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Cyclic amine derivatives and their medicinal uses

A technology of cyclic amines and derivatives, applied in the field of cyclic amine derivatives and their medical applications, can solve the problem of not showing multiple sclerosis drug efficacy data, not disclosing the structure of piperidine-2-carboxamide, not suggesting And other issues

Active Publication Date: 2021-09-07
TORAY IND INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] On the other hand, as RORγ antagonists, N-(5-(N-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzene base)aminosulfonyl)-4-methylthiazol-2-yl)acetamide (non-patent literature 11) and 6-(2-chloro-4-methylphenyl)-3-(4-cyclopropyl- Substituted azole derivatives headed by 5-(3-neopentylcyclobutyl)isoxazol-3-yl)-5-oxohexanoic acid (patent document 1); N-(5-(2-chlorobenzene Sulfonylbenzene derivatives such as formyl)-4-(3-chlorophenyl)thiazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide (Patent Document 2), undisclosed Substances having a cyclic amine structure such as 1-substituted piperidine-2-carboxamide
[0010] In addition, (S)-1-(2-(3,3-di Fluoropyrrolidin-1-yl)acetyl)-N-(1-ethyl-5-phenyl-1H-1,2,4-triazol-3-yl)piperidine-2-carboxamide etc. (patent Document 3), (R)-N-(5-benzyl-4-phenylthiazol-2-yl)-1-(2- Cyclopentylacetyl) piperidine-2-carboxamide, etc. (Patent Document 4), but regarding the effect of these compounds on RORγ, there is neither disclosure nor suggestion
[0011] In addition, as a therapeutic or preventive agent for multiple sclerosis, (S)-(3-(5-(4-fluorobenzyl) -1,2,4-oxadiazol-3-yl)piperidin-1-yl)(4-fluorophenyl)methanone, etc. (Patent Document 5), but it is not shown that these compounds have any effect on multiple sclerosis specific pharmacodynamic data, and there is absolutely no indication of its usefulness
In addition, in this patent document 5, regarding the effect of these compounds on RORγ, there is neither disclosure nor suggestion, and there is no disclosure of a substance having a piperidine-2-carboxamide structure substituted at the 1-position.

Method used

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  • Cyclic amine derivatives and their medicinal uses
  • Cyclic amine derivatives and their medicinal uses
  • Cyclic amine derivatives and their medicinal uses

Examples

Experimental program
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Embodiment

[0181] Among the compounds used in the synthesis of the compounds in Reference Examples and Examples, commercially available compounds were used for those whose synthesis methods were not described. "Room temperature" in the following Reference Examples and Examples usually means about 10°C to about 35°C. % represents mol / mol% for yield, represents volume % for solvents used in column chromatography and high-speed liquid chromatography, and represents weight % for others unless otherwise specified. The solvent names shown in the NMR data indicate the solvents used in the measurement. In addition, the 400 MHz NMR spectrum was measured using the JNM-AL400 nuclear magnetic resonance apparatus (JEOL Ltd.) or the JNM-ECS400 nuclear magnetic resonance apparatus (JEOL Ltd.). The chemical shift is based on tetramethylsilane, expressed in δ (unit: ppm), and the signals are represented by s (single line), d (double line), t (triple line), q (quadruple line), quint ( Quintuplet), sept ...

reference example 1

[0182] (Reference Example 1) Synthesis of 2-chloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-amine:

[0183] [chemical 4]

[0184]

[0185] To a solution of 2-trifluoromethoxyphenylboronic acid (1.10 g, 5.33 mmol) in acetonitrile (9.0 mL) was added 4-bromo-3-chloroaniline (1.00 g, 4.84 mmol), potassium carbonate ( 1.00 g, 7.27 mmol), 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) dichloromethane adduct (0.396 g, 0.484 mmol) and distilled water (3.0 mL), warming After reaching 90°C, stir for 18 hours. After the reaction solution was filtered through silica gel, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, n-hexane / ethyl acetate=85 / 15~67 / 33), and 2-chloro-2'-(trifluoromethoxy)-[1,1 '-Biphenyl]-4-amine (hereinafter referred to as the compound of Reference Example 1) (1.03 g, 3.57 mmol, 73.6%).

[0186] .

reference example 2

[0187] (Reference example 2) tert-butyl 2-((2-chloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)carbamoyl)piperidine-1-carboxylate Synthesis of esters:

[0188] [chemical 5]

[0189]

[0190] To a solution of 1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (0.263 g, 1.15 mmol) in DMF (2.0 mL), add the compound of Reference Example 1 (0.300 g, 1.04 mmol) in DMF at room temperature (2.0 mL), HATU (0.436 g, 1.15 mmol) and diisopropylethylamine (0.273 mL, 1.56 mmol) were stirred at this temperature for 16 hours. Distilled water was added to the reaction liquid, followed by extraction with a mixed solvent of n-hexane / ethyl acetate=20 / 80 (v / v). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, n-hexane / ethyl acetate=90 / 10~67 / 33) to obtain 2-((2-chloro-2'-(trifluoromethoxy)-[ tert-butyl 1,1'-biphenyl]-4-yl)...

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Abstract

The object of the present invention is to provide a retinoid-related orphan receptor gamma antagonist activity that is effective against autoimmune diseases such as multiple sclerosis or psoriasis, or allergic dermatitis such as contact dermatitis or atopic dermatitis, etc. Novel compounds that exert therapeutic or preventive effects on allergic diseases. The present invention provides a cyclic amine derivative represented by the following formula or a pharmacologically acceptable salt thereof.

Description

technical field [0001] The present invention relates to cyclic amine derivatives and their medical use. Background technique [0002] Autoimmune disease is a general term for diseases that cause symptoms due to excessive immune response attacking your own normal cells and tissues. Examples include multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and ankylosing spondylosis. inflammation, uveitis, or polymyalgia rheumatica. [0003] Allergic disease is a disease caused by an excessive immune response to a specific antigen, and examples thereof include allergic dermatitis, atopic dermatitis, allergic rhinitis (hay fever), allergic conjunctivitis, allergic gastroenteritis, and bronchial asthma , children with asthma or food allergies. [0004] Various mechanisms have been proposed for the onset and progression of autoimmune diseases and allergic diseases. As one of them, it is known that Th17 cells, one of the subsets of helper T cells, and th...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/36A61K31/451A61K31/454A61P1/00A61P17/06A61P19/02A61P25/00A61P27/02A61P29/00A61P37/02A61P43/00C07D211/38C07D211/44C07D211/96C07D401/06C07D405/06C07D413/06
CPCA61K31/451A61K31/454C07D401/06C07D405/06C07D413/06C07D211/36C07D211/38C07D211/44C07D211/96A61P17/06A61P37/06A61P25/00C07D211/60A61K31/4525A61K31/445A61P17/00A61P37/02
Inventor 林新之助M.瓦尔勒特横坂慎也大角和也青木拓实目黑裕之戒能美枝高垣梢高桥雄大
Owner TORAY IND INC
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