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Hexahydrobenzonaphthyridine-type optically active compound and pharmaceutical use thereof

A technology for hexahydrobenzene and compound, which is applied in the field of hexahydrobenzonaphthyridine optically active compounds and their pharmaceutical uses, and can solve the problems that biological activity and therapeutic effect have not been studied and revealed.

Inactive Publication Date: 2016-04-13
龚兆龙
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, to the best of our knowledge, there are no reports of resolution or other methods of separating this racemate into single enantiomers, nor any reports of the formation of
Therefore, a single left-handed (S) or right-handed (R) 5-amino-4-(2-chlorophenyl)-2,7,7-trimethyl-1,4,6,7,8,9- The biological activities and therapeutic effects of the enantiomers of hexahydrobenzo[b][1,8]naphthyridine-3-carboxylate have not yet been studied and revealed

Method used

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  • Hexahydrobenzonaphthyridine-type optically active compound and pharmaceutical use thereof
  • Hexahydrobenzonaphthyridine-type optically active compound and pharmaceutical use thereof
  • Hexahydrobenzonaphthyridine-type optically active compound and pharmaceutical use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1: Racemic 5-amino-4-(2-chlorophenyl)-2,7,7-trimethyl-1,4,6,7,8,9-hexahydrobenzo[b][ Preparation of ethyl 1,8]naphthyridine-3-carboxylate (compound T)

[0031]

[0032] Synthesis of Step 1 Raw Material A

[0033] Mix and dissolve malononitrile (330g, 5mol) and absolute ethanol (460.7g, 10mol) in 1.5L ethyl acetate, stir evenly at room temperature, add acetyl chloride (392.5g, 5mol) dropwise under ice bath, dropwise React overnight below 5°C, a large amount of solids precipitate out, filter, wash, and dry to obtain A600g, yield 80.76%

[0034] Synthesis of Step 2 Compound B

[0035] Dissolve 2-chlorobenzaldehyde (421.5g, 3mol) and ethyl acetoacetate (390.4g, 3mol) in 1L of n-hexane, add acetic acid (9.01g, 0.15mol) and piperidine (12.77g, 0.15mol), After stirring and refluxing with water for 3 hours, TLC monitored the completion of the reaction, cooled and concentrated to obtain product B, 690.2 g of light yellow oil, with a yield of 91.04%.

[0036] Synth...

Embodiment 2

[0040] Example 2: Left-handed (S) 5-amino-4-(2-chlorophenyl)-2,7,7-trimethyl-1,4,6,7,8,9-hexahydrobenzo[b ][1,8]Naphthyridine-3-carboxylic acid ethyl ester (compound T1) and dextrorotatory (R) 5-amino-4-(2-chlorophenyl)-2,7,7-trimethyl-1 , Preparation of ethyl 4,6,7,8,9-hexahydrobenzo[b][1,8]naphthyridine-3-carboxylate (compound T2)

[0041]

[0042] Compound C was resolved to obtain compounds D1 and D2

[0043] Main equipment and chromatographic parameters: Waters company SFC-350 preparative chromatograph (equipped with Guangzhou Yanchuang ChiralCNOD preparative column, specification: 50×250mm, 5μm). Column temperature: 35°C, mobile phase: CO 2 / Ethanol=80 / 20, flow rate: 280g / min, cycle time: 2.5min, back pressure: 100Bar, detection wavelength: 214nm, sample concentration: 0.080g / mL, injection volume: 5mL (maximum sample load 500mg / time ).

[0044] Table 1 resolves the SFC chromatogram data of compound C

[0045] Optical isomers

retention time (min)

P...

Embodiment 3

[0056] Example 3: Single crystal preparation of compound T1 hydrochloride.

[0057] Take 9 mg of compound T1 hydrochloride, dissolve it in a mixed solvent of 400 μL of acetonitrile and 300 μL of dichloromethane, and place it at room temperature for natural volatilization and crystallization to obtain a single crystal, which is Form A. Molecular structure diagram such as figure 1 shown.

[0058] Molecular formula C 24 h 28 ClN 3 o 2 ·CH 3 CN·HCl, the crystal structure is orthorhombic, the space group P212121, and the unit cell parameters are: α=90°, β=90°, V=2621.1(9)A, F(000)=1064, Dc=1.276g / cm 3 .

[0059] Crystal X-single crystal diffraction data:

[0060] loop_

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[0068] _atom_site_occupancy

[0069] _atom_site_symmetry_multiplicity

[0070] _atom_sit...

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Abstract

The invention discloses a hexahydrobenzonaphthyridine-type optically active compound and a pharmaceutical use thereof. The compound is L-(S)-5-amino-4-(2-chlorophenyl)-2,7,7-trimethyl-1,4,6,7,8,9-hexahydrobenzo[b][1,8]naphthyridine-3-ethyl carboxylate with a T1 structure, or a pharmaceutically acceptable salt thereof. The invention also discloses a composition of the optical isomer, and an application thereof. Compared with the dextroisomer compound T2 and the racemic compound T of the compound T1 provided by the invention, the compound T1 shows higher inhibitory activity on acetylcholinesterase and calcium channels, better drug absorption and metabolism properties, and comprehensively high in-vivo efficacy results.

Description

technical field [0001] The present invention relates to an optically active 1,4-dihydro-1,8-naphthyridine compound or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof, involving the The application of the compound or its pharmaceutically acceptable salt and the pharmaceutical composition comprising the compound or its pharmaceutically acceptable salt as L-type calcium channel blocker or / and acetylcholinesterase inhibitor, especially in the preparation of Use in drugs for the treatment of cardiovascular disease, cerebrovascular disease or dementia. Background technique [0002] Alzheimer's disease is a degenerative disease of the central nervous system characterized by chronic, progressive cognitive impairment and memory impairment. The main pathological features are senile plaques, neurofibrillary tangles and neuron loss, which seriously affects patients. Cognition, memory, lang...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/4745A61P9/00A61P9/10A61P25/28
Inventor 龚兆龙
Owner 龚兆龙
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