JP2598921B2 - Novel quinoline derivatives and their salts - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] Wherein R ¹ is a hydrogen atom or a carboxy protecting group; R ²
Is a halogen atom, cyano group, carboxyl group, hydroxyl group, amino group, alkyl group, alkoxy group, alkoxycarbonyl group, aryl group, cycloalkyl group, acylamino group, acyloxy group, lower alkenyl group, trihalogenoalkyl group, mono- A lower alkyl, lower alkenyl, cycloalkyl or aryl group which may be substituted with one or more substituents selected from di-alkylamino groups; X represents a hydrogen atom or a halogen atom;
³ is selected from a halogen atom, a lower alkyl group, an optionally protected hydroxyl group, an optionally protected amino group, an optionally protected carboxyl group, and an optionally protected hydroxy lower alkyl group Indicates a cyclopropyl or cyclobutyl group which may be substituted with one or more substituents. And a salt thereof.

An object of the present invention is to provide Gram-positive and Gram-negative bacteria,
Particularly, the compound of the general formula [I], which has a strong antibacterial action against antibiotics, has a high blood concentration by oral or parenteral administration, and has excellent properties such as high safety. An object of the present invention is to provide a novel compound represented by the formula and a salt thereof.

[Related Art] Conventionally, norfloxacin, enoxacin, ofloxacin, and the like have been widely used as synthetic quinolone antibacterial agents. All of these compounds have been used as oral preparations but have poor solubility under physiological conditions and are not suitable for parenteral administration.

[Problems to be Solved by the Invention] It is effective against Gram-positive bacteria and Gram-negative bacteria, has a wide range of antibacterial spectrum, has excellent solubility, has a high blood concentration, and has an effect on the central system. The development of highly safe synthetic antibacterial agents has been desired.

[Means for Solving the Problems] Under such circumstances, the present inventors have conducted intensive studies and found that the quinoline derivative of the general formula [I] and the salt thereof achieve the above object. Thus, the present invention has been completed.

In the present specification, unless otherwise specified, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom;
For example, a _C1-10 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, octyl, etc .; as the lower alkenyl group, for example, vinyl, allyl, 1-propenyl, _{C 2 to 5} alkenyl group such as 1-butenyl;; _{C 1 to 5} alkyl groups of the alkyl group and the cycloalkyl group, for example, cyclopropyl ,
The aryl group, e.g., phenyl, naphthyl and the like; cyclobutyl, cyclopentyl, _{C 3 to 6} cycloalkyl group such as cyclohexyl As the alkoxy group, for example, -O- alkyl group (the alkyl group, _{C 1 to 10} described above Examples of the alkoxycarbonyl group include, for example, a -CO-O-alkyl group (the alkyl group represents the above-described _C1-10 alkyl group);
As the acylamino group, for example, formylamino,
The acyloxy group, e.g., formyloxy, acetyloxy, propionyloxy, C _{1 to 4} acyloxy group such as butyryloxy; acetylamino, propionylamino, C _{1 to 4} acylamino group such butyrylamino as tri haloalkyl group, e.g. Trihalogeno C _1-4 alkyl groups such as trifluoromethyl, trichloromethyl and the like; mono- or di-alkylamino groups include, for example, mono- or di-alkyl such as methylamino, ethylamino, propylamino, dimethylamino, diethylamino and the like. It shall mean a group such as a _C1-5 alkylamino group, respectively.

 Hereinafter, the present invention will be described in detail.

In the compound of the formula [I] and salts thereof, the carboxy-protecting group for R ¹ is, for example, an ester-forming group which is eliminated by treatment under catalytic reduction, chemical reduction or other mild conditions, or in vivo. Carboxyl protection described in JP-A-59-80665, such as an ester-forming group which easily dissociates, or an organic silyl group, an organic phosphorus group or an organotin group which easily dissociates upon treatment with water or alcohol. Groups.

In the substituent of R ³ , examples of the protecting group for the carboxyl group include the same protecting groups as described for R ¹ .

Examples of the amino-protecting group include those usually used in the art, for example, formyl, acetyl, te
Examples of the protective group include a normal amino group protecting group described in JP-A-59-80665 such as rt-butoxycarbonyl.

Examples of the hydroxyl-protecting group include those usually used in the art. For example, organic silyl groups, formyl, acetyl, benzyl and the like which are easily eliminated by treatment with water or alcohol are disclosed in Showa 59
And the usual protecting groups for hydroxyl groups described in -80665.

Examples of the salt of the compound of the general formula [I] include a commonly known salt in a basic group such as an amino group or an acidic group such as a hydroxyl or carboxyl group. Examples of the salt in the basic group include salts with mineral acids such as hydrochloric acid and sulfuric acid; salts with organic carboxylic acids such as formic acid, citric acid, trichloroacetic acid and trifluoroacetic acid; methanesulfonic acid, benzenesulfonic acid, p A salt with a sulfonic acid such as toluenesulfonic acid, mesitylenesulfonic acid, or naphthalenesulfonic acid; and a salt in an acidic group, for example, a salt with an alkali metal such as sodium or potassium; an alkaline earth such as calcium or magnesium. Salts with similar metals; ammonium salts; trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-
Benzyl-β-phenethylamine, 1-ephenamine,
Examples thereof include salts with a nitrogen-containing organic base such as N, N'-dibenzylethylenediamine.

Further, in the compound of the general formula [I] and a salt thereof,
When isomers exist (eg, optical isomers, geometric isomers, tautomers, and the like), the present invention includes all such isomers and extends to all crystalline forms and hydrates. It is.

 Next, a method for producing the compound of the present invention will be described.

The compound of the present invention can be produced, for example, by the following production route.

In ^{"wherein, R 1, R 2, R} 3 and X are the same meaning as described above; R ^1a is the same carboxy protecting group as those described in R ^1; n pieces of R ⁴ are the same or different and each is hydrogen An atom, a halogen atom, a lower alkyl group, or an optionally protected hydroxyl, an optionally protected amino, an optionally protected carboxyl or an as described for the substituent of R ³ A good hydroxy lower alkyl group; X ¹
And X ² are the same or different leaving groups; n represents 2, 3, 4, and 5. Examples of the leaving group for X ¹ and X ^{2 in} the compound of the general formula [III] include halogen atoms such as chlorine, bromine and iodine; alkanesulfonyloxy groups such as methanesulfonyloxy; arenesulfonyl such as toluenesulfonyloxy Oxy groups and the like can be mentioned.

Examples of the salts of the compounds of the general formulas [II], [III] and [Ia] include the same salts as described for the compounds of the general formula [I].

Examples of the active methylene salt of the compound of the general formula [II] include salts with alkali metals such as sodium and potassium.

The compound of general formula [Ia] or a salt thereof can be obtained by reacting a compound of general formula [II] or a salt thereof with a compound of general formula [III] or a salt thereof in the presence or absence of a base. Can be.

The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. Examples thereof include water; alcohols such as methanol, ethanol, and 2-propanol; diethyl ether, tetrahydrofuran, dioxane, and the like. Ethers; aromatic hydrocarbons such as benzene, toluene and xylene; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; sulfoxides such as dimethylsulfoxide. You may mix and use two or more types.

Examples of the base used in this reaction include, for example,
Inorganic bases such as alkali hydroxide, alkali hydrogen carbonate and alkali carbonate; metal hydrides such as sodium hydride and potassium hydride; metal alkoxides such as sodium ethoxide and sodium methoxide; 1,8-diazabicyclo [5,4, 0] Organic bases such as undec-7-ene. The amount of the compound of the general formula [III] or a salt thereof to be used is 1 mol or more, preferably 1 to 5 mol, per mol of the compound of the general formula [II] or a salt thereof.

The amount of the base to be used is 1 mole or more, preferably 1 to 5 moles, per 1 mole of the compound of the formula [II] or a salt thereof.

