CN104039762B - Nampt抑制剂 - Google Patents
Nampt抑制剂 Download PDFInfo
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- CN104039762B CN104039762B CN201180076240.4A CN201180076240A CN104039762B CN 104039762 B CN104039762 B CN 104039762B CN 201180076240 A CN201180076240 A CN 201180076240A CN 104039762 B CN104039762 B CN 104039762B
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- base
- dihydro
- indoles
- iso
- pyridazine
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Abstract
公开了抑制NAMPT活性的化合物、包含所述化合物的组合物和治疗期间表达NAMPT的疾病的方法。
Description
发明领域
本发明涉及抑制NAMPT活性的化合物,包含所述化合物的组合物,和治疗期间表达NAMPT的疾病的方法。
发明背景
NAD+(烟酰胺腺嘌呤二核苷酸)是在许多生理基本过程中发挥关键作用的辅酶(Ziegkel, M. Eur. J. Biochem.267,1550-1564, 2000)。NAD是几种信号转导通路必需的,其中包括DNA修复中的聚ADP-核糖基化、免疫系统和G-蛋白偶联信号传导中的单-ADP-核糖基化,由于它们的脱乙酰酶活性,去乙酰化酶也需要NAD(Garten, A.等人,Trends in Endocrinology and Metabolism,20, 130-138, 2008)。
NAMPT(也被称作前B细胞集落增强因子(PBEF)和内脂素)是催化烟酰胺的磷酸核糖基化的酶并且是挽救NAD的两种途径之一中的限速酶。
越来越多证据表明,NAMPT抑制剂具有作为抗癌剂的潜力。与正常细胞相比,癌细胞具有较高的基础NAD转化率,也表现出较高的能量需求。另外,在结肠直肠癌中报道了提高的NAMPT表达(Van Beijnum, J.R.等人,Int. J. Cancer 101, 118-127, 2002),并且在血管生成中牵涉NAMPT(Kim, S.R.等人,Biochem. Biophys. Res. Commun.357, 150-156,2007)。NAMPT的小分子抑制剂已表明造成细胞内NAD+水平的消耗并最终诱发肿瘤细胞死亡(Hansen, CM等人,Anticancer Res.20, 42111-4220, 2000)以及抑制异种移植模型中的肿瘤生长(Olese, U.H.等人,Mol Cancer Ther. 9, 1609-1617, 2010)。
NAMPT抑制剂还具有作为炎症和代谢紊乱中的治疗剂的潜力(Galli, M.等人Cancer Res.70, 8-11, 2010)。例如,NAMPT是T和B淋巴细胞中的主导酶。NAMPT的选择性抑制导致淋巴细胞中的NAD+消耗,从而阻断伴随自身免疫病进展发生的扩展(expansion),而表达其它NAD+生成通路的细胞类型可能幸免。小分子NAMPT抑制剂(FK866)已表明选择性阻断增殖和诱导活化T细胞的凋亡,并在关节炎(胶原诱导性关节炎)的动物模型中有效(Busso, N.等人,Plos One 3, e2267, 2008)。FK866改善实验性自身免疫性脑脊髓炎(EAE)(T-细胞介导的自身免疫紊乱的模型)的表现(Bruzzone, S等人,Plos One 4,e7897, 2009)。NaMPT活性提高人血管内皮细胞中的NF-kB转录活性,以造成MMP-2和MMP-9活化,表明NAMPT抑制剂在肥胖症和2型糖尿病的炎症介导并发症的预防中的作用(Adya,R.等人Diabetes Care,31, 758-760, 2008)。
发明概述
本发明的一个实施方案涉及化合物及其药学上可接受的盐,其适用作NAMPT的抑制剂,所述化合物选自
N-(4-{[2-(氮杂环庚烷-1-基)乙基]氨基甲酰基}苯基)-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{4-[(2-羟基丙基)氨基甲酰基]苯基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-(4-{[2-(2-氧代咪唑烷-1-基)乙基]氨基甲酰基}苯基)-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-(4-{[2-(四氢-2H-吡喃-2-基)乙基]氨基甲酰基}苯基)-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-(4-{[(2-甲基四氢呋喃-2-基)甲基]氨基甲酰基}苯基)-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-(4-{[2-甲基-2-(吗啉-4-基)丙基]氨基甲酰基}苯基)-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{4-[(1-氧杂-8-氮杂螺[4.5]癸-3-基甲基)氨基甲酰基]苯基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2-氧杂-7-氮杂螺[3.5]壬-7-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(六氢呋喃并[3,2-c]吡啶-5(4H)-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(六氢-5H-呋喃并[2,3-c]吡咯-5-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2,6-二氧杂-9-氮杂螺[4.5]癸-9-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2-氧杂-6-氮杂螺[3.3]庚-6-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2-氧杂-6-氮杂螺[3.5]壬-6-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2-氧杂-7-氮杂螺[4.4]壬-7-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(10,10-二氟-2,7-二氮杂螺[4.5]癸-2-基)羰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(3-氰基-1-氧杂-8-氮杂螺[4.5]癸-8-基)羰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(7-氧杂-2-氮杂螺[3.5]壬-2-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(1-氧杂-7-氮杂螺[4.4]壬-7-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(10-氟-2,7-二氮杂螺[4.5]癸-2-基)羰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(3,9-二氮杂螺[5.5]十一烷-3-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2,7-二氮杂螺[4.5]癸-7-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2,8-二氮杂螺[4.5]癸-8-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(7-氮杂螺[3.5]壬-1-基氨基甲酰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2-氮杂螺[3.3]庚-5-基氨基甲酰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(1R,5S)-3-氮杂双环[3.1.0]己-6-基氨基甲酰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-(6-{[(7R)-八氢吡咯并[1,2-a]吡嗪-7-基甲基]氨基甲酰基}哒嗪-3-基)-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2,6-二氮杂螺[3.5]壬-2-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2,7-二氮杂螺[3.5]壬-2-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2,6-二氮杂螺[3.4]辛-6-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(2-氧杂-9-氮杂螺[5.5]十一烷-3-基甲基)氨基甲酰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(1-氧杂-8-氮杂螺[4.5]癸-2-基甲基)氨基甲酰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(1-氧杂-8-氮杂螺[4.5]癸-3-基甲基)氨基甲酰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2,7-二氮杂螺[3.5]壬-7-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2,8-二氮杂螺[4.5]癸-2-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-(6-{[3-(氮杂环丁烷-3-基)吡咯烷-1-基]羰基}哒嗪-3-基)-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-2-基甲基)氨基甲酰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(1-氧杂-8-氮杂螺[4.5]癸-3-基氨基甲酰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(6,7,8,9-四氢-5H-[1,2,4]三唑并[4,3-a][1,4]二氮杂环庚三烯-3-基甲基)氨基甲酰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(6-氮杂螺[2.5]辛-1-基甲基)氨基甲酰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(5-氧杂-2-氮杂螺[3.4]辛-2-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(5,6,7,8-四氢[1,2,4]三唑并[4,3-a]吡嗪-3-基甲基)氨基甲酰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-(6-{[(4-氟哌啶-4-基)甲基]氨基甲酰基}哒嗪-3-基)-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2,6-二氮杂螺[3.3]庚-2-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(6-氧杂-2-氮杂螺[3.4]辛-7-基甲基)氨基甲酰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(5-氧杂-2-氮杂螺[3.5]壬-2-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-(6-{[1-(三氟甲基)-2,8-二氮杂螺[4.5]癸-2-基]羰基}哒嗪-3-基)-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(7-氮杂螺[3.5]壬-2-基甲基)氨基甲酰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(5,6,7,8-四氢-4H-[1,2,3]三唑并[1,5-a][1,4]二氮杂环庚三烯-3-基甲基)氨基甲酰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;及其药学上可接受的盐。
