CN104557495A - 一类gabab受体负向变构调节剂及其医药用途 - Google Patents
一类gabab受体负向变构调节剂及其医药用途 Download PDFInfo
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- CN104557495A CN104557495A CN201310471661.8A CN201310471661A CN104557495A CN 104557495 A CN104557495 A CN 104557495A CN 201310471661 A CN201310471661 A CN 201310471661A CN 104557495 A CN104557495 A CN 104557495A
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- alkylidene group
- gaba
- straight chained
- chained alkyl
- compound
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Classifications
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- C07C49/245—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing hydroxy groups containing six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
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- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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Abstract
本发明涉及药物化学领域。具体地，涉及一类γ氨基丁酸B型受体(Gamma Aminobutyric Acid B Receptor，简称GABABR或GABAB受体)的配体分子及其医药用途，所述配体分子具有式I的结构。本发明所涉及的配体分子为GABAB受体的负向变构调节剂，可以非竞争性的抑制GABAB受体的激动剂引起的该受体的激活，可用于制备治疗因GABAB受体兴奋性过高所导致的相关疾病的药物，所述疾病包括癫痫、焦虑、抑郁或者因神经损伤而导致的认知能力低下等。
Description
技术领域
本发明涉及一类γ氨基丁酸B型受体(Gamma Aminobutyric Acid B Receptor,简称GABABR或GABAB受体)的配体分子。本发明所涉及的配体分子具有GABAB受体的负向变构调节能力，可以非竞争性的抑制GABAB受体的激动剂引起的该受体的激活，可用于因GABAB受体兴奋性过高所导致的相关疾病的治疗，如癫痫、焦虑、抑郁或者因神经损伤而导致的认知能力低下等。
背景技术
γ-氨基丁酸(GABA)是哺乳动物中枢神经系统中重要的抑制性神经递质，在体内通过作用于离子通道型的GABAA受体、GABAC受体及代谢型的GABAB受体而发挥生理功能(Trends in neurosciences2001,24,277-282)。GABAB受体主要存在于神经元的突触前及突触后部位，介导慢的抑制性效应，在脑内参与许多重要的生理活动和病理变化，包括认知损害、癫痫、痉挛及药物成瘾等(Pharmacology&Therapeutics2006,110,533-543)。GABAB受体属于G蛋白偶联受体(G protein-coupled receptor,GPCR)家族的C家族，具有七次跨膜结构，N端处于胞外，C端处于胞内。完整功能的GABAB受体是由GB1亚基和GB2亚基组成的异源二聚体，GB1亚基上含有正构位点，它能够与激动剂(如GABA、Baclofen)和竞争性拮抗剂(如CGP54626)结合，GB2亚基负责偶联与激活G蛋白。此外GB2亚基上还含有变构位点，正向变构调节剂与其结合后可以直接引起受体的激活。
