JPH05310703A - New quinolonecarboxylic acid derivative, its ester, its salt and production thereof - Google Patents

Abstract

PURPOSE:To provide a new quinolonecarboxylic acid derivative exhibiting an excellent antimicrobial activity. CONSTITUTION:A new quinolonecarboxylic acid of formula I (R1 is H, an alkyl, an acyl, an alkoxycarbonyl, a mono- or di-alkylaminoalkyl, etc.; R2 is H or an alkyl; A three- to six-membered cyclic amino may be formed in combination of R1 and R2 together with the adjacent N; R3 and R4 are each H or an alkyl. A ring may be formed in combination of R3 and R4; R5 is an alkyl, an alkenyl, a cyclopropyl or a fluorinated phenyl; X is C-H, C-Cl, C-F, C-CH3, C-OCH3 or N), its ester or its salt, e.g. 7 (3-amino-1-propynyl)-1-cyclopropyl-6,8- difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. The compound of formula I can be obtained by reacting a quinolonecarboxylic acid of formula II (Y is a halogen) or its ester with a compound of formula III.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel quinolonecarboxylic acid derivative having extremely excellent antibacterial activity, its ester and its salt, and a method for producing the same.

[0002]

BACKGROUND OF THE INVENTION Certain quinolonecarboxylic acid derivatives having a substituted alkynyl group directly bonded to the 7-position and a method for producing the same are known and disclosed in JP-A-2-45469.

[0003]

It is an object of the present invention to provide a novel quinolonecarboxylic acid derivative having a 3-amino-1-propynyl group at the 7-position which exhibits excellent antibacterial activity.

[0004]

DETAILED DESCRIPTION OF THE INVENTION

[0005]

[Chemical 4]

[Wherein R ₁ represents a hydrogen atom, a lower alkyl group, an acyl group, a lower alkoxycarbonyl group, a mono- or di-lower alkylamino lower alkyl group, or an amino lower alkyl group, and R ₂ represents a hydrogen atom or A lower alkyl group, or R ₁ and R ₂ are taken together to form a 3- to 6-membered cyclic amino group together with the nitrogen atom to which they are bonded (the cyclic amino group may also contain a hetero atom). R ₃ and R ₄ are the same or different and each represents a hydrogen atom or a lower alkyl group, or R ₃ and R ₄ may together form a ring, R ₅ is a linear or branched alkyl group having 1 to 4 carbon atoms, an alkenyl group, a cyclopropyl group or 1
Means phenyl group substituted with ~ 2 fluorine atoms, X is CH, C-Cl, C- F, C-CH 3, C-
It means OCH ₃ or a nitrogen atom. ] The present invention relates to a novel quinolonecarboxylic acid derivative, its ester and its salt, and a method for producing the same.

In the present specification, the "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and the "lower alkyl group" includes, for example, methyl, ethyl, propyl, butyl, isobutyl, ter
Examples include t-butyl, pentyl, neopentyl and the like.
Examples of the “acyl group” include formyl, acetyl,
Examples include propionyl, butyryl, isobutyryl, pivaloyl and the like. Examples of the "lower alkoxycarbonyl group" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the like. Examples of the “mono- or di-lower alkylamino lower alkyl group” include monomethylaminoethyl, dimethylaminoethyl and the like. Examples of the “amino lower alkyl group” include aminomethyl, aminoethyl, aminopropyl and the like. Examples of the "hetero atom" include a nitrogen atom, an oxygen atom or a sulfur atom.

The ester of the compound of Chemical formula 4 is a known ester such as a methyl ester, a lower alkyl ester such as an ethyl ester, which can be easily eliminated by hydrolysis or in vivo. Acetoxymethyl ester, pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester, choline ester,
It means aminoethyl esters such as dimethylaminoethyl ester and piperidinoethyl ester, 5-indanyl ester, phthalidyl ester and the like.

