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STAT modulators

a stat4 and stat6-mediated signal transduction technology, applied in the field of compound and pharmaceutical compositions, can solve the problems of hampered identification of agents that can modulate stat4 and stat6-mediated signal transduction, undesirable side effects,

Inactive Publication Date: 2005-05-12
AMGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Disruption of cytokine function itself can cause a variety of undesirable side effects.
Identification of agents that can modulate STAT4 and STAT6-mediated signal transduction has heretofore been hampered by the lack of suitable assays.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

[0099] This example illustrates the synthesis of compound 1.

Preparation of Compound 1.1

[0100] To a cooled (−78° C.) solution of tert-butyl methyl bromomalonate (10 g, 39.5 mmol) and 2-chloromethyl-4-bromophenol (8.75 g, 39.6 mmol) at −78° C. was added lithium bis(hexamethyldisilyl)amide (42 mL, 1.0 M in THF) dropwise. After 60 minutes at −78° C., the cooling bath was removed and the reaction mixture was allowed to warm to room temperature, diluted with saturated NH4Cl aqueous solution (200 mL). The phases were separated. The aqueous phase was extracted with Et2O (2×100 mL). The combined organic phases were dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (EtOAc / hexanes) to afford 12 g (85 %) of white solid.

Preparation of Compound 1.2

[0101] To a solution of 1.1 (3.0 g, 8.4 mmol) and acrylic acid (3 mL, 43.8 mmol) in Et3N (10 mL) and toluene (15 mL) was added Pd(OAc)2 (0.56 g, 2.5 mmol) and tri-o-tolylphosphine (1.52 g, ...

example 2

[0110] This example illustrates the synthesis of compound 2.

Preparation of Compound 2.1

[0111] To a solution of di-tert-butyl bromomalonate (3 g, 10.2 mmol) and 5-bromosalicylaldehyde (2.25 g,, 11.1 mmol) in 2-butanone (18 mL) was added potassium carbonate (2.1 g, 15 mmol). The reaction mixture was stirred at refluxing temperature for 1 hr. The reaction was cooled to room temperature, diluted with water and the phases were separated. The aqueous phase was extracted with Et2O (3×100 mL). The combined organic phases were washed with brine (100 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc / hexanes) to afford 3.0 g (71%) of 2.1 as a clear oil.

Preparation of Compound 2.2

[0112] To a solution of tert-butyldimethylsilyl chloride (0.55 g, 3.6 mmol) and 2.1 (1 g, 2.4 mmol) in DMF (10 mL) was added imidazole (0.32 g, 4.8 mmol). The reaction mixture was stirred at room temperature for 48 hr. The reaction was diluted with E...

example 3

[0128]

Preparation of Compound 3.1

[0129] To a solution of 2-aminobenzyl alcohol (7.12 g, 58 mmol) in methylene chloride (200 mL) at −10° C., 2,4,4,6-tetrabromo-2,5-cyclohexadien-1-one (25 g, 61 mmol) was added in portions. During the addition, the temperature of the reaction mixture was maintained between −10° C. and 0° C. The reaction mixture was warmed up to room temperature and then extracted with 2 N sodium hydroxide solution (2×50 mL). The organic layer was washed with water and dried over MgSO4, filtered and concentrated in vacuo to afford 2-amino-5-bromobenzylalcohol as a yellow solid which was used without further purification.

[0130] To a solution of 2-amino-5-bromobenzylalcohol (6.81 g, 33.7 mmol) and NEt3 (6.63 mL, 47.2 mmol) in ethyl ether (120 mL) at 0° C., a solution of triflouroacetic anhydride (5.23 mL, 37 mmol) in ether (10 mL) was added dropwise. The mixture was then stirred at 0° C. for addition 1 hr. The reaction mixture was washed with 10% H2SO4 aqueous soluti...

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Abstract

The present invention provides compounds, compositions and methods for the inhibition or treatment of conditions or disorders modulated by the STAT transcription factors, particularly STAT4 and STAT6. Additionally, the compounds are useful for the diagnosis of conditions dependent on STAT signaling.

Description

CROSS REFERENCE TO REALTED APPLICATIONS [0001] This application claims priority to U.S. Provisional Patent Application No. 60 / 246,876, filed Nov. 8, 2000, which is incorporated herein by reference in its entirety for all purposes.FIELD OF THE INVENTION [0002] The present invention relates generally, to novel compounds and pharmaceutical compositions and, more particularly, to STAT inhibitors, such as STAT6 inhibitors and their use as modulators of the immune system. BACKGROUND OF THE INVENTION [0003] New therapeutic and diagnostic agents have begun to emerge from discovery efforts, which use high-throughput screening directed to certain gene-specific transcription factors. [0004] One family of transcription factors responsible for transmitting a signal to a cell's nucleus are the proteins known as Signal Transducers and Activators of Transcription (STATs; see: Darnell et al. (1994) Science 264: 1415; for review, see: e.g., Ihle et al. (1994) Trends Biochem. Sci. 19: 222; Ihle et al....

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/00A61K45/06C07D307/85C07D405/12C07K5/02C07K5/06C07K5/062
CPCA61K38/00A61K45/06C07K5/0606C07D405/12C07K5/06034C07D307/85
Inventor HUANG, ALANLIU, JIWENMEDINA, JULIOWANG, XUEMEIXU, FENGZHU, LIUSHENG
Owner AMGEN INC
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