离非对映异构体并将单独的非对映异构体转化(例如,水解)为相应的纯对映异构体。也可以使用手性HPLC柱分离对映异构体。
本发明的手性中心可具有IUPAC 1974 Recommendations定义的S或R构型。术语“盐”、“溶剂化物”、“酯”、“前药”等的使用旨在同样适用于本发明化合物的对映异构体、立体异构体、旋转异构体、互变异构体、位置异构体、外消旋体或前药的盐、溶剂化物、酯和前药。
盐
术语“药学上可接受的盐”是指由药学上可接受的无毒碱制备的盐,所述碱包括无机碱和有机碱。衍生自无机碱的盐包括铝、铵、钙、铜、铁、亚铁、锂、镁、三价锰盐、二价锰、钾、钠、锌等。衍生自药学上可接受的有机无毒碱的盐包括以下的盐:伯、仲和叔胺,取代的胺,包括天然存在的取代的胺,环胺和碱性离子交换树脂,例如精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、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、哈胺(hydrabamine)、异丙胺、赖氨酸、甲基葡糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等。
当本发明的化合物是碱性时,盐可以由药学上可接受的无毒酸制备,包括无机酸和有机酸。这种酸包括乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、富马酸、葡萄糖酸、谷氨酸、氢溴酸、盐酸、羟乙基磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、粘酸、硝酸、双羟萘酸、泛酸、磷酸、琥珀酸、硫酸、酒石酸、对甲苯磺酸等。
应理解,除非另有说明,否则提及式I的化合物以及特定化合物也意味着包括药学上可接受的盐。
此外,本发明化合物的一些结晶形式可以以多晶型形式存在,因此所有形式都意图包括在本发明中。此外,本发明的一些化合物可与水(水合物)或普通有机溶剂形成溶剂化物。这种溶剂化物包括在本发明的范围内。
标记化合物
在通式I的化合物中,原子可以表现出它们的天然同位素丰度,或者一个或多个原子可以人工富集在具有相同原子序数但具有与在自然界中主要发现的原子质量或质量数不同的原子质量或质量数的特定同位素中。本发明旨在包括通式I的化合物的所有合适的同位素变体。例如,氢(H)的不同同位素形式包括氕(1H)和氘(2H)。氕是自然界中发现的主要氢同位素。富集氘可以提供某些治疗优势,例如增加体内半衰期或减少剂量需求,或者可以提供可用作生物样品表征标准的化合物。通式I中的同位素富集的化合物可以通过本领域技术人员熟知的常规技术或通过类似于本文的方案和实施例中描述的那些的方法,使用适当的同位素富集的试剂和/或中间体来制备,而无需过度实验。
用途
式I的化合物或其药学上可接受的盐和药物组合物可用于治疗或预防由Janus激酶介导的多种病况或疾病,特别是可通过抑制Janus激酶如JAK1、JAK2或JAK3改善的疾病或病况。这些病况和疾病包括但不限于:
(1)关节炎,包括类风湿性关节炎、幼年型关节炎和银屑病性关节炎;(2)哮喘和其他阻塞性气道疾病,包括慢性哮喘、迟发性哮喘、气道高反应性、支气管炎、支气管哮喘、过敏性哮喘、内源性哮喘、外源性哮喘、尘埃哮喘、复发性气道阻塞和慢性阻塞性肺病包括肺气肿;(3)自身免疫性疾病或病症,包括指定为单器官或单细胞型自身免疫性病症的那些,例如自身免疫性甲状腺炎、自身免疫性溶血性贫血、恶性贫血的自身免疫性萎缩性胃炎、自身免疫性脑脊髓炎、自身免疫性睾丸炎、自身免疫性血小板减少症、交感性眼炎、重症肌无力、格雷夫斯病、原发性胆汁性肝硬化、慢性侵袭性肝炎、溃疡性结肠炎和膜性肾小球病,指定为涉及全身性自身免疫性病症的那些,例如系统性红斑狼疮、类风湿性关节炎、干燥综合征、多肌炎-皮肌炎、系统性硬化症、结节性多动脉炎和天疱疮,和其他可以基于B细胞(体液)或基于T细胞的自身免疫性疾病,包括强直性脊柱炎、韦格纳肉芽肿病、自身免疫性脱发、I型或青少年型糖尿病和甲状腺炎;(4)癌症或肿瘤,包括消化道/胃肠道癌症、结肠癌、肝癌、皮肤癌(包括肥大细胞瘤和鳞状细胞癌)、乳房和乳腺癌、卵巢癌、前列腺癌、淋巴瘤、白血病(包括急性髓性白血病和慢性髓性白血病)、肾癌、肺癌、肌肉癌、骨癌、膀胱癌、脑癌、黑色素瘤(包括口腔和转移性黑色素瘤)、卡波西氏肉瘤、骨髓瘤(包括多发性骨髓瘤)、骨髓增生性病症、增生性糖尿病视网膜病变,以及血管生成相关病症(包括实体瘤);(5)糖尿病,包括I型糖尿病和糖尿病并发症;(6)眼睛的疾病、病症或病况,包括眼睛的自身免疫性疾病、角膜结膜炎、春季结膜炎、葡萄膜炎和晶状体引起的葡萄膜炎、角膜炎、疱疹性角膜炎、conical keratitis、角膜上皮营养不良、角膜白斑、眼天疱疮、巩膜炎、Vogt-Koyanagi-Harada-样综合征、干燥性角膜结膜炎(干眼)、小水疱、虹膜睫状体炎、结节病、内分泌眼病、交感性眼炎、过敏性结膜炎和眼部新生血管;(7)肠道的炎症、过敏或病况,包括克罗恩病和/或溃疡性结肠炎、炎性肠病、乳糜泻、直肠炎、嗜酸细胞性胃肠炎和肥大细胞增多症;(8)神经退行性疾病,包括运动神经元病、认知功能障碍综合征、帕金森病、肌萎缩侧索硬化、脑缺血、或由外伤、中风、谷氨酸神经毒性或缺氧引起的神经退行性疾病;中风的缺血/再灌注损伤、心肌缺血、肾缺血、心脏病发作、心肌肥厚、动脉粥样硬化和动脉硬化、器官缺氧和血小板聚集;(9)皮肤的疾病、病况或病症,包括特应性皮炎、湿疹、牛皮癣、硬皮病、瘙痒和其他瘙痒病况;(10)过敏反应,包括过敏症、过敏性鼻炎、过敏性皮炎、过敏性荨麻疹、血管性水肿、过敏性哮喘、或对昆虫叮咬、食物、药物或花粉的过敏反应;(11)移植排斥,包括胰岛移植排斥、骨髓移植排斥、移植物抗宿主病、器官和细胞移植排斥,如骨髓、软骨、角膜、心脏、椎间盘、胰岛、肾、肢体、肝、肺、肌肉、成肌细胞、神经、胰腺、皮肤、小肠或气管、以及异种移植。
