JPH02174784A - Isothiazoloquinoline derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is lower (hydroxy)alkyl; R<2> and R<3> are H or lower alkyl; n is 2 or 3; R<2> and R<3> are not H at the same time when R<1> is methyl]. EXAMPLE:9-Cyclopropyl-6-fluoro-7-(3-hydroxymethyl-1-piperazinyl)-isoth iazolo[5,4- b]quinoline-3,4(2H,9H)-dione. USE:Antibacterial agent against gram-positive bacteria and gram-negative bacteria. PREPARATION:A 7-halogenoisothiazoloquinoline derivative of formula II (x is halogen) is made to react with a cyclic amine compound of formula III in a solvent optionally in the presence of a base.

Description

DETAILED DESCRIPTION OF THE INVENTION (1) The present invention relates to novel inthiazoloquinoline derivatives that have excellent antibacterial activity and are useful as pharmaceuticals, and their pharmacologically acceptable phosphoric acid addition salts.

Synthetic antibacterial agents that have been developed following the trend from nalidixic acid are mainly synthetic antibacterial agents that have a naphthyridine ring, benzoxanone ring, or quinoline ring as their core, and the present invention Nothing is known about inthiazoloquinoline derivatives.

Synthetic antibacterial agents based on naphthyridine rings and quinolines have brought breakthroughs since the discovery of norfloxacin, and 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 stericase, and that transmission of resistance by plasmids, such as with antibiotics, does not occur.

However, it is also true that in recent years there has been a steady increase in the number of non-susceptible patients in the clinical setting. For these reasons, it is difficult to say that existing synthetic antibacterial agents are perfect drugs, and the emergence of better antibacterial agents is strongly desired due to clinical necessity.

As a result of intensive research in view of the above-mentioned circumstances, the present inventors have discovered that the novel inthiazoloquinoline derivative and its pharmacologically acceptable acid addition salt thereof according to the present invention have excellent antibacterial activity, The present invention has been completed.

That is, the present invention relates to the following general formula (I) (wherein R1 represents a lower alkyl group or a hydroxy lower alkyl group, R2 and R3 are the same or different and represent a hydrogen atom or a lower alkyl group, and n is 2 or 3 (However, when R1 represents a methyl group, R2 and R3 do not represent a hydrogen atom at the same time.) and its pharmacologically acceptable acid addition salts. .

In the general formula (I) of the present invention, the lower alkyl group represented by R, R2 and R3 includes, for example, a methyl group,
An example of the hydroxy lower alkyl group represented by R1 is a hydroxymethyl group.

2-hydroxyethyl group, 3-hydroxypropyl group,
Examples include 4-hydroxybutyl group.

Examples of the pharmacologically acceptable acid addition salts of the compound represented by the general formula (I) of the present invention include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid. salt,
Or acetic acid, maleic acid, fumaric acid, citric acid, malic acid, oxalic acid.

Examples include organic acid salts such as tartaric acid, methanesulfonic acid, 10-camphorsulfonic acid, and mandelic acid.

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

The inthiazoloquinoline 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) is represented by the following general formula (I).
I) 7- represented by (wherein, X represents a halogen atom)
A balogen isothiazoquinoline derivative and the following general formula (
III) (In the formula, R2, R3 and n represent the same meanings as above.) Produced by reacting a cyclic amine compound represented by the formula in the presence or absence of a base in a solvent. Can be done.

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, dimethylsulfoxide, hexamethylphosphoric acid, etc. Aprotic polar solvents such as amides, benzene.

Aromatic hydrocarbon solvents such as toluene, pyrinone.

Examples include organic bases such as picoline, lutidine, and collidine, and mixed solvents thereof.

Bases used in the method of the invention include, for example, triethylamine, 1,8-diazabicyclo[:5
．． 4.0]-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.

In the method of the present invention, the starting material is the general formula (n
The 7-valogenoisothiazoloquinoline derivatives represented by ) are also new compounds, and were produced as shown in the figures below, and are described in Reference Examples.

