JP2008231067A - Manufacturing method of lyophilized formulation containing quionolone - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a lyophilized formulation containing only a quionolone type synthetic antibacterial compound and a pH regulating agent, and excellent in remelting property. <P>SOLUTION: In this manufacturing method of a non-crystalline lyophilized formulation containing a quionolone type synthetic antibacterial compound as an effective component, a congelation is obtained by cooling an aqueous solution containing a quionolone type synthetic antibacterial compound and a pH regulating agent, once raising its temperature, and cooling it again and lyophilized. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a method for producing an amorphous lyophilized preparation containing a quinolone synthetic antibacterial compound.

Quinolone synthetic antibacterial compounds are widely used as therapeutic agents for various bacterial infections because they have a broad antibacterial spectrum and strong antibacterial activity (see Non-Patent Document 1). For example, compounds such as levofloxacin, ofloxacin, ciprofloxacin, moxifloxacin, trovafloxacin and the like have a wide antibacterial spectrum and high antibacterial activity, and are particularly widely used. In addition, sitafloxacin, the compound of the following formula (I), and the compound of the formula (II) described in the examples also have excellent antibacterial activity and also have excellent antibacterial activity against drug-resistant bacteria. Therefore, it is expected as an excellent antibacterial drug.
Formula (I)

A quinolone compound having a structure represented by (7- [3- (R)-(1-aminocyclopropyl) pyrrolidin-1-yl] -1- [2- (S) -fluoro-1- (R)- Cyclopropyl] -1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid; hereinafter abbreviated as compound (I))) is particularly methicillin-resistant staphylococci, penicillin-resistant pneumococci, vancomycin-resistant intestines It has excellent antibacterial activity such as exhibiting high antibacterial activity against drug-resistant gram-positive bacteria such as cocci. Furthermore, this compound is highly safe and is expected to have an excellent therapeutic effect (see Patent Document 1). In addition, the compound (II) shown below is also an excellent quinolone compound having high safety and excellent antibacterial activity including resistant bacteria (see Patent Document 2).

  Quinolone compounds, particularly those exhibiting excellent antibacterial activity against resistant bacteria, can be expected to have an excellent therapeutic effect on severe infections due to their antibacterial properties. In severe cases, intravascular administration is often performed in the form of a solution. Therefore, a drug solution containing a quinolone compound is required, and a lyophilized preparation containing only a drug substance and a pH adjuster for preparing a drug solution of a quinolone compound at the time of use is provided.

As a method for preparing a freeze-dried preparation, a method of providing an annealing step is known. An annealing process is a process of once raising the temperature of the frozen body of the raw material aqueous solution obtained by the cooling process of an initial process, and hold | maintaining for a fixed time. When preparing freeze-dried preparations containing excipients or consisting only of excipients, freeze-dried preparations prepared with an annealing step exhibit different resolubility than lyophilized preparations prepared without an annealing step It is known that there is. However, in these cases, there is no certain tendency with respect to re-solubility, and either improvement or deterioration is observed, and the influence of the annealing process on the re-solubility of the lyophilized preparation varies depending on the substance (Non-Patent Document 2, 3).
In freeze-dried preparations, excipients were originally a component for improving re-dissolvability, and the influence of the annealing process was known. However, it has not been clarified what kind of influence is exerted on the re-dissolution property of the obtained lyophilized preparation by providing an annealing step in the production process of the lyophilized preparation containing no excipient.
International Publication No. 02/40478 Pamphlet International Application PCT / JP2006 / 310069 Specification Hooper D.H. C. and Rubinstein E. (Eds) 3rd Edition Quinoleone Antimicrobial Agents. 2003. ASM Press Books Journal of Pharmaceutical Sciences, Vol. 90, No. 7, pp. 872-887, 2001 Journal of Pharmaceutical Sciences, Vol. 92, No. 4, pp. 715-729, 2003

The lyophilized preparation containing a quinolone synthetic antibacterial compound such as compound (I) is preferably provided as a preparation containing only the drug substance and the pH regulator. It has been found that when a freeze-drying method that is usually performed in preparing such a freeze-dried preparation is applied, a slightly soluble freeze-dried cake that requires a long time for re-dissolution may be formed. That is, when a redissolved solution is injected to obtain a drug solution, the freeze-dried cake does not dissolve immediately but changes to a hardly soluble bulk material. Even such a hardly soluble bulk substance is finally completely dissolved to obtain a drug solution. However, if the re-dissolution time is excessively long, the convenience of use is remarkably impaired.
Accordingly, an object of the present invention is to provide a freeze-dried preparation that contains only a quinolone-based synthetic antibacterial compound and a pH adjuster and is excellent in resolubility.

As a result of intensive studies by the present inventors, an amorphous lyophilized preparation prepared by a method of providing an annealing step in a series of freezing steps when preparing a lyophilized preparation comprising only a quinolone synthetic antibacterial compound and a pH regulator. If so, it was found that the re-dissolution time was greatly shortened.
That is, after the aqueous solution for preparing a lyophilized preparation containing a quinolone synthetic antibacterial compound and a pH regulator is cooled to obtain an amorphous frozen body, the temperature is once raised and maintained for a certain period of time. This is a production method in which an amorphous lyophilized preparation is obtained by refrigeration after being provided and then lyophilized. Thus, the present inventors have found that an amorphous freeze-dried preparation excellent in re-dissolution property can be obtained by adding an annealing step in which the temperature of the frozen body is once raised, thereby completing the invention.

  That is, the present invention provides the following formula (1):

[Wherein, R ¹ represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, or a carbon atom having 3 to 6 carbon atoms optionally substituted by a halogen atom. A cyclic alkyl group, a halogen atom, a hydroxyl group, an amino group, a nitro group, an alkyl group having 1 to 6 carbon atoms, an aryl group which may be substituted by an alkoxy group having 1 to 6 carbon atoms, a halogen atom or 1 to carbon atoms 6 represents an optionally substituted heteroaryl group, an alkoxy group having 1 to 6 carbon atoms, or an alkylamino group having 1 to 6 carbon atoms;
R ² represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms; R ¹ and R ² may be integrated to form a cyclic structure including a part of the mother nucleus. May contain a sulfur atom as a constituent atom of the ring, and this ring may have an alkyl group having 1 to 6 carbon atoms as a substituent.
R ³ represents a hydrogen atom, an amino group (this amino group may be substituted by a formyl group, an alkyl group having 1 to 6 carbon atoms, or an acyl group having 2 to 5 carbon atoms), a thiol group, or halogenomethyl. A 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;
A ¹ is a nitrogen atom or formula (2)

(In the formula, X ² is a hydrogen atom, an amino group (this amino group may be substituted by a formyl group, an alkyl group having 1 to 6 carbon atoms, or an acyl group having 2 to 5 carbon atoms), halogen. An atom, a cyano group, a halogenomethyl group, a halogenomethoxy 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 X ² and R ¹ may be integrated so as to include a part of the mother nucleus to form a cyclic structure, and the ring formed in this way is an oxygen atom, a nitrogen atom, or A sulfur atom may be included as a constituent atom of the ring, and this ring may have an alkyl group having 1 to 6 carbon atoms as a substituent.)
Represents a partial structure represented by
A ² and A ³ each independently represent a nitrogen atom or a carbon atom, and A ¹ , A ² and A ³ and the carbon atom to which they are bonded are a partial structure

Or partial structure

Form.
X ¹ represents a halogen atom or a hydrogen atom;
Y is a hydrogen atom, phenyl group, acetoxymethyl group, pivaloyloxymethyl group, ethoxycarbonyl group, choline group, dimethylaminoethyl group, 5-indanyl group, phthalidyl group, 5-alkyl-2-oxo-1, A 3-dioxol-4-ylmethyl group, a 3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms, or an alkylene group having 1 to 6 carbon atoms and a phenyl group; Represents a phenylalkyl group composed of:
Z represents a monocyclic, bicyclic or tricyclic heterocyclic substituent, which is saturated or partially saturated and is selected from a nitrogen atom, an oxygen atom and a sulfur atom. May contain one or more different atoms, may be a bicyclo structure or a spirocyclic structure, and may be a halogen atom, a hydroxyl group, an amino group, a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, a carbon number of 1 To 6 halogenoalkyl groups, aryl groups, heteroaryl groups, alkoxy groups having 1 to 6 carbon atoms, alkylamino groups having 1 to 6 carbon atoms, alkylthio groups having 1 to 6 carbon atoms, and amino acids having 1 to 6 carbon atoms One or more atoms or groups selected from the group consisting of alkyl groups may be substituted. ]
A compound of formula (1), wherein a frozen body is obtained by cooling an aqueous solution containing the compound represented by formula (1) and a pH regulator, then the temperature is once raised, then cooled again and freeze-dried The present invention relates to a method for producing an amorphous freeze-dried preparation containing as an active ingredient.

  By preparing an amorphous lyophilized formulation containing a quinolone synthetic antibacterial compound by providing an annealing process, an amorphous lyophilized formulation consisting of a lyophilized cake with excellent resolubility can be obtained and frozen. The convenience of using the dry preparation is improved.

In the formula (1), R ¹ is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, or a carbon atom 3 optionally substituted by a halogen atom. To 6 cyclic alkyl groups, halogen atoms, hydroxyl groups, amino groups, nitro groups, alkyl groups having 1 to 6 carbon atoms, aryl groups which may be substituted by alkoxy groups having 1 to 6 carbon atoms, halogen atoms or carbon numbers It represents a heteroaryl group, an alkoxy group having 1 to 6 carbon atoms, or an alkylamino group having 1 to 6 carbon atoms, which may be substituted by an alkyl group having 1 to 6 alkyl groups.

  As the alkyl group having 1 to 6 carbon atoms, an ethyl group is particularly preferable. As the alkenyl group having 2 to 6 carbon atoms, a vinyl group or a 1-isopropenyl group is particularly preferable. Examples of the halogenoalkyl group having 1 to 6 carbon atoms include an alkyl group having 1 to 6 carbon atoms having a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Particularly preferred. As the cyclic alkyl group having 3 to 6 carbon atoms, a cyclopropyl group is particularly preferable. When the cyclic alkyl group has a substituent, a halogen atom is preferable as the substituent, and a fluorine atom is particularly preferable. The fluorocyclopropyl group is particularly preferably a 2- (S) -fluoro-1- (R) -cyclopropyl group.

  The aryl group is, for example, selected from the group consisting of halogen atoms such as fluorine atom, chlorine atom, bromine atom, hydroxyl group, amino group, nitro group, alkyl group having 1 to 6 carbon atoms, and alkoxy group having 1 to 6 carbon atoms. And a phenyl group optionally having 1 to 3 atoms or groups as a substituent, such as phenyl group, 2-fluorophenyl group, 4-fluorophenyl group, 2,4-difluorophenyl group, 2 -Fluoro-4-hydroxyphenyl group, 3-amino-4,6-difluorophenyl group and 4,6-difluoro-3-methylaminophenyl group are preferred.

