MXPA00004398A - Piperazine-cyclodextrin complexes - Google Patents

Abstract

Piperazine-cyclodextrin complexes composed of compounds represented by general formula (I) or salts thereof and easily water-soluble cyclodextrin derivatives:(wherein Q is aryl, a heterocyclic group, diarylmethyl or aralkyl each of which may be substituted;R is a nitrogeous heterobicyclic group or phenyl which may be substituted;and Z is C1-C3 alkylene, C2-C4 alkenylene, C1-C3 monohydroxyalkylene, carbonyl, C1-C2 alkylene having one carbonylgroup at the end of the carbon chain or in the middle thereof, or oxalyl). The complexes are improved in water solubility and stability and lowered in local stimulation, and are useful as remedies for circulatory diseases and brain diseases.

Description

COMPLEXES OF PIPERAZINE-CICLODEXTRIN The present invention relates to a piperazine-cyclodextrin complex which has improved water solubility, excellent stability, and low topical stimulation and is useful as a therapeutic agent for diseases of the circulatory system and for diseases of the brain region.

TECHNICAL BACKGROUND The piperazine derivatives represented by the formula (I) described below have been known to exhibit inhibition of calmodulin and to be useful as therapeutic agents for diseases of the circulatory system and for diseases of the brain region (Japanese Patent Application Open to the public ( kokai) No. 7-97364). However, due to its low solubility in water, it is difficult to incorporate the piperazine derivatives (I) into a formulation for injection. Although a formulation for injection is prepared from the piperazine derivatives (I), when the content of the derivatives increases, the formulation tends to provide topical stimulation caused by hemolytic activity and vascular permeability attributed to the piperazine derivatives . Moreover, there has also been a problem that the formulation has relatively low stability against light and the active component thereof is adsorbed by the container, depending on the material of the container, thereby reducing efficiency. Therefore, an object of the present invention is to provide a piperazine-cyclodextrin complex that exhibits improved water solubility, excellent stability and low topical stimulation.

DESCRIPTION OF THE INVENTION In view of the foregoing, the inventors of the present invention have conducted serious investigations and have discovered a piperazine-cyclodextrin complex represented by the formula (I) described below and a water-soluble cyclodextrin derivative having improved water solubility, excellent stability and low topical stimulation and which are useful as therapeutic agents for diseases of the circulatory system and for diseases of the cerebral region. The present invention was achieved based on these findings. Accordingly, the present invention provides a piperazine-cyclodextrin complex formed from a piperazine derivative or a salt thereof and a water-soluble cyclodextrin derivative, in which the piperazine derivative is represented by the formula (I) : RZN NQ (I) in which Q represents (1) an aryl group, (2) a heterocyclic group, (3) a diarylmethyl group, (4) an aralkyl group formed from an aryl group and an alkylene group of C1-C6 , (5) a C 1 -C 8 alkyl group, or (6) a C 1 -C 8 cycloalkyl group, wherein each of the aryl group, the heterocyclic group and the aryl groups in the diarylmethyl group and the aralkyl group may have one or more substituents that are selected from the following groups: 1) a C1-C6 alkyl group, 2) a C1-C6 alkoxy group, 3) a trifluoromethyl group and a 2,2,2-trifluoroethyl group, 4) a trifluoromethoxy group and a 2,2,2-trifluoroethoxy group, 5) a C 1 -C 6 alkylthio group, 6) a C 1 -C 6 alkylsulfinyl group, 7) a C 1 -C 6 alkylsulfonyl group, 8) an alkanoyl group formed of a C 1 -C 6 alkyl group and a carbonyl group, 9) a C 2 -C 7 alkanoyloxy group, 10) a C 2 -C 7 alkanoylamino group, 11) an amino group, 12) a monoalkylamino group which has a C1-C6 alkyl group, 13) a dialkylamino group in which each of the alkyl groups is a C1-C6 alkyl group, 14) a hydroxyl group, 15) a halogen atom 16) a perfluoroalkyl group of C2-C6, 17) a cyano group, 18) a nitro group, 19) a carboxyl group, 20) an alkoxycarbonyl group formed of a C1-C6 alkoxy group and a carbonyl group, 21) a tetrazolyl group, 22) a sulfamoyl group, 23) a methylenedioxy group, an ethylenedioxy group and a propylenedioxy group, 24) a morpholinosulfonyl group, 25) a piperazinesulfonyl group, 26) a 4-alkylpiperazinesulfonyl group having a C1-C6 alkyl group, 27) a 4- (dialkylamino) piperidino group having a dialkylamino group having two C1-C6 alkyl groups which may be identical to or different from each other, 28) a 4- (monoalkylamino) piperidino group having a C1-6 alkyl group C6 and 29) a 4-aminopiperidyl group; R represents a bicyclic heterocyclic group containing nitrogen (i) or a phenyl group (ii), in which the nitrogen-containing heterocyclic group has a fused ring structure formed of a 5-membered ring and a 6-membered ring; one or two nitrogen atoms are contained in the 5-membered ring portion; the nitrogen-containing ring can be an aromatic or saturated ring; and the saturated ring may contain a ketone moiety; wherein the 5-membered ring portion of the bicyclic heterocyclic group (i) or the phenyl group (ii) is substituted with the substituent G which is selected from the group consisting of the following groups: (aa) an alkyl group of C1 -C6, (ab) a phenyl group which may have a substituent, (ac) a benzyl group which may have a substituent on the phenyl group portion, (ad) a benzoyl group which may have a substituent on the of the phenyl group, (ae) a benzylcarbonyl group which may have a substituent on the phenyl group portion, (af) a benzoylmethyl group which may have a substituent on the phenyl group portion, (ag) an a-hydroxybenzyl group which may have a substituent on the phenyl group portion, (ah) a 5-membered aromatic heterocyclic group which may have a substituent and which contains as a heteroatom a nitrogen atom, an oxygen atom or a sulfur atom; wherein when the hetero atom is a nitrogen atom, the nitrogen atom is attached to a hydrogen atom or a C 1 -C 6 alkyl group, or the nitrogen atom serves as the binding site for the heterocyclic group containing nitrogen or for the phenyl group, (ai) a 5-membered aromatic heterocyclic group which may have a substituent and which contains as a hetero atom a nitrogen atom and as a second hetero atom a nitrogen atom, an oxygen atom or a sulfur atom; wherein when the second hetero atom is a nitrogen atom, the nitrogen atom is attached to a hydrogen atom or a C1-C6 alkyl group, or the nitrogen atom serves as the binding site for the nitrogen-containing heterocyclic group or for the phenyl group, (aj) a 5-membered aromatic heterocyclic group which may have one substituent and which contains as two hetero atoms two nitrogen atoms and as a third hetero atom one nitrogen atom, one oxygen atom or one sulfur atom; wherein when the third hetero atom is a nitrogen atom, the nitrogen atom is attached to a hydrogen atom or a C1-C6 alkyl group, or the nitrogen atom serves as the binding site for the nitrogen-containing heterocyclic group or for the phenyl group, (ak) a 6-membered aromatic heterocyclic group which may have a substituent and which contains one or two nitrogen atoms, (al) an alkyl group substituted with a heterocyclic group formed of an alkylene group of C 1 - C3 and a 5-membered aromatic heterocyclic group, which may have a substituent and which contains as a heteroatom a nitrogen atom, an oxygen atom or a sulfur atom; wherein when the heteroatom is a nitrogen atom, the nitrogen atom is attached to a hydrogen atom or a C1-C6 alkyl group, (am) an alkyl group substituted with a heterocyclic group formed from an alkylene group of C1-C3 and a 5-membered aromatic heterocyclic group, which may have a substituent and which contains as a hetero atom a nitrogen atom and as a second hetero atom a nitrogen atom, an oxygen atom or a sulfur atom; wherein when the second hetero atom is a nitrogen atom, the nitrogen atom is attached to a hydrogen atom or a C 1 -C 6 alkyl group, or the nitrogen atom serves as the binding site for the alkylene group, (an ) an alkyl group substituted with a heterocyclic group consisting of a C 1 -C 3 alkylene group and a 5-membered aromatic heterocyclic group, whose 5-membered aromatic heterocyclic group can have a substituent and which contains two nitrogen atoms as heteroatoms and as a third hetero atom a nitrogen atom, an oxygen atom or a sulfur atom; wherein when the third hetero atom is a nitrogen atom, the nitrogen atom is attached to a hydrogen atom or a C1-C6 alkyl group, or the nitrogen atom serves as the binding site for the alkylene group, (ao) ) an alkyl group substituted with a heterocyclic group formed of a C 1 -C 3 alkylene group and a 6-membered aromatic heterocyclic group which may have a substituent and which contains one or two nitrogen atoms, (ap) a phenylhydroxyalkyl group formed of a C2-C3 alkylene group having a hydroxyl group and a phenyl group which may have a substituent, (aq) a 2-phenylethynyl group in which its phenyl group may have a substituent, (ar) a tetrazolyl group, ( as) a morpholino group, (at) an alkanoylamino group of C2-C7, (au) a tetrazolylalkyl group formed of a tetrazolyl group and an alkylene group of C1-C3 in which the alkylene group is attached to the carbon atom or a nitrogen atom of the tetrazolyl group, (av) a morpholinoalkyl group formed of a morpholino group and a C 1 -C 3 alkylene group, (aw) a 4-alkoxycarbonylcyclohexyl group in which its alkoxy group has from one to six carbon atoms, ( ax) an alkoxycarbonyl group in which its alkoxy group has from one to six carbon atoms, (ay) an alkoxycarbonylalkyl group formed from an alkylene group of C1-C3 and an alkoxycarbonyl group in which its alkoxy group has from one to six carbon atoms, (az) a 1-alkylpinol-2-yl group in which its alkyl group has from one to six carbon atoms and the idol group can also have a substituent, (ba) a pyrrolidone-1 group -yl, (bb) a 2-guanidinothiazolyl group, (be) a (2-guanidinothiazolyl) -alkyl group formed of a 2-guanidinothiazolyl group and an alkylene group of C1-C3, (bd) a group 1, 4- dihydropyridyl which may have a substituent, (be) a 4-alkylpiperadinoalkyl group formed from an alkylene group not of C1-C6 and of a 4-alkylpiperazino group having a C1-C6 alkyl group, (bf) a 4- (morpholinosulfonyl) phenylalkyl group formed of a 4- (morpholinosulfonyl) phenyl group and an alkylene group of C1 -C6, (bg) a 4- (piperazinesulfonyl) phenylalkyl group formed from a 4- (piperazinesulfonyl) phenyl group and from a C 1 -C 6 alkylene group, (bh) a 4- (piperazinesulfonyl) phenylalkyl group formed from an alkylene group of C1-C6 and a 4- (4-alkylpiperazinesulfonyl) phenyl group having a C1-C6 alkyl group, (bi) an alkoxycarbonylalkyl group formed from a C2-C7 alkoxycarbonyl group and an alkylene group of C1-C6 , (bj) a carboxylalkyl group formed from a carboxyl group and a C 1 -C 6 alkylene group, (bk) a [4- (4-dialkylaminopiperidino) phenyl] alkyl group formed from an alkylene group of C 1 -C 6 and a 4- (4-dialkylaminopiperidino) phenyl group in which a 4-dialkylaminopiperidino group having, in the 4-position of the piperidine, a dialkylamino group e contains two C1-C6 alkyl groups is attached to the 4- position of the phenyl group, (bl) a 4- (4-monoalkylaminophenylperidino) phenylalkyl group formed from an alkylene group of C1-C6 and a group 4- (4-monoalkylamide) piperidinyl) phenyl in which a 4-monoalkylaminopiperidino group having, in the 4- position of the piperidine, a monoalkylamino group containing a C1-C6 alkyl group is attached to the 4- position of the phenyl group, (bm) a [4- (4-aminopiperidino) phenyl] alkyl group formed of an alkylene group of C 1 -C 6 and a group 4- (4-aminopiperidino) phenyl in which a group 4 -aminopiperidino is linked to the 4- position of the phenyl group, (bn) a (4-dialkylaminopiperidino) alkyl group formed of an alkylene group of C 1 -C 6 and a 4-dialkylaminopiperidino group in which a dialkylamino group having two C1-C6 alkyl groups is attached to the 4- position of the piperidine, (bo) a (4-monoalkylaminopiperidino) alkyl group formed from an alkylene group of C1-C6 and a 4-monoalkylaminopiperidino group in which a monoalkylamino group having a C1-C6 alkyl group is attached to the 4- position of the piperidine, (bp) a (4-aminopiperidino) alkyl group formed of a 4-aminopiperidino group and an alkylene group of C1-C6 and, (bq) a hydrogen atom, in which when the substituents represented by (aa) ) up to (ap) have substituents, the substituents are one or more members which are selected from the group consisting of the following substituents: 1) a C1-C6 alkyl group, 2) a C1-C6 alkoxy group, 3) a trifluoromethyl group and a 2,2,2-trifluoroethyl group, 4) a trifluoromethoxy group and a 2,2,2-trifluoroethoxy group, 5) a C 1 -C 6 alkylthio group, 6) a C 1 -C 6 alkylsulfinyl group, ) a C1-C6 alkylsulfonyl group, 8) an alkanoyl group formed of a C1-C6 alkyl group and a carbonyl group, 9) a C2-C7 alkanoyloxy group, 10) a C2-C7 alkanoylamino group, ) an amino group, 12) a monoalkylamino group having a C 1 -C 6 alkyl group, 13) a dialkylamino group in which each of the alkyl groups is an alkyl group of C1-C6, 14) a hydroxyl group, 15) a halogen atom, 16) a C2-C6 perfluoroalkyl group, 17) a cyano group, 18) a nitro group, 19) a carboxyl group, 20) a group alkoxycarbonyl formed from a C 1 -C 6 alkoxy group and a carbonyl group, 21) a tetrazolyl group, 22) a sulfamoyl group, 23) a methylenedioxy group, an ethylenedioxy group and a propylenedioxy group, 24) a morpholinosulfonyl group, 25) a piperazinesulfonyl group, 26) a 4-alkylpiperazinesulfonyl group having a C1-C6 alkyl group, 27) a 4- (dialkylamino) piperidino group having a dialkylamino group having two C1-C6 alkyl groups which may be identical ao different from each other, 28) a 4- (monoalkylamino) piperidino group having a C 1 -C 6 alkyl group and 29) a 4-aminopiperidino group; wherein the 6-membered ring portion of the bicyclic heterocyclic group (i) or the phenyl group (ii) can have one or more groups selected from a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a trifluoromethoxy group, a 2,2,2-trifluoroethoxy group, a C1-C6 alkylthio group, a C1-C6 alkylsulfinyl group, a C1-6 alkylsulfonyl group, C6, an alkanoyl group formed from a C1-C6 alkylene group and a carbonyl group, a C2-C7 alkanoyloxy group, a C2-C7 alkanoylamino group, an amino group, a monoalkylamino group having an alkyl group of C1 -C6, a dialkylamino group having two C1-C6 alkyl groups which may be identical to or different from one another, a hydroxyl group, a halogen atom, a C2-C6 perfluoroalkyl group, a cyano group, a nitro group , a carboxyl group, an alkoxycarbonyl group formed from a C1-C6 alkoxy group and a carb group an onyl, a tetrazolyl group, a sulfamoyl group, a methylenedioxy group, an ethylendioxy group, a morpholinosulfonyl group, a piperazinesulfonyl group, a 4-alkylpiperazinesulfonyl group having a C1-C6 alkyl group, a 4-dialkylaminopiperidino group having position 4 a dialkylamino group having two C1-C6 alkyl groups which may be identical to or different from each other, a 4-monoalkylaminopiperidino group having a C1-C6 alkyl group or a 4-aminopiperidino group; and Z represents (1) a C1-C3 alkylene group, (2) a C2-C4 alkenylene group, (3) a C1-C3 alkylene group having a hydroxyl group, (4) a carbonyl portion, (5) ) a C1-C2 alkylene group containing a carbonyl portion at one end or at an intermediate position of the carbon chain, or (6) an oxalyl group. The present invention also provides an injection formulation containing the piperazine-cyclodextrin complex. The present invention further provides a therapeutic agent for diseases of the circulatory system, a therapeutic agent for diseases of the brain, and a protective agent for the brain containing the piperazine-cyclodextrin complex as an active component. The present invention also provides for the use of the piperazine-cyclodextrin complex as a pharmaceutical compound. The present invention also provides a method for the treatment of diseases of the circulatory system and diseases of the brain, characterized by the administration of the piperazine-cyclodextrin complex.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph showing the data of hemolytic activity obtained in example 2, in which ß-cyclodextrin was added in a variety of concentrations. Figure 2 is a graph showing vascular permeability (expressed by the area of exudated dye) in the case in which, in Example 3, SEB7-ß-CD was added in a variety of concentrations.

