JPH09136886A - Substituted aminomethylpyrrolidine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the new compound useful as an antibacterial agent and especially exhibiting a storing antibacterial activity against gram-positive bacteria, particularly quinolone-resistant bacteria including MRSA. SOLUTION: This compound of formula I (Q is a group of formula II, etc.; R<1> , R<2> , R<6> -R<9> , R<11> are each H, a 1-6C alkyl; R<3> -R<5> are each H, a halogen, OH, a 1-6C alkyl, a 1-6C alkoxy, etc.; A<1> is N, =C(X<2> )-; X<1> is a halogen, H; X<2> is H, amino, a halogen, etc.; Y<1> is H, phenyl, acetoxymethyl, etc.; R<10> is a 1-6C alkyl, etc.; R<12> is H, amino, OH, etc.,), e.g. 5-amino-7-[(3R)-aminomethyl-(4R) propyl-1-pyrrolidinyl]-6-fluoro-1-[(2S)-fluoro-(1R)cyclopropyl]-1,4-di hydro-8- methyl-4-oxoquinoline-3-carboxylic acid. The compound of formula I is obtained by reacting a compound of formula III (X<5> is F, a releasing group, etc.; Y<3> is Y<1> , etc.; R<15> -R<17> , A<3> , X<6> are the same as R<10> -R<12> , A<1> , X<1> , respectively) with a compound of formula IV (R<61> is R<6> , etc.).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an antibacterial compound useful as a medicine, veterinary drug, aquatic drug, or antibacterial preservative, and further to an antibacterial agent containing this compound.

[0002]

2. Description of the Related Art Since the discovery of norfloxacin, a quinolone synthetic antibacterial agent has been improved in antibacterial activity and pharmacokinetics, and many compounds have been put to clinical use as chemotherapeutic agents effective for almost all infectious diseases.

[0003]

However, in recent years,
In the clinical setting, low-susceptibility bacteria to these drugs are increasing. In addition, for example, among bacteria resistant to drugs other than quinolone synthetic antibacterial agents such as Staphylococcus aureus (MRSA) which is insensitive to β-lactam antibiotics, bacteria less sensitive to quinolone synthetic antibacterial agents are increased. ing. Therefore,
A highly effective drug was desired in the clinical setting.

Furthermore, side effects such as convulsion-induced and side effects such as phototoxicity have been clarified by taking a non-steroidal anti-inflammatory drug, and development of a safer quinolone has been demanded. There is.

[0005]

In view of such circumstances, the present inventor has diligently studied to provide an excellent compound satisfying the above-mentioned requirements, and as a result, a substituted aminomethylpyrrolidine derivative represented by the following general formula (I) has been obtained. And a salt thereof having a wide range of antibacterial activity, particularly showing strong antibacterial activity against Gram-positive bacteria, especially against quinolone resistant bacteria including MRSA, and having good pharmacokinetics and safety. Completed the invention.

That is, the present invention has the general formula (I)

[0007]

[Chemical 6] [In the formula, R ¹ and R ² each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the alkyl group is a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms or a carbon number. It may be substituted with one or more substituents selected from the group consisting of 1 to 6 alkoxyl groups. R ³ , R ⁴ and R ⁵ are each independently
A hydrogen atom, a hydroxyl group, a halogen atom, a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, and an alkylthio group having 1 to 6 carbon atoms. The alkyl group is a hydroxyl group or a halogen atom. And carbon number 1
1 to 6 may be substituted by one or more substituents selected from the group consisting of alkoxyl groups, and R ⁴ and R ⁵ may be integrated to form a methylene chain having 3 to 6 carbon atoms (pyrrolidine ring). To form a spiro ring system), a hydroxyimino group or an alkyloxyimino group having 1 to 6 carbon atoms. R ⁶ is a hydrogen atom or 1 to 6 carbon atoms
R ⁷ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the alkyl group is selected from the group consisting of a hydroxyl group, an alkoxyl group having 1 to 6 carbon atoms and a halogen atom. May be substituted by one or more substituents. R ⁸ and R ⁹ each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and Q is represented by the formula (II)

[0008]

Embedded image [In the formula, R ¹⁰ is an alkyl group having 1 to 6 carbon atoms and 2 carbon atoms.
To C6 alkenyl group, C1 to C6 halogenoalkyl group, C3 to C6 optionally substituted cyclic alkyl group, and optionally substituted aryl group,
A heteroaryl group which may have a substituent, and has 1 carbon atom
To R 6 represent an alkoxyl group or an alkylamino group having 1 to 6 carbon atoms, R ¹¹ represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms, and R ¹¹ and R ¹⁰ further represent a part of the mother nucleus. The ring may be integrated to form a cyclic structure (the size of the ring is a 4-membered ring to a 6-membered ring, which may be saturated or unsaturated). May contain a sulfur atom as a constituent atom, and the ring may be substituted with an alkyl group having 1 to 6 carbon atoms. X ¹
Represents a halogen atom or a hydrogen atom, and R ¹² represents a hydrogen atom, an amino group, a hydroxyl group, a thiol group, a halogenomethyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, or 2 to 6 carbon atoms. Represents an alkynyl group or an alkoxyl group having 1 to 6 carbon atoms, and the amino group is selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms.
It may be substituted with the above substituents. A ¹ is a nitrogen atom or formula (III)

[0009]

Embedded image (In the formula, X ² is a hydrogen atom, amino group, halogen atom, cyano group, halogenomethyl group, halogenomethoxy group, alkyl group having 1 to 6 carbon atoms, alkenyl group having 2 to 6 carbon atoms, or 2 to 6 carbon atoms. Represents an alkynyl group or an alkoxyl group having 1 to 6 carbon atoms, and the amino group is a formyl group, an alkyl group having 1 to 6 carbon atoms and a carbon number of 2 to 5
It may be substituted with one or more substituents selected from the group consisting of the acyl group. Furthermore this X ² and R
¹⁰ is a ring structure containing a part of the nucleus (ring size is 4
A membered ring to a 7-membered ring, which may be saturated or unsaturated. ) May be integrated to form
This ring may contain an oxygen atom, a nitrogen atom or a sulfur atom as a constituent atom, and further this ring has 1 to 6 carbon atoms.
The alkyl group of may be substituted. ) Represents a partial structure represented by. Y ¹ is a hydrogen atom, phenyl group, acetoxymethyl group, pivaloyloxymethyl group, ethoxycarbonyl group, choline group, dimethylaminoethyl group, 5-indanyl group, phthalidinyl 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 alkylene group having 1 to 6 carbon atoms and phenyl group Represents a phenylalkyl group composed of ] Or formula (IV)

[0010]

Embedded image [In the formula, R ¹³ is an alkyl group having 1 to 6 carbon atoms and 2 carbon atoms.
To C6 alkenyl group, C1 to C6 halogenoalkyl group, C3 to C6 optionally substituted cyclic alkyl group, and optionally substituted aryl group,
A heteroaryl group which may have a substituent, and has 1 carbon atom
Represents an alkoxyl group having 1 to 6 carbon atoms or an alkylamino group having 1 to 6 carbon atoms, and R ¹⁴ represents a hydrogen atom, amino group, hydroxyl group, thiol group, halogenomethyl group, alkyl group having 1 to 6 carbon atoms, or 2 to 6 carbon atoms. Alkenyl group with 2 carbon atoms
Represents an alkynyl group having 1 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms.
It may be substituted with one or more substituents selected from the group consisting of alkyl groups having 1 to 6 and acyl groups having 2 to 5 carbon atoms. X ³ represents a halogen atom or a hydrogen atom, A ² represents a nitrogen atom or the formula (V).

