CN1042329C - 用于治疗疾病的取代的环己烷衍生物 - Google Patents
用于治疗疾病的取代的环己烷衍生物 Download PDFInfo
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- CN1042329C CN1042329C CN93116663A CN93116663A CN1042329C CN 1042329 C CN1042329 C CN 1042329C CN 93116663 A CN93116663 A CN 93116663A CN 93116663 A CN93116663 A CN 93116663A CN 1042329 C CN1042329 C CN 1042329C
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Abstract
本发明涉及式Ⅰ的环己烷衍生物、其制备方法、含有这些化合物的药物以及这些药物用于治疗与肝脏葡萄糖的释放量或葡萄糖-6-磷酸酯酶系统的活性增高有关的Ⅱ型糖尿病的其它疾病,
式中R1-R6、X、Y、Z和n的定义详见本说明书。
Description
糖尿病的疾病特征是血糖值的增高。依赖于胰岛素的或Ⅰ型糖尿病的原因是胰腺中产生胰岛素的β-细胞的坏死,因而可用给胰岛素加以治疗(代替治疗)。不依赖于胰岛素的或Ⅱ型糖尿病的特征则是降低了胰岛素对肌肉和脂肪组织的作用(胰岛素抗性),并增高了肝产生的葡萄糖。代谢紊乱的原因仍不很清楚。磺酰脲类开创性的治疗引起胰岛素抗性是由于代偿性地提高了机体特有的胰岛素的释放,但在所有情况下都不会使血糖水平正常化,不能阻止疾病的发展;许多Ⅱ型糖尿病患者最后由于产生胰岛素的β-细胞耗尽,造成晚期损伤,如白内障、肾病和血管病。因而希望有对Ⅱ型糖尿病的新的治疗原理。
空腹状态下血中葡萄糖浓度由于肝脏产生葡萄糖而是固定的。不同的研究组指出,Ⅱ型糖尿病的血糖值的增高与肝脏产生的葡萄糖呈比例关系。自肝脏向血液中分泌的葡萄糖既可以是由于肝糖原的降解(糖原分解),也可由于葡萄糖异生作用。
6-磷酸葡萄糖是葡萄糖异生作用和糖原分解作用的共同的终产物。自6-磷酸葡萄糖经肝脏作用释放的葡萄糖的最终步骤是经葡萄糖-6-磷酸酯酶(EC 3.1.3.9)催化。葡萄糖-6-磷酸酯酶是存在于内质网中的多酶复合物。该多酶复合物是由处在内质网膜上的葡萄糖-6-磷酸移位酯、在内质网腔内的葡萄糖-6-磷酸酯酶和-种磷酸酯移位酶所组成〔见综述Ashmore,J和Weber,G:“肝脏葡萄糖-6-磷酸酯酶对调节碳水化合物代谢的作用”,于“维生素和激素”上发表,卷ⅩⅦ(Harris,R.S.,Marrian G.F.,Thi-mann K.V.,编),92-132(1959);Burchell A.,和Waddell I.D.,“肝微粒体葡萄糖-6-磷酸酯酶系统的分子基础”,Biochim.Biophys.Acta 1092,129-137(1990)。上述内容丰富的文献提示,在所有被研究的条件下,例如用链氮霉素、四氧嘧啶、可的松、甲状腺激素和饥饿导致试验动物血糖值增高时,许多复合酶的活性也提高了。许多研究还表明,Ⅱ型糖尿病患者被观测到提高了的葡萄糖产生与增高了葡萄糖-6-磷酸酯酶活性相联系。在葡萄糖正常的自行调节中,Ⅰb型糖原贮存疾病的患者所具有的低血糖症状进一步强调说明了葡萄糖-6-磷酸酯酶系统的意义,它缺乏葡萄糖-6-磷酸系统中的移位酶成分。
用适宜的有效物质(抑制剂)降低葡萄糖-6-磷酸酯酶活性,应使肝脏的葡萄糖释放也相应减少。这样的有效物质能够使肝脏产生的葡萄糖在外周发生有效的消耗。因而Ⅱ型糖尿病患者在空腹状态下应有降低的血糖值,此外,也应对糖尿病的晚期损伤有预防作用。在文献中叙述了一系列非特异的葡萄糖-6-磷酸酯酶抑制剂,例如Phlorrizin〔Soodsma,J.F.,Legler,B.和Nordlie,R.C.,J,Biol.Chem.242,1955-1960(1967)〕,5,5′-二硫代-双-2-硝基苯甲酸〔Wallin,B.K.和Arion,W.,J.Biochem.Biophys.Res.Com-mun.48,694-699(1972)〕,2,2′-二硫代异氰酸基芪和2-异硫氰酸基-2′-乙酰氧基芪〔Zuccoli.M.A.和Karnowski,M.L.,J.Bi-ol.Chem.255,1113-1119(1980)〕。最近还有无治疗价值的葡萄糖-6-磷酸酯酶系统的抑制剂。