另一实施方案涉及用于治疗炎症和组织修复障碍;特别是类风湿性关节炎、炎性肠病、哮喘和COPD(慢性阻塞性肺病)、骨关节炎、骨质疏松症和纤维化疾病;皮肤病,包括牛皮癣、特应性皮炎和紫外线引起的皮肤损伤;自身免疫病,包括系统性红斑狼疮、多发性硬化、银屑病关节炎、关节强硬性脊椎炎、组织和器官排斥、阿尔茨海默氏症、中风、动脉粥样硬化、再狭窄、糖尿病、肾小球肾炎、癌症,其中该癌症特别选自乳腺癌、前列腺癌、肺癌、结肠癌、宫颈癌、卵巢癌、皮肤癌、CNS癌、膀胱癌、胰腺癌、白血病、淋巴瘤或霍奇金病、恶病质、与感染和某些病毒性感染,包括获得性免疫缺陷综合征(AIDS)相关的炎症、成人呼吸窘迫综合征和共济失调毛细血管扩张的组合物,所述组合物包含赋形剂和治疗有效量的选自本文实施例1-49的化合物或其药学上可接受的盐。
另一实施方案涉及治疗患者的炎症和组织修复障碍;特别是类风湿性关节炎、炎性肠病、哮喘和COPD(慢性阻塞性肺病)、骨关节炎、骨质疏松症和纤维化疾病;皮肤病,包括牛皮癣、特应性皮炎和紫外线引起的皮肤损伤;自身免疫病,包括系统性红斑狼疮、多发性硬化、银屑病关节炎、关节强硬性脊椎炎、组织和器官排斥、阿尔茨海默氏症、中风、动脉粥样硬化、再狭窄、糖尿病、肾小球肾炎、癌症,其中该癌症特别选自乳腺癌、前列腺癌、肺癌、结肠癌、宫颈癌、卵巢癌、皮肤癌、CNS癌、膀胱癌、胰腺癌、白血病、淋巴瘤或霍奇金病、恶病质、与感染和某些病毒性感染,包括获得性免疫缺陷综合征(AIDS)相关的炎症、成人呼吸窘迫综合征和共济失调毛细血管扩张的方法,所述方法包括给予患者治疗有效量的选自本文实施例1-49的化合物或其药学上可接受的盐。
另一实施方案涉及治疗患者的炎症和组织修复障碍;特别是类风湿性关节炎、炎性肠病、哮喘和COPD(慢性阻塞性肺病)、骨关节炎、骨质疏松症和纤维化疾病;皮肤病,包括牛皮癣、特应性皮炎和紫外线引起的皮肤损伤;自身免疫病,包括系统性红斑狼疮、多发性硬化、银屑病关节炎、关节强硬性脊椎炎、组织和器官排斥、阿尔茨海默氏症、中风、动脉粥样硬化、再狭窄、糖尿病、肾小球肾炎、癌症,其中该癌症特别选自乳腺癌、前列腺癌、肺癌、结肠癌、宫颈癌、卵巢癌、皮肤癌、CNS癌、膀胱癌、胰腺癌、白血病、淋巴瘤或霍奇金病、恶病质、与感染和某些病毒性感染,包括获得性免疫缺陷综合征(AIDS)相关的炎症、成人呼吸窘迫综合征和共济失调毛细血管扩张或脾癌的方法,所述方法包括给予患者治疗有效量的选自本文实施例1-49的化合物或其药学上可接受的盐;和治疗有效量的一种附加治疗剂或多于一种附加治疗剂。
发明详述
此详述仅意在使本领域其他技术人员了解申请人的发明、其原理及其实际应用,以使本领域其他技术人员可以以许多形式修改和应用本发明,以使它们可最佳地适应特定用途的要求。本说明书及其具体实施例仅意在举例说明。因此,本发明不限于此专利申请中描述的实施方案并可以各种各样地修改。
缩写和定义
除非本文中另行规定,与本发明相关使用的科学和技术术语应具有本领域普通技术人员通常理解的含义。这些术语的含义和范围清晰,但如果有任何潜在歧义,本文中提供的定义优先于任何词典或外来定义。在本申请中,除非另行指明,“或”的使用是指“和/或”。此外,术语“包括(including)”以及其它形式,如“包括(includes)”和“包括(included)”的使用不是限制性的。关于本专利申请(包括权利要求)中的词语“包含(comprise)”或“包含(comprises)”或“包含(comprising)”的使用,申请人指出,除非文中另行要求,这些词语基于它们应可兼性而非排他性解释的清楚理解使用,申请人希望在解释此专利申请,包括下列权利要求时如此解释各个这样的词语。关于在本文中在任何取代基中或在本发明的化合物或任何其它式中出现多于一次的变量,其在每一处的定义独立于其在其它每一处的定义。取代基的组合只有在这样的组合产生稳定化合物时才可容许。稳定的化合物是可以以有用的纯度从反应混合物中分离的化合物。
要理解的是,本文中的所有组合保持适当的化合价,具有多于一个原子的一价部分通过它们的左端连接,二价部分从左向右绘制。
如说明书和所附权利要求中所用,除非作出相反的规定,下列术语具有所示含义:
术语“烷基”(独自或与其它术语结合)是指通常含有1至大约10个碳原子;或在另一实施方案中1至大约8个碳原子;在另一实施方案中1至大约6个碳原子;和在另一实施方案中1至大约4个碳原子的直链或支链饱和烃基取代基。这样的取代基的实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基、异戊基和己基等。
术语“烯基”(独自或与其它术语结合)是指含有一个或多个双键和通常2至大约10个碳原子;或在另一实施方案中2至大约8个碳原子;在另一实施方案中2至大约6个碳原子;和在另一实施方案中2至大约4个碳原子的直链或支链烃基取代基。这样的取代基的实例包括乙烯基(ethenyl或vinyl)、2-丙烯基、3-丙烯基、1,4-戊二烯基、1,4-丁二烯基、1-丁烯基、2-丁烯基和3-丁烯基等。
术语“炔基”(独自或与其它术语结合)是指含有一个或多个三键和通常2至大约10个碳原子;或在另一实施方案中2至大约8个碳原子;在另一实施方案中2至大约6个碳原子;和在另一实施方案中2至大约4个碳原子的直链或支链烃基取代基。这样的取代基的实例包括乙炔基、2-丙炔基、3-丙炔基、2-丁炔基和3-丁炔基等。
术语“碳环基”(独自或与其它术语结合)是指含有3至14个碳环原子(“环原子”是键合在一起形成环状取代基的一个或多个环的原子)的饱和环状(即“环烷基”)、部分饱和环状(即“环烯基”)或完全不饱和的(即“芳基”)烃基取代基。碳环基可以是单环(单环的)或多环的环结构。
碳环基可以是通常含有3至8个环原子,更通常3至6个环原子,再更通常5至6个环原子的单环结构。这样的单环碳环基的实例包括环丙基(环丙烷基)、环丁基(环丁烷基)、环戊基(环戊烷基)、环戊烯基、环戊二烯基、环己基(环己烷基)、环己烯基、环己二烯基和苯基。碳环基或者可以是多环的(即可含有多于一个环)。多环碳环基的实例包括桥连、稠合和螺环碳环基。在螺环碳环基中,一个原子是两个不同环共有的。螺环碳环基的一个实例是螺环戊烷基。在桥连碳环基中,环共享至少两个共有非相邻原子。桥连碳环基的实例包括双环[2.2.1]庚烷基、双环[2.2.1]庚-2-烯基和金刚烷基。在稠环碳环基体系中,两个或更多个环可稠合在一起,以致两个环共享一个共用键。二-或三-稠环碳环基的实例包括萘基、四氢化萘基(tetralinyl)、茚基、茚满基(二氢茚基)、蒽基、菲基和十氢化萘基。
术语“环烷基”(独自或与其它术语结合)是指含有3至14个碳环原子的饱和环烃基取代基。环烷基可以是通常含有3至8个碳环原子,更通常3至6个环原子的单碳环。单环环烷基的实例包括环丙基、环丁基、环戊基和环己基。环烷基或者可以是多环的或含有多于一个环。多环环烷基的实例包括桥连、稠合和螺环碳环基。
术语“芳基”(独自或与其它术语结合)是指含有6至14个碳环原子的芳族碳环基。芳基可以是单环或多环的(即可含有多于一个环)。在多环芳环的情况下,该多环体系只需要一个环是不饱和的,而其余环可以是饱和、部分饱和或不饱和的。芳基的实例包括苯基、萘基、茚基、茚满基和四氢化萘基。
在一些情况下,烃基取代基(例如烷基、烯基、炔基或环烷基)中的碳原子数由前缀“Cx-Cy-”表示,其中x为取代基中碳原子的最小数量,y为最大数量。因此,例如,“C1-C6-烷基”是指含有1至6个碳原子的烷基取代基。进一步举例说明,C3-C8-环烷基是指含有3至8个碳环原子的饱和烃基环。
术语“氢”(独自或与其它术语结合)是指氢基并可以被描述为-H。
术语“羟基”(独自或与其它术语结合)是指-OH。
术语“羧基”(独自或与其它术语结合)是指-C(O)-OH。
术语“氨基”(独自或与其它术语结合)是指-NH2。
术语“卤素”或“卤基”(独自或与其它术语结合)是指氟基(其可被描述为-F)、氯基(其可被描述为-Cl)、溴基(其可被描述为-Br)或碘基(其可被描述为-I)。
如果取代基被描述为“取代的”,非氢基团代替该取代基的碳或氮上的氢基。因此,例如,取代的烷基取代基是其中至少一个非氢基团代替该烷基取代基上的氢基的烷基取代基。例如,单氟烷基是被氟基取代的烷基,二氟烷基是被两个氟基取代的烷基。应该认识到,如果在取代基上存在多于一个取代,各非氢基团可以相同或不同(除非另行指明)。
如果取代基被描述为“任选取代的”,该取代基可以(1) 未取代,或(2) 被取代。如果取代基被描述为任选被最多特定数量的非氢基团取代,该取代基可以(1) 未取代;或(2)被最多该特定数量的非氢基团或被最多该取代基上的可取代位置的最大数量取代,看哪个更小。因此,例如,如果取代基被描述为任选被最多3个非氢基团取代的杂芳基,则具有小于3个可取代位置的任何杂芳基任选被最多仅与该杂芳基所具有的可取代位置一样多的非氢基团取代。例如,四唑基(其只有一个可取代位置)任选被最多一个非氢基团取代。为进一步举例说明,如果氨基氮被描述为任选被最多2个非氢基团取代,则伯氨基氮任选被最多2个非氢基团取代,而仲氨基氮任选被最多仅1个非氢基团取代。
此专利申请可互换使用术语“取代基(substituent)”和“基团(radical)”。
前缀“卤代”是指该前缀连接的取代基被一个或多个独立选择的卤素基团取代。例如,卤代烷基是指其中至少一个氢基被卤素基团替代的烷基取代基。卤代烷基的实例包括氯甲基、1-溴乙基、氟甲基、二氟甲基、三氟甲基和1,1,1-三氟乙基。应该认识到,如果取代基被多于一个卤素基团取代,这些卤素基团可以相同或不同(除非另行指明)。
前缀“全卤代”是指该前缀连接的取代基上的每个氢基被独立选择的卤素基团替代,即该取代基上的各氢基被卤素基团替代。如果所有卤素基团相同,该前缀通常会指定卤素基团。因此,例如,术语“全氟”是指该前缀连接的取代基上的每个氢基被氟基取代。例如,术语“全氟烷基”是指其中氟基代替各氢基的烷基取代基。
术语“羰基”(独自或与其它术语结合)是指-C(O)-。
术语“氨基羰基”(独自或与其它术语结合)是指-C(O)-NH2。
术语“氧代”(独自或与其它术语结合)是指(=O)。
术语“氧基”(独自或与其它术语结合)是指醚取代基并可以被描述为-O-。
术语“烷基羟基”(独自或与其它术语结合)是指–烷基-OH。
术语“烷基氨基”(独自或与其它术语结合)是指–烷基-NH2。
术语“烷氧基”(独自或与其它术语结合)是指烷基醚取代基,即-O-烷基。这种取代基的实例包括甲氧基(-O-CH3)、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基和叔丁氧基。
术语“烷基羰基”(独自或与其它术语结合)是指-C(O)-烷基。
术语“氨基烷基羰基”(独自或与其它术语结合)是指-C(O)-烷基-NH2。
术语“烷氧基羰基”(独自或与其它术语结合)是指-C(O)-O-烷基。
术语“碳环基羰基”(独自或与其它术语结合)是指-C(O)-碳环基。
类似地,术语“杂环基羰基”(独自或与其它术语结合)是指-C(O)-杂环基。
术语“碳环基烷基羰基”(独自或与其它术语结合)是指-C(O)-烷基-碳环基。
类似地,术语“杂环基烷基羰基”(独自或与其它术语结合)是指-C(O)-烷基-杂环基。
术语“碳环基氧基羰基”(独自或与其它术语结合)是指-C(O)-O-碳环基。
术语“碳环基烷氧基羰基”(独自或与其它术语结合)是指-C(O)-O-烷基-碳环基。
术语“硫代”或“硫杂”(独自或与其它术语结合)是指硫醚取代基,即其中二价硫原子代替醚氧原子的醚取代基。这种取代基可以被描述为-S-。这种例如“烷基-硫代-烷基”是指烷基-S-烷基(烷基-硫烷基-烷基)。
术语“硫醇”或“巯基”(独自或与其它术语结合)是指巯基取代基并可以被描述为-SH。
