JPH06145167A - 8-Methoxy-5-methylquinoline-3-carboxylic acid derivative - Google Patents

Abstract

PURPOSE:To obtain the subject new compound useful as antimicrobial agent, antitumor agent and therapeutic agent for AIDS. CONSTITUTION:A compound of formula I {R<1> is H or lower alkyl; R<2> is group of formula II [R<3> is H, lower alkyl, (halogeno) lower alkanoyl or ester type protecting group; R<4> and R<5> are H or lower alkyl; R<6> is lower alkyl] or group of formula III ((n) is 0-3)) such as 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-5- methyl-7-(4-methyl-3-trifluoroacetylamino-1-pyrrolidinyl)-4-oxoquinoli ne-3- carboxylic acid. The compound of formula I is obtained by reacting a 8- methoxy-5-methylquinoline-3-carboxylic acid derivative of formula IV (X is halogen) with a pyrrolidine derivative of the formula R<2>-H in a solvent optionally in the presence of a base.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention has novel antibacterial activity, antitumor activity and anti-AIDS virus activity, and is a novel 8-methoxy-5-methyl useful as an antibacterial agent, antitumor agent and AIDS therapeutic agent. The present invention relates to a quinoline-3-carboxylic acid derivative and a pharmaceutically acceptable salt thereof.

[0002]

2. Description of the Related Art An 8-methoxy-5-methylquinoline-3-carboxylic acid derivative having an amine according to the present invention at the 7-position of the quinoline ring has not been known at all.

[0003]

As the pyridonecarboxylic acid-based synthetic antibacterial agent, a large number of compounds collectively referred to as new quinolone in which a piperazine derivative is introduced at a 7-position adjacent to a fluorine atom at a position corresponding to the 6-position have been announced, It has reached its heyday.

[0004] However, among the clinically used drugs, ciprofloxacin (T
(He Merck Index 11th Edition, 2315), the antibacterial activity against Gram-positive bacteria such as Streptococcus pneumoniae and Staphylococcus is not sufficient, and recently, quinolone-resistant bacteria due to heavy use of quinolone drugs have become a clinical problem. ing. In addition, some of the drugs in this system have problems such as induction of convulsions, side effects such as hypersensitivity to light, and low tissue migration to the infected site during oral administration, when used in combination with certain anti-inflammatory drugs. Is also left.

From the above, it has been strongly desired to develop a synthetic antibacterial agent which shows a well-balanced antibacterial activity not only to Gram-negative bacteria but also to Gram-positive bacteria and which is excellent in safety and tissue transferability.

[0006]

DISCLOSURE OF THE INVENTION The inventors of the present invention have conducted extensive studies in view of the above-mentioned circumstances, and as a result, a novel 8-
It has been found that a methoxy-5-methylquinoline-3-carboxylic acid derivative is an excellent compound that solves these problems. Furthermore, they have also found that these compounds have excellent antitumor activity and anti-AIDS virus activity, and completed the present invention.

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

[Chemical 4] (In the formula, R ¹ represents a hydrogen atom or a lower alkyl group;
² is the following general formula

[Chemical 5] (In the formula, R ³ is a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a halogeno lower alkanoyl group or an ester-type protecting group, R ⁴ and R ⁵ are the same or different and a hydrogen atom or a lower alkyl group, and R ⁶ is Represents a lower alkyl group) or the following general formula:

[Chemical 6] (In the formula, R ³ and R ⁴ have the same meanings as described above, and n is 0 to
Represents an integer of 3. ) Represents a group represented by. ), A novel 8-methoxy-5-methylquinoline-3-carboxylic acid derivative and a pharmacologically acceptable salt thereof.

