JPH0676400B2 - Novel pyridonecarboxylic acid derivative, its ester and its salt - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel pyridonecarboxylic acid derivative which shows excellent antibacterial activity, a lower alkyl ester thereof and a salt thereof.

2. Description of the Related Art Japanese Patent Application Laid-Open Nos. 59-67269 and 60-214773 describe a pyridonecarboxylic acid derivative having a diazabicyclo ring at the 7-position.

OBJECT OF THE INVENTION The present invention provides a novel pyridonecarboxylic acid derivative having an excellent antibacterial action.

Structure of the Invention The compound of the present invention has the following general formula (I): (In the formula, X means a nitrogen atom or C—A, where A
Represents a hydrogen atom or a halogen atom, R represents a hydrogen atom, a lower alkyloxycarbonyl group, or a lower alkanoyl group optionally substituted with a halogen atom, and m represents 0 or 2. , N means 0 or 1. ) Is a pyridonecarboxylic acid, a lower alkyl ester thereof and a salt thereof.

In the present specification, examples of the halogen atom include fluorine and chlorine. Examples of the lower alkyl in the lower alkyloxycarbonyl group include methyl, ethyl,
Examples include propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl and the like. Examples of the optionally substituted lower alkanoyl group include acetyl and trifluoroacetyl.

Examples of the salt of the compound of the present invention include salts with inorganic acids such as hydrochloric acid and phosphoric acid; and salts with organic acids such as acetic acid, lactic acid, oxalic acid, succinic acid, methanesulfonic acid, maleic acid, malonic acid and gluconic acid. Salts; salts with acidic amino acids such as aspartic acid and glutamic acid; or metal salts of the compound of formula (I) such as sodium, potassium, calcium, magnesium, zinc, silver; dimethylamine, triethylamine, dicyclohexylamine, benzylamine, etc. Salts with organic bases: Salts with basic amino acids such as lysine and arginine can be mentioned.

Examples of the lower alkyl ester of the compound of formula (I) include methyl ester and ethyl ester of compound (I).

The compounds of the present invention may also exist as hydrates. Therefore, such forms are naturally included in the compound of the present invention.

Further, the compounds of the present invention include those having an asymmetric carbon atom in the substituent at the 7-position, and they can exist as an optically active substance. These optically active compounds are also included in the compound of the present invention.

Furthermore, some of the compounds of the present invention have a plurality of asymmetric carbon atoms in the substituent at the 7-position, and they may exist as different stereoisomers thereof. These stereoisomers are also included in the compound of the present invention.

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

The compound of the present invention has the following general formula: (Wherein Y represents a halogen atom and X is the same as the above) and a compound represented by the following general formula: (In the formula, R, m and n are the same as those described above.) The compound can be produced by reacting the compound and isolating the product by a conventional method.

This reaction includes alcohols such as ethanol, ethers such as dioxane, tetrahydrofuran, 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene, toluene and xylene, acetonitrile, dimethylformamide, dimethylsulfoxide, pyridine, water, etc. Of the starting compounds (II) and (III) in an inert solvent of 10 to 180 ° C
Can be carried out by stirring for 10 minutes to 24 hours.

This reaction is generally carried out in the presence of an acid acceptor using the starting compound (III) in an equivalent amount to a slight excess of the starting compound (II). It may also be used as an acid acceptor.

As the acid acceptor, hydroxides such as sodium hydroxide and potassium hydroxide, carbonates such as sodium carbonate and potassium carbonate, bicarbonates such as sodium bicarbonate and potassium bicarbonate,
Organic bases such as triethylamine, dimethylaniline, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undecene-7 (DBU) are mentioned.

If possible, the starting compound (III) used in this reaction may be carried out in a form in which an amino group not involved in the reaction is protected, and the protecting group may be removed by a conventional method after completion of the reaction. The protecting group may be any as long as it can be removed without destroying the structure of the compound of the present invention formed by the reaction, and it is protected in the field of chemistry of peptide or amino sugar or nucleic acid or β-lactam compound. A protecting group usually used as a group is used. Examples of preferable protecting groups include easily hydrolyzable groups such as acetyl, trifluoroacetyl and ethoxycarbonyl, or benzyl groups.

The starting compound (II) is a known compound and can be produced, for example, by the method described in the following documents or a method analogous thereto.

The raw material compound (III) is a novel compound and is used in Reference Examples 1 to 3.
It can be produced by the method described in 1) or a method analogous thereto.

When the compound of the present invention obtained by the above method is an ester, it can be converted to the compound of formula (I) by hydrolyzing the ester portion by a conventional method. Furthermore, if necessary, the compound of formula (I) can be esterified by a conventional method to give an ester of formula (I).

The compound of the present invention thus produced is isolated and purified by a conventional method. Depending on the isolation and purification conditions, it can be obtained in the form of a salt or a free form, which are mutually converted depending on the purpose to produce the desired form of the compound of the present invention.

The stereoisomers of the compound of the present invention can be separated from each other by a conventional method such as fractional crystallization and chromatographic separation.

The optically active substance of the compound of the present invention can also be separated by applying a known method.

