JP2598737B2 - 8-Alkoxyquinolone carboxylic acid excellent in selective toxicity, salt thereof, and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel quinolonecarboxylic acid derivative which is extremely excellent as an antibacterial agent, a method for producing the same, and an antibacterial agent containing the novel compound as an active ingredient.

[0002]

2. Description of the Related Art The quinolone carboxylic acid derivative of the present invention is characterized by having a cyclopropyl group at the 1-position and an alkoxy group at the 8-position.

With respect to 8-alkoxyquinolone carboxylic acid derivatives, the following 8-methoxy derivatives described in JP-A-60-214773 are known.

However, its antibacterial activity is weak, and no advantageous properties as an antibacterial agent are described.

[0005]

In recent years, norfloxacin developed by the present inventors has a strong activity against Gram-negative bacteria including Pseudomonas aeruginosa, and a new quinolone carboxylic acid which is also effective against Gram-positive bacteria. It is currently widely used clinically as an antibacterial agent. Subsequently, quinolone carboxylic acids having similar substituents, for example, ofloxacin and ciprofloxacin, were developed, and efforts have been made to improve the bioavailability of norfloxacin or to enhance the antibacterial activity.

These new quinolone carboxylic acid antibacterial agents have extremely good antibacterial activity against Gram-negative bacteria even when compared with other agents such as β-lactam antibacterial agents or aminoglycosides. Furthermore, a low rate of resistance improvement is also a preferred feature of these agents. On the other hand, since the antibacterial activity against Gram-positive bacteria is considerably inferior to that of Gram-negative bacteria, the problem of increasing the frequency of isolation of Gram-positive bacteria in modern clinical settings has not been solved unfortunately.

According to the study of the present inventors, some quinolone carboxylic acid derivatives have excellent antibacterial activity but cannot be used as pharmaceuticals due to potential toxicity. Excellent selectivity besides strength is an important factor as an antibacterial agent.

[0008]

Means for Solving the Problems and Actions The present inventors have conducted intensive studies to solve these problems and to develop a truly clinically advantageous drug. In addition to showing unparalleled high activity not only against anaerobic gram-negative bacteria but also against gram-positive bacteria, it has strong antibacterial activity against anaerobic bacteria and mycoplasmas, which showed only weak activity with conventional quinolone carboxylic acid drugs. Was shown.

Further, the compound of the present invention has excellent selective toxicity between eukaryotes and prokaryotes, and exhibits not only a very good absorbability when administered orally to animals but also oral and parenteral administration. Since it shows a wide safety margin and does not show particularly problematic toxic effects, it is very useful as a pharmaceutical for humans and livestock, and as an antibacterial agent for seafood and plants.

The present invention provides a compound represented by the general formula [I]: [Wherein, R is a hydrogen atom or a lower alkyl group, R ¹ is a lower alkyl group, X is a halogen atom, Z is a halogen atom or (Where k is 0, 1 or 2; R ⁶ is a hydrogen atom;
A halogen atom, a lower alkyl group or a hydroxyl group, R ⁷
Represents a hydrogen atom, a lower alkyl group or a substituted lower alkyl group, and R ⁸ represents a hydrogen atom, a lower alkyl group, an acyl group, an alkoxycarbonyl group or an aralkyl group. )
Or a pyrrolidino group or a 3-hydroxypyrrolidino group. 8-alkoxyquinolone carboxylic acid derivatives, salts thereof, and hydrates thereof.

The term "lower alkyl group" as used herein means a linear or branched alkyl group having 1 to 5 carbon atoms, for example, a methyl group, an ethyl group, an isopropyl group, an n-butyl group, a t-butyl group.
-Butyl, amyl, isoamyl and the like.

The halogen atom is a fluorine, chlorine, bromine or iodine atom, preferably a fluorine, chlorine or bromine atom. An acyl group is
An aliphatic or aromatic acyl group having 1 to 10 carbon atoms, for example, a formyl group, an acetyl group, a benzoyl group and the like.

The alkoxycarbonyl group is an aliphatic or aromatic alkoxycarbonyl group having 1 to 10 carbon atoms, such as an ethoxycarbonyl group, a t-butoxycarbonyl group, a benzyloxycarbonyl group and the like.

The aralkyl group is an aralkyl group having 7 to 20 carbon atoms, such as a benzyl group, a benzhydryl group and a trityl group.

