JPH1081682A - Cis-substituted aminocyclopropane derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound having a wide antibacterial activity, especially strong antibacterial activities against gram-positive bacteria, particularly against quinolone-resistant bacteria, and capable of exhibiting good safety and actions in bodies. SOLUTION: A compound of formula I R<1> , R<2> are each independently H, a 1-6C alkyl; (n) is an integer of 1-3; Q is a group of formula II [R<3> is a 1-6C alkyl, a 2-6C alkenyl, etc.; R<4> is H, a 1-6C alkylthio; R<5> is H, amino, hydroxyl group, etc.; X<1> is a halogen, H; A is N atom, a group of formula III (X<2> is H, amino, a halogen, etc.); Y is H, phenyl, acetoxymethyl, etc.], but the two substituents existing on the cyclopropane ring are placed in a cis-configuration}, its salt and their hydrates. The compound of formula I can be produced by various kinds of methods. Thereby, the compound of formula I can be used as a medicine for human bodies, animals and fishes, and further as an agricultural chemical and a food preservative.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an antibacterial compound useful as a medicament, an animal drug, a marine drug, or an antibacterial preservative, and further relates to an antibacterial agent and an antibacterial preparation containing this compound.

[0002]

2. Description of the Related Art Since the discovery of norfloxacin, quinolone synthetic antibacterial drugs have improved antibacterial activity and pharmacokinetics, and many compounds have been used in clinical practice as chemotherapeutic agents effective for almost systemic infections. .

[0003]

In recent years, in the clinical setting, bacteria that are insensitive to quinolone synthetic antibacterial drugs are increasing. Bacteria that are resistant to drugs other than quinolone-based synthetic antibacterials, such as Staphylococcus aureus (MRSA) that is insensitive to β-lactam antibiotics, and that have become less sensitive to quinolone-based synthetic antibacterials. Is increasing. Therefore, in the clinical setting, a drug with higher efficacy has been desired. In addition, side effects such as convulsions induced by taking nonsteroidal anti-inflammatory drugs and side effects such as phototoxicity have been clarified, and the development of safer quinolone-based synthetic antibacterial agents has been required. I have.

[0004]

In view of such circumstances, the inventors of the present invention have made intensive studies to provide an excellent compound satisfying the above requirements, and as a result, a cis-substituted aminocyclopropane represented by the following formula (I) is described. Derivatives and their salts have a wide range of antibacterial activity, especially Gram-positive bacteria, especially MRSA
The present invention has been found to exhibit strong antibacterial activity against quinolone-resistant bacteria containing, and also has good pharmacokinetics and safety.

That is, the present invention relates to a compound represented by the following formula (I), a salt thereof, and a hydrate thereof.

[0006]

Embedded image In the formula, R ¹ and R ² each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, wherein the alkyl group is a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms and It may have, as a substituent, one or more groups selected from the group consisting of alkoxyl groups having 1 to 6 carbon atoms, n represents an integer of 1 to 3, and Q represents
This is a partial structure represented by the following formula.

[0007]

Embedded image [Wherein, R ³ 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 which may have a substituent. A cyclic alkyl group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an alkoxyl group having 1 to 6 carbon atoms, or an alkylamino group having 1 to 6 carbon atoms. represents, R ⁴ is a hydrogen atom, or represents a 6 alkylthio group with carbon atoms of 1, the R ⁴
And the above R ³ may be integrated so as to form a cyclic structure including a part of the mother nucleus.
A sulfur atom may be contained as a constituent atom of the ring, and this ring may further have an alkyl group having 1 to 6 carbon atoms as a substituent. R ⁵ 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, and 2 carbon atoms.
Represents an alkynyl group having 1 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms, of which an amino group includes a formyl group, an alkyl group having 1 to 6 carbon atoms and a 2 to 5 carbon atoms.
Well at least one group selected from the group of radicals consisting of acyl group as a substituent, X ¹ is a halogen atom,
Or A represents a hydrogen atom, and A represents a nitrogen atom or a compound represented by the formula (II)

[0008]

Embedded image (Wherein, X ² represents a hydrogen atom, an amino group, a halogen atom,
Cyano group, halogenomethyl group, halogenomethoxyl group,
Represents 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, of which an amino group is a formyl group, It may have as a substituent one or more groups selected from the group consisting of an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms.

Further, X ² and R ³ may be integrated so as to form a cyclic structure including a part of the mother nucleus, but the ring formed here is an oxygen atom or a nitrogen atom. Alternatively, a sulfur atom may be included as a constituent atom of the ring, and the ring may have an alkyl group having 1 to 6 carbon atoms as a substituent. ) Represents a partial structure. Y is a hydrogen atom, a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a 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 And a phenylalkyl group consisting of And the following two groups present on the cyclopropane ring (these are shown in Chemical formulas 13 and 14):

[0010]

Embedded image and

[0011]

Embedded image Is a cis configuration. ｝

The present invention further provides a compound of the formula (I) wherein Q is

[0013]

Embedded image (In the above formula, R ³ , R ⁴ , R ⁵ , A, X ¹ , X ² and Y are the same as those defined above.) And hydrates thereof; wherein Q in the formula (I) is 6-carboxy-9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1,2, 3-de]
[1,4] benzoxazin-10-yl group [following formula]:

[0014]

Embedded image A compound as described above, a salt thereof, and a hydrate thereof;
In the formula (I), Q is 8-amino-6-carboxy-
9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1,2,3-de]
[1,4] benzoxazin-10-yl group [following formula]:

[0015]

Embedded image A compound as described above, a salt thereof, and a hydrate thereof;
In the formula (I), Q is 5-amino-3-carboxy-
6-fluoro-1- [2- (S) -fluoro-1-
(R) -cyclopropyl] -1,4-dihydro-8-methoxy-4-oxoquinolin-7-yl group [the following formula]:

[0016]

Embedded image A compound as described above, a salt thereof, and a hydrate thereof;
In the formula (I), Q is 5-amino-3-carboxy-
6-fluoro-1- [2- (S) -fluoro-1-
(R) -cyclopropyl] -1,4-dihydro-8-methyl-4-oxoquinolin-7-yl group [the following formula]:

[0017]

Embedded image A compound as described above, a salt thereof, and a hydrate thereof;
In the formula (I), Q represents 3-carboxy-6-fluoro-1- [2- (S) -fluoro-1- (R) -cyclopropyl] -1,4-dihydro-8-methoxy-4-oxo A quinolin-7-yl group [the following formula]:

[0018]

Embedded image A compound as described above, a salt thereof, and a hydrate thereof;
The above compound, a salt thereof, and a hydrate thereof, wherein n is 2; the above compound, a salt thereof, and a hydrate thereof, wherein each of the substituents R ¹ and R ² is a hydrogen atom.
The above compounds, wherein the substituent R ³ is a halogenocyclopropyl group, salts thereof, and hydrates thereof;
^The above compound, wherein R ³ is a 1,2-cis-2-halogenocyclopropyl group, a salt thereof, and a hydrate thereof; the above compound, wherein the substituent R ³ is a stereochemically single group , A salt thereof, and a hydrate thereof; wherein the substituent R ³ is
The above compound, which is a (1R, 2S) -2-halogenocyclopropyl group, a salt thereof, and a hydrate thereof; wherein the substituent R ³ is a (1R, 2S) -2-fluorocyclopropyl group. Compounds, salts thereof, and hydrates thereof; the above-mentioned compounds, wherein the substituent X ¹ is a halogen atom,
Compounds of the above formula, wherein the substituent X ¹ is a fluorine atom, salts thereof, and hydrates thereof; compounds of the formula (I) wherein the compound of formula (I) is That is, the above-mentioned compound which is a compound consisting of a single diastereomer), a salt thereof, and a hydrate thereof; 5-amino-7- {3-[(1S, 2S) -2-aminocyclopropyl] -1-pyrrolidinyl} -6-fluoro-1-
[(1R, 2S) -2-fluorocyclopropyl] -8
-Methyl-1,4-dihydro-4-oxoquinoline-3
-A carboxylic acid, a salt thereof, and a hydrate thereof; a compound containing the above compound, a hydrate thereof, a salt of the compound, or a hydrate of the salt thereof as an active ingredient; a compound of the above, a hydrate thereof , An antibacterial agent containing a salt of a compound or a hydrate of the salt as an active ingredient; and the like.

The present invention further relates to compounds represented by the following formula, salts thereof, and hydrates thereof.

[0020]

Embedded image (Wherein, R ¹ and R ² each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, wherein the alkyl group is a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms, and It may have, as a substituent, at least one group selected from the group consisting of alkoxyl groups having 1 to 6 carbon atoms, and one of R ¹ and R ² is a protecting group for an amino group, N represents an integer of 1 to 3, and Q ′ represents a protecting group for an amino group or a hydrogen atom, and a group existing on the cyclopropane ring (these are represented by the following formulas 22 and 23). Shown.)

[0021]

Embedded image And group

[0022]

Embedded image Is a cis configuration. In the present invention, the amino-protecting group may further comprise (substituted) alkoxycarbonyl groups, (substituted) aralkyloxycarbonyl groups, (substituted) acyl groups, (substituted) alkyl groups, (substituted) aralkyl groups. A compound selected from the group consisting of groups and substituted silyl groups, a salt thereof, and a hydrate thereof; wherein the amino-protecting group is a tertiary butoxycarbonyl group, 2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, formyl group, benzoyl group , Tertiary butyl group, benzyl group, paranitrobenzyl group, paramethoxybenzyl group , Triphenylmethyl, methoxymethyl, tert-butoxymethyl, tetrahydropyranyl, 2,2,2-trichloroethoxymethyl, trimethylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, Benzylsilyl group,
A compound represented by the above formula VI, which is a protecting group selected from a group consisting of a tertiary butyldiphenylsilyl group;
A salt thereof, or a hydrate thereof; a compound represented by the above formula VI, wherein ^one of R ¹ and R ² and Q ′ are a protecting group for an amino group and are not the same protecting group; , And hydrates thereof; the above-mentioned compounds, wherein the compound of formula (VI) is a stereochemically single compound (ie, consisting of a single diastereomer), salts thereof, and hydration thereof 1-benzyloxycarbonyl-3-
[(1S, 2S) -2-tert-butoxycarbonylaminocyclopropyl] pyrrolidine, salts thereof, and hydrates thereof; and the like.

[0023]

DETAILED DESCRIPTION OF THE INVENTION Formula (I) of the present invention

[0024]

Embedded image A compound represented by the formula:

[0025]

Embedded image Each substituent of the compound represented by is 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 may have, as a substituent, at least one group selected from the group consisting of a hydroxyl group, a halogen atom, an alkylthio having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms. The alkyl group may be linear or branched having 1 to 6 carbon atoms, and 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 preferred examples include a hydroxyethyl group and a hydroxypropyl group.

