JPH04253982A - Optically active thiazetoquinoline-3-carboxylic acid derivative, its production and use - Google Patents

Abstract

PURPOSE:To provide the subject compound having remarkably increased antibacterial activity especially against clinical isolate, free from convulsion-inducing action caused by the combined use with anti-inflammatory agent and useful as an antibacterial agent, anti-tumor agent and therapeutic agent for AIDS. CONSTITUTION:The compound of formula I (R<1> is H or lower alkyl; R<2> is H, carboxylic acid ester residue, etc.; C atom labeled with * is asymmetric C atom having absolute configuration of R or S) and its salt, e.g. (1S,3'S)-7-(3- amino-1-pyrrolidinyl)-6-fluoro-1-methyl-4-oxo-1H,4H-[1,3]thiazeto[3,2- a]quinoline-3- carboxylic acid. The compound can be produced by reducing and dehalogenating an optically active 8-halogenothiazetoquinoline-3-carboxylic acid derivative of formula II (X is halogen) and, as necessary, hydrolyzing the product. The compound of formula II is also a new compound, which can be produced e.g. by reacting a compound of formula III (Y is X) with a compound of formula IV and halogenating the reaction product.

Description

[Detailed description of the invention]

0001

[Industrial Field of Application] The present invention is a novel optically active thiazetoquinoline-3-3 which has excellent antibacterial, antitumor and anti-AIDS virus effects and is useful as an antibacterial agent, an antitumor agent and a therapeutic agent for AIDS. This invention relates to carboxylic acid derivatives, pharmacologically acceptable salts thereof, methods for producing them, and uses thereof.

0002

[Prior Art] Compounds having the same two-dimensional structure as the compounds of the present invention are disclosed in JP-A No. 63-107990 by the following formula (I
V)

Although the compound represented by the formula [Image Omitted] is described, only the data for a mixture of diastereomers are shown, and the compound represented by Until now, no compound has been known in which all four types of diastereomers derived from two asymmetric carbon atoms originating from the nucleus and side chain are separated.

0003

[Problem to be solved by the invention] Pyridonecarboxylic acid-based synthetic antibacterial agents have made revolutionary progress since the discovery of norfloxacin, and their indications are not limited to urinary tract infections but are effective against a wide variety of infectious diseases. It has been shown that It is also known that its mechanism of action is the inhibition of DNA gyrase, a DNA stericase, and that transmission of resistance by plasmids, such as with antibiotics, does not occur.

However, in recent years, in clinical practice, the number of bacteria that are insensitive to these drugs has been increasing, and these drugs are not suitable for the treatment of chronic Pseudomonas aeruginosa infections and Gram-positive bacterial infections, which are intractable diseases. Drugs are far from satisfactory. Furthermore, among pyridonecarboxylic acid-based synthetic antibacterial agents, some compounds are known to induce convulsions when used in combination with certain anti-inflammatory agents.

[0005] For these reasons, it is difficult to say that the existing synthetic antibacterial agents are perfect drugs, and it is difficult to say that the existing synthetic antibacterial agents are perfect drugs.Therefore, there is a need for a synthetic antibacterial agent that has excellent efficacy against non-susceptible bacteria isolated from clinical practice and is highly safe. The appearance of was strongly desired.

[0006]

[Means for Solving the Problems] In researching a new pyridonecarboxylic acid-based antibacterial agent, the present inventors have discovered that it exhibits excellent antibacterial activity against not only standard bacteria but especially clinical isolates, and that it can be used in combination with anti-inflammatory agents. Research focused on finding compounds that did not cause side effects such as convulsions. As a result, a methyl group and an aminopyrrolidinyl group were simultaneously introduced at the 1st and 7th positions of the thiazetoquinoline skeleton, and diastereomers based on the asymmetric carbon atoms on the aminopyrrolidinyl groups at the 1st and 7th positions were separated. The optically active thiazetoquinoline-3-carboxylic acid derivative has dramatically enhanced antibacterial activity, especially against clinically isolated bacteria, compared to conventionally known compounds with this skeleton.
It was also found that no convulsion-inducing effect was observed when used in combination with anti-inflammatory drugs. Furthermore, it was discovered that these compounds have excellent anti-tumor activity and anti-AIDS virus activity, and the present invention was completed.

That is, the present invention provides the following general formula (I)

embedded image (wherein, R1 represents a hydrogen atom or a lower alkyl group, R2 represents a hydrogen atom, a lower alkanoyl group, a halogeno lower alkanoyl group, or a carboxylic acid ester residue,
A carbon atom marked with * represents an asymmetric carbon atom having an absolute configuration of R or S. The present invention relates to a novel optically active thiazetoquinoline-3-carboxylic acid derivative represented by the following formula, a pharmacologically acceptable salt thereof, a method for producing the same, and a use thereof.

In the general formula (I) of the present invention, the lower alkyl group represented by R1 includes, for example, a methyl group,
Examples of the lower alkanoyl group represented by R2 include ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, and tert-butyl group. Examples of the lower alkanoyl group represented by R2 include formyl group, acetyl group, and propanoyl group. , butyroyl group, trimethylacetyl group, etc., and examples of halogeno lower alkanoyl group include fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, dichloroacetyl group, trichloroacetyl group, etc., and carboxylic acid ester As a residue,
Examples include benzyloxycarbonyl group, ethoxycarbonyl group, methoxycarbonyl group, and tert-butoxycarbonyl group.

Particularly preferred compounds of the present invention include the following compounds. (1S,3'S)-7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-methyl-4-oxo-1H,
4H-[1,3]thiazeto[3,2-a]quinoline-3
-carboxylic acid (1R,3'S)-7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-methyl-4-oxo-1H,
4H-[1,3]thiazeto[3,2-a]quinoline-3
-carboxylic acid (1S,3'R)-7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-methyl-4-oxo-1H,
4H-[1,3]thiazeto[3,2-a]quinoline-3
-carboxylic acid (1R,3'R)-7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-methyl-4-oxo-1H,
4H-[1,3]thiazeto[3,2-a]quinoline-3
-Carboxylic acid (1S,3'S)-6-fluoro-1-methyl-4-oxo-7-(3-trifluoroacetylamino-1-pyrrolidinyl)-1H,4H-[1,3]thiazeto[3 ，
2-a] Ethyl quinoline-3-carboxylate (1R,3'
S)-6-fluoro-1-methyl-4-oxo-7-(
3-trifluoroacetylamino-1-pyrrolidinyl)
-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid ethyl (1S,3'R)-6-fluoro-1-methyl-4-oxo-7-(3- trifluoroacetylamino-1-pyrrolidinyl)-1H,4H
-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid ethyl (1R,3'R)-6-fluoro-1-
Methyl-4-oxo-7-(3-trifluoroacetylamino-1-pyrrolidinyl)-1H,4H-[1,3]
Ethyl thiazeto[3,2-a]quinoline-3-carboxylate (1S,3'S)-6-fluoro-1-methyl-4-
Oxo-7-(3-trifluoroacetylamino-1-
pyrrolidinyl)-1H,4H-[1,3]thiazeto[3
,2-a]quinoline-3-carboxylic acid (1R,3'S)-6-fluoro-1-methyl-4-oxo-7-(3-trifluoroacetylamino-1-pyrrolidinyl)-1H,4H- [1,3] Thiazeto [3,
2-a] Quinoline-3-carboxylic acid (1S,3'R)-6-fluoro-1-methyl-4-oxo-7-(3-trifluoroacetylamino-1-pyrrolidinyl)-1H,4H-[ 1,3] Thiazeto [3,
2-a] Quinoline-3-carboxylic acid (1R,3'R)-6-fluoro-1-methyl-4-oxo-7-(3-trifluoroacetylamino-1-pyrrolidinyl)-1H,4H-[ 1,3] Thiazeto [3,
2-a] Quinoline-3-carboxylic acid (1S,3'S)-7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-methyl-4-oxo-1H,
4H-[1,3]thiazeto[3,2-a]quinoline-3
-ethyl carboxylate (1R,3'S)-7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-methyl-4-oxo-1H,
4H-[1,3]thiazeto[3,2-a]quinoline-3
-ethyl carboxylate (1S,3'R)-7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-methyl-4-oxo-1H,
4H-[1,3]thiazeto[3,2-a]quinoline-3
-ethyl carboxylate (1R,3'R)-7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-methyl-4-oxo-1H,
4H-[1,3]thiazeto[3,2-a]quinoline-3
-ethyl carboxylate

