WO2008047883A1 - Piperazine-substituted benzothiophenes for treatment of mental disorders - Google Patents

Piperazine-substituted benzothiophenes for treatment of mental disorders Download PDF

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Publication number
WO2008047883A1
WO2008047883A1 PCT/JP2007/070386 JP2007070386W WO2008047883A1 WO 2008047883 A1 WO2008047883 A1 WO 2008047883A1 JP 2007070386 W JP2007070386 W JP 2007070386W WO 2008047883 A1 WO2008047883 A1 WO 2008047883A1
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Prior art keywords
group
lower alkyl
alkyl group
halogen
benzo
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PCT/JP2007/070386
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French (fr)
Inventor
Hiroshi Yamashita
Jun Matsubara
Kunio Oshima
Hideaki Kuroda
Satoshi Shimizu
Tatsuyoshi Tanaka
Shinichi Taira
Kazumi Kondo
Haruka Takahashi
Tae Fukushima
Yohji Sakurai
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Otsuka Pharmaceutical Co., Ltd.
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Publication of WO2008047883A1 publication Critical patent/WO2008047883A1/en

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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
    • C07D409/12—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/66—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel, heterocyclic compound.
  • WO2004/026864A1 discloses that a carbostyril derivative represented by a general formula:
  • A' represents - (CH2) m CH2- f -(CH 2 ) m O-, etc.
  • m represents an integar of 1 to 4
  • R A represents C 1 - 4 alkyl group that may be substituted with a hydrogen atom and one to three fluorine atoms, etc.
  • the carbostyril derivative shown in the above formula has D 2 receptor antagonist action, and serotonin 2A (5-HT 2A ) receptor antagonist action, being effective for treatment for schizophrenia and other central nervous system diseases.
  • WO2004/026864A1 does not disclose at all that the carbostyril derivative described in the document concomitantly has D 2 receptor partial agonist action, 5-HT 2A receptor antagonist action, ofi receptor antagonist action, and serotonin uptake inhibiting action, and has a wide treatment spectrum.
  • WO2005/043309A1 discloses a ce-rtain type of [1, 8]naphthyridine-2-one derivative.
  • WO2004/043309A1 as well, it is not disclosed at all that the [1, 8] naphthyridine-2-one derivative described in the document concomitantly has D 2 receptor partial agonist action, 5-HT 2 A receptor antagonist action, ⁇ i receptor antagonist action, and serotonin uptake inhibiting action, and has a wide treatment spectrum.
  • the problem to be solved by the present invention is to provide an antipsychotic drug with a wider treatment spectrum, less side effects and ' excellent tolerability and safety ' compared to known typical antipsychotic drugs and atypical antipsychotic drugs .
  • the inventors succeeded in synthesizing a novel compound having serotonin uptake inhibiting action (or serotonin reuptake inhibiting action) as well as dopaminergic D 2 receptor partial agonist action (D 2 receptor partial agonist action) , serotonin-5-HT.2a receptor antagonist action (5-HT 2 A receptor antagonist action) , and adrenaline ⁇ i receptor antagonist action (o£i receptor antagonist action) .
  • the present invention was accomplished based on such knowledge. Item 1.
  • the present invention provides a heterocyclic compound or a salt thereof represented by the general formula (1) :
  • a 1 represents a lower alkylene group
  • Z represents 0 or S
  • R 11 represents (1-1) hydrogen, (1-2) a lower alkyl group
  • a hydroxysulfonyl group (xviii) a hydroxysulfonyl group, (xix) an amino group which may have a group (s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a cyclo (C3- C8) alkyl group, an aryl group, and an aroyl group, (xx) a morpholinylcarbonyl lower alkenyl group,
  • (xxxiii) a dihydropyrazolyl group which may have a group (s) selected from the group . consisting of an oxo group and a lower alkyl group) ,
  • heterocyclic group (wherein the heterocyclic group may be substituted by at least one group selected from the group consisting of the following substituents (i) to (xix) : (i) a lower alkyl group, (ii) a halogen substituted lower alkyl group,
  • an aryl group which may have, on the aryl group, a group (s) selected from the group consisting of halogen and a halogen substituted lower alkyl group,
  • a lower alkanoyl group (ix) an aroyl group, (x) an amino lower alkanoyl group which may have, on the amino group, a lower alkanoyl group, (xi) a lower alkylthio group, (xii) a pyrrolyl group, (xiii) an oxo group, (xiv) a thioxo group,
  • an amino lower alkyl group which may have, on the amino group and/or the lower alkyl group, a group (s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a hydroxy lower alkyl group, a lower alkoxycarbonyl group, a carbamoyl lower alkyl group, an indolylcarbonyl group, an aryl group (the aryl group may have a group (s) selected from the group consisting of halogen and a lower alkoxy group) , and an aryl lower alkoxycarbonyl group,
  • an aryloxy lower alkyl group which may have, on the aryl group, a group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, halogen, and a cyano group,
  • an adamantyl lower alkyl group (1-11) an aryl lower alkenyl group which may have, on the aryl group, a group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen substituted lower alkyl group, a halogen substituted lower alkoxy group, an amino group which may have a lower alkyl group (s), halogen, and a nitro group,
  • a cyclo (C3-C8) alkyl group which may have a group (s) selected from the group consisting of: an amino group which may have a lower alkyl group (s); an amino lower alkyl group which may have a lower alkyl group (s); and an aryl group which may have a group (s) selected from the group consisting of halogen and a lower alkyl group, (1-13) a cyclo (C3-C8) alkyl lower alkyl group,
  • an arylthio lower alkyl group (1-15) a lower alkyl group substituted by a heterocyclic group selected from the group consisting of a piperidyl group, a tetrahydropyranyl group, a pyridyl group, a thienyl group, an • imidazolyl group, a tetrazolyl group, a benzimidazolyl group, an isoindolyl group, a thiazolidinyl group, and an indolyl group (wherein the heterocyclic group may have a group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, halogen, an oxo group, and a thioxo group) ,
  • an aryl lower alkyl group which may have, on the aryl group, a group (s) selected from the group consisting of an amino group which may have a lower alkyl group (s) and an aryloxy group, (2-13) a tetrahydrofuryl group, (2-14) a lower alkyl group substituted by a heterocyclic group selected from the group consisting of a furyl group and a pyridyl group, (2-15) a tetrahydropyranyl group, or
  • -A 2 - represents a lower alkylene group, a lower alkenylene group, or a group -A 21 -0-A 22 -, wherein A 21 and A 22 are the same or different and each represents a C1-C5 alkylene group (provided that the total number of carbon atoms constituting the alkylene group of A 21 and the alkylene group of A 22 does not exceed 6) ;
  • R 21 represents a N-containing heterocyclic group, . , wherein • the N-containing heterocyclic ring represented by R 21 may be substituted by at least one group selected from the group consisting of the following (1) to (13) :
  • Q represents a group represented by the following formula (I) :
  • a 1 represents a lower alkylene group
  • Z represents 0 or S
  • R 1 * represents
  • xviii a hydroxysulfonyl group
  • xix a an amino group which may have one to two group (s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a cyclo(C3- C8) alkyl group, a phenyl group, and a benzoyl group,
  • a heterocyclic group selected from the group consisting of pyrrolidinyl, piperidyl, thiazolidinyl, tetrahydropyranyl, pyrrolyl, imidazolyl, pyrazolyl, dihydropyrazolyl, pyridyl, dihydropyridyl, tetrahydropyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, thienyl, furyl, indolyl, indolinyl, isoindolinyl, benzimidazolyl, imidazopyridyl, quinolyl, dihydroquinolyl, tetrahydroquinolyl, isoquinolyl, cinnolinyl, indazolyl, quinoxalinyl, benzotriazolyl, dihydronaphthyridinyl, benzothiazolyl, dihydro
  • a phenyl group which may have, on the phenyl group, one to three group (s) selected from the group consisting of halogen and a halogen substituted lower alkyl group,
  • an amino lower alkyl group which may have, on the amino group' and/or the lower alkyl group, one to two group (s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a hydroxy lower alkyl group, a lower alkoxycarbonyl group, a carbamoyl lower alkyl group, an indolylcarbonyl group, a phenyl group (the phenyl group may have' one to three group (s) selected from the group consisting of halogen and a lower alkoxy group) , and a phenyl lower alkoxycarbonyl group, (1-6) a lower alkoxy lower alkyl group,
  • a benzoyl lower alkyl group (1-8 a) a phenyl lower alkyl group which may have, on the phenyl group, one to three group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, a hydroxy group, halogen, and a nitro group,
  • a phenoxy lower alkyl group which may have, on the phenyl group, one to three group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, halogen, and a cyano group,
  • an adamantyl lower alkyl group (1-11 a) a phenyl lower alkenyl group which may have, on the phenyl group, one to three group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen substituted lower alkyl group, a halogen substituted lower alkoxy group, an amino group which may have one to two lower alkyl group (s), halogen, and a nitro group,
  • a cyclo (C3-C8) alkyl group which may have one to two group (s) selected from the group consisting of: an amino group which may have one to two lower alkyl group (s) ; an amino lower alkyl group which may have one to two lower alkyl group (s); and a phenyl group which may have one to three group (s) selected from the group consisting of halogen and a lower alkyl group, (1-13) a cyclo (C3-C8) alkyl lower alkyl group,
  • a phenylthio lower alkyl group (1-15 a) a lower alkyl group substituted by a heterocyclic group selected from the group consisting of a piperidyl group, a tetrahydropyranyl group, a pyridyl group, a thienyl group, an imidazolyl group, a tetrazolyl group, a benzimidazolyl group, an isoindolyl group, a thiazolidinyl group, and an indolyl group (wherein the heterocyclic group may have one to three group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, halogen, an oxo group, and a thioxo group) ,
  • a phenyl lower alkenyl group (which may have, on the lower alkenyl group, one to two phenyl group(s)), (1-17) a lower alkenyl group substituted by a heterocyclic group selected from the group consisting of a benzodioxolyl group, a pyridyl group, a furyl group, and an imidazolyl group, (1-18) a benzodioxolyloxy lower alkyl group, (1-19) a pyridylthio lower alkyl group, or (1-20 a) an amino group which may have one to two lower alkyl group (s); and R 12 represents
  • (2-5) a lower alkynyl group, (2-6) a lower alkanoyl group, (2-7) a hydroxy lower alkyl group, (2-8) a lower alkoxy lower alkyl group, (2-9) a cyclo(C3-C8) alkyl group,
  • a phenyl lower alkyl group which may have, on the phenyl group, one to three group (s) selected from the group consisting of an amino group which may have one to two lower alkyl group (s) and a phenoxy group,
  • R 21 represents a N-containing heterocyclic group selected from the group consisting of pyrrolidinyl, imidazolidinyl, piperidyl, hexahydropyrimidinyl, piperazinyl, octahydroisoindolyl, azepanyl, azocanyl, azaspirononanyl, azaspirodecanyl, diazaspirononanyl, dihydropyrrolyl, ir ⁇ idazolyl, dihydroimidazolyl, triazolyl,
  • R 21 may be substituted by one to three group (s) selected from the group consisting of the following (1) to (4), (5 a), (6 a), (7) to (9), (10 a), (11 a) , (12) , and (13) :
  • the present invention provides the heterocyclic compound or a salt thereof according to item 2, wherein Q represents a group represented by the following formula (I) :
  • a 1 represents a lower alkylene group; Z represents O or S; R 11 represents (1-1) hydrogen,
  • (l-4aa) a heterocyclic group selected from the group consisting of pyrazinyl and thienyl (wherein the heterocyclic group may be substituted by one lower alkyl group) ,
  • an amino lower alkyl. group which may have, on the amino group and/or the lower alkyl group, one or two group (s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a hydroxy lower alkyl group, a lower alkoxycarbonyl group, a carbamoyl lower alkyl group, an indolylcarbonyl group, a phenyl group (the phenyl group may have one group selected from the group consisting of halogen and a lower aikoxy group) , and a phenyl lower alkoxycarbonyl group, or
  • R 12 represents
  • Q represents a group represented by the following general formula (II) :
  • R 21 represents a N-containing heterocyclic group selected from the group consisting of pyrrolidinyl, imidazolidinyl, piperidyl, azepanyl, oxazolidinyl, and oxazinanyl, wherein the N-containi ⁇ g heterocyclic ring represented by R 21 may be substituted by one to three group (s) selected from the group consisting of the following (1), (12), and (13): (1) a halogen substituted or unsubstituted alkyl group,
  • the present invention provides the heterocyclic compound of the formula (1) or a salt thereof, according to item 3. selected from the group consisting of:
  • the present invention provides The heterocyclic compound of the formula (1) or a salt thereof according to item 4 selected from the group consisting of:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a heterocyclic compound of the formula (1) or a salt thereof according to any one of items 1 to 6, as an. active ingredient and a pharmaceutically acceptable carrier.
  • the present invention provides the pharmaceutical composition according to item 7 for treating or preventing central nervous system disorders.
  • the present invention provides the pharmaceutical composition according to item 8 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; anhedonia; i
  • the present invention provides a process for producing a pharmaceutical composition comprising mixing a heterocyclic compound of the formula (1) or a salt thereof according to any one of claims 1 to 6 with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier for a pharmaceutical composition
  • the present invention relates to use of a heterocyclic compound of the formula (1) or a salt thereof according to any one. of items 1 to 6 as a drug.
  • the present invention relates to use of a heterocyclic compound of the formula (1) or a salt thereof according to any one of items 1 to 6 as a dopamine D2 receptor partial agonist and/or a serotonin 5-HT2A receptor antagonist and/or an adrenaline ⁇ i receptor antagonist and/or a serotonin uptake inhibitor and/or a serotonin reuptake inhibitor.
  • a dopamine D2 receptor partial agonist and/or a serotonin 5-HT2A receptor antagonist and/or an adrenaline ⁇ i receptor antagonist and/or a serotonin uptake inhibitor and/or a serotonin reuptake inhibitor Item 13.
  • the present invention provides a method for treating or preventing a central nervous system disorder comprising administering a heterocyclic compound of the formula (1) or a salt thereof according to any one of items 1 to 6 to human or animal. Claims of specific compounds of an amide type/heterocyclic ring type are described in items 5 and 6.
  • R 1 *, R 12 , and A 1 in the formula (I) representing Q and R 21 and A 2 in the formula (II) representing Q . should represent the following substituents: a heterocyclic compound or a salt thereof represented by the general formula (1) :
  • a 1 represents a lower alkylene group; Z represents 0 or S; R 11 represents
  • halogen (ix a) a phenyl group, (x a) a phenoxy group, (xi) a lower alkoxycarbonyl group, (xii) a hydroxy group,
  • a lower alkylthio group (xvii) a lower alkylsulfonyl group, (xviii) a hydroxysulfonyl group, (xix a) an ⁇ itiino group which may have one to two group (s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a cyclo (C3- C8)alkyl group, a phenyl group, and a benzoyl group (more preferably, a N,N-di lower alkylamino group, a lower alkanoylamino group, a N-lower alkanoyl-N cyclo (C3-C8) alkylamino group, a phenylaraino group, or a benzoylamino group) ,
  • a heterocyclic group selected from the group consisting of pyrrolidinyl, piperidyl, thiazolidinyl, tetrahydropyranyl, pyrrolyl, imidazolyl, pyrazolyl, dihydropyrazolyl, pyridyl, dihydropyridyl, tetrahydropyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, thienyl, furyl, indolyl, indolinyl, isoindolinyl, benzimidazolyl, imidazopyridyl, quinolyl, dihydroquinolyl, tetrahydroquinolyl, isoquinolyl, cinnoliriyl, indazolyl, quinoxalinyl, benzotriazolyl, dihydronaphthyridinyl, benzothiazolyl, di
  • a phenyl group which may have, on the phenyl group, one to three (preferably, one) group (s) selected from the group consisting of halogen and a halogen substituted lower alkyl group,
  • a lower alkanoyl group (viii) a lower alkanoyl group, (ix a) a benzoyl group, (x a) an amino lower alkanoyl group which may have, on the amino group, one to two (preferably, one) lower alkanoyl group (s),
  • an amino lower alkyl group which may have, on the amino group and/or the lower alkyl group, one to two group (s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a hydroxy lower alkyl group, a lower alkoxycarbonyl group, a carbamoyl lower alkyl group, an indolylcarbonyl group, a phenyl group (the phenyl group may have one to three (preferably, one) group (s) selected from the group consisting of halogen and a lower alkoxy group) , and a phenyl lower alkoxycarbonyl group,
  • a phenoxy lower alkyl group which may have, on the phenyl group, one to three group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, halogen, and a cyano group,
  • an adamantyl lower alkyl group (1-11 a) a phenyl lower alkenyl group which may have, on the phenyl group, one to three (preferably, one to two) group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen substituted lower alkyl group, a halogen substituted lower alkoxy group, an amino group which may have one to two lower alkyl group (s) (preferably, a N,N-di lower alkylamino group), halogen, and a nitro group,
  • a cyclo (C3-C8) alkyl group which may have one group selected from the group consisting of: an amino group which may have one to two lower alkyl group(s) (preferably, a N,N-di lower alkylamino group); an amino lower alkyl group which may have one to two lower alkyl group (s) (preferably, a N,N-di lower alkylamino lower alkyl group) ; and a phenyl group which may have one to three (preferably, one) group (s) selected from the group consisting of halogen and a lower alkyl group,
  • a phenyl lower alkenyl group (which may have, on the lower alkenyl group, one to two (preferably, one) phenyl group(s)),
  • R 11 includes (1-1) hydrogen, (1-2) a lower alkyl group,
  • an amino lower alkyl group having, on the amino group and/or the lower alkyl group, one group selected from, the group consisting of a lower alkanoyl group and a lower alkoxycarbonyl group, or
  • a phenyl lower alkyl group which may have, on the phenyl group, one to three. (preferably, one) group (s) selected from the group consisting of an amino group which may have one to two lower alkyl group (s) (more preferably, a N,N-di lower alkylamino group) and a phenoxy group,
  • R 12 includes (2-1) hydrogen, (2-2) a lower alkyl group, (2-4) a lower alkenyl group, (2-6) a lower alkanoyl group,
  • -A 2 - represents a lower alkylene group, a lower alkenylene group, or a group -A 21 -0-A 22 -, wherein A 21 and A 22 are the same or different and each represents a C1-C5 alkylene group (provided that the total number of carbon atoms constituting the alkylene group of A 1 and the alkylene group of A 2 does not exceed
  • R 21 represents a N-containing heterocyclic group selected from the group consisting of pyrrolidinyl, imidazolidinyl, piperidyl, hexahydropyrimidinyl, piperazinyl, octahydroisoindole, azepanyl, azocanyl, azaspirononanyl, azaspirodecanyl, diazaspirononanyl, dihydropyrrolyl, imidazolyl, dihydroimidazolyl, triazolyl, dihydrotriazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidinyl, dihydropyrimidinyl, pyrazinyl, dihydropyrazinyl, pyridazinyl, tetrazolyl, indolyl/ isoindolyl, indolinyl, isoindolinyl, hexahydrois
  • a phenyl lower alkyl group (which may have, on the phenyl group, one to two lower alkoxy group (s) ) , .
  • R 21 includes: an imidazolidinyl group having one to two group (s) selected from the group consisting of a lower alkyl group and an oxo group; a piperidyl group having one to two group (s) selected from the group consisting of a lower alkyl group, an oxo group, and a thioxo group; an oxazolidinyl group having one to three group (s) selected from the group consisting of a lower alkyl group and an oxo group; and an oxazinanyl group having one to two group (s) selected from the group consisting of a lower alkyl group and an oxo group) ] .
  • each group shown in the above general formula is as follows.
  • lower alkyl group linear or branched alkyl group with carbon number 1 to 6 (preferably, carbon number 1 to 4) can be cited. 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, and 3- methylpentyl groups, etc., are included.
  • lower alkylene group linear or branched alkylene group with carbon number 1 to 6 (preferably, carbon number 1 to 4) can be cited. More specifically, methylene, ethylene, trimethylene, • 2- methyltrimethylene, 2,2-dimethylethylene, 2,2- dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, 1- methyltetramethylene, 1-ethyltetramethylene, 2- methyltetramethylene, 2-ethyltetramethylene, pentamethylene, and hexamethylene groups, etc., are included.
  • lower alkenylene group linear or branched alkynylene group with carbon number 2 to 6 (preferably, carbon number 2 to 4) having one to three double bonds
  • 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-ynylene, 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, and 1,4- hexadienylene groups, etc
  • C1-C5 alkylene group linear or branched alkylene group with carbon number 1 to 5 can be cited. More specifically, methylene, ethylene, trimethylene, 2-methyltrimethylene, 2, 2-dimethylethylene, ' 2,2- dimethyl ' trimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, and pentamethylene groups, etc., are included.
  • lower alkenyl group linear or branched alkenyl group with carbon number 2 to 6 (preferably, carbon number 2 to 4) having one to three double bonds can be cited, and includes both trans isomer and cis isomer. More specifically, vinyl, 1-propenyl, 2- propenyl, 1-methyl-1-propenyl, 2-methyl-l-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-pentene-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,
  • alkynyl group linear or branched alkynyl group with carbon number 2 to 6 (preferably, carbon number 2 to 4) can be ⁇ cited. More specifically, ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, l-methyl-2- • propynyl, 2-pentynyl, and 2-hexynyl groups, etc., are included.
  • halogen atom fluorine atom, chlorine atom, bromine atom and iodine atom can be cited.
  • halogen substituted lower alkyl group the above exemplified lower alkyl group with one to seven halogen atoms substituted, more preferably one to three halogen atoms substituted, can be cited. 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-pent
  • lower alkoxy group linear or branched alkoxy group with carbon number 1 to 6 (preferably, carbon number 1 to 4) can be cited. More specifically, methoxy, ethoxyl, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, and 3-methylpentyloxy groups, etc., are included.
  • aryl group for example, phenyl, biphenyl, naphthyl, dihydroindenyl, and 9H-fluorenyl groups, etc., can be cited.
  • aryloxy group for example, phenyloxy, and naphthyloxy groups, etc., can be cited.
  • arylthio group for example, phenylthio, and naphthylthio groups, etc., can be cited.
  • lower alkylthio group linear or branched alkylthio group with carbon number 1 to 6 (preferably, carbon number 1 to 4) can be cited. More specifically, methylthio, ethylthio, n-propylthio, isopropylthio, n- butylthio, tert-butylthio, n-pentylthio, and n- hexylthio groups, etc., are included.
  • halogen substituted lower alkoxy group As halogen substituted lower alkoxy group, the above exemplified lower alkoxy group with one to seven halogen atoms substituted, preferably one to three halogen atoms substituted, can be- cited. More specifically, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, bromomethoxy, dibromomethoxy, dichlorofluoromethoxy, 2,2, 2-trifluoroethoxy, pentafluoroethoxy, 2-chloroethoxy, 3,3,3- trifluoropropoxy, heptafluoropropoxy, heptafluoroisopropoxy, 3-chloropropoxy, 2- chloropropoxy, 3-bromopropoxy, 4, 4, 4-trifluorobutoxy, 4, 4, 4,3, 3-pentafluorobutoxy, 4-chlorobutoxy, A- ⁇ bromobutoxy, 2-
  • alkanoyl group linear or branched alkanoyl group with carbon number 1 to 6 (preferably, carbon number 1 to 4) can be cited. More specifically, formyl, acetyl, propionyl, butyryl> isobutyryl, pentanoyl, tert-butylcarbonyl, and hexanoyl groups, etc., are included.
  • alkanoyloxy group with the alkanoyl part being linear or branched alkanoyl group with carbon number 1 to 6 (preferably, carbon number 1 to 4) can be cited. More specifically, formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, tert-butylcarbonyloxy, and hexanoyloxy groups, etc., are included.
  • lower alkanoyloxy lower alkyl group linear or branched alkyl group with carbon number 1 to 6 (preferably, carbon number 1 to 4) having one to three of the above exemplified lower alkanoyloxy groups, preferably one, can be cited. More specifically, formyloxymethyl, 3-acetyloxypropyl, 2- propionyloxyethyl, butyryloxymethyl, 2- isobutyryloxyethyl, 3- ⁇ entanoyloxypropyl, tert- butylcarbonyloxymethyl, and hexanoyloxymethyl groups, etc., are included.
  • lower alkyl group linear or branched alkyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4)
  • lower alkanoyl group linear or branched alkanoyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4)
  • phenyl lower alkyl group with the lower alkyl part being linear or branched alkyl group with carbon number 1 to 6 (preferably, carbon number 1 to 4) that may have one to three substituent groups such as halogen atom, etc., preferably one, on the phenyl group, can be cited.
  • linear or branched alkyl group with carbon number 1 to 6 preferably, carbon number 1 to 4
  • lower alkanoyl group linear or branched alkanoyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4)
  • phenyl lower alkyl group with the lower alkyl part being linear or branched alkyl group with carbon number 1 to 6 (preferably, carbon number 1 to 4)
  • the above exemplified lower alkoxy group phenyl lower alkoxy group with the lower alkanoyl part being the above exemplified lower alkanoyloxy group and the lower alkoxy part being the above exemplified lower alkoxy group (that may have one to three substituent groups such as halogen atom, etc., preferably one, on the phenyl group) can be cited.
  • hydroxy lower alkyl group the above exemplified lower alkyl group having one to five hydroxy groups, preferably one to three (linear or branched alkyl group with preferably carbon number 1 to 6 (more, preferably, carbon number 1 to 4)) can be cited. More specifically, hydroxymethy1, 2- hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2,3- dihydroxypropyl, 4-hydroxybutyl, 3, 4-dihydroxybutyl, l,-l-dimethyl-2-hydroxyethyl, 5-hydroxypentyl, 6- hydroxyhexyl, 3, 3-dimethyl-3-hydroxypropyl, 2-methyl-3- hydroxypropy1,.
  • hydroxy lower alkyl group for example, linear or branched alkyl group with carbon number 1 to 6 (preferably, carbon number 1 to 4) , lower alkanoyl group (linear or branched alkanoyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4) ) , and phenyl lower alkyl group with the lower alkyl part being linear or branched alkyl group with carbon number 1 to 6 (preferably, carbon number 1 to 4) can be cited.
  • the above exemplified lower alkyl group (linear or branched alkyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4) ) having one to five, preferably one to three, of the above exemplified protected hydroxy groups (preferably, lower alkoxy group, lower alkanoyloxy group or phenyl lower alkoxy group (that may have one to three substituent groups such as halogen atom, preferably one, on phenyl group) ) can be cited.
  • methoxymethyl 2- methoxyethyl, 2-ethoxyethyl, 2-n-propox ' yethyl, 2- isopropoxyethyl, 2-n-butoxyethyl, 2-isobutoxyethyl, 2- tert-butoxyethyl, 2-sec-butoxyethyl, 2-n- pentyloxyethyl, 2-isopentyloxyethyl, 2- neopentyloxyethyl, 2-n-hexyloxyethyl, 2- isohexyloxyethyl, 2- (3-methylpentyloxy) ethyl, 2- formyloxyethyl, 2-acetyloxyethyl, 2-propionyloxyethyl, 2-butyryloxyethyl, 2-isobutyryloxyethyl, 2- pentanoyloxyethyl, 2-tert-butylcarbonyloxyethyl,
  • alkoxycarbonyl group with the lower alkoxy part being the above exemplified lower alkoxy group (linear or branched alkoxy group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4)) can be cited.
  • alkyl sulfonyl group with the lower alkyl part being the above exemplified lower alkyl group (linear or branched alkyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4) ) can be cited.
  • cyclo C3-C8 alkyl group for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups, etc., can be cited.
  • amino group that may have a group (s) selected from the group consisting of lower alkyl group, lower alkanoyl group, cyclo C3-C8 alkyl group, aryl group, and aroyl group as substituent group amino group that may have one to two groups selected from the group consisting of the above exemplified lower alkyl group (linear or branched alkyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4) ) ; the above exemplified lower alkanoyl group (linear or branched alkanoyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4) ) ; the above exemplified cyclo C3-C8 alkyl group, and aryl group (preferably phenyl group) ; and the above exemplified aryl group (preferably, phenyl group) , and the exemplified aroyl group (preferably, benzoyl group) as substituent
  • morpholinylcarbonyl lower alkenyl group As morpholinylcarbonyl lower alkenyl group, morpholinylcarbonyl lower alkenyl group with the lower alkenyl part being the above exemplified lower alkenyl group (linear or branched alkenyl group with preferably carbon number 2 to 6 (more preferably, carbon number 2 to 4)) can be cited. More specifically, 1- (or 2-) (4- morpholinylcarbonyl) vinyl, 1- (or 2- or 3-) (4- morpholinylcarbonyl) 1- (or 2-)propenyl groups are included. . .
  • morpholinylcarbonyl lower alkyl group with the lower alkyl part being the above exemplified lower alkyl group (linear or branched alkyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to- 4) can be cited. More specifically, 4- morpholinylcarbonylmethyl, 1- (or 2-) (4- morpholinylcarbonyl) ethyl, 1- (or 2- or 3-) (4- morpholinylcarbonyl) 1- (or 2-) propropyl groups are included.
  • pyrrolidinyl group that may have an oxo group pyrrolidinyl group that may have one to two oxo groups (preferably, one) is cited. Specifically, (1-, 2-, or 3-) pyrrolidinyl, (2- or 3-) oxo-1- pyrrolidinyl, (3-, 4-, or 5-) oxo-2-pyrrolidinyl, (2-, 4-, or 5-) oxo-3-pyrrolidinyl groups can be cited.
  • dihydropyrazolyl group that may have a group (s) selected from the group consisting of oxo group and lower alkyl group
  • dihydropyrazolyl group that may have one to two groups selected from the group consisting of oxo group and the above exemplified lower alkyl group is cited.
  • aryl group that may have a group (s) selected from the group consisting of halogen and halogen substituted lower alkyl group on aryl group, aryl group with the aryl part being phenyl, naphthyl, etc., that may have one to five, preferably one to three, more preferably one, of the above exemplified halogen ' and the above exemplified halogen substituted lower alkyl group (linear or branched alkyl group with preferably halogen substituted carbon number 1 to 6 (more preferably, carbon number 1 to 4)) on said aryl part, can be cited.
  • aryl lower alkyl group that may have a halogen atom(s)
  • the above exemplified lower alkyl group linear or branched alkyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4) ) having one to three, preferably one, aryl groups with the aryl part being phenyl, and naphthyl, etc.
  • substituent group on aryl group one to five, preferably one to three, more preferably one to two, of the above exemplified halogen may be substituted.
  • amino lower alkanoyl group As amino lower alkanoyl group, the above exemplified lower alkanoyl group (linear or branched alkanoyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4)) having one to three amino groups (preferably, one) can be cited. More specifically, aminoacetyl, 3-aminopropionyl, A- aminobutyryl, 3, 4-diaminobutyryl, 3, 3-dimethyl-3- aminopropionyl, 4-aminob ⁇ tyryl r and 5-aminovaleryl groups, etc., are included.
  • amino lower alkanoyl group that may have a lower alkanoyl group (s) on amino group
  • the above exemplified amino lower alkanoyl group having one to two (preferably, one) of the above exemplified lower alkanoyl group as substituent group can be cited.
  • carbamoyl lower alkyl group As carbamoyl lower alkyl group, the above exemplified lower alkyl group (linear or branched alkyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4)) having one to three carbamoyl groups, more preferably one to two, can be cited.
  • amino lower alkyl group As amino lower alkyl group, the above exemplified lower alkyl group (linear or branched alkyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4)) having one to five amino groups, preferably one, can be cited.
  • amino lower alkyl group that may have a group (s) selected from the group consisting of lower alkyl group, lower alkanoyl group, hydroxy lower alkyl group, carbamoyl lower alkyl groups indolylcarbonyl group, aryl group (that may have a group (s) selected from the group consisting of halogen and lower alkoxy group on said aryl group) , and aryl lower alkoxy carbonyl group, on amino group and/or on lower alkyl group
  • the above exemplified lower alkyl group linear or branched alkyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4) ) having one to five amino groups, preferably one, can be cited.
  • On amino group and/or on lower alkyl group there may be one to two groups selected from the group consisting of the above exemplified lower alkyl group (linear or branched alkyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4)), the above exemplified lower alkanoyl group (linear or branched alkanoyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4)), the above exemplified hydroxy lower alkyl group (preferably, linear or branched alkyl group with carbon number 1 to 6 (preferably, carbon number 1 to 4) having one to three hydroxy groups) , the above exemplified carbamoyl lower alkyl group (preferably, linear or branched alkyl group with carbon number 1 to 6 (preferably, carbon number 1 to 4) having one to three carbamoyl groups), indolylcarbonyl group, aryl group that may have a group (s)' selected from the group consisting of the
  • the above exemplified lower alkyl group (linear or branched alkyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4) ) having one to three, preferably one, of the above exemplified lower alkoxy group (linear or branched alkoxy group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4) ) can be cited.
  • An aroyl lower alkyl group refers to a lower alkyl group (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl group) as the above, having 1 to 5 preferably one aroyl goup (preferably benzoyl) as the above. More specific examples includes benzoylmethyl, 2- benzoylethyl, 1-benzoylethyl, 1- (or 2 ⁇ ) naphthoylmethyl group.
  • An aryl lower alkyl group which may have a group (s,) selected from the group consisting of a lower alkyl, a lower alkoxy, a hydroxy, a halogen and a nitro on the aryl, refers to a lower alkyl group (preferably, carbon number 1 to 6 (more preferably, carbon numberl to 4) linear or branched alkyl group) as the above, which has 1 to 3 (preferably one) aryl wherein an aryl moiety is phenyl, naphthyl or the like.
  • Substituent groups on the aryl group may be 1 to 5, preferably 1 to 3, more preferably 1 to 2 groups selected from the group consisting of a lower alkyl (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl groups) as the above, a lower alkoxy (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkoxy groups) as the above, hydroxy, a halogen and nitro as the above.
  • a lower alkyl preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl groups
  • a lower alkoxy preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkoxy groups
  • An aryloxy lower alkyl group which may have a group (s) selected from the group consisting of a lower alkyl, a lower alkoxy, a halogen and cyano on the aryl, refers to a lower alkyl (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl groups) as the above, which has 1 to 3 (preferably one) aryl wherein the aryl moiety is phenyl, naphthyl or the like.
  • Substituent groups on the aryl may be 1 to 5, preferably 1 to 3 groups selected from the group consisting of a lower alkyl (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl groups) as the above, a lower alkoxy (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl groups) as the above, a halogen and cyano as the above.
  • a lower alkyl preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl groups
  • a lower alkoxy preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl groups
  • a halogen and cyano as the above.
  • An aryl lower alkoxy group refers to a lower alkoxy (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkoxy groups) as the above, which has 1 to 3 (more preferably one) aryl wherein the aryl moiety is phenyl, naphthyl or the like.
  • An amino group which may have a lower alkyl group refers to an amino which may have 1 to 2 lower alkyl groups (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl groups) as the above. More specific • examples include amino, N-methylamino, N, N- dimethylamino, N-ethylamino, N,N-diethylamino, N-n- propylamino, N-isopropylamino and the like.
  • An aryl lower alkenyl group refers to a lower alkenyl (preferably, carbon number 2 to 6 (more preferably, carbon number 2 to 4) linear or branched alkenyl groups) as the above, which has 1 to 3 (more preferably one) aryl wherein the aryl moiety is phenyl, naphthyl or the like.
  • An aryl lower alkenyl group which may have a group (s) selected from the group consisting of a lower alkyl, a lower alkoxy, a halogen substituted lower alkyl, a halogen substituted lower alkoxy, an amino which may have a lower alkyl, a halogen and nitro on the aryl group, refers to an aryl lower alkenyl (carbon number 2 to 6 (preferably, carbon number 2 to 4) linear or branched alkenyl groups, which preferably has one phenyl substituted), as the above.
  • Substituent groups on the aryl group may be 1 to 5, preferably 1 to 3, more preferably 1 to 2 groups selected from the group consisting of a lower alkyl (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl groups) as the above, a lower alkoxy (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkoxy groups) as the above, a halogen substituted lower alkyl (carbon number 1 to 6 (preferably, carbon number 1 to 4) linear or branched alkyl groups preferably having 1 to 3 halogens) as the above, a halogen substituted lower alkoxy (carbon number 1 to 6 (preferably, carbon number 1 to 4) linear or branched alkoxy groups preferably .
  • a lower alkyl preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl groups
  • a lower alkoxy preferably, carbon number 1 to
  • amino which may have a lower alkyl group (s) as the above (amino group which may have one or two linear or branched alkyl groups (preferably, with carbon number 1 to 6, more preferably, with carbon number 1 to 4), a halogen and nitro as the above.
  • An aryl group which may have a group (s) selected from the group consisting of a halogen and a lower alkyl refers to an aryl group in which the aryl moiety is phenyl, naphtyl or the like, and which has on the aryl moiety 1 to 5, preferably 1 to 3, more preferably one of a halogen and a lower alkyl (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl groups) as the above.
  • a C3-C8 cycloalkyl which may have a group(s) selected from the group consisting of an amino group which may have a lower alkyl group (s); an amino lower alkyl group which may have a lower alkyl and an aryl group which may have a group (s) selected from the group consisting of a halogen and a lower alkyl, refers to an C3-C8 cycloalkyl as the above which may have 1 to 3, preferably one group selected from the group consisting of an amino group which may have a lower alkyl group (s) as the above, which preferably may have 1 to 2 linear or branched alkyl groups with carbon number 1 to 6 (more preferably, carbon number 1 to 4), an amino lower alkyl as the above which may have a lower alkyl group (s) as the above (wherein the amino lower alkyl is preferably a linear or branched alkyl group with carbon number 1 to 6 (more preferably, carbon number 1 to 4) which has 1 to 5,
  • a C3-C8 cycloalkyl lower alkyl group refers to a lower alkyl (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl group) as the above, which has 1 to 3, preferably one C3-C8 cycloalkyl as the above.
  • An arylthio lower alkyl group refers to a lower alkyl (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl group) as the above, which has 1 to 3, preferably one arylthio group as the above.
  • An adamanthyl lower alkyl group refers to a lower alkyl (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl group) as the above, which has 1 to 3, preferably one adamanthyl group.
  • a lower alkyl group which is substituted by a heterocyclic group (wherein the heterocyclic group may be substituted by a group (s) selected from the group consisting of a lower alkyl, a lower alkoxy, a halogen, oxo and thioxo on the heterocyclic group) selected from the group consisting of piperidyl, tetrahydropyranyl, pyridyl, thienyl, imidazolyl, tetrazolyl, benzimidazolyl, isoindolyl, thiazoridinyl, and indolyl refers to a lower alkyl group (preferably a 1 to 6 (more preferably 1 to 4) linear or branched alkyl group) as the above, which is substituted by 1 to 3, preferably one heterocyclic group selected from the group consisting of piperidyl, tetrahydropyranyl, pyridyl, thienyl, imidazolyl,
  • Substituent groups on the heterocyclic group may be 1 to 5, preferably 1 to 3 groups selected from the group consisting of a lower alkyl (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl group) as the above, a lower alkoxy (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkoxy group) as the above, a halogen, oxo and thioxo as the above.
  • a lower alkyl preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl group
  • a lower alkoxy preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkoxy group
  • a halogen, oxo and thioxo as the above.
  • An aryl lower alkenyl group (which may have an aryl group (s) on the lower alkenyl) refers to an aryl lower alkenyl (preferably, carbon number 2 to 6 (more preferably, carbon number 2 to 4) linear or branched alkenyl group which is substituted by one phenyl) as the above.
  • Substituent groups on the lower alkenyl may be 1 to 3, preferably 1 to 2, more preferably one aryl (preferably a phenyl group) as the above .
  • a lower alkenyl group which is substituted by a heterocyclic group (s) selected from the group consisting of benzodioxolyl, pyridyl, furyl and imidazolyl refers to a lower alkenyl group (preferably, carbon number 2 to 6 (more preferably, carbon number 2 to 4) linear or branched alkenyl group) as the above, which is substituted by 1 to 3, preferably one heterocyclic group selected from the group consisting of benzodioxolyl, pyridyl, and imidazolyl.
  • a benzodioxolyloxy lower alkyl group refers to a lower alkyl (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl group) as the above, which has 1 to 3, preferably one benzodioxolyloxy.
  • a pyridylthio lower alkyl group refers to a lower alkyl (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl group) as the above, which has 1 to 3, preferably one pyridylthio.
  • An aryl lower alkyl group which may have a group (s) selected from the group consisting of an amino which may have a lower alkyl group (s) and aryloxy on the aryl group refers to a lower alkyl (preferably, . carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl group) as the above, which may have 1 to 3, preferably one aryl wherein an aryl moiety is a phenyl, naphtyl and the like.
  • Substituent groups on the aryl may be 1 to 5, preferably 1 to 3, more preferably 1 group selected from the group consisting of an amino which may have a lower alkyl as the above (an amino group which may have one or two alkyl) (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl group) and an aryl oxy (preferably phenoxy) as the above.
  • a lower alkyl group which is substituted by a heterocyclic group (s) selected from the group consisting of furyl and pyridyl refers to a lower alkyl (preferably, carbon number 1 to 6 (more .preferably, carbon number 1 to 4) linear or branched alkyl group) as the above, which is substituted by 1 to 3, preferably one heterocyclic group ' selected from the group consisting of furyl and pyridyl.