In the general formula (I) of the present invention, R ¹ , R ³ , R
Examples of the lower alkyl group represented by ⁴ , R ⁵ and R ⁶ include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, te
Examples of the lower alkanoyl group represented by R ³ include a formyl group, an acetyl group, a propanoyl group, a butyroyl group and a trimethylacetyl group, and a halogeno lower alkanoyl group includes, for example, a fluoro group. An acetyl group, a difluoroacetyl group, a trifluoroacetyl group, a chloroacetyl group, a dichloroacetyl group, a trichloroacetyl group and the like are ester-type protecting groups such as a benzyloxycarbonyl group,
Ethoxycarbonyl group, methoxycarbonyl group, tert-
Examples thereof include butoxycarbonyl group.

The compound represented by the general formula (I) of the present invention can be converted into a pharmacologically acceptable salt, or a base or an acid can be liberated from the produced salt, if desired. .

Examples of the pharmaceutically acceptable salt of the compound represented by the general formula (I) of the present invention include acid addition salts and alkali addition salts. Examples of the acid addition salts include hydrochloric acid and odor. Hydrochloric acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, and other mineral salts, or acetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, malic acid, methanesulfonic acid, p-toluenesulfonic acid, mandel Organic acid salts such as acids, 10-camphorsulfonic acid, tartaric acid, etc., as the alkali addition salts, for example, inorganic alkali salts such as sodium, potassium, calcium, silver, zinc, lead, ammonium,
Alternatively, salts of organic bases such as ethanolamine, N, N-dialkylethanolamine and the like can be mentioned.

The compound represented by the general formula (I) of the present invention has one or a plurality of asymmetric carbon atoms and may have several stereoisomers. These isomers and mixtures thereof are also included.

