JP2008115175A - Heterocyclic compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a heterocyclic compound having a wide therapeutic spectrum for mental diseases, and having high safety. <P>SOLUTION: The heterocyclic compound is represented by general formula (1), wherein Q is formula (I), wherein A<SP>1</SP>represents a lower alkylene group; Z represents O or S; R<SP>11</SP>represents hydrogen or the like; and R<SP>12</SP>represents hydrogen or the like. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a novel heterocyclic compound.

  Since the etiology of schizophrenia, bipolar disorder, mood disorder, and emotional disorder is heterogeneous, the drug has multiple pharmacological actions to develop a broad therapeutic spectrum. It is hoped that

  Patent Document 1 discloses a general formula.

[Wherein, A ′ represents — (CH ₂ ) _m CH ₂ —, — (CH ₂ ) _m O—, or the like. m shows the integer of 1-4. R ^A represents a hydrogen atom, a C _1-4 alkyl group which may be substituted with 1 to 3 fluorine atoms, or the like. ]
It is disclosed that the carbostyril derivative represented by the formula has a D ₂ receptor antagonistic action and a serotonin 2A (5-HT _2A ) receptor antagonistic action, and is effective in the treatment of schizophrenia and other central nervous diseases. Has been.

However, in Patent Document 1, the carbostyril derivative described in the document has a D ₂ receptor partial agonist action, a 5-HT _2A receptor antagonist action, an α ₁ receptor antagonist action, and a serotonin uptake inhibitory action. However, there is no disclosure regarding the point of having a wide therapeutic spectrum.

  Patent Document 2 discloses certain [1,8] naphthyridin-2-one derivatives.

However, also in Patent Document 2, the [1,8] naphthyridin-2-one derivative described in the above document has a D ₂ receptor partial agonist action, a 5-HT _2A receptor antagonist action, an α ₁ receptor antagonist action. In addition, there is no disclosure of the fact that it has both serotonin uptake inhibitory action and a broad therapeutic spectrum.
WO2004 / 026864A1 WO2005 / 043309A1

  An object of the present invention is to provide an antipsychotic drug having a broader therapeutic spectrum, fewer side effects, and excellent tolerability and safety compared to known typical antipsychotic drugs and atypical antipsychotic drugs. And

As a result of intensive studies in order to solve the above problems, the present inventors have conducted a dopamine D ₂ receptor partial agonist action (D ₂ receptor partial agonist action), a serotonin 5-HT _2A receptor antagonist action (5- HT _2A receptor antagonistic action) and adrenergic α ₁ receptor antagonistic action (α ₁ receptor antagonistic action), and in addition to these actions, serotonin uptake inhibitory action (or serotonin reuptake inhibitory action) The compound was successfully synthesized. The present invention has been completed based on such findings.

  The present invention provides a heterocyclic compound or a salt thereof shown in the following section.

Item 1.
General formula (1):

[Wherein, Q represents a group represented by the following general formula (I) or a group represented by the general formula (II).
Formula (I)

(In the formula, A ¹ represents a lower alkylene group.
Z represents O or S.
R ¹¹ is (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 was selected from the group consisting of (i) to (xxxiii) below as a substituent At least one group may be substituted:
(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) sulfamoyl group,
(xvi) a lower alkylthio group,
(xvii) a lower alkylsulfonyl group,
(xviii) hydroxysulfonyl group,
(xix) an amino group optionally having a group 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) morpholinylcarbonyl lower alkenyl group,
(xxi) morpholinylcarbonyl lower alkyl group,
(xxii) pyrrolyl group,
(xxiii) pyrazolyl group,
(xxiv) an imidazolyl group,
(xxv) triazolyl group,
(xxvi) pyridyl group,
(xxvii) an pyrrolidinyl group optionally having an oxo group,
(xxviii) morpholinyl group,
(xxix) thiomorpholinyl group,
(xxx) a lower alkynyl group,
(xxxi) a cyclo C3-C8 alkyl group,
(xxxii) guanidino group,
(xxxiii) a dihydropyrazolyl group optionally having a group selected from the group consisting of an oxo group and a lower alkyl group),
(1-4) Heterocyclic group (here, at least one group selected from the group consisting of the following (i) to (xix) may be substituted as a substituent on the heterocyclic group:
(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 optionally having a group selected from the group consisting of halogen and halogen-substituted lower alkyl groups on the aryl group;
(vii) aryl lower alkyl group optionally having halogen,
(viii) a lower alkanoyl group,
(ix) aroyl group,
(x) an amino lower alkanoyl group optionally having a lower alkanoyl group on the amino group,
(xi) a lower alkylthio group,
(xii) pyrrolyl group,
(xiii) an oxo group,
(xiv) a thioxo group,
(xv) a carbamoyl group,
(xvi) a hydroxy group,
(xvii) pyranyl group,
(xviii) thienyl group,
(xix) furyl group),
(1-5) On an amino group and / or a lower alkyl group, 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) An amino lower alkyl group optionally having a group selected from the group consisting of a 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 a group selected from the group consisting of a lower alkyl group, a lower alkoxy group, a hydroxy group, a halogen and a nitro group on the aryl group;
(1-9) an aryloxy lower alkyl group which may have a group selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen and a cyano group on the aryl group;
(1-10) adamantyl lower alkyl group (1-11) amino optionally having a lower alkyl group, a lower alkoxy group, a halogen-substituted lower alkyl group, a halogen-substituted lower alkoxy group or a lower alkyl group on the aryl group An aryl lower alkenyl group optionally having a group selected from the group consisting of a group, a halogen and a nitro group,
(1-12) an amino group optionally having a lower alkyl group; an amino lower alkyl group optionally having a lower alkyl group, and a group selected from the group consisting of a halogen and a lower alkyl group; A cyclo C3-C8 alkyl group optionally having a group selected from the group consisting of aryl groups,
(1-13) a cyclo C3-C8 alkyl lower alkyl group,
(1-14) arylthio lower alkyl group,
(1-15) Lower alkyl substituted with a heterocyclic group selected from the group consisting of piperidyl group, tetrahydropyranyl group, pyridyl group, thienyl group, imidazolyl group, tetrazolyl group, benzimidazolyl group, isoindolyl group, thiazolidinyl group and indolyl group A group (which may have a group selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen, an oxo group and a thioxo group on the heterocyclic group),
(1-16) aryl lower alkenyl group (which may have an aryl group on the lower alkenyl group),
(1-17) a lower alkenyl group substituted with a heterocyclic group selected from the group consisting of a benzodioxolyl group, a pyridyl group, a furyl group, and an imidazolyl group,
(1-18) benzodioxolyloxy lower alkyl group,
(1-19) A pyridylthio lower alkyl group, or (1-20) an amino group optionally having a lower alkyl group.
R ¹² is
(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) lower alkanoyl group,
(2-7) hydroxy lower alkyl group,
(2-8) a lower alkoxy lower alkyl group,
(2-9) a cyclo C3-C8 alkyl group,
(2-10) cyclo C3-C8 alkyl lower alkyl group,
(2-11) aryl group,
(2-12) an aryl lower alkyl group which may have a group selected from the group consisting of an amino group and an aryloxy group which may have a lower alkyl group on the aryl group;
(2-13) 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) represents a tetrahydropyranyl group or (2-16) a lower alkanoyloxy lower alkyl group. )
General formula (II):
R ²¹ -A ^2- (II)
(In the formula, —A ² — represents a lower alkylene group, a lower alkenylene group or a group —A ²¹ —O—A ²² —.

Here, A ²¹ and A ²² are the same or different and each represents a C1-C5 alkylene group. However, 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 an N-containing heterocyclic group:
Here, on the N-containing heterocyclic ring represented by R ²¹ , at least one group selected from the group consisting of the following (1) to (13) may be substituted:
(1) halogen-substituted or unsubstituted lower alkyl group (2) lower alkenyl group (3) lower alkoxy group (4) hydroxy group (5) protected hydroxy group (6) aryl group (7) lower alkanoyl group (8) Carboxy group (9) lower alkoxycarbonyl group (10) carbamoyl group optionally having lower alkyl group (11) aryl lower alkyl group (wherein the aryl group may have a lower alkoxy group) )
(12) Oxo group (13) Thioxo group)]
Or a salt thereof.

Item 2.
Q is a group represented by the following general formula (I):

[Wherein, A ¹ represents a lower alkylene group.
Z represents O or S.
R ¹¹ is (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 following (i) to (viii), (ix a), (xa), (xii), (xiii a), (xiv) to (xviii), (xix a), (xx) to (xxvi), (xxvii a), and (xxviii) to (xxxiii) 1 to 3 groups selected from may be substituted:
(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,
(xa) a phenoxy group,
(xi) a lower alkoxycarbonyl group,
(xii) a hydroxy group,
(xiii a) a phenyl lower alkoxy group optionally having 1 to 3 halogen atoms on the lower alkanoyloxy group or phenyl group,
(xiv) a lower alkanoyl group,
(xv) sulfamoyl group,
(xvi) a lower alkylthio group,
(xvii) a lower alkylsulfonyl group,
(xviii) hydroxysulfonyl group,
(xix a) an amino group optionally having 1 or 2 groups 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) morpholinylcarbonyl lower alkenyl group,
(xxi) morpholinylcarbonyl lower alkyl group,
(xxii) pyrrolyl group,
(xxiii) pyrazolyl group,
(xxiv) an imidazolyl group,
(xxv) triazolyl group,
(xxvi) pyridyl group,
(xxviia) pyrrolidinyl group optionally having 1 to 2 oxo groups,
(xxviii) morpholinyl group,
(xxix) thiomorpholinyl group,
(xxx) a lower alkynyl group,
(xxxi) a cyclo C3-C8 alkyl group,
(xxxii) guanidino group,
(xxxiii) a dihydropyrazolyl group having one oxo group and one lower alkyl group),
(1-4 a) pyrrolidinyl, piperidyl, thiazolidinyl, tetrahydropyranyl, pyrrolyl, imidazolyl, pyrazolyl, dihydropyrazolyl (eg 4,5-dihydropyrazolyl etc.), pyridyl, dihydropyridyl (eg 1,2-dihydropyridyl etc. ), Tetrahydropyrimidinyl (such as 1,2,3,4-tetrahydropyrimidinyl), pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, thienyl, furyl, indolyl, indolinyl, isoindolinyl, benzimidazolyl, imidasopyridylquinolyl, dihydroquinolyl, tetrahydroquinol Ril, isoquinolyl, cinolinyl, indazolyl, quinoxalinyl, benzotriazolyl, dihydronaphthyridyl, benzothiazolyl, dihydrobenzothiazolyl, dihydrobenzothia A heterocyclic group selected from the group consisting of dinyl, thienopyrazinyl, benzoxazolyl, dihydrobenzoxazolyl, dihydrobenzoxazinyl, furopyrrolyl, benzodioxolyl, dihydrobenzodioxinyl and benzothienyl, wherein From the group consisting of the following (i) to (v), (vi a), (vii a), (viii), (ix a), (xa) and (xi) to (xix) as substituents on the ring group 1-3 selected groups may be substituted:
(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 optionally having 1 to 3 groups selected from the group consisting of halogen and halogen-substituted lower alkyl groups on the phenyl group;
(viia) a phenyl lower alkyl group optionally having 1 to 3 halogen atoms,
(viii) a lower alkanoyl group,
(ix a) a benzoyl group,
(xa) an amino lower alkanoyl group optionally having 1 to 2 lower alkanoyl groups on the amino group;
(xi) a lower alkylthio group,
(xii) pyrrolyl group,
(xiii) an oxo group,
(xiv) a thioxo group,
(xv) a carbamoyl group,
(xvi) a hydroxy group,
(xvii) pyranyl group,
(xviii) thienyl group,
(xix) furyl group),
(1-5 a) On an amino group and / or a lower alkyl group, 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 1 to 2 groups selected from the group consisting of halogen and lower alkoxy groups may be present on the phenyl group) and 1 to 2 groups selected from the group consisting of phenyl lower alkoxycarbonyl groups. An amino lower alkyl group,
(1-6) a lower alkoxy lower alkyl group,
(1-7 a) benzoyl lower alkyl group,
(1-8 a) a phenyl lower alkyl group which may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a lower alkoxy group, a hydroxy group, a halogen and a nitro group on the phenyl group;
(1-9 a) a phenoxy lower alkyl group which may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen and a cyano group on the phenyl group;
(1-10) adamantyl lower alkyl group,
(1-11 a) On the phenyl group, a lower alkyl group, a lower alkoxy group, a halogen-substituted lower alkyl group, a halogen-substituted lower alkoxy group, an amino group optionally having 1-2 lower alkyl groups, a halogen, and A phenyl lower alkenyl group optionally having 1 to 3 groups selected from the group consisting of nitro groups,
(1-12 a) an amino group optionally having 1 to 2 lower alkyl groups; an amino lower alkyl group optionally having 1 to 2 lower alkyl groups, and a group consisting of a halogen and a lower alkyl group A cyclo C3-C8 alkyl group optionally having a group selected from the group consisting of phenyl groups optionally having 1 to 3 groups selected from
(1-13) a cyclo C3-C8 alkyl lower alkyl group,
(1-14 a) a phenylthio lower alkyl group,
(1-15 a) Lower substituted by a heterocyclic group selected from the group consisting of piperidyl group, tetrahydropyranyl group, pyridyl group, thienyl group, imidazolyl group, tetrazolyl group, benzimidazolyl group, isoindolyl group, thiazolidinyl group and indolyl group An alkyl group (which may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen, an oxo group and a thioxo group on the heterocyclic group),
(1-16 a) a phenyl lower alkenyl group (which may have 1 to 2 phenyl groups on the lower alkenyl group),
(1-17) a lower alkenyl group substituted with a heterocyclic group selected from the group consisting of a benzodioxolyl group, a pyridyl group, a furyl group, and an imidazolyl group,
(1-18) benzodioxolyloxy lower alkyl group,
(1-19) A pyridylthio lower alkyl group or (1-20 a) an amino group optionally having 1 to 2 lower alkyl groups.
R ¹² is
(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) lower alkanoyl group,
(2-7) hydroxy lower alkyl group,
(2-8) a lower alkoxy lower alkyl group,
(2-9) a cyclo C3-C8 alkyl group,
(2-10) cyclo C3-C8 alkyl lower alkyl group,
(2-11 a) a phenyl group,
(2-12 a) A phenyl lower group optionally having 1 to 3 groups selected from the group consisting of an amino group and a phenoxy group which may have 1 to 2 lower alkyl groups on the phenyl group An alkyl group,
(2-13) 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) represents a tetrahydropyranyl group or (2-16) a lower alkanoyloxy lower alkyl group. ]
Or a group represented by the following general formula (II):
R ²¹ -A ^2- (II)
Wherein, -A ² - is lower alkylene, lower alkenylene group or a group ^-A 21 ^{-O-A 22} - shows the.
Here, A ²¹ and A ²² are the same or different and each represents a C1-C5 alkylene group. However, 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 is pyrrolidinyl, imidazolidinyl, piperidyl, hexahydropyrimidinyl, piperazinyl, octahydroisoindole, azepanyl, azocanyl, azaspirononyl, azaspirodecanyl, diazaspirononyl, 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, cal Basolyl, spiro [cyclopentaneindolinyl, oxazolyl, isoxazolyl, oxadiazolyl, oxazolidinyl, isoxazolidinyl, oxadinanyl, morpholinyl, benzoxazolyl, dihydrobenzoxazolyl, benzooxazinyl, dihydrobenzoxazinyl, benzo Represents an N-containing heterocyclic group selected from the group consisting of oxazolyl, benzooxadiazolyl, thiazolyl, dihydrothiazolyl, isothiazolyl, thiadiazolyl, dihydrothiazinyl, thiazolidinylbenzothiazolyl and benzothiadiazolyl :
Here, on the N-containing heterocycle represented by R ²¹ , the following (1) to (4), (5 a), (6 a), (7) to (9), (10 a), 1 to 3 groups selected from the group consisting of (11 a), (12) and (13) may be substituted:
(1) halogen-substituted or unsubstituted lower alkyl group (2) lower alkenyl group (3) lower alkoxy group (4) hydroxy group (5a) lower alkanoyloxy group or phenyl lower alkoxy group (6a) phenyl group (7) lower alkanoyl Group (8) carboxy group (9) lower alkoxycarbonyl group (10a) carbamoyl group optionally having 1 to 2 lower alkyl groups (11a) phenyl lower alkyl group (here, lower alkoxy on the phenyl group) (You may have 1-2 groups)
(12) Oxo group (13) Thioxo group]
The heterocyclic compound or its salt of claim | item 1 which shows these.

  Item 3. General formula (1):

Wherein Q is a group represented by the following general formula (I),

[Wherein, A ¹ represents a lower alkylene group.
Z represents O or S.
R ¹¹ is (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 (here, the following (i) to (viii), (ix a), (xa), (xii), (xiii a), (xiv) to (xviii), (xix a), (xx) to (xxvi), (xxvii a), (xxviii) to (xxxii) and (xxxiii a 1 to 3 groups selected from the group consisting of:
(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,
(xa) a phenoxy group,
(xi) a lower alkoxycarbonyl group,
(xii) a hydroxy group,
(xiii a) a phenyl lower alkoxy group optionally having 1 to 3 halogen atoms on the lower alkanoyloxy group or phenyl group,
(xiv) a lower alkanoyl group,
(xv) sulfamoyl group,
(xvi) a lower alkylthio group,
(xvii) a lower alkylsulfonyl group,
(xviii) hydroxysulfonyl group,
(xix a) an amino group optionally having 1 to 2 groups 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 N N-dilower alkylamino group, lower alkanoylamino group, N-lower alkanoyl-N-cycloC3-C8 alkylamino group, phenylamino group, benzoylamino group),
(xx) morpholinylcarbonyl lower alkenyl group,
(xxi) morpholinylcarbonyl lower alkyl group,
(xxii) pyrrolyl group,
(xxiii) pyrazolyl group,
(xxiv) an imidazolyl group,
(xxv) triazolyl group,
(xxvi) pyridyl group,
(xxviia) pyrrolidinyl group optionally having 1 to 2 (preferably 1) oxo groups,
(xxviii) morpholinyl group,
(xxix) thiomorpholinyl group,
(xxx) a lower alkynyl group,
(xxxi) a cyclo C3-C8 alkyl group,
(xxxii) guanidino group,
(xxxiii a) a dihydropyrazolyl group having one oxo group and one lower alkyl group),
(1-4 a) pyrrolidinyl, piperidyl, thiazolidinyl, tetrahydropyranyl, pyrrolyl, imidazolyl, pyrazolyl, dihydropyrazolyl (eg 4,5-dihydropyrazolyl etc.), pyridyl, dihydropyridyl (eg 1,2-dihydropyridyl etc. ), Tetrahydropyrimidinyl (such as 1,2,3,4-tetrahydropyrimidinyl), pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, thienyl, furyl, indolyl, indolinyl, isoindolinyl, benzimidazolyl, imidasopyridylquinolyl, dihydroquinolyl, tetrahydroquinol Ril, isoquinolyl, cinolinyl, indazolyl, quinoxalinyl, benzotriazolyl, dihydronaphthyridyl, benzothiazolyl, dihydrobenzothiazolyl, dihydrobenzothia A heterocyclic group selected from the group consisting of dinyl, thienopyrazinyl, benzoxazolyl, dihydrobenzoxazolyl, dihydrobenzoxazinyl, furopyrrolyl, benzodioxolyl, dihydrobenzodioxinyl and benzothienyl, wherein From the group consisting of the following (i) to (v), (vi a), (vii a), (viii), (ix a), (xa) and (xi) to (xix) as substituents on the ring group 1-3 selected groups may be substituted:
(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 1 to 3 (preferably 1) groups selected from the group consisting of halogen and halogen-substituted lower alkyl groups on the phenyl group;
(viia) a phenyl lower alkyl group optionally having 1 to 3 (preferably 1 to 2) halogens;
(viii) a lower alkanoyl group,
(ix a) a benzoyl group,
(xa) an amino lower alkanoyl group optionally having 1 to 2 (preferably 1) lower alkanoyl groups on the amino group;
(xi) a lower alkylthio group,
(xii) pyrrolyl group,
(xiii) an oxo group,
(xiv) a thioxo group,
(xv) a carbamoyl group,
(xvi) a hydroxy group,
(xvii) pyranyl group,
(xviii) thienyl group,
(xix) furyl group),
(1-5 a) On an amino group and / or a lower alkyl group, 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 A group selected from the group consisting of 1 to 3 (preferably 1) groups selected from the group consisting of halogen and lower alkoxy groups on the phenyl group and a group consisting of phenyl lower alkoxycarbonyl groups is 1 ~ 2 amino lower alkyl groups optionally having,
(1-6) a lower alkoxy lower alkyl group,
(1-7 a) benzoyl lower alkyl group,
(1-8 a) having 1 to 3 (preferably 1 to 2) groups selected from the group consisting of a lower alkyl group, a lower alkoxy group, a hydroxy group, a halogen and a nitro group on the phenyl group; A phenyl lower alkyl group,
(1-9 a) a phenoxy lower alkyl group which may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen and a cyano group on the phenyl group;
(1-10) adamantyl lower alkyl group,
(1-11 a) An amino group optionally having 1 to 2 lower alkyl groups, lower alkoxy groups, halogen-substituted lower alkyl groups, halogen-substituted lower alkoxy groups or lower alkyl groups on the phenyl group (preferably N, N-di-lower alkylamino group), a phenyl lower alkenyl group optionally having 1 to 3 (preferably 1 to 2) groups selected from the group consisting of halogen and nitro group,
(1-12 a) an amino group which may have 1 to 2 lower alkyl groups (preferably an N, N-dilower alkylamino group); may have 1 to 2 lower alkyl groups Phenyl optionally having 1 to 3 (preferably 1) groups selected from the group consisting of amino lower alkyl groups (preferably N, N-di-lower alkylamino lower alkyl groups) and halogens and lower alkyl groups A cyclo C3-C8 alkyl group optionally having a group selected from the group consisting of groups;
(1-13) a cyclo C3-C8 alkyl lower alkyl group,
(1-14 a) a phenylthio lower alkyl group,
(1-15 a) a lower group substituted with 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 benzoimidazolyl group, an isoindolyl group, a thiazolidinyl group, and an indolyl group An alkyl group (wherein the heterocyclic group has 1 to 3 (preferably 1 to 2) groups selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen, an oxo group and a thioxo group; You may)
(1-16 a) a phenyl lower alkenyl group (which may have 1 to 2 (preferably 1) phenyl groups on the lower alkenyl group),
(1-17) a lower alkenyl group substituted with a heterocyclic group selected from the group consisting of a benzodioxolyl group, a pyridyl group, a furyl group, and an imidazolyl group,
(1-18) benzodioxolyloxy lower alkyl group,
(1-19) A pyridylthio lower alkyl group or (1-20 a) an amino group optionally having 1 to 2 lower alkyl groups.
Furthermore, a more preferred definition of R ¹¹ is
(1-1) hydrogen,
(1-2) a lower alkyl group,
(1-5 aaa) an amino lower alkyl group having one group selected from the group consisting of a lower alkanoyl group and a lower alkoxycarbonyl group on an amino group and / or a lower alkyl group or (1-20 aa) lower alkyl Examples include amino groups having 1 to 2 groups.
R ¹² is
(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) lower alkanoyl group,
(2-7) hydroxy lower alkyl group,
(2-8) a lower alkoxy lower alkyl group,
(2-9) a cyclo C3-C8 alkyl group,
(2-10) cyclo C3-C8 alkyl lower alkyl group,
(2-11 a) a phenyl group,
(2-12 a) selected from the group consisting of an amino group (more preferably N, N-di-lower alkylamino group) optionally having 1 to 2 lower alkyl groups on the phenyl group and a phenoxy group Phenyl lower alkyl group optionally having 1 to 3 (preferably 1) groups,
(2-13) 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) represents a tetrahydropyranyl group or (2-16) a lower alkanoyloxy lower alkyl group.
Furthermore, a more preferred definition of R ¹² is
(2-2) a lower alkyl group,
(2-4) a lower alkenyl group,
(2-6) lower alkanoyl group,
(2-7) hydroxy lower alkyl group,
(2-8) lower alkoxy lower alkyl group or (2-9) cyclo C3-C8 alkyl group. )
Or a group represented by the following general formula (II):
R ²¹ -A ^2- (II)
Wherein, -A ² - is lower alkylene, lower alkenylene group or a group ^-A 21 ^{-O-A 22} - shows the.

