CN1918119B - 双环酯类衍生物 - Google Patents
双环酯类衍生物 Download PDFInfo
- Publication number
- CN1918119B CN1918119B CN2005800041918A CN200580004191A CN1918119B CN 1918119 B CN1918119 B CN 1918119B CN 2005800041918 A CN2005800041918 A CN 2005800041918A CN 200580004191 A CN200580004191 A CN 200580004191A CN 1918119 B CN1918119 B CN 1918119B
- Authority
- CN
- China
- Prior art keywords
- amino
- ethanoyl
- dicyclo
- nitrile
- suffering
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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Abstract
本发明的目的为提供一种具有优异的DPP-IV抑制活性的新型双环酯类衍生物、或其可药用的盐,即通式(1)所表示的新型双环酯类衍生物、或其可药用的盐(具体例:(2S,4S)-1-[[N-(4-乙氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈)。[化1]
Description
技术领域
本发明涉及一种具有二肽基肽酶IV(DPP-IV)抑制活性的、可用于II型糖尿病等的DPP-IV相关疾病的预防和/或治疗的双环酯类衍生物、或其可药用的盐。
背景技术
二肽基肽酶IV(EC 3.4.14.5,以下称为DPP-IV或CD26)为从N末端第2位上具有脯氨酸或丙氨酸的多肽链开始,在C末端侧对Xaa-Pro或Xaa-Ala(Xaa表示任意氨基酸)所表示的二肽进行特异性水解的丝氨酸蛋白酶的一种。
作为DPP-IV在生物体内的功能的一种,已知有其通过水解胰高血糖素样肽-1(以下称为GLP-1)的N末端的His-Ala的二肽使GLP-1失活的作用(非专利文献1)。除此之外,还认为通过显示由DPP-IV去活化后的非活性型GLP-1对GLP-1受体的拮抗作用,进一步减弱了GLP-1的生理作用(非专利文献2)。GLP-1主要为在小肠肠道上皮上存在的内分泌细胞的L细胞所分泌的肽类激素,可葡糖糖浓度依赖性地对存在与胰岛上的β细胞起作用而促进胰岛素的释放,从而使血糖下降(非专利文献3、4)。另外GLP-1由于刺激胰岛素的合成,并促进β细胞的增殖,是维持β细胞不可或缺的因子(非专利文献5、6)。另外,还有报道证实GLP-1具有在末梢组织促进糖的利用的作用、以及通过在脑内以GLP-1进行给药引起的饮食抑制作用、消化道运动抑制作用等(非专利文献7~10)。
抑制DPP-IV的醇活性的物质,通过其抑制作用抑制内源性的GLP-1的分解以提高GLP-1的作用,其结果可以刺激胰岛素分泌并改善糖代谢。因此,DPP-IV抑制剂被期待作为对糖尿病、特别是对于II型糖尿病的预防和/或治疗剂(非专利文献11、12)。并也很期待其发挥对于由于糖代谢的降低而引发、或恶化的其他疾病(例如糖尿病并发症、高胰岛素血症、血糖过高、脂类代谢异常、肥胖等)的预防和/或治疗的效果。
除了对GLP-1的去活化以外,下面还对DPP-IV在生物体内的功能、与疾病之间的关系进行描述。
(a)DPP-IV的抑制剂或其抗体抑制HIV病毒对细胞内的侵入。在HIV-1感染者来源的T细胞中,CD26的表达减少(非专利文献13)。或者HIV-1Tat蛋白质与DPP-IV相结合(非专利文献14)。
(b)DPP-IV参与免疫应答。DPP-IV的抑制剂或其抗体可抑制因抗原的刺激引起的T细胞增殖(非专利文献15)。而因抗原刺激,T细胞中的DPP-IV的表达增加(非专利文献16)。DPP-IV参与细胞因子的产生等的T细胞的功能(非专利文献17)。而DPP-IV与T细胞表面的腺苷脱氨酶(ADA)相结合(非专利文献18)。
(c)在慢性风湿性关节炎、牛皮癣及扁平苔藓患者的皮肤的成纤维细胞中DPP-IV的表达增加(非专利文献19)。
(d)在良性前列腺肥大的患者及前列腺组织的匀浆中,DPP-IV活性亢进(非专利文献20)。在肺内皮中存在的DPP-IV发挥对于大鼠的肺转移性乳腺癌及前列腺癌的粘合分子的作用(非专利文献21)。
(e)对DPP-IV活性缺失的突变型F344大鼠与野生型F344大鼠相比血压更低、及对在肾脏的钠的再吸收起着重要作用的蛋白质与DPP-IV相互发生作用(专利文献1、2)。
(f)通过抑制DPP-IV活性,可期待骨髓抑制性疾病的预防和/或治疗,DPP-IV活化剂可期待作为白血球数增加剂和/或感染治疗剂(专利文献3)。
从上述信息可知DPP-IV抑制剂可期待成为糖尿病(尤其是II型糖尿病)和/或糖尿病并发症以外的由DPP-IV参与的疾病的预防和/或治疗剂。例如,可用作基于HIV-1感染的AIDS、器官、组织移植中发生的排异反应、多发性硬化症、慢性风湿性关节炎、炎症、过敏、骨质疏松症、牛皮癣及扁平苔癣、良性前列腺肥大、乳腺癌及前列腺癌的肺转移抑制、高血压、利尿、骨髓抑制的降低、白血球数增加、及感染并发症等疾病的有效的药剂。
迄今为止,作为DPP-IV抑制剂在(专利文献4-11)中公开了吡咯烷衍生物,在(专利文献12、13)中公开了杂环衍生物,在(专利文献14、15)中公开了β氨基酸衍生物。
另外,虽然在(专利文献16)中公开了具有DPP-IV抑制活性的 双环[2.2.2]辛烷衍生物的1种化合物,但本发明与该美国的专利在结构、DPP-IV抑制活性方面是完全不同的。而在(专利文献17)中,有与本发明在结构上近似的双环衍生物的记载,但其记载的内容对本发明的化合物并无任何具体的说明,而也不是本发明中经实施例说明的任何一种化合物。
迄今为止公开的DPP-IV抑制剂中的任一种的均无法满足DPP-IV抑制活性、DPP-IV选择性、稳定性、毒性、及体内动态的理想的要求,对优异的DPP-IV抑制剂的需求时刻存在。
非专利文献1:American Journal of Physiology,271卷,E458-E464页(1996年)
非专利文献2:European Journal of Pharmacology,318卷,429-435页(1996年)
非专利文献3:European Journal Clinical Investigation,22卷,154页(1992年)
非专利文献4:Lancet,2卷,1300页(1987年)
非专利文献5:Endocrinology,42卷,856页(1992年)
非专利文献6:Diabetologia,42卷,856页(1999年)
非专利文献7:Endocrinology,135卷,2070页(1994年)
非专利文献8:Diabetologia,37卷,1163页(1994年)
非专利文献9:Digestion,54卷,392页(1993年)
非专利文献10:Dig.Dis.Sci.,43卷,1113页(1998年)
非专利文献11:Diabetes,47卷,1663-1670页(1998年)
非专利文献12:Diabetologia,42卷,1324-1331页(1999年)
非专利文献13:Journal of Immunology,149卷,3073页(1992年)
非专利文献14:Journal of Immunology,150卷,2544页(1993年)
非专利文献15:Biological Chemistry,305页(1991年)
非专利文献16:Scandinavian Journal of Immunology,33卷,737页(1991年)
非专利文献17:Scandinavian Journal of Immunology,29卷,127页(1989年)
非专利文献18:Science,261卷,446页(1993年)
非专利文献19:Journal of Cellular Physiology,151卷,378页(1992 年)
非专利文献20:European Journal of Clinical Chemistry andClinical Biochemistry,30卷,333页(1992年)
非专利文献21:Journal of Cellular Physiology,121卷,1423页(1993年)
专利文献1:WO 03/015775小册子
专利文献2:WO 03/017936小册子
