CN1034171C - 制备新的取代的4-嘧啶酮衍生物的方法 - Google Patents
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Abstract
以下式(I)、(I′)(I″)表示的互变异构形式的化合物,
本发明化合物可用于治疗疾病。
Description
本发明涉及新的取代的4-嘧啶酮类化合物,它们的衍生物、它们的制备方法以及它们在治疗中的应用。
R2代表氢原子,或者链或者支链的(C1-7)烷基,或环(C3-7)烷基(C1-3)烷基,或在环上任意取代的芳基(C1-3)烷基,或在环上任意取代的芳氧基(C1-3)烷基,或在环上任意取代的芳基硫(C1-3)烷基,或在环上任意取代的芳基磺酰基(C1-3)烷基,或在环上任意取代的杂环芳基(C1-3)烷基,
R3为CO2H、1H-四唑-5-基、NHCOR11、NHSO2R11、CONHSO2R11或CONHOR12基团,这里R11代表甲基、三氟甲基或任意取代的苯基,R12代表氢原子、甲基或任意取代的苯基。
本发明的优选化合物是以下所述的式(I)化合物,其中
R1代表直链或者支链的(C1-7)烷基,
R2代表直链或者支链的(C1-7)烷基,或环(C3-7)烷基(C1-3)烷基,或在环上任意取代的芳基(C1-3)烷基,或在环上任意取代的杂环芳基(C1-3)烷基,
R3为CO2H或1H-四唑-5-基。
在上述化合物中,优选的化合物是下述式(I)化合物,其中
R1代表直链的丙基、丁基或戊基,
R2代表在环上任意取代的芳甲基、芳乙基或者杂环芳基乙基R3为CO2H或1H-四唑-5-基。
最优选的化合物是下述式(I)化合物,其中
R1代表直链的丁基,
R2代表在环上任意取代的苄基或者苯乙基或者吡啶基乙基或者噻吩基乙基或者噻唑基乙基,
R3为CO2H或1H-四唑-5-基。
选用的化合物是以下所述的式(I)化合物,其中R1代表直链的丁基,
R2代表苯甲基、4-羧基苯甲基、苯乙基、4-甲氧基苯乙基、4-氟苯乙基、3,4,5-三甲氧基苯乙基、3-氟-4-甲氧基苯乙基、3-吡啶基乙基、4-吡啶基乙基、5-(4-甲基噻唑)-基-乙基或3-噻吩基乙基,
R3为CO2H或1H-四唑-5-基。
本发明化合物可以游离的形式,或以有机或者无机的药学上适用的盐的形式存在。
第一步,使β-酮酯(通式II)与通式(III)的衍生物缩合,得到β-酮酯衍生物(通式IV),在通式(II)中,R1的定义同上,R4代表甲基或乙基,在通式(III)衍生物中,L代表离去基团,如氯、溴、碘、对甲苯磺酰氧基或甲磺酰氧基,R5代表羧基CO2R6,这里R6为甲基、乙基、1,1-二甲基乙基或者苄基,或为硝基,或为由例如三苯基甲基取代基或1,1-二甲基乙基取代基保护的1H-四唑-5-基,
在通式(IV)中,R1、R4和R5的定义同上。
通式(III)的衍生物在欧洲专利申请(253310、291969、323841、400835、400974、401030)中已有叙述。缩合反应在溶剂如甲醇、乙醇、1,1-二甲基乙醇或二甲基甲酰胺中,于-20℃~-80℃之间,在碱(如氢化钠、甲醇钠或1,1-二甲基乙醇钾)以及有选择地在催化剂,如溴化或碘化锂、镁或锌存在下进行。
在第二步中,使β-酮酯(通式IV)与脒(通式V)反应,得到嘧啶酮(通式VI),其中R1、R2和R5的定义同上。该反应按下述条件进行:于40℃~120℃将以上2个化合物的混合物加热,反应有选择地在溶剂如甲醇、乙醇、丁醇或甲苯中,以及有选择地在碱如甲醇钠、碳酸钾、乙酸钠、吡啶、三乙胺或4-二甲氨基吡啶中进行。
在第三步中,根据基团的性质,使基团R5脱去保护和/或将基团R5转变成基团R3:·如果R5为羧酸酯,那么通过酸性或碱性水解,使通式(VI)化合物转变成通式(I)化合物,其中R1和R2的定义同上,并且R3为CO2H基团;在经典的条件下,用各种试剂进行活化,然后再与胺或磺酰胺反应,可以使上述CO2H基团进一步转变,得到通式(I)化合物,其中R3为CONHSO2R11或CONHOR12,并且R1、R2、R11和R12的定义同上。·如果R5为三苯基甲基-1H-四唑-5-基或1,1-二甲基乙基-1H-四唑-5-基,那么可以在酸性介质中于经典条件下脱去保护,得到通式(I)化合物,其中R3为1H-四唑-5-基,R1和R2的定义同上。·如果R5为硝基,那么可以通过还原将其转变成氨基,得到通式(VI)化合物,再在经典条件下将通式(VI)化合物进行酰化或磺酰化,得到通式(I)化合物,其中R3为NHCOR11或NHSO2R11,并且R1、R2和R11的定义同上。
以下述实例详细说明制备通式(I)化合物的方法。经分析确证它们的结构。实例1
4’-[(6-丁基-2-乙基-4-氧-1,4-二氢-嘧啶-5-基)甲基][1,1’-联苯基]-2-羧酸
1.1 4’-[(2-甲氧基羰基)-3-氧庚基][1,1’-联苯基]-2-羧酸甲酯
搅拌下,向用冰浴冷却的16g 3-氧-庚酸甲酯的145ml甲醇溶液中加入5.57g甲醇钠溶液(由2.36g钠和60ml甲醇制得)。混合物于室温下搅拌1小时,然后用冰浴冷却。逐滴加入40.12g 4’-(溴甲基)[1,1’-联苯基]-2-羧酸甲酯的60ml甲醇溶液。混合物于室温搅拌24小时。在减压下浓缩。残余物溶于二氯甲烷中,依次用1N盐酸水溶液和水洗涤。经硫酸钠干燥,并于真空下蒸发,得到42.4g产物,直接用于下一步反应。
