CN102946726B - 新型降血糖化合物 - Google Patents
新型降血糖化合物 Download PDFInfo
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- CN102946726B CN102946726B CN201180022812.0A CN201180022812A CN102946726B CN 102946726 B CN102946726 B CN 102946726B CN 201180022812 A CN201180022812 A CN 201180022812A CN 102946726 B CN102946726 B CN 102946726B
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- 239000012047 saturated solution Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
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Abstract
本发明涉及式(1)的新型降血糖化合物及其药学可接受盐。本发明涉及式(1)的新型氨基酸衍生物,其中,A为氨基酸,B为肽键,R-NH-中的R在说明书中限定。
Description
技术领域
本发明涉及式1的新型降血糖化合物及其药学可接受盐。本发明涉及式1的新型氨基酸衍生物,
其中,
A为氨基酸,B为肽键
R-NH-中的R在说明书中限定。
背景技术
糖尿病(DM)是一组以高水平的血液葡萄糖为特征的疾病,其源自胰岛素生成、胰岛素作用、或二者的缺陷。术语糖尿病描述以慢性高血糖及碳水化合物、脂肪和蛋白质代谢扰乱为特征的多病因代谢紊乱。代谢扰乱效应源自胰岛素分泌、胰岛素作用、或二者的缺陷。糖尿病的影响包括多种器官的长期损害、功能障碍和衰竭。
有至少7类不同的药剂作为单一疗法或组合用于治疗糖尿病。这些包括二甲双胍(metformin)、磺脲(sulphonylureas)、美格列奈(meglinitide,meglitinide)、α-葡萄糖苷酶抑制剂、噻唑烷二酮(thiazolidinediones)、胰高血糖素样肽-1激动剂和胰岛素。许多常规药剂常常表现出功效随时间降低,导致血糖控制不当。几种这些药剂还与不良反应有关,包括重量增加、低血糖和胃肠不适。因此需要能克服与常规抗高血糖药疗有关的限制的备选疗法。
用于治疗2型糖尿病的常规药剂常常表现出功效随时间降低,导致血糖控制不当,而且还与不良反应有关。因此,需要能克服与常规抗糖尿病药有关的限制的备选疗法。
附图说明
图1:CPL-2009-030和CPL-2009-031的体内筛选结果。
图2:CPL-2009-011、CPL-2009-012、CPL-2009-015和CPL-2009-020的体内筛选结果。
图3:CPL-2010-079、CPL-2011-085的体内筛选结果。
图4:CPL-2010-079、CPL-2011-085的体内筛选结果(AUC)。
发明内容
本发明的一个目的是提供式1的新型降血糖化合物及其药学可接受盐。
本发明的另一个目的是提供用于制备式1的新型降血糖化合物的方法。
本发明的又一个目的是提供与DPP IV酶起反应的新型降血糖化合物。
具体实施方式
合成化合物是用于治疗与糖尿病有关的代谢紊乱的潜在候选。我们在本文中公开一系列新型化合物,它们是潜在的降血糖化合物。本发明涉及式1的新型氨基酸衍生物,
其中,A为氨基酸,B为肽键
R-NH-中的R-NH-一起具有式2到6的基团
式2-式6的化合物的化学名称为
●2-({6-[(3R)-3-取代的-氨基哌啶-1-基]-3-甲基-2,4-二氧-3,4-二氢嘧啶-1(2H)-基}甲基)-苄腈(式2);
●1-[2-取代的氨基-3,3-二-(4-氟-苯基)-丙酰基]-4-氟-吡咯烷-2-腈(式3);
●(2R)-2-取代的-氨基-4-氧-4-[3-(三氟甲基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]-1-(2,4,5-三氟苯基)丁(式4);
●8-[(3R)-3-2-取代的-氨基哌啶-1-基]-7-(丁-2-炔-1-基)-3-甲基-1-[(4-甲基喹唑啉-2-基)甲基]-3,7-二氢-1H-嘌呤-2,6-二酮(式5);
●(1S,3S,5S)-2-[(2S)-2-2-取代的-氨基-2-(3-羟基-1-金刚烷基)乙酰基]-2-氮杂二环-[3.1.0]-己-3-腈(式6);及其盐。