  As the heteroaryl group, an aromatic heterocyclic substituent derived from a 5-membered or 6-membered aromatic heterocyclic compound which may have a halogen atom or an alkyl group having 1 to 6 carbon atoms as a substituent Can be mentioned. The heteroaryl group includes one or more hetero atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and examples thereof include a pyridyl group and a pyrimidyl group. 6-amino-3,5-difluoro-2- A pyridyl group is particularly preferred.

  As the alkoxy group having 1 to 6 carbon atoms, a methoxy group is particularly preferable. As the alkylamino group having 1 to 6 carbon atoms, a methylamino group is particularly preferable.

As the substituent R ¹ , a cyclic alkyl group or a halogenocycloalkyl group is preferable. As the cyclic alkyl group, a cyclopropyl group is particularly preferable. As the halogenocyclopropyl group, a 2-halogenocyclopropyl group is preferable, and a 2-fluorocyclopropyl group is particularly preferable.

In formula (1), R ² represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms. As the alkylthio group having 1 to 6 carbon atoms, a methylthio group and an ethylthio group are particularly preferable.
As the substituent R ² , a hydrogen atom is preferable.

In the formula (1), R ¹ and R ² may be integrated so as to include a part of the mother nucleus and form a cyclic structure. This ring may contain a sulfur atom as a constituent atom of the ring, and this ring may have an alkyl group having 1 to 6 carbon atoms as a substituent. The alkyl group is preferably a methyl group.

In Formula (1), R ³ is a hydrogen atom or an amino group (this amino group may be substituted by a formyl group, an alkyl group having 1 to 6 carbon atoms, or an acyl group having 2 to 5 carbon atoms). , A thiol group, a halogenomethyl 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.

Examples of the amino group which may be substituted by a formyl group, an alkyl group having 1 to 6 carbon atoms or an acyl group having 2 to 5 carbon atoms include a formylamino group and an acetylamino group. Is particularly preferred. Examples of the alkyl group having 1 to 6 carbon atoms include a methyl group and an ethyl group, and a methyl group is particularly preferable. As the alkenyl group having 2 to 6 carbon atoms, a vinyl group is particularly preferable. As the alkynyl group having 2 to 6 carbon atoms, an ethynyl group is particularly preferable. Moreover, as a C1-C6 alkoxy group, a methoxy group is especially preferable.
As the substituent R ³ , a hydrogen atom is preferable.

In formula (1), A ¹ represents a nitrogen atom or formula (2)

Represents a partial structure represented by
In formula (2), X ² is a hydrogen atom or an amino group (this amino group may be substituted by a formyl group, an alkyl group having 1 to 6 carbon atoms, or an acyl group having 2 to 5 carbon atoms). , Halogen atom, cyano group, halogenomethyl group, halogenomethoxy group, alkyl group having 1 to 6 carbon atoms, alkenyl group having 2 to 6 carbon atoms, alkynyl group having 2 to 6 carbon atoms, or alkoxy having 1 to 6 carbon atoms Represents a group.

  As an amino group which may be substituted by a formyl group, an alkyl group having 1 to 6 carbon atoms or an acyl group having 2 to 5 carbon atoms, an acetylamino group is particularly preferable. As the alkyl group having 1 to 6 carbon atoms, a methyl group is particularly preferable. As the alkenyl group having 2 to 6 carbon atoms, a vinyl group is particularly preferable. As the alkynyl group having 2 to 6 carbon atoms, an ethynyl group is particularly preferable. Moreover, as a C1-C6 alkoxy group, a methoxy group is especially preferable.

X ² and R ¹ may be integrated so as to include a part of the mother nucleus to form a cyclic structure, and the ring formed in this way is an oxygen atom, a nitrogen atom, or a sulfur atom As a ring-constituting atom. Further, this ring may have an alkyl group having 1 to 6 carbon atoms as a substituent.
As the ring structure thus formed, a pyridobenzoxazine skeleton which is a skeleton such as ofloxacin is preferable. Further, the alkyl substituent of this skeleton is preferably a methyl group, particularly preferably a (3S) -methyl group.

The substituent A ¹ is preferably a partial structure represented by the formula (2), and the substituent X ² is preferably a methyl group, a methoxy group, or a difluoromethoxy group.

In formula (1), A ² and A ³ are each different and represent a nitrogen atom or a carbon atom. Here, A ¹ , A ² and A ³ and the carbon atom to which they are bonded are the following partial structures:

Or partial structure

Form.
That is, the following structure
It is what has.
Of these substructures,

The partial structure represented by
Are preferred.
Further, A ¹ is preferably a structure represented by the above formula (2).
Are preferred.

In the formula (1), X ¹ represents a halogen atom or a hydrogen atom, and in the case of a halogen atom, a fluorine atom is preferable.
As the substituent X ¹ , a fluorine atom or a hydrogen atom is preferable.

In the formula (1), Y represents a hydrogen atom, phenyl group, acetoxymethyl group, pivaloyloxymethyl group, ethoxycarbonyl group, choline group, dimethylaminoethyl group, 5-indanyl group, phthalidyl group, 5-alkyl- 2-oxo-1,3-dioxol-4-ylmethyl group, 3-acetoxy-2-oxobutyl group, alkyl group having 1 to 6 carbon atoms, alkoxymethyl group having 2 to 7 carbon atoms, or 1 to 6 carbon atoms A phenylalkyl group composed of an alkylene group and a phenyl group is represented.
As the substituent Y ¹ , a hydrogen atom is preferable.

  In the formula (1), Z represents a monocyclic, bicyclic or tricyclic heterocyclic substituent. This heterocyclic substituent is saturated or partially saturated and may contain one or more hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Further, it may be a bicyclo structure or a spiro cyclic structure. This heterocyclic substituent may have a substituent, for example, a halogen atom, a hydroxyl group, an amino group, a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, an aryl group , A heteroaryl group, an alkoxy group having 1 to 6 carbon atoms, an alkylamino group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, or an aminoalkyl group having 1 to 6 carbon atoms may be substituted. The number of atoms or groups that can be substituted for the heterocyclic substituent may be one or two or more.

  The alkyl group having 1 to 6 carbon atoms that can be substituted with the heterocyclic substituent is a halogen atom, a hydroxyl group, an amino group, a carbamoyl group, a halogenoalkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, The substituent may have one or more atoms or groups selected from the group consisting of an alkylamino group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, and an aminoalkyl group having 1 to 6 carbon atoms. The alkyl group that can be substituted with a heterocyclic substituent, the halogenoalkyl group that can be substituted with the alkyl group, the alkylamino group, the alkylthio group, and the alkyl group part of the aminoalkyl group may have a cyclic structure, Furthermore, 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 having 1 to 6 carbon atoms are substituted. It may have been.

  The amino group of the above amino group, alkylamino group and aminoalkyl group is an alkyl group having 1 to 6 carbon atoms (this alkyl group may have a cyclic structure, and may be a hydroxyl group, halogen atom, carbon One or two atoms or groups 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 may be used as a substituent. You may have and when it is two, it may be the same or different. Furthermore, this amino group moiety may be protected by a commonly used protecting group.

  C 1-6 halogenoalkyl group, C 1-6 alkylamino group, C 1-6 alkylthio group and C 1-6 aminoalkyl group alkyl which can be substituted on the above heterocyclic substituent The group portion may have a cyclic structure, and more than one 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 These atoms or groups may be substituted.

The amino group that can be substituted on the heterocyclic substituent, the alkylamino group having 1 to 6 carbon atoms, and the aminoalkyl moiety of the aminoalkyl group having 1 to 6 carbon atoms is one of alkyl groups having 1 to 6 carbon atoms Or you may have 2 as a substituent or may be protected by a protecting group. When there are two alkyl groups on the amino group, they may be the same or different.
Here, the alkyl group having 1 to 6 carbon atoms may have a cyclic structure, and is a 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. One or more selected atoms or groups may be substituted.
The amino-protecting group is not particularly limited as long as it is widely used in this field. For example, alkoxycarbonyl groups such as tertiary butoxycarbonyl group and 2,2,2-trichloroethoxycarbonyl group; benzyloxy Aralkyloxycarbonyl groups such as carbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group; acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, formyl group, benzoyl group, etc. Acyl groups: tertiary butyl group, benzyl group, paranitrobenzyl group, paramethoxybenzyl group, triphenylmethyl group and other alkyl groups, or aralkyl groups; methoxymethyl group, tertiary butoxymethyl group, teto Hydropyranyl group, 2,2,2-tri Ethers such as loroethoxymethyl group; (alkyl and / or aralkyl) substituted silyl groups such as trimethylsilyl group, isopropyldimethylsilyl group, tertiary butyldimethylsilyl group, tribenzylsilyl group, tertiary butyldiphenylsilyl group Can be mentioned.

  The aryl group that can be substituted with the heterocyclic substituent has 6 to 10 carbon atoms, and the heteroaryl group is a 5-membered or 6-membered ring, and includes a nitrogen atom, an oxygen atom, and a sulfur atom. It may contain 1 to 4 selected heteroatoms.

The aryl group and heteroaryl group that can be substituted on the above heterocyclic substituent are a halogen atom, hydroxyl group, thiol group, amino group, nitro group, cyano group, carboxyl group, carbamoyl group, phenyl group, carbon number 1 to 6 An alkyl group, 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, an acyl group having 2 to 5 carbon atoms, and a heteroaryl group (5-membered ring or 6-membered ring) The ring may contain one or more atoms or groups selected from the group consisting of 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms.
Here, a phenyl group which can be 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 1 to 6 carbon atoms, an alkoxy having 2 to 6 carbon atoms The carbonyl group, the acyl group having 2 to 5 carbon atoms, and the heteroaryl group are one or more atoms 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. Or you may have a group as a substituent. The amino group that can be substituted with an aryl group and a heteroaryl group further comprises a formyl group, an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 5 carbon atoms, and an alkoxycarbonyl group having 2 to 5 carbon atoms. It may have 1 or 2 groups selected more as a substituent.