术语“(硫代羰基)”(独自或与其它术语结合)是指其中氧原子被硫替代的羰基。这种取代基可以被描述为-C(S)-。
术语“磺酰基”(独自或与其它术语结合)是指-S(O)2-。
术语“氨基磺酰基”(独自或与其它术语结合)是指-S(O)2-NH2。
术语“亚硫酰基”或“亚砜基”(独自或与其它术语结合)是指-S(O)-。
术语“杂环基”(独自或与其它术语结合)是指含有总共3至14个环原子的饱和的(即“杂环烷基”)、部分饱和的(即“杂环烯基”)或完全不饱和的(即“杂芳基”)环结构。至少一个环原子是杂原子(即氧、氮或硫),其余环原子独立地选自碳、氧、氮和硫。杂环基可以是单环(单环的)或多环的环结构。
杂环基可以是通常含有3至7个环原子,更通常3至6个环原子,再更通常5至6个环原子的单环。单环杂环基的实例包括1,2,3,6-四氢吡啶、硫代吗啉基、四氢吡喃基、呋喃基、二氢呋喃基、四氢呋喃基、噻吩基(硫代呋喃基)、二氢噻吩基、四氢噻吩基、吡咯基、吡咯啉基、吡咯烷基、咪唑基、咪唑啉基、咪唑烷基、吡唑基、吡唑啉基、吡唑烷基、三唑基、四唑基、噁唑基、噁唑烷基、异噁唑烷基、异噁唑基、噻唑基、异噻唑基、噻唑啉基、异噻唑啉基、噻唑烷基、异噻唑烷基、噻二唑基、噁二唑基(包括1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基(呋咱基)或1,3,4-噁二唑基)、噁三唑基(包括1,2,3,4-噁三唑基或1,2,3,5-噁三唑基)、二噁唑基(包括1,2,3-二噁唑基、1,2,4-二噁唑基、1,3,2-二噁唑基或1,3,4-二噁唑基)、氧杂噻唑基、氧硫杂环戊二烯基(oxathiolyl)、氧硫杂环戊烷基、吡喃基、二氢吡喃基、噻喃基、四氢噻喃基、吡啶基(azinyl)、哌啶基、二嗪基(包括哒嗪基(1,2-二嗪基)、嘧啶基(1,3-二嗪基)或吡嗪基(1,4-二嗪基))、哌嗪基、吡咯烷-2-酮基、三嗪基(包括1,3,5-三嗪基、1,2,4-三嗪基和1,2,3-三嗪基)、噁嗪基(包括1,2-噁嗪基、1,3-噁嗪基或1,4-噁嗪基)、噁噻嗪基(包括1,2,3-噁噻嗪基、1,2,4-噁噻嗪基、1,2,5-噁噻嗪基或1,2,6-噁噻嗪基)、噁二嗪基(包括1,2,3-噁二嗪基、1,2,4-噁二嗪基、1,4,2-噁二嗪基或1,3,5-噁二嗪基)、吗啉基、氮杂环庚三烯基(azepinyl)、氧杂环庚三烯基(oxepinyl)、硫杂环庚三烯基(thiepinyl)和二氮杂环庚三烯基(diazepinyl)。
杂环基或者可以是多环的(即可含有多于一个环)。多环杂环基的实例包括桥连、稠合和螺环杂环基。在螺环杂环基中,一个原子是两个不同环共有的。在桥连杂环基中,环共享至少两个共有非相邻原子。在稠环杂环基中,两个或更多个环可稠合在一起,以致两个环共享一个共用键。实例包括六氢-呋喃并[3,4-c]吡咯、六氢-呋喃并[3,4-b]吡咯、八氢-吡咯并[3,4-b]吡啶、八氢-吡咯并[3,4-c]吡啶、(3aR,6aR)-5-甲基-八氢-吡咯并[3,4-b]吡咯、(3aR,6aR)-八氢-吡咯并[3,4-b]吡咯、6-甲基-2,6-二氮杂-双环[3.2.0]庚烷、(3aS,6aR)-2-甲基-八氢-吡咯并[3,4-c]吡咯、十氢-[1,5]萘啶、2,3-二氢苯并呋喃基、2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚基、噻吩并[3,2-c]吡啶基、呋喃并[3,2-c]吡啶基、酞嗪-1(2H)-酮基、异喹啉基、异喹啉-1(2H)-酮基、5,6,7,8-四氢酞嗪-1(2H)-酮基、氟酞嗪-1(2H)-酮基、(Z)-3H-苯并[d][1,2]二氮杂环庚三烯-4(5H)-酮基、(三氟甲基)酞嗪-1(2H)-酮基、吡咯并[1,2-d][1,2,4]三嗪-1(2H)-酮基、1,2,3,4-四氢异喹啉基、2,3-二氢苯并[b][1,4]二氧杂芑基、5,6,7,8-四氢酞嗪-1(2H)-酮基、5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡嗪基、5,6,7,8-四氢咪唑并[1,5-a]吡嗪基、噻吩并[3,2-c]吡啶基、呋喃并[3,2-c]吡啶基、中氮茚基(indolizinyl)、吡喃并吡咯基、4H-喹嗪基、嘌呤基、萘啶基、吡啶并吡啶基(包括吡啶并[3,4-b]-吡啶基、吡啶并[3,2-b]-吡啶基或吡啶并[4,3-b]-吡啶基)和蝶啶基。稠环杂环基的其它实例包括苯并稠合杂环基,如苯并咪唑基、苯并[d][1,3]间二氧杂环戊烯基、吲哚基、异吲哚基(isobenzazolyl、假异吲哚基)、indoleninyl(假吲哚基)、异吲唑基(苯并吡唑基)、喹啉基(包括喹啉基(1-benzazinyl)或异喹啉基(2-benzazinyl))、酞嗪基、喹喔啉基、喹唑啉基、苯并二嗪基(包括噌啉基(1,2-苯并二嗪基)或喹唑啉基(1,3-苯并二嗪基))、苯并吡喃基(包括苯并二氢吡喃基或异苯并二氢吡喃基)、苯并噁嗪基(包括1,3,2-苯并噁嗪基、1,4,2-苯并噁嗪基、2,3,1-苯并噁嗪基或3,1,4-苯并噁嗪基)和苯并异噁嗪基(包括1,2-苯并异噁嗪基或1,4-苯并异噁嗪基)。螺环杂环基的实例包括1,4-二氧杂-8-氮杂螺[4.5]癸基。
术语“杂环烷基”(独自或与其它术语结合)是指饱和杂环基。
术语“杂芳基”(独自或与其它术语结合)是指含有5至14个环原子的芳族杂环基。杂芳基可以是单环或2或3稠合环。杂芳基取代基的实例包括6元环取代基,如吡啶基、吡嗪基、嘧啶基、哒嗪基和1,3,5-、1,2,4-或1,2,3-三嗪基;5-元环取代基,如咪唑基、呋喃基、噻吩基、吡唑基、噁唑基、异噁唑基、噻唑基、1,2,3-、1,2,4-、1,2,5-或1,3,4-噁二唑基和异噻唑基;6/5-元稠环取代基,如苯并硫代呋喃基、苯并异噁唑基、苯并噁唑基、嘌呤基和苯邻甲内酰胺基(anthranilyl);和6/6-元稠环,如苯并吡喃基、喹啉基、异喹啉基、噌啉基、喹唑啉基和苯并噁嗪基。
连接多组分取代基的前缀仅适用于第一组分。例如,术语“烷基环烷基”含有两个组分:烷基和环烷基。因此,C1-C6-烷基环烷基上的C1-C6-前缀是指烷基环烷基的烷基组分含有1至6个碳原子;C1-C6-前缀不描述环烷基组分。为进一步举例说明,卤代烷氧基烷基上的前缀“卤代”是指烷氧基烷基取代基的仅烷氧基组分被一个或多个卤素基团取代。如果可以取而代之地或另外地在烷基组分上发生卤素取代,该取代基将改为描述为“卤素取代的烷氧基烷基”而非“卤代烷氧基烷基”。最后,如果仅在烷基组分上发生卤素取代,该取代基将改为描述为“烷氧基卤代烷基”。
术语“治疗(treat, treating及treatment)”是指减轻或消除疾病和/或其附随症状的方法。
术语“预防(prevent, preventing及prevention)”是指防止疾病和/或其附随症状发作或防止主体得病的方法。本文所用的“预防”还包括延迟疾病和/或其附随症状发作和降低主体的得病风险。
术语“治疗有效量”是指足以防止所治疗的病症或障碍的一种或多种症状的发展或在一定程度上减轻所治疗的病症或障碍的一种或多种症状的化合物给药量。
术语“调制”是指化合物提高或降低激酶的功能或活性的能力。本文中以其各种形式使用的“调制”意在包括与激酶相关的活性的拮抗、激动、部分拮抗和/或部分激动。激酶抑制剂是例如结合、部分或完全阻碍刺激、降低、防止、延迟活化、钝化、减敏或下调信号转导的化合物。激酶活化剂是例如结合、刺激、提高、开启、活化、促进、增活、敏化或上调信号转导的化合物。
本文所用的术语“组合物”意在包括包含规定量的规定成分以及由规定量的规定成分的结合直接或间接产生的任何产物的产品。“药学上可接受的”是指载体、稀释剂或赋形剂必须与制剂的其它成分相容并对其受体无害。
“主体”在本文中被定义为包括动物,如哺乳动物,包括但不限于,灵长类动物(例如人)、牛、绵羊、山羊、马、狗、猫、兔、大鼠、小鼠等。在优选实施方案中,该主体是人。
同位素富集或标记的化合物
本发明的化合物可以以同位素标记或富集形式存在,其含有一个或多个原子质量或质量数不同于自然界中最丰富存在的原子质量或质量数的原子。同位素可以是放射性或非放射性同位素。原子,如氢、碳、磷、硫、氟、氯和碘的同位素包括,但不限于,2H、3H、13C、14C、15N、18O、32P、35S、18F、36Cl和125I。含有这些和/或其它原子的其它同位素的化合物在本发明的范围内。
在另一实施方案中,该同位素标记的化合物含有氘(2H)、氚(3H)或14C同位素。本发明的同位素标记的化合物可通过本领域普通技术人员公知的一般方法制备。可以便利地通过用易得的同位素标记试剂取代未标记试剂来进行本文公开的实施例和方案中公开的程序,以制备这样的同位素标记的化合物。在一些情况下,可以用同位素标记的试剂处理化合物以将正常原子与其同位素交换,例如通过氘酸,如D2SO4/D2O的作用,可以将氢换成氘。除上文这些外,例如在Lizondo, J等人, Drugs Fut, 21(11), 1116 (1996);Brickner, S J等人, J Med Chem, 39(3), 673 (1996);Mallesham, B等人, Org Lett, 5(7), 963(2003);PCT公开WO1997010223、WO2005099353、WO1995007271、WO2006008754;美国专利Nos. 7538189;7534814;7531685;7528131;7521421;7514068;7511013;和美国专利申请公开Nos. 20090137457;20090131485;20090131363;20090118238;20090111840;20090105338;20090105307;20090105147;20090093422;20090088416;和20090082471中公开了相关程序和中间体,这些方法并入本文作为参考。
本发明的同位素标记的化合物可用作在结合检测中测定Bcl-2抑制剂的效力的标准。含同位素的化合物已经在药学研究中用于通过评估非同位素标记的母体化合物的作用机制和代谢途径来研究该化合物的体内代谢归宿(Blake等人,J. Pharm. Sci. 64, 3,367-391 (1975))。这样的代谢研究在安全有效的治疗药物的设计中是重要的,因为给药于患者的体内活性化合物或由母体化合物生成的代谢物经证实有毒或致癌(Foster等人,Advances in Drug Research Vol. 14, 第2-36页, Academic press, London, 1985;Kato等人, J. Labelled Comp. Radiopharmaceut., 36(10):927-932 (1995);Kushner等人, Can. J. Physiol. Pharmacol., 77, 79-88 (1999))。
此外,含有非放射性同位素的药物,如被称作“重药”的氘化药物可用于治疗与Bcl-2活性相关的疾病和病症。将化合物中存在的同位素的量提高在其天然丰度以上被称作富集。富集量的实例包括大约0.5、1、2、3、4、5、6、7、8、9、10、12、16、21、25、29、33、37、42、46、50、54、58、63、67、71、75、79、84、88、92、96至大约100摩尔%。在哺乳动物,包括啮齿动物和犬类中已实现用重同位素替代最多大约15%的正常原子并保持数天至数周,观察到最低副作用(Czajka D M和Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770;Thomson J F,Ann. New York Acad. Sci 1960 84: 736;Czakja D M等人, Am. J. Physiol. 1961201: 357)。在人体体液中高达15%-23%的氘急性替换没有发现造成毒性(Blagojevic N等人 "Dosimetry & Treatment Planning for Neutron Capture Therapy"中, ZamenhofR, Solares G和Harling O Eds. 1994. Advanced Medical Publishing, Madison Wis.第125-134页;Diabetes Metab. 23: 251 (1997))。
