CN100375619C - 改善脑功能的药物组合物及其用途 - Google Patents
改善脑功能的药物组合物及其用途 Download PDFInfo
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- CN100375619C CN100375619C CNB038138573A CN03813857A CN100375619C CN 100375619 C CN100375619 C CN 100375619C CN B038138573 A CNB038138573 A CN B038138573A CN 03813857 A CN03813857 A CN 03813857A CN 100375619 C CN100375619 C CN 100375619C
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 6
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- 229960003530 donepezil Drugs 0.000 claims description 9
- 229960001685 tacrine Drugs 0.000 claims description 9
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 claims description 9
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- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
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- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 125000005530 alkylenedioxy group Chemical group 0.000 description 3
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- 208000029028 brain injury Diseases 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
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- 239000000544 cholinesterase inhibitor Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 3
- JGPMMRGNQUBGND-UHFFFAOYSA-N idebenone Chemical compound COC1=C(OC)C(=O)C(CCCCCCCCCCO)=C(C)C1=O JGPMMRGNQUBGND-UHFFFAOYSA-N 0.000 description 3
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
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- 125000003386 piperidinyl group Chemical group 0.000 description 3
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- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
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Abstract
当与具有乙酰胆碱酯酶抑制作用的化合物联用时，由下式[1]表示的烷基醚衍生物或其盐以协同作用方式提高抗低氧作用，在一般通式[1]表示的烷基醚衍生物或其盐中，R1、R2、R3、R4、m和n各自如本说明书中所定义。因此，所述组合用作改进脑功能的方法。含有如上所述的化合物组合的药物组合物用于治疗和预防因缺血性脑病和脑中风作用后脑血管性痴呆、老年性痴呆、阿尔茨海默病中发生的大脑内乙酰胆碱神经机能减退或选择性细胞死亡导致的记忆障碍。