The substituent Z may be bonded to the quinolone parent via any atom constituting the ring, but is more preferably bonded with a nitrogen atom. Examples of the heterocyclic substituent bonded with such a nitrogen atom include substituents having structures represented by the following formulas (3) to (7).
Formula (3)

(Wherein R ⁴ , R ⁵ , R ⁵ ′, R ⁶ , R ⁶ ′, R ⁷ and R ⁸ represent a substituent of the heterocyclic substituent represented by Z. More specifically, ,
R ⁴ , R ⁵ and R ⁶ each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
This alkyl group includes a halogen atom, a hydroxyl group, an amino group, a carbamoyl group, an alkylthio group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkylamino group having 1 to 6 carbon atoms, and an alkyl group having 1 to 6 carbon atoms. One or more groups selected from the group consisting of a halogenoalkyl group and an aminoalkyl group having 1 to 6 carbon atoms may be substituted.
The alkyl group of the alkyl group, the alkylthio group that can be substituted with the alkyl, the alkylamino group, the halogenoalkyl group, and the alkyl group part of the aminoalkyl group may have a cyclic structure, and further have a halogen atom, a carbon number of 1 to One or more atoms or groups selected from the group consisting of alkyl groups and alkoxy groups may be substituted.
The amino group that can be substituted with alkyl, the aminoalkyl group, and the amino group portion of the alkylamino group are alkyl groups having 1 to 6 carbon atoms (this alkyl group may have a cyclic structure, 1 or 2 atoms may be substituted as one or more atoms or groups selected from the group consisting of an atom, a hydroxyl group, an alkylthio group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms. As a substituent (in the case of two, they may be the same or different), and this amino group moiety may be protected by a commonly used protecting group.
R ⁵ ′ and R ⁶ ′ each independently represents a hydrogen atom, an aryl group, or a heteroaryl group,
The aryl group has 6 to 10 carbon atoms, and the heteroaryl group is a 5-membered ring or 6-membered ring, and includes one heteroatom arbitrarily selected from a nitrogen atom, an oxygen atom and a sulfur atom. May contain four,
The aryl group and heteroaryl group include a halogen atom, a hydroxyl group, a thiol group, an amino group, a nitro group, a cyano group, a carboxyl group, a carbamoyl group, a phenyl group, an alkyl group having 1 to 6 carbon atoms, and an alkyl group having 1 to 6 carbon atoms. An alkoxy group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 6 carbon atoms, an acyl group having 2 to 5 carbon atoms and a heteroaryl group (a 5- or 6-membered ring, a nitrogen atom, 1 to 4 heteroatoms arbitrarily selected from an oxygen atom and a sulfur atom may be included as a substituent, and one or more atoms or groups selected from the group consisting of:
Of these, an alkyl group, an alkoxy group, an alkylthio group, an alkoxycarbonyl group, an acyl group, a phenyl group, and a heteroaryl group are formed from 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. One or more atoms or groups selected from the group may be substituted, and the amino group is a formyl group, an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 5 carbon atoms, and 2 carbon atoms. 1 to 2 groups selected from the group consisting of alkoxycarbonyl groups of 1 to 5 may be substituted.
R ⁷ and R ⁸ each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
Any two selected from the above R ⁵ , R ⁵ ′, R ⁶ and R ⁶ ′ may be integrated so as to form a cyclic structure, and arbitrarily selected from an oxygen atom, a nitrogen atom and a sulfur atom One or more heteroatoms may be included as constituent atoms of the ring.
The ring thus formed is selected from the group consisting of a halogen atom, a hydroxyl group, an amino 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. One or more atoms or groups may be substituted, and this amino group is a formyl group, an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 5 carbon atoms, and an alkoxy group having 2 to 5 carbon atoms. One or two groups selected from the group consisting of carbonyl groups may be substituted. )
Or the following formula (4)

Wherein R ⁷ , R ⁷ ′, R ⁸ , R ⁸ ′, R ⁹ , R ¹⁰ , R ¹⁰ ′, R ¹¹ and R ¹¹ ′ are substituted on the heterocyclic substituent represented by Z. Represents a group, more specifically,
R ¹¹ and R ¹¹ ′ each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
This alkyl group includes a halogen atom, a hydroxyl group, an amino group, a carbamoyl group, an alkylthio group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkylamino group having 1 to 6 carbon atoms, and an alkyl group having 1 to 6 carbon atoms. One or more atoms or groups selected from the group consisting of a halogenoalkyl group and an aminoalkyl group having 1 to 6 carbon atoms may be substituted.
R ⁹ , R ¹⁰ and R ¹⁰ ′ are each independently a hydrogen atom, halogen atom, amino group, hydroxyl group, carbamoyl group, alkyl group having 1 to 6 carbon atoms, alkylamino group having 1 to 6 carbon atoms, aryl A group, a heteroaryl group, an alkoxy group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, or an aminoalkyl group having 1 to 6 carbon atoms,
The alkyl group portion of the alkyl group, alkylthio group, halogenoalkyl group, aminoalkyl group and alkylamino group may have a cyclic structure,
Furthermore, it may have 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 having 1 to 6 carbon atoms as a substituent.
The amino group of the above amino group, alkylamino group and aminoalkyl group is an alkyl group having 1 to 6 carbon atoms (this alkyl group may have a cyclic structure, and may be a halogen atom, hydroxyl group One or two atoms 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 may be used as a substituent. (In the case of two, they may be the same or different.) Further, this amino group moiety may be protected by a commonly used protecting group.
Further, the aryl group has 6 to 10 carbon atoms, and the heteroaryl group is a 5-membered or 6-membered ring, and includes 1 hetero atom arbitrarily selected from a nitrogen atom, an oxygen atom and a sulfur atom. From 4 to 4,
The aryl group and heteroaryl group include a halogen atom, a hydroxyl group, a thiol group, an amino group, a nitro group, a cyano group, a carboxyl group, a carbamoyl group, a phenyl group, an alkyl group having 1 to 6 carbon atoms, and an alkyl group having 1 to 6 carbon atoms. An alkoxy group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 6 carbon atoms, an acyl group having 2 to 5 carbon atoms and a heteroaryl group (a 5- or 6-membered ring, a nitrogen atom, 1 to 4 heteroatoms arbitrarily selected from an oxygen atom and a sulfur atom may be included as a substituent, and one or more atoms or groups selected from the group consisting of:
Of these, an alkyl group, an alkoxy group, an alkylthio group, an alkoxycarbonyl group, an acyl group, a phenyl group, and a heteroaryl group are formed from 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. One or more atoms or groups selected from the group may be substituted, and the amino group is a formyl group, an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 5 carbon atoms, and 2 carbon atoms. 1 to 2 groups selected from the group consisting of alkoxycarbonyl groups of 1 to 5 may be substituted.
R ⁷ , R ⁷ ′, R ⁸ and R ⁸ ′ each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
Any two selected from R ⁷ , R ⁷ ′, R ⁸ , R ⁸ ′, R ⁹ , R ¹⁰ and R ¹⁰ ′ may be integrated to form a cyclic structure, and an oxygen atom One or more heteroatoms arbitrarily selected from a nitrogen atom and a sulfur atom may be included as a constituent atom of the ring.
The ring thus formed is selected from the group consisting of a halogen atom, a hydroxyl group, an amino 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. One or more atoms or groups may be substituted, and this amino group is a formyl group, an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 5 carbon atoms, and an alkoxy group having 2 to 5 carbon atoms. One or two groups selected from the group consisting of carbonyl groups may be substituted. )
Or the following formula (5)

Wherein R ⁷ , R ⁷ ′, R ⁸ , R ⁸ ′, R ⁹ , R ¹⁰ , R ¹⁰ ′, R ¹¹ , R ¹¹ ′, R ¹² and R ¹² ′ are complex represented by Z Represents a substituent on a cyclic substituent, more specifically,
R ¹¹ and R ¹¹ ′ each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
This alkyl group includes a halogen atom, a hydroxyl group, an amino group, a carbamoyl group, an alkylthio group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms, an alkylamino group having 1 to 6 carbon atoms, and an alkyl group having 1 to 6 carbon atoms. One or more atoms or groups selected from the group consisting of a halogenoalkyl group and an aminoalkyl group having 1 to 6 carbon atoms may be substituted.
R ⁹ , R ¹⁰ and R ¹⁰ ′ are each independently a hydrogen atom, halogen atom, hydroxyl group, amino group, carbamoyl group, alkyl group having 1 to 6 carbon atoms, alkylamino group having 1 to 6 carbon atoms, aryl A group, a heteroaryl group, an alkoxy group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, or an aminoalkyl group having 1 to 6 carbon atoms,
The alkyl group part of the above alkyl group, alkylthio group, halogenoalkyl group, aminoalkyl group and carbon number alkylamino group may have a cyclic structure, and further a halogen atom, an alkyl group having 1 to 6 carbon atoms, One or more atoms or groups selected from the group consisting of alkoxy groups having 1 to 6 carbon atoms may be substituted.
The amino group of the above amino group, alkylamino group and aminoalkyl group is an alkyl group having 1 to 6 carbon atoms (this alkyl group may have a cyclic structure, and may be a halogen atom, hydroxyl group One or two atoms 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 may be used as a substituent. (In the case of two, they may be the same or different.) Further, this amino group moiety may be protected by a commonly used protecting group.
R ¹² and R ¹² ′ each independently represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, or a heteroaryl group,
The aryl group has 6 to 10 carbon atoms, and the heteroaryl group is a 5-membered ring or 6-membered ring, and includes one heteroatom arbitrarily selected from a nitrogen atom, an oxygen atom and a sulfur atom. May contain four,
The aryl group and heteroaryl group include a halogen atom, a hydroxyl group, a thiol group, an amino group, a nitro group, a cyano group, a carboxyl group, a carbamoyl group, a phenyl group, an alkyl group having 1 to 6 carbon atoms, and an alkyl group having 1 to 6 carbon atoms. An alkoxy group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 6 carbon atoms, an acyl group having 2 to 5 carbon atoms and a heteroaryl group (a 5- or 6-membered ring, a nitrogen atom, 1 to 4 heteroatoms arbitrarily selected from an oxygen atom and a sulfur atom may be included as a substituent, and one or more atoms or groups selected from the group consisting of:
Of these, an alkyl group, an alkoxy group, an alkylthio group, an alkoxycarbonyl group, an acyl group, a phenyl group, and a heteroaryl group are formed from 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. One or more atoms or groups selected from the group may be substituted, and the amino group is a formyl group, an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 5 carbon atoms, and 2 carbon atoms. 1 to 2 groups selected from the group consisting of alkoxycarbonyl groups of 1 to 5 may be substituted.
R ⁷ , R ⁷ ′, R ⁸ and R ⁸ ′ each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
Any two selected from R ⁷ , R ⁷ ′, R ⁸ , R ⁸ ′, R ⁹ , R ¹⁰ , R ¹⁰ ′, R ¹² and R ¹² ′ are integrated to form a cyclic structure. And may contain one or more heteroatoms arbitrarily selected from an oxygen atom, a nitrogen atom, and a sulfur atom as constituent atoms of the ring.
The ring thus formed is selected from the group consisting of a halogen atom, a hydroxyl group, an amino 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. One or more atoms or groups may be substituted, and this amino group is a formyl group, an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 5 carbon atoms, and an alkoxy group having 2 to 5 carbon atoms. One or two groups selected from the group consisting of carbonyl groups may be substituted. )
Or the following formula (6)