The substituent R ³ includes 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, and a carbon atom having 3 to 6 carbon atoms which may have a substituent. A cyclic alkyl group of 6; an aryl group which may have a substituent; a heteroaryl group which may have a substituent; an alkoxyl group having 1 to 6 carbon atoms;
To 6 represent an alkylamino group. Here, carbon number 1
As the alkyl groups from to 6, an ethyl group is particularly preferred.
As the alkenyl group having 2 to 6 carbon atoms, a vinyl group or a 1-isopropenyl group is preferable. 1 to 6 carbon atoms
Is preferably a 2-fluoroethyl group. As the cyclic alkyl group, a cyclopropyl group is particularly preferred. As a substituent of the cyclic alkyl group, a halogen atom is preferred, and as the halogen atom, a fluorine atom is particularly preferred. Examples of the aryl group which may have a substituent include a halogen atom such as a fluorine atom, a chlorine atom and a bromine atom, a lower alkyl group having 1 to 6 carbon atoms, a hydroxyl group,
A phenyl group which may be substituted by 1 to 3 groups 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, and a phenyl group, 2-fluorophenyl Groups, 4-fluorophenyl, 2,4-difluorophenyl and 2-fluoro-4-hydroxyphenyl are preferred. Examples of the heteroaryl group include a pyridyl group and a pyrimidyl group, which are groups derived from an aromatic heterocyclic compound containing at least one heteroatom selected from a nitrogen atom, an oxygen atom, and a sulfur atom. As the substituent on these rings, an alkyl group, a halogen atom and the like are preferable. As the alkoxyl group having 1 to 6 carbon atoms, a methoxyl group is preferable. The alkylamino group having 1 to 6 carbon atoms is preferably a methylamino group. The substituent R ³ cycloalkyl group or halogenoalkyl cycloalkyl group, is preferred. Among these, a cyclopropyl group or a 2-halogenocyclopropyl group is preferred. The halogen atom is preferably a fluorine atom.

The substituent R ⁴ is a hydrogen atom or a group having 1 carbon atom.
Represents from 6 to 6 alkylthio groups, or R ³ and R
⁴ and are comprise a portion of the mother nucleus (i.e., to include the carbon atom to which the nitrogen atom and R ⁴ which R ³ is attached is attached) be integrated to form a cyclic structure Good. The ring thus formed may contain a sulfur atom as a constituent atom, and the ring may be further substituted with an alkyl group of 1 to 6 carbon atoms. The ring formed here may be of the size of a 4- to 6-membered ring, and this ring may be saturated, partially saturated or unsaturated. As the fused ring structure thus formed,
The following can be mentioned.

[0029]

Embedded image

X ¹ is a halogen atom or a hydrogen atom, and 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.

A is a compound represented by the formula (II)

[0032]

Embedded image X ² is a hydrogen atom, an amino group,
Halogen atom, cyano group, halogenomethyl group, halogenomethoxyl group, alkyl group having 1 to 6 carbon atoms, 2 carbon atoms
Represents an alkenyl group having from 6 to 6, an alkynyl group having 2 to 6 carbon atoms, or an alkoxyl group having 1 to 6 carbon atoms,
Among these, the amino group may have, as a substituent, at least one group 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 linear or branched having 1 to 6 carbon atoms, and is preferably a methyl group, an ethyl group, a normal propyl group, or an isopropyl group. The alkenyl group may be a linear or branched one 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,
Preferably it is a methoxyl group. The halogen of the halogenomethoxyl group is particularly preferably a fluorine atom, and the number thereof may be 1 to 3.

Further, R ³ and X ² include a part of the mother nucleus (that is, the nitrogen atom to which R ³ is bonded and X 2
^A cyclic structure (including a carbon atom to which ² is bonded) (ring size is a 4- to 7-membered ring, which may be saturated, partially saturated, or unsaturated) )), This ring may be an oxygen atom,
The ring may contain a nitrogen atom or a sulfur atom as a constituent atom, and this ring may have an alkyl group having 1 to 6 carbon atoms as a substituent. Examples of the condensed ring structure thus formed include the following.

[0034]

Embedded image Among them, particularly, 6-carboxy-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-1
A 0-yl ring structure is preferred.

The substituent R ⁵ includes 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, and 2 carbon atoms.
Represents an alkynyl group having 1 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms, of which an amino group includes a formyl group, an alkyl group having 1 to 6 carbon atoms and a
And one or more groups selected from the group consisting of the acyl groups of the above. The alkyl group may be linear or branched having 1 to 6 carbon atoms,
Preferred are a methyl group, an ethyl group, a normal propyl group and an isopropyl group. The alkenyl group may be linear or branched having 2 to 6 carbon atoms,
Preferably it is a vinyl group. The alkynyl group may be linear or branched having 2 to 6 carbon atoms,
Preferably it is 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. When the substituent X ² or R ⁵ is an amino group, a hydroxyl group, or a thiol group, these may be protected by a commonly used protecting group. Examples of such protecting groups include, for example, (substituted) alkoxycarbonyl groups,
Substituted by (substituted) aralkyloxycarbonyl groups, (substituted) acyl groups, (substituted) alkyl groups, (substituted) aralkyl groups, alkyl groups or aralkyl groups (which may be the same or different) [In the specification of the present application, "(substituted)" means "may have a substituent." ]. Specifically, a tertiary butoxycarbonyl group, 2,2,2
(Substituted) alkoxycarbonyl groups such as -trichloroethoxycarbonyl group; (substituted) aralkyloxycarbonyl groups such as benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group; acetyl group, methoxyacetyl group ,
(Substituted) acyl groups such as trifluoroacetyl group, chloroacetyl group, pivaloyl group, formyl group, benzoyl group; tertiary butyl group, benzyl group, paranitrobenzyl group, paramethoxybenzyl group, triphenylmethyl group,
(Substituted) alkyl groups such as phenethyl group or (substituted) aralkyl groups; ethers such as methoxymethyl group, tert-butoxymethyl group, tetrahydropyranyl group, 2,2,2-trichloroethoxymethyl group; Substituted silyl groups such as a trimethylsilyl group, an isopropyldimethylsilyl group, a tert-butyldimethylsilyl group, a tribenzylsilyl group, and a tert-butyldiphenylsilyl group. Compounds protected by these groups are particularly preferred as production intermediates.

Y is a hydrogen atom, a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a 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 a phenylalkyl group composed of a phenyl group.

When A is a partial structure represented by the formula (II), as a preferable combination of R ⁵ and X ^{2 in} the formula (I), R ⁵ is an amino group, a hydrogen atom, a hydroxyl group or a group having 1 carbon atom. X ² is an alkyl group having 1 to 6 carbon atoms.
Alkyl group, an alkoxyl group having 1 to 6 carbon atoms, a halogenomethoxyl group, or a hydrogen atom. A more preferable combination is a case where R ⁵ 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 difluoromethoxyl group, or a hydrogen atom. For these R ⁵ and X ² , X ¹ is preferably a fluorine atom. When the substituents X ¹ and X ² are each a halogen atom, X ¹ is particularly preferably a fluorine atom, and X ² is preferably a fluorine atom or a chlorine atom.

The compound of the present invention is characterized in that the compound represented by the formula

[0039]

Embedded image Having a group represented by That is, an amino group moiety which may have a substituent (alkyl group) (this is shown in Chemical formula 30).

[0040]

Embedded image And a nitrogen-containing saturated heterocyclic substituent moiety having a size from a four-membered ring (when n = 1) to a six-membered ring (when n is 3) (this is shown in Chemical Formula 31).

[0041]

Embedded image Has a structure bonded to a cyclopropyl group, which is a feature of this group. In this cyclopropyl group (that is, with respect to the cyclopan ring), there are two types of bonding between the amino group and the nitrogen-containing saturated heterocyclic substituent, such as cis or trans. Are preferred.

[0042]

Embedded image When n is 2 or 3, two types of bonding between the nitrogen-containing saturated heterocyclic substituent and the cyclopropane ring occur. This is shown below for n = 2, but similar isomers also occur when n = 3.
The present invention includes any of these.

[0043]

Embedded image In addition, a substituent may be further present in the cyclopropyl group portion. For example, it is a fluorine atom, a methyl group, an ethyl group, a trifluoromethyl group, or the like.

Next, the halogenocyclopropyl group for R ³ 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. The steric environment at this moiety is particularly preferably that the halogen atom and the pyridonecarboxylic acid moiety are in a cis configuration with respect to the cyclopropane ring. The cis-2-halogenocyclopropyl moiety of R ³ alone has a so-called enantiomer-related isomer regardless of the stereoisomerism of the 7-position substituent. High safety was recognized.

When the compound of the formula (I) of the present invention has a structure in which diastereomers are present, when the compound of the present invention is administered to humans or animals, the compound consisting of a single diastereomer may be used. It is preferred 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. In other words, it is interpreted that other diastereomers may be contained as long as they have no influence on physical constants or physiological activities. The term "stereochemically single" means that when a compound or the like contains an asymmetric carbon atom, and there are a plurality of types that are in an isomer relationship, only one of them is used. Means something. 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 in the form of an acid addition salt or a salt of a carboxyl group. Examples of the acid addition salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, and phosphate, or acetate, methanesulfonate, and benzene. Organic acid salts such as sulfonate, toluene sulfonate, citrate, maleate, fumarate, lactate and the like can be mentioned. Examples of the salt of a carboxyl group include, for example, 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-methylglucamine salt, Any of inorganic salts and organic salts such as tris- (hydroxylmethyl) aminomethane salt may be used. The free form, acid addition salt and carboxyl group salt of these pyridonecarboxylic acid derivatives may exist as hydrates.

On the other hand, quinolone derivatives in which the carboxylic acid moiety is an ester are useful as synthetic intermediates and prodrugs. 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 that is easily cleaved in a living body to generate a free form of a carboxylic acid.
Acetoxymethyl ester, pivaloyloxymethyl ester, ethoxycarbonyl ester, choline ester, dimethylaminoethyl ester, 5-indanyl ester and phthalidinyl ester, 5-alkyl-2
And oxoalkyl esters such as -oxo-1,3-dioxol-4-ylmethyl ester and 3-acetoxy-2-oxobutyl ester.

The compounds of the present invention of the formula (I)
It is produced by various methods, and one preferable example is, for example, a compound represented by the formula (III)

[0049]

Embedded image [In the formula, X ³ represents a leaving group such as a fluorine atom, a chlorine atom, a bromine atom, an arylsulfonyl group having 1 to 3 carbon atoms, or an arylsulfonyl group such as a benzenesulfonyl group or a toluenesulfonyl group. Wherein Y is the same as defined for Y in formula (I), or is a group of formula (IV)

[0050]

A boron-containing group represented by -B (R ⁶ ) R ⁷ IV (where R ⁶ and R ⁷ are a fluorine atom or a lower alkylcarbonyloxy group); ³ , R ⁴ , R ⁵ , X ¹ , X ² and A are as defined in formula (I). A compound represented by the formula (V):

[0051]

Embedded image [Wherein R ¹ and R ² represent a protecting group R wherein R ¹ is a nitrogen atom.
Except that it may be _X , it is as defined in formula (I). The protecting group R _X may be any protecting group commonly used in this field, and examples of these protecting groups include, for example, an alkoxy group such as a tertiary butoxycarbonyl group and a 2,2,2-trichloroethoxycarbonyl group. Carbonyl groups, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, aralkyloxycarbonyl groups such as paranitrobenzyloxycarbonyl group, acetyl group,
Acyl groups such as methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, formyl group, benzoyl group, tertiary butyl group, benzyl group, paranitrobenzyl group, paramethoxybenzyl group, triphenylmethyl group Such as alkyl groups or aralkyl groups, methoxymethyl group, tertiary butoxymethyl group, tetrahydropyranyl group, ethers such as 2,2,2-trichloroethoxymethyl group, trimethylsilyl group, isopropyldimethylsilyl group, Substituted silyl groups such as a tertiary butyldimethylsilyl group, a tribenzylsilyl group and a tertiary butyldiphenylsilyl group can be exemplified. Or an acid addition salt thereof.

When Y is 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, the conversion to the corresponding carboxylic acid is The hydrolysis of the acid ester is carried out under general acidic or basic conditions, and when deprotection is required, the protecting group is removed under appropriate conditions corresponding to the protecting group to remove the desired compound represented by the formula (I). Can be obtained. In the compound of the formula (III), in the case where Y is a compound represented by the formula (IV), the substitution is carried out with the compound of the formula (V), followed by treatment with an acidic or basic compound. It can be converted to a carboxylic acid.

