CN101508671B - 氮杂糖类化合物及其合成方法和用途 - Google Patents
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Abstract
本发明公开了通式(I)的氮杂糖类化合物及其制备方法和用途。本发明化合物具有很强的免疫增强作用,可用于制备免疫增强药物、以及抗感染和抗肿瘤药物。
Description
技术领域
本发明涉及氮杂糖类化合物,它们的合成方法,以及作为免疫增强剂和抗肿瘤、抗感染化合物的用途。
背景技术
干扰素(IFN-γ)是由淋巴细胞所分泌的,能够促进原发性及适应性免疫的一种细胞因子(Farrar M.A.等,Annu.Rev.Immunol.1993,11,571-611.及Boehm U.等,Annu.Rev.Immunol.1997,15,749-795.)。IFN-γ在免疫反应的调节中具有重要作用。例如,IFN-γ在促进宿主抵抗微生物感染方面发挥着至关重要的作用。如果没有IFN-γ的产生,人或实验动物对IFN-γ的反应性消失都会显著的使宿主变得易于感染(Dalton D.K.等,Science 1993,259,1739-1742.及Huang S.等,Science 1993,259,1742-1745.)。并且,最近发现IFN-γ具有抑制肿瘤发展的作用。有证据表明内源性产生的IFN-γ不仅可以排斥移植的肿瘤,并且能够抑制原发性肿瘤的发展(Dighe A.S.等,Immunity 1994,1,447-456.及Kaplan D.H.等,Proc.Natl.Acad.Sci.USA 1998,95,7556-7561.)。
氮杂糖是指糖环中的氧原子被氮原子所取代而形成的一类化合物,可看作糖的模拟物。氮杂糖已知是多种糖加工酶的抑制剂(Stutz A.E.,Iminosugarsas Glycosidase Inhibitors-Norjirimycin and Beyond,Wiley-VCH,Weinheim,1999.;Compain P.等,Iminosugars:from synthesis to therapeuticapplications,John Wiley & Sons,Ltd,2007.;Lillelund V.H.等,Chem.Rev.2002,102,515-553;及Compain P.等,Curr.Top.Med.Chem.2003,3,541-560.)。氮杂糖表现出多种生物活性,但是迄今为止对它们免疫调节活性的研究相对较少,对它们在免疫***中发挥的作用知道的并不多。叶新山小组最近发现氮杂糖具有免疫抑制的活性(Ye,X.S等.J.Med.Chem.2005,48,3688)。
发明内容
本发明目的是为了克服现有技术的不足,提供一种氮杂糖类化合物,该氮杂糖类化合物具有免疫增强的作用。
本发明通过以下技术方案来实现:
下述式(I)所示通式结构的氮杂糖类化合物或它们药用的盐或溶剂化物:
上述化合物为式(II)所示的化合物:
上述化合物为式(III)所示的化合物:
本发明化合物与酸形成的盐包括在本发明之中。
本发明化合物的酸形成盐优选为药学上可接受的,与适当的酸(例如盐酸、醋酸、硫酸)形成无毒的盐,除了药物上可接受的盐以外,其它的盐也包括在本发明之中。
本发明的另一个目的是提供以上通式(I)的化合物的制备方法:
包括由已知的化合物(2R,3S,4R,5S,6S)-2-(氨基甲基)-6-(羟甲基)哌啶-3,4,5-三醇(化合物A)或(2R,3S,4R,5S,6R)-2-(氨基甲基)-6-(羟甲基)哌啶-3,4,5-三醇(化合物B)(化合物A和B的制备参见Ye,X.S.等.J.Med.Chem.2005,48,3688;Zhang,L.等Chem.Med.Chem 2007,2,1594)出发,在碱性条件下利用缩合剂与取代的羧酸形成酰胺,其中碱是二异丙基乙基氨(简称为:DIEA)等,缩合剂是O-苯并三氮唑-N,N,N’,N’-四甲基-脲正离子-六氟磷酸酯(简称为:HBTU)等,溶剂是N,N-二甲基甲酰胺等。
以下为其合成路线:
本发明的又一个目的是提供上述化合物在制备免疫增强药物中的用途。尤其在制备抗感染或抗肿瘤药物中的用途。初步的体外细胞因子分泌实验表明,本发明化合物具有较强的促进IFN-γ分泌的活性。小鼠体内抗菌实验表明,本发明化合物能够明显增强实验小鼠对细菌感染的抵抗力,提高小鼠染菌后的存活率。
本发明的再一目的是提供含有有效量的上述化合物的药物组合物。本发明的药物组合物可以药学可接受的载体(如赋型剂、稀释剂等)以及任选的其他添加剂如甜味剂、香味剂、崩解剂等。药物组合物的制备方法为本领域常规方法。
