WO2008069726A1 - Treatment of resistant schizophrenia and other cns disorders by the use of thioxanthenes - Google Patents

Treatment of resistant schizophrenia and other cns disorders by the use of thioxanthenes Download PDF

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Publication number
WO2008069726A1
WO2008069726A1 PCT/SE2007/001077 SE2007001077W WO2008069726A1 WO 2008069726 A1 WO2008069726 A1 WO 2008069726A1 SE 2007001077 W SE2007001077 W SE 2007001077W WO 2008069726 A1 WO2008069726 A1 WO 2008069726A1
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WO
WIPO (PCT)
Prior art keywords
piperazinyl
schizophrenia
resistant
therapy
depression
Prior art date
Application number
PCT/SE2007/001077
Other languages
English (en)
French (fr)
Inventor
Christophe Lacon
Jean-Michel Azorin
Original Assignee
Copharm
HILLDÉN, Maria
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 Copharm, HILLDÉN, Maria filed Critical Copharm
Publication of WO2008069726A1 publication Critical patent/WO2008069726A1/en

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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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • 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
    • A61P25/24—Antidepressants

Definitions

  • the present invention relates to a method of treating resistant depression, chronic and recurrent depression and resistant bipolar disorders.
  • the invention relates to the treatment of naive schizophrenic patients, therapy resistant schizophrenic patients, and therapy refractory schizophrenic patients.
  • the invention also relates to a means for use in the method.
  • Schizophrenia is one of the most debilitating diseases that psychiatrists have to treat.
  • Schizophrenia is a psychiatric condition that is characterised by delusion, hallucination, disorganized speech, grossly disorganised or catatonic behaviour and negative symptoms (i.e. affective flattening, alogia, or avolition).
  • Schizophrenia is a severe condition associated with increased mortality (two to three times the average for the general population), comorbidity as well as social exclusion.
  • Life time prevalence is high, one percent, and may vary between different studies depending on the definition criteria of the target population. It is also known that the prevalence increases with age until the age of 40 where after it declines. The course of illness is characterized by relapses which occur in 80% over a two year period. The disease starts in men in their late teens or early 20s and for women in their 20s or early 30s. According to NIMH, schizophrenia affects men and women with equal frequency.
  • the pharmacological management of schizophrenia is based on typical antipsychotics (haloperidol, chlorpromazine, thioridazine, fluphenazine, perphenazine, trifluoroperazine, amisulpride, sulpiride,) which induce motor side effects and extrapyramidal side effects (EPS).
  • typical antipsychotics haloperidol, chlorpromazine, thioridazine, fluphenazine, perphenazine, trifluoroperazine, amisulpride, sulpiride,
  • EPS extrapyramidal side effects
  • Clozapine The only antipsychotic agent that is indicated in therapy resistant schizophrenic patients is clozapine.
  • Clozapine's potential side effects include a loss of disease-fighting white blood cells with neutropenia in 3.6% and agranulocytosis in 1%, an overall seizure rate of 2.8%, and potentially myocarditis with resultant cardiomyopathy and fatal heart failure and pulmonary embolism.
  • clozapine was approved by the US FDA for a restricted population: therapy resistant schizophrenia. Careful periodic monitoring of blood cell count is mandatory to diagnose the occurrence of agranulocytosis and therefore strongly limits its use.
  • therapy resistant schizophrenic patient therapy refractory schizophrenic patient and naive schizophrenic patient is defined as follows.
  • Therapy resistant schizophrenic patient is a schizophrenic patient who has tried two successive antipsychotic agents for a period of 6 weeks at an appropriate dosage with no significant symptomatic relief of symptoms and who was compliant to pharmacological treatment.