[0010] Examples of the pharmacologically acceptable salts of the compound represented by the general formula (I) of the present invention include acid addition salts, alkali addition salts, and amino acid addition salts. , mineral acid salts such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, malic acid, methanesulfonic acid, p-toluene Sulfonic acid, mandelic acid, 10-camphorsulfonic acid, tartaric acid, benzoic acid,
Organic acid salts such as succinic acid, lactic acid, D-galacturonic acid,
Examples of alkali addition salts include inorganic alkali salts such as sodium, potassium, calcium, silver, zinc, lead, and ammonium, or ethanolamine, N,N-
Salts of organic bases such as dialkylethanolamine, and amino acid addition salts include L-alanine, L-aspartic acid, L-glutamic acid, L-cysteine, L-phenylalanine, glycine, L-arginine, and the like.

The novel optically active thiazetoquinoline-3-carboxylic acid derivative represented by the general formula (I) of the present invention can be produced by the following method.

According to the first mode of the method for producing a compound according to the present invention, the compound represented by the general formula (I) is represented by the following general formula (II).

[Image Omitted] Optically active 8-halogenothiazetoquinoline represented by (wherein R1, R2 and * represent the same meanings as above, and X represents a halogen atom)
3-carboxylic acid derivative, without solvent or in a solvent, acid,
It can be produced by dehalogenation by reducing with or without the action of a metal, alloy, or metal salt in the presence or absence of a base or inorganic salt, followed by hydrolysis if necessary.

[0013] Examples of metals used for dehalogenation in this manufacturing method include zinc, tin, iron, nickel, chromium, aluminum, copper, etc., and examples of alloys include zinc amalgam, tin amalgam, Metal amalgams such as aluminum amalgam, brass, bronze,
Examples include aluminum-nickel alloys, aluminum-lead alloys, and alloys with other metals. Examples of metal salts include ferrous chloride, cuprous chloride, stannous chloride, silver chloride, stannous sulfate, ferrous sulfate, cuprous sulfate, and the like.

The solvent used for dehalogenation in this production method may be any solvent as long as it does not inhibit the reaction, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, allyl alcohol, and furfuryl alcohol. , ethylene glycol, propylene glycol, glycerin, alcoholic solvents such as polyethylene glycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, ethylene glycol dimethyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol dimethyl ether, diethylene glycol Alcohol solvents with ether bonds such as diethyl ether, acetonitrile, N,
Aprotic polar solvents such as N-dimethylformamide, N-methyl-2-pyrrolidone, dimethylsulfoxide, hexamethylphosphoric triamide, aromatic hydrocarbon solvents such as benzene and toluene, pyridine, picoline,
Organic base solvents such as lutidine and collidine, ether solvents such as tetrahydrofuran, 1,4-dioxane, ethyl ether, and isopropyl ether, dichloromethane,
Halogenated hydrocarbon solvents such as chloroform and 1,2-dichloroethane, ester solvents such as ethyl formate, methyl acetate, ethyl acetate, and propyl acetate, n-pentane, n
Examples include hydrocarbon solvents such as -hexane, n-heptane, cyclopentane, and cyclohexane, and mixed solvents thereof, and mixed solvents with water or water-soluble organic solvents are preferred.

Examples of acids used for dehalogenation in this production method include mineral acids such as sulfuric acid, hydrochloric acid, nitric acid, hydrobromic acid, hydroiodic acid, and phosphoric acid, or acetic acid, oxalic acid, and benzoic acid. Acids, organic acids such as phthalic anhydride, p-toluenesulfonic acid, methanesulfonic acid, etc., and bases include, for example, sodium hydroxide, potassium hydroxide,
Inorganic bases such as barium hydroxide, aqueous ammonia, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, etc., or organic bases such as ethanolamine, N,N-dialkylethanolamine, etc. , ammonium chloride, sodium chloride, potassium chloride, ammonium sulfate, potassium sulfate, sodium sulfate, sodium hydrogen sulfate, potassium hydrogen sulfate, etc., and the reaction temperature ranges from ice cooling to 200°C.

[0016] Hydrolysis is carried out using an acid or an alkali by a method known per se. For acidic hydrolysis, hydrochloric acid,
Acids such as sulfuric acid and fuming sulfuric acid are used for alkaline hydrolysis, and alkalis such as sodium hydroxide and potassium hydroxide are used for alkaline hydrolysis.
Ethanol, n-butanol, sec-butanol, t
It can be used in the reaction as a solution of ert-butanol or the like or a solution of a water-containing organic solvent, and the reaction is carried out from room temperature to the heating reflux temperature of the solvent.

The optically active 8-halogenothiazetoquinoline-3-carboxylic acid derivative represented by the general formula (II), which is the starting material in this production method, is also a new compound, and is shown in the figure below (Chemical formula 10). ) is manufactured as shown in
The details are described in the reference example.

embedded image (wherein R1, R2, X and * represent the same meanings as above, and Y represents a halogen atom).

According to the second method of the method for producing a compound according to the present invention, the compound represented by the general formula (I) is an optically active 8-halogenothiazetoquinoline represented by the general formula (II). It can be synthesized by adding a catalyst to a -3-carboxylic acid derivative in a solvent in the presence or absence of an acid or a base, performing catalytic reduction to perform dehalogenation, followed by hydrolysis if necessary.

The catalyst used for the catalytic reduction in this production method is, for example, 5% palladium on carbon, 10%
% palladium on carbon, Raney nickel, platinum oxide, etc. The acids used include mineral acids such as sulfuric acid, hydrochloric acid, nitric acid, hydrobromic acid, hydroiodic acid, and phosphoric acid, and organic acids such as acetic acid, methanesulfonic acid, and oxalic acid. is, for example, an inorganic base such as sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, aqueous ammonia, or ethanolamine,
Examples include organic bases such as N,N-dialkylethanolamine and triethylamine.

