WO1990006305A1

WO1990006305A1 - Quinolonecarboxylic acid derivatives, process for their preparation and medicinal composition containing same

Info

Publication number: WO1990006305A1
Application number: PCT/JP1989/001217
Authority: WO
Inventors: Jun-Ichi Matsumoto; Akira Minamida; Tohru Hirose; Junji Nakano; Shinichi Nakamura
Original assignee: Dainippon Pharmaceutical Co., Ltd.
Priority date: 1988-12-09
Filing date: 1989-12-05
Publication date: 1990-06-14
Also published as: AU4638889A; CA2005015A1

Abstract

1-Cyclopropyl-6-fluoro-8-methoxy-5-methyl-7-(3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and salts thereof, a process for their preparation, and a medicinal composition containing same are disclosed. The compound of the present invention and salts thereof have excellent properties as quinolone antibacterial agents and are useful for prophylaxis and treatment of infectious diseases of warm-blooded animals induced by bacteria.

Description

Specification Quinolone carboxylate derivative, method for producing the same, and pharmaceutical composition containing the same

Technical field

In the present invention, at the 1,5,6 », 7,8 positions, respectively, the cycle-open-provision group, the methyl group, the fluorine atom, and the 3,5-dimethyl — A new quinoline carcinoma that has a 1-biperazinyl group and a methoxy group, and has the characteristic of being affected as a quinolone antibacterial agent. The present invention relates to a rubic acid derivative, a method for producing the same, and a pharmaceutical composition containing the same.

Background of technology

The compound of the present invention is included in the Patent Application for Patent Cooperation Agreement WO 89/06649, which was published on July 27, 1989, after the date of the sovereignty claim of the present application, published on July 27, 1989. General formulas, including, are disclosed. However, for the 8-methoxy-5-methylquinololoncarbonic acid derivative, the names of a few compounds are described. A

European Patent Application Disclosure 700 276700, Ρ 287951 and 319 319906 disclose a variety of 5-methylquinolone carbonate derivatives. . However, these compounds do not have a methoxy group at the 8 position. European Patent Application Publications EP 230295 and EP 241206 disclose a variety of 8-methoxyquinoline carboxylic acid derivatives. However, these compounds do not have a methyl group at the 5-position.

In recent years, as quinolone antibacterial agents have become more and more popular, they have been frequently used together with these agents. Drug interactions with other drugs, such as carcinogens, have been problematic. C Japanese J. Phar aaco log, 43 (Supp 1.), 60P (1987); Clinical Pharaacokinetics, 15, 194 (1988) 3 ₀ or, in general onboard b emission antibacterial agents because solubility you pair water had been small, actually Note Ysaye and also that have been found have use in the Is extremely small. Disclosure of the invention

This invention is based on the following formula

Quinolonic carboxylic acid derivative represented by the following formula: 1-cyclolobule 1-6-fluoro8-methoxy-5 Chill-7-(¾ 5-dimethyl-1-vinyl)-1,

• 4-dihydro-4-oxoquinoline-3-carboxylic acid and its pharmaceutically acceptable clay, its manufacturing method, and its It is intended to provide a pharmaceutical composition containing the same.

Pharmaceutically acceptable salts of the compounds of the present invention include, for example, salts with inorganic acids such as hydrochloric acid, phosphoric acid, and the like; acetic acid, lactic acid, and oxalic acid. Salts with organic acids such as succinic acid, methansulphonic acid, toluenesulphonic acid, maleic acid, malonic acid, gluconic acid; A salt with an acidic amic acid such as aspartic acid or glutamic acid; or a sodium, potassium or potassium compound of the formula (I); Metal salts such as calcium, magnesium, zinc, zinc, etc .; dimethinoleamine, triethylamine, dicyclohexylamine And salts with an organic salt such as benzene and benzylamine; and salts with a basic amino acid such as lysine and arginine.

The compounds of the present invention can exist as hydrates. Therefore, such a form is naturally included in the compound of the present invention, and the compound of the present invention has a 7-position virazine ring. Since there are two asymmetric carbon atoms above, there are optical isomers and cubic isomers based on these, and these areomers that can exist. These compounds are also included in the compounds of the present invention.

Next, the production method of the compound of the present invention will be described.

(a) The compound of the present invention has the following formula:

(Π)

(In the formula, X 1 represents a halogen atom.)