Description
技术领域
本发明涉及用于改善脑功能的含有烷基醚衍生物和具有乙酰胆碱酯酶抑制活性的化合物的药物组合物，并涉及使用烷基醚衍生物与具有乙酰胆碱酯酶抑制活性的化合物的组合改善脑功能的方法。
背景技术
一般认为，在脑血管疾病或多种神经元变性疾病的后遗症中，大脑神经元机能障碍和大脑神经元死亡紧密相关。特别在脑血管性痴呆、老年性痴呆、阿尔茨海默病和缺血性大脑损伤的后遗症以及大脑卒中，看起来存在因大脑内乙酰胆碱神经元机能减退或选择性神经元死亡导致的记忆受损。
作为对这种记忆受损进行症状治疗的药物，例如，使用具有乙酰胆碱酯酶抑制活性的化合物，诸如他克林、多奈哌齐等。
另一方面，将抗低氧活性用于评价体外神经保护活性，且据报导，在体内实验中，具有神经保护活性的化合物也表现出与上述相同的作用[《纽约科学院年鉴》(Ann.N.Y.Acad.Sci.),Vol.890,406-420页，1999]。此外，据报导使用激活大脑内乙酰胆碱神经元的化合物并使用表现出乙酰胆碱酯酶抑制活性的他克林(1,2，3，4-四氢-9-吖啶胺盐酸盐)证实了抗低氧活性[《日本药理学杂志》(Jpn.J.Pharmacol.)，Vol.62，81-86页，1993]。
因此，可以将用于研究体内抗低氧活性的工作看作用于评价具有神经保护作用和大脑内乙酰胆碱神经元激活作用之一或具有这两种作用的化合物的方法。
将描述在JP 3-232830A和JP 4-95070A中的1，2-乙二醇衍生物或其盐为用作改善脑功能的活性剂的化合物，特别是(R)-1-{苯并[b]噻吩-5-基}-2-[2-(N,N-二乙氨基}乙氧基]乙醇盐酸盐(下文称作T-588)为优选的化合物。据报导T-588具有抗低氧活性和抗遗忘活性并促进大脑内乙酰胆碱的释放(SOCIETY FOR NEUROSCIENCE，摘要，Vol.21,947页，1995)。还已知T-588表现出对因淀粉样-β-蛋白导致的神经元死亡的预防作用(SOCIETY FOR NEUROSCIENCE，摘要，Vol.24,228页，1998)，且T-588表现出对神经生长因子功能的增强作用(WO96/12717)。然而，对T-588改善脑功能的作用且特别是对改善抗低氧作用的化学物质及其方法尚未报导。
目前，根据预防脑血管性痴呆、老年性痴呆、阿尔茨海默病和缺血性大脑损伤中的后遗症以及脑卒中中大脑内乙酰胆碱神经元机能减退或选择性神经元死亡的观点，研究了具有神经保护活性的化合物。然而，这些化合物的治疗作用尚未得到充分了解。尽管乙酰胆碱酯酶抑制药物，诸如他克林、多奈哌齐(Donepezil)、加兰他敏(Galanthamine)等作为改善脑功能的药物，包括治愈阿尔茨海默病的药物业已市售，但是这些药物在不良反应方面存在问题，因为它们中的某些具有肝毒性，而另一些存在伴随激活非中枢神经系统的乙酰胆碱神经元的不良反应。因此，为了达到减轻乙酰胆碱酯酶抑制药物的不良反应的目的，例如，尝试使用脑循环代谢改善药、诸如艾地苯醌(Idebenone)与乙酰胆碱酯酶抑制剂的组合(JP 10-259126A)，或具有神经生长因子类活性的化合物(SR57746A)与乙酰胆碱酯酶抑制剂(WO99/25363)的组合等。
本发明的公开内容
在进行深入研究后，本发明者发现可以通过使用具有乙酰胆碱酯酶抑制活性的化合物与下式[1]表示的烷基醚衍生物或其盐(包括T-588)的组合以协同作用方式改善抗低氧活性：
其中R1表示取代或未被取代的杂环基；R2表示氢原子或羟基；R3和R4可以相同或不同，它们各自表示取代或未被取代的烷基；或R3和R4与R3和R4连接的氮原子共同结合成取代或未被取代的环氨基；m表示1-5的整数；且n表示1-6的整数。基于联用式[1]的烷基醚衍生物或其盐与具有乙酰胆碱酯酶抑制活性的化合物可以作为改善脑功能的知识，完成了本发明。
下面具体解释本发明。