The substituted lower alkyl group is an alkyl group as defined above substituted with an amino group, a hydroxyl group or a halogen atom, such as an aminomethyl group, a hydroxymethyl group, an aminoethyl group, a hydroxyethyl group, a fluoroethyl group and the like. It is.

The cycloalkyl group is a cyclic alkyl group having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

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

General formula [II] (Wherein Y represents a halogen atom, and R, R ¹ and X are the same as those described above) by converting a compound represented by the general formula [III] Z ¹ H [III] wherein Z ¹ is (Where k is 0, 1 or 2; R ⁶ is a hydrogen atom;
A halogen atom, a lower alkyl group or a hydroxyl group, R ⁷
Represents a hydrogen atom, a lower alkyl group or a substituted lower alkyl group, and R ⁸ represents a hydrogen atom, a lower alkyl group, an acyl group, an alkoxycarbonyl group or an aralkyl group. )
Or a pyrrolidino group or a 3-hydroxypyrrolidino group. By condensation with a cyclic amine represented by the general formula [IV] Wherein R, R ¹ , X and Z ¹ are the same as described above.

The compound represented by the formula [II] and the compound represented by the formula [II]
The reaction of the compound represented by the formula [I] can be carried out without solvent or with water,
Alcohols, acetonitrile, dimethylformamide (DMF), dimethylsulfoxide (DMS0), hexamethylphosphoric amide (HMPA), pyridine,
It can be carried out in the presence of a polar solvent such as picoline.
The reaction temperature is between room temperature and 200 ° C., preferably between room temperature and 160 ° C.
Is appropriately selected within the range. More specifically, a compound represented by the formula [II] and 1 to 5 moles of the compound represented by the formula [III] are mixed in a 2 to 10 times volume of the solvent at room temperature to 12
It is preferable to react at 0 ° C. for 1 to 50 hours.

At this time, it is also preferable to use a deoxidizing agent such as triethylamine, diazabicyclo bases or potassium carbonate.

Further, among the compounds represented by the general formula [I], compounds wherein R is lower alkyl, that is, a compound represented by the general formula [V] (In the formula, AlK represents a lower alkyl group, and R ¹ , X and Z are the same as those described above.) In the case of a compound represented by the general formula [VI] (Wherein R ¹ , X and Z are the same as described above).

Such hydrolysis can be easily carried out by using an alkali such as caustic soda or caustic or an acid such as hydrochloric acid or sulfuric acid in water, alcohols or a mixture thereof at room temperature to the boiling point of the solvent.

Next, among the compounds represented by the general formula [I], a compound represented by the general formula [VII]: [Wherein Z ² is (Where R ¹⁰ represents an acyl group, an alkoxycarbonyl group or an aralkyl group, k, R ⁶ and R ⁷ are the same as described above), and R, R ¹ and X are the same as described above. By deacylation or dearalkylation, the compound represented by the general formula [VIII] [Wherein, Z ³ is (Where k, R ⁶ and R ⁷ are the same as described above), and R, R ¹ and X are the same as described above. ] Can be converted to the compound represented by the formula:

This reaction can be easily carried out by a commonly known method such as acid or alkali catalyzed hydrolysis, catalytic reduction and the like.

The general formula [I] for producing the compound of the present invention
The synthetic intermediate represented by I] is also a novel compound,
For example, it can be manufactured from the following route.

[0026]

The compound of the present invention represented by the general formula [IV] can also be produced by reacting a compound represented by the general formula [IX] with an alcohol represented by the general formula [X] as shown below. it can.

[0028] (In the formula, Hal represents a halogen atom, and R, R ¹ , X and Z ¹ are the same as described above.)

This reaction is carried out in the absence of a solvent or in a solvent such as alcohols, acetonitrile, DMSO, DMF, HMPA, dioxane, and benzene in the presence of a deoxidizing agent. Desired for. As the deoxidizing agent, an alkali fluoride, an alkali metal alcoholate, an alkali hydride, or the like can be used. An alcohol represented by the general formula R ¹ OH is used as a solvent, and an alkali such as sodium, potassium, lithium or the like is added thereto. It is preferable that a metal is allowed to act and the reaction is directly performed.