The substitution reaction between the compound of the formula (III) and the compound of the formula (V) can be carried out with or without a solvent. When a solvent is used, the solvent may be any that is inert under the reaction conditions. Suitable solvents include, for example, dimethylsulfoxide, pyridine, acetonitrile, ethanol, chloroform, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, water, 3-methoxybutanol. Alternatively, these solvents may be used as a mixture. The reaction temperature is usually from room temperature to 2
It can be carried out in a temperature range of 00 ° C, preferably from 25 ° C to 1 ° C.
It is in the range of 50 ° C. The reaction time is 30 minutes to 48 hours, and usually completes in about 30 minutes to 2 hours. The reaction is
Acid acceptors such as inorganic or organic bases, for example,
Alkali metal or alkaline earth metal carbonate or bicarbonate, or triethylamine, pyridine,
It is advantageous to carry out in the presence of an organic basic compound such as 1,8-diazabicycloundecene.

The compound of the formula (V) can be produced by various methods. As a preferred example, the compound can be synthesized by the method shown in Reference Examples, but is not limited thereto. In the compound of the formula (V), the nitrogen atom of the compound has a protecting group Q ′.
Having the structure shown below (V
It is most commonly prepared by removing the protecting groups from I).

[0055]

Embedded image (Wherein, R ¹ and R ² each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, wherein the alkyl group is a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms, and As a substituent, one or more groups selected from the group consisting of alkoxyl groups having 1 to 6 carbon atoms may be present, and ^one of R ¹ and R ² may be a protecting group for an amino group. N is an integer of from 1 to 3, and Q ′ is an amino-protecting group, which includes (substituted) alkoxycarbonyl groups, (substituted) aralkyloxycarbonyl groups, (substituted) ) Acyl groups,
It may be selected from the group consisting of (substituted) alkyl groups, (substituted) aralkyl groups, and substituted silyl groups (substituted by alkyl or aralkyl groups, which may be the same or different). Then, groups present on the cyclopropane ring (these are shown in Chemical Formulas 38 and 39)

[0056]

Embedded image And group

[0057]

Embedded image Is a cis configuration. This compound VI may also exist as a salt, a hydrate, or a hydrate of a salt. Examples of acid addition salts include inorganic and organic acid salts. Specific examples thereof include inorganic salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide and phosphate, or methanesulfonate, benzenesulfonate, and toluenesulfonic acid. Organic acid salts such as salts (sulfonates), acetates, citrates, maleates, fumarates, and lactates (carboxylates) can be mentioned.

When R ¹ , R ² , and Q ′ are all amino-protecting groups, they may be the same or different, but each may be cleaved under different reaction conditions. Is convenient for producing compound (I). R ¹ or R which is an amino-protecting group;
² and Q 'include the following. That is, (substituted) alkoxycarbonyl groups,
(Substituted) aralkyloxycarbonyl groups, (substituted) acyl groups, (substituted) alkyl groups, (substituted) aralkyl groups, and substituted silyl groups. Specifically, (substituted) alkoxycarbonyl groups such as tertiary butoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group; benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group (Substituted) aralkyloxycarbonyl groups such as acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, formyl group, (substituted) acyl groups such as benzoyl group; tertiary butyl group,
(Substituted) alkyl groups such as benzyl group, paranitrobenzyl group, paramethoxybenzyl group, and triphenylmethyl group, or (substituted) aralkyl groups; methoxymethyl group, tertiary butoxymethyl group, tetrahydropyranyl group, Ethers such as 2,2,2-trichloroethoxymethyl group; substituted silyl groups such as trimethylsilyl group, isopropyldimethylsilyl group, tert-butyldimethylsilyl group, tribenzylsilyl group and tert-butyldiphenylsilyl group; .

The cis-2-fluorocyclopropylamine composed of a single isomer, which is preferable for the synthesis of the compound of the formula (I) composed of a single isomer, is disclosed in, for example, JP-A-2-23.
The compound can be synthesized by the method described in No. 1475. The synthesis of the compound of the formula (I) consisting of a single isomer from the optically active cis-2-fluorocyclopropylamine derivative thus obtained is described in, for example, JP-A-2-231475. It can be performed by a method.

Since the compound of the present invention has a strong antibacterial action, it can be used as a medicament for humans, animals and fish, or as a pesticide or food preservative. When the compound of the present invention is used as a medicine for the human body, the dose is
Adult 50mg to 1g per day, preferably 100m
g to 300 mg. The dosage for animals may vary depending on the purpose of administration (treatment or prevention), the type and size of the animal to be treated, the type and extent of the infected pathogen, but is generally used as a daily dose. 1 mg to 200 mg, preferably 5 mg to 10 mg / kg body weight
The range is 0 mg. This daily dose is administered once a day or divided into 2 to 4 times. The daily dose may exceed the above-mentioned amount if necessary.

The compounds of the present invention are active against a wide range of microorganisms that cause various infectious diseases and can treat, prevent or reduce the diseases caused by these pathogens. Staphylococci, S. pyogenes, hemolytic streptococci, enterococci, pneumococci, peptostreptococci, gonococci, Escherichia coli, Citrobacter, Shigella, Klebsiella , Enterobacter, Serratia, Proteus, Pseudomonas aeruginosa, Haemophilus influenzae,
Acinetobacter, Campylobacter, Chlamydia trachomatis and the like can be exemplified. Diseases caused by these pathogens include folliculitis, cough, syphilis, erysipelas, cellulitis, lymphatic (node) inflammation, glanders, subcutaneous abscess, sweat glanditis, acne conglomerate, infectious nodules, anus Peripheral abscess, mastitis, superficial secondary infection such as trauma / burn / surgical wound, pharyngolaryngitis, acute bronchitis, tonsillitis, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, chronic respiratory disease Secondary infection, pneumonia, pyelonephritis, cystitis, prostatitis, epididymitis, gonococcal urethritis, nongonococcal urethritis, cholecystitis, cholangitis, bacterial dysentery, enteritis, uterine appendixitis, in utero infection,
Bartholin's glanditis, blepharitis, stye, lacrimal cystitis, blepharitis,
Examples include corneal ulcer, otitis media, sinusitis, periodontitis, pericoronitis, jaw inflammation, peritonitis, endocarditis, sepsis, meningitis, skin infection and the like.

The present invention is also effective against various microorganisms that cause infectious diseases of animals, for example, Escherichia, Salmonella, Pasteurella, Haemophilus, Bordetella, Staphylococcus, Mycoplasma and the like. Illustrative disease names in birds include colibacillosis, chick white dysentery, chicken paratyphoid, poultry cholera, infectious coryza, staphylococci,
In swine, such as mycoplasma infection, colibacillosis, salmonellosis, pasteurella disease, hemophilus infection, 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 which are generally used. Examples of the dosage form of the antimicrobial preparation containing the compound of the present invention as a main component include, for example, tablets, powders, granules, capsules, solutions, syrups, elixirs, oily or aqueous suspensions, and the like as oral preparations. Can be mentioned. Injectables may use stabilizers, preservatives, and solubilizing agents in the preparation.After storing the solution that may contain these adjuvants in a container, freeze-drying or the like to prepare a solid preparation at the time of use. It may be a formulation. One dose may be stored in a container, or multiple doses may be stored in the same container. In addition, solution preparations as external preparations,
Suspensions, emulsions, ointments, gels, creams, lotions,
Spray etc. can be illustrated. Solid preparations include pharmaceutically acceptable additives together with the active compound, such as fillers, extenders, binders, disintegrants, dissolution enhancers, wetting agents, lubricants and the like. They can be selected and mixed as needed to form a formulation. Solutions as liquid preparations,
Suspensions, emulsions and the like can be mentioned, but they may also contain suspending agents, emulsifiers and the like as additives.

The method of administering the compound of the present invention to animals may be the method of orally administering the compound directly or by mixing it in a feed, or the method of orally administering the solution directly or by adding it to drinking water or feed. And administration by injection. Formulations for administering the compound of the present invention to animals include powders, fine granules, soluble powders, and the like, as appropriate, using techniques generally used in this field.
It can be a syrup, solution or injection. Next, formulation examples are shown.

[0065]

Table 1 Formulation Example 1 (Capsule): Compound of Example 2 100.0 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 2 1 to 10 g Acetic acid or sodium hydroxide 0.5 to 2 g Ethyl parahydroxybenzoate 0.1 g Purified water 87.9 to 98.4 g Total 100 g Formulation Example 3. (Powder for mixing feed): Compound of Example 2 1 to 10 g Corn starch 98.5 to 89.5 g Light anhydrous silicic acid 0.5 g Total 100 g

[0066]

Next, the present invention will be described with reference to examples and reference examples, but the present invention is not limited to these examples. Also,
The antibacterial activity of the target compound was measured in accordance with the standard method specified by the Japanese Society of Chemotherapy, and the result was determined as MIC (μg /
ml).

Example 1 5-amino-7- [3- (1,2-cis-2-aminocy
Clopropyl) -1-pyrrolidinyl] -6-fluoro-
1-[(1R, 2S) -2-fluorocyclopropyl]
-8-Methyl-1,4-dihydro-4-oxoquinoline
-3-carboxylic acid (isomer A) 5-amino-6,7-difluoro-1-[(1R, 2
S) -2-Fluorocyclopropyl] -8-methyl-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid (316.1 mg, 1.01 mmol) and 1-benzyloxycarbonyl-3- (cis-2-tert-butoxycarbonylaminocyclopropyl) pyrrolidine (isomerism) Triethylamine (2.5 ml) was added to a dimethyl sulfoxide solution (5 ml) of Compound A (343.6 mg, 1.52 mmol), and the mixture was heated under reflux at 130 ° C. for 4 days. Chloroform was added to the residue obtained by evaporating the solvent under reduced pressure, and the residue was washed with a 10% aqueous citric acid solution and saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
ml) and stirred at room temperature for 30 minutes. Water was added to the reaction solution, and the mixture was extracted with dichloromethane.
The mixture was neutralized with an aqueous solution of N sodium hydroxide and extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethanol and diethyl ether to give 5-amino-7- [3-
(1,2-cis-2-aminocyclopropyl) -1-pyrrolidinyl] -6-fluoro-1-[(1R, 2S)-
2-fluorocyclopropyl] -8-methyl-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid (isomer A; 122.8 mg, 29.0%) was obtained as yellow crystals. ¹ H-NMR (0.1 N NaOD) δ: 0.00-0.
10 (1H, m), 0.55-0.75 (2H, m),
1.00-1.15 (1H, m), 1.35-1.50
(1H, m), 1.55-1.80 (1H, m), 1.
85-2.00 (1H, m), 2.00-2.15 (1
H, m), 2.15-2.30 (4H, m), 3.10
-3.70 (4H, m), 3.80-3.90 (1H,
m), 4.60-5.00 (1H, m), 8.18,
8.20 (1H, each d, each J = 2, 9, 2.4 Hz). Elemental analysis; as C ₂₁ H ₂₄ F ₂ N ₄ O ₃ : Calculated: C, 60.28; H, 5.78; N, 13.39. Analytical values: C, 60.09; H, 5.96; N, 13.06.