[0011]

Embedded image (In the formula, X ⁴ is a hydrogen atom, amino group, halogen atom, cyano group, halogenomethyl group, halogenomethoxy group, alkyl group having 1 to 6 carbon atoms, alkenyl group having 2 to 6 carbon atoms, or 2 to 6 carbon atoms. Represents an alkynyl group or an alkoxyl group having 1 to 6 carbon atoms, and the amino group is a formyl group, an alkyl group having 1 to 6 carbon atoms and a carbon number of 2 to 5
It may be substituted with one or more substituents selected from the group consisting of the acyl group. Furthermore this X ⁴ and R
¹³ is a ring structure containing a part of the nucleus (ring size is 4
A membered ring to a 7-membered ring, which may be saturated or unsaturated. ) May be integrated to form
This ring may contain an oxygen atom, a nitrogen atom or a sulfur atom as a constituent atom, and further this ring has 1 to 6 carbon atoms.
The alkyl group of may be substituted. ) Represents a partial structure represented by. Y ² is hydrogen atom, phenyl group, acetoxymethyl group, pivaloyloxymethyl group, ethoxycarbonyl group, choline group, dimethylaminoethyl group, 5-indanyl group, phthalidinyl 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 alkylene group having 1 to 6 carbon atoms and phenyl group Represents a phenylalkyl group composed of ] Means] and a salt thereof.

The present invention further provides the above compound and its salt, wherein Q is a structure represented by the formula (III) in the general formula (I); and the above compound and salt, wherein R ¹⁰ is a halogenocyclopropyl group. In the general formula (I), the halogenocyclopropyl group is a 1,2-cis-2-halogenocyclopropyl group, and a salt thereof; in the general formula (I), the halogenocyclopropyl group is sterically monovalent. In the general formula (I), the halogenocyclopropyl group is (1R,
The compound and salt thereof according to claim 6, wherein the halogen atom of the halogenocyclopropyl group in the general formula (I) is a fluorine atom; The above compound or a salt thereof, wherein the compound of (I) is a sterically single compound;
The present invention relates to a drug containing a compound of general formula (I) or a salt thereof as an active ingredient; an antibacterial agent containing a compound of general formula (I) or a salt thereof as an active ingredient;

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION The substituents of the compound represented by formula (I) of the present invention will be described. The substituents R ¹ and R ² each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. The alkyl group is a hydroxyl group, a halogen atom,
Alkylthio group having 1 to 6 carbon atoms and 1 to 6 carbon atoms
It may be substituted with one or more substituents selected from the group consisting of the alkoxyl groups.

Here, the alkyl group has 1 to 6 carbon atoms.
It may be linear or branched, but is preferably a methyl group, an ethyl group, a normal propyl group or an isopropyl group.

When the hydroxyl group is substituted on the alkyl group, the alkyl group may be linear or branched having 1 to 6 carbon atoms, and the substitution position of the hydroxyl group is substituted on the terminal carbon atom of the alkyl group. What was done is more preferable. The alkyl group having a hydroxyl group is preferably an alkyl group having up to 3 carbon atoms, such as a hydroxymethyl group, a 2-hydroxyethyl group,
-Hydroxypropyl, 3-hydroxypropyl and the like are preferred.

When the alkyl group is substituted with a halogen atom, the alkyl group may be linear or branched having 1 to 6 carbon atoms, and the halogen atom is preferably a fluorine atom.

When the alkyl group is substituted with an alkylthio group, the alkyl group may be linear or branched having 1 to 6 carbon atoms, and the alkylthio group also has 1 to 6 carbon atoms.
And may be linear or branched. As the alkyl group having an alkylthio group, an alkylthiomethyl group,
An alkylthioethyl group and an alkylthiopropyl group are preferred, and an alkylthio group having up to 3 carbon atoms is also preferred. More preferred are a methylthiomethyl group, an ethylthiomethyl group and a methylthioethyl group.

When the alkyl group is substituted with an alkoxyl group, the alkyl group may be linear or branched having 1 to 6 carbon atoms, and the alkoxyl group also has 1 to 6 carbon atoms.
And may be linear or branched. As the alkyl group having an alkoxyl group, an alkoxymethyl group, an alkoxyethyl group, and an alkoxypropyl group are preferable, and the alkoxyl group is also preferably one having up to 3 carbon atoms.
More preferred are a methoxymethyl group, an ethoxymethyl group and a methoxyethyl group.

Of the above substituents, a hydrogen atom or an alkyl group is particularly preferable, and a methyl group is preferable as the alkyl group. That is, it is preferable that both R ¹ and R ² are methyl groups, or that one is a methyl group and the other is a hydrogen atom, and that both are hydrogen atoms. The carbon atoms to which R ¹ and R ² are bound are asymmetric carbons when these substituents are different from each other, resulting in isomers. It

The substituents R ³ , R ⁴ and R ⁵ are each independently a hydrogen atom, a hydroxyl group, a halogen atom, a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, or a carbon number. It represents an alkylthio group of 1 to 6, and the alkyl group may be substituted with one or more substituents selected from the group consisting of a hydroxyl group, a halogen atom and an alkoxyl group having 1 to 6 carbon atoms. Furthermore, even if R ⁴ and R ⁵ are integrated to form a methylene chain having 3 to 6 carbon atoms (forming a pyrrolidine ring and a spiro ring system), a hydroxyimino group, or an alkyloxyimino group having 1 to 6 carbon atoms. Good.

The halogen atom is preferably a fluorine atom or a chlorine atom.

The alkyl group may be linear or branched having 1 to 6 carbon atoms, but is preferably a methyl group, an ethyl group, a normal propyl group or an isopropyl group.

The alkoxyl group may be a straight chain or branched chain having 1 to 6 carbon atoms, and is preferably a methoxy group or an ethoxy group.

The alkylthio group may be a linear or branched chain having 1 to 6 carbon atoms, and preferably a methylthio group or an ethylthio group.

The alkyl group having 1 to 6 carbon atoms in which the hydroxyl group is substituted may be linear or branched. Preferred examples of the alkyl group having 1 to 6 carbon atoms substituted with a hydroxyl group include a hydroxymethyl group, a 2-hydroxyethyl group and a 3-hydroxypropyl group.

The halogen atom of the alkyl group having a halogen atom is preferably fluorine or chlorine atom, and particularly preferably fluorine atom. The alkyl group may be linear or branched.

Any alkyl group having 1 to 6 carbon atoms having an alkoxyl group may be linear or branched, and is preferably an alkoxymethyl group or an alkoxyethyl group. More preferred are a methoxymethyl group, an ethoxymethyl group and a 2-methoxyethyl group.

When the substituents R ⁴ and R ⁵ are integrated to form a methylene chain, 3 to 6 are newly added to the pyrrolidine ring.
The member ring is added to form a spiro ring structure. The size of the newly formed ring is preferably a cyclopropyl ring or cyclobutyl ring having 2 or 3 carbon atoms.

Further, R ⁴ and R ⁵ are integrated to form an alkyloxyimino group.

[0030]

When embedded image is NO-Alkyl, the alkyl group may be linear or branched. Preferred as the alkyloxyimino group are a methoxyimino group and an ethoxyimino group.

The substituent R ⁶ is a hydrogen atom or has 1 to 6 carbon atoms.
Is an alkyl group. This alkyl group has 1 carbon atom
Nos. 6 to 6 may be linear or branched, but are preferably a methyl group, an ethyl group, a normal propyl group and an isopropyl group.

