EP2413940A1 - Compositions comprising 2, 4, 6-triamino-1, 3, 5-triazine derivatives for treatment of schizophrenia - Google Patents

Compositions comprising 2, 4, 6-triamino-1, 3, 5-triazine derivatives for treatment of schizophrenia

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Publication number
EP2413940A1
EP2413940A1 EP10719652A EP10719652A EP2413940A1 EP 2413940 A1 EP2413940 A1 EP 2413940A1 EP 10719652 A EP10719652 A EP 10719652A EP 10719652 A EP10719652 A EP 10719652A EP 2413940 A1 EP2413940 A1 EP 2413940A1
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European Patent Office
Prior art keywords
lower alkyl
substituted
aryl
schizophrenia
different
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EP10719652A
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German (de)
English (en)
French (fr)
Inventor
Shinji Takahashi
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Astellas Pharma Inc
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Astellas Pharma Inc
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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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a novel pharmaceutical use of BECl potassium channel inhibitor as an agent for treating schizophrenia .
  • Schizophrenia is one of major mental disorders, is a disease with poor prognosis, and has a relatively high lifetime-prevalence, as high as 0.7 to 2.0% (PLoS Med. 2:413-433, 2005, herein incorporated by reference).
  • the symptoms of schizophrenia are classified into positive symptoms, negative symptoms, cognitive impairments and mood disorder.
  • the treatment of schizophrenia utilizes psychotherapy, occupational therapy and pharmacotherapy. Among these, pharmacotherapy achieves an important role.
  • schizophrenic patients still suffer from the problems of the disease becoming recurrent, chronic and incurable, or of tardive dyskinesia or extrapyramidal adverse side effects of antipsychotics.
  • antipsychotics are primarily used.
  • the antipsychotics may be classified into first generation antipsychotics and second generation antipsychotics.
  • the first generation antipsychotics are central dopamine receptor antagonists, and particularly dopamine D2 receptor antagonists. Specifically, chlorpromazine, haloperidol, bromperidol, perphenazine and the like may be mentioned.
  • the second generation antipsychotics include those having additional blocking action against serotonin receptors in addition to that against dopamine D2 receptors (risperidone, perospirone, ziprasidone, and the like) , or those having additional blocking action against many other receptors (clozapine, olanzapine, and the like) , those acting as partial agonists for dopamine D2 receptors (aripiprazole and the like), and the like.
  • Potassium channels are proteins which are present in the plasma membrane of cells and selectively pass potassium ions, and are conceived to be in charge of an important role for the control of membrane potential in cells.
  • the potassium channels contribute to the neurotransmission of central and peripheral nerves, heart pace-making, contraction of muscles, and the like, by regulating the frequency, durability and the like of the action potential in neurons and muscle cells.
  • voltage-dependent potassium channels, inwardly rectifying potassium channels, calcium-dependent potassium channels, receptor coupled potassium channels, and the like have been identified hitherto.
  • the voltage-dependent potassium channels have a characteristic of being opened when the membrane potential is depolarized.
  • potassium ions exist in a non-equilibrium state of about 5 mM in the extracellular moiety and about 150 mM in the intracellular moiety. For this reason, when the voltage-dependent potassium channels open due to depolarization, potassium ions are discharged from the intracellular part to the extracellular part, and consequently induce recovery (repolarization) of the membrane potential. Therefore, a decrease in the excitability of neurons and muscle cells is induced, concomitantly with the opening of the voltage-dependent channels (Ionic Channels of Excited Membranes, Sinauer Associates, Sunderland, 1992, herein incorporated by reference).
  • a compound modifying the opening of the voltage-dependent channels regulates various physiological phenomena by regulating the excitability of neurons, muscle cells and the like, and also has a possibility of serving as a therapeutic drug for various diseases.
  • 4-aminopyridine which is an inhibitor of A-type voltage-dependent potassium channels found in nerve cells, is known to induce epilepsy by increasing the nerve excitability (Epilepsy Res . 11:9-16, 2002, herein incorporated by reference).