BEST WAYS TO MAKE THEINVENTION The piperazine derivative which is used in the present invention is represented by the formula (I) described above, and has a partial structure, represented by Q connecting to a nitrogen atom of the piperazine and a partial structure represented by R connecting to the other nitrogen atom by a Z-bond portion. The partial structure Q represents a substituent selected from (1) an aryl group, (2) a heterocyclic group, (3) a diarylmethyl group, (4) an aralkyl group formed of an aryl group and a C 1 -C 6 alkylene group, (5) a C 1 -C 8 alkyl group, or (6) a C 3 -C 8 cycloalkyl group. An aryl group is a substituent obtained from an aromatic compound, and typical examples include a phenyl group and a naphthyl group. Although the aromatic compounds also include heterocyclic compounds, the aryl group in the present invention refers in particular to a substituent obtained from an aromatic hydrocarbon compound. A heterocyclic group is a substituent obtained from a heterocyclic compound. Among heterocyclic compounds, nitrogen-containing heterocyclic compounds are preferred in the present invention. There are several types of nitrogen-containing heterocyclic compounds, such as aromatic, partially saturated and saturated species. Of these, aromatic heterocyclic compounds are preferred. Examples of the nitrogen-containing aromatic heterocyclic compounds include pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, indole, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, naphthyridine, pyridopyridines, carbazole, carboline, phenanthridine and acridine. . The compounds of the present invention may have a substituent obtained from these heterocyclic compounds. Among these substituents, the most preferred are a pyridyl group, a pyrimidyl group and an isoquinolyl group.

In addition to heterocyclic groups containing nitrogen, heterocyclic groups containing an oxygen atom or a sulfur atom could be used. In this case, the heterocyclic compounds can be aromatic, partially saturated or saturated. For example, thienyl, benzothienyl, furyl, furanyl, benzofuranyl or chromenyl could be used. Of these, a group such as a benzofuranyl group or a dihydrobenzofuranyl group is preferred. Even apart from these groups, a heterocyclic substituent containing a plurality of heteroatom species such as isothiazolyl, isoxazolyl or oxazinyl could also be used. The diarylmethyl group is a substituent in which two hydrogen atoms of the methyl group are substituted with two aryl groups. the aryl groups can be those as described above. The most typical diarylmethyl group is a diphenylmethyl group. The aralkyl group formed of an aryl group and a C 1 -C 6 alkylene group is a substituent in which one end of the alkylene group is attached to the aryl group described above. Typical examples include a benzyl group and a phenethyl group. The alkyl group can be a linear or branched C1-C8 alkyl group. The cycloalkyl group may have 3-8 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cyclooctyl group.