应用GABAB受体的激动剂，可以通过降低神经系统的兴奋性而治疗痉挛、疼痛以及药物成瘾等。而GABAB受体的拮抗剂，可以抑制癫痫的发作，改善因神经损伤而导致的认知能力低下，也有其用于治疗焦虑、抑郁以及神经变性的报道。传统的靶向GABAB受体药物开发主要集中于激动剂和拮抗剂，激动剂Baclofen是至今唯一一个靶向于GABAB受体的上市药物，临床上用于痉挛的治疗，然而由于其穿透血脑屏障的能力较差而导致的外周神经系统的副作用，使其临床应用受到一定限制(Archives of Physical Medicine and Rehabilitation2003,84,1194-1199)。
变构调节剂不同于激动剂或者竞争性拮抗剂，它通过作用受体的变构位点来调节(增强或减弱)激动剂对受体的激活作用。由于其避免了外源性激动剂所导致的受体脱敏和内化，仍然保持了内源性激动剂GABA对GABAB受体在空间和时序上的调控作用，因而能够实现高选择性和安全性(Nature Review DrugDiscovery.2002,1,198-210)。至今为止，有两类GABAB受体的正向变构调节剂被发现，代表性的化合物分别为CGP7930和GS39783，这些化合物能够增强激动剂GABA对GABAB受体的激活能力(EC50)和最大激活强度(Emax)。此外，它们在体内实验中也表现出明显的正向调节GABAB受体的作用。在大鼠模型中，CGP7930可以增强氯苯氨丁酸(Baclofen)或者GABA的镇静和催眠的效应，能够减少酗酒大鼠的乙醇摄入量；GS39783能够减弱可卡因(cocaine)对大鼠的奖励促进效应(European Journal of Pharmacology2004,504,213-216；Neuropharmacology2006,50,632-639；Neuropsychopharmacology2006,32,388-398)。
然而，目前对GABAB受体的负向变构调节功能的研究还不成熟，迄今仍无GABAB受体的负向变构调节剂的报道。因此，发现GABAB受体的负向变构调节剂，不仅可以丰富我们对GABAB受体的结构与功能调控机理的认识，而且对靶向于GABAB受体的新型药物的开发具有重要意义。
发明内容
本发明的一个目的是提供一类GABAB受体的负向变构调节剂。
本发明的另一个目的是提供上述负向变构调节剂的制备方法。
本发明的另一个目的是提供上述负向变构调节剂的用途。
根据本发明的第一个目的，本发明提供了一类具有式I结构的化合物：
其中：
R1和R1’各自独立地为C1～C6直链烷基或C3～C6支链烷基；优选地，R1和R1’相同，均为C3～C6支链烷基；更优选地，R1和R1’均为叔丁基；
R2为H、卤素取代或未取代的C1～C6直链烷基、羧基、C1～C6直链烷基氧基羰基、-C(O)-NH-(C1～C5亚烷基)m-(O-C1～C5亚烷基)n-OH或者-C(O)-NH-(C1～C5亚烷基)m-(O-C1～C5亚烷基)n-NH-生物素；其中，m和n各自独立地为0、1、2、3或4，并且m和n不同时为0；所述卤素为F、Cl、Br或I；
优选地，R2为H、C1～C5直链烷基、F取代的C1～C5直链烷基、羧基、C1～C5直链烷基氧基羰基、-C(O)-NH-(C1～C5亚烷基)m-(O-C1～C5亚烷基)n-OH或者-C(O)-NH-(C1～C5亚烷基)m-(O-C1～C5亚烷基)n-NH-生物素；其中，m和n各自独立地为1、2或3；
更优选地，R2为H、C1～C2直链烷基、三氟甲基、羧基、C1～C2直链烷基氧基羰基、-C(O)-NH-(C1～C5亚烷基)m-(O-C1～C5亚烷基)n-OH或者-C(O)-NH-(C1～C5亚烷基)m-(O-C1～C5亚烷基)n-NH-生物素；其中，m和n各自独立地为1或2；
最优选地，R2为H、C1～C2直链烷基、三氟甲基、羧基、C1～C2直链烷基氧基羰基、-C(O)-NH-C1～C2亚烷基-O-C1～C2亚烷基-OH或者-C(O)-NH-C1～C2亚烷基-O-C1～C2亚烷基-NH-生物素；
