US 5,681,954 A · Piperazine derivatives

Abstract

A compound represented by formula (I): ##STR1## wherein Q represents an aryl group, a heterocyclic group, a diarylmethyl group, an aralkyl group composed of an aryl group and an alkylene group, an alkyl group or a cycloalkyl group, in which the aryl group, heterocyclic group, and the aryl moiety of the diarylmethyl group and aralkyl group may be substituted with one or more substituents; R represents a bicyclic, substituted, nitrogen-containing heterocyclic group or a substituted phenyl group, in which the nitrogen-containing heterocyclic group is composed of a 5-membered, substituted, aromatic or saturated ring containing one or two nitrogen atoms and a 6-membered ring; and Z represents an alkylene group, an alkenylene group, an alkylene group, a carbonyl group, an alkylene group containing a carbonyl group or an oxalyl group, or a salt thereof. The compound has calmodulin inhibitory activity and is useful as a treating agent for diseases in the circulatory organs or in the cerebral region which are caused by excessive activation of calmodulin.

A compound represented by formula (I):

##STR136## wherein Q is a phenyl group substituted with one or more substituents selected from the group consisting of:
an alkyl group having from 1 to 6 carbon atoms,
an alkoxyl group having from 1 to 6 carbon atoms,
a trifluoromethyl group,
a 2,2,2-trifluoroethyl group,
a trifluoromethoxyl group,
a 2,2,2-trifluoroethoxyl group,
an alkylthio group having from 1 to 6 carbon atoms,
an alkylsulfinyl group having from 1 to 6 carbon atoms,
an alkylsulfonyl group having from 1 to 6 carbon atoms,
an alkanoyl group composed of an alkyl group having from 1 to 6 carbon atoms and a carbonyl group,
an alkanoyloxy group having from 2 to 7 carbon atoms,
an alkanoylamino group having from 2 to 7 carbon atoms,
an amino group,
a monoalkylamino group having from 1 to 6 carbon atoms in the alkyl group thereof,
a dialkylamino group having from 1 to 6 carbon atoms in each alkyl group thereof,
a hydroxyl group,
a halogen atom,
a perfluoroalkyl group having from 2 to 6 carbon atoms,
a cyano group,
a nitro group,
a carboxyl group,
an alkoxycarbonyl group composed of an alkoxyl group having from 1 to 6 carbon atoms and a carbonyl group,
a tetrazolyl group,
a sulfamoyl group,
a methylenedioxy group,
an ethylenedioxy group,
a morpholinosulfonyl group,
a piperazinosulfonyl group,
a 4-alkylpiperazinosulfonyl group having from 1 to 6 carbon atoms,
a 4-dialkylaminopiperidino group having from 1 to 6 carbon atoms in each alkyl group thereof,
a 4-monoalkylaminopiperidino group having from 1 to 6 carbon atoms in the alkyl group thereof, and
a 4-aminopiperidino group,
R is ##STR137## wherein G is:
an alkyl group having from 1 to 6 carbon atoms,
a substituted or unsubstituted phenyl group,
a benzoyl group with the phenyl group thereof substituted or unsubstituted,
a benzylcarbonyl group with the phenyl group thereof substituted or unsubstituted,
a benzoylmethyl group with the phenyl group thereof substituted or unsubstituted,
an .alpha.-hydroxybenzyl group with the phenyl group thereof substituted or unsubstituted,
a substituted or unsubstituted 5-membered aromatic heterocyclic group containing a nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom, wherein when a nitrogen atom is present as the hetero atom, this has a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, or is the site of bonding to the bicyclic nitrogen-containing heterocyclic group or the phenyl group,
a substituted or unsubstituted 5-membered aromatic heterocyclic group containing one nitrogen atom and, a nitrogen atom, an oxygen atom or a sulfur atom as the second hetero atom, wherein when a nitrogen atom is present as the second hetero atom, this has a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, or is the site of bonding to the bicyclic nitrogen-containing heterocyclic group or the phenyl group,
a substituted or unsubstituted 5-membered aromatic heterocyclic group containing two nitrogen atoms and, a nitrogen atom, an oxygen atom or a sulfur atom as the third hetero atom, wherein when a nitrogen atom is present as the third hetero atom, this has a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, or is the site of bonding to the bicyclic nitrogen-containing heterocyclic group or the phenyl group,
a substituted or unsubstituted 6-membered aromatic heterocyclic group containing one or two nitrogen atoms,
