JPH07278139A - New quinolonecarboxylic acid derivative and its production - Google Patents

Abstract

PURPOSE: To provide new derivatives which have a wide range of strong antibacterial activity and are effective against quinoline resistant microorganisms such as methicillin-resistant Staphylococcus aureus.

CONSTITUTION: These derivatives (salts) are represented by formula I [wherein X is N or C-Y (wherein Y is H, F, methoxy or the like); R₁ is a 1-6C alkyl which may substituted with a halogen or OH, an alkynyl or the like; R₂ is H, a carboxy protective group or the like; R₃ and R₄ are each H, a lower alkyl or the like; Z is H, a halogen or the like; and n is 1-3] and include, e.g. 7-{6-amino-3-azabicyclo[3,3,0]octa-1(5)en-3-yl}-1-cyclopropyl-6,8-difluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid. The derivatives can be obtained, e.g. by reacting a compound of formula II (wherein L is F, Cl, methanesulfonyl or the like) with a compound of formula III.

COPYRIGHT: (C)1995,JPO

Description

Detailed Description of the Invention

The present invention relates to a novel quinolonecarboxylic acid derivative substituted at the 7-position of quinolone or at the 10-position of pyridobenzoxazine and a pharmaceutically acceptable salt thereof, which has a broad spectrum of potent antibacterial activity. And a novel method for producing these compounds.

[0002] Enoxacin, norfloxacin, ofloxacin,
Quinolones such as ciprofloxacin, tosufloxacin, etc. have sometimes been commercially available. However, most of these prior art materials are known to have relatively weak antibacterial activity, especially against Gram-positive bacteria, and it has been found that there are microorganisms resistant to these agents. There is.

Therefore, it has a wide range of potent antibacterial activities and is resistant to quinolones, such as clinically important methicillin-resistant staphylococcus aureus (MRS).
There was a need to develop new medicinal compounds that were effective against A).

Unexpectedly, the inventors of quinolone 7
It has been found that certain quinolonecarboxylic acid derivatives substituted at the -position or at the 10-position of pyridobenzoxazine meet the above requirements.

Therefore, the present invention is mainly concerned with these novel quinolone compounds and their pharmaceutically acceptable salts,
It also relates to new processes for producing these compounds.

The novel quinolone compound of the present invention has the following formula (I)

[Chemical formula 23] [Wherein X is a nitrogen atom or a C—Y group (wherein Y is a hydrogen, fluorine, chlorine or bromine atom, or a methoxy or methyl group); R ₁ is a halogen atom or a hydroxy group as the case may be. Substituted C ₁ ~
A C ₆ -alkyl group, an alkenyl group, a C ₃ -C ₆ -cycloalkyl group, a phenyl group substituted with a halogen atom, or a nitrogen atom bonded to R ₁ and X (where X is C—Y); taken together -OCH ₂ to form the oxazine or thiazine ring _{C (*) H (CH 3} ) -, - SCH 2 C
(*) H ₂ — or —SCH ₂ C (*) H (CH ₃ ) — is a divalent group; R ₂ is a hydrogen atom, a carboxy protecting group or a pharmaceutically acceptable metal or organic cation. ; R
₃ and R ₄ are the same or different and each is a hydrogen atom, a lower alkyl group, an acyl group or a nitrogen protecting group which can be metabolized in vivo; Z is a hydrogen or halogen atom, an amino, hydroxy or methyl group; and n is 1 Is ~ 3].

The compounds of formula (I) include their acid or base addition salts and hydrates. In the definition of R ₁ , C ₁ ~
C ₆ - alkyl group is preferably methyl, ethyl, n- propyl, isobutyl, t- butyl, n- pentyl or n- hexyl group, more preferably ethyl or t
A butyl group; a C ₁ -C ₆ -haloalkyl group is preferably a C ₂ -C ₄ -alkyl group substituted by a fluorine atom, for example a 2-fluoroethyl group; a C ₁ -C ₆ -hydroxyalkyl group is preferably be a C ₂ -C ₄ hydroxyalkyl group such as 2-hydroxyethyl group; C ₃ -C ₆ - cycloalkyl group is preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, more preferably cyclopropyl group; Alkenyl groups are preferably vinyl, isopropenyl, propenyl or isobutenyl groups; phenyl groups substituted by halogen atoms are preferably phenyl groups substituted by 1 or 2 fluorine atoms, more preferably 4-fluorophenyl or 2,4-difluorophenyl group; and -OCH _{2
C (*) H (CH 3} ) - or _{-SCH 2 C (*) H (} CH 3) -
The stereochemical configuration of the asymmetric atoms of the group may be (R), (S) or a combination thereof.

In the definition of R ₂ , a carboxy protecting group is easily an ester moiety, eg methyl, ethyl, n-, which can be hydrolyzed to give the free carboxylic acid.
Lower alkyl groups such as propyl or t-butyl groups; lower alkanoyloxy-lower alkyl groups such as acetoxymethyl or pivaloyloxymethyl groups;
Lower alkoxycarbonyloxy-lower alkyl group such as methoxycarbonyloxymethyl or 1-ethoxycarbonyloxyethyl group; lower alkoxymethyl group such as methoxymethyl group; di (lower alkyl) amino such as 1-dimethylaminoethyl group A lower alkyl group, or a 4-methylene-5-methyl-1,3-dioxolen-2-one group; and a pharmaceutically acceptable metal or organic cation is an alkali metal alkaline earth metal such as sodium, potassium, Silver, calcium or magnesium cations, or organic cations such as tertiary or quaternary C ₁ -C ₄ -alkylammonium cations.

In the definition of R ₃ and R ₄ , the lower alkyl group is preferably a methyl, ethyl, propyl or butyl group, more preferably the methyl or ethyl group; the acyl group is preferably an acetyl, propionyl or benzoyl group. And the in vivo metabolizable nitrogen protecting group is preferably a formyl, alkoxycarbonyl, alkylcarbonylmethylene, alkoxycarbonylmethylene or 4-methylene-5-methyl-1,3-dioxolen-2-one group.

In the definition of Z, the halogen atom is preferably a fluorine atom. In the definition of n, n is preferably 2 or 3. The stereochemical configuration of the 7-position substituted azabicycloamine of the compound of formula (I) is (R),
It may be (S) or a combination thereof.

Among the compounds of the present invention, 7- [6-amino-3-azabicyclo [3,3,0] octa-1 (5) en-3-yl] -1-cyclopropyl-6,8-difluoro. -1,4-dihydro-4-oxoquinoline-3-carboxylic acid or its hydrochloride or its lactate; 1-cyclopropyl-6,8-difluoro-7- [6-methylamino-3-azabicyclo [3, 3,0] octa-1 (5) en-3-yl] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid; 7- [6-amino-3-azabicyclo [3,3,0] Octa-1 (5) en-3-yl]-
1-cyclopropyl-8-chloro-6-fluoro-1,
4-dihydro-4-oxoquinoline-3-carboxylic acid or its hydrochloride or its lactate; 7- [6-methylamino-3-azabicyclo [3,3,0] octa-1 (5)
En-3-yl] -8-chloro-1-cyclopropyl-
6-Fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid; 7- [6-amino-3-azabicyclo [3,3,0] octa-1 (5) en-3-yl]- 8
-Bromo-1-cyclopropyl-6-fluoro-1,4
-Dihydro-4-oxoquinoline-3-carboxylic acid;

7- [6-amino-3-azabicyclo [3,3,0] oct-1 (5) en-3-yl] -1-
Cyclopropyl-6-fluoro-8-methoxy-1,4
-Dihydro-4-oxoquinoline-3-carboxylic acid; 1
-Cyclopropyl-6-fluoro-7- [6-methylamino-3-azabicyclo [3,3,0] octa-1 (5)
En-3-yl] -1,4-dihydro-4-oxo-1,
8-naphthyridine-3-carboxylic acid; 7- [6-amino-3-azabicyclo [3,3,0] octa-1 (5) en-3-yl] -6,8-difluoro-1-ethyl-1 , 4
-Dihydro-4-oxoquinoline-3-carboxylic acid; 7
-[6-amino-3-azabicyclo [4,3,0] nona-
1 (6) en-3-yl] -1-cyclopropyl-6,
8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid; 7- [6-amino-3-azabicyclo [3,3,0] octa-1 (5) en-3-yl]-
5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

7- [6-methylamino-3-azabicyclo [3,3,0] octa-1 (5) en-3-yl] -5
-Amino-1-cyclopropyl-6,8-difluoro-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid; 7- [6-amino-3-azabicyclo [3,3,0]
Octa-1 (5) en-3-yl] -1- (2,4-difluorophenyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid; 7- [6-
Methylamino-3-azabicyclo [3,3,0] octa
1 (5) en-3-yl] -1- (2,4-difluorophenyl-6,8-difluoro-1,4-dihydro-4-
Oxoquinoline-3-carboxylic acid; 7- [6-amino-
3-azabicyclo [3,3,0] octa-1 (5) ene-
3-yl] -1-cyclopropyl-6-fluoro-1,
4-dihydro-4-oxo-1,8-naphthyridine-3
-Carboxylic acid; 7- [6-methylamino-3-azabicyclo [3,3,0] oct-1 (5) en-3-yl]-
1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid;

9-Fluoro-7- [6-amino-3-azabicyclo [3,3,0] octa-1 (5) en-3-yl] -3- (S) -methyl-7-oxo-2 , 3-Dihydro-7H-pyrido [1,2,3-de] -1,4-benzoxazine-6-carboxylic acid; 9-fluoro-7- [6-
Methylamino-3-azabicyclo [3,3,0] octa
1 (5) en-3-yl] -3- (S) -methyl-7-
Oxo-2,3-dihydro-7H-pyrido [1,2,3-
De] -1,4-benzoxazine-6-carboxylic acid; 7-
[6-amino-3-azabicyclo [3,3,0] octa-
1 (5) en-3-yl] -1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid; 7- [6-methylamino-3-azabicyclo [3,3] , 0] octa-1 (5) en-3-yl] -1-
Ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid; 7- [6-amino-3-azabicyclo [3,3,0] octa-1 (5) en-3-yl ] -1-Ethyl-6-fluoro-1,4-dihydro-
4-oxoquinoline-3-carboxylic acid;

7- [6-methylamino-3-azabicyclo [3,3,0] octa-1 (5) en-3-yl] -1
-Ethyl-6-fluoro-8-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid; 7- [6-
Amino-3-azabicyclo [3,3,0] octa-1
(5) En-3-yl] -1-ethyl-5-amino-
6,8-Difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid; 7- [6-methylamino-3-
Azabicyclo [3,3,0] octa-1 (5) ene-3-
1-Ethyl-5-amino-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid; 7- [6-amino-3-azabicyclo [3,3,
0] octa-1 (5) en-3-yl] -1- (t-butyl) -6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid; 7- [6- Methylamino-3-azabicyclo [3,3,0] octa-1 (5) en-3-yl] -1- (t-butyl) -6,8-difluoro-1,4-dihydro-4-oxoquinoline -3-carboxylic acid;

7- [6-amino-3-azabicyclo [3,3,0] oct-1 (5) en-3-yl] -1-
(T-Butyl) -6-fluoro-8-chloro-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid; 7-
[6-Methylamino-3-azabicyclo [3,3,0] oct-1 (5) en-3-yl] -1- (t-butyl)
-6-Fluoro-8-chloro-1,4-dihydro-4-
Oxoquinoline-3-carboxylic acid; 7- [6-amino-
3-azabicyclo [3,3,0] octa-1 (5) ene-
3-yl] -1- (4-fluorophenyl) -6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid; 7- [6-amino-3-azabicyclo [3,
3,0] octa-1 (5) en-3-yl] -1- (4
-Fluorophenyl) -6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid; 7-
[6-methylamino-3-azabicyclo [3,3,0] octa-1 (5) en-3-yl] -1- (4-fluorophenyl) -6,8-difluoro-1,4-dihydro- Four
-Oxoquinoline-3-carboxylic acid;

7- [6-amino-3-azabicyclo [3,3,0] oct-1 (5) en-3-yl] -1-
Ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid; 7- [6-
Methylamino-3-azabicyclo [3,3,0] octa
1 (5) en-3-yl] -1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid; 7- [6-amino-3-azabicyclo [3,3,0] octa-1 (5) en-3-yl] -1
-(T-butyl) -6-fluoro-1,4-dihydro-
4-oxoquinoline-3-carboxylic acid; 7- [6-methylamino-3-azabicyclo [3,3,0] octa-1
(5) En-3-yl] -1- (t-butyl) -6-fluoro-1,4-dihydro-4-oxoquinoline-3-
Carboxylic acid 7- [6-acetamino-3-azabicyclo [3,3,0] octa-1 (5) en-3-yl] -1
-Cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid; and 7-
[6-t-Butoxycarbonylamino-3-azabicyclo [3,3,0] octa-1 (5) en-3-yl] -1
-Cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid methoxymethyl ester is preferred.