The solvent used in the catalytic reduction in this production method may be any solvent as long as it does not inhibit the reaction. Examples include alcohols such as methanol, ethanol, n-propanol, isopropanol, and n-butanol, acetonitrile, and , N-dimethylformamide, N-methyl-2-pyrrolidone, aprotic polar solvents such as dimethyl sulfoxide, aromatic hydrocarbon solvents such as benzene and toluene, organic basic solvents such as pyridine, picoline, lutidine, collidine, etc. Tetrahydrofuran,
Ether solvents such as 1,4-dioxane, ethyl ether, and isopropyl ether, halogenated hydrocarbon solvents such as dichloromethane, chloroform, and 1,2-dichloroethane, and ester solvents such as ethyl formate, ethyl acetate, methyl acetate, and propyl acetate. Examples include solvents, hydrocarbon solvents such as n-pentane, n-hexane, n-heptane, cyclopentane, and cyclohexane, and mixed solvents thereof. Further, the reaction temperature is preferably from room temperature to 200°C, and the reaction pressure is preferably from normal pressure to 150 atm.

[0021] Further, hydrolysis is carried out using an acid or an alkali by a method known per se. For acidic hydrolysis, hydrochloric acid,
Acids such as sulfuric acid and fuming sulfuric acid are used for alkaline hydrolysis, and alkalis such as sodium hydroxide and potassium hydroxide are used for alkaline hydrolysis.
Ethanol, n-butanol, sec-butanol, t
It can be used in the reaction as a solution of ert-butanol or the like or a solution of a water-containing organic solvent, and the reaction is carried out from room temperature to the heating reflux temperature of the solvent.

According to the third mode of the method for producing a compound according to the present invention, the compound represented by the general formula (I) is represented by the following general formula (III).

embedded image (wherein R1, R2 and * represent the same meanings as above). The thiazetoquinoline-3-carboxylic acid derivative, which is a mixture of R and S in the absolute configuration of the carbon atom at the 1st position, is converted into a salt as necessary, and then separated by fractional recrystallization or column chromatography to obtain the necessary If so, it can be synthesized by hydrolysis.

[0023] Examples of the salts used in this production method include acid addition salts, alkali addition salts, and amino acid addition salts. Examples of acid addition salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, and nitric acid. , mineral acid salts such as sulfuric acid, phosphoric acid, or acetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, malic acid, methanesulfonic acid, p-toluenesulfonic acid, mandelic acid, 10-camphorsulfonic acid, tartaric acid, Organic acid salts such as benzoic acid, succinic acid, lactic acid, and D-galacturonic acid are examples of alkali addition salts such as;
Examples of amino acid addition salts include inorganic alkali salts such as sodium, potassium, calcium, silver, zinc, lead, and ammonium, and salts of organic bases such as ethanolamine and N,N-dialkylethanolamine. Examples include L-aspartic acid, L-glutamic acid, L-cysteine, L-phenylalanine, glycine, and L-arginine.

Solvents used for fractional recrystallization include, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, and n-butanol, acetonitrile, N,N-dimethylformamide,
Aprotic polar solvents such as N-methylformamide, N-methyl-2-pyrrolidone, dimethylsulfoxide, hexamethylphosphoric triamide, aromatic hydrocarbon solvents such as benzene and toluene, pyridine, picoline, lutidine, collidine organic base solvents such as tetrahydrofuran, 1,4-dioxane, ethyl ether, isopropyl ether, halogenated hydrocarbon solvents such as dichloromethane, chloroform, 1,2-dichloroethane, ethyl formate, ethyl acetate, Ester solvents such as methyl acetate and propyl acetate, n-pentane,
Examples include hydrocarbon solvents such as n-hexane, n-heptane, cyclopentane, and cyclohexane, water, and mixed solvents thereof.

[0025] Examples of carriers for column chromatography include silica gel and alumina. Effluent solvents used include, for example, methanol, ethanol, n-propanol, isopropanol,
Alcohol solvents such as n-butanol, aprotic polar solvents such as acetonitrile, N,N-dimethylformamide, N-methylformamide, N-methyl-2-pyrrolidone, aromatic hydrocarbon solvents such as benzene and toluene, Organic bases such as pyridine, picoline, lutidine, and collidine; ethereal solvents such as tetrahydrofuran, 1,4-dioxane, ethyl ether, and isopropyl ether;
Halogenated hydrocarbon solvents such as dichloromethane, chloroform, and 1,2-dichloroethane; ester solvents such as ethyl formate, methyl acetate, ethyl acetate, and propyl acetate;
Examples include hydrocarbon solvents such as n-pentane, n-hexane, n-heptane, cyclopentane, and cyclohexane, and water, which are used as a single solvent or a mixed solvent.

[0026] Further, hydrolysis is carried out using an acid or an alkali by a method known per se. For acidic hydrolysis, hydrochloric acid,
Acids such as sulfuric acid and fuming sulfuric acid are used for alkaline hydrolysis, and alkalis such as sodium hydroxide and potassium hydroxide are used for alkaline hydrolysis.
Ethanol, n-butanol, sec-butanol, t
It can be used in the reaction as a solution of ert-butanol or the like or a solution of a water-containing organic solvent, and the reaction is carried out from room temperature to the heating reflux temperature of the solvent. Pharmaceuticals containing the novel optically active thiazetoquinoline-3-carboxylic acid derivative represented by the general formula (I) and its pharmacologically acceptable salts produced in this way as active ingredients are usually capsuled. orally administered drugs such as tablets, fine granules, granules, powders, syrups, injections, suppositories, eye drops, etc.
It is administered as an eye ointment, ear drops, or topical preparation. These preparations can be manufactured by conventional methods by adding pharmacologically and pharmaceutically acceptable additives. That is, for oral preparations and suppositories, excipients (lactose, D-mannitol, corn starch, crystalline cellulose, etc.), disintegrants (carboxymethyl cellulose, carboxymethyl cellulose calcium, etc.), binders (hydroxypropyl cellulose, hydroxypropyl cellulose, etc.) Pharmaceutical ingredients such as methylcellulose, polyvinylpyrrolidone, etc.), lubricants (magnesium stearate, talc, etc.), coating agents (hydroxypropylmethylcellulose, sucrose, titanium oxide, etc.), and bases (polyethylene glycol, hard fat, etc.)
For injections, eye drops, and ear drops, solubilizing agents or solubilizing agents (distilled water for injection, physiological saline, propylene glycol, etc.) that can constitute an aqueous or ready-to-use dosage form;
Formulation components such as pH adjusters (inorganic or organic acids or bases), isotonic agents (salt, glucose, glycerin, etc.), stabilizers, etc., and in the case of eye ointments and external skin preparations, ointments Appropriate formulation ingredients (white petrolatum, macrogol, glycerin, cotton cloth, etc.) are used as agents, creams, and patches.

[0027] The dosage of this drug for patients to be treated depends on the patient's symptoms, but for adults, the daily dose is usually about 10 to 1000 mg for oral administration, and 1 to 500 mg for parenteral administration.
It is about g.

As an example of the excellent effects of the compounds of the present invention, the antibacterial spectra against standard bacteria and clinical isolates are shown in Tables 1 and 2. The following compounds were used as control drugs. Control drug A: Ciprofloxacin hydrochloride [The Merck Index, 11th edition, 23
15] Control drug B: 7-(3-
Amino-1-pyrrolidinyl)-6-fluoro-1-methyl-4-oxo-1H,4H-[1,3]thiazeto[3
, 2-a] Quinoline-3-carboxylic acid hydrochloride [JP-A-63-107990] The antibacterial test was performed using the method specified by the Japanese Society of Chemotherapy (Journal of the Japanese Society of Chemotherapy, 29(1), 76).
(1981)).

