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WO1995001357A1 - 1-(4-nitrophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5h2-,3 -benzodiazepine optiquement actif et procede de preparation - Google Patents

1-(4-nitrophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5h2-,3 -benzodiazepine optiquement actif et procede de preparation Download PDF

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Publication number
WO1995001357A1
WO1995001357A1 PCT/HU1994/000024 HU9400024W WO9501357A1 WO 1995001357 A1 WO1995001357 A1 WO 1995001357A1 HU 9400024 W HU9400024 W HU 9400024W WO 9501357 A1 WO9501357 A1 WO 9501357A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
benzodiazepine
dihydro
methylenedioxy
nitrophenyl
Prior art date
Application number
PCT/HU1994/000024
Other languages
English (en)
Inventor
István LING
Tamás HÁMORI
Péter Botka
Sándor SÓLYOM
Antal Simay
Imre Moravcsik
Original Assignee
Gyógyszerkutató Intézet Kft.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gyógyszerkutató Intézet Kft. filed Critical Gyógyszerkutató Intézet Kft.
Priority to AU72363/94A priority Critical patent/AU7236394A/en
Publication of WO1995001357A1 publication Critical patent/WO1995001357A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • OPTICALLY ACTIVE 1- (4-NITROPHENYL) -4-METHYL-7 , 8- -METHYLENEDIOXY-3 - 4-DIHYDRO-5H-2 , 3-BENZODIAZEPINE AND PROCESS FOR PREPARING SAME
  • This invention relates to the enantiomers of l- (4- nitrophenyl) -4-methyl-7 , 8-methylenedioxy-3 , 4-dihydro-5H- -2 , 3-benzodiazepine of the formula (I)
  • -benzodiazepines e.g. the l-(4-aminophenyl)-3-acetyl-4- -methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodi- azepine and l-(4-aminophenyl)-3-(N-methylcarbamoyl)-4- -methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodi- azepine, possess anticonvulsive, muscle relaxant and neuroprotective effects.
  • the basis of these valuable pharmacological effects is a noncompetitive antagonism of quisqualate/AMPA receptors.
  • l-(4-amino- phenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3- -benzodiazepine and l-(4-acetylaminophenyl)-4-methyl-7,8- -methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine are dopamine-uptake-inhibiting and psychostimulatory in their character; therefore, these compounds may potentially be useful for the treatment of parkinsonism. These compounds have chiral structure.
  • the most preferred possibility of preparing optically pure enantiomers consists in that the enantiomers of the first chiral molecule of the synthesis, in the given case the compound of formula (I) , are prepared and the subsequent steps of the synthesis are carried out by starting from these enantiomers.
  • the traditional resolution based on the separation of diastereomeric salt or compound pairs can theoretically provide the pure enantiomers of a racemic compound in a yield of at most 50%
  • the desired enantiomer(s) can be prepared in yields substantially higher than 50 %.
  • the invention is aimed at providing a process, by which the double bond in 3,4-position of the achiral derivative of formula (II)
  • the peparation of enan- tiomers of 1-(4-nitrophenyl)-4-methyl-7,8-methylenedioxy- -3,4-dihydro-5H-2,3-benzodiazepine of formula (I) com ⁇ prises reducing 1-(4-nitrophenyl)-4-methyl-7,8-methylene- dioxy-5H-2,3-benzodiazepine of formula (II) by using an adduct formed from an (R)- or (S)-, respectively, 2- -amino-1,1-diphenylalkan-l-ol derivative of formula (III), wherein R l and R2, which are different, stand for hydrogen; a straight or branched chain C ⁇ -4 alkyl group; or an unsubstituted phenyl or benzyl group, with one molar equivalent of borane or a borane complex.
  • the enantiomers of the compound of formula (I) are valuable intermediates which, after acylation and subsequent reduction, lead to the enantio ⁇ mers of l-(4-aminophenyl)-3-acyl-4-methyl-7,8-methylene- dioxy-3,4-dihydro-5H-2,3-benzodiazepines, which are anta ⁇ gonists of the quisqualate/AMPA receptors; or, by reduc ⁇ ing and then, if desired, acetylating the enantiomers of the compound of formula (I), l-(4-aminophenyl)-4-methyl- -7,8-methylenedioxy-3,4-dhydro-5H-2,3-benzodiazepine and 1-(4-acetylaminophenyl)-4-methyl-7,8-methylenedioxy-3, - -dihydro-5H-2,3-benzodiazepine can be obtained, which have psychostimulant character.
  • the reaction mixture is suitably worked up as follows: the mixture is mixed with sodium carbonate solution, the organic phase is washed with water until neutral and evaporated under reduced pressure.
  • the crystalline product obtained is suspended in a C 1 _ 3 al- kanol, preferably ethanol, and the product is isolated by filtration.
  • the primary product obtained is characterized by its specific rotary power.
  • the enantiomeric purity of the product is qualified by the percentage of enantiomers, which can be determined by the following methods: 1) by ⁇ -H-N R techniques using a complex of para ⁇ magnetic rare earth element (shift reagent) ; or
  • the primary product has a high enantiomeric purity, which can be in ⁇ creased nearly to 100% even by a single recrystalliza- tion.
  • Example 1 The invention is illustrated in detail by the following non-limiting Examples.
  • Example 1 The invention is illustrated in detail by the following non-limiting Examples.
  • the ratio of (-) enantiomer to the (+) enantiomer was found to be 90:10 as determined by 1 H-NMR spectro- scopy by using Eu(hfc) 3 shift reagent (by weighing 5 mg of shift reagent to 10 mg of substance and dissolving this mixture in deuterochloroform) .
  • Example 2 (Daicel Chemical Industries, LTD)] with a 35:65 mixture of hexane and isopropanol as eluent.
  • Example 2 Method A
  • the therapeutically valuable products may be pre ⁇ pared from the enantiomers of formula (I) according to the invention e.g. in the following way.
  • 1. Preparation of (+)-l-(4-aminophenyl)-3-acetyl- -4-methyl-7,8-methylenedioxy-3, -dihydro-5H-2 ,3- -benzodiazepine Step a)
  • (+)-1-(4-Aminophenyl)-3-acetyl-4-methyl-7,8-methy- lenedioxy-3 ,4-dihydro-5H-2 ,3-benzodiazepine To a suspension containing 2.6 g (7.08 mmol) of (-)-l-(4-nitrophenyl)-3-acetyl-4-methyl-7,8-methylene- dioxy-3,4-dihydro-5H-2,3-benzodiazepine in 52 ml of methanol, 0.5 g of wet Raney nickel catalyst and 1.2 ml (24.8 mmol) of 100% hydrazine hydrate were added and the reaction mixture was stirred for 1 hour.
  • This product contained the minor enantiomer in an amount lower than 1% (based on HPLC analysis and 1 H-NMR shift reagent method) .
  • This product contained the minor enantiomer in an amount lower than 1% (HPLC: CHIRALCEL OF by using a 1:1 mixture of n-hexane and isopropanol containing 0.1% by vol. of diethylamine as eluent; 1 H-NMR: 10 ml of product + + 10 or 20 mg of Eu(hfc) 3 shift reagent in deutero- chloroform) .

