CN103936737B - 黄嘌呤衍生物 - Google Patents
黄嘌呤衍生物 Download PDFInfo
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- CN103936737B CN103936737B CN201310024815.9A CN201310024815A CN103936737B CN 103936737 B CN103936737 B CN 103936737B CN 201310024815 A CN201310024815 A CN 201310024815A CN 103936737 B CN103936737 B CN 103936737B
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- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
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Abstract
本发明公开了一类黄嘌呤衍生物及异构体,通过正常小鼠糖耐量的影响试验和体外DPP‑IV活性抑制试验,本发明化合物显示出优异的DPP‑IV抑制活性,能够用于制备治疗与二肽基肽酶Ⅳ相关的疾病药物中的用途。
Description
技术领域
本发明涉及药物化学领域,具体涉及一类黄嘌呤衍生物、其制备方法及其衍生物作为一周给药一次的治疗药物特别是作为二肽基肽酶IV(DPP-IV)抑制剂的用途。
背景技术
糖尿病是一种多病因的代谢疾病,其特点是慢性高血糖,伴随因胰岛素分泌及/或作用缺陷引起的糖、脂肪和蛋白质代谢紊乱。糖尿病也是一种非常古老的疾病,是由于人体内胰岛素相对或绝对缺乏而引起的血中葡萄糖浓度升高,导致糖大量从尿中排出,并伴随多饮、多尿、多食、消瘦、头晕、乏力等症状。
在糖尿病治疗中,运动疗法和饮食疗法是两种必不可少的糖尿病治疗方法。当这两种疗法不足以控制病情时,可以使用胰岛素或者口服降糖药。但由于这些降糖药物存在很多副作用,开发出一种新型的、低副作用且能够有效治疗糖尿病的药物尤为重要。
二肽基肽酶IV(DPP-IV)是一种丝氨酸蛋白酶,它可以在次末端含有一个脯氨酸残基的肽链里裂解N-末端二肽酶,尽管(DPP-IV)对哺乳动物的生理作用还没有得到完全的证实,但其在神经酶代谢,T-细胞激活,癌细胞转移入内皮以及HIV病毒进入淋巴样细胞过程中都起到非常重要的作用(WO98/19998)。
有研究表明(DPP-IV)可以阻止胰升糖素样肽(GLP)-1的分泌,裂解(GLP)-1中N-末端的组-丙二肽酶,使其从活性形式的(GLP)-1降解为无活性的(GLP)-1(7-36)酰胺降解为无活性的(GLP)-1(9-36)酰胺Endocrinology,1999,140:5356-5363)。在生理情况下,循环血中完整(GLP)-1的半衰期很短,DPP-IV降解为(GLP)-1后的无活性代谢物能与(GLP)-1受体结合拮抗活性(GLP)-1从而缩短了对(GLP)-1的生理反应,而(DPP-IV)抑制剂能完全保护内源性甚至外源性的(GLP)-1不被(DPP-IV)灭活,极大的提高(GLP)-1的生理活性(5-10倍),由于(GLP)-1对胰腺胰岛素的分泌是一个重要的刺激器并能直接影响葡萄糖的分配,因此DPP-IV抑制剂对非胰岛素依赖型糖尿病例的治疗起到很好的作用(US6110949)。
虽然目前已经上市了几种DPP-IV抑制剂,如磷酸西格列汀、维格列汀、苯甲酸阿格列汀等,但均为一天给药一次,为了增加病人的顺应性,需要一周给药一次的DPP-IV抑制剂,因此临床上依然存在对新的长效DPP-IV抑制剂的需求。
发明内容
本发明涉及黄嘌呤取代衍生物及其制备方法和在医药上的应用,特别是通式(I)所示的 黄嘌呤取代衍生物或其所有的立体异构体,及其作为一周给药一次的治疗剂特别是对于二肽基肽酶Ⅳ(DPP-Ⅳ)的活性抑制作用。
