TW200900066A - Quinolone medical composition containing alcohols - Google Patents

Abstract

The present invention provides a steady aqueous composition containing quinolone. A steady aqueous composition containing quinolone is obtained by controlling the formation of unsoluble microcorpuscle and/or the analogous material through adding alcohols, more desirably a alcohol of carbons. number from one to three.

Description

。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 [Prior Art] When an aqueous preparation is selected as a dosage form for a quinophthalone compound having an excellent antibacterial agent, insoluble microparticles in the form of a brown gel sometimes occur. The number of insoluble fine particles in the aqueous liquid preparation is not limited unless it is specified as the limit. Inhibition of the occurrence of insoluble fine particles, the addition of an organic acid, an amino acid, a polyaminocarboxylic acid or a polyvalent alcohol to the ozagrel sodium injection to suppress the formation of insoluble fine particles (Patent Documents 1 and 2). Further, a sugar alcohol is added to the quinacridone carboxylic acid-based antibacterial agent to suppress the decrease in the content during storage and the increase in the insoluble fine particles, thereby improving the stability (Patent Document 3). However, in these methods, there is a case where the effect of suppressing the formation of insoluble fine particles is insufficient. In the case of an aqueous preparation containing an alcohol, difloxacin is used as an active ingredient in an injection; L-arginine, propylene glycol, ethanol and benzyl alcohol are added to reduce the tissue damage at the site of administration (Patent Document 4) ). However, the effect of stabilization of aqueous preparations such as the effect of suppressing the formation of insoluble microparticles is still unknown. [Patent Document 1] JP-A-2003-63963 (PATENT DOCUMENT 2) JP-A-2006-63963 [PATENT DOCUMENT 3] US Patent No. 6,872,723 Contents 200900066 (Problem to be Solved by the Invention) The object of the present invention is to obtain a more stable aqueous preparation containing quinacridone. (Means for Solving the Problem) The inventors of the present invention have made efforts to review the suppression of insoluble fine particles by various additives. As a result, it was found that the addition of alcohols such as concentrated glycerin, absolute ethanol, and propylene glycol reduced the number of insoluble fine particles. Further, it has been found that the addition of the alcohol not only reduces the insoluble fine particles but also suppresses the formation of the terpenoids, and finally completed the present invention. C', i.e., the present invention is an aqueous preparation relating to the stability of a quinophthalone compound and an alcohol. Further, the present invention relates to a method for stabilizing an aqueous preparation containing quinacridone characterized by adding an alcohol to an aqueous solution containing a quinophthalone compound. (Effect of the Invention) The aqueous alcohol-added preparation of the present invention inhibits the occurrence of insoluble fine particles by the addition of an alcohol, and improves storage stability. Further, the addition of an alcohol can also inhibit the formation of an anthraquinone-like substance, and an aqueous preparation containing quinacridone which is stable in stability and stability can be improved. [Embodiment] (Best Mode for Carrying Out the Invention) The present invention relates to an aqueous preparation of an alcohol containing a quinophthalone compound as an active ingredient and a stabilizer component. The stilbene compound of the active ingredient of the aqueous preparation of the present invention is not limited, and may be a structure of the following formula (1). 200900066

[wherein R1 is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a chiral alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms which may be substituted by a halogen atom, The alkoxy group having 1 to 6 carbon atoms, the alkylamino group having 1 to 6 carbon atoms, the phenyl group, or the carbon may include a nucleus atom as a nucleus. The alkane of the alkyl group having 1 to 6 alkyl groups may have a halogen atom, a hydroxyl group 'amine group, a nitro group, an alkoxy group substituted with a carbon number of 1 to 6 2 and 1 to 6 or an alkoxy group substituted with an alkoxy group, or a heteroaryl group which may have a halogen atom or an alkyl group having 1 to 6 carbon atoms; R2 is a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms; and R1 and a part of R are integrated to form a cyclic structure, and the ring is formed. It may have a narrow constituent atom, and the ring may have an alkyl group having 1 to 6 carbon atoms, and R3 is a hydrogen atom or an amine group (the amine group may have a methyl group, a carbon number or a carbon number of 2 to 5). Substituted), thiol group, halomethyl group, β group, alkenyl group having 2 to 6 carbon atoms, alkynyl group having 2 to 6 carbon atoms, or oxy group; Α1 is a nitrogen atom or a partial structure of the following formula (2),

(2) (wherein X2 is a hydrogen atom or an amine group (the amine group may have a methyl group, a carbon number of 1 to 6 of 200900066 alkyl or a carbon number of 2 to 5 thiol), a halogen atom, a cyano group, a halomethyl group, a halomethoxy group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms; The above R1 may include a part of the mother nucleus and integrally form a ring structure, and the ring thus formed may contain an oxygen atom, a nitrogen atom, or a sulfur atom as a constituent atom of the ring, and the ring may have a carbon number of 1 to 6. The alkyl group is a substituent); each of A2 and A3 is a nitrogen atom or a carbon atom, but a1, A2 and A3 form a partial structure with these bonded carbon atoms as follows.

Or X1 is a halogen atom or a hydrogen atom; Y is a hydrogen atom, a phenyl group, an acetoxymethyl group, a p-pentyloxymethyl 'ethoxycarbonyl group, a methylpyridyl group, a dimethylaminoethyl group, 5 -hydroindolyl, fluorenyl, 5-alkyl-2-oxo-1,3-dioxan-4-ylmethyl, 3-ethyloxy-2-oxobutyl, carbon number 1~6 An alkyl group, an alkoxymethyl group having 2 to 7 carbon atoms or a phenylalkyl group having a C 1 to 6 alkyl group and a phenyl group; Z is a monocyclic, bicyclic or tricyclic ring. a heterocyclic substituent which may be saturated or partially saturated 'may contain a hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and may be a bicyclic structure or a spiro ring structure, but may be There are an atomic atom, a hydroxyl group, an amine group, an amine carbenyl group, an alkyl group having a carbon number of 200900066 1 to 6, a haloalkyl group having a carbon number of 1 to 6, an aryl group, a heteroaryl group, and an alkoxy group having a carbon number of 1 to 6. One or two or more atoms or groups of the group selected from the group consisting of an alkylamine having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, and an amine alkyl group having 1 to 6 carbon atoms are selected]. In the compound of the above formula (1), R1 is an alkyl group having 1 to 6 carbon atoms; an alkenyl group having 2 to 6 carbon atoms; a haloalkyl group having 1 to 6 carbon atoms; and a carbon number of 3 to 6 which may be substituted by a halogen atom. a cyclic alkyl group; an alkoxy group having 1 to 6 carbon atoms; an alkylamino group having 1 to 6 carbon atoms; may have a halogen atom, a hydroxyl group, an amine group, a nitro group, an alkyl group having 1 to 6 carbon atoms, or carbon An alkoxy-substituted aryl group of 1 to 6; or a heteroaryl group which may have a halogen atom or an alkyl group having 1 to 6 carbon atoms. The alkyl group having 1 to 6 carbon atoms is particularly preferably ethyl. The alkenyl group having 2 to 6 carbon atoms is particularly preferably a vinyl group or a 1-isopropenyl group. The haloalkyl group having a carbon number may be an alkyl group having 1 to 6 carbon atoms which has a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and is preferably a 2-fluoroethyl group. A cyclic alkyl group having 3 to 6 carbon atoms is particularly preferred as a cyclopropyl group. When the cyclic alkyl group has a substituent, the substituent is preferably a halogen atom, and the fluorine atom is particularly preferably f. This fluorocyclopropyl group is particularly preferably 2-(S)-fluoro-1-(R)-cyclopropyl. The aryl group may be selected from the group consisting of a halogen atom such as a fluorine atom, a chlorine atom or a bromine atom, a hydroxyl group, an amine group, a nitro group, an alkyl group having 1 to 6 carbon atoms, and an alkoxy group having 1 to 6 carbon atoms. a phenyl group having 1 to 3 atoms or a substituent, and a phenyl group, a 2-fluorophenyl group, a 4-fluorophenyl group, a 2,4-difluorophenyl group, a 2-fluoro-4-hydroxyphenyl group, 3-Amino-4,6-difluorophenyl and 4,6-difluoro-3-methylaminophenyl are preferred. The heteroaryl group is an aromatic heterocyclic substituent which is induced by an aromatic heterocyclic compound which may have a 5-membered ring or a 6-membered ring which is a halogen atom or an alkyl group having 1 to 6 carbon atoms. The heteroaryl group is a hetero atom having a nitrogen atom, an oxygen atom or a sulfur atom selected from 200900066, such as a pyridyl group, a pyrimidinyl group or the like, and a 6-amino-3,5-difluoro-2-pyridyl group. good. The oxy group having a carbon number of 1 to 6 is particularly preferred as a methoxy group. The amine group having a carbon number of 1 to 6 is preferably a methylamino group. The substituent R1 is preferably a cyclic alkyl group or a ring-shaped cycloalkyl group. The cyclic alkyl group is preferably a cyclopropyl group, the halocyclopropyl group is preferably a 2-halocyclopropyl group, and the 2-fluorocyclopropyl group is preferably a formula (1), and R 2 is a hydrogen atom or a carbon number of 1~ 6 alkylthio. The carbon number is 1 to 6 ('the alkylthio group is preferably a methylthio group or an ethylthio group. The substituent R2 is preferably a hydrogen atom. In the formula (1), R1 and R2 may include a part of the mother nucleus and are integrally formed. The ring structure may contain a sulfur atom as a constituent atom of the ring, and the ring may have a carbon number of 1 to 6 as a substituent. The alkyl group is preferably a methyl group. • In the formula U), 'R3 is a hydrogen atom or an amine group (the amine group may have a methyl group, an alkyl group having 1 to 6 carbon atoms or a mercapto group having 2 to 5 carbon atoms (alkylcarbonyl group)), a thiol group halomethyl group, and a carbon number of 1 An alkyl group of ~6, an alkenyl group having 2 to 6 carbon atoms, an alkyne having a carbon number of 2 to 6 f:j" group, or an alkoxy group having 1 to 6 carbon atoms. The amine group which may have a mercapto group, an alkyl group having 1 to 6 carbon atoms or a mercapto group having 2 to 5 carbon atoms may be, for example, a formamidine group, an ethenyl group or the like, and is particularly preferably an acetamino group. The alkyl group having 1 to 6 carbon atoms may be a methyl group or an ethyl group, and is preferably a methyl group. The alkenyl group having 2 to 6 carbon atoms is particularly excellent in vinyl. The alkynyl group having 2 to 6 carbon atoms is particularly preferred as an ethynyl group. Further, the alkoxy group having 1 to 6 carbon atoms is particularly preferred as the methoxy group. The substituent R3 is preferably a hydrogen atom. In the formula (1), A1 is a nitrogen atom or a moiety as defined in the formula (2)-10-200900066 T(2) ο In the formula (2), X2 is a hydrogen atom or an amine group (this amine group may have a methyl group, a carbon number of 1) a group of ~6 or a carbon number of 2 to 5 substituted), a halogen atom, a cyano 'halomethyl group, a halomethoxy group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, An alkynyl group having 2 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms. The amine group which may have a mercapto group, an alkyl group having 1 to 6 carbon atoms or a mercapto group having 2 to 5 carbon atoms is particularly preferably an acetamino group. The alkyl group having 1 to 6 carbon atoms is particularly preferred as a methyl group. The alkenyl group having 2 to 6 carbon atoms is particularly excellent in vinyl. The alkynyl group having a carbon number of 2 to 6 is particularly preferably an ethynyl group. Further, the alkoxy group having 1 to 6 carbon atoms is particularly preferred as the methoxy group. The X2 and the above R1 may include a part of the mother nucleus and be integrated to form a cyclic structure, and the ring thus formed may contain an oxygen atom, a nitrogen atom, or a constituent atom in which a sulfur atom is a ring. The ring may further have an alkyl group having 1 to 6 carbon atoms as a substituent. The ring structure thus formed is preferably a pyridobenzoindole skeleton of a framework such as ofloxacin. The alkyl substituent of this skeleton is more preferably a methyl group, and particularly preferably a (3S)-methyl group. The substituent A1 is preferably a moiety of the formula (2). The substituent X2 is preferably a methyl group, a methoxy group or a difluoromethoxy group. In the formula (1), each of A2 and A3 is a nitrogen atom or a carbon atom. A1, A2 and A3 form a partial structure with these bonded carbon atoms as follows

