CN1361776A - 新的氟化咪唑啉苯并二噁烷,其制备及其治疗用途 - Google Patents
新的氟化咪唑啉苯并二噁烷,其制备及其治疗用途 Download PDFInfo
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- CN1361776A CN1361776A CN00810622A CN00810622A CN1361776A CN 1361776 A CN1361776 A CN 1361776A CN 00810622 A CN00810622 A CN 00810622A CN 00810622 A CN00810622 A CN 00810622A CN 1361776 A CN1361776 A CN 1361776A
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Abstract
本发明涉及新的氟化咪唑啉苯并二噁烷,其制备和其治疗用途。更为具体而言,本发明涉及对应于通式(1)结构的化合物,其中:R代表含有1-7个碳原子的直链、支链或环化的烷基或链烯基,或者苄基,该氟原子可以在5、6、7或8位;该化合物为其外消旋形式或其纯右旋或左旋的对映异构体形式,以及其加成盐。
Description
本发明涉及对应于式1的新的氟化苯并二噁烷咪唑啉衍生物,
其中:
-R代表含有1-7个碳原子的直链、支链或环化的烷基或链烯基,或者苄基,
-该在同素环上的氟原子可以在5、6、7或8位。
本发明涉及其外消旋和纯对映异构体的形式,及其盐形式和其制备方法。
本发明还涉及这些组合物作为药品的用途,并涉及用作α2-肾上腺素能受体拮抗剂并期望用于治疗神经变性的疾病及其发展的药品的制备。
有利地,基团R为甲基、乙基、正丙基、异丙基、异丁基、环丙基甲基、烯丙基或苄基。
优选该氟原子在5位。
已知(Mavridis,神经科学(Neuroscience)(1991),41,507)蓝斑在恢复通过给予猴子MPTP而改变的多巴胺功能中起主要作用。其破坏导致恢复的降低。而且,具有α2拮抗剂作用的化合物表现为增加多巴胺的释放(Marien,M.,Colpaert,F.(+)-efaroxan对小鼠纹状体多巴胺体内代谢的作用(Effect of(+)-efaroxan on mousestriatal dopamine metabolism in vivo.)多巴胺(DOPAMINE)第十二届国际药理学卫星大会(94-Satellite Meeting of the XIIthInt.Congr.Pharmacology),加拿大,魁北克市(Quebec City,Canada),7月20-24,1994)而减少猴子(Colpaert,脑研究通报(Brain Res.Bull.),26,627,1991)或大鼠(Colpaert,神经药理学(Neuropharmacology),26,1431,10 1987)的帕金森氏综合症。
而且,α2-拮抗剂,咪唑克生,表现为对大脑局部缺血的有害结果(Gustafson,实验脑研究(Exp.Brain Res.),86,555,1991 etJ.Cereb.Blood Flow Metab.,1990,10,835)和在渐进性核上性麻痹和神经变性疾病(Ghika,神经学(Neurology),41,986,1991)具有良好的作用。还已表明具有α2-拮抗剂活性的化合物导致前额皮层中乙酰胆碱释放的增加(Tellez,神经化学杂志(J.Neurochem.)(1997),68,778)。
因此,激活非肾上腺素能系统的物质可能通过激活各种大脑局部系统而具有对抗相关神经元退化发展的的性质,不管它们是多巴胺能或胆碱能的,或者是否其涉及生长因子的释放(Fawcctt等神经科学(J.Neurosci.)(1998),18,2808-2821)。因此这些化合物用于神经变性类型的疾病如:帕金森氏病或阿耳茨海默氏病及其发展、杭廷顿氏舞蹈病、肌萎缩性侧索硬化、克罗伊茨费尔特-雅各布综合症、渐进性核上性麻痹、认识及记忆障碍、中年时注意力和警觉性不足以及这些疾病或病症的发展或演变。局部出血性和后局部缺血性大脑病症、脑血管的意外事件及其后果、抑郁、发作性睡眠和男性性功能障碍也被认为是与后天免疫缺陷综合症相关的病症。
还已知苯并二噁烷衍生物如咪唑克生:2-(1,4-苯并二噁烷-2-基)-2-咪唑啉,或烷氧基咪唑克生:2-(2-烷氧基-1,4-苯并二噁烷-2-基)-2-咪唑啉,具有α2-拮抗剂性质(医药化学杂志(J.Med.Chem.)(1983),26,823;J.Med.Chem.(1985),28,1054)。这些化合物已在关于咪唑克生的GB 2 068 376和关于烷氧基-咪唑克生的EP92328中取得专利权。