(Wherein R ¹³ , R ¹³ ′, R ¹⁴ , R ¹⁴ ′, R ¹⁵ , R ¹⁶ and R ¹⁶ ′ represent a substituent on the heterocyclic substituent represented by Z. More specifically, In
R ¹³ and R ¹³ ′ each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
This alkyl group includes a halogen atom, a hydroxyl group, an amino group, a carbamoyl group, an alkylthio group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms, an alkylamino group having 1 to 6 carbon atoms, and an alkyl group having 1 to 6 carbon atoms. One or more atoms or groups selected from the group consisting of a halogenoalkyl group and an aminoalkyl group having 1 to 6 carbon atoms may be substituted.
R ¹⁴ , R ¹⁴ ′, R ¹⁵ , R ¹⁶ and R ¹⁶ ′ are each independently a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, or an alkyl group having 1 to carbon atoms. 6 alkylamino groups, aryl groups, heteroaryl groups, alkoxy groups having 1 to 6 carbon atoms, alkylthio groups having 1 to 6 carbon atoms, halogenoalkyl groups having 1 to 6 carbon atoms, or aminoalkyls having 1 to 6 carbon atoms Represents a group,
The alkyl group of the above alkyl group, alkylthio group, halogenoalkyl group, aminoalkyl group and alkylamino group may have a cyclic structure, and further have a halogen atom, an alkyl group having 1 to 6 carbon atoms, a carbon number One or more atoms or groups selected from the group consisting of 1 to 6 alkoxy groups may be substituted.
The amino group of the above amino group, aminoalkyl group and alkylamino group is an alkyl group having 1 to 6 carbon atoms (this alkyl group may have a cyclic structure, and may be a halogen atom, a hydroxyl group One or two atoms 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 may be used as a substituent. (In the case of two, they may be the same or different.) Further, this amino group moiety may be protected by a commonly used protecting group.
The aryl group has 6 to 10 carbon atoms, and the heteroaryl group is a 5-membered or 6-membered ring, and includes one heteroatom arbitrarily selected from a nitrogen atom, an oxygen atom and a sulfur atom. 4 may be included,
The aryl group and heteroaryl group include a halogen atom, a hydroxyl group, a thiol group, an amino group, a nitro group, a cyano group, a carboxyl group, a carbamoyl group, a phenyl group, an alkyl group having 1 to 6 carbon atoms, and an alkyl group having 1 to 6 carbon atoms. An alkoxy group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 6 carbon atoms, an acyl group having 2 to 5 carbon atoms and a heteroaryl group (a 5- or 6-membered ring, a nitrogen atom, 1 to 4 heteroatoms arbitrarily selected from an oxygen atom and a sulfur atom may be included as a substituent, and one or more atoms or groups selected from the group consisting of:
Of these, an alkyl group, an alkoxy group, an alkylthio group, an alkoxycarbonyl group, an acyl group, a phenyl group, and a heteroaryl group are formed from 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. One or more atoms or groups selected from the group may be substituted, and the amino group is a formyl group, an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 5 carbon atoms, and 2 carbon atoms. 1 to 2 groups selected from the group consisting of alkoxycarbonyl groups of 1 to 5 may be substituted.
Any two selected from the above R ¹⁴ , R ¹⁴ ′, R ¹⁵ , R ¹⁶ and R ¹⁶ ′ may be integrated so as to form a cyclic structure, and are formed from an oxygen atom, a nitrogen atom, and a sulfur atom. One or more arbitrarily selected hetero atoms may be contained as constituent atoms of the ring.
The ring thus formed is selected from the group consisting of a halogen atom, a hydroxyl group, an amino 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. One or more atoms or groups may be substituted, and this amino group is a formyl group, an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 5 carbon atoms, and an alkoxy group having 2 to 5 carbon atoms. One or two groups selected from the group consisting of carbonyl groups may be substituted. )
Or the following formula (7)

Wherein R ¹³ , R ¹³ ′, R ¹⁴ , R ¹⁴ ′, R ¹⁵ , R ¹⁶ , R ¹⁶ ′, R ¹⁷ and R ¹⁷ ′ are substituted on the heterocyclic substituent represented by Z. Represents a group, more specifically,
R ¹³ and R ¹³ ′ each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
This alkyl group includes a halogen atom, a hydroxyl group, an amino group, a carbamoyl group, an alkylthio group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms, an alkylamino group having 1 to 6 carbon atoms, and an alkyl group having 1 to 6 carbon atoms. One or more groups selected from the group consisting of a halogenoalkyl group and an aminoalkyl group having 1 to 6 carbon atoms may be substituted.
In the formula, R ¹⁴ , R ¹⁴ ′, R ¹⁵ , R ¹⁶ and R ¹⁶ ′ are each independently a hydrogen atom, a halogen atom, an amino group, a hydroxyl group, a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, carbon 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 halogenoalkyl group having 1 to 6 carbon atoms, or 1 to 6 carbon atoms Represents an aminoalkyl group of
The alkyl group of the above alkyl group, alkylthio group, halogenoalkyl group, aminoalkyl group and alkylamino group may have a cyclic structure, and further have a halogen atom, an alkyl group having 1 to 6 carbon atoms, a carbon number One or more atoms or groups selected from the group consisting of 1 to 6 alkoxy groups may be substituted.
The amino group of the above amino group, aminoalkyl group and alkylamino group is an alkyl group having 1 to 6 carbon atoms (this alkyl group may have a cyclic structure, and may be a halogen atom, a hydroxyl group One or two atoms 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 may be used as a substituent. (In the case of two, they may be the same or different.) Further, this amino group moiety may be protected by a commonly used protecting group.
R ¹⁷ and R ¹⁷ ′ each independently represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, or a heteroaryl group, and this aryl group has 6 to 10 carbon atoms, The aryl group is a 5-membered or 6-membered ring, and may contain 1 to 4 heteroatoms arbitrarily selected from a nitrogen atom, an oxygen atom and a sulfur atom,
The aryl group and heteroaryl group include a halogen atom, a hydroxyl group, a thiol group, an amino group, a nitro group, a cyano group, a carboxyl group, a carbamoyl group, a phenyl group, an alkyl group having 1 to 6 carbon atoms, and an alkyl group having 1 to 6 carbon atoms. An alkoxy group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 6 carbon atoms, an acyl group having 2 to 5 carbon atoms and a heteroaryl group (a 5- or 6-membered ring, a nitrogen atom, 1 to 4 heteroatoms arbitrarily selected from an oxygen atom and a sulfur atom may be included as a substituent, and one or more atoms or groups selected from the group consisting of:
Of these, an alkyl group, an alkoxy group, an alkylthio group, an alkoxycarbonyl group, an acyl group, a phenyl group, and a heteroaryl group are formed from 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. One or more atoms or groups selected from the group may be substituted, and the amino group is a formyl group, an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 5 carbon atoms, and 2 carbon atoms. 1 to 2 groups selected from the group consisting of alkoxycarbonyl groups of 1 to 5 may be substituted.
Any two selected from R ¹⁴ , R ¹⁴ ′, R ¹⁵ , R ¹⁶ , R ¹⁶ ′, R ¹⁷ and R ¹⁷ ′ may be integrated to form a cyclic structure, and an oxygen atom One or more heteroatoms arbitrarily selected from a nitrogen atom and a sulfur atom may be included as a constituent atom of the ring.
The ring thus formed is selected from the group consisting of a halogen atom, a hydroxyl group, an amino 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. One or more atoms or groups may be substituted, and this amino group is a formyl group, an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 5 carbon atoms, and an alkoxy group having 2 to 5 carbon atoms. One or two groups selected from the group consisting of carbonyl groups may be substituted. )

  Preferred among these substituents are those represented by formulas (3), (4), and (5). Particularly preferred are substituents having the structures of formulas (4) and (5). Further, when the quinolone mother nucleus is a pyridobenzoxazine skeleton, the substituent of the formula (3) is preferable.

  Specific examples of the substituent Z by the structural formula include the following substituents, but are not limited thereto. Further, when these substituents have an asymmetric carbon and become optically active, the optically active substituent is naturally included in Z.

Specific examples of the quinolone synthetic antibacterial compound represented by the formula (1) include levofloxacin, ofloxacin, sitafloxacin, (7- [3- (R)-(1-aminocyclopropyl) pyrrolidin-1-yl] -1- [2- (S) -Fluoro-1- (R) -cyclopropyl] -1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (compound (I)), (+)-7 -[(7S) -7-amino-7-methyl-5-azaspiro [2.4] heptan-5-yl] -6-fluoro-1-[(1R, 2S) -2-fluoro-1-cyclopropyl ] -1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid hemihydrate (compound (II)), ciprofloxacin, moxifloxacin, trovafloxacin, etc. To mention Of these, preferably sitafloxacin, (7- [3- (R)-(1-aminocyclopropyl) pyrrolidin-1-yl] -1- [2- (S) -fluoro-1- (R) -Cyclopropyl] -1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (compound (I)), (+)-7-[(7S) -7-amino-7-methyl- 5-Azaspiro [2.4] heptan-5-yl] -6-fluoro-1-[(1R, 2S) -2-fluoro-1-cyclopropyl] -1,4-dihydro-8-methoxy-4- Oxo-3-quinolinecarboxylic acid hemihydrate (compound (II)).
When the lyophilized preparation of the present invention is prepared from a quinolone compound, the quinolone compound can be used in any form, whether it is a free form or an adduct such as a hydrate or salt.

  When the quinolone synthetic antibacterial compound (1) according to the present invention has a structure in which a diastereomer is present, when the compound of the present invention is administered to a human or an animal, a compound composed of a single diastereomer may be administered. preferable. This “consisting of a single diastereomer” is understood to include not only the case where no other diastereomer is contained, but also the case of chemical purity. That is, it is interpreted that other diastereomers may be included as long as they do not affect physical constants and physiological activities. The same applies to the case where an enantiomer is present.

The manufacturing method of the freeze-dried preparation of the present invention can be extended as follows.
In the present invention, the freeze-dried preparation is prepared from an aqueous solution (stock solution) for preparing a freeze-dried preparation containing only a quinolone synthetic antibacterial compound having a structure represented by the above formula (1) and a pH regulator. The freeze-drying process itself other than the annealing process performed in the present invention may be performed according to a freeze-drying method that is usually performed in this field.

  Examples of the pH adjuster used in the present invention include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid; sodium hydrogen carbonate, sodium carbonate, sodium hydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, and phosphoric acid. Inorganic acid salts such as dipotassium, potassium dihydrogen phosphate, sodium sulfite, sodium hydrogen sulfite, sodium thiosulfate; acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, ascorbic acid, salicylic acid, benzoic acid, methanesulfone Acids, organic acids such as thioglycolic acid; organic acid ester compounds such as ethyl lactate; sodium citrate, disodium citrate, sodium gluconate, calcium citrate, sodium lactate, sodium acetate, sodium pyrophosphate, sodium benzoate, Sodium caprylate, sodium thioglycolate Can be mentioned monoethanolamine, diethanolamine, triethanolamine, ethylenediamine, meglumine, an organic amine compound such as trometamol and the like; organic acid salts such as potassium; inorganic salts such as sodium hydroxide. The pH of the aqueous solution may be 7 or less, preferably 6.5 or less, particularly preferably 2.5 to 6.0, from the viewpoint of the solubility of the compound (1).

The concentration of the compound (1) in the aqueous solution for preparing the lyophilized preparation is preferably 10 mg / mL or more, more preferably 15 mg / mL or more, and particularly preferably 20 mg / mL or more from the viewpoint of lyophilized cake formation.
As the aqueous solution for preparing a lyophilized preparation, for example, in the case of Compound (I), one having a formulation shown in Table 1 can be preferably used.

