- Preparation, characterization and in vivo conversion of new water-soluble sulfenamide prodrugs of carbamazepine
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Improved synthetic methods are reported for the preparation of sulfenamide derivatives of carbamazepine (CBZ) for evaluation as prodrugs. These sulfenamide prodrugs were designed to rapidly release CBZ in vivo by cleavage of the sulfenamide bond by chemical reaction with glutathione and other sulfhydryl compounds. Physicochemical characterization and in vivo conversion of a new prodrug of CBZ was evaluated to further establish the proof of concept of the sulfenamide prodrug approach.
- Hemenway, Jeffrey N.,Nti-Addae, Kwame,Guarino, Victor R.,Stella, Valentino J.
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Read Online
- Site-Selective Acceptorless Dehydrogenation of Aliphatics Enabled by Organophotoredox/Cobalt Dual Catalysis
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The value of catalytic dehydrogenation of aliphatics (CDA) in organic synthesis has remained largely underexplored. Known homogeneous CDA systems often require the use of sacrificial hydrogen acceptors (or oxidants), precious metal catalysts, and harsh reaction conditions, thus limiting most existing methods to dehydrogenation of non- or low-functionalized alkanes. Here we describe a visible-light-driven, dual-catalyst system consisting of inexpensive organophotoredox and base-metal catalysts for room-temperature, acceptorless-CDA (Al-CDA). Initiated by photoexited 2-chloroanthraquinone, the process involves H atom transfer (HAT) of aliphatics to form alkyl radicals, which then react with cobaloxime to produce olefins and H2. This operationally simple method enables direct dehydrogenation of readily available chemical feedstocks to diversely functionalized olefins. For example, we demonstrate, for the first time, the oxidant-free desaturation of thioethers and amides to alkenyl sulfides and enamides, respectively. Moreover, the system's exceptional site selectivity and functional group tolerance are illustrated by late-stage dehydrogenation and synthesis of 14 biologically relevant molecules and pharmaceutical ingredients. Mechanistic studies have revealed a dual HAT process and provided insights into the origin of reactivity and site selectivity.
- Zhou, Min-Jie,Zhang, Lei,Liu, Guixia,Xu, Chen,Huang, Zheng
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supporting information
p. 16470 - 16485
(2021/10/20)
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- Clean and efficient preparation method of carbamazepine
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The invention relates to a clean and efficient preparation method of carbamazepine, which is characterized by comprising the following steps: uniformly mixing iminostilbene and urea, then carrying out a first-stage solid-phase heating melting reaction, continuously conducting heating, carrying out a second-stage solid-phase heating melting reaction, after the reaction is finished, conducting cooling to room temperature, conducting crushing, conducting washing with water, and conducting drying to obtain a crude product carbamazepine; and subjecting the crude product carbamazepine to melt crystallization to prepare a purified product carbamazepine. The preparation method further comprises the step of carrying out ultrasonic treatment in the processes of the first-stage solid-phase heating melting reaction and the second-stage solid-phase heating melting reaction. The temperature of the first-stage solid-phase heating melting reaction is 133-140 DEG C, and the reaction time is 45-60 minutes; and the temperature of the second-stage solid-phase heating melting reaction is 140-150 DEG C, and the reaction time is 45-60 minutes. The method is clean and efficient, and the yield of carbamazepine is 90% or above.
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Paragraph 0036-0053
(2021/06/21)
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- Access to N-Carbonyl Derivatives of Iminosydnones by Carbonylimidazolium Activation
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A new methodology for N-exocyclic functionalization of iminosydnones was developed involving the addition of a large variety of nucleophiles on carbonyl-imidazolium-activated iminosydnones. This practical and highly versatile method provided access to new classes of iminosydnones and opened a straightforward synthetic route to prepare iminosydnone-based prodrugs.
