CN110582501B - Tyk2抑制剂、其用途和生产方法 - Google Patents
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Abstract
本发明提供可用作酪氨酸激酶2(Tyk2)抑制剂的化合物、其固体形式和组合物、其生产方法和使用其治疗Tyk2介导疾病的方法。
Description
技术领域
本发明涉及可用于抑制非受体酪氨酸-蛋白激酶2(“TYK2”)(也称为酪氨酸激酶2)的化合物和方法。本发明还提供所述化合物的固体形式、包含所述化合物的药学上可接受的组合物、所述化合物的生产方法和使用所述化合物和组合物治疗各种病症的方法。
背景技术
近年来,通过更好地理解与疾病相关的酶和其它生物分子的结构来大力辅助对于新治疗剂的研究。已成为广泛研究的标的物的一类重要酶是蛋白激酶家族。
蛋白质激酶构成负责控制细胞内的各种信号转导过程的结构相关酶的大家族。蛋白质激酶可视为是源自常见祖先基因(因其结构和催化功能的保守)。几乎所有激酶都含有类似的250-300个氨基酸催化结构域。激酶可通过其所磷酸化的底物(例如蛋白质-酪氨酸、蛋白质-丝氨酸/苏氨酸、脂质等)而分成诸多家族。
一般来说,蛋白质激酶通过实现从三磷酸核苷到蛋白质受体的涉及信号传导路径的磷酰基转移来介导细胞内信号传导。这些磷酸化事件用作可调节或调控靶蛋白生物功能的分子导通/关断开关。这些磷酸化事件最终响应各种细胞外刺激和其它刺激而触发。所述刺激的实例包括环境和化学应力信号(例如渗透冲击、热冲击、紫外线辐射、细菌内毒素和H2O2)、细胞因子(例如白介素-1(IL-1)、白介素-8(IL-8)和肿瘤坏死因子α(TNF-a))和生长因子(例如粒细胞巨噬细胞集落刺激因子(GM-CSF)和成纤维细胞生长因子(FGF))。细胞外刺激可影响一或多种与以下有关的细胞反应:细胞生长、迁移、分化、激素分泌、转录因子活化、肌肉收缩、葡萄糖代谢、蛋白质合成的控制和细胞循环的调控。
许多疾病与由激酶介导事件触发的异常细胞反应相关。这些疾病包括(但不限于)自体免疫疾病、炎症性疾病、骨病、代谢疾病、神经学和神经退化性疾病、癌症、心血管疾病、过敏和气喘、阿兹海默氏病(Alzheimer’s disease)和激素相关疾病。因此,仍需要探寻可用作治疗剂的蛋白质激酶抑制剂。
附图说明
图1绘示化合物1的游离碱的形式I’的X-射线粉末衍射(XRPD)图案。
图2绘示化合物1的甲磺酸盐的形式I的X射线粉末衍射图案。
图3绘示化合物1的甲磺酸盐的形式II的X射线粉末衍射图案。
图4绘示化合物1的甲磺酸盐的形式III的X射线粉末衍射图案。
图5绘示化合物1的甲磺酸盐的形式IV的X射线粉末衍射图案。
图6绘示化合物1的甲磺酸盐的形式V的X射线粉末衍射图案。
图7绘示化合物1和化合物9在狗中的药物代谢动力学研究的结果。
具体实施方式
本发明的某些方面的一般说明:
现已惊人地发现,下式I的化合物和其药学上可接受的盐是具有有利的类药性的强效选择性Tyk2抑制剂:
其中X、Y和Z中的每一者独立地是氢或氘。
式I化合物在各种分析和治疗模型(包括展现Tyk2的抑制、增殖性病症和炎症性疾病的治疗的那些)中有活性。
另外,本发明提供式I化合物的固体形式和其药学上可接受的盐,其赋予所需特征,例如改良的水性溶解性、稳定性和调配便利性。
还揭示用于生产式I化合物的新颖合成方法、以及所述化合物的合成中的新颖中间体。所述方法和中间体由于高产率、有利的物理化学性质和与最新技术相比减少使用毒性试剂或溶剂而适用于大规模生产。
化合物
如上文概述,本发明提供式I化合物:
其中X、Y和Z中的每一者独立地是氢或氘。
在一些实施例中,X是氢。在一些实施例中,X是氘。
在一些实施例中,Y是氢。在一些实施例中,Y是氘。
在一些实施例中,Z是氢。在一些实施例中,Z是氘。
在一些实施例中,X、Y和Z中的每一者是氢,由此提供化合物1:
此处绘示为其游离碱。然而,为了避免疑问,除非另外陈述,否则术语“化合物1”打算涵盖上文绘示为其游离碱或其药学上可接受的盐的化合物。
在一些实施例中,本发明提供化合物1的甲磺酸盐,本文中还表示为化合物1M:
在一些实施例中,本发明提供带有一或多个氘原子替代氢(即其中X、Y或Z中的一或多者是氘)的式I化合物或其药学上可接受的盐。在一些实施例中,所述化合物包括以下化合物或其药学上可接受的盐:
在一些实施例中,本发明提供式I化合物的甲磺酸盐。在一些实施例中,本发明提供上表中的化合物2、3、4、5或6中的一者的甲磺酸盐。
化合物1的固体形式
在一些实施例中,本发明提供化合物1的固体形式。在一些实施例中,本发明提供大体上不含杂质的化合物1的固体形式。如本文所用术语“大体上不含杂质”意指化合物不含大量外来物质。所述外来物质可包括残余溶剂或可从化合物1的制备和/或分离产生的任何其它杂质。在某些实施例中,存在至少约95重量%的化合物1。在本发明的又一些实施例中,存在至少约99重量%的化合物1。
根据一实施例,化合物1是以至少约97.0重量%、97.5重量%、98.0重量%、98.5重量%、99.0重量%、99.5重量%或99.8重量%的量存在,其中重量比是基于组合物的总重量。根据另一实施例,相对于HPLC色谱图的总面积,化合物1含有不超过约3.0面积%HPLC的总有机杂质,并且在某些实施例中不超过约1.5面积%HPLC的总有机杂质。在其它实施例中,相对于HPLC色谱图的总面积,化合物1含有不超过约1.0%面积%HPLC的任何单一杂质,并且在某些实施例中不超过约0.5面积%HPLC的任何单一杂质。
在一些实施例中,化合物1是以游离碱形式存在。在一些实施例中,化合物1是以药学上可接受的盐形式存在。
在一些实施例中,本发明提供化合物1的游离碱的固体形式。在一些实施例中,本发明提供呈药学上可接受的盐形式的化合物1的固体形式。在一些实施例中,本发明提供化合物1M的固体形式。
针对化合物1绘示的结果还意指包括化合物1的所有互变异构形式。另外,此处绘示的结构还意指包括除明确定义的任何同位素富集原子外仅一或多个同位素富集的原子的存在不同的化合物。举例来说,具有本发明结构的化合物(氢由氘或氚置换、或碳由13C-或14C-富集碳置换者除外)都属于本发明范围内。
已发现,化合物1可以各种固体形式存在。所述形式包括多形体、溶剂合物、水合物和非晶形。本发明涵盖所有所述形式。在某些实施例中,本发明提供呈一或多种选自多形体、溶剂合物、水合物和非晶形化合物1的固体形式的混合物形式的化合物1。
在一些实施例中,化合物1的固体形式是非晶形固体。在某些实施例中,本发明提供呈大体上不含结晶化合物1的非晶形固体形式的化合物1。如本文所用术语“大体上不含结晶化合物1”意指化合物不含大量结晶化合物1。在某些实施例中,存在至少约95重量%的非晶形化合物1。在本发明的其它实施例中,存在至少约99重量%的非晶形化合物1。在一些实施例中,本发明提供非晶形化合物1游离碱。在一些实施例中,本发明提供呈其药学上可接受的盐形式的非晶形化合物1。在一些实施例中,本发明提供非晶形化合物1M。
如本文所用术语“多形体”是指化合物可结晶的不同晶体结构中的任一者。如本文所用术语“溶剂合物”是指具有化学计量或非化学计算量的纳入晶体结构中的溶剂的晶体形式。类似地,术语“水合物”尤其是指具有化学计量或非化学计算量的纳入晶体结构中的水的晶体形式。
在某些实施例中,化合物1的固体形式是结晶固体。在一些实施例中,化合物1是大体上不含非晶形化合物1的结晶固体。如本文所用术语“大体上不含非晶形化合物1”意指化合物不含大量非晶形化合物1。在某些实施例中,存在至少约95重量%的结晶化合物1。在本发明的其它实施例中,存在至少约99重量%的结晶化合物1。
在一些实施例中,化合物1的固体形式是净晶体形式,并且因此其晶体结构中未纳入任何水或其它溶剂。现已发现,化合物1可以至少一种不同净(即无水、非溶剂合物)晶体形式存在。化合物1的所述净晶体形式包括化合物1甲磺酸盐的形式I,其详细描述于本文中。
在一些实施例中,本发明提供化合物1的溶剂化结晶型。化合物1的所述溶剂化结晶型包括化合物1甲磺酸盐的形式II、形式III、形式IV和形式V和化合物1游离碱的形式I’。
在一些实施例中,本发明提供选自称作形式I、形式II、形式III、形式IV或形式V的那些中的任一者的化合物1的结晶型。本文描述制备化合物1的形式I到V和I’中的每一者的方法。
在一些实施例中,本发明提供称作形式I’的化合物1游离碱的多晶型。
在一些实施例中,本发明提供化合物1的形式I’,其具有大体上类似于图1中所绘示的粉末X射线衍射图案。
如本文所用术语“约”在提到°2θ值使用时是指在示例中描述的试样制备和数据收集条件下获得的所述值±0.1°2θ。所属领域技术人员应了解,特定XRPD获取参数的变化将影响XRPD图案和所获得的°2θ的特定值。
在一些实施例中,化合物1游离碱的形式I’的特征在于其在其粉末X射线衍射图案中具有一或多个选自下表1中的那些的峰。
表1:化合物1形式I’的XRPD峰
在一些实施例中,化合物1游离碱的形式I’的特征在于其在其粉末X射线衍射图案中具有两个以上选自表1中的那些的峰。在一些实施例中,化合物1的形式I’的特征在于其在其粉末X射线衍射图案中具有三个以上选自表1中的那些的峰。在一些实施例中,化合物1的形式I’的特征在于其在其粉末X射线衍射图案中具有四个以上选自表1中的那些的峰。在一些实施例中,化合物1的形式I’的特征在于其在其粉末X射线衍射图案中具有五个以上选自表1中的那些的峰。在一些实施例中,化合物1的形式I’的特征在于其在其X射线衍射图案中具有表1中的10个峰。在一些实施例中,化合物1的形式I’的特征在于其在其X射线衍射图案中具有表1中的15个峰。在一些实施例中,化合物1的形式I’的特征在于其在其X射线衍射图案中具有表1中的20个峰。在一些实施例中,化合物1的形式I’的特征在于其在其X射线衍射图案中具有表1中的所有峰。
在一些实施例中,化合物1的形式I的特征在于其在其粉末X射线衍射图案中具有一或多个选自在约6.07、约11.90、约16.62和约13.95°2θ的那些峰的峰。在一些实施例中,化合物1的形式I的特征在于其在其粉末X射线衍射图案中具有两个以上选自在约6.07、约11.90、约16.62和约13.95°2θ的那些峰的峰。在一些实施例中,化合物1的形式I的特征在于其在其粉末X射线衍射图案中具有三个以上选自在约6.07、约11.90、约16.62和约13.95°2θ的那些峰的峰。在一些实施例中,化合物1的形式I的特征在于其在其粉末X射线衍射图案中具有四个以上选自在约6.07、约11.90、约16.62和约13.95°2θ的那些峰的峰。
在一些实施例中,本发明提供称作形式I的化合物1甲磺酸盐的净结晶型。在一些实施例中,本发明提供化合物1的形式I,其具有大体上类似于图2中所绘示的粉末X射线衍射图案。在一些实施例中,化合物1的形式I的特征在于其在其粉末X射线衍射图案中具有一或多个选自下表2中的那些的峰。
表2.化合物1形式I的XRPD峰
在一些实施例中,化合物1的形式I的特征在于其在其粉末X射线衍射图案中具有两个以上选自表2中的那些的峰。在一些实施例中,化合物1的形式I的特征在于其在其粉末X射线衍射图案中具有三个以上选自表2中的那些的峰。在一些实施例中,化合物1的形式I的特征在于其在其粉末X射线衍射图案中具有四个以上选自表2中的那些的峰。在一些实施例中,化合物1的形式I的特征在于其在其粉末X射线衍射图案中具有五个以上选自表2中的那些的峰。在一些实施例中,化合物1的形式I的特征在于其在其X射线衍射图案中具有表2中的所有峰。
在一些实施例中,化合物1的形式I的特征在于其在其粉末X射线衍射图案中具有一或多个选自在约19.89、约9.17、约16.88、约14.37和约22.09°2θ的那些峰的峰。在一些实施例中,化合物1的形式I的特征在于其在其粉末X射线衍射图案中具有两个以上选自在约19.89、约9.17、约16.88、约14.37和约22.09°2θ的那些峰的峰。在一些实施例中,化合物1的形式I的特征在于其在其粉末X射线衍射图案中具有三个以上选自在约19.89、约9.17、约16.88、约14.37和约22.09°2θ的那些峰的峰。在一些实施例中,化合物1的形式I的特征在于其在其粉末X射线衍射图案中具有四个以上选自在约19.89、约9.17、约16.88、约14.37和约22.09°2θ的那些峰的峰。在一些实施例中,化合物1的形式I的特征在于其在其粉末X射线衍射图案中具有选自在约19.89、约9.17、约16.88、约14.37和约22.09°2θ的那些峰的所有五个峰。
在一些实施例中,本发明提供称作形式II的化合物1甲磺酸盐的溶剂化结晶型。在一些实施例中,本发明提供化合物1的形式II,其具有大体上类似于图3中所绘示的粉末X射线衍射图案。在一些实施例中,化合物1的形式II的特征在于其在其粉末X射线衍射图案中具有一或多个选自下表3中的那些的峰。
表3.化合物1形式II的XRPD峰
在一些实施例中,化合物1的形式II的特征在于其在其粉末X射线衍射图案中具有两个以上选自表3中的那些的峰。在一些实施例中,化合物1的形式II的特征在于其在其粉末X射线衍射图案中具有三个以上选自表3中的那些的峰。在一些实施例中,化合物1的形式II的特征在于其在其粉末X射线衍射图案中具有四个以上选自表3中的那些的峰。在一些实施例中,化合物1的形式II的特征在于其在其粉末X射线衍射图案中具有五个以上选自表3中的那些的峰。在一些实施例中,化合物1的形式II的特征在于其在其X射线衍射图案中具有表3中的所有峰。
在一些实施例中,化合物1的形式II的特征在于其在其粉末X射线衍射图案中具有一或多个选自在约22.27、约26.45、约26.02、约16.34和约17.06°2θ的那些峰的峰。在一些实施例中,化合物1的形式II的特征在于其在其粉末X射线衍射图案中具有两个以上选自在约22.27、约26.45、约26.02、约16.34和约17.06°2θ的那些峰的峰。在一些实施例中,化合物1的形式II的特征在于其在其粉末X射线衍射图案中具有三个以上选自在约22.27、约26.45、约26.02、约16.34和约17.06°2θ的那些峰的峰。在一些实施例中,化合物1的形式II的特征在于其在其粉末X射线衍射图案中具有四个以上选自在约22.27、约26.45、约26.02、约16.34和约17.06°2θ的那些峰的峰。在一些实施例中,化合物1的形式II的特征在于其在其粉末X射线衍射图案中具有选自在约22.27、约26.45、约26.02、约16.34和约17.06°2θ的那些峰的所有五个峰。
在一些实施例中,本发明提供称作形式III的化合物1甲磺酸盐的溶剂化结晶型。在一些实施例中,本发明提供化合物1的形式III,其具有大体上类似于图4中所绘示的粉末X射线衍射图案。在一些实施例中,化合物1的形式III的特征在于其在其粉末X射线衍射图案中具有一或多个选自下表4中所列示的那些的峰。
表4.化合物1形式III的XRPD峰
位置(°2θ) | 高度(cts) | 相对强度(%) |
7.6100 | 318.58 | 34.04 |
9.0773 | 96.96 | 10.36 |
9.8524 | 353.97 | 37.82 |
11.1997 | 78.66 | 8.41 |
11.8535 | 255.91 | 27.35 |
13.1453 | 165.85 | 17.72 |
14.2078 | 273.03 | 29.18 |
15.6943 | 148.26 | 15.84 |
16.9586 | 550.52 | 58.83 |
17.2500 | 324.76 | 34.70 |
18.1827 | 935.85 | 100.00 |
18.5648 | 603.68 | 64.51 |
19.7502 | 116.00 | 12.40 |
20.1432 | 91.76 | 9.81 |
21.9569 | 470.43 | 50.27 |
24.3804 | 135.50 | 14.48 |
25.4532 | 333.87 | 35.68 |
26.4804 | 285.80 | 30.54 |
在一些实施例中,化合物1的形式III的特征在于其在其粉末X射线衍射图案中具有两个以上选自表4中的那些的峰。在一些实施例中,化合物1的形式IV的特征在于其在其粉末X射线衍射图案中具有三个以上选自表4中的那些的峰。在一些实施例中,化合物1的形式IV的特征在于其在其粉末X射线衍射图案中具有四个以上选自表4中的那些的峰。在一些实施例中,化合物1的形式IV的特征在于其在其粉末X射线衍射图案中具有五个以上选自表4中的那些的峰。在一些实施例中,化合物1的形式IV的特征在于其在其X射线衍射图案中具有表4中的所有峰。
在一些实施例中,化合物1的形式IV的特征在于其在其粉末X射线衍射图案中具有一或多个选自在约18.18、约18.56、约16.95、约21.95和约9.85°2θ的那些峰的峰。在一些实施例中,化合物1的形式IV的特征在于其在其粉末X射线衍射图案中具有两个以上选自在约18.18、约18.56、约16.95、约21.95和约9.85°2θ的那些峰的峰。在一些实施例中,化合物1的形式IV的特征在于其在其粉末X射线衍射图案中具有三个以上选自在约18.18、约18.56、约16.95、约21.95和约9.85°2θ的那些峰的峰。在一些实施例中,化合物1的形式IV的特征在于其在其粉末X射线衍射图案中具有四个以上选自在约18.18、约18.56、约16.95、约21.95和约9.85°2θ的那些峰的峰。在一些实施例中,化合物1的形式IV的特征在于其在其粉末X射线衍射图案中具有选自在约18.18、约18.56、约16.95、约21.95和约9.85°2θ的那些峰的所有五个峰。
在一些实施例中,本发明提供称作形式IV的化合物1甲磺酸盐的溶剂化结晶型。在一些实施例中,本发明提供化合物1的形式IV,其具有大体上类似于图5中所绘示的粉末X射线衍射图案。在一些实施例中,化合物1的形式IV的特征在于其在其粉末X射线衍射图案中具有一或多个选自下表5中的那些的峰。
表5.化合物1形式IV的XRPD峰
在一些实施例中,化合物1的形式IV的特征在于其在其粉末X射线衍射图案中具有两个以上选自表5中的那些的峰。在一些实施例中,化合物1的形式IV的特征在于其在其粉末X射线衍射图案中具有三个以上选自表5中的那些的峰。在一些实施例中,化合物1的形式IV的特征在于其在其粉末X射线衍射图案中具有四个以上选自表5中的那些的峰。在一些实施例中,化合物1的形式IV的特征在于其在其粉末X射线衍射图案中具有五个以上选自表5中的那些的峰。在一些实施例中,化合物1的形式IV的特征在于其在其X射线衍射图案中具有表5中的所有峰。
在一些实施例中,化合物1的形式IV的特征在于其在其粉末X射线衍射图案中具有一或多个选自在约17.79、约12.45、约24.38、约26.00和约16.28°2θ的那些峰的峰。在一些实施例中,化合物1的形式IV的特征在于其在其粉末X射线衍射图案中具有两个以上选自在约17.79、约12.45、约24.38、约26.00和约16.28°2θ的那些峰的峰。在一些实施例中,化合物1的形式IV的特征在于其在其粉末X射线衍射图案中具有三个以上选自在约17.79、约12.45、约24.38、约26.00和约16.28°2θ的那些峰的峰。在一些实施例中,化合物1的形式IV的特征在于其在其粉末X射线衍射图案中具有四个以上选自在约17.79、约12.45、约24.38、约26.00和约16.28°2θ的那些峰的峰。在一些实施例中,化合物1的形式IV的特征在于其在其粉末X射线衍射图案中具有选自在约17.79、约12.45、约24.38、约26.00和约16.28°2θ的那些峰的所有五个峰。
在一些实施例中,本发明提供称作形式V的化合物1甲磺酸盐的溶剂化结晶型。在一些实施例中,本发明提供化合物1的形式V,其具有大体上类似于图6中所绘示的粉末X射线衍射图案。在一些实施例中,化合物1的形式V的特征在于其在其粉末X射线衍射图案中具有选自下表6中的那些的峰。
表6.化合物1形式V的XRPD峰
在一些实施例中,化合物1的形式V的特征在于其在其粉末X射线衍射图案中具有两个以上选自表5中的那些的峰。在一些实施例中,化合物1的形式V的特征在于其在其粉末X射线衍射图案中具有三个以上选自表5中的那些的峰。在一些实施例中,化合物1的形式V的特征在于其在其粉末X射线衍射图案中具有四个以上选自表5中的那些的峰。在一些实施例中,化合物1的形式V的特征在于其在其粉末X射线衍射图案中具有五个以上选自表5中的那些的峰。在一些实施例中,化合物1的形式V的特征在于其在其X射线衍射图案中具有表5中的所有峰。
在一些实施例中,化合物1的形式V的特征在于其在其粉末X射线衍射图案中具有一或多个选自在约13.34、约8.80、约11.10、约16.85和约25.49°2θ的那些峰的峰。在一些实施例中,化合物1的形式V的特征在于其在其粉末X射线衍射图案中具有两个以上选自在约13.34、约8.80、约11.10、约16.85和约25.49°2θ的那些峰的峰。在一些实施例中,化合物1的形式V的特征在于其在其粉末X射线衍射图案中具有三个以上选自在约13.34、约8.80、约11.10、约16.85和约25.49°2θ的那些峰的峰。在一些实施例中,化合物1的形式V的特征在于其在其粉末X射线衍射图案中具有四个以上选自在约13.34、约8.80、约11.10、约16.85和约25.49°2θ的那些峰的峰。在一些实施例中,化合物1的形式V的特征在于其在其粉末X射线衍射图案中具有选自在约13.34、约8.80、约11.10、约16.85和约25.49°2θ的那些峰的所有五个峰。
化合物和定义:
本发明化合物包括概述于上文中的那些,并且进一步由本文所揭示的种类、子类和物质予以阐释。除非另有说明,否则如本文中所使用,以下定义应适用。出于本发明的目的,根据元素周期表(CAS版,化学和物理手册(Handbook of Chemistry and Physics),第75版)鉴别化学元素。另外,有机化学的一般原理描述于“有机化学(Organic Chemistry)”,托马斯-索雷尔(Thomas Sorrell),大学科学书籍(University Science Books),索萨利托(Sausalito):1999和“马奇高等有机化学(March’s Advanced Organic Chemistry)”,第5版,编辑:史密斯M.B(Smith,M.B.)和马奇J.(March,J.),约翰威利父子公司(John Wiley&Sons),纽约:2001中,其全部内容是以引用方式并入本文中。
如本文中所用术语“药学上可接受的盐”是指在正确医学判断范围内适用于接触人类和低等动物组织而不会产生过度毒性、刺激、过敏反应和诸如此类且具有与合理效益/风险比相称的那些盐。药学上可接受的盐为业内所熟知。举例来说,S.M.贝格(S.M.Berge)等人在医学科学杂志(J.Pharmaceutical Sciences),1977,66,1-19中详细描述药学上可接受的盐,还描述于药用盐手册:性质、选择和用途(Handbook of Pharmaceutical Salts:Properties,Selection,and Use),第2修订版,P.海因里希·斯塔尔(P.Heinrich Stahl)和卡米尔·G·韦尔穆思(Camille G.Wermuth)编辑,威利公司(Wiley),2011年4月中,其中的每一者以引用方式并入本文中。本发明化合物的药学上可接受的盐包括衍生自适宜无机和有机酸和碱的那些。药学上可接受的无毒酸加成盐的实例是氨基与无机酸(例如盐酸、氢溴酸、磷酸、硫酸和高氯酸)或与有机酸(例如乙酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸或丙二酸)或通过使用业内所用的其它方法(例如离子交换)形成的盐。其它药学上可接受的盐包括己二酸盐、海藻酸盐、抗坏血酸盐、天门冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊烷丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚酸盐、已酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟碱酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对-甲苯磺酸盐、十一烷酸盐、戊酸盐和诸如此类。
衍生自适当碱的盐包括金属离子(包括铝、锌、碱金属、碱土金属)、铵和N+(C1-4烷基)4盐。代表性碱金属或碱土金属盐包括钠盐、锂盐、钾盐、钙盐、镁盐和诸如此类。其它药学上可接受的盐包括(如果适当)衍生自无毒铵、季铵和伯胺、仲胺或叔胺胺阳离子的那些,包括(但不限于)衍生自天然或非天然氨基酸的那些。代表性基于胺或铵的盐包括(但不限于)衍生自以下的那些:精氨酸、甜菜碱、哈胺、胆碱、二乙胺、赖氨酸、苄星青霉素、2-(二乙基氨基)-乙醇、乙醇胺、1-(2-羟基乙基)-吡咯烷、二乙醇胺、氨、地阿诺(deanol)、N-甲基-葡萄糖胺、胺丁三醇、三乙醇胺、4-(2-羟基乙基)-吗啉、1H-咪唑、乙二胺、哌嗪、普鲁卡因(procaine)和苯乙苄胺。
3.提供本发明化合物的一般方法
在一些实施例中,本发明提供用于生产式I化合物的合成方法和合成中间体。
在一些实施例中,本发明的式I化合物(包括(但不限于)化合物1)通常可根据下文方案1中绘示的方法来制备,其中X、Y、Z、RE和RPG中的每一者是如本文中的种类和子类中所定义(单独和组合)。
合成1.式I化合物的合成.