Or the following part of the structure -11 - 200900066

That is, the following constructor R3 Q

C00Y

N1R

R

These partial configurations are preferably constructed in the following parts.

Further, A1 is preferably constructed as in the above formula (2), so that it is preferably constructed as follows.

C00Y .3

In the formula (1), X1 is a halogen atom or a hydrogen atom, and when it is a halogen atom, it is preferably a fluorogenic -12-200900066. The substituent X1 is preferably a fluorine atom or a hydrogen atom. In the formula (π, γ is a hydrogen atom, phenyl, acetoxymethyl, thiol, ethoxycarbonyl, methylpyridyl, dimethylaminoethyl, 5-entributyl, 5-alkyl-2- Oxygen, iota, 3-dimethyl-4-ylmethyl, 3-ethyl@oxybutyl, alkyl having 1 to 6 carbon atoms, alkyloxymethyl group having 1 to 6 carbon atoms and 1 to 6 alkylene The phenyl group consisting of a phenyl group and a phenyl group. The substituent Υ is preferably a nitrogen atom. k is a compound of the formula (1), and z is a monocyclic, bicyclic or tricyclic substituent. The substituent is saturated or partially saturated, and may have a hetero atom of one or more selected from the group consisting of a donor, an oxygen atom and a sulfur atom. A more structural or spirocyclic structure. The heterocyclic substituent may have a substituent atom, a hydroxyl group, an amine group, Aminomethyl fluorenyl group, a C 1~6 alkane '1~6 haloalkyl group, an aryl group, a heteroaryl group, an alkyl alkoxy group having 1 to 6 carbon atoms of 1 to 6 and a carbon number of 1 to 6 An alkylthio group or a carbon number of 1 to 6. The atom or group which may be substituted with a heterocyclic substituent may be 1 or more. The alkyl halide having 1 to 6 carbon atoms which may be substituted with the above heterocyclic substituent Atom, a hydroxyl group, an amine group, an amine carbenyl group, an alkoxy group having a carbon number of 1 to 6 and a halogen number of 1 to 6, and an alkylamine having 1 to 6 carbon atoms An alkyl group having 1 to 6 carbon atoms and 1 to 6 carbon atoms selected from the group consisting of an original substituent of 1 or more, and an alkyl group which may be substituted with a heterocyclic substituent may be a haloalkyl group or an alkane The alkyl moiety of the amine group, the alkylthio group and the amine alkyl group may further have a halogen atom, a carbon number of 1 to 6 and a carbon number pentamyl methoxymethyl hydrazine group, an oxy group, or The carbon heterocyclic ring may be a bicyclic ring derived from a nitrogen atom, for example, a halogen group, a carbon number group, or a carbon number amino group, or two may be substituted by an alkyl group, a carbon alkyl group or a group. One or more atoms or groups selected from the group consisting of a cyclic 1 to 6 alkane-13-200900066 oxy group may be a substituent. Further, the amine group of the above amine group, alkylamino group and amine alkyl group may have carbon. a number of alkyl groups (the alkyl group may have a cyclic structure, or may be selected from the group consisting of a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms, and an alkoxy group having 1 to 6 carbon atoms; One or two of the substituents are one or two substituents, and if they are two, they may be the same or different. Further, the amine moiety may be protected by a protecting group which is usually used, and may be substituted with the above heterocyclic substituent. The alkyl group having 1 to 6 haloalkyl groups, the carbon number f \ I 1 to 6 alkyl group, the alkyl group having 1 to 6 carbon atoms, and the alkyl group having 1 to 6 carbon atoms may have a cyclic structure. Further, an atom or a group selected from the group consisting of a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an aryl group and a heteroaryl group may be a substituent. The amine group having an amino group substituted with the above heterocyclic substituent, an alkylamino group having 1 to 6 carbon atoms, and an amine alkyl group having 1 to 6 carbon atoms may have 1 or more alkyl groups having 1 to 6 carbon atoms. The substituents may be protected by a protecting group. The alkyl group on the amine group may be the same or different in the case of two alkyl groups. Here, the alkyl group having 1 to 6 carbon atoms may have a cyclic structure or may be One or more atoms or groups selected from the group consisting of a halogen atom, a hydroxyl group, an alkylthio group having 1 to 6 carbon atoms, and an alkoxy group having 1 to 6 carbon atoms are substituents. The protecting group of the amine group is not limited as long as it is widely used in the field, for example, an alkoxycarbonyl group such as a third butoxycarbonyl group or a 2,2,2-trichloroethoxycarbonyl group; a benzyloxycarbonyl group and a p-methoxybenzyl group; An aralkoxycarbonyl group such as an oxycarbonyl group or a p-benzyloxycarbonyl group; an ethyl fluorenyl group, a methoxyethyl fluorenyl group, a trifluoroethyl fluorenyl group, a chloroethylene group, a pentamidine group, a decyl group, a benzhydryl group, or the like. Terpenyl; butyl, benzyl, p-nitrobenzyl-14- 200900066, p-methoxybenzyl, trityl, etc. alkyl, or aralkyl; methoxymethyl, third Ethers such as butoxymethyl, tetrahydropyranyl, 2,2,2-trichloroethoxymethyl; trimethyldecyl, isopropyldimethylhydrazine, tert-butyldimethylsilane The alkyl group, the tribenzyl decyl group, the tert-butyl diphenyl fluorenyl group, etc. (alkyl and/or aralkyl) are substituted for the decyl group. The aryl group which may be substituted with the above heterocyclic substituent is a carbon number of 6 to 10, and the heteroaryl group is a 5-membered ring or a 6-membered ring, and may have 1 to 4 kinds of impurities selected from a nitrogen atom, an oxygen atom and a sulfur atom. atom. (' The aryl and heteroaryl group which may be substituted with the above heterocyclic substituent may be a halogen atom, a hydroxyl group, a thiol group, an amine group, a nitro group, a cyano group, a carboxyl group, an amine carbaryl group, a phenyl group, Alkyl groups having 1 to 6 carbon atoms, alkoxy groups having 1 to 6 carbon atoms, alkylthio groups having 1 to 6 carbon atoms, alkoxycarbonyl groups having 2 to 6 carbon atoms, fluorenyl groups having 2 to 5 carbon atoms, and heteroaryl groups One or more atoms or groups selected from the group consisting of a 5-membered ring or a 6-membered ring and having 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a 'sulfur atom are substituted groups. a phenyl group substituted with an aryl group and a heteroaryl group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkylthio group having a carbon number of 1 to 6 and a carbon number of 2 to 6 The oxycarbonyl group, the fluorenyl group having 2 to 5 carbon atoms and the heteroaryl group are selected from the group consisting of a halogen atom, a meridine group, an alkoxy group having 1 to 6 carbon atoms, and an alkylthio group having 1 to 6 carbon atoms. One or more of the atoms or groups are a substituent. The amine group which may be substituted with an aryl group and a heteroaryl group may be an alkyl group having a methyl group, a carbon number of 丨6, or an acid group having a carbon number of 2 to 5. And the group of 1 or 2 selected from the group of carbon number 2 to 5 is a substituent. The substituent Z can be a ring to form a ring. Any atom is bonded to the quinacridone parent group -15-200900066, and the nitrogen atom is preferably bonded only. The heterocyclic substituent bonded to the nitrogen atom is a substituent of the following formula (3) to (7): Formula (3)