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne les énantiomères -(+) et les énantiomères -(-) du composé dont la formule est indiquée en (I), ainsi qu'un procédé de préparation de ces énantiomères. Ce procédé implique la réduction du 1-(4-nitrohényl)-4-méthyl-7,8-méthylènedioxy-5H^_-2,3-benzodiazépine dont la formule est indiquée en (II); on utilise à cette fin un composé d'addition obtenu à partir d'un dérivé 2-aminé-1,1-diphényl-alcane-1-ol respectivement-(R) ou -(S) dont la formule est indiquée en (III), où R1 et R2, qui sont différents, représentent un groupe alkyle C1-4 à chaîne droite ou ramifiée, ou un groupe phényle ou benzyle non substitué, comportant un équivalent molaire de borane ou un complexe de borane. Les énantiomères du composé dont la formule est indiquée en (I) constituent de précieux intermédiaires intervenant dans la synthèse des composés actifs sur le plan thérapeutique.
PCT/HU1994/000024 1993-07-02 1994-06-30 1-(4-nitrophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5h2-,3 -benzodiazepine optiquement actif et procede de preparation WO1995001357A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU72363/94A AU7236394A (en) 1993-07-02 1994-06-30 Optically active 1-(4-nitrophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5h -2,3-benzodiazepine and process for preparing same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HUP9301922 1993-07-02
HU9301922A HU219777B (hu) 1993-07-02 1993-07-02 Optikailag aktív 1-(4-nitro-fenil)-4-metil-7,8-metiléndioxi-3,4-dihidro-5H-2,3-benzodiazepin és eljárás előállítására

Publications (1)

Publication Number Publication Date
WO1995001357A1 true WO1995001357A1 (fr) 1995-01-12

