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CN101137645A - Aryl piperazine derivatives for the treatment of neuropsychiatric disorders - Google Patents

Aryl piperazine derivatives for the treatment of neuropsychiatric disorders Download PDF

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Publication number
CN101137645A
CN101137645A CNA2006800017275A CN200680001727A CN101137645A CN 101137645 A CN101137645 A CN 101137645A CN A2006800017275 A CNA2006800017275 A CN A2006800017275A CN 200680001727 A CN200680001727 A CN 200680001727A CN 101137645 A CN101137645 A CN 101137645A
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Prior art keywords
alkyl
piperazin
butyl
alkoxy
halo
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Inventor
G·坎比亚尼
S·布迪尼
C·法托鲁索
F·特洛塔
S·弗朗西斯奇尼
M·德安吉里斯
K·S·尼尔森
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Universita degli Studi di Siena
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Universita degli Studi di Siena
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Abstract

This invention provides novel aryl piperazine derivatives having medical utility, in particular as modulators of dopamine and serotonin receptors, preferably the D3, D2-like and 5-HT2 receptor subtypes, and in particular useful for the treatment of neuropsychiatric disorders incl. schizophrenia. Formula (I) an enantiomer thereof or a mixture of its enantiomers, or a pharmaceutically acceptable salt thereof, or an N-oxide thereof.

Description

Arylpiperazine derivatives for the treatment of neuropsychiatric disorders
Technical Field
The present invention provides novel arylpiperazine derivatives having pharmaceutical utility, particularly as modulators of dopamine and 5-hydroxytryptamine receptors, preferably D3、D2-sample and 5-HT2Receptor subtypes, especiallyFor the treatment of neuropsychiatric disorders, including schizophrenia.
Background
Dopamine participates in several important excitatory and inhibitory functions via dopaminergic receptors in the central and peripheral nervous systems. Dopamine receptors were originally divided into two main classes: d1And D2. Five cloned dopamine receptors currently fall into these classes. Thus, D1-the sample receptor comprises D1And D5And D is2-the sample receptor comprises D2、D3And D4
Dopamine receptors, in particular D2Like receptors are considered as potential therapeutic targets for a variety of neurological and psychiatric disorders, particularly psychotic disorders including schizophrenia. Other therapeutic indications associated with dopamine receptors include depression, parkinson's disease, huntington's disease, movement disorders (e.g. dystonia), anxiety, immobility, obsessive compulsive disorders, mania, senile diseases, dementia, sexual dysfunction, muscular-skeletal pain symptoms (e.g. pain associated with fibromyalgia), substance abuse (cocaine abuse and addiction), withdrawal symptoms of drug addiction and sleep disorders.
Finally, receptor-selective ligands are used as diagnostic tools in diagnostic methods, in particular for in vivo receptor imaging (neuroimaging).
Selective dopamine receptor ligands have been described in the literature, for example WO 2004024878, Leopoldo et al (J.Med.Chem.2002 45 5727-5733)、Campiani et al.(J.Med.Chem.2003463822-J.Med.Chem.2003 46 3883-3899)。
Summary of The Invention
In accordance with the present invention, it has now been found that certain aryl piperazine derivatives exhibit excellent dopamine and 5-hydroxytryptamine receptor modulator activityPreferably D3、D2-sample and 5-HT2Receptor subtypes, and are therefore particularly useful as antipsychotic agents.
Thus in a first aspect, the present invention provides novel arylpiperazine derivatives represented by formula I
Figure A20068000172700181
An enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt thereof, or an N-oxide thereof, wherein,
R1、R2and R3Independently of one another, represents hydrogen, alkyl, cycloalkyl-alkyl, alkenyl, hydroxyl, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro, cyano and/or carboxyl;
Figure A20068000172700182
represents an optional double bond; if it is not
Figure A20068000172700183
Represents a single bond, then A represents CH or N; if it is not
Figure A20068000172700184
Represents a double bond, then A represents C;
-B-may be absent or present: -B-is absent; z represents CH or N; or- -B- -exists and represents a methylene bridge (- -CH)2-), a vinyl bridge (-CH-), or a bridge-NH-, connected as shown; and Z represents C (carbon);
w represents CH, N or CR4Wherein R is4Represents hydrogen, alkyl, cycloalkyl-alkyl, alkenyl, hydroxy, alkoxy, cycloalkoxy, haloAlkyl, haloalkoxy, amino, nitro or cyano;
m and n are independently of each other 0, 1 or 2;
x may be absent or present:
x is present and represents O, S, NR', CO, SO2、CH2、CH2-O、O-CH2、CH2-S、S-CH2、CH2-NR’、CH2-CO、CH2-SO2、NR’-CO、CO-NR’、NR’-SO2、SO2-NR’、CH2-CH2、O-CO、CO-O、O-CH=CH、S-CH=CH、NR’-CH=CH、CO-CH=CH、SO2-CH=CH、CH2-O-CH=CH、CH2-S-CH=CH、CH2-NR’-CH=CH、CH2-CO-CH=CH、CONHCH2CH2Or CH2-SO2-CH ═ CH, where R' represents hydrogen or alkyl; and is
Y represents phenyl or an aromatic monocyclic or polycyclic heterocyclic group, which phenyl or heterocyclic group may be optionally substituted one or more times by a substituent selected from the group consisting of: alkyl, cycloalkyl-alkyl, alkenyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano; or
Y represents a hydrogenated heterocyclic group which may be optionally substituted one or more times with a substituent selected from the group consisting of: alkyl, cycloalkyl-alkyl, alkenyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano; or
Y represents a group of formula III
Figure A20068000172700191
Wherein
R7Represents hydrogen, alkyl, alkoxy, halo or haloalkyl; or
X is absent; and is
Y represents a diazo heterocyclic group of formula II
Figure A20068000172700192
Wherein,
o is 1, 2 or 3;
d represents alkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano;
e represents alkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano; or
D and E together with the diazoheterocyclic group form a fused ring system, which may be optionally substituted one or more times by substituents selected from the group consisting of: alkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano;
or Y represents a group of formula IV
Figure A20068000172700201
Wherein A' represents CH or N; and is
R8Represents hydrogen, alkyl, alkoxy, halo or haloalkyl.
In another aspect, the present invention relates to the use of an arylpiperazine derivative of the present invention or a pharmaceutically acceptable salt thereof or a prodrug thereof for the preparation of a pharmaceutical composition.
In another aspect, the invention relates to the use of an arylpiperazine derivative of the invention, or a pharmaceutically acceptable salt or prodrug thereof, for the preparation of a pharmaceutical composition for the treatment, prevention or alleviation of a disease or a disorder or a condition of a mammal, including a human, which disease, disorder or condition is responsive to modulation of dopamine and 5-hydroxytryptamine receptors.
In a final aspect, the invention provides a method of diagnosis, treatment, prevention or alleviation of a disease or a disorder or a condition of a living animal body, including a human, which disorder, disease or condition is responsive to modulation of dopamine and 5-hydroxytryptamine receptors, in particular D3、D2-sample and 5-HT2Receptor subtype, preferably dopamine D3Receptor subtype and/or D3/5-HT1AOr D3/5-HT2AA receptor subtype, which method comprises administering to a living animal body in need thereof a therapeutically effective amount of an arylpiperazine derivative of the present invention or a pharmaceutically acceptable salt or prodrug thereof.
Other aspects of the present invention will become apparent to those skilled in the art from the following detailed description and examples.
Detailed disclosure of the invention
In accordance with the present invention, it has now been found that a particular group of arylpiperazine derivatives exhibit excellent biological behaviour as modulators of dopamine and 5-hydroxytryptamine receptors.
Thus in a first aspect, the present invention provides novel arylpiperazine derivatives represented by formula I
Figure A20068000172700211
An enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt thereof, or an N-oxide thereof, wherein,
R1、R2and R3Independently of one another, represents hydrogen, alkyl, cycloalkyl-alkyl, alkenyl, hydroxyl, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro, cyano and/or carboxyl;
Figure A20068000172700212
represents an optional double bond; if it is notRepresents a single bond, then A represents CH or N; if it is not
Figure A20068000172700214
Represents a double bond, then A represents C;
-B-may be absent or present: -B-is absent; z represents CH or N; or- -B- -exists and represents a methylene bridge (- -CH)2-), a vinyl bridge (-CH-), or a bridge-NH-, connected as shown; z represents C (carbon);
w represents CH, N or CR4Wherein R is4Represents hydrogen, alkyl, cycloalkyl-alkyl, alkenyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro or cyano;
m and n are independently of each other 0, 1 or 2; and is
X may be absent or present:
x is present and represents O, S, NR', CO, SO2、CH2、CH2-O、O-CH2、CH2-S、S-CH2、CH2-NR’、CH2-CO、CH2-SO2、NR’-CO、CO-NR’、NR’-SO2、SO2-NR’、CH2-CH2、O-CO、CO-O、O-CH=CH、S-CH=CH、NR’-CH=CH、CO-CH=CH、SO2-CH=CH、CH2-O-CH=CH、CH2-S-CH=CH、CH2-NR’-CH=CH、CH2-CO-CH=CH、CONHCH2CH2Or CH2-SO2-CH ═ CH, where R' represents hydrogen or alkyl; and is
Y represents phenyl or an aromatic monocyclic or polycyclic heterocyclic group, which phenyl or heterocyclic group may be optionally substituted one or more times by a substituent selected from the group consisting of: alkyl, cycloalkyl-alkyl, alkenyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano; or Y represents a hydrogenated heterocyclic group which may be optionally substituted one or more times with a substituent selected from the group consisting of: alkyl, cycloalkyl-alkyl, alkenyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano; or
Y represents a group of formula III
Figure A20068000172700221
Wherein
R7Represents hydrogen, alkyl, alkoxy, halo or haloalkyl; or
X is absent;
y represents a diazo heterocyclic group of formula II
Figure A20068000172700222
Wherein,
o is 1, 2 or 3;
d represents alkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano; and is
E represents alkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano; or
D and E together with the diazoheterocyclic group form a fused ring system, which may be optionally substituted one or more times by substituents selected from the group consisting of: alkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano;
or Y represents a group of formula IV
Figure A20068000172700223
Wherein A' represents CH or N; and is
R8Represents hydrogen, alkyl, alkoxy, halo or haloalkyl.
In a more preferred embodiment, the arylpiperazine derivatives of the present invention are compounds of formula I wherein
R1、R2And R3Independently of one another, represents hydrogen, alkyl, cycloalkyl-alkyl, alkenyl, hydroxyl, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and/or cyano, carboxyl;
Figure A20068000172700231
represents an optional double bond; if it is not
Figure A20068000172700232
Represents a single bond, then A represents CH or N; if it is notRepresents a double bond, then A represents C (carbon);
-B-may be absent or present: -B-is absent; and Z represents CH or N; or- -B- -exists and represents a methylene bridge (- -CH)2-), a vinyl bridge (-CH-), or a bridge-NH-, connected as shown; and is
Z represents C (carbon);
w represents CH, N or CR4Wherein R is4Represents hydrogen, alkyl, cycloalkyl-alkyl, alkenyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro or cyano;
m and n are independently of each other 0, 1 or 2; and is
X may be absent or present:
x is present and represents O, S, NR', CO, SO2、CH2、CH2-O、O-CH2、CH2-S、S-CH2、CH2-NR’、CH2-CO、CH2-SO2、NR’-CO、CO-NR’、NR’-SO2、SO2-NR’、CH2-CH2、O-CO、CO-O、O-CH=CH、S-CH=CH、NR’-CH=CH、CO-CH=CH、SO2-CH=CH、CH2-O-CH=CH、CH2-S-CH=CH、CH2-NR’-CH=CH、CH2-CO-CH=CH、CONHCH2CH2Or CH2-SO2-CH ═ CH, where R' represents hydrogen or alkyl; and is
Y represents phenyl or an aromatic monocyclic or polycyclic heterocyclic group, which phenyl or heterocyclic group may be optionally substituted one or more times by a substituent selected from the group consisting of: alkyl, cycloalkyl-alkyl, alkenyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano; or
Y represents a hydrogenated heterocyclic group which may be optionally substituted one or more times with a substituent selected from the group consisting of: alkyl, cycloalkyl-alkyl, alkenyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano; or
X is absent;
y represents a diazo heterocyclic group of formula II
Figure A20068000172700241
Wherein,
o is 1, 2 or 3;
d represents alkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano; and is
E represents alkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano; or
D and E together with the diazoheterocyclic group form a fused ring system, which may be optionally substituted one or more times by substituents selected from the group consisting of: alkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano.
In another preferred embodiment, the arylpiperazine derivatives of the present invention are compounds of formula I, whereinRepresents a single bond, and A represents CH or N.
In a more preferred embodiment of the present invention,
Figure A20068000172700243
represents a single bond, and A represents N.
In the most preferred embodiment of the present invention,
Figure A20068000172700244
represents a double bond, and A represents C (carbon).
In a third preferred embodiment, the arylpiperazine derivatives of the invention are compounds of formula I, wherein W represents CH, N or CR4Wherein R is4Represents hydrogen, alkyl, cycloalkyl-alkyl, alkenyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro or cyano.
In a more preferred embodiment, W represents CR4Wherein R is4Represents hydrogen, alkyl, in particular methyl, alkoxy, in particular methoxy, or halo, in particular chloro.
In a still more preferred embodiment, W represents CR4Wherein R is4Represents hydrogen, methyl, ethyl, methoxy, fluorine or chlorine.
In a most preferred embodiment, W represents CH or N.
In a fourth preferred embodiment, the arylpiperazine derivative of the invention is a compound of formula I, wherein — B-is absent and Z represents CH or N.
In a more preferred embodiment, - -B- -is present and represents a methylene bridge (- -CH)2-), a vinyl bridge (-CH-), or a bridge-NH-, connected as shown; z represents C (carbon).
In a still more preferred embodiment, - -B- -is present and represents a methylene bridge (- -CH)2-), a vinyl bridge (-CH-), or a bridge-NH-, connected as shown;and Z represents C (carbon); w represents CR4Wherein R is4Represents hydrogen, alkyl, in particular methyl, alkoxy, in particular methoxy, halo, in particular chloro, haloalkyl, haloalkoxy, amino, nitro or cyano.
In a fourth preferred embodiment, the arylpiperazine derivatives of the invention are compounds of formula I, wherein W represents CR4Wherein R is4Represents hydrogen, alkyl, in particular methyl, alkoxy, in particular methoxy, or halo, in particular chloro.
In a more preferred embodiment, W represents CR4Wherein R is4Represents hydrogen, methyl, ethyl, methoxy, fluorine or chlorine.
In a still more preferred embodiment, W represents CR4Wherein R is4Represents hydrogen, alkyl or alkoxy [ methoxy ]]。
In a fifth preferred embodiment, the arylpiperazine derivatives of the invention are compounds of the following formula I, wherein m and n are independently of each other 0, 1 or 2.
In a more preferred embodiment, m is 1 or 2; n is 0 or 2.
In a still more preferred embodiment, m is 1; n is 0.
In another preferred embodiment, m is 1; n is 1.
In a third preferred embodiment, m is 1; n is 2.
In a more preferred embodiment, m is 2; n is 0.
In a sixth preferred embodiment, the arylpiperazine derivatives of the present invention are compounds of formula I wherein R is1、R2And R3Independently of one another, represents hydrogen, alkyl, in particular methyl, ethyl or propyl, cycloalkyl-alkyl, alkenyl, hydroxy, alkoxy, in particular methoxy or ethoxy, cycloalkoxy, haloRadicals, in particular fluorine, chlorine or bromine, haloalkyl radicals, in particular trifluoromethyl radicals, haloalkoxy radicals, amino radicals, nitro radicals, cyano radicals and/or carboxyl radicals.
In a more preferred embodiment, R1、R2And R3Represents hydrogen.
In a still more preferred embodiment, R1Represents alkyl, in particular methyl, ethyl or propyl, cycloalkyl-alkyl, hydroxy, alkoxy, in particular methoxy or ethoxy, cycloalkoxy, halo, in particular fluoro, chloro or bromo, haloalkyl, in particular trifluoromethyl, haloalkoxy, amino, nitro, cyano or carboxy; and R is2And R3Represents hydrogen.
In a more preferred embodiment, R1Represents alkyl, in particular methyl, ethyl or propyl, cycloalkyl-alkyl, hydroxy, alkoxy, in particular methoxy or ethoxy, cycloalkoxy, halo, in particular fluoro, chloro or bromo, haloalkyl, in particular trifluoromethyl, haloalkoxy, amino, nitro or cyano; and R is2And R3Represents hydrogen.
In a more preferred embodiment, R1Represents alkyl, in particular methyl, ethyl or propyl, cycloalkyl-alkyl, hydroxy, alkoxy, in particular methoxy or ethoxy, cycloalkoxy, halo, in particular fluoro, chloro or bromo, haloalkyl, in particular trifluoromethyl, haloalkoxy, amino, nitro or cyano.
In a further preferred embodiment, R1Represents alkyl, in particular methyl, ethyl or propyl, alkoxy, in particular methoxy or ethoxy, halo, in particular fluorine, chlorine or bromine, haloalkyl, in particular trifluoromethyl, haloalkoxy, amino, nitro or cyano.
In a still further preferred embodiment, R1Represents methyl, ethyl, methoxy, chlorine, trifluoromethyl, trifluoromethoxy or cyano.
In a still further preferred embodiment, R1Represents methyl, ethyl, methoxy, chlorine, trifluoromethyl, trifluoromethoxy, cyano or carboxyl.
In another preferred embodiment, R2Represents alkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, halo, especially chloro, haloalkyl, haloalkoxy, amino, nitro or cyano; and R is1And R3Represents hydrogen.
In a more preferred embodiment, R2Represents alkyl, cycloalkyl, alkoxy, halo, trifluoromethyl, trifluoromethoxy, amino, nitro or cyano.
In a still more preferred embodiment, R2Represents methyl, ethyl, methoxy, chlorine, trifluoromethyl, trifluoromethoxy or cyano.
In a seventh preferred embodiment, the arylpiperazine derivative of the invention is a compound of formula I, wherein X is present and represents O, S, NR', CO, SO2、CH2、CH2-O、O-CH2、CH2-S、S-CH2、CH2-NR’、CH2-CO、CH2-SO2、NR’-CO、CO-NR’、CH2-CH2、O-CO、CO-O、O-CH=CH、S-CH=CH、NR’-CH=CH、CO-CH=CH、SO2-CH=CH、CH2-O-CH=CH、CH2-S-CH=CH、CH2-NR’-CH=CH、CH2-CO-CH=CH、CONHCH2CH2Or CH2-SO2-CH ═ CH, where R' represents hydrogen or alkyl.
In a more preferred embodiment, X represents O, CH2-O、O-CH2、CH2-S、S-CH2、CH2-NR’、CH2-CO、CH2-SO2、NR’-CO、CO-NR’、NR’-SO2、SO2-NR', O-CO or CH2-O-CH ═ CH; wherein R'Represents hydrogen or alkyl.
In a still more preferred embodiment, X represents O, CH2-O、O-CH2、CH2-S、S-CH2、CH2-NR’、CH2-CO、CH2-SO2NR '-CO, CO-NR', O-CO or CH2-O-CH ═ CH; wherein R' represents hydrogen or alkyl.
In a more preferred embodiment, X represents O, CH2-O、NR’-CO、CO-NR’、NR’-SO2Or O-CO; wherein R' represents hydrogen or alkyl.
In a more preferred embodiment, X represents O, CH2-O, NR '-CO, CO-NR' or O-CO; wherein R' represents hydrogen or alkyl.
In a most preferred embodiment, X represents O, CH2-O, NH-CO, CO-NH or O-CO.
In an eighth preferred embodiment, the arylpiperazine derivative of the present invention is a compound of formula I, wherein Y represents phenyl or an aromatic mono-or polycyclic heterocyclic group, in particular pyridyl, benzo [ b ] furanyl, indolyl, quinolinyl or isoquinolinyl, which phenyl or heterocyclic group may optionally be substituted one or more times with substituents selected from the group consisting of: alkyl, in particular methyl, cycloalkyl-alkyl, alkenyl, hydroxy, alkoxy, cycloalkoxy, halo, in particular chloro, haloalkyl, haloalkoxy, amino, nitro and cyano; or Y represents a hydrogenated heterocyclic group, in particular a tetrahydroquinolyl group, which may be optionally substituted one or more times by a substituent selected from the group consisting of: alkyl, cycloalkyl-alkyl, alkenyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano.
In a more preferred embodiment, Y represents phenyl, which phenyl may be optionally substituted one or more times with substituents selected from the group consisting of: alkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, halo, especially chloro, haloalkyl, haloalkoxy, amino, nitro and cyano.
In a still more preferred embodiment, Y represents phenyl, optionally substituted once or twice with alkyl, alkoxy, chloro, trifluoromethyl and/or trifluoromethoxy.
In a most preferred embodiment, Y represents phenyl.
In a ninth preferred embodiment, the arylpiperazine derivative of the present invention is a compound of formula I wherein Y represents an aromatic monocyclic heterocyclic group selected from furanyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, pyridyl, pyridazinyl and pyrimidinyl, which aromatic monocyclic heterocyclic group may be optionally substituted one or more times with a substituent selected from the group consisting of: alkyl, in particular methyl, cycloalkyl-alkyl, alkenyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano.
In a more preferred embodiment, Y represents furyl, thienyl or pyridyl, which aromatic monocyclic heterocyclic group may be optionally substituted one or two times by a substituent selected from the group consisting of: alkyl, in particular methyl, alkoxy, chlorine, trifluoromethyl and trifluoromethoxy.
In a most preferred embodiment, Y represents pyridyl, optionally substituted by methyl, ethyl, methoxy, chloro or trifluoromethyl.
In a tenth preferred embodiment, the arylpiperazine derivative of the present invention is a compound of formula I wherein Y represents an aromatic bicyclic heterocyclic group selected from indolyl, isoindolyl, benzo [ b ] furanyl, benzo [ b ] thienyl, benzimidazolyl, benzothiazolyl, quinolinyl, and isoquinolinyl, which aromatic bicyclic heterocyclic group may be optionally substituted one or two times with a substituent selected from the group consisting of: alkyl, in particular methyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, halo, in particular chloro, haloalkyl, haloalkoxy, amino, nitro and cyano.
In a more preferred embodiment, Y represents indolyl, in particular indol-2-yl or indol-3-yl; benzo [ b ] furanyl, especially benzo [ b ] furan-2-yl or benzo [ b ] furan-3-yl; benzo [ b ] thiophenyl, especially benzo [ b ] thiophen-2-yl or benzo [ b ] thiophen-3-yl; quinolinyl, in particular quinolin-2-yl, quinolin-3-yl or quinolin-4-yl; or isoquinolinyl, especially isoquinolin-1-yl, isoquinolin-3-yl or isoquinolin-4-yl; the aromatic bicyclic heterocyclic group may be optionally substituted one or two times with a substituent selected from the group consisting of: alkyl, in particular methyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, halo, in particular chloro, haloalkyl, haloalkoxy, amino, nitro and cyano.
In a still more preferred embodiment, Y represents indolyl, in particular indol-2-yl or indol-3-yl; benzo [ b ] furanyl, especially benzo [ b ] furan-2-yl or benzo [ b ] furan-3-yl; quinolinyl, in particular quinolin-2-yl, quinolin-3-yl or quinolin-4-yl; or isoquinolinyl, especially isoquinolin-1-yl, isoquinolin-3-yl or isoquinolin-4-yl; the benzo [ b ] furanyl or isoquinolinyl group may optionally be substituted once or twice with a substituent selected from: alkyl, in particular methyl, hydroxy, alkoxy, chlorine, trifluoromethyl, trifluoromethoxy, amino, nitro and cyano.
