Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-05-08
2003-07-22
Ponda, Kathleen K. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S252120, C514S252130, C514S255030
Reexamination Certificate
active
06596706
ABSTRACT:
This application is the National Stage filed under 35 USC 371 of PCT/JP98/04896, filed Oct. 29, 1998.
The present invention relates to a piperazine-cyclodextrin complex which exhibits enhanced water solubility, excellent stability, and low topical stimulation and is useful as a therapeutic agent for circulatory diseases and diseases of the brain region.
BACKGROUND ART
Piperazine derivatives represented by the below-described formula (I) have been known to exhibit calmodulin-inhibition and to be useful as therapeutic agents for circulatory diseases and diseases of the brain region (Japanese Patent Application Laid-Open (kokai) No. 7-97364).
However, due to their poor water solubility, the piperazine derivatives (I) are difficult to be incorporated into an injection formulation. Even though an injection formulation is prepared from the piperazine derivatives (I), when the content of the derivatives increases, the formulation tends to provide topical stimulation due to hemolysis activity and vascular permeability attributed to the piperazine derivatives. Furthermore, there has also been a problem that the formulation has relatively low stability against light and its active component thereof is adsorbed on the container, depending on the material of the container, to thereby reduce the efficacy.
Therefore, an object of the present invention is to provide a piperazine-cyclodextrin complex which exhibits enhanced water solubility, excellent stability, and low topical stimulation.
DISCLOSURE OF THE INVENTION
In the light of the foregoing, the present inventors have conducted earnest studies and have found that a piperazine-cyclodextrin complex formed of a piperazine derivative represented by the below-described formula (I) and a water-soluble cyclodextrin derivative exhibits enhanced water solubility, excellent stability, and low topical stimulation and is useful as a therapeutic agent for circulatory diseases and diseases of the brain region. The present invention was accomplished based on this finding.
Accordingly, the present invention provides a piperazine-cyclodextrin complex formed of a piperazine derivative or a salt thereof and a water-soluble cyclodextrin derivative, wherein the piperazine derivative is represented by formula (I):
wherein Q represents
(1) an aryl group,
(2) a heterocyclic group,
(3) a diarylmethyl group,
(4) an aralkyl group formed of an aryl group and a C1-C6 alkylene group,
(5) a C1-C8 alkyl group, or
(6) a C3-C8 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 selected from among the following groups:
1) a C1-C6 alkyl group,
2) a C1-C6 alkoxyl group,
3) a trifluoromethyl group and a 2,2,2-trifluoroethyl group,
4) a trifluoromethoxyl group and a 2,2,2-trifluoroethoxyl group,
5) a C1-C6 alkylthio group,
6) a C1-C6 alkylsulfinyl group,
7) 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,
11) an amino group,
12) a monoalkylamino group having a C1-C6 alkyl group,
13) a dialkylamino group wherein 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 of a C1-C6 alkoxyl 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 piperazinosulfonyl group,
26) a 4-alkylpiperazinosulfonyl 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-C6 alkyl group, and
29) a 4-aminopiperidyl group;
R represents a bicyclic nitrogen-containing heterocyclic group (i) or a phenyl group (ii), wherein the nitrogen-containing heterocyclic group has a condensed 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 may 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 substituent G selected from the group consisting of the following groups:
(aa) a C1-C6 alkyl group,
(ab) a phenyl group which may have a substituent,
(ac) a benzyl group which may have a substituent in the phenyl group portion,
(ad) a benzoyl group which may have a substituent in the phenyl group portion,
(ae) a benzylcarbonyl group which may have a substituent in the phenyl group portion,
(af) a benzoylmethyl group which may have a substituent in the phenyl group portion,
(ag) an &agr;-hydroxybenzyl group which may have a substituent in 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 heteroatom is a nitrogen atom, the nitrogen atom is bonded to a hydrogen atom or to a C1-C6 alkyl group, or the nitrogen atom serves as the bonding site for the nitrogen-containing heterocyclic group or for the phenyl group,
(ai) a 5-membered aromatic heterocyclic group which may have a substituent and which contains as a heteroatom one nitrogen atom and as a second heteroatom a nitrogen atom, an oxygen atom, or a sulfur atom; wherein when the second heteroatom is a nitrogen atom, the nitrogen atom is bonded to a hydrogen atom or to a C1-C6 alkyl group, or the nitrogen atom serves as the bonding 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 heteroatoms two nitrogen atoms and as a third heteroatom a nitrogen atom, an oxygen atom, or a sulfur atom; wherein when the third heteroatom is a nitrogen atom, the nitrogen atom is bonded to a hydrogen atom or to a C1-C6 alkyl group, or the nitrogen atom serves as the bonding 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) a heterocyclic group-substituted alkyl group formed of a C1-C3 alkylene group and a 5-membered aromatic heterocyclic group, which may 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 bonded to a hydrogen atom or to a C1-C6 alkyl group,
(am) a heterocyclic group-substituted alkyl group formed of a C1-C3 alkylene group and a 5-membered aromatic heterocyclic group, which may have a substituent and contains as a heteroatom one nitrogen atom and as a second heteroatom a nitrogen atom, an oxygen atom, or a sulfur atom; wherein when the second heteroatom is a nitrogen atom, the nitrogen atom is bonded to a hydrogen atom or to a C1-C6 alkyl group, or the nitrogen atom serves as the bonding site for the alkylene group,
(an) a heterocyclic group-substituted alkyl group formed of a C1-C3 alkylene group and a 5-membered aromatic heterocyclic group, which 5-membered aromatic heterocyclic group may have a substituent and contains as heteroatoms two nitrogen atoms and as a third heteroatom a nitrogen atom, an oxygen atom, or a sulfur atom; wherein when the third heteroatom is a nitrogen atom, the nitrogen atom is bonded to a hydrogen atom or to a C1-C6 alkyl group, or the nitrogen atom serves as the bonding site for the alkylene group,
(ao) a heterocyclic group-substituted alkyl group formed of a C1-C3 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 for
Kikuchi Masahiko
Nagase Yukihiko
Uekama Kaneto
Daiichi Pharmaceutical Co. Ltd.
Maier Leigh C.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Ponda Kathleen K.
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