More preferably, 7- [6-amino-3-
Azabicyclo [3,3,0] octa-1 (5) ene-3-
Il] -1-cyclopropyl-6,8-difluoro-1,
4-dihydro-4-oxoquinoline-3-carboxylic acid or its hydrochloride or its lactate; 1-cyclopropyl-6,8-difluoro-7- [6-methylamino-3-
Azabicyclo [3,3,0] octa-1 (5) ene-3-
Il] -1,4-dihydro-4-oxoquinoline-3-
Carboxylic acid; 7- [6-amino-3-azabicyclo [3,3,0] octa-1 (5) en-3-yl] -1-
Cyclopropyl-8-chloro-6-fluoro-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid or its hydrochloride or its lactate; 7- [6-methylamino-3-azabicyclo [3,3,0] octa-1 (5) en-3-yl] -8-chloro-1-cyclopropyl-6-
Fluoro-1,4-dihydro-4-oxoquinoline-3
-Carboxylic acid; 7- [6-amino-3-azabicyclo [3,3,0] oct-1 (5) en-3-yl] -1-
Cyclopropyl-6-fluoro-8-methoxy-1,4
-Dihydro-4-oxoquinoline-3-carboxylic acid;

7- [6-methylamino-3-azabicyclo [3,3,0] octa-1 (5) en-3-yl] -1
-Cyclopropyl-6-fluoro-1,4-dihydro-
4-oxo-1,8-naphthyridine-3-carboxylic acid;
7- [6-amino-3-azabicyclo [3,3,0] octa-1 (5) en-3-yl] -5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro -4
-Oxoquinoline-3-carboxylic acid; 7- [6-amino-3-azabicyclo [3,3,0] oct-1 (5) en-3-yl] -1-cyclopropyl-6-fluoro-
1,4-dihydro-4-oxoquinoline-1,8-naphthyridine-3-carboxylic acid; 9-fluoro-10- [6-
Amino-3-azabicyclo [3,3,0] octa-1
(5) En-3-yl] -3- (S) -methyl-7-oxo-2,3-dihydro-7H-pyrido (1,2,3-
De] -1,4-benzoxazine-6-carboxylic acid;

9-Fluoro-10- [6-methylamino-3-azabicyclo [3,3,0] oct-1 (5) en-3-yl] -3- (S) -methyl-7-oxo- Two,
3-dihydro-7H-pyrido (1,2,3-de] -1,4
-Benzoxazine-6-carboxylic acid; 7- [6-amino-3-azabicyclo [3,3,0] oct-1 (5) en-3-yl] -1- (t-butyl) -6-fluoro-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid; 7- [6-t-butoxycarbonylamino-3-azabicyclo [3,3,0] octa-1 (5) en-3-yl]- 1-cyclopropyl-6,8-difluoro-1,4
-Dihydro-4-oxoquinoline-3-carboxylic acid.

The quinolone compound of the present invention can be represented by the formula (I), and its pharmaceutically acceptable salt can be prepared as follows.

Step A

[Chemical formula 24] (In the formula, R ₁ , R ₃ , R ₄ , X, Z and n are as defined above; R ₂ is a hydrogen atom or a carboxy protecting group; L is a fluorine, chlorine or bromine atom, methanesulfonyl. Or a leaving group which is a para-toluenesulfonyl group; and A is hydrochloric acid, bromic acid, sulfuric acid or trifluoroacetic acid)

According to the above step A, the quinolone compound of formula (I) wherein R ₂ is a hydrogen atom or a carboxy protecting group (hereinafter referred to as the compound of formula (Ia)) is obtained by converting the compound of formula (II) into the compound of formula (III) Alternatively, it can be produced by reacting the compound of (IIIa) in the presence of a base.

Compounds of formula (II) are well known in the art, and compounds of formula (III) are new and can be prepared according to the methods described below.

The above reaction is carried out in an inert solvent such as methanol, ethanol, isopropanol, acetonitrile,
In the presence of pyridine, dimethylformamide, dimethylsulfoxide, dioxane, etc. or mixtures thereof, 1
10 at a temperature of 0 to 200 ° C., preferably 50 to 120 ° C.
It can be done from minutes to 24 hours.

To neutralize the acid formed in the above reaction, for example, triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo [5,4,0]
Bases such as undec-7-ene or alkali metal or alkaline earth metal carbonates can be used.

The compound of formula (Ia) obtained in step A wherein R ₂ is a hydrogen atom (hereinafter referred to as compound of formula (Ia-1)) is prepared according to the following step B and R ₂ is a carboxy protecting group. It can be converted into a compound of formula (Ia) (hereinafter referred to as a compound of formula (Ia-2)).

Step B

[Chemical 25] Where R ₁ , R ₃ , R ₄ , Z, X and n are as defined above; Hal is a chlorine, bromine or iodine atom; and R ₂ is a lower alkyl group such as methyl,
Ethyl, n-propyl or t-butyl group, lower alkanoyloxy-lower alkyl group such as acetoxymethyl or pivaloyloxymethyl group, lower alkoxycarbonyloxy-lower alkyl group such as methoxycarbonyloxymethyl or 1-ethoxycarbonyloxyethyl group , A lower alkoxymethyl group such as a methoxymethyl group, a di (lower alkyl) amino-lower alkyl group such as a dimethylaminoethyl group, or 4-methylene-
5-methyl-1,3-dioxolen-2-one group)

According to step B above, the compound of formula (Ia-2) is obtained by reacting the compound of formula (Ia-1) with a compound of formula R ₂ -Hal in an inert solvent such as haloalkane or dimethylformamide and a base such as diisopropylethylamine. It can be produced by reacting in the presence.

The compound of formula (Ia-1) obtained in step A can be prepared according to the following step C by a compound of formula (Ia) wherein R ₂ is a pharmaceutically acceptable metal or organic cation (hereinafter
It can be converted to a compound of formula (Ia-3).

Step C

[Chemical formula 26] Where R ₁ , R ₃ , R ₄ , Z, X and n are as defined above, and R ₂ is a pharmaceutically acceptable metal or organic cation.

According to Step C above, the compound of formula (Ia-3) is prepared by dissolving the compound of formula (Ia-1) in a lower alcohol or haloalkane solvent; to which is added the R ₂ -donor in water or lower alcohol. And can be produced by collecting the formed precipitate or removing the solvent.

The R ₂ -donor used in the above reaction may be sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, silver nitrate or an organic cationic compound.

The compound of formula (Ia-3) may further include its hydrate. The compound of formula (Ia) obtained in step A wherein R ₄ is a hydrogen atom (hereinafter referred to as compound of formula (Ia-4)) is prepared by the following step D except that R ₄ is a hydrogen atom. Can be converted to a compound of formula (Ia) as defined for formula (Ia) (hereinafter referred to as compound of formula (Ia-5)).

Process D

[Chemical 27] (In the formulae, R ₁ , R ₂ , R ₃ , Z, X and n are represented by the formula (Ia)
And R ₄ is as defined in formula (Ia) except for a hydrogen atom).

[0036] R ₄ in accordance with the above process D, the formula (Ia-5) compounds of the formula (Ia-4) a compound of formula R ₄ -Hal (wherein, Hal is chlorine, bromine or iodine atom)
-Donor and base such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5,4,0]
It can be produced by reacting in the presence of undec-7-ene, sodium hydride, potassium hydride, calcium hydride or an alkali metal carbonate.

The above steps are particularly advantageous when R ₃ is a hydrogen atom or an alkyl group and R ₄ is a nitrogen protecting group which can be metabolized in vivo.

When R ₄ is a formyl group, the formula (Ia-
The compound of 4) is reacted with acetic anhydride or sodium acetate in formic acid; and 2 to ₄ when R ₄ is an acyl group.
Reaction with an acid anhydride or halide having 1 carbon atom in the presence of a base such as triethylamine or pyridine.

The compounds of formula (Ia) are inorganic or organic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, acetic acid, formic acid, furupionic acid, lactic acid, maleic acid, malonic acid, fumaric acid, tartaric acid, citric acid. It can be converted into acid addition salts with acids, ascorbic acid, glutamic acid, paratoluenesulfonic acid, and the like; and hydrates thereof.

The above conversion reaction involves dissolving a compound of formula (Ia) in a solvent such as a lower alcohol such as methanol or ethanol, or a haloalkane such as chloroform, dichloromethane or dichloroethane; an aqueous or alcoholic organic or inorganic acid of interest. By adding a sex solution; and collecting the precipitate formed therefrom, or removing the solvent.

The invention further includes pharmaceutical compositions containing one or more compounds of formula (I) and non-toxic inert excipients.

The compounds according to the invention can be administered topically, orally, parenterally or enterally, preferably intravenously or intramuscularly. In general, it has been found to be advantageous to administer the compounds of the invention in single or divided doses in an amount of about 0.5 to 500, preferably 1 to 100 mg / kg body weight per day. About 1
Dosages in the range of ˜200 mg / kg body weight, especially 1 to 50 mg / kg body weight are preferred. However, the actual amount of compound administered will depend on relevant environmental factors such as formulation form, selected route of administration, individual patient age, weight and response (re
It will be understood that it can be adjusted in terms of sponse), as well as the degree of symptom of the patient.

The one or more compounds of the present invention may be administered neat or they may be non-toxic, inert pharmaceutically acceptable excipients such as solid, semi-solid or liquid diluents, It can be formulated for administration by mixing with fillers and carriers. Examples of such formulations are tablets, troches, capsules, granules, suppositories, solutions, suspensions, emulsions, pastes, ointments, creams,
It is in the form of lotion, powder, spray and the like.

In the case of tablets, troches, capsules and granules, the active compounds of the present invention may be formulated with conventional excipients such as fillers and fillers such as starch, lactose, sucrose, glucose mannitol and the like; carboxymethylcellulose, alginic acid. Binders such as salts, gelatin, polyvinylpyrrolidone etc .; disintegrators such as calcium carbonate, sodium bicarbonate etc .; absorption enhancers such as quaternary ammonium compounds etc .; wetting such as cetyl alcohol, glycerin monostearate etc. Agents; adsorbents such as kaolin, bentonite and the like; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol and the like or mixtures thereof. Tablets, troches, capsules, pills and granules can be coated with conventional coatings such as any opacifier.

Suppositories include, in addition to the active compound, conventional soluble or insoluble excipients such as polyethylene glycol, fats,
It may contain polymeric esters or mixtures thereof.

Ointments, pastes, creams and the like include, in addition to the active compound, conventional excipients such as animal or vegetable fats, waxes, paraffins, starches, cellulose derivatives, polyethylene glycol, bentonite, talc,
It may contain zinc oxide or mixtures thereof.

Solutions or emulsions for oral administration include, in addition to the active compound, conventional excipients such as solvents, solubilizers and emulsifiers such as water, ethyl alcohol, benzyl benzoate,
It may contain propylene glycol, cottonseed oil, peanut oil, corn oil, olive oil, fatty esters such as glycerin, polyethylene glycol or sorbitan, or mixtures thereof.

Solutions, suspensions or emulsions for parenteral administration may contain sterile equal volume solutions or emulsions.
In particular, the suspension may contain excipients such as liquid diluents or suspending agents such as water, ethyl alcohol or propylene glycol.

The formulations contain about 0.1 to 9 of the active compounds according to the invention.
9.5% by weight, preferably 0.5-95% by weight, and further customary acceptable amounts of dyestuffs,
Preservatives, sweeteners and additives may be included.

The present invention also relates to unsaturated azabicycloamine compounds and processes for their preparation, more particularly unsaturated aza useful as intermediates for the preparation of quinolonecarboxylic acids, cephalosporin compounds and other related antibacterial compounds. The present invention relates to a bicycloamine compound, and a process for producing these novel compounds and salts thereof.

The unsaturated azabicycloamine compounds of the present invention, which have no stereoisomers with respect to their ring morphology, but which are in planar molecular form, have a variety of different properties, such as cetearosporine and quinolonecarboxylic acid derivatives, with improved activity. Useful for producing antibacterial compounds.

Accordingly, the present invention also relates to a novel azabicycloamine compound useful as an intermediate compound for producing such various effective antibacterial compounds, and a novel method for producing the same.

The present invention has the formula (I)

[Chemical 28] Wherein R is a hydrogen atom or a protecting group; R ₁ and R ₂ are the same or different and are hydrogen, optionally substituted lower alkyl, alkanoyl, optionally substituted benzoyl or naphthoyl, optionally Is a substituted alkoxycarbonyl, or an optionally substituted benzyloxycarbonyl; and n is an integer from 1 to 4) and an azabicycloamine compound and salts thereof.

In formula (I), the amine protecting group of R is benzenesulfonyl, paratoluenesulfonyl, methanesulfonyl, C ₁ -C ₄ -alkoxycarbonyl, benzyloxycarbonyl, paranitrobenzyloxycarbonyl, 2,2,2- Trichloroethoxycarbonyl, C ₁ ~
It may be C ₂₀ -alkanoyl, or optionally substituted benzoyl or naphthoyl; R ₁
Or R ₂ is optionally substituted lower alkyl such as C ₁ -C ₇ -alkyl, preferably C ₁ -C ₄ -alkyl, especially methyl or ethyl, alkanoy, preferably C ₁ -C ₁₈ -alkanoy, for example formyl. , Acetyl, propionyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, decanoyl, undecanoyl, palmitoyl, oleoyl, stearoyl and cyclohexanoyl, optionally substituted benzoyl or naphthoyl, optionally substituted alkoxycarbonyl, preferably the C ₁ -C ₄ - alkoxycarbonyl e.g. ethoxycarbonyl, and 2,2,2-trichloroethoxycarbonyl or benzyloxycarbonyl example Paranitorobe which is optionally substituted, It may be a benzyloxycarbonyl.

In another aspect, the invention features at least one
Acid addition salts of compounds of formula (I) in which the nitrogen atoms are basic nitrogens, which include inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, and organic acids such as formic acid, acetic acid, propionic acid , Methanesulfonic acid, trichloroacetic acid, trifluoroacetic acid, lactic acid, maleic acid, malonic acid,
Includes salts of fumaric acid, citric acid, tartaric acid, paratoluenesulfonic acid, benzenesulfonic acid, palmitic acid, oleic acid or stearic acid.

The method for preparing the compound of formula (Ia-1) is described in the following scheme (A).