More specifically, the compound represented by the formula [IX] and at least an equimolar amount of the deoxidizing agent and the compound represented by the general formula R
^It is preferable to react the alcohol represented by ¹ OH with the solvent in a volume of 1 to 50 times at room temperature to 200 ° C. for 1 to 200 hours. When a solvent having a low boiling point is used, the reaction is carried out at a high temperature in a sealed tube. It is more advantageous to do so.

Next, the compound represented by the formula [I] can be converted into a salt thereof according to a conventional method, if desired. Examples of the salt include salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and the like.
Examples thereof include salts with organic acids such as methanesulfonic acid, lactic acid, oxalic acid, and acetic acid, and salts of sodium, potassium, magnesium, calcium, aluminum, cerium, chromium, cobalt, copper, iron, zinc, platinum, and silver.

Further, when the compound of the present invention is administered to humans, animals and plants, pharmaceutically well-known forms and routes are conventionally applied. For example, it is used orally or parenterally with powders, tablets, capsules, ointments, injections, syrups, solutions, eye drops, suppositories and the like.

[0033]

The compounds of the present invention and the method for producing the same will be described in detail with reference to examples.

Reference Example 1 Synthesis of 3-methoxy-2,4,5-trifluorobenzoic acid

[0035] 1,2,3,4-preparative tetrafluorobenzene 50g of Burdon et al method [Tetrahedron 22 25
41 (1966)] and subjected to bromination and methoxylation to form a colorless oily 1-bromo-3-methoxy-2,4,4.
22.21 g of 5-trifluorobenzene was obtained.

[0036] Anhydrous N-methyl-
A 37-ml solution of 2-pyrrolidone was charged into a pressure tube, 10 g of cuprous cyanide was added, and the mixture was heated at 140 to 150 ° C for 4.5 hours. After cooling, 44 g of ferric chloride hexahydrate and 11 ml of concentrated hydrochloric acid (60 ml) were added to the reaction solution, and the mixture was heated to 50 to 60 ° C. and stirred for 20 minutes. The reaction was extracted with ether,
The organic layer was washed with a dilute aqueous hydrochloric acid solution and then with water, and further washed with saturated saline. The resultant was dried over sodium sulfate and concentrated, and the residue was distilled under reduced pressure to obtain 14.25 g of 3-methoxy-2,4,5-trifluorobenzonitrile as a colorless oil. Boiling point 94 ° C / 8mm
Hg

8.5 g of concentrated sulfuric acid was added to 14.2 g of the obtained oil.
ml and 40 ml of water were added and stirred at 110 ° C. for 1 hour.
After cooling, the reaction solution was poured into 50 ml of ice water, the precipitated crystals were collected by filtration, washed with water, and the obtained crystals were recrystallized from a mixed solution of methylene chloride and n-hexane to give white needle-like 3-methoxy-2,4,4. 5
11.59 g of -trifluorobenzamide were obtained. 130-133 ° C

Next, 150 m of 18N sulfuric acid was added to the crystals.
and heated to 100 ° C. for 3.5 hours. Water 400 after cooling
The resulting crystals were recrystallized from n-hexane to give 9.61 g of the target compound as colorless needles.

Melting point: 98-101 ° C. Elemental analysis: C₈H₅F₃O₃  Calculated value: C; 46.62, H; 2.45 Analysis value: C; 46.68, H; 2.48

Example 1 Synthesis of 1 -cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid

To 9.4 g of 3-methoxy-2,4,5-trifluorobenzoic acid was added 50 ml of thionyl chloride, and the mixture was refluxed for 3 hours. After the thionyl chloride was distilled off, the residue was distilled under reduced pressure to obtain 8.86 g of 3-methoxy-2,4,5-trifluorobenzoyl chloride as a yellow oil. Boiling point 108-112 ° C / 20mmHg

A solution of 7 g of diethyl malonate in 35 ml of anhydrous toluene was added dropwise to 5.9 g of magnesium ethoxide, and the mixture was heated at 50 to 60 ° C. for 2 hours. Next, after cooling to −10 ° C., a solution of 8.86 g of the above acid chloride in 10 ml of anhydrous toluene was added dropwise over 15 minutes. After stirring at -5 ° C to 0 ° C for 1 hour, 30 ml of ice water containing 8 ml of concentrated sulfuric acid was added, and the toluene layer was separated. The organic layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated to give a brown oil, diethyl-3-methoxy-2,
4,64-trifluorobenzoylmalonate 13.64
g was obtained.

