JPS60142980A - Bicyclic compound - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [R<1> is lower alkyl, halogeno-lower- alkyl, vinyl; R<2> is lower alkyl; X<1> is halogen; Q is N, CH, CX<2> (X<2> is halogen)] and its salt. EXAMPLE:1-Ethyl-6-fluoro-7-( 3-methyl-1-piperazinyl )-1,4-dihydro-4-oxoquinoline-3- carboxylic acid. USE:An antibacterial: it can be expected to be used as a drug for humans, animals and fishes, as a food preservant, external bactericide and antiseptic. PREPARATION:The reaction of a compound of formula II (X<3> is halogen; R<3> is lower alkyl, H) with another compound of formula III is carried out in a solvent such as DMSO, DMF, pyridine, or 4-methoxygutanol at 50-150 deg.C, preferably 80-130 deg.C to give the compound of formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION [In the formula, R1 is a lower alkyl group, a halogeno lower alkyl group or a vinyl group, and R2 is a lower alkyl group.

Xl represents a halogen atom, Q represents -N, -C-H or 1-c-X", and x2 represents a halogen atom.]
(2) The present invention relates to a compound represented by (1) and a salt thereof.

norfloxacin (1-ethyl-6-fluoro-7-biperazinyl-1,4-dihydro-4-oxoquinoline-
3-carboxylic acid) is an excellent antibacterial agent (3-carboxylic acid) due to its strong antibacterial activity.
However, it has become clear that there are problems with absorption and bioavailability during oral administration.

The inventor believes that these difficulties are due to the fact that water solubility is too high and water solubility is low compared to fat solubility, and that the balance between fat solubility and water solubility and water solubility are important for absorption and oral administration. The present invention was completed as a result of intensive study based on the idea that bioavailability is important.

That is, the present invention relates to a compound represented by formula (1) and a salt thereof.

Examples of salts include salts with organic acids such as methanesulfonic acid, acetic acid and glutamic acid, as well as inorganic acids such as hydrochloric acid and sulfuric acid, and alkali metal salts and alkaline earth salts such as sodium, potassium and calcium salts of carboxylic acids. Examples include metal salts.

The compound of formula (1) also exists as a hydrate, and can also be administered as a compound (for example, a prodrug) that is absorbed and metabolically yields the target compound.

The method for producing the compound of formula (1) is represented by the following reaction formula, where "+Q+R" and R2 are the same as above.

x3 represents a halogen atom, and R3 represents a lower alkyl group or a hydrogen atom. ) That is, the compound of formula (II) and the compound of formula (Ml) are combined in dimethyl sulfoxide, dimethylformamide, pyridine or 4. -50 to 150 in a solvent such as methoxybutanol
The formula (
The substitution reaction between the compound of 1) and the halogen atom (x3) is completed. When the atom of the compound of formula (II) is a hydrogen atom, the desired compound of formula (I) can be obtained by a single substitution reaction, but when R3 of the formula ([[) is a lower alkyl group, 9 After completion of this reaction, the desired compound of formula (1) can be obtained by hydrolyzing the ester product.

The compound of formula (1) of the present invention has a favorable partition coefficient and excellent antibacterial activity and antibacterial spectrum as shown below.

Therefore, the compounds of the present invention are expected to be used as medicines, veterinary medicines, fish medicines, food preservatives, external disinfectants, and disinfectants.

Minimum inhibitory concentration (UIC) of the compound of formula (4) of the present invention
; μ9/-) is shown in the table below. Furthermore, MI
The test method for C was in accordance with the method specified by the Japanese Society of Chemotherapy.

Table Minimum Inhibitory Concentration (μ/-=4) Next, the present invention will be explained with reference to Examples.

Example 1 1-ethyl-6,7-difluoro-1,4-dihydro-
200vn9 of 4-oxoquinoline-3-carboxylic acid and 8007++9 of 2-methylpiperazine are heated and stirred in 5fnt of dimethyl sulfoxide at a bath temperature of 120 to 180°C for 6 hours. The solvent was removed under reduced pressure and the residue was partitioned between water and chloroform (large quantity). The chloroform layer is dried with Glauber's salt and chloroborum is distilled off. The residual solution was subjected to column chromatography on 15 ml of silica gel and developed with 7% methanol-chloroform. When the distillate is collected and recrystallized from ethanol, 1-ethyl-6-
Fluoro-7-(3-methyl-1-piperazinyl)-1
, 110 m9 of 4-dihydro-4-oxoquinoline-3-carboxylic acid decahydrate are obtained.

7.91 (I H, 6”-, 1&5Hz, Cs-
H) 8.96 (LH, s, Cz once) Elemental analysis value Cl 7H20FN3034HzO, total 1 C[itk C59,64,H6,18,N 1
2.27 Analysis value C59.91, H6.00, N 12
．． 29 The above hydrate 100rn9 was dissolved in 10% HCt.

After drying under reduced pressure, the residue is recrystallized from aqueous ethanol to obtain the hydrochloride salt 901n9 of the above compound having a melting point of ao'c or higher.