Each of the aryl groups, of the heterocyclic groups, of the diarylmethyl groups, of the C 1 -C 8 alkyl groups, of the C 3 -C 8 cycloalkyl groups and of the aralkyl groups formed of an aryl group and of a C 1 -C 6 alkylene group described above can be substituted with a variety of substituents. In particular, the aryl groups, the heterocyclic groups and the aryl groups of the arylmethyl groups may have a substituent. The substituents are selected from the following group consisting of the following substituents 1) to 29): 1) a C1-C6 alkyl group, which may be straight or branched and may be a cycloalkyl group when it has three or more carbon atoms; carbon, 2) a C 1 -C 6 alkoxyl group, which can be formed from the above alkyl group and from an oxygen atom, that is, its alkyl portion can be linear, branched or cyclic; 3) a trifluoromethyl group and a 2,2,2-trifluoroethyl group, 4) a trifluoromethoxy group and a 2,2,2-trifluoroethoxy group, 5) an alkylthio group, which can be formed from the C1-C6 alkyl group and of a sulfur atom and has an "alkyl-S-" structure, in which its alkyl portion can be linear, branched or cyclic; 6) an alkylsulfinyl group, which is a substituent obtained by oxidation of the sulfur atom of the above alkylthio group by an oxygen atom and has an "alkyl-SO-" structure; 7) an alkylsulfonyl group, which is a substituent obtained by oxidation of the sulfur atom of the above alkylthio group by two oxygen atoms and has an "alkyl-SO2-" structure; 8) an alkanoyl group, which is a substituent produced by removing a hydroxyl group from a carboxylic acid portion of an aliphatic carboxylic acid and has an "alkyl-CO-" structure; 9) an alkanoyloxy group, which is a substituent having a structure of the above alkanoyl group to which is added an oxygen atom or a structure of a carboxylic acid portion of an aliphatic carboxylic acid from which a hydrogen atom was removed, that is, whose alkanoyloxy group has an "alkyl-CO-O-" structure; 10) an alkanoylamino group, which has a structure in which one of the two hydrogen atoms of its amino group is substituted with an alkanoyl group, ie, an "alkyl-CO-NH-" structure; 11) an amino group, 12) a monoalkylamino group, which has a structure in which one of the two hydrogen atoms of its amino group is substituted with an alkyl group, and 13) a dialkylamino group, which has a structure wherein both of the two hydrogen atoms of their amino group are substituted with an alkyl group; 14) a hydroxyl group, 15) a halogen atom 16) a perfluoroalkyl group, which has a structure in which all the hydrogen atoms in its alkyl group are substituted with a fluorine atom and have a linear, branched or cyclical 17) a cyano group, 18) a nitro group, 19) a carboxyl group, 20) an alkoxycarbonyl group in which its alkyl group and its carbonyl group are linked by an oxygen atom and its alkyl portion can have a linear structure, branched or cyclic, that is, the alkoxycarbonyl group has an "alkyl-O-CO-" structure; 21) a tetrazolyl group, which is a 5-membered heterocyclic group; 22) a sulfamoyl group, 23) each of a methylenedioxy group, an ethylendioxy group and a propylenedioxy group has a structure -O- (CH2) qO- in which q represents a number between 1 and 3 inclusive and two carbon atoms which connect with the oxygen atoms are bonded adjacently, 24) a morpholinosulfonyl group, which has a structure represented by "morpholino (ie, 4-morphonyl group) -SO2-"; 25) a piperazinesulfonyl group, which has a structure represented by "(1-piperazinyl) -SO2-"; 26) a 4-alkylpiperazinesulfonyl group, which has a structure represented by "(4-alkyl-1-piperazinyl) -SO2-" in which the alkyl group connecting to the 4- position of the piperazinyl group is an alkyl group of C1-C6; 27) a 4- (dialkylamino) piperidino group, which has a structure represented by "4-dialkylamino-1-piperidinyl" in which the dialkylamino group connecting to the 4- position of the piperazinyl group has two C1- alkyl groups C6 which may be identical to or different from one another; 28) a 4- (monoalkylamino) piperidino group, which has a structure represented by "4-monoalkylamino-1-piperidinyl" in which the monoalkylamino group connecting to the 4- position of the piperazinyl group has a C1- alkyl group C6 and 29) a 4-aminopiperidino group, which has an amino group in the 4- position of the piperidinyl group. One or more substituents can be selected from the group consisting of the above substituents. When two substituents are chosen, the substituents may be of a single species or of a plurality of species. In addition, the substituent selected from the group of substituents may be attached to the alkyl group or the cycloalkyl group of the substituents included in Q. The R portion of a bicyclic heterocyclic group (1) containing nitrogen or a phenyl group (2) is attached to the other nitrogen atom in the piperazine ring of the piperazine derivative (I) by a Z-linking portion selected from (1) an alkylene group of C 1 -C 3, (2) a C2-C4 alkenylene group, (3) a C1-C3 alkylene group having a hydroxyl group, (4) a carbonyl portion, (5) an alkylene group of C1-C2 containing a carbonyl moiety at one end or at an intermediate position of the carbon chain, or (6) an oxalyl group. The alkylene group forming the Z-portion has the following formula described: - (CH2) r-in which r represents a number between 1 and 3 inclusive. The alkenylene group is a C2-C4 alkenylene group in which a carbon-carbon bond is a double bond that may exist at one end or at an intermediate position. The C1-C3 alkylene group having a hydroxyl group is a C1-C3 alkylene group in which a carbon atom has a hydroxyl group. No limitation is imposed on the position of the hydroxyl group, and this may exist at one end or at an intermediate position. The carbonyl (or carbonyl group) portion has a structure represented by "-CO-". The C1-C2 alkylene group containing a carbonyl moiety at one end or at an intermediate position of the carbon chain has one of the following structures: -CO-CH2-, -CH2-CO-, -CO-CH2-CH2 -, -CH2-CO-CH2-, or -CH2-CH2-CO-. The oxalyl group has a structure of "-CO-CO-". The partial structure represented by R comprises a bicyclic heterocyclic group containing nitrogen (i) or a phenyl group (ii). Of the two groups, the bicyclic heterocyclic group has the structural characteristics that (1) has a condensed ring structure formed of a 5-membered ring and a 6-membered ring; (2) one or two nitrogen atoms are contained in the 5-membered ring portion; (3) the nitrogen-containing ring can be an aromatic ring or a saturated ring; and (4) the saturated ring may contain a ketone moiety. Specifically, the heterocyclic group is a group obtained from indole, isoindole, indazole or benzo [d] imidazole. In addition, groups obtained from heterocyclic compounds containing an internuclear nitrogen atom, such as indolidine, benzo [a] pyrazole, benzo [e] pyrazole, benzo [a] imidazole or benzo [e] imidazole should be mentioned. The heterocyclic substituents are bonded to the aforementioned Z-bond portion by a nitrogen atom or a carbon atom of the 5-membered ring. More specific examples of such heterocyclic substituents include indole-1-yl, indole-2-yl, indole-3-yl, 2,3-dihydroindol-1-yl, 2,3-dihydroindol-2-yl, 2.3 -dihydroindol-3-yl, 3H-indol-2-yl, 3H-indol-3-yl, 2-oxoindol-1-yl, 2-oxoindol-3-yl, indazol-1-yl, indazol-3-yl , 2,3-dihydroindazol-1-yl, 2,3-dihydroindazol-2-yl, 2,3-dihydroindazol-3-yl, 3H-indazol-3-yl, 2,3-dihydro-3-oxoindazol-1 -yl, 2,3-dihydro-3-oxoindazol-2-yl, isoindol-1-yl, isoindol-2-yl, isoindol-3-yl, 1,3-dihydroisoindole-1-yl, 1, 3- dihydroisoindol-2-yl, 1,3-dihydroisoindol-3-yl, 1,3-dihydro-3-oxoisoindol-1-yl, 1,3-dihydro-3-oxoisoindol-2-yl, 1,3-dihydro- 1-oxoisoindol-2-yl, 1,3-dihydro-1-oxoisoindol-3-yl, benzo [d] imidazol-1-yl, benzo [d] imidazol-2-yl, 2,3-dihydro-benzo [d] ] imidazol-1-yl, 2,3-dihydro-benzo [d] imidazol-2-yl and 2,3-dihydro-2-oxo-benzo [d] imidazol-1-yl. The nitrogen-containing bicyclic heterocyclic group or the phenyl group, which is the partial structure represented by R, is substituted with the substituent G which is selected from the group consisting of the following groups. When R is a phenyl group, a particularly preferred substitution site is a carbon atom adjacent to the carbon atom that connects to the Z portion, ie, an ortho position. When the R portion is a heterocyclic substituent, a preferable substitution site is in the nitrogen-containing 5-membered ring portion. In this case, the site can be a nitrogen atom or a carbon atom. (aa) a C1-C6 alkyl group, which may be cyclic, linear or branched; (ab) a phenyl group which may have a substituent; (ac) a benzyl group which may have a substituent on the phenyl group portion; (ad) a benzoyl group which may have a substituent on the phenyl group portion; (ae) a benzylcarbonyl group which may have a substituent on the phenyl group portion, (af) a benzoylmethyl group which may have a substituent on the phenyl group portion, (ag) an a-hydroxybenzyl group which may have a substituent on the phenyl group portion, (ah) a 5-membered aromatic heterocyclic group which may have a substituent and which contains as a heteroatom a nitrogen atom, an oxygen atom or a sulfur atom; wherein when the hetero atom is a nitrogen atom, the nitrogen atom is attached to a hydrogen atom or a C1-C6 alkyl group, or the nitrogen atom serves as the binding site for the heterocyclic group containing nitrogen or for the phenyl group, examples of the 5-membered aromatic heterocyclic group include a pyrrolyl group, a furyl group and a thienyl group. This substituent may be linked to the nitrogen-containing bicyclic heterocyclic group or the phenyl group at any of the possible sites thereof; (ai) a 5-membered aromatic heterocyclic group which may have a substituent and which contains as a hetero atom a nitrogen atom and as a second hetero atom a nitrogen atom, an oxygen atom or a sulfur atom; wherein when the second hetero atom is a nitrogen atom, the nitrogen atom is attached to a hydrogen atom or a C1-C6 alkyl group, or the nitrogen atom serves as the binding site for the nitrogen-containing heterocyclic group or for the phenyl group, examples of the 5-membered aromatic heterocyclic group include a pyrazolyl group, an imidazolyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl group and an isoxazolyl group. This substituent may be linked to the nitrogen-containing bicyclic heterocyclic group or the phenyl group at any of the possible sites thereof; (aj) a 5-membered aromatic heterocyclic group which may have a substituent and which contains two nitrogen atoms as heteroatoms and a nitrogen atom, an oxygen atom or a sulfur atom as a third heteroatom; wherein when the third hetero atom is a nitrogen atom, the nitrogen atom is attached to a hydrogen atom or a C1-C6 alkyl group, or the nitrogen atom serves as the binding site for the bicyclic heterocyclic group containing nitrogen or for the phenyl group, examples of the 5-membered aromatic heterocyclic group include a group 1, 2,3-triazolyl, a group 1, 2,4-triazolyl, a group 1, 2,3-thiadiazyl, a group 1, 2,4-thiadiazil, a group 1, 2,5-thiadiazil, a group 1, 3,4-thiadiazil, a group 1, 2,3-oxadiazil, a group 1, 2,4-oxadiazil, a group 1, 2,5-oxadiazil and a group 1, 3,4-oxadiazil. This substituent may be linked to the nitrogen-containing bicyclic heterocyclic group or the phenyl group at any of the possible sites thereof; (ak) a 6-membered aromatic heterocyclic group which may have a substituent and containing one or two nitrogen atoms, examples of the 6-membered aromatic heterocyclic group include a pyridyl group, a pyridazinyl group, a pyrimidyl group and a pyradynyl group . This substituent may be linked to the nitrogen-containing bicyclic heterocyclic group or the phenyl group at any of the possible sites thereof; (al) an alkyl group substituted with a heterocyclic group formed of a C 1 -C 3 alkylene group and a 5-membered aromatic heterocyclic group, the 5-membered aromatic heterocyclic group of which may have a substituent and which contains as a hetero atom a nitrogen atom , an oxygen atom or a sulfur atom; wherein when the heteroatom is a nitrogen atom, the nitrogen atom is attached to a hydrogen atom or a C 1 -C 6 alkyl group, examples of the alkyl group substituted with heterocyclic group include a pyrrolyl-methyl-ethyl or propyl group, a thienyl-methyl-ethyl or propyl group and a furyl-methyl, ethyl or propyl group, in which the alkylene group can be attached to any of the possible binding sites of the heterocyclic portion; (am) an alkyl group substituted with a heterocyclic group formed of an alkylene group of C 1 -C 3 and a 5-membered aromatic heterocyclic group, whose 5-membered aromatic heterocyclic group can have a substituent and which contains as a hetero atom a nitrogen atom and as a second hetero atom a nitrogen atom, an oxygen atom or a sulfur atom; wherein when the second hetero atom is a nitrogen atom, the nitrogen atom is linked to a hydrogen atom or a C 1 -C 6 alkyl group, or the nitrogen atom serves as the binding site for the alkylene group, examples of alkyl group substituted with heterocyclic group include a pyrazolyl-methyl, ethyl or propyl group, an imidazolyl-methyl, ethyl or propyl group, a thiazolyl-methyl, ethyl or propyl group and an oxazolyl-methyl, ethyl or propyl group, in which the alkylene group can be attached to any of the possible binding sites of the heterocyclic portion; (an) an alkyl group substituted with a heterocyclic group formed of a C 1 -C 3 alkylene group and a 5-membered aromatic heterocyclic group, the 5-membered aromatic heterocyclic group of which may have a substituent and which contains two nitrogen atoms as heteroatoms and as a third hetero atom a nitrogen atom, an oxygen atom or a sulfur atom; wherein when the third hetero atom is a nitrogen atom, the nitrogen atom is linked to a hydrogen atom or a C1-C6 alkyl group, or the nitrogen atom serves as the binding site for the alkylene group, examples of the alkyl group substituted with heterocyclic group include a 1, 2,3-triazolyl-methyl, ethyl or propyl group, a 1, 2,4-triazolyl-methyl, ethyl or propyl group, a 1, 2,3-thiadiazyl- group methyl, ethyl or propyl, a 1, 2,4-thiadiazyl-methyl, ethyl or propyl group, a 1, 2,5-thiadiazyl-methyl, ethyl or propyl group, a 1, 3,4-thiadiazyl-methyl group, ethyl or propyl, a 1, 2,3-oxadiazyl-methyl, ethyl or propyl group, a 1, 2,4-oxadiazyl-methyl, ethyl or propyl group, a 1, 2,5-oxadiazyl-methyl, ethyl or propyl and a 1, 3,4-oxadiazyl-methyl, ethyl or propyl group, in which the alkylene group can be attached to any of the possible binding sites of the heterocyclic portion; (ao) an alkyl group substituted with a heterocyclic group formed of a C 1 -C 3 alkylene group and a 6-membered aromatic heterocyclic group which may have a substituent and which contains one or two nitrogen atoms, examples of the aromatic heterocyclic group of 6 members include a pyridyl-methyl, ethyl or propyl group, a pyridazinyl-methyl, ethyl or propyl group, a pyrimidyl-methyl, ethyl or propyl group and a pyradynyl-methyl, ethyl or propyl group, in which the alkylene group may be attached to any of the possible binding sites of the heterocyclic portion; (ap) a phenylhydroxyalkyl group formed from an alkylene group of C2-C3 having a hydroxyl group and a phenyl group which may have a substituent, examples of which include a 1-hydroxy-2-phenylethyl group, a 2- group hydroxy-2-phenylethyl, a 1-hydroxy-3-phenylpropyl group, a 2-hydroxy-3-phenylpropyl group and a 3-hydroxy-3-phenylpropyl group; (aq) a 2-phenylethynyl group in which its phenyl group may have a substituent; (ar) a tetrazolyl group; (as) a morpholino group; (at) an alkanoylamino group of C2-C7; (au) a tetrazolylalkyl group formed of a tetrazolyl group and a C 1 -C 3 alkylene group in which the alkylene group is attached to the carbon atom or a nitrogen atom of the tetrazolyl group, examples thereof include a tetrazolyl group methyl, ethyl or propyl; (av) a morpholinoalkyl group formed of a morpholino group and a C 1 -C 3 alkylene group, examples of which include a morpholino-methyl, ethyl or propyl group; (aw) an alkoxycarbonylcyclohexyl group in which its alkoxy group has from one to six carbon atoms; the binding site between the alkoxycarbonyl group and the 1- position can be a trans form or a cis form or it can be an axial bond or an equatorial bond; (ax) an alkoxycarbonyl group in which its alkoxy group has from one to six carbon atoms; (ay) an alkoxycarbonylalkyl group formed of an alkylene group of C1-C3 and an alkoxycarbonyl group in which its alkoxy group has from one to six carbon atoms, examples thereof include an alkoxycarbonyl-methyl, ethyl or propyl group; (az) a 1-alkylquinol-2-yl group in which its alkyl group has from one to six carbon atoms and the indole group may also have a substituent; (ba) a pyrrolidone-1-yl group in which an oxygen atom occupies the 2- or 3- position; (bb) a 2-guanidinothiazolyl group; (b) a (2-guanidinothiazolyl) -alkyl group formed of a 2-guanidinothiazolyl group and an alkylene group of C 1 -C 3, (bd) a 1,4-dihydropyridyl group which may have a substituent such as alkyl groups and carboxyl groups, examples thereof include a 2,6-bis (methoxycarbonyl) -3,5-dimethyl-1,4-dihydropyridyl group; (b) a 4-alkylpiperadinoalkyl group formed from a C 1 -C 6 alkylene group and a 4-alkylpiperazino group having a C 1 -C 6 alkyl group, (bf) a 4- (morpholinosulfonyl) phenylalkyl group formed from a group 4 - (morpholinosulfonyl) phenyl and a C 1 -C 6 alkylene group, (bg) a 4- (piperazinesulfonyl) phenylalkyl group formed of a 4- (piperazinesulfonyl) phenyl group and an alkylene group of C 1 -C 6, (bh) a 4- (Piperazinesulfonyl) phenylalkyl group formed from a C 1 -C 6 alkylene group and a 4- (4-alkylpiperazinesulfonyl) phenyl group having a C 1 -C 6 alkyl group, (bi) an alkoxycarbonylalkyl group formed from an alkoxycarbonyl group of C2-C7 and a C1-C6 alkylene group, (bj) a carboxylalkyl group formed from a carboxyl group and an alkylene group of C1-C6, (bk) a [4- (4-dialkylaminoopiperidino) phenyl group ] alkyl formed from an alkylene group of C 1 -C 6 and a group 4- (4-dialkylaminopiperidino) phenyl in which a 4-dialkylaminopiperidino group has, in the 4- position of the piperidine, a dialkylamino group containing two C1-C6 alkyl groups is attached to the 4- position of the phenyl group, (bl) a 4- (4-monoalkylaminopiperidino) phenylalkyl group formed from a C1-C6 alkylene group and a 4- (4-monoalkylaminopiperidino) phenyl group in which a 4-monoalkylaminopiperidino group having, in the 4- position of the piperidine, a monoalkylamino group containing an alkyl group of C1 -C6 is attached to the 4- position of the phenyl group; (bm) a [4- (4-aminopiperidino) phenyl] alkyl group formed from a C 1 -C 6 alkylene group and a 4- (4-aminopiperidino) phenyl group in which a 4-aminopiperidino group is attached to the 4- position of the phenyl group; (bn) a (4-dialkylaminopiperidino) alkyl group formed of a C1-C6 alkylene group and a 4-dialkylaminopiperidino group in which a dialkylamino group having two C1-C6 alkyl groups is attached to the 4- position of piperidine; (b) a (4-monoalkylaminopiperidino) alkyl group formed of a C 1 -C 6 alkylene group and a 4-monoalkylaminopiperidino group in which a monoalkylamino group having a C 1 -C 6 alkyl group is attached to the 4-position of piperidine; (bp) a (4-aminopiperidino) alkyl group formed of a 4-aminopiperidino group and an alkylene group of C 1 -C 6; and (bq) a hydrogen atom.

