JPH03218384A - Novel quinolinecarboxylic acid derivative, antibacterial agent containing the compound as active component and intermediate for production of the compound - Google Patents

Abstract

NEW MATERIAL:The compound of formula I {Z is group of formula II to IV [R<1> and R<2> are H or lower alkyl; R<3> is H, OH or lower alkyl; R<4> is H, OH, amino, aminomethyl or (di)lower alkylaminomethyl]}. EXAMPLE:9,1-(Methylimino)methano-7-fluoro-8-(4-methyl-1-piperazinyl)-5 -oxo-5H- thioazolo[3,2-a]quinoline-4-carboxylic acid. USE:An antibacterial agent. PREPARATION:The objective compound can be produced by reacting 9,1-(methylimino)methano-7,8-difluoro-5-oxo-5H-thiazolo-[3,2-a]quinoli ne-4- carboxylic acid of formula V with a cyclic amine (acid addition salt) of formula ZH in a polar organic solvent (e.g. dimethyl sulfoxide) in the presence of an acid acceptor (e.g. triethylamine).

Description

Detailed Description of the Invention [Field of Industrial Application] The present invention relates to a novel quinolinecarphonic acid conductor or a pharmaceutically acceptable salt thereof, an antibacterial agent containing the compound as an active ingredient, and an intermediate for producing the compound. Regarding the body.

More specifically, the following formula (I) n is shown, R1 and R2 each represent a hydrogen atom or a lower alkyl group, R3 represents a hydrogen atom, a hydroxyl group, or a lower alkyl group, and R4 represents a hydrogen atom, a hydroxyl group, an amino group, or an aminomethyl group. group, lower alkylaminomethyl group or di-lower alkylaminomethyl group. ) A novel quinolinecarphonic acid derivative or a pharmaceutically acceptable salt thereof, an antibacterial agent containing the compound as an active ingredient, and an intermediate for producing the compound.

[Conventional technology]

Since the discovery of nalidixic acid as a synthetic antibacterial agent, various quinoline carboxylic acid derivatives have been studied with the aim of improving antibacterial activity, and fused tricyclic compounds and fused tetracyclic compounds have also been studied.

That is, in JP-A No. 57-46986, virid [1, 2.
3-del [1.41 A fused tricyclic compound having a penzoxazine skeleton, for example, the following compound ] A fused tetracyclic compound having a quinoline skeleton, such as the following compound Y, is disclosed.

Compound X Compound Y However, each of the above publications describes the 9
, 1-iminomethano-5H-thiazolo[3.2-a]quinoline skeleton is not disclosed at all.

[Invention or problem to be solved]

The present inventors conducted studies to find a novel fused tetracyclic skeleton compound having excellent antibacterial activity. An object of the present invention is to provide a novel compound with a fused four-ring skeleton useful as an antibacterial agent or a pharmaceutically acceptable salt thereof, an antibacterial agent containing the compound as an active ingredient, and an intermediate for producing the compound. There is a particular thing.

(Means for Solving the Problems) As a result of various studies, the present inventors have developed a novel condensed four-functional skeleton compound represented by the following formula (I)n, that is,
9.1-iminomethanol 5H-thiazolo[3.2-a]
The present invention was completed by successfully synthesizing a quinoline-4-carboxylic acid derivative and its salt and confirming its excellent antibacterial activity.

or a cyclic amino group represented by -CO, where R1 and R2 each represent a hydrogen atom or a lower alkyl group, R3 represents a hydrogen atom, a hydroxyl group, or a lower alkyl group, and R4 represents a hydrogen atom, a hydroxyl group, an amino group, or an amino group. It means a methyl group, a lower alkylaminomethyl group or a di-lower alkylaminomethyl group.

Specific examples of the cyclic amino group (Z) include 1-biverazinyl group, 4-methyl-1-biverazinyl group, 4-ethyl-1-biverazinyl group, 35-dimethyl-1-biverazinyl group, 3-methyl-1 -Biverazinyl group, 3.4-
Dimethyl-1-biperazinyl group, 3,4,5-trimedyl-1-biperazinyl group, 4-hydroxy-1-biverazinyl group, 1-pyrrolidinyl group, 3-humanoxy-1-pyrrolidinyl group, 3-amino-1-pyrrolidinyl group, 3 -aminomethyl-1-pyrrolidinyl group, 3-dimethylaminomethyl-1-pyrrolidinyl group, 3-ethylaminomethyl-
Examples include a 1-pyrrolidinyl group and a morpholino group.

The compounds of the present invention also include pharmaceutically acceptable salts of the compound represented by formula (I).

Pharmaceutically acceptable salts of the compound (1) of the present invention include:
There are metal salts or ammonium salts such as sodium salts, potassium salts, calcium salts, etc. on the carboxyl group, or basic amino acid salts such as lysine or arginine. In the case of a pyrrolidinyl group having an amino group, an aminomethyl group, a lower alkylaminomethyl group or a di-lower alkylaminomethyl group, an addition salt of an inorganic acid such as a hydrochloride or a sulfate;
or addition salts of organic acids such as maleate, fumarate, tartrate, methanesulfonate, and paratoluenesulfonate.

Compound (I) of the present invention or a salt thereof is, for example, the compound (I) of the following formula (I
+) (In the formula, R1 is as described above.) It can be produced by the following three methods (Method A, Method B, and Method C) using the novel intermediate for production shown. In the formula (■!), a compound in which R1 is a hydrogen atom is indicated as a compound (n-1), and a compound in which R1 is a lower alkyl group is indicated as a compound (I+-2).

First, method A will be explained.

Method A: (In the formula, Z is as described above.) That is, in the compound (I+), R1 is a hydrogen atom [compound (nt)], dimethyl sulfoxide,
N. In a polar organic solvent such as N-dimethylformamide,
The compound (1) of the present invention is produced by reacting a cyclic amine (ZH) or an acid addition salt thereof in the presence of an acid scavenger.

As the acid scavenger, tertiary amines such as triethylamine, inorganic bases such as sodium carbonate and potassium carbonate, or an excess amount of the above-mentioned cyclic amine (ZH) can be used as the acid scavenger.

When using excess cyclic amine (ZH) as an acid scavenger, the reaction is usually carried out using 3 to 7 mol of cyclic amine (ZH) per 1 mol of compound (I+-1). When using a tertiary amine or an inorganic base as an acid scavenger, usually 1 to 1.5 mol of the cyclic amine (ZH) or its acid addition salt and 2 mol of the acid scavenger are added to 1 mol of compound (I+-1). The reaction is carried out using ~6 mol.

Reaction temperature is 30-150°C, preferably 50-120°C
Although the reaction time varies depending on the type of cyclic amine (ZH) and the reaction temperature, it is usually about 30 seconds. Method B will be explained below.

Method B (In the formula, Z is as described above, and R5 represents a lower alkyl group.) That is, in compound (II), R1 is a lower alkyl group [compound (I+-2>]) using Method A. Similarly, a cyclic amine (ZH) or an acid addition salt thereof is reacted in the presence of an acid scavenger for 5 to 85 hours, and the resulting compound (II+) is hydrated in a conventional manner.11 Next, Method C will be explained.

Method C・ (In the formula, R5 and Z are as described above, and R6 represents a lower alkyl group.) That is, first, a compound in which R1 is a lower alkyl group in compound (I+) [Compound (■1-2)] Then, a tri-lower alkylcarboxyporan is reacted in a lower alkylcarboxylic anhydride to obtain compound (IV).

1 2 Next, a cyclic amine (ZH) or an acid addition salt thereof is added to compound (IV) in a polar solvent such as dimethyl sulfoxide or N,N-dimethylformamide in the presence of an acid scavenger, usually at room temperature to The compound (
V) is obtained. For acid scavenging, tertiary amines such as triethylamine or an excess amount of the above-mentioned cyclic amine (ZH) can be used.

Finally, compound (V) is hydrolyzed under acidic conditions, preferably hydrochloric acid, to obtain compound (I) of the present invention or an acid addition salt thereof.

Of the compounds (I) of the present invention, compounds (I') in which Z is a 3-amino-1-pyrrolicinyl group or a 3-aminomethyl-1-pyrrolidinyl group can also be produced by the following method.

(In the formula, R1 and R5 are as described above, and n represents an integer of 0 or 1.) That is, compound (Vl) [compound (
II), 3-acylaminobi-lysine or 3
- (obtained by reacting acylaminomethyl) virolysine] is hydrolyzed by a conventional method, preferably using an alkali, to obtain the compound (I') of the present invention.

(Rl and R2 are the same as above) is reacted with a lower alkyl halide in a polar solvent such as N,N-dimethylformamide in the presence of an acid scavenger such as potassium carbonate, and if necessary, It can also be produced by alkaline hydrolysis of by-products.

Furthermore, among the compounds (1) of the present invention, it can also be produced by reacting the compound (Z and R2 are the same as above) with formalin and formic acid to perform a reductive methylation reaction.

The compound (1) of the present invention or its acid addition salt produced by each of the above-mentioned methods is isolated and purified by conventional purification means such as silica gel column chromatography or recrystallization. Further, the compound (1) of the present invention can be converted into the above-mentioned pharmaceutically acceptable salt according to a conventional method.

In addition, the compound (I) of the present invention used in each of the above-mentioned production methods
Intermediate (I1) for the production of is a new compound, and the following 3
Three methods (method a, method b, and method C) 1 5 First, method a will be explained.

a method・ (In the formula, R5 is as described above.

) That is, first, compound (■) (see European Patent Publication No. 285089) is reacted with 1,3-dichloroacetone in a 16 polar organic solvent such as N N dimethylformamide, dimethyl sulfoxide, acetonitrile, etc. (2,3,4-trifluoroanilino)
(3-chloro-2-oxobutylthio)methylene]malonic acid di-lower alkyl ester (■) is obtained.

Next, compound (■) was treated with sulfuric acid to [3(2,3.4
-trifluorophenyl)-4-chloromethyl-3H-
Thiazol-2-ylidene] malonic acid di-lower alkyl ester (IX) is obtained.

Next, compound (IX) and methylamine are reacted in an organic solvent such as acetonitrile or N,N-dimethylpolamide to form (IH,4H-thiazolo[3.4-a
] Quinoxalin-1-ylidene) malonic acid lower alkyl ester derivative (X) is obtained.

Next, compound (X) is heated and cyclized with a condensing agent such as polyphosphoric acid or polyphosphoric acid ethyl ester to form compound (I
I), a compound in which R1 is a lower alkyl ester [
Compound (I+-2)] is obtained.

Finally, compound (o-2) was dissolved in concentrated sulfuric acid at 60-1
By heating to 00°C and hydrolyzing, or by reacting compound (II-2) with tri-lower alkylcarboxyborane in lower alkylcarboxylic acid anhydride to form the compound (+V), which is hydrolyzed under acidic conditions. By doing so, a compound [compound (I+1)] in which R1 is a hydrogen atom in compound (II) is obtained.

Note that the compound (n-1) is produced by reacting the compound (X) with fuming sulfuric acid at around room temperature. Next, method b will be explained.