专利文献3:WO 03/080633小册子
专利文献4:WO 95/15309小册子
专利文献5:WO 98/19998小册子
专利文献6:WO 00/34241小册子
专利文献7:WO 02/14271小册子
专利文献8:WO 02/30890小册子
专利文献9:WO 02/38541小册子
专利文献10:WO 03/002553小册子
专利文献11:US 02/0193390公报
专利文献12:WO 02/062764小册子
专利文献13:WO 03/004496小册子
专利文献14:WO 03/000180小册子
专利文献15:WO 03/004498小册子
专利文献16:US 02/0193390公报
专利文献17:WO 02/38541小册子
发明内容
本发明要解决的问题在于提供一种具有优异的DPP-IV抑制活性的新型化合物、或其可药用的盐。另外,还提供一种含有具有优异的DPP-IV抑制活性的新型化合物或其可药用的盐的药物组合物、以及糖尿病及其并发症的预防和/或治疗剂或对DPP-IV相关的疾病的预防和/或治疗剂。
本发明提供一种具有优异的DPP-IV抑制活性的新型双环酯类衍生物、或其可药用的盐。另外,还提供一种含有具有优异的DPP-IV抑制活性的新型双环酯类衍生物或其可药用的盐的药物组合物、以及糖 尿病及其并发症的预防和/或治疗剂或对DPP-IV相关的疾病的预防和/或治疗剂。
即,本发明涉及:
1)通式(1)所表示的双环酯类衍生物、或其可药用的盐,
[化1]
[式中,R1表示可以被取代的C1~C6的烷基、可被取代的芳甲基、可被取代的芳乙基,
X表示CH2、CHF或CF2,
n表示1或2。];
2).1)所述的双环酯类衍生物、或其可药用的盐,通式(1)中,X是CH2。
3).1)所述的双环酯类衍生物、或其可药用的盐,通式(1)中,X是CHF。
4).1)-3)任意一项所述的双环酯类衍生物、或其可药用的盐,通式(1)中,n是1。
5).1)-3)所述的双环酯类衍生物、或其可药用的盐,通式(1)中,n是2。
6).1)-5)任意一项所述的双环酯类衍生物、或其可药用的盐,通式(1)中,R1是C1~C6的烷基,所述C1~C6的烷基可以具有1-5个选自卤素原子、羟基、氰基、C1~C6的烷氧基、可被取代的芳氧基、C1~C6的烷基羰基、C1~C6的烷氧基羰基、C1~C6的烷硫基、氨基、单或二取代的C1~C6的烷基氨基、可含有1~3个杂环原子的4~9元的环状氨基、甲酰氨基、C1~C6的烷基羰基氨基、C1~C6的烷氧基羰基氨基、C1~C6的烷基磺酰氨基、及可被取代的芳基磺酰氨基的取代基。
7).1)-5)任意一项所述的双环酯类衍生物、或其可药用的盐,通式(1)中,R1是选自甲基、乙基、丙基、1-甲基乙基、1-甲基丙基、2-甲基丙基、1-乙基丙基、2-乙基丙基、丁基、及己基中之一的烷基。
8).1)所述的双环酯类衍生物、或其可药用的盐,通式(1)表示的化合物是选自:
(2S,4S)-1-[[N-(4-乙氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈、
(2S)-1-[[N-(4-乙氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]吡咯烷-2-腈、
(2S,4S)-1-[[N-(4-乙氧基羰基双环[2.2.1]庚-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈、
(2S)-1-[[N-(4-乙氧基羰基双环[2.2.1]庚-1-基)氨基]乙酰基]吡咯烷-2-腈、
(2S,4S)-1-[[N-(4-苄氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈、
(2S,4S)-4-氟-1-[[N-[4-(4-三氟甲基)苄氧基羰基双环[2.2.2]辛-1-基]氨基]乙酰基]吡咯烷-2-腈、
(2S,4S)-4-氟-1-[[N-(4-异丁氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]吡咯烷-2-腈、和
(2S,4S)-4-氟-1-[[N-(4-异丙氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]吡咯烷-2-腈中之一的化合物。9)药物,其特征为含有1)-8)任意一项所述的双环酯类衍生物、或其可药用的盐作为有效成分;
10)DPP-IV抑制剂,其特征为含有1)-8)任意一项所述的双环酯类衍生物、或其可药用的盐作为有效成分;
11)糖尿病和/或糖尿病并发症的治疗剂,其特征为含有权利要求1-8任意一项所述的双环酯类衍生物、或其可药用的盐作为有效成分。
此处的可被取代的C1~C6的烷基指可以含有1~5个选自下面的取代基:卤素原子、羟基、氰基、C1~C6的烷氧基、可被取代的芳氧基、 C1~C6的烷基羰基、C1~C6的烷氧基羰基、C1~C6的烷硫基、氨基、单或二取代的C1~C6的烷基氨基、可含有1~3个杂环原子的4~9元的环状氨基、甲酰氨基、C1~C6的烷基羰基氨基、C1~C6的烷氧基羰基氨基、C1~C6的烷基磺酰氨基、及可被取代的芳基磺酰氨基的C1~C6的烷基(甲基、环丙基甲基、乙基、丙基、1-甲基乙基、1-甲基丙基、2-甲基丙基、1-乙基丙基、2-乙基丙基、丁基、叔丁基、或己基)。
可被取代的芳甲基指可以含有1~5个选自下面的取代基:卤素原子、可被取代的C1~C6的烷基、羟基、氰基、硝基、可被取代的C1~C6的烷氧基、可被取代的芳氧基、C1~C6的烷基羰基、C1~C6的烷氧基羰基、C1~C6的烷硫基、氨基、单或二取代的C1~C6的烷基氨基、可被取代的芳基氨基、可含有1~3个杂环原子的4~9元的环状氨基、甲酰氨基、C1~C6的烷基羰基氨基、C1~C6的烷氧基羰基氨基、C1~C6的烷基磺酰氨基、及可被取代的芳基磺酰氨基的芳甲基(苄基、萘甲基、吡啶甲基、喹啉甲基、或吲哚基甲基)。
可被取代的芳乙基指可以含有1~5个选自下面的取代基:卤素原子、可被取代的C1~C6的烷基、羟基、氰基、硝基、可被取代的C1~C6的烷氧基、可被取代的芳氧基、C1~C6的烷基羰基、C1~C6的烷氧基羰基、C1~C6的烷硫基、氨基、单或二取代的C1~C6的烷基氨基、可被取代的芳基氨基、可含有1~3个杂环原子的4~9元的环状氨基、甲酰氨基、C1~C6的烷基羰基氨基、C1~C6的烷氧基羰基氨基、C1~C6的烷基磺酰氨基、及可被取代的芳基磺酰氨基的芳乙基(1-苯乙基、2-苯乙基、1-萘乙基、或2-萘乙基)。
本发明优选的化合物可举出例如
(2S,4S)-1-[[N-(4-乙氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈、
(2S)-1-[[N-(4-乙氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]吡咯烷-2-腈、
(2S)-1-[[N-(4-叔丁氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]吡咯烷-2-腈、
(2S,4S)-1-[[N-[4-(2-四氢吡喃基)氧基羰基双环[2.2.2]辛-1-基]氨基]乙酰基]-4-氟代吡咯烷-2-腈、
(2S)-1-[[N-[4-(2-四氢吡喃基)氧基羰基双环[2.2.2]辛-1-基]氨基] 乙酰基]吡咯烷-2-腈、
(2S,4S)-1-[[N-(4-乙氧基羰基双环[2.2.1]庚-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈、
(2S)-1-[[N-(4-乙氧基羰基双环[2.2.1]庚-1-基)氨基]乙酰基]吡咯烷-2-腈、
(2S,4S)-1-[[N-(4-苄氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈、
(2S,4S)-1-[[N-(4-环丙甲氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈、
(2S,4S)-4-氟-1-[[N-[4-(4-三氟甲基)苄氧基羰基双环[2.2.2]辛-1-基]氨基]乙酰基]吡咯烷-2-腈、
(2S,4S)-4-氟-1-[[N-(4-异丁氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]吡咯烷-2-腈、
(2S,4S)-4-氟-1-[[N-(4-异丙氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]吡咯烷-2-腈等。