X为-CH=CH-、-CH=CH-CH=CH-、-CH=CH-CH=CH-CH=CH-、-CH2CH2-、-CH2CH2CH2CH2-或-CH2CH2CH2CH2CH2CH2-；优选-CH=CH-、-CH=CH-CH=CH-、-CH2CH2-或-CH2CH2CH2CH2-；更优选地，X为-CH=CH-或-CH2CH2-；
Y为O、N或S；优选地，Y为O。
最优选地，本发明所述的式I化合物为如下化合物：
或
本申请的发明人在测试所述化合物活性数据的基础上结合现有技术，发现所述化合物具有如下构效关系。
首先，关于苯环的取代基R1和R1’：
本发明所述的化合物由GABAB受体正向变构调节剂CGP7930衍生而来。CGP7930中苯环上为两个叔丁基取代，而两个异丙基取代的类似物也同样具有活性，虽然活性稍弱（J.Braz.Chem.Soc.2007,18,721-727），由此可以推测，在式I所示的负向变构调节剂中，R1，R1’可以为多种烷基取代基，尽管它们的活性会有一定的差异。
其次关于侧链R2：
式I中，R2为亲水性取代基对活性有利，若R2为疏水性取代基，则活性减弱甚至丧失。
根据本发明的第二个目的，本发明提供式I化合物的制备方法。
根据通式I中X与R2的定义，制备方法按以下八种情形论述：
(1)当X为-CH=CH-、-CH=CH-CH=CH-或-CH=CH-CH=CH-CH=CH-，R2为H时，式Ia化合物按如下反应式来制备：
Y为O、N或S；
反应在如下溶剂中进行：苯、甲苯或上述溶剂的混合溶剂；反应温度为60℃～100℃；反应时间约需1～24小时；反应完成后用AcOEt、Et2O、CH2Cl2、CHCl3等溶剂提取，饱和食盐水洗，经干燥后，低温减压除去溶剂，浓缩物经柱层析得目标产物，所得产物用NMR等方法来确认。
(2)当X为-CH=CH-、-CH=CH-CH=CH-或-CH=CH-CH=CH-CH=CH-，R2为C1～C6直链烷基氧基羰基时，式Ib化合物按如下反应式来制备：
Y的定义同上；
其中，路易斯酸为BF3-Et2O。反应在如下溶剂中进行：CH2Cl2、CHCl3或上述溶剂的混合溶剂；反应温度从-78℃～0℃；反应时间约需1～24小时；反应完成后用AcOEt、Et2O、CH2Cl2、CHCl3等溶剂提取，饱和食盐水洗，经干燥后，低温减压除去溶剂，浓缩物经柱层析得目标产物，所得产物用NMR等方法来确认。
(3)当X为-CH=CH-、-CH=CH-CH=CH-或-CH=CH-CH=CH-CH=CH-时，式Ic化合物由R2为乙氧羰基的式Ib化合物按如下反应式来制备：
化合物Ic可由化合物Ib经碱水解得到。反应在如下溶剂中进行：MeOH、EtOH、H2O或上述溶剂的混合溶剂；反应温度为0℃～50℃；反应时间约需0.1～1小时；反应完成后用稀HCl、H2SO4等酸化，用AcOEt、Et2O、CH2Cl2、CHCl3等溶剂提取，饱和食盐水洗，经干燥后，低温减压除去溶剂，浓缩物经柱层析得目标产物，所得产物用NMR等方法来确认。
(4)当X为-CH=CH-、-CH=CH-CH=CH-或-CH=CH-CH=CH-CH=CH-，R2为-C(O)-NH-(C1～C5亚烷基)m-(O-C1～C5亚烷基)n-OH或者-C(O)-NH-(C1～C5亚烷基)m-(O-C1～C5亚烷基)n-NH-生物素(m和n各自独立地为0、1、2、3或4，并且m和n不同时为0)时，式Id化合物按如下反应式来制备：
其中，Y的定义同上；
化合物Id可由化合物Ic与相应的胺（NH2-(C1～C5亚烷基)m-(O-C1～C5亚烷基)n-OH或NH2-(C1～C5亚烷基)m-(O-C1～C5亚烷基)n-NH-生物素）经缩合反应得到。反应在如下溶剂中进行：DMF、CH2Cl2或上述溶剂的混合溶剂；反应加入Et3N或i-Pr2NEt作碱；BOPCl、DCC、CDI等作缩合剂；通常反应温度从0℃～60℃；反应时间约需1～24小时；反应完成后用AcOEt、Et2O、CH2Cl2、CHCl3等溶剂提取，饱和食盐水洗，经干燥后，低温减压除去溶剂，浓缩物经柱层析得目标产物，所得产物用NMR等方法来确认。
(5)当X为-CH2CH2-、-CH2CH2CH2CH2-或-CH2CH2CH2CH2CH2CH2-，R2为卤素取代或未取代的C1～C6直链烷基时，式Ie化合物按如下反应来制备：
其中，Y的定义同上；