本文所述的化合物或其药学上可接受的加成盐或水合物可以利用各种给药途径或方式供给患者。适合的给药途径包括但不限于吸入、透皮、口服、直肠、经黏膜、肠内或肠胃外给药,肠胃外给药包括肌肉、皮下或静脉内注射。
本文所用的术语“给药”包括所有直接与间接释放化合物到其预期作用部位的手段。
本文所述的化合物或其药学上可接受的衍生物可以单独给药,和/或以与其他已知免疫增强药物或抗感染或抗肿瘤药物联合的形式给药。
本发明的活性化合物可以本身形式给药,或者以药物组合物形式给药,其中活性化合物是与一种或多种药学上可接受的载体、赋形剂或稀释剂混和的。本发明使用的药物组合物通常是按照常规方式配制的,使用一种或多种生理学上可接受的载体,包含赋形剂或助剂,它们有利于将活性化合物加工成可以在药学上使用的制剂。适当的制剂取决于所选择的给药途径,可以按照本领域熟知的常识进行制备。
本发明具有的优点:(1)本发明氮杂糖类化合物具有免疫促进作用,较强的促进IFN-γ分泌,如能够明显增强小鼠的抗感染能力,为发展抗肿瘤、抗感染药物提供了一种化合物;(2)本发明制备方法简单。
附图说明
图1.伤寒感染后小鼠的生存率示意图。
具体实施方式
以下通过实施例来说明本发明,应该理解的是,这些实施例仅限于说明的目的,不构成对本发明保护范围的限制。
实施例1化合物A45的合成
(2R,3S,4R,5S,6S)-2-(苯甲胺基甲基)-6-(羟甲基)哌啶-3,4,5-三醇(化合物A45)合成步骤:
将化合物A(10.0mg,0.0518mmol),HBTU(21.6mg,0.0570mmol),苯甲酸(0.0570mmol)共置25mL圆底烧瓶中,油泵抽真空,通N2;注入减压蒸馏的N,N-二甲基甲酰胺5mL,再注入DIEA(30.0μL,0.171mmol)。室温下反应。0.5h后TLC检测反应完全,停止反应,蒸干溶剂,柱层析分离[洗脱剂(V/V)二氯甲烷∶甲醇=15∶1,8∶1,5∶1,3∶1,1∶1];产物收集后再以反相柱纯化[洗脱剂(V/V)水∶甲醇=10∶1,5∶1,2∶1,1∶1],将产物部分收集,浓缩,冷冻干燥得12.0mg白色固体。产率:80%。1H NMR(300MHz,CD3OD)7.87(d,J=7.2Hz,2H),7.56-7.45(m,3H),3.95-3.91(m,4H),3.79(dd,J=11.7,6.3Hz,1H),3.68-3.66(m,2H),3.56(t,J=7.2Hz,1H),3.25-3.18(m,1H).13C NMR(125MHz,CD3OD)171.32,134.80,133.12,129.65,128.47,71.27,69.83,65.64,60.69,58.06,55.29,40.49.HRMS:calcd for C14H20N2O5+Na 319.1270,found 319.1271。
实施例2化合物B8的合成
(2R,3S,4R,5S,6R)-2-[(S)-2-羟基苯乙酰胺基甲基]-6-(羟甲基)哌啶-3,4,5-三醇(化合物B8)合成步骤:
将化合物B(10.0mg,0.0518mmol),HBTU(21.6mg,0.0570mmol),(s)-2-羟基苯乙酸(0.0570mmol)共置25mL圆底烧瓶中,油泵抽真空,通N2;注入减压蒸馏的N,N-二甲基甲酰胺5mL,再注入DIEA(30.0μL,0.171mmol)。室温下反应。0.5h后TLC检测反应完全,停止反应,蒸干溶剂,柱层析分离[洗脱剂(V/V)二氯甲烷∶甲醇=15∶1,8∶1,5∶1,3∶1,1∶1];产物收集后再以反相柱纯化[洗脱剂(V/V)水∶甲醇=10∶1,5∶1,2∶1,1∶1],将产物部分收集,浓缩,冷冻干燥得12.6mg白色固体。产率:75%。1H NMR(500MHz,CD3OD)7.46-7.44(m,2H),7.34-7.31(m,2H),7.29-7.26(m,1H),5.01(s,1H),3.91-3.88(m,2H),3.65(d,J=6.5Hz,2H),3.58(dd,J=9.0,3.0Hz,1H),3.49(dd,J=14.0,5.5Hz,1H),3.42(dd,J=13.5,9.5Hz,1H),3.23-3.19(m,1H),2.96(td,J=6.5,2.5Hz,1H).13C NMR(125MHz,CD3OD)176.00,141.73,129.40,129.09,127.95,75.64,72.83,70.79,70.44,62.92,55.62,37.09.HRMS:calcd for C15H22lN2O6+Na 349.1370,found 349.1369.