The salt of the compound of formula 4 or its ester is
Salts with inorganic acids such as hydrochloric acid and phosphoric acid; salts with organic acids such as acetic acid, lactic acid, oxalic acid, succinic acid, methanesulfonic acid, maleic acid, malonic acid and gluconic acid; acidic amino acids such as aspartic acid and glutamic acid Or a metal salt of the compound of formula 4 with sodium, potassium, calcium, magnesium, zinc, silver, etc .; a salt with an organic base such as dimethylamine, triethylamine, dicyclohexylamine, benzylamine; a base such as lysine, arginine, etc. It is a salt with a soluble amino acid.

Some of the compounds of the present invention exist as hydrates. Therefore, such forms are of course included in the compound of the present invention. Further, the compound of the present invention includes a compound having an asymmetric carbon atom in the substituent at the 7-position,
They can exist as optically active forms. Therefore, these optically active substances are also included in the compound of the present invention.

The preferred compounds among the compounds of the present invention include the following compounds. 7- (3-amino-1-propynyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-
Oxoquinoline-3-carboxylic acid. * 1-cyclopropyl-6,8-difluoro-1,4-
Dihydro-7- (3-methylamino-1-propynyl)
-4-oxoquinoline-3-carboxylic acid. 7- (3-amino-1-propynyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. -1-Cyclopropyl-6-fluoro-1,4-dihydro-7- (3-methylamino-1-propynyl) -4-
Oxoquinoline-3-carboxylic acid. * 7- (3-amino-1-propynyl) -8-chloro-
1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. 7- (3-amino-1-propynyl) -1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. 7- (3-amino-1-propynyl) -1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. 7- (3-amino-1-propynyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.

The method for producing the compound of the present invention is described below. (1) The compound of the present invention has the following chemical formula

[0013]

[Chemical 5]

(In the formula, Y means a halogen atom,
R ₃ , R ₄ and R ₅ are the same as above. ) And a quinolonecarboxylic acid or ester thereof (preferably a lower alkyl ester) represented by the following chemical formula 6

[0015]

[Chemical 6]

(In the formula, R ₁ and R ₂ are the same as the above.)
It can be produced by reacting the compound represented by and isolating the product by a conventional method.

This reaction does not influence the reaction, such as alcohols such as ethanol, dioxane, terahydrofuran, ethers such as 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene, toluene and xylene, 10 to 180 in an inert solvent such as acetonitrile, dimethylformamide, dimethylsulfoxide, pyridine and water
C., preferably 10 to 120.degree. C., starting compound 5 or its ester and starting compound 6 for 10 minutes to 2
It can be carried out by mixing and stirring for 4 hours.

If possible, the starting compound compound 6 used in this reaction may be used in a form protected with a group not participating in the reaction, and the protecting group may be removed by a conventional method after completion of the reaction. The protecting group may be any as long as it removes the structure of the compound of the present invention formed by the reaction without destroying it, and may be a peptide, an amino acid, a nucleic acid, or α.
A group commonly used as a protecting group in the field of chemistry of lactam compounds, which is a substituted carbonyl group such as formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, benzyloxycal, and tert-butoxycarbonyl; a benzyl group; Specific examples include a trityl group; a tri-lower alkylsilyl group such as a trimethylsilyl group; a p-toluenesulfonyl group; an o-nitrophenylsulfenyl group; a diphenylphosphinyl group; or a tetrahydropyranyl group. Preferred protecting groups include, for example, formyl, acetyl, trifluoroacetyl, tert.
Examples are easily hydrolyzable groups such as -butoxycarbonyl or benzyl groups.

In addition, this reaction is generally carried out in the presence of an acid acceptor, using the starting compound 6 as an equivalent or a slight excess to the starting compound 5 or its ester. Chemical formula 6 may be used in excess to serve also as the acid acceptor. Examples of the acid acceptor include hydroxides such as sodium hydroxide and potassium hydroxide, carbonates such as sodium carbonate and potassium carbonate, bicarbonates such as sodium bicarbonate and potassium bicarbonate, triethylamine, dimethylaniline, and N. , N-diisopropylethylamine, and organic bases such as 1,8-diazabicyclo [5.4.0] undecene-7 (DBU).

