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Heterocyclic compound

a technology of cyclic compound and compound, applied in the field of cyclic compound, to achieve the effect of superior rort inhibitory action

Inactive Publication Date: 2018-11-08
ACTION MEDICAL TECH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The compound in this patent has the ability to inhibit RORγt, which is a protein involved in the development of various autoimmune diseases such as psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, uveitis, asthma, ankylopoietic spondylarthritis, systemic lupus erythematosus, and others.

Problems solved by technology

However, the existing therapeutic drugs show only limited effects, and therefore, the earliest possible development of a novel therapeutic drug has been desired.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-methoxy-N-(4-(trimethylsilyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

(Step 1)

[1906]To a 0.5M (4-(bis(trimethylsilyl)amino)phenyl)magnesium chloride / THF solution (100 mL, 50.00 mmol) was added trimethylsilyl chloride (7.03 mL, 55.00 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added 0.1N hydrochloric acid with cooling, and the mixture was stirred for 10 min. Then, aqueous sodium hydrogen carbonate solution and ethyl acetate were added thereto, and the organic layer was separated. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5→30% ethyl acetate / hexane) to give 4-(trimethylsilyl)aniline (6.51 g, 39.4 mmol, 79%) as a pale yellow oil.

[1907]1H NMR (300 MHz, DMSO-dr): δ 0.09-0.19 (9H, m), 5.14 (2H, s), 6.49-6.60 (2H,...

example 2

6-methoxy-2-((6-oxo-1,6-dihydropyridin-3-yl)carbonyl)-N-(4-(trimethylsilyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

[1923]HATU (319 mg, 0.84 mmol) was added to a solution of 6-methoxy-N-(4-(trimethylsilyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide (248 mg, 0.70 mmol), 6-oxo-1,6-dihydropyridine-3-carboxylic acid (102 mg, 0.73 mmol) and DIEA (244 μL, 1.40 mmol) in DMF (3.5 mL) at room temperature, and the mixture was stirred at room temperature for 15 hr. To the reaction mixture was added water, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 0→8% MeOH / ethyl acetate), and the precipitate was washed with ethyl acetate / IPE to give the title compound (58.2 mg, 0.122 mmol, 17.49%) as white crystals.

[1924]MS(API): Calculated 475.6. Found 47...

example 3

N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-((3-hydroxy-1,2-oxazol-5-yl)carbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

(Step 1)

[1926]A solution of 1-chloro-2-fluoro-4-nitrobenzene (2.63 g, 15 mmol), HMDS (8.12 g, 55.50 mmol) and Pd(PPh3)4 (0.433 g, 0.38 mmol) in xylene (6.5 mL) was stirred under microwave irradiation at 200° C. for 1 hr. To the reaction mixture was added ethyl acetate (about 150 mL), and the insoluble substance was removed by filtration. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by NH-silica gel column chromatography (solvent gradient; 2→5% ethyl acetate / hexane) to give (2-fluoro-4-nitrophenyl)trimethylsilane (3.22 g, 15.10 mmol, 101%) as a yellow oil.

[1927]1H NMR (300 MHz, CDCl3): δ 0.36 (9H, d, J=1.1 Hz), 7.57 (1H, dd, J=8.1, 5.5 Hz), 7.82 (1H, dd, J=8.1, 2.1 Hz), 7.99 (1H, dd, J=8.1, 2.1 Hz).

(Step 2)

[1928]A solution of (2-fluoro-4-nitrophenyl)trimethylsilane (3.22 g, 15.10 mmol) and 10% palladium-carb...

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Abstract

The present invention relates to compound (I) or a salt thereof which has a RORγt inhibitory action.wherein each symbol is as defined in the specification.

Description

TECHNICAL FIELD[0001]The present invention relates to a heterocyclic compound having an RORγt inhibitory action, a medicament containing the compound, and the like.Background of the Invention[0002]Th17 cell and inflammatory cytokine (IL-17A, IL-17F, etc.) produced thereby cause a decrease in QOL as a severe etiology cell and factor accompanying enhancement of a systemic new immune response, in various autoimmune disease such as inflammatory bowel disease (IBD), rheumatoid arthritis, multiple sclerosis or psoriasis. However, the existing therapeutic drugs show only limited effects, and therefore, the earliest possible development of a novel therapeutic drug has been desired.[0003]Involvement of T cells, inter alia, Th17 cell and inflammatory cytokines (IL-17A, IL-17F, etc.) produced thereby, in the pathology of these immune disease has been drawing attention in recent years.[0004]Moreover, it has been recently clarified that a Retinoid-related Orphan Receptor (ROR) γt, which is one o...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D491/056C07F7/08C07D217/26C07D413/12C07D401/12C07D405/12C07D401/04C07D413/14C07D491/048C07D471/04C07D417/06C07D413/06C07D409/06C07D405/06C07D401/06C07D491/04
CPCC07D491/056C07F7/0812C07D491/04C07D413/12C07D401/12C07D405/12C07D401/04C07D413/14C07D491/048C07D471/04C07D417/06C07D413/06C07D409/06C07D405/06C07D401/06C07D217/26A61P1/04A61P11/06A61P17/00A61P17/06A61P19/00A61P19/02A61P25/00A61P27/14A61P29/00A61P37/00A61P43/00
Inventor YAMAMOTO, SATOSHISHIRAI, JUNYAWATANABE, HIROYUKIFUKUMOTO, SHOJIODA, TSUNEOTOKUHARA, HIDEKAZUTOMATA, YOSHIHIDEISHII, NAOKITAWADA, MICHIKOKONO, MITSUNORIOCHIDA, ATSUKOIMADA, TAKASHIFUKASE, YOSHIYUKIYUKAWA, TOMOYA
Owner ACTION MEDICAL TECH LLC
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