  • a heterocyclic group refers to a saturated 3 to 8 membered (preferably 5 to 8 membered) monocyclic group which contains 1 to 4 (preferably 1 to 2) nitrogen atoms (for example, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, hexahydropyrimidinyl, piperazinyl, octahydroisoindole, azepanyl, azokanyl, etc.); a saturated 3 to 8 membered (more preferably 5 or 6 membered) monocyclic group which contains 1 to 2 (preferably one) oxygen atom and 1 to 3 (preferably 1 to 2) nitrogen atoms (for example, oxazolidinyl, isoxazolidinyl, morpholinyl, etc.); a saturated spiroheterocyclic group which contains 1 to 2 nitrogen atoms (for example, azaspirononanyl (for example, 1-azaspiro [4, 4]non
  • a saturated 3 to 8 memberd (more preferably 5 or 6 membered) heteromonocyclic group which contains 1 to 2 oxygen atoms for example, tetrahydrofuryl, tetrahydropyranyl, oxyranyl, oxoranyl, dioxoranyl, etc; a saturated 3 to 8 memberd (more preferably 5 or 6 membered) heteromonocyclic group which contains 1 to 2 (preferably one) sulphur atom, for example, tetrathienyl, tetrahydrothiopyranyl, etc.; • an unsaturated 3 to 8 itierabered (more preferably 5 or 6 membered) heteromonocyclic group which contains 1 to 4 (preferably 1 to 3) nitrogen atoms (for example, pyrrolyl, dihydropyrrolyl (for example, lH-2,5- dihydropyrrolyl etc.), imidazolyl (for example, IH- imidazolyl etc.), dihydroimi
  • pyrazolyl dihydropyrazolyl (for example, 4, 5-dihydropyrazolyl etc.), pyridyl, dihydropyridyl (for example, 1,2- dihydropyridyl etc.), pyrimidinyl, dihydropyrimidinyl (for example, 1, 6-dihydropyrimidinyl etc.), tetrahydropyrimidinyl (for example, 1,2,3,4- tetrahydropyrimidinyl etc.), pyrazinyl, dihydropyrazinyl (for example, 1,2-dihydropyrazinyl etc.), pyridazinyl, tetrazolyl (for example, IH- tetrazolyl, 2H-tetrazolyl, etc.), etc.); • an unsaturated, 3 to 8 membered (more preferably 5 membered) heteromonocyclic group which, contains 1 to 2 sulphur atoms and 1
  • an unsaturated, fused heterocyclic group which contains 1 to 4 (preferably 1 to 2) nitrogen atoms for example, indolyl, isoindolyl, indolinyl, isoindolinyl, hexahydroisoindolinyl (for example, 2, 3, 3a, 4, 7, 7a- hexahydroisoindolinyl, etc.) benzoimidazolyl, imidazopyridyl (for example, imidazo[l, 2-a]pyridyl, etc.), quinolyl, dihydroquinolyl (for example, 1,2- dihydroquinolyl etc.), tetrahydroquinolyl (1,2,3,4- tetraquinolyl etc.), isoquinolyl, cynolinyl, indazolyl, quinazolinyl, dihydroquinazolinyl (3,4- dihydroquinazolinyl etc.), benzotriazolyl (for example
  • An N-containing heterocyclic group refers to a saturated 3 to 8 membered (preferably 5 to 8 membered) heterocyclic group which contains 1 to 4 (preferably 1 to 2) nitrogen atoms; a saturated spiroheterocyclic group which contains 1 to 2 nitrogen atoms; an unsaturated 3 to 8 membered (preferably 5 or 6 membered) heteromonocyclic group which contains 1 to 4 (preferably 1 to 3) nitrogen atoms; an unsaturated fused heterocyclic group which contains 1 to 4 (preferably 1 to 2) nigrogen atoms; an unsaturated spiroheterocyclic group which contains 1 to 2 nigrogen atoms; an unsaturated 3 to 8 membered (more preferably 5 or 6 membered) heteromonocyclic group which contains 1 to 2 (preferably one) oxygen atom and 1 to 3 (preferably 1 to 2) nitrogen atoms; a saturated 3 to 8 membered (more preferably 5 or 6 membered) heteromonocyclic group which contains 1 to 2 (preferably one
  • a saturated 3 to 8 membered (preferably 5 to 8 membered) heteromonocyclic group- which contains 1 to 4 (preferably 1 to 2) nitrogen atoms refers to, for example, pyrolydinyl, imidazolidinyl, pyperidyl, hexahydropyrimidinyl, piperadinyl, octahydroisoindole, azepanyl, azokanyl, etc.
  • saturated spiroheterocyclic group which contains 1 to 2 nitrogen atoms refers to, for example, azaspirononanyl (for example, 1-azaspiro [4, 4]nonanyl, 2-azaspiro[4, 4]nonanyl, etc.
  • azaspirodecanyl for example, 1-azaspiro [4, 5]decanyl, 2-azaspiro[4, 5]decanyl, etc.
  • diazaspirononanyl for example, 1,3- diazaspiro[4, 4]nonanyl, 1, 4-diazaspiro [4, 4]nonanyl, etc.
  • An unsaturated 3 to 8 membered (preferably 5 or 6 membered) heteromonocyclic group which contains 1 to 4 (preferably 1 to 3) nigrogen atoms refers to, for example, pyrrolyl, dihydropyrrolyl (for example, IH- 2, 5-dihydropyrrolyl etc.), imidazolyl (for example, IH- imidazolyl etc.), dihydroimidazolyl (for example, IH- 2, 3-dihydroimidazolyl etc.), triazolyl (for example, 4H-l,2,4-triazolyl, IH-I, 2, 3-triazolyl, 2H-1,2,3- triazolyl, etc.), dihydrotriazolyl (for example, IH- 4, 5,-dihydro-l,2, 4-triazolyl etc.) / pyrazolyl, pyridyl, dihydropyridyl (for example, 1,2-dihydropyridyl etc.),
  • An unsaturated fused heterocyclic group which contains 1 to 4 (preferably 1 to 2) nitrogen atoms refers to, for example, indolyl, isoindolyl, indolinyl, isoindolinyl, hexahydroisoindolyl (for example, 2, 3, 3a, 4, 7, 7a-hexahydroisoindolyl etc.), octahydroisoindolyl, benzoimidazolyl, quinolyl, isoquinolyl, indazolyl, quinazolinyl, dihydroquinazolinyl (3, 4-dihydroquinazolinyl etc.), benzotriazolyl, carbazolyl, etc.
  • An unsaturated fused spiro heterocyclic group which contains 1 to 2 nitrogen atoms refers to, for example, spiro [cyclopentaneindolinyl] (for example, spiro [cyclopentane-1, 3' -indolinyl] etc.) .
  • An unsaturated 3 to 8 membered (preferably 5 or 6 membered) heteromonocyclic group which contains 1 to 2 (preferably one) oxygen atoms and 1 to 3 (preferably 1 to 2) nitrogen atoms refers to, for example, oxazolyl, isoxazolyl, oxadiazolyl (for example, 1, 2, 4-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1,2,5- oxadiazolyl, etc.)/ etc.
  • a saturated 3 to 8 membered (preferably 5 or 6 membered) heteromonocyclic group which contains 1 to 2 (preferably one) oxygen atoms and 1 to 3 (preferably
  • nitrogen atoms refers to, for example, oxazolidinyl, isoxazolidinyl, morpholinyl, etc.
  • An unsaturated fused heterocyclic group which contains 1 to 2 (preferably one) oxygen atoms and 1 to 3 (preferably 1 to 2) nitrogen atoms refers to, for example, benzoxazolyl (for example, benzo [d] oxazolyl etc.), dihydrobenzoxazolyl (for example, 2,3- dihydroxybenzo [d] oxazolyl etc.), beozoxadinyl (for example, benzo [b] [1 / 4] oxadinyl etc.), dihydrobenzoxadinyl (for example, 2H-3,4- dihydroxybenzo [b] [1, 4] oxadinyl etc.), benzoxazolyl, benzoxadiazolyl, etc.
  • benzoxazolyl for example, benzo [d] oxazolyl etc.
  • dihydrobenzoxazolyl for example, 2,3- dihydroxybenzo [d] oxazolyl etc.
  • beozoxadinyl
  • An unsaturated 3 to 8 membered (preferably 5 membered) heteromonocyclic group which contains 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms refers to, for example, thiazolyl, dihydrothiazolyl (for example, 2,3- dihydrothiazolyl) , isothiazolyl, thiadiazolyl (for example, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1,3,4- thiadiazolyl, 1, 2, 5-thiadiazolyl, etc.), dihydrothiadinyl, etc.
  • 2 sulphur atoms and 1 to 3 nitrogen atoms refers to, for example, thiazolidinyl etc.
  • An unsaturated fused heterocyclic group which contains 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms refers to, for example, benzothiazolyl, benzothiadiazolyl, etc.
  • a carbamoyl group which may have a lower alkyl group refers to a carbamoyl group which may have 1 to 2 lower alkyl (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl group) as the above: More specifically, for example, a carbamoyl group which may have said lower alkyl includes carbamoyl, N-methylcarbamoyl, N, N- dimethylcarbamoyl, N-methyl-N-ethylcarbamoyl, N- ethylcarbamoyl group, etc.
  • An aryl lower alkyl group (which may have a lower alkoxy group (s) on the aryl group) refers to a lower alkyl (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl group) as the above, which has 1 to 3 (preferably one) aryl group (s) as the above.
  • 1 to 7, preferably 1 to 5, more preferably 1 to 2 lower alkoxy as the above may substitute on the aryl group.
  • an aryl lower alkyl group (may have a lower alkoxy group on an aryl group) includes benzyl, 1-phenylethyl, 2-phenylethyl, 1-methyl-l- phenylethyl, 1, l-dimethy-2-phenylethyl, 1, l-dimethyl-3- phenylpropyl, (2-, 3- or
  • Compound (I) A heterocyclic Compound represented in the above General Formula (1) can be produced by various methods, but as an example, it is produced by a method shown in Reaction Formula-1 to 4, 7, 8 12 or 13 below.
  • R 11 , R 12 , A 1 and Z mean the same as the above, and Xii represents halogen atom or a group that causes the same substitution reaction as halogen atom.
  • groups that cause the same substitution reaction as halogen atom for example, lower alkanesulfonyloxy group, arylsulfonyloxy group, and aralkylsulfonyloxy group, etc., can be exemplified.
  • the halogen atom represented by Xn is fluorine atom, chlorine atom, bromine atom, and iodine atom.
  • lower alkanesulfonyloxy group represented by Xn linear or branched alkanesulfonyloxy group with carbon number 1 to 6 such as methanesulfonyloxy, ethanesulfonyloxy, isopropanesulfonyloxy, n-propanesulfonyloxy, n- butanesulfonyloxy, tert-butanesulfonyloxy, n- pentanesulfonyloxy, and n-hexanesulfonyloxy groups, etc., can be exemplified.
  • arylsulfonyloxy group represented by Xn for example, phenylsulfonyloxy group and naphthylsulfonyloxy group, etc., that may have 1 to 3 groups selected from the group consisting of linear or branched alkyl group with carbon number 1 to 6, linear or branched alkoxy group with carbon number 1 to 6, nitro group, and halogen atom as a substituent group on phenyl ring can be cited.
  • phenylsulfonyloxy group that may have the above substituent group, phenylsulfonyloxy, 4- methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4- nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 2- nitrophenylsulfonyloxy, and 3-chlorophenylsulfonyloxy, etc., can be exemplified.
  • naphthylsulfonyloxy group ⁇ -naphthylsulfonyloxy and ⁇ - naphthylsulfonyloxy group, etc.
  • Xxi for example, linear or branched alkylsulfonyloxy group with carbon number 1 to 6 substituted by phenyl group and linear or branched alkylsulfonyloxy group with carbon number 1 to 6 substituted by naphthyl group that may have 1 to 3 groups selected from the group consisting of linear or branched alkyl group with carbon number 1 to 6, linear or branched alkoxy group with carbon number 1 to 6, nitro group, and halogen atom as a substituent group on phenyl ring can be . - cited.
  • alkylsulfonyloxy group substituted by the above phenyl group benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4- phenylbutylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4- methoxybenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, and 3-chlorobenzylsulfonyloxy, etc., can be exemplified.
  • alkylsulfonyloxy group substituted by the above naphthyl group a- naphthylmethylsulfonyloxy and ⁇ - naphthylmethylsulfonyloxy groups, etc., can be exemplified.
  • Compound (Ia) can be produced by reacting a compound of General Formula (2) (hereinafter called “Compound (2)”) with a compound of General Formula (3) (hereinafter called “Compound (3)”).
  • This reaction is normally performed in a commonly used solvent that does not effect reaction, for example, water; alcohol solvent such as methanol, ethanol, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol, etc.; ketone solvent such as acetone, and methyIethy1ketone, etc.; ether solvent such as tetrahydrofuran, dioxane, diethyl ether, and diglyme, etc.; ester solvent such ' as methyl acetate, and ethyl acetate, etc.; aprotic polar solvent such as acetonitrile, N,N-dimethylforiaamide, and dimethyl sulfoxide, etc.; halogenated hydrocarbon solvent such as methylene chloride, and ethylene chloride, etc.; or other organic solvents.
  • alcohol solvent such as methanol, ethanol, isopropanol, n-butanol, trifluoroethanol, and
  • this reaction is performed in a mixed solvent of these commonly used solvents.
  • This reaction is normally performed in the presence of an inorganic base such as alkali metal (for example, sodium, and potassium, etc.), alkali metal hydrogen carbonate (for example, lithium hydrogen carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate, etc.), alkali metal hydroxide (for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide, etc.), alkali metal carbonate (for example, lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate, etc.), alkali metal lower alkoxide (for example, sodium methoxide, and sodium ethoxide, etc.), hydride (for example, sodium hydride, and potassium hydride, etc.), etc., and an organic base such as trialkylamine (for example, trimethylamine, triethylamine, and N- ethyldiisopropylamine, etc.), pyridine, quinoline,
  • the above reaction can be performed by adding alkali metal iodide such as potassium iodide, and sodium iodide, etc., as a reaction accelerator, if needed.
  • alkali metal iodide such as potassium iodide, and sodium iodide, etc.
  • the usage ratio of Compound (2) and Compound (3) in the above Reaction Formula-1 may normally have the latter at least 0.5-fold mole of the former, preferably approximately 0.5 to 5-fold mole.
  • Reaction temperature is not particularly limited., and reaction is normally performed under cooling or heating. Preferably, the reaction is performed under a temperature condition from around room temperature to approximately 150 0 C for 1 to 30 hours.
  • Compound (1) can be produced by reacting a compound of General Formula (4) (hereinafter called “Compound (4)”) with a compound of General Formula (5) (hereinafter called “Compound (5)”).
  • This reaction is performed under the same reaction condition as the reaction in the above Reaction Formula-1. If Compound (4) has X3 .2 representing a hydroxyl group, this reaction can be achieved by subjecting Compound (5) and Compound (4) to normal amide bond formation reaction.
  • Known amide bond formation reaction can be widely applied to this amide bond formation reaction. Specifically, the following methods are cited: (a) a mixed anhydride method, i.e. a method of reacting Compound (4) with an. alkylhalocarboxylate to obtain mixed acid anhydride, and reacting this with Compound (5) ; (b) an active ester method, i.e.
  • an activating agent such as dicyclohexylcarbodiimide, l-(3- dimethylaminopropyl) -3-ethylcarbodiimide (WSC), and' carbonyldiimidazole, etc.
  • other methods for example, a method of making Compound (4) carb
  • a basic compound used compounds commonly used for Schotten-Baumann, for example, inorganic bases such as alkali metal (for example, sodium, and potassium, etc.), alkali metal hydrogen carbonate (for example, lithium hydrogen carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate, etc.), alkali metal hydroxide (for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide, etc.), alkaline earth metal hydroxide (for example, calcium hydroxide, etc.); alkali metal carbonate (for example, lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate, etc.), alkali metal lower alkoxide (for example, sodium methoxide, and sodium ethoxide, etc.), hydride (for example, sodium hydride, potassium hydride, etc.), and sodium amide, etc., and organic bases such as trialkylamine (for example, trimethyl
  • reaction is normally performed at approximately -20 to 100 0 C, preferably approximately 0 to 50 0 C, and reaction time is approximately 5 minutes to 10 hours, preferably approximately 5 minutes to 2 hours.
  • Reaction of the obtained mixed acid anhydride and Compound (5) is normally performed at approximately -20 to 150 0 C, preferably approximately 10 to 50 0 C, and the reaction time is approximately 5 minutes to 10 hours, preferably approximately 5 minutes to 5 hours.
  • the mixed anhydride method is generally performed in a solvent.
  • a solvent used any solvent commonly used for the mixed anhydride method can be used, and specifically, water; halogenated hydrocarbon solvent such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride, etc.; aromatic hydrocarbon solvent such as benzene, toluene, and xylene, etc.; ether solvent such as diethyl ether, diisopropylether, tetrahydrofuran, and dimethoxyethane, etc.; ester solvent such as methyl acetate, ethyl acetate, and isopropyl acetate, etc.; and aprotic polar solvent such as acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide, . etc. or mixed solvent thereof, etc., are cited.
  • alkyl halocarboxylate used in the mixed anhydride method for example, methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, and isobutyl chloroformate, etc., are cited.
  • the usage ratio of Compound (4) , alkylhalocarboxylate and Compound (5) in the mixed anhydride method is normally preferably at least equal mole each, but alkylhalocarboxylate and Compound (4) can be used in a range of approximately equimolar to 6- fold molar amount to the Compound (5) , respectively.
  • the method of condensation reaction in the presence of the activating agent (c) is performed in an appropriate solvent in the presence or absence of a basic compound.
  • any solvent and basic compound used in the Reaction Formula-1 can be used.
  • the used amount of the activating agent is normally at least an equimolar amount, preferably equimolar to 5-fold molar amount, to Compound (4) .
  • reaction can be efficiently progressed by adding acid such as 1-hydroxybenzotriazole and/or hydrochloric acid into the reaction system.
  • Said reaction is normally performed at approximately -20 to 180 0 C, preferably approximately 0 to 150°C, and is generally completed for approximately 5 minutes to 90 hours.
  • this amide bond formation reaction can also be performed by a method of reacting Compound (4) with Compound (5) in the presence of a condensation agent of a phosphorus compound such as triphenylphosphine, diphenylphosphinylchloride, phenyl- N-phenylphosphoramide chloridate, diethylchlorophosphate, diethyl cyanophosphate, diphenylphosphoryl azide, and bis(2-oxo-3- oxazolidinyl)phosphinic chloride, etc.
  • the condensation agent is used independently or by mixing one or more of the agents.
  • Said reaction is normally performed in the presence of solvent and basic compound used in the above Reaction Formula-1 at approximately -20 to 150 0 C, preferably approximately 0 to 100 0 C, and the reaction is generally completed for approximately 5 minutes to 30 hours. It is preferable that the condensation agent and Compound (5) are used in at least approximately an equimolar amount, preferably approximately equimolar to 3-fold molar amount, to Compound (4) .
  • Compound ' (4) a starting compound of the compound of the present invention, is a known compound, or can be easily produced from a known compound.
  • R 12 and A 1 mean the same as the above.
  • R 14 means hydrogen or lower alkyl group.
  • a compound of General Formula , (Ib) (hereinafter called “Compound (Ib)") can be produced by reacting a compound of General Formula (10) (hereinafter called “Compound (10)") with Compound (5).
  • This reaction is performed in various solvents that do not effect reaction, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, and cyclopentylmethyl ether, etc.; halogenated hydrocarbons such as chloroform, methylene chloride, and ethylene chloride, etc.; esters such as methyl acetate, ethyl acetate, and n-butyl acetate, etc.; and others, organic solvent such as acetonitrile, and N,N-dimethylformamide, etc., or mixture thereof. Moreover, if the Compound (10) or (5) is liquid, these also function as solvents.
  • ethers such as diethyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, and cyclopentylmethyl ether, etc.
  • halogenated hydrocarbons such as chloroform, methylene
  • the used amount of Compound (5) to Compound (10) is normally 1 to 10-fold molar amount, preferably 1 to 3-fold molar amount.
  • the reaction can be performed under any temperature condition of cooling to heating. Preferably, a temperature condition of -10 0 C to 150 0 C can be adopted. The reaction is completed for approximately 10 minutes to 10 hours under said temperature condition. This reaction can be performed in the presence of a base.
  • organic bases such as tri (lower) alkylamine (for example, trimethylamine, triethylamine, and N- ethyldiisopropylamine, etc.), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N- (lower) alkyl-morpholine (for example,, N-methylmorpholine, etc.), 1,5- diazabicyclo [4.3.0] nonene-5 (DBN), 1,8- diazabicyclo[5.4.0]undecene-7 (DBU), and 1,4- diazabicyclo[2.2.2]octane (DABCO), etc., are cited.
  • tri (lower) alkylamine for example, trimethylamine, triethylamine, and N- ethyldiisopropylamine, etc.
  • pyridine quinoline
  • piperidine imidazole
  • picoline dimethylaminopyr
  • a compound of General Formula (Id) (hereinafter called “Compound (Id)") can be performed by reacting a compound of General Formula (Ic) (hereinafter called “Compound (Ic)”) with a thioxo agent.
  • a thioxo agent commonly used agents that can change oxo group such as phosphorus pentasulfide, and Lawesson' s reagent (2, 4-bis (4-methoxyphenyl) -1, 3-dithia-2, 4-diphosphetane- 2, 4-disulfide) , etc., into thioxo group, are cited.
  • halogenated hydrocarbon solvents such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride, etc.
  • aromatic hydrocarbon solvents such as benzene, toluene, and xylene, etc.
  • ether solvents such as diethyl ether, diisopropylether, tetrahydrofuran, and dimethoxyethane, etc.; or mixed solvents thereof, etc.; are cited.
  • reaction temperature is not particularly limited to, under heating, preferably 65 to 150°C, . and the reaction time is approximately 30 minutes to 10 hours, preferably approximately 30 minutes to 5 hours.
  • a thioxo agent can be normally used in a range of equimolar amount to very excessive molar amount, preferably equimolar amount to 1.3 molar amount, to Compound (Ic).
  • Compound (5) a starting compound of the compound of the present invention, contains a novel compound and can be produced by various methods, but as an example, it can be produced by a method shown in Reaction Formula-5 to Reaction Formula-6 below.
  • R 12 , Xn and A 1 mean the same as the above, and R 13 represents hydrogen or lower alkoxycarbonyl group.
  • lower alkoxycarbonyl group represented by R 13 methoxycarbonyl, ethoxycarbonyl, and tert- butoxycarbonyl groups, etc. can be cited.
  • lower alkoxycarbonyl group (C 1 -C 4 ) alkoxycarbonyl group can be exemplified.
  • tert-butoxycarbonyl group is particularly preferred.
  • Compound (5a) can be produced by reacting a compound of General Formula (6) (hereinafter called “Compound (6)”) with a compound of General Formula (3) (hereinafter called “Compound (3)”). This reaction is performed under the same reaction condition as reaction in the Reaction Formula-1.
  • Compounds (3) and (6), starting compounds of the compound of the present invention are known compounds, or can be easily produced from known compounds .
  • Compound (5) a compound of General Formula (5) (hereinafter called "Compound (5)”) can be produced by subjecting the compound to elimination reaction of the lower alkoxycarbonyl group. This elimination reaction is performed according to a commonly used method such as hydrolysis.
  • Hydrolysis is preferably performed in the presence of an acid containing Lewis acid.
  • organic acids for example, formic acid, acetic acid, propionic acid, trichloroacetic acid, and trifluoroacetic acid, etc.
  • inorganic acids for example, hydrochloric acid, hydrobromic acid, and vitriol, etc.
  • Reaction using Lewis acid for example, trihaloacetic acid, etc., such as trichloroacetic acid, and trifluoroacetic acid, etc.
  • a cation scavenger for example, anisole, and phenol, etc.
  • This hydrolysis reaction is performed in various solvents that do not effect reaction, for example, water; alcohols such as methanol, ethanol, trifluoroethanol, and ethylene glycol, etc.; ketones such as acetone, etc.; ethers such as diethyl ether, dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, and cyclopentylmethyl ether, etc.; halogenated hydrocarbons such as chloroform, methylene chloride, and ethylene chloride, etc.; esters such as methyl acetate, ethyl acetate, and n-butyl acetate, etc.; and others, organic solvent, such as acetonitrile, and N, N- dir ⁇ ethylformamide, etc. or mixture thereof. Moreover, if a liquid acid is used as the acid, these also function as solvents.
  • the reaction can be performed under any temperature condition of cooling to heating.
  • a temperature condition of 0 0 C to room temperature can be adopted.
  • the reaction is completed for approximately 0.5 to 10 hours under said temperature condition.
  • Compound (8) can be produced by reacting a compound of General Formula (7) (hereinafter called “Compound (7)”) with a compound of General Formula (3) (hereinafter called “"Compound (3)”). This reaction is performed under the same reaction condition as reaction in the Reaction Formula-1.
  • Compound (5b) can be produced by reacting a compound of General Formula (8) (hereinafter called “Compound (8)”) with a compound of General Formula (9) (hereinafter called “Compound (9)”).
  • This reaction is performed in various solvents that do not effect reaction, for example, water; alcohols such as methanol, ethanol, trifluoroethanol, and ethylene glycol, etc; ketones such as acetone, etc.; ethers- such as diethyl ether, dioxane, tetrahydrofuran, 1,2- dimethoxyethane, and cyclopentylmethyl ether, etc.; halogenated hydrocarbons such as chloroform, methylene chloride, and ethylene chloride, etc.; esters such as methyl acetate, ethyl acetate, and n-butyl acetate, etc.; and others, organic solvent such as acetonitrile, and N,N-dimethylformamide, etc., or mixture thereof.
  • the reaction can be performed under any temperature condition of cooling to heating. Preferably, a temperature condition of 50 0 C to 100°C can be adopted. The reaction is completed for 0.5 to 10 hours under such temperature condition.
  • R 21 and A mean the' same as aforementioned, and X 21 represents a halogen atom or a group which causes the same substitution reaction as a halogen atom.
  • X 21 represents a halogen atom or a group which causes the same substitution reaction as a halogen atom.
  • an example of a group which causes the same substitution reaction as a halogen atom is the same group mentioned above. This reaction is carried out under the same reaction conditions as in Reaction Formula-1.
  • Compound (11) which is the starting material compound of the compound of the invention, includes a novel compound, and can be produced by a variety of methods, for example, the compound is procured by the method shown in the following Reaction Formula-9.
  • Compound (1) the compound (hereinafter called "Compound (If)") in which A 21 and A 22 have the same as aforementioned, wherein -A 2 is -A 21 -0- A 22 -, is for example, produced by the method shown in the following Reaction Formula-8.
  • the Compound (If) can be produced by reacting the compound of General Formula (12) (hereinafter called “Compound (12)") with the compound of General Formula (13) (hereinafter called “Compound (13)”).
  • This reaction is carried out under the same reaction conditions as in the aforementioned Reaction Formula-1.
  • the reaction can be carried out in a suitable solvent in the presence of a condensation agent . .
  • the reaction is usually carried out in conventional solvents which do not effect reaction, for example, water; alcohol solvents such as methanol, ethanol, isopropanol, n-butanol, trifluoroethanol, ethyleneglycol; ketone solvents such as.
  • solvents that are used herein can include mixtures of conventional solvents thereof.
  • Condensation agents include azodicarboxylats such as diethyl azodicarboxylate and phosphorous compounds such as triphenylphosphin ⁇ .
  • At least equimolar, preferably equimolar to 2-fold molar, is recommended for the amount of condensation agent used for Compound (12) .
  • the second is usually at least equimolar, preferably equimolar to about 2-fold molar compared to the first.
  • the reaction temperature is not precisely controlled, and the reaction is usually carried out under cooled or heated conditions. Preferably, the reaction is carried out under a temperature condition ranging from 0 0 C to 150°C for 1 to 10 hours.
  • Compound (12) which is a starting compound of the compound of the invention, are a known compound or can be readily produced from a known compound.
  • Compound (13) which is the starting material compound of the compound of the invention, includes a novel compound, and can be produced by a variety of methods, for example, the compound is produced by the method shown in the following Reaction Formula-10 or Reaction F ⁇ rmula-11.
  • R 21 , X 21 and A 2 have the same as aforementioned, and X 23 represents a halogen atom or a group which causes the same substitution reaction as a halogen atom.
  • Compound (11) can be produced by reacting the compound of General Formula (14) (hereinafter called "Compound (14)”) with the compound of General Formula (15) (hereinafter called X ⁇ Compound (15)").
  • This reaction is carried out under the same reaction conditions as in the aforementioned Reaction Formula-1.
  • the starting compound of the compound of the invention (14) and (15) are a known compound or can be readily produced from a known compound.
  • Compound (13) can be produced by reacting Compound (3) with a compound of General Formula (16) (hereinafter called "Compound (16)").
  • This reaction is carried out under the same reaction conditions as in the aforementioned Reaction Formula-1.
  • the Compound (16) which is a starting compound of the compound of the invention, is a known compound or can be readily produced from a known compound.
  • R 23 represents a lower alkanoyl group and X24 represents a halogen atom or a group which causes the same substitution reaction as the halogen atom.
  • X24 represents a halogen atom or a group which causes the same substitution reaction as the halogen atom.
  • Compound of General Formula .(18) (hereinafter called "Compound (18)") can be produced- by reacting Compound (3) with Compound (17) . This reaction is carried out under the same reaction conditions as in the aforementioned Reaction Formula-1.
  • Compound (17) which is a starting compound of the compound of the invention, is a known compound or can be readily produced from a known compound.
  • a preferred method for this reaction is a conventional method such as hydrolysis.
  • the hydrolysis reaction is preferably performed under the presence of base or an acid including Lewis acid.
  • Suitable bases include inorganic bases such as alkali metal (for example, sodium, potassium etc.), alkali metal bicarbonate salt (for example, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal hydroxides (for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.), alkali metal carbonate salt (for example, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal lower alkoxides (for example, sodium methoxide, sodium ethoxide, etc.) and hydrides (for example, sodium hydride, potassium hydride, etc.), and organic bases such as trialkylamine (for example, trimethylamine, toriethylamine, N- e
  • Suitable acids include organic acids (for example, formic acid, acetic acid, propanoic acid, trichloro acetic acid, trifluoroacetic acid, etc.), and inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride hydrogen bromide, etc.)- Isolation by acid such as trihaloacetate (for example, torichloroacetic acid, trifluoroacetic acid, etc.) is preferably perfomed under the presence of cation adjuvants (such as anisole, phenol) .
  • organic acids for example, formic acid, acetic acid, propanoic acid, trichloro acetic acid, trifluoroacetic acid, etc.
  • inorganic acids for example, hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride hydrogen bromide, etc.
  • Isolation by acid such as trihaloacetate (for example, torichloroacetic acid, trifluoroacetic
  • the reaction is usually carried out in conventional solvents which do not effect reaction, for example, water; alcohol solvents such as methanol, ethanol, isopropanol, n-butanol, trifluoroethanol, ethyleneglycol; ketone solvents such as acetone, methylethylketone; ether solvents such as tetrahydrofuran, dioxane, diethyl ether, diglyr ⁇ e; ester solvents such as methyl acetate, ethyl acetate; aprotic polar solvents such as acetonitrile, N, N- dimethylformamide, dimethyl sulfoxide; halogenated hydrocarbon solvents such as methylene chloride, ethylene chloride; or other organic solvents, and also mixtures thereof- Ethanol is preferred among them.
  • the reaction temperature is not precisely controlled, and generally is carried out under cooled or heated conditions.
  • the reaction may be carried out for 0.5 to 75 hours under a condition ranging from
  • R 21a refers to said N-containing heterocyclic group where (8) carboxyl group is substituted with at least one in the group referred to in the aforementioned R 21 .
  • R 21b refers to said N-containing heterocyclic group where (10) a carbamoyl group, which may have (10) a lower alkyl group, is substituted with at least one in the group referred to in said R 21 .
  • R 22 and R 23 are same or different, and refer to a hydrogen atom or a lower alkyl group.
  • the reaction between Compound (Ig) and Compound (19) is the method in which amine in Compound (19) and carboxylic acid in Compound (Ig) are reacted by using a usual amide bond forming reaction.
  • the known amide bond forming reaction can be widely applied to this type of amide bond forming reaction. Specific examples include (a) mixed acid anhydride method, i.e. the method of reaction of alkylhalocarboxylate to carboxylic acid (Ig) provides mixed acid anhydride which is then reacted with amine (19), (b) activated ester method, i.e.
  • activation agents such as dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3- ethylcarbodiimide (WS
  • the mixed acid anhydride used in the above mixed anhydride method (a) is provided by Schotten- Baumann reaction, which is reacted with amine (19) , usually without isolation, to yield the General Formula (Ih) of the compound of the invention..
  • the basic compounds used include known compounds in Schotten-Baumann reaction, for example, inorganic bases such as alkali metal (for example, sodium, potassium, etc.), alkali metal bicarbonate salt (for example, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal hydroxides (for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.), alkalin earth metal hydroxides (for example, calcium hydrate etc.), alkali metal carbonate salt (for example, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal lower alkoxides (for example, sodium methoxide, sodium ethoxide, etc.), hydrides (for example, sodium hydride, potassium hydride, etc.) and sodium amide, and organic bases such as trialkylamine (for example, trimethylamine, toriethylamine, N- ethyldiisopropylamine, etc.),
  • the said reaction is usually performed in conditions ranging from about -20 to 100 0 C, preferably about 0 to 50 0 C, and the reaction time is about 5 min. to 10 hours, preferably about 5 min. to 2 hours.
  • the reaction of the resulting mixed anhydride and amine (19) is usually performed in conditions ranging from about -20 to 150 0 C, preferably about 10 to 50 0 C, and the reaction time is about 5 min. to 10 hours, preferably about 5 min. to 5 hours.
  • the mixed acid ' anhydride method is generally performed in solvents.
  • Any solvent used in the mixed acid anhydride method can be used, and specific examples include water; halogenated hydrocarbon solvents such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride; aromatic hydrocarbon solvents such as benzene, toluene, xylene; ether solvents such as diethyle ether, diisopropyl ether, tetrahidrofran, dimethoxyethane; ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate; aprotic polar aolvents such as acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, or a mixture thereof.
  • halogenated hydrocarbon solvents such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride
  • aromatic hydrocarbon solvents such as benzene,
  • the alkylhalocarboxylate used in the mixed acid anhydride method includes, for example, methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate, etc.
  • the usage ratio of carboxylic acid (Ig), alkylhalocarboxylate and amine (19) in the mixed acid anhydride method is generally at least . equimolar for each, but alkylhalocarboxylate and carboxylic acid (Ig) can be used within a range of equimolar to 6 molar for amine (19) .
  • the method of condensation reaction in the presence of said activating agent (c) is performed in a suitable solvent, in the presence or absence of basic compounds.
  • any of the solvents and basic compounds used in the method of reaction of amine (19) to carboxylic halide in the other method (d) in the following can be used.
  • the amount of activating agent used is generally at least equimolar for Compound (11) , preferably ranging from equimolar to 5 molar.
  • the reaction can be facilitated by adding 1-hydroxybenzotriazole and/or acid such as hydrochloric acid within the reaction.
  • Said reaction is generally performed at -20 to 180 0 C, preferably 0 to 150 0 C, and the reaction is usually completed in about 5min to 90 hours.
  • the said reaction is carried out in a suitable solvent, in the presence of basic compounds.
  • suitable solvent for the basic compounds used, known compounds are widely used, for example, any of the basic compounds used in the above Schotten-Baurnann reaction can be used.
  • the solvents for example, other than those used in the above mixed acid anhydride method, include alcohol solvents such as methanol, ethanol, isopropanol, puropanol, butanol, 3-methoxy-l-buanol, ethylcellosolve, methylcellosolve, and acetonitrile, pyridine, acetone and water.
  • the ratio of the amounts used between amine (19) and carboxylic acid halide is not controlled, and can be selected appropriately from within a wide range, but it is recommended to be at least equimolar, preferably equimolar to 5 molar respectively.
  • Said reaction is generally performed at about -20 to 180°C, preferably about 0 to 150 0 C, and the reaction is usually completed in about 5 min. to 50 hours .
  • the amide bond forming reaction • shown in the above Reaction Formula-6 can be carried out by using the method of reaction of carboxylic acid (Ig) with amine (19) in the presence of a phosphorus compound condensation agent, such as triphenyl phosphine, diphenyl phosphinyl chloride, phenyl-N- phenylphosphoramide chloridate, diethyl chlorophosphate, diethyl phosphorocyanidate, diphenyl phosphorazidate, bis- (2-oxo-3-oxazolidinyl)phosphinic chloride.
  • a phosphorus compound condensation agent such as triphenyl phosphine, diphenyl phosphinyl chloride, phenyl-N- phenylphosphoramide chloridate, diethyl chlorophosphate, diethyl phosphorocyanidate, diphenyl phosphorazidate, bis- (2-oxo-3-oxazolidinyl)phosphinic
  • reaction is usually carried out in the presence of solvents and basic compounds used in the method of reaction of amine (19) to the above carboxylic halide, at about -20 to 150 0 C, preferably 0 to 100 0 C, and the reaction is generally completed in about 5 min to 30 hours. It is recommended to use each of the condensation agents and amine (19) at least in about equimolar amounts, preferably equimolar to 3 molar amounts for carboxylic acid (Ig) .
  • R 21c represents the following group
  • R - represents the following, group
  • R ,21e represents the following group
  • X 25 and X 26 represents a halogen atom or a group which causes the same substitution reaction as the halogen atom respectively.
  • R 24 represents the same group as said substituents (1) to (13) of R 21 .
  • p is 4 or 5. 3
  • the reaction between the Compound (Ii) and the Compound (20) is carried out in the suitable inert • solvent under the presence of basic compounds.
  • the basic compounds used here include, for example, metallic sodium, metallic potassium, metallic magneciur ⁇ ; sodium hydride; sodium amide; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide; alkyl, and aryl lithium or lithium amide such as methyl lithium, n-buthyl lithium, phenyl lithium, lithium isopropylamide; sylilamide such as s lithium hexamethyldisilazide. These basic compounds are used independently or in mixtures of two or more.
  • the amount of the basic compound is generally at least equimolar., preferably equimolar to 5 ⁇ fold molar of Compound (Ii) .
  • the inert solvents used include, for example, aromatic hydrocarbon solvents such as benzen, toluene, xylene; ether solvents such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme; aliphatic hydrocarbon solvents such as n-hexane, . heptane, cyclohexane; halogenated hydrocarbon solvents such as chloroform, dichloroform, dichloroethane, carbon tetrachloride; dimethyl sulfoxide and N, N- dimethylformamide, or a mixture thereof.
  • aromatic hydrocarbon solvents such as benzen, toluene, xylene
  • ether solvents such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme
  • aliphatic hydrocarbon solvents such as n-hexane, . heptane, cycl
  • the reaction is generally carried out at -90 to 150 0 C, preferably at -90 to 120°C, and ends usually in about 10 min to 30 hours.
  • the amount of Compound (20) used may be at least equimolar, preferably equimolar to 5-fold molar for Compound (Ii) .
  • reaction transforming (Ij) to (Ik) is carried out in the same condition as that transforming Compound (Ii) to Compound (Ij).
  • a compound having a group in which Q is represented by the General Formula (2) in Compound (1) can be converted into a variety of compounds by applying the following Reactions A- to G.
  • Reaction A
  • Reducing agents used in the above reducing reaction include, for example, hydrogenated reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetyloxyborohydride and lithium alminiuna hydride, or the mixture of hydrogenated reducing agents thereof.
  • the hydrogenarated reducing agent is generally used in about equimolar to 5-fold molar amounts, preferably equimolar to 2-fold molar for a starting material.
  • the reducing agent is generally performed in a suitable solvent.
  • solvents are ether solvents such as diethyether, tetrahydrofuran, dioxane, monoglyme, diglyme; and aromatic hydrocarbon solvents such as benzen, toluene and xylene.
  • reaction temperature is generally about 0 to 150 0 C, preferably 0 to 100 0 C, and said reaction is usually completed in 30 min to 10 hours.
  • the solvents used are, for example, water; lower alcohol solvents such as methanol, ethanol, isopropanol, tert-butanol; ketone solvents such as acetone, methylethylketone; ether solvents such as diethyl ether, dioxane, tetrahydrofran, monoglyme, diglyme; ester solvents such as methyl acetate, ethyl acetate; fatty acid solvent such as formic acid, acetic acid; halogenated hydrocarbon solvents such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride; amide solvents such as N,N- dimethylformamide, N,N-dimethylacetamide, N- methylpyrrolidone; dimethyl sulfoxide, hexamethylphosphoric triainide; or mixtures thereof.
  • lower alcohol solvents such as methanol, ethanol, isopropanol, tert
  • acids include inorganic acids • such as hydrochloric acid, sulfuric acid and hydrobromic acid, and organic acid such as formic acid, acetic acid, trifluoroacetic acid, p-toluene sulfonic acid.
  • basic compounds include, for- example, carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate; and metal hydroxides such as sodium hydroxide, calcium hydroxide, potassium hydroxide, lithium hydroxide.
  • the amount of acid and basic compound used is generally at least 1 mole, preferably 1 to 10 moles for a starting material, but for acid, it can be used excessively as a reaction solvent.
  • This reaction preferably progresses generally at about 0 to 200°C, preferably 0 to 150 0 C, and is usually completed in 10 min to 30 hours.
  • deprotection can be performed by treating it in a suitable solvent in -the presence of dealkylating agent. Any of the solvents in the above deprotection reaction can be used.
  • Dealkylation agents include, for example, trihalogenated boron such as boron tribromide.
  • the amount of dealkylation agent used is generally at least equimolar, preferably equimolar to 10-fold molar for a starting material. Said reaction is completed in about 1 to 50 hours generally at 0 to 150 0 C, preferably at around room temperature to 100°C.
  • the protecting group is a lower alkyl r deprotection
  • This reduction treatment is carried out, for example, in a suitable solvent in the presence of a catalyst by catalytic hydrogenation.
  • the solvents used are, for example, water; alcohol solvent such as methanol, ethanol, isopropanol; hydrocarbon solvent such as n-hexane, cyclohexane; ether solvent such as dioxane, tetrahydrofuran, diethyl ether, ethyleneglycoldimethyl ether; ester solvent such as ethyl acetate, methyl acetate; aprotic polar solvent such as dimethy formamide, or mixtures thereof.
  • a catalyst used include paradium, paradium black, paradium carbon, platinum, platinum oxide, copper chromite, Raney nickel, or mixtures thereof.
  • the amount of catalyst used may generally be 0.02 to one time w/w of a starting material.
  • the reaction temperature is around -20 to
  • N-containing heterocyclic group represented by R 21 is an unsaturated heterocyclic group, said compound is reduced to give Compound (1) in which part of the corresponding N-containi ⁇ g heterocyclic group becomes saturated.
  • the above reducing reaction is carried out, for example, in a nonsolvent or in a suitable solvent in the presence of a reducing agent.
  • the solvents used in this reaction are, for example, water; lower alcohol solvents such as methanol, ethanol, isopropanol, butanol, tert-butanol, ethyleneglycol; fatty acid solvent such as acetonitlil, formic acid, acetic acid; ether solvents such as diethyl ether, tetrahydrofran, dioxane, monoglyme, diglyme; aromatic hydrocarbon solvent such as benzen, toluene, xylene; halogenated hydrocarbon solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride; or mixtures thereof.