药物的稳定同位素标记可改变其物理化学性质,如pKa和脂溶性。如果同位素置换作用于配体-受体相互作用中牵涉的区域,这些作用和变动可影响药物分子的药效学响应。尽管稳定同位素标记分子的一些物理性质不同于未标记的那些,但化学和生物学性质相同,一个重要的例外是:由于重同位素的提高的质量,涉及重同位素和另一原子的任何键比轻同位素与该原子之间的相同键更强。因此,在代谢或酶法转化位点并入同位素会减慢所述反应,与非同位素化合物相比可能改变药代动力学特征或效力。
化合物
另一实施方案涉及化合物,其为
N-(4-{[2-(氮杂环庚烷-1-基)乙基]氨基甲酰基}苯基)-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{4-[(2-羟基丙基)氨基甲酰基]苯基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-(4-{[2-(2-氧代咪唑烷-1-基)乙基]氨基甲酰基}苯基)-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-(4-{[2-(四氢-2H-吡喃-2-基)乙基]氨基甲酰基}苯基)-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-(4-{[(2-甲基四氢呋喃-2-基)甲基]氨基甲酰基}苯基)-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-(4-{[2-甲基-2-(吗啉-4-基)丙基]氨基甲酰基}苯基)-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{4-[(1-氧杂-8-氮杂螺[4.5]癸-3-基甲基)氨基甲酰基]苯基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2-氧杂-7-氮杂螺[3.5]壬-7-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(六氢呋喃并[3,2-c]吡啶-5(4H)-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(六氢-5H-呋喃并[2,3-c]吡咯-5-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2,6-二氧杂-9-氮杂螺[4.5]癸-9-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2-氧杂-6-氮杂螺[3.3]庚-6-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2-氧杂-6-氮杂螺[3.5]壬-6-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2-氧杂-7-氮杂螺[4.4]壬-7-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(10,10-二氟-2,7-二氮杂螺[4.5]癸-2-基)羰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(3-氰基-1-氧杂-8-氮杂螺[4.5]癸-8-基)羰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(7-氧杂-2-氮杂螺[3.5]壬-2-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(1-氧杂-7-氮杂螺[4.4]壬-7-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(10-氟-2,7-二氮杂螺[4.5]癸-2-基)羰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(3,9-二氮杂螺[5.5]十一烷-3-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2,7-二氮杂螺[4.5]癸-7-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2,8-二氮杂螺[4.5]癸-8-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(7-氮杂螺[3.5]壬-1-基氨基甲酰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2-氮杂螺[3.3]庚-5-基氨基甲酰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(1R,5S)-3-氮杂双环[3.1.0]己-6-基氨基甲酰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-(6-{[(7R)-八氢吡咯并[1,2-a]吡嗪-7-基甲基]氨基甲酰基}哒嗪-3-基)-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2,6-二氮杂螺[3.5]壬-2-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2,7-二氮杂螺[3.5]壬-2-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2,6-二氮杂螺[3.4]辛-6-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(2-氧杂-9-氮杂螺[5.5]十一烷-3-基甲基)氨基甲酰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(1-氧杂-8-氮杂螺[4.5]癸-2-基甲基)氨基甲酰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(1-氧杂-8-氮杂螺[4.5]癸-3-基甲基)氨基甲酰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2,7-二氮杂螺[3.5]壬-7-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2,8-二氮杂螺[4.5]癸-2-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-(6-{[3-(氮杂环丁烷-3-基)吡咯烷-1-基]羰基}哒嗪-3-基)-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-2-基甲基)氨基甲酰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(1-氧杂-8-氮杂螺[4.5]癸-3-基氨基甲酰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(6,7,8,9-四氢-5H-[1,2,4]三唑并[4,3-a][1,4]二氮杂环庚三烯-3-基甲基)氨基甲酰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(6-氮杂螺[2.5]辛-1-基甲基)氨基甲酰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(5-氧杂-2-氮杂螺[3.4]辛-2-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(5,6,7,8-四氢[1,2,4]三唑并[4,3-a]吡嗪-3-基甲基)氨基甲酰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-(6-{[(4-氟哌啶-4-基)甲基]氨基甲酰基}哒嗪-3-基)-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2,6-二氮杂螺[3.3]庚-2-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(6-氧杂-2-氮杂螺[3.4]辛-7-基甲基)氨基甲酰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(5-氧杂-2-氮杂螺[3.5]壬-2-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-(6-{[1-(三氟甲基)-2,8-二氮杂螺[4.5]癸-2-基]羰基}哒嗪-3-基)-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(7-氮杂螺[3.5]壬-2-基甲基)氨基甲酰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(5,6,7,8-四氢-4H-[1,2,3]三唑并[1,5-a][1,4]二氮杂环庚三烯-3-基甲基)氨基甲酰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;及其药学上可接受的盐。
药物组合物、 联合疗法、 治疗方法和给药
另一实施方案包括包含选自本文实施例1-49的化合物或其药学上可接受的盐和赋形剂的药物组合物。
再一实施方案包括治疗哺乳动物癌症的方法,包括给予其治疗可接受的量的选自本文实施例1-49的化合物或其药学上可接受的盐。
再一实施方案涉及用于治疗期间表达NAMPT的疾病的组合物,所述组合物包含赋形剂和治疗有效量的选自本文实施例1-49的化合物及其药学上可接受的盐。
再一实施方案涉及治疗患者的期间表达NAMPT的疾病的方法,所述方法包括给予患者治疗有效量的选自本文实施例1-49的化合物或其药学上可接受的盐。
再一实施方案涉及用于治疗炎症和组织修复障碍;特别是类风湿性关节炎、炎性肠病、哮喘和COPD(慢性阻塞性肺病)、骨关节炎、骨质疏松症和纤维化疾病;皮肤病,包括牛皮癣、特应性皮炎和紫外线引起的皮肤损伤;自身免疫病,包括系统性红斑狼疮、多发性硬化、银屑病关节炎、关节强硬性脊椎炎、组织和器官排斥、阿尔茨海默氏症、中风、动脉粥样硬化、再狭窄、糖尿病、肾小球肾炎、癌症,其中该癌症特别选自乳腺癌、前列腺癌、肺癌、结肠癌、宫颈癌、卵巢癌、皮肤癌、CNS癌、膀胱癌、胰腺癌、白血病、淋巴瘤或霍奇金病、恶病质、与感染和某些病毒性感染,包括获得性免疫缺陷综合征(AIDS)相关的炎症、成人呼吸窘迫综合征和共济失调毛细血管扩张的组合物,所述组合物包含赋形剂和治疗有效量的选自本文实施例1-49的化合物或其药学上可接受的盐。
再一实施方案涉及治疗患者的炎症和组织修复障碍;特别是类风湿性关节炎、炎性肠病、哮喘和COPD(慢性阻塞性肺病)、骨关节炎、骨质疏松症和纤维化疾病;皮肤病,包括牛皮癣、特应性皮炎和紫外线引起的皮肤损伤;自身免疫病,包括系统性红斑狼疮、多发性硬化、银屑病关节炎、关节强硬性脊椎炎、组织和器官排斥、阿尔茨海默氏症、中风、动脉粥样硬化、再狭窄、糖尿病、肾小球肾炎、癌症,其中该癌症特别选自乳腺癌、前列腺癌、肺癌、结肠癌、宫颈癌、卵巢癌、皮肤癌、CNS癌、膀胱癌、胰腺癌、白血病、淋巴瘤或霍奇金病、恶病质、与感染和某些病毒性感染,包括获得性免疫缺陷综合征(AIDS)相关的炎症、成人呼吸窘迫综合征和共济失调毛细血管扩张的方法,所述方法包括给予患者治疗有效量的选自本文实施例1-49的化合物或其药学上可接受的盐。
再一实施方案涉及用于治疗期间表达NAMPT的疾病的组合物,所述组合物包含赋形剂和治疗有效量的选自本文实施例1-49的化合物或其药学上可接受的盐和治疗有效量的一种附加治疗剂或多于一种附加治疗剂。
再一实施方案涉及治疗患者的期间表达NAMPT的疾病的方法,所述方法包括给予患者治疗有效量的选自本文实施例1-49的化合物或其药学上可接受的盐和治疗有效量的一种附加治疗剂或多于一种附加治疗剂。