除非另有说明，本说明书中所用的技术术语具有下列含义。卤原子指的是氟原子、氯原子、溴原子或碘原子；烷基指的是直链或支链C1-12烷基，诸如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、己基、庚基、辛基等；低级烷基指的是直链或支链C1-6烷基，诸如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、己基等；烷氧基指的是直链或支链C1-12烷氧基，诸如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基、戊氧基、己氧基、庚氧基、辛氧基等；低级烷氧基指的是直链或支链C1-6烷氧基，诸如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基、戊氧基、己氧基等；链烯基指的是C2-12链烯基，诸如乙烯基、丙烯基、丁烯基、戊烯基、己烯基、庚烯基、辛烯基等；低级链烯基指的是C2-6链烯基，诸如乙烯基、丙烯基、丁烯基、戊烯基、己烯基等；链烯氧基指的是C2-12链烯氧基，诸如乙烯氧基、丙烯氧基、丁烯氧基、戊烯氧基、己烯氧基、庚烯氧基、辛烯氧基等；低级链烯氧基指的是C2-6链烯氧基，诸如乙烯氧基、丙烯氧基、丁烯氧基、戊烯氧基、己烯氧基等；炔基指的是C2-6炔基，诸如乙炔基、丙炔基、丁炔基、戊炔基等；环烷基指的是环丙基、环丁基、环戊基和环己基；烷硫基指的是C1-12烷硫基，诸如甲硫基、乙硫基、丙硫基、异丙硫基、丁硫基、异丁硫基、叔丁硫基、戊硫基、己硫基、庚硫基、辛硫基等；低级烷硫基指的是C1-6烷硫基，诸如甲硫基、乙硫基、丙硫基、异丙硫基、丁硫基、异丁硫基、叔丁硫基、戊硫基、己硫基等；芳基指的是苯基、萘基、2，3-二氢化茚基和茚基；芳氧基指的是苯氧基、萘氧基、2，3-二氢化茚氧基和茚氧基；芳-低级烷基指的是芳-C1-6烷基，诸如苄基、二苯基甲基、苯乙基等；芳-低级链烯基指的是芳-C2-6链烯基，诸如肉桂基等；芳-低级烷氧基指的是芳-C1-6烷氧基，诸如苯基甲氧基、萘基甲氧基等；芳-低级烷硫基指的是芳-C1-6烷硫基，诸如苯基甲硫基、萘基甲硫基等；低级亚烷二氧基指的是C1-6亚烷二氧基，诸如亚甲二氧基、亚乙二氧基等；低级酰基指的是C1-6酰基，诸如甲酰基、乙酰基、乙基羰基等；芳酰基指的是芳基羰基，诸如苯甲酰基、萘基羰基等；芳-低级链烯酰基指的是芳-C2-6链烯酰基，诸如肉桂酰基等；低级烷基磺酰基指的是C1-6烷基磺酰基，诸如甲基磺酰基、乙基磺酰基、正丙基磺酰基、异丙基磺酰基、正丁基磺酰基、异丁基磺酰基、仲丁基磺酰基、叔丁基磺酰基、戊基磺酰基等；芳基磺酰基指的是苯基磺酰基、对甲苯磺酰基、萘基磺酰基等；低级烷基磺酰氧基指的是C1-6烷基磺酰氧基，诸如甲基磺酰氧基、乙基磺酰氧基、正丙基磺酰氧基、异丙基磺酰氧基、正丁基磺酰氧基、异丁基磺酰氧基、仲丁基磺酰氧基、叔丁基磺酰氧基、戊基磺酰氧基等；芳基磺酰氧基指的是苯基磺酰氧基、对甲苯磺酰氧基、萘基磺酰氧基等；芳-低级烷基磺酰基指的是芳-C1-6烷基磺酰基，诸如苄基磺酰基等；低级烷基磺酰氨基指的是C1-6烷基磺酰氨基，诸如甲基磺酰氨基、乙基磺酰氨基、丙基磺酰氨基等；芳基磺酰氨基指的是苯基磺酰氨基、对甲苯磺酰氨基和萘基磺酰氨基等；环氨基指的是具有4-7元环、稠合环或交联环的环氨基，所述的环含有至少一个氮原子作为构成所述环的杂原子，且可以另外含有至少一个氧原子或硫原子，诸如氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、高哌嗪基、高哌啶基、吗啉基、硫代吗啉基、四氢喹啉基、四氢异喹啉基、奎宁环基、咪唑啉基等；杂环基指的是上述环氨基，还指可以含有至少一个选自氮、氧和硫原子的杂原子作为构成所述环的杂原子且含有至少一个5-或6-元环结构或稠合环结构或交联环结构的杂环基，诸如吡咯基、咪唑基、吡唑基、吡啶基、嘧啶基、喹啉基、喹嗪基、噻唑基、四唑基、噻二唑基、吡咯啉基、吡唑啉基、吡唑烷基、嘌呤基、呋喃基、噻吩基、苯并噻吩基、吡喃基、异苯并呋喃基、噁唑基、异噁唑基、苯并呋喃基、吲哚基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、喹喔啉基、二氢喹喔啉基、2,3-二氢苯并噻吩基、2，3-二氢苯并吡咯基、2,3-4H-1-硫茚基(thianaphthyl)、2，3-二氢苯并呋喃基、苯并[b]二噁烷基、咪唑并[2，3-a]吡啶基、苯并[b]哌嗪基、色烯基、异噻唑基、异噁唑基、噁二唑基、哒嗪基、异吲哚基、异喹啉基、1，3-苯并间二氧杂环戊烯基、1，4-苯并二噁烷基等；且含氮的饱和6-元杂环指的是含有氮原子作为杂原子的饱和6-元环，诸如哌啶、哌嗪、全氢嘧啶、全氢哒嗪等。
R1的杂环基可以被至少一个残基取代，所述的残基选自卤原子、任选取代的氨基、低级烷基、芳基、芳-低级烷基、低级烷氧基、芳-低级烷氧基、芳氧基、氨基甲酰基氧基、低级烷硫基、低级链烯基、低级链烯氧基、芳-低级烷硫基、芳-低级烷基磺酰基、芳基磺酰基、低级烷基磺酰氨基、芳基磺酰氨基或任选被保护的氨基、任选被保护的羟基、硝基、杂环基、氧代基团、低级亚烷二氧基等。