With respect to the substituents listed in the group of substituents above, the description "which may be substituted" or "which may have a substituent" refers to the substituent may have a substituent selected from the group of substituents described right away. One or more substituents can be selected from the group consisting of the substituents described below: 1) a C 1 -C 6 alkyl group, 2) a C 1 -C 6 alkoxy group, 3) a trifluoromethyl group and a 2 group, 2,2-trifluoroethyl, 4) a trifluoromethoxy group and a 2,2,2-trifluoroethoxy group, 5) a C 1 -C 6 alkylthio group, 6) a C 1 -C 6 alkylsulfinyl group, 7) a C1-6 alkylsulfonyl group C6, 8) an alkanoyl group formed of a C1-C6 alkyl group and a carbonyl group, 9) a C2-C7 alkanoyloxy group, 10) a C2-C7 alkanoylamino group, 11) an amino group, 12) a monoalkylamino group having a C1-C6 alkyl group, 13) a dialkylamino group in which each of the alkyl groups is a C1-C6 alkyl group, 14) a hydroxyl group, 15) a halogen atom 16) a C2-C6 perfluoroalkyl group, 17) a cyano group, 18) a nitro group, 19) a carboxyl group, 20) an alkoxycarbonyl group formed from a C-alkoxy group, 1-C6 and a carbonyl group, 21) a tetrazolyl group, 22) a sulfamoyl group, 23) a methylenedioxy group, an ethylenedioxy group and a propylenedioxy group, 24) a morpholinosulfonyl group, 25) a piperazinesulfonyl group, 26) a 4-alkylpiperazinesulfonyl group having a C 1 -C 6 alkyl group, 27) a 4- (dialkylamino) piperidino group having a dialkylamino group having two C 1 -C 6 alkyl groups which may be identical to or different from one another, ) a 4- (monoalkylamino) piperidino group having a C 1 -C 6 alkyl group and 29) a 4-aminopiperidino group. When two substituents are chosen, they may be of a single species or of a plurality of species.

The 6-membered ring portion of the bicyclic heterocyclic group (i) or the phenyl group (i) may have one or more groups selected from a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a trifluoromethoxy group, a 2,2,2-trifluoroethoxy group, a C 1 -C 6 alkylthio group, a C 1 -C 6 alkylsulfinyl group, a C 1 -C 6 alkylsulfonyl group , an alkanoyl group formed of a C1-C6 alkylene group and a carbonyl group, a C2-C7 alkanoyloxy group, a C2-C7 alkanoylamino group, an amino group, a monoalkylamino group having a C1-6 alkyl group C6, a dialkylamino group having two C1-C6 alkyl groups which may be identical to or different from one another, a hydroxyl group, a halogen atom, a perfluoroalkyl group of C2-C6, a cyano group, a nitro group, a carboxyl group, an alkoxycarbonyl group formed of a C1-C6 alkoxy group and a carbonyl group, or a tetrazolyl group, a sulfamoyl group, a methylenedioxy group, an ethylendioxy group, a morpholinosulfonyl group, a piperazinesulfonyl group, a 4-alkylpiperazinesulfonyl group having a C1-C6 alkyl group, a 4-dialkylaminopiperidino group having the 4-position - a dialkylamino group having two C1-C6 alkyl groups which may be identical to or different from each other, a 4-monoalkylaminopiperidino group having a C1-C6 alkyl group or a 4-aminopiperidino group.

Examples of nitrogen-containing bicyclic heterocyclic groups which serve as substituents R include groups having a structure represented by the following formula: wherein the substituent G has the same meaning as described above; each of R 1 and R 2, which may be identical or different from one another, represent a group selected from a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxyl group, a trifluoromethyl group, a 2 group, 2,2-trifluoroethyl, a trifluoromethoxy group, a 2,2,2-trifluoroethoxy group, a C 1 -C 6 alkylthio group, a C 1 -C 6 alkylsulfinyl group, a C 1 -C 6 alkylsulfonyl group, an alkanoyl group formed of a C1-C6 alkylene group and a carbonyl group, a C2-C7 alkanoyloxy group, a C2-C7 alkanoylamino group, an amino group, a monoalkylamino group having a C1-C6 alkyl group, a dialkylamino group which have two C1-C6 alkyl groups which may be identical to or different from one another, a hydroxyl group, a halogen atom, a C2-C6 perfluoroalkyl group, a cyano group, a nitro group, a carboxyl group, a group alkoxycarbonyl formed from a C1-C6 alkoxy group and a carbonyl group, a tetrazolyl group, a sulfamoyl group, a methylenedioxy group, an ethylenedioxy group, a morpholinosulfonyl group, a piperazinesulfonyl group, a 4-alkylpiperazinesulfonyl group having an alkyl group of C1-C6, a 4-dialkylaminopiper group I mean that it has in the 4- position a dialkylamino group having two C 1 -C 6 alkyl groups which may be identical to or different from one another, a 4-monoalkylaminopiperidino group having a C 1 -C 6 alkyl group or a 4- group aminopiperidino; and K represents N (nitrogen atom), C (carbon atom) or C = O (carbonyl group), and substituent G may be attached at the 2- position of indazole. Examples of the phenyl group serving as R include groups having a structure represented by the following formula: wherein R1, R2 and G have the same meanings as those described above. Examples of the nitrogen-containing bicyclic heterocyclic groups having a preferable structure include the groups represented by the following formula: wherein the substituent G can be attached in the 2- position of the indazole. An indazole structure or a phenyl group structure is preferred as the R substituent. Of these, an indazole structure is most preferred.