The starting compound 5 or its ester can be produced by the method described in Reference Examples 2 to 5 or a method analogous thereto. (2) Further, the compound of the present invention has the following chemical formula

[0021]

[Chemical 7]

(In the formula, Z means a chlorine atom, a bromine atom or an iodine atom, and X and R ₅ are the same as those mentioned above.) And a quinolonecarboxylic acid or its ester (preferably a lower alkyl ester) 8

[0023]

[Chemical 8]

(In the formula, R ₁ , R ₂ , R ₃ and R ₄ are the same as those mentioned above.) The compound represented by the formula (1) is used in the presence of a base in the atmosphere of an inert gas to form a zero-valent or divalent palladium catalyst. Can be used for the reaction, and the product can be isolated by a conventional method. As a palladium catalyst, tetrakis (triphenylphosphine) palladium, tetrakis (triphenylphosphine) palladium / copper (I) iodide, dichlorobistriphenylphosphine palladium / copper (I) iodide, dichlorobistriphenylphosphine palladium / copper iodide (I) ) / Triphenylphosphine, palladium acetate / triphenylphosphine and the like.

This reaction is carried out in an inert solvent in the range of 10-150.
It can be carried out by reacting the raw material compound 7 or its ester with the raw material compound 8 at 48 ° C., preferably 50 to 120 ° C. for 1 to 48 hours. On the other hand, it is generally performed using an equivalent amount or a slight excess amount, but an excess amount may be used. As the solvent, dioxane,
Terahydrofuran, ethers such as 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene, xylene; acetonitrile, dimethylformamide,
Pyridine or the like is used. As the base, secondary amines such as dimethylamine and diethylamine; tertiary amines such as trimethylamine and triethylamine, organic bases such as piperidine, and inorganic bases such as sodium hydroxide, sodium ethoxide, potassium carbonate and potassium phosphate are used. It These bases are usually used in an equivalent amount or an excess amount. Further, a secondary amine such as dimethylamine or diethylamine, a tertiary amine such as trimethylamine or triethylamine, or an organic base such as piperidine may also serve as a solvent.

The starting compound 8 used in this reaction is, if possible, used in a form protected with a group that does not participate in the reaction as described in (1) above. May be removed.

When the compound of the present invention obtained by each of the above methods is an ester, it can be converted to the compound of Chemical formula 4 by hydrolyzing the ester portion by a conventional method.

The starting compound 7 or its ester can be produced by the method described in Reference Example 1 or a method analogous thereto.

Furthermore, if necessary, the compound of Chemical formula 4 can be esterified by a conventional method to give an ester of the compound of Chemical formula 4. Further, the compound of the present invention having a primary and / or secondary amino group can be alkylated by a conventional method (for example, by treating with a lower alkyl aldehyde and formic acid).

The compound of the present invention thus produced is isolated and purified by a conventional method. Depending on the isolation / purification conditions, it can be obtained in the form of a salt or a free form, which are mutually converted depending on the purpose to produce the desired form of the compound of the present invention.

The optically active form of the compound of the present invention can be obtained by a conventional method, for example, fractional crystallization, chromatographic separation, etc.
Can be separated from each other. A compound of the present invention having a specific optically active substance can also be produced by each of the above methods using a starting compound having a specific optically active substance.

The compound of the present invention, which is a compound represented by Chemical formula 4, an ester thereof or a salt thereof, is a novel compound. Since these compounds show extremely excellent antibacterial activity, they are valuable as antibacterial agents, and can be used not only as drugs for humans and animals but also as fish disease drugs, agricultural chemicals, preservatives for foods, etc. Is.

When the compound of the present invention is used as an antibacterial agent in humans, its dose varies depending on age, body weight, symptoms, administration route, etc., but 5 mg to 5 g per day is administered once or in several divided doses. Is recommended. The route of administration may be oral or parenteral.