Or a lower alkyl ester of the compound represented by

2> 6-Dimethylbiperazine (Π) is reacted with a lower alkyl ester, and when it is obtained, it is hydrolyzed. It can be manufactured more.

Examples of the halogen atom include a fluorine atom, a chlorine atom, and a bromine atom. The lower alkyl includes, for example, methyl, ethyl, probiol, -isoprovinol, petiru, t-butyl, pentyl and the like. Be raised.

This reaction is carried out by reacting the raw material compound (Π) or its lower alkyl ester with the starting material (m) in an inert solvent at 10 to 180 minutes. By stirring the mixture for 10 minutes to 24 hours. Examples of the inert solvent include alcohols such as ethanol, dioxane, tetrahydrofuran, and 1,2-dimethyol. Ethers such as shetane, aromatic hydrocarbons such as benzene, toluene and xylene, and acetonitrile dimethyl methyl Examples include muamid, dimethylsulfoxyd, viridine, and water.

In this reaction, the starting compound (m) is used in the presence of an acid acceptor in an equivalent amount or an excess amount relative to the starting compound (π) or the lower alkyl ester. Although it is common to carry out the reaction, the raw material compound (BI) may be used in excess to serve as the acid acceptor, and the acid acceptor may be used as the acid acceptor. , For example, hydroxylation Hydride such as sodium and potassium hydroxide, sodium carbonate, calcium carbonate and other sodium salts, sodium bicarbonate such as sodium bicarbonate, etc. Bicarbonate, Triethylamine, Diisoprovirethylamine, 1,8-Diazavincro [5,4.0] Organic bases, such as N-I7 (DBU) and pyridine.

The raw material compound (in) used in this reaction is used in a protected form, and after the reaction is completed, the protecting group may be removed by an ordinary law.

The protecting group may be one that can be removed without destroying the structure of the compound of the invention formed by the reaction. In any case, the preservation of amino groups in the chemical field of peptides, amino sugars, nucleoacids, or ^ -lactam compounds. Normally used protecting groups are used.

The removal of the amino protecting group is carried out by solvent decomposition (including hydrothermal decomposition) or hydrogen decomposition depending on the nature of the group. Protecting groups that can be removed by dissolution of the solvent include acyl groups such as holmil, acetyl, and trifluoroacetyl. Toxicbonyl, t-butoxylbonil, benzyloxylbonyl, P-methodoxyl benzyloxyl Nil, β- (ρ-toluenesulfonyl) substituted or non-replaced alkoxycarbonyl base, such as ethoxyquinboninole Lithyl group; Trimethylsilyl group; 0-Nitrofurylsulfenyl group; Diphenylmethylphosphine group; Tetrahi Drobilanil groups are mentioned as specific examples.

This solvolysis reaction is carried out in the presence or absence of a catalyst such as an acid or a base at 0 to 150 in the solvent.

Examples of the acid include an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like; drusic acid, trifluoric drunk acid, formic acid, and toluene sulfonic acid And organic acids such as shun; and lysic acids such as boron tribromide and aluminum chloride. Examples of the salt group include: hydroxides such as sodium hydroxide and barium hydroxide; carbonates such as sodium carbonate and carbonated carbonate; Alkoxides such as sodium methoxide and sodium ethoxide; sodium acetate and the like. Water is usually used as a solvent, but depending on the nature of the compound, for example, ethanol, dioxane, ethyl alcohol, etc. Solvents such as dimethylene, benzene, acetic acid, etc., or a mixed solvent of these solvents and water are used.

Protecting groups that can be removed by hydrogenolysis include, but are not limited to, benzyl, trityl, and benzyloxymethyl. Methyl group replaced with benzyl or benzyloxy, benzyloxy carbonyl, P-methoxy benzene carbonyl, etc. An example is an arylmethoxycarbonyl group such as nil.

This hydrogenolysis reaction depends on the nature of the protecting group. But in an inert solvent at 10 to 60'C, treated with a stream of hydrogen in the presence of a catalyst such as platinum, palladium, and lanthanum.

(Contacting source) or treated with liquid sodium in liquid ammonia for 50 to 120 minutes, or in acetic acid or In alcohol such as methanol, it is carried out by treating with metal such as zinc. Solvents in the contact reduction reaction include, for example, ethylene glycol, methyl ether, dioxane, and dimethyl methyl. Examples include muamid, ethanol, ethyl acetate, and acetic acid.