在下面定义的取代的环己烷衍生物(有一部分在化学和生物学文献中是已知的化合物)是从许多植物中分离出的(R.Krase-mann,Arch.Pharm.293,721(1960),但这些酯的药理和生化作用却很少报导。这类化合物中有代表性的为绿原酸,报导为脂氧合酶的抑制剂(M.Nishzawa等,Chem.Pharm.Bull,34(3),1419(1986))。
我们发现,取代的环己烷羧酸的一些酯例如绿原酸的酯(我们的研究的化合物No.17)是葡萄糖-6-磷酸酯酶的抑制剂。
(C1-C4-烷基)、SO3H、PO(OH)2、PO(OH)(O-C1-C4-烷
基)或PO(O-C1-C4-烷基)2,R2:H、OH或F,R3:H、苯基、萘基、吡啶基、噻吩基、呋喃基,其中的芳环或杂芳环上
可被、相同或不同的如下基团取代一次或多次:F、Cl、Br、I、OH、
-NO2、C1-C4-链烷酰基、C1-C4-烷氧基、C1-C4-烷基、苯
基、苯氧基、噻吩基、呋喃基、吡啶基、咪唑基或苄氧基,R4、R5、R6:H、OH、F、Cl、Br、C1-C4-链烷酰基、C1-C4-烷基、苯
基、苯氧基、噻吩基、呋喃基、吡啶基、咪唑基或苄氧基,其
中,R4、R5、R6可以相同或不同,X:-(CH2)n-、-CH=CH-或-CH2-O-CH2-,Y:-(CH2)n-、O、S或NH,Z:-(CH2)n-或-CH=CH-,n:0、1、2、3或4。
优选应用的式Ⅰ化合物具有如下的基团:R1:COOH、COO(C1-C4-烷基)、PO(OH)2、PO(OH)(O-C1-C4
-烷基)、或PO(O-C1-C4-烷基)2,R2:H或OH,R3:H、苯基、萘基、吡啶基、噻吩基、呋喃基,其中的芳环或杂芳环可被相同或不同的如下基团取代1次、2次或3次:F、Cl、Br、I、NO2、OH、C1-C4-链烷酰基、C1-C4-烷氧基、C1-C4-烷基、苯基、苯氧基、噻吩基、呋喃基、吡啶基、咪唑基或苄氧基,R4、R5和R6:H、OH、F、Cl、Br、C1-C4-链烷酰基、C1-C4-烷基、
苯基、苯氧基、噻吩基、呋喃基、吡啶基、咪唑基或苄氧
基,R4、R5、R6可以相同或不相同,X:-(CH2)n-、-CH=CH-或-CH2-O-CH2-,Y:-(CH2)n-、O、S或NH,Z:-(CH2)n-或-CH=CH-,n:0、1、2、3或4。
优选应用如下的式Ⅰ化合物,它们的基团具有如下的意义:R1:COOH或COO(C1-C4-烷基),R2:H或OH,R3:H、苯基、萘基、吡啶基、噻吩基、呋喃基、其中的芳环或杂芳环上
可被相同或不相同的如下取代基取代1、2或3次:F、Cl、OH、
NO2、C1-C4-链烷酰基、C1-C4-烷氧基、C1-C4-烷基、苯
基、苯氧基或苄氧基,R4、R5和R6:H或OH,具中R4、R5、R6可以相同或不相同,X:-(CH2)n-,n=0、1或2,Y:O或NH,Z:-(CH2)n-,其中n=0或2;或者-CH=CH-,
在式Ⅰ化合物中存在的烷基、烷氧基和链烷酰基可以是直链或支链的。
本发明还涉及式Ⅰ化合物用于治疗与葡萄糖-6-磷酸酯酶增高的活性相关的疾病。
本发明还涉及式Ⅰ化合物在治疗与肝脏产生葡萄糖增高有关的疾病方面的应用。
本发明还涉及式1化合物在治疗Ⅱ型糖尿病(不依赖于胰岛素的或老年性糖尿病)方面的用途。
本发明还包括式Ⅰ化合物在制造用于治疗糖尿病或其它疾病的药物的用途,这些疾病的特点是:肝脏提高了葡萄糖的释放量,或者葡萄糖-6-磷酸酯酶活性增高了。
本发明化合物对葡萄糖-6-磷酰酯酶的作用是在肝微粒体的酶测定中研究的。
为了制备含有葡萄糖-6-磷酸酯酶的微粒体,用雄性Wistar大鼠新鲜肝脏按文献方法处理〔Canfield,W.K.和Arion,W.J.,Biol.Chem.,263,7458-7460(1988)〕。这种微粒体于-70℃贮存至少2个月,其活性不会有显著的丢失。
