CN114846012A - 可用作hdac6抑制剂的2-异吲哚-1,3,4-噁二唑衍生物 - Google Patents
可用作hdac6抑制剂的2-异吲哚-1,3,4-噁二唑衍生物 Download PDFInfo
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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Abstract
本发明提供一种具有HDAC6抑制作用的杂环化合物和包含所述化合物的药物,所述杂环化合物可用于治疗包括神经变性疾病等的中枢神经系统疾病。本发明涉及一种由式(I)表示的化合物或其盐:其中每个符号如本说明书中所定义。
Description
技术领域
本发明涉及一种具有组蛋白脱乙酰酶(下文中有时称为“HDAC”)抑制活性、优选II类HDAC抑制活性、更优选HDAC6抑制活性的杂环化合物和包含所述化合物的药物等,所述杂环化合物可以用于治疗包括神经变性疾病(阿尔茨海默病、进行性核上性麻痹等)等的中枢神经系统疾病。
背景技术
已知神经轴突在营养因子、神经递质、细胞器等在神经细胞中的运输中起着重要作用,并且在各种神经变性疾病中观察到轴突功能障碍、轴突变性和轴突结合蛋白tau的细胞内积累(非专利文件1和非专利文件2)。以细胞内tau积累为特征的疾病在病理上统称为tau蛋白病(tauopathy),并且它们包括阿尔茨海默病、进行性核上性麻痹等(非专利文件3)。HDAC6是在轴突组分微管蛋白的脱乙酰化中起作用的酶(非专利文件4),并且已知含有乙酰化微管蛋白的微管有助于稳定性(非专利文件5)。另外,据报道,具有HDAC6抑制活性的Tubastatin A在tau蛋白病小鼠模型中增加微管蛋白的乙酰化,并且示出治疗有效性(非专利文件6)。因此,上述报道表明,HDAC6抑制剂可能经由轴突的稳定作用成为阿尔茨海默病和进行性核上性麻痹的治疗药物。
作为杂环化合物,例如已知以下化合物。
(1)专利文件1披露了由下式表示的化合物:
其中每个符号如文件中所定义,其为HDAC抑制剂,并且有效治疗自身免疫病、炎性疾病、代谢性/骨关节退行性疾病、神经变性疾病/中枢性疾病(例如,精神分裂症、阿尔茨海默病(阿尔茨海默型痴呆)、帕金森病、亨廷顿病、鲁宾斯坦-泰比综合征、肌营养不良、雷特综合征、腓骨肌萎缩症、抑郁症)、赘生性疾病等。
(2)专利文件2披露了由下式表示的化合物:
其中每个符号如文件中所定义,其为HDAC抑制剂,并且有效治疗自身免疫病、炎性疾病、代谢性/骨关节退行性疾病、神经变性疾病/中枢性疾病(例如,精神分裂症、阿尔茨海默病(阿尔茨海默型痴呆)、帕金森病、亨廷顿病、鲁宾斯坦-泰比综合征、肌营养不良、雷特综合征、腓骨肌萎缩症、抑郁症)、赘生性疾病等。
(3)专利文件3披露了由下式表示的化合物:
其中每个符号如文件中所定义,其为HDAC抑制剂,并且有效治疗自身免疫病、炎性疾病、代谢性/骨关节退行性疾病、神经变性疾病/中枢性疾病(例如,精神分裂症、阿尔茨海默病(阿尔茨海默型痴呆)、帕金森病、亨廷顿病、鲁宾斯坦-泰比综合征、肌营养不良、雷特综合征、腓骨肌萎缩症、抑郁症)、赘生性疾病等。
(4)专利文件4披露了由下式表示的化合物:
其中每个符号如文件中所定义,其为HDAC抑制剂,并且有效治疗自身免疫病、炎性疾病、代谢性/骨关节退行性疾病、神经变性疾病/中枢性疾病(例如,精神分裂症、阿尔茨海默病(阿尔茨海默型痴呆)、帕金森病、亨廷顿病、鲁宾斯坦-泰比综合征、肌营养不良、雷特综合征、腓骨肌萎缩症、抑郁症)、赘生性疾病等。
(5)专利文件5披露了由下式表示的化合物:
其中每个符号如文件中所定义,其为HDAC抑制剂,并且有效治疗自身免疫病、炎性疾病、代谢性/骨关节退行性疾病、神经变性疾病/中枢性疾病(例如,精神分裂症、阿尔茨海默病(阿尔茨海默型痴呆)、帕金森病、亨廷顿病、鲁宾斯坦-泰比综合征、肌营养不良、雷特综合征、腓骨肌萎缩症、抑郁症)、赘生性疾病等。
(6)专利文件6披露了由下式表示的化合物:
其中每个符号如文件中所定义,其为HDAC6抑制剂,并且有效用于治疗HDAC6介导的疾病(例如,感染、肿瘤、内分泌/营养/代谢疾病、精神和行为障碍、神经系统疾病、眼睛和附属器的疾病、心血管疾病、呼吸系统疾病、消化系统疾病、皮肤和皮下组织疾病、肌肉骨骼系统和结缔组织疾病或先天性畸形、变形和染色体异常)。
(7)专利文件7披露了由下式表示的化合物:
其中每个符号如文件中所定义,其为HDAC6抑制剂,并且有效用于治疗HDAC6介导的疾病(例如,感染、肿瘤、内分泌/营养/代谢疾病、精神和行为障碍、神经系统疾病、眼睛和附属器的疾病、心血管疾病、呼吸系统疾病、消化系统疾病、皮肤和皮下组织疾病、肌肉骨骼系统和结缔组织疾病或先天性畸形、变形和染色体异常)。
(8)专利文件8披露了由下式表示的化合物:
其中每个符号如文件中所定义,其为HDAC6抑制剂,并且有效用于治疗HDAC6介导的疾病(例如,感染、肿瘤、内分泌/营养/代谢疾病、精神和行为障碍、神经系统疾病、眼睛和附属器的疾病、心血管疾病、呼吸系统疾病、消化系统疾病、皮肤和皮下组织疾病、肌肉骨骼系统和结缔组织疾病或先天性畸形、变形和染色体异常)。
(9)专利文件9披露了由下式表示的化合物:
其中每个符号如文件中所定义,其为HDAC6抑制剂,并且有效用于治疗HDAC6介导的疾病(例如,感染、肿瘤、内分泌/营养/代谢疾病、精神和行为障碍、神经系统疾病、眼睛和附属器的疾病、心血管疾病、呼吸系统疾病、消化系统疾病、皮肤和皮下组织疾病、肌肉骨骼系统和结缔组织疾病或先天性畸形、变形和染色体异常)。
(10)专利文件10披露了由下式表示的化合物:
其中每个符号如文件中所定义,其为HDAC抑制剂,并且有效治疗癫痫、注意缺陷障碍、抑郁症、焦虑、阿尔茨海默病、帕金森病、亨廷顿病等。
(11)专利文件11披露了由下式表示的化合物:
其中每个符号如文件中所定义,其为HDAC抑制剂,并且有效治疗感染性疾病、肿瘤、内分泌疾病、营养和代谢疾病等。
(12)专利文件12披露了由下式表示的化合物:
其中每个符号如文件中所定义,其为HDAC抑制剂,并且有效治疗自身免疫病、炎性疾病、代谢性/骨关节退行性疾病、神经变性疾病/中枢性疾病(例如,精神分裂症、阿尔茨海默病(阿尔茨海默型痴呆)、帕金森病、亨廷顿病、鲁宾斯坦-泰比综合征、肌营养不良、雷特综合征、腓骨肌萎缩症、抑郁症)、赘生性疾病等。
文件列表
专利文件
专利文件1:WO 2016/031815
专利文件2:WO 2017/014321
专利文件3:WO 2017/014170
专利文件4:WO 2017/033946
专利文件5:WO 2019/027054
专利文件6:WO 2017/018803
专利文件7:WO 2017/018804
专利文件8:WO 2017/018805
专利文件9:WO 2017/023133
专利文件10:WO 2018/165520
专利文件11:WO 2020/022794
专利文件12:WO 2020/158762
非专利文件
非专利文件1:Front Cell Neurosci.9,343,(2015)。
非专利文件2:Neuromolecular Med.2:89-99,(2002)。
非专利文件3:Cold Spring Harb Perspect Med.2:a006254(2012)。
非专利文件4:Nature.417:455-458,(2002)。
非专利文件5:Proc Natl Acad Sci U S A.107:21238-21239,(2010)。
非专利文件6:Alzheimers Res Ther.6:12,(2014)。
发明内容
本发明要解决的问题
本发明旨在提供一种具有HDAC抑制作用的杂环化合物和包含所述化合物的药物,所述杂环化合物可用于治疗包括神经变性疾病(阿尔茨海默病、进行性核上性麻痹等)等的中枢神经系统疾病。
解决问题的手段
诸位发明人已经进行了深入研究以解决上述问题,并且发现由下式(I)表示的化合物具有优异的HDAC抑制作用,并且基于这些发现完成本发明。
因此,本发明提供以下内容。
[1]一种由式(I)表示的化合物:
其中
R1为任选经取代的环状基团,并且
R2为任选经取代的环状基团,
或其盐(下文中有时称为“化合物(I)”)。
[2]根据上述[1]所述的化合物或盐,其由式(I')表示:
其中每个符号如上述[1]中所定义。
[3]根据上述[1]所述的化合物或盐,其中
R1为
(1)C3-10环烷基,其任选地经1至3个卤原子取代,
(2)C6-14芳基,其任选地经1至3个选自以下的取代基取代:(i)卤原子,(ii)氰基,和(iii)任选地经1至3个卤原子取代的C1-6烷基,
(3)5或6元单环芳族杂环基团,其任选地经1至3个选自以下的取代基取代:(i)卤原子,(ii)任选地经1至3个卤原子取代的C1-6烷基,和(iii)C1-6烷氧基,或
(4)3至8元单环非芳族杂环基团,并且
R2为
(1)C3-10环烷基,其任选地经1至3个卤原子取代,
(2)C6-14芳基,其任选地经1至3个选自以下的取代基取代:(i)卤原子,和(ii)任选地经1至3个卤原子取代的C1-6烷基,
(3)5或6元单环芳族杂环基团,其任选地经1至3个选自以下的取代基取代:(i)卤原子,(ii)任选地经1至3个卤原子取代的C1-6烷基,和(iii)C1-6烷氧基,或
(4)3至8元单环非芳族杂环基团。
[4]根据上述[1]所述的化合物或盐,其中
R1为
(1)C3-10环烷基,其任选地经1至3个卤原子取代,或
(2)5或6元单环芳族杂环基团,其任选地经1至3个选自以下的取代基取代:(i)卤原子,(ii)任选地经1至3个卤原子取代的C1-6烷基,和(iii)C1-6烷氧基,并且
R2为
(1)C6-14芳基,其任选地经1至3个选自以下的取代基取代:(i)卤原子,和(ii)任选地经1至3个卤原子取代的C1-6烷基,或
(2)5或6元单环芳族杂环基团,其任选地经1至3个选自以下的取代基取代:(i)卤原子,(ii)任选地经1至3个卤原子取代的C1-6烷基,和(iii)C1-6烷氧基。
[5]根据上述[1]所述的化合物或盐,其中
R1为
(1)C3-10环烷基,或
(2)6元单环芳族杂环基团,其任选地经1至3个卤原子取代,并且
R2为
(1)C6-14芳基,其任选地经1至3个卤原子取代,或
(2)6元单环芳族杂环基团,其任选地经1至3个卤原子取代。
[6]6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2-[(1R,2R)-2-羟基-1,2-二(吡啶-2-基)乙基]-2,3-二氢-1H-异吲哚-1-酮或其盐。
[7]6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2-[(1R,2R)-2-(5-氟吡啶-2-基)-2-羟基-1-(吡啶-2-基)乙基]-2,3-二氢-1H-异吲哚-1-酮或其盐。
[8]2-[(1R,2R)-1,2-双(5-氟吡啶-2-基)-2-羟基乙基]-6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2,3-二氢-1H-异吲哚-1-酮或其盐。
[9]一种药物,其包含根据上述[1]所述的化合物或盐。
[10]根据上述[9]所述的药物,其是组蛋白脱乙酰酶6抑制剂。
[11]根据上述[9]所述的药物,其是用于预防或治疗阿尔茨海默病或进行性核上性麻痹的药剂。
[12]根据上述[1]所述的化合物或盐,其用于预防或治疗阿尔茨海默病或进行性核上性麻痹。
[13]一种抑制哺乳动物中的组蛋白脱乙酰酶6的方法,所述方法包括向所述哺乳动物施用有效量的根据上述[1]所述的化合物或盐。
[14]一种用于预防或治疗哺乳动物中的阿尔茨海默病或进行性核上性麻痹的方法,所述方法包括向所述哺乳动物施用有效量的根据上述[1]所述的化合物或盐。
[15]一种根据上述[1]所述的化合物或盐用于产生用于预防或治疗阿尔茨海默病或进行性核上性麻痹的药剂的用途。
发明效果
化合物(I)具有HDAC6抑制活性,并且可以用于治疗包括神经变性疾病(阿尔茨海默病、进行性核上性麻痹等)等的中枢神经系统疾病。
附图说明
[图1]图1是示出由实施例1的化合物引起的小鼠脑中的乙酰化微管蛋白的增加的图。纵轴是相对微管蛋白乙酰化水平,并且横轴是剂量(mg/kg)。
[图2]图2是示出由实施例3的化合物引起的小鼠脑中的乙酰化微管蛋白的增加的图。纵轴是相对微管蛋白乙酰化水平,并且横轴是剂量(mg/kg)。
[图3]图3是示出由实施例5的化合物引起的小鼠脑中的乙酰化微管蛋白的增加的图。纵轴是相对微管蛋白乙酰化水平,并且横轴是剂量(mg/kg)。
[图4]图4是示出由实施例1的化合物引起的小鼠中的认知改善作用的图。纵轴是新物鉴别的相对探索时间(%),并且横轴是剂量(mg/kg)。
[图5]图5是示出由实施例3的化合物引起的小鼠中的认知改善作用的图。纵轴是新物鉴别相对探索时间(%),并且横轴是剂量(mg/kg)。
具体实施方式
下面详细解释本发明。
解释了式(I)中使用的每个符号的定义。
R1和R2相同或不同,并且各自为任选经取代的环状基团。“任选经取代的环状基团”中的“环状基团”的例子包括烃环基团和杂环基团。
“烃环基团”的例子包括C3-10环烷基(例如,环丙基、环丁基、环戊基、环己基、环庚基、环辛基、双环[2.2.1]庚基、双环[2.2.2]辛基、双环[3.2.1]辛基、金刚烷基等)、C3-10环烯基(例如,环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、环辛烯基)、C6-14芳基(例如,苯基、1-萘基、2-萘基、1-蒽基、2-蒽基、9-蒽基)等。
“杂环基团”的例子包括(i)芳族杂环基团、(ii)非芳族杂环基团和(iii)7至10元桥接杂环基团,各自除了碳原子以外还含有1至4个选自氮原子、硫原子和氧原子的杂原子作为环构成原子。
“芳族杂环基团”的例子包括除了碳原子以外还含有1至4个选自氮原子、硫原子和氧原子的杂原子作为环构成原子的5至14元(优选5至10元)芳族杂环基团。
“芳族杂环基团”的优选例子包括:5或6元单环芳族杂环基团,如噻吩基、呋喃基、吡咯基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、1,2,4-噁二唑基、1,3,4-噁二唑基、1,2,4-噻二唑基、1,3,4-噻二唑基、三唑基、四唑基、三嗪基等;以及
8至14元稠合多环(优选双环或三环)芳族杂环基团,如苯并苯硫基、苯并呋喃基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、苯并三唑基、咪唑并吡啶基、噻吩并吡啶基、呋喃并吡啶基、吡咯并吡啶基、吡唑并吡啶基、噁唑并吡啶基、噻唑并吡啶基、咪唑并吡嗪基、咪唑并嘧啶基、噻吩并嘧啶基、呋喃并嘧啶基、吡咯并嘧啶基、吡唑并嘧啶基、噁唑并嘧啶基、噻唑并嘧啶基、吡唑并三嗪基、萘并[2,3-b]噻吩基、吩噁噻基(phenoxathiinyl)、吲哚基、异吲哚基、1H-吲唑基、嘌呤基、异喹啉基、喹啉基、酞嗪基、萘啶基、喹喔啉基、喹唑啉基、噌啉基、咔唑基、β-咔啉基、菲啶基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基等。
“非芳族杂环基团”的例子包括3至14元(优选4至10元)非芳族杂环基团,其除了碳原子以外还含有1至4个选自氮原子、硫原子和氧原子的杂原子作为环构成原子。
“非芳族杂环基团”的优选例子包括3至8元单环非芳族杂环基团,如氮丙啶基、氧杂环丙烷基、噻丙环基(thiiranyl)、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、四氢噻吩基、四氢呋喃基、吡咯啉基、吡咯烷基、咪唑啉基、咪唑烷基、噁唑啉基、噁唑烷基、吡唑啉基、吡唑烷基、噻唑啉基、噻唑烷基、四氢异噻唑基、四氢噁唑基、四氢异噁唑基、哌啶基、哌嗪基、四氢吡啶基、二氢吡啶基、二氢硫代吡喃基、四氢嘧啶基、四氢哒嗪基、二氢吡喃基、四氢吡喃基、四氢硫代吡喃基、吗啉基、硫代吗啉基、氮杂环庚烷基、二氮杂环庚烷基、氮杂卓基(azepinyl)、氧杂环庚烷基、氮杂环辛烷基(azocanyl)和二氮杂环辛烷基(diazocanyl)等;以及
9至14元稠合多环(优选双环或三环)非芳族杂环基团,如二氢苯并呋喃基、二氢苯并咪唑基、二氢苯并噁唑基、二氢苯并噻唑基、二氢苯并异噻唑基、二氢萘并[2,3-b]噻吩基、四氢异喹啉基、四氢喹啉基、4H-喹嗪基、吲哚啉基、异吲哚啉基、四氢噻吩并[2,3-c]吡啶基、四氢苯并氮杂卓基、四氢喹喔啉基、四氢菲啶基、六氢吩噻嗪基、六氢吩噁嗪基、四氢酞嗪基、四氢萘啶基、四氢喹唑啉基、四氢噌啉基、四氢咔唑基、四氢-β-咔啉基、四氢吖啶基、四氢吩嗪基、四氢噻吨基、八氢异喹啉基等。
“7至10元桥接杂环基团”的优选例子包括奎宁环基和7-氮杂双环[2.2.1]庚烷基。
由R1或R2表示的“任选经取代的环状基团”的例子包括任选地具有一个或多个选自以下取代基组A的取代基的环状基团。
“任选经取代的环状基团”中的取代基的数目是例如1至3。当取代基的数目是两个或更多个时,相应取代基可以相同或不同。
[取代基组A]
(1)卤原子(例如,氟、氯、溴、碘),
(2)硝基,
(3)氰基,
(4)氧代基,
(5)羟基,
(6)任选卤代的C1-6烷氧基(例如,甲氧基、二氟甲氧基、三氟甲氧基、乙氧基、2,2,2-三氟乙氧基、丙氧基、异丙氧基、丁氧基、4,4,4-三氟丁氧基、异丁氧基、仲丁氧基、戊氧基、己氧基),
(7)C6-14芳氧基(例如,苯氧基、萘氧基),
(8)C7-16芳烷氧基(例如,苄氧基),
(9)5至14元芳族杂环氧基(例如,吡啶氧基),
(10)3至14元非芳族杂环氧基(例如,吗啉氧基、哌啶氧基),
(11)C1-6烷基-羰氧基(例如,乙酰氧基、丙酰氧基),
(12)C6-14芳基-羰氧基(例如,苯甲酰氧基、1-萘甲酰氧基、2-萘甲酰氧基),
(13)C1-6烷氧基-羰氧基(例如,甲氧基羰氧基、乙氧基羰氧基、丙氧基羰氧基、丁氧基羰氧基),
(14)单-或二-C1-6烷基-氨基甲酰氧基(例如,甲基氨基甲酰氧基、乙基氨基甲酰氧基、二甲基氨基甲酰氧基、二乙基氨基甲酰氧基),
(15)C6-14芳基-氨基甲酰氧基(例如,苯基氨基甲酰氧基、萘基氨基甲酰氧基),
(16)5至14元芳族杂环基羰氧基(例如,烟酰氧基);
(17)3至14元非芳族杂环基羰氧基(例如,吗啉基羰氧基、哌啶基羰氧基),
(18)任选卤代的C1-6烷基磺酰氧基(例如,甲基磺酰氧基、三氟甲基磺酰氧基),
(19)任选地经一个或多个C1-6烷基取代的C6-14芳基磺酰氧基(例如,苯基磺酰氧基、甲苯磺酰氧基),
