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WO2004016287A1 - Medicaments contre la schizophrenie - Google Patents

Medicaments contre la schizophrenie Download PDF

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Publication number
WO2004016287A1
WO2004016287A1 PCT/JP2003/010286 JP0310286W WO2004016287A1 WO 2004016287 A1 WO2004016287 A1 WO 2004016287A1 JP 0310286 W JP0310286 W JP 0310286W WO 2004016287 A1 WO2004016287 A1 WO 2004016287A1
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Prior art keywords
group
lower alkyl
methyl
alkyl group
hydrogen atom
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PCT/JP2003/010286
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English (en)
Japanese (ja)
Inventor
Hisashi Ohta
Takeshi Tanaka
Akio Sato
Mitsuru Ohkubo
Naohiro Tsukamoto
Morihiro Mitsuya
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MSD KK
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Banyu Phamaceutical Co Ltd
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Priority to AU2003255022A priority Critical patent/AU2003255022A1/en
Publication of WO2004016287A1 publication Critical patent/WO2004016287A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • 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
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • 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 therapeutic and / or prophylactic agent for schizophrenia comprising a compound having an mG 1 uR 1 antagonistic activity or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Glutamate is a neurotransmitter that mediates excitatory transmission in the central nervous system. Glutamate, in addition to a variety of neurotransmitter effects, is responsible for many important brain functions such as neuronal survival and death, differentiation and proliferation, neuronal and glial cell development, and plastic changes in neurotransmission efficiency of the mature or developed brain. (Annu. Rev. Biophysics and Biomolecular Structure (Annu. Rev. Biophys. Biomol. Struct.), S. Nak anishi, M. Ma su, 23, 319-348, 1994).
  • mGluR metapotropic dalmic acid receptors
  • the ion channel-type glutamate receptor is an ion channel composed of a complex of different subunit proteins and opened and closed by ligand binding.
  • mGluR is conjugated to a GTP-binding protein and acts by regulating the production of intracellular second messengers or the activity of ion channels through the GTP-binding protein (Brain Lisa-Breath Res. Rev.), S. Nakanisi et al., Vol. 26, p. 230-p.
  • mG 1 uR exists as eight different subtypes of mG 1 uR 1 to 8. It has been reported. They are divided into three subgroups based on amino acid sequence homology, signal transduction, and pharmacological properties.
  • Group I mGluRl and 5
  • group II mGluR2 and 3
  • group III mGluR4, 6, 7 and 8
  • rate cyclase activity By regulating rate cyclase activity, it inhibits forskolin-stimulated accumulation of cyclic adenosine monophosphate (cAMP).
  • Group II is selectively selected by LY 354740 described in Journal of Medicinal Chemistry 1 (Journa 1 of Medicin 1 Chemistry, Vol. 42, pp. 1027-1 pp. 1040, 1999).
  • Group III is selectively activated by L-AP4.
  • L-AP4 L-AP4.
  • various receptors are expressed in a wide range of the brain and nervous system, and each shows a characteristic distribution in the brain, and each receptor is different It is thought to play a physiological role (Neuro chem. Int.), D. Shoe pp, et al., Vol. 24, pp. 439-449, 1994 J. Ph. J. Pharma Col., J. Pin et al., Vol. 375, pp. 277-294, 1999.
  • R S_l aminoind an 1,5-dicar box i 1 icacid (hereinafter referred to as AI DA), which is a typical mG 1 uR1 antagonist with excellent selectivity.
  • AI DA 1,5-dicar box i 1 icacid
  • AI pen exhibits a dose-dependent anticonvulsant effect in a pentyl en etetrazo 1 e-induced seizure model that is widely used for evaluating the effects of anticonvulsants (Neuropharmacology (Neu 37, p. 1465-p. 1473, 1998. In addition, it has an inhibitory effect on sound stimulus-induced convulsions in genetically labile mice and rats.
  • the reaction by DHPG is the reaction observed with dopamine receptor stimulants (eg, apomorphine) or dopamine releasing drugs such as amphetamine and methamphetamine. It is thought that existing antipsychotics exert their effects by suppressing excessively excited dopaminergic nerves. Therefore, a similar response to dopamine stimulation by DHPG suggests that mG1uR1 and mG1uR5 are involved in mental dysfunction in the nucleus accumbens, and antagonists improve those symptoms. The possibility is suggested.
  • dopamine receptor stimulants eg, apomorphine
  • dopamine releasing drugs such as amphetamine and methamphetamine.