This reaction may be carried out at 0 ° C. to the boiling point of the solvent used, preferably at 20 to 100 ° C., usually for 30 minutes to 50 hours, preferably for 3 to 20 hours.

In addition, the compound of the general formula [Ia] or a salt thereof is deprotected and then subjected to a reaction known per se such as a decarboxylation reaction, a reduction reaction or a rearrangement reaction to obtain a compound of the general formula [I] or a salt thereof. The salt can be derived.

The compound of the general formula [II] or a salt thereof is a novel compound and can be synthesized, for example, according to the following production route.

"Wherein, R ^1, R ^1a, the same meanings as R ² and X are described above; R ^1b is the same carboxy protecting group as those described in R ^1; X ³
Represents a halogen atom. As the salts of the compounds of the general formulas [IV] and [VI], the same salts as described for the compounds of the general formula [I] can be mentioned.

Examples of the salt of the active methylene of the compound of the general formula [V] and the salt of the active methine of the compound of the general formula [VI] include salts with alkali metals such as sodium and potassium.

The compound of the general formula [II] or a salt thereof has the general formula [IV]
By reacting the compound of the general formula [V] or a salt thereof according to the method described in U.S. Pat. No. 3590036 to obtain a compound of the general formula [VI] or a salt thereof. Can be obtained by performing a deprotection and decarboxylation reaction by a conventional method, and then introducing a carboxy protecting group.

“Wherein R ¹ , R ² and X have the same meanings as described above.” As the salts of the compounds of the general formulas [VII] and [I b],
Salts similar to those described for the compound of the general formula [I] can be mentioned.

The compound of the general formula [Ib] or a salt thereof can be obtained by reacting the compound of the general formula [VII] or a salt thereof with diiodosamarium and diiodomethane in the presence of a base.

The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. Examples thereof include ethers such as diethyl ether, tetrahydrofuran and dimethoxyethane; and aromatic hydrocarbons such as benzene and toluene. And hydrocarbons such as heptane and heptane. These solvents may be used in combination of two or more.

The amount of diiodosamarium and diiodomethane used in this reaction is at least equimolar, preferably 1 to 10 moles, per mole of the compound of the general formula [VII] or a salt thereof.

Examples of the base used in this reaction include metal hydrides such as sodium hydride and potassium hydride; and organic lithium compounds such as n-, butyllithium and lithium diisopropylamide.

The amount of the base to be used is 1 mol or more, preferably 1 to 1.5 mol, per mol of the compound of the formula [VII] or a salt thereof.

The reaction is carried out from -100 ° C to the boiling point of the solvent used.
The reaction may be carried out preferably at -80 to 30 ° C, usually for 30 minutes to 20 hours, preferably for 1 to 10 hours.

In the compound of the general formula [VII] or a salt thereof, R ¹ =
For compounds of ethyl, R ² = ethyl and X = H,
Although other compounds are novel compounds described in JP-A-59-67269, they can be synthesized, for example, according to the following production route.

"In the formula, R ¹ , R ^1b , R ² and X have the same meaning as described above." As a salt of the compound of the general formula [VIII], a compound of the general formula [I]
And the same salts as described in the above compound.

The compound of the general formula [VII] or a salt thereof has the general formula [V
The compound of the formula [I] or a salt thereof is methylated to give a compound of the general formula [VII]
I] or a salt thereof, and subjected to a usual deprotection and decarboxylation reaction, followed by the Journal of American Chemical Society (J. Am. Chem. Soc.) Vol. 89,
It can be obtained by subjecting it to the reaction described on page 4968 (1967).

"In the formula, R ¹ , R ^1b , R ² and X have the same meanings as described above; R ⁵ represents a hydrogen atom or a lower alkyl group." As a salt of the compound of the general formula [Ic], Formula [I]
And the same salts as described in the above compound.

The compound of the general formula [Ic] or a salt thereof has the general formula [Ic]
The compound of general formula [XI] can be obtained by deriving the compound of general formula [XI] to a compound of general formula [XI] by a 1,3-dipole addition reaction with the compound of general formula [X] and further subjecting it to a heating reaction.

The solvent used in Steps I and II is not particularly limited as long as it does not adversely affect the reaction. Examples of the solvent include ethers such as diethyl ether, tetrahydrofuron and dioxane; benzene,
Examples thereof include aromatic hydrocarbons such as toluene and xylene, and these solvents may be used as a mixture of two or more kinds.

In Step I, the amount of the compound of the general formula [X] used is
It is at least equimolar, preferably 1 to 10 moles, per mole of the compound of the formula [IX]. In addition, the reaction is carried out at -20 ° C to the boiling point of the solvent used, preferably at 0 to 30 ° C, usually for 5 minutes to
It may be carried out for 50 hours, preferably 30 minutes to 20 hours.

The reaction in step II may be carried out at a temperature of preferably from 30C to 150C from 0C to the boiling point of the solvent used, usually for 5 minutes to 50 hours, preferably for 30 minutes to 20 hours.

The compound of the general formula [IX] is a novel compound and can be synthesized, for example, according to the following production route.

"In the formula, R ^1a , R ^1b , R ² and X have the same meanings as described above." As the salts of the compounds of the general formulas [IIa] and [XII], compounds of the general formula [I] Salts similar to those described are mentioned.

The compound of general formula [IIa] or a salt thereof is derived into a compound of general formula [XII] or a salt thereof by the method described in Chem. Ber., Vol. 99, p. 2407 (1966),
Subsequently, the compound of the general formula [IX] can be derived by subjecting it to deprotection and decarboxylation by a conventional method.

"Wherein R ¹ , R ^1a , R ² , R ³ , R ⁴ , X, X ¹ , X ² and n have the same meanings as described above.” Compounds of general formulas [XIII] and [XIV] As the salt of, the same salts as described in the compound of the general formula [I] can be mentioned.

Examples of the salt of active methylene of the general formula [XIII] include the same salts as described for the compound of the general formula [II].

The compound of general formula [XIV] or a salt thereof can be derived from the compound of general formula [XIII] by carrying out the reaction under the same reaction conditions as described in Production method 1.

The compound of the general formula [XIV] or a salt thereof is, for example,
Anne Gevante Hemi International Edition in English (Angew.Chem.Int.Ed.Eng)
l.) The compound of general formula [I] or a salt thereof can be derived according to the method described in Vol. 18, p. 72 (1979) and JP-B-62-37006.

Further, the compound of the general formula [XIII] or a salt thereof is a novel compound, and these can be synthesized, for example, according to the following production route.

"In the formula, R ¹ , R ^1a , R ^1b , X and X ³ have the same meanings as described above." As the salts of the compounds of the general formulas [XV] and [XVI],
Salts similar to those described for the compound of the general formula [I] can be mentioned.

Examples of the salt of active methylene of the compound of the general formula [XVI] include salts with alkali metals such as sodium and potassium.

The compound of the general formula [XIII] or a salt thereof has the general formula [XIII]
The compound of the general formula [XVI] or a salt thereof is reacted with the compound of the general formula [V] or a salt thereof according to a method similar to that described in Production Method 1 to convert the compound of the general formula [XVI] or a salt thereof. After subjecting to ordinary deprotection and decarboxylation reactions, and then introducing a carboxyl protecting group.

"In the formula, R ¹ , R ^1b , R ² , R ⁵ and X have the same meaning as described above.” As a salt of the compound of the general formula [XIX], a compound of the general formula [I]
And the same salts as described in the above compound.

This reaction may be carried out under the same reaction conditions as described in Production Method 3 and Production Method 4.

The compound of the general formula [XVII] or a salt thereof is a novel compound, and can be synthesized, for example, according to the following production route.

“In the formula, R ^1a , R ^1b and X have the same meanings as described above.” As the salts of the compounds of the general formulas [XIIIa] and [XX], those described with reference to the compounds of the general formula [I] Similar salts are mentioned.

