C-21 thioethers as glucocorticoid receptor agonists

A halogen and solvate technology, applied in the field of new C-21 steroid derivatives, can solve the problem of reduced safety

Inactive Publication Date: 2011-06-15
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] A problem associated with inhaled glucocorticoids is that although they show improved safety at low therapeutic doses, their safety is reduced at higher doses or when these agents are administered for prolonged periods of time

Method used

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  • C-21 thioethers as glucocorticoid receptor agonists
  • C-21 thioethers as glucocorticoid receptor agonists
  • C-21 thioethers as glucocorticoid receptor agonists

Examples

Experimental program
Comparison scheme
Effect test

preparation example

[0274] In general, the compounds of the present invention can be produced by various methods known to those skilled in the art, for example, by the following methods. These examples should not be considered as limiting the scope of the present disclosure. Alternative mechanistic pathways and analogous structures will be apparent to those skilled in the art.

[0275] Compounds of the invention are most commonly converted by conversion of the C-21 hydroxyl group on the core of a commercially available steroid to a leaving group (e.g. mesylate, triflate) followed by reaction with an appropriate nucleophile (e.g. thiol, alcohol or amine) reaction to prepare (see scheme 1). Commercially available steroid cores can be modified as desired as described in the following examples.

[0276]

[0277] Flowchart 1

[0278] For the purposes of these preparative schemes only, the structures of the compounds are described using simplified terminology. The stereochemistry of the methyl g...

Embodiment 1

[0283] step 1

[0284]

[0285] A solution of hydrocortisone 11 (5 g, 0.0138 mol) in dichloromethane (100 mL) was treated with diisopropylethylamine (8.9 g, 0.0691 mol) at 0°C. The reaction mixture was stirred for 5 minutes; methanesulfonyl chloride (2.9 g, 0.02486 mol) was added dropwise at 0 °C and stirred for 4-6 hours. The reaction mixture was diluted with dichloromethane, transferred to a separatory funnel and washed with dilute HCl, water, brine, and dried over anhydrous sodium sulfate. Removal of solvent gave crude mesylate salt which was purified using column chromatography with dichloromethane and methanol (20:1 ) to afford mesylate salt 12 as a crystalline solid. Yield = 5.5 g (82%).

[0286] step 2

[0287]

[0288] To a solution of hydrocortisone-21-mesylate 12 (10 g, 0.0227 mol) in dichloromethane was added diisopropylethylamine (14.65 g, 0.114 mol) dropwise at 0°C. The reaction mixture was then treated with 2-mercaptobenzothiazole (5.69 g, 0.0341 mo...

Embodiment 2

[0290]

[0291] The title compound was prepared in two steps from desonide 21 using the procedure of Example 1, except that refluxing potassium carbonate in acetone was used in the second step instead of diisopropylethylamine in dichloromethane. The reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated to give crude product. The crude product was purified by column chromatography. M H + 566

[0292] The compounds shown in Table I are non-limiting examples of compounds of the invention synthesized using the procedures described herein (or procedures analogous thereto).

[0293] Table 1

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[0323] ...

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PUM

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Abstract

The present invention provides compounds of Formula (VII) and 11-keto analogs thereof, and pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers of said compounds and said 11-keto analogs, having the general structure formula (VII): wherein L, R1, R2, R3, R4, and R5 are selected independently of each other and as defined herein. Also provided are pharmaceutical compositions, methods of preparing, and methods of using such compounds in the treatment and prophylaxis of a wide range of immune, autoimmune, and inflammatory diseases and conditions. The novel compounds of the present invention possess useful pharmacological activity while having unexpectedly low systemic activiy. Thus, the compounds of the invention represent a safer alternative to those known glucocorticoids which have poor side-effect profiles.

Description

[0001] related application [0002] This application is related to and claims the benefit of US Provisional Patent Application No. 61 / 016,144, filed December 21, 2007, the contents of which are hereby incorporated by reference in their entirety. field of invention [0003] The present invention relates to novel C-21 steroid derivatives as glucocorticoid receptor agonists and their preparation methods. The invention also relates to pharmaceutical formulations comprising the C-21 steroid derivatives of the invention and their use in the treatment of conditions involving inflammatory and allergic conditions. The C-21 steroid derivatives of the present invention exhibit "dissociative" properties, i.e., dissociate the metabolic effects associated with adverse side effects from the anti-inflammatory and anti-allergic effects, thereby providing Better therapeutic effect of glucocorticoid receptor agonists. Background of the invention [0004] The glucocorticoid receptor is part ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J43/00C07J31/00C07J71/00A61P5/44A61K31/573A61K31/58
CPCC07J71/0031C07J31/006C07J43/003A61P1/04A61P11/00A61P11/02A61P11/04A61P11/06A61P11/10A61P17/00A61P17/04A61P17/06A61P19/02A61P25/00A61P27/02A61P27/14A61P29/00A61P31/00A61P31/12A61P37/00A61P37/02A61P37/06A61P37/08A61P43/00A61P5/34A61P5/44
Inventor J·C·安瑟斯K·D·麦科尔米克J·A·黑R·G·阿斯拉尼安P·J·比于M·Y·伯林D·M·索罗蒙王鸿武林勇希李伦珠雷马·丹妮尔·比塔尔
Owner MERCK & CO INC
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