Here, A ²¹ and A ²² are the same or different and each represents a C1-C5 alkylene group. However, 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 is pyrrolidinyl, imidazolidinyl, piperidyl, hexahydropyrimidinyl, piperazinyl, octahydroisoindole, azepanyl, azocanyl, azaspirononyl, azaspirodecanyl, diazaspirononyl, 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, cal Basolyl, spiro [cyclopentaneindolinyl, oxazolyl, isoxazolyl, oxadiazolyl, oxazolidinyl, isoxazolidinyl, oxadinanyl, morpholinyl, benzoxazolyl, dihydrobenzoxazolyl, benzooxazinyl, dihydrobenzoxazinyl, benzo Represents an N-containing heterocyclic group selected from the group consisting of oxazolyl, benzooxadiazolyl, thiazolyl, dihydrothiazolyl, isothiazolyl, thiadiazolyl, dihydrothiazinyl, thiazolidinylbenzothiazolyl and benzothiadiazolyl :
Here, on the N-containing heterocycle represented by R ²¹ , the following (1) to (4), (5 a), (6 a), (7) to (9), (10 a), 1 to 3 groups selected from the group consisting of (11 a), (12) and (13) may be substituted:
(1) halogen-substituted or unsubstituted lower alkyl group (2) lower alkenyl group (3) lower alkoxy group (4) hydroxy group (5 a) lower alkanoyloxy group or phenyl lower alkoxy group (6 a) phenyl group (7) Lower alkanoyl group (8) Carboxy group (9) Lower alkoxycarbonyl group (10a) Carbamoyl group which may have one or two lower alkyl groups (11a) Phenyl lower alkyl group (here, on the phenyl group, (It may have 1 to 2 lower alkoxy groups)
(12) Oxo group (13) Thioxo group Further, R ²¹ is more preferably defined as an imidazolidinyl group having 1 to 2 groups selected from the group consisting of a lower alkyl group and an oxo group; a lower alkyl group, an oxo group and a thioxo group. A piperidyl group having 1 to 2 groups selected from the group consisting of groups; an oxazolidinyl group having 1 to 2 groups selected from the group consisting of lower alkyl groups and oxo groups; selected from the group consisting of lower alkyl groups and oxo groups And an oxadinanyl group having 1 to 2 groups.]
Or a salt thereof.

Item 4.
Q is a group represented by the following general formula (I):

[Wherein, A ¹ represents a lower alkylene group.
Z represents O or S.
R ¹¹ is (1-1) hydrogen,
(1-2) a lower alkyl group,
(1-5 aa) On an amino group and / or a lower alkyl group, 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 (Preferably one group selected from the group consisting of halogen and lower alkoxy groups may be present on the phenyl group) and 1 to 2 groups selected from the group consisting of phenyl lower alkoxycarbonyl groups. An amino lower alkyl group which may be optionally substituted or an amino group which may have 1 to 2 (1-20a) lower alkyl groups.
R ¹² is
(2-1) Hydrogen,
(2-2) a lower alkyl group,
(2-4) a lower alkenyl group,
(2-6) lower alkanoyl group,
(2-7) hydroxy lower alkyl group,
(2-8) represents a lower alkoxy lower alkyl group or (2-9) a cyclo C3-C8 alkyl group. ]
The heterocyclic compound or its salt of claim | item 2 which shows these.

Item 5.
Q is a group represented by the following general formula (II):
R ²¹ -A ^2- (II)
[Wherein, -A ² -represents a lower alkylene group or a lower alkenylene group.
R ²¹ represents an N-containing heterocyclic group selected from the group consisting of pyrrolidinyl, imidazolidinyl, piperidyl, azepanyl, oxazolidinyl and oxadinanyl:
Here, on the N-containing heterocyclic ring represented by R ²¹ , 1 to 2 groups selected from the group consisting of the following (1), (12) and (13) may be substituted. :
(1) Halogen-substituted or unsubstituted lower alkyl group (12) oxo group (13) thioxo group]
The heterocyclic compound or its salt of claim | item 2 which shows these.

Item 6. The heterocyclic compound represented by the general formula (1) is
N- [5- (4-Benzo [b] thiophen-4-ylpiperazin-1-yl) pentyl] acetamide,
N- [5- (4-Benzo [b] thiophen-4-ylpiperazin-1-yl) pentyl] -2,4-difluorobenzamide,
N- [4- (4-Benzo [b] thiophen-4-ylpiperazin-1-yl) butyl] -N-cyclopropylacetamide,
5-methyl-2-pyrazinecarboxylic acid [4- (4-benzo [b] thiophen-4-ylpiperazin-1-yl) butyl] ethylamide,
4-thiazolecarboxylic acid [4- (4-benzo [b] thiophen-4-ylpiperazin-1-yl) butyl] ethylamide,
N- [4- (4-Benzo [b] thiophen-4-ylpiperazin-1-yl) butyl] -N-ethyl-acetamide,
N- [4- (4-Benzo [b] thiophen-4-ylpiperazin-1-yl) butyl] -N-isopropylacetamide,
N- [4- (4-Benzo [b] thiophen-4-ylpiperazin-1-yl) butyl] -N-ethylthioacetamide,
N-allyl-N- [4- (4-benzo [b] thiophen-4-ylpiperazin-1-yl) butyl] acetamide or N- [4- (4-benzo [b] thiophen-4-ylpiperazine- Item 5. The heterocyclic compound or a salt thereof according to Item 4, which is [1-yl) butyl] -N-tert-butylformamide.

Item 7. The heterocyclic compound represented by the general formula (1) is
1- [5- (4-Benzo [b] thiophen-4-ylpiperazin-1-yl) pentyl] -imidazolidin-2-one,
1- [5- (4-benzo [b] thiophen-4-ylpiperazin-1-yl) pentyl] -3-methylimidazolidin-2-one,
1- [5- (4-benzo [b] thiophen-4-ylpiperazin-1-yl) pentyl] -pyrrolidin-2-one,
1- [5- (4-benzo [b] thiophen-4-ylpiperazin-1-yl) pentyl] -pyrrolidine-2,5-dione,
1- [4- (4-benzo [b] thiophen-4-ylpiperazin-1-yl) butyl] azepan-2-one,
3- [6- (4-benzo [b] thiophen-4-ylpiperazin-1-yl) hexyl] oxazolidine-2-one,
3- [4- (4-Benzo [b] thiophen-4-ylpiperazin-1-yl) butyl] -4,4-dimethyloxazolidine-2-one,
3- [4- (4-Benzo [b] thiophen-4-ylpiperazin-1-yl) butyl] -4-methyloxazolidine-2-one,
3- [4- (4-Benzo [b] thiophen-4-ylpiperazin-1-yl) butyl] -oxazolidine-2-one,
1- [4- (4-benzo [b] thiophen-4-ylpiperazin-1-yl) butyl] pyrrolidin-2-one,
1- [4- (4-benzo [b] thiophen-4-ylpiperazin-1-yl) butyl] piperidin-2-one,
1-[(E) -4- (4-benzo [b] thiophen-4-ylpiperazin-1-yl) -2-butenyl] -3-methylimidazolidin-2-one,
1- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] piperidin-2-thione or 3- [4- (4-benzo [b] thiophen-4-ylpiperazine Item 6. The heterocyclic compound or a salt thereof according to Item 5, which is -1-yl) butyl] -4-methyloxazolidine-2-one.

  Specific examples of the groups shown in the general formula are as follows.

  Examples of the lower alkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms). More specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-ethylpropyl, isopentyl, neopentyl, n-hexyl, 1,2 , 2-trimethylpropyl, 3,3-dimethylbutyl, 2-ethylbutyl, isohexyl, 3-methylpentyl group and the like.

  Examples of the lower alkylene group include linear or branched alkylene groups having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms). More specifically, methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethylethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, 1- Examples include methyltetramethylene, 1-ethyltetramethylene, 2-methyltetramethylene, 2-ethyltetramethylene, pentamethylene, hexamethylene groups and the like.

  Examples of the lower alkenylene group include straight-chain or branched alkenylene groups having 1 to 2 carbon atoms and having 2 to 6 carbon atoms (preferably 2 to 4 carbon atoms). More specifically, vinylene, 1-propenylene, 1-methyl-1-propenylene, 2-methyl-1-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-hexene Xenylene, 3,3-dimethyl-1-propenylene, 2-ethyl-1-propenylene, 1,3,5-hexatrienylene, 1,3-hexadienylene, 1,4-hexadienylene group and the like are included.

  Examples of the C1-C5 alkylene group include linear or branched alkylene groups having 1 to 5 carbon atoms. More specifically, methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethylethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene Groups etc. are included.

In the general formula, examples of the group represented by —A ²¹ —O—A ²² — include —CH ₂ —O—CH ₂ —, —CH ₂ —O— (CH ₂ ) ₂ —, —CH ₂ —O. _{- (CH 2) 3 -,} - CH 2 -O- (CH 2) 4 -, - CH 2 -O- (CH 2) 5 -, - (CH 2) 2 -O- (CH 2) 2 -, _{- (CH 2) 3 -O- (} CH 2) 3 -, - CH (CH 3) -CH 2 -O-CH (CH 3) -CH 2 - and the like.

  Examples of the lower alkenyl group include a straight chain or branched alkenyl group having 1 to 3 carbon atoms and having 2 to 6 carbon atoms (preferably 2 to 4 carbon atoms). Of both. More specifically, vinyl, 1-propenyl, 2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-propenyl, 2-butenyl, 1- Butenyl, 3-butenyl, 2-pentenyl, 1-pentenyl, 3-pentenyl, 4-pentenyl, 1,3-butadienyl, 1,3-pentadienyl, 2-penten-4-yl, 2-hexenyl, 1-hexenyl, 5-hexenyl, 3-hexenyl, 4-hexenyl, 3,3-dimethyl-1-propenyl, 2-ethyl-1-propenyl, 1,3,5-hexatrienyl, 1,3-hexadienyl, 1, 4-hexadienyl group and the like are included.

  Examples of the lower alkynyl group include linear or branched alkynyl groups having 2 to 6 carbon atoms (preferably 2 to 4 carbon atoms). More specifically, ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 2-hexynyl group and the like are included.

  Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

  Examples of the halogen-substituted lower alkyl group include the above-described lower alkyl groups substituted with 1 to 7, more preferably 1 to 3, halogen atoms. 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, , Hexyl 6-trifluoromethyl, 6-chloro hexyl, perfluorohexyl group or the like.

  Examples of the lower alkoxy group include linear or branched alkoxy groups having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms). More specifically, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, iso Hexyloxy, 3-methylpentyloxy groups and the like are included.

  Examples of the aryl group include phenyl, biphenyl, naphthyl, dihydroindenyl, 9H-fluorenyl group and the like.

  Examples of the aryloxy group include phenyloxy and naphthyloxy groups.

  Examples of the arylthio group include phenylthio and naphthylthio groups.

  Examples of aroyl groups include benzoyl and naphthoyl groups.

  Examples of the lower alkylthio group include linear or branched alkylthio groups having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms). More specifically, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, tert-butylthio, n-pentylthio, n-hexylthio group and the like are included.

  Examples of the halogen-substituted lower alkoxy group include the exemplified lower alkoxy groups substituted with 1 to 7, preferably 1 to 3, halogen atoms. 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, 4-bromobutoxy, 2-chlorobutoxy, 5,5,5-trifluoropentoxy, 5-chloropentoxy, 6,6,6- Trifluorohexyloxy, 6- Rollo hexyloxy group and the like.

  Examples of the lower alkanoyl group include linear or branched alkanoyl groups having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms). More specifically, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, hexanoyl group and the like are included.

  Examples of the lower alkanoyloxy group include an alkanoyloxy group in which the alkanoyl moiety is a linear or branched alkanoyl group having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms). More specifically, formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, tert-butylcarbonyloxy, hexanoyloxy groups and the like are included.

  The lower alkanoyloxy lower alkyl group has 1 to 3 and preferably 1 lower alkanoyloxy groups exemplified above, and is a straight chain or branched chain having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms). An alkyl group can be mentioned. More specifically, formyloxymethyl, 3-acetyloxypropyl, 2-propionyloxyethyl, butyryloxymethyl, 2-isobutyryloxyethyl, 3-pentanoyloxypropyl, tert-butylcarbonyloxymethyl, hexa Noyloxymethyl group and the like are included.

  Examples of the protective group for the hydroxy group include a lower alkyl group (preferably a linear or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)) and a lower alkanoyl group (preferably carbon atoms). Straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms), straight chain or branched chain whose lower alkyl moiety is 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms) A phenyl lower alkyl group which is a chain alkyl group and may have 1 to 3, preferably 1 substituent such as a halogen atom on the phenyl group.

  Examples of the protected hydroxy group include a lower alkoxy group exemplified above, a phenyl lower alkoxy group wherein the lower alkanoyl moiety is the lower alkanoyloxy group exemplified above, and the lower alkoxy moiety is the lower alkoxy group exemplified above (on the phenyl group). 1 to 3 substituents such as a halogen atom, and preferably 1 substituent). More specifically, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, iso Hexyloxy, 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, 1,1-dimethyl-2-phenylethoxy, 2-methyl-3- Enirupuropokishi group, and the like.

  As the hydroxy lower alkyl group, the above-described lower alkyl group having 1 to 5, preferably 1 to 3 hydroxy groups (preferably a straight chain having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms) or A branched alkyl group). More specifically, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 3,4-dihydroxybutyl, 1,1-dimethyl-2 -Hydroxyethyl, 5-hydroxypentyl, 6-hydroxyhexyl, 3,3-dimethyl-3-hydroxypropyl, 2-methyl-3-hydroxypropyl, 2,3,4-trihydroxybutyl, perhydroxyhexyl group, etc. included.

  Examples of the protective group for the hydroxy lower alkyl group include a linear or branched alkyl group having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms) and a lower alkanoyl group (preferably having 1 to 6 carbon atoms (more Preferably, it is a linear or branched alkanoyl group having 1 to 4 carbon atoms), and the lower alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms). Mention may be made of phenyl lower alkyl groups.

  Examples of the protected hydroxy lower alkyl group include the protected hydroxy groups exemplified above (preferably a lower alkoxy group, a lower alkanoyloxy group or a phenyl lower alkoxy group (1 to 3 substituents such as a halogen atom on the phenyl group). , Preferably 1 may be present)) 1-5, preferably 1-3, of the above-described lower alkyl group (preferably having 1 to 6 carbon atoms (more preferably having 1 to 4 carbon atoms)) Straight chain or branched alkyl group). More specifically, methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-n-propoxyethyl, 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-benzene Zyloxyethyl, 2- (2-phenylethoxy) ethyl, 2- (1-phenylethoxy) ethyl, 2- (3-phenylpropoxy) ethyl, 2- (4-phenylbutoxy) ethyl, 2- (5-phenyl) Pentyloxy) ethyl, 2- (6-phenylhexyloxy) ethyl, 2- (1,1-dimethyl-2-phenylethoxy) ethyl, 2- (2-methyl-3-phenylpropoxy) ethyl, 3-ethoxypropyl 2,3-diethoxypropyl, 4-ethoxybutyl, 3,4-diethoxybutyl, 1,1-dimethyl-2-ethoxyethyl, 5-ethoxypentyl, 6-ethoxyhexyl, 3,3-dimethyl-3 -Ethoxypropyl, 2-methyl-3-ethoxypropyl, 2,3,4-triethoxybutyl group and the like are included.

  The lower alkoxycarbonyl group is an alkoxy in which the lower alkoxy moiety is the lower alkoxy group exemplified above (preferably a linear or branched alkoxy group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)). A carbonyl group can be mentioned. More specifically, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, n-pentyloxycarbonyl, neopentyloxy, n-hexyloxycarbonyl, isohexyloxycarbonyl, 3-methylpentyloxycarbonyl group and the like are included.

  As the lower alkylsulfonyl group, an alkylsulfonyl in which the lower alkyl moiety is the above-exemplified lower alkyl group (preferably a linear or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)). The group can be mentioned. More specifically, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl, sec-butylsulfonyl, n-pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl , N-hexylsulfonyl, isohexylsulfonyl, 3-methylpentylsulfonyl group and the like.

  Examples of the cyclo C3-C8 alkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.

  The amino group optionally having a group 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 as a substituent includes Lower alkyl group (preferably linear or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)); lower alkanoyl group exemplified above (preferably 1 to 6 carbon atoms (more preferably) Is a linear or branched alkanoyl group having 1 to 4 carbon atoms); the above-exemplified cyclo C3-C8 alkyl group, aryl group (preferably phenyl group); the above-exemplified aryl group (preferably phenyl group); Mention may be made of amino groups which may have 1 to 2 groups selected from the group consisting of the exemplified aroyl groups (preferably benzoyl groups). More specifically, for example, amino, N-methylamino, N, N-dimethylamino, N-ethylamino, N, N-diethylamino, Nn-propylamino, N-isopropylamino, N-formylamino, N-acetylamino, N-phenylamino, N-benzoylamino, N-acetyl-N-cycloC3-C8 alkylamino group and the like can be mentioned.

  As the morpholinylcarbonyl lower alkenyl group, the lower alkenyl moiety is the above-exemplified lower alkenyl group (preferably a linear or branched alkenyl group having 2 to 6 carbon atoms (more preferably 2 to 4 carbon atoms)). Mention may be made of certain morpholinylcarbonyl lower alkenyl groups. More specifically, 1- (or 2-) (4-morpholinylcarbonyl) vinyl, 1- (or 2- or 3-) (4-morpholinyl) 1- (or 2-) propenyl groups are included. .

  As the morpholinylcarbonyl lower alkyl group, the lower alkyl moiety is the above-exemplified lower alkyl group (preferably a linear or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)). Mention may be made of certain morpholinylcarbonyl lower alkyl groups. More specifically, 4-morpholinylcarbonylmethyl, 1- (or 2-) (4-morpholinylcarbonyl) ethyl, 1- (or 2- or 3-) (4-morpholinylcarbonyl)- 1- (or 2-) propyl groups are included.

  Examples of the pyrrolidinyl group optionally having an oxo group include pyrrolidinyl groups optionally having 1 to 2 (preferably 1) oxo groups. Specifically, (1-, 2-, or 3-) pyrrolidinyl, (2- or 3-) oxo-1-pyrrolidinyl, (3-, 4-, or 5-) oxo-2-pyrrolidinyl, (2 Mention may be made of the group-, 4- or 5-) oxo-3-pyrrolidinyl.

  The dihydropyrazolyl group optionally having a group selected from the group consisting of an oxo group and a lower alkyl group has 1 to 2 groups selected from the group consisting of an oxo group and the lower alkyl group exemplified above. The dihydropyrazolyl group which may be sufficient is mentioned.

  As the aryl group which may have a group selected from the group consisting of halogen and halogen-substituted lower alkyl group on the aryl group, the aryl moiety is phenyl, naphthyl, etc. 1 to 5, preferably halogen and the above-exemplified halogen-substituted lower alkyl group (preferably a linear or branched alkyl group having 1 to 6 halogen atoms (more preferably 1 to 4 carbon atoms)), preferably Mention may be made of aryl groups which may have 1 to 3, more preferably 1.

  As the aryl lower alkyl group optionally having halogen, the above-exemplified lower alkyl group (preferably having a carbon number of 1 to 3 and preferably 1 aryl group in which the aryl moiety is phenyl, naphthyl, etc.) 1 to 6 (more preferably, a linear or branched alkyl group having 1 to 4 carbon atoms). The substituent on the aryl group may be substituted with 1 to 5, preferably 1 to 3, and more preferably 1 to 2 halogens as exemplified above.

  As the amino lower alkanoyl group, a linear or branched lower alkanoyl group (preferably having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)) having 1 to 3 (preferably 1) amino groups. A branched alkanoyl group). More specifically, aminoacetyl, 3-aminopropionyl, 4-aminobutyryl, 3,4-diaminobutyryl, 3,3-dimethyl-3-aminopropionyl, 4-aminobutyryl, 5-aminovaleryl group and the like are included.

  As the amino lower alkanoyl group optionally having a lower alkanoyl group on the amino group, the exemplified amino lower alkanoyl group having 1 to 2 (preferably 1) of the lower alkanoyl groups exemplified above as substituents Can be mentioned. 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-propynylamino) propionyl, 4- (N-formylamino) butyryl, 5- (N-acetylamino) valeryl group and the like are included.

  As the carbamoyl lower alkyl group, the lower alkyl group described above having 1 to 3, more preferably 1 to 2 carbamoyl groups (preferably having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)). Chain or branched alkyl group).

  The amino lower alkyl group has 1 to 5 amino groups, preferably 1 amino group, preferably the above-described lower alkyl groups (preferably having 1 to 6 carbon atoms (more preferably having 1 to 4 carbon atoms), linear or branched. A branched alkyl group). More specific examples include aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1,1-dimethyl-2-aminoethyl, 2-methyl-3-aminopropyl, N, N-dimethylaminomethyl, N-methyl-N-ethylaminomethyl, N-methylaminomethyl, 2- (N-methylamino) ethyl, 1-methyl-2- ( N, N-dimethylamino) ethyl, 1-methyl-2- (N, N-diethylamino) ethyl, 2- (N, N-dimethylamino) ethyl, 2- (N, N-diethylamino) ethyl, 2- ( N, N-diisopropylamino) ethyl, 3- (N, N-dimethylamino) propyl, 3- (N, N-diethylamino) propyl and the like can be mentioned.

  On the amino group and / or on the lower alkyl group, a lower alkyl group, a lower alkanoyl group, a hydroxy lower alkyl group, a carbamoyl lower alkyl group, an indolylcarbonyl group, an aryl group (on the aryl group, from a halogen and a lower alkoxy group) An amino lower alkyl group optionally having a group selected from the group consisting of an aryl lower alkoxycarbonyl group, and 1-5 amino groups, The lower alkyl group exemplified above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)) is preferable. On the amino group and / or the lower alkyl group, the exemplified lower alkyl group (preferably a linear or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)), Illustrative lower alkanoyl group (preferably a linear or branched alkanoyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)), the above exemplified hydroxy lower alkyl group (preferably 1 hydroxy group) A straight chain or branched alkyl group having 1 to 3 carbon atoms (preferably 1 to 4 carbon atoms) having 3 carbon atoms, a carbamoyl lower alkyl group exemplified above (preferably a carbon having 1 to 3 carbamoyl groups). A straight or branched alkyl group having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms), an indolylcarbonyl group, a halogen selected from the group consisting of the above-mentioned halogens and lower alkoxy groups. 1 to 5 groups, preferably 1 selected from the group consisting of an aryl group (preferably a halogen and a linear or branched alkoxy group having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms). A phenyl group which may have ˜3), and an alkoxy moiety having a lower alkoxy group as exemplified above (preferably a linear or branched alkoxy having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms). 1 to 2 and preferably 1 to 2 groups selected from the group consisting of alkoxycarbonyl groups having 1 to 3 and preferably 1 aryl group as exemplified above.

  As the lower alkoxy lower alkyl group, 1 to 3 lower alkoxy groups exemplified above (preferably linear or branched alkoxy groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms) are preferable, preferably Can be exemplified by the lower alkyl group exemplified above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)). More specifically, methoxymethyl, 2-methoxyethyl, 1-ethoxyethyl, 2-ethoxyethyl, 2-isobutoxyethyl, 2,2-dimethoxyethyl, 2-methoxy-1-methylethyl, 2-methoxy- 1-ethylethyl, 3-methoxypropyl, 3-ethoxypropyl, 2-isopropoxyethyl, 3-isopropoxypropyl, 3-n-butoxypropyl, 4-n-propoxybutyl, 1-methyl-3-isobutoxypropyl, 1,1-dimethyl-2-n-pentyloxyethyl, 5-n-hexyloxypentyl, 6-methoxyhexyl, 1-ethoxyisopropyl, 2-methyl-3-methoxypropyl group and the like are included.

  As the aroyl lower alkyl group, the above exemplified lower alkyl group (preferably having 1 to 6 carbon atoms (preferably 1 carbon atom) having 1 to 5, preferably 1 aroyl group (preferably benzoyl group) exemplified above. -4) linear or branched alkyl groups). More specific examples include benzoylmethyl, 2-benzoylethyl, 1-benzoylethyl, 1- (or 2-) naphthoylmethyl group and the like.

  As the aryl lower alkyl group which may have a group selected from a group consisting of a lower alkyl group, a lower alkoxy group, a hydroxy group, a halogen and a nitro group on the aryl group, the aryl moiety is phenyl, naphthyl or the like. The above-described lower alkyl group having 1 to 3 and preferably 1 aryl group (preferably a linear or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)) Can be mentioned. Examples of the substituent on the aryl group include the lower alkyl group exemplified above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)), and the lower alkoxy group exemplified above. 1 group selected from the group consisting of a group (preferably a linear or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)), a hydroxy group, the above-exemplified halogen and nitro group. -5, preferably 1-3, more preferably 1-2 may be substituted.