  • lower alcohol solvents such as methanol, ethanol, isopropanol, butanol, tert-butanol, ethyleneglycol
  • fatty acid solvent such as acetonitlil, formic acid, acetic acid
  • ether solvents such as diethyl ether
  • Examples of a reducing agent used include, a catalytic hydrogenation recuding agent such as paradium black, paradium carbon, platinum oxide, platinum black, Raney nickel.
  • the amount of catalytic hydrogenation recuding agent used is usually 1 to 5 times w/w f preferably about 1 to 3 w/w of a starting material.
  • reaction D is carried out under hydrogen atmosphere of ambient pressure to about 20 atm, preferably ambient pressure to 10 atm, at usually about -30 to 100°C, preferably 0 to 60 0 C.
  • the reaction is completed in about 1 to 20 hours.
  • the above hydrolysis reaction is carried out in a suitable solvent or nonsolvent in the presence of an acid or basic compound.
  • the solvents used are, for example, water; lower alcohol solvents such as methanol, ethanol, isopropanol, tert-butanol; ketone solvents such as acetone, methylethylketone; ether solvents such as diethyl ether, dioxane, tetrahydrofran, monoglyme, diglyme; fatty acid solvent such as acetic acid, formic acid; ester solvents such as methyl acetate, ethyl acetate-; halogenated hydrocarbon solvents such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride; amide solvents such as dimethl sulfoxide, N,N-dimethylformamide, hexamethylphosphoric triamide, or mixtures thereof.
  • acids examples include inorganic acids such as hydrochloric acid, sulfuric acid and hydrobromic acid, and organic acids such as formic acid, acetic acid, trifluoroacetic acid, p-toluene sulfonic acid. These acids can be used independently or in mixtures of two or more.
  • Examples of basic compounds include, for example, carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate; and metal hydroxides such as sodium hydroxide, potassium hydroxide, calucium hydroxide, lithium hydroxide. These basic compounds can be used independently or in mixtures of two or more.
  • any usual ester reaction condition can be used in the above reaction.
  • the reaction is carried out in the presence of an inorganic acid and/or halogenating agent.
  • inorganic acids are hydrochloric acid, sulfuric acid, etc.
  • halogenating agents are thionylchloride, phosphorous oxychloride, phosphoric chloride, phosphoric trichloride, etc.
  • the lower alcohol is excessively used for a starting material.
  • the reaction progresses at usually about 0 to 150°C, preferably about 50 to 100 0 C, and is usually completed in about 1 to 10 hours.
  • the solvents used the above reaction are, for example, water; lower alcohol solvents such as methanol, ethanol, isopropanol, tert-butanol; ketone solvents such as acetone, methylethylketone; ether solvents such as diethyl ether, dioxane, tetrahydrofran, monoglyme, diglyme; fatty acid solvent such as acetic acid, formic acid; ester solvents such as methyl acetate, ethyl acetate; halogenated hydrocarbon solvents such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride; amide solvents such as N,N-dimethylformamide, N, N- dimethyl acetoamide, N-metylpyrrodone; dimethyl sulfoxide, hexamethylphosphoric triamide, or mixtures thereof.
  • lower alcohol solvents such as methanol, ethanol, isopropanol, ter
  • acids examples include inorganic acids such as hydrochloric acid, sulfuric acid and hydrobromic acid, and organic acids such as formic acid, acetic acid, trifluoroacetic acid, p-toluene sulfonic acid.
  • the amount of acid used is usually at least 1 mole, preferably 1 to 30 moles of starting material, and the acid may be used excessively as a reaction solvent.
  • reaction G the compound, in which (7) lower alkanoyl group is substituted on a N atom of a he'tero ring of a N-containing heterocyclic group represented by R 21 , is produced by reacting Compound (1) (in which at least one N atom of a N-containing heterocyclic group is unsubstituted) with an alkanoylation agent in a suitable solvent or nonsolvent in the presence or absence of a basic compound.
  • the inert solvent used in the above reaction is, for example, an aromatic hydrocarbon solvent such as benzene, toluene, xylene; an ether solvent such as diethylether, tetrahydrofuran, dioxane, monoglyme, diglyme; a halogenated hydrocarbon solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride; a lower alcohol solvent such as methanol, ethanol, isopropanol, butanol, tert-butanol, ethylene glycol; a fatty acid solvent such as acetic acid; ester solvents such as methyl acetate, ethyl acetate; a ketone solvent such as acetone, methylethylketone; aceto ⁇ itrile, pyridine, dimethyl sulfoxide, N,N-dimethylformamide, N- methylpyrrolidone, hexamethylphosphoric triamide
  • the basic compounds include, for example, inorganic bases such as alkali metal (for example, sodium, potassium, etc.), alkali metal bicarbonate salt (for example, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal hydroxides (for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.), alkali earth metal hydroxides (for example, calcium hydrate etc.), alkali metal carbonate salt (for example, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal lower alkoxides (for example, sodium methoxide, sodium ethoxide, etc.), hydrides (for example, sodium hydride, potassium hydride, etc.) and sodium amide, and organic bases such as trialkylamine (for example, trimethylamine, toriethylamine, N- ethyldiisopropylamine, etc.), pyridine, quinoline, piperidine, imi
  • the amount of basic compound used may be at least equimolar, preferably equimolar to 5-fold mole for a starting material.
  • Alkanoylation agents include, for example, lower alkanoyl halides such as acetyl chloride and fatty acid anhydride such as acetic anhydride.
  • a lower alkanoylation agent is usually used at least equimolar, preferably equimolar to 5-fold moles for a starting material.
  • the reaction is carried out usually at 0 to 200°C, preferably about 0 to 150 0 C, and is generally completed in about 5 min to 5 hours.
  • Alkali metal halogen compounds such as sodium iodide or potassium iodide may be added to this reaction within the reaction system.
  • the starting compounds used in each of the above reaction formulas may be preferred salt, and moreover, final compounds obtained in each reaction may form preferred salt.
  • preferred salt of Compound (1) exemplified below is cited.
  • Preferred salt of Compound (1) is pharmacologically acceptable salt, for example, metal salt such as alkali metal salt (for example, sodium salt, and potassium salt, etc.), alkaline earth metal salt (for example, calcium salt, and magnesium salt, etc.), etc., salt of inorganic base such as ammonium salt, alkali metal carbonate (for example, lithium carbonate, potassium carbonate, sodium carbonate, and cesium carbonate, etc.) , alkali metal hydrogen carbonate (for example, lithium hydrogen carbonate, sodium hydrogen carbonate, and potassium hydrogen .
  • metal salt such as alkali metal salt (for example, sodium salt, and potassium salt, etc.), alkaline earth metal salt (for example, calcium salt, and magnesium salt, etc.), etc.
  • salt of inorganic base such as ammonium salt, alkali metal carbonate (for example, lithium carbonate, potassium carbonate, sodium carbonate, and cesium carbonate, etc.) , alkali metal hydrogen carbonate (for example, lithium hydrogen carbonate, sodium hydrogen carbonate, and
  • alkali metal hydroxide for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide, etc.
  • alkali metal hydroxide for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide, etc.
  • alkali metal hydroxide for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide, etc.
  • salt of organic base such as tri (lower) alkylamine (for example, trimethylamine, triethylamine, and N-ethyldiisopropylamine, etc.), pyridine, quinoline, piperidine, imidazole, picoline, dimethylami.nopyridine, dimethylaniline, N- (lower) alkyl-morpholine (for example, N-methylmorpholine, etc.), l,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8- diazabicyclo[5.
  • solvate for example, hydrate, and ethanolate, etc.
  • hydrate is cited.
  • Each final compound obtained in each of the above reaction formulae can be isolated from reaction mixture and purified, for example, by cooling the reaction mixture, and then isolating the crude reaction product by an isolation operation such as filtering, concentrating and extracting, etc., and a normal purification operation such as column chromatography, arid recrystallization, etc.
  • isomers such as geometric isomer, stereoisomer, and optical isomer, etc., are also deservingly included.
  • the compound of General Formula (1) and salt thereof is used in a form of common pharmaceutical formulation.
  • the formulation is prepared using diluents or excipients normally used such as fillers, expanders, binders, wetting agents, disintegrants, interfacial active agents, and lubricants, etc.
  • various forms can be selected for the purpose of treatment, and as representative examples, tablets, pills, powder, liquid medicines, suspensions, emulsions, granules, capsule, suppository, and injections (liquid medicines, and suspensions, etc.), etc., are cited.
  • excipients such as lactose, saccharose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silic acid, etc.
  • binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, and polyvinylpyrrolidone, etc.
  • disintegrants such as dry starch, sodium alginate, powdered agar, powdered laminara ' n, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, starch, and lactose, etc.
  • disintegration inhibitors such as saccharose,, stearin, cocoa butter, and hydrogenated oil, etc.
  • absorption promoters such as lactose, saccharose, sodium chloride, glucose, urea
  • carriers known in this field can be widely used.
  • excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, and talc, etc.
  • binders such as powdered acacia, powdered tragacanth, gelatine, and ethanol, etc.
  • disintegrants such as laminaran, and agar, etc.
  • esters such as polyethylene glycol, cacao butter, higher alcohol, and higher alcohol, and gelatine, and semisynthetic glyceride, etc., can be cited.
  • Capsules are normally prepared by mixing the active ingredient compound with various carriers exemplified above and filling in hard gelatine capsules or soft capsules, etc., according to a common procedure .
  • liquid medicines, emulsions and suspensions are sterilized,- and preferably as isotonic as blood, and in forming into these forms, what is commonly used in this field as diluents can all be used, for example, water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters, etc.
  • an efficient amount of salt, glucose or glycerin to prepare an isotonic solution may be contained in the pharmaceutical formulation, and normal solubilizing agents, buffers, and analgesic agents, etc., may also be added.
  • coloring agents, preservatives, aromatic agents, flavoring agents, and sweetening agents, etc., or other pharmaceuticals can be contained in the pharmaceutical formulation, if needed.
  • the amount of the compound of General Formula (1) that should be contained in the pharmaceutical formulation of the present invention or salt thereof is, but not particularly limited and accordingly selected from- a wide range, normally approximately 1 to 70 weight% in the formulation composition, preferably approximately 1 to 30 weight%.
  • Administration method of the pharmaceutical formulation, of the present invention is not particularly limited, and the pharmaceutical formulation is administered by a method according to various dosage forms, age of the patient, gender, other conditions, and degree of disorder, etc. For example, tablets, pills, liquid medicines, suspensions, emulsions, granules, and capsules are orally administered.
  • injections are independently administered, or intravenously administered after being mixed with a normal replacement fluid such as glucose, amino acid, etc., and, moreover, are independently intramuscularly, intradermally, subcutaneously or intraperitoneally administered, if needed.
  • Suppository is intrarectally administered.
  • Doses of the pharmaceutical formulation of the present invention are selected according to usage, age of the patient, gender, other conditions, and degree of disorder, etc., but it is preferable that an amount of the active ingredient compound is normally approximately 0.1 to 10 mg per kg of body weight per day. Moreover, it is desirable that the active ingredient compound is contained in a range of approximately 1 to 200 mg in the formulation of an administration form.
  • the compound of the present invention has D2 receptor partial agonist effect, 5-WU 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. 855-864 (2004), Tetsuro Kikuchi and
  • 5-HT 2& 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.
  • Serotonin uptake inhibitory effect (or serotonin reuptake inhibitory effect) is effective for improving depressive symptoms, for example (See Mitsukuni Murasaki: Rinsho-Seishin-Yakuri (Japanese 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.
  • some of the compounds of the present invention have ⁇ i receptor antagonist effect in addition to the above-described effects.
  • the ⁇ i receptor antagonist effect is effective for improving positive symptoms of schizophrenia (See Svensson, T. H. : 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 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 nervosa, bul
  • the compounds of the present invention have little or no side effects and they are excellent in safety and tolerability.
  • the compound of the invention can exert effects such as reducing dosages, diminishing side effects, enhancing therapeutic effects, etc., which could not be achieved by conventional treatments by administrating the compound of the present invention in combination with at least one agent currently used in clinical practice selected from (1) mood stabilizer, (2) serotonin reuptake inhibitor, (3) norepinephrine reuptake inhibitor, (4) serotonin and norepinephrine reuptake inhibitor, and (5) anti-anxiety.
  • at least one agent currently used in clinical practice selected from (1) mood stabilizer, (2) serotonin reuptake inhibitor, (3) norepinephrine reuptake inhibitor, (4) serotonin and norepinephrine reuptake inhibitor, and (5) anti-anxiety.
  • (1) Mood stabilizer (1) Mood stabilizer
  • mood stabilizers compounds which function as mood stabilizers can be widely used and known in the art .
  • Mood stabilizers used in the present invention include, but are not limited to, lithium, valproic acid, divaproex sodium, carbamazepine, oxcarbamazepine, zonisamide, lamotrigine, topirarnate, gabapentin, levetiracetam, clonazepam, phenitoin, thyroid hormone, tiagabine and omega-3-fatty acids.
  • Lamotrigine, zonisamide, topiramate, lithium, valproic acid and carbamazepine are preferable.
  • serotonin reuptake inhibitors known compounds which function as serotonin reuptake inhibitors can be widely used.
  • IC50 values a concentration of an agent that inhibits reuptake of serotonin by 50% of about 1000 nM or less are preferred among serotonin reuptake inhibitors.
  • Such serotonin reuptake inhibitors include, for example, fluvoxamine (5-methoxy-l- [4- (trifluoromethyl) phenyl] -1-pentanone-O- (2- aminoethyl) oxime) , fluoxetine (N-metyl-3- (p- trifluoromethylphenoxy) -3-phenylpropylamine) , paroxetine (trans- (-) -3- [ (1, 3-benzodioxole-5- yloxy) methyl] -4- (4-fluorophenyl) piperidine) , sertraline (IS-cis) -4- (3, 4-dichlorophenyl) -1, 2, 3, 4- tetrahydro-N-methyl-1-naphthylamine hydrochloride) , venlafaxine (1- [2- (Dimethylamino) -1- (4- methoxyphenyl) ethyl] cyclohexanol
  • norepinephrine reuptake inhibitors known compounds which function as norepinephrine reuptake inhibitor can be widely used.
  • Such norepinephrine reuptake inhibitors include levoxetine, atomoxetine and bupropion, preferably levoxetine and atomoxetine.
  • serotonin and norepinephrine reuptake inhibitors known compounds which function as serotonin and norepinephrine reuptake inhibitors can be widely used.
  • serotonin and norepinephrine reuptake inhibitors include, for example, venlafaxine, duloxetine and milnacipran.
  • Anti-anxiety drugs used in the present invention include, but are not limited to, benzodiazepine type drug such as diazepam, chlordiazepoxide, cloxazolam, clotiazepam, alprazolam, etizolarri and oxazolam, and serotonin 5-HT1A receptor agonist type antianxieties such as tandospirone and buspirone.
  • mood stabilizers (2) serotonin reuptake inhibitors, (3) norepinephrine reuptake inhibitors, (4) serotonin and norepinephrine reuptake inhibitors, and (5) anti-anxiety drugs, may be in the form either of free bases or salts (acid addtion salt) .
  • these Agents can be racemic forms, or R and S enantiomers. These can be used singly or in combination with two or more as required. Singly use is preferred.
  • These agents can readily form an acid addition salt with a pharmacologically acceptable acid.
  • These acids include, for example, inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, phosphorus acid, hydrobromic acid and organic acids such as acetic acid, p-toluenesulfonic acid, methansulfonic acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, and benzoic acid.
  • These acid addition salts can also be used as active ingredient compounds in the present invention as well as the ' drugs in a free form.
  • Salts can be readily formed by reacting pharmacologically acceptable basic compounds with those • compounds having acid groups among the drugs.
  • Basic compounds include, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, and calcium hydroxide, alkali metal carbonate salts such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, or bicarbonate; metal alcoholates such as sodium methylate and potassium methylate.
  • the purified product was concentrated under a reduced pressure to obtain 7.22 g (yield: 82%) of a colorless oily 4-(tert- butoxycarbonyl-ethyl-amino) butyl methanesulfonate.
  • This reaction solution was heated to reflux for one hour, and then cooled to room temperature.
  • To this reaction solution cooled in ice were added in this order water (50 ⁇ l) , a 15% aqueous solution of sodium hydroxide (50 ⁇ l) , and water (150 ⁇ l) , and the resultant mixture was stirred at room temperature for 30 ' minutes.
  • Thus obtained solution was filtered to remove insoluble matters, and the filtrate was concentrated under a reduced pressure.
  • This reaction solution was cooled in an ice-methanol bath, and a THF solution of 1.1 M lithium hexamethyl disilazide (1.9 ml, 2.09 mmol) was added dropwise thereto, and the resultant mixture was stirred at room temperature for 19 hours.
  • An aqueous solution of ammonium chloride was added to this reaction solution, and the resultant mixture was extracted with ethyl acetate.
  • An organic layer thus obtained was dried with anhydrous sodium sulfate and concentrated under a reduced pressure.
  • Trifluoroacetic acid (1.0 ml, 13 mmol) was added to a dichloromethane solution (10 ml) of tert- butyl 4- [4- ( 4-benzo [b] thiophen-4-yl-piperazin-l- yl) butyl] -3-oxo-piperazine-l-carboxylate (280 mg, 0.59 mmol) , and the resultant mixture was stirred at room temperature for 14 hours. An aqueous solution of sodium hydrogen carbonate was added to this reaction solution, thereby rendering the solution basic. The solution was extracted with dichloromethane.
  • Triethylamine (0.15 ml, 1.08 mmol) was added to a dichloromethane solution (5 ml) of l-[4-(4- benzo [b] thiophen-4-yl-piperazin-l-yl) butyl] piperazin-2- one (260 mg, 0.70 mmol).
  • acetic anhydride (0.1 ml, 1.06 mmol) was added- thereto and the resultant mixture was stirred at room temperature for 2 hours. Water was added to this reaction solution, and the resultant mixture was stirred for 30 minutes. An aqueous solution of sodium hydrogen carbonate was added thereto, and the resultant mixture was extracted with dichloromethane.
  • Trifluoroacetic acid (1.0 ml, 13 mmol) was added to a dichloromethane solution (10 ml) of l-[3-(4- benzo [b] thiophen-4-yl-piperazin-l-yl) propyl] -3- (2, 4- dimethoxybenzyl) imidazolidin-2-one (0.32 g, 0.65 mmol), and the resultant mixture was stirred at room temperature overnight. An aqueous solution of sodium hydroxide was added to this reaction solution, thereby rendering the solution basic. The solution was extracted with dichloromethane.
  • Triethylamine (0.14 ml, 1.04 mmol) and isobutyl chlorocarbonate (0.07 ml, 0.52 mmol) were added under ice cooling to an acetonitrile solution (3 ml) of 1- [3- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) propyl] -6-oxo-l, 6-dihydropyridine-3-carboxylic acid (0.15 g, 0.35 mmol), and the resultant mixture was stirred for 30 minutes.
  • Triethylamine (0.24 ml, 1.7 mmol) , dimethylamine hydrochloride (0.09 g, 1.04 mmol) and diethyl cyanophosphate (0.07 ml, 0.42 mmol) were added under ice cooling to a DMF solution (3 ml) of 1- [3— (4— benzo [b] thiophen-4-yl-piperazin-l-yl) propyl] -6-oxo-l, 6- dihydropyridine-3-carboxylic acid, and the resultant mixture was stirred at room temperature overnight.
  • Triethylamine (0.24 ml, 1.7 mmol), dimethylamine hydrochloride (0.09 g, 1.04 mmol) and diethyl cyanophosphate (DEPC) (0.07 ml, 0.42 mmol) were further added to the reaction solution and the resultant mixture was stirred at room temperature for 26 hours.
  • a (40%) aqueous solution (3 ml) of methylamine was added to a methanol solution (3 ml) of ethyl 3- [4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) butyl] -2-oxo-2, 3-dihydrothiazole-4-carboxylate hydrochloride (0.25 g, 0.52 mmol) , and heated to reflux for 7 hours. This solution was cooled to room temperature. Water was added to this reaction solution, and the solution was extracted with ethyl acetate. An organic layer thus obtained was washed with water, and dried with anhydrous magnesium sulfate. Thus obtained solution was concentrated under a reduced pressure-.
  • Example 1545 by using 1- [4- (4-benzo [b] thiophen-4-yl- piperazin-1-yl) butyl] -2-pyrrolidone. Slightly Yellow Needle Crystals (ethanol) Melting Point 122.0 to 124.0°C
  • Example 1449 by using l-benzyl-4- (4-chlorobutyl) - piperazine-2, 5-dione and 1-benzo [b] thiophen-4-yl- piperazine hydrochloride.
  • 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°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.
  • 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. The results are shown in the following Table.
  • 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 weight 40 times of the weight of the tissue with 50 mM Tris-hydrochloric acid buffer (pH 7.4), and centrifuged at 4 0 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
  • 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.
  • IC5 0 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. [Table 117]
  • CMOS cells 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. /ml penicillin, 50 ⁇ g/ml streptomycin, 200 ⁇ g/ml geneticin, 0.1 mM sodium hypoxanthine, 16 ⁇ M thymidine) at 37 0 C and 5% carbon dioxide condition. Cells were seeded at 10 4 cells/well on a 9 ⁇ -well microtiter plate coated with poly-L-lysine and grown under the same condition for 2 days.
  • IMDM culture medium Iscove's Modified Dulbecco's Medium
  • fetal bovine serum 50 I. U. /ml penicillin, 50 ⁇ g/ml streptomycin, 200 ⁇ g/ml geneticin, 0.1 mM sodium hypoxant
  • IMDM culture medium 0.1 mM sodium hypoxanthine, 16 ⁇ M thymidine
  • 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.
  • 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.
  • 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.

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Abstract

An object of the present invention is to provide a heterocyclic compound having a wide therapeutic spectrum, not causing adverse effects and having high safety. A heterocyclic compound according to the present invention is represented by a general formula, wherein A represents a lower alkylene group or a lower alkenylene group; Z represents O or S; R1 represents hydrogen or the like; and R2 represents hydrogen or the like.

Description

DESCRIPTION
PIPERAZINE-SUBSTITUTEDBENZOTHIOPHENES FOR TREATMENT OF MENTAL DISORDERS
TECHNICAL FIELD
The present invention relates to a novel, heterocyclic compound.
BACKGROUND ART It is desirable to concomitantly have several pharmacological actions in order to express a wide treatment spectrum in a drug because the ethilogy. of bipolar disorder, mood disorder and affective disorder including schizophrenia is heterogeneous. WO2004/026864A1 discloses that a carbostyril derivative represented by a general formula:
Figure imgf000002_0001
[wherein A' represents - (CH2)mCH2-f -(CH2)mO-, etc., m represents an integar of 1 to 4, and RA represents C1-4 alkyl group that may be substituted with a hydrogen atom and one to three fluorine atoms, etc.]
It is disclosed that the carbostyril derivative shown in the above formula has D2 receptor antagonist action, and serotonin 2A (5-HT2A) receptor antagonist action, being effective for treatment for schizophrenia and other central nervous system diseases. However WO2004/026864A1 does not disclose at all that the carbostyril derivative described in the document concomitantly has D2 receptor partial agonist action, 5-HT2A receptor antagonist action, ofi receptor antagonist action, and serotonin uptake inhibiting action, and has a wide treatment spectrum.
Furthermore, WO2005/043309A1 discloses a ce-rtain type of [1, 8]naphthyridine-2-one derivative. However, WO2004/043309A1 as well, it is not disclosed at all that the [1, 8] naphthyridine-2-one derivative described in the document concomitantly has D2 receptor partial agonist action, 5-HT2A receptor antagonist action, αi receptor antagonist action, and serotonin uptake inhibiting action, and has a wide treatment spectrum.
DISCLOSURE OF THE INVENTION
The problem to be solved by the present invention is to provide an antipsychotic drug with a wider treatment spectrum, less side effects and ' excellent tolerability and safety' compared to known typical antipsychotic drugs and atypical antipsychotic drugs . As a result of' keen examination to solve the above problem, the inventors succeeded in synthesizing a novel compound having serotonin uptake inhibiting action (or serotonin reuptake inhibiting action) as well as dopaminergic D2 receptor partial agonist action (D2 receptor partial agonist action) , serotonin-5-HT.2a receptor antagonist action (5-HT2A receptor antagonist action) , and adrenaline αi receptor antagonist action (o£i receptor antagonist action) . The present invention was accomplished based on such knowledge. Item 1.
The present invention provides a heterocyclic compound or a salt thereof represented by the general formula (1) :
Figure imgf000004_0001
[wherein, Q represents a group represented by the following formula (I) :
Figure imgf000004_0002
(wherein, A1 represents a lower alkylene group; Z represents 0 or S; R11 represents (1-1) hydrogen, (1-2) a lower alkyl group,
(1-3) an aryl group selected from the group consisting of a phenyl group, a naphthyl group, and a dihydroindenyl group (wherein the aryl group may be substituted by at least one group selected from the . group consisting of the following substituents (i) to (xxxiii) :
(i) a lower alkyl group,
(ii) a lower alkenyl group,
(iii) a halogen substituted lower alkyl group,
(iv) a lower alkoxy group,
(v) a halogen substituted lower alkoxy group,
(vi) a nitro group,
(vii) a cyano group,
(viii) halogen,
(ix) an aryl group,
(x) an aryloxy group,
(xi) a lower alkoxycarbonyl group,
(xii) a hydroxy group,
(xiii) a protected hydroxy group,
(xiv) a lower alkanoyl group,
(xv) a sulfamoyl group,
(xvi) a lower alkylthio group,
(xvii) a lower alkylsulfonyl group,
(xviii) a hydroxysulfonyl group, (xix) an amino group which may have a group (s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a cyclo (C3- C8) alkyl group, an aryl group, and an aroyl group, (xx) a morpholinylcarbonyl lower alkenyl group,
(xxi) a morpholinylcarbonyl lower alkyl group,
(xxii) a pyrrolyl group, (xxiii) a pyrazolyl group,
(xxiv) an imidazolyl group, (xxv) a triazolyl group, (xxvi) a pyridyl group,
(xxvii) a pyrrolidinyl group which may have an oxo group (s),
(xxviii) a morpholinyl group, (xxix) a thiomorpholinyl group, (xxx) a lower alkynyl group, (xxxi) a cyclo (C3-C8) alkyl group, (xxxii) a guanidino group, and.
(xxxiii) a dihydropyrazolyl group which may have a group (s) selected from the group . consisting of an oxo group and a lower alkyl group) ,
(1-4) a heterocyclic group (wherein the heterocyclic group may be substituted by at least one group selected from the group consisting of the following substituents (i) to (xix) : (i) a lower alkyl group, (ii) a halogen substituted lower alkyl group,
(iii) a lower alkoxy group, (iv) a halogen substituted lower alkoxy group,
(v) halogen, . .
(vi) an aryl group which may have, on the aryl group, a group (s) selected from the group consisting of halogen and a halogen substituted lower alkyl group,
(vii) an aryl lower alkyl group which may have halogen atom(s),
(viii) a lower alkanoyl group, (ix) an aroyl group, (x) an amino lower alkanoyl group which may have, on the amino group, a lower alkanoyl group, (xi) a lower alkylthio group, (xii) a pyrrolyl group, (xiii) an oxo group, (xiv) a thioxo group,
(xv) a carbamoyl group, (xvi) a hydroxy group, (xvii) a pyranyl group, (xviii) a thienyl group, and (xix) a furyl group),
(1-5) an amino lower alkyl group which may have, on the amino group and/or the lower alkyl group, a group (s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a hydroxy lower alkyl group, a lower alkoxycarbonyl group, a carbamoyl lower alkyl group, an indolylcarbonyl group, an aryl group (the aryl group may have a group (s) selected from the group consisting of halogen and a lower alkoxy group) , and an aryl lower alkoxycarbonyl group,
(1-6) a lower alkoxy lower alkyl group, (1-7) an aroyl lower alkyl group, (1-8) an aryl lower alkyl group which may have, on the aryl group, a group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, a hydroxy group, halogen, and a nitro group,
(1-9) an aryloxy lower alkyl group which may have, on the aryl group, a group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, halogen, and a cyano group,
(1-10) an adamantyl lower alkyl group, (1-11) an aryl lower alkenyl group which may have, on the aryl group, a group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen substituted lower alkyl group, a halogen substituted lower alkoxy group, an amino group which may have a lower alkyl group (s), halogen, and a nitro group,
(1-12) a cyclo (C3-C8) alkyl group which may have a group (s) selected from the group consisting of: an amino group which may have a lower alkyl group (s); an amino lower alkyl group which may have a lower alkyl group (s); and an aryl group which may have a group (s) selected from the group consisting of halogen and a lower alkyl group, (1-13) a cyclo (C3-C8) alkyl lower alkyl group,
(1-14) an arylthio lower alkyl group, (1-15) a lower alkyl group substituted by a heterocyclic group selected from the group consisting of a piperidyl group, a tetrahydropyranyl group, a pyridyl group, a thienyl group, an • imidazolyl group, a tetrazolyl group, a benzimidazolyl group, an isoindolyl group, a thiazolidinyl group, and an indolyl group (wherein the heterocyclic group may have a group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, halogen, an oxo group, and a thioxo group) ,
(1-16) an aryl lower alkenyl group (which may have, on the lower alkenyl group, an aryl group(s)),
(1-17) a lower alkenyl group substituted by a heterocyclic group selected from the group consisting of a benzodioxolyl group, a pyridyl group, a furyl group, and an imidazolyl group,
(1-18) a benzodioxolyloxy lower alkyl group, (1-19) a pyridylthio lower alkyl group, or (1-20) an amino group which may have a lower alkyl group (s); and R12 represents
(2-1) hydrogen, (2-2) a lower alkyl group, (2-3) a halogen substituted lower alkyl group,
(2-4) a lower alkenyl group, (2-5) a lower alkynyl group,
(2-6) a lower alkanoyl group,
(2-7) a hydroxy lower alkyl group, (2-8) a lower alkoxy lower alkyl group, (2-9) a cyclo(C3-C8) alkyl group, (2-10) a cyclo(C3-C8) alkyl lower alkyl group,
(2-11) an aryl group,
(2-12) an aryl lower alkyl group which may have, on the aryl group, a group (s) selected from the group consisting of an amino group which may have a lower alkyl group (s) and an aryloxy group, (2-13) a tetrahydrofuryl group, (2-14) a lower alkyl group substituted by a heterocyclic group selected from the group consisting of a furyl group and a pyridyl group, (2-15) a tetrahydropyranyl group, or
(2-16) a lower alkanoyloxy lower alkyl group) , or a group represented by the following general formula (II) :
Figure imgf000010_0001
(wherein, -A2- represents a lower alkylene group, a lower alkenylene group, or a group -A21-0-A22-, wherein A21 and A22 are the same or different and each represents a C1-C5 alkylene group (provided that the total number of carbon atoms constituting the alkylene group of A21 and the alkylene group of A22 does not exceed 6) ; and
R21 represents a N-containing heterocyclic group, . , wherein • the N-containing heterocyclic ring represented by R21 may be substituted by at least one group selected from the group consisting of the following (1) to (13) :
(1) a halogen substituted or unsubstituted lower alkyl group,
(2) a lower alkenyl group, (3) a lower alkoxy group,
(4) a hydroxy group,
(5) a protected hydroxy group,
(6) an aryl group,
(7) a lower alkanoyl group, (8) a carboxy group,
(9) a lower alkoxycarbonyl group,
(10) a carbamoyl group which may have a lower alkyl group (s) , .
(11) an aryl lower alkyl group (which may have, on the aryl group, a lower alkoxy group (s)),
(12) an oxo group, and
(13) a thioxo group)]. Item 2. The present invention provides the heterocyclic compound or a salt thereof according to item 1, wherein,
Q represents a group represented by the following formula (I) :
Figure imgf000012_0001
(wherein, A1 represents a lower alkylene group; Z represents 0 or S; R1* represents
(1-1) hydrogen, (1-2) a lower alkyl group,
(1-3 a) an aryl group selected from the group consisting of a phenyl group, a naphthyl group, and a dihydroindenyl group (wherein the aryl group may be substituted by one to three group (s) selected from the group consisting of the following substituents (i) to (viii) , (ix a), (x a), (xii) , (xiii a), (xiv) to (xviii) , (xix a), (xx) to (xxvi) , (xxvii a), and (xxviii) to (xxxiii) :
(i) a lower alkyl group, (ii) a lower alkenyl group,
(iii) a halogen substituted lower alkyl group,
(iv) a lower alkoxy group,
(v) a halogen substituted lower alkoxy group,
(vi) a nitro group, (vii) a cyano group, (viii) halogen, (ix a) a phenyl group,
(x a) a phenoxy group,
(xi) a lower alkoxycarbonyl group, (xii) a hydroxy group,
(xiii a) a lower alkanoyloxy or a phenyl lower alkoxy group which may have one to three halogen atom(s) on the phenyl group,
(xiv) a lower alkanoyl group, (xv) a sulfamoyl group, (xvi) a lower alkylthio group, (xvii) a lower alkylsulfonyl group,
(xviii) a hydroxysulfonyl group, (xix a) an amino group which may have one to two group (s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a cyclo(C3- C8) alkyl group, a phenyl group, and a benzoyl group,
(xx) a morpholinylcarbonyl lower alkenyl group,
(xxi) a morpholinylcarbonyl lower alkyl group, (xxii) a pyrrolyl group,
(xxiii) a pyrazolyl group, (xxiv) an imidazolyl group, (xxv) a triazolyl group, (xxvi) a pyridyl group,
(xxvii a) a pyrrolidinyl group which may have one to two oxo group (s),
(xxviii) a morpholinyl group, (xxix) a thiomorpholinyl group,
(xxx) a lower alkynyl group, . . (xxxi) a cyclo (C3-C8) alkyl group, (xxxii) a guanidino group,, and (xxxiii) a dihydropyrazolyl group having one oxo group and one lower alkyl group) ,
(1-4 a) a heterocyclic group selected from the group consisting of pyrrolidinyl, piperidyl, thiazolidinyl, tetrahydropyranyl, pyrrolyl, imidazolyl, pyrazolyl, dihydropyrazolyl, pyridyl, dihydropyridyl, tetrahydropyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, thienyl, furyl, indolyl, indolinyl, isoindolinyl, benzimidazolyl, imidazopyridyl, quinolyl, dihydroquinolyl, tetrahydroquinolyl, isoquinolyl, cinnolinyl, indazolyl, quinoxalinyl, benzotriazolyl, dihydronaphthyridinyl, benzothiazolyl, dihydrobenzothiazolyl, dihydrobenzothiaziny1, thienopyrazinyl, benzoxazolyl, dihydrobenzoxazolyl, dihydrobenzoxazinyl, furopyrrolyl, benzodioxolyl, dihydrobenzodioxinyl, and benzothienyl (wherein the heterocyclic group may be substituted by one to three group (s) selected from the group consisting of the following substituents (i) to (v) , (vi a) , (vii a) , (viii) , (ix a) , (x a) , and (xi) to (xix) : (i) a lower alkyl group, (ii) a halogen substituted lower alkyl group,
(iii) a lower alkoxy group, (iv) a halogen substituted lower alkoxy group,
(v) halogen,
(vi a) a phenyl group which may have, on the phenyl group, one to three group (s) selected from the group consisting of halogen and a halogen substituted lower alkyl group,
(vii a) a phenyl lower alkyl group which may have one to three halogen atom(s),
(viii) a lower alkaήoyl group, (ix a) a benzoyl group,
(x a) an amino lower alkanoyl group which may have, on the amino group, one to two lower alkanoyl group (s) ,
(xi) a lower alkylthio group, (xii) a pyrrolyl group,
(xiii) an oxo group, (xiv) a thioxo group, (xv) a carbamoyl group, (xvi) a hydroxy group, (xvii) a pyranyl group,
(xviii) a thienyl group, and (xix) a furyl group) , (1-5 a) an amino lower alkyl group which may have, on the amino group' and/or the lower alkyl group, one to two group (s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a hydroxy lower alkyl group, a lower alkoxycarbonyl group, a carbamoyl lower alkyl group, an indolylcarbonyl group, a phenyl group (the phenyl group may have' one to three group (s) selected from the group consisting of halogen and a lower alkoxy group) , and a phenyl lower alkoxycarbonyl group, (1-6) a lower alkoxy lower alkyl group,
(1-7 a) a benzoyl lower alkyl group, (1-8 a) a phenyl lower alkyl group which may have, on the phenyl group, one to three group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, a hydroxy group, halogen, and a nitro group,
(1-9 a) a phenoxy lower alkyl group which may have, on the phenyl group, one to three group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, halogen, and a cyano group,
(1-10) an adamantyl lower alkyl group, (1-11 a) a phenyl lower alkenyl group which may have, on the phenyl group, one to three group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen substituted lower alkyl group, a halogen substituted lower alkoxy group, an amino group which may have one to two lower alkyl group (s), halogen, and a nitro group,
(1-12 a) a cyclo (C3-C8) alkyl group which may have one to two group (s) selected from the group consisting of: an amino group which may have one to two lower alkyl group (s) ; an amino lower alkyl group which may have one to two lower alkyl group (s); and a phenyl group which may have one to three group (s) selected from the group consisting of halogen and a lower alkyl group, (1-13) a cyclo (C3-C8) alkyl lower alkyl group,
(1-14 a) a phenylthio lower alkyl group, (1-15 a) a lower alkyl group substituted by a heterocyclic group selected from the group consisting of a piperidyl group, a tetrahydropyranyl group, a pyridyl group, a thienyl group, an imidazolyl group, a tetrazolyl group, a benzimidazolyl group, an isoindolyl group, a thiazolidinyl group, and an indolyl group (wherein the heterocyclic group may have one to three group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, halogen, an oxo group, and a thioxo group) ,
(1-16 a) a phenyl lower alkenyl group (which may have, on the lower alkenyl group, one to two phenyl group(s)), (1-17) a lower alkenyl group substituted by a heterocyclic group selected from the group consisting of a benzodioxolyl group, a pyridyl group, a furyl group, and an imidazolyl group, (1-18) a benzodioxolyloxy lower alkyl group, (1-19) a pyridylthio lower alkyl group, or (1-20 a) an amino group which may have one to two lower alkyl group (s); and R12 represents
(2-1) hydrogen . .
(2-2) a lower alkyl group, (2-3) a halogen substituted . lower alkyl group, (2-4) a lower alkenyl group,
(2-5) a lower alkynyl group, (2-6) a lower alkanoyl group, (2-7) a hydroxy lower alkyl group, (2-8) a lower alkoxy lower alkyl group, (2-9) a cyclo(C3-C8) alkyl group,
(2-10) a cyclo(C3-C8) alkyl lower alkyl group, (2-11 a) a phenyl group
(2-12 a) a phenyl lower alkyl group which may have, on the phenyl group, one to three group (s) selected from the group consisting of an amino group which may have one to two lower alkyl group (s) and a phenoxy group,
(2-13) a tetrahydrofuryl group, (2-14) a lower alkyl group substituted by a heterocyclic group selected from the group consisting of a furyl group and a pyridyl group,
(2-15) a tetrahydropyranyl group, or (2-16) a lower alkanoyloxy lower alkyl group) , or a group represented by the following general formula (II) :
Figure imgf000019_0001
(wherein, -A2- represents a lower alkylene group, a lower alkenylene group, or a group -A21-0-A22-, wherein A21 and A22 are the same or different and each represents a C1-C5 alkylene group (provided that the total number of carbon atoms constituting the alkylene group of A1 and the alkylene group of A2 does not exceed β)-; and R21 represents a N-containing heterocyclic group selected from the group consisting of pyrrolidinyl, imidazolidinyl, piperidyl, hexahydropyrimidinyl, piperazinyl, octahydroisoindolyl, azepanyl, azocanyl, azaspirononanyl, azaspirodecanyl, diazaspirononanyl, dihydropyrrolyl, irαidazolyl, dihydroimidazolyl, triazolyl, dihydrotriazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidinyl, dihydropyrimidinyl, pyrazinyl, dihydropyrazinyl, pyridazinyl, tetrazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, hexahydroisoindolyl, octahydroisoindolyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, quinazolinyl, dihydroquinazolinyl, benzotriazolyl, carbazolyl, spirocyclopentanindolinyl, oxazolyl, isoxazolyl, oxadiazolyl, oxazolidinyl, isoxazolidinyl, oxazinanyl, morpholinyl, benzoxazolyl, dihydrobenzoxazolyl, benzoxazinyl, dihydrobenzoxazinyl, benzoxazolyl, benzoxadiazolyl, thiazolyl, dihydrothiazolyl, isothiazolyl, thiadiazolyl, dihydrothiazinyl, thiazolidinyl, benzothiazolyl, and benzothiadiazolyl, wherein the N-containing heterocyclic ring . . represented by R21 may be substituted by one to three group (s) selected from the group consisting of the following (1) to (4), (5 a), (6 a), (7) to (9), (10 a), (11 a) , (12) , and (13) :
(1) a halogen substituted or unsubstituted lower alkyl group,
(2) a lower alkenyl group,
(3) a lower alkoxy group, (4) a hydroxy group,
(5 a) a lower alkanoyloxy group or a phenyl lower alkoxy group,
(β a) a phenyl group,
(7) a lower alkanoyl group, (8) a carboxy group,
(9) a lower alkoxycarbonyl group,
(10 a) a carbamoyl group which may have one to two lower alkyl group (s),
(11 a) a phenyl lower alkyl group (which may have, on the phenyl group, one to two lower alkoxy group (s) ) ,
(12) an oxo group, and
(13) a thioxo group) . Item 3.
The present invention provides the heterocyclic compound or a salt thereof according to item 2, wherein Q represents a group represented by the following formula (I) :
Figure imgf000021_0001
(wherein, A1 represents a lower alkylene group; Z represents O or S; R11 represents (1-1) hydrogen,
(1-2) a lower alkyl group,
(l-3aa) a phenyl group which may have one to two halogen atom(s),
(l-4aa) a heterocyclic group selected from the group consisting of pyrazinyl and thienyl (wherein the heterocyclic group may be substituted by one lower alkyl group) ,
(1-5 aa) an amino lower alkyl. group which may have, on the amino group and/or the lower alkyl group, one or two group (s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a hydroxy lower alkyl group, a lower alkoxycarbonyl group, a carbamoyl lower alkyl group, an indolylcarbonyl group, a phenyl group (the phenyl group may have one group selected from the group consisting of halogen and a lower aikoxy group) , and a phenyl lower alkoxycarbonyl group, or
(1-20 a) an amino group which may have one to two lower alkyl group(s); and
R12 represents
(2-1) hydrogen,
(2-2) a lower alkyl group, .
