Compound used as RORgamma conditioning agent

A technology of compounds, solvates, applied in the field of compounds as ROR gamma modulators

Active Publication Date: 2015-09-23
BEIJING HANMI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The ligands of nuclear receptors include thyroid hormones, steroid hormones, retinoic acid, fatty acids, sterols, etc. In addition, there is a class of nuclear receptors that have not yet identified ligands, called orphan nuclear receptors

Method used

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  • Compound used as RORgamma conditioning agent
  • Compound used as RORgamma conditioning agent
  • Compound used as RORgamma conditioning agent

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0201] Preparation of compounds of the present invention

[0202] The following reaction schemes illustrate the preparation of compounds of formula I of the present invention.

[0203] It should be understood by those skilled in the art that in the following description, combinations of substituents are permissible only when such combination can result in a stable compound.

[0204] Those skilled in the art will also understand that in the methods described below, the functional groups of intermediate compounds may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amino, amidino, guanidino, mercapto and carboxyl groups. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (eg tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, etc. Suitable protecting groups for amino, amidino and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl and the like. S...

Embodiment 1

[0226] Example 1: 4-(3-(2,6-dichlorobenzoyl)-7-fluoro-2-one-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzene formic acid

[0227]

[0228] The concrete steps of preparation embodiment 1 compound are as follows:

[0229] (1) Preparation of 4-(2-fluoro-6-nitro-phenylamino)methylbenzoate (1-1):

[0230]

[0231] Methyl 4-aminobenzoate (302 mg, 2 mmol) was dissolved in tetrahydrofuran (THF) (20 mL) and dimethylformamide (DMF) (4 mL), and sodium hydride (NaH) (60%, 120mg, 3mmol), stirred for 10min, then added 1,2-difluoro-3-nitrobenzene (318mg, 2mmol) and stirred for 5 hours, quenched with water (10mL), extracted with ethyl acetate (50mL), and the organic phase Dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify the concentrate by silica gel column chromatography (eluent: n-hexane:ethyl acetate=50:1) to obtain 4-(2-fluoro-6-nitro Phenylamino)methylbenzoate 1-1 (300 mg) as a yellow solid. Yield 52%. MS+H + =291.

[0232] (2) Prepar...

Embodiment 2

[0244] Example 2: 4-(3-(2,6-dichlorobenzoyl)-7-methyl-2-one-2,3-dihydro-1H-benzo[d]imidazol-1-yl) benzoic acid

[0245]

[0246] The compound of this example can be prepared according to the steps similar to the previous example 1, the difference is that in step 1, 1-methyl-2-fluoro-3-nitrobenzene is used as the raw material instead of 1,2-difluoro- 3-nitrobenzene. Relevant characterization data are as follows: MS+H + = 441.7; 1 H-NMR (CDCl 3 , 300MHz) δ:ppm 8.36(d, J=8.1Hz, 1H), 8.22(d, J=8.4Hz, 2H), 7.51(d, J 1 =8.4Hz, 1H), 7.37~7.19(m, 4H), 7.06(d, J=8.1Hz, 1H), 1.87(s, 3H).

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Abstract

The present invention relates to a compound which can be used as a retinoid-related orphan receptor γ (RORγ) modifier, a pharmaceutical composition of said compound, the use of said compound in the manufacture of pharmaceuticals, and a method for using said compound for treatment and/or prophylaxis of a RORγ-mediated disease in a mammal (especially a human). The compound has the structural formula I.

Description

technical field [0001] The present invention relates to compounds useful as retinoic acid-related orphan receptor gamma (RORy) modulators, their pharmaceutical compositions and their use in pharmacy. Background technique [0002] Nuclear receptors are a ligand-dependent superfamily of transcription factors, which are widely distributed in organisms and play roles in metabolism, development, biological rhythm, inflammation and immune regulation. The ligands of nuclear receptors include thyroid hormones, steroid hormones, retinoic acid, fatty acids, sterols, etc. In addition, there is a class of nuclear receptors that have not yet identified ligands, called orphan nuclear receptors. Retinoic acid-related orphan receptors (retinoid-related orphan receptors, RORs), also known as NF1R, this type of nuclear receptor due to the gene sequence and retinoic acid receptor (retinoic acid receptor, RAR) and retinoic acid X The receptor (retinoid X receptor, RXR) is similarly named. The...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D235/26C07D241/44C07D241/42C07D471/04A61K31/4184A61K31/437A61K31/498A61P29/00A61P19/02A61P17/06A61P11/06A61P11/00A61P37/06A61P37/02A61P7/00A61P1/00A61P19/08A61P11/02A61P37/08A61P17/00A61P1/18A61P3/10A61P27/02A61P1/04A61P25/00A61P21/04A61P5/14
CPCA61K45/06A61P1/00A61P1/04A61P1/18A61P3/10A61P5/14A61P7/00A61P11/00A61P11/02A61P11/06A61P17/00A61P17/06A61P19/02A61P19/08A61P21/04A61P25/00A61P27/02A61P29/00A61P37/02A61P37/06A61P37/08C07D235/26C07D241/42C07D241/44C07D471/04
Inventor 薛海赵涛马涛车美英
Owner BEIJING HANMI PHARMA CO LTD
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