在步骤1中，溶剂为：吡啶、吗啉或上述溶剂的混合溶剂；反应加入哌啶作碱；反应温度从50℃～100℃；反应时间约需1～5小时；反应完成后加入无机酸酸化，析出的固体用PE60～90℃重结晶，得产物，产物用NMR等方法来确认。
在步骤2中，溶剂为：EtOH、EtOAc或上述溶剂的混合溶剂；反应以Pd/C为催化剂，H2为氢源；反应温度从0℃～50℃；反应时间约需1～24小时；反应完成后垫硅藻土过滤，滤液浓缩后所得的产物直接用于下一步反应，产物用NMR等方法来确认。
在步骤3中，溶剂为：重蒸的CH2Cl2、甲苯或上述溶剂的混合溶剂；反应以SOCl2、草酰氯等为卤代试剂，DMF为催化剂；反应温度从0℃～50℃；反应时间约需1～5小时；反应完成后浓缩除去溶剂，所得产物可直接用于下一步反应。
在步骤4中，溶剂为：CHCl3、CH2Cl2或上述溶剂的混合溶剂；反应加入嘧啶作碱；酸酐R2C(Y)OC(Y)R2作为酰化试剂；反应温度从-78℃～-20℃；反应时间约需1～24小时；反应完成后用AcOEt、Et2O、CH2Cl2、CHCl3等溶剂提取，饱和食盐水洗，经干燥后，低温减压除去溶剂，浓缩物经柱层析得化合物Ie；所得产物用NMR等方法来确认。
(6)当X为-CH2CH2-、-CH2CH2CH2CH2-或-CH2CH2CH2CH2CH2CH2-，R2为C1～C6直链烷基氧基羰基时，相应的式I化合物(If)可由X为亚烯基时的化合物Ib经氢化反应得到来制备：
其中，Y的定义同上；
反应在如下溶剂中进行：EtOH、EtOAc或上述溶剂的混合溶剂；反应以Pd/C为催化剂，H2为氢源；反应温度从0℃～50℃；反应时间约需1～24小时；反应完成后垫硅藻土过滤，滤液浓缩后经柱层析得目标产物，所得产物用NMR等方法来确认。
(7)当X为-CH2CH2-、-CH2CH2CH2CH2-或-CH2CH2CH2CH2CH2CH2-时，式Ig化合物由R2为乙氧羰基的式If化合物按如下反应式来制备：
其中，Y的定义同上；
化合物Ig可由化合物If经碱水解得到。反应条件与化合物Ic的制备类似。
(8)当X为-CH2CH2-、-CH2CH2CH2CH2-或-CH2CH2CH2CH2CH2CH2-，R2为-C(O)-NH-(C1～C5亚烷基)m-(O-C1～C5亚烷基)n-OH或者-C(O)-NH-(C1～C5亚烷基)m-(O-C1～C5亚烷基)n-NH-生物素时(m和n各自独立地为0、1、2、3或4，并且m和n不同时为0)，式Ih化合物按如下反应式来制备：
化合物Ih可由化合物Ig与相应的胺（NH2-(C1～C5亚烷基)m-(O-C1～C5亚烷基)n-OH或NH2-(C1～C5亚烷基)m-(O-C1～C5亚烷基)n-NH-生物素）经缩合反应得到。反应条件与化合物Id的制备类似。
根据本发明的第三个目的，本发明提供了式I化合物在制备GABAB受体负向调节剂中的用途。式I化合物作为GABAB受体的负向变构调节剂，能够非竞争性的抑制GABAB受体的激动剂引起的该受体的激活，因此能够用于制备因GABAB受体兴奋性过高所导致的相关疾病的治疗药物，所述相关疾病包括：癫痫、焦虑、抑郁或者因神经损伤而导致的认知能力低下等。
附图说明
图1为化合物D31、D51、D52、D60、D62、D67、D69、D73和D74影响细胞内磷酸肌醇产生量的定性测试结果。在共转染GB1、GB2以及Gqi9的HEK293细胞中，上述化合物均能抑制激动剂GABA引起的GABAB受体的激活。
具体实施方式
以下通过具体实施例来进一步说明本发明。应理解，以下实施例仅用于说明本发明而不用于限定本发明的范围。
制备实施例
制备实施例1——化合物D31的制备
原料醛D1(100mg,0.427mmol，合成参考中国药物化学杂志2005,15,4)和Ph3P=CH-CHO(156mg,0.512mmol，购自百灵威试剂公司)混合后，加入甲苯(2ml)，N2保护下，100℃加热过夜。反应液冷却至室温，减压浓缩，硅胶柱层析(PE/EA=40/1～10/1)，分得浅红棕色固体D31(19.2mg,17%)。1H NMR(CDCl3,300MHz):δ9.64(d,J=8.1Hz,1H),7.43(d,J=15.6Hz,1H),7.41(s,2H),6.62(dd,J=7.5Hz,15.6Hz,1H),5.63(s,1H),1.46(s,18H).