Example 2 5-amino-7- [3- (1,2-cis-2-aminocy
Clopropyl) -1-pyrrolidinyl] -6-fluoro-
1-[(1R, 2S) -2-fluorocyclopropyl]
-8-Methyl-1,4-dihydro-4-oxoquinoline
-3-carboxylic acid (isomer B) 5-amino-6,7-difluoro-1-[(1R, 2
S) -2-Fluorocyclopropyl] -8-methyl-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid (195.9 mg, 0.63 mmol) and 1-benzyloxycarbonyl-3- (cis-2-tert-butoxycarbonylaminocyclopropyl) pyrrolidine (isomerism) Compound B (213.0 mg, 0.94 mmol) in dimethylsulfoxide solution (4 ml) was added to triethylamine (2 ml).
ml), and the mixture was heated under reflux at 130 ° C. for 45 hours. Chloroform was added to the residue obtained by evaporating the solvent under reduced pressure, and the residue was washed with a 10% aqueous citric acid solution and saturated saline. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and concentrated hydrochloric acid (10 m
l) was added and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, extracted with dichloromethane, and the aqueous layer was separated into 5N and 1N.
After neutralization with an aqueous sodium hydroxide solution, the mixture was extracted with chloroform. The aqueous layer was adjusted to pH 1 with a 5N aqueous sodium hydroxide solution.
After extracting with chloroform, the aqueous layer was neutralized with concentrated hydrochloric acid and 1N hydrochloric acid and then extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethanol and diethyl ether to give 5-amino-7- [3- (1,2-cis-2). -Aminocyclopropyl) -1-pyrrolidinyl]-
6-fluoro-1-[(1R, 2S) -2-fluorocyclopropyl] -8-methyl-1,4-dihydro-4-
Oxoquinoline-3-carboxylic acid (isomer B; 65.9
mg, 25.1%) as yellow crystals. ¹ H-NMR (0.1 N NaOD) δ: 0.00-0.
10 (1H, m), 0.55-0.70 (2H, m),
0.95-1.15 (1H, m), 1.30-1.50
(1H, m), 1.60-1.80 (1H, m), 1.
80-2.10 (2H, m), 2.10-2.25 (4
H, m), 3.00-3.70 (4H, m), 3.75
-3.85 (1H, m), 4.65-4.95 (1H,
m), 8.13, 8.14 (1H, each d, each J = 2,
9, 2.0 Hz). Elemental analysis; as C ₂₁ H ₂₄ F ₂ N ₄ O ₃ .0.5H ₂ O: Calculated: C, 59.01; H, 5.90; N, 13.11. Found: C, 59.10; H, 5.66; N, 13.06.

Example 3 5-Amino-7- {3-[(1S, 2S) -2-amino]
Cyclopropyl] -1-pyrrolidinyl} -6-fluoro
-1-[(1R, 2S) -2-fluorocyclopropyl
8-Methyl-1,4-dihydro-4-oxoquino
Phosphorus-3-carboxylic acid (isomer B ¹ ) 5-amino-6,7-difluoro-1-[(1R, 2
S) -2-Fluorocyclopropyl] -8-methyl-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid (526.3 mg, 1.69 mmol) and 1-benzyloxycarbonyl-3-[(1S, 2S) -2-
Tertiary butoxycarbonylaminocyclopropyl] pyrrolidine (isomer B; 572.2 mg, 2.53 mmol
Triethylamine (4 ml) was added to a dimethyl sulfoxide solution (8 ml) of 1), and the mixture was heated under reflux at 130 ° C. for 90 hours. Chloroform was added to the residue obtained by evaporating the solvent under reduced pressure, and the residue was washed with a 10% aqueous citric acid solution and saturated saline. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (chloroform: methanol =
9: 1) to give a protected form (551.4 mg) and a mixture of the protected form and by-products (141.4 mg) as a brown carmella. The obtained protective body (551.
4 mg), concentrated hydrochloric acid (10 ml) was added under ice-cooling, and the mixture was stirred at room temperature for 20 minutes. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The aqueous layer was neutralized with 5N and 1N aqueous sodium hydroxide and extracted with chloroform. After evaporating the organic layer, the mixture was adjusted to pH 10 with water and a 1N aqueous sodium hydroxide solution.
After extraction with chloroform as described above, the aqueous layer was neutralized with concentrated hydrochloric acid and 1N hydrochloric acid and then extracted with chloroform. Further, the first aqueous layer was adjusted to pH 10 with a 5N aqueous sodium hydroxide solution.
After extraction with chloroform as described above, the aqueous layer was neutralized with concentrated hydrochloric acid and 1N hydrochloric acid and then extracted with chloroform. After drying the combined organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain a crude carboxylic acid (286.1 mg). Similarly, a mixture of the protected compound and a by-product (141.4 mg)
More crude carboxylic acid (62.3 mg) was obtained. The obtained crude carboxylic acid was recrystallized from ethanol to give 5-amino-7.
-{3-[(1S, 2S) -2-aminocyclopropyl] -1-pyrrolidinyl} -6-fluoro-1-[(1
[R, 2S) -2-fluorocyclopropyl] -8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (isomer B; 204.4 mg, 29.0%) as yellow crystals. Was. ¹ H-NMR (0.1 N NaOD) δ: -0.05-
0.05 (1H, m), 0.55-0.65 (2H,
m), 0.90-1.10 (1H, m), 1.30-
1.40 (1H, m), 1.60-1.70 (1H,
m), 1.80-1.90 (1H, m), 2.00-
2.10 (1H, m), 2.10-2.20 (4H,
m), 3.20-3.30 (1H, m), 3.30-
3.40 (2H, m), 3.50-3.60 (1H,
m), 3.70-3.80 (1H, m), 4.70-
4.95 (1H, m), 8.11 (1H, brs). Elemental analysis: as C ₂₁ H ₂₄ F ₂ N ₄ O ₃ : Calculated: C, 60.28; H, 5.78; N, 13.39. Found: C, 60.21; H, 5.72; N, 13.15. Melting point: 193-196C

Reference Example A cis-2-methoxycarbonylcyclopropanecarboxylic
To a methanol solution (150 ml) of dimethyl cis-1,2-cyclopropanedicarboxylate (14.68 g, 92.8 mmol) was added potassium hydroxide (7.
52 g, 113.9 mmol) of an aqueous solution (67 ml) was added, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, water was added to the obtained residue, and the mixture was washed with diethyl ether. The aqueous layer was adjusted to pH 2 with concentrated hydrochloric acid and extracted with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and cis-2-methoxycarbonylcyclopropanecarboxylic acid (12.38 g, 92.5
%) As a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.35 (1H, d
t, J = 8.3, 4.9 Hz), 1.70 (1H, d
t, J = 6.8, 4.9 Hz), 2.05-2.20
(2H, m), 3.72 (3H, m).

[Reference Example B]Tertiary butyl cis-2-methoxycarbonylcycloprop
Lopan carboxylate Cis-2-methoxycarbonylcyclopropanecarboxylic
Tetrahydric anhydride of acid (6.83 g, 47.4 mmol)
Add dimethylamino to a lofuran solution (70 ml) at room temperature.
Pyridine (1.16 g, 9.48 mmol) and di-
tert-butyl dicarbonate (13.45 g, 6
1.6 mmol) and stirred at the same temperature for 4 hours. Anti
After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue obtained was treated with ethyl acetate.
Chilled and washed with 0.5N hydrochloric acid, water and saturated saline.
Was. After drying the organic layer over anhydrous sodium sulfate, the solvent was reduced.
Distill off the pressure to tertiary butyl cis 2-methoxycarbonyl
Cyclopropanecarboxylate (9.49 g, quantitative)
Was obtained as a brown oil. ¹ H-NMR (CDCl₃) Δ: 1.10-1.20
(1H, m), 1.44 (9H, s), 1.55-1.
65 (1H, m), 1.95-2.05 (2H, m),
3.67 (3H, s).

Reference Example C cis-2-tert-butoxycarbonylcyclopropane
Carboxylic acid tert-butyl cis 2-methoxycarbonyl cyclopropanecarboxylate (9.49g, 47.4mmo
An aqueous solution (40 ml) of potassium hydroxide (4.06 g, 61.5 mmol) was added to a methanol solution of l) (100 ml) under ice cooling, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, water was added to the obtained residue, and the mixture was washed with diethyl ether. The aqueous layer was adjusted to pH 2-3 with concentrated hydrochloric acid and extracted with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure and cis-
2-Tertiary butoxycarbonylcyclopropanecarboxylic acid (7.56 g, 85.7%) was obtained as a pale yellow solid. ¹ H-NMR (CDCl ₃ ) δ: 1.30-1.40
(1H, m), 1.45 (9H, s), 1.60-1.
65 (1H, m), 2.00-2.10 (2H, m).

Reference Example D Ethyl 3- (cis-2-tert-butoxycarbonyloxy)
Black propyl) -3-oxopropionate cis-2-tert-butoxycarbonyl cyclopropanecarboxylic acid (7.56 g, in anhydrous tetrahydrofuran (100ml) of 40.6 mmol), under ice-cooling 1,1
Carbonyl diimidazole (7.57 g, 46.7 mm
ol) and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and a solution of the residue obtained in anhydrous tetrahydrofuran (5.
0 ml), an anhydrous tetrahydrofuran solution (80 ml) of malonic acid monoethyl ester magnesium salt (101.5 mmol) was added thereto, and the mixture was stirred overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, and ethyl acetate was added to the obtained residue, followed by washing with 0.5N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated saline. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
7: 3) to give ethyl 3- (cis-2-tert-butoxycarbonylcyclopropyl) -3-oxopropionate (6.67 g, 64.1%) as a yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.20 (1H, d
t, J = 7.8, 4.9 Hz), 1.29 (3H, t,
J = 7.3 Hz), 1.42 (9H, s), 1.71
(1H, dt, J = 6.8, 4.9 Hz), 2.00-
2.10 (1H, m), 2.30-2.40 (1H,
m), 3.55 (1H, d, J = 15.6 Hz);
57 (1H, d, J = 15.6 Hz), 4.20 (2
H, q, J = 7.3 Hz).

Reference Example E Ethyl 3- (cis-2-tert-butoxycarbonyloxy)
Clopropyl) acrylate ethyl 3- (cis-2-tert-butoxycarbonylcyclopropapyl) -3-oxopropionate (6.6)
7 g, 26.0 mmol) in methanol (70 m
l) at -10 ° C at sodium borohydride (492.
2 mg, 13.0 mmol) and stirred at the same temperature for 20 minutes. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the crude alcohol (6.52 g,
97.0%) as a colorless oil. To a dichloromethane solution (150 ml) of the crude alcohol (6.52 g, 25.2 mmol) was added triethylamine (7.0) under ice-cooling.
4ml, 50.4mmol) and methanesulfonyl chloride (2.54ml, 32.8mmol) were added,
After stirring at the same temperature for 1 hour and 30 minutes, 1,8-diazabicyclo [5.4.0] -7-undecene (8.30 ml, 5
5.4 mmol) and stirred at room temperature for 18 hours.
Chloroform was added to the residue obtained by evaporating the solvent under reduced pressure, and the residue was washed with 0.1N hydrochloric acid and saturated saline. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain ethyl 3- (cis-2-tert-butoxycarbonylcyclopropyl) acrylate (6.07 g, quantitative) as a yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, t,
J = 7.3 Hz), 1.25-1.35 (1H, m),
1.35-1.45 (1H, m), 1.46 (9H,
s), 1.90-2.05 (2H, m), 4.10-
4.20 (2H, m), 6.00 (1H, d, J = 1
5.6 Hz), 6.90 (1H, ddd, J = 15.
6,8.8,1.5 Hz).

