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WO1999004797A1 - Utilisation de derives 2,3-benzodiazepine pour l'elaboration de compositions pharmaceutiques destinees au traitement d'affections en relation avec le systeme opioide endogene - Google Patents

Utilisation de derives 2,3-benzodiazepine pour l'elaboration de compositions pharmaceutiques destinees au traitement d'affections en relation avec le systeme opioide endogene Download PDF

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Publication number
WO1999004797A1
WO1999004797A1 PCT/HU1998/000069 HU9800069W WO9904797A1 WO 1999004797 A1 WO1999004797 A1 WO 1999004797A1 HU 9800069 W HU9800069 W HU 9800069W WO 9904797 A1 WO9904797 A1 WO 9904797A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
benzodiazepine
pharmaceutical compositions
active ingredient
azep
Prior art date
Application number
PCT/HU1998/000069
Other languages
English (en)
Inventor
Márton Fekete
József Haller
József Székely
Katalin HORVÁTH
Pál FEKETE
Original Assignee
EGIS Gyógyszergyár Rt.
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 EGIS Gyógyszergyár Rt. filed Critical EGIS Gyógyszergyár Rt.
Priority to AU85538/98A priority Critical patent/AU8553898A/en
Publication of WO1999004797A1 publication Critical patent/WO1999004797A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep

Definitions

  • This invention relates to the use of 2,3-benzod ⁇ azep ⁇ ne derivatives for the preparation of pharmaceutical compositions " useful for the treatment or prevention of diseases connected with disturbances of the opioid system Background of the invention
  • Hedonia the overstated demand of pleasure
  • ahedonia inability to feel pleasure
  • these symptoms are mentioned in the Diagnostic and Statistical Manual of Mental Disorders, IV ed (American Psychiatric Association, Washington D C , USA, 1994) among diagnostic criteria for schizophrenia and depression
  • the increased desire of pleasure is considered to play an important role by initiating the progress of disease state [Drug addiction and alcoholism and opioid signals, Koob, G F Ann N Y Acad Sci 654 1171-191 (1992)]
  • the state of pleasure is primarily the consequence of specific actions of the endogenous opioid peptides [(Ber ⁇ dge, K C Neurosci Biobehav Rev 20 1-25 (1996)]
  • the opioid peptide is released and acts only in areas of the brain performed to evoke the state of pleasure, on the other hand the appropriate receptor of the opioid peptides
  • the present invention is based on the recognition that the effect of 2 " 3-benzod ⁇ azep ⁇ ne derivatives on the behaviour of experimental animals is inhibited in states of opioid tolerance induced by morphine This means that the compounds are acting via the opioid signal transduction system Consequently, the 2,3-benzod ⁇ azep ⁇ nes may be employed in the therapy or prevention of disease states in which the endogenous opioid system is playing a role Disturbances of the hedonic state (increased or depressed ability of feeling pleasure) are the most characteristic examples of these symptoms of diseases
  • the experiments were carried out in Charles River Wistar rats The animals were treated subcutaneously with saline or morphine for 4 consecutive days Treatments were carried out twice a day between 8 and 9 o'clock a m and between 17 and 18 o'clock p m
  • the group treated with morphine received on the first day two times 5 mg/kg, on the second day two times 10 mg/kg, on the third day two times 15 mg/kg and on the fourth day two times 20 mg/kg of morphine
  • This treatment schedule decreases the analgesic potency of morphine to about one fifth 18 hours after the last treatment
  • the test compounds, that is the 2,3- benzodiazepine derivatives were administered on the fifth day On the fifth day of the experiment, 15-20 hours after the last treatment, open field tests were carried out as specified in the literature [(Van Ree, J M , G Wolternik "Motility and grooming as measures of anxiolysis with homophtalazines", Eur J Pharmacpl 72 107-
  • Control 109.9 10.8 10 4.60 1.03 10 80.6 36.8 10 nerisopam 129 3 34.0 5 3.33 1.52 5
  • Figure 1 shows the effect of tofisopam, nerisopam and girisopam on the motility and grooming behaviour of rats in open field test after treatment with saline or morpholine
  • Tables 1-3 are presented as percentages of the control values
  • the vertical bars indicate the standard errors of the mean, * P 0 05, ** P 0 01 (analysis of variance followed by Duncan test)
  • the 2,3-benzod ⁇ azep ⁇ nes induce their psychopharmacological effects (anxiolysis) due to an action on the endogenous opioid system evoking good feeling, pleasure
  • This effect envisages that the 2,3-benzod ⁇ azep ⁇ ne derivatives may be employed to treat or prevent hedonic disturbances These disturbances are present in cases of schizophrenia, depression, alcoholism or drug dependence In cases of schizophrenics with anhedonia the 2,3- benzodiazepine derivatives increasing the feeling of pleasure decrease the desire for drug or alcohol.
  • depression induced by stress or loss of weight of animals induced by stress may be counteracted by 2,3-benzodiazepines.
  • compositions of the present invention useful for the treatment or prevention of diseases connected with the opioid system can be prepared by methods known per se by admixing the active ingredient with suitable inert solid or liquid carriers and bringing the mixture to galenic form.
  • compositions of the present invention can be presented preferably in the form of orally administerable preparations (such as tablets, pills, coated pills, soft or hard gelatin capsules, solutions or suspensions etc.), or as compositions for parenteral (e.g. injection solutions), rectal (e.g. suppositories) or nasal (e.g. aerosols) administration.
  • the pharmaceutical compositions may release the active ingredient at once, in which case the duration of the effect depends only on the duration of effect of the applied ingredients When applying special pharmaceutical compositions, however, the release of the active ingredient may be prolonged, and in this case the duration of the therapeutic effect is influenced by the form of the pharmaceutical composition as well (sustained-release or controlled-release preparations)
  • compositions can be prepared by methods generally applied in the pharmaceutical industry
  • inorganic salts secondary calcium phosphate, calcium sulfate, calcium carbonate, etc
  • gelatin polyvinyl pyrrolidone, different cellulose ethers (hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, etc ), hydrolyzed starches, various vegetal gums (gum arable, guar gum) may be applied in solutions formed with water, C ⁇ - aliphatic alcohols or the mixtures thereof
  • disintegrant various kinds of starches (potato, corn, wheat, etc ) as well as super-disintegrants (carboxymethyl cellulose [the commercial product known as Ac-di-sol], carboxymethyl starch Na [commercial products known as P ⁇ mojel, Ultraamilopectin, Explo-Tab], polyvinyl
  • the preparation of the active ingredients and auxiliaries for the tabletting procedure may be carried out by dry or damp " granulation, or - when applying directly compressable auxiliaries, such as microcrystalline cellulose, spray-homogenized lactose, Tablettose, Ceilactose, etc. - by a simple spray-homogenization.
  • auxiliaries such as microcrystalline cellulose, spray-homogenized lactose, Tablettose, Ceilactose, etc. - by a simple spray-homogenization.
  • the granules or the spray-homogenized ingredients instead of being tabletted, may also be filled into hard gelatin capsules. In this way hard gelatin capsule formulations can be prepared.
  • hydrophilic polymers such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, polyacrylic acid derivatives, polysaccharoses, guar gum, xanthan gum, etc.
  • hydrophobic polymers such as ethyl cellulose, metacrylic acid esther copolymers, polyvinyl acetate, polyvinyl butyral, etc. and mixtures thereof
  • the matrix having a function of retarding the release of the active ingredient may, however, be produced by the application of mixtures of hydrophilic and hydrophobic polymers, as well as by the application of mixtures of polymer substances and fat-like substances
  • the matrix preparations may also be prepared in the form of multi-layer tablets by incorporating the ingredients in different layers each In this way the release profile of the ingredients can more readily be adjusted to their individual pharmacokinetic properties
  • the coTitrolled-release preparations containing the active ingredients according to the present invention may also be produced in the form of coated pellets
  • the preparation of pellets can be carried out either from the individual active ingredients or from mixtures thereof
  • the pellets may be prepared by extrusion spheronization, rotogranulation or placebo layering methods
  • the pellets may be coated in rotating or fluidization apparatus
  • As coating agent solutions of water-insoluble polymer substances in organic solvents usually in C 1 . 3 aliphatic alcohols and/or C ⁇ -2 chlorinated carbohydrates containing two or more chlorine atoms, acetone and/or ethyl acetate or the mixtures thereof), or aqueous dispersions of same may be applied
  • the active ingredients of the present invention may also be finished in the form of osmotic or diffusion-osmotic preparations
  • tablets containing hydrophilic polymers e g hydroxypropyl methyl cellulose
  • these tablets are then coated by methods known from the literature with a semipermeable (such as cellulose acetate) or permeable (such as aminomethacrylate copolymer) film layer, and a passageway is bored into the layer through which the active ingredient can be osmotically pressed into the aqueous medium
  • the setting free velocity of the active ingredient may be preferably adjusted to the rate that at least 80 % of the active ingredient should be released in vitro within 2 to 24 hours (measured as specified in the pharmacopoeias)
  • cosolvents may be e g the following substances ethyl alcohol propylene glycol, polyethylene glycol, sorbite, cyclodext ⁇ nes, surface active agents, polyethylene glycol/polypropylene glycol copolymers, etc
  • compositions When injectable compositions are produced, usually only preparations containing organic cosolvents may be formed because of the above considerations In these preparations, in addition to the above-mentioned cosolvents further substances (such as benzyl alcohol, dimethyl acetamide methylpyrrolidone, etc ) may also be applied If desired the injections may be produced in the form of emulsion preparations as well In this case the ingredients, in the form of bases, are dissolved in liquid, fat-like auxiliary substances (such as soya oil) and the emulsification of the oily solution in aqueous medium is carried out by the application of surface active agents (e g lecithins)
  • surface active agents e g lecithins
  • Suppository preparations may be prepared by methods known from the literature The ingredients are dissolved or suspended in the melted suppository matrix then the liquid "mixture is poured into suppository forms or into small suppository-shaped polymer blisters pre-fab ⁇ cated from a polymer film and solidified by cooling
  • binding material either natural (e g cocoa butter) or synthetic fat-like substances (e g commercial products of the trade name Witepsol) may be applied
  • the active ingredient gets to the respiratory system in the form of sprayed drops or powder/air suspension
  • the active ingredients according to the invention primarily formulations suitable for nasal administration may be applied
  • the solution or suspension of the active ingredients is filled into holders supplied with a proportioning valve either with or without the application of a power-gas
  • a nozzle supplemented with a proportioning pump is to be applied

