WO1997023477A1

WO1997023477A1 - Dibenzothiepin derivatives and pharmaceutical compositions

Info

Publication number: WO1997023477A1
Application number: PCT/EP1996/005631
Authority: WO
Inventors: Stephen Jason Cooper; David John King; Joher Raniwalla
Original assignee: Knoll GmbH
Current assignee: Abbott GmbH and Co KG
Priority date: 1995-12-21
Filing date: 1996-12-16
Publication date: 1997-07-03
Anticipated expiration: 1998-06-21
Also published as: ZA9610761B; EP0874840A1; HRP960600A2; AU1195597A; GB9526264D0

Abstract

A compound of formula (I) or a pharmaceutically acceptable salt thereof in which R1 and R2 are independently H or methyl (for example 2-[(8-chlorodibenzo[b,f]thiepin-10-yl)oxy]-N,N-dimethylethyl-amine) is used for preventing relapse in chronic schizophrenic patients.

Description

DIBENZOTHIEPIN DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS

This invention relates to a method for preventing relapse in chronic schizophrenic patients.

According to the present invention there is provided a method for preventing relapse in chronic schizophrenic patients which comprises the administration of a therapeutically effective amount of a compound of formula I

or pharmaceutically acceptable salts thereof in which R₁ and R₂ 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.

The preparation and psychotropic and neurotropic activity of compounds of . formula I, such as 2-[(8-chlorodibenzo[b,f]thiepin-10-yl)oxy]-N_rN-dimethylethylamine and salts thereof, is described in British Patent Specification 1247067 (Fujisawa). The use of compounds of formula I such as 2-[(8-chlorodibenzo[b,f]thiepin-10-yl)oxy]-N,N- dimethyiethylamine and salts thereof in the treatment of gout is described in United States patent specification 4,443,469 (Fujisawa). 2-[(8-Chlorodibenzo[b,f]thiepin-10- yl)oxy]-N,jN-dimethylethylamine has been available on prescription for the treatment of schizophrenia in Japan since 1982 under the tradename "Lodopin®", and in Germany since 1990 under the tradename "Nipolept®". 2-[(8-Ch.orodibenzo[b,f]thiepin-10- yl)oxy]-N,N-dimethylethylamine is also known as zotepine.

Many drugs are known to be useful in the treatment of schizophrenia. However, the potential for relapse in chronic schizophrenic patients remains a problem. The ability of drugs to prevent relapse is a highly desirable advantage for schizophrenia treatments. Surprisingly it has now been found that administration of a compound of formula I is useful in the prevention of relapse in schizophrenic patients.

The term 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. Similarly, 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. Other 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. Altematively 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.

In some formulations it may be beneficial to use the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling.

In the compositions of the present invention 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.

In a further aspect, 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. In yet another aspect, 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

or a pharmaceutically acceptable salt thereof in which R-| and R₂ 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.

The ability of zotepine to prevent relapse in chronic schizophrenia is illustrated by the following clinical investigation.

In a clinically supervised study, 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.

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.

The term "relapse" was defined in the study as follows: at weeks 2, 4, 8, 16,

20 and 26 the patients were assessed using the five assessment scales namely BPRS, CGI Severity, SANS, AIMS (Abnormal Involuntary Movement Scale) and EPMS

(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.

a) Has there been deterioration requiring hospitalisation?. This must include an increase in CGI severity score of at least 2 points with an increase in score of 2 points on at least 2 positive symptoms items on BPRS

b) Has there been a SEVERE deterioration for 24 hours (ie to CGI score of Severely III), or if in hospital, deterioration to the point of requiring special nursing observation because of suicidal or aggressive behaviour?

c) Has the BPRS score increased by 2 points on at least two of the positive symptoms and the Clinical Global Severity score increased by 2 points or more?

If the patient showed deterioration requiring hospitalisation (a) or severe deterioration (b), this was defined as a relapse and the withdrawal/relapse assessment and final evaluation forms were completed. An increase by 2 points on at least two of the positive symptoms of the BPRS score with an increase in score of 2 points in the ^' Clinical Global Severity score (c) was defined as clinical deterioration of a moderate degree. In this case the additional BPRS and CGI scales were completed 2 days later. A second result of clinical deterioration of a moderate degree was defined as a relapse and the withdrawal/relapse assessment and final evaluation forms were completed. If the criteria above, (a) or (b) or (c), were not met then the patient had not relapsed and therefore remained in the study.

A total of 121 patients entered the double-blind phase of the study; 63 were randomised to receive zotepine and 58 to receive placebo. During the 26 week course of the study 25 patients relapsed, 4 (6.3%) from the zotepine group and 21 (36.2%) from the placebo group. Patients in the zotepine group relapsed less frequently than patients in the placebo group and the difference in the rate of relapse between the treatment groups was statistically significant (intent-to-treat analysis p=0.0001). It appears that the distribution of relapse is even between week 1-16 in the placebo group while in the week of treatment in the zotepine group the majority of relapses occur (3 patients out of 4). 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.