The compound of the present invention may be a raw powder,
Usually, it is administered in the form prepared with a pharmaceutical carrier. Specific examples are tablets, liquids, capsules, granules,
Examples include fine granules, powders, syrups, injections, ointments and the like. These preparations are prepared according to a conventional method. As the oral pharmaceutical carrier, substances commonly used in the pharmaceutical field such as starch, mannitol, crystalline cellulose, CMC Na, water and ethanol and which do not react with the compound of the present invention are used. Examples of carriers for injection include carriers commonly used in the field of injectables such as water, physiological saline, glucose solutions, and infusions. In addition, the above liquids and ointments are
It can also be used in otolaryngology and ophthalmology treatments.

[0035]

The antibacterial activity of the compounds of the present invention is shown below.

[0036]

[Table 1]

* Experimental conditions The minimum inhibitory concentration (MIC: μg / ml) is Chemotherap.
y, Vol. 29, No. 1, page 76 (1981).

The compounds of the present invention show excellent antibacterial activity as indicated above. In addition, it shows an excellent in vivo protective effect against local or systemic infection by various bacteria, and also shows good safety in general toxicity tests in animals.

[0039]

EXAMPLES Next, the production method of the compound of the present invention will be explained more specifically with reference to Examples and Reference Examples.

Reference Example 1 Ethyl 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-iodo-4-oxoquinoline-3-carboxylate: Known 7-amino-1-cyclo Propyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-
Ethyl carboxylate 161.1 g, cuprous iodide 129.
A mixture of 5 g and 1.5 l of acetonitrile was stirred 6
Warmed to 0 ° C. 80.9 g of tert-butyl nitrite was added dropwise over 45 minutes. After dropping, continue at the same temperature for 4.
Stir for 5 hours. After cooling, 3 l of water was added, and the precipitated crystals were collected by filtration. The residue was subjected to silica gel chromatography (eluent: mixed solvent of chloroform and ethanol) to obtain 63.5 g of the desired product. m. p. 215-218 ° C (recrystallized from chloroform-ethanol).

Reference Example 2 Ethyl 7- (3-chloro-1-propynyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate :-( 1a) 1-Cyclopropyl-6,8-difluoro-
1,4-dihydro-7-iodo-4-oxoquinoline-
40 g of ethyl 3-carboxylate and 1 of propargyl alcohol
5.0 g of tetrakis (triphenylphosphine) palladium as a catalyst in 0.7 ml of 600 ml of triethylamine
And 1.82 g of cuprous iodide were heated to reflux for 4.5 hours in a nitrogen atmosphere. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to dryness. The residue was subjected to silica gel column chromatography (eluent: mixed solvent of chloroform and ethanol), and 1
-Cyclopropyl-6,8-difluoro-1,4-dihydro-7- (3-hydroxy-1-propynyl) -4-
21.4 g of ethyl oxo-quinoline-3-carboxylate was obtained. m. p. 231-233 ° C (recrystallized from chloroform-ethanol).

(1b) 8.0 g of ethyl 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-iodo-4-oxoquinoline-3-carboxylate and 3-tetrahydropyranyloxy-1- 5.35 g of propyne was heated to reflux in a nitrogen atmosphere for 2 hours using 1.1 g of tetrakis (triphenylphosphine) palladium and 364 mg of cuprous iodide as catalysts in 100 ml of triethylamine, and concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: mixed solvent of chloroform and ethanol) to give 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (3-tetrahydropyranyloxy. -1-Propinyl) -quinoline-3
-6.18 g of ethyl carboxylate was obtained. m. p. 138
~ 140 ° C (recrystallized from chloroform-ethanol).
This compound 1.50 g, p-toluenesulfonic acid monohydrate 80 mg, ethanol 30 ml and dichloromethane 1
5 ml of the mixture was stirred at room temperature for 20 hours and concentrated to dryness under reduced pressure. Ethanol was added to the residue, the crystals were collected by filtration, and 1-
1.04 g of ethyl cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (3-hydroxy-1-propynyl) -quinoline-3-carboxylate was obtained. m. p. 231-233 ° C (recrystallized from chloroform-ethanol).