The following compounds may be mentioned as preferred embodiments of the 8-methoxy-5-methylquinoline-3-carboxylic acid derivative of the present invention, but the present invention is not limited to these examples. (1) 7- (3-amino-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-5-methyl-4-oxoquinoline-3-carboxylic Acid (2) 7- (cis-3-amino-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,
4-Dihydro-8-methoxy-5-methyl-4-oxoquinoline-3-carboxylic acid (3) 7- (trans-3-amino-4-methyl-1-
Pyrrolidinyl) -1-cyclopropyl-6-fluoro-
1,4-Dihydro-8-methoxy-5-methyl-4-oxoquinoline-3-carboxylic acid (4) 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-5-methyl-7 -(4-Methyl-3-methylamino-1-pyrrolidinyl) -4-oxoquinoline-3-carboxylic acid (5) 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-5-methyl -7- (cis-4-
Methyl-3-methylamino-1-pyrrolidinyl) -4-
Oxoquinoline-3-carboxylic acid (6) 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-5-methyl-7- (trans-
4-methyl-3-methylamino-1-pyrrolidinyl)-
4-oxoquinoline-3-carboxylic acid (7) 1-cyclopropyl-7- (3-dimethylamino-4-methyl-1-pyrrolidinyl) -6-fluoro-
1,4-Dihydro-8-methoxy-5-methyl-4-oxoquinoline-3-carboxylic acid (8) 1-cyclopropyl-7- (cis-3-dimethylamino-4-methyl-1-pyrrolidinyl)- 6-Fluoro-1,4-dihydro-8-methoxy-5-methyl-4
-Oxoquinoline-3-carboxylic acid (9) 1-cyclopropyl-7- (trans-3-dimethylamino-4-methyl-1-pyrrolidinyl) -6-fluoro-1,4-dihydro-8-methoxy-5 -Methyl-4-oxoquinoline-3-carboxylic acid (10) 7- (3-amino-4,4-dimethyl-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-
1,4-Dihydro-8-methoxy-5-methyl-4-oxoquinoline-3-carboxylic acid (11) 7-((S) -3-amino-4,4-dimethyl-1-pyrrolidinyl) -1- Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-5-methyl-
4-oxoquinoline-3-carboxylic acid (12) 7-((R) -3-amino-4,4-dimethyl-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8 -Methoxy-5-methyl-
4-oxoquinoline-3-carboxylic acid (13) 1-cyclopropyl-7- (4,4-dimethyl-3-methylamino-1-pyrrolidinyl) -6-fluoro-1,4-dihydro-8-methoxy- 5-methyl-4
-Oxoquinoline-3-carboxylic acid (14) 1-cyclopropyl-7-((S) -4,4-
Dimethyl-3-methylamino-1-pyrrolidinyl) -6
-Fluoro-1,4-dihydro-8-methoxy-5-methyl-4-oxoquinoline-3-carboxylic acid (15) 1-cyclopropyl-7-((R) -4,4-
Dimethyl-3-methylamino-1-pyrrolidinyl) -6
-Fluoro-1,4-dihydro-8-methoxy-5-methyl-4-oxoquinoline-3-carboxylic acid (16) 1-cyclopropyl-7- (4,4-dimethyl-3-dimethylamino-1- Pyrrolidinyl) -6-fluoro-1,4-dihydro-8-methoxy-5-methyl-
4-oxoquinoline-3-carboxylic acid (17) 1-cyclopropyl-7-((S) -4,4-
Dimethyl-3-dimethylamino-1-pyrrolidinyl)-
6-fluoro-1,4-dihydro-8-methoxy-5-
Methyl-4-oxoquinoline-3-carboxylic acid (18) 1-cyclopropyl-7-((R) -4,4-
Dimethyl-3-dimethylamino-1-pyrrolidinyl)-
6-fluoro-1,4-dihydro-8-methoxy-5-
Methyl-4-oxoquinoline-3-carboxylic acid (19) 7- (7-amino-5-azaspiro [2,4]
Heptan-5-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-5-methyl-
4-Oxoquinoline-3-carboxylic acid (20) 7-((S) -7-amino-5-azaspiro [2,4] heptan-5-yl) -1-cyclopropyl-6-fluoro-1,4 -Dihydro-8-methoxy-5
-Methyl-4-oxoquinoline-3-carboxylic acid (21) 7-((R) -7-amino-5-azaspiro [2,4] heptan-5-yl) -1-cyclopropyl-6-fluoro- 1,4-dihydro-8-methoxy-5
-Methyl-4-oxoquinoline-3-carboxylic acid (22) 1-cyclopropyl-6-fluoro-1,4-
Dihydro-8-methoxy-5-methyl-7- (7-methylamino-5-azaspiro [2,4] heptan-5-yl) -4-oxoquinoline-3-carboxylic acid (23) 1-cyclopropyl- 6-fluoro-1,4-
Dihydro-8-methoxy-5-methyl-7-((S)-
7-Methylamino-5-azaspiro [2,4] heptan-5-yl) -4-oxoquinoline-3-carboxylic acid (24) 1-cyclopropyl-6-fluoro-1,4-
Dihydro-8-methoxy-5-methyl-7-((R)-
7-Methylamino-5-azaspiro [2,4] heptan-5-yl) -4-oxoquinoline-3-carboxylic acid (25) 1-cyclopropyl-7- (7-dimethylamino-5-azaspiro [2 , 4] Heptan-5-yl)-
6-fluoro-1,4-dihydro-8-methoxy-5-
Methyl-4-oxoquinoline-3-carboxylic acid (26) 1-cyclopropyl-7-((S) -7-dimethylamino-5-azaspiro [2,4] heptane-5-
Yl) -6-Fluoro-1,4-dihydro-8-methoxy-5-methyl-4-oxoquinoline-3-carboxylic acid (27) 1-cyclopropyl-7-((R) -7-dimethylamino- 5-azaspiro [2,4] heptane-5-
Yl) -6-Fluoro-1,4-dihydro-8-methoxy-5-methyl-4-oxoquinoline-3-carboxylic acid

The novel 8-methoxy-5-methylquinoline-3-carboxylic acid derivative represented by the general formula (I) of the present invention can be produced by the following production method. It is not limited to these methods.

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) has the following general formula (II):

[Chemical 7] (In the formula, R ¹ has the same meaning as described above, and X represents a halogen atom.) An 8-methoxy-5-methylquinoline-3-carboxylic acid derivative represented by the following general formula (III) R ² It can be produced by reacting a pyrrolidine derivative represented by —H (III) (wherein R ² has the same meaning as described above) in a solvent in the presence or absence of a base.

