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Compounds and methods for treatment of asthma, allergy and inflammatory disorders

A compound, an independent technology, applied in the direction of active ingredients of heterocyclic compounds, allergic diseases, anti-inflammatory agents, etc.

Inactive Publication Date: 2005-01-05
UCB SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, none of the documents teach or suggest or consider combining the 5-LO and 15-LO inhibiting functionality of the hydroxyurea group with [bis(substituted and / or unsubstituted aryl)methyl- and methylene The antihistaminergic properties of ]-1-piperidinyl or -1-piperazinyl are combined in a single entity, resulting in a compound that acts as both an antihistaminergic and a 5-LO / 15-LO inhibitor Compounds with dual functions

Method used

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  • Compounds and methods for treatment of asthma, allergy and inflammatory disorders
  • Compounds and methods for treatment of asthma, allergy and inflammatory disorders
  • Compounds and methods for treatment of asthma, allergy and inflammatory disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0135] N-{[4-(2-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperazinyl}ethoxy)phenyl]methyl}-amino-N-hydroxylamide ( Compound 1, figure 1 ) preparation

[0136] 4-(2-Bromoethoxy)benzyl alcohol (compound 101)

[0137] To a solution of 4-hydroxybenzyl alcohol (2.0 g, 16.11 mmol) in DMF (10 mL) was added potassium carbonate (2.67 g, 19.32 mmol) and the reaction mixture was stirred at room temperature for 30 minutes before adding 1,2-dibromoethane (3.03 g, 16.13 mmol), the reaction mixture was stirred at room temperature for another 20 hours, then quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine and evaporated to give an oil, the residue was purified by flash column chromatography (silica gel, 3:1 hexane / ethyl acetate) to give compound 101 (1.7 g, 45.7%):

[0138] 1 H NMR (CDCl 3 ) δ 3.64 (t, 2H), 4.29 (t, 2H), 4.62 (s, 2H), 6.91 (d, 2H), 7.30 (d, 2H).

[0139] 4-{2-[4-((1R)(4-chlorophenyl)phenylmethyl)piperazinyl]ethoxy}b...

Embodiment 2

[0148] N-{4-[4-(2-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperazinyl}ethoxy)phenyl]but-3-ynyl}-amino -N-hydroxyamide (compound 12, figure 2 ) preparation

[0149] 4-(2-Bromoethoxy)-1-iodobenzene (compound 105)

[0150] To a solution of 4-iodophenol (10.0 g, 45.45 mmol) in DMF (50 mL) was added potassium carbonate (12.6 g, 91.17 mmol), the reaction mixture was stirred at room temperature for 30 minutes, then 1,2-dibromoethane was added (17.07 g, 90.91 mmol), the reaction mixture was stirred at room temperature for an additional 16 hours, then quenched with water and extracted with dichloromethane. The organic layer was washed with water and brine and evaporated to give an oil, the residue was purified by flash column chromatography (silica gel, hexanes) to give compound 105 (2.7 g, 18.2%):

[0151] 1 H NMR (CDCl 3 ) δ 3.63 (t, 2H), 4.26 (t, 2H), 6.70 (d, 2H), 7.58 (d, 2H).

[0152] 4-[4-(2-Bromoethoxy)phenyl]but-3-yn-1-ol (Compound 106)

[0153] To compound 105 (2.7g,...

Embodiment 3

[0163] N-{4-[4-(2-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperazinyl}ethoxy)phenyl]butyl}-amino-N-hydroxy Preparation of Amide (Compound 17, Figure 3)

[0164] 4-[4-(2-Bromoethoxy)phenyl]butan-1-ol (compound 109)

[0165] A solution of compound 106 (1.3 g, 4.83 mmol) in methanol (15 mL) was hydrogenated over 10% palladium / charcoal (130 mg) under balloon pressure for 7 hours, the catalyst was filtered off and the filtrate was evaporated to give compound 109 (1.31 g, 99.2% ): 1 H NMR (CDCl 3 ) δ 1.65 (m, 4H), 2.60 (t, 2H), 3.66 (m, 4H), 4.28 (m, 2H), 6.83 (d, 2H), 7.10 (d, 2H).