The substituent R ⁷ is a hydrogen atom or has 1 to 6 carbon atoms.
The alkyl group may be substituted with one or more substituents selected from the group consisting of a hydroxyl group, an alkoxyl group having 1 to 6 carbon atoms and a halogen atom.

The alkyl group may be a linear or branched chain having 1 to 6 carbon atoms, but is preferably a methyl group, an ethyl group, a normal propyl group or an isopropyl group. The alkyl group having 1 to 6 carbon atoms substituted with a hydroxyl group may be linear or branched, and the substitution position of the hydroxyl group is more preferably substituted at the terminal carbon atom of the alkyl group. Preferred as the alkyl group having 1 to 6 carbon atoms in which a hydroxyl group is substituted are a hydroxymethyl group and 2
Examples thereof include a hydroxyethyl group and a 3-hydroxypropyl group.

The halogen atom of the alkyl group having 1 to 6 carbon atoms having a halogen atom is preferably a fluorine atom, the number of fluorine atoms is preferably 1 to 3, and the number of carbon atoms is preferably 2 or less. As the alkyl group having a halogen atom, a 2-fluoroethyl group, 2,2-
A difluoroethyl group and a 2,2,2-trioloethyl group are particularly preferable.

The substituents R ⁶ and R ⁷ are preferably both hydrogen atoms, preferably one is a hydrogen atom and the other is an alkyl group, and both are preferably alkyl groups.

The substituents R ⁸ and R ⁹ are each independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. The alkyl group may be a linear or branched chain having 1 to 6 carbon atoms, but is preferably a methyl group, an ethyl group, a normal propyl group or an isopropyl group. Of these, it is preferable that each is a hydrogen atom.

Q is the formula (II)

[0038]

Embedded image Or formula (IV)

[0039]

Embedded image It has a condensed heterocyclic ring structure represented by.

The substituents R ¹⁰ and R ¹³ each have 1 carbon atom.
To 6 alkyl groups, alkenyl groups having 2 to 6 carbon atoms,
A halogenoalkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms which may have a substituent, an aryl group which may have a substituent, and a substituent which may have a substituent A heteroaryl group, an alkoxyl group having 1 to 6 carbon atoms, or an alkylamino group having 1 to 6 carbon atoms.

Here, an ethyl group is particularly preferable as the alkyl group having 1 to 6 carbon atoms. The alkenyl group having 2 to 6 carbon atoms is preferably vinyl group or 1-isopropenyl group. A 2-fluoroethyl group is preferable as the halogenoalkyl group having 1 to 6 carbon atoms. The cycloalkyl group having 3 to 6 carbon atoms which may have a substituent is preferably a cyclopropyl group and a 2-halogenocyclopropyl group, and the halogen atom of the 2-halogenocyclopropyl group is particularly preferably a fluorine atom.

The aryl group which may have a substituent is, for example, a halogen atom such as a fluorine atom, a chlorine atom or a bromine atom, a lower alkyl group having 1 to 6 carbon atoms, a hydroxyl group,
Examples thereof include a phenyl group which may be substituted with 1 to 3 substituents selected from the group consisting of an amino group, a nitro group, a lower alkoxyl group having 1 to 6 carbon atoms, and the like. Fluorophenyl group, 4-fluorophenyl group, 2,4-difluorophenyl group and 2
A -fluoro-4-hydroxyphenyl group and the like are preferable.

The heteroaryl group is a nitrogen atom, an oxygen atom,
It is a substituent derived from an aromatic heterocyclic compound containing one or more heteroatoms selected from sulfur atoms. Examples thereof include a pyridyl group and a pyrimidyl group. As a substituent on these rings, an alkyl group, a halogen atom and the like are preferable. Carbon number 1
A methoxy group is preferred as the alkoxyl groups of to 6. The alkylamino group having 1 to 6 carbon atoms is preferably a methylamino group.

The substituents R ¹⁰ and R ¹³ are preferably cyclic alkyl groups or halogenocycloalkyl groups. Among these, a cyclopropyl group or a 2-halogenocyclopropyl group is preferred. The halogen atom is preferably a fluorine atom.

The substituent R ¹¹ represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms, or R ¹¹ and R ¹⁰ are integrated so as to form a cyclic structure containing a part of the mother nucleus. Good. The ring thus formed may contain a sulfur atom as a constituent atom, and the ring may be substituted with an alkyl group having 1 to 6 carbon atoms. The ring formed here may have a size of a 4-membered ring to a 6-membered ring, and the ring may be saturated or unsaturated.

The substituents X ¹ and X ³ are a halogen atom or a hydrogen atom, but in the case of a halogen atom, a fluorine atom is preferable. Among these, a fluorine atom or a hydrogen atom is preferred as a substituent.

Substituents R ¹² and R ¹⁴ are hydrogen atom, amino group, hydroxyl group, thiol group, halogenomethyl group, carbon number 1
To 6 alkyl groups, alkenyl groups having 2 to 6 carbon atoms,
It represents an alkynyl group having 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms. The amino group is a formyl group,
It may be substituted with one or more substituents selected from the group consisting of alkyl groups having 1 to 6 carbon atoms and acyl groups having 2 to 5 carbon atoms.

The alkyl group may be a straight chain or branched chain having 1 to 6 carbon atoms, but is preferably a methyl group, an ethyl group, a normal propyl group or an isopropyl group. The alkenyl group may be a straight chain or branched chain having 2 to 6 carbon atoms, but is preferably a vinyl group. The alkynyl group may be linear or branched having 2 to 6 carbon atoms, and is preferably an ethynyl group. The halogen of the halogenomethyl group is particularly preferably a fluorine atom, and the number thereof may be 1 to 3. The alkoxyl group may have 1 to 6 carbon atoms, but is preferably a methoxy group.

The substituents R ¹² and R ¹⁴ are preferably an alkyl group or an amino group, and of these, a methyl group or an unsubstituted amino group is preferable.

When the substituents R ¹² and R ¹⁴ are an amino group, a hydroxyl group or a thiol group, these may be protected by a commonly used protecting group.

Examples of such a protecting group include alkoxycarbonyl groups such as tertiary butoxycarbonyl group and 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, Aralkyloxycarbonyl groups such as paranitrobenzyloxycarbonyl group, acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, formyl group, acyl groups such as benzoyl group, tertiary butyl group, Alkyl groups such as benzyl group, paranitrobenzyl group, paramethoxybenzyl group, triphenylmethyl group or aralkyl groups, methoxymethyl group, tertiary butoxymethyl group, tethydropyranyl group, 2,2,2- Ethers such as trichloroethoxymethyl group, tris Chirushiriru group, an isopropyl dimethyl silyl group, tert-butyldimethylsilyl group, and tribenzylsilyl group, a silyl group such as tert-butyldiphenylsilyl group. A compound having a substituent protected by these substituents is particularly preferable as a production intermediate.

A ¹ is of the formula (III)

[0053]

Embedded image X ² is a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, or a carbon number It represents an alkynyl group having 2 to 6 or an alkoxyl group having 1 to 6 carbon atoms. This amino group may be substituted with one or more substituents selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms.

The alkyl group may be a straight chain or branched chain having 1 to 6 carbon atoms, but is preferably a methyl group or an ethyl group. 2 carbon atoms as alkenyl group
It may be a straight-chain or branched-chain group from 1 to 6, but is preferably a vinyl group. The alkynyl group may be linear or branched having 2 to 6 carbon atoms, and is preferably an ethynyl group. The halogen of the halogenomethyl group is particularly preferably a fluorine atom, and the number thereof may be 1 to 3. The alkoxyl group may have 1 to 6 carbon atoms, but is preferably a methoxyl group. As the halogen of the halogenomethoxyl group, a fluorine atom is particularly preferable,
The number may be from one to three.

