WO2006112464A1 - Piperazine-substituted benzothiophenes for treatment of mental disorders - Google Patents
Piperazine-substituted benzothiophenes for treatment of mental disorders Download PDFInfo
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- WO2006112464A1 WO2006112464A1 PCT/JP2006/308162 JP2006308162W WO2006112464A1 WO 2006112464 A1 WO2006112464 A1 WO 2006112464A1 JP 2006308162 W JP2006308162 W JP 2006308162W WO 2006112464 A1 WO2006112464 A1 WO 2006112464A1
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- lower alkyl
- alkyl group
- benzo
- thiophen
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- 0 O=C1N*Cc2c1cccc2 Chemical compound O=C1N*Cc2c1cccc2 0.000 description 2
- UWYZHKAOTLEWKK-UHFFFAOYSA-N C1c2ccccc2CNC1 Chemical compound C1c2ccccc2CNC1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 1
- GMTIYTAPFZUMOZ-UHFFFAOYSA-N CN(CC1)CCN1c1cccc2c1cc[s]2 Chemical compound CN(CC1)CCN1c1cccc2c1cc[s]2 GMTIYTAPFZUMOZ-UHFFFAOYSA-N 0.000 description 1
- TZOYXRMEFDYWDQ-UHFFFAOYSA-N O=C(CC1)Nc2c1cccc2 Chemical compound O=C(CC1)Nc2c1cccc2 TZOYXRMEFDYWDQ-UHFFFAOYSA-N 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N c1cc2cccnc2cc1 Chemical compound c1cc2cccnc2cc1 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
-
- 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
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- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- 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
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- 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
- A61P25/22—Anxiolytics
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- 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
- A61P25/32—Alcohol-abuse
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
Definitions
- the present invention relates to a novel heterocyclic compound.
- WO2004/026864A1 discloses that a carbostyril derivative represented by the general formula:
- A' represents - (CH 2 ) m CH 2 -, - (CH 2 ) m O-, etc.
- m represents an integer of 1 to 4
- R A represents a hydrogen atom, a Ci_ 4 alkyl group which may be substituted with 1 to 3 fluorine atoms, etc.
- WO2004/026864A1 that carbostyril derivatives described in the document have D 2 receptor partial agonist activity, 5-HT 2 A receptor antagonist activity, oc ⁇ receptor antagonist activity and serotonin uptake inhibitory activity together and have a wide treatment spectrum.
- WO 2005/019215 Al discloses the compounds represented by the following formula:
- A is -(CH 2 ) m CH 2 -, -(CHa) 1n O- or the like; m is an integer of 2 to 5; D is N, C or the like; Z and Q are independently N, C or CH, provided that at least one of Z and Q is N; X and Y are independently C, N or the like, and the bond between X and Y is a single or double bond; R 1 is hydrogen, (C ⁇ -C 3 )alkyl group or the like; R 4 , R 5 , R 6 and R 7 each represents hydrogen, alkyl group or the like; and G represents a group of monocyclic or bicyclic compound) , which bind to dopamine D 2 receptors.
- WO 2005/019215 Al teaches that ⁇ some compounds disclosed therein have an activity as partial agonists of D 2 receptors or an activity as antagonists of D 2 receptors, and may be effective for the treatment of schizophrenia and other central nervous system. However, WO 2005/019215 Al does not specifically disclose the compounds of the present invention.
- An object of the present invention is to provide an antipsychotic drug which has a wider treatment spectrum, less side effects and excellent tolerability and safety as compared with well-known typical and atypical antipsychotic drugs.
- the present inventors have conducted intensive studies on the above-described problem and consequently succeeded in synthesizing a novel compound which has dopamine D 2 receptor partial agonist activity (D 2 receptor partial agonist activity) , serotonin 5-HT 2A receptor antagonist activity (5-HT 2A receptor antagonist activity) and adrenalin ⁇ i receptor antagonist activity ( ⁇ i receptor antagonist activity) and further has serotonin uptake inhibitory effect (or serotonin reuptake inhibitory effect) together in addition to these effects.
- D 2 receptor partial agonist activity dopamine D 2 receptor partial agonist activity
- serotonin 5-HT 2A receptor antagonist activity (5-HT 2A receptor antagonist activity)
- adrenalin ⁇ i receptor antagonist activity ⁇ i receptor antagonist activity
- serotonin uptake inhibitory effect or serotonin reuptake inhibitory effect
- the present invention provides a heterocyclic compound represented by the general formula (1):
- the ring Q may have at least one substituent selected from the group consisting of a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a hydroxy group, a lower alkoxy group, a halogenated lower alkyl group, an aryl group, an aryl lower alkyl group, an aryl lower alkoxy group, an arylcarbonyl group, a lower alkenyloxy group, a lower alkanoyl group, a lower alkanoyloxy group, a cycloalkyl group, a cycloalkyl lower alkyl group, a halogen atom, a carbamoyl group which may have a lower alkyl group, a carboxy group, a lower alkoxycarbonyl group, an amino group which may have a lower alkanoyl group,
- R 2 represents a hydrogen atom or a lower alkyl group
- A represents -0-A 1 - (wherein Ai represents an alkylene group which may be substituted with a hydroxy group (wherein the alkylene group may contain one oxygen atom) or a lower alkenylene group) or a lower alkylene group; provided that when A represents a lower alkylene group, the ring Q represents a bicyclic group selected from the group consisting of:
- the present invention provides a heterocyclic compound represented by the general formula (1), wherein the ring Q represents a bicyclic group selected from the group consisting of:
- the ring Q may have 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a hydroxy group, a lower alkoxy group, a halogenated lower alkyl group, a phenyl group, a phenyl lower alkyl group, a naphthyl lower alkyl group, a phenyl lower alkoxy group, a naphthyl lower alkoxy group, a benzoyl group, a lower alkenyloxy group, a lower alkanoyl group, a lower alkanoyloxy group, a cyclo C3-C8 alkyl group, a cyclo C3-C8 alkyl lower alkyl group, a halogen atom, a carbamoyl group which may have a
- Cl-C ⁇ alkylene group which may be substituted with a hydroxy group (wherein the alkylene group may contain one oxygen atom)), or a salt thereof.
- the present invention provides a heterocyclic compound represented by the general formula (1) , wherein the ring Q represents a bicyclic group selected from the group consisting of:
- the ring Q may have 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a hydroxy group, a lower alkoxy group, a halogenated lower alkyl group, a phenyl group, a phenyl lower alkyl group, a naphthyl lower alkyl group, a phenyl lower alkoxy group, a naphthyl lower alkoxy group, a benzoyl group, a lower alkenyloxy group, a lower alkanoyl group, a lower alkanoyloxy group, a cyclo C3-C8 alkyl group, a cyclo C3-C8 alkyl lower alkyl group, a halogen atom, a carbamoyl group which may have a lower alkyl group, a carboxy group, a lower alkoxycarbonyl group, an amino group which may have
- A represents -0-Ai- (wherein Ai represents a C1-C6 alkylene group which may be substituted with a hydroxy group (wherein the alkylene group may contain one oxygen atom)), or a salt thereof.
- the present invention provides a heterocyclic compound represented by the general formula (1) , wherein the ring Q represents a bicyclic group selected from the group consisting of :
- the ring Q may have 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a hydroxy group, a lower alkoxy group, a halogenated lower alkyl group, a phenyl group, a phenyl lower alkyl group, a naphthyl lower alkyl group, a phenyl lower alkoxy group, a naphthyl lower alkoxy group, a benzoyl group, a lower alkenyloxy group, a lower alkanoyl group, a lower alkanoyloxy group, a cyclo C3-C8 alkyl group, a cyclo C3-C8 alkyl lower alkyl group, a halogen atom, a carbamoyl group which may have a lower alkyl group, a carboxy group, a lower alkoxycarbonyl group, an amino group which may have
- the ring Q may have 1 to 3 substituents thereon selected from the group consisting of a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a hydroxy group, a lower alkoxy group, a halogenated lower alkyl group, a phenyl group, a phenyl lower alkyl group, a naphthyl lower alkyl group, a phenyl lower alkoxy group, a naphthyl lower alkoxy group, a benzoyl group, a lower alkenyloxy group, a lower alkanoyl group, a lower alkanoyloxy group, a cyclo C3-C8 alkyl group, a cyclo C3-C8 alkyl lower alkyl group, a halogen atom, a carbamoyl group
- A represents a lower alkylene group, or a salt thereof.