  The aryloxy lower alkyl group optionally having a group selected from a group consisting of a lower alkyl group, a lower alkoxy group, a halogen and a cyano group on the aryl group is an aryl whose aryl moiety is phenyl, naphthyl or the like. Examples of the lower alkyl group exemplified above having 1 to 3 groups, preferably 1 (preferably a linear or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)) be able to. Examples of the substituent on the aryl group include the lower alkyl group exemplified above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)), and the lower alkoxy group exemplified above. 1 to 5 groups selected from the group consisting of a group (preferably a linear or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)) and the halogens exemplified above and a cyano group , Preferably 1 to 3 may be substituted.

  As the aryl lower alkoxy group, the above exemplified lower alkoxy group (preferably having 1 to 6 carbon atoms (more preferably carbon atoms) having 1 to 3 aryl groups, preferably 1 aryl group such as phenyl, naphthyl, etc.) And straight chain or branched alkoxy groups of formulas 1 to 4).

  Examples of the amino group optionally having a lower alkyl group include the lower alkyl groups exemplified above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)). An amino group which may have 1 to 2 can be mentioned. More specifically, examples include amino, N-methylamino, N, N-dimethylamino, N-ethylamino, N, N-diethylamino, Nn-propylamino, N-isopropylamino and the like. .

  As the aryl lower alkenyl group, the above-exemplified lower alkenyl group (preferably having 2 to 6 carbon atoms (more preferably carbon atoms) having 1 to 3, preferably 1 aryl groups in which the aryl moiety is phenyl, naphthyl, or the like. And a linear or branched alkenyl group represented by formulas 2 to 4).

  A group 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 optionally having a lower alkyl group, a halogen, and a nitro group on the aryl group. As the aryl lower alkenyl group which may be contained, the aryl lower alkenyl group exemplified above (preferably a straight chain or branched chain having 2 to 6 carbon atoms (preferably 2 to 4 carbon atoms) substituted with one phenyl. Alkenyl group). Examples of the substituent on the aryl group include the lower alkyl group exemplified above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)), and the lower alkoxy group exemplified above. A group (preferably a linear or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)), the above-described halogen-substituted lower alkyl group (preferably carbon having 1 to 3 halogen atoms) A linear or branched alkyl group having 1 to 6 (preferably 1 to 4 carbon atoms), the above-described halogen-substituted lower alkoxy group (preferably 1 to 6 carbon atoms having 1 to 3 halogen atoms (preferably Is a linear or branched alkyl group having 1 to 4 carbon atoms) and an amino group (preferably having 1 to 6 carbon atoms (preferably having 1 to 4 carbon atoms), which may have the lower alkyl group exemplified above. ) Linear or branched 1 to 5 groups, preferably 1 to 3, more preferably 1 to 2 groups selected from the group consisting of the halogens and nitro groups exemplified above. May be substituted. As the aryl group which may have a group selected from the group consisting of halogen and lower alkyl groups, the aryl moiety is phenyl, naphthyl, etc., and the above exemplified halogen and the above exemplified lower group are present on the aryl moiety. 1 to 5, preferably 1 to 3, more preferably 1 alkyl group (preferably a linear or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)) The aryl group which may have may be mentioned.

  An amino group optionally having a lower alkyl group; an amino lower alkyl group optionally having a lower alkyl group and an aryl group optionally having a group selected from the group consisting of a halogen and a lower alkyl group; As the cyclo C3-C8 alkyl group optionally having a group selected from the group consisting of the above-mentioned amino groups optionally having a lower alkyl group (preferably having 1 to 6 carbon atoms (more preferably carbon The amino group optionally having 1 to 2 linear or branched alkyl groups of formulas 1 to 4), and the above-described amino lower alkyl group (which may have the above-mentioned lower alkyl group) Preferably, 1 to 5 amino groups which may have 1 to 2 linear or branched alkyl groups having 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms) on the amino group, Preferably 1 carbon number 6 (preferably a linear or branched alkyl group having 1 to 4 carbon atoms), and an aryl group which may have a group selected from the group consisting of the above-exemplified halogen and lower alkyl groups ( Preferably, the aryl moiety is phenyl, naphthyl or the like, and on the aryl moiety, the exemplified halogen and the exemplified lower alkyl group (preferably having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)). 1 to 5 and preferably 1 to 3 groups, preferably 1 group selected from the group consisting of 1 to 5, preferably 1 to 3 aryl groups which may have 1 to 3 linear or branched alkyl groups) And the exemplified cyclo C3-C8 alkyl group.

  As the cyclo C3-C8 alkyl lower alkyl group, the above-exemplified lower alkyl group (preferably having 1 to 6 carbon atoms (more preferably) having 1 to 3, preferably 1 cyclo C3-C8 alkyl group described above. And straight chain or branched alkyl groups having 1 to 4 carbon atoms).

  As the arylthio lower alkyl group, the above exemplified lower alkyl group (preferably having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)) having 1 to 3, preferably 1 arylthio groups as described above. Chain or branched alkyl group).

  The adamantyl lower alkyl group has 1 to 3 and preferably 1 adamantyl groups, and is preferably a linear or branched lower alkyl group (preferably having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)). A branched alkyl group).

  Lower alkyl group substituted by a heterocyclic group selected from the group consisting of piperidyl group, tetrahydropyranyl group, pyridyl group, thienyl group, imidazolyl group, tetrazolyl group, benzimidazolyl group, isoindolyl group, thiazolidinyl group and indolyl group (wherein On the heterocyclic group, a group selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen, an oxo group, and a thioxo group) may be used as a piperidyl group, a tetrahydropyranyl group, a pyridyl group, The above-mentioned lower alkyl groups exemplified above substituted with 1 to 3, preferably 1 heterocyclic group selected from the group consisting of thienyl group, imidazolyl group, tetrazolyl group, benzimidazolyl group, isoindolyl group, thiazolidinyl group and indolyl group Is carbon number 1-6 (more preferably carbon number Include a linear or branched alkyl group having to 4)). Examples of the substituent on the heterocyclic group include the lower alkyl group exemplified above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)), and the lower moiety exemplified above. A group selected from the group consisting of an alkoxy group (preferably a linear or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)), the above-exemplified halogen, oxo group and thioxo group; 1 to 5, preferably 1 to 3, may be substituted.

  As the aryl lower alkenyl group (which may have an aryl group on the lower alkenyl group), the aryl lower alkenyl group exemplified above (preferably having 2 to 6 carbon atoms (preferably having 1 carbon atom substituted) 2-4) linear or branched alkenyl groups). As a substituent on the lower alkenyl group, 1 to 3, preferably 1 to 2, more preferably 1 of the above exemplified aryl groups (preferably phenyl group) may be substituted.

  The lower alkenyl group substituted by the heterocyclic group selected from the group consisting of benzodioxolyl group, pyridyl group, furyl group and imidazolyl group is a complex selected from the group consisting of benzodioxolyl group, pyridyl group and imidazolyl group. The above-mentioned lower alkenyl groups exemplified above substituted with 1 to 3 ring groups, preferably 1 (preferably linear or branched alkenyl groups having 2 to 6 carbon atoms (more preferably 2 to 4 carbon atoms)) Can be mentioned.

  The benzodioxolyloxy lower alkyl group has 1 to 3, preferably 1 benzodioxolyloxy groups as exemplified above, preferably 1 to 6 carbon atoms (preferably 1 carbon atoms). -4) linear or branched alkyl groups).

  The pyridylthio lower alkyl group has 1 to 3 and preferably 1 pyridylthio groups, and is preferably a straight or branched lower alkyl group (preferably having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)). A branched alkyl group).

  An aryl lower alkyl group which may have a group selected from the group consisting of an amino group and an aryloxy group optionally having a lower alkyl group on the aryl group includes an aryl moiety such as phenyl, naphthyl, etc. The above-described lower alkyl group (preferably having 1 to 6 carbon atoms (more preferably having 1 to 4 carbon atoms), which may have 1 to 3 aryl groups, preferably 1 A branched alkyl group). As the substituent on the aryl group, an amino group (preferably having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms), which may have the above-described lower alkyl group, is linear or branched. 1 to 5, preferably 1 to 3 groups selected from the group consisting of the above-exemplified aryloxy groups (preferably phenoxy groups) and amino groups optionally having 1 to 2 alkyl groups) Preferably one may be substituted.

  As the lower alkyl group substituted by a heterocyclic group selected from the group consisting of a furyl group and a pyridyl group, 1 to 3 heterocyclic groups selected from the group consisting of a furyl group and a pyridyl group are substituted. Examples thereof include the lower alkyl groups exemplified above (preferably linear or branched alkyl groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)).

As the heterocyclic group,
A saturated 3-8 membered (preferably 5-8 membered) heteromonocyclic group containing from 1 to 4 (preferably 1 to 2) nitrogen atoms (eg pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, hexahydropyrimidinyl) , Piperazinyl, octahydroisoindole, azepanyl, azocanyl, etc.);
A saturated 3 to 8 membered (more preferably 5 or 6 membered) complex unit containing 1 to 2 (preferably 1) oxygen atoms and 1 to 3 (preferably 1 to 2) nitrogen atoms A cyclic group (eg, oxazolidinyl, isoxazolidinyl, morpholinyl, etc.);
A spiro saturated heterocyclic group containing 1 to 2 nitrogen atoms (for example, azaspirononanyl (for example, 1-azaspiro [4,4] nonanyl, 2-azaspiro [4,4] nonanyl, etc.), azaspiro Decanyl (eg, 1-azaspiro [4,5] decanyl, 2-azaspiro [4,5] decanyl, etc.), diazaspirononanyl (eg, 1,3-diazaspiro [4,4] nonanyl, 1,4 -Diazaspiro [4,4] nonanyl etc.));
A saturated 3-8 membered (more preferably 5 or 6 membered) heteromonocyclic group containing 1-2 sulfur atoms and 1-3 nitrogen atoms (eg, thiazolidinyl, etc.);
A saturated 3-8 membered (more preferably 5 or 6 membered) heteromonocyclic group containing 1-2 oxygen atoms (eg, tetrahydrofuryl, tetrahydropyranyl, oxiranyl, oxolanyl, dioxolanyl, etc.);
A saturated 3-8 membered (more preferably 5 or 6 membered) heteromonocyclic group containing 1 to 2 sulfur atoms (preferably 1), such as tetrathienyl, tetrahydrothiopyranyl, etc .;
An unsaturated 3-8 membered (more preferably 5 or 6 membered) heteromonocyclic group containing 1 to 4 (preferably 1 to 3) nitrogen atoms (eg pyrrolyl, dihydropyrrolyl (eg 1H- 2,5-dihydropyrrolyl etc.), imidazolyl (eg 1H-imidazolyl etc.), dihydroimidazolyl (eg 1H-2,3-dihydroimidazolyl etc.), triazolyl (eg 4H-1,2,4-triazolyl 1H -1,2,3-triazolyl, 2H-1,2,3-triazolyl etc.), dihydrotriazolyl (eg 1H-4,5-dihydro-1,2,4-triazolyl etc.), pyrazolyl, dihydropyrazolyl (For example, 4,5-dihydropyrazolyl and the like), pyridyl, dihydropyridyl (for example, 1,2-dihydropyridyl and the like), pyrimidinyl, dihydropyridyl and the like. Limidinyl (such as 1,6-dihydropyrimidinyl), tetrahydropyrimidinyl (such as 1,2,3,4-tetrahydropyrimidinyl), pyrazinyl, dihydropyrazinyl (such as 1,2-dihydropyrazinyl), pyridazinyl, tetrazolyl (For example, 1H-tetrazolyl, 2H-tetrazolyl, etc.) etc.);
An unsaturated 3-8 membered (more preferably 5 membered) heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (eg thiazolyl, dihydrothiazolyl (eg 2 , 3-dihydrothiazolyl), isothiazolyl, thiadiazolyl (eg, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydro Thiazinyl, etc.);
Unsaturated 3 to 8 membered (more preferably 5 or 6 membered) complex containing 1 to 2 (preferably 1) oxygen atom and 1 to 3 (preferably 1 to 2) nitrogen atoms Monocyclic groups (eg, oxazolyl, isoxazolyl, oxadiazolyl (eg, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.));
3 to 8 membered (more preferably 5 or 6 membered) unsaturated heteromonocyclic groups having 1 to 2 sulfur atoms (eg thienyl, dihydrothienyl etc.);
3 to 8 membered (more preferably 5 or 6 membered) unsaturated heterocyclic monocyclic group having 1 to 2 oxygen atoms (for example, furyl group, pyranyl group, etc.);
A 3- to 8-membered (more preferably 5- or 6-membered) unsaturated heteromonocyclic group having 1 oxygen atom and 1 to 2 sulfur atoms (for example, dihydrooxathinyl, etc.);
An unsaturated condensed heterocyclic group containing 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.), benzimidazolyl, imidasopyridyl (eg, imidazo [1,2-a] pyridyl, etc.), quinolyl, dihydroquinolyl (eg, 1,2-dihydroquinolyl, etc.), Tetrahydroquinolyl (such as 1,2,3,4-tetrahydroquinolyl), isoquinolyl, cinolinyl, indazolyl, quinazolinyl, dihydroquinazolinyl (such as 3,4-dihydroquinazolinyl), benzotriazolyl (such as benzotriazolyl) [D] [1,2,3] triazolyl, etc.), naphthyridyl (eg, 1.8-naphth Chylidyl etc.), dihydronaphthylidyl (eg 1,2 dihydro-1.8-naphthyridyl etc.), carbazolyl etc.);
An unsaturated condensed heterocyclic group containing 1 to 2 sulfur 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, dihydrobenzothiazinyl (2H-3,4-dihydrobenzo [b] [1,4] thiazinyl etc.) thienopyrazinyl (eg thieno [3,2- b] pyrazinyl and the like));
An unsaturated condensed heterocyclic group containing 1 to 2 (preferably 1) oxygen atom and 1 to 3 (preferably 1 to 2) nitrogen atoms (for example, benzoxazolyl (for example, Benzo [d] oxazolyl etc.), dihydrobenzoxazolyl (eg 2,3-dihydroxybenzo [d] oxazolyl etc.), benzoxazinyl (eg benzo [b] [1,4] oxazinyl etc.), dihydro Benzoxazinyl (eg, 2H-3,4-dihydroxybenzo [b] [1,4] oxazinyl, etc.), benzoxazolyl, benzoxdiazolyl, furopyrrolyl (eg, 4H-furo [3,2-b ] Pyrrolyl etc.));
A spiro unsaturated fused heterocyclic group containing 1 to 2 nitrogen atoms (eg spiro [cyclopentaneindolinyl] (eg spiro [cyclopentane-1,3′-indolinyl] etc.);
An unsaturated condensed heterocyclic group having 1 to 4 oxygen atoms (for example, benzofuryl, dihydrobenzofuryl (for example, 2,3-dihydrobenzofuryl and the like)), benzodioxolyl (for example, benzo [d] [1, 3] oxolyl, etc.), dihydrobenzodioxinyl (eg, 2,3-dihydrobenzo [b] [1,4] dioxinyl, etc.);
.Unsaturated condensed heterocyclic groups having 1 to 2 sulfur atoms (for example, benzothienyl, etc.)
And the like, and the like.

  As an N-containing heterocyclic group, a saturated 3 to 8 member (preferably 5 to 8 member) heterocyclic monocyclic group containing 1 to 4 (preferably 1 to 2) nitrogen atoms, 1 to 2 Spiro saturated heterocyclic group containing nitrogen atom, unsaturated 3-8 membered (more preferably 5 or 6 membered) heterocyclic monocyclic group containing 1 to 4 (preferably 1 to 3) nitrogen atoms, 1 Unsaturated fused heterocyclic group containing -4 (preferably 1 to 2) nitrogen atoms, Spiro unsaturated fused heterocyclic group containing 1 to 2 nitrogen atoms, 1 to 2 (preferably 1 Unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heterocyclic monocyclic group containing 1 to 3 oxygen atoms and 1 to 3 (preferably 1 to 2) nitrogen atoms, 1 to 2 ( Saturated 3 to 8 member (preferably 5 or preferably 1) containing 1 oxygen atom and 1 to 3 (preferably 1 to 2) nitrogen atoms 6-membered) heterocyclic monocyclic group, an unsaturated condensed heterocyclic group containing 1 to 2 (preferably 1) oxygen atoms and 1 to 3 (preferably 1 to 2) nitrogen atoms, 1 to An unsaturated 3- to 8-membered (preferably 5-membered) heteromonocyclic group containing 2 sulfur atoms and 1 to 3 nitrogen atoms, 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms; Saturated 3- to 8-membered (preferably 5- or 6-membered) heterocyclic monocyclic group, and unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms. .

  Examples of the saturated 3 to 8 member (preferably 5 to 8 member) heteromonocyclic group containing 1 to 4 (preferably 1 to 2) nitrogen atoms include pyrrolidinyl, imidazolidinyl, piperidyl, hexahydropyrimidinyl, Piperazinyl, octahydroisoindole, azepanyl, azocanyl and the like can be mentioned.

  Examples of the spiro saturated heterocyclic group containing 1 to 2 nitrogen atoms include azaspirononanyl (for example, 1-azaspiro [4,4] nonanyl, 2-azaspiro [4,4] nonanyl, etc.), aza Spirodecanyl (eg, 1-azaspiro [4,5] decanyl, 2-azaspiro [4,5] decanyl, etc.), diazaspirononyl (eg, 1,3-diazaspiro [4,4] nonanyl, 1, 4-diazaspiro [4,4] nonanyl and the like).

  Examples of unsaturated 3-8 membered (preferably 5 or 6 membered) heteromonocyclic groups containing 1 to 4 (preferably 1 to 3) nitrogen atoms include, for example, pyrrolyl, dihydropyrrolyl (for example, 1H -2,5-dihydropyrrolyl etc.), imidazolyl (eg 1H-imidazolyl etc.), dihydroimidazolyl (eg 1H-2,3-dihydroimidazolyl etc.), triazolyl (eg 4H-1,2,4-triazolyl) 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), dihydrotriazolyl (eg, 1H-4,5-dihydro-1,2,4-triazolyl, etc.), pyrazolyl, Pyridyl, dihydropyridyl (eg, 1,2-dihydropyridyl), pyrimidinyl, dihydropyrimidinyl (eg, 1,6-dihydropyrimidinyl), pyrazin Le, dihydro pyrazinyl (e.g., 1,2-dihydro-pyrazinyl, etc.), pyridazinyl, tetrazolyl (e.g., 1H-tetrazolyl, 2H- tetrazolyl, etc.) and the like.

  Examples of the unsaturated condensed heterocyclic group containing 1 to 4 (preferably 1 to 2) nitrogen atoms include indolyl, isoindolyl, indolinyl, isoindolinyl, hexahydroisoindolyl (for example, 2,3,3a , 4,7,7a-hexahydroisoindolyl, etc.), octahydroisoindolyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, quinazolinyl, dihydroquinazolinyl (3,4-dihydroquinazolinyl etc.), benzotriazolyl And carbazolyl.

  Examples of the spiro unsaturated condensed heterocyclic group containing 1 to 2 nitrogen atoms include spiro [cyclopentaneindolinyl] (for example, spiro [cyclopentane-1,3'-indolinyl] and the like).

  Unsaturated 3 to 8 membered (more preferably 5 or 6 membered) complex unit containing 1 to 2 (preferably 1) oxygen atom and 1 to 3 (preferably 1 to 2) nitrogen atoms Examples of the ring group include oxazolyl, isoxazolyl, oxadiazolyl (for example, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) and the like.

  Saturated 3 to 8 membered (preferably 5 or 6 membered) heteromonocyclic group containing 1 to 2 (preferably 1) oxygen atom and 1 to 3 (preferably 1 to 2) nitrogen atoms Examples thereof include oxazolidinyl, isoxazolidinyl, oxadinanyl, morpholinyl and the like.

  Examples of the unsaturated condensed heterocyclic group containing 1 to 2 (preferably 1) oxygen atom and 1 to 3 (preferably 1 to 2) nitrogen atoms include benzoxazolyl (for example, Benzo [d] oxazolyl, etc.), dihydrobenzoxazolyl (eg 2,3-dihydroxybenzo [d] oxazolyl etc.), benzoxazinyl (eg benzo [b] [1,4] oxazinyl etc.), Examples include dihydrobenzoxazinyl (for example, 2H-3,4-dihydroxybenzo [b] [1,4] oxazinyl and the like), benzoxazolyl, benzooxadiazolyl, and the like.

  Examples of the unsaturated 3- to 8-membered (preferably 5-membered) heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms include thiazolyl and dihydrothiazolyl (for example, 2 , 3-dihydrothiazolyl), isothiazolyl, thiadiazolyl (eg, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydro Thiazinyl and the like.

  Examples of the saturated 3- to 8-membered (preferably 5- or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms include thiazolidinyl.

  Examples of the unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms include benzothiazolyl and benzothiadiazolyl.

  Examples of the carbamoyl group optionally having a lower alkyl group include the lower alkyl groups exemplified above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms)). A carbamoyl group which may have 1 or 2 of. More specifically, for example, the carbamoyl group which may have the lower alkyl group includes carbamoyl, N-methylcarbamoyl, N, N-dimethylcarbamoyl, N-methyl-N-ethylcarbamoyl and N-ethylcarbamoyl groups. Etc.

As the aryl lower alkyl group (wherein the aryl group may have a lower alkoxy group), the above exemplified lower alkyl group having 1 to 3, preferably 1, of the above exemplified aryl groups ( Preferable examples include linear or branched alkyl groups having 1 to 6 carbon atoms (more preferably 1 to 4 carbon atoms). Here, 1 to 7, preferably 1 to 5, more preferably 1 to 2 of the exemplified lower alkoxy groups may be substituted on the aryl group. Specific examples of the aryl lower alkyl group (which may have a lower alkoxy group on the aryl group) include benzyl, 1-phenylethyl, 2-phenylethyl, 1-methyl-1-phenylethyl, 1, 1-dimethyl-2-phenylethyl, 1,1-dimethyl-3-phenylpropyl, (2-, 3- or 4-) methoxybenzyl, 2-[(2-, 3- or 4-) methoxyphenyl] ethyl 1-[(2-, 3- or 4-) methoxyphenyl] ethyl, 1-[(2-, 3- or 4-) methoxyphenyl] propyl, (2-, 3- or 4-) ethoxybenzyl, (2,4-, 3,4- or 3,5-) dimethoxybenzyl, 2-[(3,5- or 3,4-) dimethoxyphenyl] ethyl, 2- (2-ethoxyphenyl) ethyl, 1- ( - methoxyphenyl) butyl, naphthylmethyl group.







The heterocyclic compound represented by the general formula (1) (hereinafter referred to as the compound (1)) can be produced by various methods. , 8, 12 or 13.
[Reaction Formula-1]

[Wherein, R ¹¹ , R ¹² , A ¹ , and Z have the same meaning as described above, and X ₁₁ represents a halogen atom or a group that causes a substitution reaction similar to a halogen atom. ]
Here, examples of the group that causes the same substitution reaction as the halogen atom include a lower alkanesulfonyloxy group, an arylsulfonyloxy group, an aralkylsulfonyloxy group, and the like.

In the general formula (2), the halogen atom represented by X ₁₁ is a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The lower alkanesulfonyloxy group represented by X _11, specifically, methanesulfonyloxy, ethanesulfonyloxy, isopropanesulfonyl oxy, n- propane sulfonyloxy, n- butane sulfonyloxy, tert- butane sulfonyloxy, n Examples thereof include linear or branched alkanesulfonyloxy groups having 1 to 6 carbon atoms such as -pentanesulfonyloxy group and n-hexanesulfonyloxy group.

The arylsulfonyloxy group represented by X _11, for example, straight-chain or branched alkyl group having 1 to 6 carbon atoms as a substituent on the phenyl ring, 1 to 6 carbon atoms straight chain or branched Examples thereof include a phenylsulfonyloxy group and a naphthylsulfonyloxy group which may have 1 to 3 groups selected from the group consisting of an alkoxy group, a nitro group and a halogen atom. Specific examples of the phenylsulfonyloxy group which may have a substituent include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, Examples thereof include 2-nitrophenylsulfonyloxy and 3-chlorophenylsulfonyloxy. Specific examples of the naphthylsulfonyloxy group include an α-naphthylsulfonyloxy group and a β-naphthylsulfonyloxy group.