R3和R4的氨基以及R3和R4与R3和R4连接的氮原子结合成的环氨基的氨基可以被至少一个基团取代，所述基团选自卤原子、任选取代的氨基、低级烷基、芳基、芳-低级烷基、芳-低级链烯基、芳酰基、芳-低级链烯酰基、杂环基等。
上述R1、R3、R4以及R3和R4与R3和R4连接的氮原子结合成的环氨基上的取代基可以进一步被至少一个基团取代，所述基团选自卤原子、任选被保护的羟基、任选被保护的羧基、任选被保护的氨基、低级烷基、低级烷氧基、低级酰基、环烷基、芳-低级烷基等。
羧基保护基包括通常可以用作羧基保护基的所有残基，其实例包括：低级烷基，诸如甲基、乙基、丙基、异丙基、1,1-二甲基丙基、丁基、叔丁基等；芳基，诸如苯基、萘基等；芳-低级烷基，诸如苄基、二苯基甲基、三苯甲基、对硝基苄基、对甲氧基苄基、双(对甲氧基苯基)甲基等；酰基-低级烷基，诸如乙酰基甲基、苯甲酰基甲基、对硝基苯甲酰基甲基、对溴苯甲酰基甲基、对甲磺酰基苯甲酰基甲基等；含氧的杂环基，诸如2-四氢吡喃基、2-四氢呋喃基等；卤代低级烷基，诸如2，2，2-三氯乙基等；低级烷基甲硅烷基-低级烷基，诸如2-(三甲代甲硅烷基)乙基等；酰氧基-低级烷基，诸如乙酰氧基甲基、丙酰氧基甲基、新戊酰氧基甲基等；含氮杂环-低级烷基，诸如苯二酰亚氨基甲基、琥珀酰亚氨基甲基等；环烷基，诸如环己基等；低级烷氧基-低级烷基，诸如甲氧基甲基、甲氧基乙氧基甲基、2-(三甲代甲硅烷基)乙氧基甲基等；芳-低级烷氧基-低级烷基，诸如苄氧基甲基等；低级烷硫基-低级烷基，诸如甲硫基甲基、2-甲硫基乙基等；芳硫基-低级烷基，诸如苯硫基甲基等；低级链烯基，诸如1,1-二甲基-2-丙烯基、3-甲基-3-丁烯基、烯丙基等；取代的甲硅烷基，诸如三甲代甲硅烷基、三乙基甲硅烷基、三异丙基甲硅烷基、二乙基异丙基甲硅烷基、叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基、二苯基甲基甲硅烷基、叔丁基甲氧基苯基甲硅烷基等；等。
羟基的保护基包括通常可以用于保护羟基的所有残基，其实例包括：酰基，诸如苄氧羰基、4-硝基苄氧羰基、4-溴苄氧羰基、4-甲氧基苄氧羰基、2，3-二甲氧基羰基、甲氧羰基、乙氧羰基、叔丁氧羰基、1,1-二甲基丙氧羰基、异丙氧羰基、叔丁氧羰基、二苯基甲氧羰基、2，2，2-三氯乙氧羰基、2，2，2-三溴乙氧羰基、2-(三甲代甲硅烷基)-乙氧羰基、2-(苯基磺酰基)乙氧羰基、2-(三苯基磷基)乙氧羰基、2-糠基氧基羰基、1-金刚烷基氧基羰基、乙烯氧基羰基、烯丙氧基羰基、S-苄硫基羰基、4-乙氧基-1-萘氧基羰基、8-喹啉基氧基羰基、乙酰基、甲酰基、氯乙酰基、二氯乙酰基、三氯乙酰基、三氟乙酰基、甲氧基乙酰基、苯氧基乙酰基、新戊酰基、苯甲酰基等；低级烷基，诸如甲基、叔丁基、2，2，2-三氯乙基、2-三甲代甲硅烷基乙基等；低级链烯基，诸如烯丙基等；芳-低级烷基，诸如苄基、对甲氧基苄基、3，4-二甲氧基苄基、二苯基甲基、三苯甲基等；含氧和含硫的杂环基，诸如四氢呋喃基、四氢吡喃基、四氢硫代吡喃基等；低级烷氧基-和低级烷硫基-低级烷基，诸如甲氧基甲基、甲硫基甲基、苄氧基甲基、2-甲氧基乙氧基甲基、2，2，2-三氯乙氧基甲基、2-(三甲代甲硅烷基)乙氧基甲基、1-乙氧基乙基、1-甲基-1-甲氧基乙基等；低级烷基-和芳基-磺酰基，诸如甲磺酰基、对甲苯磺酰基等；取代的甲硅烷基，诸如三甲代甲硅烷基、三乙基甲硅烷基、三异丙基甲硅烷基、二乙基异丙基甲硅烷基、叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基、二苯基甲基甲硅烷基、叔丁基甲氧基苯基甲硅烷基等；等。