In a more preferred embodiment, Y represents indol-2-yl, benzo [ b ] furan-2-yl or isoquinolin-3-yl; the benzo [ b ] furanyl or isoquinolinyl group may optionally be substituted once or twice with a substituent selected from: alkyl, in particular methyl, hydroxy, alkoxy, chlorine, trifluoromethyl, trifluoromethoxy, amino, nitro and cyano.
In a more preferred embodiment, Y represents indol-2-yl, benzo [ b ] furan-2-yl or isoquinolin-3-yl; the benzo [ b ] furanyl or isoquinolinyl group may optionally be substituted by alkyl, especially methyl, halo, especially chloro or trifluoromethyl.
In a further preferred embodiment, Y represents indol-2-yl, benzo [ b ] furan-2-yl or isoquinolin-3-yl; the benzo [ b ] furanyl or isoquinolinyl group may be optionally substituted by methyl, ethyl, fluoro, chloro or trifluoromethyl.
In a most preferred embodiment, Y represents indolyl, benzo [ b ] furyl or isoquinolinyl.
In an eleventh preferred embodiment, the arylpiperazine derivative of the present invention is a compound of formula I, wherein Y represents a hydrogenated heterocyclic group, in particular a tetrahydroquinolyl group, which may be optionally substituted one or more times with a substituent selected from the group consisting of: alkyl, cycloalkyl-alkyl, alkenyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano.
In a more preferred embodiment, Y represents a tetrahydroquinolinyl or tetrahydroisoquinolinyl group, and the heterocyclic group may be optionally substituted one or two times by a substituent selected from the group consisting of: alkyl, cycloalkyl-alkyl, alkenyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano.
In a most preferred embodiment, Y represents tetrahydroquinolinyl or tetrahydroisoquinolinyl.
In another preferred embodiment, X represents O, CH2-O、NH-CO、CO-NH、NR’-SO2Or CO-O; y represents phenyl, methyl-phenyl, pyridyl, indolyl, methyl-indolyl, benzo [ b ]]Furyl, tetrahydroquinolyl, isoquinolyl or tetrahydroisoquinolyl.
In a more preferred embodiment, X represents CH2-O, NH-CO, CO-NH or CO-O; and Y represents indolyl, benzo [ b ]]Furyl, tetrahydroquinolyl, isoquinolyl or tetrahydroisoquinolyl.
In a still more preferred embodiment, X represents O, CH2-O、NH-CO、CO-NH、NR’-SO2Or CO-O;y represents phenyl, methyl-phenyl, pyridyl, methyl-pyridyl, indolyl, methyl-indolyl, benzo [ b ]]Furyl, tetrahydroquinolyl, isoquinolyl or tetrahydroisoquinolyl; r1Represents alkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro or cyano; and R is2And R3Represents hydrogen.
In a more preferred embodiment, X represents CH2-O, NH-CO, CO-NH or CO-O; y represents indolyl, benzo [ b ]]Furyl, tetrahydroquinolyl, isoquinolyl or tetrahydroisoquinolyl; r1Represents alkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro or cyano; and R is2And R3Represents hydrogen.
In a most preferred embodiment, the arylpiperazine derivative of the present invention is
N- [4- [4- (3-trifluoromethylphenyl) piperazin-1-yl ] butyl ] indole-2-carboxamide;
n- [2- (1H-indol-3-yl) ethyl ] -3- (4-m-tolylpiperazin-1-yl) propionamide;
n- [2- (1H-indol-3-yl) ethyl ] -3- [4- (3-methoxyphenyl) piperazin-1-yl ] propionamide;
benzo [ b ] furan-2-carboxylic acid {4- [4- (3-methoxy-phenyl) -piperazin-1-yl ] -butyl } -amide;
n- [4- [4- (3-cyanophenyl) piperazin-1-yl ] butyl ] benzo [ b ] furan-2-carboxamide;
benzo [ b ] furan-2-carboxylic acid {4- [4- (3-chloro-phenyl) -piperazin-1-yl ] -butyl } -amide;
benzo [ b ] furan-2-carboxylic acid {4- [4- (3-carboxy-phenyl) -piperazin-1-yl ] -butyl } -amide;
n- [4- [4- (m-tolyl) piperazin-1-yl ] butyl ] benzo [ b ] furan-2-carboxamide;
isoquinoline-3-carboxylic acid {4- [4- (3-cyano-phenyl) -piperazin-1-yl ] -butyl } -amide;
n- [4- [4- (3-chlorophenyl) piperazin-1-yl ] butyl ] isoquinoline-3-carboxamide;
n- [4- [4- (m-tolyl) piperazin-1-yl ] butyl ] isoquinoline-3-carboxamide;
n- [4- [4- (3-methoxyphenyl) piperazin-1-yl ] butyl ] isoquinoline-3-carboxamide;
3- [5- [4- (3-chlorophenyl) piperazin-1-yl ] pentyloxy ] isoquinoline;
3- {5- [4- (3-methoxy-phenyl) -piperazin-1-yl ] -pentyloxy } -isoquinoline;
3- [5- (4-m-tolylpiperazin-1-yl) pentyloxy ] isoquinoline;
3- {5- [4- (3-cyano-phenyl) -piperazin-1-yl ] -pentyloxy } -isoquinoline;
n- [4- (1, 2, 3, 4-tetrahydro-5-methoxy- β -carbolin-2-yl) butyl ] isoquinoline-3-carboxamide;
n- [4- (3, 4-dihydro-6-methoxypyrazino [1, 2-a ] indol-2 (1H) -yl) butyl ] isoquinoline-3-carboxamide;
n- [4- [4- (pyridin-2-yl) piperazin-1-yl ] butyl ] isoquinoline-3-carboxamide;
1, 2, 3, 4-tetrahydro-quinoline-2-carboxylic acid [4- (4-phenyl-piperazin-1-yl) -butyl ] -amide;
(S) - (-) -N- [4- [4- (m-tolyl) piperazin-1-yl ] butyl ] -1, 2, 3, 4-tetrahydroisoquinoline-2-carboxamide;
(R) - (+) -N- [4- [4- (m-tolyl) piperazin-1-yl ] butyl ] -1, 2, 3, 4-tetrahydroisoquinoline-2-carboxamide;
1H-indole-2-carboxylic acid {4- [4- (2, 4-dichloro-phenyl) -piperazin-1-yl ] -butyl } -amide;
5-chloro-1H-indole-2-carboxylic acid {4- [4- (2, 4-dichloro-phenyl) -piperazin-1-yl ] -butyl } -amide;
isoquinoline-3-carboxylic acid {4- [4- (2, 3-dichloro-phenyl) -piperazin-1-yl ] -butyl } -amide;
3- {4- [4- (2, 3-dichloro-phenyl) -piperazin-1-yl ] -butoxy } -isoquinoline;
3- {5- [4- (2, 3-dichloro-phenyl) -piperazin-1-yl ] -pentyloxy } -isoquinoline;
4- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] butyl 1H-indole-2-carboxylate;
n- (4- (4- (phenylpiperazin-1-yl) butyl) benzo [ b ] furan-2-carboxamide;
benzo [ b ] furan-2-carboxylic acid {4- [4- (2, 3-dimethyl-phenyl) -piperazin-1-yl ] -butyl } -amide;
n- (4- (4- (3-methoxyphenyl) piperazin-1-yl) butyl) benzo [ b ] furan-2-carboxamide;
n- (4- (4- (6-methylpyridin-2-yl) piperazin-1-yl) butyl) isoquinoline-3-carboxamide;
n- (4- (4-phenylpiperazin-1-yl) butyl) isoquinoline-3-carboxamide;
n- (4- (4- (6-methylpyridin-2-yl) piperazin-1-yl) butyl) benzo [ b ] furan-2-carboxamide;
n- (4- (4-phenylpiperazin-1-yl) butyl) quinoline-2-carboxamide;
n- (4- (4-m-tolylpiperazin-1-yl) butyl) quinoline-2-carboxamide;
n- (4- (4- (3-methoxyphenyl) piperazin-1-yl) butyl) -1-methyl-1H-indole-2-amide;
n- (4- (4- (3-methoxyphenyl) piperazin-1-yl) butyl) -1H-indole-3-carboxamide;
(S) -1, 2, 3, 4-tetrahydro-N- (4- (4-phenylpiperazin-1-yl) butyl) quinoline-2-carboxamide;
n- (4- (4-m-tolylpiperazin-1-yl) butyl) pyridinecarboxamide;
n- (4- (4- (quinolin-3-yl) piperazin-1-yl) butyl) isoquinoline-3-carboxamide;
n- (4- (4- (3-methoxyphenyl) piperazin-1-yl) butyl) -6-methylpyridine-2-carboxamide;
n- (4- (4- (3-methoxyphenyl) piperazin-1-yl) butyl) quinoline-3-carboxamide;
n- (4- (4- (pyridin-2-yl) piperazin-1-yl) butyl) quinoline-3-carboxamide;
n- (4- (4-phenylpiperazin-1-yl) butyl) pyridinecarboxamide;
n- (4- (4- (3-methoxyphenyl) piperazin-1-yl) butyl) pyridinecarboxamide;
n- (4- (4- (3-methoxyphenyl) piperazin-1-yl) butyl) benzamide;
n- (4- (4-m-tolylpiperazin-1-yl) butyl) benzamide;
n- (4- (4-phenylpiperazin-1-yl) butyl) nicotinamide;
n- (4- (4- (6-methylpyridin-2-yl) piperazin-1-yl) butyl) benzamide;
n- (4- (4- (6-methoxypyridin-2-yl) piperazin-1-yl) butyl) benzamide;
n- (4- (4- (6-methoxypyridin-2-yl) piperazin-1-yl) butyl) pyridinecarboxamide; or
N- (4- (4- (6-methylpyridin-2-yl) piperazin-1-yl) butyl) pyridinecarboxamide;
or a pharmaceutically acceptable salt thereof.
In a twelfth preferred embodiment, the arylpiperazine derivative of the invention is a compound of formula I, wherein Y represents a group of formula III
Figure A20068000172700331
Wherein R is7Represents hydrogen, alkyl, alkoxy, halo or haloalkyl.
In a most preferred embodiment, the arylpiperazine derivative of the present invention is
7- [4- [4- (2, 3-dichloro-phenyl) -piperazin-1-yl ] -butoxy ] -pyrrolo [1, 2-a ] quinoxalin-4 (5H) -one;
7- (5- (4-phenylpiperazin-1-yl) pentyloxy) pyrrolo [1, 2-a ] quinoxalin-4 (5H) -one; or
7- (4- (4-phenylpiperazin-1-yl) butoxy) pyrrolo [1, 2-a ] quinoxalin-4 (5H) -one;
or a pharmaceutically acceptable salt thereof.
In a thirteenth preferred embodiment, the arylpiperazine derivative of the present invention is a compound of formula I, wherein X is absent; y represents a diazo heterocyclic group of formula II
Figure A20068000172700332
Wherein o is 1, 2 or 3;
d represents alkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano; and E represents alkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano; or D and E together with the diazacyclo group form a fused ring system, which may be optionally substituted one or more times with substituents selected from the group consisting of: alkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano.
In a more preferred embodiment, Y represents a bicyclic heterocyclic group (i.e. a fused ring system) selected from the following groups:
Figure A20068000172700341
wherein R is5And R6Independently of one another, represent hydrogen, alkyl, cycloalkyl-alkyl, hydroxyl, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and/or cyano.
In a still more preferred embodiment, Y represents a bicyclic group selected from
Figure A20068000172700342
Wherein R is5And R6Independently of one another, represent hydrogen, alkyl, cycloalkyl-alkyl, hydroxyl, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and/or cyano.
In a more preferred embodiment, Y represents
Figure A20068000172700351
Wherein R is5Represents hydrogen, alkyl, halo, trifluoromethyl or trifluoromethoxy.
In a most preferred embodiment, the arylpiperazine derivative of the present invention is
2- {4- [4- (3-cyano-phenyl) -piperazin-1-yl ] -butyl } -3, 4-dihydro-2H-pyrazino [1, 2-a ] indol-1-one;
2- [4- [4- (3-chlorophenyl) piperazin-1-yl ] butyl ] -3, 4-dihydropyrazino [1, 2-a ] indol-1 (2H) -one;
2- {4- [4- (3-methoxy-phenyl) -piperazin-1-yl ] -butyl } -3, 4-dihydro-2H-pyrazino [1, 2-a ] indol-1-one;
2- [4- (4-m-tolyl) piperazin-1-yl ] butyl ] -3, 4-dihydropyrazino [1, 2-a ] indol-1 (2H) -one;
3, 4-dihydro-2- [4- (3, 4-dihydro-6-methoxypyrazino [1, 2-a ] indol-2 (1H) -yl) butyl ] pyrazino [1, 2-a ] indol-1 (2H) -one;
2- {4- [4- (2-methoxy-phenyl) -piperazin-1-yl ] -butyl } -3, 4-dihydro-2H-pyrazino [1, 2-a ] indol-1-one; or
2- {4- [4- (2, 3-dichloro-phenyl) -piperazin-1-yl ] -butyl } -3, 4-dihydro-2H-pyrazino [1, 2-a ] indol-1-one;
or a pharmaceutically acceptable salt thereof.
In a fourteenth preferred embodiment, the arylpiperazine derivatives of the present invention are compounds of formula I wherein X is absent; and Y represents a radical of the formula IV
Figure A20068000172700352
Wherein A' represents CH or N; r8Represents hydrogen, alkyl, in particular methyl, alkoxy, in particular methoxy, halo, in particular chloro, or haloalkyl.
In a most preferred embodiment, the arylpiperazine derivative of the present invention is
1, 6-bis (4- (3-chlorophenyl) piperazin-1-yl) hexane;
1, 6-bis (4- (3-methoxyphenyl) piperazin-1-yl) hexane;
1, 6-bis (4-phenylpiperazin-1-yl) hexane;
1- (3-chlorophenyl) -4- (6- (4- (3-methoxyphenyl) piperazin-1-yl) hexyl) piperazine;
1-phenyl-4- (6- (4- (pyridin-2-yl) piperazin-1-yl) hexyl) piperazine;
1- (6-methylpyridin-2-yl) -4- (6- (4-m-tolylpiperazin-1-yl) hexyl) piperazine;
1- (6-methylpyridin-2-yl) -4- (6- (4-phenylpiperazin-1-yl) hexyl) piperazine;
1-phenyl-4- (6- (4-m-tolylpiperazin-1-yl) hexyl) piperazine;
4- (4- (6- (4-phenylpiperazin-1-yl) hexyl) piperazin-1-yl) quinoline;
1, 6-bis (4- (pyridin-2-yl) piperazin-1-yl) hexane;
4- (4- (6- (4-m-tolylpiperazin-1-yl) hexyl) piperazin-1-yl) quinoline;
1, 6-bis (4-m-tolylpiperazin-1-yl) hexane;
1- (pyridin-2-yl) -4- (6- (4-m-tolylpiperazin-1-yl) hexyl) piperazine; or
1- (3-methoxyphenyl) -4- (6- (4-m-tolylpiperazin-1-yl) hexyl) piperazine;
or a pharmaceutically acceptable salt thereof.
Any combination of two or more of the embodiments described herein is considered to be within the scope of the present invention.
Definition of substituents
In the context of the present invention halo represents fluoro, chloro, bromo or iodo.
In the context of the present invention, alkyl denotes a monovalent saturated, straight or branched hydrocarbon chain. The hydrocarbon chain preferably contains one to eighteen carbon atoms (C)1-18-alkyl), more preferably one to six carbon atoms (C)1-6-an alkyl group; lower alkyl) including pentyl, isopentyl, neopentyl, tert-pentyl, hexyl and isohexyl. In a preferred embodiment, alkyl represents C1-4Alkyl groups including butyl, isobutyl, sec-butyl and tert-butyl. In another preferred embodiment of the invention, alkyl represents C1-3-an alkyl group, which may be exactly methyl, ethyl, propyl or isopropyl.
In the context of the present invention haloalkyl denotes an alkyl group as defined herein, which alkyl group is substituted one or more times with halo. Preferred haloalkyl groups of the present invention include trihalomethyl, preferably-CF3
In the context of the present invention, alkoxy denotes an "alkyl-O-" group, wherein alkyl is as defined above. Examples of preferred alkoxy groups of the present invention include methoxy and ethoxy.
In the context of the present invention, haloalkoxy denotes alkoxy as defined herein, which alkoxy is substituted one or more times by halo. Preferred haloalkoxy groups of the present invention include trihalomethoxy groups, preferably-OCF3
In the context of the present invention, cycloalkyl denotes cyclic alkyl, preferably containing three to seven carbon atoms (C)3-7Cycloalkyl) including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
In the context of the present invention, cycloalkyl-alkyl denotes cycloalkyl as defined above, which is substituted on alkyl as defined above. Examples of preferred cycloalkyl-alkyl groups of the present invention include cyclopropylmethyl and cyclopropylethyl.
In the context of the present invention, cycloalkoxy denotes a "cycloalkyl-O-" group, wherein cycloalkyl is as defined above. Examples of the preferred cycloalkoxy group of the present invention include cyclopropylmethoxy group and cyclopropylethoxy group.
In the context of the present invention, an aromatic monocyclic or polycyclic heterocyclic group is a monocyclic or polycyclic compound which possesses one or more heteroatoms in its ring structure. The term "polyheterocyclic group" includes benzo-fused five-and six-membered heterocyclic groups containing one or more heteroatoms. Preferred heteroatoms include nitrogen (N), oxygen (O) and sulfur (S).
Pharmaceutically acceptable salts
The arylpiperazine derivatives of the present invention may be provided in any form suitable for administration. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salts, and prodrug or prodrug forms of the arylpiperazine derivatives of the present invention.
Examples of pharmaceutically acceptable salts include, without limitation, nontoxic inorganic and organic acid salts such as hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulfate, formate, acetate, aconate, ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, pamoate, heptanoate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene-2-sulfonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, toluene-p-sulfonate, and the like. Such salts can be formed by procedures known and described in the art.
Stereoisomers
Some of the arylpiperazine derivatives of the present invention may exist in (+) and (-) forms as well as in racemic form (±). Both the racemates of these isomers and the individual isomers themselves are within the scope of the present invention.
The racemic forms can be resolved into the optical enantiomers by known methods and techniques. One way to separate diastereomeric salts is to use an optically active acid and treat with a base to release an optically active amine compound. Another method for resolving racemates into optical enantiomers is based on optically active matrix chromatography. Stereoselective synthesis means may be employed. The racemic compounds of the present invention can thus be resolved into their optical enantiomers, for example the fractional crystallisation of D-or L-salts (tartrate, mandelate or camphorsulfonate).
The starting materials and/or intermediates used in the production of the compounds of the present invention may also be resolved by reacting the arylpiperazine derivatives of the present invention with an optically active activated carboxylic acid, for example, derived from (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) camphanoic acid, to produce the diastereomeric amides, or by reacting the starting materials or intermediates used in the present invention with an optically active chloroformate or the like to produce the diastereomeric carbamates.
Other methods of resolving optical isomers are known in the art. Such methods include those described by JaquesJ, colelet a,&wilen S at "Enant iomers,Racemates,and Resolutions", John Wiley and Sons, New York (1981).
Optically active compounds can also be prepared from optically active starting materials.
Preparation method
The arylpiperazine derivatives of the invention can be prepared by means of conventional chemical synthesis methods, such as those described in the examples.
In general, amides can be prepared by converting an acid or acid chloride to the corresponding hydroxyamide by standard procedures. The ester can be obtained by reacting the acidic starting material with 1, 4-dihydroxybutane. After the terminal hydroxyl group has been substituted with bromine, the hydroxyamide can be treated with an arylpiperazine in the presence of a base to give the desired end product. The ether-based compounds can be synthesized starting from the appropriate phenol and then condensed with 1, 4-dihydroxybutane or 1, 5-dihydroxypentane, followed by conversion to the final product as described above.
The intermediate compounds of the present invention may be resolved by reaction with an optically active activated carboxylic acid, e.g., derived from (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) camphanoic acid, to produce the diastereomeric amides, or by reaction of the intermediate compound with an optically active chloroformate or the like to produce the diastereomeric carbamates.
Biological activity
The arylpiperazine derivatives of the present invention are found to be selective for dopamine and 5-hydroxytryptamine receptors, particularly D3、D2-sample and 5-HT2The receptor subtype. Thus, in a preferred embodiment, the present invention relates to the use of the arylpiperazine derivatives of the present invention for the treatment, prevention or alleviation of a disease or a disorder or a condition of a mammal, including a human, which disease, disorder or condition is responsive to modulation of dopamine and 5-hydroxytryptamine receptors, in particular D3、D2-sample and 5-HT2Receptor subtype, preferably D3Dopamine receptor subtype and/or D3/5-HT1AOr D3/5-HT2AThe receptor subtype.
In a more preferred embodiment, the disease, disorder or condition is a neurological or psychiatric disorder, particularly a psychotic disorder including schizophrenia, depression, parkinson's disease, huntington's disease, movement disorders (particularly dystonia), anxiety, inactivity, obsessive-compulsive disorders, mania, senile diseases, dementia, sexual dysfunction, muscular-skeletal pain symptoms (e.g. pain associated with fibromyalgia), sleep disorders, substance abuse or addiction and withdrawal symptoms from drug addiction, cocaine abuse or addiction.
In a still more preferred embodiment, the disease, disorder or condition is a neurological or psychiatric disorder, in particular a psychosis, preferably schizophrenia.
In another preferred embodiment, the disease, disorder or condition according to the invention is schizophrenia or parkinson's disease.
In another preferred embodiment, the arylpiperazine derivatives of the invention are used as diagnostic tools in diagnostic methods, in particular for in vivo receptor imaging (neuroimaging).
Pharmaceutical composition
In another aspect, the present invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of an arylpiperazine derivative of the present invention.
Although the arylpiperazine derivatives of the present invention used in therapy may be administered as the original compound, it is preferred to incorporate the active ingredient, optionally in the form of a physiologically acceptable salt, in a pharmaceutical composition comprising one or more adjuvants, excipients, carriers, buffers, diluents and/or other customary pharmaceutical auxiliary ingredients.
In a preferred embodiment, the present invention provides a pharmaceutical composition comprising an arylpiperazine derivative of the present invention, or a pharmaceutically acceptable salt or derivative thereof, together with one or more pharmaceutically acceptable carriers, and optionally other therapeutic and/or prophylactic ingredients, as are known and used in the art. A carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The pharmaceutical compositions of the invention may be administered by any suitable route, which is appropriate for the desired therapy. Preferred routes of administration include oral administration, especially in the form of tablets, capsules, lozenges, powders or liquids, and parenteral administration, especially cutaneous, subcutaneous, intramuscular or intravenous injection. The pharmaceutical compositions of the present invention may be prepared by any person skilled in the art, using standard methods and conventional techniques appropriate for the desired formulation. Compositions that provide sustained release of the active ingredient may be employed if desired.
For further details on formulation and administration techniques, reference may be made to the latest editionRemington’s Pharmaceutical Sciences(Maack Publishing Co.,Easton,PA)。
The actual dosage will depend on the nature and severity of the condition being treated, on the physician, and may be varied according to the particular circumstances of the invention to produce the desired therapeutic effect. However, it is currently contemplated that suitable for therapeutic treatment are pharmaceutical compositions containing from about 0.1 to about 500mg of active ingredient per dose, preferably from about 1 to about 100mg, most preferably from about 1 to about 10 mg.