[Chemical 29] (Wherein n is an integer from ₁ to ₄ ; R ₁₀ is a C ₁ -C ₄ -alkyl group; R ₃ is an amine protecting group such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, 2,2, 2-trichloroethoxycarbonyl, benzyloxycarbonyl, or paranitrobenzyloxycarbonyl; R ₄ has the meaning defined for R in formula (I), especially benzenesulfonyl, paratoluenesulfonyl, methanesulfonyl or C _1- C ₄ -alkoxycarbonyl; X is an iodine, bromine or chlorine atom, or an O-mesyl or O-tosyl group; and A
Is hydrochloric acid, hydrobromic acid, sulfuric acid or trifluoroacetic acid).

The compound of formula (IV) is a compound of formula (III) which comprises sodium azide together with a compound of formula (II) together with N-bromo (or chloro) succinimide as a free radical generator such as benzoyl peroxide or AIBN. It can be produced by heating in the presence of (azoisobutyronitrile)].

The compound of formula (V) is prepared by reacting the compound of formula (IV) with triphenylphosphine in the presence of tetrahydrofuran and a solvent of water; and thereafter the compound of formula (VI) is V) with an amine protecting agent such as di-t-butyl dicarbonate or methyl (or ethyl, trichloromethyl, benzyl or paranitrobenzyl) chloroformate and a base such as pyridine, triethylamine, sodium hydride, sodium hydroxide or carbonic acid. It is produced by reacting in the presence of potassium.

The compound of formula (VI) is reduced with an ester reducing agent such as diisobutylaluminum hydride to give a compound of formula (VII)
Of alcohol, which is then reacted with a halogenating agent such as phosphorus trichloride, phosphorus trifluoride, thionyl chloride or oxalyl, or with triphenylphosphine and carbon tetrachloride or carbon tetrabromide.

The compound of formula (IX) is obtained by converting the compound of formula (VIII) into an R ₄ imparting agent such as paratoluenesulfonamide, benzenesulfonamide, acetamide, benzamide, methanesulfonamide and urethane and a base such as sodium hydride, triethylamine or carbonic acid. It can be produced by reacting in the presence of potassium.

A compound of formula (IX) is heated in hydrochloric acid, sulfuric acid, hydrobromic acid or trifluoroacetic acid to give a compound of formula (Ia-1)
Can be used to prepare compounds of formula (I-1) by removing the amine protecting group in the presence of a base such as sodium hydroxide or sodium ammonia.

Compounds of formula (I) wherein R and R ₁ are hydrogen and R ₂ is lower alkyl (compounds I-2, I
a-2) is the following scheme (B)

[Chemical 30] (Wherein n, R ₁₀ , R ₂ , R ₃ and A are as defined above).

In scheme (B), the compound of formula (X) is obtained by reacting the compound of formula (III) with sodium acetate or silver acetate, and then deacetylating the compound of formula (X) to give a compound of formula (X) XI) is obtained.

A compound of formula (XII) may be tosylated or mesylated and then reacted with an amine compound which imparts R ₂ or by carrying out a Mitsunobu reaction.
To produce the compound of.

The nitrogen atom of formula (XII) is protected with an amine protecting agent by using the same method used for the preparation of compounds of formula (VI) to give formula (I-2) or (I
The compound of a-2) is produced by repeating the process for producing the compound of formula (I-1) or (Ia-1).

Further, a compound of formula (I) in which R and R ₁ are hydrogen and R ₂ is a lower alkyl group is represented by the following scheme (C)

[Chemical 31] (In the formula, n, R ₂ , R ₃ , R ₄ and A are as defined above).

In Scheme (C), a compound of formula (IX) is reacted with an alkyl halide in the presence of a strong base such as sodium hydride to give a compound of formula (XIV) from which the amine protecting groups R ₃ and R ₃ Formula (I-3) with ₄ removed
Alternatively, the compound (Ia-3) is produced.

Further, the compound of the formula (I) in which R ₁ is a methyl group is represented by the following scheme (D)

[Chemical 32] Wherein n, A, R ₂ and R ₃ are as defined above; and R ₆ is a (para) toluenesulfonyl or methanesulfonyl group, a compound of formula (XV) Is reduced in the presence of lithium aluminum hydride to give a compound of formula (XVI) and then R ₆
It can be manufactured by removing.

More specifically, a compound of formula (I) in which _one of R ₁ and R ₂ is a methyl group and the other is a hydrogen atom is represented by the following scheme (E)

[Chemical 33] Where n, A, R ₃ and R ₆ are as defined above; and R ₆ is a (para) toluenesulfonyl or methanesulfonyl group.

The compound of formula (I-5) or (Ia-5) is obtained by reducing R ₃ of the compound of formula (XVII) to a methyl group in the presence of lithium aluminum hydride to obtain a compound of formula (XVIII). , And then removing R ₆ .

The following examples serve to illustrate the synthesis of particular intermediates in more detail.

【Example】

Example 1 Synthesis of 3-Bromo-1-cyclopentene-1,2-dicarboxylic acid dimethyl ester To a solution of 18 g of 1-cyclopentene-1,2-dicarboxylic acid dimethyl ester dissolved in 180 ml of carbon tetrachloride. 4 g of N-bromosuccinimide (NBS) and 1.6 g of α, α-azobis (isobutyronitrile)
(AIBN) was added and the resulting mixture was refluxed for 5 hours. After the reaction mixture was filtered, the filtrate was concentrated under reduced pressure and produced by fractionating by silica gel column chromatography to obtain 18.8 g of the title compound as a yellow oily substance. Yield 73% MS m / z (relative intensity,%): 263 (M ⁺ , 43), 231 (23), 183 (10
0), 151 (63) ¹ H-NMR (CDCl ₃ , δ ppm): 2.45 (1H, m), 2.57 (1H, m),
2.7 (1H, m), 3.05 (1H, m), 3.73 (6H, s), 5.25 (1H, m)

Example 2 Synthesis of 3-azido-1-cyclopentene-1,2-dicarboxylic acid dimethyl ester 18 g of 3-bromo-dissolved in 200 ml of carbon tetrachloride.
To the solution of 1-cyclopentene-1,2-dicarboxylic acid dimethyl ester was added a solution of 15.6 g of sodium azide in 65 ml of water and the resulting solution was added to 1
Stir for 6 hours. The reaction solution was refluxed for 1 hour, cooled and the organic phase was separated. The remaining aqueous phase was extracted twice with carbon tetrachloride, then the organic phases were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 13.4 g of the title compound as a yellow oil. Yield 92% MS m / z (relative intensity,%): 226 (M ⁺ , 3.3), 187 (67), 151 (1
00), 138 (45), 106 (30), 93 (27), 68 (27) ¹ H-NMR (CDCl ₃ , δ ppm): 2.0 (1H, m), 2.4 (1H, m), 2.6
7 (1H, m), 2.9 (1H, m), 3.8 (6H, s), 4.77 (1H, m)

Example 3 Synthesis of 3-Amino-1-cyclopentene-1,2-dicarboxylic acid dimethyl ester 13.4 g of 3-azido-1-cyclopentene-1,2-dicarboxylic acid dissolved in 135 ml of tetrahydrofuran To the solution of dimethyl ester was added 15.5 g of triphenylphosphine and the resulting mixture was stirred under nitrogen gas for 16 hours.

After adding 1.6 ml of water, the reaction mixture is stirred at room temperature for 5 hours, concentrated under reduced pressure and the residue is taken to 25
It was dissolved in 0 ml of dichloromethane. 350 ml of reaction solution
Extracted with 2N hydrochloric acid, then the aqueous phase is separated and washed with 15% Na
It was neutralized with an aqueous OH solution.

The aqueous solution was extracted with 300 ml of dichloromethane, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5.9 g of the title compound as a pale yellow oil.
Yield 50% MS m / z (relative intensity,%): 199 (M ⁺ , 4), 184 (3.5), 152 (1
5), 140 (100), 108 (28), 80 (55) ¹ H-NMR (CDCl ₃ , δ ppm): 1.6 (2H, m), 2.4 (1H, m), 2.6
(1H, m), 2.75 (1H, m), 3.7 (1H, m), 3.73 (3H, s), 3.7
5 (3H, s), 4.2 (1H, m)

Example 4 Synthesis of 3- (Nt-butoxycarbonyl) amino-1-cyclopentene-1,2-dicarboxylic acid dimethyl ester 5.9 g 3-amino-dissolved in 80 ml methanol.
To a solution of 1-cyclopentene-1,2-dicarboxylic acid dimethyl ester was added 7.1 g di-t-butyl dicarboxylic acid and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and fractionated by silica gel column chromatography to obtain 8.42 g of the title compound as a white precipitate. Yield 95% MS m / z (relative intensity,%): 300 (M ⁺ , 28), 244 (88), 200 (3
8), 183 (49), 167 (53), 140 (46), 57 (100) ¹ H-NMR (CDCl ₃ , δ ppm): 1.4 (9H, s), 1.73 (1H, m), 2.
8-2.4 (3H, m), 3.74 (3H, s), 3.76 (3H, s), 4.76 (1H,
br.s), 5.03 (1H, br.s)

Example 5 3- (Nt-butoxycarbonyl) amino-1,2-
Synthesis of bis (hydroxymethyl) -1-cyclopentene A solution of 18 g of diisobutylaluminum hydroxide dissolved in 100 ml of anhydrous tetrahydrofuran was cooled to -78 ° C and then 9.4 g of 3-amino (N) dissolved in 90 ml of tetrahydrofuran. -T-butoxycarbonyl)
A solution of amino-1-cyclopentene-1,2-dicarboxylic acid dimethyl ester was added dropwise thereto over 1 hour.
The resulting solution was stirred for 2 hours and 9 ml of methanol and 3 ml of water were added cautiously thereto.

The reaction mixture was extracted with a 50% solution of methanol and dichloromethane (1: 1, v / v) and concentrated under reduced pressure to give 3.03 g of the title compound as a pale yellow oil. Yield 40% MS m / z (relative intensity,%): 243 (M ⁺ ) ¹ H-NMR (CDCl ₃ , δ ppm): 1.39 (9H, s), 1.45 (1H, m),
2.5 to 2.25 (3H, m), 4.03 (1H, m), 4.2 (4H, m), 4.68 (1
H, m)

Example 6 3- (Nt-butoxycarbonyl) amino-1,2-
Synthesis of bis (bromomethyl) -1-cyclopentene 3.03 g 3-amino (Nt-butoxycarbonyl) amino-1,2-dissolved in 30 ml dichloromethane.
A solution of bis (hydroxymethyl) -1-cyclopentene and 9.94 g of carbon tetrabromide was added dropwise to a solution of 9.8 g of triphenylphosphine in 20 ml of dichloromethane in a cold water bath over 10 minutes. The resulting solution was stirred in cold water for 30 minutes, concentrated under reduced pressure and the residue was dissolved in ethyl ether which was filtered to remove undissolved solids. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give 1.85 g of the title compound as a white precipitate. Yield 40% Melting point: 104 ° to 106 ° MS m / z (relative intensity,%): 369 (M ⁺ ), 312 (50), 253 (22), 2
34 (90), 188 (15), 152 (100), 108 (27), 91 (23), 57 (55) 1H-NMR (CDCl ₃ , δ ppm): 1.58 (9H, s), 1.65 (1H , m),
2.35 ~ 2.65 (3H, m), 4.03 (4H, m), 4.61 (1H, br.s), 4.
88 (1H, br.s)

Example 7 3- (Nt-butoxycarbonyl) amino-1,2-
Synthesis of bis (chloromethyl) -1-cyclopentene A solution of 3.03 g of 3-amino (Nt-butoxycarbonyl) -1,2-bis (hydroxymethyl) -1-cyclopentene dissolved in 30 ml of carbon tetrachloride. To 6.86
g triphenylphosphine, and the resulting mixture was refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure,
Fractionation by silica gel column chromatography gave 1.21 g of the title compound as a white precipitate. Yield 35% Melting point: 85 ° to 88 ° MS m / z (relative intensity,%): 377 (M ⁺ , 5), 222 (85), 187 (7
0), 163 (50), 152 (95), 127 (27), 91 (45), 57 (100) ¹ H-NMR (CDCl ₃ , δ ppm): 1.39 (9H, s), 1.6 (1H, m), 2.
4-2.6 (3H, m), 4.1 (4H, m), 4.5 (1H, br.s), 4.8 (1H,
br.s)

Example 8 6- (Nt-butoxycarbonyl) amino-3- (paratoluenesulfonyl) -3-azabicyclo [3,3,3
0] Octa-1 (5) ene Synthesis 1.85 g of 3-amino (Nt-butoxycarbonyl) amino-dissolved in 20 ml of dimethylformamide.
A solution of 1,2-bis (bromomethyl) -1-cyclopentene and 943 mg paratoluenesulfonamide was added to 500 mg sodium hydride (55-60%) in a cold water bath. The resulting mixture was stirred for 5 hours and 60 ml of water was added to it. The reaction solution was extracted with dichloromethane, concentrated under reduced pressure and purified by fractionation by silica gel column chromatography to give 950 mg of the title compound as a white precipitate. Yield 50% Melting point: 159 ° -160 ° C MS m / z (relative intensity,%): 378 (M ⁺ , 0.5), 321 (18), 260 (9
5), 234 (20), 167 (100), 155 (17), 106 (93), 91 (27), 8
0 (18), 57 (17) ¹ H-NMR (CDCl ₃ , δ ppm): 1.5 (9H, s), 1.88 (1H, m), 2.
09 (1H, m), 2.20 (1H, m), 2.44 (3H, s), 2.69 (1H, s),
3.99 (4H, br.s), 4.45 (1H, br.s), 4.56 (1H, br.s), 7.
31 (2H, d, J = 8Hz), 7.73 (2H, d, J = 8Hz)

