JPS6110574A - 6-fluoro-1,4-dihydro-4-oxo-7-substituted piperazinylquinoline-3-carboxylic acid derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R1 is lower alkyl; R2 and R4 are different H or CH3; R3 is H or lower alkyl; R5 is H or F) and a pharmacologically acceptable salt thereof. EXAMPLE:7-( 3,5-Dimethyl-1-piperazinyl )-1-ethyl-6-fluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride. USE:An antimicrobial agent useful as a medicine having wide antimicobial action on Gram-positive and Gram-negative bacteria. PREPARATION:(a) A compound expressed by formula II (X is Cl or F) is reacted with a compound expressed by formula III without or in a solvent or (b) a compound expressed by formula IV is reacted with a compound expressed by the formula R6CHO (R6 is H or lower alkyl) in the presence of formic acid. Alternatively, (c) the compound expressed by formula IV is reacted with a compound expressed by the formula R3A (A is halogen) in a solvent to afford the aimed compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION OBJECTS OF THE INVENTION The present invention provides novel 6-fluoro-
The present invention relates to 1,4-dihydro-4-oxo-7-substituted piperazinyl/phosphorus-3-carboxylic acid derivatives and pharmacologically acceptable salts thereof.

Structure of the Invention More specifically, the present invention relates to the general formula (+) (wherein R1
#i represents a lower alkyl group, R2 and R4 each represent a hydrogen atom or a methyl group, R3 represents a hydrogen atom or a lower alkyl group, and R5 represents a hydrogen atom or a fluorine atom. ) Novel 6-fluoro-1,4-dihydro-4 represented by
-Oquine-7-substituted piperazinylquinoline-8-carboxylic acid derivatives and pharmacologically acceptable salts thereof.

In the general formula (, I) of the present invention, examples of the lower alkyl group represented by R and R3 include a 1-methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and the like.

Examples of pharmacologically acceptable salts of the compound represented by the general formula (1) include acid addition salts and alkali addition salts. Examples of acid addition salts include hydrochloric acid, sulfuric acid, nitric acid,
Hydrogen bromide, hydroiodic acid.

Examples of alkali addition salts include mineral acid salts such as phosphoric acid, organic acid salts such as acetic acid, maleic acid, fumaric acid, citric acid, and tartaric acid.

Examples include inorganic alkali salts such as potassium, calcium, and ammonium salts, and salts of organic bases such as ethanolamine and N,N-dialkylethanolamine.

The novel 6-fluoro-1,4-dihydro-4-okyne-7-substituted piperazinylquinoline-8-carboxylic acid derivative of the present invention represented by the above general formula (1) can be produced by various methods. Can be done.

According to the first method of producing the compound according to the present invention, the compound represented by the general formula (1) is produced by the following general formula (
II) 6-fluoro-twohalogeno-1,4-dihydro-4-oxoquinoline-8-carboxylic compound represented by (wherein R1 and Rsu have the same meanings as above, and X represents a chlorine atom or a fluorine atom) Acid derivatives and the following general formula (Ill
) (In the formula, R2, R3 and R4 represent the same meanings as above.

) can be produced by reacting the piperazine derivative represented by (9) in the absence of a solvent or in the presence of a solvent. Examples of the solvent used in this reaction include water, butyl, and 8-methoxybutanol. .

Alcohols such as isoamyl alcohol, ethylene glycol dimethyl ether (monoglyme).

Diethylene glycol dimethyl ether (Jigly A)
, Tri: ethers such as r-1-rengelicol dimethyl ether (triglyme), aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide, hexamethyl 7-osphorinoctriamide, benzene,
Examples include aromatic hydrocarbon solvents such as luene, and organic bases such as pyridine, bifrin, lutidine, collidine, and triethylamine.

Further, the reaction is carried out at a temperature ranging from room temperature to 200°, preferably appropriately selected from a range of 100 to 180°.

