JPH01135770A - Novel pyridonecarboxylic acid derivative, ester and salt thereof - Google Patents

Abstract

NEW MATERIAL:A pyridonecarboxylic acid derivative of formula I (Y1, Y2 are halogen; Y3 is carboxyl, lower alkoxycarbonyl, cyano, carbamoyl; R1 is lower alkyl, halogeno-lower-alkyl, lower alkenyl, cycloalkyl; A is halogen atom, formula II; Z is O, S; R2, R3, R4 are H, lower alkyl; R5 is H, lower alkyl, benzyl; R6 is H, halogen, lower alkyl; n is 0, 1), its ester, ester. EXAMPLE:Diethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3,5- dicarboxylate. USE:It is used as an antibacterial. It can be administered orally and parenterally. The solution and ointment can be used in otoraryngology or ophthalmology. PREPARATION:Ring closure of a compound of formula III (X2 is halogen; R is H, etc.) is conducted in the presence of a base to give the compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel pyridonecarboxylic acid derivatives, esters thereof, and salts thereof, which exhibit excellent antibacterial activity.

JLL's J1 Since it was revealed that lunalidixic acid is useful as an antibacterial agent, various pyridone carboxylic acid compounds have been synthesized.

The present invention provides novel pyridonecarboxylic acid derivatives having excellent antibacterial activity.

(Left space below) The compound of the present invention has the following formula (wherein Y and Y2 are the same or different and represent a halogen atom, and Y3 is a carboxyl group, a lower alkyloxycarbonyl group, or a cyano group). or a carbamoyl group which may have a substituent, and R means a lower alkyl group, a halogeno-lower alkyl group, a lower alkenyl group, a cycloalkyl group, or a phenyl group which may have a substituent. , A means a halogen atom or represented by the following formula,
Here Z is oxygen atom, sulfur atom, R? -N or R, HN -
CH, R7 means a hydrogen atom, a lower alkyl group, a benzyl group, or an acyl group optionally substituted with halogen, and R2, R and R4 are the same or different and are a hydrogen atom, a lower alkyl group, or an acyl group optionally substituted with a halogen. means an arylalkyl group, R5 means a hydrogen atom, a lower alkyl group, a benzyl group, or an acyl group optionally substituted with a halogen, R6 represents a hydrogen atom, a halogen atom, a lower alkyl group, or a halogeno-lower alkyl group , n is an integer 0 or 1
means. ) Pyridonecarboxylic acid derivatives, esters thereof, and salts thereof.

In this specification, halogen atom means fluorine.

It means chlorine or bromine, and examples of lower alkyl groups include methyl, ethyl, propyl, butyl.

Examples include isobutyl, t-butyl, pentyl, neopentyl, and the like. Examples of lower alkenyl groups include vinyl, allyl, -propenyl, and isopropenyl. Examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of the substituent on the phenyl group which may have a substituent include halogen, lower alkyl, lower alkyloxy, amino, and nitro. Examples of the aryl of the arylalkyl group include phenyl, naphthyl, and the like. Examples of the acyl group which may be substituted with halogen include formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, trifluoroacetyl, chloroacetyl, and the like. Examples of the lower alkyloxycarbonyl group include methoxycarbonyl and ethoxycarbonyl. Examples of the substituent in the carbamoyl group which may have a substituent include lower alkyl.

Examples include halogeno lower alkyl.

Salts of the compound of the present invention include salts with inorganic acids such as hydrochloric acid and phosphoric acid; salts with organic acids such as acetic acid, oxalic acid, succinic acid, methanesulfonic acid, maleic acid, malonic acid, and glucuronic acid; aspartic acid; , salts with acidic amino acids such as glutamic acid;
Or metal salts such as sodium, potassium, calcium, magnesium, zinc, silver, etc. of the compound of formula (1); dimethylamine, triethylamine, dicyclohexylamine.

Salts with organic bases such as benzylamine; salts with basic amino acids such as lysine and arginine.