氨基的保护基包括通常可以用作氨基保护基的所有残基，其实例包括：酰基，诸如三氯乙氧羰基、三溴乙氧羰基、苄氧羰基、对硝基苄氧羰基、邻溴苄氧羰基、(单-、二-和三-)氯乙酰基、三氟乙酰基、苯基乙酰基、甲酰基、乙酰基、苯甲酰基、叔戊氧羰基、叔丁氧羰基、对甲氧基苄氧羰基、3,4-二甲氧基苄氧羰基、4-(苯偶氮基)苄氧羰基、2-糠基氧基羰基、二苯基甲氧羰基、1，1-二甲基丙氧羰基、异丙氧羰基、邻苯二甲酰基、琥珀酰基、丙氨酰基、亮氨酰基、1-金刚烷基氧基羰基、8-喹啉基氧基羰基等；芳-低级烷基，诸如苄基、二苯基甲基、三苯甲基等；芳硫基，诸如2-硝基苯硫基、2,4--二硝基苯硫基等；烷基-或芳基-磺酰基，诸如甲磺酰基、对甲苯磺酰基等；二低级烷氨基-低级亚烷基，诸如N,N-二甲氨基亚甲基等；芳-低级亚烷基，诸如亚苄基、2-羟基亚苄基、2-羟基-5-氯亚苄基、2-羟基-1-萘基亚甲基等；含氮杂环-亚烷基，诸如3-羟基-4-吡啶基亚甲基等；环亚烷基，诸如环亚己基、2-乙氧羰基环亚己基、2-乙氧羰基环亚戊基、2-乙酰基环亚己基、3,3-二甲基-5-氧环亚己基等；二芳基-或二芳-低级烷基磷酰基，诸如二苯基磷酰基、二苄基磷酰基等；含氧杂环烷基，诸如5-甲基-2-氧代-2H-1，3-间二氧杂环戊烯-4-基-甲基等；取代的甲硅烷基，诸如三甲代甲硅烷基等；等。
作为通式[1]的化合物的盐，可提及通常在碱性基团(诸如氨基等)和酸性基团(诸如羟基、羧基等)的位置上形成的已知的盐。例如，在碱性基团位置上形成的盐可提及与无机酸形成的盐、与有机羧酸形成的盐和与磺酸形成的盐，所述的无机酸诸如盐酸、氢溴酸、硫酸等，所述的有机羧酸诸如甲酸、乙酸、柠檬酸、草酸、富马酸、马来酸、苹果酸、酒石酸、天冬氨酸等，所述的磺酸诸如甲磺酸、苯磺酸、对甲苯磺酸、米磺酸、萘磺酸等。作为在酸性基团上形成的盐，可提及例如：与碱金属形成的盐，所述的碱金属诸如钠、钾等；与碱土金属形成的盐，所述的碱土金属诸如钙、镁等；铵盐；与含氮有机碱形成的盐，诸如三甲胺、三乙胺、叔丁胺、吡啶、N,N-二甲基苯胺、N-甲基哌啶、N-甲基吗啉、二乙胺、二环己胺、普鲁卡因、二苄胺、N-苄基-β-苯乙胺、1-麻黄胺(1-ephenamine)、N,N-二苄基乙二胺等；等。
通式[1]的烷基醚衍生物中的某些或其盐具有异构体，诸如旋光异构体、几何异构体、互变体等。在这类情况中，本发明包括所有这些异构体且进一步包括水合物、溶剂合物和所有晶形。
作为用作组分(A)的烷基醚衍生物或其盐，优选由通式[1]表示的化合物，其中取代基选自下列组合。
(1)烷基醚衍生物或其盐，其中R1为可以被选自卤原子、烷基和苯基的基团取代的苯并噻吩基或苯并呋喃基；R2为羟基；R3为烷基；R4为可以被烷氧基取代的苯基取代的烷基；或R3和R4与R3和R4连接的氮原子共同结合成吡咯烷环、哌啶环、哌嗪环或吗啉环；m为1；且n为2；
这类化合物的具体实例为(苯并[b]噻吩-5-基)-2-[2-(N,N-二乙氨基)乙氧基]乙醇。
(2)烷基醚衍生物或其盐，其中R1为可以被选自下列的基团取代的苯并噻吩基或苯并呋喃基：卤原子、任选被羟基取代的烷基、烷氧基、羧基、氨基羰基、羟基、烷硫基、苯基和吡啶基；R2为氢原子；R3为可以被选自下列的基团取代的烷基：任选被卤原子、烷氧基或硝基取代的苯基、任选被保护的羟基、烷氨基和炔基；R4为可以被苯基取代的烷基；m为l；且n为2-3；
这类化合物的具体实例为2-[[3-(2-苯并[b]噻吩-5-基乙氧基)丙基](甲基)氨基]-1-乙醇。
(3)烷基醚衍生物或其盐，其中R1为可以被选自卤原子、烷基和苯基的基团取代的苯并噻吩基或苯并呋喃基；R2为氢原子；R3或R4为可以被选自羟基、任选被保护的氨基和烷氨基的基团取代的烷基；或R3和R4表示氮杂环丁烷环、吡咯烷环、哌啶环、哌嗪环或吗啉环，其由R3和R4连接的氮一起形成；m为1；且n为2-3。
这类化合物的具体实例为1-[2-[2-(1-苯并噻吩-5-基)乙氧基]乙基]-3-氮杂环丁醇。
可以按照JP 3-47158A、JP 3-232830A、JP 4-95070A、WO99/31056、WO00/76957、PCT/JP02/10827等中所述的方法生产通式[1]的烷基醚衍生物或其盐。
作为用于本发明的组分(B)的具有乙酰胆碱酯酶抑制活性的化合物，例如可以提及的有下列化合物：
他克林；JP 1-79151A中所述的以多奈哌齐为代表的化合物；JP61-225158A中所述的以利凡斯的明(Rivastigmine)为代表的化合物；JP 62-215527A中所述的以加兰他敏为代表的化合物；美国专利US5177082中所述的以石杉碱(Huperzine)为代表的化合物；依匹达克林(Ipidacrant)；JP 5-140149A中所述的以扎那哌齐(Zanapezil)为代表的化合物；苯丝氨(Phenserine)；奎洛斯的明(Quilostigmine)；更斯的明(Ganstigmine)；WO92/18493中所述的以恩沙库林(Ensaculin)为代表的化合物；JP 5-279355A中所述的以T-82为代表的化合物；等。在这些化合物中，进一步优选作为组分(B)的为他克林和多奈哌齐。
