JPS591468A - Quinoline compound, manufacture and antibacterial - 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 The present invention relates to novel quinoline compounds, their use as antibacterial agents, and processes for their preparation.

It is known that certain substituted 4-quinolone-3-carboxylic acids have antimicrobial activity. Representative examples of these compounds are those of the following formula.

[X is H (invention of U.S. Patent No. 4,146,719 issued by Kozai Seiyaku on June 27, 1979) or methyl (R, Be1
lon/ Dainippon Pharmaceutical's U.S. Patent No. 4,292,317 issued on September 29, 1981)] U.S. Pat. are disclosed and stated to have antibacterial activity. Examples of disclosed compounds are 1-:) methylamino-6-nitro-2-methyl-4-kr/ron-3-carboxylic acid methyl ester (Example 4); 1-:) methylamino-7- Chloro-6-nitro-2-methyl-4-quinolone-3-carboxylic acid methyl ester (Example 5); 1-dimethylamine-7-(
n-butylmercabuto-6-nitro-2-methyl-4
-quinolone-3-carboxylic acid methyl ester (actual flow side 1
7). There are no examples of compounds having a heterocyclic group at the 7-position.

The present invention relates to a compound represented by the following formula (2), a pharmaceutically acceptable acid addition salt thereof, and an alkali metal or amine salt of the compound in which R' is H.

1 ■ [R is amino, lower alkylamino, 2-pro is nylamino, N-formyl-lower alkylamino or di-lower alkylamino; R' is H or lower alkyl; Z=N- is the following complex Any cyclic group.

is H2 lower alkyl or acetyl) H A preferred group of compounds is 1-piperazinyl or 4-lower alkyl of formula I where Z=N- is formula IA: (R" is H or lower alkyl) 1-
The first one is radinyl. Particularly preferred is R
is methylamine, R' is H and R'' is methyl, and their pharmaceutically acceptable salts.

The present invention further relates to a compound represented by the following formula (1).

0 ■ (R/ is H or lower alkyl; RO is amine, lower alkylamino, 2-proynylamino, di-lower alkylamino, N-formylamino, N-formyl-lower alkylamino, or N-formyl-2- propenylamino) Does the compound of formula ■ serve as an intermediate for the compound of formula l? - The antibacterial agent of the present invention comprises an antibacterial effective amount of the compound of formula (1) and one or more pharmaceutically acceptable excipients.

A compound of formula I can be prepared by reacting a compound of formula (1) in which Ro is amino, lower alkylamino, 2-propenylamino, or di-lower alkylamino with a metal compound of formula: Z=NH.

Bacteria can be eradicated by contacting an antimicrobially effective amount of a compound of Formula I with a bacterial habitat.

In the definitions of the symbols in the above formulas (1) and (2), the term "1 lower alkyl" refers to alkyl, preferably 00 to 3 alkyl, such as methyl, ethyl, propyl, impropyl and alkyl.

The amino group can be prepared using an aminating agent such as chloralamine or 0-arylhydroxylamine such as 0-(2,4-dinitrophenyl)hydroxylamine (2,4-(02N)2C6H3ONH2) using a known starting material of the formula
[Tamura et al., J, Org, Ohem, 38° 1239 (
(1973)].

1 This results in a compound of the formula ■ in which Ro is NH2 (formula ■
) occurs. The reaction takes place in the presence of a base such as carbonic acid at ambient temperature in an inert organic solvent.

The general synthesis of compounds of Formula I is as follows.

■IV ■■ Lower alkyl-NH 1 (R-lower alkylamino, R'=H) In the above flow sheet, when compound (III) is formylated with a mixture of formic acid and acetic anhydride, the N-formyl derivative (IV) is obtained. can get. This is then alkylated with a lower 1 alkyl halide (preferably iodite or bromide) in the presence of a base such as carbonic acid to obtain the N-lower alkyl-N-formyl compound (V). This is NaO
When hydrolyzed with a base such as H and acidifying the reaction mixture, N
- Lower alkyl carboxylic acid (■) is formed.

The final step involves combining a compound of formula (■) with a suitable heterocyclic compound Z=N
In formula I by reaction with H, R is lower alkylamino, R'
is the production of a compound where is H. This reaction occurs in the presence of an acid acceptor that absorbs the HGt formed, from about 100 to about 1
It is produced by heating the reactants at a temperature of 50°C. Is this acid acceptor also for alkali metal carbonates? T-amines such as lysine, triethylamine, (:)inpropyl)ethylamine and the like may be used. Alternatively, an excess of the heterocyclic reactant can be used as the acid acceptor. In a preferred method, the reactant mixture is heated at reflux temperature in another solvent such as pyridine or 2-methoxyethanol using 3 to 6 moles of heterocyclic reactant per mole of compound (■).

Compounds of formula I in which R is 2-pronylamino are ■→
It is prepared in an entirely similar manner using allyl halide in place of the lower alkyl halide in the V conversion.

Again in the flow sheet, if desired, R in the formula
Compounds where ′ is lower alkyl can be hydrolyzed to form the free acid (
R' =)(). This is converted into an N-formyl compound (
IV, R'=H).

Then, by alkylation, the carboxyl group is esterified to form v<R/==lower alkyl). ``Lower alkyl ester (VI) can be produced by a conventional esterification reaction or selective hydrolysis of compound V (R'=lower alkyl). This lower alkyl ester (Vl) is a potential intermediate for preparing compounds of formula (1) in which R' is lower alkyl. However, ester (■) and Z=
Preferably, the ester of formula (1) is prepared by direct esterification of the free acid of formula I, as there is a tendency for amide formation on reaction with NH).

Compounds of formula I in which R is amino (NH2) are intermediates (
III) and Z=Nf().

Compounds of formula I in which R is N-formyl-lower alkylamino are prepared by formylation of compounds of formula I in which R is lower alkylamino.

Compounds of formula I in which R is di-lower alkylamino are prepared as follows. N-alkylation of a compound of formula (1) by heating with a di-lower alkyl sulfate, which is a lower alkyl ester, forms a compound of formula (2) in which R' is lower alkyl and RO is di-lower alkylamino. Hydrolysis with an aqueous alkaline solution yields a compound of the formula (2) in which R' is H and R' is di-lower alkylamino. This is then reacted with a heterocyclic compound Z=NH to yield the desired compound of formula I in which R is di-lower alkylamino. This synthetic route allows the lower alkyl group of di-lower alkylamino to be separated,
It is clear that it is possible to prepare compounds such as methylethylamino.