确定葡萄糖-6-磷酸酯酶的活性是按文献所述(Arion,W.J.于Methods Enzymol.174,Academic Press,1989,58~67页)、通过测定由6-磷酸葡萄糖中释放的磷酸进行的。0.1ml试液含有6-磷酸葡萄糖(1mmol/l)、受试物质、0.1mg微粒体和100m-mol/l HEPES-缓冲液(4-(2-羟乙基)哌嗪-1-乙磺酸),pH为7.0。加入酶使反应开始,室温反应20分钟后,加入0.2ml磷酸试剂使反应终止。反应物于37℃温育30分钟,于570nm测定蓝色光的吸收度(A),受试物质的抑制活性由与不含受试物质的对照反应比较而得,按如下公式求出:
表1~3列出了一系列的示范性式Ⅰ化合物的抑制值,所研究的化合物有一部分是文献已知的,制备方法叙述于实施例中。
表2
表3(续)
在按照常规方法制备的本发明药物中,除含有式Ⅰ化合物外,还可含有药学上安全的赋加剂,如稀释剂和/或载体物质。为此,将生理上安全的物质与有效物质混合,并将其制成适宜的剂型。口服用药是优选的。
适宜的固体或液体格林制剂是例如片剂、糖锭剂、粉剂、胶囊剂、糖浆剂、乳剂、悬浮剂、滴剂以及控释有效物质的制剂。常用的载体物质或稀释剂是例如各种糖或淀粉类、纤维素衍生物、碳酸镁、明胶、动物和植物油、聚乙二醇、水或其它适宜的溶剂和含水的缓冲剂,后者可加入盐制成等渗溶液。此外,在本发明的药物制剂中可任选地使用表面活性剂、色料、矫味剂、稳定剂以及防腐剂等作为赋加剂。
制剂可优选地制成剂量单位,尤其是制成剂量单位的片剂和胶囊。每个剂量单位、特别是口服应用的单位含有效成分可达500mg,优选为10~200mg,剂量单位在使用时也可高于或低于它,给药时可任选地将剂量单位分成份,或用多个剂量单位。剂量单位作口服应用时可任选为微囊化,以便例如延缓释放。控释给药也可例如将微粒状的物料包以适宜的聚合物、蜡或其它物质。
163.3g(0.85mol)化合物a(Fischer,Dangschat.Cher.Ber.65,1009(1932))悬浮于186ml(1.8mol)环己酮中,加入0.5ml浓硫酸。然后在200℃热浴中慢慢加热,蒸出水/环己酮共沸物。当不再蒸出共沸物后,于200℃浴温下将浅褐色反应液再搅拌2小时。冷却至70℃、加入10g碳酸氢钠,再加入700ml乙酸乙酯,用水和饱和氯化钠溶液洗涤有机相。减压浓缩有机相后,浅黄色剩余物于1∶1异丙醇/水中结晶,得到142.1g(75%)内酯b,为无色结晶,熔点:140-141℃。自b制备c
38.14g(0.15mol)羟基内酯b溶解于180ml二氯甲烷中,加入53.0ml(0.3mol)二异丙基乙基胺。室温下向此溶液中滴入45.0ml(0.254mol)三甲基甲硅烷基乙氧甲基氯化物,回流搅拌6小时。反应液中加入饱和氯化铵溶液,乙酸乙酯萃取。合并后的有机相用大约6℃的1N硫酸氢钠冷溶液萃取,硫酸钠干燥,减压浓缩后得到浅黄色剩余物。用6∶1庚烷/乙酸乙酯结晶,得57.0g(98%)的C。熔点:100-102℃。自c制备d
1.38g(3.6mmol)C溶解于8ml二恶烷中。加入0.4ml水后,于室温下滴入3.8ml 1N氢氧化钠,反应液搅拌2小时,减压浓缩。得到1.3g(85%)d.为无定形固体物。1H-NMR(270MHz,d6-DMSO):d=0.01ppm(s,9H),0.72-0.89(m,2H),1.21-1.62(m,10H),1.65-1.78(m,1H),1.82-1.92(m,1H),1.94-2.08(m,2H),3.38-3.63(m,3H),3.82-3.88(m,1H),4.18-4.27(m,1H),4.61-4.72(m,2H),7.80-7.90(m,1H).步骤d、e和f按制备化合物8的举例所述。化合物8的制备:反应式2 SEM=三甲基甲硅烷氧甲基-制备8C(自8A经8B)