The compound of the general formula [XIIIa] or a salt thereof is derived into a compound of the general formula [XX] or a salt thereof according to the same method as described in Production method 3, and then deprotected and deprotected by a conventional method. By subjecting it to a decarboxylation reaction, the general formula [XVI
I].

In each of the above reactions, when the resulting compound has a protecting group, it may be subjected to a usual deprotection reaction.

The compound of the general formula [I] of the present invention or a salt thereof obtained as described above can be isolated and purified according to a conventional method.

When the compound of the present invention is used as a medicine, a carrier usually used for preparation is appropriately used, and a tablet,
Capsules, powders, syrups, granules, suppositories, ointments, injections and the like may be prepared. The administration method, dosage and number of administrations can be appropriately selected according to the patient's condition. Oral or parenteral administration (for example, injection, eye drops, administration to rectal site, etc.) is usually performed for adults. The dose may be 0.1 to 100 mg / kg / day in 1 to several divided doses.

[Effects of the Invention] Next, the pharmacological actions of the representative compounds of the present invention will be described.

1. Antimicrobial activity test method Japanese Society of Chemotherapy standard method [CHEMOTHERA
PY) Vol. 29, No. 1, pp. 76-79 (1981)], and Heart Infu
Inoculation of the bacterial solution cultured at 37 ° C for 20 hours with E.sion broth (manufactured by Eiken Chemical Co., Ltd.) into Heart Infusion agar medium (manufactured by Eiken Chemical Co., Ltd.) containing the drug, followed by 2 hours at 37 ° C. After culturing, the presence or absence of bacterial growth is observed, and the MIC (μg / m
l) However, the amount of inoculated bacteria was 10 ⁴ cells / plate (10 ⁶
/ Ml). Table 1 shows the results.

R ² , R ³ and X in Table 1 are the following formulas, respectively. Represents a substituent of the compound represented by

2. Solubility test method 1 mg of Compound 6 is precisely weighed and dissolved in 2.88 ml of a pH 7.0 buffer solution (0.1 M-disodium hydrogen phosphate-0.1 N-hydrochloric acid). This solution was appropriately diluted with a buffer solution, the absorbance value (UV260 nm) was determined, and the concentration was determined from the absorbance value of a separately prepared known concentration solution ^* .

As a result, the solubility of compound 6 in water at pH 7 was 350
μg / ml.

* 1 mg of the sample is precisely weighed and dissolved in a 0.1 N aqueous solution of sodium hydroxide, and then diluted with a buffer to obtain a solution of about 5 μg / ml.

[Examples] Next, examples will be described, but the present invention is not limited thereto. The symbols used in the examples have the following meanings.

Me; methyl Et; ethyl Φ; phenyl Boc; tert-butoxycarbonyl In addition, the carrier in column chromatography is Kieselgel 60, art 7334 (Kieselgel 60, Art.7734).
(Merck) was used. Further, the mixing ratio in the eluent depends on the volume ratio.

Reference Example 1 27.8 g of 60% sodium hydride was added to N, N-dimethylformamide 1, and 150 g of ice-cooled malonic acid di-tert-butyl ester was added dropwise over 2 hours. After dropping, 1-
Cyclopropyl-6,7-difluoro-1,4-dihydro-4
-Oxo-3-quinolinecarboxylic acid ethyl ester 51.0
g, and the mixture was stirred at 40 to 50 ° C for 5 hours.
Stir for 2 hours. Then, the reaction solution is added to a mixture of ice water 1.5 and ethyl acetate 1 and adjusted to pH 2 with 6N hydrochloric acid. The organic layer is separated, washed sequentially with dilute hydrochloric acid, water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and diisopropyl ether was added to the obtained crystalline substance.
76.0 g (89.3% yield) of ethyl 7- (di-tert-butoxycarbonylmethyl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate is obtained.

Melting point: 160-162 ° C. (resolved solvent; ethyl acetate) IR (KBr) cm ⁻¹ ; ν _{C = 0} 1475,1730 Similarly, the compounds in Table 2 are obtained.

Reference Example 2 1-cyclopropyl-7- (di-tert-butoxycarbonylmethyl) -6-fluoro-1,4-dihydro-4-
Oxo-3-quinolinecarboxylic acid ethyl ester 55.0 g
Is dissolved in 110 ml of methylene chloride, 110 ml of trifluoroacetic acid is added under ice cooling, and the mixture is stirred at room temperature for 24 hours. Then, the reaction solution is concentrated under reduced pressure, and diethyl ether is added to the obtained crystalline substance, and the mixture is collected to give 7-carboxymethyl-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo. 37.0 g (98.8% yield) of -3-quinolinecarboxylic acid ethyl ester was obtained.

Melting point: 217 to 220 ° C. (decomposition) (Resolvent: chloroform-methanol) IR (KBr) cm ⁻¹ ; ν _{C = 0} 1725 Similarly, the compounds in Table 3 are obtained.

Reference Example 3 20.0 g of ethyl 7-carboxymethyl-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate was suspended in a mixed solvent of 100 ml of methanol and 300 ml of chloroform, 1N at room temperature
70 ml of diphenyldiazomethane-petroleum ether solution are added dropwise. Next, after the excess diphenyldiazomethane is decomposed with acetic acid, the solvent is distilled off under reduced pressure. Diethyl ether was added to the obtained crystalline substance to give 1-cyclopropyl-7-diphenylmethoxycarbonylmethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester 29.0 g (96.8% yield)
Get.

Melting point: 177 to 179 ° C. (resolved solvent; ethyl acetate) IR (KBr) cm ⁻¹ ; ν _{C = 0} 1720 Similarly, the compounds in Table 4 are obtained.

Reference Example 4 5.0 g of 60% sodium hydride was added to 200 ml of N, N-dimethylformamide, and 27.0 g of malonic acid di-tert-butyl ester was added dropwise over 1 hour under ice cooling. After dropping,
20.0 g of 2,4,5-trifluorobenzoic acid methyl ester is added, and the mixture is stirred at room temperature for 16 hours. Then, the reaction solution was added to a mixture of 300 ml and 400 ml of ethyl acetate, and pH 1.0 with 2N-hydrochloric acid.
Adjust to The organic layer is separated, washed successively with 2N-hydrochloric acid, water and saturated saline, and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure gives 46.5 g of methyl 4- (di-tert-butoxycarbonylmethyl) -2,5-difluorobenzoate. Then, this is dissolved in 50 ml of trifluoroacetic acid and stirred at room temperature for 12 hours. After concentrating the reaction solution under reduced pressure, 150 ml of diethyl ether and 100 ml of water are added, and the organic layer is separated. After washing with water and saturated saline in this order, the extract is dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure.
Dissolve in 30 ml and reflux for 1 hour. The solvent was distilled off under reduced pressure, and n-hexane was added to the obtained crystalline substance, and the residue was collected to give 4-carboxymethyl-2,5-difluorobenzoic acid methyl ester (12.0 g, yield 49.6%). obtain.

133-135 ° C (decomposition) (Reconstitution solvent: ethyl acetate-n-hexane) IR (KBr) cm ^-1 ; νC _{= 0} 1720 (sh), 1705 Similarly, 4-carboxymethyl-2,3 , 5-Trifluorobenzoic acid ethyl ester is obtained.

Melting point: 96-97 ° C (decomposition) (Resolvent: ethyl acetate-n-hexane) IR (KBr) cm ^-1 ; νC _{= 0} 1710 Reference Example 5 Methyl 4-carboxymethyl-2,5-difluorobenzoate 6.0 g was suspended in 30 ml of chloroform, and 1N-diphenyldiazomethane-petroleum ether solution 30 ml at room temperature.
And stirred at the same temperature for 1 hour. Then, the reaction solution is concentrated under reduced pressure to obtain 4- (diphenylmethoxycarbonylmethyl) -2,5-difluorobenzoic acid methyl ester 10.0 g. Then, this was dissolved in 100 ml of N, N-dimethylformamide, (a) 1.2 g of 60% sodium hydride was added at room temperature, stirred at the same temperature for 30 minutes, and 5.7 g of 1,2-dibromoethane was added. Stir at room temperature for 12 hours.