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne l'utilisation de dérivés 2,3-benzodiazépine pour l'élaboration de compositions pharmaceutiques convenant au traitement ou à la prévention d'affections en relations avec le système opioïde endogène, et plus particulièrement les troubles de l'hédonisme. Les dérivés 2,3-benzodiazépine particulièrement préférés en utilisation aux termes de la présente invention sont, d'une part, la 1-(3,4-diméthoxyphényle)-4-méthyle-5-éthyle-7,8-diméthoxy-5H-2,3-benzodiazépine (tofisopam), d'autre part la 1-(3-chlorophényle)-4-méthyle-7,8-diméthoxy-5H-2,3-benzodiazépine, et enfin la 1-(4-aminophényle)-4-méthyle-7,8-diméthoxy-5H-2,3-benzodiazépine (nérisopam).
PCT/HU1998/000069 1997-07-24 1998-07-23 Utilisation de derives 2,3-benzodiazepine pour l'elaboration de compositions pharmaceutiques destinees au traitement d'affections en relation avec le systeme opioide endogene WO1999004797A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU85538/98A AU8553898A (en) 1997-07-24 1998-07-23 Use of 2,3-benzodiazepine derivatives for the preparation of pharmaceutical compositions to treat diseases connected with the endogenous opioid system

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HUP9701284 1997-07-24
HU9701284A HUP9701284A3 (en) 1997-07-24 1997-07-24 Use of 2,3-benzodiazepine derivatives for producing pharmaceutical compositions for treating and prophylacting illnesses and conditions connected with the endogene opioide system

Publications (1)

