WO2004014429A1 - Regulateur pour fragilite du cerveau par rapport a un risque de maladie mentale - Google Patents

Regulateur pour fragilite du cerveau par rapport a un risque de maladie mentale Download PDF

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Publication number
WO2004014429A1
WO2004014429A1 PCT/JP2003/009796 JP0309796W WO2004014429A1 WO 2004014429 A1 WO2004014429 A1 WO 2004014429A1 JP 0309796 W JP0309796 W JP 0309796W WO 2004014429 A1 WO2004014429 A1 WO 2004014429A1
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Prior art keywords
mental
administration
vulnerability
compound
cerebral dysfunction
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Application number
PCT/JP2003/009796
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English (en)
Japanese (ja)
Inventor
Yasushi Kajii
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Mitsubishi Pharma Corporation
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Publication date
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Priority to JP2004527324A priority Critical patent/JPWO2004014429A1/ja
Priority to AU2003252318A priority patent/AU2003252318A1/en
Publication of WO2004014429A1 publication Critical patent/WO2004014429A1/fr

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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • 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
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a novel compound or a therapeutic agent for a psychiatric disorder, which is used as a marker for the control of progressive cerebral dysfunction corresponding to onset vulnerability, and to a novel compound or a therapeutic agent for a mental disorder that is screened.
  • Laruelle showed an increase in dopamine release by amphetamine in patients with acute schizophrenia, but no difference from the normal control group in remission.
  • the role of endogenous rehabilitation is shown to be possible, and it is necessary to replace therapies with an index of symptom suppression in the acute phase to prevent recurrence (Laruelle M.
  • the role of endogenous sensitization m the pathophysiology of schizophrenia: implications from recent brain imaging studies. Brain Res Rev 31, 371-384, 2000
  • the main cause of schizophrenia is due to the vulnerability of the brain in the early stages of the disease. It is formed. Experiencing a psychotic episode during the illness phase is then fed back to maintaining 'vulnerability' after the illness and prepares for a relapse.
  • Such a system is known as a schizophrenia stress vulnerability modenole (Ciompi L.
  • the present invention is intended to provide a therapeutic agent for a mental disease which compensates for the drawbacks of existing antipsychotics and carries a novel mechanism of action, by focusing on the mechanism of cerebral disease onset vulnerability as described above.
  • the present invention stably stabilizes the stress response in remission by controlling progressive cerebral dysfunction corresponding to psychiatric disease onset vulnerability to mental illness whose symptoms show a wavy appearance course pattern, Mental illness consisting of a novel mechanism to suppress relapse of symptoms
  • schizophrenia schizophrenia, schizophrenia, Schizophrenia
  • stimulant psychosis and manic depression.
  • Therapeutic treatment for mental illness in which a compound mainly comprising a compound that has a function of controlling progressive cerebral dysfunction corresponding to vulnerability to mental illness has a wavy pattern of appearance.
  • a drug is administered in a model animal to cause a progressive cerebral dysfunction corresponding to the vulnerability to the onset of mental illness, and then the candidate compound is administered during the drug withdrawal period, resulting in a subsequent stress load.
  • the compound described in the above item 1 or 2 mainly comprising a compound having a pharmacological effect of specifically preventing the formation of behavioral sensitization, which is an indicator of progressive cerebral dysfunction equivalent to the vulnerability to mental illness development Remedies for mental illness,
  • the stress treatment according to the above 3 or 4 wherein the stress load is selected from amphetamine compound administration, apomorphine administration, fleafensin administration, other direct or indirect dopamine agonist administration, and tail cribing.
  • Markers for controlling progressive cerebral dysfunction corresponding to vulnerability to mental illness A novel compound or a disease symptom characterized by a wavy appearance course pattern, a screening method of a therapeutic drug for mental illness,
  • a drug is administered in a model animal in which a progressive cerebral dysfunction corresponding to psychiatric illness vulnerability is induced, and then the candidate compound is administered during the drug withdrawal period.
  • the dosing schedule was indicated.
  • a therapeutic agent for mental illness comprising the novel mechanism of the present invention was achieved by a neuroscience approach to a stress vulnerability model. That is, at least some of the feed-forward and feed-back loops in schizophrenia (schizophrenia, schizophrenia) are neuroplastic changes common to stimulant psychosis, and Neuroplastic changes in stimulant psychosis are based on the reproducibility of behavioral sensitization in experimental animals.
  • a healthy person responds to a small amount of a central stimulant such as amphetamines that does not cause a psychotic condition, and responds to a psychostimulant, and responds sensitively to psychosocial stress. Vulnerability is recognized (Lieberman JA, Seitman BB, Kmon Bd.
  • the present inventors hypothesized that an experimental animal model for the control of onset vulnerability in mental illness in which the symptoms show a wavy appearance pattern was used in pharmacology during multiple administration of stimulant and stimulant withdrawal period.