In order to prepare a freeze-dried preparation, the first step is to obtain an amorphous frozen body by first cooling the stock solution by a freezing step. The ultimate temperature of the freezing step may be set to a temperature lower than the so-called glass transition temperature in the frozen body of the aqueous solution containing compound (1). For example, in the case of a drug aqueous solution having the composition shown in Table 1, the glass transition temperature of the frozen body is approximately Since it is in the vicinity of −15 ° C., it may be set up to −40 ° C. as is usually done in this field.
In the case of the present invention, the temperature may be set in the range of -20 ° C to -40 ° C. Can be acquired.

Next, it is a feature of the method for preparing an amorphous lyophilized preparation in the present invention that a step (annealing step) of relaxing and increasing the cooling temperature of the freezing step and holding it for a certain time is provided (temperature profile in FIG. 1). Note that this temperature profile is the set temperature of the equipment used for lyophilization, and does not necessarily indicate the temperature of individual containers (vials, etc.) contained in the equipment. In the drying process, it is considered that the container in the equipment has reached this temperature, but in the primary drying process, the temperature of the container in the equipment has decreased due to the sublimation of moisture, and is below the set temperature. it is conceivable that.).
The temperature setting in the annealing step may be based on the glass transition temperature of the amorphous frozen body of the aqueous solution containing compound (1) obtained in the freezing step. That is, the frozen body may be heated to the glass transition temperature or higher and held for a certain period of time. The glass transition temperature of the frozen body can be determined, for example, by DSC measurement of the frozen body, and this DSC measurement may be performed according to a method that is usually performed. Since the glass transition temperature of the frozen body varies depending on the component composition of the stock solution, the glass transition temperature may be determined by performing DSC measurement in each case.

  For example, according to the DSC measurement result of the frozen body containing the compound (I) having the composition shown in Table 1 and the pH regulator, it was found that the peak of the glass transition point rises from about -14.0 ° C. (FIG. 5). Therefore, by maintaining the temperature above this temperature and in a range where the amorphous frozen body does not thaw, the effect of improving the re-dissolution property of the lyophilized cake in the amorphous lyophilized preparation can be imparted. According to the DSC measurement results, the rise of the peak itself is about −17 ° C. If the temperature is higher than this temperature, the effect of annealing can be expected.

The upper limit of the temperature of the annealing step is an upper limit temperature at which the frozen body can maintain freezing because it is essential that the amorphous frozen body does not thaw in the annealing step. In normal cases, it may be considered that the aqueous drug solution is kept frozen until approximately 0 ° C. The effect of annealing is achieved more efficiently as the temperature in the annealing process is set higher, but care should be taken because the frozen body will thaw if the set temperature is too high.
In the method of the present invention, the temperature in the annealing step may be in the range of −20 ° C. to −2 ° C., and more preferably in the range of −15 ° C. to −5 ° C.

The holding time of the annealing step, that is, the time for holding the amorphous frozen body in the elevated temperature state may be a time sufficient for the entire frozen body to reach the set temperature or longer. The time required for this step varies depending on the temperature at which annealing is performed (in addition to this, it goes without saying that it also varies depending on the number of freeze-dried products to be produced). The closer the annealing temperature is to the glass transition temperature (the lower the temperature), the longer it takes, and the higher the temperature than the glass transition temperature, the shorter the time required for the annealing process.
In the method of the present invention, it is usually sufficient that the time for maintaining the frozen body at the elevated temperature in the annealing step is about 15 minutes to 48 hours, more preferably about 30 minutes to 12 hours.

  In the method for producing an amorphous lyophilized preparation of the present invention, there is no particular limitation on the speed at which the temperature at the time of cooling or raising the temperature is lowered or raised, and it is based on factors such as the capability of the equipment used and the management time of the production process. It is clear that there is no particular effect on the freeze-dried preparation.

  After the annealing step, the amorphous frozen body is cooled again and subjected to reduced pressure treatment to proceed to the preparation step of the amorphous lyophilized preparation (primary drying step). This is performed in accordance with the usual lyophilization method. do it. That is, when the set temperature for recooling is reached, the decompression process is started and lyophilization is performed. As long as the temperature reached in this recooling is equal to or lower than the glass transition temperature, it is the same as the cooling step before the annealing step, but it should be -40 ° C set when preparing a normal lyophilized preparation. . Moreover, the ultimate pressure reduction degree of the pressure reduction process in this step may be in the range of 6 to 27 Pa, and preferably in the range of 13 to 20 Pa.

  The primary drying step is performed under reduced pressure and under a temperature condition below the glass transition point. This temperature is the temperature reached by a small container (such as a vial) housed in a freeze-drying device, but the temperature drops with the sublimation of moisture from the frozen body, so the actual set temperature of the device is It may be higher than the glass transition temperature. In the case of the present invention, the set temperature of the device may be in the range of approximately 25 ° C. to −15 ° C.

  The time required for the primary drying step varies depending on the amount of moisture to be sublimated, but may be in the range of about 16 hours to 80 hours, more preferably 16 hours to 50 hours. In addition, as the moisture to sublimate decreases, the temperature decrease becomes milder. As a result, the product temperature starts to rise, but this time can be said to be the end point of the primary drying step.

A secondary drying step is performed after the primary drying step. In other words, the temperature is raised from the temperature of the device set in the primary drying process and reached the set temperature as the secondary drying process, and then held for a certain time. The temperature of the secondary drying step may be room temperature or higher, and may be set in a range of approximately 25 ° C to 45 ° C, but is preferably in a range of 25 ° C to 30 ° C. The time required for the secondary drying step may be about 2 hours to 20 hours, and more preferably 3 hours to 15 hours. Although the reduced pressure state is continuously maintained even in the secondary drying step, it is preferable to increase the degree of reduced pressure in order to promote the desorption of moisture in the secondary drying step. The degree of vacuum may be in the range of 0.5 Pa to 10 Pa, but more preferably in the range of 1 Pa to 5 Pa.
In the production of the amorphous lyophilized preparation of the present invention, sterilization and the like may be carried out in accordance with a routine procedure.

  The present invention will be described in detail below with reference to examples. However, the present invention is not limited to these examples, and these examples should not be construed as limiting in any way.

Example 1
[Freeze-dried drug substance and pH regulator formulation]
1 mol / L hydrochloric acid (1400 mL) was added to water for injection (25 L). Compound (I) (600 g) was dissolved in this aqueous solution, and 1 mol / L hydrochloric acid was further added to adjust the pH to 3.4. Water for injection was added to this solution to adjust the content of compound (I) to 20 mg / mL to obtain a stock solution for preparing a lyophilized preparation. 10 mL of this solution was filled into a small container, freeze-dried according to the following steps, and sealed.

[Freeze drying process]
1) The container filled with the compound (I) solution is loaded on the shelf of a freeze dryer set at 5 ° C,
2) The shelf temperature was cooled to −30 ° C. at a cooling rate of 0.15 ° C./min and held for 6 hours.
3) The shelf temperature was raised to -10 ° C at a rate of 0.5 ° C / min and held for 6 hours.
4) The shelf temperature was cooled to −40 ° C. at a cooling rate of 1.0 ° C./min.
5) After holding at shelf temperature −40 ° C. for 3 hours or more,
6) Depressurization treatment was started, the shelf temperature was set to -5 ° C and held for 30 hours or more. During this time, the degree of vacuum was maintained at 20 Pa.
7) After the product temperature reached -5 ° C or higher, the shelf temperature was set to 25 ° C and held for 6 hours or longer. During this time, the degree of vacuum was maintained at 1 Pa.

  FIG. 9 shows the results of powder X-ray diffraction measurement of compound (I) (crystal), its lyophilized preparation (with an annealing step), and a lyophilized preparation obtained without providing the annealing step. As is clear from FIG. 9, the lyophilized preparation did not show an obvious diffraction peak and was confirmed to be amorphous.

  Moreover, after preparing a chemical | medical solution on the conditions similar to the above, it filled with the container, it frozen on the conditions shown in Table 2, and freeze-dried in the same procedure, Then, the re-dissolution time was measured. The results are shown in FIG. Further, the state about 30 seconds after the re-dissolved solution is injected is shown in FIG. 2 (without the annealing step) and FIG. 3 (with the annealing step).

  Freeze-drying was performed by changing the annealing process temperature, holding time, and the like according to the contents of Table 3. The time required for re-dissolution of the obtained lyophilized preparation is shown in FIG. As a procedure for measuring the re-dissolution time, the same amount of water for injection as that of the filling solution was added to one vial after freeze-drying and gently mixed to measure the time until the contents were completely dissolved.

Example 2
Freeze-dried preparations were prepared for the four quinolone synthetic antibacterial compounds of levofloxacin, ofloxacin, sitafloxacin and compound (II), and the effect of improving the resolubility by the annealing process was confirmed.
As a result, it was confirmed that the re-dissolution time was shortened in the freeze-dried preparations prepared by adding the annealing step to the freeze-dried preparations of any of the quinolone synthetic antibacterial compounds (FIG. 8).

  10 and 11 show the results of powder X-ray diffraction measurement of compound (II) and its lyophilized preparation, and sitafloxacin and its lyophilized preparation. As is clear from FIGS. 10 and 11, none of the lyophilized preparations showed an obvious diffraction peak, confirming that the lyophilized preparation of the present invention was amorphous.

The structure of each quinolone synthetic antibacterial compound is as follows.
1) Levofloxacin [(−)-(S) -9-fluor-2,3-dihydro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7H-pyrido [1,2, 3-de] [1,4] benzoxazine-6-carboxylic acid hemihydrate]

2) Ofloxacin [(±) -9-fluor-2,3-dihydro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid]

3) Sitafloxacin [(−)-7-[(7S) -7-Amino-5-azaspiro [2.4] heptan-5-yl] -8-chloro-6-fluoro-1-[(1R, 2S) -2-fluoro-1-cyclopropyl] -1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid acid sequihydrate]]

4) Compound (II) [(+)-7-[(7S) -7-Amino-7-methyl-5-azaspiro [2.4] heptan-5-yl] -6-fluoro-1-[(1R , 2S) -2-fluoro-1-cyclopropyl] -1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid hemihydrate]

In addition, the said compound (II) can be manufactured with the following method.
(1) Acetoacetic acid tert-butyl ester (497 mL, 3.00 mol), 1,2-dibromoethane (310 mL, 3.60 mmol), potassium carbonate (1.16 kg, 8.00 mmol), and dimethylformamide (2.0 L) The mixture was heated and stirred for 1.5 hours in a 30 ° C. water bath, 3.5 hours in a 60 ° C. water bath, and then in a 30 ° C. water bath for 4 days. The reaction mixture was filtered through celite, and the filtered product was washed with diethyl ether (3.5 L). The filtrate and diethyl ether washing were combined and added to water (2 L), and the organic layer was separated. The aqueous layer was extracted with diethyl ether (2 L), water (1 L) was added to the obtained aqueous layer, and then extracted with diethyl ether (2 L). The organic layers were all combined, washed with 10% aqueous citric acid solution (2 L), water (2 L × 3), and saturated brine (2 L × 3), dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was distilled under reduced pressure to give 371.8 g of 1-acetyl-1-cyclopropanecarboxylic acid tert-butyl ester (10 mmHg, 72-78 ° C. Min, 2.02 mol, 67%) was obtained as a colorless transparent oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.37-1.40 (4H, m), 1.49 (9H, s), 2.44 (3H, s).

