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Methods of modulating the activity of the mc5 receptor and treatment of conditions related to this receptor

An active, C2-C12 technology, applied in the direction of organic active ingredients, skin diseases, pharmaceutical formulations, etc., can solve serious, side effects and other problems

Active Publication Date: 2011-04-06
马普治疗私人有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unfortunately, oral isotretinoin has serious side effects; most notably, it is a teratogen and requires a registration process for use in the United States

Method used

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  • Methods of modulating the activity of the mc5 receptor and treatment of conditions related to this receptor
  • Methods of modulating the activity of the mc5 receptor and treatment of conditions related to this receptor
  • Methods of modulating the activity of the mc5 receptor and treatment of conditions related to this receptor

Examples

Experimental program
Comparison scheme
Effect test

example

[0832] The following examples are intended to illustrate the disclosed embodiments and should not be construed as limitations thereon. In addition to those illustrated below, additional compounds can be prepared using the reaction schemes illustrated below (as discussed above) or appropriate variations or variations thereof. All starting materials illustrated in the following examples are either commercially available or readily synthesized by one of ordinary skill in the art.

[0833] Equipment

[0834] HPLC analysis was performed on an Agilent 1100 series purification system equipped with a Phenomenex Synergi 4μ Max-RP 80A, 50x2.00mm analytical HPLC column with peak detection by UV light. The standard assay employed 0.05% trifluoroacetic acid (TFA) in water (solvent A) and 0.05% TFA in 90:10 acetonitrile:water (solvent B) at a flow rate of 1 mL / min over 9 minutes. A gradient of 5% B (initial) to 95% B was used. Mass spectra were performed on an Applied Biosystems MDS Scie...

example 1

[0836] Example 1 - General Operations - Formation of Weinreb Amides

[0837]

[0838] BOP reagent (100 mmol) and diisopropylethylamine (DIPEA) (100 mmol) were added to a stirred solution of amino acid (1) (100 mmol) in dichloromethane (DCM) (100 mL). The solution was then stirred at room temperature for 10 minutes before adding a premixed solution of N,O-dimethylhydroxylamine hydrochloride (100 mmol) and DIPEA (100 mmol), followed by overnight stirring at room temperature. Then, DCM was removed by rotary evaporation and the residue was taken up in ethyl acetate (EtOAc) (200 mL). Then, the organic phase was washed with 1N HCl (3x100 mL), H 2 O (3x100mL), saturated NaHCO 3 Aqueous solution (3x100 mL) and brine (1x10 mL) were washed. Then, the organic phase was dried (MgSO 4 ) and EtOAc was removed to give Weinreb amide (2) as a white solid or an oil.

example 2

[0839] Example 2 - General operation - Vinyl Grignard addition to Weinreb amides to form β-unsaturated ketones

[0840]

[0841] To Weinreb amide (2) (15 mmol) in DCM (10 mL) at 0°C was added vinylmagnesium bromide (45 mmol) in THF (45 mL). The reaction was stirred for 2 hours and monitored by HPLC. The reaction was then quenched by adding the reaction to a mixture of ice and 1M HCl (200 mL). The aqueous mixture was extracted with DCM (3x100 mL), and the organic layers were combined and washed with 1M HCl (2x200 mL) and H 2 O (3x100 mL) was used for washing. The organic phase was dried (MgSO 4 ) to provide Solutions of β-unsaturated ketones (3). The β-unsaturated ketone (3) can be isolated by rotary evaporation, or it can be used in solution without further purification. If the purpose is to use in solution β-Unsaturated ketone (3), the volume was reduced to 100 mL by rotary evaporation and saved for later use.

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Abstract

The present invention provides compounds of Formula (I) that are useful for modulating the biological activity of the melanocortin-5 receptor (MC5R). Compounds of this invention can be used to treat diseases and / or conditions in which downregulation of MC5R is beneficial. Such diseases and / or conditions include, but are not limited to, acne, seborrhea, seborrheic dermatitis, cancer, and inflammatory diseases.

Description

technical field [0001] The present invention relates to methods of modulating the activity of the melanocortin-5 receptor. In particular the present invention relates to 1,4-diazepine - Use of a family of 2-ketones and their derivatives for modulating the activity of the melanocortin-5 receptor. The invention also relates to methods and uses of these compounds in the treatment of conditions in which antagonism of the melanocortin-5 receptor is beneficial. Background technique [0002] Melanocortin-5 receptor (MC5R) is a G-protein coupled receptor (GPCR), which belongs to the melanocortin receptor family. So far, five melanocortin receptors have been isolated and cloned: MC1R, MC2R, MC3R, MC4R, and MC5R. These melanocortin receptors are involved in a variety of physiological functions by altering (i.e., a statistically significant increase or decrease) or modulating (e.g., upregulating or downregulating) the activity of melanocortin receptor signaling during physiological...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/551C07D401/06C07D409/12A61P17/08C07D401/12C07D413/12A61P17/10C07D403/06C07D413/14C07D243/08C07D403/12C07D417/12C07D401/04C07D405/12
CPCC07D413/12C07D409/12C07D243/08C07D403/12C07D405/12C07D401/12A61K8/494A61Q19/008A61P17/00A61P17/02A61P17/08A61P17/10A61P43/00
Inventor M·A·T·布莱斯科维克P·J·凯西弟
Owner 马普治疗私人有限公司
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