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1H-indole-2-carboxamide derivative and preparation method and applications thereof

A technology of formamide and derivatives, applied in the field of medicine, can solve problems such as no marketed drugs yet

Inactive Publication Date: 2018-11-13
EAST CHINA NORMAL UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] At present, research on CB2 receptor agonists is still in the preclinical and clinical stages, and there is no marketed drug

Method used

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  • 1H-indole-2-carboxamide derivative and preparation method and applications thereof
  • 1H-indole-2-carboxamide derivative and preparation method and applications thereof
  • 1H-indole-2-carboxamide derivative and preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0125] Example 1: N-(adamantan-1-yl)-1H-indole-2-carboxamide (1)

[0126] (a) Preparation of 1H-indole-2-carboxylic acid 1a Ethyl-1H-indole-2-carboxylate (1.0g, 5.3mmol) was added to 10ml of water, and then potassium hydroxide (2.0g , 31.8mmol), refluxed at 120°C for 0.5 hour, cooled to room temperature, adjusted pH to 3 to 4 with 10M hydrochloric acid, a large amount of white solid precipitated, filtered, and the filter cake was dried to obtain 853mg (99.9%) of white solid.

[0127] (b) Preparation of N-(adamantan-1-yl)-1H-indole-2-carboxamide (1) 1a (500mg, 3.1mmol) was added to 5ml of dichloromethane, and a catalytic amount of DMF was added , then add oxalyl chloride (787mg, 6.2mmol), stir at room temperature for 1 hour, spin dry the system, add amantadine (562mg, 3.72mmol), triethylamine (1.25g, 12.4mmol) into 5ml of dichloromethane, Stir at room temperature for 8 hours, spin the system to dryness, and purify by silica gel column chromatography (dichloromethane) to obtain...

Embodiment 2

[0128] Example 2: Preparation of N-(adamantan-1-yl)-1-pentyl-1H-indole-2-carboxamide (2) (1) (150 mg, 0.51 mmol) was added to 4 ml of anhydrous DMF In, add NaH (40mg, 0.77mmol), stir at room temperature for 15 minutes, then add 1-bromopentane, stir at room temperature for 3 hours, add 15ml of water to quench the reaction, then extract with ethyl acetate (20ml×3), combine The organic layer was washed with water (30ml×3), and then washed with saturated brine, the organic layer was dried over anhydrous sodium sulfate, the organic layer was spin-dried, and purified by silica gel column chromatography (dichloromethane) to obtain (2) 135 mg of a white solid ( 73%) 1 H NMR (400MHz, CDCl 3 )δ7.59(d, J=7.9Hz, 1H), 7.36(d, J=8.4Hz, 1H), 7.30–7.23(m, 1H), 7.11(t, J=7.4Hz, 1H), 6.73( s,1H),5.90(s,1H),4.51(t,J=7.3Hz,2H),2.14(d,J=8.9Hz,9H),1.81–1.67(m,8H),1.34–1.23(m ,4H),0.87(t,J=6.8Hz,3H). 13 C NMR (101MHz, CDCl 3 )δ162.11, 138.13, 133.40, 126.20, 123.58, 121.70, 120.28, 110.43, 103....

Embodiment 3

[0129] Example 3: N-(Adamantan-1-yl)-5-methoxy-1H-indole-2-carboxamide (3)

[0130] (a) Preparation of 5-methoxy-1H-indole-2-carboxylic acid 3a The preparation method of 3a is the same as that of 1a, except that ethyl-5-methoxy-1H-indole is used Ethyl-1H-indole-2-carboxylate (500 mg, 2.3 mmol) was substituted for ethyl-1H-indole-2-carboxylate to afford 340 mg (77%) of 3a as a white solid.

[0131] (b) the preparation of N-(adamantan-1-yl)-5-methoxy-1H-indole-2-carboxamide (3) The preparation method of (3) is the same as the preparation method of (1), different The difference is that 3a (340mg, 1.78mmol) was used instead of 1a to give (3) 100mg (17.4%) pale yellow solid 1 H NMR (400MHz, CDCl 3)δ10.23(s,1H),7.43(d,J=8.9Hz,1H),7.03(d,J=1.8Hz,1H),6.93(dd,J=8.9,2.3Hz,1H),6.69( d,J=1.1Hz,1H),5.92(s,1H),3.84(s,3H),2.17(d,J=10.2Hz,9H),1.83–1.68(m,6H). 13 C NMR (101MHz, CDCl 3 )δ161.13, 154.57, 132.45, 132.02, 128.05, 115.28, 113.22, 102.24, 100.96, 55.82, 52.58, 41.93, 36.46, 29....

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Abstract

The invention belongs to the technical field of medicine, and discloses a 1H-indole-2-carboxamide derivative of a formula (I) and a preparation method thereof. The preparation method includes the following steps: a compound of a formula (II) and sodium hydroxide are subjected to a hydrolysis reaction to synthetize a compound of a formula (III); the compound of the formula (III) and H2NR2 are subjected to an amidation reaction to synthetize a compound of a formula (IV); the compound of the formula (IV) and halogenated R1 are subjected to a nucleophilic substitution reaction to synthetize a compound of a formula (V); the compound of the formula (V) and a selectfluor are subjected to an electrophilic substitution reaction to synthetize a compound of a compound (VI), and the compound of the formula (VI) and the halogenated R1 are subjected to the nucleophilic substitution reaction to synthetize the compound of the formula (I). The 1H-indole-2-carboxamide derivative of the formula (I) is aagonist with high affinity, selectivity and activity for CB2 receptors, and can be potentially used for treating a plurality of diseases such as multiple sclerosis, autoimmune diseases, osteoporosis,arthralgia, inflammatory pain, and neurodegenerative diseases.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to 1H-indole-2-carboxamide derivatives and their preparation methods and applications. As selective cannabinoid type 2 receptor agonists, they can be used to prepare and treat Drugs for multiple sclerosis. Background technique [0002] Cannabinoid receptors belong to the large family of G protein-coupled receptors, with 7 transmembrane structures, and there are two subtypes, one subtype is cannabinoid 1 receptor (CB1); the other subtype is cannabinoid 2 type receptor (CB2). The complete amino acid sequence of CB1 receptor and CB2 receptor has 44% homologous similarity, and there is 68% homologous similarity in the 7 transmembrane regions. Human CB1 receptor consists of 472 amino acids and is mainly distributed in the central nervous system , CB2 receptor consists of 360 amino acids, mainly distributed in the peripheral nervous system (Van Sickle, M.D et al. Science 2005, 310, 329-3...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/42C07D405/06C07D413/06C07D409/06C07D409/14A61P37/02A61P25/28A61P29/00A61P19/02A61P35/00A61P19/10
CPCC07D209/42C07D405/06C07D409/06C07D409/14C07D413/06
Inventor 于丽芳谢欣石英王志龙计悦阳段彦辉杨帆李静汤杰
Owner EAST CHINA NORMAL UNIV
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