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WO2005013969A1 - Agent antipsychotique a proprietes favorisant la socialisation - Google Patents

Agent antipsychotique a proprietes favorisant la socialisation Download PDF

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Publication number
WO2005013969A1
WO2005013969A1 PCT/EP2004/007838 EP2004007838W WO2005013969A1 WO 2005013969 A1 WO2005013969 A1 WO 2005013969A1 EP 2004007838 W EP2004007838 W EP 2004007838W WO 2005013969 A1 WO2005013969 A1 WO 2005013969A1
Authority
WO
WIPO (PCT)
Prior art keywords
dogs
compound
socializing
properties
social
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/EP2004/007838
Other languages
English (en)
Inventor
Antonius Adrianus Hendrikus Petrus Megens
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.)
Janssen Pharmaceutica NV
Original Assignee
Janssen Pharmaceutica NV
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 Janssen Pharmaceutica NV filed Critical Janssen Pharmaceutica NV
Publication of WO2005013969A1 publication Critical patent/WO2005013969A1/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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

  • This invention concerns the use of the combination of a predominant 5HT2c antagonist and a D2 antagonist for use as an antipsychotic with socializing properties.
  • the invention more specifically concerns the use of a compound of formula (I), its pharmaceutically acceptable salts, more preferably the tartrate and mandelate salts for the preparation of a medicament with socializing properties for treating schizophrenia.
  • the compounds of formula (A) may be used as therapeutic agents in the treatment or the prevention of C ⁇ S disorders, cardiovascular disorders or gastrointestinal disorders.
  • WO 99/19317 discloses compounds of formula (B)
  • the compounds of formula (B) may be used as therapeutic agents.
  • WO 03/040122 discloses novel mandelate salts of a substituted tetracyclic tetrahydrofuran derivative according to Formula (C)
  • the novel mandelate salt is not light-sensitive and is far more stable than the prior art salts at room temperature, enhanced temperature and at relative high humidities and in aqueous media.
  • pharmaceutical compositions comprising mandelate salts according to the invention, mandelate salts according to the invention for use as a medicine, a process for preparing the mandelate salts according to the invention and the use of the mandelate salts and pharmaceutical compositions comprising mandelate salts according to the invention for the treatment or the prevention of C ⁇ S disorders, cardiovascular disorders and gastrointestinal disorders.
  • the present compound unexpectedly also has socializing properties next to its antispychotic activity, due to the pharmacological profile.
  • the compound of formula (I) is a predominant 5HT2c antagonist.
  • Central 5HT2c antagonism is the basis for its ability to antagonize the anxiety-like effects induced by the serotonin agonist meta-chlorophenylpiperazine (mCPP) in animals.
  • mCPP antagonism starts already at low doses of compound of formula (I) and is complete (i.e., resulting in full normalisation of the behavior) at doses just below those inducing the behavioral depression that results from the progressively increasing occupancy of central D2 receptors ( Figure 1). Based on this predominant mCPP antagonism in rats, the compound of formula (I) can be differentiated from other available antispychotics.
  • mCPP also induces symptoms of anxiety in man, which show a prolonged duration in schizophrenic patients as compared with healthy subjects. In schizophrenics, moreover, mCPP increases positive symptoms.
  • the anxiolytic activity suggested by mCPP antagonism in animals may thus contribute to therapeutic effects in schizophrenia, in particular to effects against negative and affective symptoms.
  • the compound of formula (I) has been found to induce 'socializing' effects in dogs. These 'socializing' effects are predominantly related to anxiolytic and/or 'disinhibiting' effects arising from central 5HT2c antagonism.
  • the most preferred compounds are the (+)-L-tartrate salt and the (S) mandelate salt form of the ( ⁇ )(2 ⁇ ,3a ,12b ⁇ )-forms of the structure of formula (I) (11-fluoro- 3,3a,8,12b-tetrahydro-N-methyl-2H-dibenzo-[3,4:6,7]cyclohepta-[l,2-b]furan-2 methanamine), more specifically the 2R-(2 ⁇ ,3a ,12b ⁇ ) isomer of the structure of formula (I).
  • An effective therapeutic daily amount would be from about 0.01 mg/kg to about 10 mg kg body weight, more preferably from about 0.05 mg/kg to about 1 mg/kg body weight.
  • the subject compounds may be formulated into various pharmaceutical forms for administration purposes.
  • a therapeutically effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration.
  • a pharmaceutically acceptable carrier which may take a wide variety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally, percutaneously, or by parenteral injection.
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed.
  • the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
  • Injectable solutions may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
  • Injectable solutions containing compounds of formula (I) may be formulated in an oil for prolonged action.
  • Appropriate oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soy bean oil, synthetic glycerol esters of long chain fatty acids and mixtures of these and other oils.
  • Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
  • These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment. Acid or base addition salts of compounds of formula (I) due to their increased water solubility over the conesponding base or acid form, are more suitable in the preparation of aqueous compositions.
  • Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier.
  • dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
  • test compounds were prepared as solutions either in distilled water (Compound 1), in distilled water containing one equivalent (haloperidol) or two equivalents
  • each pair of dogs was taken out of the experimental cages separately from the other dogs at 0.5 h, 1 h, 2 h and 4 h after injection and allowed to walk together throughout the experimental room and adjacent corridor.
  • the starting dose for each compound was 0.31 mg/kg, bv.
  • lower doses selected from the geometrical series 0.005-0.02-0.08-0.31 mg/kg
  • At least this dose and a four times higher dose (inducing a clear behavioral effect) were tested on 5 pairs of dogs.
  • ED 50 values and corresponding 95% confidence limits were estimated according to the method of Finney for categorical data.
  • Haloperidol induced dose-dependent sedation (ED 5 o: 0.030 mg kg) and catalepsy (in 2 and 4 out of 10 dogs tested at 0.02 and 0.08 mg/kg, respectively); compulsive biting was observed in 2 out of 10 dogs tested at 0.08 mg/kg. Social attention was not and social whining was only occasionally observed (in 2 out of 10 dogs tested at 0.08 mg/kg).
  • Olanzapine dose-dependently induced sedation [EDs 0 : 0.16 mg kg]; at 0.31 mg/kg, 4 out of 10 dogs displayed compulsive scratching and biting behavior and 3 dogs tended to show aggressive behavior (score -1 for social behavior).
  • Compound 1 can be differentiated from saline, haloperidol, risperidone and olanzapine, based on socializing effects in dogs. Disregarding its exact nature and mechanism of action, this apparent socializing effect might be a valuable property in the treatment of schizophrenic patients.