Reference Example F Ethyl 3- (cis-2-tert-butoxycarbonyloxy)
Black propyl) -3-nitro-ethyl propionate Ethyl 3- (cis-2-tert-butoxycarbonyl-cyclopropyl) acrylate (6.07g, 25.2m
mol) of nitromethane (60 ml) at room temperature in tetramethylguanidine (3.48 ml, 27.7 mm).
ol) and stirred for 6 hours. Further, tramethylguanidine (0.32 ml, 2.52 mmol) was added, and the mixture was stirred for 18 hours. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 85: 15), and ethyl 3- (cis-2) was purified.
-Tert-butoxycarbonylcyclopropyl) -3-nitroethylpropionate (6.536 g, 85.9)
%) As a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 0.95-1.10
(2H, m), 1.20-1.30 (4H, m), 1.
46, 1.48 (9H, each s), 1.65-1.80
(1H, m), 2.40-2.70 (2H, m), 2.
70-2.80 (1H, m), 4.10-4.20 (2
H, m), 4.45-4.55, 4.60-4.75.
(2H, each m).

Reference Example G 3- (cis-2-tert-butoxycarbonylcyclopro
Pills) pyrrolidin-2-one Ethyl 3- (cis-2-tert-butoxycarbonyl-cyclopropyl) -3-nitro-ethyl propionate (6.536G, the methanol solution (200ml) of 21.7 mmol), room temperature 10% palladium on carbon (5
g) and ammonium formate (13.68 g, 217 m
mol), and the mixture was stirred at the same temperature for 1 hour and 30 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, water was added to the obtained residue, and the mixture was extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain a crude amine.

A toluene solution of the obtained crude amine (150
ml) was heated at 110-120 ° C for 2 hours. The solvent was evaporated under reduced pressure to give 3- (cis-2-tert-butoxycarbonylcyclopropyl) pyrrolidin-2-one (4.89).
g, quant.) as yellow crystals. ¹ H-NMR (CDCl ₃ ) δ: 0.90-1.10
(2H, m), 1.20-1.35 (1H, m), 1.
45 (9H, s), 1.65-1.75 (1H, m),
2.10-2.70 (3H, m), 3.10-3.2
0, 3.20-3.30 (1H, each m), 3.35-
3.45, 3.55-3.65 (1H, m for each), 6.0
6 (1H, brs).

Reference Example H 1-benzyl-3- (cis-2-tert-butoxycarbo
Nylcyclopropyl ) pyrrolidin-2-one 3- (cis-2-tert-butoxycarbonylcyclopropyl) pyrrolidin-2-one (2.288 g, 10.2)
mmol) in dimethylformamide (30 ml)
Then, sodium hydride (406.2 mg, 10.
2 mmol) and stirred at room temperature for 1 hour and 30 minutes. Then benzyl chloride (1.81 ml, 15.3 mmol)
l) was added dropwise, and the mixture was stirred for 2 hours and 30 minutes. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
7: 3), and purified by 1-benzyl-3- (2-tert-butoxycarbonylcyclopropyl) pyrrolidine-2-.
ON (isomer A: a cyclopropyl group is bonded to a carbon atom constituting a pyrrolidine ring, and is an isomer derived from a configuration on this carbon atom; 1.121 g, 35.0
%) As a colorless solid. Then, elution was carried out with a mixed solvent of hexane: ethyl acetate = 1: 1, and 1-benzyl-3
-(Cis-2-tert-butoxycarbonylcyclopropyl) pyrrolidin-2-one (isomer B: a cyclopropyl group is bonded to a carbon atom constituting a pyrrolidine ring, and is derived from a configuration on this carbon atom. Isomers; 6
(70.9 mg, 20.9%) as a colorless solid. Isomer A ¹ H-NMR (CDCl ₃ ) δ: 0.85-1.00
(2H, m), 1.10-1.25 (1H, m), 1.
45 (9H, s), 1.65-1.75 (1H, m),
2.25 (1H, dd, J = 16.1, 6.4 Hz),
2.35-2.45 (1H, m), 2.50 (1H, d
d, J = 16.1, 8.8 Hz), 3.08 (1H, d
d, J = 9.8, 5.9 Hz), 3.43 (1H, t,
J = 8.8 Hz), 4.45 (1H, d, J = 14.7)
Hz), 4.46 (1H, d, J = 14.7 Hz),
7.20-7.40 (5H, m). Isomer B ¹ H-NMR (CDCl ₃ ) δ: 0.90-1.00
(1H, m), 1.00-1.10 (1H, m), 1.
15-1.25 (1H, m), 1.37 (9H, s),
1.55-1.65 (1H, m), 2.33 (1H, d
d, J = 16.1, 7.3 Hz), 2.35-2.45
(1H, m), 2.68 (1H, dd, J = 16.1,
8.3 Hz), 2.99 (1H, dd, J = 9.3,
5.9 Hz), 3.20 (1H, dd, J = 9.3,
7.8 Hz), 4.39 (1H, d, J = 14.7H)
z), 4.48 (1H, d, J = 14.7 Hz), 7.
20-7.40 (5H, m).

Reference Example I 1-benzyl-3- (cis-2-tert-butoxycarbo)
Nylcyclopropyl) pyrrolidine-2-thione (isomer)
A) A solution of 1-benzyl-3- (cis-2-tert-butoxycarbonylcyclopropyl) pyrrolidin-2-one (isomer A; 1.990 g, 6.31 mmol) in toluene (40 ml) was treated with Lawesson's reagent (1 .378 g, 3.41
mmol), and the mixture was stirred at 50-60 ° C for 1 hour and 30 minutes. After completion of the reaction, the mixture was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3) to give 1-
Benzyl-3- (cis-2-tert-butoxycarbonylcyclopropyl) pyrrolidine-2-thione (isomer A;
1.707 g, 81.6%) as a pale yellow solid. ¹ H-NMR (CDCl ₃ ) δ: 0.80-0.90
(1H, m), 0.90-1.00 (1H, m), 1.
10-1.20 (1H, m), 1.45 (9H, s),
1.65-1.75 (1H, m), 2.40-2.55
(1H, m), 2.90 (1H, dd, J = 17.6,
5.4 Hz), 3.12 (1H, dd, J = 17.6,
8.3 Hz), 3.41 (1H, dd, J = 11.2,
5.4 Hz), 3.75 (1H, dd, J = 11.2,
7.8 Hz), 4.97 (1H, d, J = 14.2H)
z), 5.01 (1H, d, J = 14.2 Hz), 7.
30-7.40 (5H, m).

Reference Example J 1-benzyl-3- (cis-2-tert-butoxycarbo
Nylcyclopropyl) pyrrolidine (isomer A) 1-benzyl-3- (cis-2-tert-butoxycarbonylcyclopropyl) pyrrolidine-2-thione (isomer A; 1.70 g, 5.13 mmol) in ethanol (50 ml) was added with Raney nickel (14 ml), and the mixture was stirred at room temperature for 1 hour and 30 minutes. After removing the insoluble matter by filtration, the solvent was distilled off under reduced pressure, and chloroform was added to the obtained residue.
It was washed with 0% aqueous ammonia. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give 1-benzyl-
3- (cis-2-tert-butoxycarbonylcyclopropyl) pyrrolidine (isomer A; 1.479 g, 95.7)
%) As a pale yellow oil. _{^{1 H-NMR (CDCl 3)}} δ: 0.85-0.95
(2H, m), 1.20-1.30 (1H, m), 1.
44 (9H, s), 1.50-1.65 (2H, m),
1.85-1.95 (1H, m), 2.10-2.25
(1H, m), 2.40 (1H, dd, J = 8.8,
5.9 Hz), 2.51 (1H, q, J = 7.8H)
z), 2.62 (1H, dt, J = 8.8, 5.4H
z), 2.72 (1H, t, J = 8.7 Hz), 3.5
9 (1H, d, J = 12.7 Hz), 3.62 (1H, d, J = 12.7 Hz)
d, J = 12.7 Hz), 7.20-7.40 (5H,
m).

Reference Example K 1-benzyloxycarbonyl-3- (cis-2-third
Butoxycarbonylcyclopropyl) pyrrolidine (different
Sex A) 1-benzyl-3- (cis-2-tert-butoxycarbonylcyclopropyl) pyrrolidine (isomer A; 1.46)
6g, 4.86 mmol) in dichloromethane (30
benzyl chloroformate (1.ml) at room temperature.
39 ml, 9.72 mmol), and the mixture was stirred at the same temperature for 15 hours and 30 minutes, and then heated under reflux for 1 hour. More benzyl
Chloroformate (0.70 ml, 4.86 mmol)
Was added and the mixture was refluxed for 1 hour and 30 minutes. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3), and 1-benzyloxycarbonyl-3- (cis-2-tert-butoxycarbonyl) was purified. Cyclopropyl) pyrrolidine (isomer A; 1.261 g, 75.1%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.90-1.00
(2H, m), 1.05-1.15 (1H, m), 1.
46 (9H, s), 1.60-1.70 (2H, m),
1.80-1.95 (1H, m), 2.20-2.30
(1H, m), 3.15-3.30 (1H, m), 3.
30-3.40 (1H, m), 3.50-3.70 (2
H, m), 5.14 (2H, s), 7.25-7.40.
(5H, m).

Reference Example L 1-benzyloxycarbonyl-3- (cis-2-third
Butoxycarbonylaminocyclopropyl) pyrrolidi
(Isomer A ) To a dichloromethane solution (10 ml) of 1-benzyloxycarbonyl-3- (cis-2-tert-butoxycarbonylcyclopropyl) pyrrolidine (isomer A; 1.252 g, 3.62 mmol) was added ice. Under cooling, trifluoroacetic acid (5 ml) was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and toluene was added to the obtained residue to distill it off, thereby obtaining a crude carboxylic acid. 2-Methyl-2-propanol solution of the obtained crude carboxylic acid (30 ml)
In addition, diphenyl phosphate azide (0.781 ml, 3.6
2 mmol) and triethylamine (0.758 m
1, 5.43 mmol), and the mixture was stirred at room temperature for 1 hour and then heated and refluxed for 31 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and ethyl acetate was added to the obtained residue, followed by washing with a 5% aqueous citric acid solution, a saturated aqueous sodium carbonate solution, and saturated saline. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3) to give ethyl 3- (cis-2). -Tert-butoxycarbonylcyclopropyl) -3-oxopropionate (6.67 g, 64.1%) was obtained as a yellow oil.
1-Benzyloxycarbonyl-3- (cis-2-tert-butoxycarbonylaminocyclopropyl) pyrrolidine (isomer A; 575.2 mg, 44.0%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.20-0.30
(1H, m), 0.75-0.95 (2H, m), 1.
44 (9H, s), 1.70-1.90 (2H, m),
2.00-2.10 (1H, m), 2.65-2.75
(1H, m), 3.15-3.30 (1H, m), 3.
30-3.40 (1H, m), 3.50-3.65 (2
H, m), 4.50-4.65 (1H, brs), 5.
13 (2H, s), 7.30-7.40 (5H, m).

Reference Example M 3- (cis-2-tert-butoxycarbonylaminocyclyl)
(Propyl) pyrrolidine (isomer A) 1-benzyloxycarbonyl-3- (cis-2-tert-butoxycarbonylaminocyclopropyl) pyrrolidine (isomer A; 547.3 mg, 1.52 mmol) in ethanol solution (15 ml) 5% palladium on carbon (5
50 mg) and added under a hydrogen stream (4 kg / cm ² ) 1
Shake for 30 minutes. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure and 1-benzyloxycarbonyl-3- (cis-2-
Tertiary butoxycarbonylaminocyclopropyl) pyrrolidine (isomer A; 343.6 mg, quantitative) was obtained as a brown oil. ¹ H-NMR (CDCl ₃ ) δ: 0.20-0.30
(1H, m), 0.75-0.95 (2H, m), 1.
45 (9H, s), 1.55-1.75 (2H, m),
1.90-2.00 (1H, m), 2.60-2.70
(1H, m), 2.70-2.80 (1H, m), 2.
90-3.00 (1H, m), 3.00-3.15 (2
H, m), 4.70-4.80 (1H, brs).