制备实施例2——化合物D73、D60的制备
化合物D72的制备
原料醛D1(1.17g,5.0mmol)、原甲酸三乙酯(4.1g,38.6mmol)、NH4Cl(0.05g,0.935mmol)与MeOH(3ml)混合，加热回流3.5h。反应液渐冷至室温，减压浓缩。粗品溶于DCM(10ml)，加入PE60～90℃(20ml)稀释，有黄色固体析出，常压蒸馏至馏分为60℃，冷却至室温。过滤除去原料，滤液浓缩，得黄色固体D72(0.647g,46%)。1H NMR(CDCl3,300MHz):δ7.22(s,2H),5.25(s,1H),5.22(s,1H),3.35(s,6H),1.44(s,18H).
化合物E25的制备
TMSCl(2.049g,18.9mmol)，DMAP(0.089g,0.727mmol)，丙酮酸乙酯(1.690g,14.55mmol)依次加入重蒸的甲苯中(20ml)，加热回流，反应液呈白色悬浊液。回流下加入Et3N(1.841g,18.91mmol)，继续回流。3h后，反应液冷却至室温，过滤，滤饼用重蒸的甲苯洗涤，滤液减压浓缩，所得粗品减压蒸馏，油浴90℃水泵减压蒸馏除去杂质，然后油浴90℃油泵减压蒸馏，得无色油状物E25。1HNMR(CDCl3,300MHz):δ5.51(d,J=0.9Hz,1H),4.87(d,J=0.9Hz,1H),4.22(q,J=7.2Hz,2H),1.31(t,J=7.2Hz,3H),0.24(s,9H).
化合物D73的制备
D72(489mg,1.74mmol)与E25(305mg,1.59mmol)溶于重蒸的DCM(6.3ml)，冷却至-78℃，滴加BF3-Et2O，然后升温至0℃，反应3h。反应液由橙红色渐加深至棕色。3h后，反应液用DCM稀释，饱和NaHCO3洗涤，饱和食盐水洗，无水Na2SO4干燥，过滤、浓缩，硅胶柱层析(PE/EA=10/1)，得产物D73(380mg,72%)。1H NMR(CDCl3,300MHz):δ7.85(d,J=15.9Hz,1H),7.48(s,2H),7.19(d,J=15.9Hz,1H),5.68(s,1H),4.39(q,J=7.2Hz,2H),1.46(s,18H),1.39(t,J=7.2Hz,3H).
化合物D60的制备
原料D73(93mg,0.280mmol)溶于MeOH(9ml)与H2O(2.2ml)的混合液中，加入K2CO3，反应液迅速变成粉红色，室温搅拌。10min后，TLC显示原料已反应完全，反应液减压浓缩，加水稀释，1N HCl调pH=2，DCM萃取，饱和食盐水洗涤，无水Na2SO4干燥。过滤、浓缩，硅胶柱层析(CHCl3/MeOH=5/1)，得产物D60(82.4mg,97%)。1H NMR(CDCl3,300MHz):δ8.14(d,J=16.2Hz,1H),7.53(s,2H),7.44(d,J=16.2Hz,1H),5.78(s,1H),4.03(s,2H),1.43(s,18H).
制备实施例3——化合物D51的制备
化合物D38的制备
原料醛D1(0.234g,1.00mmol)、丙二酸(0.310g,3.0mmol)混合后，N2下，加入重蒸的吡啶(0.85ml)、哌啶(0.03ml)，100℃加热1.5h。反应液倒入12NHCl(0.5ml)与冰水(0.8ml)的混合液中，搅拌1h，有大量橙色固体析出。过滤，滤饼水洗。滤饼溶于DCM后，加入PE60-90℃，常压蒸馏至馏分为60℃，有白色固体析出。冷却至室温，过滤，滤饼用PE洗涤，得乳白色固体D38(196mg,71%)。1H NMR(CDCl3,300MHz):δ7.75(d,J=15.6Hz,1H),7.40(s,2H),6.31(d,J=15.6Hz,1H),5.56(s,1H),1.46(s,18H).