The raw material compound (Π) or its lower alkyl ester is manufactured by the method described in Reference Example 1 or a method analogous thereto. sell .

(b) The compound of the present invention also has the following general formula:

(In the formula, X 2 means a halogen atom, and W means a fluorine atom or an acyloxy group.)

Reacting a boron chelate compound represented by the formula with 2 »6-dimethylbiperazine (ΙΠ) to obtain a general formula JP89 / 01217

-8-

(Where W is the same as above.)

The compound can be produced by dissolving the compound in the following step.

The reaction between the raw material compound (Π ') and the raw material compound (き) can be carried out under the same conditions as described in the above-mentioned method (a).

The decomposition of the compound (I ') is carried out by treating the compound (I') with an acid or a base in a solvent. Examples of the acid include, for example, hydrochloric acid, sulfuric acid, and transsulfonic acid, and examples of the base include, for example, sodium hydroxide, potassium hydroxide, and the like. , Trietry games, etc. are listed. The solvent is not particularly limited, but water or a hydrated solvent is preferred. The reaction temperature is between 10 and 150 * C.

The raw material compound (m) used in this reaction shall be used in a protected form, as described in method (a), and shall always be used after completion of the reaction. You may remove the protecting group by law.

The raw material compound (Π ') can be manufactured by the method described in Reference Example 2 or a method analogous thereto.

(c) The compound of the invention also has the general formula T JP89 / 01217

(In the formula, X ₃ means a halogen atom.)

The compound can be manufactured by reacting a metal compound or a lower alkyl estenolate represented by the above formula with methanol.

In this reaction, the raw material compound (IV) or its lower phenolic ester and methanol are converted to 0 to: 150 in the presence of a salt group in the solvent. This can be achieved by stirring at 'C for 1 to 48 hours. Solvents include, for example, alcohols, acetonitril, dioxan, dimethylaminoamide, dimethinoles and amides. Examples of the base include hydrogenated anorecalides, alkali metal alkoxides, and the like. The metal is used as a solvent to dissolve the metal alloy (eg, sodium), which is then dissolved in the raw material halogenated compound (IV ) Alternatively, it is convenient to react the lower alkyl ester in a sealed tube.

The raw material compound (IV) or its lower alkyl ester used in this reaction is the same as described in method (a). May be used in a protected form, and after completion of the reaction, the protecting group may be removed by ordinary law.

The raw material compound (W) or its lower alkyl ester is It can be manufactured by the method described in Reference Example 3 or a method according to this method.

When a lower alkyl ester is obtained by any of the above methods, it is converted to the formula (I) by hydrolysis using a conventional method. It can be converted to a compound.

Pharmaceutically acceptable salts of the compounds of the present invention can be prepared by treating compound (I) with an acid, a base or a metal salt. Examples of the acids formed in the salt formation include, for example, hydrochloric acid, phosphoric acid, acetic acid, lactic acid, oxalic acid, konolic acid, methansulfonic acid, tosoleic acid and the like. Examples include snolephonic acid, maleic acid, malonic acid, gluconic acid, aspartic acid, and glutamic acid. Suitable bases or metal salts for salt formation include, for example, sodium hydroxide, sodium hydroxide, and other hydroxides, and sodium carbonate. , Calcium carbonate and other carbonates, zinc chloride, zinc sulfate, nitrite nitrite, silver nitrate, dimethylamine, triethylamine, dichloride B) Hexylamine, Benzylamin, Rigid, Arginine and so on.

"The compound of the present invention produced in this way is difficult and purified according to a conventional method. Depending on the conditions of isolation and purification, the salt form and the dissociation may occur. Which are converted into each other according to the purpose to produce the compound of the present invention in the desired form.

The stereoisomers of the compounds of the present invention may be prepared by conventional methods, for example, by separation. They can be separated from each other by separate crystals or chromatographic separation. In addition, the present invention uses a raw material compound having a specific configuration, and has a corresponding configuration according to each of the above methods. The compounds of the present invention can also be produced.

The optical isomers of the compounds of the present invention can be separated by applying known methods.

The compound (I) and its salt thus obtained are both new compounds, and have antibacterial activity, absorption, metabolic stability, toxicity, and toxicity. Since it shows extremely superior properties in terms of properties, side effects, and solubility, it is valuable as an antibacterial agent. The compound (I) or its salt can be used for human and animal drugs, fish disease drugs, pesticides, food preservatives, etc. You can still use it.