如本文所用,RE是C1-6脂肪族基团。在一些实施例中,RE是C1-6烷基。在一些实施例中,RE是甲基或乙基。在一些实施例中,RE是乙基。
如本文所用,RPG是胺保护基团。在一些实施例中,RPG是任选地经取代的苄基或二苯甲基。在一些实施例中,RPG是任选地经取代的苄基。在一些实施例中,RPG是由一或多个甲氧基取代的苄基。在一些实施例中,RPG是2,4-二甲氧基苄基。
在一些实施例中,步骤S-1包含中间体A-1的氧化,由此形成中间体A-2。在一些实施例中,氧化是由过碘酸盐和钌介导。在一些实施例中,过碘酸盐是过碘酸钠。在一些实施例中,钌是RuCl3水合物。
在一些实施例中,步骤S-2包含二酸中间体A-2的酯化,由此形成二酯中间体A-3。在一些实施例中,酯化是碱催化的。在一些实施例中,酯化试剂是硫酸二烷基酯。在一些实施例中,酯化试剂是硫酸二乙基酯。在一些实施例中,碱是碳酸盐碱。在一些实施例中,碱是碳酸钾。在一些实施例中,酯化是在极性非质子溶剂中执行。在一些实施例中,极性非质子溶剂是环状脲。在一些实施例中,极性非质子溶剂是DMPU。
在一些实施例中,步骤S-3包含二酯中间体A-3的选择性单还原以提供式A-4的中间体。在一些实施例中,选择性单还原是利用氢化物还原剂来实现。在一些实施例中,氢化物还原剂是氢化铝。在一些实施例中,氢化物还原剂是DIBAL-H。在一些实施例中,选择性单还原是在有机溶剂中执行。在一些实施例中,有机溶剂是甲苯。在一些实施例中,反应是在介于-70℃到-80℃之间的温度下进行。在一些实施例中,反应保持于介于-70℃到-80℃之间的温度直到经测定完全消耗A-3,并且随后于介于-70℃到-80℃之间的温度下淬灭。在一些实施例中,用于淬灭反应的试剂包含甲醇。在一些实施例中,用于淬灭反应的试剂包含甲醇和盐酸。
在一些实施例中,步骤S-4包含利用经保护氨合成子还原环化式A-4的中间体以提供式A-5的中间体。在一些实施例中,经保护的氨合成子具有式RPG-NH2。在一些实施例中,还原是使用氢化物试剂来实现。在一些实施例中,氢化物试剂是硼氢化物。在一些实施例中,氢化物试剂是三乙酰氧基硼氢化物。在一些实施例中,氢化物试剂是三乙酰氧基硼氢化钠。在一些实施例中,反应是在有机溶剂中进行。在一些实施例中,有机溶剂是甲苯。
在一些实施例中,步骤S-5包含利用二氟苯基合成子使式A-5的中间体进行芳基偶合以提供式A-6的中间体。在一些实施例中,二氟苯基合成子是有机金属试剂。在一些实施例中,二氟苯基合成子是芳基锌试剂。在一些实施例中,芳基偶合是钯催化的偶合。在一些实施例中,芳基偶合是根岸偶合(Negishi coupling)。在一些实施例中,芳基锌试剂是从相应2-溴-1,3-二氟苯制备。在一些实施例中,用有机金属前体处理2-溴-1,3-二氟苯。在一些实施例中,用异丙基氯化镁–氯化锂复合物处理2-溴-1,3-二氟苯以形成芳基镁氯化锂中间体。在一些实施例中,使芳基镁氯化锂中间体与锌盐接触以形成芳基锌试剂。在一些实施例中,锌盐是ZnCl2。在一些实施例中,与式A-5的中间体的芳基偶合是由钯催化剂催化。在一些实施例中,钯催化剂是Pd(PPh3)4。在一些实施例中,芳基偶合是在醚溶剂中进行。在一些实施例中,醚溶剂是THF。
在一些实施例中,步骤S-6包含用式A-6a的苯胺使式A-6的中间体芳基胺化:
其中Y和Z独立地是氢或氘,由此形成式A-7的中间体。在一些实施例中,式A-6a的苯胺是通过用式A6-b的相应吡咯烷胺化对-氨基苯甲酰氯来形成:
其中Y和Z独立地是氢或氘。在一些实施例中,芳基胺化是由钯催化剂系统催化。在一些实施例中,钯催化剂系统包含Pd2(dba)3和山特福斯(Xantphos)。在一些实施例中,芳基胺化是在有机溶剂中进行。在一些实施例中,有机溶剂是二噁烷。
在一些实施例中,步骤S-7包含从式A-7的中间体移除RPG,由此形成式I化合物,其中X是氢。在一些实施例中,RPG的移除包含使式A-7的中间体与酸接触。在一些实施例中,酸包含白蛋白酸。在一些实施例中,酸包含氢溴酸。在一些实施例中,酸包含于乙酸中的氢溴酸。在一些实施例中,反应是在额外溶剂中进行。在一些实施例中,额外溶剂是二氯甲烷。
在一些实施例中,步骤S-8包含式I化合物(其中X是氢)的氢/氘交换,由此形成式I化合物(其中X是氘)。在一些实施例中,氢/氘交换是在氘化溶剂中发生。在一些实施例中,氘化溶剂包含D2O。在一些实施例中,氘化溶剂包含氘化甲醇。在一些实施例中,氘化溶剂包含CH3OD。在一些实施例中,氘化溶剂包含CD3OD。在一些实施例,氘化溶剂包含CDCl3。在一些实施例中,氘化溶剂包含D2O、CH3OD、CD3OD或CDCl3中的两者或两者以上的混合物。在一些实施例中,氢/氘交换是由碱促进。在一些实施例中,碱是衍生自氘化溶剂中的钠金属。
使用、调配和投与以及药学上可接受的组合物
根据另一实施例,本发明提供包含本发明化合物或其药学上可接受的盐、酯或酯盐和药学上可接受的载剂、佐剂或媒剂的组合物。本发明组合物中的化合物的量使得可有效地可测量地抑制生物试样或患者中的Tyk2。在某些实施例中,本发明组合物中的化合物的量使得可有效地可测量地抑制生物试样或患者中的Tyk2。在某些实施例中,本发明组合物经调配用于投与需要所述组合物的患者。在一些实施例中,本发明组合物是经调配用于向患者经口投与。
如本文所用术语“化合物”意指式I(包括(但不限于)化合物1)或其固体形式的Tyk2抑制剂。在一些实施例中,化合物是化合物1或其药学上可接受的盐。在一些实施例中,化合物是化合物1的游离碱。在一些实施例中,化合物是化合物1的固体形式。在一些实施例中,化合物是化合物1的结晶型。在一些实施例中,化合物是化合物1的形式I’、形式I、形式II、形式III、形式IV或形式V。在一些实施例中,化合物是化合物1的游离碱的多形体。在一些实施例中,化合物是化合物1的形式I’。在一些实施例中,化合物是化合物1的甲磺酸盐。在一些实施例中,化合物是化合物1的形式I。在一些实施例中,化合物是化合物1的溶剂合物。在一些实施例中,化合物是非晶形化合物1。
如本文中所用术语“患者”意指动物,优选是哺乳动物,并且最优选是人类。
术语“药学上可接受的载剂、佐剂或稀释剂”是指不破坏与其一起调配的化合物的药理学活性的无毒载剂、佐剂或媒剂。可用于本发明组合物中的药学上可接受的载剂、佐剂或稀释剂包括(但不限于)抗粘着剂、粘合剂、涂料、着色剂、崩解剂、矫味剂、助流剂、润滑剂、防腐剂、吸收剂和媒剂。载剂、佐剂和稀释剂的实例包括(但不限于)离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(例如人类血清白蛋白)、缓冲物质(例如磷酸盐)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(例如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶状二氧化硅、三硅酸镁、聚乙烯基吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯嵌段聚合物、聚乙二醇和羊毛脂。
“药学上可接受的衍生物”意指本发明化合物的任何无毒盐、酯、酯盐或其它衍生物,其在投与接受者时能直接或间接提供本发明化合物或其抑制性活性代谢物或残余物。
本文所用术语“其抑制性活性代谢物或残余物”意指其代谢物或残余物还是Tyk2的抑制剂。
本发明组合物可经口、非经肠、通过吸入喷雾、经局部、经直肠、经鼻、经颊、经阴道或通过植入型储存器投与。如本文中所用术语“非经肠”包括皮下、静脉内、肌内、关节内、滑膜内、胸骨内、鞘内、肝内、病灶内和颅内注射或输注技术。优选地,经口、经腹膜腔内或经静脉内投与所述组合物。本发明组合物的无菌可注射形式可为水性或油性悬浮液。这些悬浮液可根据业内已知的技术使用适宜的分散剂或湿润剂和悬浮剂进行调配。无菌可注射制剂还可为存于无毒性非经肠可接受的稀释剂或溶剂中的无菌可注射溶液或悬浮液,例如作为于1,3-丁二醇中的溶液。可采用的可接受媒剂和溶剂尤其是水、林格氏溶液(Ringer'ssolution)和等渗氯化钠溶液。另外,照惯例采用无菌不挥发性油作为溶剂或悬浮介质。
出于此目的,可采用任一温和不挥发性油,包括合成的单-或二-甘油酯。脂肪酸(例如油酸和其甘油酯衍生物)可用于制备可注射物,例如天然的药学上可接受的油类,例如橄榄油或蓖麻油,其尤其呈其聚氧乙烯化型式。这些油溶液或悬浮液还可含有长链醇稀释剂或分散剂,例如羧甲基纤维素或类似分散剂,其通常用于调配包括乳液和悬浮液在内的药学上可接受的剂型。还可将其它常用表面活性剂(例如吐温(Tween)、斯潘(Span)和其它通常用于制造药学上可接受的固体、液体或其它剂型的乳化剂或生物利用度增强剂)用于调配目的。
本发明的药学上可接受的组合物可以任何经口可接受剂型经口投与,所述剂型包括(但不限于)胶囊、片剂、水性悬浮液或溶液。在供经口使用的片剂的情形下,通常使用的载剂包括乳糖和玉米淀粉。通常还添加润滑剂,例如硬脂酸镁。对于以胶囊形式经口投与来说,有用的稀释剂包括乳糖和干玉米淀粉。在经口使用需要水性悬浮液时,将活性成分与乳化剂和悬浮剂组合。如果需要,那么还可添加某些甜味剂、矫味剂或着色剂。
或者,本发明的药学上可接受的组合物可以直肠投与的栓剂形式投与。可通过将药剂与适宜非刺激性赋形剂混合来制备这些组合物,所述赋形剂在室温下为固体但在直肠温度下为液体,并且因此可在直肠中融化而释放药物。所述材料包括可可脂、蜂蜡和聚乙二醇。
本发明的药学上可接受的组合物还可局部投与,尤其在治疗靶包括可通过局部施加易于达到的区域或器官(包括眼睛、皮肤或下肠道的疾病)时。易于制备针对这些区域或器官中的每一者的适宜局部调配物。
可以直肠栓剂调配物(参见上文)或适宜灌肠调配物来实现下肠道的局部施加。还可使用局部经皮贴剂。
对于局部施加来说,可将所提供的药学上可接受的组合物调配于含有悬浮或溶解于一或多种载剂中的活性组分的适宜软膏中。用于局部投与本发明化合物的载剂包括(但不限于)矿物油、液体矿脂、白矿脂、丙二醇、聚氧乙烯、聚氧丙烯化合物、乳化蜡和水。或者,可将所提供的药学上可接受的组合物调配于含有悬浮或溶解于一或多种药学上可接受的载剂中的活性组分的适宜洗剂或乳霜中。适宜载剂包括(但不限于)矿物油、山梨醇酐单硬脂酸酯、聚山梨醇酯60、十六烷基酯蜡、鲸蜡醇、2-辛基十二烷醇、苯甲醇和水。
对于眼部应用来说,可将所提供的药学上可接受的组合物调配为于等渗、pH经调节的无菌盐水中的微粒化悬浮液,或优选调配为于等渗、pH经调节的无菌盐水中的溶液,其含有或不含防腐剂,例如氯苄烷铵。或者,对于眼部应用来说,可将药学上可接受的组合物调配于软膏(例如矿脂)中。
还可通过经鼻气溶胶或吸入来投与本发明的药学上可接受的组合物。根据药物调配领域熟知的技术来制备所述组合物且可采用苯甲醇或其它适宜防腐剂、用于增强生物利用度的吸收促进剂、碳氟化合物和/或其它常规增溶剂或分散剂将其制备为盐水溶液。
最优选地,将本发明的药学上可接受的组合物调配用于经口投与。所述调配物可与或不与食物一起投与。在一些实施例中,本发明的药学上可接受的组合物不与食物一起投与。在其它实施例中,本发明的药学上可接受的组合物是与食物一起投与。
可与载剂材料组合以产生呈单一剂型的组合物的本发明化合物的量应根据所治疗主体、特定投与模式而改变。优选地,所提供的组合物应经调配,以使得可向接受这些组合物的患者投与介于0.01mg/kg体重/天到100mg/kg体重/天的抑制剂之间的剂量。
还应了解,用于任一特定患者的具体剂量和治疗方案可取决于多种因素,包括所采用具体化合物的活性、年龄、体重、一般健康状况、性别、饮食、投与时间、排泄速率、药物组合和治疗医师的判断和所治疗特定疾病的严重程度。组合物中本发明化合物的量还将取决于组合物中的特定化合物。
化合物和其组合物的用途
药物用途
本文所述化合物和组合物通常可用于抑制一或多种酶的激酶活性。在一些实施例中,由本发明的化合物和方法抑制的激酶是TYK2。
TYK2是蛋白激酶的杰纳斯激酶(Janus kinase,JAK)家族的非受体酪氨酸激酶成员。哺乳动物JAK家族由四个成员组成:TYK2、JAK1、JAK2和JAK3。JAK蛋白(包括TYK2)对于细胞因子信号传导是必不可少的。TYK2与I型和II型细胞因子受体以及干扰素I和III型受体的细胞质结构域相关,并且在细胞因子结合时由那些受体活化。参与TYK2活化的细胞因子包括干扰素(例如IFN-α、IFN-β、IFN-κ、IFN-δ、IFN-ε、IFN-τ、IFN-ω和IFN-ζ(也称为限制素(limitin)))和白介素(例如IL-4、IL-6、IL-10、IL-11、IL-12、IL-13、IL-22、IL-23、IL-27、IL-31、制瘤素M、睫状神经营养因子、心脏营养素1、心脏营养素样细胞因子和LIF)。贝拉斯克斯(Velasquez)等人,“干扰素α/β信号传导路径中的蛋白激酶(A protein kinase inthe interferonα/βsignaling pathway)”,细胞(Cell)(1992)70:313;斯塔尔(Stahl)等人,“通过CNTF-LIF-OSM-IL-6β受体组分结合且活化Jak-Tyk激酶(Association andactivation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6βreceptor components)”,科学(Science)(1994)263:92;芬布鲁姆(Finbloom)等人,“IL-10诱导Tyk2和Jak1的酪氨酸磷酸化以及Stat1和Stat3复合物在人类T细胞和单核细胞中的差异性组装(IL-10induces thetyrosine phosphorylation of Tyk2 and Jak1 and the differential assembly ofStat1 and Stat3 complexes in human T cells and monocytes)”,免疫学杂志(J.Immunol.)(1995)155:1079;巴孔(Bacon)等人,“白介素12(IL-12)诱导Jak2和Tyk2的酪氨酸磷酸化:IL-2和IL-12对杰纳斯家族激酶的不同用途(Interleukin 12(IL-12)inducestyrosine phosphorylation of Jak2 and Tyk2:differential use of Janus familykinases by IL-2 and IL-12)”,实验医学杂志(J.Exp.Med.)(1995)181:399;韦勒姆(Welham)等人,“淋巴造血细胞中的白介素-13信号转导:与白介素-4和胰岛素的信号转导的类似性和差异性(Interleukin-13 signal transduction in lymphohemopoieticcells:similarities and differences in signal transduction with interleukin-4and insulin)”,生物化学杂志(J.Biol.Chem.)(1995)270:12286;帕哈姆(Parham)等人,“异二聚体细胞介素IL-23的受体是由IL-12Rβ1和新颖细胞介素受体亚单元IL-23R构成(Areceptor for the heterodimeric cytokine IL-23 is composed of IL-12Rβ1 and anovel cytokine receptor subunit,IL-23R)”,免疫学杂志(2002)168:5699。活化的TYK2随后继续进一步磷酸化信号传导蛋白(例如STAT家族的成员,包括STAT1、STAT2、STAT4和STAT6)。
由IL-23的TYK2活化与炎症性肠病(IBD)、克隆氏病(Crohn’s disease)和溃疡性结肠炎相关联。杜尔(Duerr)等人,“全基因体关联研究将IL23R鉴别为炎症性肠病基因(AGenome-Wide Association Study Identifies IL23R as an Inflammatory BowelDisease Gene)”,科学(2006)314:1461-1463。TYK2作为IL-23的下游效应物还在牛皮癣、关节粘连性脊椎炎和贝歇氏症(disease)中起作用。赵(Cho)等人,“人类自体免疫疾病的基因组学和多因性(Genomics and the multifactorial nature of human auto-immune disease)”,新英格兰医学杂志(N.Engl.J.Med)(2011)365:1612-1623;科尔特斯(Cortes)等人,“通过高密度基因分型免疫相关基因座来鉴别关节粘连性脊椎炎的多个风险变体(Identification of multiple risk variants for ankylosing spondylitisthrough high-density genotyping of immune-related loci)”,自然遗传学(Nat.Genet.)(2013)45(7):730-738;雷默斯(Remmers)等人,“全基因体关联研究鉴别MHC种类I、IL10和IL23R-IL12RB2区域中与贝歇氏症相关的变体(Genome-wide associationstudy identifies variants in the MHC class I,IL10,and IL23R-IL 12RB2 regionsassociated withdisease)”,自然遗传学(2010)42:698-702。2,622名患有牛皮癣的个体的全基因体关联研究鉴别疾病易感性与TYK2之间的关联。斯特兰奇(Strange)等人,“全基因体关联研究鉴别新牛皮癣易感性基因座和HLA-C与ERAP1之间的相互作用(Agenome-wide association study identifies new psoriasis susceptibility lociand an interaction between HLA-C and ERAP1)”,自然遗传学(2010)42:985-992。TYK2的剔除或酪氨酸磷酸化抑制剂抑制显著减轻IL-23和IL-22二者诱导的皮肤炎。石崎(Ishizaki)等人,“Tyk2是牛皮癣样皮肤炎症的治疗靶(Tyk2 is a therapeutic targetfor psoriasis-like skin inflammation)”,国际免疫学(Intl.Immunol.)(2013),doi:10.1093/intimm/dxt062。