A为氨基酸,其选自天然存在的或合成的氨基酸类似物。优选的氨基酸选自甘氨酸、丙氨酸、缬氨酸、组氨酸、丝氨酸、亮氨酸、异亮氨酸、苯丙氨酸、甲硫氨酸、色氨酸、赖氨酸、谷氨酰胺、谷氨酸、脯氨酸、半胱氨酸、酪氨酸、精氨酸、天冬酰胺、天冬氨酸、苏氨酸或上述氨基酸的混合物。
标题化合物通过方案1,通过氨基酸(A-OH)的羧基和R-NH2的氨基的反应来合成,其中R-NH具有式2-6。
其中,
A为氨基酸,B为肽键
R-NH-中的R-NH-一起具有式2到6的基团
本文中公开的方法不限于制备本文中制备的特定化合物,而是描述用于制备本发明化合物的一般技术状态。式2-6的化合物通过文献中已知的方法来制备。本发明的范围还包括选自式2-6化合物或其药学可接受盐的化合物,用于类似地制备其它化合物套组。
本发明涉及所公开的化合物作为降血糖活性的用途。下述合成化合物可作为降血糖化合物用于需要此类糖尿病治疗(包括施用有效量的该化合物)的患者诸如哺乳动物。
下述实施例用来例示本发明,本发明致力于提供在人和动物中具有降血糖活性的式1的新型降血糖化合物及其药学可接受盐,包括组合本发明化合物与制药学载剂或稀释剂的药物组合物。
实施例1:
于0℃在二氯甲烷(20ml)中溶解叔-丁氧羰基氨基-乙酸(0.33克,0.0018摩尔)并添加二环己基二碳二亚胺(0.51克,0.0025摩尔)。将反应混合物搅动10分钟。于0℃添加3-氨基-1-(3-三氟甲基-5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡啶-7-基)-4-(2,4,5-三氟-苯基)-丁-1-酮(式4)(0.59克,0.00123摩尔)并搅动,搅动反应混合物后除去二环己基脲。将反应混合物过滤并在真空下浓缩滤液。通过柱层析来纯化残留物以产生{[3-氧-l-(2,4,5-三氟-苄基)-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基氨基甲酰基]-甲基}-氨基甲酸叔-丁基酯(式7)。(产量:0.62克,89%)
实施例2:
于室温在EtoAc中溶解{[3-氧-l-(2,4,5-三氟-苄基)-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并-[4,3-a]-吡嗪-7-基)-丙基氨基甲酰基]-甲基}-氨基甲酸叔-丁基酯(式7)(0.52克,0.0009摩尔)并搅动。于室温将3M HCl-EtoAc(3ml)添加至反应混合物并搅动。在真空下浓缩反应物质以产生2-氨基-N-[3-氧-1-(2,4,5-三氟-苄基)-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-乙酰胺盐酸盐(式8)。(0.447克,96%)
实施例3:
与实施例1类似,化合物{3-甲基-1-[3-氧-1-(2,4,5-三氟-苄基)-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基-氨基甲酰基]-丁基}-氨基甲酸叔-丁基酯(式9)通过具有式4的化合物(0.59克)和2-叔-丁氧羰基氨基-4-甲基戊酸(0.43克)的反应来制备。将反应混合物在真空下浓缩并通过柱层析来纯化。(产量0.62克,81%)
实施例4:
与实施例2类似,化合物[3-氧-1-(2,4,5-三氟-苄基)-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-酰胺盐酸盐(式10)通过使用盐酸盐化式9化合物(0.52克)来制备。(产量:0.45克,96%)。
实施例5:
与实施例1类似,化合物{2-甲基-1-[3-氧-1-(2,4,5-三氟-苄基)-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基-氨基甲酰基]-丁基}-氨基甲酸叔-丁基酯(式11)通过具有式4的化合物(0.5克)和2-叔-丁氧羰基氨基-3-甲基戊酸(0.283克)的反应来制备。通过柱层析来纯化残留物。(产量0.47克,62.7%)
实施例6:
与实施例2类似,2-氨基-3-甲基-戊酸[3-氧-1-(2,4,5-三氟-苄基)-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-酰胺盐酸盐(式12)通过于室温使用盐酸盐化式11化合物(0.44克)来制备。(产量=0.39克,98.73%)。
实施例7:
与实施例1类似,化合物2-[3-氧-1-(2,4,5-三氟-苄基)-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基氨基甲酰基]-吡咯烷-1-羧酸叔-丁基酯(式13)通过具有式4的化合物(0.5克)和吡咯烷-1,2-二羧酸1-叔-丁基酯(0.464克)的反应来制备。通过柱来纯化残留物。(产量=0.42克,89%)