Of these substituents, an alkyl group, an alkoxyl group or a halogenomethoxyl group is preferable.
More preferred are methyl group, methoxy group and difluoromethoxy group.

Further, X ² and R ¹⁰ include a part of the mother nucleus and have a cyclic structure (the size of the ring is a 4-membered ring to a 7-membered ring,
It may be saturated or unsaturated. ), The ring may contain an oxygen atom, a nitrogen atom or a sulfur atom as a constituent atom, and the ring may be substituted with an alkyl group having 1 to 6 carbon atoms. .

A ² is the formula (V)

[0058]

Embedded image X ⁴ is a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, and a carbon number It represents an alkynyl group having 2 to 6 or an alkoxyl group having 1 to 6 carbon atoms. The amino group may be substituted with one or more substituents selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms.

The alkyl group may be a straight chain or branched chain having 1 to 6 carbon atoms, but is preferably a methyl group or an ethyl group. 2 carbon atoms as alkenyl group
It may be a straight-chain or branched-chain group from 1 to 6, but is preferably a vinyl group. The alkynyl group may be linear or branched having 2 to 6 carbon atoms, and is preferably an ethynyl group. The halogen of the halogenomethyl group is particularly preferably a fluorine atom, and the number thereof may be 1 to 3. The alkoxyl group may have 1 to 6 carbon atoms, but is preferably a methoxyl group. As the halogen of the halogenomethoxyl group, a fluorine atom is particularly preferable,
The number may be from one to three.

Further, X ⁴ and R ¹³ include a cyclic structure containing a part of the mother nucleus (the size of the ring is a 4-membered ring to a 7-membered ring,
It may be saturated or unsaturated. ), The ring may contain an oxygen atom, a nitrogen atom or a sulfur atom as a constituent atom, and the ring may be substituted with an alkyl group having 1 to 6 carbon atoms. .

A ¹ is of the formula (III)

[0062]

Embedded image In the case of the partial structure of, the combination of R ¹² and X ² is preferably R ¹² is an amino group, a hydrogen atom, a hydroxyl group or an alkyl group having 1 to 6 carbon atoms, and X ² is 1 to 6 carbon atoms.
Is an alkyl group, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, a halogenomethoxyl group or a hydrogen atom.

A more preferable combination is R ¹²
Is an amino group, a hydrogen atom, a hydroxyl group or a methyl group, and X ² is a methyl group, a methoxyl group, a fluorine atom, a chlorine atom, a difluoromethoxyl group or a hydrogen atom.

A particularly preferable combination is R ¹²
Is an amino group, a hydrogen atom, a hydroxyl group or a methyl group, and X ² is a methyl group or a methoxyl group.

For these R ¹² and X ² , X ¹ is preferably a fluorine atom.

When each of the substituents X ¹ and X ² is a halogen atom, X ¹ is particularly preferably a fluorine atom, and X ² is preferably a fluorine atom or a chlorine atom.

A ² is the formula (V)

[0068]

Embedded image In the case of the partial structure of, the combination of R ¹⁴ and X ⁴ is preferably R ¹⁴ is an amino group, a hydrogen atom, a hydroxyl group or an alkyl group having 1 to 6 carbon atoms, and X ⁴ is 1 to 6 carbon atoms.
Is an alkyl group, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, a halogenomethoxyl group or a hydrogen atom.

A more preferable combination is R ¹⁴
Is an amino group, a hydrogen atom, a hydroxyl group or a methyl group, and X ⁴ is a methyl group, a methoxyl group, a fluorine atom, a chlorine atom, a difluoromethoxyl group or a hydrogen atom.

A particularly preferable combination is R ¹⁴
Is an amino group, a hydrogen atom, a hydroxyl group or a methyl group, and X ⁴ is a methyl group or a methoxyl group.

When each of the substituents X ³ and X ⁴ is a halogen atom, X ³ fluorine atom is particularly preferable, and X ⁴ is preferably fluorine atom or chlorine atom.

Next, the halogenocyclopropyl group of R ¹⁰ will be described.

Examples of the halogen atom to be substituted include a fluorine atom and a chlorine atom, and a fluorine atom is particularly preferable.

As for the steric environment in this portion, it is particularly preferable that the halogen atom and the pyridonecarboxylic acid portion have a cis configuration with respect to the cyclopropane ring.

Although only the cis-2-halogenocyclopropyl moiety of R ¹⁰ has isomers of so-called enantiomers, strong antibacterial activity and high safety were observed for all of them.

When the compound of the formula (I) which is a compound of the present invention has a structure in which a diastereomer exists, when the compound of the present invention is administered to humans or animals, a compound of a single diastereomer It is preferable to administer. this,
“Consisting of a single diastereomer” is understood to include not only the case where no other diastereomer is contained, but also the case where it is chemically pure. That is, it is understood that other diastereomers may be contained as long as they do not affect the physical constants and physiological activities.

The term "sterically single" means that when a compound or the like contains an asymmetric carbon atom, and there are a plurality of isomers, only one of them is constituted. It means that it has been done. In this case, the “unity” is also considered in the same manner as described above.

The pyridonecarboxylic acid derivative of the present invention may be in a free form, but may be an acid addition salt or a carboxyl group salt. Examples of acid addition salts include inorganic salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, and phosphate, or acetate,
Organic acid salts such as methanesulfonate, benzenesulfonate, toluenesulfonate, citrate, maleate, fumarate and lactate can be mentioned.

Examples of the carboxyl group salt include alkali metal salts such as lithium salt, sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, ammonium salt, triethylamine salt and N salt.
-Methylglucamine salt, tris- (hydroxylmethyl) aminomethane salt and the like, which may be inorganic salts or organic salts.

In addition, free forms of these pyridonecarboxylic acid derivatives, acid addition salts, and salts of carboxyl groups may exist as hydrates.

On the other hand, the quinolone derivative in which the carboxylic acid moiety is an ester is useful as a synthetic intermediate or a prodrug. For example, alkyl esters, benzyl esters, alkoxyalkyl esters, phenylalkyl esters, and phenyl esters are useful as synthetic intermediates.

Further, the ester used as a prodrug is an ester which is easily cleaved in vivo to form a free form of carboxylic acid, and examples thereof include acetoxymethyl ester, pivaloyloxymethyl ester and ethoxy. Carbonyl ester, choline ester, dimethylaminoethyl ester, 5-indanyl ester and phthalidinyl ester, 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl ester and 3-acetoxy-2-oxobutyl Examples thereof include oxoalkyl esters such as esters.

The compound of the present invention represented by the formula (I) can be produced by various methods, and a preferred example thereof is, for example, the formula (VI).

[0084]

Embedded image [In the formula, X ⁵ represents a fluorine atom, a chlorine atom, a bromine atom, a substituted or unsubstituted phenylsulfonyl group, or a substituted or unsubstituted alkylsulfonyl group having 1 to 3 carbon atoms, or a substituent functioning as a leaving group. Y ³ is the general formula (II)
Y ¹ defined in or the formula (VII)

[0085]

Embedded image (Wherein Y ³¹ and Y ³² represent a fluorine atom or an alkylcarbonyloxy group having 2 to 4 carbon atoms), and R ¹⁵ , R ¹⁶ , R ¹⁷ , A ³ and X ⁶ are each a general formula. The same meaning as R ¹⁰ , R ¹¹ , R ¹² , A ¹ and X ¹ defined in (II)], or a compound of formula (VIII)

[0086]

Embedded image [In the formula, X ⁷ represents a fluorine atom, a chlorine atom, a bromine atom, a substituted or unsubstituted phenylsulfonyl group, or a substituted or unsubstituted alkylsulfonyl group having 1 to 3 carbon atoms or a substituent functioning as a leaving group. Representation R ¹⁸ , R ¹⁹ , A ⁴ ,
X ⁸ and Y ⁴ are R ¹³ , R ¹⁴ , A ² defined in the general formula (VI),
X ³ and Y ² have the same meanings as those of formula (IX)

[0087]

Embedded image [Wherein R ⁶¹ is the same as R ⁶ defined in formula (I) or represents a protecting group for an amino group, and R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁷ , R ⁸ and R ⁹ are the same as defined in formula (I). ] Or an addition salt thereof.