(2) A mixture of 302 mg of the compound obtained in the above (1a) or (1b), 0.2 ml of thionyl chloride and 10 ml of 1,2-dichloroethane was stirred at room temperature for 1.5 hours. The mixture was concentrated to dryness under reduced pressure, and ethanol and isopropyl ether were added to the residue. The precipitated crystals were collected by filtration to obtain 266 mg of the desired product. m. p. 209-210 ° C.

Reference Example 3 7- (3-Chloro-1-propynyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid: -7- 260 mg of ethyl (3-chloro-1-propynyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate and glacial acetic acid / water / concentrated sulfuric acid (8: 6) : 1, v / v) 3 ml of a mixture was heated under reflux for 1 hour. After the reaction was completed, ice water was added, and the precipitated crystals were collected by filtration and dried to obtain 228 mg of the desired product.
m. p. 253-255 ° C (decomposition).

Reference Example 4 Ethyl 7- (3-bromo-1-propynyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate: -1 3.55 g of ethyl cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (3-hydroxy-1-propynyl) -quinoline-3-carboxylate
And 1.58 ml of thionyl bromide were treated in the same manner as in Reference Example 2 (2) to obtain 3.76 g of the desired product. m. p. 208 ~
210 ° C. (recrystallized from chloroform-ethanol).

Reference Example 5 7- (3-Bromo-1-propynyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid: -7- 3.0 g of ethyl (3-bromo-1-propynyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate was treated in the same manner as in Reference Example 3. Thus, 2.74 g of the desired product was obtained.
m. p. 229-231 ° C (recrystallized from chloroform-ethanol).

Example 1 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7- [3- (1-pyrrolidinyl)
-1-Propinyl] -quinoline-3-carboxylic acid: -7- (3-chloro-1-propynyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3- Carboxylic acid 221mg, pyrrolidine 1
A mixture of 39 mg and 4 ml dichloromethane was heated to reflux for 1 hour. The mixture was concentrated to dryness under reduced pressure, and acetonitrile was added to the residue. The precipitated crystals were collected by filtration to obtain 124 mg of the desired product.
m. p. 188-191 ° C (decomposition) (recrystallized from chloroform-acetonitrile).

Example 2 1-Cyclopropyl-7- (3-dimethylamino-1-
Propinyl) -6,8-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid: -7- (3-Bromo-1-propynyl) -1-cyclopropyl-6,8-difluoro- A mixture of 300 mg of 1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.3 ml of 50% dimethylamine aqueous solution and 9 ml of ethanol was stirred at room temperature for 2 hours. The mixture was concentrated to dryness under reduced pressure, and ethanol was added to the residue. The precipitated crystals were collected by filtration to give the desired product 89
to obtain mg. m. p. 195-197 ° C (decomposition) (recrystallized from chloroform-ethanol).

In the same manner as in Example 2, using the corresponding amine, the compounds of Examples 3 to 5 were obtained.

Example 3 7- (3-Amino-1-propynyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid: -m. p. 231-234 ° C (decomposition).

Example 4 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7- (3-methylamino-1-propynyl)-
4-oxoquinoline-3-carboxylic acid: -m. p. 233-235 ° C (decomposition).

Example 5 7- [3- (2-Aminoethylamino) -1-propynyl] -1-cyclopropyl-6,8-difluoro-1,
4-dihydro-4-oxoquinoline-3-carboxylic acid:
-M. p. 195-200 ° C (decomposition).