实施例8:
与实施例2类似,吡咯烷-2-羧酸[3-氧-1-(2,4,5-三氟-苄基)-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-酰胺盐酸盐(式14)通过使用盐酸盐化式13化合物(0.55克)来制备。(0.49克,产量=81%)
实施例9:
与实施例1类似,化合物{2-甲基-1-[3-氧-1-(2,4,5-三氟-苄基)-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基氨基甲酰基]-丙基}-氨基甲酸叔-丁基酯(式15)通过具有式4的化合物(1克)和2-叔-丁氧羰基氨基-3-甲基-丁酸(0.59克)的反应来制备。(产量:1.2克,82%)
与实施例2类似,2-氨基-3-甲基-N-[3-氧-1-(2,4,5-三氟-苄基)-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-丁酰胺盐酸盐(式16)通过使用盐酸盐化式15化合物(1.2克)来制备。(产量:1.03克,95%)
实施例11:
与实施例1类似,{1-[3-氧-1-(2,4,5-三氟-苄基)-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基氨基甲酰基]-乙基}-氨基甲酸叔-丁基酯(式17)通过具有式4的化合物(1克)和2-叔-丁氧羰基氨基-丙酸(0.464)的反应来制备。通过硅石凝胶层析来纯化残留物,使用CH2Cl2/MeOH(9.8:0.2)作为洗脱液。(产量:1.3克,90%)
实施例12:
与实施例2类似,2-氨基-N-[3-氧-1-(2,4,5-三氟-苄基)-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-丙酰胺盐酸盐(式18)通过使用盐酸盐化式17化合物(0.6克)来制备。在NaHCO3饱和水溶液中溶解该盐酸盐并用EtoAC萃取(50ml x3)。将合并的EtoAC层在Na2SO4上干燥并在真空下浓缩以给出标题化合物。(产量:0.454克,89%)
实施例13:
与实施例1类似,{2-(4-苄基氧-苯基)-1-[3-氧-1-(2,4,5-三氟-苄基)-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基氨基甲酰基]-乙基}-氨基甲酸叔-丁基酯(式19)通过具有式4的化合物(0.49克)和3-(3-苄基氧-苯基)-2-叔-丁氧羰基氨基-丙酸(0.44克)的反应来制备。通过硅石凝胶层析来纯化残留物,使用CH2Cl2/MeOH(9.25:0.75)作为洗脱液。(产量=0.62克,68%)
实施例14:
与实施例2类似,2-氨基-3-(3-苄基氧-苯基)-N-[3-氧-1-(2,4,5-三氟-苄基)-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-丙酰胺盐酸盐(式20)(0.5克)通过于室温使用盐酸盐化式19化合物来制备。(产量=0.43克,93.48%)
实施例15:
与实施例1类似,{1-[3-氧-1-(2,4,5-三氟-苄基)-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基氨基甲酰基]-2-苯基-乙基}-氨基甲酸叔-丁基酯(式21)通过具有式4的化合物(0.5克)和2-叔-丁氧羰基氨基-3-苯基-丙酸(0.325克)的反应来制备。通过硅石凝胶层析来纯化残留物,使用CH2Cl2/MeOH(9.5:0.5)作为洗脱液。(产量=0.49克,61.25%)
实施例16:
与实施例2类似,2-氨基-N-[3-氧-1-(2,4,5-三氟-苄基)-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-3-苯基-丙酰胺盐酸盐(式22)通过于室温使用盐酸盐化式21化合物(0.42克)来制备,接着在真空下浓缩滤液。(产量=0.37克,97.37%)
实施例17:
与实施例1类似,{2-[3-氧-1-(2,4,5-三氟-苄基)-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基氨基甲酰基]-乙基}-氨基甲酸叔-丁基酯(式23)通过具有式4的化合物(1克)和2-叔-丁氧羰基氨基-丙酸(0.464克)的反应来制备。通过硅石凝胶层析来纯化残留物,使用CH2Cl2/MeOH(9.5:0.5)作为洗脱液。(产量=0.91克,65%)
实施例18:
与实施例2类似,3-氨基-N-[3-氧-1-(2,4,5-三氟-苄基)-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-丙酰胺盐酸盐(式24)通过于室温使用盐酸盐化式23化合物(0.89克)来制备,接着在真空下浓缩滤液。(产量:0.78克,98.73%)
实施例19:
对2-叔-丁氧羰基氨基-3-甲基-丁酸(式25的化合物)(8克,0.037摩尔)和三乙胺(5.15ml,0.037摩尔)在THF(120ml)中的搅动溶液,于0-5℃逐滴添加氯甲酸乙酯(3.52ml,0.037摩尔)。将反应于0℃搅动15分钟并于室温搅动1小时。然后将反应保持于0℃并添加三乙胺(10.3ml,0.074摩尔)和THF(60ml)的混合物。
最后,于0℃将L-脯氨酸(4.25克,0.037摩尔)添加至上述混合物。将反应于0℃搅动30分钟并于室温搅动过夜。搅动后,在真空下浓缩THF并用1N HCl酸化残留物(直至pH~3)。用乙酸乙酯萃取产物层。将有机萃取液在Na2SO4上干燥并浓缩。将所得产物进行柱层析,使用EtoAC/己烷5/5作为洗脱液以给出1-(2-叔-丁氧羰基氨基-3-甲基-丁酰基)-吡咯烷-2-羧酸(式26)。(产量=3.6克,31%)
实施例20:
对1-(2-叔-丁氧羰基氨基-3-甲基-丁酰基)-吡咯烷-2-羧酸(式26)(0.39克,1.23毫摩尔)在MDC(40ml)中的搅动溶液,于0℃添加二环己基二碳二亚胺(0.4克,0.0019摩尔),将反应混合物于0℃搅动5-10分钟。然后于0℃将3-氨基-1-(3-三氟甲基-5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡啶-7-基)-4-(2,4,5-三氟-苯基)-丁-1-酮(0.5克,0.00123摩尔)添加至此混合物。然后将反应于室温搅动4小时。用TLC完成反应。将反应混合物过滤以除去DCC的脲衍生物。然后在真空中浓缩滤液。用柱层析来纯化此化合物,使用CHCl3/MeOH(9/1)作为溶剂系统来给出(2-甲基-1-{2-[3-氧-1-(2,4,5-三氟-苄基)-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基氨基甲酰基]-吡咯烷-1-羰基}-丙基)-氨基甲酸叔-丁基酯(式27化合物)(0.54克,62%收率)。
实施例21:
对(2-甲基-1-{2-[3-氧-1-(2,4,5-三氟-苄基)-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基氨基甲酰基]-吡咯烷-1-羰基}-丙基)-氨基甲酸叔-丁基酯(式27)(0.54克,0.00077摩尔)在乙酸乙酯(5ml)中的搅动溶液,于室温添加3M HCl在乙酸乙酯(5ml)中的溶液。然后将反应于室温搅动1小时。用TLC完成反应。然后最后,在真空中浓缩反应混合物以给出1-(2-氨基-3-甲基-丁酰基)-吡咯烷-2-羧酸[3-氧-1-(2,4,5-三氟-苄基)-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-酰胺的盐酸盐。如此用碳酸氢钠处理所得化合物盐酸盐以给出式28的相应游离碱化合物。(0.46gm,93.88%收率)
实施例22:
用于制备3-[2-(2-氨基-3-苯基-丙基氨基)-2-(3-羟基-金刚烷-1-基)-乙酰基]-3-氮杂-二环-[3.1.0]-己烷-2-腈三氟乙酸(式29的化合物)的方法
步骤A:于室温将叔-丁氧羰基氨基-(3-羟基-金刚烷-1-基)-乙酸(13.56克,0.0418摩尔)和3-氮杂-二环[3.1.0]己烷-2-羧酸酰胺甲磺酸(9.3克,0.0418摩尔)在CAN中搅动并在搅动中添加至HoBT和DIPEA的混合物。于0℃将上述搅动溶液添加至EDC.HCl,接着添加DIPEA并于室温搅动超过12小时。蒸发乙腈并用EtOAC取残留物。用1N HCl和碳酸氢盐饱和溶液清洗EtOAC层。将饱和混合物在Na2SO4上干燥并在真空中浓缩。通过柱层析来获得式27的纯化合物,使用MeOH:CH2Cl2(0.5:9.5)作为流动相。(产量:13克)
步骤B:于室温用CH2Cl2(30ml)取13克[2-(2-氨基甲酰基-3-氮杂-二环[3.1.0]己-3-基)-1-(3-羟基-金刚烷-1-基)-2-氧-乙基]-氨基甲酸叔-丁基酯(0.0300摩尔)并将三氟乙酸(15ml)添加至该溶液。将反应混合物搅动3小时。蒸发二氯甲烷以给出油性残留物,其在用Et2O滴定时给出具有式27a的白色固体。(产量13克)
方案:03