The reaction can be carried out with or without a solvent. The solvent used in the reaction may be inert under the reaction conditions, for example, dimethyl sulfoxide, pyridine, acetonitrile, ethanol, chloroform, dimethylformamide, dimethylacetamide,
N-methylpyrrolidone, tetrahydrofuran, water, 3-
Mention may be made of methoxybutanol or mixtures thereof.

The reaction is carried out in the presence of an acid acceptor such as an inorganic base or an organic base, for example, an alkali metal or alkaline earth metal carbonate or hydrogen carbonate, or triethylamine, pyridine or 1,8-diazabicycloundecene. It is preferable to carry out.

The reaction temperature is usually room temperature to 200 ° C., preferably 25 to 150 ° C. The reaction time may be 30 minutes to 48 hours, but it is usually completed in 30 minutes to 2 hours.

The protecting group for the amino group may be any protecting group usually used in this field, and examples thereof include alkoxycarbonyl groups such as tertiary butoxycarbonyl group and 2,2,2-trichloroethoxycarbonyl group. , Benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group and other aralkyloxycarbonyl groups, acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, formyl group, benzoyl Groups such as acyl groups, tertiary butyl groups, benzyl groups, paranitrobenzyl groups, paramethoxybenzyl groups, alkyl groups such as triphenylmethyl groups, or aralkyl groups, methoxymethyl groups, tertiary butoxymethyl groups, Tetrahydropyranyl group, 2,2,2 Ethers such as trichloroethoxymethyl group, a trimethylsilyl group, an isopropyl dimethyl silyl group, tert-butyldimethylsilyl group, may be mentioned tribenzylsilyl group, a silyl group such as tert-butyldiphenylsilyl group.

When Y ³ and Y ⁴ are an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms or a phenylalkyl group composed of an alkylene group having 1 to 6 carbon atoms and a phenyl group, The carboxylic acid can be converted to the corresponding carboxylic acid by treating under acidic or basic conditions used for the hydrolysis of the carboxylic acid ester.

Y ³ is of the formula (VII)

[0094]

Embedded image (Wherein Y ³¹ and Y ³² represent a fluorine atom or an alkylcarbonyloxy group having 2 to 4 carbon atoms), the compound (VI) is reacted with the compound (IX), and then the compound is acidic or basic. It can be converted to the corresponding carboxylic acid by treating under conditions.

When deprotection is necessary, the protecting group can be removed under appropriate conditions corresponding to the protecting group to give the desired compound of formula (I).

The compound of the present invention represented by the formula (I) can also be produced by the following method. That is, a method of constructing a quinoline ring after introducing a pyrrolidine substituent moiety in advance is described by the formula (IX)

[0097]

Embedded image And a compound represented by the formula (X)

[0098]

Embedded image (In the formula, X ⁹ , X ¹⁰ , X ¹¹ , X ¹² and R ²⁰ are the same as X ⁵ defined in the formula (VI), and R ²¹ represents a nitrile, a carboxyl group, a lower alkoxycarbonyl group or an acetyl group. .) To react with a compound (XI)

[0099]

Embedded image It is converted to the compound represented by. The compound of the general formula (I) can be obtained by further applying a commonly used conversion method based on a carboxylic acid compound obtained by applying a commonly used method to this compound.

Since the compound of the present invention has a strong antibacterial action, it is used as a medicine for humans, animals and fish, or as an agricultural chemical,
It can be used as a food preservative.

When the compound of the present invention is used as a medicine for humans, the daily dose for an adult is 50 mg to 1 g, preferably 100 mg to 300 mg.

The dose for animals varies depending on the purpose of administration (treatment or prophylaxis), the type and size of the animal to be treated, the type and degree of the infectious pathogen, but it is generally a daily dose. Is 1 mg to 20 per kg of animal weight
It is in the range of 0 mg, preferably 5 mg to 100 mg.

This daily dose should be taken once a day or from 2 to 4
Administer in divided doses. The daily dose may exceed the above-mentioned amount if necessary.

The compounds of the invention are active against a wide variety of microorganisms responsible for various infectious diseases and can treat, prevent or ameliorate the diseases caused by these pathogens.

As bacteria or bacteria-like microorganisms for which the compound of the present invention is effective, Staphylococcus, Streptococcus pyogenes, Hemolytic streptococcus, Enterococcus, Streptococcus pneumoniae, Peptostreptococcus, Neisseria gonorrhoeae, Escherichia coli, Citrobacter, Shigella , Klebsiella pneumoniae, Enterobacter, Serratia,
Proteus, Pseudomonas aeruginosa, Haemophilus influenzae, Acinetobacter, Campylobacter, Chlamydia trachomatis and the like can be exemplified.

Further, as diseases caused by these pathogens, folliculitis, setting, erythema, erysipelas, cellulitis,
Lymphatic (node) inflammation, whitlow, subcutaneous abscess, sweat glanditis, acne condensate, infectious nodules, perianal abscess, mastitis, superficial secondary infection such as trauma / burn / surgical wound, pharynx Inflammation, acute bronchitis, tonsillitis, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, secondary infection of chronic respiratory disease, pneumonia, pyelonephritis, cystitis, prostatitis, epididymitis, gonococcal urethra Inflammation, nongonococcal urethritis, cholecystitis, cholangitis, bacterial dysentery, enteritis, uterine appendixitis, intrauterine infection, Bartholin's adenitis, blepharitis, stye, lacrimal cystitis, tarsal adenitis, corneal ulcer, otitis media , Sinusitis, periodontitis, pericoronitis, jawitis, peritonitis, endocarditis, sepsis, meningitis, skin infection and the like.

It is also effective against various microorganisms which cause infectious diseases of animals, for example, Escherichia, Salmonella, Pasteurella, Haemophilus, Bordetella, Staphylococcus, Mycoplasma and the like. Specific examples of disease names include colibacillosis, chicken dysentery, chicken paratyphoidosis, poultry cholera, infectious coryza, staphylococcal disease, mycoplasma infection in birds, and colibacillosis, salmonellosis, pasteurella infection, hemophilus infection in pigs. , Atrophic rhinitis,
Exudative epidermitis, mycoplasma infection, etc. in cattle, colibacillosis, salmonellosis, hemorrhagic sepsis, mycoplasma infection, bovine lung disease, mastitis, etc., Escherichia coli sepsis in dogs, salmonella infection, hemorrhagic sepsis, pyometra Cystitis, etc., and in cats, exudative pleurisy, cystitis, chronic rhinitis, hemophilus infection, kitten diarrhea, mycoplasma infection and the like.

The antibacterial preparation comprising the compound of the present invention can be prepared by selecting an appropriate preparation according to the administration method and preparing various preparations usually used. Examples of the dosage form of the antibacterial agent containing the compound of the present invention as the main ingredient include tablets, powders, granules,
Examples of the oral preparation include capsules, solutions, syrups, elixirs, oily or aqueous suspensions, and the like.