The solvent used in the present production method may be any solvent as long as it does not inhibit the reaction. For example, alcohol solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, acetonitrile, N, N. -Aprotic polar solvents such as dimethylformamide, N-methyl-2-pyrrolidone, dimethylsulfoxide and hexamethylphosphoric triamide, aromatic hydrocarbon solvents such as benzene and toluene,
Examples thereof include organic bases such as pyridine, picoline, lutidine, collidine, and mixed solvents thereof.

Examples of the base used in the present production method include triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5,4,0] -7.
-Undecene, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate and the like can be mentioned, and the reaction is carried out in the range from ice cooling to the reflux temperature of the solvent.

According to the second mode of the method for producing a compound according to the present invention, the compound represented by the general formula (I) has the following general formula (IV):

[Chemical 8] (In the formula, X has the same meaning as described above, and R ⁷ represents a halogen atom, an aliphatic acyloxy group, an aliphatic acyloxy group optionally substituted with a halogen atom, or an aromatic acyloxy group.) Derivatives and the general formula (II
After the reaction with the pyrrolidine derivative represented by I) in a solvent in the presence or absence of a base, further treatment with a protic polar solvent in the presence or absence of a base, if necessary. It can be produced by carrying out dechelation by.

In the present production method, the solvent used for the reaction between the compound represented by the general formula (IV) and the compound represented by the general formula (III) may be any solvent as long as it does not inhibit the reaction. Alcohol solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, aprotons such as acetonitrile, N, N-dimethylformamide, N-methyl-2-pyrrolidone, dimethylsulfoxide, hexamethylphosphoric triamide, etc. Polar solvents, aromatic hydrocarbon solvents such as benzene and toluene, organic bases such as pyridine, picoline, lutidine and collidine, halogen-containing hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane and chloroform, or mixed solvents thereof. Etc.

Examples of the base used in the present production method include triethylamine, diisopropylamine, 1,8-diazabicyclo [5,4,0] -7-undecene, sodium carbonate, potassium carbonate, sodium hydrogencarbonate and hydrogencarbonate. Examples thereof include potassium, and the reaction is carried out in the range from under ice cooling to the reflux temperature of the solvent.

The protic polar solvent used in the dechelation reaction is, for example, methanol,
Alcohol solvents such as ethanol, n-propanol, isopropanol, n-butanol, etc., or water, and mixed solvents thereof, or acetonitrile, N, N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, hexamethylphosphine. For example, a mixed solvent of a solvent such as folic triamide, benzene, toluene, pyridine, picoline, lutidine, collidine, dichloromethane, 1,2-dichloroethane, chloroform and methanol or water may be used. It is carried out up to the reflux temperature.

According to the third mode of the method for producing a compound according to the present invention, among the compounds represented by the general formula (I), the compound in which R ¹ is a hydrogen atom is represented by the general formula (I). It can be produced by hydrolyzing a compound in which R ¹ is a lower alkyl group among the compounds described above.

This hydrolysis is carried out by a method known per se using an acid or an alkali. For the acidic hydrolysis, hydrochloric acid,
Acids such as sulfuric acid are used for alkaline hydrolysis, and alkalis such as sodium hydroxide and potassium hydroxide are used. These acids or alkalis are aqueous solutions or methanol, ethanol, n-butanol, sec-butanol, tert-butanol, etc. It can be used in the reaction as a solution with an organic solvent or 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 fourth mode of the method for producing a compound according to the present invention, among the compounds represented by the general formula (I), the compound in which R ³ is a hydrogen atom is the compound represented by the general formula (I).
A compound represented by the formula ( ^{3) wherein} R ³ is a lower alkanoyl group or a halogeno lower alkanoyl group is hydrolyzed, or a compound wherein R ³ is an ester-type protecting group is hydrolyzed in the presence or absence of a cation scavenger in a solvent or in a solvent. It can be produced by treating with acid and deprotecting in the presence.