Reference Example 6 3-tert-Butoxycarbonylamino-1-propyne: 4 g of commercially available 3-amino-1-propyne was dissolved in 40 ml of dichloromethane, and 15.8 g of ditert-butyl dicarbonate was added at room temperature. Was added little by little and stirred for 2 hours. The mixture was concentrated to dryness under reduced pressure, and n-hexane was added to the residue. The precipitated crystals were collected by filtration to obtain 9.07 g of the desired product. m.
p. 41-42 ° C

Similarly, 3-amino-1-butyne [Jo
urnal of Organic Chemistry, 21 , 791 (1956)] and 3-amino-3-methyl-1.
The corresponding compounds below were obtained from butyne (commercially available). 3-tert-butoxycarbonylamino-1-butyne: -m. p. 84-85 ° C 3-tert-butoxycarbonylamino-3-methyl-1-butyne: -m. p. 59-61 ° C

Example 6 7- (3-tert-butoxycarbonylamino-1-
Ethyl propynyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate: -1-cyclopropyl-6,8-difluoro-1,4-dihydro-7 2.0 g of ethyl iodo-4-oxoquinoline-3-carboxylate and 1.48 g of 3-tert-butoxycarbonylamino-1-propyne in 50 ml of triethylamine were used as catalysts in an amount of 276 mg of tetrakis (triphenylphosphine) palladium and iodide. The mixture was heated to reflux for 4 hours under a nitrogen atmosphere using 91 mg of cuprous copper. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to dryness. The residue was subjected to silica gel column chromatography (eluent: mixed solvent of chloroform and ethanol) to obtain 1.25 g of the desired product. m. p. 182
˜183 ° C. (recrystallized from dichloromethane-isopropyl ether).

The compounds of Examples 7 and 8 were obtained in the same manner as in Example 6 using the corresponding 3-substituted amino-1-butyne.

Example 7 7- (3-tert-butoxycarbonylamino-1-
Butynyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate ethyl: -m. p. 155-156 ° C (recrystallized from dichloromethane-isopropyl ether).

Example 8 7- (3-tert-butoxycarbonylamino-3-
Methyl-1-butynyl) -1-cyclopropyl-6,8
-Ethyl difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate: -m. p. 208-209 ° C (recrystallized from ethyl acetate).

Example 9 7- (3-Amino-1-propynyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid :-( 1 ) 7- (3-tert-Butoxycarbonylamino-
1-propynyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-
A mixture of 736 mg of ethyl carboxylate and 7.4 ml of 10% hydrochloric acid was heated with stirring at 80 ° C. for 2.5 hours. After cooling, the crystals were collected by filtration and dried to obtain 489 mg of the desired hydrochloride. (2) This hydrochloride was dissolved in 1N sodium hydroxide, treated with activated carbon, and then neutralized with dilute acetic acid. The precipitated crystals were collected by filtration and dried to obtain 358 mg of the desired product. m. p. 230-233
° C (decomposition). Similar to Example 9, Examples 10 and 1
1 compound was obtained.

Example 10 7- (3-Amino-1-butynyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid: -m. p. 183-186 ° C (decomposition).

Example 11 7- (3-Amino-3-methyl-1-butynyl) -1-
Cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid: -m. p. 228 ~ 229 ℃

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[Procedure amendment]

[Submission date] April 5, 1993

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0061

[Correction method] Change

[Correction content]

