JPH0356489A - Thiazetoquinoline-3-carboxylic acid derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a novel thiazetoquinoline-3-carboxylic acid derivative having excellent antibacterial activity and useful as a pharmaceutical, and a pharmacologically acceptable salt thereof.

Conventional technology A synthetic antibacterial agent that has been developed by inheriting the flow from nalidixic acid is a naphthyridine ring. Antibacterial agents containing a penzoxazine ring or a quinoline ring as a main component are mainstream, and the thiazetoquinoline-3-carboxylic acid derivative according to the present invention has not been studied at all.

Problems to be Solved by the Invention The combined antibacterial agents of naphthyridine and quinoline have made revolutionary progress since the discovery of norfloxacin, and are effective for all kinds of infections, not just urinary tract infections. It has been shown that In addition, its mechanism of action is the inhibition of DNA gyrase, which is a DNA steric enzyme,
It is also known that transmission of resistance by plasmids such as 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 existing antibacterial agents are perfect drugs, and the emergence of better antibacterial agents is strongly desired due to clinical necessity.

Means for Solving the Problems In view of the above-mentioned circumstances, the present inventors have conducted extensive research and have found that the novel thiazetoquinoline-3-carboxylic acid derivative and its pharmacologically acceptable salt thereof according to the present invention are excellent antibacterial agents. It was discovered that the present invention has an effect, and the present invention was completed. That is,
The present invention is represented by the following general formula (wherein R+ and R2 represent a hydrogen atom or a lower alkyl group, R3 represents a lower alkyl group or a halogeno lower alkyl group, and R represents a hydrogen atom or a halogen atom) This invention relates to thiazetoquinoline-3-carboxylic acid derivatives and pharmacologically acceptable salts thereof.

In the general formula (I) of the present invention, the lower alkyl groups represented by R+, R* and R include, for example, a methyl group.
Ethyl group. n-probyl group. Isoprobyl group, n-butyl group. sec-butyl group. Examples of the halogeno lower alkyl group represented by R include a tert-butyl group, a fluoromethyl group, and the like. Difluoromethyl group. Trifluoromethyl group. 2.2.2-Trifluoroethyl group. 2-fluoroethyl group and the like, R. The halogen atom represented by is a fluorine atom. Examples include chlorine atom and bromine atom.

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 , hydroiodic acid, nitric acid. Sulfuric acid. Mineral salts such as phosphoric acid,
Or acetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, malic acid, methanesulfonic acid, mandelic acid.
Organic acid salts such as 10-camphorsulfonic acid and tartaric acid,
Examples of alkali addition salts include sodium, potassium, calcium, silver. Inorganic salts such as zinc, lead, ammonium, etc., or ethanolamine. N. Examples include salts of organic bases such as N-dialkylethanolamine.

The compound represented by the general formula (1) of the present invention has one or more asymmetric carbon atoms and may exist in optically active forms and diastereomers, but the present invention also includes these compounds. Ru.

The novel thiazetoquinoline-3-carboxylic acid derivative represented by the general formula (I) of the present invention can be produced 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) has the following general formula (n
) 7-halogenothiazetoquinoline-3-carboxylic acid derivative represented by O (wherein R and R have the same meanings as above, and X represents a halogen atom) and the following general formula (III )R. (In the formula, R2 and R1 represent the same meanings as described above.) It can be produced by reacting the piperazine derivative represented by the following formula in a solvent in the presence or absence of a base.

Any solvent may be used in the method of the present invention as long as it does not inhibit the reaction, such as acetonitrile. N. N-dimethylformamide, N-methyl-2-pyrrolidone. Dimethyl sulfoxide. Aprotic polar solvents such as hexamethylphosphoric triamide, aromatic hydrocarbon solvents such as benzenetoluene, pyridine. Picoline. Lutidine. Examples include organic bases such as collidine and mixed solvents thereof.

Bases used in the method of the invention include, for example, triethylamine, 1,8-diazabicyclo-(5
, 4,O)-7-undecene, sodium carbonate, potassium carbonate, etc., and the reaction is carried out at a temperature ranging from water cooling to the reflux temperature of the solvent.

The 7-halogenothiazetoquinoline-3-carboxylic acid derivative represented by the general formula (I[), which is the starting material in the production method of the present invention, is disclosed in JP-A No. 63-107990.
It is a known compound already disclosed in No.

According to the second mode of the method for producing a compound according to the present invention,
The compound in which R in the general formula (I) is a hydrogen atom can be produced by hydrolyzing a compound in which R in the general formula (I) is a lower alkyl group using an acid or an alkali. .

