CN1169721A - 吡啶衍生物 - Google Patents
吡啶衍生物 Download PDFInfo
- Publication number
- CN1169721A CN1169721A CN95196484A CN95196484A CN1169721A CN 1169721 A CN1169721 A CN 1169721A CN 95196484 A CN95196484 A CN 95196484A CN 95196484 A CN95196484 A CN 95196484A CN 1169721 A CN1169721 A CN 1169721A
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- China
- Prior art keywords
- formula
- salt
- compound
- pyridine derivate
- phenyl
- Prior art date
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- 150000003222 pyridines Chemical class 0.000 title 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 70
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 35
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 125000000524 functional group Chemical group 0.000 claims abstract description 10
- 239000000203 mixture Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 7
- 230000004770 neurodegeneration Effects 0.000 claims description 7
- 230000006872 improvement Effects 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 208000015122 neurodegenerative disease Diseases 0.000 claims 6
- 239000000470 constituent Substances 0.000 claims 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 18
- 230000000694 effects Effects 0.000 abstract description 15
- 206010008118 cerebral infarction Diseases 0.000 abstract description 9
- 201000006474 Brain Ischemia Diseases 0.000 abstract description 6
- 208000028389 Nerve injury Diseases 0.000 abstract description 6
- 230000008764 nerve damage Effects 0.000 abstract description 6
- 206010008120 Cerebral ischaemia Diseases 0.000 abstract description 5
- 208000024891 symptom Diseases 0.000 abstract description 5
- 208000026106 cerebrovascular disease Diseases 0.000 abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 4
- 210000000578 peripheral nerve Anatomy 0.000 abstract description 4
- 208000024827 Alzheimer disease Diseases 0.000 abstract description 3
- 206010036631 Presenile dementia Diseases 0.000 abstract description 3
- 210000005036 nerve Anatomy 0.000 abstract description 3
- 230000001537 neural effect Effects 0.000 abstract description 3
- 208000000044 Amnesia Diseases 0.000 abstract description 2
- 208000031091 Amnestic disease Diseases 0.000 abstract description 2
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- 206010044688 Trisomy 21 Diseases 0.000 abstract description 2
