CN1059442C - 1,2－桥连的1,4－二氢吡啶类化合物作为药物的用途 - Google Patents
1,2－桥连的1,4－二氢吡啶类化合物作为药物的用途 Download PDFInfo
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- CN1059442C CN1059442C CN95120851A CN95120851A CN1059442C CN 1059442 C CN1059442 C CN 1059442C CN 95120851 A CN95120851 A CN 95120851A CN 95120851 A CN95120851 A CN 95120851A CN 1059442 C CN1059442 C CN 1059442C
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- methyl
- phenyl
- oxo
- ethanoyl
- dichlorophenyl
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- 239000003814 drug Substances 0.000 title claims abstract description 11
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical class C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 title claims abstract description 7
- 102000004257 Potassium Channel Human genes 0.000 claims abstract description 5
- 108020001213 potassium channel Proteins 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 41
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- -1 methylidene, ethyl Chemical group 0.000 claims description 9
- 239000000460 chlorine Substances 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
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- 229910052731 fluorine Inorganic materials 0.000 claims description 4
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- OENLEHTYJXMVBG-UHFFFAOYSA-N pyridine;hydrate Chemical class [OH-].C1=CC=[NH+]C=C1 OENLEHTYJXMVBG-UHFFFAOYSA-N 0.000 claims description 4
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- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
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- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- VQMSRUREDGBWKT-UHFFFAOYSA-N quinoline-4-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=CC=NC2=C1 VQMSRUREDGBWKT-UHFFFAOYSA-N 0.000 claims 10
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- LIPPUZZVFCEJGO-UHFFFAOYSA-N methyl indolizine-8-carboxylate Chemical compound COC(=O)C1=CC=CN2C=CC=C12 LIPPUZZVFCEJGO-UHFFFAOYSA-N 0.000 claims 2
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- 230000036541 health Effects 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