The active ingredient may be administered once or several doses per day. In some cases satisfactory results can be obtained at doses as low as 0.1. mu.g/kg i.v. and 1. mu.g/kg p.o.. The upper limit of the dosage range is currently considered to be about 10mg/kg i.v. and 100mg/kg p.o.. Preferred ranges are from about 0.1 μ g/kg to about 10 mg/kg/day i.v. and from about 1 μ g/kg to about 100 mg/kg/day p.o..
Method of treatment
In another aspect, the present invention provides a method of diagnosis, treatment, prevention or alleviation of a disease or a disorder or a condition of a living animal body, including a human, which disease, disorder or condition is responsive to modulation of dopamine and 5-hydroxytryptamine receptors, which method comprises administering to a living animal body, including a human, in need thereof an effective amount of an arylpiperazine derivative of the present invention.
In the context of the present invention, the term "treatment" encompasses treating, preventing or alleviating and the term "disease" encompasses diseases, disorders and conditions involving the disease.
Preferred indications according to the invention are those as described above.
It is currently contemplated that suitable dosages of the Active Pharmaceutical Ingredient (API) range from about o.1 to about 1000mg API per day, more preferably from about 10 to about 500mg API per day, most preferably from about 30 to about 100mg API per day, depending upon the exact mode of administration, form of administration, indication in question, the weight of the subject, particularly the subject involved, and further the preferences and experience of the attending physician or veterinarian.
Examples
The invention is further illustrated with reference to the following examples, which are not intended to limit the scope of the claimed invention in any way.
Example 1
Preparation examples
This example describes the synthesis of the compounds listed in table 1. These compounds can be considered as having the following general structure:
head-linker-tail
TABLE 1
Compounds of the invention
Figure A20068000172700411
Figure A20068000172700441
Figure A20068000172700451
Figure A20068000172700461
Figure A20068000172700471
General description of the Synthesis
Schemes 1-11 outline the synthetic routes according to this example.
Table 2 specifies the variables indicated in the flow.
Scheme 1
Figure A20068000172700481
Schemes 1-2
Figure A20068000172700482
Scheme 2
Figure A20068000172700491
Scheme 2-2
Figure A20068000172700492
TABLE 2
Description of variables
Cp.No. X Y W Z R
1-1 NH N - CH 3-CN
1-3 NH N - CH 3-Cl
1-4 NH C NH CH 2-OMe
1-5 NH N CH CH 2-0Me
1-7 NH N - CH 3-Me
1-8 0 N - CH 2, 3-di-C1
1-10 NH N - N -
1-13 NH N - CH 3-Me
1-15 NH N - CH 3-OMe
1-16 NH N - CH 3-CF3
1-22 NH N - CH CH
1-23 NH N Me CH CH
1-24 NH N - CH CH
1-25 NH N - N CH
1-26 NH N - CH CH
1-27 NH N - N CH
1-28 NH N CH CH CH
1-29 NH N - CH CH
1-30 NH N - CH CH
1-31 NH N - CH CH
1-32 NH N - CH CH
1-33 NH N - CH CH
1-36 NH N - CH N
1-37 NH N - CH CH
1-39 NH N - CH N
1-40 NH N - CH CH
1-41 NH N - CH CH
1-42 NH N - N CH
1-43 NH N - CH CH
1-44 NH N - CH CH
1-45 NH N - CH CH
1-46 NH N - CH CH
1-47 NH N - N CH
Cp.No. X Y W Z R
1-48 NH N - N CH
1-49 NH N - N CH
1-50 NH N - CH CH
1-51 NH N - CH CH
Scheme 3
Figure A20068000172700511
Scheme 4
Figure A20068000172700521
Scheme 5
Figure A20068000172700522
Scheme 6
Scheme 7
Figure A20068000172700532
Scheme 8
Figure A20068000172700533
Scheme 9
Figure A20068000172700541
Scheme 10
Figure A20068000172700551
Scheme 11
Melting points were determined using an Electrothermal 8103 instrument. IR spectra were collected using a Perkin-Elmer 398 and FT 1600 spectrophotometer. Recording on a Bruker 200MHz spectrometer1H NMR spectroscopy with TMS as internal standard; the chemical drift values (δ) are given in ppm and the coupling constants (J) are given in Hertz (Hz). All reactions were carried out under argon atmosphere. GC-MS was performed on a Saturn 3(Varian) or Saturn 2000(Varian) GC-MS System using a ChrompackDB5 capillary column (30 m. times.0.25 mm i.d.; 0.25 μm film thickness). The mass spectrum was recorded using a VG 70-250S spectrometer. ESI-MS and APCI-MS spectra were collected using an LCQDeca-Thermofininnigan spectrometer. Optical rotations were recorded on a Perkin-Elmer Model 343 polarimeter, provided sodium D-line and 20 ℃. In the Perkin-Elmer 240C elementElemental analysis was performed on the analyzer to within 0.4% of theoretical unless otherwise noted. The yields represent the purified compounds, without optimization. For testing, the claimed compounds were converted to the corresponding hydrochloride salts by standard procedures.
N- [4- [4- (3-cyanophenyl) piperazin-1-yl ] butyl ] benzo [ b ] furan-2-carboxamide (Compound 1-1/1a)
Figure A20068000172700571
1- (3-cyanophenyl) piperazine (3) A mixture of 3-bromobenzonitrile (0.50g, 2.74mmol), piperazine (0.71g, 8.24mmol), sodium tert-butoxide (0.37g, 3.8mmol), tris (dibenzylideneacetone) dipalladium- (O) (6.27mg, 0.0068mmol) and rac-2, 2 '-bis (diphenylphosphino) -1, 1' -Binaphthyl (BINAP) in anhydrous toluene (8.0mL) was heated to 80 ℃ under argon. After stirring for 2h, the mixture was cooled to room temperature, dissolved in ether (30.0mL), filtered, and concentrated. The crude product was then purified by flash chromatography (10% methanol in chloroform) to give 0.32g (63% yield) 3 as a yellow oil:1H NMR(CDCl3)δ1.87(br s,1H),3.03(t,4H;J=4.4Hz),3.17(t,4H;J=4.3Hz),7.08(m,3H),7.31(m,1H);IR(CHCl3)vmax2230cm-1elemental analysis (C)11H13N3)C,H,N.
N- [4- (1-hydroxy) butyl]Benzo [ b ]]Furan-2-amide (5a) to a solution of 2-benzofurancarboxylic acid 4a (0.50g, 3.08mmol) in dry dichloromethane (10.0mL) at 0 ℃ under argon was added 1-hydroxybenzotriazole Hydrate (HOBT) (0.46g, 3.40mmol) and 1, 3-dicyclohexylcarbodiimide (0.70g, 3.40 mmol); the suspension was allowed to warm to room temperature and stirred for 1 h. 4-amino-1-butanol (0.28mL, 3.08mmol) was then added and the mixture was stirred at room temperature overnight. The resulting suspension was passed through Celite®Filtration, washing with chloroform (3X 10mL) and evaporation of the filtrate. The crude product was purified by flash chromatography (10% methanol in chloroform) to yield0.70g (97%) 5a as a white solid: mp (methanol) 95-96 ℃;1H NMR(CDCl3) δ 1.67(m, 4H), 2.14(br s, 1H), 3.53(m, 2H), 3.73(m, 2H), 6.89(br s, 1H), 7.25-7.48(m, 4H), 7.63(d, 1H; j ═ 7.7 Hz.) elemental analysis (C)13H15NO3)C,H,N.
N- [4- (1-bromo) butyl]Benzo [ b ]]Furan-2-carboxamide (6a) to a vigorously stirred solution of 5a (0.50g, 2.14mmol) in dry acetonitrile (25.0mL) was added triphenylphosphine (0.86g, 3.22mmol) and carbon tetrabromide (1.06g, 3.22mmol) at room temperature. After 2h the mixture was quenched with 15% NaOH and the heterogeneous mixture was extracted with Et0Ac (3X 25 mL). The organic layer was dried and evaporated. The residue was chromatographed (20% n-hexane in ethyl acetate) to give 0.58g (91% yield) 6a as a white solid: mp (EtOAc)65-66 ℃;1H NMR(CDCl3)δ1.67(m,4H),3.37(m,4H),7.36(m,4H),7.63(d,1H;J=7.7Hz);GC-MS m/z297[M+H]+216(100), 202, 188, 174, 161, 145, 118, 89 elemental analysis (C)13H14BrNO2)C,H,N.
N- [4- [4- (3-cyanophenyl) piperazin-1-yl]Butyl radical]Benzo [ b ]]Furan-2-carboxamide (1-1/1 a.) to a stirred solution of 6a (50.0mg, 0.17 mmol) in dry acetonitrile (3.0mL) under argon was added 1- (3-cyanophenyl) piperazine 3(31.7mg, 0.17 mmol) and triethylamine (38.2 μ L, 0.27 mmol); the solution was refluxed overnight with stirring. The solvent was removed under reduced pressure, water was added and the mixture was extracted with dichloromethane (3X 10 mL). The organic layer was dried, concentrated and the crude product was chromatographed (10% methanol in chloroform) to give 60.0mg of 1a (90% yield) as a colorless oil.1H NMR(CDCl3)δ1.72(m,4H),2.46(t,2H,J=6.7Hz),2.61(t,4H,J=4.9Hz),3.24(t,4,J=5.0Hz),3.52(q,2H,J=6.1Hz),6.89(br s,1H),7.09(m,3H),7.47-7.25(m,5H),7.66(d,1H,J=7.5);FAB-MS m/z403[M+H]+Element analysis (C)24H26N4O2)C,H,N.
3, 4-dihydro-2- [4- (3, 4-dihydro-6-methoxypyrazino [1, 2-a ] indol-2 (1H) -yl) butyl ] pyrazino [1, 2-a ] indol-1 (2H) -one (compound 1-2/1b)
Figure A20068000172700581
Ethyl 3- (3-methoxy-2-nitrophenyl) -2-oxopropanoate (8) to a suspension of potassium tert-butoxide (2.0g, 18.0mmol) in dry diethyl ether (50.0mL) was added diethyl oxalate (3.16mL, 23.3mmol) dropwise at room temperature, and the mixture was stirred for 15 min. 3-methoxy-2-nitrotoluene 7(3.0g, 18.0mmol) was then added and the mixture was stirred for 30min and left to stand for 12h without stirring. The solvent was removed in vacuo and water and solid ammonium chloride were added to the residue. The aqueous mixture was extracted with ethyl acetate (3X 25mL), and the organic layer was collected over anhydrous sodium sulfate (Na)2SO4) Drying and evaporating the solvent. The crude product was chromatographed (30% EtOAc in n-hexane) to give 4.2g of pure 8 as a yellow oil in 88% yield;1H NMR(CDCl3)δ1.27(m,3H),2.18(s,3H),3.75(m,2H),4.25(m,2H),6.78(m,2H),7.20(m,1H);GC-MSm/z267[M]+194,166(100),135,121;ES-MS m/z 268[M+H]+elemental analysis (C)12H13NO6)C,H,N.
7-methoxy-1H-indole-2-carboxylic acid ethyl ester (9) prepared in advance under N2Next, degassed 8(4.8g, 18.0mmol) solution in absolute ethanol (120.0mL) was added catalytic 5% Pd/C and the mixture was placed under hydrogen atmosphere at room temperature for 24 h. Passing the mixture through Celite®Filtered, washed with ethanol and the filtrate evaporated under reduced pressure. The crude product was purified by flash chromatography (20% E t OAc in hexanes) to afford 9 as a yellow solid (79%): mp69-72 ℃;1H NMR(CDCl3)δ1.42(t,3H,J=6.94Hz),3.96(s,3H),4.41(q,2H,J=7.2Hz),6.72(d,1H,J=7.5Hz),7.07(t,1H,J=7.9Hz),7.25(m,2H),9.18(brs,1H).ESI-MSm/z220[M+H]+,ES-MS/MS of[M+H]+192,176174(100), 176, 148 elemental analysis (C)12H13NO3)C,H,N.
1- (cyanomethyl) -7-methoxy-1H-indole-2-carboxylic acid ethyl ester (10) A mixture of sodium hydride (60% dispersion in mineral oil, 509.6mg, 21.23 mmols) and ethyl 7-methoxyindole-2-carboxylate 9(3.1g, 14.15 mmols) in dry N, N-Dimethylformamide (DMF) (15.0mL) was stirred at room temperature for 30min, to which was added a solution of bromoacetonitrile (2.0mL, 28.3mmol) in dry DMF (2.0 mL). The reaction mixture was then maintained at 60-65 ℃ for 30min, stirred at room temperature for an additional 6h, left overnight, and decomposed with ice. The isolated solid was filtered and purified by flash chromatography (33% n-hexane in dichloromethane) to give 10 (30% yield) as a white solid: mp (ethanol) 99-101 ℃;1H NMR(CDCl3)δ1.41(t,3HJ=7.2Hz),3.99(s,3H),4.40(q,2H,J=7.1Hz),5.96(s,2H),6.80(d,1H,J=7.7Hz),7.10(t,1H,J=7.9Hz),7.25m,1H),7.33(s,1H).GC-MS m/z258(100)[M]+232, 213, 201, 187, 172, 144, 130, 114, 89 elemental analysis (C)14H11N2O3)C,H,N.
1, 2, 3, 4-tetrahydro-6-methoxypyrazino [1, 2-a ]]Indole (11) 10(0.50g, 1.93mmol) of dry diethyl ether (Et)2O) (20.0mL) suspension was added slowly to well-stirred lithium aluminum hydride (LiAlH)4) (293.4mg, 7.72mmo l) of dried Et2O (10.0mL) in a slurry. The mixture was refluxed for 8 h. The reaction mixture was poured into an ice-water bath and 1N NaOH (10.0mL) was added. The aqueous phase was extracted with EtOAc (3X 30mL) and the organic layer was collected, dried and evaporated. The crude product was chromatographed (10% methanol in chloroform) to give 11 as a yellow solid (40% yield): mp120-122 ℃;1H NMR(CDCl3)δ7.14(d,1H,J=7.8Hz),6.97(t,1H,J=7.7Hz),6.58(d,1H,J=7.7Hz),6.14(s,1H),4.47(t,2H,J=5.8Hz),4.17(s,2H),3.90(s,3H),3.26(t,2H,J=5.7Hz);ES-MS m/z405[2M+H]+,203(100)[M+H]+elemental analysis (C)12H14N2O)C,H,N.
1- (cyanomethyl) -1H-indole-2-carboxylic acid ethyl ester (13) A mixture of sodium hydride (60% dispersion in mineral oil, 190.0mg, 7.94mmol) and ethyl indole-2-carboxylate 12(1.0g, 5.29mmol) in dry DMF (4.6mL) was stirred at room temperature for 30min, to which was added a solution of bromoacetonitrile (0.74mL, 10.60mmol) in dry DMF (1.0 mL). The reaction mixture was then maintained at 65 ℃ for 30min, stirred at room temperature for an additional 6h, left overnight, and decomposed with ice. The isolated solid was recrystallized from ethanol to give 13 (90% yield) as a white solid: mp (ethanol) 83-84 ℃;1H NMR(CDCl3)δ1.42(t,3H;J=7.3Hz),4.41(q,2H;J=14.2,7.2Hz),5,60(s,2H),7.37(m,4H),7.71(d,1H;J=7.9Hz);GC-MSm/z228[M]+(100) 199, 182, 154, 128, 115, 101, 89, 77 elemental analysis (C13H12N2O2) C, H, N.
1, 2, 3, 4-tetrahydropyrazino (2H) -1-one [1, 2-a]Indole (14) to a warm (60 ℃ C.) solution of 13(200.0mg, 0.87mmol) in dry methanol (8.0mL) under argon was added freshly prepared cobalt boride (450.0mg, 3.50mmol) with stirring. Sodium borohydride (166.0mg, 4.38 mmol) was added carefully in portions and the mixture was refluxed for 3 h. The mixture was cooled, the solvent removed under reduced pressure, then water was added and the mixture extracted with EtOAc (3X 25 mL). The organic layer was dried, evaporated and the crude product purified by flash chromatography (10% methanol in chloroform) to give 14 (68% yield) as a white solid: mp (methanol) 261-;1H NMR(CDCl3)δ3.82(m,2H),4.27(m,2H),6.65(br s,1H),7.23(m,4H),7.72(d,1H;J=8.0Hz);APC I-MS m/z187[M+H]+;APCI-MS/MS of[M+H]+159(100), 144 elemental analysis (C)11H10N2O)C,H,N.
N- [1- (4-bromo) butyl]-1, 2, 3, 4-tetrahydropyrazino (2H) -1-one [1, 2-a]Indole (15) to a suspension of 14(130.0mg, 0.69mmol) in dry DMF (1.0mL) was added sodium hydride 60% dispersion in mineral oil (20.0mg, 0.83 mmol). After stirring at 60 ℃ under argon for 1h, 1, 4-dibromobutane (0.41mL, 3.47mmol) was added dropwise without stirringAqueous DMF (0.50 mL). The mixture was refluxed for 3h at 110 ℃ under argon. The solvent was then evaporated under reduced pressure and the residue was resuspended in water and extracted with dichloromethane (3X 10 mL). The combined organic layers were dried, evaporated and the residue chromatographed (30% EtOAc in hexanes) to give 15 as a yellow solid (41% yield): mp (EtOAc)101-102 ℃;1H NMR(CDCl3)δδ1.85(m,4H),3.67(m,4H),3.81(m,2H),4.29(m,2H),7.20(m,4H),7.70(d,1H;J=8.0Hz);APC I-MS m/z321[M+H]+241, 227, 199(100), 187, 159, 144, 117 elemental analysis (C)15H17BrN2O)C,H,N.
3, 4-dihydro-2- [4- (3, 4-dihydro-6-methoxypyrazino [1, 2-a ]]Indol-2 (1H) -yl) butyl]Pyrazino [1, 2-a ] s]Indol-1 (2H) -one (1b) to 1, 2, 3, 4-tetrahydro-6-methoxypyrazino [1, 2-a ]]Indole 11(30.0mg, 0.15mmol) and K2CO3(71.6mg, 0.52 mo) was suspended in dry acetonitrile (5.0mL) and bromo-derivative 15(47.7mg, 0.15 mmo) and a catalytic amount of sodium iodide (NaI) were added and the resulting mixture was heated at reflux for 18 h. The mixture was then filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was suspended in water (10.0mL) and extracted with E t2O (2X 25 mL). The ether extracts were combined and evaporated under reduced pressure and the crude product purified by flash chromatography (5% methanol in chloroform) to give 1b as a yellow oil (62% yield);1H NMR(CDCl3)δ1.69(m,4H),2.58(t,2H,J=6.6Hz),2.88(t,2H,J=5.5Hz),3.66(t,2H,J=6.7Hz),3.77(m,4H),3.88(s,3H),4.24(t,2H,J=5.8Hz),4.45(t,2H,J=5.6Hz),6.10(s,1H),6.54(d,1H,J=7.6Hz),6.93(t,1H,J=7.8Hz),7.13(m,3H),7.29(m,2H),7.70(d,1H,J=7.9Hz);ES-MS m/z907[2M+Na]+,884[2M+H]+,443(100)[M+H]+13C NMR(CDCl3) Delta 24.3, 25.3, 29.6, 40.2, 45.5, 45.9, 46.1, 51.2, 51.7, 55.3, 57.2, 97.1, 101.8, 106.0, 109.5, 112.9, 120.6, 122.6, 124.3, 125.9, 127.5, 129.4, 130.3, 134.5, 136.3, 147.7, 159.9, elemental analysis (C. sub.24, C. sub.3, C.sub.27H30N4O2)C,H,N.
N- [4- [4- (3-chlorophenyl) piperazin-1-yl ] butyl ] isoquinoline-3-carboxamide (Compound 1-3/1c)
Figure A20068000172700621
N- [1- (4-hydroxy) butyl]Isoquinoline-3-carboxamide (5b) the title compound was prepared as follows, starting from 3-isoquinolinecarboxylic acid 4b (100.0mg, 0.57mmo l), following the procedure described to give 5 a. Derivative 5b was obtained as a white solid (96% yield): mp (methanol) 126-127 ℃;1H NMR(CDCl3)δ1.74(m,4H),3.57(q,2H;J=6.3Hz),3.73(t,2H;J=5.9Hz),7.40(m,2H),7.75(m,2H),8.39(br s,1H),8.57(s,1H),9.14(s,1H);ES-MS m/z510[2M+Na+],267(100)[M+Na]+,245[M+H]+,ES-MS/MS of[M+H]+227, 174 elemental analysis (C)14H16N2O2)C,H,N.
N- [1- (4-bromo) butyl]Isoquinoline-3-carboxamide (6b) to a solution of 5b (140.0mg, 0.57mmol) in dry acetonitrile (10.0mL) was added triphenylphosphine (225.0mg, 0.86mmol) and carbon tetrabromide (285.0mg, 0.86mmol) at room temperature with vigorous stirring. After 2h the mixture was quenched with 15% NaOH and extracted with EtOAc (3X 10 mL). The organic layer was dried and evaporated. The residue was chromatographed (30% n-hexane in EtOAc) to give 130.0mg of 6b (75% yield) as a yellow solid: mp (E tOAc)72-73 deg.C;1H NMR(CDCl3)δ2.06(m,4H),3.48(m,4H),7.66(m,2H),7.93(m,2H),8.36(brs,1H),8.55(s,1H),9.08(s,1H);ES-MS m/z329[M+Na]+,308(100)[M+Na]+elemental analysis (C)14H15BrN2O)C,H,N.
N- [4- [4- (3-chlorophenyl) piperazin-1-yl]Butyl radical]Isoquinoline-3-carboxamide (1c) to a stirred dry solution of 6b (190.0mg, 0.62mmol) under argonAcetonitrile (20.0mL) solution was added 1- (3-chlorophenyl) piperazine hydrochloride (144.0mg, 0.62mmol) and triethylamine (141.0. mu.L, 1.0 mmol); the solution was refluxed overnight with stirring. The solvent was removed under reduced pressure, water was added and the mixture was extracted with dichloromethane (3X 10 mL). The organic layer was dried, concentrated and the crude product was chromatographed (10% methanol in chloroform) to give 130.0mg of 1c (50% yield) as a white solid: mp (methanol) 156-157 ℃;1H NMR(CDCl3)δ1.65(m,4H),2.46(t,2H,J=6.7Hz),2.60(t,4H,J=4.9Hz),3.21(t,4H,J=5.0Hz),3.57(q,2H,J=6.5Hz),6.78(m,2H),6.86(d,1H,J=1.6Hz),7.14(t,1H,J=8.0Hz),7.72(m,2H),8.00(t,2H,J=8.2Hz),8.33(br s,1H),8.61(s,1H),9.14(s,1H);ES-MSm/z445(100)[M+Na]+,423[M+H]+,ES-MS/MS of[M+H]+251,227(100);13CNMR(CDCl3) Delta 24.4, 27.8, 29.8, 39.5, 48.7, 53.1, 58.2, 114.0, 115.9, 119.4, 120.4, 127.8, 128.3, 128.9, 129.8, 130.2, 131.2, 135.1, 136.2, 144.0, 151.2, 152.5, 165.0 elemental analysis (C.sub.24.8, C.sub.1, C.sub.2, C.sub.1, C.sub24H27ClN4O)C,H,N.