Method b (In the formula, R5 is as described above.) That is, first, known compound (XI) (see European Patent Publication No. 286089) is added with 1,3-dichloro in a halogenated solvent such as chloroform or methylene chloride. Reacting acetone in the presence of a tertiary amine such as triethylamine yields 2-(3-chloro-2-19-year-old xobutubiruthio)-6.7.8-1-refluoro-
4-hydroxyquinoline-3-carboxylic acid lower alkyl ester (■) is obtained.

The compound (Kari) was then treated with sulfuric acid to give 7.89-trifluoro-1-chloromethyl-5-oxo-5H-thiazolo[3. 2-alquinoline-4 monocarboxylic acid lower alkyl ester is obtained.

Next, acetonitrile, N. Compound (XIU) and methylamine are reacted in an organic solvent such as N-dimethylformamide to obtain a compound (I+) in which R1 is a lower alkyl group [Compound (I+-2)].

Among compounds (I1), the compound in which R1 is a hydrogen atom [compound (n-N]) is the same as in the case of method a.Next, method C will be explained.

Method C (in the formula, R5 is as described above). That is, first, a known compound (grass) (see European Patent Publication No. 286089) is mixed with 1.3 ml of chloride in an organic solvent such as chloroform, methylene chloride, or lower alcohol. −
By reacting dichloroacetone, N- (2.3.4-1
-Rifle (phenyl) dithiocarbamic acid 3-chloro-2-oxobutyl ester (XV) is obtained.

Next, compound (XV) is heated with hydrogen chloride, an inorganic acid such as sulfuric acid, etc. in a lower alcohol such as ethanol to obtain 4-chloromethyl-3-(2,3.4-trifluorophenyl)-2(3H). One thiazole compound (XVI) is obtained.

Next, compound (xvi) and methylamine were reacted in an aprotic organic solvent such as N,N-dimethylformamide or acetonitrile to produce IH4H-thiazolo[3.4
-a] Quinoxaline-1 thione derivative (X■) is obtained.

Next, compound (X■) and lower alkyl iodide are reacted in a polar organic solvent such as N,N-dimethylformamide, acetonitrile, or ethanol, and 1-lower alkylthioquinoxalino[1.2C]thiazolium An iodide derivative (X■) is obtained.

Next, compound (X■) and malonic acid di-lower alkyl ester in an organic solvent such as tetrahydrofuran or dioxane.
By reacting sodium (prepared from malonic acid di-lower alkyl ester and sodium hydride) (IH.4H
- Thiazolo[3.4-a]quinoxalin-1-ylidene) malonic acid di-lower alkyl ester derivative (X>) is obtained.

Compound (X) can be obtained by reacting compound (X) with phosgene or trichlormethylchloroformate in an inert solvent such as toluene or benzene, and then reacting this product with malon in a polar medium such as acetonitrile. It can also be produced by reacting an acid di-lower alkyl ester in the presence of a tertiary amine such as triethylamine.

Thereafter, compound (I+2) and compound (n-1) are obtained in the same manner as in method a.

Compound (1) of the present invention and its pharmaceutically acceptable salts exhibit excellent antibacterial activity as described below, have low toxicity, and are useful as antibacterial agents.

Compound (1) of the present invention and its pharmaceutically acceptable salts are administered to humans orally or parenterally, such as by injection, as antibacterial agents.

Dosage forms for oral administration include solid preparations such as tablets, granules, powders, fine granules, and hard capsules, as well as liquid preparations such as syrups and soft capsules.

Such preparations are manufactured by conventional methods, and tablets, granules, powders, and fine granules are prepared by combining the compound (1) of the present invention or a pharmaceutically acceptable salt thereof with, for example, lactose, starch, crystalline cellulose, stearic acid. It is produced by mixing it with ordinary pharmaceutical additives such as magnesium, hydroxybutyl cellulose, and talc, and hard capsules are produced by filling appropriate capsules with the above-mentioned fine granules and powders.

In addition, syrups are produced by dissolving or suspending the compound (I) of the present invention or a pharmaceutically acceptable salt thereof in an aqueous solution containing sucrose, carboxymethyl cellulose, etc. For example, the compound (1) of the present invention or a pharmaceutically acceptable salt thereof is dissolved or suspended in vegetable oil, oily emulsion, glycols, etc., and the solution is filled into soft turnip cells.

Injections can be prepared by dissolving or emulsifying the compound (1) of the present invention or a pharmaceutically acceptable salt thereof in saline solution or a lipid excipient such as vegetable oil, oily emulsion, or glycol, and aseptically preparing an ampoule or Manufactured by sealing in vials.

Compound (1) of the present invention and its pharmaceutically acceptable salts are administered orally or parenterally to humans as antibacterial agents.

The dosage varies depending on the patient's age, weight, symptoms, etc., but in general, the dosage is 0.5% as Compound (I). 5-3
0H/kg body weight/day, preferably 2-20 mg/day
A range of kg body weight for 7 days is appropriate, and this is administered once a day or divided into 2 to 4 times a day.

〔Effect of the invention〕

Compound (1) of the present invention and its pharmaceutically acceptable salts have a broad antibacterial spectrum and strong antibacterial activity (see Test Example 1 below). In particular, it has excellent antibacterial activity against Gram-positive bacteria, and also shows strong antibacterial activity against clinically isolated methicillin-resistant Staphylococcus aureus (see Test Example 2 below).

In addition, the compound (1) of the present invention and its pharmaceutically acceptable salts, such as the compounds of Example 7-(a), Example 15, Example 24, and Example 25, were tested using experimental animals. showed an excellent infection prevention effect (Test Example 3 below)
and Test Example 4) and low toxicity (see Test Example 5 and Test Example 6 below).

Therefore, the compound (1) of the present invention and its pharmaceutically acceptable salts can serve as excellent preventive and therapeutic agents for various infectious diseases.

Test examples are described below.

[Test Example 1] Antibacterial activity (minimum inhibitory concentration: MIC) 1
．． Test Compounds The following compounds of the present invention were tested for antibacterial activity.

For reference, the antibacterial activity of the above-mentioned known compounds X and Y was also tested.

・Compound A of the present invention 9.1-(methylimino)methanol 7-fluoro8-(4-methyl-1-biverazinyl)-5-oxo-51{-thiazolo[3.2-
a] Quinoline 4-carboxylic acid [Example 7 - Compound (a)]・Compound B of the present invention 9.1-(methylimino)methanol 7-fluoro-8(4-methyl-1
-piverazinyl)-5-oxo5H-thiazolo[3,
2-a] Quinoline-4-carboxylic acid hydrochloride (Example 7
Compound 1(b)] - Compound C of the present invention 9.1-(methylimino)methanol 7-fluoro 8(1-piverazinyl)-5
-Oxo5Hdiazolo[3.2-a]quinoline-4-
Carboxylic acid (compound of Example 8) Compound D of the present invention 9.1-(Methylimino)methanol7-fluoro8(3-methyl-1-biperazinyl)-5-oxo5H-thiazolo[3.2 -a
] Quinoline-4-carboxylic acid [Compound of Example 9] 27 ・Compound E of the present invention 9.1-(Methylimino)methanol 7-fluoro8 (3.5-dimethyl-1-
biverazinyl) 5-oxo 5H-thiazolo[3.2-
a] Quinoline-4-carboxylic acid [compound of Example 1o] Compound F of the present invention 9.1-(methylimino)methanol 7-fluoro 8(1-pyrrolidinyl)-5
-Oxo5H-thiazolo[3.2-a]quinoline-4
-carboxylic acid [compound of Example 11] - Compound G of the present invention 9.1-(methylimino)methanol 7-fluoro-8-(3hydroxy-1-bibutyridinyl)-5-oxo 5H-thiazolo[ 3,2-
a-coquinoline-4-carboxylic acid (compound of Example 12)
-Compound H of the present invention...9.1-(methylimino)methanol7-fluoro8-(3-amino-1-pyrrolidinyl)-5-oxo5H-thiazolo[3.2-a]
Quinoline 2 8 4-carboxylic acid [compound of Example 13]・Compound I of the present invention 9.1-(methylimino)methanol 7-
Fluoro-8-morpholino-5-oxo-5H-thiazolo[32-a]quinoline-4-carboxylic acid [Example 14
Compound of the present invention J...9.1-(methylimino)methanol7-fluoro8(4-ethyl-1-biverazinyl)-5-oxo5H-thiazolo[3.2-a]
Quinoline-4-carboxylic acid (compound of Example 15) / Compound K of the present invention 9.1-(medylimino)methanol 7-fluoro 8(4-ethyl-1-biverazinyl)-5-oxo 5H-thiazolo [3.2-a] Quinoline-4-carboxylic acid hydrochloride (compound of Example 19) - Compound L of the present invention 9.1-(methylimino)methanol 7-fluoro-8 (4-hydroxy 1-Biverazinyl)-5oxo-5H-thiazolo[3.2~a
] Quinoline-4-carboxylic acid [Compound of Example 16] Compound M of the present invention 9.1 - (Methylimino)methanol 7-fluoro 8-(3-ethylaminomethyl-1-pyrrolidinyl)-5- Oxo 5H-thiazolo[3,2-a]quinoline-4-carboxylic acid hydrochloride (compound of Example 17) - Compound N of the present invention 9.1-(methylimino)methanol 7-fluoro 8 (3 -Methylaminomethyl-1-pyrrolidinyl)-5-oxo5H-thiazolo3.2-a]quinoline-4-carboxylic acid hydrochloride [Compound of Example 18] - Compound of the present invention 0...9. 1-(Methylimino)methanol 7-fluoro-8(3,4-dimethyl-1-
biverazinyl)-5-oxo-5H-thiazolo[3.2
-a] Quinoline-4-carboxylic acid (compound of Example 24) Compound P of the present invention 9.1-(medylimino)
Methanol 7-fluoro 8-(3,4.5-trimethyl-1-biverazinyl)-5-oxo 5H-thiazolo[32-a]quinoline-4-carphonic acid [compound of Example 25] - Known compound X... ... 9-fluoro3-methyl-10-(4-methyl-1-biverazinyl)-7-oxo2,3-dihydro7H-pyrido[1,2.3-de
] [14-cobenzoxazine-6-carboxylic acid/known compound Y... 9.1-Eboxymethano-7-
Fluoro-8-(4-methyl-1-biperazinyl)-5-
Oxo-5H-thiazolo[3.2-a coquinoline-4-
Carphonic acid/hydrochloride 2 test method Compound of the present invention A. C, D, E, F, G, H, IJ, L,
0, P and known compound X, respectively, at 31 0. Dissolved in IN sodium hydroxide aqueous solution, 5000μ
A solution of g/ml was prepared. Compounds of the present invention B, K, M.
N and known compound Y are each dissolved in sterile purified water,
A 5000 μg/ml solution was prepared.

Next, each of the above solutions was diluted with sterile purified water to prepare a standard solution having a concentration of 1000 μg/ml of each test compound. After that, the method specified by the Japanese Society of Chemotherapy (Chemo
therapy, 29.78-79 (1981),
TOKYO).