Hereinafter, the antibacterial activity and other properties of the compound of the present invention will be described with reference to test examples. The compounds used in the test examples are as follows.

Compound 1: 1-Cyclic mouth building-6-Fluoro mouth-8-Methoxy 5-Methyl 7-(Sys 10 5-Dimethyl 1 -Biperazinyl) 1,4-dihydroxy-4,1-oxoquinoline-13-carboxylic acid [compound of the present invention]

Compound A: 1 — Cyclobrovinol-6-phenolic mouth-7-(1-vinyl) 1 1, 4-dihydro 1 4 -Oxoquinolin-3-carboxylate [sib mouth floxacin]

匕合 B B: 1 — Cyclopro I-6-

Methoxy 5-methyl-7-(1-biperazine)-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid

[This compound is a new compound, but is included in the general formula of WO 89/06649. mp 228 ~ 230 ^e C] Compound C: 7- (3-amino-1 -pyrrolidinyl)-1-Cyclob mouth building 6-Fluoro 8- Methoxy 5-methyl 1, 4- dihydro 1-4-oxo quinoline 1-3-carboxylic acid

[This compound is new, but is included in the general formula of WO 89/06649. Compound D: 1-Cyclob mouth-6-Fluoro mouth-5-Methyl-7-(3-Methyl 1-1-Biperazini) ) 1, 1-4-Hydroxy-4 -oxoquinoline-3-carboxylic acid

[This compound is described in Example 5 (4) of EP 287951 and Example 7 of WO 89/06649. ]

Test Example 1 (antimicrobial activity in the test tube)

The minimum growth inhibitory concentration (MIC: ^ g / m1) was determined by Cheaotherapy, According to the method described in 29 ^ (1), 76 (1981), the measurement was carried out by the agar-flat method using a micro-hinton culture medium. . The results are shown in Table 1.

(The following margin)

Table 1 In vitro antibacterial activity (MIC: ^ g / m1)

Bacterial strain Compound Compound Compound Compound Compound

1 A B C D

[Gram-positive bacteria]

STAFFY ΠKokukas * Aureus 209PJC-1 0.025 0.1 0.05 0.025 0.05 (S. aureus 209P JC-1)

Staff ίΒ cococus ♦ 7 Ureus 50774 0.025 0.2 0.025 0.0125 0.05 (S, aureus 50774)

Staphylococcus * Aureus 80 0.0125 0.39 0.0125 0.0063 0.0125 (S. aureus 80)

STAFFY B Kokukasu * 1 pitilum paste 8 0.025 0.1 0.025 0.025 0.05 (S.

Streptococcus ♦ Pyones A65 0.2 0.2 0.39 0.1 0.39 (S. pyogenes A65)

Strebutokoku ;! 1 S. pyogenes Cook 0.2 0.39 0.2 0.1 0.2 (S. pyogenes Cook)

mitococcus -ΐ-ϊ ΐΐneufeet 0.2 0.78

(S. pneumon iae INeufeld)

7 コ Calis 2473 0.39 1 .56 0.39 0.2 0.39 (E. faecal is 2473)

[Gram-negative bacteria]

Escherichih 7 'coli P-51212 x 0.0031 x 0.0031 <0.0031 <0.0031 x 0.0031 (E. col i P-51212)

エリ ρ 0.0125 0.0031 0.00 0.0031 0.0063 0.025 (E. col i p)

', EW33 0.00 0.0031 0.0031 0.0125 0.025 0.39 (S. sonne i E 33)

Ι-Ρΐ eggplant * IH no-12 1.56 0.1 0.78 0.78 0.2 (P. aeru inosa 12)

Moraki t * * Pis P-7101 0.2 3.13 0.1 0.1 0.39 (. Bov is P-7101)

mm s? .p-7201 0.1 0.39 0.1 0.1 0.1

(F vobacter im sp-P-72 () 1) Test Example 2 (Effect of controlling infection)

The effect on the whole body infectious disease was measured under the following conditions.

