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N-substituted alpha-amino acid derivatives and preparation method and application thereof

A technology of amino acids and derivatives, which is applied in the directions of drug combinations, pharmaceutical formulations, active ingredients of heterocyclic compounds, etc.

Active Publication Date: 2011-06-08
深圳市天明医药科技开发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the specific mechanism of the neuroprotective effect of neurotrophic factor is still unclear, it has been shown that its interaction with FKBP-12 leads to its inhibition of calcineurin, which in turn inhibits the regulation of apoptotic cell death Dephosphorylation of protein BAD
This would inhibit the role of BAD in initiating pre-apoptotic signaling

Method used

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  • N-substituted alpha-amino acid derivatives and preparation method and application thereof
  • N-substituted alpha-amino acid derivatives and preparation method and application thereof
  • N-substituted alpha-amino acid derivatives and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Example 1: (S)-1-[3,3-Dimethyl-2-oxo-4-(2-piperonyl-5-yl-ethylcarbamoyloxy)butyryl]piperidine-2 -carboxylic acid

[0064] Structure of (S)-1-[3,3-dimethyl-2-oxo-4-(2-piperonan-5-ylethylcarbamoyloxy)butyryl]piperidine-2-carboxylic acid as follows:

[0065]

[0066] 1. Preparation of (S)-piperidine-2-carboxylic acid benzyl ester (compound 2):

[0067] Compound 1 (50 g, 0.39 mol) was dissolved in 500 mL of toluene at room temperature, and p-toluenesulfonic acid (66.7 g, 0.39 mol) and benzyl alcohol (50.5 g, 0.468 mol) were added. After the addition, the reaction was refluxed overnight. After cooling to room temperature, 300 mL of ethyl acetate was added and stirred for 30 minutes. The mixture was then filtered and the filter cake was washed with ethyl acetate (3*100 mL). The filter cake was dissolved in 500 mL saturated aqueous potassium carbonate and extracted with ethyl acetate (2*300 mL). The organic phases were combined and dried over anhydrous sodium sulfate,...

Embodiment 2

[0076] Example 2: 2-[3,3-Dimethyl-2-oxo-4-(2-piperon-5-yl-ethylcarbamoyloxy)butyryl]-1,2,3,4 -Tetrahydroisoquinoline-3-carboxylic acid

[0077] 2-[3,3-Dimethyl-2-oxo-4-(2-piperonyl-5-ylethylcarbamoyloxy)butyryl]-1,2,3,4-tetrahydroisoquinoyl The structure of line-3-carboxylic acid is as follows:

[0078]

[0079] Its preparation method is as follows:

[0080]

[0081] 1.1,2,3,4-tetrahydroisoquinoline-3-carboxylate ethyl ester (compound 7):

[0082] Thionyl chloride (8 mL, 113 mmol) was added dropwise to a solution of compound 6 (10 g, 56.5 mmol) in 100 mL of ethanol at room temperature. After the dropwise addition was completed, it was heated to reflux overnight. Then the solvent was removed and saturated aqueous potassium carbonate was added to pH = 8, and extracted with ethyl acetate (2*100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and then subjected to column chromatography to obtain 10 g of an oily product with a yi...

Embodiment 3

[0089] Example 3: (S)-1-[3,3-Dimethyl-2-oxo-4-(2-piperonyl-5-yl-ethylcarbamoyloxy)butyryl]indoline- 2-Carboxylic acid

[0090] (S)-1-[3,3-Dimethyl-2-oxo-4-(2-piperonyl-5-ylethylcarbamoyloxy)butyryl]indoline-2-carboxylic acid The structure is as follows:

[0091]

[0092] Its preparation method is as follows:

[0093]

[0094] 1. Preparation of (S)-indoline-2-carboxylic acid ethyl ester (compound 11):

[0095] Thionyl chloride (9.1 mL, 122.7 mmol) was added dropwise to a solution of compound 10 (10 g, 61.3 mmol) in 100 mL of ethanol at room temperature. After the dropwise addition was completed, it was heated to reflux overnight. Then the solvent was removed and saturated aqueous potassium carbonate was added to pH = 8, and extracted with ethyl acetate (2*100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain 11.0 g of an oily product with a yield of 94%. Low resolution mass spec...

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Abstract

The invention relates to N-substituted alpha-amino acid derivatives shown in a general formula (I), various salts thereof, hydrates of the salts, monomers of various optical isomers, and mixtures of the various optical isomers, wherein substituents represented by A1 and A2 are groups which are connected to a NCHCOOH structure in the general formula (I) to form alpha-amino, or A1 and A2 are connected to form a five- or six-membered heterocycle or benzohetercyclic ring containing a N heteroatom; A3 represents H or straight-chain or branched alkyl containing 1 to 3 carbon atoms; and A4 and A5 represent H or straight-chain or branched alkyl containing 1 to 3 carbon atoms, or A4 and A5 are connected to form a five- or six-membered heterocycle containing two O heteroatoms. The invention also relates to a preparation method for the N-substituted alpha-amino acid derivatives, a medicinal composition with effects of regenerating and protecting neurone, and application of the N-substituted alpha-amino acid derivatives in preparing medicinal preparations favorable for improving nervous function and treating brain dysfunction, memory decay, dysfunction caused by cerebral circulation insufficiency or neurotransmitter deficiency, and other diseases.

Description

technical field [0001] The present invention relates to N-substituted α-amino acid derivatives, a preparation method thereof, a pharmaceutical composition with regenerative and protective effects on neurons, and a pharmaceutical composition useful in improving nervous system functions including the treatment of brain dysfunction, memory decline, and cerebral blood supply. Use in pharmaceutical preparations for dysfunctional diseases caused by insufficiency or deficiency of neurotransmitters. Background technique [0002] In the early 1990s, scientists discovered that the compound FK506 had a regeneration effect on the axonal synapses of chick embryo neurons, and this compound was also known as neurotrophic factors (Neuroimminophilins). In 1995, Bruce G. Gold et al. found that small doses of neurotrophic factors could amplify the regeneration and functional recovery of comminuted sciatic nerves in vitro. In 2002, further studies by Esther Udina et al. showed that neurotrophi...

Claims

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Application Information

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IPC IPC(8): C07D405/12C07D317/58C07D211/60A61K31/4525A61K31/4725A61K31/404A61K31/4025A61K31/36A61K31/445A61P25/00A61P25/28A61P9/10
Inventor 李嘉和王颖实
Owner 深圳市天明医药科技开发有限公司
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