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Pyridylphenyl compounds for inflammation and immune-related uses

a technology of pyridylphenyl and compounds, applied in the field of biologically active chemical compounds, can solve the problems of inability to achieve antigenic stimulation, and inability to inhibit il-2 production, so as to prevent inflammatory conditions and immune disorders, and inhibit activity

Inactive Publication Date: 2007-11-01
SYNTA PHARMA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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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  • Pyridylphenyl compounds for inflammation and immune-related uses
  • Pyridylphenyl compounds for inflammation and immune-related uses
  • Pyridylphenyl compounds for inflammation and immune-related uses

Examples

Experimental program
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specific embodiments

[0090] 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.

[0091] One embodiment of the invention relates to compounds of formula (I):

[0092] or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein:

[0093] Y is a monocyclic optionally substituted aryl or a monocyclic optionally substituted heteroaryl;

[0094] L is a linker selected from the group consisting of —NRCR2—, —CR2NR—, —C(O)—, —NR—C(O)—, —C(O)—NR—, —OC(O)—, —C(O)O—, —C(S)—, —NR—C(S)—, —C(S)—NR—;

[0095] one of X1 or X2 is CH or CZ and the other is N;

[0096] each Z is independently selected from the group consisting of a lower alkyl, a lower haloalkyl, a halo, a lower alkoxy, a lower alkyl sufanyl, —S(O)p-alkyl, —C(O)NRR, —(CH2)kNRR, —(CH2)kOR, —(CH2)kSR, cyano, nitro, or lower haloalkoxy;

[0097] R, for each occurrence is independently select...

example 1

Synthesis of Representative Exemplary Compounds of this Invention

Compound 1

N-[6-(2-chloro-5-trifluoromethyl-phenyl)-pyridin-3-yl]-2,6-difluoro-benzamide

[0287]

[0288] A mixture of 2-chloro-5-trifluoromethyl-phenylboronic acid (a, 1 mmol), 6-bromo-pyridin-3-ylamine (b, 1 mmol), palladium catalyst (0.1 mmol), sodium bicarbonate (1 mmol) in a mixture of toluene (5 mL), water (1 mL), ethanol (1 mL) was heated at 100° C. for 24 h. The mixture was taken up with EtOAc (100 mL), washed with water (2×100 mL) and dried (Na2SO4). The oil obtained on concentration was purified by flash chromatography to give c as a yellowish oil (0.20 mg).

[0289] The above oil was treated with 2,6-difluorobenzoic chloride (0.6 mmol) in DCM (5 mL) and pyridine (0.2 mL) at rt for 2 h. Removal of solvents and purification of the residue by chromatography gave product d as yellow solid (0.15 g). 1H-NMR (CDCl3) δ 8.8 (d, 1H, J=2), 8.5 (dd, 1H, J1=9, J2=2), 7.91 (s, 2H), 7.8 (d, 1H, J=8), 7.6 (m, 2H), 7.5 (m, 1H), 7...

example 2

Inhibition of IL-2 Production

[0334] Jurkat cells were placed in a 96 well plate (0.5 million cells per well in 1% FBS medium) 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 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 5% of maximum IL-2 production after stimulation was inhibited versus a non-stimulation control.

Compound #IC50 (nM)6674831021314141615981615172181219720122131677683869737097117721773177425759876977117810791080180

[0335] Inhibition of other cytokines, such as IL-4, IL-...

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Abstract

The invention relates to compounds of structural formula (I): or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Y, L, X1, X2, Z, R3, R4, and n are defined herein. These compounds 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. 60 / 763,782, filed Jan. 31, 2006, the entire teachings of which are incorporated herein by reference.FIELD OF THE INVENTION [0002] This invention relates to biologically active chemical compounds, namely pyridylphenyl derivatives 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 initiat...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/44C07D211/70C07D211/72C07D213/72
CPCC07D211/70C07D211/72C07D213/72C07D213/75C07D213/81C07D401/12C07D417/14C07D409/10C07D413/10C07D413/14C07D417/10C07D417/12C07D405/10A61P1/02A61P1/04A61P1/16A61P3/06A61P3/10A61P7/04A61P7/06A61P9/00A61P9/10A61P11/00A61P11/06A61P13/12A61P15/00A61P17/00A61P17/06A61P19/02A61P19/08A61P21/00A61P21/04A61P25/00A61P25/14A61P25/16A61P25/28A61P27/02A61P27/16A61P29/00A61P35/00A61P37/00A61P37/02A61P37/06A61P37/08A61P43/00
Inventor JIANG, JUNXIA, ZHI-QIANGZHANG, JUNYIBOHNERT, GARYCHEN, SHOUJUNXIE, YU
Owner SYNTA PHARMA CORP
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