10.0g(0.052mol)对-羟基肉桂酸酯(8A)溶解于60ml无水二氯甲烷中,加入27ml(0.156mol)二异丙基乙基胺,在氩气氛和室温下滴加19.5ml(0.11mol)三甲基甲硅烷基乙氧基甲基氯化物。室温搅拌4小时,然后将反应液倾入冰冷的氯化铵溶液中,用乙酸乙酯萃取,合并有机相,先后用冰冷的1N硫酸氢钾溶液和饱和氯化钠溶液洗涤。有机相经硫酸钠干燥后,减压浓缩,得到16.8g醚8b,不必纯化,将其溶解于600ml二噁烷中,室温下加入160ml(0.8mol)5N氢氧化钠。24小时后减压蒸出甲醇,8C的钠盐水悬浮液用2N盐酸酸化至pH4。酸8C几乎定量地析出,吸滤,水洗涤,得到16.02g8C。熔点93-96℃。自8C和d制备8E(相当于反应通式1中的步骤e)a)7.95g(27mmol)8C溶解于35ml无水二甲基甲酰胺中,室温下滴加4.54g(27mmol)羰基二咪唑(Carbonyldiimidazol)溶于35ml无水二甲基甲酰胺的溶液。然后将此溶液于60-70℃温热1小时,可观察到有CO2逸出。6)室温和氩气氛下,向8.92g(0.021mol)钠盐d于50ml无水二甲基甲酰胺的溶液中加入0.75g(0.025mol)氢化钠(80%),室温下搅拌此悬浮液1小时,然后将α)步中制得的酰咪唑8D溶液于0°~5℃下加入。于0-5℃搅拌此溶液2.5小时,向反应物中加入饱和氯化铵溶液。加入1N硫酸氢钠溶液,混合物酸化至pH4后,用乙酸乙酯萃取。合并有机相,先后用饱和氯化铵溶液、水和饱和氯化钠溶液洗涤。硫酸钠干燥有机相,减压浓缩后,油状剩余物作硅胶层析(洗脱剂:乙酸乙酯/正庚烷/乙酸20∶60∶1).得到10.3g(78%)8E.为无色油状物。1H-NMR(270MHz,CDCl3):d=0.02ppm(s,9H),0.05(s,9H),0.91-1.03(m,4H),1.5-1.78(m,10H),1.91-2.05(m,1H),2.28-2.42(m,2H),2.57-2.63(m,1H),3.68-3.90(m,4H),4.14-4.20(m,1H),4.42-4.52(m,1H),4.91-4.96(m,1H),5.11-5.18(m,1H),5.24(s,2H),5.21-5.34(m,1H),6.32(d,J=10Hz,1H),7.02-7.08(m,2H),7.42-7.5(m,2H),7.65(d,J=10Hz,1H),13(s,br,COOH,1H).自8E制备8(相当于反应通式1中的步骤f)
5.02g(7.4mmol)8E溶解于130ml二噁烷中,室温搅拌下加入95ml(0.19mol)2N盐酸,室温下搅拌20小时。反应结束后,加入2N氢氧化钠冷溶液,使pH为3-4减压浓缩。固体剩余物于3∶1乙酸乙酯/甲醇中搅拌,滤除不溶解的氯化钠。滤液再浓缩,剩余物经硅胶层析(洗脱剂∶乙酸乙酯/甲醇/水/乙酸100/100/10/5),得到1.95g(70%)化合物8,熔点:235-238℃。
表4中所列的实例(化合物)是按上述方法制备的。区别在于,在合成通式1中基团R3含有羟基的化合物时,通过相应的保护操作对其余基团保护,这些其余基团不是必需的。
4.0g(17.5mmol)已知化合物20A(S.A.Bowles等:Tetra-hedron 46,3981(1990)溶解于30ml无水二甲基甲酰胺中,加入1.61g(23.7mmol)咪唑和2.64g(12.5mmol)叔丁基二甲基甲硅烷基氯化物。25℃12小时后,向反应液中加入200ml饱和氯化铵溶液,用300ml甲基叔丁基醚分数次萃取,合并有机层,用水和饱和盐水溶液洗涤,硫酸镁干燥,得到5.4g(90%)20B,为无色油状物。1H-NMR(270MHz,CDCl3):δ=0.06ppm(s,3H),0.09(s,3H),0.76(s,9H),1.39(s,6H),2.23-2.40(m,1H),2.48-2.62(m,1H9,3.76(s,3H),4.0-4.12(m,2H),4.66-4.72(m,1H),6.80-6.86(m,1H).由20B制备20C或20D
5.4g(15.8mmol)20B溶解于100ml叔丁醇中,加入1.9g(25.3mmol)三乙胺-N-氧化物和20ml水。然后加入100mg(0.4m-mol)四氧化饿与2.0g聚乙烯吡啶的复合物,沸腾温度下搅拌4小时。然后滤除催化剂,浓缩滤液,剩余物经硅胶层析(洗脱剂∶乙酸乙酯/正庚烷1∶1),得到2.5g(42%)20C/20D的混合物,比例为3∶1,为无色油状物。