  • dofetilide which is an inhibitor of hERG potassium channels expressed in the heart among the voltage-dependent potassium channels, is used as a drug for treatment arrhythmia based on the controlling of the excitability of myocardial cells (J. Pharmacol . Exp. Ther . 256: 318-324, 1991, herein incorporated by reference).
  • the potassium channel as set forth in SEQ IDNO:2 in Example 1 of U.S. Patent No. 6,326,168 is a voltage-dependent potassium channel showing a distribution of expression localized in the brain (U.S. Patent No. 6,326,168 is herein incorporated by reference) .
  • Expression of this channel is conspicuous in the hippocampus or the cerebral cortex .
  • the hippocampus and cerebral cortex are regions suggested to be strongly associated with learning and memory (The Neuron: Cell and Molecular Biology, Oxford University Press, New York, NY, 1991, herein incorporated by reference) .
  • the BECl potassium channel is associated with learning and memory.
  • An object of the present invention is to provide a therapeutic agent for schizophrenia having a novel mechanism of action which is different from conventional antipsychotics.
  • the inventors of the present invention conducted research based on a unique idea, and found that BECl potassium channel inhibitors exhibit a remarkable therapeutic effect on schizophrenia, thus completing the present invention.
  • a pharmaceutical composition for prevention and/or treatment of schizophrenia containing an effective amount of a BECl potassium channel inhibitor or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier .
  • a prophylactic agent and/or therapeutic agent for schizophrenia containing a BECl potassium channel inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient .
  • a BECl potassium channel inhibitor or a pharmaceutically acceptable salt thereof for the prevention and/or treatment of schizophrenia.
  • a BECl potassium channel inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating schizophrenia.
  • a method of preventing and/or treating schizophrenia comprising administering an effective amount of a BECl potassium channel inhibitor or a pharmaceutically acceptable salt thereof in a patient in need of such disease.
  • a method for preparing a pharmaceutical composition for treating schizophrenia comprising mixing a BECl potassium channel inhibitor or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient .
  • a commercial package comprising a pharmaceutical composition comprising a BECl potassium channel inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient, and an instruction describing that the BECl potassium channel inhibitor or a pharmaceutically acceptable salt thereof can be used or should be used to treat schizophrenia.
  • a pharmaceutical composition for prevention and/or treatment of schizophrenia containing an effective amount of a compound of formula (I) :
  • R 1 and R 2 which may be the same or different, each represents H, OH, lower alkyl-O-, aryl-CO-, NH 2 , lower alkyl-NH which may be substituted with OH, (lower alkyl) 2 N, a lower alkyl which may be substituted, or a heterocyclic group which may be substituted; and
  • R 3 , R 4 , R 5 and R 6 which may be the same or different, each represents (i) H, (ii) CN, (iii) NO 2 , (iv) halogen, (v) lower alkyl which may be substituted with (1) CN, (2) halogen, or (3) OH, (vi) cycloalkyl, (vii) aryl which may be substituted with lower alkyl, (viii) a heterocyclic group which may be substituted with lower alkyl, (ix) R 7 R 8 N- (wherein R 7 and R 8 may be the same or different, and each represents (1) H, (2) aryl, or (3) lower alkyl which may be substituted with R 9 -O-CO- (wherein R 9 represents (1) H, or (2) lower alkyl which may be substituted with aryl)), (x) R ⁇ -T 1 - (wherein R 10 represents (1) H, (2) lower alkyl which may be substituted with aryl, HO-Ci- I0 alkylene
  • R 1 and R 2 which may be the same or different , each represents H, or lower alkyl which may be substituted with a heterocyclic group selected from pyrimidine and pyridine, which may be substituted with a substituent selected from the group consisting of halogen, lower alkyl and lower alkyl-O-.
  • R 1 represents H
  • R 2 represents lower alkyl substituted with pyrimidine which may be substituted with a substituent selected from the group consisting of halogen, lower alkyl and lower alkyl-O-
  • R 3 and R 6 each represents H
  • R 4 and R 5 which may be the same or different, each represents (i) H, (ii) halogen, or (iii) R 10 -! *1 - (wherein RlO represents lower alkyl; and T 1 represents 0) .