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- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 230000000955 neuroendocrine Effects 0.000 description 1
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- TZMFJUDUGYTVRY-UHFFFAOYSA-N pentane-2,3-dione Chemical compound CCC(=O)C(C)=O TZMFJUDUGYTVRY-UHFFFAOYSA-N 0.000 description 1
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
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- 229910052701 rubidium Inorganic materials 0.000 description 1
- IGLNJRXAVVLDKE-UHFFFAOYSA-N rubidium atom Chemical compound [Rb] IGLNJRXAVVLDKE-UHFFFAOYSA-N 0.000 description 1
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- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- 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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- A—HUMAN NECESSITIES
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/02—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing not further condensed quinolizine ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Hospice & Palliative Care (AREA)
- Anesthesiology (AREA)
- Addiction (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyridine Compounds (AREA)
- Manufacture Of Tobacco Products (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
本发明涉及部分为已知的通式(Ⅰ)的1，2-桥连的1，4-二氢吡啶类化合物的新用途，其制备方法及其作为药物、作为选择性钾通道调节剂，特别是用于治疗中枢神经系统的用途。
其中R1至R4和a具有说明书中所述意义。
Description
本发明涉及部分为已知的1，2-桥连的1，4-二氢吡啶类化合物的新用途，其制备方法及其作为药物、作为选择性钾通道调节剂，特别是用于治疗中枢神经系统的用途。
1，2-桥连的1，4-二氢吡啶-3，5-二羧酸酯类由出版物Justus Liebigs Ann.Chem.(1977)，11-12，1888-94已知。
另外描述了具有循环作用的1，2-亚己基-和1，2-亚戊基-1，4-二氮吡啶衍生物[参见，US 39 519 88：US 39 35 220和DE22 10 633]。
现已发现，在某些情况下是已知的通式(I)的1，2-桥连的1，4-二氢吡啶类化合物令人惊奇地具有选择性的钾通道调节作用，并适用于控制中枢神经系统疾病和镰形细胞贫血：
其中：
R1代表具有6-10个碳原子的芳基，该芳基任选被相同或不同的硝基、氰基、卤素或三氟甲基取代基或被具有最多达6个碳原子的直链或支链烷硫基取代最多达5次。
R2和R3可相同或不同，并各自代表具有最多达8个碳原子的直链或支链烷基或烷氧基或苯基，
a代表数字1、2或3，
R4代表甲基，或
R3和R4一起形成式-CH2-CH2-CH2-或-CH2-C(CH3)2-CH2-基团。
本发明化合物可以以立体异构体形式存在，表现为像与镜像(对映体)，或不表现为像与镜像(非对映体)。本发明涉及对映体、外消旋体形式，以及非对映体混合物。正如非对映体一样，外消旋体也可以按已知方式分离成立体异构的单一成份。
优选使用的通式(I)化合物是用于控制中枢神经系统疾病的下列化合物，其中，
R1代表苯基或萘基，它们各自任选被相同或不同的硝基、氰基、氟、氯、溴、碘或三氟甲基取代基或被具有至多4个碳原子的直链或支链烷硫基取代至多达3次，
R2和R3可相同或不同，并各自代表具有最多达4个碳原子的直链或支链烷基或烷氧基、或苯基。
a代表数字1或2。
R4代表甲基，或
