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Applications of tetrahydroisoquinoline-3-carboxylic acid derivatives in preparation of medicines treating dopaminergic nerve diseases

A tetrahydroisoquinoline, dopaminergic technology, applied in the field of biomedicine, can solve problems such as rare pharmacological activity, and achieve the effects of enhancing and brain bioavailability and reducing the rate of LD degradation

Active Publication Date: 2014-11-26
苏州必益必诚医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

3-Carboxylic acid tetrahydroisoquinolines are simple amino acids, but there are few reports on their pharmacological activities, especially neuropharmacological activities.

Method used

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  • Applications of tetrahydroisoquinoline-3-carboxylic acid derivatives in preparation of medicines treating dopaminergic nerve diseases
  • Applications of tetrahydroisoquinoline-3-carboxylic acid derivatives in preparation of medicines treating dopaminergic nerve diseases
  • Applications of tetrahydroisoquinoline-3-carboxylic acid derivatives in preparation of medicines treating dopaminergic nerve diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Preparation of 3-Carboxylic Acid Tetrahydroisoquinoline Derivatives from Cat Bean

[0022] The medicinal material of cat bean (MD20091101) was collected in Baise, Guangxi, and was identified as the seed of Mucuna pruriens var. utilis A. Cheval. Take 3.0 kg of dried cat bean, grind it into coarse powder, extract it with acetone at room temperature for 24 hours to remove the oil, and continue to extract the dregs with methanol for 2 times under reflux, each time for 2 hours, and recover methanol to obtain 214 g of cat bean extract (MDE). Take MDE104g, after repeated medium-pressure silica gel column chromatography, elute with chloroform-methanol-0.5% acetic acid 7:3:0.5 (volume ratio) to obtain MD02 (30mg); continue to elute with 6.5:3.5:0.5 to obtain MD01 (200 mg), MD03 (12 mg); continue to elute at 5:5:0.5, and obtain MD04 (15 mg), LD (35 mg); in sequence. The chemical structures of MD01-MD04 have been 1 H-NMR, IR, MS and other spectral analysis, compared with the lit...

Embodiment 2

[0024] Chemical Synthesis of (3S)-3-carboxy-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (MD03)

[0025] Take 100mg of levodopa, add appropriate amount of 0.1N hydrochloric acid to dissolve, neutralize with sodium hydroxide solution, add 0.35ml of 40% formaldehyde solution, shake and mix, stir and react at 30°C for 72h. The reaction solution was centrifuged (4000r / min, 10min), and the precipitate was collected and dried under reduced pressure to obtain 20 mg of the target product.

Embodiment 3

[0027] Chemical Synthesis of 1-methyl-3-carboxy-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline

[0028]Take 100mg of levodopa, add appropriate amount of 0.1N hydrochloric acid to dissolve, neutralize with sodium hydroxide solution, add 0.35ml of acetaldehyde solution, shake and mix, stir and react at 30°C for 72h. The reaction solution was centrifuged (4000r / min, 10min), and the precipitate was collected and dried under reduced pressure to obtain 50mg of the product. The product was further separated by HPLC. The chromatographic conditions were: ODS chromatographic column, 20×250mm, 10% methanol-0.1% acetic acid as the mobile phase, to obtain 1α-methyl-3-carboxy-6,7-dihydroxy-1 , 15 mg of 2,3,4-tetrahydroisoquinoline, 8 mg of 1β-methyl-3-carboxy-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline.

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Abstract

Applications of tetrahydroisoquinoline-3-carboxylic acid derivatives in preparation of medicines treating dopaminergic nerve diseases are disclosed. The derivatives can be separated and obtained from the seed of stizolobium cochinchinensis, and can also be obtained by chemical synthesis by subjecting amino acid precursors phenylalanine and tyrosine, or levodopa with corresponding aldehydes or ketones to Pictet-Spengler condensation. Rat experiments show that: when the derivatives are administrated in combination with a levodopa component, the concentration of the levodopa in blood and brain tissues can be significantly increased, thus improving the bioavailability of the levodopa. In addition, the derivatives significantly inhibit highly-spontaneous rat movement induced by morphine, and penetrate the blood brain barrier, so that the derivatives can adjust the dopaminergic nerve functions. The derivatives can be used for treating the Parkinson's disease, psychosis, and other dopaminergic nerve diseases.

Description

technical field [0001] The present invention relates to the application of a 3-carboxylic acid tetrahydroisoquinoline derivative, more specifically, the application of the 3-carboxylic acid tetrahydroisoquinoline derivative in the preparation of drugs for the treatment of dopaminergic neurological diseases, belonging to biological field of medicine. Background technique [0002] Parkinson's disease is one of the most common neurodegenerative disorders among older adults, affecting approximately 1.7 percent of those over 65 and 2 percent of those over 80. About 18 million people in the world suffer from this disease at present, and there are about 1.7 million patients in my country. The main pathological changes of Parkinson's disease are the progressive degeneration and death of dopaminergic neurons in the substantia nigra of the midbrain, which leads to the loss of the motor regulation function of the nervous system in this part, and the appearance of resting tremor, muscl...

Claims

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Application Information

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IPC IPC(8): A61K31/472A61P25/16A61P25/18A61P25/00A61K31/198
Inventor 刘江云谭蓓蓓窦冕郑龙太杨世林
Owner 苏州必益必诚医药科技有限公司
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