  • positive symptoms associated with schizophrenia hallucinations, delusions, xenopathic experiences, disorganized speech, highly disorganized or catatonic behavior, and the like
  • negative symptoms associated with schizophrenia adjective flattening, poverty of thinking, apathy, autism, anhedonia, and the like
  • cognitive impairments associated with schizophrenia and mood disorder associated with schizophrenia (depression, anxiety, and the like).
  • N- (4-fluorophenyl) -N'-phenyl-N"- (pyrimidin-2-ylmethyl) -l,3,5-triazine-2,4, 6-triamine N, N 1 -bis (4-fluorophenyl) -N"- (pyrimidin-2-ylmethyl) -1,3,5-tri azine-2, 4, 6-triamine, N- (4 -fluorophenyl) -N ' - (4-methoxyphenyl ) -N"- (pyrimidin-2-ylme thyl)-l,3,5-triazine-2,4, 6-tiramine,
  • lower alkyl means linear or branched alkyl having 1 to 6 carbon atoms (hereinafter, abbreviated to Cl-6), and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl groups and the like.
  • the lower alkyl is Cl-4 alkyl, and in still another embodiment, the lower alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl.
  • Ci-io alkylene means linear or branched Ci-io alkylene, and includes, for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene, propylene, methylmethylene, ethylethylene, 1 , 2-dimethylethylene, 1 , 1 , 2 , 2-tetramethylethylene group, and the like.
  • cycloalkyl means a C 3 - 10 saturated hydrocarbon cyclic group, and may be bridged.
  • the cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl groups, and the like.
  • the cycloalkyl is C3- 8 cycloalkyl
  • the cycloalkyl is C 3 - 6 cycloalkyl.
  • aryl means a C 6 -i 4 monocyclic to tricyclic aromatic hydrocarbon cyclic group, and includes, for example, phenyl and naphthyl. In another embodiment, the aryl is phenyl.
  • heterocyclic group means a 3- to 15-membered, in another embodiment, 5- to 10-membered, monocyclic to tricyclic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, and includes a saturated cyclic group, an aromatic cyclic group, and a partially hydrogenated cyclic group.
  • the sulfur or nitrogen atom, both of which are ring atoms may be oxidized to form oxide or dioxide.
  • monocyclic heteroaryl such as pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, triazolyl, triazinyl, tetrazolyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl , oxadiazolyl, thienyl, or furyl; bicyclic heteroaryl such as indolyl, isoindolyl, benzimidazolyl , indazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl , benzothiazolyl , benzisothiazolyl, benzothiadiazolyl, benzoxazolyl, benzisoxazolyl, benzofuranyl or benzothienyl
  • the heterocyclic group is a 5- to 10-membered monocyclic or bicyclic heterocyclic group, and in still another embodiment, the heterocyclic group is a 5- to 6-membered monocyclic heterocyclic group, and in still another embodiment, the heterocyclic group is 5- to 6-membered monocyclic heteroaryl.
  • the "lower alkyl which may be substituted” and “heterocyclic group which may be substituted” mean that the “lower alkyl" and “heterocyclic group” may be respectively substituted with substituents including one or two or more groups shown below.
  • BECl or "BECl potassium channel” means a protein as set forth in SEQ ID NO.2, which has been known in U.S. Patent No. 6,326,168 or U.S. Patent No. 7,375,222.
  • BECl potassium channel inhibitor means a substance inhibiting the BECl potassium channel, and for example, it means a substance having an IC 50 value of 10 ⁇ M or less; in another embodiment, 1 ⁇ M or less; and in still another embodiment,
  • the BECl potassium channel inhibitor is obtained by subjecting a test compound to a representative screening method, for example, the method described in U.S. Patent No. 6,326,168 or U.S. Patent
  • the compound of the formula (I) may have tautomers or geometric isomers, depending on the type of substituent.
  • the compound of the formula (I) may be described only as one form of isomers in some cases, but the present invention also includes the other isomers, as well as separated isomers or mixtures thereof.
  • the compound of the formula (I) may also have asymmetric carbon atoms or axial asymmetry, and optical isomers based thereon may also exist.