Animal: Std-ddY male mouse (body weight approx. 20 g)

Infected bacteria amount and infection method:

Staphylococcus * Aureus 50774

5 X 10 ⁸ Viable bacteria No mouse (Static vein injection) Streptococcus ♦ Pneumonia 1 Neufeld

3 X 10 ³ live bacteria mouse (intraperitoneal injection)

Storrefuto: Iku * Piogenes A65

3 X 10 ⁷ Viable bacteria mouse (intraperitoneal injection)

Chou F Monas ♦ I Lugino One 12

5 X 10 ³ live bacteria / mouse (intraperitoneal injection)

Injection method: 0.4% carboxymethylcellulose compound

In the case of Streptococcus spp. 2 eumonier 1 Neufeld, four times after direct infection, after 6 hours, after 24 hours and after 30 hours, and in the case of other bacteria, Two oral doses were given immediately after infection and 6 hours later.

Fi ¾ © fij ¾ ^ ：: Staphylococcus * Aureus 50774 and Streptococcus ♦ Nu: :: I 1 Neuf Ilt 2 weeks later, if other bacteria, feel The EDso value (mg / kg) was calculated by the probit method from the later survival rate of some.

The results are shown in Table 2. 6 - the second table feeling Somebo your effect _{(. _ED S: mg / kg} )

Test Example 3 (Plasma concentration)

The suspension of the compound is orally administered once (5 Dg / kg) to the mouse, and the concentration of the compound in the plasma is determined by using I. coli ♦ Kp as the indicator bacterium. It was quantified by Io Atsuse. Table 3 shows the highest plasma concentrations.

Test Example 4 (Urine excretion)

The suspension of the compound was orally administered to the mouse once (5 ig / kg), and urine was collected for 24 hours after the administration, and the concentration of the compound in the urine was measured. The recovery rate was calculated using a bioassay which uses I. coli ♦ coli P as the indicator bacterium. The results are shown in Table 3. One one

Table 3

Test example 5 (acute poisonous)

S td one dd Y male Ma cormorant this nest versus the oral toxicity of that of compound 1 to the Ri tone was base by the ordinary law filtration, LD ₅₀ values of the Soviet Union on the 2000 nig / k or less there were .

Test example 6 (drug interaction)

Suspend the compound in 0.5% Tragant solution and orally administer it to the mouse. Ten minutes later, a 0.5% tragacanth suspension of noodles (made by Ledley Co., Ltd.) (500 tg / kg) was orally administered, and the mouse was moved. As a result, the compound tj 1 was as high as 5010 eg / kg B, and the amount of chemical compound tj 1 was 50 hours. However, it did not cause spasticity, while compound A was 200 Bg.

At an oral dose of / k, 80% of the mice bowed with spasticity. Test example 7_ (Solubility in water)

Add compound 1 (60 gg) to distilled water (10 邇 1) and shake vigorously in a saturated state for 30 minutes. Filter with a mouth filter. The filtrate was diluted with 0.1N hydrochloric acid, the absorbance at 294ηι was measured, and the compound concentration was calculated from a separately prepared calibration curve. As a result, the solubility of Compound 1 in water was 3840 ng / el.

From the results of Tests 1 to 7 above, the following theory is drawn.

(1) The compounds of the present invention have extremely strong antibacterial activities in vitro and in vivo against Gram-positive bacteria. In particular, the compound of the present invention exhibits a strong in vivo antibacterial effect against Gram-positive bacteria. In other words, the in vivo effect of compound 1 is similar to that of compound 1 except for compound A, which is commercially available, known compound D, which has a relatively similar chemical structure, and a substituent at the 7-position. It is much stronger than the new compounds B and C having the same substitution groups.

(B) The in vitro antibacterial activity of the compounds of the present invention against Gram-negative bacteria is similar or slightly inferior to that of Compounds A, B, C and D, but is lower than that of Compounds A, B, C and D. The anti-bacterial effect on gram-negative bacteria is clearly stronger than that of compounds A, B, C and D.

(3) The compound of the present invention is well absorbed after oral administration and shows a maximum plasma concentration that is about 5 times higher than that of compound A. Further, the urinary recovery of the compound of the present invention is about 2.5 times larger than that of compound A. This good absorption and metabolic stability contribute to the excellent in vivo antibacterial effect of the present invention.

毒性 The toxicity of the compound of the present invention is very low.

Drug interaction between the compound of the present invention and n: nbuphen Is much weaker than Compound A. Further, although no experimental results are shown, the interaction of the drug with theophylline is also extremely weak.

⑥ The compounds of the present invention show a solubility in extremely large water, which is not only possible for oral administration but also for non-dual administration.

As explained above, the compounds of the present invention have an extremely high antibacterial activity and a broad antibacterial spectrum in the VnV itr0 test. Against mycoplasmas and anaerobic bacteria that show no bleeding and are only weakly active with conventional quinoline carboxylate drugs. Also show strong antibacterial activity.