a heterocyclic group substituted-alkyl group composed of a substituted or unsubstituted 5-membered aromatic heterocyclic group containing a nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom, wherein when a nitrogen atom is present as the hetero atom, this has a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, and an alkylene group of from 1 to 3 carbon atoms,
a heterocyclic group substituted-alkyl group composed of a substituted or unsubstituted 5-membered aromatic heterocyclic group containing one nitrogen atom and, a nitrogen atom, an oxygen atom or a sulfur atom as the second hetero atom, wherein when a nitrogen atom is present as the second hetero atom, this has a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms or is the site of bonding to the alkylene group, and an alkylene group of from 1 to 3 carbon atoms,
a heterocyclic group substituted-alkyl group composed of a substituted or unsubstituted 5-membered aromatic heterocyclic group containing two nitrogen atoms and, a nitrogen atom, an oxygen atom or a sulfur atom as the third hetero atom, wherein when a nitrogen atom is present as the third hetero atom, this has a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms or is the site of bonding to the alkylene group, and an alkylene group of from 1 to 3 carbon atoms,
a heterocyclic group substituted-alkyl group composed of a substituted or unsubstituted 6-membered aromatic heterocyclic group containing one or two nitrogen atoms and an alkylene group of from 1 to 3 carbon atoms,
a phenylhydroxyalkyl group composed of an alkylene group having one hydroxyl group and 2 to 3 carbon atoms, and a substituted or unsubstituted phenyl group,
a 2-phenylethenyl group wherein the phenyl group may be substituted,
a tetrazolyl group,
a morpholino group,
an alkanoylamino group having from 2 to 7 carbon atoms,
a tetrazolylalkyl group composed of a tetrazolyl group and an alkylene group having from 1 to 3 carbon atoms wherein the alkylene group is bonded to the carbon atom or nitrogen atom of the tetrazolyl group,
a morpholinoalkyl group composed of a morpholino group and an alkylene group having from 1 to 3 carbon atoms,
a 4-alkoxycarbonylcyclohexyl group having from 1 to 6 carbon atoms in the alkoxyl group thereof,
an alkoxycarbonyl group having from 1 to 6 carbon atoms in the alkoxyl group thereof,
an alkoxycarbonylalkyl group composed of an alkoxyl group having from 1 to 6 carbon atoms and an alkylene group having from 1 to 3 carbon atoms,
a 1-alkylindol-2-yl group having from 1 to 6 carbon atoms in the alkyl group thereof wherein the indole group may further be substituted,
a substituted or unsubstituted pyrrolidon-1-yl group,
a 2-guanidinothiazolyl group,
a (2-guanidinothiazolyl) alkyl group composed of a 2-guanidinothiazolyl group and an alkylene group having from 1 to 3 carbon atoms,
a substituted or unsubstituted 1,4-dihydropyridyl group,
a (4-alkylpiperazino)alkyl group composed of a 4-alkyl-piperazine having an alkyl group of from 1 to 6 carbon atoms and an alkylene group of from 1 to 6 carbon atoms,
a 4-(morpholinosulfonyl)phenyl!alkyl group composed of a 4-(morpholinosulfonyl)phenyl group and an alkylene group of from 1 to 6 carbon atoms,
a 4-(piperazinosulfonyl)phenyl!alkyl group composed of a 4-(piperazinosulfonyl)phenyl group and an alkylene group of from 1 to 6 carbon atoms,
a 4-(4-alkylpiperazinosulfonyl)phenyl!alkyl group composed of a 4-(4-alkylpiperazinosulfonyl)phenyl group wherein the alkyl group on the piperazino group is from 1 to 6 carbon atoms, and an alkylene group of from 1 to 6 carbon atoms,
an alkoxycarbonylalkyl group composed of an alkoxyl group of from 1 to 6 carbon atoms and a carbonyl group, and an alkylene group of from 1 to 6 carbon atoms,
a carboxyalkyl group composed of a carboxyl group and an alkylene group of from 1 to 6 carbon atoms,
a 4-(4-dialkylaminopiperidino)phenyl!alkyl group composed of a phenyl group having a 4-dialkylaminopiperidino group at the 4-position, wherein each alkyl group of the dialkylamino group has from 1 to 6 carbon atoms independently, and an alkylene group of from 1 to 6 carbon atoms,
a 4-(4-monoalkylaminopiperidino)phenyl!alkyl group composed of a phenyl group having a 4-monoalkylaminopiperidino group at the 4-position, wherein the alkyl group of the monoalkylamino group has from 1 to 6 carbon atoms, and an alkylene group of from 1 to 6 carbon atoms,