TYK2还在诸如气喘、慢性阻塞性肺病(COPD)、肺癌和囊性纤维化等呼吸疾病中起作用。杯形细胞增生(GCH)和粘液分泌过多是由IL-13诱导的TYK2活化介导,其进而活化STAT6。张(Zhang)等人,“停泊蛋白通过TYK2/STAT6路径来调控粘蛋白表现和杯形细胞增生(Docking protein Gab2 regulates mucin expression and goblet cell hyperplasiathrough TYK2/STAT6 pathway)”,美国实验生物学学会联合会杂志(FASEB J.)(2012)26:1-11。
降低的TYK2活性可保护关节免于胶原抗体诱导的关节炎,即人类类风湿性关节炎的模型。在机理上,降低的Tyk2活性降低Th1/Th17相关细胞因子和基质金属蛋白酶和炎症的主要标记的产生。石崎等人,“Tyk2缺乏中小鼠抗II型胶原抗体诱导性关节炎中可保护关节免于破坏(Tyk2 deficiency protects joints against destruction in anti-type IIcollagen antibody-induced arthritis in mice)”,国际免疫学(2011)23(9):575-582。
与对照相比,TYK2剔除小鼠在实验性自体免疫脑脊髓炎(EAE,多发性硬化(MS)的动物模型)中显示完全抵抗,在脊髓中无CD4 T细胞的浸润,此表明在MS中,TYK2对致病性CD4介导疾病的发展至关重要。小山田(Oyamada)等人,“酪氨酸激酶2在实验性自体免疫脑脊髓炎发展的致病性CD4 T细胞反应中发挥关键作用(Tyrosine Kinase 2Plays CriticalRoles in the Pathogenic CD4 T Cell Responses for the Development ofExperimental Autoimmune Encephalomyelitis)”,免疫学杂志(2009)183:7539-7546。此确证先前研究将增加的TYK2表达与MS易感性联系起来。班(Ban)等人,“复制分析将TYK2鉴别为多发性硬化易感性因素(Replication analysis identifies TYK2 as a multiplesclerosis susceptibility factor)”,欧洲人类遗传学杂志(Eur J.Hum.Genet.)(2009)17:1309-1313。TYK2的功能丧失型突变导致神经元的脱髓鞘减少和髓鞘再生增加,此进一步表明TYK2抑制剂在治疗MS和其它CNS脱髓鞘病症中的作用。
TYK2是IL-12和IL-23二者共同的唯一信号传导信使。TYK2剔除减少小鼠中甲基化BSA注射诱导的足垫厚度、咪喹莫特(imiquimod)诱导的牛皮癣样皮肤炎症和硫酸葡聚糖钠或2,4,6-三硝基苯磺酸诱导的结肠炎。
各种I型IFN信号传导基因与全身性红斑狼疮(SLE,一种自体免疫病症)的联合联系和相关性研究显示,在受影响成员的家族中,TYK2功能丧失型突变与SLE盛行率降低之间具有强烈且显著的相关性。西古德松(Sigurdsson)等人,“酪氨酸激酶2和干扰素调控因子5基因的多型性与全身性红斑狼疮相关(Polymorphisms in the Tyrosine Kinase 2andInterferon Regulatory Factor 5Genes Are Associated with Systemic LupusErythematosus)”,美国人类遗传学杂志(Am.J.Hum.Genet.)(2005)76:528-537。患有SLE的个体针对未受影响的小组的全基因体相关性研究显示TYK2基因座与SLE之间的高度相关性。格拉罕姆(Graham)等人,“NCF2、IKZF1、IRF8、IFIH1和TYK2与全身性红斑狼疮的相关性(Association of with Systemic Lupus Erythematosus)”,PLoS遗传学(2011)7(10):e1002341。
已显示TYK2在维持肿瘤监督中起重要作用,并且TYK2剔除小鼠显示受损的细胞毒性T细胞反应,并且加速肿瘤发展。然而,这些效应与天然杀手(NK)和细胞毒性T淋巴细胞的有效抑制相关,表明TYK2抑制剂将高度适于自体免疫病症或移植排斥的治疗。尽管其它JAK家族成员(例如JAK3)在免疫系统中具有相似作用,但由于TYK2涉及更少且更密切相关的信号传导路径从而导致更少脱靶效应,因此被视为优异靶标。希马(Simma)等人,“赖氨酸激酶2在CTL介导的肿瘤监督中的不可或缺的作用的鉴别(Identification of anIndispensable Role for Tyrosine Kinase 2in CTL-Mediated Tumor Surveillance)”,癌症研究(Cancer Res.)(2009)69:203-211。
然而,与希马等人所观察到的肿瘤监督降低矛盾的是,T细胞急性淋巴母细胞性白血病(T-ALL)中的研究指示,T-ALL通过TYK2且通过STAT1介导的信号转导高度依赖于IL-10以通过上调抗细胞凋亡蛋白BCL2来维持癌细胞存活。TYK2、而非其它JAK家族成员的敲低减少细胞生长。促使癌细胞存活的TYK2的特异性活化突变包括FERM结构域(G36D、S47N和R425H)、JH2结构域(V731I)和激酶结构域(E957D和R1027H)的那些活化突变。然而,还鉴别出TYK2的激酶功能对于增加癌细胞存活是必需的,这是因为除了活化突变(E957D)外特征还在于激酶失活突变(M978Y或M978F)的TYK2酶导致转变失败。桑达(Sanda)等人,“T细胞急性淋巴母细胞性白血病中的TYK2-STAT1-BCL2路径依赖性(TYK2-STAT1-BCL2 PathwayDependence in T-Cell Acute Lymphoblastic Leukemia)”,癌症研究(Cancer Disc.)(2013)3(5):564-577。
因此,TYK2的选择性抑制已视为患有IL-10和/或BCL2成瘾肿瘤的患者的适宜靶标,例如70%的成人T细胞白血病病例。方坦(Fontan)等人,“研究T-ALL中的STAT信号传导TYK的原因(Discovering What Makes STAT Signaling TYK in T-ALL)”,癌症研究(2013)3:494-496。
TYK2介导的STAT3信号传导还已显示可介导由类淀粉-β(Aβ)肽引起的神经元细胞死亡。Aβ投与后STAT3的降低的TYK2磷酸化导致减少的神经元细胞死亡,并且在阿兹海默氏病患者的死后脑中观察到STAT3的磷酸化增加。万(Wan)等人,“Tyk/STAT3信号传导介导β-类淀粉诱导的神经元细胞死亡:阿兹海默氏病中的关联(Tyk/STAT3 Signaling Mediatesβ-Amyloid-Induced Neuronal Cell Death:Implications in Alzheimer’s Disease)”,神经科学杂志(J.Neurosci.)(2010)30(20):6873-6881。
JAK-STAT信号传导路径的抑制还参与毛发生长以及与斑秃相关的脱发的逆转。邢(Xing)等人,“斑秃是由细胞毒性T淋巴细胞驱动且由JAK抑制逆转(Alopecia areata isdriven by cytotoxic T lymphocytes and is reversed by JAK inhibition)”,自然医学(Nat.Med.)(2014)20:1043-1049;哈雷尔(Harel)等人,“JAK-STAT信号传导的药理学抑制会促进毛发生长(Pharmacologic inhibition of JAK-STAT signaling promotes hairgrowth)”,科学进展(Sci.Adv.)(2015)1(9):e1500973。
因此,抑制TYK2活性的化合物是有益的,尤其对JAK2具有选择性的那些化合物。所述化合物应递送有利地治疗本文所述病况中的一或多者而无与JAK2抑制相关的副作用的药理学反应。
即使TYK2抑制剂为业内已知,但仍继续需要提供具有更有效或有利的药物相关性质的新颖抑制剂。举例来说,具有增加的活性、对其它JAK激酶(尤其JAK2)具有选择性和ADMET(吸收、分布、代谢、排泄和/或毒性)性质的化合物。因此,在一些实施例中,本发明提供对JAK2显示选择性的TYK2抑制剂。
可在活体外、在活体内或在细胞系中分析本发明中所用化合物作为TYK2或其突变体的抑制剂的活性。活体外分析包括测定活化TYK2或其突变体的磷酸化活性和/或后续功能后果或ATP酶活性的抑制的分析。替代活体外分析量化抑制剂结合TYK2的能力。可通过以下方式测量抑制剂结合:在结合之前对抑制剂实施放射性标记,分离抑制剂/TYK2复合物且测定所结合放射性标记的量。或者,可通过运行竞争实验测定抑制剂结合,其中将新抑制剂与结合到已知放射性配体的TYK2一起培育。可用于分析TYK2抑制剂的代表性活体外和活体内分析包括(例如)全文以引用方式并入本文中的每一参考文献中描述和揭示的那些分析。用于分析在本发明用作TYK2或其突变体的抑制剂的化合物的详细条件陈述于下文实例中。
如本文中所用术语“治疗(treatment、treat和treating)”是指逆转、缓解如本文所描述的疾病或病症或其一或多种症状、延迟其发作或抑制其进展。在一些实施例中,可在已发生一或多种症状后投与治疗。在其它实施例中,可在不存在症状的情况下投与治疗。举例来说,可在症状发作前(例如,鉴于症状的历史和/或鉴于遗传或其它易感性因素)向易感个体投与治疗。还可在症状消退后继续治疗以(例如)预防或延迟其复发。
所提供化合物是TYK2抑制剂且因此可用于治疗一或多种与TYK2或其突变体的活性相关的病症。因此,在一些实施例中,本发明提供治疗TYK2介导病症的方法,其包含向有需要的患者投与本发明化合物或其药学上可接受的组合物的步骤。
如本文中所使用,本文所用的术语“TYK2介导的”病症、疾病和/或病况意指已知TYK2或其突变体起作用的任一疾病或其它有害病况。因此,本发明的另一实施例涉及治疗一或多种已知TYK2或其突变体起作用的疾病或减弱其严重程度。所述TYK2介导的病况包括(但不限于)自体免疫病症、炎症病症、增殖性病症、内分泌病症、神经病症和与移植相关的病症。
在一些实施例中,本发明提供治疗一或多种病症的方法,其中所述病症是选自自体免疫病症、炎症病症、增殖性病症、内分泌病症、神经病症和与移植相关的病症,所述方法包含向有需要的患者投与包含有效量的本发明化合物或其药学上可接受的盐的药物组合物。
在一些实施例中,所述病症是自体免疫病症。在一些实施例中,所述病症是选自1型糖尿病、全身性红斑狼疮、多发性硬化、牛皮癣、贝歇氏症、POEMS综合症、克隆氏病、溃疡性结肠炎和炎症性肠病。
在一些实施例中,所述病症是炎症病症。在一些实施例中,炎症病症是类风湿性关节炎、气喘、慢性阻塞性肺病、牛皮癣、肝肿大、克隆氏病、溃疡性结肠炎、炎症性肠病。
在一些实施例中,所述病症是增殖性病症。在一些实施例中,增殖性病症是血液癌症。在一些实施例中,增殖性病症是白血病。在一些实施例中,白血病是T细胞白血病。在一些实施例中,T细胞白血病是T细胞急性淋巴母细胞性白血病(T-ALL)。在一些实施例中,增殖性病症是真性红血球增多症、骨髓纤维化、特发性或血小板增多症。
在一些实施例中,所述病症是内分泌病症。在一些实施例中,内分泌病症是多囊性卵巢综合症、克鲁松氏综合症(Crouzon’s syndrome)或1型糖尿病。
在一些实施例中,所述病症是神经病症。在一些实施例中,神经病症是阿兹海默氏病。
在一些实施例中,增殖性病症与TYK2的一或多个活化突变相关。在一些实施例中,TYK2的活化突变是FERM结构域、JH2结构域或激酶结构域的突变。在一些实施例中,TYK2的活化突变是选自G36D、S47N、R425H、V731I、E957D和R1027H。
在一些实施例中,所述病症与移植相关。在一些实施例中,与移植相关的病症是移植排斥或移植物抗宿主病。
在一些实施例中,所述病症与I型干扰素、IL-10、IL-12或IL-23信号传导相关。在一些实施例中,所述病症与I型干扰素信号传导相关。在一些实施例中,所述病症与IL-10信号传导相关。在一些实施例中,所述病症与IL-12信号传导相关。在一些实施例中,所述病症与IL-23信号传导相关。
本发明化合物还可用于治疗皮肤的炎症性或过敏性病况,例如牛皮癣、接触性皮肤炎、变构性皮肤炎、斑秃、多形性红斑、疱疹样皮肤炎、硬皮症、白斑病、过敏性血管炎、荨麻疹、大疱性类天疱疮、红斑狼疮、全身性红斑狼疮、寻常天疱疮、落叶型天疱疮、副肿瘤性天疱疮、后天性水疱性表皮松解症、寻常痤疮和皮肤的其它炎症性或过敏性病况。
本发明化合物还可用于治疗其它疾病或病况(例如具有炎症性组分的疾病或病况),例如,治疗眼睛疾病和病况(例如眼过敏性、结膜炎、干燥性角结膜炎和春季结膜炎)、侵袭鼻子的疾病(包括过敏性鼻炎)和涉及或具有自体免疫组分或病因的炎症性疾病,包括自体免疫血液学病症(例如溶血性贫血、再生障碍性贫血、单纯红血球性贫血和特发性血小板减少症)、全身性红斑狼疮、类风湿性关节炎、多软骨炎、硬皮症、韦格纳氏肉芽肿病(Wegener granulamatosis)、皮肌炎、慢性活动型肝炎、重症肌无力、史蒂文斯-约翰逊综合症(Steven-Johnson syndrome)、特发性口炎性腹泻、自体免疫炎症性肠病(例如溃疡性结肠炎和克隆氏病)、肠躁综合症、乳糜泻、齿根骨膜炎、透明膜病、肾病、肾小球疾病、酒精性肝病、多发性硬化、内分泌眼病、格雷夫斯氏病(Grave's disease)、类肉瘤病、肺泡炎、慢性过敏性肺炎、多发性硬化、原发性胆汁性硬化、葡萄膜炎(前葡萄膜炎和后葡萄膜炎)、薛格连氏综合症(Sjogren’s syndrome)、干燥性角结膜炎和春季角结膜炎、间质性肺纤维化、牛皮癣性关节炎、全身性幼年型特发性关节炎、隐热蛋白相关的周期性综合症、肾炎、血管炎、憩室炎、间质性膀胱炎、肾小球性肾炎(具有和无肾病综合症,例如包括特发性肾病综合症或微小病变肾病变)、慢性肉芽肿病、子宫内膜变构症、钩端螺旋体病肾病、青光眼、视网膜疾病、老化、头痛、疼痛、复杂性区域疼痛综合症、心肥大、肌萎缩、异化病症、肥胖症、胎儿生长迟缓、高胆固醇血症、心脏病、慢性心脏衰竭、间皮瘤、止汗外胚层发育不良、贝赛特氏病(Behcet’s disease)、色素失调症、柏哲德氏病(Paget’s disease)、胰脏炎、遗传性周期性发热综合症、气喘(过敏性和非过敏性、轻度、中度、严重、支气管炎和锻炼诱导的气喘)、急性肺损伤、急性呼吸窘迫综合症、嗜伊红球增多症、过敏性、过敏反应、鼻窦炎、眼过敏性、二氧化硅诱导的疾病、COPD(损害、气道炎症、支气管高反应性、重塑或疾病进展减少)、肺病、囊性纤维化、酸诱导的肺损伤、肺高血压、多神经病变、白内障、肌肉炎症结合全身性硬化、包涵体肌炎、重症肌无力、甲状腺炎、艾迪森氏病(Addison’s disease)、扁平苔癣、1型糖尿病或2型糖尿病、阑尾炎、变构性皮肤炎、气喘、过敏症、眼睑炎、细支气管炎、支气管炎、滑囊炎、子宫颈炎、胆管炎、胆囊炎、慢性移植物排斥、结肠炎、结膜炎、克隆氏病、膀胱炎、泪腺炎、皮肤炎、皮肌炎、脑炎、心内膜炎、子宫内膜炎、肠炎、小肠结肠炎、上髁炎、附睾炎、筋膜炎、纤维组织炎、胃炎、胃肠炎、亨-舒二氏紫斑病(Henoch-Schonlein purpura)、肝炎、化脓性汗腺炎、免疫球蛋白A肾病变、间质性肺病、喉炎、乳腺炎、脑膜炎、脊髓炎心肌炎、肌炎、肾炎、卵巢炎、睾丸炎、骨炎、耳炎、胰脏炎、腮腺炎、心包炎、腹膜炎、咽炎、胸膜炎、静脉炎、肺炎(pneumonitis)、肺炎(pneumonia)、多肌炎、直肠炎、前列腺炎、肾盂肾炎、鼻炎、输卵管炎、鼻窦炎、口炎、滑膜炎、肌腱炎、扁桃腺炎、溃疡性结肠炎、眼色素层炎、阴道炎、血管炎或外阴炎。
在一些实施例中,可根据本发明方法治疗的炎症性疾病是选自急性和慢性痛风、慢性痛风性关节炎、牛皮癣、牛皮癣性关节炎、类风湿性关节炎、幼年型类风湿性关节炎、全身性幼年型特发性关节炎(SJIA)、隐热蛋白相关的周期性综合症(CAPS)和骨关节炎。
在一些实施例中,可根据本发明方法治疗的炎症性疾病是Th1或Th17介导的疾病。在一些实施例中,Th17介导的疾病是选自全身性红斑狼疮、多发性硬化和炎症性肠病(包括克隆氏病或溃疡性结肠炎)。
在一些实施例中,可根据本发明方法治疗的炎症性疾病是选自薛格连氏综合症、过敏性病症、骨关节炎、眼睛病况(例如眼过敏性、结膜炎、干燥性角结膜炎和春季结膜炎)和侵袭鼻子的疾病(例如过敏性鼻炎)。
此外,本发明提供根据本文定义的化合物或其药学上可接受的盐或水合物或溶剂合物的用途,其用于制备用于治疗自体免疫病症、炎症病症或增殖性病症或结合移植通常出现的病症的药剂。
组合疗法
根据要治疗的特定病况或疾病而定,可与本发明化合物和组合物组合投与额外治疗剂,所述治疗剂通常经投与以治疗所述病况。如本文中所使用,通常投与以治疗特定疾病或病况的额外治疗剂称为“适于所治疗的疾病或病况”。
在某些实施例中,所提供组合或其组合物与另一治疗剂组合投与。
还可与本发明组合组合的药剂的实例包括(不限于):用于阿兹海默氏病的治疗剂,例如和用于HIV的治疗剂,例如利托那韦(ritonavir);用于帕金森病的治疗剂,例如L-DOPA/卡比多巴(carbidopa)、恩他卡朋(entacapone)、罗吡尼洛(ropinrole)、普拉克索(pramipexole)、溴隐亭(bromocriptine)、培高利特(pergolide)、苯海索(trihexephendyl)和金刚烷胺;用于治疗多发性硬化(MS)的药剂,例如β干扰素(例如,和)、和米托蒽醌(mitoxantrone);用于气喘的治疗剂,例如沙丁胺醇(albuterol)和用于治疗精神分裂症的药剂,例如再普乐(zyprexa)、维思通(risperdal)、思瑞康(seroquel)和氟派醇(haloperidol);抗炎症剂,例如皮质类固醇、TNF阻断剂、IL-1RA、硫唑嘌呤(azathioprine)、环磷酰胺(cyclophosphamide)和磺胺塞拉金(sulfasalazine);免疫调节和免疫阻抑性药剂,例如环孢素(cyclosporine)、他克莫司(tacrolimus)、雷帕霉素(rapamycin)、吗替麦考酚酯(mycophenolate mofetil)、干扰素、皮质类固醇、环磷酰胺、硫唑嘌呤和磺胺塞拉金;神经营养因子,例如,乙酰胆碱酯酶抑制剂、MAO抑制剂、干扰素、抗惊厥药、离子通道阻断剂、利芦噻唑(riluzole)和抗帕金森病药;用于治疗心血管疾病的药剂,例如β-阻断剂、ACE抑制剂、利尿药、硝酸盐、钙通道阻断剂和史他汀(statin);用于治疗肝病的药剂,例如皮质类固醇、消胆胺(cholestyramine)、干扰素和抗病毒药;用于治疗血液病症的药剂,例如皮质类固醇、抗白血病药和生长因子;延长或改良药物代谢动力学的药剂,例如细胞色素P450抑制剂(即,代谢破坏抑制剂)和CYP3A4抑制剂(例如,酮康唑(ketokenozole)和利托那韦)和用于治疗免疫缺陷病症的药剂,例如γ-球蛋白。