  • the relationship between control and relapse of cerebral dysfunction equivalent to mental illness vulnerability was established as an animal model.
  • a compound that specifically regulates the cerebral dysfunction equivalent to the fragility to develop mental illness was evaluated, and a therapeutic agent for psychiatric illness having a novel mechanism of action was provided to complete the present invention.
  • the cerebral dysfunction corresponding to the psychiatric disease onset vulnerability means the progression of weakening of the psychosis state relapse resistance based on the long-lasting change of the biological function caused by the psychotic state experience. Progression means greater vulnerability and less resistance.
  • the effect of controlling this is, for example, that a drug means for causing progressive cerebral dysfunction corresponding to vulnerability to the onset of mental illness in an animal model system is administered, and thereafter, the candidate compound during the drug withdrawal period of the drug means is This can be confirmed by the presence or absence of a pharmacological effect that prevents the formation of behavioral sensitization, which is an index of progressive cerebral dysfunction equivalent to the fragility of mental illness, in response to stress after drug administration.
  • a compound selected from the candidate compounds based on the presence or absence of such a pharmacological effect can be a therapeutic drug for a psychiatric disorder in which the disease symptom shows a wavy appearance course pattern.
  • the dosing means in which a progressive cerebral dysfunction corresponding to the fragility of mental illness is induced is performed, for example, by subcutaneous or intraperitoneal administration of an amphetamine compound (eg, amphetamine, methamphetamine).
  • an amphetamine compound eg, amphetamine, methamphetamine.
  • the means varies depending on the model animal.For example, if the animal model is a rat, 0.5 to 10 mg / kg body weight / day for 3 days to several weeks (3 to 5 days in some cases, Or several times (3 to 5 times) over 10 days to 2 weeks).
  • This medication introduces a cause of progressive brain dysfunction corresponding to mental illness vulnerability, and it is presumed that the cerebral dysfunction equivalent to fragility progresses after discontinuation of the medication, that is, during drug withdrawal. You.
  • the therapeutic agent for a psychiatric disorder according to the present invention is specifically selected because it exerts its efficacy by administering the candidate compound during the drug holiday. Therefore, it has the ability to control the progression of cerebral dysfunction equivalent to mental illness vulnerability, and antagonizes the increased vulnerability to progression during the remission period of mental illness.
  • Candidate compounds are dependent on the individual drug, but are generally 0.05 mg to 3 O mg / kg body weight per day for 3 days to several weeks (3-5 days or 10 days depending on the case). (2 to 2 weeks) multiple times (3 to 5 times).
  • a compound having a pharmacological effect of controlling the brain dysfunction corresponding to the onset vulnerability to mental illness and preventing its progression is effective against a mental illness in which the symptoms show a wavy appearance pattern.
  • the therapeutic agent for psychiatric disorders according to the present invention suppresses the cerebral dysfunction equivalent to the vulnerability to the onset of mental illness, and suppresses the stress during the remission phase of psychiatric illness for mental illness in which the symptoms show a wavy pattern. It has the effect of stabilizing the response continuously and suppressing the relapse (relapse) of symptoms.
  • the mental illness that shows a wavy pattern of appearance is generally schizophrenia (schizophrenia, schizophrenia, Schizophrenia), stimulant psychosis, manic depression, or autism.
  • Therapeutic agents for psychiatric disorders consisting of compounds that have a mechanism of action such as It is useful as a treatment for schizophrenia (schizophrenia, schizophrenia, Schizophrenia), stimulant psychosis, manic depression, or autism.
  • the remedy for psychiatric disorders of the present invention can be referred to as a psychiatric disorder onset vulnerability control agent or a psychiatric disorder remission stabilizing drug, and prevents relapse by being administered during the remission phase of psychiatric disorders.
  • a psychiatric disorder onset vulnerability control agent or a psychiatric disorder remission stabilizing drug, and prevents relapse by being administered during the remission phase of psychiatric disorders.
  • As the administration method generally known oral and parenteral preparations are prepared by pharmaceutical improvement, but oral administration is preferable due to its function as a prophylactic agent.
  • the dose is determined by the correlation between the optimal dose of each candidate compound and the ability to suppress the progression of fragility of mental illness and toxicity. Generally, for oral use, 0.01 to lmg / kg is envisaged.
  • a 5-HT 3 receptor blocker is a compound having an effect of controlling the progression of brain dysfunction corresponding to onset vulnerability, However, it has been confirmed that it may be a therapeutic agent for mental illness showing a wavy appearance progress pattern.
  • the present invention clarified the relationship between the effect of controlling progressive cerebral dysfunction corresponding to vulnerability to mental illness onset and a therapeutic agent for mental illness in which the disease symptom shows a wavy appearance pattern.