  • Known compounds having a mG 1 uR 1 antagonistic activity include, for example, WO 95/25110, WO 96/15099, WO 96/15100, WO 97/05109 JP, WO97Z05137, JP-B-08-169884, W-98706724, JP-T-11-189596, W099 / 44639, W-99 / 26297, JP-A-2000-351782, It is listed in JP-A-2002-105085 and the like. This will be specifically described in the following (6) to (15).
  • the disclosed use is for epilepsy, senile dementia, Parkinson's disease, Huntington's chorea, pain, and lack of psychomotor ability seen after cerebral ischemia.
  • WO 98X06724 discloses imidazo [2,1-b] indole derivatives, which are used for functional and organic disorders in the brain, such as sequelae of cerebral infarction and sequelae of cerebral hemorrhage Improvement of symptoms caused by cerebral ischemic injury such as sequelae of atherosclerosis and various organic disorders caused by senile dementia, sequelae of head injury, sequelae of brain surgery, Alzheimer's disease, Parkinson's disease, etc. , Treatment.
  • WO099Z26297 discloses a compound such as N- [6- (2-methylquinolyl)]-11-adamantanecarboxamide, but the compound described in the publication is glutamic acid. It is described that it is useful for the treatment of a disease associated with nerve damage induced by.
  • Various uses of the compound having the mGluR1 antagonistic activity described in the above (6) to (11) are described, but the compound having the mG1uR1 antagonistic activity is useful for the treatment of schizophrenia There is no statement that this is the case, nor is there any statement suggesting this.
  • JP-A-2002-105085 describes imidazothiazole derivatives.
  • imidazothiazol derivatives include epilepsy, pain, neurodegenerative diseases (cerebral insufficiency after cardiac bypass surgery and transplantation, stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's disease, Huntington's disease, fungi) Amyotrophic lateral sclerosis, AIDS-induced dementia, perinatal hypoxia, cardiac arrest, hypoglycemic ⁇ Euron damage, visual impairment and retinopathy, idiopathic and drug-induced Parkinson's disease), anxiety It is described as being useful for stress-related diseases (benzodiazepine withdrawal syndrome, irritable bowel syndrome).
  • the publication states that a compound that acts on mG1uRl contains convulsions caused by impaired neurotransmission caused by glutamate, migraine, urinary incontinence, mental illness, opiate tolerance and withdrawal symptoms, cocaine withdrawal symptoms, anxiety, vomiting, cerebral edema, chronic pain It is described that it is considered to be useful also for dyskinesia and dyskinesia.
  • Patent No. 3260350 describes 1,2,3,4-tetrahydro-benzo [d] azepines as compounds having mG1uR1 antagonistic activity.
  • One of the uses of compounds is as a therapeutic agent for schizophrenia.However, there is a direct relationship between a compound having an mG 1 uR 1 antagonistic activity and being useful for treating schizophrenia. Not shown. Disclosure of the invention
  • a therapeutic agent for schizophrenia comprising a compound having an mG 1 uR 1 antagonistic activity as an active ingredient
  • a therapeutic agent for schizophrenia comprising as an active ingredient a compound having a mG 1 uR 1 selective antagonism or a pharmaceutically acceptable salt thereof,
  • R 1 (1) -A x -CO-N (R 5 ) one R '
  • a 1 a lower alkylene group which may be substituted with a bond or a hydroxy group.
  • a 2 a bond, a lower alkylene group or a lower alkenylene group.
  • R 5 and R 6 are the same or different and are a hydrogen atom, —N (R 19 ) -R 2Q , an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group. However, R 5 and R 6 may be combined with an adjacent nitrogen atom to form a heterocyclic group which may have a substituent or may have another hetero atom. Is also good.
  • R 19 and R 2G are the same or different and are a hydrogen atom, —CO—lower alkyl group, —CO 18- octal lower alkyl group, 1 C ⁇ OR 18 .
  • R 7 a hydrogen atom, a hydrocarbon which may have a substituent or a heterocyclic group which may have a substituent, a hydroxy group or a lower alkyl-O— group.
  • a 3 a lower alkylene group which may be substituted with a hydroxy group.
  • R 8 a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group.
  • R 9 a hydrogen atom or a lower alkyl group.
  • R 10 a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent.