再一实施方案涉及用于治疗炎症和组织修复障碍;特别是类风湿性关节炎、炎性肠病、哮喘和COPD(慢性阻塞性肺病)、骨关节炎、骨质疏松症和纤维化疾病;皮肤病,包括牛皮癣、特应性皮炎和紫外线引起的皮肤损伤;自身免疫病,包括系统性红斑狼疮、多发性硬化、银屑病关节炎、关节强硬性脊椎炎、组织和器官排斥、阿尔茨海默氏症、中风、动脉粥样硬化、再狭窄、糖尿病、肾小球肾炎、癌症,其中该癌症特别选自乳腺癌、前列腺癌、肺癌、结肠癌、宫颈癌、卵巢癌、皮肤癌、CNS癌、膀胱癌、胰腺癌、白血病、淋巴瘤或霍奇金病、恶病质、与感染和某些病毒性感染,包括获得性免疫缺陷综合征(AIDS)相关的炎症、成人呼吸窘迫综合征和共济失调毛细血管扩张的组合物,所述组合物包含赋形剂和治疗有效量的选自本文实施例1-49的化合物及其药学上可接受的盐,或治疗有效量的一种附加治疗剂或多于一种附加治疗剂。
再一实施方案涉及治疗患者的炎症和组织修复障碍;特别是类风湿性关节炎、炎性肠病、哮喘和COPD(慢性阻塞性肺病)、骨关节炎、骨质疏松症和纤维化疾病;皮肤病,包括牛皮癣、特应性皮炎和紫外线引起的皮肤损伤;自身免疫病,包括系统性红斑狼疮、多发性硬化、银屑病关节炎、关节强硬性脊椎炎、组织和器官排斥、阿尔茨海默氏症、中风、动脉粥样硬化、再狭窄、糖尿病、肾小球肾炎、癌症,其中该癌症特别选自乳腺癌、前列腺癌、肺癌、结肠癌、宫颈癌、卵巢癌、皮肤癌、CNS癌、膀胱癌、胰腺癌、白血病、淋巴瘤或霍奇金病、恶病质、与感染和某些病毒性感染,包括获得性免疫缺陷综合征(AIDS)相关的炎症、成人呼吸窘迫综合征和共济失调毛细血管扩张的方法,所述方法包括给予患者治疗有效量的选自本文实施例1-49的化合物或其药学上可接受的盐和治疗有效量的一种附加治疗剂或多于一种附加治疗剂。
通过体外或体内代谢过程生成的选自本文实施例1-49的化合物或其药学上可接受的盐的代谢物也可用于治疗与NAMPT相关的疾病。
可体外或体内代谢形成选自本文实施例1-49的化合物或其药学上可接受的盐的某些前体化合物也可用于治疗与NAMPT相关的疾病。
选自本文实施例1-49的化合物和其药学上可接受的盐可以以酸加成盐、碱性加成盐或两性离子的形式存在。在该化合物的分离或随后提纯过程中制备该化合物的盐。该化合物的酸加成盐是源自该化合物与酸的反应的那些。例如,该化合物的乙酸盐、己二酸盐、藻酸盐、碳酸氢盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、二葡糖酸盐、甲酸盐、富马酸盐、甘油磷酸盐、谷氨酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、乳糖醛酸盐、乳酸盐、马来酸盐、均三甲苯磺酸盐、甲磺酸盐、萘磺酸盐、烟酸盐、草酸盐、双羟萘酸盐、果胶脂酸盐(pectinate)、过硫酸盐、磷酸盐、苦味酸盐、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、三氯乙酸盐、三氟乙酸盐、对甲苯磺酸盐和十一烷酸盐被认为涵盖在本发明中。该化合物的碱性加成盐是源自该化合物与阳离子如锂、钠、钾、钙和镁的氢氧化物、碳酸盐或碳酸氢盐的反应的那些。
选自本文实施例1-49的化合物或其药学上可接受的盐可以例如口颊、经眼、经口、渗透、肠胃外(肌肉内、腹膜内、胸骨内、静脉内、皮下)、直肠、局部、经皮或阴道给药。
选自本文实施例1-49的化合物及其药学上可接受的盐的治疗有效量取决于治疗接受者、所治疗的疾病及其严重程度、含有该化合物的组合物、给药时间、给药途径、治疗持续时间、化合物效力、其清除率和是否有另一药物共同给药。用于制备每日以单剂量或分剂量给药于患者的组合物的具有式(I)的本发明的化合物的量是大约0.03至大约200 mg/kg体重。单剂量组合物含有这些量或其约数的组合。
选自本文实施例1-49的化合物及其药学上可接受的盐可以与或不与赋形剂一起给药。赋形剂包括例如包囊材料或添加剂,如吸收促进剂、抗氧化剂、粘合剂、缓冲剂、包衣剂、着色剂、稀释剂、崩解剂、乳化剂、增量剂、填料、调味剂、保湿剂、润滑剂、香精、防腐剂、推进剂、释放剂、消毒剂、甜味剂、增溶剂、润湿剂及其混合物。
用于制备要以固体剂型口服给药的包含选自本文实施例1-49的化合物及其药学上可接受的盐的组合物的赋形剂包括例如琼脂、褐藻酸、氢氧化铝、苄醇、苯甲酸苄酯、1,3-丁二醇、卡波姆、蓖麻油、纤维素、乙酸纤维素、可可脂、玉米淀粉、玉米油、棉籽油、交聚维酮、甘油二酯、乙醇、乙基纤维素、月桂酸乙酯、油酸乙酯、脂肪酸酯、明胶、胚芽油、葡萄糖、甘油、花生(groundnut)油、羟丙基甲基纤维素、异丙醇、等渗盐水、乳糖、氢氧化镁、硬脂酸镁、麦芽、甘露醇、甘油单酯、橄榄油、花生(peanut)油、磷酸钾盐、马铃薯淀粉、聚维酮、丙二醇、林格氏溶液、红花油、芝麻油、羧甲基纤维素钠、磷酸钠盐、十二烷基硫酸钠、山梨糖醇钠、大豆油、硬脂酸、十八烷基富马酸盐、蔗糖、表面活性剂、滑石、黄蓍胶、四氢糠醇、甘油三酯、水及其混合物。用于制备要以液体剂型经眼或经口给药的包含具有式(I)的本发明的化合物的组合物的赋形剂包括例如1,3-丁二醇、蓖麻油、玉米油、棉籽油、乙醇、山梨糖醇酐的脂肪酸酯、胚芽油、花生油、甘油、异丙醇、橄榄油、聚乙二醇、丙二醇、芝麻油、水及其混合物。用于制备要渗透给药的包含具有式(I)的本发明的化合物的组合物的赋形剂包括例如氯氟烃、乙醇、水及其混合物。用于制备要肠胃外给药的包含具有式(I)的本发明的化合物的组合物的赋形剂包括例如1,3-丁二醇、蓖麻油、玉米油、棉籽油、右旋糖、胚芽油、花生(groundnut)油、脂质体、油酸、橄榄油、花生(peanut)油、林格氏溶液、红花油、芝麻油、大豆油、U.S.P.或等渗氯化钠溶液、水及其混合物。用于制备要直肠或阴道给药的包含具有式(I)的本发明的化合物的组合物的赋形剂包括例如可可脂、聚乙二醇、蜡及其混合物。
选自本文实施例1-49的化合物及其药学上可接受的盐预计与烷基化剂、血管生成抑制剂、抗体、抗代谢物、抗有丝分裂剂、抗增殖剂、抗病毒药、极光激酶抑制剂、凋亡促进剂(例如Bcl-xL、Bcl-w和Bfl-1)抑制剂、死亡受体途径活化剂、Bcr-Abl激酶抑制剂、BiTE(Bi-Specific T cell Engager)抗体、抗体药物偶联物、生物反应改进剂、细胞周期蛋白依赖性激酶抑制剂、细胞周期抑制剂、环加氧酶-2抑制剂、DVDs、白血病病毒癌基因同源物(ErbB2)受体抑制剂、生长因子抑制剂、热休克蛋白(HSP)-90抑制剂、组蛋白去乙酰化酶(HDAC)抑制剂、激素治疗药、免疫药、凋亡蛋白(IAPs)抑制剂的抑制剂、插层抗生素、激酶抑制剂、驱动蛋白抑制剂、Jak2抑制剂、雷帕霉素抑制剂的哺乳动物靶、microRNA’s、丝裂原激活的细胞外信号调节激酶抑制剂、多价结合蛋白、非类固醇抗炎药(NSAIDs)、聚ADP(二磷酸腺苷)-核糖聚合酶(PARP)抑制剂、铂化疗药物、polo-样激酶(Plk)抑制剂、磷酸肌醇-3激酶(PI3K)抑制剂、蛋白体抑制剂、嘌呤类似物、嘧啶类似物、受体酪氨酸激酶抑制剂、类维生素A/deltoids、植物生物碱、小抑制核糖核酸(siRNAs)、拓扑异构酶抑制剂、泛素连接酶抑制剂等一起使用和与一种或多种这些试剂联合使用时是有用的。
BiTE抗体是通过同时结合两个细胞而引导T-细胞攻击癌细胞的双特异性抗体。T-细胞随后攻击靶癌细胞。BiTE抗体的实例包括阿德木单抗(Micromet MT201)、blinatumomab (Micromet MT103)等。不受制于理论,但T-细胞引发靶癌细胞凋亡的机制之一是通过细胞毒性颗粒组分(包括穿孔素和粒酶B)的胞吐作用。在这方面,Bcl-2已表明通过穿孔素和粒酶B减弱凋亡的诱发。这些数据表明在靶向癌细胞时,Bcl-2的抑制可增强T-细胞引发的细胞毒性效应(V.R. Sutton, D.L. Vaux和J.A. Trapani, J. of Immunology 1997, 158 (12), 5783)。
SiRNAs是具有内源性RNA碱基或化学改性核苷酸的分子。该改性不消除细胞活性,而是赋予提高的稳定性和/或提高的细胞效力。化学改性的实例包括硫代磷酸酯类、2'-脱氧核苷酸、含2'-OCH3的核糖核苷酸、2'-F-核糖核苷酸、2'-甲氧基乙基核糖核苷酸、它们的组合等。siRNA可具有不同长度(例如10-200 bps)和结构(例如发夹结构、单/双链、鼓胀、缺口/间隙、失配)并在细胞中加工以提供活性基因沉默。双链siRNA(dsRNA)可以在各链(钝端)或不对称端(突出端)上具有相同数量的核苷酸。1-2个核苷酸的突出端可存在于有义和/或反义链上,以及存在于给定链的5'-和/或3'-端上。
多价结合蛋白是包含两个或更多个抗原结合位点的结合蛋白。多价结合蛋白被设计成具有三个或更多个抗原结合位点并通常不是天然存在的抗体。术语“多特异性结合蛋白”是指能结合两个或更多个相关或不相关靶的结合蛋白。双可变区(DVD)结合蛋白是包含两个或更多个抗原结合位点的四价或多价结合蛋白。这样的DVDs可以是单特异性的(即能结合一个抗原)或多特异性的(即能结合两个或更多个抗原)。包含两个重链DVD多肽和两个轻链DVD多肽的DVD结合蛋白被称作DVD Ig's。DVD Ig的每一半包含重链DVD多肽、轻链DVD多肽和两个抗原结合位点。各结合位点包含重链可变区和轻链可变区,每个抗原结合位点在抗原结合中涉及总共6个CDRs。
烷基化剂包括六甲蜜胺、AMD-473、AP-5280、apaziquone、苯达莫司汀、brostallicin、白消安、卡波醌、卡莫司汀(BCNU)、苯丁酸氮芥、CLORETAZINE®(laromustine,VNP 40101M)、环磷酰胺、达卡巴嗪、雌氮芥、福莫司汀、葡磷酰胺、异环磷酰胺、KW-2170、洛莫司汀(CCNU)、马磷酰胺、美法仑、二溴甘露醇、二溴卫矛醇、尼莫司汀、氮芥N-氧化物、雷莫司汀、替莫唑胺、噻替哌、TREANDA®(苯达莫司汀)、苏消安、曲洛磷胺等。
血管生成抑制剂包括内皮特异性受体酪氨酸激酶(Tie-2)抑制剂、表皮生长因子受体(EGFR)抑制剂、胰岛素生长因子-2受体(IGFR-2)抑制剂、基质金属蛋白酶-2(MMP-2)抑制剂、基质金属蛋白酶-9(MMP-9)抑制剂、血小板源生长因子受体(PDGFR)抑制剂、血小板反应蛋白类似物、血管内皮生长因子受体酪氨酸激酶(VEGFR)抑制剂等。
抗代谢物包括ALIMTA®(培美曲塞二钠, LY231514, MTA)、5-阿扎胞苷、XELODA®(卡培他滨)、卡莫氟、LEUSTAT®(克拉屈滨)、氯法拉滨、阿糖胞苷、阿糖胞苷十八烷基磷酸盐、胞嘧啶阿拉伯糖苷、地西他滨、去铁胺、去氧氟尿苷、依氟鸟氨酸、EICAR(5-乙炔基-1-β-D-呋喃核糖基咪唑-4-羧酰胺)、依诺他滨、ethnylcytidine、氟达拉滨、单独或与甲酰四氢叶酸结合的5-氟尿嘧啶、GEMZAR®(吉西他滨)、羟基脲、ALKERAN®(美法仑)、巯基嘌呤、6-巯基嘌呤核糖苷、甲氨蝶呤、霉酚酸、奈拉滨、诺拉曲塞、ocfosfate、pelitrexol、喷司他丁、雷替曲塞、利巴韦林、triapine、曲美沙特、S-1、噻唑呋林、替加氟、TS-1、阿糖腺苷、UFT等。
抗病毒药包括利托那韦、羟基氯喹等。
极光激酶抑制剂包括ABT-348、AZD-1152、MLN-8054、VX-680、极光A-特异性激酶抑制剂、极光B-特异性激酶抑制剂和pan-极光激酶抑制剂等。
Bcl-2蛋白抑制剂包括AT-101((-)棉酚)、GENASENSE®(G3139或oblimersen(Bcl-2-靶向反义寡核苷酸))、IPI-194、IPI-565、N-(4-(4-((4'-氯(1,1'-联苯)-2-基)甲基)哌嗪-1-基)苯甲酰基)-4-(((1R)-3-(二甲基氨基)-1-((苯基硫烷基)甲基)丙基)氨基)-3-硝基苯磺酰胺)(ABT-737)、N-(4-(4-((2-(4-氯苯基)-5,5-二甲基-1-环己-1-烯-1-基)甲基)哌嗪-1-基)苯甲酰基)-4-(((1R)-3-(吗啉-4-基)-1-((苯基硫烷基)甲基)丙基)氨基)-3-((三氟甲基)磺酰基)苯磺酰胺(ABT-263)、GX-070(obatoclax)等。
Bcr-Abl激酶抑制剂包括达沙替尼®(BMS-354825)、GLEEVEC®(伊马替尼)等。
CDK抑制剂包括AZD-5438、BMI-1040、BMS-032、BMS-387、CVT-2584、flavopyridol、GPC-286199、MCS-5A、PD0332991、PHA-690509、seliciclib(CYC-202,R-roscovitine)、ZK-304709等。