本发明具体涉及下面通式(I)结构所示的化合物:
其中:R1独立选自氢原子、氟原子、氯原子、溴原子、碘原子、氨基或氰基;
R2独立选自氢原子、-SO2R4、-PO(OR4)2、-COCHR5R6、-COOR7或-CONHR7;
R4为氢原子、金属离子或C1-C5直链或支链烷基,且该烷基上任意氢原子可以
被羟基、巯基、氨基取代;其中金属离子为碱金属离子或碱土金属离子;
R5为氢原子或C1-C5直链或支链烷基,且该烷基上任意氢原子可以被羟基、巯基、氨基取代;
R6为羟基、巯基、氨基或C1-C5直链或支链烷基,且该烷基上任意氢原子可以被羟基、巯基、氨基取代;
R7为C1-C5直链或支链烷基,其中,C1-C5直链或支链烷基上任意氢原子可以被羟基、巯基、氨基取代;
R3独立选自氢原子、甲基、乙基或乙酰基;
A独立选自N或CH。
进一步,本发明通式(I)化合物,其中:
R1独立选自氢原子、氟原子或氯原子;
R2独立选自氢原子、-SO2R4、-PO(OR4)2或-COCHR5R6;
R4为氢原子、C1-C3直链或支链烷基;
R5为氢原子或C1-C5直链或支链烷基,其中C1-C5直链或支链烷基上任意氢原子可进一步被羟基或氨基取代;
R6为羟基、氨基或C1-C3直链或支链烷基,其中C1-C3直链或支链烷基上任意氢原子可进一步被羟基或氨基取代;
R3独立选自氢原子、甲基或乙基;
A独立选自N或CH。
更进一步,本发明通式(I)化合物,其中:
R1独立选自氟原子或氯原子;
R4为氢原子或C1-C3直链烷基;
R5为氢原子或C1-C4直链或支链烷基,其中C1-C4直链或支链烷基上任意氢原子可进一步被羟基或氨基取代;
R6为羟基或氨基;
R3独立选自氢原子或甲基;
A独立选自N或CH。
此外,本发明通式(I)结构所示的化合物还包括:
R1独立选自氢原子、氟原子、氯原子、溴原子、碘原子、氨基或氰基;
R2独立选自-COCHR5R6;R5、R6为不同取代基;以及R5为C1-C4直链或支链烷基,其中C1-C4直链或支链烷基上任意氢原子可进一步被羟基或氨基取代时,与R5、R6连接的手性碳原子可以为R、S、或R和S的混合构型;
R3独立选自氢原子、甲基、乙基或乙酰基;
A独立选自N或CH。
优选的本发明化合物,但不限于:
本发明通式所述的化合物及其立体异构体的制备方法,包括以下步骤:
在室温(10~25℃)条件下,将起始原料8-溴-3-甲基黄嘌呤与1-溴-2-丁炔反应,生成的产物a进一步与原料b经取代反应生成产物c,中间体c与(R)-3-叔丁氧羰基氨基哌啶反应生成d,中间体d在酸性条件下脱去Boc保护基后得到化合物e,将e与R2-X(其中R2为SO2R4、PO(OR4)2、COCHR5R6、COOR7或CONHR7,X为卤素或羟基)取代反应后生成化合物f,f与R3-X(其中,R3为甲基、乙基或乙酰基,X为卤素或羟基)反应生成产物g。若原料R2-X中R2为SO2R4或PO(OR4)2,生成的产物水解后就得到R4为氢原子的对应产物。若原料R2-X中R2含有保护基团,生成的产物进一步脱去保护,即可得到目标化合物。
本发明公开了通式1化合物所述的化合物及立体异构体在制备治疗与二肽基肽酶Ⅳ相关疾病中的用途,进一步是在治疗Ⅱ型糖尿病或葡萄糖耐量异常疾病药物中的用途和在制备治疗糖尿病并发症相关疾病中的用途。
具体实施方式
以下结合实施例对本发明作进一步的详细描述,但并非对本发明的限制,凡依照本发明公开内容所作的任何本领域的等同替换,均属于本发明的保护范围。
化合物的结构是通过质谱(MS)或核磁共振(1HNMR)来确定的;
核磁共振(1HNMR)位移(δ)以百万分之一(ppm)的单位给出;
核磁共振(1HNMR)的测定是用BrukerAVANCE-300核磁仪,测定溶剂为六氘代二甲基亚砜(DMSO-d6),内标为四甲基硅烷(TMS),化学位移是以10-6(ppm)作为单位给出;
质谱(MS)的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商:Therm,型号:FinniganLCQ advantage MAX);