实施例3本发明化合物注射剂的制备
将25mg的以上本发明的化合物用5ml注射用生理盐水配制成注射剂。
实施例4本发明口服片剂的制备
将50mg的以上本发明的化合物,乳糖70mg,玉米淀粉125mg和硬脂酸镁5mg按常规片剂制备工艺制成片剂。
实施例5细胞因子分泌活性试验
一、试验材料及来源
1、供试化合物:实施例1和实施例2所制备的化合物;
2、实验材料:细胞株选用鼠脾细胞。其余材料均经商业途径获得。
二、试验方法
(一)制备和培养脾细胞
常规制备BALB/c小鼠和C57B1/6小鼠脾淋巴细胞,用含10%胎牛血清的RPMI-1640培养液调整细胞浓度至4×106/ml,细胞以100μl/孔接种于96孔平板。concanavalin A每孔50μl,终浓度2.5μg/ml。设样品组:化合物A45组或化合物B8组(加样品50μl,样品浓度60μM),阴性对照组(生理盐水加培养液50μl);每孔终体积为200μl。
(二)脾细胞分泌的IFN-γ的检测。
将制备好的BALB/c小鼠和C57B1/6小鼠脾淋巴细胞于37℃,5% CO2孵箱中培养48h。取出培养板离心:4℃,1500×g,15分钟,取上清,保存于-20℃。在测IFN-γ含量前,需将冷冻凝固后的样品融化至室温。IFN-γ含量的测定使用酶联免疫吸附法。
三.试验结果
体外细胞因子分泌实验表明,在60μM的剂量上,化合物A45和B8分别能够使BALB/c小鼠脾细胞IFN-γ分泌增强3.20倍和2.85倍;分别能够使C57B1/6小鼠脾细胞IFN-γ分泌增强3.00倍和2.53倍。说明本发明化合物能明显促进IFN-γ的分泌。
实施例6动物体内抗菌试验
一、试验材料及来源
1、供试化合物:实施例1和实施例2所制备的化合物;
2、实验材料:年龄7-8周BALB/C雄性小鼠级别为ABSL-III(购于武汉大学医学院实验动物中心)。
二、试验方法
将年龄7-8周BALB/C雄性小鼠随机分为三组,每组6只。在小鼠被Salmonella typhimurium C5感染前两天,化合物A45(每只小鼠5毫克)和B8(每只小鼠5毫克),PBS缓冲液(每只小鼠5毫克)分别被注射入每组小鼠(方法见Q.Pan等,Antimicrob Agents Chemother.2005,49,4052-4060.)。两天后,将小鼠用致命剂量(1×105cfu)的S.typhimurium C5细菌感染,每天观察记载小鼠的存活率。
三.试验结果
结果(见图1)化合物B8能够提高小鼠存活率约50%。化合物A45也表现出很强的拮抗Salmonella typhimurium C5致死性的作用。说明了本发明化合物具有明显的体内抗菌活性。与以往的抗菌化合物不同的是,本发明化合物是通过促进生物体的自身保护(增强IFN-γ分泌)而不是杀死细菌来发挥其抗菌活性。
Claims (9)
6.按照权利要求4所述的用途,其特征在于所述的化合物是式(III)所示的化合物:
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