The ester of the compound of formula (I) refers to a lower alkyl ester such as methyl ester or ethyl ester of compound (I), or a compound that is easily eliminated by hydrolysis or in vivo to become compound (1). known esters,
For example, acetoxymethyl ester, pivaloyloxymethyl ester.

It means ethoxycarbonyloxyethyl ester, choline ester, aminoethyl esters such as dimethylaminoethyl ester and 1-piperidinylethyl ester, 5-indanyl ester, phthalidyl ester, and the like.

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

The compounds of the present invention include those having an asymmetric carbon atom in the substituent at the 7-position, and these may exist as optically active forms. Therefore, these optically active substances are included in the compounds 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 these may exist as different stereoisomers. These stereoisomers are also included in the compounds of the present invention.

(Margin below) The method for producing the compound of the present invention will be explained below.

(1) The compound of the present invention has the following formula (II) (wherein,
Xz means a halogen atom, R means a hydrogen atom or a lower alkyl group, and A.

RL, Yi, Yz and Y3 are the same as above. It can be produced by ring-closing a β-7 minoacryl acid derivative represented by ) in the presence of a base and isolating the product by a conventional method.

In this reaction, starting compound (II) is mixed in an inert solvent such as ethanol, isopropyl alcohol, t-butyl alcohol, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, etc.
Hydroxides such as sodium hydroxide and potassium hydroxide, carbonates such as sodium carbonate and potassium carbonate 1 Bicarbonates such as sodium bicarbonate and potassium bicarbonate, potassium fluoride, sodium hydride, sodium ethylate, potassium t -butyrad, butyl lithium, triethylamine t1+8
-Diazabicyclo(5,4,0)-7-undecene (D
This can be carried out by intramolecular ring closure in the presence of a base such as BU). The reaction temperature is usually in the range of -20 to 150°C, preferably -10 to 100°C.

If possible, the starting compound (II) used in this reaction may be used in a protected form with an amino group that does not participate in the reaction, and after the reaction is completed, the protecting group may be removed by a conventional method.

Raw material compound *(II) can be produced by the method shown in the reference example or a method analogous thereto. -(2) The compound of the present invention in which A is a group other than a halogen atom also has the following formula (III) (X2 means a halogen atom, YLI Y21Y3.
R and R1 are the same as above. ) is reacted with the compound (IV) represented by the following formula % (in the formula, Ao means a group other than the halogen atom in the definition of A above), and the product is It can be produced by isolation according to a method.

In this reaction, the starting compounds (III) and (IV) are mixed in an inert solvent at 10 to 180''C1, preferably 20 to 130'C, for 10 minutes to 24 hours, preferably 15 minutes to 3 hours.
This can be carried out by stirring for a period of time.

As a solvent, for example, dimethylformamide.

Ethanol, methanol, acetonitrile, water.

Examples include chloroform and pyridine. These solvents may be used alone or in combination.

This reaction is generally carried out in the presence of an acid acceptor using starting compound (IV) in an equivalent or slightly excess amount to starting compound (III); It may also serve as an acid receptor. Examples of acid acceptors include triethylamine, 1,8-diazabicyclo(5,4°0)-7-undecene (DBU
), organic bases such as pyridine, quinoline, and picoline, hydroxides such as sodium hydroxide and potassium hydroxide, carbonates such as sodium carbonate and potassium carbonate, and bicarbonates such as sodium bicarbonate and potassium bicarbonate. It will be done. Note that pyridine, quinoline, picoline, etc. may be used in excess to serve as a solvent.

If possible, the starting compound (IV) used in this reaction may be used in a protected form with an amino group that does not participate in the reaction, and after the completion of the reaction, the protecting group may be removed by a conventional method.

Starting compound (III) can be produced by the method (1) described above.

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

The compound of the present invention produced in this manner is isolated and purified according to conventional methods. Depending on the isolation and purification conditions, it can be obtained in the form of a salt or a free form, but these can be mutually converted depending on the purpose to produce the desired compound of the present invention.