  • R 2 hydrogen atom, lower alkyl group, halo lower alkyl group, hydroxy-lower alkyl group, lower alkyl, lower alkyl group, amino-lower alkyl group, or
  • R 11 hydrogen atom, hydroxy group or saturated heterocyclic group
  • R 14 hydrogen atom or lower alkyl group
  • R 15 hydrogen atom, hydroxy group or saturated heterocyclic group
  • R 16 and R 17 are the same or different and are a hydrogen atom, a lower alkyl group which may be substituted, or a heteroaryl group which may have another hetero atom as a ring atom and may be substituted. Alternatively, a saturated heterocyclic group which may be substituted may be formed.
  • R 18 hydrogen atom or lower alkyl group
  • Ring A The ring may have one or two double bonds in the ring, the ring atom may be a carbon atom, or one to three carbon atoms may be a heteroatom, and a substituent may be present on the ring. It represents a carbocyclic group which may be possessed or an aromatic hetero ring which may be substituted.
  • ring A may have one or two double bonds in the ring, and the ring atom may be a carbon atom, or one to three carbon atoms may be replaced by a heteroatom.
  • the ring A may have one or two double bonds in the ring, the ring atom may be a carbon atom, or 1 to 3 carbon atoms may be a hetero atom, A carbon ring which may have a substituent on the ring or an aromatic hetero ring which may be substituted], and one R 1 in the above formula [1] is The following formula [3]
  • R 19 and R 2Q are the same or different and each represent a hydrogen atom, an optionally substituted lower alkyl group, or an optionally substituted cycloalkyl group, and X represents an oxygen atom or a hydrogen atom. Represents an atom, Equation [4] Equation [4]
  • R 21 , R 22 and R 23 are the same or different and are each a hydrogen atom, a halogen atom, Lower alkyl group, halo lower alkyl group, N 3 -lower alkyl group, hydroxy-lower alkyl group, hydroxy group, lower alkyl mono-, cyano group, C ⁇ OR 18 , acyl group, formyl group, formyl lower alkyl group , Ashiru -0-, Ashiru - ⁇ - lower alkyl group, a nitro group, -A 4 - N (R 24 ) - (R 25), one S_ ⁇ 3 H, or one A 5 -0-A 4 -N ( R 24) - (R 25) .
  • R 24 and R 25 the same or different, a hydrogen atom, one C_ ⁇ _ lower alkyl - N (R 1 9) one R 2G, One CO- halo-lower alkyl group, or an optionally substituted lower ⁇ alkyl group Or an optionally substituted heterocyclic group.
  • R 24 and R 25 may be combined with an adjacent nitrogen atom to form a heterocyclic ring which may have a substituent or may additionally have a hetero atom.
  • R 18 a hydrogen atom or a lower alkyl group.
  • a 4 a lower alkylene group which may be substituted with a bond or a hydroxy group.
  • a 5 a bond or a lower alkylene group.
  • R 1 in the above formula [1] is a group represented by the following formula [3]
  • R 19 and R 2G are the same or different and each represent a hydrogen atom, an optionally substituted lower alkyl group, or an optionally substituted cycloalkyl group, and X represents an oxygen atom or a hydrogen atom. Represents an atom, Equation [4] Equation [4]
  • R 19 and R 20 are the same or different and are a hydrogen atom, an optionally substituted lower alkyl group, or a cycloalkyl group.
  • X oxygen atom or hydrogen atom.
  • Formula [4] A single bond or a double bond.
  • R 222 bond, lower alkylene or lower alkenylene group.
  • R 201 — A 4 — N (R 24 ) one (R 25 ).
  • a 4 a lower alkylene group which may be substituted with a bond or a hydroxy group.
  • R 24 and R 25 the same or different, a hydrogen atom, -CO - lower alkyl _N (R 1 9) _R 2G , -C_ ⁇ - halo-lower alkyl group, or an optionally substituted lower ⁇ alkyl group, or A heterocyclic group which may be substituted; However, R 24 and R 25 may be combined with an adjacent nitrogen atom to form a heterocyclic ring which may have a substituent or may additionally have a hetero atom.
  • R 211 and R 221 identical or different, a hydrogen atom, a lower alkyl, a halo lower alkyl, a hydroxy-lower alkyl.
  • R 18 a hydrogen atom or a lower alkyl group.
  • the “compound having an mG 1 uR 1 antagonistic action” includes, for example, JP-A-8-169884, WO 95/25110, WO 96/15099, WO 96/15100, WO 97 No. 05109, WO 97/05137, WO 98Z06724, Japanese Patent Application No. 9-357552, Japanese Patent Application Laid-Open No. 2000-351782, Japanese Patent Application Laid-Open No. 2002-105085, and the like. But not limited to these.
