JPS5862113A - Drug having activity against acid-fast germ - Google Patents

Abstract

PURPOSE:The titled drug, containing a pyrido[1,2,3-de][1,4]benzoxazine derivative, and capable of producing a wide and remarkable effect of germs resistant to the existing antituberculotic agent and atypical acid-fast germs. CONSTITUTION:A drug containing a compound of formulaI(R1 and R2 are H or lower alkyl; X is halogen) or a salt thereof, e.g. 9-fluoro-3-methyl-10-(4-methyl- 1-piperazinyl )-7-oxo-2,3-dihydro-7H-pyrido[ 1,2,3-de ][1,4]benzoxazine-6-carboxylic acid, as an active constituent. The dose thereof is preperably in the range of 0.2-1.0g/day. The compound of formulaIis obtained by reacting a compound of formula II with a compound of formula III in a polar solvent preferably under heating at 70-150 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a drug that exhibits strong antibacterial activity against acid-fast bacteria, and more specifically, a drug of the general formula (I> (wherein R1 and tortoise independently represent hydrogen or a lower alkyl group, means halogen.) pyrido (
l,! , 8-de] [l, 4] This invention relates to an acid-fast bacterium active agent containing a benzoxazine derivative or a salt thereof.

It is well known that acid-fast bacteria include Mycobacterium tuberculosis and atypical antimycobacteria. Conventionally, for Mycobacterium tuberculosis, streptomycin ('M) tpass (PAS) and isoniacyto (xnH)* have been used. Ethambutol (xn)e rifampicin (RF P ).

Excellent drugs such as kanamycin (KM) have been developed.

However, the occurrence of bacteria resistant to these existing tuberculosis drugs reduces the intended effects of existing drugs, and conventional drugs alone are no longer necessarily sufficient as tuberculosis treatment drugs. Therefore, there is a desire to develop drugs that are effective against existing tuberculosis drug-resistant bacteria, and exploratory research is underway, and to date a certain number of drugs that are effective against specific drug-resistant bacteria have been discovered.

However, there is no drug to date that is broadly effective against all bacteria resistant to existing tuberculosis drugs, and there is a strong desire to develop a drug that exhibits such effects. On the other hand, no drug has been found so far that clearly acts effectively against atypical acid-fast bacteria, which is one type of acid-fast bacteria, and there is a strong desire to develop a drug that has such an effect.

The present inventors aimed to respond to the above-mentioned background.

We conducted extensive research to find a drug that has excellent effects against acid-fast bacteria. In other words, the expression of mycobacterial activity requires an optimal balance between ribophilicity and hydrophilicity in the bacterial cell membrane permeability of the drug, and the presence of basic and acidic groups in the aromatic ring. This is the result of an attempt to find a compound that would meet the purpose.

The present invention was completed by discovering that the compound represented by the general formula (I) exhibits excellent acid-fast bactericidal activity.

The compound of general formula (1) according to the present invention is a new compound, and its production method is shown by the following reaction formula.

(In) (II) (wherein Ri, % and Compound (1) is obtained by heating the compound at room temperature to zoo''c, preferably 70 to 150°C for 1N48 hours.The thus obtained formula (1)
The compound can be converted into a salt with an inorganic or organic acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid, or a sodium or potassium salt of a carboxylic acid by a conventional method.

The compound of formula (1) produced in this manner exhibits excellent acid-fast bactericidal activity.1 As a representative example of the compound of formula (I), 9-fluocy-8-methyl-10-(4-Example 2) was added to Ogawa medium. Low concentrations of drug (25-0.89 vnog
) was added, but the MIC was measured in the same manner as in Example 1.

Bacterial growth rate of control medium II R means resistance (Re5stance).

Reference example 1 2.4-dichloro-8-fluoronitrobenzene 5.0
g and powder7. Add 5.89 g of potassium chloride to dimethyl sulfoxide 5- and stir at 155° C. for 4.5 hours. The solvent was distilled off under reduced pressure.

Partition the residue between water and chloroform. After washing the OO form layer with water and drying it, the chloroform is distilled off, leaving an oily substance! , 8.4-)lifluoronitrobenzene s,
5yttnru.

20'l of this material is dissolved in 150 ml of dimethyl sulfoxide, and a 10% aqueous potassium hydroxide solution is added dropwise at 18-20°C. The mixture was further stirred at room temperature for 2 hours, and 11 parts of water was added, followed by chloroform and shaking. The aqueous layer is acidified with hydrochloric acid and extracted with chloroform. The extract is washed with water, dried, and the chloroform is concentrated. The residue was purified by silica gel chromatography to give 2,8-difluoro-
5.8 g of 6-nitrophenol are obtained.

Add 5.8g of this to 6g of monochloroacetone, Of! .

Add 8.02% of potassium carbonate, 0.89% of potassium iodide and 100% of acetone and reflux for 4 hours.