因此,本发明的另一方面提供了治疗或预防JAK介导的疾病或病症的方法,包括向有此需要的哺乳动物给予治疗有效量的式I的化合物。在一个实施方案中,这些疾病包括哮喘和类风湿性关节炎。在另一个实施方案中,该疾病是特应性皮炎。
本发明的另一方面提供式I的化合物在制备用于治疗或预防JAK介导的疾病或病症的药物中的用途。
剂量范围
当然,式I的化合物的预防或治疗剂量的大小将随待治疗病况的性质和严重程度以及特定的式I的化合物及其给药途径而变化。它还将根据多种因素而变化,包括年龄、体重、一般健康状况、性别、饮食、给药时间、排泄率、药物组合和个体患者的反应。通常,日剂量为约0.001 mg至约100 mg/kg哺乳动物体重,优选0.01 mg至约10 mg/kg。在另一个实施方案中,日剂量为约0.2 mg/kg至约1.0 mg/kg哺乳动物体重。在另一个实施方案中,日剂量为约0.1 mg/kg至约3.0 mg/kg哺乳动物体重。另一方面,在某些情况下可能需要使用超出这些限制的剂量。
可以与载体物质组合以产生单一剂型的活性成分的量将根据所治疗的宿主和特定的给药方式而变化。例如,意图用于口服给药的制剂可含有0.05 mg至5 g活性剂,其混合有适当和方便量的载体物质,该载体物质可在总组合物的约5至约99.95%变化。剂量单位形式通常含有约0.1 mg至约0.4 g活性成分,通常为0.5 mg、1 mg、2 mg、5 mg、10 mg、25mg、50 mg、100 mg、200 mg或400 mg。
药物组合物
本发明的另一方面提供药物组合物,其包含式I的化合物和药学上可接受的载体。生理学上可接受的制剂载体和赋形剂是本领域已知的,并且描述于例如“Gennaro,Remington: The Science and Practice of Pharmacy” (第20版, 2000)中。所有这些成分、载体和赋形剂必须基本上是药学上或兽医学上纯的并且在使用的量下是无毒的并且必须与药物活性成分(即式I的化合物)相容。对于任何疾病的治疗,式I的化合物可以以含有常规无毒药学上可接受的载体、佐剂和媒介物的剂量单位制剂口服、通过吸入喷雾、局部、肠胃外或直肠给药。本文所用的术语肠胃外包括皮下注射、静脉内、肌肉内、胸骨内注射或输注技术。除了治疗温血动物如小鼠、大鼠、马、牛、绵羊、狗、猫等外,本发明化合物对于治疗人类也是有效的。
含有活性成分的药物组合物可以是适于口服使用的形式,例如片剂、糖锭剂、锭剂、水性或油性悬浮液、可分散的粉末或颗粒、乳液、硬或软胶囊、或糖浆或酏剂。意图用于口服使用的组合物可以根据本领域已知的用于制备药物组合物的任何方法制备,并且这样的组合物可以含有一种或多种选自甜味剂、调味剂、着色剂和防腐剂的试剂以提供药学上精妙和适口的制剂。片剂含有活性成分与适合制备片剂的无毒的药学上可接受的赋形剂的混合物。这些赋形剂可以是例如惰性稀释剂,例如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;制粒和崩解剂,例如玉米淀粉或海藻酸;粘合剂,例如淀粉、明胶或阿拉伯胶,和润滑剂,例如硬脂酸镁、硬脂酸或滑石。片剂可以是未包衣的,或者可以通过已知技术包衣,以延迟在胃肠道中的崩解和吸收,从而在较长时段内提供持续作用。例如,可以使用延时材料,例如单硬脂酸甘油酯或二硬脂酸甘油酯。它们也可以通过美国专利4,256,108;4,166,452;和4,265,874中描述的技术包衣以形成用于控制释放的渗透性治疗片剂。
口服使用的制剂也可以呈现为硬明胶胶囊,其中活性成分与惰性固体稀释剂(例如碳酸钙、磷酸钙或高岭土)混合,或呈现为软明胶胶囊,其中活性成分与水混溶性溶剂(例如丙二醇、PEG和乙醇)或油介质(例如花生油、液体石蜡或橄榄油)混合。
水性悬浮液含有活性物质与适于制备水性悬浮液的赋形剂的混合物。这些赋形剂是悬浮剂,例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、聚乙烯吡咯烷酮、黄蓍胶和阿拉伯树胶;分散剂或润湿剂可以是天然存在的磷脂,例如卵磷脂,或环氧烷与脂肪酸的缩合产物,例如聚氧乙烯硬脂酸酯,或环氧乙烷与长链脂族醇的缩合产物,例如十七碳亚乙基氧基鲸蜡醇(heptadecaethyleneoxycetanol),或环氧乙烷与衍生自脂肪酸和己糖醇的偏酯的缩合产物,例如聚氧乙烯山梨糖醇单油酸酯,或环氧乙烷与衍生自脂肪酸和己糖醇酐的偏酯的缩合产物,例如聚乙烯脱水山梨糖醇单油酸酯。水性悬浮液还可含有一种或多种防腐剂,例如对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯,一种或多种着色剂,一种或多种调味剂,和一种或多种甜味剂,例如蔗糖、糖精或阿斯巴甜。
油性悬浮液可以通过将活性成分悬浮在植物油(例如花生油、橄榄油、芝麻油或椰子油)或矿物油(例如液体石蜡)中来配制。油性悬浮液可含有增稠剂,例如蜂蜡、硬石蜡或鲸蜡醇。可加入诸如上面列出的那些的甜味剂和调味剂以提供适口的口服制剂。这些组合物可以通过加入抗氧化剂如抗坏血酸来保存。
适于通过加入水制备水性悬浮液的可分散粉末和颗粒提供活性成分与分散剂或润湿剂、悬浮剂和一种或多种防腐剂的混合物。合适的分散剂或润湿剂和悬浮剂的例子是上面已经提到的那些。还可以存在另外的赋形剂,例如甜味剂、调味剂和着色剂。