As an injection, a stabilizer, a preservative,
In some cases, a solubilizing agent may be used, and a solution that may include these adjuvants may be stored in a container, and then may be prepared as a solid preparation by freeze-drying or the like before use as a solid preparation. Also, one dose may be stored in one container, or multiple doses may be stored in the same container.

Examples of the external preparation include solutions, suspensions, emulsions, ointments, gels, creams, lotions and sprays.

The solid preparation contains additives which are pharmaceutically acceptable together with the active compound, and examples thereof include fillers, extenders, binders, disintegrants, dissolution promoters, wetting agents and lubricants. It is possible to select the types and the like as required and mix them to prepare a formulation.

Examples of liquid preparations include solutions, suspensions, emulsions and the like, but they may contain suspending agents, emulsifiers and the like as additives.

The compounds of the present invention can be administered to animals directly or by mixing them in a feed, and then orally. Alternatively, once prepared as a solution, they can be directly orally added to drinking water or feed and administered orally. The method of administration, the method of administration by injection and the like can be illustrated.

As the preparation for administering the compound of the present invention to animals, a powder, a fine granule, a soluble powder, a syrup, a solution, or an injection is appropriately prepared by a technique usually used in this field. can do.

[0115] Next, an example of pharmaceutical formulation will be shown.

Formulation Example 1. (Capsule): Compound of Example 1 100.0 mg Corn starch 23.0 mg CMC calcium 22.5 mg Hydroxymethylcellulose 3.0 mg Magnesium stearate 1.5 mg Total 150.0 mg

Formulation Example 2. (Solution): Compound of Example 1 1 to 10 g Acetic acid or sodium hydroxide 0.5 to 2 g Ethyl paraoxybenzoate 0.1 g Purified water 88.9 to 98.4 g Total 100 g

Formulation Example 3. (Powder for mixing feed): Compound of Example 1 1-10 g Corn starch 98.5-89.5 g Light anhydrous silicic acid 0.5 g Total 100 g

[0119]

Next, the present invention will be described with reference to examples and reference examples, but the present invention is not limited to these examples. The test method for the antibacterial activity of the target compound is performed according to the standard method specified by the Japanese Society of Chemotherapy, and the result is MIC (μg / m
l).

Reference Example 1-1 (4R) -4-hydroxymethyl-2-oxo-1-
((1R) -Phenylethyl) -pyrrolidinemethyl (4R) -2-oxo-1-((1R) -phenylethyl) pyrrolidine-4-carboxylate 59.
20 g (239.4 mmol) of ethanol (1000
ml) and sodium borohydride (27.17 g, 718.2 mmol) was added with stirring at room temperature. After stirring for 16 hours at the same temperature, water (500 m
l) was added. Ethanol was distilled off under reduced pressure, ethyl acetate (1 liter) was added to the residue, and the layers were separated. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was distilled off under reduced pressure to give the title compound 51.2.
8 g (233.9 mmol) was obtained as an oil.

¹ H-NMR (400 MHz, CDC
l ₃ ) δ: 1.51 (3H, d, J = 7.3 Hz),
2.26 (1H, dd, J = 16.1, 5.9Hz),
2.39-2.56 (2H, m), 3.01 (1H, b
rs), 3.08 (1H, dd, J = 9.8, 7.8H
z), 3.19 (1H, dd, J = 9.8, 5.4H)
z), 3.52-3.61 (2H, m), 5.46 (1
H, q, J = 7.3 Hz), 7.24-7.35 (5
H, m).

Reference Example 1-2 (4R) -4-t-butyldimethylsilyloxymethyl
-2-oxo-1-((1R) -phenylethyl) -pi
Roridin (4R) -4-hydroxymethyl-2-oxo-1-
((1R) -phenylethyl) -pyrrolidine 50.34
g (229.6 mmol) to dimethylformamide 50
It was dissolved in 0 ml, and 41.52 g (275.5 mmol) of t-butyldimethylsilane chloride and 39.07 g (573.9 mmol) of imidazole were added while stirring with ice cooling. The ice bath was removed and the reaction was stirred in the chamber for 18 hours. Water (500 ml) was added to the reaction mixture under ice-cooling stirring, and then ethyl acetate (1000 ml) was added to separate the layers. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was distilled off under reduced pressure, the obtained residue was subjected to silica gel column chromatography, and n-hexane: ethyl acetate =
51.28 g (233.
9 mmol) was obtained as an oil.

¹ H-NMR (400 MHz, CDC
l ₃ ) δ: −0.01 (3H, s), 0.00 (3H,
s), 0.84 (9H, s), 1.47 (3H, d, J
= 6.8 Hz), 2.21 (1H, dd, J = 16.
1, 5.4 Hz), 2.34-2.47 (2H, m),
2.97 (1H, dd, J = 9.7, 8.3Hz),
3.12 (1H, dd, J = 9.7, 4.9Hz),
3.44-3.54 (2H, m), 5.45 (1H,
q, J = 6.8 Hz), 7.21-7.31 (5H,
m).

[Reference Example 1-3] (4R)-(tertiary butyldimethylsilyloxymethyi)
) -1-[(1R) -phenylethyl]-(3R)-
To a tetrahydrofuran solution (5 ml) of (2-propenyl) -2-pyrrolidone (4R)-(tertiary butyldimethylsilyloxymethyl) -1-[(1R) -phenylethyl] -2-pyrrolidone (667 mg, 2 mmol). Lithium bis (trimethylsilyl) amide 1.0M tetrahydrofuran solution (2.5 ml) was added at −78 ° C., and the mixture was stirred at the same temperature for 1 hour. The temperature was raised to 0 ° C., and allyl bromide (1.21 g, 10
(mmol) and the reaction was stirred at room temperature for 15 hours. The reaction mixture was poured into 10% aqueous citric acid solution (15 ml) and extracted with ethyl acetate (20 ml × 3). The organic layer was dried over sodium sulfate, and the solvent was evaporated. The obtained residue was subjected to silica gel column chromatography,
The title compound (316 mg, 42%) was obtained as an oil from the elution with -hexane: ethyl acetate = 4: 1.

¹ H-NMR (400 MHz, CDC
l ₃ ) δ: 0.04 (3H, s), 0.05 (3H,
s), 0.88 (9H, s), 1.47 (3H, d, J
= 7.32 Hz), 2.03-2.55 (4H, m),
2.85-2.94 (1H, m), 3.03-3.11
(1H, m), 3.46-3.61 (2H, m), 4.
96-5.07 (2H, m), 5.43-5.50 (1
H, m), 5.65-5.70 (1H, m), 7.20.
-7.35 (5H, m).

[Reference Example 1-4] (4R)-(tertiary butyldimethylsilyloxymethyi)
) -1-[(1R) -phenylethyl]-(3R)-
Propyl-2-pyrrolidone (4R)-(tertiary butyldimethylsilyloxymethyl) -1-[(1R) -phenylethyl]-(3R)-
(2-Propenyl) -2-pyrrolidone (3.74 g, 1
10% Palladium carbon (3.5 g) was added to 0 mmol of ethanol (80 ml), and catalytic hydrogenation was carried out at room temperature and normal pressure for 6 hours. After the catalyst was filtered off, the solvent was distilled off to obtain 2.75 g (73%) of the title compound as an oily substance.

¹ H-NMR (400 MHz, CDC
l ₃ ) δ: 0.04 (3H, s), 0.05 (3H,
s), 0.88-0.95 (12H, m), 1.35-
1.81 (8H, m), 2.03-2.20 (1H,
m), 2.23-2.34 (1H, m), 2.92-
3.18 (2H, m), 3.50-3.75 (2H,
m), 5.42-5.52 (1H, m), 7.25-
7.38 (5H, m).