[wherein R4, R5, R5', R6, R6', R7 and R8 are a substituent of the heterocyclic substituent as shown in the above Z. More specifically, each of R4, R5 and R6 is independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and if the alkyl group is a halogen atom, a hydroxyl group, an amine group or an amine group, the carbon number is 6 a group of an alkylthio group, an alkoxy group having 1 to 6 carbon atoms, an alkylamino group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, and an amine alkyl group having 1 to 6 carbon atoms. The alkyl group selected as the substituent or the alkyl group may have a cyclic structure in the alkyl moiety of the alkyl-substituted alkylthio group, the alkylamino group, the haloalkyl group and the amine alkyl group, and more preferably One or more atoms or groups selected from the group consisting of a halogen atom, an alkyl group having 1 to 6 carbon atoms, and an alkoxy group are substituents. Further, the amino group substituted with an alkyl group, an amine alkyl group and an alkylamino group may have an alkyl group having 1 to 6 carbon atoms (the alkyl group may have a cyclic structure or may have a halogen atom, a hydroxyl group, or One or two or more substituents are selected from the group consisting of an alkylthio group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms, and a substituent (if two, The same or different), and more preferably the amine moiety can be protected by a protecting group which is usually used. R5' and R6' are each independently a hydrogen atom, an aryl group or a heteroaryl group, and the -16-200900066 aryl group has a carbon number of 6 to 10, and the heteroaryl group is a 5-membered ring or a 6-membered ring. ~4 hetero atoms selected arbitrarily from a nitrogen atom, an oxygen atom and a sulfur atom, the above aryl and heteroaryl groups may have a halogen atom, a hydroxyl group, a thiol group, an amine group, a nitro group, a cyano group, a carboxyl group, an amine group Mercapto group, phenyl group, alkyl group having 1 to 6 carbon atoms, alkoxy group having 1 to 6 carbon atoms, alkylthio group having 1 to 6 carbon atoms, alkoxycarbonyl group having 2 to 6 carbon atoms, carbon number 2~ a group of 5 or more selected from the group consisting of a sulfhydryl group and a heteroaryl group (a 5-membered ring or a 6-membered ring may have one to four hetero atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom) The substituent is a substituent, Γ' k wherein the alkyl group, the alkoxy group, the alkylthio group, the alkoxycarbonyl group, the fluorenyl group, the phenyl group and the heteroaryl group may have an alkoxy group having a halogen atom, a hydroxyl group and a carbon number of 1 to 6. One or more atoms or groups selected from the group consisting of an alkylthio group having 1 to 6 carbon atoms are a substituent, and the amine group may have a methyl group, an alkyl group having 1 to 6 carbon atoms, and a carbon number of 2 to 2. Base selection of a group of 5 thiol groups and alkoxycarbonyl groups having 2 to 5 carbon atoms The base of 1 or 2 is chosen as a substituent. R7 and R8 are each independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. Any two selected from the above R5, R5', R6, and R6' may form a cyclic structure integrally, and may have a hetero atom of one or more selected from an oxygen atom, a nitrogen atom, and a sulfur atom. atom. The ring thus formed may have a group selected from the group consisting of a halogen atom, a hydroxyl group, an amine group, an alkyl group having a carbon number of 丨6, an alkoxy group having 1 to 6 carbon atoms, and an alkylthio group having 1 to 6 carbon atoms. The above atom or group is a substituent, and the amine group may further comprise a mercapto group, an alkyl group having 1 to 6 carbon atoms, a fluorenyl group having 2 to 5 carbon atoms, and an alkoxycarbonyl group having 2 to 5 carbon atoms. The group 1 or 2 of the group is selected as a substituent], or the following formula (4) -17- 200900066

[wherein R7, R7', R8, R8' 'R9 'R10 'R10>, R11 and R11' are the substituents on the heterocyclic substituent represented by the above Z. More specifically, each of R11 and R11' is independently a hydrogen atom or an alkyl group having a carbon number of 6, and the alkyl group may have an alkylthio group having a halogen atom, a hydroxyl group, an amine group, an amine formazan group, and a carbon number of 1 to 6. One or more groups selected from the group consisting of alkoxy groups having 1 to 6 carbon atoms, alkylamino groups having 1 to 6 carbon atoms, haloalkyl groups having 1 to 6 carbon atoms, and amine alkyl groups having 1 to 6 carbon atoms. The atom or the group is a substituent, and R9, R1() and R1()' are each independently a hydrogen atom, a halogen atom, an amine group, a hydroxyl group, an amine carbenyl group, an alkyl group having 1 to 6 carbon atoms, and a carbon number of 1 to 6 An alkylamino group, an aryl group, a heteroaryl group, an alkoxy group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, or an amine having 1 to 6 carbon atoms. The alkyl group, the alkyl moiety of the alkyl group, the alkylthio group, the haloalkyl group, the amine alkyl group and the alkylamino group may have a cyclic structure, and may further have a halogen atom, an alkyl group having 1 to 6 carbon atoms, and a carbon number. One or more atoms or groups selected from the group consisting of 1 to 6 alkoxy groups are substituents, and the amino group of the above amine group, alkylamino group and amine alkyl group may have an alkyl group having a carbon number (this alkyl group) It may have a cyclic structure, and may have a halogen atom, a hydroxyl group, an alkylthio group having 1 to 6 carbon atoms, and a carbon number of 1 to 6 The group in which the oxy group is selected is one or more atoms or a substituent is a substituent. One or two are substituents (if two or more may be the same or different), the amine moiety may be protected by a commonly used protecting group. -18- 200900066 Further, the above aryl group is a carbon number of 6 to 10, and the heteroaryl group is a 5-membered ring or a 6-membered ring, and may have 1 to 4 hetero atoms selected arbitrarily by a nitrogen atom, an oxygen atom and a sulfur atom. The above aryl and heteroaryl groups may have a halogen atom, a hydroxyl group, a thiol 'amine group, a nitro group, a cyano group, a carboxyl group, an amine methyl group, a phenyl group, an alkyl group having 1 to 6 carbon atoms, and a carbon number of 1. Alkoxy group of ~6, alkylthio group having 1 to 6 carbon atoms, alkoxycarbonyl group having 2 to 6 carbon atoms, mercapto group having 2 to 5 carbon atoms, and heteroaryl group (5-membered ring or 6-membered ring) One or more atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, optionally selected, are selected from the group consisting of more than one atom or a substituent, wherein the alkyl group, the alkoxy group, and the alkylthio group are selected. The alkoxycarbonyl group, the fluorenyl 'phenyl group and the heteroaryl group may be selected from the group consisting of a halogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, and an alkylthio group having 1 to 6 carbon atoms. An atom or a base is a substituent, and The amine group may have a base of 1 or 2 selected from the group consisting of a methyl group, a carbon number of 丨~6, a carbon number of 2 to 5, and an alkoxycarbonyl group having 2 to 5 carbon atoms. As a substituent. R7, R7', R8 and R8' are each independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. Any two selected from the above, R7, R7', R8, R8', R9, Rl(), and R1()' may be integrated to form a cyclic structure, and may be optionally composed of an oxygen atom, a nitrogen atom, and a sulfur atom. The hetero atom selected as one or more is a constituent atom of the ring, and the ring thus formed may have a halogen atom, a hydroxyl group, an amine group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and a carbon number. The group of 1 to 6 alkylthio groups is selected to be more than 1 atom or the substituent is a substituent. The amine group may further have a methyl group 19-200900066, an alkyl group having 1 to 6 carbon atoms, and a carbon number of 2 The base of the group of ~5 and the alkoxy group of 2 to 5 carbon atoms are selected as the substituent or the substituent is as follows] or the following formula (5)

