EP0874840A1 - Dibenzothiepin derivatives and pharmaceutical compositions - Google Patents
Dibenzothiepin derivatives and pharmaceutical compositionsInfo
- Publication number
- EP0874840A1 EP0874840A1 EP96943126A EP96943126A EP0874840A1 EP 0874840 A1 EP0874840 A1 EP 0874840A1 EP 96943126 A EP96943126 A EP 96943126A EP 96943126 A EP96943126 A EP 96943126A EP 0874840 A1 EP0874840 A1 EP 0874840A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- pharmaceutically acceptable
- compound
- relapse
- schizophrenic patients
- formula
- 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.)
- Withdrawn
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 7
- 150000008510 dibenzothiepins Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 49
- HDOZVRUNCMBHFH-UHFFFAOYSA-N zotepine Chemical compound CN(C)CCOC1=CC2=CC=CC=C2SC2=CC=C(Cl)C=C12 HDOZVRUNCMBHFH-UHFFFAOYSA-N 0.000 claims abstract description 23
- 230000000698 schizophrenic effect Effects 0.000 claims abstract description 19
- 230000001684 chronic effect Effects 0.000 claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 10
- 239000003085 diluting agent Substances 0.000 claims description 7
- -1 8-chlorodibenzo[b,f]thiepin-10-yl Chemical group 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 239000004615 ingredient Substances 0.000 claims description 2
- 239000002075 main ingredient Substances 0.000 claims 1
- 238000011282 treatment Methods 0.000 description 16
- 229960004496 zotepine Drugs 0.000 description 15
- 239000000902 placebo Substances 0.000 description 12
- 229940068196 placebo Drugs 0.000 description 12
- 201000000980 schizophrenia Diseases 0.000 description 8
- 230000006866 deterioration Effects 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 239000008187 granular material Substances 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
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- 206010001488 Aggression Diseases 0.000 description 2
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- 206010065604 Suicidal behaviour Diseases 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
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- 238000009505 enteric coating Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 235000019271 petrolatum Nutrition 0.000 description 2
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 206010012239 Delusion Diseases 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 208000004547 Hallucinations Diseases 0.000 description 1
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
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- 230000006399 behavior Effects 0.000 description 1
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- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 231100000868 delusion Toxicity 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- DAZXVJBJRMWXJP-UHFFFAOYSA-N n,n-dimethylethylamine Chemical compound CCN(C)C DAZXVJBJRMWXJP-UHFFFAOYSA-N 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 230000002276 neurotropic effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000000474 nursing effect Effects 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 235000019809 paraffin wax Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000000506 psychotropic effect Effects 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 239000000057 synthetic resin Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
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.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical 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)
- Materials For Medical Uses (AREA)
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]-NrN-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.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9526264.8A GB9526264D0 (en) | 1995-12-21 | 1995-12-21 | Medical treatment |
| GB9526264 | 1995-12-21 | ||
| PCT/EP1996/005631 WO1997023477A1 (en) | 1995-12-21 | 1996-12-16 | Dibenzothiepin derivatives and pharmaceutical compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0874840A1 true EP0874840A1 (en) | 1998-11-04 |
Family
ID=10785883
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP96943126A Withdrawn EP0874840A1 (en) | 1995-12-21 | 1996-12-16 | Dibenzothiepin derivatives and pharmaceutical compositions |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0874840A1 (en) |
| AU (1) | AU1195597A (en) |
| GB (1) | GB9526264D0 (en) |
| HR (1) | HRP960600A2 (en) |
| WO (1) | WO1997023477A1 (en) |
| ZA (1) | ZA9610761B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9802617D0 (en) | 1998-02-07 | 1998-04-01 | Knoll Ag | Pharmaceutical formulation |
| US8697735B2 (en) | 2008-07-25 | 2014-04-15 | Bionevia Pharmaceuticals, Inc. | Solid forms of epalrestat |
| LT2326632T (en) | 2008-09-06 | 2017-09-25 | Bionevia Pharmaceuticals, Inc. | Novel choline cocrystal of epalrestat |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NO129043B (en) * | 1968-02-16 | 1974-02-18 | Fujisawa Pharmaceutical Co | |
| JPH08145472A (en) * | 1994-11-17 | 1996-06-07 | Tokyo Gas Co Ltd | Warm air furnace |
-
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/en not_active Withdrawn
- 1996-12-16 WO PCT/EP1996/005631 patent/WO1997023477A1/en not_active Application Discontinuation
- 1996-12-19 HR HRP960600 patent/HRP960600A2/en not_active Application Discontinuation
- 1996-12-20 ZA ZA9610761A patent/ZA9610761B/en unknown
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9723477A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA9610761B (en) | 1998-06-22 |
| AU1195597A (en) | 1997-07-17 |
| WO1997023477A1 (en) | 1997-07-03 |
| GB9526264D0 (en) | 1996-02-21 |
| HRP960600A2 (en) | 1998-02-28 |
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