a 4-(4-aminopiperidino)phenyl!alkyl group composed of a phenyl group having a 4-aminopiperidino group at the 4-position and an alkylene group of from 1 to 6 carbon atoms,
a (4-dialkylaminopiperidino)alkyl group composed of a 4-dialkylaminopiperidino group, wherein each alkyl group of the dialkylamino group has from 1 to 6 carbon atoms independently, and an alkylene group of from 1 to 6 carbon atoms,
a (4-alkylaminopiperidino)alkyl group composed of a 4-alkylaminopiperidino group, wherein the alkyl group of the alkylamino group has from 1 to 6 carbon atoms, and an alkylene group of from 1 to 6 carbon atoms,
a (4-aminopiperidino)alkyl group composed of a 4-aminopiperidino group and an alkylene group of from 1 to 6 carbon atoms, a phenylalkyl group composed of a substituted or unsubstituted phenyl group and an alkylene group of from 1 to 6 carbon atoms or
a hydrogen atom,
wherein in case G has a substituent(s), the substituent(s) is:
an alkyl group having from 1 to 6 carbon atoms,
an alkoxyl group having from 1 to 6 carbon atoms,
a trifluoromethyl group,
a 2,2,2-trifluoroethyl group,
a trifluoromethoxyl group,
a 2,2,2-trifluoroethoxyl group,
an alkylthio group having from 1 to 6 carbon atoms,
an alkylsulfinyl group having from 1 to 6 carbon atoms,
an alkylsulfonyl group having from 1 to 6 carbon atoms,
an alkanoyl group composed of an alkyl group having from 1 to 6 carbon atoms and a carbonyl group,
an alkanoyloxy group having from 2 to 7 carbon atoms,
an alkanoylamino group having from 2 to 7 carbon atoms,
an amino group,
a monoalkylamino group having from 1 to 6 carbon atoms in the alkyl group thereof,
a dialkylamino group having from 1 to 6 carbon atoms in each alkyl group thereof,
a hydroxyl group,
a halogen atom,
a perfluoroalkyl group having from 2 to 6 carbon atoms,
a cyano group,
a nitro group,
a carboxyl group,
an alkoxycarbonyl group composed of an alkoxyl group having from 1 to 6 carbon atoms and a carbonyl group,
a tetrazolyl group,
a sulfamoyl group,
a methylenedioxy group,
an ethylenedioxy group,
a morpholinosulfonyl group,
a piperazinosulfonyl group,
a 4-alkylpiperazinosulfonyl group having from 1 to 6 carbon atoms,
a 4-dialkylaminopiperidino group having from 1 to 6 carbon atoms in each alkyl group thereof,
a 4-monoalkylaminopiperidino group having from 1 to 6 carbon atoms in the alkyl group thereof, or
a 4-aminopiperidino group;
R.sup.1 and R.sup.2 independently is:
an alkyl group having from 1 to 6 carbon atoms,
an alkoxyl group having from 1 to 6 carbon atoms,
a trifluoromethyl group,
a 2,2,2-trifluoroethyl group,
a trifluoromethoxyl group,
a 2,2,2-trifluoroethoxyl group,
an alkylthio group having from 1 to 6 carbon atoms,
an alkylsulfinyl group having from 1 to 6 carbon atoms,
an alkylsulfonyl group having from 1 to 6 carbon atoms,
an alkanoyl group composed of an alkyl group having from 1 to 6 carbon atoms and a carbonyl group,
an alkanoyloxy group having from 2 to 7 carbon atoms,
an alkanoylamino group having from 2 to 7 carbon atoms,
an amino group,
a monoalkylamino group having from 1 to 6 carbon atoms in the alkyl group thereof,
a dialkylamino group having from 1 to 6 carbon atoms in each alkyl group thereof,
a hydroxyl group,
a halogen atom,
a perfluoroalkyl group having from 2 to 6 carbon atoms,
a cyano group,
a nitro group,
a carboxyl group,
an alkoxycarbonyl group composed of an alkoxyl group having from 1 to 6 carbon atoms and a carbonyl group,
a tetrazolyl group,
a sulfamoyl group,
a methylenedioxy group,
an ethylenedioxy group,
a morpholinosulfonyl group,
a piperazinosulfonyl group,
a 4-alkylpiperazinosulfonyl group having from 1 to 6 carbon atoms,
a 4-dialkylaminopiperidino group having from 1 to 6 carbon atoms in each alkyl group thereof,
a 4-monoalkylaminopiperidino group having from 1 to 6 carbon atoms in the alkyl group thereof, or
a 4-aminopiperidino group;
and Z is:
an alkylene group having from 1 to 3 carbon atoms,
an alkenylene group having from 2 to 4 carbon atoms,
an alkylene group having one hydroxyl group and from 1 to 3 carbon atoms,
a carbonyl group,
an alkylene group containing a carbonyl group at one end or on the middle of the carbon chain thereof,
and an oxalyl group,
or a pharmaceutically acceptable salt thereof.

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Piperazine derivatives

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Piperazine derivatives

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Abstract

Claims14