于室温将2.27克(0.00507摩尔)化合物27a和1.34克(0.00507摩尔)2-叔-丁氧羰基氨基-3-苯基-丙酸在TFA中的溶液添加至HoBT(0.93克)和DIPEA(1.72ml)并搅动10分钟。对此搅动溶液,于0℃添加EDC-HCl(1.2克)和DIPEA(1.76ml)并将反应混合物于室温搅动超过12小时。蒸发THF并用EtOAC(40ml)取残留物。将EtOAC层用1N HCl和NaHCO3水溶液清洗,在Na2SO4上干燥并在真空中浓缩以给出粗产物。通过硅石凝胶柱层析来纯化粗产物,使用MeOH:CH2Cl2(0.5:9.5)作为流动相以给出纯{1-[2-(2-氨基甲酰基-3-氮杂-二环[3.1.0]己-3-基)-1-(3-羟基-金刚烷-1-基)-2-氧-乙基氨基甲酰基]-2-苯基-乙基}-氨基甲酸叔-丁基酯(式33)。(产量:1.5克)
步骤C:将THF中1.5克式33的{1-[2-(2-氨基甲酰基-3-氮杂-二环[3.1.0]己-3-基)-1-(3-羟基-金刚烷-1-基)-2-氧-乙基氨基甲酰基]-2-苯基-乙基}-氨基甲酸叔-丁基酯(0.0031摩尔)添加至吡啶(1.26ml)的混合物。于0℃添加三氟乙酸酐(10ml)并于室温搅动3小时。蒸发THF并用MeOH(30ml)取残留物并添加10ml10%K2CO3溶液。将反应混合物于室温进一步搅动3小时。蒸发MeOH并用EtoAC萃取水层。将合并的EtoAC层用1N HCl和碳酸氢盐溶液清洗,在硫酸钠上干燥并在真空中浓缩以得到粗产物。通过硅石凝胶柱层析来纯化粗产物,使用MeOH:CH2Cl2(9.8:0.2)作为流动相以得到式33a的纯化合物。(产量:0.8克)于室温将0.8克式33a化合物(0.0014摩尔)添加至CH2Cl2(10ml)和三氟乙酸(5ml)的混合物并搅动3小时。搅动后,蒸发CH2Cl2并将二乙醚添加至剩余残留物以给出白色固体2-氨基-N-[2-(2-氰基-3-氮杂-二环[3.1.0]己-3-基)-1-(3-羟基-金刚烷-1-基)-2-氧-乙基]-3-苯基-丙酰胺的三氟乙酸盐(式34)。(产量:0.8克)
实施例23:
于室温将1.7克(0.00380摩尔)式35的3-[2-氨基-2-(5-羟基-金刚烷-2-基)-乙酰基]-3-氮杂-二环[3.1.0]己烷-2-羧酸酰胺三氟乙酸和1.19克(0.00380摩尔)1-(2-叔-丁氧羰基氨基-3-甲基-丁酰基)-吡咯烷-2-羧酸(式26)在THF中的搅动溶液添加至HoBT(0.6克)和DIPEA(1.3ml)并搅动10分钟。对此搅动溶液,于0℃添加EDC.HCl(0.94克)和DIPEA(1.10ml)并将反应混合物于室温搅动过夜。蒸发THF并用EtOAC取残留物。将EtOAC层用1N HCl和NaHCO3水溶液清洗,干燥并在真空中浓缩以得到粗产物。通过硅石凝胶柱层析来纯化粗产物以得到纯(1-{2-[2-(2-氨基甲酰基-3-氮杂-二环[3.1.0]己-3-基)-1-(5-羟基-金刚烷-2-基)-2-氧-乙基氨基甲酰基]-吡咯烷-1-羰基}-2-甲基-丙基)-氨基甲酸叔-丁基酯(式36)。(产量:1.7克)
与实施例23类似,将1.7克(2-{2-[2-(2-氨基甲酰基-3-氮杂-二环[3.1.0]己-3-基)-1-(5-羟基-金刚烷-2-基)-2-氧-乙基氨基甲酰基]-吡咯烷-1-基}-1-甲基-2-氧-乙基)-氨基甲酸叔-丁基酯在THF中的溶液添加至吡啶(1.0ml)和三氟乙酸酐(0.95ml)的混合物。于室温搅动反应混合物。蒸发THF并用MeOH取残留物并添加10ml10%K2CO3溶液。蒸发MeOH并用EtoAC萃取水层。将合并的EtoAC层用1N HCl和NaHCO3水溶液清洗,在硫酸钠上干燥并在真空中浓缩以给出粗产物。通过柱层析来纯化粗产物以得到纯式37的1-(2-氨基-3-甲基-丁酰基)-吡咯烷-2-羧酸[2-(2-氰基-3-氮杂-二环[3.1.0]己-3-基)-1-(5-羟基-金刚烷-2-基)-2-氧-乙基]-酰胺三氟乙酸盐。(产量:0.7克)
根据本发明的范围,另外,下述新型化合物也通过本说明书中例示的方法来合成。筛选合成化合物以检查它们的降血糖效果,这经由体内筛选进行,使用西他列汀(Sitagliptin)、沙格列汀(Saxagliptin)和其它商品化化合物作为对照。根据本发明中描述的方法制备的一些化合物的结构如下:
●表1给出依照本说明书中例示的方法合成的氨基酸类似物2-({6-[(3R)-3-取代的-氨基哌啶-1-基]-3-甲基-2,4-二氧-3,4-二氢嘧啶-1(2H)-基}甲基)-苄腈及药学可接受盐:
表:1
●表2给出依照本说明书中例示的方法合成的氨基酸类似物1-[2-氨基-3,3-双-(4-氟-苯基)-丙酰基]-4-氟-吡咯烷-2-腈及药学可接受盐。
表:2
