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Carbazole amide derivatives or salts thereof, preparation method and use thereof

A technology of carbazole amide and derivatives, applied in the field of chemical medicine, can solve the problem of ignorance of Th17 function

Active Publication Date: 2022-05-17
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] At present, studies have found that Th17 cells are widely present in tumor tissues, however, nothing is known about the function of Th17 in tumor tissues

Method used

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  • Carbazole amide derivatives or salts thereof, preparation method and use thereof
  • Carbazole amide derivatives or salts thereof, preparation method and use thereof
  • Carbazole amide derivatives or salts thereof, preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0085] Example 1: 9-Ethyl-N-(4-(ethylsulfonyl)phenyl)-9H-carbazole-3-carboxamide

[0086] 9-ethyl-N-(4-(ethylsulfonyl)benzyl)-9H-carbazole-3-carboxamide

[0087]

[0088] Intermediate 1: Synthesis of 9-ethyl-9H-carbazole-3-carboxylic acid

[0089] Step 1: Synthesis of methyl 4-anilinobenzoate

[0090] To a 25mL microwave tube was added aniline (1.82g, 19.5mmol), methyl 4-bromobenzoate (3.5g, 16.28mmol), potassium carbonate (6.72g, 49.4mmol), rac-BINAP (506mg, 0.81mmol), Palladium acetate (218mg, 0.97mmol), toluene (10mL), microwave heating reaction at 130°C for 2 hours, after the reaction is complete, dilute with ethyl acetate, filter with diatomaceous earth, spin dry the solvent under reduced pressure, and separate on a silica gel column (petroleum ether: acetic acid Ethyl ester=10:1-5:1) to obtain 3.5 g of a yellow solid product with a yield of 94.6%. 1 H NMR (400MHz, CDCl 3 )δ7.92(d, J=8.5Hz, 2H), 7.34(t, J=7.7Hz, 2H), 7.17(d, J=7.7Hz, 2H), 7.07(t, J=7.3Hz, 1H) , 6...

Embodiment 2

[0104] Example 2: 9-Ethyl-N-(4-ethylsulfonyl)benzyl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamide (9-ethyl-N-(4-(ethylsulfonyl)benzyl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamide)

[0105]

[0106] Step 1: Synthesis of 2,3,4,9-tetrahydro-1H-carbazole-6-carboxylic acid

[0107] Add 4-hydrazinobenzoic acid (1g, 6.6mmol), cyclohexanone (647mg, 6.6mmol), 1,4-dioxane (10mL), concentrated hydrochloric acid (5mL) into a 25mL single-necked bottle, and reflux at 120°C After reacting overnight, a large amount of solids were produced. After filtration, the obtained solids were put into water (10 mL) and stirred for 30 minutes, and then filtered. The obtained solids were vacuum-dried to obtain 1.13 g of a brown solid product, with a yield of 80.1%. MS(ESI)m / z:216.1(MH + ).

[0108] Step 2: Synthesis of N-(4-(ethylsulfonyl)benzyl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamide

[0109] Add 2,3,4,9-tetrahydro-1H-carbazole-6-carboxylic acid (169mg, 0.78mmol), 4-(ethylsulfonyl)benzy...

Embodiment 3

[0112] Example 3: N-(4-(ethylsulfone)benzyl)-9H-carbazole-3-carboxamide

[0113] N-(4-(ethylsulfonyl)benzyl)-9H-carbazole-3-carboxamide

[0114]

[0115] Step 1: Synthesis of methyl 4-(phenylamino)benzoate

[0116] Under the protection of argon, add aniline (1.82g, 19.53mmol), methyl 4-bromobenzoate (3.5g, 16.28mmol), palladium acetate (218mg, 0.97mmol), rac-BINAP (506mg , 0.81mmol), potassium carbonate (6.72g, 48.62mmol), toluene (10mL). Microwave at 160°C for 2 hours and cool to room temperature. After the reaction, the solvent was spin-dried under reduced pressure, dichloromethane was added to dilute and filtered. After the organic phase was spin-dried, water (15 mL) was added, extracted with ethyl acetate (3×30 mL), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure to obtain a crude product. Separated by column chromatography, 3.32 g of a light brown solid was obtained, with a yield of 89.7%. ...

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Abstract

The present invention discloses a novel carbazole amide derivative or its salt represented by the general formula I with RORγt activity regulating effect and a preparation method thereof, and also discloses the use of the carbazole amide derivative or its salt in preparing therapeutic Use in medicine for diseases associated with RORγt. Experimental results show that the carbazole amide derivatives of the present invention or their salts can effectively regulate the activity of RORγt protein receptors, thereby regulating the differentiation of Th17 cells and the production of IL-17, and further serve as therapeutic drugs for the treatment of related diseases mediated by RORγt , especially for the treatment of multiple sclerosis, rheumatoid arthritis, collagen-induced arthritis, psoriasis, inflammatory bowel disease, encephalomyelitis, clonal disease, asthma and various cancers and other related diseases.

Description

technical field [0001] The invention belongs to the technical field of chemistry and medicine, and relates to novel carbazole amide derivatives with general formula I and RORγt regulating activity and a preparation method thereof, and also relates to the use of such compounds in treating diseases related to RORγt. Background technique [0002] Retinoic acid receptor-related orphan receptors (retinoic acid receptor-related orphan receptors, RORs), also known as NF1R, is a member of the nuclear receptor superfamily of ligand-dependent transcription factors. The RORs subfamily mainly includes three members: RORα, RORβ and RORγ. There are two different subtypes of RORγ: RORγ1 and RORγt (also known as RORγ2), 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 . [0003] Littman et al. first reported RORγt for initial CD4 + It is necessary for the differentiation of T...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/88C07D471/04A61K31/437A61K31/403A61P25/00A61P19/02A61P17/06A61P1/00A61P31/04A61P35/00A61P11/06
CPCA61P1/00A61P11/06A61P17/06A61P19/02A61P25/00A61P31/04A61P35/00C07D209/88C07D471/04A61K31/403A61K31/437A61K31/4439A61P25/28A61P29/00A61P31/12A61P37/02
Inventor 王永辉黄亚飞郁明诚谢琼
Owner FUDAN UNIV
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