N- [4- (1, 2, 3, 4-tetrahydro-5-methoxy-beta-carbolin-2-yl) butyl ] isoquinoline-3-amide (Compound 1-4/1d)
Figure A20068000172700631
4-methoxy-1H-indole-3-carbaldehyde (17) N-chlorosuccinimide (2.72g, 20.41mmol) was added portionwise to a solution of triphenylphosphine (5.35g, 20.41mmol) in tetrahydrofuran (100.0mL) and stirred at room temperature for 30 min. DMF (1.54mL, 40.8mmol) was added to the suspension and the mixture was heated to reflux for 1 h. 4-methoxy-1H-indole 16(1.0g, 6.80mmol) was then added and the mixture heated to reflux for 1H. After cooling, the tetrahydrofuran was evaporated, water (80.0mL) was added, the mixture was heated to reflux for 1h, then basified with 10% NaOH. The aqueous phase was extracted with EtOAc (3X 50mL) and collectedThe organic layer was dried and evaporated. The crude product was purified by flash chromatography (50% EtOAc in n-hexane) to afford 17 as an orange solid in quantitative yield: mp (EtOAc)154-156 ℃;1H NMR(CDCl3)δ4.00(s,3H),6.72(m,1H),7.07(d,1H,J=8.1Hz),7.19(d,1H,J=8.1Hz),7.92(d,1H,J=2.9Hz),9.05(br s,1H),10.50(s.1H);FAB-MSm/z175(100)[M]+160, 144, 129, 116, 104, 89, 77 elemental analysis (C)10H9NO2)C,H,N.
4-methoxy-3- (2-nitrovinyl) -1H-indole (18) ammonium acetate (168.0mg, 2.19mmol) was added to a solution of 4-methoxy-1H-indole-3-carbaldehyde 17(1.20g, 7.27mmol) in nitromethane (12.0mL), and the mixture was stirred vigorously while heating to reflux for 1H. The resulting solution was concentrated under reduced pressure and the crude product was purified by flash chromatography (50% n-hexane in EtOAc) to give 0.95g18 as a light yellow solid (64% yield): mp (EtOAc)179 and 181 ℃ dec;1H NMR(DMSO-d6) δ 3.95(s, 3H), 6.73(d, 1H, J ═ 7.3Hz), 7.13(m, 2H), 8.08(d, 1H, J ═ 13.4Hz), 8.24(s, 1H), 8.55(d, 1H, J ═ 13.0Hz), 12.20(br s, 1H), elemental analysis (C)11H10N2O3)C,H,N.
4-Methoxytryptamine (19) A solution of 18(0.90g, 4.33mmol) in dry tetrahydrofuran (40.0mL) was added dropwise to LiAlH4(1.73g, 45.22mmol) in dry tetrahydrofuran (17.0mL) was heated at reflux for 1h with stirring. Excess LiAlH was quenched by careful addition of methanol4While cooling in an ice bath. Then water and s.s. potassium sodium tartrate were added and the mixture was extracted with dichloromethane-methanol solution (95: 5 v/v). The organic layer was washed with brine, over Na2SO4Dried and evaporated under reduced pressure. The crude product was purified by flash chromatography (CHCl)3-MeOH-NH4OH 20: 5: 1v/v) to give 0.60g19 as a white solid (77% yield): mp (methanol) 139-140 ℃;1H NMR(CDCl3)δ2.00(br s,2H),3.00(m,4H),3.89(s,3H),6.46(d,1H,J=7.6Hz),6.80(s,1H),6.92(d,1H,J=8.1hz), 7.06(t, 1H, J ═ 7.9Hz), 8.85(br s, 1H)11H14N2O)C,H,N.
1, 2, 3, 4-tetrahydro-5-methoxy- β -carboline (20) 4-methoxytryptamine 19(375.0mg, 1.97mmol) was converted beforehand to the corresponding hydrochloride salt by means of standard procedures. To a solution of 4-methoxytryptamine hydrochloride (445.0mg, 1.97mmol) in water (50.0mL) was added glyoxylic acid monohydrate (181.2mg, 1.97mmol) and the mixture was stirred at reflux for 1 h. After cooling at room temperature, 20% NaOH solution was added, the mixture was extracted with EtOAc (3X 30mL), the organic layer was dried and evaporated. The crude product was chromatographed (CHCl)3-MeOH-NH4OH 20: 5: 0.5v/v) to give 20 as an amorphous solid (63% yield);1H NMR(CDCl3) δ 1.67(br s, 2H), 2.96(m, 2H), 3.13(m, 2H), 3.88(s, 3H), 3.98(s, 2H), 6.47(d, 1H, J ═ 7.6Hz), 6.89(d, 1H, J ═ 8.1Hz), 7.01(t, 1H, J ═ 7.9Hz), 7.75(br s, 1H) elemental analysis (C)12H14NXO)C,H,N.
N- [4- (1, 2, 3, 4-tetrahydro-5-methoxy-beta-carbolin-2-yl) butyl]Isoquinoline-3-carboxamide (1d) to 1, 2, 3, 4-tetrahydro-5-methoxy- β -carboline 20(94.0mg, 0.55 mmol) and K2CO3(218.6mg, 1.57mol) of a suspension of dry acetonitrile (10.0mL) was added bromo-derivative 6b (137.0mg, 0.45mmol) and a catalytic amount of NaI and the resulting mixture was heated at reflux for 18 h. The mixture was then filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was suspended in water (10.0mL) and treated with Et2O (2X 25mL) and dichloromethane (1X 25 mL). The organic layers were combined, evaporated under reduced pressure and the crude product purified by flash chromatography (0.5% methanol in chloroform) to give 1d as a yellow oil (30% yield);1H NMR(CDCl3)δ1.74(m,4H),2.64(m,2H),2.82(m,2H),3.03(m,2H),3.57(m,4H),3.86(s,3H),6.44(d,1H,J=7.5Hz),6.92(m,2H),7.72(m,2H),7.97(m,2H),8.39(br s,1H),8.59(s,1H),9.07(s,1H);ES-MS m/z 429(100)[M+H]+256, 227 elemental analysis (C)26H28N4O2)C,H,N.
N- [4- (3, 4-dihydro-6-methoxypyrazino [1, 2-a ] indol-2 (1H) -yl) butyl ] isoquinoline-3-carboxamide (Compound 1-5/1e)
Figure A20068000172700651
N- [4- (3, 4-dihydro-6-methoxypyrazino [1, 2-a ]]Indol-2 (1H) -yl) butyl]Isoquinoline-3-carboxamide (1 e.) the title compound is prepared as described below using bromo-derivative 6b (98.0mg, 0.32mmol) and amino-derivative 11(0.32mmol) as described for 1 b. Compound 1e was obtained as colorless oil (55% yield);1H NMR(CDCl3)δ1.75(m,4H),2.60(m,2H),2.89(t,2H,J=5.5Hz),3.57(q,2H,J=6.1Hz),3.79(s,2H),3.86(s,3H),4.49(t,2H,J=5.6Hz),6.12(s,1H),6.53(d,1H,J=7.6Hz),6.93(t,1H,J=7.7Hz),7.10(d,1H,J=7.9Hz),7.70(m,2H),7.97(m,2H),8.39(brs,1H),8.59(s,1H),9.05(s,1H);ES-MSm/z879[2M+Na]+,451[M+Na]+,429(100)[M+H]+elemental analysis (C)26H28N4O2)C,H,N.
3- [5- [4- (3-chlorophenyl) piperazin-1-yl ] pentyloxy ] isoquinoline (Compound 1-6/1f)
Figure A20068000172700661
3- (5-Bromopentyloxy) isoquinoline (22) to a solution of isoquinolin-3-ol 21(200.0mg, 1.37mmol) in dry DMF (5.0mL) was added 1, 5-dibromopentane (204.0. mu.L, 1.50mmol) and the mixture was stirred at room temperature for 10 min. Cesium carbonate (538.0mg, 1.64mmol) was then added and the mixture was heated at 65 ℃ for 12 h. After cooling at room temperature, methyl tert-butyl ether (MTBE) (20.0mL) and water (15.0mL) were added and the mixture was extracted with MTBETake (3X 25 mL). Collecting the organic layer, passing through Na2SO4Drying, filtering and evaporating. The residue was chromatographed (dichloromethane) to give 197.0mg of pure 22 as a yellow oil (49% yield).1H NMR(CDCl3)δ1.64(m,2H),1.89(m,4H),3.43(t,2H,J=6.5Hz),4.34(t,2H,J=6.3Hz),6.97(s,1H),7.33(m,1H),7.54(t,1H,J=7.2Hz),7.66(d,1H,J=8.3Hz),7.85(d,1H,J=8.2Hz),8.92(s,1H);ES-MS m/z296(100)[M+H]+146 elemental analysis (C)14H16BrNO)C,H,N.
3- [5- [4- (3-chlorophenyl) piperazin-1-yl]Pentoxy radical]Isoquinoline (1 f.) to a stirred solution of 22(430.0mg, 1.46mmol) in dry acetonitrile (30.0mL) under argon was added 1- (3-chlorophenyl) piperazine hydrochloride (338.7mg, 1.46mmol) and triethylamine (329.0. mu.L, 2.36mmol), and the solution was refluxed for 4h with stirring. The solvent was removed under reduced pressure, water was added and the mixture was extracted with dichloromethane (3X 10 mL). The organic layer was dried, concentrated, and the crude product was chromatographed (50% n-hexane in EtOAc) to give 320.0mg of 1f (78.2% yield) as a white solid: mp (EtOAc)88-89 ℃;1H NMR(CDCl3)δ1.52-1.76(m,4H),1.88(q,2H,J=6.6Hz),2.42(t,2H,J=7.2Hz),2.57(m,4H),3.18(m,4H),4.35(t,2H,J=6.4Hz),6.73-6.85(m,3H),6.97(s,1H),7.13(t,1H,J=8.0Hz),7.34(dd,1H,J=8.3,6.4Hz),7.54(dd,1H,J=7.9,6.4Hz),7.66(d,1H,J=8.1Hz),7.85(d,1H,J=8.2Hz),8.93(s,1H);ES-MS m/z410(100)[M+H]+265. elemental analysis (C)24H28ClN3O)C,H,N.
N- [4- [4- (m-tolyl) piperazin-1-yl ] butyl ] benzo [ b ] furan-2-carboxamide (Compound 1-7/1g)
Figure A20068000172700671
N- [4- [4- (m-tolyl) piperazin-1-yl]Butyl radical]Benzo [ b ]]Furan-2-carboxamide (1g) to a stirred solution of 6a (0.62g, 2.09mmol) in dry acetonitrile (30.0mL) under argon was added 1- (m-tolyl) piperazine dihydrochloride (0, 52g, 2.09mmol) and triethylamine (0.62mL, 4.60mmol), and the solution was refluxed overnight with stirring. The solvent was removed under reduced pressure, water was added and the mixture was extracted with dichloromethane (3X 30 mL). The organic layer was dried, concentrated and the crude product was chromatographed (6% methanol in chloroform) to give 0.42g 1g (52% yield) as a white solid: mp119-120 ℃;1H NMR(CDCl3)δ1.70(m,4H),2.31(s,3H),2.46(t,2H,J=6.6Hz),2.62(t,4H,J=4.9Hz),3.23(t,4H,J=4.9Hz),3.52(q,2H,J=6.1Hz),6.70(m,3H),7.00(brs,1H),7.13(t,1H,J=4.4Hz),7.18-7.48(m,4H),7.66(d,1H,J=7.7Hz);ES-MS m/z805(100)[2M+Na]+,414[M+Na]+,392[M+H]+13C NMR(CDCl3) Delta 22.0, 24.5, 27.7, 39.4, 49.3, 53.5, 58.1, 110.5, 111.9, 113.4, 117.1, 120.9, 122.9, 123.9, 127.0, 127.9, 129.2, 139.0, 149.2, 151.5, 154.9, 159.124H29N3O2)C,H,N.
4- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] butyl 1H-indole-2-carboxylic acid ester (Compound 1-8/1H)
Figure A20068000172700681
4-hydroxybutyl 1H-indole-2-carboxylate (5 c.) to a solution of butane-1, 4-diol (0.46mL, 5.21mmol), Dimethylaminopyridine (DMAP) (68.41mg, 0.56mmol) and 1H-indole-2-carboxylic acid 4c (1.0g, 6.20mmol) in dry dichloromethane (20.0mL) at 0 deg.C was added dropwise a solution of DCC (1.4g, 6.76mmol) in dry dichloromethane (10.0mL) over 45 min. The resulting suspension was stirred at 0 ℃ for an additional 1h, the cooling bath was removed and the mixture was stirred for an additional 12 h. Through Celite®The mixture was filtered and evaporated to dryness under reduced pressure. The product was purified by flash chromatography (7.5% methanol in chloroform) to give 5c as a white amorphous solid (45% yield).1H NMR(CDCl3)δ1.81(m,4H),2.08(br s,1H),3.73(t,2H,J=6.0Hz),4.39(t,2H,J=6.2Hz),7.14(t,1H,J=7.4Hz),7.27(m,3H),7.42(d,1H,J=8.2Hz),7.68(d,1H,J=8.0Hz),9.39(brs,1H);ES-MS m/z 232(100)[M-H]160, 116 elemental analysis (C)13H15NO3)C,H,N.
4-Bromobutyl 1H-indole-2-carboxylate (6 c.) the title compound is prepared as follows, starting from 5c (0.45g, 1.93mmol), following the procedure described to give 6 a. Compound 6c was obtained as a white solid (91% yield): mp (ethyl acetate) 85-85 ℃;1H NMR(CDCl3) δ 1.93(m, 4H), 3.44(t, 2H, J ═ 6.2Hz), 4.37(t, 2H, J ═ 6.0Hz), 7.15(t, 1H, J ═ 7.3Hz), 7.30(m, 2H), 7.45(d, 1H, J ═ 8.2Hz), 7.69(d, 1H, J ═ 8.0Hz), 9.81(br s, 1H) elemental analysis (C, 1H)13H14BrNO2)C,H,N.
4- [4- (2, 3-dichlorophenyl) piperazin-1-yl]Butyl 1H-indole-2-carboxylate (1H) to a stirred solution of 6c (220.0mg, 0.74mmol) in dry acetonitrile (20.0mL) under argon was added 1- (2, 3-dichloro) piperazine hydrochloride (198.0mg, 0.74mmol) and triethylamine (167.0 μ L, 1.20mmol) and the solution was refluxed under stirring overnight. The solvent was removed under reduced pressure, water was added and the mixture was extracted with dichloromethane (3X 30 mL). The organic layer was dried, concentrated and the crude product was chromatographed (5% methanol in chloroform) to give 1h (60% yield) as a white solid: mp (methanol) 136-137 ℃;1H NMR(CDCl3)δ1.79(m,4H),2.50(t,2H,J=6.7Hz),2.66(m,4H),3.07(m,4H),4.40(t,2H,J=5.9Hz),6.93(m,1H),7.08-7.35(m,5H),7.43(d,1H,J=8.1Hz),7.69(d,1H,J=7.9Hz),9.16(br s,1H);ES-MS m/z 468[H+Na]+,446(100)[M+Na]+elemental analysis (C)23H25Cl2N3O2)C,H,N.
2- [4- [4- (3-chlorophenyl) piperazin-1-yl ] butyl ] -3, 4-dihydropyrazino [1, 2-a ] indol-1 (2H) -one (compound 1-9/1i)
Figure A20068000172700691
2- [4- [4- (3-chlorophenyl) piperazin-1-yl]Butyl radical]-3, 4-dihydropyrazino [1, 2-a]Indol-1 (2H) -one (1 i.) the title compound was prepared as follows, starting from 15(410.0mg, 1.28mmol), following the procedure described to give 1 c. Compound 1i was obtained as a white solid (68% yield): mp (E tOAc)180-181 ℃;1H NMR(CDCl3)δ1.64(m,4H),2.43(t,2H,J=7.1Hz),2.56(t,4H,J=4.9Hz),3.17(t,4H,J=4.9Hz),3.62(t,2H,J=6.8Hz),3.75(t,2H,J=5.9Hz),4.22(m,3H),6.76(m,3H),6.84(d,1H,J=2.0Hz),7.14(m,2H),7.30(m,2H),7.69(d,1H,J=7.9Hz);ES-MS m/z 437[M+H]+13CNMR(CDCl3) Delta 24.0, 25.5, 40.2, 46.0, 46.2, 48.5, 53.0, 58.0, 106.0, 109.4, 113.7, 115.6, 119.1, 120.6, 122.6, 124.3, 127.5, 129.4, 129.9, 134.9, 136.3, 152.3, 159.8 elemental analysis (C.sub.24.0, 25.5, 40.2, 46.0, 46.2, 48.5, 53.0, 58.0, 106.0, 109.4, 113.7, 115.6, 11925H29ClN4O)C,H,N.
N- [4- [4- (pyridin-2-yl) piperazin-1-yl ] butyl ] isoquinoline-3-carboxamide (Compound 1-10/1j)
N- [4- [4- (pyridin-2-yl) piperazin-1-yl]Butyl radical]Isoquinoline-3-carboxamide (1 j.) to a stirred solution of 6b (190.0mg, 0.62mmol) in dry acetonitrile (20.0mL) under argon was added 1- (2-pyridin-2-yl) piperazine hydrochloride (101.0mg, 0.62mmol) and triethylamine (141.0 μ L, 1.0mmol), and the solution was refluxed overnight with stirring. The solvent was removed and the crude product was chromatographed (10% methanol in chloroform) to give 225.0mg of 1j (93.4% yield) as a white solidBody: mp (methanol) 108-109 ℃;1H NMR(CDCl3)δ1.62(m,4H),2.38(m,2H),2.49(m,4H),3.52(m,6H),6.54(m,2H),7.40(m,1H),7.65(m,2H),7.91(t,2H,J=8.6Hz),8.11(d,1H,J=4.7Hz),8.32(br s,1H),8.54(s,1H),9.06(s,1H);ES-MS m/z412(100)[M+Na+],390[M+H+]element analysis (C) 24223H27N5O)C,H,N.
2- [4- (4-m-tolyl) piperazin-1-yl ] butyl ] -3, 4-dihydropyrazino [1, 2-a ] indol-1 (2H) -one (compound 1-11/1k)
Figure A20068000172700711
2- [4- (4-m-tolyl) piperazin-1-yl]Butyl radical]-3, 4-dihydropyrazino [1, 2-a]Indol-1 (2H) -one (1k) starting from 15(127.0mg, 0.40mmol) and 1- (m-tolyl) piperazine dihydrochloride (0.40mmol), the title compound was prepared as described for 1 g. Product 1k was obtained as a white solid (40.0% yield): mp (methanol) 155-156 ℃;1H NMR(CDCl3)δ1.68(m,4H),2.36(s,3H),2.49(m,2H),2.60(t,4H,J=5.0Hz),3.18(t,4H,J=4.9Hz),3.66(m,2H),3.78(t,2H,J=3.0Hz),4.25(m,2H),6.70(m,4H),7.14(m,2H),7.31(m,2H),7.70(d,1H,J=8.2Hz);ES-MS m/z 416[M+H]+elemental analysis (C)26H32N4O)C,H,N.
3- [5- (4-m-tolylpiperazin-1-yl) pentyloxy ] isoquinoline (Compound 1-12/11)
Figure A20068000172700712
3- [5- (4-m-tolylpiperazin-1-yl) pentyloxy group]Isoquinoline (11). starting with 22(101.0mg, 0.34mmol) and 1- (m-tolyl) piperazineOxazine dihydrochloride (0.34mmol), the title compound was prepared as described for 1 f. Product 11 was obtained as a white solid (65.0% yield): mp (methanol) 94-95 ℃;1H NMR(CDCl3) δ 1.72(m, 4H), 1.92(m, 2H), 2.30(s, 3H), 2.42(t, 2H, J ═ 6.8Hz), 2.60(m, 4H), 3.19(m, 4H), 4.34(t, 2H, J ═ 6.5Hz), 6.70(m, 3H), 6.97(s, 1H), 7.13(t, 1H, J ═ 8.1Hz), 7.55(t, 1H, J ═ 7.2Hz), 7.67(d, 1H, J ═ 8.1Hz), 7.86(d, 1H, J ═ 8.2Hz), 8.93(s, 1H). elemental analysis (C)25H31N3O)C,H,N.
N- [4- [4- (m-tolyl) piperazin-1-yl ] butyl ] isoquinoline-3-carboxamide (Compound 1-13/1m)
Figure A20068000172700721
N- [4- [4- (m-tolyl) piperazin-1-yl]Butyl radical]Isoquinoline-3-carboxamide (1 m.) starting from 6b (1.0g, 3.26mmol) and 1- (m-tolyl) piperazine dihydrochloride (3.26mmol), the title compound is prepared as described for the 1g step. The product was obtained as 1m as a pale yellow solid (48.0% yield): mp (methanol) 152-153 ℃;1H NMR(CDCl3)δ1.68(m,4H),2.30(s,3H),2.46(t,2H,J=6.8Hz),2.60(t,4H,J=5.0Hz),3.20(t,4H,J=4.9Hz),3.58(q,2H,J=6.4Hz),6.70(m,3H),7.14(t,1H,J=8.1Hz),7.72(m,2H),8.00(t,2H,J=8.0Hz),8.33(br s,1H),8.61(s,1H),9.14(s,1H);ES-MS m/z 403[M+H]+13C NMR(DMSO-d6)21.3, 22.0, 27.1, 39.1, 46.2, 51.1, 55.7, 114.1, 117.5, 121.1, 121.9, 128.7, 129.0, 129.7, 130.2, 133.0, 136.5, 139.0, 143.0, 150.0, 151.7, 164.1, 170.025H30N4O)C,H,N.
7- [4- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] butoxy ] pyrrolo [1, 2-a ] quinoxalin-4 (5H) -one (Compound 1-14/1n)
Figure A20068000172700722
7-hydroxypyrrolo [1, 2-a ]]Quinoxaline-4 (5H) -one (24) A solution of 23(100.0mg, 0.35mmol) in THF (70.0mL) was hydrogenated at atmospheric pressure with 10% Pd-C (1.62mg) for 16H. The catalyst was removed by filtration, the solvent was evaporated and the residue was purified by flash chromatography (15% methanol in chloroform) to give compound 24 in quantitative yield as an amorphous solid. 1H NMR (DMSO-d6) δ 6.57(m, 2H), 6.69(m, 1H), 6.90(m, 1H), 7.80(d, 1H, J ═ 8.8Hz), 7.98(s, 1H), 9.62(s, 1H), 11.03(s, 1H) elemental analysis (C)11H8N2O2)C,H,N.
7- (4-Bromobutoxy) pyrrolo [1, 2-a)]Quinoxalin-4 (5H) -one (25) to a solution of compound 24(50.0mg, 0.25mmol) in dry DMF (5.0mL) was added 1, 4-dibromobutane (64.0. mu.L, 0.29mmol) and the mixture was stirred at room temperature for 10 min. Cesium carbonate (98.0mg, 0.30mmol) was then added and the mixture was heated at 65 ℃ for 12 h. After cooling at room temperature, methyl tert-butyl ether (MTBE) (10.0mL) and water (5.0mL) were added and the mixture was extracted with MTBE (3X 25 mL). Collecting the organic layer, passing through Na2SO4Drying, filtering and evaporating. The residue was chromatographed (15% n-hexane in EtOAc) to give pure 25 as a yellow oil (22.5% yield).1H NMR(CD3OD) δ 1.64(m, 2H), 1.96(m, 4H), 3.52(m, 2H), 3.99(m, 2H), 6.62(m, 1H), 6.77(m, 2H), 7.10(d, 1H, J ═ 3.5Hz), 7.73(m, 1H), 7.83(d, 1H, J ═ 1.5Hz)15H15BrN2O2)C,H,N.
