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 I type 11-β-hydroxysteroid dehydrogenase inhibitors, can solve the problems of low plasma glucose level and the like

Inactive Publication Date: 2008-08-06
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Conversely, reduction of 11β-HSD1 activity will downregulate gluconeogenesis, which leads to lower plasma glucose 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

[0339] 3-cycloheptyl-8-((2,6-dichlorophenoxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine

[0340]

[0341] Compound 1A.1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)hydrazine

[0342]

[0343] Add imidazole (2.4 g, 35.3 mmol) and tert-butyldimethylsilyl chloride (4.3 g, 28.5 mmol) to (2-chloropyridin-3-yl)methanol (3.4 g, 23.7 mmol) at RT 50 mL of dichloromethane solution. The mixture was stirred at RT for 60 min, then diluted with 100 mL of hexane. The white solid was filtered off, and the filtrate was concentrated under reduced pressure. Additional solids were removed by trituration with 5% ethyl acetate in hexanes to give a light yellow oil. The light yellow oil was dissolved in 40 mL of dioxane, then hydrazine (7.5 mL, 238.7 mmol) was added. The resulting mixture was heated to reflux for 36h. After this time, the mixture was cooled to RT and the solvent was removed in vacuo to give a residue. The residue was diluted with ethyl acetate, washed with water, was...

Embodiment 2

[0356] 3-cycloheptyl-8-((2,6-dichlorophenylthio)methyl)-[1,2,4]triazolo[4,3-a]pyridine

[0357]

[0358] A solution of compound 1D (140 mg, 0.57 mmol) in 15 mL of dichloromethane was washed with SOCl at RT 2 (0.166 mL, 2.28 mmol) was treated. The reaction mixture was stirred at RT for 2 h. After this time, the solvent was evaporated under reduced pressure to obtain a white powder. The white powder was suspended in 20 mL of dichloromethane, treated with DIEA (0.478 mL, 2.85 mmol) then 2,6-dichlorothiophenol (0.206 g, 1.15 mmol) at RT, then stirred at RT for 2 h. The resulting mixture was concentrated and purified by silica gel chromatography (20-50% ethyl acetate in hexanes) to afford Example 2 (212 mg, 91%) as a colorless oil. HPLCR t (Method A): 3.44 min. LC / MS(m / z)=406(M+H) + . 1 H NMR: δ7.69(d, J=7Hz, 1H), 7.25(d, J=8Hz, 2H), 7.08(t, J=8Hz, 1H), 6.65(d, J=7Hz, 1H), 6.53 (t, J=7Hz, 1H), 4.40(s, 2H), 3.12-3.24(m, 1H), 1.92-2.10(m, 4H), 1.72-1.89(m, 2H), 1.48-1.72(m...

Embodiment 3

[0360] 3-cycloheptyl-8-((2,6-dichlorophenylsulfonyl)methyl)-[1,2,4]triazolo[4,3-a]pyridine

[0361]

[0362] A solution of Example 2 (110 mg, 0.271 mmol) in 20 mL of dichloromethane was treated with mCPBA (390 mg, 1.35 mmol) for 4 h at RT. After this time, the reaction mixture was analyzed by LCMS, indicating the presence of sulfoxide. Additional mCPBA (156 mg, 0.542 mmol) was added. After the addition was complete, the reaction mixture was stirred for an additional 2 h. After this time, the reaction mixture was diluted with dichloromethane, washed with 1N NaOH, brine and water, washed with MgSO 4 Drying and concentration gave crude product. The crude product was purified by silica gel chromatography (50% ethyl acetate in hexanes) to afford Example 3 (57.5 mg, 48%) as a light brown thick oil. HPLCR t (Method A): 2.99 min. LC / MS(m / z)=438(M+H) + . 1 H NMR: δ7.78(dd, J=1, 7Hz, 1H), 7.39(dd, J=1, 7Hz, 1H), 7.19-7.29(m, 3H), 6.78(t, J=7Hz, 1H) , 5.08 (s, 2H), 3.07-3.17 ...

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Abstract

The present invention provides novel compounds that are inhibitors of type I 11-beta-hydroxysteroid dehydrogenase. Type I 11-beta-hydroxysteroid dehydrogenase inhibitors may be used to treat, prevent or delay the progression of diseases requiring treatment with a type I 11-beta-hydroxysteroid dehydrogenase inhibitor. These novel compounds or stereoisomers or pharmaceutically acceptable salts thereof have the structure of formula (I), wherein W, L, R3, R3a, R3b and R4 are as defined in this application.

Description

Background of the invention [0001] The steroid hormone cortisol is a key regulator of many physiological processes. However, excess cortisol, as seen in Cushing's Disease, leads to serious metabolic abnormalities, including type II diabetes, cardiovascular disease, obesity, and osteoporosis. However, many patients with these disorders do not experience significant increases in plasma cortisol levels. In addition to plasma Cortisol, individual tissues can regulate their glucocorticoid status by converting inactive cortisone to the active hormone cortisol in situ. Indeed, normally high plasma concentrations of cortisone are immediately available as precursors for conversion to cortisol by the intracellular enzyme 11-β-hydroxysteroid dehydrogenase type I (11β-HSD1). body. [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 t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61P3/00A61K31/435
Inventor 詹姆士·J·李劳伦斯·G·哈曼王海夏阮哲明克里斯托弗·B·库珀李俊杰弗里·A·罗布尔
Owner BRISTOL MYERS SQUIBB CO
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