- the present invention provides a heterocyclic compound represented by the general formula (1), wherein the ring Q represents a bicyclic group selected from the group consisting of:
- the ring Q may have 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a hydroxy group, a lower alkoxy group, a halogenated lower alkyl group, a phenyl group, a phenyl lower alkyl group, a naphthyl lower alkyl group, a phenyl lower alkoxy group, a naphthyl lower alkoxy group, a benzoyl group, a lower alkenyloxy group, a lower alkanoyl group, a lower alkanoyloxy group, a cyclo C3-C8 alkyl group, a cyclo C3-C8 alkyl lower alkyl group, a halogen atom, a carbamoyl group which may
- preferable compounds include a compound or a salt thereof selected from:
- preferable compounds include a compound or a salt thereof selected from:
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a heterocyclic compound represented by the formula (1) or a salt thereof as an active ingredient mixed with a pharmaceutically acceptable carrier.
- the pharmaceutical composition according to the present invention can be effectively used for the treatment or prevention of central nervous system disorders.
- the pharmaceutical composition according to the present invention can be used as a pharmaceutical composition for treating or preventing central nervous system disorders selected from the group consisting of schizophrenia; refractory, intractable or chronic schizophrenia; emotional disturbance; psychotic disorder; mood disorder; bipolar I type disorder; bipolar II type disorder; depression; endogenous depression; major depression; melancholy and refractory depression; dysthymic disorder; cyclothymic disorder; panic attack; panic disorder; agoraphobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; generalized anxiety disorder; acute stress disorder; hysteria; somatization disorder; conversion disorder; pain disorder; hypochondriasis; factitious disorder; dissociative disorder; sexual dysfunction; sexual desire disorder; sexual arousal disorder; erectile dysfunction; anorexia nervosa; bulimia nervosa; sleep disorder; adjustment disorder; alcohol abuse; alcohol intoxication; drug addiction; stimulant intoxication; narcotism; anhe
- the present invention provides a process for producing a pharmaceutical composition comprising mixing a heterocyclic compound represented by the above-described formula (1) or a salt thereof with a pharmaceutically acceptable carrier.
- the present invention provides use of a heterocyclic compound represented by the above- described formula (1) or a salt thereof as a drug.
- a heterocyclic compound represented by the above-described formula (1) or a salt thereof as a dopamine D 2 receptor partial agonist and/or a serotonin 5-HT 2A receptor antagonist and/or an adrenaline ⁇ i receptor antagonist and/or a serotonin uptake inhibitor (or a serotonin reuptake inhibitor) .
- the present invention provides a method for treating or preventing a central nervous system disorder comprising administering a compound represented by the above-described formula (1) or a salt thereof to human or animal.
- the present invention provides a process for producing a heterocyclic compound represented by the above-described formula (1):
- a linear or branched alkyl group having 1 to 6 carbon atoms can be mentioned. More specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n- pentyl, 1-ethylpropyl, isopentyl, neopentyl, n-hexyl, 1, 2, 2-trimethylpropyl, 3, 3-dimethylbutyl, 2-ethylbutyl, isohexyl, 3-methylpentyl groups are included.
- a linear or branched alkoxy group having 1 to 6 carbon atoms can be mentioned. More specifically, methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, n- hexyloxy, isohexyloxy, 3-methylpentyloxy groups are included.
- a linear or branched alkenyl group having 1 to 3 double bonds and 2 to 6 carbon atoms can be mentioned including the both of trans and cis configurations. More specifically, vinyl, 1-propenyl, 2-propenyl, 1-methyl-l-propenyl, 2- methyl-1-propenyl, 2-methyl-2-propenyl, 2-propenyl, 2- butenyl, 1-butenyl, 3-butenyl, 2-pentenyl, 1-pentenyl, 3-pentenyl, 4-pentenyl, 1, 3-butadienyl, 1,3- pentadienyl, 2-penten-4-yl, 2-hexenyl, 1-hexenyl, 5- hexenyl, 3-hexenyl, 4-hexenyl, 3, 3-dimethyl-l-propenyl, 2-ethyl-l-propenyl, 1, 3, 5-hexatrienyl, 1, 3-hexadienyl,
- a linear or branched alkynyl group having 2 to 6 carbon atoms can be mentioned. More specifically, ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, l-methyl-2-propynyl, 2-pentynyl, 2-hexynyl groups are included.
- a halogen atom fluorine atom, chlorine atom, bromine atom and iodine atom can be mentioned.
- halogenated lower alkyl group a lower alkyl group as illustrated above substituted with 1 to 7 halogen atoms, preferably 1 to 3 halogen atoms can be mentioned. More specifically, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, dichlorofluoromethyl, 2, 2-difluoroethyl, 2, 2, 2-trifluoroethyl, pentafluoroethyl, 2-fluoroethyl, 2-chloroethyl, 3,3, 3-trifluoropropyl, heptafluoropropyl, 2,2,3,3, 3-pentafluoropropyl, heptafluoroisopropyl, 3-chloropropyl, 2-chloropropyl, 3-bromopropyl, 4 , 4, 4-trifluorobutyl, 4,4,4,3,3- pentaflufluoro
- aryl group for example, phenyl, biphenyl, naphthyl groups can be mentioned and as a substituent on the phenyl ring or naphthalene ring, a lower alkyl group (preferably linear or branched alkyl group having 1 to 6 carbon atoms) as illustrated above, lower alkoxy group (preferably linear or branched alkoxy group having 1 to 6 carbon atoms) as illustrated above, and phenyl, biphenyl, or naphthyl groups which may have 1 to 3 groups selected from a nitro group and a halogen atom are included.
- a lower alkyl group preferably linear or branched alkyl group having 1 to 6 carbon atoms
- lower alkoxy group preferably linear or branched alkoxy group having 1 to 6 carbon atoms
- phenyl, biphenyl, or naphthyl groups which may have 1 to 3 groups selected from a nitro group and a halogen atom are included.
- an aryl group examples include phenyl, 2- (or 3- or 4-) methylphenyl, 2- (or 3- or 4- ) nitrophenyl, 2- (or 3- or 4-) methoxyphenyl, 2- (or 3- or 4-) chlorophenyl, biphenyl, cc-naphthyl, ⁇ -naphthyl groups .
- aryl lower alkyl group a lower alkyl group (preferably linear or branched alkyl group having 1 to 6 carbon atoms) as illustrated above which has 1 to 3, preferably one aryl group as illustrated above can be mentioned.
- an aryl lower alkyl group examples include benzyl, 2- (or 3- or 4-)methylbenzyl, 2- (or 3- or 4-) nitrobenzyl, 2- (or 3- or 4- )methoxybenzyl, 2- (or 3- or 4-) chlorobenzyl, 1- (or 2-) phenylethyl, 1-methyl-l-phenylethyl, 1, l-dimethyl-2- phenylethyl, 1, l-dimethyl-3-phenylpropyl, ⁇ - naphthylmethyl, ⁇ -naphthylmethyl groups.
- an aryl lower alkoxy group a lower alkoxy group (preferably linear or branched alkoxy group having 1 to 6 carbon atoms) as illustrated above which has 1 to 3, preferably one aryl group as illustrated above can be mentioned.
- Specific examples of an aryl lower alkoxy group include benzyloxy, 2- (or 3- or 4- )methylbenzyloxy, 2- (or 3- or 4-) nitrobenzyloxy, 2- (or 3- or 4-)methoxy benzyloxy, 2- (or 3- or 4-
- chlorobenzyl 1- (or 2-) phenylethoxy, 1-methyl-l- phenyl ethoxy, 1, l-dimethyl-2-phenyl ethoxy, 1,1- dimethyl-3-phenyl propoxy, ⁇ -naphth ' ylmethoxy, ⁇ - naphthylmethoxy groups .