The compounds of the present invention also show an excellent inhibitory effect against infectious diseases caused by various bacteria.

Furthermore, the compounds of the present invention show excellent oral absorption and metabolic stability.

The antibacterial activity of the compounds of the present invention is well separated from toxic (including phototoxic) and side effects.

Therefore, the compound of the present invention is an extremely useful compound as an antibacterial agent for prevention and treatment of infectious diseases of warm blood and organisms caused by bacteria. .

When the compound of the present invention is used in humans as an antibacterial agent, the amount administered depends on age, body weight, medical condition, administration route, and the like. However, it is recommended that 5 ig to 5 g be administered once or several times per day. The administration route is oral, non-administrative Either is acceptable.

The i-danied product of the present invention may be administered in the form of its bulk powder, usually in the form of a preparation together with a carrier for the drug product. Specific examples include tablets, liquids, suspensions, capsules, granules, fine granules, pills, powders, syrups, injections, ointments and the like. It is. These preparations are prepared according to a standard method. Oral carriers include starch, mannite, tragacanth, crystal sesolose, CMC sodium, water, ethanol, etc. A substance that is commonly used in the field of pharmaceutical products and does not react with the compound of the present invention is used. Examples of the carrier for injection include carriers that are commonly used in the field of injectors such as water, physiological saline, glucose solution, and infusion. .

The above solutions and ointments can also be used in the treatment of otorhinolaryngology and ophthalmology.

Yara of the invention to carry out the invention! _State_

Next, the present invention will be described more specifically with reference to examples and reference examples.

Reference Example 1

1-Cyclic mouth building-6> 7-Diffusion 8-Methoxy-5-Methyl 1, 4-Djihdro 4 -3-carboxylic acid:

(1) Annealed compound ¾ 6-trifluorene mouth 4-4 dimethyl phthalate methoxide [Journal of the Chemical Society of Japan, (1976), 200] 223 g, The mixture was reduced to 45.8 g of hydrogen sodium and boron sodium, and the mixture was reduced with methanol to reduce the mixture. -Trifluoro mouth-4-Methoxy-1, 2-Benzene metal ethanol 154g is obtained. m.P. 70-71'C.

(2) Dissolve 145 g of the above compound in acetic acid, and perform contact reduction using 5% palladium carbon as a catalyst. The reaction is stopped at the point when hydrogen is absorbed by one mole equivalent, and the product is separated and purified by slicing gel ram chromatograph. As a result, 56.5 g of 2 »4,5-trifluoro-3-methoxy-6-methylbenzyl alcohol is obtained. m. P. 60-61.

(3) Oxidize 28.7 g of the above compound with nitric acid to give 23.9 g of 2 »45-trifluoro-3-methoxy-6-methylbenzoic acid M.P. 122-124'C.

(4) 23.9 g of the above compound is treated with sodium chloride to give 2 ^ 4,5-trifluoro mouth-3-methoxy-6-methyl benzoate This gives 24.6 g of perfumed lead. b. p. 107-108 (10 aiHg).

(5) 24.6 g of the above compound was reacted with sodium salt of dimethyl malonate in anhydrous toluene to obtain (¾4,5-trif). 3-Methoxy 6-methylbenzino) di-malonate is obtained, and water and a catalytic amount of P-toluene are obtained. Strengthen sulfonate! After heating and refluxing for 2 hours and 40 minutes, (2 ^ 4,5-trifluoro mouth 13-methoxy 16-methylbenzene) acetic acid 23.5 g of chill are obtained. bp 141-143 (4 fflfflHg).

(6) Treatment of 4.35 g of the above compound with ortho-formic acid and acetic anhydride to give 3-ethoxyquin-2-4,5-trifluoro-3- 6-Methyl benzoyl) acrylate, which is then reacted with vialamine, which is a cyclobutate, to give 3 -Cyclic mouth bilamino-2-(2 »4, 5-Trifluoro mouth 13-metoxy. 16-Methyl benzoyl) Clear This yields 4.8 g of phosphoric acid. -m.P. 101 ~ 102 * C.

(7) Dissolve 10 · 8 g of the above compound in 50 ml of tetrahydrofuran, and cool with water while cooling with talium t-butoxide 3.73 Add g and stir for 30 minutes. After stirring the mixture at room temperature for 3 hours, add ice water to the reaction mixture, and filter out the crystals that precipitate. This is recrystallized from ethyl acetate to give 8. & 3 g of the desired ester. m.P. 181-183'C.