本发明的化合物为具有优异的DPP-IV抑制活性的新型化合物,并提供糖尿病及其并发症的预防和/或治疗剂、或对于DPP-IV参与的疾 病的预防和/或治疗剂。
附图说明
[图1]表示实验例3的测定结果的图表。
具体实施方式
本发明化合物在形成可药用的盐的情况下,可例举出与盐酸、氢溴酸、硫酸、硝酸、及磷酸等无机酸、或醋酸、马来酸、富马酸、琥珀酸、乳酸、苹果酸、酒石酸、柠檬酸、甲磺酸、对甲苯磺酸、苯磺酸、水杨酸、硬脂酸、棕榈酸、及三氟醋酸等有机酸形成的盐、钠盐、钾盐、钙盐、镁盐、铝盐、及锌盐等金属盐、铵盐及四甲基铵盐等铵盐、吗啉、及哌啶等有机铵盐、及与甘氨酸、赖氨酸、精氨酸、苯丙氨酸及脯氨酸等氨基酸所成的盐。
上述通式(1)所表示的本发明的化合物或其盐中可能存在基于1个或2个以上的手性中心的多个光学异构体,本发明包含这些光学异构体或非对映异构体中的任一种,及它们的任意比率的混合物或外消旋体。另外,上述通式(1)表示的本发明化合物或其盐含有双键时,其配置可为Z或E中的任一种,本发明中还包含它们任意比率的混合物。另外,上述通式(1)表示的本发明化合物或其盐中可能存在互变异构体、内旋异构体,本发明中还包含它们各自的异构体及它们任意比率的混合物。
上述通式(1)表示的本发明的化合物或其盐可含有分子内盐或加成产物、其溶剂合物或水合物等中的任一种。
上述通式(1)表示的本发明化合物或其盐可采用单独或一种以上的制剂上允许的辅料形成药物组合物进行使用,例如可混合可药用的载体、赋形剂(例如淀粉、乳糖、磷酸钙、或碳酸钙等)、润滑剂(例如硬脂酸镁、硬脂酸钙滑石粉、或硬脂酸等)、粘合剂(例如淀粉、结晶纤维素、羧甲基纤维素、阿拉伯胶、聚乙烯吡咯烷酮、或藻酸等)、崩解剂(例如滑石粉、或羧甲基纤维素钙等)、稀释剂(例如生理盐水、葡萄糖、甘露糖、或乳糖等的水溶液等)等,采用常用的方法制成片剂、胶囊剂、颗粒剂、散剂、细粒剂、粉针剂或注射剂等形态以口服或非口服的方式进行给药。给药量根据上述通式(1)表示的本发明的化合物或 其盐类的种类、给药方法、患者的年龄、体重、症状等而不同,通常对于包含人的哺乳动物,上述通式(1)表示的本发明的化合物或其盐为0.0001~1000mg/kg/天。给药可例如为1天1次或数次分开给药。
上述通式(1)表示的本发明的化合物及其盐可根据需要与一种以上的DPP-IV抑制剂以外的糖尿病治疗剂合并使用。作为与本发明的化合物或其盐合并使用的糖尿病治疗剂,可举出胰岛素及其衍生物、GLP-1及其衍生物、其他口服糖尿病治疗剂。作为口服糖尿病治疗剂可举出磺酰脲类糖尿病治疗剂、非磺酰脲类胰岛素分泌促进剂、双胍类糖尿病治疗剂、α-糖苷酶抑制剂、胰高血糖素拮抗剂、GLP-1激动剂、PPAR激动剂、β3激动剂、SGLT抑制剂、PKC抑制剂、胰高血糖素合成酶激酶-3(GSK-3)抑制剂、蛋白酪氨酸磷酸酶-1B(PTP-1B)抑制剂、钾离子通道活化剂、胰岛素增敏剂、葡萄糖摄取调节剂、脂质代谢作用剂、食欲抑制剂等。
其中作为GLP-1、其衍生物可举出ベタトロピン或NN-2211等;磺酰脲类糖尿病治疗剂可举出甲苯磺丁脲、格列本脲、格列齐特、格列美脲、格列吡嗪等;非磺酰脲类胰岛素分泌促进剂可举出那格列萘、瑞格列奈、米格列奈(ミチグリニド)、及JTT-608等;双胍类糖尿病治疗剂可举出甲福明二甲双胍等;α-糖苷酶抑制剂可举出伏格列波糖、米格列醇等;PPAR激动剂可举出曲格列酮、罗格列酮、吡格列酮、环格列酮、KRP-297(MK-767)、Isaglitazone、GI-262570、JTT-501等;β3激动剂可举出AJ-9677、YM-178或N-5984等。
本发明化合物(1)可通过各种合成法制造。本发明化合物(1)可通过常用的分离方法(例如提取、重结晶、蒸馏、色谱等)进行分离、纯化。另外,得到的化合物形成盐的时候,可通过常用的方法或类似的方法(例如中和等)制造各种盐。
下面,对本发明化合物及其盐的代表性的制造工序进行说明。
A法
[化3]
A法第一工序
本工序为,使通式(3)(式中R1及n的意义与上述相同)所表示的双环胺类衍生物,与通式(4)(式中,Y1表示Cl或Br。X的意义与上述相同)所表示的卤代醋酸衍生物反应,以制造通式(1)(式中R1、n及X的意义与上述相同)表示的双环酯类衍生物的工序。本反应在碱的存在下或无碱存在下进行。本反应中使用碱时,可例举出氢氧化钠、氢氧化钾、碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、碳酸铯等无机碱;或三乙胺、二异丙基乙基胺、N,N,N,N-四甲基乙二胺、二氮杂双环[5.4.0]-7-十一碳烯、二氮杂双环[4.3.0]-5-壬烯、磷腈碱或五异丙基胍等有机碱类。本反应中使用催化剂时,可例举出溴化四丁基铵、碘化四丁基铵、溴化苄基三乙基铵、溴化锂、碘化锂、碘化钠、溴化钾、碘化钾、溴化铯、碘化铯等相关的相转移催化剂或无机盐。本反应中使用的溶剂可使用不参与反应的惰性溶剂,例如丙酮、乙醇、甲苯、乙腈、四氢呋喃、二噁烷、乙醚、叔丁基甲基醚、二甲氧基乙烷、醋酸乙酯、二氯甲烷、N,N-二甲基甲酰胺、二甲基亚砜、N-甲基-2-吡咯烷酮等。反应可在0~150℃下顺利进行。
B法
B法第一工序
本工序为,使通式(5)(式中P2为羧基的保护基,n的意义与上述相同)所表示的双环胺类衍生物,与通式(4)(式中,X及Y1的意义与上述相同)所表示的卤代醋酸衍生物相反应,以制造通式(6)(式中P2、n及X的意义与上述相同)表示的双环酯类衍生物的工序。本 反应在碱的存在下或无碱存在下进行。本反应中使用碱时,可例举出氢氧化钠、氢氧化钾、碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、碳酸铯等无机碱;或三乙胺、二异丙基乙基胺、N,N,N,N-四甲基乙二胺、二氮杂双环[5.4.0]-7-十一碳烯、二氮杂双环[4.3.0]-5-壬烯、磷腈碱或五异丙基胍等有机碱类。本反应中使用催化剂时,可例举出溴化四丁基铵、碘化四丁基铵、溴化苄基三乙基铵、溴化锂、碘化锂、碘化钠、溴化钾、碘化钾、溴化铯、碘化铯等相关的相转移催化剂或无机盐。本发明中使用的溶剂可使用不参与反应的惰性溶剂,例如丙酮、乙醇、甲苯、乙腈、四氢呋喃、二噁烷、乙醚、叔丁基甲基醚、二甲氧基乙烷、醋酸乙酯、二氯甲烷、N,N-二甲基甲酰胺、二甲基亚砜、N-甲基-2-吡咯烷酮等。反应可在0~150℃下顺利进行。
B法第二工序
本工序为,对通式(6)(式中P2、n及X的意义与上述相同)所表示的双环酯类衍生物的仲胺基进行保护,以制造通式(7)(式中P1 为氨基的保护基,P2、n及X的意义与上述相同)表示的权利要求2所述的双环酯类衍生物的工序。仲胺基的保护基的P1可例举出叔丁氧基羰基、苄氧基羰基、三氟乙酰基等,分别经公知的方法导入。例如P1为叔丁氧基羰基时,可使用通式(6)(式中P2、n及X的意义与上述相同)所表示的双环酯类衍生物,与二叔丁基二碳酸酯在三乙胺或4-二甲基氨基吡啶存在或不存在的情况下进行反应而容易地制得。P1 为苄氧基羰基时,可使用通式(6)(式中P2、n及X的意义与上述相同)所表示的双环酯类衍生物,与苄氧基碳酰氯在三乙胺、二异丙基乙胺、或碳酸钾的存在下进行反应而容易地制得。P1为三氟乙酰基时,可使用通式(6)(式中P2、n及X的意义与上述相同)所表示的双环酯类衍生物,与三氟醋酸酐在三乙胺、N,N-二甲基氨基吡啶的存在下进行反应而容易地制得。
B法第三工序
本工序为,除去通式(7)(式中P2、P1、n及X的意义与上述相同)所表示的双环酯类衍生物的羧基保护基P2,以制造通式(8)(式中P1、n及X的意义与上述相同)表示的双环酯类衍生物的工序。P2 的除去可通过公知的方法进行实施。例如,P2为叔丁基时,可通过使用三氟醋酸、氯化氢-二噁烷溶液等,容易地进行除去。而P2为苄基时, 可通过组合使用钯碳和氢或钯碳和甲酸铵的方法,容易地进行除去。而P2为四氢吡喃基时,可通过醋酸或对甲苯磺酸、或盐酸等容易地进行除去。
B法第四工序
本工序为,通过对通式(8)(式中P1、n及X的意义与上述相同)所表示的双环衍生物进行酯化或烷基化,以制造通式(9)(式中R1、P1、n及X的意义与上述相同)表示的双环酯类衍生物的工序。通过酯化制造通式(9)(式中R1、P1、n及X的意义与上述相同)表示的双环酯类衍生物时,可使用通式(8)(式中P1、n及X的意义与上述相同)所表示的双环衍生物与R1OH(式中,R1的意义与上述相同)表示的醇类衍生物在缩合剂的存在下酯化,以制造通式(9)(式中R1、P1、n及X的意义与上述相同)表示的双环酯类衍生物。作为本工序的酯化反应的缩合剂可举出二环己基碳二亚胺(DCC)、3-乙基-1-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDCI)、氯化二甲基咪唑鎓(DMC)、氯代甲酸乙酯、氯代甲酸异丁酯、或新戊酰氯等,它们可以固态、液态或溶解于适当的溶剂的溶液状态进行添加。本缩合反应中使用碱时,可例举出碳酸氢钠或碳酸钾等碱性碳酸盐、三乙胺、二异丙基乙胺、N-甲基吗啉、二氮杂双环[5.4.0]-7-十一碳烯、吡啶、4-二甲基氨基吡啶或1,8-双(二甲氨基)萘等叔胺类。本缩合反应中使用的溶剂可使用不参与反应的惰性溶剂,例如N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜、乙腈、四氢呋喃、二噁烷、乙醚、二甲氧乙烷、醋酸乙酯、甲苯、二氯甲烷等。本缩合反应可在-20~150℃下顺利进行。