在这些出版物中已知大量的咪唑克生衍生物已被合成并被测试其对α1或α2受体的兴奋或拮抗作用,其中已发现在芳香核上被取代的卤化衍生物相对于其未取代的咪唑克生类似物(尤其是6/7-氟、氯或溴衍生物,5,8-二氯或8-氯衍生物)而言活性较小或无活性。而且,在6,7位被两个甲氧基取代的2-甲氧基咪唑克生衍生物仅表现出最低限度的α2-突触前拮抗剂的活性。
本发明的化合物不同于已知化合物之处在于其具有一个在芳香核的5、6、7或8位的氟原子。它们具有作为强有效的α2-肾上腺素能受体拮抗剂的性质。
已发现,在这些位置出现的氟原子明显地赋予了这些分子相对其未氟化的类似物的特别有益的性质。
已研究了本发明产品的药理学性质,尤其与2-甲氧基咪唑克生(RX 821002)和2-乙氧基咪唑克生(RX 811059)进行了比较,这两种化合物是在芳香核上没有被取代的衍生物的结构相关的化合物。
特别地,我们在以下试验中表明了本发明产品的体内药理学性质:由东莨菪碱诱导的记忆缺陷试验、由胍那苄,一种α2-激动剂物质,诱导的低温拮抗作用试验,和基于皮层中去甲变肾上腺素,去甲肾上腺素释放的代谢物和选择性标记,的水平。
由东莨菪碱诱导的记忆缺陷试验:
根据认识和记忆现象的胆碱能假说,东莨菪碱在动物和人体上具有遗忘性质。将其给予健康人体导致某种类似于在阿耳茨海默氏病中所观察到的健忘综合症。已提出东莨菪碱用作这种病变的实验药理学模型。阿耳茨海默氏病和由东莨菪碱诱导的记忆缺陷之间的相似性已被公开(P.Chopin et M.Briley,阿吗碱和二氢麦角汀碱对大鼠消极避让学习的年龄相关的缺陷的作用,药物药理学杂志(J.Pharm.Pharmacol.)42,375-376,1990)。在大鼠的消极逃避试验中东莨菪碱降低了获得、记忆和回忆的能力。它包括测定在动物在学会进入黑暗隔室之后的沉默,在隔室中动物接受轻微的电击。给予东莨菪碱抑制了这种沉默,而试验化合物对抗东莨菪碱的作用。
将本发明的产品与已知的化合物RX 821002,右旋对映异构体进行比较。实验方案由F.Chopin和N.Briley公开(四种非胆碱能认知增强剂较之于他克林和加兰他敏对东莨菪碱诱导的大鼠记忆缺陷的作用:精神药理学(Psychopharmacology,106,26-30,1992))。结果如下表所示:
东莨菪碱诱导的记忆缺陷 | |
化合物范围为0.04-2.5mg/kg的活性剂量 | 相对于只接受多巴胺的动物而言增加了治疗动物进入黑暗隔室所用的时间(%效果的幅度) |
(+)RX 821002 | 不显著 |
实施例1的右旋化合物 | 201% |
实施例2的右旋化合物 | 198% |
他克林 | 191% |
Donepezil | 67% |
与不具有显著活性的(+)RX 821002相比,本发明化合物在宽剂量范围内表现出显著活性。其效果的幅度至少与他克林一样大,并大于用于治疗阿耳茨海默氏病的参照化合物donepezil。
这样显示了本发明产品的价值和幅度的差别。
胍那苄诱导的低温抑制:
还根据S.C.Dilsaver,药理生化行为(Pharmacol.Biochem.Behav.),45,247,1993的方案,通过研究由中枢α2-激动剂如胍那苄诱导的低温抑制而进行本发明化合物体内生物活性的评价。
该试验表明本发明化合物的体内α2-肾上腺素能受体拮抗作用及其在中枢水平的活性。其抑制能力表示为ED50,它代表一方面导致显著地抑制由胍那苄诱导的低温,而另一方面使动物在注射胍那苄之前回复到正常温度的标准化剂量。采用J.T.Litchfield和F.Wilcoxon(实验治疗药理学杂志J.Pharmacol.Exp Ther.),96,99,1949)的方法得到这些值。这种比较在5位氟化的2-甲氧基化合物(实施例1的右旋化合物)和未氟化的化合物:(+)RX 821002之间,以及在5位氟化的2-乙氧基(实施例2中的右旋化合物)与未氟化的化合物:(+)RX 811059之间进行。
(+)RX821002 | 实施例1的右旋化合物 | |
活性剂量范围:(i.p)抑制作用(mg/kg)ED50(mg/kg) | 0.01-100.01 | 0.0025-400.003 |
标准化(mg/kg)ED50(mg/kg) | 0.04-2.50.05 | 0-0025-100.02 |
活性剂量范围(口服)标准化(mg/kg)ED50(mg/kg) | 0.16-100.56 | 0.04-400.22 |
(+)RX811059 | 实施例2的右旋化合物 | |
活性剂量范围:(i.p)抑制作用(mg/kg)ED50(mg/kg) | 0.04-100.08 | 0.0025-400.02 |
标准化(mg/kg)ED50(mg/kg) | 0.16-100.32 | 0.01-100.16 |
由此可以看出本发明化合物比它的类似物(+)RX 821002和(+)RX 811059的作用强度更大。还通过测定在100%动物中诱发低温抑制的剂量而证明其作用的范围,其中6种剂量(各剂量被因数4分离)用于实施例1的右旋化合物而2种剂量用于(+)RX 821002。类似地,3种剂量的实施例1的右旋化合物使100%的动物的低温正常化,而(+)RX 821002则不然,它仅在2种剂量处使80%的动物正常化。