Reference Example N 1-benzyl-3- (cis-2-tert-butoxycarbo
Nylcyclopropyl) pyrrolidine-2-thione (isomer)
B) A solution of 1-benzyl-3- (cis-2-tert-butoxycarbonylcyclopropyl) pyrrolidin-2-one (isomer B; 1.534 g, 4.86 mmol) in toluene (30 ml) was treated with Lawesson's reagent (1). 0.062 g, 2.62
mmol), and the mixture was stirred at 50-60 ° C for 1 hour and 30 minutes. After completion of the reaction, the mixture was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3) to give 1-
Benzyl-3- (cis-2-tert-butoxycarbonylcyclopropyl) pyrrolidine-2-thione (isomer B;
1.198 g, 74.3%) as a pale yellow solid. ¹ H-NMR (CDCl ₃ ) δ: 0.90-1.00
(1H, m), 1.00-1.10 (1H, m), 1.
10-1.20 (1H, m), 1.35 (9H, s),
1.55-1.65 (1H, m), 2.40-2.50
(1H, m), 2.97 (1H, dd, J = 18.1,
6.3 Hz), 3.25-3.35 (2H, m),
52 (1H, dd, J = 11.2, 6.8 Hz);
92 (1H, d, J = 14.2 Hz), 5.01 (1
H, d, J = 14.2 Hz), 7.25-7.40 (5
H, m).

Reference Example O 1-benzyl-3- (cis-2-tert-butoxycarbo
Nylcyclopropyl) pyrrolidine (isomer B) 1-benzyl-3- (cis-2-tert-butoxycarbonylcyclopropyl) pyrrolidine-2-thione (isomer B; 1.19 g, 3.59 mmol) in ethanol (50 ml) was added to Raney nickel (10 ml), and the mixture was stirred at room temperature for 30 minutes. After filtering off the insoluble matter, the solvent was distilled off under reduced pressure, chloroform was added to the obtained residue, and the mixture was washed with 10% aqueous ammonia. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give 1-benzyl-3-.
(Cis-2-tert-butoxycarbonylcyclopropyl) pyrrolidine (isomer B; 929.0 mg, 85.8)
%) As a pale yellow oil. _{^{1 H-NMR (CDCl 3)}} δ: 0.85-0.95
(2H, m), 1.15-1.30 (1H, m), 1.
38 (9H, s), 1.55-1.70 (2H, m),
2.05-2.25 (2H, m), 2.25-2.35
(1H, m), 2.50-2.75 (3H, m), 3.
56 (1H, d, J = 12.7 Hz), 3.60 (1
H, d, J = 12.7 Hz), 7.20-7.40 (5
H, m).

Reference Example P 1-benzyloxycarbonyl-3- (cis-2-third
Butoxycarbonylcyclopropyl) pyrrolidine (different
Sex B) 1-benzyl-3- (cis-2-tert-butoxycarbonylcyclopropyl) pyrrolidine (isomer B; 922.
6 mg, 3.06 mmol) in dichloromethane (1
Benzyl chloroformate (0.874 ml, 6.12 mmol) at room temperature and stirred overnight at the same temperature.
(502 ml, 3.52 mmol) and stirred for 2 days. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (hexane: ethyl acetate = 7:
Purified in 3), 1-benzyloxycarbonyl-3-
(Cis-2-tert-butoxycarbonylcyclopropyl) pyrrolidine (isomer B; 685.5 mg, 64.8)
%) As a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.90 to 1.15
(3H, m), 1.43, 1.46 (9H, each s),
1.60-1.80 (2H, m), 2.00-2.15
(1H, m), 2.20-2.30 (1H, m), 3.
05-3.20 (1H, m), 3.30-3.50 (2
H, m), 3.50-3.65 (1H, m), 5.10
−5.20 (2H, m), 7.25-7.40 (5H,
m).

Reference Example Q 1-benzyloxycarbonyl-3- (cis-2-third
Butoxycarbonylaminocyclopropyl) pyrrolidi
(Isomer B ) To a dichloromethane solution (3 ml) of 1-benzyloxycarbonyl-3- (cis-2-tert-butoxycarbonylcyclopropyl) pyrrolidine (isomer B; 685.5 mg, 1.98 mmol) was added ice Under cooling, trifluoroacetic acid (3 ml) was added and the mixture was stirred at room temperature for 1 hour and 30 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, and toluene was added to the obtained residue to distill it off, thereby obtaining a crude carboxylic acid.

The resulting crude carboxylic acid, 2-methyl-2-
To a propanol solution (20 ml) were added diphenylphosphoric azide (0.411 ml, 1.98 mmol) and triethylamine (0.399 ml, 2.97 mmol), and the mixture was stirred at room temperature for 1 hour and 30 minutes, and then heated and refluxed for 16 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and ethyl acetate was added to the obtained residue, followed by washing with a 5% aqueous citric acid solution, a saturated aqueous sodium carbonate solution, and saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3) to give 1-benzyloxycarbonyl-3. -(Cis-2-tert-butoxycarbonylaminocyclopropyl) pyrrolidine (isomer B; 345.2 mg, 48.3%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.20-0.35
(1H, m), 0.75-0.85 (1H, m), 0.
90-1.00 (1H, m), 1.40 (9H, s),
1.70-1.85 (2H, m), 1.95-2.10
(1H, m), 2.60-2.70 (1H, m), 3.
10-3.25 (1H, m), 3.30-3.40 (1
H, m), 3.50-3.70 (2H, m), 4.50
-4.65 (1H, brs), 5.05-5.20 (2
H, m), 7.25-7.40 (5H, m).

Reference Example R 3- (cis-2-tert-butoxycarbonylaminocyclyl)
(Propyl) pyrrolidine (isomer B) 1-benzyloxycarbonyl-3- (cis-2-tert-butoxycarbonylaminocyclopropyl) pyrrolidine (isomer B; 340.4 mg, 0.94 mmol) in ethanol solution (10 ml) 5% palladium on carbon (3
50 mg) and added under a stream of hydrogen (3.5 kg / cm
² ) Shake for 1 hour and 30 minutes. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure, and 3- (cis-2-tert-butoxycarbonylaminocyclopropyl) pyrrolidine (isomer B; 21
(3.0 mg, 99.7%) as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 0.20-0.30
(1H, m), 0.75-1.00 (2H, m), 1.
45 (9H, s), 1.60-1.80 (2H, m),
1.90-2.05 (1H, m), 2.60-2.80
(2H, m), 2.80-3.20 (3H, m), 4.
65-4.80 (1H, m).

Reference Example S (1S, 2R) -tert-butyl cis-2-methoxyca
Rubonylcyclopropanecarboxylate (-)-(1S, 2R) -2-methoxycarbonylcyclopropanecarboxylic acid (11.38 g, 79.0 mmol
l) in anhydrous tetrahydrofuran solution (120 ml),
At room temperature, dimethylaminopyridine (1.93 g, 15.
80 mmol) and di-tert-butyl dicarbonate (22.41 g, 102.67 mmol), and the mixture was stirred at the same temperature for 18 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and ethyl acetate was added to the obtained residue.
Washed with N hydrochloric acid, water and saturated saline. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure (1S,
2R) -Tertiary butyl 2-methoxycarbonylcyclopropanecarboxylate (15.81 g, quant.) Was obtained as a brown oil. ¹ H-NMR (CDCl ₃ ) δ: 1.17 (1H, d
t, J = 8.3, 4.9 Hz), 1.44 (9H,
s), 1.55-1.65 (1H, m), 1.95-
2.05 (2H, m), 3.69 (3H, s).

Reference Example T (1R, 2S) -cis-2-tert-butoxycarbonyl
Cyclopropanecarboxylic acid (1S, 2R) -tert-butyl 2-methoxycarbonylcyclopropanecarboxylate (15.81 g, 7
9.0 mmol) in a methanol solution (150 ml),
Potassium hydroxide (6.77 g, 102.6 mmol under ice cooling)
1) Aqueous solution (50 ml) was added and stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, water was added to the obtained residue, and the mixture was washed with diethyl ether. The aqueous layer was adjusted to pH 2-3 with concentrated hydrochloric acid and extracted with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain (1R, 2S) -2-tert-butoxycarbonylcyclopropanecarboxylic acid (14.71 g, quantitative) as a pale yellow solid. . ¹ H-NMR (CDCl ₃ ) δ: 1.25 to 1.35
(1H, m), 1.44 (9H, s), 1.60-1.
65 (1H, m), 2.00-2.10 (2H, m).

Reference Example U Ethyl 3-[(1R, 2S) -2-tert-butoxyca
Rubonylcyclopropyl] -3-oxopropionate (1R, 2S) -2-tert-butoxycarbonylcyclopropanecarboxylic acid (14.71 g, 79.0 mmol)
l) in anhydrous tetrahydrofuran solution (170 ml)
1,1-carbonyldiimidazole (16.49) under ice-cooling
g, 90.6 mmol) and stirred at room temperature for 1 hour and 30 minutes. The solvent was distilled off under reduced pressure, and a solution of the residue obtained in anhydrous tetrahydrofuran (60 ml) was added with a magnesium salt of malonic acid monoethyl ester (19).
7.5 mmol) in anhydrous tetrahydrofuran (15
0 ml) and stirred for 3 days. After completion of the reaction, the solvent was distilled off under reduced pressure, and ethyl acetate was added to the obtained residue.
Washed with 5N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated saline. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3) to give ethyl 3-[(1R, 2S) -2-tert-butoxycarbonylcyclopropyl] -3-oxopropionate (1
8.53 g, 91.8%) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.15-1.30
(4H, m), 1.42 (9H, s), 1.65-1.
75 (1H, m), 2.00-2.10 (1H, m),
2.25-2.35 (1H, m), 3.50-3.65
(2H, m), 4.15-4.25 (2H, m).

Reference Example V Ethyl 3-[(1R, 2S) -2-tert-butoxyca
Rubonylcyclopropyl] -acrylateethyl 3-[(1R, 2S) -2-tert-butoxycarbonylcyclopropyl] -3-oxopropionate (18.48 g, 72.1 mmol) in methanol solution (200 ml) Sodium borohydride (1.36 g, 36.1 mmol) was added at −10 ° C., and the mixture was stirred at the same temperature for 30 minutes. Add a saturated aqueous ammonium chloride solution,
Extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure and the crude alcohol (1
8.62 g, quantitative) as a colorless oil.

Crude alcohol (18.62 g, 72.1 m)
mol) in dichloromethane solution (400 ml) under ice cooling with triethylamine (20.10 ml, 144.2 mm).
ol) and methanesulfonyl chloride (7.25 m
After stirring at the same temperature for 1 hour and 30 minutes, 1,8-diazabicyclo [5.4.0] -7-
Undecene (23.72 ml, 158.6 mmol) was added, and the mixture was stirred at room temperature for 15 hours. Chloroform was added to the residue obtained by evaporating the solvent under reduced pressure, 0.1N hydrochloric acid,
Washed with water and saturated saline. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give ethyl 3
-[(1R, 2S) -2-tert-butoxycarbonylcyclopropyl] acrylate (17.33 g, quantitative) was obtained as a yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, t,
J = 7.3 Hz), 1.25-1.35 (1H, m),
1.35-1.45 (1H, m), 1.45 (9H,
s), 1.90-2.05 (2H, m), 4.10-
4.25 (2H, m), 5.98 (1H, d, J = 1
5.6 Hz), 6.91 (1H, ddd, J = 15.
6,8.8,1.5 Hz).