薄层硅胶使用烟台黄海HSGF254或青岛GF254硅胶板;
IC50值的测定用envision(PerkinElmer公司);
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体;
实施例中无特殊说明,反应均在氮气氛下进行;
氮气氛是指反应瓶连接一个1L容积的氮气气球;
实施例中无特殊说明,反应中的溶液是指水溶液;
实施例中室温是指10至25摄氏度的环境温度。
实施例1
第一步化合物1a的合成
采用公知的方法,将8-溴-3-甲基黄嘌呤(20g,81.6mmol)溶于DMF(120ml)中,加入N,N-二异丙基乙胺(15.8g,122.4mmol)、1-溴-2-丁炔(10.9g,81.6mmol),室温反应过夜,薄层色谱跟踪反应进程,反应完全后,将反应液倒入水中,抽滤,固体水洗3次,干燥得产品化合物1a(20.8g,淡黄色固体),收率:85.5%。
MS m/z(ES):297,299[M+1]
第二步化合物1b的合成
采用公知的方法,将1a(5g,16.8mmol)溶于DMF(30ml)中,加入DBU(3.8g,25.2mmol)、化合物b(5.8g,17.6mmol),室温反应过夜。薄层色谱跟踪反应进程,反应完全后,将反应液倒入水中,抽滤,固体水洗3次,干燥得产品化合物1b(8.3g,黄色固体),收率:90.5%。
MS m/z(ES):545,547[M+1]
第三步化合物1c的合成
采用公知的方法,将1b(8.3g,15.2mmol)溶于DMF(50ml)中,加入(R)-3-叔丁氧羰基氨基哌啶(3.3g,16.7mmol)、碳酸钾(4.2g,30.4mmol),升温至75℃反应2小时。薄层色谱跟踪反应进程,反应完全后,将反应液倒入水中,抽滤,固体水洗3次,干燥得产品化合物1c(8.1g,黄色固体),收率:80.3%。
MS m/z(ES):665[M+1]
第四步化合物1的合成
采用公知的方法,将1c(8.1g,12.2mmol)溶于DCM(100ml)中,滴入TFA(15ml), 滴毕室温反应过夜。薄层色谱跟踪反应进程,反应完全后,将反应液浓缩至干,加入DCM(50ml),搅拌降温至0℃左右,滴入饱和NaHCO3溶液,调节pH≈8,分液,水相用适量DCM萃取两次,有机相合并,浓缩至干后过柱(DCM:MeOH=10:1)纯化,得产品化合物1(4.7g,黄色固体),收率:82.8%。
MS m/z(ES):465[M+1]
1H NMR(300MHz,DMSO)δ1.69-1.72(m,2H),1.80(s,3H),1.94-2.03(m,2H),2.93–3.00(m,1H),3.10–3.13(m,2H),3.40(s,3H),3.53–3.73(m,2H),4.92(s,2H),5.43(s,2H),7.01-7.09(m,1H),7.30(dd,J=2.6,9.2Hz,1H),7.51-7.55(m,1H),8.21(s,br,1H)。
实施例2
第一步同实施例1第一步;
第二步同实施例1第二步;
第三步同实施例1第三步;
第四步同实施例1第四步;
第五步化合物2的合成
采用公知的方法,将1(500mg,1.08mmol)溶于DCM(10ml)中,加入三乙胺(217mg,2.15mmol),搅拌下滴入甲烷磺酰氯(135mg,1.18mmol),滴毕室温反应过夜。薄层色谱跟踪反应,原料消耗完全后,反应液用饱和食盐水洗涤两次,有机相浓缩,制备薄层色谱(DCM:MeOH=10:1)纯化,得产品化合物2(261mg,黄色固体),收率:44.4%。
MS m/z(ES):543[M+1]
1H NMR(300MHz,DMSO)1.46-1.52(m,1H),1.67-1.73(m,1H),1.80(s,3H),1.90-1.98(m,2H),2.89(s,3H),3.05-3.10(m,3H),3.41(s,3H),3.56-3.61(m,1H),3.73-3.77(m,1H),4.90(s,2H),5.42(s,2H),7.02-7.10(m,1H),7.28-7.36(m,2H),7.51-7.55(m,1H),8.10(s,br,H,)。