This hydrolysis is carried out by a method known per se using an acid or an alkali. For acidic hydrolysis, hydrochloric acid,
Acids such as sulfuric acid are used for alkaline hydrolysis, and alkalis such as sodium hydroxide and potassium hydroxide are used. These acids or alkalis are aqueous solutions or methanol, ethanol, n-butanol, sec-butanol, tert-butanol, etc. It can be used in the reaction as a solution with an organic solvent or a water-containing organic solvent, and the reaction is carried out from room temperature to the heating reflux temperature of the solvent.

The solvent used in the deprotection reaction of the ester type protecting group may be, for example, acetic acid, ethyl acetate, dioxane, water, methanol, ethanol or a mixed solvent thereof. As the cation scavenger, Examples thereof include anisole and thioanisole, and examples of the acid include hydrochloric acid, hydrobromic acid, trifluoroacetic acid, and the like, and the reaction is carried out in the temperature range from ice cooling to room temperature.

According to the fifth mode of the method for producing a compound of the present invention, the compound of the formula (I) wherein R ³ and / or R ⁴ is a lower alkyl group is:
In the general formula (I), a compound in which R ³ and / or R ⁴ is a hydrogen atom is reacted with a halogeno lower alkyl in a solvent in the presence or absence of a base, or (V)

[Chemical 9] (In the formula, R ⁸ represents a hydrogen atom or a lower alkyl group.)
It can be produced by reacting with an aldehyde compound represented by: in the presence of formic acid.

As the solvent when halogeno lower alkyl is used in the present production method, for example, N, N-dimethylformamide, acetone, ethanol, tetrahydrofuran, benzene, chloroform and the like can be mentioned, and as the base, for example, triethylamine, Examples thereof include potassium carbonate.

The aldehyde compound represented by the general formula (V) when an aldehyde compound is used in the present production method includes formaldehyde, acetaldehyde,
Propionaldehyde and the like can be mentioned. Formaldehyde is preferably used as an aqueous formaldehyde solution (formalin), and when acetaldehyde and propionaldehyde are used, nitrobenzene is preferably used as a solvent.

In the present production method, among the compounds as starting materials, the compound represented by the general formula (II) is WO 9
It is a known compound disclosed in 0-6305.

The above-mentioned general formula (I) produced in this manner
A novel 8-methoxy-5-methylquinoline-
A drug containing a 3-carboxylic acid derivative and a pharmacologically acceptable salt thereof as an active ingredient is usually a capsule, tablet,
It is administered orally as fine granules, granules, powders, syrups, etc., or as injections, suppositories, eye drops, eye ointments, ear drops, or skin agents. These preparations can be manufactured by a conventional method 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) Pharmaceutical ingredients such as methylcellulose, polyvinylpyrrolidone, etc., lubricants (magnesium stearate, talc, etc.), coating agents (hydroxypropylmethylcellulose, sucrose, titanium oxide, etc.), bases (polyethylene glycol, hard fat, etc.), For injections, eye drops, and ear drops, solubilizers or solubilizers (distilled water for injection, physiological saline,
Propylene glycol, etc.), pH regulators (inorganic or organic acids or bases), isotonic agents (salt, glucose, glycerin, etc.), stabilizers, and other formulation components are also used as ophthalmic ointments and dermatological agents. In this case, formulation components (white petrolatum, macrogol, glycerin, cotton cloth, etc.) suitable for ointments, creams and patches are used.

The dose of this drug to a treated patient depends on the symptoms of the patient, but in the case of an adult, the daily dose is usually about 10 to 1000 mg by oral administration and about 1 to 500 mg by parenteral administration. .

[0032]

EXAMPLES The present invention will be described below with reference to examples.
The invention is not limited to these examples.