(20)任选卤代的C1-6烷硫基(例如,甲硫基、二氟甲硫基、三氟甲硫基、乙硫基、丙硫基、异丙硫基、丁硫基、4,4,4-三氟丁硫基、戊硫基、己硫基),
(21)5至14元芳族杂环基团(例如,噻吩基、呋喃基、吡咯基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、1,2,4-噁二唑基、1,3,4-噁二唑基、1,2,4-噻二唑基、1,3,4-噻二唑基、三唑基、四唑基、三嗪基、苯并苯硫基、苯并呋喃基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、苯并三唑基、咪唑并吡啶基、噻吩并吡啶基、呋喃并吡啶基、吡咯并吡啶基、吡唑并吡啶基、噁唑并吡啶基、噻唑并吡啶基、咪唑并吡嗪基、咪唑并嘧啶基、噻吩并嘧啶基、呋喃并嘧啶基、吡咯并嘧啶基、吡唑并嘧啶基、噁唑并嘧啶基、噻唑并嘧啶基、吡唑并三嗪基、萘并[2,3-b]噻吩基、吩噁噻基、吲哚基、异吲哚基、1H-吲唑基、嘌呤基、异喹啉基、喹啉基、酞嗪基、萘啶基、喹喔啉基、喹唑啉基、噌啉基、咔唑基、β-咔啉基、菲啶基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基),
(22)3至14元非芳族杂环基团(例如,氮丙啶基、氧杂环丙烷基、噻丙环基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、四氢噻吩基、四氢呋喃基、吡咯啉基、吡咯烷基、咪唑啉基、咪唑烷基、噁唑啉基、噁唑烷基、吡唑啉基、吡唑烷基、噻唑啉基、噻唑烷基、四氢异噻唑基、四氢噁唑基、四氢异噁唑基、哌啶基、哌嗪基、四氢吡啶基、二氢吡啶基、二氢硫代吡喃基、四氢嘧啶基、四氢哒嗪基、二氢吡喃基、四氢吡喃基、四氢硫代吡喃基、吗啉基、硫代吗啉基、氮杂环庚烷基、二氮杂环庚烷基、氮杂卓基、氧杂环庚烷基、氮杂环辛烷基、二氮杂环辛烷基、二氢苯并呋喃基、二氢苯并咪唑基、二氢苯并噁唑基、二氢苯并噻唑基、二氢苯并异噻唑基、二氢萘并[2,3-b]噻吩基、四氢异喹啉基、四氢喹啉基、4H-喹嗪基、吲哚啉基、异吲哚啉基、四氢噻吩并[2,3-c]吡啶基、四氢苯并氮杂卓基、四氢喹喔啉基、四氢菲啶基、四氢吩噻嗪基、六氢吩噁嗪基、四氢酞嗪基、四氢萘啶基、四氢喹唑啉基、四氢噌啉基、四氢咔唑基、四氢-β-咔啉基、四氢吖啶基、四氢吩嗪基、四氢噻吨基、八氢异喹啉基),
(23)甲酰基,
(24)羧基,
(25)任选卤代的C1-6烷基-羰基(例如,乙酰基、氯乙酰基、三氟乙酰基、三氯乙酰基、丙酰基、丁酰基、戊酰基、己酰基),
(26)C6-14芳基-羰基(例如,苯甲酰基、1-萘甲酰基、2-萘甲酰基),
(27)5至14元芳族杂环基羰基(例如,烟酰基、异烟酰基、噻吩甲酰基、呋喃甲酰基),
(28)3至14元非芳族杂环基羰基(例如,吗啉基羰基、哌啶基羰基、吡咯烷基羰基),
(29)C1-6烷氧基-羰基(例如,甲氧基羰基、乙氧基羰基、丙氧基羰基、异丙氧基羰基、丁氧基羰基、异丁氧基羰基、仲丁氧基羰基、叔丁氧基羰基、戊氧基羰基、己氧基羰基),
(30)C6-14芳氧基-羰基(例如,苯氧基羰基、1-萘氧基羰基、2-萘氧基羰基),
(31)C7-16芳烷氧基-羰基(例如,苄氧基羰基、苯乙基氧基羰基),
(32)氨基甲酰基,
(33)硫代氨基甲酰基,
(34)单-或二-C1-6烷基-氨基甲酰基(例如,甲基氨基甲酰基、乙基氨基甲酰基、二甲基氨基甲酰基、二乙基氨基甲酰基、N-乙基-N-甲基氨基甲酰基),
(35)C6-14芳基-氨基甲酰基(例如,苯基氨基甲酰基),
(36)5至14元芳族杂环基氨基甲酰基(例如,吡啶基氨基甲酰基、噻吩基氨基甲酰基),(37)3至14元非芳族杂环基氨基甲酰基(例如,吗啉基氨基甲酰基、哌啶基氨基甲酰基),(38)任选卤代的C1-6烷基磺酰基(例如,甲基磺酰基、二氟甲基磺酰基、三氟甲基磺酰基、乙基磺酰基、丙基磺酰基、异丙基磺酰基、丁基磺酰基、4,4,4-三氟丁基磺酰基、戊基磺酰基、己基磺酰基),
(39)C6-14芳基磺酰基(例如,苯基磺酰基、1-萘基磺酰基、2-萘基磺酰基),
(40)5至14元芳族杂环基磺酰基(例如,吡啶基磺酰基、噻吩基磺酰基),
(41)任选卤代的C1-6烷基亚磺酰基(例如,甲基亚磺酰基、乙基亚磺酰基),
(42)C6-14芳基亚磺酰基(例如,苯基亚磺酰基、1-萘基亚磺酰基、2-萘基亚磺酰基),
(43)5至14元芳族杂环基亚磺酰基(例如,吡啶基亚磺酰基、噻吩基亚磺酰基),
(44)氨基,
(45)单-或二-C1-6烷基氨基(例如,甲基氨基、乙基氨基、丙基氨基、异丙基氨基、丁基氨基、二甲基氨基、二乙基氨基、二丙基氨基、二丁基氨基、N-乙基-N-甲基氨基),
(46)单-或二-C6-14芳基氨基(例如,苯基氨基),
(47)5至14元芳族杂环基氨基(例如,吡啶基氨基),
(48)C7-16芳烷基氨基(例如,苄基氨基),
(49)甲酰基氨基,
(50)C1-6烷基-羰基氨基(例如,乙酰基氨基、丙酰基氨基、丁酰基氨基),
(51)(C1-6烷基)(C1-6烷基-羰基)氨基(例如,N-乙酰基-N-甲基氨基),
(52)C6-14芳基-羰基氨基(例如,苯基羰基氨基、萘基羰基氨基),
(53)C1-6烷氧基-羰基氨基(例如,甲氧基羰基氨基、乙氧基羰基氨基、丙氧基羰基氨基、丁氧基羰基氨基、叔丁氧基羰基氨基),
(54)C7-16芳烷氧基-羰基氨基(例如,苄氧基羰基氨基),
(55)C1-6烷基磺酰基氨基(例如,甲基磺酰基氨基、乙基磺酰基氨基),
(56)任选地经一个或多个C1-6烷基取代的C6-14芳基磺酰基氨基(例如,苯基磺酰基氨基、甲苯磺酰基氨基),
(57)任选卤代的C1-6烷基(例如,甲基、氯甲基、二氟甲基、三氯甲基、三氟甲基、乙基、2-溴乙基、2,2,2-三氟乙基、四氟乙基、五氟乙基、丙基、2,2-二氟丙基、3,3,3-三氟丙基、异丙基、丁基、4,4,4-三氟丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、5,5,5-三氟戊基、己基、6,6,6-三氟己基),
(58)C2-6烯基(例如,乙烯基、1-丙烯基、2-丙烯基、2-甲基-1-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、3-甲基-2-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、4-甲基-3-戊烯基、1-己烯基、3-己烯基、5-己烯基),
(59)C2-6炔基(例如,乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、1-戊炔基、2-戊炔基、3-戊炔基、4-戊炔基、1-己炔基、2-己炔基、3-己炔基、4-己炔基、5-己炔基、4-甲基-2-戊炔基),
(60)C3-10环烷基(例如,环丙基、环丁基、环戊基、环己基、环庚基、环辛基、双环[2.2.1]庚基、双环[2.2.2]辛基、双环[3.2.1]辛基、金刚烷基),
(61)C3-10环烯基(例如,环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、环辛烯基),以及
(62)C6-14芳基(例如,苯基、1-萘基、2-萘基、1-蒽基、2-蒽基、9-蒽基)。
R1优选是
(1)C3-10环烷基(例如,环丙基、环己基),其任选地经1至3个卤原子(例如,氟原子)取代,
(2)C6-14芳基(例如,苯基),其任选地经1至3个选自以下的取代基取代:
(i)卤原子(例如,氟原子),
(ii)氰基,以及
(iii)C1-6烷基(例如,甲基),其任选地经1至3个卤原子(例如,氟原子)取代,
(3)5或6元单环芳族杂环基团(例如,吡唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基),其任选地经1至3个选自以下的取代基取代:
(i)卤原子(例如,氟原子),
(ii)C1-6烷基(例如,甲基),其任选地经1至3个卤原子(例如,氟原子)取代,以及
(iii)C1-6烷氧基(例如,乙氧基),或
(4)3至8元单环非芳族杂环基团(例如,四氢吡喃基)。
R1更优选是
(1)C3-10环烷基(例如,环丙基、环己基),其任选地经1至3个卤原子(例如,氟原子)取代,或
(2)5或6元单环芳族杂环基团(例如,吡唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基),其任选地经1至3个选自以下的取代基取代:
(i)卤原子(例如,氟原子),
(ii)C1-6烷基(例如,甲基),其任选地经1至3个卤原子(例如,氟原子)取代,以及
(iii)C1-6烷氧基(例如,乙氧基)。
R1特别优选是
(1)C3-10环烷基(例如,环丙基、环己基),或
(2)6元单环芳族杂环基团(例如,吡啶基、嘧啶基、吡嗪基、哒嗪基),其任选地经1至3个卤原子(例如,氟原子)取代。
R2优选是
(1)C3-10环烷基(例如,环丙基、环己基),其任选地经1至3个卤原子(例如,氟原子)取代,
(2)C6-14芳基(例如,苯基),其任选地经1至3个选自以下的取代基取代:
(i)卤原子(例如,氟原子、氯原子),以及
(ii)C1-6烷基(例如,甲基),其任选地经1至3个卤原子(例如,氟原子)取代,
(3)5或6元单环芳族杂环基团(例如,吡啶基、嘧啶基),其任选地经1至3个选自以下的取代基取代:
(i)卤原子(例如,氟原子、氯原子),
(ii)C1-6烷基(例如,甲基),其任选地经1至3个卤原子(例如,氟原子)取代,以及
(iii)C1-6烷氧基(例如,乙氧基),或
(4)3至8元单环非芳族杂环基团(例如,四氢吡喃基)。
R2更优选是
(1)C6-14芳基(例如,苯基),其任选地经1至3个选自以下的取代基取代:
(i)卤原子(例如,氟原子、氯原子),以及
(ii)C1-6烷基(例如,甲基),其任选地经1至3个卤原子(例如,氟原子)取代,或
(2)5或6元单环芳族杂环基团(例如,吡啶基、嘧啶基),其任选地经1至3个选自以下的取代基取代:
(i)卤原子(例如,氟原子、氯原子),
(ii)C1-6烷基(例如,甲基),其任选地经1至3个卤原子(例如,氟原子)取代,以及
(iii)C1-6烷氧基(例如,乙氧基)。
R2特别优选是
(1)C6-14芳基(例如,苯基),其任选地经1至3个卤原子(例如,氟原子、氯原子)取代,或
(2)6元单环芳族杂环基团(例如,吡啶基、嘧啶基),其任选地经1至3个卤原子(例如,氟原子、氯原子)取代。
优选的化合物是如下化合物(I),其中
R1为
(1)C3-10环烷基(例如,环丙基、环己基),其任选地经1至3个卤原子(例如,氟原子)取代,
(2)C6-14芳基(例如,苯基),其任选地经1至3个选自以下的取代基取代:
(i)卤原子(例如,氟原子),
(ii)氰基,以及
(iii)C1-6烷基(例如,甲基),其任选地经1至3个卤原子(例如,氟原子)取代,
(3)5或6元单环芳族杂环基团(例如,吡唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基),其任选地经1至3个选自以下的取代基取代:
(i)卤原子(例如,氟原子),
(ii)C1-6烷基(例如,甲基),其任选地经1至3个卤原子(例如,氟原子)取代,以及
(iii)C1-6烷氧基(例如,乙氧基),或
(4)3至8元单环非芳族杂环基团(例如,四氢吡喃基),并且
R2为
(1)C3-10环烷基(例如,环丙基、环己基),其任选地经1至3个卤原子(例如,氟原子)取代,
(2)C6-14芳基(例如,苯基),其任选地经1至3个选自以下的取代基取代:
(i)卤原子(例如,氟原子、氯原子),以及
(ii)C1-6烷基(例如,甲基),其任选地经1至3个卤原子(例如,氟原子)取代,
(3)5或6元单环芳族杂环基团(例如,吡啶基、嘧啶基),其任选地经1至3个选自以下的取代基取代:
(i)卤原子(例如,氟原子、氯原子),
(ii)C1-6烷基(例如,甲基),其任选地经1至3个卤原子(例如,氟原子)取代,以及
(iii)C1-6烷氧基(例如,乙氧基),或
(4)3至8元单环非芳族杂环基团(例如,四氢吡喃基)。
更优选的化合物是如下化合物(I),其中
R1为
(1)C3-10环烷基(例如,环丙基、环己基),其任选地经1至3个卤原子(例如,氟原子)取代,或
(2)5或6元单环芳族杂环基团(例如,吡唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基),其任选地经1至3个选自以下的取代基取代:
(i)卤原子(例如,氟原子),
(ii)C1-6烷基(例如,甲基),其任选地经1至3个卤原子(例如,氟原子)取代,以及
(iii)C1-6烷氧基(例如,乙氧基),并且
R2为
(1)C6-14芳基(例如,苯基),其任选地经1至3个选自以下的取代基取代:
(i)卤原子(例如,氟原子、氯原子),以及
(ii)C1-6烷基(例如,甲基),其任选地经1至3个卤原子(例如,氟原子)取代,或(2)5或6元单环芳族杂环基团(例如,吡啶基、嘧啶基),其任选地经1至3个选自以下的取代基取代:
(i)卤原子(例如,氟原子、氯原子),
(ii)C1-6烷基(例如,甲基),其任选地经1至3个卤原子(例如,氟原子)取代,以及
(iii)C1-6烷氧基(例如,乙氧基)。
特别优选的化合物是如下化合物(I),其中
R1为
(1)C3-10环烷基(例如,环丙基、环己基),或
(2)6元单环芳族杂环基团(例如,吡啶基、嘧啶基、吡嗪基、哒嗪基),其任选地经1至3个卤原子(例如,氟原子)取代,并且
R2为
(1)C6-14芳基(例如,苯基),其任选地经1至3个卤原子(例如,氟原子、氯原子)取代,或
(2)6元单环芳族杂环基团(例如,吡啶基、嘧啶基),其任选地经1至3个卤原子(例如,氟原子、氯原子)取代。
化合物(I)的构型优选由式(I')表示:
其中每个符号如上所定义,
(下文中有时称为化合物(I'))。
作为化合物(I)的实施方案,举例说明了以下化合物(化合物(I'-1)和化合物(I'-2))。
化合物(I'-1)
化合物(I'),其中
R1为任选经取代的烃环基团,并且
R2为任选经取代的烃环基团。
化合物(I'-1a)
化合物(I'),其中
R1为
(1)C3-10环烷基(例如,环丙基、环己基),其任选地经1至3个卤原子(例如,氟原子)取代,或
(2)C6-14芳基(例如,苯基),其任选地经1至3个选自以下的取代基取代:
(i)卤原子(例如,氟原子),
(ii)氰基,以及
(iii)C1-6烷基(例如,甲基),其任选地经1至3个卤原子(例如,氟原子)取代,并且R2为
(1)C3-10环烷基(例如,环丙基、环己基),其任选地经1至3个卤原子(例如,氟原子)取代,或
(2)C6-14芳基(例如,苯基),其任选地经1至3个选自以下的取代基取代:
(i)卤原子(例如,氟原子、氯原子),以及
(ii)C1-6烷基(例如,甲基),其任选地经1至3个卤原子(例如,氟原子)取代。
化合物(I'-1b)
化合物(I'),其中
R1为C3-10环烷基(例如,环丙基、环己基),其任选地经1至3个卤原子(例如,氟原子)取代,并且
R2为C6-14芳基(例如,苯基),其任选地经1至3个选自以下的取代基取代:(i)卤原子(例如,氟原子、氯原子),和(ii)C1-6烷基(例如,甲基),其任选地经1至3个卤原子(例如,氟原子)取代。
化合物(I'-1c)
化合物(I'),其中
R1为C3-10环烷基(例如,环丙基、环己基),
并且
R2为C6-14芳基(例如,苯基),其任选地经1至3个卤原子(例如,氟原子、氯原子)取代。
化合物(I'-2)
化合物(I'),其中
R1为任选经取代的杂环基团,并且
R2为任选经取代的杂环基团。
化合物(I'-2a)
化合物(I'),其中
R1为
(1)5或6元单环芳族杂环基团(例如,吡唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基),其任选地经1至3个选自以下的取代基取代:
(i)卤原子(例如,氟原子),
(ii)C1-6烷基(例如,甲基),其任选地经1至3个卤原子(例如,氟原子)取代,以及
(iii)C1-6烷氧基(例如,乙氧基),或
(2)3至8元单环非芳族杂环基团(例如,四氢吡喃基),并且
R2为
(1)5或6元单环芳族杂环基团(例如,吡啶基、嘧啶基),其任选地经1至3个选自以下的取代基取代:
(i)卤原子(例如,氟原子、氯原子),
(ii)C1-6烷基(例如,甲基),其任选地经1至3个卤原子(例如,氟原子)取代,以及
(iii)C1-6烷氧基(例如,乙氧基),或
(2)3至8元单环非芳族杂环基团(例如,四氢吡喃基)。
化合物(I'-2b)
化合物(I'),其中
R1为5或6元单环芳族杂环基团(例如,吡唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基),其任选地经1至3个选自以下的取代基取代:(i)卤原子(例如,氟原子),(ii)C1-6烷基(例如,甲基),其任选地经1至3个卤原子(例如,氟原子)取代,和(iii)C1-6烷氧基(例如,乙氧基),并且
R2为5或6元单环芳族杂环基团(例如,吡啶基、嘧啶基),其任选地经1至3个选自以下的取代基取代:(i)卤原子(例如,氟原子、氯原子),(ii)C1-6烷基(例如,甲基),其任选地经1至3个卤原子(例如,氟原子)取代,和(iii)C1-6烷氧基(例如,乙氧基)。
化合物(I'-2c)
化合物(I'),其中
R1为6元单环芳族杂环基团(例如,吡啶基、嘧啶基、吡嗪基、哒嗪基),其任选地经1至3个卤原子(例如,氟原子)取代,并且
R2为6元单环芳族杂环基团(例如,吡啶基、嘧啶基),其任选地经1至3个卤原子(例如,氟原子、氯原子)取代。
化合物(I)的具体例子包括实施例1至150的化合物。其中,化合物(I)优选为6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2-[(1R,2R)-2-羟基-1,2-二(吡啶-2-基)乙基]-2,3-二氢-1H-异吲哚-1-酮(实施例1)或其盐,
6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2-[(1R,2R)-2-(5-氟吡啶-2-基)-2-羟基-1-(吡啶-2-基)乙基]-2,3-二氢-1H-异吲哚-1-酮(实施例3)或其盐,
2-[(1R,2R)-1,2-双(5-氟吡啶-2-基)-2-羟基乙基]-6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2,3-二氢-1H-异吲哚-1-酮(实施例5)或其盐,