  • This definition comprises determining relief of symptoms by measurment on a clinical scale such as PANSS (positive and negative schizophrenia scale). The relief should correspond to a reduction of the PANSS scale of at least 20% after a period of 6 weeks treatment. Lack of relief of symptoms should be assessed prospectively and should not be documented on the basis of historical information. Compliance to treatment should be documented through a third party such as nurse or care giver. Lack of compliance is often a reason for unsatisfactory outcome of schizophrenia therapy; if compliance is not documented the diagnosis of schizophrenia cannot be ascertained. Appropriate dosage is defined as an equivalent chlorpromazine of at least 300 mg per day.
  • Therapy refractory schizophrenic patient is a schizophrenic patient who, after 6 weeks of treatment with an antipsychotic agent, has achieved significant relief of symptoms, but who nevertheless exhibits residual symptoms that prevent the patient to achieve remission.
  • Naive schizophrenic patient is a schizophrenic patient who had never been treated with an antipsychotic agent.
  • the course of illness of schizophrenia is characterized by more or less frequent relapse defined as an acute exacerbation of schizophrenic symptoms: the higher the number of previous relapses the higher risk of further relapse.
  • patient In a naive patient early control of symptoms with longer relapse-free periods patient is predictive of a better outcome.
  • a treatment that would delay occurrence of relapse in na ⁇ ve patient would fulfil an important unmet need and would dramatically affect the long term course of schizophrenia.
  • the object of the present invention is to provide a pharmacological treatment that delays the occurrence of relapse thus addressing an important unmet medical need in na ⁇ ve patients
  • clozapine is normally used for these patients but, as has been described above, it is linked to serious side effects thus limiting its use.
  • some schizophrenia unrelated drugs have been used as adjuvant in treatment-resistant schizophrenic patients such as:
  • Recurrent depressive patient is defined as a patient experiencing two or more successive major depressive episodes that are separated by at least two months of not experiencing adequate symptoms of depression to qualify for major depressive disorder (DSM-IV).
  • Chronic depression patient is defined as a patient experiencing two years or more of persistent depressive symptoms (DSM-IV).
  • Resistant depression patient is defined as a patient not responding to an appropriate pharmacological treatment.
  • Resistant bipolar disorder patient is defined as a patient not responding to an appropriate pharmacological treatment.
  • Recurrent depression, chronic depression, resistant depression, and resistant bipolar disorder are correspondingly defined.
  • the object of the present invention is to provide a pharmacological treatment that addresses the unmet medical need in therapy resistant and therapy refractory schizophrenic patients by providing an efficacious pharmacological option with a more favourable safety profile than clozapine.
  • Another objective of the present invention is to provide a pharmacological treatment that offers an early control of symptoms and delays occurrence of relapse in na ⁇ ve schizophrenic patients.
  • thioxantenes such as thiotixene, chlorprothixene, flupenthixol, zuclopenthixol, zuclopenthixol acetate, zuclopenthixol decanoate, pharmaceutically acceptable salts, prodrugs and mixtures thereof, ⁇ are effective as mono-therapy in therapy resistant schizophrenic patient
  • ⁇ are effective as monotherapy in therapy refractory schizophrenic patient
  • zuclopenthixol is an efficient drug for therapy resistant schizophrenic patients not responding to drugs such as haloperidol, risperidone, olanzapine and clozapine and that zuclopenthixol is an efficient drug for naive schizophrenic patient where it delays relapse
  • thioxantenes such as thiotixene, chlorprothixene, flupenthixol, zuclopenthixol, zuclopenthixol acetate, zuclopenthixol decanoate, pharmaceutically acceptable salts, prodrugs and mixtures thereof, are effective as mono-therapy in
  • a method of treating a patient suffering from a condition selected from na ⁇ ve schizophrenia, therapy resistant schizophrenia, therapy refractory schizophrenia, therapy resistant depression, chronic depression, recurrent depression, and resistant bipolar disorder comprising the administration of a pharmacologically effective amount of a thioxanthene of the general formula (I) as monotherapy.