Example 1 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-5-methyl-7- (4-methyl-3-
Trifluoroacetylamino-1-pyrrolidinyl) -4
-Oxoquinoline-3-carboxylic acid 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-5-methyl-4-oxoquinoline-3-carboxylic acid 2.50 g, 4-methyl- 3-trifluoroacetylaminopyrrolidine hydrochloride 2.82 g
And a mixture of 1,8-diazabicyclo [5,4,0] -7-undecene 3.08 g and acetonitrile 50 ml 1
The mixture was heated under reflux for 9 hours. The reaction mixture was concentrated under reduced pressure, and the residue was mixed with water 5
0 ml was added, and the pH was adjusted to 3 with 10% hydrochloric acid with stirring. The precipitated crystals were collected by suction filtration to obtain 4.17 g of pale tan crystals. The crystals were purified by column chromatography (methylene chloride: methanol 50: 1 to 10: 1) to obtain 2.46 g of light tan crystals. Recrystallization from a mixed solution of methylene chloride-diethyl ether gave pale tan needle crystals having a melting point of 211.5 to 213.5 ° C. Elemental analysis value C ₂₂ H ₂₃ F ₄ N ₃ O ₅ theoretical value C _, 54.43; H, 4.78; N, 8.66 experimental value C _, 54.11; H, 4.70; N, 8.60

In accordance with the method of Example 1, Examples 2-4
Was obtained.

Example 2 1-Cyclopropyl-7-((S) -4,4-dimethyl-3-trifluoroacetylamino-1-pyrrolidinyl) -6-fluoro-1,4-dihydro-8-methoxy- 5-Methyl-4-oxoquinoline-3-carboxylic acid (S) -4,4-dimethyl-3-trifluoroacetylaminopyrrolidine hydrochloride [α] ²⁰ _D + 24.7 ° (c = 0.
It was synthesized using 1, MeOH). Behavior slightly yellow needles (MeOH) mp two hundred sixty-eight to two hundred seventy ° C. Elemental analysis _{C 23 H 25 F 4 N 3} O 5 theory _{C, 55.31; H, 5.05;} N, 8.41 Found _C, 55.15; _H, 4.94; N, 8.36 Specific rotation [α] _D ²⁰ + 84.8 ° (c = 0.1, MeOH)

Example 3 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-5-methyl-4-oxo-7-
((R) -7-Trifluoroacetylamino-5-azaspiro [2,4] heptan-5-yl) quinoline-3-
Carboxylic acid (R)-7-trifluoroacetyl-amino-5-azaspiro [2,4] heptane hydrochloride [α] ²⁰ _D - 55.7 °
It was synthesized using (c = 0.1, H ₂ O). Behavior slightly brown needles (CH ₃ CN) mp 208 to 210 ° C. Elemental analysis _{C 23 H 23 F 4 N 3} O 5 theory _{C, 55.53; H, 4.66;} N, 8.45 Found _C, 55.55; _H, 4.69; N, 8.55 Specific rotation [α] ²⁰ _D + 162.0 ° (c = 0.1, MeOH)

Example 4 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-5-methyl-4-oxo-7-
((S) -7-Trifluoroacetylamino-5-azaspiro [2,4] heptan-5-yl) quinoline-3-
Carboxylic acid (S) -7-trifluoroacetylamino-5-azaspiro [2,4] heptane / hydrochloride [α] ²⁰ _D + 54.9 °
It was synthesized using (c = 0.1, H ₂ O). Properties Light brown needle crystals (CH ₃ CN) Melting point 207-209 ° C Elemental analysis C ₂₃ H ₂₃ F ₄ N ₃ O ₅ Theoretical C _, 55.53; H, 4.66; N, 8.45 Experimental C _, 55.50; H, 4.65; N, 8.59 specific rotation [α] ^{_{D 20 - 162.3 ° (c =}} 0.1, MeOH)