As the aralkylsulfonyloxy group represented by X ₁₁ , for example, a linear or branched alkyl group having 1 to 6 carbon atoms or a linear or branched alkoxy group having 1 to 6 carbon atoms as a substituent on the phenyl ring. A linear or branched alkylsulfonyloxy group having 1 to 3 carbon atoms or a naphthyl group substituted with a phenyl group which may have 1 to 3 groups selected from the group consisting of a group, a nitro group and a halogen atom Examples thereof include a substituted or straight chain or branched alkylsulfonyloxy group having 1 to 6 carbon atoms. Specific examples of the alkylsulfonyloxy group substituted with the phenyl group include benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, 4- Examples thereof include nitrobenzylsulfonyloxy and 3-chlorobenzylsulfonyloxy. Specific examples of the alkylsulfonyloxy group substituted with the naphthyl group include α-naphthylmethylsulfonyloxy and β-naphthylmethylsulfonyloxy groups.

  Compound (1a) is produced by reacting a compound of general formula (2) (hereinafter referred to as compound (2)) with a compound of general formula (3) (hereinafter referred to as compound (3)). Can do.

  This reaction is usually a conventional solvent that does not adversely influence the reaction, such as water; alcohol solvents such as methanol, ethanol, isopropanol, n-butanol, trifluoroethanol, ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone. Ether solvents such as tetrahydrofuran, dioxane, diethyl ether and diglyme; ester solvents such as methyl acetate and ethyl acetate; aprotic polar solvents such as acetonitrile, N, N-dimethylformamide and dimethyl sulfoxide; methylene chloride and ethylene chloride In a halogenated hydrocarbon-based solvent; or other organic solvents. Furthermore, this reaction is carried out in a mixed solvent of these conventional solvents. This reaction usually involves alkali metal (eg, sodium, potassium, etc.), alkali metal hydrogen carbonate (eg, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal hydroxide (eg, lithium hydroxide) Sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.), alkali metal carbonates (eg, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal lower alkoxides (eg, sodium methoxide, sodium ethoxide) Etc.), hydrides (eg, sodium hydride, potassium hydride, etc.), inorganic bases, trialkylamines (eg, 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), 1,4-diazabicyclo [2.2.2] octane (DABCO), The reaction is carried out in the presence of an organic base such as 1,8-diazabicyclo [5.4.0] undecene-7 (DBU). Moreover, when these bases are liquid, it can be used as a solvent.

  These basic compounds are used individually by 1 type or in mixture of 2 or more types.

  The usage-amount of a basic compound is 0.5-10 times mole normally with respect to a compound (2), Preferably it is 0.5-6 times mole.

  The above reaction can be carried out by adding an alkali metal iodide such as potassium iodide or sodium iodide as a reaction accelerator if necessary.

  The use ratio of the compound (2) and the compound (3) in the above reaction formula-1 is usually at least 0.5 times mol, preferably about 0.5 to 5 times mol of the latter with respect to the former.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating. Preferably, the reaction is performed at a temperature of about room temperature to about 150 ° C. for 1 to 30 hours.
[Reaction Formula-2]

[Wherein, R ¹¹ , R ¹² , A ¹ and Z have the same meaning as described above, and X ₁₂ represents a hydroxyl group, a halogen atom or a group causing a substitution reaction similar to a halogen atom. ]
Here, in the general formula (4), as the group which causes the same substitution reaction as halogen atom and a halogen atom represented by X _12, it can be exemplified the same groups as the X _11.

  Compound (1) is produced by reacting a compound of general formula (4) (hereinafter referred to as compound (4)) with a compound of general formula (5) (hereinafter referred to as compound (5)). Can do.

This reaction is performed under the same reaction conditions as in the reaction of Reaction Scheme-1.
In the case of compound (4) in which X ₁₂ represents a hydroxyl group, this reaction can be produced by subjecting compound (5) and compound (4) to a normal amide bond forming reaction. Known amide bond formation reactions can be widely applied to this amide bond formation reaction. Specifically, (b) a mixed acid anhydride method, that is, a method of reacting compound (4) with an alkylhalocarboxylic acid to form a mixed acid anhydride, and reacting this with compound (5), (b) an active ester The compound (4) is an active ester such as phenyl, p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, or active amide with benzoxazoline-2-thione. A method of reacting compound (5), (c) a carbodiimide method, that is, compound (4) is converted to compound (5) by dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (WSC), carbonyldiimidazole A method of condensation reaction in the presence of an activator such as (d) other methods, examples For example, compound (4) is converted to a carboxylic acid anhydride with a dehydrating agent such as acetic anhydride and compound (5) is reacted therewith, compound (4) is reacted with an ester of lower alcohol and compound (5) is reacted Can be mentioned.

  The mixed acid anhydride used in the mixed anhydride method (I) is obtained by a normal Schotten-Baumann reaction, and is usually reacted with the compound (5) without isolation, to obtain a compound of the general formula (1a). The compound of the present invention is produced.

  The Schotten-Baumann reaction is performed in the presence of a basic compound.

  Examples of the basic compound used include compounds commonly used in the Schotten-Baumann reaction, such as alkali metals (for example, sodium and potassium), alkali metal hydrogen carbonates (for example, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like). ), Alkali metal hydroxide (eg, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.), alkaline earth metal hydroxide (eg, calcium hydroxide, etc.), alkali metal carbonate (eg, Lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal lower alkoxides (eg, sodium methoxide, sodium ethoxide, etc.), hydrides (eg, sodium hydride, potassium hydride, etc.), sodium amide, etc. Inorganic bases, trialkylamines (e.g., Limethylamine, triethylamine, N-ethyldiisopropylamine, etc.), pyridine, quinoline, N-methylpiperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] non Organic bases such as -5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undecene-7 (DBU) . These basic compounds are used singly or in combination of two or more. The reaction is usually performed at about -20 to 100 ° C, preferably about 0 to 50 ° C, and the reaction time is about 5 minutes to 10 hours, preferably about 5 minutes to 2 hours.

  The reaction between the obtained mixed acid anhydride and compound (5) is usually performed at about -20 to 150 ° C, preferably about 10 to 50 ° C, and the reaction time is about 5 minutes to 10 hours, preferably 5 About minutes to 5 hours.

  The mixed acid anhydride method is generally performed in a solvent. As the solvent used, any solvent commonly used in the mixed acid anhydride method can be used. Specifically, water; halogenated hydrocarbon solvents such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride; benzene Aromatic solvents such as toluene, xylene; ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane; ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate; acetonitrile, N, N-dimethyl Examples include aprotic polar solvents such as formamide, dimethyl sulfoxide, hexamethylphosphoric triamide, and mixed solvents thereof.

  Examples of the alkylhalocarboxylic acid used in the mixed acid anhydride method include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, and isobutyl chloroformate.

  The ratio of compound (4), alkylhalocarboxylic acid and compound (5) used in the mixed acid anhydride method is usually preferably at least equimolar, but alkylhalocarboxylic acid and compound relative to compound (5). (4) can be used within the range of about equimolar to 6-fold molar amount.

  In the method (c) in which the condensation reaction is carried out in the presence of the activator, the reaction is carried out in a suitable solvent in the presence or absence of a basic compound. As the solvent and basic compound used here, any of the solvent and basic compound used in Reaction Scheme-1 can be used. The amount of activator used is usually at least equimolar, preferably equimolar to 5-fold molar relative to compound (4). When using WSC as an activator, the reaction can be advantageously advanced by adding an acid such as 1-hydroxybenzotriazole and / or hydrochloric acid to the reaction system. The reaction is usually performed at about -20 to 180 ° C, preferably about 0 to 150 ° C, and the reaction is generally completed in about 5 minutes to 90 hours.

  Furthermore, this amide bond formation reaction is carried out by converting compound (4) and compound (5) into triphenylphosphine, diphenylphosphinyl chloride, phenyl-N-phenylphosphoramide chloride, diethyl chlorophosphate, diethyl cyanophosphate, diphenylphosphorus. It can also be performed by a method of reacting in the presence of a condensing agent of a phosphorus compound such as acid azide or bis (2-oxo-3-oxazolidinyl) phosphinic chloride. The condensing agent may be used alone or in combination of two or more.

  The reaction is usually performed at about −20 to 150 ° C., preferably about 0 to 100 ° C. in the presence of the solvent and basic compound used in the above reaction scheme-1, and generally about 5 minutes to 30 hours. The reaction ends at. The condensing agent and the compound (5) may be used at least in an equimolar amount, preferably in an equimolar to 3 times molar amount with respect to the compound (4).

Here, the compound (4) which is a raw material compound of the compound of this invention is a well-known compound, or can be easily manufactured from a well-known compound.
[Reaction Formula-3]

[Wherein R ¹² and A ¹ have the same meaning as described above. R ¹⁴ represents hydrogen or a lower alkyl group. ]
A compound of general formula (1b) (hereinafter referred to as compound (1b)) can be produced by reacting a compound of general formula (10) (hereinafter referred to as compound (10)) with compound (5). it can.

  This reaction can be carried out in various solvents that do not adversely influence the reaction, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, cyclopentyl methyl ether; halogenated carbonization such as chloroform, methylene chloride, and ethylene chloride. Hydrogens; esters such as methyl acetate, ethyl acetate, n-butyl acetate; etc .; in addition, in an organic solvent such as acetonitrile, N, N-dimethylformamide, or a mixture thereof. In addition, when the said compound (10) or (5) uses a liquid thing, these also function as a solvent. The amount of the compound (5) used relative to the compound (10) is usually 1 to 10 times the molar amount, preferably 1 to 3 times the molar amount. The reaction can be performed under any temperature condition from cooling to heating. Preferably, a temperature condition of −10 ° C. to 150 ° C. can be adopted. The reaction is completed in about 10 minutes to 10 hours under the temperature conditions.

This reaction may be performed in the presence of a base. Suitable bases include, for example, tri (lower) alkylamine (eg, trimethylamine, triethylamine, 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 organic bases such as 1,4-diazabicyclo [2.2.2] octane (DABCO).
[Scheme-4]

[Wherein R ¹¹ , R ¹² and A ¹ have the same meaning as described above. ]
A compound of the general formula (1d) (hereinafter referred to as compound (1d)) can be produced by reacting a compound of the general formula (1c) (hereinafter referred to as compound (1c)) with a thioxo agent. .
Here, preferred examples of the thioxolating agent include phosphorus pentasulfide, Lawesson's reagent (2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide). And the like which can change an oxo group such as thioxo group into a thioxo group. Solvents used in this reaction include various solvents that do not adversely affect the reaction, such as halogenated hydrocarbon solvents such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene, and xylene. Examples of the solvent include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran and dimethoxyethane, or mixed solvents thereof.

  The reaction temperature is not particularly limited, but this reaction is usually carried out under heating, preferably at 65 to 150 ° C., and the reaction time is about 30 minutes to 10 hours, preferably about 30 minutes to 5 hours.

  The ratio of the compound (1c) and the thioxating agent used in this reaction is usually equimolar to large excess molar amount, preferably equimolar to 1.3 molar equivalents of the thioxating agent relative to the compound (1c). Can be used within the range.

Compound (5), which is a raw material compound of the compound of the present invention, includes a novel compound and can be produced by various methods. For example, the following reaction formula-5 to reaction formula-6 are shown. It is manufactured by the method.
[Reaction Formula-5]

[Wherein, R ¹² , X ₁₁ and A ¹ have the same meaning as described above, and R ¹³ represents hydrogen or a lower alkoxycarbonyl group. ]
Here, in the general formula (6), as a group which causes the same substitution reaction as halogen atom and a halogen atom represented by X _11, it can be exemplified the same groups as above.

Preferable specific examples of the lower alkoxycarbonyl group represented by R ¹³ include methoxycarbonyl, ethoxycarbonyl, tertiary butoxycarbonyl group and the like. More preferred examples of the lower alkoxycarbonyl group include a (C ₁ -C ₄ ) alkoxycarbonyl group. Of these, the tertiary butoxycarbonyl group is particularly preferred.
Compound (5a) is produced by reacting a compound of general formula (6) (hereinafter referred to as compound (6)) with a compound of general formula (3) (hereinafter referred to as compound (3)). Can do. This reaction is performed under the same reaction conditions as in the reaction of Reaction Scheme-1.

  Here, the compounds (3) and (6), which are raw material compounds of the compound of the present invention, are known compounds or can be easily produced from known compounds.

In the case where R ¹³ of the compound (5a) represents a lower alkoxycarbonyl group, the compound is subjected to elimination reaction of the lower alkoxycarbonyl group to give a compound of the general formula (5) (hereinafter referred to as compound (5) Can be manufactured. This elimination reaction is performed according to a conventional method such as hydrolysis.

  The hydrolysis is preferably performed in the presence of an acid including a Lewis acid. Suitable acids include organic acids (eg, formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.) and inorganic acids (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, etc.).

  The reaction using a Lewis acid such as trihaloacetic acid such as trichloroacetic acid or trifluoroacetic acid can be preferably carried out in the presence of a cation scavenger (eg anisole or phenol).

  This hydrolysis reaction is carried out in various solvents that do not adversely affect the reaction, such as water; alcohols such as methanol, ethanol, trifluoroethanol, and ethylene glycol; ketones such as acetone; diethyl ether, dioxane, tetrahydrofuran, 1, 2 -Ethers such as dimethoxyethane and cyclopentyl methyl ether; Halogenated hydrocarbons such as chloroform, methylene chloride and ethylene chloride; Esters such as methyl acetate, ethyl acetate and n-butyl acetate; Others, acetonitrile, N, N- It is carried out in an organic solvent such as dimethylformamide or in a mixture thereof. In addition, when using a liquid thing as said acid, these also function as a solvent. The reaction can be performed under any temperature condition from cooling to warming.

Preferably, a temperature condition of 0 ° C. to room temperature can be employed. The reaction is completed in about 0.5 to 10 hours under the temperature condition.
[Reaction formula -6]

[Wherein X ₁₁ and A ¹ have the same meaning as described above. ]
Here, in the general formula (7), as a group which causes the same substitution reaction as halogen atom and a halogen atom represented by X _11, it can be exemplified the same groups as above.

  Compound (8) is produced by reacting a compound of general formula (7) (hereinafter referred to as compound (7)) with a compound of general formula (3) (hereinafter referred to as compound (3)). Can do. This reaction is carried out under the same reaction conditions as those in the reaction scheme-1.

  Here, the compounds (7) and (3), which are raw material compounds of the compound of the present invention, are known compounds or can be easily produced from known compounds.

  Compound (5b) is produced by reacting a compound of general formula (8) (hereinafter referred to as compound (8)) with a compound of general formula (9) (hereinafter referred to as compound (9)). Can do. This reaction is carried out in various solvents that do not adversely influence the reaction, such as water; alcohols such as methanol, ethanol, trifluoroethanol, and ethylene glycol; ketones such as acetone; diethyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxy. Ethers such as ethane and cyclopentyl methyl ether; Halogenated hydrocarbons such as chloroform, methylene chloride, and ethylene chloride; Esters such as methyl acetate, ethyl acetate, and n-butyl acetate; Others, acetonitrile, N, N-dimethylformamide In an organic solvent such as, or a mixture thereof. In addition, when using a liquid thing as said acid, these also function as a solvent. The reaction can be performed under any temperature condition from cooling to heating.

Preferably, a temperature condition of 50 ° C to 100 ° C can be adopted. The reaction is completed in about 0.5 to 10 hours under the temperature condition.
Manufactured.
Reaction formula-7

[Wherein, R ²¹ and A ² have the same meaning as described above, and X ₂₁ represents a halogen atom or a group that causes a substitution reaction similar to a halogen atom. ]
Here, examples of the group causing the same substitution reaction as the halogen atom include the same groups as described above.

  This reaction is carried out under the same reaction conditions as those in the reaction scheme-1.

  Here, the compound (11) which is a raw material compound of the compound of the present invention includes a novel compound and can be produced by various methods. For example, the compound (11) can be produced by the method represented by the following reaction formula-9. Is done.

Further, in the compound (1) -A ² - is ^-A 21 ^{-O-A 22} -, compound [wherein, A ²¹ and ^{A 22} are as defined above. ] (Hereinafter referred to as compound (1f)) is produced, for example, by the method represented by the following reaction formula-8.
Reaction formula-8

[Wherein, R ²¹ , A ²¹ and A ²² have the same meaning as described above, and X ₂₂ represents a hydroxyl group, a halogen atom or a group causing a substitution reaction similar to a halogen atom. ]
Here, in the general formula (12), as the group which causes the same substitution reaction as halogen atom and a halogen atom represented by X _22, can be exemplified the same groups as above.

  Compound (1f) is produced by reacting a compound of general formula (12) (hereinafter referred to as compound (12)) with a compound of general formula (13) (hereinafter referred to as compound (13)). Can do.

  This reaction is carried out under the same reaction conditions as those in the reaction scheme-1.

In the case of the compound (12) in which X ₂₂ represents a hydroxyl group, this reaction can also be carried out in a suitable solvent in the presence of a suitable condensing agent.

  This reaction is usually a conventional solvent that does not adversely influence the reaction, such as water; alcohol solvents such as methanol, ethanol, isopropanol, n-butanol, trifluoroethanol, ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone. Ether solvents such as tetrahydrofuran, dioxane, diethyl ether and diglyme; ester solvents such as methyl acetate and ethyl acetate; aprotic polar solvents such as acetonitrile, N, N-dimethylformamide and dimethyl sulfoxide; methylene chloride and ethylene chloride In a halogenated hydrocarbon-based solvent; or other organic solvents. Furthermore, as a solvent used here, the mixed solvent of these usual solvents can also be mentioned.

  Examples of the condensing agent include a mixture of azocarboxylates such as diethyl azodicarboxylate and a phosphorus compound such as triphenylphosphine.

  The amount of the condensing agent to be used is usually at least equimolar amount, preferably equimolar to 2-fold molar relative to compound (12).

  The use ratio of the compound (12) and the compound (13) in the above Reaction Scheme-8 is usually such that the latter is at least equimolar, preferably equimolar to 2-fold molar, relative to the former.

  The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating. Preferably, the reaction is performed for 1 to 10 hours under a temperature condition of 0 ° C to 150 ° C.

  Here, the compound (12) which is a raw material compound of the compound of this invention is a well-known compound, or can be easily manufactured from a well-known compound.

In addition, the compound (13) which is a raw material compound of the compound of the present invention includes a novel compound and can be produced by various methods. It is manufactured by the method.
Reaction Formula- 9

[Wherein, R ²¹ , X ₂₁ and A ² have the same meaning as described above, and X ₂₃ represents a halogen atom or a group that causes a substitution reaction similar to a halogen atom. ]
Here, in the general formula (15), as the group which causes the same substitution reaction as halogen atom and a halogen atom represented by X _23, can be exemplified the same groups as above.

  Compound (11) is produced by reacting a compound of general formula (14) (hereinafter referred to as compound (14)) with a compound of general formula (15) (hereinafter referred to as compound (15)). Can do.

  This reaction is carried out under the same reaction conditions as those in the reaction scheme-1.

Here, the compounds (14) and (15), which are raw material compounds of the compound of the present invention, are known compounds or can be easily produced from known compounds.
Reaction formula- 10

[Wherein A ²² has the same meaning as described above, and X ₂₄ represents a halogen atom or a group that causes a substitution reaction similar to a halogen atom. ]
Here, in the general formula (16), as the group which causes the same substitution reaction as halogen atom and a halogen atom represented by X _24, can be exemplified the same groups as above.

  Compound (13) can be produced by reacting compound (3) with a compound of general formula (16) (hereinafter referred to as compound (16)).

  This reaction is carried out under the same reaction conditions as those in the reaction scheme-1.

Here, the compound (16) which is a raw material compound of the compound of this invention is a well-known compound, or can be easily manufactured from a well-known compound.
Reaction Formula- 11

[Wherein, A ²² has the same meaning as described above, R ²³ represents a lower alkanoyl group, and X ₂₄ represents a halogen atom or a group that causes a substitution reaction similar to a halogen atom. ]
Here, in the general formulas (17) and (18), examples of the lower alkanoyl group for R ²³ include the same groups as described above.

In the general formula (17), as the group which causes the same substitution reaction as halogen atom and a halogen atom represented by X _24, can be exemplified the same groups as above.

  The compound of general formula (18) (hereinafter referred to as compound (18)) can be produced by reacting compound (3) with compound (17).

  This reaction is carried out under the same reaction conditions as those in the reaction scheme-1.

  Here, the compound (17) which is a raw material compound of the compound of the present invention is a known compound or can be easily produced from a known compound.

  Next, compound (13) can be produced by subjecting compound (18) to a deacylation reaction.

  Suitable methods for this reaction include conventional methods such as hydrolysis. The hydrolysis reaction is preferably carried out in the presence of an acid including a base or a Lewis acid. Suitable bases include alkali metals (eg, sodium, potassium, etc.), alkali metal bicarbonates (eg, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, etc.), alkali metal hydroxides (eg, lithium hydroxide) Sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.), alkali metal carbonates (eg, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal lower alkoxides (eg, sodium methoxide, sodium ethoxide) Etc.), inorganic bases such as hydrides (eg, sodium hydride, potassium hydride, etc.), trialkylamines (eg, trimethylamine, triethylamine, N-ethyldiisopropylamine, etc.), pyridine, quinoline, piperidine, imidazole, picoline, Zimechi Aminopyridine, dimethylaniline, N- methylmorpholine, DBN, DABCO, and organic bases DBU or the like. Suitable acids include organic acids (eg, formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.) and inorganic acids (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.). . The elimination using a Lewis acid such as trihaloacetic acid (for example, trichloroacetic acid or trifluoroacetic acid) is preferably carried out in the presence of a cation-trapping agent (for example, anisole or phenol).

This reaction is usually performed using a conventional solvent that does not adversely influence the reaction, such as water; alcohol solvents such as methanol, ethanol, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone. Ether solvents such as tetrahydrofuran, dioxane, diethyl ether and diglyme; ester solvents such as methyl acetate and ethyl acetate; aprotic polar solvents such as acetonitrile, N, N-dimethylformamide and dimethyl sulfoxide; methylene chloride and ethylene chloride In a halogenated hydrocarbon-based solvent; or other organic solvents. Furthermore, this reaction may be carried out in a mixed solvent of these conventional solvents. Of these, ethanol is preferred. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating. Preferably, the reaction is carried out for 0.5 to 75 hours under temperature conditions from around room temperature to around the boiling point of the solvent used.
Reaction Formula- 12

[Wherein A is the same as defined above. R ^21a is, the of the groups indicated by ^{R 21,} showing the (8) carboxy group of at least one substituted the N- containing heterocyclic group. R ^21b represents the N-containing heterocyclic group in which at least one carbamoyl group optionally having (10) a lower alkyl group is substituted among the groups represented by R ²¹ . R ²² and R ²³ are the same or different and each represents a hydrogen atom or a lower alkyl group. ]
The reaction between the compound (1g) and the compound (19) is a method in which the amine of the compound (19) and the carboxylic acid of the compound (1g) are reacted in a normal amide bond forming reaction. Known amide bond formation reactions can be widely applied to this amide bond formation reaction. Specifically, (b) a mixed acid anhydride method, that is, a method in which an alkylhalocarboxylic acid is reacted with a carboxylic acid (1 g) to form a mixed acid anhydride, and this is reacted with an amine (19), (b) activity Ester method, ie carboxylic acid (1 g) as an active amide with phenyl, p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester or benzoxazoline-2-thione, A method of reacting this with an amine (19), (c) a carbodiimide method, that is, a carboxylic acid (1 g) with an amine (19) as dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (WSC), Method of condensation reaction in the presence of an activating agent such as carbonyldiimidazole (D) Other methods, for example, a method in which carboxylic acid (1 g) is converted to a carboxylic acid anhydride with a dehydrating agent such as acetic anhydride, and this is reacted with amine (19), an ester of carboxylic acid (1 g) with a lower alcohol Examples thereof include a method of reacting amine (19), a method of reacting an acid halide of carboxylic acid (1 g), that is, a carboxylic acid halide with amine (19), and the like.

  The mixed anhydride used in the mixed anhydride method (I) is obtained by a normal Schotten-Baumann reaction, and is usually reacted with an amine (19) without isolation to give a general formula (1h) The compound of the present invention is produced.

  The Schotten-Baumann reaction is performed in the presence of a basic compound.