[wherein R7, R7', R8, R8' 'R9 ' R10 ' R10' ' R" 'R11', R12 and R12' are the substituents on the heterocyclic substituent represented by the above Z. More specifically, R11 and R11' are each independently a hydrogen atom or a carbon number of 丨~6, and the base may have a halogen atom, a hydroxyl group, an amine group, an amine mercapto group, and a carbon number of 1 to 6. A group selected from the group consisting of an alkylthio group and an alkoxy group having a carbon number of 丨6, an alkylamino group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, and an amine alkyl group having a carbon number of 丨6. The above atom or group is a substituent. R9, R1() and Rl°' are each independently a hydrogen atom, a quiescent atom, a hydroxyl group, an amine group, an amine carbenyl group, an alkyl group having a carbon number, an alkylamino group having 1 to 6 carbon atoms, an aryl group or a heteroaryl group. , an alkoxy group having a carbon number of 1 to 6, a thiol group having a carbon number of 1 to 6, a haloalkyl group having a carbon number of 1 to 6, or an alkyl group having a carbon number of 1 to 6 'the above alkyl group, an alkylthio group, The alkyl moiety of the haloalkyl group, the amine alkyl group and the carbon number alkylamino group may have a cyclic structure, and may further comprise a halogen atom, a hospital group having 1 to 6 carbon atoms, and an alkoxy group having 1 to 6 carbon atoms. One or more of the atoms or groups selected as the group are substituents. Further, the amine group of the above amino group, alkylamino group and amine alkyl group may have an alkyl group having 1 carbon number (the alkyl group may have a cyclic structure, or may have a halogen atom, a hydroxyl group, or a carbon-20-200900066 number 1 One or two or more substituents selected from the group consisting of an alkylthio group of 1-6 and an alkoxy group having 1 to 6 carbon atoms are one or two substituents (the same or different if two) This amine moiety can be protected by a protecting group which is usually used. R12 and R12' are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group or a heteroaryl group. The aryl group is a carbon number of 6 to 10, and the heteroaryl group is a 5-membered ring or a 6-membered ring, and may have one to four hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. The aryl group may have a halogen atom, a hydroxyl group, a thiol group, an amine group, a nitro group, a cyano group, a carboxyl group, an amine group, a phenyl group, an alkyl group having 1 to 6 carbon atoms, and a carbon number of 6 Base, carbon number 1~6 sulphur base, carbon number 2~6 兀 兀 oxycarbonyl, carbon number 2~5 sulfhydryl and heteroaryl (5 member ring or 6 member ring ' and may have 1 ~ Four or more atoms or groups selected from the group consisting of four nitrogen atoms, oxygen atoms and sulfur atoms arbitrarily selected as a substituent, 'alkyl group, alkoxy group, alkylthio group, alkoxycarbonyl group The mercapto group, the phenyl group and the heteroaryl group may be substituted by a group of 1 or more atoms selected from the group consisting of a halogen atom 'hydroxy group, an alkoxy group having 1 to 6 carbon atoms, and an alkylthio group having 1 to 6 carbon atoms. Base, ^ and the amine group may have a group consisting of a fluorenyl group, an alkyl group having 1 to 6 carbon atoms, a fluorenyl group having 2 to 5 carbon atoms, and an alkoxycarbonyl group having 2 to 5 carbon atoms. Or 2 is a substituent. R7, R7', R8 and R8' are each independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. Any two selected from the above, H7, R7, R8, R8' 'R9 'R10 'R10, R12 and R12' may be integrated to form a cyclic structure, and may have an oxygen atom, a nitrogen atom, and a sulfur atom. Any one or more of the heteroatoms selected is the constituent atom of the -21 - 200900066 ring. The ring thus formed may have a group selected from the group consisting of a halogen atom, a hydroxyl group, an amine group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and an alkylthio group having 1 to 6 carbon atoms. The above atom or group is a substituent, and the amine group may further comprise a group consisting of a fluorenyl group, an alkyl group having 1 to 6 carbon atoms, a fluorenyl group having 2 to 5 carbon atoms, and an alkoxycarbonyl group having 2 to 5 carbon atoms. The base of choice 1 or 2 is a substituent] or the following formula (6)

[wherein R", R13, 'R'4' R14', R15, R16 and R16 are the substituents on the heterocyclic substituent represented by the above Z. More specifically, R13 and R13' are each independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the alkyl group may have an alkyl group having a halogen atom, a hydroxyl group, an amine group, an amine carbenyl group, and a carbon number of 1 to 6. One or more selected from the group consisting of a sulfur group and an alkoxy group having 1 to 6 carbon atoms, an alkylamino group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, and an amine alkyl group having a carbon number of 6 An atom or a base is a substituent. R14, R14', R15, R16 and R16' are each independently a hydrogen atom, a halogen atom, a hydroxyl group, an amine group, an amine carbenyl group, an alkyl group having 1 to 6 carbon atoms, an alkylamino group having 1 to 6 carbon atoms, and an aromatic group. a base, a heteroaryl group, an alkoxy group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, or an alkyl group having 1 to 6 carbon atoms, and the above alkyl group The alkyl moiety of the alkylthio group, the haloalkyl group, the amine alkyl group and the alkylamino group may have a cyclic structure, and may further have a halogen atom, an alkyl group having a carbon number, and an alkoxy group having a carbon number of 1 to 6. The group or group of atoms or groups selected by the group is substituted for the -22-200900066 base. Further, the amine group of the above amine group, amine alkyl group and alkylamino group may have an alkyl group having 1 to 6 carbon atoms (the alkyl group may have a cyclic structure, or may have a halogen atom, a hydroxyl group, or a carbon number of 1 to 6). One or two or more substituents selected from the group consisting of an alkylthio group and an alkoxy group having 1 to 6 carbon atoms are one or two substituents (the same or different if two) The amine moiety can be protected by a protecting group which is usually used. The above aryl group has a carbon number of 6 to 10, and the heteroaryl group is a 5-membered ring or a 6-membered ring, and may have one to four heterogeneously selected from a nitrogen atom, an oxygen atom and a sulfur atom. The above aryl and heteroaryl groups may have a halogen atom, a hydroxyl group, a thiol group, an amine group, a nitro group, a cyano group, a carboxyl group, an aminomethyl group, a phenyl group, an alkyl group having 1 to 6 carbon atoms, and a carbon number of 1. ~6 alkoxy group, carbon number 1 to 6 alkylthio group, carbon number 2 to 6 alkoxycarbonyl group, carbon number 2 to 5 fluorenyl group and heteroaryl group (5 member ring or 6 member ring, but 'A group having 1 to 4 hetero atoms selected arbitrarily selected from a nitrogen atom, an oxygen atom and a sulfur atom, or a substituent selected from the group consisting of an alkyl group, an alkoxy group, an alkylthio group, The alkoxycarbonyl group, the fluorenyl group, the phenyl group, and the heteroaryl group may be selected from the group consisting of a halogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, and an alkylthio group having 1 to 6 carbon atoms. The atom or the group is a substituent, and the amine group may further comprise a group consisting of a fluorenyl group, an alkyl group having 1 to 6 carbon atoms, a fluorenyl group having 2 to 5 carbon atoms, and an alkoxycarbonyl group having 2 to 5 carbon atoms. The 1 or 2 group selected by the group is a substituent. Any two of Rm, R14', R15, R16, and R16' may be integrally formed into a cyclic structure, and one or more hetero atoms selected arbitrarily from an oxygen atom, a nitrogen atom, and a sulfur atom may be a ring. atom. -23 - 200900066 The ring thus formed may have a halogen atom, a trans group, an amine group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and an alkylthio group having 1 to 6 carbon atoms. The group of atoms or groups selected by the group is a substituent, and the amine group may further have a methyl group, a carbon number of 1 to 6, an alkyl group having 2 to 5 carbon atoms, and an alkoxy group having 2 to 5 carbon atoms. The base of the group formed by the carbonyl group is selected to be a substituent or a formula (7)