The present invention also relates to pharmaceutically acceptable acid addition salts of compounds of formula (1). The nature of the acid addition salt is not critical as long as the anion is derived from an acid that is essentially non-toxic to the animal body. Examples of suitable acid addition salts are hydrochloride, hydrobromide,
These include sulfate, methanesulfonate, maleate, citrate, tartrate, p-)luenesulfonate, cyclohexane sulfamate, and the like. Although compounds of formula I theoretically have one or more N atoms, they tend to form only stable monoacid addition salts.

Compounds of formula I in which H' is H can also be prepared and used in the form of alkali metal or amine salts, preferably Na, K or N-methylglucamine salts.

The following is an illustration of the invention.

Production example 1゜a) 1-amino-7-chloro-6-oroh 1.4-:
) Ethyl hydro-4-oxo-3-quinolinecarboxylate [■: 15, Of (0,0556 mol] of 7-chloro-6-fluoro-1,4-:)hydro-4-oxo-6
- ethyl quinolinecarboxylate, 15.3f (0,111
A mixture of 2 mol) of carbonic acid and 500 d of dimethylformamide was stirred at room temperature for 6 hours. Then o-<2.4-
:) Nitrophenyl) Hydroxylamine (14,3F
.

0.072 mol) and stirred for about 16 hours. Thin layer chromatography (tIC) showed incomplete reaction.
．． (IN') 0-(2,4-dinitrophenyl)hydroxylamine was added and stirring continued for 2 hours.
．． 8 f 0-(2,4-dinitrophenyl)human 90
Additional xylamine was added and stirring continued for 2 hours.

The solvent was removed in vacuo at 50° C. and the residue was stirred with 600° C. water for 2 hours and filtered. The resulting solid was slurried with 700 ml of refluxing acetonitrile and filtered. When the p solution was cooled, 5.4f of ethyl 1-amino-7-chloro-6-fluoro-1,4-dihyto90-4-oxo-6-chitulincarboxylate, mp 254-258°C, crystallized.

The solid remaining on the filter was recrystallized from dimethylformamide to obtain an additional 6.7 t of pure product. Total income 11
12.1f.

b) 1-amino-7-chloro-6-fluoro-1,4-
DihyP-Rho 4-oxo-6-chitulincarboxylic acid [■;
R/=H] 100% NaOH (0.91?, 0.0228 mol)
-〇Dissolved in water, 2.6F (0,0091 mol) of 1-
Amino-7-chloro-6-fluoro-1,4-oxo-
Ethyl 6-quinolinecarboxylate was added. The mixture was stirred in a steam bath for 2 hours and neutralized with acetic acid (1.6 Wt) while hot. The solid suspension was stirred at room temperature for about 16 hours, and the solid was separated and washed with water. The product was recrystallized from dimethylformamide 9.2. Of 1-amino-7-chloro-6-fluoro-1,4-u Hibilow 4-oxo-6-quinolinecarboxylic acid, beige powder, mp 312-615°C,
I got it.

Alternatively, 1-amino-7-chloro-6- Fluoro-1,4-u human 50-
H production of 4-oxo-6-quinolinecarboxylic acid was completed. The former is 7-chloro-6-fluoro-1,4-dihydro90-
Ethyl 4-oxo-6-chitulincarboxylate with NaOH
Hydrolysis with aqueous solution yielded a colorless solid, mp 274°C (decomposed).

Production example 2゜7-chloro-6-fluoro-1-(formylamino)-
1,4-dihyro-4-okino-3-quinolinecarboxylic acid Formic acid (24,5 0.625 mol) was added dropwise to 59-(0,625 mol) acetic anhydride while stirring at 0°C. C. for 15 minutes, stirred at 50.degree. C. for 15 minutes, and then cooled to 0.degree. 1-Amino-7-chloro-6-fluoro-1
, 4-dihydro-4-oxo-6-quinolinecarboxylic acid ethyl [Production Example 1 (a), 17.8 f (0,
A solution of 0,625 mol)] in formic acid (130 g/) was added dropwise. The mixture was stirred at room temperature for 3.5 days. At this point tlc showed the presence of a small amount of starting material so 48m of mixed anhydride was added to the reaction mixture and then stirred for 6 more hours.

The solid product was separated and thoroughly washed with water to obtain 19.65r of solid. This was recrystallized from a dimethylformamide-ethanol mixture, dried over phosphorous pentoxide at 110°C for 2.5 days, and then 7-chloro-6-fluoro-1-(formylamino)-1,4-dihyto10-4- Ethyl oxo-3-quinolinecarboxylate, mp 263-264°C (decomposition), was obtained.

Similarly, 1-amino-7-chloro-6-fluoro-1,
4-:)hydro-4-oxo-6-chiralincarboxylic acid was formylated to give 7-chloro-6-fluoro-1-(formylamino)-1,4-:)hydro-4-oxo-6
- Chiralin carboxylic acid [:lV; R' = H).

Manufacturing example 3A.

7-chloro-6-fluoro-1,4-:) human 90-5
-[(formyl)methylamino)-4-oxo-6-quinolinecarboxylic acid ethyl [v; lower alkyl=GH3,
R' = C2H5) 14.65y (0,047 mol) of 7-chloro-6-fluoro-1-(formylamino)
-1,4-dihuman 90-4-oxo-6-chitulinecarboxylic acid ethyl (ff Preparation Example 2), 12.9 F (0,0
A mixture of 94 mol) potassium carbonate, 200 d17) dimethylformamide 9 was stirred at 25° C. for 90 minutes. Add methyl iodide (20,Of, 0.141 mol) and stir at room temperature.
Stirred for 0 minutes. The dimethylformamide was removed under high vacuum at 50° C. and the residue was partitioned between 250° of water and 500° of chloroform. The chloroform layer was separated and dried with anhydrous sulfuric acid M1. 7 of 13.85' by concentration of chloroform solution
-chloro-6-fluoro-1,4-:)hydro-5-[
Ethyl (formyl)methylamine]-4-oxo-6-chitulinecarboxylate, mp 213-216°C, was obtained.