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- 230000004054 inflammatory process Effects 0.000 abstract 1
- 230000008733 trauma Effects 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 62
- 238000012360 testing method Methods 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 14
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- 239000000523 sample Substances 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 241000700159 Rattus Species 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
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- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 7
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- 238000006243 chemical reaction Methods 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 6
- UDSRUCAJZSIRHZ-UHFFFAOYSA-N benzamide dihydrochloride Chemical compound Cl.Cl.NC(=O)C1=CC=CC=C1.NC(=O)C1=CC=CC=C1 UDSRUCAJZSIRHZ-UHFFFAOYSA-N 0.000 description 6
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- DSFVQIUBODXRLL-UHFFFAOYSA-N acetamide;dihydrochloride Chemical compound Cl.Cl.CC(N)=O DSFVQIUBODXRLL-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
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- 125000004494 ethyl ester group Chemical group 0.000 description 5
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
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- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000010998 test method Methods 0.000 description 4
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 3
- 239000005695 Ammonium acetate Substances 0.000 description 3
- GIDSVRNZXHHKSU-UHFFFAOYSA-N CC(NC(C=C1)=CC=C1C1=NC(C2=CC=CC=C2)=CC(C2=CC=C(CN)C=C2)=C1)=O Chemical compound CC(NC(C=C1)=CC=C1C1=NC(C2=CC=CC=C2)=CC(C2=CC=C(CN)C=C2)=C1)=O GIDSVRNZXHHKSU-UHFFFAOYSA-N 0.000 description 3
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- 239000003513 alkali Substances 0.000 description 3
- 229940043376 ammonium acetate Drugs 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
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- BMUDPLZKKRQECS-UHFFFAOYSA-K 3-[18-(2-carboxyethyl)-8,13-bis(ethenyl)-3,7,12,17-tetramethylporphyrin-21,24-diid-2-yl]propanoic acid iron(3+) hydroxide Chemical compound [OH-].[Fe+3].[N-]1C2=C(C)C(CCC(O)=O)=C1C=C([N-]1)C(CCC(O)=O)=C(C)C1=CC(C(C)=C1C=C)=NC1=CC(C(C)=C1C=C)=NC1=C2 BMUDPLZKKRQECS-UHFFFAOYSA-K 0.000 description 2