(2-4) a lower alkenyl group, (2-6) a lower alkanoyl group,
(2-7) a hydroxy lower alkyl group,
(2-8) a lower aikoxy lower alkyl group, or
(2-9) a cyclo(C3-C8) alkyl group). Item 4. The present invention provides the heterocyclic compound or a salt thereof according to item 2,, wherein
Q represents a group represented by the following general formula (II) :
Figure imgf000022_0001
(wherein, -A2- represents a lower alkylene group or a lower alkenylene group; and
R21 represents a N-containing heterocyclic group selected from the group consisting of pyrrolidinyl, imidazolidinyl, piperidyl, azepanyl, oxazolidinyl, and oxazinanyl, wherein the N-containiήg heterocyclic ring represented by R21 may be substituted by one to three group (s) selected from the group consisting of the following (1), (12), and (13): (1) a halogen substituted or unsubstituted alkyl group,
(12) an oxo group, and
(13) a thioxo group) . Item 5. The present invention provides the heterocyclic compound of the formula (1) or a salt thereof, according to item 3. selected from the group consisting of:
N- [5- (4-Benzo[b] thiophen-4-yl-piperazin-l-yl) -pentyl]- acetamide,
N- [5- (4-Benzo [b] thiophen-4-yl-piperazin-l-yl) -pentyl] -
2, 4-difluoro-benzamide,
N- [4- (4-Benzo [b] thiophen-4-yl-piperazin-l-yl) -butyl] -N- cyclopropyl-acetamide, 5-Methyl-pyrazine-2-carboxylic acid [4- (4- benzo [b] thiophen-4-yl-piperazin-l-yl) -butyl] -ethyl- amide,
Thiazole-4-carboxylic acid [4- (4-benzo [b] thiophen-4-yl- piperazin-1-yl) -butyl] -ethyl-amide, N- [4- (4-Benzo [b] thiophen-4-yl-piperazin-l-yl) -butyl] -N- ethyl-acetamide,
N- [4- (4-Benzo [b] thiophen^-4-yl-piperazin-l-yl) -butyl] -N- isopropyl-acetamide, N- [4- (4-Benzo [b] thiophen-4-yl-piperazin-l-yl) -butyl] -N- ethyl-thioacetamide,
N-Allyl-N- [4- (4-benzo [b] thiophen-4-yl-piperazin-l-yl) - butyl] -acetamide, and N- [4- (4~Benzo[b] thiophen-4-yl-piperazin-l-yl) -butyl] -N- tert-~butyl-formamide.
Item 6. '
The present invention provides The heterocyclic compound of the formula (1) or a salt thereof according to item 4 selected from the group consisting of:
1—[5- (4-Benzo [b] thiophen-4-yl-piperazin-l-yl) -pentyl] - imidazolidin-2-one,
1- [5- (4-Benzo [b] thiophen-4-yl-piperazin-l-yl) -pentyl] - 3-methyl-imidazolidin-2-one,
1- [5- (4-Benzo [b] thiophen-4-yl-piperazin-l-yl) -pentyl] - pyrrolidin-2-one,
1- [5- (4-Benzo [b] thiophen-4-yl-piperazin-l-yl) -pentyl] - pyrrolidine-2, 5-dione, 1- [4- (4-Benzo [b] thiophen-4-yl-piperazin~l-yl) -butyl] - azepan-2-one,
3- [6- (4-Benzo [b] thiophen-4-yl-piρerazinτ-l-yl) -hexyl] - oxazolidin-2~one,
3- [4- (4-Benzo [b] thiophen-4-yl-piperazin-l-yl) -butyl] - 4r 4-dimethyl-oxazolidin-2-one,
3- [4- (4-Benzo [b] thiophen-4-yl-piperazin-l-yl) -butyl] -4- methyl-oxazolidin-2-one,
3- [4- (4-Benzo [b] thiophen-4-yl-piperazin-l-yl) -butyl] - oxazolidin-2-one,
1- [4-(4-Benzo[b] thiophen-4-yl-piperazin-l-yl) -butyl] - pyrrolidin-2-one, l-[4- (4-Benzo[b] thiophen-4-yl-piperazin-l-yl) -butyl] - piperidin-2-one,
1- [ (E) -4- (4-Benzo [b] thiophen-4-yl-piperazin-l-yl) -but-
2-enyl]-'3-methyl-imidazolidin-2-one,
1- [4- (4-Benzo [b] thiophen-4-yl-piperazin-l-yl) -butyl] - piperidine-2-thione, and 3- [4- (4-Benzo [b] thiophen-4-yl-piperazin-l-yl) -butyl] -A- methyl-oxazolidin-2-one .
Item 7.
The present invention provides a pharmaceutical composition comprising a heterocyclic compound of the formula (1) or a salt thereof according to any one of items 1 to 6, as an. active ingredient and a pharmaceutically acceptable carrier.
Item 8.
The present invention provides the pharmaceutical composition according to item 7 for treating or preventing central nervous system disorders.
Item 9.
The present invention provides the pharmaceutical composition according to item 8 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; anhedonia; iatrogenic anhedonia; anhedonia of a psychic or mental cause; anhedonia associated with depression; anhedonia associated with schizophrenia; delirium; cognitive impairment; cognitive impairment associated with Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases; cognitive impairment caused by Alzheimer's disease; Parkinson's disease and associated neurodegenerative diseases; cognitive impairment of schizophrenia; cognitive impairment caused by refractory, intractable or chronic schizophrenia; vomiting; motion sickness; obesity; migraine; pain (ache) ; mental retardation; autism disorder (autism); Tourette's disorder; tic disorder; attention-deficit/hyperactivity disorder; conduct disorder; and Down's syndrome. Item 10.
The present invention provides a process for producing a pharmaceutical composition comprising mixing a heterocyclic compound of the formula (1) or a salt thereof according to any one of claims 1 to 6 with a pharmaceutically acceptable carrier. Item 11. The present invention relates to use of a heterocyclic compound of the formula (1) or a salt thereof according to any one. of items 1 to 6 as a drug. Item 12.
The present invention relates to use of a heterocyclic compound of the formula (1) or a salt thereof according to any one of items 1 to 6 as a dopamine D2 receptor partial agonist and/or a serotonin 5-HT2A receptor antagonist and/or an adrenaline αi receptor antagonist and/or a serotonin uptake inhibitor and/or a serotonin reuptake inhibitor. Item 13.
The present invention provides a method for treating or preventing a central nervous system disorder comprising administering a heterocyclic compound of the formula (1) or a salt thereof according to any one of items 1 to 6 to human or animal. Claims of specific compounds of an amide type/heterocyclic ring type are described in items 5 and 6.
BEST MODE FOR CARRYING OUT THE INVENTION
For a heterocyclic compound or a salt thereof of the present invention represented by the general formula (1) , it is preferred that in the formula, R1*, R12, and A1 in the formula (I) representing Q and R21 and A2 in the formula (II) representing Q .should represent the following substituents: a heterocyclic compound or a salt thereof represented by the general formula (1) :
Figure imgf000028_0001
[wherein, Q represents a group represented by the following formula (I) :
Figure imgf000028_0002
(wherein, A1 represents a lower alkylene group; Z represents 0 or S; R11 represents
(1-1) hydrogen,
(1-2) a lower alkyl group,
(1-3 a) an aryl group selected from the group consisting of a phenyl group, a naphthyl group, and a dihydroindenyl group (wherein the aryl group may be substituted by one to three group (s) selected from the group consisting of the following substituents (i) to (viii) , (ix a), (x a), (xii), (xiii a), (xiv) to (xviii) , (xix a), (xx) to (xxvi) , (xxvii a), (xxviii) to (xxxii) , and (xxxiii a) :
(i) a lower alkyl group, (ii) a lower alkenyl group, (iii) a halogen substituted lower alkyl group,
(iv) a lower alkoxy group, (v) a halogen substituted lower alkoxy group,
(vi) a nitro group, (vii) a cyano group,
(viii) halogen, (ix a) a phenyl group, (x a) a phenoxy group, (xi) a lower alkoxycarbonyl group, (xii) a hydroxy group,
(xiii a) a lower alkanoyloxy or a phenyl lower alkoxy group which may have one to three halogen atom(s) on the phenyl group,
(xiv) a lower alkanoyl group, (xv) a sulfamoyl group,
(xvi) a lower alkylthio group, (xvii) a lower alkylsulfonyl group, (xviii) a hydroxysulfonyl group, (xix a) an Ηitiino group which may have one to two group (s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a cyclo (C3- C8)alkyl group, a phenyl group, and a benzoyl group (more preferably, a N,N-di lower alkylamino group, a lower alkanoylamino group, a N-lower alkanoyl-N cyclo (C3-C8) alkylamino group, a phenylaraino group, or a benzoylamino group) ,
(xx) a morpholinylcarbonyl lower alkenyl group,
(xxi) a morpholinylcarbonyl lower alkyl group,
(xxii) a pyrrolyl group, (xxiii) a pyrazolyl group, (xxiv) an imidazolyl group,
(xxv) a triazolyl group, (xxvi) a pyridyl group,
(xxvii a) a pyrrolidinyl group which may have one to two (preferably, one) oxo group (s), (xxviii) a morpholinyl group,
(xxix) a thiomorpholinyl group, (xxx) a lower alkynyl group,, (xxxi) a cyclo (C3-C8) alkyl group, (xxxii) a guanidino group, and (xxxiii a) a dihydropyrazolyl group having one oxo group and one lower alkyl group) ,
(1-4 a) a heterocyclic group selected from the group consisting of pyrrolidinyl, piperidyl, thiazolidinyl, tetrahydropyranyl, pyrrolyl, imidazolyl, pyrazolyl, dihydropyrazolyl, pyridyl, dihydropyridyl, tetrahydropyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, thienyl, furyl, indolyl, indolinyl, isoindolinyl, benzimidazolyl, imidazopyridyl, quinolyl, dihydroquinolyl, tetrahydroquinolyl, isoquinolyl, cinnoliriyl, indazolyl, quinoxalinyl, benzotriazolyl, dihydronaphthyridinyl, benzothiazolyl, dihydrobenzothiazolyl, dihydrobenzothiazinyl, thienopyrazinyl, benzoxazolyl, dihydrobenzoxazolyl, dihydrobenzoxazinyl, furopyrrolyl, benzodioxolyl, dihydrobenzodioxinyl, and benzothienyl (wherein the heterocyclic group may be substituted by one to three group (s) selected from the group consisting of the following substituents (i) to (v) , (vi a) , (vii a) , (viii) , (ix a) , (x a) , and (xi) to (xix) : (i) a lower alkyl group, (ii) a halogen substituted lower alkyl group, (iii) a lower alkoxy group,
(iv) a halogen substituted lower alkoxy group,
(v) halogen,
(vi a) a phenyl group which may have, on the phenyl group, one to three (preferably, one) group (s) selected from the group consisting of halogen and a halogen substituted lower alkyl group,
(vii a) a phenyl lower alkyl group which may have one to three "(preferably, one to two) halogen atom(s) ,
(viii) a lower alkanoyl group, (ix a) a benzoyl group, (x a) an amino lower alkanoyl group which may have, on the amino group, one to two (preferably, one) lower alkanoyl group (s),
(xi) a lower alkylthio group, (xii) a pyrrolyl group, (xiii) an oxo group,
(xiv) a thioxo group, (xv) a carbamoyl group, (xvi) a hydroxy group, (xvii) a pyranyl group, (xviii) a thienyl group, and
(xix) a furyl group) ,
(1-5 a) an amino lower alkyl group which may have, on the amino group and/or the lower alkyl group, one to two group (s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a hydroxy lower alkyl group, a lower alkoxycarbonyl group, a carbamoyl lower alkyl group, an indolylcarbonyl group, a phenyl group (the phenyl group may have one to three (preferably, one) group (s) selected from the group consisting of halogen and a lower alkoxy group) , and a phenyl lower alkoxycarbonyl group,
(1-6) a lower alkoxy lower alkyl group, (1-7 a) a benzoyl lower alkyl group, (1-8 a) a phenyl lower alkyl group which may have, on the phenyl group, one to three (preferably, one to two) group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, a hydroxy group, halogen, and a nitro group, . .
(1-9 a) a phenoxy lower alkyl group which may have, on the phenyl group, one to three group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, halogen, and a cyano group,
(1-10) an adamantyl lower alkyl group, (1-11 a) a phenyl lower alkenyl group which may have, on the phenyl group, one to three (preferably, one to two) group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen substituted lower alkyl group, a halogen substituted lower alkoxy group, an amino group which may have one to two lower alkyl group (s) (preferably, a N,N-di lower alkylamino group), halogen, and a nitro group,
(1-12 a) a cyclo (C3-C8) alkyl group which may have one group selected from the group consisting of: an amino group which may have one to two lower alkyl group(s) (preferably, a N,N-di lower alkylamino group); an amino lower alkyl group which may have one to two lower alkyl group (s) (preferably, a N,N-di lower alkylamino lower alkyl group) ; and a phenyl group which may have one to three (preferably, one) group (s) selected from the group consisting of halogen and a lower alkyl group,
(1-13) a cyclo(C3-C8) alkyl lower alkyl group, (1-14 a) a phenylthio lower alkyl group,
(1-15 a) a lower alkyl group substituted. by a heterocyclic group selected from the group consisting of a piperidyl group, a tetrahydropyranyl group, a pyridyl group, a thienyl group, an imidazolyl group, a tetrazolyl group, a benzimidazolyl group, an isoindolyl group, a thiazolidinyl group, and an indolyl group (wherein the heterocyclic group may have one to three (preferably, one to two) group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, halogen, an oxo group, and a thioxo group) ,
(1-16 a) a phenyl lower alkenyl group (which may have, on the lower alkenyl group, one to two (preferably, one) phenyl group(s)),
(1-17) a lower alkenyl group substituted by a heterocyclic group selected from the group consisting of a benzodioxolyl group, a pyridyl group, a furyl group, and an imidazolyl group,
(1-18) a benzodioxolyloxy lower alkyl group, (1-19) a pyridylthio lower alkyl group, or (1-20 a) an amino group which may have one to two lower alkyl group (s) , and even more preferable definition of R11 includes (1-1) hydrogen, (1-2) a lower alkyl group,
(1-5 aaa) an amino lower alkyl group having, on the amino group and/or the lower alkyl group, one group selected from, the group consisting of a lower alkanoyl group and a lower alkoxycarbonyl group, or
(1-20 aa) an amino group having one to two lower alkyl group (s); and R12 represents
(2-1) hydrogen, (2-2) a lower alkyl group,
(2-3) a halogen substituted lower alkyl group,
(2-4) a- lower alkenyl group, (2-5) a lower alkynyl group, (2-6) a lower alkanoyl group,
(2-7) a hydroxy lower alkyl group, (2-8) a lower alkoxy lower alkyl group, (2-9) a cyclo(C3-C8) alkyl group, (2-10) a cyclo (C3-C8) alkyl lower alkyl group, (2-11 a) a phenyl group,
(2-12 a) a phenyl lower alkyl group which may have, on the phenyl group, one to three. (preferably, one) group (s) selected from the group consisting of an amino group which may have one to two lower alkyl group (s) (more preferably, a N,N-di lower alkylamino group) and a phenoxy group,
(2-13) a tetrahydrofuryl group,
(2-14) a lower alkyl group substituted by a heterocyclic group selected from the group consisting of a furyl group and a pyridyl group,
(2-15) a tetrahydropyranyl group, or (2-16) a lower alkanoyloxy lower alkyl group, and even more preferable definition of R12 includes (2-1) hydrogen, (2-2) a lower alkyl group, (2-4) a lower alkenyl group, (2-6) a lower alkanoyl group,
(2-7) a hydroxy lower alkyl group, (2-8) a lower alkoxy lower alkyl group, or (2-9) a cyclo(C3-C8) alkyl group), or a group represented by the following general formula (II) :
Figure imgf000036_0001
(wherein, -A2- represents a lower alkylene group, a lower alkenylene group, or a group -A21-0-A22-, wherein A21 and A22 are the same or different and each represents a C1-C5 alkylene group (provided that the total number of carbon atoms constituting the alkylene group of A1 and the alkylene group of A2 does not exceed
6) ; and
R21 represents a N-containing heterocyclic group selected from the group consisting of pyrrolidinyl, imidazolidinyl, piperidyl, hexahydropyrimidinyl, piperazinyl, octahydroisoindole, azepanyl, azocanyl, azaspirononanyl, azaspirodecanyl, diazaspirononanyl, dihydropyrrolyl, imidazolyl, dihydroimidazolyl, triazolyl, dihydrotriazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidinyl, dihydropyrimidinyl, pyrazinyl, dihydropyrazinyl, pyridazinyl, tetrazolyl, indolyl/ isoindolyl, indolinyl, isoindolinyl, hexahydroisoindolyl, octahydroisoindolyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, quinazolinyl, dihydroquinazolinyl, benzotriazolyl, carbazolyl, spiro [cyclopentanindolinyl] , oxazolyl, isoxazolyl, oxadiazolyl, oxazolidinyl, isoxazolidinyl, oxazinanyl, morpholinyl, benzoxazolyl, dihydrobenzoxazolyl, benzoxazinyl, dihydrobenzoxazinyl, benzoxazolyl, benzoxadiazolylr thiazolyl, dihydrothiazolyl, isothiazolyl, thiadiazolyl, dihydrothiazinyl, thiazolidinylbenzothiazolyl, and benzothiadiazolyl, wherein the N-containing heterocyclic ring represented by R21 may be substituted by one to three group (s) selected from the group consisting of the following (1) to (4), (5 a), (6 a), (7). to (9) , (10 a), (11 a) , (12) , and (13) :
(1) a halogen substituted or unsubstituted lower alkyl group,
(2) a lower alkenyl group,
(3) a lower alkoxy group,
(4) a hydroxy group, (5 a) a lower alkanoyloxy group or a phenyl lower alkoxy group,
(6 a) a phenyl group, (7) a lower alkanoyl group, (8) a carboxy group,
(9) a lower alkoxycarbonyl group, (10 a) a carbamoyl group which may have one to two lower alkyl group (s),
(11 a) a phenyl lower alkyl group (which may have, on the phenyl group, one to two lower alkoxy group (s) ) , .
(12) an oxo group, and
(13) a thioxo group, and even more preferable definition of R21 includes: an imidazolidinyl group having one to two group (s) selected from the group consisting of a lower alkyl group and an oxo group; a piperidyl group having one to two group (s) selected from the group consisting of a lower alkyl group, an oxo group, and a thioxo group; an oxazolidinyl group having one to three group (s) selected from the group consisting of a lower alkyl group and an oxo group; and an oxazinanyl group having one to two group (s) selected from the group consisting of a lower alkyl group and an oxo group) ] . Specifically, each group shown in the above general formula is as follows.
As lower alkyl group, linear or branched alkyl group with carbon number 1 to 6 (preferably, carbon number 1 to 4) can be cited. 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, and 3- methylpentyl groups, etc., are included.
As lower alkylene group, linear or branched alkylene group with carbon number 1 to 6 (preferably, carbon number 1 to 4) can be cited. More specifically, methylene, ethylene, trimethylene,• 2- methyltrimethylene, 2,2-dimethylethylene, 2,2- dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, 1- methyltetramethylene, 1-ethyltetramethylene, 2- methyltetramethylene, 2-ethyltetramethylene, pentamethylene, and hexamethylene groups, etc., are included.
As lower alkenylene group, linear or branched alkynylene group with carbon number 2 to 6 (preferably, carbon number 2 to 4) having one to three double bonds can be cited. More specifically, 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-ynylene, 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, and 1,4- hexadienylene groups, etc., are included.
As C1-C5 alkylene group, linear or branched alkylene group with carbon number 1 to 5 can be cited. More specifically, methylene, ethylene, trimethylene, 2-methyltrimethylene, 2, 2-dimethylethylene, '2,2- dimethyl'trimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, and pentamethylene groups, etc., are included. In the general formula, as a group represented by the above -A1-O-A2-, for example, -CH2-O- CHi-, -CH2-O-(CHa)2-, -CH2-O- (CH2) 3-, -CH2-O- (CH2) «-, -CH2- 0-(CH2)S-, -(CH2) 2-0- (CH2) 2-, -(CH2) 3-0- (CH2) 3-, and - CH (CH3) -CH2-O-CH (CH3) -CH2-, etc., can be cited. As lower alkenyl group, linear or branched alkenyl group with carbon number 2 to 6 (preferably, carbon number 2 to 4) having one to three double bonds can be cited, and includes both trans isomer and cis isomer. More specifically, vinyl, 1-propenyl, 2- propenyl, 1-methyl-1-propenyl, 2-methyl-l-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-pentene-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, and 1, 4-hexadienyl groups, etc., are included.
As lower alkynyl group, linear or branched alkynyl group with carbon number 2 to 6 (preferably, carbon number 2 to 4) can be ^cited. More specifically, ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, l-methyl-2- • propynyl, 2-pentynyl, and 2-hexynyl groups, etc., are included.
As halogen atom, fluorine atom, chlorine atom, bromine atom and iodine atom can be cited.
As halogen substituted lower alkyl group, the above exemplified lower alkyl group with one to seven halogen atoms substituted, more preferably one to three halogen atoms substituted, can be cited. 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-pentafluorobutyl, 4- chlorobutyl, 4-bromobutyl, 2-chlorobutyl, 5,5,5- trifluoropentyl, 5-chloropentyl, 6, 6, 6-trifluorohexyl, 6-chlorohexyl, and perfluorohexyl groups, etc., are included. As lower alkoxy group, linear or branched alkoxy group with carbon number 1 to 6 (preferably, carbon number 1 to 4) can be cited. More specifically, methoxy, ethoxyl, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, and 3-methylpentyloxy groups, etc., are included.
As aryl group, for example, phenyl, biphenyl, naphthyl, dihydroindenyl, and 9H-fluorenyl groups, etc., can be cited.
As aryloxy group, for example, phenyloxy, and naphthyloxy groups, etc., can be cited.
As arylthio group, for example, phenylthio, and naphthylthio groups, etc., can be cited.
As aroyl group, benzoyl, and naphthoyl groups, etc., can be cited.
As lower alkylthio group, linear or branched alkylthio group with carbon number 1 to 6 (preferably, carbon number 1 to 4) can be cited. More specifically, methylthio, ethylthio, n-propylthio, isopropylthio, n- butylthio, tert-butylthio, n-pentylthio, and n- hexylthio groups, etc., are included.
As halogen substituted lower alkoxy group, the above exemplified lower alkoxy group with one to seven halogen atoms substituted, preferably one to three halogen atoms substituted, can be- cited. More specifically, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, bromomethoxy, dibromomethoxy, dichlorofluoromethoxy, 2,2, 2-trifluoroethoxy, pentafluoroethoxy, 2-chloroethoxy, 3,3,3- trifluoropropoxy, heptafluoropropoxy, heptafluoroisopropoxy, 3-chloropropoxy, 2- chloropropoxy, 3-bromopropoxy, 4, 4, 4-trifluorobutoxy, 4, 4, 4,3, 3-pentafluorobutoxy, 4-chlorobutoxy, A- ■ bromobutoxy, 2-chlorobutoxy, 5, 5, 5-trifluoropentoxy, 5- chloropentoxy, 6, 6, 6-trifluorohexyloxy, and 6- chlorohexyloxy groups, etc., are included.
As lower alkanoyl group, linear or branched alkanoyl group with carbon number 1 to 6 (preferably, carbon number 1 to 4) can be cited. More specifically, formyl, acetyl, propionyl, butyryl> isobutyryl, pentanoyl, tert-butylcarbonyl, and hexanoyl groups, etc., are included.
As lower alkanoyloxy group, alkanoyloxy group with the alkanoyl part being linear or branched alkanoyl group with carbon number 1 to 6 (preferably, carbon number 1 to 4) can be cited. More specifically, formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, tert-butylcarbonyloxy, and hexanoyloxy groups, etc., are included. As lower alkanoyloxy lower alkyl group, linear or branched alkyl group with carbon number 1 to 6 (preferably, carbon number 1 to 4) having one to three of the above exemplified lower alkanoyloxy groups, preferably one, can be cited. More specifically, formyloxymethyl, 3-acetyloxypropyl, 2- propionyloxyethyl, butyryloxymethyl, 2- isobutyryloxyethyl, 3-ρentanoyloxypropyl, tert- butylcarbonyloxymethyl, and hexanoyloxymethyl groups, etc., are included.
As protecting group of hydroxy group, for example, lower alkyl group (linear or branched alkyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4)), lower alkanoyl group (linear or branched alkanoyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4) ) , and phenyl lower alkyl group with the lower alkyl part being linear or branched alkyl group with carbon number 1 to 6 (preferably, carbon number 1 to 4) that may have one to three substituent groups such as halogen atom, etc., preferably one, on the phenyl group, can be cited. As protecting group of hydroxy group, for example, linear or branched alkyl group with carbon number 1 to 6 (preferably, carbon number 1 to 4) , lower alkanoyl group (linear or branched alkanoyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4)), and phenyl lower alkyl group with the lower alkyl part being linear or branched alkyl group with carbon number 1 to 6 (preferably, carbon number 1 to 4) , can be cited.
As protected hydroxy group, for example, the above exemplified lower alkoxy group, phenyl lower alkoxy group with the lower alkanoyl part being the above exemplified lower alkanoyloxy group and the lower alkoxy part being the above exemplified lower alkoxy group (that may have one to three substituent groups such as halogen atom, etc., preferably one, on the phenyl group) can be cited. More specifically, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, 3- methylpentyloxy, formyloxy, acetyloxy, propionyloxy,' butyryloxy, isobutyryloxy, pentanoyloxy, tert- butylcarbonyloxy, hexanoyloxy, benzyloxy, 4- chlorobenzyloxy, 2-phenylethoxy, 1-phenylethoxy, 3- phenylpropoxy, 4-phenylbutoxy, 5-phenylpentyloxy, 6- phenylhexyloxy, 1, l-dimethyl-2~phenylethoxy, 2-methyl- 3-phenylpropoxy groups, etc., are cited.
As hydroxy lower alkyl group, the above exemplified lower alkyl group having one to five hydroxy groups, preferably one to three (linear or branched alkyl group with preferably carbon number 1 to 6 (more, preferably, carbon number 1 to 4)) can be cited. More specifically, hydroxymethy1, 2- hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2,3- dihydroxypropyl, 4-hydroxybutyl, 3, 4-dihydroxybutyl, l,-l-dimethyl-2-hydroxyethyl, 5-hydroxypentyl, 6- hydroxyhexyl, 3, 3-dimethyl-3-hydroxypropyl, 2-methyl-3- hydroxypropy1,. 2, 3, 4-trihydroxybutyl, and perhydroxyhexyl groups, etc., are included. As protecting group of hydroxy lower alkyl group, for example, linear or branched alkyl group with carbon number 1 to 6 (preferably, carbon number 1 to 4) , lower alkanoyl group (linear or branched alkanoyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4) ) , and phenyl lower alkyl group with the lower alkyl part being linear or branched alkyl group with carbon number 1 to 6 (preferably, carbon number 1 to 4) can be cited.
As protected hydroxy lower alkyl group, the above exemplified lower alkyl group (linear or branched alkyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4) ) having one to five, preferably one to three, of the above exemplified protected hydroxy groups (preferably, lower alkoxy group, lower alkanoyloxy group or phenyl lower alkoxy group (that may have one to three substituent groups such as halogen atom, preferably one, on phenyl group) ) can be cited. More specifically, methoxymethyl, 2- methoxyethyl, 2-ethoxyethyl, 2-n-propox'yethyl, 2- isopropoxyethyl, 2-n-butoxyethyl, 2-isobutoxyethyl, 2- tert-butoxyethyl, 2-sec-butoxyethyl, 2-n- pentyloxyethyl, 2-isopentyloxyethyl, 2- neopentyloxyethyl, 2-n-hexyloxyethyl, 2- isohexyloxyethyl, 2- (3-methylpentyloxy) ethyl, 2- formyloxyethyl, 2-acetyloxyethyl, 2-propionyloxyethyl, 2-butyryloxyethyl, 2-isobutyryloxyethyl, 2- pentanoyloxyethyl, 2-tert-butylcarbonyloxyethyl, 2- hexanoyloxyethyl, 2-benzyloxyethyl, 2- (2- phenylethoxyl) ethyl, 2- (1-ρhenylethoxyl) ethyl, 2-(3- phenylpropoxy) ethyl, 2- (4-phenylbutoxy) ethyl, 2- (5- phenylpentyloxy) ethyl, 2- (6-phenylhexyloxy) ethyl, 2- ( 1, l-dimethyl-2-phenylethoxyl) ethyl, 2- (2-methyl-3- phenylpropoxy) ethyl, 3-ethoxypropyl, 2,3- diethoxypropyl, 4-ethoxylbutyl, 3, 4-diethoxylbutyl, • l,l-dimethyl-2-ethoxyethyl, 5-ethoxylpentyl, 6- ethoxylhexyl, 3, 3-dimethyl-3-ethoxypropyl, 2-methyl-3- ethoxypropyl, and 2, 3, 4-triethoxylbutyl groups, etc., are included.
As lower alkoxycarbonyl group, alkoxycarbonyl group with the lower alkoxy part being the above exemplified lower alkoxy group (linear or branched alkoxy group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4)) can be cited. More specifically, methoxycarbonyl, ethoxylcarbonyl, n- propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, sec- butoxycarbonyl, n-pentyloxycarbonyl, neopentyloxy, n- hexyloxycarbonyl, isohexyloxycarbonyl, and 3- methylpentyloxycarbonyl groups, etc., are included.
As lower alkyl sulfonyl group, alkyl sulfonyl group with the lower alkyl part being the above exemplified lower alkyl group (linear or branched alkyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4) ) can be cited. More specifically, methylsulfonyl, ethylsulfonyl, n- propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl, sec- butylsulfonyl, n-pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, n-hexylsulfonyl, isohexylsulfonyl, and 3-methylpentylsulfonyl groups, etc., are included.
As cyclo C3-C8 alkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups, etc., can be cited. As amino group that may have a group (s) selected from the group consisting of lower alkyl group, lower alkanoyl group, cyclo C3-C8 alkyl group, aryl group, and aroyl group as substituent group, amino group that may have one to two groups selected from the group consisting of the above exemplified lower alkyl group (linear or branched alkyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4) ) ; the above exemplified lower alkanoyl group (linear or branched alkanoyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4) ) ; the above exemplified cyclo C3-C8 alkyl group, and aryl group (preferably phenyl group) ; and the above exemplified aryl group (preferably, phenyl group) , and the exemplified aroyl group (preferably, benzoyl group) as substituent group, can be cited. More specifically, for example, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-n-propylamino, N- isopropylamino, N-formylamino, N-acetylamino, N- phenylamino, N-benzoylamino, and N-acetyl-N-cyclo C3-C8 alkylamino groups, etc., can be cited.
As morpholinylcarbonyl lower alkenyl group, morpholinylcarbonyl lower alkenyl group with the lower alkenyl part being the above exemplified lower alkenyl group (linear or branched alkenyl group with preferably carbon number 2 to 6 (more preferably, carbon number 2 to 4)) can be cited. More specifically, 1- (or 2-) (4- morpholinylcarbonyl) vinyl, 1- (or 2- or 3-) (4- morpholinylcarbonyl) 1- (or 2-)propenyl groups are included. . .
' As morpholinylcarbonyl lower alkyl group, morpholinylcarbonyl lower alkyl group with the lower alkyl part being the above exemplified lower alkyl group (linear or branched alkyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to- 4) can be cited. More specifically, 4- morpholinylcarbonylmethyl, 1- (or 2-) (4- morpholinylcarbonyl) ethyl, 1- (or 2- or 3-) (4- morpholinylcarbonyl) 1- (or 2-) propropyl groups are included.
As pyrrolidinyl group that may have an oxo group (s), pyrrolidinyl group that may have one to two oxo groups (preferably, one) is cited. Specifically, (1-, 2-, or 3-) pyrrolidinyl, (2- or 3-) oxo-1- pyrrolidinyl, (3-, 4-, or 5-) oxo-2-pyrrolidinyl, (2-, 4-, or 5-) oxo-3-pyrrolidinyl groups can be cited.
As dihydropyrazolyl group that may have a group (s) selected from the group consisting of oxo group and lower alkyl group, dihydropyrazolyl group that may have one to two groups selected from the group consisting of oxo group and the above exemplified lower alkyl group is cited. As aryl group that may have a group (s) selected from the group consisting of halogen and halogen substituted lower alkyl group on aryl group, aryl group with the aryl part being phenyl, naphthyl, etc., that may have one to five, preferably one to three, more preferably one, of the above exemplified halogen 'and the above exemplified halogen substituted lower alkyl group (linear or branched alkyl group with preferably halogen substituted carbon number 1 to 6 (more preferably, carbon number 1 to 4)) on said aryl part, can be cited.
As aryl lower alkyl group that may have a halogen atom(s) , the above exemplified lower alkyl group (linear or branched alkyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4) ) having one to three, preferably one, aryl groups with the aryl part being phenyl, and naphthyl, etc., can be cited. As substituent group on aryl group, one to five, preferably one to three, more preferably one to two, of the above exemplified halogen may be substituted.
As amino lower alkanoyl group, the above exemplified lower alkanoyl group (linear or branched alkanoyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4)) having one to three amino groups (preferably, one) can be cited. More specifically, aminoacetyl, 3-aminopropionyl, A- aminobutyryl, 3, 4-diaminobutyryl, 3, 3-dimethyl-3- aminopropionyl, 4-aminobύtyrylr and 5-aminovaleryl groups, etc., are included.
As amino lower alkanoyl group that may have a lower alkanoyl group (s) on amino group, the above exemplified amino lower alkanoyl group having one to two (preferably, one) of the above exemplified lower alkanoyl group as substituent group, can be cited. More specifically, N-formylaminoacetyl, N- acetylaminoacetyl, N-propionylaminoacetyl, 3- (N- acetylamino) propionyl, 4- (N-acetylamino)butyryl, 3,4- di (N-acetylamino)butyryl, 3, 3-dimethyl~3- (N- propylamino) propionyl, 4- (N-formylamino)butyryl, and 5- (N-acetylamino) valeryl groups, etc., are included. As carbamoyl lower alkyl group, the above exemplified lower alkyl group (linear or branched alkyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4)) having one to three carbamoyl groups, more preferably one to two, can be cited. As amino lower alkyl group, the above exemplified lower alkyl group (linear or branched alkyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4)) having one to five amino groups, preferably one, can be cited. As more specific examples, aminomethyl, 2-aminoethyl, 1- aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1, l-dimethyl-2-aminoethyl, 2-methyl-3- aminopropyl, N, N-dimethylaminomethyl, N-methyl-N- ethylaminomethyl, N-methylaminomethyl, 2- (N- methyianaino) ethyl, l-methyl-2- (N,N-dimethylamino) ethyl, l-methyl-2- (N,N-diethylamino) ethyl, 2- (N,N- dimethy1amino) ethyl, 2- (N,N-diethylamino) ethyl, 2- (N, N- diisopropylamino) ethyl, 3- (N,N-dimethylamino) propyl, and 3- (N, N-diethylamino) propyl, etc., are cited.
As amino lower alkyl group that may have a group (s) selected from the group consisting of lower alkyl group, lower alkanoyl group, hydroxy lower alkyl group, carbamoyl lower alkyl groups indolylcarbonyl group, aryl group (that may have a group (s) selected from the group consisting of halogen and lower alkoxy group on said aryl group) , and aryl lower alkoxy carbonyl group, on amino group and/or on lower alkyl group, the above exemplified lower alkyl group (linear or branched alkyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4) ) having one to five amino groups, preferably one, can be cited. On amino group and/or on lower alkyl group, there may be one to two groups selected from the group consisting of the above exemplified lower alkyl group (linear or branched alkyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4)), the above exemplified lower alkanoyl group (linear or branched alkanoyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4)), the above exemplified hydroxy lower alkyl group (preferably, linear or branched alkyl group with carbon number 1 to 6 (preferably, carbon number 1 to 4) having one to three hydroxy groups) , the above exemplified carbamoyl lower alkyl group (preferably, linear or branched alkyl group with carbon number 1 to 6 (preferably, carbon number 1 to 4) having one to three carbamoyl groups), indolylcarbonyl group, aryl group that may have a group (s)' selected from the group consisting of the above exemplified halogen and lower alkoxy group (preferably, phenyl group that may have one to five groups, preferably one to three, selected from the group consisting of halogen and linear or branched alkoxy group with carbon number 1 to 6 (preferably, carbon number 1 to 4)), and alkoxy carbonyl group with the alkoxy part being the above exemplified lower alkoxy group (linear or branched alkoxy group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4)) having one to three of the above exemplified aryl group, preferably one.
As lower alkoxy lower alkyl group, the above exemplified lower alkyl group (linear or branched alkyl group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4) ) having one to three, preferably one, of the above exemplified lower alkoxy group (linear or branched alkoxy group with preferably carbon number 1 to 6 (more preferably, carbon number 1 to 4) ) can be cited. More specifically, methoxymethyll, 2-methoxyethyl, 1-ethoxyethyl, 2- ethoxyethyl, 2-isobutoxyethyl, 2, 2-dimethoxyethyl, 2- methoxy-1-methylethyl/ 2-methoxy-l-ethylethyl, 3- methoxypropyl, 3-ethoxypropyl, 2-isopropoχyethyl, 3- isopropoxypropyl, 3-n-butoxypropyl, 4-n-propoxybutyl, l-methyl-3-isobutoxypropyl, 1, l-dimethyl-2-n- pentyloxyethyl, 5-n-hexyloxypentyl, 6-methoxyhexyl, 1- ethoxyisopropyl, 2-methyl-3-methoxypropyl groups, etc., are included.
An aroyl lower alkyl group refers to a lower alkyl group (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl group) as the above, having 1 to 5 preferably one aroyl goup (preferably benzoyl) as the above. More specific examples includes benzoylmethyl, 2- benzoylethyl, 1-benzoylethyl, 1- (or 2~) naphthoylmethyl group.
An aryl lower alkyl group which may have a group (s,) selected from the group consisting of a lower alkyl, a lower alkoxy, a hydroxy, a halogen and a nitro on the aryl, refers to a lower alkyl group (preferably, carbon number 1 to 6 (more preferably, carbon numberl to 4) linear or branched alkyl group) as the above, which has 1 to 3 (preferably one) aryl wherein an aryl moiety is phenyl, naphthyl or the like. Substituent groups on the aryl group may be 1 to 5, preferably 1 to 3, more preferably 1 to 2 groups selected from the group consisting of a lower alkyl (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl groups) as the above, a lower alkoxy (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkoxy groups) as the above, hydroxy, a halogen and nitro as the above. An aryloxy lower alkyl group which may have a group (s) selected from the group consisting of a lower alkyl, a lower alkoxy, a halogen and cyano on the aryl, refers to a lower alkyl (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl groups) as the above, which has 1 to 3 (preferably one) aryl wherein the aryl moiety is phenyl, naphthyl or the like. Substituent groups on the aryl may be 1 to 5, preferably 1 to 3 groups selected from the group consisting of a lower alkyl (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl groups) as the above, a lower alkoxy (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl groups) as the above, a halogen and cyano as the above.
An aryl lower alkoxy group refers to a lower alkoxy (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkoxy groups) as the above, which has 1 to 3 (more preferably one) aryl wherein the aryl moiety is phenyl, naphthyl or the like.
An amino group which may have a lower alkyl group (s), refers to an amino which may have 1 to 2 lower alkyl groups (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl groups) as the above. More specific • examples include amino, N-methylamino, N, N- dimethylamino, N-ethylamino, N,N-diethylamino, N-n- propylamino, N-isopropylamino and the like. • •
An aryl lower alkenyl group refers to a lower alkenyl (preferably, carbon number 2 to 6 (more preferably, carbon number 2 to 4) linear or branched alkenyl groups) as the above, which has 1 to 3 (more preferably one) aryl wherein the aryl moiety is phenyl, naphthyl or the like.
An aryl lower alkenyl group which may have a group (s) selected from the group consisting of a lower alkyl, a lower alkoxy, a halogen substituted lower alkyl, a halogen substituted lower alkoxy, an amino which may have a lower alkyl, a halogen and nitro on the aryl group, refers to an aryl lower alkenyl (carbon number 2 to 6 (preferably, carbon number 2 to 4) linear or branched alkenyl groups, which preferably has one phenyl substituted), as the above. Substituent groups on the aryl group may be 1 to 5, preferably 1 to 3, more preferably 1 to 2 groups selected from the group consisting of a lower alkyl (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl groups) as the above, a lower alkoxy (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkoxy groups) as the above, a halogen substituted lower alkyl (carbon number 1 to 6 (preferably, carbon number 1 to 4) linear or branched alkyl groups preferably having 1 to 3 halogens) as the above, a halogen substituted lower alkoxy (carbon number 1 to 6 (preferably, carbon number 1 to 4) linear or branched alkoxy groups preferably . having 1 to 3 halogens) as the above, an amino which may have a lower alkyl group (s) as the above (amino group which may have one or two linear or branched alkyl groups (preferably, with carbon number 1 to 6, more preferably, with carbon number 1 to 4), a halogen and nitro as the above. An aryl group which may have a group (s) selected from the group consisting of a halogen and a lower alkyl refers to an aryl group in which the aryl moiety is phenyl, naphtyl or the like, and which has on the aryl moiety 1 to 5, preferably 1 to 3, more preferably one of a halogen and a lower alkyl (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl groups) as the above.
A C3-C8 cycloalkyl which may have a group(s) selected from the group consisting of an amino group which may have a lower alkyl group (s); an amino lower alkyl group which may have a lower alkyl and an aryl group which may have a group (s) selected from the group consisting of a halogen and a lower alkyl, refers to an C3-C8 cycloalkyl as the above which may have 1 to 3, preferably one group selected from the group consisting of an amino group which may have a lower alkyl group (s) as the above, which preferably may have 1 to 2 linear or branched alkyl groups with carbon number 1 to 6 (more preferably, carbon number 1 to 4), an amino lower alkyl as the above which may have a lower alkyl group (s) as the above (wherein the amino lower alkyl is preferably a linear or branched alkyl group with carbon number 1 to 6 (more preferably, carbon number 1 to 4) which has 1 to 5, preferably one amino group which may preferably have on the amino group- 1 to 2 linear or branched alkyl groups with carbon number 1 to 6 (more preferably, carbon number 1 to 4) ) , and an aryl group which may have a group (s) selected from the group consisting of a halogen as the above and .a lower alkyl as the above (aryl group in which the aryl moiety is preferably a phenyl, naphthyl or the like, and which has on the aryl moiety 1 to 5, preferably 1 to 3 of a halogen as the above and a lower alkyl as the above (preferably, carbon number 1 to β (more preferably, carbon number 1 to 4) linear or branched alkyl group) . A C3-C8 cycloalkyl lower alkyl group refers to a lower alkyl (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl group) as the above, which has 1 to 3, preferably one C3-C8 cycloalkyl as the above.