6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2-[(1R,2R)-2-(6-氟吡啶-2-基)-2-羟基-1-(吡啶-2-基)乙基]-2,3-二氢-1H-异吲哚-1-酮(实施例7)或其盐,或
2-[(1R,2S)-1-环丙基-2-(4-氟苯基)-2-羟基乙基]-6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2,3-二氢-1H-异吲哚-1-酮(实施例9)或其盐,
更优选
6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2-[(1R,2R)-2-羟基-1,2-二(吡啶-2-基)乙基]-2,3-二氢-1H-异吲哚-1-酮(实施例1)或其盐,
6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2-[(1R,2R)-2-(5-氟吡啶-2-基)-2-羟基-1-(吡啶-2-基)乙基]-2,3-二氢-1H-异吲哚-1-酮(实施例3)或其盐,或
2-[(1R,2R)-1,2-双(5-氟吡啶-2-基)-2-羟基乙基]-6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2,3-二氢-1H-异吲哚-1-酮(实施例5)或其盐。
当化合物(I)呈盐的形式时,其例子包括金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或酸性氨基酸形成的盐等。所述金属盐的优选例子包括碱金属盐,如钠盐、钾盐等;碱土金属盐,如钙盐、镁盐、钡盐等;铝盐;等。所述与有机碱形成的盐的优选例子包括与以下形成的盐:三甲胺、三乙胺、吡啶、甲基吡啶、2,6-二甲基吡啶、乙醇胺、二乙醇胺、三乙醇胺、环己胺、二环己胺、N,N'-二苄基乙二胺等。所述与无机酸形成的盐的优选例子包括与以下形成的盐:盐酸、氢溴酸、硝酸、硫酸、磷酸等。所述与有机酸形成的盐的优选例子包括与以下形成的盐:甲酸、乙酸、三氟乙酸、邻苯二甲酸、富马酸、草酸、酒石酸、马来酸、柠檬酸、琥珀酸、苹果酸、甲磺酸、苯磺酸、对甲苯磺酸等。所述与碱性氨基酸形成的盐的优选例子包括与以下形成的盐:精氨酸、赖氨酸、鸟氨酸等。所述与酸性氨基酸形成的盐的优选例子包括与以下形成的盐:天冬氨酸、谷氨酸等。
其中,优选药学上可接受的盐。例如,当化合物具有酸性官能团时,其例子包括无机盐,如碱金属盐(例如,钠盐、钾盐等)、碱土金属盐(例如,钙盐、镁盐等)等、铵盐等,并且当化合物具有碱性官能团时,其例子包括与无机酸(如盐酸、氢溴酸、硝酸、硫酸、磷酸等)形成的盐,和与有机酸(如乙酸、邻苯二甲酸、富马酸、草酸、酒石酸、马来酸、柠檬酸、琥珀酸、甲磺酸、苯磺酸、对甲苯磺酸等)形成的盐。
[产生方法]
下面解释化合物(I)的产生方法。
在以下产生方法中的每个步骤中,所使用的原料化合物和试剂以及所获得的化合物各自可以呈盐的形式,并且这样的盐的例子包括与化合物(I)的盐相似的那些盐等。
当每个步骤中获得的化合物是游离形式时,可以根据本身已知的方法将其转化为目标盐。当每个步骤中获得的化合物是盐时,可以根据本身已知的方法将其转化为目标游离形式或其他盐。
每个步骤中获得的化合物可以作为反应混合物或作为粗产物直接用于下一反应。替代性地,每个步骤中获得的化合物可以根据本身已知的方法从反应混合物中分离并纯化,所述方法例如分离手段,如浓缩、结晶、重结晶、蒸馏、溶剂萃取、分馏、色谱等。
当每个步骤中使用的原料化合物和试剂可商购时,也可以直接使用可商购的产品。
在每个步骤中的反应中,尽管反应时间根据待使用的试剂和溶剂的种类而变化,但除非另有说明,否则通常是1min至48h,优选10min至8h。
在每个步骤中的反应中,尽管反应温度根据待使用的试剂和溶剂的种类而变化,但除非另有说明,否则通常是-78℃-300℃,优选-78℃-150℃。
在每个步骤中的反应中,尽管压力根据待使用的试剂和溶剂的种类而变化,但除非另有说明,否则通常是1atm-20atm,优选1atm-3atm。
每个步骤的反应可以使用微波合成器,如由Biotage制造的Initiator等。尽管反应温度根据待使用的试剂和溶剂的种类而变化,但除非另有说明,否则通常是室温-300℃,优选50℃-250℃。尽管反应时间根据待使用的试剂和溶剂的种类而变化,但除非另有说明,否则通常是1min-48h,优选1min-8h。
在每个步骤中的反应中,除非另有说明,否则试剂的用量相对于底物是0.5当量-20当量,优选0.8当量-5当量。当试剂作为催化剂使用时,试剂的用量相对于底物是0.001当量-1当量,优选0.01当量-0.2当量。当试剂作为反应溶剂使用时,试剂以溶剂量使用。
除非另有说明,否则在不使用溶剂的情况下或者通过将原料化合物溶解或悬浮在合适的溶剂中来进行每个步骤中的反应。溶剂的例子包括实施例中描述的那些溶剂和以下溶剂。
醇:甲醇、乙醇、叔丁醇、2-甲氧基乙醇等;
醚:乙醚、二苯醚、四氢呋喃、1,2-二甲氧基乙烷等;
芳族烃:氯苯、甲苯、二甲苯等;
饱和烃:环己烷、己烷等;
酰胺:N,N-二甲基甲酰胺、N-甲基吡咯烷酮等;
卤代烃:二氯甲烷、四氯化碳等;
腈:乙腈等;
亚砜:二甲亚砜等;
芳族有机碱:吡啶等;
酸酐:乙酸酐等;
有机酸:甲酸、乙酸、三氟乙酸等;
无机酸:盐酸、硫酸等;
酯:乙酸乙酯等;
酮:丙酮、甲乙酮等;
水。
上述溶剂可以以适当比率的其中两种或更多种的混合物来使用。
当将碱用于每个步骤中的反应时,其例子包括实施例中描述的那些碱和以下碱。
无机碱:氢氧化钠、氢氧化镁、碳酸钠、碳酸钙、碳酸氢钠、碳酸铯、乙酸钾等;
有机碱:三乙胺、二乙胺、N,N-二异丙基乙胺(DIPEA)、吡啶、4-二甲基氨基吡啶、N,N-二甲基苯胺、1,4-二氮杂双环[2.2.2]辛烷、1,8-二氮杂双环[5.4.0]-7-十一碳烯、咪唑、哌啶等;金属醇盐;乙醇钠、叔丁醇钾等;碱金属氢化物:氢化钠等;金属酰胺:氨基钠、二异丙基氨基锂、六甲基二硅基胺基锂等;有机锂:正丁基锂等。
当每个步骤中的反应使用酸或酸催化剂时,其例子包括实施例中描述的那些以及以下酸和酸催化剂。无机酸:盐酸、硫酸、硝酸、氢溴酸、磷酸等;有机酸:乙酸、三氟乙酸、柠檬酸、对甲苯磺酸、10-樟脑磺酸等;路易斯酸:三氟化硼乙醚络合物、碘化锌、无水氯化铝、无水氯化锌、无水氯化铁等。
除非另有说明,否则每个步骤中的反应都根据本身已知的方法进行,例如,以下中描述的方法:Jikken Kagaku Kouza,第5版,第13-19卷(日本化学会编);Shin JikkenKagaku Kouza,第14-15卷(日本化学会编);Fine Organic Chemistry,修改后的第2版(L.F.Tietze,Th.Eicher,Nankodo);Organic Name Reactions,the Reaction Mechanismand Essence,修订版(Hideo Togo,Kodansha);ORGANIC SYNTHESES集合卷I至VII(JohnWiley&Sons Inc.);Modern Organic Synthesis in the Laboratory A Collection ofStandard Experimental Procedures(Jie Jack Li,OXFORD UNIVERSITY);ComprehensiveHeterocyclic Chemistry III,第1卷至第14卷(Elsevier Japan);StrategicApplications of Named Reactions in Organic Synthesis(由Kiyoshi Tomioka翻译,Kagakudojin);Comprehensive Organic Transformations(VCH Publishers Inc.),1989等,或实施例中描述的方法。
在每个步骤中,官能团的保护或脱保护反应根据本身已知的方法进行,例如,以下中描述的方法:“Protective Groups in Organic Synthesis,第4版”,Wiley-Interscience,Inc.,2007(Theodora W.Greene,Peter G.M.Wuts);“Protecting Groups第3版”Thieme,2004(P.J.Kocienski)等,或实施例中描述的方法。
用于醇等的羟基和酚羟基的保护基团的例子包括醚类保护基团,如甲氧基甲基醚、苄基醚、叔丁基二甲基甲硅烷基醚、四氢吡喃基醚等;羧酸酯类保护基团,如乙酸酯等;磺酸酯类保护基团,如甲磺酸酯等;碳酸酯类保护基团,如碳酸叔丁酯等,等等。
用于醛的羰基的保护基团的例子包括乙缩醛类保护基团,如二甲基乙缩醛等;环乙缩醛类保护基团,如1,3-二噁烷等,等等。
用于酮的羰基的保护基团的例子包括缩酮类保护基团,如二甲基缩酮等;环缩酮类保护基团,如1,3-二噁烷等;肟类保护基团,如O-甲基肟等;腙类保护基团,如N,N-二甲基腙等,等等。
用于羧基的保护基团的例子包括酯类保护基团,如甲基酯等;酰胺类保护基团,如N,N-二甲基酰胺等,等等。
用于硫醇的保护基团的例子包括醚类保护基团,如苄基硫醚等;酯类保护基团,如硫代乙酸酯、硫代碳酸酯、硫代氨基甲酸酯等,等等。
用于氨基和芳族杂环如咪唑、吡咯、吲哚等的保护基团的例子包括氨基甲酸酯类保护基团,如氨基甲酸苄酯等;酰胺类保护基团,如乙酰胺等;烷基胺类保护基团,如N-三苯基甲胺等;磺酰胺类保护基团,如甲磺酰胺等,等等。
保护基团可以根据本身已知的方法去除,例如通过采用使用酸、碱、紫外线、肼、苯基肼、N-甲基二硫代氨基甲酸钠、四丁基氟化铵、乙酸钯、三烷基甲硅烷基卤(trialkylsilyl halide)(例如,三甲基甲硅烷基碘、三甲基甲硅烷基溴)等的方法,还原法等。
当在每个步骤中进行还原反应时,待使用的还原剂的例子包括金属氢化物,如氢化铝锂、三乙酰氧基硼氢化钠、氰基硼氢化钠、二异丁基氢化铝(DIBAL-H)、硼氢化钠、四甲基三乙酰氧基硼氢化铵等,硼烷,如硼烷四氢呋喃络合物等;雷尼镍;雷尼钴;氢气;甲酸;三乙基硅烷等。当碳-碳双键或三键被还原时,可以采用使用如钯炭、林德拉(Lindlar)催化剂等催化剂的方法。
当在每个步骤中进行氧化反应时,待使用的氧化剂的例子包括过氧化物,如间氯过苯甲酸(mCPBA)、过氧化氢、叔丁基过氧化氢等;高氯酸盐,如四丁基高氯酸铵等;氯酸盐,如氯酸钠等;亚氯酸盐,如亚氯酸钠等;高碘酸盐,如高碘酸钠等;高价碘试剂,如亚碘酰苯等;含锰的试剂,如二氧化锰、高锰酸钾等;铅,如四乙酸铅等;含铬的试剂,如氯铬酸吡啶鎓(PCC)、重铬酸吡啶鎓(PDC)、琼斯试剂等;卤素化合物,如N-溴代琥珀酰亚胺(NBS)等;氧气;臭氧;三氧化硫-吡啶络合物;四氧化锇;二氧化硒;2,3-二氯-5,6-二氰基-1,4-苯醌(DDQ)等。
当在每个步骤中进行自由基环化反应时,待使用的自由基引发剂的例子包括偶氮化合物,如偶氮二异丁腈(AIBN)等;水溶性自由基引发剂,如4-4'-偶氮双-4-氰基戊酸(ACPA)等;在空气或氧气存在下的三乙基硼;过氧化苯甲酰等。待使用的自由基试剂的例子包括三丁基锡烷、三(三甲基甲硅烷基)硅烷、1,1,2,2-四苯基二硅烷、二苯基硅烷、碘化钐等。
当在每个步骤中进行维蒂希(Wittig)反应时,待使用的维蒂希试剂的例子包括亚烷基膦烷(alkylidene phosphorane)等。所述亚烷基膦烷可以根据本身已知的方法,例如通过使鏻盐与强碱反应来制备。
当在每个步骤中进行霍纳尔-埃蒙斯(Horner-Emmons)反应时,待使用的试剂的例子包括膦酰基乙酸酯,如二甲基膦酰基乙酸甲酯、二乙基膦酰基乙酸乙酯等;和碱,如碱金属氢化物、有机锂等。
当在每个步骤中进行弗里德-克拉夫茨反应(Friedel-Crafts reaction)时,待使用的试剂的例子包括路易斯酸与酰基氯的组合或路易斯酸与烷基化剂(例如,烷基卤化物、醇、烯烃等)的组合。替代性地,还可以使用有机酸或无机酸替代路易斯酸,并且还可以使用如乙酸酐等酸酐替代酰基氯。
当在每个步骤中进行芳族亲核取代反应时,使用亲核试剂(例如,胺、咪唑等)和碱(例如,有机碱等)作为试剂。
当在每个步骤中进行碳阴离子的亲核加成反应、碳阴离子的亲核1,4-加成反应(迈克尔加成反应)或碳阴离子的亲核取代反应时,用于产生碳阴离子的碱的例子包括有机锂、金属醇盐、无机碱、有机碱等。
当在每个步骤中进行格氏反应时,待使用的格氏试剂的例子包括芳基卤化镁,如苯基溴化镁等;和烷基卤化镁,如甲基溴化镁等。所述格氏试剂可以根据本身已知的方法,例如通过使烷基卤化物或芳基卤化物与金属镁或异丙基氯化镁-氯化锂络合物在作为溶剂的醚、四氢呋喃等中反应来制备。
当在每个步骤中进行克诺维纳盖尔(Knoevenagel)缩合反应时,使用具有带有两个吸电子基团的活化亚甲基的化合物(例如,丙二酸、丙二酸二乙酯、丙二腈等)和碱(例如,有机碱、金属醇盐、无机碱)作为试剂。
当在每个步骤中进行维尔斯迈尔-哈克(Vilsmeier-Haack)反应时,使用磷酰氯和酰胺衍生物(例如,N,N-二甲基甲酰胺等)作为试剂。
当在每个步骤中进行醇、烷基卤化物或磺酸盐的叠氮化反应时,待使用的叠氮化剂的例子包括二苯基磷酰基叠氮化物(DPPA)、三甲基甲硅烷基叠氮化物、叠氮化钠等。例如,对于醇的叠氮化反应,采用使用二苯基磷酰基叠氮化物和1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)的方法、使用三甲基甲硅烷基叠氮化物和路易斯酸的方法、使用二苯基磷酰基叠氮化物、三苯基膦和偶氮二甲酸酯的方法等。
当在每个步骤中进行还原胺化反应时,待使用的还原剂的例子包括三乙酰氧基硼氢化钠、氰基硼氢化钠、氢气、甲酸等。当底物为胺化合物时,待使用的羰基化合物的例子包括多聚甲醛;醛,如乙醛等;和酮,如环己酮等。当底物为羰基化合物时,待使用的胺的例子包括氨;伯胺,如甲胺等;仲胺,如二甲胺等,等等。
当在每个步骤中进行光延(Mitsunobu)反应时,使用偶氮二甲酸酯(例如,偶氮二甲酸二乙酯(DEAD)、偶氮二甲酸二异丙酯(DIAD)等)和三苯基膦作为试剂。
当在每个步骤中进行酯化反应、酰胺化反应或脲化(ureation)反应时,待使用的试剂的例子包括酰基卤,如酰基氯、酰基溴等;活化羧酸,如酸酐,活化酯,硫酸酯等。羧酸的活化剂的例子包括碳二亚胺缩合剂,如1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC HCl)等;三嗪缩合剂,如4-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4-甲基氯化吗啉鎓n-水合物(DMT-MM)等;碳酸酯缩合剂,如1,1-羰基二咪唑(CDI)等;二苯基磷酰基叠氮化物(DPPA);苯并三唑-1-基氧基-三(二甲基氨基)鏻盐(BOP试剂);2-氯-1-甲基-碘化吡啶鎓(向山(Mukaiyama)试剂);亚硫酰氯;卤代甲酸低级烷基酯,如氯甲酸乙酯等;O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓六氟磷酸盐(HATU);硫酸;其组合等。当使用碳二亚胺缩合剂时,可以向反应体系中添加添加剂,如1-羟基苯并三唑(HOBt)、N-羟基琥珀酰亚胺(HOSu)、二甲基氨基吡啶(DMAP)等。
当在每个步骤中进行偶联反应时,待使用的金属催化剂的例子包括钯化合物,如乙酸钯(II)、四(三苯基膦)钯(0)、二氯双(三苯基膦)钯(II)、二氯双(三乙基膦)钯(II)、三(二亚苄基丙酮)二钯(0)、1,1'-双(二苯基膦基)二茂铁氯化钯(II)等;镍化合物,如四(三苯基膦)镍(0)等;铑化合物,如三(三苯基膦)氯化铑(III)等;钴化合物;铜化合物,如氧化铜、碘化铜(I)等;铂化合物等。另外,可以将碱添加到反应体系中,并且其例子包括无机碱等。
当在每个步骤中进行硫羰基化反应时,通常使用五硫化二磷作为硫羰基化剂。替代性地,也可以使用具有1,3,2,4-二硫杂二磷杂环丁烷-2,4-二硫化物结构的试剂(例如,2,4-双(4-甲氧基苯基)-1,3,2,4-二硫杂二磷杂环丁烷-2,4-二硫化物(劳森(Lawesson)试剂)等)替代五硫化二磷。
当在每个步骤中进行卤化反应时,待使用的卤化剂的例子包括N-碘代琥珀酰亚胺、N-溴代琥珀酰亚胺(NBS)、N-氯代琥珀酰亚胺(NCS)、溴、硫酰氯、三氯异氰尿酸等。另外,可以通过使自由基引发剂(如热、光、过氧化苯甲酰、偶氮二异丁腈等)经受反应体系反应来加速反应。
当在每个步骤中进行羟基的卤化反应时,待使用的卤化剂的例子包括氢卤酸和无机酸的酰基卤,具体地,用于氯化的盐酸、亚硫酰氯、三氯氧磷等,用于溴化的48%氢溴酸等。另外,可以采用通过使醇与三苯基膦和四氯化碳或四溴化碳等反应来产生烷基卤化物的方法。替代性地,也可以采用经由两个步骤产生烷基卤化物的方法,所述步骤包括将醇转化为对应的磺酸酯,然后使磺酸酯与溴化锂、氯化锂或碘化钠反应。
当在每个步骤中进行阿尔布佐夫(Arbuzov)反应时,待使用的试剂的例子包括烷基卤化物,如溴乙酸乙酯等;和亚磷酸酯,如亚磷酸三乙酯、亚磷酸三(异丙基)酯等。
当在每个步骤中进行磺酸酯化反应时,待使用的磺化剂的例子包括甲磺酰氯、对甲苯磺酰氯、甲磺酸酐、对甲苯磺酸酐等。
当在每个步骤中进行水解反应时,使用酸或碱作为试剂。对于叔丁酯的酸水解反应,可以添加甲酸、三乙基硅烷等以还原捕获作为副产物的叔丁基阳离子。
当在每个步骤中进行脱水反应时,待使用的脱水剂的例子包括硫酸、五氧化二磷、三氯氧磷、N,N'-二环己基碳二亚胺、氧化铝、多磷酸等。
当在每个步骤中进行烷基化反应时,使用亲电试剂(例如,烷基卤化物等)和碱(例如,有机碱、无机碱、金属醇盐、金属酰胺等)作为试剂。
当在每个步骤中进行氰化反应时,待使用的试剂的例子包括金属氰化物,如氰化铜、氰化钾等。
化合物(I)可以根据以下方案1或方案2所示的产生方法来产生。除非另有说明,否则方案的式中的每个符号如上定义。
此外,化合物(I)可以通过进行如下反应(单独或其两种或更多种的组合)来产生:保护反应、脱保护反应、酰胺化反应、磺酰胺化反应、脲化反应、氨基甲酰化反应、烷基化反应、光延反应、氢化反应、氧化反应、还原反应、卤化反应、偶联反应、碳阴离子的亲核加成反应、格氏反应、脱氧氟化反应、脱水反应等。
下述化合物(Ia)(其中R1为R1a的化合物(I))可以根据以下方案1中所示的方法来产生。R1a为任选经取代的环丙基、任选经取代的C6-14芳基或任选经取代的5或6元单环芳族杂环基团。其他符号如上所定义。