7- [4- [4- (2, 3-dichlorophenyl) piperazin-1-yl]Butoxy radical]Pyrrolo [1, 2-a]Quinoxalin-4 (5H) -one (1n) starting from 25(100.0mg, 0.50mmol) and (2, 3-dichloro) phenylpiperazine dihydrochloride (0.50mmol), the title compound was prepared according to the procedure described for 1 f. Product 1n was obtained as a white amorphous solid (81.0% yield).1H NMR(DMSO-d6) δ 1.67(m, 4H), 2.44(m, 6H), 2.95(m, 4H), 3.99(t, 2H, J ═ 5.9Hz), 6.77(m, 2H), 6.94(m, 1H), 7.08(m, 1H), 7.25(m, 2H), 7.92(d, 1H, J ═ 8.6Hz), 8.04(s, 1H), 11.03(s, 1H). elemental analysis (C, H)25H26Cl2N4O2)C,H,N.
N- [4- [4- (3-methoxyphenyl) piperazin-1-yl ] butyl ] isoquinoline-3-carboxamide (Compound 1-15/10)
Figure A20068000172700741
N- [4- [4- (3-methoxyphenyl) piperazin-1-yl]Butyl radical]Isoquinoline-3-carboxamide (10) starting from 6b (1.0g, 2.39mmol) and (3-methoxy) phenylpiperazine (458.9mg, 2.39mmol), the title compound was prepared as described for 1 g. The product, 1o, was obtained as a colorless oil (54.0% yield).1H NMR(CDCl3)δ1.66(m,4H),2.44(t,2H,J=6.8Hz),2.59(t,4H,J=4.9Hz),3.19(t,4H,J=4.9Hz),3.56(q,2H,J=6.3Hz),3.77(s,3H),6.47(m,3H),7.14(t,1H,J=8.1Hz),7.73(m,2H),7.99(t,2H,J=8.2Hz),8.32(brs,1H),8.60(s,1H),9.12(s,1H);ES-MSm/z441[M+Na]+,419[M+H]+Elemental analysis (C)25H30N4O2)C,H,N.
N- [4- [4- (3-trifluoromethylphenyl) piperazin-1-yl ] butyl ] indole-2-carboxamide (Compound 1-16/1p)
Figure A20068000172700742
N- [1- (4-hydroxy) butyl]Indole-2-carboxamide (5d) to a solution of 2-indolecarboxylic acid 4c (150.0mg, 0.93mmol) in dry dichloromethane (20.0mL) at 0 deg.C under argon was added 1-hydroxybenzotriazole hydrate (4 d)60.0mg, 1.03mmol) and 1, 3-dicyclohexylcarbodiimide (210.0mg, 1.03 mmol); the suspension was allowed to warm to room temperature and stirred for 1 h. 4-amino-1-butanol (93.6. mu.L, 1.03mmol) was then added and the mixture was stirred at room temperature for 16 h. The resulting suspension was filtered through Celite, washed with chloroform and the filtrate was evaporated. The crude product was purified by flash chromatography (10% methanol in chloroform) to give 5d as colorless prisms (93% yield): mp (methanol) 108-109 ℃;1H NMR(CDCl3) δ 1.67(m, 4H), 3.52(q, 2H, J)11.5, 5.6)3.72(t, 2H, J)5.8Hz), 6.65(br s, 1H), 6.82(s, 1H), 7.11(d, 1H, J)8.0Hz), 7.29(m, 1H), 7.39(d, 1H, J)7.7Hz), 7.59(d, 1H, J)7.8Hz), 9.25(br s, 1H) elemental analysis (C13H16N2O2)C,H,N.
N- [1- (4-bromo) butyl]Indole-2-carboxamide (6d) to a stirred solution of 5d (170.0mg, 0.73mmol) in acetonitrile (25.0mL) was added triphenylphosphine (0.86g, 3.22mmol) and carbon tetrabromide (1.06g, 3.22mmol) at room temperature. After 2h, the mixture was quenched with 15% NaOH and extracted with ethyl acetate. The organic layer was dried and evaporated. The residue was purified by flash chromatography (20% n-hexane in ethyl acetate) to give 6b as colorless prisms (84% yield): mp (ethyl acetate) 133-134 ℃;1H NMR(CDCl3) Δ 1.96(m, 4H), 3.56(m, 4H), 7.28(m, 5H), 7.60(d, 1H, J)7.6Hz), 9.80(br s, 1H). elemental analysis (C)13H15BrN2O)C,H,N.
N- [4- [4- (3-trifluoromethylphenyl) piperazin-1-yl]Butyl radical]Indole-2-carboxamide (1p) starting from 6d (35.0mg, 0.12mmol) and (3-trifluoromethyl) phenylpiperazine (27.3mg, 0.12mmol), the title compound was prepared as a yellow oil (56.0% yield) following the procedure described for 1 g.1H NMR(CDCl3)δ1.82(m,4H),2.43(m,2H),2.57(m,4H),3.21(m,4H),3.54(m,2H),6.58(m,1H),6.83(s,1H),7.11(m,3H),7.31(m,2H),7.45(d,1H,J=8.0Hz),7.61(d,1H,J=7.9Hz),10.08(br s,1H);ES-MS m/z445[M+H]+Elemental analysis (C)24H27F3N4O)C,H,N.
N- [2- (1H-indol-3-yl) ethyl ] -3- (4-m-tolylpiperazin-1-yl) propanamide (Compound 1-17/1q)
Figure A20068000172700751
N- [2- (1H-indol-3-yl) ethyl]3-Bromopropionamide (27) to a solution of tryptamine (1.0g, 6.24mmol) in dry dichloromethane (10.0mL) was added 3-bromopropionyl chloride (691.0. mu.l, 6.86mmol) and triethylamine (870.0. mu.l, 6.24mmol) and the solution was stirred in a 200W microwave oven for 1 min. The solvent was then evaporated, water was added to the residue and extracted with EtOAc (3X 20 mL). The crude product was purified by flash chromatography (10% methanol in chloroform) to afford 27 as a white solid (22.0% yield): mp (etoac) 106-.1H NMR(CDCl3)δ2.64(t,2H,J=6.4Hz),2.98(t,2H,J=6.6Hz),3.56(m,4H),5.61(br s,1H),7.06(m,1H),7.18(m,2H),7.36(d,1H,J=7.9Hz),7.60(d,1H,J=7.6Hz),8.10(br s,1H);ES-MS m/z 319[M+Na]+,295[M+H]+Elemental analysis (C)13H15BrN2O)C,H,N.
N- [2- (1H-indol-3-yl) ethyl]-3- (4-m-tolylpiperazin-1-yl) propanamide (1q) to a stirred solution of 27(200.0mg, 0.68mmol) in dry acetonitrile (20.0mL) under argon was added 1- (m-tolyl) piperazine dihydrochloride (0.68mmol) and triethylamine (141.0 μ L, 1.0 mmol); the solution was refluxed overnight while stirring. The solvent was removed under reduced pressure, water was added and the mixture was extracted with dichloromethane (3X 10 mL). The organic layer was dried, concentrated and the crude product was chromatographed (10% methanol in chloroform) to give 1q (50% yield) as a white amorphous solid.1H NMR(CDCl3)δ2.23-2.41(m,9H),2.51(m,2H),2.74(m,4H),2.96(t,2H,J=6.5Hz),3.64(q,2H,J=6.3Hz),6.60(m,2H),6.69(m,1H),6.98-7.28(m,5H),7.58(m,1H),8.09(brs,1H),8.20(br s,1H);ES-MS m/z 413[M+Na]+,391[M+H]+Elemental analysis (C)24H30N4O)C,H,N.
N- [2- (1H-indol-3-yl) ethyl ] -3- [4- (3-methoxyphenyl) piperazin-1-yl ] propanamide (Compound 1-18/1r)
Figure A20068000172700771
N- [2- (1H-indol-3-yl) ethyl]-3- [4- (3-methoxyphenyl) piperazin-1-yl]Starting from 27(100.0mg, 0.34mmol) and (3-methoxy) phenylpiperazine (0.34mmol), the title compound was prepared following the procedure described for 1q to give a white amorphous solid (47.0% yield).1H NMR(CDCl3) δ 2.33(m, 6H), 2.46(m, 2H), 2.73(m, 4H), 2.95(m, 2H), 3.62(m, 2H), 3.79(s, 3H), 6.38(m, 3H), 6.97(s, 1H), 7.03-7.27(m, 4H), 7.57(d, 1H, J ═ 7.4Hz), 8.24(br s, 1H), 8.48(br s, 1H) elemental analysis (C, 1H)24H30N4O2)C,H,N.
(S) - (-) -N- [4- [4- (m-tolyl) piperazin-1-yl ] butyl ] -1, 2, 3, 4-tetrahydroisoquinoline-2-carboxamide (Compound 1-19/1S)
Figure A20068000172700772
2-methyl (S) - (-) -1- (benzyloxycarbonyl) -1, 2, 3, 4-tetrahydroquinoline-2-carboxylate ((S) -30) to amino ester (S) -28(160.0mg, 0.84mmol) aq3(2M) solution benzyl chloroformate (158.2mg, 0.92mmol) was added dropwise over 30 min. The mixture was stirred at room temperature for 1.5h and then evaporated. The residue was extracted with EtOAc (3X 20mL), and the organic layer was dried and evaporated. The crude product was purified by flash chromatography (20% acetone in n-hexane) to give compound (S) -30 as a colorless oil (80% yield). [ alpha ] to]20 D=-50.0°(c=0.94,MeOH);1H NMR(CDCl3)δ1.81(m,1H),2.31-2.43(m,1H),2.43-2.69(m,2H),3.61(s,3H),4.96(t,1H,J=7.6Hz),5.24(s,2H),6.97-7.08(m,2H),7.16-7.23(m,1H),7.24-7.35(m,5H),7.81(d,1H,j=7.4Hz);ESI-MS m/z325[M+]281, 266, 222, 190, 130, 91 elemental analysis (C)19H19NO4)C,H,N.
(S) - (-) -1- (benzyloxycarbonyl) -1, 2, 3, 4-tetrahydroquinoline-2-carboxylic acid [ (S) -31]To a solution of (S) -30(218.5mg, 0.67mmol) in methanol and water (3: 2) was added NaOH (27.0mg, 0.67mmol) and the mixture was heated to reflux for 2 h. The solvent was then evaporated, water was added to the residue and the mixture was acidified with HCl 1N. The aqueous layer was extracted with chloroform (3X 15mL) and the organic layer was collected, dried and evaporated. The crude product was purified by flash chromatography (CHCl)3/MeOH/CH3COOH 9: 1: 0.1) to give (S) -31 as an amorphous solid in quantitative yield.1H NMR(CDCl3)δ1.81-1.99(m,1H),2.31-2.43(m,1H),2.46-2.69(m,2H),3.61(s,3H),4.96(t,1H,J=7.6Hz),5.24(s,2H),6.97-7.08(m,2H),7.16-7.23(m,1H),7.24-7.35(m,5H),7.81(d,1H,J=7.4Hz);ESI-MS m/z 310[M]+(100) 266, 202 elemental analysis (C)18H17NO4)C,H,N.[α]20 D-50°(c=0.98,MeOH).
(S) - (-) -N- [4- (1-hydroxy) butyl]-1- (benzyloxycarbonyl) -1, 2, 3, 4-tetrahydroisoquinoline-2-carboxamide [ (S) -32)]To a solution of acid (S) -31(980.5mg, 3.15mmol) in dry dichloromethane (20.0mL) at 0 deg.C under argon was added 1-hydroxybenzotriazole Hydrate (HOBT) (920.0mg, 6.80mmol) and 1, 3-dicyclohexylcarbodiimide (1.40g, 6.80 mmol); the suspension was allowed to warm to room temperature and stirred for 1 h. 4-amino-1-butanol (0.56mL, 6.16mmol) was then added and the mixture was stirred at room temperature overnight. The resulting suspension was passed through Celite®Filtration, washing with chloroform (3X 25mL) and evaporation of the filtrate. The crude product was purified by flash chromatography (10% methanol in chloroform) to give (S) -32 as a colorless oil (84% yield).1H NMR(CDCl3)δ1.17-1.40(m,4H),2.03-2.32(m,2H),2.50-2.74(m,2H),3.11(m,2H),3.36-3.43(m,2H),4.92(t,1H,J=6.8Hz),5.12-5.27(m,2H),6.43(br s,1H),6.96-7.17(m,3H),7.31(m,5H),7.63(d,1H,J=8.10Hz);ESI-MS m/z 405[M+Na]+(100);MS/MS(405)m/z 361,270.[α]20 D+41.9°(c=1.56、CHCl3) Elemental analysis (C)22H26N2O4)C,H,N.
(S) - (-) -N- [4- (1-bromo) butyl]-1- (benzyloxycarbonyl) -1, 2, 3, 4-tetrahydroisoquinoline-2-carboxamide [ (S) -33)]To a vigorously stirred solution of (S) -32(1.0g, 2.62mmol) in dry acetonitrile (50.0mL) was added triphenylphosphine (0.86g, 3.22mmol) and carbon tetrabromide (1.06g, 3.22mmol) at room temperature. After 2h, the mixture was quenched with 15% NaOH and the heterogeneous mixture was extracted with ethyl acetate (EtOAc) (3X 25 mL). The organic layer was dried and evaporated. The residue was chromatographed (20% n-hexane in ethyl acetate) to give 0.58g (91% yield) (S) -33 as a yellow oil (33% yield).1H NMR(CDCl3)δ1.34-1.61(m,4H),2.15-2.26(m,2H),2.57-2.78(m,2H),3.02-3.30(m,4H),5.00(t,1H,J=6.70Hz),5.14-5.30(m,2H),6.07(br s,1H),6.99-7.21(m,3H),7.33(m,5H),7.61(d,1H,J=8.02Hz);ESI-MS m/z 467[M+Na]+.[α]20 D-50.9°(c=0.53、CHCl3) Elemental analysis (C)22H25BrN2O3)C,H,N.
(S) - (-) -N- [4- [4- (m-tolyl) piperazin-1-yl]Butyl radical]-2- (benzyloxycarbonyl) -1, 2, 3, 4-tetrahydroisoquinoline-2-carboxamide [ (S) -34 a)]To a stirred solution of (S) -33(180.4mg, 0.40mmol) in dry acetonitrile (10.0mL) under argon was added 1- (m-tolyl) piperazine dihydrochloride (150.9mg, 0.40mmol) and triethylamine (62.0 μ L, 0.46mmol), and the solution was refluxed under stirring overnight. The solvent was removed under reduced pressure, water was added and the mixture was extracted with dichloromethane (3X 30 mL). The organic layer was dried, concentrated and the crude product was chromatographed (6% methanol in chloroform) to give (S) -34a asYellow oil (40% yield).1H NMR(CDCl3)δ1.25-1.37(m,4H),2.15-2.33(m,7H),2.47-2.57(m,4H),2.62-2.79(m,2H),3.12-3.27(m,6H),4.97(t,1H,J=6.65Hz),5.16-5.31(m,2H),6.12(br s,1H),6.65-6.73(m,3H),7.03-7.24(m,3H),7.34(m,5H),7.64(d,1H,J=8.10Hz).[α]20 D=-34,3°(c=1.75、CHCl3) Elemental analysis (C)33H40N4O3)C,H,N.
(S) - (-) -N- [4- [4- (m-tolyl) piperazin-1-yl]Butyl radical]-1, 2, 3, 4-tetrahydroisoquinoline-2-carboxamide (1S) to a solution of (S) -34a (50.0mg, 0.15mmol) in methanol and EtOAc (1: 1) under argon was added catalytic palladium on carbon 5% and the suspension was hydrogenated at 60psi for 8 h. Then passing through Celite®The mixture was filtered and the filtrate was evaporated. The crude product was chromatographed (10% methanol in chloroform) to give 1s as a colorless oil (90% yield).1H NMR(CDCl3)δ1.20-1.58(m,4H),1.86-1.95(m,4H),2.19-1.37(m,3H),2.39-2.46(m,2H),2.57-2.77(m,4H),3.22-3.33(m,6H),3.64-3.84(m,1H),6.63-6.73(m,3H),6.96-7.03(m,2H),7.07-7.18(m,);ESI-MS m/z 407[M]+(100);MS/MS(407)m/z 300,276,258,248,231,189,177,161,132.[α]20 DElemental analysis (C ═ 42.1 ° (C ═ 1.26, MeOH)25H34N4O)C,H,N.
(R) - (+) -N- [4- [4- (m-tolyl) piperazin-1-yl ] butyl ] -1, 2, 3, 4-tetrahydroisoquinoline-2-amide (Compound 1-20/1t)
Figure A20068000172700801
(R) - (+) -1- (benzyloxycarbonyl) -1, 2, 3, 4-tetrahydroquinoline-2-carboxylic acid [ (R) -31)]The title compound was prepared as follows starting from (R) -29(1.30g, 7.34mmol) following the procedure described to afford (S) -31. To give compound (R) -29 as a colorless oil(81% yield).1H NMR(CDCl3)δ1.85-1.99(m,1H),2.35-2.50(m,1H),2.58-2.79(m,2H),4.99(t,1H,J=7.74Hz),5.19-5.34(m,2H),6.99-7.10(m,2H),7.18-7.25(m,1H),7.32-7.38(m,5H),7.78(d,1H,J=7.92Hz),9.94(br s,1H).[α]20 D+44.6 ° (C ═ 0.74, MeOH), elemental analysis (C)18H17NO4)C,H,N.
(R) - (+) -N- [4- (1-hydroxy) butyl]-1- (benzyloxycarbonyl) -1, 2, 3, 4-tetrahydroisoquinoline-2-carboxamide [ (R) -32)]The title compound was prepared as described below starting from (R) -31(418.2mg, 1.34mmol) following the procedure described to give (S) -32. Compound (R) -32 was obtained as a colorless oil (72% yield).1H NMR(CDCl3)δ1.21-1.40(m,4H),2.01-2.10(m,1H),2.14-2.28(m,1H),2.56-2.74(m,2H),2.82(br s,1H),3.10-3.13(m,2H),3.40-3.45(m,2H),4.87-4.94(m,1H),5.11-5.26(m,2H),6.51(br s,1H),6.95-7.17(m,3H),7.30(m,5H),7.64(d,1H,J=8.14Hz);ES I-MS m/z405[M+Na]+(100),267.[α]20 D+50°(c=1.94、CHCl3) Elemental analysis (C)22H26N2O4)C,H,N.
(R) - (+) -N- [4- (1-bromo) butyl]-1- (benzyloxycarbonyl) -1, 2, 3, 4-tetrahydroisoquinoline-2-carboxamide [ (R) -33)]The title compound was prepared as described below starting from (R) -32(368.9mg, 0.97mmol) and following the procedure to give (S) -33. Compound (R) -33 was obtained as a colorless oil (33% yield).1H NMR(CDCl3)δ1.40-1.64(m,4H),2.20-2.31(m,2H),2.62-2.80(m,2H),3.07-3.28(m,4H),4.99(t,1H,j=6.67Hz),5.16-5.31(m,2H),6.07(br s,1H),7.04-7.21(m,3H),7.34(m,5H),7.62(d,1H,j=8.06Hz);[α]20 D+50.9°(c=0.15、CHCl3) Elemental analysis (C)22H25BrN2O3)C,H,N.
(R) - (+) -N- [4- [4- (m-tolyl) piperazin-1-yl group]Butyl radical]-2- (benzyloxycarbonyl) -1, 2, 3, 4-tetrahydroisoquinoline-2-methylAmides [ (R) -34a]The title compound was prepared as follows starting from (R) -33(70.0mg, 0.16mmol) and (m-tolyl) piperazine dihydrochloride (39mg, 0.16mmol), following the procedure described to give (S) -34 a. Compound (R) -34a was obtained as a colorless oil (40% yield).1H NMR(CDCl3)δ1.25-1.46(m,4H),2.16-2.28(m,4H),2.31(s,3H),2.48-2.58(m,4H),2.64-2.80(m,2H),3.12-3.25(m,6H),4.95-5.01(m,1H),5.16-5.32(m,2H),6.05(br s,1H),6.66-6.73(m,3H),7.04-7.21(m,3H),7.25(s,1H),7.35(m,5H),7.63(d,1H,J=8.11Hz).[α]20 D=+34,3°(c=0.19、CHCl3) Elemental analysis (C)33H40N4O3)C,H,N.
(R) - (+) -N- [4- [4- (m-tolyl) piperazin-1-yl group]Butyl radical]-1, 2, 3, 4-tetrahydroisoquinoline-2-carboxamide (1t) the title compound was prepared starting from (R) -34a (50.0mg, 0.15mmol) according to the procedure described to give 1 s. Compound 1t was obtained as colorless oil (85% yield).1H NMR(CDCl3)δ1.20-1.58(m,4H),1.86-1.95(m,4H),2.19-1.37(m,3H),2.39-2.46(m,2H),2.57-2.77(m,4H),3.22-3.33(m,6H),3.64-3.84(m,1H),6.63-6.73(m,3H),6.96-7.03(m,2H),7.07-7.18(m,);ES I-MSm/z407[M+](100);MS/MS(407)m/z300,276,258,248,231,189,177,161,132.[α]20 DElemental analysis (C ═ 42.1 ° (C ═ 1.26, MeOH)25H34N4O)C,H,N.
(R) - (+) -N- [4- (4-phenylpiperazin-1-yl) butyl ] -1, 2, 3, 4-tetrahydroisoquinoline-2-carboxamide (Compound 1-21/1u)
Figure A20068000172700821
(R) - (+) -N- [4- [4- (3-chloro) phenylpiperazin-1-yl]Butyl radical]-2- (benzyloxycarbonyl) -1, 2, 3, 4-tetrahydroisoquinoline-2-carboxamide [ (R) -34 b)]The title compound is prepared by starting from (A)R) -33(140.0mg, 0.31mmol) and (3-chloro) phenylpiperazine hydrochloride (73.4mg, 0.31mmol), as described to give (S) -34 a. Compound (R) -34b was obtained as a colorless oil (40% yield).1H NMR(CDCl3)δ1.25-1.36(m,4H),2.20-2.45(m,4H),2.48-2.59(m,4H),2.64-2.80(m,2H),3.12-3.21(m,6H),4.98(t,1H,J=6.65Hz),5.16-5.31(m,2H),6.02(br s,1H),6.74-6.85(m,3H),7.04-7.21(m,3H),7.25(s,1H),7.34(m,5H),7.63(d,1H,J=7.97Hz);ESI-MS m/z584[M+Na+],561[M+H+](100),508.Anal(C32H37N4O3)C,H,N.[α]20 D+31°(c=0.19、CHCl3) Elemental analysis (C)32H37ClN4O3)C,H,N.
(R) - (+) -N- [4- (4-phenylpiperazin-1-yl) butyl]-1, 2, 3, 4-tetrahydroisoquinoline-2-amide (1 u.) the title compound was prepared starting from (R) -34b (50.0mg, 0.15mmol) according to the procedure described to give 1 s. Compound 1u was obtained as a colorless oil (92% yield).1H NMR(CDCl3)δ1.49-1.53(m,4H),1.79-1.95(m,2H),2.24-2.46(m,2H),2.48-2.61(m,5H),2.65-2.78(m,1H),3.13-3.18(m,4H),3.24-3.33(m,2H),3.93-4.00(m,1H),6.59-6.74(m,2H),6.80-7.06(m,5H),7.20-7.28(m,2H).ES I-MS m/z393[M+](100),132.Anal(C24H32N4O)C,H,N.[α]20 D=+41,66°(c=0.24、CHCl3) Elemental analysis (C)23H30N4O)C,H,N.
