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Amido compounds and their use as pharmaceuticals

A technology of compounds and prodrugs, applied in the field of modulators of type 1 11-β hydroxysteroid dehydrogenase and/or mineralocorticoid receptors, capable of solving problems such as increased risk of fractures

Inactive Publication Date: 2007-07-18
INCYTE CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Continuous exposure to even moderate doses of glucocorticoids can cause osteoporosis (Cannalis (1996) J. Clin. Endocrinol. Metab. 81: 3441-3447) and increased risk of fractures

Method used

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  • Amido compounds and their use as pharmaceuticals
  • Amido compounds and their use as pharmaceuticals
  • Amido compounds and their use as pharmaceuticals

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0413] Preparation of compounds may involve protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of suitable protecting groups, are readily determined by those skilled in the art. The chemistry of protecting groups can be found in Green et al., Protective Groups in Organic Synthesis (Second Edition, Wiley & Sons, 1991), the contents of which are incorporated herein by reference in their entirety.

[0414] The reactions in the methods described herein can be carried out in suitable solvents which can be readily selected by those skilled in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), intermediates or products at the temperature at which the reaction is carried out (ie, can be a temperature ranging from the solvent's freezing point to the solvent's boiling point). A given reaction can be carried out in one solvent or a mixture of more than ...

Embodiment 1

[0476]

[0477] 3-(1-{[1-(phenylsulfonyl)piperidin-3-yl]carbonyl}pyrrolidin-3-yl)pyridine

[0478] step 1:

[0479] To 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (46mg, 0.2mmol), 3-pyrrolidin-3-ylpyridine (30mg, 0.20mmol), hexafluorophosphonic acid benzotriazole-1- To a solution of oxotris(dimethylamino)phosphonium salt (94 mg, 0.21 mmol) in dichloromethane (1.0 ml) was added N,N-diisopropylethylamine (46 μL, 0.26 mmol). The reaction mixture was stirred overnight at room temperature and directly purified by flash chromatography to obtain 65 mg (yield: 89%) of 3-[(3-pyridin-3-ylpyrrolidin-1-yl)carbonyl]piperidine-1 - tert-butyl carboxylate.

[0480] Step 2:

[0481] A solution of tert-butyl 3-[(3-pyridin-3-ylpyrrolidin-1-yl)carbonyl]piperidine-1-carboxylate (65 mg, 0.18 mmol) in 1.0 ml dichloromethane and 1.0 ml TFA After stirring at room temperature for 2 hours, concentration gave 88 mg (100%) of 3-[1-(piperidin-3-ylcarbonyl)pyrrolidin-3-yl]pyridine bis(trifluo...

Embodiment 2

[0485]

[0486] 3-[1-({1-[(2-nitrophenyl)sulfonyl]piperidin-3-yl}carbonyl)pyrrolidin-3-yl]pyridine

[0487] 3-[1-(Piperidin-3-ylcarbonyl)pyrrolidin-3-yl]pyridine bis(trifluoroacetic acid) salt (21mg, 0.043mmol), o-nitrobenzenesulfonyl chloride (9.5mg, 0.043mmol) and a mixture of triethylamine (21 μl, 0.151 mmol) in acetonitrile (200 μl) was stirred at room temperature for 2 hours. The reaction mixture was directly purified by HPLC to obtain 13.6 mg of the desired product (yield: 71%). LCMS: m / z 445.0 (M+H) + .

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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 1 and / or diseases associated with aldosterone excess.

Description

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

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/02C07D405/00C07D211/96A61K31/438A61K31/4439A61K31/444A61K31/40A61K31/445A61K31/4709A61K31/4745C07D401/04C07D401/06C07D401/14C07D491/10
CPCC07D401/14C07D491/10C07D401/06C07D211/96C07D401/04A61P13/12A61P19/10A61P25/28A61P29/00A61P3/04A61P3/06A61P43/00A61P9/00A61P9/04A61P9/10A61P9/12A61P3/10
Inventor W·姚Y·李M·徐J·卓C·张B·梅特卡夫
Owner INCYTE CORP
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