CN1055292C - 抗炎、抗增生戊糖单糖衍生物及含该化合物的药物组合物 - Google Patents
抗炎、抗增生戊糖单糖衍生物及含该化合物的药物组合物 Download PDFInfo
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- CN1055292C CN1055292C CN96113413A CN96113413A CN1055292C CN 1055292 C CN1055292 C CN 1055292C CN 96113413 A CN96113413 A CN 96113413A CN 96113413 A CN96113413 A CN 96113413A CN 1055292 C CN1055292 C CN 1055292C
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- isopropylidene
- compound
- alkyl
- compounds
- heptyl
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Abstract
本发明化合物为具有抗增生和抗炎活性的戊糖单糖衍生物以及合成该类化合物的中间体。揭示了制备方法,含该类化合物的药物组合物及用该类化合物治疗炎症和自身免疫性疾病的方法。
Description
本发明专利申请是CN93114265.2发明专利申请的分案申请。
本发明涉及具有抗增生和抗炎活性的戊糖单糖衍生物和用于合成这些化合物的中间体。本发明化合物对于治疗患有炎症性和/或自身免疫性疾病的哺乳动物是有用的。本发明还涉及含有所揭示化合物的药物组合物和应用所揭示化合物治疗炎症性和/或自身免疫性疾病的方法。
已经知道某些单糖及其衍生物在治疗炎症和自身免疫性疾病上具有治疗价值。单糖,尤其戊糖和己糖是众所周知的化合物。这些糖衍生物的合成一般可按照该领域已知的合成技术来完成。
制备单糖衍生物,通常是阻断或保护一个或多个带有缩醛阻断基团如异亚丙基或环亚己基的羟基,仅留一个或二个游离羟基以进一步反应。U.S.专利Nos.2,715,121和4,056,322揭示了各种阻断基团的方法,并且本文也参考了这些专利所揭示的内容。例如,为制备α,D-葡萄糖的衍生物其呋喃糖环结构上被阻断,1,2-和5,6-羟基可用异亚丙基阻断基阻断,3-号位开放以经历进一步反应。完成3-位上衍生化反应后,如需要可以选择除去阻断基团以进一步在其它位置上衍生反应。
U.S.专利Nos.Re,30,354,Re.30,379,Re.32,268,4,056,322,4,735,934,4,738,953,4,996,195和5,010,058揭示了各种单糖衍生物和制备他们的合成方法。上述文献中也揭示了各种单糖的治疗活性及其衍生物。本文参考了这些文献的揭示内容。
两种熟知的具有较好治疗性能的α,D-葡萄糖的衍生物是amiprilose,1,2-O-异亚丙基-3-O-3′-(N,N′-二甲基氨-正丙基)-α-D-呋喃葡萄糖,及其盐酸盐,amiprilose HCI(THERAFECTIN呫)。已知这些化合物具有抗炎活性和证明在控制类风湿性关节炎体征和症状和上有用的。比较通常地,这些化合物具有作为免疫调节剂的活性,因而具有对其他自身免疫性疾病如牛皮癣,湿疹或狼疮的治疗效果。
U.S.专利No.5,010,058揭示了1,2-O-异亚丙基-α,D-呋喃葡萄糖的脱氧衍生物。该专利揭示了制备1,2-O-异亚丙基-α,D-呋喃葡萄糖的脱氧衍生物的方法,以及这些化合物在治疗患有炎症和/或自身免疫性疾病的哺乳动物上应用。
尽管某些现有技术的单糖衍生物表现出较好的治疗活性,这些单糖经常需要高剂量才有效并产生所需结果。由于这些炎症和自身免疫性疾病的疗法经常是慢性的,因而需要发展强效的,无毒的化合物,它们可以口服以使治疗方便病人可耐受。
因而本发明的一个目的是提供比现有化合物显示更大强度的新化合物。
本发明的另一个目的是提供一种治疗罹患炎症和/或自身免疫性疾病的动物或人的方法。