After this operation (a) is repeated twice more, the reaction mixture is added to a mixture of 200 ml of ethyl acetate and 200 ml of water, and the pH is adjusted to 1.0 with 2N hydrochloric acid. The organic layer is separated, washed successively with 2N-hydrochloric acid, water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent; toluene) to give oily 4- (1-diphenylmethoxycarbonylcyclopropyl) -2,5-difluorobenzoic acid 7.7 g of methyl ester are obtained. Furthermore, 5.7 g of 4- (1-diphenylmethoxycarbonylcyclopropyl) -2,5-difluorobenzoic acid methyl ester is dissolved in 114 ml of dioxane, 57 ml of a 1N aqueous solution of sodium hydroxide is added, and the mixture is stirred at room temperature for 15 minutes. Then, after adjusting the pH to 1.0 with 6N-hydrochloric acid, 100 ml of ethyl acetate and 200 ml of water are added, and the organic layer is separated. After washing with water and saturated saline in this order, the extract is dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained oil was crystallized from petroleum ether and collected to give 4.25 g of 4- (1-diphenylmethoxycarbonylcyclopropyl) -2,5-difluorobenzoic acid (yield 53.9 g).
%).

Melting point: 145 to 146 ° C (resolved solvent; ethyl acetate-n-hexane) IR (KBr) cm ^-1 ; ν _{C = 0} 1715,1680 (sh) Reference Example 6 4-carboxymethyl-2,3,5-tri 10.0 g of ethyl fluorobenzoate is dissolved in a mixed solvent of 70 ml of chloroform and 30 ml of methanol, and 42 ml of a 1N-diphenyldiazomethane-petroleum ether solution is added at room temperature, followed by stirring for 1 hour. After decomposing excess diphenyldiazomethane with acetic acid, the solvent is distilled off under reduced pressure. 100 ml of ethyl acetate and 100 ml of water are added to the obtained residue, and the mixture is adjusted to pH 8.0 with sodium hydrogen carbonate. The organic layer is separated, washed sequentially with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent; toluene: n-hexane = 1: 1) to give 4-diphenylmethoxycarbonylmethyl-2,3,5- 11.0 g (yield 67.3%) of trifluorobenzoic acid ethyl ester is obtained.

Melting point: 70-71 ° C (resolved solvent: n-hexane) IR (KBr) cm ^-1 ; νC _{= 0} 1730 Reference Example 7 4-diphenylmethoxycarbonylmethyl-2,3,5-
7.0 g of trifluorobenzoic acid ethyl ester is dissolved in 70 ml of N, N-dimethylformamide, and 490 ml of paraformaldehyde is added at room temperature. Then, a catalytic amount of sodium ethoxide is added and stirred at the same temperature for 24 hours. The reaction solution is added to a mixture of 70 ml of ethyl acetate and 70 ml of water, and adjusted to pH 2.0 with 2N-hydrochloric acid. The organic layer is separated, washed successively with diluted hydrochloric acid, water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent; toluene: ethyl acetate = 20: 1) to give oily 4- (1-diphenylmethoxycarbonyl-2-hydroxy). Ethyl) -2,3,
3.60 g of 5-trifluorobenzoic acid ethyl ester (yield 4
8.1%).

IR (neat) cm ^-1 ; ν _{C = 0} 1720 Reference Example 8 4.8 g of ethyl 4- (1-diphenylmethoxycarbonyl-2-hydroxyethyl) -2,3,5-trifluorobenzoate was added to 48 ml of methylene chloride. Allow to dissolve. Under ice cooling, 1.80 g of methanesulfonyl chloride was added, and then 2.65 g of triethylamine was added dropwise over 3 minutes, followed by stirring at room temperature for 1 hour. 50 ml of water is added to the reaction solution, and 2N-hydrochloric acid is used.
Adjust to pH 1.0. The organic layer is separated, washed sequentially with dilute hydrochloric acid, water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent; toluene) to give oily 4- (1-diphenylmethoxycarbonyl) -2,3,5-trifluorobenzoic acid. Acid ethyl ester 4.0
7 g (88.3% yield) are obtained.

IR (neat) cm ^-1 ; ν _{C = 0} 1720 Reference Example 9 4- (1-diphenylmethoxycarbonylvinyl)-
Dissolve 4.07 g of 2,3,5-trifluorobenzoic acid ethyl ester in 20 ml of anisole and 20 ml of trifluoroacetic acid under ice cooling
And then stirred at room temperature for 13 hours. Subsequently, the solvent was distilled off under reduced pressure, and cold n-hexane was added to the obtained residue, and the residue was collected to give 4- (1-carboxyvinyl) -2,3,5.
2.01 g of trifluorobenzoic acid ethyl ester (yield 79.
4%).

Melting point: 66 to 67 ° C (decomposition) (Resolvent: ethyl acetate-n-hexane) IR (KBr) cm ^-1 ; νC _{= 0} 1710,1695 (sh) Reference Example 10 4- (1-carboxyvinyl) 2.25 g of ethyl 2,3,5-trifluorobenzoic acid ester is dissolved in 45 ml of N, N-dimethylformamide and refluxed for 7 hours. Then, the reaction solution is added to a mixture of 50 ml of ethyl acetate and 50 ml of water, and the organic layer is separated. After washing with water and saturated saline in this order, the extract is dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent: toluene) to give 1.55 g of ethyl 2,3,5-trifluoro-4-vinylbenzoic acid ethyl ester (yield Rate 82.0%).

IR (neat) cm ^-1 ; ν _{C = 0} 1720 Reference Example 11 1.50 g of 2,3,5-trifluoro-4-vinylbenzoic acid ethyl ester was dissolved in 15 ml of tetrahydrofuran, and N-methyl-N -Add a diazomethane-diethyl ether solution prepared from 2.5 g of nitrosourea, and at the same temperature
Stir for 2.5 hours. The reaction solution is concentrated under reduced pressure, and the obtained residue is dissolved in 30 ml of xylene and refluxed for 1 hour. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent; toluene) to give 1.50 g of oily 4-cyclopropyl-2,3,5-trifluorobenzoic acid ethyl ester (94.3% yield).

IR (neat) cm ^-1 ; ν _{C = 0} 1715 Reference Example 12 1.50 g of ethyl 4-cyclopropyl-2,3,5-trifluorobenzoate was added to a mixed solution of 15 ml of ethanol and 15 ml of a 1N aqueous solution of sodium hydroxide. Add and stir at room temperature for 18 hours. 45 ml of water is added to the reaction solution, and pH 1.5 with 2N-hydrochloric acid.
If the precipitated crystals are collected, 4-cyclopropyl-
1.15 g (86.5% yield) of 2,3,5-trifluorobenzoic acid are obtained.

Melting point: 141 to 142 ° C (resolved solvent; ethyl acetate-n-hexane) IR (KBr) cm ^-1 ; νC _{= 0} 1700 Reference Example 13 4- (1-diphenylmethoxycarbonylcyclopropyl) -2,5- Dissolve 4.00 g of difluorobenzoic acid in 40 ml of tetrahydrofuran, add 2.38 g of carbonyldiimidazole under ice cooling, stir at the same temperature for 30 minutes, add 2.10 g of magnesium salt of ethoxycarbonylacetic acid, and stir at room temperature for 20 hours . The reaction solution is concentrated under reduced pressure, 50 ml of ethyl acetate and 50 ml of water are added, and the pH is adjusted to 2.0 with 2N-hydrochloric acid. The organic layer is separated, washed successively with water, a saturated aqueous solution of sodium hydrogen carbonate, water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent; toluene: ethyl acetate = 10: 1) to give oily 4- (1).
-Diphenylmethoxycarbonylcyclopropyl) -2,
4.60 g (98.1% yield) of 5-difluorobenzoylacetic acid ethyl ester are obtained.