- Audisio, Davide,Madegard, Leá,Porte, Karine,Riomet, Margaux,Taran, Frédéric,Thuéry, Pierre
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supporting information
(2020/03/26)
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- Intermediate compound, carbamazepine and derivative thereof as well as preparation method of oxcarbazepine and derivative thereof
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The invention provides an intermediate compound, carbamazepine and a derivative thereof as well as a preparation method of oxcarbazepine and a derivative thereof. 2-substituted aminophenylacetate or 2-substituted aminophenylacetonitrile and 2-halobenzonitrile are used as raw materials, substitution reaction, intramolecular condensation reaction, hydrolysis and hydrochloric acid acidification are carried out to obtain the oxcarbazepine and the derivative 5-substituent-10-oxa-10, 11-dihydro-5H-dibenzo [b, f] aza thereof, and the derivative of the oxcarbazepine can be used as a raw material to prepare the carbamazepine and the derivative 5-substituted iminostilbene thereof, an intermediate compound iminostilbene and intermediate compounds 5-substituted-10-methoxyiminostilbene and 10-methoxyiminostilbene. The raw materials used in the method are cheap and easy to obtain, and the cost is low; the preparation method is simple, conditions are easy to realize, the method is simple, convenientand safe to operate, and the process flow is short; the production amount of three wastes is small, and thus, the method is environmentally friendly; and a target product has high yield and purity, and is suitable for industrial production.
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- Convenient syntheses of halo-dibenz[b,f]azepines and carbamazepine analogues via N-arylindoles
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The dibenz[b,f]azepine heterocyclic system and related molecules with a single 10,11-bond are important templates for well-prescribed drug molecules, notably carbamazepine (anticonvulsant), clomipramine and imipramine (antidepressants). We synthesised a range of halogenated carbamazepine analogues, in connection with metabolic and immunological studies, as probes for structure-metabolism and hypersensitive effects and have published on their metabolic behaviour. While a number of synthetic routes to such analogues are possible, we naturally sought short and efficient methods for our target compounds. In the following report we present an effective two-step synthesis of a range of dibenz[b,f]azepines from appropriate indoles via N-arylation, then acid-catalysed rearrangement, with a critical analysis of other approaches. We showed earlier that this route was effective for fluoro analogues and here present a broader review of its scope. The 5-(carboxamido) side chain of carbamazepine may be added in various ways, affording overall a convenient access to drug molecules.
- Elliott, Emma-Claire,Maggs, James L.,Park, B. Kevin,O'Neill, Paul M.,Stachulski, Andrew V.
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p. 8426 - 8434
(2013/12/04)
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- An efficient synthesis for eslicarbazepine acetate, oxcarbazepine, and carbamazepine
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Efficient methods have been developed for the synthesis of three active pharmaceutical ingredients (APIs) carbamazepine (Tegretol) 1, oxcarbazepine (Trileptal) 2, and eslicarbazepine acetate (Exalief) 3 by employing enantioselective reduction and carboxamidation reaction.
- Ravinder,Rajeshwar Reddy,Sridhar,Murali Mohan,Srinivas, Katkam,Panasa Reddy,Bandichhor, Rakeshwar
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p. 2841 - 2844
(2013/06/26)
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- Solid Pharmaceutical Preparations Containing Copolymers Based On Polyethers Combined With Poorly Water-Soluble Polymers
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The invention relates to dosage forms which contain preparations of poorly water-soluble substances in a polymer matrix of polyether copolymers, said polyether copolymers being obtained by the radically initiated polymerization of a mixture from 30 to 80% by weight of N-vinyl lactam, 10 to 50% by weight of vinyl acetate and 10 to 50% by weight of a polyether, and at least one poorly water-soluble polymer, the poorly water-soluble substance being present in the polymer matrix as an amorphous substance.
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- PROCESS FOR THE PREPARATION OF OXCARBAZEPINE
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The present invention relates to an improved process for the preparation of 10-oxo-10,11-dihydiO-5H-dibenz[b,fjazepine-5-carboxamide (Oxcarbazepine) by reacting 10-methoxy-5H-dibenz[b,f]azepine (10-methoxyiminostilbene) and alkali metal cyanate in presence of α-hydroxy acids, and also relates to the process for the preparation of carbamazepine from iminostilbene. Further the present invention is directed to the novel crystalline form of 10-methoxy carbamazepine.