  • the present invention includes separated optical isomers of the compound of the formula (I), or mixtures thereof.
  • the present invention also includes pharmaceutically acceptable prodrugs of the compound represented by the formula (I) .
  • a pharmaceutically acceptable prodrug is a compound having a group which can be converted to the amino group, hydroxyl group, carboxyl group or the like (of the present invention) by solvolysis or under physiological conditions. Examples of the group forming a prodrug include the groups described in Prog. Med., 5, 2157-2161 (1985) or "Development of Pharmaceutical Products” (Hirokawa-Shoten, Ltd., 1990), Vol. 7 Molecular Design, 163-198, both are herein .incorporated by reference .
  • the compound of the formula (I) may also form a salt with an acid addition salt depending on the type of substituent, and such salt is included in the present invention so long as it is a pharmaceutically acceptable salt.
  • Specific examples include acid addition salts with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, or phosphoric acid; or an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citr-ic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, or glutamic acid; and the like.
  • the compound of the formula (I) and/or pharmaceutically acceptable salts thereof can be obtained by the production method described in U.S. Patent No. 7,375,222, herein incorporated by reference, or by a production method equivalent thereto.
  • a pharmaceutical composition containing the compound of the formula (I) , oroneortwoormoreof pharmaceutically acceptable salts thereof, as an active ingredient can be prepared by using pharmaceutical excipients, pharmaceutical carriers and the like that are conventionally used in the pertinent art, according to a conventionally used method.
  • Administration may be carried out by any of the oral administration mode by means of tablets, pills, capsules, granules, powders, liquids or the like, and the parenteral administration mode by means of injectable preparations via intraarticular, intravenous, intramuscular routes, suppositories, eye drops, eye ointments, transdermal liquids, ointments, transdermal adhesive patches, transmucosal liquids, transmucosal adhesive patches, inhalants or the like.
  • solid compositions for oral administration tablets, powders, granules and the like are used.
  • one or two or more active ingredients are mixed with at least one inert excipient, for example, lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, and/or magnesium metasilicate aluminate, and the like.
  • the composition may also contain inert additives, for example, a gliding agent such as magnesium stearate, a disintegrant such as carboxymethyl starch sodium, a stabilizer, and a dissolution aid, according to standard methods.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs, and the like, and include a generally used inert diluent , for example, purified water or ethanol .
  • the liquid compositions may also contain, in addition to the inert diluent, an auxiliary agent such as a solubilizer, a wetting agent or a suspending agent, a sweetener, a flavor, an aromatic, or an antiseptic .
  • An injectable preparation for parenteral administration contains a sterile, aqueous or non-aqueous solution, suspension oremulsion.
  • aqueous solvents include distilled water for injection and physiological saline.
  • non-aqueous solvents include propylene glycol, polyethylene glycol, plant oils such as olive oil, alcohols such as ethanol, Polysorbate 80 (name in the Japanese Pharmacopoeia) , and the like.
  • These compositions may further include an isotonic agent , an antiseptic, a wetting agent, an emulsifier, a dispersant, a stabilizer, or a dissolution aid.
  • These are sterilized by, for example, filtration through a bacteria-retaining filter, incorporation of a bactericide, or irradiation. Furthermore, these can be used such that a sterile solid composition is prepared, and then dissolved or suspended in sterilized water or in a sterile solvent for injection before use.
  • Topical preparations include ointments, plasters, creams, jellies, adhesive skin patches, sprays, lotions, eye drops, eye ointments and the like.
  • the topical preparations contain generally used ointment bases, lotion bases, aqueous or non-aqueous liquids, suspensions, emulsions and the like.
  • ointment or lotion base polyethylene glycol, propylene glycol, white petrolatum, bleached beeswax, , polyoxyethylene hydrogenated castor oil , glycerin monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol , sorbitan sesquioleate, and the like may be mentioned.
  • the transmucous preparations such as inhalants or transnasal preparations are used in a solid, liquid or semi-solid form, and can be produced according to conventionally known methods.