Reference Example W Ethyl 3-[(1R, 2S) -2-tert-butoxyca
Rubonylcyclopropyl] -3-nitroethylpropio
Sulfonate ethyl 3 - [(1R, 2S) -2- tert-butoxycarbonyl-cyclopropyl) acrylate (17.33
g, 72.1 mmol) in nitromethane (150 m
1) At room temperature, tetramethylguanidine (14.47)
ml, 115.4 mmol) at 70 ° C. for 3 hours 3
Stirred for 0 minutes. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 85: 15), and ethyl 3-[(1
R, 2S) -2-tert-butoxycarbonylcyclopropyl] -3-nitroethylpropionate (18.95
g, 87.2%) as a colorless oil. _{^{1 H-NMR (CDCl 3)}} δ: 0.95-1.15
(2H, m), 1.25-1.35 (4H, m), 1.
46, 1.48 (9H, each s), 1.65-1.80
(1H, m), 2.40-2.70 (2H, m), 2.
70-2.85 (1H, m), 4.10-4.20 (2
H, m), 4.45-4.55, 4.60-4.75.
(2H, each m).

Reference Example X 3-[(1R, 2S) -2-tert-butoxycarbonyl
Cyclopropyl) pyrrolidin-2-ethyl-3 - [(1R, 2S) -2- tert-butoxycarbonyl-cyclopropyl] -3-methanol solution (600ml nitro propionate (18.99g, 63.0mmol) ), 10% palladium on carbon (about 5 g), 5% palladium on carbon (7 g) and ammonium formate (51.67 g, 819 mmol) were added to the mixture at room temperature, and the mixture was stirred at the same temperature for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, water was added to the obtained residue, and the mixture was extracted with chloroform. After drying the organic layer over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure to remove the crude amine (14.67 g, 8
5.8%).

A toluene solution (500 ml) of the obtained crude amine (14.67 g) was heated at 110 to 120 ° C. for 1 hour and 30 minutes. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 98: 2), and 3-[(1
R, 2S) -2-tert-butoxycarbonylcyclopropyl] pyrrolidin-2-one and 3-[(1R, 2
S) -2-Tertiary butoxycarbonylcyclopropyl]
A mixture of -1-hydroxypyrrolidin-2-one (1
0.38 g) and 3-[(1R, 2S) -2-tert-butoxycarbonylcyclopropyl] -1-hydroxypyrrolidin-2-one (2.08 g) as colorless crystals.

The obtained 3-[(1R, 2S) -2-tert-butoxycarbonylcyclopropyl] -1-hydroxypyrrolidin-2-one (1.85 g) in methanol
To a water mixed solution (100 m, 3: 1) was added a titanium trichloride solution (4.45 ml) at room temperature while maintaining the reaction solution neutral with a 1N aqueous sodium hydroxide solution.
Stirred for 0 minutes. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give 3-[(1R, 2S) -2-tert-butoxycarbonylcyclopropyl] pyrrolidine-2-.
On (1.53 g, 88.4%) was obtained.

Similarly, 3-[(1R, 2S) -2-tert-butoxycarbonylcyclopropyl] pyrrolidine-
From a mixture of 2-one and 3-[(1R, 2S) -2-tert-butoxycarbonylcyclopropyl] -1-hydroxypyrrolidin-2-one (9.49 g), 3-
[(1R, 2S) -2-tert-butoxycarbonylcyclopropyl] pyrrolidin-2-one (7.30 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.95-1.10
(2H, m), 1.20-1.35 (1H, m), 1.
45 (9H, s), 1.65-1.75 (1H, m),
2.05-2.60 (3H, m), 3.10-3.2
0, 3.20-3.30 (1H, each m), 3.35-
3.45, 3.55-3.65 (1H, m for each), 5.9
0-6.10 (1H, m).

Reference Example Y 1-Benzyl-3-[(1R, 2S) -2-tert-butene
Xycarbonylcyclopropyl ] pyrrolidin-2-one A suspension of sodium hydride (1.72 g, 43.0 mmol) in dimethylformamide (20 ml) was added under ice-cooling.
-[(1R, 2S) -2-tert-butoxycarbonylcyclopropyl] pyrrolidin-2-one (8.816 g,
39.1 mmol) of a mixed solution of tetrahydrofuran-dimethylformamide (100 ml, 3: 2) was added dropwise,
The mixture was stirred at room temperature for 1 hour and 30 minutes. Then, a solution of benzyl chloride (6.76 ml, 58.7 mmol) in tetrahydrofuran (40 ml) was added dropwise to the reaction solution, and the mixture was stirred for 3 hours. After completion of the reaction, a saturated aqueous solution of ammonium chloride was added, and the mixture was distilled off under reduced pressure. Water was added to the residue, extracted with ethyl acetate, and the organic layer was washed with water and saturated saline. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3).
1-benzyl -3 - [(1R, 2S) -2- tert-butoxycarbonyl-cyclopropyl] pyrrolidin-2-one (isomer ^A 1; ^5.710g, 44.8%) as a colorless solid . Then, elution was carried out with a mixed solvent of hexane: ethyl acetate = 1: 1, and 1-benzyl-3-[(1R, 2
S) -2-Tertiary butoxycarbonylcyclopropyl]
Pyrrolidin-2-one (isomer B ¹ ; 3.959 g, 3
1.1%) as a pale yellow oil. Isomer ^{A 1 1 H-NMR (CDCl} 3) δ: 0.85-1.00
(2H, m), 1.10-1.20 (1H, m), 1.
45 (9H, s), 1.65-1.75 (1H, m),
2.25 (1H, dd, J = 16.1, 6.3 Hz),
2.35-2.45 (1H, m), 2.50 (1H, d
d, J = 16.1, 8.8 Hz), 3.08 (1H, d
d, J = 9.8, 5.9 Hz), 3.43 (1H, d
d, J = 9.8, 7.8 Hz), 4.45 (1H, d,
J = 14.7 Hz), 4.46 (1H, d, J = 14.0).
7 Hz), 7.20-7.40 (5H, m). Isomer ^{B 1 1 H-NMR (CDCl} 3) δ: 0.90-1.00
(1H, m), 1.00-1.05 (1H, m), 1.
10-1.25 (1H, m), 1.37 (9H, s),
1.55-1.65 (1H, m), 2.33 (1H, d
d, J = 16.1, 7.3 Hz), 2.35-2.50
(1H, m), 2.67 (1H, dd, J = 16.1,
8.3 Hz), 2.99 (1H, dd, J = 9.8,
6.3 Hz), 3.21 (1H, dd, J = 9.8,
7.8 Hz), 4.40 (1H, d, J = 14.7H)
z), 4.48 (1H, d, J = 14.7 Hz), 7.
20-7.40 (5H, m). [Α] _D ²² +75.980 (c = 1.045, CH
Cl ₃ ).

REFERENCE EXAMPLE Z 1-benzyl-3-[(1R, 2S) -2-tert-butene
Xycarbonylcyclopropyl] pyrrolidine-2-thio
(Isomer B ¹ ) of 1-benzyl-3-[(1R, 2S) -2-tert-butoxycarbonylcyclopropyl] pyrrolidin-2-one (Isomer B ¹ ; 3.999 g, 12.69 mmol) To a toluene solution (80 ml) was added Lawson's reagent (2.769).
g, 6.85 mmol) and stirred at 50-60 ° C. for 1 hour and 40 minutes. After completion of the reaction, the mixture was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give 1-benzyl-3-[(1R, 2S) -2-tert-butoxycarbonylcyclopropyl] pyrrolidine-.
2- thione (isomer ^B 1; ^4.044g, 96.2%)
Was obtained as a pale yellow solid. ¹ H-NMR (CDCl ₃ ) δ: 0.90-1.00
(1H, m), 1.00-1.10 (1H, m), 1.
10-1.20 (1H, m), 1.35 (9H, s),
1.55-1.65 (1H, m), 2.40-2.55
(1H, m), 2.97 (1H, dd, J = 17.6,
6.4 Hz), 3.25-3.35 (2H, m), 3.
52 (1H, dd, J = 11.2, 7.8 Hz);
92 (1H, d, J = 14.2 Hz), 5.01 (1
H, d, J = 14.2 Hz), 7.25-7.40 (5
H, m).

Reference Example AA 1-benzyl-3-[(1R, 2S) -2-tert-butene
Xycarbonylcarbonylpropyl] pyrrolidine (isomer B
¹⁾ 1-Benzyl -3 - [(1R, 2S) -2- tert-butoxycarbonyl-cyclopropyl] pyrrolidine-2-thione (isomer ^B 1; ^{4.040g, 12.19mmol)}
Raney nickel (20 ml) in ethanol solution (60 ml)
ml) and stirred at room temperature for 40 minutes. After removing the insoluble matter by filtration, the solvent was distilled off under reduced pressure, and chloroform was added to the obtained residue, followed by washing with 10% aqueous ammonia. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and 1-benzyl-3-[(1R, 2S) -2-tert-butoxycarbonylcyclopropyl] pyrrolidine (isomer B ¹ ; 2.988 g, 81.3%) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.85-1.00
(2H, m), 1.15-1.30 (1H, m), 1.
38 (9H, s), 1.55-1.70 (2H, m),
2.00-2.25 (2H, m), 2.30 (1H, d
d, J = 9.3, 5.9 Hz), 2.50-2.65
(3H, m), 3.56 (1H, d, J = 12.7H
z), 3.60 (1H, d, J = 12.7 Hz), 7.
20-7.35 (5H, m).

Reference Example BB 1-benzyloxycarbonyl-3-[(1R, 2S)
-2-tert-butoxycarbonylcyclopropyl] pyro
Lysine (isomer B ¹ ) 1-benzyl-3-[(1R, 2S) -2-tert-butoxycarbonylcyclopropyl] pyrrolidine (isomer B
¹ ; 2.984 g, 9.90 mmol) in dichloromethane solution (50 ml) at room temperature was added with benzyl chloroformate (2.83 ml, 19.82 mmol), and the mixture was stirred at the same temperature for 14 hours, and then further treated with benzyl chloroformate. (1.98 ml, 13.86 mmol) was added and the mixture was heated under reflux for 2 hours. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3), and 1-benzyloxycarbonyl-3-[(1R, 2S) -2 was obtained. -Tert-butoxycarbonylcyclopropyl] pyrrolidine (isomer B ¹ ;
2.188 g, 64.0%) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.90 to 1.05
(2H, m), 1.05-1.15 (1H, m), 1.
43, 1.46 (9H, each s), 1.60-1.80
(2H, m), 2.00-2.15 (1H, m), 2.
20-2.30 (1H, m), 3.05-3.20 (1
H, m), 3.30-3.40 (1H, m), 3.40
-3.50 (1H, m), 3.50-3.65 (1H,
m), 5.05-5.20 (2H, m), 7.25-
7.40 (5H, m).

