- An industrial perspective fermentative bioreduction of aromatic ketones by Penicillium rubens VIT SS1 and Penicillium citrinum VIT SS2
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Microbial mediated, especially the fungi mediated asymmetric reduction of the ketone is one of the most promising tools for the synthesis of chiral alcohols. Many fungal cultures were isolated from soil and screened for the stereo selective bioreduction of acetophenone. The potential isolates are characterised using molecular techniques and found to be Penicillium rubens VIT SS1 (Genbank ID: MK063869) and Penicillium citrinum VIT SS2 (Genbank ID: MW960208). Both the isolates were tested for the bioreduction of few aromatic ketones such as 4-fluoro acetophenone, 3-hydroxy acetophenone, and oxcarbazepine, which are the key chiral intermediates of various pharmaceutical drugs. The P. rubens VIT SS1 produced (S)-alcohol obeying Prelog’s rule, and P. citrinum was anti-Prelog configuration in nature. Preparatory scale reactions were conducted using the optimised bioreduction process, and the keto loading was significantly increased by 12-fold (from 0.5 to 6 g/L) with >99% conversion and >98% enantiomeric excess. The study discloses the vast prospective approach of exploring filamentous fungi for sustainable synthesis of chiral alcohols in an environment-friendly, novel, and cost competent way.
- Jothi, Saravanan,Vuppu, Suneetha
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- Brain-targeting eslicarbazepine ester prodrug and application thereof
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The invention relates to an eslicarbazepine ester prodrug and an application thereof, wherein the prodrug is a compound represented by the formula (I) or optical isomers or physiologically acceptable salts of the compound represented by the formula (I), wherein R represents a lipophilic substituent. The compound represented by the formula (I) is the eslicarbazepine ester prodrug containing the lipophilic substituent, is converted into eslicarbazepine through metabolism in vivo to play pharmacological effects, and can be applied in preparation of drugs for treatment, prevention or adjuvant treatment of central nervous system diseases, such as epilepsy and the like.
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Paragraph 0093; 0094; 0095; 0096
(2017/08/28)
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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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Paragraph 0028; 0029; 0034; 0035; 0036
(2017/09/01)
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- COMPOSITIONS AND METHODS FOR THE TREATMENT OF NEUROLOGICAL DISORDERS
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The invention relates to the compounds of formula I and formula IA or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I and formula IA; and methods for treating or preventing neurological diseases may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of epilepsy, bipolar disorder, trigeminal neuralgia, attention-deficit hyperactivity disorder (ADHD), schizophrenia, neuropathic pain, seizures, bipolar disorder, mania, phantom limb syndrome, complex regional pain syndrome, paroxysmal extreme pain disorder, neuromyotonia, intermittent explosive disorder, borderline personality disorder, Myotonia congenita and post-traumatic stress disorder.
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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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p. 98730 - 98736
(2016/11/06)
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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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Paragraph 0072
(2015/03/16)
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- Carbamazepine derivatives with P2X4 receptor-blocking activity
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Antagonists for the P2 receptor subtype P2X4, an ATP-activated cation channel receptor, have potential as novel drugs for the treatment of neuropathic pain and other inflammatory diseases In the present study, a series of 47 carbamazepine derivatives including 32 novel compounds were designed, synthesized, and evaluated as P2X4 receptor antagonists Their potency to inhibit ATP-induced calcium influx in 1321N1 astrocytoma cells stably transfected with the human P2X4 receptor was determined Additionally, species selectivity (human, rat, mouse) and receptor subtype selectivity (P2X4 vs P2X1, 2, 3, 7) were investigated for selected derivatives The most potent compound of the present series, which exhibited an allosteric mechanism of P2X4 inhibition, was N,N-diisopropyl-5H-dibenz[b,f]azepine-5-carboxamide (34, IC50 of 3.44 μM) The present study extends the so far very limited knowledge on structure-activity relationships of P2X4 receptor antagonists
- Tian, Maoqun,Abdelrahman, Aliaa,Weinhausen, Stephanie,Hinz, Sonja,Weyer, Stefanie,Dosa, Stefan,El-Tayeb, Ali,Müller, Christa E.
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p. 1077 - 1088
(2014/02/14)
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- COMPOSITIONS AND METHODS FOR THE TREATMENT OF NEUROLOGICAL DISORDERS
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The invention relates to the compounds of formula (I) and formula (1A) or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula (I) and formula (IA); and methods for treating or preventing neurological diseases may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment, of epilepsy, bipolar disorder, trigeminal neuralgia, attention-deficit, hyperactivity disorder (ADHD), schizophrenia, neuropathic pain, seizures, bipolar disorder, mania, phantom limb syndrome, complex regional pain syndrome, paroxysmal extreme pain disorder, neuromyotonia, intermittent explosive disorder, borderline personality disorder. Myotonia congenita and post-traumatic stress disorder.