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Page/Page column 4
(2011/04/18)
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- METHOD AND PRODUCT
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The present invention provides a method of producing a co-crystal, the method comprising the steps of providing a first substance and a second substance, wherein the first and second substances are compatible to form a co-crystal, mixing said first and second substances together, and exposing the mixture of said first and second substances to prolonged and sustained conditions of pressure and shear, sufficient to form a co-crystal of said first and second substance. The prolonged and sustained conditions of pressure and shear are preferably applied in an extrusion process. Associated compositions and uses thereof are also provided.
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- Methods for predicting the response to statins
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The invention provides methods for optimizing therapeutic efficacy for treating hypercholesterolemia in a subject having a cardiovascular disease (CVD), comprising (a) determining subject characteristics that affect the likelihood of reaching a goal level of low density lipoprotein (LDL); and (b) obtaining success probabilities of a variety of statin treatments for reaching said goal level of LDL using said subject characteristics and a multivariate model; and (c) administrating the optimal statin treatment with the highest success probability of step (b) to said subject thereby optimizing therapeutic efficacy for treating hypercholesterolemia in said subject.
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- Preparation and physicochemical characterization of a novel water-soluble prodrug of carbamazepine
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N-Acyl-urea derivatives of carbamazepine (CBZ) were synthesized through the reactions of iminostilbene with acyl-isocyanates to form N-glycyl-carbamazepine (N-Gly-CBZ, after a deprotection step) or N-acetyl-carbamazepine (N-acetyl-CBZ). N-Gly-CBZ was isolated as its water-soluble HCl salt and was designed to act as a prodrug and convert to CBZ and glycine in vivo by enzymatic cleavage of the acyl-urea bond. The stability pH-rate profiles for N-Gly-CBZ and N-acetyl-CBZ were determined. The stability of N-Gly-CBZ was found to range over four orders of magnitude with its greatest stability at pH 3-4 and a t 90 value of 5.9 day at pH 4 at 25°C. From the fit of the pH rate profile two pKa values were estimated to be 7.2 (terminal amine) and 10.0 (imide), which were independently verified using UV-visible spectroscopic analysis. The solubility of N-Gly-CBZ in aqueous solution was determined in the range of pH 5.5-7.5. The intrinsic solubility of the neutral form of the prodrug was found to be 4.4 mg/mL, and the solubility of the prodrug increased exponentially (log linear) as pH was decreased below its pKa1 value. N-Gly-CBZ was found to have an aqueous solubility in excess of 50 mg/mL at pH 4. The presence of N-Gly-CBZ was found to increase the aqueous solubility of CBZ, a degradation product. CBZ showed an 8.6-fold greater solubility in an aqueous solution containing 23 mg/mL of N-Gly-CBZ than in water alone. The solubilization of CBZ by N-Gly-CBZ was investigated by examining the diffusion coefficients of the predominant species in D2O and was found to be more consistent with stacking complex formation than micelle formation. The stability ofN-Gly-CBZ makes a ready-to-use parenteral formulation impractical, but a freeze-dried preparation for reconstitution appears to be feasible.
- Hemenway, Jeffrey N.,Jarho, Pekka,Henri, John T.,Nair, Sajiv K.,Vandervelde, David,Georg, Gunda I.,Stella, Valentino J.