IR (neat) cm ^-1 ; ν _{C = 0} 1725,1685 Similarly, oily 4-cyclopropyl-2,3,5-trifluorobenzoyl acetic acid ethyl ester is obtained.

IR (neat) cm ^-1 ; ν _{C = 0} 1740,1685 Reference Example 14 1.05 g of ethyl 4- (1-diphenylmethoxycarbonylcyclopropyl) -2,5-difluorobenzoylacetate was dissolved in 8 ml of benzene, and N, 570 mg of N-dimethylformamide dimethyl acetal is added, and the mixture is refluxed for 1.5 hours. The reaction solution is concentrated under reduced pressure, and after adding 5.0 ml of ethanol, 550 mg of 2-fluoro-4-methoxyaniline is added, followed by stirring at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (eluent; toluene: ethyl acetate = 10: 1) to give oily 2- [4- (1-diphenylmethoxycarbonylcyclo). Propyl) -2,5-difluorobenzoyl] -3-
1.20 g (yield 87.0%) of ethyl (2-fluoro-4-methoxyphenylamino) acrylate was obtained.

IR (neat) cm ^-1 ; ν _{C = 0} 1710 Similarly, 2- (4-cyclopropyl-2,3,5-trifluorobenzoyl) -3- (4-methoxyphenylamino) acrylic acid ethyl ester was obtained. obtain.

Melting point 91-92 ° C (resolved solvent; ethyl acetate-n-hexane) IR (KBr) cm ^-1 ; νC _{= 0} 1685 Reference Example 15 1-cyclopropyl-7- (di-tert-butoxycarbonylmethyl)- 6-fluoro-1,4-dihydro-4-
Oxo-3-quinoline carboxylic acid ethyl ester 11.8 g
Was dissolved in 118 ml of N, N-dimethylformamide, 4.00 g of potassium carbonate and 6.84 g of iodomethane were added, and 70 to 80 was added.
Stir at C for 6 hours. The reaction solution is added to a mixture of 200 ml of ethyl acetate and 200 ml of water, and adjusted to pH 1.5 with 6N hydrochloric acid.
The organic layer is separated, washed sequentially with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystalline substance was added with diethyl ether and taken out to give 1-cyclopropyl-7- (1,1-di-t
ert-butoxycarbonylmethyl) -6-fluoro-1,4
10.5 g (86.5% yield) of -dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester are obtained.

Melting point: 130-133 ° C (resolved solvent; ethyl acetate-diisopropyl ether) IR (KBr) cm ^-1 ; ν _{C = 0} 1750 (sh), 1720 Reference Example 16 1-cyclopropyl-7- (1,1- Di-tert-butoxycarbonylethyl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester
Dissolve 10.5 g in 52.5 ml of methylene chloride, add 52.5 ml of trifluoroacetic acid under ice cooling, and stir at room temperature for 16 hours.
Concentrate the reaction under reduced pressure. Diethyl ether is added to the obtained residue, and the crystals are collected. The obtained crystals are suspended in 120 ml of xylene and stirred at 100 to 110 ° C. for 1.5 hours.
Then, the crystals were taken out to give 7.33 g of ethyl 7- (1-carboxyethyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (87.4% yield). Get)

Melting point: 215 to 220 ° C (decomposition) IR (KBr) cm ^-1 ; ν _{C = 0} 1720 Reference Example 17 7- (1-Carboxyethyl) ^-1 -cyclopropyl-6-fluoro-1,4-dihydro-4 -Oxo-3-quinolinecarboxylic acid ethyl ester 6.30 g in benzene 100 ml
And 4.63 g of acetic anhydride and 6.90 g of pyridine N-oxide are added and refluxed for 27 hours. The reaction solution is concentrated under reduced pressure, and the obtained residue is purified by column chromatography (eluent; toluene: ethyl acetate = 1: 2) to give 7-acetyl-1-cyclopropyl-6-fluoro-1 There are obtained 3.43 g (yield 59.5%) of 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester.

Melting point: 219 to 220 ° C (resolved solvent; ethyl acetate) IR (KBr) cm ^-1 ; ν _{C = 0} 1690 Reference Example 18 7-acetyl-1-cyclopropyl-6-fluoro-
To 4.33 g of 1,4-dihydro-4-oxo-3-quinoline carboxylic acid ethyl ester, 22 ml of dioxane and 6N-hydrochloric acid 4
Add 4 ml and reflux for 30 minutes. After the reaction solution was cooled to room temperature, the precipitated crystals were collected and washed with water to give 7-acetyl-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid 3.50. g (yield 88.
6%).

Melting point: 217 to 220 ° C (resolved solvent; ethyl acetate) IR (KBr) cm ^-1 ; νC _{= 0} 1720,1685 Reference Example 19 7-acetyl-1-cyclopropyl-6-fluoro-
1,4-dihydro-4-oxo-3-quinolinecarboxylic acid
1.30 g is dissolved in a mixture of 40 ml of methylene chloride, 40 ml of tert-butyl acetate and 0.83 ml of a 60% aqueous solution of perchloric acid, and the mixture is stirred at room temperature for 14 hours. Then, under ice cooling, the reaction solution is added to 50 ml of water while adjusting the pH to 6 with a saturated aqueous solution of sodium hydrogen carbonate. The organic layer is separated and the solvent is distilled off under reduced pressure. The obtained residue is dissolved in ethyl acetate (100 ml), washed successively with a saturated aqueous solution of sodium bicarbonate, water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent; toluene: ethyl acetate = 10: 1) to give 7-acetyl-1-cyclopropyl-6-fluoro-1. 950 mg (61.3% yield) of tert-butyl 4-, 4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained.

Melting point: 224 to 225 ° C. (resolved solvent: ethyl acetate) IR (KBr) cm ⁻¹ ; ν _{C = 0} 1715,1685 Reference Example 20 1-cyclopropyl-6,8-difluoro-7-diphenylmethoxycarbonylmethyl 1, 2.00 g of 4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester
It is dissolved in 40 ml of N, N-dimethylformamide, and 116 mg of paraformaldehyde is added under ice cooling. Then, a catalytic amount of sodium ethoxide is added and stirred at room temperature for 48 hours.
The reaction solution was added to a mixture of 40 ml of ethyl acetate and 40 ml of water,
Adjust to pH 2 with 2N hydrochloric acid. Separate the organic layer, dilute hydrochloric acid,
After washing with water and saturated saline in this order, the extract is dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (eluent: toluene:
Purification with ethyl acetate = 2: 1) gives amorphous 1-
Cyclopropyl-6,8-difluoro-7- (2-hydroxy-1-diphenylmethoxycarbonylethyl) -1,
1.58 g (74.5% yield) of 4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester is obtained.

IR (KBr) cm ^-1 ; ν _{C = 0} 1725,1685 Reference Example 21 1-cyclopropyl-6,8-difluoro-7- (2-
Hydroxy-1-diphenylmethoxycarbonylmethyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester (1.50 g) was dissolved in methylene chloride (15 ml). Under ice cooling, methanesulfonyl chloride (0.63 g) was added. Then, 1.11 g of triethylamine was added dropwise over 3 minutes, followed by stirring at room temperature for 5 hours. 15 ml of water is added to the reaction solution, and the pH is adjusted to 1 with 2N-hydrochloric acid. The organic layer is separated, washed sequentially with dilute hydrochloric acid, water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent; toluene: ethyl acetate = 3: 1) to give 1-cyclopropyl-6,8-difluoro-7- ( 820 g of ethyl 1-diphenylmethoxycarbonylmethyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylate (yield 5
6.6%).