本发明的其他目的和优点将在下面的说明书中阐述,部分从说明书中即明了,或可由本发明的实践可体会到。本发明的目的和优点可以通过所附权利要求书中所述的化合物,药物组合物和治疗方法而认识和达到。
为了达到上述目的,根据如在本文所包含的和较宽描述的本发明目的,本文提供了:
R1为C5-C15烷基;
R2为离去基团NHR,NH(CH2)mCH(Q)(CH2)pNR′R″,或O(CH2)mCH(Q)(CH2)PNR′R″,其中R是C3-C8烷基,C3-C8羟烷基,环己基-C1-C5-烷基,苯基-C2-C5-烷基或吡啶基-C1-C5-烷基,Q是H,CH3或C2H5,且m从1到4,P从0到4或Q是OH且m和p为从1到3,R′和R″为H或低级烷基或与携带他们的氮原子一起,构成下式饱和杂环取代基。其中X为CH2,NH或O,及n为3-6,
R3和R4一起形成一个缩醛保护基团,或其生理学上可接受的盐。
R5是C5-C15烷基,
R6是离去基团,NHR,NH(CH2)mCH(Q)(CH2)PNR′R″,或O(CH2)mCH(Q)(CH2)PNR′R″,其中R是C3-C8烷基,C3-C8羟烷基,环己基-C1-C5-烷基,苯基-C2-C5-烷基或吡啶基-C1-C5-烷基,Q是H,CH3,或C2H5,且m是1-4和P是0-4或Q是OH且m和p是1-3,R′和R″为H或低级烷基或,与携带它们的氮原子,一起形成下式饱和杂环取代基;其中X为CH2,NH或O,及n为3-6,
或R6为下式饱和杂环:其中X为CH2,NH或O,及n为3-6;和
R7和R8一起构成缩醛保护基团,或其生理学上可接受的盐。
根据本发明的抗增生和/或抗炎化合物表现了极好的治疗性能,在治疗炎症和自身免疫性疾病上有用。具体地,在体外筛选试验中,这些化合物具有证实的,本领域已认识的抑制淋巴细胞增生作用和免疫调节活性。具有这些活性的化合物对于治疗动物或人的各种皮肤和/或关节炎有用如牛皮癣,特异反应性皮炎,类风湿性关节炎,骨关节炎,硬皮病和系统性红斑狼疮。
本发明还提供了含有戊糖单糖化合物的药物组合物,和应用这些化合物治疗炎症性和/或自身免疫性疾病的方法。该药物组合物包括有效量的至少一种目的化合物或其生理上可接受的盐及药物学上可接受的载体。
进一步地,本发明化合物表现了更大的疗效,在其活性上优于其他已知单糖。
取代基R1是C5-C15烷基。根据本发明并贯穿于本发明的始终的烷基包括直链和支链烷基。较好的C5-C15烷基是庚基,癸基,十二烷基,十五烷基。
作为制备式I的抗增生和/或抗炎化合物中的中间体,R2可为离去基团例如Br或含氧离去基团(O-离去基团)例如对甲苯磺酸酯(甲苯磺酸酯),对溴苯磺酸酯(溴苯磺酸酯)对硝基苯磺酸酯(硝基苯磺酸酯),甲磺酸酯(甲磺酸酯),或三氟甲磺酸酯(triflate)。较好的离去基团是对甲苯磺酸酯。这些离去基团衍生化合物可按已有技术制备。
当R2为NHR,取代基R是C3-C8烷基,C3-C8羟烷基,环己基-C1-C5-烷基,苯基-C2-C5-烷基或吡啶基-C1-C5-烷基。较好的C3-C8烷基是丁基,己基和庚基。较好的C3-C8羟烷基是羟丙基和羟戊基。较好的环己基-C1-C5-烷基是甲基环己基,较好的苯基-C2-C5-烷基是丙基苯基。较好的吡啶基-C1-C5烷基是甲基吡啶基。
当R2是NH(CH2)mCH(Q)(CH2)PNR′R″或O(CH2)mCH(Q)(CH2)PNR′R″基时,Q是H,CH3或C2H5,m是1-4P是0-4,或Q是OH,m和P是1-3当Q是H或CH3时,m和p是1或2当Q是OH时,m和P是1或2。最好地,Q是H,m和P是1。R′和R″分别是H或低级(C1-C6)烷基,或与携带它们的氮原子一起,构成下式的饱和杂环取代基:其中X是CH2,NH或O;n为3-6,R′和R″较好地各自选自H,甲基,乙基,丙基或异丙基,其中最好的是R′和R″都为甲基。当R′和R″与携带它们的氮原子一起构成杂环取代基,较好的取代基选自吡咯烷基环,哌啶基环,和吗啉基环。
取代基R3和R4一起构成缩醛保护基团。较好的缩醛保护基团包括异亚丙基和环亚己基。
式I的戊糖单糖包括木糖衍生物和核糖衍生物。下列是较好的抗增生和/或抗炎化合物:
1,2-O-异亚丙基-3-O-庚基-5-0-3′-(N′,N′-二甲基氨丙基)-α,D-呋喃木糖,(Ia);
1,2-O-异亚丙基-3-O-庚基-5-脱氧-5-氨基庚基-α,D-呋喃木糖,(Ib);
1,2-O-异亚丙基-3-O-庚基-5-脱氧-5-N-3′-(N′,N′-二甲氨丙基)-α,D-呋喃核糖,(Ic);
1,2-O-异亚丙基-3-O-十二烷基-5-O-3′-(N′,N′-二甲氨丙基)-α,D-呋喃核糖,(Id);
1,2-O-异亚丙基-3-O-十二烷基-5-脱氧-5-吡咯烷基-α,D-呋喃核糖,(Ie);
1,2-O-异亚丙基-3-O-十二烷基-5-脱氧-5-N-3-(N′,N′-二甲氨丙基)-α,D-呋喃核糖,(If);
1,2-O-异亚丙基-3-O-癸基-5-O-3′-(N′,N′-二甲氨丙基)-α,D-呋喃核糖,(Ig);
1,2-O-异亚丙基-3-O-癸基-5-脱氧-5-N-3′-(N′,N′-二甲氨丙基)-α,D-呋喃核糖,(Ih);
1,2-O-异亚丙基-3-O-庚基-5-脱氧-5-N-氨基己基-α,D-呋喃核糖,(Ii);
1,2-O-异亚丙基-3-O-十五烷基-5-O-3′-(N′,N′-二甲氨基丙基)-α,D-呋喃核糖,(Ij);
1,2-O-异亚丙基-3-O-十五烷基-5-脱氧-5-氨丙基苯基-α,D-呋喃核糖,(Ik);
1,2-O-异亚丙基-3-O-癸基-5-O-2′-(N′,N′-二异丙氨乙基)-α,D-呋喃核糖,(Il);
1,2-O-异亚丙基-3-O-癸基-5-0-3′-(N′-哌啶基丙基)-α,D-呋喃核糖,(Im);和
1,2-O-异亚丙基-3-O-庚基-5-脱氧-5-吡咯烷基-α,D-呋喃核糖,(In)。
特别好的化合物是化合物(Ia)和(Ih)。
取代基R5是C5-C15烷基。R5具有上述式I中R1相同的实施方案。
取代基R6是离去基团,NHR,NH(CH2)mCH(Q)(CH2)PNR′R″,O(CH2)mCH(Q)(CH2)PNR′R″,或下式所示饱和杂环取代基
作为式II的抗增生和/或抗炎化合物制备中的中间体,R6是离去基团例如Br或含氧离去基团(O-离去基团)例如对甲苯磺酸酯(甲苯磺酸酯),对溴苯磺酸酯(溴苯磺酸酯)对硝基苯磺酸酯(硝基苯磺酸酯),甲磺酸酯(甲磺酸酯),或三氟甲磺酸酯(triflate)。较好的离去基团是对甲苯磺酸酯。这些离去基团衍生化合物可按已有技术制备。
当R6为NHR,取代基R是C3-C8烷基,C3-C8羟烷基,环己基-C1-C5-烷基,苯基-C2-C5烷基或吡啶基-C1-C5-烷基。较好的C3-C8烷基是丁基,己基和庚基。较好的C3-C8羟烷基是羟丙基和羟戊基。较好的环己基-C1-C5-烷基是甲基环己基,较好的苯基-C2-C5-烷基是丙基苯基。较好的吡啶基-C1-C5烷基是甲基吡啶基。
当R6是NH(CH2)mCH(Q)(CH2)PNR′R″或m是O(CH=2)mCH(Q)(CH2)PNR′R″基时,Q是H,CH3或C2H5,m是1-4,P是0-4,或Q是OH,m和P是1-3,较好地,当Q是H或CH3时,m和p是1或2,当Q是OH时,m和P是1或2。最好地,Q是H,m和P是1。R′和R″分别是H或低级(C1-C6)烷基或与携带它们的氮原子一起,构成下式的饱和杂环取代基:其中X是CH2,NH或O;n为3-6,R′和R″较好地各自选自H,甲基,乙基,丙基或异丙基,其中最好的是R′和R″都为甲基。当R′和R″,当与携带的氮原子一起构成杂环取代基时,较好的取代基选自吡咯烷基环,哌啶基环,和吗啉基环。如上所示,取代基R6也可以是下式所示的饱和杂环其中X是CH2,NH或O;n为3-6。较好的杂环选自吡咯烷基环,哌啶基环,和吗啉基环。
取代基R7和R8一起构成缩醛保护基团。较好的缩醛保护基团包括异亚丙基和环亚己基。
式II的戊糖单糖是单糖来苏糖的衍生物且包括α和β异构体。下列化合物较好:
2,3-0-异亚丙基-5-脱氧-5-吡咯烷基-α,D-呋喃来苏糖十一甙,(IIa);和
2,3-0-异亚丙基-5-脱氧-5-氨丁基-α,D-呋喃来苏糖十-甙,(IIb)。