●表3给出依照本说明书中例示的方法合成的氨基酸类似物(2R)
-4-氧-4-[3-(三氟甲基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-
基]-1-(2,4,5-三氟苯基)丁-2-胺及药学可接受盐
表:3
●表4给出依照本说明书中例示的方法合成的氨基酸类似物8-[(3R)-3-氨基哌啶-1-基]-7-(丁-2-炔-1-基)-3-甲基-1-[(4-甲基喹唑啉-2-基)甲基]-3,7-二氢-1H-嘌呤-2,6-二酮并药学可接受盐:
表:4
●表5给出依照本说明书中例示的方法合成的氨基酸类似物(1S,3S,5S)-2-[(2S)-2-氨基-2-(3-羟基-1-金刚烷基)乙酰基]-2-氮杂二环-[3.1.0]-己-3-腈并药学可接受盐:
表:5
依照本发明的新型降血糖化合物在与DPP IV酶起反应时释放抑制DPP IV酶的实体。式1化合物对DPP IV酶的抑制归于依照本发明合成的特定氨基酸类似物。这些通过本发明化合物的体内筛选来评估。
合成化合物的体内研究:
依照本发明制备功效化合物CPL-2009-0030和CPL-2009-0031。在动物中经由口服葡萄糖耐量试验(OGTT)来评估它们。每个组包括10-12周龄Wistar雌性大鼠。将动物分成4个不同组,每个组6只动物。组I接受媒介(WFI安慰剂),组II接受作为阳性对照的西他列汀,组III接受CPL-2009-0030,而组IV接受CPL-2009-0031。所有动物禁食过夜。
表:01体内研究的剂量组、动物数和药物剂量:
依照表01于0小时以10mL/kg剂量体积给所有研究组动物施用药物。口服施用化合物。施用化合物后3小时施用葡萄糖(2克/Kg体重)。在施用化合物时,在施用葡萄糖时,在施用葡萄糖后1小时、2小时、3小时和4小时时测量血液葡萄糖。图1显示葡萄糖水平随时间的变化。所有动物显示出施用葡萄糖后血液葡萄糖水平升高。升高在施用葡萄糖后30分钟最大。与无处理组相比,施用本发明化合物时葡萄糖的升高显著较低。无处理组和其它三个组之间的差异在30分钟时最大,而且它随时间降低(图01)。所述发现还显示本发明化合物不改变0到3小时的禁食葡萄糖水平。如此,本发明的化合物降低葡萄糖的升血糖效应,不诱导低血糖。换言之,本发明的化合物提供如下的降血糖效果,即只降低进食后高血糖,不诱导禁食低血糖。
为了确认所述发现,实验重复3次并在表02中呈现三次实验中葡萄糖水平随时间的百分比变化。重复实验也确认了所述发现。
表:02新型降血糖化合物的体内结果
类似地,实施同样的实验来评估依照本发明的化合物的体内筛选。图2给出用于评估CPL-2009-0011、CPL-2009-0012、CPL-2009-0015和CPL-2009-0020的降血糖效果的体内筛选的结果。图3给出针对作为对照化合物的沙格列汀,用于评估CPL-2010-0079、CPL-2010-0085的降血糖效果的体内筛选的结果,而图4给出相同化合物针对西他列汀对照进行筛选的结果。
上述结果指示新合成的化合物与标准品相比显示出降血糖活性。依照本发明的新型降血糖化合物在与DPP IV酶起反应时释放抑制DPP IV酶的实体。通过下述分析方法进行进一步评估。
用于分析本发明DPP IV化合物的分析方法:
试剂和溶剂:用于分析本发明DPP IV化合物的试剂、溶剂、标准品和设备如下:
●三氟乙酸(AR级)
●乙腈(HPLC级)
●Milli Q水
●用作标准DPP IV抑制剂的西他列汀碱
●配有UV检测仪和自动取样仪的Shimadzu LC-2010
●稀释剂:乙腈
缓冲液的制备
在烧杯中转移精确量取的1000mL Milli Q水。用三氟乙酸调节pH2.00±0.05。温和搅动并经0.45μ滤膜过滤。
流动相的制备
在1000mL量瓶中转移300mL乙腈并用pH2.00±0.05的缓冲液补足体积至标记。
标准品的制备
在10mL量瓶中精确称取约20mg西他列汀碱工作标准品。添加5.0mL稀释剂并超声处理(如果需要的话)以溶解固体并用稀释剂补足体积至标记,给出浓度为2000ppm的标准溶液(储备溶液)。
进一步稀释上述储备溶液以得到从0.025μM到100μM的不同浓度的溶液。对不同浓度绘制峰面积对以μM计的浓度的线性曲线。样品的制备
提供来自不同器官(肝、肾和胰)和血清样品的提取样品(除去蛋白质物质后),将它们直接注射到HPLC系统上。
层析条件:
液体层析配有可变波长UV检测仪、自动取样仪和数据处理器
●柱:ypersil BDS C8,4.6mm x250mm,5μ
●检测仪波长:54nm
●流速:1.0mL/min
●注射体积:20μL
●柱温:60℃
规程