Melting point: 220 to 222 ° C (resolved solvent: chloroform-ethanol) IR (KBr) cm ^-1 ; νC _{= 0} 1720 Reference Example 22 1-cyclopropyl-6,8-difluoro-7- (1-
900 mg of diphenylmethoxycarbonylmethyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester is suspended in 4.5 ml of anisole, 4.5 ml of trifluoroacetic acid is added under ice cooling, and the mixture is stirred at room temperature for 1.5 hours. . Then, the reaction solution is concentrated under reduced pressure, and diethyl ether is added to the obtained song residue, and the residue is collected to give 7- (1-carboxyvinyl) -1-cyclopropyl-6,8-difluoro-.
570 mg (92.5% yield) of 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester are obtained.

Melting point: 189 to 190 ° C. (decomposition) (Reconstitution solvent: methanol) IR (KBr) cm ⁻¹ ; ν _{C = 0} 1725,1690 Reference Example 23 7- (1-carboxyvinyl) -1-cyclopropyl-6, 8-difluoro-1,4-dihydro-4-oxo-3-
570 g of quinoline carboxylic acid ethyl ester is dissolved in 10 ml of N, N-dimethylformamide and refluxed for 6.5 hours. The reaction solution was added to a mixture of 15 ml of ethyl acetate and 15 ml of water, and 2N
-Adjust to pH 1.5 with hydrochloric acid. Separate the organic layer, dilute hydrochloric acid,
After washing with water and saturated saline in this order, the extract is dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent; toluene: ethyl acetate = 2: 1) to give 1-cyclopropyl-
6,8-difluoro-7-vinyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester 180 mg
(38.6% yield).

Melting point: 189 to 192 ° C. (resolved solvent; ethyl acetate-diisopropyl ether) IR (KBr) cm ⁻¹ ; ν _{C = 0} 1725,1690 Example 1 1-cyclopropyl-7-diphenylmethoxycarbonylmethyl-6-fluoro 2.00 g of 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester was N, N
-Suspended in 20 ml of dimethylformamide, (a) 190 mg of 60% sodium hydride was added at room temperature, stirred for 30 minutes at the same temperature, 930 mg of 1,2-dibromoethane was added, and the mixture was stirred at 45 to 55 ° C for 5 hours. I do.

After this operation (a) is repeated twice more, the reaction solution is added to a mixture of 60 ml of ice water and 60 ml of ethyl acetate, and then adjusted to pH 1 with 6N hydrochloric acid. The organic layer is separated, washed sequentially with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (eluent: chloroform).
1.00 g (47.6%) of 1-cyclopropyl-7- (1-diphenylmethoxycarbonylcyclopropyl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester obtain.

Melting point: 174 to 175 ° C (resolved solvent; ethanol) IR (KBr) cm ^-1 ; ν _{C =} 1720,1685 NMR (CDCl ₃ ) δ value: 0.70 to 2.00 (11H, m), 3.10 to 3.80 (1H , m), 4.40 (2H, q,
J = 7.0Hz), 6.30 ~ 7.50 (11H, m), 7.82 (1H, d, J = 6.0H
z), 8.13 (1H, d, J = 10.0 Hz) 8.56 (1H, s) In the same manner, the compounds in Table 5 are obtained.

Example 2 2- [4- (1-diphenylmethoxycarbonylcyclopropyl) -2,5-difluorobenzoyl] -3-
1.20 g of (2-fluoro-4-methoxyphenylamino) acrylic acid ethyl ester was treated with N, N-dimethylformamide
Dissolve in 10 ml, add potassium carbonate 290 mg, 95 ° C
And stir for 40 minutes. The reaction solution was treated with 30 ml of ethyl acetate and 50
Add to 2 ml of the mixture and adjust to pH 1.0 with 2N-hydrochloric acid. The organic layer is separated, washed successively with 2N-hydrochloric acid, water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting oil was crystallized from diethyl ether and collected to give 7- (1-diphenylmethoxycarbonylcyclopropyl) -6-fluoro-1- (2-fluoro-4. -Methoxyphenyl) -1,4-dihydro-4
-Oxo-3-quinolinecarboxylic acid ethyl ester 710m
g (61.2% yield) are obtained.

Melting point: 198 to 199 ° C (resolved solvent; ethyl acetate-diisopropyl ether) IR (KBr) cm ^-1 ; ν _{C = 0} 1725 Similarly, 7-cyclopropyl-6,8-difluoro-1- (4-methoxy) Phenyl) -1,4-dihydro-4
-Oxo-3-quinolinecarboxylic acid ethyl ester is obtained.

Melting point: 202-203 ° C. (resolved solvent; ethyl acetate-n-hexane) IR (KBr) cm ⁻¹ ; νC _{= 0} 1730,1690 Example 3 1-cyclopropyl-7- (1-diphenylmethoxycarbonylcyclopropyl) ) -6-Fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester (900 mg) is suspended in anisole (4.5 ml), trifluoroacetic acid (4.5 ml) is added at room temperature, and the mixture is stirred at the same temperature for 2 hours. .
Then, the reaction solution is concentrated under reduced pressure, and diethyl ether is added to the obtained residue, and the residue is collected to give 7- (1-carboxycyclopropyl) -1-cyclopropyl-6-fluoro-1,4-dihydrofuran. 580 mg (94.3% yield) of 4-oxo-3-quinolinecarboxylic acid ethyl ester is obtained.

Melting point: 237 to 239 ° C (decomposition) (Resolved solvent: ethyl acetate) IR (KBr) cm ^-1 ; ν _{C =} 1720,1700 (sh) NMR (TFA-d ₁ ) δ value; 1.20 to 2.35 (11H , m), 3.90-4.45 (1H, m), 4.73 (2H, q,
J = 7.0Hz), 8.37 (1H, d, J = 9.0Hz), 8.70 (1H, d, J = 6.0
Hz), 9.38 (1H, s) Similarly, the compounds in Table 6 are obtained.

Example 4 500 mg of 7- (1-carboxycyclopropyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester was allowed to react for about 10 seconds on a burner directly. Complete decarboxylation. The resulting residue was purified by column chromatography (eluent: chloroform) to give 1,7-dicyclopropyl-6.
This gives 200 mg (yield 45.6%) of -fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester.

Melting point: 231 to 233 ° C. (resolved solvent; ethanol) IR (KBr) cm ⁻¹ ; ν _{C = 0} 1720 NMR (CDCl ₃ ) δ value: 0.50 to 1.70 (11H, m), 1.85 to 2.50 (1 H, m) ), 3.15-3.65
(1H, m), 4.38 (2H, q, J = 7.0Hz), 7.42 (1H, d, J = 6.0H
z), 8.00 (1H, d, J = 10.5 Hz), 8.51 (1H, s) Similarly, the compounds in Table 7 are obtained.

Example 5 (1) 250 mg of ethyl 7- (2-benzyloxymethylcyclopropyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate was suspended in 10 ml of ethanol. Cloudy, then 5%
10 mg of palladium-carbon is added, and the mixture is stirred at room temperature under a normal pressure under a hydrogen stream for 5 hours. After removing the catalyst, the solvent was distilled off under reduced pressure, and diethyl ether was added to the obtained residue, and the residue was collected to give 1-cyclopropyl-6-fluoro-7-.
170 mg (85.9% yield) of (2-hydroxymethylcyclopropyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester are obtained.

Melting point: 174 to 175 ° C. (resolved solvent; ethyl acetate) IR (KBr) cm ⁻¹ ; ν _{C = 0} 1715,1690 (sh) NMR (CDCl ₃ ) δ value: 0.70 to 2.50 (12H, m), 3.10 ~ 3.85 (3H, m), 4.37 (2H, q,
J = 7.0Hz), Similarly, compounds of Table-8 are obtained.