本发明的抗增生和/或抗炎化合物还包括式I和II化合物的生理学上可接受的盐。较好的生理学上可接受的盐为酸加成盐。普通的生理学上可接受的酸加成盐是盐酸盐,草酸盐和酒石酸盐。
本发明化合物可以按照下列一般合成步骤加以制备。具有单个游离羟基的适当保护的呋喃已糖是用碱和适当的烷基卤化物在羟基上烷基化。选择除去保护基团,得到1,2-二醇官能度,它可以氧化分裂得到烷基化呋喃戊糖衍生物,将这种呋喃戊糖衍生物用还原剂处理,得到一种新的含游离羟基的呋喃戊糖。游离羟基可以用适当的烷基卤化物和碱烷基化,得到本发明化合物。或者,游离羟基也可以衍生构成一种适当的离去基团如甲苯磺酸酯,然后用氨替代所得到的衍生物的离去基团,得到本发明的脱氧,N-取代化合物。下列实施例证实了这些步骤,以及本发明化合物特殊制备的方法。无论如何,实施例是阐述性的,而不是限制所要求保护的发明。
本发明化合物在生物试验中具有可证实的免疫调节和抗增殖效果。对本发明化合物进行了标准体外免疫试验以估测抗增殖和免疫调节活性。包括混和的淋巴的细胞反应(MLR),和由小鼠脾细胞分裂素诱导的胚细胞样转变试验。MLR作为对T:淋巴细胞活性的抑制效果该化合物免疫调节作用的测试和抗原存在的证实。抗增生效果通过测定本发明化合物对由刀豆球蛋白A激发的鼠脾细胞。细胞增生的抑制效果来测定。因为炎症和包含在自身免疫疾病的发病机理中的机理包括细胞激活和增生以及异常免疫系统激活,这些试验适用作为炎症和/或自身免疫疾病治疗中新型化合物的筛选。
本发明化合物证实了增生和免疫调节活性。受试浓度在3到300微摩尔。强活性定为小于30微摩尔的半数最大抑制浓度,本发明化合物一致地证实了在体外有强的抗增生效果。相似的,本发明化合物还发现是强的免疫调节剂,这些结果表明本发明化合物在体外激活中是极高激活剂。
本发明戊糖单糖衍生物用以治疗动物和哺乳动物炎症和/或自身免疫性疾病如牛皮癣,特异反应性皮炎,风湿性关节炎,骨关节炎,硬皮病和系统性红斑狼疮。由于其有价值的药理学性能,本发明化合物及其生理学上可接受的盐尤其适用为治疗如风湿性炎症性疾病药物治疗组合物中的有效化合物。
抗增生和/或抗炎化合物可以单独以微胶囊的形式,互相混合的混合物形式或与药物学上可接受的载体混和服用。因此本发明还涉及药物组合物,它们包括有效量的至少一种本发明化合物,含有或不含有药物学或生理学上可接受的载体。如果合适的话,该化合物还可以生理学上可接受的盐的形式如酸加成盐的形式加以服用。
本发明还涉及罹患炎症或自身免疫性疾病的动物或人的治疗方法,包括对动物或人投与含有或不含有药物学上可接受的载体的有效量的至少一种本发明化合物,或其酸加成盐,本发明化合物可口服,表面使用,直肠给药,先期服用(anterally),体内给药,通过大药丸(boluses),或如果需要非经胃肠道地给药。最好是口服给药。
适当固体或液体盖仑派医学配方,例如颗粒剂,粉剂,包衣片剂,微胶囊,栓剂,糖浆剂,酏剂,悬浮剂,乳剂,滴剂或可注射的溶液。而且,本发明化合物可应用在活性化合物延缓释放的制剂中。在延缓释放的制剂中通常所用的添加剂是赋形剂,崩离剂,粘结剂,包衣剂,溶胀剂,助流剂,或润滑剂,调味剂,甜味剂或稳定剂,更具体地,经常所用的添加剂是例如,碳酸镁,二氧化钛,乳糖,甘露糖醇和其他糖,滑石粉,乳白蛋白,明胶,淀粉,纤维素及其衍生物,动物和植物油,聚乙二醇和溶剂。溶剂包括灭菌水和一元醇或多元醇如甘油。
药物组合物较好是制成剂量单位给药,每单位包括有效量的至少一种本发明化合物和/或至少一种其药物上可接受的盐作为活性单位组份。以哺乳动物为例,治疗自身免疫和/或炎症性疾病的有效量为每kg体重每天约1到100mg。
实施例
VarianXL-300MHz以TMS作为内标记录NMR谱。采用Nicolet MX-1仪用KBr极板记录FTIR谱用Perkin-Elnor 241旋光仪测定旋光度。用带有INCOS数字系统的FinniganMAT4510质谱仪得到CIMS,一般地,采用直接暴露探针和氨气和甲醇作为试剂气体(0.35mmHg,120°温度)。实施例11,2-0-异亚丙基-3-0-庚基-5-吡咯烷基-5-脱氧-α,D-呋喃木糖。步骤1:1,2-0-异亚丙基-3-0-庚基-α,D-呋喃木糖。