  Examples of the basic compound used include compounds commonly used in the Schotten-Baumann reaction, such as alkali metals (for example, sodium and potassium), alkali metal hydrogen carbonates (for example, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like). ), Alkali metal hydroxide (eg, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.), alkaline earth metal hydroxide (eg, calcium hydroxide, etc.), alkali metal carbonate (eg, Lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal lower alkoxides (eg, sodium methoxide, sodium ethoxide, etc.), hydrides (eg, sodium hydride, potassium hydride, etc.), sodium amide, etc. Inorganic bases, trialkylamines (e.g., Limethylamine, triethylamine, N-ethyldiisopropylamine, etc.), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] non-5 And organic bases such as ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undecene-7 (DBU). These basic compounds are used singly or in combination of two or more. The reaction is usually performed at about -20 to 100 ° C, preferably about 0 to 50 ° C, and the reaction time is about 5 minutes to 10 hours, preferably about 5 minutes to 2 hours.

  The reaction of the obtained mixed acid anhydride and amine (19) is usually performed at about -20 to 150 ° C, preferably about 10 to 50 ° C, and the reaction time is about 5 minutes to 10 hours, preferably 5 About minutes to 5 hours.

  The mixed acid anhydride method is generally performed in a solvent. As the solvent used, any solvent commonly used in the mixed acid anhydride method can be used. Specifically, water; halogenated hydrocarbon solvents such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride; benzene Aromatic solvents such as toluene, xylene; ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane; ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate; acetonitrile, N, N-dimethyl Examples include aprotic polar solvents such as formamide, dimethyl sulfoxide, hexamethylphosphoric triamide, and mixed solvents thereof.

  Examples of the alkylhalocarboxylic acid used in the mixed acid anhydride method include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, and isobutyl chloroformate.

  The ratio of the carboxylic acid (1 g), alkylhalocarboxylic acid and amine (19) used in the mixed acid anhydride method is usually at least equimolar, but the alkylhalocarboxylic acid and amine (19) Carboxylic acid (1 g) can be used in the range of about equimolar to 6 times molar amount.

  In the method (c) in which the condensation reaction is carried out in the presence of the activator, the reaction is carried out in a suitable solvent in the presence or absence of a basic compound. As the solvent and basic compound used here, any of the solvent and basic compound used in the method of reacting the amine (19) with the carboxylic acid halide of the following other method (d) can be used. The amount of activator used is usually at least equimolar, preferably equimolar to 5-fold molar relative to compound (19). When using WSC as an activator, the reaction can be advantageously advanced by adding an acid such as 1-hydroxybenzotriazole and / or hydrochloric acid to the reaction system. The reaction is usually performed at about -20 to 180 ° C, preferably about 0 to 150 ° C, and the reaction is generally completed in about 5 minutes to 90 hours.

  Of the other methods (d), when the method of reacting a carboxylic acid halide with an amine (19) is employed, the reaction is carried out in a suitable solvent in the presence of a basic compound. As the basic compound used, known compounds can be widely used. For example, any of the basic compounds used in the Schotten-Baumann reaction can be used. As the solvent, for example, in addition to the solvent used in the mixed acid anhydride method, alcohol solvents such as methanol, ethanol, isopropanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, methyl cellosolve, acetonitrile, Pyridine, acetone, water, etc. can be mentioned. The proportion of amine (19) and carboxylic acid halide used is not particularly limited and may be appropriately selected within a wide range. Usually, the latter is at least about equimolar amount, preferably equimolar to 5 times the former. The molar amount is good. The reaction is usually carried out at about -20 to 180 ° C, preferably about 0 to 150 ° C, and the reaction is generally completed in about 5 minutes to 50 hours.

  Further, the amide bond formation reaction shown in the above reaction formula-6 is carried out by converting carboxylic acid (1 g) and amine (19) into triphenylphosphine, diphenylphosphinyl chloride, phenyl-N-phenylphosphoramide chloride, diethyl chlorophosphate. It can also be carried out by a method of reacting in the presence of a condensing agent of a phosphorus compound such as diethyl cyanophosphate, diphenyl phosphate azide, and bis (2-oxo-3-oxazolidinyl) phosphinic chloride. The condensing agent may be used alone or in combination of two or more.

The reaction is usually performed at about −20 to 150 ° C., preferably about 0 to 100 ° C. in the presence of a solvent and a basic compound used in the method of reacting the carboxylic acid halide with amine (19). In general, the reaction is completed in about 5 minutes to 30 hours. The condensing agent and amine (19) may be used in an amount of at least about equimolar amount, preferably about equimolar to 3 times molar amount with respect to carboxylic acid (1 g).
Reaction formula-13

[Wherein A ² is the same as defined above.
R ^21c is a group

Indicates.
R ^21d is a group

Indicates.
R ^21e is

Indicates.
X ₂₅ and X ₂₆ each represent a halogen atom or a group that causes a substitution reaction similar to a halogen atom. R ²⁴ represents the same group as the substituents (1) to (13) of R ²¹ . p represents 4 or 5. ]
The reaction between compound (1i) and compound (20) is carried out in a suitable inert solvent in the presence of a basic compound.

  Examples of the basic compound used herein include metal sodium, metal potassium, metal magnesium; sodium hydride; sodium amide; metal alkoxide such as sodium methoxide, sodium ethoxide, potassium tert-butoxide; methyl lithium, n- Examples include alkyl and aryl lithium such as butyl lithium, phenyl lithium and lithium diisopropylamide, or lithium amide; silylamide such as lithium hexamethyldisilazide. These basic compounds are used singly or in combination of two or more.

  The amount of the basic compound to be used is generally at least equimolar amount, preferably equimolar to 5-fold molar amount relative to compound (1i).

  Examples of the inert solvent used include aromatic hydrocarbon solvents such as benzene, toluene and xylene; ether solvents such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; n-hexane, heptane and cyclohexane. Aliphatic hydrocarbon solvents; halogenated hydrocarbon solvents such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; dimethyl sulfoxide, N, N-dimethylformamide, and a mixed solvent thereof.

  The reaction is usually carried out at -90 to 150 ° C, preferably around -90 to 120 ° C, and the reaction is generally completed in about 10 minutes to 30 hours.

The amount of compound (20) to be used is generally at least equimolar amount, preferably equimolar to 5-fold molar amount relative to compound (1i).
The reaction that leads (1j) to (1k) can be carried out under the same conditions as the reaction that leads compound (1i) to compound (1j).

  Among the compounds (1), compounds in which Q is a group represented by the general formula (II) can be converted into various compounds by applying the following reactions A to G.

Reaction A
In the compound (1), in the case of the compound in which the (12) oxo group is substituted on the heterocyclic ring of the N-containing heterocyclic group represented by R ²¹ , the corresponding N-containing heterocyclic group is reduced by reducing the compound. To the compound (1) in which the oxo group on the heterocyclic ring is deoxoated.

  Examples of the reducing agent used in the reduction reaction include hydrogenation reducing agents such as sodium borohydride, sodium cyanoborohydride, sodium triacetyloxyborohydride, lithium aluminum hydride, and the like. A mixture etc. can be illustrated. The hydrogenation reducing agent is usually used in an amount of about equimolar to 5-fold molar amount, preferably about equimolar to 2-fold molar relative to the starting material.

  The reduction reaction is usually performed in a suitable solvent. Examples of the solvent include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; aromatic hydrocarbon solvents such as benzene, toluene and xylene.

  The reaction temperature is usually about 0 to 150 ° C., preferably about 0 to 100 ° C., and the reaction is generally completed in about 30 minutes to 10 hours.

Reaction B
In the compound (1), in the case where (5) a protected hydroxy group is substituted on the heterocyclic ring of the N-containing heterocyclic group represented by R ²¹ , the corresponding N- The compound (1) in which (4) a hydroxy group is substituted on the heterocyclic ring of the containing heterocyclic group can be derived.

  The deprotection reaction is performed in the presence of an acid or a basic compound in a suitable solvent or without a solvent.

  Examples of the solvent used include water; lower alcohol solvents such as methanol, ethanol, isopropanol and tert-butanol; ketone solvents such as acetone and methyl ethyl ketone; ether solvents such as diethyl ether, dioxane, tetrahydrofuran, monoglyme and diglyme. Fatty acid solvents such as acetic acid and formic acid; ester solvents such as methyl acetate and ethyl acetate; halogenated hydrocarbon solvents such as chloroform, dichloromethane, dichloroethane and carbon tetrachloride; N, N-dimethylformamide, N, N- Examples thereof include amide solvents such as dimethylacetamide and N-methylpyrrolidone; dimethyl sulfoxide, hexamethylphosphoric triamide, and mixed solvents thereof.

  Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and organic acids such as formic acid, acetic acid, trifluoroacetic acid, and sulfonic acid such as p-toluenesulfonic acid. Examples of the basic compound include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide and lithium hydroxide. be able to.

  The amount of the acid or basic compound used is usually at least 1 mol, preferably 1 to 10 mol, relative to 1 mol of the starting material, but the acid may be used in a large excess as the reaction solvent.

  This reaction normally proceeds suitably at about 0 to 200 ° C., preferably about 0 to 150 ° C., and is generally completed in about 10 minutes to 30 hours.

  When the protecting group is a lower alkyl group, deprotection can be achieved by treatment in a suitable solvent in the presence of a dealkylating agent. As the solvent used, any of the solvents used in the above deprotection reaction can be used. Examples of the dealkylating agent include boron trihalides such as boron tribromide. The amount of the dealkylating agent to be used is usually at least equimolar, preferably equimolar to 10-fold molar amount with respect to 1 mol of the starting material. The reaction is usually completed in about 1 to 50 hours at 0 to 150 ° C., preferably at room temperature to about 100 ° C.

  When the protecting group is a phenyl lower alkyl group, it can also be deprotected by carrying out a reduction treatment. This reduction treatment can be performed, for example, by catalytic hydrogenation in a suitable solvent in the presence of a catalyst.

  Examples of the solvent used include water; alcohol solvents such as acetic acid, methanol, ethanol and isopropanol; hydrocarbon solvents such as n-hexane and cyclohexane; ether solvents such as dioxane, tetrahydrofuran, diethyl ether and ethylene glycol dimethyl ether; Examples thereof include ester solvents such as ethyl acetate and methyl acetate; aprotic polar solvents such as dimethylformamide or mixed solvents thereof.

  Examples of the catalyst to be used include palladium, palladium-black, palladium-carbon, platinum, platinum oxide, copper chromite, Raney nickel, and a mixture thereof. The amount of catalyst used is generally about 0.02 to 1 times the weight of the starting material.

  The reaction temperature is usually around −20 to 100 ° C., preferably around 0 to 80 ° C., the hydrogen pressure is usually 1 to 10 atm, and the reaction is generally completed in about 0.5 to 20 hours.

Reaction C
In the compound (1), in the case where the N-containing heterocyclic group represented by R ²¹ is an unsaturated heterocyclic group, by reducing the compound, the heterocyclic group of the corresponding N-containing heterocyclic group is reduced. It can lead to compound (1) which is partially saturated.

  The above reduction reaction is performed, for example, in the absence of a solvent or in a suitable solvent in the presence of a reducing agent.

  Examples of the solvent used here include water; lower alcohol solvents such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol; fatty acid solvents such as acetonitrile, formic acid, and acetic acid; diethyl ether, tetrahydrofuran, Ether solvents such as dioxane, monoglyme and diglyme; aromatic hydrocarbon solvents such as benzene, toluene and xylene; halogenated hydrocarbon solvents such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride or mixed solvents thereof It is done.

  Examples of the reducing agent include catalytic hydrogen reducing agents such as palladium-black, palladium-carbon, platinum oxide, platinum black, and Raney nickel. The catalytic hydrogen reducing agent is usually used in an amount of 1 to 5 times, preferably 1 to 3 times the weight of the starting material.

  The reaction is usually performed at a temperature of about −30 to 100 ° C., preferably about 0 to 60 ° C. in a hydrogen atmosphere of about normal pressure to 20 atm, preferably about 10 to 10 atm. The reaction is generally completed in about 1 to 20 hours.

Reaction D
In the compound (1), in the case of (9) a compound in which a lower alkoxycarbonyl group is substituted on the heterocyclic ring of the N-containing heterocyclic group represented by R ²¹ , the corresponding N- The compound (1) in which (8) a carboxy group is substituted on the heterocyclic ring of the containing heterocyclic group can be derived.

  The hydrolysis reaction can be carried out in the presence of an acid or a basic compound in a suitable solvent or without a solvent.

  Examples of the solvent used include water; lower alcohol solvents such as methanol, ethanol, isopropanol and tert-butanol; ketone solvents such as acetone and methyl ethyl ketone; ether solvents such as diethyl ether, dioxane, tetrahydrofuran, monoglyme and diglyme. Fatty acid solvents such as acetic acid and formic acid; ester solvents such as methyl acetate and ethyl acetate; halogenated hydrocarbon solvents such as chloroform, dichloromethane, dichloroethane and carbon tetrachloride; dimethyl sulfoxide, N, N-dimethylformamide, hexamethyl Examples thereof include phosphoric triamide or a mixed solvent thereof.

  Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid and hydrobromic acid, organic acids such as sulfonic acid such as formic acid, acetic acid, trifluoroacetic acid and p-toluenesulfonic acid. These acids are used singly or in combination of two or more.

  Examples of the basic compound include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate, metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide and lithium hydroxide. be able to. These basic compounds are used singly or in combination of two or more.

  The hydrolysis reaction proceeds normally at about 0 to 200 ° C., preferably about 0 to 150 ° C., and is generally completed in about 10 minutes to 80 hours.

Reaction E
In the compound (1), in the case of the compound in which (8) a carboxy group is substituted on the heterocyclic ring of the N-containing heterocyclic group represented by R ²¹ , the compound and a lower alcohol (for example, methanol, ethanol, tert-butanol) Etc.) can be led to the compound (1) in which (9) a lower alkoxycarbonyl group is substituted on the heterocyclic ring of the corresponding N-containing heterocyclic group.

  For the above reaction, any of ordinary esterification reaction conditions can be used. For example, the reaction is performed in the presence of an inorganic acid and / or a halogenating agent. Examples of inorganic acids include hydrochloric acid and sulfuric acid. Examples of the halogenating agent include thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride and the like. The lower alcohol is used in a large excess with respect to the starting material. The reaction normally proceeds suitably at about 0 to 150 ° C., preferably about 50 to 100 ° C., and is generally completed in about 1 to 10 hours.

Reaction F
In the compound (1), (11) an aryl lower alkyl group (wherein the aryl group has a lower alkoxy group) on the N atom of the heterocyclic ring of the N-containing heterocyclic group represented by R ²¹ Or a compound substituted with an aryl lower alkyl group on the N atom of the corresponding N-containing heterocyclic group by treating the compound in an appropriate solvent or without solvent in the presence of an acid. It can lead to the detached compound (1).

  Examples of the solvent used in the above reaction include water; lower alcohol solvents such as methanol, ethanol, isopropanol, and tert-butanol; ketone solvents such as acetone and methyl ethyl ketone; diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, and the like. Ether solvents; fatty acid solvents such as acetic acid and formic acid; ester solvents such as methyl acetate and ethyl acetate; halogenated hydrocarbon solvents such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; N, N-dimethylformamide, N Amide solvents such as N, dimethylacetamide and N-methylpyrrolidone; dimethyl sulfoxide, hexamethylphosphoric triamide or a mixed solvent thereof.

  Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and organic acids such as formic acid, acetic acid, trifluoroacetic acid, and sulfonic acid such as p-toluenesulfonic acid. The amount of the acid used is usually at least 1 mol, preferably 1 to 30 mol, relative to 1 mol of the starting material, but the acid may be used in a large excess as the reaction solvent.

  This reaction normally proceeds suitably at about 0 to 200 ° C., preferably about 0 to 150 ° C., and is generally completed in about 10 minutes to 30 hours.

Reaction G
In the compound (1), the compound in which (7) a lower alkanoyl group is substituted on the heterocyclic N atom of the N-containing heterocyclic group represented by R ²¹ is at least one N of the corresponding N-containing heterocyclic ring. In general, it is produced by reacting compound (1) having an unsubstituted atom with an alkanoylating agent in the presence or absence of a basic compound in a suitable solvent or in the absence of a solvent.

  Examples of the inert solvent used in the above reaction include aromatic hydrocarbon solvents such as benzene, toluene, and xylene; ether solvents such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme; dichloromethane, dichloroethane, chloroform, and four Halogenated hydrocarbon solvents such as carbon chloride; lower alcohol solvents such as methanol, ethanol, isopropanol, butanol, tert-butanol and ethylene glycol; fatty acid solvents such as acetic acid; ester solvents such as ethyl acetate and methyl acetate; Ketone solvents such as acetone and methyl ethyl ketone; acetonitrile, pyridine, dimethyl sulfoxide, N, N-dimethylformamide, N-methylpyrrolidone, hexamethylphosphoric triamide or a mixed solvent thereof. Rukoto can.

  Examples of the basic compound include alkali metals (for example, sodium, potassium, etc.), alkali metal hydrogen carbonates (for example, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal hydroxides (for example, water Lithium oxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.), alkaline earth metal hydroxides (eg, calcium hydroxide), alkali metal carbonates (eg, lithium carbonate, sodium carbonate, potassium carbonate, carbonic acid) Cesium, etc.), alkali metal lower alkoxides (eg, sodium methoxide, sodium ethoxide, etc.), hydrides (eg, sodium hydride, potassium hydride, etc.), inorganic bases such as sodium amide, trialkylamines (eg, trimethylamine) , Triethylamine, N-ethyldi Propylamine, etc.), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1, An organic base such as 4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undecene-7 (DBU) or a mixture thereof can be given.

  When the reaction is carried out in the presence of a basic compound, the basic compound is usually used in an amount of at least equimolar amount, preferably equimolar to 5-fold molar amount relative to the starting material.

  Examples of the alkanoylating agent include lower alkanoyl halides such as acetyl chloride, fatty acid anhydrides such as acetic anhydride, and the like.

  The lower alkanoylating agent is generally used in an amount of at least equimolar amount, preferably equimolar to 5-fold molar amount based on the starting material.

  The reaction is usually performed at 0 to 200 ° C., preferably about 0 to 150 ° C., and the reaction is generally completed in about 5 minutes to 5 hours.

  In the reaction system of this reaction, an alkali metal halogen compound such as sodium iodide or potassium iodide may be added.

  The starting compound used in each of the above reaction formulas may be a suitable salt, and the target compound obtained in each reaction may form a suitable salt. Suitable salts thereof include suitable salts of the compound (1) exemplified below.

  Suitable salts of the compound (1) are pharmacologically acceptable salts such as alkali metal salts (for example, sodium salts and potassium salts), alkaline earth metal salts (for example, calcium salts and magnesium salts). Metal salts such as ammonium salts, alkali metal carbonates (eg, lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, etc.), alkali metal hydrogen carbonates (eg, lithium hydrogen carbonate, sodium bicarbonate, potassium hydrogen carbonate, etc.), alkalis Salts of inorganic bases such as metal hydroxides (eg, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.); eg, tri (lower) alkylamines (eg, trimethylamine, triethylamine, N-ethyldiisopropyl) Amines), pyridine, quinoline, piperidine, imidazole, picoline Dimethylaminopyridine, dimethylaniline, N- (lower) alkyl-morpholine (eg, N-methylmorpholine), 1,5-diazabicyclo [4.3.0] nonene-5 (DBN), 1,8-diazabicyclo [ 5.4.0] Salts of organic bases such as undecene-7 (DBU), 1,4-diazabicyclo [2.2.2] octane (DABCO); hydrochlorides, hydrobromides, hydroiodides , Inorganic acid salts such as sulfate, nitrate, phosphate; formic acid, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malic acid Examples thereof include salts of organic acids such as salts, citrates, tartrates, carbonates, picrates, methanesulfonates, ethanesulfonates, p-toluenesulfonates, and glutamates.

  In addition, compounds in a form in which a solvate (eg, hydrate, ethanolate, etc.) is added to the raw materials and target compounds shown in each reaction formula are also included in each general formula. Preferred solvates include hydrates.

  Each target compound obtained in each of the above reaction formulas is obtained by cooling the reaction mixture, for example, separating the crude reaction product by an isolation operation such as filtration, concentration, extraction, etc., and performing column chromatography, recrystallization, etc. It can be isolated and purified from the reaction mixture by ordinary purification procedures.

  The compound represented by the general formula (1) of the present invention naturally includes isomers such as geometric isomers, stereoisomers, and optical isomers.

  The compound of the general formula (1) and a salt thereof are used in the form of a general pharmaceutical preparation. The preparation is prepared by using diluents or excipients such as fillers, extenders, binders, moisturizers, disintegrants, surfactants, lubricants and the like that are usually used. Various forms of this pharmaceutical preparation can be selected according to the purpose of treatment. Representative examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections ( Liquid, suspension, etc.).

  In molding into a tablet form, various carriers well known in the art can be widely used as carriers. Examples thereof include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, Gelatin solution, binders such as carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, lauryl sulfate Disintegrators such as sodium, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, absorption accelerators such as quaternary ammonium base, sodium lauryl sulfate, glyce Emissions, moisturizing agents such as starch, starch, lactose, kaolin, bentonite, adsorbent such as colloidal silicic acid, purified talc, stearates, boric acid powder, a lubricant such as polyethylene glycol can be used. Further, the tablets can be made into tablets with ordinary coatings as necessary, for example, sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets.

  When forming into the form of a pill, those conventionally known in this field can be widely used as the carrier. Examples include excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin and talc, binders such as gum arabic powder, tragacanth powder, gelatin, ethanol, and disintegrants such as laminaran and agar. Can be used.

  In molding into a suppository form, conventionally known carriers can be widely used. Examples thereof include polyethylene glycol, cocoa butter, higher alcohols, higher alcohol esters, gelatin, semi-synthetic glycerides and the like.

  Capsules are usually prepared by mixing the active ingredient compound with the various carriers exemplified above and filling them into hard gelatin capsules, soft capsules and the like according to conventional methods.

  When prepared as injections, solutions, emulsions and suspensions are preferably sterilized and isotonic with blood, and are commonly used in this field as diluents when molded into these forms For example, water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used.

  In this case, a sufficient amount of sodium chloride, glucose or glycerin may be contained in the pharmaceutical preparation to prepare an isotonic solution, and a normal solubilizing agent, buffering agent, soothing agent, etc. may be added. May be. Furthermore, a coloring agent, a preservative, a fragrance | flavor, a flavor agent, a sweetening agent, etc. and other pharmaceuticals can also be contained in a pharmaceutical formulation as needed.

  The amount of the compound of the general formula (1) or a salt thereof to be contained in the pharmaceutical preparation of the present invention is not particularly limited and is appropriately selected from a wide range, but is usually about 1 to 70% by weight in the preparation composition. , Preferably about 1 to 30% by weight.

  The administration method of the pharmaceutical preparation of the present invention is not particularly limited, and it is administered according to various preparation forms, patient age, sex and other conditions, the degree of disease, and the like. For example, in the case of tablets, pills, solutions, suspensions, emulsions, granules and capsules, they are administered orally. In the case of an injection, it is administered intravenously alone or mixed with a normal replacement fluid such as glucose and amino acids, and further administered alone intramuscularly, intradermally, subcutaneously or intraperitoneally as needed. In the case of a suppository, it is administered intrarectally.

  The dosage of the pharmaceutical preparation of the present invention is appropriately selected depending on the usage, the patient's age, sex and other conditions, the degree of disease, etc., but the amount of the active ingredient compound is usually about 0.1 to 0.1 kg / kg body weight per day. It should be about 10 mg. In addition, the active ingredient compound is desirably contained in the dosage unit form in a range of about 1 to 200 mg.

The compound of the present invention has a D ₂ receptor partial agonist action, a 5-HT _2A receptor antagonist action and a serotonin uptake inhibitory action (or a serotonin reuptake inhibitory action).

The D ₂ receptor partial agonist action suppresses this when dopamine (DA) -acting neurotransmission is enhanced, while promoting it when DA-acting neurotransmission is reduced. It has a function to stabilize DA neurotransmission to a normal state (dopamine system stabilizer, dopamine system stabilizer). By this function, without causing side effects, excellent clinical improvement action, such as positive and negative symptom improvement action, cognitive impairment improvement action, depressive symptom improvement, on symptoms based on DA neurotransmission abnormality (up and down) (Miyako: Psychiatry, 46, 855-864 (2004), Tetsuro Kikuchi and Satoshi Hirose: Brain Science, 25, 579-583 (2004) and Harrison) , TS and Perry, CM: Drugs 64: 1715-1736, 2004).

The 5-HT _2A receptor antagonistic action reduces the extrapyramidal side effects and exhibits an excellent clinical effect, and is effective for improving negative symptoms, cognitive impairment, depressive symptoms, insomnia, etc. ( Jun Ishigoka and Ken Inada: Clinical Psychopharmacology, Vol. 4, pp. 1653-1664 (2001), Mitsuaki Murasaki: Clinical Psychopharmacology, Vol. 1, pp. 5-22 (1998), Pullar, IA et al., : Eur. J. Pharmacol., 407: _39-46, 2000 and Meltzer, HY et al .: Prog. Neuro-psychopharmacol. Biol. Psychiatry 27: 1159-1172, 2003).