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- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 2
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
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- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
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- C07D213/56—Amides
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Abstract
右式所代表的吡啶衍生物或它的盐[式中R1代表Ⅰ式中任一个所表示的官能团,R2代表氢原子、氨基或Ⅱ式中任一个所表示的官能团],可在体内直接或间接地作用于神经细胞,表现出改善和治疗因神经变性引起的神经损伤的效果,例如,可以用作外伤性、醇和抗癌剂等的药剂性、炎症性、糖尿病等病症中见到的代谢性、以及用特发性末梢性神经变性而引起的病症的改善和治疗剂。另外也可以用作因中枢性神经变性而引发的症状和疾病的改善和治疗剂,例如用作阿尔茨海默型早老性和脑血管性疾呆、唐氏综合症、帕金森病、享廷顿氏舞蹈病、脑缺血和脑梗塞以及脑出血和头部外伤等的后遗症、健忘症、脊髓性神经麻痹症等病的改善和治疗剂。
Description
本发明涉及具有神经营养因子作用的吡啶衍生物和它的盐。
近年来不断增加的阿尔茨海默型早老性痴呆症显示出作为大脑基底核神经细胞的乙酰胆碱能的神经原的变性、脱落与记忆障碍、智力活动低下有密切的关系[“Witehorse Science”、第215卷、第1237页(1982)]。有报告说NGF不仅抑制因纤维中断引起的中枢性乙酰胆碱能的神经原的变性、脱落[Korsing等人著、“Neccroscience Lett”、第66卷、第175页(1986年)]和改善老龄大鼠迷路学习障碍，而且抑制乙酰胆碱能的神经细胞的萎缩[茂野卓等人著、“医学进展”、第145卷、第579页(1986)]。这些工作表明NGF有可能成为阿尔茨海默型早老性痴呆的治疗药。同时已证实NGF也可防止脑缺血大鼠的海马神经细胞的死亡，所以可认为NGF作为脑中风后遗症治疗药也是很有用的。
另外NGF具有加速末梢神经损伤恢复的作用，很清楚它也可用作末稍神经损伤的治疗药。除了NGF之外还发现了很多显示出维持细胞生存和功能作用或变性修复活性的生物体成分，称之为神经营养因子。人们认为，这些神经营养因子作为伴随细胞变性而引起的中枢性神经损伤和末稍神经损伤的治疗药是很有用的。蛋白质用作中枢神经损伤治疗药时，从其物理特性判断，必需直接向脑室内给药，在实用中问题很多。
因此，人们期待着更简单的给药方法以及具有神经营养因子作用的低分子化合物的治疗药。本发明的目的就在于提供具有神经营养因子作用的新的化合物。
本发明人为达到上述目的，对很多化合物进行了各种研究，结果发现了某种吡啶衍生物是具有神经营养因子作用的化合物，完成了本发明。
即，本发明是式(I)表示的吡啶衍生物或它的盐，[式中，R1代表用式(II)-1～(II)-6中任一个表示的官能团]-CONHCH2CH2N(CH3)2 (II)-1-CONHCH2CH2CH2N(CH3)2 (II)-2-COOCH2CH2N(CH3)2 (II)-3-COOCH2CH2N(CH2CH3)2 (II)-4-NHCOCH2N(CH3)2 (II)-5-NHCOCH2N(CH2CH3)2 (II)-6以及式(III)表示的吡啶衍生物或它的盐，(式中R2代表氨基或式(IV)-1～(IV)-5中任一个表示的官能团]。-CONHCH2CH2N(CH3)2 (IV)-1
-COOCH2CH2N(CH3)2 (IV)-3-NHCOCH2N(CH3)2 (IV)-4-NHCOCH2N(CH2CH3)2 (IV)-5本发明中，所说的吡啶衍生物的盐是指药理学上容许的吡啶衍生物，例如是与盐酸、硫酸、磷酸、硝酸等无机酸形成的盐，或是与柠檬酸、琥珀酸、酒石酸、甲磺酸等有机酸形成的盐。
本发明的化合物例如可以按以下所示方法制造。
即，首先通过使式(V)[式中，R3代表甲基、羧基、或乙酰胺基]所示的化合物与式(VI)
[式中，R4代表氢原子、羧基、或乙酰胺基]表示的化合物于碱存在条件下缩合可得到式[VII]
[式中R3，R4与上述相同]表示的化合物。
缩合反应中使用的碱有氢氧化钾、氢氧化钠、甲醇钠、叔丁醇钾、碳酸钾、碳酸钠、碳酸氢钠、碳酸氢钾等，反应溶剂可单独使用甲醇、乙醇、正丙醇、异丙醇、叔丁醇，或加水后再用。反应温度可在0℃至使用的溶剂的沸点之间选择合适的温度。
接下来通过使式(VII)化合物与式(VIII)代表的化合物于乙酸铵存在下进行反应可得到式(IX)
[式中，R3，R4与上述相同]代表的化合物。这里使用的乙酸铵是式(VII)化合物的1-10倍的摩尔量，反应溶剂可使用甲醇、乙醇、正丙醇、异丙醇、叔丁醇、乙酸等。反应温度可在室温至使用溶剂沸点之间选择合适的温度。
1)式(I)中R1是式(II)-1～(II)-4中任一式表示的官能团的化合物以及式(III)中R2为式(IV)-1～(IV)-3中任一式表示的官能团的化合物可如下制造。即首先使卤化剂作用于用上述方法得到的式(X)