  • the “compound having an mG 1 uR 1 antagonism” refers to any compound that has an mG 1 uR 1 antagonism and is useful as a therapeutic agent for schizophrenia. Or a peptide compound.
  • mG 1 uRl antagonistic activity and selectivity for mG 1 uR1 of the compound according to the present invention or a pharmaceutically acceptable salt thereof are determined by the method described in Example 1 of the present specification, WO 99/44639, and the like. Can be measured by the method described in (1).
  • Treatment agent refers to a drug that is used for the purpose of treatment, prevention or prevention of various diseases.
  • the “lower alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms, and preferably has 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group and a t-butyl group.
  • the “lower alkylene group” is an alkylene group having 1 to 6 carbon atoms, preferably an alkylene group having 1 to 4 carbon atoms such as a methylene group, an ethylene group, a propylene group, an isopropylene group, a t-butylene group, and the like. It is preferably an alkylene group having 1 to 3 carbon atoms.
  • hydrocarbon group of the optionally substituted hydrocarbon group means one shown below.
  • aryl group which is a 6- to 14-membered aromatic hydrocarbon ring group as a whole, including biphenyl.
  • aryl group which is a 6- to 14-membered aromatic hydrocarbon ring group as a whole, including biphenyl.
  • a cycloalkyl group having 3 to 8 carbon atoms preferably a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group and the like.
  • a cycloalkenyl group having 3 to 8 carbon atoms preferably a cyclohexenyl group or the like.
  • Nonyl group piciclo [3.2.1] octenyl group, adamantyl group, etc. These may have one or more substituents.
  • heterocyclic group of the optionally substituted heterocyclic group means a group shown below.
  • bicyclic means a 3- to 14-membered saturated or unsaturated heterocyclic group as a whole, including a bicyclo form and a spiro form.
  • a pyrrolidinyl group a piperidyl group, a piperazinyl group, a homopiperazinyl group, a hexahydroazepinyl group, a morpholinyl group, a pyridyl group and the like.
  • a benzofuranyl group, a tetrahydrobenzozofuranyl group, an indolyl group, an isoindolinyl group, a benzoazepinyl group, a tetrahydroquinolyl group, a tetrahydroisoquinolyl group, or the like is used.
  • a decahydroquinolyl group a 2-azabicyclo [2.2.1] heptyl group, a 1-azaspiro [4.5] decyl group, a 1-oxaspiro [4.5] decyl group, a 1,4-dioxaspiro
  • Decyl group pyridoxazinyl group, octahydrobenzozoxazinyl These may have one or more substituents.
  • Light mouth means a halogen atom, for example, a fluorine, chlorine, bromine or iodine atom.
  • “Mono or di-lower alkylamino” means an amino group substituted by 1 or 2 of the lower alkyl.
  • Aryl is as defined in the hydrocarbon group above.
  • acyl means lower alkyl-1 CO— or aryl-1CO—, and preferably lower alkyl-1CO—.
  • the “substituent of a group which may be substituted or may have a substituent” is as follows.
  • the substituent means an ordinary substituent commonly used in the art for the group to be substituted, but may be a lower alkyl group optionally substituted with a hydroxy group, a halo lower alkyl group, ⁇ H, a lower alkyl group.
  • a halogen atom a lower alkyl group, a halo-lower alkyl group, a hydroxy group, a hydroxy-lower alkyl group, a lower alkyl-O—, an oxo group, an acyl group, an acyl- ⁇ , CO ⁇ H, a lower alkyl-O—CO —, Lower alkyl—O—lower alkyl group, nitro group, cyano group, amino group, mono- or di-lower alkyl-amino group and phthaloyl group.
  • the number of substituents is not particularly limited as long as it can be substituted, but is preferably 1 to 4.
  • R 1 in the above formula [1] represents a group represented by the following (1) to (8) (the symbols are as defined above).
  • R 1 is a group represented by the above (1) —A 1 —CO—N (R 5 ) —R 6 or (6) -A x -N (R 5 ) —R 8 Preferably, there is.
  • R 1 is represented by the above (1) — A 1 — C ⁇ — N (R 5 ) — R 6 (each symbol is as defined above), A 1 is substituted with a hydroxy group A preferable alkylene group is more preferable, and a methylene group which may be substituted with a hydroxy group is more preferable.
