- Anticonvulsant and sodium channel-blocking properties of novel 10,11- dihydro-5H-dibenz[b,f]azepine-5-carboxamide derivatives
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A series of esters of the major metabolite of oxcarbazepine (2), 10,11- dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide, were synthesized and evaluated for their anticonvulsant and brain sodium channel-blocking properties. The compounds were assayed intraperitoneally and per os in rats against seizures induced by maximal electroshock (MES). Neurologic deficit was evaluated by the rotarod test. The enantiomeric acetates (R)-11 and (S)- 12 were the most active of the series against MES-induced seizures with oral ED50 values at t(max) of 10.9 ± 2.3 and 4.7 ± 0.9 mg/kg, respectively. After intraperitoneal administration, carbamazepine (1) behaved more potently than 2 and all other new dibenz[b,f]azepine-5-carboxamide derivatives in the MES test; compounds 2 and 12 were equally potent. In the rotarod test, low doses of 1 produced considerable motor impairment, which did not occur with 2, enantiomeric alcohols (S)-6, (R)-7, and racemic alcohol 8, or racemic acetate 10 or (R)-11. The potencies of the racemic and enantiomerically pure alcohols 8, (S)-6, and (R)-7 derived from 2 in the MES and rotarod test were found to be similar between them, and consequently they exhibit similar protective index values. All three forms of the alcohol and their corresponding acetates (pairs 8 and 10, 6 and 12, and 7 and 11) were found to differ in the MES or rotarod tests; the ED50 value for (S)-6 against MES- induced seizures was nearly 3-fold that for (S)-12. The protective index also differed markedly between all stereoisomers of the alcohol and their corresponding acetates, most pronouncedly for compound (S)-12 which attained the highest value (12.5) among all compounds tested. Blockade of voltage- sensitive sodium channels was studied by investigating [3H]-batrachotoxinin A 20-α-benzoate ([3H]BTX) binding. Acetates (R)-11 and (S)-12 were more potent than the standards 1 and 2 at inhibiting the binding of [3H]BTX to sodium channels and the influx of 22Na+ into rat brain synaptosomes. It is concluded that acetates (R)-11 and (S)-12 are not simple metabolic precursors of alcohols (R)-7 and (S)-6 in rodents but that they possess anticonvulsant and sodium channel-blocking properties in their own right.
- Benes, Jan,Parada, António,Figueiredo, Anabela A.,Alves, Paula C.,Freitas, Ana P.,Learmonth, David A.,Cunha, Rodrigo A.,Garrett, José,Soares-Da-Silva, Patrício
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- One-step lipase-catalysed preparation of eslicarbazepine
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The antiepileptic eslicarbazepine (S-licarbazepine) has been prepared in one step from its racemic form RS-licarbazepine via lipase catalysed kinetic resolution. A novel stereoselective simultaneous HPLC separations of RS-licarbazepine (1) and its racemic esters RS-2-5 have been developed on Lux cellulose-2 column using cyclohexane/ethanol 1/1 v/v as mobile phase. The developed enantioselective HPLC separations have been utilized for monitoring of lipase catalyzed kinetic resolution of RS-licarbazepine (1). Lipase catalysed trans-esterification and hydrolysis reactions have been performed. Four different esters (acetate (2), propionate (3), butyrate (4) and benzoate (5)) have been investigated for both trans-esterification and hydrolysis using ten lipases from versatile origins. The best enantioselectivity was shown by trans-esterification of RS-licarbazepine with vinyl benzoate in MtBE as solvent and lipase from Candida rugosa where the pharmacologically active enantiomer, S-(+)-licarbazepine, has been accomplished [E = 31, ee = 97%, yield 84%, α20D = +105, c 0.001 g mL-1, CH3OH]. Molecular docking attributed the high enantioselectivity of the transesterification when using Candida rugosa lipase to unfavorable ligand contacts between the S-enantiomer and phenylalanine 296.