3 2 (Test Example 2) Minimum inhibitory concentration 1 against clinically isolated methicillin-resistant Staphylococcus aureus Test compound/Compound A of the present invention 9.1-(Methylimino)methanol 7-fluoro8(4-methyl- 1-biperazinyl)-5-oxo5H-thiazolo[3.2-a]
Quinoline-4-carboxylic acid [Example 7 - (a) compound] Compound J of the present invention 9.1-(methylimino)methanol 7-fluoro 8(4-ethyl-1-piverazinyl)-5- Oxo 5H-thiazolo[3.2-a]
Quinoline-4-carboxylic acid [compound of Example 15]/Known compound X...9-fluoro3-methyl-10
-(4-methyl-1-biverazinyl)-7-oxo2
, 3-Dihuman mouth 7 H-Hylide [1,
2. 3-de co[ 14-cobenzooxazine-6-carboxylic acid 37 ・Known compound Y... 9.1-Eboxymethano-
7-Full Sairo 8-(4-medyl 1-piverazinyl)-
5-oxo 5H-diazolo [3. 2-a] Quinoline-4-carboxylic acid hydrochloride 2. Test method Compound A of the present invention, Compound J of the present invention and Known compound X were tested at 0. Known compound Y was dissolved in IN sodium hydroxide aqueous solution and sterile purified water to prepare solutions of 5000 μg/ml, respectively. Next, each of the above solutions was diluted with sterile purified water to prepare a standard solution having a concentration of 1000 μg/ml of each test compound. After that, the method specified by the Japanese Society of Chemotherapy (
Chemotherapy, 29.76-79 (19
Minimum inhibitory concentration (MIC) against 54 clinically isolated methicillin-resistant Staphylococcus aureus strains according to 81), TOκyo)
The minimum inhibitory concentration range (MIC, .ne) of the test compound against these resistant strains, the minimum concentration that inhibits the growth of 50% of the strains (MIC5o) and 9
The minimum concentration 38 (MIC, .) that inhibits the growth of 0% of the bacterial strain was determined.

3. Test results Shown in Table 2.

Table 2 [Test Example 3] Treatment effect on systemic infections 1. Same as for test compound test example 2.

2 Test bacteria and inoculum amount Staphylococcus aureus (s. aureus)
IID 803, 5. O X lO'c
FU/Mouse shoot Monas aeruginosa (P.a.
erugi-nosa) E-2. 3. I
X 10'CFII/mouse 3. Test method: After culturing the test bacteria in tributosa bouillon (manufactured by Nissui Pharmaceutical Co., Ltd.) at 37°C for 16 to 18 hours, PBS
(Dulbeccosphosphatebuffer
ed saline) and diluted with an equal volume of 1096 (w/
v) Mucin [BACTO MUCIN BAII:
TERIOLOGICAL (manufactured by Difco)] to prepare a bacterial solution. This bacterial solution was applied to ddY male mice (
0.5 m into the abdominal cavity of a group of 5 animals (5 weeks old, weight 25-28 g)
1 was inoculated and infected. One hour after infection, l96(W
/V) Compound A of the present invention suspended in a gum arabic aqueous solution
, Compound J of the present invention, known compound X, or known compound Y dissolved in sterile purified water was orally administered.

From then on, the mice were orally observed for one week to see if they were alive or dead, and based on the number of survivors after one week, the Weil method was used to determine the 50% effective dose (
EDso) was calculated.

4. Test Results Table 3 (Test Example 4) Therapeutic Effect on Systemic Infections 1 Test Compound Compound of the Present Invention 0 9.1-(Methylimino) Methanol 7-Flu Rho 8 (3.4-dimethyl-1 −
biverazinyl)-5-year-old xo-5H-thiazolo[3.2
-a] Quinoline-4-carboxylic acid [Compound of Example 24] Compound P of the present invention 9.1-(methylimino)methanol 7-fluoro 8 (3,4.5-trimethyl-1-piverazinyl) -5-oxo5H-thiazolo[
3.2-a] Quinoline-4-carboxylic acid [Compound of Example 25] 41 2. Test bacteria and inoculum amount - Staphylococcus aureus (S. aureus)
IID 803, 2. I X io'cF
u7'v Pseudomonas aeruginosa (P.a
erugi-nosa) E-2. 3.4
x 10'CFtl/mouse3. Test method Same as in Test Example 3 except that the weight of the ddY mice used was 24 to 28 g.

4. Test results It is shown in Table 4.

Table 4 [Test Example 5] Acute toxicity test 1. Test method 9 1-(methylimino)methanol 7-fluoro a-
(4-methyl-1-piverazinyl)-5-oxo 5H
-thiazolo[3.2-aco42quinoline-4-carboxylic acid [Compound A of the present invention: Example 7
-(a) compound] or 9,1-(methylimino)
Methanol 7-fluoro 8-(4-ethyl-1-biverazinyl)-5-oxo 5H-thiazolo[3.2-a]
Quinoline 4-carboxylic acid [Compound J of the present invention, Example 15
compound] was suspended in a 1% (W/V) gum arabic aqueous solution (concentration 100 mg/ml), and this suspension was used as Inventive Compound A or Inventive Compound J at 2000 mg/kg.
It was orally administered to ddY male mice (5 weeks old, body weight 20 to 25 g, 5 mice per group) that had been fasted for 18 hours at a rate of 5 g body weight. Thereafter, the number of deaths of mice was observed up to 2 weeks.

2. Test results: 2000 mg of the present invention compound A or the present invention compound J
No deaths were observed even when administered at a ratio of 1 kg/kg body weight.

[Test Example 6] Acute toxicity test l. Test method 9.1-(Methylimino)methanol 7-fluoro 8-
(3.4-dimethyl-1-biverazinyl)-5-oxo5H-thiazolo[3.2-a]quinoline-4-carboxylic acid [Compound O of the present invention: compound of Example 24] or 9.1-(methylimino ) Methanol 7-Fluoro 8-
(3,4.5-trimethyl-1-piverazinyl)-5-
Oxo 5H-thiazolo[3.2-a]quinoline-4-
Each carboxylic acid (compound P of the present invention: the compound of Example 25) was suspended in sterile purified water, and this suspension was added to ddY male mice (5 weeks old, body weight 20-24
g, 5 animals per group). Thereafter, the number of mouse deaths up to the first week was observed, and the acute toxicity value (LD5o) was calculated by the Weil method.

2. Test results LD5 of the present compound 0 and the present compound P.

The value is 1414mg/kg. 1071mg/
It was kg.

〔Example) The present invention will be described below with reference to Reference Examples and Examples.

Reference Example 1 3.5 g of diethyl sodium [(2,3,4-trifluoroanilino)(merkabuto)methylene]malonate (see European Patent Publication No. 288H9) was dissolved in N,N-
Dissolve in 15 ml of dimethylformamide and add 1,3
-1.2 g of cycloacetone was added and stirred at room temperature for 30 minutes. The reaction solution was filtered to remove insoluble matter, the filtrate was dried under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 4.0 g of the title compound as a pale yellow oil.

Mass spectrum (m/e): 439 (M”) Reference example 2 [3-(2.3.4-trifluoro-phenyl)45 4-chloromethyl-3H-thiazol-2-yli[(2
,3.4-trifluoroanilino)(3-chloro-2-
3. Ogl. : 6 ml of concentrated sulfuric acid was added and stirred at room temperature for 90 minutes. Next, 6 g of wood chips were added and after stirring for 1 hour, cold water was added and extraction was performed with chloroform. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ether to obtain 1.76 g of the title compound as colorless crystals.

Melting point = 133-136°C Elemental analysis value (as Cl7Hl5NO4 SF3 [:I). Calculated value (%) C, 48.40; H, 3.58
．． N, 3.32 analysis value (%) C, 48.5B. }1
, 3.54. N, 3.28 Reference Example 3 Lyden) malonic acid diethyl ester (a compound in which formula (X) has 46 ? and R5 is an ethyl group) [3-(2,3.4-trifluorophenyl)4-chloromethyl-3H -thiazol-2-ylidene]malonic acid diethyl ester 2,0g in acetonitrile 20[+
11, 6 ml of 40% methanol solution of methylamine was added thereto, stirred at room temperature for 20 minutes, and then dissolved at 50°C.
Heated for 00 minutes. The reaction mixture was dried under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was recrystallized from a mixed solvent of hexane-ethyl acetate to obtain the title compound 1.58 as yellow crystals.

Melting point = 146-148°C NMR (CDCI3) δ: 1.2 (6H, t
, J-7Hz), 3.1 (3Hd, J-4.5Hz)
J. 9 (4H, q, J-17Hz) ,4.0 (
2H,s)6.5(11{,t,J-IHz),6.
8 (IH.dt, J-8Hz, J-9}1z). 7.
3 (1) I, ddd, J■2Hz. J-5Hz. J.
9Hz). I R (KBr) 'l/alaXc
m-'+1700.1642 1506 142612
94.1188 1082 Elemental analysis value (C +aH 18N 2 0 4 S
As F2) Calculated value [:,54.54.1+,4.58. N7.
07 analysis value C, 54.45: I+, 4.61; N 6
．． 89 Reference Example 4 4-Hydroxy-2-mercabuto-6.7.8-trifluoroquinoline-3-carboxylic acid ethyl ester (European Publication No. 2880) was added to 200 ml of methylene chloride.
See No. 89 > 16g. 8 g of triethylamine and 1.
6.72 g of 3-dichloroacetone was added, and the mixture was stirred for 1 hour under ice and further stirred for 1 hour at room temperature. 400 ml of chloroform was added to the reaction solution, and 0.0 ml of chloroform was added to the reaction solution. It was washed with IN hydrochloric acid, water and brine, dried over anhydrous magnesium sulfate, and then evaporated to dryness. The residue was recrystallized from a mixed solvent of chloroform and isobrobyl to give the title compound 17 as colorless crystals.
．． 5g was obtained.

Melting point 175-181℃ NMR (DMSO-d.) δ 1.4 (3H
, t, J-7Hz). 4.1 (21+s). 4.
5 (2B, q, J-7Hz). 4.8 (2}1,
s) ,7.9 (illddd, J-2}1z, J-
8Hz, J-10Hz) I R (KBr) u. ．．
cm-': 2990.1739, 1656.159+1
513. Elemental analysis value (as Cl5HllNO4 S F3Cl)/calculated value (%) C, 45.75.1+. 2.82
．． N, 3.5 [i-split value (%) C, 45.59. H
．． 2.87. N, 3.50 Reference Example 5 2-(3-chloro-2-oxobuvirthio)6,7.
175 g of 8-trifluoro-4-hydroxyquinoline-3-carphonic acid ethyl ester was added to 80 ml of concentrated sulfuric acid, and the mixture was stirred at room temperature for 20 hours. The reaction solution was poured into ice water and the precipitated crystals were collected and washed with water, and then recrystallized from a mixed solvent of chloroform-isobrobyl ether to give the title compound 1 as pale yellow crystals.
4.2g was obtained.

Melting point: 158-160℃ NMR (DMSO-d6) δ+1.3 (3H
,t,J-7HZ) ,4.3(21-1.q,J-7
Hz), 5.2 (2tl, d, J-5Hz), 7.8
(l}Is) ,8.0 (IH, ddd, J-2Hz
, 8Hz, 10Hz). I R (KBr) vII
ll. cm-': 3094.1873 1809
1522 elemental analysis value (Cl589 NO3 S F3
(as CI) Calculated value (%) C, 47.95. H.
3.41N3.73 Analysis value (%) G, 47.80;
l{. 3.53; N, 3.71 Reference Example 6 20 g of 1,3-dichloroacetone was mixed with 10 g of methylene chloride.
N-(2,3
．． Triethylammonium 4-trifluorophenyl)dithiocarpamate (European Publication No. 2860)
(See No. 89) 5. Add 50 og. Thereafter, the mixture was stirred for 60 minutes and washed with 3N hydrochloric acid and then with water. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was crystallized from a mixed solvent of hexane-acetic acid ethyl ether to obtain 4.2 g of the title compound.