COX-2抑制剂包括ABT-963、ARCOXIA®(依托考昔)、BEXTRA®(伐地考昔)、BMS347070、CELEBREX®(塞来昔布)、COX-189(罗美昔布)、CT-3、DERAMAXX®(德拉昔布)、JTE-522、4-甲基-2-(3,4-二甲基苯基)-1-(4-氨磺酰基苯基-1H-吡咯)、MK-663(依托考昔)、NS-398、帕瑞昔布、RS-57067、SC-58125、SD-8381、SVT-2016、S-2474、T-614、VIOXX®(罗非昔布)等。
EGFR抑制剂包括ABX-EGF、抗-EGFR免疫脂质体、EGF-疫苗、EMD-7200、ERBITUX®(西妥昔单抗)、HR3、IgA抗体、IRESSA®(吉非替尼)、TARCEVA®(埃罗替尼或OSI-774)、TP-38、EGFR融合蛋白、TYKERB®(拉帕替尼)等。
ErbB2受体抑制剂包括CP-724-714、CI-1033(卡奈替尼)、HERCEPTIN®(曲妥单抗)、TYKERB®(拉帕替尼)、OMNITARG®(2C4,petuzumab)、TAK-165、GW-572016(ionafarnib)、GW-282974、EKB-569、PI-166、dHER2(HER2疫苗)、APC-8024(HER-2疫苗)、抗-HER/2neu双特异性抗体、B7.her2IgG3、AS HER2三功能双特异性抗体、mAB AR-209、mAB 2B-1等。
组蛋白去乙酰化酶抑制剂包括缩酚酸肽、LAQ-824、MS-275、托普辛(trapoxin)、伏立诺他(SAHA)、TSA、丙戊酸等。
HSP-90抑制剂包括17-AAG-nab、17-AAG、CNF-101、CNF-1010、CNF-2024、17-DMAG、格尔德霉素、IPI-504、KOS-953、MYCOGRAB®(对HSP-90的人重组抗体)、NCS-683664、PU24FCl、PU-3、根赤壳菌素、SNX-2112、STA-9090、VER49009等。
凋亡蛋白抑制剂的抑制剂包括HGS1029、GDC-0145、GDC-0152、LCL-161、LBW-242等。
抗体药物偶联物包括抗-CD22-MC-MMAF、抗-CD22-MC-MMAE、抗-CD22-MCC-DM1、CR-011-vcMMAE、PSMA-ADC、MEDI-547、SGN-19Am SGN-35、SGN-75等。
死亡受体途径活化剂包括TRAIL、靶向TRAIL或死亡受体(例如DR4和DR5)的抗体或其它试剂,如Apomab、西他土珠(conatumumab)、ETR2-ST01、GDC0145(来沙木单抗)、HGS-1029、LBY-135、PRO-1762和曲妥单抗。
驱动蛋白抑制剂包括Eg5抑制剂,如AZD4877、ARRY-520;CENPE抑制剂,如GSK923295A等。
JAK-2抑制剂包括CEP-701(lesaurtinib)、XL019和INCB018424等。
MEK抑制剂包括ARRY-142886、ARRY-438162、PD-325901、PD-98059等。
mTOR抑制剂包括AP-23573、CCI-779、依维莫司、RAD-001、雷帕霉素、西罗莫司脂化物、ATP-竞争性TORC1/TORC2抑制剂,包括PI-103、PP242、PP30、Torin 1等。
非类固醇抗炎药包括AMIGESIC®(双水杨酯)、DOLOBID®(二氟尼柳)、MOTRIN®(布洛芬)、ORUDIS®(酮基布洛芬)、RELAFEN®(萘丁美酮)、FELDENE®(吡罗昔康(piroxicam))、布洛芬乳膏、ALEVE®(萘普生)和NAPROSYN®(萘普生)、VOLTAREN®(双氯芬酸)、INDOCIN®(吲哚美辛)、CLINORIL®(舒林酸)、TOLECTIN®(托美丁)、LODINE®(依托度酸)、TORADOL®(酮咯酸)、DAYPRO®(奥沙普秦)等。
PDGFR抑制剂包括C-451、CP-673、CP-868596等。
铂化疗药物包括顺铂、ELOXATIN®(奥沙利铂)、依铂、洛铂、奈达铂、PARAPLATIN®(卡铂)、沙铂、吡铂等。
Polo-样激酶抑制剂包括BI-2536等。
磷酸肌醇-3激酶(PI3K)抑制剂包括渥曼青霉素、LY294002、XL-147、CAL-120、ONC-21、AEZS-127、ETP-45658、PX-866、GDC-0941、BGT226、BEZ235、XL765等。
血小板反应蛋白类似物包括ABT-510、ABT-567、ABT-898、TSP-1等。
VEGFR抑制剂包括AVASTIN®(贝伐单抗)、ABT-869、AEE-788、ANGIOZYME™(抑制血管生成的核酶(Ribozyme Pharmaceuticals (Boulder, CO.)和Chiron (Emeryville,CA))、阿西替尼(AG-13736)、AZD-2171、CP-547,632、IM-862、MACUGEN(哌加他尼)、NEXAVAR®(索拉非尼,BAY43-9006)、帕唑帕尼(GW-786034)、瓦他拉尼(PTK-787、ZK-222584)、SUTENT®(舒尼替尼、SU-11248)、VEGF trap、ZACTIMA™(凡德他尼、ZD-6474)等。
抗生素包括插层抗生素阿柔比星、放线菌素D、氨柔比星、annamycin、阿霉素、BLENOXANE®(博来霉素)、柔红霉素、CAELYX®或MYOCET®(脂质体阿霉素)、依沙芦星、表柔比星、glarbuicin、ZAVEDOS®(伊达比星)、丝裂霉素C、奈莫柔比星、新制癌菌素、培洛霉素、吡柔比星、蝴蝶霉素、stimalamer、链脲菌素、VALSTAR®(戊柔比星)、净司他丁等。
拓扑异构酶抑制剂包括阿柔比星、9-氨基喜树碱、氨萘非特、安吖啶、becatecarin、贝洛替康、BN-80915、CAMPTOSAR®(伊立替康盐酸盐)、喜树碱、CARDIOXANE®(右丙亚胺)、diflomotecan、edotecarin、ELLENCE®或PHARMORUBICIN®(表柔比星)、依托泊苷、依喜替康、10-羟基喜树碱、吉马替康(gimatecan)、勒托替康、米托蒽醌、orathecin、pirarbucin、匹杉琼、鲁比替康、索布佐生、SN-38、tafluposide、拓扑替康等。
抗体包括AVASTIN®(贝伐单抗)、CD40-特异性抗体、chTNT-1/B、地诺单抗、ERBITUX®(西妥昔单抗)、HUMAX-CD4®(zanolimumab)、IGF1R-特异性抗体、林妥珠单抗、PANOREX®(依决洛单抗)、RENCAREX®(WX G250)、RITUXAN®(利妥昔单抗)、ticilimumab、trastuzimab、CD20抗体类型I和II等。
激素治疗药包括ARIMIDEX®(阿那曲唑)、AROMASIN®(依西美坦)、阿佐昔芬、CASODEX®(比卡鲁胺)、CETROTIDE®(西曲瑞克)、地加瑞克、地洛瑞林、DESOPAN®(曲洛司坦)、地塞米松、DROGENIL®(氟他米特)、EVISTA®(雷洛昔芬)、AFEMA™(法倔唑)、FARESTON®(托瑞米芬)、FASLODEX®(氟维司群)、FEMARA®(来曲唑)、福美司坦、糖皮质激素、HECTOROL®(度骨化醇)、RENAGEL®(碳酸司维拉姆)、拉索昔芬、醋酸亮丙瑞林、MEGACE®(甲地孕酮)、MIFEPREX®(米非司酮)、NILANDRON™(尼鲁米特)、NOLVADEX®(柠檬酸三苯氧胺)、PLENAXIS™(阿巴瑞克)、强的松、PROPECIA®(非那雄胺)、rilostane、SUPREFACT®(布舍瑞林)、TRELSTAR®(促黄体激素释放激素(LHRH))、VANTAS®(组氨瑞林植入物)、VETORYL®(曲洛司坦或modrastane)、ZOLADEX®(fosrelin、戈舍瑞林)等。
Deltoids和类维生素A包括西奥骨化醇(EB1089、CB1093)、来沙骨化醇(lexacalcitrol)(KH1060)、fenretinide、PANRETIN®(aliretinoin)、ATRAGEN®(脂质体维甲酸)、TARGRETIN®(贝沙罗汀)、LGD-1550等。
PARP抑制剂包括ABT-888(veliparib)、奥拉帕尼、KU-59436、AZD-2281、AG-014699、BSI-201、BGP-15、INO-1001、ONO-2231等。
植物生物碱包括,但不限于,长春新碱、长春碱、长春地辛、长春瑞滨等。
蛋白酶体抑制剂包括VELCADE®(硼替佐米)、MG132、NPI-0052、PR-171等。
免疫药的实例包括干扰素和其它免疫增强剂。干扰素包括干扰素α、干扰素α-2a、干扰素α-2b、干扰素β、干扰素γ-1a、ACTIMMUNE®(干扰素γ-1b)或干扰素γ-n1、它们的组合等。其它试剂包括ALFAFERONE®(IFN-α)、BAM-002(氧化谷胱甘肽)、BEROMUN®(他索纳明)、BEXXAR®(托西莫单抗)、CAMPATH®(阿仑单抗)、CTLA4(细胞毒性淋巴细胞抗原4)、达卡巴嗪、地尼白介素(denileukin)、依帕珠单抗、GRANOCYTE®(来格司亭)、香菇多糖、白细胞α干扰素、咪喹莫特、MDX-010(抗-CTLA-4)、黑素瘤疫苗、米妥莫单抗、莫拉司亭、MYLOTARG™(吉妥单抗奥佐米星)、NEUPOGEN®(非格司亭)、OncoVAC-CL、OVAREX®(奥戈伏单抗(oregovomab))、pemtumomab(Y-muHMFG1)、PROVENGE®(sipuleucel-T)、sargaramostim、裂褶菌素、替西白介素、THERACYS®(卡介苗)、乌苯美司、VIRULIZIN®(免疫治疗,Lorus Pharmaceuticals)、Z-100(Specific Substance of Maruyama(SSM))、WF-10(四氯十氧化物(TCDO))、PROLEUKIN®(阿地白介素)、ZADAXIN®(胸腺法新)、ZENAPAX®(赛尼哌)、ZEVALIN®(90Y-替伊莫单抗)等。
生物反应改进剂是改变活生物体的防卫机制或生物反应,如组织细胞的存活、生长或分化以使它们具有抗肿瘤活性的试剂,并包括云芝多糖、香菇多糖、西佐糖、溶链菌、PF-3512676(CpG-8954)、乌苯美司等。
嘧啶类似物包括阿糖胞苷(ara C或阿拉伯糖苷C)、胞嘧啶阿拉伯糖苷、去氧氟尿苷、FLUDARA®(氟达拉滨)、5-FU(5-氟尿嘧啶)、氟尿苷、GEMZAR®(吉西他滨)、TOMUDEX®(雷替曲塞)、TROXATYL™(三乙酰基尿苷曲沙他滨)等。
嘌呤类似物包括LANVIS®(硫鸟嘌呤)和PURI-NETHOL®(巯基嘌呤)。
抗有丝分裂剂包括batabulin、埃博霉素D(KOS-862)、N-(2-((4-羟苯基)氨基)吡啶-3-基)-4-甲氧基苯磺酰胺、伊沙匹隆(BMS 247550)、紫杉醇、TAXOTERE®(多西他赛)、PNU100940(109881)、帕土匹龙、XRP-9881(larotaxel)、长春氟宁、ZK-EPO(合成埃博霉素)等。
泛素连接酶抑制剂包括MDM2抑制剂如nutlins、NEDD8抑制剂如MLN4924等。
本发明的组合物还可用作增强放射疗法的效力的放射致敏剂。放射疗法的实例包括外粒子束放射治疗、远距放射疗法、近距放射疗法、密封源放射疗法、非密封源放射疗法等。