1.2 4’-[(6-丁基-2-乙基-4-氧-1,4-二氢-嘧啶-5-基)甲基][1,1-联苯基]-2-羧酸甲酯
将0.48g丙脒和2.5g上述化合物的混合物于氩气流下在90℃加热7小时。粗品经硅胶柱层析纯化,用二氯甲烷与甲醇的混合液洗脱,得到1.1g产物,为糖浆状物,可直接用于下一步。
1.3 4’-[(6-丁基-2-乙基-4-氧-1,4-二氢嘧啶-5-基)甲基][1,1’-联苯基]-2-羧酸
将1.1g上述化合物和1.4g氢氧化钠于30ml甲醇和3ml水混合液中的溶液回流2小时。减压浓缩。水相用乙醚洗涤,过滤,用3N盐酸水溶液酸化。过滤收集沉淀,并用甲醇重结晶,得到0.55g标题化合物,为白色粉末状物。熔点207℃。实例2
4’-[(6-丁基-2-苯基甲基-4-氧-1,4-二氢-嘧啶-5-基)甲基][ 1,1’-联苯基]-2-羧酸
按实例1所述方法,得0.56g苯乙脒和1.7g 4’-[(2-甲氧基羰基)-3-氧庚基[1,1’-联苯基]-2-羧酸甲酯的混合物在氩气流下于95℃加热4小时。产物经氧化铝柱层析纯化,用二氯甲烷和甲醇的混合液洗脱,得到1.0g产物。将该产物溶于30ml甲醇和含有1.0g氢氧化钠的3ml水的混合液中。将其回流3小时并减压浓缩。残余物溶于水中。水相用乙醚洗涤,过滤,用3N盐酸水溶液酸化。过滤收集沉淀并用甲醇重结晶,得到0.60g标题化合物,为白色粉末状物。熔点219℃。实例3
4’-[[6-丁基-2-(2-苯基乙基)-4-氧-1,4二氢-嘧啶-5-基]甲基][1,1’-联苯基]-2-羧酸
按实例1所述方法,将1.0g苯丙脒和2.4g 4’-[(2-甲氧基羰基)-3-氧庚基][1,1’-联苯基]-2-羧酸甲酯的混合物于95℃加热6小时。粗产物经硅胶柱层析纯化,用二氯甲烷和甲醇的混合液洗脱,得到1.0g产物,为糖浆状物。将该产物溶于30ml甲醇和含有1.1g氢氧化钠的3ml水的混合液中。回流3小时并减压浓缩。残余物溶于水中。水相用乙醚洗涤,过滤,用3N盐酸水溶液酸化。过滤收集沉淀,并用甲醇重结晶,得到0.60g标题化合物,为白色粉末状物。溶点194℃。实例4
6-丁基-2-(2-苯基乙基)-5-[[2’-(1H-四唑-5-基)[ 1.1’-联苯]-4-基]甲基]-嘧啶-4(1H)-酮
4.1 3-氧-2-[[2’-(1-三苯基甲基-1H-四唑-5-基)[1,1’-联苯]-4-基]甲基]庚酸甲酯
在氩气流下,向用冰浴冷却的0.97g 1,1-二甲基乙醇钾的15ml二甲基甲酰胺溶液中加入1.3g 3-氧-庚酸甲酯的13ml二甲基甲酰胺溶液,接着加入1.67g溴化锂和5g 5-[4’-(溴甲基)[1,1’-联苯]-2-基]-1-三苯基甲基-1H-四唑的25ml二甲基甲酰胺溶液。反应混合物于室温下搅拌5小时,然后用300ml乙醚稀释。混合物用100ml水洗涤2次,然后用100ml饱和氯化铵水溶液洗涤2次。经硫酸镁干燥,并于真空蒸发,得到4.6g产物,为黄色油状物,用于下一步。
4.2 6-丁基-2-(2-苯基乙基)-5-[[2’-(1-三苯基甲基-1H-四唑-5-基)[1,1’-联苯]-4-基]甲基]嘧啶-4(1H)-酮
将0.7g苯丙脒和3g上述化合物的混合物在氩气流下于90℃加热2小时。残余物溶于120ml二氯甲烷中,并且该混合物用50ml 1M碳酸钾水溶液洗涤2次,然后用50ml 0.1N盐酸水溶液洗涤2次。经硫酸镁干燥和蒸发。残余物经硅胶柱层析纯化,用二氯甲烷和甲醇的混合液洗脱,得到0.85g产物,为类白色泡沫状物。
4.3 6-丁基-2-(2-苯基乙基)-5-[[2’-(1H-四唑-5-基)[1,1’-联苯]-4-基]甲基]-嘧啶-4(1H)-酮
将0.6g上述化合物溶于5ml甲醇和3ml乙醚的混合液中。加入2.7ml 1.57M盐酸的乙醚溶液。混合物于室温下放置2小时,然后蒸发。残余物溶于70ml氢氧化钠水溶液中。用30ml乙醚洗涤3次,并用盐酸酸化。过滤收集沉淀,并用甲醇重结晶,得到0.22g标题化合物,为白色粉末状物。熔点226-228℃。实例5
4’[(2,6-二丁基-4-氧-1,4-二氢-嘧啶-5-基)甲基][1,1’-联苯基]-2-羧酸
按实例1所述方法,将1.1g戊脒和2.5g 4’-[(2-甲氧基羰基)-3-氧庚基][1,1’-联苯基]-2-羧酸甲酯的混合物在氩气流下于90℃加热10小时。粗品经硅胶柱层析纯化,用二氯甲烷和甲醇的混合液洗脱,得到1.2g产物。将1g产物溶于含有1.2g氢氧化钠的30ml甲醇和1ml水的混合液中。混合物回流4小时,并在减压下浓缩。残余物溶于水中。水相用乙醚洗涤,过滤,用3N盐酸水溶液酸化。过滤收集点119℃。实例6
4’[[6-丁基-2-(3,3’-二甲基)丁基-4-氧-1,4-二氢-嘧啶-5-基]甲基][1,1’-联苯基]-2-羧酸
按实例1所述方法,将1.3g 4,4-二甲基戊脒和2g 4’-[(2-甲氧基羰基)-3-氧庚基][1,1’-联苯基]-2-羧酸甲酯的混合物在氩气流下于100℃加热8小时。粗品经硅胶柱层析纯化,用二氯甲烷和甲醇的混合液洗脱,得到1.48g产物。
将上述产物溶于含有1.67g氢氧化钠的60ml甲醇和6ml水的混合液中。混合物回流6小时,并在减压下浓缩。残余物溶于25ml水中。水相用25ml乙醚洗涤,过滤,用2N盐酸水溶液酸化。过滤收集沉淀,用水洗涤,用甲醇重结晶,得到0.6g标题化合物,为白色粉末状物。熔点222℃。实例7