该表显示了这些结果:
(+)RX821002 | 实施例1的右旋化合物 | |
抑制100%动物低温的剂量 | 0.16和2.5mg/kg | 0.01-0.04-0.16-0.63-2.5-10mg/kg |
使100%动物低温正常化的剂量 | 无 | 0.16-0.63-2.5mg/kg |
由此引可见本发明产品具有非常宽的活性剂量范围,因而是更好的α2-肾上腺素能拮抗剂。
去甲肾上腺素的释放:
大脑组织中去甲变肾上腺素,去甲肾上腺素的代谢产物的水平是去甲肾上腺素释放的尺度,Wood,P.L.和coll.药理学综述(Pharmacological Rev.)40,163-187,(1988),和神经化学杂志(J.Neurochem.)48,574-579,(1987))。通过儿茶酚O-甲基转移酶的作用而形成去甲变肾上腺素发生在去甲肾上腺素能神经元的外侧,而且其测定考虑了去甲肾上腺素释放的变化。其测定是在前额皮层,主要受蓝斑神经支配的区域进行。
将该试验化合物腹膜内给予小鼠,60分钟后用微波照射处死该小鼠(以避免代谢产物水平的任何人为变化)。解剖后,在皮层组织提取物上用HFLC测定去甲变肾上腺素。在0.01-2.5mg/kg的剂量时,所测定的去甲变肾上腺上素代表相同条件下,实施例1的化合物水平比(+)RX 821002高125-150%。这表明该化合物释放去甲肾上腺素的效力比RX 821002更大。
在体内结合α2-肾上腺素能受体:
还根据与α2-肾上腺素能受体亚型结合试验,采用含氚2-甲氧基-咪唑克生、[3H]RX821002作为放射性配基,证明了本发明的化合物具有对人α2-肾上腺素能受体的纳摩尔水平的亲合力(J.C.Devedjian和coll.欧洲药理学杂志(Eur.J.Pharmacol.)(1994),252,43-49)。
该体内试验表明了在芳核上氟原子的取代与缺少这种取代的化合物相比所带来的优点。
由于本发明化合物含有不对称碳,因而它们是右旋形式和左旋形式。因此本发明还涉及对映异构体纯的化合物,其加成盐,还涉及包括至少一种式1的化合物和适宜赋形剂的组合物。可以适宜的方式提供该药物组合物用于口服、注射或肠道外给药,其剂型为糯米纸胶囊、凝胶胶囊、片剂或注射制剂,日剂量为0.1-200mg。
本发明的化合物可以由3-氟儿茶酚(在美国化学会杂志(J.Amer.Chem.Soc.)77,5314-5317,1955中所述)制备,它是通过在K2CO3的存在下在乙腈中与2,3-二溴丙酰胺偶合而得到区域异构体5-和8-氟-1,4-苯并二噁烷-2-甲酰胺。多次重结晶可以分离出纯形式的5-氟衍生物,同时要损失掉在这些条件下更为可溶的8-氟衍生物。将在苯并二噁烷的2位的酰胺官能团脱水形成腈。然后通过NBS的作用将该腈溴化得到溴腈,将其接受醇钠如在甲醇中的甲醇钠的作用形成中间产物亚胺酯(imidate),将该中间产物原位与乙二胺反应形成期望的α-甲氧基咪唑啉衍生物。以类似的方式,采用对应用的碱金属醇盐处理前述的溴腈衍生物而得到在2位的醇盐衍生物。
这两种旋光对映异构体可由多种方法制备:通过手性酸如可能为酒石酸或其衍生物如二苯甲酰酒石酸的非对映选择性结晶,或通过在手性相上的色谱分离,制备HPLC,得到右旋异构体和左旋异构体,可以采用常规方法得到其结晶形式的盐酸盐。
芳环上的6-和7-氟衍生物得自(6-或7-氟-2,3-二氢-苯并[1,4-二氧芑(dioxin)-2-基)甲醇,如在药化杂志(J.Med.Chem.)(1987),30,814中所述。将这些甲醇衍生物氧化成酸,然后根据J.Med.Chem.(1983),26,823,或J.Med.Chem.(1985),28,1054所述的方法将其酰胺化和脱水成腈,接着如上述处理。
各阶段合成的过程说明本发明:
实施例1:2-(5-氟-2-甲氧基-1,4-苯并二噁烷-2-基)-2-咪唑啉阶段1:5-氟-1,4-苯并二噁烷-2-甲酰胺.60℃下将在400ml乙腈中的含有50g的3-氟儿茶酚(391mmol)、99.3g的2,3-二溴丙酰胺(430mmol,1.1eq.)和108.1g重质碳酸钾的溶液加热16小时。过滤反应混合物,然后将滤液蒸发至干。得到70.5g淡黄色固体(92%产率;两种区域异构体的1/1混合物)。从热乙醇中连续重结晶得到16.7g纯5-氟-1,4-苯并二噁烷-2-甲酰胺(22%产率)。熔点:167℃。1H NMR(400MHz,CDCl3):6.86-6.71(m,3H,芳香化合物);6.52(宽 s,1H,NH);6.11(宽 s,1H,NH);4.72(dd,J=2.4和7.2Hz,1H,H2);4.62(dd,J=2.4和11.6Hz,1H,H3A);4.23(dd,J=7.2和11.6Hz,1H,H3B).
