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WO1992011262A1 - 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 - Google Patents

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 Download PDF

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Publication number
WO1992011262A1
WO1992011262A1 PCT/HU1991/000053 HU9100053W WO9211262A1 WO 1992011262 A1 WO1992011262 A1 WO 1992011262A1 HU 9100053 W HU9100053 W HU 9100053W WO 9211262 A1 WO9211262 A1 WO 9211262A1
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WIPO (PCT)
Prior art keywords
general formula
compound
acid
methylenedioxy
defined above
Prior art date
Application number
PCT/HU1991/000053
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English (en)
Inventor
Ferenc ANDRÁSI
Pál BERZSENYI
Péter Botka
Horváth Katalin GOLDSCHMIDTNÉ
Tamás HÁMORI
Jenö KÖRÖSI
Imre Moravcsik
István SZIRÁKI
Original Assignee
Gyógyszerkutató Intézet K.V.
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 K.V. filed Critical Gyógyszerkutató Intézet K.V.
Priority to KR1019930701833A priority Critical patent/KR930703324A/ko
Priority to JP4502171A priority patent/JPH06506442A/ja
Publication of WO1992011262A1 publication Critical patent/WO1992011262A1/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
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine

Definitions

  • This invention relates to novel l-(4-acylaminophenyl) -7,8-methylenedioxy-5H-2,3-be ⁇ zodiazepine derivatives of th general formula (I) ,
  • R stands for hydrogen or a C ⁇ _ 4 al yl group optionally substituted by a carboxyl or C2-5 alkoxycarbonyl grou and R 1 means an aliphatic ⁇ - ⁇ acyl, benzoyl or phenylacetyl group, as well as their acid-addition salts and pharmaceutical compositions containing these compounds.
  • the compounds o the general formula (I) can exist in the form of optically active enantio ers.
  • the invention also relates to the race- mates, pure individual enantiomers and any mixture thereof.
  • a process for the preparation of the new compounds of general formula (I) and acid addition salts thereof is provided.
  • the aim of the present invention is to provide novel 5H-2,3-benzodiazepine derivatives possessing valuable centra nervous system (CNS) effects, namely antidepressive and/or antiparkinsonian action, i.e. showing CNS-stimulating character and more advantageous properties than the l-(4- -aminophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3 -benzodiazepine (see United States patent specification No. 4,835,152), the single 5H-2,3-benzodiazepine derivative know in this therapeutic area.
  • CNS centra nervous system
  • the novel compounds of general formula (I) are prepared by ai) transforming a compound of the general formula (III)
  • R is as defined above and X means chloride, bromide, hemisulfate or methanesulfonate anion, by usin an organic or inorganic acid, then acylating the produc obtained, optionally without separating it, with a C ⁇ _ 6 aliphatic carboxylic acid, benzoic or phenylacetic acid or a reactive derivative of these acids; or -2 ) acylating a compound of the general formula (II) , wherein R is as defined above and X means chloride, bromide, hemisulfate or methanesulfonate anion, with C*L_6 aliphatic carboxylic, benzoic or phenylacetic ac or a reactive derivative of these acids; or b) reducing a compound of the general formula (IV) ,
  • R 1 is as defined above, by using an inorganic inorganic-organic complex metal hydride in a suitable solvent, to obtain compounds of the general formula (I wherein R 1 is as defined above and R means hydrogen; and, if desired, alkylating a compound of the general formu (I) , wherein R 1 is as defined above and R stands for hydro ⁇ gen, prepared by using any of the above processes a ⁇ ) , a2) b) , with a C ⁇ _4 alkyl halide optionally substituted by a C2 alkoxycarbonyl group or with a C2- 8 dialkyl sulfate in a suitable solvent, in the presence of an acid-binding agent and/or, if desired, hydrolyzing and then treating with an acid a compound of the general formula (I) , wherein R 1 is a defined above and R stands for a C** ⁇ alkyl group substitut by a C 2 -5 alkoxycarbonyl group, to obtain a compound of the general formula (I where
  • a compound of the general formula (III) wherein R is as defined above, is transformed to a salt by using an organic or inorganic acid and then the salt of the general formula (II) thus obtained, wherein R is as defined above and X represents an inorganic or organic anion, prefe ably chloride, bromide, hemisulfate or methanesulfonate anion, optionally without separation, is acylated with a C ⁇ aliphatic carboxylic, benzoic or phenylacetic acid or a rea tive derivative of these acids.
  • the quaternary nitrogen is present in the 7-membered cycle, therefore the aromatic primary amino group is free and can relatively readily be acylated.