  The serotonin uptake inhibitory action (or serotonin reuptake inhibitory action) is effective, for example, in the improvement of depressive symptoms (Murazaki Mitsukuni: Clinical Psychopharmacology, Vol. 1, pp. 5-22 (1998)).

  The compounds of the present invention are all excellent in these three actions, or one or two of these actions are remarkably excellent.

Further, some of the compounds of the present invention have an α ₁ receptor antagonistic action in addition to the above action. α ₁ receptor antagonistic action is effective in improving the positive symptoms of schizophrenia (see Svensson, TH: Prog. Neuro-psychopharmacol. Biol. Psychiatry 27: 1145-1158, 2003).

  Therefore, the compound of the present invention has a broad therapeutic spectrum for central nervous disease and has an excellent clinical effect.

  Accordingly, the compounds of the present invention can be used to treat schizophrenia, refractory, refractory or chronic schizophrenia, ataxic emotional disorder, psychotic disorder, mood disorder, bipolar disorder (eg, bipolar I disorder and bipolar II Type disorders), depression, intrinsic depression, major depression, melancholic and treatment-resistant depression, mood modulation disorders, mood circulation disorders, anxiety disorders (eg, panic attacks, panic disorders, agoraphobia, social phobia) Obsessive-compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, acute stress disorder, etc.), somatic expression disorder (eg hysteria, somatization disorder, conversion disorder, pain disorder, psychosis), falseness Disorders, dissociative disorders, sexual disorders (eg, sexual dysfunction, sexual desire disorder, sexual arousal disorder, erectile dysfunction), eating disorders (eg, anorexia nervosa, bulimia nervosa, etc.), Sleep disorders, adaptation disorders, substance-related Harm (eg alcohol abuse, addiction and drug abuse, stimulant addiction, narcotic addiction, etc.), annoyance (loss of anxiety, anhedonia, eg iatrogenic annoynia, psychological, mental annoyance , Anorexia associated with depression, anxiety associated with schizophrenia), delirium, cognitive impairment, Alzheimer's disease, Parkinson's disease, cognitive impairment associated with other neurodegenerative diseases, Alzheimer's disease, Parkinson's disease and related disorders Cognitive impairment due to degenerative disease, cognitive impairment of schizophrenia, treatment resistance, refractory or cognitive impairment due to chronic schizophrenia, vomiting, motion sickness, obesity, migraine, pain, mental retardation, autism Extremely effective in improving central nervous system disorders such as various disorders of the central nervous system such as disability (autism), towlet disorder, tic disorder, attention deficit / hyperactivity disorder, behavioral disorder, and Down's syndrome It is.

  Furthermore, the compound of the present invention has few side effects and is excellent in terms of tolerability and safety.

  In addition, the compounds of the present invention are used in the present clinical examples exemplified below: (1) mood stabilizers, (2) serotonin reuptake inhibitors, (3) norepinephrine reuptake inhibitors, (4) serotonin and Norepinephrine reuptake inhibitor and (5) administration in combination with at least one drug selected from the group consisting of anti-anxiety drugs, dose reduction, side effect improvement, treatment not obtained by conventional treatment methods Effects such as effect enhancement can be obtained.

(1) Mood stabilizers As mood stabilizers, compounds that function as mood stabilizers can be widely used and are known to those skilled in the art.

  Non-limiting lists of mood stabilizers that can be used in the present invention include lithium, valproic acid, divalprox sodium, carbamazepine, oxcarbamazepine, zonisamide, lamotrigine, topiramate, gabapentin, levetiracetam, clonazepam, phenytoin, thyroid hormone Tiagabine and omega-3 fatty acids. Preferred are lamotrigine, zonisamide, topiramate, lithium, valproic acid and carbamazepine.

(2) Serotonin reuptake inhibitor As the serotonin reuptake inhibitor, known compounds can be widely used as long as they function as serotonin reuptake inhibitors.

  Among serotonin reuptake inhibitors, a drug that inhibits 50% of the serotonin reuptake by the conventional standard pharmacological assay method, Wong et al. (Neuropsychopharmacology, 8, pp337-344 (1993)). Is preferably about 1000 nM or less.

  Examples of such serotonin reuptake inhibitors include fluvoxamine (5-methoxy-1- [4- (trifluoromethyl) phenyl] -1-pentanone-O- (2-aminoethyl) oxime), fluoxetine (N -Methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine), paroxetine (trans-(-)-3-[(1,3-benzodioxol-5-yloxy) methyl] -4- (4-fluorophenyl) piperidine), sertraline (1S-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-diethyl-2-aminomethyl-1-phenylcyclopropanecarboxamide), citalopram (1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydro-5 Isobenzofurancarbonitrile), duloxetine (N-methyl-3- (1-naphthalenyloxy) -3- (2-thienyl) propanamine), escitalopram (S-(+)-1- [3- (dimethylamino) ) Propyl] -1- (4-fluorophenyl) -1,3-dihydro-5-isobenzofurancarbonitrile oxalate) and the like.

(3) Norepinephrine reuptake inhibitor Norepinephrine reuptake inhibitors can be widely used as long as they function as norepinephrine reuptake inhibitors. Examples of such norepinephrine reuptake inhibitors include reboxetine, atomoxetine and bupropion. Preferably, reboxetine and atomoxetine are used.

(4) Serotonin and Norepinephrine Reuptake Inhibitor Drugs As serotonin and norepinephrine reuptake inhibitor drugs, known compounds can be widely used as long as they function as serotonin and norepinephrine reuptake inhibitor drugs. Examples of such serotonin and norepinephrine reuptake inhibitors include venlafaxine, duloxetine and milnacipran.

(5) Anti-anxiety drugs A non-limiting list of anti-anxiety drugs includes diazepam, chlordiazepoxide, cloxazolam, clothiazepam, alprazolam, benzodiazepine anti-anxiety drugs such as tandospirone, buspirone, serotonin 5-HT1A receptors And body agonist anti-anxiety 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) anxiolytics. The drug may be in any form such as free base, salt (acid addition salt, etc.). These drugs may be racemic or R and S enantiomers. These drugs may be used alone or in combination of two or more drugs as necessary. A single drug is preferred.

  These agents can readily form acid addition salts with pharmaceutically acceptable acids. Examples of such acids include inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, phosphoric acid, hydrobromic acid, acetic acid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid. And organic acids such as citric acid, succinic acid and benzoic acid. These acid addition salts can also be used as active ingredient compounds in the present invention, as are free form reuptake inhibitors.

  Among these drugs, a compound having an acidic group can easily form a salt by allowing a pharmaceutically acceptable basic compound to act on the compound. Examples of such basic compounds include metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, and calcium hydroxide, and alkali metal carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate. Or, alkali metal alcoholates such as bicarbonate, sodium methylate, potassium ethylate and the like can be exemplified.

  Hereinafter, the present invention will be further clarified with reference examples, examples, pharmacological test examples and formulation examples.

Reference example 1
Synthesis of ethyl- (4-hydroxybutyl) carbamic acid tert-butyl ester To a dichloromethane solution (100 ml) of 5.0 ml (39 mmol) of 4-ethylamino-1-butanol and 6.5 ml (47 mmol) of triethylamine under ice-cooling. 9.32 g (43 mmol) of di-t-butyl dicarbonate was added and the mixture was stirred at room temperature for 21 hours. Water was added to the reaction solution and the phases were separated, and the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 1: 1). The purified product was concentrated under reduced pressure to obtain 7.40 g (yield 88%) of colorless oily ethyl- (4-hydroxybutyl) carbamic acid tert-butyl ester.

Reference example 2
Synthesis of methanesulfonic acid 4- (tert-butoxycarbonyl-ethyl-amino) butyl ester 6.50 g (30 mmol) of ethyl- (4-hydroxybutyl) carbamic acid tert-butyl ester and 5.0 ml (36 mmol) of triethylamine To the dichloromethane solution (130 ml), 2.5 ml (32 mmol) of methanesulfonyl chloride was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction solution and the phases were separated, and the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 1.5: 1). The purified product was concentrated under reduced pressure to obtain 7.22 g (yield 82%) of methanesulfonic acid 4- (tert-butoxycarbonyl-ethyl-amino) butyl ester as a colorless oil.

Reference example 3
Synthesis of [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -ethyl-carbamic acid tert-butyl ester hydrochloride Methanesulfonic acid 4- (tert-butoxycarbonyl-ethyl- Amino) butyl ester 7.20 g (24.4 mmol) in DMF solution (150 ml) in 4-benzo [b] thiophen-4-yl-piperazine hydrochloride 6.83 g (26.8 mmol) and potassium carbonate 7.75 g (56.1 mmol) was added and the mixture was stirred at 80 ° C. for 3.5 hours. The reaction solution was cooled to room temperature, water was added thereto, and the reaction product was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 1: 2). The purified product was concentrated under reduced pressure to give colorless oil [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -ethyl-carbamic acid tert-butyl ester 4.84 g ( Yield 48%) was obtained. 340 mg of the obtained concentrate was dissolved in 2 ml of ethanol, 0.9 ml of 1N-HCl ethanol solution was added to the solution, and the precipitated crystals were collected by filtration and dried to give [4- (4-benzo [ b] Thiophen-4-yl-piperazin-1-yl) butyl] -ethyl-carbamic acid tert-butyl ester hydrochloride was obtained.
Melting point 230-232 ° C.

Reference example 4
Synthesis of [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -ethyl-amine dihydrochloride [4- (4-Benzo [b] thiophen-4-yl-piperazine To a dichloromethane solution (80 ml) of 4.20 g (10.1 mmol) of -1-yl) butyl] -ethyl-carbamic acid tert-butyl ester was added 7.8 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, an aqueous sodium hydrogen carbonate solution was added to the residue, and the reaction product was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (dichloromethane: methanol = 1: 0 → 9: 1). The purified product was concentrated under reduced pressure to give 2.71 g (yield 85%) of [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -ethyl-amine as a pale yellow oil. ) 260 mg of the obtained concentrate was dissolved in 2 ml of ethanol, 1.8 ml of 1N-HCl ethanol solution was added, and the precipitated crystals were collected by filtration and dried to give [4- (4-benzo [b] Thiophen-4-yl-piperazin-1-yl) butyl] -ethyl-amine dihydrochloride was obtained.
Melting point 265-267 ° C.

Reference Example 5
Synthesis of 2- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] isoindole-1,3-dione hydrochloride 2- (4-bromobutyl) isoindole-1, 3-dione 200 mg (0.71 mmol), 1-benzo [b] thiophen-4-ylpiperazine hydrochloride 200 mg (0.78 mmol), potassium carbonate (230 mg, 1.66 mmol) and sodium iodide (130 mg, 0.87 mmol) was added to dimethylformamide (DMF) (4 ml) and the mixture was stirred at 80 degrees for 5 hours. The reaction solution was cooled to room temperature, water was added thereto, and the reaction product was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The organic layer after drying was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 30: 1). The purified product was concentrated under reduced pressure, the residue was dissolved in ethanol (2 ml), and concentrated hydrochloric acid (0.65 ml) was added to the solution. The solution after addition of hydrochloric acid was concentrated under reduced pressure, and the residue was recrystallized from ethanol-ethyl acetate to give 2- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) as a pale yellow powder. )] Butyl] isoindole-1,3-dione hydrochloride 210 mg (yield 65%) was obtained.
Melting point 295 ° C (decomposition).

Reference Example 6
Synthesis of 4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butylamine 2- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] To an ethanol solution (8 ml) of 789 mg (1.89 mmol) of isoindole-1,3-dione was added 0.27 ml (5.6 mmol) of hydrazine monohydrate, and the mixture was stirred for 2 hours under heating to reflux. The reaction solution was concentrated under reduced pressure, 1N aqueous sodium hydroxide solution was added to the residue, the reaction product was extracted and washed with dichloromethane, and dried over anhydrous sodium sulfate. The dried product was concentrated under reduced pressure to obtain 581 mg (yield quantitative) of 4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butylamine as a yellow oily substance.

Reference Example 7
N- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -propyn-2-ylamine 4- (4-benzo [b] thiophen-4-yl-piperazine-1 -Ill) To a solution of 330 mg (1.14 mmol) of butylamine in dichloromethane was added 0.084 ml (1.14 mmol) of propargyl bromide under ice cooling, and the mixture was stirred at room temperature for 15 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the reaction product was extracted with dichloromethane and dried over anhydrous sodium sulfate. The dried product was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (hexane: ethyl acetate = 1: 2). The purified product was concentrated under reduced pressure to give 75 mg (yield) of white amorphous solid N- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -propyn-2-ylamine 20%).

Reference Example 8
Synthesis of 1-benzo [b] thiophen-4-yl-piperazine hydrochloride 14.4 g of 4-bromobenzo [b] thiophene, 29.8 g of anhydrous piperazine, 9.3 g of sodium t-butoxide, (R)-(+)- A mixture consisting of 0.65 g of 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), 0.63 g of tris (dibenzylideneacetone) dipalladium (0) and 250 ml of toluene was placed under a nitrogen atmosphere. Heated to reflux for 1 hour. Water was poured into the reaction solution, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol: 25% aqueous ammonia = 100: 10: 1) to obtain 9.5 g of 1-benzo [b] thiophen-4-yl-piperazine as a yellow oil.

To a methanol solution of 9.5 g of 1-benzo [b] thiophen-4-yl-piperazine was added 3.7 ml of concentrated hydrochloric acid, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration and recrystallized from methanol to obtain colorless needle-like 1-benzo [b] thiophen-4-yl-piperazine hydrochloride.
Melting point: 276-280 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm:
3.25-3.35 (8H, m), 6.94 (1H, d, J = 7.6 Hz), 7.30 (1H, dd, J = 7.8 Hz, 7.8 Hz), 7.51 (1H, d, J = 5.5 Hz), 7.68 (1H, d, J = 8.1 Hz), 7.73 (1H, d, J = 5.5 Hz), 9.35 (2H, brs) .

Reference Example 9
Synthesis of 1-benzo [b] thiophen-4-ylpiperazine hydrochloride 4-bromobenzo [b] thiophene 14.4 g, anhydrous piperazine 29.8 g, sodium tert-butoxide 9.3 g, (R)-(+)-2 , 2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP) 0.65 g, tris (dibenzylideneacetone) dipalladium (0) 0.63 g and toluene 250 ml under nitrogen atmosphere. Heated to reflux for 1 hour. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol: 25% aqueous ammonia = 100: 10: 1) to obtain 9.5 g of 1-benzo [b] thiophen-4-ylpiperazine as a yellow oil.

To a methanol solution of 9.5 g of 1-benzo [b] thiophen-4-ylpiperazine was added 3.7 ml of concentrated hydrochloric acid, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration and recrystallized from methanol to obtain colorless needle-like 1-benzo [b] thiophen-4-yl-piperazine hydrochloride.
Melting point: 276-280 ° C
¹ H-NMR (DMSO-d ₆ ) δ ppm: 3.25-3.35 (8H, m), 6.94 (1H, d, J = 7.6 Hz), 7.30 (1H, dd, J = 7.8 Hz, J = 7.8 Hz), 7.51 (1H, d, J = 5.5 Hz), 7.68 (1H, d, J = 8.1 Hz), 7.73 (1H, d, J = 5.5 Hz), 9.35 (2H, brs).

Reference Example 10
Synthesis of 4-benzo [b] thiophen-4-yl-3-methylpiperazine-1-carboxylic acid tert-butyl ester 3-methylpiperazine-1-carboxylic acid tert-butyl ester and 4-bromobenzo [b] as raw material compounds The title compound was obtained in the same manner as in Reference Example 9 using thiophene.
¹ H-NMR (CDCl ₃ ) δ ppm: 1.85-1.95 (3H, m), 1.50 (9H, s), 2.8-2.9 (1H, m), 3.15-3 .35 (2H, m), 3.4-3.5 (1H, m), 3.5-3.65 (1H, m), 3.65-3.7 (1H, m), 3.7 −3.9 (1H, m), 6.98 (1H, d, J = 7.5 Hz), 7.29 (1H, dd, J = 8 Hz, J = 8 Hz), 7.38 (1H, d, J = 5.5 Hz), 7.61 (1H, d, J = 8 Hz).

Reference Example 11
Synthesis of 1-benzo [b] thiophen-4-yl-2-methylpiperazine dihydrochloride 4-benzo [b] thiophen-4-yl-3-methylpiperazine-1-carboxylic acid tert-butyl ester 1.22 g ( 3.7 ml) in dichloromethane (12 ml) was added 6 ml of trifluoroacetic acid and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, 5% aqueous potassium carbonate solution was added to the residue, and the mixture was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Concentrated hydrochloric acid (0.6 ml) and methanol (10 ml) were added to the residue, and the mixture was concentrated under reduced pressure. The residue was crystallized from acetonitrile to obtain 0.98 g of 1-benzo [b] thiophen-4-yl-2-methylpiperazine dihydrochloride as a fine brown powder.
¹ H-NMR (DMSO-d ₆ ) δ ppm: 0.92 (3H, d, J = 6.5 Hz), 2.8-3.6 (6H, m), 3.6-4.0 (1H, m), 5.3-6.8 (1H, m), 7.20 (1H, br), 7.38 (1H, 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 Using 2-methylpiperazine and 4-bromobenzo [b] thiophene as starting compounds, the title compound was obtained in the same manner as in Reference Example 9. It was.
¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.34 (3H, d, J = 6.5 Hz), 2.85-2.95 (1H, m), 3.05-3.15 (1H, m), 3.2-3.6 (6H, m), 6.97 (1H, d, J = 7.5 Hz), 7.31 (1H, dd, J = 8 Hz, J = 8 Hz), 7. 54 (1H, d, J = 5.5 Hz), 7.69 (1H, d, J = 8 Hz), 7.75 (1H, d, J = 5.5 Hz), 9.2-9.3 (1H , M), 9.64 (1H, br).

Reference Example 13
Synthesis of 1- (4-chlorobutyl) -2-pyrrolidone To a solution of 2-pyrrolidone (5.0 g, 58.7 mmol) in dimethylformamide (50 ml) under ice-cooling sodium hydride (60% oily) (2.47 g, 61.8 mmol) was added and stirred at the same temperature for 1 hour. Furthermore, the reaction was stirred at room temperature for 1 hour, 1-bromo-4-chlorobutane (13.5 ml, 117.3 mmol) was added thereto, and the mixture was stirred at 80 ° C. for 2 hours.

The reaction mixture was cooled to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1 → ethyl acetate). The resulting purified product was concentrated under reduced pressure to obtain 1- (4-chlorobutyl) -2-pyrrolidone (3.88 g) as a pale yellow oil.
¹ H-NMR (CDCl ₃ ) 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).

  The compound of Reference Example 14-40 was synthesized in the same manner as in Reference Example 9-13 using an appropriate raw material compound.

Example 1
Synthesis of N- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -N-ethyl-acetamide hydrochloride
N- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] ethylamine 270 mg (0.85 mmol) and triethylamine 0.15 ml (1.08 mmol) in dichloromethane (10 ml ) Was added 0.10 ml (1.06 mmol) of acetic anhydride and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 30: 1 → 9: 1). The purified product was concentrated under reduced pressure, the residue was dissolved in 2 ml of ethanol, and 0.85 ml of 1N-HCl ethanol solution was added to the resulting solution. The precipitated crystals were collected by filtration and dried to give 240 mg of white powder of N- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -N-ethyl-acetamide hydrochloride ( Yield 71%) was obtained.
Melting point 198-200 ° C.

Example 2
Synthesis of N- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] benzamide hydrochloride 4- (4-Benzo [b] thiophen-4-yl-piperazine-1- Yl) To a solution of 220 mg (0.76 mmol) of butylamine and 0.15 ml (1.9 mmol) of pyridine in dichloromethane (5 ml) was added 0.15 ml (1.3 mmol) of benzoyl chloride under ice-cooling and the same temperature for 2 hours. Stir. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane and washed with an aqueous sodium bicarbonate solution. The washed extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 30: 1). The purified product was concentrated under reduced pressure, the residue was dissolved in 2 ml of ethanol, and 0.8 ml of 1N-HCl ethanol solution was added to the resulting solution. The precipitated crystals were collected by filtration and dried to obtain 230 mg (yield 70%) of N- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] benzamide hydrochloride as a white powder. Obtained.
Melting point 209-210 ° C.

Example 3
Synthesis of 3-acetylamino-N- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] benzamide 4- (4-Benzo [b] thiophen-4-yl-piperazine 1-yl) butylamine 150 mg (0.52 mmol) and 3-acetamidobenzoic acid 110 mg (0.61 mmol) in DMF (3 ml) were added triethylamine 0.15 ml (1.06 mmol) and diethylphosphorocyanidate ( DEPC) 0.1 ml (0.67 mmol) was added and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction solution, and the reaction product was extracted with ethyl acetate and washed with water. The washed product was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (dichloromethane: methanol = 30: 1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethanol-hexane to give pale yellow needles of 3-acetylamino-N- [4- (4-benzo [b] thiophen-4-yl-piperazine- 170 mg (yield 73%) of 1-yl) butyl] benzamide were obtained.
Melting point 178-180 ° C.

Example 4
Synthesis of N- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -N-propyl-acetamide hydrochloride 4- (4-Benzo [b] thiophen-4-yl -To a solution (7 ml) of 246 mg (0.85 mmol) of piperazin-1-yl) butylamine under ice cooling, 1 ml of methyl orthoformate and 73 mg (1.3 mmol) of propionaldehyde were added, and the mixture was stirred for 5 minutes. Stir at temperature. To the obtained liquid, 0.4 g (1.3 mmol) of MP-borohydride (3.18 mmol / g) was added, and the mixture was stirred at room temperature for 1 hour. The resin was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in 7 ml of dichloromethane, 0.12 ml (1.3 mmol) of acetic anhydride was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (hexane: ethyl acetate = 2: 1). The purified product was concentrated under reduced pressure, the residue was dissolved in 2 ml of ethanol, and 0.3 ml of 1N-HCl ethanol solution was added to the resulting solution. The precipitated crystals were collected by filtration and dried to obtain 83 mg (yield) of white powder of N- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -N-propyl-acetamide hydrochloride. 24%).
Melting point 198-200 ° C.

Example 5
Synthesis of N- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -N-methyl-acetamide hydrochloride N- [4- (4-Benzo [b] thiophene- 50 mg (1.04 mmol) of lithium aluminum hydride was added to 166 mg (0.52 mmol) of 4-yl-piperazin-1-yl) butyl] -formamide in THF (15 ml) and the mixture was heated under reflux for 2 hours. Stir. The reaction solution was cooled to room temperature, a small amount of water, methanol, and celite were added thereto, and the mixture was stirred for 5 minutes. Celite filtration was performed, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 15 ml of dichloromethane, 0.074 ml (0.78 mmol) of acetic anhydride was added and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, the reaction product was extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. The dried product was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (hexane: ethyl acetate = 1: 2). The purified product was concentrated under reduced pressure, the residue was dissolved in 1 ml of ethanol, and 0.2 ml of 1N-HCl ethanol solution was added. Ether was added to the resulting solution and the mixture was allowed to stand. The precipitated crystals were collected by filtration and dried to give white powder of N- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl). 58 mg (yield 29%) of butyl] -N-methyl-acetamide hydrochloride were obtained.
Melting point 216-217 ° C.

Example 6
Synthesis of N- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -N-phenyl-acetamide hydrochloride N- (4-Bromobutyl) -N-phenyl-acetamide 367 mg To a solution of (1.35 mmol) in DMF was added 288 mg (1.13 mmol) of 4-benzo [b] thiophen-4-yl-piperazine hydrochloride and 468 mg (3.4 mmol) of potassium carbonate, and the mixture was heated at 80 ° C. Stir for 3 hours. The obtained reaction liquid was cooled to room temperature, water was added thereto, and the reaction product was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The dried organic layer was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (hexane: ethyl acetate = 1: 1). The purified product was concentrated under reduced pressure, the residue was dissolved in 5 ml of ethanol, and 1.05 ml of 1N-HCl ethanol solution was added. The precipitated crystals were collected by filtration and dried to give 153 mg of N- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -N-phenyl-acetamide hydrochloride as a white powder ( Yield 31%) was obtained.
Melting point 216.5-218.0 ° C.