在某些实施例中,本发明的组合疗法或其药学上可接受的组合物与单克隆抗体或siRNA治疗剂组合投与。
那些额外药剂可作为多个剂量方案的一部分与所提供组合疗法分开投与。或者,那些药剂可为单一剂型的一部分,其以单一组合物与本发明化合物混合到一起。如果作为多个剂量方案的一部分投与,那么两种活性剂可同时、依序或在一段时间内彼此、通常在5小时内彼此提交。
如本文中所用术语“组合(combination、combined)”和相关术语是指同时或依序投与本发明治疗剂。举例来说,本发明组合可与另一治疗剂同时或依序以分开的单位剂型或以单一单位剂型一起投与。
存在于本发明组合物中的额外治疗剂的量将不超过在包含所述治疗剂作为唯一活性药剂的组合物中通常投与的量。优选地,本文所揭示组合物中额外治疗剂的量将在包含所述药剂作为唯一治疗活性药剂的组合物中通常所存在量的约50%到100%的范围内。
在一个实施例中,本发明提供包含式I化合物和一或多种额外治疗剂的组合物。所述治疗剂可与式I化合物一起投与,或可在式I化合物投与之前或之后投与。在下文中进一步详细描述适宜治疗剂。在某些实施例中,式I化合物可在治疗剂之前高达5分钟、10分钟、15分钟、30分钟、1小时、2小时、3小时、4小时、5小时、6小时、7小时、8小时、9小时、10小时、11小时、12小时、13小时、14小时、15小时、16小时、17小时或18小时投与。在其它实施例中,式I化合物可在治疗剂之后高达5分钟、10分钟、15分钟、30分钟、1小时、2小时、3小时、4小时、5小时、6小时、7小时、8小时、9小时、10小时、11小时、12小时、13小时、14小时、15小时、16小时、17小时或18小时投与。
在另一实施例中,本发明提供通过向有需要的患者投与式I化合物和一或多种额外治疗剂来治疗炎症性疾病、病症或病况的方法。所述额外治疗剂可为小分子或重组生物试剂且包括(例如)乙酰胺酚(acetaminophen)、非类固醇抗炎症药物(NSAID)(例如阿斯匹林(aspirin)、布洛芬(ibuprofen)、萘普生(naproxen)、依托度酸(etodolac)和塞来昔布(celecoxib))、秋水仙碱(colchicine)皮质类固醇(例如普赖松(prednisone)、普赖苏秾(prednisolone)、甲基普赖苏秾、氢化可体松(hydrocortisone)和诸如此类)、丙磺舒(probenecid)、别嘌呤醇(allopurinol)、非布索坦(febuxostat)磺胺塞拉金抗疟疾药(例如羟基氯喹(hydroxychloroquine)和氯喹(chloroquine))、甲氨蝶呤(methotrexate)金盐(例如硫化葡糖金硫苹果酸金和金诺芬(auranofin))、D-青霉胺(D-penicillamine)(或)、硫唑嘌呤环磷酰胺氮芥苯丁酸(chlorambucil)环孢素来氟米特(leflunomide)和“抗TNF”药剂(例如依那西普(etanercept)英利昔单抗(infliximab)戈利木单抗(golimumab)聚乙二醇化赛妥珠单抗(certolizumab pegol)和阿达木单抗(adalimumab))、“抗IL-1”药剂(例如阿那白滞素(anakinra)和利纳西普(rilonacept))、卡那单抗(canakinumab)抗Jak抑制剂(例如托法替尼(tofacitinib))、抗体(例如利妥昔单抗(rituximab))、“抗T细胞”药剂(例如阿巴西普(abatacept))、“抗IL-6”药剂(例如托珠单抗(tocilizumab))、双氯芬酸(diclofenac)、可体松(cortisone)、玻尿酸(或)、单克隆抗体(例如他尼珠单抗(tanezumab))、抗凝剂(例如肝素(或)和杀鼠灵(warfarin))、止泻药(例如地芬诺酯(diphenoxylate)和洛哌丁胺(loperamide))、胆汁酸结合剂(例如消胆胺)、阿洛司琼(alosetron)鲁比前列酮(lubiprostone)轻泻剂(例如镁乳(Milk of Magnesia)、聚乙二醇和)、抗胆碱药或镇痉药(例如双环维林(dicyclomine))、β-2激动剂(例如沙丁胺醇(HFA、HFA)、左旋沙丁胺醇异丙喘宁(metaproterenol)乙酸吡布特罗(pirbuterol acetate)硫酸特布他林(terbutaline sulfate)昔萘酸沙美特罗(salmeterolxinafoate)和福莫特罗(formoterol))、抗胆碱药剂(例如异丙托溴铵(ipratropium bromide)和噻托铵(tiotropium))、吸入皮质类固醇(例如二丙酸倍氯米松(beclomethasone dipropionate)(和)、曲安奈德(triamcinolone acetonide)莫米松(mometasone)布地奈德(budesonide)和氟尼缩松(flunisolide))、 色甘酸钠(cromolyn sodium)甲基黄嘌呤(例如茶碱(theophylline)和胺茶碱)、IgE抗体(例如奥马珠单抗(omalizumab))、核苷逆转录酶抑制剂(例如齐多夫定(zidovudine)阿巴卡韦(abacavir)阿巴卡韦/拉米夫定(lamivudine)阿巴卡韦/拉米夫定/齐多夫定去羟肌苷(didanosine)恩曲他滨(emtricitabine)拉米夫定拉米夫定/齐多夫定司他夫定(stavudine)和扎昔他宾(zalcitabine))、非核苷逆转录酶抑制剂(例如地拉韦定(delavirdine)依法韦伦(efavirenz)奈韦拉平(nevairapine)和依曲韦林(etravirine))、核苷酸逆转录酶抑制剂(例如泰诺福韦(tenofovir))、蛋白酶抑制剂(例如氨普那韦(amprenavir)阿扎那韦(atazanavir)达如那韦(darunavir)呋山那韦(fosamprenavir)茚地那韦(indinavir)洛匹那韦(lopinavir)和利托那韦奈芬那韦(nelfinavir)利托那韦沙奎那韦(saquinavir)(或)和替拉那韦(tipranavir))、进入抑制剂(例如恩夫韦肽(enfuvirtide)和马拉维洛(maraviroc))、整合酶抑制剂(例如雷特格韦(raltegravir)多柔比星(doxorubicin)长春新碱(vincristine)硼替佐米(bortezomib)和地塞米松(dexamethasone)与雷利度胺(lenalidomide)的组合)或其任一组合。
在另一实施例中,本发明提供治疗类风湿性关节炎的方法,其包含向有需要的患者投与式I化合物和一或多种选自以下的额外治疗剂:非类固醇抗炎症药物(NSAID)(例如阿斯匹林、布洛芬、萘普生、依托度酸和塞来昔布)、皮质类固醇(例如普赖松、普赖苏秾、甲基普赖苏秾、氢化可体松和诸如此类)、磺胺塞拉金抗疟疾药(例如羟基氯喹和氯喹)、甲氨蝶呤金盐(例如硫化葡糖金硫苹果酸金和金诺芬)、D-青霉胺(或)、硫唑嘌呤环磷酰胺氮芥苯丁酸环孢素来氟米特和“抗TNF”药剂(例如依那西普英利昔单抗戈利木单抗聚乙二醇化赛妥珠单抗和阿达木单抗)、“抗IL-1”药剂(例如阿那白滞素和利纳西普)、抗体(例如利妥昔单抗)、“抗T细胞”药剂(例如阿巴西普)和“抗IL-6”药剂(例如托珠单抗)。
在一些实施例中,本发明提供治疗骨关节炎的方法,其包含向有需要的患者投与式I化合物和一或多种选自以下的额外治疗剂:乙酰胺酚、非类固醇抗炎症药物(NSAID)(例如阿斯匹林、布洛芬、萘普生、依托度酸和塞来昔布)、双氯芬酸、可体松、玻尿酸(或)和单克隆抗体(例如他尼珠单抗)。
在一些实施例中,本发明提供治疗全身性红斑狼疮的方法,其包含向有需要的患者投与式I化合物和一或多种选自以下的额外治疗剂:乙酰胺酚、非类固醇抗炎症药物(NSAID)(例如阿斯匹林、布洛芬、萘普生、依托度酸和塞来昔布)、皮质类固醇(例如普赖松、普赖苏秾、甲基普赖苏秾、氢化可体松和诸如此类)、抗疟疾药(例如羟基氯喹和氯喹)、环磷酰胺甲氨蝶呤硫唑嘌呤和抗凝剂(例如肝素(或)和杀鼠灵)。
在一些实施例中,本发明提供治疗克隆氏病、溃疡性结肠炎或炎症性肠病的方法,其包含向有需要的患者投与式I化合物和一或多种选自以下的额外治疗剂:美沙拉明(mesalamine)磺胺塞拉金止泻药(例如地芬诺酯和洛哌丁胺)、胆汁酸结合剂(例如消胆胺)、阿洛司琼鲁比前列酮轻泻剂(例如镁乳、聚乙二醇和)和抗胆碱药或镇痉药(例如双环维林)、抗TNF疗法、类固醇和抗生素(例如甲硝唑(Flagyl)或赛普沙辛(ciprofloxacin))。
在一些实施例中,本发明提供治疗气喘的方法,其包含向有需要的患者投与式I化合物和一或多种选自以下的额外治疗剂:β-2激动剂(例如沙丁胺醇(HFA、HFA)、左旋沙丁胺醇异丙喘宁乙酸吡布特罗硫酸特布他林昔萘酸沙美特罗和福莫特罗)、抗胆碱药(例如异丙托溴铵和噻托铵)、吸入皮质类固醇(例如普赖松、普赖苏秾、二丙酸倍氯米松(和)、曲安奈德莫米松布地奈德氟尼缩松和)、色甘酸钠甲基黄嘌呤(例如茶碱和胺茶碱)和IgE抗体(例如奥马珠单抗)。
在一些实施例中,本发明提供治疗COPD的方法,其包含向有需要的患者投与式I化合物和一或多种选自以下的额外治疗剂:β-2激动剂(例如沙丁胺醇(HFA、HFA)、左旋沙丁胺醇异丙喘宁乙酸吡布特罗硫酸特布他林昔萘酸沙美特罗和福莫特罗)、抗胆碱药(例如异丙托溴铵和噻托铵)、甲基黄嘌呤(例如茶碱和胺茶碱)、吸入皮质类固醇(例如普赖松、普赖苏秾、二丙酸倍氯米松(和)、曲安奈德莫米松布地奈德氟尼缩松和)。
在另一实施例中,本发明提供治疗血液学恶性病的方法,其包含向有需要的患者投与式I化合物和一或多种选自以下的额外治疗剂:利妥昔单抗环磷酰胺多柔比星长春新碱普赖松、刺猬(Hedgehog)信号传导抑制剂、BTK抑制剂、JAK/泛-JAK抑制剂、PI3K抑制剂、SYK抑制剂和其组合。
在另一实施例中,本发明提供治疗实体肿瘤的方法,其包含向有需要的患者投与式I化合物和一或多种选自以下的额外治疗剂:利妥昔单抗环磷酰胺多柔比星长春新碱普赖松、刺猬信号传导抑制剂、BTK抑制剂、JAK/泛-JAK抑制剂、PI3K抑制剂、SYK抑制剂和其组合。
在另一实施例中,本发明提供治疗血液学恶性病的方法,其包含向有需要的患者投与式I化合物和刺猬(Hh)信号传导路径抑制剂。在一些实施例中,血液学恶性病是DLBCL(拉米雷斯(Ramirez)等人,“定义有助于弥漫性大B细胞淋巴瘤中的刺猬信号传导活化的诱发因素(Defining causative factors contributing in the activation of hedgehogsignaling in diffuse large B-cell lymphoma)”,白血病研究(Leuk.Res.)(2012),于7月17日在线发布,并且其全部内容以引用方式并入本文中)。
在另一实施例中,本发明提供治疗弥漫性大B细胞淋巴瘤(DLBCL)的方法,其包含向有需要的患者投与式I化合物和一或多种选自以下的额外治疗剂:利妥昔单抗环磷酰胺多柔比星长春新碱普赖松、刺猬信号传导抑制剂和其组合。
在另一实施例中,本发明提供治疗多发性骨髓瘤的方法,其包含向有需要的患者投与式I化合物和一或多种选自以下的额外治疗剂:硼替佐米和地塞米松刺猬信号传导抑制剂、BTK抑制剂、JAK/泛-JAK抑制剂、TYK2抑制剂、PI3K抑制剂、SYK抑制剂与雷利度胺的组合。
在另一实施例中,本发明提供治疗疾病或减轻疾病的严重程度的方法,其包含向有需要的患者投与式I化合物和BTK抑制剂,其中所述疾病是选自炎症性肠病、关节炎、全身性红斑狼疮(SLE)、血管炎、特发性血小板减少紫斑症(ITP)、类风湿性关节炎、牛皮癣性关节炎、骨关节炎、斯蒂尔病(Still’s disease)、幼年型关节炎、糖尿病、重症肌无力、桥本氏甲状腺炎(Hashimoto’s thyroiditis)、奥德甲状腺炎(Ord’s thyroiditis)、格雷氏病(Graves’disease)、自体免疫甲状腺炎、薛格连氏综合症、多发性硬化、全身性硬化、神经莱姆病(Lyme neuroborreliosis)、格林-巴利综合症(Guillain-Barre syndrome)、急性弥漫性脑脊髓炎、艾迪森氏病、斜视性眼阵挛-肌阵挛综合症、关节粘连性脊椎炎、抗磷脂抗体综合症、再生障碍性贫血、自体免疫肝炎、自体免疫胃炎、恶性贫血、乳糜泻、古巴士德氏综合症(Goodpasture’s syndrome)、特发性血小板减少紫斑症、视神经炎、硬皮症、原发性胆汁性硬化、赖特氏综合症(Reiter’s syndrome)、高安氏动脉炎(Takayasu’s arteritis)、颞动脉炎、温自体免疫溶血性贫血、韦格纳氏肉芽肿病、牛皮癣、全身脱毛、贝赛特氏病、慢性疲劳、自主神经障碍、膜性肾小球性肾病变、子宫内膜变构症、间质性膀胱炎、寻常天疱疮、大疱性类天疱疮、神经性肌强直、硬皮症、外阴痛、过度增殖疾病、移植器官或组织排斥、获得性免疫缺陷综合症(AIDS,还称作HIV)、1型糖尿病、移植物抗宿主病、移植、转输、过敏反应、过敏(例如,对植物花粉、乳胶、药物、食物、昆虫毒素、动物毛发、动物皮屑、尘螨或蟑螂萼过敏)、I型过敏性、过敏性结膜炎、过敏性鼻炎和变构性皮肤炎、气喘、阑尾炎、变构性皮肤炎、气喘、过敏症、眼睑炎、细支气管炎、支气管炎、滑囊炎、子宫颈炎、胆管炎、胆囊炎、慢性移植物排斥、结肠炎、结膜炎、克隆氏病、膀胱炎、泪腺炎、皮肤炎、皮肌炎、脑炎、心内膜炎、子宫内膜炎、肠炎、小肠结肠炎、上髁炎、附睾炎、筋膜炎、纤维组织炎、胃炎、胃肠炎、亨-舒二氏紫斑病、肝炎、化脓性汗腺炎、免疫球蛋白A肾病变、间质性肺病、喉炎、乳腺炎、脑膜炎、脊髓炎心肌炎、肌炎、肾炎、卵巢炎、睾丸炎、骨炎、耳炎、胰脏炎、腮腺炎、心包炎、腹膜炎、咽炎、胸膜炎、静脉炎、肺炎(pneumonitis)、肺炎(pneumonia)、多肌炎、直肠炎、前列腺炎、肾盂肾炎、鼻炎、输卵管炎、鼻窦炎、口炎、滑膜炎、肌腱炎、扁桃腺炎、溃疡性结肠炎、眼色素层炎、阴道炎、血管炎、或外阴炎、B细胞增殖病症(例如弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、慢性淋巴细胞性淋巴瘤、慢性淋巴细胞性白血病、急性淋巴细胞性白血病、B细胞前淋巴细胞性白血病、淋巴浆细胞淋巴瘤/瓦尔登斯特伦氏巨球蛋白血症(Waldenstrommacroglobulinemia)、脾边缘区淋巴瘤、多发性骨髓瘤(还称作浆细胞骨髓瘤)、非何杰金氏淋巴瘤(non-Hodgkin’s lymphoma)、何杰金氏淋巴瘤、浆细胞瘤、结节外边缘区B细胞淋巴瘤、结节边缘区B细胞淋巴瘤、外套细胞淋巴瘤、纵膈(胸腺)大B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发性积液淋巴瘤、伯基特氏淋巴瘤(Burkitt lymphoma)/白血病或淋巴瘤样肉芽肿病)、乳癌、前列腺癌或肥大细胞癌(例如,肥大细胞瘤、肥大细胞白血病、肥大细胞肉瘤、全身性肥大细胞增多症)、骨癌、结肠直肠癌、胰脏癌、骨和关节疾病(包括(但不限于)类风湿性关节炎、血清阴性脊椎关节病(包括关节粘连性脊椎炎、牛皮癣性关节炎和赖特氏疾病)、贝赛特氏病、薛格连氏综合症、全身性硬化、骨质疏松症、骨癌、骨转移)、血栓栓塞性病症(例如,心肌梗塞、心绞痛、血管成形术后再闭塞、血管成形术后再狭窄、主动脉冠状动脉分流术后再闭塞、主动脉冠状动脉分流术后再狭窄、中风、短暂缺血、周边动脉阻塞性病症、肺栓塞、深静脉血栓形成)、炎症性骨盆疾病、尿道炎、皮肤晒伤、鼻窦炎、肺炎、脑炎、脑膜炎、心肌炎、肾炎、骨髓炎、肌炎、肝炎、胃炎、肠炎、皮肤炎、牙龈炎、阑尾炎、胰脏炎、胆囊炎、无γ球蛋白血症、牛皮癣、过敏症、克隆氏病、肠躁综合症、溃疡性结肠炎、薛格连氏疾病、组织移植物排斥、移植器官超急性排斥、气喘、过敏性鼻炎、慢性阻塞性肺病(COPD)、自体免疫多腺疾病(还称作自体免疫多腺综合症)、自体免疫脱发、恶性贫血、肾小球性肾炎、皮肌炎、多发性硬化、硬皮症、血管炎、自体免疫溶血和血小板减少状态、古巴士德氏综合症、动脉粥样硬化、艾迪森氏病、帕金森氏病、阿兹海默氏病、糖尿病、败血性休克、全身性红斑狼疮(SLE)、类风湿性关节炎、牛皮癣性关节炎、幼年型关节炎、骨关节炎、慢性特发性血小板减少紫斑症、瓦尔登斯特伦氏巨球蛋白血症、重症肌无力、桥本氏甲状腺炎、变构性皮肤炎、变性关节疾病、白斑病、自体免疫垂体功能减退、格林-巴利综合症、贝赛特氏病、硬皮病、蕈样真菌病、急性炎症反应(例如急性呼吸窘迫综合症和缺血/再灌注损伤)和格雷氏病。
在另一实施例中,本发明提供治疗疾病或减轻疾病的严重程度的方法,其包含向有需要的患者投与式I化合物和PI3K抑制剂,其中所述疾病是选自癌症、神经变性病症、血管生成病症、病毒疾病、自体免疫疾病、炎症病症、激素相关疾病、与器官移植相关的病况、免疫缺陷病症、破坏性骨病症、增殖病症、传染病、与细胞死亡相关的病况、凝血酶诱导的血小板聚集、慢性骨髓性白血病(CML)、慢性淋巴细胞性白血病(CLL)、肝病、涉及T细胞活化的病理性免疫病况、心血管病症和CNS病症。