[wherein R13, R13, R14, R14, R15, R16, R16, and R17 and R17' are the substituents on the heterocyclic substituent represented by the above Z. More specifically, R13 and R13' are each independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the alkyl group may have a halogen atom, a hydroxyl group, an amine group, an amine methyl group, and a carbon number of 1 to 6. Group selection of alkylthio groups and alkoxy groups having 1 to 6 carbon atoms, alkylamino groups having 1 to 6 carbon atoms, haloalkyl groups having 1 to 6 carbon atoms and amine alkyl groups having 1 to 6 carbon atoms The base of 1 or more is a substituent. Wherein R14, R14', R15, R16 and R16' are each independently a hydrogen atom, a halogen atom, an amine group, a hydroxyl group, an amine carbenyl group, an alkyl group having 1 to 6 carbon atoms, and an alkylamino group having 1 to 6 carbon atoms. , an aryl group, a heteroaryl group, an alkoxy group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, a haloalkyl group having a carbon number of 1-6 or an alkyl group having a carbon number of 1 to 6 > The alkyl moiety of the above alkyl group, alkylthio group, haloalkyl group, amine alkyl group and alkylamino group may have a cyclic structure, and may further have a halogen atom, a carbon number, an alkyl group of 1 to 6, and a carbon-24-. 200900066 A group of 1 or more atoms or groups selected from the group consisting of alkoxy groups of 1 to 6 is a substituent. Further, the amine group of the above amine group, amine alkyl group and alkylamino group may have an alkyl group having 1 to 6 carbon atoms (the alkyl group may have a cyclic structure, or may have a halogen atom, a hydroxyl group, or a carbon number of 1 to 6). One or two or more substituents selected from the group consisting of an alkylthio group and an alkoxy group having 1 to 6 carbon atoms are one or two substituents (the same or different if two) The amine moiety can be protected by a protecting group which is usually used. R17 and R17' are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group or a heteroaryl group, and the aryl group is a carbon number of 6 to 10, and the heteroaryl group is a 5-membered ring or a 6-membered ring. There may be one to four hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and the above aryl group and heteroaryl group may have a halogen atom, a hydroxyl group, a thiol group, an amine group, a nitro group, a cyano group, a carboxyl group, an amine carbenyl group, a phenyl group, an alkyl group having a carbon number, an alkoxy group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 6 carbon atoms, and a carbon number of 2~ A group of 5 or more atoms selected from the group consisting of a sulfhydryl group and a heteroaryl group (a 5-membered ring or a 6-membered ring and having 1 to 4 hetero atoms selected arbitrarily by a nitrogen atom, an oxygen atom, and a sulfur atom) Or a substituent: wherein the alkyl group, the alkoxy group, the alkylthio group, the alkoxycarbonyl group, the fluorenyl group, the phenyl group and the heteroaryl group may have a halogen atom, a hydroxyl group, an alkoxy group having a carbon number of 丨6 and The group of the alkylthio group having 1 to 6 carbon atoms is selected from the group consisting of 1 or more atoms or the substituent is a substituent. The more amine group may have a methyl group, an alkyl group having 1 to 6 carbon atoms, and a carbon number of 2 to 5. One or two bases selected from the group consisting of alkoxycarbonyl groups having 2 to 5 carbon atoms Substituents. From the above, R14, R14, , R15, R16, R16', R17 and R17, any two of -25-200900066 may be selected to form a cyclic structure, and may have an oxygen atom, a nitrogen atom, and sulfur. Any one or more of the atoms selected by the atom is a constituent atom of the ring. The ring thus formed may have a group selected from the group consisting of a halogen atom, a hydroxyl group, an amine group, an alkyl group having a carbon number of 66, an alkoxy group having 1 to 6 carbon atoms, and an alkylthio group having 1 to 6 carbon atoms. The above atom or group is a substituent, and the amine group may have a group consisting of a fluorenyl group, an alkyl group having 1 to 6 carbon atoms, a fluorenyl group having 2 to 5 carbon atoms, and an alkoxycarbonyl group having 2 to 5 carbon atoms. The substituent 1 or 2 is selected as a substituent] (If the substituent Z is represented by a more specific structural formula, the following substituents may be listed, but are not limited thereto. Further, these substituents have an asymmetric carbon and become Optically active substituents are of course contained in Z when optically active. -26- 200900066

In the aqueous preparation of the present invention which is stabilized by the addition of an alcohol, the quinacridone-based synthetic antibacterial compound of the formula (1) which is contained as an active ingredient, and the substituent at the 7-position represented by Z are the above formulas (4) and (5). , (6) and (7) quinacridone compounds. Further, an aqueous preparation having a high stabilization effect in the quinacridone compound having a substituent at the 7-position of the primary amino group which is characteristic of these substituents can be obtained. -27- 200900066 These compounds can be used as a raw material for the preparation of aqueous preparations, and as their raw materials, their salts and/or their hydrates. The compounding amount of the quinophthalone compound depends on the individual solubility, and is not particularly limited as long as it is within the solubility, and may be, for example, in the range of 1.0 to 5.0 mg/mL. Various alcohol compounds can be used for the alcohol to which the aqueous preparation of the present invention is added. For example, aliphatic alcohols having 1 to 6 carbon atoms and benzyl alcohol. Further, the aliphatic alcohol is preferably one-valent, two-valent, and three-valent, and a polyvalent alcohol of the above may be used. These examples may be methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-(] 2-propanol, 2-methyl-1-propanol, a monovalent alcohol such as benzyl alcohol; a divalent alcohol such as ethylene glycol or propylene glycol; or a polyvalent alcohol such as glycerin. Among these alcohol compounds, ethanol, ethylene glycol, propylene glycol, glycerin and benzyl alcohol are preferred, and ethanol and glycerin are particularly preferred. These alcohol compounds may be used singly or in combination of a plurality of them. The compounding amount of the alcohol compound is preferably 0.5 w/v% or more, particularly preferably 0.5 to 10 w/v%. The pH of the aqueous injection of the present invention is 3 to 8 The range is particularly preferably in the range of 3 to 6. In the aqueous liquid preparation of the present invention, a pH adjuster or the like is added as needed, and the pH adjuster may be an inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid; Inorganic acid salts such as sodium carbonate, sodium hydrogencarbonate, sodium hydrogen phosphate, sodium dihydrogen phosphate; organic acids such as acetic acid, lactic acid, citric acid, tartaric acid, methanesulfonic acid, etc.: organic acid salts such as sodium citrate, sodium lactate, sodium acetate An inorganic salt such as sodium hydroxide, etc. The isotonic agent may be an inorganic salt such as sodium chloride, magnesium chloride, calcium chloride or iron chloride. Inorganic acid salts such as magnesium sulfate and calcium sulfate; sugars such as glucose, refined white sugar, and polydextrose; D-sorbitol, mannitol, inositol, etc. -28-200900066 Sugar alcohols. The production method can be carried out according to a method for producing an aqueous injection which is usually carried out, that is, a quinophthalone compound, an alcohol compound, and other additives are added in an appropriate order to dissolve the water for injection, and a pH adjuster is added as necessary to adjust the pH. The aqueous preparation can be sterilized by a usual method such as filtration or high-pressure steam sterilization according to a filter sterilization filter. The aqueous preparation can also be sterilized and filled in a container, and then sterilized after the container is filled.

(Examples) The present invention is illustrated in more detail by the following examples, but the invention is not limited thereto, and these are not to be construed as limiting.

The structures of compounds 1 to 4 used in these examples are as follows:

[Examples 1 to 3] Examples 1 to 3 are as shown in Table 1. Add 1 m ο 1 / L hydrochloric acid 25 mL to the physiological saline solution (〇· 9 % sodium carbonated water solution), and dissolve the original drug i〇, 66 g (as anhydrous i〇g). -29- 200900066 After the addition of a 0.1 mol/L sodium hydroxide aqueous solution to adjust to ph4.0, a physiological saline solution was further added to adjust the amount of liquid to 2,000 mL, which was used as a mother liquid of Compound 1. To the mother liquor of 200 ml, mixed anhydrous ethanol 9,3 7 5 m g or concentrated glycerin 32.5 g or propylene glycol 4,125 mg, and a physiological saline solution was added, and the individual liquid amount was adjusted to 25 OmL. The solution was filtered through a 0.22 // m filter, filled in a polyethylene plastic bottle with 50 mL, and heat-sterilized at 102 ° C for 60 minutes. 【Table 1】

Ingredients - Example 1 Example 2 Example 3 Compound 1 2 13.2 mg 2 13.2 mg 2 13. 2 mg (as anhydrous) (200 mg) (200 mg) (200 mg) Sodium chloride 4 5 0 mg 4 5 0 mg 4 5 0 mg Anhydrous ethanol 1,875 mg - One concentrated glycerol - 6,500 mg of 1-propylene glycol - 8 2 5 mg Hydrochloric acid suitable (It is pH 4. 0) Suitable (pH 4. 0) Suitable (pH 4. 0) Hydroxide Sodium suitable (ρΗ4· 0) Appropriate (PH4.0) Appropriate amount (ρΗ4· 0) Water for injection 5 OmL Total 5 OmL Full 5 Om L

[Comparative Example 1] The contents of Comparative Example 1 are shown in Table 2. The mother liquor of the compound 1 of Examples 1 to 3 was collected in 200 mL, and the physiological saline solution was added to adjust the amount of the solution to 250 mL. The solution was filtered through a 0.22/m m crucible, filled with 5 OmL in a polyethylene plastic bottle, and heat-sterilized at 102 °C for 60 minutes [Table 2]