Mass spectrum (m/e): 313 (M'') Reference example 7 N-(2,3.4-trifluorophenyl)cythiocarbamic acid 3-chloro-2-oxobutyryl ester 4
．． 0 g was added to 1.5 ml of 30% hydrogen chloride methanol solution and heated under reflux for 3 hours. Then, the solvent was distilled off under reduced pressure,
Cold water was added to the residue and extracted with chloroform. The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from cyclohexane to obtain 2.6 g of the title compound as pale yellow crystals.

Melting point 127-130℃? M R (CDCIs) δ: 4.1
(lH.d, J-13Hz), 4.2 (IH, d.J-
13Hz), 6.8 (IH, s). 7.2(21{,m
). IR(κBr) v■X cm-': 30
72,151B,1504,13141260.110
2 Elemental analysis value (C, .H, as NS2F3CI) Calculated value (%) C, 40.61, H, 1.70. N, 4.7
4 Analysis value (%) C, 40.59.1+. l. 80;
N, 4.71 Reference Example 8 4-chloromethyl-3-(2,3.4-trifluorophenyl)-2 (3H) monothiazolethione 2 5g
was dissolved in 25 ml of acetonitrile, 3.3 g of a 40% methanol solution of methylamine was added thereto, and the mixture was heated at 50°C for 16
Stir for hours. The reaction mixture was dried under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The extract was washed with brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure.

The resulting residue was recrystallized from a mixed solvent of cyclohexane and ethyl acetate to obtain 2.0 g of the title compound as pale yellow crystals.

Melting point: 165-167°C NMR (CDCl3) δ・3.0 (3H.d,
J-2.5}1z) ,4.0(2H.d,J-IH
z), 6.4(ll+.t, J-IHz), 6.9(
IHdt, J-8Hzj-9Hz), 9.3(LH,
ddd, J-2.5Hz, J-5Hz J-9.5Hz
) IR(κBr) νmax Cm-' + 1502
．． 1492,1306.12901032 Elemental analysis value (as CIIH8 N2 52 F2) Calculated value (%) C, 48.87, H, 2.98; N, 1
0.36 Analysis value (%) C, 49.04; H, 2. !
16;N, 10.41 Reference Example 9 Group Compound]: 5-methyl-6,7-difluoro-IH. 0.4 g of 4H thiazolo[3.4-alquinoxaline-1-thione and 0.4 g of methyl iodide were dissolved in 3 ml of N,N53 dimethylformamide and left in the dark at room temperature for 40 hours. The precipitate was collected by filtration and washed successively with acetonitrile and ether to give the title compound 0,5 as yellow crystals.
I got g.

NMR (DMSO-d6)δ: 3.0(:D
I, d, J-4.0Hz) 3.1 (31-1, s)
,4.4 (2N,s) ,7.3 (18,dt,J
-8Hz, 9.5Hz), 7.9(IH, ddd, J
-21-1z, J-5Hz. J-9.5Hz), 8.
0 (IH.s) Reference example 10 Oily sodium hydride (content rate approximately Bow/w%) 54m
g was suspended in 3 ml of tetrahydrofuran, 0.2 g of diethyl malonate was added dropwise at 20°C, and the mixture was stirred for 20 minutes. Next, 0.5 g of the above 5-methyl6.7-difluoro-1-methylthio-4H-quinoxalino[1.2-c]thiazolium iodite was added at 10°C, and the mixture was stirred at room temperature for 30 minutes. 4. The reaction mixture was dried under reduced pressure, cold water was added, insoluble materials were collected by filtration, washed with water, dried, and recrystallized from a mixed solvent of hexane-ethyl acetate to give the title compound as yellow crystals (0.3%).
4g was obtained. The physical property analysis values of this compound correspond to those of (5-methyl6.7-difluoro-IH,4H-thiazolo[3.4-a]quinoxalin-1-ylidene) malonic acid diethyl ester obtained in Reference Example 3. did.

Reference Example 11 5-Methyl-6,7-difluoro-IH. 4}{-thiazolo[3.4-8]quinoxaline-1-thione (18 g) toluene (110 ml) and trichloromethyl chloroformate (9.74 ml) were added and stirred at 80° C. for 17 hours.

The generated precipitate was collected by decantation in a state containing a small amount of toluene, and this was added with 60 mL of acetonitrile.
1 and 12.88 g of diethyl malonate were added. After adding 14.9 g of triethylamine under water cooling, the mixture was stirred at room temperature for 40 minutes. The reaction mixture was dried under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was washed with isobrobyl ether to obtain the title compound 2.
4.3g was obtained. The physical property analysis values of this compound were obtained in Reference Example 3 (5-methyl-6,7-difluoro-IH.4
It corresponded to that of H-thiazolo[3.4-a]quinoxalin-1-ylidene) malonic acid diethyl ester.

Example 1 Product D: (5-methyl-6.7-difluoro-IH,4H-thiazolo[3.4-a]quinoxaline-1-ylidene) malonic acid diethyl ester (see Example 3) +. A mixture of 2 g and 10 g of polyphosphoric acid was stirred at 100° C. for 5 hours.

Cold water was added to the reaction mixture and extracted with chloroporum. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of chloroform-ethanol to give the title compound 0 as pale yellow crystals.
．． 6g was obtained.

Melting point: decomposed near 285°C NMR (oyso-d6)δ: 1.3 (3H,
t, J-7Hz). 3.2 (311, dj-5.5H
z)． 4.3 (2H,Q,J-7HZ). C5
(2Hd.J-IHz), 7.3 (ILs). 7
．． 4 (ILdd, J-7.5Hz.J-10.5Hz
)． IR(κBr) v max Cm-': 3060
,1708.1574,14951478.1456,
1050. Elemental analysis value (as CI8Hl2N2 03S F2) Calculated value (%) C, 54.85. H. 3.45. N
, 8.00 Analysis value (%) C, 54.65; H. 3.
59; N+7-97 Example 2 5 7 a] Quinoline-4-carboxylic acid [compound of formula (II-1)]: 9,1-(methylimino)methanol 7,8-difluoro-5-oxo-5H-thiazolo [3.2-a] 1.6 g of quinoline-4-carboxylic acid ethyl ester and 18 g of concentrated sulfuric acid
ml was added and stirred at 85°C for 6 hours. Wood chips were added, and the resulting precipitate was collected by filtration and washed with water to obtain 1.25 g of a pale yellow powder, which was recrystallized from a mixed solvent of dimethyl sulfoxide and ethanol to obtain 1.0 g of the title compound.

Decomposition NMR (DMSO-de) δ: 3.2 (3
H. d. J-8Hz), 4.6 (2H, s), 7.
5 (ILs). 7.6 (1}1, dd, J-71
1z, J-9HZ) ,15.8 (llLbs)I
R (KBr) ZIIIa, cm-': 169
0,1552.1506,14801472.1455
, 1404. Elemental analysis value (as Cl4HII N2 03S F2): Calculated value (%) C, 52.17; H, 2.50;
N, 8. Fl9 analysis value (%) C, 52.07; H,
2.77; N, 8.47 Example 3 5 8 You 7, 8. 9-1-Refluoro-1-chloromethyl 5-oxo 5H-thiazolo[3.2-a]quinoline-4-carboxylic acid 14 g of ethyl ester (see Reference Example 5), 3.5 g of methylamine dissolved in 40% methanol, and 4.5 g of l-ethinoleamine were added to 250 ml of acetonitrile and stirred at room temperature for 23 hours. Insoluble materials were collected by filtration and washed successively with acetonitrile, water, and ethanol. This was recrystallized from a mixed solvent of chloroform-ethanol to obtain 8 g of the title compound. The physical property analysis values of the compound obtained here are as follows: 9.1-(methylimino)methanol 7.8-difluoro-5-oxo 5H-thiazolo[3
．． 2-a] It corresponded to that of quinoline-4-carboxylic acid ethyl ester.

Example 4 Compound]: 0.3 g of (5-methyl-6,7-difluoroIH.4H-thiazolo[3.4-a]quinoxaline-1=ylidene) malonic acid diethyl ester (see Reference Example 10) A mixture of 2.5 g of polyphosphoric acid was heated and stirred at 120° C. for 5 hours to carry out a cyclization reaction. Next, 2 g of concentrated sulfuric acid was added to the reaction mixture, and the mixture was stirred at 130° C. for 3 hours. Wood chips were added to the reaction mixture, and the resulting precipitate was collected by filtration, washed with water, dried, and then recrystallized from a mixed solvent of dimethyl sulfoxide and ethanol to obtain 0.2 g of the title compound. The physical property analysis values of this compound are as follows: 9.1-(methylimino)methanol 7 obtained in Example 2
．． 8-difluoro-5-oxo-5H-thiazolo [3.
2-a] corresponded to that of quinoline 4-carboxylic acid.

Example 5 Luolo-5-oxo 5H-thiazolo [3.2-compound]; The title compound was obtained in the following two steps.

(1) Dibrobionyloxy (9,1.-(methylimino)methanol7,8-difluoro-5-oxo5
8-Diazolo[3.2-a coquinoline-4-carboxy]phoran [compound in which R6 is an ethyl group in formula (IV)] A mixture of 11 g of boric acid and 8.0 g of brobionic anhydride was heated at 75 to 80°C for 50 minutes. The mixture was stirred to obtain a solution of tribrobionyloxyborane. To this, 9.1-(methylimino)methanol 7,8-difluoro-5-oxo 5H
40 g of -thiazolo[3.2a]quinoline-4-carphonic acid ethyl ester was added, and the mixture was stirred for 40 minutes while heating under reflux. After cooling to room temperature, the resulting crystals were collected by filtration, washed with isobrobyl ether, and recrystallized from acetonitrile to obtain 5.1 g of the title compound.

Melting point: Decomposes around 256°C 6 1 NMR (DMSO-d6) δ・0.9(ti
ll,t. J・7.5HZ), 2.2f4H. q. J-
7.5Hz), 3.3 (3H, s), 4.8 (21-1
,S),7. [i(111, dd, J-101-1z,
J-7.2}1z) ,8. fl (LH,s)I
R (KBr) υmax Cm-':
1724.1702.1534 elemental analysis value (C20H
l7N2 07 SF2 B): Calculated value (%): C. 50.23;H, 3.58;N
, 5.86 Analysis value (%): C. 50.21. }1,
3.62. N, 5.92 (2) 9.1-(methylimino)methanol 7.8 difluoro-5-oxo-5H-thiazolo[3.2-a coquinoline-4-carphonic acid (formula (l
l-1) Compound] dibropionyloxy (9.1-(methylimino)methanol7.8-difluoro-5-oxo5H-thiazolo[3,2-a coquinoson-4carboxy]borane 0 5
g was suspended in 2 ml of acetone, 0.15 ml of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature.