在另一实施例中,本发明提供治疗疾病或减轻疾病的严重程度的方法,其包含向有需要的患者投与式I化合物和PI3K抑制剂,其中所述疾病是选自良性或恶性肿瘤、脑、肾(例如,肾细胞癌(RCC))、肝、肾上腺、膀胱、乳房、胃、胃肿瘤、卵巢、结肠、直肠、前列腺、胰脏、肺、阴道、子宫内膜、子宫颈、睾丸、生殖泌尿道、食管、喉、皮肤、骨或甲状腺癌或实体肿瘤、肉瘤、神经胶母细胞瘤、神经胚细胞瘤、多发性骨髓瘤或胃肠癌(尤其结肠癌或结肠直肠腺瘤)或头颈肿瘤、表皮增殖过度、牛皮癣、前列腺增生、赘瘤形成、上皮特征赘瘤形成、腺瘤、腺癌、角质棘皮瘤、表皮样癌、大细胞癌、非小细胞肺癌、淋巴瘤(包括(例如)非何杰金氏淋巴瘤(NHL)和何杰金氏淋巴瘤(还称作何杰金氏或何杰金氏病))、乳房癌、滤泡癌、未分化癌、乳头状癌、精原细胞瘤、黑色素瘤或白血病、包括考登综合症(Cowden syndrome)、莱尔米特-杜多斯病(Lhermitte-Dudos disease)和潘纳扬-佐纳纳综合症(Bannayan-Zonanasyndrome)的疾病或PI3K/PKB路径异常活化的疾病、任何类型或成因的气喘(包括固有(非过敏性)气喘和非固有(过敏性)气喘、轻度气喘、中度气喘、严重气喘、支气管炎气喘、锻炼诱导的气喘、职业性气喘和细菌感染后诱导的气喘)、急性肺损伤(ALI)、成人/急性呼吸窘迫综合症(ARDS)、慢性阻塞性肺、气道或肺病(COPD、COAD或COLD)(包括慢性支气管炎或与其相关的呼吸困难、肺气肿)以及随其它药物疗法(具体来说,其它吸入药物疗法)发生的气道超敏反应加剧、任何类型或成因的支气管炎(包括(但不限于)急性、花生仁吸入性、卡他性、格鲁布性、慢性或结核性支气管炎)、任何类型或成因的尘肺病(一种炎症性、通常为职业性的肺病,无论慢性或急性都常常伴有气道阻塞且由反复吸入粉尘而引发)(包括(例如)铝尘肺、炭尘肺、石棉尘肺、石末尘肺、毛发尘肺、铁尘肺、硅尘肺、烟草尘肺和棉尘肺)、吕弗勒氏综合症(Loffler's syndrome)、嗜伊红球性、肺炎、寄生性(具体来说后生动物)感染(包括热带嗜伊红球增多症)、支气管肺曲霉菌病、结节性多动脉炎(包括丘格-斯特劳斯综合症(Churg-Strauss syndrome))、嗜伊红球性肉芽肿和由药物-反应引发的侵袭气道的嗜伊红球相关病症、牛皮癣、接触性皮肤炎、变构性皮肤炎、斑秃、多形性红斑、疱疹样皮肤炎、硬皮症、白斑病、过敏性血管炎、荨麻疹、大疱性类天疱疮、红斑狼疮、天疱疮、后天性水疱性表皮松解症、结膜炎、干燥性角结膜炎和春季结膜炎、侵袭鼻子的疾病(包括过敏性鼻炎)和涉及或具有自体免疫组分或病因的炎症性疾病,包括自体免疫血液学病症(例如溶血性贫血、再生障碍性贫血、单纯红血球性贫血和特发性血小板减少症)、全身性红斑狼疮、类风湿性关节炎、多软骨炎、硬皮症、韦格纳氏肉芽肿病、皮肌炎、慢性活动型肝炎、重症肌无力、史蒂文斯-约翰逊综合症、特发性口炎性腹泻、自体免疫炎症性肠病(例如溃疡性结肠炎和克隆氏病)、内分泌眼病、格雷夫斯氏病、类肉瘤病、肺泡炎、慢性过敏性肺炎、多发性硬化、原发性胆汁性硬化、葡萄膜炎(前葡萄膜炎和后葡萄膜炎)、干燥性角结膜炎和春季角结膜炎、间质性肺纤维化、牛皮癣性关节炎和肾小球性肾炎(具有和无肾病综合症,例如包括特发性肾病综合症或微小病变肾病变、再狭窄、心脏扩大、动脉粥样硬化、心肌梗塞、缺血性中风和郁血性心脏衰竭、阿兹海默氏病、帕金森氏病、肌肉萎缩性脊髓侧索硬化症、杭丁顿氏病(Huntington's disease)、和脑缺血和由创伤性损伤、谷氨酸盐神经毒性和低氧引起的神经变性疾病。
在一些实施例中,本发明提供治疗疾病或减轻疾病的严重程度的方法,其包含向有需要的患者投与式I化合物和Bcl-2抑制剂,其中所述疾病是炎症病症、自体免疫病症、增殖病症、内分泌病症、神经病症或与移植相关的病症。在一些实施例中,所述病症是增殖病症、狼疮或狼疮性肾炎。在一些实施例中,增殖病症是慢性淋巴细胞性白血病、弥漫性大B细胞淋巴瘤、何杰金氏病、小细胞肺癌、非小细胞肺癌、骨髓发育不良综合症、淋巴瘤、血液肿瘤或实体肿瘤。
在一些实施例中,本发明提供治疗疾病或减轻疾病的严重程度的方法,其包含向有需要的患者投与TYK2假激酶(JH2)结构域结合化合物和TYK2激酶(JH1)结构域结合化合物。在一些实施例中,所述疾病是自体免疫病症、炎症病症、增殖性病症、内分泌病症、神经病症或与移植相关的病症。在一些实施例中,JH2结合化合物是式I化合物。其它适宜JH2结构域结合化合物包括以下中所述的那些:WO2014074660A1、WO2014074661A1、WO2015089143A1,每一者的内容以引用方式并入本文中。适宜JH1结构域结合化合物包括WO2015131080A1中所述的那些,所述案件的内容以引用方式并入本文中。
根据本发明方法的化合物和组合物可使用可有效治疗自体免疫病症、炎症病症、增殖性病症、内分泌病症、神经病症或与移植相关的病症或减轻其严重程度的任何量和任何投与途径来投与。根据个体物种、年龄和一般状况、感染严重程度、特定药剂、其投与模式和诸如此类,所需确切量可随个体而变化。本发明化合物优选调配为剂量单位形式以便于投与和统一剂量。如本文中所使用,表达“剂量单位形式”是指适于要治疗患者的药剂的物理离散单位。然而,应理解,本发明化合物和组合物的总日用量将由主治医师在合理的医学判断范围内决定。任一特定患者或生物体的具体有效剂量值可取决于多个因素,包括所治疗病症和病症的严重程度;所用具体化合物的活性;所用具体组合物;患者的年龄、体重、一般健康状况、性别和饮食;所用具体化合物的投与时间、投与途径和排泄速率;治疗持续时间;与所用具体化合物组合或同时使用的药物;和医疗技术中熟知的类似因素。如本文中所用术语“患者”意指动物,优选是哺乳动物,并且最优选是人类。
根据所治疗感染的严重程度而定,本发明的药学上可接受的组合物可以下列方式投与人类和其它动物:经口、经直肠、非经肠、脑池内、阴道内、腹膜腔内、局部(以粉剂、软膏或滴剂形式)、经颊(以经口或鼻喷雾形式)或诸如此类。在某些实施例中,本发明化合物可以约0.01mg/kg到约50mg/kg且优选约1mg/kg到约25mg/kg个体体重/天的剂量值每天一或多次经口或非经肠投与以获得所需治疗效应。
用于经口投与的液体剂型包括(但不限于)药学上可接受的乳液、微乳液、溶液、悬浮液、糖浆和酏剂。除活性化合物外,液体剂型可含有业内通常使用的惰性稀释剂(例如水或其它溶剂)、增溶剂和乳化剂,例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄基酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(具体来说棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇和山梨醇酐的脂肪酸酯和其混合物。除惰性稀释剂外,经口组合物还可包括佐剂,例如润湿剂、乳化和悬浮剂、甜味剂、矫味剂和芳香剂。
可根据已知技术使用适宜分散或润湿剂和悬浮剂来调配可注射制剂,例如无菌可注射水性或油性悬浮液。无菌可注射制剂还可为存于无毒非经肠可接受的稀释剂或溶剂中的无菌可注射溶液、悬浮液或乳液,例如于1,3-丁二醇中的溶液。可采用的可接受的媒剂和溶剂尤其是水、林格氏溶液、U.S.P.和等渗氯化钠溶液。另外,照惯例采用无菌不挥发性油作为溶剂或悬浮介质。出于此目的,可采用任何温和的不挥发性油,包括合成甘油单酸酯或甘油二酸酯。此外,在可注射制剂中使用诸如油酸等脂肪酸。
可注射调配物可通过(例如)通过细菌截留过滤器过滤或通过纳入灭菌剂来灭菌,所述灭菌剂呈无菌固体组合物形式且可在使用前溶解或分散于无菌水或其它无菌可注射介质中。
为延长本发明化合物的效应,通常期望从皮下或肌内注射来减缓化合物的吸收。此可通过使用具有较差水溶性的结晶或非晶型材料的液体悬浮液来实现。化合物的吸收速率则取决于其溶解速率,而溶解速率进而可取决于晶体大小和晶体形式。或者,非经肠投与化合物的延迟吸收是通过将化合物溶解或悬浮于油媒剂中来实现。可注射储积形式是通过在生物可降解聚合物(例如聚乳酸-聚甘醇酸)中形成化合物的微囊基质来制备。根据化合物对聚合物的比率和所采用特定聚合物的性质,可控制化合物的释放速率。其它生物可降解聚合物的实例包括聚(原酸酯)和聚(酐)。储积可注射调配物还通过使化合物陷获于与身体组织相容的脂质体或微乳液中来制备。
用于直肠或阴道投与的组合物优选为栓剂,其可通过将本发明化合物与适宜无刺激性赋形剂或载剂(例如可可油、聚乙二醇或栓剂蜡)混合来制备,所述赋形剂或载剂在环境温度下为固体但在体温下为液体,并且由此可在直肠或阴道腔内融化并释放活性化合物。
用于经口投与的固体剂型包括胶囊、片剂、丸剂、粉剂和粒剂。在所述固体剂型中,将活性化合物与至少一种惰性、药学上可接受的赋形剂或载剂(例如柠檬酸钠或磷酸二钙)和/或以下各项混合:a)填充剂或增量剂,例如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;b)粘合剂,例如羧甲基纤维素、海藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;c)保湿剂,例如甘油;d)崩解剂,例如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐和碳酸钠;e)溶解阻滞剂,例如石蜡;f)吸收促进剂,例如季铵化合物;g)润湿剂,例如鲸蜡醇和甘油单硬脂酸酯;h)吸收剂,例如高岭土和膨润土;和i)润滑剂,例如滑石粉、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠;和其混合物。在胶囊、片剂和丸剂的情形下,剂型还可包含缓冲剂。
在使用诸如乳糖(lactose或milk sugar)以及高分子量聚乙二醇等赋形剂的软质和硬质填充明胶胶囊中,还可采用相似类型的固体组合物作为填充剂。片剂、糖衣锭、胶囊、丸剂和粒剂的固体剂型可制备有包衣和包壳,例如肠溶包衣和药物调配领域熟知的其它包衣。其可任选地含有遮光剂且还可为任选地以延迟方式仅或优先在肠道的某一部分中释放活性成分的组合物。可使用的包埋用组合物的实例包括聚合物质和蜡。在使用诸如乳糖(lactose或milk sugar)以及高分子量聚乙二醇等赋形剂的软质和硬质填充明胶胶囊中,还可采用相似类型的固体组合物作为填充剂。
活性化合物还可呈具有一或多种上述赋形剂的微囊封形式。可使用诸如肠溶包衣、释放控制包衣和药物调配技术中熟知的其它包衣等包衣和包壳来制备片剂、糖衣锭、胶囊、丸剂和粒剂的固体剂型。在所述固体剂型中,可将活性化合物与至少一种惰性稀释剂(例如蔗糖、乳糖或淀粉)混合。所述剂型除惰性稀释剂以外还可包括如同通常实践一般的额外物质,例如压片润滑剂和其它压片助剂(例如硬脂酸镁和微晶纤维素)。在胶囊、片剂和丸剂的情形下,剂型还可包含缓冲剂。其可任选地含有遮光剂且还可为任选地以延迟方式仅或优先在肠道的某一部分中释放活性成分的组合物。可使用的包埋用组合物的实例包括聚合物质和蜡。
用于局部或经皮投与本发明化合物的剂型包括软膏、膏糊、乳霜、洗剂、凝胶、粉剂、溶液、喷雾剂、吸入剂或贴剂。在无菌条件下将活性组分与药学上可接受的载剂和可能需要的任何所需防腐剂或缓冲剂混合。眼用调配物、滴耳剂和滴眼剂还在本发明的范围内。另外,本发明涵盖使用经皮贴剂,其具有提供化合物到身体的受控递送的额外优点。所述剂型可通过将化合物溶解或分散于适当介质中来制备。还可使用吸收增强剂来增加化合物横跨皮肤的通量。可通过提供速率控制膜或通过将化合物分散于聚合物基质或凝胶中来控制速率。
根据一个实施例,本发明涉及抑制生物试样中的蛋白激酶活性的方法,其包含使所述生物试样与本发明化合物或包含所述化合物的组合物接触的步骤。
根据另一实施例,本发明涉及抑制生物试样中的TYK2或其突变体的方法,其包含使所述生物试样与本发明化合物或包含所述化合物的组合物接触的步骤。在某些实施例中,本发明涉及不可逆地抑制生物试样中的TYK2或其突变体的方法,其包含使所述生物试样与本发明化合物或包含所述化合物的组合物接触的步骤。
在另一实施例中,本发明提供相对于JAK1、JAK2和JAK3中的一或多者选择性抑制TYK2的方法。在一些实施例中,本发明化合物相对于JAK1/2/3超过2倍选择性。在一些实施例中,本发明化合物相对于JAK1/2/3超过5倍选择性。在一些实施例中,本发明化合物相对于JAK1/2/3超过10倍选择性。在一些实施例中,本发明化合物相对于JAK1/2/3超过50倍选择性。在一些实施例中,本发明化合物相对于JAK1/2/3超过100倍选择性。
本文所用术语“生物试样”包括(但不限于)细胞培养物或其萃取物;从哺乳动物获得的活体组织检查材料或其萃取物;和血液、唾液、尿、粪便、精液、眼泪或其它体液或其萃取物。
生物试样中TYK2(或其突变体)活性的抑制可用于所属领域技术人员已知的多种目的。所述目的的实例包括(但不限于)输血、器官移植、生物样品储存和生物分析。
本发明的另一实施例涉及抑制患者的蛋白激酶活性的方法,其包含向所述患者投与本发明化合物或包含所述化合物的组合物的步骤。
根据另一实施例,本发明涉及抑制患者中TYK2或其突变体的活性的方法,其包含向所述患者投与本发明化合物或包含所述化合物的组合物的步骤。根据某些实施例,本发明涉及不可逆地抑制患者中TYK2或其突变体中的一或多者的活性的方法,其包含向所述患者投与本发明化合物或包含所述化合物的组合物的步骤。在其它实施例中,本发明提供治疗有需要的患者的由TYK2或其突变体介导的病症的方法,其包含向所述患者投与本发明化合物或其药学上可接受的组合物的步骤。所述病症详细描述于本文中。
根据要治疗的特定病况或疾病而定,通常投与以治疗所述病况的额外治疗剂还可存于本发明组合物中。如本文中所使用,通常投与以治疗特定疾病或病况的额外治疗剂称为“适于所治疗的疾病或病况”。
本发明化合物还可有利地与其它治疗性化合物组合使用。在一些实施例中,其它治疗性化合物是抗增殖性化合物。所述抗增殖性化合物包括(但不限于)芳香酶抑制剂;抗雌激素;拓朴异构酶I抑制剂;拓朴异构酶II抑制剂;微管活性化合物;烷基化化合物;组蛋白脱乙酰基酶抑制剂;诱导细胞分化过程的化合物;环氧合酶抑制剂;MMP抑制剂;mTOR抑制剂;抗肿瘤抗代谢药物;铂化合物;靶向/降低蛋白或脂质激酶活性的化合物和其它抗血管生成化合物;靶向、降低或抑制蛋白或脂质磷酸酶活性的化合物;戈那瑞林(gonadorelin)激动剂;抗雄激素;甲硫氨酸氨基肽酶抑制剂;基质金属蛋白酶抑制剂;双膦酸化合物;生物反应调节剂;抗增殖性抗体;类肝素酶抑制剂;Ras致癌同型异构体的抑制剂;端粒酶抑制剂;蛋白酶体抑制剂;用于治疗血液恶性病的化合物;靶向、降低或抑制Flt-3活性的化合物;Hsp90抑制剂,例如购自康福玛医药公司(Conforma Therapeutics)的17-AAG(17-丙烯氨基格尔德霉素(allylaminogeldanamycin),NSC330507)、17-DMAG(17-二甲基氨基乙基氨基-17-脱甲氧基-格尔德霉素,NSC707545)、IPI-504、CNF1010、CNF2024、CNF1010;替莫唑胺(temozolomide)驱动蛋白纺锤蛋白抑制剂,例如购自葛兰素史克公司(GlaxoSmithKline)的SB715992或SB743921,或购自科姆特里克公司(CombinatoRx)的喷他脒(pentamidine)/氯丙嗪(chlorpromazine);MEK抑制剂,例如购自阿尔雷生物制药公司(Array BioPharma)的ARRY142886、购自阿斯利康公司(AstraZeneca)的AZD6244、购自辉瑞公司(Pfizer)的PD181461和甲酰四氢叶酸(leucovori)。本文所用术语“芳香酶抑制剂”是指抑制雌激素产生(例如,底物雄烯二酮和睾固酮分别转化成雌酮和雌二醇)的化合物。所述术语包括(但不限于)类固醇,尤其是阿他美坦(atamestane)、依西美坦(exemestane)和福美司坦(formestane),并且具体来说非类固醇,尤其胺鲁米特(aminoglutethimide)、罗谷亚胺(rogletimide)、吡啶并格鲁米特(pyridoglutethimide)、曲洛司坦(trilostane)、睾内酯(testolactone)、酮康唑(ketokonazole)、伏氯唑(vorozole)、法曲唑(fadrozole)、阿那曲唑(anastrozole)和来曲唑(letrozole)。依西美坦是以商品名AromasinTM销售。福美司坦是以商品名LentaronTM销售。法曲唑是以商品名AfemaTM销售。阿那曲唑是以商品名ArimidexTM销售。来曲唑是以商品名FemaraTM或FemarTM销售。胺鲁米特是以商品名OrimetenTM销售。本发明包含芳香酶抑制剂的化学治疗剂的组合特别可用于治疗激素受体阳性肿瘤(例如乳房肿瘤)。
如本文所用术语“抗雌激素药”是指在雌激素受体水平上拮抗雌激素作用的化合物。所述术语包括(但不限于)他莫昔芬(tamoxifen)、氟维司群(fulvestrant)、雷洛昔芬(raloxifene)和盐酸雷洛昔芬。他莫昔芬是以商品名NolvadexTM销售。盐酸雷洛昔芬是以商品名EvistaTM销售。氟维司群可以商品名FaslodexTM投与。本发明包含本身为抗雌激素的化学治疗剂的组合特别可用于治疗雌激素受体阳性肿瘤(例如,乳房肿瘤)。
如本文所用术语“抗雄激素”是指任何能够抑制雄性激素的效应的物质且包括(但不限于)比卡鲁胺(bicalutamide)(CasodexTM)。如本文所用术语“戈那瑞林激动剂”包括(但不限于)阿巴瑞克(abarelix)、戈舍瑞林(goserelin)和乙酸戈舍瑞林。戈舍瑞林可以商品名ZoladexTM投与。
如本文所用术语“拓朴异构酶I抑制剂”包括(但不限于)托泊替康(topotecan)、吉马替康(gimatecan)、伊立替康(irinotecan)、喜树碱(camptothecian)和其类似物9-硝基喜树碱和巨分子喜树碱结合物PNU-166148。伊立替康可以(例如)其市售形式(例如以商标CamptosarTM)投与。托泊替康是以商品名HycamptinTM销售。
如本文所用术语“拓朴异构酶II抑制剂”包括(但不限于)蒽环类抗生素(anthracycline),例如多柔比星(包括脂质体调配物,例如CaelyxTM)、道诺霉素(daunorubicin)、表柔比星(epirubicin)、伊达比星(idarubicin)和奈莫柔比星(nemorubicin)、蒽醌类米托蒽醌和洛索蒽醌(losoxantrone)、和鬼臼毒素(podophillotoxine)类依托泊苷(etoposide)和替尼泊苷(teniposide)。依托泊苷是以商品名EtopophosTM销售。替尼泊苷是以商品名VM 26-Bristol销售。多柔比星是以商品名AcriblastinTM或AdriamycinTM销售。表柔比星是以商品名FarmorubicinTM销售。伊达比星是以商品名ZavedosTM销售。米托蒽醌是以商品名诺娃特隆(Novantron)销售。