- an aryl group as illustrated above can be mentioned.
- Specific examples of an arylcarbonyl group include benzoyl, 2- (or 3- or 4-) methylbenzoyl, 2- (or 3- or 4- )nitrobenzoyl, 2- (or 3- or 4-) methoxybenzoyl, 2- (or 3- or 4-) chlorobenzoyl, ⁇ -naphthoyl, ⁇ -naphthoyl groups .
- a lower alkenyloxy group As a lower alkenyloxy group, a lower alkenyloxy group having a lower alkenyl group
- a linear or branched alkanoyl group having 1 to 6 carbon atoms can be mentioned. More specifically, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert- butylcarbonyl, hexanoyl groups are included.
- a linear or branched alkanoyloxy group having 1 to 6 carbon atoms can be mentioned. More specifically, formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, tert-butylcarbonyloxy, hexanoyloxy groups are included.
- a cycloalkyl group a cyclo C3-C8 alkyl group having 3 to 8 carbon atoms can be mentioned. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl groups .
- a cycloalkyl lower alkyl group As a cycloalkyl lower alkyl group, a lower alkyl group as illustrated above which has 1 to 3, preferably one cycloalkyl group (preferably, cyclo C3- C8 alkyl group having 3 to 8 carbon atoms) as illustrated above can be mentioned.
- carbamoyl group which may have a lower alkyl group a carbamoyl group which may have 1 to 2 lower alkyl group (preferably, alkyl group having 1 to 6 carbon atoms) as illustrated above can be mentioned. More specifically included are carbamoyl, N- methylcarbamoyl, N, N-dimethylcarbamoyl, N-methyl-N- ethylcarbamoyl groups .
- lower alkoxycarbonyl group those having a lower alkoxy moiety as illustrated above, preferably a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms can be mentioned. More specifically included are methoxycarbonyl, ethoxycarbonyl, n- propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, sec- butoxycarbonyl, n-pentyloxycarbonyl, neopentyloxy, n- hexyloxy carbonyl, isohexyloxycarbonyl, 3- methylpentyloxycarbonyl groups .
- amino group which may have a lower alkanoyl group those having one lower alkanoyl group as illustrated above (preferably a linear or branched alkanoyl group having 1 to 6 carbon atoms) can be mentioned. More specifically, examples include amino, N-formylamino, N-acetylamino groups.
- a hydroxy lower alkyl group a lower alkyl group (preferably, a linear or branched alkyl group having 1 to 6 carbon atoms) as illustrated above having 1 to 5, preferably 1 to 3 hydroxy groups can be mentioned. More specifically included are hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3- hydroxypropyl, 2, 3-dihydroxypropyl, 4-hydroxybutyl, 3, 4-dihydroxybutyl, 1, l-dimethyl-2-hydroxyethyl, 5- hydroxypentyl, 6-hydroxyhexyl, 3, 3-dimethyl-3- hydroxypropyl, 2-methyl-3-hydroxypropyl, 2,3,4- trihydroxybutyl, perhydroxyhexyl groups.
- a lower alkyl group which may have a lower alkyl group
- a lower alkyl group preferably, a linear or branched alkyl group having 1 to 6 carbon atoms
- 1 to 5 preferably one amino group which may have 1 to 2 lower alkyl group (preferably, a linear or branched alkyl group having 1 to 6 carbon atoms) as illustrated above can be mentioned.
- examples of such an amino lower alkyl group which may have a lower alkyl group include aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6- aminohexyl, 1, l-dimethyl-2-methyl-3-aminopropyl, N, N- dimethylaminomethyl, N-methyl-N-ethylaminomethyl, N- methylaminomethyl, 2- (N-methylamino) ethyl, l-methyl-2- (N, N-dimethylamino) ethyl, 2- (N, N-dimethylamino) ethyl, 2-(N,N-diethylamino)ethyl, 2- (N, N- diisopropylamino) ethyl, 3- (N, N-dimethylamino) propyl, 3- (N, N-diethylamino)
- a saturated 3- to 8-membered heteror ⁇ onocyclic group containing 1 to 2 nitrogen atoms group for example, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl morpholinyl, thiomorpholinyl groups (preferably a saturated 5- to 6-membered heteromonocyclic group containing 1 to 2 nitrogen atoms group such as pyrrolidinyl, imidazolidinyl, piperidinyl, piperidino, pyrazolidinyl and piperazinyl) can be mentioned.
- a saturated 3- to 8-membered heteromonocyclic group containing 1 to 2 nitrogen atoms-substituted lower alkyl group a lower alkyl (preferably, a linear or branched alkyl group having 1 to 6 carbon atoms) as illustrated above having 1 to 2 (preferably one) a saturated 3- to 8-membered (preferably 5- to 6-membered) heteromonocyclic group containing 1 to 2 nitrogen atoms as illustrated above can be mentioned.
- Examples of an alkylene group which may be substituted with a hydroxy group include a linear or branched alkylene group (wherein the alkylene group may contain one oxygen atom) having 1 to 12 (preferably 1 to 6) carbon atoms such as methylene, ethylene, trimethylene, 2-methyltrimethylene, 2- hydroxytrimethylene, 3-hydroxytetramethylene, 3- methyltetramethylene, 2, 2-dimethyltrimethylene, 1- methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene, hexamethylene, 2- ethoxyethylene (-CH 2 CH 2 OCH 2 CH 2 -) , methoxymethylene (-CH 2 OCH 2 -), 1-ethoxyethylene (-CH 2 CH 2 OCH(CH 3 )-), 2- methoxyethylene (-CH 2 OCH 2 CH 2 -) , 2-propoxyethylene (-CH 2 CH 2 CH 2 OCH 2 CH
- Examples of a lower alkenylene group include a linear or branched alkenylene group having 1 to 3 double bonds and 2 to 6 carbon atoms such as vinylene, 1-propenylene, 1-methyl-l-propenylene, 2-methyl-l- propenylene, 2-propenylene, 2-butenylene, 1-butenylene, 3-butenylene, 2-pentenylene, 1-pentenylene, 3- pentenylene, 4-pentenylene, 1, 3-butadienylene, 1,3- pentadienylene, 2-pentene-4-ylene, 2-hexenylene, 1- hexenylene, 5-hexenylene, 3-hexenylene, 4-hexenylene, 3, 3-dimethyl-l-propenylene, 2-ethyl-l-propenylene, 1, 3, 5-hexatrienylene, 1, 3-hexadienylene, 1,4- hexadienylene groups .
- vinylene 1-propenylene, 1-
- Examples of a lower alkylene group include a linear or branched alkenylene group having 1 to 6 carbon atoms such as methylene, ethylene, trimethylene, 2-methyltrimethylene, 3-methyltetramethylene, 2,2- dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene and hexamethylene groups.
- the heterocyclic compound represented by the above-described general formula (1) can be produced in various kinds of methods, but, for example, it can be produced by a method shown in the following reaction formula .
- reaction formula 1 [Reaction Formula 1]
- examples of a group which causes a substitution reaction the same as in a halogen atom include a lower alkanesulfonyloxy group, an arylsulfonyloxy group and an aralkylsulfonyloxy group.
- a halogen atom shown as X 1 in the general formula (2) is the same as defined above.
- examples include a linear or branched alkanesulfonyloxy group having 1 to 6 carbon atoms such as methanesulfonyloxy, ethanesulfonyloxy, n- propanesulfonyloxy, isopropanesulfonyloxy, n- butanesulfonyloxy, tert-butanesulfonyloxy, n- pentanesulfonyloxy and n-hexanesulfonyloxy groups.
- a linear or branched alkanesulfonyloxy group having 1 to 6 carbon atoms such as methanesulfonyloxy, ethanesulfonyloxy, n- propanesulfonyloxy, isopropanesulfonyloxy, n- butanesulfonyloxy, tert-butanesulfonyloxy, n- pentanesulfonyloxy and n-
- examples include phenylsulfonyloxy and naphthylsulfonyloxy groups which may have 1 to 3 substituents selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkoxy group having 1 to ⁇ carbon atoms, a nitro group and a halogen atom on the phenyl ring, for example.