EFFECTS OF THE INVENTION The compound (I) of the present invention thus obtained, its lower alkyl ester and its salt are all novel compounds.
In particular, compound (I) and its salt exhibit excellent antibacterial activity and are therefore valuable as antibacterial agents. Compound (I)
Or a salt thereof, as well as human and veterinary medicine,
It can also be used as a fish disease drug, an agricultural chemical, a food preservative, and the like. The ester form of compound (I) is of course valuable as a direct raw material for compound (I).

Next, data on the antibacterial activity of the compound of the present invention will be given below.

When the compound of the present invention is used as an antibacterial agent in humans, its dosage varies depending on age, body weight, symptoms, administration route, etc., but it is recommended to administer 5 mg to 5 g per day in one or several divided doses. To be done. The route of administration may be oral or parenteral.

Although the compound of the present invention may be used as the bulk powder, it is usually administered in the form prepared with a carrier for formulation. Specific examples thereof include tablets, liquids, capsules, granules, fine granules, powders,
Examples include syrups, injections and ointments. These preparations are prepared according to a conventional method. Oral pharmaceutical carriers include starch, mannitol, crystalline cellulose, CMC Na,
Substances which are commonly used in the field of pharmaceutical preparations such as water and ethanol and which do not react with the compound of the present invention are used. Examples of carriers for injection include carriers commonly used in the field of injectables such as water, physiological saline, glucose solutions, and infusions.

Further, the above-mentioned solutions and ointments can also be used in otolaryngology and ophthalmology treatment.

Next, the production method of the compound of the present invention will be described more specifically with reference to Examples.

Reference Example 1 6-trifluoroacetylamino-3-azabicyclo [3.3.0] octane: (1) N-benzylglycine 5 g, 2-cyclopentene-
While dehydrating a mixture of 1-one 5 ml, paraformaldehyde 1.8 g, 1,2-dichloroethane, and n-hexane,
After heating under reflux for 3 hours, 3-benzyl-3-azabicyclo [3.3.0] octane-6-one (3.4 g) was obtained as an oil.

(2) 3.4 g of this compound was added to hydroxylamine hydrochloride in ethanol in the presence of 6 ml of 20% aqueous sodium hydroxide solution.
React with 0 g to give 3-benzyl-3-azabicyclo [3.
3.0] Octane-6-one oxime (1.7 g) was obtained.

IR spectrum (liquid film) cm ^-1 : 3300,1450,1050. Mass spectrum m / z: 230 (M ⁺ ), 213,91. (3) 1.7 g of this compound was dissolved in 70 ml of 11% ammonia-ethanol solution. , Raney nickel 5ml as catalyst 50
Catalytic reduction was performed at ° C. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform, reacted with 5 ml of trifluoroacetic anhydride under ice cooling for 40 minutes, and then separated and purified by column chromatography to obtain the following compound as a colorless oil.

Compound A: 5,6-cis-3-benzyl-6-trifluoroacetylamino-3-azabicyclo [3.3.0] octane (0.5g). IR spectrum (liquid film) cm ^-1 : 3220,1715,1205,1175,1150. Mass spectrum m / z: 312 (M ⁺ ), 235,221,91. NMR spectrum (CDCl ₃ ) δ: 4.26 (1H, m , C ₆ -H) compound B: 5,6-trans-3-benzyl-6-trifluoroacetyl-amino-3-azabicyclo [3.3.0] octane (0.4 g). IR spectrum (liquid film) cm ^-1 : 3300,1700,1550,1210,1185,
1160. Mass spectrum m / z: 312 (M ⁺ ), 235, 221, 91. NMR spectrum (CDCl ₃ ) δ: 4.06 (1H, m, C ₆ -H) (4) The above compound A was dissolved in ethanol to obtain palladium. -Catalytic reduction using carbon as a catalyst to obtain the desired product (cis form)
Got

Similarly, the target compound (trans form) was obtained from the compound B.

Reference Example 2 1-Methoxycarbonylamino-3-azabicyclo [3.
1.0] Hexane: (1) Known compound 3-benzyl-3-azabicyclo [3.1.0] hexane-1-carbonitrile [Tetrahedron
Letters, 369 (1975)] 2.0 g and concentrated sulfuric acid are stirred at room temperature for 5 hours to give 3-benzyl-3-azabicyclo [3.1.0].
1.6 g of hexane-1-carboxamide was obtained. mp62-63
° C. (2) 1.5 g of this compound was dissolved in methanol and treated with antiformin to give 3-benzyl-1-methoxycarbonylamino-3-azabicyclo [3.1.0] hexane 0.7.
got g. mp102-104 ° C. (3) This compound was treated in the same manner as in Reference Example 1 (4) to obtain the desired product.

Reference Example 3 1-Trifluoroacetylaminomethyl-3-azabicyclo [3.1.0] hexane: (1) The known compound 3-benzyl-3-azabicyclo [3.1.0] hexane-1-carbonitrile was used in Reference Example 1
Treated in the same manner as in (3), 3-benzyl-1-trifluoroacetylaminomethyl-3-azabicyclo [3.1.
0] Hexane was obtained.

(2) This compound was treated in the same manner as in Reference Example 1 (4) to obtain the desired product.