  • the use of a marker as a marker for controlling the progressive cerebral dysfunction corresponding to disease onset vulnerability is useful as a screening method for a novel compound or a therapeutic drug for a psychiatric disorder in which the disease symptom shows a wavy appearance course pattern. This involves the application of medications that cause progressive cerebral dysfunction equivalent to the above-mentioned psychiatric disease vulnerability, the administration of candidate compounds during this drug withdrawal, and the re-stressing and response to stress. It is possible to make a car and screen-jung.
  • a model system in which a cerebral illness that is susceptible to mental illness and progressive brain dysfunction is caused by multiple administration of an amphetamine compound to a mammal.
  • a novel compound obtained by such a screening method or a therapeutic drug for a psychiatric disorder in which the disease symptoms show a wavy appearance progress pattern is provided.
  • Example 1 is a representative example, and the present invention is not limited to these Examples.
  • Example 1 is a representative example, and the present invention is not limited to these Examples.
  • the administered compounds were haloperidol (1.0 mg / kg body weight), clozapine (20 mg / kg body weight), ondansetron (ondansetoron) (0.1 mg / kg body weight), control (vehicle: A saline solution containing 0.1 NHCL used as a solvent and the pH was adjusted to near neutral with NaOH) was intraperitoneally administered once a day. After a further drug-free period of 10 days, all animals were subcutaneously administered a small amount of methamphetamine (0.16 mg / kg) again on day 31 (54 days after birth). Behavior (spontaneous locomotor activity) for 20 minutes after administration was measured and evaluated as the number of light passages in a transparent breeding cage using a small animal locomotion measurement system (Merquest, Toyama).
  • Behavioral evaluation was performed by statistical analysis as follows. Spontaneous locomotor data was used for each drug treatment to detect the Si echo of the drug treatment (haloperidoL clozapine ⁇ ondansetron or vehicle Tia 'administration) on the effect of pretreatment (saline or MAP subchronic administration). There was no t-test, and the presence or absence of a sense of behavior under each drug treatment condition was individually determined. If the effect of drug treatment was found, multiple comparisons using Tukey's test were performed for each saline or MAP pretreatment, and the significance of the difference between drug treatments was determined.
  • Haloperidol and clozapine which are typical examples of typical and atypical antipsychotics, are both sensitized to cerebral dysfunction, a model of cerebral dysfunction equivalent to onset vulnerability when administered during the discontinuation period after MAP subchronic administration It was suggested that these antipsychotics could antagonize the positive symptoms in the acute phase, but could not be expected to improve the vulnerability of the disease, although they could be antagonized. It has been reported that the atypical antipsychotic clozapine has a lower recurrence rate than the typical antipsychotic haloperidol, but in this study, haloperidol administered during the withdrawal period caused behavioral sensitization. Rather, it was shown to be a factor in the high recurrence rate in haloperidol-treated patients as well as poor compliance as well as increased vulnerability to development.
  • the present inventor has established the concept of a remission-phase stabilizing agent, a psychostabilizer, as a new type of therapeutic agent for psychiatric disorders that compensates for the disadvantages of existing antipsychotics.
  • a psychostabilizer as a new type of therapeutic agent for psychiatric disorders that compensates for the disadvantages of existing antipsychotics.
  • Drugs that are effective are schizophrenia (schizophrenia, schizophrenia,
  • the present invention provides a therapeutic agent for a psychiatric disorder having a novel mechanism of action, and a cerebral disease-equivalent progressive brain using a model animal system involved in a psychiatric disorder showing a wavy pattern of appearance with the progression of the onset vulnerability.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Pain & Pain Management (AREA)
  • Addiction (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un mécanisme associé à la fragilité du cerveau par rapport à un risque de maladie mentale. L'invention concerne un remède pour des maladies mentales couvrant des déficiences au niveau de psychotropes existants et présentant un nouveau mécanisme de fonctionnement, lequel mécanisme concernant la fragilité par rapport à un risque de maladie mentale. En particulier, l'invention concerne un nouveau remède pour des maladies mentales. Ce remède présente un nouveau mécanisme permettant de réguler une perturbation progressive d'une fonction du cerveau correspondant à la fragilité de risque d'une maladie mentale, lequel mécanisme présentant un aspect ondulatoire et un motif de progression, ce qui permet ainsi de stabiliser des réponses de stress de manière continue, dans l'étape de rémission, et d'inhiber la réapparition de symptômes. Le remède est également utile dans le traitement du syndrome de troubles d'intégration (schizophrénie), d'une maladie mentale induite par des amphétamines, de la psychose maniaco-dépressive etc. L'invention concerne un remède pour des maladies mentales présentant un aspect ondulatoire et un motif progressif, comprenant, en tant que principal ingrédient, un composé présentant un effet de régulation de perturbation progressive d'une fonction du cerveau correspondant à la fragilité du cerveau par rapport à un risque de maladie mentale.
PCT/JP2003/009796 2002-08-09 2003-08-01 Regulateur pour fragilite du cerveau par rapport a un risque de maladie mentale WO2004014429A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2004527324A JPWO2004014429A1 (ja) 2002-08-09 2003-08-01 精神疾患発症脆弱性制御剤
AU2003252318A AU2003252318A1 (en) 2002-08-09 2003-08-01 Regulator for mental disease risk fragility