- a phenylsulfonyloxy group which may have a substituent include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulphonyloxy, 4-methoxyphenylsulfonyloxy, 2-nitrophenylsulphonyloxy, 3-chlorophenylsulphonyloxy groups.
- a naphthylsulfonyloxy group include ⁇ -naphthyl sulfonyloxy, ⁇ -naphthyl sulfonyloxy groups.
- examples include a linear or branched alkanesulfonyloxy group having 1 to 6 carbon atoms and substituted with a phenyl group, a linear or branched alkanesulfonyloxy group having 1 to 6 carbon atoms and substituted with a naphthyl group, which groups which may have 1 to 3 substituents selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 6 carbon atoms, a nitro group and a halogen atom on the phenyl ring, for example.
- a phenylsulfonyloxy group substituted with a naphthyl group include benzylsulfonyloxy, 2- phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4- methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4- nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, 3- chlorobenzylsulfonyloxy groups.
- alkanesulfonyloxy group substituted with a naphthyl group include ⁇ -naphthylmethyl sulfonyloxy, ⁇ -naphthylmethyl sulfonyloxy groups.
- reaction of a compound represented by the general formula (2) and a compound represented by the general formula (3) is performed without solvent or in an inert solvent in the absence or presence of a basic compound.
- an inert solvent examples include water; ethers such as dioxane, tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene, xylene; lower alcohols such as methanol, ethanol, isopropanol; ketones such as acetone, methyl ethyl ketone; polar solvents such as N, N- dimethylformamide (DMF) , dimethylsulfoxide (DMSO) , hexamethylphosphoric triamide, acetonitrile.
- ethers such as dioxane, tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether
- aromatic hydrocarbons such as benzene, toluene, xylene
- lower alcohols such as methanol, ethanol, isopropanol
- known compounds can be widely used and examples include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate; alkaline metal hydrogen carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate, potassium bicarbonate; alkaline metals such as sodium, potassium; inorganic bases such as sodium amide, sodium hydride, potassium hydride and alkaline metal alcoholates such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide; organic bases such as triethylamine, tripropylamine, pyridine, quinoline, piperidine, imidazole, N- ethyldiisopropylamine, dimethylaminopyridine, trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] nonene-5 (DBN), 1,
- the amount to be used of a basic compound is usually 0.5 to 10 times, preferably 0.5 to 6 times molar amount of a compound of the general formula (2) .
- reaction can be performed with addition of an alkaline metal iodide such as potassium iodide, sodium iodide as a reaction accelerator, if necessary.
- an alkaline metal iodide such as potassium iodide, sodium iodide as a reaction accelerator, if necessary.
- the ratio to be used of a compound of the general formula (2) and a compound of the general formula (3) in the above-mentioned reaction Formula 1 may be usually at least 0.5 times, preferably, 0.5 to 5 times molar amount of the former.
- X 2 represents a hydroxy group, a halogen atom or a group which causes a substitution reaction similar to a halogen atom
- reaction of a compound represented by the general formula (4) and a compound represented by the 5 general formula (5a) is performed under similar reaction condition as in the reaction of a compound represented by the general formula (2) and a compound represented by the general formula (3) in the above- mentioned Reaction Formula 1.
- a compound ' (5a) in which X 2 represents a hydroxy group the reaction of a compound (4) and a compound (5a) can be performed in an appropriate solvent in the presence of a condensing agent.
- halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane; esters such as methyl acetate, ethyl acetate, isopropyl acetate; polar solvent such as acetonitrile, pyridine, acetone, DMF, DMSO, hexamethylphosphoric triamide or a mixed solvent of these.
- polar solvent such as acetonitrile, pyridine, acetone, DMF, DMSO, hexamethylphosphoric triamide or a mixed solvent of these.
- azocarboxylates such as diethyl azodicarboxylate and a mixture of phosphorus compounds such as triphenylphosphine can be mentioned.
- the amount of a condensing agent to be used is usually at least equimolar, preferably equimolar to 2 times the amount of compound (4) .
- the amount of compound (5a) to be used is usually at least equimolar, preferably equimolar to 2 times the amount of compound (4) .
- reaction Formula 3 This reaction precedes usually 0 to 200°C, preferably 0 to 150 0 C and generally completed in about 1 to 10 hours.
- R 2 is the same as above, X 3 represents a halogen atom or a group which causes a substitution reaction similar to a halogen atom, A 2 represents a lower alkylene group, and the ring Ql represents a bicyclic group selected from the group consisting of:
- the ring Ql may have at least one substituent selected from the group consisting of a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a hydroxy group, a lower alkoxy group, an aryl group, an aryl lower alkyl group, an aryl lower alkoxy group, a lower alkenyloxy group, a lower alkanoyl group, a lower alkanoyloxy group, a cycloalkyl group, a cycloalkyl (lower) alkyl group, a halogen atom, a carbamoyl group which may have a lower alkyl group, a carboxy group, a lower alkoxycarbonyl group, an amino group which may have a lower alkanoyl group, a nitro group, a hydroxy lower alkyl group, an amino lower alkyl group which may have a lower alkyl group, a thi
- reaction of a compound represented by the general formula (6) and a compound represented by the general formula (5b) is performed under similar reaction condition as in the reaction of a compound represented by the general formula (2) and a compound represented by the general formula (3) in the above- mentioned Reaction Formula 1.
- reaction Formula 4 The compound represented by the general formula (2) , which is used as a starting material, can be produced, for example, according to the following reaction Formula 4 and the compound represented by the general formula (5) can be produced, for example, according to the Reaction Formula 5 below respectively.
- reaction of a compound represented by the general formula (4) and a compound represented by the general formula (8) is performed under similar reaction condition as in the reaction of a compound represented by the general formula (4) and a compound represented by the general formula (5a) in the above-mentioned Reaction Formula 2.
- reaction of a compound represented by the general formula (3) and a compound represented by the general formula (9) is performed under similar reaction condition as in the reaction of a compound represented by the general formula (2) and a compound represented by the general formula (3) in the above-mentioned Reaction Formula 1.
- Both the compound of the general formula (3) and the compound of the general formula (9) are well-known compounds readily available.
- compound (1) a compound having a hydroxy group at ring Q can be produced by treating a compound having a methoxy group at ring Q in compound (1) in the presence of an acid in an appropriate solvent or without solvent.
- examples include water; aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride; lower alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, ethylene glycol; fatty acids such as acetic acid; esters such as ethyl acetate, methyl acetate; ketones such as acetone, methyl ethyl ketone; acetonitrile, pyridine, DMF, DMSO, hexamethylphosphoric triamide or a mixed solvent of these .
- aromatic hydrocarbons such as benzene, toluene, xylene
- ethers such as diethyl
- examples include mineral acids such as hydrobromic acid, hydrochloric acid, concentrated sulfuric acid; fatty acids such as formic acid, acetic acid, organic acids such as p- toluenesulfonic acid; Lewis acids such as aluminum chloride, zinc chloride, iron chloride, tin chloride, boron trifluoride, boron tribromide; iodides such as sodium iodide, potassium iodides; a mixture of a Lewis acid and an iodide as mentioned above.
- mineral acids such as hydrobromic acid, hydrochloric acid, concentrated sulfuric acid
- fatty acids such as formic acid, acetic acid, organic acids such as p- toluenesulfonic acid
- Lewis acids such as aluminum chloride, zinc chloride, iron chloride, tin chloride, boron trifluoride, boron tribromide
- iodides such as sodium iodide, potassium iodides
- Such an acid is usually used at 0.1 to 15 times, preferably 0.5 to 10 times molar amount of compound (1) .
- the acid is usually used in a large excess amount.
- This reaction is performed usually 0 to 15O 0 C, preferably at around 0 to 100 0 C, and generally completed for about 0.5 to 75 hours.
- the starting compounds used in each of the above reaction formula may be suitable salt, the object compound obtained by each of the reaction may form a suitable salt.
- suitable salts include the preferable salts of compound (1) exemplified below.
