2-Phenoxy- and 2-Phenylsulfonamide Derivatives with CCR3 Antagonistic Activity for the Treatment of Inflammatory or Immunological Disorders

a technology of ccr3 and derivatives, which is applied in the field of benzenesulfonamide derivatives, can solve the problems that no reference and other reference disclose simple benzenesulfonamide derivatives with ccr3 antagonistic activity, and achieve excellent ccr3 antagonistic activity, treatment and prophylaxis of diseases, and effective treatment and prophylaxis

Inactive Publication Date: 2009-11-19
LI YINGFU +10
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, none of the reference and other reference discloses simple benzenesulfonamide derivatives having CCR3 antagonistic activity.

Method used

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  • 2-Phenoxy- and 2-Phenylsulfonamide Derivatives with CCR3 Antagonistic Activity for the Treatment of Inflammatory or Immunological Disorders
  • 2-Phenoxy- and 2-Phenylsulfonamide Derivatives with CCR3 Antagonistic Activity for the Treatment of Inflammatory or Immunological Disorders
  • 2-Phenoxy- and 2-Phenylsulfonamide Derivatives with CCR3 Antagonistic Activity for the Treatment of Inflammatory or Immunological Disorders

Examples

Experimental program
Comparison scheme
Effect test

example 1-1

N—(R-(+)-(1-aza-bicyclo[2.2.2]oct-3-yl)-5-cyano-2-(3,5-dichloro-phenoxy)-benzenesulfonamide

[0252]

[0253]To a suspension of (R)-(+)-3-aminoquinuclidine 2HCl (2.87 g, 14.4 mmol) in dry CH2Cl2 (25 ml) was added Et3N (5.88 ml, 42.0 mmol). The mixture was stirred for 2 hours at room temperature followed by the addition of the solution of 5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl-chloride (90%, 4.83 g, 12 mmol) in dry CH2Cl2 (10 ml) dropwise. After stirred for 5 hours at room temperature, CH2Cl2 (160 mL) was added and the mixture was washed with water, sat. Na2CO3 aq., brine and dried over MgSO4. The solvent was evaporated, and the product was recrystallized from the mixture of EtOAc and hexane to give N—(R)-(+)-(1-aza-bicyclo[2.2.2]oct-3-yl)-5-cyano-2-(3,5-dichloro-phenoxy)-benzenesulfonamide (4.30 g, 79.2%) as white solid.

[0254]1H NMR (300 MHz, CDCl3): 1.46-1.59 (2H, m), 1.68-1.72 (1H, m), 1.86-1.88 (2H, m), 2.69-2.99 (6H, m), 3.20-3.28 (1H, m), 3.46-3.51 (1H, m), 7.00 (1H, d, J=8.67...

example 1-2

5-cyano-2-(3,5-dichloro-phenoxy)-N-(2-dimethylamino-ethyl)-N-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethyl]-benzenesulfonamide

(1) 5-cyano-2-(3,5-dichloro-phenoxy)-N-(2-dimethylamino-ethyl)-benzenesulfonamide

[0259]

[0260]To a solution of N1, N1-dimethyl-ethane-1,2-diamine (74.0 mg, 0.84 mmol) and Et3N in dry CH2Cl2 (3 ml) was added the solution of 5-cyano-2-(3,5-dichlorophenoxy)phenylsul-fonylchloride (90%, 282 mg, 0.7 mmol) in dry CH2Cl2 (6 ml) dropwise. The resulting solution was stirred at room temperature for 1 hour. CH2Cl2 (60 ml) was added and the mixture was washed with water, brine, and dried over MgSO4. The solvent was evaporated, and the residue was purified by column chromatography (CH2Cl2 / CH3OH=10:1) to give 5-cyano-2-(3,5-dichloro-phenoxy)-N-(2-dimethylamino-ethyl)-benzene-sulfonamide as white solid (220 mg, 75.9%): HPLC-MS (ESI): Calcd for C19H21Cl2N3O4S [M+H]+ 414. Found: 414

(2) 1-(2-bromo-ethyl)-pyrrolidine-2,5-dione

[0261]

[0262]To a mixture of dihydro-furan-2,5-dione (396 mg, 4...