化合物D53的制备
D38(507mg,1.83mmol)溶于EA(25ml)中，加入10%Pd/C(50mg)，体系用H2置换，室温反应3h。3h后，体系N2置换，反应液硅藻土过滤，滤饼用EA洗涤，滤液浓缩，得白色固体D53(511mg,100%)。1H NMR(CDCl3,300MHz):δ7.01(s,2H),5.10(s,1H),2.90(t,J=7.2Hz,2H),2.67(t,J=7.2Hz,2H),1.44(s,18H).ESI-MS:m/z=277.2(M-H)-.
化合物D51的制备
D53(83.5mg,0.30mmol)溶于重蒸的DCM(0.6ml)以及甲苯(1.2ml)，室温搅拌下滴加SOCl2(0.15ml)以及DMF(1滴)，室温反应2h。2h后，反应液减压浓缩干，油泵抽干，得浅黄色固体。该固体溶于DCM(1ml)，N2保护，-78℃下，慢慢滴加TFAA(504mg,2.40mmol)，以及重蒸的Py(94.9mg,1.20mmol)。改用冰盐浴冷却，反应4h。反应液用DCM稀释，水洗，饱和食盐水洗，无水Na2SO4干燥。过滤、浓缩，硅胶柱层析(PE/EA=30/1)，得棕黄色油状物D51(69mg,70%)。1H NMR(CDCl3,300MHz):δ6.99(s,2H),5.13(br,1H),3.03(t,J=7.2Hz,2H),2.91(t,J=7.2Hz,2H),1.44(s,18H).13C NMR(CDCl3,75MHz):δ191.2(q,J=34.7Hz),152.7,136.4,130.1,125.0,115.8(q,J=290.6Hz),38.9,34.5,30.4,28.5.
制备实施例4——化合物D62、D52的制备
化合物D62的制备
D73(100mg,0.30mmol)溶于二噁烷(Dixoane,10ml)，加入5%Pd/C(20mg)，H2换气后室温反应6h，TLC显示原料已反应完全。反应液用硅藻土过滤，滤液浓缩，硅胶柱层析(PE/EA=20/1)，得无色油状物D62(38mg，31%)。1H NMR(CDCl3,300MHz):δ6.99(s,1H),5.09(s,1H),3.86(s,3H),3.16(t,J=7.5Hz,2H),2.87(t,J=7.5Hz,2H),1.43(s,18H).ESI-MS:m/z=343.1(M+Na)+.
化合物D52的制备
反应过程与D60的制备相近。原料D62(94.8mg,0.296mmol)，得无色油状物D52(65.8mg,73%)，反应中会有聚合的杂质生成。1H NMR(CDCl3,300MHz):δ6.99(s,2H),5.85(br,1H),5.10(br,1H),3.25(t,J=7.2Hz,2H),2.89(t,J=7.2Hz,2H),1.43(s,18H).ESI-MS:m/z=305.2(M-H)-.
制备实施例5——化合物D67、D69的制备
化合物D67的制备
原料D52(9.0mg,29.4umol)溶于重蒸的DCM(1ml)，N2保护下，加入Et3N(10.1mg,100umol)，反应液变成浅粉红色。冰水浴冷却下，加入BOPCl(10mg,35.2umol)，0℃反应40min后，反应液渐呈棕色。40min后，再加入醇E24(6.0mg,购自TCI Shanghai)的DCM(1ml)溶液，室温搅拌过夜。反应液用EA稀释，1N HCl洗涤，盐水洗，无水Na2SO4干燥，过滤、浓缩，硅胶柱层析(DCM/MeOH=50/1)，得棕色油状物D67(1.6mg,14%)。1H NMR(CDCl3,300MHz):δ7.33(br,1H),6.99(s,2H),5.06(s,1H),3.76(t,J=4.8Hz,2H),3.57-3.63(m,4H),3.52(t,J=5.1Hz,2H),3.26(t,J=7.8Hz,2H),2.85(t,J=7.8Hz,2H),1.42(s,18H).ESI-MS:m/z=416.2(M+Na)+.