  • the acylation can be performed in a suitable solvent or in an excess of the acylating agent. It is particularly preferable to carry out the acylation in an excess of the carboxylic acid anhydride at a temperature between 10 °C and 50 °C. This reaction lasts in general 1 t 5 hours.
  • a preferred embodiment of preparing compounds of the general formula (I) , wherein R 1 is as defined above and R means hydrogen comprises reducing a compound of the genera formula (IV) , wherein R 1 is as defined above, by using an inorganic or inorganic-organic complex metal hydride in a suitable solvent.
  • an inorganic or inorganic-organic complex metal hydride e.g. lithium aluminum hydride, sodium borohydride, potassium borohydride sodium borohydride-aluminum chloride, sodium cyanoboro- -hydride, sodium dihydro-bis(2-methoxyethoxy)-aluminate, lithium trimethoxyaluminum hydride or sodium borohydride- triethyloxonium fluoborate may be used as complex metal hydrides.
  • solvents or solvent mixtures is defined by the reducing agent used in the given case: it should be chosen in such a way that it reacts with the reducing agent very slowly if at all.
  • sodium borohydride is used as complex metal hydride
  • pyridine is employed as solvent and the reduction is suitably carried out at a temperature between 50 °C and 115 °C.
  • compounds of the general formula (I) wherein R stands for C ⁇ _4 alkyl unsubstituted o substituted by a C2-5 alkoxycarbonyl group and R 1 is as defined above, can preferably be prepared also by alkylating a compound of the general formula (I) , wherein R 1 is as defined above and R represents hydrogen, with a C 1 - 4 alkyl halide optionally substituted by a C2-5 alkoxycarbonyl group or with a C2-8 dialkyl sulfate in a suitable solvent, prefer ably dimethylformamide or dimethylacetamide, in the presence of an acid-binding agent such as e.g. an anhydrous alkali metal carbonate or hydrogen carbonate.
  • an acid-binding agent such as e.g. an anhydrous alkali metal carbonate or hydrogen carbonate.
  • Free carboxylic acids can be obtained by the hydrolys of esters, preferably by using an alkali metal hydroxide in hot 50 % ethanol and liberating the carboxylic acid from it alkali metal salt thus obtained by using an acid, preferabl acetic acid.
  • bases of the general formula (I to their acid-addition salts, suitably to pharmaceutically acceptable acid-addition salts, is carried out in a known way, e.g. by dissolving or suspending the base in an appro ⁇ priate solvent and adding the corresponding acid or its sol tion prepared in a suitable solvent.
  • the salts are separate either directly by filtration or after evaporating the sol- vent; if desired, the product obtained is suspended or re- crystallized and/or dried under reduced pressure.
  • novel compounds of general formula (I) prepared by the process according to the invention possess significant central nervous system effects.
  • the behavioural effects of the compounds according to the invention were evaluated on male CFLP mice with an average body weight of 20 g (see Table 1) after oral or intraperitoneal treatment, respectively, by using Irwin's method [Psychopharmacologia, .13., 222 (1968) ] .
  • Example 2 The effect of the compound of Example 1 on the motility in mice was more precisely analysed by means of a motimeter functioning on the basis of the capacitive re ⁇ sistance principle. The measurement was immediately commenc after the treatment and lasted for 2 hours. The number of animals was at least 12 in each group. The percentage chang determined from the total counts during 2 hours in relation to the vehicle as control are shown in Table 2. The signifi cance was calculated from the number of counts by using Duncan's test.
  • Example 1 exerted in this test an ant depressive effect being similar to that of the reference compound: it resulted in a significant escape-directed fight-strengthening effect even in an oral dose of 3 mg/kg. 4.
  • Anti-parkinsonian effect in mice [inhibition of the neurotoxicity of N-methyl-4-phenyltetrahydropyridin (abbreviated: MPTP) ]
  • Biochemical investigations were carried out in order 15 elucidate the action mechanism functioning in the anti- depressive and anti-parkinsonian as well as stimulatory effects of the compound of Example 1 and appearing in the pharmacological investigations.
  • the reference compound and the compound of Example 1 inhibit the dopamine and MPP + upake into the neuron with the same effectivity.
  • the pharmacological activity can be explained by this biochemical effect. 6.
  • Other central nervous system effects can be explained by this biochemical effect. 6.
  • the animals were orally treated with the test substances and 30 minutes later they received an intravenous dose of 50 mg/kg of hexobarbital inducing narcosis.
  • the pro ⁇ longation of the duration of narcosis was measured in relation to the vehicle conrol group.
  • mice Compound Anticonvulsive Narcosis-potentiatin
  • Oral LD50 > 500 mg/kg