Applications Claiming Priority (2)

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JP2002-232448 2002-08-09
JP2002232448 2002-08-09

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10519175B2 (en) 2017-10-09 2019-12-31 Compass Pathways Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11564935B2 (en) 2019-04-17 2023-01-31 Compass Pathfinder Limited Method for treating anxiety disorders, headache disorders, and eating disorders with psilocybin

Citations (3)

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Publication number Priority date Publication date Assignee Title
EP0450757A2 (fr) * 1990-02-22 1991-10-09 Glaxo Group Limited Utilisation des antagonistes du 5-hydroxytryptamine pour le traitement des maladies mentales dès l'origine de l'enfance
WO1999059593A1 (fr) * 1998-05-21 1999-11-25 Eli Lilly And Company Therapie combinee destinee au traitement de la depression
WO2000037073A1 (fr) * 1998-12-22 2000-06-29 Novartis Pharma Gmbh Utilisation d'antagonistes de recepteurs de 5ht3 aux fins de traitement du syndrome de fatigue chronique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0450757A2 (fr) * 1990-02-22 1991-10-09 Glaxo Group Limited Utilisation des antagonistes du 5-hydroxytryptamine pour le traitement des maladies mentales dès l'origine de l'enfance
WO1999059593A1 (fr) * 1998-05-21 1999-11-25 Eli Lilly And Company Therapie combinee destinee au traitement de la depression
WO2000037073A1 (fr) * 1998-12-22 2000-06-29 Novartis Pharma Gmbh Utilisation d'antagonistes de recepteurs de 5ht3 aux fins de traitement du syndrome de fatigue chronique

Non-Patent Citations (5)

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Title
COSTALL BRENDA ET AL.: "The psychopharmacology of 5-HT3 receptors", PHARMACOLOGY & TOXICOLOGY, vol. 71, no. 6, December 1992 (1992-12-01), pages 401 - 415, XP002976539 *
JONES BRIAN: "5-HT3 receptor antagonists in anxiety and schizophrenia", DRUG NEWS & PERSPECTIVES, vol. 3, no. 2, March 1990 (1990-03-01), pages 106 - 111, XP002976536 *
MORAN PAULA M. ET AL.: "MDL 73,147EF, a 5-HT3 antagonist, facilitates latent inhibition in the rat", PHARMACOLOGY BIOCHEMISTRY AND BIHAVIOR, vol. 42, no. 3, July 1992 (1992-07-01), pages 519 - 522, XP002976538 *
WEINER INA ET AL.: "Screening of antipsychotic drugs in animal models", DRUG DEVELOPMENT RESEARCH, vol. 50, no. 3/4, July 2000 (2000-07-01) - August 2000 (2000-08-01), pages 235 - 249, XP002976540 *
WHITE ALFRED ET AL.: "Ondansetron in treatment of schizophrenia", LANCET, vol. 337, no. 8750, 11 May 1991 (1991-05-11), pages 1173, XP002976537 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10519175B2 (en) 2017-10-09 2019-12-31 Compass Pathways Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US10947257B2 (en) 2017-10-09 2021-03-16 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US10954259B1 (en) 2017-10-09 2021-03-23 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11149044B2 (en) 2017-10-09 2021-10-19 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11180517B2 (en) 2017-10-09 2021-11-23 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11447510B2 (en) 2017-10-09 2022-09-20 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11505564B2 (en) 2017-10-09 2022-11-22 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11629159B2 (en) 2017-10-09 2023-04-18 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11851451B2 (en) 2017-10-09 2023-12-26 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11939346B2 (en) 2017-10-09 2024-03-26 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11564935B2 (en) 2019-04-17 2023-01-31 Compass Pathfinder Limited Method for treating anxiety disorders, headache disorders, and eating disorders with psilocybin
US11738035B2 (en) 2019-04-17 2023-08-29 Compass Pathfinder Limited Method for treating anxiety disorders, headache disorders, and eating disorders with psilocybin

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