另外,具有式(I)的化合物可以与以下的其它化疗剂结合,如ABRAXANE™(ABI-007)、ABT-100(法尼基转移酶抑制剂)、ADVEXIN®(Ad5CMV-p53疫苗)、ALTOCOR®或MEVACOR®(洛伐他汀)、AMPLIGEN®(聚I:聚C12U,合成RNA)、APTOSYN®(依昔舒林)、AREDIA®(帕米膦酸)、arglabin、L-天冬酰胺酶、阿他美坦(1-甲基-3,17-二酮-雄甾-1,4-二烯)、AVAGE®(他扎罗汀)、AVE-8062(combreastatin衍生物)、BEC2(米妥莫单抗)、恶病质素或cachexin(肿瘤坏死因子)、canvaxin(疫苗)、CEAVAC®(癌症疫苗)、CELEUK®(西莫白介素)、CEPLENE®(组胺二盐酸盐)、CERVARIX®(人乳头瘤病毒疫苗)、CHOP®(C: CYTOXAN®(环磷酰胺);H:ADRIAMYCIN®(羟基阿霉素);O: 长春新碱(ONCOVIN®);P: 强的松)、CYPAT™(醋酸环丙孕酮)、combrestatin A4P、DAB(389)EGF (经由His-Ala连接子融合到人表皮生长因子上的白喉毒素的催化和易位结构域)或TransMID-107R™(白喉毒素)、达卡巴嗪、放线菌素、5,6-二甲基氧杂蒽酮-4-乙酸(DMXAA)、恩尿嘧啶、EVIZON™(乳酸角鲨胺)、DIMERICINE®(T4N5脂质体乳液)、圆皮海绵内酯(discodermolide)、DX-8951f(依喜替康甲磺酸盐)、enzastaurin、EPO906(埃博霉素B)、GARDASIL®(四价人乳头瘤病毒(6、11、16、18型)重组疫苗)、GASTRIMMUNE®、GENASENSE®、GMK(神经节苷脂结合疫苗)、GVAX®(前列腺癌疫苗)、常山酮、组氨瑞林、羟基尿素、伊班膦酸、IGN-101、IL-13-PE38、IL-13-PE38QQR(cintredekinbesudotox)、IL-13-假单胞菌外毒素、干扰素-α、干扰素-γ、JUNOVAN™或MEPACT™(米伐木肽)、lonafarnib、5,10-亚甲基四氢叶酸、米替福新(十六烷基磷酸胆碱)、NEOVASTAT®(AE-941)、NEUTREXIN®(葡糖醛酸三甲曲沙)、NIPENT®(喷司他丁)、ONCONASE®(核糖核酸酶酶)、ONCOPHAGE®(黑素瘤疫苗治疗)、ONCOVAX®(IL-2疫苗)、ORATHECIN™(鲁比替康)、OSIDEM®(抗体基细胞药物)、OVAREX® MAb(鼠单克隆抗体)、紫杉醇、PANDIMEX™(包含20(S)-原人参二醇(aPPD)和20(S)-原人参三醇(aPPT)的来自人参的糖苷配基皂素)、帕尼单抗、PANVAC®-VF(研究中的癌症疫苗)、培门冬酶、PEG干扰素A、苯妥帝尔、丙卡巴肼、rebimastat、REMOVAB®(卡妥索单抗)、REVLIMID®(来那度胺)、RSR13(乙丙昔罗)、SOMATULINE® LA(兰瑞肽)、SORIATANE®(阿维A)、十字孢碱(链霉菌星状孢子)、talabostat (PT100)、TARGRETIN®(贝沙罗汀)、TAXOPREXIN®(DHA-紫杉醇)、TELCYTA®(canfosfamide、TLK286)、temilifene、TEMODAR®(替莫唑胺)、替米利芬、反应停、THERATOPE®(STn-KLH)、thymitaq(2-氨基-3,4-二氢-6-甲基-4-氧代-5-(4-吡啶基硫代)喹唑啉二盐酸盐)、TNFERADE™(腺病毒载体: 含有肿瘤坏死因子-α的基因的DNA载体)、TRACLEER®或ZAVESCA®(波生坦)、维甲酸(全反维生素A酸)、粉防己碱、TRISENOX®(三氧化二砷)、VIRULIZIN®、ukrain(来自白屈菜植物的生物碱衍生物)、vitaxin(抗-αvβ3抗体)、XCYTRIN®(莫特沙芬钆)、XINLAY™(阿曲生坦)、XYOTAX™(聚谷氨酸紫杉醇)、YONDELIS®(曲贝替定)、ZD-6126、ZINECARD®(右丙亚胺)、ZOMETA®(唑来膦酸)、佐柔比星等。
数据
使用时间分辨荧光共振能量转移(TR-FRET)结合试验进行选自本文实施例1-49的化合物及其药学上可接受的盐作为NAMPT的结合剂和抑制剂的效用的测定。
NAMPT的时间分辨荧光共振能量转移(TR-FRET)结合试验
在18 μL低体积板(Owens Corning)中在反应缓冲液(50 mM HEPES (NaOH), pH7.5, 100 mM NaCl, 10 mM MgCl2, 1 mM DTT, 1%甘油)中使用6.8 nM重组人C-末端-His标记NAMPT、1 nM Tb-抗-His抗体(Invitrogen, Cat # PV5895)和200 nM探针(OregonGreen 488-结合的APO866;A-1251667.0)进行试验。覆盖板,反应进行2-3小时。在2至3小时后用Envision(Laser Lantha low volume protocol)读取板。在337 nm下进行激发,测定Oregon Green(520 nm)与铽(492 nm)的发射比并用于计算受试化合物的IC50值。
表1显示选自本文实施例1-49的化合物或其药学上可接受的盐用于功能性抑制NAMPT的效用。
表1
抑制NAMPT的化合物可用于治疗其中涉及NF-KB活化的疾病。这种方法可用于治疗各种疾病,包括炎症和组织修复障碍;特别是类风湿性关节炎、炎性肠病、哮喘和COPD(慢性阻塞性肺病)、骨关节炎、骨质疏松症和纤维化疾病;皮肤病,包括牛皮癣、特应性皮炎和紫外线引起的皮肤损伤;自身免疫病,包括系统性红斑狼疮、多发性硬化、银屑病关节炎、关节强硬性脊椎炎、组织和器官排斥、阿尔茨海默氏症、中风、动脉粥样硬化、再狭窄、糖尿病、肾小球肾炎、癌症,其中该癌症特别选自乳腺癌、前列腺癌、肺癌、结肠癌、宫颈癌、卵巢癌、皮肤癌、CNS癌、膀胱癌、胰腺癌、白血病、淋巴瘤或霍奇金病、恶病质、与感染和某些病毒性感染,包括获得性免疫缺陷综合征(AIDS)相关的炎症、成人呼吸窘迫综合征和共济失调毛细血管扩张。
WO 97/48696中描述了NAMPT参与癌症的治疗。在WO 97/48397中描述了NAMPT参与免疫抑制。在WO 2003/80054中描述了NAMPT参与涉及血管生产的疾病的治疗。在WO 2008/025857中描述了NAMPT参与类风湿性关节炎和败血性休克的治疗。在WO 2009/109610中描述了NAMPT参与缺血的预防和治疗。
癌症包括,但不限于,血液肿瘤和实体瘤类型,如听神经瘤、急性白血病、急性淋巴细胞性白血病、急性髓细胞性白血病(单核细胞的、成髓细胞的、腺癌、血管肉瘤、星形细胞瘤、髓单核细胞和早幼粒细胞性)、急性t-细胞白血病、基底细胞癌、胆管癌、膀胱癌、脑癌、乳腺癌(包括雌激素受体阳性乳腺癌)、支气管癌、伯基特氏淋巴瘤、宫颈癌、软骨肉瘤、脊索瘤、绒毛膜癌、慢性白血病、慢性淋巴细胞白血病、慢性髓细胞性(粒细胞)白血病、慢性骨髓性白血病、结肠癌、结肠直肠癌、颅咽管瘤、囊腺癌、不良增生性变化(dysproliferativechanges)(发育不良和化生)、胚胎癌、子宫内膜癌、内皮肉瘤、室管膜瘤、上皮癌、红白血病、食管癌、雌激素受体阳性乳腺癌、原发性血小板增多症、尤因氏瘤、纤维肉瘤、胃癌、生殖细胞睾丸癌、妊娠滋养细胞疾病、胶质母细胞瘤、头颈癌、重链病、血管母细胞瘤、肝癌、肝细胞癌、激素不敏感的前列腺癌、平滑肌肉瘤、脂肪肉瘤、肺癌(包括小细胞肺癌和非小细胞肺癌)、淋巴内皮肉瘤(lymphagioendothelio-sarcoma)、淋巴管肉瘤、淋巴细胞白血病、淋巴瘤(淋巴瘤,包括弥漫性大B-细胞淋巴瘤、滤泡性淋巴瘤、霍奇金淋巴瘤和非霍奇金淋巴瘤)、膀胱、乳腺、结肠、肺、卵巢、胰腺、前列腺癌、皮肤和子宫的恶性肿瘤和过度增生障碍、T-细胞或B-细胞来源的淋巴恶性肿瘤、白血病、髓样癌、髓母细胞瘤、黑色素瘤、脑膜瘤、间皮瘤、多发性骨髓瘤、骨髓性白血病、骨髓瘤、粘液肉瘤、神经母细胞瘤、少突神经胶质瘤、口腔癌、骨原性肉瘤、卵巢癌、胰腺癌、乳头状腺癌、乳头状癌、外周T-细胞淋巴瘤、松果体瘤、真性红细胞增多症、前列腺癌(包括激素不敏感的(难治性)前列腺癌)、直肠癌、肾细胞癌、成视网膜细胞瘤、横纹肌肉瘤、肉瘤、皮脂腺癌、精原细胞瘤、皮肤癌、小细胞肺癌、实体瘤(癌和肉瘤)、胃癌、鳞状细胞癌、滑膜瘤、汗腺瘤、睾丸癌(包括生殖细胞睾丸癌)、甲状腺癌、原发性巨球蛋白血症(Waldenström’s macroglobulinemia)、睾丸肿瘤、子宫癌症和肾母细胞瘤等。
方案和实验
下列缩写具有所示含义。ADDP是指1,1'-(偶氮二羰基)二哌啶;AD-mix-β是指(DHQD)2PHAL、K3Fe(CN)6、K2CO3和K2SO4的混合物;9-BBN是指9-硼双环(3.3.1)壬烷;Boc是指叔丁氧基羰基;(DHQD)2PHAL是指氢化奎尼丁1,4-酞嗪二基二乙醚;DBU是指1,8-二氮杂双环[5.4.0]十一-7-烯;DIBAL是指二异丁基氢化铝;DIEA是指二异丙基乙胺;DMAP是指N,N-二甲基氨基吡啶;DMF是指N,N-二甲基甲酰胺;dmpe是指1,2-双(二甲基膦基)乙烷;DMSO是指二甲亚砜;dppb是指1,4-双(二苯基膦基)-丁烷;dppe是指1,2-双(二苯基膦基)乙烷;dppf是指1,1'-双(二苯基膦基)二茂铁;dppm是指1,1-双(二苯基膦基)甲烷;EDAC·HCl是指1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐;Fmoc是指芴基甲氧基羰基;HATU是指O-(7-氮杂苯并三唑-1-基)-N,N'N'N'-四甲基六氟磷酸脲鎓;HMPA是指六甲基磷酰胺;IPA是指异丙醇;MP-BH3是指大孔甲基聚苯乙烯氰基硼氢化三乙基铵;TEA是指三乙胺;TFA是指三氟乙酸;THF是指四氢呋喃;NCS是指N-氯代琥珀酰亚胺;NMM是指N-甲基吗啉;NMP是指N-甲基吡咯烷;PPh3是指三苯基膦。
给出下列方案以提供据信是本发明的步骤和概念方面的最有用和容易理解的描述。本发明的化合物可通过合成化学法制备,其实例显示在本文中。要理解的是,这些方法中的步骤的次序可变,试剂、溶剂和反应条件可以用具体提到的那些替换,易变部分可以按需要保护和脱保护。
方案
方案1
如方案1所示,能使异吲哚与其中X1和X2为CH或N的式(1)的化合物反应以提供式(2)的化合物。通常在例如但不限于四氢呋喃的溶剂中进行反应。通常在低温下添加式(2)的化合物,随后在室温下搅拌。能通过使式(2)的化合物与氢氧化锂水溶液反应制备式(3)的化合物。通常在例如但不限于四氢呋喃、甲醇或其混合物的溶剂中进行反应。能使用本领域技术人员已知和文献中容易获得的偶联条件使式(3)的化合物与式(3A)的胺反应,其中各个R5在本文的实施例1-49中描述以提供式(4)的化合物,其代表本发明的化合物。
实验
提出下列方案以提供认为是最有用和容易理解的本发明的步骤和概念方面的描述。使用ACD/ChemSketch版本12.01 (2009年5月13日),Advanced Chemistry DevelopmentInc., Toronto, Ontario)或ChemDraw® Ver. 9.0.5 (CambridgeSoft, Cambridge, MA)命名示例性化合物。使用ChemDraw® Ver. 9.0.5 (CambridgeSoft, Cambridge, MA)命名中间体。
实施例1
N-(4-{[2-(氮杂环庚烷-1-基)乙基]氨基甲酰基}苯基)-1,3-二氢-2H-异吲哚-2-甲酰胺
实施例1A
4-异氰酸基苯甲酸乙酯
在0℃下,向化合物4-氨基苯甲酸乙酯 (20 g, 121 mmol)和三乙胺 (14.6 g,145 mmol)的无水甲苯 (1.5 L)溶液缓慢添加三光气 (36 g, 121 mmol)的无水甲苯 (0.2L)溶液。将反应混合物在室温下搅拌2小时并在90℃下搅拌4 hrs。在反应完成后,将另外的甲苯 (500 mL)和水 (500 mL)加入至混合物。在Na2SO4上干燥有机层,过滤并在减压下浓缩以提供标题化合物。
实施例1B
4-(异吲哚啉-2-甲酰胺基)苯甲酸乙酯
在0℃下搅拌化合物4-异氰酸基苯甲酸乙酯 (24 g, 126 mmol)的四氢呋喃 (600mL)溶液。然后,添加异吲哚 (16.5 g, 138 mmol)的四氢呋喃 (100 mL)。将反应在室温下搅拌过夜。在去除溶剂后,使用乙酸乙酯洗涤固体以提供白色固体形式的标题化合物。
实施例1C
4-(异吲哚啉-2-甲酰胺基)苯甲酸
将化合物4-(异吲哚啉-2-甲酰胺基)苯甲酸乙酯 (29 g, 94 mmol)溶于乙醇/四氢呋喃 (1:1, 460 mL)并添加LiOH水溶液 (2 mol/L, 230 mL)。将混合物在80℃下加热2小时。在去除溶剂后,通过添加1 N HCl将溶液调整至pH=3并过滤。使用水洗涤固体并干燥以提供标题化合物。
实施例1D
N-(4-{[2-(氮杂环庚烷-1-基)乙基]氨基甲酰基}苯基)-1,3-二氢-2H-异吲哚-2-甲酰胺
将4-(异吲哚啉-2-甲酰胺基)苯甲酸 (100 mg, 0.35 mmol)、1-乙基-3-[3-(二甲基氨基)丙基]-碳二亚胺盐酸盐 (82 mg, 0.43 mmol)、1-羟基苯并三唑水合物 (48 mg,0.35 mmol)和三乙胺 (107 mg, 1.06 mmol)的二氯甲烷 (2 mL)溶液在室温下搅拌30分钟。然后,添加2-(氮杂环庚烷-1-基)乙胺 (61 mg, 0.43 mmol)。将混合物在室温下搅拌过夜。在减压下去除溶剂以提供剩余物,通过制备-HPLC将其纯化以提供标题化合物。
表1.