(8) Add 4.93 g of the above compound to 48 il of a mixture of concentrated sulfuric acid, glacial acetic acid and water (1: 8: 6), and heat and stir for 2 hours at 100 for 2 hours. Ice water is added to the mixture, and the precipitated crystals are collected by filtration and washed with water. By recrystallizing from sodium nitric acid, 4.23 g of the desired product is obtained. m.p.189-192 * C.

Example 1

1-Cyclic mouth building-6-Fluoro-8-Methoxy 5-Methyl-7-(Ciss-5-Dimethyl 1-Biperazini )-1,4-dihydro-4-oxoquinoline-3- carboxylic acid :

1-Cyclopro vinole 1 ft 7-Diffusion 8-Methoxy — 5 — Methanol 1, 4-Dihydro 4-Oxoquinoline Add 0.55 g of cis-one 2 »8-dimethylbiperazine to a mixture of 0.50 g of -3-carboxylic acid and 10 al of acetonitrile, and add 14 hours Heating and returning. After cooling with ice, the crystals that evolve are collected by filtration and recrystallized from acetonitrile to give 0.23 g of the desired product. m.P. 241-243'C.

Reference Example 2

1-Cyclopro. 1 6, 7-Difluoro mouth-8-Methoxy-5-Methyl-1, 4-Dihydro 4-1-oxo quino Lin-3-carboxylate — BF ₂ -Chelate:

1-Cyclopro-6 »7-Difluoro-8-Methoxy-5-Methyl 1, 4-Dihydro-4-Oxokinori A mixture of 2.0 g of carboxylic acid and 30 Bl of 42% borofluoric acid is heated and stirred at 100'C for 4 hours. After cooling the reaction solution to ice, the crystals are collected and subjected to sequential washing with water and a small amount of ethanol to obtain 2.15 g of the intended product. m.P. 258-260.

Example 2

1-CYCLOB OPEN BILL-6-FULL LOW 8-METHOLIC 1-5-METHYL-7-(SYN--5-DIMENSION-1-BIPERAGE (Nil)-1,4 dihydro-4 oxoquinoline-3-carboxylic acid: 1-Cyclopro-7 _ difluoro-8-METOKIN-5-METHIRO1, 4-GIHYDRO-4 oxoquinoline -3 One-sided rubonic acid BF _2- Chelate 2. Suspend Og in dimethylsulphoside 20 leak 1 and add cis to it. Add 2.56 g of tilviperazine and stir at 50 for 4.5 hours. After cooling, add water to the reaction mixture to determine the crystals that will be precipitated. A 4% aqueous solution of caustic soda 3011 is added to the crystals and heated. After filtering off the insoluble matter, the filtrate is cooled with ice, and the precipitated crystals are collected by filtration. Dissolve this in water, adjust the pH to 8 with a 10% aqueous acetic acid solution, cool on ice, and filter out the precipitated crystals by filtration. After washing with water and drying, 1.74 g of the target substance is obtained. m.P. 241-243.

Reference example 3_

1-Cyclic mouth building-6 »8-Gifnorole 5-Methyl-7-(Silver 1-5-Dimethyl 1-Biperazinyl) 1 1,4 AGE HYDRO-4-4 oxoquinoline 1 3 —Carbonic acid:

(1) Known compounds ¾45-tetrafluoro mouth-6-methyl benzoic acid C J. Fluorine Che Rei, 28, 361 (1985)] and Reference Examples 1 (4) to (8) ), And the reaction is processed in the same manner as 1), and the 1-cyclo-opening-6, 7, 8-trifluoro-5-methyl-1,4-dihydro-4- To obtain oxoquinoline-3-carboxylate.

m.p. 242-243 * C.

(2) A mixture of 0.50 g of the above compound, 0.61 g of cis-2 »6-dimethylbiperazine, and pyridine 3011 was applied for 4 hours. Heat return. The solvent is distilled off, and the residue is covered with ethanol [], and the precipitated crystals are collected by filtration. The crystals are dissolved in a 3% aqueous solution of acid, treated with activated charcoal, adjusted to pH 8 with a 1 aqueous solution of caustic soda, and ice-cooled. The precipitated crystals are collected by filtration, washed with water and dried to obtain 0.42 g of the target substance. mp 200-202 * C.