Example 9 6-Amino-3-azabicyclo [3,3,0] octa-1
(5) Synthesis of enedihydrobromide 760 mg 6-amino (Nt-butoxycarbonyl) amino-3 dissolved in 2.6 ml 30% aqueous hydrogen bromide.
To a solution of-(paratoluenesulfonyl) -3-azabicycloocta-1 (5) ene was added 430 mg of phenol. The resulting mixture is refluxed for 5 hours and then 60
ml of water was added. The reaction mixture was washed with chloroform until the chloroform phase had no color. The aqueous phase was separated, decolorized by filtration using activated carbon and concentrated under reduced pressure. The residue was suspended in a solvent of ethanol and ethyl ether (1: 2, v / v) to obtain 330 mg of the title compound as a white precipitate. Yield 65% Melting point: 195 ° to 198 ° C MS m / z (relative intensity,%): 124 (M ⁺ , 7), 107 (100), 95 (3
3), 82 (53), 80 (90) ¹ H-NMR (CDCl ₃ , δ ppm): 2.1 ~ 2.8 (4H, m), 3.95 (2H,
s), 3.96 (2H, s), 4.29 (1H, m)

Example 10 6-Methylamino-3- (paratoluenesulfonyl)-
Synthesis of 3-azabicyclo [3,3,0] octa-1 (5) ene 100 mg 6-amino (Nt-butoxycarbonyl) -3- (paratoluenesulfonyl) -3-azabicyclo dissolved in 3 ml tetrahydrofuran. To a solution of [3,3,0] octa-1 (5) ene was added 23 mg of lithium aluminum hydride. Reflux the resulting mixture for 20 minutes,
Then 10 ml of methanol and 0.1 ml of water were added thereto. The reaction mixture was extracted with 50% solution of methanol / dichloromethane (1: 1, v / v), concentrated under reduced pressure and purified by fractionation by silica gel column chromatography to give 70 mg of the title compound as a white precipitate. Obtained. Yield 83% MS m / z (relative intensity,%): 292 (M ⁺ ) ¹ H-NMR (CDCl ₃ , δ ppm): 1.89 (1H, m), 2.13 (1H, m),
2.23 (1H, br.s), 2.24 (3H, s), 2.46 (1H, m), 2.52 (3H,
s), 3.66 (1H, br.m), 3.84 ~ 4.16 (4H, m), 7.27 (2H,
d, J = 8Hz), 7.63 (2H, d, J = 8Hz)

Example 11 Synthesis of 6-methylamino-3-azabicyclo [3,3,0] octa-1 (5) ene dihydrobromide 70 mg 6-methyl suspended in 0.2 ml hydrogen bromide. A solution of amino-3- (paratoluenesulfonyl) -3-azabicyclo [3,3,0] octa-1 (5) ene was refluxed for 5 hours and 10 ml of water was added to it. The reaction mixture was washed with chloroform until the chloroform phase had no color. The aqueous phase was separated, decolorized by filtration through activated carbon and concentrated under reduced pressure. The residue was suspended in a solvent of ethanol and ethyl ether (1: 2, v / v) to obtain 40 mg of the title compound as a white precipitate. Yield 55% MS m / z (relative intensity,%): 138 (M ⁺ , 7), 107 (100), 94 (1
8), 80 (55), 68 (12) ¹ H-NMR (CDCl ₃ , δ ppm): 2.2〜2.8 (4H, m), 2.51 (3H,
s), 3.96 (4H, m), 4.22 (1H, br.m)

Example 12 Of 6- (Nt-butoxycarbonyl-N-ethyl) amino-3- (paratoluenesulfonyl) -3-azabicyclo [3,3,0] octa-1 (5) ene Synthesis 1.89 g of 6-amino (Nt-butoxycarbonyl) -3- (paratoluenesulfonyl) -3-azabicyclo [3,3,3,3 dissolved in 20 ml of dimethylformamide.
0] octa-1 (5) ene solution in a nitrogen atmosphere at 28
0 mg of sodium hydride was added. The resulting mixture was stirred at room temperature for 2 hours and to it was added 850 mg of ethyl iodide. The reaction mixture was stirred for 5 hours, concentrated under reduced pressure and purified by fractionation by silica gel column chromatography to give 1.73 mg of the title compound. Yield 85% ¹ H-NMR (CDCl ₃ , δ ppm): 1.45 (3H, t, J = 7Hz), 1.89〜
2.05 (2H, m), 2.21 (1H, m), 2.46 (3H, s), 270 (1H, m),
4.01 (4H, br.s), 4.20 (2H, q, J = 7Hz), 4.47 (1H, m),
7.30 (2H, d, J = 8Hz), 7.74 (2H, d, J = 8Hz)

Example 13 Synthesis of 6-ethylamino-3-azabicyclo [3,3,0] octa-1 (5) ene dihydrobromide 406 mg 6- (Nt-butoxycarbonyl-N-ethyl) Amino-3- (paratoluenesulfonyl) -3-
Azabicyclo [3,3,0] octa-1 (5) ene and 100 mg of phenol were suspended in 10 ml of 30% hydrobromide solution. The resulting mixture was refluxed for 5 hours, cooled and washed 5 times with 20 ml of chloroform. The aqueous solution was decolorized by using activated carbon, filtered and concentrated. The residue was solidified in a mixed solution of ethanol and ethyl ether (1: 2, v / v) to obtain 200 mg of the title compound as a white precipitate. Yield 63% Melting point: 185 ° to 188 ° C. ¹ H-NMR (CDCl ₃ , δ ppm): 1.40 (3H, t, J = 7Hz), 2.50〜
2.81 (4H, m), 3.94 (4H, br.s), 4.18 (2H, q, J = 7Hz), 4.
24 (1H, m)

Example 14 Synthesis of 6- (N-ethyl-N-methyl) amino-3- (paratoluenesulfonyl) -3-azabicyclo [3,3,0] octa-1 (5) ene 10 ml 400 mg of 6-dissolved in tetrahydrofuran
(Nt-butoxycarbonyl-N-ethyl) amino-
To a solution of 3- (paratoluenesulfonyl) -3-azabicyclo [3,3,0] octa-1 (5) ene was added 100 mg lithium aluminum hydride. The resulting mixture was refluxed for 25 minutes and to it was added 10 ml of methanol and 0.5 ml of water.

After filtering the reaction mixture, the filtrate was concentrated under reduced pressure and purified by fractionation by silica gel column chromatography to give 250 mg of the title compound. Yield 75% ¹ H-NMR (CDCl ₃ , δ ppm): 1.42 (3H, t, J = 7Hz), 1.90 (1
H, m), 2.17 to 2.20 (2H, m), 2.23 (3H, s), 2.43 (1H, m),
2.53 (3H, s), 3.71 (1H, m), 3.95 (4H, br.s), 4.24 (2H,
q, J = 7Hz), 7.26 (2H, d, J = 8Hz), 7.64 (2H, d, J = 8Hz)

Example 15 Synthesis of 6- (N-ethyl-N-methyl) amino-3-azabicyclo [3,3,0] octa-1 (5) ene dihydrobromide 160 mg 6- (N-ethyl -N-methyl) amino-3
-(Paratoluenesulfonyl) -3-azabicyclo [3,3,0] octa-1 (5) ene was suspended in 5 ml of 30% hydrogen bromide solution. The resulting mixture is refluxed for 5 hours,
Then 10 ml of water was added. The reaction mixture was washed with chloroform, the aqueous phase was separated, decolorized by filtration through activated charcoal and concentrated under reduced pressure. The residue was suspended in 20 ml of a mixture of ethanol and ethyl ether (1: 2, v / v) and the precipitate formed therefrom was subsequently filtered and dried to give 123 mg of the title compound. Yield 7
5% Melting point: 165 ° to 168 ° C. ¹ H-NMR (D ₂ O, δ ppm): 1.42 (3H, t, J = 7Hz), 2.25 (3H,
s), 2.51 to 2.80 (4H, m), 3.90 (4H, br.s), 4.15 (2H, q,
J = 7Hz), 4.1 (1H, m)

Example 16 Synthesis of 3-Bromo-1-cyclohexene-1,2-dicarboxylic acid dimethyl ester A solution of 18 g of 1-cyclohexene-1,2-dicarboxylic acid dimethyl ester dissolved in 180 ml of carbon tetrachloride. To 16.1 g of N-bromosuccinimide and 1.49
g of α, α-azobis (isobutyronitrile) was added,
The resulting mixture was then refluxed for 5 hours. The reaction mixture was filtered, concentrated under reduced pressure, and fractionated by silica gel column chromatography to obtain 17.6 g of the title compound. Yield 70% MS m / z (relative intensity,%): 277 (M ⁺ ) ¹ H-NMR (CDCl ₃ , δ ppm): 5.23 (1H, m), 3.81 (6H, s),
3.1 (1H, m), 2.7 ~ 2.4 (3H, m), 1.51 (2H, m)

Example 17 Synthesis of 3-azido-1-cyclohexene-1,2-dicarboxylic acid dimethyl ester 17 g of 3-bromo-dissolved in 180 ml of carbon tetrachloride.
To the solution of 1-cyclohexene-1,2-dicarboxylic acid dimethyl ester was added a solution of 14 g of sodium azide in 55 ml of water and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was refluxed for 1 hour, cooled, the organic phase was separated and the remaining aqueous phase was extracted twice with carbon tetrachloride. All organic phases were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 13.4 g of the title compound as a yellow oil. Yield 91% MS m / z (relative intensity,%): 240 (M ⁺ ) ¹ H-NMR (CDCl ₃ , δ ppm): 4.79 (1H, m), 3.79 (6H, s),
2.9 (1H, m), 2.7 (1H, m), 2.41 (1H, m), 2.1 (1H, m),
1.45 (2H, m)

Example 18 Synthesis of 3-amino-1-cyclohexene-1,2-dicarboxylic acid dimethyl ester 13.4 g of 3-azido-1-cyclohexene-1,2-dicarboxylic acid dissolved in 135 ml of tetrahydrofuran To the solution of dimethyl ester was added 14.5 g of triphenylphosphine. The resulting mixture was placed under nitrogen gas 16
Stir for a period of time and add to it 1.55 ml of water. The reaction mixture was further stirred at room temperature for 5 hours, concentrated under reduced pressure,
Then the residue was dissolved in 240 ml of dichloromethane.
The solution was extracted with 350 ml of 2N hydrochloric acid solution, then the aqueous phase was separated and neutralized with 15% NaOH solution.
The neutralized solution is extracted with 300 ml of dichloromethane, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to 5.
7 g of the title compound was obtained as a pale yellow oil. Yield 4
8% MS m / z (relative intensity,%): 213 (M ⁺ ) ¹ H-NMR (CDCl ₃ , δ ppm): 4.21 (1H, m), 3.73 (3H, s),
3.72 (3H, s), 3.56 (1H, m), 2.75 (1H, m), 2.6 (1H, m),
2.41 (1H, m), 1.49 (2H, m)

Example 19 Synthesis of 3- (Nt-butoxycarbonyl) amino-1-cyclohexene-1,2-dicarboxylic acid dimethyl ester 5.7 g 3-amino-dissolved in 80 ml methanol.
To the solution of 1-cyclohexene-1,2-dicarboxylic acid dimethyl ester was added 6.4 g of di-t-butyl carbonate. The resulting mixture was stirred at room temperature for 16 hours, concentrated under reduced pressure and fractionated by silica gel column chromatography to give 7.95 g of the title compound as a white precipitate. Yield 95% MS m / z (relative intensity,%): 314 (M ⁺ ) ¹ H-NMR (CDCl ₃ , δ ppm): 5.09 (1H, br.s), 4.71 (1H, b
rs), 3.74 (3H, s), 3.73 (3H, s), 2.75 (1H, m), 2.61
(1H, m), 2.43 (1H, m), 1.48 (2H, m), 1.43 (9H, s)

Example 20 3- (Nt-butoxycarbonyl) amino-1,2-
Synthesis of bis (hydroxymethyl) -1-cyclohexene 90 ml of 14.4 g of diisobutylaluminium hydride
Dissolved in anhydrous tetrahydrofuran, and the solution is -7
Cooled to 8 ° C. Then, a solution of 7.9 g of 3-amino (Nt-butoxycarbonyl) amino-1-cyclohexene-1,2-dicarboxylic acid dimethyl ester dissolved in 80 ml of tetrahydrofuran was added dropwise to the cooled solution over 1 hour. , And it was stirred at room temperature for 16 hours.
8 ml of methanol and 2.7 ml of water were carefully added to the reaction mixture and it was extracted with 200 ml of 50% solution of methanol / dichloromethane (1: 1, v / v).
Concentration under reduced pressure gave 2.78 g of the title compound as a pale yellow oil. Yield 43% MS m / z (relative intensity,%): 257 (M ⁺ ) ¹ H-NMR (CDCl ₃ , δ ppm): 4.69 (1H, br.s), 4.31 to 4.05
(5H, m), 2.55 ~ 2.25 (3H, m), 4.31 ~ 4.05 (5H, m), 2.55
~ 2.25 (3H, m), 1.45 (2H, m), 1.41 (9H, s)

Example 21 3- (Nt-butoxycarbonyl) amino-1,2-
Synthesis of bis (bromomethyl) -1-cyclohexene 2.7 g 3-amino (Nt-butoxycarbonyl) amino-1,2-bis (hydroxymethyl) -1-cyclohexene and 8.35 g dissolved in 25 ml dichloromethane. To the above solution of carbon tetrabromide was added dropwise a solution of 8.1 g of triphenylphosphine in 20 ml of dichloromethane in a cold water bath. The resulting solution is 30 in a cold water bath.
Stir for 1 min, concentrate under reduced pressure, and dissolve the residue in ethyl ether, filter to remove water-soluble solids, and concentrate the filtrate under reduced pressure, and fractionate by silica gel column chromatography to 1.65 g. The title compound was obtained as a white precipitate. Yield 41% MS m / z (relative intensity,%): 383 (M ⁺ ) ¹ H-NMR (CDCl ₃ , δ ppm): 4.90 (1H, br.s), 4.62 (1H, b
rs), 4.01 (4H, m), 2.7 ~ 2.35 (3H, m), 1.75 ~ 1.45 (3
H, m), 1.43 (9H, s)