Production example 3B.

Ethyl 7-chloro-6-fluoro-5-C(formyl)ethyl avonate [■; lower alkyl-C2H5,R'=
C2H5) Ethyl 7-chloro-6-fluoro-1-(formylamino)-1,4-dihydro-4-oxo-3-quinolinecarboxylate of 121 by the method of Production Example 3A,
Prepared in 166 g of dimethylformamide from 9.4 tILt of ethyl iodide in 10.52 g of carbonic acid. 1
1.5f product, tan-colored powder, ml) 185-18
7°C was obtained.

Manufacturing example 3C.

7-/'Roro6-Fluoro5-((formyl)furobylamine]-1,4-:)hydro-4-okino6-
Quinoline [Lower alkyl-(OH2) 20H, R No C
2H5] 7-chloro-6-fluoro- of 122 in dimethylformamide 9 of 163- by the method of Preparation Example 3A above.
Ethyl 1-(formylamino)-1,4-:)hibilow 4-oxo-6-quinolinecarboxylate, prepared from 110.6-n-propyl bromide in 10.5y carbonate. 1
Product of 22, light yellow powder, mp185-187"C1
I got it.

Manufacturing example 3D.

Ethyl 7-chloro-6-fluoro-5-(formyl(1-methylethyl)amino)-1,4-dihydro-4-oxo-3-quinolinecarboxylate [v; lower 7pv+ru(OH3)2G) (, R'=
c2n5) 7-chloro-6-fluoro-1-(formylamino)-1,4-:)human90- of 11.3F in dimethylformamide of 122- by the method of Preparation Example 6A above.
Ethyl 4-oxo-6-quinolinecarboxylate, prepared from 8.3 m/m of isopropyl bromide in 82 m/m of carbonic acid. 1
Product of 02, tan-colored powder, mp 148-155°C,
I got it.

Production Example 3L Ethyl 7-chloro-6-fluoro-1-[formyl-(2-propenyl)amino]-1,4-dihydro-4-oxo-6-quinolinecarboxylate (II; Ft' = C2H5,R' =OC)(-N(
OH2CH(3H2)) 16 by the method of Preparation Example 6A above
7-chloro-6-fluoro-1-(formylamino)-1,4- of 102 in dimethylformamide 9 of
Ethyl dihydro-4-oxo-3-quinolinecarboxylate, prepared from 18.4-allyl bromide in 8.8F carbonic acid. Product of 9.49, tangent powder, mp 178-18
2°C was obtained.

Production Example 4A 7-chloro-6-fluoro-1,4-dihydro-1-methy[■; lower alkyl-CH3] 11.8 F of 7-chloro-6-fluoro-1,4-:
) Hydro-5-[(formyl)methylamine]-4-ox7-5-quinol/ethyl carboxylate (Production Example 3A),
A mixture of 5.82% NaOH, 30o* water was stirred on a steam bath for 2 hours. The reaction mixture was decolorized with activated carbon and acidified with warm 195F acetic acid obtained by filtration.

The mixture was stirred at 0° C. for 60 minutes, and the solid product was separated and washed with water.

The product was crystallized from 150 m/m of dimethylformamibi to give 8.7 f of 7-chloro-6-fluoro-1,4-
:) Hibilow 1-methylamino-4-oxo-3-quinolinecarboxylic acid, pale yellow crystals, mp275-279℃ (
decomposition), was obtained.

7-chloro-6-fluoro-1,4-dihydro-1-methylamino-4-oxo-6-quinolinecarboxylic acid was tested using the biological method described below and was found to have antibacterial activity. 1.0.1.95 for Escherichia coli, Klebsiella pneumoniae, and Mycobacterium, respectively. It was active in vitro with a minimum inhibitory concentration (MIO) of 1.0 mlg/*. It was active in vivo in mice against Escherichia coli and Klebsiella pneumoniae at a protective dose of 56.186'mgA, respectively.

Production example 4B.

7-chloro-1-ethylamino-6-fluoro-1,4
-[■: Lower alkyl-C2H5] 7-chloro-6-fluoro-5-[(formyl)neethylamino)-1,4-dihydro-4-oxo-6-chitulinecarboxylic acid ethyl [Production Example 3B, 10 y ( 0
,029 mol)] in absolute ethanol (260 mg) was heated to reflux, and a solution of 85% KOH (4,3r (0,068 mol)) in water (14,4-) was added. Then about 10
0-95% ethanol was added, and the mixture was stirred and refluxed for 1 hour. Filter while hot, wash the collected solid with absolute ethanol and ether, and vacuum dry at 70°C to obtain 7-chloro-1 of 5,42.
-fluoramino-6-fluoro-1,4-)hydro-4
-Oxo-3-quinolinecarboxylic acid salt/hemihydrate,
mp258°C (decomposed). Further, s, sr, mp' of 260 to 262°C were obtained from the alcohol P solution.

7-chloro-1-ethylamino-6-fluoro-1,4
-Dihydro-4-oxo-3-quinolinecarboxylic acid is used to treat Staphylococcus aureus (M I G = i 5.6 mag/
* ), Escherichia coli (MIC = 1.95 mcg/d)
, Klebsiella pneumoniae (MIC=3.9 mcg/d).

Mysterious deforming bacteria (MIC=5.9 mcg/d)
, M. vulgaris (M I G = 0.25 mcg/m
/ ), p, oreginosa (MIC = 31.3
mcg/+g), Streptococcus nigra (MIC=31.3m
It was discovered that it has antibacterial activity against cg/go).

Manufacturing example 4C.

7-chloro-6-fluoro-1,4-:) human 90-4
-Oxo-1-propylamino-3-quinolinecarboxylic acid [■: lower alkyl = (CH2)2CH3]
-Chloro-6-fluoro-5-[(formyl)-propylamino) -1,4-dihyto90-4-oxo6-
Ethyl chitulin carboxylate (Preparation Example 3G) was prepared from 4.42 85% KOH. 5. Salt the product of 72.
Obtained in the form of hemihydrate, mp 267°C (decomposed).

7-Chloro-6-fluoro-1,4-dihydro-4-oxo-1-propylamino-6-quinolinecarboxylic acid is effective against S. aureus (MIG=15.6 mCg/y+/),
Escherichia coli (MIC=15.6 mcg/*), Klebsiella pneumoniae (MIG-31, 3rncg/mυ), Klebsiella vulgaris (M[
= 3.9 mCg/d).