[Reference Example 1-5] (4R) -Hydroxymethyl-1-[(1R) -phenyl]
Ruethyl]-(3R) -propyl-2-pyrrolidone (4R)-(tertiary butyldimethylsilyloxymethyl) -1-[(1R) -phenylethyl]- (3R)-
Propyl-2-pyrrolidone (2.75 g, 7.3 mmo
Tetrabutylammonium fluoride 1.0M tetrahydrofuran solution (8 ml) was added to the tetrahydrofuran solution (30 ml) of 1), and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated, the residue was dissolved in ethyl acetate (50 ml) and washed with saturated brine (30 ml × 2). The organic layer was dried over sodium sulfate, the solvent was evaporated, and the residue was subjected to silica gel column chromatography. n-Hexane: ethyl acetate = 1: 3 From the elution part, the title compound was 1.91.
g (100%) was obtained as an oil.

¹ H-NMR (400 MHz, CDC
l ₃ ) δ: 0.93 (3H, t, J = 7.32Hz),
1.35-1.80 (8H, m), 2.08-2.20
(1H, m), 2.22-2.30 (1H, m), 3.
00-3.15 (2H, m), 3.51-3.60 (1
H, m), 3.69-3.67 (1H, m), 5.45.
-5.53 (1H, m), 7.23-7.35 (5H,
m).

Reference Example 1-6! (4R) -Methylsulfonyloxymethyl-1-[(1
R) -Phenylethyl]-(3R) -propyl-2-pi
Loridone (4R) -hydroxymethyl-1-[(1R) -phenylethyl ]-(3R) -propyl-2-pyrrolidone (1.9 g, 7,28 mmol) in methylene chloride (30
ml) solution with triethylamine (1.84 g, 18.2).
mmol) was added, and methanesulfonyl chloride (1.
(0 g, 8.73 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with saturated brine (10 ml × 2), the organic layer was dried over sodium sulfate, and the solvent was evaporated to give the title compound (2.37 g, 96%) as an oil. This was directly used for the next reaction.

[Reference Example 1-7] (4R) -Azidomethyl-1-[(1R) -phenylene
Cyl]-(3R) -propyl-2-pyrrolidone (4R) -methylsulfonyloxymethyl-1-[(1
R) -Phenylethyl]-(3R) -propyl-2-pyrrolidone (2.36 g, 6.96 mmol) in dimethylformamide (20 ml) was added sodium azide (1.36 g, 20.9 mmol), and the temperature was 70 ° C. The mixture was stirred for 8 hours. Water (30 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (80 mlX3). The organic layers were combined, washed with saturated brine (30 ml × 2) and dried over sodium sulfate, and then the solvent was distilled off to give 1.65 g of the title compound (83
%).

¹ H-NMR (400 MHz, CDC
l ₃ ) δ: 0.94 (3H, t, J = 7.33Hz),
1.34-1.80 (7H, m), 2.10-2.29
(2H, m), 2.95-3.08 (2H, m), 3.
27-3.35 (1H, m), 3.46-3.52 (1
H, m), 5.46-5.53 (1H, m), 7.25.
-7.40 (5H, m).

[Reference Example 1-8] (3R)-(tertiary butoxycarbonylaminomethyl)
-1-[(1R) -phenylethyl]-(4R) -pro
Pirupirorijin (4R) - azidomethyl -1 - [(1R) - phenylethyl] - (3R) - propyl-2-pyrrolidone (1.6
4 g, 5.73 mmol) of tetrahydrofuran (80
Lithium aluminum hydride (1.
6 g, 42.1 mmol) was added and the mixture was stirred at room temperature for 30 minutes and then heated under reflux for 4 hours. Water (1.6 m
l), 15% aqueous sodium hydroxide solution (1.6 ml),
After adding water (4.8 ml), the mixture was stirred at room temperature for 1 hour.
After the insoluble material was filtered off, the solvent of the filtrate was distilled off and the residue was dissolved in methylene chloride (30 ml). Triethylamine (5m
l), di-tert-butyl dicarbonate (1.42 g, 6.5 mm
ol) was added and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, the residue was subjected to silica gel column chromatography, and n-
The title compound was obtained as an oily substance in an amount of 1.99 g (100%) from a fraction eluted with hexane: ethyl acetate = 2: 1.

¹ H-NMR (400 MHz, CDC
l ₃ ) δ: 0.89 (3H, t, J = 7.32Hz),
1.25-1.52 (18H, m), 1.80-1.9
2 (2H, m), 2.30-3.34 (2H, m),
2.95-3.20 (3H, m), 5.40 (1H, b
rs), 7.19-7.35 (5H, m).

[Reference Example 1-9] (3R)-(tertiary butoxycarbonylaminomethyl)
-(4R) -Propylpyrrolidine (3R)-(tertiary butoxycarbonylaminomethyl)
10% Palladium on carbon (2 g) in ethanol (40 ml) of -1-[(1R) -phenylethyl]-(4R) -propylpyrrolidine (1.99 g, 5.75 mmol).
Was added, and catalytic hydrogenation was performed at 4 atm for 5 hours under light irradiation (irradiation with a tungsten lamp for heating). After the catalyst was filtered off, the solvent was distilled off to give the title compound 1.3.
Obtained 9 g (100%) as an oil. This was directly used for the next reaction.

Example 1 5-Amino-7-[(3R) -aminomethyl- (4R)
-Propyl-1-pyrrolidinyl] -6-fluoro-1-
[(2S) -fluoro- (1R) -cyclopropyl]-
1,4-dihydro-8-methyl-4-oxoquinoline-
3-Carboxylic Acid 5-Amino-6,7-difluoro-1-[(2S) -fluoro- (1R) -cyclopropyl] -1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (400 mg, 1.28 mmol) in dimethyl sulfoxide (5 ml) was added with (3R)-(tertiary butoxycarbonylaminomethyl)-(4R) -propylpyrrolidine (473 mg, 1.95 mmol) and triethylamine (1 ml). In addition, it heated at 150 degreeC for 16 hours.
The solvent was evaporated, the residue was dissolved in chloroform (30 ml), washed with 10% citric acid (10 ml × 2) and dried over sodium sulfate, and then the solvent was evaporated. Concentrated hydrochloric acid (5 ml) was added to the residue, and the mixture was stirred at room temperature for 5 minutes and washed with chloroform (20 ml × 3). The aqueous layer was made alkaline with a 20% aqueous sodium hydroxide solution and then pour with 1N hydrochloric acid.
It was set to H7.2 and extracted with chloroform (50 ml × 3). After drying the organic layer over sodium sulfate, the solvent was distilled off, and the residue was separated and purified by preparative TLC (developed twice in the lower layer of chloroform: methanol: water = 7: 3: 1) to give a crude notation. 70 mg of the compound was obtained. The crystals were recrystallized from chloroform-methanol to obtain 40 mg of the first crystal of the title compound. ¹ H-NMR (400 MHz, 0.1 N-NaOD)
δ: 0.78-0.95 (4H, m), 1.10-1.
52 (5H, m), 1.60-1.75 (2H, m),
2.04 (3H, brs), 2.40-2.50 (1
H, m), 2.68-2.79 (1H, m), 3.11.
-3.36 (4H, m), 4.90-5.00 (0.5
H, m), 8.23 (1H, s). Elemental _analysis; as _{C 22 H 28 F 2 N 4} O 3 · 0.5H 2 O: Calculated; C, 59.58; H, 6.59 ; N, 1
2.63. Found: C, 59.73; H, 6.61; N, 1
2.39. Melting point: 125.0-134.5 ° C (decomposition).