Example 1 1-Cyclopropyl-6,8-difluoro-7- (5,6-cis-6-trifluoroacetylamino-3-azabicyclo [3.3.0] octane-3-yl) -1,4-sihydro -4
-Oxoquinoline-3-carboxylic acid: 5,6-cis-3-benzyl-6-trifluoroacetylamino-3-azabicyclo [3.3.0] octane 640 mg was dissolved in ethanol 10 ml, and 5% palladium-carbon 100 mg was added. And stirred at 60 ° C. under hydrogen atmosphere. After absorbing the theoretical amount of hydrogen, the catalyst was filtered off and the filtrate was concentrated to give 5,6-cis-6-trifluoroacetylamino-3-azabicyclo [3.3.0] octane. This is acetonitrile 10m
0.3 ml of triethylamine and 400 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid were added to dissolve the mixture in 120 to 14
The mixture was heated to reflux at 0 ° C for 1.5 hours. The crystals that precipitate after ice-cooling are collected by filtration, washed with water, ethanol and ether to give the desired product.
0.42 g was obtained as pale yellow crystals. mp245-247 ° C. Example 2 1-Cyclopropyl-6,8-difluoro-7- (5,6-cis-6-amino-3-azabicyclo [3.3.0] octane-3-yl) -4,4-dihydro-4- Oxoquinoline-
3-carboxylic acid: 1-cyclopropyl-6,8-difluoro-7- (5,6-cis-6-trifluoroacetylamino-3-azabicyclo [3.3.0] octane-3-yl) -1,4 -Dihydro-4
-Oxoquinoline-3-carboxylic acid (0.35 g) was added with 5% aqueous caustic soda solution (2 ml) and heated at 100 ° C for 2 hours. After cooling, the reaction solution was acidified with acetic acid, and then concentrated aqueous ammonia was added to make the solution alkaline. The mixture was concentrated under reduced pressure to about half volume and left at room temperature overnight. The precipitated crystals are collected by filtration, water, ethanol,
The crystals were washed successively with ether to give the desired product (0.18 g) as a white powder. mp240-244 ℃ (decomposition). Example 3 1-Cyclopropyl-6,8-difluoro-7- (5,6-trans-6-trifluoroacetylamino-3-azabicyclo [3.3.0] octane-3-yl) 1,4-dihydro-
4-oxoquinoline-3-carboxylic acid: 5,6-trans-3-benzyl-6-trifluoroacetylamino-3-azabicyclo [3.3.0] octane Got
mp217-221 ° C. Example 4 1-Cyclopropyl-6,8-difluoro-7- (5,6-trans-6-amino-3-asabicyclo [3.3.0] octane-3-yl) -1,4-dihydro-4- Oxoquinoline-3-carboxylic acid: 1-cyclopropyl-6,8-difluoro-7- (5,6-trans-6-trifluoroacetylamino-3-azabicyclo [3.3.0] octane-3-yl)- 1,4-Dihydro-4-oxoquinoline-3-carboxylic acid was treated in the same manner as in Example 2 to obtain the target product.

Example 5 1-Cyclopropyl-6,8-difluoro-7- (1-methoxycarbonylamino-3-azabicyclo [3.1.0]
Hexan-3-yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid: Example 1 by using 3-benzyl-1-methoxycarbonylamino-3-azabicyclo [3.1.0] hexane. The target product was obtained in the same manner as. mp176-178 ° C. Example 6 7- (1-Amino-3-azabicyclo [3.1.0] hexan-3-yl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic Acid: 1-cyclopropyl-6,8-difluoro-7- (1-methoxycarbonylamino-3-azabicyclo [3.1.0]
Hexan-3-yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid was treated in the same manner as in Example 2 to obtain the target product. mp186-188 ° C. Example 7 1-Cyclopropyl-6-fluoro-7- (1-trifluoroacetylamino-3-azabicyclo [3.1.0] hexan-3-yl) -1,4-dihydro-4-oxo-1.8
Ethyl naphthyridine-3-carboxylate: 3-benzyl-1-trifluoroacetylaminomethyl-3-azabicyclo [3.1.0] hexane and 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro. The target product was obtained in the same manner as in Example 1 from ethyl-4-oxo-1,8-naphthyridine-3-carboxylate. mp23
4-235 ° C. Example 8 7- (1-aminomethyl-3-azabicyclo [3.1.0]
Hexan-3-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid: 1-cyclopropyl-6-fluoro-7- (1 -Trifluoroacetylaminomethyl-3-azabicyclo (3.1.
[0] Hexan-3-yl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate was treated in the same manner as in Example 2 to obtain the desired product. mp245-250 ° C (decomposition).

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Claims (1)

[Claims] 1. A general formula (In the formula, X means a nitrogen atom or C—A, where A
Represents a hydrogen atom or a halogen atom, R represents a hydrogen atom, a lower alkyloxycarbonyl group, or a lower alkanoyl group optionally substituted with a halogen atom, and m represents 0 or 2. , N means 0 or 1. ) Pyridonecarboxylic acid represented by the following, a lower alkyl ester thereof and a salt thereof.