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The use of substituted tetracyclic imidazole derivatives as anti-histaminics

一种颅内压、用途的技术，应用在含有效成分的医用配制品、退热药、抗炎剂等方向

Inactive Publication Date: 2009-04-15
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

So far, there are no drugs approved for rapid treatment of intracranial pressure (K.K. Jain, Chapter 4: Neuroprotection in Acute Trauma, ' in the CNS Neuroprotection in Disease: A Business Opportunity’, A Jain PharmaBiotech Report :65-73, 2000)

Method used

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  • The use of substituted tetracyclic imidazole derivatives as anti-histaminics
  • The use of substituted tetracyclic imidazole derivatives as anti-histaminics
  • The use of substituted tetracyclic imidazole derivatives as anti-histaminics

Examples

Experimental program
Comparison scheme
Effect test

Embodiment A1

[0105] a) Preparation of Intermediate 1

[0106]

[0107] Use dry glassware. A mixture of (methoxymethyl)triphenylphosphine chloride (0.35mol) and THF p.a. (molecular sieves) (21) was 2 Under air flow, stir at -50°C. BuLi2.5M / hexane (0.35mol) was added dropwise and the resulting mixture was stirred at -25°C for 30 minutes. At -25°C, a THF solution of 1,2-bis(benzyl)-4-piperidone (0.35 mol) was added dropwise. The resulting mixture was allowed to warm to room temperature, then stirred overnight at room temperature, and the mixture was decomposed with water. The organic solvent was evaporated, and the resulting aqueous concentrate was treated with CH 2 Cl 2 extraction. The organic layer was separated and dried (MgSO 4 ), filtered and evaporated to remove the solvent. The resulting residue was purified by silica gel column chromatography (eluent: CH 2 Cl 2 / CH 3 OH 97.5 / 2.5). The purified fractions were collected and the solvent was distilled off. Obtained: 121 ...

Embodiment A2

[0121] a) Preparation of Intermediate 6

[0122]

[0123]Use dry glassware. A mixture of DIPA (0.22mol) and THF p.a. (pre-dried with molecular sieves) (1400ml) in N 2 Stir at -70°C under airflow. BuLi2.5M (0.185 mol) was added dropwise and the resulting mixture was stirred at -70°C for 15 minutes. A solution of 1-(benzyl)-1H-benzimidazole (0.185 mol) dissolved in THF was added dropwise at -70°C, and the resulting mixture was stirred at -70°C for 1 hour. A solution of Intermediate 2 (0.185 mol) dissolved in THF was added dropwise at -70°C. The resulting mixture was stirred at -70°C for 1 hour, then the temperature was slowly raised to room temperature, stirred at room temperature overnight, and the mixture was decomposed with water. The organic solvent was evaporated. Aqueous concentrate with CH 2 Cl 2 extraction. The organic layer was separated and dried (MgSO 4 ), filtered and evaporated to remove the solvent. The resulting residue was purified by silica gel co...

Embodiment A3

[0133] a) Preparation of Intermediate 10

[0134]

[0135] A mixture of DIPA (0.1mol) and THF (100ml) was placed under N 2 Stirring under air flow, the mixture was cooled to -70°C and BuLi 2.5M / hexane (40ml) was added portionwise. The temperature was raised to -30°C while stirring for 10 minutes. The resulting mixture was cooled to -70°C. At this temperature, a solution of 1-(phenethyl)-1H-benzimidazole (0.1 mol) in THF (50 ml) was added dropwise, and the resulting mixture was stirred at -70°C for 2 hours. Ethyl 4-formyl-1-piperidinecarboxylate (0.1 mol) was added dropwise and the resulting mixture was stirred at -70°C for 30 minutes. The mixture was allowed to warm to room temperature and stirring was continued for 30 minutes. The mixture was decomposed with water and evaporated. The resulting residue was stirred in water with CH 2 Cl 2 Extract this mixture. The organic layer was separated and dried (MgSO 4 ), filtered and evaporated to remove the solvent. The ...

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Abstract

The invention concerns a novel histamine receptor antagonist and the use of an histamine receptor antagonist for the reduction of intracranial pressure (ICP), in particular for the prevention and treatment of elevated intracranial pressure and / or secondary ischaemia, in particular caused by brain injury, more in particular caused by traumatic (TBI) and non-traumatic brain injury. The novel compounds comprise compounds according to the general Formula (I) the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof and the N-oxide form thereof. In particular, the preferred compound is 3-[2-[4-(11,12-dihydro-6H-benzimidazo[2,1-b][3]benzazepin-6-yl)-2-(phenylmethyl)-1-piperidinyl]ethyl]-2,10-dimethyl pyrimido[1,2-a]benzimidazol-4(10H)-one, the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof and the N-oxide form thereof. Also claimed is the novel use of commercially available histamine H1-and H2-receptor antagonists for the reduction of intracranial pressure (ICP).

Description

[0001] This application is a divisional application of the invention patent application PCT / EP02 / 13180 with the filing date of November 22, 2002, entitled "Use of antihistamines for rapid reduction of high intracranial pressure", and the original Chinese patent application The number is 02823014.0. technical field [0002] The present invention relates to a novel histamine receptor antagonist and the application of the histamine receptor antagonist in reducing intracranial pressure (ICP), especially in the prevention and treatment of traumatic brain injury ( TBI) and increased intracranial pressure and / or secondary ischemia from non-traumatic brain injury. Background technique [0003] TBI is a serious problem in developed countries. Each year in the United States, approximately 500,000 head injuries are so severe that they require hospitalization. Mortality is high, and approximately 80,000 TBI patients face lifelong debilitating loss of sexual function, 5,000 develop epi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K45/00A61P9/10A61P37/02A61P37/08A61P1/04A61P43/00C07D487/04A61K31/415A61K31/425A61K31/513A61K31/517A61K31/519A61K31/55A61P29/00A61P37/06C07D471/00C07D471/04C07D487/00C07D519/00
CPCC07D519/00C07D471/00C07D487/00A61P1/04A61P1/14A61P11/02A61P11/06A61P17/04A61P29/00A61P3/00A61P37/00A61P37/02A61P37/06A61P37/08A61P43/00A61P9/00A61P9/10A61P9/12A61K31/513
Inventor F·特格特梅尔F·E·扬森斯J·E·莱奈茨K·A·范罗塞姆M·J·阿尔卡扎-瓦卡P·马丁内斯-斯门尼斯J·M·巴托洛梅-涅夫雷达A·戈麦斯-桑切斯F·J·费尔南德斯-格德亚J·L·H·范雷姆普茨
Owner JANSSEN PHARMA NV
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