Reference Example CC 1-benzyloxycarbonyl-3-[(1S, 2S)
-2-tert-butoxycarbonylaminocyclopropyl
Le] pyrrolidine (isomer ^B 1) 1-benzyloxycarbonyl -3 - [(1R, 2S)
2-tert-butoxycarbonyl-cyclopropyl] pyrrolidine (isomer ^B 1; ^{2.183g, 6.32mmo}
To a dichloromethane solution (10 ml) of l), trifluoroacetic acid (8 ml) was added under ice cooling, followed by stirring at room temperature for 1 hour and 30 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, and toluene was added to the obtained residue, followed by distillation under reduced pressure to obtain a crude carboxylic acid. To a 2-methyl-2-propanol solution (60 ml) of the obtained crude carboxylic acid, diphenylphosphoric azide (1.36 ml, 6.32 mmol) and triethylamine (1.32 ml, 9.48 mmol).
Was added, and the mixture was stirred at room temperature for 1 hour and 30 minutes, and then heated and refluxed for 35 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and ethyl acetate was added to the obtained residue, followed by washing with a 5% aqueous citric acid solution, a saturated aqueous sodium carbonate solution, and a saturated saline solution. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3).
-Benzyloxycarbonyl-3-[(1S, 2S)-
2-tert-butoxycarbonylaminocyclopropyl]
Pyrrolidine (isomer B ¹ ; 950.3 mg, 41.7)
%) As a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.20-0.35
(1H, m), 0.75-0.90 (1H, m), 0.
90-1.00 (1H, m), 1.40 (9H, s),
1.70-1.85 (2H, m), 1.95-2.10
(1H, m), 2.60-2.70 (1H, m), 3.
15-3.25 (1H, m), 3.30-3.40 (1
H, m), 3.50-3.70 (2H, m), 4.50
-4.65 (1H, brs), 5.05-5.15 (2
H, m), 7.25-7.40 (5H, m). [Α] _D ²³ +36.820 (c = 1.950, CH
Cl ₃ ). [Reference Example DD]

3-[(1S, 2S) -2-tert. Butoki
Cicarbonylaminocyclopropyl] pyrrolidine (isomer
Form B ¹ ) 1-benzyloxycarbonyl-3-[(1S, 2S)
-2-tert-butoxycarbonylamino-cyclopropyl] pyrrolidine (isomer ^B 1; ^911.3mg, 2.5
5% palladium on carbon (900 mg) was added to an ethanol solution (25 ml) of 3 mmol), and the mixture was added under a stream of hydrogen (4.5).
kg / cm ² ) for 1 hour and 30 minutes. Further, 5% palladium carbon (100 mg) was added, and the mixture was added under a hydrogen stream (4.
(0 kg / cm ² ) for 1 hour. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure to give 1-benzyloxycarbonyl-.
3-[(1S, 2S) -2-tert-butoxycarbonylaminocyclopropyl] pyrrolidine (isomer B ¹ ; 57
2.2 mg, quant) as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 0.20-0.30
(1H, m), 0.80-1.00 (2H, m), 1.
45 (9H, s), 1.65-1.85 (2H, m),
2.00-2.10 (1H, m), 2.60-2.70
(1H, m), 2.80-2.95 (1H, m), 2.
95-3.10 (1H, m), 3.15-3.25 (2
H, m), 4.75-4.95 (1H, m).

[0106]

[Table 2]

[0107]

The compound of the present invention exhibits excellent activity and safety and is useful as an antibacterial agent.

──────────────────────────────────────────────────の Continuation of the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical display location A61K 31/47 ADZ A61K 31/47 ADZ C07D 471/04 114 C07D 471/04 114A 498/06 498 / 06 513/06 513/06 (72) Inventor Yohei Ishida 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo Inside Daiichi Pharmaceutical Co., Ltd. Tokyo R & D Center

Claims (26)

[Claims] 1. A compound represented by the following formula (I), a salt thereof, and a hydrate thereof: In the formula, R ¹ and R ² each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, wherein the alkyl group is a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms and It may have, as a substituent, one or more groups selected from the group consisting of alkoxyl groups having 1 to 6 carbon atoms, n represents an integer of 1 to 3, and Q represents the following formula: It is a partial structure to be performed. Embedded image [Wherein, R ³ 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 which may have a substituent. A cyclic alkyl group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an alkoxyl group having 1 to 6 carbon atoms, or an alkylamino group having 1 to 6 carbon atoms. R ⁴ represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms, and R ⁴ and R ³ are integrated so as to form a cyclic structure including a part of the mother nucleus. The ring formed here may include a sulfur atom as a ring constituent atom,
Further, this ring may have an alkyl group having 1 to 6 carbon atoms as a substituent. R ⁵ represents a hydrogen atom, an amino group, a hydroxyl group, a thiol group, a halogenomethyl group,
To 6 alkyl groups, alkenyl groups having 2 to 6 carbon atoms,
An alkynyl group having 2 to 6 carbon atoms or 1 to 6 carbon atoms
Wherein the amino group is at least one group 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 as a substituent. X ¹ represents a halogen atom or a hydrogen atom, and A represents a nitrogen atom or a compound represented by the formula (II): (Wherein, X ² represents a hydrogen atom, an amino group, a halogen atom,
Cyano group, halogenomethyl group, halogenomethoxyl group,
Represents 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, of which an amino group is a formyl group, It may have as a substituent one or more groups selected from the group consisting of an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms. Further, X ² and R ³ may be integrated so as to form a cyclic structure including a part of the mother nucleus, but the ring formed here is an oxygen atom, a nitrogen atom or a sulfur atom. May be included as a constituent atom of the ring, and the ring may further have an alkyl group having 1 to 6 carbon atoms as a substituent. ) Represents a partial structure.
Y represents a hydrogen atom, a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a 5-alkyl-2-oxo-1, 3-dioxol-4-ylmethyl group, 3-acetoxy-2-
An oxobutyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms, or 1 to 6 carbon atoms
Represents a phenylalkyl group composed of an alkylene group and a phenyl group. And the following two groups present on the cyclopropane ring: And Is a cis configuration. ｝ 2. In the formula (I), Q is a compound represented by the formula: (Wherein, R ³ , R ⁴ , R ⁵ , A, X ¹ , X ² and Y are the same as defined above). The compound according to claim 1, which is a compound having a structure represented by the following formula: Compounds, their salts, and their hydrates 3. In the formula (I), Q represents 6-carboxy-9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1,2,3-de ]
The compound according to claim 1 or 2, which is a [1,4] benzoxazin-10-yl group, a salt thereof, and a hydrate thereof. 4. In the formula (I), Q is 8-amino-6
-Carboxy-9-fluoro-2,3-dihydro-3-
(S) -methyl-7-oxo-7H-pyrido [1,2,
The compound according to claim 1 or 2, which is a 3-de] [1,4] benzoxazin-10-yl group, a salt thereof, and a hydrate thereof. 5. In the formula (I), Q is 5-amino-3
-A carboxy-6-fluoro-1- [2- (S) -fluoro-1- (R) -cyclopropyl] -1,4-dihydro-8-methoxy-4-oxoquinolin-7-yl group. Item 7. The compound according to item 1 or 2, a salt thereof, and a hydrate thereof. 6. In the formula (I), Q is 5-amino-3
-A carboxy-6-fluoro-1- [2- (S) -fluoro-1- (R) -cyclopropyl] -1,4-dihydro-8-methyl-4-oxoquinolin-7-yl group. Item 7. The compound according to item 1 or 2, a salt thereof, and a hydrate thereof. 7. In the formula (I), Q is 3-carboxy-6-fluoro-1- [2- (S) -fluoro-1-
(R) -cyclopropyl] -1,4-dihydro-8-methoxy-4-oxoquinolin-7-yl group, the compound according to claim 1 or 2, a salt thereof, and a hydrate thereof. 8. The method of claim 1, wherein n is 2.
The compound according to 5, 6, or 7, a salt thereof, and a hydrate thereof 9. The compound according to claim 1, 2, 3, 4, 5, 6, 7, or 8, wherein the substituents R ¹ and R ² are both hydrogen atoms, a salt thereof, and a compound thereof. Hydrate 10. The compound according to claim 1, 2, 8, or 9, wherein the substituent R ³ is a halogenocyclopropyl group, a salt thereof, and a hydrate thereof. 11. The compound according to claim 1, 2, 8, or 9, wherein the substituent R ³ is a 1,2-cis-2-halogenocyclopropyl group, a salt thereof, and a hydrate thereof. 12. The compound according to claim 1, 2, 8, 9, 10, or 11, wherein the substituent R ³ is a stereochemically single group, a salt thereof, and a hydrate thereof. 13. The method according to claim 13, wherein the substituent R ³ is (1R, 2S) -2-
The compound according to claim 1, 2, 8, or 9, which is a halogenocyclopropyl group, a salt thereof, and a hydrate thereof. 14. When the substituent R ³ is (1R, 2S) -2-
Claims 1, 2, 8, which are fluorocyclopropyl groups.
The compound according to 9, 10, or 11, a salt thereof, and a hydrate thereof 15. The compound according to claim 1, 2, 8, 9, 10, 11, 12, 13, or 14, wherein the substituent X ¹ is a halogen atom, a salt thereof, and a hydrate thereof. 16. The compound according to claim 1, 2, 8, 9, 10, 11, 12, 13, 14, or 15, wherein the substituent X ¹ is a fluorine atom, a salt thereof, and a hydration thereof. Stuff 17. The compound according to claim 1, wherein the compound of formula (I) is a stereochemically single compound.
The compound according to 8, 9, 10, 11, 12, 13, 14, 15, or 16, a salt thereof, and a hydrate thereof 18. A compound of the formula: 5-amino-7- {3-[(1S, 2
S) -2-Aminocyclopropyl] -1-pyrrolidinyl} -6-fluoro-1-[(1R, 2S) -2-fluorocyclopropyl] -8-methyl-1,4-dihydro-4-oxoquinoline- 3-carboxylic acids, their salts, and their hydrates 19. A medicament comprising the compound according to claim 1, a hydrate thereof, a salt of the compound, or a hydrate of the salt thereof as an active ingredient. 20. An antibacterial agent comprising the compound according to claim 1 to 18, a hydrate thereof, a salt of the compound, or a hydrate of the salt as an active ingredient. 21. A compound represented by the following formula, a salt thereof, and a hydrate thereof: (Wherein, R ¹ and R ² each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, wherein the alkyl group is a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms and It may have, as a substituent, at least one group selected from the group consisting of alkoxyl groups having 1 to 6 carbon atoms, and one of R ¹ and R ² is a protecting group for an amino group, N represents an integer of 1 to 3, and Q ′ represents a protecting group for an amino group or a hydrogen atom, and a group existing on a cyclopropane ring. And the group Is a cis configuration. ) 22. The protecting group for an amino group is a group selected from the group consisting of an alkoxycarbonyl group, an aralkyloxycarbonyl group, an acyl group, an alkyl group, an aralkyl group and a substituted silyl group. 22. The compound according to claim 21, a salt thereof, and a hydrate thereof. 23. The protecting group for an amino group may be a tertiary butoxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, a benzyloxycarbonyl group, a paramethoxybenzyloxycarbonyl group, a paranitrobenzyloxycarbonyl group, or acetyl. Group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, formyl group, benzoyl group, tertiary butyl group, benzyl group, paranitrobenzyl group, paramethoxybenzyl group, triphenylmethyl group, methoxymethyl Group, tertiary butoxymethyl group, tetrahydropyranyl group, 2,2,2
A protecting group selected from the group consisting of 2-trichloroethoxymethyl group, trimethylsilyl group, isopropyldimethylsilyl group, tertiary butyldimethylsilyl group, tribenzylsilyl group, and tertiary butyldiphenylsilyl group. 21. The compound according to 21 or 22, a salt thereof, and a hydrate thereof. 24. ^One of R ¹ and R ² and Q ′
Is a protecting group for an amino group and is not the same protecting group, the compound according to claim 21, 22, or 23, a salt thereof, and a hydrate thereof. 25. The compound according to claim 21, 22, 23 or 2 wherein the compound of formula (VI) is a stereochemically single compound.
4. The compound according to 4, a salt thereof, and a hydrate thereof. 26. 1-benzyloxycarbonyl-3-
[(1S, 2S) -2-tert-butoxycarbonylaminocyclopropyl] pyrrolidine, salts thereof and hydrates thereof