- the preferable salts of compound (1) are pharmacologically acceptable salts and examples include metal salts such as alkali metal salts (for example, sodium salt potassium salt, etc.), alkaline earth metal salts (for example, calcium salt, magnesium salt, etc.), salts of inorganic bases such as ammonium salt, alkaline metal carbonates (for example, lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, etc.), alkaline metal hydrogen carbonates (for example, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium bicarbonate, etc.), alkali metal hydroxides (for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.); for example, salts of organic bases such as tri (lower) alkylamine (for example, trimethylamine, tri
- solvate for example, hydrate, ethanolate, etc.
- hydrate can be mentioned.
- Each of the object compounds obtained by each of the general formulas can be isolated and purified from the reaction mixture by, for example, subjecting the reaction mixture to isolation operation such as filtration, concentration and extraction after cooling to separate a crude reaction product followed by conventional purification operation such as column chromatography or recrystallization.
- isolation operation such as filtration, concentration and extraction after cooling to separate a crude reaction product followed by conventional purification operation such as column chromatography or recrystallization.
- the compound represented by the general formula (1) of the present invention naturally encompasses isomers such as geometrical isomer, stereoisomer and enantiomer.
- the compound of the general formula (1) and a salt thereof can be used in a common form of pharmaceutical preparation.
- the pharmaceutical preparation is prepared by using usually used diluent or excipient such as filler, extending agent, binder, humectant, disintegrating agent, surfactant and lubricant.
- diluent or excipient such as filler, extending agent, binder, humectant, disintegrating agent, surfactant and lubricant.
- various forms can be selected depending on the purpose of treatment, and typical examples include a tablet, pill, powder, solution, suspension, emulsion, granule, capsule, suppository, and injection (solution, suspension) .
- excipient such as lactose, saccharose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicate
- binder such as water, ethanol, propanol, simple syrup, glucose solution, starch liquid, gelatine solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone
- disintegrating agent such as dried starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose
- disintegration preventing agent such as saccharose, stearin, cacao butter, hydrogenated oil
- sorbefacient such as quaternary ammonium base, sodium lauryl sulfate
- moisturizing such as lactose, saccharose, saccharose, sodium chloride,
- the tablet may be a tablet provided with conventional coating as required, for example, sugar-coated tablet, gelatine encapsulated tablet, enteric coating tablet, film coated tablet or double tablet, multilayer tablet.
- various materials conventionally well known as carrier in the art can be widely used.
- excipient such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, talc; binder such as powdered gum arabic, powdered tragacanth, gelatine, ethanol; disintegrating agent such as laminaran, agar can be used, for example.
- various materials conventionally well known as carrier can be widely used.
- examples thereof include polyethylene glycol, cacao butter, higher alcohol, esters of higher alcohol, gelatine, semisynthesized glyceride, for example.
- a capsule is usually prepared according to a conventional method by mixing active ingredient compounds with various carrier exemplified above and filling them into a hard gelatin capsule, a soft capsule or the like.
- solution, emulsion and suspension are sterilized and isotonic to the blood and for forming in these modes
- any of those conventionally used in the art as diluent can be used, and, for example, water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid ester, etc. can be used.
- the pharmaceutical preparation may contain common salt, glucose or glycerine in an amount sufficient to prepare an isotonic solution in this case, and conventional solubilizer, buffer, soothing agent may be also added. Pigment, preservative, aromatic, flavor, sweetening and other pharmaceuticals may be further contained as required.
- the amount of a compound of the general formula (1) or a salt thereof to be contained in the pharmaceutical preparation of the present invention is not particularly limited but usually about 1 to 70% by weight in the preparation composition is suitable and preferably about 1 to 30% by weight.
- the pharmaceutical preparation of the present invention may be administered by a method in accordance with specific form of the preparation, age, sex and the other conditions of a patient, severity of disease, etc.
- a method in accordance with specific form of the preparation for example, in the case of tablet, pill, solution, suspension, emulsion, granule and capsule, it is orally administered.
- it is intravenously administered alone or in a mixture with conventional replacement fluid such as glucose and amino acids, and if necessary, and the preparation alone may be also administered intramuscularly, intracutaneously, subcutaneously or interperitoneally . It is administered in rectum in the case of suppository.
- Applied dose of the pharmaceutical preparation of the present invention is appropriately selected in accordance with dosage regimen, age, sex and the other conditions of a patient, severity of disease, etc., but it is suitable that the amount of the active ingredient compound is usually about 0.1 to 10 ing per 1 kg of body weight per day. In addition, it is desirable that the active ingredient compound is contained in the preparation of a dosage unit form in the range of about 1 to 200 mg.
- the compound of the present invention has D 2 receptor partial agonist effect, 5-HT 2A receptor antagonist effect and serotonin uptake inhibitory effect (or serotonin uptake inhibitory effect) .
- the D 2 receptor partial agonist effect suppresses dopaminergic (DA) neurotransmission when it is enhanced, and accelerates the DA neurotransmission when it is lowered and thus has a function to stabilize the DA neurotransmission to a normal state (dopamine system stabilizer) .
- DA dopaminergic
- lowering excellent clinically improving effect on the conditions based on the DA abnormal neurotransmission (enhancement and lowering) , for example, improving effect on positive and negative symptoms, improving effect on cognitive impairment, improving effect on depressive symptom, etc. are developed without developing side effects (See Michio Toru: Seishin-Igaku (Psychiatry) , Vol. 46, pp.
- 5-HT2A receptor antagonist effect reduces extrapyramidal side effects, develops superior clinical effects, and is effective for improvement of negative symptoms, improvement of cognitive impairment, improvement of depression condition, improvement of insomnia, for example (See Jun Ishigooka and Ken Inada : Rinsho-Seishin-Yakuri (Japanese Journal of Clinical Psychopharmacology) , Vol. 4, pp. 1653-1664 (2001), Mitsukuni Murasaki: Rinsho-Seishin-Yakuri (Japanese Journal of Clinical Psychopharmacology), Vol. 1, pp. 5- 22 (1998), Puller, I.A. et al., Eur. J. Pharmacol., 407:39-46, 2000, and Meltzer, H. Y. et al, Prog. Neuro- 5 Psychopharmacol. Biol. Psychiatry 27: 1159-1172, 2003).
- Serotonin uptake inhibitory effect is effective for improving depressive symptoms, for example (See Mitsukuni Murasaki: Rinsho-Seishin-Yakuri (Japanese 10 Journal of Clinical Psychopharmacology), Vol. 1, pp. 5- 22 (1998) ) .
- the compounds of the present invention are excellent in all of these three effects, or remarkably excellent in one or two of these effects. 15 In addition, some of the compounds of the present invention have oc ⁇ receptor antagonist effect in addition to the above-described effects.
- the cii receptor antagonist effect is effective for improving positive symptoms of schizophrenia (See Svensson, T. H.: 0 Prog. Neuro-Psychopharmacol . Biol. Psychiatry 27: 1145- 1158, 2003) .
- the compounds of the present invention have a wide treatment spectrum for and excellent clinical effect on schizophrenia and other 25 central nervous system disorders.
- the compounds of the present invention are extremely effective for the treatment or ⁇ ' prevention of central nervous system disorders including the group consisting of schizophrenia; refractory, intractable or chronic schizophrenia; emotional disturbance; psychotic disorder; mood disorder; bipolar disorder (for example, bipolar I type disorder and bipolar II type disorder) ; depression; endogenous depression; major depression; melancholy and refractory depression; dysthymic disorder; cyclothymic disorder; anxiety disorder (for example, panic attack, panic disorder, agoraphobia, social phobia, obsessive- compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, acute stress disorder, etc.); somatoform disorder (for example, hysteria, somatization disorder, conversion disorder, pain disorder, hypochondriasis, etc.); factitious disorder; dissociative disorder; sexual disorder (for example, sexual dysfunction, sexual desire disorder, sexual arousal disorder, erectile dysfunction, etc.); eating disorder (for example, anorexia nervos
- 1, 7- (4-chlorobutoxy) -3-methyl-lH-quinolin-2-one in the form of a white powder was prepared from 7-hydroxy-3- methyl-lH-quinolin-2-one using l-bromo-4-chlorobutane.