Example 7
Synthesis of N- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl]-(R) -pyrrolidine-2-carboxamide
N- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butyl]-(R) -1- (tert-butoxycarbonyl) pyrrolidine-2-carboxamide 2.01 g (4. 13 ml) in methanol (5 ml) was added 10 ml of 4N-HCl ethyl acetate solution and the mixture was stirred at room temperature for 17 hours. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution to make it basic, and the product was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a brown oily N- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl]-(R) -Pyrrolidine-2-carboxamide 1.56g (yield 98%) was obtained.
¹ H-NMR (DMSO-d ₆ ) δppm: 1.45-1.63 (4H, m), 1.63-1.80 (2H, m), 1.84-1.94 (1H, m), 2.02-2.26 (1H, 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 (1H, dd, J = 5.3, 9.0 Hz), 6.90 (1H, d, J = 7.7 Hz), 7.27 (1H, t, J = 7.8 Hz), 7.33-7.44 (2H, m), 7.55 (1H, d, J = 8.0) 7.59-7.81 (1H, brs).

Example 8
Synthesis of N- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl]-(R) -1- (2-acetylaminoacetyl) pyrrolidine-2-carboxamide
N- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butyl]-(R) -pyrrolidine-2-carboxamide in 288 mg (0.745 mmol) in dichloromethane solution (7 ml) Add 104 mg of N-acetylglycine, 214 mg (1.11 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (WSC) and 170 mg (1.11 mmol) of 1-hydroxybenzotriazole (HOBT) The mixture was stirred at room temperature for 18 hours. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution to make it basic, and the product was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (ethyl acetate: methanol = 20: 1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give white powder of N- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl]-(R ) -1- (2-acetylaminoacetyl) pyrrolidine-2-carboxamide 104 mg (yield 29%) was obtained.
Melting point 125.5-126.5 ° C.

Example 9
Synthesis of N- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -N-ethyl-thioacetamide hydrochloride N- [4- (4-Benzo [b] thiophene -4-yl-piperazin-1-yl) butyl] -N-ethyl-acetamide 2.23 g (6.2 mmol) in THF (70 ml) Lawesson's Reagent 3.01 g (7.44 mmol) Was added and the mixture was stirred under reflux with heating for 3 hours. The resulting reaction solution was cooled to room temperature and purified by basic silica gel column chromatography. The purified product was concentrated under reduced pressure, the residue was dissolved in 30 ml of ethanol, and 4.6 ml of 1N-HCl ethanol solution was added to the solution. 15 ml of ether was added and the mixture was allowed to stand. The precipitated crystals were collected by filtration, dried and dried as white powder of N- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -N— 1.47 g (yield 58%) of ethyl-thioacetamide hydrochloride was obtained.
Melting point 224.0-225.5 [deg.] C.

Example 10
Synthesis of N- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -N-isopropyl-thioacetamide hydrochloride As starting material, N- [4- (4-benzo [ b) Thiophen-4-yl-piperazin-1-yl) butyl] -N-isopropyl-acetamide was used to synthesize the title compound in the same manner as in Example 9.
White powder melting point 217.5-223.5 ° C.

Example 11
Synthesis of 1- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] ethyl-3,3-dimethylurea hydrochloride
N- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] ethylamine 0.5 g (1.6 mmol) and triethylamine 0.33 ml (2.4 mmol) in dichloromethane (20 ml) was added 0.2 g (1.9 mmol) of N, N-dimethylcarbamoyl chloride and the mixture was stirred at room temperature for 3 days. Water was added to the reaction solution, and the reaction product was extracted with dichloromethane. The organic layer was washed with water and dried over anhydrous sodium sulfate. The dried product was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 15: 1). The purified product is concentrated under reduced pressure, the residue is dissolved in methanol, and 2.5 ml of 0.5 N HCl methanol solution is added to the resulting solution. The precipitated crystals are collected by filtration, dried and dried with a white powder 1- 0.44 g (66% yield) of [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] ethyl-3,3-dimethylurea hydrochloride was obtained.
Mp 184-186 ° C.

Example 12
Synthesis of 1- [2- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) ethyl] -3-ethylurea hydrochloride 2- (4-benzo [b] thiophen-4-yl- To a solution of piperazin-1-yl) ethylamine in 319 mg (1.22 mmol) in dichloromethane (7 ml) was added 0.125 ml (1.58 mmol) of ethyl isocyanate and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate). The purified product is concentrated under reduced pressure, the residue is dissolved in ethanol, 0.7 ml of 1N-HCl ethanol solution is added to the resulting solution, and the resulting crystals are left to stand overnight in a refrigerator. 126 mg (yield 28%) of 1- [2- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) ethyl] -3-ethylurea hydrochloride as powder was obtained.
Melting point 190.5-191.5 ° C.

  The compounds of Examples 13 to 1448 and 1548 to 1585 can be produced in the same manner as in Examples 1 to 12 using an appropriate raw material compound.

The NMR data of the compounds obtained in the above examples are shown below:
NMR data of the compound obtained in Example 14
¹ H-NMR (DMSO-d ₆ ) δppm: 1.50-1.70 (2H, m), 1.70-1.90 (2H, m), 3.10-3.50 (8H, m), 3.50-3.65 (4H, m), 6.96 ( 1H, d, J = 7.5 Hz), 7.31 (1H, t, J = 7.9 Hz), 7.48 (1H, d, J = 5.6 Hz), 7.69 (1H, d, J = 8.1 Hz), 7.76 (1H, 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 (1H, m), 10.2 (1H, br).

NMR data of the compound obtained in Example 28
¹ H-NMR (DMSO-d ₆ ) 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 (1H, 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 (1H, brs).

NMR data of the compound obtained in Example 29
¹ H-NMR (DMSO-d ₆ ) 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 (1H, brs).

NMR data of the compound obtained in Example 114.
¹ H-NMR (DMSO-d ₆ ) δppm: 1.00-1.20 (3H, m), 1.50-1.80 (4H, m), 3.00-3.70 (14H, m), 6.97 (1H, d, J = 7.5 Hz) , 7.25-7.40 (3H, m), 7.48 (1H, t, J = 5.9Hz), 7.69 (1H, d, J = 8.0 Hz), 7.75 (1H, d, J = 5.6 Hz), 8.66 (2H, d, J = 5.9 Hz), 10.3 (1H, br).

NMR data of the compound obtained in Example 116.
¹ H-NMR (DMSO-d ₆ ) δppm: 1.19 (3H, t, J = 6.9 Hz), 1.60-1.75 (4H, m), 3.10-3.60 (14H, m), 6.97 (1H, d, J = 7.4 Hz), 7.13 (1H, dd, J = 3.7, 5.0 Hz), 7.30-7.35 (1H, m), 7.40-7.45 (1H, m), 7.45-7.50 (1H, m), 7.65-7.80 (3H , m), 10.3 (1H, br).

NMR data of the compound obtained in Example 117
¹ H-NMR (DMSO-d ₆ ) δppm: 1.12 (3H, t, J = 7.1 Hz), 1.55-1.75 (4H, m), 3.00-3.60 (14H, m), 6.66 (1H, dd, J = 0.6, 1.7 Hz), 6.96 (1H, d, J = 7.7 Hz), 7.30 (1H, t, J = 7.9 Hz), 7.45-7.50 (1H, m), 7.65-7.80 (3H, m), 8.01 ( 1H, s), 10.32 (1H, brs).

NMR data of the compound obtained in Example 119
¹ H-NMR (DMSO-d ₆ ) 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 (1H, d, J = 7.5 Hz), 7.30 (1H, t, J = 7.8 Hz), 7.47 (1H, d, J = 5.6 Hz), 7.69 (1H, d, J = 8.0 Hz), 7.75 (1H, d, J = 5.5 Hz), 10.5 (1H, br).

NMR data of the compound obtained in Example 138.
¹ H-NMR (DMSO-d ₆ ) 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 (1H, dd, J = 8.1, 3.5 Hz), 6.95 (1H, d, J = 7.6 Hz), 7.31 (1H, t, J = 7.8 Hz), 7.46-7.50 (1H, m), 7.68 (1H, d, J = 8.0 Hz), 7.75 (1H, d, J = 5.5 Hz), 7.98-8.07 (2H, m).

NMR data of the compound obtained in Example 150.
¹ H-NMR (DMSO-d ₆ ) δppm: 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 (1H, m), 7.20-7.50 (4H, m), 7.69 (1H, d, J = 8.0 Hz), 7.76 (1H, d, J = 5.6 Hz), 7.8 (1H, br) , 8.52 (1H, brs), 10.2 (1H, br).

NMR data of the compound obtained in Example 155.
¹ H-NMR (DMSO-d ₆ ) 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 (1H, m), 6.95 (1H, d, J = 7.6 Hz), 7.25-7.45 (6H, m), 7.47 (1H, d, J = 5.6 Hz), 7.69 (1H, d, J = 8.0 Hz) ), 7.75 (1H, d, J = 5.5 Hz), 10.2 (1H, br).

NMR data of the compound obtained in Example 1435
¹ H-NMR (DMSO-d ₆ ) 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 (1H, d, J = 7.6 Hz), 7.32 (1H, d, J = 7.8 Hz), 7.48 (1H, d, d = 5.5 Hz), 7.70 (1H, d, d = 8.0 Hz), 7.77 (1H, d, d = 5.4 Hz).

NMR data of the compound obtained in Example 1441.
¹ H-NMR (DMSO-d ₆ ) 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 (1H, d, J = 8.1 Hz), 7.32 (1H, t, J = 6.6 Hz), 7.48-7.49 (1H, m), 7.70 (1H, d, J = 7.1 Hz), 7.74-7.80 (1H, m), 10.36 (1H, brs).

Example 1449
Synthesis of 1- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -2-pyrrolidone dihydrochloride 1- (4-Chlorobutyl) -2-pyrrolidone (150 mg, 0 .85 mmol), 1-benzo [b] thiophen-4-ylpiperazine hydrochloride (240 mg, 0.94 mmol), potassium carbonate (290 mg, 2.10 mmol) and sodium iodide (170 mg, 1.13 mmol) Was added to dimethylformamide (DMF) (3 ml) and stirred at 80 ° C. for 6 hours. The reaction mixture was cooled to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The dried organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 30: 1 → 15: 1). The purified product was concentrated under reduced pressure, and the resulting residue was dissolved in ethanol (2 ml), and concentrated hydrochloric acid (0.15 ml) was added. The resulting solution was concentrated under reduced pressure, and the residue was recrystallized from ethanol-ethyl acetate to give 1- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) as a light brown powder. Butyl] -2-pyrrolidone dihydrochloride (220 mg) was obtained.
Melting point: 183.0-185.0 ° C.

  The 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 in the same manner as in Example 1449 using appropriate raw material compounds.

Example 1450
Synthesis of 4- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -6-methoxy-3,4-dihydro-2H-benzo [1,4] oxazine hydrochloride Lithium aluminum hydride (34 mg, 0.90 mmol) was suspended in tetrahydrofuran (THF) (2 ml) to which 4- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) was added. A THF solution (5 ml) of butyl] -6-methoxy-4H-benzo [1,4] oxazin-3-one (0.34 g, 0.75 mmol) was added dropwise. The reaction solution was heated to reflux for 1 hour, cooled to room temperature, and then added with water (50 μl), 15% aqueous sodium hydroxide solution (50 μl), and water (150 μl) in that order under ice cooling and stirred at room temperature for 30 minutes. . The obtained solution was filtered to remove insoluble matters, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1 → 2: 1). The purified product was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate (5 ml), and 1N-hydrochloric ethanol (0.11 ml) was added. The formed insoluble matter was collected by filtration and dried to give 4- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -6-methoxy-3,4- as white powder. Dihydro-2H-benzo [1,4] oxazine hydrochloride (39 mg) was obtained.
Melting point: 218.7-219.8 [deg.] C.

Example 1451
Synthesis of 3- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -6-hydroxy-3H-quinazolin-4-one 1.5 hydrobromide 3- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -6-methoxy-3H-quinazolin-4-one (0.41 g, 0.91 mmol) in dichloromethane (15 ml 2M-boron tribromide dichloromethane solution (1.37 ml, 2.74 mmol) was added dropwise under ice cooling. The resulting reaction solution was stirred at room temperature for 2 days, water was added thereto, and the mixture was stirred for 30 minutes. The purified insoluble matter was collected by filtration, and the filtrate was purified by silica gel column chromatography (dichloromethane: methanol = 20: 1 → 10: 1). The purified product was concentrated to dryness under reduced pressure to give 3- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -6-hydroxy-3H-quinazoline-4 as a white powder. -On 1.5 hydrobromide (0.16 g) was obtained.
Melting point: 249.0-250.2 ° C.

Example 1452
Synthesis of 2- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] octahydroisoindol-1-one hydrochloride 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) in ethanol solution of 10 % Palladium on carbon (0.2 g) was added, and the mixture was stirred at room temperature for 16 hours in a hydrogen atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (5 ml), and 1N ethanolic hydrochloric acid (0.24 ml) was added. The produced insoluble matter was collected by filtration and dried to give 2- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] octahydroisoindol-1-one hydrochloric acid as white powder Salt (50 mg) was obtained.
Melting point: 219.7-221.0 [deg.] C.

Example 1453
Synthesis of 1- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -3- (4-iodobutyl) pyrrolidin-2-one hydrochloride 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) in THF The solution was ice-cooled, and 1.1 M lithium hexamethyldisilazide THF solution (3.2 ml, 3.52 mmol) was added dropwise thereto under a nitrogen atmosphere. The mixture was stirred at room temperature for 20 hours, an aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1). The purified product was concentrated under reduced pressure, and the resulting residue was dissolved in ethanol (2 ml), and concentrated hydrochloric acid (0.15 ml) was added. The resulting solution was concentrated under reduced pressure, and the residue was recrystallized from ethanol-ethyl acetate to give 1- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) as a pale yellow powder. Butyl] -3- (4-iodobutyl) pyrrolidin-2-one hydrochloride (170 mg) was obtained.
Melting point: 118.0-120.0 ° C.

Example 1454
Synthesis of 2- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -2-azaspiro [4,4] nonan-1-one dihydrochloride 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) Of THF was cooled in an ice-methanol bath, and a solution of 1.1 M lithium hexamethyldisilazide in THF (1.9 ml, 2.09 mmol) was added dropwise thereto under a nitrogen atmosphere. The resulting reaction solution was stirred at room temperature for 22 hours. The reaction solution was cooled in an ice-methanol bath, and a THF solution of 1.1 M lithium hexamethyldisilazide (1.9 ml, 2.09 mmol) was added dropwise, followed by stirring at room temperature for 19 hours. Aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1). The purified product was concentrated under reduced pressure, and the resulting residue was dissolved in ethanol (2 ml), and 1N hydrochloric acid ethanol (0.19 ml) was added. The produced insoluble matter was collected by filtration and dried to give 2- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -2-azaspiro [4,4] nonane as a white powder. -1-one dihydrochloride (20 mg) was obtained.
Melting point: 217.0-219.0 [deg.] C.

Example 1455
Synthesis of 1- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] piperazin-2-one dihydrochloride 4- [4- (4-Benzo [b] thiophene- 4-yl-piperazin-1-yl) butyl] -3-oxopiperazine-1-carboxylic acid tert-butyl ester (280 mg, 0.59 mmol) in dichloromethane (10 ml) in trifluoroacetic acid (1.0 ml, 13 Mmol) and stirred at room temperature for 14 hours. The reaction mixture was made alkaline by adding aqueous sodium hydrogen carbonate solution, and extracted with dichloromethane. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and then dried over anhydrous sodium sulfate. The residue was purified by basic silica gel column chromatography (dichloromethane: methanol = 30: 1). The purified product was concentrated under reduced pressure, the residue was dissolved in ethanol (2 ml), and 1N-hydrochloric ethanol (1.2 ml) was added. The produced insoluble matter was collected by filtration and dried to give 1- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] piperazin-2-one dihydrochloride (210 mg) as a white powder. )
Melting point: 258.0-260.0 ° C.

Example 1456
Synthesis of 4-acetyl-1- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] piperazin-2-one hydrochloride 1- [4- (4-Benzo [b Triethylamine (0.15 ml, 1.08 mmol) was added to a solution of thiophen-4-yl-piperazin-1-yl) butyl] piperazin-2-one (260 mg, 0.70 mmol) in dichloromethane (5 ml). Under ice cooling, acetic anhydride (0.1 ml, 1.06 mmol) was added thereto and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was stirred for 30 minutes. Aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with dichloromethane. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and then dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (dichloromethane: ethyl acetate = 1: 1). The purified product was concentrated under reduced pressure, and the resulting residue was dissolved in ethanol (2 ml), and 1N hydrochloric acid ethanol (0.6 ml) was added. The resulting insoluble matter was collected by filtration and dried to give white powder of 4-acetyl-1- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] piperazin-2-one The hydrochloride (220 mg) was obtained.
Melting point: 215.0-217.0 ° C.

Example 1457
Synthesis of 1- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propyl] imidazolidin-2-one 1- [3- (4-benzo [b] thiophen-4- (Il-piperazin-1-yl) propyl] -3- (2,4-dimethoxybenzyl) imidazolidin-2-one (0.32 g, 0.65 mmol) in dichloromethane (10 ml) in trifluoroacetic acid (1. 0 ml, 13 mmol) was added and stirred at room temperature overnight. The reaction solution was made alkaline by adding an aqueous sodium hydroxide solution, and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The resulting solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 30: 1 → 10: 1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-diethyl ether to give 1- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propyl] as white powder. Imidazolidin-2-one (0.10 g) was obtained.
¹ H-NMR (DMSO-d ₆ ) 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 (1H, s), 6.90 (1H, d, J = 7.6 Hz), 7.27 (1H, dd, J = 7.8 Hz, J = 7.8 Hz), 7.40 (1H, d, J = 5.5 Hz), 7.61 (1H, d, J = 7.9 Hz), 7. 69 (1H, d, J = 5.5 Hz).

  The compounds of Examples 1514 and 1521 were synthesized in the same manner as Example 1457 using appropriate raw material compounds.

Example 1458
Synthesis of 1- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propyl] -6-oxo-1,6-dihydropyridine-3-carboxylic acid hydrochloride 1- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propyl] -6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (0.31 g, 0.73 mmol) in ethanol To the solution (3 ml) was added 6N-aqueous sodium hydroxide solution (1 ml), and the mixture was stirred at room temperature for 3 days. Under ice-cooling, 6N-hydrochloric acid was added to the reaction mixture, and the resulting insoluble material was collected by filtration and dried to give 1- [3- (4-benzo [b] thiophen-4-yl-piperazine-1- Yl) propyl] -6-oxo-1,6-dihydropyridine-3-carboxylic acid hydrochloride (181 mg).
Melting point: 265.0 ° C. (decomposition).

Example 1459
Synthesis of 1- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propyl] -6-oxo-1,6-dihydropyridine-3-carboxylic acid ethylamide hydrochloride monohydrate Of 1- [3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propyl] -6-oxo-1,6-dihydropyridine-3-carboxylic acid (015 g, 0.35 mmol) Triethylamine (0.14 ml, 1.04 mmol) and isobutyl chlorocarbonate (0.07 ml, 0.52 mmol) were added to an acetonitrile solution (3 ml) under ice cooling, and the mixture was stirred for 30 minutes. To this was added ethylamine aqueous solution (70%) (0.08 ml, 0.1 mmol), and the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The obtained solution was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (n-hexane: ethyl acetate = 2: 1 → 0: 1). The purified product was concentrated under reduced pressure, the resulting residue was dissolved in ethyl acetate, and 4N-ethyl acetate was added. The formed insoluble matter was collected by filtration and dried to give a white powder of 1- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propyl] -6-oxo-1,6- Dihydropyridine-3-carboxylic acid ethylamide hydrochloride monohydrate (71 mg) was obtained.
Melting point: 135.0-141.5 ° C.

Example 1460
Synthesis of 1- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propyl] -6-oxo-1,6-dihydropyridine-3-carboxylic acid dimethylamide hydrochloride 1- [ 3- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) propyl] -6-oxo-1,6-dihydropyridine-3-carboxylic acid (015 g, 0.35 mmol) in DMF ( 3 ml) under cooling with ice, 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). ) And stirred overnight at room temperature. To the reaction solution were further added triethylamine (0.24 ml, 1.7 mmol), dimethylamine hydrochloride (0.09 g, 1.04 mmol) and diethyl cyanophosphate (0.07 ml, 0.42 mmol), and at room temperature. Stir for 26 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The obtained solution was concentrated under reduced pressure, and the resulting residue was purified by basic silica gel column chromatography (n-hexane: ethyl acetate = 3: 1 → 0: 1). The purified product was concentrated under reduced pressure, the resulting residue was dissolved in ethyl acetate, and 4N-ethyl acetate was added. The formed insoluble matter was collected by filtration and dried to give a white powder of 1- [3- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) propyl] -6-oxo-1,6- Dihydropyridine-3-carboxylic acid dimethylamide hydrochloride (43 mg) was obtained.
Melting point: 201.5-206.0 ° C.

  The compounds of Examples 1484, 1485 and 1519 were synthesized in the same manner as in Example 1460 using appropriate raw material compounds.

Example 1461
Synthesis of 3- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -2-oxo-2,3-dihydrothiazole-4-carboxylic acid methylamide hydrochloride 3- [ 4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -2-oxo-2,3-dihydrothiazole-4-carboxylic acid ethyl ester hydrochloride (0.25 g,. A methylamine aqueous solution (40%) (3 ml) was added to a methanol solution (3 ml) of 52 mmol), and the mixture was heated to reflux for 7 hours. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The residue was purified by basic silica gel column chromatography (n-hexane: ethyl acetate = 5: 1 → 0: 1). The purified product was concentrated under reduced pressure, the resulting residue was dissolved in ethyl acetate, and 4N-ethyl acetate was added. The formed insoluble matter was collected by filtration and dried to give 3- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -2-oxo-2,3- Dihydrothiazole-4-carboxylic acid methylamide hydrochloride (181 mg) was obtained.
Melting point: 137.0-143.5 ° C (decomposition).

  The compounds of Examples 1481, 1482, 1491 and 1492 were synthesized in the same manner as in Example 1461 using appropriate raw material compounds.

  The chemical structure and physicochemical properties of the compounds obtained in Examples 1462-1544 are shown in the following table.

Example 1545
Synthesis of 1- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] piperidine-2-thione hydrochloride 1- [4- (4-Benzo [b] thiophene-4 -Ile-piperazin-1-yl) butyl] -2-piperidone 1.95 g (3.2 mmol) of Lawesson's Reagent was added to a THF solution (35 ml) of 995 mg (2.7 mmol) and heated under reflux. For 3 hours. The reaction solution was cooled to room temperature and purified by basic silica gel column chromatography (hexane: ethyl acetate = 1: 2 → 0: 1). The purified product was concentrated under reduced pressure, the residue was dissolved in ethanol, and 2.0 ml of 1N-HCl ethanol solution was added to the resulting solution and left standing. The precipitated crystals were collected by filtration and dried to give 648 mg (yield) of 1- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] piperidine-2-thione hydrochloride as a white powder. 57%) was obtained.
Mp 258.0-260.0 ° C.

Example 1546
Synthesis of 1- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] pyrrolidin-2-thione 1- [4- (4-Benzo [b] thiophen-4-yl The title compound was synthesized in the same manner as in Example 1545 using -piperazin-1-yl) butyl] -2-pyrrolidone.
Slightly yellow needles (ethanol)
Melting point 122.0-124.0 ° C.

Example 1547
Synthesis of 1- [4- (4-benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] -4-benzylpiperazine-2,5-dione hydrochloride 1-Benzyl-4- (4- The title compound was synthesized in the same manner as in Example 1449 using (chlorobutyl) piperazine-2,5-dione and 1-benzo [b] thiophen-4-yl-piperazine hydrochloride.
White powder (ethanol-ether)
Melting point 220-230 ° C
¹ H-NMR (DMSO-d ₆ ) 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 (1H, d, J = 7.5 Hz), 7.20-7.40 (6H, m), 7.47 (1H, d , J = 5.5 Hz), 7.69 (1H, d, J = 8.0 Hz), 7.75 (1H, d, J = 5.5 Hz), 10.93 (1H, brs).

Pharmacological test 1
1) Dopamine D ₂ receptor binding experiment
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 immediately removed, and the striatum was removed. Homogenize in 50 mM Tris (hydroxymethyl) aminomethane (Tris) -hydrochloric acid buffer solution (pH: 7.4) 50 times the tissue weight using a homogenizer with a high-speed rotary blade, 4 ° C., 48,000 × g And centrifuged for 10 minutes. The obtained sediment was suspended again in the above buffer of 50 times the tissue weight, incubated at 37 ° C. for 10 minutes, and then centrifuged under the above conditions. The obtained sediment is suspended in 50 mM Tris-HCl buffer (containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl ₂ , 1 mM MgCl ₂ , pH: 7.4) 25 times the tissue weight, and these are bound as a membrane specimen. The sample was stored frozen at -85 ° C until used in the experiment.