本发明的药物组合物还可以是水包油乳液的形式。油相可以是植物油,例如橄榄油或花生油,或矿物油,例如液体石蜡,或这些的混合物。合适的乳化剂可以是天然存在的磷脂,例如大豆、卵磷脂,以及衍生自脂肪酸和己糖醇酐的酯或偏酯,例如脱水山梨糖醇单油酸酯,以及所述偏酯与环氧乙烷的缩合产物,例如聚氧乙烯脱水山梨糖醇单油酸酯。乳液还可含有甜味剂和调味剂。
糖浆和酏剂可以用甜味剂配制,例如甘油、丙二醇、山梨糖醇或蔗糖。此类制剂还可含有缓和剂、防腐剂和调味剂以及着色剂。药物组合物可以是无菌可注射水性或油性悬浮液的形式。该悬浮液可以根据已知技术使用上面已经提到的那些合适的分散剂或润湿剂和悬浮剂配制。无菌可注射制剂还可以是在无毒的肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液或悬浮液,例如在1,3-丁二醇中的溶液。可以使用的可接受的媒介物和溶剂包括水、林格氏溶液和等渗氯化钠溶液。也可以使用共溶剂如乙醇、丙二醇或聚乙二醇。另外,无菌的固定油通常用作溶剂或悬浮介质。为此目的,可以使用任何温和的固定油,包括合成的甘油单酯或甘油二酯。此外,脂肪酸如油酸可用于制备注射剂。
式I的化合物也可以以用于药物的直肠给药的栓剂的形式给药。
对于局部使用,使用含有式I的化合物的乳膏、软膏、凝胶、溶液或悬浮液等。(为了本申请的目的,局部施用应包括漱口水和漱口剂。)局部制剂通常可以包含药物载体、共溶剂、乳化剂、渗透增强剂、防腐剂体系和润肤剂。
在可替换的实施方案中,本发明的组合物可以配制用于眼科给药。
与其他药物的组合
为了治疗和预防JAK介导的疾病,可以将式I的化合物与其他治疗剂共同给药。因此,在另一方面,本发明提供了用于治疗JAK介导的疾病的药物组合物,其包含治疗有效量的式I的化合物和一种或多种其他治疗剂。特别地,为了治疗炎性疾病类风湿性关节炎、牛皮癣、炎性肠病、COPD、哮喘和过敏性鼻炎,式I的化合物可以与药剂组合,所述药剂例如:(1)TNF-α抑制剂(如Remicade®和Enbrel®);(2)非选择性COX-I/COX-2抑制剂(如吡罗昔康、双氯芬酸、丙酸类如萘普生、氟比洛芬、非诺洛芬、酮洛芬和布洛芬,芬那酯类如甲芬那酸、吲哚美辛、舒林酸、阿扎丙宗,吡唑啉酮类如苯基丁氮酮,水杨酸类如阿司匹林);(3)COX-2抑制剂(如美洛昔康、塞来昔布、罗非考昔、伐地考昔和艾托考昔);(4)治疗类风湿性关节炎的其他药剂,包括低剂量甲氨蝶呤、来氟米特、环索奈德、羟氯喹、d-青霉胺、金诺芬或肠胃外或口服金(parenteral or oral gold);(5)白三烯生物合成抑制剂、5-脂氧合酶(5-LO)抑制剂或5-脂氧合酶活化蛋白(FLAP)拮抗剂如齐留通;(6)LTD4受体拮抗剂,如扎鲁司特、孟鲁司特和普仑司特;(7)PDE4抑制剂如罗氟司特;(8)抗组胺H1受体拮抗剂,如西替利嗪、氯雷他定、地氯雷他定、非索非那定、阿司咪唑、氮卓斯汀和氯苯那敏;(9)α1-和α2-肾上腺素能受体激动剂、血管收缩剂、拟交感神经药,如丙已君、苯肾上腺素、苯丙醇胺、伪麻黄碱、盐酸萘唑啉、盐酸羟甲唑啉、盐酸四氢唑啉、盐酸丁苄唑啉和盐酸乙基去甲肾上腺素;(10)抗胆碱能药,如异丙托溴铵、噻托溴铵、氧托溴铵、aclindinium bromide、胃长宁、哌仑西平和替仑西平;(11)β-肾上腺素能受体激动剂,例如间羟异丙肾上腺素(metaproterenol)、异丙特醇、异丙肾上腺素、沙丁胺醇、柳丁氨醇、福莫特罗、沙美特罗、特布他林、奥西那林、双甲苯喘定甲磺酸盐和吡布特罗,或甲基黄嘌呤类,包括茶碱和氨茶碱、色甘酸钠;(12)胰岛素样生长因子I型(IGF-1)模拟物;(13)全身副作用减少的吸入糖皮质激素,如泼尼松、泼尼松龙、氟尼缩松、曲安奈德、二丙酸倍氯米松、布地奈德、丙酸氟替卡松、环索奈德和糠酸莫米松。
合成方法
方案和实施例
本文使用的缩写具有以下列表的含义。除非另有具体说明,否则下面未列表的缩写具有其常用含义。
ACN | 乙腈 |
手性SFC | 手性超临界流体色谱 |
DBU | 1,8-二氮杂双环[5.4.0]十一碳-7-烯 |
DCM | 二氯甲烷 |
DMSO | 二甲基亚砜 |
DTT | 苏-1,4-二巯基-2,3-丁二醇(Cleland试剂) |
EtOAc | 乙酸乙酯 |
GST | 谷胱甘肽S-转移酶 |
HEPES | 4-(2-羟乙基)哌嗪-1-乙磺酸、N-(2-羟乙基)哌嗪-N’-(2-乙磺酸) |
HTRF | 均相时间分辨荧光 |
HPLC | 高压液相色谱 |
LCMS | 液相色谱质谱 |
MPLC | 中压液相色谱 |
Na2SO4 | 硫酸钠 |
NaOMe | 甲醇钠 |
Pd2(dba)3 | 三(二亚苄基丙酮)二钯(0) |
POCl3 | 三氯氧磷(V) |
t-BuOH | 叔丁醇 |
THF | 四氢呋喃 |
X-Phos | 2-二环己基膦基-2′,4′,6′-三异丙基联苯 |
Me4-tBu-X-Phos | 二叔丁基[3,4,5,6-四甲基-2',4',6'-三(丙-2-基)联苯-2-基]膦 |
NMR | 核磁共振 |
TLC | 薄层色谱 |
TMS | 三甲基硅烷 |
TRF | 时间分辨荧光 |
烷基缩写
Me | 甲基 |
Et | 乙基 |
n-Pr | 正丙基 |
i-Pr | 异丙基 |
n-Bu | 正丁基 |
i-Bu | 异丁基 |
s-Bu | 仲丁基 |
t-Bu | 叔丁基 |
c-Pr | 环丙基 |
c-Bu | 环丁基 |
c-Pen | 环戊基 |
c-Hex | 环己基 |