阶段2:5-氟-1,4-苯并二噁烷-2-甲腈
将13.7ml吡啶(169mmol,2eq.)加到在10ml0℃二噁烷中的16.7g来自步骤1的酰胺悬浮液(84.5mmcl),10分钟后,滴加入13.1ml三氟乙酐(19.5g;93mmol,1.1eq.)。使反应混合物保持冷却1小时,然后在室温下搅拌16小时。将该溶液置于Et2O/lN HCl。用1N NaOH洗涤有机相,在MgSO4上干燥,过滤然后蒸发至于。得到16.8g淡黄色油(定量产率)1H NMR(400MHz,CDCl3):6.90-6.73(m,3H,芳香化合物);5.15(dd,J=3.6和2.4Hz,1H,H2);4.50(dd,J=11.6和3.6Hz,1H,H3A);4.41(dd,J=11.6和2.4Hz,1H,H3B).
阶段3:5-氟-2-溴-1,4-苯并二噁烷-2-甲腈
70℃下将含有6.44g在步骤2中得到的腈(36mmol)、6.40g NBS(36mmol,1eq.),和在200ml的CCl4中的100mg苯甲酰基过氧化物的溶液加热48小时。将混合物冷却至室温。然后过滤反应混合物。用CCl4洗涤该固体并蒸发母液至干。得到9.3g橙黄色油(定量产率)。1H NMR(400MHz,CDCl3):6.93(m,2H,芳香化合物);6.81(m,1H,芳香化合物);4.62(d,J=11.6Hz,1H,H3A);4.48(d,J=11.6Hz,1H,H3B).
阶段4:2-(5-氟-2-甲氧基-1,4-苯并二噁烷-2-基)-2-咪唑啉
室温下将在150ml甲醇中的含有7g 2-溴-5-氟-1,4-苯并二噁烷-2-甲腈(27.1mmol)和220mg甲醇钠(4mmol,0.15eq.)的溶液搅拌3/4小时。然后加入2ml乙二胺(1.79g,29.8mmol,1.1eq.),接着加入11.3ml 3N HCl/IPrOH溶液(34mmol,1.25eq.)。室温下搅拌反应混合物1小时,然后将其置于1N NaOH/CH2Cl2混合物中。在MgSO4上干燥有机相,过滤然后蒸发至干,在二氧化硅上在压力下色谱层析纯粗产物(96/4 CH2Cl2/MeOH)。得到3.9g纯产物(57%产率)。
熔点:134℃。1H NMR(400MHz,CDCl3):6.86-6.74(m,3H,芳香化合物);5.14(宽 s,1H,NH);4.57(d,J=11.2Hz,1H,H3A);4.00(d,J=11.2Hz,1H,H3B);3.75(非常宽的多重峰4H,咪唑啉);3.39(s,3H,OCH3).
通过以下方法得到盐酸盐:将500mg的碱溶于醚,然后加入661ml 3N HCl/iPrOH溶液,滤出形成的固体,用醚洗涤,然后真空干燥,得到480mg的盐。
熔点:>260℃
元素分析:
理论:C(49.40)H(4.89)N(9.70);
实验:C(49.42)H(4.91)N(9.61)。
通过以下方法色谱层析碱形式的外消旋化合物(2g):连续注入500-800mg的量至直径为50mm的Prochrom制备HPLC柱(ChiralpackAD),用85/15/0.001己烷/异丙醇/二乙胺混合物洗脱。流速为100m1/min,依次分离出该实施例的右旋和左旋旋光对映异构体。加入化学计量的用氯化氢气体饱和的乙醇从醚中沉淀出该旋光对映异构体的盐酸盐。
特别地:
(+)对映异构体:
[αD]23°=+90.8°(c=0.58,MeOH)
熔点:从230℃升华
元素分析(C12H13N2O3F,HCl);
理论:C(49.92)H(4.89)N(9.70);
实验:C(49.94)H(4.77)N(9.57)。
(-)对映异构体:
[αD]23°=-93.9°(c=0.43,MeOH)
熔点:从230℃升华
元素分析(C12H13N2O3F,HCl);
理论:C(49.92)H(4.89)N(9.70);
实验:C(49.89)H(4.83)N(9.61)。
将115mg钠溶于200ml乙醇,然后加入8.52g从实施例1的步骤3得到的2-溴-5-氟-1,4-苯并二噁烷-2-甲腈(33mmol),室温下搅拌该混合物3/4小时。然后加入2.43ml乙二胺(2.18g;
36.3mmol;1.1mol.eq.),接着加入13.8ml 3N HCl/iPrOH溶液(41.3mmol,1.25mol.eq.)。室温下搅拌该反应混合物16小时,然后将其置于lN NaOH/CH2Cl2混合物。在MgSO4上干燥该有机相,过滤然后蒸发至干。在二氧化硅上在压力下色谱法纯化粗产物(96/4 CH2Cl2/MeOH)。得到4.17g纯产物(48%产率)。1H NMR(400MHz,CDCl3):6.80(m,3H,芳香化合物);5.14(宽 s,1H,NH);4.53(d,J=11.2Hz,1H,H3A);4.10(d,J=11.2Hz,1H,H3B);3.97-3.45非常宽的多重峰,4H,咪唑啉);3.70(m,2H,OCH2);1.12(t,J=7.2Hz,3H,CH3).