通过烷基化制造通式(9)(式中R1、P1、n及X的意义与上述相同)表示的双环酯类衍生物时,可使用(8)(式中P1、n及X的意义与上述相同)所表示的双环衍生物与R1Y2(式中,Y2为Cl、Br、I、OMs、OTs或OTf,R1的意义与上述相同)在存在或不存在碱的情况下反应,以制造通式(9)(式中R1、P1、n及X的意义与上述相同)表示的双环酯类衍生物。本反应中使用碱时,可例举出碳酸氢钠、碳酸钾或碳酸铯等碱性碳酸盐、三乙胺、二异丙基乙胺、N-甲基吗啉、二氮杂双环[5.4.0]-7-十一碳烯、吡啶、4-二甲基氨基吡啶或1,8-双(二甲氨基)萘、磷腈碱或五异丙基胍等叔胺类。本反应中使用催化剂时,可例举出溴化四丁基铵、碘化四丁基铵、溴化苄基三乙基铵、溴化锂、 碘化锂、碘化钠、溴化钾、碘化钾、溴化铯、碘化铯等相关的相转移催化剂或无机盐。本反应中使用的溶剂可使用不参与反应的惰性溶剂,例如丙酮、乙醇、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜、乙腈、四氢呋喃、二噁烷、乙醚、二甲氧基乙烷、醋酸乙酯、甲苯、二氯甲烷等。本反应可在-30~150℃下顺利进行。
B法第五工序
本工序为,将通式(8)(式中P1、n及X的意义与上述相同)所表示的双环衍生物,转化为通式(10)[式中,W为反应性残基(例如卤素原子、1-咪唑基、4-硝基苯氧基、五氟苯氧基、琥珀酸酰亚胺氧基、或1-苯并三唑氧基(或1-苯并三唑基3-氧基)等表示的羧酸的卤化物、羧酸的咪唑化物(イミダゾロド)、羧酸的活性酯),P1、n及X的意义与上述相同]表示的双环酯类衍生物的工序。本工序可通过公知的方法容易地实施。例如,W为琥珀酸酰亚胺氧基时,可通过使通式(8)(式中P1、n及X的意义与上述相同)所表示的双环衍生物,与N-羟基琥珀酸在缩合剂的存在下反应而容易地制得。而W为苯并三唑氧基(或1-苯并三唑基3-氧基)时,可通过使通式(8)(式中P1、n及X的意义与上述相同)所表示的双环衍生物,与1-羟基苯并三唑在缩合剂的存在下反应而容易地制得。作为本工序的缩合剂可举出二环己基碳二亚胺(DCC)、3-乙基-1-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDCI)、氯化二甲基咪唑鎓(DMC)、氯代甲酸乙酯、氯代甲酸异丁酯、或新戊酰氯等,它们可以固态、液态或溶解于适当的溶剂的溶液状态进行添加。本缩合反应中使用碱时,可例举出碳酸氢钠或碳酸钾等碱性碳酸盐、三乙胺、二异丙基乙胺、N-甲基吗啉、二氮杂双环[5.4.0]-7-十一碳烯、吡啶、4-二甲基氨基吡啶或1,8-双(二甲氨基)萘等叔胺类。本缩合中使用的溶剂可使用不参与反应的惰性溶剂,例如N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜、乙腈、四氢呋喃、二噁烷、乙醚、二甲氧乙烷、醋酸乙酯、甲苯、二氯甲烷等。本缩合反应可在-20~150℃下顺利进行。通式(10)(式中,W、P1、n及X的意义与上述相同)表示的双环酯类衍生物可经过分离纯化用于下一工序,也可不经分离直接以粗制产物用于下一工序。
B法第六工序
本工序为,使通式(10)(式中,W、P1、n及X的意义与上述相同)所表示的双环胺类衍生物,与R1OH(式中,R1的意义与上述相同) 所表示的醇类衍生物反应,以制造通式(9)(式中,R1、P1、n及X的意义与上述相同)表示的双环酯类衍生物的工序。本反应中使用碱时,可例举出氢氧化钠、氢氧化钾、碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、碳酸铯等无机碱;或三乙胺、二异丙基乙基胺、N,N,N,N-四甲基乙二胺、二氮杂双环[5.4.0]-7-十一碳烯、二氮杂双环[4.3.0]-5-壬烯、4-二甲基氨基吡啶、磷腈碱或五异丙基胍等有机碱类。本反应中使用的溶剂可使用不参与反应的惰性溶剂,例如甲苯、乙腈、四氢呋喃、二噁烷、乙醚、叔丁基甲基醚、二甲氧基乙烷、醋酸乙酯、二氯甲烷、N,N-二甲基甲酰胺、二甲基亚砜、N-甲基-2-吡咯烷酮等。反应可在-30~150℃下顺利进行。
B法第七工序
本工序为,除去通式(9)(式中,R1、P1、n及X的意义与上述相同)表示的双环酯类衍生物的仲氨基保护基P1,以制造通式(1)(式中R1、n及X的意义与上述相同)表示的双环酯类衍生物的工序。P1 的除去可通过公知的方法进行实施。例如,P1为叔丁氧基羰基时,可通过使用三氟醋酸、氯化氢-二噁烷溶液等,容易地进行除去。而P1 为苄氧氧基羰基时,可通过组合使用钯碳和氢、或钯碳和甲酸铵的方法,容易地进行除去。而P1为三氟乙酰基时,可通过使用氨水-甲醇溶液等容易地进行除去。
C法
C法第一工序
本工序为,通过酯化或烷基化,制造通式(1)(式中R1、n及X的意义与上述相同)表示的双环酯类衍生物的工序。通过酯化制造(1)(式中R1、n及X的意义与上述相同)表示的双环酯类衍生物时,可使用通式(11)(式中n及X的意义与上述相同)表示的双环衍生物与R1OH(式中,R1 的意义与上述相同)所表示的醇类衍生物在缩合剂的存在下进行酯化,以制造通式(1)(式中,R1、n及X的意义与上述相同)表示的双环酯类衍 生物的工序。作为本工序的酯化反应的缩合剂可举出二环己基碳二亚胺(DCC)、3-乙基-1-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDCI)、氯化二甲基咪唑鎓(DMC)、氯代甲酸乙酯、氯代甲酸异丁酯、或新戊酰氯等,它们可以固态、液态或溶解于适当的溶剂的溶液状态进行添加。本缩合反应中使用碱时,可例举出碳酸氢钠或碳酸钾等碱性碳酸盐、三乙胺、二异丙基乙胺、N-甲基吗啉、二氮杂双环[5.4.0]-7-十一碳烯、吡啶、4-二甲基氨基吡啶或1,8-双(二甲氨基)萘等叔胺类。本缩合反应中使用的溶剂可使用不参与反应的惰性溶剂,例如N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜、乙腈、四氢呋喃、二噁烷、乙醚、二甲氧乙烷、醋酸乙酯、甲苯、二氯甲烷等。本缩合反应可在-20~150℃下顺利进行。另外,本缩合反应还可经由具有以下基团:1-咪唑基、4-硝基苯氧基、五氟苯氧基、琥珀酸酰亚胺氧基、或1-苯并三唑氧基(或1-苯并三唑基3-氧基)的活性酯类、酰氯进行实施,此时,活性酯类、酰氯可经过分离纯化用于下一工序,也可不经分离直接以粗制产物用于下一工序。
通过烷基化制造(1)(式中R1、n及X的意义与上述相同)表示的双环酯类衍生物时,可使用通式(11)(式中n及X的意义与上述相同)表示的双环衍生物与R1Y2(式中,Y2及R1的意义与上述相同)在存在或不存在碱的情况下进行反应,以制造通式(1)(式中,R1、n及X的意义与上述相同)表示的双环酯类衍生物。本缩合反应中使用碱时,可例举出碳酸氢钠、碳酸钾或碳酸铯等碱性碳酸盐、三乙胺、二异丙基乙胺、N-甲基吗啉、二氮杂双环[5.4.0]-7-十一碳烯、吡啶、4-二甲基氨基吡啶或1,8-双(二甲氨基)萘、磷腈或五甲基氨基吡啶等叔胺类。本反应中使用催化剂时,可例举出溴化四丁基铵、碘化四丁基铵、溴化苄基三乙基铵、溴化锂、碘化锂、碘化钠、溴化钾、碘化钾、溴化铯、碘化铯等相关的相转移催化剂或无机盐。本反应中使用的溶剂可使用不参与反应的惰性溶剂,例如丙酮、乙醇、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜、乙腈、四氢呋喃、二氧杂环己烷、乙醚、二甲氧乙烷、醋酸乙酯、甲苯、二氯甲烷等。本反应可在-30~150℃下顺利进行。
下面通过实验例及实施例说明本发明的效果,但本发明并不受实验例及实施例的限定。
<参考例1>
4-氨基双环[2.2.2]辛烷-1-羧酸乙酯的合成
第一工序:
4-苄氧基羰基氨基双环[2.2.2]辛烷-1-羧酸甲酯的合成