注射空白(稀释剂)和空白提取样品,注射从0.025μM到100μM的不同浓度的标准品制品并绘制曲线下面积对以μM计的浓度的曲线图。注射样品制品并记录层析图。忽略空白所致任何峰并计算自不同时间间隔收集的提取样品释放的实体的浓度。西他列汀的保留时间为约5.0到6.0分钟。
对于依照本发明呈现的化合物的体内筛选,下述化合物例示本发明的非限制性范围。结果在有关实施例中讨论并呈现于图1-图4。
依照本发明的式1的新型降血糖化合物及其药学可接受盐在体内模型中显示出降血糖活性,包括组合本发明化合物与制药学载剂或稀释剂的药物组合物。
Claims (9)
1.式1的化合物或其药学可接受盐,
其中,A为选自甘氨酸、丙氨酸、缬氨酸、组氨酸、丝氨酸、亮氨酸、异亮氨酸、苯丙氨酸、甲硫氨酸、色氨酸、赖氨酸、谷氨酰胺、谷氨酸、脯氨酸、半胱氨酸、酪氨酸、精氨酸、天冬酰胺、天冬氨酸或苏氨酸的氨基酸;R-NH-选自式2至式6
。
2.如权利要求1所述的式1的化合物,其中所述化合物为降血糖化合物。
3.根据权利要求1所述的式1的化合物,其中,R-NH为式2或其药学可接受盐。
4.根据权利要求1所述的式1的化合物,其中,R-NH为式3或 其药学可接受盐。
5.根据权利要求1所述的式1的化合物,其中,R-NH为式4或其药学可接受盐。
6.根据权利要求1所述的式1的化合物,其中,R-NH为式5或其药学可接受盐。
7.根据权利要求1所述的式1的化合物,其中,R-NH为式6或其药学可接受盐。
8.一种化合物选自以下式或其药学可接受盐
。
9.一种化合物选自以下式或其药学可接受盐
。
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IN1130MU2010 | 2010-04-05 | ||
IN1130/MUM/2010 | 2010-04-05 | ||
PCT/IB2011/051407 WO2011125011A1 (en) | 2010-04-05 | 2011-04-01 | Novel hypoglycemic compounds |
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CN102946726B true CN102946726B (zh) | 2015-08-19 |
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US (1) | US9029567B2 (zh) |
EP (2) | EP2769978A1 (zh) |
CN (1) | CN102946726B (zh) |
CA (1) | CA2795514A1 (zh) |
WO (1) | WO2011125011A1 (zh) |
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CN103848817B (zh) * | 2012-12-03 | 2016-07-06 | 成都地奥制药集团有限公司 | 二肽基肽酶抑制剂的碘代制法、氯代、碘代中间体及制法 |
CN103848816B (zh) * | 2012-12-03 | 2016-06-15 | 成都地奥制药集团有限公司 | 二肽基肽酶抑制剂的还原胺化制法、中间体及制法 |
WO2014108830A1 (en) | 2013-01-10 | 2014-07-17 | Wockhardt Limited | A process for preparing pharmaceutically acceptable salt of saxagliptin |
CN106543141A (zh) * | 2015-09-21 | 2017-03-29 | 成都苑东生物制药股份有限公司 | 尿嘧啶衍生物 |
EP3389664A4 (en) * | 2015-12-14 | 2020-01-08 | Raze Therapeutics Inc. | MTHFD2 CAFFEIN INHIBITORS AND USES THEREOF |
CN115246816B (zh) * | 2022-01-12 | 2024-03-26 | 聊城大学 | 一种双靶点阿格列汀衍生物 |
CN115304604B (zh) * | 2022-01-12 | 2024-03-26 | 聊城大学 | 一种双靶点西格列汀衍生物 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1306540A (zh) * | 1998-06-24 | 2001-08-01 | 前体生物药物开发有限公司 | Dpiv抑制剂的前药 |