According to the second mode of the method for producing a compound according to the present invention, the compound represented by the general formula (1) is prepared by the general formula (
1), in which R3 is a hydrogen atom, the following general formula (IT) is represented by 6-fluoro- 1,4-dihydro-4-okine-7-substituted piperazinylquinoline-8-carboxylic acid derivative and the following general formula (V) 11(ma) R6-C-T( (wherein, R6 is a hydrogen atom or Represents a lower alkyl group.

) can be produced by reacting with the carbonyl compound shown in the following in the presence of formic acid.

The carbonyl compound represented by the general formula (V) used in the method of the present invention includes formaldehyde,
Examples include acetaldehyde, propionaldehyde, etc. Formaldehyde is preferably used as an aqueous formaldehyde solution (formalin), and when acetaldehyde and propionaldehyde are used, it is preferable to use nitrobenzene as a solvent.

Further, the reaction is carried out at a temperature in the range of 100 to 200[deg.], preferably at the reflux temperature of the reaction system.

According to the third mode of the method for producing a compound according to the present invention, the compound represented by the general formula (1) is prepared by the general formula (
6-fluoro-1°4-dihydro-4 represented by IT)
-oxo-7-substituted piperazinylquinoline-8-carboxylic acid derivative and the following general formula (MaI) R3-A' (Ma1) (wherein, R3 has the same meaning as above, and A is a halogen atom) It can be produced by reacting an alkyl halide represented by (in a solvent) in the presence or absence of a base as a deoxidizing agent.

The solvent used in the method of the present invention may be any solvent as long as it does not inhibit the reaction, and includes, for example, acetone, ethanol, ether, tetrahydroctane, dimethylformamide, dioxane, benzene, toluene, chloroform and the like.

Examples of the base used as a deoxidizing agent in the method of the present invention include triethylamine.

Examples include pyridine and potassium carbonate.

In addition, the reaction is carried out at a temperature ranging from room temperature to the heating reflux temperature of the solvent used, preferably at a temperature of 50 to 100°, which is appropriately selected. The compound represented by the general formula (1) is represented by the following general formula (
II) (wherein R1, R2, R3, R4 and R5 have the same meanings as above, and R7 represents a lower alkyl group) 6
It can be produced by hydrolyzing a -fluoro-1,4-dihydro-4-oxo-7-substituted piperazinylquinoline-8-carboxylic acid ester derivative.

Hydrolysis is carried out in a manner known per se using acids or alkalis; for acidic hydrolysis, hydrochloric acid;

For alkaline hydrolysis, an acid such as sulfuric acid is used, and an alkali such as sodium hydroxide or potassium hydroxide is used for the reaction. Can be used.

Further, the reaction is carried out at a temperature ranging from room temperature to the temperature at which the solvent is heated to reflux.

Effects of the Invention The novel 6-fluoro-1,4-dihydro-4-oxo-7 represented by the above general formula (1) produced in this way
-substituted piperazinylquinoline-3-carboxylic acid derivatives,
and its pharmacologically acceptable salts have broad antibacterial activity against Durum-positive and Durum-negative bacteria, and are extremely useful as medicines.

Hereinafter, the present invention will be explained by examples.

Example 1? -(8,5-dimethyl-1-piperazinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-8-carboxylic acid hydrochloride 7-chloro-1-ethyl-6-fluoro -1°4-dihydro-4-oxoquinoline-8-carboxylic acid 1.50. ? , a mixture of 1.60 g of 2,6-dimethylpiperazine and 8 ml of pyridine,
Heat to reflux for 26 hours. After the reaction, the solvent is distilled off. The resulting residue is dissolved in warm methanol, then cooled and the precipitated crystals are collected. The crystals are dissolved in a mixture of chloroform and methanol and ethanolic hydrochloric acid is added. The precipitated crystals are collected and recrystallized from methanol to obtain colorless crystals with a melting point of 300° or higher.