[0166] 4-{4-[2-(4-((1R)(4-chlorophenyl)phenylmethyl)piperazinyl)ethoxy]phenyl}butan-1- Alcohol (compound 110)

[0167] To a solution of compound 109 (1.3 g, 4.76 mmol) and [(1R)(4-chlorophenyl)phenylmethyl]-piperazine (102) (1.39 g, 4.86 mmol) in DMF (12 mL) was added triethyl Amine (762.3 mg, 7.55 mmol). The reaction mixture was stirred at 50°C for 16 hours, water was added and the reaction m...

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Abstract

The present invention provides 1,4 substituted piperazines, 1,4 substituted piperidines, and 1-substituted,4-alkylidenyl piperidines compounds. The compounds of the invention are dual acting molecules having both leukotriene inhibition properties as well as antihistaminergic properties. The compounds of the invention are useful for treating conditions in which there is likely to be a histamine and / or leukotriene component. These conditions include preferably asthma, seasonal and perennial allergic rhinitis, sinusitus, conjunctivitis, food allergy, scombroid poisoning, psoriasis, urticaria, pruritus, eczema, rheumatoid arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, thrombotic disease and otitis media. Also provided are methods of treating asthma and rhinitis by administering an effective asthma and rhinitis-relieving amount of the compounds to a subject in need thereof.

Description

[0001] This application is a divisional application of the Chinese patent application submitted on March 23, 2000 with the application number 00806821.6 and the invention title "Compounds and Methods for Treating Asthma, Allergy and Inflammation". technical field [0002] The present invention relates to 1,4-substituted piperazines, 1,4-substituted piperidines and 1-substituted,4-alkylene piperidines. Background technique [0003] Leukotrienes are potent local mediators that play a major role in inflammatory and allergic reactions including rhinitis, asthma, psoriasis and thrombosis. Leukotrienes are linear eicosanoids produced by the oxidation of tetracosatetraenoic acid by lipoxygenase. Tetracosatetraenoic acid is oxidized by 5-lipoxygenase and eventually converted to leukotriene A4, B4, C4, D4 or E4. 15-lipoxygenase is responsible for converting tetracosatetraenoic acid to various biological Active metabolites include 15-hydroxy-5,8,11,13-eicosanetetraenoic acid (15-HETE...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/08A61K31/435A61K31/4545A61K31/473A61K31/495A61K31/496A61P1/00A61P1/04A61P7/02A61P11/00A61P11/02A61P11/06A61P17/00A61P17/04A61P17/06A61P19/02A61P27/02A61P27/14A61P27/16A61P29/00A61P37/00A61P37/08A61P39/02A61P43/00C07C275/64C07D295/00C07D295/084C07D295/088C07D295/092C07D295/096C07D295/12C07D295/125C07D295/13C07D295/135C07D295/14C07D295/15C07D307/14C07D307/52C07D401/04C07D401/06C07D401/08C07D403/06C07D405/06
CPCC07D307/14C07D295/15C07D295/096C07D295/135C07D295/125C07D295/088C07D295/084C07D307/52C07D401/04C07D295/13A61P1/00A61P1/04A61P11/00A61P11/02A61P11/06A61P17/00A61P17/04A61P17/06A61P19/02A61P27/02A61P27/14A61P27/16A61P29/00A61P37/00A61P37/08A61P39/02A61P43/00A61P7/02
Inventor R·斯卡尼尔P·查特莱恩A·托伊-普拉米尔E·狄费尔丁J·艾里斯M-A·拉斯奥M·洋戈蔡雄S·哈森G·格勒沃T·莱维斯
Owner UCB SA
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