实施例3
第一步同实施例1第一步;
第二步同实施例1第二步;
第三步同实施例1第三步;
第四步同实施例1第四步;
第五步化合物3d的合成
采用公知的方法,将1(500mg,1.08mmol)溶于DCM(10ml)中,加入DCC(268mg,1.3mmol)、HOBT(146mg,1.08mmol)、K2CO3(224mg,1.62mmol)、N-Boc-L-丙氨酸(204mg,1.08mmol),室温反应过夜。薄层色谱跟踪反应,显示原料消耗完全。抽滤,用适量DCM洗涤滤饼,滤液浓缩至干得到产品化合物3d(412mg,黄色固体),收率:60.2%。
MS m/z(ES):636[M+1]
第六步化合物3的合成
采用公知的方法,将3d(412mg,0.65mmol)溶于DCM(10ml)中,滴入TFA(1ml),滴毕室温反应过夜,薄层色谱跟踪反应,显示原料消耗完全。反应液浓缩至干,加入10mlDCM,搅拌降温至0℃左右,滴入饱和NaHCO3溶液,调节pH≈8,分液,水相用适量DCM萃取两次,合并有机相,浓缩至干,残留物用制备薄层色谱(DCM:MeOH=10:1)纯化,得到产品化合物3(294mg,黄色固体),收率:84.6%。
MS m/z(ES):536[M+1]
1H NMR(300MHz,DMSO)δ1.13(d,J=6.8Hz,3H),1.53-1.59(m,1H),1.78-1.95(m,6H),2.98-3.17(m,2H),3.22-3.30(m,1H),3.42(s,3H),3.56-3.68(m,3H),3.88(s,br,2H),4.91(s,2H),5.44(s,2H),7.07-7.13(m,1H),7.01-7.09(m,1H),7.29(dd,J=2.7,9.3Hz,1H),7.51-7.56(m,1H),7.92(d,J=7.3Hz,1H),8.52(s,br,1H)。
实施例4
第一步同实施例1第一步;
第二步化合物4b的合成
采用公知的方法,将1a(5g,16.8mmol)溶于DMF(30ml)中,加入DBU(3.8g,25.2mmol)、化合物c(5.8g,17.6mmol),室温反应过夜。薄层色谱跟踪反应进程,反应完全后,将反应液倒入水中,抽滤,固体水洗3次,干燥得产品化合物4b(8.1g,黄色固体),收率:89%。
MS m/z(ES):544,546[M+1]
第三步化合物4c的合成
采用公知的方法,将4b(8.1g,14.9mmol)溶于DMF(50ml)中,加入(R)-3-叔丁氧羰基氨基哌啶(3.3g,16.4mmol)、碳酸钾(4.1g,29.8mmol),升温至75℃反应2小时。薄层色谱跟踪反应进程,反应完全后,将反应液倒入水中,抽滤,固体水洗3次,干燥得产品化合物4c(9.1g,黄色固体),收率:91.9%。
MS m/z(ES):664[M+1]
第四步化合物4的合成
采用公知的方法,将4c(9.1g,13.7mmol)溶于DCM(100ml)中,滴入TFA(15ml),滴毕室温反应过夜。薄层色谱跟踪反应进程,反应完全后,将反应液浓缩至干,加入DCM(50ml),搅拌降温至0℃左右,滴入饱和NaHCO3溶液,调节pH≈8,分液,水相用适量DCM萃取两次,有机相合并,浓缩至干后过柱(DCM:MeOH=10:1)纯化,得产品化合
物4(5.5g,黄色固体),收率:86.9%。
MS m/z(ES):464[M+1]
1H NMR(300MHz,DMSO)δ1.68-1.72(m,2H),1.81(s,3H),1.93-2.02(m,2H),2.85–2.90(m,1H),2.95–3.16(m,2H),3.42(s,3H),3.52–3.73(m,2H),4.94(s,2H),5.44(s,2H),6.24(s,1H),6.76-6.84(m,H),7.04(m,1H),7.41-7.47(m,1H),8.53(s,b r,1H)。