When the substituent R is an indazole, examples of the substituent G which is connected to the substituent R include groups which have been previously defined as G and which are selected from the following: • a C1-C6 alkyl group, • a a phenyl group which may have a substituent, a benzoyl group which may have a substituent on the phenyl group portion, a benzylcarbonyl group which may have a substituent on the phenyl group portion, a benzoylmethyl group which may have a substituent on the phenyl group portion, an a-hydroxybenzyl group which may have a substituent on the phenyl group portion, a 6-membered aromatic heterocyclic group which may have a substituent and which contains one or two atoms of nitrogen, • an alkylene group substituted with heterocyclic group formed of an alkylene group of C1-C3 and a 5-membered aromatic heterocyclic group, whose group 5-membered aromatic heterocyclic can have a substituent and contains as a heteroatom a nitrogen atom, a sulfur atom or an oxygen atom, an alkyl group substituted with heterocyclic group formed of an alkylene group of C 1 -C 3 and a 5-membered aromatic heterocyclic group, which 5-membered aromatic heterocyclic group can have a substituent and contains as a heteroatom a nitrogen atom and as a second hetero atom a nitrogen atom, a sulfur atom or an oxygen atom, • a alkyl group substituted with heterocyclic group formed of a C 1 -C 3 alkylene group and a 5-membered aromatic heterocyclic group whose 5-membered aromatic heterocyclic group may have one substituent and which contains as heteroatoms two nitrogen atoms and as a second heteroatom a Nitrogen atom, a sulfur atom or an oxygen atom, • an alkyl group substituted with group heterocyclic formed from a C1-C3 alkylene group and a 6-membered aromatic heterocyclic group whose 6-membered aromatic heterocyclic group can have a substituent and which contains one or two nitrogen atoms, • a phenylhydroxyalkyl group formed from an alkylene group of C2-C3 having a hydroxyl group and a phenyl group which may have a substituent, a 2-phenylethenyl group in which its phenyl group may have a substituent, a C2-C7 alkanoylamino group, a tetrazolylalkyl group formed of a C1-C3 alkylene group and a tetrazolyl group in which the alkylene group is attached to a carbon atom or a nitrogen atom of the tetrazolyl group, a morpholinoalkyl group formed of a morpholino group and an alkylene group of C1-C3, • an alkoxycarbonylalkyl group formed of a C1-C6 alkoxy group, a carbonyl group and an alkylene group of C1-C3, • a 1-alkyl-indol-2-yl group in which an alkyl group of C1- C6 is linked to the 1- position of the indole which may have a substituent, a pyrrolidone-2-yl group which may have a substituent, a (2-guanidinothiazolyl) alkyl group formed from a 2-guanidinothiazolyl group and an alkylene group of C1-C3, "a group ( 4-alkylpiperazino) alkyl formed from a C1-C6 alkylene group and a 4-alkylpiperazino group having a C1-C6 alkyl group in the 4- position of the piperazino group, • a [4- (morpholinosulfonyl) phenyl] group] alkyl formed from a C 1 -C 6 alkylene group and a 4- (morpholinosulfonyl) phenyl group having a morpholinosulfonyl group in the 4- position of the phenyl group• a [4- (piperazinesulfonyl) phenyl] alkyl group formed from a C1-C6 alkylene group and a 4- (piperazinesulfonyl) phenyl group having a piperazinesulfonyl group in the 4- position of the phenyl group, • a group [ 4- (4-alkylpiperazinesulfonyl) phenyl] alkyl formed from a C 1 -C 6 alkylene group and a 4- (4-alkylpiperazinesulfonyl) phenyl group in which a 4-alkylpiperazinesulfonyl group having a C 1 -C 6 alkyl group is attached with the 4- position of the phenyl group, an alkoxycarbonylalkyl group formed of a C 1 -C 6 alkoxy group, a carbonyl group and a C 1 -C 6 alkylene group, a carboxylalkyl group formed from a carboxyl group and an alkylene group of C1-C6, • a [4- (4-dialkylaminopiperidino) phenyl] alkyl group formed from an alkylene group of C1-C6 and a 4- (4-dialkylaminopiperidino) phenyl group in which a 4-dialkylaminopiperidino group having , in the 4- position of piperidine, a dialkylamino group containing groups C 1 -C 6 alkyl which may be identical to or different from one another is attached to the 4- position of the phenyl group, a group [4- (4-monoalkylaminopiperidino) phenyl] alkyl formed from an alkylene group of C 1 - C6 and a 4- (4-monoalkylaminopiperidino) phenyl group in which a 4-monoalkylaminopiperidino group having, in the 4 position of the piperidine, a monoalkylamino group containing a C1-C6 alkyl group is attached to the 4-position - of the phenyl group, • a [4- (4-aminopiperidino) phenyl] alkyl group formed from a C 1 -C 6 alkylene group and a 4- (aminopiperidino) phenyl group in which a 4-aminopiperidino group having, in the 4- position of the piperidine, an amino group is attached to the 4- position of the phenyl group, a (4-dialkylaminopiperidino) alkyl group formed of an alkylene group of C 1 -C 6 and a 4-dialkylaminopiperidino group in which a dialkylamino group having two C1-C6 alkyl groups which may be identical od iferentes one of the other, is linked to the 4- position of the piperidine, • a group (4-monoalkylaminopiperidino) alkyl formed of an alkylene group of C1-C6 and a group 4-monoalkylaminopiperidino in which a monoalkylamino group having a C 1 -C 6 alkyl group is attached to the 4- position of the piperidine, a (4-aminopiperidino) alkyl group formed of a C 1 -C 6 alkylene group and a 4-aminopiperidino group having an amino group in the position 4- of piperidine, • a phenylalkyl group formed from an alkylene group of C 1 -C 6 and a phenyl group which may have a substituent, and • a hydrogen atom. Of these, the most preferred examples thereof include groups which are selected from the following group: an alkyl group substituted with a heterocyclic group formed from a C 1 -C 3 alkylene group and a 5-membered aromatic heterocyclic group, the aromatic heterocyclic group thereof of 5 members can have a substituent and contains as a hetero atom a nitrogen atom, a sulfur atom or an oxygen atom, an alkyl group substituted with a heterocyclic group formed of an alkylene group of C 1 -C 3 and a heterocyclic group 5-membered aromatic whose 5-membered aromatic heterocyclic group can have a substituent and which contains as a heteroatom a nitrogen atom and as a second heteroatom a nitrogen atom, a sulfur atom or an oxygen atom, an alkyl group substituted with a heterocyclic group consisting of a C1-C3 alkylene group and a 5-membered aromatic heterocyclic group whose group 5-membered aromatic heterocyclic may have one substituent and contains as heteroatoms two nitrogen atoms and as a second heteroatom a nitrogen atom, a sulfur atom or an oxygen atom, • an alkyl group substituted with heterocyclic group formed from a group C1-C3 alkylene and a 6-membered aromatic heterocyclic group whose 6-membered aromatic heterocyclic group may have a substituent and which contains one or two nitrogen atoms• a tetrazolylalkyl group • a (2-guanidinothiazolyl) alkyl group, "a 1,4-dihydropyridyl group which may have a substituent, • a [4- (morpholinesulfonyl) phenyl] alkyl group, • a [4- (piperazinesulfonyl) phenyl] alkyl group, • a [4- (4-alkylpiperazinesulfonyl) phenyl] alkyl group, • an alkoxycarbonylalkyl group, • a carboxylalkyl group • a [4- (4-dialkylaminopiperidino) phenyl] alkyl group, • a [4- (4-aminopolyminopiperidino) phenyl] alkyl group, • a [4- (4-aminopiperidino) phenyl] alkyl group, • a (4-dialkylaminopiperidino) alkyl group, a (4-monoalkylaminopiperidino) alkyl group, a (4-aminopiperidino) alkyl group, a phenylalkyl group, and a hydrogen atom. When the substituent R contains an indazole group, the particularly preferred substituent G that connects to the substituent R is an alkyl group substituted with a heterocyclic group or a phenylalkyl group. A compound having a hydrogen atom serving as the substituent G is one of the preferred compounds in the sense that it exhibits strong inhibition of calmodulin. When the substituent R contains an indazole, preferred examples of substituent G include an aralkyl group formed of an aryl group and an alkylene group of C 1 -C 6. The aryl group contained in the aralkyl group includes a heterocyclic group obtained from an aromatic heterocyclic compound as well as from an aromatic hydrocarbon compound. Examples of the aralkyl group include the following: • an α-hydroxybenzyl group, • an alkyl group substituted with a heterocyclic group formed from a C 1 -C 3 alkylene group and a 5-membered aromatic heterocyclic group, whose 5-membered aromatic heterocyclic group it can have a substituent and contains as a hetero atom a nitrogen atom, a sulfur atom or an oxygen atom, an alkyl group substituted with a heterocyclic group formed of a C 1 -C 3 alkylene group and a 5-membered aromatic heterocyclic group whose aromatic 5-membered heterocyclic group can have a substituent and contains as a hetero atom a nitrogen atom and as a second hetero atom a nitrogen atom, a sulfur atom or an oxygen atom, an alkyl group substituted with a heterocyclic group formed of an alkylene group of C1-C3 and a 5-membered aromatic heterocyclic group, whose aromatic heterocyclic group ico of 5 members can have a substituent and contains as heteroatoms two nitrogen atoms and as a second heteroatom a nitrogen atom, a sulfur atom or an oxygen atom, • an alkyl group substituted with heterocyclic group formed of an alkylene group of C1-C3 and a 6-membered aromatic heterocyclic group, whose 6-membered aromatic heterocyclic group can have a substituent and which contains one or two nitrogen atoms, • a phenylhydroxyalkyl group formed from an alkylene group of C2-C3 having a hydroxyl group and a phenyl group which may have a substituent, a 2-phenylethenyl group in which its phenyl group may have a substituent, a tetrazolylalkyl group formed of an alkylene group of C 1 -C 3 and a tetrazolyl group in wherein the alkylene group is attached to a carbon atom or a nitrogen atom of the tetrazolyl group, • a morpholinoalkyl group formed of a morpholyl group and a C1-C3 alkylene group, a (2-guanidinothiazolyl) alkyl group formed from a 2-guanidinothiazolyl group and an alkylene group of C1-C3, • a [4- (morpholinosulfonyl) phenyl] alkyl group formed of a C1-C6 alkylene group and a 4- (morpholinosulfonyl) phenyl group having a morpholinesulfonyl group in the 4- position of the phenyl group, • a [4- (piperazinesulfonyl) phenyl] alkalo group formed from a group C1-C6 alkylene and a 4- (piperazinesulfonyl) phenyl group having a piperazinesulfonyl group in the 4- position of the phenyl group, • a [4- (4-alkylpiperazinesulfonyl) phenyl] alkyl group formed from an alkylene group of C1 -C6 and a 4- (4-alkylpiperazinesulfonyl) phenyl group in which a 4-alkylpiperazinesulfonyl group having a C1-C6 alkyl group is attached to the 4- position of the phenyl group• a [4- (4-dialkylaminopiperidino) phenyl] alkyl group formed from a C 1 -C 6 alkylene group and a 4- (4-dialkylaminopiperidino) phenyl group in which a 4-dialkylaminopiperidino group having, in the position 4 of the piperidine, a dialkylamino group having C1-C6 alkyl groups which may be identical to or different from one another is attached to the 4- position of the phenyl group, • a [4- (4-monoalkylaminopiperidino) group) phenyl] alkyl formed from a C1-C6 alkylene group and a 4- (4-monoalkylaminopiperidino) phenyl group in which a 4-monoalkylaminopiperidino group having, in the 4- position of the piperidine, a monoalkylamino group having a C.sub.1 -C.sub.6 alkyl group is attached to the 4- position of the phenyl group, • a [4- (4-aminopiperidino) phenyl] alkyl group formed from an alkylene group of C.sub.1 -C.sub.6 and a 4- (aminopiperidino) phenyl group in which a 4-aminopiperidino group having, in the 4- position of the piperidine, an amino group is linked to the 4- position of the phenyl group; and a phenylalkyl group formed of a C 1 -C 6 alkylene group and a phenyl group which may have a substituent. Among these aralkyl groups, an aralkyl group having an alkylene group of C1 or C2 is preferred, and one having an alkylene group of C1, ie an arylmethyl group, is more preferred. As mentioned above, the aryl group also includes a heterocyclic aryl group in addition to a hydrocarbon aryl group. When the substituent R contains an indazole, the indazole may have a substituent. As mentioned above, examples of preferable substituents include groups that are selected from the following groups: a C 1 -C 6 alkoxy group, a trifluoromethoxy group, a 2,2,2-trifluoroethoxy group, an alkylthio group of C1-C6, • a C1-C6 alkylsulfinyl group, • a C1-C6 alkylsulfonyl group, • an alkanoyl group formed of a C1-C6 alkyl group and a carbonyl group, • an alkanoylamino group of C2-C7 • a monoalkylamino group having a C1-C6 alkyl group, • a dialkylamino group in which each of the alkyl groups is a C1-C6 alkyl group, • a hydroxyl group, • a halogen atom, • a carboxyl group, an alkoxycarbonyl group formed of a C 1 -C 6 alkoxy group and a carbonyl group, a tetrazolyl group, a sulfamoyl group, a methylenedioxy group, an ethylenedioxy group, a morpholinosulfonyl group, a group piperazinesulfonyl , A 4-alkylpiperazinesulfonyl group having a C1-C6 alkyl group, a 4- (dialkylamino) piperidino group having a dialkylamino group having C1-C6 alkyl groups which may be identical to or different from one another, • a 4- (monoalkylamino) piperidino group having a C1-C6 alkyl group and • a 4-aminopiperidino group. When the substituent R contains an indazole, still more preferred examples thereof include groups which are selected from the following groups: a C1-C6 alkoxy group, a trifluoromethoxy group, a 2,2,2-group trifluoroethoxy, a hydroxyl group, a halogen atom, preferably a fluorine atom, a tetrazolyl group, a sulfamoyl group, a methylenedioxy group, an ethylenedioxy group, a morpholinosulfonyl group, a piperidinosulfonyl group, A 4-alkylpiperazinesulfonyl group having a C1-C6 alkyl group, a 4- (dialkylamino) p-peridino group in which each of the alkyl groups is independently a C1-C6 alkyl group, a group 4 - (monoalkylamino) piperidino having a C 1 -C 6 alkyl group and a 4-aminopiperidino group. Of these, when the substituent R includes an indazole, the most preferred are: a C1-C6 alkoxy group, a sulfamoyl group, a methylenedioxy group, and an ethylenedioxy group. Meanwhile, when the R substituent is a phenyl group, preferred examples of the substituent G that connects to the phenyl group include groups that are selected from the following: • a phenyl group, which may have a substituent, a 5-membered aromatic heterocyclic group which may have a substituent and which contains as a heteroatom a nitrogen atom, a sulfur atom or an oxygen atom, an aromatic heterocyclic group of 5 members which may have a substituent and which contains as a hetero atom a nitrogen atom and as a second hetero atom a nitrogen atom, a sulfur atom or an oxygen atom, a 5-membered aromatic heterocyclic group which may have a substituent and containing two nitrogen atoms and as a second hetero atom a nitrogen atom, a sulfur atom or an oxygen atom, a 6-membered aromatic heterocyclic group which may have a substituent and which contains one or two ring atoms nitrogen, • a tetrazolyl group, "a morpholinoalkyl group consisting of a morpholino group and an alkylene group of C1-C3, • a group 1 - alkylindol-2-yl which has a C 1 -C 6 alkyl group and which may also have a substituent, a 1,4-dihydropyridyl group which may have a substituent, and a (2-guanidinothiazolyl) group. When the R substituent is a phenyl group, an aryl group with respect to the substituent G which connects with the R substituent is preferred. Similarly, as mentioned above, the aryl group also includes a heterocyclic aryl group in addition to a hydrocarbon aryl group . When the R substituent is a phenyl group, the phenyl group may have one or more substituents. Examples of the preferable substituents include the same groups as those described for the case in which the substituent R contains an indazole. Examples of preferable structures as the substituent R include an indazole structure having two methoxyl groups or a methylenedioxy group or a phenyl group structure having two methoxyl groups or a methylenedioxy group. Among the groups as described above as the Q substituent, an aryl group is preferred. As the aryl group, a phenyl group is preferred. The phenyl group may have one or more substituents. The phenyl group is preferably substituted at the m- position, which is defined as the binding site of the phenyl group with the piperazine. A halogen atom is preferred for the substituent in the meta position, a chlorine atom and a trifluoromethyl group being most preferred. When the substituent on the meta is a halogen atom, the phenyl group may have an alkyl group as a second substituent, whereas when the latter is a trifluoromethyl group, the phenyl group may have an alkoxyl group as a second substituent. The inventors of the present invention believe that, as substituents that connect to the phenyl group, a substituent that can pull electrons is suitable for the target position, and that an electron donor group is suitable as the second substituent. With respect to the Z-linking portion between the R substituent and the piperazine, an alkylene group is preferred from the groups described above.