  • R 5 and R 6 are the same or On the other hand, it is preferably a hydrogen atom or a hydrocarbon group which may be substituted, and more preferably a hydrogen atom, a lower alkyl group which may be substituted or a cycloalkyl group which may be substituted. preferable.
  • R 1 is represented by (6) — A 1 — N (R 5 ) -R 8 (each symbol is as defined above)
  • a 1 is preferably an alkylene group which may be substituted with a hydroxy group, and more preferably a methylene group which may be substituted with a hydroxy group.
  • R 5 and R 8 may be the same or different. Is preferably a hydrogen atom or a hydrogen atom which may be substituted, and more preferably a hydrogen atom, a lower alkyl group which may be substituted or a cycloalkyl group which may be substituted. .
  • Equation [5-1] [Wherein each symbol is the same as the above definition], it is preferable to have an embodiment of the substitution position and the substituent represented by the following formula.
  • R 2 represents a hydrogen atom, a lower alkyl group, a halo lower alkyl group, a hydroxy-lower alkyl group, a lower alkyl- ⁇ -lower alkyl group, an amino-lower alkyl group, or a (mono or di-lower alkyl-amino) -lower alkyl group As shown, R 2 is preferably R 2 22 (hydrogen atom or lower alkyl group). Therefore, the above equation [1]
  • Specific examples of the compound included in the formula [1] include, for example, compounds described in JP-A-2000-351718.
  • the title compound can be synthesized by the method described in WO 99/44639, a method analogous thereto, or a combination thereof with a conventional method.
  • N-Cyclohexyl N, 3-dimethyl-6-ditrothiazolo [3,2-a] benzimidazol-2-hydropyoxamide (3.85 g) in THF-methanol solution (200 ml) at room temperature An aqueous solution of sodium sulfite (13.5 g) was added, and the mixture was heated under reflux for 5 hours. Then, THF and methanol were distilled off under reduced pressure, and this was diluted with water and neutralized with 28% aqueous ammonia. After extraction with ethyl acetate, the mixture was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • mG 1 uR 1 antagonism Using the compound 1 having mG 1 uR 1 antagonism according to the present invention, mG 1 uR 1 antagonism and mG 1 uR 1 selectivity were measured.
  • the cells were cultured in a DMEM medium containing 0% dialyzed fetal bovine serum, 1% proline, 100 uints Zm 1 enici 11 inn, 0.1 mg / m 1 strep t omyc insul, 2 mM glutamine.
  • CHO cells in which mG 1 uR2 was co-expressed with Gal 6 contained 10% dialyzed fetal calf serum, .1% proline, 100 units / ml penicillir 0.1 mg / ml strept omyc insu 1 fate, 2 mM glutamine, 0 mM
  • the cells were cultured in a DMEM medium containing 2 mg / m 1 hygromycin.
  • CH ⁇ cells in which mG 1 uR 7 and mG 1 uR 8 were co-expressed with Gal 5 were 10% dialyzed fetal calf serum, 1% proline, 100 units Zm 1 enicillin, 0.1 mg / ml stret omyc insulfate, 2
  • the cells were cultured in a DMEM medium containing mM glutamine and 0.2 mg / m 1 dieneticin.
  • compound A is agonistic to 10 10 No strike was observed.
  • Compound 1 was demonstrated to have no effect on representative subtypes of other groups of metatropic glutamates (Group I and Group II).
  • Compound 1 did not show agonism up to 10 against mG 1 uR 1.
  • 10 M glutamate suppressed the elevated calcium rise in a dose-dependent manner, with an IC 50 value of 98 nM.
  • the activity of the mouse was measured using an activity measurement device (manufactured by Neuroscience) that detects the movement of the animal with an infrared sensor.
  • the compound or physiological saline was administered to the mice, and 30 minutes later, the activity for 60 minutes was measured immediately after administration of the physiological saline or methamphetamine.
  • Subcutaneous administration of methamphetamine significantly increased the amount of activity 60 minutes after administration.
  • the compound having the mG 1 uR 1 antagonistic action (lOmgZkg) of the present invention 30 minutes before methamphetamine, the increase in the amount of action caused by methamphetamine was suppressed.
  • the administration of the compound (lOmgZkg) had no effect on the locomotor activity of mice to which physiological saline was administered instead of methamphetamine.
