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Imidazo- and triazolopyridines as inhibitors of 11-beta hydroxysteroid dehyftogenase type I

An aryl and alkyl technology, applied in the field of imidazopyridine and triazolopyridine as type I 11-β hydroxysteroid dehydrogenase inhibitors, can solve the problem of undisplayed plasma cortisol levels

Inactive Publication Date: 2008-06-04
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, many patients with these disorders do not show significant increases in plasma cortisol levels

Method used

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  • Imidazo- and triazolopyridines as inhibitors of 11-beta hydroxysteroid dehyftogenase type I
  • Imidazo- and triazolopyridines as inhibitors of 11-beta hydroxysteroid dehyftogenase type I
  • Imidazo- and triazolopyridines as inhibitors of 11-beta hydroxysteroid dehyftogenase type I

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0362] 3-cycloheptyl-8-((2,6-dichlorophenoxy)methyl)H-imidazo[1,5-a]pyridine

[0363]

[0364] Compound 1A: 3-(Bromomethyl)picoline nitrile

[0365]

[0366] To a solution of 3-methylpicolininitrile (660 mg, 5.6 mmol) in 20 mL of carbon tetrachloride was added NBS (1 g, 5.6 mmol) and benzoyl peroxide (200 mg, 0.83 mmol) at room temperature. The reaction mixture was heated at 80 °C for 2 hours and then cooled to room temperature. The resulting solid was filtered off and the filtrate was concentrated under reduced pressure to yield a residue. The residue was diluted with ethyl acetate, washed with water, washed with Na 2 SO 4 It was dried and concentrated under reduced pressure to give crude product. The crude product was purified via silica gel chromatography (10% ethyl acetate in hexanes) to yield Compound 1A as a pale yellow oil. HPLCR t (Method A): 1.72 min. LC / MS(m / z)=197(M+H) + .

[0367] Compound 1B: 3-((2,6-dichlorophenoxy)methyl)picolininitrile

[0368] ...

Embodiment 2

[0379] 3-cycloheptyl-8-((2,6-dichlorophenoxy)methyl)H-imidazo[1,2-a]pyridine

[0380]

[0381] Compound 2A: 2-Bromo-1-cycloheptylethanone

[0382]

[0383] To a solution of cycloheptanecarboxylic acid (1.5 g, 10.5 mmol) in 5 mL of dichloromethane was added oxalyl chloride (10.5 ml, 21 mmol, 2 M in dichloromethane), followed by a few drops of DMF at room temperature. The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to yield an oil. The oil was dissolved in 10 mL dry THF. The resulting solution was cooled to 0 °C and a solution of trimethylsilyldiazomethane (6.8 mL, 13.6 mmol, 2 M in diethyl ether) was added at 0 °C. When the addition was complete, the mixture was stirred overnight at 0 °C. At the end of this period, 48% aqueous HBr (2.4 mL, 80.9 mmol) was added at 0 °C and the reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was then quenched with 20% aqueous sodium carbonate. The solvent was...

Embodiment 3

[0390] 3-cycloheptyl-7-((2,6-dichlorophenoxy)methyl)-[1,2,3]triazolo[1,5-a]pyridine

[0391]

[0392] Compound 3A: (6-bromopyridin-2-yl)(cycloheptyl)methanone

[0393]

[0394] Add 30 mL THF to a dry three-neck round bottom flask. The flask was cooled to -78 °C and n-butyllithium (16.9 mL, 42.2 mmol, 2.5 N in hexanes) was added to the flask in one portion. A solution of 2,6-dibromopyridine (10 g, 42.2 mmol) in 70 mL THF was added slowly via addition funnel at -78 °C to give a dark green solution. When the addition was complete, the mixture was stirred for an additional 15 min at -78 °C. To the dark green solution was added cycloheptylnitrile over 1 min at -78 °C. The reaction mixture was then warmed to room temperature. Once at the specified temperature, 6 N HCl solution (55 mL, 330 mmol) was added and the reaction mixture was heated to reflux for 5 min, then stirred at room temperature for 30 min. The resulting solution was made basic by the addition of 1 N NaOH at...

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PUM

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Abstract

Novel compounds are provided which are 11-beta-hydroxysteroid dehydrogenase type I inhibitors. 11-beta-hydroxysteroid dehydrogenase type I inhibitors are useful in treating, preventing, or slowing the progression of diseases requiring 11-beta-hydroxysteroid dehydrogenase type I inhibitor therapy. These novel compounds have the structure: W-L-Z (I) or stereoisomers or prodrugs or pharmaceutically acceptable salts thereof, wherein W, L and Z are defined herein.

Description

Background of the invention [0001] The steroid hormone cortisol is a key regulator of numerous physiological processes. However, excess Cortisol, as occurs in Cushing's disease, causes metabolic abnormalities including type 2 diabetes, cardiovascular disease, obesity and osteoporosis. However, many patients with these disorders do not show significant increases in plasma cortisol levels. In addition to plasma Cortisol, individual tissues can regulate their glucocorticoid status via the in situ conversion of the inactive cortisone to the active hormone cortisol. Indeed, normally high plasma cortisone concentrations serve to provide a readily available precursor for conversion to Cortisol by the intracellular enzyme type I 11-beta hydroxysteroid dehydrogenase (11beta-HSD1). [0002] 11β-HSD1 is a member of the short-chain dehydrogenase superfamily of enzymes. By catalyzing the conversion of cortisone to cortisol, 11β-HSD1 controls intracellular glucocorticoid status according...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/435A61P3/00
Inventor J·J·李L·G·哈曼王海夏
Owner BRISTOL MYERS SQUIBB CO
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