  • Intraperitoneal LD50 ⁇ 150 mg/kg
  • the compound of Example 1 shows in rodents an antidepressive and anti-parkinsonian effect o the same order as the reference compound.
  • the mechanism of action of both molecules is the same: they selectively inhibit the dopamine uptake (and simultaneously the MPP + ) system.
  • the compounds of the invention can be used for treating depress ⁇ ive conditions and parkinsonism.
  • an indicated oral daily dose is in the range from about 0.05 mg/kg to about 20 mg/kg, prefer ⁇ ably from 0.1 mg/kg to 10 mg/kg, more preferably 1 mg/kg.
  • the active compounds of the invention are suitably formulated to pharmaceutical composi- tions by mixing them with nontoxic, inert solid or liquid carriers and/or additives, which are suitable for enteral parenteral administration and are commonly used in the pharmaceutical industry.
  • Suitable carriers are e.g. water, gelatin, lactose, starch, pectin, magnesium stearate, stea acid, talc and vegetable oils.
  • additives preservatives wetting (surface-active) , emulsifying or dispersing, buffering and aromatizing agents may be used.
  • the activ compounds of the invention may be formulated to the usual pharmaceutical compositions, e.g. solid forms (such as mai tablets, dragees and capsules) as well as to injectable solutions, suspensions and emulsions.
  • the invention also relates to pharmaceutical compositions containing a compound of the general formula ( or a pharmaceutically acceptable acid-addition salt thereof as active ingredient as well as to a process for preparing these compositions.
  • compositions according to the invention can be prepared by commonly known methods.
  • the invention also relates to a method for treating depressive illnesses and Parkinson's disease.
  • This method comprises administering a therapeutically effective amount an active ingredient of the general formula (I) to the patient in need of such treatment.
  • Example 1 The invention is further illustrated by the following non-limiting Examples.
  • Example 1 The invention is further illustrated by the following non-limiting Examples.
  • the crystalline precipitate was filtered and washed with 5 x 5 ml of ethyl acetate.
  • the dry weight of the product was 7.37 g, m.p.: it sintered abov 190 °C and weakly decomposed at 210-212 °C.
  • the thus-obtaine methanesulfonate salt of the starting substance could be acetylated as follows: 7.37 g of the powdered salt were suspended in 110 ml o acetic anhydride, the suspension was stirred at room tempera ture for 2 hours, then the crystalline precipitate was filtered, washed with 5 x 10 ml of ethyl acetate and dried t give 6.54 g of methanesulfonate salt of the target compound, m.p. 240-241 °C (with decomposition) .
  • the base could be liberated from the methanesulfonate salt of the target compound e.g. in the following way: 6.54 of salt were dissolved in 90 ml of water, the solution was clarified by charcoal, then 3.6 g of sodium hydrogen car ⁇ bonate were portionwise added to the clear solution. The precipitate was filtered, washed with 5 x 10 ml of water an dried to obtain 5.54 g of crude product.
  • the starting substance was prepared as follows. 10 g (34 mmol) of l-(4-aminophenyl)-4-methyl-7,8- -methylenedioxy-5H-2,3-benzodiazepine were stirred for 3 hours with 100 ml of acetic anhydride. The crystals formed were filtered, washed with 5x10 ml of anhydrous, ethanol and dried, to yield 9.2 g of raw product, m.p.: 252-254 °C (decomposition) . This product was treated with 45 ml of hot 99.5 % ethanol.
  • Example 2 The base was liberated as described in Method A) of Example 1 to obtain 1.36 g of product, m.p.: 226-233 °C (weak decomposition). The meltin point of this product was increased to 237-239 ⁇ C after re crystallization from 40 ml of 99.5 % ethanol to give the aimed compound in a yield of 1.8 g (71.5 %) .
  • the 1-(4-benzoylaminophenyl)-4-methyl-7 ,8-methylene- dioxy-5H-2,3-benzodiazepine used as starting substance was obtained as follows.
  • Example 6 The process described in Example 6 was followed, exce that methyl iodide was used instead of ethyl bromoacetate, the column chromatography was omitted and the crude product was recrystallized first from 50 % and then from 99.5 % ethanol to give the pure aimed compound, m.p.: 207-209 °C.
  • Example 9 l-(4-Acetylaminophenyl)-3-carboxymethyl-4-methyl-7,8- -metnylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine 0.59 g (1.4 mmol) of the compound of Example 6 was boiled with 15 ml of 50 % ethanol and 0.10 g (1.8 mmol) of potassium hydroxide under reflux for 30 to 40 minutes. Afte cooling 0.15 ml (2.5 mmol) of acetic acid was added to the filtered, clear solution to liberate the free carboxylic ac which was then separated by filtration after cooling.
  • the dragee-core was coated with sugar and talc in the usual way and then polished by using bee-wax. Each dragee weighed about 100 mg.