  • known excipients and furthermore, a pH adj usting agent , an antiseptic, a surfactant, a gliding agent, a stabilizer or thickening agent, and the like may be appropriately added.
  • Administration can be carried out by using appropriate devices for inhalation or insufflation.
  • the compound can be administered alone or as a powder of a prescribed mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier, using a known device such as a metered dose inhaler, or a sprayer.
  • a dry powder inhaler or the like may be for a single dose or multiple doses, and dry powders or powder-containing capsules can be used.
  • the preparation may also be in the form of an appropriate ejector, for example, a pressurized aerosol spray using a suitable gas such as chlorofluoroalkane,hydrofluoroalkane or carbon dioxide.
  • the daily dosage is appropriately about 0.001 to 100 mg/kg, preferably 0.1 to 30 mg/kg, and more preferably 0.1 to 10 mg/kg, of body weight, and this is administered once, or in two to four divided portions.
  • the daily dosage is appropriately about 0.0001 to 10 mg/kg of body weight, and this is administered once or in many divided portions per day.
  • the transmucous preparations about 0.001 to 100mg/kg of body weight is administered once or in many divided portions per day.
  • the dosage is appropriately determined in accordance with the individuals, while taking symptoms, age, gender and the like into consideration.
  • the compound of the formula (I) can be used in combination with an agent for treating or preventing schizophrenia. This combination may be administered simultaneously or separately and sequentially, or even may be administered at a desired time interval.
  • the preparation for simultaneous administration may be a blend preparation, or may be separately formulated.
  • the obtained crystal was dried at 50 0 C for 1 day under reduced pressure to obtain 108.54 g of N- (4 -fluorophenyl) -N ' -phenyl-N"- (pyrimidin-2-ylmethyl ) -1,3,5 -triazine-2, 4 , 6-triamine .
  • Reference Example 1-2 414 L of methyl ethyl ketone and 23.00 kg of the N- (4 -fluorophenyl) -N ' -phenyl-N"- (pyrimidin-2-ylmethyl) -1, 3, 5 -triazine-2 , 4 , 6-triamine were added to a reaction vessel 1, and dissolved at an inner temperature of 65.0 0 C. After filtration, the mixture was transferred to a reaction vessel 2, followed by heating again. 6.90 kg of fumaric acid and 115 L of EtOH were added to the reaction vessel 1, dissolved at an inner temperature of 58.3°C, transferred to the reaction vessel 2.
  • N, N '-bis (4-fluorophenyl) -N"- (pyrimidin-2-ylmethyl) -1, 3, 5-tri azine-2 , 4 , 6-triamine to fumaric acid of 1:1 was added thereto, followed by stirring at room temperature for 12 hours while leaving it to be cooled.
  • the precipitated crystals were collected by filtration, washed with ethanol, and dried at 60°C for 2 days under reduced pressure to obtain 970 mg of a "salt having a ratio of N, N '-bis (4-fluorophenyl) -N"- (pyrimidin-2-ylmethyl) -1,3, 5-tri azine-2 , 4 , 6-triamine to fumaric acid of 1:1" as colorless crystals .
  • the channel activity of BECl was measured according to the method described in U.S. Patent No. 6,326,168 or U.S. Patent No. 7,375,222, herein incorporatedby reference, utilizing the release of the ions of radioactive isotope 86Rb from BECl expressing cells as an index. Specifically, when BECl expressing cells which had takenin86Rbionswere stimulated with 100 mM KCl, the radioactivity released from the same cells was designated as the channel activity of BECl.
  • 86Rb ions were incorporated into cells by culturing (3 hours, 37°C) BECl stably expressing cells in the presence of 86RbCl (0.5 ⁇ Ci/ml), and the unincorporated 86Rb ions were removed by washing the cells three times with HEPES buffered physiological saline (pH 7.4, 2.5 mM KCl). The same cells were incubated for 15 minutes at room temperature in the presence of a DMSO solution containing the test compound and HEPES buffered physiological saline, and then were further incubated for 5 minutes at room temperature in the presence of a 100 mM KCl-containing HEPES buffer solution (pH7.4) containing the same compound. The extracellular fluid was recovered, and then the remaining cells were lysed in 0.1 N NaOH and recovered. The Cherenkov radioactivities of the extracellular fluid and the cell lysate were respectively measured, and the sum was designated as the total radioactivity.