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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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Page/Page column 12; 13
(2013/03/26)
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- PROCESS FOR THE RESOLUTION OF RACEMIC (±)-10,11-DIHYDRO-10-HYDROXY-5H-DIBENZ[B,F]AZEPINE-5-CARBOXAMIDE
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A process for resolving racemic (±)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5- carboxamide comprising reacting (±)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5- carboxamide with S-ibuprofen or a pharmaceutically acceptable salt thereof to form a mixture of the SS and SR diastereomer esters of 10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5- carboxamide, followed by separating the SS-ibuprofen ester from the SR ibuprofen ester, and removal of the S-ibuprofen moiety to form S-(+)-10,l l-dihydro-10-hydroxy-5H- dibenz[b,f]azepine-5-carboxamide with a chiral purity greater than 90%.
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Page/Page column 13
(2012/09/22)
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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 39
(2011/08/08)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF (S)-10-ACETOXY-10,11-DIHYDRO-5H-DIBENZ[b,f]AZEPINE-5-CARBOXAMIDE
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The present invention relates to a process for the preparation of (S)-10-acetoxy-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide compound of formula (1).
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Page/Page column 22
(2011/11/30)
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- A PROCESS FOR THE PURIFICATION OF ESLICARBAZEPINE ACETATE
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The present invention relates to the purification and particle size of eslicarbazepine acetate. The present invention also relates to the physical characteristics of solid state eslicarbazepine acetate, and pharmaceutical compositions containing the same.
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Page/Page column 13
(2010/11/03)
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- Process For The Preparation Of 10,11-Dihydro-10-Hydroxy-5H-Dibenz[B,F]Azepine-5-Carboxyamide
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A process for the preparation of 10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxyamide by hydrolysis of 5-cyano-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine with peroxy compounds in alkali medium and in the presence of solvents.
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Page/Page column 2
(2008/12/08)
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- A PROCESS FOR THE PREPARATION OF 10,11-DIHYDRO-10-HYDROXY-5H-DIBENZ[B,F]AZEPINE-5-CARBOXYAMIDE
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A process for the preparation of 10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxyamide by hydrolysis of 5-cyano-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine with peroxy compounds in alkali medium and in the presence of solvents.
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Page/Page column 6
(2008/06/13)
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- METHOD FOR PREPARATION OF 10,11-DIHYDRO-10-HYDROXY-5H-DIBENZ/B,F/AZEPINE-5-CARBOXAMIDE
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A process for the preparation of 10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide (1) by ring opening of 11a,10b-dihydro-6H-dibenz/b,f/oxireno[d]azepine-6-carboxamide (5), characterised in that the ring opening is carried out under conditions of elevated pressure.
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Page/Page column 9-10
(2008/06/13)
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- Method for racemisation of (S)-(+)- and (R)-(-)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide and optically enriched mixtures thereof
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A high-yielding method for racemisation of (S)-(+)- and (R)-(-)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide and a useful intermediate, 10-chloro-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide (VII) are disclosed. Also disclosed are methods for the racemisation of optically pure or optically enriched mixtures of (S)-(+)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide (I) and (R)-(-)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide (II) to racemic (±)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide (III).
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- Low temperature, high conversion, liquid-phase benzylic oxidation with dioxygen by metal/NHPI-catalyzed co-oxidation with benzaldehyde
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A new liquid-phase catalytic oxidation system for the low temperature, high conversion benzylic mono-oxyfunctionalization of 10,11-dihydrocarbamazepine (1) into oxcarbazepine (4) with dioxygen has been developed. The method is based on a co-oxidation of 1 with benzaldehyde in the presence of a four-component catalyst system consisting of Co(OAc)2, Ni(OAc)2, Cr(NO3)3, and N-hydroxyphthalimide (NHPI). The influence of the catalyst system on the formation and decomposition of the crucial hydroperoxide intermediate 2 has been investigated. Based on these results, the role of each of the components in the catalyst system is discussed. The scope of this method for the oxidation of other substrates has been studied, and the results are compared with those obtained by Co/NHPI catalyzed oxidation of these substrates. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.
- De Vondervoort, Lizette Schmieder-van,Bouttemy, Sabine,Heu, Ferdinand,Weissenboeck, Kurt,Alsters, Paul L.
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p. 578 - 586
(2007/10/03)
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- 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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p. 2582 - 2587
(2007/10/03)
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- Preparation of 10,11-Epoxy-carbamazepine and 10,11-Dihydro-10-hydroxy-carbamazepine by Microbial Epoxidation and Hydroxylation
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Within a microbial screening two bacterial strains were identified that epoxidize carbamazepine (CBZ) to 10,11-epoxy-CBZ.Ten strains could hydroxylate 10,11-dihydro-CBZ to 10,11-dihydro-10-hydroxy-CBZ.All active organisms belonged to the genus Streptomyces.Both reactions were done in a preparative scale using S. violascens ATCC 31560.The culture conditions for the hydroxylation with this strain were improced.
- Kittelman, Matthias,Lattmann, Rene,Ghisalba, Preste
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p. 1589 - 1590
(2007/10/02)
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