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AU (1) AU7236394A (fr)
HU (1) HU219777B (fr)
WO (1) WO1995001357A1 (fr)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0699677A1 (fr) * 1994-08-31 1996-03-06 Eli Lilly And Company Procédé stéréosélectif pour la préparation de dérivés de dihydro-2,3-benzodiazépine
EP0699678A1 (fr) * 1994-08-31 1996-03-06 Eli Lilly And Company Forme cristalline d'un dérivé de dihydro-2,3-benzodiazépine
EP0699676A1 (fr) * 1994-08-31 1996-03-06 Eli Lilly And Company Forme physique d'un dérivé de dihydro-2,3-benzodaizépine
US5665878A (en) * 1994-08-31 1997-09-09 Eli Lilly And Company Stereoselective process for producing dihydro-2,3-benzodiazepine derivatives
WO1999007707A1 (fr) * 1997-08-12 1999-02-18 EGIS Gyógyszergyár Rt. DERIVES DE 9H-1,3-DIOXOLO/4,5-h//2,3/BENZODIAZEPINE SUBSTITUEE EN HUIT UTILISES COMME INHIBITEURS DES RECEPTEURS D'AMPA/KAINATE
WO1999007708A1 (fr) * 1997-08-12 1999-02-18 EGIS Gyógyszergyár Rt. Derives de 1,3-dioxolo/4,5-h//2,3/benzodiazepine utilises comme inhibiteurs des recepteurs ampa/kainate
WO2001004122A3 (fr) * 1999-07-07 2001-05-10 Egyt Gyogyszervegyeszeti Gyar Nouveaux derives de 2,3-benzodiazepines
EP1157992A1 (fr) * 1994-08-31 2001-11-28 Eli Lilly And Company Dérivés de dihydro-2,3-benzodiazépine
US6649607B2 (en) 2001-05-18 2003-11-18 Vela Pharmaceuticals, Inc. Compositions and methods for treating or preventing convulsions or seizures
US6825192B1 (en) 1999-02-15 2004-11-30 Eisai Co., Ltd. Heterodiazinone derivatives
US6858605B2 (en) 2003-02-04 2005-02-22 Ivax Drug Research Institute, Ltd. Substituted 2,3-benzodiazepine derivatives
US6949571B2 (en) 2000-06-12 2005-09-27 Eisai Co., Ltd. 1,2-dihydropyridine compounds, process for preparation of the same and use thereof
US7759367B2 (en) 2001-12-06 2010-07-20 Eisai R&D Management Co., Ltd. Pharmaceutical compositions and their uses
US8304548B2 (en) 2004-07-06 2012-11-06 Eisai R&D Management Co., Ltd. Method for producing 1, 2-dihydropyridine-2-one compound
WO2020124090A1 (fr) 2018-12-14 2020-06-18 Eisai R&D Management Co., Ltd. Formulations pharmaceutiques à base d'eau de composés de 1,2-dihydropyridine
US12303499B2 (en) 2019-12-16 2025-05-20 Eisai R&D Management Co., Ltd. Aqueous based pharmaceutical formulations of 1,2-dihydropyridine compounds

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0492485A1 (fr) * 1990-12-21 1992-07-01 Gyogyszerkutato Intezet Dérivés de N-acyl-2,3-benzodiazépine, compositions pharmaceutiques les contenant et procédé pour leur préparation
WO1992011262A1 (fr) * 1990-12-21 1992-07-09 Gyógyszerkutató Intézet K.V. Derives de 1-(4-acylaminophenyl)-7,8-methylenedioxy-5h-2,3-benzo-diazepine, leurs sels d'addition d'acides, compositions pharmaceutiques les contenant, et leur procede de preparation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0492485A1 (fr) * 1990-12-21 1992-07-01 Gyogyszerkutato Intezet Dérivés de N-acyl-2,3-benzodiazépine, compositions pharmaceutiques les contenant et procédé pour leur préparation
WO1992011262A1 (fr) * 1990-12-21 1992-07-09 Gyógyszerkutató Intézet K.V. Derives de 1-(4-acylaminophenyl)-7,8-methylenedioxy-5h-2,3-benzo-diazepine, leurs sels d'addition d'acides, compositions pharmaceutiques les contenant, et leur procede de preparation