(2) 1-acetyl-1-cyclopropanecarboxylic acid tert-butyl ester (9.21 g, 50.0 mmol) was dissolved in 7 N ammonia / methanol solution (300 mL), and concentrated aqueous ammonia (90 mL) was cooled with ice , Ammonium chloride (53.5 g, 1.00 mol), and sodium cyanide (4.90 g, 100.0 mmol) were added, followed by stirring at room temperature for 18 hours. The solvent was concentrated under reduced pressure, water (100 mL) was added to the residual liquid, and the mixture was extracted with dichloromethane (300 mL + 2 × 100 mL). The combined organic layer was dried by adding anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure to remove tert-butyl 1- (1-amino-1-cyanoethyl) -1-cyclopropanecarboxylate. 10.15 g (48.3 mmol, 97%) of the crude ester product was obtained as a light brown oil. The obtained crude product was used in the next reaction without further purification.
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 1.02-1.12 (2H, m), 1.19-1.17 (2H, m), 1.48 (9H, s), 1.50 (3H, s), 2.13 (2H, brs).
MS (ESI) m / z: 155 (M-tBu) ^<+> .

(3) Raney nickel catalyst (Nikko Rika, R-100) was added to an ethanol solution (50 mL) of 1- (1-amino-1-cyanoethyl) -1-cyclopropanecarboxylic acid tert-butyl ester (1.12 g, 5.30 mmol). , 10 mL) ethanol suspension (30 mL) was added, and the mixture was vigorously stirred at room temperature for 6 hours under a hydrogen gas atmosphere. The catalyst was removed by filtration through Celite, and the solvent was distilled off under reduced pressure to obtain 0.84 g of crude 1- (1,2-diamino-1-methylethyl) -1-cyclopropanecarboxylic acid tert-butyl ester ( 3.92 mmol, 74%) was obtained as a colorless transparent oil. The obtained crude product was used in the next reaction without further purification.
MS (ESI) m / z: 215 (M + H) ^<+> .

(4) 0.82 g (3.83 mmol) of 1- (1,2-diamino-1-methylethyl) -1-cyclopropanecarboxylic acid tert-butyl ester crude product was dissolved in concentrated hydrochloric acid (5 mL) at room temperature. The mixture was stirred at the same temperature for 30 minutes. After adding water to the reaction solution, the solvent was distilled off under reduced pressure, followed by azeotropy with ethanol (twice). 0.82 g (3.55 mmol, 93%) of 1- (1,2-diamino-1-methylethyl) -1-cyclopropanecarboxylic acid dihydrochloride crude product was obtained as a pale yellow foamy solid. The obtained crude product was used in the next reaction without further purification.
¹ H-NMR (400 MHz, CD ₃ OD) δ ppm: 1.20-1.26 (1H, m), 1.28 (3H, s), 1.32-1.43 (2H, m), 58-1.62 (1H, m), 3.46 (1H, d, J = 13.4 Hz), 3.80 (1H, d, J = 13.4 Hz).
MS (ESI) m / z: 159 (M + H) ^<+> .

(5) 1,1,1 was added to an acetonitrile solution (70 mL) of 1- (1,2-diamino-1-methylethyl) -1-cyclopropanecarboxylic acid dihydrochloride crude product (800 mg, 3.46 mmol). 3,3,3-hexamethyldisilazane (7.38 mL, 34.6 mmol) was added, and the mixture was heated to reflux for 4 hours in an oil bath at 100 ° C. under nitrogen substitution. The crude 7-amino-7-methyl-5-azaspiro [2.4] heptan-4-one was converted to a light brown gum by cooling to room temperature and adding methanol (70 mL) followed by evaporation in vacuo. Obtained as a solid.
MS (ESI) m / z: 141 (M + H) ^<+> .

To the 7-amino-7-methyl-5-azaspiro [2.4] heptan-4-one crude product obtained above was added 1,4-dioxane (20 mL) and di-tert-butyl dicarbonate (20 mL) at room temperature. 1.528 g, 7.00 mmol) was added and the mixture was stirred at the same temperature for 5 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with chloroform (100 mL + 50 mL). The combined organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off using a short silica gel column, and the solvent was distilled off under reduced pressure. Left. Diethyl ether was added to the obtained residue to suspend it and filtered to give 7- (tert-butoxycarbonylamino) -7-methyl-5-azaspiro [2.4] heptan-4-one 502 mg (2 0.09 mmol, 2 steps, 60%) was obtained as a white powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 0.77-0.82 (1H, m), 0.94-1.04 (2H, m), 1.16-1.23 (1H, m) , 1.28 (3H, s), 1.43 (9H, s), 3.29 (1H, d, J = 10.3 Hz), 4.12 (1H, m), 4.60 (1H, brs) ), 5.82 (1H, brs).
MS (ESI) m / z: 185 (M-tBu) ^<+> .

(6) 7- (tert-Butoxycarbonylamino) -7-methyl-5-azaspiro [2.4] heptan-4-one (3.12 g, 12.97 mmol) in dimethylformamide (65 mL) Below, sodium hydride (55%, mineral oil dispersion, 538 mg, 12.33 mmol) was added over 5 minutes. After stirring at the same temperature for 40 minutes, benzyl bromide (1.851 mL, 15.56 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate (300 mL), and washed with water (100 mL × 2) and saturated brine (100 mL). After adding anhydrous sodium sulfate and drying, the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 9: 1 → 4: 1 → 2: 1.20 g (12.71 mmol, 98%) of 5-benzyl-7- (tert-butoxycarbonylamino) -7-methyl-5-azaspiro [2.4] heptan-4-one by purification in 1) Was obtained as a colorless transparent gummy solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 0.76-0.81 (1H, m), 0.93-1.06 (2H, m), 1.21-1.29 (4H, m) 1.37 (9H, m), 3.14 (1H, d, J = 10.3 Hz), 3.92-3.98 (1H, m), 4.44 (1H, d, J = 15. 1 Hz), 4.56 (1 H, d, J = 14.6 Hz), 4.56 (1 H, brs), 7.22-7.33 (5 H, m).
MS (ESI) m / z: 331 (M + H) ^<+> .

(7) Racemic 5-benzyl-7- (tert-butoxycarbonylamino) -7-methyl-5-azaspiro [2.4] heptan-4-one obtained in (6) above (2.254 g, 6.82 mmol) was optically resolved with an optically active column (CHIRALPAK AD, 20 mmφ × 250 mm, hexane-isopropyl alcohol = 90: 10, flow rate = 20 mL / min, 50 mg divided at a time) (−)-5 Benzyl-7- (tert-butoxycarbonylamino) -7-methyl-5-azaspiro [2.4] heptan-4-one (997 mg, 3.02 mmol, retention time = 7.0 min, [α] _D ^25.1 = -113.9 ° (c = 0.180, chloroform)), and (+)-5-benzyl-7- (tert-butoxycarbonylamino) -7-me -5-azaspiro [2.4] heptan-4-one (957 mg, 2.90 mmol, retention time = 11.3 ^{_{min, [α] D 25.1 = +}} 108.8 DEG (c = 0.249, chloroform)) Got.

(8) (−)-5-Benzyl-7- (tert-butoxycarbonylamino) -7-methyl-5-azaspiro [2.4] heptan-4-one (950 mg, 2.88 mmol) in dichloromethane (15 mL) ) Was added trifluoroacetic acid (7.5 mL) at room temperature and stirred at the same temperature for 40 minutes. The solvent was distilled off under reduced pressure, azeotroped with toluene (twice), saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was extracted with chloroform (100 mL + 2 × 50 mL). To the combined organic layers, anhydrous sodium sulfate was added for drying, and the desiccant was removed by filtration. The obtained residue was dissolved in tetrahydrofuran (30 mL), lithium aluminum hydride (218 mg, 5.74 mmol) was added with stirring under ice cooling, and the mixture was stirred at the same temperature for 1 hr. Further, lithium aluminum hydride (109 mg, 2.87 mmol) was added and stirred at room temperature for 2.5 hours, and then ice-cooled again, water (0.31 mL), 15% aqueous sodium hydroxide solution (0.31 mL), and Water (0.93 mL) was carefully added sequentially. The resulting mixture was stirred overnight at room temperature, dried over magnesium sulfate, and filtered through Celite. The filtrate was concentrated under reduced pressure to give a crude product of 7-amino-5-benzyl-7-methyl-5-azaspiro [2.4] heptane as a colorless transparent oil. The obtained crude product was used in the next reaction without further purification.
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 0.37-0.45 (2H, m), 0.56-0.66 (2H, m), 0.96 (3H, s), 2.48 (1H, d, J = 9.0 Hz), 2.55 (1H, d, J = 8.8 Hz), 2.74 (2H, d, J = 9.0 Hz), 3.59 (2H, s) , 7.21-7.37 (5H, m).
MS (ESI) m / z: 217 (M + H) ^<+> .

The crude 7-amino-5-benzyl-7-methyl-5-azaspiro [2.4] heptane obtained above was dissolved in dichloromethane (15 mL) and di-tert-butyl dicarbonate (1.255 g, 5.75 mmol) was added and stirred at room temperature for 22 hours. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (chloroform-methanol-triethylamine = 98: 2: 1 → 95: 5: 1) to give (−)-5-benzyl-7- 586 mg (1.852 mmol, 3 steps, 64%) of (tert-butoxycarbonylamino) -7-methyl-5-azaspiro [2.4] heptane was obtained as a colorless transparent gummy solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 0.40-0.45 (1H, m), 0.50-0.55 (1H, m), 0.63-0.69 (1H, m) , 0.80-0.85 (1H, m), 1.20 (3H, s), 1.43 (9H, s), 2.44 (1H, d, J = 8.8 Hz), 2.59 (1H, d, J = 9.5 Hz), 2.83 (1H, d, J = 8.8 Hz), 3.33 (1H, m), 3.57 (1H, d, J = 13.2 Hz) 3.68 (1H, d, J = 13.2 Hz), 4.75 (1H, brs), 7.20-7.37 (5H, m).
MS (ESI) m / z: 317 (M + H) ^<+> .
[Α] _D ^25.1 = −63.6 ° (c = 0.129, chloroform)

(9) Using (+)-5-benzyl-7- (tert-butoxycarbonylamino) -7-methyl-5-azaspiro [2.4] heptan-4-one (950 mg, 2.88 mmol) above ( In the same manner as in 8), a 7-amino-5-benzyl-7-methyl-5-azaspiro [2.4] heptane crude product was obtained as a colorless transparent oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 0.37-0.45 (2H, m), 0.56-0.66 (2H, m), 0.96 (3H, s), 2.48 (1H, d, J = 9.0 Hz), 2.55 (1H, d, J = 8.8 Hz), 2.74 (2H, d, J = 9.0 Hz), 3.59 (2H, s) , 7.21-7.37 (5H, m).
MS (ESI) m / z: 217 (M + H) ^<+> .

