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Interleukin-4 gene expression inhibitors

a technology of interleukin-4 and gene expression inhibitor, which is applied in the direction of antibacterial agents, immunological disorders, drug compositions, etc., can solve the problems of inflammation of the lower airway, additional health risks of overactivation of th2 cytokines,

Inactive Publication Date: 2008-06-05
AVENTIS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0043]Thus in accordance with the practice of this invention there is provided a method of treating a variety of inflammatory disease conditions. In general, the disease conditions that can be treated in accordance with the practice of this invention include but not limited to allergy, asthma, rhinitis...

Problems solved by technology

Med., (2001), 344, 350-362., the overactivation of Th2 cytokines has additional health risks by predisposing patients to disease conditions associated with low levels of Th1 cells.
Chemical allergy is a common and important occupational health issue.
This natural exposure may induce inflammatory cell recruitment and cytokine release, leading to inflammation of the lower airways.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

[0389]

Scheme A, Step A1: 3-Amino-6-trifluoromethyl-1H-indole-2-carboxylic acid, ethyl ester

[0390]Under nitrogen, stir and heat a mixture of 2-fluoro-4-(trifluoromethyl)benzonitrile (1.0 g, 5.29 mmol), ethyl glycinate hydrochloride (886 mg, 6.3 mmol), potassium carbonate (1.46 g, 6.3 mmol) and 1-methyl-2-pyrrolidinone (20 mL) at 115-120° C. After six hours add potassium tert-butoxide (700 mg, 6.2 mmol), and stir at ambient temperature for 2 h. Quench into ice / water, extract the aqueous mixture with ether, wash the extract with water and dry it with magnesium sulfate. Filter and concentrate under vacuum to yield the crude product. Chromatograph the crude product on silica gel (10 g, Sepack cartridge) with dichloromethane as eluent to afford 332 mg (23%) of the title compound. Identical on TLC (silica gel, dichloromethane) to the compound disclosed in U.S. Pat. No. 5,189,054.

example 2

[0391]

Scheme A, Step A1: 3-Amino-6-fluoro-1H-indole-2-carboxylic acid, ethyl ester

[0392]Under nitrogen, stir and heat a mixture of 2,4-difluorobenzonitrile (1.14 g, 8.2 mmol), ethyl glycinate hydrochloride (1.5 mg, 10.7 mmol), potassium carbonate (3.4 g, 24.6 mmol) and 1-methyl-2-pyrrolidinone (20 mL). After 2 h allow the reaction to cool to 40° C. and add potassium tert-butoxide (300 mg, 2.7 mmol). Allow the reaction to stir and for 1 h and then add additional potassium tert-butoxide (500 mg, 4.4 mmol). Cool to room temperature overnight, pour the reaction mixture onto ice. Add water to dissolve the solids in the reaction flask and add to the reaction quench. Filter off the precipitated brown solid and extract the filtrate with ethyl acetate. Wash the extract with water (2×'s), brine and dry over magnesium sulfate. Filter and concentrate under vacuum to give a residue, which is triturated with dichloromethane to afford a solid. Collect the solid, concentrate the filtrate and chroma...

example 3

[0393]

Scheme B: 3-Amino-5-chloro-1H-indole-2-carboxylic acid, ethyl ester

Step B1: 2-Amino-N-tert-butyl-5-chlorobenzamide

[0394]Stir and cool to 0° C. a solution of 2-amino-5-chlorobenzoic acid (1.21 g, 10 mmol) and N-hydroxysuccinimide (1.38 g, 12 mmol) in dichloromethane (12 mL). Add, dropwise, a 1M solution of dicyclohexylcarbodiimide in dichloromethane (12 mL, 12 mmol), and stir at 0° C. for 1 h. Add tert-butyl amine (1.74 g, 23.79 mmol) by syringe and stir at ambient temperature overnight. Filter the reaction mixture and wash the filtrate with aqueous sodium bicarbonate. Dry the organic phase with MgSO4 and chromatograph over silica gel eluting with 4% ethyl acetate / dichloromethane to afford 1.74 g of the title compound: MS 227 (M+H), m.p. 126-127° C.

Step B2: N-(4-Chloro-2-cyanophenyl)-2,2,2-trifluoroacetamide

[0395]Stir and cool to 0° C. a solution 2-amino-N-tert-butyl-5-chlorobenzamide (5.07 g, 22.36 mmol) in dichloromethane (200 mL), and add, dropwise trifluoroacetic anhydride....

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Abstract

This invention discloses and claims a class of indole and benzo(b)thiophene derivatives for use in treating allergy, asthma, rhinitis, dermatitis, B-cell lymphomas, tumors and diseases associated with bacterial, rhinovirus or respiratory syncytial virus (RSV) infections. The compounds of this invention are defined by the Formula (I):wherein X, Y, Z, R1, R2 and R3 are as defined in the specification; or a pharmaceutically acceptable salt thereof. In preferred embodiments of this invention it is also disclosed and claimed that the compounds of this invention are capable of modulating T helper (Th) cells, Th1 / Th2, and thereby capable of inhibiting the transcription of interleukin-4 (IL-4) message, IL-4 release or IL-4 production.

Description

[0001]This application is a continuation of U.S. application Ser. No. 10 / 421,597, filed Apr. 23, 2003, now pending, which claims the benefit of U.S. Provisional Application No. 60 / 375,304, filed Apr. 23, 2002.BACKGROUND OF THE INVENTION[0002]1. Field of the Invention[0003]The present invention relates to medical methods of treatment of inflammatory disease conditions, such as for example, allergy, asthma, rhinitis, dermatitis, B-cell lymphomas, tumors and diseases associated with bacterial, rhinovirus or respiratory syncytial virus (RSV) infections. More specifically, the present invention relates to treatment of aforementioned inflammatory diseases in a patient by administering to such a patient a compound capable of inhibiting the transcription of interleukin-4 (IL-4) message, IL-4 release or IL-4 production. In particular, the present invention concerns the use of various indole derivatives.[0004]2. Description of the State of the Art[0005]The immune system consists of a sophisti...

Claims

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Application Information

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IPC IPC(8): A61K31/4439A61K31/404A61K31/5355A61K31/4545A61P17/00A61P19/02A61P11/06A61K31/381A61K31/40A61K31/405A61K31/4436A61K31/454A61K31/506A61K31/5377A61P11/02A61P27/16A61P29/00A61P31/04A61P31/12A61P35/00A61P37/08A61P43/00C07D209/42C07D401/12C07D401/14C07D403/12C07D405/12C07D405/14C07D409/12C07D417/12
CPCA61K31/381A61K31/40A61K31/405C07D209/42C07D417/12C07D401/14C07D403/12C07D405/14C07D409/12C07D401/12A61P11/00A61P11/02A61P11/06A61P17/00A61P19/02A61P27/16A61P29/00A61P31/04A61P31/12A61P35/00A61P37/08A61P43/00A61K31/4045
Inventor ALKAN, SEFIK S.DINERSTEIN, ROBERT J.HRIB, NICHOLAS J.SUBRAMANIAM, ARUNJURCAK, JOHN G.
Owner AVENTIS PHARMA INC
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