Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
  • C07D337/02—Seven-membered rings
  • C07D337/06—Seven-membered rings condensed with carbocyclic rings or ring systems
  • C07D337/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
  • C07D337/14—[b,f]-condensed
• • 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
  • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom

Definitions

• This invention relates to a method for preventing relapse in chronic schizophrenic patients.
• R 1 and R 2 are independently H or methyl in conjunction with a pharmaceutically acceptable diluent or carrier to a patient in need thereof.
• a preferred compound of formula I is 2-[(8-chlorodibenzo[b,f]thiepin-10-yl)oxy]-
• N,N-dimethylethylamine or a pharmaceutically acceptable salt thereof is N,N-dimethylethylamine or a pharmaceutically acceptable salt thereof.
• relapse may be defined as a recurrence of symptoms of schizophrenia, such as hallucinations, delusions and thought disturbances, which may lead to behaviours such as suicidal or aggressive behaviour, and social withdrawal, despite therapeutic treatment with a compound useful in the treatment of schizophrenia, and may result in hospitalisation or an increased level of care.
• the compound of formula I may be administered in any of the known pharmaceutical dosage forms.
• the amount of the compound to be administered will depend on a number of factors including the age of the patient, the severity of the condition and the past medical history of the patient and always lies within the sound discretion of the administering physician but it is generally envisaged that the dosage of the compound to be administered will be in the range 0.1 to 500 mg preferably 75 to 450 mg per day given in one or more doses.
• Oral dosage forms are the preferred compositions for use in the present invention and these are the known pharmaceutical forms for such administration, for example tablets, capsules, granules, syrups and aqueous or oil suspensions and solutions.
• the excipients used in the preparation of these compositions are the excipients known in the pharmacist's art.
• Tablets may be prepared from a mixture of the active compound with fillers, for example lactose or calcium phosphate; dis ⁇ integrating agents, for example maize starch or croscarmellose sodium; lubricating agents, for example magnesium stearate; binders, for example microcrystalline cellulose, hydroxypropylcellulose or polyvinylpyrrolidone and other optional ingredients known in the art to permit tableting the mixture by known methods.
• the tablets may be formulated in a manner known to those skilled in the art so as to give a sustained release of the compounds of the present invention.
• Such tablets may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate or hydroxypropylmethylcellulose phthalate.
• capsules for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by known methods and, if desired, provided with enteric coatings in a known manner. The contents of the capsule may be formulated using known methods so as to give sustained release of the active compound.
• dosage forms for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxymethylcellulose, and oily suspensions containing a compound of the present invention in a suitable vegetable oil, for example sesame oil.
• the active compound may be formulated into granules with or without additional excipients.
• the granules may be ingested directly by the patient or they may be added to a suitable liquid carrier (for example, water) before ingestion.
• the granules may contain disinteg rants, eg an effervescent couple formed from an acid and a carbonate or bicarbonate salt to facilitate dispersion in the liquid medium.
• the therapeutically active compounds of formula I may be formulated into a composition which the patient retains in his mouth so that the active compound is administered through the mucosa of the mouth.
• Dosage forms suitable for rectal administration are the known pharmaceutical forms for such administration, for example, suppositories with cocoa butter or polyethylene glycol bases.
• Dosage forms suitable for parenteral administration are the known pharmaceutical forms for such administration, for example sterile suspensions or sterile solutions in a suitable solvent, for immediate or sustained release.
• Dosage forms for topical administration may comprise a matrix in which the pharmacologically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally.
• a suitable transdermal composition may be prepared by mixing the pharmaceutically active compound with a topical vehicle, such as a mineral oil, petrolatum and/or a wax, e.g. paraffin wax or beeswax, together with a potential transdermal accelerant such as isopropylmiristate, dimethyl sulphoxide or propylene glycol.
• a topical vehicle such as a mineral oil, petrolatum and/or a wax, e.g. paraffin wax or beeswax
• a potential transdermal accelerant such as isopropylmiristate, dimethyl sulphoxide or propylene glycol.
• the active compounds may be dispersed in a pharmaceutically acceptable cream, gel or ointment base.