实施例5
第一步同实施例1第一步;
第二步同实施例4第二步;
第三步同实施例4第三步;
第四步同实施例4第四步;
第五步化合物5d的合成
采用公知的方法,将4(500mg,1.08mmol)溶于DCM(10ml)中,加入三乙胺(218mg,2.16mmol),降温至0℃左右,滴入氯磷酸二乙酯(205mg,1.12mmol),滴毕自然升温至室温反应过夜。薄层色谱跟踪反应,原料消耗完全后,反应液用饱和食盐水洗涤两次,有机相用无水硫酸镁干燥,抽滤,滤液浓缩后用制备薄层色谱(DCM:MeOH=10:1)纯化,得产品化合物5d(334mg,黄色固体),收率:51.7%。
MS m/z(ES):600[M+1]
第六步化合物5的合成
采用公知的方法,将5d(334mg,0.56mmol)溶于DMF(5ml)中,加入碳酸钾(155mg,1.12mmol)、碘甲烷(88mg,0.62mmol),室温反应过夜。薄层色谱跟踪反应,原料消耗完全后,加入50ml饱和食盐水,用适量EA萃取两次,分液,有机相用适量饱和食盐水洗涤后干燥,过滤,滤液浓缩后用制备薄层色谱(DCM:MeOH=10:1)纯化,得产品化合物5(303.6mg,黄色固体),收率:89.3%。
MS m/z(ES):614[M+1]
1H NMR(300MHz,DMSO)δ1.22-1.26(m,6H),1.40-1.45(m,1H),1.63-1.66(m,1H),1.77(s,3H),1.88-1.94(m,2H),2.95-3.03(m,2H),3.14-3.20(m,1H),3.40(s,3H),3.58-3.63(m,1H),3.67(s,3H),3.70-3.74(m,1H),3.91-3.96(m,4H),4.90(s,2H),5.08-5.14(m,1H),5.32(s,2H),6.24(s,1H),6.76-6.84(m,H),7.04(m,1H),7.41-7.47(m,1H)。
实施例6
第一步同实施例1第一步;
第二步同实施例4第二步;
第三步同实施例4第三步;
第四步同实施例4第四步;
第五步化合物6d的合成
采用公知的方法,将4(500mg,1.08mmol)溶于DCM(10ml)中,加入DCC(268mg,1.3mmol)、HOBT(146mg,1.08mmol)、K2CO3(224mg,1.62mmol)、N-Boc-L-丙氨酸(204mg,1.08mmol),室温反应过夜。薄层色谱跟踪反应,显示原料消耗完全。抽滤,用适量DCM洗涤滤饼,滤液浓缩至干得到产品化合物6d(402mg,黄色固体),收率:58.3%。
MS m/z(ES):635[M+1]
第六步化合物6e的合成
采用公知的方法,将6d(402mg,0.63mmol)溶于DMF(5ml)中,加入碳酸钾(174mg,1.26mmol)、碘甲烷(98mg,0.69mmol),室温反应过夜。薄层色谱跟踪反应,原料消耗完 全后,加入50ml饱和食盐水,用适量EA萃取两次,分液,有机相用适量饱和食盐水洗涤后干燥,过滤,滤液浓缩后用制备薄层色谱(DCM:MeOH=10:1)纯化,得产品化合物6e(353mg,黄色固体),收率:85.7%。
MS m/z(ES):649[M+1]
第七步化合物6的合成
采用公知的方法,将6e(353mg,0.54mmol)溶于DCM(5ml)中,滴入TFA(1ml),滴毕室温反应过夜。薄层色谱跟踪反应进程,反应完全后,将反应液浓缩至干,加入DCM(5ml),搅拌降温至0℃左右,滴入饱和NaHCO3溶液,调节pH≈8,分液,水相用适量DCM萃取两次,有机相合并,浓缩至干后过柱(DCM:MeOH=10:1)纯化,得产品化合物6(235mg,黄色固体),收率:79.6%。
MS m/z(ES):549[M+1]