R3和R4一起形成式-CH2-CH2-CH2-或-CH2-C(CH3)2-CH2-基团。
特别优选使用的通式(I)化合物是用于控制中枢神经系统疾病的下列化合物，其中
R1代表苯基，该苯基任选被相同或不同的硝基、氰基、氟、氯、溴、碘、三氟甲基取代基或被甲硫基取代最多达2次，
R2和R3可相同或不同，并各自代表甲基、乙基或甲氧基，
a代表数字1或2，
R4代表甲基，或
R3和R4一起形成式-CH2-CH2-CH2-或-CH2-C(CH3)2-CH2-基团。
本发明的通式(I)化合物表现出不可预见的、有用的药理作用谱。
所述化合物是具有对于高传导性的钙依赖性钾通道(BK(Ca)通道)，特别是对于中枢神经系统的钾通道的令人惊奇选择性的通道调节剂。
基于它们的药理性质，它们可以用于制备用于治疗退行性中枢神经系统疾病的药物，所述疾病为例如痴呆的发作(多发性梗塞性痴呆(MID)、原发性退行性痴呆(PDD)、早老性和老年性阿耳茨海默氏病、HIV痴呆和其他形式的痴呆)、帕金森氏病或肌萎缩性脊髓侧索硬化及多发性硬化。
所述活性化合物还适用于治疗老年人的脑功能失调、器质性脑综合症(ORS)和与年龄有关的记忆障碍(与年龄有关的记忆损伤(AAMI))。
所述化合物适于预防、治疗和用于控制大脑循环疾病的后遗症，例如大脑局部缺血、中风、颅脑创伤和蛛网膜下出血。
所述化合物适于治疗抑郁症和精神病，例如精神分裂症。它们还可适用于治疗神经内分泌和神经递质分泌疾病和与之有关的健康疾病例如躁狂、醇中毒、药物滥用、成瘾或不正常的摄食行为。其他应用领域为治疗偏头痛、睡眠疾病和神经病，它们还适用作为止痛药。
所述活性化合物还适用于治疗免疫系统疾病，特别是T-淋巴细胞增殖和用于影响平滑肌系统，特别是子宫、膀胱和支气管道，并且用于治疗与之有关的疾病，例如哮喘和尿失禁，和用于治疗心律不齐、绞痛和糖尿病。
本发明还涉及新的所选择的通式(I)化合物及其盐，它们具有下表中所指出的取代基含义：
| R1 | R2 | a | R3 | R3+R4 | R4 |
| m-NO2-C6H4 | CH3 | 2 | - | -CH2-CH2-CH2- | - |
| p-Cl-C6H4 | CH3 | 2 | - | -CH2-CH2-CH2- | - |
| o，m-Cl-C6H3 | CH3 | 2 | - | -CH2-CH2-CH2- | - |
| p-Cl-C6H4 | CH3 | 1 | - | -CH2-CH2-CH2- | - |
| o，m-Cl-C6H3 | CH3 | 1 | - | -CH2-CH2-CH2- | - |
| p-Cl-C6H4 | CH3 | 1 | - | -CH2-C(CH3)2-CH2- | - |
| o，m-Cl-C6H3 | CH3 | 1 | - | -CH2-C(CH3)2-CH2- | - |
| m-NO2-C6H4 | CH3 | 1 | - | -CH2-C(CH3)2-CH2- | - |
| o，m-Cl-C6H3 | OCH3 | 1 | -CH3 | - | CH3 |
| p-Cl-C6H4 | OCH3 | 1 | -CH3 | - | CH3 |
| p-NO2-C6H4 | CH3 | 1 | CH3 | - | CH3 |
| m，p-Cl-C6H3 | CH3 | 1 | CH3 | - | CH3 |
| o，m-Cl-C6H3 | CH3 | 1 | CH3 | - | CH3 |
| p-CF3-C6H4 | CH3 | 1 | CH3 | - | CH3 |
| m-CF3，p-Cl-C6H3 | CH3 | 1 | CH3 | - | CH3 |
| o，m-Cl-C6H3 | OCH3 | 1 | OCH3 | - | CH3 |
| p-CF3-C6H4 | OCH3 | 1 | OCH3 | - | CH3 |
| p-Cl-C6H4 | OCH3 | 2 | OCH3 | - | CH3 |
| p-Cl-C6H4 | OCH3 | 1 | OCH3 | - | CH3 |
本发明新的和已知的式(I)化合物可以制备如下：
(A)在R3和R4各自代表开链基团的情况下，首先使通式(II)的醛与通式(III)的二氧代化合物在惰性溶剂中，如果必要在碱存在下反应，而将通式(II)的醛转化成通式(IV)的亚苄基化合物，
R1-CHO (II)
其中R1具有上述意义，
其中R3和R4具有上述意义，
其中R1、R3和R4具有上述意义，任选分离通式(IV)的亚苄基化合物：
其次，在第二步骤中，使上述通式(IV)化合物与通式(V)的胺在惰性溶剂中反应，
其中R2和a具有上述意义：或者
(B)在R3和R4一起形成上述环之一的情况下，使通式(II)的醛与通式(VI)化合物和通式(V)的环状胺在溶剂中，如果需要在碱的存在下反应，
其中
R3和R4一起形成式-CH2-CH2-CH2-或-CH2-C(CH3)2-CH2-基团。
本发明方法可以通过举例方式由下列反应路线说明：