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  • Health & Medical Sciences (AREA)
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  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
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  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Nouveaux composés répondant à la formule générale (I), dans laquelle R représente hydrogène ou un groupe alkyle C1-4 éventuellement substitué par un groupe carboxyle ou alcoxycarbonyle C2-5; et R1 représente un groupe acyle C¿1-6?, benzoyle ou phénylacétyle aliphatique; ainsi que leurs stéréoisomères et leurs sels d'addition d'acides. On décrit également des compositions pharmaceutiques contenant lesdits composés ainsi qu'un procédé de préparation desdits nouveaux composés répondant à la formule (I). Lesdits composés présentent des effets sur le système nerveux central et plus précisément des actions antidépressive et antiparkinsonienne. Ils sont non mutagènes dans le test de Ames. Ils sont donc utiles au traitement des états dépressifs et du parkinsonisme.
PCT/HU1991/000053 1990-12-21 1991-12-20 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 WO1992011262A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
KR1019930701833A KR930703324A (ko) 1990-12-21 1991-12-20 1-(4-아실아미노페닐)-7,8-메틸렌디옥시-5h-2,3-벤조디아제핀 유도체와 그의 산 첨가염및 이를 함유하는 약제학적 조성물과 그의 제조방법
JP4502171A JPH06506442A (ja) 1990-12-21 1991-12-20 １−（４−アシルアミノフェニル）−７，８−メチレンジオキシ−５ｈ−２，３−ベンゾ−ジアゼピン誘導体及びその酸付加塩、それを含む製薬学的組成物及びその製造方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU8397/90 1990-12-21
HU908397A HU206719B (en) 1990-12-21 1990-12-21 Process for producing 1-/4-acylamino-phenyl/-7,8-methylenedioxy-5h-2,3-benzodiazepine derivatives, acid addicional salts and pharmaceutical compositions containing them