Further, from the 7-amino-5-benzyl-7-methyl-5-azaspiro [2.4] heptane crude product obtained above, (+)-5-benzyl was obtained in the same manner as in the above (8). 629 mg (1.985 mmol, 3 steps, 69%) of -7- (tert-butoxycarbonylamino) -7-methyl-5-azaspiro [2.4] heptane was obtained as a colorless transparent gummy solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 0.40-0.45 (1H, m), 0.50-0.55 (1H, m), 0.63-0.69 (1H, m) , 0.80-0.85 (1H, m), 1.20 (3H, s), 1.43 (9H, s), 2.44 (1H, d, J = 8.8 Hz), 2.59 (1H, d, J = 9.5 Hz), 2.83 (1H, d, J = 8.8 Hz), 3.33 (1H, m), 3.57 (1H, d, J = 13.2 Hz) 3.68 (1H, d, J = 13.2 Hz), 4.75 (1H, brs), 7.20-7.37 (5H, m).
MS (ESI) m / z: 317 (M + H) ^<+> .
[Α] _D ^25.1 = + 76.2 ° (c = 0.290, chloroform)

(10) 10% to a solution of (−)-5-benzyl-7- (tert-butoxycarbonylamino) -7-methyl-5-azaspiro [2.4] heptane (581 mg, 1.836 mmol) in methanol (40 mL) Palladium carbon catalyst (M, about 50% water content, 349 mg) was added, and the mixture was stirred at room temperature for 2.5 hours under a hydrogen gas atmosphere. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure, and 434 mg (quantitative) of (-)-7- (tert-butoxycarbonylamino) -7-methyl-5-azaspiro [2.4] heptane crude product was colorless. Obtained as a clear gummy solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 0.38-0.43 (1H, m), 0.55-0.60 (2H, m), 0.74-0.80 (1H, m) , 1.08 (3H, s), 1.44 (9H, s), 2.75 (1H, d, J = 12.0 Hz), 2.77 (1H, d, J = 11.5 Hz), 3 .13 (1H, d, J = 11.5 Hz), 3.75 (1H, brd, J = 12.0 Hz), 4.44 (1H, brs).
MS (ESI) m / z: 227 (M + H) ^<+> .
[Α] _D ^25.1 = −63.5 ° (c = 0.277, chloroform)

(11) 10% to a solution of (+)-5-benzyl-7- (tert-butoxycarbonylamino) -7-methyl-5-azaspiro [2.4] heptane (627 mg, 1.981 mmol) in methanol (40 mL) Palladium carbon catalyst (M, about 50% water content, 376 mg) was added, and the mixture was stirred at room temperature for 5 hours in a hydrogen gas atmosphere. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure, and 452 mg (quantitative) of (+)-7- (tert-butoxycarbonylamino) -7-methyl-5-azaspiro [2.4] heptane crude product was colorless. Obtained as a clear gummy solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 0.38-0.43 (1H, m), 0.55-0.60 (2H, m), 0.74-0.80 (1H, m) , 1.08 (3H, s), 1.44 (9H, s), 2.75 (1H, d, J = 12.0 Hz), 2.77 (1H, d, J = 11.5 Hz), 3 .13 (1H, d, J = 11.5 Hz), 3.75 (1H, brd, J = 12.0 Hz), 4.44 (1H, brs).
MS (ESI) m / z: 227 (M + H) ^<+> .
[Α] _D ^25.1 = + 59.5 ° (c = 0.185, chloroform)

(12) (-)-7- (tert-butoxycarbonylamino) -7-methyl-5-azaspiro [2.4] heptane crude product (434 mg, 1.836 mmol) obtained in (10) above, 6,7-difluoro-1-[(1R, 2S) -2-fluorocyclopropyl] -8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid / difluoroboron complex (663 mg, 1. 836 mmol) and triethylamine (0.768 mL, 5.510 mmol) were dissolved in dimethyl sulfoxide (5 mL), and the mixture was heated with stirring in an oil bath at 40 ° C. for 14 hours. Ethanol: water = 4: 1 mixed solution (50 mL) and triethylamine (5 mL) were added to the reaction mixture, and the mixture was heated to reflux in an oil bath at 100 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (200 mL), and washed with 10% aqueous citric acid solution (50 mL), water (50 mL × 2) and saturated brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 7- [7- (tert-butoxycarbonylamino) -7-methyl-5-azaspiro [2.4] heptan-5-yl]. 870 mg (1.676 mmol, 91) crude product of 6-fluoro-1-[(1R, 2S) -2-fluorocyclopropyl] -8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid %) As a yellow foamy solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 0.55-0.60 (1H, m), 0.68-0.73 (1H, m), 0.74-0.80 (1H, m) , 0.92-0.97 (1H, m), 1.22 (3H, s), 1.40 (9H, s), 1.43-1.59 (2H, m), 3.13 (1H , D, J = 9.8 Hz), 3.60 (3H, s), 3.75 (1H, dd, J = 11.0, 3.7 Hz), 3.85 (1H, dt, J = 10. 2, 4.5 Hz), 4.18 (1 H, d, J = 10.0 Hz), 4.47 (1 H, m), 4.62 (1 H, s), 4.79-4.99 (1 H, dm), 7.83 (1H, d, J = 13.7 Hz), 8.68 (1H, d, J = 2.7 Hz), 14.88 (0.7 H, brs).
MS (ESI) m / z: 520 (M + H) ^<+> .
[Α] _D ^25.1 = -128.5 ° (c = 1.240, chloroform)

(13) (+)-7- (tert-butoxycarbonylamino) -7-methyl-5-azaspiro [2.4] heptane crude product obtained in (11) above (452 mg, 1.981 mmol), and 6,7-difluoro-1-[(1R, 2S) -2-fluorocyclopropyl] -8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid / difluoroboron complex (715 mg, 1. 98-mmol) and 7- [7- (tert-butoxycarbonylamino) -7-methyl-5-azaspiro [2.4] heptan-5-yl] -6-fluoro by the same method as in (12) above. -1-[(1R, 2S) -2-fluorocyclopropyl] -8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid crude product 1.0 g and (1.925mmol, 97%) as a yellow foamy solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 0.55-0.60 (1H, m), 0.68-0.80 (2H, m), 0.91-0.97 (1H, m) , 1.21 (3H, s), 1.40 (9H, s), 1.53-1.68 (2H, m), 3.04 (1H, d, J = 10.0 Hz), 3.61 (3H, s), 3.81 (1H, dd, J = 10.7, 4.4 Hz), 3.87-3.93 (1H, m), 4.24 (1H, d, J = 9. 8 Hz), 4.46 (1 H, m), 4.65-4.85 (2 H, m), 7.83 (1 H, d, J = 13.4 Hz), 8.76 (1 H, s).
MS (ESI) m / z: 520 (M + H) ^<+> .
[Α] _D ^25.1 = + 133.2 ° (c = 2.230, chloroform)

(14) 7- [7- (tert-Butoxycarbonylamino) -7-methyl-5-azaspiro [2.4] heptan-5-yl] -6-fluoro-1- [obtained in (12) above (1R, 2S) -2-fluorocyclopropyl] -8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (870 mg, 1.676 mmol) was dissolved in concentrated hydrochloric acid (10 mL) under ice-cooling. Thereafter, the mixture was stirred at room temperature for 20 minutes, and the reaction solution was washed with chloroform (20 mL × 5). A saturated aqueous sodium hydroxide solution was added to the aqueous layer under ice-cooling to adjust the pH to 12.0, and then adjusted to pH 7.4 with hydrochloric acid. Then, chloroform: methanol = 10: 1 mixed solution (200 mL × 2), and chloroform: methanol: water = Extracted with 7: 3: 1 lower layer solution (200 mL). The combined organic layers were dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by recrystallization from ethanol and dried under reduced pressure to obtain 644 mg (1.535 mmol, 92%) of Compound (II) as a pale pink powder.
mp: 195-200 ° C.
[Α] _D ^25.1 = + 40.8 ° (c = 0.147, 0.1N-NaOH).
¹ H-NMR (400 MHz, 0.1 N-NaOD) δ ppm: 0.49-0.56 (2H, m), 0.67-0.76 (2H, m), 1.12 (3H, s), 1.43-1.64 (2H, m), 3.56 (3H, s), 3.59-3.71 (4H, m), 3.99-4.04 (1H, m), 4. 80-5.03 (1H, m), 7.65 (1H, d, J = 13.9 Hz), 8.45 (1H, s).
Elemental analysis: as _{C 21 H 23 F 2 N 3} O 4 · 0.75EtOH · 0.5H 2 O;
Calculated: C, 58.37; H, 6.20; F, 8.21; N, 9.08.
Found: C, 58.23; H, 5.99; F, 8.09; N, 9.02.
MS (EI) m / z: 419 (M ^<+> ).
IR (ATR): 2964, 2843, 1726, 1612, 1572, 1537, 1452, 1439, 1387, 1360, 1346, 1311, 1294, 1265, 1207 cm ⁻¹ .

[Preparation of freeze-dried preparation]
Levofloxacin (8000 mg as an anhydride) was dissolved in water for injection (350 mL), and the pH was adjusted to 7 by adding a pH adjuster. Water for injection was added to this solution to adjust the content of the levofloxacin solution to 20 mg / mL. The solution was filled in 10 mL portions, freeze-dried, and sealed.

[Freeze drying method (with annealing step)]
1) A container filled with a solution containing levofloxacin is loaded on the shelf of a lyophilizer set at 5 ° C.
2) The shelf temperature was cooled to −30 ° C. at a cooling rate of 0.15 ° C./min and held for 3 hours.
3) The shelf temperature was raised to −5 ° C. at a rate of temperature rise of 0.5 ° C./min and held for 2 hours.
4) The shelf temperature was cooled to −40 ° C. at a cooling rate of 1.0 ° C./min.
5) After holding at shelf temperature −40 ° C. for 2 hours or more,
6) The decompression process was started, the shelf temperature was set to 15 ° C. and held for 30 hours or more. During this time, the degree of vacuum was maintained at 20 Pa.
7) After the product temperature reached 15 ° C or higher, the shelf temperature was set to 25 ° C and held for 6 hours or longer. During this time, the degree of vacuum was maintained at 1 Pa.

[Freeze drying method without annealing process]
1) A container filled with a solution containing levofloxacin is loaded on the shelf of a lyophilizer set at 5 ° C.
2) The shelf temperature was cooled to −40 ° C. at a cooling rate of 1.0 ° C./min.
3) After holding at shelf temperature −40 ° C. for 2 hours or more,
4) The decompression process was started, the shelf temperature was set to 15 ° C. and held for 30 hours or more. During this time, the degree of vacuum was maintained at 20 Pa.
5) After the product temperature reached 15 ° C or higher, the shelf temperature was set to 25 ° C and held for 6 hours or longer. During this time, the degree of vacuum was maintained at 1 Pa.