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p. 1810 - 1825
(2011/03/21)
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- One-pot radiosynthesis of [13N]urea and [13N] carbamate using no-carrier-added [13N]NH3
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The aim of this study was to develop a practical labeling method of [ 13N]ligands using no-carrier-added [13N]NH3 with high specific activity. [13N]urea analogues [13N]1a and [13N]2a or [13N]carbamate [13N]3a were synthesized by reacting isocyanate 5a, carbamoyl chloride 6a or chloroformate 7a with [13N]NH3. The precursors 5a-7a were prepared by treating amines 8a and 9a and alcohol 10a with triphosgene in situ. These reaction mixtures were not purified and were used directly for [ 13N]ammonolysis, respectively. Using the one-pot method, we synthesized [13N]carbamazepine ([13N]4), a putative positron emission tomography ligand for brain imaging. Copyright
- Kumata, Katsushi,Takei, Makoto,Ogawa, Masanao,Kato, Koichi,Suzuki, Kazutoshi,Zhang, Ming-Rong
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experimental part
p. 166 - 172
(2010/07/02)
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- Synthesis of new dibenzo[b,f]azepine derivatives
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This work is focused on synthesis and chemical characterization of new polycyclic compounds having dibenzo[b,f] azepine and 10,11-dihydrodibenzo[b,f] azepine moieties. We report the synthesis of four new compounds, obtained by reacting 5H-dibenzo[b,f]azepine-5-carbonyl chloride and 10,11-dihydro-5H- dibenzo[b,f]azepine-5-carbonyl chloride with 1-phenylpiperazine, and pyrrolidine, respectively. The newly synthesized compounds were characterized using chromatographic and spectroscopic methods (HPLC-UV-VIS 1H-NMR, 13C-NMR, mass spectrometry by ESI technique).
- Balaure, Paul Catalin,Costea, Ion,Iordache, Florin,Draghici, Constantin,Enache, Cristian
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scheme or table
p. 935 - 942
(2011/06/21)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF OXCARBAZEPINE
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The present invention relates to an improved process for the preparation of 10-oxo- 10,l l-dihydiO-5H-dibenz[b,fjazepine-5-carboxamide (Oxcarbazepine) by reacting 10-methoxy-5H-dibenz[b,f]azepine (10-methoxyiminostilbene) and alkali metal cyanate in presence of α-hydroxy acids, and also relates to the process for the preparation of carbamazepine from iminostilbene. Further the present invention is directed to the novel crystalline form of 10-methoxy carbamazepine.
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Page/Page column 10
(2009/12/23)
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- Sulfenamides as prodrugs of NH-acidic compounds: A new prodrug option for the amide bond
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The objective of this report is to introduce the novel concept of utilizing sulfenamides as prodrugs for compounds containing an NH-acidic functionality, particularly weakly acidic amide-type functionalities (amides, ureas, carbamates, etc.). Included are the syntheses and physicochemical characterizations of some model sulfenamides to illustrate the promise of this new prodrug technology.
- Guarino, Victor R.,Karunaratne, Veranja,Stella, Valentino J.
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p. 4910 - 4913
(2008/02/12)
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- Reaction co-crystallization of molecular complexes or co-crystals
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Multi-component crystals (co-crystals) are prepared by combining co-crystal components in non-stoichiometric concentrations in solution. The solubility of the molecular complex in the solvent is reduced, increasing the probability that the molecular complex is the least soluble form in the system, upon which it precipitates. A crystalline product is produced without the need for grinding, solvent evaporation, or temperature variation.
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- Process for producing carbamazepine
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The invention concerns a process for producing 5H-dibenz[b,f]azepine-5-carboxamide (carbamazepine) by reacting iminostilbene with an alkali cyanate in acetic acid or a mixture of acetic acid with water or with alcohol.
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Page/Page column 4
(2008/06/13)
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- Small organic molecules that increase the activity of Gelatinase A in ocular cells
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Small organic molecules capable of effecting a “pharmacological trabeculocanalotomy” in an eye by means of reducing juxtacanalicular meshwork as a barrier to outflow of aqueous. The small organic molecules increase Gelatinase A activity in ocular cells by increasing cell membrane expression of membrane-type matrix metalloproteinases (MT-MMPs) to increase aqueous outflow as a treatment for primary open angle glaucoma.