Streptococcus aureus (MIC= 15.6 mcg/+d
), was found to have in vitro antibacterial activity against K.

Manufacturing example 4D.

7-chloro-6-fluoro-1,4-:)hydro-4-
Oxo-1-(2-propenylamino)-3-quinolinecarboxylic acid (I; R' =) (, R' = HNGH2C
H=CH2) In Production Example 4A, 8.42 of 7-
Chloro-6-fluoro-1-(formyl-(2-proynyl)amine)-1,4-)hydro-4-oxo-3
-Quinoline\ethyl carboxylate (Production Example 3E), 5,5f NaO
Manufactured from H. 6.969 product as hydrate (4:1
).

It was obtained in the form of mp240-242°C.

Production example 5゜7-chloro-6-fluoro-1,4-dihuman-1-methyl (If; R' = CH3NH, R': C2
) (5) 148t of 7-chloro-6-fluoro-1,4
-dihyto90-1-[(formyl)methylaminoco-4
-ethyl oxo-3-quinolinecarboxylate, 70t N
aOH.

A mixture of 6 tons of water was stirred at 60° C. for 6.5 hours.

At this point, the reaction mixture contained a considerable amount of insoluble material, so a 23F solid was obtained. This was put into 2.5 tons of boiling ethanol to form a slurry, and filtered through a steam filter. After cooling the P solution, 12.4f of ethyl 7-chloro-6-fluoro-1,4-y human90-1-methylamino-4-oxo-6-quinolinecarboxylate, m'p202~
207°C was separated. A sample was obtained by recrystallization from ethanol as a tan-colored powder, mp206, -209°C.

This ethyl ester was transesterified with methanol to yield the corresponding methyl ester (If; R' ==CH3NH.

R'-OH5), mp 228-232°C was obtained.

Production example 6゜7-chloro-1-:)methylamino-6-fluoro-1
,4-dihuman90-4-oxo3-quinolinecarboy
Acid (■; R': (OH3)2N, R' = H)
5-7-chloro-6-fluoro-1,4-9 human90
A mixture of ethyl -1-methylamino-4-okino-3-quinolinecarboxylate (Production Example 5) and 50-dimethyl sulfate was stirred at 100°C for about 16 hours. Leave it at room temperature for 2 days, then add 500 tons of ice containing about 75 tons of KOH ~
injected into water. After stirring for 1 hour, the solid product was separated, slurried with tetrahydroacrylic furan, recollected and dried to give 1.6y product, mp 246-248°C. It consisted of the mixed ethyl-methyl ester of 7-chloro-1-:) methylamino-6-fluoro-1,4-dihydro-90-4-oxo-6-chitulincarboxylic acid. 0.5 parts of this mixed ester was added to 16-ml water containing 0.12 El of NaOH and stirred on a steam bath for 2 hours. Filter hot and acidify with acetic acid. The separated solid product was collected, washed with water, and dried under vacuum to give 0.22f of 7-chloro-1-dimethylamino-6-fluoro-1,4-:
) Human 90-4-oxo-3-quinolinecarboxylic acid, m
p255-256°C was obtained.

Example 1 6-Fluoro-1,4-dihydro90-1-methylamino-7-(4-methyl-1-piradinyl)-4-oxo-6-quinolinecarboxylic acid [IA; K=CH3NH, R'=)l, R"
= cu3) 5.0f (0,0185 mol) of 7-chloro-6-fluoro-1,4 dihydrogen 90-1-methylamino-4-okino-6-quinolinecarboxylic acid (Production Example 4A
), 7.49 (0.0739 mol) of N-methylbi, radin, 30d of pyridine was refluxed under N for 15 hours.

It was then cooled and the solids were filtered and washed with ether.

4.3f parts of the product thus obtained were recrystallized from 125d of boiling dimethylformamide, washed with dimethylformamide and ether, and dried under high vacuum at 70°C for 1 day.
．． Of 6-fluoro-1,4-dihydro-1-methylamino-7-(4-methyl-1-piradinyl)-4-
Oxo-6-quinolinecarboxylic acid, colorless powder, mp29
9-301°C (decomposition).

6-Fluoro-1,4-dihydro90-1-methylamino-7-(4-methyl-1-piperazinyl)-4-okino-6-quinolinecarboxylic acid is boiled with an equimolar amount of hydrochloric acid to produce monohydrochloric acid. Changed to salt, mp>300°C.

6-Fluoro-1,4-dihydro-1-methylamino-
7-(4-Methyl-1-piperazinyl)-4-oquino-3-quinolinecarboxylic acid is treated with a slightly excess amount of an aqueous methanesulfonic acid solution, and upon completion of dissolution, acetone is added to precipitate the methanesulfonic acid salt. , mp287~
Changed to 289°C (decomposition).

This salt was recrystallized from an aqueous a7tonitrile solution.

6-Fluoro-1,4-:) Hibilow 1-methylamino-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid with an equimolar amount of fumaric acid in an aqueous medium. By heating fumarate, mp
The temperature was changed to 253-254°C (decomposition).

6-Fluoro-1,4-dihydro-1-methylamino-
7-(4-methyl-1-piperazinyl)-4-oxo-
The 6-quinolinecarboxylic acid was converted to the Na salt-hydrate, mp 256° C. (decomposition), by treatment with an equimolar amount of aqueous NaOH containing some ethanol to aid solubility. The product obtained by solvent evaporation was crystallized from aqueous acetone.

6-Fluoro-1,4-dihydro-1-methylamino-
7-(4-Methyl-1-piperazinyl)-4-okino-6-quinolinecarboxylic acid was converted to 4'- by treating an aqueous solution of its Na salt with twice the molar amount of H2O2 and stirring at 45°C for 20 hours. Oxide, mp 2.31°C (decomposed), was changed. The solution was treated with 5011v Pa/c catalyst to remove excess H2O2 and then acidified to obtain the oxidized product. 4'-oxide was extracted from Escherichia coli (MIC=16mcg/m
j) p Klebsiella pneumoniae (MI O= 32 mcg/*
), was found to have in vitro antibacterial activity against Mycobacterium nigra (MIC=32 mcg//lt).