[式中R3为羧基时，R4代表氢原子；R3为甲基时，R4代表羧基]表示的吡啶衍生物，形成酰基卤化物，再使相应的胺或醇与该卤化物反应，就可得到上述化合物。这里提到的卤化剂例如可以用亚硫酰二氯、五氯化磷、磷酰氯、草酰氯、亚硫酰二溴、三溴化磷等。
2)式(I)中R1为式(II)-5和(III)-6中任一式表示的官能团的化合物以及式(III)中R2为氨基或式(IV)-4或(IV)-5任一个表示的官能团的化合物可如下制造。即，首先将用上述方法得到的式(XI)[式中，R3为乙酰胺基时，R4代表氢原子；R3为甲基时，R4代表乙酰胺基]表示的吡啶衍生物的乙酰胺基在酸或碱存在下水解，得到带有胺基的化合物，然后使它与氯代乙酰氯反应，进行酰胺化，再与相应的胺反应就可得到本发明化合物。
附图的简单说明。
图1表示化合物14和对照检测样品1对大鼠中大脑动脉闭塞模型的脑梗塞病灶面积的作用。
实施本发明的最好状态
本发明的吡啶衍生物可经口或不经过口给药。给药量因药物不同而各有不同，对成人来说，每天1～1000mg比较合适。
经口给药时，首先使药物与赋形剂、崩解剂、粘合剂、润滑剂、抗氧化剂、包衣剂、着色剂、矫味矫臭剂、表面活性剂、增塑剂等混合，以颗粒、散剂、胶囊、片剂形式给药，非经口给药时以注射液、输液剂或栓剂形式给药。制备上述制剂时，可使用通常的制剂方法。
实施例
以下，举些实施例、参考例更详细地说明本发明。
表1，2给出了本实施例的吡啶衍生物的结构式。表1表2
参考例1
(E)-3-(4-羧苯基)-1-苯基-2-丙烯-1-酮
向乙酰苯8.00g、对苯二甲醛10.00g和40ml乙醇的混合物中于0℃搅拌下滴加4.10g氢氧化钾溶于50ml水的溶液，然后再在0～10℃下搅拌6小时。
反应结束后加入3N的盐酸，使溶液成酸性，过滤生成物。用乙醇重结晶，得到11.93g标题化合物。
用与乙酰苯相当的醛，通过与上述实质上同样的操作，可得到以下化合物。
(E)-3-(3-羧苯基)-1-苯基-2-丙烯-1-酮
(E)-1-(3-羧苯基)-3-(4-甲基苯基)-2-丙烯-1-酮
(E)-1-(4-羧苯基)-3-(4-甲基苯基)-2-丙烯-1-酮
(E)-3-(4-乙酰胺基苯基)-1-苯基-2-丙烯-1-酮
(E)-1-(3-乙酰胺基苯基)-3-(4-甲基苯基)-2-丙烯-1-酮
(E)-1-(4-乙酰胺基苯基)-3-(4-甲基苯基)-2-丙烯-1-酮
参考例2
4-(4-羧苯基)-2，6-二苯基吡啶
向参考例1得到的5.00g(E)-3-(4-羧苯基)-1-苯基-2-丙烯-1-酮、5.51g苯酰溴化吡啶鎓和7.63g乙酸铵中加入40ml甲醇，回流12小时。冷却后，过滤生成物，通过乙醇重结晶可得到标题化合物3.90g。
使用相当的α，β-不饱和酮替代(E)-3-(4-羧苯基)-1-苯基-2-丙烯-1-酮进行实质上与上述同样的操作，得到如下化合物。
4-(3-羧苯基)-2，6-二苯基吡啶
2-(3-羧苯基)-4-(4-甲基苯基)-6-苯基吡啶
2-(4-羧苯基)-4-(4-甲基苯基)-6-苯基吡啶
4-(4-乙酰胺基苯基)-2，6-二苯基吡啶
2-(3-乙酰胺基苯基)-4-(4-甲基苯基)-6-苯基吡啶
2-(4-乙酰胺基苯基)-4-(4-甲基苯基)-6-苯基吡啶
参考例3
4-(4-氨基苯基)-2，6-二苯基吡啶
参照参考例2，向得到的4-(4-乙酰胺苯基)-2，6-二苯基吡啶1.50g中加入1.50g氢氧化钠、100ml乙醇和10ml水，回流46小时。冷却后，加100ml水，过滤生成物，用乙醇重结晶，得到1.17g标题化合物。
实施例1
N-[2-(二甲胺基)乙基]-4-(2，6-二苯基-4-吡啶基)苯甲酰胺(化合物5)。
将参考例2得到的4-(4-羧苯基)-2，6-二苯基吡啶1.00g溶解于50ml甲苯，加入0.62ml亚硫酰氯，回流2小时。减压蒸馏除去甲苯和过量的亚硫酰氯，得到酰氯，然后再加入50ml氯仿，冰冷搅拌下，滴入含有0.34ml N，N-二甲基乙二胺的10ml氯仿溶液，然后再于室温下搅拌30分钟。
依次用饱和碳酸氢钠水溶液、水、饱和食盐水洗涤该反应液，用无水硫酸钠干燥。减压蒸馏除去溶剂，残余物用乙酸乙酯-己烷重结晶。得到标题化合物0.65g。
m.p.143.5～144.0℃
用相当的带有羧基的吡啶衍生物和胺替代4-(4-羧苯基)-2，6-二苯基吡啶和N，N-二甲基乙二胺，进行实质上与上述同样的操作，得到以下化合物。
N-[2-(二甲胺基)乙基]-3-(2，6-二苯基-4-吡啶基)苯甲酰胺(化合物1)
m.p.162.5～164.5℃
N-[3-(二甲胺基)丙基]-3-(2，6-二苯基-4-吡啶基)苯甲酰胺(化合物3)
m.p.143.0～145.0℃
N-[3-(二甲胺基)丙基]-4-(2，6-二苯基-4-吡啶基)苯甲酰胺(化合物7)
m.p.100.0～102.0℃
N-[2-(二甲胺基)乙基]-4-[4-甲基苯基]-6-苯基-2-吡啶基)苯甲酰胺(化合物17)
m.p.149.7～150.6℃
4-(4-甲基苯基)-2-[4-(4-甲基哌嗪-1-基羰基)苯基]-6-苯基吡啶(化合物19)
m.p.133.0～134.5℃
实施例2
4-(2，6-二苯基-4-吡啶基)苯甲酸2-(二甲胺基)乙酯(化合物9)