As is clear from Tables 1 and 2, the compound of the present invention is similar to ciprofloxacin hydrochloride (comparative drug A), which is known as a typical antibacterial agent and is already on the market, and the diastereomeric mixture of the compound of the present invention. (Comparative drug B) showed superior antibacterial activity. In particular, the compound of the present invention showed excellent antibacterial activity against clinical isolates to which control drugs have difficulty showing efficacy.

[0030]

[Table 1]

[0031]

[Table 2]

[0032]

EXAMPLES The present invention will be explained below with reference to reference examples and examples, but the present invention is not limited to the specific details of these examples.

Reference Example 1 6-Fluoro-1-methyl-4-oxo-7-((R)
-3-trifluoroacetylamino-1-pyrrolidinyl)-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate ethyl 6,7-difluoro-1-methyl-4-oxo -1H,
4H-[1,3]thiazeto[3,2-a]quinoline-3
-Ethyl carboxylate 30.0 g, (R)-3-trifluoroacetylaminopyrrolidine hydrochloride [[α]20D
+26.6° (c=1, MeOH)] 25.3g, 1
, 32.3 g of 8-diazabicyclo[5.4.0]-7-undecene and 240 m of N,N-dimethylformamide
The mixture was stirred at room temperature for 63 hours. The reaction solvent was distilled off under reduced pressure, and 500 ml of water was added to the residue. The precipitated crystals were collected by filtration and recrystallized from a mixture of N,N-dimethylformamide and ethanol to give colorless needle crystals with a melting point of 262 to 265°C.
．． Obtained 0g. NMR spectrum δ(DMSO-d6) ppm
: 1.25 (3H, t, J=7Hz), 1.81-
2.45 (2H, m), 2.04 (3H, d, J=6H
z), 3.36-4.00 (4H, m), 4.17 (2
H, q, J = 7Hz), 4.32-4.69 (1H, m
), 6.11 (1H, q, J = 6Hz), 6.31 (1
H, d, J = 7.5Hz), 7.61 (1H, d, J =
15Hz), 9.44-9.76 (1H, m)

According to the method of Reference Example 1, a compound of Reference Example 2 was obtained.

Reference Example 2 6-Fluoro-1-methyl-4-oxo-7-((S)
-3-trifluoroacetylamino-1-pyrrolidinyl)-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid ethyl (S)-3-trifluoroacetylaminopyrrolidine hydrochloride [[α]20D -28.6 °(c=1,Me
OH )] to obtain the title compound. Properties Light gray crystals (CHCl3-EtOH) Melting point 259-261°C (decomposition) NMR spectrum δ (DMSO-d6) ppm
: 1.25 (3H, t, J=7Hz), 1.87-2
．． 45 (2H, m), 2.04 (3H, d, J=6Hz
), 3.36-4.64 (5H, m), 4.17 (2H
, q, J = 7Hz), 6.12 (1H, q, J = 6Hz
), 6.33 (1H, d, J = 7.5Hz), 7.62
(1H, d, J = 15Hz), 9.47-9.73 (1
H, m)

Reference Example 3 8-chloro-6-fluoro-1-methyl-4-oxo-
7-((S)-3-trifluoroacetylamino-1-
pyrrolidinyl)-1H,4H-[1,3]thiazeto[3
,2-a] Ethyl quinoline-3-carboxylate 6-fluoro-1-methyl-4-oxo-7-((S)-3-trifluoroacetylamino-1-pyrrolidinyl)-1H,
4H-[1,3]thiazeto[3,2-a]quinoline-3
- ethyl carboxylate 3.81 g dichloromethane 150
0.72 ml suspension of sulfuryl chloride under stirring at room temperature.
ml was added dropwise and stirred for 10 minutes. The reaction solution was washed with water four times, dried, and then the solvent was distilled off. The residue was subjected to column chromatography (silica gel, chloroform:methanol = 30:
1) to obtain 2.77 g of the title compound. Recrystallized from a mixture of ethyl acetate and isopropyl ether, melting point 1.
Pale yellow crystals with a temperature of 53-156°C were obtained. IR spectrum ν (KBr) cm-1
: 1710, 1602 NMR spectrum δ(
CDCl3) ppm: 1.40 (3H, t, J
=7Hz), 1.88-2.60 (2H, m), 2.2
1, 2.22 (total 3H, each d, J=
6Hz), 3.16-4.82 (5H, m), 4.36
, 4.37 (total 3H, each q, J=7
Hz), 6.34, 6.35 (total 1H, ea
ch q, J=6Hz), 7.00-7.52 (1H,
m), 7.90, 7.97 (total 1H, eac
h d, J = 13 Hz) This compound is a mixture of diastereomers, and the mixing ratio of isomer A (retention time: 15.4 minutes) and isomer B (retention time: 17.5 minutes) is as follows. The ratio was about 53:47 under HPLC conditions. Column: SUMIPAX OA-3100 φ4.6m
m × 250 mm Mobile phase: methanol Flow rate: 0.5 ml/min Detector: Ultraviolet absorption photometer (287 nm)

Reference Example 4 8-chloro-6-fluoro-1-methyl-4-oxo-
7-((R)-3-trifluoroacetylamino-1-
pyrrolidinyl)-1H,4H-[1,3]thiazeto[3
,2-a] Ethyl quinoline-3-carboxylate 6-fluoro-1-methyl-4-oxo-7-((R)-3-trifluoroacetylamino-1-pyrrolidinyl)-1H,
4H-[1,3]thiazeto[3,2-a]quinoline-3
- ethyl carboxylate 47.3 g dichloromethane 237
ml suspension under stirring at room temperature, sulfuryl chloride 9.64
ml was added dropwise and stirred for 10 minutes. The reaction solution was washed with water four times, dried, and then the solvent was distilled off. The residue was subjected to column chromatography (silica gel, dichloromethane: ethyl acetate = 2:
1) to obtain 49.1 g of the title compound. Recrystallization from isopropanol gave pale yellow crystals with a melting point of 152-156°C. NMR spectrum δ (CDCl3) ppm:
1.38 (3H, t, J=7Hz), 2.18, 2.2
1 (total 3H, each d, J=6Hz),
1.89-2.69 (2H, m), 3.19-4.87
(5H, m), 4.33, 4.35 (total 2H
, each q, J=7Hz), 6.32, 6.34(
total 1H, each q, J=6Hz), 7.
74, 7.89 (total 1H, each d, J
=13.5Hz)