An alkylene group of C2 or C3 is preferred, an alkylene group of C2 being most preferred. A typical example of a salt of the piperazine derivative (I) is an adduct-type acid salt. The acid that is added in order to produce the salt can be either an organic acid or an inorganic acid. Examples of the inorganic acid include hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid. The carboxylic acids and sulphonic acids can be used as the organic acid, and examples thereof include acetic acid, propionic acid, lactic acid, maleic acid, fumaric acid and methanesulfonic acid, benzenesulfonic acid and toluene sulfonic acid respectively. It is apparent that a compound of the piperazine derivative (I) can be used in the human body as long as the acid forming the acid adduct-type salt is not harmful to the human body. It is also apparent that when the piperazine derivative (I) contains an acidic portion such as a carboxylic group or a sulfonyl group, the derivative can form a salt with a base through the acidic portion. In addition to the above-described adduct-type salt, the piperazine derivative (I) can take the form of a hydrate or a solvated form. The hydrate and the solvate include both the free compound of the formula (I) and a salt of the compound of the formula (I). These also include a tautomer of the compound of the formula (I). Preferable examples of the piperazine derivative (I) include the following compounds: 3- [2- [4- (3-chloro-2-methylphenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-1 - (3 , 4-dimethoxybenzyl) -1H-indazole or salts thereof, • 3- (2- (4- (3-chloro-2-methylphenyl) -1-piperazinyl) ethyl) -5,6-methylenedioxy-1- ( 3,4-dimethoxybenzyl) -1 H-indazole or salts thereof, • 3- (2- (4- (3-chloro-2-methylphenyl) -1-piperazinyl) ethyl) -5,6-dimethoxy-1 - (4-imidazolylmethyl) -1H-indazole or salts thereof, • 3- (2- (4- (3-chloro-2-methylphenyl) -1-piperazinyl) ethyl) -5,6-methylenedioxy-1- ( 4-imidazolylmethyl) -1H-indazole or salts thereof, • 3- (2- (4- (3-chloro-2-methylphenyl) -1-piperazinyl) ethyl) -5,6-dimethoxy-1 - (2 -pyridylmethyl) -1H-indazole or salts thereof, • 3- (2- (4- (3-chloro-2-methylphenyl) -1-piperazinyl) ethyl) -5,6-methylenedioxy-1- (2- pyridylmethyl) -1H-indazole or salts thereof, • 3- (2- (4- (3-chloro-2-methylphenyl) -1-piperazinyl) ethyl) -5,6-dimethoxy-1- (3-pyridylmethyl) ) -1 H-indazole or salts thereof, • 3- (2- (4- (3-chloro-2-methylphenyl) -1-pipera zinyl) ethyl) -5,6-methylenedioxy-1- (3-pyridylmethyl) -1H-indazole or salts thereof, • 3- (2- (4- (3-chloro-2-methylphenyl) -1-piperazinyl ) ethyl) -5,6-dimethoxy-1- (4-pyridylmethyl) -1H-indazole or salts thereof, • 3- (2- (4- (3-chloro-2-methylphenyl) -1- piperazinyl) ethyl) -5,6-methylenedioxy-1- (4-pyridylmethyl) -1H-indazole or salts thereof, • 3- [2- [4- (3-chloro-6-methoxyphenyl) -1- piperazinyl] ethyl] -5,6-dimethoxy-1 - (3,4-dimethoxybenzyl) -1H-indazole or salts thereof, • 3- (2- (4- (3-chloro-6-methoxyphenyl) -1 -piperazinyl) ethyl) -5,6-methylenedioxy-1- (3,4-dimethoxybenzyl) -1H-indazole or salts thereof, 3- [2- [4- (3-trifluoromethylphenyl) -1-piperazinyl] ethyl ] -5,6-dimethoxy-1 - (3,4-dimethoxybenzyl) -1H-indazole or salts thereof, • 3- (2- (4- (3-trifluoromethylphenyl) -1-piperazinyl) ethyl) -5,6-methylenedioxy-1- (3,4-dimethoxybenzyl) -1H-indazole or salts thereof, • 5,6-dimethoxy-2 - [[4,5-dimethoxy-2- [4- (2 -methoxyphenyl) -1-piperazinyl] -ethyl] phenyl] -1-methylindole or salts thereof, • 5,6-dimethoxy-2 - [[4,5-methylenedioxy-2- [4- (2-meto xyphenyl) -1-piperazinyl] ethyl] phenyl] -1-methylindole or salts thereof, 1- (3-chloro-2-methylphenyl) -4- [2 - [[4,5-dimethoxy-2- (3 , 4-dimethoxy-phenyl)] - phenyl] ethyl] piperazine or salts thereof, 1- (3-chloro-2-methylphenyl) -4- [2 - [[4,5-methylenedioxy-2- ( 3,4-dimethoxyphenyl)] phenyl] ethyl] piperazine or salts thereof, • 3- [2- [4- (3-chloro-2-methylphenyl) -1-piperazinyl] propyl] -5,6-dimethoxy-1 - (3,4-dimethoxybenzyl) -1 H-indazole or salts thereof, 3- (2- (4- (3-chloro-2-methylphenyl) -1-piperazinyl) propyl) -5,6-methylenedioxy-1 - (3,4-dimethoxybenzyl) -1 H-indazole or salts thereof, • 3- (2- (4- (3-chloro-2-methylphenyl) -1-piperazinyl) propyl) -5, 6- dimethoxy-1- (4-imidazolylmethyl) -1H-indazole or salts thereof, 3- (2- (4- (3-chloro-2-methylphenyl) -1-piperazinyl) propyl) -5,6 -methylenedioxy-1- (4-imidazolylmethyl) -1H-indazole or salts thereof, • 3- (2- (4- (3-chloro-2-methylphenyl) -1-piperazinyl) propyl) -5.6- dimethoxy-1 - (2-pyridylmethyl) -1H-indazole or salts thereof, 3- (2- (4- (3-chloro-2-methylphenyl) -1-piperazinyl) propyl) -5,6-methylend Oxy-1- (2-pyridylmethyl) -1H-indazole or salts thereof, • 3- (2- (4- (3-chloro-2-methylphenyl) -1-piperazinyl) propyl) -5,6- dimethoxy-1- (3-pyridylmethyl) -1H-indazole or salts thereof, 3- (2- (4- (3-chloro-2-methylphenyl) -1-piperazinyl) propyl) -5,6-methylenedioxy- 1- (3-pyridylmethyl) -1H-indazole or salts thereof, • 3- (2- (4- (3-chloro-2-methylphenyl) -1-piperazinyl) propyl) -5,6-dimethoxy-1 - (4-pyridylmethyl) -1H-indazole or salts thereof, 3- (2- (4- (3-chloro-2-methylphenyl) -1-piperazinyl) propyl) -5,6-methylenedioxy-1- ( 4-pyridylmethyl) -1H-indazole or salts thereof, • 3- [2- [4- (3-chloro-6-methoxyphenyl) -1-piperazinyl] propyl] -5,6-dimetox i-1- (3,4-dimethoxybenzyl) -1H-indazole or salts thereof, • 3- (2- (4- (3-chloro-6-methoxyphenyl) -1-piperazinyl) propyl) -5,6 -methylenedioxy-1- (3,4-dimethoxybenzyl) -1H-indazole or salts thereof, • 3- [2- [4- (3-trifluoromethylphenyl) -1-piperazinyl] propyl] -5,6-dimethoxy- 1- (3,4-dimethoxybenzyl) -1 H-indazole or salts thereof, 3- (2- (4- (3-trifluoromethylphenyl) -1-piperazinyl) propyl) -5,6-methylenedioxy-1- (3 , 4-dimethoxybenzyl) -1 H-indazole or salts thereof, • 5,6-dimethoxy-2 - [[4,5-dimethoxy-2- [4- (2-methoxyphenyl) -1-piperazinyl] -propyl] phenyl] -1-methylindole or salts thereof, 5,6-dimethoxy-2 - [[4,5-methylenedioxy-2- [4- (2-methoxyphenyl) -1-piperazinyl] propyl] phenyl] -1-methylindole or salts thereof, 1- (3-chloro-2-methylphenyl) -4- [2 - [[4,5-dimethoxy-2- (3,4-dimethoxyphenyl)] - phenyl] propyl] piperazine or salts thereof. same, 1- (3-chloro-2-methylphenyl) -4- [2 - [[4,5-methylenedioxy-2- (3,4-dimethoxyphenyl)] phenyl] propyl] piperazine or salts thereof. Of these, the most preferred examples include the following compounds: • 3- [2- [4- (3-chloro-2-methylphenyl) -1-piperazinyl] ethyl] -5,6-dimethoxy-1 - (3-, 4-dimethoxybenzyl) -1 H-indazole or salts thereof and • 3- (2- (4- (3-chloro-2-methylphenyl) -1-piperazinyl) ethyl) -5,6-dimethoxy-1 - (4-dimethoxybenzyl) -1 H-indazole or salts thereof -imidazolylmethyl) -1H-indazole or salts thereof. With respect to salt, the compounds • 3- (2- (4- (3-Chloro-2-methylphenyl) -1-piperazinyl) ethyl) -5,6-dimethoxy-1- (4-imidazolemethyl) dihydrochloride ) -1 H-indazole 3.5 hydrate and • 3- (2- (4- (3-chloro-2-methylphenyl) -1-piperazinyl) ethyl) -5,6-dimethoxy-1 H-indazole or salts thereof are particularly preferred. The piperazine derivative (I) can be produced by a method described in, for example, Japanese Patent Application Laid-Open (kokai) No. 7-97364. The water-soluble cyclodextrin derivative used in the present invention relates to a derivative having greater water solubility than that of β-cyclodextrin. Examples of the derivative include compounds represented by the formula (II): wherein m represents an integer between 6 and 12 inclusive and each of R3, R4 and R5, which may be identical to or different from each other in each of the recurring units, represent a hydrogen atom, a group sulfoalkyl, a hydroxyalkyl group or a sugar residue. The variable m represents an integer between 6 and 12 inclusive, preferably between 6 and 9 inclusive, particularly 7, that is, a derivative of β-cyclodextrin. Among R3, R4 and R5, examples of the preferred sulfoalkyl group include sulfoalkyl groups having a C1-C6 alkyl group such as a sulfomethyl group, a sulfoethyl group, a sulfopropyl group or a sulfobutyl group, with a particularly preferred sulfobutyl group. Examples of the most preferred hydroxyalkyl group include hydroxyalkyl groups having a C1-C6 alkyl group such as a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group or a hydroxybutyl group, with a hydroxypropyl group being particularly preferred.

With respect to the sugar residue, sugar residues having 3-24 carbon atoms are preferred, and those having 6-12 carbon atoms are particularly preferred. Examples of the residue include a glycosyl group, a galactosyl group, a glycero-gluco-heptosyl group, a maltosyl group and a lactosyl group, a maltosyl group being more preferred. The water-soluble cyclodextrin derivative represented by the formula (II) has a substitution ratio, ie a ratio of a substituent other than hydrogen to the sum of R3, R4 and R5 in the water-soluble cyclodextrin derivative represented by the formula (II), preferably 70% or less, particularly preferred 20-50%. With respect to the water-soluble cyclodextrin derivative, the appropriate cyclodextrins described in, for example, Japanese Patent Publications Kohio Nos. 5-504783 (WO91 / 11172) and 6-511513 (WO94 / 02518) could also be used. Examples of the water-soluble cyclodextrin derivative include sulfobutylcyclodextrin, hydroxypropylcyclodextrin, maltosylcyclodextrin and the salts thereof. In particular, sulfobutyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, maltosyl-β-cyclodextrin and the salts thereof are preferred. In addition, of these, sulfobutyl-β-cyclodextrin or hydroxypropyl-β-cyclodextrin and salts thereof having a substitution ratio of 70% or less, particularly 20-50% are preferred, and most preferred are sodium salt of the sulfobutyl ether of β-cyclodextrin having a substitution ratio of about 33% and the hydroxypropyl-β-cyclodextrin having a substitution ratio of about 23%. The piperazine-cyclodextrin complex of the present invention can be obtained by producing an aqueous solution containing the piperazine derivative (I) or a salt thereof and a water-soluble cyclodextrin derivative. The cyclodextrin derivative readily soluble in water is used in an amount of preferably one mole or more based on one mole of the piperazine derivative (I) or a salt thereof, particularly preferably 1-10 moles. The higher the concentration of the water-soluble cyclodextrin derivative, the greater the increase in the solubility of the piperazine derivative (I). No particular limitation is imposed on the method for producing the aqueous solution, and for example this is produced using water or a buffer solution in a temperature range of about -5 to 35 ° C. The piperazine-cyclodextrin complex of the present invention obtained in this way can be used as such or in a powder form which is obtained by removing the co-existing water. Examples of the method for removing water include lyophilization and drying under reduced pressure. A powder product obtained by lyophilization is particularly preferred. The piperazine-cyclodextrin complex of the present invention shows its effect either by oral administration or parenteral administration, and is preferably formed as a formulation for parenteral administration, particularly a formulation for injection. The dose of the complex of the present invention can be appropriately modified in accordance with the age, body weight and severity of the patient's symptom. When the complex is administered orally, the daily dose for an adult, reduced as the piperazine derivative (I), is from 1 mg to 1,000 mg, preferably from 10 mg to 500 mg, and the complex may be administered once or in divided form. Examples of the form of the formulation include tablets, capsules, powders and granules. These can be produced by a known technique using typical additives such as excipients, lubricants and binders. When the complex is administered parenterally, the daily dose for an adult, reduced as the piperazine derivative (I), is from 1 mg to 500 mg, preferably from 10 mg to 200 mg, and preferably, the complex is administered in the dose by hypodermic injection, intravenous injection or by intravenous drip. The piperazine-cyclodextrin complex of the present invention shows excellent inhibition of calmodulin and has excellent anti-hypoxia action. In addition, it shows excellent efficacy against a variety of pathological models (such as inhibition of late neurocytic death or antiedemic action of gerbils) by oral and parenteral administration in a dose that does not cause central inhibition.