Example 22 6- (Nt-butoxycarbonyl) amino-3- (paratoluenesulfonyl) -3-azabicyclo [4,3,
0] Synthesis of nona-1 (5) ene 1.6 g of 3 dissolved in 15 ml of dimethylformamide
-Amino (Nt-butoxycarbonyl) amino-1,
To a solution of 2-bis (bromomethyl) -1-cyclohexene and 785 mg paratoluenesulfonamide was added 416 mg sodium hydride (55-60%) in a cold water bath and the resulting mixture was stirred for 5 hours. After adding 60 ml of water, the reaction mixture is extracted with dichloromethane,
Concentration under reduced pressure and fractionation by silica gel column chromatography gave 767 mg of the title compound as a white precipitate. Yield 47% MS m / z (relative intensity,%): 392 (M ⁺ ) ¹ H-NMR (CDCl ₃ , δ ppm): 4.51 (1H, br.s), 4.85 (1H, b
rs), 4.1 ~ 3.85 (4H, m), 2.61 (1H, m), 2.21 (1H, m),
2.11 (1H, m), 1.73 (1H, m), 1.45 (2H, m), 1.39 (9H, s)

Example 23 6-Amino-3-azabicyclo [4,3,0] nona-1
(5) Synthesis of enedihydrobromide 760 mg of 6 suspended in 2.5 ml of 30% hydrogen bromide solution.
-Amino (Nt-butoxycarbonyl) amino-3-
(Paratoluenesulfonyl) -3-azabicyclo [4,
To a solution of 3,0] nona-1 (5) ene was added 410 mg of phenol and the resulting mixture was refluxed for 5 hours.
After adding 40 ml of water, the reaction mixture is washed with chloroform until the chloroform phase is completely colorless, the aqueous phase is filtered over activated carbon, concentrated under reduced pressure and 30 ml of ethanol / ethyl ether (1: 2, v / V) to give 408 mg of the title compound as a white precipitate.
Yield 70% MS m / z (relative intensity,%): 137 (M ⁺ ) ¹ H-NMR (CDCl ₃ , δ ppm): 4.29 (1H, br.s), 3.95 (4H,
s), 2.79 (1H, m), 2.45 (1H, m), 2.35 (1H, m), 2.22 (1
H, m), 1.48 (2H, m)

Production Example 1 7- [6-amino-3-azabicyclo [3,3,0] octa-1 (5) en-3-yl] -1-cyclopropyl-
Preparation of 6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

[Chemical 34] 330 mg of 6-amino-3- in 10 ml of acetonitrile
Azabicyclo [3,3,0] octa-1 (5) ene dihydrobromide and 320 mg of 1-cyclopropyl-6,
After adding 7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 616 μl of 1,8-diazabicyclo [5,4,0] undec-7-ene, The resulting solution was refluxed for 5 hours. The reaction mixture was cooled, filtered and the residue washed with acetonitrile to give 340 mg of the desired compound as a light yellow precipitate. Yield 85% Melting point: 213-215 ° C MS m / z (relative intensity,%): 387 (M ⁺ ), 370 (100), 343 (27),
326 (73), 299 (25) ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δppm): 8.75 (1H, s), 7.76 (1
H, dd, J = 14.7, 1.5Hz), 4.63 (4H, br.s), 4.39 (1H,
m), 4.1 (1H, m), 4.39 (1H, m), 4.1 (1H, m), 2.90 (1H,
m), 2.61 (1H, m), 2.52 (1H, m), 2.35 (1H, m), 1.26 (4
H, m)

Production Example 2 7- {6-amino-3-azabicyclo [4,3,0] non-1 (5) en-3-yl} -1-cyclopropyl-
Preparation of 6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (Compound B) 400 mg 6-amino-3-azabicyclo [4,3,0] suspended in 10 ml acetonitrile. Nona-1 (5) En
To a mixture of dihydrobromide and 365 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was added 735 μl of 1,8-diazabicyclo [5,4,0]. ] Undec-7-ene was added and the resulting mixture was refluxed for 5 hours. The reaction mixture was cooled, filtered and the residue washed with acetonitrile to give 387 mg of the title compound as a pale yellow precipitate. Yield 75% MS m / z (relative intensity,%): 401 (M ⁺ ) ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm): 8.76 (1H, s), 7.73
(1H, d, J = 13Hz), 4.68 (1H, br.s), 4.64 (4H, br.s),
4.42 (1H, br.s), 4.10 (4H, br.s), 2.91 (1H, m), 2.65 (1
H, m), 2.55 (1H, m), 2.35 (1H, m), 1.47 (2H, m), 1.25
(4H, m)

In Vitro Antibacterial Activity Test Quinolone compounds can be prepared using the compounds of formula (I) as shown in the Preparation Examples. The minimum inhibitory concentration (MIC) of Compounds A and B was determined to demonstrate the efficacy of the quinolone compounds prepared with the compounds of the invention,
Compared to that of ciprofloxacin. These MIC values were obtained using a two-fold dilution method; that is, two serial dilutions of each test compound were made and dispersed in Mueller-Hinton agar and 10
^The medium was inoculated with 2 μl of the standard strain with ⁷ CFU (colony forming units) and these were incubated at 37 ° C. for 20 hours. The results of the MIC test are shown in Table 1.

[0101]

[Table 1]

Production Example 2b 1-Cyclopropyl-6,8-difluoro-7- [6-
Methylamino-3-azabicyclo [3,3,0] octa
Preparation of 1 (5) en-3-yl] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid

[Chemical 35] 40 mg of 6-methylamino-3 in 3 ml of acetonitrile
-Azabicyclo [3,3,0] octa-1 (5) ene dihydrobromide and 37.5 mg of 1-cyclopropyl-
6,7,8-Trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was added and 72 μl of 1,8-diazabicyclo [5,4,0] undec-7-
After the addition of ene, the resulting solution was refluxed for 5 hours. The reaction mixture was cooled, filtered and the residue washed with acetonitrile to give 34 mg of the desired compound as a white precipitate. Yield 65% Melting point: 194-196 ° C MS m / z (relative strength,%): 401 (M ⁺ ), 370 (89), 326 (100),
299 (15), 285 (10), 258 (10), 237 (10), 220 (20) ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm): 8.74 (1H, s), 7.73
(1H, d, J = 14Hz), 4.67 (4H, br, m), 4.39 (1H, br, s),
4.09 (1H, m), 2.85 (1H, m), 2.71 (93H, s), 2.61 (1H,
m), 2.50 (1H, m), 2.42 (1H, m), 1.21 (4H, m)

Production Example 3 7- [6-amino-3-azabicyclo [3,3,0] oct-1 (5) en-3-yl] -1-cyclopropyl-
Preparation of 8-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

[Chemical 36] 800 mg of 6-amino-3- in 25 ml of acetonitrile
Azabicyclo [3,3,0] octa-1 (5) ene dihydroquibromide and 790 mg of 1-cyclopropyl-
6,7-difluoro-8-chloro-1,4-dihydro-4
-Oxoquinoline-3-carboxylic acid was added and 1.
After adding 38 ml of 1,8-diazabicyclo [5,4,0] undec-7-ene, the resulting solution was refluxed for 5 hours. The reaction mixture was cooled, filtered and the residue washed with acetonitrile to give 400 mg of the desired white compound. Yield 38% Melting point: 193-194 ° C MS m / z (relative intensity,%): 403 (M ⁺ , 10), 386 (72), 359 (2
7), 342 (100), 307 (62), 282 (65), 252 (51), 216 (47), 2
01 (32), 172 (27), 108 (35) ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm): 8.97 (1H, s), 8.03
(1H, d, J = 12Hz), 4.46 ~ 4.34 (6H, m), 2.80 (1H, br,
s), 2.61 (1H, br, s), 2.46 (2H, br, s), 1.32 (2H, m), 0.
98 (2H, m)

Production Example 4 7- [6-methylamino-3-azabicyclo [3,3,3
0] octa-1 (5) en-3-yl] -8-chloro-
Preparation of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

[Chemical 37] 100 mg of 6-methylamino-3-azabicyclo [3,3,0] octa-1 (5) ene dihydrobromide and 95 mg of 1-cyclopropyl-6,7-difluoro-1,4-in 2.5 ml of acetonitrile. After adding dihydro-4-oxoquinoline-3-carboxylic acid and 164 μl of 1,8-diazabicyclo [5,4,0] undec-7-ene, the resulting solution was refluxed for 4 hours. The reaction mixture was cooled, filtered and the residue washed with acetonitrile to give 80 mg of the desired compound (white). Yield 60% Melting point: 207-208 ° C MS m / z (relative intensity,%): 417 (M ⁺ , 6), 386 (90), 342 (10
0), 308 (46), 288 (29), 263 (22), 216 (27), 122 (50), 10
9 (68) ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm): 8.95 (1H, s), 8.04
(1H, d, J = 14.4Hz), 4.46 ~ 4.33 (6H, br, m), 2.7 (3H,
s), 2.82 to 2.49 (4H, m), 1.32 (2H, m), 0.98 (2H, m)

Production Example 5 7- [6-Amino-3-azabicyclo [3,3,0] octa-1 (5) en-3-yl] -8-bromo-1-cyclopropyl-6-fluoro Production of -1,4-dihydro-4-oxoquinoline-3-carboxylic acid

[Chemical 38] 320 mg of 6-amino-3-azabicyclo [3,3,0]
Octa-1 (5) enedihydrobromide and 344 mg
8-Bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid of (1) was subjected to the same steps as described in Example 1 to give 271 mg of the desired compound. It was Yield 70% Melting point: 209 to 213 ° C. ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm): 8.15 (1 H, s), 7.49
(1H, d, J = 12.0Hz), 4.48 (4H, br, s), 4.35 (1H, m), 4.
01 (1H, m), 2.92 (1H, m), 2.63 (1H, m), 2.50 (1H, m),
2.34 (1H, m), 1.20 ~ 1.05 (4H, m)

Production Example 6 7- [6-amino-3-azabicyclo [3,3,0] octa-1 (5) en-3-yl] -1-cyclopropyl-
6-fluoro-8-methoxy-1,4-dihydro-4-
Production of oxoquinoline-3-carboxylic acid

[Chemical Formula 39] 320 mg of 6-amino-3-azabicyclo [3,3,0]
Octa-1 (5) enedihydrobromide and 295 mg
1-Cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was subjected to the same procedure as described in Example 1 to give 232 mg of the desired compound. It was Yield 58% Melting point: 195-198 ° C. ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm): 8.84 (1 H, s), 7.69
(1H, d, J = 13.8Hz), 4.55 ~ 4.35 (5H, br, s), 4.05 (1H,
m), 3.59 (3H, s), 2.95 ~ 2.30 (4H, m), 1.23 ~ 1.05 (4H,
m)

Production Example 7 7- [6-methylamino-3-azabicyclo [3,3,3]
0] Octa-1 (5) en-3-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

[Chemical 40] 70 mg of 6-methylamino-3 in 2 ml of acetonitrile
-Azabicyclo [3,3,0] octa-1 (5) ene dihydrobromide and 62 mg of 1-cyclopropyl-7-
Chloro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid was added and 62 mg of 1,8-
After the diazabicyclo [5,4,0] undec-7-ene was added, the resulting solution was refluxed for 4 hours. The reaction mixture is cooled, concentrated under reduced pressure and subjected to silica gel column chromatography (eluent: chloroform / methanol / water =
Fractionation (15/3/1) gave 60 mg of the desired yellow compound. Yield 71% Melting point 185 to 190 ° C MS m / z (relative intensity,%): 384 (M ⁺ , 8), 353 (17), 342 (10
0), 311 (62), 296 (55), 284 (15), 281 (15), 163 (10), 12
2 (15), 109 (15) ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm): 8.69 (1H, s), 7.98
(1H, br, s), 4,63 ~ 4.45 (5H, br, m), 3.64 (1H, br, s),
2.68 (3H, s), 2.8-2.45 (4H, m), 1.28 (2H, br, s), 1.07
(2H, br, s)

PRODUCTION EXAMPLE 8 7- [6-amino-3-azabicyclo [3,3,0] octa-1 (5) en-3-yl] -6,8-difluoro-
1-ethyl-1,4-dihydro-4-oxoquinoline-
Production of 3-carboxylic acid

[Chemical 41] 320 mg of 6-amino-3-azabicyclo [3,3,0]
Octa-1 (5) enedihydrobromide and 343 mg
1-Ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid of Example 1
Subjected to the same steps as described to give 291 mg of the desired compound. Yield 65% Melting point: 245 to 249 ° C (decomposition) ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm): 8.78 (1H, s), 7.86
(1H, d, J = 14.2Hz), 4.60 (4H, br, s), 4.31 (1H, m), 4.
23 (2H, q, J = 7Hz), 2.94 (1H, m), 2.64 (1H, m), 2.51 (1
H, m), 2.35 (1H, m), 1.45 (3H, t, J = 7Hz)

[Production Example 9] 7- [6-amino-3-azabicyclo [4,3,0] non-1 (5) en-3-yl] -1-cyclopropyl-
Preparation of 6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