20 ml of water was added to 13.55 g of the obtained oil.
And 14 mg of p-toluenesulfonic acid, and the mixture was refluxed for 9 hours. After cooling, the reaction solution was extracted with methylene chloride, and the organic layer was extracted for 7 minutes.
% Sodium bicarbonate and then with saturated saline. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain 10.29 g of ethyl 3-methoxy-2,4,5-trifluorobenzoylacetate as a yellow oil.

9.6 g of acetic anhydride and 8.4 g of ethyl orthoformate were added to 9.79 g of the obtained ethyl acetate, and the mixture was refluxed for 3 hours. Further, 3.2 g of acetic anhydride and 8.8 g of ethyl orthoformate were added and refluxed for 8 hours. The reaction solution was concentrated to obtain 9.73 g of brownish oily ethyl 2- (3-methoxy-2,4,5, trifluorobenzoyl) -3-ethoxyacrylate.

9.73 g of the obtained oil was added to ethanol 2
The solution was dissolved in 0 ml, and 2.0 g of cyclopropylamine was added dropwise under ice cooling. After stirring at room temperature for 2 hours, the mixture was concentrated, and the residue was subjected to silica gel column chromatography [solvent: n-hexane: ethyl acetate =
5: 1] to give 7.52 g of ethyl 2- (3-methoxy-2,4,5-trifluorobenzoyl) -3-cyclopropylaminoacrylate as yellow-white crystals.

Melting point: 56-58 ° C. Elemental analysis: C₁₆H₁₆F₃NO₄  Calculated value: C; 55, 98, H; 4.70, N; 4.08 Analytical value: C; 56.07, H; 4.66, N; 4.07

6.68 g of the obtained crystals were dissolved in 26 ml of anhydrous dimethylformamide, and 1.3 ml of sodium fluoride was added.
1 g was added and the mixture was refluxed for 5 hours. After cooling, the reaction solution was ice-water 100m.
The precipitate was collected by filtration, washed with water, and recrystallized from ethyl acetate to give colorless needle-like 1-cyclopropyl-
Ethyl 6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylate was converted to 4.5.
3 g were obtained.

Melting point: 178 to 180 ° C. Elemental analysis: C₁₆H_FifteenF₂NO₄  Calculated value: C; 59.44, H; 4.68, N; 4.33 Analysis value: C; 59.34, H; 4.59, N; 4.33

Then, 30 g of acetic acid was added to 4.5 g of the crystals.
l, concentrated sulfuric acid 4 ml and water 22 ml, and refluxed for 1 hour. After cooling, 100 ml of ice water was added, and the precipitated crystals were collected by filtration.
After washing with water and drying, 4 g of the target substance as a colorless powder was obtained.

Melting point: 185 to 186 ° C. Elemental analysis: C₁₄H₁₁F₂NO₄  Calculated value: C; 56, 95, H; 3.76, N; 4.74 Analytical value: C; 56.68, H; 3.70, N; 4.74

Example 2 Synthesis of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylate

To 54.0 g of 2-chloro-4,5-difluoro-3-methoxybenzoic acid was added 266 ml of thionyl chloride, and the mixture was refluxed for 4 hours. After the thionyl chloride was distilled off, the residue was distilled under reduced pressure to give colorless oily 2-chloro-4,5-difluoro-.
54.39 g of 3-methoxybenzoyl chloride was obtained. Boiling point 90-100 ° C / 3mmHg

To 32.08 g of magnesium ethoxide, 43.35 g of diethyl malonate and 190 m of anhydrous toluene
The solution was added dropwise and heated at 50-60 ° C. for 2.5 hours. Next, after cooling to −20 ° C., a solution of 52.0 g of the above acid chloride in 60 ml of anhydrous toluene was added dropwise over 30 minutes. -5 ° C ~
After stirring at 0 ° C for 1 hour, 450m of ice water containing 70ml of concentrated sulfuric acid
1 was added and the toluene layer was separated. The aqueous layer was extracted with toluene, and the organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to give pale yellow oily diethyl-2-chloro-4,5-.
Difluoro-3-methoxybenzoylmalonate85.
87 g were obtained.