N- (4- (4- (phenylpiperazin-1-yl) butyl) benzo [ b ] furan-2-carboxamide (Compound 1-22)
Figure A20068000172700831
The title compound was prepared starting from 71 and 1-phenylpiperazine following the procedure described to give 17. To obtainTo compound 122As a white solid (70% yield): mp (methanol) 149-150 ℃;1H NMR,300MHz,(CDCl3)δ1.71(m,4H),2.47(m,2H),2.64(m,4H),3.24(m,4H),3.53(m,2H),6.89(m,3H),7.02(br s,1H),7.28(m,3H),7.39(m,1H),7.46(m,2H),7.66(m,1H).ES I-MS m/z400[M+Na+],377[M+H+](100).Anal(C23H27N3O2)C,H,N.
n- (4- (4- (2, 3-dimethylphenyl) piperazin-1-yl) butyl) benzo [ b ] furan-2-carboxamide
(Compound 1-23)
Figure A20068000172700832
The title compound was prepared starting from 71 and 4- (2, 3-dimethylphenyl) piperazine following the procedure described to give 17. To obtain a compound 123As a white solid (73% yield): mp (methanol) 151-152 ℃.1H NMR,200MHz,(CDCl3)δ1.73(m,4H),2.21(s,3H),2.25(s,3H),2.47(m,2H),2.62(m,4H),2.93(m,4H),3.52(m,2H),6.87(m,2H),7.05(m,2H),7.35(m,3H),7.64(m,1H).ESI-MSm/z428[M+Na+],406[M+H+](100).Anal(C25H31N3O2)C,H,N.
N- (4- (4- (3-methoxyphenyl) piperazin-1-yl) butyl) benzo [ b ] furan-2-carboxamide
(Compounds No. 1 to 24)
Figure A20068000172700841
The title compound was prepared starting from 71 and 4- (3-methoxyphenyl) piperazine following the procedure described to give 17. Is obtained and changed intoCompound 124, as a white solid (70% yield): mp (methanol) 104-105 ℃.1H NMR,200MHz,(CDCl3)δ1.62(m,4H),2.40(m,2H),2.56(m,4H),3.19(m,4H),3.49(m,2H),3.74(s,3H),6.44(m,3H),7.25(m,5H),7.61(m,1H).ESI-MS m/z 430[M+Na+],408[M+H+](100).Anal(C24H29N3O3)C,H,N.
Experimental procedures for Compounds 1-25
Tert-butyl-4- (6-methylpyridin-2-yl) piperazine-1-carboxylate (32) in a sealed tube, 2-bromo-6-methylpyridine (461mg, 2.68mmol), Pd2(dba)2(2%), BINAP (4%) and sodium tert-butoxide (386.4mg, 4.02mmol) were added to N-Boc-piperazine (500mg, 2.68mmol) and the solid was dissolved in dry toluene (5 mL). The mixture was stirred at 70 ℃ for 90min, filtered through Celite ®, washed with ethyl acetate and the organic layer was evaporated under reduced pressure. The crude product was purified by flash chromatography (40% ethyl acetate in hexane) to afford 32As a light yellow solid (95% yield): mp (methanol) 84-85 ℃;1H NMR,200MHz,(CDCl3)δ1.41(s,9H),2.31(s,3H),3.42(m,8H),6.37(m,2H),7.28(m,1H).ESI-MS m/z300[M+Na+],278[M+H+](100).Anal(C15H23N3O2)C,H,N.
1- (6-methylpyridin-2-yl) piperazine trifluoroacetate salt (4)1) Trifluoroacetic acid (4mL) was added to 32Was cooled in an ice bath, and the mixture was stirred at room temperature for 60 min. The crude product was concentrated and washed with diethyl ether until the solid became colorless.
Preparation of the title compound starting from 72 and 41 and starting from N- (4- (4- (6-methylpyridin-2-yl) piperazin-1-yl) butyl) isoquinoline-3-carboxamide (Compound 1-25) as describedAnd (5) to step 13. To obtain a compound 125As a white solid (70% yield): mp (methanol) 124-125 ℃.1H NMR,200MHz,(CDCl3)δ1.71(m,4H),2.38(s,3H),2.47(m,2H),2.56(m,4H),3.55(m,6H),6.44(m,2H),7.30(m,1H),7.72(m,2H),8.00(m,2H),8.33(br s,1H),8.60(m,1H),9.14(m,1H).ESI-MSm/z426[M+Na+],404[M+H+](100).Anal(C24H29N5O)C,H,N.
N- (4- (4-phenylpiperazin-1-yl) butyl) isoquinoline-3-carboxamide (Compound 1-26)
Figure A20068000172700851
The title compound was prepared starting from 72 and 1-phenylpiperazine following the procedure described to give 13. To obtain a compound 126As a white solid (76% yield): mp (methanol) 153-154 ℃.1H NMR,300MHz,(CDCl3)δ1.71(m,4H),2.46(m,2H),2.62(m,4H),3.21(m,4H),3.57(m,2H),6.88(m,3H),7.26(m,2H),7.72(m,2H),8.00(m,2H),8.36(br s,1H),8.61(m,1H),9.14(m,1H).ESI-MSm/z411[M+Na+],389[M+H+](100).Anal(C24H28N4O)C,H,N.
N- (4- (4- (6-methylpyridin-2-yl) piperazin-1-yl) butyl) benzofuran-2-carboxamide
(Compounds No. 1 to 27)
Figure A20068000172700852
Starting from 71And 41Preparation of the title Compound as described to give 17The step (2). To obtain a compound 127As a white solid (75% yield): mp (methanol) 107-109℃.1H NMR,2O0MHz,(CDCl3)δ1.70(m,4H),2.39(s,3H),2.45(m,2H),2.58(m,4H),3.54(m,6H),6.45(m,2H),7.02(br s,1H),7.35(m,5H),7.65(m,1H).ESI-MS m/z415[M+Na+],393[M+H+](100).Anal(C23H28N4O2)C,H,N.
Experimental procedures for Compounds 1-28
Figure A20068000172700861
Tert-butyl-4- (naphthalen-1-yl) piperazine-1-carboxylate (33) the title compound was prepared starting from 1-bromonaphthalene (200mg, 0.97mmol) following the procedure described to give 32:1H NMR,200MHz,(CDCl3)δ1.55(s,9H),3.05(m,4H),3.72(m,4H),7.05(m,1H),7.49(m,4H),7.82(m,1H),8.22(m,1H).ES I-MSm/z335[M+Na+],313[M+H+](100).Anal(C19H24N2O2)C,H,N.
1- (Naphthalen-1-yl) piperazine trifluoroacetate (42) the title compound was prepared starting from 33 by the procedure described to give 41.
N- (4- (4- (naphthalen-1-yl) piperazin-1-yl) butyl) benzamide (compound 1-28) starting from 75And 42Preparation of the title Compound as described to give 13The step (2). To obtain a compound 128As yellow oil (70% yield):1H NMR,200MHz,(CDCl3)δ1.68(m,4H),2.49(m,4H),2.70(m,4H),3.34(m,2H),7.01(m,2H),7.43(m,6H),7.78(m,3H),8.18(m,1H).ESI-MS m/z410[M+Na+],388[M+H+](100).Anal(C25H29N3O)C,H,N.
n- (4- (4-phenylpiperazin-1-yl) butyl) quinoline-2-carboxamide (Compound 1-29)
Figure A20068000172700862
Starting from 72And 1-phenylpiperazine the title compound was prepared as described to give 13The step (2). To obtain a compound 129As a white solid (70% yield): mp (methanol) 120-121 ℃.1H NMR,200MHz,(CDCl3)δ1.69(m,4H),2.46(m,2H),2.61(m,4H),3.20(m,4H),3.56(m,2H),6.86(m,3H),7.24(m,2H),7.59(m,1H).7.75(m,1H).7.85(m,1H).8.09(m,1H).8.29(m,2H).ESI-MSm/z411[M+Na+],389[M+H+](100).Anal(C24H28N4O)C,H,N.
N- (4- (4-m-tolylpiperazin-1-yl) butyl) quinoline-2-carboxamide (Compound 1-30)
Figure A20068000172700871
The title compound was prepared starting from 72 and 4- (3-methylphenyl) piperazine as described to give 13The step (2). To obtain a compound 130Yellow oil:1H NMR,200MHz,(CDCl3)δ1.72(m,4H),2.30(s,3H),2.47(m,2H),2.61(m,4H),3.19(m,4H),3.47(m,2H),6.69(m,4H),7.11(m,1H),7.59(m,1H),7.75(m,1H),7.85(m,1H),8.09(m,1H),8.33(m,2H).ES I-MS m/z403[M+H+](100).Anal(C25H30N4O)C,H,N.
n- (4- (4- (3-methoxyphenyl) piperazin-1-yl) butyl) -1-methyl-1H-indole-2-carboxamide
(Compounds No. 1 to 31)
Starting from 77And 4- (3-methoxyphenyl) piperazine the title compound was prepared as described to give 13The step (2). To obtain a compound 131As a white solid (60% yield): mp (methanol) 141-142 ℃.1H NMR,200MHz,(CDCl3)δ1.69(m,4H),2.48(m,2H),2.65(m,4H),3.08(m,4H),3.47(m,2H),3.84(s,3H),4.03(s,3H),6.90(m,5H),7.16(m,1H),7.32(m,2H),7.60(m,1H).ESI-MSm/z421[M+H+](100).Ana l(C25H32N4O2)C,H,N.
Experimental procedures for Compounds 1-32
Figure A20068000172700881
4- (4- (3-methoxyphenyl) piperazin-1-yl) butanenitrile (37) to a stirred solution of 1- (3-methoxyphenyl) piperazine (36) (100.0mg, 0.52mmol) in acetonitrile (10.0mL) at room temperature was added 4-bromobutanenitrile (84.7mg, 0.57mmol) and potassium carbonate (107.6mg, 0.78 mmol). The mixture was heated to reflux overnight, then filtered and evaporated. The crude product was purified by flash chromatography (10% methanol in chloroform) to give 98.0mg (73% yield) of 37 as a yellow oil:1H NMR,200MHz,(CDCl3)δ1.83(m,2H),2.49(m,8H),3.17(m,4H),3.77(s,3H),6.48(m,3H),7.16(m,1H).ESI-MS m/z282[M+H+]260[M+H+](100).Anal(C15H21N3O)C,H,N.
4- (4- (3-methoxyphenyl) piperazin-1-yl) butan-1-amine (38) to a stirred solution of 37(300.0mg, 1.16mmol) in dry methanol (15.0mL) at 0 deg.C was added nickel (II) chloride hexahydrate (28.0mg, 0.12mmol) and sodium borohydride (307.2mg, 8.12 mmol). The mixture was stirred at room temperature for 90min and then passed through Celite®Filtering, washing with methanol, evaporating under reduced pressureAnd (4) liquid. The residue was extracted with EtOAc (3 × 30mL), the organic layer was dried, concentrated, and the crude product was chromatographed (15% n-hexane in EtOAc) to give 38 (60% yield):1H NMR,200MHz,(CDCl3)δ1.54(m,4H),2.40(m,4H),2.58(m,4H),3.19(m,4H),3.76(s,3H),6.46(m,3H),7.16(m,1H).ESI-MS m/z286[M+H+]264[M+H+](100).Anal(C15H25N3O)C,H,N.
1H-indole-3-carbonyl chloride (40) to a solution of 1H-indole-3-carboxylic acid (39) (100.0mg, 0.6mmol) in dry benzene (2.0mL) was added thionyl chloride (130.0. mu.L, 1.80mmol) and the mixture was heated to reflux for 120 min. The crude product was washed with benzene (2 × 10mL) and evaporated to give 40 with quantitative yield.1H NMR,200MHz,(CDCl3)δ10.85(br s,1H),8.20(m,1H),7.48(m,1H),7.30(m,1H),7.19(m,1H),7.03(m,1H).Anal(C9H6ClNO)C,H,N.
To a stirred solution of 40(100.0mg, 0.6mmol) and 37(158.0mg, 0.6mmol) in dry dichloromethane (15.0mL) was added pyridine (145. mu.L, 1.8 mmol). The mixture was stirred at room temperature overnight. A saturated solution of sodium bicarbonate was added and the mixture was extracted with EtOAc (3X 15mL), dried and evaporated. The crude product was purified by flash chromatography (10% methanol in chloroform) to give 132(50% yield) as a white solid: mp (methanol) 154-155 ℃.1HNMR,200MHz,(CDCl3)δ1.65(m,4H),2.41(m,2H),2.56(m,4H),3.13(m,4H),3.50(m,2H),3.77(s,3H),6.45(m,2H),7.19(m,3H),7.38(m,1H),7.66(m,1H),7.95(m,1H),9.79(br s,1H).ESI-MS m/z429[M+Na+],407[M+H+](100).Ana l(C24H30N4O2)C,H,N.
N- (4- (4-Benzylpiperazin-1-yl) butyl) benzofuran-2-carboxamide (Compound 1-33)
Figure A20068000172700891
Starting from 71And 1-Benzylpiperazine the title compound was prepared as described to give 17The step (2). To obtain a compound 133As yellow oil (70% yield):1H NMR,200MHz,(CDCl3)δ1.64(m,4H),2.39(m,2H),2.50(m,8H),3.49(m,4H),7.04(br s,1H),7.36(m,10H),7.65(m,1H).ESI-MS m/z414[M+Na+],392[M+H+](100).Anal(C24H29N3O2)C,H,N.
7- (5- (4-phenylpiperazin-1-yl) pentyloxy) pyrrolo [1, 2-a ] quinoxalin-4 (5H) -one (Compound 1-34)
Starting from 262And 1-phenylpiperazine the title compound was prepared as described to give 114The step (2). To obtain a compound 134As an amorphous solid (60% yield).1H NMR(CDCl3)δ1.56(m,4H),1.86(m,2H),2.45(m,2H),2.64(m,4H),3.22(m,4H),4.03(m,2H),6.66(m,1H),6.79(m,3H),6.91(m,2H),7.25(m,3H),7.56(m,2H),10.19(br s,1H).ES I-MS m/z453[M+Na+],431[M+H+](100) Elemental analysis (C)26H30N4O2)C,H,N.
(S) -1, 2, 3, 4-tetrahydro-N- (4- (4-phenylpiperazin-1-yl) butyl) quinoline-2-carboxamide (Compound 1-35)
Figure A20068000172700902
The title compound is prepared starting from (S) -34 and 1-phenylpiperazine as described to give 121The step (2). To obtain a compound 135As oil (70% yield):1H NMR(CDCl3)δ1.25-1.36(m,4H),2.20-2.45(m,4H),2.48-2.59(m,4H),2.64-2.80(m,2H),3.12-3.21(m,6H),4.98(t,1H,J=6.65Hz),5.16-5.31(m,2H),6.02(br s,1H),6.74-6.85(m,3H),7.04-7.21(m,3H),7.25(s,1H),7.34(m,5H),7.63(d,1H,J=7.97Hz);ESI-MS m/z584[M+Na+],561[M+H+](100).[α]20 D-31°(c=0.18、CHCl3) Elemental analysis (C)23H32N4O)C,H,N.
Experimental procedures for Compounds 1-36
Figure A20068000172700911
Tert-butyl-4- (quinolin-3-yl) piperazine-1-carboxylic acid ester (3)4) The title compound is prepared starting from 3-bromoquinoline as described to give 41The step (2). To obtain a compound 34As a white solid: mp (methanol) 114-.1H NMR,200MHz,(CDCl3)δ1.46(s,9H),3.18(m,4H),7.28(m,1H),7.43(m,2H),7.63(m,1H),7.96(m,1H),8.74(m,1H).ESI-MS m/z336[M+Na+](100) Elemental analysis (C)18H23N3O2)C,H,N.
3- (4-methylpiperazin-1-yl) quinoline trifluoroacetate salt (4)3) Starting from 34Preparation of the title compound as described to give (4)1) The step (2).
N- (4- (4- (quinolin-3-yl) piperazin-1-yl) butyl) benzamide (compound 1-36) starting at 75And 43Preparation of the title Compound as described to give 13The step (2). To obtain a compound 136As a white solid (70% yield): mp (methanol) 124-125 ℃.1H NMR,200MHz,(CDCl3)δ1.68(m,4H),2.45(m,2H),2.65(m,4H),3.27(m,4H),3.53(m,2H),6.63(brs,1H),7.38(m,6H),7.65(m,1H),7.75(m,2H),7.97(m,1H),8.76(m,1H).ESI-MS m/z389[M+H+](100).Anal(C24H28N4O)C,H,N.
N- (4- (4-m-tolylpiperazin-1-yl) butyl) pyridinecarboxamide (Compound 1-37)
Figure A20068000172700912
Starting from 78And 4- (3-Methylphenyl) piperazine the title compound was prepared as described to give 13The step (2). To obtain a compound 137As yellow oil (70% yield):1H NMR,200MHz,(CDCl3)δ1.67(m,4H),2.30(s,3H),2.45(m,2H),2.61(m,4H),3.20(m,4H),3.51(m,2H),6.70(m,3H),7.14(m,1H),7.40(m,1H),7.84(m,1H),8.19(m,2H),8.52(m,1H).ESI-MS m/z375[M+Na+],353[M+H+](100).Ana l(C21H28N4O)C,H,N.
7- (4- (4-phenylpiperazin-1-yl) butoxy) pyrrolo [1, 2-a ] quinoxalin-4 (5H) -one
(Compound 1-38)
Figure A20068000172700921
Starting from 261And 1-phenylpiperazine the title compound was prepared as described to give 114The step (2). To obtain a compound 138As an amorphous solid (60% yield).1H NMR(CDCl3)δ1.81(m,4H),2.49(m,2H),2.65(m,4H),3.21(m,4H),4.06(m,2H),6.66(m,1H),6.74(m,3H),6.89(m,2H),7.23(m,3H),7.56(m,2H),10.27(br s,1H).ESI-MS m/z440[M+Na+],417[M+H+](100) Elemental analysis (C)25H28N4O2)C,H,N.
N- (4- (4- (quinolin-3-yl) piperazin-1-yl) butyl) isoquinoline-3-carboxamide
(Compound 1-39)
Figure A20068000172700922
Starting from 72And 43Preparation of the title Compound as described to give 13The step (2). To obtain a compound 139As a white solid (70% yield): mp (methanol) 153-154 ℃.1H NMR,200MHz,(CDCl3)δ1.80(m,4H),2.37(m,2H),2.67(m,4H),3.32(m,4H),3.75(m,2H),7.30(m,1H),7.45(m,2H),7.67(m,4H),7.93(m,2H),8.33(br s,1H),8.60(m,1H),8.78(m,1H),9.12(m,1H).ESI-MS m/z462[M+Na+],440[M+H+](100).Anal(C27H29N5O)C,H,N.
N- (4- (4- (3-methoxyphenyl) piperazin-1-yl) butyl) -6-methylpyridine-2-carboxamide (Compound 1-40)
Figure A20068000172700931
Starting from 79And 4- (3-methoxy-1-phenyl) piperazine the title compound was prepared as described to give 13The step (2). To obtain a compound 140As yellow oil (78% yield):1H NMR,200MHz,(CDCl3)δ1.64(m,4H),2.41(m,2H),2.53(s,3H),2.59(m,4H),3.17(m,4H),3.49(m,2H),3.75(s,3H),6.45(m,3H),7.17(m,2H),7.67(m,1H),7.97(m,1H),8.14(br s,1H).ESI-MS m/z405[M+Na+],383[M+H+](100).Anal(C22H30N4O2)C,H,N.
n- (4- (4- (3-methoxyphenyl) piperazin-1-yl) butyl) quinoline-3-carboxamide
(Compound 1-41)
Starting from 76And 4- (3-methoxyphenyl) piperazine the title compound was prepared as described to give 13The step (2). To obtain a compound 141As yellow oil (78% yield):1H NMR,200MHz,(CDCl3)δ1.63(m,4H),2.41(m,2H),2.56(m,4H),3.15(m,4H),3.54(m,2H),3.73(s,3H),6.43(m,4H),7.13(m,1H),7.55(m,1H),7.70(m,1H),7.81(m,1H),8.06(m,1H),8.26(m,1H),8.31(br s,1H).ESI-MS m/z441[M+Na+],419[M+H+](100).Ana l(C25H30N4O2)C,H,N.
n- (4- (4- (pyridin-2-yl) piperazin-1-yl) butyl) quinoline-3-carboxamide (Compound 1-42)
Figure A20068000172700941
Starting from 76And 1- (pyridin-2-yl) piperazine the title compound was prepared as described to give 13The step (2). To obtain a compound 142As yellow oil (70% yield):1H NMR,200MHz,(CDCl3)δ1.82(m,4H),2.39(m,2H),2.50(m,4H),3.52(m,6H),6.55(m,2H),7.40(m,1H),7.53(m,1H),7.69(m,1H),7.80(m,1H),8.17(m,5H).ESI-MS m/z412[M+Na+],390[M+H+](100).Anal(C23H27N5O)C,H,N.
n- (4- (4-phenylpiperazin-1-yl) butyl) pyridinecarboxamide (Compound 1-43)
Figure A20068000172700942
Starting from 78And 1-phenylpiperazine the title compound was prepared as described to give 13The step (2). To obtain a compound 143As yellow oil (82% yield):1H NMR,400MHz,(CDCl3)δ1.63(m,4H),2.39(m,2H),2.56(m,4H),3.17(m,4H),3.47(m,2H),6.80(m,1H),6.88(m,2H),7.21(m,2H),7.35(m,1H),7.78(m,1H),8.16(m,1H),8.48(m,1H).ESI-MS m/z361[M+Na+],339[M+H+](100).Ana l(C20H26N4O)C,H,N.
n- (4- (4- (3-methoxyphenyl) piperazin-1-yl) butyl) pyridinecarboxamide (Compound 1-44)
Figure A20068000172700951
Starting from 78And 4- (3-methoxy-1-phenyl) piperazine the title compound was prepared as described to give 13The step (2). To obtain a compound 144As yellow oil (72% yield):1H NMR,400MHz,(CDCl3)δ1.57(m,4H),2.33(m,2H),2.49(m,4H),3.11(m,4H),3.43(m,2H),3.68(s,3H),6.32(m,2H),6.38(m,1H),6.45(m,1H),7.07(m,1H),7.30(m,1H),7.72(m,1H),8.11(m,1H),8.43(m,1H).ESI-MS m/z369[M+H+](100).Anal(C21H28N4O2)C,H,N.
n- (4- (4- (3-methoxyphenyl) piperazin-1-yl) butyl) benzamide (compound 1-45)
Figure A20068000172700952
Starting from 75And 4- (3-methoxy-1-phenyl) piperazine the title compound was prepared as described to give 13The step (2). To obtain a compound 145As a white solid (79% yield): mp (methanol) 111-:1H NMR,400MHz,(CDCl3)δ1.62(m,4H),2.39(m,2H),2.54(m,4H),3.13(m,4H),3.42(m,2H),3.75(s,3H),6.40(m,2H),6.49(m,1H),6.83(br s,1H),7.14(m,1H),7.36(m,1H),7.44(m,1H),7.74(m,2H).ESI-MS m/z390[M+Na+],368[M+H+](100).Anal(C22H29N3O2)C,H,N.
n- (4- (4-m-tolylpiperazin-1-yl) butyl) benzamide (Compound 1-46)
Figure A20068000172700953
Starting from 75And 4- (3-Methylphenyl) piperazine the title compound was prepared as described to give 13The step (2). To obtain a compound 146As a white solid (77% yield): mp (methanol) 126-127 ℃.1H NMR,400MHz,(CDCl3)δ1.64(m,4H),2.30(s,3H),2.40(m,2H),2.55(m,4H),3.13(m,4H),3.45(m,2H),6.68(m,3H),6.90(br s,1H),7.13(m,1H),7.37(m,2H),7.43(m,1H),7.75(m,2H).ESI-MS m/z374[M+Na+],352[M+H+](100).Anal(C22H29N3O)C,H,N.
