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Compounds for inflammation and immune-related uses

a technology of compounds and immune-related uses, applied in the field of biologically active chemical compounds, can solve the problems of inert antigenic stimulation, tissue damage, and agents that inhibit il-2 production, and achieve the effects of reducing side effects, reducing side effects, and reducing the amount of ion channel

Inactive Publication Date: 2012-11-08
SYNTA PHARMA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0011]The present disclosure, in an aspect, addresses the continuing need for new drugs which overcome one or more of the shortcomings of drugs currently used for immunosuppression or in the treatment or prevention of inflammatory disorders, allergic disorders and autoimmune disorders. Desirable properties of such drugs include efficacy against diseases or disorders that are currently untreatable or poorly treatable, new mechanism of action, oral bioavailability and / or reduced side effects. Accordingly, compounds that inhibit the activity of CRAC ion channels and inhibit the production of IL-2, IL-4, IL-5, IL-13, GM-CSF, TNFα, and IFN-γ are disclosed herein. These compounds are particularly useful for immunosuppression and / or to treat or prevent inflammatory conditions and immune disorders. The particular genus of compounds described herein are particularly advantageous in that they are believed to combine inhibition of CRAC ion channels (e.g., as measured by modulated ICRAC current) and cytokines including IL-2, low incidence of off-target effects, and a favorable toxicity profile.

Problems solved by technology

However, while transient inflammation is necessary to protect a mammal from infection, uncontrolled inflammation causes tissue damage and is the underlying cause of many illnesses.
IL-2, although useful in the immune response, can cause a variety of problems.
This renders them potentially inert to any antigenic stimulation they might receive in the future.
Despite this proof of concept, agents that inhibit IL-2 production remain far from ideal.
Among other problems, efficacy limitations and unwanted side effects (including dose-dependant nephrotoxicity and hypertension) hinder their use.

Method used

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  • Compounds for inflammation and immune-related uses
  • Compounds for inflammation and immune-related uses
  • Compounds for inflammation and immune-related uses

Examples

Experimental program
Comparison scheme
Effect test

specific embodiments

[0120]The invention relates to compounds and pharmaceutical compositions that are particularly useful for immunosuppression or to treat or prevent inflammatory conditions, immune disorders, and allergic disorders. Embodiments of the invention include those compounds described hereinabove in the Summary, e.g., those of formulae (I), (II) and (III).

[0121]All of the features, specific embodiments and particular substituents disclosed herein may be combined in any combination. Each feature, embodiment or substituent disclosed in this specification may be replaced by an alternative feature, embodiment or substituent serving the same, equivalent, or similar purpose. In the case of chemical compounds, specific values for variables (e.g., values shown in the exemplary compounds disclosed herein) in any chemical formula disclosed herein can be combined in any combination resulting in a stable structure. Furthermore, specific values (whether preferred or not) for substituents in one type of c...

example 1

Synthesis of Representative Exemplary Compounds of this Invention

[0170]General Procedure for Suzuki cross coupling: To a solution of [N-(3-bromo-4-methylphenyl)pyridin-2-amine] (95 mg, 0.36 mmol), dichloro-bis (triphenylphosphine)-palladium (II) (Pd(PPh3)2Cl2, 60 mg, 0.09 mmol), and 2,6-difluoro-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide (195 mg, 0.54 mmol) in toluene (10 mL) were added Na2CO3 (2 N, 1.0 mL) and ethanol (1.0 mL). The stirred mixture was heated at 80° C. for 16 hr. The solution was cooled to room temperature and diluted with H2O (10 mL) and EtOAc (10 mL). The organic phase was dried over Na2SO4, concentrated, and chromatographed to give the pure product in 61% yield.

2,6-Difluoro-N-(5-(5-methyl-2-(pyridin-2-yl)thiazol-4-yl)pyridin-2-yl)benzamide

[0171]

[0172]To the solution of 1 (1 g, 6.57 mmol) in DCM (50 mL) were added 2,6-difluorobenzoyl chloride (1.73 mL, 13.8 mmol) and pyridine (3.56 mL, 12.5 mmol) at room temperature. After stirring for 60 m...

example 2

Inhibition of IL-2 Production

[0214]Jurkat cells were placed in a 96 well plate (0.5 million cells per well in 1% FBS medium), and then a test compound of this invention was added at different concentrations. After 10 minutes, the cells were activated with PHA (final concentration 2.5 μg / mL) and incubated for 20 hours at 37° C. under 5% CO2. The final volume was 200 μL. Following incubation, the cells were centrifuged, and the supernatants collected and stored at −70° C. prior to assaying for IL-2 production. A commercial ELISA kit (IL-2 Eli-pair, Diaclone Research, Besancon, France) was used to detect production of IL-2, from which dose response curves were obtained. The IC50 value was calculated as the concentration at which 50% of maximum IL-2 production after stimulation was inhibited versus a non-stimulation control.

[0215]Inhibition of other cytokines, such as IL-4, IL-5, IL-13, GM-CSF, TNFα, and IFN-γ, can be tested in a similar manner using a commercially available ELISA kit f...

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Abstract

The invention relates to certain compounds, or pharmaceutically acceptable salts, solvates, clathrates, or prodrugs thereof, that are useful as immunosuppressive agents and for treating and preventing inflammatory conditions, allergic disorders, and immune disorders.

Description

RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Application No. 61 / 194,831, filed Oct. 1, 2008, the entire disclosure of which is incorporated herein by reference.FIELD OF THE INVENTION[0002]This invention relates to biologically active chemical compounds that may be used for immunosuppression or to treat or prevent inflammatory conditions and immune disorders.BACKGROUND OF THE INVENTION[0003]Inflammation is a mechanism that protects mammals from invading pathogens. However, while transient inflammation is necessary to protect a mammal from infection, uncontrolled inflammation causes tissue damage and is the underlying cause of many illnesses. Inflammation is typically initiated by binding of an antigen to T-cell antigen receptor. Antigen binding by a T-cell initiates calcium influx into the cell via calcium ion channels, such as Ca2+-release-activated Ca2+ channels (CRAC). Calcium ion influx in turn initiates a signaling cascade that leads to activ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/444C07D417/04A61K31/497A61K31/4436C07D409/06C07D409/14C07D417/14A61K31/4439
CPCC07D409/04C07D409/06C07D409/14C07D417/14C07D413/14C07D417/04C07D413/04A61P1/02A61P1/04A61P1/16A61P3/06A61P3/10A61P5/14A61P7/04A61P7/06A61P9/00A61P9/10A61P9/14A61P11/06A61P11/08A61P11/16A61P13/02A61P13/12A61P15/00A61P17/00A61P17/02A61P17/06A61P19/00A61P19/02A61P19/08A61P21/00A61P21/02A61P21/04A61P25/00A61P25/08A61P25/14A61P25/16A61P25/28A61P27/02A61P27/14A61P29/00A61P31/04A61P31/06A61P31/08A61P31/18A61P33/00A61P35/00A61P37/00A61P37/02A61P37/06A61P43/00
Inventor CHEN, SHOUJUNZHANG, JUNYIJIANG, JUNBOHNERT, GARYVO, NHACHE, QINGLINXIA, ZHIQIANGSUN, LIJUN
Owner SYNTA PHARMA CORP
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