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Indole derivative and application thereof

A technology of indole derivatives and compounds, applied in the field of medicinal chemistry, can solve problems such as unmet medical needs, and achieve the effect of novel structure, good drug effect and high activity

Active Publication Date: 2022-01-04
SHANGHAI MEDICILON INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There is still a huge unmet medical need in this area

Method used

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  • Indole derivative and application thereof
  • Indole derivative and application thereof
  • Indole derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0114] 3-(5-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-7-methyl-1H-indol-1-yl)propanoic acid (1)

[0115]

[0116] The first step: 1-(2-amino-5-methoxy-3-methylphenyl)-2-chloroethanone (1b)

[0117]

[0118] Dissolve 2-methyl-4-methoxyaniline (1a) (5.0g, 36.4mmol) in toluene (20mL), and add boron trichloride (37mL, 1M dichloromethane solution) and Titanium tetrachloride (37 mL, 1M in dichloromethane) and chloroacetonitrile (3.1 g, 41 mmol). The reaction solution was heated to 90°C and stirred for 3h. A 2M aqueous hydrochloric acid solution (30 mL) was added to the reaction system, and stirred at 85° C. for 45 min. Saturated sodium bicarbonate solution (100 mL) was added to the reaction system, and extracted with dichloromethane (100 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether (v / v)=1:5...

Embodiment 2

[0143] 3-(5-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-7-ethyl-1H-indol-1-yl)propanoic acid (2)

[0144]

[0145]

[0146] The first step: 2-ethyl-4-methoxy-1-nitrobenzene (2b)

[0147]

[0148] To a solution of 1-methoxy-4-nitrobenzene 2a (5 g, 32.65 mmol) in tetrahydrofuran (100 mL) was added 1M vinylmagnesium bromide solution (75.10 mL) at -15°C. The reaction solution was stirred at -15 °C for 2 h. 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (12.60 g, 55.51 mmol) was added, and the reaction solution was stirred at -40° C. for 3 h. Saturated ammonium chloride aqueous solution (50 mL) was added to the reaction liquid, and extracted with ethyl acetate (100 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether (v / v)=1:5) to obtain a dark yellow oil 2-ethyl- 4-Methoxy-1-nitrobenzene 2b (2.55 g, y...

Embodiment 3

[0172] 3-(7-Chloro-5-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1H-indol-1-yl)propanoic acid (3)

[0173]

[0174] The first step: 2-chloro-4-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1-nitrobenzene (3b)

[0175]

[0176] Add 4-(chloromethyl)-1-cyclopentyl-2- (Trifluoromethyl)benzene (1.51 g, 5.76 mmol) and cesium carbonate (3.75 g, 11.52 mmol). Reaction at 80°C for 3h. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (30 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether (v / v)=1:20) to obtain 2-chloro-4- ((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1-nitrobenzene (3b) (2.1 g, yield: 91.2%).

[0177] MS (ESI) m / z: 400 [M+1].

[0178] The second step: 7-chloro-5-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1H-indole (3c)

[0179]

[0180]Add 2-c...

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Abstract

The invention relates to an indole derivative shown in a general formula (I-1) and application of the indole derivative in preparation of drugs for preventing and / or treating indications of S1P receptor related disorders. The indole derivative is separately substituted by R1, R2, R5 and R6 at different sites, and the modified indole derivative has excellent biological activity and is an ideal efficient S1P receptor modulator. Compounds of general formula (I-1) are useful in the treatment and / or prevention of a variety of autoimmune and inflammatory diseases such as Crohn's disease, ulcerative colitis, psoriasis, rheumatoid arthritis, multiple sclerosis, atopic dermatitis, eosinophilic esophagitis, alopecia areata, primary cholangitis, pyoderma gangrenosum, graft versus host disease, amyotrophic lateral sclerosis, systemic lupus erythematosus, type I diabetic arteriosclerosis, atherosclerosis, scleroderma, autoimmune hepatitis, acne, microbial infection and virus infection.

Description

[0001] This application claims the priority of the previous application submitted to the State Intellectual Property Office of China on July 03, 2020, with the patent application number 202010638390.0, and the title of the invention is "An Indole Derivative and Its Application". The entirety of this application is incorporated by reference into this application. technical field [0002] The invention belongs to the field of medicinal chemistry, and relates to an indole derivative, its preparation method and its use in the preparation of medicines for preventing and / or treating indications related to S1P receptor-related disorders. Background technique [0003] The sphingosine 1-phosphate receptor (S1PR) belongs to the family of G protein-coupled receptors, and five subtypes have been found so far, called S1PR1, 2, 3, 4 and 5. Different subtypes are distributed differently in each tissue. Among them, S1PR1, 2 and 3 are widely distributed, S1PR4 is mainly expressed in blood c...

Claims

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Application Information

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IPC IPC(8): C07D209/08A61K31/404A61P1/04A61P37/02A61P19/02A61P9/10A61P17/00A61P29/00A61P3/10A61P31/12A61P31/04A61P31/10A61P31/00
CPCC07D209/08A61P1/04A61P37/02A61P19/02A61P9/10A61P17/00A61P29/00A61P3/10A61P31/12A61P31/04A61P31/10A61P31/00A61K31/404A61K31/405A61P1/00A61P21/00A61P25/00A61P37/00C07D209/12Y02P20/55Y02A50/30C07D209/32A61P1/06
Inventor 任峰吕裕斌王海龙任月英陈春麟罗杨春蔡金娜李邦良
Owner SHANGHAI MEDICILON INC
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