An arylthio lower alkyl group refers to a lower alkyl (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl group) as the above, which has 1 to 3, preferably one arylthio group as the above.
An adamanthyl lower alkyl group refers to a lower alkyl (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl group) as the above, which has 1 to 3, preferably one adamanthyl group.
A lower alkyl group which is substituted by a heterocyclic group (wherein the heterocyclic group may be substituted by a group (s) selected from the group consisting of a lower alkyl, a lower alkoxy, a halogen, oxo and thioxo on the heterocyclic group) selected from the group consisting of piperidyl, tetrahydropyranyl, pyridyl, thienyl, imidazolyl, tetrazolyl, benzimidazolyl, isoindolyl, thiazoridinyl, and indolyl refers to a lower alkyl group (preferably a 1 to 6 (more preferably 1 to 4) linear or branched alkyl group) as the above, which is substituted by 1 to 3, preferably one heterocyclic group selected from the group consisting of piperidyl, tetrahydropyranyl, pyridyl, thienyl, imidazolyl, tetrazolyl, benzimidazolyl, isoindolyl, thiazolidinyl, and indolyl. Substituent groups on the heterocyclic group may be 1 to 5, preferably 1 to 3 groups selected from the group consisting of a lower alkyl (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl group) as the above, a lower alkoxy (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkoxy group) as the above, a halogen, oxo and thioxo as the above. An aryl lower alkenyl group (which may have an aryl group (s) on the lower alkenyl) refers to an aryl lower alkenyl (preferably, carbon number 2 to 6 (more preferably, carbon number 2 to 4) linear or branched alkenyl group which is substituted by one phenyl) as the above. Substituent groups on the lower alkenyl may be 1 to 3, preferably 1 to 2, more preferably one aryl (preferably a phenyl group) as the above .
A lower alkenyl group which is substituted by a heterocyclic group (s) selected from the group consisting of benzodioxolyl, pyridyl, furyl and imidazolyl refers to a lower alkenyl group (preferably, carbon number 2 to 6 (more preferably, carbon number 2 to 4) linear or branched alkenyl group) as the above, which is substituted by 1 to 3, preferably one heterocyclic group selected from the group consisting of benzodioxolyl, pyridyl, and imidazolyl.
A benzodioxolyloxy lower alkyl group refers to a lower alkyl (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl group) as the above, which has 1 to 3, preferably one benzodioxolyloxy.
A pyridylthio lower alkyl group refers to a lower alkyl (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl group) as the above, which has 1 to 3, preferably one pyridylthio.
An aryl lower alkyl group which may have a group (s) selected from the group consisting of an amino which may have a lower alkyl group (s) and aryloxy on the aryl group refers to a lower alkyl (preferably, . carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl group) as the above, which may have 1 to 3, preferably one aryl wherein an aryl moiety is a phenyl, naphtyl and the like. Substituent groups on the aryl may be 1 to 5, preferably 1 to 3, more preferably 1 group selected from the group consisting of an amino which may have a lower alkyl as the above (an amino group which may have one or two alkyl) (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl group) and an aryl oxy (preferably phenoxy) as the above.
A lower alkyl group which is substituted by a heterocyclic group (s) selected from the group consisting of furyl and pyridyl refers to a lower alkyl (preferably, carbon number 1 to 6 (more .preferably, carbon number 1 to 4) linear or branched alkyl group) as the above, which is substituted by 1 to 3, preferably one heterocyclic group' selected from the group consisting of furyl and pyridyl.
A heterocyclic group refers to a saturated 3 to 8 membered (preferably 5 to 8 membered) monocyclic group which contains 1 to 4 (preferably 1 to 2) nitrogen atoms (for example, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, hexahydropyrimidinyl, piperazinyl, octahydroisoindole, azepanyl, azokanyl, etc.); a saturated 3 to 8 membered (more preferably 5 or 6 membered) monocyclic group which contains 1 to 2 (preferably one) oxygen atom and 1 to 3 (preferably 1 to 2) nitrogen atoms (for example, oxazolidinyl, isoxazolidinyl, morpholinyl, etc.); a saturated spiroheterocyclic group which contains 1 to 2 nitrogen atoms (for example, azaspirononanyl (for example, 1-azaspiro [4, 4]nonanyl, 2-azaspiro [4, 4]nonanyl, etc.), azaspirodecanyl (for example, 1- azaspiro[4, 5]decanyl, 2-azaspiro [4, 5]decanyl, etc.), diazaspirononanyl (for example, 1, 3-diazaspiro [4, 4]nonanyl, 1, 4-diazaspiro[4, 4]nonanyl, etc.); etc
• a saturated 3 to 8 membered (more preferably 5 or 6 membered) heteromonocyclic group which contains 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, for example, thiazoridinyl;
• a saturated 3 to 8 memberd (more preferably 5 or 6 membered) heteromonocyclic group which contains 1 to 2 oxygen atoms, for example, tetrahydrofuryl, tetrahydropyranyl, oxyranyl, oxoranyl, dioxoranyl, etc; a saturated 3 to 8 memberd (more preferably 5 or 6 membered) heteromonocyclic group which contains 1 to 2 (preferably one) sulphur atom, for example, tetrathienyl, tetrahydrothiopyranyl, etc.; • an unsaturated 3 to 8 itierabered (more preferably 5 or 6 membered) heteromonocyclic group which contains 1 to 4 (preferably 1 to 3) nitrogen atoms (for example, pyrrolyl, dihydropyrrolyl (for example, lH-2,5- dihydropyrrolyl etc.), imidazolyl (for example, IH- imidazolyl etc.), dihydroimidazolyl (for example, IH- 2, 3-dihydroimidazolyl etc.), triazolyl (for example, 4H-l,2,4-triazolyl, 1H-1,2, 3-triazolyl, 2H-1,2,3- triazolyl, etc.), dihydrotriazolyl (for example, IH- 4,5-dihydro-l,2, 4-triazolyl etc. ) , pyrazolyl, dihydropyrazolyl (for example, 4, 5-dihydropyrazolyl etc.), pyridyl, dihydropyridyl (for example, 1,2- dihydropyridyl etc.), pyrimidinyl, dihydropyrimidinyl (for example, 1, 6-dihydropyrimidinyl etc.), tetrahydropyrimidinyl (for example, 1,2,3,4- tetrahydropyrimidinyl etc.), pyrazinyl, dihydropyrazinyl (for example, 1,2-dihydropyrazinyl etc.), pyridazinyl, tetrazolyl (for example, IH- tetrazolyl, 2H-tetrazolyl, etc.), etc.); • an unsaturated, 3 to 8 membered (more preferably 5 membered) heteromonocyclic group which, contains 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, dihydrothiazolyl (for example, 2,3- dihydrothiazolyl etc.), isothiazolyl, thiadiazolyl (for example, 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,3,4- thiadiazolyl, 1, 2, 5-thiadiazolyl, etc.) dihydrothiadinyl, etc.;
• an unsaturated 3 to 8 membered (more preferably 5 or 6 membered) heteromonocyclic group which contains 1 to 2 (preferably one) oxygen atom and 1 to 3 (preferably 1 to 2) nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl (for example, 1,2,4- oxadiazolyl, 1, 3, 4-oxadiazlolyl, 1, 2, 5-oxadiazolyl, etc. ) , etc. ;
• an unsaturated 3 or 8 membered (more preferably 5 or 6 membered) heteromonocyclic group which contains 1 or 2 sulphur atoms, for example, thienyl, dihydrothienyl, etc.;
• an unsaturated 3 or 8 membered (more preferably 5 or 6 membered) heteromonocyclic group which contains 1 or 2 oxygen atoms, for example, furyl, pyranyl, etc.;
• an unsaturated 3 or 8 membered (more preferably 5 or 6 membered) heteromonocyclic group which contains one oxygen atom and 1 or 2 sulphur atoms, for example, dihydroxathienyl, etc.;
• an unsaturated, fused heterocyclic group which contains 1 to 4 (preferably 1 to 2) nitrogen atoms (for example, indolyl, isoindolyl, indolinyl, isoindolinyl, hexahydroisoindolinyl (for example, 2, 3, 3a, 4, 7, 7a- hexahydroisoindolinyl, etc.) benzoimidazolyl, imidazopyridyl (for example, imidazo[l, 2-a]pyridyl, etc.), quinolyl, dihydroquinolyl (for example, 1,2- dihydroquinolyl etc.), tetrahydroquinolyl (1,2,3,4- tetraquinolyl etc.), isoquinolyl, cynolinyl, indazolyl, quinazolinyl, dihydroquinazolinyl (3,4- dihydroquinazolinyl etc.), benzotriazolyl (for example, benzo[d] [1, 2, 3] triazolyl ' etc. ) , naphthilidyl (for example, 1, 8-naphthilidyi etc.), dihydrohaphthilidyl (for example, 1, 2-dihydro-l, 8-naphthilidyl etc.), carbazolyl, etc.); • an unsaturated fused heterocyclic group which contains 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, for example, benzothiazolyl (for example, benzo[d] thiazolyl etc.), dihydrobenzothiazolyl (for example, 2, 3-dihydrobenzo [d] thiazolyl etc.), benzothiadiazolyl, dihydrobenzothiadinyl (2H-3,4- dihydrobenzo [b] [1, 4] thiadinyl, etc.), thienopiradinyl (for example, thieno[3,2-b]pyradinyl etc.); • an unsaturated fused heterocyclic group which contains 1 to 2 (preferably one) oxygen atom and 1 to 3 (preferably 1 to 2) nitrogen atoms, for example, benzoxazolyl (for example, benzo [d] oxazolyl etc.), dihydrobenzoxazolyl (for example, 2,3- dihydroxybenzo[d] oxazolyl etc.), benzoxadinyl (for example, benzo [b] [1, 4]oxadinyl etc.), dihydrobenzoxadinyl (for example, 2H-3,4- dihydroxybenzo [b] [1, 4]oxadinyl etc. ),, benzoxazolyl, benzoxadiazolyl, furopyrrolyl (for example, 4H-furo[3, 2-b]pyrrolyl etc. ) , etc. ; an unsaturated fused spiroheterocyclic group which contains 1 to 2 nitrogen atoms (for example, spiro[cyclopentaneindolinyl] (for example, spiro[cyclopentane-l,3'-indolinyl] etc.) ; an unsaturated fused heterocyclic group which contains 1 to 4 oxygen atoms, for 'example, benzofuryl, dihydrobenzofuryϊ (for example, 2, 3-dihydrobenzofuryl etc.)/ benzoxolyl (for example, benzo[d][l, 3]oxolyl etc.), dihydrobenzodioxynyl (for example, 2,3- dihydrobenzo [b] [1, 4]dioxynyl etc.), etc.; and an unsaturated fused heterocyclic group which contains 1 to 2 sulphur atoms, for example, benzothienyl, etc.
An N-containing heterocyclic group refers to a saturated 3 to 8 membered (preferably 5 to 8 membered) heterocyclic group which contains 1 to 4 (preferably 1 to 2) nitrogen atoms; a saturated spiroheterocyclic group which contains 1 to 2 nitrogen atoms; an unsaturated 3 to 8 membered (preferably 5 or 6 membered) heteromonocyclic group which contains 1 to 4 (preferably 1 to 3) nitrogen atoms; an unsaturated fused heterocyclic group which contains 1 to 4 (preferably 1 to 2) nigrogen atoms; an unsaturated spiroheterocyclic group which contains 1 to 2 nigrogen atoms; an unsaturated 3 to 8 membered (more preferably 5 or 6 membered) heteromonocyclic group which contains 1 to 2 (preferably one) oxygen atom and 1 to 3 (preferably 1 to 2) nitrogen atoms; a saturated 3 to 8 membered (more preferably 5 or 6 membered) heteromonocyclic group which contains 1 to 2 (preferably one) oxygen atom and 1 to 3 (preferably 1 to 2) nitrogen atoms; an unsaturated fused heterocyclic group which contains 1 to 2 (preferably one) oxygen atom and 1 to 3 (preferably 1 to 2) nitrogen atoms; an unsaturated 3 to 8 membered (preferably 5 membered) heteromonocyclic group which contains 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms; a saturated 3 to 8 membered (more preferably 5 or 6 membered) heteromonocyclic group which contains 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms; and an unsaturated . fused heterocyclic group which contains 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms.
A saturated 3 to 8 membered (preferably 5 to 8 membered) heteromonocyclic group- which contains 1 to 4 (preferably 1 to 2) nitrogen atoms refers to, for example, pyrolydinyl, imidazolidinyl, pyperidyl, hexahydropyrimidinyl, piperadinyl, octahydroisoindole, azepanyl, azokanyl, etc. As saturated spiroheterocyclic group which contains 1 to 2 nitrogen atoms refers to, for example, azaspirononanyl (for example, 1-azaspiro [4, 4]nonanyl, 2-azaspiro[4, 4]nonanyl, etc. ) , azaspirodecanyl (for example, 1-azaspiro [4, 5]decanyl, 2-azaspiro[4, 5]decanyl, etc.), diazaspirononanyl (for example, 1,3- diazaspiro[4, 4]nonanyl, 1, 4-diazaspiro [4, 4]nonanyl, etc. ) , etc.
An unsaturated 3 to 8 membered (preferably 5 or 6 membered) heteromonocyclic group which contains 1 to 4 (preferably 1 to 3) nigrogen atoms refers to, for example, pyrrolyl, dihydropyrrolyl (for example, IH- 2, 5-dihydropyrrolyl etc.), imidazolyl (for example, IH- imidazolyl etc.), dihydroimidazolyl (for example, IH- 2, 3-dihydroimidazolyl etc.), triazolyl (for example, 4H-l,2,4-triazolyl, IH-I, 2, 3-triazolyl, 2H-1,2,3- triazolyl, etc.), dihydrotriazolyl (for example, IH- 4, 5,-dihydro-l,2, 4-triazolyl etc.)/ pyrazolyl, pyridyl, dihydropyridyl (for example, 1,2-dihydropyridyl etc.), pyrimidinyl, dihydropyrimidinyl (for example, 1,6- dihydropyrimidinyl etc.), pyrazinyl, dihydropirazinyl (for example, 1,2-dihydropirazinyl etc.), pyridazinyl, tetrazolyl (for example, lH-tetrazolyl, 2H-tetrazolyl etc. ) , etc.
An unsaturated fused heterocyclic group which contains 1 to 4 (preferably 1 to 2) nitrogen atoms refers to, for example, indolyl, isoindolyl, indolinyl, isoindolinyl, hexahydroisoindolyl (for example, 2, 3, 3a, 4, 7, 7a-hexahydroisoindolyl etc.), octahydroisoindolyl, benzoimidazolyl, quinolyl, isoquinolyl, indazolyl, quinazolinyl, dihydroquinazolinyl (3, 4-dihydroquinazolinyl etc.), benzotriazolyl, carbazolyl, etc. An unsaturated fused spiro heterocyclic group which contains 1 to 2 nitrogen atoms refers to, for example, spiro [cyclopentaneindolinyl] (for example, spiro [cyclopentane-1, 3' -indolinyl] etc.) .
An unsaturated 3 to 8 membered (preferably 5 or 6 membered) heteromonocyclic group which contains 1 to 2 (preferably one) oxygen atoms and 1 to 3 (preferably 1 to 2) nitrogen atoms refers to, for example, oxazolyl, isoxazolyl, oxadiazolyl (for example, 1, 2, 4-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1,2,5- oxadiazolyl, etc.)/ etc.
A saturated 3 to 8 membered (preferably 5 or 6 membered) heteromonocyclic group which contains 1 to 2 (preferably one) oxygen atoms and 1 to 3 (preferably
1 to 2) nitrogen atoms refers to, for example, oxazolidinyl, isoxazolidinyl, morpholinyl, etc.
An unsaturated fused heterocyclic group which contains 1 to 2 (preferably one) oxygen atoms and 1 to 3 (preferably 1 to 2) nitrogen atoms refers to, for example, benzoxazolyl (for example, benzo [d] oxazolyl etc.), dihydrobenzoxazolyl (for example, 2,3- dihydroxybenzo [d] oxazolyl etc.), beozoxadinyl (for example, benzo [b] [1/ 4] oxadinyl etc.), dihydrobenzoxadinyl (for example, 2H-3,4- dihydroxybenzo [b] [1, 4] oxadinyl etc.), benzoxazolyl, benzoxadiazolyl, etc.
An unsaturated 3 to 8 membered (preferably 5 membered) heteromonocyclic group which contains 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms refers to, for example, thiazolyl, dihydrothiazolyl (for example, 2,3- dihydrothiazolyl) , isothiazolyl, thiadiazolyl (for example, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1,3,4- thiadiazolyl, 1, 2, 5-thiadiazolyl, etc.), dihydrothiadinyl, etc.
A saturated 3 to 8 membered (preferably 5 or 6 membered) heteromonocyclic group which contains 1 to
2 sulphur atoms and 1 to 3 nitrogen atoms refers to, for example, thiazolidinyl etc.
An unsaturated fused heterocyclic group which contains 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms refers to, for example, benzothiazolyl, benzothiadiazolyl, etc.
A carbamoyl group which may have a lower alkyl group (s) refers to a carbamoyl group which may have 1 to 2 lower alkyl (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl group) as the above: More specifically, for example, a carbamoyl group which may have said lower alkyl includes carbamoyl, N-methylcarbamoyl, N, N- dimethylcarbamoyl, N-methyl-N-ethylcarbamoyl, N- ethylcarbamoyl group, etc. An aryl lower alkyl group (which may have a lower alkoxy group (s) on the aryl group) refers to a lower alkyl (preferably, carbon number 1 to 6 (more preferably, carbon number 1 to 4) linear or branched alkyl group) as the above, which has 1 to 3 (preferably one) aryl group (s) as the above. Here, 1 to 7, preferably 1 to 5, more preferably 1 to 2 lower alkoxy as the above may substitute on the aryl group. Specific examples of an aryl lower alkyl group (may have a lower alkoxy group on an aryl group) includes benzyl, 1-phenylethyl, 2-phenylethyl, 1-methyl-l- phenylethyl, 1, l-dimethy-2-phenylethyl, 1, l-dimethyl-3- phenylpropyl, (2-, 3- or
4-)methoxybenzyl> 2-[(2~, 3- or 4-)methoxyphenyl] ethyl, l-[(2-, 3- or 4-)methoxyphenyl]ethyl, l-[(2-, 3- or 4-) methoxyphenyl] propyl, (2-, 3- or 4-) ethoxybenzyl, (2, A-, 3, 4- or 3, 5-) dimethoxybenzyl, 2- [(3, 5- or 3, 4-) dimethoxyphenyl] ethyl, 2- (2-ethoxyphenyl) ethyl, 1- (4-methoxyphenyl)buthyl, naphthylmethyl, etc.
A heterocyclic Compound (hereinafter called "Compound (I)") represented in the above General Formula (1) can be produced by various methods, but as an example, it is produced by a method shown in Reaction Formula-1 to 4, 7, 8 12 or 13 below.
Reaction Formula-1
Figure imgf000071_0001
[wherein R11, R12, A1 and Z mean the same as the above, and Xii represents halogen atom or a group that causes the same substitution reaction as halogen atom.] Here, as groups that cause the same substitution reaction as halogen atom, for example, lower alkanesulfonyloxy group, arylsulfonyloxy group, and aralkylsulfonyloxy group, etc., can be exemplified. In General Formula (2), the halogen atom represented by Xn is fluorine atom, chlorine atom, bromine atom, and iodine atom. Specifically, as lower alkanesulfonyloxy group represented by Xn, linear or branched alkanesulfonyloxy group with carbon number 1 to 6 such as methanesulfonyloxy, ethanesulfonyloxy, isopropanesulfonyloxy, n-propanesulfonyloxy, n- butanesulfonyloxy, tert-butanesulfonyloxy, n- pentanesulfonyloxy, and n-hexanesulfonyloxy groups, etc., can be exemplified.
As arylsulfonyloxy group represented by Xn, for example, phenylsulfonyloxy group and naphthylsulfonyloxy group, etc., that may have 1 to 3 groups selected from the group consisting of linear or branched alkyl group with carbon number 1 to 6, linear or branched alkoxy group with carbon number 1 to 6, nitro group, and halogen atom as a substituent group on phenyl ring can be cited. As a specific example of phenylsulfonyloxy group that may have the above substituent group, phenylsulfonyloxy, 4- methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4- nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 2- nitrophenylsulfonyloxy, and 3-chlorophenylsulfonyloxy, etc., can be exemplified. As a specific example of naphthylsulfonyloxy group, α-naphthylsulfonyloxy and β- naphthylsulfonyloxy group, etc., can be exemplified. As aralkylsulfonyloxy group represented by
Xxi, for example, linear or branched alkylsulfonyloxy group with carbon number 1 to 6 substituted by phenyl group and linear or branched alkylsulfonyloxy group with carbon number 1 to 6 substituted by naphthyl group that may have 1 to 3 groups selected from the group consisting of linear or branched alkyl group with carbon number 1 to 6, linear or branched alkoxy group with carbon number 1 to 6, nitro group, and halogen atom as a substituent group on phenyl ring can be . - cited. As a specific example of alkylsulfonyloxy group substituted by the above phenyl group, benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4- phenylbutylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4- methoxybenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, and 3-chlorobenzylsulfonyloxy, etc., can be exemplified. As a specific example of alkylsulfonyloxy group substituted by the above naphthyl group, a- naphthylmethylsulfonyloxy and β- naphthylmethylsulfonyloxy groups, etc., can be exemplified.
Compound (Ia) can be produced by reacting a compound of General Formula (2) (hereinafter called "Compound (2)") with a compound of General Formula (3) (hereinafter called "Compound (3)").
This reaction is normally performed in a commonly used solvent that does not effect reaction, for example, water; alcohol solvent such as methanol, ethanol, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol, etc.; ketone solvent such as acetone, and methyIethy1ketone, etc.; ether solvent such as tetrahydrofuran, dioxane, diethyl ether, and diglyme, etc.; ester solvent such 'as methyl acetate, and ethyl acetate, etc.; aprotic polar solvent such as acetonitrile, N,N-dimethylforiaamide, and dimethyl sulfoxide, etc.; halogenated hydrocarbon solvent such as methylene chloride, and ethylene chloride, etc.; or other organic solvents. Moreover, this reaction is performed in a mixed solvent of these commonly used solvents. This reaction is normally performed in the presence of an inorganic base such as alkali metal (for example, sodium, and potassium, etc.), alkali metal hydrogen carbonate (for example, lithium hydrogen carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate, etc.), alkali metal hydroxide (for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide, etc.), alkali metal carbonate (for example, lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate, etc.), alkali metal lower alkoxide (for example, sodium methoxide, and sodium ethoxide, etc.), hydride (for example, sodium hydride, and potassium hydride, etc.), etc., and an organic base such as trialkylamine (for example, trimethylamine, triethylamine, and N- ethyldiisopropylamine, etc.), pyridine, quinoline, N- methyl piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N- methylmorpholine, 1-5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2-2-2] octane (DABCO), and 1,8- diazabicyclo[5, 4, 0]undecene-7 (DBU), etc. Furthermore, if these bases are liquid, they can be used as solvents.
These basic compounds are used independently or by mixing one or more of the compounds . A used amount of a basic compound is normally
0.5 to 10-fold mole, preferably 0.5 to 6-fold mole, to Compound (2) .
The above reaction can be performed by adding alkali metal iodide such as potassium iodide, and sodium iodide, etc., as a reaction accelerator, if needed.
The usage ratio of Compound (2) and Compound (3) in the above Reaction Formula-1 may normally have the latter at least 0.5-fold mole of the former, preferably approximately 0.5 to 5-fold mole.
Reaction temperature is not particularly limited., and reaction is normally performed under cooling or heating. Preferably, the reaction is performed under a temperature condition from around room temperature to approximately 1500C for 1 to 30 hours.
Reaction Formula-2
Figure imgf000075_0001
[wherein R11, R12, A1 and Z mean the same as the above, and Xχ2 represents hydroxyl group, halogen atom or a group that causes the same substitution reaction as halogen atom.] Here, in General Formula (4), as a group that causes the same substitution reaction as halogen atom represented by XX2 and halogen atom, the same group as Xi1 can be exemplified.
Compound (1) can be produced by reacting a compound of General Formula (4) (hereinafter called "Compound (4)") with a compound of General Formula (5) (hereinafter called "Compound (5)").
This reaction is performed under the same reaction condition as the reaction in the above Reaction Formula-1. If Compound (4) has X3.2 representing a hydroxyl group, this reaction can be achieved by subjecting Compound (5) and Compound (4) to normal amide bond formation reaction. Known amide bond formation reaction can be widely applied to this amide bond formation reaction. Specifically, the following methods are cited: (a) a mixed anhydride method, i.e. a method of reacting Compound (4) with an. alkylhalocarboxylate to obtain mixed acid anhydride, and reacting this with Compound (5) ; (b) an active ester method, i.e. a method of having Compound (4) as active amide with active ester such as phenyl ester, p- nitrophenyl ester, N-hydroxysuccinimide ester, and 1- hydroxybenzotriazole ester, etc., or active amide with benzoxazoline-2-thione, and reacting this with Compound (5); (c) a carbodiirαide method, i.e. a method for causing Compound (5) to undergo a condensation reaction with Compound (4) in the presence of an activating agent such as dicyclohexylcarbodiimide, l-(3- dimethylaminopropyl) -3-ethylcarbodiimide (WSC), and' carbonyldiimidazole, etc.; and (d) other methods, for example, a method of making Compound (4) carboxylic anhydride by a dehydrating agent such as acetic acid anhydride, etc., and reacting this- with Compound (5), and a method of reacting Compound (4) and ester with lower alcohol with Compound (5) , etc.
Mixed acid anhydride used in the above mixed anhydride method (a) is obtained by normal Schotten- Baumann reaction, and by normally reacting this with Compound (5) without isolation, General Formula (Ia) , the compound of the present invention, is produced.
The above Schotten-Baumann reaction is performed in the presence of a basic compound. As a basic compound used, compounds commonly used for Schotten-Baumann, for example, inorganic bases such as alkali metal (for example, sodium, and potassium, etc.), alkali metal hydrogen carbonate (for example, lithium hydrogen carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate, etc.), alkali metal hydroxide (for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide, etc.), alkaline earth metal hydroxide (for example, calcium hydroxide, etc.); alkali metal carbonate (for example, lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate, etc.), alkali metal lower alkoxide (for example, sodium methoxide, and sodium ethoxide, etc.), hydride (for example, sodium hydride, potassium hydride, etc.), and sodium amide, etc., and organic bases such as trialkylamine (for example, trimethylamine, triethylamine, N-ethyldiisopropylamine, etc.), pyridine, quinoline , N-methylpiperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N- methylmorpholine, 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN), l,4-diazabicyclo[2.2.2]octane (DABCO), and 1,8- diazabicyclo [5.4.0] undecene-7 (DBU), etc. These basic compounds are used independently or by mixing one or more of the compounds . Said reaction is normally performed at approximately -20 to 1000C, preferably approximately 0 to 500C, and reaction time is approximately 5 minutes to 10 hours, preferably approximately 5 minutes to 2 hours.
Reaction of the obtained mixed acid anhydride and Compound (5) is normally performed at approximately -20 to 1500C, preferably approximately 10 to 500C, and the reaction time is approximately 5 minutes to 10 hours, preferably approximately 5 minutes to 5 hours.
The mixed anhydride method is generally performed in a solvent. As a solvent used, any solvent commonly used for the mixed anhydride method can be used, and specifically, water; halogenated hydrocarbon solvent such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride, etc.; aromatic hydrocarbon solvent such as benzene, toluene, and xylene, etc.; ether solvent such as diethyl ether, diisopropylether, tetrahydrofuran, and dimethoxyethane, etc.; ester solvent such as methyl acetate, ethyl acetate, and isopropyl acetate, etc.; and aprotic polar solvent such as acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide, . etc. or mixed solvent thereof, etc., are cited.
As alkyl halocarboxylate used in the mixed anhydride method, for example, methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, and isobutyl chloroformate, etc., are cited.
The usage ratio of Compound (4) , alkylhalocarboxylate and Compound (5) in the mixed anhydride method is normally preferably at least equal mole each, but alkylhalocarboxylate and Compound (4) can be used in a range of approximately equimolar to 6- fold molar amount to the Compound (5) , respectively. The method of condensation reaction in the presence of the activating agent (c) is performed in an appropriate solvent in the presence or absence of a basic compound. As a solvent and a basic compound used here, any solvent and basic compound used in the Reaction Formula-1 can be used. The used amount of the activating agent is normally at least an equimolar amount, preferably equimolar to 5-fold molar amount, to Compound (4) . If WSC is used as an activating agent, reaction can be efficiently progressed by adding acid such as 1-hydroxybenzotriazole and/or hydrochloric acid into the reaction system. Said reaction is normally performed at approximately -20 to 1800C, preferably approximately 0 to 150°C, and is generally completed for approximately 5 minutes to 90 hours. Additionally, this amide bond formation reaction can also be performed by a method of reacting Compound (4) with Compound (5) in the presence of a condensation agent of a phosphorus compound such as triphenylphosphine, diphenylphosphinylchloride, phenyl- N-phenylphosphoramide chloridate, diethylchlorophosphate, diethyl cyanophosphate, diphenylphosphoryl azide, and bis(2-oxo-3- oxazolidinyl)phosphinic chloride, etc. The condensation agent is used independently or by mixing one or more of the agents.
Said reaction is normally performed in the presence of solvent and basic compound used in the above Reaction Formula-1 at approximately -20 to 1500C, preferably approximately 0 to 1000C, and the reaction is generally completed for approximately 5 minutes to 30 hours. It is preferable that the condensation agent and Compound (5) are used in at least approximately an equimolar amount, preferably approximately equimolar to 3-fold molar amount, to Compound (4) .
Here, Compound' (4), a starting compound of the compound of the present invention, is a known compound, or can be easily produced from a known compound.
Reaction Formula-3
Figure imgf000081_0001
[wherein R12 and A1 mean the same as the above. R14 means hydrogen or lower alkyl group.]
A compound of General Formula, (Ib) (hereinafter called "Compound (Ib)") can be produced by reacting a compound of General Formula (10) (hereinafter called "Compound (10)") with Compound (5).
This reaction is performed in various solvents that do not effect reaction, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, and cyclopentylmethyl ether, etc.; halogenated hydrocarbons such as chloroform, methylene chloride, and ethylene chloride, etc.; esters such as methyl acetate, ethyl acetate, and n-butyl acetate, etc.; and others, organic solvent such as acetonitrile, and N,N-dimethylformamide, etc., or mixture thereof. Moreover, if the Compound (10) or (5) is liquid, these also function as solvents. The used amount of Compound (5) to Compound (10) is normally 1 to 10-fold molar amount, preferably 1 to 3-fold molar amount. The reaction can be performed under any temperature condition of cooling to heating. Preferably, a temperature condition of -100C to 1500C can be adopted. The reaction is completed for approximately 10 minutes to 10 hours under said temperature condition. This reaction can be performed in the presence of a base. As a preferred base, for example, organic bases such as tri (lower) alkylamine (for example, trimethylamine, triethylamine, and N- ethyldiisopropylamine, etc.), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N- (lower) alkyl-morpholine (for example,, N-methylmorpholine, etc.), 1,5- diazabicyclo [4.3.0] nonene-5 (DBN), 1,8- diazabicyclo[5.4.0]undecene-7 (DBU), and 1,4- diazabicyclo[2.2.2]octane (DABCO), etc., are cited.
Reaction Formula-4
Figure imgf000082_0001
[wherein R11, R12 and A1 mean the same as the above.] A compound of General Formula (Id) (hereinafter called "Compound (Id)") can be performed by reacting a compound of General Formula (Ic) (hereinafter called "Compound (Ic)") with a thioxo agent. Here, as a preferred example of a thioxo agent, commonly used agents that can change oxo group such as phosphorus pentasulfide, and Lawesson' s reagent (2, 4-bis (4-methoxyphenyl) -1, 3-dithia-2, 4-diphosphetane- 2, 4-disulfide) , etc., into thioxo group, are cited. As a solvent used for this reaction, various solvents that .do not effect reaction, for example, halogenated hydrocarbon solvents such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride, etc.; aromatic hydrocarbon solvents such as benzene, toluene, and xylene, etc.; and ether solvents such as diethyl ether, diisopropylether, tetrahydrofuran, and dimethoxyethane, etc.; or mixed solvents thereof, etc.; are cited.
This reaction is normally performed, but the reaction temperature is not particularly limited to, under heating, preferably 65 to 150°C,.and the reaction time is approximately 30 minutes to 10 hours, preferably approximately 30 minutes to 5 hours.
In regard to the usage ratio of Compound (Ic) and a thioxo agent in this reaction, a thioxo agent can be normally used in a range of equimolar amount to very excessive molar amount, preferably equimolar amount to 1.3 molar amount, to Compound (Ic). Furthermore, Compound (5) , a starting compound of the compound of the present invention, contains a novel compound and can be produced by various methods, but as an example, it can be produced by a method shown in Reaction Formula-5 to Reaction Formula-6 below.
Reaction Formula-5
Figure imgf000084_0001
Figure imgf000084_0002
[wherein R12, Xn and A1 mean the same as the above, and R13 represents hydrogen or lower alkoxycarbonyl group.]
Here, in General Formula (6) , as a group that causes the same reaction as halogen atom represented by Xn and halogen atom, the same group as the above can be exemplified.
As a preferred specific example of lower alkoxycarbonyl group represented by R13, methoxycarbonyl, ethoxycarbonyl, and tert- butoxycarbonyl groups, etc. can be cited. As a more preferred example of lower alkoxycarbonyl group, (C1-C4) alkoxycarbonyl group can be exemplified. Among these, tert-butoxycarbonyl group is particularly preferred.
Compound (5a) can be produced by reacting a compound of General Formula (6) (hereinafter called "Compound (6)") with a compound of General Formula (3) (hereinafter called ""Compound (3)"). This reaction is performed under the same reaction condition as reaction in the Reaction Formula-1.
Here, Compounds (3) and (6), starting compounds of the compound of the present invention, are known compounds, or can be easily produced from known compounds .
If R13 of Compound (5a) represents lower alkoxycarbonyl group, a compound of General Formula (5) (hereinafter called "Compound (5)") can be produced by subjecting the compound to elimination reaction of the lower alkoxycarbonyl group. This elimination reaction is performed according to a commonly used method such as hydrolysis.
Hydrolysis is preferably performed in the presence of an acid containing Lewis acid. As preferred acids, organic acids (for example, formic acid, acetic acid, propionic acid, trichloroacetic acid, and trifluoroacetic acid, etc.) and inorganic acids (for example, hydrochloric acid, hydrobromic acid, and vitriol, etc.) are cited.
Reaction using Lewis acid, for example, trihaloacetic acid, etc., such as trichloroacetic acid, and trifluoroacetic acid, etc., can be preferably performed in the presence of a cation scavenger (for example, anisole, and phenol, etc.).
This hydrolysis reaction is performed in various solvents that do not effect reaction, for example, water; alcohols such as methanol, ethanol, trifluoroethanol, and ethylene glycol, etc.; ketones such as acetone, etc.; ethers such as diethyl ether, dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, and cyclopentylmethyl ether, etc.; halogenated hydrocarbons such as chloroform, methylene chloride, and ethylene chloride, etc.; esters such as methyl acetate, ethyl acetate, and n-butyl acetate, etc.; and others, organic solvent, such as acetonitrile, and N, N- dirαethylformamide, etc. or mixture thereof. Moreover, if a liquid acid is used as the acid, these also function as solvents. The reaction can be performed under any temperature condition of cooling to heating.
Preferably, a temperature condition of 00C to room temperature can be adopted. The reaction is completed for approximately 0.5 to 10 hours under said temperature condition.
Reaction Formula-6
Figure imgf000087_0001
[wherein Xn and A1 mean the same as the above.]
Here, in General Formula (7), as a group that causes the same substitution reaction as halogen atom represented by Xn and halogen atom, the same group as the above can be exemplified.
Compound (8) can be produced by reacting a compound of General Formula (7) (hereinafter called "Compound (7)") with a compound of General Formula (3) (hereinafter called ""Compound (3)"). This reaction is performed under the same reaction condition as reaction in the Reaction Formula-1.
Here, Compounds (7) and (3), starting compounds of the compound of the present invention, are known compounds, or can be easily produced from known compounds.
Compound (5b) can be produced by reacting a compound of General Formula (8) (hereinafter called "Compound (8)") with a compound of General Formula (9) (hereinafter called "Compound (9)"). This reaction is performed in various solvents that do not effect reaction, for example, water; alcohols such as methanol, ethanol, trifluoroethanol, and ethylene glycol, etc; ketones such as acetone, etc.; ethers- such as diethyl ether, dioxane, tetrahydrofuran, 1,2- dimethoxyethane, and cyclopentylmethyl ether, etc.; halogenated hydrocarbons such as chloroform, methylene chloride, and ethylene chloride, etc.; esters such as methyl acetate, ethyl acetate, and n-butyl acetate, etc.; and others, organic solvent such as acetonitrile, and N,N-dimethylformamide, etc., or mixture thereof. If a liquid acid is used as the acid, these also function as solvents. The reaction can be performed under any temperature condition of cooling to heating. Preferably, a temperature condition of 500C to 100°C can be adopted. The reaction is completed for 0.5 to 10 hours under such temperature condition.
Reaction Formula-7
Figure imgf000088_0001
[wherein R21 and A mean the' same as aforementioned, and X21 represents a halogen atom or a group which causes the same substitution reaction as a halogen atom.] Here, an example of a group which causes the same substitution reaction as a halogen atom is the same group mentioned above. This reaction is carried out under the same reaction conditions as in Reaction Formula-1.
Here, Compound (11) , which is the starting material compound of the compound of the invention, includes a novel compound, and can be produced by a variety of methods, for example, the compound is procured by the method shown in the following Reaction Formula-9.
Also, in Compound (1), the compound (hereinafter called "Compound (If)") in which A21 and A22 have the same as aforementioned, wherein -A2 is -A21-0- A22-, is for example, produced by the method shown in the following Reaction Formula-8.
Reaction Formula-8
Figure imgf000089_0001
[wherein R , A21 and A mean the same as aforementioned, and X22 represents a hydroxyl group, halogen atom or a group which causes the same substitution reaction as the halogen atom.] X22-
Here, in General Formula (12), examples of a halogen atom and a group which causes the same substitution reaction as a halogen atom referred to as X22 are the same as above.
The Compound (If) can be produced by reacting the compound of General Formula (12) (hereinafter called "Compound (12)") with the compound of General Formula (13) (hereinafter called "Compound (13)").
This reaction is carried out under the same reaction conditions as in the aforementioned Reaction Formula-1.
When the Compound (12) is X22 representing hydroxyl group, the reaction can be carried out in a suitable solvent in the presence of a condensation agent . .
The reaction is usually carried out in conventional solvents which do not effect reaction, for example, water; alcohol solvents such as methanol, ethanol, isopropanol, n-butanol, trifluoroethanol, ethyleneglycol; ketone solvents such as. acetone, methylethylketone; ether solvents such as tetrahydrofuran, dioxane, diethyl ether, diglyme; ester solvents such as methyl acetate, ethyl acetate; aprotic polar solvents such as acetonitrile, N, N- dimethylformamide, dimethyl sulfoxide; halogenated hydrocarbonsolvents such as methylene chloride, ethylene chloride; or other organic solvents, or also mixtures thereof. Furthermore, solvents that are used herein can include mixtures of conventional solvents thereof. Condensation agents include azodicarboxylats such as diethyl azodicarboxylate and phosphorous compounds such as triphenylphosphinβ .
At least equimolar, preferably equimolar to 2-fold molar, is recommended for the amount of condensation agent used for Compound (12) .
As for the ratio of Compound (12) and (13) in the above Reaction . Formula-2, the second is usually at least equimolar, preferably equimolar to about 2-fold molar compared to the first. The reaction temperature is not precisely controlled, and the reaction is usually carried out under cooled or heated conditions. Preferably, the reaction is carried out under a temperature condition ranging from 00C to 150°C for 1 to 10 hours. Here, Compound (12), which is a starting compound of the compound of the invention, are a known compound or can be readily produced from a known compound.
Also, Compound (13), which is the starting material compound of the compound of the invention, includes a novel compound, and can be produced by a variety of methods, for example, the compound is produced by the method shown in the following Reaction Formula-10 or Reaction Fόrmula-11.
Reaction Formula-9
Figure imgf000092_0001
[wherein R21, X21 and A2 have the same as aforementioned, and X23 represents a halogen atom or a group which causes the same substitution reaction as a halogen atom. ]
Here, in General Formula (15) , examples of a halogen atom and a group which causes the same substitution reaction as halogen atom referred to as X23 are the same as above. Compound (11) can be produced by reacting the compound of General Formula (14) (hereinafter called "Compound (14)") with the compound of General Formula (15) (hereinafter called XλCompound (15)").
This reaction is carried out under the same reaction conditions as in the aforementioned Reaction Formula-1.
Here, the starting compound of the compound of the invention (14) and (15) are a known compound or can be readily produced from a known compound.
Reaction Formula-10
Figure imgf000093_0001
[wherein A22 means the same as aforementioned, and X≥4 represents a halogen atom or a group which causes the same substitution reaction as a halogen atom.]
Here, in General Formula (16) , examples of a halogen atom and a group which causes the same substitution reaction as halogen atom referred to as X24 are the same as above.
Compound (13) can be produced by reacting Compound (3) with a compound of General Formula (16) (hereinafter called "Compound (16)").
This reaction is carried out under the same reaction conditions as in the aforementioned Reaction Formula-1.
Here, the Compound (16) , which is a starting compound of the compound of the invention, is a known compound or can be readily produced from a known compound.
Reaction Formula-11
Figure imgf000094_0001
Figure imgf000094_0002
[wherein A22 means the same as aforementioned, and R23 represents a lower alkanoyl group and X24 represents a halogen atom or a group which causes the same substitution reaction as the halogen atom.] Here, in General Formula (17) and (18), examples of a lower alkanoyl group in R23 are the same as above.