- Methanesulfonyl chloride (1.0 ml) was added to a dichloromethane (80 ml) solution of 2.8 g of 7- (4- hydroxy-3-methyl butoxy) -3, 4-dihydro-lH-quinolin-2-one and 2.4 ml of triethylamine while being stirred under ice-cooling and stirred at room temperature overnight. Water was added to the reaction solution, which was then extracted with dichloromethane and, after washed with water, dried over magnesium .sulfate, and the solvent was evaporated under reduced pressure.
- Lithium aluminum hydride (1.18 g, 24.8 mmol) was added to a solution of 5.26 g (16.5 mmol) of ethyl 3- (4-benzo [b] thiophen-4-yl-piperazin-l-yl) propionate in tetrahydrofuran (55 ml) with cooling in an ice-bath, followed by stirring at room temperature for 4 hours.
- Water (1.2 ml), 15 % sodium hydroxide aqueous solution (1.2 ml), and water (3.6 ml) were added to the reaction mixture in this order with stirring at room temperature. Insoluble matters were removed by filtration, and the filtrate was concentrated under reduced pressure.
- 6- [3- (4- benzo [b] thiophen-4-yl-piperazin-l-yl) propoxy] -3,4- dihydro-lH-quinolin-2-one was prepared from 6- (3- chloropropoxy) -3, 4-dihydro-lH-quinolin-2-one, and after it was made into a methanol solution, 0.5N hydrochloric acid methanol solution was added thereto, precipitated crystals were separated by filtration, recrystallized from a mixed solvent of ethyl acetate-diethyl ether and thereby 6- [3- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) propoxy] -3, 4-dihydro-lH-quinolin-2-one hydrochloride was obtained in the form of a white powder.
- 6- [3- (4-benzo [b] thiophen-4-yl-piperazin-l-yl) propoxy] -2- methyl-2H-isoquinolin-l-one was prepared from 6-[3-(4- benzo [b] thiophen-4-yl-piperazin-l-yl) propoxy] -2H- isoquinolin-1-one using methyl iodide, and after it was made into an ethyl acetate solution, IN hydrochloric acid ethanol solution was added thereto, precipitated crystals were separated by filtration, recrystallized from ethyl acetate and thereby 6- [3- (4- benzo [b] thiophen-4-yl-piperazin-l-yl) propoxy] -2-methyl- 2H-isoquinolin-l-one hydrochloride was obtained in the form of a white powder.
- Fumaric acid was added to a solution of 7- [4- ( 4-benzo [b] thiophen-4-yl-piperazin-l-yl) butoxy] -IH- quinolin-2-one in methanol and dichloromethane and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol and thereby 7- [4- (4-benzo [b] thiophen-4-yl-piperazin-l-yl) butoxy] -IH- quinolin-2-one fumarate was obtained in the form of a white powder.
- Citric acid was added to a solution of 7- [4- (4-benzo [b] thiophen-4-yl-piperazin-l-yl) butoxy] -IH- quinolin-2-one in methanol and dichloromethane and the solvent was evaporated under reduced pressure. The residue was recrystallized from 50% ethanol and thereby 7- [4- (4-benzo [b] thiophen-4-yl-piperazin-l-yl) butoxy] - lH-quinolin-2-one citrate was obtained in the form of a white powder.
- Example 47 Preparation of 7- [4- (4-benzo [b] thiophen-4-yl- piperazin-1-yl) butoxy] -lH-quinolin-2-one p- toluenesulfonate p-Toluenesulfonic acid monohydrate was added to a solution of 7- [4- (4-benzo [b] thiophen-4-yl- piperazin-1-yl) butoxy] -lH-quinolin-2-one in methanol and dichloromethane and the solvent was evaporated under reduced pressure.
- Fumaric acid was added to an ethanol solution of 7- [3- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) propoxy] -2-methyl-3, 4-dihydro-2H-isoquinolin-l-one and the solvent was evaporated under reduced pressure. The residue was recrystallized from 70% ethanol and thereby 7- [3- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) propoxy] -2-methyl-3, 4-dihydro-2H-isoquinolin-l-one fumarate was obtained in the form of a pale yellow powder.
- Fumaric acid was added to an ethanol solution of 7- [3- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) propoxy] -2-methyl-3, 4-dihydro-2H-isoquinolin-l-one and the solvent was evaporated under reduced pressure. The residue was recrystallized from 90% ethanol and thereby 7- [3- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) propoxy] -2-methyl-3, 4-dihydro-2H-isoquinolin-l-one difumarate was obtained in the form of white prism crystal . Melting point 188-189 0 C
- Methanesulfonic acid was added to an ethanol solution of 7- [3- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) propoxy] -2-methyl-3, 4-dihydro-2H-isoquinolin-l-one and the solvent was evaporated under reduced pressure. The residue was recrystallized from 80% ethanol and thereby 7- [3- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) propoxy] -2-methyl-3, 4-dihydro-2H-isoquinolin-l-one methanesulfonate was obtained in the form of pale yellow prism crystal.
- PS-triphenylphosphine 110 mg, 3 mmol/g
- dibenzyl azodicarboxylate 70 mg, 0.3 mmol
- 4- dihydroisoquinoline 80 mg, 0.45 mmol
- 3- (4- benzo [b] thiophen-4-yl-piperazin-1-yl) propan-1-ol 83 mg, 0.3 mmol
- the reaction mixture was cooled to room temperature and insoluble matters were removed by filtration. The filtrate was concentrated under reduced pressure.
- the reaction mixture was concentrated under reduced pressure, and water and ethyl acetate were added to the residue to separate the organic phase from the water phase.
- the organic phase was washed with water, saturated sodium hydrogencarbonate aqueous solution and brine in this order, and concentrated under reduced pressure.
- the resulting residue was dissolved in ethyl acetate (10 ml) , and IN-HCl - ethanol solution was added thereto.
- Triethylar ⁇ ine (0.25 ml, 1.8 mmol) and isobutyl chloroformate (0.19 ml, 1.4 mmol) were added to a solution (10 ml) of 4- [3- (4-benzo [b] thiophen-4-yl- piperazin-1-yl) propoxy] quinolin-2-carboxylic acid (0.53 g, 1.2 mmol) in acetonitrile with cooling in an ice- bath, followed by stirring at 0°C for 3 hours. 28% Aqueous ammonia (0.15 ml) was added thereto and the reaction mixture was stirred at room temperature for 5 minutes.
- Example 64 to 196 shown in the following Tables 1 to 21 can be prepared in the same manner as in Example 1, using corresponding starting materials.
- compounds with the physical properties, such as crystalline form, m.p. (melting point) , salt, 1 H-NMR and MS (mass spectrum) were prepared actually.
- the assay was performed according to the method by Kohler et al . (Kohler C, Hall H, Ogren SO and Gawell L, Specific in vitro and in vivo binding of 3H- raclopride. A potent substituted benzamide drug with high affinity for dopamine D-2 receptors in the rat brain. Biochem. Pharmacol., 1985; 34: 2251-2259).
- Wistar male rats were decapitated, the brain was retrieved immediately and corpus striatum was taken out. It was homogenized in 50 mM tris (hydroxymethyl) aminomethane (Tris) -hydrochloric acid buffer (pH 7.4) of a volume 50 times of the weight of the tissue using a homogenizer with a high-speed rotating blade, and centrifuged at 4°C, 48,000 x g for 10 minutes. The obtained precipitate was suspended again in the above-described buffer of a volume 50 times of the weight of the tissue and after incubated at 37 0 C for 10 minutes, centrifuged in the above- described condition.
- Tris tris (hydroxymethyl) aminomethane
- the obtained precipitate was suspended in 50 mM (Tris) -hydrochloric acid buffer (containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl 2 , 1 mM MgCl 2 , pH 7.4) of a volume 25 times of the weight of the tissue and preserved by freezing at -85°C till it was used for binding assay as a membrane specimen.
