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N-substituted pipecolic acid derivative, as well as preparation method and application thereof

A technology of acid derivatives and substituents, applied in the field of N-substituted pipecolic acid derivatives, which can solve the problems of weakened autophagy, reduced ability of cells to adapt to the external environment and self-defense response

Active Publication Date: 2015-04-15
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

With age, intracellular autophagy begins to weaken, resulting in a decrease in the ability of cells to adapt to the external environment and their own defense responses.

Method used

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  • N-substituted pipecolic acid derivative, as well as preparation method and application thereof
  • N-substituted pipecolic acid derivative, as well as preparation method and application thereof
  • N-substituted pipecolic acid derivative, as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 3

[0089] The general synthetic method of embodiment 3 classes:

[0090] Compound 1 (4.66 g, 10 mmol) and DMF (50 mL) were added into a 100 mL round bottom flask and stirred for 10 minutes. Add anhydrous potassium carbonate (1.66g, 12mmol) to the system, stir at room temperature for half an hour, add compound 2 (11mmol), then stir at room temperature for 2-8 hours (TLC monitors the reaction, the developer is EA / PE=2 / 1 ). After the reaction was complete, the reaction solution was diluted with ethyl acetate (500 mL), washed with water (200 mL*4), washed with saturated brine (100 mL*2), and dried over anhydrous sodium sulfate (5 g) for 2 hours. Filter off the desiccant, wash the desiccant with a small amount of ethyl acetate, pressurize the filtrate below 35°C to dry the solvent, and separate the residue with a column (the eluent is petroleum ether (PE) / ethyl acetate (EA) = 3: 1—1:1), the effective fraction was collected, concentrated to dryness under reduced pressure under 35°C t...

Embodiment 4a

[0100] Example 4a: using the general synthesis method of Example Compound 4, ethyl acetate was used as a solvent in the reaction, and the yield was 94%.

[0101] White powder. Mp.65-67℃, negative ion ESI-MS m / z: 497.6[M-H] - . 1 H-NMR (400MHz, DMSO-d6) δ: 10.349 (1H, s, 7'-NH), 4.967 (1H, d, J=4.8Hz, H-2), 4.219 (2H, m, H-4' ), 4.032 (2H, m, H-2″′), 3.403 (1H, br.d, H-6), 3.167 (1H, m, H-6), 3.348 (2H, m, H-9’) , 3.283 (4H, br.s, H-3″, 5″), 2.462 (4H, br.s, H-2″, 6″), 2.176 (1H, m, H-3), 1.596-1.702 ( 3H, m, H-3, 4), 1.297-1.348 (2H, m, H-5), 1.254 (3H, s, H-CH 3 ), 1.241 (3H, s, H-CH 3 ), 1.168(3H,t,J 1,2 =J 2,3 =6.8Hz, H-3"').

[0102] 4b: Using the general synthesis method of Example Compound 4, the reaction solvent is ethyl acetate, and the yield is 92%.

[0103]

[0104] White powder. Mp.146-148℃, positive ion ESI-MS m / z: 503.5[M+H] + . 1 H-NMR (400MHz, DMSO-d6) δ: 10.345 (1H, s, 7'-NH), 7.200 (2H, t, J 1,2 =8.4Hz,J 2,3 =7.6Hz, H-3"', 5"'), 6.926(2H,d,J...

preparation Embodiment 1

[0205] tablet:

[0206] Preparation method: mix Example compound 4K, lactose and cornstarch, moisten evenly with water, sieve and dry, then sieve, add magnesium stearate, and then press the mixture into tablets, each weighing 250 mg.

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Abstract

The invention relates to an N-substituted pipecolic acid derivative or a pharmaceutically acceptable salt thereof which is represented by the general formula (I) in the specification, wherein A1 represents H and straight-chained or branch-chained alkyl or benzyl of C1-4, and A2 represents amino, straight-chained or branch-chained alkyl amino of C1-4, straight-chained or branch-chained dialkyl amino of C1-4 and 5-7 membered heterocyclic amino containing 1-2 heteroatoms of N, O or S; and the premise condition is that a heterocyclic ring contains an N heteroatom connected with a mother nucleus of the general formula (I). The invention further relates to a preparation method of the N-substituted pipecolic acid derivative, a pharmaceutical composition which has potential application values in treatment of neurodegenerative diseases and effects of regenerating and protecting neurons, and an application in preparation of pharmaceutical preparations which are favorable for improving the functions of a nervous system, including the treatment of brain dysfunction, neurodegenerative diseases and functional disorder diseases caused by insufficient cerebral blood supply or neurotransmitter deficiency.

Description

Technical field: [0001] The invention relates to an N-substituted pipecolic acid derivative which has potential application value for treating neurodegenerative diseases and has regenerative and protective effects on neurons, its preparation method and application. Background technique: [0002] At present, the natural products Tacrolimus (FK506) and sirolimus (sirolimus, rapamycin, rapamycin), which are similar in chemical structure to the present invention, are a class of macrolide antibiotic immunosuppressants. A large number of scientific research experiments have proved that this kind of substance has a therapeutic effect on neurodegenerative diseases, and has a regenerative and protective effect on neurons. [0003] [0004] The inventors attempted to modify the chemical structure of these compounds to reduce or eliminate their immunosuppressive effects, and retain or enhance their neuroprotective and repairing effects. Then a new class of small molecular compounds...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/60C07D401/12C07D405/12A61K31/496A61K31/5377A61P25/00A61P25/28A61P9/10
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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