Example: 1 person The preparation of the compound of Example 1 was carried out on a large scale as follows.

52f (0,192 mol) of 7-chloro-6-fluoro-1,4-dihydro-1-methylamino-4-oxo-
A mixture of 3-quinolinecarboxylic acid, 53y (0,478 mol) of N-methylpiperazine, and 260-pyridine was heated under reflux for about 16 hours. Additional N-methylpiperazine (10d) was then added and reflux continued for 6 hours. After cooling, the solid product was filtered and washed with cold pyridine and ether.
2 substances were obtained. This was combined with the product from another experiment using the 7-chloro compound of 5f, recrystallized from dimethylformamide, washed with cold dimethylformamide and ether, dried under vacuum at 80°C, and 48.5f of 6 -Fluoro-1,4-dihydro-1-methylamino-7-(4
-Methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid, mp) at 300°C was obtained.

Example 1B The compound of Example 1 was prepared on a larger scale as follows.

970? of 7-chloro-6-fluoro-1,4-dihydro-1-methylamino-4-oxo-6-quinolinecarboxylic acid, 1600-N-methylpiperazine, 8t of 2
- A mixture of methoxyethanol was heated to reflux for 6 hours (approximately 1
27°C). After 20 hours at the reflux point, cool and
It was brought to 0°C and passed through the temperature. - The mass was washed with cold methoxyethanol and then with methanol. The product was dried at 40°C to give 925f 6-fluoro-1,4-:) human 90-
1-Methylamino-7-(4-methyl-1-piperazinyl)-4-oxo-6-quinolinecarboxylic acid was obtained which was purified in the form of the methanesulfonate salt.

Example 2゜1-amino-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-6-quinolinecarboxylic acid (IA; R=NH2,R'=H,R" Engineering H
] 2.8t of 1-amino-7 was prepared by the method described above in Example IA.
-chloro-6-fluoro-1,4-dihydro-4-oxo-6-quinolinecarboxylic acid (Production Example IB) and 4,72
of piperazine in 150 Mt of pyridine. The product was converted to 4-methylbenzene sulfonate, mp 293-295°C (decomposed) after recrystallization from water.

Example 6゜1-amino-6-fluoro-1,4-dihydro-10-4-
Oxo-7-(4-methyl-1-piradinyl)-6-
Quinolinecarboxylic acid [IA; R=NH2, R':H, R"=CH3]
2. in 1 to 5 pyridine as described in Example IA.
6f 1-amino-7-chloro-6-fluoro-1,4
-:) Hydro-4-oxo-6-quinolinecarboxylic acid (
Production example IB), 3. /l+r N-methylbi was prepared from radin. The product was obtained as a pale orange powder, mp 503-306°C (decomposed) after recrystallization from dimethylformamide.

Example 4 6-Fluoro-1,4-:)hydro-1-methylamino-4-oxo7-(1-piradinyl)-6-quinolinecarboxylic acid (IA; R=CI43NH, R'=H ,R"=H
) 20.5f 7-chloro-6-fluoro-1,4-:) human 90-1-methylamino-4- by the method of Example 1
Oxo-1-methylamino-4-oxo-6-quinolinecarboxylic acid (Production Example 4A) and 64.5? of piperazine in 850-m of pyridine. The product 17.91 was obtained after recrystallization from a pale yellow solid dimethylformamide, mp 288-290°C (decomposed).

The above compound CIA; R=CH3NH,R'=)(
A sample of “=H) was treated with p-methylinzenesulfonic acid aqueous solution to convert 4-methylinzenesulfoyate into mp
Obtained as straw-colored crystals at 278-280°C (after recrystallization from water).

Example 5゜1-ethylamino-6-fluoro-1,4-dihuman 90
-7-(4-methyl-1-piperazinyl)-4-oxo-6-quinolinecarboxylic acid [IA; R-C2H5NH,R/ =H,R"-O
H5) 4.72f7) 7-40rho 1-ethylamino-6- in 18.5Il+/pyridine as per Example 1
It was prepared from fluoro-1,4-=yhydro-4-oxo-3-quinolinecarboxylic acid (Preparation Example 4B) and 76-0N-methylpiperazine. 6.7t of product, mp 25
5-256°C was obtained.

Example 6 6-fluoro-1,4-:)hydro-7-(4-methyl-1-piperazinyl)-4-oxo-1-propylamino-6-quinolinecarboxylic acid (IA; R=CH3(OH2 )2NH,R'=)
(,R''=OH3) 52 7-chloro-6-fluoro-1,4-dihydro-4-oxo,1-propylamino-3-quinolinecarboxylic acid (' J! Preparation Example 4G) and Z4- N-methylpiperazine.Product of 6.72, mp210~
212°C was obtained.

6-fluoro-1-umethylamino-1,4-uhydro-7-(4-methyl-1-piperazinyl)-4-oxo-6-quinolinecarboxylic acid (IA; R-(OH3)2N, R' =H,R”
-=GH3) 1.6 in a 6.6d pin V) using the method of Example 1! M(7)7-7oo-1-dimethylamino-6
-Fluoro-1,4-dihydro-4-oxo6-quinolinecarboxylic acid (Production Example 6) and 2.64. t from N-methylpiperazine. 0.9f product, mp 2
55-255°C was obtained as a light tan powder.

Example 8 Norincarboxylic acid [IA; R=CF(3HF(, R'=
E(,R',-02H5]14.41 by the method of Example 1
6.51 of 7-chloro-6-fluoro-1,4-dihydro-90-1-methylamino-4-oxo-6-quinoli/carboxylic acid (M Preparation Example 4A) in pyridine of d and 5.9z of N-ethylpi was prepared from radin. 2.5f of product was obtained as a pale yellow powder, mp260c.

Example 9 Ethyl norincarboxylate (IA; R=CHNE(,
6-fluoro-1,4- of R'=C2H5゜R'=CH3)
dihydro-1-methylamino-7-(4-methyl-1-
A slurry of (piperazinyl)-4-oxo-6-quinolinecarboxylic acid in absolute ethanol (500 ml) was heated to reflux with stirring. Methanesulfonic acid (3,IP, [1,0
313 mol) was added and the resulting clear yellow solution was heated at reflux for 5 days. The ethanol was distilled off and the remaining 59i/ml was added to water and neutralized by gradual addition of Ha(65') bicarbonate. The separated product was separated and washed with 200+111 portions of water. To a slurry of the product in water (3011 LI) was added 1.21 m+t of methanesulfonic acid.