美国专利号,5,010,058专利中揭示了合成1,2-0-异亚丙基-3-0-烷基-α,D-呋喃葡萄糖(烷基=C7H15)的一般方法。步骤2:1,2-0-异亚丙基-3-0-庚基-α,D-呋喃木糖的制备。
将从步骤1制备的1,2-0-异亚丙基-3-0-庚基-α,D-呋喃葡萄糖(31.8g)在大气温度下溶解在60ml对二噁烷水溶液(50%V/V)中。在其中滴加过碘酸钠水溶液(21.4g/175ml)。1.5小时后,用薄层层析确定反应完成,减压微热除去溶剂。将所得的固体用二氯甲烷(3×150ml)研磨,合并二氯甲烷,经MgSO4干燥过滤并浓缩。得到的油状物(28.0g,97%)的不需进一步提纯而直接使用。
将上述所得的(28g)油状物,在常温下溶解于乙醇水溶液(500ml,75%V/V)中。在其中滴加硼氢钠的乙醇溶液(14.0g/200ml)。1小时后,通过薄层层析确定反应完成并减压除去溶剂。用二氯甲烷(3×200ml)萃取所得浆料。合并萃取液,经H2SO4干燥,过滤并浓缩。粗产品经硅胶层析(25%二乙醚的己烷溶液中)得到所需物1,2-0-异亚丙基-3-0-庚基-α,D-呋喃木糖,总收率92%。步骤3:1,2-0-异亚丙基-3-0-庚基-5-0-对甲苯磺酰基-α,D-呋喃木糖的制备
在从步骤2中制得的1,2-0-异亚丙基-3-0-庚基-α,D-呋喃木糖(22.0g)的吡啶(30ml)溶液中加甲苯磺酰氯(17.4g)的吡啶(20ml)溶液。将反应混和物在室温下搅拌且用薄层层析法监测反应过程。4小时后,浓缩反应混和物,并溶解于乙醚,用碳酸氢钠水溶液和水洗涤,经MgSO4干燥,过滤和浓缩。所得粗产品经硅胶层析(10%乙醚的己烷液)得到1,2-0-异亚丙基-3-0-庚基-5-0-对甲苯磺酰基-α,D-呋喃木糖(28.8g)。步骤4:1,2-0-异亚丙基-3-0-庚基-5-脱氧-5-对甲苯磺酰基-α,D-呋喃木糖。
从步骤3制得的1,2-0-异亚丙基-3-0-庚基-5-0-对甲苯磺酰基-α,D-呋喃木糖(3.3g)和吡咯烷(3.0g)的混和物于70-80℃下加热。1.5小时后,减压除去过量的吡咯烷。将残余物溶解在乙醚中,用饱和碳酸氢钠溶液,饱和溴水洗涤,经MgSO4干燥,过滤并浓缩。所得粗产物经硅胶层析(30%乙醚的己烷液)得到1,2-0-异亚丙基-3-0-庚基-5-脱氧-5-吡咯烷基-α,D-呋喃木糖(2.0g)。
其它的3-0-烷基衍生物如癸基,十二烷基,十五烷基衍生物按照上述方法制备。步骤1的原料通过用适当的烷基卤取代而U.S.专利号,5,010,058中应用的1-溴代庚烷制得。其他5-脱氧,5-N衍生物通过用合适的和二氨取代吡咯烷而制备得。实施例21,2-0-异亚丙基-3-0-庚基-5-0-二甲氨基丙基-α,D-呋喃木糖
根据U.S.专利No.5,010,058中实施例3,步骤1方法,用粉状氢氧化钠和二甲氨丙基氯处理1,2-0-异亚丙基-3-0-庚基-α,D-呋喃木糖(实施例1,步骤2),来制备该物质。经硅胶色谱层析(5%乙醚己烷液到100%乙醚)以59%产率获得标题化合物。用合适的烷基卤化物取代本文中所用的1-溴庚烷制得其它3-0-烷基衍生物如癸基,十二烷基,和十五烷基衍生物用合适的氨烷基卤化物取代二甲氨丙基氯制得其它5-0衍生物。实施例32,3-0-异亚丙基-5-脱氧-5-吡咯烷基-α,D-呋喃来苏糖十一甙步骤1:2,3:5,6-0-二异亚丙基-α,D-呋喃甘露糖十一甙的制备。
将氢化钠(2.2g)加入2,3:5,6-二-0-异亚丙基-α,D-呋喃甘露糖(20g)和十一烷基溴(21g)的无水DMF(50ml)溶液中。反应混和物在35℃下加热直到薄层层析表明原料不复存在为止。通过加入甲醇(20ml)然后加水(10ml)淬灭反应。减压浓缩反应混和物并将所得残余物溶解在乙醚中。醚溶液用水(2×50ml)和饱和氯化钠溶液(30ml)洗涤,经MgSO4干燥,过滤和浓缩。这样得到的粗产品经硅胶色谱层析提纯(10%醚的己烷液),得到标题化合物(14.0g)步骤2:2,3-0-异亚丙基-α,D-呋喃甘露糖十一甙的制备。