The obtained solid was collected by filtration, washed successively with water, acetone, and isopropyl ether, and recrystallized from a mixed solvent of dimethylsulfoxytoethanol to obtain 36 g of compound 62. The physical property analysis values of the compound obtained here are as follows: 9.1-(medylimino)methanol 7.8-difluoro-5-oxo 5H-thiazolo[3.2-a]quinoline-4- It matched that of carboxylic acid.

Example 6 Compound: 2.0 g of (5-methyl-6.7-cyfluoro-IH.4H diazolo[3.4-a]quinoxalin-1-ylidene) malonic acid ethyl ester (see Reference Example 10) The mixture was added to 236 g of 30% oleum and stirred at room temperature for 24 hours. The reaction solution was poured onto a piece of wood, and the precipitate precipitated was collected by filtration and washed with water to obtain 52 g of the title compound 1. The physical property analysis values of the compound obtained here are as follows:
It corresponded to that of H-thiazolo[3.2-a]quinoline-4 monocarboxylic acid.

Example 7 (δ)9,1-(methylimino)methanol7-fluoro8-(4-methyl-1-biverazinyl)5-oxo-
5H-thiazolo[3.2-a]quinoline-4-carboxylic acid9.1-(methylimino)methanol7.8-difluoro5-oxo5H-thiazolo[3.2-a]quinoline-4-carboxylic acid0 Add 0.3 g and 47 g of 1-methylbiverazine to 3 ml of dimethyl sulfoxide and add 100 g.
The mixture was stirred at ℃ for 10 hours. The reaction mixture was concentrated to dryness under reduced pressure, 30 ml of water and 5 ml of acetic acid were added thereto, and the mixture was washed with chloroform. An aqueous IN sodium hydroxide solution was added to the aqueous layer to adjust the pH to 7.5, and the precipitated solid was collected by filtration and washed successively with water and ethanol. After drying, the obtained crude crystals were recrystallized from a mixed solvent of chloroform-ethanol to obtain 21 g of the title compound as pale yellow crystals.

Melting point: Decomposition at around 257°C NMR (DMSO-tl. + D20) δ・2
．． 3 (3H.s), 2.4~2.5 (41Lm)
．． 2.8 (3M,s) ,3.3 ~3.4 (4
1-1, m) 4.4 (21Ls), 7.5 (l}
I,s) ,7. Ii (llLd, J-1311z)
I R (KBr) v, IIM-': 2928,
1696.1504cm 1462.798 Elemental analysis value (CI98 19N 40 3 S F
): Calculated value (%): C. 56.70;l1
, 4.76; N, 13.92 Analysis value (%): C,
56.55; 11.4.75. N, 13.87(b)9
．． 1-(methylimino)methanol 7-fluoro 8-(
4-Methyl-1-biperazinyl) 5-oxo 5H-thiazolo[3.2-a]quinoline-4-carboxylic acid hydrochloride 9.1-(methylimino)methanol 7-fluoro 8-
(4-Methyl-1-biverazinyl)-56 5 oxo-5H-thiazolo[3.2-a]quinoline-4-
0.2 g of carboxylic acid in 30% hydrogen chloride methanol solution 3
Dissolved in 0 ml. Ether was added and allowed to stand at room temperature, and the precipitated crystals were collected by filtration and washed successively with ethanol and ether to give yellow crystals of 9.1-(medylimino)methanol 7-fluoro-8-(4-methyl-1-biperazinyl).
0.15 g of quinoline 4-carboxylic acid hydrochloride was obtained.

Melting point. Foam decomposition NMR (D20) δ around 265°C: 2.8 (31-1, s), 2.9
(3tl, s), 3.2-3.3 (2H, m), 3.5
~3.6 (2H.m). 3.7 to 3.9 (4H, m
)． 4.5 (2H, s). 7.5 (IH.s)
．． 7.6 (111, d, J-13Hz). I R (KBr) vIlaXcm-'+3420.
1884.1472. Elemental analysis value (Cl9H20N4
03S FCl・3/2}+20): Calculated value (%) C. 48.98. H, 4.98. N,
12.03 Analysis value (%) C. 48.9LH, 4.8
9. N, 11.94 Example 8 6 6 9.1-(Methylimino)methanol 7,8-difluoro-5-oxo 5H-thiazolo[3,2a]quinoline-
0.3 g of 4-carboxylic acid and 0 biverazine hexahydrate
．． Add 61g to 10ml of dimedyl sulfoxide at 80°C.
The mixture was stirred for 32 hours. The deposited precipitate was collected by filtration and washed successively with water and ethanol. The solids were recrystallized from dimethyl sulfoxide to obtain 0.1 g of the title compound as orange crystals.

Melting point. Decomposition NMR at around 255℃ (DMSO-d. + D20)
δ: 2.8 (31-1, s), 2.8~2.9 (
4H, m), 34-3.4 (4M, m), 4.4 (2H
,s) 7.5 (IH,s) ,7.6 (IH.d.
J-13Hz) I R (KBr) ulIaXcm-
': 1699, 1612, 1489.1486 elemental analysis value (CI8H17N4 03 SF 1/21 {as 20): Calculated value (%) Analysis value (%) Example 9 C, 54.40; H, 4.57. N 14.10C,
54.52; H, 4.47. N, 14.049.1-(
0.3 g of methylimino)methanol 7.8 difluoro-5-year-old xo-5H-thiazolo[32-a]quinoline-4-carphonic acid and 0.38 g of 2-medylpiverazine were added to 10 ml of dimethylsulfoxide and stirred at 80°C for 40 hours. . The reaction mixture was concentrated under reduced pressure, and the deposited precipitate was collected by filtration and washed successively with dimethylsulfoxy F1 water and ethanol. This was recrystallized from dimethyl sulfoxide to obtain 0.03 g of the title compound as orange crystals.

Decomposes near melting point 240℃ NMR (D1lSO-d6 + D20
) δ :l. 0 (3H, d, J-5 ro 2) 2.8
(3H, s), 2.8 ~ 3.0 (4} 1, m), 3
．． 1 to 33 (lLm), 3.4 to 3.5 (2H.
m), 4.4 (2H, s), 7.5 (IILs), 7
．． 6 (IN, d, J-13Hz). I R (KB
r) νmax cl': 1702, 1610j4
90,1461 Example 10 A compound]: 9.1-(methylimino)methanol 7,8-difluoro-5-oxo 5H-thiazolo[3.2a]quinoline-4-carphonic acid 0.3 g and 2.6-dimethyl 0.36 g of Piverazine was added to 10 ml of dimethyl sulfoxide and stirred at 80° C. for 38 hours. The reaction mixture was concentrated to dryness under reduced pressure, water was added to the resulting residue, and the pH was adjusted to 3.0 with dilute hydrochloric acid.
and filtered. An aqueous sodium hydroxide solution was added to the filtrate to adjust the pH to 9.0, and the precipitate was collected by filtration and washed with water. This was recrystallized from a mixed solvent of chloroform-ethanol to obtain 0.09 g of the title compound as yellow crystals.

Melting point: Decomposition near 254°C NMR (DMSO-d6) δ: 1. O(6N, d
, J-6Hz) ,2.6~2.8 (2Lm) ,2
．． 7 (3Ls), 2.9 ~ 3.0 (2H, m)
3.3 to 3.5 (2H, m). 4.4 (21-1,
s), 7.5 (Ill, s) 7.6 (IH, d, J
i3Hz). IR(κBr) vIIa, cm-'
:1689.1B12,1595. +4861472. Elemental analysis value (as C20H21N4 03 SF) Calculated value (%) C, 57.88. H, 5.08. N. 1
3.45 Analysis value (%) C, 57.6B. H, 5. l
O. N. 13.38 Example 11 Compound with Nyl Group) 7 O 9.1-(Medylimino)methanol 7.8-Difluoro-5-oxo 5H-thiazolo[3,2-a]quinoline-4-carboxylic acid 0. 3g and pyrrolidine 0 33g
was added to 3 ml of dimethyl sulfoxide and stirred at 90°C for 8 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the resulting residue was washed successively with dimethyl sulfoxide, water, and ethanol. This was recrystallized from dimethyl sulfoxide,
0.19 g of the title compound was obtained as pale yellow crystals.

Decomposition at around melting point 275°C NMR (DMSO-d6) δ: l. 9 ~2.
0 (4H.m), 2.5 (3Hs), 3.6 to 3.
7 (4H.m). 4.4 (2H.s). 7.5
(LH,s)7.6(IH,d.JJ4Hz) ,1
6.0 (11-1,s). I R (XBr) ν
IN. ．． cm-'+ 1690.1478,1454
, 14041380. Elemental analysis value (C +sH 18N 3 0 3 S
F): Calculated value (%) C, 57.90.1{,
4.32. N, 11.25 analysis value (%) C, 57.
66;l{,4.42;N,11.12Example 12 D-9.1-(Methylimino)methanol7.8-cyfur-5-oxo5H-thiazolo[3.21a]quinoline- 4-carboxylic acid 0 3g and 3-virolidinol 0
．． 4 g was added to 3 ml of dimethyl sulfoxide and stirred at 100°C for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the resulting residue was washed successively with water and ethanol. This was recrystallized from dimethyl sulfoxide to obtain 0.18 g of the title compound as yellow crystals.

Melting point: Decomposition NMR (DMSO-d. + D
20) δ: 1.8 ~ 2.1 (2H, m)2
．． 5 (3H.s), 3.3-3.4 (LH, m),
3.5 ~ 3.6 (LH, m), 3.8 ~ 4.1
(2Lm) ,4.3 (IH, d, J-16.5Hz
)． 4.4 (IH, s) , 4.5 (1N, d,
J-16.5Hz), 7.5 (IH, s), 7.
6 (II{,d,J-14Hz). I R (M
ar) v, nIl. cm-': 1814.14
80,1456,+406. Elemental analysis value (Cl88l6
N3 04 SF) Calculated value (%) C, 55
．． 52; H, 4.14: N, 10.79 analysis value (%)
C. 55.27. }l. 4.25; N, 10.65 Example 13 Produced in the following two steps.

(1) 9.1-(Methylimino)methanol 7-fluoro 8-(3-acetylamino-1-pyrrolidinyl)-5
-Oxo5H-thiazolo[32-a]quinoline-4-
Carboxylic acid [In formula (Vl), R1 is a hydrogen atom,
Compounds in which n or 0 and R5 is a methyl group]: 9.1-(methylimino)methanol 7,8-difluoro-5-oxo-5H-thiazolo[3.2-a coquinoline-4-carphonic acid 0.3 g, 37 3 Add 0.6 g of acetylaminopic lysine to 3 ml of dimethyl sulfoxide, and heat the mixture at 90-95°C for 4.5 g.
Stir for hours. The reaction mixture was concentrated to dryness under reduced pressure, and the resulting residue was washed successively with water and ethanol, and recrystallized from a mixed solvent of dimethylsulfoxytoethanol to obtain 0.2 g of the title compound.

Melting point = 160-162°C NMR (DMSO-66) δ: 1.4-1.
5 (LH, m) , 1.7 (:HI, s) , 1.8
~2.0 (IH, m). 2.1 ~2.2 (l
L[ll). 2.6 (3}1,s), 3.6~
3.9 (2H, m), 4.0-4.1 (ILm)
,4.3 ~4.4 (LH,+n) ,4.5 (
2H, sl , 7.5 (IH, s), 7.6 (LH, d
, J-14Hz), 8.2 (1N, d, J-6Hz)
.
．． 2-a] Quinoline-4-carboxylic acid 9.1-(methylimino)methanol 7-fluoro 8-
Add 10 ml of 10% aqueous sodium hydroxide solution to 0.2 g of (3-acetylamino-1-pyrrolidinyl)-5-oxo-5H-thiazolo[3,2a]quinoline-4-carphonic acid, and stir at 100°C for 12 hours. did.

