Interconnected medicine precursor of gabapentin and pregabalin and its medicinal use

A technology of pregabalin and interconnection, which is applied in the interconnection prodrug of gabapentin and pregabalin and the field of its medical application, can solve the problems of accelerated lactam by-products, uncontrollable drug quality, etc., and achieves good antiepileptic, Good for the treatment of neuropathic pain and prolongation of biological half-life

Inactive Publication Date: 2005-09-28
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In addition, during the preparation and storage of I and II, it is easy to generate lactam impurities
Acids, bases or certain excipients may accelerate the formation of lactam by-products, resulting in uncontrollable drug quality

Method used

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  • Interconnected medicine precursor of gabapentin and pregabalin and its medicinal use
  • Interconnected medicine precursor of gabapentin and pregabalin and its medicinal use
  • Interconnected medicine precursor of gabapentin and pregabalin and its medicinal use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1 Gabapentin (IV) protected by tert-butoxycarbonyl (BOC) 1 )Synthesis

[0031] Add 0.80g (0.02mol) of NaOH to a 250ml eggplant-shaped bottle, add 20ml of water to dissolve, ice bath, and electromagnetically stir, then add 3.42g (0.02mol) of gabapentin, after the solid is completely dissolved, alternately add 5.24g (0.024mol) of BOC anhydride mol) dissolved in 30ml of dioxane and 0.88g of NaOH dissolved in 30ml of water, keeping the pH value of the reaction solution at about 9, the addition was completed in about 30 minutes. After the addition, the mixture was reacted in ice bath for 2 hours, and then at room temperature for 2 hours. The reaction is complete. Extract the excess BOC anhydride in the reaction solution with ether, 30ml x 5 times in total, discard the ether layer, add 5% citric acid to the water layer under stirring to about pH 3, solids are precipitated, add 80ml ethyl acetate to extract the precipitate, and add 80ml of ethyl acetate to extract th...

Embodiment 2

[0032] Example 2 Pregabalin (IV) protected by tert-butoxycarbonyl (BOC) 2 )Synthesis

[0033] With reference to the method of Example 1, taking pregabalin as raw material and BOC anhydride reaction, obtain the III of white solid 2 , yield 90.73%, mp: 70~71℃; MS (ESI, m / e): 258.4(M-1), 260.3(M+1), 282.3(M+Na);

[0034] TLC: developing solvent petroleum ether: EtAc: CH 3 OH (5:2:0.5), Rf = 0.34.

Embodiment 3

[0035] Synthesis of the gabapentin glycol monoester of embodiment 3 tert-butoxycarbonyl protection (V 1 )Synthesis

[0036] Add IV to 100ml eggplant-shaped bottle 1 2.5g (0.00922mol), anhydrous CH 2 Cl 2 20ml, ice bath, electromagnetic stirring, to dissolve the solid, and then add ethylene glycol 3.43g (0.00922mol × 6) dissolved in 5ml of anhydrous DMF solution. After cooling to 0°C, DCC1.99g (0.00922mol×1.05) was dissolved in 5ml anhydrous CH 2 Cl 2 After reacting in an ice bath for 1 hour, 0.25 g of DMAP was added, then the ice bath was removed, and the reaction was carried out at room temperature for 12 hours. After the reaction was completed, the precipitated DCU was filtered off, the solvent was evaporated under reduced pressure, dissolved in 100 ml of EtAc, and the precipitated DCU was filtered again, and the EtAc layer was washed with 5% NaHCO 3 Wash 30ml×3 times, wash 25ml×2 times with 5% citric acid, wash with 5% NaHCO 3 Wash 30ml x 3 times, wash 30ml x 3 time...

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Abstract

The present invention relates to the interconnected medicine precursor of gabapentin and pregabalin and its non-toxic pharmaceutically acceptable salt and their use in preparing medicines for treating epilepsy, neurogenic pain and / or anxiety neurosis.

Description

technical field [0001] The present invention relates to interbody prodrugs of Gabapentin (Gabapentin) and Pregabalin (Pregabalin) and their non-toxic pharmaceutically acceptable salts and their use in the preparation of drugs for treating epilepsy, neuropathic pain, and / or anxiety use. technical background [0002] Neuropathic pain is a major disease that seriously threatens human life and health, with an incidence rate as high as 1%. Neuropathic pain refers to pain caused by damage or lesions of the nervous system, including intractable pain caused by tumor compression, polyneuritis pain in diabetic patients, trigeminal neuralgia, herpes zoster neuralgia, and spinal cord compression in patients with spinal diseases or nerve root pain. In contrast to acute pain due to tissue damage, neuropathic pain is often long-term and chronic, lasting days or months. Persistent pain seriously affects people's quality of life. Neuropathic pain has a wide range of clinical causes, dive...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/195A61P25/04A61P25/08C07C229/08C07C237/08C07C237/10
Inventor 仲伯华史卫国杨红菊刘河郑建全赵楠李万华陈兰福宫泽辉罗质璞龚正华
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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