在5℃冰冷中冷却下,向2,3:5,6-0-二异亚丙基-α,D-呋喃甘露糖十一甙(11.5g)的THF(12ml)溶液,滴加30%HCLO4溶液(11.5ml)。将反应混和物搅拌并通过薄层层析法监测。2小时后,再加入10ml 30%HCLO4。
通过薄层层析监测在原料完全消耗时,用饱和K2CO3溶液淬灭反应,过滤并减压浓缩,将得到的残余物溶于乙醚中,经MgSO4干燥,过滤,浓缩和硅胶(1∶1-乙醚-己烷)层析得到标题化合物(4g)。步骤3:2,3-0-异亚丙基-α,D-呋喃来苏糖十一甙的制备。
在2,3-0-异亚丙基-α,D-呋喃甘露糖十一甙(5g)的1∶1=噁烷/水(10ml)溶液中加入过碘酸钠水溶液(2.9g溶液于60ml H2O)。室温下搅拌4小时,薄层层析判断反应完全,反应混和物减压浓缩并用二氯甲烷洗涤所得残余物三次。合并有机相,经MgSO4干燥,过滤并浓缩。得到的产物不需提纯而进行以下操作。
将上述所得物质(3.9g)溶解于75%乙醇水溶液(80ml)中,在其中滴加硼氢化钠(2.6g)的乙醇(70ml)溶液。反应混和物在室温下搅拌近4小时,此时薄层层析表明没有痕量原料。减压除去溶剂,用二氯甲烷萃取所得浆料。合并二氯甲烷萃取液,经MgSO4干燥,过滤并浓缩。所得粗产物经硅胶层析(30%乙醚的己烷溶液)得到标题化合物(2g)。步骤4:2,3-0-异亚丙基-5-脱氧-5-吡咯烷基-α,D-呋喃来苏糖十一甙的制备。
在2,3-0-异亚丙基-α,D-呋喃来苏糖十一甙(2g)的吡啶(5ml)溶液中加入。加入对甲苯磺酰氯(1.4g)的吡啶(5ml)溶液。得到的混和物在室温下搅拌且用薄层层析法监测反应过程。原料反应完后,浓缩反应混和物,并溶解于乙醚,用碳酸氢钠水溶液和水洗涤,经MgSO4干燥,过滤和浓缩。所得粗产品经硅胶层析(10%乙醚的己烷溶液)得到2,3-0-异亚丙基-5-对甲苯磺酰基-α,D-呋喃来苏糖十一甙。1,2-0-异亚丙基-5-对甲苯磺酰基-α,D-呋喃来苏糖十一甙(1.0g)和吡咯烷(5ml)的混和物在75℃下加热到1小时。
反应混和物减压浓缩,所得粗产物经硅胶层析(用乙醚作洗脱剂),得到灰黄色油状物2,3-0-异亚丙基-5-脱氧-5-吡咯烷基-α,D-呋喃来苏糖十一甙(0.5g)。
通过用癸基溴取代2,3-0-异亚丙基-α,D-呋喃甘露糖十一甙制备中运用的十一烷基溴来制备其它葡萄糖甙如癸基甙。类似地用合适的C5-C15烷基卤化物取代十一烷基溴和/或合适的胺或二胺取代吡咯烷可制备另外的化合物。
Claims (4)
2.如权利要求1所述的化合物,其中所述化合物为2,3-O-异亚丙基-5-脱氧-5-吡咯烷基-α,D-呋喃来苏糖十一甙。
3.药物组合物,包括如权利要求1所述的化合物和药物学上可接受的载体。
4.如权利要求3所述的药物组合物,其中所述化合物为2,3-O-异亚丙基-5-脱氧-5-吡咯烷基-α,D-呋喃来苏糖十一甙。
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-
1992
- 1992-11-13 US US07/975,700 patent/US5432163A/en not_active Expired - Fee Related
-
1993
- 1993-10-27 IL IL10742793A patent/IL107427A/en not_active IP Right Cessation
- 1993-10-28 AU AU54478/94A patent/AU5447894A/en not_active Abandoned
- 1993-10-28 DE DE69312729T patent/DE69312729T2/de not_active Expired - Fee Related
- 1993-10-28 CA CA002149205A patent/CA2149205A1/en not_active Abandoned
- 1993-10-28 JP JP6512098A patent/JPH08506321A/ja active Pending