将双环[2.2.2]辛烷-1,4-二羧酸氢甲基(25.0g)、二苯基磷酰基叠氮化物(32.5g)、三乙胺(17.3mL)及甲苯(500mL)混合,在室温下搅拌2小时,然后加热回流2小时。在反应混合物中加入苄氧醇(122mL),进一步加热回流17小时。冷却后,以10%柠檬酸水溶液、饱和碳酸氢钠水溶液、及饱和食盐水的顺序洗涤反应混合物,以无水硫酸钠干燥后,减压浓缩。以硅胶柱层析色谱(洗脱溶剂,己烷∶醋酸乙酯=2∶1)对残渣进行纯化,得到4-苄氧基羰基氨基双环[2.2.2]辛烷-1-羧酸甲酯(32.2g)。
MS(FAB+)m/z:318(MH+)。
第二工序:
4-苄氧基羰基氨基双环[2.2.2]辛烷-1-羧酸的合成
将4-苄氧基羰基氨基双环[2.2.2]辛烷-1-羧酸(64.3g)溶解在乙醇(1100mL)中,加入1mol/L氢氧化钠水溶液(1000mL),在50℃下搅拌1小时。减压蒸馏除去反应液中的乙醇,以乙醚(500mL)洗涤残渣后,以浓盐酸调成酸性(pH1)。过滤提取析出的结晶,水洗后,减压干燥得到4-苄氧基羰基氨基双环[2.2.2]辛烷-1-羧酸(56.1g)。
MS(FAB+)m/z:304(MH+)。
第三工序:
4-苄氧基羰基氨基双环[2.2.2]辛烷-1-羧酸乙酯的合成
将4-苄氧基羰基氨基双环[2.2.2]辛烷-1-羧酸(56.0g)溶解在N,N-二甲基甲酰胺(1000mL)中,加入碳酸氢钠(46.6g),然后加入乙基碘(22.2mL),在50-60℃下搅拌5小时。在反应混合物中追加碳酸氢钠(46.6g)及乙基碘(22.2mL),在50-60℃下进一步搅拌3小时。过滤除去反应混合物中的不溶物,减压浓缩滤液。将残渣溶解于醋酸乙酯(700mL)中并用水洗涤,以无水硫酸钠干燥后,减压干燥。以硅胶柱层析色谱(洗脱溶剂,己烷∶醋酸乙酯=2∶1→醋酸乙酯)对残渣进行纯化,得到4-苄氧基羰基氨基双环[2.2.2]辛烷-1-羧酸乙酯(56.8g)。
MS(FAB+)m/z:332(MH+)。
第四工序:
4-氨基双环[2.2.2]辛烷-1-羧酸乙酯的合成
将4-苄氧基羰基氨基双环[2.2.2]辛烷-1-羧酸乙酯(40.0g)溶解在乙醇(400mL)中,加入10%钯碳(4.00g),在氢气流中、室温下搅拌6小时。使用钙铁石(セライト)垫将反应混合物中的催化剂过滤除去,用乙醇洗涤催化剂及钙铁石垫。将滤液和洗涤液一同减压浓缩,对残渣减压干燥得到4-氨基双环[2.2.2]辛烷-1-羧酸乙酯(23.9g)。
MS(EI+)m/z:197(M+)。
<参考例2>
4-氨基双环[2.2.2]辛烷-1-羧酸1,1-二甲基乙酯的合成
第一工序:
双环[2.2.2]辛烷-1,4-二羧酸1,1-二甲基乙基甲酯的合成
将双环[2.2.2]辛烷-1,4-二羧酸氢甲基(500mg)溶解于二氯甲烷(5mL)中,加入硫酸(50μl),在食盐-冰浴上冷却的同时在5分钟内吹入异丁烯后,室温下搅拌4小时,进一步放置4天。在反应混合物中加入二氯甲烷(5mL)进行稀释,以饱和碳酸氢钠水溶液、然后是饱和食盐水进行洗涤,以无水硫酸钠干燥后,减压浓缩。对残渣减压干燥后,得到双环[2.2.2]辛烷-1,4-二羧酸1,1-二甲基乙基甲酯(497mg)。
MS(FAB+)m/z:269(MH+)。
第二工序:
双环[2.2.2]辛烷-1,4-二羧酸氢1,1-二甲基乙酯的合成
将双环[2.2.2]辛烷-1,4-二羧酸1,1-二甲基乙基甲酯(495mg)溶解于甲醇(5mL)中,加入2mol/L氢氧化钠水溶液(0.92mL),在室温下搅拌8小时,进一步在50℃下搅拌2小时。将反应混合物中的甲醇减压蒸馏除去,在残渣中加入水以乙醚洗涤后,用3mol/L盐酸中和。过滤提取析出的结晶并水洗后,减压干燥得到双环[2.2.2]辛烷-1,4-二羧酸氢1,1-二甲基乙酯(344mg)。
1H NMR(CDCl3)δ1.41(s,9H),1.72-1.87(m,12H)。
第三工序:
4-苄氧基羰基氨基双环[2.2.2]辛烷-1-羧酸1,1-二甲基乙酯的合成
使用双环[2.2.2]辛烷-1,4-二羧酸氢1,1-二甲基乙酯(340mg),按照参考例1的第一工序同样的方法进行反应,得到4-苯氧基羰基氨基双环[2.2.2]辛烷-1-二羧酸1,1-二甲基乙酯(433mg)。
1H NMR(CDCl3)δ1.41(s,9H),1.84(s,12H),4.48-4.62(br,1H),5.03(s,2H),7.28-7.38(m,5H)。
第四工序
4-氨基双环[2.2.2]辛烷-1-羧酸1,1-二甲基乙酯的合成
使用4-苯氧基羰基氨基双环[2.2.2]辛烷-1-羧酸1,1-二甲基乙酯(425mg),按照参考例1的第四工序同样的方法进行反应,得到4-氨基双环[2.2.2]辛烷-1-二羧酸1,1-二甲基乙酯(218mg)。
1H NMR(CDCl3)δ1.41(s,9H),1.52-1.56(m,6H)
1.80-1.84(m,6H)。
<参考例3>
4-氨基双环[2.2.2]辛烷-1-羧酸2-四氢吡喃基酯的合成
第一工序:
4-苄氧基羰基氨基双环[2.2.2]辛烷-1-羧酸2-四氢吡喃基酯的合成
将4-苄氧基羰基氨基双环[2.2.2]辛烷-1-羧酸(1.00g)混悬于二氯甲烷(10mL)中,加入3,4-二氢-2H-吡喃(1.20mL),然后是对甲苯磺酸·1水合物(6.3mg),在室温下搅拌30分钟。将反应混合物以饱和碳酸氢钠水溶液、然后是水进行洗涤,以无水硫酸钠干燥后,减压浓缩。以硅胶柱层析色谱(洗脱溶剂,己烷∶醋酸乙酯=4∶1)对残渣进行纯化,得到4-苄氧基氨基双环[2.2.2]辛烷-1-羧酸2-四氢吡喃基酯(1.18g)。
1H NMR(CDCl3)δ1.53-1.95(m,18H),3.67-3.71(m,1H)
3.82-3.89(m,1H),4.59(br,1H),5.03(s,2H),5.95(br,1H),7.29-7.38(m,5H)。
第二工序
4-氨基双环[2.2.2]辛烷-1-羧酸2-四氢吡喃基酯的合成
使用4-苄氧基氨基双环[2.2.2]辛烷-1-羧酸2-四氢吡喃基酯(548mg),按照参考例1的第四工序同样的方法进行反应,得到4-氨基双环[2.2.2]辛烷-1-羧酸2-四氢吡喃基酯(357mg)。
MS(EI+)m/z:253(M+)。
<参考例4>
(2S,4S)-1-(2-氯代乙酰基)-4-氟代吡咯烷-2-腈的合成
按照文献记载(WO 02/38541小册子)的(2S,4S)-1-(2-溴代乙酰基)-4-氟代吡咯烷-2-腈的制备方法,从(2S,4S)-4-氟代吡咯烷-2- 甲酰胺盐酸盐(5.00g)及氯代乙酰氯(2.60mL)制得(2S,4S)-1-(2-氯代乙酰基)-4-氟代吡咯烷-2-腈(4.96g)。
MS(EI+)m/z:190(M+)。
C7H8ClFN2O(M+)的HRMS(EI+):
计算值,190.0309;实测值,190.0283。
实施例1
[化6]
(2S,4S)-1-[[N-(4-乙氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈的合成
将4-氨基双环[2.2.2]辛烷-1-羧酸乙酯(92.0mg)溶解于乙腈(2mL)中,加入二异丙基乙胺(100μL)后在冰浴下滴加(2S,4S)-1-(2-溴代乙酰基)-4-氟代吡咯烷-2-腈(100mg)的乙腈(1mL)溶液,在冰浴中进一步搅拌1.5小时后,在反应液中加入水以醋酸乙酯萃取。用饱和食盐水洗涤醋酸乙酯层,用无水硫酸镁干燥,然后减压浓缩。以硅胶柱层析色谱(洗脱溶剂,醋酸乙酯∶甲醇=5∶1)对残渣进行纯化,得到(2S,4S)-1-[[N-(4-乙氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈(132mg)。
MS(EI+)m/z:351(M+)。
C18H26FN3O3(M+)的HRMS(EI+):
计算值,351.1958;实测值,351.1982。
实施例2
[化7]
(2S)-1-[[N-(4-乙氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]吡咯烷-2-腈的合成
将4-氨基双环[2.2.2]辛烷-1-羧酸乙酯(115mg)溶解于N,N-二甲基甲酰胺(1.5mL)中,加入二异丙基乙胺(100μL)后,在室温下滴加(2S)-1-(2-溴代乙酰基)吡咯烷-2-腈(120mg)的N,N-二甲基甲酰胺(1mL)溶液,在室温下进一步搅拌2小时后,减压浓缩反应液。以硅胶柱层析色谱(洗脱溶剂,氯仿∶甲醇=10∶1)对残渣进行纯化,得到(2S)-1-[[N-(4-乙氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]吡咯烷-2-腈(95.1mg)。