- El-Behairy,Sundby
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- Analysis of oxcarbazepine and the 10-hydroxycarbazepine enantiomers in plasma by LC-MS/MS: Application in a pharmacokinetic study
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Oxcarbazepine is a second-generation antiepileptic drug indicated as monotherapy or adjunctive therapy in the treatment of partial seizures or generalized tonic-clonic seizures in adults and children. It undergoes rapid presystemic reduction with formation of the active metabolite 10-hydroxycarbazepine (MHD), which has a chiral center at position 10, with the enantiomers (S)-(+)- and R-(-)-MHD showing similar antiepileptic effects. This study presents the development and validation of a method of sequential analysis of oxcarbazepine and MHD enantiomers in plasma using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Aliquots of 100 μL of plasma were extracted with a mixture of methyl tert-butyl ether: dichloromethane (2:1). The separation of oxcarbazepine and the MHD enantiomers was obtained on a chiral phase Chiralcel OD-H column, using a mixture of hexane:ethanol:isopropanol (80:15:5, v/v/v) as mobile phase at a flow rate of 1.3 mL/min with a split ratio of 1:5, and quantification was performed by LC-MS/MS. The limit of quantification was 12.5 ng oxcarbazepine and 31.25 ng of each MHD enantiomer/mL of plasma. The method was applied in the study of kinetic disposition of oxcarbazepine and the MHD enantiomers in the steady state after oral administration of 300 mg/12 h oxcarbazepine in a healthy volunteer. The maximum plasma concentration of oxcarbazepine was 1.2 μg/mL at 0.75 h. The kinetic disposition of MHD is enantioselective, with a higher proportion of the S-(+)-MHD enantiomer compared to R-(-)-MHD and an AUC0-12 S-(+)/R-(-) ratio of 5.44. Chirality 25:897-903, 2013. 2013 Wiley Periodicals, Inc.
- De Jesus Antunes, Natalicia,Wichert-Ana, Lauro,Coelho, Eduardo Barbosa,Della Pasqua, Oscar,Alexandre Jr., Veriano,Takayanagui, Osvaldo Massaiti,Tozatto, Eduardo,Lanchote, Vera Lucia
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- Preparation method of anti-epileptic drug eslicarbazepine acetate
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The invention provides a preparation method of an anti-epileptic drug eslicarbazepine acetate. The method comprises the following steps: carrying out a reduction and acetylation reaction on oxcarbazepine used as an initial raw material in order to obtain racemic eslicarbazepine acetate, and continuously carrying out lipase hydrolysis and a Mitsunobu reaction to completely convert enantiomers of eslicarbazepine acetate in the obtained racemic mixture into the eslicarbazepine acetate.
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- PROCESS FOR THE PREPARATION AND PURIFICATION OF ESLICARBAZEPINE ACETATE AND INTERMEDIATES THEREOF
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The present invention provides a novel process for the preparation of 10-oxo-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carboxamide, commonly known as oxcarbazepine, which is a medicament and a useful intermediate in the preparation of eslicarbazepine acetate. The present invention further provides a process for the preparation and purification of eslicarbazepine acetate.
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(2013/03/26)
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- PROCESS FOR THE PREPARATION OF (S)-(+)-OR (R)-(-)-10 HYDROXY DIHYDRODIBENZ[B,F]AZEPINES BY ENANTIOSELECTIVE REDUCTION OF 10, 11-DIHYDRO-10-OXO-5H-DIBENZ[B,F]AZEPINES AND POLYMORPHS THEREOF
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The present invention provides a novel process for the preparation of substituted optically pure (S)-(+)- or (R)-(-)-10-hydroxy-dihydrodibenz[b,f]azepines or derivatives thereof, starting from 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepines using boronate esters or their derivatives. The present invention also provides use of thus prepared (S)-(+)- or (R)-(-)- 10-hydroxy-dihydrodibenz[b,f]azepines for the preparation of their ester such as (S)-(-)- 10-acetoxy-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide, or (R)-(+)-10-acetoxy- 10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide. The present invention also provides novel solid state crystalline forms J1, J2, J3, J4 and amorphous form of eslicarbazepine and the process for the preparation thereof. Also, the present invention provides novel solid state crystalline form and amorphous form of eslicarbazepine acetate and the process for the preparation thereof. The novel solid state forms of eslicarbazepine are useful for the preparation of derivatives of eslicarbazepine such as eslicarbazepine acetate.
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(2012/09/22)
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- PROCESS FOR PREPARING (S)-(-)-10-ACETOXY-10,11-DIHYDRO-5H-DIBENZ[B,F]AZEPINE-5-CARBOXAMIDE AND ITS ESTERS THEREOF
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Disclosed herein an enzymatic process for preparing (S)-(-)-10-acetoxy-10,11- dihydro-5H-dibenz[b,f]azepine-5-carboxamide (eslicarbazepine) and its esters thereof. Further, the invention provides novel intermediates of eslicarbazepine and isomers thereof, enabling high purity and yield of eslicarbazepine.