example 1-3

4-(3,5-dichlorophenoxy)-3-[(3S)-(1H-indol-3-ylmethyl)-piperazine-1-sulfonyl]-benzonitrile

(1) [(2S)-benzyloxycarbonylamino-3-(1H-indol-3-yl)-propionylamino]-acetic acid ethyl ester

[0270]

[0271]To a mixture of (2S)-benzyloxycarbonylamino-3-(1H-indol-3-yl)-propionic acid (4.16 g, 12.3 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrogen chloride (2.83 g, 14.8 mmol), 1-hydroxybenzotriazole (1.99 g, 14.8 mmol) and Et3N (5.14 ml, 36.9 mmol) in dry THF (20 ml) was added amino-acetic acid ethyl ester hydrogen chloride (1.72 g, 12.3 mmol) portionwise. The reaction mixture was stirred for 3 days at room temperature. The organic solvent was evaporated in vacuo, and the residue was diluted with EtOAc. The organic layer was washed with 0.5N HCl, saturated NaHCO3aq., brine, and dried over MgSO4. The organic layer was concentrated to give [(2S)-benzyloxycarbonylamino-3-(1H-indol-3-yl)-propionylamino]-acetic acid ethyl ester (5.10 g, 97.9%) as yellow sticky oil: HPLC-MS (ESI): Calcd for C2...

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Abstract

Provided herein are 2-phenoxy- and 2-phenylsulfonamide derivatives with CCR3 antagonistic activity. These compounds are useful for the treatment of diseases associated with CCR3 activity, including but not limited to, atopic dermatitis, allergic rhinitis, rheumatoid arthritis, Grave's disease, HIV infection, Alzheimer's disease, atherosclerosis and other inflammatory and / or immunological disorders.

Description

TECHNICAL FIELD[0001]The present invention relates to a benzenesulfonamide derivative, which is useful as an active ingredient of pharmaceutical preparations. The benzenesulfonamide derivatives of the present invention have CCR3 (CC type chemokine receptor 3) antagonistic activity, and can be used for the prophylaxis and treatment of diseases associated with CCR3 activity, in particular for the treatment of asthma, atopic dermatitis, allergic rhinitis and other inflammatory / immunological disorders.BACKGROUND ART[0002]Chemokines are chemotactic cytokines of which major functions are migration of inflammatory cells that express relevant chemokine receptors on their surfaces to sites of inflammation, and activation of inflammatory cells. There are two classes of chemokines, C-X-C (.alpha.) and C-C (i), depending on whether the first two cysteines are separated by a single amino acid (C-X-C) or are adjacent (C-C).[0003]Eotaxin, one of the C-C family of chemokines, is an 8.4 kDa (74 amin...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/496A61K31/439A61K31/551A61K31/55A61P9/10A61P25/28A61P31/18A61K31/4015A61K31/405A61K31/4965A61K31/497C07C311/29C07C311/37C07D207/12C07D207/14C07D207/16C07D207/34C07D207/40C07D207/404C07D211/54C07D223/12C07D241/04C07D243/08C07D257/04C07D295/13C07D295/26C07D303/06C07D401/04C07D401/06C07D403/04C07D403/06C07D453/02C07D487/04
CPCC07C311/29C07D487/04C07D207/14C07D207/16C07D207/40C07D207/404C07D207/48C07D211/54C07D223/12C07D241/04C07D243/08C07D257/04C07D295/13C07D295/22C07D295/26C07D303/06C07D303/36C07D401/04C07D401/06C07D401/14C07D403/06C07D403/12C07D453/02C07D207/12A61K31/439C07D487/02C07D487/08A61P11/02A61P11/06A61P25/28A61P27/14A61P29/00A61P31/18A61P35/00A61P37/00A61P37/02A61P37/06A61P37/08A61P43/00A61P9/10C07C311/37C07D207/34
Inventor LI, YINGFUBACON, KEVINSUGIMOTO, HIROMIFUKUSHIMA, KEIKOHASHIMOTO, KENTAROMARUMO, MAKIKOMORIWAKI, TOSHIYANUNAMI, NORIKOTSUNO, NAOKIURBAHNS, KLAUSYOSHIDA, NAGAHIRO
Owner LI YINGFU
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