Novel 1,2-dihydroquinoline derivative having glucocorticoid receptor binding activity

A compound and hydrogen atom technology, applied in the direction of organic active ingredients, medical preparations containing active ingredients, skin diseases, etc., to achieve excellent glucocorticoid receptor binding activity

Active Publication Date: 2008-09-10
SANTEN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The compound disclosed in International Publication No. 04 / 018429 specification and JP-10-0510840 has a 1,2-dihydroquinoline structure, but is not specifically disclosed at the 5-position of the 1,2-dihydroquinoline structure Compounds with various substituents

Method used

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  • Novel 1,2-dihydroquinoline derivative having glucocorticoid receptor binding activity
  • Novel 1,2-dihydroquinoline derivative having glucocorticoid receptor binding activity
  • Novel 1,2-dihydroquinoline derivative having glucocorticoid receptor binding activity

Examples

Experimental program
Comparison scheme
Effect test

reference example 1

[0352] 2,2,4-Trimethyl-1,2-dihydro-6-oxa-1-aza -5-one (reference compound 1-1)

[0353] Methyl 2-(2-benzyloxyphenyl)-5-nitrobenzoate (reference compound 1-1-(1))

[0354] 2-benzyloxyphenylboronic acid (20.2g, 88.6mmol), methyl 2-bromo-5-nitrobenzoate (25.4g, 97.5mmol), cesium carbonate (57.7g, 177mmol) and bis(triphenyl A mixture of palladium(II) dichloride (1.16 g, 1.65 mmol) was suspended in anhydrous N,N-dimethylformamide (300 mL), and stirred at 80° C. for 3 days under an argon atmosphere. After standing to cool, ethyl acetate (500 mL), diethyl ether (300 mL) and water (500 mL) were added and partitioned. The aqueous layer was extracted with a mixture of ethyl acetate (200 mL) and diethyl ether (200 mL), and the organic layers were combined. The organic layer was washed successively with water (500 mL, twice) and saturated brine (300 mL), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purifie...

reference example 2

[0425] 7-methoxy-2,2,4-trimethyl-1,2-dihydro-6-oxa-1-aza -5-ketone (reference compound 2-1)

[0426] 7-Hydroxy-2,2,4-trimethyl-1,2-dihydro-6-oxa-1-aza A mixture of -5-ketone (reference compound 1-9, 430mg, 1.40mmol), iodomethane (87.2μl, 1.40mmol) and potassium carbonate (387mg, 2.80mmol) was suspended in anhydrous N,N-dimethylformamide (7 mL), stirred at 50°C for 3 hours. After cooling, ethyl acetate (150 mL) was added for dilution. After successively washing with water (150 mL) and saturated brine (50 mL), and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the title reference compound (384 mg) as a yellow solid. (yield 85%)

[0427]

[0428] Hereinafter, reference compounds 2-2 to 2-6 were obtained according to the production method of reference compound 2-1 using a compound selected from reference compounds 1-9, 1-...

reference example 3

[0432] 5-Hydroxymethyl-6-(2-hydroxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (reference compound 3-1)

[0433] Under an argon atmosphere, lithium aluminum hydride (1.48 g, 39.0 mmol) was suspended in anhydrous tetrahydrofuran (30 mL). Add 2,2,4-trimethyl-1,2-dihydro-6-oxa-1-aza dropwise at 0°C - A solution of 5-ketone (reference compound 1-1, 3.80 g, 13.0 mmol) in anhydrous tetrahydrofuran (40 mL) was stirred at the same temperature for 1 hour. Ethyl acetate (15 mL) and water (5 mL) were successively added dropwise to the reaction solution, and then 0.2N hydrochloric acid (350 mL) was added. After extraction with ethyl acetate (300 mL, 100 mL), the organic layers were combined. The organic layer was washed successively with water (300 mL) and saturated brine (100 mL), and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title reference compound (4.01 g) as a light brown solid. (quantitative)

[0434]

[0435...

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Abstract

The present invention aims to synthesize a novel 1,2-dihydroquinoline derivative and to find pharmacological effects of such a derivative. A compound represented by the general formula (1) below or a salt thereof is effective for treating diseases associated with a glucocorticoid receptor. In the formula below, ring X represents a benzene ring or a pyridine ring; R<1> represents a halogen atom, an alkyl group, a hydroxy group, an alkoxy group, an amino group or the like; p represents an integer of 0-5; R<2> represents a halogen atom, an alkyl group, a hydroxy group or the like; q represents an integer of 0-2; R<3> represents a hydrogen atom, an alkyl group, an alkenyl group or the like; R<4> and R<5> respectively represent a hydrogen atom or the like; R<6> represents a hydrogen atom or the like; A represents an alkylene group or the like; and R<7> represents OR<8>, NR<8>R<9>, SR<8>, S(O)R<8> or S(O)2R<8>, wherein R<8> represents an aryl group, a heterocyclic group or the like and R<9> represents a hydrogen atom or the like.

Description

technical field [0001] The present invention relates to a novel 1,2-dihydroquinoline derivative or a salt thereof useful as a medicine. The derivatives thereof have binding activity to glucocorticoid receptors and are useful as non-steroidal glucocorticoid receptor modulators (glucocorticoid receptor agonists and / or glucocorticoid receptor antagonists). Background technique [0002] The glucocorticoid receptor is a 94 kDa ligand-activated intracellular transcriptional regulator belonging to the nuclear receptor superfamily. It is generally believed that this receptor regulates the metabolism of carbohydrates, proteins, and fats, suppresses immune and inflammatory responses, activates the central nervous system, regulates cardiovascular system functions, and regulates basic and stress-related functions through its transcriptional regulation. Effects on homeostasis, etc. Diseases known to be associated with glucocorticoid receptors include metabolic disorders such as diabete...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/14A61K31/47A61K31/4709A61P1/00A61P3/04A61P3/06A61P3/10A61P3/14A61P5/48A61P9/10A61P9/12A61P11/00A61P11/06A61P17/00A61P19/02A61P25/00A61P25/18A61P25/28A61P27/02A61P27/16
CPCC07D401/12C07D215/20C07D409/12C07D405/12C07D417/12C07D215/14C07D215/48C07D401/04A61P1/00A61P11/00A61P11/02A61P11/06A61P17/00A61P19/02A61P21/00A61P25/00A61P25/18A61P25/28A61P25/30A61P27/02A61P27/06A61P27/16A61P29/00A61P3/00A61P3/10A61P3/14A61P3/04A61P3/06A61P37/00A61P37/02A61P37/08A61P43/00A61P5/00A61P5/48A61P7/00A61P9/00A61P9/10A61P9/12A61K31/47
Inventor 松田学森俊之川岛健二长塚真聪小林幸子山本实加藤雅智高井美和小田知子
Owner SANTEN PHARMA CO LTD
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