N- (4- (4-phenylpiperazin-1-yl) butyl) nicotinamide (Compound 1-47)
Figure A20068000172700961
Starting from 710And 1-phenylpiperazine the title compound was prepared as described to give 13The step (2). To obtain a compound 147As a white solid (80% yield): mp (methanol) 119-120 ℃.1H NMR,400MHz,(CDCl3)δ1.65(m,4H),2.42(m,2H),2.56(m,4H),3.12(m,4H),3.46(m,2H),6.84(m,3H),7.11(br s,1H),7.23(m,2H),7.31(m,1H),8.07(m,1H),8.65(m,1H),8.94(m,1H).ESI-MSm/z339[M+H+](100).Anal(C20H26N4O)C,H,N.
N- (4- (4- (6-methylpyridin-2-yl) piperazin-1-yl) butyl) benzamide (Compound 1-48)
Figure A20068000172700962
Starting from 75And 41Preparation of the title Compound as described to give 13The step (2). To obtain a compound 148As a white solid (82% yield): mp (methanol) 102-103 ℃.1H NMR,200MHz,(CDCl3)δ1.59(m,4H),2.34(m,5H),2.46(m,4H),3.46(m,6H),6.39(m,2H),7.07(br s,1H),7.33(m,4H),7.73(m,2H).ESI-MSm/z375[M+Na+],353[M+H+](100).Ana l(C21H28N4O)C,H,N.
Experimental procedures for Compounds 1-49
Figure A20068000172700971
Tert-butyl-4- (6-methoxypyridine-)2-yl) piperazine-1-carboxylic acid ester (3)5) The title compound was prepared starting from 2-bromo-6-methoxypyridine according to the described to give 32The steps of (1):1H NMR,200MHz,(CDCl3)δ1.42(s,9H),3.19(m,4H),3.73(s,3H),3.79(m,4H),5.70(m,1H),5.90(m,1H),7.44(m,1H),ESI-MS m/z316[M+Na+],294[M+H+](100).Ana l(C15H23N3O3)C,H,N.
1- (6-methoxypyridin-2-yl) piperazine (4)4) Starting from 35Preparation of the title Compound as described to give 41The step (2).
N- (4- (4- (6-methoxypyridin-2-yl) piperazin-1-yl) butyl) benzamide (compound 1-49) starting from 75And 44Preparation of the title Compound as described to give 13The step (2). To obtain a compound 149As a white solid (85% yield): mp (methanol) 120121-DEG C.1H NMR,200MHz,(CDCl3)δ1.61(m,4H),2.37(m,2H),2.47(m,4H),3.43(m,6H),3.81(s,3H),6.06(m,2H),6.85(br s,1H),7.38(m,4H),7.72(m,2H).ESI-MS m/z391[M+Na+],369[M+H+](100).Anal(C21H28N4O2)C,H,N.
N- (4- (4- (6-methoxypyridin-2-yl) piperazin-1-yl) butyl) pyridinecarboxamide (Compound 1-50)
Figure A20068000172700972
Starting from 78And 44Preparation of the title Compound as described to give 13The step (2). To obtain a compound 150As yellow oil (80% yield):1H NMR,300MHz,(CDCl3)δ1.63(m,4H),2.37(m,2H),2.48(m,4H),3.47(m,4H),3.80(m,3H),6.05(m,2H),7.34(m,2H),7.77(m,1H),8.14(m,2H),8.47(m,1H).ESI-MSm/z429[M+Na+],407[M+H+](100).ESI-MS m/z376[M+Na+],354[M+H+](100).Anal(C20H27N5O2)C,H,N.
n- (4- (4- (6-methylpyridin-2-yl) piperazin-1-yl) butyl) pyridinecarboxamide (Compound 1-51)
Figure A20068000172700981
Starting from 78And 41Preparation of the title Compound as described to give 13The step (2). To obtain a compound 151Yellow (90% yield):1H NMR,300MHz,(CDCl3)δ1.58(m,4H),2.31(m,5H),2.45(m,4H),3.43(m,6H),6.36(m,2H),7.29(m,2H),7.72(m,1H),8.11(m,2H),8.43(m,1H).ESI-MSm/z 376[M+Na+],354[M+H+](100).Anal(C20H27N5O)C,H,N.
experimental procedures for Compounds 1-52
Figure A20068000172700982
1, 6-bis (4- (3-chlorophenyl) piperazin-1-yl) hexane (Compound 1-52) to 3-chlorophenylpiperazine (40)6) (100.0mg, 0.51mmol) in dry acetonitrile (15.0mL) was added 1, 6-dibromohexane (34.72 μ L, 0.25mmol) and TEA (71.1 μ L, 0.51mmol) and the mixture was stirred at room temperature overnight. The crude product was extracted with dichloromethane (3X 10mL), dried and evaporated. The residue was chromatographed (10% methanol in chloroform) to give 152(90% yield) as yellow:1H NMR,200MHz,(CDCl3)δ1.37(m,4H),1.52(m,4H),2.37(m,4H),2.57(m,8H),3.20(m,8H),6.77(m,4H),6.86(m,2H),7.14(m,2H).ESI-MS m/z475[M+H+](100).Ana l(C26H36Cl2N4)C,H,N.
1, 6-bis (4- (3-methoxyphenyl) piperazin-1-yl) hexane (Compound 1-53)
Figure A20068000172700991
The title compound is prepared starting from 4- (3-methoxyphenyl) piperazine as described to give 152The step (2). To obtain a compound 153As a white solid (85% yield): mp (methanol) 109-110 ℃.1H NMR,200MHz,(CDCl3)δ1.36(m,4H),1.54(m,4H),2.38(m,4H),2.58(m,8H),3.20(m,8H),3.77(m,8H),6.44(m,6H),7.15(m,2H),ESI-MS m/z467[M+H+](100).Ana l(C28H42N4O2)C,H,N.
1, 6-bis (4-phenylpiperazin-1-yl) hexane (Compound 1-54)
Figure A20068000172700992
The title compound is prepared starting from 1-phenylpiperazine according to the stated procedure to give 152The step (2). To obtain a compound 154Yellow (95% yield):1H NMR,200MHz,(CDCl3)δ1.39(m,4H),1.57(m,4H),2.41(m,4H),2.62(m,8H),3.22(m,8H),6.89(m,6H),7.27(m,6H).ESI-MS m/z429[M+Na+],407[M+H+](100).Anal(C26H38N4)C,H,N.
1, 6-bis (4- (pyridin-2-yl) piperazin-1-yl) hexane (Compound 1-55)
Figure A20068000172701001
The title compound is prepared starting from 1- (pyridin-2-yl) piperazine as described to give 152The step (2). To obtain a compound 155Yellow oil:1H NMR,400MHz,(CDCl3)δ1.32(m,4H),1.50(m,4H),2.32(m,4H),2.49(m,8H),3.50(m,8H),6.56(m,4H),7.40(m,2H),8.14(m,2H).ESI-MS m/z431[M+Na+],409[M+H+](100).Anal(C24H36N6)C,H,N.
1, 6-bis (4-m-tolylpiperazin-1-yl) hexane (Compound 1-56)
Figure A20068000172701002
The title compound is prepared starting from 4- (3-methylphenyl) piperazine as described to give 152The step (2). To obtain a compound 156As yellow oil (95% yield):1H NMR,400MHz,(CDCl3)δ1.37(m,4H),1.55(m,4H),2.31(s,6H),2.39(m,4H),2.60(m,4H),3.20(m,4H),6.71(m,6H),7.14(m,2H).ES I-MSm/z435[M+H+](100).Anal(C28H42N4)C,H,N.
experimental procedures for Compounds 1-57
Figure A20068000172701011
1- (6-bromohexyl) -4- (3-methoxyphenyl) piperazine (42)1) To 3-methoxyphenylpiperazine (41)1) (200.0mg, 1.04mmol) in dry acetonitrile (15.0mL) was added 1, 6-dibromohexane (212.4. mu.L, 1.56mmol) and TEA (145.0. mu.L, 1.04mmol) and the mixture was stirred at room temperature overAnd (4) at night. The crude product was extracted with dichloromethane (3X 10mL), dried and evaporated. The residue was chromatographed (15% n-hexane in Et OAc) to give 421(65% yield):1HNMR,300MHz,(CDCl3)δ7.12(m,1H),7.02(m,1H),6.76(m,1H),6.60(m,1H),6.47(m,1H),6.39(m,1H),6.27(m,1H),6.15(m,1H),3.73(m,3H),3.44(m,4H),2.59(m,4H),2.36(m,4H),1.39(m,4H),1.29(m,4H).ESI-MS m/z493[M+Na+],471[M+H+](100).Anal(C27H39ClN4O)C,H,N.
1- (3-chlorophenyl) -4- (6- (4- (3-methoxyphenyl) piperazin-1-yl) hexyl) piperazine (compound 1-57) to 421(100.0mg, 0.52mmol) in dry acetonitrile (10.0mL) was added 3-chlorophenylpiperazine (101.9mg, 0.52mmol) and TEA (72.5. mu.L, 0.52mmol) and the mixture was stirred at room temperature overnight. The crude product was extracted with dichloromethane (3X 10mL), dried and evaporated. The residue was chromatographed (10% methanol in chloroform) to give 157(80% yield) as a yellow oil:1H NMR,300MHz,(CDCl3)δ1.35(m,4H),1.54(m,4H),2.39(m,4H),2.59(m,8H),3.20(m,8H),3.78(s,3H),6.42(m,2H),6.53(m,1H),6.78(m,2H),6.86(m,1H),7.15(m,2H).ESI-MSm/z493[M+Na+],471[M+H+](100).Anal(C27H39ClN4O)C,H,N.
1-phenyl-4- (6- (4- (pyridin-2-yl) piperazin-1-yl) hexyl) piperazine (Compound 1-58)
Figure A20068000172701021
Starting at 422And 1- (pyridin-2-yl) piperazine the title compound was prepared as described to give 157The step (2). To obtain a compound 158As yellow oil (60% yield):1H NMR,400MHz,(CDCl3)δ1.39(m,4H),1.58(m,4H),2.43(m,4H),2.64(m,8H),3.24(m,8H),6.88(m,1H),6.96(m,4H),7.28(m,4H).ES I-MSm/z 430[M+Na+],408[M+H+](100).Anal(C25H37N5)C,H,N.
1- (6-methylpyridin-2-yl) -4- (6- (4-m-tolylpiperazin-1-yl) hexyl) piperazine (Compound 1-59)
Figure A20068000172701022
Starting at 423And 1- (6-methylpyridin-2-yl) piperazine the title compound was prepared as described to give 157The step (2). To obtain a compound 159As yellow oil (63% yield):1H NMR,400MHz,(CDCl3)δ1.39(m,4H),1.58(m,4H),2.33(s,3H),2.40(m,7H),2.59(m,8H),3.22(m,4H),3.56(m,4H),6.47(m,2H),6.69(m,1H),6.76(m,2H),7.16(m,1H),7.38(m,1H).ESI-MS m/z458[M+Na+],436[M+H+](100).Anal(C27H41N5)C,H,N.
1- (6-methylpyridin-2-yl) -4- (6- (4-phenylpiperazin-1-yl) hexyl) piperazine
(Compounds No. 1 to 60)
Starting at 422And 1- (6-methylpyridin-2-yl) piperazine the title compound was prepared as described to give 157The step (2). To obtain a compound 160As yellow oil (60% yield):1H NMR,400MHz,(CDCl3)δ1.39(m,4H),1.58(m,4H),2.41(m,7H),3.23(m,4H),3.58(m,4H),6.47(m,2H),6.87(m,1H),6.95(m,2H),7.28(m,2H),7.38(m,1H).ESI-MS m/z422[M+H+](100).Anal(C26H39N5)C,H,N.
1-phenyl-4- (6- (4-m-tolylpiperazin-1-yl) hexyl) piperazine (Compound 1-61)
Figure A20068000172701032
Starting at 422And 4- (3-Methylphenyl) piperazine the title compound was prepared as described to give 157The step (2). To obtain a compound 161As yellow oil (70% yield):1H NMR,400MHz,(CDCl3)δ1.39(m,4H),1.57(m,4H),2.34(s,3H),2.42(m,4H),2.63(m,8H),3.23(m,8H),6.73(m,1H),6.78(m,2H),6.88(m,1H),6.96(m,2H),7.18(m,1H),7.29(m,2H).ES I-MSm/z435[M+Na+],413[M+H+](100).Anal(C27H32N4)C,H,N.
4- (4- (6- (4-phenylpiperazin-1-yl) hexyl) piperazin-1-yl) quinoline (Compound 1-62)
Figure A20068000172701041
Tert-butyl-4- (quinolin-4-yl) piperazine-1-carboxylic acid ester (3)6) The title compound is prepared starting from 4-bromoquinoline as described to yield 32The step (2). To obtain a compound 36Yellow oil:1H NMR,200MHz,(CDCl3)δ1.38(s,9H),2.98(m,4H),3.56(m,4H),6.62(m,1H),7.54(m,1H),7.72(m,1H),7.85(m,1H),7.93(m,1H),8.57(m,1H).ESI-MS m/z336[M+Na+],314[M+H+](100).Anal(C18H23N3O2)C,H,N.
4- (piperazin-1-yl) quinoline (4)5) Starting from 36Preparation of the title Compound as described to give 41The step (2).
4- (4- (6- (4-phenylpiperazin-1-yl) hexyl) piperazin-1-yl) quinoline (compound 1-62) starting from 422And 45Preparation of the title Compound as described to give 157The step (2). To obtain a compound 162As yellow oil (65% yield):1H NMR,400MHz,(CDCl3)δ1.40(m,4H),1.65(m,8H),2.46(m,4H),2.68(m,8H),3.26(m,8H),6.90(m,4H),7.27(m,2H),7.49(m,1H),7.66(m,1H),8.28(m,2H),8.74(m,1H).ESI-MS m/z480[M+Na+],458[M+H+](100).Ana l(C29H39N5)C,H,N.
4- (4- (6- (4-m-tolylpiperazin-1-yl) hexyl) piperazin-1-yl) quinoline (Compound 1-63)
Starting at 423And 45Preparation of the title Compound as described to give 157The step (2). To obtain a compound 163As yellow oil (70% yield):1H NMR,400MHz,(CDCl3)δ1.33(m,4H),1.59(m,4H),2.32(s,3H),2.47(m,4H),2.63(m,4H),2.72(m,4H),3.23(m,8H),6.72(m,3H),6.85(m,1H),7.15(m,1H),7.49(m,1H),7.66(m,1H),8.04(m,2H),8.73(m,1H).ES I-MSm/z494[M+Na+],472[M+H+](100).Anal(C30H41N5)C,H,N.
1- (pyridin-2-yl) -4- (6- (4-m-tolylpiperazin-1-yl) hexyl) piperazine (Compound 1-64)
Figure A20068000172701051
Starting at 423And 1- (pyridin-2-yl) piperazine the title compound was prepared as described to give 157The step (2). To obtain a compound 164Yellow (68% yield):1H NMR,200MHz,(CDCl3)δ1.36(m,4H),1.55(m,4H),2.30(s,3H),2.38(m,4H),2.57(m,8H),3.19(m,4H),3.55(m,4H),6.66(m,5H),7.14(m,1H),7.43(m,1H),8.18(m,1H).ESI-MS m/z422[M+H+](100).Anal(C26H39N5)C,H,N.
1- (3-methoxyphenyl) -4- (6- (4-m-tolylpiperazin-1-yl) hexyl) piperazine
(Compound 1-65)
Figure A20068000172701052
Starting at 423And 4- (3-methoxy-1-phenyl) piperazine the title compound was prepared as described to give 157The step (2). To obtain a compound 165Yellow (80% yield):1H NMR,200MHz,(CDCl3)δ1.37(m,4H),1.55(m,4H),2.31(s,3H),2.39(m,4H),2.60(m,8H),3.20(m,8H),3.78(s,3H),6.43(m,2H),6.53(m,2H),6.71(m,2H),7.15(m,2H),ES I-MS m/z451[M+H+)(100).Anal(C28H42N4O)C,H,N.
biological activity
In vitro binding studies
This example demonstrates the dopamine and 5-hydroxytryptamine receptor subtype affinity of the compounds of the present invention. According to Campiani et al;J.Med.chem.2003463822-3839 procedures for these binding assays.
Male CRL were sacrificed by decapitation: CD (SD) BR-COBS rats (Charles River, Italy); cutting their brains rapidlyIn various areas (striatum for D)1And D2Receptor, olfactory tubercle for D3Receptor, cortical, for 5-HT2Receptor) stored at-80 ℃ until assayed. Tissue was homogenized in approximately 50 volumes of buffer (2X 20s) ice-cold Tris HCl, 50mM, pH7.4 (for D) using an Ultra-Turrax TP-1810 homogenizer1、D2And 5-HT2Recipient) or 50mM Hepes Na, pH7.5 (for D3 recipient), and centrifuged at 48000g for 10 minutes (Beckman Avanti J-25 centrifuge). Each pellet was resuspended in the same volume of fresh buffer, incubated at 37 ℃ for 10 minutes, and centrifuged again at 48000g for 10 minutes. The pellet was then resuspended in fresh buffer, centrifuged as above, and washed once. The resulting pellet was resuspended in the appropriate incubation buffer (50mM Tris HCl, pH7.4, containing 10. mu.M pargyline, 0.1% ascorbic acid, 120mM NaCl, 5mM KCl, 2mM CaCl) just prior to the binding assay2,1mM MgCl2For D1And D2A receptor; 50mM Hepes Na, pH7.5, containing 1mM EDTA, 0.005% ascorbic acid, 0.1% albumin, 200nM eliprodil for D3A receptor; 50mM TrisHCl, pH7.7 for 5-HT2Receptor).
[3H]SCH 23390 (specific activity 71.1 Ci/mmol; NEN) was determined with D1Receptor-bound reference, the final incubation volume determined was 0.5mL, with a composition of 0.25mL of membrane suspension (2mg tissue/sample), 0.25mL [3H ]]Ligand (0.4nM) and 10. mu.L of displacer or solvent. Non-specific binding was obtained in the presence of 10 μ M (-) cis-flupentixol.
[3H]Determination of the specific activity of spiperone (16.5 Ci/mmol; NEN) and D2A receptor-bound reference, the final incubation volume measured was 1mL, and the composition was 0.5mL of the membrane suspension (1mg tissue/sample), 0.5mL3H]Ligand (0.2nM) and 20. mu.L of displacer or solvent. Non-specific binding was obtained in the presence of 100. mu.M (-) sulpiride.
[3H]-7-OH-DPAT (specific activity 159 Ci/mmol; Amer sham) is the determination with D3Receptor knotIn combination with the reference, the final incubation volume determined was 1mL, and it consisted of 0.5mL of a membrane suspension (rat cloned dopamine receptor D3(SignalScreen) in Sf9 cells of 10g protein/sample), 0.5mL [2 ]3H]Ligand (0.7nM) and 20. mu.L of displacer or solvent. Non-specific binding was obtained in the presence of 1 μ M dopamine.
[3H]Ketanserin (specific activity 63.3 Ci/mmol; Amer sham) was assayed against 5-HT2A receptor-bound reference, the final incubation volume measured was 1mL, and the composition was 0.5mL of the membrane suspension (5mg tissue/sample), 0.5mL3H]Ligand (0.7nM) and 20. mu.L of displacer or solvent. Non-specific binding was obtained in the presence of 1. mu.M methisergide.
Under vacuum through GF/B (for D)1、D2And 5-HT2Receptors) or GF/C (for D)3Receptor) Filter Rapid filtration stop incubation (D)1、D2And 5-HT2Acceptor was 15min 37 ℃; d3The receptor was 25 ℃ for 60 minutes, then washed (4X 3 times) with 12mL of ice-cold buffer (50mM Tris HCl, pH7.7) using a Brandel M-48R cell harvester. Radioactivity trapped on the filters was counted in 4mL Ultima Gold MV (Packard) in a LKB1214r ack β liquid scintillation spectrometer with a counting efficiency of 50%.

Claims (45)

1. Aryl piperazine derivatives represented by formula I
Figure A2006800017270002C1
An enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt thereof, or an N-oxide thereof, wherein,
R1、R2and R3Independently of one another, represents hydrogen, alkyl, cycloalkyl-alkylAlkenyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro, cyano and/or carboxy;
Figure A2006800017270002C2
represents an optional double bond;
if it is not
Figure A2006800017270002C3
Represents a single bond, then
A represents CH or N;
if it is not
Figure A2006800017270002C4
Represents a double bond, then
A represents C;
-B-may be absent or present:
-B-is absent; and is
Z represents CH or N; or
- -B- -is present and represents a methylene bridge (- -CH)2-), a vinyl bridge (-CH-), or a bridge-NH-, connected as shown; and is
Z represents C (carbon);
w represents CH, N or CR4Wherein R is4Represents hydrogen, alkyl, cycloalkyl-alkyl, alkenyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro or cyano;
m and n are independently of each other 0, 1 or 2;
x may be absent or present:
x is present and represents O, S, NR', CO, SO2、CH2、CH2-O、O-CH2、CH2-S、S-CH2、CH2-NR’、CH2-CO、CH2-SO2、NR’-CO、CO-NR’、NR’-SO2、SO2-NR’、CH2-CH2、O-CO、CO-O、O-CH=CH、S-CH=CH、NR’-CH=CH、CO-CH=CH、SO2-CH=CH、CH2-O-CH=CH、CH2-S-CH=CH、CH2-NR’-CH=CH、CH2-CO-CH=CH、CONHCH2CH2Or CH2-SO2-CH ═ CH, where R' represents hydrogen or alkyl;
y represents phenyl or an aromatic monocyclic or polycyclic heterocyclic group, which phenyl or heterocyclic group may be optionally substituted one or more times by a substituent selected from the group consisting of: alkyl, cycloalkyl-alkyl, alkenyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano; or
Y represents a hydrogenated heterocyclic group which may be optionally substituted one or more times with a substituent selected from the group consisting of: alkyl, cycloalkyl-alkyl, alkenyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano; or
Y represents a group of formula III
Figure A2006800017270003C1
Wherein
R7Represents hydrogen, alkyl, alkoxy, halo or haloalkyl; or
X is absent; and is
Y represents a diazo heterocyclic group of formula II
Figure A2006800017270004C1
Wherein,
o is 1, 2 or 3;
d represents alkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano; and is
E represents alkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano; or
D and E together with the diazoheterocyclic group form a fused ring system, which may be optionally substituted one or more times by substituents selected from the group consisting of: alkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano;
or Y represents a group of formula IV
Figure A2006800017270004C2
Wherein A' represents CH or N; and is
R8Represents hydrogen, alkyl, alkoxy, halo or haloalkyl.
2. The aryl piperazine derivative of claim 1, wherein
Figure A2006800017270004C3
Represents a single bond, and
a represents CH or N.
3. The aryl piperazine derivative of claim 1, wherein
Figure A2006800017270004C4
Represents a double bond, and
a represents C (carbon).
4. The aryl piperazine derivative of any one of claims 1-3, wherein
W represents CH, N or CR4Wherein R is4Represents hydrogen, alkyl, cycloalkyl-alkyl, alkenyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro or cyano.
5. The aryl piperazine derivative of any one of claims 1-4, wherein
- -B- -is absent, and
z represents CH or N.