Examples of the acid used in the method of the present invention include hydrochloric acid, sulfuric acid, fuming sulfuric acid, etc., and examples of the alkali include sodium hydroxide, potassium hydroxide, etc.

In addition, these acids or alkalis can be prepared in an aqueous solution or in methanol. ethanol. 11-butanol, sec-butanol. It can also be used in the reaction as a solution such as tert-butanol or a solution in a water-containing organic solvent.
The reaction is carried out at a temperature ranging from room temperature to the heating reflux temperature of the solvent.

According to the third mode of the method for producing a compound according to the present invention,
A compound in which R in the general formula (I) is a chlorine atom can be produced by directly chlorinating a compound in which R4 in the general formula (I) is a hydrogen atom.

Chlorinating agents used in the method of the present invention include chlorine, sulfuryl chloride, and the like.

Further, examples of the solvent used include chloroform. Dichloromethane. 1,2-dichloroethane, acetic acid. Examples include chlorosulfonic acid, and the reaction is carried out under water cooling for 200 min.
It is carried out in the range of °C.

Novel thiazetoquinoline-3- produced in this way
Carboxylic acid derivatives and pharmacologically acceptable salts thereof are
It can be made into tablets, powders, capsules, injections, eye drops, nasal drops, or external preparations by conventional methods, and is clinically administered by oral or parenteral administration.

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

Example l? -(3,5-dimethyl-1-piverazinyl)-6-fluoro-1-methyl-4-oxo IH. 4H- (1
, 3) Thiazeto [3,2-a) Ethyl quinoline-3-carboxylate hydrochloride 6,7-difluoro-1-methyl-4-oxo-IH.
4H- (1.3)thiazeto(3,2-a]quinoline-
2.00 g of ethyl 3-carboxylate and 2.20 g of 2,6-dimethylpiperazine. After stirring the N-dimethylformamide 6.1 suspension at room temperature for 4 days, the solvent of the reaction solution was distilled off. Add water to the residue and filter the precipitated crystals. The obtained crystals are suspended in ethanol, adjusted to pH 2 with ethanolic hydrochloric acid, ether is added, and the precipitated crystals are collected by filtration to obtain 2.34 g of pale yellow crystals. Recrystallized from a mixture of methanol and ether, melting point 280-285℃
(decomposition) to obtain colorless crystals.

Elemental analysis value C2. H! IF N)03S-H C 1
・Each H! 0 Theoretical value C, 53.27. H, 5.81; N,
．． 9.32 Experimental value C, 53.50; H, 5.67
．． N, 9.34 Example 2 6-fluoro7-(3-fluoromethyl-1-piperazinyl)-1-methyl-4-oxo1H,4H- (
1.3) Thiazeto C3.2-a) Ethyl 6,7-difluoro-1-methyl-4-oxo quinoline-3-carboxylate IH.
4H- (1.33thiazeto(3,2-a)quinoline-
A suspension of 2.00 g of ethyl 3-carboxylate and 3.27 g of 2-fluoromethylbiverazine in N,N-dimethylformamide 60 was stirred at room temperature for 48 days, and then the solvent of the reaction solution was distilled off. Add water to the ant pickle, make it alkaline with a 10% aqueous sodium hydroxide solution, and then extract with chloroform. Wash the chloroform layer with water. After dehydration, the solvent is distilled off. The residue was purified by column chromatography [silica gel, chloroform-methanol (20.:1)] to give pale yellow crystals. Get Log. Recrystallization from methanol yields pale yellow needles with a melting point of 235-240°C (decomposition).

Elemental analysis value C IIH21F zN*oss-HzO
Theoretical value C, 53.39: H. 5.42. N.
9.83 Experimental value C, 53.34. H, 5.34.
N, 9.80 Example 3 7-(3.5-dimethyl-1-biperazinyl)-6-fluoro-l-methyl-4-oxo IH,4H- (1
．． 3) Thiazeto r3.2-a) Quinoline-3-carboxylic acid 7-(3.5-dimethyl-1-piperazinyl)-6-fluoro-1-methyl-4-oxo IH,4H- (4
．． 3) Thiazeto r3.2-a) Ethyl quinoline-3-carboxylate hydrochloride 2.15 g. Potassium hydroxide1.
6 3 g. 10 parts of Lert-butanol and 30 parts of water
The first mixture was stirred at an external temperature of 50° C. for 1.5 hours, cooled to zero, adjusted to pH 8 with 10% hydrochloric acid, and the precipitated crystals were collected by filtration. Recrystallization from a mixture of methanol and chloroform yields 1.10 g of colorless crystals with a melting point of 245-250°C.