The stereoisomers of the present invention can be separated from each other by conventional methods, such as fractional crystallization, chromatographic separation, and the like. In addition, the compound of the present invention having a corresponding specific steric configuration can also be produced by the above method using a raw material compound having a specific steric configuration.

Optically active forms of the compounds of the present invention can be separated by applying known methods.

The compound thus obtained (■), its ester, and its salt are all new compounds. In particular, the compound (D) and its salts exhibit excellent antibacterial activity and are therefore valuable as antibacterial agents. Compound? Ij(I) or its salt is used not only in human and veterinary medicines, but also in fish disease medicines, agricultural chemicals,
It can also be used as a food preservative. Moreover, the ester form of compound (1) is of course valuable as a raw material for the synthesis of compound (I), but in addition, when this compound is easily converted into compound (I) in vivo, compound (I) ), it is also a useful compound as an antibacterial agent.

When the compound of the present invention is used as an antibacterial agent in humans, the dosage varies depending on age, body weight, symptoms, route of administration, etc., but it is recommended to administer 5B to 5g per day once or in divided doses. Recommended.

The route of administration may be either oral or parenteral.

Although the compound of the present invention may be administered as a bulk powder, it is usually administered in a prepared form together with a pharmaceutical carrier. Specific examples include tablets, liquids, capsules, granules, fine granules, powders,
Examples include syrups, injections, and ointments. These preparations are prepared according to conventional methods. Starch as a carrier for oral preparations.

Mannitol, crystalline cellulose, CMCNa, water.

Substances commonly used in the pharmaceutical field, such as ethanol, and which do not react with the compound of the present invention are used.

Examples of the carrier for injection include carriers commonly used in the field of injections such as water, physiological saline, glucose solution, and infusion preparations.

Furthermore, the above solutions and ointments can also be used in otorhinolaryngology and ophthalmology treatments.

Next, the method for producing the compound of the present invention will be explained in more detail with reference to Example A and Reference Example.

(Left below) sP 3-cyclopropylamino-2-(2-ethoxycarbonyl-3,4,5,6-titrafluoropenzoyl)ethyl acrylate: (1) 55 g of anhydrous tetrafluorophthalic fi, 1 zinc powder
7.5 g, 46 g of ethyl bromoacetate and toluene (
200 ml) was heated under reflux for 3 hours to give 3-ethoxycarbonylmethyl-3-hydroxy-4°5.6.
43 g of 7-titrafluorophthalide are obtained.

■, p, 112-113°C.

(2) Treat 35 g of the above compound with 25 g of ethyl orthoformate and 29 g of acetic anhydride, and then treat 7 g of cyclopropylamine.
．． 8g of 3-cyclopropylamino-2-
9.6 g of ethyl (2-ethoxycarbonyl-3,4°5.6-titrafluorobenzoyl)acrylate is obtained.

rs, p, 91-92°C.

5-dicyclopropyl-67,8-)-refluoro-1
,4-dihydro-4-oxoquinoline-3゜5-dicarboxylic acid diethyl: 13.8 g of ethyl 3-cyclopropylamino-2-(2-ethoxycarbonyl-3,4,5,6-titrafluorobenzoyl)acrylate 70m of tetrahydrofuran
Dissolve in 1. Under water cooling, potassium t-butylade 4.2
g carefully and stir for 15 minutes at room temperature. Water was added to the reaction solution, four precipitated crystals were taken, washed with water, and recrystallized from n-hexane to give l-cyclopropyl-6,7,
11.6 g of diethyl 8-trifluoro-1,4-dihydro-4-oxoquinoline-3°5-dicarboxylate is obtained.

m, p, 212-213°C.

1 Shidan-1 1-cyclopropyl-5-ethoxycarbonyl-6,7
,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid: 1-cyclopropyl-6,7
A mixture of 11.6 g of diethyl . After cooling, the precipitated crystals are collected by filtration,
After washing with water and recrystallizing from chloroform, 1-cyclopropyl-5-ethoxycarbonyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3
-10.4 g of carboxylic acid are obtained.

! 1.9.175-176°C.