化合物(4)可以通过使用钯催化剂和碱在一氧化碳气氛下使化合物(2)与化合物(3)进行偶联反应来产生。钯催化剂的例子包括4,5-双(二苯基膦基)-9,9-二甲基呫吨(别名:Xantphos)和双(二亚苄基丙酮)钯(0)的组合等。碱的例子包括N,N-二环己基甲胺。
化合物(7)可以通过使化合物(6)进行脱水环化反应来产生。伯吉斯(Burgess)试剂或对甲苯磺酰氯与碱的组合作为试剂使用。碱的例子包括上述有机碱(例如,N,N-二异丙基乙胺、三乙胺等)。
化合物(12)可以通过使化合物(9)、化合物(10)和化合物(11)进行三组分缩合反应来产生。待使用的试剂的例子包括甲酸。
化合物(14)可以通过使化合物(12)与化合物(13)进行史提特(Stetter)反应来产生。3-乙基-5-(2-羟乙基)-4-甲基溴化噻唑鎓和碱的组合作为试剂使用。碱的例子包括三乙胺。
化合物(15)可以通过使化合物(14)进行还原反应来产生。待使用的试剂的例子包括硼氢化钠和三(仲丁基)硼氢化钾。关于产物的立体异构体的比率,仅获得以下所示的反式体(15a),或者获得以下所示的反式体(15a)和顺式体(15b)的混合物(式的立体化学为相对构型)。
化合物(Ia)可以通过使化合物(16)与化合物(8)进行烷基化反应,随后进行环化反应来产生。环化反应在烷基化反应之后,但它可以分阶段进行。在这种情况下,环化反应可以在碱性或酸性条件下进行。碱的例子包括三乙胺、DIPEA、乙酸钾等。待使用的酸的例子包括乙酸等。
下述化合物(Ib)(其中R1为R1b的化合物(I))可以根据以下方案2中所示的方法由化合物(17)产生。R1b为任选经取代的环烷基、任选经取代的C6-14芳基、任选经取代的5或6元单环芳族杂环基团或任选经取代的3至8元单环非芳族杂环基团。X是卤原子。其他符号如上所定义。
方案2
化合物(23)可以通过使化合物(22)进行还原反应来产生。待使用的试剂的例子包括硼氢化钠和三(仲丁基)硼氢化钾。替代性地,也可以使用三异丙醇铝和2-丙醇的组合。关于产物的立体异构体的比率,仅获得以下所示的反式体(23a),或者获得以下所示的反式体(23a)和顺式体(23b)的混合物(式的立体化学为相对构型)。
化合物(Ib)可以通过使化合物(24)与化合物(8)进行烷基化反应,然后进行环化反应来产生。环化反应在烷基化反应之后,但它可以分阶段进行。在这种情况下,环化反应可以在碱性或酸性条件下进行。碱的例子包括三乙胺、DIPEA、乙酸钾等。待使用的酸的例子包括乙酸等。
在每种产生方法中作为原料使用的化合物(2)、(3)、(9)、(10)、(11)、(13)、(17)、(18)、(20)和(21)可以容易地商购获得,或者可以根据本身已知的方法产生。
关于化合物(I)的构型异构体(E形式、Z形式),它们可以在发生异构化时例如根据常规分离手段分离和纯化以获得纯化合物,所述常规分离手段如萃取、重结晶、蒸馏、色谱等。另外,对应的纯异构体也可以通过使用加热、酸催化剂、过渡金属络合物、金属催化剂、自由基催化剂、光照射、强碱催化剂等根据如下中描述的方法或与其类似的方法使双键异构化而获得:Shin Jikken Kagaku Kouza 14(日本化学会编),第251页至第253页,或第4版Jikken Kagaku Kouza 19(日本化学会编),第273页至第274页。
化合物(I)根据取代基的种类而含有立体异构体,并且本发明涵盖每种立体异构体及其混合物。
化合物(I)可以是水合物或非水合物。
当通过上述反应获得游离形式的目标产物时,可以将其根据常规方法转化为盐,或者当获得盐形式的目标产物时,可以将其根据常规方法转化为游离形式或其他盐。如此获得的化合物(I)也可以根据已知方法从反应混合物中分离和纯化,所述已知方法如相转移、浓缩、溶剂萃取、蒸馏、结晶、重结晶、色谱等。
当化合物(I)含有构型异构体、非对映异构体、构象异构体等时,如果需要,则各自可以根据上述分离和纯化方法进行分离。另外,当化合物(I)为外消旋时,d-形式和l-形式可以根据常规光学拆分分离,所述常规光学拆分如制备型高效液相色谱(制备型HPLC)、超临界流体色谱(制备型SFC)等。
如此获得的化合物(I)、它的其他反应中间体及其起始化合物可以根据本身已知的方法从反应混合物中分离和纯化,所述方法例如萃取、浓缩、中和、过滤、蒸馏、重结晶、柱色谱、薄层色谱、制备型高效液相色谱(制备型HPLC)、中压制备型液相色谱(中压制备型LC)等。
化合物(I)的盐可以根据本身已知的方法产生。例如,当化合物(I)为碱性化合物时,其可以通过添加无机酸或有机酸来产生,或者当化合物(I)为酸性化合物时,其可以通过添加有机碱或无机碱来产生。
当化合物(I)含有光学异构体时,每种光学异构体及其混合物都涵盖在本发明的范围内,并且如果需要,则这些异构体可以根据本身已知的方法进行光学拆分或可以分别产生。
化合物(I)可以是晶体。
化合物(I)的晶体可以根据本身已知的结晶方法产生。
结晶方法的例子包括溶液结晶法、蒸气结晶法、熔体结晶法等。
“溶液结晶法”通常是通过改变与化合物的溶解度有关的因素(溶剂组成、pH、温度、离子强度、氧化还原状态等)或溶剂量,将不饱和状态转变为过饱和状态的方法。其具体例子包括浓缩法、缓慢冷却法、反应法(扩散法、电解法)、水热生长法、助熔剂法等。待使用的溶剂的例子包括芳族烃(例如,苯、甲苯、二甲苯等)、卤代烃(例如,二氯甲烷、氯仿等)、饱和烃(例如,己烷、庚烷、环己烷等)、醚(例如,乙醚、二异丙基醚、四氢呋喃、二噁烷等)、腈(例如,乙腈等)、酮(例如,丙酮等)、亚砜(例如,二甲亚砜等)、酰胺(例如,N,N-二甲基甲酰胺等)、酯(例如,乙酸乙酯、乙酸异丙酯等)、醇(例如,甲醇、乙醇、2-丙醇等)、水等。这些溶剂单独使用或两种或更多种以合适比率(例如,1:1至1:100(体积比))组合使用。根据需要,可以使用晶种。
“蒸气结晶法”例如为汽化法(密封管法、气流法)、气相反应法、化学输运法等。
“熔体结晶法”例如为常规冷冻法(拉晶法、温度梯度法、布里奇曼(Bridgman)法)、区熔法(区域匀化法、浮区法)、特殊生长法(VLS方法、液相外延法)等。
结晶方法的优选例子包含包括以下步骤的方法:在20℃至120℃下将化合物(I)溶解在合适溶剂(例如,醇,如甲醇、乙醇等)中,并且将获得的溶液冷却至不高于溶解温度的温度(例如,0℃至50℃,优选0℃至20℃),等。
例如,可以通过过滤等分离本发明的如此获得的晶体。
获得的晶体的分析方法通常是通过粉末X射线衍射进行晶体分析的方法。作为确定晶体取向的方法,也可以使用机械方法或光学方法等。
通过上述产生方法获得的化合物(I)的晶体可以具有高纯度、高品质和低吸湿度,即使在一般条件长期保存后也不会变性,并且可以预期具有优越的稳定性。另外,其生物学特性(例如,药代动力学(吸收、分布、代谢、排泄)、功效表达等)也可以是优越的,并且作为药物可以极其有用。
化合物(I)可以是前药。化合物(I)的前药意指在活体内的生理学条件下,以由于酶、胃酸等引起的反应转化为化合物(I)的化合物,即,通过酶促氧化、还原、水解等转化为化合物(I)的化合物;通过由于胃酸等引起的水解等转化为化合物(I)的化合物。化合物(I)的前药的例子包括通过使化合物(I)中的氨基进行酰化、烷基化或磷酸化获得的化合物(例如,通过使化合物(I)中的氨基进行二十碳酰化(eicosanoylation)、丙氨酰化、戊基氨基羰基化、(5-甲基-2-氧代-1,3-间二氧杂环戊烯-4-基)甲氧基羰基化、四氢呋喃基化、吡咯烷基甲基化、新戊酰基氧基甲基化或叔丁基化获得的化合物);通过使化合物(I)中的羟基进行酰化、烷基化、磷酸化或硼化获得的化合物(例如,通过使化合物(I)中的羟基进行乙酰基化、棕榈酰化、丙酰基化、新戊酰基化、琥珀酰化、富马酰化、丙氨酰化或二甲基氨基甲基羰基化获得的化合物);通过使化合物(I)中的羧基进行酯化或酰胺化获得的化合物(例如,通过使化合物(I)中的羧基进行乙酯化、苯酯化、羧基甲酯化、二甲基氨基甲酯化、新戊酰基氧基甲酯化、乙氧基羰氧基乙酯化、邻苯二甲酸酯化、(5-甲基-2-氧代-1,3-间二氧杂环戊烯-4-基)甲酯化、环己基氧基羰基乙酯化或甲基酰胺化获得的化合物)等。这些化合物可以由化合物(I)根据本身已知的方法产生。
化合物(I)的前药也可以为如HIROKAWA SHOTEN(1990)出版的“IYAKUHIN noKAIHATSU(Development of Pharmaceuticals)”,第7卷,Design of Molecules,第163页至第198页中所述在生理学条件下转化为化合物(I)的化合物。
在本说明书中,化合物(I)和化合物(I)的前药有时统统缩写为“本发明的化合物”。
化合物(I)可以为水合物、非水合物、溶剂化物或非溶剂化物。
另外,化合物(I)可以为被同位素(例如,2H、3H、11C、14C、18F、35S、125I)等标记或取代的化合物。可以使用被同位素标记或取代的化合物,例如,作为正电子发射断层扫描(PET)中使用的示踪剂(PET示踪剂),并且在医学诊断等领域中是有用的。
化合物(I)还涵盖其中1H转化为2H(D)的氘转化形式。
化合物(I)还涵盖其互变异构体。
化合物(I)可以为药学上可接受的共晶或其盐。共晶或其盐意指在室温下由两种或更多种特殊固体构成的结晶物质,每种特殊固体具有不同的物理特性(例如,结构、熔点、熔化热、吸湿性、溶解性和稳定性)。共晶或其盐可以根据本身已知的共结晶方法产生。
化合物(I)也可以用作PET示踪剂。
由于本发明的化合物具有优越的HDAC抑制作用,优选II类HDAC抑制作用,更优选HDAC6抑制作用,因此基于这样的作用也可以用作安全药物。
例如,可以预期含有本发明化合物的本发明药物显示出低毒性(例如,急性毒性、慢性毒性、遗传毒性、血液毒性、生殖毒性、心脏毒性、致癌性),且作为HDAC相关疾病、优选II类HDAC相关疾病、更优选HDAC6相关疾病、更具体为下面(1)至(7)中描述的疾病的预防或治疗剂用于哺乳动物(例如,小鼠、大鼠、仓鼠、兔、猫、狗、牛、绵羊、猴子、人)。
特别地,可以预期本发明的化合物显示出低遗传毒性,因此,可以预期本发明的药物显示出低遗传毒性。
(1)炎性疾病(例如,急性胰腺炎、慢性胰腺炎、哮喘、成人型呼吸窘迫综合征、慢性阻塞性肺疾病(COPD)、特发性肺纤维化、炎性骨病、炎性肺病、炎性肠病、乳糜泻、肝炎、全身性炎症反应综合征(SIRS)、术后或创伤后炎症、肺炎、肾炎、脑膜炎、膀胱炎、咽炎、胃粘膜损伤、脊柱炎、关节炎、皮炎、慢性肺炎、支气管炎、肺梗塞、硅沉着病、肺结节病、糖尿病性肾病、葡萄膜炎、化脓性汗腺炎等),
(2)自身免疫病(例如,类风湿性关节炎、银屑病、炎性肠病(例如,克罗恩病、溃疡性结肠炎等)、舍格伦综合征、贝切特病、多发性硬化、系统性红斑狼疮、狼疮性肾炎、盘状红斑狼疮、卡斯尔曼病、强直性脊柱炎、多肌炎、皮肌炎(DM)、结节性多动脉炎(PN)、混合性结缔组织病(MCTD)、硬皮病、深在性红斑狼疮、慢性甲状腺炎、格雷夫斯病、自身免疫性胃炎、I型糖尿病、自身免疫性溶血性贫血、自身免疫性中性粒细胞减少症、血小板减少症、特应性皮炎、天疱疮、慢性活动性肝炎、重症肌无力、移植物抗宿主病、艾迪生病、免疫应答异常、关节炎、皮炎、放射性皮炎、原发性胆汁性肝硬化等),
(3)骨关节退行性疾病(例如,类风湿关节炎、骨质疏松症、骨关节炎等),
(4)赘生性疾病[例如,恶性肿瘤、血管生成性青光眼(angiogenesis glaucoma)、婴儿血管瘤、多发性骨髓瘤、慢性肉瘤、转移性黑色素瘤、卡波西肉瘤、血管增生、恶病质、乳腺癌转移、癌症(例如,结直肠癌(例如,家族性结直肠癌、遗传性非息肉病性结直肠癌、胃肠道间质瘤等)、肺癌(例如,非小细胞肺癌、小细胞肺癌、恶性间皮瘤等)、间皮瘤、胰腺癌(例如,胰管癌等)、胃癌(例如,乳头状腺癌、粘液性腺癌、腺鳞癌等)、乳腺癌(例如,浸润性导管癌、原位导管癌、炎性乳腺癌等)、卵巢癌(例如,卵巢上皮癌、性腺外生殖细胞肿瘤、卵巢生殖细胞肿瘤、卵巢低度恶性潜能肿瘤等)、前列腺癌(例如,激素依赖性前列腺癌、非激素依赖性前列腺癌等)、肝癌(例如,原发性肝癌、肝外胆管癌等)、甲状腺癌(例如,甲状腺髓样癌等)、肾癌(例如,肾细胞癌、肾和泌尿管的移行细胞癌等)、子宫癌、脑肿瘤(例如,松果体星形细胞瘤(pineal astrocytoma)、毛细胞型星形细胞瘤、弥漫性星形细胞瘤、间变性星形细胞瘤等)、黑色素瘤、肉瘤、膀胱癌、血液癌等(包括多发性骨髓瘤)、垂体腺瘤、神经胶质瘤、听神经瘤、视网膜母细胞瘤、咽癌、喉癌、舌癌、胸腺瘤、食道癌、十二指肠癌、结直肠癌、直肠癌、肝癌、胰腺内分泌肿瘤、胆管癌、胆囊癌、阴茎癌、泌尿管癌、睾丸肿瘤、外阴癌、子宫颈癌、子宫内膜癌、子宫肉瘤、绒膜疾病(cholionic disease)、阴道癌、皮肤癌、蕈样真菌病、基底细胞瘤、软组织肉瘤、恶性淋巴瘤、霍奇金病、骨髓增生异常综合征、成人T细胞白血病、慢性骨髓增生性疾病、胰腺内分泌肿瘤、纤维组织细胞瘤、平滑肌肉瘤、横纹肌肉瘤、原发灶不明癌症)、白血病(例如,急性白血病(例如,急性淋巴细胞白血病、急性粒细胞性白血病等)、慢性白血病(例如,慢性淋巴细胞白血病、慢性粒细胞性白血病等)、骨髓增生异常综合征)、子宫肉瘤(例如,混合性中胚叶肿瘤、子宫平滑肌肉瘤、子宫内膜间质瘤等)、骨髓纤维化等],
(5)神经变性疾病和/或中枢性疾病
(i)精神疾病[例如,抑郁症、重度抑郁症、双相抑郁症、心境恶劣障碍、情感障碍(季节性情感障碍等)、复发性抑郁症、产后抑郁症、应激障碍、抑郁症状、躁狂症、焦虑、广泛性焦虑障碍、焦虑综合征、惊恐障碍、恐惧症、社交恐惧症、社交焦虑障碍、强迫性障碍、创伤后应激综合征、创伤后应激障碍、妥瑞综合征、自闭症、自闭症谱系综合征、脆性X综合征、雷特综合征、适应障碍、双相障碍、神经症、精神分裂症(例如,阳性症状、阴性症状、认知症状(cognitive symptom))、与精神分裂症相关的认知功能障碍、慢性疲劳综合征、焦虑性神经症、强迫性神经症、癫痫、焦虑、焦虑精神状态(anxious mental state)、情绪异常、环性心境、神经异常兴奋、昏厥、成瘾、低性欲(low sex drive)、注意缺陷多动障碍(ADHD)、精神病性重度抑郁症、难治性重度抑郁症、治疗抵抗性抑郁症、遗传性痉挛性截瘫(hreditarysastic praplegia)],
(ii)神经变性疾病[例如,阿尔茨海默病、阿尔茨海默型痴呆、阿尔茨海默型老年性痴呆、帕金森病、肌营养不良、与痴呆有关的帕金森病、亨廷顿病、多发性梗死性痴呆、额颞叶变性[进行性核上性麻痹、皮质基底节变性、与MAPT突变相关的额颞叶痴呆和帕金森综合征(FTDP-17)、额颞叶痴呆、皮克病、嗜银颗粒痴呆等]、帕金森型痴呆、尼曼-皮克综合征、唐氏病、血管性痴呆、脑炎后帕金森综合征、路易体痴呆、鲁宾斯坦-泰比综合征、HIV痴呆、肌萎缩侧索硬化(ALS)、运动神经元疾病(MND)、克罗伊茨费尔特-雅各布病或朊病毒病、大脑性瘫痪、多发性硬化、赖利-戴综合征],
(iii)年龄相关性认知记忆障碍[例如,年龄相关性记忆障碍、老年性痴呆],
(iv)睡眠障碍[例如,内因性睡眠障碍(例如,心理生理性失眠等)、外因性睡眠障碍、昼夜节律障碍(例如,时差变化综合征(时差感)、轮班工作睡眠障碍、不规则的睡眠-觉醒模式、睡眠时相延迟综合征、睡眠时相前移综合征、非24小时睡眠-觉醒等)、睡眠异态、与内科或精神障碍(例如,慢性阻塞性肺疾病、阿尔茨海默病、帕金森病、脑血管性痴呆、精神分裂症、抑郁症、焦虑性神经症)相关的睡眠障碍、应激性失眠症、失眠症、失眠性神经症、睡眠呼吸暂停综合征],
(v)由麻醉药、创伤性疾病或神经变性疾病等引起的呼吸抑制,
(vi)创伤性脑损伤、脑中风、神经性食欲不振、摄食障碍、神经性厌食症、食欲过盛、其他摄食障碍、酒精依赖、酒精滥用、酒精中毒性健忘症、酒精性妄想症、酒精偏爱(alcohol preference)、戒酒、酒精中毒性精神病、酒精中毒、酒精中毒性嫉妒、酒精中毒性躁狂症、酒精依赖性精神障碍、酒精中毒性精神病、嗜药症、恐药症、药物癖、停药、偏头痛、应激性头痛、紧张性头痛、糖尿病神经病变、肥胖症、糖尿病、肌肉痉挛、梅尼埃尔氏病、植物神经性共济失调、脱发、青光眼、高血压、心脏病、心动过速、充血性心力衰竭、通气过度、支气管哮喘、呼吸暂停、婴儿猝死综合征、炎性疾病、过敏性疾病、阳萎、更年期障碍、不孕症、癌症、由HIV感染引起的免疫缺陷综合征、由应激引起的免疫缺陷综合征、脑脊髓膜炎、肢端肥大症、失禁、代谢综合征、骨质疏松症、消化性溃疡、肠易激综合征、炎性肠病、溃疡性结肠炎、克罗恩病、应激性胃肠疾病、应激性呕吐、消化性溃疡、腹泻、便秘、术后肠梗阻,
(vii)疼痛(疼痛、癌性疼痛、炎症引起的急性疼痛、慢性炎症相关疼痛、术后疼痛(切口疼痛、深部疼痛、内脏疼痛、手术后慢性疼痛等)、肌肉疼痛(慢性疼痛疾病相关的肌肉疼痛、肩膀僵硬等)、关节痛、牙痛、颞下颌关节痛、头痛(偏头痛、紧张性头痛、发热相关的头痛、高血压相关的头痛)、内脏疼痛(心痛、心绞痛、腹痛、肾痛、尿道痛、膀胱痛)、妇产科痛(经间痛、痛经、分娩痛)、神经性疼痛(椎间盘疝、神经根痛、带状疱疹后神经痛、三叉神经痛、腰痛等)、源自抗癌药物(紫杉烷抗癌剂(例如,紫杉醇(泰素(taxol))、多西紫杉醇)、长春花生物碱抗癌剂(例如,长春新碱、长春碱)、铂制剂(例如,顺铂、卡铂、奥沙利铂)、分子靶向药物(例如,硼替佐米)等)的周围神经病变(CIPN))和与之相关的神经症状(化疗引起的神经性疼痛(CINP)),
(6)慢性心力衰竭或急性心力衰竭、急性失代偿性心力衰竭、缺血性心脏病、心肌病、心肌炎、瓣膜疾病,
(7)周围神经病变等(例如,脱髓鞘疾病和神经病变(多发性硬化、格林-巴利综合征、费希尔综合征、慢性炎性脱髓鞘性多发性神经病变(CIDP)、多灶性运动神经病变(MMN)、腓骨肌萎缩症、遗传性感觉和自主神经病变、家族性淀粉样多发性神经病变))。
本发明的药物可以优选地用作用于预防或治疗如下疾病的药剂:自身免疫病、炎性疾病、骨关节退行性疾病、神经变性疾病、中枢性疾病、赘生性疾病或周围神经病变,更优选炎性肠病(优选克罗恩病或溃疡性结肠炎)、系统性红斑狼疮、类风湿性关节炎、银屑病、舍格伦综合征、贝切特综合征、多发性硬化、移植物抗宿主病、阿尔茨海默病(优选阿尔茨海默型痴呆)、精神分裂症、路易体痴呆、额颞叶变性[进行性核上性麻痹、皮质基底节变性、与MAPT突变相关的额颞叶痴呆和帕金森综合征(FTDP-17)、额颞叶痴呆、皮克病、嗜银颗粒痴呆等]、帕金森病、亨廷顿病、鲁宾斯坦-泰比综合征、肌营养不良、雷特综合征、肌萎缩侧索硬化、腓骨肌萎缩症、抑郁症、遗传性痉挛性截瘫、赖利-戴综合征、卡斯尔曼病、白血病、子宫平滑肌肉瘤、前列腺癌、结肠癌、多发性骨髓瘤、恶病质或骨髓纤维化、慢性心力衰竭或急性心力衰竭、急性失代偿性心力衰竭、缺血性心脏病、心肌病、心肌炎、瓣膜疾病、周围神经病变等。