Also, in General Formula (17) , examples of a halogen and a group which causes the same substitution reaction as the halogen atom referred to as X24 are the same as above group.
Compound of General Formula .(18) (hereinafter called "Compound (18)") can be produced- by reacting Compound (3) with Compound (17) . This reaction is carried out under the same reaction conditions as in the aforementioned Reaction Formula-1.
Here, Compound (17), which is a starting compound of the compound of the invention, is a known compound or can be readily produced from a known compound.
Next, the deacylation reaction of Compound (18) can yield Compound (13) . A preferred method for this reaction is a conventional method such as hydrolysis. The hydrolysis reaction is preferably performed under the presence of base or an acid including Lewis acid. Suitable bases include inorganic bases such as alkali metal (for example, sodium, potassium etc.), alkali metal bicarbonate salt (for example, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal hydroxides (for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.), alkali metal carbonate salt (for example, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal lower alkoxides (for example, sodium methoxide, sodium ethoxide, etc.) and hydrides (for example, sodium hydride, potassium hydride, etc.), and organic bases such as trialkylamine (for example, trimethylamine, toriethylamine, N- ethyldiisopropylamine, etc.), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-methylmorpholine, DBN, DABCO and DBU. Suitable acids include organic acids (for example, formic acid, acetic acid, propanoic acid, trichloro acetic acid, trifluoroacetic acid, etc.), and inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride hydrogen bromide, etc.)- Isolation by acid such as trihaloacetate (for example, torichloroacetic acid, trifluoroacetic acid, etc.) is preferably perfomed under the presence of cation adjuvants (such as anisole, phenol) .
The reaction is usually carried out in conventional solvents which do not effect reaction, for example, water; alcohol solvents such as methanol, ethanol, isopropanol, n-butanol, trifluoroethanol, ethyleneglycol; ketone solvents such as acetone, methylethylketone; ether solvents such as tetrahydrofuran, dioxane, diethyl ether, diglyrαe; ester solvents such as methyl acetate, ethyl acetate; aprotic polar solvents such as acetonitrile, N, N- dimethylformamide, dimethyl sulfoxide; halogenated hydrocarbon solvents such as methylene chloride, ethylene chloride; or other organic solvents, and also mixtures thereof- Ethanol is preferred among them. The reaction temperature is not precisely controlled, and generally is carried out under cooled or heated conditions. Preferably, the reaction may be carried out for 0.5 to 75 hours under a condition ranging from around room temperature to around boiling point of the solvent used. Reaction Formula-12
Figure imgf000097_0001
[wherein A means the same as the above. R21a refers to said N-containing heterocyclic group where (8) carboxyl group is substituted with at least one in the group referred to in the aforementioned R21. R21b refers to said N-containing heterocyclic group where (10) a carbamoyl group, which may have (10) a lower alkyl group, is substituted with at least one in the group referred to in said R21. R22 and R23 are same or different, and refer to a hydrogen atom or a lower alkyl group.]
The reaction between Compound (Ig) and Compound (19) is the method in which amine in Compound (19) and carboxylic acid in Compound (Ig) are reacted by using a usual amide bond forming reaction. The known amide bond forming reaction can be widely applied to this type of amide bond forming reaction. Specific examples include (a) mixed acid anhydride method, i.e. the method of reaction of alkylhalocarboxylate to carboxylic acid (Ig) provides mixed acid anhydride which is then reacted with amine (19), (b) activated ester method, i.e. the method of the reaction of carboxylic acid (Ig) to activated ester such as phenyl ester, p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, or benzoxazoline-2-thione to yield activated amide which is then reacted with amine (19), (c) carbodiimide method, i.e. the method of condensation reaction of amine (11) to carboxylic acid (Ib) in the presence of activation agents such as dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3- ethylcarbodiimide (WSC) , carbonyldiimidazole, (d) other methods, for example, the method of reaction of carboxylic acid (Ig) using a dehydrating agent such as acetic anhydride in order to yield carboxylic anhydride which is then reacted with amine (19) , the method of reacting amine (19) with ester of carboixylic acid (Ig) and a lower alcohol, and halide of carboxylic acid (Ig), i.e. the method of reaction of amine (11) to carboxylic halide.
The mixed acid anhydride used in the above mixed anhydride method (a) is provided by Schotten- Baumann reaction, which is reacted with amine (19) , usually without isolation, to yield the General Formula (Ih) of the compound of the invention..
The above Schotten-Baumann reaction is performed in the presence of basic compounds.
The basic compounds used include known compounds in Schotten-Baumann reaction, for example, inorganic bases such as alkali metal (for example, sodium, potassium, etc.), alkali metal bicarbonate salt (for example, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal hydroxides (for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.), alkalin earth metal hydroxides (for example, calcium hydrate etc.), alkali metal carbonate salt (for example, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal lower alkoxides (for example, sodium methoxide, sodium ethoxide, etc.), hydrides (for example, sodium hydride, potassium hydride, etc.) and sodium amide, and organic bases such as trialkylamine (for example, trimethylamine, toriethylamine, N- ethyldiisopropylamine, etc.), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-methylmorpholine, 1,5- diazabicyclo[4,3,0]non-5-en(DBN) , 1,4- diazabicyclo[2,2,2]octan(DABCO) and 1,8- diazabicyclo [5, 4, 0] undecene-7 (DBU) . These basic compounds are used independently or in mixtures of two or more. The said reaction is usually performed in conditions ranging from about -20 to 1000C, preferably about 0 to 500C, and the reaction time is about 5 min. to 10 hours, preferably about 5 min. to 2 hours.
The reaction of the resulting mixed anhydride and amine (19) is usually performed in conditions ranging from about -20 to 1500C, preferably about 10 to 500C, and the reaction time is about 5 min. to 10 hours, preferably about 5 min. to 5 hours. The mixed acid ' anhydride method is generally performed in solvents. Any solvent used in the mixed acid anhydride method can be used, and specific examples include water; halogenated hydrocarbon solvents such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride; aromatic hydrocarbon solvents such as benzene, toluene, xylene; ether solvents such as diethyle ether, diisopropyl ether, tetrahidrofran, dimethoxyethane; ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate; aprotic polar aolvents such as acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, or a mixture thereof. The alkylhalocarboxylate used in the mixed acid anhydride method includes, for example, methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate, etc.
The usage ratio of carboxylic acid (Ig), alkylhalocarboxylate and amine (19) in the mixed acid anhydride method is generally at least . equimolar for each, but alkylhalocarboxylate and carboxylic acid (Ig) can be used within a range of equimolar to 6 molar for amine (19) . The method of condensation reaction in the presence of said activating agent (c) is performed in a suitable solvent, in the presence or absence of basic compounds. For solvents and basic compounds used here, any of the solvents and basic compounds used in the method of reaction of amine (19) to carboxylic halide in the other method (d) in the following can be used. The amount of activating agent used is generally at least equimolar for Compound (11) , preferably ranging from equimolar to 5 molar. When using WSC as an activating agent, the reaction can be facilitated by adding 1-hydroxybenzotriazole and/or acid such as hydrochloric acid within the reaction. Said reaction is generally performed at -20 to 1800C, preferably 0 to 1500C, and the reaction is usually completed in about 5min to 90 hours.
When using the method of reaction of amine (19) to carboxylic halide within the above other method (d) , the said reaction is carried out in a suitable solvent, in the presence of basic compounds. For the basic compounds used, known compounds are widely used, for example, any of the basic compounds used in the above Schotten-Baurnann reaction can be used. The solvents, for example, other than those used in the above mixed acid anhydride method, include alcohol solvents such as methanol, ethanol, isopropanol, puropanol, butanol, 3-methoxy-l-buanol, ethylcellosolve, methylcellosolve, and acetonitrile, pyridine, acetone and water. The ratio of the amounts used between amine (19) and carboxylic acid halide is not controlled, and can be selected appropriately from within a wide range, but it is recommended to be at least equimolar, preferably equimolar to 5 molar respectively. Said reaction is generally performed at about -20 to 180°C, preferably about 0 to 1500C, and the reaction is usually completed in about 5 min. to 50 hours .
Moreover, the amide bond forming reaction • shown in the above Reaction Formula-6 can be carried out by using the method of reaction of carboxylic acid (Ig) with amine (19) in the presence of a phosphorus compound condensation agent, such as triphenyl phosphine, diphenyl phosphinyl chloride, phenyl-N- phenylphosphoramide chloridate, diethyl chlorophosphate, diethyl phosphorocyanidate, diphenyl phosphorazidate, bis- (2-oxo-3-oxazolidinyl)phosphinic chloride. The above condensation agent is used independently or in mixtures of 2 or more.
Said reaction is usually carried out in the presence of solvents and basic compounds used in the method of reaction of amine (19) to the above carboxylic halide, at about -20 to 1500C, preferably 0 to 1000C, and the reaction is generally completed in about 5 min to 30 hours. It is recommended to use each of the condensation agents and amine (19) at least in about equimolar amounts, preferably equimolar to 3 molar amounts for carboxylic acid (Ig) . Reaction Formula-13
Figure imgf000103_0001
[wherein A2 means the same as above. R21c represents the following group;
Figure imgf000103_0002
R - represents the following, group;
Figure imgf000103_0003
R ,21e represents the following group;
Figure imgf000103_0004
X25 and X26 represents a halogen atom or a group which causes the same substitution reaction as the halogen atom respectively. R24 represents the same group as said substituents (1) to (13) of R21. p is 4 or 5. 3
The reaction between the Compound (Ii) and the Compound (20) is carried out in the suitable inert • solvent under the presence of basic compounds. The basic compounds used here include, for example, metallic sodium, metallic potassium, metallic magneciurα; sodium hydride; sodium amide; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide; alkyl, and aryl lithium or lithium amide such as methyl lithium, n-buthyl lithium, phenyl lithium, lithium isopropylamide; sylilamide such ass lithium hexamethyldisilazide. These basic compounds are used independently or in mixtures of two or more.
The amount of the basic compound is generally at least equimolar., preferably equimolar to 5~fold molar of Compound (Ii) .
The inert solvents used include, for example, aromatic hydrocarbon solvents such as benzen, toluene, xylene; ether solvents such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme; aliphatic hydrocarbon solvents such as n-hexane, . heptane, cyclohexane; halogenated hydrocarbon solvents such as chloroform, dichloroform, dichloroethane, carbon tetrachloride; dimethyl sulfoxide and N, N- dimethylformamide, or a mixture thereof.
The reaction is generally carried out at -90 to 1500C, preferably at -90 to 120°C, and ends usually in about 10 min to 30 hours. The amount of Compound (20) used may be at least equimolar, preferably equimolar to 5-fold molar for Compound (Ii) .
The reaction transforming (Ij) to (Ik) is carried out in the same condition as that transforming Compound (Ii) to Compound (Ij).
A compound having a group in which Q is represented by the General Formula (2) in Compound (1) can be converted into a variety of compounds by applying the following Reactions A- to G. Reaction A
In Compound (1) , when compound in which (12) oxy group is substituted on the heterocyclic ring of N- containing heterocyclic group represented by R21, said compound is deprotected to give Compound (1) in which the oxo group on the hetero ring of corresponding N- containing heterocyclic group is deoxo.
Reducing agents used in the above reducing reaction include, for example, hydrogenated reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetyloxyborohydride and lithium alminiuna hydride, or the mixture of hydrogenated reducing agents thereof. The hydrogenarated reducing agent is generally used in about equimolar to 5-fold molar amounts, preferably equimolar to 2-fold molar for a starting material.
The reducing agent is generally performed in a suitable solvent. Examples of solvents are ether solvents such as diethyether, tetrahydrofuran, dioxane, monoglyme, diglyme; and aromatic hydrocarbon solvents such as benzen, toluene and xylene.
The reaction temperature is generally about 0 to 1500C, preferably 0 to 1000C, and said reaction is usually completed in 30 min to 10 hours. Reaction B
In Compound (1) , when the compound in which (5) protected hydroxy group is substituted on the heterocyclic ring of N-containing heterocyclic group represented by R21, said compound is deprotected to give the Compound (1) in which (4) hydroxy group is substituted on the hetero ring of corresponding N- containing heterocyclic group. The above deprotection reaction is carried out in a suitable solvent or nonsolvent in the presence of acid, or basic compounds.
The solvents used are, for example, water; lower alcohol solvents such as methanol, ethanol, isopropanol, tert-butanol; ketone solvents such as acetone, methylethylketone; ether solvents such as diethyl ether, dioxane, tetrahydrofran, monoglyme, diglyme; ester solvents such as methyl acetate, ethyl acetate; fatty acid solvent such as formic acid, acetic acid; halogenated hydrocarbon solvents such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride; amide solvents such as N,N- dimethylformamide, N,N-dimethylacetamide, N- methylpyrrolidone; dimethyl sulfoxide, hexamethylphosphoric triainide; or mixtures thereof. Examples of acids include inorganic acids • such as hydrochloric acid, sulfuric acid and hydrobromic acid, and organic acid such as formic acid, acetic acid, trifluoroacetic acid, p-toluene sulfonic acid. Also, examples of basic compounds include, for- example, carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate; and metal hydroxides such as sodium hydroxide, calcium hydroxide, potassium hydroxide, lithium hydroxide.
The amount of acid and basic compound used is generally at least 1 mole, preferably 1 to 10 moles for a starting material, but for acid, it can be used excessively as a reaction solvent.
This reaction preferably progresses generally at about 0 to 200°C, preferably 0 to 1500C, and is usually completed in 10 min to 30 hours. When the protection group is a lower alkyl, deprotection can be performed by treating it in a suitable solvent in -the presence of dealkylating agent. Any of the solvents in the above deprotection reaction can be used. Dealkylation agents include, for example, trihalogenated boron such as boron tribromide. The amount of dealkylation agent used is generally at least equimolar, preferably equimolar to 10-fold molar for a starting material. Said reaction is completed in about 1 to 50 hours generally at 0 to 1500C, preferably at around room temperature to 100°C.
When the protecting group is a lower alkylr deprotection can be performed by reduction treatment. This reduction treatment is carried out, for example, in a suitable solvent in the presence of a catalyst by catalytic hydrogenation.
The solvents used are, for example, water; alcohol solvent such as methanol, ethanol, isopropanol; hydrocarbon solvent such as n-hexane, cyclohexane; ether solvent such as dioxane, tetrahydrofuran, diethyl ether, ethyleneglycoldimethyl ether; ester solvent such as ethyl acetate, methyl acetate; aprotic polar solvent such as dimethy formamide, or mixtures thereof. Examples of a catalyst used include paradium, paradium black, paradium carbon, platinum, platinum oxide, copper chromite, Raney nickel, or mixtures thereof. The amount of catalyst used may generally be 0.02 to one time w/w of a starting material. The reaction temperature is around -20 to
1000C, preferably around 0 to 800C and hydrogen pressure is generally 1 to 10 atm, and this reaction is generally completed in about 0.5 to 20 hours. Reaction C In Compound (1), when the compound in which
N-containing heterocyclic group represented by R21 is an unsaturated heterocyclic group, said compound is reduced to give Compound (1) in which part of the corresponding N-containiήg heterocyclic group becomes saturated.
The above reducing reaction is carried out, for example, in a nonsolvent or in a suitable solvent in the presence of a reducing agent.
The solvents used in this reaction are, for example, water; lower alcohol solvents such as methanol, ethanol, isopropanol, butanol, tert-butanol, ethyleneglycol; fatty acid solvent such as acetonitlil, formic acid, acetic acid; ether solvents such as diethyl ether, tetrahydrofran, dioxane, monoglyme, diglyme; aromatic hydrocarbon solvent such as benzen, toluene, xylene; halogenated hydrocarbon solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride; or mixtures thereof.
Examples of a reducing agent used include, a catalytic hydrogenation recuding agent such as paradium black, paradium carbon, platinum oxide, platinum black, Raney nickel. The amount of catalytic hydrogenation recuding agent used is usually 1 to 5 times w/wf preferably about 1 to 3 w/w of a starting material.
The reaction is carried out under hydrogen atmosphere of ambient pressure to about 20 atm, preferably ambient pressure to 10 atm, at usually about -30 to 100°C, preferably 0 to 600C. The reaction is completed in about 1 to 20 hours. Reaction D
In Compound (1) , when the compound in which (9) a lower alkoxycarbonyl group is substituted on the hetero ring of N-containing heterocyclic group represented by R21, said compound is hydrolysed to give • Compound (1) in which (8) carboxy is substituted on a hetero ring of the corresponding N-containing heterocyclic group.
The above hydrolysis reaction is carried out in a suitable solvent or nonsolvent in the presence of an acid or basic compound. The solvents used are, for example, water; lower alcohol solvents such as methanol, ethanol, isopropanol, tert-butanol; ketone solvents such as acetone, methylethylketone; ether solvents such as diethyl ether, dioxane, tetrahydrofran, monoglyme, diglyme; fatty acid solvent such as acetic acid, formic acid; ester solvents such as methyl acetate, ethyl acetate-; halogenated hydrocarbon solvents such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride; amide solvents such as dimethl sulfoxide, N,N-dimethylformamide, hexamethylphosphoric triamide, or mixtures thereof.
Examples of acids include inorganic acids such as hydrochloric acid, sulfuric acid and hydrobromic acid, and organic acids such as formic acid, acetic acid, trifluoroacetic acid, p-toluene sulfonic acid. These acids can be used independently or in mixtures of two or more.
Examples of basic compounds include, for example, carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate; and metal hydroxides such as sodium hydroxide, potassium hydroxide, calucium hydroxide, lithium hydroxide. These basic compounds can be used independently or in mixtures of two or more.
The above hydrolysis reaction progresses at about 0 to 200°C, preferably about 0 to 15O0C, and is usually completed in about 10 min to 80 hours. Reaction E
In Compound (1) , when the compound in which (8) carboxy group is substituted on the hetero ring of a N-containing heterocyclic group represented R21, said compound and a lower alcohol (such as methanol, ethanol, tert-buthyl) are reacted to give Compound (1) in which (9) lower alcohol alkoxycarbonyl is substituted on a hetero ring of the corresponding N- containing heterocyclic group.
Any usual ester reaction condition can be used in the above reaction. For example, the reaction is carried out in the presence of an inorganic acid and/or halogenating agent. Examples of' inorganic acids are hydrochloric acid, sulfuric acid, etc. Examples of halogenating agents are thionylchloride, phosphorous oxychloride, phosphoric chloride, phosphoric trichloride, etc. The lower alcohol is excessively used for a starting material. The reaction progresses at usually about 0 to 150°C, preferably about 50 to 1000C, and is usually completed in about 1 to 10 hours. Reaction F
• In Compound (1), when the compound in which (11) a lower alkyl group (which may contains a lower alkoxy group on an aryl group) is substituted on a N atom of the hetero ring of N-containing heterocyclic group represented by R21, said compounds are treated in a suitable solvent or nonsolvent in the presence of an acid to give Compound (1) in which an aryl lower alkyl group on a N atom of the corresponding N-containing heterocyclic group is eliminated.
The solvents used the above reaction are, for example, water; lower alcohol solvents such as methanol, ethanol, isopropanol, tert-butanol; ketone solvents such as acetone, methylethylketone; ether solvents such as diethyl ether, dioxane, tetrahydrofran, monoglyme, diglyme; fatty acid solvent such as acetic acid, formic acid; ester solvents such as methyl acetate, ethyl acetate; halogenated hydrocarbon solvents such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride; amide solvents such as N,N-dimethylformamide, N, N- dimethyl acetoamide, N-metylpyrrodone; dimethyl sulfoxide, hexamethylphosphoric triamide, or mixtures thereof.
Examples of acids include inorganic acids such as hydrochloric acid, sulfuric acid and hydrobromic acid, and organic acids such as formic acid, acetic acid, trifluoroacetic acid, p-toluene sulfonic acid. The amount of acid used is usually at least 1 mole, preferably 1 to 30 moles of starting material, and the acid may be used excessively as a reaction solvent.
The reaction preferably progresses at about 0 to 2000Ci, preferably 0 to 1500C, and is generally completed in about 10 min to 30 hours. Reaction G In Compound (1) , the compound, in which (7) lower alkanoyl group is substituted on a N atom of a he'tero ring of a N-containing heterocyclic group represented by R21, is produced by reacting Compound (1) (in which at least one N atom of a N-containing heterocyclic group is unsubstituted) with an alkanoylation agent in a suitable solvent or nonsolvent in the presence or absence of a basic compound.
The inert solvent used in the above reaction is, for example, an aromatic hydrocarbon solvent such as benzene, toluene, xylene; an ether solvent such as diethylether, tetrahydrofuran, dioxane, monoglyme, diglyme; a halogenated hydrocarbon solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride; a lower alcohol solvent such as methanol, ethanol, isopropanol, butanol, tert-butanol, ethylene glycol; a fatty acid solvent such as acetic acid; ester solvents such as methyl acetate, ethyl acetate; a ketone solvent such as acetone, methylethylketone; acetoήitrile, pyridine, dimethyl sulfoxide, N,N-dimethylformamide, N- methylpyrrolidone, hexamethylphosphoric triamide; or a mixture thereof. The basic compounds include, for example, inorganic bases such as alkali metal (for example, sodium, potassium, etc.), alkali metal bicarbonate salt (for example, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal hydroxides (for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.), alkali earth metal hydroxides (for example, calcium hydrate etc.), alkali metal carbonate salt (for example, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal lower alkoxides (for example, sodium methoxide, sodium ethoxide, etc.), hydrides (for example, sodium hydride, potassium hydride, etc.) and sodium amide, and organic bases such as trialkylamine (for example, trimethylamine, toriethylamine, N- ethyldiisopropylamine, etc.), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-methylmorpholine, 1,5- diazabicyclo[4,3,0]non-5-en(DBN) , 1,4- diazabicyclo[2,2,2]octan(DABCO) and 1,8- diazabicyclo[5,4,0]undecene-7 (DBU) or mixtures thereof.
When carrying out the reaction in the presence of a basic compound, the amount of basic compound used may be at least equimolar, preferably equimolar to 5-fold mole for a starting material.
Alkanoylation agents include, for example, lower alkanoyl halides such as acetyl chloride and fatty acid anhydride such as acetic anhydride.
A lower alkanoylation agent is usually used at least equimolar, preferably equimolar to 5-fold moles for a starting material.
The reaction is carried out usually at 0 to 200°C, preferably about 0 to 1500C, and is generally completed in about 5 min to 5 hours.
Alkali metal halogen compounds such as sodium iodide or potassium iodide may be added to this reaction within the reaction system. The starting compounds used in each of the above reaction formulas may be preferred salt, and moreover, final compounds obtained in each reaction may form preferred salt. As those preferred salts, preferred salt of Compound (1) exemplified below is cited.
Preferred salt of Compound (1) is pharmacologically acceptable salt, for example, metal salt such as alkali metal salt (for example, sodium salt, and potassium salt, etc.), alkaline earth metal salt (for example, calcium salt, and magnesium salt, etc.), etc., salt of inorganic base such as ammonium salt, alkali metal carbonate (for example, lithium carbonate, potassium carbonate, sodium carbonate, and cesium carbonate, etc.) , alkali metal hydrogen carbonate (for example, lithium hydrogen carbonate, sodium hydrogen carbonate, and potassium hydrogen . carbonate, etc.), and alkali metal hydroxide (for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide, etc.)/ etc.; for example/ salt of organic base such as tri (lower) alkylamine (for example, trimethylamine, triethylamine, and N-ethyldiisopropylamine, etc.), pyridine, quinoline, piperidine, imidazole, picoline, dimethylami.nopyridine, dimethylaniline, N- (lower) alkyl-morpholine (for example, N-methylmorpholine, etc.), l,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8- diazabicyclo[5.4.0]undecene-7 (DBU), and 1,4- diazabicyclo[2.2.2]octane (DABCO), etc.; salt of inorganic acid such as hydrochloride, hydrobrornate, hydroiodide, hydrosulfate, nitrate salt, and phosphate, etc.; and salt of organic acid such as formate, acetate, propionate, oxalate, malonate compound, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, picrate, methanesulfonate, ethane sulfonate, p-toluene sulfonate, and glutamate, etc.
Moreover, a compound in a form in which solvate (for example, hydrate, and ethanolate, etc.) is added to raw materials and final compounds shown in each reaction formula is also included in each general formula. As a preferred solvate, hydrate is cited.
Each final compound obtained in each of the above reaction formulae can be isolated from reaction mixture and purified, for example, by cooling the reaction mixture, and then isolating the crude reaction product by an isolation operation such as filtering, concentrating and extracting, etc., and a normal purification operation such as column chromatography, arid recrystallization, etc.
In the compound shown in General Formula (1) of the present invention, isomers such as geometric isomer, stereoisomer, and optical isomer, etc., are also deservingly included.
The compound of General Formula (1) and salt thereof is used in a form of common pharmaceutical formulation. The formulation is prepared using diluents or excipients normally used such as fillers, expanders, binders, wetting agents, disintegrants, interfacial active agents, and lubricants, etc. For this pharmaceutical formulation, various forms can be selected for the purpose of treatment, and as representative examples, tablets, pills, powder, liquid medicines, suspensions, emulsions, granules, capsule, suppository, and injections (liquid medicines, and suspensions, etc.), etc., are cited.
In forming into a tablet form, various carriers well known in this field can be widely used. For example, excipients such as lactose, saccharose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silic acid, etc., binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, and polyvinylpyrrolidone, etc., disintegrants such as dry starch, sodium alginate, powdered agar, powdered laminara'n, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, starch, and lactose, etc., disintegration inhibitors such as saccharose,, stearin, cocoa butter, and hydrogenated oil, etc., absorption promoters such as quaternary ammonium base, and sodium lauryl sulfate, etc., moisturizing agent such as glycerin, starch, etc., adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silic acid, etc., and lubricants such as purified talc, stearate, powdered boric acid, and polyethylene glycol, etc., can be used. Furthermore, tablets can be tablets coated with normal coating agents, for example, dragee, gelatine-coated tablets, enteric coated tablets, film-coated tablets or double tablets and multilayer tablets, if needed.
In forming into a pill form, carriers known in this field can be widely used. For example, excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, and talc, etc., binders such as powdered acacia, powdered tragacanth, gelatine, and ethanol, etc., and disintegrants such as laminaran, and agar, etc., can be used.
In forming into a suppository form, carriers known in this field can be widely used. For example, esters such as polyethylene glycol, cacao butter, higher alcohol, and higher alcohol, and gelatine, and semisynthetic glyceride, etc., can be cited.
Capsules are normally prepared by mixing the active ingredient compound with various carriers exemplified above and filling in hard gelatine capsules or soft capsules, etc., according to a common procedure .
If prepared as injections, liquid medicines, emulsions and suspensions are sterilized,- and preferably as isotonic as blood, and in forming into these forms, what is commonly used in this field as diluents can all be used, for example, water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters, etc.
Furthermore, in this case, an efficient amount of salt, glucose or glycerin to prepare an isotonic solution may be contained in the pharmaceutical formulation, and normal solubilizing agents, buffers, and analgesic agents, etc., may also be added. Moreover, coloring agents, preservatives, aromatic agents, flavoring agents, and sweetening agents, etc., or other pharmaceuticals can be contained in the pharmaceutical formulation, if needed.
It is preferable that the amount of the compound of General Formula (1) that should be contained in the pharmaceutical formulation of the present invention or salt thereof is, but not particularly limited and accordingly selected from- a wide range, normally approximately 1 to 70 weight% in the formulation composition, preferably approximately 1 to 30 weight%. Administration method of the pharmaceutical formulation, of the present invention is not particularly limited, and the pharmaceutical formulation is administered by a method according to various dosage forms, age of the patient, gender, other conditions, and degree of disorder, etc. For example, tablets, pills, liquid medicines, suspensions, emulsions, granules, and capsules are orally administered. Furthermore, injections are independently administered, or intravenously administered after being mixed with a normal replacement fluid such as glucose, amino acid, etc., and, moreover, are independently intramuscularly, intradermally, subcutaneously or intraperitoneally administered, if needed. Suppository is intrarectally administered.
Doses of the pharmaceutical formulation of the present invention are selected according to usage, age of the patient, gender, other conditions, and degree of disorder, etc., but it is preferable that an amount of the active ingredient compound is normally approximately 0.1 to 10 mg per kg of body weight per day. Moreover, it is desirable that the active ingredient compound is contained in a range of approximately 1 to 200 mg in the formulation of an administration form.
The compound of the present invention has D2 receptor partial agonist effect, 5-WU2A receptor antagonist effect and serotonin uptake inhibitory effect (or serotonin uptake inhibitory effect) .
The D2 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) . According to this function, 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. 855-864 (2004), Tetsuro Kikuchi and
Tsuyoshi Hirose: Nou-no-Kagaku (Brain Science), Vol. 25, pp. 579-583 (2003) and Harrison, T. S. and Perry, CM.: Drugs 64: 1715-1736, 2004). 5-HT2& 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- Psychopharmacol . Biol. Psychiatry 27: 1159-1172, 2003). Serotonin uptake inhibitory effect (or serotonin reuptake inhibitory effect) is effective for improving depressive symptoms, for example (See Mitsukuni Murasaki: Rinsho-Seishin-Yakuri (Japanese 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.
In addition, some of the compounds of the present invention have αi receptor antagonist effect in addition to the above-described effects. The αi receptor antagonist effect is effective for improving positive symptoms of schizophrenia (See Svensson, T. H. : Prog. Neuro-Psychopharmacol. Biol. Psychiatry 27: 1145- 1158 , 2003 ) .
Therefore, the compounds of the present invention have a wide treatment spectrum for and excellent clinical effect on schizophrenia and other central nervous system disorders.
Accordingly, 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 nervosa, bulimia nervosa, etc.); sleep disorder; adjustment disorder; substance-related disorder (for example, alcohol abuse, alcohol intoxication, drug addiction, stimulant intoxication, narcotism, etc.); anhedonia (for example, iatrogenic anhedonia, anhedonia of a psychic or mental cause, anhedonia associated with depression, anhedonia associated with schizophrenia, etc.); delirium; cognitive impairment; cognitive impairment associated with Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases; cognitive impairment caused by Alzheimer's disease, Parkinson's disease and associated neurodegenerative diseases; cognitive impairment of schizophrenia; cognitive impairment caused by refractory, intractable or chronic schizophrenia; vomiting; motion sickness; obesity; migraine; pain (ache) ; mental retardation; autism disorder (autism); Tourette's disorder; tic disorder; attention-deficit/hyperactivity disorder; conduct disorder; and Down's syndrome.
Furthermore, the compounds of the present invention have little or no side effects and they are excellent in safety and tolerability.
Also, the compound of the invention can exert effects such as reducing dosages, diminishing side effects, enhancing therapeutic effects, etc., which could not be achieved by conventional treatments by administrating the compound of the present invention in combination with at least one agent currently used in clinical practice selected from (1) mood stabilizer, (2) serotonin reuptake inhibitor, (3) norepinephrine reuptake inhibitor, (4) serotonin and norepinephrine reuptake inhibitor, and (5) anti-anxiety. (1) Mood stabilizer
For mood stabilizers, compounds which function as mood stabilizers can be widely used and known in the art .
Mood stabilizers used in the present invention include, but are not limited to, lithium, valproic acid, divaproex sodium, carbamazepine, oxcarbamazepine, zonisamide, lamotrigine, topirarnate, gabapentin, levetiracetam, clonazepam, phenitoin, thyroid hormone, tiagabine and omega-3-fatty acids. Lamotrigine, zonisamide, topiramate, lithium, valproic acid and carbamazepine are preferable. (2) Serotonin reuptake inhibitor
For serotonin reuptake inhibitors, known compounds which function as serotonin reuptake inhibitors can be widely used.
According to the method by Wong et al. (Neuropsychophamacology, 8, pp.337-344 (1993)) which is a conventional standard pharmacological assay, IC50 values (a concentration of an agent that inhibits reuptake of serotonin by 50%) of about 1000 nM or less are preferred among serotonin reuptake inhibitors. Such serotonin reuptake inhibitors include, for example, fluvoxamine (5-methoxy-l- [4- (trifluoromethyl) phenyl] -1-pentanone-O- (2- aminoethyl) oxime) , fluoxetine (N-metyl-3- (p- trifluoromethylphenoxy) -3-phenylpropylamine) , paroxetine (trans- (-) -3- [ (1, 3-benzodioxole-5- yloxy) methyl] -4- (4-fluorophenyl) piperidine) , sertraline (IS-cis) -4- (3, 4-dichlorophenyl) -1, 2, 3, 4- tetrahydro-N-methyl-1-naphthylamine hydrochloride) , venlafaxine (1- [2- (Dimethylamino) -1- (4- methoxyphenyl) ethyl] cyclohexanol, milnacipran (N,N- diethyl-2-aminomethyl-l-phenylcyclopropanecarboxamide) , citalopram(l- [3- (dimethylamino) propyl] -1- (4- fluorophenyl) -1, 3-dihydro-5- isobenzofurancarbonitorile) , duloxetine (N-methyl-3- (1- naphthalenyloxy) -3- (2-thienyl)propaneamine) , and escitalopram(S- (+) -l-[3- (dimethylamino) propyl] -1- (4- fluorophenyl) -1, 3-dihydro-5-isobenzofuran carbonitrile oxalate.
(3) Norepinephrine reuptake inhibitors
For norepinephrine reuptake inhibitors, known compounds which function as norepinephrine reuptake inhibitor can be widely used. Such norepinephrine reuptake inhibitors include levoxetine, atomoxetine and bupropion, preferably levoxetine and atomoxetine.
(4) Serotonin and norepinephrine reuptake inhibitors
For serotonin and norepinephrine reuptake inhibitors, known compounds which function as serotonin and norepinephrine reuptake inhibitors can be widely used. Such serotonin and norepinephrine reuptake inhibitors include, for example, venlafaxine, duloxetine and milnacipran. (5) Anti-anxiety drugs
Anti-anxiety drugs used in the present invention include, but are not limited to, benzodiazepine type drug such as diazepam, chlordiazepoxide, cloxazolam, clotiazepam, alprazolam, etizolarri and oxazolam, and serotonin 5-HT1A receptor agonist type antianxieties such as tandospirone and buspirone. Agents selected, from the group consisting of
(1) mood stabilizers, (2) serotonin reuptake inhibitors, (3) norepinephrine reuptake inhibitors, (4) serotonin and norepinephrine reuptake inhibitors, and (5) anti-anxiety drugs, may be in the form either of free bases or salts (acid addtion salt) . Also, these Agents can be racemic forms, or R and S enantiomers. These can be used singly or in combination with two or more as required. Singly use is preferred.
These agents can readily form an acid addition salt with a pharmacologically acceptable acid. These acids include, for example, inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, phosphorus acid, hydrobromic acid and organic acids such as acetic acid, p-toluenesulfonic acid, methansulfonic acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, and benzoic acid. These acid addition salts can also be used as active ingredient compounds in the present invention as well as the' drugs in a free form.
Salts can be readily formed by reacting pharmacologically acceptable basic compounds with those • compounds having acid groups among the drugs. Basic compounds include, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, and calcium hydroxide, alkali metal carbonate salts such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, or bicarbonate; metal alcoholates such as sodium methylate and potassium methylate.
Hereinafter, the present invention will be further clear with reference to Reference Examples, Examples, Pharmacological Test Examples, and Preparation Example.
Reference Example 1
Synthesis of tert-butyl ethyl- (4-hydroxybutyl) carbamate 9.32 g (43 mmol) of di-t-butyldicarbonate was added under ice cooling to a dichloromethane solution (100 ml) of 5.0 ml (39 mmol) of 4-ethylamino-l-butanol and 6.5 ml (47 mmol) of triethylamine. .This mixture was stirred at room temperature for 21 hours. Water was added to this reaction solution for separation. An organic layer thus obtained was dried with anhydrous sodium sulfate and concentrated under a reduced pressure. A residue thus obtained was purified with silica gel column chromatography (hexane: ethyl acetate = 2:1 to 1:1). The purified product was concentrated under a reduced pressure to obtain 7.40 g (yield: 88%) of a colorless oily tert-butyl ethyl- (4- hydroxybutyl) carbamate.
Reference Example 2
Synthesis of 4- (tert-butoxycarbonyl-ethyl-amino) butyl methanesulfonate
2.5 ml (32 mmol) of methanesulfonyl chloride was added dropwise under ice cooling to a dichloromethane solution (130 ml) of 6.50 g (30 mmol) of- tert-butyl ethyl- (4-hydroxybutyl) carbamate and 5.0 ml (36 mmol) of triethylamine, and the resultant mixture was stirred at the same temperature for one hour. Water was added to this reaction solution for separation. An organic layer thus obtained was dried with anhydrous sodium sulfate and concentrated under a reduced pressure. A residue thus obtained was purified with silica gel column chromatography (hexane: ethyl acetate = 2:1 to 1.5:1). The purified product was concentrated under a reduced pressure to obtain 7.22 g (yield: 82%) of a colorless oily 4-(tert- butoxycarbonyl-ethyl-amino) butyl methanesulfonate.
Reference Example 3
Synthesis of tert-butyl [4- (4-benzo [b] thiophen-4-yl- piperazin-1-yl) butyl] -ethyl-carbamate hydrochloride
6.83 g (26.8 mmol) of 4-benzo [b] thiophen-4- yl-piperazine hydrochloride and 7.75 g (56.1 mmol) of potassium carbonate were added to a DMF solution (150 ml) of 7.20 g (24.4 mmol) of 4- (tert-butoxycarbonyl- ethyl-amino) butyl methanesulfonate. This mixture was stirred at 80°C for 3.5 hours. This reaction solution was cooled to room temperature, water was added thereto, and a reaction product was extracted with ethyl acetate. An organic layer thus obtained was washed with water, dried with anhydrous sodium sulfate and concentrated under a reduced pressure. A residue thus obtained was purified with silica gel column chromatography (hexane: ethyl acetate = 2:1 to 1:2). The purified product was concentrated under a reduced pressure to obtain 4.84 g (yield: 48%) of a colorless oily tert-butyl [4-(4- benzo [b] thiophen-4-yl-piperazin-l-yl) butyl] -ethyl- carbamate. 340 mg out of the obtained concentrate was dissolved in 2 ml of ethanol, and 0.9 ml of 1 N HCl ethanol solution was added thereto. Precipitated crystals were filtered out and dried to obtain a white powder of tert-butyl [4- (4-benzo [b] thiophen-4-yl- piperazin-1-yl) butyl] -ethyl-carbamate hydrochloride. Melting Point 230 to 2320C
Reference Example 4
Synthesis of [4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) butyl] -ethyl-amine dihydrochloride
7.8 ml of trifluoroacetic acid was added to a dichloromethane solution (80 ml) of 4.20 g (10.1 mmol) of tert-butyl [4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) butyl] -ethyl-carbamate. This mixture was stirred at room temperature for 16 hours. This reaction mixture was concentrated under a reduced pressure, an aqueous solution of sodium hydrogen carbonate was added to a residue thus obtained, and a reaction product was extracted with dichloromethane. The reaction product was dried with anhydrous sodium sulfate and concentrated under a reduced pressure. A residue thus obtained was purified with basic silica gel column chromatography (dichloromethane: methanol = 1:0 to 9:1) . The purified product was concentrated under a reduced pressure to obtain 2.71 g (yield: 85%) of a pale yellow oily [4- (4-benzo [bj thiophen-4-yl-piperazin-l-yl) butyl] - ethyl-amine. 260 mg out of the obtained concentrate was dissolved in 2 ml of ethanol, and 1.8 ml of 1 N HCl ethanol, solution was added thereto. Precipitated crystals were filtered out and dried to obtain a white powder of [4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) butyl] -ethyl-amine dihydrochloride. Melting Point 265 to 267°C
Reference Example 5
Synthesis of 2- [4-,(4-benzo [b] thiophen-4-yl-piperazin-l- yl) butyl] isoindole-1, 3-dione hydrochloride 200 mg (0.71 mmol) of 2-(4- bromobutyl) isoindole—1, 3-dione, 200 mg (0.78 mmol) of 1-benzo [b] thiophen-4-yl-piperazine hydrochloride, potassium carbonate (230' mg, 1.66 itimol) and sodium iodide (130 mg, 0.87 πunol) were added to dimethylformamide (DMF) (4 ml) . This mixture was stirred at 80°C for 5 hours. This reaction solution was cooled to room temperature, water was added thereto, and a reaction product was extracted with ethyl acetate, An organic layer thus obtained was washed with water, and dried with anhydrous sodium sulfate. The dried organic layer was concentrated under a reduced pressure. A residue thus obtained was purified with silica gel column chromatography (dichloromethane: methanol = 30:1). The purified product was concentrated under a reduced pressure. A residue thus obtained was dissolved in ethanol (2 ml) , and concentrated hydrochloric acid (0.65 ml) was added thereto. This solution after the addition of hydrochloric acid was concentrated under a reduced pressure. A residue thus obtained was recrystallized from ethanol-ethyl acetate to obtain 210 mg (yield: 65%) of a pale yellow powder of 2- [4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) butyl] isoindole-1, 3-dione hydrochloride. Melting Point 295°C (Decomposition)
Reference Example 6
Synthesis of 4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl)butylamine
0.27 ml (5.6 mmol) of hydrazine monohydrate was added to an ethanol solution (8 ml) of 789 mg (1.89 inmol) of 2- [4- (4-benzo[b] thiophen-4-yl-piperazin-l- yl) butyl] isoindole-1, 3-dione. This mixture was stirred with being heated to reflux for 2 hours. This reaction solution was concentrated under a reduced pressure, and a 1 N aqueous solution of sodium hydroxide was added to a residue thus obtained. A reaction product thus obtained was extracted with dichloromethane, and washed and dried with anhydrous sodium sulfate. The dried product was concentrated under a reduced pressure to obtain 581 mg (quantitative yield) of yellow oily 4-(4- benzo [b] thiophen-4-yl-piperazin-l-yl) butylamine .
Reference Example 7
N- [4- (4-benzo [b] thiophen-4-yl-piperazin-l-yl) butyl] - propyn-2-ylamine 0.084 ml (1.14 mmol) of propargyl bromide was added to a dichloromethane solution of 330 mg (1.14 mmol) of 4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) butylamine. This mixture was stirred at room temperature for 15 hours. A saturated aqueous solution of sodium hydrogen carbonate was added to this reaction solution, a reaction product was extracted with dichloromethane and dried with anhydrous sodium sulfate. The dried product was concentrated under a reduced pressure. A residue thus obtained was purified with basic silica gel column chromatography (hexane: ethyl acetate = 1:2). The purified product was concentrated under a reduced pressure to obtain 75 mg (yield: 20%) of a colorless amorphous solid of N- [4- (4- benzo [b] thiophen-4-yl-piperazin-l-yl) butyl] -propyn-2- ylamine .