4’-[[ 6-丁基-2-[2-(噻吩-3-基)乙基]-4-氧-1,4-二氢-嘧啶-5-基]甲基][1,1’-联苯基]-2-羧酸
按实例1所述方法,将1.2g 3-噻吩丙脒和2.2g 4’-[(2-甲氧基羰基)-3-氧庚基][1,1’-联苯基]-2羧酸甲酯的混合物在氩气流下于110℃加热3.5小时。粗品经硅胶柱层析纯化,用二氯甲烷和甲醇的混合液洗脱,得到0.87g产物。
将上述产物溶于20ml甲醇和2ml 10N氢氧化钠水溶液的混合液中。混合物回流3小时,并在减压下浓缩。残余物溶于120ml水中。水相用乙醚洗涤3次,每次40ml,过滤,用6N盐酸水溶液酸化。过滤收集沉淀,用水洗涤,并用甲醇重结晶,得到0.41g标题化合物。熔点184-185℃。实例8
4’-[[6-丁基-2-(苯磺酰)甲基-4-氧-1,4-.二氢-嘧啶-5基]甲基][1,1’-联苯基]-2-羧酸
按实例1所述方法,得2.6g 2-苯磺酰基乙脒和2g 4’-[(2-甲氧基羰基)-3-氧庚基][1,1’-联苯基]-2-羧酸甲酯的混合物在氩气流下于80℃加热6小时。粗品经硅胶柱层析纯化,用二氯甲烷和甲醇的混合液洗脱,得到0.5g产物。
将上述产物溶于15ml甲醇和含有0.5g氢氧化钠的1.5ml水的混合液中。混合物回流3.5小时,并在减压下浓缩。残余物溶于150ml水中。水相用乙醚洗涤3次,每次80ml,过滤,用3N盐酸水溶液酸化。过滤收集沉淀,用水洗涤,并用乙醇重结晶,得到0.19g标题化合物。熔点210-212℃。实例9
4’[[6-丁基-2-(2-氯苯氧基)甲基-4-氧-1,4-二氢-嘧啶-5-基]甲基][1,1’-联苯基]-2-羧酸
按实例1所述方法,将1.2g 2-(2-氯苯氧基)乙脒和2g 4’-[(2-甲氧基羰基)-3-氧庚基][1,1’-联苯基]-2-羧酸甲酯在氩气流下于80℃加热4小对。在反应开始1小时和2.5小时之后,2次加入0.5g2-(2-氯苯氧基)乙脒。粗品经硅胶柱层析纯化,用二氯甲烷和甲醇的混合液洗脱,得到0.8g产物。
将上述产物溶于20ml甲醇和含有0.8g氢氧化钠的2ml水的混合液中。混合物回流4.5小时,并在减压下浓缩。残余物溶于150ml水中。水相用乙醚洗涤3次,每次80ml,过滤,用3N盐酸水溶液酸化。过滤收集沉淀,用水洗涤,用乙醇重结晶,得到0.29g标题化合物。熔点159-164℃。实例10
4’[[6-丁基-2-[2-(4-羧基苯基)乙基]-4-氧-1,4-二氢-嘧啶-5-基]甲基][1,1’-联苯基]-2-羧酸
按实例1所述方法,将1.4g 4-甲氧基羰基苯丙脒和2g 4’-[(2-甲氧基羰基)-3-氧庚基][1,1’-联苯基]-2-羧酸甲酯在氩气流下于90℃加热3小时。粗品经硅胶柱层析纯化,用二氯甲烷和甲醇的混合液洗脱,得到1,3g产物。
将1.1g上述产物溶于25ml甲醇和2ml 10N氢氧化钠水溶液的混合液中。混合物回流3小时,并在减压下浓缩。残余物溶于水中。水相依次用乙醚和乙酸乙酯洗涤。用盐酸水溶液酸化。油状物用二氯甲烷萃取,并浓缩萃取液。残余物用含有几滴二异丙基醚的甲醇重结晶,得到0.37g标题化合物。熔点227℃。实例11
6-丁基-2-[2-(3,4-亚甲二氧基苯基)乙基]-5-[[2’-(1H-四唑-5-基)[1,1’-联苯]-4-基]甲基]-嘧啶-4(1H)-酮
按实例4.2所述方法,将1.4g 3,4-亚甲二氧基苯丙脒和2.6g 3-氧-2-[[2’-(1-三苯基甲基-1H-四唑-5-基)[1,1’-联苯基]-4-基]甲基]庚酸甲酯在3ml甲苯中的混合物回流4小时。在真空下蒸发,粗品经硅胶柱层析纯化,用二氯甲烷和甲醇的混合液洗脱,得到1g产物。
将上述产物溶于15ml甲醇和含有1ml乙酸的5ml四氢呋喃的混合液中。溶液回流5小时,并在真空下蒸发。残余物与乙醚一起研磨。过滤收集沉淀,并用乙醚洗涤3次,每次30ml,得到0.45g标题化合物。熔点230-232℃。实例12
6-丁基-2-[2-(萘-2-基)乙基]-5-[[2’-(1H-四唑-5-基)[1,1’-联苯]-4-基]甲基]嘧啶-4(1H)-酮
按实例4.2所述方法,将1.75g 3-(萘-2-基)丙脒和3.3g 3-氧-2-[[2’-(1-[1,1-二甲基乙基]-1H-四唑-5-基)[1,1’-联苯]-4-基]甲基]-庚酸甲酯于100℃加热3.5小时。粗品经硅胶柱层析纯化,用二氯甲烷和甲醇的混合液洗脱,得到2.9g产物,为淡黄色糊状物。
将1.5g上述产物溶于30%氢溴酸的乙酸溶液中。于90℃加热5小时,并在真空下蒸发。残余物溶于二氯甲烷中。有机相用水洗涤,经硫酸钠干燥。蒸去溶剂,得到1.1g粗产物,为粉状物。粗品经硅胶柱层析纯化,用二氯甲烷和甲醇的混合液洗脱,得到0.63g标题产物,为白色粉末状物。熔点163-166℃。
下表详细列出了本发明一些化合物的结构和物理性质。
表
药理学研究证明,本发明化合物具有对抗血管紧张素II的作用。
化合物 | R1 | R2 | R3 | 熔点(℃) |
1234567 | C4H9C4H9C4H9C4H9C4H9C4H9C4H9 | CH3-C2H5-C6H5-C6H5-CH2-C6H5-(CH2)2-C6H5-(CH2)2-C6H5-CH2- | CO2HCO2HCO2HCO2HCO2H1H-四唑-5-基1H-四唑-5-基 | 217207259219194226-228226-228 |
化合物 | R1 | R2 | R3 | 熔点(℃) |