合成方法
本发明化合物可以使用适当的物质根据以下一般方案制备,并且通过随后的具体实施例进一步举例说明。实施例中说明的化合物不应解释为形成被认为是本发明的唯一类型。因此,下面的说明性实施例不受所列化合物或用于说明目的的任何特定取代基的限制。如方案中所示的取代基编号不一定与权利要求中使用的相关,并且为清楚起见,在上文本发明的定义下允许多个取代基的情况下,通常显示单个取代基与化合物连接。
本领域技术人员将容易理解,可以使用以下制备程序的条件和方法的已知变化来制备这些化合物。现在将在以下非限制性实施例中说明本发明,其中除非另有说明,否则:
除非另有具体说明,否则所有反应被搅拌(机械、搅拌棒/搅拌板或摇动)并在氮气或氩气的惰性气氛下进行。
除非另有说明,否则所有温度均为摄氏度(℃)。
环境温度为15-25℃。
大多数化合物通过反相制备型HPLC、硅胶MPLC、重结晶和/或swish(在溶剂中悬浮,然后过滤固体)纯化。
通过薄层色谱(TLC)和/或LCMS和/或NMR跟踪反应过程,并且给出反应时间仅用于说明。
通过NMR和LCMS分析所有最终产物。
通过NMR和/或TLC和/或LCMS分析中间体。
方法1
商业上可用/以前描述的物质
下表列出了用于合成中间体和本发明实施例的化学物质的商业来源和先前公开的合成路线。该列表并非旨在以任何方式成为详尽、排他或限制性的。
结构 | IUPAC名称 | 供应商 |
四氢-2H-吡喃-3-甲醛 | J&W Pharmlab LLC | |
四氢-2H-吡喃-4-基乙醛 | Maybridge |
中间体
以下实验程序详述了用于合成本发明实施例的化学物质的制备。示例性程序仅用于说明目的,并不意图以任何方式限制本发明的范围。
合成方案:
中间体2: 3,6-二氢-2H-吡喃-4-甲腈
在0℃下向三甲基氰硅烷(28.0 g, 288 mmol)的二氯甲烷(100 mL)溶液中依次加入四氢-4H-吡喃-4-酮1 (24 g, 243 mmol)和三氟甲磺酸三甲基甲硅烷基酯(1.6 g, 7.2mmol)。将所得溶液在0℃搅拌1小时,然后加入吡啶(300 mL)和磷酰氯(110 g, 719 mmol)。将混合物回流12小时,然后在0℃下倒入2N盐酸水溶液(600 mL)、碎冰(180 mL)和乙醚(600mL)的混合物中。将混合物剧烈搅拌15分钟,然后用乙醚(3x1 L)萃取。将所有有机溶液用盐水(2x300 mL)洗涤,经无水硫酸钠干燥,过滤并真空浓缩。通过快速柱色谱用1-2%乙酸乙酯/己烷纯化粗残余物,得到标题化合物,为黄色油状物。1H NMR (300 MHz, CDCl3) δ 6.62– 6.59 (m, 1H), 4.29 – 4.21 (m, 2H), 3.78 (t, J = 5.4 Hz, 2H), 2.34 – 2.30(m, 2H)。
中间体5: 3-氨基-1-((3R,4S)或(3S,4R)-4-氰基-四氢-2H-吡喃-3-基)-1H-吡唑-4-甲酰胺
将3-氨基-1H-吡唑-4-甲酰胺4 (804 g, 4.59 mol)、3,6-二氢-2H-吡喃-4-甲腈2(1000 g, 9.17 mol)和DBU (2435 g, 16 mol)的乙醇(800 mL)混合物在70℃下在氮气下搅拌过夜,然后真空浓缩。将粗残余物通过硅胶快速柱色谱用2-5%甲醇/二氯甲烷纯化,得到标题化合物和其对映异构体的外消旋混合物,为黄色固体(269 g, 产率25%)。
手性分离:将380 g外消旋化合物溶解在ACN/MeOH (1:1)中至25 mg/mL的浓度。在Thar 350制备型SFC(柱:ChiralPak IC-10μM,300×50mm;流动相:45% 2-丙醇,55%CO2;流速:220 mL/min;柱温:38℃)上注射16 mL。分离后,通过旋转蒸发干燥级分。第二(较慢洗脱)峰用于制备以下化合物。
1H NMR (500 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.36 (brs, 1H), 6.80 (brs,1H), 5.36 (s, 2H), 4.86-4.31 (td, J = 10.5, 4.5 Hz, 1H), 3.91-3.88 (dd, J =11.5, 4.5 Hz 1H), 3.86 – 3.83 (m, 1H), 3.53-3.50 (m, 2H), 3.39-3.33 (td, J =11.5, 2 Hz, 1H), 2.10-2.07 (m, 1H), 1.95-1.87 (m, 1H). LRMS (ESI) C10H14N5O2计算值[M+H]+: 236, 实测值:236。
中间体10: 2,6-二氟-4-肼基吡啶
在N2气氛下,向具有磁力搅拌棒的烘箱干燥的圆底烧瓶中加入2,4,6-三氟吡啶9(7g, 52.6 mmol, 1当量)、THF (52.6 mL, 1 M)和肼 (5.1 mL, 105 mmol, 2当量)。将反应混合物加热至50℃保持2小时,然后冷却至室温。将粗物质用水(2 x 25 mL)和己烷(25mL)研磨,然后真空干燥过夜。将得到的固体在EtOAc中重结晶,得到2,6-二氟-4-肼基吡啶10 (4.5 g, 31 mmol)。1H NMR (500 MHz, DMSO-d6) δ 8.42 (s, 1H), 6.16 (brs, 2H),4.46 (s, 2H)。
中间体11: 4-溴-2,6-二氟吡啶