本发明的药物可以更优选地用作用于预防或治疗如下疾病的药剂:阿尔茨海默病、额颞叶变性[进行性核上性麻痹、皮质基底节变性、与MAPT突变相关的额颞叶痴呆和帕金森综合征(FTDP-17)、额颞叶痴呆、皮克病、嗜银颗粒痴呆等]、腓骨肌萎缩症等,特别是阿尔茨海默病或进行性核上性麻痹。
此处,疾病的上述“预防”意指,例如,向由于与疾病有关的一些因素而预期具有高发作风险但尚未发展为所述疾病的患者或向已经发展为所述疾病但不具有主观症状的患者施用含有本发明的化合物的药物,或向担心在疾病治疗后显示出疾病复发的患者施用含有本发明的化合物的药物。
含有本发明的化合物的药物可以根据作为药物制剂的产生方法而本身已知的方法(例如,日本药典中描述的方法等)单独地或通过与药理学上可接受的载体混合并且以如下形式口服或肠胃外(例如,静脉内、肌内、皮下、器官内、鼻内、皮内、滴注、大脑内、直肠内、阴道内、腹腔内和肿瘤内施用,向肿瘤附近施用和向病灶施用)安全地施用:例如片剂(包括糖衣片、薄膜包衣片、舌下片、口腔崩解片、颊含片等)、丸剂、散剂、颗粒剂、胶囊剂(包括软胶囊剂、微胶囊剂)、锭剂、糖浆剂、液剂、乳剂、混悬剂、释放控制制剂(例如,速释制剂、缓释制剂、缓释微胶囊剂)、气溶胶剂、薄膜剂(例如,口腔崩解薄膜剂、口腔粘膜粘附薄膜剂)、注射剂(例如,皮下注射剂、静脉内注射剂、肌肉内注射剂、腹腔内注射剂)、点滴输注剂、经皮吸收型制剂、乳膏、软膏剂、洗剂、粘附剂、栓剂(例如,肛门栓剂、阴道栓剂)、颗粒剂、鼻用制剂、经肺剂(吸入剂)、滴眼剂等。
本发明的药物中本发明化合物的含量为整个药物重量的约0.01%至100%。本发明的药物的剂量可以根据施用受试者、施用途径、疾病等而变化。例如,对于口服施用到患有神经变性疾病(例如,阿尔茨海默病、进行性核上性麻痹等)的患者(体重约60kg),可以每天一次至几次施用约0.01mg/kg体重至约50mg/kg体重、优选约0.05mg/kg体重至约25mg/kg体重、更优选地约0.1mg/kg体重至约2mg/kg体重的活性成分(化合物(I))。
药学上可接受的载体的例子包括常规用作制剂材料的各种有机或无机载体材料,例如用于固体制剂的赋形剂、润滑剂、粘合剂和崩解剂;或用于液体制剂的溶剂、增溶剂、助悬剂、等渗剂、缓冲剂、舒缓剂(soothing agent)等。此外,根据需要,也可以酌情以适当量使用普通添加剂,如防腐剂、抗氧化剂、着色剂、甜味剂、吸附剂、湿润剂等。
本发明的药物作为缓释制剂的剂量根据化合物(I)的种类和含量、剂型、药物缓释时间、施用受试者动物(例如,哺乳动物,如小鼠、大鼠、仓鼠、豚鼠、兔、猫、狗、牛、马、猪、绵羊、猴子、人等)和施用物体而变化。例如,对于肠胃外施用的应用,需要每1周从施用的制剂中释放约0.1mg至约100g的化合物(I)。
赋形剂的例子包括乳糖、白糖、D-甘露糖醇、淀粉、玉米淀粉、结晶纤维素和轻质无水硅酸。
润滑剂的例子包括硬脂酸镁、硬脂酸钙、滑石粉和胶态二氧化硅。
粘合剂的例子包括结晶纤维素、白糖、D-甘露糖醇、糊精、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、淀粉、蔗糖、明胶、甲基纤维素和羧甲基纤维素钠。
崩解剂的例子包括淀粉、羧甲基纤维素、羧甲基纤维素钙、羧甲基淀粉钠和L-羟丙基纤维素。
溶剂的例子包括注射用水、醇、丙二醇、Macrogol、芝麻油、玉米油和橄榄油。
增溶剂的例子包括聚乙二醇、丙二醇、D-甘露糖醇、苯甲酸苄酯、乙醇、三氨基甲烷、胆固醇、三乙醇胺、和碳酸钠、柠檬酸钠。
助悬剂的例子包括表面活性剂,如硬脂基三乙醇胺、月桂基硫酸钠、月桂基氨基丙酸、卵磷脂、苯扎氯铵、苄索氯铵、单硬脂酸甘油酯等;和亲水性聚合物,如聚乙烯醇、聚乙烯吡咯烷酮、羧甲基纤维素钠、甲基纤维素、羟甲基纤维素、羟乙基纤维素、羟丙基纤维素等。
等渗剂的例子包括葡萄糖、D-山梨糖醇、氯化钠、甘油和D-甘露糖醇。
缓冲剂的例子包括缓冲溶液,如磷酸盐、乙酸盐、碳酸盐和柠檬酸盐。
舒缓剂的例子包括苄醇。
防腐剂的例子包括对羟基苯甲酸酯、氯丁醇、苄醇、苯乙醇、脱氢乙酸和山梨酸。
抗氧化剂的例子包括亚硫酸盐、抗坏血酸和α-生育酚。
为了预防或治疗各种疾病,本发明的化合物也可以与其他药物(下文中称为伴随药物)一起使用。在下文中,当本发明的化合物与其他药物一起使用时待使用的药物称为“本发明的组合药剂”。
例如,当本发明的化合物用作HDAC抑制剂、优选II类HDAC抑制剂、更优选HDAC6抑制剂时,其可以与以下药物一起使用。
镇静剂(地西泮、氯羟去甲安定、氯卓酸二钾、奥沙西泮、氯氮卓、美达西泮、噁唑仑、氯噁唑仑、氯噻西泮、溴西泮、依替唑仑、氟地西泮、羟嗪、硝西泮、三唑仑、阿普唑仑等),抗精神病药(盐酸氯丙嗪、普鲁氯嗪、三氟拉嗪、盐酸甲硫哒嗪、马来酸奋乃静、庚酸氟奋乃静、马来酸普鲁氯嗪、马来酸左美丙嗪、盐酸普鲁米近、氟哌啶醇、氯氮平、二盐酸三氟拉嗪、盐酸氟奋乃静、奥氮平、富马酸喹硫平、利司哌酮、阿立哌唑、溴哌醇、螺哌隆、利血平、盐酸氯卡帕明、舒必利、佐替平、替沃噻吨等),抗颠痫药(苯妥英、乙琥胺、乙酰唑胺、氯氮卓、三甲双酮、卡马西平、苯巴比妥、扑米酮、舒噻美、丙戊酸钠、氯硝西泮、地西泮、硝西泮等),用于狂病(manic psychosis)的抗抑郁药和治疗药物[三环类或四环类抗抑郁药(盐酸丙咪嗪、盐酸氯米帕明、盐酸地昔帕明、盐酸阿米替林、盐酸去甲替林、阿莫沙平、盐酸米安色林、盐酸马普替林等)、诺昔替林、苯乙肼、舒必利、盐酸曲唑酮、碳酸锂、选择性血清素再摄取抑制剂(马来酸氟伏沙明、盐酸氟西汀、氢溴酸西酞普兰、盐酸舍曲林、盐酸帕罗西汀、盐酸帕罗西汀水合物、草酸艾司西酞普兰等)、血清素-去甲肾上腺素再摄取抑制剂(盐酸文拉法辛、盐酸度洛西汀、盐酸文拉法辛等)、去甲肾上腺素再摄取抑制剂(甲磺酸瑞波西汀等)、去甲肾上腺素-多巴胺再摄取抑制剂(盐酸安非他酮等)、米氮平、盐酸曲唑酮、盐酸奈法唑酮、马来酸司普替林、5-HT1A激动剂(盐酸丁螺环酮、柠檬酸坦度螺酮、盐酸奥塞佐坦)等]苯并二氮杂卓(氯硝西泮等)、L型钙通道抑制剂(普瑞巴林等)、5-HT1A激动剂(盐酸丁螺环酮、柠檬酸坦度螺酮、盐酸奥塞佐坦等)、5-HT3拮抗剂(氰美马嗪等)、心脏非选择性β抑制剂(盐酸普萘洛尔、盐酸氧烯洛尔等)、组胺H1拮抗剂(盐酸羟嗪等),精神分裂症治疗药(氯丙嗪、氟哌啶醇、舒必利、氯氮平、盐酸三氟拉嗪、盐酸氟奋乃静、奥氮平、富马酸喹硫平、利司哌酮、阿立哌唑等)、CRF拮抗剂、其他抗焦虑药(甲丙氨酯等)、速激肽拮抗剂(MK-869、沙瑞度坦等)、作用于代谢型谷氨酸受体的药物、CCK拮抗剂、β3肾上腺素拮抗剂(盐酸阿米勃隆(amibegron)等)、GAT-1抑制剂(盐酸噻加宾等)、N-型钙通道抑制剂、II型碳酸酐酶抑制剂、NMDA甘氨酸位点激动剂、NMDA拮抗剂(美金刚等)、外周型苯并二氮杂卓受体激动剂、加压素拮抗剂、加压素V1b拮抗剂、加压素V1a拮抗剂、磷酸二酯酶抑制剂、阿片类拮抗剂、阿片类激动剂、尿苷、烟酸受体激动剂、甲状腺激素(T3、T4)、TSH、TRH、MAO抑制剂(硫酸苯乙肼、硫酸反苯环丙胺、吗氯贝胺等)、5-HT2A拮抗剂、5-HT2A反向激动剂、COMT抑制剂(恩他卡朋等)、双相障碍治疗药(碳酸锂、丙戊酸钠、拉莫三嗪、利鲁唑、非尔氨酯等)、大麻素CB1拮抗剂(利莫那班等)、FAAH抑制剂、钠通道抑制剂、抗ADHD药(盐酸哌甲酯、盐酸脱氧麻黄碱等)、酒精中毒治疗药、自闭症治疗药、慢性疲劳综合征治疗药、痉挛治疗药、纤维肌痛治疗药、头痛治疗药、失眠症治疗药(依替唑仑、佐匹克隆、三唑仑、唑吡坦(xolpidem)、雷美替胺、茚地普隆等)、戒烟治疗药、重症肌无力症治疗药、脑梗塞治疗药、狂病治疗药、睡眠过多治疗药、疼痛治疗药、心境恶劣治疗药、自主神经功能障碍治疗药、男性及女性的性功能障碍治疗药、偏头痛治疗药、病态性赌博治疗药、不宁腿综合征治疗药、物质依赖治疗药、酒精相关疾病治疗药、肠易激综合征治疗药、阿尔茨海默病治疗药(多奈哌齐、加兰他敏、美金刚、利凡斯的明等)、帕金森病治疗药(左旋多巴、卡比多巴、苄丝肼、司来吉兰、雷沙吉兰、唑尼沙胺、恩他卡朋、金刚烷胺、他利克索、普拉克索、罗匹尼罗、罗替戈汀、阿扑吗啡、卡麦角林、培高利特、溴隐亭、伊曲茶碱、苯海索、比哌立登、吡咯庚汀、普罗吩胺、异丙嗪、屈昔多巴、盐酸金刚烷胺、甲磺酸溴隐亭、盐酸苯海索、盐酸司来吉兰、其组合等)、与痴呆相关的帕金森病治疗药(利凡斯的明)、路易体痴呆治疗药(多奈哌齐)、ALS治疗药(利鲁唑、神经营养因子等)、高脂血症治疗药如胆固醇降低药(抑制素系列(普伐他汀钠、阿托伐他汀、辛伐他汀、罗苏伐他汀等)、贝特类(fibrate)(氯贝特等)、角鲨烯合酶抑制剂)、行为异常或与痴呆相关的漫游的治疗药(镇静药、抗焦虑药等)、细胞凋亡抑制剂、抗肥胖药、抗糖尿病药、高血压治疗药、低血压治疗药、风湿病治疗药(DMARD)、抗癌药、甲状旁腺功能减退症治疗药(PTH)、钙受体拮抗剂、性激素或其衍生物(黄体酮、雌二醇、苯甲酸雌二醇等)、神经元分化加速剂、神经再生促进剂、非甾类抗炎药(美洛昔康、替诺昔康、吲哚美辛、布洛芬、塞来考昔、罗非考昔、阿司匹林等)、类固醇(地塞米松、醋酸可的松等)、抗细胞因子药(TNF抑制剂、MAP激酶抑制剂等)、抗体药物、核酸或核酸衍生物、适体等。
对于组合使用,本发明的化合物和伴随药物的施用时间不受限制,并且本发明的化合物或伴随药物可以同时施用于施用受试者,或可以在不同时间施用。伴随药物的剂量可以根据临床使用的剂量确定,并且可以根据施用受试者、施用途径、疾病、组合等适当选择。
组合使用的施用形式没有特别限制,并且本发明的化合物和伴随药物仅需在施用时进行组合。这种施用模式的例子包括以下:
(1)施用通过同时加工本发明的化合物和伴随药物获得的单一制剂,(2)通过相同的施用途径同时施用已单独产生的本发明的化合物和伴随药物的两种制剂,(3)通过相同的施用途径以交错方式施用已单独产生的本发明的化合物和伴随药物的两种制剂,(4)通过不同的施用途径同时施用已单独产生的本发明的化合物和伴随药物的两种制剂,(5)通过不同的施用途径以交错方式(例如,以本发明的化合物和伴随药物的顺序施用,或以相反顺序施用)施用已单独产生的本发明的化合物和伴随药物的两种制剂,等。
本发明的组合药剂中的本发明的化合物与伴随药物的混合比率可以基于施用受试者、施用途径、疾病等适当地选择。
例如,尽管本发明的组合药剂中本发明的化合物的含量根据制剂形式而变化,但其通常为整个制剂的约0.01-100wt%、优选约0.1-50wt%、更优选约0.5-20wt%。
本发明的组合药剂中伴随药物的含量根据制剂形式而变化,并且通常为整个制剂的按重量计约0.01%至100%、优选按重量计约0.1%至50%、进一步优选按重量计约0.5%至20%。
尽管本发明的组合药剂中如载体等添加剂的含量根据制剂形式而变化,但其基于制剂通常为按重量计约1%至99.99%、优选按重量计约10%至90%。
当单独制备本发明的化合物和伴随药物时,可以采用相同的含量。
只要副作用不引起问题,就可以采用任何量的伴随药物。伴随药物的每日剂量根据受试者的严重程度、年龄、性别、体重、敏感性差异、施用周期、间隔和性质、药理学、药物制剂的种类、有效成分的种类等而变化,并且没有特别限制,并且在口服施用的情况下,药物的量例如通常为每1kg哺乳动物约0.001mg至2000mg、优选约0.01mg至500mg、进一步优选约0.1mg至100mg,并且通常在一天内分开施用一次至四次。
当施用本发明的组合药剂时,本发明的化合物和伴随药物可以同时施用,或者可以以交错方式施用。当以一定时间间隔施用时,所述间隔根据有效成分、剂型和施用方法而变化,并且例如,当首先施用伴随药物时,其中在施用伴随药物之后的1分钟至3天、优选10分钟至1天、更优选15分钟至1小时的时间范围内施用本发明的化合物的方法为例子。当首先施用本发明的化合物时,其中在施用本发明的化合物之后的1分钟至1天、优选10分钟至6小时、更优选15分钟至1小时的时间范围内施用伴随药物的方法为例子。
实施例
下面通过参考实施例、实验实施例和配制品实施例对本发明进行详细解释,这些实施例、实验实施例和配制品实施例不应被解释为限制性的,并且本发明可以在本发明的范围内改变。
在以下实施例中,“室温”通常意指约10°℃至约35°℃。除非另有说明,否则对于混合溶剂所指示的比率为体积混合比率。除非另有说明,否则%意指wt%。
除非另有说明,否则实施例中通过柱色谱的洗脱是在通过TLC(薄层色谱)的观察下进行的。在通过TLC进行的观察中,使用由Merck制造的60F254作为TLC板,使用在柱色谱中用作洗脱溶剂的溶剂作为展开溶剂,并且使用UV检测器进行检测。在硅胶柱色谱中,NH的指示意指使用氨基丙基硅烷键合的硅胶,并且二醇的指示意指使用3-(2,3-二羟基丙氧基)丙基硅烷键合的硅胶。在制备型HPLC(高效液相色谱)中,C18的指示意指使用十八烷基键合的硅胶。除非另有说明,否则洗脱溶剂的比率为体积混合比率。
为了分析1H NMR,使用ACD/SpecManager(商品名)软件等。有时不描述具有非常平缓的质子峰的羟基、氨基等的峰。
MS(质谱)通过LC/MS(液相色谱质谱仪)测量。作为电离法,使用ESI(电喷雾电离)方法或APCI(大气压化学电离)方法。数据指示实际测量值(实测)。尽管通常观察到分子离子峰,但有时观察到碎片离子。在盐的情况下,通常观察到游离形式的分子离子峰或碎片离子峰。元素分析值(Anal.)描述为计算值(Calcd)和实际测量值(实测)。
使用来自Rigaku Ultima IV的Cu-Kα特征辐射测量粉末X射线衍射图,并且描述特征峰。
在以下实施例中,使用以下缩写。
MS:质谱
M:摩尔浓度
CDCl3:氘代氯仿
DMSO-d6:氘代二甲亚砜
1H NMR:质子核磁共振
LC/MS:液相色谱质谱仪
ESI:电喷雾电离
APCI:大气压化学电离
AIBN:2,2'-偶氮二(异丁腈)
Boc:叔丁氧基羰基
CDI:1,1'-羰基二咪唑
CO2:二氧化碳
DIPEA:N,N-二异丙基乙胺
DMF:N,N-二甲基甲酰胺
DMSO:二甲亚砜
NBS:N-溴代琥珀酰亚胺
TEA:三乙胺
THF:四氢呋喃
XANTPHOS:4,5-双(二苯基膦基)-9,9-二甲基呫吨
实施例1和实施例2
6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2-[(1R,2R)-2-羟基-1,2-二(吡啶-2-基)乙基]-2,3-二氢-1H-异吲哚-1-酮(实施例1的化合物)
6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2-[(1S,2S)-2-羟基-1,2-二(吡啶-2-基)乙基]-2,3-二氢-1H-异吲哚-1-酮(实施例2的化合物)
A)2-[3-(甲氧基羰基)-4-甲基苯甲酰基]肼-1-甲酸叔丁酯
通过将所述规模分成5个反应进行以下反应。将5-溴-2-甲基苯甲酸甲酯(42.0g)、肼甲酸叔丁酯(29.1g)、双(二亚苄基丙酮)钯(0)(5.27g)、XANTPHOS(5.30g)、N,N-二环己基甲胺(58.3mL)和环戊基甲基醚(1000mL)的混合物在一氧化碳气氛(0.5MPa)下在95℃下搅拌5h。将五种反应混合物合并,并通过硅藻土过滤,并且减压浓缩滤液。将获得的残余物溶解在乙酸乙酯和THF的混合物中,并且将溶液用水和饱和盐水洗涤,用无水硫酸钠干燥,并减压浓缩。将残余物通过硅胶柱色谱(NH,乙酸乙酯)纯化,并从己烷/THF中结晶,得到标题化合物(45.7g)。
1H NMR(300MHz,DMSO-d6)δ1.32-1.53(9H,m),2.57(3H,s),3.86(3H,s),7.46(1H,d,J=7.9Hz),7.94(1H,dd,J=7.9,1.5Hz),8.33(1H,s),8.93(1H,s),10.30(1H,s)。
MS:[M-H]- 307.0。
B)5-(肼羰基)-2-甲基苯甲酸甲酯盐酸盐
在室温下,向2-[3-(甲氧基羰基)-4-甲基苯甲酰基]肼-1-甲酸叔丁酯(45.7g)中添加4M氯化氢环戊基甲基醚溶液(200mL)。将混合物在室温下搅拌3天。将沉淀的固体通过过滤收集并干燥,得到标题化合物(36.3g)。
1H NMR(300MHz,DMSO-d6)δ2.59(3H,s),3.88(3H,s),7.52(1H,d,J=8.1Hz),8.03(1H,dd,J=7.9,2.1Hz),8.36(1H,d,J=1.9Hz),9.71-10.80(2H,m),11.64(1H,br s)。
MS:[M+H]+ 209.0。
C)5-(5-(二氟甲基)-1,3,4-噁二唑-2-基)-2-甲基苯甲酸甲酯
在室温下向5-(肼羰基)-2-甲基苯甲酸甲酯盐酸盐(36.3g)和THF(750mL)的混合物中添加DIPEA(129mL)。在0℃下向混合物中滴加二氟乙酸酐(27.6mL)。将混合物在室温下搅拌2h,并在室温下向混合物中添加4-甲基苯磺酰氯(56.5g)。将混合物在室温下搅拌过夜,在室温下向混合物中添加水,并且将混合物用乙酸乙酯萃取。将有机层分离,用饱和碳酸氢钠水溶液、水和饱和盐水洗涤,用无水硫酸钠干燥,并减压浓缩。将残余物从己烷/乙酸乙酯中结晶,得到标题化合物(24.9g)。
1H NMR(300MHz,DMSO-d6)δ2.63(3H,s),3.90(3H,s),7.37-7.75(2H,m),8.15(1H,dd,J=8.1,2.1Hz),8.44(1H,d,J=2.3Hz)。
D)2-(溴甲基)-5-((5-(二氟甲基)-1,3,4-噁二唑-2-基))苯甲酸甲酯
在室温下,向5-(5-(二氟甲基)-1,3,4-噁二唑-2-基)-2-甲基苯甲酸甲酯(14.0g)和三氟甲苯(500mL)的混合物中添加NBS(16.7g)和AIBN(0.857g)。将混合物在氩气氛下在90℃下搅拌1h。在室温下向混合物中添加水,并且将混合物用乙酸乙酯萃取。将有机层分离,用饱和盐水洗涤,用无水硫酸钠干燥并减压浓缩。在室温下向残余物和THF(500mL)的混合物中添加DIPEA(10.0mL)。在0℃下向混合物中滴加膦酸二乙酯(7.40mL),并且将混合物在室温下搅拌过夜。在室温下向混合物中添加水,并且将混合物用乙酸乙酯萃取。将有机层分离,用饱和氯化铵水溶液、水和饱和盐水洗涤,用无水硫酸钠干燥,并减压浓缩。将残余物通过硅胶柱色谱(乙酸乙酯/己烷)纯化,并从己烷/乙酸乙酯中结晶,得到标题化合物(12.7g)。
1H NMR(300MHz,CDCl3)δ4.01(3H,s),5.01(2H,s),6.94(1H,t,J=51.6Hz),7.69(1H,d,J=8.3Hz),8.24(1H,dd,J=7.9,1.9Hz),8.71(1H,d,J=1.9Hz)。
MS:[M+H]+ 347.0。
E)[(4-甲基苯-1-磺酰基)(吡啶-2-基)甲基]氨基甲酸叔丁酯