两个异构体20C/20D的混合物NMR为:1H-NMR(270MHz,CDCl3):δ=0.08-0.14(m,6H),0.88-0.92(m,9H),1.38-1.40(m,3H),1.51-1.55(m,3H),1.80-2.0(m,1H),2.28-2.48(m,1H),3.61-4.52(m,7H).自20C或20D制备20E和20F
2.5g(6.6mmol)的20C/20D的混合物(3∶1)溶解于60ml无水二氯甲烷中,加入5ml 2,2-二甲氧基丙烷和200mg吡啶-对甲苯磺酸盐,反应液于沸腾温度下加热6小时,然后减压浓缩。剩余物是20E和20F的混合物,经硅胶分离(洗脱剂∶乙酸乙酯/正庚烷3∶1)得到20E和20F的混合物,总计2.4g(87%),为无色油状物。1H-NMR(270MHz,CDCl3):δ=0.08ppm(s,3H),0.09(s,3H),0.90(s,9H),1.34(s,3H),1.39(s,3H),1.45(s,3H),1.50(s,3H),1.72(dd,J=13.5,J=12Hz,1H),2.19(dd,J=4.0,J=14.5Hz,1H),3.81(s,3H),3.81-3.92(m,1H),4.05-4.11(m,1H),4.42-4.48(m,1H),4.68-4.70(m,1H).自20E制备20G
1.4g(3.4mmol)20E溶解于30ml二噁烷,滴加入2ml 6N氢氧化钠溶液,2小时后浓缩反应液,加入200ml乙酸乙酯和200ml饱和氯化铵溶液。该混合物用1N硫酸氢钾溶液酸化至pH为5,有机层用饱和氯化钠溶液洗涤,硫酸钠干燥。浓缩后将油状剩物溶解于15ml无水THF,加入3.0g(9.5mmol)氟化四丁基铵(三水合物),并加入0.5ml三乙胺,然后于60℃温热该溶液12小时。浓缩溶液,剩余物经硅胶纯化(洗脱液∶乙酸乙酯/正庚烷/乙酸30∶10∶1)。分离出600mg(54%)20G,为无色油状物。自20F制备20H
用由20E制备20G相类似的方法,由20F制备20H。自20H制备20或由20G制备20a:
按照类似于合成步骤d-f(如化合物8所述),合成20或20a。
20:熔点:275℃(分解)
按照合成步骤d-f(如化合物8所述)的类似方法,将已知化合物22A(S.Mills等Tetrahedron Let.29,281(1988)转变成22。熔点:204-206℃。制备23反应式4由23A制备23B
20.0g(88.4mmol)文献已知的化合物23A(J.C.Barriere等,Helv.Chim.Acta 66,296(1983)溶解于无水二氯甲烷中,25℃下加入14.9g(176.8mmol)二氢吡喃和200mg对甲苯磺酸吡啶盐。该溶液于室温下搅拌12小时。然后加入500ml乙酸乙酯,有机相用碳酸氢钠溶液和饱和氯化铵溶液洗涤。有机相经硫酸镁干燥后,减压浓缩,得到26.0g(95%)20B,为无色固体。熔点:55-58℃。自23B制备23C
3.66g(36mmol)二异丙胺溶解于100ml无水四氢呋喃中。在氩气氛和-20℃下滴加25ml 1.5M正丁基锂于已烷的溶液。反应液温至0℃后再冷至-60℃。于此温度下慢慢滴加4.1g(35.3mmol)乙酸叔丁酯于20ml无水四氢呋喃的溶液,于-60℃搅拌30分钟。然后于-60℃将10.0g(32,2mmol)23B于30ml无水四氢呋喃的溶液滴入,于此温度下搅拌1小时,加入饱和碳酸氢钠溶液使反应混合物水解。用乙酸乙酯萃取,合并有机相,饱和氯化钠溶液洗涤有机相后,硫酸镁干燥,浓缩后得11.9g(87%)23C,为淡褐色油状物。自23C制备23D
11.9g(27.9mmol)23C溶解于200ml甲醇中,加入1.8g对甲苯磺酸吡啶盐,加热回流1小时,然后浓缩反应液。剩余物溶解于200ml无水二氯甲烷中,加入8.6g(93.5mmol)二甲氧基丙烷。室温放置72小时后,减压浓缩,剩余物用硅胶层析(洗脱剂∶乙酸乙酯/正庚烷1∶1)纯化,得6.6g(82%)23D。1H-NMR(270MHz,CDCl3)d=1.35ppm(s,3H),1.47(s,9H),1.53(s,3H),1.9-2.12(m,1H),2.22-2.32(m,1H),2.43(s,1H),3.87-3.94(m,1H),4.12-4.25(m,1H),4.35-4.45(m,1H).