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WO1992011262A1 true WO1992011262A1 (fr) 1992-07-09

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PCT/HU1991/000053 WO1992011262A1 (fr) 1990-12-21 1991-12-20 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

Country Status (7)

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EP (1) EP0565557A1 (fr)
JP (1) JPH06506442A (fr)
KR (1) KR930703324A (fr)
AU (1) AU9122691A (fr)
CA (1) CA2098291A1 (fr)
HU (1) HU206719B (fr)
WO (1) WO1992011262A1 (fr)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995001357A1 (fr) * 1993-07-02 1995-01-12 Gyógyszerkutató Intézet Kft. 1-(4-nitrophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5h2-,3 -benzodiazepine optiquement actif et procede de preparation
EP0699677A1 (fr) 1994-08-31 1996-03-06 Eli Lilly And Company Procédé stéréosélectif pour la préparation de dérivés de dihydro-2,3-benzodiazépine
US5665878A (en) * 1994-08-31 1997-09-09 Eli Lilly And Company Stereoselective process for producing dihydro-2,3-benzodiazepine derivatives
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
WO2000053166A3 (fr) * 1999-02-15 2000-12-21 Egyt Gyogyszervegyeszeti Gyar Utilisation de derives de 2,3-benzodiazepine pour le traitement et la prevention de maladies liees a l'inhibition de peroxydation lipidique
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
WO2001098280A3 (fr) * 2000-06-16 2002-05-30 Annovis Inc Antagonistes 5h-2,3-benzodiazepine de recepteurs d'acide amine excitateurs
US6638928B1 (en) 2002-12-03 2003-10-28 Vela Pharmaceuticals, Inc. Treatment of irritable bowel syndrome and nonulcer dyspepsia with substituted 2,3-benzodiazepines
US6649607B2 (en) 2001-05-18 2003-11-18 Vela Pharmaceuticals, Inc. Compositions and methods for treating or preventing convulsions or seizures
US6858605B2 (en) 2003-02-04 2005-02-22 Ivax Drug Research Institute, Ltd. Substituted 2,3-benzodiazepine derivatives
US6864251B2 (en) 2002-12-03 2005-03-08 Vela Pharmaceuticals, Inc. Treatment of LTB4-mediated inflammatory disorders with optically-pure (R)-2,3-benzodiazepines
US7022700B2 (en) 2002-12-03 2006-04-04 Vela Pharmaceuticals, Inc. Method of increasing neutrophil production using optically-pure (R)-2,3-benzodiazepines
US7745431B2 (en) 2002-12-03 2010-06-29 Vela Acquisition Corporation Pharmaceutical composition of 1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7-methoxy-8-hydroxy-5H-2,3-benzodiazepine and uses thereof
US7960375B2 (en) 2003-08-04 2011-06-14 Egis Gyogyszergyar Rt. 8-chloro-2,3-benzodiazepine derivatives

Citations (2)

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US4423044A (en) * 1981-03-12 1983-12-27 Egyt Gyogyszervegyeszeti Gyar 3,4-Dihydro-5H-2,3-benzodiazepine derivatives and pharmaceutical use thereof
US4835152A (en) * 1986-08-15 1989-05-30 Biogal Gyogyszergyar 1-(4-Aminophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine and acid addition salts thereof same

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4423044A (en) * 1981-03-12 1983-12-27 Egyt Gyogyszervegyeszeti Gyar 3,4-Dihydro-5H-2,3-benzodiazepine derivatives and pharmaceutical use thereof
US4835152A (en) * 1986-08-15 1989-05-30 Biogal Gyogyszergyar 1-(4-Aminophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine and acid addition salts thereof same

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995001357A1 (fr) * 1993-07-02 1995-01-12 Gyógyszerkutató Intézet Kft. 1-(4-nitrophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5h2-,3 -benzodiazepine optiquement actif et procede de preparation
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
US5665878A (en) * 1994-08-31 1997-09-09 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
EP1157992A1 (fr) * 1994-08-31 2001-11-28 Eli Lilly And Company Dérivés de dihydro-2,3-benzodiazépine
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
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
WO2000053166A3 (fr) * 1999-02-15 2000-12-21 Egyt Gyogyszervegyeszeti Gyar Utilisation de derives de 2,3-benzodiazepine pour le traitement et la prevention de maladies liees a l'inhibition de peroxydation lipidique
WO2001004122A3 (fr) * 1999-07-07 2001-05-10 Egyt Gyogyszervegyeszeti Gyar Nouveaux derives de 2,3-benzodiazepines
WO2001098280A3 (fr) * 2000-06-16 2002-05-30 Annovis Inc Antagonistes 5h-2,3-benzodiazepine de recepteurs d'acide amine excitateurs
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
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US7022700B2 (en) 2002-12-03 2006-04-04 Vela Pharmaceuticals, Inc. Method of increasing neutrophil production using optically-pure (R)-2,3-benzodiazepines
US6638928B1 (en) 2002-12-03 2003-10-28 Vela Pharmaceuticals, Inc. Treatment of irritable bowel syndrome and nonulcer dyspepsia with substituted 2,3-benzodiazepines
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CA2098291A1 (fr) 1992-06-22
JPH06506442A (ja) 1994-07-21
HU206719B (en) 1992-12-28
HUT59683A (en) 1992-06-29
AU9122691A (en) 1992-07-22
HU908397D0 (en) 1991-07-29
KR930703324A (ko) 1993-11-29
EP0565557A1 (fr) 1993-10-20

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