化合物D69的制备
反应过程与D67的制备相近。原料D60(10.4mg,34.2umol)，得产物D69(2.4mg,18%)。1H NMR(CDCl3,300MHz):δ7.95(d,J=15.9Hz,1H),7.60(d,J=15.9Hz,1H),7.52(s,2H),5.68(s,1H),3.77(t,J=4.2Hz,2H),3.55-3.67(m,6H),1.46(s,18H).
制备实施例6——化合物D74的制备
化合物E27的制备
原料E23(36mg,0.18mmol,购自Sigma-Aldrich试剂公司)溶于MeOH，室温搅拌下加入NaHCO3(27mg,0.32mmol)以及B9(72mg,0.21mmol，合成参考Biochemical Journal2012,443,627–634)，室温反应过夜。反应液减压浓缩，硅胶柱层析(CHCl3/MeOH=15/1)，得白色固体(47mg,62%)，为缩合产物。1HNMR(CDCl3,300MHz):δ4.95(br,1H),3.45-3.53(m,4H),3.31(q,J=5.1Hz,2H),2.86(s,2H),1.69(s,2H),1.44(s,9H).上述缩合产物经TFA/DCM=1/2中反应5h便可得产物E27。
化合物D74的制备:
反应过程与D67的制备相近。原料D52(13.5mg,44.1umol)，得产物D74(3.1mg,11%)。1H NMR(CDCl3,300MHz):δ7.43(br,1H),6.99(s,2H),6.22(br,1H),5.70(s,1H),5.08(s,1H),4.97(s,1H),4.51(dd,J=4.8,7.2Hz,1H),4.33(dd,J=4.8,7.5Hz,1H),3.40-3.80(m,8H),3.24(t,J=7.2Hz,2H),3.16(dd,J=7.5,12.3Hz,1H),2.92(dd,J=4.8Hz,13.2Hz,1H),2.84(t,J=7.2Hz,2H),2.72(d,J=13.2Hz,1H),2.24(t,J=6.6Hz,2H),1.60-1.80(m,6H),1.42(s,18H).ESI-MS:m/z=491.2(M+Na)+.
实验实施例
实验实施例1：GABAB受体负向变构调节剂能够非竞争性的抑制激动剂GABA引起的GABAB受体的激活。
GABAB受体为Gi/o偶联的G蛋白偶联受体，其激活后通过抑制腺苷酸环化酶(AC)进而抑制cAMP产生，因而可以通过检测cAMP的产生来检测GABAB受体激活情况；另外可以在该细胞系中转染Gqi9嵌合型G蛋白，可以将GABAB受体激活的信号偶联到PLC信号通路来，继而PLC-β催化水解膜磷脂酰肌醇二磷酸(PIP2)裂解并积累肌醇三磷酸(IP3)和二酰甘油(DAG)。本实施例中，3H标记的肌醇标记靶细胞后，用药物抑制或刺激细胞，通过阴离子交换层析柱分离洗脱，收集IP3洗脱峰后进行液闪测定，并以IP3积累量来衡量受体的激活。
GABAB受体负向调节剂化合物对GABA激活转染细胞的抑制效应的检测：取1×107个人胚肾细胞HEK293(购自中国科学院细胞库)与野生型GB1(4μg)，GB2(4μg)Gqi9(2μg)cDNA(制备参见Nature,1993,363,274–276)混合，进行电穿孔转染后，将细胞接种于96孔板中过夜。待6小时后，培养基换成带有3H标记肌醇(购自PerkinElmer Inc.,USA)的不含谷氨酸的DMEM培养基(购自Invitrogen Inc.,Shanghai)，孵育16h。将细胞用100μM的D60处理15min后，加入或者不加10-6mol/L的GABA进行刺激。用Micobeta工作站测定各组诱导的IP3积累量。IP3积累量用磷酸肌醇积累量/总肌醇量的比率来表示，取三次独立实验的平均值。用GraphPad PRISM软件进行计算分析。
结果：图1为化合物D31、D51、D52、D60、D62、D67、D69、D73和D74影响细胞内磷酸肌醇产生量的定性测试结果。在共转染GB1、GB2以及Gqi9的HEK293细胞中，上述化合物均能抑制激动剂GABA引起的GABAB受体的激活。具体实验数据如下表1所示。