术语“微管活性剂”是指微管稳定、微管去稳定化合物和微管蛋白(microtublin)聚合抑制剂,包括(但不限于)紫杉烷(taxane),例如太平洋紫杉醇(paclitaxel)和多西他赛(docetaxel);长春花生物碱,例如长春碱(vinblastine)或硫酸长春碱、长春新碱或硫酸长春新碱和长春瑞滨(vinorelbine);迪莫利德(discodermolide);秋水仙碱(cochicine)和埃博霉素(epothilone)和其衍生物。太平洋紫杉醇是以商品名TaxolTM销售。多西他赛是以商品名TaxotereTM销售。硫酸长春碱是以商品名Vinblastin R.PTM销售。硫酸长春新碱是以商品名FarmistinTM销售。
本文所用术语“烷基化化合物”包括(但不限于)环磷酰胺、异环磷酰胺(ifosfamide)、美法仑(melphalan)或亚硝基脲(BCNU或格立得尔(Gliadel))。环磷酰胺是以商品名CyclostinTM销售。异环磷酰胺是以商品名HoloxanTM销售。
术语“组蛋白脱乙酰基酶抑制剂”或“HDAC抑制剂”是指抑制组蛋白脱乙酰基酶并具有抗增殖活性的化合物。此包括(但不限于)辛二酰苯胺异羟肟酸(SAHA)。
术语“抗肿瘤抗代谢药物”包括(但不限于)5-氟尿嘧啶或5-FU、卡培他滨(capecitabine)、吉西他滨(gemcitabine)、DNA脱甲基化化合物(例如5-氮胞苷(5-azacytidine)和地西他滨(decitabine))、甲氨蝶呤和依达曲沙(edatrexate)和叶酸拮抗剂(例如培美曲塞(pemetrexed))。卡培他滨是以商品名XelodaTM销售。吉西他滨是以商品名GemzarTM销售。
本文所用术语“铂化合物”包括(但不限于)碳铂、顺铂(cis-platin、cisplatinum)和奥沙利铂(oxaliplatin)。碳铂可(例如)以其市售形式(例如以商标CarboplatTM)投与。奥沙利铂可(例如)以其市售形式(例如以商标EloxatinTM)投与。
如本文所用术语“靶向/降低蛋白或脂质激酶活性、或蛋白或脂质磷酸酶活性的化合物;或其它抗血管生成化合物”包括(但不限于)蛋白酪氨酸激酶和/或丝氨酸和/或苏氨酸激酶抑制剂或脂质激酶抑制剂,例如a)靶向、降低或抑制血小板衍生的生长因子-受体(PDGFR)的活性的化合物,例如靶向、降低或抑制PDGFR的活性的化合物,尤其抑制PDGF受体的化合物,例如N-苯基-2-嘧啶-胺衍生物,例如伊马替尼(imatinib)、SU101、SU6668和GFB111;b)靶向、降低或抑制纤维母细胞生长因子-受体(FGFR)的活性的化合物;c)靶向、降低或抑制胰岛素样生长因子受体I(IGF-IR)的活性的化合物,例如靶向、降低或抑制IGF-IR的活性的化合物,尤其抑制IGF-I受体或靶向IGF-I受体或其生长因子的细胞外结构域的抗体的激酶活性的化合物;d)靶向、降低或抑制Trk受体酪氨酸激酶家族的活性的化合物或艾普林(ephrin)B4抑制剂;e)靶向、降低或抑制Axl受体酪氨酸激酶家族的活性的化合物;f)靶向、降低或抑制Ret受体酪氨酸激酶的活性的化合物;g)靶向、降低或抑制Kit/SCFR受体酪氨酸激酶的活性的化合物,例如伊马替尼;h)靶向、降低或抑制作为PDGFR家族的一部分的C-kit受体酪氨酸激酶的活性的化合物,例如靶向、降低或抑制c-Kit受体酪氨酸激酶家族的活性的化合物,尤其抑制c-Kit受体的化合物,例如伊马替尼;i)靶向、降低或抑制c-Abl家族的成员、其基因融合产物(例如BCR-Abl激酶)和突变体的活性的化合物,例如靶向、降低或抑制c-Abl家族成员和其基因融合产物的活性的化合物,例如N-苯基-2-嘧啶-胺衍生物,例如伊马替尼或尼罗替尼(nilotinib)(AMN107);PD180970;AG957;NSC 680410;来自帕克戴维公司(ParkeDavis)的PD173955;或达沙替尼(dasatinib)(BMS-354825);j)靶向、降低或抑制蛋白激酶C(PKC)和丝氨酸/苏氨酸激酶的Raf家族的成员、MEK、SRC、JAK/泛-JAK、FAK、PDK1、PKB/Akt、Ras/MAPK、PI3K、SYK、BTK和TEC家族的成员和/或细胞周期蛋白依赖性激酶家族(CDK)的成员的活性的化合物,包括星状孢菌素(staurosporine)衍生物,例如米哚妥林(midostaurin);其它化合物的实例包括UCN-01、沙芬戈(safingol)、BAY 43-9006、苔藓抑素1(Bryostatin 1)、哌立福辛(Perifosine);伊莫福辛(llmofosine);RO318220和RO 320432;GO 6976;Isis 3521;LY333531/LY379196;异喹啉化合物;FTI;PD184352或QAN697(P13K抑制剂)或AT7519(CDK抑制剂);k)靶向、降低或抑制蛋白酪氨酸激酶抑制剂的活性的化合物,例如靶向、降低或抑制蛋白酪氨酸激酶抑制剂的活性的化合物,包括甲磺酸伊马替尼(GleevecTM)或酪氨酸磷酸化抑制剂,例如酪氨酸磷酸化抑制剂A23/RG-50810;AG 99;酪氨酸磷酸化抑制剂AG 213;酪氨酸磷酸化抑制剂AG 1748;酪氨酸磷酸化抑制剂AG 490;酪氨酸磷酸化抑制剂B44;酪氨酸磷酸化抑制剂B44(+)对映异构体;酪氨酸磷酸化抑制剂AG 555;AG 494;酪氨酸磷酸化抑制剂AG 556、AG957和阿达福汀(adaphostin)(4-{[(2,5-二羟基苯基)甲基]氨基}-苯甲酸金刚烷基酯;NSC 680410,阿达福汀);l)靶向、降低或抑制受体酪氨酸激酶的表皮生长因子家族(呈均-或异二聚体形式的EGFR1 ErbB2、ErbB3、ErbB4)和其突变体的活性的化合物,例如靶向、降低或抑制表皮生长因子受体家族的活性的化合物尤其是抑制EGF受体酪氨酸激酶家族的成员(例如EGF受体、ErbB2、ErbB3和ErbB4)或结合到EGF或EGF相关配体的化合物、蛋白质或抗体,CP 358774、ZD1839、ZM 105180;曲妥珠单抗(trastuzumab)(HerceptinTM)、西妥昔单抗(cetuximab)(ErbituxTM)、艾瑞莎(Iressa)、塔西法(Tarceva)、OSI-774、Cl-1033、EKB-569、GW-2016、E1.1、E2.4、E2.5、E6.2、E6.4、E2.11、E6.3或E7.6.3和7H-吡咯并-[2,3-d]嘧啶衍生物;m)靶向、降低或抑制c-Met受体的活性的化合物,例如靶向、降低或抑制c-Met的活性的化合物,尤其抑制c-Met受体或靶向c-Met的细胞外结构域或结合到HGF的抗体的激酶活性的化合物,n)靶向、降低或抑制一或多个JAK家族成员(JAK1/JAK2/JAK3/TYK2和/或泛-JAK)的激酶活性的化合物,包括(但不限于)PRT-062070、SB-1578、巴瑞替尼(baricitinib)、帕克替尼(pacritinib)、莫麦乐替尼(momelotinib)、VX-509、AZD-1480、TG-101348、托法替尼和鲁索替尼(ruxolitinib);o)靶向、降低或抑制PI3激酶(PI3K)的激酶活性的化合物,包括(但不限于)ATU-027、SF-1126、DS-7423、PBI-05204、GSK-2126458、ZSTK-474、布帕利昔(buparlisib)、匹曲利昔(pictrelisib)、PF-4691502、BYL-719、达特利昔(dactolisib)、XL-147、XL-765和艾代拉里斯(idelalisib);和q)靶向、降低或抑制刺猬蛋白(Hh)或平滑受体(SMO)路径的信号传导效应的化合物,包括(但不限于)环杷明(cyclopamine)、维莫德吉(vismodegib)、伊曲康唑(itraconazole)、艾瑞斯莫德吉(erismodegib)和IPI-926(萨瑞德吉(saridegib))。
如本文所用术语“PI3K抑制剂”包括(但不限于)针对磷脂酰肌醇-3-激酶家族(包括(但不限于)PI3Kα、PI3Kγ、PI3Kδ、PI3Kβ、PI3K-C2α、PI3K-C2β、PI3K-C2γ、Vps34、p110-α、p110-β、p110-γ、p110-δ、p85-α、p85-β、p55-γ、p150、p101和p87)中的一或多种酶具有抑制活性的化合物。可用于本发明中的PI3K抑制剂的实例包括(但不限于)ATU-027、SF-1126、DS-7423、PBI-05204、GSK-2126458、ZSTK-474、布帕利昔、匹曲利昔、PF-4691502、BYL-719、达特利昔、XL-147、XL-765和艾代拉里斯。
如本文所用术语“BTK抑制剂”包括(但不限于)针对布鲁顿氏酪氨酸激酶(Bruton’s Tyrosine Kinase,BTK)具有抑制活性的化合物,包括(但不限于)AVL-292和依鲁替尼(ibrutinib)。
如本文所用术语“SYK抑制剂”包括(但不限于)具有针对脾酪氨酸激酶(SYK)的抑制活性的化合物,包括(但不限于)PRT-062070、R-343、R-333、爱思莱尔(Excellair)、PRT-062607和福他替尼(fostamatinib)。
如本文所用术语“Bcl-2抑制剂”包括(但不限于)针对B细胞淋巴瘤2蛋白(Bcl-2)具有抑制活性的化合物,包括(但不限于)ABT-199、ABT-731、ABT-737、阿朴棉子酚(apogossypol)、艾森塔公司(Ascenta)的泛-Bcl-2抑制剂、姜黄素(curcumin)(和其类似物)、双重Bcl-2/Bcl-xL抑制剂(英菲尼迪制药公司(Infinity Pharmaceuticals)/诺华制药公司(Novartis Pharmaceuticals))、根纳三思(Genasense)(G3139)、HA14-1(和其类似物;参见WO2008118802)、纳韦托克斯(navitoclax)(和其类似物,参见US7390799)、NH-1(沈阳药科大学(Shenayng Pharmaceutical University))、奥巴克拉(obatoclax)(和其类似物,参见WO2004106328)、S-001(格洛里亚制药公司(Gloria Pharmaceuticals))、TW系列化合物(密歇根大学(Univ.of Michigan))和维尼托克莱克斯(venetoclax)。在一些实施例中,Bcl-2抑制剂是小分子治疗剂。在一些实施例中,Bcl-2抑制剂是拟肽。
BTK抑制性化合物的其它实例和可由所述化合物与本发明化合物的组合治疗的病况可参见WO2008039218和WO2011090760,所述案件的内容以引用方式并入本文中。
SYK抑制性化合物的其它实例和可由所述化合物与本发明化合物的组合治疗的病况可参见WO2003063794、WO2005007623和WO2006078846,所述案件的内容以引用方式并入本文中。
PI3K抑制性化合物的其它实例和可由所述化合物与本发明化合物的组合治疗的病况可参见WO2004019973、WO2004089925、WO2007016176、US8138347、WO2002088112、WO2007084786、WO2007129161、WO2006122806、WO2005113554和WO2007044729,所述案件的内容以引用方式并入本文中。
JAK抑制性化合物的其它实例和可由所述化合物与本发明化合物的组合治疗的病况可参见WO2009114512、WO2008109943、WO2007053452、WO2000142246和WO2007070514,所述案件的内容以引用方式并入本文中。
其它抗血管生成化合物包括关于其活性具有另一机制(例如与蛋白质或脂质激酶抑制无关)的化合物,例如沙利度胺(thalidomide)(ThalomidTM)和TNP-470。
可用于与本发明化合物组合使用的蛋白酶体抑制剂的实例包括(但不限于)硼替佐米、双硫仑(disulfiram)、儿茶素-3-没食子酸酯(EGCG)、盐孢菌酰胺A(salinosporamideA)、卡非佐米(carfilzomib)、ONX-0912、CEP-18770和MLN9708。
靶向、降低或抑制蛋白或脂质磷酸酶的活性的化合物是(例如)磷酸酶1、磷酸酶2A或CDC25的抑制剂,例如冈田酸(okadaic acid)或其衍生物。
诱导细胞分化过程的化合物包括(但不限于)视黄酸、α-、γ-或δ-生育酚或α-、γ-或δ-生育三烯酚。
本文所用术语环氧合酶抑制剂包括(但不限于)Cox-2抑制剂、5-烷基取代的2-芳基氨基苯基乙酸和衍生物(例如塞来昔布(CelebrexTM)、罗非昔布(rofecoxib)(VioxxTM)、依托昔布(etoricoxib)、伐地昔布(valdecoxib))或5-烷基-2-芳基氨基苯基乙酸(例如5-甲基-2-(2'-氯-6'-氟苯胺基)苯基乙酸、罗美昔布(lumiracoxib)。
本文所用术语“双膦酸化合物”包括(但不限于)依替膦酸(etridonic acid)、氯膦酸(clodronic)、替鲁膦酸(tiludronic acid)、帕米膦酸(pamidronic)、阿仑膦酸(alendronic)、伊班膦酸(ibandronic)、利塞膦酸(risedronic)和唑来膦酸(zoledronicacid)。依替膦酸是以商品名DidronelTM销售。氯膦酸是以商品名BonefosTM销售。替鲁膦酸是以商品名SkelidTM销售。帕米膦酸是以商品名ArediaTM销售。阿仑膦酸是以商品名FosamaxTM销售。伊班膦酸是以商品名BondranatTM销售。利塞膦酸是以商品名ActonelTM销售。唑来膦酸是以商品名ZometaTM销售。术语“mTOR抑制剂”是指抑制哺乳动物雷帕霉素靶标(mTOR)且具有抗增殖活性的化合物,例如西罗莫司(sirolimus)依维莫司(everolimus)(CerticanTM)、CCI-779和ABT578。
本文所用术语“类肝素酶抑制剂”是指靶向、降低或抑制硫酸肝素降解的化合物。所述术语包括(但不限于)PI-88。如本文所用术语“生物反应调节剂”是指淋巴因子或干扰素。
本文所用术语“Ras致癌同型异构体抑制剂”(例如H-Ras、K-Ras或N-Ras)是指靶向、降低或抑制Ras的致癌活性的化合物,例如“法尼基(farnesyl)转移酶抑制剂”,例如L-744832、DK8G557或R115777(ZarnestraTM)。本文所用术语“端粒酶抑制剂”是指靶向、降低或抑制端粒酶活性的化合物。靶向、降低或抑制端粒酶活性的化合物尤其是抑制端粒酶受体的化合物,例如特洛他汀(telomestatin)。
本文所用术语“甲硫氨酸氨基肽酶抑制剂”是指靶向、降低或抑制甲硫氨酸氨基肽酶活性的化合物。靶向、降低或抑制甲硫氨酸氨基肽酶活性的化合物包括(但不限于)本阿米德(bengamide)或其衍生物。
本文所用术语“蛋白酶体抑制剂”是指靶向、降低或抑制蛋白酶体活性的化合物。靶向、降低或抑制蛋白酶体活性的化合物包括(但不限于)波替单抗(Bortezomid)(VelcadeTM)和MLN 341。
本文所用术语“基质金属蛋白酶抑制剂”或(“MMP”抑制剂)包括(但不限于)胶原拟肽和非拟肽抑制剂、四环素衍生物,例如氧肟酸盐拟肽抑制剂巴马司他(batimastat)和其可口服生物利用的类似物马立马司他(marimastat)(BB-2516)、普啉司他(prinomastat)(AG3340)、美斯大(metastat)(NSC 683551)BMS-279251、BAY 12-9566、TAA211、MMI270B或AAJ996。
本文所用术语“用于治疗血液恶性病的化合物”包括(但不限于)FMS样酪氨酸激酶抑制剂,其是靶向、降低或抑制FMS样酪氨酸激酶受体(Flt-3R)活性的化合物;干扰素、1-β-D-阿拉伯呋喃基胞嘧啶(arabinofuransylcytosine)(ara-c)和必速凡(bisulfan);ALK抑制剂,其是靶向、降低或抑制间变型淋巴瘤激酶的化合物;和Bcl-2抑制剂。
靶向、降低或抑制FMS样酪氨酸激酶受体(Flt-3R)活性的化合物尤其是抑制Flt-3R受体激酶家族成员的化合物、蛋白质或抗体,例如PKC412、米哚妥林、星状孢菌素衍生物、SU11248和MLN518。
本文所用术语“HSP90抑制剂”包括(但不限于)靶向、降低或抑制HSP90的固有ATP酶活性的化合物;通过泛素蛋白酶体路径降解、靶向、降低或抑制HSP90客体蛋白的化合物。靶向、降低或抑制HSP90的固有ATP酶活性的化合物尤其是抑制HSP90的ATP酶活性的化合物、蛋白质或抗体,例如,17-烯丙基氨基、17-脱甲氧基格尔德霉素(17AAG,一种格尔德霉素衍生物);其它格尔德霉素相关化合物;根赤壳菌素(radicicol)和HDAC抑制剂。
本文所用术语“抗增殖性抗体”包括(但不限于)曲妥珠单抗(HerceptinTM)、曲妥珠单抗-DM1、尔必得舒(erbitux)、贝伐珠单抗(bevacizumab)(AvastinTM)、利妥昔单抗(rituximab)PRO64553(抗CD40)和2C4抗体。抗体意指完整单克隆抗体、多克隆抗体、由至少2个完整抗体形成的多特异性抗体和抗体片段,只要其呈现所需的生物活性即可。
为治疗急性髓性白血病(AML),本发明化合物可与标准白血病疗法组合使用、尤其与用于治疗AML的疗法组合使用。具体来说,可组合投与本发明化合物与(例如)法尼基转移酶抑制剂和/或用于治疗AML的其它药物,例如道诺霉素、阿德力霉素(Adriamycin)、Ara-C、VP-16、替尼泊苷、米托蒽醌、伊达比星、碳铂和PKC412。在一些实施例中,本发明提供治疗与ITD和/或D835Y突变相关的AML的方法,其包含一起投与本发明化合物与一或多种FLT3抑制剂。在一些实施例中,FLT3抑制剂是选自奎扎替尼(quizartinib)(AC220)、星状孢菌素衍生物(例如米哚妥林或来他替尼(lestaurtinib))、索拉菲尼(sorafenib)、坦度替尼(tandutinib)、LY-2401401、LS-104、EB-10、法米替尼(famitinib)、NOV-110302、NMS-P948、AST-487、G-749、SB-1317、S-209、SC-110219、AKN-028、飞达替尼(fedratinib)、陶扎替尼(tozasertib)和舒尼替尼(sunitinib)。在一些实施例中,FLT3抑制剂是选自奎扎替尼、米哚妥林、来他替尼、索拉菲尼和舒尼替尼。