  • Specific thioxanthenes include, but are not limited to chlorprothixene (Ia; (3Z)-N 1 N- dimethyl-3-(2-chloro-9/-/-thioxanthen-9-ylidene)propan-1 -amine), flupenthixol (Ib; 4-[(3Z)- 3-(2-trifluoromethyl-9H-thioxanthen-9-ylidene)propyl]-1-piperazineethanol), thiotixene (Ic; (3Z)- ⁇ /, ⁇ /-dimethyl-9-[3-(4-methyl-1-piperazinyl)-1-propylidene]-9/-/-thioxanthene-2- sulfonamide), zuclopenthixol (Id; 4-[(3Z)-3-(2-chloro-9/-/-thioxanthen-9-ylidene)propyl]-1- piperazineethanol dihydrochloride), and esters of compound (Id) such as
  • a compound of the invention or a pharmaceutically acceptable salt thereof for mono-therapeutic treatment of a condition selected from the group consisting of na ⁇ ve schizophrenia, therapy resistant schizophrenia, therapy refractory schizophrenia, therapy resistant depression, chronic depression, recurrent depression, and resistant bipolar disorder.
  • a compound of the invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for mono- therapeutic treatment of a condition selected from the group consisting of naive schizophrenia, therapy resistant schizophrenia, therapy refractory schizophrenia, therapy resistant depression, chronic depression, recurrent depression, and resistant bipolar disorder.
  • the present invention provides a method of treating na ⁇ ve schizophrenic patients, therapy resistant schizophrenic patients and therapy refractory schizophrenic patients by orally administering a thioxanthene selected from the group consisting of thiotixene, chlorprothixene, flupenthixol, zuclopenthixol, zuclopenthixol acetate, and zuclopenthixol decanoate.
  • a thioxanthene selected from the group consisting of thiotixene, chlorprothixene, flupenthixol, zuclopenthixol, zuclopenthixol acetate, and zuclopenthixol decanoate.
  • the invention provides a method of treating na ⁇ ve schizophrenic patients, therapy resistant schizophrenic patients and therapy refractory schizophrenic patients by oral administration of zuclopenthixol.
  • Administration for gastrointestinal absorption can be by the oral or rectal route, such as by tablets and suppositories, respectively. It is also within the scope of the invention to provide liquid formulations, in particular aqueous formulations, for oral administration. A further route of administration is by intravenous or intra-muscular injection in a liquid carrier such as physiological saline.
  • a liquid carrier such as physiological saline.
  • zuclopenthixol exerts a clinically beneficial effect on symptoms of schizophrenia, in particular on positive symptoms, and on cognitive dysfunction. No deterioration of any other aspect of schizophrenia, such as cognitive or negative symptoms or excitement, accompanies the beneficial effects of zuclopenthixol on positive symptoms, even during long term administration of zuclopenthixol, such as over more than half a year and even a year or more.
  • a therapy resistant schizophrenic patient did not respond to the successive administration of four antipsychotic agents, each prescribed for a sufficient period of time and at a relevant dosage, and for whom compliance was controlled.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • Psychiatry (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/SE2007/001077 2006-12-08 2007-12-04 Treatment of resistant schizophrenia and other cns disorders by the use of thioxanthenes WO2008069726A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US11/635,677 2006-12-08
US11/635,677 US20080139573A1 (en) 2006-12-08 2006-12-08 Treatment of resistant Schizophrenia and other CNS disorders

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WO2008069726A1 true WO2008069726A1 (en) 2008-06-12

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JP (2) JP2008143899A (US20080242721A1-20081002-C00053.png)
WO (1) WO2008069726A1 (US20080242721A1-20081002-C00053.png)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024110577A1 (en) * 2022-11-24 2024-05-30 H. Lundbeck A/S Composition comprising zuclopenthixol

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CN110013476A (zh) * 2019-04-08 2019-07-16 南昌大学 6-羟基-1,2,3,7-四甲氧基呫吨酮在制备促海马神经发生的药物中的应用

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024110577A1 (en) * 2022-11-24 2024-05-30 H. Lundbeck A/S Composition comprising zuclopenthixol

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US20080139573A1 (en) 2008-06-12
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