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Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme

An alkyl, selected technology, applied in medical preparations containing active ingredients, metabolic diseases, drug combinations, etc., can solve problems such as weight gain, peripheral edema, and side effects

Inactive Publication Date: 2008-03-05
ABBVIE INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Adverse effects of commercially available glitazones include weight gain and peripheral edema

Method used

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  • Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
  • Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
  • Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0526] E-4-(2-Methyl-2-phenoxy-propionylamino)-adamantane-1-carboxylic acid amide

Embodiment 1A

[0528] E- and Z-5-hydroxy-2-adamantanamine

[0529]A solution of 5-hydroxy-2-adamantanone (10 g, 60.161 mmoles) and 4 A molecular sieves (5 g) in methanolic ammonia (7N, 100 mL) was stirred overnight at room temperature. The mixture was cooled in an ice bath, treated with portionwise addition of sodium borohydride (9.1 g, 240.64 mmoles), followed by stirring at room temperature for 2 hours. The mixture was filtered and MeOH was removed under reduced pressure. The mixture was taken up in DCM (100 mL), acidified to pH=3 with 1 N HCl, and the layers were separated. The aqueous layer was treated with 2N NaOH solution to pH = 12, then extracted three times with 4:1 THF:DCM. The combined organic extracts were dried (MgSO 4 ), followed by filtering. The filtrate was concentrated under reduced pressure to obtain the title compound (9.84 g, 97.9%) in the form of a white solid.

Embodiment 1B

[0530] Example 1B E-2-bromo-N-(5-hydroxy-adamantan-2-yl)-2-methyl-propionamide

[0531] A solution of E- and Z-5-hydroxy-2-adamantanamine (0.868g, 5.2mmoles) in DCM (15.0mL) and DIPEA (2.5mL) was cooled in an ice bath, then dissolved in DCM (2.5mL ) in 2-bromoisobutyryl bromide (0.72 mL, 5.8 mmoles). The mixture was stirred at room temperature for 2 hours, then DCM was removed under reduced pressure. The residue was partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and water, dried (MgSO 4 ), followed by filtering. The filtrate was concentrated under reduced pressure to give the title compound (1.17 g, 71%) in the form of a dark beige solid. The isomers were separated by column chromatography (silica gel, 5-35% acetone in hexane) to afford 0.78 g of E-2-bromo-N-(5-hydroxy-adamantan-2-yl)-2-methanol phenyl-propionamide and 0.39 g of Z-2-bromo-N-(5-hydroxy-adamantan-2-yl)-2-methyl-propionamide.

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PUM

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Abstract

The present invention relates to compounds which are inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme. The present invention further relates to the use of inhibitors of 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme for the treatment of non-insulin dependent type 2 diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome and other diseases and conditions that are mediated by excessive glucocorticoid action.

Description

field of invention [0001] The present invention relates to compounds which are 11-beta-hydroxysteroid dehydrogenase type 1 enzyme inhibitors. Furthermore, the present invention relates to inhibitors of 11-beta-hydroxysteroid dehydrogenase type 1 enzyme for the treatment of non-insulin-dependent type II diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome and use in other diseases and conditions mediated by excessive glucocorticoid action. Background of the invention [0002] Insulin is a hormone that regulates glucose and lipid metabolism. Impairing effects of insulin (i.e., insulin resistance) result in decreased insulin-induced glucose uptake, oxidation, and storage, decreased insulin-dependent inhibition of fatty acid release from adipose tissue (i.e., lipolysis), and insulin-mediated inhibition of hepatic glucose production and secretion. Reduced inhibition of induction. Insulin resistance frequently occurs in diseases leading to increased and pr...

Claims

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Application Information

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IPC IPC(8): C07C235/14C07C317/16C07C323/41C07D257/04C07D233/54C07D261/08C07D213/64C07D207/48A61K31/4402A61P3/10
Inventor J·R·佩特尔Q·帅J·T·林克J·J·罗德J·丁格斯B·K·索伦森M·温H·雍V·S·叶
Owner ABBVIE INC
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