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N-substituted piperidines and their use as pharmaceuticals

A pharmaceutical and prodrug technology, applied in the field of modulators of 11-beta hydroxysteroid dehydrogenase type 1 and/or mineralocorticoid receptors, which can solve problems such as blindness and visual field loss

Inactive Publication Date: 2007-07-04
INCYTE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In its most advanced and untreated form, IOP can cause partial visual field loss and eventually blindness

Method used

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  • N-substituted piperidines and their use as pharmaceuticals
  • N-substituted piperidines and their use as pharmaceuticals
  • N-substituted piperidines and their use as pharmaceuticals

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0237]

[0238] N-Cyclohexyl-1-[(2-nitrophenyl)sulfonyl]piperidine-3-carboxamide

[0239] step 1.

[0240] To a solution of 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (69 mg, 0.3 mmol), cyclohexanamine (30 mg, 0.3) and BOP (140 mg) in 1.0 mL of dichloromethane was added 68.5 μL of N,N-diisopropylethylamine. The reaction mixture was stirred overnight at room temperature and directly purified with Combi-Flash eluting with EtOAc / hexanes to provide 70 mg of the desired product.

[0241] Step 2.

[0242] To a solution of tert-butyl 3-(cyclohexylcarbamoyl)piperidine-1-carboxylate (70 mg) in 4.5 mL of dichloromethane and 0.5 mL of water was added 5 mL of TFA. The reaction mixture was stirred at room temperature for 50 min, then concentrated under reduced pressure to give a residue.

[0243] Step 3.

[0244]Triethylamine ( 19.3 μL). The reaction mixture was stirred at room temperature for 2 hours and directly purified by HPLC to give 13.2 mg of the desired product. ...

Embodiment 2

[0246]

[0247] N-cyclohexyl-1-(phenylsulfonyl)piperidine-3-carboxamide

[0248] This compound was prepared using a procedure similar to that described in Example 1. LCMS: m / z 351.1 (M+H)+; 373.0 (M+Na)+; 723.2 (2M+Na)+.

Embodiment 3

[0250]

[0251] N-cyclohexyl-N-cyclopropyl-1-(benzenesulfonyl)piperidine-3-carboxamide

[0252] step 1.

[0253] To a solution of benzyl piperidine-3-carboxylate (TFA salt, 1.5 g) and potassium carbonate (2.2 g) in 10 mL of acetonitrile was added 0.409 mL of benzenesulfonyl chloride. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water, brine and washed with Na 2 SO 4 dry. After filtration, the filtrate was concentrated to obtain a residue.

[0254] Step 2.

[0255] The residue from step 1 was hydrogenated using Pd / C as catalyst.

[0256] Step 3.

[0257] To 1-(phenylsulfonyl)piperidine-3-carboxylic acid (20mg), N-cyclopropylcyclohexylamine (10mg) and benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluoro To a solution of phosphate (36 mg) in DMF (200 μL) was added N,N-diisopropylethylamine (26 μL). The resulting solution was stirred at room temperature for 2 hours and di...

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PUM

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Abstract

The present invention relates to inhibitors of 11-beta hydroxyl steroid dehydrogenase type 1, antagonists of the mineralocorticoid receptor (MR), and pharmaceutical compositions thereof. The compounds of the invention can be useful in the treatment of various diseases associated with expression or activity of 11-beta hydroxyl steroid dehydrogenase type I and / or diseases associated with aldosterone excess.

Description

field of invention [0001] The present invention relates to modulators of 11-beta hydroxysteroid dehydrogenase type 1 (11βHSD1) and / or the mineralocorticoid receptor (MR), compositions thereof, and methods of using the same. Background of the invention [0002] Glucocorticoids are steroid hormones that regulate fat metabolism, function and distribution. In vertebrates, glucocorticoids also have profound and diverse physiological effects on growth, neurobiology, inflammation, blood pressure, metabolism, and apoptosis. In humans, the major endogenous glucocorticoid is cortisol. Cortisol is synthesized in the zona fascicularis of the adrenal cortex and is controlled by a short-term neuroendocrine feedback loop known as the hypothalamic-pituitary-adrenal (HPA) axis. Adrenal production of Cortisol is under the control of adrenocorticotropic hormone (ACTH), a factor produced and secreted by the anterior pituitary gland. ACTH production in the anterior pituitary is itself highly ...

Claims

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Application Information

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IPC IPC(8): A61K31/445A61K31/505A61K31/451A61K31/47A61K31/495C07D401/12
Inventor W·姚M·徐C·张Y·李J·卓B·梅特卡夫
Owner INCYTE
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