(In the formula, X represents the same meaning as defined above.) According to the second mode of the method for producing a compound according to the present invention,
) Among the compounds represented by formula (1), a compound in which R2 is a lower alkyl group can be produced by alkylating a compound in which R2 is a hydrogen atom in the general formula (I).

The alkylating agent used in the method of the present invention includes a halogenated lower alkyl or an aldehyde compound, and when a halogenated lower alkyl is used, the alkylating agent is used in a solvent, in the presence or absence of a base as a deoxidizing agent. Alternatively, when an aldehyde compound is used, it can be produced by reacting it in the presence of formic acid.

Examples of the lower alkyl halide used in the method of the present invention include methyl iodide.

Examples of solvents include ethyl iodide, ethyl bromide, butyl bromide, etc.; examples of solvents include N,N-dimethylformamide, acetone, ethanol, tetrahydrofuran, benzene, and chloroform; examples of bases as deoxidizers include: Examples include triethylamine, potassium carbonate, and the like.

Further, in the method of the present invention, when an aldehyde compound is used, examples of the aldehyde compound include formaldehyde, acetaldehyde, propionaldehyde, etc., and formaldehyde is preferably used as an aqueous formaldehyde solution (formalin); When using propionaldehyde, it is preferable to use nitrobenzene as a solvent.

Further, the reaction is carried out in a range from 1' to 200'.

The novel inthiazoloquinoline derivative represented by the general formula (I) and its pharmacologically acceptable acid addition salt produced in this way can be prepared by a conventional method using formulation additives commonly used as pharmaceuticals. Tablets, powders, capsules, injections and 1 eye drop.

It can be made into formulations such as nasal drops or external preparations, and is clinically administered by oral or parenteral administration.

Ltane ■ The present invention will be explained below by reference examples and examples.
The invention is not limited to the specific details of these examples.

Reference example 1 1-7 clopropyl-6,7-difluoro-14-dihydro-2-methylsulfinyl-4-oxoquinoline-
Ethyl 3-carboxylate 1-cyclopropyl-8,7-difluoro-14-dihydro-2-methylthio-4-oxoquinoline-3-carboxylate 1. 0.70 g of 80% metachloroperbenzoic acid was added to a solution of OOg in 100 ml of methylene chloride, and the mixture was stirred at room temperature for 5.5 hours. Water is added to the reaction solution, washed with water, and after drying, the solvent is distilled off under reduced pressure. Ether was added to the residue and the precipitated crystals were collected by filtration to obtain 0.71 g of colorless crystals. Recrystallization from benzene gives colorless needle crystals with a melting point of 213-214°.

Elemental analysis value C engineering. H engineering, F2N04S theoretical value C, 5
4,08; H, 4,25; N, 3.94 Experimental value C, 54,87; H, 4,39; N, 3.9
1 Reference Example 2 Ethyl 1-7-difluoro-14-dihydro-2-mercapto-4-oxoquinoline-3-carboxylate 1-cyclopropyl-6,7-difluoro-14-nohydro-2-methyl Sulfinyl-4-oxoquinoline-
To a suspension of 0.71 g of ethyl 3-carboxylate in tetrahydrofuran 10-1, IN sodium hydrogen sulfide water/8 solution 2.
Add 21 and stir at room temperature for 3 hours. Concentrate the reaction solution under reduced pressure,
The residue is dissolved in 0.25 g of sodium bicarbonate and 20 parts of water.

After washing the aqueous solution with ether, dilute hydrochloric acid was added to the aqueous layer to adjust the pH to 3, and the precipitated crystals were collected by filtration.
．． Obtain 50g.