其它抗白血病化合物包括(例如)Ara-C(一种嘧啶类似物),其是脱氧胞苷的2-α-羟基核糖(阿拉伯糖苷(arabinoside))衍生物。还包括次黄嘌呤、6-巯基嘌呤(6-MP)和磷酸氟达拉滨(fludarabine)的嘌呤类似物。靶向、降低或抑制组织蛋白去乙酰酶(HDAC)抑制剂活性的化合物(例如丁酸钠和辛二酰苯胺异羟肟酸(SAHA))抑制称作组织蛋白去乙酰酶的酶的活性。具体HDAC抑制剂包括MS275、SAHA、FK228(先前称作FR901228)、曲古抑菌素A(Trichostatin A)和揭示于US 6,552,065中的化合物,包括(但不限于)N-羟基-3-[4-[[[2-(2-甲基-1H-吲哚-3-基)-乙基]-氨基]甲基]苯基]-2E-2-丙烯酰胺或其药学上可接受的盐和N-羟基-3-[4-[(2-羟基乙基){2-(1H-吲哚-3-基)乙基]-氨基]甲基]苯基]-2E-2-丙烯酰胺或其药学上可接受的盐,尤其乳酸盐。本文所用的生长抑素受体拮抗剂是指靶向、治疗或抑制生长抑素受体的化合物,例如奥曲肽(octreotide)和SOM230。肿瘤细胞破坏方法是指诸如电离辐射等方法。上文和下文所提到的术语“电离辐射”意指以电磁射线(例如X-射线和γ射线)或粒子(例如α和β粒子)形式发生的电离辐射。电离辐射提供于(但不限于)辐射疗法中且已为业内所知。参见赫尔曼(Hellman)的肿瘤学原理与实践(Principlesand Practice of Oncology)中的辐射疗法在癌症中的原理(Principles of RadiationTherapy,Cancer),德维塔(Devita)等人编辑,第4版,第1卷,第248页到第275页(1993))。
还包括EDG粘合剂和核糖核苷酸还原酶抑制剂。本文所用术语“EDG粘合剂”是指一类调节淋巴细胞再循环的免疫抑制剂,例如FTY720。术语“核糖核苷酸还原酶抑制剂”是指嘧啶或嘌呤核苷类似物,包括(但不限于)氟达拉滨和/或胞嘧啶阿拉伯糖苷(ara-C)、6-硫鸟嘌呤、5-氟尿嘧啶、克拉屈滨(cladribine)、6-巯基嘌呤(尤其与抗ALL的ara-C组合)和/或喷司他汀(pentostatin)。核糖核苷酸还原酶抑制剂尤其是羟基脲或2-羟基-1H-异吲哚-1,3-二酮衍生物。
具体来说,还包括VEGF的那些化合物、蛋白质或单克隆抗体,例如1-(4-氯苯胺基)-4-(4-吡啶基甲基)酞嗪或其药学上可接受的盐、琥珀酸1-(4-氯苯胺基)-4-(4-吡啶基甲基)酞嗪;AngiostatinTM;EndostatinTM;邻氨基苯甲酸酰胺;ZD4190;ZD6474;SU5416;SU6668;贝伐珠单抗;或抗VEGF抗体或抗VEGF受体抗体,例如rhuMAb和RHUFab、VEGF适配体,例如马库根(Macugon);FLT-4抑制剂、FLT-3抑制剂、VEGFR-2IgGI抗体、血管酶(Angiozyme)(RPI 4610)和贝伐珠单抗(AvastinTM)。
本文所用的“光动力学疗法”是指使用某些习知作为光敏化合物的化学物质来治疗或预防癌症的疗法。光动力学疗法的实例包括使用诸如VisudyneTM和卟吩姆钠(porfimersodium)等化合物进行治疗。
本文所用的“血管稳定类固醇”是指阻断或抑制血管生成的化合物,例如阿奈可他(anecortave)、曲安奈德(triamcinolone)、氢化可体松、11-α-表位氢化皮质醇、11-脱氢皮甾醇(cortexolone)、17α-羟孕酮、皮质酮、脱氧皮质酮、睾酮、雌酮和地塞米松。
含有皮质类固醇的植入体是指诸如氟轻松(fluocinolone)和地塞米松等化合物。
其它化学治疗化合物包括(但不限于)植物碱、激素化合物和拮抗剂;生物反应调节剂,优选是淋巴因子或干扰素;反义寡核苷酸或寡核苷酸衍生物;shRNA或siRNA;或各种化合物或具有其它或未知作用机制的化合物。
本发明化合物还可用作共治疗化合物与其它药物(例如,抗炎症、支气管扩张或抗组胺原料药)组合使用,特别在治疗阻塞性或炎症性气道疾病(例如,那些上文所提到者)中作为(例如)所述药物治疗活性的增效剂或作为降低所述药物所需剂量或潜在副作用的方法。本发明化合物可与其它药物混合于固定药物组合物中或其可在其它原料药之前、同时或之后单独投与。因此,本发明包括如上文所述本发明化合物与抗炎症、支气管扩张、抗组胺或镇咳原料药的组合,本发明的所述化合物和所述原料药是于相同或不同药物组合物中。
适宜抗炎症药物包括类固醇,具体来说糖皮质类固醇,例如布地奈德、二丙酸倍氯米松、丙酸氟替卡松(fluticasone propionate)、环索奈德(ciclesonide)或糠酸莫米松;非类固醇糖皮质激素受体激动剂;LTB4拮抗剂,例如LY293111、CGS025019C、CP-195543、SC-53228、BIIL 284、ONO 4057、SB 209247;LTD4拮抗剂,例如孟鲁斯特(montelukast)和扎鲁司特(zafirlukast);PDE4抑制剂,例如西洛司特(cilomilast)(葛兰素史克)、罗氟司特(Roflumilast)(拜克古德公司(Byk Gulden))、V-11294A(纳普公司(Napp))、BAY19-8004(拜耳公司(Bayer))、SCH-351591(先灵-葆雅公司(Schering-Plough))、阿罗茶碱(Arofylline)(阿尔米雷尔普罗迪斯制药有限公司(Almirall Prodesfarma))、PD189659/PD168787(帕克戴维公司(Parke-Davis))、AWD-12-281(爱斯达制药公司(Asta Medica))、CDC-801(赛尔基因公司(Celgene))、SeICID、阿普斯特(Apremilast)(赛尔基因公司)、VM554/UM565(弗纳里斯公司(Vernalis))、T-440(田边公司(Tanabe))、KW-4490(协和发酵工业公司(Kyowa Hakko Kogyo));A2a激动剂;A2b拮抗剂;和β-2肾上腺素受体激动剂,例如沙丁胺醇(albuterol,salbutamol)、异丙喘宁、特布他林、沙美特罗、非诺特罗(fenoterol)、丙卡特罗(procaterol)和尤其福莫特罗和其药学上可接受的盐。适宜支气管扩张药物包括抗胆碱能或抗毒蕈碱化合物,具体来说异丙托溴铵、氧托溴铵(oxitropiumbromide)、噻托铵盐和CHF 4226(凯西公司(Chiesi))和格隆溴铵(glycopyrrolate)。在一些实施例中,根据本发明的化合物或组合物是与阿普斯特一起在相同组合物中或在不同药物组合物中投与。
适宜抗组胺原料药包括盐酸西替利嗪(cetirizine hydrochloride)、乙酰胺酚、延胡索酸克雷满汀(clemastine fumarate)、异丙嗪(promethazine)、氯雷他定(loratidine)、地氯雷他定(desloratidine)、苯海拉明(diphenhydramine)和盐酸非索非那定(fexofenadine hydrochloride)、阿伐斯汀(activastine)、阿司咪唑(astemizole)、氮卓斯汀(azelastine)、依巴斯汀(ebastine)、依匹斯汀(epinastine)、咪唑斯汀(mizolastine)和特非那定(tefenadine)。
本发明化合物与抗炎症药物的其它有用的组合是具有以下的那些:趋化介素受体(例如CCR-1、CCR-2、CCR-3、CCR-4、CCR-5、CCR-6、CCR-7、CCR-8、CCR-9和CCR10、CXCR1、CXCR2、CXCR3、CXCR4、CXCR5)拮抗剂,尤其CCR-5拮抗剂,例如先灵-葆雅公司拮抗剂SC-351125、SCH-55700和SCH-D以及武田公司(Takeda)拮抗剂,例如N-[[4-[[[6,7-二氢-2-(4-甲基苯基)-5H-苯并-环庚烯-8-基]羰基]氨基]苯基]-甲基]四氢-N,N-二甲基-2H-吡喃-4-氯化铵(TAK-770)。
通过代号、通用名或商品名鉴别的活性化合物的结构可从标准纲要“默克索引(The Merck Index)”的现行版本或从(例如)国际专利(例如IMS世界公开案)等数据库获得。
本发明化合物还可与已知治疗过程(例如投与激素或辐射)组合使用。在某些实施例中,所提供化合物作为辐射敏化剂尤其用于治疗对放射疗法展现较差敏感性的肿瘤。
本发明化合物可单独或与一或多种其它治疗化合物组合投与,可能组合疗法采取固定组合或彼此独立地交错或给予的本发明化合物和一或多种其它治疗化合物的投与、或固定组合和一或多种其它治疗化合物的组合投与的形式。除外或另外,本发明化合物尤其可与化学疗法、放射疗法、免疫疗法、光电疗法、手术介入或这些疗法的组合组合投与用于肿瘤疗法。长期疗法同样可能,如同在其它治疗策略背景中的佐剂疗法一般,如上文所述。其它可能治疗是用以维持患者肿瘤消退后的状态的疗法或甚至(例如)处于风险的患者中的化学预防疗法。
那些额外药剂可作为多个剂量方案的一部分与含有本发明化合物的组合物分开投与。或者,那些药剂可为单一剂型的一部分,其以单一组合物与本发明化合物混合到一起。如果作为多个剂量方案的一部分投与,那么两种活性剂可同时、依序或在一段时间内彼此、通常在5小时内彼此提交。
如本文中所用术语“组合(combination、combined)”和相关术语是指同时或依序投与本发明治疗剂。举例来说,本发明化合物可与另一治疗剂以分开单位剂型或以单一单位剂型一起同时或依序投与。因此,本发明提供包含本发明化合物、额外治疗剂和药学上可接受的载剂、佐剂或媒剂的单一单位剂型。
可与载剂材料组合以产生单一剂型的本发明化合物和额外治疗剂(于包含如上文所述治疗剂的那些组合物中)的量可根据所治疗宿主和特定投与模式而变化。优选地,本发明组合物应经调配使得可投与0.01-100mg/kg体重/天本发明化合物的剂量。
在包含额外治疗剂的那些组合物中,所述额外治疗剂和本发明化合物可协同地起作用。因此,所述组合物中额外治疗剂的量将小于仅利用所述治疗剂的单一疗法中所需量。在所述组合物中,可投与0.01-1,000μg/kg体重/天额外治疗剂的剂量。
存在于本发明组合物中的额外治疗剂的量将不超过在包含所述治疗剂作为唯一活性药剂的组合物中通常投与的量。优选地,本文所揭示组合物中额外治疗剂的量将在包含所述药剂作为唯一治疗活性药剂的组合物中通常所存在量的约50%到100%的范围内。
本发明化合物或其药物组合物还可纳入组合物中用于涂布可植入医疗装置(例如假体、人工瓣膜、血管移植物、支架和导管)。例如,血管支架已用于克服再狭窄(损伤后血管壁再狭窄)。然而,使用支架或其它可植入装置的患者存在血块形成或血小板活化的风险。这些不需要的效应可通过用包含激酶抑制剂的药学上可接受的组合物预涂布所述装置得以预防或减轻。经本发明化合物涂布的可植入装置是本发明的另一实施例。
例示
如下文实例中所绘示,在某些实例性实施例中,化合物和固体形式是根据前述一般程序制备。应了解,尽管一般方法绘示本发明某些化合物的合成,但以下方法和所属领域技术人员已知的其它方法可适用于如本文所述所有化合物和这些化合物中每一者的子类和物质。
实验程序:
实例1.
将过碘酸钠(10.4kg,12.0eq.)、乙腈(8L,10V)、四氯化碳(8L,10V)和水(12L,15V)装入50L反应器中。添加氯化钌三水合物(4.9g,0.6%eq.)并将混合物于25℃下搅拌30分钟。于25℃下经60分钟逐份添加2,4-二氯喹啉(800g,1.0eq.),随后将混合物于所述温度下剧烈搅拌24小时。在起始喹啉完全消耗时,过滤混合物并用34L热乙酸乙酯洗涤滤饼。分离水层并用13L热乙酸乙酯萃取,合并有机层并经无水硫酸钠干燥,随后过滤,于50℃下在真空下蒸发。将残余物与4.8L二氯甲烷一起研磨,并且过滤所形成的固体并在真空下干燥,从而产生灰白色固体状产物A-2(1153g,97.2%产率)。
实例2.
将前述步骤的二酸A-2(1153g,1.0eq.)和DMPU(8L,7V)装入20L反应器中并将混合物加热到85℃并保持1小时。经10分钟分两批添加碳酸钾(1553g,2.3eq.)并将混合物于85℃下搅拌20分钟。经90分钟添加硫酸二乙酯(1.73L,4.3eq.),将温度维持于80℃到90℃,并且于所述温度下将混合物再搅拌10小时。一旦起始二酸和单酯通过LC-MS测定为以小于2%存在,即经50分钟将混合物冷却到室温,随后进一步冷却到0℃。添加水(17L,15V)和庚烷(11.5L,10V),并使水层和有机层分离。将水层用庚烷(11.5L,随后6L)萃取两次,并且将合并的有机层用盐水(11.5L)洗涤,随后于50℃下在真空下浓缩,从而产生油状二酯产物(1112g,78%产率)。
实例3.
将实例2的二酯(500g,1.0eq.)和甲苯(10L,20V)装入20L反应器中并冷却到-78℃。经70分钟向反应器中逐滴添加DIBAL-H(1M,于甲苯中,3L,1.75eq.),将温度维持介于-80℃与-70℃之间,随后于所述温度下将混合物额外搅拌20分钟。在通过TLC显示起始材料完全消耗时,经40分钟逐滴添加甲醇(1L,2V),将温度维持介于-80℃与-70℃之间。经30分钟向上述反应混合物中逐滴添加4N HCl(400mL,8V),保持温度低于-50℃。使反应升温到室温并分离水层并用甲苯(2.5L,5V)萃取。合并有机层,经无水硫酸钠干燥,随后于50℃下在真空下浓缩,从而产生7.5L溶液,其直接用于下一步骤。
实例4.
向10L反应器中添加实例3的醛于甲苯中的溶液(7.5L,1.0eq.)并冷却到0℃。经20分钟向反应器中逐滴添加2,4-二甲氧基苄基胺(286g,1.0eq.),将温度维持介于0℃与10℃之间。经50分钟向反应器中逐份添加三乙酰氧基硼氢化钠(544.5g,1.5eq.),并将混合物于室温下搅拌3小时。在通过TLC显示起始材料完全消耗时,添加1N NaOH(aq.)直到pH介于6-7,之后添加饱和Na2CO3(aq.)直到pH介于9-10。分离水层并用乙酸乙酯(2×5L)洗涤,并且将合并的有机层用盐水(1.25L)洗涤且经无水硫酸钠干燥,随后于50℃下在真空下浓缩,从而得到粗产物。于80℃下将粗产物溶解于乙腈(6L)中以获得澄清溶液,经2小时将其冷却到0℃,随后额外搅拌1小时。通过过滤收集形成的固体并于50℃下在真空下干燥,从而产生所需产物(1.57kg,经2个步骤65%产率,98.9%纯度)。
实例5.
将2-溴-1,3-二氟苯(700g,1.6eq.)和THF(8L,10V)装入20L反应器中并冷却到-78℃。经2小时向反应器中逐滴添加THF中的异丙基氯化镁–氯化锂复合物(4L,2.3eq.),将温度维持介于-80℃与-70℃之间,并且于所述温度下搅拌混合物直到TLC分析指示起始2-溴-1,3-二氟苯完全消耗。向反应器中以单批添加氯化锌(1.5kg,4.8eq.)并于介于-80℃与-70℃之间的温度下搅拌30分钟,随后升温到0℃。向反应器中添加Pd(PPh3)4(131g,0.05eq.),之后添加实例4的产物(800g,1.0eq.),并将混合物于室温下搅拌15小时,于是通过HPLC测定二氯吡啶起始材料完全消耗。将混合物冷却到0℃,并经1小时向反应器中逐滴添加饱和NH4Cl水溶液(8L,10V),并且将混合物搅拌30分钟,随后过滤。将水溶液用8L乙酸乙酯萃取两次,并且将合并的有机层用盐水(4L)洗涤,经无水硫酸钠干燥,随后于50℃下在真空下浓缩,从而得到粗产物。将此粗产物与利用900g实例4的产物的单独批料的粗产物合并,并与MTBE(34L)一起研磨并过滤,随后将固体装入具有3.8L乙腈的20L反应器并于室温下搅拌1小时。于室温下逐滴添加MTBE(9.5L)并保持1小时并额外搅拌1小时。通过过滤收集固体并于室温下干燥,以提供1.1kg具有97%纯度的所需产物。蒸发来自纯化的母液并通过硅胶色谱(于石油醚中的乙酸乙酯的33%到55%梯度)纯化,从而产生额外550g粗产物,将其溶解于乙腈(500mL)中并通过逐滴添加MTBE(1500mL)沉淀。通过过滤收集所形成固体并干燥,以提供额外430g具有100%纯度的产物。
实例6.
向20L反应器中添加实例5的产物(500g,1.0eq.)和N-(对-氨基苯甲酰基)吡咯烷(224g,1.0eq.)、碳酸钾(400g,2.5eq.)和1,4-二噁烷(12.5L,25V)并搅拌30分钟,同时用氮气流脱气。向反应器中添加Pd2(dba)3(72.2g,0.06eq.)和山特福斯(80.6g,0.12eq.)并将混合物于室温下搅拌10分钟,随后加热到100℃并搅拌15小时,于是通过HPLC测定氯吡啶起始材料完全消耗。过滤混合物并向滤液中添加水(12.5L),随后将混合物用5L乙酸乙酯萃取两次。合并有机层并用0.15N柠檬酸水溶液(各自5L)洗涤四次,用饱和碳酸氢钠水溶液(2.5L)洗涤一次并用盐水(2.5L)洗涤一次,随后经无水硫酸钠干燥并于50℃下在真空下浓缩,以提供固体状粗产物。于室温下将粗固体与乙腈(2V)和MTBE(10V)一起制浆30分钟,并且过滤所得固体并干燥,以提供95%纯度的所需化合物。可通过重复乙腈/MTBE制浆过程将所述化合物进一步纯化到98.6%纯度。
实例7.化合物1游离碱
将实例6的产物(1.2kg,1.0eq.)和二氯甲烷(12L,10V)装入20L反应器中。在氮气氛下于20℃到30℃下向反应器中添加氢溴酸(33%,于乙酸中,7.2L,6V),并于室温下搅拌15小时,于是通过HPLC测定二甲氧基苄基起始材料完全消耗。将溶液冷却到0℃到10℃并添加2N氢氧化钠水溶液直到pH大于2,随后添加固体碳酸氢钠粉末直到pH介于8与9之间。过滤混合物并将滤液用二氯甲烷(12L)萃取两次,并合并有机层,用盐水(20L)洗涤,并且经无水硫酸钠干燥,随后过滤并在真空下于40℃下浓缩,从而得到粗产物(1.5kg,95%纯度)。将粗固体装入具有二氯甲烷(3L)和MTBE(7.5L)的20L反应器中,并于20℃到30℃下将混合物搅拌过夜。通过过滤收集所得固体并于50℃下干燥到恒定重量(800g,97%纯度)。在升温到30℃的同时将此中间纯度产物溶解于32L二氯甲烷中,并过滤溶液。于50℃下在真空下浓缩滤液直到剩余3体积,随后冷却到室温。收集所形成固体并于50℃下干燥到恒定重量(700g,98.7%纯度)。于30℃下将产物溶解于32L二氯甲烷中,并添加SiliaMetS(30%w/w)并将混合物加热回流过夜,随后冷却到室温。过滤混合物并将滤液再次用SiliaMetS(30%w/w)处理并加热回流过夜,随后冷却到室温。过滤混合物并于30℃到40℃下在真空下浓缩滤液。向残余物中添加MTBE(5V)并于室温下搅拌1小时。通过过滤收集所形成固体,于70℃下在真空下干燥到恒定重量,以获得575g化合物1游离碱(99.5%纯度)。此物质经测定为化合物1游离碱的形式I’,其具有图1中绘示的XRPD图案。通过将形式I’溶解于二氯甲烷中、之后快速蒸发来制备非晶形化合物1游离碱。
实例8.