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(2008/06/13)
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- Compositions of a cyclooxygenase-2 selective inhibitor and a sodium ion channel blocker for the treatment of pain, inflammation or inflammation mediated disorders
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The present invention provides compositions and methods for the treatment of pain, inflammation or inflammation-mediated disorders in a subject. More particularly, the invention provides a combination therapy for the treatment of pain, inflammation or inflammation mediated disorders comprising the administration to a subject of a sodium ion channel blocker in combination with a cyclooxygenase-2 selective inhibitor.
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- METHOD OF PREPARING A 5H-DIBENZ[B,F]AZEPINE-5-CARBOXAMIDE
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The present invention provides a method of preparing a 5H-dibenz[b,f]azepine-5-carboxamide of formula (1) wherein R1, R2, R3, and R4 are independently selected from the group consisting of hydrogen, halogen, nitro, cyano, carboxyl, A, -CO(A), -OCO(A), -O(A), -N(A)2, -CON(A)2, and -COO(A), wherein A is selected from the group consisting of C-1-C10 alkyl, C3-C10 cycloalkyl, C-2-C10 alkenyl, C-5-C10 cycloalkenyl, C-2-C10 alkynyl, and C-6-C20 aryl, wherein the two A groups of -N(A)2 and -CON(A)2 can be the same or different, and wherein R2 and R3 can together form a bond; comprising reacting a 5H-dibenz[b,f]azepine of formula (2) with a) a cyanate salt selected from the group consisting of alkali metal cyanate salts and alkaline-earth metal cyanate salts, and b) a salt of an amino compound having no N-H bonds, wherein the salt has a Ka (25° C) of at least about 10 x 10-11.
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- Process for preparing carbamazepine from iminostilbene
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A process for preparing carbamazepine from iminostilbene is disclosed. The iminostilbene is reacted with urea in a protonating medium. This process results in improvements over prior art processes involving iminostilbene. Carbamazepine is a known muscle relaxant, anticonvulsant and antidepressant drug.
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- Process for the preparation of 5-carbamoyl-5H-dibenz(b,f)azepine
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A process for the preparation of an N-carboxamido-cyclic secondary amine, such as carbamazepine, is disclosed. The process comprises reaction of the corresponding cyclic secondary amine, such as iminostilbene, with urea, preferably in a protonating medium. The compound thereby produced, such as carbamazepine, may then be brought into association with a pharmaceutically acceptable carrier for administration to a patient in need thereof.
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- Water dispersion containing ultrafine particles of organic compounds
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A water-dispersible condensate of water-insoluble ultrafine particles of medicine or hormones having a particle size of at largest 4 μm prepared by the steps of heating the medicine or hormone in a vacuum vessel at a temperature of 30° C. higher than the boiling point and at a pressure between 0.01 Torr and 10 Torr to evaporate the medicine or hormone and condensing the medicine or hormone on a recovery plate to obtain the condensate.
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- Electrochemical reduction of 5H-dibenz[b, f]azepine derivatives. Part 7: Cathodic dehalogenation reactions of 10-bromo-, 10,11-dibromo- and 10,11-dibromo-10,11-dihydro-5H-dibenz[b,f]azepines. Synthesis of 10-cycloalkylamino-5H-DIBENZ[B.F]AZEPINES
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The dcp and cv investigations of 10-bromo-5 H-dibenz[b, f]azepines 1 inaprotic medium [0.11 mol/l (C2H5)4NClO4/dimethyl formamide], the interpretation of the mechanism of the cathodic debromination and the application of the debromination reactions to preparative electrolysis have been extended to vicinal dibromides as 10,11-dibromo-5 H-dibenz[b,f]azepines 3 or 4 and 10,11-dibromo-10,11-dihydro-5 H-dibenz[b,f]azepines 5 or 6. The bromo compounds 4 can be converted into the appropriate 5 H-dibenz[b, f]azepines, the bromo compounds 5 and 6 on cathodic reduction undergothe formation of the 10,11-C,C double bond. The electrochemical debromination of 3 or 4 gives the reactive intermediates 10,11-dehydro-5 Hdibenz[b,f]azepines 11, which have been trapped to 10-cycloalkylamino-5 H-dibenz[b,f]azepines 12. An alternative synthetic sequence starting from 10-bromo-5-carbamoyl-5 H-dibenz-[b,f]azepine has been used for the preparation of 12.