Publication Number Publication Date
WO1999004797A1 true WO1999004797A1 (fr) 1999-02-04

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/HU1998/000069 WO1999004797A1 (fr) 1997-07-24 1998-07-23 Utilisation de derives 2,3-benzodiazepine pour l'elaboration de compositions pharmaceutiques destinees au traitement d'affections en relation avec le systeme opioide endogene

Country Status (3)

Country Link
AU (1) AU8553898A (fr)
HU (1) HUP9701284A3 (fr)
WO (1) WO1999004797A1 (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7090830B2 (en) 2001-05-24 2006-08-15 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
US7458374B2 (en) 2002-05-13 2008-12-02 Alexza Pharmaceuticals, Inc. Method and apparatus for vaporizing a compound
AU2003263357B2 (en) * 2002-09-13 2009-02-26 Motac Neuroscience Limited Treatment of basal ganglia-related movement disorders with 2,3-benzodiazepines
US7537009B2 (en) 2001-06-05 2009-05-26 Alexza Pharmaceuticals, Inc. Method of forming an aerosol for inhalation delivery
US7540286B2 (en) 2004-06-03 2009-06-02 Alexza Pharmaceuticals, Inc. Multiple dose condensation aerosol devices and methods of forming condensation aerosols
US7581540B2 (en) 2004-08-12 2009-09-01 Alexza Pharmaceuticals, Inc. Aerosol drug delivery device incorporating percussively activated heat packages
US7585493B2 (en) 2001-05-24 2009-09-08 Alexza Pharmaceuticals, Inc. Thin-film drug delivery article and method of use
US8991387B2 (en) 2003-05-21 2015-03-31 Alexza Pharmaceuticals, Inc. Self-contained heating unit and drug-supply unit employing same
US9211382B2 (en) 2001-05-24 2015-12-15 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
US11642473B2 (en) 2007-03-09 2023-05-09 Alexza Pharmaceuticals, Inc. Heating unit for use in a drug delivery device
US12214118B2 (en) 2018-02-02 2025-02-04 Alexza Pharmaceuticals, Inc. Electrical condensation aerosol device

Citations (3)

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US3736315A (en) * 1966-12-09 1973-05-29 Egyt Gyogyszervegyeszeti Gyar 1-(3,4-dimethoxy-phenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5h-2,3-benzodi-azepine
US4322346A (en) * 1978-10-19 1982-03-30 Jeno Korosi 5H-2,3-Benzodiazepine derivatives
GB2248838A (en) * 1990-10-17 1992-04-22 Egyt Gyogyszervegyeszeti Gyar A new 5h-benzodiazepine derivative, pharmaceutical compositions containing same and process for preparing them

Patent Citations (3)

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US3736315A (en) * 1966-12-09 1973-05-29 Egyt Gyogyszervegyeszeti Gyar 1-(3,4-dimethoxy-phenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5h-2,3-benzodi-azepine
US4322346A (en) * 1978-10-19 1982-03-30 Jeno Korosi 5H-2,3-Benzodiazepine derivatives
GB2248838A (en) * 1990-10-17 1992-04-22 Egyt Gyogyszervegyeszeti Gyar A new 5h-benzodiazepine derivative, pharmaceutical compositions containing same and process for preparing them