将参考例2得到的4-(4-羧苯基)-2，6-二苯基吡啶0.60g溶解于50ml甲苯，加入亚硫酰氯0.37ml回流5小时。减压蒸馏除去甲苯和过量的亚硫酰氯得到酰氯。向其中加入20ml氯仿，冰冷搅拌下滴入含有0.19ml N，N-二甲基乙醇胺的氯仿5ml，然后于室温下搅拌17小时，依次用饱和碳酸氢钠水溶液、水、饱和食盐水洗涤该反应液，最后用无水硫酸钠干燥。减压蒸馏除去溶剂，残余物用柱色谱法(展开溶剂；二氯甲烷∶甲醇＝20∶1)纯化，得到标题化合物0.41g。
m.p.104.7～105.7℃
用带有相应羧基的吡啶衍生物和N，N-二烷基乙醇胺代替4-(4-羧苯基)-2，6-二苯基吡啶和N，N-二甲基乙醇胺进行实质上与上述同样的操作，得到以下化合物。
4-(2，6-二苯基-4-吡啶基)苯甲酸2-(二乙胺基)乙酯(化合物11)
m.p.207.00～209.0℃(分解)
4-[4-(4-甲基苯基)-6-苯基-2-吡啶基]苯甲酸2-(二甲胺基)乙酯(化合物21)
m.p.117.2～118.8℃
实施例3
2-(4-氨基苯基)-4-(4-甲基苯基)-6-苯基吡啶(化合物28)
参照参考例2，向得到的2-(4-乙酰胺基苯基)-4-(4-甲基苯基)-6-苯基吡啶3.05g中加入3N盐酸70ml，回流2小时。冷却后加入10％氢氧化钠水溶液使其成碱性，用乙酸乙酯萃取，再依次用水、饱和食盐水洗涤后，用无水硫酸钠干燥。减压蒸馏除去溶剂，残余物用乙酸乙酯-正己烷重结晶，得到2.26g标题化合物。
m.p.137.0～139.0℃
用相应的带有乙酰胺基的吡啶衍生物替代2-(4-乙酰胺基苯基)-4-(4-甲基苯基)-6-苯基吡啶进行实质上与上述同样的操作，得到以下的化合物。
2-(3-氨基苯基)-4-(4-甲基苯基)-6-苯基吡啶(化合物23)
m.p.132.5～134.0℃
实施例4
2-二甲胺基-N-[4-(2，6-二苯基-4-吡啶基)苯基]乙酰胺(化合物13)
(1)向参考例3中得到的4-(4-氨基苯基)-2，6-二苯基吡啶1.30g中加入氯仿50ml，冰冷搅拌下滴入含有0.32ml的氯代乙酰氯的10ml氯仿，于室温下搅拌1小时。将反应液依次用饱和碳酸氢钠水溶液、水、饱和食盐水洗涤，然后用无水硫酸钠干燥。减压蒸馏除去溶剂，剩余物用乙酸乙酯-正-己烷重结晶，得到1.33g 2-氯-N-[4-(2，6-二苯基-4-吡啶基)苯基]乙酰胺。
m.p.214.5～215.2℃
(2)将上述得到的2-氯-N-[4-(2，6-二苯基-4-吡啶基)苯基]乙酰胺0.87g溶解于50ml甲醇中，加入2.24ml 50％二甲胺水溶液，回流7小时。减压蒸馏除去溶剂，残余物中加入饱和碳酸氢钠水溶液，用乙酸乙酯萃取。依次用水、饱和食盐水洗涤后，再用无水硫酸钠干燥。减压蒸馏除去溶剂，残余物用乙酸乙酯-正-己烷重结晶，得到0.81g标题化合物。
m.p.173.5～174.9℃
用带有相应氨基的吡啶衍生物和胺替代4-(4-氨基苯基)-2，6-二苯基吡啶和二甲胺，进行实质上与上述同样的操作，得到以下化合物。
2-二甲胺基-N-[[3-[4-(4-甲基苯基)-6-苯基-2-吡啶基]苯基]乙酰胺(化合物24)
m.p.118.0～120.0℃
2-二甲胺基-N-[[4-[4-(4-甲基苯基)-6-苯基-2-吡啶基]苯基]乙酰胺(化合物29)
m.p.130.8～132.8
2-二乙胺基-N-[4-(2，6-二苯基-4-吡啶基)苯基]乙酰胺(化合物15)
1H NMR(CDCl3)δ(ppm)；1.13(6H，t，J＝7.1Hz)、2.69(4H，quart.，J＝7.2Hz)、3.20(2H，s)、7.41～7.57(6H，m)、7.76(4H，s)、7.88(2H，s)、8.17～8.23(4H，m)、9.57(1H，br.s)。
MS(EI)435(M+)
2-二乙胺基-N-[[3-[4-(4-甲基苯基)-6-苯基-2-吡啶基]苯基]乙酰胺(化合物26)
1H NMR(CDCl3)δ(ppm)；1.13(6H，t，J＝7.1Hz)、2.45(3H，s)、2.69(4H，quart.，J＝7.2Hz)、3.20(2H，s)、7.32～8.30(15H，m)、9.53(1H，br.s)
MS(CI)450(M+1)
实施例5
N-[2-(二甲胺基)乙基]-4-(2，6-二苯基-4-吡啶基)苯甲酰胺二盐酸盐(化合物6)
向实施例1得到的N-[2-(二甲胺基)乙基]-4-(2，6-二苯基-4-吡啶基)苯甲酰胺0.50g、乙酸乙酯30ml的混合物中搅拌下加入4N盐酸-乙酸乙酯溶液1.50ml，室温下搅拌10分钟，经过滤得到结晶，获得标题化合物0.46g。
m.p.250.0～251.5℃(分解)
用相应的吡啶衍生物代替N-[2-(二甲胺基)乙基]-4-(2，6-二苯基-4-吡啶基)苯甲酰胺，进行实质上与上述同样操作，获得如下化合物。
N-[2-(二甲胺基)乙基]-3-(2，6-二苯基-4-吡啶基)苯甲酰胺二盐酸盐(化合物2)
m.p.135.0～137.0℃
N-[3-(二甲胺基)丙基]-3-(2，6-二苯基-4-吡啶基)苯甲酰胺二盐酸盐(化合物4)
m.p.119.0～121.0℃
N-[3-(二甲胺基)丙基]-4-(2，6-二苯基-4-吡啶基)苯甲酰胺二盐酸盐(化合物8)
m.p.242.0～244.0℃
4-(2，6-二苯基-4-吡啶基)苯甲酸2-(二甲胺基)乙酯二盐酸盐(化合物10)
m.p.203.0～205.0℃
4-(2，6-二苯基-4-吡啶基)苯甲酸2-(二乙胺基)乙酯二盐酸盐(化合物12)
m.p.204.0～206.0℃
2-二甲胺基-N-[4-(2，6-二苯基-4-吡啶基)苯基]乙酰胺二盐酸盐(化合物14)