Insoluble materials were filtered, the filtrate was adjusted to pH 7 with 3N hydrochloric acid, and the precipitate was collected by filtration and washed successively with water and ethanol.

This was recrystallized from a mixed solvent of ethanol and hexane to obtain 0.1 g of the title compound as pale yellow crystals.

Decomposition NMR (DMSO-ds + [l2o)δ: around melting point 230°C:
1.7~1.8 (1}1,m)2.0~2.1 (
1}1, m). 2.5 (3H, s), 3.4~
3.5 (IH.m), 3.5 ~ 3.9 (4H, m
) ,4.4 (2Ls) ,7.5(IH,s) ,
7.6 (IN, d, J-14Hz). I R (K
Br) vIIllXC[I-': 3440,1B9
6,1494,140e1380 Elemental analysis value (C+aH+tN4o3S F-172 8
20): Calculated value (%) C. 54.40. H, 4.55. N.
14.09 Analysis value (%) C, 54.24; H, 4.
46; N, 14.11 Example 14 Product Q-9.1-(Methylimino)methanol 7.8-difluoro-5-oxo 5H-thiazolo[3.2-a]quinoline-4-carboxylic acid 0.3 g and morpholine 0.32g
was added to 10 ml of dimethyl sulfoxide and stirred at 80°C for 39 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the resulting residue was washed with water. This was recrystallized from a mixed solvent of chloroform-ethanol to obtain 0.12 g of the title compound as orange crystals.

Decomposition NMR (DMSO-d.) δ: 2.8 (3
H, s), 3.4-3.5 (41-1, m), 3.
7 ~ 3.8 (4H, m), 4.5 (2H, s)
,7.6(IH,s) ,7.7(ILd.J-1
:Hlz), 15.9 (IH,s). IR(κB
r) v. ．． ．． cm-': 17104612,14
89.1470 elemental analysis value (C+aH+aN30a S
F・1/4 (as H20) Calculated value (%) C, 54.88. H, 4.22. N,
10.67 Analysis value (%) C, 54.88・H 4.
20.N 10.55 Example 15 9.1-(medylimino)methanol 7.8-cyfur 51 xo-5H-thiazolo[3.2-a]quinoline-4-carboxylic acid 0. sog, 1-edilbiverazine 0
．． 19 g and 0.62 g of triethylamine were added to 4 ml of dimethylsulpoginate and stirred at 90° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, and the resulting solid was washed successively with water and ethanol. This was recrystallized from a mixed solvent of chloroform-ethanol to obtain 0.49 g of the title compound as pale yellow crystals.

Melting point. Decomposition at around 276°C 77 NMR (DMSO-da) δ: 1.
05 (3H, t, J-71-1z) . 2.4 (2L
q, J-71+Z), 2.7 (3M, s), 3.
3 (4H, bs), 3.4 (4N, bs). 4
．． 4 (2H.s). 7.5 (1}1,s) ,7
．． 6 (ltl, d.J-13Hz), 15.7 (IH
,s) I R (KBr)υnlaxcm-':3060,
1710, 1615, 1494. Elemental analysis value (C20H
21N4 03 SF) Calculated value (%) C,
57.68; l-1.5.08; N 13.45 Analysis value (%) C, 57.59. H 5.0! l・N 13
．． 43 Example 16 Product) The title compound was obtained in the following two steps.

(1) diacetoxy (9.1-(methylimino)methanol7.8-difluoro-5-oxo5H-thiazolo[3.2-a]quinoline-4-carboxy]borane [in formula (IV), R6 is 8 Chill group compound) A mixture of 0.27 g of boric acid and 3 g of acetic anhydride was
Stirring at 80°C for 50 minutes gave a triacetoxyborane solution for 7 nights, to which 9.1-(methylimino)methanol 7.8-
Schiffle 5-oxo 5H-thiazolo [3.2-a
] 1.0 g of quinoline-4-carboxylic acid ethyl ester was added, and the mixture was stirred at 100°C for 40 minutes. The reaction mixture was allowed to cool to room temperature, and the crystals formed were collected by filtration and washed with isopropyl ether to obtain 26 g of the title compound 1. The title compound recrystallized from acetonitrile had the following physical properties.

Melting point: 285°C or higher NMR (DMSO-d.) at-1z). 4.8 (2N 10H7.) . 7.9 (IH IR(κBr) ν.8 Elemental analysis value (Cte) Calculated value (%) C 6 1.9 (6Ls).3.3 (3Ld, J-d
．． J-IHz), 7.6 (IH, dd, J-7Hz.t
, J・11{z) cm-': 1718 1697+aH+3N
207 SF2 B and 48 02 1{ 2 91 N, 6.22 Analysis value (%) C. 47.92. l{, 3.02. N
, 6.21 (2) 9.1-(methylimino) methanol 7
-Fluoro8-(4-hydroxy-1-biveracinyl)-5-oxo5H-thiazolo[3.2-a]quinoline-4-carboxylic acid diacetoxy (9.1-(medylimino)methanol 7
8-Difur sairo 5-oxo 5+{-thiazolo [3
．． 2-a] 1 g of quinoline-4-carboxy)borane,
10 ml of dimethyl sulfoxide. 0.78 g of 4-human xypiverazine dihydrochloride and triethylamine 1.
It was added to 57 g of the mixture and stirred at room temperature overnight. Dimethyl sulfoxide was distilled off under reduced pressure to obtain crude cyacetoxy.
(9.1-(methylimino)methanol 7-full-year low 8
-(4-Humanoxy-1-biverazinyl)-5-oxo5H-diazolo[3.2-a]quinoline-4-carboxy]borane was obtained.

Add 10 ml of water to this, adjust to pl{2 with concentrated hydrochloric acid, and add 3 ml of water.
Stirred for 0 minutes. The precipitated crystals were collected by filtration and washed with a small amount of water. Add this to water, remove insoluble matter by filtration,
1N sodium hydroxide was added to the filtrate to adjust the pH to 7.5. The precipitated solid was collected by filtration, washed successively with water and ethanol, and then recrystallized from a mixed solvent of chloroform-ethanol to obtain 0.25 g of the title compound.

Melting point, 285℃ or higher NMR (DMSO-da) δ: 2.6 (2
H. m) ,2.8 (3H,s) ,3.1 (21
{,m) ,33(2H,m) ,3.6(2Lm)
,4.4 (2H,s). 7.5 (ILs).
7.6 (Ill, d, J-12.6Hz), 8.2
(]H.s) ,15.8(11+,bS)IR(κB
r) v max cm-' : 1690,1484
．． 1454 elemental analysis value (Cl8Hl7N4 04 S
F) Calculated value (%) C. 53.46;H. 4.
24;N. 13.85 Analysis value (%') C, 53.2
0], 4.34; , 0.5 g of coquinoline-4-carboxylic acid, 0.94 g of 3ethylaminomethylpyrrolidine dihydrochloride, and 125 g of triethylamine were added to 5 ml of dimethyl sulfoxide, and the mixture was stirred at 95° C. for 7 hours.

The reaction mixture was allowed to reach room temperature, and the precipitate was collected by filtration.
Washed sequentially with dimethyl sulfoxide, ethanol and ether. This is N. Recrystallization from N-dimethylformamide gave 0.3 g of the title compound as pale yellow crystals.

Decomposes near melting point 254℃ NMR (DMSO-d6”D20) δ.1
．． 2-1.3 (3H, bt) 1.7-1.8 (18
, m). 2.1 ~ 2.3 (11-1, m), 2.5 (
31-1, s), 2.5 to 2.7 (ILm), 2.9
~3.2 (1, m). 3.5 to 3.9 (4H, m)
, 4.4 to 4.6 (2H, +n), 7.49 (11-
1.8). 7.5 (u+,a,J-x:u+z)
．． IR(κBr) 1Jmax cm-': 1702,
lF120,1458 elemental analysis value (C 21 H 2
4N 4 0 3S F Cl・8208 2): Necropsy value (%) C, 52.00; H Analysis value (%) C, 51.73;}I Example 18 5 5 40・N 53 N 11 55 11.65 9.1-(Methylimino)methanol7.8-cyfur-5-oxo5H-thiazolo[3.28]quinoline-
0.57 g of 4-carboxylic acid 0.322+1;,3-methylaminomethyl bilysine dihydrochloride and 0.81 g of triethylamine were added to 3 ml of dimedyl sulfoxide and stirred at 95°C for 8 hours. The reaction mixture was allowed to reach room temperature, and the precipitate that formed was collected by filtration and washed successively with dimethyl sulfoxide, ethanol, and ether. This is N, N-
Recrystallization from dimedylformamide gave 0.26 g of the title compound as pale yellow crystals.

Melting point. Decomposition at around 250℃ NMR (DIISO-d6+ 1120) δ
: 1.7 ~ 1.8 (LH.m) 2.2 ~ 2.3 (1
M, m), 2.5 (31+.s), 2.5-2.8 (
IH, m), 2.6 (311, s). 3.1 (21-1
．． d. J-7.1Hz). 3.5 to 3.6 (1N, m
), 3.6 ~ 3.8 (3}1, m), 4.4 (IH
．． d, J-16.811z) ,4.5 (IH, d,
J"16.6Hz) ,7.5 (01s) ,7.5
(IH, d, J・141{z). I R (KBr
) vl. ffiaxcm-':1684,1616.
1498 elemental analysis value (C20H22N403 S FC
I.3/2H20) Calculated value (%) C. 50.05. H. 5.25. N.
11.67 Analysis value (%) (:.5Q.Q1.H,5
．． 23. N.L.L. 89 Hydrochloride of Example 19] Diacetoxy (9.1-(methylimino)methanol 7
8-difluoro-5-oxo-5H thiazolo[3.2
-a]quinoline-4-carboxy]borane [Example 1
6-(1)] 2g to 10% dimethyl sulfoxide
ml and a mixture of 0.6 g of 4-ethylbiverazine and 2 g of triethylamine, and the mixture was stirred at room temperature overnight.

Dimethyl sulfoxide was distilled off under reduced pressure to obtain crude diacetoxy(9.1-(methylimino)methanol 7-fluoro8-(4-ethyl-1-biverazinyl)-5oxo 5H-thiazolo[3.2-a]quinoline -4-carboxy]borane was obtained. 10 ml of water was added to this, and the mixture was stirred for 30 minutes with concentrated hydrochloric acid as p}It. The precipitated crystals were collected by filtration, washed with a small amount of water, and recrystallized from water. 1.1 g of the title compound was obtained.

Melting point: 295°C or higher NMR (D20) δ: 1.4 (3H.t.J-
7.3Hz). 2.8 (3H.s), 3.2-3.4
(4H, m) , 3.8-3.9 (6H, m) ,
4.4 (2Hs) ,8.8(l}l.d, J-12
．． 2Hz). 7.4 (1N, s). 8 5 I R (KBr)v,aX cm-': 1
B90,1464.1390 elemental analysis value (C20H
22N a O 3 SF CI ・H20): Calculated value (%) C, 50.05; } 1, 5.25; N
, 11 analysis value (%) C, 50.21:H, 5.09
;N, 11 Example 20 3/2 67 72 Produced in the following two steps.

