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11 beta-hsd1 modulators

a technology of hydroxysteroid dehydrogenase and modulator, which is applied in the direction of biocide, drug composition, metabolic disorder, etc., can solve the problems of reducing central obesity, reducing food intake, and reducing expansion

Inactive Publication Date: 2010-04-29
EXELIXIS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The compounds effectively inhibit 11 β-HSD1 activity, providing therapeutic benefits in treating diabetes, obesity, cardiovascular diseases, and other conditions by modulating glucocorticoid activity, thereby reducing glucose production, adipocyte differentiation, and improving metabolic and cardiovascular health.

Problems solved by technology

This is predicted to result in diminished expansion (possibly reduction) of the omental fat depot, which may lead to reduced central obesity.
This suggests that glucocorticoids play a role in promoting food intake and that inhibition of 11β-HSD1s in the brain may increase satiety, thus resulting in a decreased food intake.
11 β-HSD1 reactivates 11-DHC to corticosterone in hippocampal cells and can potentiate kinase neurotoxicity, resulting in age-related learning impairments.
Recent reports suggest that the levels of glucocorticoid target receptors and of HSDs are connected with the risks of developing glaucoma.
Glucocorticoids also play an essential role in skeletal development and function but are detrimental to such development and function when present in excess.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1 (

Example 1(B)

tert-butyl 8-azabicyclo[3.2.1]octan-3-endo-ylcarbamate

[0588]

[0589] STEP 1: To a 5 L round-bottom flask was added 8-methyl-8-azabicyclo[3.2.1]octan-3-endo-amine (432 g, 3.1 mol), 2 L of dry 1,4-dioxane, 675 mL of deionized water and 468 g of dry triethylamine. Di-tert-butyl dicarbonate (solution in 1.2 L of dioxane) was added dropwise to the stirring solution at room temperature over 16 h. The reaction mixture was concentrated and the resulting residue suspended in 2.5 L of methylene chloride, then washed twice with 1 L of water, dried with anhydrous magnesium sulfate, filtered, and volatile organics removed by rotary evaporation to yield 617 g (83%) of tert-butyl 8-methyl-8-azabicyclo[3.2.1]octan-3-ylcarbamate (mp 79-81° C.).

[0590] STEP 2: To a 5 L round-bottom flask was added 480 g (2.0 mol) of tert-butyl 8-methyl-8-azabicyclo[3.2.]octan-3-endo-ylcarbamate, 2 L of toluene, and 69 g (0.5 mol) of potassium carbonate. 2,2,2-Trichloroethyl chloroformate (347 mL, 2.4 mol) ...

example 2

6-[3-endo-({[1-(4-chlorophenyl)cyclopropyl]carbonyl}amino)-8-azabicyclo[3.2.1]oct-8-yl]pyridine-3-carboxylic acid,

[0592]

[0593] A suspension of methyl 6-(3-endo-(1-(4-chlorophenyl)-cyclopropanecarboxamido)-8-azabicyclo[3.2.1]octan-8-yl)nicotinate (0.30 g, 0.69 mmol) from Example 1 in methanol (5 mL) was charged with 3N NaOH (1.0 mL, 3.0 mmol) and then heated 2 h at 50° C. After cooling to ambient temperature, the reaction mixture was neutralized to pH 5 using 1N HCl and then extracted with DCM (3×25 mL). The combined extracts were dried (anhyd Na2SO4) and concentrated under reduced pressure to afford the title compound (0.29 g, quant) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.83 (d, J=2.4 Hz, 1H), 8.01 (dd, J=9.1, 2.4 Hz, 1H), 7.44-7.38 (m, 4H), 6.43 (d, J=9.1 Hz, 1H), 5.83 (d, J=7.9 Hz, 1H), 4.51 (br s, 2H), 4.04-3.98 (m, 1H), 2.19-2.10 (m, 2H), 2.02-1.96 (m, 2H), 1.63-1.52 (m, 4H), 1.39-1.31 (2H), 1.07-1.02 (2H); MS (EI): 426 (MH+).

example 3

6-[3-endo-({[1-(4-chlorophenyl)cyclopropyl]carbonyl}amino)-8-azabicyclo[3.2.1]oct-8-yl]-N-cyclopropylpyridine-3-carboxamide,

[0594]

[0595] To a suspension of 6-[3-endo-({[1-(4-chlorophenyl)cyclopropyl]carbonyl}amino)-8-azabicyclo[3.2.1]oct-8-yl]pyridine-3-carboxylic acid (0.29 g, 0.68 mmol) from Example 2 in DCM (6 mL) was added 1,1′-carbonyldiimidazole (0.12 g. 0.75 mmol) with stirring. After 20 minutes, the reaction mixture was charged with DMAP (10 mg) and cyclopropylamine (46 μL, 0.80 mmol). After stirring 12 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography (silica, EtOAc / Hex, 50:50 to 100:0) to give the title compound (99 mg, 31%) as a white solid. 1H NMR (400 MHz, CDCl2): δ 8.47 (d, J=2.4 Hz, 1H), 7.84 (dd, J=8.7, 2.4 Hz, 1H), 7.43-7.37 (m, 4H), 6.43 (d, J=9.2 Hz, 1H), 6.04 (br s, 1H), 5.83 (d, J=6.8 Hz, 1H), 4.43 (br s, 2H), 4.00-3.94 (m, 1H), 2.89-2.82 (m, 1H), 2.16-2.08 (m, 2H), 2.01-1.95 (m, 2H), 1.62-1.58 (m, 4H), ...

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Abstract

A compound according to Formula I: or a pharmaceutically acceptable salt thereof, wherein R1, R2, R11, L1 and X are as defined in the specification, pharmaceutical compositions thereof, and methods of use thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. provisional application 61 / 069,648, filed Mar. 14, 2008, and U.S. provisional application 61 / 203,720 filed on Dec. 23, 2008, both of which are incorporated by reference in its entirety.FIELD OF THE INVENTION [0002] This disclosure relates to compounds, compositions thereof, and methods of use thereof. More particularly, this disclosure relates to hydroxysteroid dehydrogenase modulators, such as 11 β-HSD1 modulators, compositions thereof, and methods of treating diseases associated with the modulation of hydroxysteroid dehydrogenases, such as diabetes and obesity. BACKGROUND OF THE INVENTION [0003] Hydroxysteroid dehydrogenases (HSDs) regulate the occupancy and activation of steroid hormone receptors by converting steroid hormones into their inactive metabolites. [0004] There exist numerous classes of HSDs. The 11 β-hydroxysteroid dehydrogenases catalyze the interconversion of active glucocorticoi...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/46C07D451/02A61K31/5377A61P3/00
CPCC07D451/04A61P1/18A61P13/12A61P25/00A61P27/02A61P3/00A61P3/04A61P3/06A61P9/10A61P3/10
Inventor MARTIN, RICHARDFLATT, BRENTONDALGARD, JACKLINEBOLLU, VENKATAIAHHUANG, PINGMOHAN, RAJUSCHWEIGER, EDWINWANG, TIE LIN
Owner EXELIXIS INC
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