在由包括通式[1]的烷基醚衍生物或其盐和具有乙酰胆碱酯酶抑制活性的化合物或其盐的组合物制备药物制剂的过程中，可以通过适当使用药物上可接受的助剂，诸如赋形剂、载体、稀释剂、稳定剂等按照常规方式制成药物制剂，诸如片剂、胶囊、粉剂、颗粒、细颗粒、丸剂、混悬剂、乳剂、溶液、糖浆剂、注射剂、滴眼液等。可以通过口服或非口服的方式给予由此形成的药物制剂。尽管可以根据年龄、体重和患者症状适当选择给药方法、给药剂量和给药频率，但是在对成人口服给药的情况中，通常每天给予0.01-500mg，分一次至几次给药。
尽管可以适当选择组分(A)和(B)的比例，但是每重量份组分(A)使用的组分(B)的用量为0.0005-1重量份。
例如，尽管组分(A)和(B)的用量根据其组合的不同而改变，但是组分(B)(具有乙酰胆碱酯酶抑制活性的化合物)的用量可以为不会使外周神经症状的反应(主要由副交感神经系统导致的反应，诸如腹泻、流泪、流涎)明显出现的用量。例如，就多奈哌齐而言，用量约为0.05mg-10mg/天；就扎那哌齐而言，用量约为1mg-120mg/天；就他克林而言，用量约为5mg-200mg/天；就依匹达克林而言，用量约为10mg-300mg/天；且就利凡斯的明而言，用量约为0.5mg-20mg/天。
尽管组分(A)的用量随组分(B)、即具有乙酰胆碱酯酶抑制活性的化合物的种类的不同而改变，但是其用量为0.01-500mg/天。
实施例
接下来提及的是通过联用通式[1]的烷基醚衍生物或其盐与具有乙酰胆碱酯酶抑制活性的化合物而产生的对神经元的激活和保护作用。
抗低氧活性
化合物A1：T-588
化合物A2：2-[[3-(2-苯并[b]噻吩-5-基乙氧基)丙基](甲基)氨基]-1-乙醇·1/2富马酸盐
化合物A3：1-[3-[2-(1-苯并噻吩-5-基)乙氧基]丙基]-3-氮杂环丁醇·马来酸盐
化合物B1：多奈哌齐
化合物B2：他克林
化合物C1：艾地苯醌
化合物C2：SR57746A
在将测试化合物A1、A2、A3、B1和B2溶于蒸馏水后使用。在将测试化合物C1和C2悬浮于0.5％甲基纤维素溶液后使用。
(测试方法)
按照《日本药理学杂志》(Japanese Journal of Pharmacology)，Vol.62，81页，1993中所述的方法进行测试。
对1组(6-10只动物)具有4-5周龄的ddY雄性小鼠口服给予溶于蒸馏水或悬浮于0.5％甲基纤维素溶液的测试化合物。给药后30分钟，将小鼠放入体积为300mL的玻璃容器并使由4％的氧和96％的氮组成的气体混合物以5L/分钟的流速通过该玻璃容器。测定从气体混合物开始通过到小鼠死亡的时间期限。向对照组口服给予蒸馏水。
按照下列公式计算各测试化合物的抗低氧活性：
(给予测试化合物组的小鼠存活时间/对照组小鼠的存活时间)×100％
结果如表1-3中所示。
表1
| 化合物(1) | 剂量(mg/kg) | 化合物(2) | 剂量(mg/kg) | 抗低氧活性(％) |
| 对照组化合物A1化合物B1化合物B2化合物A1化合物A1 | -103101010 | 化合物B1化合物B2 | ----310 | 100137119127211172 |
表2
| 化合物(1) | 剂量(mg/kg) | 化合物(2) | 剂量(mg/kg) | 抗低氧活性(％) |
| 对照组化合物A2化合物A3化合物B1化合物B2化合物A2化合物A2化合物A3化合物A3 | -101031010101010 | 化合物B1化合物B2化合物B1化合物B2 | -----310310 | 100114111104107168172190149 |
表3
| 化合物(1) | 剂量(mg/kg) | 化合物(2) | 剂量(mg/kg) | 抗低氧活性(％) |
| 对照组化合物C1化合物C1化合物C1化合物C2化合物C2化合物C2 | 10030030030100100 | 化合物B1化合物B1 | ---3--3 | 100104108100100123111 |
工业实用性
通过联用通式[1]的烷基醚衍生物或其盐与具有乙酰胆碱酯酶抑制活性的化合物可以以协同作用方式改善抗低氧活性。因此，本发明的联合用药用作改善脑功能的方法。含有本发明组合的化合物的药物组合物用于治疗和预防脑血管性痴呆、老年性痴呆、阿尔茨海默病和缺血性脑损伤后遗症中和脑卒中的大脑乙酰胆碱神经元机能减退或因选择性神经元死亡导致的记忆受损。
Claims (4)