m.p.232.0～234.0℃MS(EI)；407(M+-2HCl)1HNMR(DMSO-d6)δ(ppm)；2.91(6H，d，J＝3.5Hz)、4.25(2H，d，J＝3.9Hz)、7.45～7.62(6H，m)、7.86(2H，d，J＝8.8Hz)、8.12(2H，d，J＝8.6Hz)、8.21(2H，s)、8.33(4H，dd，J＝8.0，1.5Hz)1013(1H，brs)、11.25(1H，s)
2-二乙胺基-N-[4-(2，6-二苯基-4-吡啶基)苯基]乙酰胺二盐酸盐(化合物16)
m.p.236.0～238.0℃
N-[2-(二甲胺基)乙基]-4-[4-(4-甲基苯基)-6-苯基-2-吡啶基]苯甲酰胺二盐酸盐(化合物18)
m.p.221.0～223.0℃
4-(4-甲基苯基)-2-[4-(4-甲基哌嗪-1-基羰基)苯基]-6-苯基吡啶二盐酸盐(化合物20)
m.p.167.0～169.0℃
4-[4-甲基苯基)-6-苯基-2-吡啶基]苯甲酸2-(二甲胺基)-乙酯盐酸盐(化合物22)
m.p.106.0～108.0℃
2-二甲胺基-N-[[3-[4-(4-甲基苯基)-6-苯基-2-吡啶基]苯基]乙酰胺二盐酸盐(化合物25)
m.p.143.0～145.0℃
2-二乙胺基-N-[[3-[4-(4-甲基苯基)-6-苯基-2-吡啶基]苯基]乙酰胺二盐酸盐(化合物27)
m.p.123.0～125.0℃
2-二甲胺基-N-[[4-[4-(4-甲基苯基)-6-苯基-2-吡啶基]苯基]乙酰胺二盐酸盐(化合物30)
m.p.257.0～259.0℃
产业上利用的可能性
NGF担负着某种神经细胞的生存和功能维持，具有变性修复和保护作用。本发明的吡啶衍生物显示出培养的大脑皮质神经细胞的生存延长活性。因此，本发明的吡啶衍生物在体内直接或间接地作用于神经细胞，人们期待它表现出由于神经变性而引起的神经损伤的改善和治疗效果。例如，它可用作外伤性的、醇或抗癌剂等的药剂性的、炎症性的、糖尿病中出现的代谢性的以及因特发性末稍神经变性而引起的病症的改善和治疗剂。
另外也可用作因中枢神经变性引起的病症，例如阿尔茨海默型早老性和脑血管性痴呆、唐氏综合症、帕金森病、亨廷顿氏舞蹈病、脑缺血和脑梗塞以及脑出血和头部外伤等的后遗症、健忘症、脊髓性神经麻痹症等病的改善和治疗剂。
试验例1[神经营养因子作用试验]
神经营养因子作用用以下方法评价。
(检测样品)
将表1、2中给出的各个化合物溶解于DMSO，浓度配成2mg/ml～10mg/ml。
(试验细胞)
来自于胎生18天的大鼠皮质的神经细胞
(试验方法)
将含有20％胎牛血清的ダルベツコ的最小必需量的培养基(ギグコ社制)和HamF-12培养基(ギグコ社制)等量混合配成DF培养基，然后将试验细胞用该DF培养基调成3.2×106细胞/ml，再以0.5ml/每孔的量加到涂布了聚乙烯亚胺的24孔板中(每个培养孔的面积为2cm2，コ-ニング社制)，于37℃，5％CO2中培养。24小时后，除去培养基，再向每孔中加入含有各种浓度的检测样品、5μg/ml铁转移蛋白、5μg/ml胰岛素20pmole/ml孕酮的无血清的上述DF培养基0.5ml。其中，本发明化合物溶解于DMSO，添加后其终浓度如下述表3所示的各种浓度。另外，作为对照，也制备了只添加DMSO的培养基。这一实验过程作了2块相同培养板实验，上述细胞于各种培养基培养72小时后，对其中一块板通过N2-O2-CO2培养箱(クバィ社制，BNP-100型)，将氧浓度降至最低设定浓度的1％，实施4小时低氧负荷培养。而另一块板不加负荷，仍于5％CO2、95％空气的条件下直接培养。再培养48小时后定量测定活细胞数目。除去培养基，使Fluorescien Diacetate(FDA)试剂作用，然后用磷酸缓冲液(pH7.4)洗涤后，测定荧光强度(Ex485/Em530)(ミリポァ社制，Cyto FlourTM2300)。
本发明化合物的神经营养因子活性以对照(添加DMSO)的荧光强度为1.0时的比值表示。
结果如表3所示。表3
| 检测样品 浓度 神经营养因子活性低氧负荷 无负荷 |
| 对照(DMSO) 1.0 1.0化合物 2 2μg/ml 3.3 3.510μg/ml 1.2 1.2化合物 4 2μg/ml 1.7 2.1化合物 6 2μg/ml 3.3 3.510μg/ml 1.1 1.2化合物 8 2μg/ml 2.7 2.410μg/ml 1.2 1.2化合物 10 2μg/ml 3.6 4.6化合物 12 2μg/ml 3.2 3.3化合物 14 2μg/ml 4.3 4.0化合物 16 2μg/ml 3.7 3.5化合物 18 2μg/ml 3.9 3.9化合物 20 2μg/ml 3.9 4.3化合物 22 2μg/ml 4.2 4.2化合物 23 2μg/ml 8.1 8.010μg/ml 9.7 9.4化合物 25 2μg/ml 6.0 5.5化合物 27 2μg/ml 3.2 3.410μg/ml 2.8 2.5化合物 28 2μg/ml 6.6 6.010μg/ml 2.9 2.9化合物 30 2μg/ml 4.6 4.7 |
试验例2[对大鼠脑缺血引起的迟发性神经细胞坏死的作用试验]
利用闭塞大鼠两侧总颈动脉模型来评价对脑缺血引起的神经细胞障碍的抑制作用。
(实验动物)
使用体重60-90g雄性大鼠(新日本动物、琦玉、日本)
(试验方法)