MS(EI+)m/z:333(M+)。
C18H27N3O3(M+)的HRMS(EI+):
计算值,333.2052;实测值,333.2037。
实施例3
[化8]
(2S)-1-[[N-(4-叔丁氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]吡咯烷-2-腈的合成
以实施例2同样的方法,从4-氨基双环[2.2.2]辛烷-1-羧酸叔丁酯(100mg)及(2S)-1-(2-溴代乙酰基)吡咯烷-2-腈(90.0mg),制得(2S)-1-[[N-(4-叔丁氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]吡咯烷-2-腈(97.6mg)。
MS(EI+)m/z:361(M+)。
C20H31N3O3(M+)的HRMS(EI+):
计算值,361.2365;实测值,361.2373。
实施例4
[化9]
(2S,4S)-1-[[N-[4-(2-四氢吡喃基)氧基羰基双环[2.2.2]辛-1-基]氨基]乙酰基]-4-氟代吡咯烷-2-腈的合成
以实施例2同样的方法,从4-氨基双环[2.2.2]辛烷-1-羧酸2-四氢 吡喃基酯(62.9mg)及(2S,4S)-1-(2-溴代乙酰基)-4-氟代吡咯烷-2-腈(53.1mg),制得(2S,4S)-1-[[N-[4-(2-四氢吡喃基)氧基羰基双环[2.2.2]辛-1-基]氨基]乙酰基]-4-氟代吡咯烷-2-腈(73.3mg)。
MS(FAB+)m/z:408(MH+)。
C21H31FN3O4(MH+)的HRMS(FAB+):
计算值,408.2299;实测值,408.2295。
实施例5
[化10]
(2S)-1-[[N-[4-(2-四氢吡喃基)氧基羰基双环[2.2.2]辛-1-基]氨基]乙酰基]吡咯烷-2-腈的合成
以实施例2同样的方法,从4-氨基双环[2.2.2]辛烷-1-羧酸2-四氢吡喃基酯(90.0mg)及(2S)-1-(2-溴代乙酰基)吡咯烷-2-腈(70.0mg),制得(2S)-1-[[N-[4-(2-四氢吡喃基)氧基羰基双环[2.2.2]辛-1-基]氨基]乙酰基]吡咯烷-2-腈(85.2mg)。
MS(EI+)m/z:389(M+)。
C21H31N3O4(M+)的HRMS(EI+):
计算值,389.2315;实测值,389.2296。
实施例6
[化11]
(2S,4S)-1-[[N-(4-乙氧基羰基双环[2.2.1]庚-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈的合成
将4-氨基双环[2.2.1]庚烷-1-羧酸乙酯(50.0mg)溶解于N,N-二甲基甲酰胺(2mL)中,加入碳酸钾(40.0mg)后,在室温下滴加(2S,4S)-1-(2-溴代乙酰基)-4-氟代吡咯烷-2-腈(64.2mg)的N,N-二甲基甲酰胺(1mL)溶液,进一步搅拌1小时后。过滤除去不溶物,浓缩滤液 得到残渣,以硅胶柱层析色谱(NH二氧化硅,洗脱溶剂,醋酸乙酯)对残渣进行纯化,得到(2S,4S)-1-[[N-(4-乙氧基羰基双环[2.2.1]庚-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈(89.0mg)。
MS(FAB+)m/z:338(MH+)。
C17H25FN3O3(MH+)的HRMS(FAB+):
计算值,338.1880;实测值,338.1835。
实施例7
[化12]
(2S)-1-[[N-(4-乙氧基羰基双环[2.2.1]庚-1-基)氨基]乙酰基]吡咯烷-2-腈的合成
以实施例6同样的方法,从4-氨基双环[2.2.1]庚烷-1-羧酸乙酯(50.0mg)及(2S)-1-(2-溴代乙酰基)-2-吡咯烷基酯(59.3mg),制得(2S)-1-[[N-(4-乙氧基羰基双环[2.2.1]庚-1-基)氨基]乙酰基]吡咯烷-2-腈(79.4mg)。
MS(FAB+)m/z:320(MH+)。
C17H26N3O3(MH+)的HRMS(FAB+):
计算值,320.1974;实测值,320.1975。
实施例8
[化13]
(2S,4S)-1-[[N-(4-苄氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈的合成
将(2S,4S)-1-[[N-(4-羧基双环[2.2.2]辛-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈(30.0mg)溶解于N,N-二甲基甲酰胺(1.0mL)中,加入碳酸铯(45.3mg)后,在冰浴下滴加苄基溴(17.5mg)的N,N-二甲基甲酰胺(0.5mL)溶液搅拌1小时。在反应液中加入水,以醋酸乙 酯萃取。用水及饱和食盐水洗涤醋酸乙酯层,用无水硫酸钠干燥后,减压浓缩。以硅胶柱层析色谱(洗脱溶剂,二氯甲烷∶甲醇=10∶1)对残渣进行纯化,得到(2S,4S)-1-[[N-(4-苄氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈(30.6mg)。
MS(FAB+)m/z:414(MH+)。
C23H29FN3O3(MH+)的HRMS(FAB+):
计算值,414.2193;实测值,414.2176。
实施例9
[化14]
(2S,4S)-1-[[N-(4-环丙基甲氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]4-氟代吡咯烷-2-腈的合成
以实施例8同样的方法,从(2S,4S)-1-[[N-(4-羧基双环[2.2.2]辛-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈(20.0mg)及环丙基甲基溴(12.8mg),制得(2S,4S)-1-[[N-(4-环丙基甲氧基羧基双环[2.2.2]辛-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈(13.7mg)。
MS(FAB+)m/z:378(MH+)。
C20H29FN3O3(MH+)的HRMS(FAB+):
计算值,378.2193;实测值,378.2207。
实施例10
[化15]
(2S,4S)-4-氟代-1-[[N-[4-(4-三氟甲基苄基)氧基羰基双环[2.2.2]
辛-1-基)氨基]乙酰基]吡咯烷-2-腈的合成
以实施例8同样的方法,从(2S,4S)-1-[[N-(4-羧基双环[2.2.2]辛-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈(20.0mg)及4-三氟甲基苄基溴(16.2mg),制得(2S,4S)-4-氟代-1-[[N-[4-(4-三氟甲基苄基)氧基羰 基双环[2.2.2]辛-1-基)氨基]乙酰基]吡咯烷-2-腈(22.2mg)。
MS(FAB+)m/z:482(MH+)。
C24H28F4N3O3(MH+)的HRMS(FAB+):
计算值,482.2067;实测值,482.2068。
实施例11
[化16]
(2S,4S)-4-氟代-1-[[N-[4-(2-甲基丙基)氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]吡咯烷-2-腈合成
以实施例8同样的方法,从(2S,4S)-1-[[N-(4-羧基双环[2.2.2]辛-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈(20.0mg)及异丁基溴(9.3mg),制得(2S,4S)-4-氟代-1-[[N-[4-(2-甲基丙基)氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]吡咯烷-2-腈(14.2mg)。
MS(FAB+)m/z:380(MH+)。
C20H31FN3O3(MH+)的HRMS(FAB+):
计算值,380.2349;实测值,380.2361。
实施例12
[化17]
(2S,4S)-4-氟代-1-[[N-[4-(2-甲基乙基)氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]吡咯烷-2-腈的合成
以实施例8同样的方法,从(2S,4S)-1-[[N-(4-羧基双环[2.2.2]辛-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈(20.0mg)及异丙基碘(10.5mg),制得(2S,4S)-4-氟代-1-[[N-[4-(2-甲基乙基)氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]吡咯烷-2-腈(11.2mg)。