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(2011/05/05)
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- PROCESS FOR PREPARATION OF ENANTIOMERS OF LICARBAZEPINE
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The present invention provides a process for the preparation of eslicarbazepine and rlicarbazepine and their acetates by resolution of racemic licarbazepine using acetyl mandelic acid.
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- ESLICARBAZEPINE ACETATE AND ITS POLYMORPHS
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Processes for the preparation of eslicarbazepine acetate and intermediates thereof. Also provided are polymorphic forms of eslicarbazepine acetate and methods for their preparation.
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Page/Page column 40
(2011/08/08)
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- ASYMMETRIC CATALYTIC REDUCTION OF OXCARBAZEPINE
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A process for preparing (S)-(+)- 10,11 -dihydro-10-hydroxy-5H- dibenz/b,f/azepine-5-carboxamide or (R)-(-)-10,l l-dihydro-10-hydroxy-5H- dibenz/b,f/azepine-5-carboxamide, by reduction of oxcarbazepine in the presence of a catalyst and a hydride source is disclosed. The catalyst is prepared from a combination of [RuX2 (L)]2 wherein X is chlorine, bromine or iodine, and L is an aryl or aryl-aliphatic ligand, with a ligand of formula (A) or formula (B): wherein R1 is chosen from C1-6 alkoxy and C1-6 alkyl, n is a number from 0 to 5, and when n is a number from 2 to 5, R1 can be the same or different, and R2 is alkyl, substituted alkyl, aryl, substituted aryl, alkaryl or substituted alkaryl. The hydride source is either NR3R4R5 and formic acid, [R3R4R5NH][OOCH] and optionally formic acid, or [M][OOCH]x and formic acid, wherein R3, R4 and R5 are C1-6 alkyl, M is an alkali metal or alkaline earth metal and x is 1 or 2. A pH from 6.5 to 8 is maintained during the process.
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(2008/06/13)
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- Use of s-10-hydroxy-10,11-dihydro-carbamazepine for the treatment of anxiety and bipolar disorders
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The present invention relates to the use of a racemate of the compound of formula (1) consisting of at least 85% S-enantiomer and not more than 15% R-enantiomer or of pharmaceutically acceptable salts of said racemate or of the S-enantiomer of formula I or of pharmaceutically acceptable salts of said enantiomer for the treatment of anxiety or other psychiatric disorders with underlying anxiety symptomatologies or for the treatment of affective and attention disorders; pharmaceutical compositions for that purpose and packages comprising said pharmaceutical compositions together with instructions for the use of said compositions for the treatment of anxiety or other psychiatric disorders with underlying anxiety symptomatologies or of affective and attention disorders.
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(2008/06/13)
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- DISINTEGRATING TABLETS COMPRISING LICARBAZEPINE
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The invention relates to pharmaceutical compositions comprising 10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide (also referred to as “licarbazepine”) as drug substance.
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(2008/06/13)
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- ORAL MATRIX FORMULATIONS COMPRISING LICARBAZEPINE
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The invention relates to pharmaceutical compositions comprising 10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide (also referred to as "licarbazepine") as drug substance.
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(2008/06/13)
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- Enantioselective process for the preparation of both enantiomers of 10,11-dihydro-10-hydroxy-5Hdibenz[b,f]azepine-5-carboxamide and new crystal forms thereof
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The invention relates to a novel process for the manufacture of substituted enantiopure 10hydroxy--dihydrodibenz[b,f]azepines (la), (lb) wherein each of R1and R2, independently, are hydrogen, halogen, amino or nitro; and each of R3 and R4, independently, are hydrogen or C1-C6alkyl; by transfer hydrogenation of 10-oxo-dihydrodibenz[b,f]azepines; and to novel catalysts of formula (III'a) and (III'b) wherein M is Ru, Rh, Ir, Fe, Co or Ni; L1 is hydrogen; L2 represents an aryl or aryl-aliphatic residue; and the further radicals have the meanings as defined herein; and to new crystal forms of both enantiomers of 10,11-dihydro-10 hydroxy-5Hdibenz[b,f]azepine-5-carboxamide, obtainable by the new processes, their usage in the production of pharmaceutical preparations, new pharmaceutical preparations comprising these new crystal forms and/or the use of these new crystal forms in the treatment of disorders such as epilepsy, or in the production of pharmaceutical formulations which are suitable for this treatment.
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