通过手性HPLC(Chiralpack AD柱;96/4/0.1己烷/iPrOH/二乙胺;100ml/分;230nm)分离这两种对映异构体。
通过以下方法得到盐酸盐:将500mg的碱溶于醚,然后加入3NHCl/iPrOH溶液,滤出形成的固体,用醚洗涤,然后真空干燥。
(+)对映异构体:
[αD]24(c=0.380;MeOH)=+80.9°
熔点:>260℃
元素分析(C13H15N2O3F,HCl);
理论:C(51.58)H(5.33)N(9.25);
实验:C(51.24)H(5.36)N(8.94)。
(-)对映异构体:
[αD]24(c=0.380;MeOH)=-77.6°
熔点:>260℃
元素分析(C13H15N2O3F,HCl);
理论:C(51.58)H(5.33)N(9.25);
实验:C(51.80)H(5.39)N(9.02)。
根据上述同样的方法得到以下的化合物。
实施例3:2-(5-氟-2-丙氧基-1,4-苯并二噁烷-2-基)-咪唑啉盐酸盐
1H NMR(400MHz,DMSO d6):11.02(s,2H,NH,HCl);6.99
(m,2H,芳香化合物);6.92(m,1H,芳香化合物);4.63(d,
J=11.5Hz,1H,H3A);4.23(d,J=11.5Hz,1H,H3B);3.99
(s,4H,咪唑啉);3.55(m,2H,OCH2);1.44(m,2H,
OCH2CH2);1.12(t,J=7.2Hz,3H,CH3).
熔点:206℃。
元素分析(C14H17N2O3F,HCl)
理论:C(53.09)H(5.73)N(8.84);
实验:C(52.29)H(5.82)N(8.63)。
1H NMR(400MHz,DMSO d6):10.99(s,2H,NH,HCl);6.99
(m,2H,芳香化合物);6.90(m,1H,芳香化合物);4.59(d,
J=11.6Hz,1H,H3A);4.18((d,J=11.6Hz,1H,H3B);4.08
(m,1H,OCH);3.99(s,4H,咪唑啉);1.18(d,J=6
Hz,3H,CH3);0.96(d,J=6Hz,3H,CH3).
元素分析(C14H17N2O3F,HCl,1/2 H2O)
理论:C(51.55)H(5.82)N(8.30);
实验:C(51.62)H(5.88)N(8.60)。
实施例5:2-(5-氟-2-异丁氧基-1,4-苯并二噁烷-2-基)-咪唑啉盐酸盐
1H NMR(400MHz,DMSO d6):10.79(s,2H,NH,HCl);6.97m,
2H,芳香化合物);6.90(m,1H,芳香化合物);4.61(d,J=11.4
Hz,1H,H3A);4.22(d,J=11.4Hz,1H,H3B);3.97(s,4H,
咪唑啉);3.37(m,2H,OCH2);1.70(m,1H,CH);0.75
(d,J=6.8Hz,3H,CH3);0.65(d,J=6.8Hz,3H,CH3).
熔点:206℃。
元素分析(C15H19N2O3F,HCl,HCl)
理论:C(54.47)H(6.09)N(8.47);
实验:C(53.83)H(6.36)N(8.27)。
实施例6:2-(5-氟-2-环丙基甲氧基-1,4-苯并-二噁烷-2-基)-咪唑啉盐酸盐
1H NMR(400MHz,DMSO d6):10.98(s,2H,NH,HCl);6.99
(m,2H,芳香化合物);6.90(m,1H,芳香化合物);4.61(d,
J=11,5Hz,1H,H3A);4.22(d,J=11,5Hz,1H,H3B);3.98
(s,4H,咪唑啉);3.44(m,2H,OCH2);0.93(m,1H,CH);
0.42(m,2H,环丙基);0.18(m,1H,环丙基);
0.00(m,1H,环丙基).
元素分析(C15H17N2O3F,HCl)
理论:C(54.80)H(5.52)N(8.52);
实验:C(54.09)H(5.23)N(8.33)。
实施例7:2-(5-氟-2-烯丙氧基-1,4-苯并二噁烷-2-基)-咪唑啉盐酸盐 1H NMR(400MHz,DMSO d6):11.10(s,2H,NH,HCl);6.99(m,2H,芳香化合物);6.92(m,1H,芳香化合物);5.78(m,1H,CH=CH2);5.25(d,J=17.2Hz,1H,CH=CH2);5.13(d,J=10.4Hz,1H,CH=CH2)4.68(d,J=11.6Hz,1H,H3A);4.26(d,J=11.6Hz,1H,H3B);4.07(m,2H,OCH2);3.98(s,4H,
咪唑啉).