[Chemical 42] 400 mg of 6-amino-3- in 10 ml of acetonitrile
Azabicyclo [4,3,0] nona-1 (5) ene dihydrobromide and 365 mg of 1-cyclopropyl-6,7,
After adding 8-trifluoro-4-oxoquinoline-3-carboxylic acid and 735 μl of 1,8-diazabicyclo [5,4,0] undec-7-ene, the resulting solution was refluxed for 5 hours. did. The reaction mixture is cooled, filtered,
The residue was then washed with acetonitrile to give 387 mg of the desired compound as a light yellow precipitate. Yield 75% Melting point: 200 to 204 ° C. ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm): 8.76 (1 H, s), 7.73
(1H, d, J = 13Hz), 4.68 (1H, br, s), 4,64 (4H, br, s),
4.42 (1H, br, s), 4.10 (1H, br, s), 2.91 (1H, m), 2.65 (1
H, m), 2.55 (1H, m), 2.35 (1H, m), 1.47 (2H, m), 1.25
(4H, m)

Production Example 10 7- [6-amino-3-azabicyclo [3,3,0] octa-1 (5) en-3-yl] -5-amino-1-cyclopropyl-6,8 -Difluoro-1,4-dihydro-4
-Production of oxoquinoline-3-carboxylic acid

[Chemical 43] 50 ml of 6-amino-3-azabicyclo [3,3,0] octa-1 (5) ene dihydrobromide and 50 mg of 5-amino-1-cyclopropyl-6,7,8-trifluoro-in 2 ml of acetonitrile. 1,4-dihydro-4-oxoquinoline-3-carboxylic acid was added and 86 μl
1,8-diazabicyclo [5,4,0] undec-7-
After the addition of ene, the resulting solution was refluxed for 5 hours. The reaction mixture was cooled, filtered and the residue washed with acetonitrile to give 35 mg of the desired pale yellow compound. Yield 50% Melting point: 134-137 ° C MS m / z (relative intensity,%): 407 (M ⁺ , 23), 385 (14), 358 (4
5), 295 (23), 231 (15), 50 (100), 137 (40) ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm): 8.63 (1H, s), 4.55
(5H, br, s), 3.91 (1H, br, s), 2.78 ~ 2.43 (4H, br, m),
1.18 (2H, br, s), 1.04 (2H, br, s)

Production Example 11 7- [6-methylamino-3-azabicyclo [3,3,
0] octa-1 (5) en-3-yl] -5-amino-
Preparation of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

[Chemical 44] 70 mg of 6-methylamino-3 in 2 ml of acetonitrile
-Azabicyclo [3,3,0] octa-1 (5) ene dihydrobromide and 66 mg of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-
4-oxoquinoline-3-carboxylic acid was added, and 1
After adding 15 μl of 1,8-diazabicyclo [5,4,0] undec-7-ene, the resulting solution was refluxed for 4 hours. The reaction mixture was cooled, filtered and the residue washed with acetonitrile to give 73 mg of the desired pale yellow compound. Yield 80% Melting point: 222-224 ° C MS m / s (relative intensity,%): 416 (M ⁺ , 95), 385 (100), 372 (3
7), 320 (38), 300 (45), 231 (87), 216 (25), 122 (56), 10
9 (57) ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm); 8.63 (1H, s), 4.65
~ 4.41 (5H, m), 3.90 (1H, br, s), 2.68 (3H, s), 2.80 ~
2.44 (4H, m), 1.19 (2H, m), 1.05 (2H, m)

Production Example 12 7- [6-amino-3-azabicyclo [3,3,0] octa-1 (5) en-3-yl] -1- (2,4-difluorophenyl) -6 Preparation of 2,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

[Chemical formula 45] 65 mg of 6-amino-3- in 1.2 ml of acetonitrile
Azabicyclo [3,3,0] octa-1 (5) ene dihydrobromide and 70 mg of 1- (2,4-difluorophenyl) -6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline After addition of -3-carboxylic acid and 91 μl of 1,8-diazabicyclo [5,4,0] undec-7-ene, the resulting solution was refluxed for 4 hours. The reaction mixture was cooled, filtered and the residue washed with acetonitrile and ethyl ether to give 45 mg of the desired compound. Yield 50% Melting point: 185 to 190 ° C (decomposition) MS m / z (relative intensity,%): 459 (M ⁺ , 1), 442 (3), 415 (30),
398 (100), 371 (40), 321 (15), 292 (17), 151 (10), 123
(14) ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm): 8.49 (1H, s), 7.91
(1H, d, J = 14Hz), 8.17 (1H, m), 7.08 (2H, m), 4.50 ~
4.30 (5H, m), 2.71 ~ 2.32 (4H, m)

[Production Example 13] 7- [6-methylamino-3-azabicyclo [3,3,
0] octa-1 (5) en-3-yl] -1- (2,4
-Difluorophenyl) -6,8-difluoro-1,4-
Preparation of dihydro-4-oxoquinoline-3-carboxylic acid

[Chemical formula 46] 65 mg of 6-methylamino-3-azabicyclo [3,3,0] octa-1 (5) ene in 1.2 ml of acetonitrile.
Dihydrobromide and 70 mg of 1- (2,4-difluorophenyl) -6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid were added,
And 91 μl of 1,8-diazabicyclo [5,4,0]
After adding undec-7-ene, the resulting solution was refluxed for 4 hours. The reaction mixture is cooled, filtered and the residue washed with acetonitrile and ethyl ether 60
Obtained mg of the desired compound. Yield 65% Melting point: 228-300 ° C MS m / z (relative strength,%): 473 (M ⁺ , 3), 441 (13), 430 (25),
399 (100), 372 (23), 307 (10), 237 (6), 122 (10), 109 (1
5), 94 (10) ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm): 8.48 (1H, s), 7.89
(1H, dd, J = 13, 1.5Hz), 7.50 (1H, m), 7.08 (2H, m),
4.56 ~ 4.31 (5H, m), 2.74 ~ 2.39 (4H, m), 2.62 (3H, s)

[Production Example 14] 7- [6-amino-3-azabicyclo [3,3,0] oct-1 (5) en-3-yl] -1-cyclopropyl-
6-fluoro-1,4-dihydro-4-oxo-1,8-
Production of naphthyridine-3-carboxylic acid

[Chemical 47] 320 mg of 6-amino-3-azabicyclo [3,3,0]
Octa-1 (5) enedihydrobromide and 282 mg
1-cyclopropyl-7-chloro-6-fluoro-4
The -oxo-1,8-naphthyridine-3-carboxylic acid was subjected to the same steps as described in Example 1 to give 229 mg of the desired compound. Yield 59% Melting point: 175-179 ° C ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm); 8.72 (1H, s), 7.82
(1H, br, s), 4.71 ~ 4.52 (5H, br, m), 3.61 (1H, br, s),
2.8 ~ 2.39 (4H, m), 1.28 (2H, br, s), 1.05 (2H, br, s)

[Production Example 15] 7- [6-methylamino-3-azabicyclo [3,3,3]
0] Octa-1 (5) en-3-yl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

[Chemical 48] 70 mg of 6-methylamino-3 in 2 ml of acetonitrile
-Azabicyclo [3,3,0] octa-1 (5) enedihydrobromide and 62 mg of 1-cyclopropyl-7-
Chloro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid was added and 62 mg of 1,8-
After the diazabicyclo [5,4,0] undec-7-ene was added, the resulting solution was refluxed for 4 hours. The reaction mixture is cooled, concentrated under reduced pressure and subjected to silica gel column chromatography (eluent: chloroform / methanol / water =
Fractionation (15/3/1) gave 60 mg of the desired yellow compound. Yield 71% Melting point: 185 to 190 ° C MS m / z (relative intensity,%): 384 (M ⁺ , 8), 353 (17), 342 (10
0), 311 (62), 296 (55), 284 (15), 218 (15), 163 (10), 12
2 (15), 109 (15) ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm); 8.69 (1H, s), 7.98
(1H, br, s), 4.63 ~ 4.45 (5H, br, m), 3.64 (1H, br, s),
2.68 (3H, s), 2.8 ~ 2.45 (4H, m), 1.28 (2H, br, s), 1.0
7 (2H, br, s)

Production Example 16 9-Fluoro-10- [6-amino-3-azabicyclo [3,3,0] octa-1 (5) en-3-yl] -3-
(S) -Methyl-7-oxo-2,3-dihydro-7H
-Pyrido [1,2,3-de] -1,4-benzoxazine-
Production of 6-carboxylic acid

[Chemical 49] 32 mg 6-amino-3-azabicyclo [3,3,0] octa-1 (5) ene dihydrobromide and 295 mg 9,10-difluoro-3- (S) -methyl-7-oxo-2,3- Dihydro-7H-pyrido [1,2,3-de]
Example 1, -1,4-benzoxazine-6-carboxylic acid
Subjected to the same steps as described to give 196 mg of the desired compound. Yield 49% Melting point: 183-186 ° C MS m / z (relative intensity,%): 399 (M ⁺ , 7), 368 (40), 357 (27),
326 (100), 234 (57), 219 (67), 205 (35), 193 (31), 122
(44), 109 (47) ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm): 8.75 (1H, s), 7.65
(1H, d, J = 14.2Hz), 4.65 ~ 4.30 (6H, m), 4.25 (2H, br,
s), 2.98 to 2.35 (4H, m), 1.67 (3H, d, J = 6.5Hz)

Production Example 17 9-fluoro-10- [6-methylamino-3-azabicyclo [3,3,0] octa-1 (5) en-3-yl]
Preparation of -3- (S) -methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] 1,4-benzoxazine-6-carboxylic acid

[Chemical 50] 70 ml of 6-methylamino-3-azabicyclo [3,3,0] octa-1 (5) ene in 1.5 ml of acetonitrile.
Dihydrobromide and 63 mg of 9,10-difluoro-3- (S) -methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] -1,4-benzoxazine-6- Carboxylic acid was added and 115 μl of 1,
After adding 8-diazabicyclo [5,4,0] undec-7-ene, the resulting solution was refluxed for 4 hours. The reaction mixture was cooled, filtered and the residue washed with acetonitrile to give 45 mg of the desired compound. Yield 50% Melting point: 186-188 ° C MS m / z (relative intensity,%): 399 (M ⁺ , 7), 368 (40), 357 (27),
326 (100), 234 (57), 219 (67), 205 (35), 193 (31), 122
(44), 109 (47) ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm): 8.78 (1H, s), 7.68
(1H, dd, J = 13Hz, 1.2Hz), 4.67 ~ 4.28 (8H, m), 2.67 (3
H, s), 2.80 to 2.47 (4H, m), 1.61 (3H, d, J = 6.7Hz)

Production Example 18 7- [6-amino-3-azabicyclo [3,3,0] octa-1 (5) en-3-yl] -1-ethyl-6-fluoro-1,4- Preparation of dihydro-4-oxoquinoline-3-carboxylic acid

[Chemical 51] 320 mg of 6-amino-3-azabicyclo [3,3,0]
Octa-1 (5) enedihydrobromide and 252 mg
6,7-difluoro-1-ethyl-1,4-dihydro-
4-oxoquinoline-3-carboxylic acid was subjected to the same steps as described in Example 1 to give 260 mg of the desired compound. Yield 73% Melting point: 212-215 ° C ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm); 8.75 (1H, s), 7.85
(1H, d, J = 12.4Hz), 7.12 (1H, d, J = 7.3Hz), 4.45 (4H,
br, s), 4.31 (1H, m), 4.09 (2H, q, J = 7Hz), 2.42 (2H,
m), 2.18 (2H, m), 1.42 (3H, t, J = 7Hz)

Production Example 19 7- [6-methylamino-3-azabicyclo [3,3,
0] octa-1 (5) en-3-yl] -1-ethyl-
Preparation of 6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

[Chemical 52] 350 mg of 6-methylamino-3-azabicyclo [3,
3,0] octa-1 (5) ene dihydrobromide and 252 mg of 6,7-difluoro-1-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid in the same procedure as described in Example 1. 241 mg of the desired compound was obtained. Yield 65% Melting point: 220-224 ° C ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm); 8.69 (1 H, s), 7.76
(1H, d, J = 12.4Hz), 7.69 (1H, d, J = 7.3Hz), 4.50 ~ 4.3
9 (5H, br, s), 4.05 (2H, q, J = 7Hz), 2.91 (1H, m), 2.70
(3H, s), 2.49 to 2.20 (3H, br, s), 1.41 (3H, t, J = 7Hz)

Production Example 20 7- [6-amino-3-azabicyclo [3,3,0] octa-1 (5) en-3-yl] -1-ethyl-6-fluoro-8-chloro- Preparation of 1,4-dihydro-4-oxoquinoline-3-carboxylic acid

[Chemical 53] 320 mg of 6-amino-3-azabicyclo [3,3,0]
Octa-1 (5) enedihydrobromide and 286 mg
1-ethyl-6,7-difluoro-8-chloro-1,4
-Dihydro-4-oxoquinoline-3-carboxylic acid was subjected to the same steps as described in Example 1 to give 246 mg of the desired compound. Yield 63% Melting point: 218-221 ° C ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm); 8.95 (1H, s), 7.98
(1H, d, J = 14.1Hz), 4.58 (5H, br, s), 4.21 (2H, q, J = 7
Hz), 2.62 (1H, m), 2.51 (2H, m), 2.31 (1H, m), 1.44 (3
(H, t, J = 7Hz)

Production Example 21 7- [6-methylamino-3-azabicyclo [3,3,
0] octa-1 (5) en-3-yl] -1-ethyl-
Preparation of 6-fluoro-8-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

[Chemical 54] 350 mg of 6-methylamino-3-azabicyclo [3,
3,0] octa-1 (5) enedihydrobromide and 286 mg of 1-ethyl-6,7-difluoro-8-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid are described in Example 1. Following the same steps as above, 223 mg of the desired compound was obtained. Yield 55% Melting point: 223-227 ° C ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm); 8.93 (1H, s), 7.89
(1H, d, J = 14.1Hz), 4.59-4.39 (5H, br, s), 4.20 (2H,
q, J = 7Hz), 2.69 (3H, s), 2.60 (1H, m), 2.53 (2H, m),
2.30 (1H, m), 1.43 (3H, t, J = 7Hz)