1H NMR(300MHz,DMSO)δ1.12(d,J=6.8Hz,3H),1.52-1.58(m,1H),1.78-1.95(m,6H),2.97-3.16(m,2H),3.22-3.29(m,1H),3.41(s,3H),3.56-3.64(m,3H),3.68(s,3H),3.86(s,br,2H),4.89(s,2H),5.45(s,2H),6.25(s,1H),6.75-6.84(m,H),7.04(m,1H),7.40-7.47(m,1H),7.92(d,J=7.9Hz,1H)。
试验例1:体外DPP-IV活性抑制试验
1、试验目的:
观察样品对二肽基肽酶IV(DPP-IV)酶的活性抑制,以评价样品的抑制效果。
2、试验材料:
2.1、二肽基肽酶IV(DPP-IV):SIGMA产品,货号D4943-1VL。
2.2、底物:Gly-Pro-7-amido-4-methylcoumarin溶液:SIGMA产品,货号G2761-25mg,FW=41.03。
2.3、DPP-IV Buffer:含25mM Hepes、140mM NaCl、1%BSA、80mM MgCl2,调pH为8.0。
2.4、阳性对照药:利拉利汀(linagliptin),由上海赢瑞化学科技有限公司提供,规格2g,CAT:YRY0687,LCT#:YR120503;DMSO溶解为10mM储液,工作液用蒸馏水稀释为10uM,终浓度为1uM。
2.5、检测仪器:envision(PerkinElmer公司)
3、试验原理:
二肽基肽酶Ⅳ(DPP-Ⅳ)在室温下可水解Gly-Pro-7-amido-4-methylcoumarinhydrobromide,生成7-amido-4-methyl coumarin(7-氨基-4-甲基香豆素),该物质在355nm激发波长下,可发射出460nm波长的荧光,通过检测产物量变化反映酶的活性。
4、试验方法:
200μL反应体系中含DPP-IV(Sigma)、25mM HEPES缓冲液(含140mM NaCl,1%BSA,80mM MgCl2)和待测样品,同时设立空白对照(不含酶和样品)和阴性对照(不含样品),室温反应10min,加入二肽基肽酶Ⅳ底物GLY-PRO-GLY-GLY,室温反应30min,测定荧光强度F,激发波长355nm,发射波长460nm。根据荧光强度F值计算抑制率,抑制率=[1-(F样品-F空白)/(F阴性-F空白)]×100。初筛时每个样品单浓度设双复孔,抑制率大于70%的样品进行假阳性排除试验,确证为阳性的测定IC50值,测定时每个样品梯度稀释六个浓度,每个浓度设双复孔。根据抑制率,应用Xlfit软件中的4Parameter Logistic Model计算IC50。
5、试验结果:本发明化合物IC50测定数据如下:
根据上述实施例化合物对DPP-IV酶抑制活性的体外试验数据可知,和阳性药比较,本发明实施例化合物具有显著的DPP-IV抑制活性。
试验例Ⅱ:对正常小鼠糖耐量的影响
试验目的:研究实施例化合物一周给药1次对小鼠糖耐量的作用,并与结构类似物利拉利汀比较。
1.1.1、试验材料
(1)药品
工具药:葡萄糖,GC≧99.5%,由sigma公司提供,批号101021941,规格100g/瓶;
阳性对照药:利拉利汀(linagliptin),由上海赢瑞化学科技有限公司提供,规格2g,CAT:YRY0687,LCT#:YR120503;
实施例1化合物,由成都苑东药业公司合成研究室提供,灰白色固体,批号:20120929;
实施例3化合物,由成都苑东药业公司合成研究室提供,淡黄色固体,批号:20120827;
实施例5化合物,由成都苑东药业公司合成研究室提供,黄色固体,批号:20121015;
实施例6化合物,由成都苑东药业公司合成研究室提供,淡黄色固体,批号:20121015;
表1实施例化合物对小鼠糖耐量的作用的给药方案
(2)试验器材:
FA2204B电子天平,由上海精密仪器科学仪器有限公司提供;
METTLER-toledo分析天平,XS-105型,由瑞士梅特勒-托利多公司生产;
血糖试纸:罗康全活力型血糖试纸,规格:50条装,批号23435532,由罗氏诊断产品(上海)有限公司提供;
手术剪、注射器等;