- 50 mM (Tris) -hydrochloric acid buffer containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl 2 , 1 mM MgCl 2 , pH 7.4
- the binding assay was performed using 40 ⁇ l of the membrane specimen, 20 ⁇ l of [ 3 H] -raclopride (final concentration 1 to 2 nM) , 20- ⁇ l of a test drug and 50 mM Tris-hydrochloric acid buffer (containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl 2 , 1 mM MgCl 2 , pH 7.4) so that the total amount was 200 ⁇ l (final dimethylsulfoxide concentration 1%) .
- the reaction was performed at room temperature for 1 hour and terminated by conducting suction filtration with a cell harvester on a glass fiber filter plate.
- the filter plate made of glass fiber was washed with 50 mM Tris-hydrochloric acid buffer (pH 7.4), and after dried, a microplate liquid scintillation cocktail was added and the radioactivity was measured with a microplate scintillation counter. Radioactivity in the presence of 10 ⁇ M (+) -butaclamol hydrochloride was assumed as nonspecific binding.
- IC50 value was calculated from concentration- dependent reaction using a non-linear analysis program. Ki value was calculated from IC 50 value using Cheng- Prussoff formula. The results are shown in the following Table 22.
- the assay was performed according to the method by Leysen JE et al. (Leysen JE, Niemegeers CJE, Van Nueten JM and Laduron PM. [3H] Ketanserin (R 41 468), a selective 3H-ligand for serotonin 2 receptor binding sites. MoI. Pharmacol., 1982, 21: 301-314).
- Wistar male rats were decapitated, the brain was retrieved immediately and frontal cortex was taken out. It was homogenized in 0.25 M sucrose of a volume 10 times of the weight of the tissue using a Teflon glass homogenizer, and centrifuged at 4°C, 1,000 x g for 10 minutes. The obtained supernatant was transferred to another centrifuge tube and suspended in 0.25 M sucrose of a volume 5 times of the weight of the tissue and the precipitate was centrifuged in the above- described condition.
- the obtained supernatant was combined with the supernatant obtained above and adjusted to a volume 40 times of the weight of the tissue with 50 mM Tris-hydrochloric acid buffer (pH 7.4), and centrifuged at 4°C, 35,000 x g for 10 minutes.
- the obtained precipitate was suspended again in the above-described buffer of a volume 40 times of the weight of the tissue and centrifuged in the above- described condition.
- the obtained precipitate was suspended in the above-described buffer of a volume 20 times of the weight of the tissue and preserved by freezing at -85°C till it was used for binding assay as a membrane specimen.
- the binding assay was performed using 40 ⁇ l of the membrane specimen, 20 ⁇ l of [ 3 H] -Ketanserin (final concentration 1 to 3 nM) , 20 ⁇ l of a test drug and 50 mM Tris-hydrochloric acid buffer (pH 7.4) so that the total amount was 200 ⁇ l (final dimethylsulfoxide concentration 1%) .
- the reaction was performed at 37 0 C for 20 minutes and terminated by conducting suction filtration with a cell harvester on a glass fiber filter plate.
- the filter plate made of glass fiber was washed with 50 mM Tris-hydrochloric acid buffer (pH 7.4), and after dried, a microplate liquid scintillation cocktail was added and the radioactivity was measured with a microplate scintillation counter. Radioactivity in the presence of 10 ⁇ M spiperone was assumed as nonspecific binding.
- IC50 value was calculated from concentration- dependent reaction using a non-linear analysis program. Ki value was calculated from IC 50 value using Cheng- Prussoff formula. The results are shown in the following Table 23.
- the assay was performed according to the method by Gro ⁇ G et al . (Gro ⁇ G, Hanft G and Kolassa N. Urapidil and some analogues with hypotensive properties show high affinities for 5-hydroxytryptamine (5-HT) binding sites of the 5-HT1A subtype and for ⁇ l- adrenoceptor binding sites. Naunyn-Schmiedeberg' s Arch Pharmacol., 1987, 336: 597-601).
- Wistar male rats were decapitated, the brain was retrieved immediately and cerebral cortex was taken out. It was homogenized in 50 mM Tris-hydrochloric acid buffer (100 mM NaCl, containing 2 mM dihydrogen disodium ethylene diamine tetraacetate, pH 7.4) of a volume 20 times of the weight of the tissue using a homogenizer with a high-speed rotating blade, and centrifuged at 4°C, 80,000 x g for 20 minutes. The obtained precipitate was suspended in the above- described buffer of a volume 20 times of the weight of the tissue and after incubated at 37°C for 10 minutes, centrifuged in the above-described condition.
- Tris-hydrochloric acid buffer 100 mM NaCl, containing 2 mM dihydrogen disodium ethylene diamine tetraacetate, pH 7.4
- the obtained precipitate was suspended again in the above- described buffer of a volume 20 times of the weight of the tissue and centrifuged in the above-described condition.
- the obtained precipitate was suspended in 50 mM (Tris) -hydrochloric acid buffer (containing 1 mM dihydrogen disodium ethylene diamine tetraacetate, pH 7.4) of a volume 20 times of the weight of the tissue and preserved by freezing at -85 0 C till it was used for binding assay as a -membrane specimen.
- the binding assay was performed using 40 ⁇ l of the membrane specimen, 20 ⁇ l of [ 3 H] -prazosin (final concentration 0.2 to 0.5 nM) , 20 ⁇ l of a test drug and 50 mM Tris-hydrochloric acid buffer (containing 1 mM EDTA, pH 7.4) so that the total amount was 200 ⁇ l (final dimethylsulfoxide concentration 1%) .
- the reaction was performed at 30 0 C for 45 minutes and terminated by conducting suction filtration with a cell harvester on a glass fiber filter plate.
- the filter plate made of glass fiber was washed with 50 mM Tris-hydrochloric acid buffer (pH 7.4), and after dried, a microplate liquid scintillation cocktail was added and the radioactivity was measured with a microplate scintillation counter. Radioactivity in the presence of 10 ⁇ M phentolamine hydrochloride was assumed as nonspecific binding.
- IC 50 value was calculated from concentration- dependent reaction using a non-linear analysis program. Ki value was calculated from IC 50 value using Cheng- Prussoff formula.
- Partial agonistic activity on dopamine D 2 receptor was evaluated by quantitatively determining cyclic AMP production inhibitory effect of a test compound in dopamine D 2 receptor expression cells in ⁇ which adenosine 3', 5' -cyclic monophosphate (cyclic AMP) production was induced by forskolin stimulation.
- Human recombinant dopamine D 2 receptor expressing Chinese hamster ovary/DHFR (-) cells were cultured in a culture medium (Iscove's Modified Dulbecco's Medium (IMDM culture medium), 10% fetal bovine serum, 50 I. U.
- the culture medium was replaced with 50 ⁇ l of culture medium (IMDM culture medium, 0.1% sodium ascorbate, 0.1 mM sodium hypoxanthine, 16 ⁇ M thymidine) having dissolved therein 3 ⁇ M of a test compound.
- IMDM culture medium 0.1% sodium ascorbate, 0.1 mM sodium hypoxanthine, 16 ⁇ M thymidine
- the culture medium was replaced with 100 ⁇ l of forskolin stimulative culture medium (IMDM culture medium, 0.1% sodium ascorbate, 0.1 mM sodium hypoxanthine, 16 ⁇ M thymidine, 10 ⁇ M forskolin, 500 ⁇ M 3-isobutyl-l-methylxanthine) having 3 ⁇ M of the test compound dissolved therein and allowed to incubate at 37 0 C, 5% carbon dioxide condition for 10 minutes.
- forskolin stimulative culture medium IMDM culture medium, 0.1% sodium ascorbate, 0.1 mM sodium hypoxanthine, 16 ⁇ M thymidine, 10 ⁇ M forskolin, 500 ⁇ M 3-isobutyl-l-methylxanthine
- Lysis IB aqueous solution (Amersham Bioscience, reagent attached to cyclic AMP biotrack enzyme immunoassay system) was dispensed and shaken for 10 minutes. The aqueous solution of each well was used as a sample for measurement. Samples for measurement quadruply diluted were subjected to measurement of the quantity of cyclic AMP using the above-described enzyme immunoassay system. Inhibition ratio of the respective test compound was calculated assuming that the quantity of cyclic AMP of the well to which no test compound was added was 100%. In this empiric test system, dopamine which was used as a control drug suppressed the quantity of cyclic AMP to about 10% as the maximum activity.