The resulting clear yellow solution was filtered and diluted with 200 g of acetone to give 6-fluoro-1,4-dihydro-1-
Methylamino-7-(4-methyl-1-hyherazinyl)
-4-oxo-6-quinolinecarboxylate ethyl methanesulfonate, mp25 after vacuum drying in 6511r for 1 day
5G (min N).

Example 10 R"(CHa)2C[() 5y-07 using the method of Example 1, but using (diisopropyl)ethylamide/(70 ml) tt instead of pyridine.
-Chloro-6-fluoro-1,4-dihydro-90-1-methylamino-4-oxo-6-quinolinecarboxylic acid (Production Example 4A) and 14.65' N-isoprobilpiverazine dihydrochloride Manufactured.

2.4? The product is a grayish tan solid, mp
Obtained as 245-25DC1.

Example 11 CH3Ct (2 CHz) Using the method of Example 1 but using (diisopropyl)ethylamine (45 Kg) instead of pyridine, 5ff of 7-chloro-6-fluoro-1,4-dihydro-90-1-methylamino-4 -Oxo-6-quinolinecarboxylic acid (Production Example 4
A) and 21.5 P of N-propylpiperazine dihydrobromide.

A 4.8i product, mp272-277C1, was obtained.

Example 12 6-fluoro-1,4-dihydro-7-(4-methyl-
1-R/=E(,R'=Cl-l3) 5. in 22.5 rnl of pyridine according to the method of Example 1.
9P117) 7-10 rho 6-fluoro-1,4-dihydro-4-oxo-1-(2-propenylamino)-6
-Quinolinecarboxylic acid (Preparation Example 4D) and 8.7 ml of N-methylpiperazine. The 2.8y-product was obtained as a pale yellow powder, mp 220-222C1.

Example 16 y acid (I; R=CI(3N[(, R'=E(, Z=N=
4- Morho! J = L) 5y-7-chloro-6-fluoro-1, in 40 ml of pyridine as in Example 1.
It was prepared from 4-dihydro-1-methylamino-4-oxo-6-quinolinecarboxylic acid (Preparation Example 4A) and 1 Qrnl of morpholine. The product of 6.7y- was obtained as a colorless to pale yellow powder, mp 288-289c.

Example 14 4-acetyl-1-piperazinyl 4.3y-07 in pyridine of 35d by the method of Example 1
-Chloro-6-fluoro-1,4-dihydro-1-methylamino-4-oxo-6-quinolinecarboxylic acid (Preparation Example 4A) and 6.5f N-acetylbi were prepared from radin. 6t product, m, p295-600C1 was obtained.

Example 15 72 (I; R=CH3NH, R'-H, z=N-1
4.81<7) 7-chloro-6-fluoro-1,4 in 5Qml of pyridine according to the method of Example 1.
-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid (Preparation Example 4A) and 14.8m P were prepared from lysine. The product of 1.7y-, mp 208-211C1 was obtained after recrystallization from dimethylformamide.

Example 16 Acid (I; R=CH3NH, R=F(, Z-N= i
-hyo+)dinyl] 5fI of 7-chloro-6-fluoro-1,4 in 53m/pyridine according to the method of Example 1.
-Dihuman 90-1-Methylamino-4-oxo-6-quinolinecarboxylic acid (Preparation Example 4A) and pyrrolidine 12.51d. 2.3y-product as yellow powder,
After recrystallization from dimethylformamide mp 314-61
Obtained as 8C1.

Example 17 - Human 90xy-1-lysinyl] 7-chloro-6-fluoro-1,4-dihydro-1-methylamino-4-oxo-3 of 51 in pyridine of 30d by the method of Example 1 -Quinolinecarboxylic acid (Production Example 4A
) and 72F of 4-hydroxypi<17dine. 2.6? The product is colorless and pale yellow powder, mp 230-236C after recrystallization with dimethylformamide color.
I got .

Example 18 = 6-hydroxy-1-piperidinyl] 5y-07-chloro-6 in 0rnl pyridine according to the method of Example 1
-Fluoro-1,4-dihydro-1-methylamino-4
-Oxo-3-quinolinecarboxylic acid (Production Example 4A) and 7
．． Prepared from 29-06-hydroxypiperidine. 1
．． mp180C1 was obtained after recrystallization from IJ.

Example 19 6-fluoro-7-(hexahydro-1)1-1.4-
Shea R'=[(,Z-N-,Kisahi)'I:I-I
F(-1,4-diazapin-1-yl) 6Lt of 7-
Chloro-6-fluoro-1,4-:)hydro-1-methylamino-4-oxo-6-quinolinecarboxylic acid (Production Example 4A) and 22F hexahydro-1,4-diazepine were produced. The product of 1.3i was obtained in the form of the hydrochloride salt as a yellow powder, mp305c (decomposed).

Example 20 (I; Ft=CH3NE(, R'=H, 22N haxahydro-4-methyl-1t(-1,4-diazapine-1-
] 3QmA using the method of Example 1! 5 in pyridine?
7-di-4-6-fluoro-1,4-dihydro-1-
Prepared from methylamino-4-2rxo-6-quinolinecarboxylic acid (Preparation 4A) and 8.61 hexahydro-4-methyl-1,4-:) azapine.

The product of 1.7y- was obtained in the form of the hydrochloride hemihydrate as a pale yellow powder, mp288U.

Example 21 Rubonic acid (R=cH3NH,R-H,z-s=
4-Thiomorpholinyl] 6.5f of 7 in 80a/m of pyridine according to the method of Example 1
-chloro-6-fluoro-1,4-:)human90-1-
Methylamino-4-oxo-3-quinolinecarboxylic acid (
Preparation Example 4A) and 6.511/ml of thiomorpholine. The product of 22~ was a pale yellow solid, mp260~261C1 was obtained after recrystallization from dimethylformamide.

Example 22 6-Fluoro-1,4-dihydro-7-(6-hydroxy Z = N-3-hydroxy-1-pyrrolidinyl) 7-10 of 7.7 F in pyridine of 3Qd by the method of Example 1
Rho-6-fluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid (Production Example 4A
) and 3-hydroxypyrrolidine of 975i. The product of 4.71 was obtained as a yellow powder, mp 319-321C (decomposed) after recrystallization from dimethylformamide.