6. The aryl piperazine derivative of any one of claims 1-5, wherein
- -B- -is present and represents a methylene bridge (- -CH)2-), a vinyl bridge (-CH-), or a bridge-NH-, connected as shown; and is
Z represents C (carbon).
7. The aryl piperazine derivative of claim 6, wherein
- -B- -is present and represents a methylene bridge (- -CH)2-), a vinyl bridge (-CH-), or a bridge-NH-, connected as shown; and is
Z represents C (carbon); and is
W represents CR4Wherein R is4Represents hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, nitro or cyano.
8. The aryl piperazine derivative of any one of claims 1-7, wherein
m and n are independently of each other 0, 1 or 2.
9. The aryl piperazine derivative of claim 8, wherein
m is 1 or 2; and is
n is 0 or 2.
10. The aryl piperazine derivative of any one of claims 1-9, wherein
R1、R2And R3Independently of one another represent hydrogen,Alkyl, cycloalkyl-alkyl, alkenyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro, cyano and/or carboxy.
11. The aryl piperazine derivative of claim 10, wherein
R1Represents alkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro, cyano or carboxy; and is
R2And R3Represents hydrogen.
12. The aryl piperazine derivative of claim 10, wherein
R2Represents alkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro or cyano; and is
R1And R3Represents hydrogen.
13. The aryl piperazine derivative of any one of claims 1-12, wherein
X is present and represents O, S, NR', CO, SO2、CH2、CH2-O、O-CH2、CH2-S、S-CH2、CH2-NR’、CH2-CO、CH2-SO2、NR’-CO、CO-NR’、CH2-CH2、O-CO、CO-O、O-CH=CH、S-CH=CH、NR’-CH=CH、CO-CH=CH、SO2-CH=CH、CH2-O-CH=CH、CH2-S-CH=CH、CH2-NR’-CH=CH、CH2-CO-CH=CH、CONHCH2CH2Or CH2-SO2-CH ═ CH, where R' represents hydrogen or alkyl.
14. The aryl piperazine derivative of claim 13Wherein X represents O, CH2-O、O-CH2、CH2-S、S-CH2、CH2-NR’、CH2-CO、CH2-SO2、NR’-CO、CO-NR’、NR’-SO2、SO2-NR', O-CO or CH2-O-CH ═ CH; wherein R' represents hydrogen or alkyl.
15. Arylpiperazine derivative according to claim 14, wherein X represents O, CH2-O、NR’-CO、CO-NR’、NR’-SO2Or O-CO; wherein R' represents hydrogen or alkyl.
16. The aryl piperazine derivative of any one of claims 13-15, wherein
Y represents phenyl or an aromatic monocyclic or polycyclic heterocyclic group, which phenyl or heterocyclic group may be optionally substituted one or more times by a substituent selected from the group consisting of: alkyl, cycloalkyl-alkyl, alkenyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano; or
Y represents a hydrogenated heterocyclic group which may be optionally substituted one or more times with a substituent selected from the group consisting of: alkyl, cycloalkyl-alkyl, alkenyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano.
17. The aryl piperazine derivative of claim 16, wherein Y represents phenyl, which phenyl may be optionally substituted one or more times with a substituent selected from the group consisting of: alkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano.
18. An arylpiperazine derivative according to any one of claims 13 to 15, wherein Y represents an aromatic monocyclic heterocyclic group selected from the group consisting of furyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, pyridyl, pyridazinyl and pyrimidinyl, which aromatic monocyclic heterocyclic group may be optionally substituted one or more times with a substituent selected from the group consisting of: alkyl, cycloalkyl-alkyl, alkenyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano.
19. The aryl piperazine derivative of claim 18, wherein Y represents furyl, thienyl or pyridyl, and the aromatic monocyclic heterocyclic group may be optionally substituted one or two times with a substituent selected from the group consisting of: alkyl, alkoxy, chloro, trifluoromethyl and trifluoromethoxy.
20. An arylpiperazine derivative according to any one of claims 13 to 15, wherein Y represents an aromatic bicyclic heterocyclic group selected from indolyl, isoindolyl, benzo [ b ] furanyl, benzo [ b ] thienyl, benzimidazolyl, benzothiazolyl, quinolinyl and isoquinolinyl, which aromatic bicyclic heterocyclic group may be optionally substituted one or two times by a substituent selected from the group consisting of: alkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano.
21. An arylpiperazine derivative according to claim 20, wherein Y represents indolyl, in particular indol-2-yl or indol-3-yl; benzo [ b ] furanyl, especially benzo [ b ] furan-2-yl or benzo [ b ] furan-3-yl; benzo [ b ] thiophenyl, especially benzo [ b ] thiophen-2-yl or benzo [ b ] thiophen-3-yl; quinolinyl, in particular quinolin-2-yl, quinolin-3-yl or quinolin-4-yl; or isoquinolinyl, especially isoquinolin-1-yl, isoquinolin-3-yl or isoquinolin-4-yl; the aromatic bicyclic heterocyclic group may be optionally substituted one or two times with a substituent selected from the group consisting of: alkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano.
22. An arylpiperazine derivative according to claim 21, wherein Y represents indolyl, in particular indol-2-yl or indol-3-yl; benzo [ b ] furanyl, especially benzo [ b ] furan-2-yl or benzo [ b ] furan-3-yl; quinolinyl, in particular quinolin-2-yl, quinolin-3-yl or quinolin-4-yl; or isoquinolinyl, especially isoquinolin-1-yl, isoquinolin-3-yl or isoquinolin-4-yl; the benzo [ b ] furanyl or isoquinolinyl group may optionally be substituted once or twice with a substituent selected from: alkyl, hydroxy, alkoxy, chloro, trifluoromethyl, trifluoromethoxy, amino, nitro and cyano.
23. The aryl piperazine derivative of claim 22, wherein Y represents indol-2-yl, benzo [ b ] furan-2-yl, or isoquinolin-3-yl; the benzo [ b ] furanyl or isoquinolinyl group may optionally be substituted once or twice with a substituent selected from: alkyl, hydroxy, alkoxy, chloro, trifluoromethyl, trifluoromethoxy, amino, nitro and cyano.
24. The aryl piperazine derivative of claim 23, wherein Y represents indolyl, benzo [ b ] furyl, or isoquinolinyl.
25. The aryl piperazine derivative of any one of claims 13 to 15, wherein Y represents a hydrogenated heterocyclic group, which may be optionally substituted one or more times with a substituent selected from the group consisting of: alkyl, cycloalkyl-alkyl, alkenyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano.
26. An arylpiperazine derivative according to claim 25, wherein Y represents a tetrahydroquinolinyl or tetrahydroisoquinolinyl group, and the heterocyclic group may be optionally substituted one or two times by a substituent selected from the group consisting of: alkyl, cycloalkyl-alkyl, alkenyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano.
27. An arylpiperazine derivative according to claim 26, wherein Y represents a tetrahydroquinolinyl or tetrahydroisoquinolinyl group.
28. The aryl piperazine derivative of claim 13, wherein
X represents O, CH2-O、NH-CO、CO-NH、NR’-SO2Or CO-O; and is
Y represents phenyl, methyl-phenyl, pyridyl, indolyl, methyl-indolyl, benzo [ b ] furanyl, tetrahydroquinolinyl, isoquinolinyl or tetrahydroisoquinolinyl.
29. The aryl piperazine derivative of claim 28, wherein
X represents O, CH2-O、NH-CO、CO-NH、NR’-SO2Or CO-O;
y represents phenyl, methyl-phenyl, pyridyl, methyl-pyridyl, indolyl, methyl-indolyl, benzo [ b ] furanyl, tetrahydroquinolinyl, isoquinolinyl or tetrahydroisoquinolinyl;
R1represents alkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro or cyano; and is
R2And R3Represents hydrogen.
30. The aryl piperazine derivative of claim 28, which is
N- [4- [4- (3-trifluoromethylphenyl) piperazin-1-yl ] butyl ] indole-2-carboxamide;
n- [2- (1H-indol-3-yl) ethyl ] -3- (4-m-tolylpiperazin-1-yl) propionamide;
n- [2- (1H-indol-3-yl) ethyl ] -3- [4- (3-methoxyphenyl) piperazin-1-yl ] propionamide;
benzo [ b ] furan-2-carboxylic acid {4- [4- (3-methoxy-phenyl) -piperazin-1-yl ] -butyl } -amide;
n- [4- [4- (3-cyanophenyl) piperazin-1-yl ] butyl ] benzo [ b ] furan-2-carboxamide;
benzo [ b ] furan-2-carboxylic acid {4- [4- (3-chloro-phenyl) -piperazin-1-yl ] -butyl } -amide;
benzo [ b ] furan-2-carboxylic acid {4- [4- (3-carboxy-phenyl) -piperazin-1-yl ] -butyl } -amide;
n- [4- [4- (m-tolyl) piperazin-1-yl ] butyl ] benzo [ b ] furan-2-carboxamide;
isoquinoline-3-carboxylic acid {4- [4- (3-cyano-phenyl) -piperazin-1-yl ] -butyl } -amide;
n- [4- [4- (3-chlorophenyl) piperazin-1-yl ] butyl ] isoquinoline-3-carboxamide;
n- [4- [4- (m-tolyl) piperazin-1-yl ] butyl ] isoquinoline-3-carboxamide;
n- [4- [4- (3-methoxyphenyl) piperazin-1-yl ] butyl ] isoquinoline-3-carboxamide;
3- [5- [4- (3-chlorophenyl) piperazin-1-yl ] pentyloxy ] isoquinoline;
3- {5- [4- (3-methoxy-phenyl) -piperazin-1-yl ] -pentyloxy } -isoquinoline;
3- [5- (4-m-tolylpiperazin-1-yl) pentyloxy ] isoquinoline;
3- {5- [4- (3-cyano-phenyl) -piperazin-1-yl ] -pentyloxy } -isoquinoline;
n- [4- (1, 2, 3, 4-tetrahydro-5-methoxy- β -carbolin-2-yl) butyl ] isoquinoline-3-carboxamide;
n- [4- (3, 4-dihydro-6-methoxypyrazino [1, 2-a ] indol-2 (1H) -yl) butyl ] isoquinoline-3-carboxamide;
n- [4- [4- (pyridin-2-yl) piperazin-1-yl ] butyl ] isoquinoline-3-carboxamide;
1, 2, 3, 4-tetrahydro-quinoline-2-carboxylic acid [4- (4-phenyl-piperazin-1-yl) -butyl ] -amide;
(S) - (-) -N- [4- [4- (m-tolyl) piperazin-1-yl ] butyl ] -1, 2, 3, 4-tetrahydroisoquinoline-2-carboxamide;
(R) - (+) -N- [4- [4- (m-tolyl) piperazin-1-yl ] butyl ] -1, 2, 3, 4-tetrahydroisoquinoline-2-carboxamide;
1H-indole-2-carboxylic acid {4- [4- (2, 4-dichloro-phenyl) -piperazin-1-yl ] -butyl } -amide;
5-chloro-1H-indole-2-carboxylic acid {4- [4- (2, 4-dichloro-phenyl) -piperazin-1-yl ] -butyl } -amide;
isoquinoline-3-carboxylic acid {4- [4- (2, 3-dichloro-phenyl) -piperazin-1-yl ] -butyl } -amide;
3- {4- [4- (2, 3-dichloro-phenyl) -piperazin-1-yl ] -butoxy } -isoquinoline;
3- {5- [4- (2, 3-dichloro-phenyl) -piperazin-1-yl ] -pentyloxy } -isoquinoline;
4- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] butyl 1H-indole-2-carboxylate;
n- (4- (4- (phenylpiperazin-1-yl) butyl) benzo [ b ] furan-2-carboxamide;
benzo [ b ] furan-2-carboxylic acid {4- [4- (2, 3-dimethyl-phenyl) -piperazin-1-yl ] -butyl } -amide;
n- (4- (4- (3-methoxyphenyl) piperazin-1-yl) butyl) benzo [ b ] furan-2-carboxamide;
n- (4- (4- (6-methylpyridin-2-yl) piperazin-1-yl) butyl) isoquinoline-3-carboxamide;
n- (4- (4-phenylpiperazin-1-yl) butyl) isoquinoline-3-carboxamide;
n- (4- (4- (6-methylpyridin-2-yl) piperazin-1-yl) butyl) benzo [ b ] furan-2-carboxamide;
n- (4- (4-phenylpiperazin-1-yl) butyl) quinoline-2-carboxamide;
n- (4- (4-m-tolylpiperazin-1-yl) butyl) quinoline-2-carboxamide;
n- (4- (4- (3-methoxyphenyl) piperazin-1-yl) butyl) -1-methyl-1H-indole-2-carboxamide;
n- (4- (4- (3-methoxyphenyl) piperazin-1-yl) butyl) -1H-indole-3-carboxamide;
(S) -1, 2, 3, 4-tetrahydro-N- (4- (4-phenylpiperazin-1-yl) butyl) quinoline-2-carboxamide;
n- (4- (4-m-tolylpiperazin-1-yl) butyl) pyridinecarboxamide;
n- (4- (4- (quinolin-3-yl) piperazin-1-yl) butyl) isoquinoline-3-carboxamide;
n- (4- (4- (3-methoxyphenyl) piperazin-1-yl) butyl) -6-methylpyridine-2-carboxamide;
n- (4- (4- (3-methoxyphenyl) piperazin-1-yl) butyl) quinoline-3-carboxamide;
n- (4- (4- (pyridin-2-yl) piperazin-1-yl) butyl) quinoline-3-carboxamide;
n- (4- (4-phenylpiperazin-1-yl) butyl) pyridinecarboxamide;
n- (4- (4- (3-methoxyphenyl) piperazin-1-yl) butyl) pyridinecarboxamide;
n- (4- (4- (3-methoxyphenyl) piperazin-1-yl) butyl) benzamide;
n- (4- (4-m-tolylpiperazin-1-yl) butyl) benzamide;
n- (4- (4-phenylpiperazin-1-yl) butyl) nicotinamide;
n- (4- (4- (6-methylpyridin-2-yl) piperazin-1-yl) butyl) benzamide;
n- (4- (4- (6-methoxypyridin-2-yl) piperazin-1-yl) butyl) benzamide;
n- (4- (4- (6-methoxypyridin-2-yl) piperazin-1-yl) butyl) pyridinecarboxamide; or
N- (4- (4- (6-methylpyridin-2-yl) piperazin-1-yl) butyl) pyridinecarboxamide;
or a pharmaceutically acceptable salt thereof.
31. The aryl piperazine derivative of any one of claims 13-15, wherein
Y represents a group of formula III
Figure A2006800017270012C1
Wherein
R7Represents hydrogen, alkyl, alkoxy, halo or haloalkyl.
32. The aryl piperazine derivative of claim 31, which is
7- [4- [4- (2, 3-dichloro-phenyl) -piperazin-1-yl ] -butoxy ] -pyrrolo [1, 2-a ] quinoxalin-4 (5H) -one;
7- (5- (4-phenylpiperazin-1-yl) pentyloxy) pyrrolo [1, 2-a ] quinoxalin-4 (5H) -one; or
7- (4- (4-phenylpiperazin-1-yl) butoxy) pyrrolo [1, 2-a ] quinoxalin-4 (5H) -one;
or a pharmaceutically acceptable salt thereof.
33. The aryl piperazine derivative of any one of claims 1-12, wherein
X is absent; and is
Y represents a diazo heterocyclic group of formula II
Figure A2006800017270012C2
Wherein,
o is 1, 2 or 3;
d represents alkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano; and is
E represents alkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano; or
D and E together with the diazoheterocyclic group form a fused ring system, which may be optionally substituted one or more times by substituents selected from the group consisting of: alkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and cyano.
34. The aryl piperazine derivative of claim 33, wherein
Y represents a bicyclic heterocyclic group (i.e. a fused ring system) selected from the following groups:
wherein R is5And R6Independently of one another, represents hydrogen, alkyl, cycloalkyl-alkyl, hydroxy, alkoxy,Cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and/or cyano.
35. The aryl piperazine derivative of claim 34, wherein
Y represents a bicyclic heterocyclic group selected from
Figure A2006800017270014C1
Wherein R is5And R6Independently of one another, represent hydrogen, alkyl, cycloalkyl-alkyl, hydroxyl, alkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, amino, nitro and/or cyano.
36. The aryl piperazine derivative of claim 35, wherein
Y represents
Figure A2006800017270014C2
Wherein
R5Represents hydrogen, alkyl, halo, trifluoromethyl or trifluoromethoxy.
37. The aryl piperazine derivative of claim 36, which is
2- {4- [4- (3-cyano-phenyl) -piperazin-1-yl ] -butyl } -3, 4-dihydro-2H-pyrazino [1, 2-a ] indol-1-one;
2- [4- [4- (3-chlorophenyl) piperazin-1-yl ] butyl ] -3, 4-dihydropyrazino [1, 2-a ] indol-1 (2H) -one;
2- {4- [4- (3-methoxy-phenyl) -piperazin-1-yl ] -butyl } -3, 4-dihydro-2H-pyrazino [1, 2-a ] indol-1-one;
2- [4- (4-m-tolyl) piperazin-1-yl ] butyl ] -3, 4-dihydropyrazino [1, 2-a ] indol-1 (2H) -one;
3, 4-dihydro-2- [4- (3, 4-dihydro-6-methoxypyrazino [1, 2-a ] indol-2 (1H) -yl) butyl ] pyrazino [1, 2-a ] indol-1 (2H) -one;
2- {4- [4- (2-methoxy-phenyl) -piperazin-1-yl ] -butyl } -3, 4-dihydro-2H-pyrazino [1, 2-a ] indol-1-one; or
2- {4- [4- (2, 3-dichloro-phenyl) -piperazin-1-yl ] -butyl } -3, 4-dihydro-2H-pyrazino [1, 2-a ] indol-1-one;
or a pharmaceutically acceptable salt thereof.
38. The aryl piperazine derivative of any one of claims 1-12, wherein
X is absent;
y represents a radical of formula IV
Wherein A' represents CH or N; and is
R8Represents hydrogen, alkyl, alkoxy, halo or haloalkyl.
39. The aryl piperazine derivative of claim 38, which is
1, 6-bis (4- (3-chlorophenyl) piperazin-1-yl) hexane;
1, 6-bis (4- (3-methoxyphenyl) piperazin-1-yl) hexane;
1, 6-bis (4-phenylpiperazin-1-yl) hexane;
1- (3-chlorophenyl) -4- (6- (4- (3-methoxyphenyl) piperazin-1-yl) hexyl) piperazine;
1-phenyl-4- (6- (4- (pyridin-2-yl) piperazin-1-yl) hexyl) piperazine;
1- (6-methylpyridin-2-yl) -4- (6- (4-m-tolylpiperazin-1-yl) hexyl) piperazine;
1- (6-methylpyridin-2-yl) -4- (6- (4-phenylpiperazin-1-yl) hexyl) piperazine;
1-phenyl-4- (6- (4-m-tolylpiperazin-1-yl) hexyl) piperazine;
4- (4- (6- (4-phenylpiperazin-1-yl) hexyl) piperazin-1-yl) quinoline;
1, 6-bis (4- (pyridin-2-yl) piperazin-1-yl) hexane;
4- (4- (6- (4-m-tolylpiperazin-1-yl) hexyl) piperazin-1-yl) quinoline;
1, 6-bis (4-m-tolylpiperazin-1-yl) hexane;
1- (pyridin-2-yl) -4- (6- (4-m-tolylpiperazin-1-yl) hexyl) piperazine; or
1- (3-methoxyphenyl) -4- (6- (4-m-tolylpiperazin-1-yl) hexyl) piperazine;
or a pharmaceutically acceptable salt thereof.
40. A pharmaceutical composition comprising a therapeutically effective amount of an arylpiperazine derivative according to any one of claims 1 to 39, or a pharmaceutically acceptable addition salt or prodrug thereof, and at least one pharmaceutically acceptable carrier or diluent.
41. Use of the arylpiperazine derivative of any one of claims 1-39, or a pharmaceutically acceptable salt or prodrug thereof, for the preparation of a pharmaceutical composition.
42. Use of an arylpiperazine derivative according to any one of claims 1-39, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment, prevention or alleviation of a disease or a disorder or a condition of a mammal, including a human, which disease, disorder or condition is responsive to modulation of dopamine and 5-hydroxytryptamine receptors.
43. The use according to claim 42, wherein the disease or disorder or condition is a neurological or psychiatric disorder, in particular psychosis, schizophrenia, depression, Parkinson's disease, Huntington's disease, dyskinesias, dystonia, anxiety, akinesia, obsessive-compulsive disorders, mania, senile disorders, dementia, sexual dysfunction, musculo-skeletal pain symptoms, pain associated with fibromyalgia, sleep disorders, substance and drug addiction, withdrawal symptoms of cocaine abuse or addiction.
44. The use according to claim 43, wherein the disease or disorder or condition is a neurological or psychiatric disorder, in particular a psychosis, preferably schizophrenia.
45. Methods of diagnosing, treating, preventing or ameliorating a disease or disorder or condition in a living animal body, including a human, which disorder, disease or condition is responsive to dopamine and 5-hydroxytryptamine receptors, particularly D3、D2-sample and 5-HT2Receptor subtype, preferably dopamine D3Receptor subtype and/or D3/5-HT1AOr D3/5-HT2AModulation of receptor subtype, which method comprises the step of administering to a living animal body in need thereof a therapeutically effective amount of an arylpiperazine derivative, pharmaceutically acceptable salt thereof or prodrug thereof according to any one of claims 1-39.
CNA2006800017275A 2005-01-03 2006-01-02 Aryl piperazine derivatives for the treatment of neuropsychiatric disorders Pending CN101137645A (en)

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CN105339369A (en) * 2013-04-23 2016-02-17 埃斯蒂维实验室股份有限公司 Pyrazino[1,2-a]indole compounds, their preparation and use in medicaments
CN106187873A (en) * 2016-07-25 2016-12-07 宜春学院 A kind of aryl amine alkyl oxygen compounds and preparation method thereof
CN114560862A (en) * 2022-03-08 2022-05-31 山东龙辰药业有限公司 Synthesis method of pyrrolo [1,2-A ] quinoxaline-4 (5H) -ketone and derivative thereof

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104755083A (en) * 2012-10-11 2015-07-01 南方研究所 Urea and amide derivatives of aminoalkylpiperazines and use thereof
US9598387B2 (en) 2012-10-11 2017-03-21 Southern Research Institute Urea and amide derivatives of aminoalkylpiperazines and use thereof
CN104755083B (en) * 2012-10-11 2018-04-10 南方研究所 Urea and amide derivatives of aminoalkyl piperazine and application thereof
CN105339369A (en) * 2013-04-23 2016-02-17 埃斯蒂维实验室股份有限公司 Pyrazino[1,2-a]indole compounds, their preparation and use in medicaments
CN105339369B (en) * 2013-04-23 2017-12-22 埃斯蒂维实验室股份有限公司 A kind of simultaneously [1,2 a] benzazolyl compounds and preparation method thereof and the application in medicine of pyrazine
CN106187873A (en) * 2016-07-25 2016-12-07 宜春学院 A kind of aryl amine alkyl oxygen compounds and preparation method thereof
CN106187873B (en) * 2016-07-25 2019-11-05 宜春学院 A kind of aryl amine alkyl oxygen class compound and preparation method thereof
CN114560862A (en) * 2022-03-08 2022-05-31 山东龙辰药业有限公司 Synthesis method of pyrrolo [1,2-A ] quinoxaline-4 (5H) -ketone and derivative thereof

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