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WO1993016696A1 - Utilisation de la brofaromine comme agent de traitement de la nevrose phobique - Google Patents

Utilisation de la brofaromine comme agent de traitement de la nevrose phobique Download PDF

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Publication number
WO1993016696A1
WO1993016696A1 PCT/US1993/000729 US9300729W WO9316696A1 WO 1993016696 A1 WO1993016696 A1 WO 1993016696A1 US 9300729 W US9300729 W US 9300729W WO 9316696 A1 WO9316696 A1 WO 9316696A1
Authority
WO
WIPO (PCT)
Prior art keywords
brofaromine
social phobia
treating
pharmaceutically acceptable
salt
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US1993/000729
Other languages
English (en)
Inventor
Richard Katz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
Original Assignee
Ciba Geigy AG
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 Ciba Geigy AG filed Critical Ciba Geigy AG
Publication of WO1993016696A1 publication Critical patent/WO1993016696A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine

Definitions

  • the present invention relates to psychological disorders clinically classified as phobia associated with social settings and their management.
  • the invention further deals witi brofaromine, a selective, reversible monoamine oxidase type A inhibitor, with serotonin uptake inhibitory properties.
  • Brofaromine is an Monoamine Oxidase (MAO) inhibitor antidepressant compound, first patented in the US in 1980 by Schenker et al. (US 4,210,655), which patent is incorporated herein by reference.
  • MAO Monoamine Oxidase
  • This patent states that brofaromine, i.e. 4-(5-methoxy-2- benzofuranyl)-piperidine, is a selective MAO type A inhibitor, blocks serotonin reuptake, and that the compound is useful in the treatment of depression.
  • This invention relates to the treatment of social phobia.
  • the disease state is characterized by:
  • the Journal of Clinical Psychiatry article mentions the use of classical MAO inhibitors as well as beta-adrenergic-blockers in the treatment of social phobia. This article specifically refers to the use of the MAO inhibitor phenelzine, and while the number of patients were small, the results tended to favor the MAO inhibitor.
  • moclobemide and brofaromine are selective, inhibitors of type A MAO. As such, one would expect reduced efficacy as compared to the classical MAO inhibitors since with moclobemide and brofaromine, type B MAO is still available to act in its normal course. Moclobemide also has a potential safety problem similar to the classical MAO inhibitors since its metabolite is an MAO type B inhibitor. MAO type B is primarily responsible for removing tyramine.
  • Another object of the invention is to provide a social phobia treatment and or a medicament for the treatment of social phobia which will reduce or eliminate the avoidant behavior of the disorder.
  • the present invention is a method of treating social phobia in a warm-blooded animal in need of such treatment comprising administering to said animal a social phobia treating effective amount of brofaromine or a pharmaceutically acceptable salt thereof.
  • Brofaromine and its pharmaceutically acceptable salts are disclosed in US Patent 4,210,655, which is incorporated herein by reference.
  • the cited patent also discloses the synthesis of brofaromine and its pharmaceutically acceptable salts, their uses in depression, their pharmaceutical compositions, antidepressant dosages, and routes of administration. All of this disclosure is applicable to the instant invention.
  • Especially preferred salts of brofaromine for use in the instant invention include, without limitation, the salts formed from the combination of brofaromine with one of the acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic , acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid, and embonic acid.
  • the salt is the hydrochloride.
  • Particularly advantageous dosage amounts and regimens are selected from about 0.1 to about 5.0 mg/kg, more preferably about 0.5 to about 2.0 mg kg, most preferably about 1.0 to about 1.5 mg/kg, given from 1 to 4 times a day in single or divided doses, more preferably from 1 to 3 times a day, and typically given orally or by intravenous injection twice daily.
  • compositions of brofaromine contain 25 to 100 mg, preferably 50 or 75 mg of brofaromine per dosage unit intended for mammals of 40 to 70 kg.
  • the compositions typically contain generally acceptable pharmaceutical carriers, such as lactose, saccharose, sorbitol, and mannitol; starches, such as potato starch, co starch, and amylopectin; cellulose derivatives; or gelatin.
  • the compositions may also contain a lubricant, such as magnesium stearate, calcium stearate, or polyethylene glycol.
  • Other standard agents used in the manufacture of tablets, capsules, or intravenous solutions may also be present as appropriate.
  • Example 1 An adult individual suffering from a social phobia and satisfying the DSM-IU-R criteria for social phobia is given brofaromine hydrochloride (in an amount sufficient to administer 50 mg of free brofaromine) twice daily. The normally present psychological anxiety and avoidant behavior of the condition are all significantly reduced.
  • Example 2 Tablets, each comprising 50 mg of 4-(7-bromc ⁇ 5-me ⁇ oxyben__)_ur_n-2-yl)- piperidine or of a salt, for example the hydrochloride, thereof, can be prepared as follows:
  • composition (10000 tablets)
  • active ingredient 500.0 g lactose 1000.0 g potato starch 852.0 g gelatin 8.0 g talc 60.0 g magnesium stearate 10.0 g silica (highly disperse) 20.0 g ethanol q.s.
  • the active ingredient is mixed with the lactose and 792 g of potato starch, and the mixture is moistened with an ethanolic solution of the gelatin and granulated through a sieve. After drying, the remaining potato starch, the magnesium stearate, the talc and the silica are mixed in and the mixture is compressed to form tablets which each weigh 295.0 mg and comprise 50.0 mg of active ingredient, and which may, if desired, be provided with dividing notches for finer adjustment of the dose.
  • Example 3 Film-coated tablets, each comprising 50 mg of 4-(7-bromo-5-methoxybenzo- furan-2-yl)piperidine or of a salt, for example the hydrochloride, thereof, can be prepared as follows:
  • composition for 1000 film-coated tablets '
  • active ingredient 50.0 g lactose 200.0 g corn starch 120.0 g talc 17.0 g calcium stearate 10.0 g hydroxypropylmethylcellulose 2.36 g shellac 0.64 g water q.s. methylene chloride q.s.
  • the active ingredient, the lactose and 90 g of the com starch are mixed, and the mixture is moistened with a paste, prepared from 30 g of corn starch and water (with heating), and granulated.
  • the granules are dried, and the remaining com starch, the talc and the calcium stearate are added and mixed with the granules.
  • the mixture is compressed to form tablets (weight: 400 mg), which are coated with a solution of the hydroxypropylmethylcellulose and the shellac in methylene chloride; final weight of each film-coated tablet: 583 mg.
  • Example 4 Hard gelatin capsules, each containing 500 mg of 4-(7-bromo-5-methoxy- benzofuran-2-yl)piperidine or of a salt, for example the hydrochloride, thereof, can be prepared, for example, as follows:
  • Composition for 1000 capsules
  • active ingredient 500.0 g lactose 250.0 g microcrystalline cellulose 30.0 g sodium lauryl sulfate 2.0 g magnesium stearate 8.0 g
  • the sodium lauryl sulfate is added to the lyophilised active ingredient through a sieve having a mesh size of 0.2 mm.
  • the two components are mixed intimately.
  • the lactose is added through a sieve having a mesh size of 0.6 mm and then the micro ⁇ crystalline cellulose through a sieve having a mesh size of 0.9 mm.
  • the mixture is mixed intimately again for 10 minutes.
  • the magnesium stearate is added through a sieve having a mesh size of 0.8 mm.
  • hard gelatin capsules of a suitable size are each filled with 790 mg of the resulting formulation.
  • Example 5 A 5 % injection or infusion solution of 4-(7-bro__o-5-methoxybenzof uran-2- yl)piperidine or of a salt, for example the hydrochloride, thereof can be prepared, for example, as follows:
  • composition for 1000 or 400 ampoules
  • the active ingredient and the sodium chloride are dissolved in 1000 ml of water and filtered through a microfilter.
  • the buffer solution is added, and the mixture is made up to 2500 ml with water.
  • To prepare unit dose forms 1.0 or 2.5 ml are introduced into each glass ampoule, which then contains 50 or 125 mg, respectively, of active ingredient.