Elemental analysis value 018H22F'N303・HCI theoretical value C,56,82;H,6,04;N, 10.95Experimental value C,56,05iH,6,27;N, 10.8
4 Example 2 7-(8,5-dimethyl-1-piperazinyl)-1-ethyl-6,8-Schiff/I/Olor 1,4-dihydro-4
-oxoquinoline-8-carboxylic acid 1-ethyl-6,7
,8,-) A mixture of 2.80 g of refluoro-1°4-dihydro-4-oxoquinoline-3-carboxylic acid, 1.909 g of 2,6-dimethylpiperazine and 2 Fdat of pyridine is heated under reflux for 15 minutes. After the reaction, the solvent was distilled off,
Add methanol to the residue. Separate the precipitated crystals, dissolve them in a mixture of tetraroform and methanol, and add ethanolic hydrochloric acid. Separate the precipitated crystals and dissolve them in water. Neutralize with sodium hydrogen carbonate and extract with chloroform. After the chloroform layer is dehydrated, the solvent is distilled off. The obtained residue was recrystallized from a mixture of chloroform and ethanol,
1.61# of colorless crystals with a melting point of 233-234° are obtained.

Elemental analysis value Cl8H21F2N303 theoretical value C,5
9,17jH, 5,79iN, 11.50 experimental value C
,59,28iH,5,95;N, 11.49Example 8 7-(8,8-dimethyl-1-piperazinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline- 7-chloro-1-ethyl-6-3-carboxylic acid
Fluoro-1゜4-dihydro-4-oxoquinoline-8
- A mixture of 1.50 i of carboxylic acid 1.601 I of 2,2-dimethylpiperazine and 6 ml of pyridine was added to 88.5
Heat to reflux for an hour. After the reaction, the solvent is distilled off and methanol is added to the residue. The precipitated crystals are dissolved in water and neutralized with an aqueous solution of sodium bicarbonate. The precipitated crystals are collected and recrystallized from ethanol. Melting point 208.5-209
0.7011 colorless crystals of 5° are obtained.

Elemental analysis value Cl8H22FN303 Theoretical value C, 62,28; H, 6,88iN, 12.
10 experimental value C, 62, 10iH, 6, 62; N, 1
186 Example 4? -(8,8-dimethyl-1-piperazinyl)-1-ethyl-6,8-Schiff A/Olor 1,4-dihydro-4-
1-ethyl-6,7, oxoquinoline-3-carboxylate
A mixture of 2.00 gt of 8-1 refluoro-1+4-dihydro-4-oxoquinoline-8-carboxylic acid, 1.701 gt of 2,2-dimethylpiperazine and 15 gt of pyridine,
After the reaction is heated under reflux for 20 minutes, the solvent is distilled off, and water is added to the resulting residue. The precipitated crystals are collected and recrystallized from ethanol to obtain pale yellow needle-like crystals of 1.50F with a melting point of 207-208°.

Mass spectrum m/e: 865 (M+) Example 5 1-ethyl-6,8-difluoro-1,4,-dihydro-4-oxo-7-(8,4,5-)limethyl-■-piperazinyl)quinoline -3-carboxylic acid 7-(8,5-dimethyl-1=piperazinyl)-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-8-carboxylic acid obtained in Example 2 0.70
, 9. A mixture of 2.4 tel of 90% formic acid and 2.0 ml of 87% formalin was heated to reflux for 8 hours after cooling to 0.
The solvent was distilled off, water was added to the residual liquid, and the mixture was neutralized with sodium hydrogen carbonate. The aqueous layer is extracted with chloroform, and the chloroform layer is washed with water and then dehydrated. The solvent is distilled off, ethanol is added to the residual liquid, and the precipitated crystals are collected. Recrystallization from ethanol gives colorless needles with a melting point of 216-217°.

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1 is a lower alkyl group, R_2 and R_4
are different and each represents a hydrogen atom or a methyl group, R_3 represents a hydrogen atom or a lower alkyl group, and R_5 represents a hydrogen atom or a fluorine atom. ) A 6-fluoro-1,4-dihydro-4-oxo-7-substituted piperazinylquinoline-3-carboxylic acid derivative, and a pharmacologically acceptable salt thereof.