  • the release amount of 86Rb ions was expressed as the percentage of the radioactivity of the extracellular fluid with respect to the total radiation activity.
  • the value obtained in the presence of the compound was designated as a test value
  • the value obtained in the absence of the compound was designated as a control value
  • the value obtained when the cells were not stimulated with 100 mM KCl was designated as a blank value.
  • the inhibitory action of the compound was indicated as the IC 50 value determined from the inhibition % (that is, (control value - test value) xlOO/ (control value - blank value) ) .
  • Methamphetamine is a psychostimulant, and is known to cause symptoms that are similar to schizophrenia by increasing the transmission in the dopaminergic neurons.
  • the abnormal behavior produced when methamphetamine is administered to an animal is generally used as a screening method for a therapeutic drug for schizophrenia (Oka et al., 1993, J. Pharmacol. Exp. Ther., 264:158-165, herein incorporated by reference) . That is, a male ddY mouse was placed in an activity monitoring apparatus, and after 30 minutes, methamphetamine was administered.
  • the solvent used was a 0.5% aqueous solution of methylcellulose .
  • the statistical analysis was carried out between the solvent administered group and the drug administered groups, using Dunnett's test. (Results)
  • the results of the methamphetamine induced hyperlocomotion suppressive action are presented in Table 3.
  • the numerical values in the table represent the respective minimum effective doses for the compound administered groups (the smallest dose inducing a significantly small activity with respect to the activity of the solvent administered group).
  • the test compounds (1) to (5) all suppressed methamphetamine induced hyperlocomotion. In other words, these five compounds were shown to have an effect of improving the symptoms of schizophrenia, especially the positive symptoms of schizophrenia .
  • Example 3 Verification of the therapeutic effect on schizophrenia was carried out using a phencyclidine induced prolonged immmobility model.
  • Phencyclidine is a non-competitive antagonist of the N-methyl-D-aspartate receptor, a type of glutamate receptor, and abuse of this agent causes development of psychotic symptoms indistinguishable from those of schizophrenia. It was suggested that chronic treatment of phencyclidine enhances immobility in forced swimming test (Noda et al., 2000, Neuropsychopharmacol . , 23:375-87, herein incorporated by reference) . Forced swimming test is used as a screening assay for antidepressants, because immobility in this test is thought to reflect some aspect of depression such as lowering of motivation.
  • Negative symptoms of schizophrenia also includes similar aspects, we could evaluate the efficacy of drugs for negative symptoms, such as apathy, using this test. Briefly, a male ddY mouse was gently placed in a cylindrical pool, and activity wasmeasured for 3 min with SCANET (MV20-LAN, MELQUEST) . Afterward immobility time was calculated with the SCANET file integrating software. Two days later, Mice were anesthetized with sodium pentobarbital. The Osmotic mini pumps (Alzet model 1002, DURECT Corporation) were subcutaneously implanted to mice. The pump infused saline or phencyclidine 1.2 mg/day/mouse with pumping rate of 0.25 ⁇ L/hour.
  • the numerical values in the table represent the respective minimum effective doses for the compound administered groups (the smallest dose inducing a significantly short immobility time with respect to the immobility time of the solvent administered group) .
  • the test compounds (1) and (2b) suppressed phencyclidine induced prolongation of immobility time. In other words, these two compounds were shown to have an effect of improving the symptoms of schizophrenia, especially the negative symptoms of schizophrenia .
  • Example 4
  • Verification of the therapeutic effect on schizophrenia was carried out using a water finding task in mice after neonatal treatment with phencyclidine. It was suggested that treatment with phencyclidine at the neonatal stage produced schizophrenic cognitive impairment (Depoortere et al., 2005, Neuropsychopharmacology, 30:1963-85, herein incorporated by reference) . In addition, it has been reported that chronic treatment of PCP prolonged finding latency in the water-finding task (Mouri et al., 2007, MoI. Pharmacol., 180:152-60, herein incorporated by reference) . Finding latency in the water-finding task provides a measure of latent learning in animals, which is thought to reflect attention.