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ANDRASI ET AL: "neuropharmacology of a new psychotropic 2,3-benzodiazepine", ARZNEIMITTELFORSCHUNG, vol. 37, no. 10, 1987, pages 1119 - 1124, XP002081293 *
BANKI: "comparative study with grandaxin and diazepam in alcohol withdrawal syndrome and gerontopsychiatric diseases", THER HUNGAR, vol. 31, no. 3, 1983, pages 120 - 125, XP002081298 *
BOSZORMENYI: "clinical and therapeutical problems of mild mental depressions", THERAP HUNGAR, vol. 23, no. 4, 1975, pages 156 - 162, XP002081297 *
HORVATH ET AL: "a new psychoactive 5H-2,3-benzodiazepine with a unique spectrum of activity", ARZNEIMITTELFORSCHUNG, vol. 39, no. 8, 1989, pages 894 - 899, XP002081294 *
KARDOS: "alcohol dependence, withdrawal syndrome and "tapering off" therapy", ORV HETIL, vol. 120, no. 39, 1979, pages 2343 - 2349, XP002081296 *
MOLCAN: "tofizopam in the therapy of anxious-depressive syndromes", AGRESSOLOGIE, vol. 22, 1981, pages 23 - 24, XP002081300 *
NAKAGAWA: "treatment of psychosomatic disorders", ASIAN MED J, vol. 33, no. 5, 1990, pages 250 - 258, XP002081301 *
POIRIER: "indications des benzodiazepines dans la prise en charge des toxicomanes", ANN MED INTERNE, vol. 145, no. 3, 1994, pages 52 - 53, XP002081299 *
VARADY ET AL: "clinical evaluation of grandaxin used in the treatment of outpatients", THERAP HUNGAR, vol. 23, no. 4, 1975, pages 153 - 158, XP002081295 *

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7585493B2 (en) 2001-05-24 2009-09-08 Alexza Pharmaceuticals, Inc. Thin-film drug delivery article and method of use
US10350157B2 (en) 2001-05-24 2019-07-16 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
US9440034B2 (en) 2001-05-24 2016-09-13 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
US7090830B2 (en) 2001-05-24 2006-08-15 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
US9211382B2 (en) 2001-05-24 2015-12-15 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
US9308208B2 (en) 2001-06-05 2016-04-12 Alexza Pharmaceuticals, Inc. Aerosol generating method and device
US9439907B2 (en) 2001-06-05 2016-09-13 Alexza Pharmaceutical, Inc. Method of forming an aerosol for inhalation delivery
US8955512B2 (en) 2001-06-05 2015-02-17 Alexza Pharmaceuticals, Inc. Method of forming an aerosol for inhalation delivery
US11065400B2 (en) 2001-06-05 2021-07-20 Alexza Pharmaceuticals, Inc. Aerosol forming device for use in inhalation therapy
US7537009B2 (en) 2001-06-05 2009-05-26 Alexza Pharmaceuticals, Inc. Method of forming an aerosol for inhalation delivery
US9687487B2 (en) 2001-06-05 2017-06-27 Alexza Pharmaceuticals, Inc. Aerosol forming device for use in inhalation therapy
US7458374B2 (en) 2002-05-13 2008-12-02 Alexza Pharmaceuticals, Inc. Method and apparatus for vaporizing a compound
AU2003263357B2 (en) * 2002-09-13 2009-02-26 Motac Neuroscience Limited Treatment of basal ganglia-related movement disorders with 2,3-benzodiazepines
US9370629B2 (en) 2003-05-21 2016-06-21 Alexza Pharmaceuticals, Inc. Self-contained heating unit and drug-supply unit employing same
US8991387B2 (en) 2003-05-21 2015-03-31 Alexza Pharmaceuticals, Inc. Self-contained heating unit and drug-supply unit employing same
US7540286B2 (en) 2004-06-03 2009-06-02 Alexza Pharmaceuticals, Inc. Multiple dose condensation aerosol devices and methods of forming condensation aerosols
US7581540B2 (en) 2004-08-12 2009-09-01 Alexza Pharmaceuticals, Inc. Aerosol drug delivery device incorporating percussively activated heat packages
US11642473B2 (en) 2007-03-09 2023-05-09 Alexza Pharmaceuticals, Inc. Heating unit for use in a drug delivery device
US12138383B2 (en) 2007-03-09 2024-11-12 Alexza Pharmaceuticals, Inc. Heating unit for use in a drug delivery device
US12214118B2 (en) 2018-02-02 2025-02-04 Alexza Pharmaceuticals, Inc. Electrical condensation aerosol device
US12214119B2 (en) 2018-02-02 2025-02-04 Alexza Pharmaceuticals, Inc. Electrical condensation aerosol device

Also Published As

Publication number Publication date
AU8553898A (en) 1999-02-16
HUP9701284A2 (hu) 1999-03-29
HU9701284D0 (en) 1997-09-29
HUP9701284A3 (en) 2005-11-28

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