Production Example 22 7- [6-amino-3-azabicyclo [3,3,0] octa-1 (5) en-3-yl] -1-ethyl-5-amino-6,8- Preparation of difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

[Chemical 55] 320 mg of 6-amino-3-azabicyclo [3,3,0]
Octa-1 (5) enedihydrobromide and 286 mg
1-ethyl-5-amino-6,7,8-trifluoro-
The 1,4-dihydro-4-oxoquinoline-3-carboxylic acid was subjected to the same procedure as described in Example 1 to give 242 mg of the desired compound. Yield 62% Melting point: 238-243 ° C ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm); 8.71 (1H, s), 4.52
(4H, br, s), 4.31 (1H, m), 4.21 (2H, t, J = 7Hz), 2.92 (1
H, m), 2.64 (1H, m), 2.48 (1H, m), 2.33 (1H, m), 1.42
(3H, t, J = 7Hz)

[Production Example 23] 7- [6-methylamino-3-azabicyclo [3,3,3]
0] octa-1 (5) en-3-yl] -1-ethyl-
5-amino-6,8-difluoro-1,4-dihydro-4
-Production of oxoquinoline-3-carboxylic acid

[Chemical 56] 350 mg of 6-methylamino-3-azabicyclo [3,
3,0] octa-1 (5) ene dihydrobromide and 286 mg of 1-ethyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-
Carboxylic acid was subjected to the same steps as described in Example 1 to obtain 223 mg.
The desired compound of Yield 55% Melting point: 218-221 ° C ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm); 8.69 (1H, s), 4.50
~ 4.41 (5H, br, s), 4.18 (2H, t, J = 7Hz), 2.90 (1H, m),
2.70 (3H, s), 2.65 (1H, m), 2.47 (1H, m), 2.31 (1H,
m), 1.38 (3H, t, J = 7Hz)

Production Example 24 7- [6-amino-3-azabicyclo [3,3,0] oct-1 (5) en-3-yl] -1- (t-butyl)-
Preparation of 6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

[Chemical 57] 330 mg of 6-amino-3-azabicyclo [3,3,0]
Octa-1 (5) enedihydrobromide and 299 mg
6,7,8-trifluoro-1- (t-butyl) -1,
4-Dihydro-4-oxoquinoline-3-carboxylic acid was subjected to the same procedure as described in Example 1 to give 222 mg of the desired compound. Yield 55% Melting point: 189-192 ° C ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm); 8.58 (1H, s), 8.12
(1H, d, J = 14.2Hz), 4.51 ~ 4.35 (5H, m), 2.91 (1H, m),
2.60 ~ 2.45 (2H, m), 2.31 (1H, m), 1.83 (9H, s)

Production Example 25 7- [6-methylamino-3-azabicyclo [3,3,3]
0] Octa-1 (5) en-3-yl] -1- (t-butyl) -6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

[Chemical 58] 355 mg of 6-methylamino-3-azabicyclo [3,
3,0] octa-1 (5) enedihydrobromide and 299 mg of 6,7,8-trifluoro-1- (t-butyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid were carried out. Subjected to the same steps as described in Example 1 to give 238 mg of the desired compound. Yield 57% Melting point: 205-208 ° C ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm); 8.56 (1H, s), 8.15
(1H, d, J = 14.2Hz), 4.50 ~ 4.30 (5H, br, s), 2.93 (1H,
m), 2.71 (3H, s), 2.62 ~ 2.43 (2H, m), 2.30 (1H, m),
1.81 (9H, s)

Production Example 26 7- [6-amino-3-azabicyclo [3,3,0] oct-1 (5) en-3-yl] -1- (t-butyl)-
Preparation of 6-fluoro-8-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

[Chemical 59] 325 mg of 6-amino-3-azabicyclo [3,3,0]
Octa-1 (5) enedihydrobromide and 315 mg
Of 6,7-difluoro-8-chloro-1- (t-butyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid were subjected to the same steps as described in Example 1 to give 206 mg of the desired compound. The compound was obtained. Yield 49% Melting point: 179 to 184 ° C ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm); 8.55 (1 H, s), 8.09
(1H, d, J = 14.2Hz), 4.51 ~ 4.32 (5H, m), 2.95 (1H, m),
2.65 ~ 2.42 (2H, m), 2.25 (1H, m), 1.85 (9H, s)

Production Example 27 7- [6-methylamino-3-azabicyclo [3,3,
0] Octa-1 (5) en-3-yl] -1- (t-butyl) -6-fluoro-8-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

[Chemical 60] 355 mg of 6-methylamino-3-azabicyclo [3,
3,0] octa-1 (5) ene dihydrobromide and 315 mg of 6,7-difluoro-8-chloro-1- (t
-Butyl) -1,4-dihydro-4-oxoquinoline-
The 3-carboxylic acid was subjected to the same steps as described in Example 1 to give 19
Obtained 5 mg of the desired compound. Yield 45% Melting point: 175 to 178 ° C ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm); 8.54 (1H, s), 8.05
(1H, d, J = 14.2Hz), 4.55 to 4.30 (5H, m), 2.95 (1H, m),
2.72 (3H, s), 2.65 ~ 2.45 (2H, m), 2.24 (1H, m), 1.84
(9H, s) [Production Example 28] 7- [6-amino-3-azabicyclo [3,3,0] octa-1 (5) en-3-yl] -1- (4-fluorophenyl) -6 , 8-Difluoro-1,4-dihydro-4-
Production of oxoquinoline-3-carboxylic acid

[Chemical formula 61] 325 mg of 6-amino-3-azabicyclo [3,3,0]
Octa-1 (5) enedihydrobromide and 337 mg
Of 1- (4-fluorophenyl) -6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid were subjected to the same steps as described in Example 1 to give 274 mg of the desired product. The compound was obtained. Yield 62% Melting point: 221-224 ° C ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm); 8.59 (1H, s), 8.01
(1H, d, J = 14.2Hz), 7.49 (2H, m), 7.25 (2H, m), 4.75
~ 4.49 (5H, m), 2.91 ~ 2.37 (4H, m)

Production Example 29 7- [6-methylamino-3-azabicyclo [3,3,3
0] Octa-1 (5) en-3-yl] -1- (4-fluorophenyl) -6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

[Chemical formula 62] 355 mg of 6-methylamino-3-azabicyclo [3,
3,0] octa-1 (5) ene dihydrobromide and 337 mg of 1- (4-fluorophenyl) -6,7,8-
Trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was subjected to the same procedure as described in Example 1 to give 2
Obtained 96 mg of the desired compound. Yield 65% Melting point: 227 to 230 ° C. ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm); 8.57 (1 H, s), 7.99
(1H, d, J = 14.2Hz), 7.48 (2H, m), 7.26 (2H, m), 4.76
~ 4.51 (5H, m), 2.73 (3H, s), 2.90 ~ 2.36 (4H, m)

PRODUCTION EXAMPLE 30 7- [6-amino-3-azabicyclo [3,3,0] octa-1 (5) en-3-yl] -1-ethyl-6-fluoro-1,4- Preparation of dihydro-4-exo-1,8-naphthyridine-3-carboxylic acid

[Chemical formula 63] 325 mg of 6-amino-3-azabicyclo [3,3,0]
Octa-1 (5) enedihydrobromide and 270 mg
1-Ethyl-7-chloro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid was subjected to the same steps as described in Example 1 to give 205 mg of the desired compound.
Yield 57% Melting point: 179 to 183 ° C ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm): 8.75 (1H, s), 8.09
(1H, d, J = 12.4Hz), 4.75 ~ 4.35 (7H, m), 2.90 ~ 2.45 (4
H, m), 1.51 (3H, t, J = 7Hz)

[Production Example 31] 7- [6-methylamino-3-azabicyclo [3,3,
0] octa-1 (5) en-3-yl] -1-ethyl-
6-fluoro-1,4-dihydro-4-oxo-1,8-
Production of naphthyridine-3-carboxylic acid

[Chemical 64] 355 mg of 6-methylamino-3-azabicyclo [3,
3,0] octa-1 (5) ene dihydrobromide and 270 mg of 1-ethyl-7-chloro-6-fluoro-4.
The -oxo-1,8-naphthyridine-3-carboxylic acid was subjected to the same steps as described in Example 1 to give 231 mg of the desired compound. Yield 62% Melting point: 185-189 ° C ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm): 8.74 (1H, s), 8.07
(1H, d, J = 12.4Hz), 4.76 ~ 4.36 (7H, m), 2.71 (3H, s),
2.90 ~ 2.44 (4H, m), 1.51 (3H, t, J = 7Hz)

Production Example 32 7- [6-amino-3-azabicyclo [3,3,0] oct-1 (5) en-3-yl] -1- (t-butyl)-
Preparation of 6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

[Chemical 65] 320 mg of 6-amino-3-azabicyclo [3,3,0]
Octa-1 (5) enedihydrobromide and 281 mg
Of 1- (t-butyl) -6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was subjected to the same procedure as described in Example 1 to give 205 mg of the desired compound. . Yield 53% Melting point: 193-196 ° C. ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm): 8.55 (1 H, s), 7.83
(1H, d, J = 12.3Hz), 7.21 (1H, s), 4.70 ~ 4.49 (5H, m),
2.85 ~ 2.43 (4H, m), 1.91 (9H, s)

Production Example 33 7- [6-methylamino-3-azabicyclo [3,3,3
0] Octa-1 (5) en-3-yl] -1- (t-butyl) -6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

[Chemical formula 66] 350 mg of 6-methylamino-3-azabicyclo [3,
3,0] octa-1 (5) ene dihydrobromide and 281 mg of 1- (t-butyl) -6,7-difluoro-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid was subjected to the same procedure as described in Example 1 to give 248 mg of the desired compound. Yield 62% Melting point: 198-202 ° C ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm): 8.82 (1H, s), 7.81
(1H, d, J = 12.3Hz), 7.19 (1H, s), 4.70 ~ 4.48 (5H, m),
2.85 ~ 2.40 (4H, m), 2.72 (3H, s), 1.90 (9H, s)

[Production Example 34] 7- [6-acetamino-3-azabicyclo [3,3,
0] Octa-1 (5) en-3-yl] -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

[Chemical formula 67] 193 mg of 7- [6-amino-3-azabicyclo [3,
3,0] octa-1 (5) en-3-yl] -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4
-Oxoquinoline-3-carboxylic acid was dissolved in a mixture of 3 ml of pyridine and 2.5 ml of acetic anhydride and the resulting solution was stirred at room temperature overnight. The reaction mixture was poured into 20 ml of water and stirred at room temperature for 2 hours. The precipitate formed was filtered, washed with water, isopropanol and ethyl ether and dried under reduced pressure to give 174 mg of the desired compound. Yield 90% Melting point: 199 to 203 ° C. ¹ H-NMR (CDCl ₃ + CD ₃ COOD, δ ppm): 8.77 (1 H, s), 7.78
(1H, d, J = 14.6Hz), 4.60 (4H, br, s), 4.50 (1H, m), 4.
05 (1H, m), 2.91 (1H, m), 2.60 (1H, m), 2.52 (1H, m),
2.35 (1H, m), 2.01 (3H, s), 1.26 (4H, m)

Production Example 35 7- [6-t-Butoxycarbonylamino-3-azabicyclo [3,3,0] octa-1 (5) en-3-yl]
Preparation of -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid methoxymethyl ester

[Chemical 68] 487 mg of 7- [6-t-butoxycarbonylamino-
3-azabicyclo [3,3,0] octa-1 (5) ene-
3-yl] -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was suspended in a mixture of 10 ml hexamethylphosphoramide and 5 ml tetrahydrofuran. To the resulting solution was added 250 ml methoxymethyl iodide and 200 mg potassium carbonate powder and the reaction mixture was stirred at room temperature for 24 hours, then 50 ml dichloromethane were added. What was obtained was washed with water and 5% NaHCO ₃ , and the organic phase was dried over anhydrous sodium sulfate and concentrated. The residue thus obtained was crystallized from chloroform / hexane to give 298 mg of the desired compound. Yield 56
% Melting point: 155 to 158 ° C. ¹ H-NMR (CDCl ₃ , δ ppm): 8.79 (1H, s), 7.75 (1H, d, J =
14.5Hz), 4.62 (4H, br, s), 4.51 (1H, m), 4.25 (2H, br,
s), 4.06 (1H, m), 3.81 (3H, s), 2.90 (1H, m), 2.61 (1H,
m), 2.54 (1H, m), 2.33 (1H, m), 1.92 (9H, s), 1.25 ~
1.15 (4H, m)

Production Example 36 7- [6-amino-3-azabicyclo [3,3,0] octa-1 (5) en-3-yl] -6,8-difluoro-
Preparation of 1,4-dihydro-4-oxoquinoline-3-carboxylic acid lactate

[Chemical 69] 387 mg of 7- [6-amino-3-azabicyclo [3,
3,0] octa-1 (5) en-3-yl] -6,8-difluoro-1,4-dihydro-4-oxoquinoline-3
The carboxylic acid was dissolved in a mixture of 10 ml of dichloromethane and 2 ml of ethanol, and after addition of 87 μl of 85% lactic acid, the resulting solution was stirred for 2 hours at room temperature.
The solvent was evaporated under reduced pressure to quantitatively obtain the desired compound.