CN1861077A (zh) * | 2001-07-06 | 2006-11-15 | 麦克公司 | 作为治疗或预防糖尿病的二肽基肽酶抑制剂的β-氨基四氢咪唑并(1,2-A)吡嗪和四氢三唑并(4,3-A)吡嗪 |
WO2010029422A1 (en) * | 2008-09-12 | 2010-03-18 | Cadila Pharmaceuticals Ltd. | Novel dipeptidyl peptidase (dp-iv) compounds |
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US6395767B2 (en) * | 2000-03-10 | 2002-05-28 | Bristol-Myers Squibb Company | Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method |
JP2010540635A (ja) * | 2007-10-02 | 2010-12-24 | コンサート ファーマシューティカルズ インコーポレイテッド | ピリミジンジオン誘導体 |
CN101925603B (zh) * | 2007-12-13 | 2013-12-04 | 沃泰克斯药物股份有限公司 | 囊性纤维化跨膜通道调节因子的调节剂 |
-
2011
- 2011-04-01 US US13/639,596 patent/US9029567B2/en not_active Expired - Fee Related
- 2011-04-01 WO PCT/IB2011/051407 patent/WO2011125011A1/en active Application Filing
- 2011-04-01 EP EP14154684.6A patent/EP2769978A1/en not_active Withdrawn
- 2011-04-01 CA CA2795514A patent/CA2795514A1/en not_active Abandoned
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1306540A (zh) * | 1998-06-24 | 2001-08-01 | 前体生物药物开发有限公司 | Dpiv抑制剂的前药 |
CN1861077A (zh) * | 2001-07-06 | 2006-11-15 | 麦克公司 | 作为治疗或预防糖尿病的二肽基肽酶抑制剂的β-氨基四氢咪唑并(1,2-A)吡嗪和四氢三唑并(4,3-A)吡嗪 |
WO2010029422A1 (en) * | 2008-09-12 | 2010-03-18 | Cadila Pharmaceuticals Ltd. | Novel dipeptidyl peptidase (dp-iv) compounds |
Non-Patent Citations (2)
Title |
---|
Dipeptidyl peptidase IV inhib itors: How do they work as new antidiabetic agents?;Christopher H.S. McIntosh 等;《Regulatory Peptides》;20040728;第128卷;第159-165页 * |
Improved glucose tolerance in Zucker fatty rats by oral administration of the dipeptidyl peptidase IV inhibitor isoleucine thiazolidide;Raymond A Pederson 等;《DIABETES》;19980831;第47卷(第8期);第1253-1258页 * |
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CN102946726A (zh) | 2013-02-27 |
US9029567B2 (en) | 2015-05-12 |
EP2555617A1 (en) | 2013-02-13 |
WO2011125011A1 (en) | 2011-10-13 |
EP2769978A1 (en) | 2014-08-27 |
EP2555617A4 (en) | 2013-08-14 |
US20130150578A1 (en) | 2013-06-13 |
CA2795514A1 (en) | 2011-10-13 |
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