一般地，对于所述方法的第一和第二步骤，方法(A)的适宜溶剂是在反应条件下不发生变化的所有惰性有机溶剂。所述溶剂优选包括醇，例如甲醇、乙醇、丙醇或异丙醇，或醚类，例如乙醚、二噁烷、四氢呋喃、乙二醇二甲醚或二甘醇二甲醚、乙腈、丙酮或酰胺类(例如六甲基磷酰胺或二甲基甲酰胺)，或卤代烃类(例如二氯甲烷、四氯化碳)或烃类(例如苯或甲苯)、吡啶或乙酸。第一步骤优选二氯甲烷，而第二步骤优选吡啶或DMF。
适用于第一步骤的碱一般为碱金属碳酸盐或醇盐(例如碳酸钾或叔丁醇钾)、或环状胺类(例如哌啶或二甲氨基吡啶或吡啶)、或C1-C4烷基胺类，例如三乙胺。
在进行本发明方法时，可以使用任何所需比例的参与反应的物质，但是，反应一般是用摩尔用量的反应物进行的。
反应温度可以在相当宽的范围内进行。一般，反应在+10℃～+200℃，优选+20℃～+100℃，特别是在各溶剂的沸点下进行。
所述反应可以在常压下进行，但也可在高压或低压(例如0.5～3bar)下进行。一般地，反应是在常压下进行的。
适用于方法(B)的溶剂也是上述溶剂。优选二甲基甲酰胺或吡啶。
反应温度可以在相对宽的范围内进行。一般地，反应在+10℃～+200℃，优选+20℃～+150℃，特别是在各溶剂的沸点下进行。
对映体纯形式是例如按常规方法分离通式(I)化合物的非对映体混合物，其中R2或R3代表旋光酯基，然后，或者直接进行酯基转移作用，或者首先制备手性羧酸，然后通过酯化作用制备对映体纯的二氢吡啶类化合物得到的。
一般地，非对映体是通过分级结晶、柱色谱法、或逆流分配法分离。哪种方法是最佳方法必须视具体情况而定，有时也适宜使用上述各种方法的组合。特别适宜的是通过结晶法或逆流分配法或这两种方法的组合进行分离。
对映体纯化合物也可以通过在手性相上色谱分离外消旋酯来得到。
通式(II)、(III)、(IV)、(V)和(VI)化合物是本身已知的，或可以按常规方法制备。
本发明的通式(I)化合物具有不可预见的作用谱，特别是基于其对高传导性的钙依赖性钾通道的选择性。C6-BU1神经胶质瘤细胞的86铷流量
实验是按照Tas等人所述方法(Neurosci.Lett，94，279-284，(1988))并稍作改动来进行的。为此，使用了大鼠C6-BU1神经胶质瘤细胞。由液体闪烁计数所得的数据计算高出由伊屋诺霉素所产生的基本流量的流量增加，并确定为100％。然后将试验物质存在下的刺激与该值联系起来。
本发明还包括药物制剂，该药物制剂除含有惰性、无毒、适于药用的助剂和赋形剂(incipients)外，还含有一种或多种通式(I)化合物，或者该药物制剂由一种或多种式(I)活性化合物组成。本发明还包括这些制剂的制备方法。
式(I)活性化合物应以占全部混合物重量的0.1～99.5％，优选0.5～95％的浓度存在于这些制剂中。
除式(I)活性化合物外，所述药物制剂还可含有其他药物活性化合物。
上述药物制剂可以以常规方式按已知方法例如使用助剂或赋形剂来制备。
一般地，已证明有利地是，为达到所需结果，每千克体重每24小时给药的式(I)活性化合物的总量为约0.01～约100mg，优选总量为约1mg至50mg，如果必要，以几次单次剂量的形式给药。
然而，如果必要，也可以偏离上述用量是有利的，即这取决于待治疗的受试者的类型和体重，个体对药物的行为、疾病的性质和严重性、制剂和给药的类型，以及给药的时间或间隔。
起始化合物
实施例A2-乙酰基-3-(2，3-二氯苯基)-丙烯酸甲酯
将17.5g(100mmol)2，3-二氯苯甲醛和11.6g(100mmol)乙酰乙酸甲酯与1ml哌啶和0.5ml HOAc在350ml CH2Cl2中于脱水器中沸腾3小时。然后该混合物用水洗涤两次，用MgSO4干燥、并浓缩。残余物用石油醚/乙醚结晶，产量：15.0g(55％)。
实施例B
3-(4-硝基亚苄基)-戊-2，4-二酮
将30.2g(0.2mol)4-硝基苯甲醛和30.0g(0.3mol)乙酰丙酮溶于200ml异丙醇中，并用1.2ml哌啶和1ml冰醋酸处理。将该混合物在水浴中温热至形成澄清溶液为止，然后在室温下搅拌4小时。产物沉淀出，并进行抽滤。
用异丙醇和乙醚洗涤后，得到39.3g(84％)标题化合物。
制备实施例
实施例1
7-(2，3-二氯苯基)-5-甲基-1，2，3，7-四氢中氮茚-6，8-二甲酸二甲酯
将2.7g(10mmol)2-乙酰基-3-(2，3-二氯苯基)-丙烯酸甲酯和1.4g(10mmol)亚吡咯烷-2-基-乙酸甲酯在50ml异丙醇中加热回流12小时。然后将反应混合物冷却至室温，并用20ml石油醚处理。沉淀出的沉淀物抽滤出，并用异丙醇重结晶。得到1.5g(37％)标题化合物。
MS：395
Rf＝0.33(PE/AcOEt＝1∶1)
m.p.：173℃
表1中所列化合物用类似于实施例1的方法制备，若a＝2，任选使用亚哌啶-2-基-乙酸甲酯。
表1：
| 实施例编号 | D/E | a | 产率(理论值的％) | MS | m.p.(0℃) |
| 2 | 4-CF3/H | 1 | 15 | 395 | 129 |
| 3 | 4-Cl/H | 1 | 47 | 361 | 155 |
| 4 | 4-Cl/H | 2 | 51 | 375 | 135 |
实施例5
1-[6-乙酰基-5-甲基-7-(4-硝基苯基)-1，2，3，7-四氯中氮茚-8-基]乙酮