Ingredient Comparative Example 1 Compound 1 (as anhydrate) 2 13. 2 mg (200 mg) Sodium chloride 4 5 0 mg Hydrochloric acid (ρΗ4·0) Sodium hydroxide (ρΗ4.0) Water for injection ft 5 0 m L

[Test Example 1] -30-200900066 The preparations of Examples 1 to 3 and Comparative Example 1 were stored at 80 ° C for 5 days, and the appearance and insoluble fine particles after storage were evaluated. The appearance was visually observed, and the insoluble microparticles were measured by the microscopic method of the Japanese Pharmacopoeia general test method. The results are shown in Table 3. In comparison with the number of insoluble fine particles in the chemical solution of Comparative Example 1, the number of insoluble fine particles in the chemical solutions of Examples 1 to 3 was small, and it was confirmed that the formation of insoluble fine particles was suppressed by the addition of alcohol. [Table 3] Sample appearance insoluble fine particles 1 0 jU m or more (pieces/m L) 2 5 m or more Example 1 Yellow 0. 03 0.0 2 Example 2 Yellow 0. 19 0. 09 寅 Example 3 Yellow 0. 60 0. 28 Comparative Example 4 Yellow 0. 99 0. 59 [Examples 4 to 15] Examples 4 to 15 are shown in Tables 4 and 5. After adding 4.55 mL of 1 mol/L hydrochloric acid and 2.665 g of the original drug of Compound 1 (2.5 g of anhydrate) to 450 mL of water for injection, the solution was dissolved in an aqueous solution of 0.1 mol/L sodium hydroxide and adjusted to pH 4.0, and then added. The amount of the solution was adjusted to 500 mL of water for injection as the mother liquor of Compound 1. To the mother liquor of 20 mL, 1 · 2 5 g of each alcohol was added, and water for injection was further added, and the amount of each liquid was adjusted to 2 5 m L . This solution was filtered through a 0.22 /z m filter and dispensed in a polypropylene test tube 1 OmL 〇 -31 - 200900066

C

-32- 200900066

-33 - 200900066 [Comparative Example 2] The mother liquid of the compound 1 shown in Examples 4 to 15 was collected. The amount of the liquid was adjusted to 25 mL with water. This solution was dispensed to 10 mL in a polypropylene test tube at 0.22 M m. [Test Example 2] The preparations of Examples 4 to 15 and Comparative Example 2 were observed in an optical microscope (magnification: 100 times) of a membrane filter of 0.45 /zm at 8 mL (10 mL of the drug solution after TC). In Comparative Example 2, most of the insoluble fine particles were filtered, but on the filter surface of Examples 4 to 15, the number of fine particles was small due to the decrease in coloration. The above-mentioned effect was confirmed in other alcohols. [Example 1 6 to 21] The results of Examples 16 to 21 are shown in Table 6. The pH of the solution was adjusted to 3.0 to 4 / Compound 2 with hydrochloric acid and sodium hydroxide, and 5 mL of this solution was added and mixed 2 · 5 g, 5.0 g, more force α water for injection and adjust another [] name in the aqueous solution of compound 2 5 m L added mixed concentrated 5.0 g, add water for injection to adjust the amount of individual liquid to 0.22; zm filter, 20mL of polyethylene plastic, filtered with an injection filter, and stored for 5 days. Preserved, the filter surface is colored brown by the microscopic photo of the surface, the fruit of the insoluble microparticles, the microparticles of the 20mg/mL of water. Ethanol l.Og, the amount of 50mL. Same r oil l.Og, 2.5g, 50mL. Dispense these liquid bottles into 10mL. -34- 200900066

CD 撇

-35 - 200900066 [Comparative Example 3] An aqueous solution of Compound 2 having a pH of 3.0 adjusted with hydrochloric acid and sodium hydroxide was prepared. The 5 mL addition column of this solution was 50 mL. This solution was dispensed by a filter of 0.22/z m to dispense 10 m L of the baby. [Test Example 3] The insoluble fine particles of the preparations of Examples 16 to 21 and Comparative Example 3 were stored at a price. Insoluble microparticles were measured by microscopic method of the general test method. As a result, the chemical solution of the insoluble fine particles 3 16 to 2 1 in the chemical solution of Table 7 and Comparative Example 3 confirmed that the number of insoluble fine particles was reduced, and the inhibitory effect of the insoluble fine particles added with the alcohol was confirmed. ~4.0 of 20mg/mL: Water is used to adjust the amount of liquid: It is stored in polyethylene plastic at 80 °C for 5 days, and the evaluation is based on the Japanese Pharmacopoeia. From the above results, due to the inclusion of compound 2 -36- 200900066 [z嗽] g -Μ ε 3 \ ε S ^ ΙΟ Ν 屮 U 1 00 d CSJ inch 〇 <0 cut your d K · acupoint % m I < ο P - § 1 to csi inch csi r- r - Sample 1 "Example 19 Example 20 窜 裤 21 ί particles (e / mL) 2 5 / / ΓΤ 1 or more 00 inch 〇 r · inch d 6 m chain If ^ m fc ^ 〇P - § 0) T-inch 〇 Gan 6 sample Comparative Example 3 Example 16 Example 17 Example 18 -37- 200900066 [Example 22] Example 2 8.

The preparation contains compound 3 (as anhydrous) 5 mg / mL, D-sorbitol 50 mg / mL, magnesium chloride 6 hydrate 〇 4 mg / m: L, absolute ethanol 5 〇 mg / mL ' and adjusted with sulfuric acid and sodium hydroxide An aqueous solution having a pH of 4.5. This solution was filtered through a 0.22 // m furnace and dispensed in a polyethylene plastic bottle of 2 〇 mL.

Ingredient Example 2 2 Compound 3 10 2. 14 mg (as anhydrous) (10 0 mg) D-sorbitol - 1.0 g Magnesium chloride 6 hydrate ~- 8.0 mg Anhydrous ethanol 1.0 κ Sulfuric acid... Η4· 5) Sodium hydroxide»Λ (ρΗ4. 5) Water for injection S20 mL

[Comparative Example 4] The contents of Comparative Example 4 are shown in Table 9. An aqueous solution containing 5 mg/mL of the compound 3 (as an anhydride), 50 mg/mL of D-sorbitol, and 4 mg/mL of magnesium chloride hexahydrate was prepared, and the pH was adjusted to 4.5 with sulfuric acid and sodium hydroxide. This solution was filtered through a 0.22 # m filter and dispensed in a polyethylene-fired plastic bottle. [Table 9]

Ingredient Comparative Example 4 Compound 3 10 2. 14 mg (as anhydrous) (10 0 mg) D-sorbitol 1.0 g Magnesium chloride 6 hydrate 8. 0 mg Suitable (pH 4.5) Sodium hydroxide (pH 4) 5) Water for injection - 20 mL of total - 38 - 200900066 [Test Example 4] The preparations of Example 22 and Comparative Example 4 were stored at 80 ° C for 1 ' day to evaluate the insoluble fine particles after storage. The insoluble fine particles were determined by a microscopic method in accordance with the general test method of the Japanese Pharmacopoeia. The results are shown in Table 1. Comparison with the number of insoluble fine particles in the chemical solution of Comparative Example 4 The chemical liquid of Example 22 was confirmed to have a reduced number of insoluble fine particles. From the above results, the inhibitory effect of the addition of the insoluble fine particles of the alcohol was confirmed in the preparation containing the compound 3. Further, the inhibitory effect of the insoluble fine particles was confirmed to be advantageous over the prescription of adding the sugar alcohol Γ'. [Table 1〇] The sample was insoluble in 10#m or more fine particles (fi/mL) after 801/10 days. 2 5"m or more Example 2 0. 1 0. 0 Comparative Example 4 2. 3 0. 5 [Example 23 ~28] Examples 23 to 28 are as shown in Table 11. 2,268 mg of the original drug of Compound 4 (2,000 mg in free form) was dissolved in water for injection, and 200 mL of water for injection was added thereto. 20 mL of this solution was added with 1.0 g of anhydrous ethanol, 2.5 g, and 5.0 g, and water for injection was added to adjust the amount of the individual liquid to 50 ml. Similarly, an aqueous solution of Compound 4 was added at a concentration of 20. 0 g of concentrated glycerin, 2.5 g, 5.0 g, and water for injection was added to adjust the amount of the individual liquid to 50 mL. These liquids were filtered through a 0.22 /i m filter and dispensed in a polyethylene plastic bottle. -39- 200900066 [Γ-Iτ撇] Example 28 4 5. 3 6 mg (40 mg) 1 1 000 ms Full ft1OmL Example 27 4 5. 3 6 mg (40 mg) 1 '500 mg Full amount 1 0 m L Example 26 4 5. 3 6 mg (40 mg) 1 1 200 mg Fully 10 m L Example 25 4 5. 3 6 mg (40 mg) 1000 mg 1 full hydrazine; 10 m L Example 24 4 5.36 mg (40 ms) 5 0 0 mg 1 Full set 1 Om L Example 23 4 5. 3 6 ms (40 mg) 2 0 0 mg ! Total amount 1OmL Ingredient compound 4 (free body) Anhydrous Ethanol concentrated glycerin water for injection-40-200900066 [Comparative Example 5] 2,268 mg of the original drug of Compound 4 (2,000 mg in free form) was dissolved in water for injection, and 200 mL of water for injection was further added. 20 mL of this solution was added with water for injection to adjust the amount of the solution to 50 mL. The solution was filtered through a 0.22 g filter and dispensed in a polyethylene plastic bottle. [Test Example 5] The preparations of Examples 23 to 28 and Comparative Example 5 were stored at 80 ° C for 10 days, and the insoluble fine particles after storage were evaluated. The insoluble fine particles were determined according to the Japanese Pharmacopoeia 1 (the microscopic method of the general test method. The results are shown in Table 12. The comparison with the number of insoluble fine particles of Comparative Example 5) The chemical solutions of Examples 23 to 28 were confirmed to have a reduced number of insoluble fine particles. 'The inhibitory effect of the insoluble fine particles added with alcohol is also obtained in the preparation containing the compound 4. Confirmation. -41 - 200900066 /E%^ [2 T漱] <«-s ^ i si in 屮«Μ 藜4 4 D D D D D D 1 10 屮«Μ 藜 CM τ— Ο d Ο d key If class-Μ m ϊ} s 1 Ρ ο § - σ> inch 0) CO 04 6 ο d sample control example 5 m CM 匡 | ι Example 24 Example 25 - 42 - 200900066 [Examples 29 to 34] Examples 29 to 34 are as shown in Table 13 ^ After adding the original drug of Compound 1 to water for injection, 1 mol/L hydrochloric acid was added to dissolve, and then added. 〇.lmol/L hydrochloric acid or O.lmol/L sodium hydroxide to adjust the pH to 4.0, add mixed absolute ethanol or concentrated glycerol to each concentration, and add for injection. Water is used to adjust the liquid volume. The solution was filtered through a 0.22 // m filter and dispensed in a Non-PVC plastic bag of 50 mL. After the dispensing, the package was applied twice in aluminum foil and sterilized at 31 °C for 30 minutes.