在N2气氛下,在室温下,向具有磁力搅拌棒的烘箱干燥的圆底烧瓶中加入2,6-二氟-4-肼基吡啶10 (13.24 g, 91 mmol)和氯仿(97 mL, 0.78 M),然后滴加(通过加料漏斗)溴(9.40 mL, 182 mmol, 2当量)。将反应混合物加热至回流6小时,然后冷却至室温并通过硅藻土过滤。将滤液用饱和Na2CO3水溶液(25 mL)、盐水(25 mL)洗涤,经Na2SO4干燥,然后通过硅藻土过滤并真空浓缩。使用粗制的4-溴-2,6-二氟吡啶11 (11.8 g, 60.8 mmol)而不进行进一步纯化。1H NMR (500 MHz, CDCl3) δ 7.04 (s, 2H)。
中间体8: 4-溴-2-氟-6-甲氧基吡啶
在N2气氛下,在室温下,向具有磁力搅拌棒的烘箱干燥的圆底烧瓶中加入4-溴-2,6-二氟吡啶11 (10.8 g, 55.7 mmol)和甲醇(111 mL, 0.5 M),然后加入甲醇钠(10.83 g,50.1 mmol, 0.9当量)。将反应混合物加热至40℃保持1小时,然后冷却至室温。将悬浮液在EtAOc (100 mL)和水(50 mL)之间分配。将有机物用盐水(25 mL)洗涤,经Na2SO4干燥,通过硅藻土过滤,并真空浓缩。使用柱色谱(0-100%EtOAc/己烷,梯度)纯化粗残余物,得到4-溴-2-氟-6-甲氧基吡啶8 (7.29 g, 35.4 mmol)。1H NMR (500 MHz, CDCl3) δ 7.77 (s,1H), 7.63 (s, 1H), 3.86 (2, 3H)。
实施例1: 1-((3R,4S)或(3S,4R)-4-氰基四氢-2H-吡喃-3-基)-3-((2-氟-6-甲氧基吡啶-4-基)氨基)-1H-吡唑-4-甲酰胺
在500 mL三颈烧瓶上安装回流冷凝器和J-KEM热电偶,然后加入3-氨基-1-((3R,4S)-4-氰基四氢-2H-吡喃-3-基)-1H-吡唑-4-甲酰胺5 (10.0 g, 42.5 mmol)、4-溴-2-氟-6-甲氧基吡啶8 (14.1 g, 63.7 mmol)、乙酸钾(6.26 g, 63.8 mmol)和2-丙醇(150 ml)。将反应混合物用双氮气体喷射20分钟,然后加入Pd2(dba)3 (1.95 g, 2.13 mmol)和2-二叔丁基膦基-2',4',6'-三异丙基联苯(2.00 g, 4.71 mmol)。然后将反应混合物加热至80℃保持16.5小时。冷却至23℃后,加入丙酮(150 mL)并将混合物搅拌10分钟,然后通过硅藻土过滤,用丙酮洗脱。将滤液真空浓缩到硅胶上,并通过快速柱色谱纯化(ISCO 220g小柱,用3-6%甲醇-二氯甲烷梯度洗脱)。浓缩含产物的级分,得到1-((3R,4S)或(3S,4R)-4-氰基四氢-2H-吡喃-3-基)-3-((2-氟-6-甲氧基吡啶4-基)氨基)-1H-吡唑-4-甲酰胺,为亮黄色固体。
1H NMR (600 MHz, DMSO-d6): δ 9.63 (s, 1H), 8.34 (s, 1H), 7.29 (s,1H), 7.28 (s, 1H), 6.66 (d, 2H), 4.59 (m, 1H), 4.00 (m, 1H), 3.87 (m, 1H),3.76 (s, 3H), 3.65 – 3.58 (m, 2H), 3.46 (m, 1H), 2.12 (m, 1H), 1.94 (m, 1H).LRMS (ESI) C16H17FN6O3计算值[M+H]+: 361, 实测值: 361。
生物测定
实验程序
Jak生物化学HTRF酶测定方案
在HTRF形式的生化测定中,使用每种酶的重组纯化的GST标记的催化结构域(InVitrogen/ Life Technologies/ ThermoFisher, 目录号: JAK1, #M4290; JAK2, #M4290; JAK3, #M4290; TYK2 #M4290) 定量化合物抑制JAK1、JAK2、JAK3和TYK2的催化活性的能力。反应采用常见的肽底物LCB-EQEDEPEGDYFEWLW-NH2 (Merck)。基本测定方案如下:首先,使用Labcyte Echo 555声学分配器(acoustic dispenser)将50 nL稀释的化合物的DMSO溶液分配到干燥的384孔测定板(Perkin Elmer Opti-plate, 目录号 6007290)的孔中。随后的试剂添加采用Agilent Bravo自动移液器。接下来,将18μL的1.11X酶(以可得到背景对照10倍的最低浓度加入,该浓度使反应在反应过程中保持在初始速度(参见下表))和在1X测定缓冲液 (Invitrogen激酶缓冲液# PV3189, 2 mM DTT, 0.05% BSA)中的1.11X底物加入孔中,摇动,然后在室温下孵育30分钟以使化合物结合并达到平衡。在该步骤之后,加入2μL的在1X测定缓冲液中的10X ATP以启动激酶反应,保持ATP浓度在等于针对每种酶制剂计算的表观Km的浓度(参见下表),摇动板,然后在23℃下孵育80分钟。在孵育结束时,加入20μL 2X终止缓冲液(链霉亲和素-Dylight 650 (ThermoFisher #84547B/100mL)、铕标记的pY20抗体(Perkin Elmer #AD0067)、EDTA、HEPES和Triton)以淬灭反应。摇动平板并离心,然后在室温下孵育60分钟,然后在Perkin Elmer Envision (λex = 337nm, λem = 665和615 nm, TRF延迟时间= 20 µs)上读数。HTRF信号= 10,000 * 665 nm读数/615nm读数。在相对未处理对照标准化后,计算每种化合物浓度下HTRF信号的抑制百分比。如上所述对于细胞测定进行抑制百分比vs.化合物浓度对数值的作图以计算IC50值。最终反应条件是:
测试的化合物浓度为1496、499、175、49.9、18.7、6.2、2.1、0.75、0.24、0.075和0.0125 nM。最终[DMSO]调节为0.25 %。
测定性能和数据质量控制:
通过计算泛-JAK和选择性-JAK参考分子在测定组中的最小显著性比(MSR)值来跟踪酶测定的性能:
参考化合物 | 结构 | 名称 | 来源 |
A | 3-[(4-氯苯基)氨基]-1-[(1S,2S,4S或1R,2R,4R)-2-氰基-4-(二甲基氨基)环己基]-1H-吡唑-4-甲酰胺 | WO2013/040863,第225页,化合物28-117 | |
B | (1S,2S)-2-(3-{[4-(甲基磺酰基)苯基]氨基}-4-氧代-4,5-二氢-1H-吡唑并[4,3-c]吡啶-1-基)环己烷甲腈 | WO2014/146490,第163页,化合物3-5 |
参考化合物No.1(JAK1选择性)的效力为:JAK1 IC50 = 1.47 nM +/- 0.40, N=392;JAK2 IC50 = 19.04 +/- 4.15 nM, N = 393;JAK3 IC50 = 1351.45 nM +/- 129.93,N = 398和TYK2 IC50 = 13.96 nM +/- 3.17, N = 394。
参考化合物No.2(JAK1泛抑制剂)的效力为:JAK1 IC50 = 0.17 nM +/- 0.06, N=399;JAK2 IC50 = 1.00 +/- 0.29 nM, N = 400;JAK3 IC50 = 21.95 nM +/- 6.08, N =404和TYK2 IC50 = 0.28 nM +/- 0.09, N = 401。
JAK细胞途径参与测定:
使用CellSensor®转录报告子技术(Life Technologies/ ThermoFisher:https://www.thermofisher.com/us/en/home/industrial/pharma-biopharma/drug- discovery- development/target-and-lead-identification-and-validation/pathway- biology/cellular-pathway-analysis/cellsensor-cell-lines.html),在两个独立的经工程改造以检测IL4、IL6和EPO信号传导的细胞系中,以拮抗剂模式对完整细胞中JAK1和JAK2激酶活性的抑制进行定量。简而言之,对受监测途径有响应的、携带在特定顺式调控STAT元件的控制下的稳定整合β-内酰胺酶报告基因的CellSensor®细胞系(参见下面每个测定的详细信息)用在DMSO中连续稀释的测试化合物进行预处理(参见化合物和激动剂细胞因子的制备和给药部分)。在与化合物一起孵育后,将IL6或EPO以等于达到最大响应的80%所需的剂量(EC80)的浓度添加到每个同源细胞系中。在细胞因子刺激后,使用LiveBLAzerTM Loading试剂盒(LiveBLAzer™-FRET B/G底物, CCF4-AM,来自LifeTechnologies)原位检测β-内酰胺酶活性的细胞水平,其中底物(在405 nm发射荧光)和裂解产物(在488 nm发射荧光)的荧光在Acumen Explorer ex3读数器(TTP Labtech)中定量。将报告测试化合物处理孔的抑制百分比的标准化荧光值相对于选择的10个剂量中的每一个的浓度的对数值作图,以使用4-参数拟合剂量响应方程来建立剂量响应曲线(DRC)以在Assay Data Analyzer软件(Merck Frosst Canada & Co - 2003)中计算实现50%的最大活性抑制所需的浓度(IC50或效力值)。作为在DMSO对照处理孔中测量的β内酰胺酶水平(0%抑制)vs. 用足以实现100%的β-内酰胺酶生成阻断的剂量的泛-JAK抑制剂处理的孔中的β-内酰胺酶水平的函数,计算抑制百分比。与化合物、细胞因子和LiveBLAzerTM 一起在37℃下在保持在90%湿度和5%CO2下的组织培养箱中进行孵育。
用于量化JAK调节途径的功能抑制的激动剂和细胞系配对如下:
白细胞介素6 (IL6) - JAK1/JAK2 - STAT4途径:CellSensor™ SIE-bla ME-180细胞,其携带在Sis-诱导元件(SIE)控制下的稳定整合β-内酰胺酶报告基因。
促红细胞生成素(EPO) - JAK2 - STAT5途径:CellSensor irf1-bla TF-1细胞携带在存在于干扰素调节因子I(IRF1)基因启动子中的STAT5响应元件的控制下的稳定整合β-内酰胺酶报告基因。
化合物和细胞因子的制备和给药:使用Tecan Freedom EVO-2 200自动移液器在平底透明的Echo Qualified384孔聚丙烯微板(384PP)(Labcyte, Cat# P-05525)中将在DMSO中制备的10 mM储备化合物储备液在DMSO中以1:3连续稀释10倍。使用ECHO声学分配器550(Labcyte)在干燥的384孔透明平底黑色聚苯乙烯TC-处理的微板(Corning Cat# 3712)中分配60 nL的每种剂量的化合物。随后按照供应商的说明将各CellSensor®细胞系铺板(于32μL中的30,000个细胞/孔)并与化合物混合。孵育60分钟后,随后通过加入8μL同源细胞因子(IL6和EPO的EC80剂量)刺激细胞并再孵育3小时,然后加入LiveBLAzer™-FRET B/G底物。测试化合物的最终剂量为:14977;4992;1664;554;184;61.6;20.5;6.8;2.3和0.76nM。最终的DMSO浓度保持在0.15%。