  • Asolvent (vehicle) ordilutions prepared by diluting the test compounds (1) and (2b) , with a solvent at multiple concentrations (as a free form which does not include salt) , were orally administered to the mice in each group.
  • the solvent used was a 0.5% aqueous solution of methylcellulose .
  • the statistical analysis was carried out between the solvent administered group and the drug administered groups, using Dunnett's test.
  • the results of the phencyclidine induced prolonged finding latency improving action are presented in Table 3.
  • the numerical values in the table represent the respective minimum effective doses for the compounds administered groups (the smallest dose inducing a significantly short finding latency with respect to the finding latency of the solvent administered group) .
  • the test compounds (1) and (2b) suppressed phencyclidine induced prolongation of finding latency. In other words, these two compounds were shown to have an effect of improving the symptoms of schizophrenia, especially the cognitive impairment of schizophrenia .
  • Compound (1) means the compound of REx 1-2
  • compound (2a) means the compound of REx 2-2
  • compound (2b) means the compound of REx 2-3
  • compound (3) means the compound of REx 3
  • compound (4) means the compound of REx 4
  • compound (5) means the compound of REx (5)
  • the data shows that BECl potassium channel inhibitors are useful for the prevention and/or treatment of schizophrenia.
  • the pharmaceutical composition of the present invention is useful for providing an excellent prophylactic agent and/or therapeutic agent for schizophrenia, and is particularly useful for providing a prophylactic agent and/or therapeutic agent for the positive symptoms, negative symptoms and cognitive impairments and the like of schizophrenia.
  • the present invention is useful in providing an excellent prophylactic agent and/or therapeutic agent for schizophrenia.
  • the present invention is also particularly useful in providing a prophylactic agent and/or therapeutic agent for positive symptoms (hallucinations, delusions, xenopathic experiences, disorganized speech, highly disorganized or catatonic behavior, and the like), negative symptoms (affective flattening, poverty of thinking, apathy, autism, anhedonia, and the like), cognitive impairments, mood disorder (depression, anxiety, and the like) or the like associated with schizophrenia.

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EP10719652A 2009-03-31 2010-03-30 Compositions comprising 2, 4, 6-triamino-1, 3, 5-triazine derivatives for treatment of schizophrenia Withdrawn EP2413940A1 (en)

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CA2660962A CA2660962A1 (en) 2009-03-31 2009-03-31 Novel pharmaceutical composition for treatment of schizophrenia
PCT/JP2010/056144 WO2010114163A1 (en) 2009-03-31 2010-03-30 Compositions comprising 2, 4, 6-triamino-1, 3, 5-triazine derivatives for treatment of schizophrenia

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CA (1) CA2660962A1 (enExample)
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CN103351348A (zh) * 2013-07-15 2013-10-16 黄河三角洲京博化工研究院有限公司 一种2-甲胺基嘧啶盐酸盐的合成方法
KR200492485Y1 (ko) 2016-02-16 2020-10-23 주식회사 마르시끄 일회용 마스카라

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AU1982799A (en) 1998-01-23 1999-08-09 Yamanouchi Pharmaceutical Co., Ltd. Novel potassium channel protein
MXPA03005609A (es) 2000-12-21 2003-10-06 Vertex Pharma Compuestos de pirazol utiles como inhibidores de la proteina cinasa.
MXPA04007590A (es) * 2002-02-05 2004-12-06 Yamanouchi Pharma Co Ltd Derivado de 2,4,6-triamino-1,3,5-triacina.
US8101380B2 (en) * 2007-03-26 2012-01-24 The United States Of America As Represented By The Secretary Of Health And Human Services Schizophrenia-related isoform of KCNH2 and development of antipsychotic drugs

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CN102378630A (zh) 2012-03-14
CA2660962A1 (en) 2010-09-30
JP2012521963A (ja) 2012-09-20
TW201035081A (en) 2010-10-01
WO2010114163A1 (en) 2010-10-07

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