891011121314151617181920212223 | C4H9C4H9C4H9C4H9C4H9C4H9C4H9C4H9C4H9C4H9CH3C2H5C3H7c-C5H9-(CH2)2C5H11C4H9 | 4-Cl-C6H4-CH2-3-CH3O-C6H4-CH2-C6H5-(CH2)3-C4H9-(CH3)2-(CH2)2-(CH3)3-C-(CH2)2-c-C5H9-(CH2)2-c-C6H11-(CH2)2-3-Cl-C6H4-CH2-萘基-1-CH2-C6H5(CH2)2-C6H5(CH2)2-C6H5(CH2)2-C6H5(CH2)2-C6H5(CH2)2-噻吩基-2-(CH2)2- | CO2HCO2HCO2HCO2HCO2HCO2HCO2HCO2HCO2HCO2HCO2HCO2HCO2HCO2HCO2HCO2H | 230177149119130222159205186235265-267207-208206-207189-190176-179192-193 |
化合物 | R1 | R2 | R3 | 熔点(℃) |
24252627282930313233343536373839 | C4H9C4H9C4H9C4H9C4H9C4H9C4H9C4H9C4H9C4H9C4H9C4H9C4H9C4H9C4H9C4H9 | 噻吩基-3-(CH2)2-C6H5-OCH2-C6H5-SCH2-C6H5-SO2CH2-4-Cl-C6H4-OCH2-3-Cl-C6H4-OCH2-2-Cl-C6H4-OCH2-4-CH3O-C6H4-OCH2-3-CH3O-C6H4-OCH2-4-HO2C-C6H4-OCH2-3-HO2C-C6H4-OCH2-4-CH3-C6H4-(CH2)2-4-CH3O-C6H4-(CH2)2-3,4-OCH2O-C6H4-(CH2)2-4-HO2C-C6H4-(CH2)2-4-CH3O-C6H4-(CH2)2- | CO2HCO2HCO2HCO2HCO2HCO2HCO2HCO2HCO2HCO2HCO2HCO2HCO2HCO2HCO2H1H-四唑-5-基 | 184-185228152210-212252-256227-232159-164214-219209-212265-268>270107113213227194-198 |
化合物 | R1 | R2 | R3 | 熔点(℃) |
40414243444546474849505152535455 | C4H9C4H9C4H9C4H9C4H9C4H9C4H9C4H9C4H9C4H9C4H9C4H9C4H9C4H9C4H9C4H9 | 3,4-OCH2O-C6H4-(CH2)2-4-F-C6H4-(CH2)2-3-F-C6H4-(CH2)2-3,4-F2-C6H3-(CH2)2-4-CH3S-C6H4-(CH2)2-萘基-2-(CH2)2-萘基-1-(CH2)2-3,4-(CH3O)2-C6H3-(CH2)2-3-CH3O-C6H4-(CH2)2-3,4,5-(CH3O)3-C6H2-(CH2)2-3-CF3-C6H4-(CH2)2-4-Cl-C6H4-(CH2)2-4-CF3-C6H4-(CH2)2-2,4-(CH3O)2-C6H3-(CH2)2-3-Cl-C6H4-(CH2)2-吡啶基-3-(CH2)2- | 1H-四唑-5-基1H-四唑-5-基1H-四唑-5-基1H-四唑-5-基1H-四唑-5-基CO2HCO2H1H-四唑-5-基1H-四唑-5-基1H-四唑-5-基1H-四唑-5-基1H-四唑-5-基1H-四唑-5-基1H-四唑-5-基1H-四唑-5-基1H-四唑-5-基 | 230-232198-203234-236228-230190-194222-223185-186178-180226-229198-200209-210217-218230-231205-208225-226174-178 |
化合物 | R1 | R2 | R3 | 熔点(℃) |
5657585960616263646566 | C4H9C4H9C4H9C4H9C4H9C4H9C4H9C4H9C4H9C4H9C4H9 | 吡啶基-4-(CH2)2-3-F,4-CH3O-C6H3-(CH2)2-4-HO2C-C6H4-CH2-3-HO2C-C6H4-CH2-4-CH3SO-C6H4-(CH2)2-4-CH3SO2-C6H4-(CH2)2-3,5-(CH3O)2-C6H3-(CH2)2-(4-甲基噻唑)-5-基-(CH2)2-C6H5-(CH2)3-CH3-萘基-2-(CH2)2- | 1H-四唑-5-基1H-四唑-5-基1H-四唑-5-基1H-四唑-5-基1H-四唑-5-基1H-四唑-5-基1H-四唑-5-基1H-四唑-5-基1H-四唑-5-基1H-四唑-5-基1H-四唑-5-基 | 239-241213-214272-275232-233195-196205-215205-215171-174185-190236-237163-166 |
[3H]-血管紧张素II与兔肾上腺皮质的结合试验。
