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Phenyl Linked Quinolinyl Modulators Of Ror-Gamma-T

A phenyl and methyl technology, applied in anti-inflammatory agents, non-central analgesics, medical preparations containing active ingredients, etc., can solve the problems of EAE sensitivity reduction and Th17 cell population reduction

Inactive Publication Date: 2016-08-03
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

RORt-deficient mice were apparently healthy and reproduced normally, but displayed impaired Th17 cell differentiation in vitro, significantly reduced numbers of Th17 cell populations in vivo, and reduced EAE susceptibility (Ivanov, II, B.S. McKenzie et al., (2006)." Theorphannuclear receptorRORgammatdirectsthedifferentiationprogramofproinflammatoryIL-17+Thelpercells."Cell126(6):1121-33)

Method used

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  • Phenyl Linked Quinolinyl Modulators Of Ror-Gamma-T
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  • Phenyl Linked Quinolinyl Modulators Of Ror-Gamma-T

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1a

[0545] Example 1a: 1-(4-((4-Chloro-2-methoxy-3-(3-(trifluoromethyl)phenyl)quinolin-6-yl)(hydroxyl)(1- Methyl-1H-imidazol-5-yl)methyl)piperidin-1-yl)ethanone

[0546]

[0547]n-Butyllithium (1.6M in hexane, 0.585 mL, 0.937 mmol) was added to 6-bromo-4-chloro-2-methoxy-3-(3-(tri Fluoromethyl)phenyl)quinoline (409.8 mg, 0.984 mmol, Intermediate 5: step e) in THF (3 mL). After 1 min, 1-(4-(1-methyl-1H-imidazol-5-carbonyl)piperidin-1-yl)ethanone (231.4 mg, 0.984 mmol, Intermediate 1: step c) was added via cannula solution in THF (5 mL). The mixture was stirred at -78°C for 10 minutes, then transferred to an ice bath and stirred for an additional 45 minutes. Add saturated NH 4 The reaction mixture was quenched with aqueous Cl, diluted with water and extracted with EtOAc (3x). dry (Na 2 SO 4 ) organic phase, filtered and concentrated to dryness. The residue was purified by flash column chromatography (silica gel, 0-8% MeOH-DCM) to afford the title compound as a white so...

Embodiment 1b

Embodiment 2a

[0549] Example 2a: 6-((1-acetylpiperidin-4-yl)(hydroxyl)(1-methyl-1H-imidazol-5-yl)methyl)-2-methanol Oxy-3-(3-(trifluoromethyl)phenyl)quinoline-4-carbonitrile

[0550]

[0551] A round bottom flask was charged with 1-(4-((4-chloro-2-methoxy-3-(3-(trifluoromethyl)phenyl)quinolin-6-yl)(hydroxy)(1 -Methyl-1H-imidazol-5-yl)methyl)piperidin-1-yl)ethanone (158mg, 0.276mmol, Example 1a), Zn(CN) 2 (58.3mg, 0.496mmol), Pd 2 (dba) 3 (37.9mg, 0.041mmol), nano zinc powder (5.4mg, 0.083mmol) and dicyclohexyl (2',4',6'-triisopropyl-[1,1'-diphenyl]-2- yl)phosphine (X-Phos, 27.1 mg, 0.055 mmol). The flask was evacuated and refilled with argon (three cycles). Dimethylacetamide (1.4 mL, under argon for 30 minutes) was then added, and the mixture was heated at 120° C. for 4 hours. The mixture was cooled to room temperature, filtered Washed with EtOAc. 2MNH 4 The filtrate was washed with aqueous OH, water and saturated aqueous NaCl. dry (Na 2 SO 4 ) organic phase, filtered and...

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Abstract

The present invention comprises compounds of Formula I. Formula I wherein: R1, R2, R3, R4, R5, R6, R7, R8, and R9 are defined in the specification. The invention also comprises a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is rheumatoid arthritis or psoriasis. The invention also comprises a method of modulating ROR[gamma]t activity in a mammal by administration of a therapeutically effective amount of at least one compound of claim 1.

Description

technical field [0001] The present invention relates to substituted quinoline compounds that are modulators of the nuclear receptor RORyt, pharmaceutical compositions and methods of use thereof. More specifically, RORyt modulators are useful for preventing, treating or ameliorating RORyt-mediated inflammatory syndromes, disorders or diseases. Background technique [0002] Retinoic acid-related nuclear receptor γt (RORγt) is a nuclear receptor expressed only in cells of the immune system and is a key transcription factor driving Th17 cell differentiation. Th17 cells are CD4 + A subpopulation of T cells, Th17 cells express CCR6 on their surface to mediate their migration to sites of inflammation and are dependent on IL-23 stimulation for maintenance and expansion through the IL-23 receptor. Th17 cells produce a variety of proinflammatory cytokines, including IL-17A, IL-17F, IL-21, and IL-22 (Korn, T., E. Bettelli et al., (2009). "IL-17andTh17Cells."AnnuRevImmunol27 :485-517...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D401/06C07D409/14C07D413/06C07D417/06C07D417/14A61K31/4709A61P29/00
CPCC07D401/14C07D401/06C07D409/14C07D413/06C07D417/06C07D417/14A61P1/04A61P11/00A61P11/06A61P17/06A61P19/00A61P19/02A61P25/00A61P29/00A61P37/02A61P37/08A61K31/4709A61K31/4725
Inventor K.巴贝J.P.爱德华斯K.D.克雷特D.A.库梅U.马哈鲁夫R.尼斯穆拉M.厄班斯基H.文卡特桑A.王R.L.沃林C.R.伍德斯A.福里伊X.薛M.D.库明斯K.A.伦纳德
Owner JANSSEN PHARMA NV
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