Beta-carboline selective monoamine oxidase B inhibitor and pharmaceutical application thereof

A carboline, compound technology, applied in the fields of drug combination, digestive system, organic chemistry, etc., can solve the problem of only showing

Pending Publication Date: 2021-08-27
陈冬寅
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Medicinal chemists have carried out a series of structural optimization and modification work using β-carboline alkaloids such as Norharman as lead compounds, and the MAO-A inhibitory activity of their derivatives can reach nanomolar levels (IC 50 = 1.0-5.3 nM), but exhibited only moderate micromolar MAO-B inhibitory activity (Beato A, et al. J Med Chem, 2021, 64, 1392-1422)
So far, β-carboline derivatives have not been reported as efficient, reversible and selective MAO-B inhibitors.

Method used

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  • Beta-carboline selective monoamine oxidase B inhibitor and pharmaceutical application thereof
  • Beta-carboline selective monoamine oxidase B inhibitor and pharmaceutical application thereof
  • Beta-carboline selective monoamine oxidase B inhibitor and pharmaceutical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030]

[0031] Six-fluoro-2,3,4,9-tetrahydro-1H-pyridine and [3,4-b] indole-1-carboxylate (3)

[0032] In a 100 mL round bottom flask, 5-fluorohamine (1) (1 g, 5.6 mmol) was added to 15 ml of dichloromethane, and ethyl aracethane (2) (0.69 g, 6.7 mmol) and trifluoroacetic acid (0.7 mL), the reaction mixture was stirred at room temperature overnight. The TLC was measured by the raw material, and pH was adjusted with 1 m aqueous sodium hydroxide (20 mL × 3) extraction, combined with organic layers, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a pale yellow solid (3) (1.06 g, yield 72%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.60 (S, 1H), 8.23 ​​(D, J = 7.7 Hz, 1H), 7.75 (D,J = 8.2 Hz, 1H), 7.30-7.18 (m, 1H), 4.43 (Q, J = 6.8 hz, 2h), 3.23-3.20 (m, 2H), 2.67-2.63 (m, 2H), 1.34 (T, J = 7.0 hz, 3h); MS (ESI) m / z 263.3 [M + H] + .

[0033] 6-fluoro-9H-pyridine and [3,4-b] indole-1-ca...

Embodiment 2

[0038] Preparation of 7-fluoro-9H-pyridine and [3,4-B] indole-1-carboxylic acid n-butyl ester (I-2)

[0039]

[0040] The preparation method of Compound I-1 was obtained in a starting material in 6-fluoroidethylamine and acetate (2), and the compound I-2 was prepared by three-step reaction, and the yield was 42%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.62 (S, 1H), 8.45 (D, J = 5.0 hz, 1h), 8.36 (D, J = 5.1 Hz, 1H), 8.22 (D, J = 7.9 Hz, 1H), 7.58-7.51 (m, 1H), 7.31-7.20 (M, 1H), 4.41 (T, J = 6.7 Hz, 2H), 1.84-1.67 (m, 2H), 1.49-1.35 (m, 2H), 0.92 (T, J = 7.4 Hz, 3H); MS (ESI) M / Z 287.3 [M + H] + .

Embodiment 3

[0042] Preparation of N-n-butyl-6-fluoro-9H-pyridine and [3,4-B] indole-1-amide (I-3)

[0043]

[0044] The intermediate 4 was obtained by a two-step reaction with 5-fluorone ethalamine (1) and acetanlate (2). In a 50 ml round bottom flask, Compound 4 (0.5 g, 1.9 mmol) was added to 10 mL of ethanol, and n-butylamine (0.15 g, 2.1 mmol) was added, and the reaction was refluxed under reflux 4 h. After TLC was monitored, the reaction was complete, ethyl acetate (20 mL × 3) extracted, combined with organic layers, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. Decapulsted and evaporated and evaporated, the crude product was purified by silica gel column (eluent volume ratio: petroleum ether / ethyl acetate = 40 / 1 ~ 5 / 1), obtained light yellow solid I-3 (442 mg, yield 80%) ). 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.66 (S, 1H), 8.85 (T, J = 6.1 Hz, 1H), 8.35-8.22 (M, 2H), 8.15 (D, J = 7.9 Hz, 1H), 7.74 (D, J = 8.3 Hz, 1H), 7.21 (T, J = 7.6 hz, 1h...

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Abstract

The invention discloses beta-carboline derivatives with structural characteristics shown in a formula (I), and also discloses pharmaceutically acceptable salts of the beta-carboline derivatives, a preparation method of the beta-carboline derivatives and application of the beta-carboline derivatives as selective monoamine oxidase B inhibitors. The compounds of the invention are useful for the treatment of neuropsychiatric and degenerative diseases modulated by selective monoamine oxidase B inhibitors, including Parkinson's disease, Alzheimer's disease, obsessive-compulsive disorder, depression, schizophrenia, anorexia nervosa and migraine.

Description

Technical field [0001] The present invention belongs to the sect of the pharmaceutical field, and more particularly to β-pyridine derivatives or a pharmaceutically acceptable salt thereof, the preparation method thereof, and their use as a selective monoamine oxidase B inhibitor. Background technique [0002] Single amine oxidase B (MAO-B) is a vulcanne adenine dinucleotide enzyme, mainly located on the cellular mitochondrial membrane of organisms such as brain, liver and intestinal mucosa, which is one of the key enzymes of dopamine (DA) decomposition metabolism. . As age growth, MAO-B activity is gradually enhanced in glial cells, which promotes oxidation degradation in the brain, while producing high levels of hydrogen peroxide, aldehyde, amine, etc. toxic metabolites, and cause nerves Cell oxidative damage, this is considered to be one of the important events in the pathogenesis of Parkinson's disease (PD), Alzheimer's disease (AD) (Jones DN, ET Al. J Chem Neuroanat, 2021, 14...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/437A61P25/16A61P25/28A61P25/24A61P25/18A61P1/14A61P25/06
CPCA61P1/14A61P25/06A61P25/16A61P25/18A61P25/24A61P25/28C07D471/04
Inventor 陈冬寅陈轩李迎春李飞张宇韩峰
Owner 陈冬寅
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