Reference Example 5 8-chloro-6-fluoro-1-methyl-4-oxo-
7-((S)-3-trifluoroacetylamino-1-
pyrrolidinyl)-1H,4H-[1,3]thiazeto[3
, 2-a] ethyl quinoline-3-carboxylate (isomer A
) is a mixture of diastereomers (isomers A and B) 8
-chloro-6-fluoro-1-methyl-4-oxo-7
-((S)-3-trifluoroacetylamino-1-pyrrolidinyl)-1H,4H-[1,3]thiazeto[3,
2-a] 129 g of ethyl quinoline-3-carboxylate was dissolved in 400 ml of isopropanol under heating, and insoluble matter was filtered off. The filtrate was cooled on ice for 45 minutes, and the precipitated crystals were collected by filtration to determine the content of isomer A. 20.3 g of tall pale yellow crystals were obtained. Furthermore, the filtrate was allowed to stand as it was, and the precipitated crystals were collected by filtration, and 93.7 g of the obtained yellow crystals were mixed with 350 ml of isopropanol.
After heating and dissolving the mixture in 1 liter of water, the mixture was cooled on ice. The precipitated crystals were collected by filtration to obtain 30.5 g of colorless crystals. Combined with the crystals obtained earlier,
Recrystallized from 350 ml of isopropanol, melting point 19
36.6 g of colorless needle crystals of isomer A were obtained at 3-194°C. IR spectrum ν (KBr) cm-1:
1712, 1672, 1602 NMR spectrum
δ (CDCl3) ppm: 1.38 (3H, t
, J=7Hz), 2.05-2.60 (2H, m), 2
．． 19 (3H, d, J=6Hz), 3.15-3.50
(2H, m), 3.80-4.15 (2H, m), 4.
34 (2H, q, J = 7Hz), 4.50-4.80 (
1H, m), 6.34 (1H, q, J=6Hz), 7.
55-7.80 (1H, m), 7.84 (1H, d, J
= 13.5Hz) Specific rotation [α] 20D -294.1° (c = 0.
1, CHCl3) This compound had a retention time of 15.4 minutes under the following HPLC conditions. Column: SUMIPAX OA-3100 φ4.6m
m × 250 mm Mobile phase: methanol Flow rate: 0.5 ml/min Detector: Ultraviolet absorption photometer (287 nm)

Reference Example 6 8-chloro-6-fluoro-1-methyl-4-oxo-
7-((S)-3-trifluoroacetylamino-1-
pyrrolidinyl)-1H,4H-[1,3]thiazeto[3
, 2-a] ethyl quinoline-3-carboxylate (isomer B
) is a mixture of diastereomers (isomers A and B) 8
-chloro-6-fluoro-1-methyl-4-oxo-7
-((S)-3-trifluoroacetylamino-1-pyrrolidinyl)-1H,4H-[1,3]thiazeto[3,
2-a] 129 g of ethyl quinoline-3-carboxylate was dissolved in 400 ml of isopropanol under heating, insoluble matter was removed, the filtrate was cooled on ice for 45 minutes, and pale yellow precipitated crystals were filtered off. Further, the filtrate was left as it was, and the precipitated crystals were collected by filtration to obtain 93.7 g of yellow crystals. Further, the filtrate was concentrated to obtain a brown viscous liquid. The previously obtained yellow crystals were dissolved in 350 ml of isopropanol by heating, and then cooled with ice. The precipitated crystals were filtered off, and the filtrate was concentrated. The residue was combined with the brown viscous liquid obtained earlier and dissolved in ethyl acetate while heating. After cooling, the precipitated crystals were filtered off, and the filtrate was concentrated. The residue was recrystallized twice from isopropanol to obtain 2.43 g of colorless needles of isomer B with a melting point of 161-164.5°C. IR spectrum ν (KBr) cm-1:
1716, 1678, 1602 NMR spectrum
δ (CDCl3) ppm: 1.39 (3H
, t, J=7Hz), 1.90-2.68 (2H, m)
, 2.22 (3H, d, J=6Hz), 3.36-3.
88 (4H, m), 4.36 (2H, q, J=7Hz)
, 4.18-4.80 (1H, m), 6.34 (1H,
q, J=6Hz), 7.12-7.44 (1H, m),
7.93 (1H, d, J = 13Hz) Specific rotation [α] 2
0D +219.1 ° (c=0.1, CHCl3)
This compound had a retention time of 17.5 minutes under the following HPLC conditions. Column: SUMIPAX OA-3100 φ4.6m
m × 250 mm Mobile phase: methanol Flow rate: 0.5 ml/min Detector: Ultraviolet absorption photometer (287 nm)

Reference Example 7 8-chloro-6-fluoro-1-methyl-4-oxo-
7-((R)-3-trifluoroacetylamino-1-
pyrrolidinyl)-1H,4H-[1,3]thiazeto[3
, 2-a] ethyl quinoline-3-carboxylate (isomer A
) is a mixture of diastereomers (isomers A and B) 8
-chloro-6-fluoro-1-methyl-4-oxo-7
-((R)-3-trifluoroacetylamino-1-pyrrolidinyl)-1H,4H-[1,3]thiazeto[3,
2-a] 30.2 g of ethyl quinoline-3-carboxylate was dissolved in ethyl acetate under heating, and after cooling, the precipitated crystals were filtered off. The filtrate was concentrated and the residue was recrystallized three times from isopropanol to obtain 6.91 g of colorless needles of isomer A with a melting point of 192-193.5°C. IR spectrum ν (KBr) cm-1:
1712, 1672, 1602 NMR spectrum
δ (CDCl3) ppm: 1.39 (3H
, t, J=7Hz), 1.92-2.60 (2H, m)
, 2.20 (3H, d, J=6Hz), 3.13-3.
60 (2H, m), 3.72-4.16 (2H, m),
4.35 (2H, q, J=7Hz), 4.48-4.8
0 (1H, m), 6.35 (1H, q, J=6Hz),
7.48-7.76 (1H, m), 7.86 (1H, d
, J=13Hz) Specific rotation [α] 20D + 293.7° (c=0.
1, CHCl3) This compound had a retention time of 17.5 minutes under the following HPLC conditions. Column: SUMIPAX OA-3100 φ4.6m
m × 250 mm Mobile phase: methanol Flow rate: 0.5 ml/min Detector: Ultraviolet absorption photometer (287 nm)

Reference Example 8 8-chloro-6-fluoro-1-methyl-4-oxo-
7-((R)-3-trifluoroacetylamino-1-
pyrrolidinyl)-1H,4H-[1,3]thiazeto[3
, 2-a] ethyl quinoline-3-carboxylate (isomer B
) is a mixture of diastereomers (isomers A and B) 8
-chloro-6-fluoro-1-methyl-4-oxo-7
-((R)-3-trifluoroacetylamino-1-pyrrolidinyl)-1H,4H-[1,3]thiazeto[3,
2-a] 45.5 g of ethyl quinoline-3-carboxylate was dissolved in ethyl acetate under heating, and after cooling, the precipitated crystals were collected by filtration. The obtained crystals were recrystallized three times from isopropanol to obtain 8.70 g of colorless needle crystals of isomer B with a melting point of 161-165°C.
I got it. IR spectrum ν (KBr) cm-1
: 1716, 1676, 1604 NMR spectrum δ (CDCl3) ppm
: 1.39 (3H, t, J=7Hz), 1.81-2
．． 70 (2H, m), 2.22 (3H, d, J = 6Hz
), 3.35-3.94 (4H, m), 4.36 (2H
, q, J=7Hz), 4.19-4.81 (1H, m)
, 6.34 (1H, q, J=6Hz), 7.18-7.
43 (1H, m), 7.92 (1H, d, J = 13Hz
) Specific optical rotation [α] 20D -213.2 ° (c=0
．． 1, CHCl3) This compound had a retention time of 15.4 minutes under the following HPLC conditions. Column: SUMIPAX OA-3100 φ4.6m
m × 250 mm Mobile phase: methanol Flow rate: 0.5 ml/min Detector: Ultraviolet absorption photometer (287 nm)