Example 23 0H3NCF(O, R'=E(, R'=CF(3:])
6-Fluoro-1-methylamino-1,4-dihydro-7
-(4-methyl-1-piperazinyl)-4-oxo-3
-quinolinecarboxylic acid (Example 1) (2,7SL) to 6
．． A mixed formic anhydride-acetic anhydride prepared from 9t096% formic acid and 8.3i acetic anhydride was added.

Stirred at room temperature for 16 hours, then concentrated in vacuo. The solid residue was dissolved in 50 FrLl of water and made basic with pyridine. The solid product was collected and recrystallized from acetonitrile to give 2.0z of 6-fluoro-1-(N-formylmethylamino)-1,4-dihydro-9O-7-(4-methyl-1-
piperazinyl)-4-oxo-6-chitulincarboxylic acid as cream-colored powder, mp252-253C (decomposed),
obtained as.

The in vitro anti-inflammatory activity of the compounds of the invention was determined by a conventional serial dilution method. Cultures were grown overnight in tryptose phosphate Zolos or brain heart infusion Zolos (tests with Streptococcus pyogenes included heat-inactivated normal horse serum).
The inoculum was grown at 7C and then diluted to 2x concentration to prepare approximately 2X105 bacteria/go. Aqueous solutions of compounds of the invention were prepared by dissolving the free acid form in 0.5N NaOH. Dilute these with sterile distilled water and
A compound containing 1000 mcg/at in terms of free acid was prepared. Prepare serial 2-fold dilutions of these compound stock solutions with water,
0.5 d of each dilution was transferred to several sets of tubes (one set for each inoculum). 0 for each tube
, 5 d of appropriate cultured bacteria, and the final bacterial concentration was approximately 1×.
It was set to 105 pieces/d. Minimum inhibitory concentration (defined as the lowest concentration of a test compound that inhibits macroscopic bacterial growth)
MIC) was recorded after 18-20 hours of static incubation at 37C. The results are shown in Table ■.

The in vivo antibacterial activity of the compounds of the invention was determined in 18 to 201 female mice each by the long method.

An aqueous solution of the test compound was dissolved in dilute Na0E (
The resulting solution was prepared by diluting the resulting solution with distilled water to the desired amount.

E. coli Voge' cultures prepared in brain-heart infusion Noros, hepatitis frames grown using 5% rabbit serum diluted to the same amount in tryptose phosphate Pros [59
645 Cultured prisoners, brain heart effusion - Zinite 9 Monas aureginosa M grown on agar and suspended in physiological saline
Mice were infected using GE (-2 culture cups) as follows.

E. coli and P. aureginosa: Q, 5 ml of test bacteria (1.87x 107.5X106 each
/d) were inoculated intraperitoneally.

Klebsiella hepatitis: 0.2 d of test specimen on the right hind leg of the mouse
(2,05 x 10' pieces/m) were incised into the muscle for $1i.

0.5 hours after infection, Q
, 5 ml was administered. Test compounds were administered subcutaneously (s, c
, ) or orally (p-o, ). Mortality was recorded every 7 days.

K. hepatitis infected mice were dosed at the following time points:

17 hours and 1 hour before infection, 6 hours after infection, and 3 hours after infection.
Twice a day for days.

Test compounds were administered subcutaneously (0,2III) and orally (0,5
+d). Mortality was recorded every 144 days.

P. 0.5.4.7 infecting M. aureuginosa infected mice.
The dose was administered after an hour. The test compound was administered subcutaneously (0.2 ml'
) or orally (0,5111 J). Mortality was recorded every 7 days.

Each group of 10 animals was treated as described above with 4 to 5 children, and the number of survivors in each group was recorded. Then the 50% protective dose (“D
50) was calculated. The results obtained are shown in Table...

Table ■ 1 0.551.03 8,8 10.6
2,50 3.132 >200
>2003 3.13 30.54
0.32 6,25 0
．． 465 4.1 90 6 32 >200 7 1.66 29 8 1.4 15.19
4.4 >20010 2.7
5011 14.8 81
．． 512 18.9 14113
16.3 20014 1(+0
10015 >200 >2001
5 >200 ) 20017 12
．． 5 200 H338>200 1g 2.5 >50o3633 2,>200 2210.4 118 23 10.4 >200 Active in vitro but relatively ineffective in vivo Compounds of the invention can be used topically to disinfect inanimate objects .

The compounds of the present invention can be prepared and used by conventional pharmaceutical methods. i.e., for parenteral or oral administration by dissolving or suspending them in a pharmaceutically acceptable vehicle such as water, aqueous alcohol, glycol, oil solution or oil-water emulsion).
, or they may be used alone as capsules or tablets for oral administration, with conventional adjuvants or excipients, such as Ca carbonate.
, starch, lactose, talc, stearin rRMg
, gum acacia, etc., in a unit dosage form.

Patent applicant Sterling Drug Incorporated (4 others) Continued from page 1 @Int, C1,3 identification code Office serial number priority claim 02/14/1983 [Phase] United States (US) ■
466095 ＠）R Ming F Niss Marlon Bailay East Green Bush, New York, United States of America Johnny Brace 4 Procedural Amendment (Method) % Formula % 1. Indication of the case Showa I year 2015 request No. Vt '/, <-f No. 4 quinoline included i, n false = t, 疋・1 (from ゛now 3f
Relationship with the case of the person making the amendment 3. Application Person's address: Kuq・ζ x'z−+tnk゛・Dranofinf−T
I' L -j, )-"4 Agent 5 Date of amendment order June 4, Showa era (shipment date) 6
35

Claims (1)