1.用于改善脑功能的药物组合物，包括下列组分(A)和(B)：
组分(A)：下式表示的烷基醚衍生物或其盐：
其中R1表示苯并噻吩基；R2表示氢原子；R3和R4各自表示任选被羟基取代的C1-6烷基；或R3和R4与R3和R4连接的氮原子共同结合成任选被羟基取代的氮杂环丁烷环；m表示1的整数；且n表示3的整数；
组分(B)：他克林或多奈哌齐。
2.权利要求1的用于改善脑功能的药物组合物，其中在组分(A)的式中组分(A)为2-[[3-(2-苯比[b]噻吩-5-基-乙氧基)丙基](甲基)氨基]-1-乙醇或其盐，或1-[3-[2-(1-苯并噻吩-5-基)乙氧基]-丙基]-3-氮杂环丁醇或其盐。
3.下列组分(A)和(B)的组合用于制备改善脑功能的药物的用途，
组分(A)：下式表示的烷基醚衍生物或其盐：
其中R1表示苯并噻吩基；R2表示氢原子；R3和R4各自表示任选被羟基取代的C1-6烷基；或R3和R4与R3和R4连接的氮原子共同结合成任选被羟基取代的氮杂环丁烷环；m表示1的整数；且n表示3的整数；
组分(B)：他克林或多奈哌齐。
4.权利要求3的用途，其中在组分(A)的式中组分(A)为2-[[3-(2-苯比[b]噻吩-5-基-乙氧基)丙基](甲基)氨基]-1-乙醇或其盐，或1-[3-[2-(1-苯并噻吩-5-基)乙氧基]-丙基]-3-氮杂环丁醇或其盐。
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| PT (2) | PT2389937T (zh) |
| SI (2) | SI1514542T1 (zh) |
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| CN100500662C (zh) | 2001-10-19 | 2009-06-17 | 富山化学工业株式会社 | 烷基醚衍生物或其盐 |
| PT2389937T (pt) * | 2002-06-14 | 2018-10-26 | Toyama Chemical Co Ltd | Composição farmacêutica para melhorar as funções cerebrais |
| ZA200508166B (en) * | 2003-04-17 | 2007-03-28 | Toyama Chemical Co Ltd | Preventive/remedy for retinal nerve diseases containing alkyl ether derivatives or salts thereof |
| US7435837B2 (en) | 2003-10-24 | 2008-10-14 | Wyeth | Dihydrobenzofuranyl alkanamine derivatives and methods for using same |
| EP2258357A3 (en) * | 2005-08-26 | 2011-04-06 | Braincells, Inc. | Neurogenesis with acetylcholinesterase inhibitor |
| EP2011796B1 (en) * | 2006-04-26 | 2014-10-08 | Toyama Chemical Co., Ltd. | Neurogenesis inducer or neuropathy therapeutic agent comprising alkyl ether derivative or salt thereof |
| US8119625B2 (en) * | 2006-04-26 | 2012-02-21 | Toyama Chemical Co., Ltd. | Neurogenesis inducer or neuropathy therapeutic agent comprising alkyl ether derivative or salt thereof |
| BRPI0715056A2 (pt) * | 2006-08-04 | 2013-05-28 | Toyama Chemical Co Ltd | intensificador de atividade de proteÍna cinase c |