Accordingly, the piperazine-cyclodextrin complex of the present invention serves as an inhibitor for the physiological action induced by calmodulin caused by intracellular calcium, and is useful as a therapeutic agent, particularly as a therapeutic agent and as a preventive agent for a variety of diseases induced by excessive activation of calmodulin such as hypertension and ischemic diseases of the brain, heart and kidneys such as cerebral infarction, cerebral embolism, transient ischemic attack, cerebral thrombosis, heart infarction, angina pectoris, heart failure, renal failure acute or nephritis; diseases of the brain region such as Alzheimer's disease, Parkinson's disease or Binswanger's disease; drug intoxication; poisoning by toxic gases; traumatic brain diseases and diseases caused by them such as lack of spontaneity, depression or memory disorders. In addition, the complex is particularly useful as a therapeutic agent for diseases of the circulatory system and for diseases of the brain or as a protective agent of the brain.

EXAMPLES The invention will now be described by way of examples, but the present invention should not be considered as limited thereto.

EXAMPLE 1 To an aqueous solution of a sodium salt of sulfobutyl ether of β-cyclodextrin (product of CyDex, can be abbreviated hereafter as SBE7-β-CD, molecular weight 2162.01, substitution ratio: 7/21 (approximately 33%) ) (26, 40 or 72 mM, 2.5 ml) an excess amount of 3- [2- [4- (3-chloro-2-methylphenyl) -1-piperadinyl] ethyl] -5,6-dimethoxy- was added. 1- (4-methyldazolylmet) -1 H-ndazoU2HC 3.5H2O (can be abbreviated hereinafter as compound (1), molecular weight: 631.0) (400 mg). The mixture was allowed to stand for 7 days in a water bath at 25 ° C. During the resting period, the mixture was sonicated once a day for 15 minutes, followed by agitation for 2 minutes. On the first, fifth and seventh days, the pH of the mixture was adjusted to 4.0 by addition of an appropriate amount of HCl. After the pH was adjusted on the seventh day, the amount of the entire mixture was adjusted to 5 ml (thereby achieving a concentration of SBE7-β-CD of 15, 20 or 30 mM). Six days later, the mixture was subjected to centrifugal separation, whereby a supernatant was collected. The supernatant was filtered through a 0.22 μm filter, and the concentration of the compound (1) contained in the filtrate was determined quantitatively by high performance liquid chromatography (HPLC) under the following conditions.

Similarly, the solubility of the piperazine derivative (I) in water was determined by HPLC. The results are shown in table 1.

Conditions for high performance liquid chromatography (HPLC) Column: Intersil ODS-2 Mobile phase: 50 mM phosphate buffer (pH 5.5) / acetonitrile (1: 1) Column temperature: 40 ° C Flow rate: 1.0 ml / min Wavelength: 210 nm.

TABLE 1 As seen in table 1, the solubility of the compound (1) is improved when SBE7-β-CD is added to form a complex and when the concentration of SBE7-β-CD increases.

In this sense, the formation of a complex was confirmed through visual observation of the Cotton effect. Briefly, while the DC spectrum (Circular Dichroism) of a solution containing only compound (1) shows a simple curve, when a cyclodextrin solution is added to it, a negative Cotton effect is observed in the vicinity of 245 nm. It is known that the Cotton effect is obtained only when a host molecule is included in the intramolecular cavity of the cyclodextrin ("Rotatory Dispersion -Its Application to Organic Chemistry", written by Carldjerassi, translated by Koji NAKANISHI and Fufaba YAMAZAKI (Tokyo Kagaku Dojin) Therefore, it was confirmed that the compound (1) is included in a cyclodextrin molecule thus forming a complex.

EXAMPLE 2 To an isotonic 10 mM phosphate buffer solution (pH 6.0, 2 ml) containing SBE7-β-CD or hydroxypropyl-β-cyclodextrin (product of Nihon Shokuhin Kako, hereinafter referred to as HP-β-CD; molecular weight 1413, substitution ratio: 4.8 / 21 (approximately 23%)) at a different concentration and 0.6 mM of compound (1) (concentration permitting complete hemolysis) a suspension (0.2 ml) of red blood cell suspension was added ( 5%). The mixture was maintained at 37 ° C for 30 minutes. After the centrifugal separation (1, 000 x g, 5 minutes), the oxyhemoglobin and methaemoglobin contained in the supernatant were determined based on the absorbance at 588 nm, whereby the hemolytic activity of the compound (1) is investigated. The results are shown in Figure 1. When a complex was formed by the addition of SBE7-β-CD or HP-β-CD, the hemolytic activity of compound (1) was suppressed, and the higher the concentration of the composed of cyclodextrin, the greater the suppression of hemolytic activity.

EXAMPLE 3 An aqueous solution having the composition shown in Table 2 was prepared. This solution was injected subcutaneously into the back of a rat. Thirty minutes after injection, a solution of 0.5% Evans blue was injected intravenously, and thirty minutes after this, the area of the skin on which the dye exuded was checked to verify vascular permeability. Figure 2 shows that the vascular permeability caused by the complex of compound (1) and SBE7-β-CD was lower than that of compound (1).

TABLE 2 The numbers in () represent the pH.

EXAMPLE 4 A solution having a composition shown in Table 3 was prepared, and 10 ml aliquots were placed individually in ampoules.

The solution was prepared as follows. The compound (1) (2.55 g) was dissolved in water for injection (700 ml). Independently, SBE7-β-CD (18.04 g) was dissolved in water for injection (200 ml), and the solutions were mixed.

The pH was adjusted, and water for injection was added to make the total volume equal to 1 liter. The ampules obtained in this way were stored for 20 days under a light of 2,500 lux. After this, the content of compound (1) was determined quantitatively in each case by high performance liquid chromatography (HPLC) under the same conditions as those used in example 1.

The results expressed as the residual ratio of the compound (1) are also shown in table 3.

TABLE 3 * 1: 20.0 mg (4 mM), reduced as an anhydrate of the free base. * 2: Corresponding to a pH of 8. * 3: To adjust the pH to 4.0.

As can be seen from Table 3, the complex of the present invention is excellent in terms of stability against adverse photolytic conditions.

EXAMPLE 5 The solutions A and B prepared in example 4 were respectively diluted with an EL-1 transfusion (product of Morishita-Roussel) of so that the concentration of compound (1) was 20 μg / ml. The solution was placed in a drip tube (made of polyvinyl chloride) from a transfusion set, and stored at 25 ° C for 2 hours under protected light conditions. The content of compound (1) of the diluted solution was determined quantitatively after storage by high performance liquid chromatography (HPLC) under the same conditions as those described in example 1. The recovery rate of compound (1) was 102 % for the case of solution A and 87% for the case of solution B. Therefore, the complex of the present invention showed to have improved adsorption in the equipment for transfusion.

Industrial Applicability The piperazine-cyclodextrin complexes of the present invention exhibit markedly improved solubility compared to the case of using the piperazine derivative (I) alone. In addition, these suppress hemolytic activity and vascular permeability, and exhibit reduced local stimulation. In addition, they exhibit excellent stability against adverse photolytic conditions and reduced adsorption in the container thereof.

Claims (21)