To 85.87 g of the obtained oil, 150 m of water was added.
1 and 0.1 g of p-toluenesulfonic acid were added and refluxed for 9 hours. The cooled reaction solution was extracted with chloroform, and the organic layer was washed with 7% sodium hydrogen carbonate and then with saturated saline. The organic layer was dried over anhydrous sodium sulfate and concentrated, and the residue was distilled under reduced pressure to give 2-chloro-4.5-difluoro-3 as a pale yellow oil.
34.65 g of ethyl -methoxybenzoylacetate was obtained. Boiling point 110-120 ° C / 6mmHg

20.93 g of acetic anhydride and 18,22 g of ethyl orthoformate were added to 24.0 g of the obtained ethyl acetate, and the mixture was refluxed for 5 hours.
Ethyl (2-chloro-4,5-difluoro-3-methoxybenzoyl) -3-ethoxyacrylate was obtained.

The obtained oily substance was dissolved in ethanol (60 ml), and cyclopropylamine (5.62 g) was added dropwise under ice cooling. After stirring at room temperature for 1 hour, the precipitated crystals were collected by filtration, washed with ether and colorless needle-like crystals of 2- (2-chloro-4,5-difluoro-).
16.0 g of ethyl 3-methoxybenzoyl) -1-cyclopropylaminoacrylate was obtained.

Melting point: 87-88 ° C. Elemental analysis value: C₁₆H₁₆ClF₂NO₄  Calculated: C; 53.41, H; 4.48, N; 3.89 Found: C; 53.40, H; 4.53, N; 3.93

1.0 g of the obtained crystals were added little by little to a suspension of 0.14 g of 60% sodium hydride in 6 ml of anhydrous dioxane under ice cooling, and the mixture was refluxed for 1 hour. 20 ml of water after cooling
Was added, and the precipitated crystals were collected by filtration, washed successively with a small amount of methanol and ether, and washed with colorless needles of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline. 0.68 g of ethyl carboxylate was obtained.

Melting point: 177 to 178 ° C.

Example 3 Synthesis of 7- (3-amino-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid

1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-
Quinolinecarboxylic acid 2g anhydrous acetonitrile 20ml
1.86 g of 3-t-butoxycarbonylaminopyrrolidine and 1,8-diazabicyclo [5,4,0] were added to the suspension.
1.02 g of undec-7-ene (DBU) was added, and the mixture was refluxed for 3 hours. The reaction mixture was concentrated and chloroform was added to the residue.
Was added and dissolved, and washed with 20 ml of a 10% aqueous citric acid solution. The organic layer was further washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. To the residue was added 20 ml of hot methanol, and after cooling, the precipitated crystals were collected by filtration to give 7- (3-t-butoxycarbonylamino) as yellow-white prism crystals. -2-pyrrolidinyl) -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-4-oxo-3-quinolinecarboxylic acid 2.25 g
I got

Melting point: 224 to 226 ° C. (decomposition) Elemental analysis: C ₂₃ H ₂₈ FN ₃ O ₆ １ ／ H ₂ O Calculated: C; 59.28, H; 6.22, N; 9.02 Actual measurement Values: C; 59.18, H; 6.08, N; 8.82

Next, 16 ml of methanol was added to 2.23 g of the crystal to form a suspension, and 16 ml of concentrated hydrochloric acid was slowly added dropwise. The reaction solution was stirred at room temperature for 3 hours, cooled on ice, neutralized with concentrated aqueous ammonia, and the precipitated crystals were collected by filtration and washed thoroughly with water. This was further washed successively with methanol and ether to obtain 1.52 g of the desired product as a white powder.

[0064] melting point two hundred seventeen to two hundred and eighteen ° C. Elemental _{analysis: C 18 H 20 FN 3 O} 4 · 1 / 2H 2 O Calculated: C; 58.37, H; 5.71 , N; 11.3
5 Found: C; 58.68, H; 6.10, N; 11.1
4

Example 4 7- (cis-3amino-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic Acid synthesis

1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-
Quinoline carboxylic acid 200 mg, cis-3-t-butoxycarbonylamino-4-methylpyrrolidine 150 m
g, 110 mg of DBU and 3 ml of anhydrous acetonitrile were refluxed for 5 hours. After cooling, the precipitate was collected by filtration and then added to 6 ml of a concentrated hydrochloric acid-methanol (1: 1) mixed solution, followed by stirring at room temperature for 1.5 hours. The reaction solution was neutralized with concentrated aqueous ammonia and allowed to stand in an ice room, and the precipitated crystals were collected by filtration and washed with cold water to obtain 90 mg of the desired product as colorless prisms.