熔点:214℃。
元素分析(C14H15N2O3F,HCl):
理论:C(53.43)H(5.12)N(8.90);
实验:C(52.86)H(5.23)N(8.81).
实施例8:2-(5-氟-2-苄氧基-1,4-苯并二噁烷-2-基)-咪唑啉盐酸盐 1H NMR(400MHz,DMSO d6):11.15(s,2H,NH,HCl);7.30(m,3H,芳香化合物);7.23(m,2H,芳香化合物);6.99(m,2H,芳香化合物);6.91(m,1H,芳香化合物);4.70(m,3H,H3A和PhCH2);4.29(d,J=11.6Hz,1H,H3B);3.96(s,4H,
咪唑啉).
熔点:218℃。
元素分析(C16H17N2O3F,HCl,H2O):
理论:C(56.48)H(5.27)N(7.32);
实验:C(56.50)H(5.31)N(7.21)。
通过在J.Med.Chem.(1987),30,814中所述的2-(6-氟-2-甲氧基-1,4-苯并二噁烷-2-基)甲醇制备该化合物,然后根据J.Me.d.Chem.(19A3),26,823,或J.Med.Chem.(1985),28,1054,将其转化为咪唑啉。元素分析:(C12H13N2O3F,HCl)。
实施例10:2-(7-氟-2-甲氧基-1,4-苯并二噁烷-2-基)-咪唑啉盐酸盐:
通过在J.Med.Chem.(1987),30,814中所述的2-(7-氟-2-甲氧基-1,4-苯并二噁烷-2-基)甲醇制备该化合物,然后根据J.Me.d.Chem.(19A3),26,823,或J.Med.Chem.(1985),28,1054,将其转化为咪唑啉。元素分析:(C12H13N2O3F,HCl)。
将15.8ml三氟乙酸酐(23.4g,0.11mol)滴加到含有20g在实施例1的步骤1中得到的5/8-氟苯并二噁烷-2-甲酰胺,和16.4ml保持在0℃冰浴上的处在20ml的二噁烷中的吡啶(16,1g,20 0.2mol)的溶液。使反应物保持冷却2小时,然后用Et2O/IN Hcl提取。用醚洗涤酸相3次。在MgSO4上干燥醚相,过滤,然后蒸发至干。得到16.34g粗制混合物,将其不经进一步纯化而再次用于以下步骤。
阶段2:2-溴-8-氟-1,4-苯并二噁烷-2-甲腈:
将含有16.34g 5/6-氟-1,4-苯并二噁烷-2-甲腈(91.3mmol)、17.87g N-溴琥珀酰亚胺(100mmol)和在500ml的四氯化碳中的200mg苯甲酰基过氧化物的溶液回流5天。冷却反应混合物至室温,然后过滤除去琥珀酰亚胺沉淀。蒸发滤液至干得到22.2g含有2-溴-5-氟-1,4-苯并二噁烷-2-甲腈和2-溴-8-氟-1,4-苯并二噁烷-2-甲腈的粗制混合物。在二氧化硅柱上采用闪烁色谱法分离这两种异构体(99.5/0.5石油醚/乙酸乙酯)。得到7g 2-溴-5-氟-1,4-苯并二噁烷-2-甲腈和6.2g期望的2-溴-8-氟-1,4-苯并二噁烷-2-甲腈。
2-溴-8-氟-1,4-苯并二噁烷-2-甲腈:1H NMR(400MHz,CDCl3):7.02(m,1H,芳香化合物);6.83(m,2H,芳香化合物);4.58(d,J=11.6Hz,1H,H3A);4.48(d,J=11.6Hz,1H,H3B).
步骤3:2-(8-氟-2-甲氧基-1,4-苯并二噁烷-2-基)-咪唑啉
室温下将含有1.6g 2-溴-8-氟1,4-苯并二噁烷-2-甲腈(6.2mmol)和在50ml甲醇中的40mg甲醇钠(0.7mmol;0.12mol.eq.)溶液搅拌3/4小时。然后加入0.456ml乙二胺(0.41g;6.8mmol;1.1mol.eq.),接着加入2.3ml 3N HCl/iPrOH溶液(6.8mmol;1.1mol.eq.)。室温下搅拌该反应混合物16小时,然后将其置于1NNaOH/CH2Cl2混合物。在MgSO4上干燥该有机相,过滤,然后蒸发至干。在二氧化硅上在压力下色谱法纯化该粗产物(96/4CH2Cl2/MeOH)。得到0.75g纯产物(48%产率)。1H NMR(400MHz,CDCl3):6.85(m,1H,芳香化合物);6.73(m,2H,芳香化合物);4.57(d,J=11.6Hz,1H,H3A);4.00(d,J=11.6Hz,1H,H3B);3.76(宽的多重峰,4H,
咪唑啉);3.42(s,3H,OCH3).13C NMR(100.03Hz,CDCl3):162.34(C quat.咪唑啉),151.99(d,J=244Hz,C8),14 4.31(C4a),128.90(d,J=14Hz,C8a),121.23(d,J=9Hz,C6),112.51(d,J=3.7Hz,C5),108.79(d,J=18Hz,C7),94.15(C2),67.93(C3),51.58(OCH3),50.5(非常宽的多重峰,CH2咪唑啉).