向20L反应器中装入对-氨基苯甲酸(700g,1.0eq.)和亚硫酰氯(4L,13eq.)并于50℃到60℃下搅拌过夜,随后于50℃下在真空下浓缩,以提供粗制酰氯,其不经进一步纯化即使用。向20L反应器中装入吡咯烷(1300g,5eq.)和二氯甲烷(3.5L,5V)并将混合物冷却到0℃。于0℃到5℃下向反应器中逐滴添加二氯甲烷中的酰氯(3.5L,5V)。一旦通过HPLC测定反应完成,即添加水(7L),并且过滤混合物。用二氯甲烷(1.4L)和水(2.8L)洗涤滤饼。分离水相并用二氯甲烷(7L)萃取,并且合并有机层,随后用盐水(3.5L)洗涤且经无水硫酸钠干燥,随后于50℃下在真空下浓缩,从而得到粗产物。将粗制物于正庚烷:二氯甲烷(5:1,3.5L)中于室温下搅拌过夜,随后通过过滤收集固体。用二氯甲烷(1.4L)和水(2.8L)洗涤滤饼且合并两种滤饼,随后于35℃到40℃下与二氯甲烷(2.8L)一起搅拌过夜,随后冷却到15℃并搅拌4小时。通过过滤收集固体并于50℃下在真空下干燥到恒定重量,以提供所需产物(660g,99%纯度)。氘化类似物(即其中Y和或Z是D的那些)是通过相同程序使用相应氘化吡咯烷制备。
实例9.形式I和非晶形化合物1甲磺酸盐
于60℃下在搅拌下将化合物1游离碱(418.5mg,0.963mmol)溶解于THF(15mL)中。经5分钟以逐滴方式向此混合物中添加净甲磺酸(62.6uL,0.963mmol),从而产生奶油色固体的沉淀。维持加热30分钟,随后将混合物冷却到室温并过滤,用冷异丙醇洗涤并在真空下干燥。此物质经测定为化合物1甲磺酸盐的形式I,其具有图2中绘示的XRPD图案。将所述物质再溶解于50%水中的1,4-二噁烷中并冻干,以提供非晶形化合物1甲磺酸盐。
实例10.化合物1甲磺酸盐的形式II的生产
将非晶形化合物1甲磺酸盐(10mg)溶解于95%乙腈、5%水(%v/v)中并使其蒸发一周。发现所生产的结晶物质为化合物1甲磺酸盐的形式II,其具有图3中绘示的XRPD图案。
实例11.化合物1甲磺酸盐的形式III和形式IV的生产
将非晶形化合物1甲磺酸盐(10mg)溶解于N,N’-二甲基甲酰胺中以形成饱和溶液,使其经受-20℃下的速冷,引起形成结晶固体。发现此物质为化合物1甲磺酸盐的形式III,其具有图4中绘示的XRPD图案。在环境条件下干燥时,发现形式III转变成化合物1甲磺酸盐的形式IV,其具有图5中绘示的XRPD图案。发现形式IV在环境条件下稳定。
实例12.化合物1甲磺酸盐的形式V的生产
将非晶形化合物1甲磺酸盐(10mg)溶解于50%水中的二噁烷(%v/v)中并使其蒸发一周。发现所形成结晶物质为化合物1甲磺酸盐的形式V,其具有图6中绘示的XRPD图案。在研磨时,发现形式V转变成形式I。
实例13:X射线粉末衍射(XRPD)分析方法
在PANalytical X’pert Pro衍射仪上实施化合物1的形式I’、I、II、III、IV和V的XRPD分析。将物质轻柔研磨以释放任何聚集物并装载到具有卡普顿(Kapton)或迈拉(Mylar)聚合物膜的多孔板上以支撑试样。随后将多孔板放置于衍射仪中并使用Cu K辐射(α1:α2比率=0.5)分析,使用40kV/40mA生成器设置以透射模式运行(步长0.0130°2θ),于3.0100°2θ开始扫描且于35.0100°2θ结束。
实例14.Tyk2放射性激酶分析
在反应缓冲液(20mM海佩斯(Hepes)pH 7.5、10mM MgCl2、1mM EGTA、0.02%布里杰(Brij)35、0.02mg/mL BSA、0.1mM Na3PO4、2mM DTT、1%DMSO)中制备肽底物[KKSRGDYMTMQIG](20μM)。添加TYK2(英杰)激酶,随后添加DMSO中的化合物。添加33PATP以在10μM的ATP中起始反应。将激酶反应于室温下培育120min并点样于P81离子交换纸(沃特曼(Whatman)编号3698-915)上,并且随后在0.75%磷酸中充分洗涤,之后读取放射性计数。
对于Tyk2放射性激酶分析,化合物1和其同位素异构体(isotopolog)2、3、4和5各自提供小于1nM的IC50值。
实例15.人类PBMC中IL-12诱导的pSTAT4
从肤色血球层分离人类PBMC且视需要冷冻储存用于分析。将用于分析的细胞解冻并重新悬浮于含有血清的完全培养基中,随后将细胞稀释到1.67E6个细胞/ml,使得每孔120μl为200,000个细胞。将15μl化合物或DMSO以所需浓度添加到孔中并于37℃培育1hr。在使用根据制造商的方案由MSD试剂制备和分析的细胞溶解物的pSTAT4和总STAT4分析之前,添加15μl刺激物(最终浓度为1.7ng/mL IL-12)达30分钟。分析中化合物的最终DMSO浓度为0.1%。
对于人类PBMC中IL-12诱导的pSTAT4分析,化合物1和其同位素异构体2、3、4和5各自提供小于150nM的IC50值。
实例16.CACO-2细胞渗透性分析
将Caco-2细胞用培养基稀释到6.86×10 5个细胞/mL,并且将50μL细胞悬浮液分配到96孔HTS特拉斯韦尔(Transwell)板的滤孔中。将细胞于37℃、5%CO2、95%相对湿度下在细胞培养培育器中培养14~18天。每2天更换一次细胞培养基,开始时间不得晚于初始平板接种后24小时。3)14~18天培育后,将板从培育器移出。将插入物用预热的HBSS(10mMHEPES,pH7.4)洗涤两次并放置于接收器板中。向每一特拉斯韦尔插入物和接收器孔中分别添加75μL和235μL缓冲液。随后将板于37℃下在以150rpm振荡下培育30min。在DMSO中以10mM制备对照化合物原液,并且随后用DMSO稀释到1mM,之后用HBSS(10mM HEPES,pH 7.4)进一步稀释以得到化合物工作溶液。在DMSO中以10mM制备测试化合物原液,并且随后用DMSO稀释到1mM,之后用HBSS(10mM HEPES,pH 7.4,4%BSA)进一步稀释以得到化合物工作溶液。测试化合物和对照化合物的最终浓度为5μM。为测定在顶端到基底外侧方向上的药物转运速率,将75μL化合物工作溶液添加到滤孔(顶端隔室)并将235μL HBSS(10mM HEPES,pH7.4,或4%BSA)添加到接收器板(基底外侧隔室)。为测定在基底外侧到顶端方向上的药物转运速率,将235μL化合物工作溶液添加到接收器板(基底外侧隔室)的每一孔中,并且将75μL HBSS(10mM HEPES,pH 7.4,或4%BSA)添加到滤孔(顶端隔室)。所述分析一式两份地执行。6)将板于37℃下培养2小时。在转运时段结束时,直接从顶端和基底外侧孔移出50μL等分试样并转移到新板的孔。向每一孔中添加4体积含有内标准品(IS、100nM阿普唑仑(Alprazolam)、200nM拉贝洛尔(Labetalol)和200nM双氯芬酸(Diclofenac))的冷甲醇。将试样以3,220g离心30分钟。使用与100μL超纯水混合的100μL上清液的等分试样进行LC-MS/MS分析。7)从特拉斯韦尔板丢弃溶液。将100μL荧虾黄溶液(100μM,于HBSS中)和300μL HBSS分别添加到特拉斯韦尔插入物和接收器的每一孔中用于泄漏测定。将板于37℃下培育30分钟。将来自顶端和基底外侧孔的80μL等分试样转移到固体黑色板,并且用帝肯-英飞尼迪(Tecan Infinite)M 200(激发/发射波长485nm/530nm)读取板。通过LC-MS分析液体部分、顶端和基底外侧层以测定Papp(A-B)、Papp(B-A)和回收率。
实例17.1mM ATP Tyk2测径器分析
将化合物在DMSO中连续稀释,随后在1x激酶缓冲液中进一步稀释:首先向孔中添加5uL经缓冲液稀释的化合物,随后向孔中添加10uL Tyk2酶混合物,之后添加10uL底物混合物以开始反应。将反应在28℃下培育25min,并且随后添加25uL终止缓冲液。通过测径器质谱仪读取反应混合物。分析条件的最终浓度是:25mM HEPES pH 7.5、0.01%布里杰-35、0.01%特里同(Triton)、0.5mM EGTA、2mM DTT、10mM MgCl2、TYK2 4nM、ATP浓度1000uM和P30 3uM。
各种化合物的1mM ATP Tyk2测径器分析的结果提供于表8中。
实例18.微粒体中的代谢清除率分析
制备含有0.5mg/mL大鼠或人类肝微粒体、5mM MgCl2、100mM磷酸盐缓冲液和25ug/mL丙甲菌素(alamethacin)的主溶液。向每一孔中添加40μL 10mM NADPH溶液和40μL 20mMUDPGA溶液。NADPH和UDPGA的最终浓度分别是1mM和2mM。将混合物于37℃下预升温5分钟。通过用80μL超纯H2O代替NADPH和UDPGA溶液来制备阴性对照试样。阴性对照用于排除化学品本身不稳定导致的误导因素。此研究一式两份地执行。利用添加2μL 400μM对照化合物或测试化合物溶液开始反应。此研究中使用双氯芬酸作为阳性对照。测试化合物或对照化合物的最终浓度为2μM。在0、15、30、45和60分钟时从反应溶液获取50μL等分试样。通过在指定时间点添加4体积的具有内标准品(IS)(100nM阿普唑仑、200nM伊米帕明(imipramine)、200nM拉贝洛尔和2μM酮洛芬(ketoprofen))的冷乙腈(或甲醇)终止反应。将试样以3,220g离心40分钟以沉淀蛋白质。使用由100μL水稀释的100μL上清液的等分试样进行LC-MS/MS分析。根据标准计算来计算活体外半衰期、放大固有清除率和预测的肝清除率。
针对所选化合物的人类肝微粒体中的固有清除率值(HLM Clint)提供于表8中。
实例19.动力学溶解性测定分析
在DMSO中以10mM的浓度制备测试化合物的原液。在DMSO中以30mM的浓度制备阳性对照化合物的原液。本分析中使用助孕酮作为阳性对照。将30μL每一化合物的原液依序放入其适当96孔架中,之后将970μL PBS(pH7.4)添加到无帽的溶解性试样板的每一小瓶中。此研究一式两份地执行。向每一小瓶中添加一个搅拌棒,并且随后使用模制的PTDE/SIL 96孔板盖密封小瓶。将溶解性试样板转移到特尔米克-科姆里特(Thermomixer Comfort)板振荡器并于室温下培育2小时,同时以1100rpm振荡。2小时培育后,使用大磁铁移除搅拌棒,并且将溶解性试样板的所有试样转移到滤板中。通过使用真空歧管过滤所有试样。用甲醇稀释过滤试样。制备0.3μM、0.09μM和0.15μM浓度的每一测试化合物的标准物,并且通过LC-MS分析测试试样和标准物,并且使用质谱峰鉴别和量化针对DMSO中已知浓度的标准物量化测试试样。
针对所选化合物的动力学溶解性测定的结果提供于表8中。
实例21.进食和禁食模拟胃液和肠液中的溶解分析
向溶解浴中填充900mL用于测试的培养基,浴温保持在37℃,设备的旋转速率为50rpm,取样探针的拉伸点恰好设置在培养基表面与盘表面之间的中途。使用伍德斯(Woods)设备将检品(0.4g)压缩到盘中。取样时间点分别是10、30、60、90、120、150和180。通过HPLC分析试样的浓度对已知浓度的试样制剂(约0.5mg/ml)。从浓度对时间的曲线得出溶解速率。
化合物1在禁食模拟胃液(FaSSGF)中的溶解速率是57.5μg/cm2/min,并且化合物9在禁食模拟胃液中的溶解速率是21.2μg/cm2/min。
实例22.狗中的药物代谢动力学研究
将在标准试验条件每笼圈养一支的雄性比格(Beagle)狗(9-14kg;2.5到5.5岁)禁食约16到17小时,之后投用食物,投用后约2小时返回。通过经口胃管灌食以10mg/kg投与检品,所述检品以1.0mg/mL调配于20%HPβCD aq.(pH=5)中,之后用自来水进行10mL冲洗。通过静脉穿刺从颈静脉收集血样(约1.5mL),并且储存于经K2EDTA处理的管中,随后离心(3000g,4℃,5min)。转移血浆试样并在-70℃下储存直到分析。生物分析:在通过用含有维拉帕米(verapamil)作为内标准品的冷乙腈(4:1ACN/血浆,以体积计)的血浆沉淀进行萃取后,通过LC/MS/MS(API-5500,反相色谱,APCI)测定实验试样和血浆校正标准物的浓度。PK分析:使用PK索尔沃(Solver)软件(v2.0)通过非分室分析(线性梯形拟合)分析个别动物血浆浓度-时间数据。
使用化合物1和9的狗中药物代谢动力学研究的结果绘示于图7中。化合物1展现2105ng/mL的Cmax,而化合物9展现1071ng/mL的Cmax。化合物1展现18747ng*hr/mL的AUC(0-t)且化合物9展现10182ng*hr/mL的AUC(0-t)。
实例22.局部解剖学极性表面积的计算
根据埃特尔(Ertl)等人,医药化学杂志(J.Med.Chem.)(2000),43,3714-3717的方法计算极性表面积,并且所选化合物的值报告于表8中。
实例23.基于原子的分配系数的计算
使用薛定谔-利维西根(Schrodinger LiveDesign)8.1中的AlogP函数计算AlogP值,并且所选化合物的值提供于表8中。
可用作用作Tyk2抑制剂的化合物的各种额外化合物的结构绘示于表7中。
表7.化合物的结构
表8.物理化学、药效学和药物代谢动力学数据
尽管已对本发明的许多实施例进行了描述,但显而易见,可改变基本实例以提供利用发明化合物和方法的其它实施例。因此,应了解,本发明的范围将由所附权利要求书而非以实例方式所代表的具体实施例界定。
Claims (50)
3.一种根据权利要求2所述的化合物的甲磺酸盐。
4.一种根据权利要求2所述的化合物的游离碱。
6.一种根据权利要求1所述的化合物的固体形式。
7.一种根据权利要求2所述的化合物的固体形式。
8.一种根据权利要求4所述的游离碱的结晶型,其具有如图1中所示的粉末X射线衍射XRPD图案。
9.一种根据权利要求4所述的游离碱的结晶型,其中所述结晶型的特征在于其粉末X射线衍射图案中具有约6.07、约11.90、约16.62和约13.95的2θ值的衍射峰。
11.一种根据权利要求3所述的甲磺酸盐的结晶型,其具有如图2中所示的粉末X射线衍射XRPD图案。
12.一种根据权利要求3所述的甲磺酸盐的结晶型,其中所述结晶型的特征在于其粉末X射线衍射图案中具有约19.89、约9.17、约16.88、约14.37和约22.09的2θ值的衍射峰。
14.一种根据权利要求3所述的甲磺酸盐的结晶型,其具有如图3中所示的粉末X射线衍射XRPD图案。
15.一种根据权利要求3所述的甲磺酸盐的结晶型,其中所述结晶型的特征在于其粉末X射线衍射图案中具有约22.27、约26.45、约26.02、约16.34和约17.06的2θ值的衍射峰。
17.一种根据权利要求3所述的甲磺酸盐的结晶型,其具有如图4中所示的粉末X射线衍射XRPD图案。
18.一种根据权利要求3所述的甲磺酸盐的结晶型,其中所述结晶型的特征在于其粉末X射线衍射图案中具有约18.18、约18.56、约16.95、约21.95和约9.85的2θ的衍射峰。
20.一种根据权利要求3所述的甲磺酸盐的结晶型,其具有如图5中所示的粉末X射线衍射XRPD图案。
21.一种根据权利要求3所述的甲磺酸盐的结晶型,其中所述结晶型的特征在于其粉末X射线衍射图案中具有约17.79、约12.45、约24.38、约26.00和约16.28的2θ值的衍射峰。
23.一种根据权利要求3所述的甲磺酸盐的结晶型,其具有如图6中所示的粉末X射线衍射XRPD图案。
24.一种根据权利要求3所述的甲磺酸盐的结晶型,其中所述结晶型的特征在于其粉末X射线衍射图案中具有约13.34、约8.80、约11.10、约16.85和约25.49的2θ值的衍射峰。
29.一种药物组合物,其包含治疗有效量的根据权利要求1、2和5中任一权利要求所述的化合物或根据权利要求3所述的甲磺酸盐或根据权利要求4所述的游离碱,和药学上可接受的载剂、佐剂或稀释剂。
30.一种药物组合物,其包含治疗有效量的根据权利要求3所述的甲磺酸盐和药学上可接受的载剂、佐剂或稀释剂。
31.一种根据权利要求1、2和5中任一权利要求所述的化合物或根据权利要求3所述的甲磺酸盐或根据权利要求4所述的游离碱的用途,其用以制造用于抑制患者或生物试样中的Tyk2酶的药剂。
32.一种根据权利要求1、2和5中任一权利要求所述的化合物或根据权利要求3所述的甲磺酸盐或根据权利要求4所述的游离碱的用途,其用以制造用于治疗Tyk2介导病症的药剂。
33.根据权利要求32所述的用途,其中所述Tyk2介导病症是选自自体免疫病症、炎症病症、增殖性病症、内分泌病症、神经病症或与移植相关的病症。
34.根据权利要求33所述的用途,其中所述病症是自体免疫病症。
35.根据权利要求34所述的用途,其中所述自体免疫病症是选自1型糖尿病、关节粘连性脊椎炎、全身性红斑狼疮、多发性硬化、全身性硬化、牛皮癣、克隆氏病、溃疡性结肠炎和炎症性肠病。
36.根据权利要求33所述的用途,其中所述病症是炎症病症。
37.根据权利要求36所述的用途,其中所述炎症病症是选自类风湿性关节炎、气喘、慢性阻塞性肺病、牛皮癣、克隆氏病、溃疡性结肠炎和炎症性肠病。
38.根据权利要求33所述的用途,其中所述病症是增殖性病症。
39.根据权利要求38所述的用途,其中所述增殖性病症是血液癌症。
40.根据权利要求38所述的用途,其中所述增殖性病症是白血病。
41.根据权利要求40所述的用途,其中所述白血病是T细胞白血病。
42.根据权利要求41所述的用途,其中所述T细胞白血病是T细胞急性淋巴母细胞性白血病T-ALL。
43.根据权利要求38所述的用途,其中所述增殖性病症与TYK2的一或多个活化突变相关。
44.根据权利要求33所述的用途,其中所述病症与移植相关。
45.根据权利要求44所述的用途,其中所述病症是移植排斥或移植物抗宿主病。
46.根据权利要求33所述的用途,其中所述病症是内分泌病症。
47.根据权利要求46所述的用途,其中所述内分泌病症是多囊性卵巢综合症、克鲁松氏综合症或1型糖尿病。
48.根据权利要求33所述的用途,其中所述病症是神经病症。
49.根据权利要求48所述的用途,其中所述神经病症是阿兹海默氏病。
50.根据权利要求32所述的用途,其中所述病症与I型干扰素、IL-10、IL-12或IL-23信号传导相关。
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JP2022185139A (ja) | 2022-12-13 |
AU2018230737B2 (en) | 2022-09-22 |
IL269036B (en) | 2022-11-01 |
AR111233A1 (es) | 2019-06-19 |
TW201840559A (zh) | 2018-11-16 |
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