[0067] melting point 185 to 188 ° C. (decomposition) Elemental analysis _{(%): C 19 H 22} FN 3 O 4 · 3 / 2H 2 O Calculated: C; 56.71, H; 6.26 , N; 10 .44 found: C; 56.53, H; 6.17, N; 10.37

Example 5 7- (Trans-3-amino-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4
Of dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid

1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-
Quinolinecarboxylic acid 0.40 g, trans-3-t-butoxycarbonylamino-4-methylpyrrolidine 0.4
1 g, DBU 0.21 g and anhydrous acetonitrile 5 ml
After refluxing the mixture for 2.5 hours, the reaction solution was concentrated under reduced pressure.
To the residue was added 40 ml of chloroform, washed successively with 20 ml each of a 10% aqueous citric acid solution and saturated saline, dried over sodium sulfate and concentrated under reduced pressure.
-(Trans-3-t-butoxycarbonylamino-4
-Methyl-1-pyrrolidinyl) -1-cyclopropyl-
6-fluoro-1,4-dihydro-8-methoxy-4-
An oxo-3-quinolinecarboxylic acid was obtained. Next, the crystals were suspended in 5 ml of methanol, 5 ml of concentrated hydrochloric acid was added dropwise, and the mixture was stirred at room temperature for 1.5 hours. 0.29 g of the desired product was obtained.

Melting point: 214 to 215 ° C. Elemental analysis value (%): C₁₉H₂₂FN₃O₄  Calculated: C; 60.07, H; 5.97, N; 11.06 Found: C; 60.41, H; 5.80, N; 11.05

Example 6 7- (3-Aminomethyl-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-
Synthesis of methoxy-4-oxo-3-quinolinecarboxylic acid

1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-
A mixture of 200 mg of quinoline carboxylic acid, 80 mg of 3-aminomethylpyrrolidine, 110 mg of DBU, and 3 ml of anhydrous acetonitrile was refluxed for 2.5 hours. After cooling, the precipitate was collected by filtration and recrystallized from a mixed solution of methylene chloride-methanol (1: 1) to obtain 90 mg of the target substance as white powdery crystals.

Melting point: 198 to 200 ° C. Elemental analysis: C₁₉H₂₂FN₃O₄  Calculated: C; 60.79, H; 5.91, N; 11.19 Found: C; 60.39, H; 5.87, N; 11.07

Example 7 1-Cyclopropyl-6-fluoro-1,4 dihydro-
Synthesis of 8-methoxy-7- (3-methylaminomethyl-1-pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid

1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-
A mixture of 200 mg of quinolinecarboxylic acid, 90 mg of 3-methylaminomethylpyrrolidine, 110 mg of DBU, and 3 ml of anhydrous acetonitrile was refluxed for 75 minutes. After cooling down,
The precipitate is collected by filtration, and methylene chloride-methanol (1: 1)
Recrystallized from the mixture to obtain 130 mg of the desired product as white powdery crystals
I got

Melting point: 226.5 to 230 ° C. Elemental analysis: C ₂₀ H ₂₄ FN ₃ O ₄ .1 / 2H ₂ O Calculated: C; 60.29, H; 6.32, N; 10.54 : C; 60.49, H; 6.08, N; 10, 48

Example 8 1-Cyclopropyl-7- (3-ethylaminomethyl-
Synthesis of 1-pyrrolidinyl) -6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid

1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-
A mixture of 200 mg of quinolinecarboxylic acid, 100 mg of 3-ethylaminomethylpyrrolidine, 110 mg of DBU, and 3 ml of anhydrous acetonitrile was refluxed for 6 hours. After cooling down,
The precipitate was collected by filtration and recrystallized from methanol to obtain 120 mg of the target compound as colorless prism crystals.

[0079] melting point two hundred and seventeen to two hundred and nineteen ° C. Elemental _{analysis: C 21 H 26 FN 3 O} 4 · 2 / 3H 2 O Calculated: C; 60.71, H; 6.63 , N; 10.11 Found: C 60.59, H; 6.43, N; 10.03

Example 9 Synthesis of 7- (3-amino-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid

7- (3-amino-1-pyrrolidinyl)-
1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid 0.47
g, 0.2 g of metallic sodium and 10 m of anhydrous methanol
to the methylate solution prepared from
Stirred at ~ 150 ° C for 49 hours. After the solvent was distilled off, the residue was subjected to silica gel column chromatography [silica gel 25
g, developing solvent: chloroform-methanol-concentrated aqueous ammonia (20: 6: 1)].
Recrystallization from a mixed solution of methanol (1: 1) gave 6 mg of the desired product as pale yellow prism crystals.