NOVELTY OF THE INVENTION CLAIMS

1. - A piperazine-cyclodextrin complex formed from a piperazine derivative or a salt thereof and a cyclodextrin derivative readily soluble in water, in which the piperazine derivative is represented by the formula (I): R-Z-N N-Q (I) wherein Q represents (1) an aryl group, (2) a heterocyclic group, (3) a diarylmethyl group, (4) an aralkyl group formed from an aryl group and a C1-C6 alkylene group, (5) a C 1 -C 8 alkyl group, or (6) a C 1 -C 8 cycloalkyl group, wherein each of the aryl group, the heterocyclic group and the aryl groups in the diarylmethyl group and the aralkyl group may have one or more substituents that are selected from the following groups: 1) a C1-C6 alkyl group, 2) a C1-C6 alkoxy group, 3) a trifluoromethyl group and a 2,2,2-trifluoroethyl group, 4) a trifluoromethoxy group and a 2,2,2-trifluoroethoxy group, 5) a C 1 -C 6 alkylthio group, 6) a C 1 -C 6 alkylsulfinyl group, 7) a C 1 -C 6 alkylsulfonyl group, 8) an alkanoyl group formed from an alkyl group of C1-C6 and a carbonyl group, 9) a C2-C7 alkanoyloxy group, 10) a C2-C7 alkanoylamino group, 11) an amino group, 12) a monoalkylamino group having a C1-C6 alkyl group, 13) a dialkylamino group in which each of the alkyl groups is a C1-C6 alkyl group, 14) a hydroxyl group, 15) a halogen atom, 16) a C2-C6 perfluoroalkyl group, 17) a group cyano, 18) a nitro group, 19) a carboxyl group, 20) an alkoxycarbonyl group formed of a C1-C6 alkoxy group and a carbonyl group, 21) a tetrazolyl group, 22) a sulfamoyl group, 23) a group methylenedioxy, an ethylenedioxy group and a propylenedioxy group, 24) a morpholinosulfonyl group, 25) a piperazinesulfonyl group, 26) a 4-alkylpiperazinesulfonyl group having a C1-C6 alkyl group, 27) a 4- (dialkylamino) piperidyl group; not having a dialkylamino group having two C1-C6 alkyl groups which may be identical to or different from each other, 28) a 4- (monoalkylamino) piperidino group having a C1-C6 alkyl group and 29) a group 4-aminopiperidino; R represents a bicyclic heterocyclic group containing nitrogen (i) or a phenyl group (ii), in which the nitrogen-containing heterocyclic group has a fused ring structure formed of a 5-membered ring and a 6-membered ring; one or two nitrogen atoms are contained in the 5-membered ring portion; the nitrogen-containing ring can be an aromatic or saturated ring; and the saturated ring may contain a ketone moiety; wherein the 5-membered ring portion of the bicyclic heterocyclic group (i) or the phenyl group (ii) is substituted with the substituent G which is selected from the group consisting of the following groups: (aa) a C1- alkyl group C6, (ab) a phenyl group which may have a substituent, (ac) a benzyl group which may have a substituent on the phenyl group portion, (ad) a benzoyl group which may have a substituent on the phenyl group, (ae) a benzylcarbonyl group which may have a substituent on the phenyl group portion, (af) a benzoylmethyl group which may have a substituent on the phenyl group portion, (ag) an a-hydroxybenzyl group on the which may have a substituent on the phenyl group portion, (ah) a 5-membered aromatic heterocyclic group which may have a substituent and which contains as a heteroatom a nitrogen atom, an oxygen atom or a sulfur atom; wherein when the hetero atom is a nitrogen atom, the nitrogen atom is attached to a hydrogen atom or a C 1 -C 6 alkyl group, or the nitrogen atom serves as the binding site for the heterocyclic group containing nitrogen or for the phenyl group, (ai) a 5-membered aromatic heterocyclic group which may have a substituent and which contains as a hetero atom a nitrogen atom and as a second hetero atom a nitrogen atom, an oxygen atom or a sulfur atom; wherein when the second hetero atom is a nitrogen atom, the nitrogen atom is attached to a hydrogen atom or a C1-C6 alkyl group, or the nitrogen atom serves as the binding site for the nitrogen-containing heterocyclic group or for the phenyl group, (aj) a 5-membered aromatic heterocyclic group which may have a substituent and which contains as two heteroatoms nitrogen atoms and as a third heteroatom a nitrogen atom, an oxygen atom or a sulfur atom; wherein when the third hetero atom is a nitrogen atom, the nitrogen atom is attached to a hydrogen atom or a C1-C6 alkyl group, or the nitrogen atom serves as the binding site for the nitrogen-containing heterocyclic group or for the phenyl group, (ak) a 6-membered aromatic heterocyclic group which may have a substituent and which contains one or two nitrogen atoms, (al) an alkyl group substituted with a heterocyclic group formed of an alkylene group of C1- C3 and a 5-membered aromatic heterocyclic group, whose 5-membered aromatic heterocyclic group can have a substituent and contains as a heteroatom a nitrogen atom, an oxygen atom or a sulfur atom; wherein when the heteroatom is a nitrogen atom, the nitrogen atom is attached to a hydrogen atom or a C1-C6 alkyl group, (am) an alkyl group substituted with a heterocyclic group formed from an alkylene group of C1-C3 and a 5-membered aromatic heterocyclic group, which 5-membered aromatic heterocyclic group can have a substituent and contains as a hetero atom a nitrogen atom and as a second hetero atom a nitrogen atom, an oxygen atom or a sulfur atom; wherein when the second hetero atom is a nitrogen atom, the nitrogen atom is attached to a hydrogen atom or a C1-C6 alkyl group, or the nitrogen atom serves as the binding site for the alkylene group, (an ) an alkyl group substituted with a heterocyclic group formed of a C 1 -C 3 alkylene group and a 5-membered aromatic heterocyclic group, whose 5-membered aromatic heterocyclic group can have a substituent and contains two nitrogen atoms as heteroatoms and as a third heteroatom a nitrogen atom, an oxygen atom or a sulfur atom; wherein when the third hetero atom is a nitrogen atom, the nitrogen atom is attached to a hydrogen atom or a C1-C6 alkyl group, or the nitrogen atom serves as the binding site for the alkylene group, (ao) ) an alkyl group substituted with a heterocyclic group formed of a C 1 -C 3 alkylene group and a 6-membered aromatic heterocyclic group which may have a substituent and which contains one or two nitrogen atoms, (ap) a phenylhydroxyalkyl group formed of a C2-C3 alkylene group having a hydroxyl group and a phenyl group which may have a substituent, (aq) a 2-phenylethynyl group in which its phenyl group may have a substituent, (ar) a tetrazolyl group, (as) a morpholino group, (at) an alkanoylamino group of C2-C7, (au) a tetrazolylalkyl group formed of a tetrazolyl group and an alkylene group of C1-C3 in which the alkylene group is attached to the carbon atom or to a nitrogen atom of the tetrazolyl group, (av) a morpholinoalkyl group formed of a morpholino group and a C1-C3 alkylene group, (aw) a 4-alkoxycarbonylcyclohexyl group in which its alkoxy group has from one to six carbon atoms, (ax) ) an alkoxycarbonyl group in which its alkoxy group has from one to six carbon atoms, (ay) an alkoxycarbonylalkyl group formed from an alkylene group of C1-C3 and an alkoxycarbonyl group in which its alkoxy group has from one to six carbon atoms, (az) a 1-alkylindol-2-yl group in which its alkyl group has from one to six carbon atoms and the indole group may also have a substituent, (ba) a pyrrolidone-1-yl group, (bb) a 2-guanidinothiazolyl group, (be) a (2-guanidinothiazolyl) -alkyl group formed of a 2-guanidinothiazolyl group and an alkylene group of C 1 -C 3, (bd) a 1,4-dihydropyridyl group which may have a substituent, (b) a 4-alkylpiperadinoalkyl group formed of a C 1 -C 6 alkylene group and a 4-alkylpiperazino group having a C 1 -C 6 alkyl group , (bf) a 4- (morpholinosulfonyl) phenylalkyl group formed of a 4- (morpholinosulfonyl) phenol group and a C 1 -C 6 alkylene group, (bg) a 4- (piperazinesulfonyl) phenylalkyl group formed from a group 4 - (piperazinesulfonyl) phenyl and a C 1 -C 6 alkylene group, (bh) a 4- (piperazinesulfonyl) phenylalkyl group formed from an alkylene group of C 1 -C 6 and a 4- (4-alkylpiperazinesulfonyl) phenyl group having a C1-C6 alkyl group, (bi) an alkoxycarbonylalkyl group formed of a C2-C7 alkoxycarbonyl group and an alkylene group of C1-C6, (bj) a carboxylalkyl group formed or of a carboxyl group and a C 1 -C 6 alkylene group, (bk) a [4- (4-dialkylaminopiperidino) phenyl] alkyl group formed from an alkylene group of C 1 -C 6 and a group 4- (4-dialkylaminopiperidino) ) phenyl in which a 4-dialkylaminopiperidino group having, in the 4- position of the piperidine, a dialkylamino group containing two C1-C6 alkyl groups is attached to the 4- position of the phenyl group, (bl) a group 4- (4-monoalkylaminopiperidino) phenylalkyl formed from a C 1 -C 6 alkylene group and a 4- (4-monoalkylaminopiperidino) phenyl group in which a 4-monoalkylaminopiperidino group having, in the 4- position of the piperidine, a a monoalkylamino group containing a C1-C6 alkyl group is attached to the 4- position of the phenyl group, (bm) a [4- (4-aminopiperidino) phenyl] alkyl group formed from an alkylene group of C1-C6 and a 4- (4-aminopiperidino) phenyl group in which a 4-aminopiperidino group is attached to the 4- position of the phenyl group, (bn) a group (4-dialkylaminopiperidino) alkyl formed from a C1-C6 alkylene group and a 4-dialkylaminopiperidino group in which a dialkylamino group having two C1-C6 alkyl groups is attached to the 4- position of the piperidine, (bo ) a (4-monoalkylaminopiperidino) alkyl group formed of a C 1 -C 6 alkylene group and a 4-monoalkylaminopiperidino group in which a monoalkylamino group having a C 1 -C 6 alkyl group is attached to the 4-position of the piperidine, (bp) a (4-aminopiperidino) alkyl group formed of a 4-aminopiperidino group and a C 1 -C 6 alkylene group and (bq) a hydrogen atom, in which when the substituents represented by (aa) up to (ap) have substituents, the substituents are one or more members that are selected from the group consisting of the following substituents: 1) a C1-C6 alkyl group, 2) a C1-C6 alkoxy group, 3) a group trifluoromethyl and a 2,2,2-trifluoroethyl group, 4) a trifluoromethoxy group and a or 2,2,2-trifluoroethoxy, 5) a C 1 -C 6 alkylthio group, 6) a C 1 -C 6 alkylsulfinyl group, 7) a C 1 -C 6 alkylsulfonyl group, 8) an alkanoyl group formed from an alkyl group of C1-C6 and a carbonyl group, 9) a C2-C7 alkanoyloxy group, 10) a C2-C7 alkanoylamino group, 11) an amino group, 12) a monoalkylamino group having a C1-C6 alkyl group, 13) a dialkylamino group in which each of the alkyl groups is a C1-C6 alkyl group, 14) a hydroxyl group, 15) a halogen atom, 16) a C2-C6 perfluoroalkyl group, 17) a group cyano, 18) a nitro group, 19) a carboxyl group, 20) an alkoxycarbonyl group formed of a C1-C6 alkoxy group and a carbonyl group, 21) a tetrazolyl group, 22) a sulfamoyl group, 23) a group methylenedioxy, an ethylenedioxy group and a propylenedioxy group, 24) a morpholinosulfonyl group, 25) a piperazinesulfonyl group, 26) a 4-alkylpiperazinesulfonyl group having a C1-C6 alkyl group, 27) a 4- (dialkylamino) piperidino group having a dialkylamino group having two C1-C6 alkyl groups which may be identical to or different from one another, 28) a 4- (monoalkylamino) piperidino group having a C 1 -C 6 alkyl group and 29) a 4-aminopiperidyl group; wherein the 6-membered ring portion of the bicyclic heterocyclic group (i) or the phenyl group (ii) may have one or more groups which are selected from a C1-C6 alkyl group, a C1-C6 alkoxy group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a trifluoromethoxy group, a 2,2,2-trifluoroethoxy group, a C1-C6 alkylthio group, a C1-C6 alkylsulfinyl group, a C1-6 alkylsulfonyl group, C6, an alkanoyl group formed from a C1-C6 alkylene group and a carbonyl group, a C2-C7 alkanoyloxy group, a C2-C7 alkanoylamino group, an amino group, a monoalkylamino group having an alkyl group of C1 -C6, a dialkylamino group having two C1-C6 alkyl groups which may be identical to or different from one another, a hydroxyl group, a halogen atom, a C2-C6 perfluoroalkyl group, a cyano group, a nitro group , a carboxyl group, an alkoxycarbonyl group formed from a C1-C6 alkoxy group and a carb group an onyl, a tetrazolyl group, a sulfamoyl group, a methylenedioxy group, an ethylendioxy group, a morpholinosulfonyl group, a piperazinesulfonyl group, a 4-alkylpiperazinesulfonyl group having a C1-C6 alkyl group, a 4-dialkylaminopiperidino group having 4- a dialkylamino group having two C1-C6 alkyl groups which may be identical to or different from each other, a 4-monoalkylaminopiperidino group having a C1-C6 alkyl group or a 4-aminopiperidino group; and Z represents (1) a C1-C3 alkylene group, (2) a C2-C4 alkenylene group, (3) a C1-C3 alkylene group having a hydroxyl group, (4) a carbonyl portion, (5) ) a C1-C2 alkylene group containing a carbonyl portion at one end or at an intermediate position of the carbon chain, or (6) an oxalyl group.

2. The piperazine-cyclodextrin complex according to claim 1, further characterized in that the piperazine derivative is 3- [2- [4- (3-chloro-2-methylphenyl) -1-piperazinyl] ethyl] -5 , 6-dimethoxy-1- (4-imidazolylmethyl) -1H-indazole or a salt thereof.

3. The piperazine-cyclodextrin complex according to claim 2, which is obtained through the use of 3- [2- [4- (3-chloro-2-methylphenyl) -1-piperazinyl] dihydrochloride] ethyl] -5,6-dimethoxy-1- (4-imidazolylmethyl) -1H-indazole 3.5 hydrate as the piperazine derivative.

4. The piperazine-cyclodextrin complex according to any of claims 1 to 3, further characterized in that the water-soluble cyclodextrin derivative is sulfobutylcyclodextrin or a salt thereof.

5. The piperazine-cyclodextrin complex according to any of claims 1 to 4, further characterized in that the water-soluble cyclodextrin derivative is sulfobutyl-β-cyclodextrin or a salt thereof.

6. The piperazine-cyclodextrin complex according to any of claims 1 to 5, further characterized in that the water-soluble cyclodextrin derivative is sulfobutyl-β-cyclodextrin having a substitution ratio of 70% or less, or a come out of it.

7. The piperazine-cyclodextrin complex according to any of claims 1 to 6, further characterized in that the water-soluble cyclodextrin derivative is sulfobutyl-β-cyclodextrin having a substitution ratio of 20% -50%, or a salt of it.

8. The piperazine-cyclodextrin complex according to any of claims 1 to 7, further characterized in that the water-soluble cyclodextrin derivative is the sodium salt of the sulfobutyl ether of β-cyclodextrin having a substitution ratio of about 33%.

9. The piperazine-cyclodextrin complex according to any of claims 1 to 3, further characterized in that the water-soluble cyclodextrin derivative is hydroxypropylcyclodextrin or a salt thereof.

10. The piperazine-cyclodextrin complex according to any of claims 1, 2, 3 or 9, further characterized in that the water-soluble cyclodextrin derivative is hydroxypropyl-β-cyclodextrin or a salt thereof.

11. The piperazine-cyclodextrin complex according to any of claims 1, 2, 3 or 10, further characterized in that the water-soluble cyclodextrin derivative is hydroxypropyl-β-cyclodextrin having a substitution ratio of 70% or less, or a salt of it.

12. The piperazine-cyclodextrin complex according to any of claims 1, 2, 3 or 11, further characterized in that the water-soluble cyclodextrin derivative is hydroxypropyl-β-cyclodextrin having a substitution ratio of 20-50 %, or a salt of it.

13. The piperazine-cyclodextrin complex according to any of claims 1, 2, 3 or 12, further characterized in that the water-soluble cyclodextrin derivative is hydroxypropyl-β-cyclodextrin having a substitution ratio of about 23% , or a salt of it.

14. The piperazine-cyclodextrin complex according to any of claims 1 to 3, further characterized in that the water-soluble cyclodextrin derivative is maltosylcyclodextrin or a salt thereof.

15. The piperazine-cyclodextrin complex according to any of claims 1, 2, 3 or 14, further characterized in that the water-soluble cyclodextrin derivative is maltosyl-β-cyclodextrin or a salt thereof.

16. An injection formulation containing a piperazine-cyclodextrin complex as defined in any of claims 1 to 15.

17. An injection formulation obtained by lyophilization of an aqueous solution containing a piperazine-cyclodextrin complex as described above. the one defined in any of claims 1 to 15.

18.- A therapeutic agent for the treatment of circulatory diseases containing as the active ingredient a piperazine-cyclodextrin complex as defined in any of claims 1 to 15.

19.- A therapeutic agent for the treatment of brain diseases which contains as the active ingredient a piperazine-cyclodextrin complex as defined in any of claims 1 to 15.

20. An agent for protecting the brain which contains as the active ingredient a piperazine-cyclodextrin complex as defined in any of claims 1 to 15.

21. The use of a piperazine-cyclodextrin complex as defined in any of claims 1 to 15 for the manufacture of a drug for the treatment of diseases of the circulatory system or diseases of the brain.