本试验用体重为2~3kg的雄性Fauves de Bourgogne兔。用颈脱位法处死免,剪下肾上腺,并迅速在4℃条件下将其剖开,切下皮质。将皮质组织置于10ml冰冷的10mM三(羟甲基)氨基甲烷缓冲液(内含0.33M蔗糖,1mM乙二胺四乙酸)中,用盐酸校正pH至7.4,用电动Potter氏匀浆器,以1200rpm速度将其制成匀浆。用Tris-蔗糖缓冲液将组织匀浆体积调至25ml,然后以1075g速度离心15分钟。取出上清液保存,沉渣则按上述方法重新悬于10ml Tris-蔗糖缓冲液中,再制成匀浆,按以上所述进行离心。合并2次匀浆的上清液,以47800g速度离心30分钟。所得沉淀重新悬于150倍体积(即,100mg组织重新悬于15ml缓冲液)的含50mM Tris-Hcl,150mM Nacl,5mM乙二胺四乙酸,1.25μg/ml杆菌肽,100μM苯基甲基磺酰氟和0.2%牛血清白蛋白(pH=7.4,25℃)的温育缓冲液中。
在2nM[3H]-血管紧张素II(New England Nuclear公司,比活61Ci/mmol)存在下,在终体积为0.5ml温育缓冲液中,将肾上腺皮质微粒体(100μl混悬液)在25℃温育30分钟。温育后,采用微孔滤膜过滤法,将微粒体富集于孔径为0.45μM的预先用牛血清白蛋白处理的Millipore HAWPTM硝酸纤维素滤膜上,用冰冷却的Tris-Hcl缓冲液洗涤3次,每次5ml。用液体闪烁分光计计数被滤膜截留的膜结合放射性。特异的[3H]-血管紧张素II结合力定义为:在1μM未标记血管紧管紧张素II存在下,通过温育能够抑制的滤膜截留的放射性量。它表示滤膜截留的放射性总量的90-95%。
在不同浓度试验化合物存在下,测定特异的[3H]-血管紧张素II结合力,然后用图解法求出抑制50%特异的[3H]-血管紧张素II结合所需要的试验化合物浓度,即IC50。
本发明化合物的IC50为5nM和10μM之间。
对大鼠血管紧张素II加压反应的抑制
雄性Sprague-Dawley大鼠(体重250~280g,Charles RiverFrance)用戊巴比妥钠(55mg/kg,i.P.)麻醉,并维持人工呼吸(HarvardTM呼吸机,速率为每分钟70ml,每100g体重1ml空气体积)。用一金属棒穿过大鼠右眼眼框,将脑脊髓刺毁。切开右侧和左侧迷走神经(双侧迷走神经切开术);结扎右颈动脉,而左颈动脉插入导管,以便用压力计(StathamTM P23 Db型)测量血压。股静脉插入导管,以便静脉注入药物。在静脉注射0.5μg/kg血管紧张素II后测量血压。在注射血管紧张素II之前5分钟(静注给药研究)或60分钟(口服给药研究),将本发明化合物或生理盐水给予大鼠。本发明化合物的给药剂量范围是0.01-100mg/kg。
血管紧张素II加压反应对照的抑制百分率用于评价本发明化合物对血管紧张素II的对抗作用。
本发明化合物或它们的合适的盐可用于治疗不同类型的高血
也可以将本发明化合物或它们的适用盐与其他具有心血管作用的物质(如利尿剂、α-阻滞剂、β-阻滞剂、钙拮抗剂或血管紧张素I转变酶抑制剂)一起应用。
本发明化合物或它们的适用盐可以制成下列适用于口服、非经胃肠道给药、肌肉或直肠给药的任一药用形式,如片剂、胶囊剂、硬明胶胶囊剂、无菌溶液剂或混悬剂、栓剂等。
为了治疗青光眼,可以将本发明化合物或它们的适用盐制成片剂、硬明胶胶囊剂、可注射的溶液剂或局部应用的眼制剂。
可以给患者服用的本发明组合物其剂量范围是每名患者每天1-1000mg,可以一次服用,或者分多次服用。
Claims (8)
R1代表直链或者支链(C1-7)烷基、直链或支链(C3-9)链烯基、或(C3-7)环烷基(C1-6)烷基;
R2代表氢原子、直链或者支链的(C1-7)烷基、(C3-7)环烷基(C1-3)烷基,或代表在环上可被1-3个取代基任意取代的芳基(C1-3)烷基、芳氧基(C1-3)烷基、芳硫基(C1-3)烷基、芳基磺酰基(C1-3)烷基或杂环芳基(C1-3)烷基,所述芳基是苯基和萘基,所述杂环芳基是吡啶基、噻吩基和噻唑基,所述取代基选自卤素、C1-C6烷基、C1-C6烷氧基、羧基、氨基、三氟甲基和-OCH2O-;
R3为CO2H或1H-四唑-5-基;
该方法的特征在于使式(II)的β-酮与式(III)化合物反应,得到式(IV)化合物,式(II)中R1的定义同前和R4代表甲基或乙基,
2.权利要求1的方法,其特征在于:使其中R5为三苯基甲基-1-H四唑-5-基或1,1-二甲基乙基-1H-四唑-5-基的式(VI)化合物在酸性介质中脱去保护基,得到通式(I)化合物,其中R3为1H-四唑-5-基,R1和R2的定义同权利要求1中的定义。
3.权利要求1的方法,其特征在于:使其中R5为羧酸酯并且R1和R2的定义同权利要求1的式(VI)化合物,通过酸性或碱性水解转变为通式(I)化合物,其中R1和R2的定义同权利要求1中定义,R3为CO2H。
4.权利要求1的方法,其特征在于:
R1代表直链或支链(C1-7)烷基;
R2代表直链或者支链(C1-7)烷基、(C3-7)环烷基(C1-3)烷基,或在环上可被1-3取代基任意取代的芳基(C1-3)烷基或杂环芳基(C1-3)烷基,这里所述的芳基、杂环芳基和取代基的定义同权利要求1;
R3为CO2H或1H-四唑-5-基。
5.权利要求4的方法,其特征在于:
R1代表直链丙基、丁基或戊基;
R2代表在环上可被1-3个取代基任意取代的芳基甲基、芳基乙基或杂环芳基乙基,这里所述的芳基、杂环芳基和取代基的定义同权利要求1;
R3为CO2H或1H-四唑-5-基。
6.权利要求5的方法,其特征在于:
R1代表直链丁基;
R2代表在环上可被1-3个取代基任意取代的苄基、苯基乙基、吡啶基乙基,噻吩基乙基或噻唑乙基,这里所述的取代基的定义同权利要求1;
R3为CO2H或1H-四唑-5-基。