Melting point: 207.5 to 212 ° C. Elemental analysis value (%): C ₁₈ H ₂₀ FN ₃ O ₄ .H ₂ O Calculated value: C; 56.99, H; 5.82, N; 11.13 Actual measurement Values: C; 57.19, H; 5.38, N; 10.86 Mass spectrometry (m / e): 361 (M ⁺ ), 362 (M ⁺ +1).

[0083]

Example 10 7- (3-Amino-4-methyl-1-pyrrolidinyl)-
Synthesis of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid

80 mg of 7- (3-amino-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was treated with sodium methylate -It was added to a methanol solution (50 mg of metallic sodium, 3 ml of anhydrous methanol), sealed and reacted in an oil bath at 140 to 150 ° C for 86 hours. After cooling, the solvent was distilled off, a small amount of water was added, and the pH was adjusted to 7 with acetic acid. The residue obtained by evaporating the solvent again was subjected to silica gel column chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (2.
0: 6: 1)], and recrystallized from methanol to obtain 9 mg of the desired product as pale yellow prism crystals.

[0086] mp: from 191.5 to 193.5 ° C. Elemental analysis _{(%): C 19 H 22} FN 3 O 4 · 7 / 5H 2 O Calculated: C; 56.96, H; 6.24 , N 10.49 Found: C; 57.10, H; 5.98, N; 10.42

[0087]

Example 11 7- (3-Aminomethyl-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-
Synthesis of methoxy-4-oxo-3-quinolinecarboxylic acid

7- (3-aminomethyl-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,
0.5 g of 4-dihydro-4-oxo-3-quinolinecarboxylic acid is added to a methanol solution of sodium methylate (0.2 g of sodium metal, 9 ml of anhydrous methanol) and reacted in an oil bath at 140 to 150 ° C. for 86 hours. Was. After cooling, the solvent was distilled off, a small amount of water was added, and the pH was adjusted to 7 with acetic acid. The solvent was distilled off again, and the residue was separated by silica gel chromatography [developing solvent: chloroform-methanol-concentrated aqueous ammonia (20: 6: 1)], and then recrystallized from methanol to obtain colorless flaky crystals. Thing 40m
g was obtained.

[0090] melting point from 225 to 228.5 ° C. (decomposition) Elemental _{analysis: C 19 H 22 FN 3 O} 4 · 2 / 3H 2 O Calculated: C; 58.91, H; 6.07 , N; 10. 85 found: C; 58.73, H; 5.92, N; 10.88.

(Test Example 1) Antibacterial Spectrum An antibacterial test was carried out according to a method specified by the Japanese Society of Chemotherapy. The results are shown in Tables 1 to 6.

[0092]

[Table 1]

[0093]

[Table 2]

[0094]

[Table 3]

[0095]

[Table 4]

[0096]

[Table 5]

[0097]

[Table 6]

[0098]

The compound of the present invention is superior to the conventionally known ciprofloxacin against gram-positive bacteria and has a high activity against anaerobic bacteria comparable to metronidazole recommended by a specialist.

 ──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-60-214777 (JP, A) JP-A-60-126271 (JP, A) JP-A-59-67269 (JP, A)

Claims (7)