(3)试验动物:KM小鼠,体重18~22g,雌雄各半,由成都达硕生物科技有限公司提供,生产设施许可证:SCXK(川)2008-24。动物购回后饲养于动物房,适应性观察至少3天,检疫合格后用于试验。
1.1.2、试验方法:
(1)试验开始前禁食至少12小时;
(2)分组:对禁食后的小鼠测定其空腹血糖值,根据其结果按照表1分为6组,每组10只,雌雄各半,组间无统计学差异;
(3)给药:按照表1分组完毕后,每组灌胃给予相应受试药,空白组灌相应体积的蒸馏水;
(4)给药后168小时血糖值测定:给药后167.5小时,灌胃给予葡萄糖(8g/kg),分别测定给予葡萄糖后30min、60min的血糖值;
(5)统计学方法:采用Excel进行统计,试验数据采用(x±SD)表示,多组之间比较采用双侧T检验方法进行统计学比较。
1.1.3、试验结果
表2实施例化合物对小鼠糖耐量的作用统计结果(5mg/kg,给药168小时,(x±SD))
注:与空白组相比,*P<0.05,**P<0.01;
与阳性组相比,▲P<0.05。
1.1.4、结论
结果表明,在5mg/kg剂量下给药后168小时,实施例1化合物、实施例3化合物、实施例5化合物、实施例6化合物均表现出优于阳性的降糖作用(P<0.05),其中实施例3化合物的效果最好,说明本发明化合物具有长效的降糖作用。
根据上述结果表明本发明实施例化合物显示出长效的降糖作用,对于本领域的普通技术人员而言明显的是在不偏离本发明的精神或者范围,可对本发明化合物、组合物以及方法进行的多种修饰和变化,因此,本发明包含对本发明的修饰和变化,只要在权利要求和其等同的范围内。
Claims (7)
1.通式I所示的化合物:
其中:R1独立选自氟原子、氯原子、溴原子、碘原子;
R2独立选自氢原子、-SO2R4、-PO(OR4)2、-COCHR5R6;
R4为C1_C5直链或支链烷基,其中C1_C5直链或支链烷基上任意氢原子可进一步被羟基、巯基或氨基取代;
R5为C1_C5直链或支链烷基,其中C1_C5直链或支链烷基上任意氢原子可进一步被羟基、巯基或氨基取代;
R6为氨基或C1_C5直链或支链烷基,其中C1_C5直链或支链烷基上任意氢原子可进一步被羟基、巯基或氨基取代;
R3独立选自氢原子、甲基、乙基或乙酰基;
A独立选自N或CH。
2.根据权利要求1所述的化合物,其中:
R1独立选自氟原子或氯原子;
R2独立选自氢原子、-SO2R4、-PO(OR4)2、-COCHR5R6;
R4为氢原子、C1_C3直链或支链烷基;
R5为C1_C5直链或支链烷基,其中C1_C5直链或支链烷基上任意氢原子可进一步被羟基或氨基取代;
R6为氨基或C1-C3直链或支链烷基,其中C1_C3直链或支链烷基上任意氢原子可进一步被羟基或氨基取代;
R3独立选自氢原子、甲基或乙基;
A独立选自N或CH。
3.根据权利要求2所述的化合物,
R1独立选自氟原子或氯原子;
R2独立选自氢原子、-SO2R4、-PO(OR4)2或-COCHR5R6;
R4为氢原子或C1_C3直链烷基;
R5为C1_C4直链或支链烷基,其中C1_C4直链或支链烷基上任意氢原子可进一步被羟基或氨基取代;
R6为氨基;
R3独立选自氢原子或甲基;
A独立选自N或CH。
4.根据权利要求1所述的化合物,
R1独立选自氟原子、氯原子、溴原子、碘原子;
R2独立选自-COCHR5R6;R5、R6为不同取代基;以及R5为C1_C4直链或支链烷基,其中C1_C4直链或支链烷基上任意氢原子可进一步被羟基或氨基取代时,与R5、R6连接的手性碳原子可以为R、S、或R和S的混合构型;
R3独立选自氢原子、甲基、乙基或乙酰基;
A独立选自N或CH。
5.根据权利要求1所述的化合物,其特征在于,所述化合物选自:
6.根据权利要求1~5任一项所述的化合物在制备治疗与二肽基肽酶Ⅳ相关疾病的药物中的用途。
7.根据权利要求1~5任一项所述的化合物在制备治疗Ⅱ型糖尿病或葡萄糖耐量异常疾病药物中的用途。
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