  • Table 1 shows the effect of the compound on the spontaneous locomotor activity of mice, which is increased by methamphetamine. Locomotor activity in mice
  • Startle response to a sound stimulus (pulse stimulus) of 120 dB and a pulse of 70 dB preceding the pulse stimulus were measured using a startle response measuring device (San Diego Instruments) that senses the body movement of the rat.
  • the startle response when a stimulus was given in combination with a sound stimulus (prepulse) was measured.
  • the compound or physiological saline according to the present invention was administered to rats, and 30 minutes later, physiological saline or methamphetamine was administered to measure the startle response.
  • the startle response during pulse stimulation and the presence of prepulse are assumed to be A and B, respectively. [)% ⁇ ⁇
  • PPI The value of the population
  • the startle response was attenuated to about 50% in the presence of the prepulse in contrast to the startle response to the pulse stimulus (prepulse inhibition).
  • Pretreatment with methamphetamine attenuated the startle response by only about 20% and reduced prepulse inhibition.
  • a decrease in prepulse inhibition due to methamphetamine tended to be restored by subcutaneously administering a compound having an mG 1 uR 1 antagonistic activity (10 mgZkg) 30 minutes before methamphetamine.
  • the compound according to the present invention having mG 1 uR 1 antagonistic activity is a useful drug for treating and / or preventing schizophrenia.
  • the compound having an mG 1 uRl antagonistic activity or a pharmaceutically acceptable salt thereof according to the present invention has a strong antagonistic effect on mG 1 uR 1, and is used for the treatment of diseases involving mG 1 uR 1, particularly schizophrenia. And / or useful for prevention.

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Abstract

L'invention concerne un médicament permettant de traiter la schizophrénie qui comprend comme ingrédient actif un composé présentant un antagonisme pour mG1uR1 ou un sel pharmaceutiquement acceptable de ce composé. L'invention concerne plus spécifiquement un médicament permettant de traiter la schizophrénie qui comprend comme ingrédient actif un composé présentant un antagonisme pour mG1uR1 et représenté par la formule (1); ou un sel pharmaceutiquement acceptable de ce composé
PCT/JP2003/010286 2002-08-14 2003-08-13 Medicaments contre la schizophrenie Ceased WO2004016287A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020127735A1 (fr) 2018-12-20 2020-06-25 Intervet International B.V. Nouveaux procédés de production de (2-amino-4-[6-(4-fluorophényl)-2-[(4-méthyl-1-pipérazinyl)méthyl]imidazo[2,1-b]thiazol-5-yl]-pyrimidine

Citations (4)

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Publication number Priority date Publication date Assignee Title
WO1999044639A1 (fr) * 1998-03-03 1999-09-10 Yamanouchi Pharmaceutical Co., Ltd. Medicaments contre l'infarcissement du cerveau
WO2000059913A1 (fr) * 1999-04-06 2000-10-12 Yamanouchi Pharmaceutical Co., Ltd. Nouveaux derives de thiazolobenzimidazole
EP1074549A2 (fr) * 1999-08-06 2001-02-07 F. Hoffmann-La Roche Ag Tétrahydro-benzo(d)azépines et leurs utilisations en tant qu'antagonistes du récepteur de glutamate métabotropique
JP2002105085A (ja) * 2000-09-28 2002-04-10 Yamanouchi Pharmaceut Co Ltd 新規イミダゾチアゾール誘導体

Patent Citations (4)

* Cited by examiner, † Cited by third party
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WO1999044639A1 (fr) * 1998-03-03 1999-09-10 Yamanouchi Pharmaceutical Co., Ltd. Medicaments contre l'infarcissement du cerveau
WO2000059913A1 (fr) * 1999-04-06 2000-10-12 Yamanouchi Pharmaceutical Co., Ltd. Nouveaux derives de thiazolobenzimidazole
EP1074549A2 (fr) * 1999-08-06 2001-02-07 F. Hoffmann-La Roche Ag Tétrahydro-benzo(d)azépines et leurs utilisations en tant qu'antagonistes du récepteur de glutamate métabotropique
JP2002105085A (ja) * 2000-09-28 2002-04-10 Yamanouchi Pharmaceut Co Ltd 新規イミダゾチアゾール誘導体

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WO2020127735A1 (fr) 2018-12-20 2020-06-25 Intervet International B.V. Nouveaux procédés de production de (2-amino-4-[6-(4-fluorophényl)-2-[(4-méthyl-1-pipérazinyl)méthyl]imidazo[2,1-b]thiazol-5-yl]-pyrimidine

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