Binding experiments consisted of 40 μl membrane specimen, 20 μl [ ³ H] -Raclopride (final concentration 1-2 nM), 20 μl test drug and 50 mM Tris-HCl buffer (120 mM NaCl, 5 mM KCl, 2 mM CaCl ₂ , 1 mM MgCl ₂ , pH 7.4) with a total volume of 200 μl (final dimethyl sulfoxide concentration 1%). The reaction was carried out at room temperature for 1 hour and terminated by suction filtration using a cell harvester onto a glass fiber filter plate. The glass fiber filter plate was washed with 50 mM Tris-HCl buffer (pH: 7.4), dried, then added with a microplate liquid scintillation cocktail, and the radioactivity was measured with a microplate scintillation counter. Nonspecific binding was defined as radioactivity in the presence of 10 μM (+)-butaclamol hydrochloride.

IC ₅₀ values were calculated from concentration-dependent reactions using a non-linear analysis program. Ki values were calculated from IC ₅₀ values using the Cheng-Prussoff equation. The results are shown in the following table.

2) Serotonin 5-HT _2A receptor binding experiment
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. Mol. Pharmacol., 1982; 21 : 301-314).

  Wistar male rats were decapitated, the brain was immediately removed, and the frontal cortex was removed. The tissue was homogenized using a Teflon (registered trademark) glass homogenizer in 0.25 M sucrose of 10 times the tissue weight, and centrifuged at 4 ° C. and 1,000 × g for 10 minutes. The obtained supernatant was transferred to another centrifuge tube, and the sediment was suspended in 0.25M sucrose, which is 5 times the tissue weight, and centrifuged under the above conditions. The obtained supernatant was combined with the previously obtained supernatant and adjusted to a volume 40 times the tissue weight with 50 mM Tris-HCl buffer (pH: 7.4), and 10 minutes at 4 ° C. and 35,000 × g. Centrifuged. The obtained sediment was suspended again in the buffer solution 40 times the tissue weight and centrifuged under the above conditions. The obtained sediment was suspended in the above buffer solution having an amount 20 times the weight of the tissue, and these were frozen and stored at −85 ° C. until used as a membrane specimen for binding experiments.

The binding experiment was performed with a membrane sample of 40 μl, [ ³ H] -ketanserin 20 μl (final concentration 1-3 nM), a test drug 20 μl, and 50 mM Tris-HCl buffer (pH: 7.4) in a total volume of 200 μl (final) Dimethyl sulfoxide concentration 1%). The reaction was performed at 37 ° C. for 20 minutes and terminated by suction filtration through a glass fiber filter plate using a cell harvester.

  The glass fiber filter plate was washed with 50 mM Tris-HCl buffer (pH: 7.4), dried, then added with a microplate liquid scintillation cocktail, and the radioactivity was measured with a microplate scintillation counter. Radioactivity in the presence of 10 μM spiperone was defined as nonspecific binding.

IC ₅₀ values were calculated from concentration-dependent reactions using a non-linear analysis program. Ki values were calculated from IC ₅₀ values using the Cheng-Prussoff equation. The results are shown in the following table.

Human dopamine D ₂ receptor-expressing Chinese hamster ovary / DHFR (−) cells in medium (Iscob modified Dulbecco medium (IMDM medium), 10% fetal calf serum, 50 IU / ml penicillin, 50 μg / ml streptomycin, 200 μg / ml geneticin, 0.1 mM sodium hypoxanthine, 16 μM thymidine) at 37 ° C. and 5% carbon dioxide gas. 10 ⁴ cells / well of cells were seeded in a 96-well microplate coated with poly-L-lysine and cultured under the same conditions for 2 days. Each well was washed with 100 μl of washing solution (IMDM medium, 0.1 mM sodium hypoxanthine, 16 μM thymidine), and 50 μl of test compound-supplemented medium in which 3 μM of the test compound was dissolved (IMDM medium, 0.1% sodium ascorbate, 0.1 mM hypopoxin). (Xanthine sodium, 16 μM thymidine). After standing at 37 ° C. and 5% carbon dioxide for 20 minutes, 100 μl of test compound-added forskolin-stimulated medium in which 3 μM of the same test compound was dissolved (IMDM medium, 0.1% sodium ascorbate, 0.1 mM sodium hypoxanthine, 16 μM thymidine, 10 μM forskolin, 500 μM 3-isobutyl-1-methylxanthine) and allowed to stand at 37 ° C. under 5% carbon dioxide for 10 minutes. After removing the medium, 200 μl of Lysis 1B aqueous solution (Amersham Biosciences Cyclic AMP Biotrac Enzyme Immunoassay System attached reagent) was dispensed and shaken for about 10 minutes. The aqueous solution in each well was used as a measurement sample. Using the enzyme immunoassay system, a cyclic AMP amount was measured on a measurement sample diluted 4-fold. The inhibition rate of each test compound was calculated with the amount of cyclic AMP in a well to which no test compound was added as 100%. In this experimental system, dopamine used as a control drug suppressed the amount of cyclic AMP to about 10% as the maximum activity.

In the above test, it was confirmed that the test compound has a partial agonistic property to the dopamine D ₂ receptor.

Since the test compound has a partial agonistic property with respect to the dopamine D ₂ receptor, dopamine neurotransmission can be stabilized in a normal state in a schizophrenic patient, and as a result, without causing side effects, For example, clinical improvement effects such as positive and negative symptom improvement effects and cognitive impairment improvement effects can be exhibited.

Formulation Example 100 g of the compound of the present invention, 40 g of Avicel (trade name, manufactured by Asahi Kasei Co., Ltd.), 30 g of corn starch and 2 g of magnesium stearate were mixed and polished, and tableted with a sugar coated R10 mm kine.

  The obtained tablets were coated with a film coating agent consisting of 10 g of TC-5 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd., hydroxypropylmethylcellulose), 3 g of polyethylene glycol 6000, 40 g of castor oil, and an appropriate amount of ethanol. A film coating tablet having the above composition was produced.

Claims (6)

General formula (1):

[Wherein, Q represents a group represented by the following general formula (I) or a group represented by the general formula (II).
Formula (I):

(In the formula, A ¹ represents a lower alkylene group.
Z represents O or S.
R ¹¹ is (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 was selected from the group consisting of (i) to (xxxiii) below as a substituent At least one group may be substituted:
(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) sulfamoyl group,
(xvi) a lower alkylthio group,
(xvii) a lower alkylsulfonyl group,
(xviii) hydroxysulfonyl group,
(xix) an amino group optionally having a group 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) morpholinylcarbonyl lower alkenyl group,
(xxi) morpholinylcarbonyl lower alkyl group,
(xxii) pyrrolyl group,
(xxiii) pyrazolyl group,
(xxiv) an imidazolyl group,
(xxv) triazolyl group,
(xxvi) pyridyl group,
(xxvii) an pyrrolidinyl group optionally having an oxo group,
(xxviii) morpholinyl group,
(xxix) thiomorpholinyl group,
(xxx) a lower alkynyl group,
(xxxi) a cyclo C3-C8 alkyl group,
(xxxii) guanidino group,
(xxxiii) a dihydropyrazolyl group optionally having a group selected from the group consisting of an oxo group and a lower alkyl group),
(1-4) Heterocyclic group (here, at least one group selected from the group consisting of the following (i) to (xix) may be substituted as a substituent on the heterocyclic group:
(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 optionally having a group selected from the group consisting of halogen and halogen-substituted lower alkyl groups on the aryl group;
(vii) aryl lower alkyl group optionally having halogen,
(viii) a lower alkanoyl group,
(ix) aroyl group,
(x) an amino lower alkanoyl group optionally having a lower alkanoyl group on the amino group,
(xi) a lower alkylthio group,
(xii) pyrrolyl group,
(xiii) an oxo group,
(xiv) a thioxo group,
(xv) a carbamoyl group,
(xvi) a hydroxy group,
(xvii) pyranyl group,
(xviii) thienyl group,
(xix) furyl group),
(1-5) On an amino group and / or a lower alkyl group, 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) An amino lower alkyl group optionally having a group selected from the group consisting of a 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 a group selected from the group consisting of a lower alkyl group, a lower alkoxy group, a hydroxy group, a halogen and a nitro group on the aryl group;
(1-9) an aryloxy lower alkyl group which may have a group selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen and a cyano group on the aryl group;
(1-10) adamantyl lower alkyl group (1-11) amino optionally having a lower alkyl group, a lower alkoxy group, a halogen-substituted lower alkyl group, a halogen-substituted lower alkoxy group or a lower alkyl group on the aryl group An aryl lower alkenyl group optionally having a group selected from the group consisting of a group, a halogen and a nitro group,
(1-12) an amino group optionally having a lower alkyl group; an amino lower alkyl group optionally having a lower alkyl group, and a group selected from the group consisting of a halogen and a lower alkyl group; A cyclo C3-C8 alkyl group optionally having a group selected from the group consisting of aryl groups,
(1-13) a cyclo C3-C8 alkyl lower alkyl group,
(1-14) arylthio lower alkyl group,
(1-15) Lower alkyl substituted with a heterocyclic group selected from the group consisting of piperidyl group, tetrahydropyranyl group, pyridyl group, thienyl group, imidazolyl group, tetrazolyl group, benzimidazolyl group, isoindolyl group, thiazolidinyl group and indolyl group A group (which may have a group selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen, an oxo group and a thioxo group on the heterocyclic group),
(1-16) aryl lower alkenyl group (which may have an aryl group on the lower alkenyl group),
(1-17) a lower alkenyl group substituted with a heterocyclic group selected from the group consisting of a benzodioxolyl group, a pyridyl group, a furyl group, and an imidazolyl group,
(1-18) benzodioxolyloxy lower alkyl group,
(1-19) A pyridylthio lower alkyl group, or (1-20) an amino group optionally having a lower alkyl group.
R ¹² is
(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) lower alkanoyl group,
(2-7) hydroxy lower alkyl group,
(2-8) a lower alkoxy lower alkyl group,
(2-9) a cyclo C3-C8 alkyl group,
(2-10) cyclo C3-C8 alkyl lower alkyl group,
(2-11) aryl group,
(2-12) an aryl lower alkyl group which may have a group selected from the group consisting of an amino group and an aryloxy group which may have a lower alkyl group on the aryl group;
(2-13) 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) represents a tetrahydropyranyl group or (2-16) a lower alkanoyloxy lower alkyl group. )
General formula (II):
R ²¹ -A ^2- (II)
(In the formula, —A ² — represents a lower alkylene group, a lower alkenylene group or a group —A ²¹ —O—A ²² —.
Here, A ²¹ and A ²² are the same or different and each represents a C1-C5 alkylene group. However, 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 an N-containing heterocyclic group:
Here, on the N-containing heterocyclic ring represented by R ²¹ , at least one group selected from the group consisting of the following (1) to (13) may be substituted:
(1) halogen-substituted or unsubstituted lower alkyl group (2) lower alkenyl group (3) lower alkoxy group (4) hydroxy group (5) protected hydroxy group (6) aryl group (7) lower alkanoyl group (8) Carboxy group (9) lower alkoxycarbonyl group (10) carbamoyl group optionally having lower alkyl group (11) aryl lower alkyl group (wherein the aryl group may have a lower alkoxy group) )
(12) Oxo group (13) Thioxo group)]
Or a salt thereof. Q is a group represented by the following general formula (I):

[Wherein, A ¹ represents a lower alkylene group.
Z represents O or S.
R ¹¹ is (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 following (i) to (viii), (ix a), (xa), (xii), (xiii a), (xiv) to (xviii), (xix a), (xx) to (xxvi), (xxvii a), and (xxviii) to (xxxiii) 1 to 3 groups selected from may be substituted:
(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,
(xa) a phenoxy group,
(xi) a lower alkoxycarbonyl group,
(xii) a hydroxy group,
(xiii a) a phenyl lower alkoxy group optionally having 1 to 3 halogen atoms on the lower alkanoyloxy group or phenyl group,
(xiv) a lower alkanoyl group,
(xv) sulfamoyl group,
(xvi) a lower alkylthio group,
(xvii) a lower alkylsulfonyl group,
(xviii) hydroxysulfonyl group,
(xix a) an amino group optionally having 1 or 2 groups 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) morpholinylcarbonyl lower alkenyl group,
(xxi) morpholinylcarbonyl lower alkyl group,
(xxii) pyrrolyl group,
(xxiii) pyrazolyl group,
(xxiv) an imidazolyl group,
(xxv) triazolyl group,
(xxvi) pyridyl group,
(xxviia) pyrrolidinyl group optionally having 1 to 2 oxo groups,
(xxviii) morpholinyl group,
(xxix) thiomorpholinyl group,
(xxx) a lower alkynyl group,
(xxxi) a cyclo C3-C8 alkyl group,
(xxxii) guanidino group,
(xxxiii) a dihydropyrazolyl group having one oxo group and one lower alkyl group),
(1-4 a) pyrrolidinyl, piperidyl, thiazolidinyl, tetrahydropyranyl, pyrrolyl, imidazolyl, pyrazolyl, dihydropyrazolyl, pyridyl, dihydropyridyl, tetrahydropyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, thienyl, furyl, indolyl, indolinyl, isoindolinyl , Benzimidazolyl, imidazolopyridylquinolyl, dihydroquinolyl, tetrahydroquinolyl, isoquinolyl, cinolinyl, indazolyl, quinoxalinyl, benzotriazolyl, dihydronaphthylidyl, benzothiazolyl, dihydrobenzothiazolyl, dihydrobenzothiazinyl, thienopyrazinyl, benzox Zolyl, dihydrobenzoxazolyl, dihydrobenzoxazinyl, furopyrrolyl, ben A heterocyclic group selected from the group consisting of dioxolyl, dihydrobenzodioxinyl and benzothienyl (wherein (i) to (v), (vi a), (vii a), One to three groups selected from the group consisting of (viii), (ix a), (xa) and (xi) to (xix) may be substituted:
(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 optionally having 1 to 3 groups selected from the group consisting of halogen and halogen-substituted lower alkyl groups on the phenyl group;
(viia) a phenyl lower alkyl group optionally having 1 to 3 halogen atoms,
(viii) a lower alkanoyl group,
(ix a) a benzoyl group,
(xa) an amino lower alkanoyl group optionally having 1 to 2 lower alkanoyl groups on the amino group;
(xi) a lower alkylthio group,
(xii) pyrrolyl group,
(xiii) an oxo group,
(xiv) a thioxo group,
(xv) a carbamoyl group,
(xvi) a hydroxy group,
(xvii) pyranyl group,
(xviii) thienyl group,
(xix) furyl group),
(1-5 a) On an amino group and / or a lower alkyl group, 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 1 to 2 groups selected from the group consisting of halogen and lower alkoxy groups may be present on the phenyl group) and 1 to 2 groups selected from the group consisting of phenyl lower alkoxycarbonyl groups. An amino lower alkyl group,
(1-6) a lower alkoxy lower alkyl group,
(1-7 a) benzoyl lower alkyl group,
(1-8 a) a phenyl lower alkyl group which may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a lower alkoxy group, a hydroxy group, a halogen and a nitro group on the phenyl group;
(1-9 a) a phenoxy lower alkyl group which may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen and a cyano group on the phenyl group;
(1-10) adamantyl lower alkyl group,
(1-11 a) On the phenyl group, a lower alkyl group, a lower alkoxy group, a halogen-substituted lower alkyl group, a halogen-substituted lower alkoxy group, an amino group optionally having 1-2 lower alkyl groups, a halogen, and A phenyl lower alkenyl group optionally having 1 to 3 groups selected from the group consisting of nitro groups,
(1-12 a) an amino group optionally having 1 to 2 lower alkyl groups; an amino lower alkyl group optionally having 1 to 2 lower alkyl groups, and a group consisting of a halogen and a lower alkyl group A cyclo C3-C8 alkyl group optionally having a group selected from the group consisting of phenyl groups optionally having 1 to 3 groups selected from
(1-13) a cyclo C3-C8 alkyl lower alkyl group,
(1-14 a) a phenylthio lower alkyl group,
(1-15 a) Lower substituted by a heterocyclic group selected from the group consisting of piperidyl group, tetrahydropyranyl group, pyridyl group, thienyl group, imidazolyl group, tetrazolyl group, benzimidazolyl group, isoindolyl group, thiazolidinyl group and indolyl group An alkyl group (which may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen, an oxo group and a thioxo group on the heterocyclic group),
(1-16 a) a phenyl lower alkenyl group (which may have 1 to 2 phenyl groups on the lower alkenyl group),
(1-17) a lower alkenyl group substituted with a heterocyclic group selected from the group consisting of a benzodioxolyl group, a pyridyl group, a furyl group, and an imidazolyl group,
(1-18) benzodioxolyloxy lower alkyl group,
(1-19) A pyridylthio lower alkyl group or (1-20 a) an amino group optionally having 1 to 2 lower alkyl groups.
R ¹² is
(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) lower alkanoyl group,
(2-7) hydroxy lower alkyl group,
(2-8) a lower alkoxy lower alkyl group,
(2-9) a cyclo C3-C8 alkyl group,
(2-10) cyclo C3-C8 alkyl lower alkyl group,
(2-11 a) a phenyl group,
(2-12 a) A phenyl lower group optionally having 1 to 3 groups selected from the group consisting of an amino group and a phenoxy group which may have 1 to 2 lower alkyl groups on the phenyl group An alkyl group,
(2-13) 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) represents a tetrahydropyranyl group or (2-16) a lower alkanoyloxy lower alkyl group. ]
Or a group represented by the following general formula (II):
R ²¹ -A ^2- (II)
Wherein, -A ² - is lower alkylene, lower alkenylene group or a group ^-A 21 ^{-O-A 22} - shows the.
Here, A ²¹ and A ²² are the same or different and each represents a C1-C5 alkylene group. However, 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 is pyrrolidinyl, imidazolidinyl, piperidyl, hexahydropyrimidinyl, piperazinyl, octahydroisoindole, azepanyl, azocanyl, azaspirononyl, azaspirodecanyl, diazaspirononyl, 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, cal Basolyl, spiro [cyclopentaneindolinyl, oxazolyl, isoxazolyl, oxadiazolyl, oxazolidinyl, isoxazolidinyl, oxadinanyl, morpholinyl, benzoxazolyl, dihydrobenzoxazolyl, benzooxazinyl, dihydrobenzoxazinyl, benzo Represents an N-containing heterocyclic group selected from the group consisting of oxazolyl, benzooxadiazolyl, thiazolyl, dihydrothiazolyl, isothiazolyl, thiadiazolyl, dihydrothiazinyl, thiazolidinylbenzothiazolyl and benzothiadiazolyl :
Here, on the N-containing heterocycle represented by R ²¹ , the following (1) to (4), (5 a), (6 a), (7) to (9), (10 a), 1 to 3 groups selected from the group consisting of (11 a), (12) and (13) may be substituted:
(1) halogen-substituted or unsubstituted lower alkyl group (2) lower alkenyl group (3) lower alkoxy group (4) hydroxy group (5a) lower alkanoyloxy group or phenyl lower alkoxy group (6a) phenyl group (7) lower alkanoyl Group (8) carboxy group (9) lower alkoxycarbonyl group (10a) carbamoyl group optionally having 1 to 2 lower alkyl groups (11a) phenyl lower alkyl group (here, lower alkoxy on the phenyl group) (You may have 1-2 groups)
(12) Oxo group (13) Thioxo group]
The heterocyclic compound or its salt of Claim 1 which shows these. Q is a group represented by the following general formula (I):

[Wherein, A ¹ represents a lower alkylene group.
Z represents O or S.
R ¹¹ is (1-1) hydrogen,
(1-2) a lower alkyl group,
(1-5 aa) On an amino group and / or a lower alkyl group, 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 An amino group which may have a group selected from the group consisting of halogen and a lower alkoxy group on a phenyl group) and a group selected from the group consisting of a phenyl lower alkoxycarbonyl group; An amino group optionally having 1 to 2 lower alkyl groups or (1-20a) lower alkyl groups is shown.
R ¹² is
(2-1) Hydrogen,
(2-2) a lower alkyl group,
(2-4) a lower alkenyl group,
(2-6) lower alkanoyl group,
(2-7) hydroxy lower alkyl group,
(2-8) represents a lower alkoxy lower alkyl group or (2-9) a cyclo C3-C8 alkyl group. ]
The heterocyclic compound or its salt of Claim 2 which shows these. Q is a group represented by the following general formula (II):
R ²¹ -A ^2- (II)
[Wherein, -A ² -represents a lower alkylene group or a lower alkenylene group.
R ²¹ represents an N-containing heterocyclic group selected from the group consisting of pyrrolidinyl, imidazolidinyl, piperidyl, azepanyl, oxazolidinyl and oxadinanyl:
Here, on the N-containing heterocyclic ring represented by R ²¹ , 1 to 2 groups selected from the group consisting of the following (1), (12) and (13) may be substituted. :
(1) Halogen-substituted or unsubstituted lower alkyl group (12) oxo group (13) thioxo group]
The heterocyclic compound or its salt of Claim 2 which shows these. The heterocyclic compound represented by the general formula (1) is
N- [5- (4-Benzo [b] thiophen-4-ylpiperazin-1-yl) pentyl] acetamide,
N- [5- (4-Benzo [b] thiophen-4-ylpiperazin-1-yl) pentyl] -2,4-difluorobenzamide,
N- [4- (4-Benzo [b] thiophen-4-ylpiperazin-1-yl) butyl] -N-cyclopropylacetamide,
5-methyl-2-pyrazinecarboxylic acid [4- (4-benzo [b] thiophen-4-ylpiperazin-1-yl) butyl] ethylamide,
4-thiazolecarboxylic acid [4- (4-benzo [b] thiophen-4-ylpiperazin-1-yl) butyl] ethylamide,
N- [4- (4-Benzo [b] thiophen-4-ylpiperazin-1-yl) butyl] -N-ethyl-acetamide,
N- [4- (4-Benzo [b] thiophen-4-ylpiperazin-1-yl) butyl] -N-isopropylacetamide,
N- [4- (4-Benzo [b] thiophen-4-ylpiperazin-1-yl) butyl] -N-ethylthioacetamide,
N-allyl-N- [4- (4-benzo [b] thiophen-4-ylpiperazin-1-yl) butyl] acetamide or N- [4- (4-benzo [b] thiophen-4-ylpiperazine- The heterocyclic compound or a salt thereof according to claim 3, which is 1-yl) butyl] -N-tert-butylformamide. The heterocyclic compound represented by the general formula (1) is
1- [5- (4-Benzo [b] thiophen-4-ylpiperazin-1-yl) pentyl] -imidazolidin-2-one,
1- [5- (4-benzo [b] thiophen-4-ylpiperazin-1-yl) pentyl] -3-methylimidazolidin-2-one,
1- [5- (4-benzo [b] thiophen-4-ylpiperazin-1-yl) pentyl] -pyrrolidin-2-one,
1- [5- (4-benzo [b] thiophen-4-ylpiperazin-1-yl) pentyl] -pyrrolidine-2,5-dione,
1- [4- (4-benzo [b] thiophen-4-ylpiperazin-1-yl) butyl] azepan-2-one,
3- [6- (4-benzo [b] thiophen-4-ylpiperazin-1-yl) hexyl] oxazolidine-2-one,
3- [4- (4-Benzo [b] thiophen-4-ylpiperazin-1-yl) butyl] -4,4-dimethyloxazolidine-2-one,
3- [4- (4-Benzo [b] thiophen-4-ylpiperazin-1-yl) butyl] -4-methyloxazolidine-2-one,
3- [4- (4-Benzo [b] thiophen-4-ylpiperazin-1-yl) butyl] -oxazolidine-2-one,
1- [4- (4-benzo [b] thiophen-4-ylpiperazin-1-yl) butyl] pyrrolidin-2-one,
1- [4- (4-benzo [b] thiophen-4-ylpiperazin-1-yl) butyl] piperidin-2-one,
1-[(E) -4- (4-benzo [b] thiophen-4-ylpiperazin-1-yl) -2-butenyl] -3-methylimidazolidin-2-one,
1- [4- (4-Benzo [b] thiophen-4-yl-piperazin-1-yl) butyl] piperidin-2-thione or 3- [4- (4-benzo [b] thiophen-4-ylpiperazine The heterocyclic compound or a salt thereof according to claim 4, which is -1-yl) butyl] -4-methyloxazolidine-2-one.