Melting point: 180 to 184 ° C. ¹ H-NMR (CD ₃ OD + CD ₃ COOD, δ ppm): 8.74 (1 H, s), 7.72
(1H, d, J = 14Hz), 4.8 ~ 4.1 (7H, m), 2.85 ~ 2.35 (4H,
m), 1.50 ~ 1.16 (7H, m)

Formulation Example 1 Capsules were produced according to the following composition:Component amount Compound obtained in Preparative Example 1 100.0 mg Corn starch 25.0 mg Calcium carboxymethyl cellulose 23.0 mgMagnesium stearate 2.0 mg  Total amount 150.0 mg

[0138] [Formulation Example 2] solution was prepared according to the following composition: Ingredient Quantity Preparation of the compound obtained in 36 1 to 10 g lactic acid or sodium 0.1~2g mannitol hydroxide 0.1g deionized water 87. 9-98.8g Total 150g

1. In Vitro Antibacterial Activity Test In order to prove the excellent efficacy of the quinoline derivative of the present invention, the minimum inhibitory concentration (MIC) of several compounds synthesized in this Example against a standard strain was measured, and ofloxacin (ofloxane) was tested.
xacin) and ciprofloxacin. These MIC values were obtained using the two-fold dilution method; that is, two serial dilutions of each test compound were made, dispersed in Mueller-Hinton agar and
Inoculating the medium with a standard strain having a value of 0 ⁷ CFU / ml,
And these were incubated at 37 degreeC for 18 hours.
The results of the MIC test are shown in Tables 2-4.

[0140]

[Table 2]

[0141]

[Table 3]

[0142]

[Table 4]

2. Preventive effect in systemic infection 10 of pathogens that cause 100% lethality
Double doses were injected intraperitoneally into male and female NMRI mice weighing 18-20 g. Immediately after 4 hours, the test compound was orally or subcutaneously administered at a dose of 2 times as measured by the serial dilution method, and effective on the 7th day by ED ₅₀ calculated from the number of surviving mice by probit analysis. The sex was evaluated.

[0144]

[Table 5]

3. Acute toxicity test The test compound was administered to female ICR mice weighing 20 to 25 g, and LD ₅₀ was calculated from the number of surviving mice by probit analysis on the 14th day.

[0146]

[Table 6]

As can be seen from the results, the compounds of the invention have a broad spectrum of potent antibacterial activity against gram-positive and gram-negative bacteria compared to the known quinolone antibacterial agents ciprofloxacin and ofloxacin. . The compounds of the present invention also affect 50 in systemic bacterial infections.
It exhibits superior activity over known effective quinolone antibacterial agents in terms of% effective dose (ED ₅₀ ). Further, the compound of the present invention has a sufficiently low toxicity that it can be regarded as a drug.

Accordingly, the compounds of this invention will be useful as therapeutic compounds and preservatives for inorganic and organic materials.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical indication location C07D 471/04 114 A 498/06 513/06 (72) Inventor Lee, Ta-suk Republic of Daejeon, Republic of Korea 1-203 Sanchang Apartment, Jiadong, West-gu (72) Inventor Park Tae-Ho, Republic of Korea Daejeon-gu, Yuseong-gu, Daegu-dong 431-6, 72 72) Inventor Kim Fenglin, 305-16 Yumdong, Yuseong-gu, Yuseong-gu, Korea

Claims (25)

[Claims] 1. Formula (I): [Wherein X is a nitrogen atom or a C—Y group (wherein Y is a hydrogen, fluorine, chlorine or bromine atom, or a methoxy or methyl group); R ₁ is a halogen atom or a hydroxy group as the case may be. Substituted C ₁ ~
A C ₆ -alkyl group, an alkenyl group, a C ₃ -C ₆ -cycloalkyl group, a phenyl group substituted with a halogen atom, or a nitrogen atom bonded to R ₁ and X (where X is C—Y); taken together -OCH ₂ to form the oxazine or thiazine ring _{C (*) H (CH 3} ) -, - SCH 2 C
(*) H ₂ — or —SCH ₂ C (*) H (CH ₃ ) — is a divalent group; R ₂ is a hydrogen atom, a carboxy protecting group or a pharmaceutically acceptable metal or organic cation. ; R
₃ and R ₄ are the same or different and are a hydrogen atom, a lower alkyl group, an acyl group or a nitrogen protecting group which can be metabolized in vivo; Z is a hydrogen or halogen atom, an amino, hydroxy or methyl group; and n is 1 Is a quinolonecarboxylic acid derivative and a pharmaceutically acceptable salt thereof. 2. A carboxy protecting group is lower alkyl, lower alkanoyloxy-lower alkyl, lower alkoxycarbonyloxy-lower alkyl, lower alkoxymethyl, di (lower alkyl) amino-lower alkyl or 4
-Methylene-5-methyl-1,3-dioxolen-2-
The compound according to claim 1, which is an on group. 3. Hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, acetic acid, formic acid, propionic acid, lactic acid, maleic acid, malonic acid, fumaric acid, tartaric acid, citric acid, paratoluenesulfonic acid, ascorbic acid or glutamic acid. The compound according to claim 1, which is a salt of 4. Formula (II): Wherein R ₁ , X and Z are as defined in claim 1; R ₂ is a hydrogen atom or a carboxy protecting group as defined in claim 2; and L is a fluorine, chlorine or bromine atom. , A methanesulfonyl group or a para-toluenesulfonyl group, which is a leaving group) is represented by the formula (III): Wherein R ₃ , R ₄ and n are as defined in claim 1 or formula (IIIa) A compound of formula (Ia) comprising reacting with a compound of the formula where R ₃ , R ₄ and n are as defined in claim 1 and A is hydrochloric acid, bromic acid, sulfuric acid or trifluoroacetic acid. [Chemical 5] A method for producing a compound of the formula: wherein R ₁ , R ₂ , R ₃ , R ₄ , X, Z and n are as defined above. 5. The formula (Ia-1): _{(Wherein, R 1, R 3, R} 4, X, Z and n are claims is as defined in 1) wherein R ₂ -Hal (wherein the compound of, R ₂ is as defined in claim 2 A carboxy protecting group, and Hal is a chlorine, bromine or iodine atom), and a compound of formula (Ia-2) A method for producing a compound of the formula: wherein R ₁ , R ₂ , R ₃ , R ₄ , X, Z and n are as defined above. 6. Formula (Ia-1): (Wherein R ₁ , R ₃ , R ₄ , X, Z and n are as defined in claim 1), the compound of R ₂ -donor (R ₂ -donor is sodium hydroxide, Potassium hydroxide,
Calcium hydroxide, magnesium hydroxide, silver nitrate or a tertiary or 4-C ₁ -C ₄ -alkylammonium) of formula (Ia-3) embedded image A method of making a compound of the formula where R ₁ , R ₃ , R ₄ , X, Z and n are as defined above, and R ₂ is a pharmaceutically acceptable metal or organic atican. 7. Formula (Ia-4): Wherein R ₁ , R ₃ , R ₄ , X, Z and n are as defined in claim 1 and R ₂ is a hydrogen atom or a carboxy protecting group as defined in claim 2. the compound R ₄ - compound donor [R ₄ - donor R ₄ -Ha
l (where Hal is a chlorine, bromine or iodine atom,
And R ₄ is as defined in claim 1 with the exception of a hydrogen atom.]
-5) [Chemical formula 11] A method for producing a compound of the formula: wherein R ₁ , R ₂ , R ₃ , R ₄ , X, Z and n are as defined above. 8. At least one compound of formula (I) as active ingredient: An antibacterial agent containing a compound of the formula: wherein R ₁ , R ₂ , R ₃ , R ₄ , X, Z and n are as defined in claim 1. 9. Formula (I): Wherein R is hydrogen or an amine protecting group; R ₁ and R ₂ are the same or different and are hydrogen, optionally substituted lower alkyl, alkanoyl, optionally substituted benzoyl or naphthoyl, optionally Is a substituted alkoxycarbonyl, or an optionally substituted benzyloxycarbonyl; and n is an integer from 1 to 4) azabicycloamine and salts thereof. 10. The amine protecting group of R is benzenesulfonyl, paratoluenesulfonyl, methanesulfonyl, C ₁
-C ₄ - alkoxycarbonyl, benzyloxycarbonyl, para-nitrobenzyloxycarbonyl, 2,2,2
- trichloroethoxycarbonyl, C ₁ -C ₂₀ - azabicyclo amine and its salt according to claim 9 wherein the alkanoyl or benzoyl or naphthoyl, which is optionally substituted. 11. Formula (I-1): A compound of claim 9 of formula (wherein R, R ₁ and R ₂ are hydrogen) and a compound of formula (Ia-1): An acid addition salt thereof represented by the formula: wherein A is hydrochloric acid, hydrobromic acid, sulfuric acid or trifluoroacetic acid. 12. Formula (I-2): Where R and R ₁ are hydrogen atoms and R ₂ is optionally substituted lower alkyl, alkanoyl,
Optionally substituted benzoyl or naphthoyl, optionally substituted alkoxycarbonyl or optionally substituted benzyloxycarbonyl) and a compound of formula (Ia-2) ] An acid addition salt thereof represented by the formula: wherein A is hydrochloric acid, hydrobromic acid, sulfuric acid or trifluoroacetic acid. 13. The compound according to claim 9, wherein n is 2 or 3, and a salt thereof. 14. The acid of the acid addition salt is an inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, or formic acid, acetic acid, propionic acid, methanesulfonic acid, trichloroacetic acid, trifluoroacetic acid. , An acid addition salt which is an organic acid selected from the group consisting of lactic acid, maleic acid, malonic acid, fumaric acid, citric acid, tartaric acid, p-toluenesulfonic acid, benzenesulfonic acid, palmitic acid, oleic acid and stearic acid. The salt according to claim 9. 15. The following reaction formula: (Wherein n is an integer of ₁ to ₄ ; R ₁₀ is C ₁ -C ₄ -alkyl; R ₃ is an amine protecting group; R ₄ is a hydrogen atom or an amino protecting group; X is An iodine, bromine or chlorine atom, or an O-mesyl or O-tosyl group; and A is hydrochloric acid, hydrobromic acid, sulfuric acid or trifluoroacetic acid). -Bromo (or chloro)
Heating with succinimide in the presence of a free radical generator to give a compound of formula (III); (b) reacting a compound of formula (III) with an azide to give a compound of formula (I
(C) a compound of formula (IV) is reacted with triphenylphosphine in a solvent to obtain a compound of formula (V); (d) a compound of formula (V) with an amine protecting agent. Reacting to obtain a compound of formula (VI); (e) reducing a compound of formula (VI) with a reducing agent to give a compound of formula (VII)
(F) adding a compound of formula (VII) to a halogenating agent selected from the group consisting of phosphorus trichloride, phosphorus trifluoride, thionyl chloride and oxalyl chloride, or triphenylphosphine and carbon tetrachloride or tetrachloride. Reacting with carbon bromide to give a compound of formula (VIII); (g) a compound of formula (VIII) selected from the group consisting of paratoluenesulfonamide, benzenesulfonamide, acetamide, benzamide, methanesulfonamide and urethane. A compound of formula (IX) by reacting with a R ₄ donor in the presence of a base; and (h) a compound of formula (IX) from the group consisting of hydrochloric acid, sulfuric acid, hydrobromic acid and trifluoroacetic acid. A process for preparing a compound of formula (Ia-1) according to claim 11 which comprises heating in a selected acid. 16. The method according to claim 15, wherein R ₃ is methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl and paranitrobenzyloxycarbonyl. 17. The amino protecting group is benzenesulfonyl,
16. The method according to claim 15, which is paratoluenesulfonyl, methanesulfonyl or lower alkoxycarbonyl. 18. The method of claim 15, wherein the free radical generator is benzoyl peroxide or azaisobutyronitrile. 19. Di-t-butyl dicarbonate or methyl, ethyl, trichloromethyl, benzyl or paranitrobenzyl chloroformate in the presence of the amine protecting group pyridine, sodium hydride, potassium carbonate, triethylamine, sodium hydroxide. 16. The method of claim 15 selected from the group consisting of: 20. A process for preparing a compound of formula (I-1) which comprises removing the nitrogen protecting group in the presence of a base. 21. The method of claim 20, wherein the base is sodium hydroxide or sodium ammonia. 22. The following reaction formula: According to the formula (n, R, R ₂ , R ₃ and A are as defined above): (a) reacting a compound of formula (III) with sodium acetate or silver acetate to give a compound of formula (X) A compound of formula (X) is deacetylated to obtain a compound of formula (XI); (c) a compound of formula (XI) is mesylated or tosylated,
React with an amine compound that imparts R ₂ ; or Mitsu
By reacting the compound of formula (XI) by nobu reaction,
Protecting the amine of the compound of I); and (d) a formula (I-2) comprising the following steps of steps (e), (f), (g) and (h).
Or the manufacturing method of the compound of (Ia-2). 23. The following reaction formula: A compound of formula (IX) is reacted with an alkyl halide in the presence of a strong base according to formula (XIV), wherein n, R ₂ , R ₃ , R ₄ and A are as defined above. Of a compound of formula (I-3) or (Ia-3), which comprises removing a R ₂ and R ₄ amino protecting group therefrom to produce a compound of formula (I-3) or (Ia-3). ) The manufacturing method of the compound of. 24. The following reaction formula: According to the formula, wherein n, A, R ₂ and R ₃ are as defined above, and R ₆ is p-toluenesulfonyl or methanesulfonyl. The formula (XV
A process for the preparation of compounds of formula (I-4) or (Ia-4) which comprises obtaining a compound of I) and removing the protecting group R ₆ . 25. The following reaction formula: Hydrogenation of R ₃ of a compound of formula (XVII) according to, where n, A, R ₃ and R ₆ are as defined above, and R ₆ is p-toluenesulfonyl or methanesulfonyl. was reduced to a methyl group in the presence of lithium aluminum give the compound of formula (XVIII), then consists of removing the protective group R ₆ formula (I-5) or (Ia
-5) A method for producing the compound.