Insoluble materials are filtered off, the solvent is distilled off, and the residue is partitioned between chloroform and water. After washing the chloroform layer with water and drying, the solvent was distilled off and the residue was treated with 2-hexane to give 2-acetonyloxy-8,4-difluoronitrobenzene of 2-acetonyloxy-8,4-difluoronitrobenzene as pale yellow-white crystals with a melting point of 61" obtain.

7.1 g of this product was dissolved in 200% of ethanol, and 14% of Raneyi and Kel were added thereto for atmospheric catalytic reduction. After filtering off the catalyst and distilling off the solvent.

Once the residue is decolorized through a layer of silica gel.

7.8-difluoro-2,8-dihydro a-B-methyl-
4H-benzoxazine as pale yellow oil 5.11
You can get it.

A mixture of Konomo's (D4.89 and 5.8 g of diethyl ethoxymethylene malonate) is heated at 140 ~ b ~ for 1 hour. After the raw materials have disappeared, a small amount of ethanol is distilled off under reduced pressure, and 86 g of ethyl polyphosphate is added to the resulting oil. In addition, bath temperature 140
Stir at ~145°C for 1 hour, cool, pour into ice water, and extract the precipitate with chloroform 600s/(SOOX8).

The chloroform layer was partitioned with a 5% aqueous potassium carbonate solution and then with water, and then dried with Glauber's salt to give 9.10-difluoro-a-3-methyl-7-oxo-2,8-dihydro-7H-pyrido (
XI L 8- ae ) (1,4) White powder of benzoxazine-6-carboxylic acid ethyl ester 6.19
(melting point 261°C) is obtained.

4.02% of this product was dissolved in 50% of concentrated hydrochloric acid-acetic acid (1:4) and refluxed in an oil bath for 3 hours. After cooling, the precipitated crystals were collected by filtration, thoroughly washed with water, washed with a mixture of ethanol and ether (1:4), and dried under reduced pressure to obtain 8.7 g of carboxylic acid in the form of transparent plate-like crystals.
(melting point>800°C).

9.10-difluoro-8-methyl-7-oki'/-2
, B-dihydro 0-? H-pyrido(1,2,8-dQ(1
, 4) Benzoxazine-6-carboxylic acid 1, (1) and N-methylbiperazine 2.859 are added to dimethyl sulfoxide 15- and stirred at 100-110°C for 12 hours. The reaction mixture is dried under reduced pressure and water is added to the residue. 40- was added and extracted with proform. The extract was dried and then dried under reduced pressure.

When the residue is recrystallized from ethanol, the melting point is 260-257.
9-Fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,8-cyhydro a-7H-pyrido (1,ie,8
-da)(1,4)hendioxazine-6-carboxylic acid 550''9 is obtained.

Elemental analysis value Calculated value as CuHu'tNsO4 0
59.8g, H5,58, N 11.68 Analysis value 0 59.6g, H5,59, N 11.66
Reference Example 2 9,1O-difluoro-7-oki'/-2,8-dihydro Elf-7H-pyrido (1,2,8-(16) (1,
4) Benzoxazine-6-carboxylic acid 1881m19
and N-methylbiperazine j! +00q is dissolved in dimethyl sulfoxide 2- and stirred at 90-110°C for 6 hours. From now on, if the precipitate is collected by filtration, washed with methanol and water, and then recrystallized from ethanol, 9-fluoro a-10-
(4-methyl-1-piperazinyl)-7-oxo-8,
8-dihydro a-7H-pyrido (1,!, 8-66) [
1,4] 58 m9 of benzoxazine-6-carboxylic acid are obtained.

Elemental analysis value Calculated value as precious HssFNsO* 0
58.78. H5, 2g, N IJ, 10 analysis value C58J? , H6,8B, N 12.
04 Reference Example 8 9, 1O-difluoro0-7-oki/-1.8-dit0
−? H-pyrido(1,!,8-lie) (1,4
)'Benzoxazine-6-carboxylic acid 584m! and 688 ml of piperazine were dissolved in 10-dimethyl sulfoxide and stirred at 90-100°C for 5 hours. In the future, the precipitate will be collected by filtration, washed with methanol, and then recrystallized from water to form pale yellow needle crystals with a melting point of 258-268°C (decomposition). )-a,8-dihydro-? H-pi 9F (1, 2, 8-4
o) (1,4)benzoxazine-6-carboxylic acid $8
Get 61119.

Elemental analysis value C1sH1@F Calculated value as N304
C67,66, H4,84, N 1g, 61 analysis value
0 5? , i5. H479, N 12.69 Reference Example 4 9, 1O-difluoro-3-methyl-7-oxy-s,
s-dihydro-? H-pyrido (1,!, 8-ae)
(1,4)benzoxazine-6-carboxylic acid 1.6g
, anhydrous piperazine 1.99 to dimethyl sulfoxide 80
- and react at a bath temperature of 10G to 110°C for 8 hours. The solvent was distilled off under reduced pressure, and the residue was washed with chloroform and then with ether, and then stirred at room temperature for 2 hours with 50% aqueous methanol, and the precipitate was collected by filtration and washed with a small amount of the same solvent and then with methanol. Recrystallizing the white powder from ethanol yields 9-fluoro with a melting point of 260°C (decomposition).
-8-Methyl-7-oxo-10-(1-piperazinyl)-8-dihydro-7H-pyrido(1,!, B -a
s) Pale yellow-white crystals 910119 of (1,4) benzoxazine-6-carboxylic acid are obtained.