将4.66g(20mmol)实施例B的化合物和2.50g(20mmol)1-亚吡咯烷-2-基-丙-2-酮在100℃下在80ml吡啶中搅拌20小时。然后浓缩混合物，并用色谱法纯化(CH2Cl2/AcOEt＝10+1)。用AcOEt结晶出4.6g(75％)标题化合物。
MS：340
Rf＝0.16(PE/AcOEt＝1+1)
表2中所列化合物按类似于实施例5中的方法制备：
表2
*PE/AcOEt＝1∶1
| 实施例编号 | D/E | 产率(理论值的％) | MS | Rf * |
| 6 | 3，4-Cl | 42 | 363 | 0.27 |
| 7 | 2，3-Cl | 72 | 363 | 0.21 |
| 8 | 4-CF3 | 26 | 363 | 0.26 |
| 9 | 4-Cl，3-CF3 | 61 | 397 | 0.22 |
实施例106-(3-硝基苯基)-7-氧代-1，2，3，4，6，7，8，9，10-九氢吡啶并[1，2-a]喹啉-5-甲酸甲酯
将4.23g(28.3mmol)3-硝基苯甲醛、3.17g(28.3mmol)环己-1，3-二酮和4.5g(28.3mmol)亚哌啶-2-基-乙酸甲酯在80ml DMF中保持回流。4小时后，浓缩混合物，残余物与甲苯共同蒸馏两次，并用硅胶纯化(石油醚/CH2Cl2＝2∶1)。浓缩适当的级分，并用乙醚结晶。得到2.1g标题化合物。
MS：382
Rf＝0.23
表3中所列化合物是按与实施例10类似的方法制备的，若a＝1，则任选使用吡咯烷-2-乙酸甲酯：表3
*＝PE/AcOEt 1∶1
| 实施例编号 | W/X | Y | Z | a | Rf * | 产率(理论值的％) | MS |
| 11 | 3-H，4-Cl | H | H | 2 | 0.30 | 17 | 371 |
| 12 | 2-Cl，3-Cl | H | H | 2 | 0.34 | 19 | 405 |
| 13 | 3-H，4-Cl | H | H | 1 | 0.18 | 55 | 357 |
| 14 | 2-Cl，3-Cl | H | H | 1 | 0.19 | 25 | 391 |
| 15 | 3-H，4-Cl | CH3 | CH3 | 1 | 0.38 | 79 | 385 |
| 16 | 2-Cl，3-Cl | CH3 | CH3 | 1 | 0.39 | 79 | 419 |
| 17 | 2-H，3-NO2 | H | H | 1 | 0.17 | 35 | 368 |
实施例18
6-乙酰基-7-(2，3-二氯苯基)-5-甲基-1，2，3，7-四氢中氮茚-8-甲酸甲酯
将2.57g(10mmol)实施例A的化合物与1.4g(10mmol)亚吡咯烷-2-基-乙酸甲酯一起溶于吡啶中，将混合物在100℃保持12小时。将反应溶液冷却，并与甲苯一起蒸馏两次，残余物用快速色谱法纯化(石油醚/AcOEt＝8∶1)。标题化合物用Et2O结晶。得到产量为250mg(7％)。
Rf＝0.50(PE/AcOEt＝1∶1)
MS：379
表4中所列化合物用类似于实施例18的方法来制备：表4
*＝PE/AcOEt＝1∶1
| 实施例编号 | W/X | a | MS | 产率(理论值的％) | Rf * |
| 19 | 3-H，4-Cl | 1 | 345 | 35 | 0.46 |
Claims (4)
1.通式(I)的1，2-桥连的1，4-二氢吡啶类化合物用于制备对钾通道具有选择性调节作用、用于控制中枢神经系统疾病的药物的用途，
其中：
R1代表具有6-10个碳原子的芳基，该芳基任选被相同或不同的硝基、氰基、卤素或三氟甲基取代基或被具有最多达6个碳原子的直链或支链烷硫基取代最多达5次，
R2和R3可相同或不同，并各自代表具有最多达8个碳原子的直链或支链烷基或烷氧基或苯基，
a代表数字1、2或3；
R4代表甲基，或
R3和R4一起形成式-CH2-CH2-CH2-或-CH2-C(CH3)2-CH2-基团。
2.权利要求1所述的通式(I)化合物用于制备权利要求1的药物的用途，其中
R1代表苯基或萘基，它们各自任选被相同或不同的硝基、氰基、氟、氯、溴、碘或三氟甲基取代基或被具有至多4个碳原子的直链或支链烷硫基取代至多达3次，
R2和R3可相同或不同，并各自代表具有最多达4个碳原子的直链或支链烷基或烷氧基、或苯基，
a代表数字1或2，
R4代表甲基，或
R3和R4一起形成式-CH2-CH2-CH2-或-CH2-C(CH3)2-CH2-基团。
3.权利要求1所述的通式(I)化合物用于制备权利要求1的药物的用途，其中
R1代表苯基，该苯基任选被相同或不同的硝基、氰基、氟、氯、溴、碘、三氟甲基取代基或被甲硫基取代最多达2次，
R2和R3可相同或不同，并各自代表甲基、乙基或甲氧基，
a代表数字1或2，
R4代表甲基，或
R3和R4-起形成式-CH2-CH2-CH2-或-CH2-C(CH3)2-CH2-基团。
4.权利要求1所述的通式(I)化合物，它们选自下列化合物：
7-(2，3-二氯苯基)-5-甲基-1，2，3，7-四氢中氮茚-6，8-二羧酸二甲酯，