表1
| 对照 | D31 | D51 | D52 | D60 | |
| ‐GABA | 0.092±0.004 | 0.075±0.007 | 0.107±0.003 | 0.064±0.004 | 0.080±0.010 |
| +GABA | 0.126±0.017 | 0.065±0.005 | 0.106±0.013 | 0.070±0.009 | 0.094±0.008 |
| D62 | D67 | D69 | D72 | D74 | |
| ‐GABA | 0.088±0.009 | 0.090±0.002 | 0.083±0.017 | 0.093±0.016 | 0.101±0.013 |
| +GABA | 0.095±0.008 | 0.083±0.023 | 0.071±0.008 | 0.101±0.013 | 0.104±0.012 |
Claims (8)
1.一类具有式I结构的化合物：
其中：
R1和R1’各自独立地为C1～C6直链烷基或C3～C6支链烷基；
R2为H、卤素取代或未取代的C1～C6直链烷基、羧基、C1～C6直链烷基氧基羰基、-C(O)-NH-(C1～C5亚烷基)m-(O-C1～C5亚烷基)n-OH或者-C(O)-NH-(C1～C5亚烷基)m-(O-C1～C5亚烷基)n-NH-生物素；其中，m和n各自独立地为0、1、2、3或4，并且m和n不同时为0；所述卤素为F、Cl、Br或I；
X为-CH=CH-、-CH=CH-CH=CH-、-CH=CH-CH=CH-CH=CH-、-CH2CH2-、-CH2CH2CH2CH2-或-CH2CH2CH2CH2CH2CH2-；
Y为O、N或S。
2.根据权利要求1所述的化合物，其中，
R1和R1’相同，均为C3～C6支链烷基；
R2为H、C1～C5直链烷基、F取代的C1～C5直链烷基、羧基、C1～C5直链烷基氧基羰基、-C(O)-NH-(C1～C5亚烷基)m-(O-C1～C5亚烷基)n-OH或者-C(O)-NH-(C1～C5亚烷基)m-(O-C1～C5亚烷基)n-NH-生物素；其中，m和n各自独立地为1、2或3；
X为-CH=CH-、-CH=CH-CH=CH-、-CH2CH2-或-CH2CH2CH2CH2-；
Y为O。
3.根据权利要求2所述的化合物，其中，
R1和R1’均为叔丁基；
R2为H、C1～C2直链烷基、三氟甲基、羧基、C1～C2直链烷基氧基羰基、-C(O)-NH-(C1～C5亚烷基)m-(O-C1～C5亚烷基)n-OH或者-C(O)-NH-(C1～C5亚烷基)m-(O-C1～C5亚烷基)n-NH-生物素；其中，m和n各自独立地为1或2；
X为-CH=CH-或-CH2CH2-。
4.根据权利要求3所述的化合物，其中，
R2为H、C1～C2直链烷基、三氟甲基、羧基、C1～C2直链烷基氧基羰基、-C(O)-NH-C1～C2亚烷基-O-C1～C2亚烷基-OH或者-C(O)-NH-C1～C2亚烷基-O-C1～C2亚烷基-NH-生物素。
5.根据权利要求1所述的化合物，该化合物选自下列化合物中：
或
6.根据权利要求1至5中任一项所述的化合物在制备GABAB受体的负向变构调节剂中的用途。
7.根据权利要求1至5中任一项所述的化合物在制备用于治疗因GABAB受体兴奋性过高所导致的相关疾病的药物中的用途。
8.根据权利要求7所述的用途，其中，所述相关疾病为癫痫、焦虑、抑郁或者因神经损伤而导致的认知能力低下。
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| US3714122A (en) * | 1970-07-20 | 1973-01-30 | Goodyear Tire & Rubber | Antioxidants and age resistant polymeric compositions |
| CN103025808A (zh) * | 2010-05-10 | 2013-04-03 | 拜耳知识产权有限责任公司 | 稳定剂结合物 |
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