Medicine precursor containing long chain fatty acyl group substituted venlafaxine and its prepn and use

A fatty acyl, prodrug technology, applied in the application of diseases, the field of pharmaceutical composition of prodrugs, can solve the problems of increased psychological burden, limitations in the treatment of neuropsychiatric diseases, frequent medication for patients, etc., and achieve excellent long-term effect of effect

Active Publication Date: 2005-12-14
RADIOLOGY INST ACAD OF MILITARY MEDICINE SCI PLA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This limits the drug's use in the treatment of neuropsychiatric diseases, and patients need to take frequent medications, which adds a new psychological burden

Method used

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  • Medicine precursor containing long chain fatty acyl group substituted venlafaxine and its prepn and use
  • Medicine precursor containing long chain fatty acyl group substituted venlafaxine and its prepn and use
  • Medicine precursor containing long chain fatty acyl group substituted venlafaxine and its prepn and use

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preparation example Construction

[0023] Chiral venlafaxine can be prepared according to the method described in Yardley et al., J Med Chem, 1990, 33(10): 2899-2905. Optically active enantiomers may also be separated by other resolution techniques routine in the art.

[0024] The pharmaceutically acceptable salt of the compound of the present invention is prepared by direct salt-forming reaction with the free base of the compound and an inorganic or organic acid. The inorganic or organic acid may be selected from hydrochloric acid, hydrobromic acid, phosphoric acid, citric acid, maleic acid and the like.

[0025] The present invention also relates to a pharmaceutical composition prepared by co-preparing a compound as described in general formula I containing a pharmaceutically effective dose and a pharmaceutically acceptable carrier or excipient. Pharmaceutical compositions containing effective doses of the compounds of the present invention can be formulated using pharmaceutical carriers well known to those ...

Embodiment 1

[0035] Embodiment 1: Preparation of octanoic acid 1-[2-(dimethylamino)-1-(4-methoxyphenyl)-ethyl]cyclohexyl ester (B1)

[0036] In a 100ml eggplant-shaped bottle, add 0.50g (1.59mmol) of venlafaxine and 0.46g (3.19mmol) of octanoic acid, dissolve in 15ml of anhydrous dichloromethane, and stir in an ice bath. Add N,N-dicyclohexylcarboimide 0.69g (3.34mmol) and anhydrous dichloromethane 5ml to form a solution, gradually form a white precipitate, ice bath reaction for 2 hours, add N,N-dimethylaminopyridine 0.1 g was used as a catalyst. After removing the ice bath, the mixture was stirred at room temperature for 24 hours. TLC (dichloromethane:methanol 15:1, adding 2 drops of ammonia) showed that the reaction was complete. After the white precipitate N,N-dicyclohexylurea was removed by filtration, the solution was extracted with 5% citric acid aqueous solution (25ml×3), then with saturated sodium chloride aqueous solution (30ml×3), and the dichloromethane solution was added with an...

Embodiment 2

[0040] Embodiment 2: Preparation of nonanoic acid 1-[2-(dimethylamino)-1-(4-methoxyphenyl)-ethyl]cyclohexyl ester (B2)

[0041] The synthesis method is the same as B1. Get 0.50g (1.59mmol) of venlafaxine and 0.56g (3.54mmol) of nonanoic acid to react, the halogenated alkane solvent used is chloroform, and the dehydrating agent is 1-dimethylaminopropyl-3-ethyl carbodiyl imine, the catalyst is 2,4,6-collidine. 0.43 g of white solid (B2) was obtained, with a yield of 64.9%. The hydrochloride was prepared in a similar manner, mp136-138°C. 1 HNMR (CDCl 3 )δ (ppm): 7.16 (d, 2H, J = 8.6Hz, Ph-H), 6.84 (d, 2H, J = 8.6Hz, Ph-H), 3.96-3.93 (dd, 1H, J = 3.1Hz , J'=10.7Hz, CH), 3.78(s, 3H, CH 3 O), 2.96-2.14(tt, 2H, J=3.1Hz, J'=10.7Hz, CH 2 N), 2.26(t, 2H, COCH 2 ), 2.15(s, 6H, N(CH 3 ) 2 ), 1.61-0.86 (m, 25H, cyclohexyl, (CH 2 ) 6 CH 3 ). MS (FAB) m / z: 418.3 (M + ), 260.1 (M + -OCO(CH 2 ) 6 CH 3 ), 58 (CH 2 N(CH 3 ) 2 , base peak).

[0042] Elemental analysis: C H N...

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Abstract

The present invention discloses one kind of medicine precursors containing long chain fatty acyl group substituted venlafaxine in the structure as shown in general expression I and its medicinal salt and hydrate. The present invention also discloses the preparation process of the medicine precursors and their application in preventing and treating diseases of central nerve system. The medicine precursors of the present invention has half life near or over 10 hr, and compared with venlafaxine, they has excellent long-acting effect.

Description

Technical field [0001] The present invention relates to a class of long-chain fatty acyl-substituted venlafaxine prodrugs (I), including a group of new drug compounds and their pharmaceutically acceptable salts or hydrates, and also to a prodrug containing an effective dosage The pharmaceutical composition of the medicine, the preparation method of the prodrug thereof, and the application of the prodrug and the composition in the prevention and treatment of central nervous system and other diseases. Background technique [0002] Venlafaxine (Venlafaxine) is a clinically used drug with dual effects of 5-HT reuptake inhibition and norepinephrine reuptake inhibition, and is mainly used for the prevention and treatment of depression. The potency is stronger or similar than tricyclic and tetracyclic antidepressants (TCAs), has no inhibitory effect on MAOI, and has no affinity with cholinergic, histaminergic, adrenergic receptors, so there is no activity related to these receptors...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C217/60
Inventor 王林徐娟彭涛张首国温晓雪李鲁
Owner RADIOLOGY INST ACAD OF MILITARY MEDICINE SCI PLA
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