- test compounds had partial agonistic activity for dopamine D 2 receptor in the above-described test.
- test compounds Since the test compounds has partial agonistic activity for dopamine D 2 receptor, they can stabilize dopamine neurotransmission to a normal condition in a schizophrenia patient and as a result, exhibit, for example, positive and negative condition improving effect, cognitive impairment improving effect and the other symptom improving effects without causing side effects.
- Wistar rats male, six-seven weeks old, Japan SLC, Inc. were used as test animals.
- a test compound was suspended in 5% gum arabic/ (physiological saline or water) using an agate mortar and was diluted with the same solvent if necessary. Test animals were fasted overnight from the day before.
- Apomorphine 0.7 mg/kg was subcutaneously administered (1 ml/kg) 1 hour after each test compound was orally administered (5 ml/kg) . Stereotyped behavior was observed for 1 minute respectively 20, 30 and 40 minutes after apomorphine injection.
- the stereotyped behavior of each animal was quantified according to the following condition and score made at three points were summed up and the anti- apomorphine effect was evaluated. Six test animals were used for each group.
- Non-clinical statistical analysis system was used for all statistical processing. When the significance probability value was lower than 0.05, it was judged that a significant difference existed. The difference of the score between the solvent administration group and each test compound administration group was analyzed using Wilcoxon rank- sum test or Steel test. In addition, linear regression analysis was used for calculating 50% effective dose (95 % confidence interval).
- test compounds showed inhibitory effect for apomorphine-induced stereotyped behavior, it was confirmed that the test compounds have D 2 receptor antagonistic effect.
- Wistar rats male, six-seven weeks old, Japan SLC, Inc. were used as test animals.
- a test compound was suspended in 5% gum arabic/ (physiological saline or water) using an agate mortar and was diluted with the same solvent if necessary.
- Test animals were fasted overnight from the day before. DOI (5.0 mg/kg) was subcutaneously administered (1 ml/kg) 1 hour after each test compound was orally administered (5 ml/kg) . The number of head twitches was counted for 10 minutes immediately after DOI injection. Six test animals were used for each group. Non-clinical statistical analysis was used for all statistical processing. When the significance probability value was lower than 0.05, it was judged that a significant difference existed. The difference of the number of head twitches between the solvent administration group and each test compound administration group was analyzed using t-test or Dunnett ' s test. In addition, linear regression analysis was used for calculating 50% effective dose (95 % confidence interval).
- test compounds showed inhibitory effect for DOI-induced head twitch, it was confirmed that the test compounds have serotonin 5H ⁇ 2A receptor antagonistic effect.
- Test animals were fasted overnight from the day before observation on catalepsy and ptosis was performed 1, -2, 4, 6 and 8 hours after each test compound was orally administered (5 ml/kg) . Six test animals were used for each group.
- catalepsy induction effect of a test compound was dissociated from inhibitory effect on apomorphine-induced stereotyped behavior, therefore it was suggested that apprehension for extrapyramidal side effect in clinic would be low.
- Wistar male rats were decapitated, the brain was retrieved and frontal cortex was dissected out, and it was homogenized in 0.32 M sucrose solution of a weight 20 times of the weight of the tissue using a Potter type homogenizer.
- the homogenate was centrifuged at 4°C, 1,000 x g for 10 minutes, the obtained supernatant was further centrifuged at 4 0 C, 20,000 x g for 20 minutes, and the pellet was suspended in an incubation buffer (20 mM Hepes buffer (pH 7.4) containing 10 mM glucose, 145 mM sodium chloride, 4.5 mM potassium chloride, 1.2 mM magne-sium chloride, 1.5 mM calcium chloride) , which was used as crude synaptosome fraction.
- 5-HT uptake reaction was performed in a volume of 200 ⁇ l using a 96-well round bottom plate and pargyline (final concentration 10 ⁇ M) and sodium ascorbate (final concentration 0.2 mg/ml) were contained in the incubation buffer upon reaction and used.
- the uptake time was 10 minutes and the reaction was terminated by vacuum filtration through a 9 ⁇ -well fiber glass filter paper plate, and after the filter paper was washed with cold normal saline, it was dried enough and MicroscintO (Perkin-Elmer) was added to the filter and remaining radioactivity on the filter was measured.
- MicroscintO Perkin-Elmer
- the obtained tablet was coated with a film using a film coating agent made up of 10 g of TC-5 (trade name, product of Shin-Etsu Chemical Co., Ltd., hydroxypropyl methylcellulose) , 3 g of polyethylene glycol 6000, 40 g of castor oil and an appropriate amount of ethanol to produce a film coated tablet of the above composition.
- a film coating agent made up of 10 g of TC-5 (trade name, product of Shin-Etsu Chemical Co., Ltd., hydroxypropyl methylcellulose) , 3 g of polyethylene glycol 6000, 40 g of castor oil and an appropriate amount of ethanol to produce a film coated tablet of the above composition.
Abstract
Description
Claims
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ES06732069.7T ES2358631T7 (en) | 2005-04-14 | 2006-04-12 | Benzothiophenes with substituted piperazin for the treatment of mental illness |
BRPI0609785A BRPI0609785B8 (en) | 2005-04-14 | 2006-04-12 | Piperazine-substituted benzothiophenes, pharmaceutical composition, process for producing a pharmaceutical composition, use of piperazine-substituted benzothiophenes or a salt thereof, and, process for producing piperazine-substituted benzothiophenes |
EP06732069.7A EP1869025B3 (en) | 2005-04-14 | 2006-04-12 | Piperazine-substituted benzothiophenes for treatment of mental disorders |
CN2006800119230A CN101155804B (en) | 2005-04-14 | 2006-04-12 | Piperazine-substituted benzothiophenes for treatment of mental disorders |
CA2602247A CA2602247C (en) | 2005-04-14 | 2006-04-12 | Piperazine-substituted benzothiophenes for treatment of mental disorders |
US15/815,650 USRE48059E1 (en) | 2005-04-14 | 2006-04-12 | Piperazine-substituted benzothiophenes for treatment of mental disorders |
IL185909A IL185909A (en) | 2005-04-14 | 2007-09-11 | Compounds comprising benzo[b]thiophene, piperazine and optionally hydrogenated quinoline/isoquinoline rings, process for their preparation and pharmaceutical compositions comprising them for treating cns disorders |
HK08107408.3A HK1112236A1 (en) | 2005-04-14 | 2008-07-04 | Piperazine-substituted benzothiophenes for treatment of mental disorders |
US12/970,690 US8349840B2 (en) | 2005-04-14 | 2010-12-16 | Piperazine-substituted benzothiophenes for treatment of mental disorders |
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US14/928,972 US9480686B2 (en) | 2005-04-14 | 2015-10-30 | Piperazine-substituted benzothiophenes for treatment of mental disorders |
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US15/697,196 US9839637B1 (en) | 2005-04-14 | 2017-09-06 | Piperazine-substituted benzothiophenes for treatment of mental disorders |
US15/799,520 US20180214444A1 (en) | 2005-04-14 | 2017-10-31 | Piperazine-Substituted Benzothiophenes For Treatment of Mental Disorders |
LTPA2018509C LTC1869025I2 (en) | 2005-04-14 | 2018-08-09 | Piperazine replaced benzothiophenes for the treatment of mental disorders |
NL300946C NL300946I2 (en) | 2005-04-14 | 2018-08-10 | Brexpiprazole, optionally in the form of a salt |
CY2018028C CY2018028I1 (en) | 2005-04-14 | 2018-10-15 | PIPERAZINE SUBSTITUTED BENZOTHIOPHENES FOR THE TREATMENT OF MENTAL DISORDERS |
HUS1800041C HUS1800041I1 (en) | 2005-04-14 | 2018-10-26 | Piperazine-substituted benzothiophenes for treatment of mental disorders |
US16/228,284 US20190117648A1 (en) | 2005-04-14 | 2018-12-20 | Piperazine-Substituted Benzothiophenes For Treatment of Mental Disorders |
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