Reference Example 8 Synthesis of 1-benzo [b] thiophen-4-yl-piperazine
A mixture consisting of 14.4 g of 4- bromobenzo[b] thiophene, 29.8 g of piperazine anhydride, 9.3 g of sodium t-butoxide, 0.65 g of (R) - (+) -2, 2 ' - bis (diphenylphosphino) -1, 1 ' -binaphthyl (BINAP), 0,63 g of tris (dibenzylideneacetone) dipalladium(O) and 250 ml of toluene was heated to reflux for one hour. Water was added to this reaction solution, and the solution was extracted with ethyl acetate. The extract was washed with water, dried with magnesium sulfate, and the solvent was evaporated under a reduced pressure. A residue, thus obtained was purified with silica gel column chromatography (dichloromethane: methanol: 25% aqueous ammonia = 100:10:1) to obtain 9.5 g of yellow oily 1-benzo [b] thiophen-4-yl-piperazine . 3.7 ml of concentrated hydrochloric acid was added to a methanol solution of 9.5 g of 1- benzo [b] thiophen-4-yl-piperazine, and the solvent was evaporated under a reduced pressure. Ethyl acetate was added to a residue thus obtained, and precipitated crystals were filtered out. Recrystallization was conducted from methanol to obtain colorless needle crystals of 1-benzo [b] thiophen-4-yl-piperazine hydrochloride. Melting Point: 276 to 28O0C 1H-NMR (DMS0-d6) 6 ppm:
3.25-3.35 (8H, m) , 6.94 (IH, d, J = 7.6 Hz), 7.30 (IH, dd, J = 7.8 Hz, 7.8 Hz), 7.51 (IH, d, J = 5.5 Hz), 7.68 (IH, d, J = 8.1 Hz), 7.73 (IH, d, J = 5.5 Hz), 9.35 (2H, brs) .
Reference Example 9
Synthesis of l-benzo[b] thiophen-4-ylpiperazine A mixture consisting of 14.4 g of 4- bromobenzo [b] thiophene, 29.8 g of piperazine anhydride, 9.3 g of sodium t-butoxide, 0.65 g of (R) - (+) -2,2 '- bis (diphenylphosphino) -1,1' -binaphthyl (BINAP) , 0.63 g of tris (dibenzylideneacetone) dipalladium(O) and 250 ml of toluene was heated to reflux for one hour under nitrogen atmosphere. Water was added to this reaction solution, and the solution was extracted with ethyl acetate. An organic layer thus obtained was washed with water, dried with magnesium sulfate, and the solvent was evaporated under a reduced pressure. A residue thus obtained was purified with. silica gel column chromatography (dichloromethane: methanol: 25% aqueous ammonia = 100:10:1) to obtain 9.5 g of yellow oily 1-benzo [b] thiophen-4-ylpiperazine . 3.7 ml of concentrated hydrochloric acid was added to a methanol solution of 9.5 g of 1- benzo[b] thiophen-4-yl-piρerazine, and the solvent was evaporated under a reduced pressure. Ethyl acetate was added to a residue thus obtained, and precipitated crystals were filtered out. Recrystallization was conducted from methanol to obtain colorless needle crystals of 1-benzo [b] thiophen-4-yl-piperazine hydrochloride.
Melting 'Point: 276 to 280°C
1H-NMR (DMSO-d6) δ ppm: 3.25-3.35 (8H, .m) , 6.94 (IH, d, J = 7.6 Hz), 7.30 (IH, dd, J = 7.8 Hz, J = 7.8 Hz), 7.51 (IH, d, J = 5.5 Hz), 7.68 (IH/ d, J = 8.1 Hz), 7.73 (IH, d, J = 5.5 Hz), 9.35 (2H, brs) .
Reference Example 10
Synthesis of tert-butyl 4-benzo [b] thiophen-4-yl- methylpiperazine-1-carboxylate The title compound was obtained as with
Referenpe Example 9 by using tert-butyl 3- methylpiperazine-1-carboxylate and 4- bromobenzo [b] thiophene as the material compounds.
1H-NMR (CDCl3) δ ppm: 1.85-1.95 (3H, m) , 1.50 (9H, s) , 2.8-2.9 (IH, m) , 3.15-3.35 (2H, m) , 3.4-3.5 (IH, m) ,
3.5-3.65 (IH, m), 3.65-3.7 (IH, m) , 3.7-3.9 (IH, m) ,
6.98 (IH, d, J = 7.5 Hz), 7.29 (IH, dd, J = 8 Hz, J = 8
Hz), 7.38 (IH, d, J = 5.5 Hz), 7.61 (IH, d, J = 8 Hz).
Reference Example 11 Synthesis of 1-benzo [b]thiophen-4-yl-2-methylpiperazine dihydrochloride 6 ml of trifluoroacetic acid was added to a dichloromethane solution (12 ml) of 1.22 g (3.7 mmol) of tert-butyl 4-benzo[b] thiophen-4~yl-3- methylpiperazine-1-carboxylate, and the resultant mixture was stirred at room temperature for one hour. This reaction solution was concentrated under a reduced pressure'. A 5% aqueous solution of potassium carbonate was added to a residue thus obtained, .and this solution was extracted with dichloromethane. An organic layer thus obtained was dried with magnesium sulfate, and concentrated under a reduced pressure. 0.6 ml of concentrated hydrochloric acid and 10 ml of methanol were added to a residue thus obtained, and this solution was concentrated under a reduced pressure. A residue thus obtained was recrystallized from acetonitrile to obtain 0.98 g of a slightly brown powder of 1-benzo [b] thiophen-4-yl-2-methylpiperazine dihydrochloride . 1H-NMR (DMSO-d6) δ ppm: 0.92 (3H, d, J = 6.5 Hz), 2.8- 3.6 (6H, m) , 3.6-4.0 (IH, m) , 5.3-6.8 (IH, m) , 7.20 (IH, br), 7.38 (IH, dd, J = 8 Hz, J = 8 Hz), 7.5-8.0 (3H, m) , 9.4-10.1 (2H, m) .
Reference Example 12
Synthesis of 1-benzo [b] thiophen-4-yl-3-methylpiperazine dihydrochloride
The title compound was obtained as with Reference Example 9 by using 2-methylpiperazine and 4- bromobenzo [b] thiophene as the material compounds. 1H-NMR (DMSO-de) δ ppm: 1.34 (3H, d, J = 6.5 Hz), 2.85- 2.95 (IH, m) , 3.05-3.15 (IH, m) , 3.2-3.6 (6H, m) , 6.97 (IH, d, J = 7.5 Hz), 7.31 (IH, dd, J = 8 Hz, J = 8 Hz), 7.54 (IH, d, J = 5.5 Hz), 7.69 (IH, d, J = 8 Hz), 7.75 (IH, d, J = 5.5 Hz), 9.2-9.3 (IH, ra) , 9.64 (IH, br) „
Reference Example 13
Synthesis of 1- (4-chlorobutyl) -2-pyrrolidone
Sodium hydroxide (60% oil) (2.47 g, 61.8 mmol) was added under ice cooling to a dimethylformamide solution (50 ml) of 2-pyrrolidone (5.0 g, 58.7 mmol), and the resultant mixture was stirred at the same temperature for one hour. This reaction product was further stirred at room temperature for one hour. l-bromo-4-chlorobutane (13.5 ml, 117.3 mmol) was added thereto and the resultant mixture was stirred at 8O0C for 2 hours.
This reaction solution was cooled to room temperature, water was added thereto, and the resultant mixture was extracted with ethyl acetate. An organic layer thus obtained was washed with water, dried with anhydrous sodium sulfate and concentrated under a reduced pressure. A residue thus obtained was purified with silica gel column chromatography (n-hexane: ethyl acetate = 1:1 to ethyl acetate) . The purified product was concentrated under a reduced pressure to obtain a pale yellow oily 1- (4-chlorobutyl) -2-pyrrolidone (3.88 1H-NMR (CDCl3) δ ppm: 1.65-1.90 (4H, m) , 2.00-2.10 (2H, m) , 2.39 (2H, t, J = 8.3 Hz), 3.32 (2H, t, J = 7.1 Hz), 3.39 (2H, t,. J = 7.1 Hz), 3.58 (2H, t, J = 6.4 Hz). Compounds of Reference Examples 14 to 40 were synthesized as with Reference Examples 9 to 13 by using relevant material compounds .
Figure imgf000141_0001
Figure imgf000142_0001
[Table 5]
Figure imgf000143_0001
Figure imgf000143_0002
Example 1
Synthesis of N- [4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) butyl] -N-ethyl-acetamide hydrochloride 0.10 ml (1.06 mmol) of acetic anhydride was added to a dichloromethane solution (10 ml) of 270 mg (0.85 mmol) of N- [4- (4-benzo [b] thiophen-4-yl-piρerazin- 1-yl) butyl] ethyl-amine and 0.15 ml (1.08 mmol) of triethylamine. This mixture was stirred at room temperature for one hour. Water was added to this reaction solution, and the resultant mixture was extracted with dichloromethane. The extract was dried with anhydrous sodium sulfate and concentrated under a reduced pressure. A residue thus obtained was purified with silica gel column chromatography (dichloromethane: methanol = 30:1 to 9:1). The purified product was concentrated under a reduced pressure. A residue thus obtained was dissolved in 2 ml of ethanol, and 0.85 ml of 1 N HCl ethanol solution was added thereto. Precipitated crystals were filtered out and dried to obtain 240 mg (yield: 71%) of a white powder of N- [4- (4-benzo [b] thiophen-4-yl-piperazin-l-yl) butyl] -N-ethyl- acetamide hydrochloride. Melting Point 198 to 200°C
Example 2
Synthesis of N- [4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) butyl]benzamide hydrochloride
0.15 ml (1.3 mmol) of benzoyl chloride was added under ice cooling to a dichloromethane solution (5 ml) of 220 mg (0.76 mmol) of 4- (4-benzo [b] thiophen- 4-yl-piperazin-l-yl) butylamine and 0.15 ml (1.9 mmol) of pyridine, and the resultant mixture was stirred at the same temperature for two hours . Water was added to this reaction solution. The reaction solution was extracted with dichloromethane, and washed with an aqueous, solution of sodium hydrogen carbonate. The washed extract was dried with anhydrous sodium sulfate and concentrated under a reduced pressure. A residue thus obtained was purified with silica gel column chromatography (dichloromethane: methanol = 30:1). The purified product was concentrated under . a reduced pressure. A residue thus obtained was dissolved in 2 ml of ethanol, and 0.8 ml of 1 N HCl ethanol solution was added thereto. Precipitated crystals were filtered out and dried to obtain 230 mg (yield: 70%) of a white powder of N- [4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) butyl] -benzamide hydrochloride. Melting Point 209 to 21O0C
Example 3
Synthesis of 3-acetylamino-N- [4- (4-benzo [b] thiophen-4- yl-piperazin-1-yl) butyl] -benzamide 0.15 ml (1.06 itimol) of triethylamine and.0.1 ml (0.67 mmol) of diethyl phosphorocyanidate (DEPC) were added to a DMF solution (3 ml) of 150 mg (0.52 mmol) of 4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl)butylamine and 110 mg (0.61 mmol) of 3- acetamidebenzoic acid. This mixture was stirred at room temperature for 1.5 hours. Water was added to this reaction solution. A reaction product was extracted with ethyl acetate, and washed with water. The washed product was dried with anhydrous sodium sulfate and concentrated under a reduced pressure. A residue, thus obtained was purified with basic silica gel column chromatography (dichloromethane: methanol = 30:1). The purified product was concentrated under a reduced pressure. A residue thus obtained was recrystallized from ethanol-hexane to obtain 170 mg (yield: 73%) of yellow needle crystals of 3- acetylamino-N- [4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) butyl]benzamide . Melting Point 178 to 180 Ϊ£°C
Example 4
Synthesis of N- [4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) butyl] -N-propyl-acetaitiide hydrochloride
1 ml of methyl ortho-formate and 73 mg (1.3 mmol) of propionaldehyde were added under ice cooling to a methanol solution (7 ml) of 246 mg (0.85 mmol) of 4- (4-benzo [b] thiophen-4-yl-piperazin-l-yl) butylamine. This mixture was stirred at the same temperature for 5 minutes. 0.4 g (1.3 mmol) of MP-borohydride (3.18 mmol/g) was added to thus obtained solution, and this mixture was stirred at room temperature for one hour. A resin was filtered off and a filtrate was concentrated under a reduced pressure. A residue thus obtained was dissolved in 7 ml of dichloromethane. 0.12 ml (1.3 mmol) of acetic anhydride was added thereto, and the resultant mixture was stirred at room temperature for one hour. This reaction mixture was concentrated under a reduced pressure, and a residue thus obtained was purified with basic silica gel column chromatography (hexane: ethyl acetate = 2:1). The purified product was concentrated under a reduced pressure. A residue thus obtained was dissolved in 2 ml of ethanol. 0.3 ml of 1 N HCl ethanol solution was added to thus obtained solution. Precipitated crystals were filtered out and dried to obtain 83 mg (yield: 24%) of a white powder of N- [4- (4-benzo [b] thiophen-4- yl-piperazin-1-yl) butyl] -N-propyl-acetamide hydrochloride . Melting Point 198 to 2000C Example 5
Synthesis of N- [4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl)butyl] -N-methyl-acetamide hydrochloride
50 mg (1.04 mmol) of lithium aluminum hydride was added to a THF solution (15 ml) of 166 mg (0.52 mmol) of N- [4- (4-benzo [b] thiophen-4-yl-piperazin-l÷- yl) butyl] -formamide. This mixture was stirred with being heated to reflux for 2 hours. This reaction solution was cooled to room temperature. Small amounts of water, methanol, and Celite were added thereto, and this mixture was stirred for 5 minutes. This mixture waιs filtered with Celite and a filtrate thus obtained was concentrated under a reduced pressure. A residue thus obtained was dissolved in 15 ml of dichloromethane. 0.074 ml (0.78 mmol) of acetic anhydride was added thereto, and this mixture was stirred at room temperature for one hour. Water was added to this reaction solution, and a reaction product was extracted with dichloromethane. An organic layer thus obtained was dried with anhydrous sodium sulfate. The dried product was concentrated under a reduced pressure. A residue thus obtained was purified with. basic silica gel column chromatography (hexane: ethyl acetate = 1:2). The purified product was concentrated under a reduced pressure. A residue thus obtained was dissolved in 1 ml of ethanol, and 0.2 ml of 1 N HCl ethanol solution was added thereto. Ether was added to thus obtained solution, and left to precipitate crystals. The crystals were filtered out and dried to obtain 58 mg (yield: 29%) of a white powder of N- [4- (4- benzo [b] thiophen-4-yl-piperazin-l-yl) butyl] -N-methyl- acetamide hydrochloride. Melting Point 216 to 217°C
Example 6
Synthesis of N- [4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl ) butyl] -N-phenyl-acetamide hydrochloride
288 mg (1.13 mmol) of 4-benzo [b] thiophen-4- yl-piperazine hydrochloride and 468 mg (3.4 mmol) of potassium carbonate were added to a DMF solution of 367 mg (1.35 mmol) of N- (4-bromobutyl) -N-phenyl-acetamide. This mixture was stirred at 80°C for 3 hours. A reaction solution thus obtained was cooled to room temperature. Water was added thereto, and a reaction product, was extracted with ethyl acetate. An organic layer thus obtained was washed with water, and dried with anhydrous sodium sulfate. The dried organic layer was concentrated under a reduced pressure. A residue thus obtained was purified with basic silica gel column chromatography (hexane: ethyl. acetate =.1:1). The purified product was concentrated under a reduced pressure. A residue thus obtained was dissolved in 5 ml of ethanol, and 1.05 ml of 1 N HCl ethanol solution was added thereto. Precipitated crystals were filtered out and dried to obtain 153 mg (yield: 31%) of a white powder of N- [4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) butyl] -N-phenyl-acetamide hydrochloride. Melting Point 216.5 to 2i8.0°C
Example 7
Synthesis of N- [4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) butyl] - (R) -pyrrolidine-2-carboxamide
10 ml of 4 N HCl ethyl acetate solution was add to a methanol solution (5 ml) of 2.01 g (4.13 mmol) of N- [4- (4-benzo [b] thiophen-4-yl-piperazin-l-yl) butyl] - (R) -1- (tert-butoxycarbonyl) pyrrolidine-2-carboxamide. This mixture was stirred at room temperature for 17 hours. Water and a saturated aqueous solution of sodium hydrogen carbonate were added to this reaction solution, rendering the solution basic. A product was extracted with dichloromethane. An organic layer thus obtained was dried with anhydrous sodium sulfate and concentrated under a reduced pressure to obtain 1.56 g (yield: 98%) of brown oily N- [4- (4-benzo [b] thiophen-4- yl-piperazin-1-yl) butyl] - (R) -pyrrolidine-2-carboxamide. 1H-NMR (DMSO-d6) δ ppm: 1.45-1.63 (4H, m) , 1.63-1.80 (2H, m) , 1.84-1.94 (IH, m) , 2.02-2.26 (IH, m) , 2.37-2.56 (2H, m), 2.59-2.79 (4H, m) , 2.84-3.06 (2H, m) , 3.09-3.23 (4H, m), 3.23-3.37 (2H, m) , 3.72 (IH, dd, J = 5.3, 9.0 Hz), 6.90 (IH, d, J = 7.7 Hz), 7.27 (IH, t, J = 7.8 Hz), 7.33-7.44 (2H, m) , 7.55 (IH, d, J = 8.0) 7.59-7.81 (IH, brs) . Example 8
Synthesis of N- [4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) butyl] - (R) -1- (2-acetylaminoacetyl) pyrrolidine-2- carboxamide 104 mg of N-acetylglycine, 214 mg (1.11 mmol) of 1- (3-dimethylaminoproρyl) -3-ethylcarbodiimide hydrochloride (WSC) and 170 mg (1.11 mmol) of 1- hydroxybenzotriazole (HOBT) were added to a dichloromethane solution (7 ml) of 288 mg (0.745 mmol) of N- [4- (4-benzo [b] thiophen-4-yl-piperazin-l-yl) butyl] - (R) -pyrrolidine-2-carboxamide. This mixture was stirred at room temperature for 18 hours. Water and a saturated aqueous solution of sodium hydrogen carbonate were added to this reaction solution, rendering the solution basic. A product was extracted with dichloromethane. An organic layer thus obtained was dried with anhydrous sodium sulfate and concentrated under a reduced pressure. A residue thus obtained was purified with basic silica gel column chromatography (ethyl acetate: methanol = 20:1). The purified product was concentrated under a reduced pressure. A residue thus obtained was recrystallized from ethyl acetate to obtain 104 mg (yield: 29%) of N- [4- (4-benzo [b] thiophen- 4-yl-piperazin-l-yl) butyl] - (R) -1- (2- acetylaminoacetyl)pyrrolidine-2-carboxamide. Melting Point 125.5 to 126.5°C Example 9
Synthesis of N- [4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) butyl] -N-ethyl-thioacetamide hydrochloride
3.01 g (7.44 mmol) of Lawesson's Reagent was added to a THF solution (70 ml) of 2.23 g (6.2 mmol) of N- [4- (4-benzo [b] thiophen-4-yl-piperazin-l-yl) butyl] -N- ethyl-th'ioacetamide. This mixture was stirred with being heated to reflux for 3 hours. Thus obtained reaction solution was cooled to room temperature and purified with basic silica gel column chromatography. The purified product was concentrated under a reduced pressure. A residue thus obtained was dissolved in 30 ml of ethanol, and 4.6 ml of 1 N HCl solution in ethanol was added thereto. 15 ml of ether was added to thus obtained solution, and left to precipitate crystals. The crystals were filtered out and dried to obtain 1.47 g (yield: 58%) of N- [4- (4-benzo [b] thiophen- 4-yl-piperazin-l-yl) butyl] -N-ethyl-thioacetamide hydrochloride. Melting Point 224.0 to 225.5°C
Example 10
Synthesis of N- [4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) butyl] -N-isopropyl-thioacetamide hydrochloride
The title compound was synthesized as with Example 9 by using N- [4- (4-benzo [b] thiophen-4-yl- piperazin-1-yl) butyl] -N-isopropyl-acetamide as the starting material. White Powder Melting 'Point 217.5 to 223.5°C
Example 11
Synthesis of 1- [4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) butyl] ethyl-3, 3-dimethylurea hydrochloride
0.2 g (1.9 mmol) of N, N-dimethylcarbamoyl chloride was added to a dichloromethane solution (20 ml) of 0.5 g (1.6 mmol) of N- [4- (4-benzo [b] thiophen-4- yl-piperazin-1-yl) butyl] -ethylamine and 0.33 ml (2.4 mmol) of triethylamine. This mixture was stirred at room temperature for 3 days. Water was added to this reaction solution, and a reaction product was extracted with ethyl acetate. An organic layer thus obtained was washed with water, and dried with anhydrous sodium sulfate. The dried product was concentrated under a reduced pressure. A residue thus obtained was purified with silica gel column chromatography (dichloromethane: methanol = 15:1). The purified product was concentrated under a reduced pressure. A residue thus obtained was dissolved in methanol, and 2.5 ml of 0.5 N HCl solution in methanol was added thereto. Precipitated crystals were filtered out and dried to obtain 0.44 g (yield: 66%) of a white powder of l-[4- (4-benzo [b] thiophen-4-yl-piperazin-l-yl) butyl] ethyl- 3, 3-dimethylurea hydrochloride. Melting Point 184 to 186°C Example 12
Synthesis of 1- [2- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) ethyl] -3-ethylurea hydrochloride
0.125 ml (1.58 mmol) of ethylisocyanate was added to a dichloromethane solution (7 ml) of 319 mg (1.22 mmol) of 2- (4-benzo [b] thiophen-4-yl-piperazin^-l- yl) ethylamine. This mixture was stirred at room temperature for one hour. This reaction solution was concentrated under a reduced pressure. A residue thus obtained was purified with basic silica gel column chromatography (ethyl acetate) . The purified product was concentrated under a reduced pressure. A residue thus obtained was dissolved in ethanol, and 0.7 ml of 1 N HCl solution in ethanol was added thereto. This solution was left in a refrigerator overnight to precipitate crystals. The crystals were filtered out and dried to obtain 126 mg (yield: 28%) of a white powder of 1- [2- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) ethyl] -3-ethylurea hydrochloride . Melting Point 190.5 to 191.5°C
Examples 13 to 1448
Compounds of Examples 13 to 1448 and 1548 to 1585 shown in the following Tables 1 to 89 and 108 to 112 can be prepared in the same manners as in Examples 1-12, using corresponding starting materials. In the following Tables, compounds with the physical properties, such as crystalline form, m.p. (melting point), salt, 1H-NMR and MS (mass spectrum), were prepared actually.
[Table 6]
Figure imgf000155_0001
Figure imgf000155_0002
*NMR data of Example 14
1H-NMR (DMSO-d6) δpprn: 1.50-1.70 (2H, m) , 1.70-1.90 (2H, m) , 3.10-3.50 (8H, in), 3.50-3.65 (4H, m) , 6.96 (IH, d, J=7.5 Hz), 7.31 (IH, t, J=7.9Hz), 7.48 (IH, d, J=5.6 Hz), 7.69 (IH, d, J=8.1 Hz), 7.76 (IH, d, J=5.5 Hz), 8.09 (2H, dd, J=2.0, 6.9 Hz), 8.32. (2H, dd, J=2.0, 6.9 Hz), 8.9 (IH, m) , 10.2 (IH, br) . [Table 7]
Figure imgf000156_0001
Figure imgf000156_0002
*NMR data of Example 28
1H-NMR (DMS0-d6) δppm: 0.90-1.10 (3H, br) , 1.40-1.70 (4H, br), 2.03 (3H, s) , 3.00-3.70 (14H, m) , 6.9 (IH, br) , 7.28 (2H, d, J=8.3 Hz), 7.4 (2H, br) , 7.61 (2H, d, J=8.6 Hz), 7.7 (2H, br) , 10.06 (IH, brs) .
*NMR data of Example 29
1H-NMR (DMS0-d6) δppm: 1.00-1.20 (3H, br) , 1.50-1.70 (4H, br), 2.03 (3H, s), 2.50-3.60 (14H, m) , 6.80-7.00 (2H, m), 7.10-7.80 (7H, m) , 10.03 (IH, brs). [Table 8]
Figure imgf000157_0001
Figure imgf000157_0002
[Table 9]
Figure imgf000158_0001
Figure imgf000158_0002
[Table 10]
Figure imgf000159_0001
Figure imgf000159_0002
[Table 11]
Figure imgf000160_0001
Figure imgf000160_0002
[Table 12]
Figure imgf000161_0001
Figure imgf000161_0002
[Table 13]
Figure imgf000162_0001
Figure imgf000162_0002
*NMR data of Example 114
1H-NMR (DMSO-de) δppm: 1.00-1.20 (3H, m) , 1.50-1.80 (4H, m) , 3.00-3.70 (14H, m) , 6.97 (IH, d, J=7.5 Hz), 7.25- 7.40 (3H, m) , 7.48 (IH, t, J=5.9Hz), 7.69 (IH, d, J=8.0 Hz), 7.75 (IH, d, J=5.6 Hz), 8.66 (2H, d, J=5.9 Hz), 10.3 (IH, br) .
*NMR data of Example 116
1H-NMR (DMSO-d6) δppra: 1.19 (3H, t, J=6.9 Hz ), 1.60- 1.75 (4H, m), 3.10-3.60 (14H, m) , 6.97 (IH, d, J=7.4 Hz), 7.13 (IH, dd, J=3.7, 5.0 Hz), 7.30-7.35 (IH, m) , 7.40-7.45 (IH, m) , 7.45-7.50 (IH, m) , 7.65-7.80 (3H, m) , 10.3 (IH, br) .
*NMR data of Example 117
1H-NMR (DMSO-de) δppm: 1.12 (3H, t, J=7.1 Hz ), 1.55- 1.75 (4H, m) , 3.00-3.60 (14H, m) , 6.66 (IH, dd, J=O.6, 1.7 Hz), 6.96 (IH, d, J=7.7 Hz), 7.30 (IH, t, J=7.9 Hz), 7.45-7.50 (IH, m) , 7.65-7.80 (3H, m) , 8.01 (IH, s) , 10.32 (IH, brs) .
*NMR data of Example 119
1H-NMR (DMSO-de) δppm: 1.02,1.09 (total 3H, t, J=7.0 Hz ), 1.50-1.80 (4H, m) , 3.10-3.60 (17H, m) , 4.06 (2H, s), 6.95 (IH, d, J=7.5 Hz), 7.30 (IH, t, J=7.8 Hz), 7.47 (IH, d, J=5.6 Hz), 7.69 (IH, d, J=8.0 Hz), 7.75 (IH, d, J=5.5 Hz), 10.5 (IH, br) . [Table 14]
Figure imgf000164_0001
Figure imgf000164_0003
[Table 15]
Figure imgf000164_0002
Figure imgf000164_0004
[Table 16]
Figure imgf000165_0001
*NMR data of Example 138
1H-NMR (DMSO-d6) δppm: 1.78-1.80 (2H, m) , 1.84 (3H, s) , 1.86-2.10 (4H, m) , 2.80-3.01 (2H, m) , 3.13-3.30 (15H, m) , 3.91 (2H, m) , 4.20 (3.H, dd, J=8.1, 3.5 Hz), 6.95 (IH, d, J=I. β Hz), 7.31 (IH, t, J=7.8 Hz), 7.46-7.50 (IH, m) , 7.68 (IH, d, J=8.0 Hz), 7.75 (IH, d, J=5.5 Hz), 7.98-8.07 (2H, m) .
[Table 17]
Figure imgf000167_0001
Figure imgf000167_0002
*NMR data of Example 150'
1H-NMR (DMSO-Cl6) δppra: 1.03,1.12 (total 3H, t, J=7.1 Hz ), 1.50-1.80 (4H, m) , 3.00-3.60 (14H, m) , 3.91 (2H, s), 6.90-7.00 (IH, m), 7.20-7.50 (4H, m) , 7.69 (IH, d, J=8.0 Hz), 7.76 (IH, d, J=5.6 Hz), 7.8 (IH, br) , 8.52 (IH, brs), 10.2 (IH, br) .
*NMR data of Example 155
1H-NMR (DMSO-d6) δppm: 1.10-1.20 (3H, m) , 1.40-1.80 (8H, m), 2.80-3.50 (14H, m) , 3.50-3.60 (4H, m) , 4.30-4.60 (IH, m) , 6.95 (IH, d, J=7.6 Hz), 7.25-7.45 (6H, m) , 7.47 (IH, d, J=5.6 Hz), 7.69 (IH, d, J=8.0 Hz), 7.75 (IH, d, J=5.5 Hz), 10.2 (IH, br) .
[Table 18]
Figure imgf000169_0001
[Table 19]
Figure imgf000170_0001
[Table 20]
Figure imgf000171_0001
Figure imgf000171_0002
[Table 21]
Figure imgf000172_0001
Figure imgf000172_0002
[Table 22]
Figure imgf000173_0001
Figure imgf000173_0002
[Table 23]
Figure imgf000174_0001
Figure imgf000174_0002
[Table 24]
Figure imgf000175_0001
Figure imgf000175_0002
[Table 25]
Figure imgf000176_0001
Figure imgf000176_0002
[Table 26]
Figure imgf000177_0001
Figure imgf000177_0002
[Table 27]
Figure imgf000178_0001
[Table 28]
Figure imgf000179_0001
Figure imgf000179_0002
[Table 29]
Figure imgf000180_0001
Figure imgf000180_0002
[Table 30]
Figure imgf000181_0001
Figure imgf000181_0002
[Table 31]
Figure imgf000182_0001
Figure imgf000182_0002
[Table 32]
Figure imgf000183_0001
Figure imgf000183_0002
[Table 33]
Figure imgf000184_0001
Figure imgf000184_0002
[Table 34]
Figure imgf000185_0001
[Table 35]
Figure imgf000186_0001
[Table 36]
Figure imgf000187_0001
Figure imgf000187_0002
[Table 37]
Figure imgf000188_0001
Figure imgf000188_0002
[Table 38]
Figure imgf000189_0001
Figure imgf000189_0002
[Table 39]
Figure imgf000190_0001
Figure imgf000190_0002
[Table 40]
Figure imgf000191_0001
[Table 41]
Figure imgf000192_0001
[Table 42]
Figure imgf000193_0001
Figure imgf000193_0002
[Table 43]
Figure imgf000194_0001
[Table 44]
Figure imgf000195_0001
Figure imgf000195_0002
[Table 45]
Figure imgf000196_0001
Figure imgf000196_0002
[Table 46]
Figure imgf000197_0001
[Table 47]
Figure imgf000198_0001
Figure imgf000198_0002
[Table 48]
Figure imgf000199_0001
[Table 49]
Figure imgf000200_0001
[Table 50]
Figure imgf000201_0001
Figure imgf000201_0002
[Table 51]
Figure imgf000202_0001
Figure imgf000202_0002
[Table 52]
Figure imgf000203_0001
[Table 53]
Figure imgf000204_0001
[Table 54]
Figure imgf000205_0001
Figure imgf000205_0002
[Table 55]
Figure imgf000206_0001
Figure imgf000206_0002
[Table 56]
Figure imgf000207_0001
Figure imgf000207_0002
Figure imgf000208_0001
Figure imgf000208_0002
[Table 58]
Figure imgf000209_0001
[Table 59]
Figure imgf000210_0001
[Table 60]
Figure imgf000211_0001
[Table 61]
Figure imgf000212_0001
Figure imgf000212_0002
[Table 62]
Figure imgf000213_0001
Figure imgf000213_0002
[Table 63]
Figure imgf000214_0001
Figure imgf000214_0002
[Table 64]
Figure imgf000215_0002
Figure imgf000216_0001
[Table 66]
Figure imgf000217_0001
Figure imgf000217_0002
[Table 67]
Figure imgf000218_0001
Figure imgf000218_0002
[Table 68]
Figure imgf000219_0001
Figure imgf000219_0002
[Table 69]
Figure imgf000220_0001
Figure imgf000220_0002
[Table 70]
Figure imgf000221_0001
[Table 71]
Figure imgf000222_0001
Figure imgf000222_0002
[Table 72]
Figure imgf000223_0001
[Table 73]
Figure imgf000224_0001
[Table 74]
Figure imgf000225_0001
[Table 75]
Figure imgf000226_0001
[Table 76]
Figure imgf000227_0001
[Table 77]
Figure imgf000228_0001
[Table 78]
Figure imgf000229_0001
Figure imgf000229_0002
[Table 79.]
Figure imgf000230_0001
[Table 80]
Figure imgf000231_0001
Figure imgf000231_0002
[Table 81]
Figure imgf000232_0001
[Table 82]
Figure imgf000233_0001
[Table 83]
Figure imgf000234_0001
[Table 84]
Figure imgf000235_0001
[Table 85]
Figure imgf000236_0001
Figure imgf000236_0002
[Table 86]
Figure imgf000237_0001
[Table 87]
Figure imgf000238_0001
[Table 88]
Figure imgf000239_0001
[Table 89]
Figure imgf000240_0001
[Table 90]
Figure imgf000241_0001
Figure imgf000241_0002
[Table 91]
Figure imgf000242_0001
[Table 92]
Figure imgf000243_0001
[Table 93]
Figure imgf000244_0001
Figure imgf000244_0002
*NMR data of Example 1435
1H-NMR (DMSO-Cl6) δppm: 1.07 (6H, t, d=7.0 Hz), 1.11 (3H, t, J=7.0 Hz), 3.12-3.21 (8H, m) , 3.28-3.41 (2H, m) , 3.47-3.49 (2H, m) , 3.54-3.57 (2H, m) , 3.63-3.66 (2H, m) , 6.98 (IH, d, J=7.6 Hz), 7.32 (IH, d, J=7.8 Hz), 7.48 (IH, d, d=5.5 Hz), 7.70 (IH, d, d=8.0 Hz), 7.77 (IH/ d, d=5.4 Hz) .
*NMR data of Example 1441
1H-NMR (DMSO-de) δppm: 1.00-1.10 (9H, m) , 1.27-1.29 (2H, m) , 1.48-1.50 (2H, m) , 1.70-1.75 (2H, m) , 3.04-3.20 (8H, m)', 3.20-3.25 (4H, m) , 3.30-3.34 (2H, m) , 3.50-3.60 (4H, m) , 6.97 (IH, d, J=8.1 Hz), 7.32 (IH, t, J=6.6 Hz),7.48-7.49 (IH, m) , 7.70 (IH, d, J=7.1 Hz), 7.74-7.80 (IH, in) , 10.36 (IH, brs) .
[Table 94]
Figure imgf000246_0001
Figure imgf000246_0002
Example 1449
Synthesis of 1— [4— (4-benzo[b] thiophen-4-yl-piperazin-l- yl) butyl] -2-pyrrolidone dihydrochloride l-(4-chlorobutyl)-2-pyrrolidone (150 mg, 0.85 mmol) , l-benzo[b] thiophen-4-yl-piperazine hydrochloride (240 mg, 0.94 mmol), potassium carbonate (290 mg, 2.10 mmol) and sodium iodide (170 mgf 1.13 mmol) were added to dimethyl formamide (DMF) (3 ml) , and the resultant mixture was stirred at 800C for 6 hours. This reaction solution was cooled to room temperature, water was added thereto, and the resultant mixture was extracted with ethyl acetate. An organic layer thus obtained was washed with water, and dried with anhydrous sodium sulfate. The dried organic layer was concentrated under a reduced pressure. A residue thus obtained was purified with silica gel column chromatography (dichloromethane: methanol = 30:1 to 15:1). The purified product was concentrated under a reduced pressure. A residue thus obtained was dissolved in ethanol (2 ml) , and concentrated hydrochloric acid (0.15 ml) was added thereto. Thus obtained solution was concentrated under a reduced pressure. A residue thus obtained was recrystallized from ethanol-ethyl acetate to obtain a pale brown powder of l-[4-(4- benzo [b] thiophen-4-yl-piperazin-l-yl) butyl] -2- pyrrolidone dihydrochloride (220 mg) . Melting Point: 183.0 to 185.00C Compounds of Examples 1462 to 1480, 1483,
1486 to 1490, 1493 to 1513, 1515 to 1518, 1520, 1522 to 1544 and 1586 to 1593 were synthesized as with Example 1449 by using relevant material compounds.
Example 1450 Synthesis of 4- [4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) butyl] -6-methoxy-3, 4-dihydro-2H-benzo [1,4] oxazine hydrochloride Lithium aluminum hydroxide (34 mg, 0.90 imtiol) was suspended in tetrahydrofuran (THF) (2 ml) , and a THF solution (5 ml) of 4- [4- (4-benzo [b] thiophen-4-yl- piperazin-1-yl) butyl] -6-methoxy-4H-benzo [1, 4] oxazin-3- one (0.34 g, 0.75 πtmol) was added dropwise thereto. This reaction solution was heated to reflux for one hour, and then cooled to room temperature. To this reaction solution cooled in ice were added in this order water (50 μl) , a 15% aqueous solution of sodium hydroxide (50 μl) , and water (150 μl) , and the resultant mixture was stirred at room temperature for 30' minutes. Thus obtained solution was filtered to remove insoluble matters, and the filtrate was concentrated under a reduced pressure. A residue thus obtained was purified with silica gel column chromatography (n-hexane: ethyl acetate = 5:1 to 2:1). The purified product was concentrated under a reduced pressure. A residue thus obtained was dissolved in ethyl acetate (5 ml), and 1 N HCl ethanol (0.11 ml) was added thereto. Thus generated insoluble matters were filtered out and dried to obtain a white powder of 4- [4- (4-benzo [b] thiophen-4-yl-piperazin-l-yl) butyl] -6- methoxy-3,4-dihydro-2H-benzo[l, 4] oxazine hydrochloride (39 mg) . Melting Point: 218.7 to 219.8°C
Example 1451
Synthesis of 3- [4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) butyl] -6-hydroxy-3H-quinazolin-4-one 1.5 hydrotaromide
3- [4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) butyl] -6-hydroxy-3H-quinazolin-4-one (0.41 g, 0.91 mmol) was dissolved in dichloromethane (15 ml) , and 2 M boron tribromide solution in dichloromethane (1.37 ml, 2.74 mmol) was added dropwise thereto. Thus obtained reaction solution was stirred at room temperature for 2 days, and water was added thereto and the resultant mixture was stirred for 30 minutes. A purified insoluble matters were filtered out, and the filtered matters were purified with silica gel column chromatography (dichloromethane: methanol = 20:1 to 10:1) . The purified product was concentrated and exsiccated under a reduced pressure to obtain a white powder of 3- [4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) butyl] -6-hydroxy-3H-quinazolin-4-one 1.5 hydrobromide (0.16 g) . Melting Point: 249.0 to 250.20C
Example 1452
Synthesis of 2- [4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) butyl] octahydroisoindol-1-one hydrochloride
0.2 g of 10% palladium carbon was added to an ethanol solution of 2- [4- (4-benzo [b] thiophen-4-yl- piperazin-1-yl) butyl] -2,3, 3a, 4, 7, 7a-hexahydroisoindol- 1-one (0.10 g, 0.24 mmol), and the resultant mixture was stirred at room temperature for 16 hours in a hydrogen atmosphere. This reaction solution was filtered with Celite, and a filtrate was concentrated under a reduced pressure. A residue thus obtained was dissolved in ethyl acetate (5 ml) , and 1 N hydrochloric acid ethanol (0.24 ml) was added thereto. Thus generated insoluble matters were filtered out and dried to obtain a white powder of 2- [4- (4-benzo [b] thiophen-4- yl-piperazin-1-yl) butyl] octahydroisoindol-1-one hydrochloride (50 mg) . Melting Point: 219.7 to 221.00C
Example 1453
Synthesis of 1- [4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) butyl] -3- (4-iodobutyl) pyrrolidin-2-one hydrochloride
A THF solution of 1- [4- (4-benzo [b] thiophen-4- yl-piperazin-1-yl) butyl] pyrrolidin-2-one (500 mg, 1.40 mmol) and 1, 4-diiodobutane (0.35 ml, 2.65 mmol) were cooled in ice and a THF solution of 1.1 M lithium hexamethyl disilazide (3.2 ml, 3.52 mmol) was added dropwise thereto under a nitrogen atmosphere. This solution was stirred at room temperature for 20 hours. An aqueous solution of ammonium chloride was added to this reaction solution, and the resultant mixture was extracted with ethyl acetate. An organic layer thus obtained was dried with anhydrous sodium sulfate and concentrated under a reduced pressure. A residue thus obtained was purified with silica gel column chromatography (n-hexane: ethyl acetate = 2:1) . The purified product was concentrated under a reduced pressure. A residue thus obtained was dissolved in ethanol (2 ml) , and concentrated hydrophloric acid (0.15 ml) was added thereto. Thus obtained solution was concentrated under a reduced pressure. A residue thus obtained was recrystallized from ethanol-ethyl acetate to obtain a pale yellow powder of l-[4-(4- benzo [b] thiophen-4-yl-piperazin-l-yl) butyl] -3- (4- iodobutyl)pyrrolidin-2-one hydrochloride (170 mg) . Melting Point: 118.0 to 120.00C
Example 1454
Synthesis of 2- [4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) butyl] -2-azaspiro [4,4] nonan-1-one dihydrochloride
A THF solution of 1- [4- (4-benzo [b] thiophen-4- yl-piperazin-1-yl) butyl] pyrrolidin-2-one (500 mg, 1.40 mmol) and 1, 4-diiodobutane (0.35 ml, 2.65 mmol) were cooled in an ice-methanol bath, and a THF solution of 1.1 M lithium hexamethyl disilazide (1.9 ml, 2.09 mmol) was added dropwise thereto under a nitrogen atmosphere. Thus obtained reaction solution was stirred at room temperature for 22 hours. This reaction solution was cooled in an ice-methanol bath, and a THF solution of 1.1 M lithium hexamethyl disilazide (1.9 ml, 2.09 mmol) was added dropwise thereto, and the resultant mixture was stirred at room temperature for 19 hours. An aqueous solution of ammonium chloride was added to this reaction solution, and the resultant mixture was extracted with ethyl acetate. An organic layer thus obtained was dried with anhydrous sodium sulfate and concentrated under a reduced pressure. A residue thus obtained was purified with silica gel column chromatography (n-hexane: ethyl acetate = 4:1). The purified product was concentrated under a reduced pressure. A residue thus obtained was dissolved in ethanol (2 ml), and 1 N hydrochloric acid ethanol (0.19 ml) was added thereto. Thus generated insoluble matters were filtered out and dried to obtain a white powder of 2- [4- (4-benzo[b] thiophen-4-yl-piperazin-l- yl) butyl] -2-azaspiro [4,4] nonan-1-one dihydrochloride (20 mg) . Melting Point: 217.0 to 219.00C
Example 1455
Synthesis of 1- [4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) butyl] piperazin-2-one dihydrochloride
Trifluoroacetic acid (1.0 ml, 13 mmol) was added to a dichloromethane solution (10 ml) of tert- butyl 4- [4- ( 4-benzo [b] thiophen-4-yl-piperazin-l- yl) butyl] -3-oxo-piperazine-l-carboxylate (280 mg, 0.59 mmol) , and the resultant mixture was stirred at room temperature for 14 hours. An aqueous solution of sodium hydrogen carbonate was added to this reaction solution, thereby rendering the solution basic. The solution was extracted with dichloromethane. An organic layer thus obtained was washed with an aqueous solution of sodium hydrogen carbonate, dried with anhydrous sodium sulfate, and concentrated under a reduced pressure. A residue thus obtained was purified with basic silica gel column chromatography (dichloromethane: methanol = 30:1). The purified product was concentrated under a reduced pressure. A residue thus obtained was dissolved in ethanol (2 ml) , and 1 N hydrochloric acid ethanol (1.2 ml) was added thereto. Thus generated insoluble matters were filtered out and dried to obtain a' white powder of 1- [4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) butyl]piperazin-2-one dihydrochloride (210 mg) . Melting Point: 258.0 to 260.00C
Example 1456 Synthesis of 4-acetyl-l- [4- (4-benzo [b] thiophen-4-yl- piperazin-1-yl) butyl] piperazin-2-one hydrochloride
Triethylamine (0.15 ml, 1.08 mmol) was added to a dichloromethane solution (5 ml) of l-[4-(4- benzo [b] thiophen-4-yl-piperazin-l-yl) butyl] piperazin-2- one (260 mg, 0.70 mmol). Under ice cooling, acetic anhydride (0.1 ml, 1.06 mmol) was added- thereto and the resultant mixture was stirred at room temperature for 2 hours. Water was added to this reaction solution, and the resultant mixture was stirred for 30 minutes. An aqueous solution of sodium hydrogen carbonate was added thereto, and the resultant mixture was extracted with dichloromethane. An organic layer thus obtained was washed with an aqueous solution of sodium hydrogen carbonate, dried with anhydrous sodium sulfate, and concentrated under a reduced pressure. A residue thus obtained was purified with basic silica gel column chromatography (dichloromethane: ethyl acetate = 1:1). The purified product was concentrated under a reduced pressure. A residue thus obtained was dissolved in ethanol (2 ml), and 1 N hydrochloric acid ethanol (0.6 ml) was added thereto. Thus generated insoluble matters were filtered out and dried to obtain a white powder of 4-acetyl-l- [4- (4-benzo [b] thiophen-4-yl- piperazin-1-yl) butyl]piperazin-2-one hydrochloride (220 mg) . Melting Point: 215.0 to 217.00C
Example 1457
Synthesis of 1- [3- (4-benzo [b] thiophen-4-yl-piperazin-1- yl) propyl] imidazolidin-2-one
Trifluoroacetic acid (1.0 ml, 13 mmol) was added to a dichloromethane solution (10 ml) of l-[3-(4- benzo [b] thiophen-4-yl-piperazin-l-yl) propyl] -3- (2, 4- dimethoxybenzyl) imidazolidin-2-one (0.32 g, 0.65 mmol), and the resultant mixture was stirred at room temperature overnight. An aqueous solution of sodium hydroxide was added to this reaction solution, thereby rendering the solution basic. The solution was extracted with dichloromethane. An organic layer thus obtained was washed with a saturated brine, dried with anhydrous sodium sulfate, and the solution thus obtained was concentrated under a reduced pressure. A residue thus obtained was purified with silica gel column chromatography (dichloromethane: methanol = 30:1 to 10:1). The purified product was concentrated under a reduced pressure. A residue thus obtained was recrystallized from ethyl acetate-diethyl ether to obtain a white powder of l-[3- (4-benzo[bj thiophen-4-yl- piperazin-1-yl) propyl] imidazolidin-2-one (0.10 g) . 1H-NMR (DMSO-d6) δ ppm: 1.60-1.70 (2H, m) , 2.30-2.40 (2H, m) , 2.61 (4H, brs) , 3.00-3.15 (6H, m) , 3.15-3.50 (4H, m)", 6.23 (IH, s) , 6.90 (IH, d, J = 7.6 Hz), 7.27 (IH, dd, J - 7.8 Hz, J = 7.8 Hz), 7.40 (IH, d, J = 5.5 Hz), 7.61 (IH, d, J = 7.9 Hz), 7.69 (IH, d, J = 5.5 Hz). Compounds of Examples 1514 and 1521 were synthesized as with Example 1457 by using relevant material compounds .