MS(EI+)m/z:365(M+)。
C19H28FN3O3(M+)的HRMS(EI+):
计算值,365.2115;实测值,365.2096。
实施例13
[化18]
(2S,4S)-1-[[N-[4-(4-乙氧基羰基苄基)氧基羰基双环[2.2.2]辛-1-基]氨基]乙酰基]-4-氟代吡咯烷-2-腈的合成
以实施例8同样的方法,从(2S,4S)-1-[[N-(4-羧基双环[2.2.2]辛-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈(32.3mg)及4-乙氧基羰基苄基溴(28.1mg),制得(2S,4S)-1-[[N-[4-(4-乙氧基羰基苄基)氧基羰基双环[2.2.2]辛-1-基]氨基]乙酰基]-4-氟代吡咯烷-2-腈(34.7mg)。
MS(EI+)m/z:485(M+)。
C26H32FN3O5(M+)的HRMS(EI+):
计算值,485.2326;实测值,485.2309。
实施例14
[化19]
(2S,4S)-1-[[N-[4-[4-(2,2-二甲基乙基)苄基]氧基羰基双环[2.2.2]辛-1-基]氨基]乙酰基]-4-氟代吡咯烷-2-腈的合成
以实施例8同样的方法,从(2S,4S)-1-[[N-(4-羧基双环[2.2.2]辛-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈(30.0mg)及4-(2,2-二甲基乙基)苄基溴(23.2mg),制得(2S,4S)-1-[[N-[4-[4-(2,2-二甲基乙基)苄基]氧基羰基双环[2.2.2]辛-1-基]氨基]乙酰基]-4-氟代吡咯烷-2-腈(29.9mg)。
MS(FAB+)m/z:470(MH+)。
C27H37FN3O3(MH+)的HRMS(FAB+):
计算值,470.2819;实测值,470.2859。
实施例15
[化20]
(2S,4S)-1-[[N-[4-(4-氯代苄基)氧基羰基双环[2.2.2]辛-1-基]氨基]乙酰基]-4-氟代吡咯烷-2-腈的合成
以实施例8同样的方法,从(2S,4S)-1-[[N-(4-羧基双环[2.2.2]辛-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈(30.0mg)及4-氯代苄氧基溴(21.0mg),制得(2S,4S)-1-[[N-[4-(4-氯代苄基)氧基羰基双环[2.2.2]辛-1-基]氨基]乙酰基]-4-氟代吡咯烷-2-腈(25.5mg)。
MS(FAB+)m/z:448(MH+)。
C23H28ClFN3O3(MH+)的HRMS(FAB+):
计算值,448.1803;实测值,448.1794。
实施例16
[化21]
(2S,4S)-4-氟代-1-[[N-[4-(4-甲基苄基)氧基羰基双环[2.2.2]辛-1-基]氨基]乙酰基]吡咯烷-2-腈的合成
以实施例8同样的方法,从(2S,4S)-1-[[N-(4-羧基双环[2.2.2]辛-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈(30.0mg)及4-甲基苄基溴(18.9mg),制得(2S,4S)-4-氟代-1-[[N-[4-(4-甲基苄基)氧基羰基双环[2.2.2]辛-1-基]氨基]乙酰基]吡咯烷-2-腈(9.2mg)。
MS(FAB+)m/z:428(MH+)。
C24H31FN3O3(MH+)的HRMS(FAB+):
计算值,428.2349;实测值,428.2382。
实施例17
[化22]
(2S,4S)-4-氟代-1-[[N-[4-(4-甲氧基苄基)氧基羰基双环[2.2.2]辛-1-基]氨基]乙酰基]吡咯烷-2-腈的合成
以实施例8同样的方法,从(2S,4S)-1-[[N-(4-羧基双环[2.2.2]辛-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈(30.0mg)及4-甲氧基苄基氯(16.0mg),制得(2S,4S)-4-氟代-1-[[N-[4-(4-甲氧基苄基)氧基羰基双环[2.2.2]辛-1-基]氨基]乙酰基]吡咯烷-2-腈(29.8mg)。
MS(FAB+)m/z:444(MH+)。
C24H31FN3O4(MH+)的HRMS(FAB+):
计算值,444.2299;实测值,444.2269。
实施例18
[化23]
(2S,4S)-4-氟代-1-[[N-[4-(2-三氟甲基苄基)氧基羰基双环[2.2.2]辛-1-基]氨基]乙酰基]吡咯烷-2-腈的合成
以实施例8同样的方法,从(2S,4S)-1-[[N-(4-羧基双环[2.2.2]辛-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈(30.0mg)及2-三氟甲基苄基溴(25.4mg),制得(2S,4S)-4-氟代-1-[[N-[4-(2-三氟甲基苄基)氧基羰基双环[2.2.2]辛-1-基]氨基]乙酰基]吡咯烷-2-腈(39.9mg)。
MS(EI+)m/z:481(M+)。
C24H27F4N3O3(M+)的HRMS(EI+):
计算值,481.1989;实测值,481.1944。
实施例19
[化24]
(2S,4S)-1-[[N-[4-(2,6-二氯苄基)氧基羰基双环[2.2.2]辛-1-基]氨基]乙酰基]-4-氟代吡咯烷-2-腈的合成
以实施例8同样的方法,从(2S,4S)-1-[[N-(4-羧基双环[2.2.2]辛-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈(30.0mg)及2,6-二氯代苄基溴(24.5mg),制得(2S,4S)-1-[[N-[4-(2,6-二氯苄基)氧基羰基双环[2.2.2]辛-1-基]氨基]乙酰基]-4-氟代吡咯烷-2-腈(40.0mg)。
MS(EI+)m/z:481(M+)。
C23H26Cl2FN3O3(M+)的HRMS(EI+):
计算值,481.1335;实测值,481.1366。
实施例20
[化25]
(2S,4S)-4-氟代-1-[[N-[4-(2,3,4,5,6-五氟苄基)氧基羰基双环[2.2.2]辛-1-基]氨基]乙酰基]吡咯烷-2-腈的合成
以实施例8同样的方法,从(2S,4S)-1-[[N-(4-羧基双环[2.2.2]辛-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈(30.0mg)及2,3,4,5,6-五氟苄基溴(26.6mg),制得(2S,4S)-4-氟代-1-[[N-[4-(2,3,4,5,6-五氟苄基)氧基羰基双环[2.2.2]辛-1-基]氨基]乙酰基]吡咯烷-2-腈(41.9mg)。
MS(EI+)m/z:503(M+)。
C23H23F6N3O3(M+)的HRMS(EI+):
计算值,503.1644;实测值,503.1681。
实施例21
[化26]
(2S,4S)-4-氟代-1-[[N-[4-(2-甲基苄基)氧基羰基双环[2.2.2]辛-1-基]氨基]乙酰基]吡咯烷-2-腈的合成
以实施例8同样的方法,从(2S,4S)-1-[[N-(4-羧基双环[2.2.2] 辛-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈(30.0mg)及溴化-2-甲基苄基(18.9mg),制得(2S,4S)-4-氟代-1-[[N-[4-(2-甲基苄基)氧基羰基双环[2.2.2]辛-1-基]氨基]乙酰基]吡咯烷-2-腈(34.1mg)。
MS(EI+)m/z:427(M+)。
C24H30FN3O3(M+)的HRMS(EI+):
计算值,427.2271;实测值,427.2312。
实施例22
[化27]
(2S,4S,1’S)-1-[[N-(1-苯基乙基氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈的合成
将(2S,4S)-1-[[N-(4-羧基双环[2.2.2]辛-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈(50.0mg)、1-羟基苯并三唑(26.0mg)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(32.5mg)及(1S)-苯乙醇(0.094mL)溶解于N,N-二甲基甲酰胺(0.9mL)中,在室温下溶液搅拌22天后,减压浓缩.