在室温下,向对甲苯亚磺酸钠(25.0g)、氨基甲酸叔丁酯(10.9g)和水(140mL)的混合物中添加吡啶-2-甲醛(10.0g)和甲醇(70mL)的混合物。将混合物在室温下搅拌30min,直到悬浮液变成澄清溶液。在室温下向混合物中添加甲酸(7.16mL),并且将混合物在室温下搅拌3天。将沉淀的固体通过过滤收集,并且用水和二异丙醚洗涤,得到标题化合物(23.0g)。
1H NMR(300MHz,DMSO-d6)δ1.02-1.31(9H,m),2.39(3H,s),6.06(1H,br d,J=10.2Hz),7.31-7.52(3H,m),7.66(2H,d,J=8.3Hz),7.77-7.84(1H,m),7.85-8.00(1H,m),8.15(1H,br d,J=10.5Hz),8.49-8.63(1H,m)。
F)[2-氧代-1,2-二(吡啶-2-基)乙基]氨基甲酸叔丁酯
将[(4-甲基苯-1-磺酰基)(吡啶-2-基)甲基]氨基甲酸叔丁酯(11.0g)、吡啶-2-甲醛(3.41
g)、3-乙基-5-(2-羟基乙基)-4-甲基溴化噻唑鎓(1.53g)和THF(121mL)的混合物脱气,并且在氩气氛下在室温下向混合物中滴加三乙胺(63.3mL)。再次将混合物脱气,并且将混合物在氩气氛下在60℃下搅拌过夜。在室温下向混合物中添加饱和氯化铵水溶液,并且将混合物在水与乙酸乙酯之间分配。将分离的有机层用水和饱和盐水洗涤,用无水硫酸钠干燥,并减压浓缩。将残余物通过硅胶柱色谱(NH,乙酸乙酯/己烷)纯化,得到作为粗产物的标题化合物(9.81g)。将获得的化合物不经进一步纯化而用于下一步骤。MS:[M+H-Boc]+214.0。
G)[(1RS,2RS)-2-羟基-1,2-二(吡啶-2-基)乙基]氨基甲酸叔丁酯
在0℃下,向[2-氧代-1,2-二(吡啶-2-基)乙基]氨基甲酸叔丁酯(9.81g)、甲醇(60mL)和THF(60mL)的混合物中添加硼氢化钠(1.72g),并且将混合物在室温下搅拌过夜。在0℃下向混合物中添加水,并且将混合物在室温下搅拌1h,并且在水与乙酸乙酯之间分配。将分离的有机层用水和饱和盐水洗涤。将合并的水层用乙酸乙酯再萃取,并且将萃取物用水和饱和盐水洗涤。将合并的有机层用无水硫酸钠干燥,并减压浓缩。将残余物用乙酸乙酯/己烷固化,并且将获得的固体从乙酸乙酯/己烷中重结晶,得到标题化合物(6.64g)。
1H NMR(300MHz,DMSO-d6)δ1.11-1.35(9H,m),4.82-5.09(2H,m),5.61(1H,d,J=5.1Hz),7.02(1H,br d,J=8.7Hz),7.10(1H,br d,J=7.9Hz),7.15-7.30(3H,m),7.57-7.80(2H,m),8.42(1H,d,J=4.3Hz),8.52(1H,br d,J=4.1Hz)。
MS:[M+H]+ 316.1。
H)6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2-[(1RS,2RS)-2-羟基-1,2-二(吡啶-2-基)乙基]-2,3-二氢-1H-异吲哚-1-酮
在室温下向[(1RS,2RS)-2-羟基-1,2-二(吡啶-2-基)乙基]氨基甲酸叔丁酯(2.21g)和乙酸(20mL)的混合物中滴加溴化氢(30%乙酸溶液(约5.1M),11.0mL),并且将混合物在室温下搅拌过夜。将混合物减压浓缩,并且与甲苯和甲苯/乙醇一起进行共沸,得到白色固体(3.54g)。在0℃下,向获得的固体(2.83g)、2-(溴甲基)-5-(5-(二氟甲基)-1,3,4-噁二唑-2-基)苯甲酸甲酯(2.15g)和DMF(50mL)的混合物中滴加DIPEA(6.46mL),并且将混合物在室温下搅拌3h。在室温下向混合物中滴加乙酸(2.12mL),并且将混合物在室温下搅拌过夜。在室温下将混合物倒入水中,并且用乙酸乙酯萃取。将萃取物用水和饱和盐水洗涤,用无水硫酸钠干燥,并且减压浓缩。将残余物通过硅胶柱色谱(甲醇/乙酸乙酯)纯化,并从乙酸乙酯/二异丙醚中结晶,得到标题化合物(2.36g)。
1H NMR(300MHz,DMSO-d6)δ4.75(1H,d,J=18.8Hz),5.03(1H,d,J=18.8Hz),5.49(1H,dd,J=8.8,5.8Hz),5.76(1H,d,J=9.0Hz),5.98(1H,d,J=5.6Hz),7.17(1H,ddd,J=7.3,4.9,1.3Hz),7.30-7.72(4H,m),7.72-7.89(3H,m),8.04(1H,d,J=0.8Hz),8.17-8.24(1H,m),8.25-8.31(1H,m),8.60-8.66(1H,m)。
MS:[M+H]+ 450.1。
I)6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2-[(1R,2R)-2-羟基-1,2-二(吡啶-2-基)乙基]-2,3-二氢-1H-异吲哚-1-酮(实施例1的化合物)和
6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2-[(1S,2S)-2-羟基-1,2-二(吡啶-2-基)乙基]-2,3-二氢-1H-异吲哚-1-酮(实施例2的化合物)
将6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2-[(1RS,2RS)-2-羟基-1,2-二(吡啶-2-基)乙基]-2,3-二氢-1H-异吲哚-1-酮通过制备型SFC(柱:CHIRALCEL OD-H,20mmID×250mmL,5μm,流动相:CO2/乙醇=770/230(v/v))进行光学拆分。
减压浓缩保留时间较长的旋光异构体的级分,并且将残余物从己烷/乙酸乙酯中结晶,得到白色固体(1.20g)。在70℃下将获得的固体(1.17g)溶解在乙酸乙酯(12mL)中,并且在70℃下向混合物中滴加庚烷(10mL)。将混合物在70℃下搅拌30min,然后在50℃至75℃下向混合物中滴加另外的庚烷(30mL)。将混合物在50℃下搅拌30min,然后在室温下搅拌1h。将沉淀的固体通过过滤收集,并用庚烷洗涤,得到6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2-[(1R,2R)-2-羟基-1,2-二(吡啶-2-基)乙基]-2,3-二氢-1H-异吲哚-1-酮(1.09g,>99%e.e.,保留时间:5.48min(分析柱,柱:CHIRALCEL OD-H,4.6mmID×150mmL,5μm,流动相:CO2/乙醇=770/230(v/v)))。通过X射线晶体学确定化合物的绝对立体化学。
1H NMR(300MHz,DMSO-d6)δ4.75(1H,d,J=18.8Hz),5.03(1H,d,J=18.8Hz),5.49(1H,dd,J=8.8,5.5Hz),5.76(1H,d,J=9.0Hz),5.98(1H,d,J=5.6Hz),7.17(1H,ddd,J=7.3,4.9,1.3Hz),7.28-7.72(4H,m),7.72-7.91(3H,m),8.04(1H,d,J=0.8Hz),8.18-8.24(1H,m),8.25-8.32(1H,m),8.60-8.67(1H,m)。
MS:[M+H]+ 450.1。
C23H17F2N5O3的分析计算值:C,61.47;H,3.81;N,15.58,实测值:C,61.68;H,4.01;N,15.80。粉末X射线晶体衍射图(衍射角2θ):5.0°、7.1°、9.1°、10.8°、16.6°、18.3°、19.8°、21.6°、22.8°、23.7°、26.1°
减压浓缩保留时间较短的旋光异构体的级分,并且在70℃下将残余物溶解在乙酸乙酯(15mL)中。在50℃至70℃下向混合物中滴加二异丙醚(30mL),并且将获得的悬浮液在50℃下搅拌1h。在50℃下向混合物中滴加二异丙醚(30mL),并且将混合物在50℃下搅拌30min,然后在室温下搅拌1h。将沉淀的固体通过过滤收集,并且用二异丙醚洗涤,得到6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2-[(1S,2S)-2-羟基-1,2-二(吡啶-2-基)乙基]-2,3-二氢-1H-异吲哚-1-酮(1.02g,>99%e.e.,保留时间:4.52min(分析柱:柱:CHIRALCELOD-H,4.6mmID×150mmL,5μm,流动相:CO2/乙醇=770/230(v/v)))。
MS:[M+H]+ 450.1。
实施例3和实施例4
6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2-[(1R,2R)-2-(5-氟吡啶-2-基)-2-羟基-1-(吡啶-2-基)乙基]-2,3-二氢-1H-异吲哚-1-酮(实施例3的化合物)
6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2-[(1S,2S)-2-(5-氟吡啶-2-基)-2-羟基-1-(吡啶-2-基)乙基]-2,3-二氢-1H-异吲哚-1-酮(实施例4的化合物)
A)[2-(5-氟吡啶-2-基)-2-氧代-1-(吡啶-2-基)乙基]氨基甲酸叔丁酯
将[(4-甲基苯-1-磺酰基)(吡啶-2-基)甲基]氨基甲酸叔丁酯(12.1g)、5-氟吡啶-2-甲醛(4.18g)、3-乙基-5-(2-羟基乙基)-4-甲基溴化噻唑鎓(1.68g)和THF(134mL)的混合物脱气,并且在氩气氛下在室温下向混合物中滴加三乙胺(69.6mL)。再次将混合物脱气,并且将混合物在氩气氛下在60℃下搅拌过夜。在0℃下向混合物中添加饱和氯化铵水溶液,并且将混合物在水与乙酸乙酯之间分配。将分离的有机层用水和饱和盐水洗涤,用无水硫酸钠干燥,并减压浓缩。将残余物通过硅胶柱色谱(NH,乙酸乙酯/己烷)纯化,并从乙酸乙酯/己烷中结晶,得到标题化合物(7.14g)。
1H NMR(300MHz,DMSO-d6)δ1.12-1.51(9H,m),6.76(1H,d,J=8.7Hz),7.25(1H,ddd,J=7.5,4.9,1.1Hz),7.45(1H,br d,J=8.3Hz),7.53(1H,d,J=7.9Hz),7.78(1H,td,J=7.7,1.9Hz),7.90(1H,td,J=8.7,2.6Hz),8.11(1H,dd,J=8.8,4.7Hz),8.33(1H,br d,J=4.5Hz),8.64(1H,d,J=2.6Hz)。
B)[(1RS,2RS)-2-(5-氟吡啶-2-基)-2-羟基-1-(吡啶-2-基)乙基]氨基甲酸叔丁酯
在氩气氛下在-78℃下向[2-(5-氟吡啶-2-基)-2-氧代-1-(吡啶-2-基)乙基]氨基甲酸叔丁酯(6.59g)和THF(100mL)的混合物中滴加三(仲丁基)硼氢化钾(1M THF溶液,23.9mL),并且将混合物在-78℃下搅拌2h。在-78℃下向混合物中添加水(40mL),并且在保持内部温度为0℃或更低的同时,向混合物中添加2M氢氧化钠水溶液(99mL)和30%水性过氧化氢(20.3mL)。将混合物在室温下搅拌2h。然后,将五水合硫代硫酸钠(49.4g)溶解在水(190mL)中,并且在0℃下将获得的溶液滴加到混合物中。将混合物在室温下搅拌2h,并且用乙酸乙酯萃取。将萃取物用水和饱和盐水洗涤,用无水硫酸钠干燥,并且减压浓缩。将残余物从乙酸乙酯/庚烷中重结晶,得到标题化合物(5.62g)。
1H NMR(300MHz,DMSO-d6)δ1.02-1.46(9H,m),4.84-5.10(2H,m),5.69(1H,br d,J=4.5Hz),6.98(1H,br d,J=8.7Hz),7.13-7.25(2H,m),7.29(1H,dd,J=8.7,4.5Hz),7.50-7.78(2H,m),8.43(1H,dd,J=4.9,0.8Hz),8.51(1H,d,J=2.6Hz)。
MS:[M+H-Boc]+ 234.0。
C)6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2-[(1RS,2RS)-2-(5-氟吡啶-2-基)-2-羟基-1-(吡啶-2-基)乙基]-2,3-二氢-1H-异吲哚-1-酮
在室温下向[(1RS,2RS)-2-(5-氟吡啶-2-基)-2-羟基-1-(吡啶-2-基)乙基]氨基甲酸叔丁酯(4.09g)和乙酸(40mL)的混合物中添加溴化氢(25%乙酸溶液,10mL)。在室温下向混合物中添加乙酸(20mL),并且将混合物在室温下搅拌30min。将混合物减压浓缩,并且将残余物与甲苯一起共沸三次,并干燥。在室温下,向获得的残余物、DIPEA(13.5mL)和DMF(29mL)的混合物中滴加通过将2-(溴甲基)-5-(5-(二氟甲基)-1,3,4-噁二唑-2-基)苯甲酸甲酯(3.87g)溶解在DMF(10mL)中制备的溶液,并且将混合物在室温下搅拌60h。向混合物中添加水,并且将混合物用乙酸乙酯萃取。将分离的有机层用水和饱和盐水洗涤,用无水硫酸镁干燥,并减压浓缩。将残余物通过硅胶柱色谱(乙酸乙酯/己烷)纯化。将获得的固体悬浮于二异丙醚/乙酸乙酯中,并且通过过滤收集。将固体悬浮在己烷/乙酸乙酯=1/1(50mL)中,超声处理,并在50℃下搅拌10min。将固体通过过滤收集,并用己烷/乙酸乙酯洗涤,得到标题化合物(4.09g)。
1H NMR(300MHz,DMSO-d6)δ4.70(1H,d,J=19.6Hz),4.97(1H,d,J=20.0Hz),5.47-5.57(1H,m),5.72(1H,d,J=9.0Hz),6.05(1H,d,J=5.3Hz),7.31-7.74(5H,m),7.77-7.87(2H,m),8.05(1H,d,J=1.1Hz),8.22(1H,dd,J=7.9,1.5Hz),8.26(1H,t,J=1.5Hz),8.57-8.69(1H,m)。
MS:[M+H]+ 468.1。
D)6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2-[(1R,2R)-2-(5-氟吡啶-2-基)-2-羟基-1-(吡啶-2-基)乙基]-2,3-二氢-1H-异吲哚-1-酮(实施例3的化合物)和
6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2-[(1S,2S)-2-(5-氟吡啶-2-基)-2-羟基-1-(吡啶-2-基)乙基]-2,3-二氢-1H-异吲哚-1-酮(实施例4的化合物)
将6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2-[(1RS,2RS)-2-(5-氟吡啶-2-基)-2-羟基-1-(吡啶-2-基)乙基]-2,3-二氢-1H-异吲哚-1-酮(3.09g)通过制备型HPLC(柱:CHIRALCEL OD,50mmID×500mmL,20μm,流动相:己烷/乙醇=700/300(v/v))进行光学拆分。
减压浓缩保留时间较长的旋光异构体的级分,并且将残余物从庚烷/乙酸异丙酯中结晶,得到6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2-[(1R,2R)-2-(5-氟吡啶-2-基)-2-羟基-1-(吡啶-2-基)乙基]-2,3-二氢-1H-异吲哚-1-酮(1.35g,>99%e.e.,保留时间:9.16min(分析条件,柱:CHIRALCEL OD-H,4.6mmID×250mmL,5μm,流动相:己烷/乙醇=700/300(v/v))。通过X射线晶体学确定化合物的绝对立体化学。
1H NMR(300MHz,DMSO-d6)δ4.71(1H,d,J=18.8Hz),4.97(1H,d,J=18.8Hz),5.52(1H,dd,J=9.0,5.3Hz),5.72(1H,d,J=9.0Hz),6.05(1H,d,J=5.3Hz),7.31-7.74(5H,m),7.77-7.89(2H,m),8.05(1H,d,J=1.1Hz),8.22(1H,dd,J=8.1,1.7Hz),8.26(1H,t,J=1.5Hz),8.53-8.72(1H,m)。
MS:[M+H]+ 468.1。
C23H16F3N5O3·0.3H2O的分析计算值:C,58.43;H,3.54;N,14.81,实测值:C,58.53;H,3.53;N,14.78。
粉末X射线晶体衍射图(衍射角2θ):7.2°、11.3°、16.2°、19.2°、22.1°、22.7°、24.2°、26.5°
减压浓缩保留时间较短的旋光异构体的级分,并且将残余物从庚烷/乙酸异丙酯中结晶,得到6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2-[(1S,2S)-2-(5-氟吡啶-2-基)-2-羟基-1-(吡啶-2-基)乙基]-2,3-二氢-1H-异吲哚-1-酮(1.37g,>99%e.e.,保留时间:7.35min(分析条件:柱:CHIRALCEL OD-H,4.6mmID×250mmL,5μm,流动相:己烷/乙醇=700/300(v/v))。MS:[M+H]+ 468.1。
实施例5和实施例6
2-[(1R,2R)-1,2-双(5-氟吡啶-2-基)-2-羟基乙基]-6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2,3-二氢-1H-异吲哚-1-酮(实施例5的化合物)
2-[(1S,2S)-1,2-双(5-氟吡啶-2-基)-2-羟基乙基]-6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2,3-二氢-1H-异吲哚-1-酮(实施例6的化合物)
A)[(5-氟吡啶-2-基)(4-甲基苯-1-磺酰基)甲基]氨基甲酸叔丁酯
在室温下,向对甲苯亚磺酸钠(21.4g)、氨基甲酸叔丁酯(9.36g)和水(120mL)的混合物中添加通过将5-氟吡啶-2-甲醛(10g)溶解在甲醇(60mL)中制备的溶液。将混合物在室温下搅拌30min,直到悬浮液变成澄清溶液。在室温下向混合物中添加甲酸(6.13mL),并且将混合物在室温下搅拌3天。将沉淀的固体通过过滤收集,用水和二异丙醚洗涤,并且减压干燥,得到标题化合物(24.4g)。
1H NMR(300MHz,DMSO-d6)1.10-1.28(9H,m),2.39(3H,s),6.09(1H,d,J=10.5Hz),7.44(2H,d,J=7.9Hz),7.67(2H,d,J=7.9Hz),7.81-7.97(2H,m),8.26(1H,d,J=10.2Hz),8.56(1H,d,J=2.3Hz)。