大鼠用乙醚轻度麻醉，固定。用刮多卡因局部浸润麻醉后，切开颈部正中线，露出两侧总颈动脉，加倍小心将它与旁边的迷走神经剥离开。用小的动脉瘤夹使动脉阻断3分钟，然后卸掉夹子，将皮肤缝好。假性手术组除了不闭塞两侧总颈动脉之外其它处置都一样。3分钟脑缺血7天后，用乙醚麻醉动物，然后再用10％福尔马林缓冲液从左心室灌流脑。
从海马区切出3-4mm厚的冠状切片，石蜡包埋后作成切片，切片用苏木精和曙红染色。缺血性细胞损伤分为0～3的4个阶段评价。
0(-)：正常神经细胞、1(+)：数个神经细胞损伤(1个或数个神经细胞的损伤)、2(+，+)：多个神经细胞损伤、3(+ ++)：几乎所有神经细胞损伤。
(控制样品)
检测样品溶于水后，于缺血结束后立刻按10mg/kg将样品注入腹腔内。
(结果)
假性手术组大鼠海马CA1神经细胞都未受到损伤，但3分钟两侧总颈动脉模型中，通过光学显微镜观察，清楚地看到海马CA1神经细胞受到了损伤。
然而，通过将本发明化合物注入腹腔内可以抑制海马CA1神经细胞的崩溃和消失。结果如表4所示。表4
| 检测样品 给药量 例数 神经损伤出现的频率(％)(mg/kg) - + ++ +++ |
| 假性手术组 - 8 100 0 0 0 |
| 3分钟缺血组 - 8 0 0 0 100化合物14 10 8 0 50 25 25 |
试验例3[对大鼠中大脑动脉闭塞模型的脑梗塞病灶面积的作用]
(检测样品)
使用化合物14和对照检测样品1[WO94/14440记载的化合物6，4′-(4-甲基苯基)-2，2′：6′，2′-三联吡啶＝三盐酸盐]
对照检测样品1的结构式
(试验方法)
使SHRSP大鼠(雄性、12-20周龄)吸入氟烷麻醉，将其体温保持在37℃左右。侧卧位固定，切开硬膜，于鼻裂(rhinal fissure)的0.7～1mm背侧对中大脑动脉干进行电凝固、切断。同时连接灌注泵(infusion pump)，分别将被检验化合物以10mg/kg/h由尾静脉连续注入4小时。设定作为对照组的溶剂组。手术7天后于10％福尔马林溶液中固定，摘出脑，纵行连续切片。脑切片用苏木精和曙红染色后，通过梗塞病灶的图像解析装置求出面积，算出相对于全脑面积的梗塞比率。
(结果)
就象图1所示那样，对照检测样品1中看不到梗塞病灶缩小作用，而化合物14相对于对照组表现出用量依赖性的明显的梗塞缩小作用。
试验例4[观察给与被检验化合物时的症状]
(试验方法)
将对照检测样品1、化合物14分别以10，40mg/kg的量静脉内注射到与试验例3同系的大鼠体内，观察当时表现出的症状。
(结果)
对照检测样品1的两种用量都呈现出镇静症状，但对于化合物14没看到什么症状变化。
Claims (12)
1.由式(I)表示的吡啶衍生物或它的盐
[式I中R1代表式(II)-1～(II)-6中任一个表示的官能团]-CONHCH2CH2N(CH3)2 (II)-1-CONHCH2CH2CH2N(CH3)2 (II)-2-COOCH2CH2N(CH3)2 (II)-3-COOCH2CH2N(CH2CH3)2 (II)-4-NHCOCH2N(CH3)2 (II)-5-NHCOCH2N(CH2CH3)2 (II)-6
2.由式(III)表示的吡啶衍生物或它的盐，
[式III中R2代表氨基或式(IV)-1～(IV)-5中任一个表示的官能团]-CONHCH2CH2N(CH3)2 (IV)-1
-COOCH2CH2N(CH3)2 (IV)-3-NHCOCH2N(CH3)2 (IV)-4-NHCOCH2N(CH2CH3)2 (IV)-5
3.含有权利要求1记载的吡啶衍生物或它的盐作为有效成分的医药组合物。
4.含有权利要求2记载的吡啶衍生物或它的盐作为有效成分的医药组合物。
5.用于改善或治疗神经变性疾病的权利要求1记载的医药组合物。
6.用于改善或治疗神经变性疾病的权利要求2记载的医药组合物。
7.权利要求1记载的吡啶衍生物或它的盐，作为医药组合物的有效成分使用。
8.权利要求2记载的吡啶衍生物或它的盐，作为医药组合物的有效成分使用。
9.权利要求1记载的吡啶衍生物或它的盐，用于制造改善或治疗神经变性疾病用的医药组合物。
10.权利要求2记载的吡啶衍生物或它的盐，用于制造改善或治疗神经变性疾病用的医药组合物。
11.改善或治疗神经变性疾病的方法，即对人给以有效量的权利要求1记载的吡啶衍生物或它的盐。
12.改善或治疗神经变性疾病的方法，即对人给以有效量的权利要求2记载的吡啶衍生物或它的盐。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP29260894 | 1994-11-28 | ||
| JP292608/94 | 1994-11-28 |
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| Publication Number | Publication Date |
|---|---|
| CN1169721A true CN1169721A (zh) | 1998-01-07 |
| CN1087015C CN1087015C (zh) | 2002-07-03 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95196484A Expired - Fee Related CN1087015C (zh) | 1994-11-28 | 1995-11-27 | 吡啶衍生物 |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US5922743A (zh) |