  For the other three compounds, solutions were prepared according to the conditions shown in Table 4, then lyophilized in the same procedure as levofloxacin, and sealed.

[Remelting time]
10 mL of water for injection was added to one vial and gently shaken, and the time until the contents were completely dissolved was measured.

The temperature profile about the freeze-drying method which provided the annealing process, and the freeze-drying method without an annealing process is shown. The state after about 30 seconds after adding a redissolved solution to the freeze-dried preparation of compound (I) prepared by a freeze-drying method without an annealing step is shown. The state after about 30 seconds after adding the redissolved solution to the freeze-dried preparation of Compound (I) prepared by the freeze-drying method provided with the annealing step is shown. The change of the re-dissolution time by the presence or absence of the annealing process with respect to a lyophilized formulation is shown. The DSC measurement result measured by freezing the compound (I) -containing aqueous solution (20 mg / mL) by cooling to about −40 ° C. is shown. The difference of the DSC measurement result by the addition amount of sodium chloride is shown. The change of the remelting time by the change of the conditions of an annealing process is shown. The change of the re-dissolution time by the presence or absence of the annealing process with respect to a lyophilized formulation is shown. The powder X-ray diffraction measurement result of compound (I) and its lyophilized preparation is shown. The powder X-ray diffraction measurement result of compound (II) and its lyophilized preparation is shown. The powder X-ray diffraction measurement result of sitafloxacin and its freeze-dried preparation is shown.

Claims (13)

The following formula (1)
[Wherein, R ¹ represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, or a carbon atom having 3 to 6 carbon atoms optionally substituted by a halogen atom. A cyclic alkyl group, a halogen atom, a hydroxyl group, an amino group, a nitro group, an alkyl group having 1 to 6 carbon atoms, an aryl group which may be substituted by an alkoxy group having 1 to 6 carbon atoms, a halogen atom or 1 to carbon atoms 6 represents an optionally substituted heteroaryl group, an alkoxy group having 1 to 6 carbon atoms, or an alkylamino group having 1 to 6 carbon atoms;
R ² represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms; R ¹ and R ² may be integrated to form a cyclic structure including a part of the mother nucleus. May contain a sulfur atom as a constituent atom of the ring, and this ring may have an alkyl group having 1 to 6 carbon atoms as a substituent.
R ³ represents a hydrogen atom, an amino group (this amino group may be substituted by a formyl group, an alkyl group having 1 to 6 carbon atoms, or an acyl group having 2 to 5 carbon atoms), a thiol group, or halogenomethyl. A 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;
A ¹ is a nitrogen atom or formula (2)
(In the formula, X ² is a hydrogen atom, an amino group (this amino group may be substituted by a formyl group, an alkyl group having 1 to 6 carbon atoms, or an acyl group having 2 to 5 carbon atoms), halogen. An atom, a cyano group, a halogenomethyl group, a halogenomethoxy 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 X ² and R ¹ may be integrated so as to include a part of the mother nucleus to form a cyclic structure, and the ring formed in this way is an oxygen atom, a nitrogen atom, or A sulfur atom may be included as a constituent atom of the ring, and this ring may have an alkyl group having 1 to 6 carbon atoms as a substituent.)
Represents a partial structure represented by
A ² and A ³ each independently represent a nitrogen atom or a carbon atom, and A ¹ , A ² and A ³ and the carbon atom to which they are bonded are a partial structure
Or partial structure
Form.
X ¹ represents a halogen atom or a hydrogen atom;
Y is a hydrogen atom, phenyl group, acetoxymethyl group, pivaloyloxymethyl group, ethoxycarbonyl group, choline group, dimethylaminoethyl group, 5-indanyl group, phthalidyl group, 5-alkyl-2-oxo-1, A 3-dioxol-4-ylmethyl group, a 3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms, or an alkylene group having 1 to 6 carbon atoms and a phenyl group; Represents a phenylalkyl group composed of:
Z represents a monocyclic, bicyclic or tricyclic heterocyclic substituent, which is saturated or partially saturated and is selected from a nitrogen atom, an oxygen atom and a sulfur atom. May contain one or more different atoms, may be a bicyclo structure or a spirocyclic structure, and may be a halogen atom, a hydroxyl group, an amino group, a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, a carbon number of 1 To 6 halogenoalkyl groups, aryl groups, heteroaryl groups, alkoxy groups having 1 to 6 carbon atoms, alkylamino groups having 1 to 6 carbon atoms, alkylthio groups having 1 to 6 carbon atoms, and amino acids having 1 to 6 carbon atoms One or more atoms or groups selected from the group consisting of alkyl groups may be substituted. ]
A compound of formula (1) is obtained by cooling an aqueous solution containing a compound represented by the formula (1) and a pH regulator to obtain a frozen body, then raising the temperature once, cooling again and freeze-drying A method for producing an amorphous freeze-dried preparation containing as an active ingredient. The method for producing an amorphous lyophilized preparation according to claim 1, wherein R ¹ is a cyclic alkyl group or a halogenocycloalkyl group. The method for producing an amorphous lyophilized preparation according to claim 1 or 2, wherein R ² and R ³ are hydrogen atoms. A ¹ is a partial structure represented by the formula (2), and X ^{2 includes} an alkoxy group having 1 to 6 carbon atoms or X ² , R ¹ and a part of the mother nucleus, oxygen atom, nitrogen atom Or the manufacturing method of the amorphous lyophilized formulation of any one of Claims 1-3 which forms the cyclic structure which contains a sulfur atom as a ring structural atom. X ¹ is The method for producing an amorphous lyophilized preparation according to claim 1 is a hydrogen atom or a fluorine atom.   The compound represented by formula (1) is levofloxacin, ofloxacin, sitafloxacin, (7- [3- (R)-(1-aminocyclopropyl) pyrrolidin-1-yl] -1- [2- (S)- Fluoro-1- (R) -cyclopropyl] -1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid, (+)-7-[(7S) -7-amino-7-methyl -5-azaspiro [2.4] heptan-5-yl] -6-fluoro-1-[(1R, 2S) -2-fluoro-1-cyclopropyl] -1,4-dihydro-8-methoxy-4 The method for producing an amorphous lyophilized preparation according to claim 1, which is -oxo-3-quinolinecarboxylic acid hemihydrate, ciprofloxacin, moxifloxacin or trovafloxacin.   The method for producing an amorphous lyophilized preparation according to any one of claims 1 to 6, wherein the temperature reached by the frozen body at the time of temperature rise is in the range from the glass transition temperature of the frozen body to the freezing temperature of the aqueous solution.   The method for producing an amorphous lyophilized preparation according to any one of claims 1 to 6, wherein the reached temperature of the frozen body at the time of temperature rise is in the range of -20 ° C to -2 ° C.   The method for producing an amorphous lyophilized preparation according to any one of claims 1 to 6, wherein the reached temperature of the frozen body at the time of temperature rise is in the range of -15 ° C to -5 ° C. Formula (1)
[Wherein, R ¹ represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, or a carbon atom having 3 to 6 carbon atoms optionally substituted by a halogen atom. A cyclic alkyl group, a halogen atom, a hydroxyl group, an amino group, a nitro group, an alkyl group having 1 to 6 carbon atoms, an aryl group which may be substituted by an alkoxy group having 1 to 6 carbon atoms, a halogen atom or 1 to carbon atoms 6 represents an optionally substituted heteroaryl group, an alkoxy group having 1 to 6 carbon atoms, or an alkylamino group having 1 to 6 carbon atoms;
R ² represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms; R ¹ and R ² may be integrated to form a cyclic structure including a part of the mother nucleus. May contain a sulfur atom as a constituent atom of the ring, and this ring may have an alkyl group having 1 to 6 carbon atoms as a substituent.
R ³ represents a hydrogen atom, an amino group (this amino group may be substituted by a formyl group, an alkyl group having 1 to 6 carbon atoms, or an acyl group having 2 to 5 carbon atoms), a thiol group, or halogenomethyl. A 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;
A ¹ is a nitrogen atom or formula (2)
(In the formula, X ² is a hydrogen atom, an amino group (this amino group may be substituted by a formyl group, an alkyl group having 1 to 6 carbon atoms, or an acyl group having 2 to 5 carbon atoms), halogen. An atom, a cyano group, a halogenomethyl group, a halogenomethoxy 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 X ² and R ¹ may be integrated so as to include a part of the mother nucleus to form a cyclic structure, and the ring formed in this way is an oxygen atom, a nitrogen atom, or A sulfur atom may be included as a constituent atom of the ring, and this ring may have an alkyl group having 1 to 6 carbon atoms as a substituent.)
Represents a partial structure represented by
A ² and A ³ each independently represent a nitrogen atom or a carbon atom, and A ¹ , A ² and A ³ and the carbon atom to which they are bonded are a partial structure
Or partial structure
Form.
X ¹ represents a halogen atom or a hydrogen atom;
Y is a hydrogen atom, phenyl group, acetoxymethyl group, pivaloyloxymethyl group, ethoxycarbonyl group, choline group, dimethylaminoethyl group, 5-indanyl group, phthalidyl group, 5-alkyl-2-oxo-1, A 3-dioxol-4-ylmethyl group, a 3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms, or an alkylene group having 1 to 6 carbon atoms and a phenyl group; Represents a phenylalkyl group composed of:
Z represents a monocyclic, bicyclic or tricyclic heterocyclic substituent, which is saturated or partially saturated and is selected from a nitrogen atom, an oxygen atom and a sulfur atom. May contain one or more different atoms, may be a bicyclo structure or a spirocyclic structure, and may be a halogen atom, a hydroxyl group, an amino group, a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, a carbon number of 1 To 6 halogenoalkyl groups, aryl groups, heteroaryl groups, alkoxy groups having 1 to 6 carbon atoms, alkylamino groups having 1 to 6 carbon atoms, alkylthio groups having 1 to 6 carbon atoms, and amino acids having 1 to 6 carbon atoms One or more atoms or groups selected from the group consisting of alkyl groups may be substituted. ]
A method for producing an amorphous lyophilized preparation comprising the compound of formula (1) as an active ingredient, wherein the aqueous solution containing the compound represented by formula (1) and a pH regulator is subjected to the following series of steps;
1) Step of cooling the aqueous solution to obtain a frozen body 2) Annealing step of raising the temperature of the frozen body 3) Step of cooling again and freeze-drying   The method for producing an amorphous lyophilized preparation according to claim 10, wherein the temperature of the annealing step is in the range from the glass transition temperature of the frozen body to the freezing temperature of the aqueous solution.   The method for producing an amorphous lyophilized preparation according to claim 10, wherein the temperature of the annealing step is in the range of -20 ° C to -2 ° C.   The method for producing an amorphous lyophilized preparation according to claim 10, wherein the temperature of the annealing step is in the range of -15 ° C to -5 ° C.