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)

Abstract

L'invention concerne un procédé de traitement de la névrose phobique chez un animal à sang chaud nécessitant ce traitement, et qui consiste à administrer audit animal une quantité efficace de brofaromine ou d'un sel pharmaceutiquement acceptable de celle-ci pour traiter la névrose phobique.
PCT/US1993/000729 1992-02-21 1993-01-27 Utilisation de la brofaromine comme agent de traitement de la nevrose phobique Ceased WO1993016696A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US83964392A 1992-02-21 1992-02-21
US07/839,643 1992-02-21

Publications (1)

Publication Number Publication Date
WO1993016696A1 true WO1993016696A1 (fr) 1993-09-02

Family

ID=25280298

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1993/000729 Ceased WO1993016696A1 (fr) 1992-02-21 1993-01-27 Utilisation de la brofaromine comme agent de traitement de la nevrose phobique

Country Status (2)

Country Link
AU (1) AU3595093A (fr)
WO (1) WO1993016696A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU676672B2 (en) * 1992-02-21 1997-03-20 Novartis Ag Brofaromine as an agent for treating post-traumatic stress

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0499586A1 (fr) * 1991-02-15 1992-08-19 Ciba-Geigy Ag Benzofuranyl pipéridine substitué comme agent nootropique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0499586A1 (fr) * 1991-02-15 1992-08-19 Ciba-Geigy Ag Benzofuranyl pipéridine substitué comme agent nootropique

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
Abstracts of the 17th Congress of CINP (Collegium Internationale Neuro-Psycho pharmacologicum). Kyoto, Japan, 10-14th Sept. 1990. Vol. 1, p. 140, abs. O-12-7-6. I.M. van VLIET et al., 'The efficacy of a reversible MAO inhibitor, brofaromine, in social phobia'. *
DRUGS OF THE FUTURE vol. 10, no. 5, 1985, pages 371 - 373 P.C. WALDMEIER 'Brofaremine hydrochloride.' *
EUR. NEUROPSYCHOPHARMACOL. vol. 2, no. 1, March 1992, pages 21 - 29 I.M. VAN VLIET 'Psychopharmacological treatment of social phobia: clinical and biochemical effects of brofaromine, a selective MAO-A inhibitor.' *
EUR. PSYCHIATRY vol. 7, no. 2, 1992, pages 93 - 94 D. GARCIA-BORREGUERO, 'Improvement of social phobic symptoms after treatment with brofaromine, a reversible and selective inhibitor of MAO-A.' *
PROG. NEUROPSYCHOPHARMACOL. BIOL. PSYCHIATR. vol. 16, no. 5, 1992, pages 635 - 646 N.L.S. POTTS, 'Social phobia: Biological aspects and pharmacotherapy.' *
STN INTERNATIONAL, KARLSRUHE. FILE PHAR, PHARMAPROJECTS. AN=1891 PHAR. "Brofaromine". *

Also Published As

Publication number Publication date
AU3595093A (en) 1993-09-13

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