JPH02184685A - Quinoline-3-carboxylic acid derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R represents H or lower alkyl). EXAMPLE:5-Amino-8-chloro-1-cyclopropyl-7-(3,5-dimethyl-1-piperazinyl)- 6-fluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid. USE:An antimicrobial agent. PREPARATION:A 7-halogenoquinoline-3-carboxlic acid derivative expressed by formula II (X represents halogen) (example; 5-amino-8-chloro-1-cyclopropyl-6,7- difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid) is reacted with a piperazine derivative expressed by formula III (example; 2,6-dimethylpiperazine), as necessary, in the presence of a solvent in the presence or absence of a base as a deacidifying agent at ambient temperature to 200 deg.C.

Description

[Detailed Description of the Invention] No. 1 The present invention provides novel quinoline-3-
This invention relates to carboxylic acid derivatives and pharmacologically acceptable salts thereof.

Support Δ Good E Although many antibacterial agents having a quinoline carboxylic acid skeleton are known, including norfloxacin, the quinoline-3-carboxylic acid-derived naphthyridine-based and quinoline-based synthetic antibacterial agents of the present invention have been developed since the discovery of norfloxacin. , has brought about a breakthrough, and its indications have been shown to be effective for all kinds of infections, not just urinary tract infections.

It is also known that its mechanism of action is the inhibition of DNA gyrase, a DNA steric enzyme, and that transmission of resistance by plasmids such as with antibiotics does not occur. However, it is also true that the number of non-susceptible bacteria has been steadily increasing in clinical practice in recent years. For these reasons, it is difficult to say that synthetic antibacterial agents are perfect drugs, and the emergence of new antibacterial agents is strongly desired due to their usefulness.

As a result of intensive research in view of the above circumstances, the present inventors have discovered that quinoline-3-carboxylic acid derivatives and pharmacologically acceptable salts thereof have excellent antibacterial effects,
The present invention has been completed.

That is, the present invention relates to a quinoline-3-carbonquino conductor represented by the general formula (I) (wherein R represents a hydrogen atom or a lower alkyl group), and a pharmacologically acceptable salt thereof. .

In the general formula (I) of the present invention, examples of the lower alkyl group represented by R include methyl and ethyl.

Examples include n-propyl, isopropyl, n-butyl, isobutyl, 5ec-butyl, and tert-butyl groups.

Examples of the pharmacologically acceptable salts of the compound represented by the general formula (I) of the present invention include acid addition salts and alkali addition salts. Examples of acid addition salts include hydrochloric acid, hydrobromic acid , mineral acid salts such as hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid,
Alternatively, organic acid salts such as acetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, tartaric acid, methanesulfonic acid, etc. can be used as alkali addition salts such as sodium, potassium, calcium, silver, zinc, lead, ammonium, etc. inorganic alkali salts, or ethanolamine.

Examples include salts of organic bases such as N,N-dialkylethanolamine.

The compound represented by the general formula (I) of the present invention has an asymmetric carbon atom in the 7-position cyclic amino group, and these can exist as optically active forms. Therefore, these optically active forms are also included in the present invention. It is included in the compounds of

A novel quinoline represented by the general formula (I) of the present invention
The 3-carbonquino conductor can be manufactured by various methods.

According to the first mode of the method for producing a compound according to the present invention,
The compound represented by the general formula (I) is represented by the following general formula (I).
I) 7- represented by (wherein, X represents a halogen atom)
A halogenoquinoline-3-carboxylic acid derivative and a piperazine-based conductor represented by the following general formula (■) (wherein R represents the same meaning as above) in the absence of a solvent or in a solvent,
It can be produced by reacting in the presence or absence of a base as a deoxidizing agent.

Any solvent may be used in the method of the present invention as long as it does not inhibit the reaction, such as water,
Methanol, ethanol, n-propanol, n-butanol, 3-methoxybutanol.

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

Diethylene glycol dimethyl ether (diglyme)
, ethers such as triethylene glycol dimethyl ether (triglyme), aprotic polar solvents such as acetonitrile, dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, and hexamethylphosphoric triamide, aromatic solvents such as benzene and toluene. Examples include hydrocarbon solvents and basic solvents such as pyridine, picoline, lutidine, and collidine. Examples of bases as deoxidizers include triethylamine, 1.
Examples include 8-diazabicyclo[5,4,0]-7-undecene and potassium carbonate.