Example 1458
Synthesis of l-[3- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) propyl] -6-oxo-l, 6-dihydropyridine-3--carboxylic acid hydrochloride
A 6 N aqueous solution (1 ml) of sodium hydroxide was added to an ethanol solution (3 ml) of ethyl 1- [3- (4-benzo [b] thiophen-4-yl-piperazin-1- yl) propyl] -6-oxo-l, 6-dihydropyridine-3-carboxylate
(0.31 g, 0.73 mmol) , and the resultant mixture was stirred at room temperature for 3 days. Under ice cooling, 6 N hydrochloric acid was added to this reaction solution. Thus generated insoluble matters were filtered out and dried to obtain a white powder of l-[3- (4-benzo[b]thiophen-4-yl-piperazin-l-yl) propyl] -6- oxo-1, 6-dihydropyridine-3-carboxylic acid hydrochloride (181 mg) . Melting Point: 265.O0C (decomposition)
Example 1459
Synthesis of 1- [3- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) propyl] -.6-oxo-l, 6-dihydropyridine-3-carboxylic acid ethylamide hydrochloride monohydrate
Triethylamine (0.14 ml, 1.04 mmol) and isobutyl chlorocarbonate (0.07 ml, 0.52 mmol) were added under ice cooling to an acetonitrile solution (3 ml) of 1- [3- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) propyl] -6-oxo-l, 6-dihydropyridine-3-carboxylic acid (0.15 g, 0.35 mmol), and the resultant mixture was stirred for 30 minutes. A (70%) aqueous solution of ethylamine (0.08 ml, 0.1 mmol) was added thereto, and the resultant mixture was stirred at room temperature for 15 minutes. Water was added to this reaction solution, and the solution was extracted with ethyl acetate. An organic layer thus obtained was dried with anhydrous magnesium sulfate. Thus obtained solution was concentrated under a reduced pressure. A residue thus obtained was purified with basic silica gel column chromatography (n-hexane: ethyl acetate = 2:1 to 0:1). The purified product was concentrated under a reduced pressure. A residue thus obtained was dissolved in ethyl acetate, and 4 N hydrochloric acid ethyl acetate was added thereto. Thus generated insoluble matters were filtered out and dried to obtain a white powder of 1- [3- (4-benzo [b] thiophen-4-yl-piperazin-l-yl) propyl] -6- oxo-1, β-dihydropyridine-3-carboxylic acid ethylamide hydrochloride monohydrate (71 mg) . Melting Point: 135.0 to 141.5°C
Example 1460
Synthesis of 1- [3- (4-benzo [b] thiophen-4-yl-piperazin-1- yl) propyl] -6-oxo-l, 6-dihydropyridine-3-carboxylic acid dimethylamide hydrochloride
Triethylamine (0.24 ml, 1.7 mmol) , dimethylamine hydrochloride (0.09 g, 1.04 mmol) and diethyl cyanophosphate (0.07 ml, 0.42 mmol) were added under ice cooling to a DMF solution (3 ml) of 1- [3— (4— benzo [b] thiophen-4-yl-piperazin-l-yl) propyl] -6-oxo-l, 6- dihydropyridine-3-carboxylic acid, and the resultant mixture was stirred at room temperature overnight. Triethylamine (0.24 ml, 1.7 mmol), dimethylamine hydrochloride (0.09 g, 1.04 mmol) and diethyl cyanophosphate (DEPC) (0.07 ml, 0.42 mmol) were further added to the reaction solution and the resultant mixture was stirred at room temperature for 26 hours. Water was added to this reaction solution, and the solution was extracted with ethyl acetate. An organic layer thus obtained was washed with water, and dried with anhydrous magnesium sulfate. Thus obtained solution was concentrated under a reduced pressure. A residue thus obtained was purified with basic silica gel column chromatography (n-hexane: ethyl acetate = 3:1 to 0:1). The purified product was concentrated1 under a reduced pressure. A residue thus obtained was dissolved in ethyl acetate, and 4 N hydrochloric acid ethyl acetate was added thereto. Thus generated insoluble matters were filtered out and dried to obtain a white powder of 1- [3- (4-benzo [b] thiophen-4-yl- piperazin-1-yl) propyl] -6-oxo-l, 6-dihydropyridine-3- carboxylic acid dimethylamide hydrochloride (43 mg) . Melting Point: 201.5 to 206.00C
Compounds of Examples 1484, 1485 and 1519 were synthesized as with Example 1460 by using relevant material compounds .
Example 1461
Synthesis of 3- [4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) butyl] -2-oxo-2, 3-dihydrothiazole-4-carboxylic acid methylamide hydrochloride
A (40%) aqueous solution (3 ml) of methylamine was added to a methanol solution (3 ml) of ethyl 3- [4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) butyl] -2-oxo-2, 3-dihydrothiazole-4-carboxylate hydrochloride (0.25 g, 0.52 mmol) , and heated to reflux for 7 hours. This solution was cooled to room temperature. Water was added to this reaction solution, and the solution was extracted with ethyl acetate. An organic layer thus obtained was washed with water, and dried with anhydrous magnesium sulfate. Thus obtained solution was concentrated under a reduced pressure-. A residue thus obtained was purified with basic silica gel column chromatography (n-hexane: ethyl acetate = 5:1 to 0:1). The purified product was concentrated under a reduced pressure. A residue thus obtained was dissolved in ethyl acetate, and 4 N hydrochloric acid ethyl acetate was added thereto. Thus generated insoluble matters were filtered out and dried to obtain a white powder of 3- [4- (4-benzo[b] thiophen-4-yl- piperazin-1-yl) butyl] -2-oxo-2, 3-dihydrothiazole-4- carboxylic acid methylamide hydrochloride (181 mg) . Melting Point: 137.0 to 143.5°C (decomposition)
Compounds of Examples 1481, 1482, 1491 and 1492 were synthesized as with Example 1461 by using relevant material compounds.
Chemical structures and physical and chemical properties of compounds • obtained in Examples 1462 to 1544 are shown in the following tables. [Table 95]
Figure imgf000260_0001
Figure imgf000260_0002
[Table 96]
Figure imgf000261_0001
Figure imgf000261_0002
[Table 97]
Figure imgf000262_0001
Figure imgf000262_0002
[Table 98]
Figure imgf000263_0001
Figure imgf000263_0002
[Table 99]
Figure imgf000264_0001
Figure imgf000264_0002
[Table 100]
Figure imgf000265_0001
Figure imgf000265_0002
[Table 101]
Figure imgf000266_0001
Figure imgf000266_0002
[Table 102]
Figure imgf000267_0001
Figure imgf000267_0002
[Table 103]
Figure imgf000268_0001
Figure imgf000268_0002
[Table 104]
Figure imgf000269_0001
Figure imgf000269_0002
[Table 105]
Figure imgf000270_0001
Figure imgf000270_0003
[Table 106],
Figure imgf000270_0002
Figure imgf000270_0004
[Table 107 ]
Figure imgf000271_0001
Figure imgf000271_0002
Example 1545
Synthesis of l-[4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) butyl] piperizine-2-thione hydrochloride
1.30 g (3.2 mmol) of Lawesson's Reagent was added to a THF solution (35 ml) of 995 mg of l-[4-(4- benzo [b] thiophen-4-yl-piperazin~l-yl) butyl] -2- piperidone (2.7 mmol), and the resultant mixture was stirred for 3 hours with being heated to reflux. This reaction solution was cooled to room temperature, and purified with basic silica gel column chromatography (hexane: ethyl acetate = 1:2 to 0:1) . The purified product was concentrated under a reduced pressure. A residue thus obtained was dissolved in ethanol, and 2.0 ml of 1 N HCl ethanol solution was added to the obtained solution, and left standing. Precipitated' crystals were filtered out and dried to obtain 648 mg (yield: 57%) of a white powder of l-[4-(4- benzo [b] thiophen-4-yl-piperazin-l-yl) butyl] piperizine- 2-thione hydrochloride.
Melting Point 258.0 to 260.00C
Example 1546
Synthesis of 1- [4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) butyl] pyrrolidine-2-thione The title compound was synthesized as with
Example 1545 by using 1- [4- (4-benzo [b] thiophen-4-yl- piperazin-1-yl) butyl] -2-pyrrolidone. Slightly Yellow Needle Crystals (ethanol) Melting Point 122.0 to 124.0°C
Example 1547
Synthesis of 1- [4- (4-benzo [b] thiophen-4-yl-piperazin-l- yl) butyl] -4-benzylpiperazine-2, 5-dione hydrochloride The title compound was synthesized as with
Example 1449 by using l-benzyl-4- (4-chlorobutyl) - piperazine-2, 5-dione and 1-benzo [b] thiophen-4-yl- piperazine hydrochloride. White Powder (ethanol-ether) Melting Point 220 to 2300C
1H-NMR (DMSO-ds) δ ppm: 1.50-1.80 (4H, m) , 3.00-3.60 (12H, m), 3.87 (2H, s) , 4.07 (2H, s) , 4.52 (2H, s) , 6.95 (IH, d, J = 7.5 Hz), 7.20-7.40 (6H, m) , 7.47 (IH, d, J = 5.5 Hz), 7.69 (IH, d, J = 8.0 Hz), 7.75 (IH, d, J = 5.5 Hz), 10.93 (IH, brs) [Table 108]
Figure imgf000273_0001
Figure imgf000273_0002
[Table 109]
Figure imgf000274_0001
Figure imgf000274_0002
[Table 110]
Figure imgf000275_0001
Figure imgf000275_0002
[Table 111]
Figure imgf000276_0001
Figure imgf000276_0003
[Table 112]
Figure imgf000276_0002
Figure imgf000276_0004
[Table 113]
Figure imgf000277_0001
Figure imgf000277_0002
[Table 114 ]
Figure imgf000278_0001
Figure imgf000278_0003
[Table 115 ]
Figure imgf000278_0002
Figure imgf000278_0004
Pharmacological Test 1
1) Dopamine D2 receptor binding assay
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°C for 10 minutes, centrifuged in the above- described condition. The obtained precipitate was suspended in 50 mM (Tris) -hydrochloric acid buffer (containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 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.
The binding assay was performed using 40 μl of the membrane specimen, 20 μl of [3H] -raclopride (final concentration 1 to 2 nM) , 20 μl of a test drug and 50 mM Tris-hydrochloric acid buffer (containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl2, 1 mM MgCl2, pH 7.4) so that the total amount was 200 μl (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 μM (+) -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 IC50 value using Cheng- Prussoff formula. The results are shown in the following Table.
[Table 116]
Figure imgf000281_0001
2) Serotonin 5-HT2A receptor binding assay
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 weight 40 times of the weight of the tissue with 50 mM Tris-hydrochloric acid buffer (pH 7.4), and centrifuged at 40C, 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 μl of the membrane specimen, 20 μl of [3H] -Ketanserin
(final concentration 1 to 3 nM) , 20 μl. of a test drug and 50 mM Tris-hydrochloric acid buffer- (pH 7.4) so that the total amount was 200 μl (final dimethylsulfoxide concentration 1%) . The reaction was performed at 37°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 μM 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 IC50 value using Cheng- Prussoff formula. The results are shown in the following Table. [Table 117]
Figure imgf000283_0001
Human recombinant dopamine D2 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. /ml penicillin, 50 μg/ml streptomycin, 200 μg/ml geneticin, 0.1 mM sodium hypoxanthine, 16 μM thymidine) at 370C and 5% carbon dioxide condition. Cells were seeded at 104 cells/well on a 9β-well microtiter plate coated with poly-L-lysine and grown under the same condition for 2 days. Each well was washed with 100 μl of a culture medium (IMDM culture medium, 0.1 mM sodium hypoxanthine, 16 μM thymidine) . The culture medium was replaced with 50 μl of culture medium (IMDM culture medium, 0.1% sodium ascorbate, 0.1 mM sodium hypoxanthine, 16 μM thymidine) having dissolved therein 3 μM of- a test compound. After allowed to incubate at 37°C, 5% carbon dioxide condition for 20 minutes, the culture medium was replaced with 100 μl of forskolin stimulative culture medium (IMDM culture medium, 0.1% sodium ascorbate, 0.1 mM sodium hypoxanthine, 16 μM thymidine, 10 μM forskolin, 500 μM 3-isobutyl-l- methylxanthine) having 3 μM of the test compound dissolved therein and allowed to incubate at 370C, 5% carbon dioxide condition for 10 minutes. After the culture medium was removed, 200 μl of 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.
It was confirmed that test compounds had partial agonistic activity for dopamine D2 receptor in the above-described test.
Since the test compounds has partial agonistic activity for dopamine D2 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.
Preparation Examples 100 g of a compound of the present invention,
40 g of Avicel (trade name, product of Asahi Chemical Industry Co., Ltd.), 30 g of corn starch and 2 g of magnesium stearate was mixed and polished and tableted with a pestle for glycocalyx RlO mm.
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.

Claims

1. A heterocyclic compound or a salt thereof represented by the general formula (1) :
Figure imgf000287_0001
[wherein, Q represents a group represented by the following formula (I) :
Figure imgf000287_0002
(wherein, A1 represents a lower alkylene group; Z represents 0 or S; R11 represents
(1-1) hydrogen, (1-2) a lower alkyl group,
(1-3) an aryl group selected from the group consisting of a phenyl group, a naphthyl group, and a dihydroindenyl group (wherein the aryl group may be substituted by at least one group selected from the group consisting of the following substituents (i) to (xxxiii) :
(i) a lower alkyl group,
(ii) a lower alkenyl group,
(iii) a halogen substituted lower alkyl group,
(iv) a lower alkoxy group,
(v) a halogen substituted lower alkoxy group,
(vi) a nitro group, (vii) a cyano group, (viii) halogen, (ix) an aryl. group, (x)' an aryloxy group, (xi) a lower alkoxycarbonyl group, (xii) a hydroxy group, (xiii) a protected hydroxy group, (xiv) a lower alkanoyl group, (xv) a sulfamoyl group, (xvi) a lower alkylthio group, (xvii) a lower alkylsulfonyl group, (xviii) a hydroxysulfonyl group, (xix) an amino group which may have a group (s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a cyclo(C3- C8)alkyl group, an aryl group, and an aroyl group,
(xx) a morpholinylcarbonyl lower alkenyl group,
(xxi) a morpholinylcarbonyl lower alkyl group,
(xxii) a pyrrolyl group, (xxiii) a pyrazolyl group, (xxiv) an imidazolyl group, (xxv) a triazolyl group, (xxvi) a pyridyl group, (xxvii) a pyrrolidinyl group which may have an oxo group (s) ,
(xxviii) a morpholinyl group,
(xxix) a thiomorpholinyl group,
(xxx) a lower alkynyl group,
(xxxi) a cyclo (C3-C8) alkyl group,
(xxxii) a guanidino group, and
(xxxiii) a dihydropyrazolyl group which may have a group (s) selected from the group consisting of an' oxo group and a lower alkyl group) ,
(1-4) a heterocyclic group (wherein the heterocyclic group may be substituted by at least one group selected from the group consisting of the following substituents (i) to (xix) : (i) a lower alkyl group, (ii) a halogen substituted lower alkyl group,
(iii) a lower alkoxy group,
(iv) a halogen substituted lower alkoxy group,
(v) halogen,
(vi) an aryl group which may have, on the aryl group, a group (s) selected from the group consisting of halogen and a halogen substituted lower alkyl group,
(vii) an aryl lower alkyl group which may have halogen atom(s),
(viii) a lower alkanoyl group, (ix) an aroyl group,
(x) an amino lower alkanoyl group which may have, on the amino group, a lower alkanoyl group, (xi) a lower alkylthio group, (xii) a pyrrolyl group, (xiii) an oxo group, (xiv) a thioxo group, (xv) a carbamoyl group, . (xvi) a hydroxy group, (xvii) a pyranyl group, (xviii) a thienyl group, and (xix) a furyl group) ,
(1-5) an amino lower alkyl group which may have, on the amino group and/or the lower alkyl group, a group(s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a hydroxy lower alkyl group, a lower alkoxycarbonyl group, a carbamoyl lower alkyl group, an indolylcarbonyl group, an aryl group (the aryl group may have. a group (s) selected from the group consisting of halogen and a lower alkoxy group) , and an aryl lower alkoxycarbonyl group,
(1-6) a lower alkoxy lower alkyl group, (1-7) an aroyl lower alkyl group, (1-8) an aryl lower alkyl group which may have, on the aryl group, a group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, a hydroxy group, halogen, and a nitro group,
(1-9) an aryloxy lower alkyl group which may have, on the aryl group, a group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, halogen, and a cyano group,
(1-10) an adamantyl lower alkyl group, (1-11) an aryl lower alkenyl group which may have, on the aryl group, a group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen substituted lower alkyl group, a halogen substituted lower alkoxy group, an amino group which may have a lower alkyl group (s), halogen, and a nitro group,
(1-12) a cyclo (C3-C8) alkyl group which may have a group (s) selected from the group consisting of: an amino group which may have a lower alkyl group (s); an amino lower alkyl group which may have a lower alkyl group (s); and an aryl group which may have a group (s) selected from the group consisting of halogen and a lower alkyl group,
(1-13) a cyclo (C3-C8) alkyl lower alkyl group, (1-14) an arylthio lower alkyl group, (1-15) a lower alkyl group substituted by a heterocyclic group selected from the group consisting of a piperidyl group, a tetrahydropyranyl group, a pyridyl group, a thienyl group, an imidazolyl group, a tetrazolyl group, a benzimidazolyl group, an isoindolyl group, a thiazolidinyl group, and an indolyl group (wherein the heterocyclic group may have a group (s) selected from, the group consisting of a lower alkyl group, a lower alkoxy group, halogen, an oxo group, and a thioxo group) ,
(1-16) an aryl lower alkenyl group (which may have, on the lower alkenyl group, an aryl group(s)),
(1-17) a lower alkenyl group substituted by a heterocyclic group selected from the group consisting of a benzodioxolyl group, a pyridyl group, a furyl group, and an imidazolyl group,
(1-18) a benzodioxolyloxy lower alkyl group, (1-19) a pyridylthio lower alkyl group, or (1-20) an amino group which may have a lower alkyl group (s); and R12 represents
(2-1) hydrogen, (2-2) a lower alkyl group, (2-3) a halogen substituted lower alkyl group,
(2-4) a lower alkenyl group,-
(2-5) a lower alkynyl group,
(2-6) a lower alkanoyl group,
(2-7) a hydroxy lower alkyl group,
(2-8) a lower alkoxy lower alkyl group,
(2-9) a cyclo(C3-C8) alkyl group,
(2-10) a cyclo(C3-C8) alkyl lower alkyl group,
(2-11) an aryl group, (2-12) an aryl lower alkyl group which may have, on the aryl group, a group (s) selected from the group consisting of an amino group which may have a lower alkyl group (s) and an aryloxy group, (2-13) a tetrahydrofuryl group, (2-14) a lower alkyl group substituted by a heterocyclic group selected from the group consisting of a furyl group and a pyridyl group,
(2-15) a tetrahydropyranyl group, or (2-16) a lower alkanoyloxy lower alkyl group) , or a group represented by the following general formula (II) :
Figure imgf000293_0001
(wherein, -A2- represents a lower alkylene group, a lower alkenylene group, or a group -A21-0-A22-, wherein
A21 and A22 are the same or different and each represents a C1-C5 alkylene group (provided that the total number of carbon atoms constituting the alkylene group of A21 and the alkylene group of A22 does not exceed 6) ; and
R21 represents a N-containing heterocyclic group, wherein the N-containing heterocyclic ring represented by R21 may be substituted by at least one group selected from the group consisting of the following (1) to (13) : (1) a halogen substituted or unsubstituted lower alkyl group,
(2) a lower alkenyl group,
(3) a lower alkoxy group,
(4) a hydroxy group,
(5) a protected hydroxy group,
(6) an aryl group,
(7) a lower alkanoyl group,
(8) a carboxy group,
(9) a lower alkoxycarbonyl group,
(10) a carbamoyl group which may have a lower alkyl group (s) ,
(11) an aryl lower alkyl group (which may have, on the aryl group, a lower alkoxy group(s)),
(12) an oxo group, and
(13) a thioxo group) ] .
2. The heterocyclic compound or a salt thereof according to claim 1, wherein,
Q represents a group represented by the following formula (I) :
Figure imgf000294_0001
(wherein, A1 represents a lower alkylene group; Z represents 0 or S; R11 represents
(1-1) hydrogen, (1-2) a lower alkyl group,
(1-3 a) an aryl group selected from the group consisting of a phenyl group, a naphthyl group, and a dihydroindenyl group (wherein the aryl group may be substituted by one to three group (s) selected from the group consisting of the following substituents (i) to (viii), (ix a), (x a), (xii) , (xiii a), (xiv) to (xviii) , (xix a) , (xx) to (xxvi) , (xxvii a) , and (xxviii) to (xxxiii) :
(i) a lower alkyl group, . (i±) a lower alkenyl group,
(iii) a halogen substituted lower alkyl group,
(iv) a lower alkoxy group,
(v) a halogen substituted lower alkoxy group,
(vi) a nitro group,
(vii) a cyano group,
(viii) halogen,
(ix a) a phenyl group,
(x a) a phenoxy group,
(xi) a lower alkoxycarbonyl group,
(xii) a hydroxy group,
(xiii a) a lower alkanoyloxy or a phenyl lower alkoxy group which may have one to three halogen atom(s) on the phenyl group,
(xiv) a lower alkanoyl group,
(xv) a sulfamoyl group, (xvi) a lower alkylthio group, (xvii) a lower alkylsulfonyl group, (xviii) a hydroxysulfonyl group, (xix a) an amino group which may have one to two group (s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a cyclo(C3- C8) alkyl' group, a phenyl group, and a benzoyl group, (xx) a morpholinylcarbonyl lower alkenyl group,
(xxi) a morpholinylcarbonyl lower alkyl group,
(xxii) a pyrrolyl group, (xxiii) a pyrazolyl group, (xxiv) an imidazolyl group, (xxv) a triazolyl group, (xxvi) a pyridyl group,
(xxvii a) a pyrrolidinyl group which may have one to two oxo group (s),
(xxviii) a morpholinyl group, (xxix) a thiomorpholinyl group, (xxx) a lower alkynyl group, (xxxi) a cyclo (C3-C8) alkyl group, (xxxii) a guanidino group, and (xxxiii) a dihydropyrazolyl group having one oxo group and one lower alkyl group) ,
(1-4 a) a heterocyclic group selected from the group consisting of pyrrolidinyl, piperidyl, thiazolidinyl, tetrahydropyranyl, pyrrolyl, imidazolyl, pyrazolyl, dihydropyrazolyl, pyridyl, dihydropyridyl, tetrahydropyrinaidinyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, thienyl, furyl, indolyl, indolinyl, isoindolinyl, benzimidazolyl, imidazopyridyl, quinolyl, dihydroquinolyl, tetrahydroquinolyl, isoquinolyl, cinnolinyl, indazolyl, quinoxalinyl, benzotriazolyl; dihydronaphthyridinyl, benzothiazolyl, dihydrobenzothiazolyl, dihydrobenzothiazinyl, thienopyrazinyl, benzoxazolyl, dihydrobenzoxazolylr dihydrobenzoxazinyl, furopyrrolyl, benzodioxolyl, dihydrobenzodioxinyl, and benzothienyl (wherein the heterocyclic qroup may be substituted by one to three group (s) selected from the group consisting of the following substituents (i) to (v) , (vi a) , (vii a) , (viii) , (ix a)-, (x a), and (xi) to (xix) :
(i) a lower alkyl group,
(ii) a halogen substituted lower alkyl group,
(iii) a lower alkoxy group,
(iv) a halogen substituted lower alkoxy group,
(v) halogen,
(vi a) a phenyl group which may have, on the phenyl group, one to three group (s) selected from the group consisting of halogen and a halogen substituted lower alkyl group,
(vii a) a phenyl lower alkyl group which may have one to three halogen atom(s), (viii) a lower alkanoyl group, (ix a) a benzoyl group,
(x a) an amino lower alkanoyl group which ■ may have, on the amino group, one to two lower alkanoyl group (s) ,
(xi) a lower alkylthio group, (xii) a pyrrolyl group, (xiii) an oxo group, (xiv) a thioxo group, (xv) a carbamoyl group, . (xvi) a hydroxy group, (xvii) a pyranyl group, (xviii) a thienyl group, and (xix) a furyl group) ,
(1-5 a) an amino lower alkyl group which may have, on the amino group and/or the lower alkyl group, one to two group (s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a hydroxy lower alkyl group, a lower alkoxycarbonyl group, a carbamoyl lower alkyl group, an indolylcarbonyl group, a phenyl group (the phenyl group may have one to three group (s) selected- from the group consisting of halogen and a lower alkoxy group) , and a phenyl lower alkoxycarbonyl group,
(1-6) a lower alkoxy lower alkyl group, (1-7 a) a benzoyl lower alkyl group, (1-8 a) a phenyl lower alkyl group which may have, on the phenyl group, one to three group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, a hydroxy group, halogen, and a nitro group,
(1-9 a) a phenoxy lower alkyl group which may have, on the phenyl group, one to three group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, halogen, and a cyano group,
(1-10) an adamantyl lower alkyl group, (1-11 a) a phenyl lower alkenyl group which may have, on the phenyl group, one to three group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen substituted lower alkyl group, a halogen substituted lower alkoxy group, an amino group which may have one to two lower alkyl group (s), halogen, and a nitro group,
(1-12 a) a cyclo (C3-C8) alkyl group which may have one to two group (s) selected from the group consisting of: an amino group which may have one to two lower alkyl group (s); an amino lower alkyl group which may have one to two lower alkyl group (s); and a phenyl group which may have one to three group (s) selected from the group consisting of halogen and a lower alkyl group,
(1-13) a cyclo (C3-C8) alkyl lower alkyl group, (1-14 a) a phenylthio lower alkyl group, (1-15 a) a lower alkyl group substituted by a heterocyclic group selected from the group consisting of a piperidyl group, a tetrahydropyranyl group, a pyridyl group, a thienyl group, an imidazolyl group, a tetrazolyl group, a benzimidazolyl group, an isoindolyl group, a thiazolidinyl group, and an indolyl group (wherein the heterocyclic group may have one to three group (s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, halogen, an oxo group, and a thioxo group) ,
(1-16 a) a phenyl lower alkenyl group (which may have, on the lower alkenyl group, one to two phenyl group(s)), .
(1-17) a lower alkenyl group substituted by a heterocyclic group selected from the group consisting of a benzodioxolyl group, a pyridyl group, a furyl group, and an imidazolyl group,
(1-18) a benzodioxolyloxy lower alkyl group, (1-19) a pyridylthio lower alkyl group, or (1-20 a) an amino group which may have one to two lower alkyl group (s); and R12 represents
(2-1) hydrogen, (2-2) a lower alkyl group, (2-3) a halogen substituted lower alkyl group,
(2-4) a lower alkenyl group, (2-5) a lower alkynyl group, (2-6) a lower alkanoyl group, (2-7) a hydroxy lower alkyl group, (2-8) a lower alkoxy lower alkyl group, (2-9) a cyclo(C3-C8) alkyl group, (2-10) a cyclo(C3-C8) alkyl lower alkyl group, (2-11 a) a phenyl group (2-12 a) a phenyl lower alkyl group which may have, on the phenyl group, one to three group (s) selected from the group consisting of an amino group which may have one to two lower alkyl group (s) and a phenoxy group,
(2-13) a tetrahydrofuryl' group,
(2-14) a lower alkyl group substituted by a heterocyclic group selected from the group consisting of a furyl group and a pyridyl group,
(2-15) a tetrahydropyranyl group, or (2-16) a lower alkanoyloxy lower alkyl group) , or a group represented by the following general formula- (II) :
Figure imgf000301_0001
(wherein, -A2- represents a lower alkylene group, a lower alkenylene group, or a group -A21-O-A22-, wherein
A21 and A22 are the same or different and each represents a C1-C5 alkylene group (provided that the total number of carbon atoms constituting the alkylene group of A1 and the alkylene group of A2 does not exceed 6) ; and R21 represents a N-containing heterocyclic group selected from the group consisting of pyrrolidinyl, imidazolidinyl, piperidyl, hexahydropyrimidinyl, piperazinyl, octahydroisoindolyl, azepanyl, azocanyl, azaspirononanyl, azaspirodecanyl, diazaspirononanyl, dihydropyrrolyl, imidazolyl, dihydroimidazolyl, triazolyl, dihydrotriazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyriitiidinyl, dihydropyrimidinyl, pyrazinyl, dihydropyrazinyl, pyridazinyl, tetrazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, hexahydroisoindolyl, octahydroisoindolyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, quinazolinyl, dihydroquinazolinyl, benzotriazolyl, carbazolyl, spirocyclopentanindolinyl, oxazolyl, isoxazolyl/ oxadiazolyl, oxazolidinyl, isoxazolidinyl, oxazinanyl, morpholinyl, benzoxazolyl, dihydrobenzoxazolyl, benzoxazinyl, dihydrobenzoxazinyl, benzoxazolyl, benzoxadiazolyl, thiazolyl, dihydrothiazolyl, isothiazolyl, thiadiazolyl, dihydrothiazinyl, thiazolidinyl, benzothiazolyl, and benzothiadiazolyl, wherein the N-containing heterocyclic ring represented by R21 may be substituted by one to three group (s) selected from the group consisting of the following (1) to (4), (5 a), (6 a), (7) to (9), (10 a), (11 a), (12), and (13) :
(1) a halogen substituted or unsubstituted lower alkyl group,
(2) a lower alkenyl group, (3) a lower alkoxy group,
(4) a hydroxy group,
(5 a), a lower alkanoyloxy group or a phenyl lower alkoxy group,
(6 a) a phenyl group,
(7) a lower alkanoyl group,
(8) a carboxy group,
(9) a lower alkoxycarbonyl group,
(10 a) a carbamoyl group which may have one to two lower alkyl group (s),
(11 a) a phenyl lower alkyl group (which may have, on the phenyl group, one to two lower alkoxy group (s) ) ,
(12) an oxo group, and
(13) a thioxo group) .
3. The heterocyclic compound or a salt thereof according to claim 2, wherein
Q represents a group represented by the following formula (I) :
Figure imgf000303_0001
(wherein, A1 represents a lower alkylene group; Z represents 0 or S; R11 represents
(1-1) hydrogen,
(1-2) a lower alkyl group, (l-3aa) a phenyl group which may have one to two halogen atom(s),
(l-4aa)a heterocyclic group selected from the group consisting of pyrazinyl and thienyl (wherein the heterocyclic group may be substituted by one lower alkyl group) ,
(1-5 aa) an amino lower alkyl group which may have, on the amino group and/or the lower alkyl group, one or two group (s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a hydroxy lower alkyl group, a lower alkoxycarbonyl group, a carbamoyl lower alkyl group, an indolylcarbonyl group, a phenyl group (the phenyl group may have one group selected from the group consisting of halogen and a lower alkoxy group) , and a phenyl lower alkoxycarbonyl group, or
(1-20 a) an amino group which may have one to two lower alkyl group (s); and R12 represents
(2-1) hydrogen,
(2-2) a lower alkyl group,
(2-4) a lower alkenyl group,
(2-6) a lower alkanoyl group,
(2-7) a hydroxy lower alkyl group,
(2-8) a lower alkoxy lower alkyl group, or
(2-9) a cyclo(C3-C8) alkyl group).
4. The heterocyclic compound or a salt thereof according to claim 2, wherein Q represents a group represented by the following general formula (II) :
Figure imgf000305_0001
(wherein, -A2- represents a lower alkylene group or a lower alkenylene group; and
R21 represents a N-containing heterocyclic group selected from the group consisting of pyrrolidinyl, imidazolidinyl, piperidyl, azepanyl, oxazolidinyl, and oxazinanyl, wherein the N-containing heterocyclic ring represented by R21 may be substituted by one to three group (s) selected from the group consisting of the following (1), (12), and (13):
(1) a halogen substituted or unsubstituted alkyl group,
(12) an oxo group, and
(13) a thioxo group) .
5. The heterocyclic compound of the formula (1), according to claim 3 selected from the group consisting of:
N- [5- (4-Benzo [b] thiophen-4-yl-piperazin-l-yl) -pentyl] - acetamide,
N- [5- (4-Benzo [b] thiophen-4-yl-piperazin-l-yl) -pentyl] -
2, 4-difluoro-benzamide,
N- [4- (4-Benzo [b] thiophen-4-yl-piperazin-l-yl) -butyl] -N- cyclopropyl-acetamide, 5-Methyl-pyrazine-2-carboxylic acid [4- (4- benzo [b] thiophen-4-yl-piρerazin-l-yl) -butyl] -ethyl- amide,
Thiazole-4-carboxylic acid [4- (4-benzo [b] thiophen-4-yl- piperazin-1-yl) -butyl] -ethyl-amide,
N- [4- (4-Benzo [b] thiophen-4-yl-piperazin-l-yl) -butyl]'-N- ethyl-acetamide,
N- [4- (4-Benzo [b] thiophen-4-yl-piperazin-l-yl) -butyl] -N- isopropyl-acetamide,
N- [4- (4-Benzo [b] thiophen-4-yl-piperazin-l-yl) -butyl] -N- ethy1-thioacetamide,
N-Allyl-N- [4- (4-benzo [b] thiophen-4-yl-piperazin-l-yl) - butyl] -acetamide, and
N- [4- (4-Benzo [b] thiophen-4-yl-piperazin-l-yl) -butyl] -N- tert-butyl-formamide.
6. The heterocyclic compound of the formula (1) according to claim 4 selected from the group consisting of:
1- [5- (4-Benzo [b] thiophen-4-yl-piperazin-l-yl) -pentyl] - imidazolidin-2-one,
1- [5- (4-Benzo [b] thiophen-4-yl-piperazin-l-yl) -pentyl] - 3-methyl-imidazolidin-2-one, l-[5- (4-Benzo [b] thiophen-4-yl-piperazin-l-yl) -pentyl] - pyrrolidin-2-one,
1- [5- (4-Benzo [b] thiophen-4-yl-piperazin-l-yl) -pentyl] - pyrrolidine-2, 5-dione,
1- [4- (4-Benzo [b] thiophen-4-yl-piperazin-l-yl) -butyl] - azepan-2-one, 3- [6- (4-Benzo[b]thiophen-4-yl-piperazin-l-yl) -hexyl]- oxazolidin-2-one,
3- [4- (4-Benzo [b] thiophen-4-yl-piperazin-l-yl) -butyl] - 4, 4-dimethyl-oxazolidin-2-one,
3- [4- (4-Benzo [b] thiophen-4-yl-piperazin-l-yl) -butyl] -A- methyl-oxazolidin-2-one,
3- [4- (4-Benzo [b] thiophen-4-yl-piperazin-l-yl) -butyl] - oxazolidin-2-one,
1- [4- (4-Benzo [b] thiophen-4-yl-piperazin-l-yl) -butyl] - pyrrolidin-2-one,
1- [4- (4-Benzo [b] thiophen-4-yl-piperazin-l-yl) -butyl] - pxperidin-2-one,
1- [ (E) -4- (4-Benzό[b] thiophen-4-yl-piperazin-l-yl) -but- 2-enyl] -3-methyl-imidazolidin-2-one,
1- [4- (4-Benzo [b] thiophen-4-yl-piperazin-l-yl) -butyl] - piperidine-2-thione, and
3- [4- (4-Benzo [b] thiophen-4-yl-piperazin-l-yl) -butyl] -4- methyl-oxazolidin-2-one .
7. A pharmaceutical composition comprising a heterocyclic compound of the formula (1) or a salt thereof according to any one of claims 1 to 6, as an active ingredient and a pharmaceutically acceptable carrier.
8. The pharmaceutical composition according to claim 7 for treating or preventing central nervous system, disorders.
9. The pharmaceutical composition according to claim 8 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; anhedonia; iatrogenic anhedonia; anhedonia of a psychic or mental cause; anhedonia associated with depression; anhedonia associated with schizophrenia; delirium; cognitive impairment; cognitive impairment associated with Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases; cognitive impairment caused by Alzheimer's disease; Parkinson's disease and associated neurodegenerative diseases; cognitive impairment of schizophrenia; cognitive impairment caused by refractory, intractable or chronic schizophrenia; vomiting; motion sickness; obesity; migraine; pain (ache) ; mental retardation; autism disorder (autism); Tourette's disorder; tic disorder; attention-deficit/hyperactivity disorder; conduct disorder; and Down's syndrome.
10. A process for producing a pharmaceutical composition comprising mixing a heterocyclic compound of the formula (1) or a salt thereof according to any one of claims 1 to 6 with a pharmaceutically acceptable carrier.
11. Use of a heterocyclic compound of the formula (T) or a salt thereof according to any one of claims 1 to 6 as a drug.
12. Use of a heterocyclic compound of the formula (1) or a salt thereof according to any one of claims 1 to 6 as a dopamine D2 receptor partial agonist and/or a serotonin 5-HT2A receptor antagonist and/or an adrenaline αi receptor antagonist and/or a serotonin uptake inhibitor and/or a serotonin reuptake inhibitor.
13. A method for treating or preventing a central nervous system disorder comprising administering a heterocyclic compound of the formula (1) or a salt thereof according to any one of claims 1 to 6 to human or animal .
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