(1) 9.1-(Methylimino)methanol 7-fluoro 8-(4-methyl-1-biverazinyl) 5-oxo 5H-thiazolo[3.2-a]quinoline-4-carboxylic acid ethyl ester 9.1- (Methylimino)methanol 7
．． 8-difluoro-5-oxo-5H-thiazolo [3.
2-a] 1.0 g of quinoline-4-carboxylic acid ethyl ester (see Example 1) and 1.42 g of 1-methylbi-86 verazine were added to 10 ml of dimethyl sulfoxide and stirred at 95° C. for 82 hours. The reaction mixture was concentrated to dryness under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated to dryness under reduced pressure. The resulting residue was recrystallized from a mixed solvent of cyclohexane and ethyl acetate to obtain 0.8 g of the title compound as pale yellow crystals.

Melting point: Decomposes near 244℃ NMR (CDC13)δ・1.5(31{,t
, J・711Z) ,2.4 (3H.s)2.6 (
4N, m) ,2.8 (:HI,s) ,3.4 (
4H, m). 4.2 (2H,s) ,4.5 (2
H, q, J-7Hz), 6.8 (ill, s),
7.8 (IH, d, J・13Hz) . I R (KBr) vmax cm-': 1710
, 1566.14 [i4 elemental analysis value (C 2LH 2
3N 40s SF): Calculated value (%)
C, 58.59], 5.39; N, 13.02 analysis value (
%) C, 58.33. }1,5.41;N,12.
88(2)9.1-(Methylimino)methanol7-funoleo-8-(4-methyl-1-piverazinyl)5-oxo5H-thiazolo[3.2-a]quinoline-4-carboxylic acid: 9. 1-(Methylimino)methanol 7 fluoro 8-(4-methyl-1-piverazinyl)-5-oxo 5H-thiazolo[3,2a]quinoline-4-carboxylic acid ethyl ester 0.5 g and IN sodium hydroxide 2
．． 6 ml was added to 130 ml of ethanol, and the mixture was heated under reflux for 5 hours. The reaction mixture was concentrated to dryness under reduced pressure.
0+nl and 2n+1 acetic acid were added, and insoluble materials were removed by filtration. The filtrate was adjusted to pH 8 by adding IN aqueous sodium hydroxide solution, and then diluted with chloroform-methanol (10:1).
) was extracted with a mixed solvent. The extract was concentrated to dryness under reduced pressure, and the residue was washed with water and dried, then recrystallized from a mixed solvent of chloroform-ethanol to give the title compound as pale yellow crystals.
27g was obtained.

The physical property analysis values of the compound obtained here are as follows: Example 7-
9.1-(Methylimino)methanol obtained in (a) 7
-fluoro8-(4-methyl-1-biverazinyl)-5
-oxo5H-thiazolo[3.2-alquinoline-4
- corresponded to that of carboxylic acids.

Example 21 hydrochloride] It was manufactured in the following two steps.

(1) Cibrobionyloxy (9.1-(methylimino)methanol7-furollow8-(4-methyl-1-biverazinyl)-5-oxo5H-thiazolo[3.2-
a] Quinoline-4-carboxy]borane [a compound in which Z is a 4-methyl-1-biverazinyl group and R6 is an ethyl group in formula (V)) dibropionyloxy (9.1-(methylimino)methanol 7 .8-Difluoro-5-oxo5H-thiazolo[3.2a]quinoline4-carboxy)phoran [see Example 5 - (1)] 89 3.0 g, dimethyl sulfoxide 10 ml and 4-methylbiverazine 1 .89 g of the mixture was stirred at room temperature for 15.5 hours. The precipitated crystals were collected by filtration. After sequentially washing this with dimethyl sulfoxide and acetonitrile,
Recrystallization from acetonitrile gave 3.2 g of the title compound.

Melting point: decomposes around 228°C NMR (Dvso-as) δ: 0.9 (6
8,t,J-7.5Hz) ,2.2(4Lq,J-7
．． 5tlx). 2.3 (3H,s) ,2.8 (
3Ls), 3J (41-1, bs), 3.5 (4
H, bs), 4.6 (2Ls), 7.7 (lL
dJ-12.5Hz), 7. il(11-1,s)I
R (KBr) νmax Cm-': 171
8,1688.1516 elemental analysis value (C25H28N4
0t S F B) Calculated value (%) C, 53
．． 77. H, 5.05; N, 10.03 analysis value (%)
C, 53.70; H, 5.02; N, 10.06 (2
)9.1-(Methylimino)methanol 7-fluoro8
-(4-methyl-1-biverazinyl)5-oxo 5H
-thiazolo[3.2-a-coquinoline-4-carboxylic acid.
Dibrobionyloxy hydrochloride [9,1-(methyl-90mino)methanol 7-fluoro-8-(4-methyl-1-
biverazinyl)-5-oxo-5H-thiazolo[3.2
-a]quinoline-4-carboxy]borane3. Og was added to 10 ml of water, converted to p}II with concentrated hydrochloric acid, and stirred at room temperature for 40 minutes. The precipitated crystals were collected by filtration and washed with water. This was recrystallized from water to obtain 1.7 g of the title compound. The physical property analysis values of the compound obtained here are those of 9.1-(medylimino)methanol7-fluoro8(4-methyl-1-viveracinyl)-5-oxo5 obtained in Example 7-(b).
H-diazolo[3.2-a]quinoline-4carphonic acid.
It matched that of hydrochloride.

Example 22 91-(Methylimino)methanol 7-fluoro8(4-
Methyl-1-biverazinyl)-5-oxo-5H-thiazolo[3.2-a-coquinoline-4carboxylic acid hydrochloride 6
．． 3 g was suspended in 100 ml of water, and the pH of the suspension was adjusted to 7.5 with a 10% aqueous sodium hydroxide solution. Insoluble materials were collected by filtration, washed with water, and then suspended in 100 ml of an ethanol solution containing 4.7 g of p-toluenesulfonic acid monohydrate. Add 200 ml of water and 200 ml of ethanol to the suspension,
After heating under reflux for 1 hour, the mixture was allowed to stand at room temperature. The precipitate was collected by filtration and washed with ethanol and water to obtain 6.3 g of the title compound as white crystals.

Melting point: Decomposes near 300℃ NMR (DMSO-d6) δ+2.3 (3
H, s), 2.8 (31+, s), 2.9 (3 days, s), 3.3 to 3.5 (8H, +1), 4.
5 (21-1, s), 7.1 (2H.d, J-8H
z), 7.5 (2Ld, J-81-121, 7.
6 (IH, s). 7.7 (ILd, J-12Hz),
9.3 ~10.1DH, bs) 15.8 (LH.s)
．． I R (KBr) v wax cm-': 3
120, 3000, 2844.2712 2&40
1696.1616, 1598.1472.1442
1400.1236.1150 Elemental analysis value (as C26H27N4 06 S2 F) Calculated value (%) C. 54.34;l+. 4.74;
N 9.75 Analysis value (%) C, 54.23; lI.
4.73:N. 9.63 Example 23 (middle): 91-(methylimino)methanol 7-ful 8 (4-diyl 1) produced by the same procedure as in Example 19
-biverazinyl)-5-oxo5H-thiazolo[3.
3.9 g of 2-a coquinoline-4=carboxylic acid hydrochloride was added to 60 ml of water, and the mixture was heated to 75°C to dissolve. Next, 25 g of sodium p-toluenesulfonate was added to 10 g of water.
ml, added, and left at room temperature. The precipitate was collected by filtration and washed with 9 3 portions of water to obtain 4.2 g of the title compound as pale yellow crystals.

Melting point. Decomposition NMR (DMSO-d.) 6 1.3 (3H
,t,J・7Hz) ,2.3(3H.s) ,2.8
(3}1,s). 3.1~3.9 (81-1, m
), 4.5 (2H.s). 7.1 (21-1, d
, J-8Hz) ,7.5 (2H, d, J-8Hz)
,7.6 (IH,s) ,7.7 (It{,d,
J-12.5Hz) ,9.3~9.5(1N, bs)
,15.8(IH,s)I R (KBr) vIIa
Xcm-': 1689, 1612. +58315
20. 1501. 1465, 1451, 122
1. Elemental analysis value (C27H2.N406S2F-
1741120) Calculated value (%) C,5467. H, 5.01; N. 9
．． 45 Analysis value (%) C, 54.64.1+. 4.9
9. N, 9.39 Example 24 3 4 Dimedyl 1-Biverazinyl group Chemical compound 9 4 "L" was produced in the following two steps.

(])9.1-(Methylimino)methanol7-fluoro8-(3-methyl-1-biverazinyl)5-oxo5H-thiazolo[3.2-a coquinoline-4-carboxylic acid hydrochloride (formula (1) ) diacetoxy (9.1-(methylimino)methanol 7
．． 8-difluoro-5-oxo-5H thiazolo[3.2
-a]quinoline-4-carboxy)porane Example 1
6-(1) See 7. Og, dimethyl sulfoxide 8m
80 g of a mixture of 3.7 g of 1 and 2-methylviveracin
The mixture was stirred at ℃ for 4 hours. The precipitated crystals were collected by filtration and washed with acetonitrile. The obtained crystals were added to 100 g of ice water, 8 [11] of concentrated hydrochloric acid were added, and the mixture was stirred at room temperature for 1.5 hours, and the crystals were collected by filtration. This was added to 50 ml of water, heated to 70°C, dissolved, and filtered. 1 ml of concentrated hydrochloric acid was added to the filtrate, and the mixture was allowed to stand at room temperature. The precipitate was collected by filtration and washed with cold water to obtain 4.3 g of the title compound as pale yellow crystals.

Decomposes near melting point 284℃ NMR (D20)δ: 1.4 (3H, dj-
6Hz), 2.7 (3H, s) 3.2 to 3.8 (71
-1. m), 4.3 (28, s), 6.6 (IH,
d, J-12Hz). 7.3 (1N, s). r R
(KBr) vIffi. Xcm-': 1690.
1615. 1462 elemental analysis value (C 19H 2
0N 4 0 3S F Cl)・Calculated value (%)
C, 51.99.1+. 4.59. N, 12.7
6 Analysis value (%) C, 51.95. H, 4.59.
N, 12.68 (2) 9.1-(Methylimino)methanol 7-fluoroEl- (3.4-dimethyl-1-biveracinyl)-5-oxo 5H-thiazolo[3,2a
Coquinoline-4-carboxylic acid: 9.1-(methylimino)methanol 7-fluoro8-(3-methyl-1-biverazinyl)-5-oxo 5H-thiazolo[3.2-a]quinoline-4- Add 0.93 g of sodium formate, 15 ml of formic acid, and 15 ml of formalin to 3.0 g of carboxylic acid/hydrochloride, and heat at 80°C for 1 hour.
Stirred for 4 hours. The reaction mixture was poured into ice water, and the pH was adjusted to 9.0 by adding an aqueous sodium hydroxide solution. The deposited precipitate was collected by filtration, dissolved in a mixed solvent of chloroform-methanol (4 liters), washed with water, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to obtain 0.92 g of the title compound as pale yellow crystals.