Example 3

1-Cycloprobinol 6-Fluoro 8-Methoxy 1-Methyl-7-(Cis 3, 5-Dimethyl-1-Pipera 1,4-Dihydro 4 -oxoquinoline-3-Forced oleonic acid:

A solution of 0.35 g of sodium metal in 30 ml of water-free methanol was added to a solution of 1-cyclolobole pinole 6, 8 — difluoro-1-methyl Chill 1 7 1 (Cys 1 3 »5-Dimethyl 1-Biperazine) 1, 4, 1-Hydro 4-Oxo 1 3 Add 1.17 g of rubic acid and heat in a sealed tube at 130-140 for 24 hours. After cooling, the solvent is distilled off under reduced pressure, water and water are added to the residue, and the aqueous layer is neutralized with acetic acid, and then the water and water are separated. . The solvent is distilled off under reduced pressure, and the residue is separated and purified by means of a chromatograph to obtain the desired product O.llg. m.p. 241-243'C,

Example 4 (encapsulation agent)

Compound 1 250 g

50 g starch Lactose 35g

Tamerek 15g

The above ingredients are mixed well with ethanol, granulated, and filled into 1000 capsules by a conventional method.

Example 5 (tablets)

Compound 1 250 g

Dumping 54 s

Carxymethyl t-lulose calcium 40 g

Microcrystalline Cellulose 50g

Magnesium sulphate 6 g

The above components are mixed well with ethanol, granulated, and tableted by a conventional method to prepare 1,000 tablets weighing 400.

Example 6 (Injection)

Compound 50 g

Lactic acid 120g

Dissolve the above components in distilled water to make a total volume of 10. The pH is adjusted to about 4 with an aqueous solution of caustic soda, and the mixture is filled into an amber (10 liters) to prepare an injection.

Industrial applicability

As described above, the compounds of the present invention and pharmaceutically acceptable salts thereof are used as antibacterial agents to prevent bacterial and infectious diseases of warm-blooded animals as antibacterial agents. Useful for treatment

Claims

The scope of the claims

, ー Cyclob pinout 6-Fluoro8-

5 Methyl-7-(¾ 5-Dimethyl-1-Biperazine) 1, 1, 4-Dihydro 4-Oxoquinoline 1-3-Carbo Acid or a pharmacologically acceptable salt thereof.

The compound is 1-cyclolobular vial-6-phenolic-8-methoxy-5-methyl-7-(cis-3,5-dimethylene) 1-Pirazil) 1,4—Dihydro-4-oxoquinoline-3-carboxylate or its pharmaceutically acceptable nature The scope of the claim which is a salt.

1-Cyclic mouth building-6-Fluoro 8-Methoxy-5-Methyl-7-(¾ 5-Dimethyl 1-Piperazinil ) 1, 1 -dihydro-4-1-oxoquinolin-3-In the preparation of carboxylic acid or its pharmaceutically acceptable salts. hand ,

(a) General formula

(Wherein, Xi means a halogen atom, Yi is a hydrogen atom, a lower alkyl group, a difluoroboryl group, Means a radical group. )

Compound represented by and general formula

(In the formula, R means a hydrogen atom or a protecting group for an amino group.)

Reacting the bismuth derivative represented by the formula (1) and, if desired, decompose the solvent and / or hydrolyze

C b) General formula

(In the formula, X a means a halogen atom, Y ₂ means a hydrogen atom or a lower alkyl group, and R is the same as described above.)

Is reacted with methanol in the presence of a base, and if desired, is subjected to solvolysis and / or hydrogenolysis, if desired. hand

(c) converting the product to a pharmaceutically acceptable salt, if desired

^ ^ ^ i ^ m o ^ ^ ^ ^ ^ ^-ε-"

^ ^-p Ί-ί — ^ ζ:. ^-Τ-

Ί /-^ ^-9 '8-^?)-L-i-^ ^-Q-^ ^ i ≠--b α Ρ ί-ΐ ^ ^' 9 ^ 玆: 蓥 ^ 军翘-ε-

(\ ^-I?-Α ^ ^-V Ί 一 (-^ ^ <-

T-^ ^-S))---S-:, key 8

-a ^ Λ (L-9-(\ a a-ΐ <-i ^ '

. ¾.? T？?

-6Z-

IlZI0 / 68df / JDd S0 £ 90/06 O