Elemental analysis value Calculated value as Cl7H20FN303-HCl 055.21. H5,72, N 11.86 Analysis value C55,04, H5,69, N 11.81 Example 2 1-ethyl-6, fudifluoro-1,4-dihydro-
4-oxoquinoline-8-carboxylic acid ethyl ester 5
0tn9 and 2-ethylpiperazine soomg are reacted in dimethyl sulfoxide 5 at a bath temperature of 120-180°C for 5 hours. The solvent was distilled off under reduced pressure, and the residue was washed with a needle.
Wash twice.

Purified by column chromatography on silica gel 109 (2% methanol-chloroform).

1-ethyl-7-(8-ethyl-1-piperazinyl)-
16'Omg of 6-fluoro-1,4-dihydro-4-oxoquinoline-8-carboxylic acid ethyl ester is obtained.

2 containing 150rn9 of the above ester and 50ml of caustic soda
Hydrolyze in 0% aqueous ethanol Grnl at a bath temperature of 50-60°C for 30 minutes. After the reaction, concentrate to approximately + and neutralize with hydrochloric acid. After filtering the obtained precipitate and washing it with a small amount of water,
1-Ethyl-7-(3-ethyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 11, which is a transparent crystal with a melting point of 222°C when recrystallized from ethanol. Get .0'n9.

Elemental analysis value 018I (calculated value as 22FN303)
C62,23,H6,38,N 12.10 Analysis value C
62,20,H6,01,N 11.98 Example 3 1-ethyl-6,7,8-)lifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 120μ and 2-methylbiperazine 200m9 is stirred in dimethylformamide 3 for 8 hours at a bath temperature of 120-130°C. The solvent was removed under reduced pressure.

The residue was diluted twice with ether and then twice with 5% aqueous ethanol.
After washing twice, when recrystallized from aqueous ethanol, the melting point is 2.
1-ethyl-6,8-difluoro-7-(8-methyl-1-piperazinyl)-1, at 44-246 °C (decomposed)
4+-dihydro-4-oxoquinoline-8-carboxylic acid 100% is obtained.

8,! l 6 (IH, s, 02-¥) Elemental analysis value
Calculated value as C17HI 9F2N303・4H20
C5&96. H5, 86, N 11.10 analysis value 0
5, 13.68. H5,68,N 11.08 Example 4 6.7-difluoro-1-vinyl-1,4-dihydro-
4-oxoquinoline-3-carboxylic acid 115m9 and 2
- Methylbiperazine 2501n9 is stirred in 5 m of dimethyl sulfoxide at a bath temperature of 120-180°C for 3 hours. Cold welding, the solvent was distilled off under reduced pressure, and the residue was diluted with ether twice for 5 hours.
% aqueous ethanol twice, ethanol-ether (1:
After washing twice with the mixture of 4), recrystallization from ethanol yields 6-fluoro-7 with a melting point of 268-271°C (decomposition).
-(3-methyl-1-piperazinyl)-1-vinyl-1
, 4-dihydro-4-oxoquinoline-3-carboxylic acid 68rn9 is obtained.

Elemental analysis value Calculated value as G+7H1sFN303 c
el, 62. H5, 47, N 12.68 analysis value
c 61.34. H5,48,N 12.47 Example 5 -(2-fluoroethyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 2oomg and 2-methylbiperazine 300rn
Dissolve g in dimethyl sulfoxide 1°-, bath temperature 180°C.
React at ~140″C for 6 hours. Remove the solvent under reduced pressure.
The residue is washed twice with ether and then twice with a small amount of 5% aqueous ethanol. Add 10% hydrochloric acid to the residual solution, remove a small amount of insoluble matter by filtration, and dry the filtrate under reduced pressure. The obtained residue was recrystallized from aqueous ethanol to obtain 6,8-difluoro-1, which is a fine needle crystal with a melting point of 290 to 297°C (indistinct decomposition).
60 m9 of -(2-fluoroethyl)-7-(8-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride is obtained.

Elemental analysis value C+ 7HIIIF3N303・Calculated value as HOI C50,22,H4,72,N 10.3
5 Analysis value 050.11. H4,55,N 10.2
1 Example 6 ■-Ethyl-7-chloro-6-fluoro-4-1,4-dihydro-4-oxo-1,8-naphthyridine-8-carboxylic acid 500rn9 and 2-methylhyherazine 600w1
was dissolved in 20 tnl of dimethyl sulfoxide, and the bath temperature was 11
React for 4 hours at 0-120°C. The solvent and excess reagents are removed under reduced pressure. The residue was washed twice with ether and twice with aqueous ethanol, and then dissolved in 10% hydrochloric acid.

Trace amounts of insoluble matter are removed by filtration, and the filtrate is dried under reduced pressure.

When the obtained residue is dissolved in aqueous ethanol, treated with activated carbon, and then recrystallized, 1-ethyl-6 with a melting point of 300°C or higher is obtained.
-Fluoro-7-(8-methyl-1-piperazinyl)-
1801 ng of 1,4-dihydro-4-ogiso-1,8-naphthyridine-3-carboxylic hydrochloride are obtained.

Claims (1)

[Scope of Claims] Formula [In the formula, R1 is a lower alkyl group, a halogeno lower alkyl group, or a vinyl group, and R2 is a lower alkyl group. xl is a halogen atom, Q is -N, -0-H or 1? -X2, and X2 represents a halogen atom. ]
A compound represented by and its salt.