Elemental analysis value C+sH2. FNsOsS・3/4HtO
Theoretical value C. 55.30; H, 5.54; N. 1
0.75 Experimental value C, 55.47; H, 5.67;
N, 10.56 Example 4 6-fluoro-7-(3-fluoromethyl-1-piperazinyl)-1-methyl-4-oxo1H,4H- [
1.3) Thiazeto (3.2-a) Quinoline-3-carboxylic acid hydrochloride 6-fluoro-7-(3-fluoromethyl-1-piperazinyl)-1-methyl-4-oxo IH. 4H- (
1.3) Thiazeto (3.2-a) Ethyl quinoline-3-carboxylate 1.95 g, potassium hydroxide 1.゛5
A mixture of 7 g, tert-butanol IOY and water is stirred for 30 minutes at an external temperature of 50°C. After cooling, 10
After adjusting the pH to 2 with % hydrochloric acid, the precipitated crystals were collected by filtration to obtain 1.38 g of light brown crystals.

Recrystallization from water yields light brown crystals with a melting point of 300°C or higher.

Elemental analysis value C1↑H +yF 2N so 3S'
H C 1・! /6HtO Theory 1ia C, 47.83. H, 4.49,
N, 9.84 Experimental value C, 47.46; H, 4.
54;N. 9.73 Example 5 8-chloro-6-fluoro7-(3-fluoromethyl-!-piperazinyl)-1-methyl-4-oxo IH
,4H- (1.3) Thiazeto[3.2-a]quinoline-3-carboxylic acid sulfate 6-fluoro-7-(3-fluoromethyl-1piperazinyl)-1-methyl-4-oxol lH,4H - (1.3) Thiazeto (3.2-a
) Quinoline-3-carboxylic acid hydrochloride A catalytic amount of iodine pieces was added to 1.08 g of chlorosulfonic acid 31, and chlorine gas was passed through the mixture for 3.5 hours while stirring under water cooling.

The reaction solution is poured into ice water, the precipitated crystals are collected by filtration, and then recrystallized from water to obtain 0.09 g of pale yellow crystals with a melting point of 300° C. or higher.

Elemental analysis value C I7H +aC I F tN so
ss・'AH! S O 4・H! O Theoretical value C, 42.28; H, 3.97. N,
8.70 Experimental value C, 42.02. H, 4.21.
N, 8.73 Example 6 8-chloro-6-fluoro7-(3-methyl-1-piperazinyl)-1-methyl-4-oxo-IH,4H-
(1.33thiazeto(3.2-a)quinoline-3-carboxylic acid 6-fluoro7-(3-methyl-l-biperazinyl)
-1-Methyl-4-oxo IH,4H-(!,3)thiazeto(3,2-a)quinoline-3-carboxylic acid hydrochloride t. A catalytic amount of iodine pieces was added to a solution of AIG's chlorosulfonic acid 6, and chlorine gas was passed through the solution for 4 hours while cooling with water and stirring.

Pour the reaction solution into ice water and filter the precipitated crystals. After dissolving the obtained crystals in an aqueous sodium hydroxide solution, the pH was adjusted to 8 with 10% hydrochloric acid. After filtering the precipitated crystals, the obtained crystals are suspended in ethanol and adjusted to pH 2 with ethanolic hydrochloric acid. After filtering the precipitated crystals, recrystallization from a mixture of methanol and ether yields colorless crystals with a melting point of 300°C or higher.
get g.

Elemental analysis value C I7H 17c I F N no
sS・HCl-y2H,O Theoretical value C. 46.06. H, 4.32; N, 9
．． 48 Experimental value C, 45.98. H, 4.22.
N, 9.27 Effects of the Invention The novel thiazetoquinoline-3-carboxylic acid derivative represented by the general formula (I) and its pharmacologically acceptable salt produced in this manner are effective against Durum-positive bacteria. It has a strong antibacterial effect against Durham-negative bacteria and is extremely useful as a medicine.

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1 and R_2 are hydrogen atoms or lower alkyl groups, R_3 is lower alkyl groups or halogeno lower alkyl groups, and R_4 is hydrogen atoms. or represents a halogen atom.) A thiazetoquinoline-3-carboxylic acid derivative and a pharmacologically acceptable salt thereof.