测定性能和数据质量控制:使用三个参数来验证每个单独测定组的质量,并确保开发精密的构效关系(SAR),这使得能够辨别效力差异低至3-4倍的化合物之间的差异:
(A)为了验证细胞因子的刺激在实现80%刺激所需剂量(EC80)的可接受的+/- 5%内,每个板中包括16点激动剂剂量响应曲线(DRC),并使用该DRC 倒推整个板达到的刺激水平。DRC的最高剂量为:IL6为500 ng/mL,EPO为100 ng/mL。
(B)每个测定板中包括两种参考化合物的DRC,每个板含有总共32种化合物:
参考化合物No. A (JAK1选择性分子)在IL6 CellSensor测定中的效力(IC50 =51.9 +/- 23.6 nM, N = 627)是在EPO CellSensor测定中的效力(IC50 = 623.5 +/-132.3 nM, N = 617)的12倍。在IL4 CellSensor测定中的活性为:IC50 = 25.7 +/- 8.4nM, N = 307。
参考化合物No. B. (泛-JAK抑制剂)表现出在两个测定中的效力差在2-3倍之内。IL6/JAK1-JAK2测定:IC50 = 21+/-9.1 nM, N = 652,EPO/JAK2测定:IC50 = 39.5+/-12.4nM, N = 626。
(C) 通过计算追踪两种参考化合物IC50效力值的最小显著性比(MSR,参见Eastwood等人,Journal of Biomolecular Screening 11(X); 2006)来监测跨重复板和独立组的测定再现性。
生物数据
如上所述,在JAK1、JAK2和JAK3体外结合测定以及IL-6和EPO细胞途径参与测定中评价本发明的实施例。表1列出了本发明在JAK1、JAK2和JAK3体外结合测定以及IL-6和EPO细胞途径参与测定中的IC50值,以及JAK2/JAK1 IC50s、JAK3/JAK1 IC50s和EPO/IL-6IC50s的比率。表2列出了IV给药后在狗中的本发明的药代动力学参数。表3显示了其他JAK1化合物的可比数据。
表1.
表2
化合物1的狗药代动力学(PK)
PK参数 | 值 |
剂量 (mg/kg I.V.) | 0.25 |
AUC (µM.h) | 1.29 |
CL (mL/min/kg) | 9.42 |
Vdss (L/kg) | 1.95 |
T1/2 (h) | 4.38 |
比较例
表3
化合物1的安全性研究
对化合物1进行6周试验性靶动物安全性研究。药物以压缩片口服给药,每天两次,持续6周给予狗,剂量为0.5 mg/kg最大暴露剂量的1倍、3倍和5倍,或每天一次,持续6周给予狗,剂量为1 mg/kg最大暴露剂量的5倍。在临床观察、粪便观察、体重、体重变化、食物消耗、身体检查参数、血压、眼科学或心脏病学中未观察到测试物相关效应。在包括器官重量和宏观和微观发现在内的死后评估中未观察到测试物相关效应。基于该研究中的发现,未观察到不良效应水平(NOAEL)为作为每日一次剂量的5.0 mg/kg/天,或2.5 mg/kg BID。假设化合物1的JAK-1选择性与较低选择性的化合物如奥拉替尼(Apoquel®)相比提供了更大的安全范围。来自试验性靶动物安全性研究的这些数据为该假设提供了证据,并且表明化合物1可以有效地治疗犬特应性皮炎并且具有改善的安全范围。
IL-31诱导的瘙痒模型中的化合物1
作为体内JAK-1抑制的量度,并且通过扩展化合物1的预期临床功效,我们在相关药效学模型中评价化合物1并包括临床参考。犬白细胞介素-31 (cIL-31)已被证实与狗的特应性和过敏性皮炎相关的瘙痒有关[Gonzales等人, Vet Dermatol 2013; 24: 48–e12 ],IL-31可以在与其受体复合物结合后激活JAK-1和JAK-2信号传导分子[Zhang等人,Cytokine & Growth Factor Reviews 19 (2008) 347–356]。对比格犬的cIL-31给药产生强烈的瘙痒反应,这可以通过用JAK抑制剂奥拉替尼预先处理来抑制[Gonzales等人, Vet Dermatol 2016; 27: 34–e10]。使用随机、非盲、交叉研究设计,在cIL-31攻击前2小时(化合物1和Apoquel®的近似Tmax)将化合物1(1 mg/kg体重)、Apoquel®或安慰剂给予实验室比格犬。在cIL-31攻击后观察狗2小时,记录动物参与瘙痒行为的时间。在该研究中,化合物1显著抑制了cIL-31诱导的瘙痒;幅度类似于Apoquel。在使用随机、非盲交叉设计的第二项研究中,评价了几个剂量的化合物1(0.5、0.1和0.05 mg/kg体重);还包括Apoquel®和安慰剂治疗。化合物1在0.5 mg/kg体重剂量下显著抑制瘙痒,但在0.1和0.5 mg/kg体重剂量下没有显著抑制瘙痒。0.5 mg/kg化合物1和Apoquel®的作用幅度相似。参见图1A和1B。
参考文献
Zhang Q., P. Putheti, Q. Zhou, Q. Liu, W. Gao. Structures andbiological functions of IL-31 and IL-31 receptors. Cytokine & Growth FactorReviews 19 (2008) 347–356.