(57) [Claims] 1. A compound of the general formula [I] [Wherein, R is a hydrogen atom or a lower alkyl group, R ¹ is a lower alkyl group, X is a halogen atom, Z is a halogen atom or (Where k is 0, 1 or 2; R ⁶ is a hydrogen atom;
A halogen atom, a lower alkyl group or a hydroxyl group, R ⁷
Represents a hydrogen atom, a lower alkyl group or a substituted lower alkyl group, and R ⁸ represents a hydrogen atom, a lower alkyl group, an acyl group, an alkoxycarbonyl group or an aralkyl group. )
Or a pyrrolidino group or a 3-hydroxypyrrolidino group. 8-alkoxyquinolone carboxylic acid derivatives, salts thereof, and hydrates thereof. 2. Formula (I) [Wherein, R is a hydrogen atom or a lower alkyl group, R ¹ is a lower alkyl group, X is a halogen atom, Z is a halogen atom or (Where k is 0, 1 or 2; R ⁶ is a hydrogen atom;
A halogen atom, a lower alkyl group or a hydroxyl group, R ⁷
Represents a hydrogen atom, a lower alkyl group or a substituted lower alkyl group, and R ⁸ represents a hydrogen atom, a lower alkyl group, an acyl group, an alkoxycarbonyl group or an aralkyl group. )
Or a pyrrolidino group or a 3-hydroxypyrrolidino group. At least one of the 8-alkoxyquinolone carboxylic acid derivatives represented by the formula:
An antibacterial agent containing at least one species as an active ingredient. 3. General formula [II] (Wherein, R represents hydrogen or a lower alkyl group, R ¹ represents a lower alkyl group, and X and Y represent the same or different halogen atoms) and a general formula [III] Z ¹ H [III Wherein Z ¹ is (Where k is 0, 1 or 2; R ⁶ is a hydrogen atom;
A halogen atom, a lower alkyl group or a hydroxyl group, R ⁷
Represents a hydrogen atom, a lower alkyl group or a substituted lower alkyl group, and R ⁸ represents a hydrogen atom, a lower alkyl group, an acyl group, an alkoxycarbonyl group or an aralkyl group. )
Or a pyrrolidino group or a 3-hydroxypyrrolidino group. Wherein the amine represented by the general formula [IV] is condensed with an amine represented by the formula: (Wherein, R, R ¹ , X and Z ¹ are the same as described above). A method for producing an 8-alkoxyquinolone carboxylic acid derivative, a salt thereof, and a hydrate thereof. 4. The general formula [V] [Wherein, AlK is a lower alkyl group, R ¹ is a lower alkyl group, X is a halogen atom, Z is a halogen atom or (Where k is 0, 1 or 2; R ⁶ is a hydrogen atom;
A halogen atom, a lower alkyl group or a hydroxyl group, R ⁷
Represents a hydrogen atom, a lower alkyl group or a substituted lower alkyl group, and R ⁸ represents a hydrogen atom, a lower alkyl group, an acyl group, an alkoxycarbonyl group or an aralkyl group. )
Or a pyrrolidino group or a 3-hydroxypyrrolidino group. Wherein the compound represented by the general formula [VI] is hydrolyzed. (Wherein R ¹ , X and Z are the same as those described above). A method for producing an 8-alkoxyquinolone carboxylic acid derivative, a salt thereof, and a hydrate thereof. 5. A compound of the general formula [VII] [Wherein, R represents hydrogen or a lower alkyl group, R ¹ represents a lower alkyl group, X represents a halogen atom, and Z ² represents (Where k is 0, 1 or 2; R ⁶ is a hydrogen atom;
A halogen atom, a lower alkyl group or a hydroxyl group, R ⁷
Represents a hydrogen atom, a lower alkyl group or a substituted lower alkyl group, and R ¹⁰ represents an acyl group, an alkoxycarbonyl group or an aralkyl group. ). Wherein the compound represented by the general formula [VIII] is deacylated or dearalkylated. [Wherein Z ³ is (Where k, R ⁶ and R ⁷ are the same as above).
R, R ¹ and X are the same as above. And a salt thereof, and a hydrate thereof. 6. The formula [IX] Wherein R is hydrogen or a lower alkyl group, X and Ha
l is the same or different halogen atom, Z ¹ is (Where k is 0, 1 or 2; R ⁶ is a hydrogen atom;
A halogen atom, a lower alkyl group or a hydroxyl group, R ⁷
Represents a hydrogen atom, a lower alkyl group or a substituted lower alkyl group, and R ⁸ represents a hydrogen atom, a lower alkyl group, an acyl group, an alkoxycarbonyl group or an aralkyl group. )
Or a pyrrolidinyl group or a 3-hydroxypyrrolidino group. A compound represented by the general formula [X] R ¹ OH [X] (wherein R ¹ represents a lower alkyl group) in the presence of a base catalyst. [IV] (Wherein, R, R ¹ , X and Z ¹ are the same as those described above). 7. The method according to claim 6, wherein the base catalyst is an alkali metal alcoholate.