| US20090221554A1 (en) * | 2008-02-28 | 2009-09-03 | Zenyaku Kogyo Kabushiki Kaisha | Method of treating cognitive impairment |
| WO2009145171A1 (ja) * | 2008-05-28 | 2009-12-03 | 富山化学工業株式会社 | 新規なベンゾチオフェンオキシド誘導体またはその塩 |
| EP2885267B1 (en) | 2012-07-12 | 2018-09-05 | Concert Pharmaceuticals, Inc. | Deuterated idebenone |
| SG11201606173TA (en) * | 2014-01-31 | 2016-08-30 | Toyama Chemical Co Ltd | Post nerve injury rehabilitation effect-enhancing agent comprising alkyl ether derivative or salt thereof |
| US11660287B2 (en) | 2017-06-02 | 2023-05-30 | Fujifilm Toyama Chemical Co., Ltd. | Agent for preventing or treating spinocerebellar ataxia |
| CN110691594A (zh) | 2017-06-02 | 2020-01-14 | 富士胶片富山化学株式会社 | Tau蛋白病预防或治疗剂 |
| EP3632429A4 (en) | 2017-06-02 | 2020-06-10 | FUJIFILM Toyama Chemical Co., Ltd. | AGENT FOR REDUCING AMYLOID PROTEIN CONTENT |
| KR20190137936A (ko) | 2017-06-02 | 2019-12-11 | 후지필름 도야마 케미컬 가부시키가이샤 | 뇌 위축 예방 또는 치료제 |
| EP3636262A4 (en) | 2017-06-02 | 2020-06-10 | FUJIFILM Toyama Chemical Co., Ltd. | AGENT FOR PREVENTING OR TREATING ALZHEIMER-LIKE DEMENTIA |
| US20200206187A1 (en) * | 2017-07-08 | 2020-07-02 | Rudolph E. Tanzi | Screening platform to identify therapeutic drugs or agents for treatment of alzheimer's disease |
| WO2019088083A1 (ja) | 2017-10-30 | 2019-05-09 | 富士フイルム富山化学株式会社 | エモパミル結合タンパク質結合剤およびその利用 |
| CN110464834B (zh) * | 2019-09-04 | 2022-12-02 | 北京豪思生物科技股份有限公司 | 铜蓝蛋白联合多奈哌齐的应用 |
| KR20220040294A (ko) | 2020-09-23 | 2022-03-30 | 씨엔지바이오 주식회사 | 6-메톡시-2-펜에틸이소인돌린-1-온 유도체 및 이를 포함하는 신경질환의 치료용 조성물 |
| KR20220040291A (ko) | 2020-09-23 | 2022-03-30 | 씨엔지바이오 주식회사 | 4-메톡시-2-펜에틸이소인돌린-1-온 유도체 및 이를 포함하는 신경질환의 치료용 조성물 |
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- 2003-04-03 WO PCT/JP2003/004292 patent/WO2003105830A1/ja active Application Filing
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- 2003-04-03 AT AT03760132T patent/ATE546140T1/de active
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