[0137]

[Table 1]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area C07D 471/04 114 114 C07D 471/04 114A 117 117A // (C07D 401/04 207: 09 215: 56 (72) Inventor Kazuyuki Sugita 1-16-13 Kita Kasai, Edogawa-ku, Tokyo Daiichi Pharmaceutical Co., Ltd. Tokyo R & D Center (72) Inventor Hitoshi Oki 1-1-16 Kita-kasai, Edogawa-ku, Tokyo Ichi Pharmaceutical Co., Ltd. Tokyo Research and Development Center

Claims (10)

[Claims] 1. A compound of the general formula (I) [In the formula, R ¹ and R ² each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the alkyl group is a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms or a carbon number. It may be substituted by one or more substituents selected from the group consisting of 1 to 6 alkoxyl groups, and R ³ , R ⁴ and R ⁵ are each independently a hydrogen atom, a hydroxyl group, a halogen atom, A carbamoyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, and an alkylthio group having 1 to 6 carbon atoms. The alkyl group includes a hydroxyl group, a halogen atom and an alkoxyl group having 1 to 6 carbon atoms. may be optionally substituted by one or more substituents selected from substituents of the group consisting of groups, yet integrated R ⁴ and R ^5, from 3 to 6 carbon atoms a methylene chain (pyrrolidine ring Form a spiro ring system) may be a hydroxyimino group or an alkyl-oximino group of 1 to 6 carbon atoms. R ⁶ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R ⁷ represents a hydrogen atom or a carbon number 1
And represents an alkyl group of 1 to 6, which may be substituted with one or more substituents selected from the group consisting of a hydroxyl group, an alkoxyl group having 1 to 6 carbon atoms and a halogen atom. R ⁸
And R ⁹ are each independently a hydrogen atom or a carbon number of 1.
To Q6 are represented by the formula (II): [In the formula, R ¹⁰ is an alkyl group having 1 to 6 carbon atoms and 2 carbon atoms.
To C6 alkenyl group, C1 to C6 halogenoalkyl group, C3 to C6 optionally substituted cyclic alkyl group, and optionally substituted aryl group,
A heteroaryl group which may have a substituent, and has 1 carbon atom
To R 6 represent an alkoxyl group or an alkylamino group having 1 to 6 carbon atoms, R ¹¹ represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms, and R ¹¹ and R ¹⁰ further represent a part of the mother nucleus. The ring may be integrated so as to form a cyclic structure, but the ring may contain a sulfur atom as a constituent atom, and the ring may be substituted with an alkyl group having 1 to 6 carbon atoms. X ¹ represents a halogen atom or a hydrogen atom, R ¹² represents a hydrogen atom, an amino group, a hydroxyl group, 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 alkoxyl group having 1 to 6 carbon atoms is shown. This amino group is a formyl group, an alkyl group having 1 to 6 carbon atoms, or an alkyl group having 2 to 6 carbon atoms. 5 may be substituted with one or more substituents selected from the group consisting of acyl groups. A ¹ is a nitrogen atom or has the formula (III) (In the formula, X ² is a hydrogen atom, amino group, halogen atom, cyano group, halogenomethyl group, halogenomethoxy group, alkyl group having 1 to 6 carbon atoms, alkenyl group having 2 to 6 carbon atoms, or 2 to 6 carbon atoms. Represents an alkynyl group or an alkoxyl group having 1 to 6 carbon atoms, and the amino group is selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms. It may be substituted by the above substituents. Further, X ² and R ¹⁰ may be integrated so as to include a part of the mother nucleus so as to form a cyclic structure. Atom or a sulfur atom may be contained as a constituent atom, and this ring may be substituted with an alkyl group having 1 to 6 carbon atoms). Y ¹
Is a hydrogen atom, phenyl group, acetoxymethyl group, pivaloyloxymethyl group, ethoxycarbonyl group, choline group, dimethylaminoethyl group, 5-indanyl group, phthalidinyl group, 5-alkyl-2-oxo-1,3- Dioxole-4-ylmethyl group, 3-acetoxy-2-oxobutyl group, alkyl group having 1 to 6 carbon atoms, 2 carbon atoms
To 7 represent an alkoxymethyl group or a phenylalkyl group composed of an alkylene group having 1 to 6 carbon atoms and a phenyl group. ] Or a compound of formula (IV): [In the formula, R ¹³ is an alkyl group having 1 to 6 carbon atoms and 2 carbon atoms.
To C6 alkenyl group, C1 to C6 halogenoalkyl group, C3 to C6 optionally substituted cyclic alkyl group, and optionally substituted aryl group,
A heteroaryl group which may have a substituent, and has 1 carbon atom
Represents an alkoxyl group having 1 to 6 carbon atoms or an alkylamino group having 1 to 6 carbon atoms, and R ¹⁴ represents a hydrogen atom, amino group, hydroxyl group, thiol group, halogenomethyl group, alkyl group having 1 to 6 carbon atoms, or 2 to 6 carbon atoms. Alkenyl group with 2 carbon atoms
Represents an alkynyl group having 1 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms, and this amino group is selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms. May be substituted by one or more substituents. X ³ represents a halogen atom or a hydrogen atom, A ² represents a nitrogen atom or the formula (V): (In the formula, X ⁴ is a hydrogen atom, amino group, halogen atom, cyano group, halogenomethyl group, halogenomethoxy group, alkyl group having 1 to 6 carbon atoms, alkenyl group having 2 to 6 carbon atoms, or 2 to 6 carbon atoms. Represents an alkynyl group or an alkoxyl group having 1 to 6 carbon atoms, and the amino group is selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms. It may be substituted by the above substituents. Further, X ⁴ and R ¹³ may be integrated so as to include a part of the mother nucleus so as to form a cyclic structure. Atom or a sulfur atom may be contained as a constituent atom, and this ring may be substituted with an alkyl group having 1 to 6 carbon atoms). Y ²
Is a hydrogen atom, phenyl group, acetoxymethyl group, pivaloyloxymethyl group, ethoxycarbonyl group, choline group, dimethylaminoethyl group, 5-indanyl group, phthalidinyl group, 5-alkyl-2-oxo-1,3- Dioxole-4-ylmethyl group, 3-acetoxy-2-oxobutyl group, alkyl group having 1 to 6 carbon atoms, 2 carbon atoms
To 7 represent an alkoxymethyl group or a phenylalkyl group composed of an alkylene group having 1 to 6 carbon atoms and a phenyl group. ] And a salt thereof 2. The compound and salt thereof according to claim 1, wherein Q in the general formula (I) is a compound having a structure represented by the formula (III). 3. The compound and its salt according to claim 2, wherein R ¹⁰ is a halogenocyclopropyl group. 4. The compound and salt thereof according to claim 1, wherein the halogenocyclopropyl group in the general formula (I) is a 1,2-cis-2-halogenocyclopropyl group. 5. The compound according to claim 2, 3 or 4, wherein the halogenocyclopropyl group in the general formula (I) is a sterically single substituent, and a salt thereof. 6. The compound and salt thereof according to claim 5, wherein the halogenocyclopropyl group in the general formula (I) is a (1R, 2S) -2-halogenocyclopropyl group. 7. The compound or salt thereof according to claim 6, wherein the halogen atom of the halogenocyclopropyl group in the general formula (I) is a fluorine atom. 8. The compound according to claim 7 and a salt thereof, wherein the compound of the general formula (I) is a sterically single compound. 9. A pharmaceutical comprising the compound of claim 1 or a salt thereof as an active ingredient. 10. An antibacterial drug containing the compound of claim 1 or a salt thereof as an active ingredient.