由23D制备23
用类似于步骤d-f(如化合物8所述)得到23,它为无色固体,
熔点:85-92℃。
15.0g(39mmol)24A(J.R.Falck,J.Org.Chem.,54,5851(1989)溶解于200ml无水甲苯中。于-70℃将38ml(43mmol)1.2M氢化二异丁基铝于己烷的溶液滴加到上面的溶液中。反应液2小时内温热至0℃,加入10ml饱和碳酸氢钠溶液使反应物水解,然后先后加入10ml 1N氢氧化钠和10ml水。反应混合物于强力搅拌下加入50g硫酸镁和50g硫酸钠,室温下搅拌30分钟,滤除作固体沉淀,浓缩滤液,得到12.9g(85%)24B,为无色油状物,0℃时结晶。熔点:20-25℃。自24B制备24C
在氩气氛和0℃下,将7.5g(33,5mmol)膦基乙酸三乙酯滴加到0.9g(29.9mmol)80%氢化钠于200ml无水四氢呋喃的悬浮液中。反应液慢慢温热至室温,将澄清的淡褐色溶液冷却至-30℃。将7.7g(19.9mmol)24B于20ml无水四氢呋喃的溶液滴入,此溶液于-20-+30℃搅拌24小时,然后加入100ml饱和氯化铵溶液。用乙酸乙酯萃取,饱和氯化钠溶液洗涤,并用硫酸镁干燥合并的有机相。减压浓缩,剩余物经硅胶层析(洗脱剂:乙酸乙酯/正庚烷,1∶1)纯化,得到7.5g(82%)24C,为无色油状物。1H-NMR(200MHz,CDCl3):δ=0.01ppm(s,9H),0.85-1.0(m,2H),1.1-1.85(m,15H),2.1-2.25(m,2H),2.35-2.5(m,1H),3.42-3.9(m,3H),4.1-4.4(m,4H),4.65-4.8(m,2H),5.92(d,J=15Hz,1H).MS(FAB):463.3(M+Li+).自24C制备24D:
1.0g(2.2mmol)24C溶解于50ml乙酸乙酯中,加入100mgRH/Al2O3(5%Rh),于常压25℃下在氢气氛中振摇3小时。滤除催化剂,滤液减压浓缩,得到0.95g(94)24D,为无色固体。自24D制备24:
按照合成步骤d-f(如化合物8所述)的类似方法,自文献已知的起始物25A(J.L.Pawlak等:J.Org.Chem.52,1765(1987))得到化合物25,熔点:75-80℃(泡沫状物)。自26A制备26
按照合成步骤d-f(如化合物8所述)的类似方法,自文献已知的起始物26A得到化合物26,为无色无定形固体。1H-NMR(270MHz,d6-DMSO):d=1.95-2.14ppm(m,1H),2.55-2.70(m,1H),3.62-3.76(m,1H9,4.08-4.26(m,2H),4.55-4.75(m,1H),4.9-5.1(m,1H),6.48(d,J=10.0Hz,1H),6.63-6.72(m,1H),6.75-6.88(m,2H),7.29-7.46(m,3H),7.89(d,J=5Hz,1H),9.70-10.0(1H),12.2-12.6(1H).MS(Cl):225.2(M+H+).制备27和28:自20B制备27A:
6.0g(17.5mmol)20B溶解于100ml无水甲苯中,-20℃下滴加29.2ml 1.2M氢化二异丁基铝于已烷中的溶液。使反应液1小时内温热至25℃后,再冷却到0℃,小心滴加甲醇/水9∶1的混合物,然后滴加30ml饱和氯化铵溶液,并于25℃搅拌反应混合物30分钟。此后乙酸乙酯萃取,合并有机相,用饱和氯化钠溶液洗涤,硫酸镁干燥,减压浓缩。剩余物经硅胶层析纯化(乙酸乙酯/正庚烷1∶3),得到3.5g(63%)27B,为无色油状物。1H-NMR(270MHz,CDCl3):d=0.08ppm(s,3H),0.11(s,3H),0.89(s,9H),1.39(s,3H),1.46(s,3H),1.97-2.09(m,1H),2.19-2.30(m,1H),3.88-3.92(m 1H),3.98-4.09(m,4H),4.62-4.68(m,1H),5.76-5.82(m,1H).自27A制备27B
于0℃下将1.43ml(19.6mmol)二甲硫醚滴加到2.9g(16.2mmol)N-溴代琥珀酰亚胺于100ml无水二氯甲烷的溶液中。5分钟后冷却到-20℃,滴入3.4g(10.8mmol)27A于20ml无水二氯甲烷中的溶液。然后将淡黄色悬浮液慢慢温热到25℃,搅拌3小时,加入100ml饱和氯化铵溶液,用500ml乙酸乙酯萃取。合并有机相,饱和氯化钠溶液洗涤,硫酸镁干燥。浓缩后剩余物用硅胶层析(洗脱剂∶乙酸乙酯/庚烷1∶3)纯化,得到3.7g(98%)27B,为无色油状物。1H-NMR(270MHz,CDCl3)δ=0.09ppm(s,3H),0.10(s,3H),0.89(s,9H),1.38(s,3H),1.41(s,3H),2.09-2.21(m,1H),2.35-2.45(m,1H),3.92(s,2H),3.97-4.05(m,2H),4.38-4.65(m,1H),5.83-5.89(m,1H).MS(Cl):377.1(M+H+).自27B制备27C:
3.0g(7.6mmol)27B于42ml亚磷酸三乙酯中90℃下加热6小时,然后减压下蒸除过剩的亚磷酸酯,硅胶层析(洗脱剂∶乙酸乙酯/甲醇5∶1)纯化,得到3.0g(93%)27C,为无色油状物。自27C制备27D:
3.0g(7.4mmol)27C溶解于50ml甲醇中,加入1ml 1N盐酸,24小时后用1N氢氧化钠中和反应液,减压浓缩至干。剩余物用50ml无水二氯甲烷溶解,加入5ml甲氧基丙烷和0.5g对甲苯磺酸吡啶盐,40℃加热4小时,然后加入饱和碳酸氢钠溶液,用500ml乙酸乙酯萃取,合并有机相,用饱和氯化钠溶液洗涤,硫酸镁干燥,减压浓缩。剩余物经硅胶层板(洗脱剂∶乙酸乙酯/甲醇10∶1)纯化,得到1.5g(70%)27D,为无色油状物。自27D制备27
按照合成步骤e-f(如化合物8所述)的类似方法,自27D得到化合物27。1H-NMR(200MHz,d6-DMSO):δ=2.05-2.22ppm(m,1H),2.55-2.8(m,1H),3.4-3.55(m,1H),3.6(s,3H),3.65(s,3H),4.05-4.15(m,1H),4.3-4.4(m,1H),4.6-4.8(m,3H),5.0-5.15(m,1H),5.55-5.68(m,1H),6.3-6.45(m,1H),6.37-6.45(m,2H),7.5-7.7(m,3H),10.0(s,1H).MS(Cl):399(M+),381(M+-H2O).自27制备28