7.权利要求6的方法,其特征在于:
R1代表直链丁基;
R2代表苯基甲基、4-羧基苯基甲基、苯基乙基、4-甲氧基苯基乙基、4-氟苯基乙基、3,4,5-三甲氧基苯基乙基、3-氟-4-甲氧基苯基乙基、3-吡啶基乙基、4-吡啶基乙基、5-(4-甲基噻唑)基-乙基或3-噻吩基乙基,
R3为CO2H或1H-四唑-5-基。
8.权利要求7的方法,其特征在于制备的化合物是6-丁基-2-(2-苯基乙基)-5-[[2′-(1H-四唑-5-基)[1,1′-联苯]-4-基]甲基]嘧啶-4(1H)-酮。
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CN92101114A Expired - Fee Related CN1034171C (zh) | 1991-02-20 | 1992-02-19 | 制备新的取代的4-嘧啶酮衍生物的方法 |
Country Status (23)
Country | Link |
---|---|
EP (1) | EP0500409B1 (zh) |
JP (1) | JP2529798B2 (zh) |
KR (1) | KR920016434A (zh) |
CN (1) | CN1034171C (zh) |
AT (1) | ATE135695T1 (zh) |
AU (1) | AU650319B2 (zh) |
CA (1) | CA2061456A1 (zh) |
CS (1) | CS49092A3 (zh) |
DE (1) | DE69209113T2 (zh) |
DK (1) | DK0500409T3 (zh) |
ES (1) | ES2086090T3 (zh) |
FI (1) | FI920720A (zh) |
FR (1) | FR2672892B1 (zh) |
GR (1) | GR3019404T3 (zh) |
HU (2) | HUT60477A (zh) |
IE (1) | IE76145B1 (zh) |
IL (1) | IL101014A (zh) |
MX (1) | MX9200690A (zh) |
NO (1) | NO920648L (zh) |
NZ (1) | NZ241659A (zh) |
PL (1) | PL168617B1 (zh) |
RU (1) | RU2073675C1 (zh) |
ZA (1) | ZA921203B (zh) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL102183A (en) * | 1991-06-27 | 1999-11-30 | Takeda Chemical Industries Ltd | The heterocyclic compounds are converted into biphenyl groups, their production and the pharmaceutical compositions containing them |
FR2700543B1 (fr) * | 1993-01-15 | 1995-03-17 | Synthelabo | Sels de dérivés de 4-pyrimidinone, leur préparation et leur application en thérapeutique. |
SE9903028D0 (sv) | 1999-08-27 | 1999-08-27 | Astra Ab | New use |
EA020466B1 (ru) | 2007-06-04 | 2014-11-28 | Синерджи Фармасьютикалз Инк. | Агонисты гуанилатциклазы, пригодные для лечения желудочно-кишечных нарушений, воспаления, рака и других заболеваний |
US8969514B2 (en) | 2007-06-04 | 2015-03-03 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
CA2726917C (en) | 2008-06-04 | 2018-06-26 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
CA2730603C (en) | 2008-07-16 | 2019-09-24 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
TW201444848A (zh) * | 2009-01-30 | 2014-12-01 | Takeda Pharmaceutical | 稠環化合物及其用途 |
US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
CA2905435A1 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Compositions useful for the treatment of gastrointestinal disorders |