B)[1,2-双(5-氟吡啶-2-基)-2-氧代乙基]氨基甲酸叔丁酯
将[(5-氟吡啶-2-基)(4-甲基苯-1-磺酰基)甲基]氨基甲酸叔丁酯(12.7g)、5-氟吡啶-2-甲醛(4.18g)、3-乙基-5-(2-羟基乙基)-4-甲基溴化噻唑鎓(1.68g)和THF(134mL)的混合物脱气,并且在氩气氛下在室温下向混合物中添加三乙胺(69.6mL)。再次将混合物脱气,并且将混合物在氩气氛下在60℃下搅拌过夜。在0℃下向混合物中添加饱和氯化铵水溶液,并且将混合物在水与乙酸乙酯之间分配。将分离的有机层用水和饱和盐水洗涤,用无水硫酸钠干燥,并减压浓缩。将残余物通过硅胶柱色谱(NH,乙酸乙酯/己烷)纯化,并从己烷/乙酸乙酯中结晶,得到标题化合物(7.68g)。
1H NMR(300MHz,DMSO-d6)δ1.13-1.58(9H,m),6.74(1H,d,J=8.7Hz),7.54(1H,brd,J=8.7Hz),7.58-7.67(1H,m),7.68-7.81(1H,m),7.91(1H,td,J=8.8,2.8Hz),8.12(1H,dd,J=8.7,4.9Hz),8.34(1H,d,J=2.6Hz),8.63(1H,d,J=3.0Hz)。
MS:[M+H-Boc]+ 250.0。
C)[(1RS,2RS)-1,2-双(5-氟吡啶-2-基)-2-羟基乙基]氨基甲酸叔丁酯
在氩气氛下在-78℃下向[1,2-双(5-氟吡啶-2-基)-2-氧代乙基]氨基甲酸叔丁酯(7.0g)和THF(100mL)的混合物中滴加三(仲丁基)硼氢化钾(1M THF溶液,30.1mL),并且将混合物在-78℃下搅拌2h。在-78℃下向混合物中添加水(20mL),并且在保持内部温度为0℃或更低的同时,向其中添加2M氢氧化钠水溶液(100mL)和30%水性过氧化氢(20.5mL)。将混合物在室温下搅拌4h。将五水硫代硫酸钠(49.7g)溶解在水(200mL)中,在0℃下将获得的溶液添加到混合物中,并且将混合物在室温下搅拌2h。将混合物用乙酸乙酯萃取。将萃取物用水和饱和盐水洗涤,用无水硫酸钠干燥,并且减压浓缩。将残余物通过硅胶柱色谱(乙酸乙酯/己烷)纯化,并从己烷/乙酸乙酯中结晶,得到标题化合物(5.97g)。
1H NMR(300MHz,DMSO-d6)δ1.01-1.48(9H,m),4.84-4.95(1H,m),4.96-5.10(1H,m),5.67(1H,d,J=5.6Hz),7.05(1H,br d,J=9.0Hz),7.22-7.41(2H,m),7.62(2H,td,J=8.8,2.8Hz),8.40(1H,d,J=3.0Hz),8.51(1H,d,J=2.6Hz)。
MS:[M+H-Boc]+ 252.0。
D)2-[(1RS,2RS)-1,2-双(5-氟吡啶-2-基)-2-羟基乙基]-6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2,3-二氢-1H-异吲哚-1-酮
在室温下向[(1RS,2RS)-1,2-双(5-氟吡啶-2-基)-2-羟基乙基]氨基甲酸叔丁酯(4.34g)和乙酸(30.9mL)的混合物中滴加溴化氢(30%乙酸溶液(约5.1M),19.4mL),并且将混合物在室温下搅拌3h。将混合物减压浓缩,并且将残余物与甲苯一起进行共沸。在0℃下,向获得的残余物、2-(溴甲基)-5-(5-(二氟甲基)-1,3,4-噁二唑-2-基)苯甲酸甲酯(4.29g)和DMF(50mL)的混合物中滴加DIPEA(21.5mL),并且将混合物在室温下搅拌过夜。将混合物倒入水中,并用乙酸乙酯萃取。将萃取物用水和饱和盐水洗涤,用无水硫酸钠干燥,并且减压浓缩。将残余物通过硅胶柱色谱(乙酸乙酯/己烷)纯化,并从二异丙醚/乙酸乙酯中结晶,得到标题化合物(3.68g)。
1H NMR(300MHz,DMSO-d6)δ4.69(1H,d,J=18.8Hz),4.95(1H,d,J=18.8Hz),5.49(1H,dd,J=9.0,5.3Hz),5.75(1H,d,J=9.0Hz),6.05(1H,d,J=5.3Hz),7.33-7.79(5H,m),7.84(1H,d,J=8.3Hz),8.06(1H,d,J=1.1Hz),8.19-8.26(1H,m),8.26-8.31(1H,m),8.62(1H,d,J=3.0Hz)。
MS:[M+H]+ 486.1。
E)2-[(1R,2R)-1,2-双(5-氟吡啶-2-基)-2-羟基乙基]-6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2,3-二氢-1H-异吲哚-1-酮(实施例5的化合物)和
2-[(1S,2S)-1,2-双(5-氟吡啶-2-基)-2-羟基乙基]-6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2,3-二氢-1H-异吲哚-1-酮(实施例6的化合物)
将2-[(1RS,2RS)-1,2-双(5-氟吡啶-2-基)-2-羟基乙基]-6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2,3-二氢-1H-异吲哚-1-酮(3.52g)通过制备型HPLC(柱:CHIRALCEL OD,50mmID×500mmL,20μm,流动相:己烷/乙醇=700/300(v/v))进行光学拆分。
减压浓缩保留时间较长的旋光异构体的级分,将残余物溶解在乙酸乙酯中并且使溶液经过短硅胶柱。减压浓缩滤液,并使残余物从二异丙醚/乙酸乙酯中结晶。将获得的固体从庚烷/乙酸乙酯中重结晶。将获得的固体进一步从庚烷/乙酸异丙酯中重结晶,并且在55°℃至60℃下减压干燥,得到白色固体(1.42g)。将593mg白色固体从戊烷/乙酸异丙酯中重结晶,得到2-[(1R,2R)-1,2-双(5-氟吡啶-2-基)-2-羟基乙基]-6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2,3-二氢-1H-异吲哚-1-酮(506mg,99%e.e.,保留时间:7.77min(分析条件,柱:CHIRALCEL OD-H,4.6mmID×250mmL,5μm,流动相:己烷/乙醇/二乙胺=700/300/1(v/v/v))。通过X射线晶体学确定化合物的绝对立体化学。
1H NMR(300MHz,DMSO-d6)δ4.68(1H,d,J=18.4Hz),4.95(1H,d,J=18.8Hz),5.49(1H,dd,J=9.0,5.6Hz),5.75(1H,d,J=9.0Hz),6.04(1H,d,J=6.0Hz),7.34-7.80(5H,m),7.84(1H,d,J=7.9Hz),8.05(1H,d,J=1.1Hz),8.23(1H,dd,J=7.9,1.5Hz),8.27(1H,t,J=1.5Hz),8.61(1H,d,J=3.0Hz)。
MS:[M+H]+ 486.1
C23H15F4N5O3·0.1H2O的分析计算值:C,56.70;H,3.14;N,14.37,实测值:C,56.57;H,3.21;N,14.32。
粉末X射线晶体衍射图(衍射角2θ):6.1°、9.0°、15.7°、16.4°、18.1°、19.9°、21.7°、22.5°、24.8°、25.3°
减压浓缩保留时间较短的旋光异构体的级分,将残余物从二异丙醚/乙酸乙酯中结晶,并且将获得的固体进一步从庚烷/乙酸异丙酯中重结晶,并减压干燥,得到白色固体(1.54g)。将100mg白色固体从戊烷/乙酸异丙酯中重结晶,得到2-[(1S,2S)-1,2-双(5-氟吡啶-2-基)-2-羟基乙基]-6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2,3-二氢-1H-异吲哚-1-酮(83mg,99%e.e.,保留时间:6.43min(分析条件,柱:CHIRALCEL OD-H,4.6mmID×250mmL,5μm,流动相:己烷/乙醇/二乙胺=700/300/1(v/v/v))。
MS:[M+H]+ 486.1
实施例7和实施例8
6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2-[(1R,2R)-2-(6-氟吡啶-2-基)-2-羟基-1-(吡啶-2-基)乙基]-2,3-二氢-1H-异吲哚-1-酮(实施例7的化合物)
6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2-[(1S,2S)-2-(6-氟吡啶-2-基)-2-羟基-1-(吡啶-2-基)乙基]-2,3-二氢-1H-异吲哚-1-酮(实施例8的化合物)
A)[2-(6-氟吡啶-2-基)-2-氧代-1-(吡啶-2-基)乙基]氨基甲酸叔丁酯
在氩气氛下在室温下,向[(4-甲基苯-1-磺酰基)(吡啶-2-基)甲基]氨基甲酸叔丁酯(11.9g)、3-乙基-5-(2-羟基乙基)-4-甲基溴化噻唑鎓(2.48g)和THF(230mL)的混合物中添加6-氟吡啶-2-甲醛(4.60g)。将混合物脱气,并用氩气替代。在60℃下向混合物中滴加三乙胺(68.5mL),并且将混合物在氩气氛下在60℃下搅拌过夜。在室温下向混合物中添加水,并且将混合物用乙酸乙酯萃取。将萃取物用水和饱和盐水洗涤,用无水硫酸钠干燥,并且减压浓缩。将残余物通过硅胶柱色谱(乙酸乙酯/己烷)纯化,得到作为粗产物的标题化合物(11.4g)。将获得的化合物不经进一步纯化而用于下一步骤。
MS:[M+H]+ 332.1。
B)[(1RS,2RS)-2-(6-氟吡啶-2-基)-2-羟基-1-(吡啶-2-基)乙基]氨基甲酸叔丁酯
在0℃下,向[2-(6-氟吡啶-2-基)-2-氧代-1-(吡啶-2-基)乙基]氨基甲酸叔丁酯(11.4g)、甲醇(100mL)和THF(100mL)的混合物中添加硼氢化钠(1.49g)。将混合物在室温下搅拌2.5h。在0℃下向混合物中添加水,并且将混合物用乙酸乙酯萃取。将分离的有机层用水和饱和盐水洗涤,用无水硫酸钠干燥,并减压浓缩。将残余物从甲苯中结晶,通过过滤收集,并且用二异丙醚洗涤。将获得的固体从己烷/乙酸乙酯中重结晶,得到标题化合物(6.92g)。
1H NMR(300MHz,DMSO-d6)δ1.16-1.32(9H,m),4.78-4.88(1H,m),4.90-5.01(1H,m),5.74(1H,d,J=5.3Hz),6.95-7.10(2H,m),7.16-7.30(3H,m),7.68(1H,t,J=6.8Hz),7.82-7.96(1H,m),8.42(1H,d,J=4.5Hz)。
MS:[M+H]+ 334.1。
C)6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2-[(1RS,2RS)-2-(6-氟吡啶-2-基)-2-羟基-1-(吡啶-2-基)乙基]-2,3-二氢-1H-异吲哚-1-酮
在室温下向[(1RS,2RS)-2-(6-氟吡啶-2-基)-2-羟基-1-(吡啶-2-基)乙基]氨基甲酸叔丁酯(4.55g)和乙酸(80mL)的混合物中添加溴化氢(30%乙酸溶液(约5.1M),21.4mL)。将混合物在室温下搅拌30min,减压浓缩,并且与甲苯一起进行共沸。在0℃下向获得的残余物和DMF(50mL)的混合物中滴加DIPEA(13.6mL),然后在0℃下向混合物中添加通过将2-(溴甲基)-5-(5-(二氟甲基)-1,3,4-噁二唑-2-基)苯甲酸甲酯(4.51g)溶解在DMF(10mL)中制备的溶液。将混合物在0℃至室温下搅拌3天。浓缩混合物,并且在室温下向残余物中添加水。将混合物用乙酸乙酯萃取。将分离的有机层用水和饱和盐水洗涤,用无水硫酸钠干燥,并减压浓缩。将残余物通过硅胶柱色谱(己烷/乙酸乙酯)纯化,并从己烷/乙酸乙酯中结晶,得到标题化合物(4.29g)。
1H NMR(300MHz,DMSO-d6)δ4.68(1H,d,J=18.8Hz),4.98(1H,d,J=18.8Hz),5.39-5.48(1H,m),5.71(1H,d,J=9.0Hz),6.11(1H,d,J=4.0Hz),6.95(1H,dd,J=8.1,2.4Hz),7.32-7.73(4H,m),7.77-7.88(2H,m),7.89-8.01(1H,m),8.06(1H,d,J=0.9Hz),8.23(1H,dd,J=8.0,1.6Hz),8.58-8.67(1H,m)。
MS:[M+H]+ 468.1。
D)6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2-[(1R,2R)-2-(6-氟吡啶-2-基)-2-羟基-1-(吡啶-2-基)乙基]-2,3-二氢-1H-异吲哚-1-酮(实施例7的化合物)和
6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2-[(1S,2S)-2-(6-氟吡啶-2-基)-2-羟基-1-(吡啶-2-基)乙基]-2,3-二氢-1H-异吲哚-1-酮(实施例8的化合物)
将6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2-[(1RS,2RS)-2-(6-氟吡啶-2-基)-2-羟基-1-(吡啶-2-基)乙基]-2,3-二氢-1H-异吲哚-1-酮(4.27g)通过制备型HPLC(柱:CHIRALPAK IA,50mmID×500mmL,20μm,流动相:己烷/乙醇=200/800(v/v))进行光学拆分。
减压浓缩保留时间较短的旋光异构体的级分,并且将残余物从庚烷/乙酸异丙酯中重结晶,得到6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2-[(1R,2R)-2-(6-氟吡啶-2-基)-2-羟基-1-(吡啶-2-基)乙基]-2,3-二氢-1H-异吲哚-1-酮(1.72g,>99%e.e.,保留时间:15.49min(分析条件,柱:CHIRALPAK IA,4.6mmID×250mmL,5μm,流动相:己烷/乙醇=200/800(v/v))。通过X射线晶体学确定化合物的绝对立体化学。
1H NMR(300MHz,DMSO-d6)δ4.68(1H,d,J=18.8Hz),4.98(1H,d,J=18.8Hz),5.43(1H,dd,J=8.8,5.8Hz),5.71(1H,d,J=8.7Hz),6.10(1H,d,J=6.0Hz),6.95(1H,dd,J=7.9,2.6Hz),7.32-7.73(4H,m),7.76-7.89(2H,m),7.89-8.00(1H,m),8.07(1H,d,J=1.1Hz),8.23(1H,dd,J=7.9,1.5Hz),8.56-8.66(1H,m)。
MS:[M+H]+ 468.1。
C23H16F3N5O3·0.2H2O的分析计算值:C,58.65;H,3.51;N,14.87,实测值:C,58.78;H,3.75;N,15.00。
粉末X射线晶体衍射图(衍射角2θ):5.7°、12.1°、13.0°、16.7°、19.0°、20.2°、21.8°、24.2°
减压浓缩保留时间较长的旋光异构体的级分,并且将残余物从庚烷/乙酸异丙酯中重结晶,得到6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2-[(1S,2S)-2-(6-氟吡啶-2-基)-2-羟基-1-(吡啶-2-基)乙基]-2,3-二氢-1H-异吲哚-1-酮(1.84g,99%e.e.,保留时间:19.48min(分析条件,柱:CHIRALPAK IA,4.6mmID×250mmL,5μm,流动相:己烷/乙醇=200/800(v/v))。
MS:[M+H]+ 468.1。
实施例9
2-[(1R,2S)-1-环丙基-2-(4-氟苯基)-2-羟基乙基]-6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2,3-二氢-1H-异吲哚-1-酮
A){(1R)-1-环丙基-2-[甲氧基(甲基)氨基]-2-氧代乙基}氨基甲酸叔丁酯
在0℃下向(2R)-((叔丁氧基羰基)氨基)(环丙基)乙酸(10.2g)和THF(150mL)的混合物中添加CDI(9.22g),并且将混合物在0℃下搅拌1h。将N-甲氧基甲胺盐酸盐(5.55g)和DIPEA(12.4mL)溶解在DMF(30mL)中,并且在0℃下将获得的溶液添加到混合物中。将混合物在室温下搅拌过夜。减压浓缩混合物。向残余物中添加水,并且将混合物用乙酸乙酯/THF萃取。将分离的有机层用水和饱和盐水洗涤,用无水硫酸钠干燥,并减压浓缩。将残余物通过硅胶柱色谱(己烷/乙酸乙酯)纯化,得到标题化合物(12.1g)。1H NMR(300MHz,DMSO-d6)δ0.21-0.32(1H,m),0.33-0.49(3H,m),0.93-1.09(1H,m),1.36(9H,s),3.11(3H,s),3.70(3H,s),3.90-4.09(1H,m),7.06(1H,d,J=8.3Hz)。
MS:[M+H-Boc]+ 159.1。
B)[(1R)-1-环丙基-2-(4-氟苯基)-2-氧代乙基]氨基甲酸叔丁酯
在40℃下,向{(1R)-1-环丙基-2-[甲氧基(甲基)氨基]-2-氧代乙基}氨基甲酸叔丁酯(8.55g)和THF(130mL)的混合物中添加4-氟苯基溴化镁(2M二乙醚溶液,42mL)。将混合物在氮气氛下在40℃下搅拌1h。在40℃下向混合物中添加4-氟苯基溴化镁(2M二乙醚溶液,3mL)。将混合物在氮气氛下在40℃下搅拌30min。在0℃下将混合物倒入饱和氯化铵水溶液中。向混合物中添加水,并且将混合物用乙酸乙酯萃取。将分离的有机层用水和饱和盐水洗涤,用无水硫酸钠干燥,并减压浓缩。将残余物通过硅胶柱色谱(己烷/乙酸乙酯)纯化,得到标题化合物(7.80g)。
1H NMR(300MHz,DMSO-d6)δ0.19-0.56(4H,m),0.91-1.10(1H,m),1.13-1.50(9H,m),4.09-4.50(1H,m),7.35(2H,t,J=8.8Hz),7.46(1H,br d,J=7.2Hz),8.04(2H,dd,J=8.7,5.6Hz)。
MS:[M+H-Boc]+ 194.1。
C)[(1R,2S)-1-环丙基-2-(4-氟苯基)-2-羟基乙基]氨基甲酸叔丁酯
在室温下,向[(1R)-1-环丙基-2-(4-氟苯基)-2-氧代乙基]氨基甲酸叔丁酯(7.80g)、甲苯(22mL)和2-丙醇(23mL)的混合物中添加三异丙醇铝(1.09g)。将混合物在70℃下搅拌3h。在0℃下,将反应混合物添加到0.5M盐酸和乙酸乙酯的混合物中,并且将混合物用乙酸乙酯萃取。将分离的有机层用饱和碳酸氢钠水溶液和饱和盐水洗涤,用无水硫酸钠干燥,并减压浓缩,得到标题化合物(7.79g)。