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation de la combinaison d'un antagoniste 5HT2c et d'un antagoniste D2 prédominants comme antipsychotique, présentant des propriétés favorisant la socialisation. L'invention concerne, de manière plus spécifique, l'utilisation d'un composé de formule (I), ses sels pharmaceutiquement acceptables, de préférence des sels de tartrate et de mandélate permettant de préparer un médicament à propriétés favorisant la socialisation pour traiter la schizophrénie.
PCT/EP2004/007838 2003-07-15 2004-07-12 Agent antipsychotique a proprietes favorisant la socialisation Ceased WO2005013969A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP03077225 2003-07-15
EP03077225.5 2003-07-15

Publications (1)

Publication Number Publication Date
WO2005013969A1 true WO2005013969A1 (fr) 2005-02-17

Family

ID=34130218

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2004/007838 Ceased WO2005013969A1 (fr) 2003-07-15 2004-07-12 Agent antipsychotique a proprietes favorisant la socialisation

Country Status (1)

Country Link
WO (1) WO2005013969A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006125812A1 (fr) * 2005-05-26 2006-11-30 Janssen Pharmaceutica N.V. Nouveaux derives de tetrahydrothiophene, pyrolidine et tetrahydrofurane tetracyclique substitues et leur utilisation en tant que medicament
US10770072B2 (en) 2018-12-10 2020-09-08 International Business Machines Corporation Cognitive triggering of human interaction strategies to facilitate collaboration, productivity, and learning

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998004289A2 (fr) * 1996-07-26 1998-02-05 Smithkline Beecham Plc Composition pharmaceutique contenant un antagoniste 5ht2c et un antagoniste d¿2?
WO2003040122A1 (fr) * 2001-11-09 2003-05-15 Janssen Pharmaceutica N.V. Nouveaux sels mandelates de derives de tetrahydrofuranes tetracycliques substitues
WO2003048146A1 (fr) * 2001-12-07 2003-06-12 Janssen Pharmaceutica N.V. Preparation de derives de 3,3a,8,12b-tetrahydro-2h-dibenzo[3,4:6,7]cyclohepta[1,2-b]furane a fusion trans

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998004289A2 (fr) * 1996-07-26 1998-02-05 Smithkline Beecham Plc Composition pharmaceutique contenant un antagoniste 5ht2c et un antagoniste d¿2?
WO2003040122A1 (fr) * 2001-11-09 2003-05-15 Janssen Pharmaceutica N.V. Nouveaux sels mandelates de derives de tetrahydrofuranes tetracycliques substitues
WO2003048146A1 (fr) * 2001-12-07 2003-06-12 Janssen Pharmaceutica N.V. Preparation de derives de 3,3a,8,12b-tetrahydro-2h-dibenzo[3,4:6,7]cyclohepta[1,2-b]furane a fusion trans

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SEEGER T F ET AL: "ZIPRASIDONE (CP-88,059): A NEW ANTIPSYCHOTIC WITH COMBINED DOPAMINEAND SEROTONIN RECEPTOR ANTAGONIST ACTIVITY", JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, AMERICAN SOCIETY FOR PHARMACOLOGY AND, US, vol. 275, no. 1, 1995, pages 101 - 113, XP002051730, ISSN: 0022-3565 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006125812A1 (fr) * 2005-05-26 2006-11-30 Janssen Pharmaceutica N.V. Nouveaux derives de tetrahydrothiophene, pyrolidine et tetrahydrofurane tetracyclique substitues et leur utilisation en tant que medicament
US10770072B2 (en) 2018-12-10 2020-09-08 International Business Machines Corporation Cognitive triggering of human interaction strategies to facilitate collaboration, productivity, and learning

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