Elemental analysis value False t Hl s F N304・±H20
Calculated value as C5, 80. H5,8? , N
11.79 Analysis value C57,01,)I 6.4
! , NIL'76 Reference Example 5 n,4-cyclo-3-fluoronitrobenzene 10.
59 (0.06 mol) in dimethyl sulfoxide 80
-, add 40% aqueous sodium hydroxide solution 8-, and stir at a bath temperature of 60 to 70°C for a period of time. After the reaction, water I
QQglt was added, unreacted raw materials were extracted and removed with ether, and the aqueous layer was made acetic acid and extracted with ether. After drying the extract over Glauber's salt, the solvent was distilled off, and the residue was purified with silica gel 1009.
The product was purified by column chromatography (developing solvent: chloroform) to obtain 8.42 g of 8-ri-2-fluoro-6-nitrophenol with a melting point of 78°C.

The above 7-nol compound 8 (15,' Fol).

Chloracetone 8- and powdered potassium iodide 800 m'
9 was refluxed for 6 hours in a 50% aqueous solution with vigorous stirring. After cooling, insoluble matter was removed by filtration.

After concentrating the filtrate, it was purified by column chromatography on silica gel 209 (developing solvent: chloroform) to obtain oily 2
-acetonyloxy-4-rep-8-fluoronitrobenzene L5FIll.

Add nickel 29 and perform catalytic reduction. After the reaction, the catalyst is filtered off, the filtrate is concentrated, and the residue is silica gel! Purified by column chromatography (developed In &: chloroform) of 09 to obtain an oily 7-lya-8-fluoro-8-methyl-2.
,8-dihydro-4H-1,4-benzoxazine IJ
Get 9.

The above benzoxazine compound 1.119 (5, inm
ol ) and diethyl ethoxymethylenemalonate 1.49
(6.2 mmol) was heated and stirred at a bath fi of 180 to 1.40°C for 2 hours. After confirming the disappearance of the raw benzoxazine compound by thin layer chromatography, ethyl polyphosphate 52 was added to the reaction mixture and the mixture was reacted again at a bath temperature of 140° C. for 1 hour. Thereafter, water zO- is added and the deposited precipitate is extracted with chloroform 150-. After drying the extract over Glauber's salt, the solvent was distilled off, and the residue was purified by silica gel get column chromatography (developing solvent: 5% methanol-chloroform) to obtain 9-chloro-10-fluoro-8 with a melting point of 868-864°C. -Methyl-7-oxo-? ! ,
8-dihydro 7H-pyrido (12B-de) (1,4
) Ethyl benzoxazine-6-carboxylate IJ is obtained.

Elemental analysis value Calculated value as 01sHssOjFNO4
0 55.81. H40! , N 4.80 Analysis value 0 55.19. H8,9? , N 4
41 Add 600% of the above ethyl carboxylic acid compound (1,8) to the reaction mixture, collect the precipitated crystals by filtration, wash thoroughly with water, add ethanol-ether (4:1.%) mixture, then add ether. 9-chloro-1O-fluoro-8-methyl-
7-Oxo-! , 8-dihydro 0-7H-pyrido (1,L
8-116) (1,4) Benzoxazine-6-carboxylic acid 411■ is obtained.

Elemental analysis value Calculated value as 0111H*0IWN04
0 6B, 45. H8,06,N 4L? 1 analysis value c 5 so, H8, 1B, N &? 4
The above carboxylic acid 160”9 (0.5 inmol)
is suspended in dimethyl sulfoxide B-, l-methylbiperazine 1s09 is added, and the mixture is reacted at a bath temperature of lSO to 180°C for 6 hours. After cooling, the solvent was distilled off under reduced pressure, and the residual liquid was washed with ether to remove soluble residue, and then purified by column chromatography on 7 g of silica gel (5% methanol-chloroform, 10-methanol-chloroform). Then, the eluate containing the target compound was collected, the solvent was distilled off, and the remaining liquid was recrystallized from ethanol, resulting in a melting point of 275-2176°C.
(decomposition) of pale yellow microneedle crystals of 9-kurota-8-methyl-
10-(4-methyl-1-piperazinyl)-7-oxo-! , 8-dihydro 7H-pyrido (1,2,8-as
) (1,4) Benzoxazine-6-carboxylic acid 6
6111j is obtained.

Claims (1)

[Claims] Acid-fast bacterium active agent fi, 9 containing a compound represented by the formula (wherein R1 and R1 independently represent hydrogen or a lower alkyl group, and X represents a halogen) or a salt thereof. -F A'oJ3-Methyl-10-(4-methyl-1-piperazinyl)-7-oxo-8,8-dihydro a-7 to monopyrido (1,!, 8-+16) (1,4
) A drug according to claim 1 containing benzoxazine-6-carboxylic acid or a salt thereof