EP2970384A1 (en) | 2013-03-15 | 2016-01-20 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
CN113388007A (zh) | 2013-06-05 | 2021-09-14 | 博士医疗爱尔兰有限公司 | 鸟苷酸环化酶c的超纯激动剂、制备和使用所述激动剂的方法 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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EP0253310A2 (en) * | 1986-07-11 | 1988-01-20 | E.I. Du Pont De Nemours And Company | Angiotensin II receptor blocking imidazoles |
EP0407342A2 (de) * | 1989-07-06 | 1991-01-09 | Ciba-Geigy Ag | Neue Pyrimidin Derivate |
WO1991000277A1 (en) * | 1989-06-30 | 1991-01-10 | E.I. Du Pont De Nemours And Company | Substituted imidazoles |
EP0424317A2 (de) * | 1989-10-19 | 1991-04-24 | Ciba-Geigy Ag | Pyrimidine |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5064825A (en) * | 1989-06-01 | 1991-11-12 | Merck & Co., Inc. | Angiotensin ii antagonists |
EP0435827A3 (en) * | 1989-12-28 | 1991-11-13 | Ciba-Geigy Ag | Diaza compounds |
CA2079344A1 (en) * | 1990-03-30 | 1991-10-01 | Eric E. Allen | Substituted pyrimidines, pyrimidinones and pyridopyrimidines |
IE912114A1 (en) * | 1990-07-02 | 1992-01-15 | Union Pharma Scient Appl | Novel pyrimidine derivatives which are angiotensin ii¹receptor antagonists, their methods of preparation and¹pharmaceutical compositions in which they are present |
-
1991
- 1991-02-20 FR FR9102032A patent/FR2672892B1/fr not_active Expired - Fee Related
-
1992
- 1992-02-03 DE DE69209113T patent/DE69209113T2/de not_active Expired - Fee Related
- 1992-02-03 ES ES92400269T patent/ES2086090T3/es not_active Expired - Lifetime
- 1992-02-03 DK DK92400269.4T patent/DK0500409T3/da active
- 1992-02-03 AT AT92400269T patent/ATE135695T1/de not_active IP Right Cessation
- 1992-02-03 EP EP92400269A patent/EP0500409B1/fr not_active Expired - Lifetime
- 1992-02-19 NO NO92920648A patent/NO920648L/no unknown
- 1992-02-19 RU SU925010817A patent/RU2073675C1/ru active
- 1992-02-19 HU HU9200532A patent/HUT60477A/hu unknown
- 1992-02-19 NZ NZ241659A patent/NZ241659A/xx unknown
- 1992-02-19 JP JP4031862A patent/JP2529798B2/ja not_active Expired - Lifetime
- 1992-02-19 CS CS92490A patent/CS49092A3/cs unknown
- 1992-02-19 KR KR1019920002504A patent/KR920016434A/ko not_active Application Discontinuation
- 1992-02-19 AU AU11059/92A patent/AU650319B2/en not_active Ceased