以分离用薄层层析色谱(洗脱溶剂,二氯甲烷∶甲醇=10∶1)对残渣进行纯化,得到(2S,4S,1’S)-1-[[N-(1-苯基乙基氧基羰基双环[2.2.2]辛-1-基]氨基]乙酰基]-4-氟代吡咯烷-2-腈(4.6mg)。
MS(FAB+)m/z:428(MH+)。
C24H31FN3O3(MH+)的HRMS(FAB+):
计算值,428.2349;实测值,428.2369。
实施例23
[化28]
(2S,4S,1’R)-1-[[N-(1-苯基乙基氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈的合成
以实施例22同样的方法,从(2S,4S)-1-[[N-(4-羧基双环[2.2.2]辛-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈(50.0mg)、1-羟基苯并三唑(26.0mg)及(1R)-苯乙醇(0.094mL),制得(2S,4S,1’R)-1-[[N-(1-苯基乙基氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈(3.6mg)。
MS(FAB+)m/z:428(MH+)。
C24H31FN3O3(MH+)的HRMS(FAB+):
计算值,428.2349;实测值,428.2342。
实施例24
[化29]
(2S,4S)-4-氟代-1-[[N-(5-羟基戊基氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]吡咯烷-2-腈的合成
将(2S,4S)-1-[[N-(4-羧基双环[2.2.2]辛-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈(50.0mg)、与5-溴代-1-戊醇(18.7μl)、碳酸钾(23.5mg)及N,N-二甲基甲酰胺(1.5mL)混合,在室温下溶液搅拌4小时。过滤除去反应混合物中的不溶物质,对滤液减压浓缩。以硅胶柱(洗脱溶剂,氯仿∶甲醇=10∶1)对残渣进行纯化,得到(2S,4S)-4-氟代-1-[[N-(5-羟基戊基氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]吡咯烷-2-腈(32.4mg)。
MS(FAB+)m/z:410(MH+)。
C21H33FN3O4(MH+)的HRMS(FAB+):
计算值,410.2455;实测值,410.2420。
<实验例1>[二肽基肽酶IV活性抑制剂实验]
作为基质的H-Gly-Pro-AMC(7-氨基-4-甲基-香豆素)·HBr通过血浆二肽基肽酶IV分解而游离的AMC浓度通过荧光强度进行测定。
方法
使用平底96孔板,将溶解了化合物的缓冲液(25mmol/L HEPES,140mmol/L氯化钠,1%牛血清白蛋白,80mmol/L 氯化镁·6水合物, pH7.4)20μL添加到以生理盐水稀释8倍的血浆20μL中,在室温下放置5分钟,然后添加0.1mmol/L的H-Gly-Pro-AMC·HBr溶液10μL开始反应。避光下在室温下放置20分钟后,添加25%醋酸溶液20μL停止反应。使用荧光板测定仪对以355nm波长激发时的460nm出的荧光强度进行测定作为游离的AMC浓度。采用PRISM3.02(GraphPad Software)从得到的结果计算出50%抑制浓度(IC50值)。结果在表1中表示。
[表1]
表1:体外二肽基肽酶IV的抑制活性
实验化合物 | IC50(nmol/L) |
实施例1 | 0.25 |
实施例9 | 0.48 |
实施例10 | 0.23 |
实施例11 | 0.13 |
化合物A | 3.3 |
化合物A:(2S)-1-[[(3-羟基-1-金刚烷基)氨基]乙酰基]-2-氰基吡咯烷(LAF-237)
<实验例2>[口服给药的小鼠的二肽基肽酶IV的抑制活性实验]
使用0.3%羧甲基纤维素钠盐混悬化合物达到0.1mg/mL的浓度,以10ml/kg的给药量对8周龄的雄性ICR小鼠(日本チヤ一ツスリバ一)进行口服给药。在给药前及给药后30分钟使用EDTA·2K处理毛细管对尾静脉进行采血,以6000转速对采取的各血液进行2分钟离心分离获得血浆。使用与实验例1相同的方法测定酶活性。将对比给药前的酶活性值的减少率作为抑制率算出结果(抑制率={(给药前值-给药后值)÷给药前值}×100)。结果在表2中表示。
[表2]
表2:口服给药的小鼠的血浆中二肽基肽酶IV的抑制活性
实验化合物 | 抑制率(%) |
实施例1 | 100 |
实施例9 | 94 |
实施例11 | 93 |
化合物A | 81 |
化合物A:(2S)-1-[[(3-羟基-1-金刚烷基)氨基]乙酰基]-2-氰基吡咯烷(LAF-237)
<实验例3>[口服给药的小鼠的葡萄糖耐量实验]
使用0.3%羧甲基纤维素钠盐(CMC-Na,シグマ)对实施例1的本发明化合物(以下,称为化合物1)进行混悬。对7周龄的雄性ICR小鼠(日本チヤ一ツスリバ一)进行1周预备饲养。此期间,可自由摄取标准饲料(CE-2,日本クレラ)及水。对8周龄的ICR小鼠绝食16小时,将0.3%CMC-Na(10mL/kg)或化合物1(1mg/kg,10mL/kg)进行进口给药后,马上以5g/kg的用量将葡萄糖溶液进行口服给药。使用EDTA-2K处理毛细血管采血,在葡萄糖溶液给药前及给药后15、30、60及120分钟后从尾静脉进行采血。使用葡萄糖Bテストワコ一(和光纯药工业)测定血浆葡萄糖值。结果以平均值±标准偏差表示。采用t检验进行统计分析,显著性水平为不足5%。结果在图1中表示。
<实验例4>[对于药源性白血球减少症的药效评价试验]
本发明化合物对于药源性白血球减少症的药效评价试验按照Okabe等人的方法(药理和治疗,19卷,6号,55页,1991年)进行。
使用8周龄的雄性ICR小鼠(日本チヤ一ツスリババ一),在第0日以环磷酰胺(200mg/kg)进行单次腹腔内给药。从第二天开始以生理盐水向对照组给药,对于药物给药组以1天1~2次,经5天以本发明的化合物(1~200mg/kg)进行口服给药。在实验开始的2、4、6及8天后分别进行采血,经时性的测定白血球数,通过将环磷酰胺给药前的白血球数作为对照,可评价本发明化合物对于药源性白血球减少症的药效。与对照相比较,本发明化合物显著的抑制了白血球的减少。
<实验例5>[血中G-CSF浓度的增加作用实验]
使用7周龄的雄性ICR小鼠(日本チヤ一ツスリババ一),对于对照组以生理盐水给药,对于药物给药组以1天1~2次,经5天以本发明的化合物(1~200mg/kg)进行口服给药。在给药结束后第二天进行麻醉采血,使用小鼠G-CSF ELISA测定试剂盒(R&D SYSTEM社)对血浆中的G-CSF浓度进行测定。与对照组比较,本发明的化合物显著的增加了血浆中的G-CSF浓度。
产业实用性
本申请的化合物为具有优异的DPP-IV抑制活性的新型双环酯类衍生物、或其可药用的盐。含有本申请的化合物作为有效成分的药物组合物,可有效用作对于糖尿病及其合并症的预防和/或治疗剂或对于DPP-IV参与的疾病的预防和/或治疗剂。
Claims (9)
1.通式(1)所表示的双环酯类衍生物、或其可药用的盐,
式中,R1是选自甲基、乙基、丙基、1-甲基乙基、1-甲基丙基、2-甲基丙基、1-乙基丙基、2-乙基丙基、丁基、及己基中之一的烷基,
X表示CH2、CHF或CF2,
n表示1或2。
2.权利要求1所述的双环酯类衍生物、或其可药用的盐,通式(1)中,X是CH2。
3.权利要求1所述的双环酯类衍生物、或其可药用的盐,通式(1)中,X是CHF。
4.权利要求1-3任意一项所述的双环酯类衍生物、或其可药用的盐,通式(1)中,n是1。
5.权利要求1-3任意一项所述的双环酯类衍生物、或其可药用的盐,通式(1)中,n是2。
6.权利要求1所述的双环酯类衍生物、或其可药用的盐,通式(1)表示的化合物是选自:
(2S,4S)-1-[[N-(4-乙氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈、
(2S)-1-[[N-(4-乙氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]吡咯烷-2-腈、
(2S,4S)-1-[[N-(4-乙氧基羰基双环[2.2.1]庚-1-基)氨基]乙酰基]-4-氟代吡咯烷-2-腈、
(2S)-1-[[N-(4-乙氧基羰基双环[2.2.1]庚-1-基)氨基]乙酰基]吡咯烷-2-腈、
(2S,4S)-4-氟-1-[[N-(4-异丁氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]吡咯烷-2-腈、和
(2S,4S)-4-氟-1-[[N-(4-异丙氧基羰基双环[2.2.2]辛-1-基)氨基]乙酰基]吡咯烷-2-腈中之一的化合物。
7.药物,其特征为含有权利要求1-6任意一项所述的双环酯类衍生物、或其可药用的盐作为有效成分。
8.DPP-IV抑制剂,其特征为含有权利要求1-6任意一项所述的双环酯类衍生物、或其可药用的盐作为有效成分。
9.糖尿病和/或糖尿病并发症的治疗剂,其特征为含有权利要求1-6任意一项所述的双环酯类衍生物、或其可药用的盐作为有效成分。
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ATE550319T1 (de) | 2007-03-22 | 2012-04-15 | Kyorin Seiyaku Kk | Verfahren zur herstellung eines aminoacetylpyrrolidincarbonitrilderivats |
JP2008239543A (ja) | 2007-03-27 | 2008-10-09 | Kyorin Pharmaceut Co Ltd | ビシクロアミノアセチルピロリジンカルボニトリル誘導体の製造方法およびその製造中間体 |
JP2008290969A (ja) | 2007-05-24 | 2008-12-04 | Kyorin Pharmaceut Co Ltd | アミノアセチルピロリジン誘導体の製造方法 |
JP2009114127A (ja) | 2007-11-07 | 2009-05-28 | Kyorin Pharmaceut Co Ltd | アミノアセチルピロリジンカルボニトリル誘導体の製造方法 |
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Also Published As
Publication number | Publication date |
---|---|
US8053465B2 (en) | 2011-11-08 |
EP1712547A1 (en) | 2006-10-18 |
NZ548440A (en) | 2009-07-31 |
DK1712547T3 (da) | 2012-03-19 |
US20100093825A1 (en) | 2010-04-15 |
EP1712547A4 (en) | 2007-09-26 |
US7754757B2 (en) | 2010-07-13 |
CA2554493C (en) | 2012-06-26 |
EP1712547B1 (en) | 2011-12-14 |
AU2005210285B2 (en) | 2008-01-24 |
SI1712547T1 (sl) | 2012-04-30 |
CY1112550T1 (el) | 2016-02-10 |
KR101130433B1 (ko) | 2012-03-27 |
ZA200606237B (en) | 2007-12-27 |
ES2375625T3 (es) | 2012-03-02 |
BRPI0506622A (pt) | 2007-05-02 |
CA2554493A1 (en) | 2005-08-18 |
PL1712547T3 (pl) | 2012-04-30 |
CN1918119A (zh) | 2007-02-21 |
JPWO2005075421A1 (ja) | 2007-10-11 |
PT1712547E (pt) | 2012-03-06 |
KR20060130641A (ko) | 2006-12-19 |
JP3954626B2 (ja) | 2007-08-08 |
NO20063486L (no) | 2006-08-29 |
ATE537141T1 (de) | 2011-12-15 |
CN101684089A (zh) | 2010-03-31 |
AU2005210285A1 (en) | 2005-08-18 |
HRP20120006T1 (hr) | 2012-01-31 |
US20080146818A1 (en) | 2008-06-19 |
HK1100511A1 (en) | 2007-09-21 |
RS52163B (en) | 2012-08-31 |
WO2005075421A1 (ja) | 2005-08-18 |
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