(2) 1,7-dicyclopropyl-6-fluoro-1,4-
150 mg of ethyl dihydro-4-oxo-3-quinolinecarboxylate is added to a mixed solution of 3 ml of ethanol and 3 ml of 1N aqueous sodium hydroxide solution, and the mixture is stirred at room temperature for 2 hours. Then, 6 ml of water and 20 ml of chloroform were added, and 6N
-Adjust to pH 1 with hydrochloric acid. The organic layer is separated, washed sequentially with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, diethyl ether is added to the obtained crystalline substance, and the mixture is collected to give 1,7-dicyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline. 120 mg of carboxylic acid (87.6% yield) are obtained.

Melting point: 226 to 228 ° C (solvent: chloroform-ethanol) IR (KBr) cm ^-1 ; ν _{C = 0} 1720 NMR (CDCl ₃ ) δ value: 0.50 to 1.80 (8H, m), 1.95 to 2.60 (1H , m), 3.15-3.85
(1H, m), 7.60 (1H, d, J = 6.0Hz), 7.98 (1H, d, J = 10.5H
z), 8.75 (1H, s) 14.66 (1H, bs) In the same manner, the compounds in Table 9 are obtained.

Example 6 50.0 mg of 7-cyclopropyl-6-fluoro-1- (4-methoxyphenyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was dissolved in 5 ml of methylene chloride, and the solution was added under ice cooling. Add 500 mg of boron bromide and stir at the same temperature for 4 hours. Then, the reaction solution was mixed with 20 ml of ice water and 20 ml of methylene chloride.
to a mixture of 2 ml of methanol and 2 ml of methanol. The organic layer is separated, washed sequentially with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, diethyl ether is added to the obtained crystalline substance, and the mixture is collected to give 7-cyclopropyl-6-fluoro-1- (4-hydroxyphenyl) -1,4-dihydro-4. -Oxo-3
-40.0 mg of quinolinecarboxylic acid (83.3% yield) are obtained.

Melting point: 280 ° C. or higher (reconstitution solvent: ethanol) IR (KBr) cm ⁻¹ ; νC _{= 0} 1700 NMR (TFA-d ₁ ) δ value: 0.60 to 1.60 (4H, m), 2.10 to 2.65 (1H, m), 6.90 ~ 7.60
(5H, m), 8.31 (1H, d, J = 9.5Hz), 9.28 (1H, s) Similarly, the compounds of Table-10 are obtained.

Example 7 1.90 g of ethyl 7- (1-carboxycyclopropyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate was suspended in 19 ml of methylene chloride, Azide diphenyl phosphate 2.20
g and 800 mg of triethylamine are added and stirred at room temperature for 3 hours. Then, 20 ml of 2H-hydrochloric acid is added, and the organic layer is separated. After washing sequentially with 2N-hydrochloric acid, water and saturated saline,
Dry over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the obtained residue is suspended in 40 ml of tert-butanol and refluxed for 3 hours. Then, the reaction solution is concentrated under reduced pressure, and the obtained residue is purified by column chromatography (eluent; chloroform: ethanol = 25: 1),
1.00 g (yield 43.9%) of ethyl 7- (1-tert-butoxycarbonylaminocyclopropyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate is obtained. .

Melting point: 161 to 163 ° C (resolved solvent; ethyl acetate-diisopropylethanol) IR (KBr) cm ^-1 ; ν _{C = 0} 1720,1700 (sh) NMR (CDCl ₃ ) δ value: 0.80 to 1.65 (20H, m ), 3.20-3.70 (1H, m), 4.38 (2H, q,
J = 7.0Hz), 5.42 (1H, bs), 8.05 (1H, d, J = 10.5Hz), 8.
15 (1H, d, J = 6.5 Hz) 8.56 (1H, s) Similarly, the compounds in Table 11 are obtained.

Example 8 7- (2-benzyloxymethyl-1-tert-butoxycarbonylaminocyclopropyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3
-800 mg of quinoline carboxylic acid ethyl ester is suspended in 20 ml of ethanol, then 5% palladium-carbon 300 m
g, and the mixture is stirred at room temperature under a normal pressure under a hydrogen stream for 2.5 hours.
After removing the catalyst, the solvent was distilled off under reduced pressure, and diisopropyl ether was added to the obtained crystalline substance, which was collected to give 7- (1-tert-butoxycarbonylamino-2-yl).
(Hydroxymethylcyclopropyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-
Quinolinecarbic acid ethyl ester 650mg (97.2% yield)
Get.

Melting point: 181 to 182 ° C. (resolved solvent; ethyl acetate) IR (KBr) cm ⁻¹ ; ν _{C = 0} 1715,1700 (sh) NMR (CDCl ₃ ) δ value: 0.80 to 2.45 (20H, m), 3.00 ~ 3.80 (3H, m), 4.37 (2H, q,
J = 7.0Hz), 5.53 (1H, S), 8.04 (1H, d, J = 10.5Hz), 8.3
5 (1H, d, J = 6.0 Hz), 8.56 (1 H, s) Example 9 (1) 7- (1-tert-butoxycarbonylaminocyclopropyl) -1-cyclopropyl-6-fluoro-1,
Dissolve 390 mg of 4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester in 2 ml of trifluoroacetic acid,
Stir at room temperature for 2 hours. Then, the reaction solution was concentrated under reduced pressure, and the obtained residue was treated with 6N-hydrochloric acid (10 ml) and chloroform.
Add 10 ml and separate the aqueous layer. PH with sodium bicarbonate
After adjusting to 7.5, chloroform 20 ml and ethanol 1
Add ml and separate the organic layer. After washing with water and saturated saline in this order, the extract is dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, diethyl ether is added to the obtained crystalline substance, and the residue is collected to give 7- (1-aminocyclopropyl) -1-cyclopropyl-6-fluoro-1,4-dihydro- 230 mg (76.9% yield) of 4-oxo-3-quinolinecarboxylic acid ethyl ester are obtained.

Melting point: 213 to 216 ° C (resolved solvent; ethanol) IR (KBr) cm ^-1 ; ν _{C =} 1720,1685 NMR (CDCl ₃ ) δ value: 0.80 to 1.60 (11H, m), 2.03 (2H, bs) ), 3.15-3.65 (1H,
m), 4.39 (2H, q, J = 7.0Hz), 7.85 (1H, d, J = 6.0Hz), 8.
04 (1H, d, J = 10.5 Hz) 8.54 (1 H, s) In the same manner, the compounds in Table-12 are obtained.

(2) 7- (1-aminocyclopropyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester (220 mg) in ethanol (2.2 ml) and 1N sodium hydroxide An aqueous solution (2.2 ml) is added and the mixture is stirred at room temperature for 4 hours. Then, pH 7.
Adjusted to 0, and if the precipitated crystals are collected, 7- (1-aminocyclopropyl) -1-cyclopropyl-6-fluoro-
1,4-dihydro-4-oxo-3-quinolinecarboxylic acid 1
20 mg (59.7% yield) are obtained.

Melting point: 250 to 251 ° C (resolved solvent; ethanol) IR (KBr) cm ^-1 ; ν _{C = 0} 1720 NMR (TFA-d ₁ ) δ value: 1.20 to 2.30 (8H, m), 3.90 to 4.50 (1H , m), 8.49 (1H, d, J
= 9.5 Hz), 8.93 (1H, d, J = 6.0 Hz), 9.51 (1H, s) Similarly, the compounds in Table 13 are obtained.

Example 10 7- (1-Aminocyclopropyl) -6-fluoro-
1- (4-methoxyphenyl) -1,4-dihydro-4-
To 120 mg of oxo-3-quinolinecarboxylic acid was added 2.4 ml of 47% hydrobromic acid, and the mixture was refluxed for 1 hour. After cooling the reaction solution to room temperature, the precipitated crystals are collected and washed sequentially with water and ethanol to give 7- (1-aminocyclopropyl) -6-
100 mg (70.4% yield) of hydrobromide of fluoro-1- (4-hydroxyphenyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained.