Gonzales, A., W.R. Humphrey, J.E. Messamore, T.J. Fleck, G.J. Fici,J.A. Shelly, J.F. Teel, G.F. Bammert, S.A. Dunham, TE. Fuller和R.B. McCall.Interleukin-31: its role in canine pruritus and naturally occurring canineatopic dermatitis. Vet Dermatol 2013; 24: 48–e12.
Gonzales, A, T.J. Fleck, W.R. Humphrey, B. A. Galvan, M.M. Aleo, S.P.Mahabir, J.-K. Tena, K.G. Greenwood和R.B. McCall. IL-31-induced pruritus indogs: a novel experimental model to evaluate nti-pruritic effects of caninetherapeutics. Vet Dermatol 2016; 27: 34–e10。
临床评估:在被诊断为特应性皮炎的狗的设盲和随机概念验证研究中评价该化合物。本研究的目的是评价化合物对客户所有狗中特应性皮炎的疗效和耐受性。该化合物以两个剂量给药,并与安慰剂对照比较。狗口服给药每天两次,最多14天,然后每天一次,最多28天,并分别使用瘙痒视觉模拟量表(PVAS)和犬特应性皮炎程度和严重指数(CADESI-4)评分工具评价瘙痒和皮肤损害。
CADESI-4是一种严重程度量表,用于在治疗患有特应性皮炎(AD)的狗的临床试验中对皮肤损害进行分级。在20个身体部位的每一个中,对三种损害类型(红斑、苔藓化和脱发/表皮脱落)从0到3评分,最高得分为180,建议的轻度、中度和重度AD皮肤损害基准分别为10、35和60。PVAS是一种视觉模拟量表,包含发痒严重程度和发痒相关行为的特征。它通常用于确定在治疗患有AD的狗的临床试验中瘙痒的严重程度。
CADESI-4: Thierry, O., Manolis, S., Nuttall, T., Bensignor, E.,Griffin, C., Hill, P., for the International Committee on Allergic Diseasesof Animals (ICADA). Validation of the Canine Atopic Dermatitis Extent andSeverity Index (CADESI)-4, a simplified severity scale for assessing skinlesions of atopic dermatitis in dogs. Vet, Dermatol. 25:77-e25, 2014
PVAS: Hill, P.B., Lau, P.,和Rybnicek, J. Development of an owner-assessed scale to measure the severity of pruritus in dogs. Vet. Dermatol.18:301-308, 2007.
Claims (23)
1.式I的化合物或其药学上可接受的盐或立体异构体:
2.权利要求1的化合物,其中所述化合物为
3.药物组合物,其包含权利要求1-2中任一项的化合物或其药学上可接受的盐或立体异构体和药学上可接受的载体。
4.治疗有效量的权利要求1-2中任一项的化合物或其药学上可接受的盐或权利要求3的药物组合物在制备用于治疗哺乳动物的JAK-1介导的疾病的药物中的用途。
5.权利要求4的用途,其中所述JAK-1介导的疾病是通过相对于JAK2和JAK3选择性抑制Janus激酶JAK1来改善的疾病。
6.权利要求4-5中任一项的用途,其中所述疾病选自过敏性皮炎、特应性皮炎、关节炎、干燥性角膜结膜炎、自身免疫疾病或病症和癌症。
7.权利要求6的用途,其中所述疾病是特应性皮炎。
8.权利要求6的用途,其中所述疾病是自身免疫疾病或病症。
9.权利要求6的用途,其中所述疾病是关节炎。
10.权利要求4-5中任一项的用途,其中所述哺乳动物是伴侣动物哺乳动物。
11.权利要求10的用途,其中所述伴侣动物是狗、猫或马。
12.权利要求6的用途,其中所述疾病是干燥性角膜结膜炎。
13.权利要求4-5中任一项的用途,其中所述药物口服、肠胃外或局部给药。
14.权利要求5的用途,其中JAK2(IC50)/JAK1(IC50)的比率为至少5。
15.权利要求5的用途,其中JAK2(IC50)/JAK1(IC50)的比率为至少10。
16.权利要求5的用途,其中JAK2(IC50)/JAK1(IC50)的比率为至少12。
17.权利要求4-5中任一项的用途,其中所述化合物的日剂量为0.001mg/kg至100mg/kg体重。
18.权利要求4-5中任一项的用途,其中所述化合物的日剂量为0.01mg/kg至10mg/kg体重。
19.权利要求4-5中任一项的用途,其中所述化合物的日剂量为0.1mg/kg至3.0mg/kg体重。
20.权利要求4-5中任一项的用途,其中所述化合物的日剂量为0.2mg/kg至1.0mg/kg体重。
21.权利要求5的用途,其中JAK3(IC50)/JAK1(IC50)的比率为至少1000。
22.权利要求5的用途,其中JAK3(IC50)/JAK1(IC50)的比率为至少750。
23.权利要求5的用途,其中JAK3(IC50)/JAK1(IC50)的比率为至少500。
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