1H NMR(300MHz,DMSO-d6)δ-0.24--0.08(1H,m),0.09-0.37(3H,m),0.95-1.13(1H,m),1.26(9H,s),3.08-3.25(1H,m),4.50(1H,t,J=5.6Hz),5.37(1H,d,J=4.5Hz),6.45(1H,br d,J=9.4Hz),7.09(2H,t,J=9.0Hz),7.29-7.41(2H,m)。
D)(1S,2R)-2-氨基-2-环丙基-1-(4-氟苯基)乙-1-醇氢溴酸盐
在室温下向[(1R,2S)-1-环丙基-2-(4-氟苯基)-2-羟基乙基]氨基甲酸叔丁酯(4.79g)和乙酸(50mL)的混合物中添加溴化氢(25%乙酸溶液,12.5mL)。将混合物在室温下搅拌30min。减压浓缩混合物。将残余物与甲苯一起共沸三次。将残余物悬浮于乙酸乙酯(10mL)和二异丙醚(40mL)中,并且将获得的悬浮液在室温下搅拌30min。将沉淀的固体通过过滤收集,用二异丙醚/乙酸乙酯(4:1)洗涤,并且干燥,得到标题化合物(4.29g)。
1H NMR(300MHz,DMSO-d6)δ-0.41--0.24(1H,m),0.12-0.34(2H,m),0.34-0.50(1H,m),0.77-0.97(1H,m),2.59(1H,dd,J=10.5,3.0Hz),4.94(1H,br s),6.15(1H,d,J=3.8Hz),7.09-7.29(2H,m),7.37-7.52(2H,m),7.89(3H,br s)。
MS:[M+H]+ 196.1。
E)2-[(1R,2S)-1-环丙基-2-(4-氟苯基)-2-羟基乙基]-6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2,3-二氢-1H-异吲哚-1-酮
在室温下,向(1S,2R)-2-氨基-2-环丙基-1-(4-氟苯基)乙-1-醇氢溴酸盐(3.65g)、DIPEA(10.5mL)和DMF(30mL)的混合物中滴加通过将2-(溴甲基)-5-(5-(二氟甲基)-1,3,4-噁二唑-2-基)苯甲酸甲酯(4.17g)溶解在DMF(12mL)中制备的溶液。将混合物在室温下搅拌过夜。在室温下向混合物中添加水,并且将混合物用乙酸乙酯萃取。将分离的有机层用饱和盐水洗涤,用无水硫酸钠干燥,并减压浓缩。将残余物通过硅胶柱色谱(己烷/乙酸乙酯)纯化,将获得的固体溶解在乙酸乙酯中,并且将溶液过滤以去除不溶物质。将滤液减压浓缩,并且将残余物从庚烷/乙酸乙酯中重结晶,得到标题化合物(3.75g)。1H NMR(300MHz,DMSO-d6)δ-0.24--0.11(1H,m),-0.11--0.01(1H,m),0.28-0.51(2H,m),1.31-1.48(1H,m),3.51(1H,dd,J=10.2,4.1Hz),4.78(1H,d,J=19.2Hz),4.88(1H,d,J=19.2Hz),5.00(1H,t,J=4.5Hz),5.74(1H,d,J=4.9Hz),7.05-7.21(2H,m),7.35-7.78(3H,m),7.90(1H,d,J=8.3Hz),8.21(1H,d,J=0.8Hz),8.29(1H,dd,J=7.9,1.9Hz)。
MS:[M+H]+ 430.1。
C22H18F3N3O3·0.1H2O的分析计算值:C,61.28;H,4.25;N,9.75,实测值:C,61.28;H,4.48;N,9.77。
粉末X射线晶体衍射图(衍射角2θ):6.9°、13.9°、16.9°、18.6°、20.2°、20.9°、22.2°、22.7°、25.6°、28.1°
实施例的化合物示于下表中。表中的MS意指实际测量值。下表中实施例10-150的化合物是根据上述实施例中所述的方法或与其类似的方法产生的。
[表1-1]
[表1-2]
[表1-3]
[表1-4]
[表1-5]
[表1-6]
[表1-7]
[表1-8]
[表1-9]
[表1-10]
[表1-11]
[表1-12]
[表1-13]
[表1-14]
[表1-15]
[表1-16]
[表1-17]
[表1-18]
[表1-19]
[表1-20]
[表1-21]
[表1-22]
实验实施例1HDAC6酶抑制测定
通过将全长HDAC6基因转导到Sf-9昆虫细胞中并且通过GST亲和柱纯化制备的HDAC6酶购自SignalChem。使用这种酶,评价本发明化合物的HDAC6酶抑制活性。酶在-70℃下保存之后使用。使用HDAC-GloTM I/II测定试剂盒(Promega)根据以下实验方法测量本发明化合物的HDAC6酶抑制活性。将用测定缓冲液(24mM Tris-HCl(pH 7.5),1mM MgCl2,0.35mM KCl,135mM NaCl,0.6mM谷胱甘肽,0.01%吐温-20)稀释的测试化合物以各自2μL添加到384孔板中。然后,向其中添加各自4μL的用测定缓冲液稀释的HDAC6酶溶液,并且在室温将板孵育60min。孵育之后,将附至测定试剂盒的根据Promega方案制备的HDAC底物-显影液以各自2μL添加到384孔板中,并且开始酶反应。在室温下反应20min之后,使用酶标仪Envision(PerkinElmer)测量发光水平。当不含酶的孔中的发光水平被认为是100%抑制时,计算各实施例化合物的抑制活性为相对活性值。结果示于表2-1和表2-2中。
[表2-1]
[表2-2]
如从表2-1和表2-2中清楚地看出,本发明的化合物具有优异的HDAC6抑制活性。
实验实施例2脑内乙酰化微管蛋白的增加
将药物悬浮于0.5%甲基纤维素中以制备具有表3中所示浓度的用于施用的悬浮液。给8至10周龄的雄性C57BL/6J小鼠口服施用悬浮液,并且在表3中所示的时间过去之后,取出脑,并且获得海马体。将海马体在添加了蛋白酶抑制剂(Thermo Fisher Scientific)和磷酸酶抑制剂(Thermo Fisher Scientific)的RIPA提取物(FUJIFILM Wako PureChemical Corporation)下匀浆,并且以15,000g离心15min以制备蛋白质提取物。通过以下ELISA法检测提取物中的乙酰化微管蛋白和总微管蛋白。将微管蛋白抗体(Sigma)固定在96孔板(Microlite2+,Thermo Fisher Scientific)上,并且将板在4℃下保存。第二天,将板用PBS-T洗涤四次,并且向其中添加封闭缓冲液(1%BSA/PBS-T),并且在37℃进行反应2h。将板用PBS-T洗涤四次,并且向其中添加上述蛋白质提取物以捕获抗体上的微管蛋白。将板在37℃下保存2h,并且用PBS-T洗涤四次。向其中添加各自用封闭缓冲液稀释的抗乙酰化微管蛋白抗体或总微管蛋白抗体(Cell Signaling Technology),并且在37℃下进行反应1h。然后,将板用PBS-T洗涤四次,并且在37℃下将反应使用抗小鼠HPR(Cell SignalingTechnology)进行30min。将板洗涤,向其中添加HRP底物,并且使用酶标仪测量发光。使用小鼠海马组织提取物,由逻辑斯谛(logistics)曲线基于稀释系列量化乙酰化微管蛋白和总微管蛋白,并且计算出相对于总微管蛋白而言乙酰化微管蛋白的量,并且作为相对微管蛋白乙酰化水平评价。测试使用SAS系统8进行。在进行媒介物组和药物组的F检验之后,通过学生t检验或韦尔奇(Welch)检验分析这两组之间的显著性差异(指示为*p<0.05,**p<0.01,n.s.:没有显著性)。图由均值±标准误差指示。结果示于图1至图3中。在向其中施用了实施例1、3或5的化合物的小鼠中,观察到微管蛋白乙酰化水平显著增加。
[表3]
实验实施例3神经变性疾病模型小鼠的认知改善作用
将药物悬浮在0.5%甲基纤维素中以制备用于施用的悬浮液。将悬浮液重复施用于六月龄的雄性P301S突变型人tau(4R1N)Tg小鼠,一天一次,持续三个月,并且通过以下方法进行新物体识别测试(novel object recogonition test)。所述测试包括第一天的物体记忆获得试验以及第二天的熟悉物体和新物体的记忆保留试验。在这两天的试验之前1h将药物施用于小鼠。对于获得试验,将小鼠放在放置有两个相同物体的测试箱(30cm x 30cmx 25cm)中,并且在50lux下测量5min内与物体的接触频率和接触持续时间。此处,接触意指使得嗅探物体的行为(嗅探(Sniffing))。第二天,用新物体替代其中一个物体,并且测量5min内与每个物体的接触频率和接触持续时间。通过新物体接触频率/(新物体接触持续时间+熟悉物体接触持续时间)%,计算新物鉴别指数(NDI)作为认知功能的指标。测试使用SAS系统8进行。在对媒介物施用野生型组和媒介物施用Tg组进行F检验之后,通过学生t检验或韦尔奇检验分析这两组之间的显著性差异(指示为**p<0.01)。另外,对媒介物施用或药物施用Tg组进行方差齐性的巴特利特(Bartlett)检验,并且通过单尾威廉姆斯(Williams)检验分析显著性差异(指示为##p<0.005)。每组由14只或15只小鼠组成。图由均值±标准误差指示。结果示于图4和图5中。
实验实施例4大鼠中的毒性测试
使用以下测试系统在大鼠中进行两周毒性测试。
测试系统:
大鼠,斯普拉格-杜勒(Sprague-Dawley)[Crl:CD(SD)]
施用方法/时间段:
选择口服施用(其是临床应用的预定途径)作为施用途径,并且施用时间段为2周。施用频率是每天一次(7天/周),其通常用于重复剂量研究。对于对啮齿动物的口服施用,施用方法是一般的口服灌胃。剂量为5mL/kg,并且使用柔软的胃管(在08:00和15:00之间)口服灌胃施用。将媒介物类似地施用于媒介物对照组。基于最近的体重计算每只动物的剂量。
媒介物和制备方法:
称量0.5w/v%甲基纤维素溶液和所需量的甲基纤维素(METOLOSE SM-100),并且在搅拌下将其逐渐添加到适量的注射用温水中,以分散甲基纤维素。将其冷却以溶解甲基纤维素,并且向其中进一步添加注射用水以得到0.5%溶液。
下面描述作为毒性评估例子的血液学方案。
材料:
在计划的尸体剖检时,在异氟烷吸入麻醉下,对从前一天开始禁食过夜(约16小时至21小时)的测试组中的所有动物进行剖腹术,并且将血液(约1mL)从腹主动脉收集到含有EDTA-2K的血液采样瓶中。对获得的血液进行项目测试,并且通过下面列出的方法进行测试。
所用设备:
自动血细胞计数仪(ADVIA2120i,Siemens Healthcare Diagnostics)
测试项目(测量方法):
·红细胞计数(2角度激光流式细胞术方法)
·血细胞比容值(由红细胞计数和MCV计算)
·血红蛋白浓度(改良的氰化高铁血红蛋白法)
·平均红细胞血红蛋白量(由MCH、红细胞计数和血红蛋白浓度计算)
·平均红细胞血红蛋白浓度(由MCHC、红细胞计数、MCV和血红蛋白浓度计算)
·平均红细胞体积(MCV,2角度激光流式细胞术方法)
·红细胞体积分布宽度(RDW,2角度激光流式细胞术方法)
·网织红细胞计数(绝对计数,通过RNA染色的激光流式细胞术)
·血小板计数(2角度激光流式细胞术方法)
·白细胞计数(2角度激光流式细胞术方法)
·白细胞分类(绝对计数,通过过氧化物酶染色的流式细胞术+2角度激光流式细胞术)·红细胞形态标记(MICRO:小红细胞,MACRO:大红细胞,HYPO:低血色素红细胞,HYPER:高血色素红细胞,ANISO:红细胞大小差异,HCVAR:血红蛋白浓度差异,RBCF:破碎红细胞)
实验实施例5细菌回变测定
材料和方法
测试菌株:
鼠伤寒沙门氏菌TA100或TA98
代谢活化系统:
从用苯巴比妥和5,6-苯并黄酮处理的7周龄雄性斯普拉格-杜勒大鼠的肝脏制备用于埃姆斯测试的S9混合物
剂量:
78.1、156.3、312.5、625、1250、2500或5000μg/板
测试方法:
在37℃下培养细菌细胞8小时之后,通过分光光度计测量细胞悬浮液的光密度(在660nm下)以确定细菌是否生长良好。由光密度计算的细胞数经证实在可接受的范围内(细胞数:≥1×109/mL)。在存在或不存在S9混合物的情况下,使用预孵育方法(37℃,20分钟),将细胞暴露于测试品。与顶层琼脂混合之后,将细胞铺展在板上。将板在37℃下孵育48小时。检查顶层琼脂、溶剂和测试品溶液的细菌污染情况。
诱变性的标准:
如果在存在或不存在S9混合物的任何测试菌株中测试品诱导回复突变菌落数的剂量依赖性增加至等于或大于平均阴性对照值2倍的水平,则确定测试品为阳性。
实验实施例6体外微核测定
材料和方法
测试系统:
源自人类淋巴母细胞的TK6细胞
培养条件:
将细胞在37℃和5%CO2下在6孔塑料板中用补充有10vol%热灭活马血清、2mmol/L丙酮酸钠、100单位/毫升青霉素和100μg/mL链霉素的RPMI1640培养。
代谢活化系统:
从用苯巴比妥和5,6-苯并黄酮处理的7周龄雄性斯普拉格-杜勒大鼠的肝脏制备大鼠肝脏S9混合物。
处理条件:
(1)用S9混合物处理3小时,随后培养21小时,(2)在没有S9混合物的情况下连续处理24小时
剂量:
450.0μg/mL至12.6μg/mL
对每一浓度制备一式两份的培养物。
细胞毒性:
对细胞数目进行计数,并且使用下式计算作为细胞毒性评价指标的相对群体倍增值(RPD):
*:1×105个细胞/毫升
微核观察:
对于每种处理条件,基于测试品的沉淀和细胞毒性选择用于微核分析的最高浓度,并且检查两种较低的连续浓度。使用显微镜对4,000个具有细胞质的单核细胞中的微核细胞的数目进行计数。
统计分析:
费歇尔精确检验在5%和1%的上尾显著性水平下进行,以比较每种处理条件下测试品组或阳性对照组中微核细胞的发生率与阴性对照组中微核细胞的发生率。如果费歇尔精确检验在测试品组中显示统计学显著性,则进行精确的科克伦-阿米蒂奇(Cochran-Armitage)趋势检验。
判断标准:
如果任何测试品组之间的微核细胞的发生率满足下面所示的标准(1)和(2)两者,则判断测试品为阳性。
(1)在统计分析中检测到与阴性对照组之间微核细胞发生率的显著差异,并且在统计分析中还检测到剂量依赖性增加。
(2)微核细胞的发生率高于历史对照范围(均值+2SD)。否则,测试品被认为是阴性的。
配制品实施例1(胶囊的产生)
将1)、2)、3)和4)混合,并且填充到明胶中。
配制品实施例2(片剂的产生)
将1)、2)和3)以及4)的总量(30g)与水捏合,真空干燥,并过筛。将过筛的粉末与4)(14g)和5)(1g)混合,并且将混合物通过压片机冲压,由此获得1000个片剂,每片含有30mg实施例1的化合物。
实用性
本发明的化合物具有HDAC抑制活性,并且可以用于治疗包括神经变性疾病(阿尔茨海默病、进行性核上性麻痹等)等的中枢神经系统疾病。
本申请基于2019年9月27日提交的日本专利申请号2019-177815,所述申请的内容全部涵盖在本文中。
Claims (15)
3.根据权利要求1所述的化合物或盐,其中
R1为
(1)C3-10环烷基,其任选地经1至3个卤原子取代,
(2)C6-14芳基,其任选地经1至3个选自以下的取代基取代:(i)卤原子,(ii)氰基,和(iii)任选地经1至3个卤原子取代的C1-6烷基,
(3)5或6元单环芳族杂环基团,其任选地经1至3个选自以下的取代基取代:(i)卤原子,(ii)任选地经1至3个卤原子取代的C1-6烷基,和(iii)C1-6烷氧基,或
(4)3至8元单环非芳族杂环基团,并且
R2为
(1)C3-10环烷基,其任选地经1至3个卤原子取代,
(2)C6-14芳基,其任选地经1至3个选自以下的取代基取代:(i)卤原子,和(ii)任选地经1至3个卤原子取代的C1-6烷基,
(3)5或6元单环芳族杂环基团,其任选地经1至3个选自以下的取代基取代:(i)卤原子,(ii)任选地经1至3个卤原子取代的C1-6烷基,和(iii)C1-6烷氧基,或
(4)3至8元单环非芳族杂环基团。
4.根据权利要求1所述的化合物或盐,其中
R1为
(1)C3-10环烷基,其任选地经1至3个卤原子取代,或
(2)5或6元单环芳族杂环基团,其任选地经1至3个选自以下的取代基取代:(i)卤原子,(ii)任选地经1至3个卤原子取代的C1-6烷基,和(iii)C1-6烷氧基,并且
R2为
(1)C6-14芳基,其任选地经1至3个选自以下的取代基取代:(i)卤原子,和(ii)任选地经1至3个卤原子取代的C1-6烷基,或
(2)5或6元单环芳族杂环基团,其任选地经1至3个选自以下的取代基取代:(i)卤原子,(ii)任选地经1至3个卤原子取代的C1-6烷基,和(iii)C1-6烷氧基。
5.根据权利要求1所述的化合物或盐,其中
R1为
(1)C3-10环烷基,或
(2)6元单环芳族杂环基团,其任选地经1至3个卤原子取代,并且
R2为
(1)C6-14芳基,其任选地经1至3个卤原子取代,或
(2)6元单环芳族杂环基团,其任选地经1至3个卤原子取代。
6.6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2-[(1R,2R)-2-羟基-1,2-二(吡啶-2-基)乙基]-2,3-二氢-1H-异吲哚-1-酮或其盐。
7.6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2-[(1R,2R)-2-(5-氟吡啶-2-基)-2-羟基-1-(吡啶-2-基)乙基]-2,3-二氢-1H-异吲哚-1-酮或其盐。
8.2-[(1R,2R)-1,2-双(5-氟吡啶-2-基)-2-羟基乙基]-6-[5-(二氟甲基)-1,3,4-噁二唑-2-基]-2,3-二氢-1H-异吲哚-1-酮或其盐。
9.一种药物,其包含根据权利要求1所述的化合物或盐。
10.根据权利要求9所述的药物,其是组蛋白脱乙酰酶6抑制剂。
11.根据权利要求9所述的药物,其是用于预防或治疗阿尔茨海默病或进行性核上性麻痹的药剂。
12.根据权利要求1所述的化合物或盐,其用于预防或治疗阿尔茨海默病或进行性核上性麻痹。
13.一种抑制哺乳动物中的组蛋白脱乙酰酶6的方法,其包括向所述哺乳动物施用有效量的根据权利要求1所述的化合物或盐。
14.一种用于预防或治疗哺乳动物中的阿尔茨海默病或进行性核上性麻痹的方法,其包括向所述哺乳动物施用有效量的根据权利要求1所述的化合物或盐。
15.一种根据权利要求1所述的化合物或盐用于产生用于预防或治疗阿尔茨海默病或进行性核上性麻痹的药剂的用途。
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