Example 5 7- (3-Amino-4-methyl-1-pyrrolidinyl)-
1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-5-methyl-4-oxoquinoline-3
-Carboxylic acid 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-5-methyl-7- (4-methyl-3-
Trifluoroacetylamino-1-pyrrolidinyl) -4
A mixture of 2.20 g of -oxoquinoline-3-carvone, 1.50 g of potassium hydroxide and 15 ml of water was stirred at room temperature for 1 hour. The reaction solution was adjusted to pH 8 with 10% hydrochloric acid, and the precipitated crystals were collected by suction filtration, dissolved in a 10% aqueous sodium hydroxide solution, naturally filtered, and adjusted to pH 8 with 10% hydrochloric acid. The precipitated crystals were collected by suction filtration to obtain 1.27 g of pale yellow crystals having a melting point of 216 to 218.5 ° C (decomposition). Elemental analysis value C ₂₀ H ₂₄ FN ₃ O ₄ theoretical value C _, 61.69; H, 6.21; N, 10.79 experimental value C _, 61.48; H, 6.10; N, 10.71

In accordance with the method of Example 5, Examples 6-8
Was obtained.

Example 6 7-((S) -3-Amino-4,4-dimethyl-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-
1,4-dihydro-8-methoxy-5-methyl-4-oxoquinoline-3-carboxylic acid hydrochloride properties pale yellow crystals (EtOH-H ₂ O) mp 218.5 to 221.5 ° C. (decomposition) Elemental Analytical value C ₂₁ H ₂₆ FN ₃ O ₄ · HCl · H ₂ O Theoretical value C _, 55.08; H, 6.38; N, 9.18 Experimental value C _, 55.04; H, 6.04; N, 8.83 Specific optical rotation [α] _D ²⁰ + 50.1 ° (c = 0.1, DMF)

Example 7 7-((R) -7-Amino-5-azaspiro [2,4]]
Heptan-5-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-5-methyl-
4-oxoquinoline-3-carboxylic acid / hydrochloric acid Properties Light yellow needle crystals (EtOH) Melting point 190-194 ° C (decomposition) Elemental analysis value C ₂₁ H ₂₄ FN ₃ O ₄ · HCl · 1 / 2H ₂
O Theoretical value C _, 56.44; H, 5.86; N, 9.40 Experimental value C _, 56.33; H, 5.64; N, 9.20 Specific optical rotation [α] _D ²⁰ + 144.4 ° (c = 0.1, MeOH)

Example 8 7-((S) -7-Amino-5-azaspiro [2,4]]
Heptan-5-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-5-methyl-
4-oxoquinoline-3-carboxylic acid / hydrochloric acid Properties Light yellow needle crystals (EtOH) Melting point 190-194 ° C (decomposition) Elemental analysis value C ₂₁ H ₂₄ FN ₃ O ₄ · HCl · 1 / 2H ₂
O theory _{C, 56.44; H, 5.86;} N, 9.40 Found _{C, 56.44; H, 5.69;} N, 9.11 Specific rotation [α] ^{_{D 20 - 148.7 ° (c =}} 0.1, MeOH)

[0043]

INDUSTRIAL APPLICABILITY The novel 8-methoxy-5-methylquinoline-3-carboxylic acid derivative represented by the above general formula (I) and the pharmacologically acceptable salt thereof produced in this manner are excellent. It also has an antibacterial action and an antitumor action and an anti-AIDS virus action, and is therefore extremely useful as a medicine.

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Yoichi Yamamoto 72 U, Hatta-cho, Nanao City, Ishikawa Prefecture

Claims (1)

[Claims] 1. The following general formula: (In the formula, R ¹ represents a hydrogen atom or a lower alkyl group;
² is the following general formula: (In the formula, R ³ is a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a halogeno lower alkanoyl group or an ester-type protecting group, R ⁴ and R ⁵ are the same or different and a hydrogen atom or a lower alkyl group, and R ⁶ is Represents a lower alkyl group) or the following general formula: (In the formula, R ³ and R ⁴ have the same meanings as described above, and n is 0 to
Represents an integer of 3. ) Represents a group represented by. ) 8-methoxy-5-methylquinoline-3-carboxylic acid derivative and a pharmacologically acceptable salt thereof.