通过以下方法得到盐酸盐:将碱溶于醚,然后加入3N HCl/iPrOH溶液,滤出形成的固体,用醚洗涤,然后真空干燥。
元素分析:理论上C(49.92)H(4.89)N(9.70);
实验:C(49.63)H(4.93)N(9.54)。
通过手性HPLC(Chiralpack AD柱;90/10/0.1己烷/iPrOH/二乙胺;100ml/分;254nm)分离这两种碱对映异构体。
通过以下方法得到盐酸盐:将碱溶于醚,然后加入3N HCl/iPrOH溶液,滤出形成的固体,用醚洗涤,然后真空干燥。
(+)对映异构体:
[αD]25(c=0.253;MeOH)=+86.2°
熔点=262℃
元素分析(C13H15N2O3F1,HCl);
理论:C(49.92)H(4.89)N(9.70);
实验:C(49.70)H(4.87)N(9.56)。
(-)对映异构体:
[αD]25(c=0.429;MeOH)=-85.8°
熔点=260℃
元素分析(C13H15N2O3F1,HCl);
理论:C(49.92)H(4.89)N(9.70);
实验:C(49.55)H(4.83)N(9.57)。
本发明还涉及式1化合物用于制备药品如α2-肾上腺素能受体拮抗剂的用途,该药品用于或期望用于治疗神经变性疾病及其发展,认识及记忆障碍,和注意力缺乏及警觉性(vigilance)不足,阿耳茨海默氏病,帕金森氏病,杭廷顿氏舞蹈病,肌萎缩性侧索硬化,克罗伊茨费尔特-雅各布综合症,渐进性核上性麻痹,和这些疾病或病症的发展。还涉及大脑性发作、局部缺血性和后局部缺血性大脑病症、抑郁、发作性睡眠和男性性功能障碍,以及与获得性免疫缺陷综合症有关的疾病。最后,还涉及与大脑性发作、局部缺血病症、脑血管的意外事件及其后果有关的病变,和抑郁,发作性睡眠,男性性功能障碍有关的疾病,与获得性免疫缺陷综合症有关的病症,以及这些疾病或病症的发展(evolution)。
Claims (19)
2.权利要求1所要求的式1的化合物,其特征在于基团R为甲基。
3.权利要求1所要求的式1的化合物,其特征在于基团R为乙基。
4.权利要求1所要求的式1的化合物,其特征在于基团R为正丙基。
5.权利要求1所要求的式1的化合物,其特征在于基团R为异丙基。
6.权利要求1所要求的式1的化合物,其特征在于基团R为异丁基。
7.权利要求1所要求的式1的化合物,其特征在于基团R为环丙基甲基。
8.权利要求1所要求的式1的化合物,其特征在于基团R为烯丙基。
9.权利要求1所要求的式1的化合物,其特征在于基团R为苄基。
10.权利要求1-9之一所要求的化合物,其特征在于氟原子在5位。
11.权利要求1所要求的式1的化合物的制备方法,其特征在于将3-氟儿茶酚与2,3-二溴-丙酰胺反应,并结晶所得的5-氟苯并二噁噁烷-2-甲酰胺衍生物,然后将其脱水形成腈,接着用NBS溴化,用醇钠处理形成中间产物亚胺酯,然后用在醇中的乙二胺处理。
12.权利要求1所要求的式1的化合物的制备方法,其特征在于将6-或7-氟-2,3-二氢-苯并[1,4]二氧芑-2-基)甲醇转化成腈,并根据权利要求11的方法处理该腈。
13.权利要求1-10之一的式1的化合物,作为药品。
14.一种药物组合物,其特征在于它包括至少一种权利要求1-10的式1的化合物和适宜的赋形剂。
15.权利要求1-10之一的式1的化合物用于制备作为α2-肾上腺素能受体拮抗剂的药品的用途,该药品用于或期望用于治疗神经变性疾病及其发展。
16.权利要求1-10之一的式1的化合物用于制备作为α2-肾上腺素能受体拮抗剂的药品的用途,该药品用于或期望用于治疗认识及记忆障碍,和注意力缺乏及警觉性不足。
17.权利要求1-10之一的式1的化合物用于制备作为α2-肾上腺素能受体拮抗剂的药品的用途,该药品用于或期望用于治疗阿耳茨海默氏病。
18.权利要求1-10之一的式1的化合物用于制备作为α2-肾上腺素能受体拮抗剂的药品的用途,该药品用于或期望用于治疗帕金森氏病,杭廷顿氏舞蹈病,肌萎缩性侧索硬化,克罗伊茨费尔特-雅各布综合症,渐进性核上性麻痹,和这些疾病或病症的发展。
19.权利要求1-10之一的式1的化合物用于制备作为α2-肾上腺素能受体拮抗剂的药品的用途,该药品用于或期望用于治疗与大脑发作、局部缺血病症、脑血管意外事件及其后果有关的病变,和抑郁,发作性睡眠,男性性功能障碍,与获得性免疫缺陷综合症有关的病症,以及这些疾病或病症的发展。
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FR9908302A FR2795727B1 (fr) | 1999-06-29 | 1999-06-29 | Nouveaux derives benzodioxanne imidazolines fluores, leur preparation et leurs applications en therapeutique |
FR99/08302 | 1999-06-29 |
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CN1361776A true CN1361776A (zh) | 2002-07-31 |
CN1139588C CN1139588C (zh) | 2004-02-25 |
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US (1) | US6610725B1 (zh) |
EP (1) | EP1192152B1 (zh) |
JP (1) | JP4608160B2 (zh) |
CN (1) | CN1139588C (zh) |
AT (1) | ATE228516T1 (zh) |
AU (1) | AU778796B2 (zh) |
BR (1) | BR0012042A (zh) |
CA (1) | CA2377186A1 (zh) |
DE (1) | DE60000880T2 (zh) |
DK (1) | DK1192152T3 (zh) |
ES (1) | ES2186654T3 (zh) |
FR (1) | FR2795727B1 (zh) |
MX (1) | MXPA02000256A (zh) |
PT (1) | PT1192152E (zh) |
WO (1) | WO2001000619A1 (zh) |
ZA (1) | ZA200200009B (zh) |
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CN109415355A (zh) * | 2016-06-29 | 2019-03-01 | 奥赖恩公司 | 苯并二噁烷衍生物及其药物用途 |