Example 11 7- (3-Amino-3-methyl-1-butynyl) -1-
Cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid: -m. p. 228 to 229 ° C. [Reference Example 7] 1- (2,4-difluoro-1-phenyl) -6,8-
Ethyl difluoro-1,4-dihydro-7-iodo-4-oxoquinoline-3-carboxylate: -known 7-amino-1- (2,4-difluoro-1-phenyl) -6,8-difluoro- 1,4-dihydro-4
Ethyl -oxoquinoline-3-carboxylate was treated in the same manner as in Reference Example 1 to obtain the desired product. m. p. 208-2
09 ° C. (recrystallized from dichloromethane-acetonitrile). Example 12 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7- (3-morpholino-1-propynyl) -4
-Oxoquinoline-3-carboxylic acid :-( 1) Known 3-morpholino-1-propyne [Zh. Organ.
Khim., 1 ( 10), 1726-1728 (1965) (Chem. Abstr., 64 ,
3340h (1966))] in the same manner as in Example 6 to give 1-cyclopropyl-6,8-difluoro-1,4.
-Dihydro-7- (3-morpholino-1-propynyl)
Obtained ethyl-4-oxoquinoline-3-carboxylate.
m. p. 185-187 ° C (recrystallized from dichloromethane-isopropyl ether). (2) Using the compound obtained in Example 12 (1), the reaction treatment was carried out in the same manner as in Example 9 to obtain the desired product. m. p. 181-18
3 ° C (decomposition). [Example 13] 7- (3-amino-1-propynyl) -1- (2,4-
Difluoro-1-phenyl) -6,8-difluoro-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid :-( 1) 1- (2,4-difluoro-1-phenyl) -6,
8-difluoro-1,4-dihydro-7-iodo-4-
A reaction treatment was carried out in the same manner as in Example 6 using ethyl oxoquinoline-3-carboxylate (compound of Reference Example 7) to give 7- (3
-Tert-butoxycarbonylamino-1-propynyl) -1- (2,4-difluoro-1-phenyl)-
Ethyl 6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate was obtained. m. p. 207
~ 208 ° C (recrystallized from dichloromethane-isopropyl ether). (2) Using the compound obtained in Example 13 (1), the reaction was treated in the same manner as in Example 9 to obtain the desired product. m. p. 260-26
5 ° C (decomposition).

Claims (3)

[Claims] 1. The following chemical formula 1 [Wherein R ₁ is a hydrogen atom, a lower alkyl group, an acyl group,
A lower alkoxycarbonyl group, a mono- or di-lower alkylamino lower alkyl group, or an amino lower alkyl group, R ₂ represents a hydrogen atom or a lower alkyl group, or R ₁ and R ₂ together form May form a 3- to 6-membered cyclic amino group (the cyclic amino group may include a hetero atom) together with the nitrogen atom to which R ₃ and R ₄ are the same or different. A hydrogen atom or a lower alkyl group, or R ₃ and R ₄ may combine together to form a ring, and R ₅ is a linear or branched alkyl group or alkenyl group having 1 to 4 carbon atoms. , A cyclopropyl group or a phenyl group substituted with 1 to 2 fluorine atoms, X is C—H,
C-Cl, C-F, means _{C-CH 3, C-OCH} 3 or a nitrogen atom. ] The novel quinolonecarboxylic acid represented by these, its ester, or its salt. 2. R ₁ , R ₂ , R ₃ and R ₄ are the same or different and each is a hydrogen atom or a lower alkyl group, and R ₅
The compound according to claim 1, wherein is a cyclopropyl group or a phenyl group substituted with 1 to 2 fluorine atoms. 3. The following chemical formula 2 (In the formula, R represents a hydrogen atom or a lower alkyl group,
Z means a chlorine atom, a bromine atom or an iodine atom, and R
₅ is a linear or branched alkyl group having 1 to 4 carbon atoms,
An alkenyl group, a cyclopropyl group or a phenyl group substituted with 1 to 2 fluorine atoms, X is C-
H, refers to C-Cl, C-F, C-CH 3, C-OCH 3 or a nitrogen atom. ) To a compound represented by the following formula: (In the formula, R ₁ is a hydrogen atom, a lower alkyl group, an acyl group,
A lower alkoxycarbonyl group, a mono- or di-lower alkylamino lower alkyl group, or an amino lower alkyl group, R ₂ represents a hydrogen atom or a lower alkyl group, or R ₁ and R ₂ together form May form a 3- to 6-membered cyclic amino group (the cyclic amino group may include a hetero atom) together with the nitrogen atom to which R ₃ and R ₄ are the same or different. It means a hydrogen atom or a lower alkyl group, or R ₃ and R ₄ together may form a ring. ) The acetylene compound represented by the formula (1) is reacted in the presence of a base in an inert gas atmosphere using a zero-valent or divalent palladium catalyst.
A method for producing the compound described in.