Example 1 6-Fluoro-1-methyl-4-oxo-7-((R)
-3-trifluoroacetylamino-1-pyrrolidinyl)-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid ethyl (isomer B) 8 obtained in Reference Example 8 -chloro-6-fluoro-1-methyl-4-
Oxo-7-((R)-3-trifluoroacetylamino-1-pyrrolidinyl)-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate ethyl
Isomer B, [α]20D −213.2°, (c=0.
1, CHCl3) ] 3.00g, zinc powder 1.14g,
Ammonium chloride 1.74g, 1,4-dioxane 20
After stirring a mixture of ml and 20 ml of water at 60°C for 30 minutes, 1.14 g of zinc powder and 1 ml of ammonium chloride were added.
．． 74 g was added thereto, and the mixture was heated and stirred at the same temperature for 30 minutes. The reaction solution was stirred under ice cooling, and the solid was collected by filtration and washed successively with ethanol and ether. A methylene chloride-methanol mixture was added to the solid, and the zinc dust was filtered off, and the filtrate was concentrated under reduced pressure. Methanol and isopropyl ether were added to the residual crystals, the crystals were collected by filtration, and recrystallized from acetonitrile to obtain 1.00 g of colorless needle crystals with a melting point of 263-266°C (decomposed). IR spectrum ν (KBr) cm-1
: 1710, 1674, 1634, 1604 NMR spectrum δ (DMSO-d6) pp
m: 1.25 (3H, t, J=7Hz), 1.95
-2.35 (2H, m), 2.04 (3H, d, J=6
Hz), 3.45-3.87 (4H, m), 4.17 (
2H, q, J = 7Hz), 4.41-4.55 (1H,
m), 6.13 (1H, q, J = 6Hz), 6.32 (
1H, d, J = 7.5Hz), 7.63 (1H, d, J
= 15Hz), 9.55-9.65 (1H, br) MS spectrum m/z: 473 (M + ) Specific optical rotation [α] 20D -97.1° (c = 0.1, DMF
) Elemental analysis value C20H19F4 N3 O4 S theoretical value C, 50.74; H, 4.04; N
, 8.88 experimental value C, 50.57; H,
4.03; N, 8.75

Compounds of Examples 2 to 4 were obtained according to the method of Example 1.

Example 2 6-Fluoro-1-methyl-4-oxo-7-((R)
-3-trifluoroacetylamino-1-pyrrolidinyl)-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid ethyl (isomer A) 8 obtained in Reference Example 7 -chloro-6-fluoro-1-methyl-4-
Oxo-7-((R)-3-trifluoroacetylamino-1-pyrrolidinyl)-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate ethyl
Isomer A, [α]20D +293.7°, (c=0.
1, CHCl3)] to obtain the title compound. Properties Colorless needle crystals (CH3CN) Melting point 258
~260℃ (decomposition) IR spectrum ν (KBr) cm-1
: 1716, 1670, 1634, 1602 NMR spectrum δ (DMSO-d6) pp
m: 1.25 (3H, t, J=7Hz), 1.99
-2.30 (2H, m), 2.04 (3H, d, J=6
Hz), 3.48-3.84 (4H, m), 4.17 (
2H, q, J = 7Hz), 4.42-4.53 (1H,
m), 6.12 (1H, q, J = 6Hz), 6.34 (
1H, d, J = 7.5Hz), 7.63 (1H, d, J
= 15Hz), 9.59-9.61 (1H, br) MS
Spectrum m/z: 473 (M + ) Specific rotation [α] 20D +84.8° (c=0.1, DMF
) Elemental analysis value C20H19F4 N3 O4 S theoretical value C, 50.74; H, 4.04; N
, 8.88 experimental value C, 50.43; H,
4.01; N, 8.77

Example 3 6-fluoro-1-methyl-4-oxo-7-((S)
-3-trifluoroacetylamino-1-pyrrolidinyl)-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid ethyl (isomer A) 8 obtained in Reference Example 5 -chloro-6-fluoro-1-methyl-4-
Oxo-7-((S)-3-trifluoroacetylamino-1-pyrrolidinyl)-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate ethyl
Isomer A, [α]20D -294.1°, (c=0.
1, CHCl3)] to obtain the title compound. Properties Colorless needle crystals (CH3CN) Melting point 255
~260℃ (decomposition) IR spectrum ν (KBr) cm-1
: 1720, 1672, 1634, 1602 NMR spectrum δ (DMSO-d6) pp
m: 1.25 (3H, t, J=7Hz), 1.95
-2.31 (2H, m), 2.04 (3H, d, J=6
Hz), 3.45-3.88 (4H, m), 4.17 (
2H, q, J=7Hz), 4.39-4.56 (1H,
m), 6.12 (1H, q, J = 6Hz), 6.33 (
1H, d, J = 7.5Hz), 7.62 (1H, d, J
= 15Hz), 9.55-9.67 (1H, br) MS spectrum m/z: 473 (M + ) Specific optical rotation [α] 20D -87.0° (c = 0.1, D
MF) Elemental analysis value C20H19F4 N3 O4
S theoretical value C, 50.74; H, 4.04;
N, 8.88 experimental value C, 50.69; H
, 3.96; N, 8.63

Example 4 6-Fluoro-1-methyl-4-oxo-7-((S)
-3-trifluoroacetylamino-1-pyrrolidinyl)-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid ethyl (isomer B) 8 obtained in Reference Example 6 -chloro-6-fluoro-1-methyl-4-
Oxo-7-((S)-3-trifluoroacetylamino-1-pyrrolidinyl)-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate ethyl
Isomer B, [α]20D +219.1°, (c=0.
1, CHCl3)] to obtain the title compound. Properties Colorless needle crystals (CH3CN) Melting point 259
~262℃ (decomposed) IR spectrum ν (KBr) cm-1
: 1712, 1674, 1634, 1606 NMR spectrum δ (DMSO-d6) pp
m: 1.25 (3H, t, J=7Hz), 1.95
-2.32 (2H, m), 2.04 (3H, d, J=6
Hz), 3.45-3.88 (4H, m), 4.17 (
2H, q, J=7Hz), 4.41-4.56 (1H,
m), 6.13 (1H, q, J = 6Hz), 6.34 (
1H, d, J = 7.5Hz), 7.63 (1H, d, J
= 15Hz), 9.57-9.68 (1H, br) MS spectrum m/z: 473 (M + ) Specific optical rotation [α] 20D +94.4° (c = 0.1, D
MF) Elemental analysis value C20H19F4 N3 O4
S theoretical value C, 50.74; H, 4.04;
N, 8.88 experimental value C, 50.70; H
, 3.92; N, 8.70