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6329364B1 (en) 1994-08-31 2001-12-11 Eli Lilly And Company Crystalline form of dihydro-2,3-benzodiazepine derivative
EP0699678A1 (fr) * 1994-08-31 1996-03-06 Eli Lilly And Company Forme cristalline d'un dérivé de dihydro-2,3-benzodiazépine
EP0699676A1 (fr) * 1994-08-31 1996-03-06 Eli Lilly And Company Forme physique d'un dérivé de dihydro-2,3-benzodaizépine
US5665878A (en) * 1994-08-31 1997-09-09 Eli Lilly And Company Stereoselective process for producing dihydro-2,3-benzodiazepine derivatives
EP1593683A3 (fr) * 1994-08-31 2006-10-25 Eli Lilly And Company Dérivés de dihydro-2,3-benzodiazépine
EP0699677A1 (fr) * 1994-08-31 1996-03-06 Eli Lilly And Company Procédé stéréosélectif pour la préparation de dérivés de dihydro-2,3-benzodiazépine
AU702658B2 (en) * 1994-08-31 1999-02-25 Eli Lilly And Company Stereoselective process for producing dihydro-2, 3-benzodiazepine derivatives
US5919954A (en) * 1994-08-31 1999-07-06 Eli Lilly And Company Stereoselective process for producing dihydro-2,3-benzodiazepine derivatives
US5986114A (en) * 1994-08-31 1999-11-16 Eli Lilly And Company Benzopyranol derivatives
CN1086705C (zh) * 1994-08-31 2002-06-26 伊莱利利公司 制备二氢－2,3－苯并二氮杂䓬衍生物立体有择方法和中间体
US6288057B1 (en) 1994-08-31 2001-09-11 Eli Lilly And Company Physical form of dihydro-2,3-benzodiazepine derivative
CN1073995C (zh) * 1994-08-31 2001-10-31 伊莱利利公司 二氢－2,3－苯并二氮杂䓬衍生物的物理形态，制备方法和用途
CN1073996C (zh) * 1994-08-31 2001-10-31 伊莱利利公司 二氢－2,3－苯并二氮杂䓬衍生物的物理形态，制备方法和用途
EP1157992A1 (fr) * 1994-08-31 2001-11-28 Eli Lilly And Company Dérivés de dihydro-2,3-benzodiazépine
US6562810B1 (en) 1997-08-12 2003-05-13 Egis Gyogyszergyar Rt. 8-substituted-9H-1,3-dioxolo/4,5-h//2,3/benzodiazepine derivatives, as AMPA/kainate receptor inhibitors
WO1999007708A1 (fr) * 1997-08-12 1999-02-18 EGIS Gyógyszergyár Rt. Derives de 1,3-dioxolo/4,5-h//2,3/benzodiazepine utilises comme inhibiteurs des recepteurs ampa/kainate
WO1999007707A1 (fr) * 1997-08-12 1999-02-18 EGIS Gyógyszergyár Rt. DERIVES DE 9H-1,3-DIOXOLO/4,5-h//2,3/BENZODIAZEPINE SUBSTITUEE EN HUIT UTILISES COMME INHIBITEURS DES RECEPTEURS D'AMPA/KAINATE
US6825192B1 (en) 1999-02-15 2004-11-30 Eisai Co., Ltd. Heterodiazinone derivatives
WO2001004122A3 (fr) * 1999-07-07 2001-05-10 Egyt Gyogyszervegyeszeti Gyar Nouveaux derives de 2,3-benzodiazepines
US7939549B2 (en) 2000-06-12 2011-05-10 Eisai R&D Management Co., Ltd. 1,2-dihydropyridine compounds, manufacturing method thereof and use thereof
US6949571B2 (en) 2000-06-12 2005-09-27 Eisai Co., Ltd. 1,2-dihydropyridine compounds, process for preparation of the same and use thereof
EP2053041A2 (fr) 2000-06-12 2009-04-29 Eisai R&D Management Co., Ltd. 2(1H)-Pyridones 1,3,5-trisubstituées commes inhibiteurs du récepteur AMPA utilisables pour le traitement par ex. de la maladie de Parkinson
US7563811B2 (en) 2000-06-12 2009-07-21 Eisai R&D Management Co., Ltd. 1,2-dihydropyridine compounds, manufacturing method thereof and use thereof
US6649607B2 (en) 2001-05-18 2003-11-18 Vela Pharmaceuticals, Inc. Compositions and methods for treating or preventing convulsions or seizures
US7078398B2 (en) 2001-05-18 2006-07-18 Vela Pharamaceuticals, Inc. Compositions and methods for treating or preventing convulsions or seizures
US7759367B2 (en) 2001-12-06 2010-07-20 Eisai R&D Management Co., Ltd. Pharmaceutical compositions and their uses
US6858605B2 (en) 2003-02-04 2005-02-22 Ivax Drug Research Institute, Ltd. Substituted 2,3-benzodiazepine derivatives
US8304548B2 (en) 2004-07-06 2012-11-06 Eisai R&D Management Co., Ltd. Method for producing 1, 2-dihydropyridine-2-one compound
US8772497B2 (en) 2004-07-06 2014-07-08 Eisai R&D Management Co., Ltd. Method for producing 1, 2-dihydropyridine-2-one compound
US9045426B2 (en) 2004-07-06 2015-06-02 Eisai R&D Management Co., Ltd. Method for producing 1,2-dihydropyridine-2-one compound
WO2020124090A1 (fr) 2018-12-14 2020-06-18 Eisai R&D Management Co., Ltd. Formulations pharmaceutiques à base d'eau de composés de 1,2-dihydropyridine
US12303499B2 (en) 2019-12-16 2025-05-20 Eisai R&D Management Co., Ltd. Aqueous based pharmaceutical formulations of 1,2-dihydropyridine compounds

Also Published As

Publication number Publication date
AU7236394A (en) 1995-01-24
HUT67611A (en) 1995-04-28
HU219777B (hu) 2001-07-30
HU9301922D0 (en) 1993-09-28

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