U -43- 200900066 -/^ [COI嗽] Example 3 4 10 6. 6 mg (100 mg) 1 ※ Daily application (pH4_ 0) inch X amm -j E 〇to m Example 3 3 10 6.6 mg (10 0 mg) «3 1 Example 3 2 15 9. 9 mg (15 0 mg) 1 * bucket rH CO m series κ 15 9. 9 mg (15 0 mg) 糸3 1 ο CO series K 2 13. 2 mg (200 mg) 1 Concentration 2 σ> (Μ in in 2 13.2 mg · (200 mg) 1 Ingredient compound 1 (as anhydrate) Anhydrous ethanol concentrated glycerol Hydrochloric acid Sodium hydroxide water for injection ^o.2o_so «, ol, sd, Id, od beach township ^ Teng chain ^ Teng!»※ yoloI-lo.go.so.CSIo.T, s ·0,0·0 Beach 埘 « 异腾银导)! inch ※ Yoo.s , ο. εο. ζο.τ , so00 beach 埘 埘 验 ^ ^^妁 ※ %ο·2ο·9ο·ε , Ο.ΖΟΊ , 90,1.0 , 00 beach 埘 goose aR Tengkan guide ^^ ※ O/OO.SOCOO.ZO.T ,so,ΙΌΟΌ Beach geese another chain Teng! -4 - 200900066 [Test Example 6] The preparations of Examples 29 to 34 were stored at 80 ° C for 5 days, and the insoluble fine particles after storage were evaluated. The insoluble fine particles were determined by a microscopic method in accordance with the general test method of the Japanese Pharmacopoeia. The measurement results of Examples 29, 31 and 33 are shown in Table 14 and Figure 2. In Examples 29 and 31, when ethanol was not added, it was confirmed that the majority of the fine particles which were not counted were decreased as the amount of ethanol added was increased. The same tendency was exhibited in Example 33, and insoluble microparticles could not be identified by the addition of 0.5% of ethanol. Γ" The measurement results of Examples 30, 32, and 34 are shown in Table 15 and Figure 3. In the examples 30 and 3, when glycerin was not added, the number of fine particles which were not counted as a whole was decreased as the amount of addition was increased, and the addition of 10% of glycerin again confirmed the tendency of the number of fine particles to increase. In the same manner as in the example 34, a small amount of unrecognizable fine particles were added to the glycerin of 1 to 2%, and a tendency to increase was confirmed by the addition of 5 to 10%. -45 - 200900066 [Table 1 4] Sample anhydrous ethanol 8 80^/5 days after insoluble microparticles l/m L) Adding concentration 1 O/im or more 2 5 or more 0. 0% Most 882 majority" 0. 1% more C2 Most "0. 5% 11.00 6. 4 0 Example 2 9 1.0% 4.3 8 2. 7 8 2. 0% 3. 6 0 2. 00 3. 0% 4. 8 7 2. 3 2 5. 0% 0. 9 0 0. 3 5 0. 0% Most "Most θ 0. 5% 8. 0 5 4. 4 3 Example 3 1 1 . 0% 1.88 0. 6 3 2. 0% 1.15 0· 4 3 5. 0% 3. 2 3 1.58 0. 0% 3. 9 5 1.45 0. 5% 0. 4 3 0. 0 5 Example 3 1.0% 0. 0 5 0. 00 2. 0% 0. 3 3 0. 18 5. 0% 0. 03 0. 0 0

*1 Insoluble fine particle size 1 O/im or more: 2fl/mL, 2 5/im or more: 2 helmets/m L *2 There are many brown gel-like foreign objects, and the number cannot be measured -46 - 200900066. [Table 1 5] The concentration of anhydrous ethanol added to the sample is 80t: 5 days after insoluble 1 or more microparticles (β/mL) 2 5//m or more 1 Example 2 9 0. 0% Most "Most" 2%. *2 Most ※2 0. 5% 11.00 6. 4 0 1. 0% 4.3 8 2.7 8 2. 0% 3.6 0 2. 00 3. 0% 4.8 7 2.3 2 5. 0% 0. 90 0. 3 5 Example 3 1 0. 0% majority "M. 5% 8. 0 5 4.4 3 1 . 0% 1.88 0.6 3 2. 0% 1.15 0.4 3 5. 0% 3.2 3 1.58 Example 3 3 0. 0 % 3.9 5 1.45 0. 5% 0.4 3 0. 0 5 1 . 0% 0.0 5 0.0 0 2. 0% 0.3 3 0. 1 8 5. 0% 0. 03 0. 00

*1 Insoluble fine particle size 1 Ojum or more: S 1 2俚/mL, 2 5//m or more: 2 cores/m L *2 There are many brown gelatinous foreign substances, and the number cannot be measured -47- 200900066. Table 1 6]

The sample is concentrated with glycerin 80W5 insoluble microparticles (β/mL·). Adding 1 0//m or more poly 1 2 or more *1 0. 0% Most *2 Most *2 0. 1% Most *2 0. 5% 12 04 6. 8 6 Example 3 0 1. 0% 8. 7 1 5. 36 2. 0% 6. 9 0 4. 23 3. 0% 7. 07 3.9 4 5. 0% 4. 7 4 2 48 1 0. 0% 7. 7 4 4.6 3 0. 0% Most M Most "0. 5% 2. 8 6 1.46 1. 0% 4. 5 3 2. 11 Example 3 2 1 . 5% 2 . 3 1 1.14 2. 0% 2. 2 4 0.9 6 3. 0% 2. 5 4 1 . 10 5. 0% 3. 16 1.63 10 0% 6. 1 2 4. 1 2 0. 0% 3. 9 5 1. 45 0. 5% 0. 9 0 0. 2 5 Example 3 4 1 . 0% 0. 2 0 0. 03 2· 0% 0. 35 0. 05 5. 0% 0. 6 0 0. 35 10 0% 0. 7 5 0. 28 Insoluble fine particles specifications 10 m or more: each 12 / m L. 2 5 or more: S2 / mL pro 2 has a large number of brown gelatinous foreign bodies, the number Unable to measure

[Test Example 7] The preparations of Examples 31 and 32 were stored at 80 ° C for 5 days to evaluate the ruthenium-like substance after storage. The terpenoids were determined according to the HPLC conditions shown below. The measurement results of the terpenoids are shown in Table 16. As a result, it was confirmed that the quality of the steroids was also lowered due to the addition of alcohols. HPLC conditions; • Detector: UV spectrophotometer (wavelength 295 nm)

• Column: TSK gel ODS-80Ts • Column temperature: 40 ° C • Mobile phase: 1-molar sodium sulfonate and ammonium acetate 0.05 mol / L phosphate buffer / -48- 200900066

Acetonitrile mixed solution (7:3) solution * Flow rate: approx. 0.9 m L / m i η • Solution injection amount: 5 // L f

-49- 200900066 0% 3 2% 10' d 0% 2 8% glycerol 卩 卩 度 in d Example 32 2. 0% [ 0. 2 7% 0% 2 9% r- d 5% 3 0 % d 6 0% 2 7% in 〇0% r- N csi 〇 Example 31 mi 1. 0% 0. 2 7% fO 5% 2 9% d O 0. 0% 0.4 6% Relative retention time Substance total -50-200900066 [Simplified description of the drawings] [Fig. 1] shows the state of insoluble fine particles filtered by a filter in each of Examples 4 to 15. 0: same as Comparative Example 2, +1: Compared with Comparative Example 2, several microparticles were reduced, +2: compared with Comparative Example 2, microparticles were reduced, +3: compared with Comparative Example 2, the reduction of microparticles was large, + 4: Compared with Comparative Example 2, the reduction of the fine particles was large and the fine particles were not recognized. [Fig. 2] shows the state of insoluble Γ' microparticles at the positions of Examples 29, 31 and 33. [Fig. 3] The conditions of the insoluble microparticles shown in Examples 30, 32 and 34 are shown. [Main component symbol description] ' ΪΕΕ.