1-cyclopropyl-5-ethoxycarbonyl-6,8
-difluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid: 1-cyclopropyl-5-ethoxycarbonyl-6,7
, 8-) 0.3 g of refluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.3 g of anhydrous piperazine.
After heating a mixture of 3 g and 10 ml of acetonitrile under reflux for 15 minutes, the solvent was distilled off under reduced pressure. Add water to the leftovers,
The precipitated crystals are collected by filtration.

After dissolving this in 3% acetic acid water and treating it with activated carbon,
Neutralize with % aqueous sodium hydroxide solution. The precipitated crystals were collected by filtration, washed with water and dried to give 1-cyclopropyl-5-ethoxycarbonyl-6,8-difluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3.
-0.25 g of carboxylic acid are obtained.

m, p, 145-146°C.

1 亙亘- 环-cyclopropyl-5-ethoxycarbonyl-6,8
-difluoro-7-(4-methyl-1-piperazinyl)
-1,4-dihydro-4-oxoquinoone-3-carboxylic acid: 1-cyclopropyl-5-ethoxycarbonyl-6,7
, 8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 0.5 g of 1-methylbiperazine were reacted in the same manner as in Example 3 to obtain 1-cyclopropyl-5- Ethoxycarbonyl-6,8-difluoro-7-(4-methyl-1-piperazinyl)-1,4
-dihydro-4-oxoquinoline-3-carboxylic acid 0.
f 7g. Il, P, 233-234°C0l standing and -dan 1-cyclopropyl-5-ethoxycarbonyl-6,8
-difluoro-7-(3-amino-1=pyrrolidinyl)
-1,4-dihydro-4-oxoquinoline-3-carboxylic acid: ■-Cyclopropyl-5-ethoxycarbonyl-6,7
, 0.3 g of 8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 0.3 g of 3-7 minopyrrolidine were reacted in the same manner as in Example 3 to obtain 1-cyclopropyl- 5-ethoxycarbonyl-6,8-difluoro-7-(3-amino-1-pyrrolidinyl)-1,4
-dihydro-4-oxoquinoline-3-carboxylic acid 0.
Obtain 23g. i, p, 215~216°C0-1
01-”-1-cyclopropyl-5-ethoxycarbonyl-6,8
-difluoro-7-(3-aminomethyl-1-pyrrolidinyl)-1,4-dihydro-4-oxoquinoline-3-
Carboxylic acid: 1-cyclopropyl-5-ethoxycarbonyl-6,7
, 8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 0.2 g of 3-aminomethylpyrrolidine were reacted in the same manner as in Example 3 to obtain 1
-cyclopropyl-5-ethoxycarbonyl-6,8-
0.22 g of difluoro-7-(3-aminomethyl-1-pyrrolidinyl)-1.4-dihydro-4-oxoquinoline-3-carboxylic acid is obtained. Shin, p. 200-201
"C.

Patent applicant: Dainippon Pharmaceutical Co., Ltd. A small island - Akira (blank below)

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (In the formula, Y_1 and Y_2 are the same or different and mean a halogen atom, and Y_3 is a carboxyl group, a lower alkyloxycarbonyl group, means a cyano group or a carbamoyl group which may have a substituent, R_1 means a lower alkyl group, a halogeno lower alkyl group, a lower alkenyl group, a cycloalkyl group, or a phenyl group which may have a substituent A means a halogen atom or a group represented by the following formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼, or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, where Z is an oxygen atom, a sulfur atom, R_7 -N or R_7HN
-CH, R_7 is a hydrogen atom, a lower alkyl group,
It means a benzyl group or an acyl group which may be substituted with halogen, R_2, R_3 and R_4 are the same or different and mean a hydrogen atom, a lower alkyl group or an arylalkyl group, and R_5 is a hydrogen atom or a lower alkyl group. , a benzyl group, or an acyl group optionally substituted with halogen; R_5 represents a hydrogen atom, a halogen atom, a lower alkyl group, or a halogeno-lower alkyl group; n represents an integer of 0 or 1; ) Pyridonecarboxylic acid derivatives, esters thereof and salts thereof.