5-甲基-7-(4-三氟甲基苯基)-1，2，3，7-四氢中氮茚-6，8-二羧酸二甲酯，
7-(4-氯苯基)-5-甲基-1，2，3，7-四氢中氮茚-6，8-二羧酸二甲酯，
2-(4-氯苯基)-4-甲基-6，7，8，9-四氢-2H-喹嗪-1，3-二羧酸二甲酯，
1-[6-乙酰基-5-甲基-7-(4-硝基苯基)-1，2，3，7-四氢中氮茚-8-基]乙酮，
1-[6-乙酰基-7-(3，4-二氯苯基)-5-甲基-1，2，3，7-四氢中氮茚-8-基]乙酮，
1-[6-乙酰基-7-(2，3-二氯苯基)-5-甲基-1，2，3，7-四氢中氮茚-8-基]乙酮，
1-[6-乙酰基-5-甲基-7-(4-三氟甲基苯基)-1，2，3，7-四氢中氮茚-8-基]乙酮，
1-[6-乙酰基-7-(4-氯-3-三氟甲基苯基)-5-甲基-1，2，3，7-四氢中氮茚-8-基]乙酮，
6-(3-硝基苯基)-7-氧代-1，2，3，4，6，7，8，9，10-九氢吡啶并[1，2-a]喹啉-5-羧酸甲酯，
6-(4-氯苯基)-7-氧代-1，2，3，4，6，7，8，9，10-九氢吡啶并[1，2-a]喹啉-5-羧酸甲酯，
6-(2，3-二氯苯基)-7-氧代-1，2，3，4，6，7，8，9，10-九氢吡啶并[1，2-a]喹啉-5-羧酸甲酯，
5-(4-氯苯基)-6-氧代-1，2，3，5，6，7，8，9-八氢-吡咯并[1，2-a]喹啉-4-羧酸甲酯，
5-(2，3-二氯苯基)-6-氧代-1，2，3，5，6，7，8，9-八氢吡咯并[1，2-a]喹啉-4-羧酸甲酯，
5-(4-氯苯基)-8，8-二甲基-6-氧代-1，2，3，5，6，7，8，9-八氢吡咯并[1，2-a]喹啉-4-羧酸甲酯，
5-(2，3-二氯苯基)-8，8-二甲基-6-氧代-1，2，3，5，6，7，8，9-八氢吡咯并[1，2-a]喹啉-4-羧酸甲酯，
5-(3-硝基苯基)-6-氧代-1，2，3，5，6，7，8，9-八氢吡咯并[1，2-a]喹啉-4-羧酸甲酯，
6-乙酰基-7-(2，3-二氯苯基)-5-甲基-1，2，3，7-四氢中氮茚-8-羧酸甲酯，和
6-乙酰基-7-(4-氯苯基)-5-甲基-1，2，3，7-四氢中氮茚-8-羧酸甲酯。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4444860.0 | 1994-12-16 | ||
| DE4444860A DE4444860A1 (de) | 1994-12-16 | 1994-12-16 | Verwendung von 1,2-überbrückten 1,4-Dihydropyridinen als Arzneimittel |
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| Publication Number | Publication Date |
|---|---|
| CN1133841A CN1133841A (zh) | 1996-10-23 |
| CN1059442C true CN1059442C (zh) | 2000-12-13 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95120851A Expired - Fee Related CN1059442C (zh) | 1994-12-16 | 1995-12-15 | 1,2－桥连的1,4－二氢吡啶类化合物作为药物的用途 |
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| Country | Link |
|---|---|
| US (2) | US5990121A (zh) |
| EP (2) | EP0717043B1 (zh) |
| JP (1) | JPH08239384A (zh) |
| KR (1) | KR960022517A (zh) |
| CN (1) | CN1059442C (zh) |
| AT (1) | ATE186536T1 (zh) |
| AU (1) | AU709760B2 (zh) |
| CA (1) | CA2165131A1 (zh) |
| CZ (1) | CZ332895A3 (zh) |
| DE (2) | DE4444860A1 (zh) |
| DK (1) | DK0717043T3 (zh) |
| EE (1) | EE9500076A (zh) |
| ES (1) | ES2139824T3 (zh) |
| FI (1) | FI956016A (zh) |
| GR (1) | GR3032394T3 (zh) |
| HU (1) | HUT74166A (zh) |
| IL (1) | IL116386A (zh) |
| MX (1) | MX9505097A (zh) |
| NO (1) | NO955103L (zh) |
| NZ (1) | NZ280661A (zh) |
| PL (1) | PL180439B1 (zh) |