/INN -51 -

Claims (1)

200900066 X. Patent application scope: 1 · An aqueous preparation containing a quinophthalone compound and an alcohol. 2. The aqueous preparation according to claim 1, wherein the alcohol is an alcohol having a carbon number of 1 to 6, which is an alcohol selected from the group consisting of a monovalent, a divalent or a trivalent aliphatic alcohol and a benzyl alcohol. . 3. An aqueous preparation according to claim 2, wherein the alcohol is ethanol, ethylene glycol, propylene glycol, glycerin, or benzyl alcohol. 4. The aqueous preparation according to any one of claims 1 to 3, wherein the oxime oxime compound is a compound of the following formula (1) [wherein R1 is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, a cyclic group having 3 to 6 carbon atoms which may be substituted by a halogen atom, An alkoxy group having 1 to 6 carbon atoms, an alkylamino group having 1 to 6 carbon atoms, a halogen atom, a hydroxyl group, an amine group, a nitro group, a hospital group having 1 to 6 carbon atoms, or an alkyl group having 1 to 6 carbon atoms An aryl-substituted aryl group or a heteroaryl group which may have a halogen atom or an alkyl group having 1 to 6 carbon atoms; R 2 is a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms; and R 1 and R 2 may include a mother nucleus a part of which is integrated to form a cyclic structure, and the ring may contain a constituent atom of a ring of sulfur-52-200900066, and the ring may have a substituent of a carbon number i to 6; R3 is a hydrogen atom, an amine Base (this amine group may have a mercapto group, a carbon number of 6~6 or a carbon number of 2 to 5 thiol), a thiol group, a halomethyl group, a carbon number of 1 to 6, a carbon number 2-6 alkenyl group, alkylene group having 2 to 6 carbon atoms, or alkoxy group having 1 to 6 carbon atoms; A1 is a nitrogen atom or a partial structure of the following formula (2), (wherein X2 is a hydrogen atom or an amine group (the amine group may have a methyl group, a carbon number of 1 to 6 or a fluorenyl group having 2 to 5 carbon atoms), a halogen atom, a cyano 'halomethyl group, a halomethoxy group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, or an alkoxy group having 6 or 6 carbon atoms; and the above R1 may include a mother One part of the core is integrated to form a cyclic structure, and the ring thus formed may contain an oxygen atom, a nitrogen atom, or a sulfur atom as a constituent atom of the ring, and the ring may have an alkyl group having 1 to 6 carbon atoms as a substituent. Α2 and Α3 are each a nitrogen atom or a carbon atom, but Ai, a2 and Α3 form a partial structure with these bonded carbon atoms. Now 5U F part construction -53 - 200900066 χ1 is a halogen atom or a hydrogen atom; Y is a hydrogen atom, a phenyl group, an ethoxymethyl group, a pentyloxymethyl group, an ethoxycarbonyl group, a methylpyridyl group, a dimethylaminoethyl group, and 5 -hydroindolyl, fluorenyl, 5-alkyl-2-oxo-1,3-dioxan-4-ylmethyl, 3-ethyloxy-2-oxobutyl, carbon number 1 to 6 An alkyl group, an alkoxymethyl group having 2 to 7 carbon atoms, or a phenylalkyl group having a C 1 to 6 alkyl group and a phenyl group; Z is a monocyclic, bicyclic or tricyclic ring. a heterocyclic substituent which may be saturated or partially saturated, may contain one or more hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and may be a bicyclic structure or a spiro ring structure. There are a halogen atom, a hydroxyl group, an amine group, an amine carbenyl group, an alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, an aryl group, a heteroaryl group, an alkoxy group having a carbon number of 6, One or two or more atoms or groups of the alkyl group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, and an amine alkyl group having 1 to 6 carbon atoms are selected]. An method for stabilizing an aqueous preparation containing quinacridone, characterized in that an alcohol is added to an aqueous solution containing a quinophthalone compound. 6. The method for stabilizing an aqueous preparation containing quinacridone according to claim 5, wherein the method of inhibiting the formation of insoluble fine particles and/or terpenoids is stabilized. 7. The method for stabilizing an aqueous preparation containing quinacridone according to claim 5 or 6, wherein the alcohol is a monovalent, divalent or trivalent aliphatic alcohol having a carbon number of 1 to 6 An alcohol selected from the group consisting of benzyl alcohol. 8. The method for stabilizing an aqueous preparation containing quinacridone according to any one of claims 5 to 7, wherein the alcohol is ethanol, ethylene glycol, propylene glycol -54-200900066, glycerin, or benzyl alcohol. The method for the stabilization of an aqueous preparation containing quinacridone according to any one of claims 5 to 8, wherein the quinophthalone compound is a compound of the following formula (1) [wherein R1 is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogen-based group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms which may be substituted by a halogen atom, An alkoxy group having 1 to 6 carbon atoms, an alkylamino group having 1 to 6 carbon atoms, a halogen atom, a hydroxyl group, an amine group, a nitro group, an alkyl group having 1 to 6 carbon atoms, or an alkyl group having 1 to 6 carbon atoms An aryl-substituted aryl group or a heteroaryl group which may have a halogen atom or an alkyl group having 1 to 6 carbon atoms; R 2 is a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms; and R 1 and R 2 may include a mother nucleus a part of which is integrated to form a cyclic structure, and the ring may contain a constituent atom in which a sulfur atom is a ring, and the ring may have an alkyl group having 1 to 6 carbon atoms as a substituent. R3 is a hydrogen atom or an amine group (this amine group may be a mercapto group, an alkyl group having 1 to 6 carbon atoms or a mercapto group having 2 to 5 carbon atoms, a thiol group, a halomethyl group, an alkyl group having 1 to 6 carbon atoms, and an alkenyl group having 2 to 6 carbon atoms An alkynyl group having a carbon number of 2 to 6, or an alkoxy group having a carbon number of -55 to 200900066 1 to 6; A1 being a nitrogen atom or a partial structure of the following formula (2) (wherein X2 is a hydrogen atom or an amine group (the amine group may have a methyl group, a carbon number or an alkyl group having 2 to 5 carbon atoms), a halogen atom, a cyano group, a halomethyl group or a halogenated methoxy group. a base, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms; and the above Ri and the above Ri may include a mother nucleus a part of which is integrated to form a ring-shaped structure, and the ring thus formed may contain an oxygen atom, a nitrogen atom, or a sulfur atom as a constituent atom of the ring, and the ring may have a substituent having a carbon number of 1 to 6 as a substituent; A2 and A3 are each a nitrogen atom or a carbon atom, but a1, a2 and A3 form a partial structure with these bonded carbon atoms. Or the following part of the structure R X1 is a halogen atom or a hydrogen atom; γ is a hydrogen atom, a phenyl group, an acetoxymethyl group, a p-pentyloxymethyl 'ethoxylated oxime group, a methyl n-steep group, a dimethylaminoethyl group, 5 -Hydroxyl group, donor group, 5-alkyl-2-oxo-I,3-didecyl-4-ylmethyl, 3·ethoxycarbonyl·2-oxybutyl, carbon number 1~6 An alkyl group, an alkoxymethyl group having 2 to 7 carbon atoms, or a phenylalkyl group having a carbon number of -56 to 200900066 1 to 6 and a phenyl group; Z is a monocyclic ring, a bicyclic ring, or a tricyclic heterocyclic substituent which may be saturated or partially saturated, and may contain a hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and may be a bicyclic structure or a spiro ring. Structure, but may have a picture of atoms, hydroxyl groups, amine groups, amine methyl sulfhydryl groups, a carbon number of 1 to 6, a carbon number of 1 to 6, a dental base, a square base, a square base, a carbon number of 1 to 6 One or more substituents of one or more selected from the group consisting of an alkoxy group, an alkylamino group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, and an amine alkyl group having 1 to 6 carbon atoms ]. -57-