Elemental analysis value C15H13F 2 NO3S theoretical value C
,55,38; H,4,03; N,4.31 Experimental value C,55,23; H,4,35; N,4
．． 32 Reference Example 3 9-Cyclopropyl-6,7-difluoroisothiazolo[5,4-b]quinoline-3,4(289H)-dione 1-cyclopropyl-6,7-difluoro-14-dihydro-2- To a solution of 0.45 g of mercapto-4-oxoquinoline-3-carboxylic acid, 0.87 g of sodium hydrogen carbonate, and 51 parts of tetrahydrofuran in 20 parts of water was added 0.36 g of hydroxylamine-〇-sulfonic acid, and the mixture was stirred at room temperature for 2 hours.

Dilute hydrochloric acid is added to the reaction solution to adjust the pH to 3, and the precipitated crystals are collected by filtration.

The obtained crystals were washed with methanol to give a melting point of 282 to 287.
0.24 g of pale yellow crystals (decomposition) are obtained.

Elemental analysis value C13H8F2 N 202 S theoretical value
C, 53,08; H, 2,74; N, 9.52
Experimental value C, 53,04; H, 3,09i N,
9.34 Example 1 9-Cyclopropyl-6-fluoro-7-(3-hydroxymethyl-l-piperazinyl)-isothiazolo[5,
4-b coquinoline-3,4(2H9H)-dione 9-cyclopropyl-6,7-difluorothiazolo[5,4-b coquinoline-3,4(2H9H)-dione 0.50 g of pyridine 8.51 M1 &! To the solution, 0.39 g of 2-hydroxymethylpiperazine and 0.52 g of 1,8-diazabicyclo[5,4,O-7-undecene were added, and the mixture was refluxed for 3 hours. Reflux for an hour. The solvent of the reaction solution was distilled off, ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration.

The crystals are suspended in water, the pH is adjusted to 11 with a 10% aqueous sodium hydroxide solution, the pH is adjusted to 8 to 9 with 10% hydrochloric acid, and the precipitated crystals are collected by filtration. The crystals are suspended in methanol and ethanolic hydrochloric acid is added to adjust the pH to 1-2. The precipitated crystals are collected by filtration, heated and dissolved in water and 10% hydrochloric acid, and adjusted to pH 8-9 with a 10% aqueous sodium hydroxide solution. The precipitated crystals are collected by filtration to obtain pale brown crystals with a melting point of 275-280° (decomposed).

Elemental analysis value C engineering. H Engineering, FN403S@H20 Theoretical value C, 52,93; H, 5, 18; N, 13.72 Experimental value C, 53, 22; H, 5, 30; N, 13
．． 59 Compounds of Examples 2 and 3 are obtained in the same manner as in Example 1.

Example 2 9-cyclopropyl-7-(3,5-dimethyl 1-piperazinyl)-6-fluoroisothiazolo[5,4-b]
Quinoline-3,4(2H,9H)-dione hydrochloride Properties Colorless crystals (F20) Melting point 288-293@ (decomposition) Elemental analysis values C-9H2□FN402S・HCI・F2
0 Theoretical value C, 51, 52; H, 5, 4G; N, 12
．． 65 experimental value C, 51, G3; H, 5, 31; N
, 12.58 Example 3 9-7 clopropyl-6-fluoro-7-(1-homopiperazinyl)-inthiazolo[5,4-b coquinoline-
3,4(2H,9H)-dione Properties Pale yellow crystals (F2
0) Melting point 290-295° (decomposition) Elemental analysis value C,, H,, FN40□S # H20 theoretical value C, 55,09; H, 5,39; N, 14
．． 28 Experimental value C, 55,03; H, 5,42; N
, 14.05 Hikari'IQ'L - The novel inthiazoloquinoline derivative represented by the general formula (1) and its pharmacologically acceptable acid addition salt produced in this manner are Gram-positive. It has a wide range of antibacterial effects against bacteria and Durham-negative bacteria, making it extremely useful as a medicine.

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. , n represents an integer of 2 or 3. However, when R_1 represents a methyl group,
R_2 and R_3 do not represent hydrogen atoms at the same time. ) isothiazoquinoline derivatives and pharmacologically acceptable acid addition salts thereof.