Glucocorticoid receptor ligands for the treatment of metabolic disorders

An alkyl and alkynyl technology, applied in the field of glucocorticoid receptor ligands for the treatment of metabolic disorders, can solve problems such as glucocorticoid deficiency, excess glucose, and death

Inactive Publication Date: 2005-08-31
KARO BIO AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] The main problem with type 2 and type 1 diabetes is the presence of excess or inappropriate amounts of glucose produced by the liver
[0007] Previous efforts to block the action of glucocorticoids as a treatment for diabetes and obesity have been hampere

Method used

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  • Glucocorticoid receptor ligands for the treatment of metabolic disorders
  • Glucocorticoid receptor ligands for the treatment of metabolic disorders
  • Glucocorticoid receptor ligands for the treatment of metabolic disorders

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0090] Scheme 1. Preparation of Activated Bile Acid Intermediates

[0091]

[0092] Scheme 2. Preparation of intermediates of glucocorticoid antagonists

[0093]

[0094] Scenario 3. Combination of Fragments

[0095]

[0096] Compounds of the invention can be prepared according to the methods described in Schemes 1-3. One approach to introduce potential linker groups on cholic acid intermediates is described in Scheme 1. Methyl cholate is selectively activated at the 3-position, for example, by treatment with a sulfonyl halide or the like. The activated 3-alcohol is replaced with ethylene glycol, and the resulting alcohol is activated as a leaving group, for example by conversion to chloride, sulfonate, etc., to obtain intermediate Z.

[0097] In Scheme 2, intermediates A and B are prepared from well-known ketone-ketals in the following steps. Addition of organometallic reagents such as propynyl-magnesium bromide etc. to C-17 ketones yields the corresponding beta ...

Embodiment 1

[0129] (3β, 5β, 7α, 12α)-7,12-dihydroxy-3-{2-[{4-[(11β, 17α)-17-hydroxy-3-oxo-17-1-prop-1-yne base-4,9- Estradien-11-yl]phenyl}(methyl)amino]ethoxy}-24-cholanic acid

[0130]

Embodiment 1A

[0132] (3α, 5β, 7α, 12α)-7,12-dihydroxy-3-(methylsulfonyloxy)-24-cholanoic acid methyl ester

[0133] To a solution of methyl cholate (25 g, 59.2 mmol) in pyridine (75 mL) was added methanesulfonyl chloride (5.04 mL, 65.1 mmol) dropwise with stirring at 0°C during 30 minutes. The reaction was warmed to room temperature and stirred for 6 hours. The reaction mixture was poured into a mixture of EtOAc (200 mL), 1N HCl (200 mL) and ice. The layers were separated, and the organic layer was washed with 1N HCl (2×50 mL), dried (Na 2 SO 4 ) and concentrated to obtain light yellow oil. The crude material was passed through a silica plug eluting with 50% EtOAc / Hexanes to afford 24.5 g (83%) of the title compound as a light yellow oil which formed a white sticky mass when placed under high vacuum pump bubbles.

[0134]

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PUM

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Abstract

This invention relates to novel compounds that are liver selective glucocorticoid receptor antagonists, to methods of preparing such compounds, and to methods for using such compounds in the regulation of metabolism, especially lowering serum glucose levels, insulin levels, or lipid levels, and/or decreasing body weight.

Description

field of invention [0001] The present invention relates to novel compounds useful as liver-selective glucocorticoid receptor antagonists, methods of preparing such compounds and methods of using such compounds to modulate metabolism, especially lowering serum glucose levels and / or reducing body weight. Background of the invention [0002] The main problem with type 2 and type 1 diabetes is the presence of excess or inappropriate amounts of glucose produced by the liver. This abnormality is a major cause of fasting hyperglycemia and is accompanied by defects in the regulation of insulin release and peripheral sensitivity to insulin. Therefore, agents that reduce hepatic glucose production would be useful in the treatment of type 2 and type 1 diabetes. [0003] Intensive treatment of hyperglycemia in type 1 diabetes has been shown to reduce the development of ocular, renal and neurological syndromes, and there is evidence that this treatment also helps type 2 diabetes. Avail...

Claims

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Application Information

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IPC IPC(8): A61K31/575A61K31/661A61P3/04A61P3/06A61P3/10A61P5/46A61P9/12A61P43/00C07J9/00C07J41/00C07J51/00
CPCC07J41/0061C07J41/0083A61P3/04A61P3/06A61P43/00A61P5/44A61P5/46A61P7/12A61P9/12A61P3/10C07J41/00A61K31/575
Inventor 托马斯·W·范格尔顿詹姆士·T·林克诺亚·子菲利普·R·许姆赖春秋史蒂文·J·理查兹皮尔·B·雅各布森理查德·D·毕晓普布雷德利·D·盖茨
Owner KARO BIO AB
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