| RU (1) | RU2155765C2 (zh) |
| SI (1) | SI0717043T1 (zh) |
| SK (1) | SK158095A3 (zh) |
| ZA (1) | ZA9510695B (zh) |
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| US20050075359A1 (en) * | 2003-03-14 | 2005-04-07 | Rikako Kono | Large conductance calcium-activated K channel opener |
| US7394475B2 (en) * | 2004-02-13 | 2008-07-01 | Infoprint Solutions Company, Llc | Apparatus, system, and method for image registration |
| WO2006000607A1 (es) * | 2004-06-23 | 2006-01-05 | Neurotec Pharma, S.L. | Uso de activadores de los canales de katp (kco), en particular el diazóxido, en el tratamiento de la inflamación crónica de snc asociada a algunas efermedades |
| ES2352203T3 (es) * | 2004-06-23 | 2011-02-16 | Neurotec Pharma, S.L. | Compuesto para uso en el diagnóstico de daño agudo del sistema nervioso central. |
| AU2006203819A1 (en) * | 2005-01-07 | 2006-07-13 | Roskamp Research Llc | Compounds for inhibiting beta-amyloid production and methods of identifying the compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2210633C2 (de) * | 1972-03-06 | 1983-09-22 | Bayer Ag, 5090 Leverkusen | Kondensierte Pyridinderivate, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel |
| US4053614A (en) * | 1972-03-06 | 1977-10-11 | Bayer Aktiengesellschaft | 1,2-pentamethylene-1,4-dihydropyridine derivatives |
| US3951988A (en) * | 1972-03-06 | 1976-04-20 | Bayer Aktiengesellschaft | 1,2-Pentamethylene-1,4-dihydropyridine derivatives |
| DE2210674C3 (de) * | 1972-03-06 | 1981-09-24 | Bayer Ag, 5090 Leverkusen | 2-Amino-6-methyl-1,4-dihydropyridine, Verfahren zu ihrer Herstellung und sie enthaltende Arzneimittel |
| US3935220A (en) * | 1972-03-06 | 1976-01-27 | Bayer Aktiengesellschaft | Tetrahydroimidazolo[1,2-a]pyridine derivatives |
| US5225566A (en) * | 1992-05-08 | 1993-07-06 | American Home Products Corporation | Indazolanonyl derivative of benzopyran |
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- 1995-12-04 EP EP99105350A patent/EP0924211A3/de not_active Withdrawn
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- 1995-12-07 AU AU40294/95A patent/AU709760B2/en not_active Ceased
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