Example 5 7-((R)-3-amino-1-pyrrolidinyl)-6-
Fluoro-1-methyl-4-oxo-1H,4H-[1
,3]thiazeto[3,2-a]quinoline-3-carboxylic acid (isomer B) 6-fluoro-1-methyl-4-oxo-7-((R)-3- Ethyl trifluoroacetylamino-1-pyrrolidinyl)-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate [isomer B, [α]20D - 97.1°, ( c=0.1
, DMF)] 0.85g, potassium hydroxide 0.76g
A mixture of 5 ml of tert-butanol and 5 ml of water was heated and stirred at 60° C. for 3 hours. The reaction solution was stirred on ice for 10 minutes.
% hydrochloric acid solution was added to adjust the pH to 8, and the precipitated crystals were collected by filtration, followed by preparation of p-toluenesulfonate according to a conventional method. Recrystallization from methanol gave 0.45 g of colorless needles with a melting point of 215-220°C (decomposed). IR spectrum ν (KBr) cm-1
: 1692, 1634 NMR spectrum δ
(DMSO-d6) ppm: 2.00-2.43
(2H, m), 2.11 (3H, d, J=6Hz), 2
．． 27 (3H, s), 3.52-4.03 (5H, m)
, 6.37 (1H, d, J = 6Hz), 6.47 (1H
, d, J=7.5Hz), 7.08(2H, d, J=8
Hz), 7.48 (2H, d, J=8Hz), 7.74
(1H, d, J=15Hz), 8.06 (2H, br)
MS spectrum m/z: 349 (M + ) Specific optical rotation [α] 20D -61.4° (c=0.1, D
MF) Elemental analysis value C16H16FN3 O3 S.
C7 H8 O3 S・H2 O Theoretical value C, 51.20; H, 4.86;
N, 7.79 Experimental value C, 51.22; H,
4.74; N, 7.38

Compounds of Examples 6 to 8 were obtained according to the method of Example 5.

Example 6 7-((R)-3-amino-1-pyrrolidinyl)-6-
Fluoro-1-methyl-4-oxo-1H,4H-[1
,3]thiazeto[3,2-a]quinoline-3-carboxylic acid (isomer A) 6-fluoro-1-methyl-4-oxo-7-((R)-3- Ethyl trifluoroacetylamino-1-pyrrolidinyl)-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate [isomer A, [α]20D + 84.8°, ( c=0.1
, DMF)] to obtain p-toluenesulfonate of the title compound. Properties Colorless crystals (EtOH-H2O) Melting point 21
8-222℃ (decomposed) IR spectrum ν (KBr) cm-1
: 1690, 1634 NMR spectrum δ
(DMSO-d6) ppm: 2.00-2.43
(2H, m), 2.10 (3H, d, J=6Hz), 2
．． 28 (3H, s), 3.52-4.03 (5H, m)
, 6.36 (1H, d, J = 6Hz), 6.48 (1H
, q, J=7.5Hz), 7.09(2H, d, J=8
Hz), 7.48 (2H, d, J=8Hz), 7.75
(1H, q, J=15Hz), 8.05 (2H, br)
MS spectrum m/z: 349 (M + ) Specific optical rotation [α] 20D +90.5° (c=0.1, D
MF) Elemental analysis value C16H16FN3 O3 S.
C7 H8 O3 S・H2 O Theoretical value C, 51.20; H, 4.86;
N, 7.79 Experimental value C, 50.97; H,
4.77; N, 7.67

Example 7 7-((S)-3-amino-1-pyrrolidinyl)-6-
Fluoro-1-methyl-4-oxo-1H,4H-[1
,3]thiazeto[3,2-a]quinoline-3-carboxylic acid (isomer A) 6-fluoro-1-methyl-4-oxo-7-((S)-3- Ethyl trifluoroacetylamino-1-pyrrolidinyl)-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate [isomer A, [α]20D - 87.0°, ( c=0.1
, DMF)] to obtain p-toluenesulfonate of the title compound. Properties Colorless needle crystals (EtOH-H2O) Melting point 2
21-225℃ (decomposition) IR spectrum ν (KBr) cm-1
: 1696, 1634 NMR spectrum δ
(DMSO-d6) ppm: 2.00-2.43
(2H, m), 2.11 (3H, d, J=6Hz), 2
．． 28 (3H, s), 3.52-4.03 (5H, m)
, 6.36 (1H, q, J = 6Hz), 6.48 (1H
, d, J=7.5Hz), 7.09(2H, d, J=8
Hz), 7.48 (2H, d, J=8Hz), 7.75
(1H, d, J = 14.5Hz), 8.03 (2H, b
r) MS spectrum m/z: 349 (M + ) Specific rotation [α] 20D -94.3° (c = 0.1, D
MF) Elemental analysis value C16H16FN3 O3 S.
C7 H8 O3 S・1/2H2 O Theoretical value C, 52.06; H, 4.75;
N, 7.92 experimental value C, 52.01; H,
4.52; N, 7.84

Hydrochloride properties Pale brown crystals (MeOH-Et2O-H2O)
Melting point 300℃ or higher IR spectrum ν (KBr) cm-1
: 1684, 1634 NMR spectrum δ
(DMSO-d6) ppm: 1.95-2.45
(5H, m), 3.43-4.13 (5H, m), 6.
39 (1H, m), 6.46 (1H, d, J = 6.5H
z), 7.68 (1H, d, J = 14.5Hz) MS spectrum m/z: 349 (M + ) Specific optical rotation [α] 20D -157 ° (c = 0.1, H2O)

Hydrobromide Properties Pale yellow crystals (EtOH-H2O) Melting point 3
IR spectrum above 00℃ ν (KBr) cm-1
: 1676, 1634 NMR spectrum δ
(DMSO-d6) ppm: 1.98-2.43
(2H, m), 2.11 (3H, d, J=6Hz), 3
．． 53-4.07 (5H, m), 6.39 (1H, q,
J=6Hz), 6.50 (1H, d, J=7.5Hz)
, 7.74 (1H, d, J = 14.5 Hz) MS spectrum m/z: 349 (M + ) Specific optical rotation [α
]20D -111 ° (c=0.1, DMF) Elemental analysis value C16H16FN3 O3 S・HBr・1
/4H2O Theoretical value C, 44.20; H, 4.06;
N, 9.66 experimental value C, 44.50; H,
3.85; N, 9.38

Methanesulfonate properties Pale yellow needle crystals (EtOH-H2O) Melting point
274-276℃ (decomposition) IR spectrum ν (KBr) cm-1
: 1684, 1634 NMR spectrum δ
(DMSO-d6) ppm: 2.02-2.45
(2H, m), 2.11 (3H, d, J=6Hz), 2
．． 35 (3H, s), 3.55-4.07 (5H, m)
, 6.37 (1H, q, J = 6Hz), 6.48 (1H
, d, J=7.5Hz), 7.73(1H, d, J=1
5Hz) MS spectrum m/z: 349 (M + ) Specific optical rotation [α] 20D -91.7° (c = 0.1, D
MF) Elemental analysis value C16H16FN3 O3 S.
CH4 O3 S・H2 O Theoretical value C, 44.05; H, 4.78;
N, 9.07 experimental value C, 44.19; H,
4.50; N, 8.97

L-Glutamate Properties Pale yellow crystals (EtOH-H2O) Melting point 2
02-203℃ IR spectrum ν (KBr) cm-1
: 1634,1602 NMR spectrum δ (
DMSO-d6) ppm: 1.73-2.27 (
2H, m), 1.88 (2H, m), 2.10 (3H,
d, J=6.5Hz), 2.33 (2H, t, J=7.
5Hz), 3.27 (1H, t, J=7Hz), 3.3
8 (1H, m), 3.48-3.83 (4H, m), 6
．． 36 (1H, m), 6.39 (1H, d, J = 7.5
Hz), 7.68 (1H, d, J = 15Hz) MS spectrum m/z: 349 (M + ) Specific optical rotation [
α]20D -120 ° (c=0.1, H2O) Elemental analysis value C16H16FN3 O3 S・C5 H
9 NO4 ・3/2H2 O Theoretical value C, 48.18; H, 5.39;
N, 10.70 experimental value C, 48.42; H
, 5.17; N, 10.89