The change in mean total BPRS score from baseline to endpoint (week 26, last observation carried forward (LOCF) dataset) was reduced in the zotepine group by 5.7 and increased by 1.8 in the placebo group. This difference was statistically significant at p=0.0078. This result is supported by the results of change from baseline to week 26 for most BPRS subscores (LOCF analysis), the CGI improvement scale and the CGI severity scale. These scales demonstrated there was a greater improvement in the zotepine treatment group compared to the placebo treatment group.

The results of the study are illustrated in Tables 1 and 2. Figure 1 (see end) shows the mean profile of change from baseline in BPRS total score, with last observation carried forward, for intent-to-treat data.

Table 1 Relapse Rate

Treatment group Intent-to-treat Relapse rate at 26 weeks

Zotepine 4 patients

Placebo 21 patients

Hazard ratio^* 0.160

P-value for treatment 0.0001

^* risk of relapse relative to placebo. Hazard ratio <1 indicates less risk of relapse at any time on zotepine.

Table 2

BPRS Total Score

Treatment group Endpoint based on LOCF data at week 26

Zotepine (B) -5.7

Placebo (A) 1.8

95.5% Confidence Intervals (A -13.5 to -1.9 ^* versus B)

P-value for treatment 0.0078

* indicates a statistically significant difference between zotepine and placebo at the 4.5% level.

It can be seen from these results that there is a significant improvement in the relapse rates in the patients treated with zotepine compared to those treated with placebo. This indicates the utility of compounds of formula I, such as zotepine, in the prevention of relapse in chronic schizophrenia.

Claims

1. A method of preventing relapse in chronic schizophrenic patients which comprises administering to a human in need thereof a therapeutically effective amount of a compound of formula I

or pharmaceutically acceptable salts thereof in which R^ and R₂ are independently H or methyl in conjunction with a pharmaceutically acceptable diluent or carrier.

2. A method as claimed in claim 1 wherein the compound of formula I is 2-[(8- chlorodibenzo[b,f]thiepin-10-yl)oxy]-N,N-dimethylethylamine.

3. A compound of formula I

or a pharmaceutically acceptable salt thereof in which R^ and R₂ are independently H or methyl for use in preventing relapse in chronic schizophrenic patients.

4. 2-[(8-Chlorodibenzo[b,f3thiepin-10-yl)oxy]-N,N-dimethylethylamine for use in preventing relapse in chronic schizophrenic patients.

5. The use of a compound of formula I

or a pharmaceutically acceptable salt thereof in which R-, and R₂ are independently H or methyl in the manufacture of a medicament for preventing relapse in chronic schizophrenic patients.

6. The use of 2-[(8-chlorodιbenzo[b,f]thιepιn-10-yl)oxy]-N,N-dιmethylethylamιne in the manufacture of a medicament for preventing relapse in chronic schizophrenic patients.

7 A pharmaceutical composition for preventing relapse in chronic schizophrenic patients comprising a therapeutically effective amount of a compound of formula I

or a pharmaceutically acceptable salt thereof in which R^ and R₂ are independently H or methyl, as a main ingredient, in conjunction with a pharmaceutically acceptable diluent or carrier

8 A pharmaceutical composition for preventing relapse in chronic schizophrenic patients comprising a therapeutically effective amount of 2-[(8- chlorodιbenzo[b,f]thιepιn-10-yl)oxy]-N,N-dιmethylethylamιne as a mam ingredient, in conjunction with a pharmaceutically acceptable diluent or carrier.

9. Use of a compound of formula I

or a pharmaceutically acceptable salt thereof in which R₁ and R₂ are independently H or methyl, characterised in that it is used in the prevention of relapse in chronic schizophrenic patients

10. Use of 2-[(8-chlorodibenzo[b,f]thiepin-10-yl)oxy]- l,N-dimethylethylamine, characterised in that it is used in the preparation of a composition for the prevention of relapse in chronic schizophrenic patients.

11. A pharmaceutical composition for preventing relapse in chronic schizophrenic patients comprising a therapeutically effective amount of a compound of formula I

or a pharmaceutically acceptable salt thereof in which R-_\ and R₂ are independently H or methyl, prepared by a process known per se, in conjunction with a pharmaceutically acceptable diluent or carrier.

12. A pharmaceutical composition for preventing relapse in chronic schizophrenic patients comprising a therapeutically effective amount of 2-[(8- chlorodibenzo[b,f]thiepin-10-yl)oxy]-N,N-dimethylethylamιne, prepared by a process known per se, in conjunction with a pharmaceutically acceptable diluent or carrier.