[Scope of Claims] Item 1: A compound of the following formula I, a pharmaceutically acceptable acid addition salt thereof, R
an alkali metal or amine salt of the compound in which ' is H; 1 [R is amine, lower alkylamino, 2-propenylamino, N-formyl-lower alkylamino or di-lower alkylamino; R' is H or lower alkyl; z=N- is the following heterocyclic group Either. H1 is lower alkyl or acetyl) The compound according to claim 1, which is a compound of the following formula IA in which R is H or lower alkyl. , R' is H. Claim 4: 6-fluoroR-1,4-dihydro-1-methylamino-
7-(4-methyl-1-piperazinyl)-4-oxo-
7. The compound according to claim 6, which is 6-quinolinecarboxylic acid or a pharmaceutically acceptable salt thereof. Item 5. The compound according to claim 2, which is 1-amino-6-fluoro-1,4-dihydro-4-okine-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Item 6: 1-Amino-6-fluoro-1,4-dihydro-4-oxo-7-(4-methyl-1-pi is radicalinyl)-3-quinolinecarboxylic acid, Claim 2 Compounds described. Item 7: 6-fluoro-1,4-:) human 90-1-methylamino-4-oxo-7-(1-piperazinyl)-6-quinolinecarboxylic acid according to claim 3. Compound. Item 8: 1-ethylamino-6-fluoro-1,s-:)hydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid, Claim 6
Compounds described in Section. Item 9: 6-Fluoro-1,4-dihyto9O-7-(4-methyl-1-piradinyl)-4-okino-1-fluorobylamino-3-quinolinecarboxylic acid; Compound according to item 6. Item 10: 6-Fluoro-1-:) Methylamino-14-:) Hydro-7-(4-methyl-1-piperazinyl)-4-okyne-6-quinolinecarboxylic acid, Claim 2 Compounds described. Item 11 7-(4-ethyl-1-piperazinyl)-6-fluoro-1,4-dihydro-1-methylamino-4-oxo-
7. The compound according to claim 6, which is 6-quinolinecarboxylic acid. Item 12: 6-Fluoro-1,4-:) Human 90-1-methylamino-7-(4-(1-methylethyl)-1-pyrazinyl]-4-oxo-3-quinolinecarboxylic acid, patent Compound according to claim 3.Claim 16: 6-fluoro-1,4-:)hydro-1-methylamino-4-oxo-7-(4-propyl-1-piperazinyl)-6-quinolinecarvone 7. The compound according to claim 6, which is an acid. Item 14 6-Fluoro-1,4-dihibiro 7-(4-methyl-
The compound according to claim 2, which is 1-piperazinyl)-4-oxo-1-(2-propenylamino)-5-quinolinecarboxylic acid. Item 15 6-Fluoro-1,4-dihydro-1-methylamino-
The compound according to claim 1, which is 7-(4-morpholinyl)-4-oxo-3-quinolinecarboxylic acid. Item 16: Claim 1, which is 7-(4-acetyl-1-piperazinyl)-6-fluoro-1,4-:)hydro-1-methylamino-4-oxo-6-quinolinecarboxylic acid. Compounds described in Section. Section 17 6-fluoro-$4-:)hydro-1-methylamino-
The compound according to claim 1, which is 4-oxo-7-(1-piperidinyl)-3-quinolinecarboxylic acid. Item 18: The compound according to claim 1, which is 6-fluoro-1,4-:)hydro-1-methylamino-4-oxo-7-(1-pyrrolidinyl)-3-quinolinecarboxylic acid. . Item 19 6-Fluoro-1,s-:)Hibilow7-(4-hydroxy-1-pi,e9:)2k)-1-1fk-Amino-
The compound according to claim 1, which is 4-okino-3-quinolinecarboxylic acid. Section 20 6-Fluoro-1,4-:) Human 9O-7-(3-hydroxy-1-piperidinyl)-1-methylamino-4-
The ambiguous compound according to claim 1, which is oxo-6-quinolinecarboxylic acid. Item 21 6-Fluoro-7-(hexahydro-IH-1,4-diazapin-1-yl)-1,4-:)hibilow 1-methylamino-4-oxo-3-quinolinecarboxylic acid, patent A compound according to claim 1. Item 22 6-fluoro-7-(hexahyto90-4-methyl-I
H-1,4-:)Azavin-1-yl') -1,4-
The compound according to claim 1, which is dihydro-1-methylamino-4-oxo-6-quinolinecarboxylic acid. Item 26: 6-Fluoro-1,4,-dihydro-1-methylamino-4-okino-7-(4-thiomorpholinyl)-3-quinolinecarboxylic acid, Claim 1, Item 24
Claim 6-Fluoro-1,4-dihydro-9O-7-(3-hydroxy-1-pyrrolidinyl)-1-methylamino-4-oxo-6-quinolinecarboxylic acid according to claim 1 Compound. Item 25 6-Fluoro-1-(N-formylmethylamino)-1
, 4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-6-quinolinecarboxylic acid. 26th term next expression! The compound according to claim 1, wherein in A, R is amino, lower alkylamino or di-lower alkylamino, and R" is H or lower alkyl. 1. Formula I, paragraph 27: [R is amine, is lower alkylamino, 2-pronylamino, N-homil-lower alkylamino or di-lower alkylamino; R' is H or lower alkyl; Z=N- is any of the following heterocyclic groups; H1 is lower alkyl or acetyl)), wherein R' is amine, lower alkylamino, 2-pro is nylamino or di-lower alkylamino, and R' is as defined above. If it is desired to react a compound of the formula: For example, by formylating a compound of the obtained formula (■) in which R is lower alkylamino, and if desired, by esterifying a compound of the obtained formula (1) in which R' is H, a corresponding compound in which R' is lower alkyl can be obtained. obtaining the compound, converting the obtained free base into its pharmaceutically acceptable acid addition salt, and, if desired, converting the obtained compound in which R' is H into its alkali metal or amine salt. Item 28 Compound 1 represented by the following formula ■ 0 ■ (R/ is H or lower alkyl, RO is amine, lower alkylamino, 2-propenylamino, di-lower alkylamino, N-formylamino, 29. The compound according to claim 28, wherein Ro is an amine. 60. Ro is lower alkylamino, R' is H. Claim 61: 7-Chloro-6-fluoro-1,4-:)Human90-1
-Methylamino-4-oxo-3-quinolinecarboxylic acid. Item 62: An antibacterial agent comprising a compound represented by the following formula I and/or a pharmaceutically acceptable acid addition salt thereof and/or an alkali metal salt and/or amine salt of the compound in which R1 is H. 1 [B is amino, lower alkylamino, 2-pronylamino, N-formyl-lower alkylamino or di-lower alkylamino; R' is H or lower alkyl; z; N- is the following heterocycle Any of the following groups. H2 is lower alkyl or acetyl)