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GB0117645D0 (en) * | 2001-07-19 | 2001-09-12 | Isis Innovation | Therapeutic stratergies for prevention and treatment of alzheimers disease |
US8188126B2 (en) | 2002-05-16 | 2012-05-29 | Pierre Fabre Medicament | Imidazolic compounds and use thereof as alpha-2 adrenergic receptors |
JP4604583B2 (ja) * | 2004-07-20 | 2011-01-05 | ダイソー株式会社 | 1−アミド−3−(2−ヒドロキシフェノキシ)−2−プロパノール誘導体、ならびに2−アミドメチル−1,4−ベンゾジオキサン誘導体の製造法 |
US8580776B2 (en) * | 2007-07-10 | 2013-11-12 | The Board Of Trustees Of The University Of Illinois | Compositions and methods for treating neurodegenerating diseases |
US20110165037A1 (en) * | 2010-01-07 | 2011-07-07 | Ismagilov Rustem F | Interfaces that eliminate non-specific adsorption, and introduce specific interactions |
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PH16249A (en) * | 1980-02-04 | 1983-08-16 | Reckitt & Colmann Prod Ltd | Imidazoline derivatives,its pharmaceutical composition and method of use |
NZ203680A (en) * | 1982-04-17 | 1985-08-16 | Reckitt & Colmann Prod Ltd | Imidazolines and pharmaceutical compositions |
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1999
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2000
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- 2000-06-29 BR BR0012042-1A patent/BR0012042A/pt not_active Application Discontinuation
- 2000-06-29 PT PT00949575T patent/PT1192152E/pt unknown
- 2000-06-29 EP EP00949575A patent/EP1192152B1/fr not_active Expired - Lifetime
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- 2000-06-29 AT AT00949575T patent/ATE228516T1/de not_active IP Right Cessation
- 2000-06-29 AU AU62890/00A patent/AU778796B2/en not_active Ceased
- 2000-06-29 DK DK00949575T patent/DK1192152T3/da active
- 2000-06-29 US US10/019,614 patent/US6610725B1/en not_active Expired - Lifetime
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- 2000-06-29 WO PCT/FR2000/001825 patent/WO2001000619A1/fr active IP Right Grant
- 2000-06-29 CN CNB008106223A patent/CN1139588C/zh not_active Expired - Fee Related
- 2000-06-29 DE DE60000880T patent/DE60000880T2/de not_active Expired - Lifetime
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CN109415355A (zh) * | 2016-06-29 | 2019-03-01 | 奥赖恩公司 | 苯并二噁烷衍生物及其药物用途 |
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WO2001000619A1 (fr) | 2001-01-04 |
EP1192152B1 (fr) | 2002-11-27 |
MXPA02000256A (es) | 2002-06-21 |
ZA200200009B (en) | 2002-09-25 |
EP1192152A1 (fr) | 2002-04-03 |
PT1192152E (pt) | 2003-04-30 |
JP2003503406A (ja) | 2003-01-28 |
ES2186654T3 (es) | 2003-05-16 |
US6610725B1 (en) | 2003-08-26 |
BR0012042A (pt) | 2002-07-09 |
CA2377186A1 (fr) | 2001-01-04 |
FR2795727B1 (fr) | 2001-09-21 |
DE60000880T2 (de) | 2003-08-28 |
AU6289000A (en) | 2001-01-31 |
JP4608160B2 (ja) | 2011-01-05 |
DK1192152T3 (da) | 2003-03-17 |
FR2795727A1 (fr) | 2001-01-05 |
DE60000880D1 (de) | 2003-01-09 |
AU778796B2 (en) | 2004-12-23 |
ATE228516T1 (de) | 2002-12-15 |
CN1139588C (zh) | 2004-02-25 |
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