135mg(0.34mmol)27溶解于10ml无水乙腈中,0℃下滴入155mg(1mmol)三甲基甲硅烷溴化物,搅拌30分钟后,加入5ml水。加1N氢氧化钠使pH达到大约5,减压浓缩。剩余物经RP-8硅胶层析(洗脱剂:水/甲醇4∶1)纯化,得到23mg(18%)28为无色固体,熔点:180~185℃。
药物制剂是按一般常规的方法制备的。实施例1:片剂
适于口服并有如下组成成分的片剂按已知的方法制成。先将有效物质和助剂制成颗粒,之后压制成片。成分(每片) 重量(mg)式Ⅰ化合物(如化合物17) 50乳糖 100玉米淀粉 30滑石粉 3胶体二氧化硅 3硬脂酸镁 2
实施例2:胶囊剂
适于口服的含有如下组成成分的胶囊剂是按已知方法制成的。将有效物质和助剂混合后,填充到明胶胶囊中。组成成分(每粒胶囊) 重量(mg)式Ⅰ化合物(例如化合物21) 50乳糖 100玉米淀粉 30滑石粉 3胶体二氧化硅 3硬脂酸镁 2
Claims (3)
1.用于抑制哺乳动物肝脏中的葡萄糖-6-磷酸酯酶系统的式Ⅰ环己烷衍生物:R1:COOH、COO-(C1-C4烷基)、PO(OH)2、PO(OH)(O-C1-C4-烷基)或PO(O-C1-C4-烷基)2,
R2:H、OH,
R3:H、苯基、萘基、吡啶基、噻吩基、呋喃基,其中的芳环或杂芳环上可被相同或不同的如下基团取代一次或多次;F、Cl、-Br、I、OH、NO2、C1-C4-链烷酰基、C1-C4-烷氧基、C1-C4烷基、苯基、苯氧基或苄氧基,
R4、R5、R6:H、OH,其中,R4、R5、R6:可以相同或不同,
X:-(CH)2)n-、-CH=CH-或-CH2-O-CH2
Y:-(CH2)n-、O、S或NH,
Z:-(CH2)n-或-CH=CH,
n:0、1、2、3或4。
2.按照权利要求1的用于抑制哺乳动物的葡萄糖6-磷酸酯酶系统的式Ⅰ化合物,其中的基团有如下意义:
R1:COOH或COO(C1-C4-烷基),
R2:H或OH,
R3:H、苯基、萘基、吡啶基、噻吩基、呋喃基、其中的芳环或杂芳环上可被相同或不相同的如下取代基取代1、2或3次:F、Cl、OH、NO2、C1-C4-链烷酰基、C1-C4-烷氧基、C1-C4-烷基、苯基、苯氧基或苄氧基,
R4、R5和R6:H或OH,R4、R5、R6可以相同或不相同,
X:-(CH2)n-,其中n=0、1或2,
Y:O或NH,
Z:-(CH2)n-,其中n=0或2;或者-CH=CH-。
3.治疗Ⅱ型糖尿病的药物,其特征是,它含有权利要求1的式Ⅰ化合物和药学上可接受的赋形剂。
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EP3413887B1 (en) | 2016-02-12 | 2021-04-07 | Eisai R&D Management Co., Ltd. | Intermediates in the synthesis of eribulin and related methods of synthesis |
CN109641917B (zh) | 2016-06-30 | 2022-06-14 | 卫材R&D管理有限公司 | 可用于合成软海绵素大环内酯类及其类似物的普林斯反应和中间体 |
IL275729B2 (en) | 2018-01-03 | 2023-09-01 | Eisai R&D Man Co Ltd | Prins reaction and compounds useful in the synthesis of helicondrin macrolides and their analogs |
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EP0163270A2 (en) * | 1984-05-23 | 1985-12-04 | Green Cross Corporation | A lipoxygenase inhibitor |
WO1987004619A1 (en) * | 1986-02-06 | 1987-08-13 | Code Kaffee-Handelsgesellschaft Mbh | Use of tannin agents and/or chlorogenic acid, foodstuffs, stimulants and/or medicines with the addition of tannin agents and/or chlorogenic acid |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
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JPS60192555A (ja) * | 1984-03-13 | 1985-10-01 | Osaka Chem Lab | 抗アレルギ−食品 |
JPS60243016A (ja) * | 1984-05-17 | 1985-12-03 | Tsumura Juntendo Inc | 抗インフルエンザウイルス剤 |
-
1993
- 1993-09-03 TW TW082107191A patent/TW255880B/zh active
- 1993-09-06 ES ES93114260T patent/ES2135429T3/es not_active Expired - Lifetime
- 1993-09-06 AT AT93114260T patent/ATE181237T1/de not_active IP Right Cessation
- 1993-09-06 DE DE59309649T patent/DE59309649D1/de not_active Expired - Fee Related
- 1993-09-06 DK DK93114260T patent/DK0587087T3/da active
- 1993-09-06 EP EP93114260A patent/EP0587087B1/de not_active Expired - Lifetime