- 1992-02-19 IL IL10101492A patent/IL101014A/en not_active IP Right Cessation
- 1992-02-19 ZA ZA921203A patent/ZA921203B/xx unknown
- 1992-02-19 FI FI920720A patent/FI920720A/fi unknown
- 1992-02-19 PL PL92293531A patent/PL168617B1/pl unknown
- 1992-02-19 CN CN92101114A patent/CN1034171C/zh not_active Expired - Fee Related
- 1992-02-19 CA CA002061456A patent/CA2061456A1/en not_active Abandoned
- 1992-02-19 MX MX9200690A patent/MX9200690A/es not_active IP Right Cessation
- 1992-02-19 IE IE920525A patent/IE76145B1/en not_active IP Right Cessation
-
1995
- 1995-06-29 HU HU95P/P00554P patent/HU211886A9/hu unknown
-
1996
- 1996-03-21 GR GR960400758T patent/GR3019404T3/el unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0253310A2 (en) * | 1986-07-11 | 1988-01-20 | E.I. Du Pont De Nemours And Company | Angiotensin II receptor blocking imidazoles |
WO1991000277A1 (en) * | 1989-06-30 | 1991-01-10 | E.I. Du Pont De Nemours And Company | Substituted imidazoles |
EP0407342A2 (de) * | 1989-07-06 | 1991-01-09 | Ciba-Geigy Ag | Neue Pyrimidin Derivate |
EP0424317A2 (de) * | 1989-10-19 | 1991-04-24 | Ciba-Geigy Ag | Pyrimidine |
Also Published As
Publication number | Publication date |
---|---|
PL168617B1 (pl) | 1996-03-29 |
HU9200532D0 (en) | 1992-05-28 |
KR920016434A (ko) | 1992-09-24 |
IE920525A1 (en) | 1992-08-26 |
EP0500409B1 (fr) | 1996-03-20 |
FR2672892A1 (fr) | 1992-08-21 |
DE69209113D1 (de) | 1996-04-25 |
AU1105992A (en) | 1992-08-27 |
FI920720A (fi) | 1992-08-21 |
FI920720A0 (fi) | 1992-02-19 |
GR3019404T3 (en) | 1996-06-30 |
IL101014A (en) | 1996-06-18 |
ATE135695T1 (de) | 1996-04-15 |
AU650319B2 (en) | 1994-06-16 |
IL101014A0 (en) | 1992-11-15 |
JP2529798B2 (ja) | 1996-09-04 |
CA2061456A1 (en) | 1992-08-21 |
MX9200690A (es) | 1992-08-01 |
CS49092A3 (en) | 1992-09-16 |
NZ241659A (en) | 1993-03-26 |
HUT60477A (en) | 1992-09-28 |
CN1064269A (zh) | 1992-09-09 |
EP0500409A1 (fr) | 1992-08-26 |
ES2086090T3 (es) | 1996-06-16 |
HU211886A9 (en) | 1995-12-28 |
NO920648D0 (no) | 1992-02-19 |
FR2672892B1 (fr) | 1994-01-14 |
RU2073675C1 (ru) | 1997-02-20 |
PL293531A1 (en) | 1992-08-24 |
NO920648L (no) | 1992-08-21 |
DK0500409T3 (da) | 1996-07-15 |
JPH04346980A (ja) | 1992-12-02 |
DE69209113T2 (de) | 1996-10-31 |
ZA921203B (en) | 1992-11-25 |
IE76145B1 (en) | 1997-10-08 |
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