- 1993-10-28 ZA ZA938049A patent/ZA938049B/xx unknown
- 1993-10-28 EP EP93924998A patent/EP0668866B1/en not_active Expired - Lifetime
- 1993-10-28 WO PCT/US1993/010134 patent/WO1994011381A1/en active IP Right Grant
- 1993-10-30 TW TW082109098A patent/TW329424B/zh active
- 1993-11-05 CN CN93114265A patent/CN1034217C/zh not_active Expired - Fee Related
-
1996
- 1996-09-11 CN CN96113413A patent/CN1055292C/zh not_active Expired - Fee Related
Patent Citations (3)
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EP0404136A2 (en) * | 1989-06-22 | 1990-12-27 | Greenwich Pharmaceuticals Incorporated | 3,5,6-Substituted derivatives of 1,2-0-isopropylidene-a,D-glucofuranose and intermediates for preparing these derivatives |
WO1992004359A2 (en) * | 1990-09-12 | 1992-03-19 | Greenwich Pharmaceuticals, Inc. | Monosaccharides having anti-proliferation and anti-inflammatory activity, compositions and uses thereof |
WO1993013117A2 (en) * | 1991-12-20 | 1993-07-08 | Greenwich Pharmaceuticals Incorporated | 5- or 6-aminodeoxyfuranoside derivatives with antiinflammatory and antiproliferative activity |
Also Published As
Publication number | Publication date |
---|---|
IL107427A (en) | 1999-03-12 |
JPH08506321A (ja) | 1996-07-09 |
US5432163A (en) | 1995-07-11 |
DE69312729T2 (de) | 1997-12-04 |
EP0668866A1 (en) | 1995-08-30 |
CA2149205A1 (en) | 1994-05-26 |
ZA938049B (en) | 1994-07-22 |
WO1994011381A1 (en) | 1994-05-26 |
CN1091745A (zh) | 1994-09-07 |
DE69312729D1 (de) | 1997-09-04 |
EP0668866B1 (en) | 1997-07-30 |
CN1163270A (zh) | 1997-10-29 |
CN1034217C (zh) | 1997-03-12 |
TW329424B (en) | 1998-04-11 |
IL107427A0 (en) | 1994-01-25 |
AU5447894A (en) | 1994-06-08 |
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