- 1993-09-07 IL IL10693593A patent/IL106935A/xx not_active IP Right Cessation
- 1993-09-07 FI FI933902A patent/FI933902A/fi unknown
- 1993-09-07 US US08/116,564 patent/US5451573A/en not_active Expired - Fee Related
- 1993-09-07 PH PH46828A patent/PH30278A/en unknown
- 1993-09-07 HU HU9302527A patent/HUT64843A/hu unknown
- 1993-09-08 PL PL93300328A patent/PL300328A1/xx unknown
- 1993-09-08 RU RU93045145A patent/RU2131248C1/ru active
- 1993-09-08 ZA ZA936610A patent/ZA936610B/xx unknown
- 1993-09-08 AU AU46170/93A patent/AU662836B2/en not_active Ceased
- 1993-09-08 JP JP5223056A patent/JPH06211737A/ja not_active Abandoned
- 1993-09-08 CN CN93116663A patent/CN1042329C/zh not_active Expired - Fee Related
- 1993-09-08 CZ CZ931867A patent/CZ284995B6/cs not_active IP Right Cessation
- 1993-09-08 CA CA002105707A patent/CA2105707A1/en not_active Abandoned
- 1993-09-08 NO NO933201A patent/NO179671C/no not_active IP Right Cessation
- 1993-09-09 KR KR1019930018066A patent/KR100299205B1/ko not_active IP Right Cessation
-
1998
- 1998-12-11 HK HK98113223A patent/HK1011934A1/xx unknown
-
1999
- 1999-08-11 GR GR990402034T patent/GR3030953T3/el unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0163270A2 (en) * | 1984-05-23 | 1985-12-04 | Green Cross Corporation | A lipoxygenase inhibitor |
WO1987004619A1 (en) * | 1986-02-06 | 1987-08-13 | Code Kaffee-Handelsgesellschaft Mbh | Use of tannin agents and/or chlorogenic acid, foodstuffs, stimulants and/or medicines with the addition of tannin agents and/or chlorogenic acid |
Also Published As
Publication number | Publication date |
---|---|
AU4617093A (en) | 1994-03-17 |
NO179671C (no) | 1996-11-27 |
HUT64843A (en) | 1994-03-28 |
CZ186793A3 (en) | 1994-03-16 |
HK1011934A1 (en) | 1999-07-23 |
ES2135429T3 (es) | 1999-11-01 |
IL106935A (en) | 1997-07-13 |
AU662836B2 (en) | 1995-09-14 |
KR940006580A (ko) | 1994-04-25 |
TW255880B (zh) | 1995-09-01 |
ATE181237T1 (de) | 1999-07-15 |
CA2105707A1 (en) | 1994-03-10 |
EP0587087B1 (de) | 1999-06-16 |
FI933902A (fi) | 1994-03-10 |
GR3030953T3 (en) | 1999-11-30 |
HU9302527D0 (en) | 1993-11-29 |
NO179671B (no) | 1996-08-19 |
US5451573A (en) | 1995-09-19 |
KR100299205B1 (ko) | 2001-11-22 |
PL300328A1 (en) | 1994-03-21 |
NO933201D0 (no) | 1993-09-08 |
IL106935A0 (en) | 1993-12-28 |
CZ284995B6 (cs) | 1999-04-14 |
RU2131248C1 (ru) | 1999-06-10 |
DE59309649D1 (de) | 1999-07-22 |
NO933201L (no) | 1994-03-10 |
FI933902A0 (fi) | 1993-09-07 |
CN1086806A (zh) | 1994-05-18 |
EP0587087A1 (de) | 1994-03-16 |
DK0587087T3 (da) | 1999-12-06 |
ZA936610B (en) | 1994-03-28 |
PH30278A (en) | 1997-02-20 |
JPH06211737A (ja) | 1994-08-02 |
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