• the amount of active compound contained in a topical formulation should be such that a therapeutically effective amount of the compound is delivered during the period of time for which the topical formulation is intended to be on the skin.
• the therapeutically active compound of formula I may be formulated into a composition which is dispersed as an aerosol into the patients oral or nasal cavity. Such aerosols may be administered from a pump pack or from a pressurised pack containing a volatile propeilant.
• the therapeutically active compounds of formula I used in the method of the present invention may also be administered by continuous infusion either from an external source, for example by intravenous infusion or from a source of the compound placed within the body.
• Internal sources include implanted reservoirs containing the compound to be infused which is continuously released for example by osmosis and implants which may be (a) liquid such as an oily suspension of the compound to be infused for example in the form of a very sparingly water-soluble derivative or (b) solid in the form of an implanted support, for example of a synthetic resin or waxy material, for the compound to be infused.
• the support may be a single body containing all the compound or a series of several bodies each containing part of the compound to be delivered.
• the amount of active compound present in an internal source should be such that a therapeutically effective amount of the compound is delivered over a long period of time.
• the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling.
• the active compound may, if desired, be associated with other compatible pharmacologically active ingredients.
• the present invention also includes a compound of formula I, preferably 2-[(8- chlorodibenzo[b,f]thiepin-10-yl)oxy]-N,N-dimethylethylamine, for use in preventing relapse in chronic schizophrenic patients.
• the present invention includes the use of a compound of formula I, preferably 2-[(8-chlorodibenzo[b,f]thiepin-10-yl)oxy]-N,N-dimethylethylamine, in the manufacture of a medicament for preventing relapse in chronic schizophrenic patients.
• the present invention includes a pharmaceutical composition for preventing relapse in chronic schizophrenic patients comprising a therapeutically effective amount of a compound of formula I
• and R 2 are independently H or methyl, preferably 2-[(8-chlorodibenzo[b,f]thiepin-10-yl)oxy]-N,N-dimethylethyl- amine, in conjunction with a pharmaceutically acceptable diluent or carrier.
• patients were selected according to the DSM- lll-R criteria for diagnosis of chronic schizophrenia. In addition, all patients had to have relapsed in the preceding 18 months and had to have a score of 3 or more (ie be at least mildly ill) according to the Clinical Global Impression (CGI) severity scale. Patients were treated initially with 150 mg daily of zotepine, or placebo, with dose titration up to 300 mg daily during the first week of treatment but could go down again to 150 mg. The study was carried out over a 26-week treatment period.
• CGI Clinical Global Impression
• the principal measure of the efficacy of zotepine in preventing relapse was the time taken to relapse. Assessments were made at weeks O(baseline), 2, 4, 8, 16, 20 and 26. Efficacy was also assessed using the Brief Psychiatric Rating Scale (BPRS), the Scale for Assessment of Negative Symptoms (SANS), and the Clinical Global Impression (CGI) severity scale at each visit, and the CGI for improvement from week 1 onwards.
• BPRS Brief Psychiatric Rating Scale
• SANS Scale for Assessment of Negative Symptoms
• CGI Clinical Global Impression
• the patients were assessed using the five assessment scales namely BPRS, CGI Severity, SANS, AIMS (Abnormal Involuntary Movement Scale) and EPMS
• relapse questionnaire (Simpson and Angus extrapyramidal scale). A relapse questionnaire and the CGI global improvement scale were also used at each assessment. The relapse questionnaire consisted of the following three items recorded as either yes or no answers.
• the relapse rate for patients receiving 150 mg zotepine was similar to those receiving 300 mg, that is 1 patient out of 16 (6.3%) and 3 patients out of 45 (6.7%) respectively.
• Figure 1 shows the mean profile of change from baseline in BPRS total score, with last observation carried forward, for intent-to-treat data.
• Hazard ratio ⁇ 1 indicates less risk of relapse at any time on zotepine.
• * indicates a statistically significant difference between zotepine and placebo at the 4.5% level.

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

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Cited By (3)

Citations (2)

• 1995
  • 1995-12-21 GB GBGB9526264.8A patent/GB9526264D0/en active Pending
• 1996
  • 1996-12-16 AU AU11955/97A patent/AU1195597A/en not_active Abandoned
  • 1996-12-16 EP EP96943126A patent/EP0874840A1/de not_active Withdrawn
  • 1996-12-16 WO PCT/EP1996/005631 patent/WO1997023477A1/en not_active Application Discontinuation
  • 1996-12-19 HR HRP960600 patent/HRP960600A2/hr not_active Application Discontinuation
  • 1996-12-20 ZA ZA9610761A patent/ZA9610761B/xx unknown

Patent Citations (2)

Non-Patent Citations (11)

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