基本上按照实施例1中的描述,替换实施例1D中合适的胺,制备下列实施例。通过反相HPLC纯化产物,并相应地分离为三氟乙酸盐。
实施例8
N-[6-(2-氧杂-7-氮杂螺[3.5]壬-7-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺
实施例8A
6-氨基哒嗪-3-甲酸甲酯
向6-氯哒嗪-3-胺 (32 g, 248 mmol)和三乙胺 (75 mL, 744 mmol)的甲醇 (500mL)溶液添加[1,1’-双(二苯基膦基)二茂铁]二氯化钯 (II)二氯甲烷 (12 g, 16.4 mmol)并在50 psi的CO环境下将混合物在60℃下加热过夜。在冷却至室温后,将反应混合物过滤并将滤液在减压下浓缩。使用甲醇洗涤剩余物并在高真空下干燥沉淀物以提供固体形式的标题化合物。
实施例8B
6-异氰酸基哒嗪-3-甲酸甲酯
向6-氨基哒嗪-3-甲酸甲酯 (14 g, 91.5 mmol)的无水甲苯 (700 mL)溶液添加三乙胺 (11.1, 109.8 mmol)。在0℃下缓慢添加三光气 (27.2 g, 91.5 mmol)的无水甲苯溶液。将反应混合物在室温下搅拌2小时然后在90℃下加热5小时。在冷却至室温后,将甲苯和水添加至混合物,将混合物分离并在无水Na2SO4上干燥有机层,过滤并在减压下浓缩以提供标题化合物。
实施例8C
6-(异吲哚啉-2-甲酰胺基)哒嗪-3-甲酸甲酯
在0℃下,向6-异氰酸基哒嗪-3-甲酸甲酯 (5.26 g, 29.4 mmol)的四氢呋喃(100 mL)溶液添加异吲哚啉 (5.24 g, 4.41 mmol)的四氢呋喃 (50 mL)溶液。将反应混合物在室温下搅拌过夜。将反应混合物过滤并使用冷乙酸乙酯洗涤沉淀物并在高真空下干燥以提供标题化合物。
实施例8D
6-(异吲哚啉-2-甲酰胺基)哒嗪-3-甲酸
在室温下,向6-(异吲哚啉-2-甲酰胺基)哒嗪-3-甲酸甲酯 (3.7 g, 12.4 mmol)的甲醇 (40 mL)和四氢呋喃 (40 mL)溶液添加LiOH (0.7 g, 29.2 mmol)的水 (10 mL)溶液。将反应混合物在室温下搅拌过夜。将反应混合物倾入水 (100 mL)中,使用乙酸乙酯(2× 50 mL)萃取并通过添加2 N HCl水溶液将水层酸化至pH 3以提供沉淀物。使用水洗涤沉淀物并在高真空下干燥以提供标题化合物。
实施例8E
N-[6-(2-氧杂-7-氮杂螺[3.5]壬-7-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺
向6-(异吲哚啉-2-甲酰胺基)哒嗪-3-甲酸 (50 mg, 0.176 mmol)和O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓六氟磷酸盐 (100 mg, 0.264 mmol)的N,N-二甲基甲酰胺 (2 mL)溶液添加二异丙基乙胺 (0.046 mL, 0.264 mmol)和2-氧杂-7-氮杂螺[3.5]壬烷 (25 mg, 0.193 mmol)。将混合物在室温下搅拌过夜。然后,使用水 (10 mL)稀释混合物。使用乙酸乙酯 (3 × 20 mL)萃取水相。使用盐水 (3×10 mL)洗涤合并的有机相,在Na2SO4上干燥,过滤并在减压下浓缩以在层析后产生标题化合物。
表2.
基本上按照实施例1的描述,替换实施例2E中合适的胺,制备下列实施例。通过快速层析纯化一些产物,通过反相HPLC纯化其他产物;在如实施例2D中的酰胺偶联后,一些化合物还需要Boc-脱保护。因此,将一些实施例分离为三氟乙酸盐。
Claims (14)
1.化合物,其选自:
N-(4-{[2-(氮杂环庚烷-1-基)乙基]氨基甲酰基}苯基)-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{4-[(2-羟基丙基)氨基甲酰基]苯基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-(4-{[2-(2-氧代咪唑烷-1-基)乙基]氨基甲酰基}苯基)-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-(4-{[2-(四氢-2H-吡喃-2-基)乙基]氨基甲酰基}苯基)-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-(4-{[(2-甲基四氢呋喃-2-基)甲基]氨基甲酰基}苯基)-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{4-[(1-氧杂-8-氮杂螺[4.5]癸-3-基甲基)氨基甲酰基]苯基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2-氧杂-7-氮杂螺[3.5]壬-7-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(六氢呋喃并[3,2-c]吡啶-5(4H)-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(六氢-5H-呋喃并[2,3-c]吡咯-5-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2,6-二氧杂-9-氮杂螺[4.5]癸-9-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2-氧杂-6-氮杂螺[3.3]庚-6-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2-氧杂-6-氮杂螺[3.5]壬-6-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2-氧杂-7-氮杂螺[4.4]壬-7-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(10,10-二氟-2,7-二氮杂螺[4.5]癸-2-基)羰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(3-氰基-1-氧杂-8-氮杂螺[4.5]癸-8-基)羰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(7-氧杂-2-氮杂螺[3.5]壬-2-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(1-氧杂-7-氮杂螺[4.4]壬-7-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(10-氟-2,7-二氮杂螺[4.5]癸-2-基)羰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(3,9-二氮杂螺[5.5]十一炕-3-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2,7-二氮杂螺[4.5]癸-7-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2,8-二氮杂螺[4.5]癸-8-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(7-氮杂螺[3.5]壬-1-基氨基甲酰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2-氮杂螺[3.3]庚-5-基氨基甲酰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(1R,5S)-3-氮杂双环[3.1.0]己-6-基氨基甲酰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-(6-{[(7R)-八氢吡咯并[1,2-a]吡嗪-7-基甲基]氨基甲酰基}哒嗪-3-基)-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2,6-二氮杂螺[3.5]壬-2-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2,7-二氮杂螺[3.5]壬-2-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2,6-二氮杂螺[3.4]辛-6-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(2-氧杂-9-氮杂螺[5.5]十一烷-3-基甲基)氨基甲酰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(1-氧杂-8-氮杂螺[4.5]癸-2-基甲基)氨基甲酰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(1-氧杂-8-氮杂螺[4.5]癸-3-基甲基)氨基甲酰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2,7-二氮杂螺[3.5]壬-7-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2,8-二氮杂螺[4.5]癸-2-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-(6-{[3-(氮杂环丁烷-3-基)吡咯烷-1-基]羰基}哒嗪-3-基)-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-2-基甲基)氨基甲酰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(1-氧杂-8-氮杂螺[4.5]癸-3-基氨基甲酰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(6,7,8,9-四氢-5H-[1,2,4]三唑并[4,3-a][1,4]二氮杂环庚三烯-3-基甲基)氨基甲酰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(6-氮杂螺[2.5]辛-1-基甲基)氨基甲酰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(5-氧杂-2-氮杂螺[3.4]辛-2-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(5,6,7,8-四氢[1,2,4]三唑并[4,3-a]吡嗪-3-基甲基)氨基甲酰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-(6-{[(4-氟哌啶-4-基)甲基]氨基甲酰基}哒嗪-3-基)-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(2,6-二氮杂螺[3.3]庚-2-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(6-氧杂-2-氮杂螺[3.4]辛-7-基甲基)氨基甲酰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-[6-(5-氧杂-2-氮杂螺[3.5]壬-2-基羰基)哒嗪-3-基]-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-(6-{[1-(三氟甲基)-2,8-二氮杂螺[4.5]癸-2-基]羰基}哒嗪-3-基)-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(7-氮杂螺[3.5]壬-2-基甲基)氨基甲酰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;
N-{6-[(5,6,7,8-四氢-4H-[1,2,3]三唑并[1,5-a][1,4]二氮杂环庚三烯-3-基甲基)氨基甲酰基]哒嗪-3-基}-1,3-二氢-2H-异吲哚-2-甲酰胺;及其药学上可接受的盐。
2.组合物,其包含赋形剂和治疗有效量的权利要求1的化合物或其药学上可接受的盐。
3.权利要求1的化合物或其药学上可接受的盐在制备药物中的用途,所述药物用于治疗患者的期间表达NAMPT的炎症和组织修复障碍,皮肤病,自身免疫病,阿尔茨海默氏症,中风,动脉粥样硬化,再狭窄,糖尿病,肾小球肾炎,癌症,恶病质,与感染和某些病毒性感染相关的炎症,成人呼吸窘迫综合征和共济失调毛细血管扩张。
4.权利要求1的化合物或其药学上可接受的盐在制备药物中的用途,所述药物用于治疗患者的期间表达NAMPT的类风湿性关节炎、炎性肠病、哮喘和COPD(慢性阻塞性肺病)、骨关节炎、骨质疏松症和纤维化疾病。
5.权利要求1的化合物或其药学上可接受的盐在制备药物中的用途,所述药物用于治疗患者的期间表达NAMPT的牛皮癣、特应性皮炎和紫外线引起的皮肤损伤。
6.权利要求1的化合物或其药学上可接受的盐在制备药物中的用途,所述药物用于治疗患者的期间表达NAMPT的系统性红斑狼疮、多发性硬化、银屑病关节炎、关节强硬性脊椎炎、组织和器官排斥。
7.权利要求1的化合物或其药学上可接受的盐在制备药物中的用途,所述药物用于治疗患者的期间表达NAMPT的乳腺癌、前列腺癌、肺癌、结肠癌、宫颈癌、卵巢癌、皮肤癌、CNS癌、膀胱癌、胰腺癌、白血病、淋巴瘤或霍奇金病。
8.权利要求1的化合物或其药学上可接受的盐在制备药物中的用途,所述药物用于治疗患者的期间表达NAMPT的与获得性免疫缺陷综合征(AIDS)相关的炎症。
9.权利要求1的化合物或其药学上可接受的盐和一种附加治疗剂或多于一种附加治疗剂在制备药物中的用途,所述药物用于治疗患者的期间表达NAMPT的炎症和组织修复障碍,皮肤病,自身免疫病,阿尔茨海默氏症,中风,动脉粥样硬化,再狭窄,糖尿病,肾小球肾炎,癌症,恶病质,与感染和某些病毒性感染相关的炎症,成人呼吸窘迫综合征和共济失调毛细血管扩张。
10.权利要求1的化合物或其药学上可接受的盐和一种附加治疗剂或多于一种附加治疗剂在制备药物中的用途,所述药物用于治疗患者的期间表达NAMPT的类风湿性关节炎、炎性肠病、哮喘和COPD(慢性阻塞性肺病)、骨关节炎、骨质疏松症和纤维化疾病。
11.权利要求1的化合物或其药学上可接受的盐和一种附加治疗剂或多于一种附加治疗剂在制备药物中的用途,所述药物用于治疗患者的期间表达NAMPT的牛皮癣、特应性皮炎和紫外线引起的皮肤损伤。
12.权利要求1的化合物或其药学上可接受的盐和一种附加治疗剂或多于一种附加治疗剂在制备药物中的用途,所述药物用于治疗患者的期间表达NAMPT的系统性红斑狼疮、多发性硬化、银屑病关节炎、关节强硬性脊椎炎、组织和器官排斥。
13.权利要求1的化合物或其药学上可接受的盐和一种附加治疗剂或多于一种附加治疗剂在制备药物中的用途,所述药物用于治疗患者的期间表达NAMPT的乳腺癌、前列腺癌、肺癌、结肠癌、宫颈癌、卵巢癌、皮肤癌、CNS癌、膀胱癌、胰腺癌、脾癌、白血病、淋巴瘤或霍奇金病。
14.权利要求1的化合物或其药学上可接受的盐和一种附加治疗剂或多于一种附加治疗剂在制备药物中的用途,所述药物用于治疗患者的期间表达NAMPT的与获得性免疫缺陷综合征(AIDS)相关的炎症。
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