Melting point: 272 to 277 ° C (decomposition) (Resolvent: methanol) IR (KBr) cm ^-1 ; ν _{C = 0} 1720 NMR (TFA-d ₁ ) δ value; 1.10 to 2.20 (4H, m), 7.10 to 7.75 (4H, m), 7.98 (1H, d, J
= 6.0 Hz), 8.52 (1H, d, J = 9.5 Hz), 9.42 (1H, s) Similarly, 7- (1-aminocyclopropyl) -1
-(3,4-dihydroxyphenyl) -6-fluoro-1,4
To give the hydrobromide salt of -dihydro-4-oxo-3-quinolinecarboxylic acid.

Melting point: 280 ° C. or more (reconstitution solvent: methanol) IR (KBr) cm ⁻¹ ; ν _{C = 0} 1720 (sh), 1670 NMR (TFA-d ₁ ) δ value; 1.05 to 2.25 (4H, m), 6.80 Up to 7.70 (3H, m), 8.02 (1H, d, J
= 6.0 Hz), 8.51 (1H, d, J = 9.5 Hz), 9.41 (1H, s) Example 11 7- (1-Amino-2-hydroxymethylcyclopropyl) -1-cyclopropyl-6-fluoro- To 100 mg of ethyl 1,4-dihydro-4-oxo-3-quinolinecarboxylate are added 1 ml of dioxane and 1 ml of 6N-hydrochloric acid, and the mixture is refluxed for 30 minutes. Then, the reaction solution is concentrated under reduced pressure, and 2-propanol is added to the obtained crystalline substance, which is collected to give 7- (1-amino-2-hydroxymethylcyclopropyl) -1-cyclopropyl-6-. Fluoro-
There are obtained 50 mg (49.0% yield) of the hydrochloride of 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

Melting point: 280 ° C. or more (resolved solvent: ethanol) IR (KBr) cm ⁻¹ ; ν _{C = 0} 1720, 1690 NMR (TFA-d ₁ ) δ value; 3H, m), 8.42 (1H, d, J
= 9.5 Hz), 8.92 (1H, d, J = 6.0 Hz), 9.43 (1H, s) Example 12 176 mg of diisopropylamine was dissolved in 2.5 ml of anhydrous tetrahydrofuran, and n-butyllithium was added at -70 to -60 ° C. 1.16 ml of a 1.5 M n-hexane solution are added. Then, at the same temperature, 7-acetyl-1-cyclopropyl-6
60 ml of anhydrous tetrahydrofuran solution containing 500 mg of tert-butyl-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate are added dropwise over 30 minutes.
After stirring at the same temperature for 1 hour, diiodosamarium prepared from 871 mg of samarium and 1.35 g of diiodoethane was immediately added at -70 to -60 ° C using a pipette, and then 969 mg of diiodomethane was added, followed by 1.5 hours. And the temperature is raised to room temperature. The reaction solution was chloroform 10
0 ml and a mixture of ice water 100 ml, and pH 1.5 with 2N hydrochloric acid.
Adjust to The organic layer is separated, washed sequentially with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent; chloroform: acetone = 4: 1) to give 1-cyclopro-6-fluoro-7- (1
-Hydroxycyclopropyl) -1,4-dihydro-4-
Oxo-3-quinolinecarboxylic acid tert-butyl ester
65 mg (12.5% yield) are obtained.

Melting point: 150-152 ° C IR (KBr) cm ^-1 ; ν _{C = 0} 1715,1680 NMR (CDCl ₃ ) δ value; 0.80-1.80 (18H, m), 3.20-3.65 (1H, m), 7.75-8.20
Example 13 1-Cyclopropyl-6-fluoro-7- (1-hydroxycyclopropyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid tert (2H, m), 8.49 (1H, s) Dissolve 60 mg of -butyl ester in 2 ml of methylene chloride, add 2 ml of trifluoroacetic acid under ice cooling, and stir at room temperature for 45 minutes. The reaction solution is concentrated under reduced pressure, 3 ml of water is added, and the mixture is extracted twice with 3 ml of chloroform. The organic layer is washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and diethyl ether was added to the obtained residue. The residue was collected to give 1-cyclopropyl-6-fluoro-7- (1-hydroxycyclopropyl) -1,4-dihydro-4. 30 mg (59.3% yield) of -oxo-3-quinolinecarboxylic acid are obtained.

Melting point: 165 to 170 ° C IR (KBr) cm ^-1 ; ν _{C = 0} 1700 NMR (CDCl ₃ ) δ value: 0.95 to 2.40 (9H, m), 3.20 to 4.00 (1H, m), 8.06 (1H, d , J
= 10.5Hz), 8.28 (1H, d, J = 6.5Hz), 8.81 (1H, s), 14.4
5 (1H, bs) Example 14 1-Cyclopropyl-6,8-difluoro-7-vinyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester (170 mg) was dissolved in tetrahydrofuran (10 ml), and dissolved in ice. 1.00 g of N-methyl-N-nitrosourea under cooling
And then stirred at the same temperature for 1 hour and further at room temperature for 13 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was diluted with 17 ml of xylene.
And reflux for 1 hour. The solvent was distilled off under reduced pressure, and n-hexane was added to the obtained crystalline substance.
167 mg (94.4% yield) of ethyl 7-dicyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate was obtained.

Melting point: 176 to 178 ° C (resolved solvent; ethyl acetate-diisopropyl ether) IR (KBr) cm ^-1 ; ν _{C =} 1730,1690 NMR (CDCl ₃ ) δ value: 0.70 to 1.60 (11H, m), 1.70 ~ 2.40 (1H, m), 3.50 ~ 4.10
(1H, m), 4.39 (2H, q, J = 7.0Hz), 7.89 (1H, dd, J = 10.5
Hz, J = 2.0 Hz), 8.55 (1H, s) Example 15 145 mg of 1,7-dicyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester in 1N -Add to a mixture of 1.45 ml of aqueous sodium hydroxide solution and 2.0 ml of ethanol and stir at room temperature for 1.5 hours. The reaction solution was adjusted to pH 3 with 2N-hydrochloric acid, and the precipitated crystals were collected to give 1,7-dicyclopropyl-6,8-difluoro-1,4.
-Dihydro-4-oxo-3-quinolinecarboxylic acid 122 mg
(91.7% yield).

Melting point: 176 to 179 ° C (resolved solvent; ethyl acetate) IR (KBr) cm ^-1 ; ν _{C = 0} 1725 NMR (CDCl ₃ ) δ value: 0.70 to 1.65 (8H, m), 1.75 to 2.45 (1H, m), 3.65-4.30
(1H, m), 7.88 (1H, dd, J = 10.5Hz, J = 2.0Hz), 8.81 (1
H, s), 14.31 (1H, bs)

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Yoshikazu Fukuoka 1-10 Shirokawara, Toyama City, Toyama Prefecture 4 Prefectural Housing 4-204 (72) Inventor Isamu 7-52 Oizuminakamachi, Toyama City, Toyama Prefecture Examiner Yoshihiro Sano

Claims (1)

(57) [Claims] (1) General formula Wherein R ¹ is a hydrogen atom or a carboxy protecting group; R ²
Is a halogen atom, a cyano group, a carboxyl group, a hydroxyl group, an amino group, an alkyl group, an alkoxy group, an alkoxycarbonyl group, an aryl group, a cycloalkyl group,
Acylamino group, acyloxy group, lower alkenyl group,
A lower alkyl, lower alkenyl, cycloalkyl or aryl group optionally substituted with one or more of the following substituents selected from a trihalogenoalkyl group, a mono- or di-alkylamino group; X represents a hydrogen atom or A halogen atom; R ³ is a halogen atom, a lower alkyl group, an optionally protected hydroxyl group, an optionally protected amino group, an optionally protected carboxyl group, an optionally protected hydroxy lower group And a cyclopropyl or cyclobutyl group which may be substituted with one or more substituents selected from alkyl groups. The quinoline derivative represented by these, and its salt.