Further, the reaction is carried out at a temperature ranging from room temperature to 200°.

The 7-halogenoquinoline-3-carboxylic acid conductor represented by the general formula (I[) which is the starting material in the production method of the present invention is, for example, a known conductor already disclosed in JP-A-62-187459. It is a substance.

According to the second mode of the method for producing a compound according to the present invention,
Among the compounds represented by the general formula (I), the compound in which R is a lower alkyl group is a compound in which R is a hydrogen atom in the general formula (I), and the compound represented by the following general formula (IV) R1-Y ( IV) (In the formula, R represents a lower alkyl group and Y represents a halogen atom.) React with a halogenated alkyl represented by the following in a solvent, in the presence or absence of a base as a deoxidizing agent. or the following general formula (V) R2-C-H(V) (wherein R2 represents a hydrogen atom or a lower alkyl group).

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

When an alkyl halide is used in the method of the present invention, examples of the alkyl halide represented by the general formula (IV) include methyl iodide, methyl bromide, ethyl iodide, ethyl bromide, propyl iodide, Examples of the solvent include propyl bromide, and any solvent may be used as long as it does not inhibit the reaction. Examples include acetone, ethanol, ether, tetrahydrofuran, N,N-dimethylformamide, dioxane, benzene, toluene, chloroform, and the like. Examples of the base as a deoxidizing agent include triethylamine, pyridine, and potassium carbonate.

Further, in the method of the present invention, when a carbonyl compound is used, examples of the carbonyl compound represented by the general formula (V) include formaldehyde, acetaldehyde, propionaldehyde, etc., and formaldehyde is used as an aqueous formaldehyde solution (formalin). Furthermore, when acetaldehyde and propionaldehyde are used, it is preferable to use nitrobenzene as a solvent. Further, the reaction is carried out at a temperature ranging from room temperature to 200°.

The novel quinoline-3-carboxylic acid derivative represented by the general formula (I) and its pharmacologically acceptable salts produced in this way can be prepared into tablets, powders, capsules, injections, etc. by conventional methods. It can be made into formulations such as 2 eye drops, 9 nasal drops, or external preparations, and is clinically administered by oral or parenteral administration. The dosage depends on the symptoms to be treated and the administration method, but when administered orally to adults, it is usually 50
~1000mg.

EXAMPLES The present invention will be explained below by way of examples, but the present invention is not limited to the specific details of these examples.

Example 1 5-amino-8-chloro-1-cyclopropyl-7-(
3,5-dimethyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 5-amino-8-chloro-1-cyclopropyl-〇,7
- A suspension of 0.50 g of difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 0.54 g of 2,6-dimethylpiperazine in 101 acetonitrile for 17
Heat to reflux for an hour.

The solvent is distilled off, water and 10% aqueous sodium hydroxide are added to dissolve the residue, and after filtration, the pH is adjusted to 8 with 10% hydrochloric acid. Collect the precipitated crystals by filtration and hydrate with water and 10%) IJ
Dissolves in aqueous solution of umum. The pH was adjusted to 8 with 10% hydrochloric acid, and the precipitated crystals were collected by filtration, and the yellow crystals with a melting point of 207 to 210° were 0.23
get g.

Elemental analysis value Theoretical value Experimental value l Milk Δ肱 and the novel quinoline-3-carboxylic acid derivative represented by the general formula (I) thus produced, and its pharmacologically acceptable salts: It has a wide range of antibacterial effects against Durham-positive bacteria and Durham-negative bacteria, and is extremely useful as a medicine.

C19R22CI F N403・l/2H20C,
54, Gl; H, 5,55; N, 13.4I
C, 54,84; H, 5,40; N, 13.
52 Patent Applicant Hokuriku Pharmaceutical Co., Ltd.

Claims (1)

[Claims] A quinoline-3-carboxylic acid derivative represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R represents a hydrogen atom or a lower alkyl group) and its pharmacological Acceptable salt.