Aniline compound useful as ROR [gamma] modulator

A technology of compound and solvate, which is applied in the field of chemical medicine and can solve the problems of reduced ability of differentiation

Pending Publication Date: 2021-12-10
SHANGHAI LITEDD CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Thp cells isolated from RORγt-deficient mice have significantly reduced ability to differentiate into Th17 cell lines

Method used

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  • Aniline compound useful as ROR [gamma] modulator
  • Aniline compound useful as ROR [gamma] modulator
  • Aniline compound useful as ROR [gamma] modulator

Examples

Experimental program
Comparison scheme
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specific Embodiment approach

[0258] The technical solutions of the present invention will be further described below in conjunction with specific examples, but the protection scope of the present invention is not limited to these examples. All changes or equivalent substitutions that do not depart from the concept of the present invention are included in the protection scope of the present invention.

[0259] The experimental methods for which specific conditions are not indicated in the following examples are usually in accordance with the conventional conditions of this type of reaction, or in accordance with the conditions suggested by the manufacturer. Percentages and parts are by weight unless otherwise indicated. Unless otherwise stated, ratios of liquids are by volume.

[0260] The experimental materials and reagents used in the following examples can be obtained from commercial sources, prepared according to methods in the prior art or prepared according to methods similar to those disclosed in t...

Embodiment 1

[0277] Example 1: 2-acetyl-6-(ethylsulfonyl)-N-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl )-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

[0278]

[0279] Step 1: Synthesis of 3-(2-aminoethyl)phenol hydrobromide

[0280]

[0281] 2-(3-Methoxyphenyl)ethanamine (9.00 g, 59.5 mmol) was dissolved in 40% aqueous hydrobromic acid (120 g, 595 mmol). The reaction solution was stirred and reacted at 110°C for 6 hours, and the reaction was complete as monitored by LC-MS. The reaction solution was concentrated under reduced pressure to obtain the target compound (9.00 g, crude product, light brown solid). LC-MS(ESI)m / z:179.1[M+ACN+H] + .

[0282] Step 2: Synthesis of ethyl 6-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylate hydrobromide

[0283]

[0284] 3-(2-Aminoethyl)phenol hydrobromide (9.00 g, 65.6 mmol) was dissolved in ethanol (90 mL). At room temperature, 50% ethyl glyoxylate toluene solution (14.7 g, 72.2 mmol) was added dropwise to the reaction sol...

Embodiment 2 and 3

[0309] Examples 2 and 3: (R)-2-Acetyl-6-(ethylsulfonyl)-N-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropane- 2-yl)phenyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide or (S)-2-acetyl-6-(ethylsulfonyl)-N-(4- (1,1,1,3,3,3-Hexafluoro-2-hydroxypropan-2-yl)phenyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide

[0310]

[0311] Racemate 2-acetyl-6-(ethylsulfonyl)-N-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl )-1,2,3,4-tetrahydroisoquinoline-1-carboxamide (500 mg dissolved in about 120 mL methanol, injection volume 6.0mL) by Waters SFC 150 (room temperature, 100bar, 214nm) and 250* 25mm 10μm Dr.maish Reprosil Chiral-OM (similar to OD) (supercritical carbon dioxide: methanol, 70:30, 3.0min, 70mL / min) separation to obtain (R)-2-acetyl-6-(ethylsulfonyl)-N-(4-(1,1 ,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide or (S)-2- Acetyl-6-(ethylsulfonyl)-N-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-1,2, 3,4-Tetrahydroisoquino...

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Abstract

The invention relates to a compound as shown in formula (I), a stereoisomer, a tautomer, a stable isotope variant, a pharmaceutically acceptable salt or a solvate thereof, a pharmaceutical composition comprising the compound, a method for treating or preventing diseases associated with ROR [gamma] t by using the compound, and use of the compound in the preparation of a medicine for treating or preventing diseases associated with ROR [gamma] t.

Description

technical field [0001] The invention belongs to the technical field of chemical medicine, and specifically relates to aniline compounds having RORγt inhibitory activity, pharmaceutical compositions containing the compounds, methods for preparing the compounds, and the preparation of the compounds for preventing or treating diseases related to RORγt. Use in medicine for disease. Background technique [0002] Retinoic acid receptor-related orphan receptors (retinoic acid receptor-related orphan receptors, RORs), also known as NF1R, belongs to a subfamily of the nuclear receptor superfamily of ligand-dependent transcription factors. The RORs subfamily mainly includes three subtypes, RORα, RORβ and RORγ. RORγ contains two members: RORγ1 (also known as RORγ) and RORγ2 (also known as RORγt), in which RORγ1 is distributed in skeletal muscle, thymus, testis, pancreas, prostate, heart and liver, etc., while RORγt is only expressed in certain immune cells. in cells. [0003] Littma...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/26C07D495/04C07D405/12A61K31/472A61K31/4725A61K31/4365A61P1/04A61P1/00A61P11/06A61P11/00A61P13/12A61P9/00A61P27/02A61P29/00A61P19/02A61P17/06A61P19/08A61P25/28A61P37/08A61P17/10A61P11/02A61P1/16A61P31/14A61P3/10A61P35/00
CPCC07D217/26C07D495/04C07D405/12A61P1/04A61P1/00A61P11/06A61P11/00A61P13/12A61P9/00A61P27/02A61P29/00A61P19/02A61P17/06A61P19/08A61P25/28A61P37/08A61P17/10A61P11/02A61P1/16A61P31/14A61P3/10A61P35/00A61P37/00A61K31/472C07D471/04
Inventor 程耀邦黄亚飞周娟董志强
Owner SHANGHAI LITEDD CO LTD
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