Rotigotine derivatives and preparation and application thereof

A technology of derivatives and saturated alkanes, which is applied in the field of medicine, can solve problems such as inability to achieve therapeutic effects, and achieve the effects of improving patient compliance, reducing costs, and high conversion rates

Active Publication Date: 2018-07-31
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Since the hydroxyl group on the naphthol in the structure of rotigotine is easily oxidized, it is metabolized rapidly and cannot achieve the desired therapeutic effect. Therefore, it is considered to add a protecting group to improve the form of the preparation to solve the above problems

Method used

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  • Rotigotine derivatives and preparation and application thereof
  • Rotigotine derivatives and preparation and application thereof
  • Rotigotine derivatives and preparation and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0059] The purification of embodiment 1 palmitic acid

[0060] Accurately weigh an appropriate amount of palmitic acid (48.30g) into a 500mL eggplant-shaped bottle, add 200mL of n-heptane, stir and reflux in an oil bath at 45°C until completely dissolved, and continue stirring for about 1h. After slowly cooling to about 30°C, stir in an ice-water bath for 20 minutes, place in a refrigerator at 4°C overnight, filter the crystals with suction, wash with 100 mL of n-heptane, and dry in vacuum at 45°C for 2 hours. (yield 35.10g, yield 72.7%)

Embodiment 2

[0061] The purification of embodiment 2 stearic acid

[0062] Accurately weigh an appropriate amount of stearic acid (99.10g) into a 1000mL eggplant-shaped bottle, add 500mL of chloroform, stir and reflux in an oil bath at 45°C until completely dissolved, and continue stirring for about 2h. Stir in an ice-water bath for 20 minutes, place in a refrigerator at 4°C for refrigeration, take it out and filter it quickly at low temperature, rinse with 30 mL of chloroform, and dry in vacuum at 45°C for 2 hours. (yield 43.22g, yield 43.6%)

Embodiment 3

[0063] The preparation of embodiment 3 rotigotine palmitate

[0064] Weigh the purified palmitic acid (4.06g, 15.83mmol, 1.0eq) into a 250mL eggplant-shaped bottle filled with about 100mL of anhydrous dichloromethane, and add EDC·HCl (3.64g, 18.99mmol , 1.2eq), DMAP (0.77g, 6.30mmol, 0.4eq) and SOCl 2 (1723μL, 23.73mmol, 1.5eq), after stirring evenly, add 2 drops of DMF for catalysis, and reflux at 50°C for 2h. Rotary steaming at 40°C, after being nearly spin-dry, add a small amount of toluene, spin-dry again, and repeat the operation once to obtain the acid chloride product. After adding a small amount of dichloromethane to it to re-dissolve, add pre-dissolved rotigotine (4.99g, 15.82mmol, 1.0eq), and add dropwise TEA (6.6mL, 47.45mmol, 3.0eq), N 2 Protected and stirred for 24h (TLC monitoring, developer petroleum ether: ethyl acetate = 10:1). After the reaction stopped, add 100mL 0.1M Na 2 HCO 3 solution, stirred for 10 min, separated the organic layer, and repeated the...

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Abstract

The invention relates to preparation and application of rotigotine derivatives, specifically to synthesis of a series of rotigotine derivatives. The rotigotine derivatives are applied to preparation of micrometer or nanometer drug suspension and are prepared by directly or indirectly acylating rotigotine with alkanes of different chain lengths or fatty acid thereof, olefins or fatty acid thereof,vitamins, polyethylene glycol, polylactic acid, amino acid and other groups containing hydroxyl groups, amino groups or carboxyl groups. According to the invention, the micrometer or nanometer drug suspensions of the rotigotine derivatives are prepared by using industrially common equipment used for reducing the particle sizes of drugs, e.g., a high-pressure homogenizer or a ball mill; and when used in an in-vivo administration manner, the prepared drug suspensions of the rotigotine derivatives greatly improve the biological half-life of rotigotine and prolong the action time of rotigotine, and can effectively reduce administration frequency and improve patient compliance during clinical administration.

Description

technical field [0001] The invention belongs to the technical field of medicine, relates to a rotigotine derivative and its preparation and application, and also relates to a nano ( / micro) suspension prepared by the derivative. Background technique [0002] Parkinson's disease (Parkinson's disease, PD) is a common neurodegenerative disease, the substantia nigra and striatum pathways are the main lesion sites, often accompanied by symptoms such as numbness tremor, muscle stiffness, slow movement, severe cases even show Dementia symptoms, motor complications may occur in patients taking levodopa for a long time. Studies have shown that the stimulation of pulsatile striatal dopamine receptors is the main cause of motor complications, so some scholars have proposed to prevent and reverse the occurrence of motor complications by prolonging the action time of dopamine drugs and providing continuous dopaminergic stimulation . [0003] Rotigotine (Rotigotine) is a non-ergot dopam...

Claims

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Application Information

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IPC IPC(8): C07D333/20A61K31/381A61K9/10A61K47/26A61K47/10A61P25/16
CPCA61K9/10A61K31/381A61K47/10A61K47/26C07D333/20
Inventor 王永军张涛刘洪卓何仲贵
Owner SHENYANG PHARMA UNIVERSITY
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