Example 8 7-((S)-3-amino-1-pyrrolidinyl)-6-
Fluoro-1-methyl-4-oxo-1H,4H-[1
,3]thiazeto[3,2-a]quinoline-3-carboxylic acid (isomer B) 6-fluoro-1-methyl-4-oxo-7-((S)-3- Ethyl trifluoroacetylamino-1-pyrrolidinyl)-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate [isomer B, [α]20D + 94.4°, ( c=0.1
, DMF)] to obtain p-toluenesulfonate of the title compound. Properties Light brown crystals (EtOH-H2O) Melting point 2
12-217℃ (decomposition) IR spectrum ν (KBr) cm-1
: 1694, 1634 NMR spectrum δ
(DMSO-d6) ppm: 2.00-2.43
(2H, m), 2.10 (3H, d, J=6Hz), 2
．． 28 (3H, s), 3.52-4.03 (5H, m)
, 6.37 (1H, q, J = 6Hz), 6.48 (1H
, d, J=7.5Hz), 7.09(2H, d, J=8
Hz), 7.48 (2H, d, J=8Hz), 7.75
(1H, d, J=14.5Hz) MS spectrum m
/z: 349 (M + ) Specific optical rotation [α] 20D
+60.3° (c=0.1, DMF) elemental analysis value
C16H16FN3 O3 S・C7 H8 O3 S
・H2O theoretical value C, 51.20; H, 4.86;
N, 7.79 Experimental value C, 51.46; H,
4.62; N, 7.76

Example 9 6-Fluoro-1-methyl-4-oxo-7-((S)
-3-trifluoroacetylamino-1-pyrrolidinyl)-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid ethyl (isomer A) Diadia obtained in Reference Example 2 6-Fluoro-1-methyl-4-oxo-7-(
(S)-3-trifluoroacetylamino-1-pyrrolidinyl)-1H,4H-[1,3]thiazeto[3,2-
a] 100.0 g of ethyl quinoline-3-carboxylate was
, N-dimethylformamide (367 ml) under heating, and insoluble matter was filtered off. 2,600 ml of water was added to the filtrate, and the precipitated crystals were collected by filtration to obtain 46.3 g of colorless crystals. Furthermore, the obtained crystals were recrystallized three times from dimethyl sulfoxide to obtain 11.0 g of colorless needle crystals. Finally, recrystallization from acetonitrile gave colorless needles of the title compound. The compound obtained here matched the compound of Example 3 in melting point, IR and NMR spectra, and specific optical rotation.

Formulation Example 1 Capsules are manufactured according to the following formulation. Compound of the present invention
0.25mg
lactose
Appropriate amount
corn starch
45mg
Magnesium stearate
1mg ━
━━━━━━━━━━━━━━━━━━━━━━

130mg
The above ingredients are mixed in a conventional manner and filled into hard capsules.

Formulation Example 2 Tablets are manufactured according to the following formulation. Compound of the present invention
0.25mg
lactose
suitable
quantity corn starch
30mg
carboxymethylcellulose calcium
10mg polyvinylpyrrolidone
3mg magnesium stearate
1mg ━━━━━━━━━━━━━━
━━━━━━━━━━━━━

130mg

Formulation Example 3 Granules are manufactured according to the following formulation. Compound of the present invention
0.5mg
lactose
Appropriate amount
Hydroxypropyl starch 200mg
Hydroxypropylcellulose
20mg talc

5mg ━━━━━
━━━━━━━━━━━━━━━━━

1000mg

006
0 Formulation Example 4 A dry syrup is manufactured according to the following formulation. Compound of the present invention
0.5mg
white sugar
Appropriate amount
━━━━━━━━━━━━
━━━━━━━━━━

1000mg

Formulation Example 5 An injection is manufactured according to the following formulation. Compound of the present invention
2.5mg
sodium chloride
40mg
distilled water for injection
Appropriate amount
━━━━━━━━━━━━━━━━━━━
━━━

5ml

Formulation Example 6 Suppositories are manufactured according to the following formulation. Compound of the present invention
0.25mg
hard fat
1299.75mg
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1300m
g

[0063]

Effect of the invention: The above general formula (I) produced in this way
) Novel optically active thiazetoquinoline-3-
Carboxylic acid derivatives and pharmacologically acceptable salts thereof are
It has a wide range of antibacterial effects against Gram-positive bacteria and Gram-negative bacteria, as well as antitumor and anti-AIDS virus effects, making it extremely useful as a medicine.

Claims (4)

[Claims] Claim 1: The following general formula (I) [Formula 1] (wherein, R1 represents a hydrogen atom or a lower alkyl group, and R2 represents a hydrogen atom, a lower alkanoyl group, a halogeno-lower alkanoyl group, or a carboxylic acid ester residue) represents,
A carbon atom marked with * represents an asymmetric carbon atom having an absolute configuration of R or S. ) An optically active thiazetoquinoline-3-carboxylic acid derivative and a pharmacologically acceptable salt thereof. Claim 2: The following general formula (II) [Formula 2] (wherein, R1 represents a hydrogen atom or a lower alkyl group, and R2 represents a hydrogen atom, a lower alkanoyl group, a halogeno-lower alkanoyl group, or a carboxylic acid ester residue) represents,
X represents a halogen atom, and a carbon atom marked with an * represents an asymmetric carbon atom having an absolute configuration of R or S. ) is dehalogenated by reducing the optically active 8-halogenothiazetoquinoline-3-carboxylic acid derivative, and then hydrolyzed if necessary, according to the following general formula (I) [Formula 3] A method for producing an optically active thiazetoquinoline-3-carboxylic acid derivative represented by the formula (wherein R1, R2 and * have the same meanings as above) and a pharmacologically acceptable salt thereof. Claim 3: The following general formula (III) [Formula 4] (wherein, R1 represents a hydrogen atom or a lower alkyl group, and R2 represents a hydrogen atom, a lower alkanoyl group, a halogeno-lower alkanoyl group, or a carboxylic acid ester residue) represents,
A carbon atom marked with * represents an asymmetric carbon atom having an absolute configuration of R or S. ) The thiazetoquinoline-3-carboxylic acid derivative, which is a mixture of R and S in the absolute configuration of the carbon atom at the 1st position, is converted into a salt as necessary, and then separated by fractional recrystallization or column chromatography, An optically active thiazetoquinoline-3 represented by the following general formula (I) (wherein R1, R2 and * represent the same meanings as above), which is hydrolyzed if necessary. - A method for producing a carboxylic acid derivative and a pharmacologically acceptable salt thereof. Claim 4: The following general formula (I): (wherein, R1 represents a hydrogen atom or a lower alkyl group, and R2 represents a hydrogen atom, a lower alkanoyl group, a halogeno-lower alkanoyl group, or a carboxylic acid ester residue) represents,
A carbon atom marked with * represents an asymmetric carbon atom having an absolute configuration of R or S. ) A synthetic antibacterial agent containing as an active ingredient an optically active thiazetoquinoline-3-carboxylic acid derivative and a pharmacologically acceptable salt thereof.