Decomposes near melting point 244℃ NMR (DMSO-da)δ 1.0(3+1
, d, J-6Hz). 2.1~2.4 (Hl, m
) , 2.2 (31Ls) , 2.7 (311
．． s), 2.7 to 3.0 (211, m), 3.
2 ~ 3.5 (3tl.m), 4.5 (2H.s)
7.5 (111.s). 7.6 (1tl.dj-12
．． 51-1z)j5.9(ills). I R (ylBr) υmax Cm-': 15
92. 1613. 14901460 Elemental analysis value (C 20H 21N 40 3 SF
) Calculation value (%) C, 57.68. }1,5
．． 08; N, 13.45 Analysis value (%) C, 57.
58;l-1.5.06;N. 13.36 Example 25 9.1-(Methylimino)methanol 7-fluoro8-(
3,4.5-Trimethyl-1-biperazi97nyl)-5-oxo5H-thiazolo [3.2-Produced in the following two steps.

(1) 9.1-(Methylimino)methanol 7-fluoro8-(3.5-dimedyl-1-biveracinyl)-5-
Oxo 5H-thiazolo[3.2-a]quinoline-4-
Carboxylic acid/hydrochloride [In formula (1), Z is 3,5-
Hydrochloride of compound having dimethyl-1 biverazinyl group] diacetoxy (9.1-(methylimino)methanol7.
8-difluoro-5-oxo-58-thiazolo[3.2
-a]quinoline-4-carboxy]porane [Example 1
6-(1)] A mixture of 7.0 g of dimethyl sulfoxide, 8 ml of dimethyl sulfoxide, and 3.9 g of 2,6-dimethylpiverazine was stirred at 80° C. for 4 hours. The precipitated crystals were collected by filtration and washed with acetone. Pour the obtained crystals into 100 g of ice water.
In addition, 7 ml of concentrated hydrochloric acid was added. Stir at room temperature for 1 hour,
Ninety eight crystals were collected by filtration. This was added to 950 ml of water, heated to 90°C to dissolve, and the solution was filtered. 2 ml of concentrated hydrochloric acid was added to the filtrate, and the mixture was allowed to stand at room temperature. The precipitate was collected by filtration and washed with cold water to obtain 4.4 g of the title compound as pale yellow crystals.

Melting point Decomposes around 295℃ NMR (D20) δ: 1.4 (68, d, J-
5Hz). 2.8 (3H, s) 3.2 ~ 3.4 (2
+-1, m), 3.6 ~ 3.8 (4tLm), 4,
4 (2H.s). 6.8(1[+.d, J-121-
1z), 7.4(IH,s)IR(κBr) 'l'
max Cm-': 1690, 1615. 14
63 elemental analysis value (C20H22N4 03 S FCI
) Calculated value (%) C, 53.04. l-1.
4.90;N. 12.37 Analysis value (%) C, 53
．． 04; H, 4.89; N, 12.36 (2) 9.1-
(Methylimino) Methanol 7-Full Rho 8- (3,
4.5-1-Limethyl-1-biverazinyl)-5-oxo5H-thiazolo[3.2-a]quinoline-4-carboxylic acid 9.1-(Methylimino)methanol7fluoro8-(3. 5-dimethyl-1-biveracinyl)
25 g of -5-oxo 5H-thiazolo[3.2-a]quinoline-4-carboxylic acid hydrochloride was heated and dissolved in about 500 ml of water. The pH of the solution was adjusted to 9.0 by adding an aqueous sodium hydroxide solution. The precipitate was collected by filtration and washed with water to give pale yellow crystals of 9.1-(methylimino)methanol 7-fluoro-8-(3.5-dimethyl-1-piverazinyl)-5-oxo 5H-diazolo[3,2a ] Quinoline-4-carboxylic acid (same compound as Example 1o)2.
1g was obtained. 0.5 g of this compound, 0.4 methyl iodide
3 g and 0.5 g of potassium carbonate were added to 20 ml of N,N-dimethylformamide and stirred at room temperature for 23 hours.

The reaction mixture was added to water, the pH of the solution was adjusted to 9.5 with diluted hydrochloric acid, and extracted with a mixed solvent of chloroform-methanol (10:1). The extract was washed with water, and the extract was concentrated to dryness under reduced pressure. 6 ml of 5% potassium hydroxide aqueous solution to the residue,
18 ml of water and 12 ml of ethanol were added and the mixture was heated to reflux for 15 minutes. The reaction mixture was added to water, the pH of the solution was adjusted to 9.5 with diluted hydrochloric acid, and then extracted with a mixed solvent of chloroform-methanol (4:1). The extract was washed with water, concentrated to dryness under reduced pressure, and the residue was recrystallized from a mixed solvent of acetonitrile-ethanol to give the title compound o. 08g was obtained.

Decomposes near melting point = 250°C NMR (DMSO-dll) δ: 1.0 (8N
, d, J・61-iz). 2.2 (3HS), 2
．． 2 to 2.4 (2}1, m). 2.7 (3H.s)
．． 2.9 to 3.1 (21-1.m). 3.4 ~
3.5 (2H, m), 4.5 (21-1, s), 7.
5 (IH, s). 7.6 (ltl, d, J-12.5
Hz). 15.9 (18.8) IR(κBr) vlnaXcm-': 1688,
1612, 1502.1463 Elemental analysis value (as C21H23N4 03 SF) Calculated value (%) C, 58.59. H, 5.39. N,
13.01 Analysis value (%) C, 58.60; H, 5
．． 39. N, 12.96 Example 26 Preparation of tablets 9,1-(methylimino)methanol 7-fluoro8-(4-methyl-1-biperazinyl)-5-oxo 5H-thiazolo[3 ．． 2-a:l
A tablet containing 100 mg of quinoline-4-carboxylic acid [Example 1 O 1 Compound of Example 7-(a)] was obtained.

[Formulation] Ingredient distribution
Total amount of active ingredient [Compound of Example 7-(a)] 100
Parts by weight Corn starch 46 parts by weight Microcrystalline cellulose 98 parts by weight Hydroxybuvir cellulose 2 parts by weight Magnesium stearate 4 parts by weight [Procedure] Mix the herbal medicine, cornstarch and microcrystalline cellulose, and dissolve in 50 parts by weight water. Added cellulose and thoroughly kneaded.

After passing this mixture through a sieve and granulating it into granules and drying,
Magnesium stearate was mixed with the obtained granules and the mixture was compressed into 250 mg tablets.

Example 27 Preparation of granules 9.1-(methylimino) in 500 mg as follows:
Methanol 7-fluoro 8-(4-methyl-1-biverazinyl)-5-oxo 5H-thia l 0 2 zolo[3.2-a]quinoline-4-carboxylic acid [Compound of Example 7-(a)] Granules containing 200 mg were obtained.

[Prescription ingredients
Total amount of main drug (compound of Example 7-(a)) 200
Weight part milk 119 185
Parts by weight Corn starch 109 parts by weight Human oral cellulose 6 parts by weight [Procedure] Mix the crude drug, lactose and corn starch, and add 1 part water to this.
Hydroxybuvir cellulose dissolved in 20 parts by weight was added and thoroughly kneaded. This wrought material was passed through a 20-mesh sieve and granulated, dried and sized to obtain granules.

Example 28 Preparation of capsules 9.1-(methylimino) in 500 mg as follows:
Methanol 7-fluoro 8-(4-methyl 1-biverazinyl)-5-oxo 5H-thiazolo[3.2-alquinoline-4-carboxylic acid (compound of Example 7-(a))
Capsules containing 100 mg were obtained.

[Prescription feeling 11111 distribution
Total amount Active ingredient (compound of Example 7-(a)) 10
0 parts by weight Lactose 35 parts by weight Corn starch 60 parts by weight Magnesium stearate 5 parts by weight [Procedure] Thoroughly mix each of the above components and prepare 200 mg of this mixed powder.
The solution was filled into capsules to obtain capsules.

Examples 29-31 Preparation of tablets Instead of the compound of Example 7-(a), 9.1
-(methylimino)methanol7-fluoro-8- (4
-Methyl-1-biverazinyl)-5-oxo5H-thiazolo[3.2-alquinoline 4-carboxylic acid hydrochloride [compound of Example 7-(b)], 9.1-(methylimino)methanol 7- fluo-8-(4-ethyl-1
-biverazinyl)-5-oxo-5H-diazolo[3.
21a] Quinoline-4-carphonic acid (compound of Example 15) or 9.1-(methylimino)methano7-fluoro8-(4-ethyl-1-biverazinyl)-5-oxo5H-thiazolo[ 3.2-a] In one tablet, Example 7-
Tablets containing 100 mg of the compound (b), the compound of Example 15, or the compound of Example 19 were manufactured.

Examples 32 to 33 Production of granules Example 7 - 9.1(methylimino)methanol 7-fluoro-8-(4-methyl-
1-Biperacinyl)-5-oxo5H-thiazolo[3,
2-a coquinoline-4-carboxylic acid hydrochloride (Example 7
-(b)] or 9.1-(methylimino)methanol7=fluoro8-(4-ethyl-1-biverazinyl)-5-oxo5H-thiazolo[3.2-
a] In the same manner as in Example 27 except for using quinoline-4-carboxylic acid hydrochloride [compound of Example 19],
Granules containing the compound of Example 7-(b) or the compound of Example 19 were produced.

Examples 34-35 Preparation of capsules Instead of the compound of Example 7-(a), 9.1
-(Methylimino)methanol 7-fluoro8-(4-methyl-1-biverazinyl)-5-oxo5H-thiazolo[3.2-a]quinoline-4-carboxylic acid hydrochloride (
Compound of Example 7-(b)), 9.1-(methylimino)methanol 7=fluoro8-(4-ethyl-1-
biverazinyl)-5-oxo-5H-thiazolo[3,2
Example 7 was carried out in the same manner as in Example 28 except that -a-coquinoline-4-carboxylic acid [compound of Example 15] was used.
- Capsules containing the compound of (b) or the compound of Example 15 were produced.

Claims (3)

[Claims] (1) The following formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(I) (In the formula, Z is ▲There are mathematical formulas, chemical formulas, tables, etc.▼, Yes▼or▲Mathematical formula, chemical formula,
There are tables, etc. ▼ where R^1 and R^2 each represent a hydrogen atom or lower alkyl group, R^3 represents a hydrogen atom, hydroxyl group, or lower alkyl group, and R^4 represents a hydrogen atom, hydroxyl group, or amino group. , means an aminomethyl group, a lower alkylaminomethyl group or a di-lower alkylaminomethyl group. ) or a pharmaceutically acceptable salt thereof. (2) The following formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(I) (In the formula, Z is ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▼ or ▲There are mathematical formulas, chemical formulas, tables, etc. 4 means a hydrogen atom, a hydroxyl group, an amino group, an aminomethyl group, a lower alkylaminomethyl group, or a di-lower alkylaminomethyl group) or a pharmaceutically acceptable salt thereof as an active ingredient. Antibacterial agent. (3) A quinoline carboxylic acid derivative represented by the following formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・(II) (In the formula, R^1 represents a hydrogen atom or a lower alkyl group.) .