| EP (1) | EP0795545A4 (zh) |
| CN (1) | CN1087015C (zh) |
| AU (1) | AU695845B2 (zh) |
| CA (1) | CA2206124A1 (zh) |
| WO (1) | WO1996016942A1 (zh) |
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| WO1998000401A1 (en) * | 1996-06-28 | 1998-01-08 | Merck & Co., Inc. | Fibrinogen receptor antagonist prodrugs |
| US5932582A (en) * | 1996-06-28 | 1999-08-03 | Merck & Co., Inc. | Fibrinogen receptor antagonist prodrugs |
| US5945545A (en) * | 1996-12-13 | 1999-08-31 | Merck & Co., Inc. | Fibrinogen receptor antagonists |
| US6384057B1 (en) | 1997-12-11 | 2002-05-07 | American Home Products Corporation | 2,4,6-trisubstituted pyridines with estrogenic activity and methods for the solid phase synthesis |
| US6503917B1 (en) | 1998-12-10 | 2003-01-07 | Wyeth, Five Giralda Farms | 2,4,6-trisubstituted pyridines with estrogenic activity and methods for the solid phase synthesis thereof |
| SE9903610D0 (sv) * | 1999-10-06 | 1999-10-06 | Astra Ab | Novel compounds II |
| AU2005286593A1 (en) * | 2004-09-23 | 2006-03-30 | Reddy Us Therapeutics, Inc. | Novel pyridine compounds, process for their preparation and compositions containing them |
| JP6512714B2 (ja) * | 2013-12-11 | 2019-05-15 | ザ スクリプス リサーチ インスティテュート | 低分子Ｃ−Ｍｙｃ阻害剤 |
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| AU5717394A (en) * | 1992-12-28 | 1994-07-19 | Taisho Pharmaceutical Co., Ltd. | Pharmaceutical use of terpyridine derivative |
| WO1994027604A1 (fr) * | 1993-05-28 | 1994-12-08 | Taisho Pharmaceutical Co., Ltd. | Utilisation medicale d'un derive de pyridine |
-
1995
- 1995-11-27 US US08/849,148 patent/US5922743A/en not_active Expired - Fee Related
- 1995-11-27 AU AU39365/95A patent/AU695845B2/en not_active Ceased
- 1995-11-27 CA CA002206124A patent/CA2206124A1/en not_active Abandoned
- 1995-11-27 CN CN95196484A patent/CN1087015C/zh not_active Expired - Fee Related
- 1995-11-27 EP EP95937181A patent/EP0795545A4/en not_active Ceased
- 1995-11-27 WO PCT/JP1995/002399 patent/WO1996016942A1/ja not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| AU695845B2 (en) | 1998-08-27 |
| AU3936595A (en) | 1996-06-19 |
| EP0795545A4 (en) | 1998-05-06 |
| WO1996016942A1 (fr) | 1996-06-06 |
| CA2206124A1 (en) | 1996-06-06 |
| US5922743A (en) | 1999-07-13 |
| EP0795545A1 (en) | 1997-09-17 |
| CN1087015C (zh) | 2002-07-03 |
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