- Jugelt,Gessner
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p. 426 - 432
(2007/10/02)
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- Process for the manufacture of N,N-(Dibenzohexatrienylene)ureas
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N,N-(dibenzohexatrienylene)urea medicaments can be manufactured in a smooth one-step reaction by reacting a corresponding N,N-(dibenzohexatrienylene)amine with cyanic acid.
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- A Convenient Synthesis of Carbamazepine (Tegretol)
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A two-step efficient procedure for the preparation of carbamazepine (3), involves intermediate preparation of N-cyanodibenzazepines (2).Hydrolysis of 2 affords 3 in 73 percent yield.
- Ahmad, S. Salman,Hafeez, Farrukh,Haider, S. Imtiaz,Mahmood, Tariq
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- Process for the production of 5-cyano-and 5-carboxamido-5H-dibenz[b,f]azepines
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The invention relates to a novel and technically advanced process for producing 5-cyano-5H-dibenz[b,f]azepine by reacting 5H-dibenz[b,f]azepine with a halocyanogen in the presence of strongly polar substances. 5-Cyano-5H-dibenz[b,f]azepine can be used as starting material for producing 5-carbamyl-10(11)-oxo-10,11-dihydro-5H-dibenz[b,f]azepine, which is known to have central-depressant, anticonvulsive and central-muscle-relaxing activity.
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- Pharmaceutical compositions having antiepileptic and antineuralgic action
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The present invention relates to novel pharmaceutical compositions having antiepileptic and antineuraglic action and containing (a) at least one anticonvulsive compound of the general formula I STR1 wherein X1 is hydrogen, halogen having an atomic number up to 35, or is cyano, and X2 and Y together are an additional bond, or X1 and X2 together are the oxo radical, or X1 is hydroxy, X2 is hydrogen and Y is also hydrogen, and (b) at least one nootropic compound of the vincamine type which has the general formula II STR2 wherein Z1 is lower alkoxycarbonyl, Z2 is hydroxy and Z3 is hydrogen, or Z2 and Z3 together are an additional bond, or one of Z1 and Z2 is hydroxy and the other is hydrogen and Z3 is also hydrogen, in particular vincamine (DCI rec.), in which Z1 is methoxycarbonyl, Z2 is hydroxy and Z3 is hydrogen, and also e.g., vinpocetin (DCI rec.), in which Z1 is ethoxycarbonyl and Z2 and Z3 together form an additional bond, as well as vincanol (DCI prop.), in which one of Z1 and Z2 is hydroxy and the other is hydrogen and Z3 is hydrogen, and the acid addition salts thereof, or at least one nootropic derivative of 2-pyrrolidinone, e.g. 2-oxo-1-pyrrolidineaetamide (piracetam) or one of its nootropic derivatives. The compounds of the general formula II e.g. vincamine, as well as the nootropic derivatives of 2-pyrrolidinone, e.g. piracetam, have in themselves virtually no anticonvulsive activity but potentiate the action of the compounds of the general formula I, e.g. carbamazepine.
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- A New Synthesis of 5H-Dibenzazepin-5-carboxamide (Carbamazepine)
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5H-Dibenzazepin-5-carboxamide (VI) has been synthesised starting from 2,2'-diformyldiphenylamine (III).III on cyclization with hydrazine hydrate in acetic acid gives the azepine (IV) which on treatment with COCl2 followed by ammonia affords VI, identical with an authentic sample.
- Sinha, A. K.,Agarwal, P. K.,Nizamuddin, S.
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p. 237 - 238
(2007/10/02)
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