JPS63275567A - Novel quinoline derivative, ester and salt thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I {X1 and X2 are halogen; R1 is formula II [R5 and R6 are H or lower alkyl; Y is O, S, R10-N (R10 is same as R5 or R6)] or formula III (R7 is H, OH, amino, etc.; R8 and R9 are same as R5 or R6; n is 3-5); R2 and R3 are R5, R6, cycloalkyl, (substituted) phenyl, etc.; R4 is lower alkyl, lower alkenyl, (substituted) phenyl, etc.}, ester and salt thereof. EXAMPLE:5-Amino-1-cyclopropyl-6, 8-difluoro-7-(3,4-dimethyl-1-piperazinyl)-1,4-di hydro-4-oxoquinoline-3-carboxylic acid. USE:A medicine and antimicrobial agent used as a madicine for human bodies and animals or drug for fish diseases, agricultural chemical, preservative for food, etc. PREPARATION:For example, a novel carboxylic acid ester expressed by formula IV (X is X1 or X2) or ester thereof is reacted with a compound expressed by the formula R1-H in an inert solvent, as necessary, in the presence of an acid acceptor to afford the aimed compound expressed by formula I.

Description

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

More specifically, the compound of the present invention has the following general formula (wherein X
l and X2 are the same or different and mean a halogen atom, RI means a group represented by the following formula, R2 and R3 are the same or different and have a hydrogen atom, a lower alkyl group, a cycloalkyl group, or a substituent. R4 is a lower alkyl group or a lower alkenyl group.

It means a cycloalkyl group or a phenyl group which may have a substituent, Y means an oxygen atom, a sulfur atom, or R1゜-N, Rs, Rs and Rho are the same or different and hydrogen a
tH or lower alkyl group, R? is a hydrogen atom,
means a hydroxyl group, an ami7 group, a mono- or di-lower alkylamino group, an amino-lower alkyl group, or a mono- or di-lower alkylamino lower alkyl group, R3 and R3 are the same or different and mean a hydrogen atom or a lower alkyl group, n means an integer 3, 4 or 5.

However, when R2 and R3 are hydrogen atoms and Ra is an ethyl group, RI is not a 1-piperazinyl group or a 4-lower alkyl-1-piperazinyl group. ), quinoline derivatives, esters thereof, and salts thereof.

In this document III, the halogen atom means fluorine.

means chlorine or bromine. As a lower alkyl group,
For example, methyl, ethyl, propyl, butyl.

Examples include isobutyl, t-butyl, pentyl, neopentyl, and the like. Examples of lower alkenyl groups include vinyl, allyl, 1-propenyl, and impropenyl W. Examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclobentyl, and cyclohexyl.

Examples of substituents on phenyl or benzyl groups that may have substituents include halogen, lower alkyl, lower flukyloxy, halogeno-lower alkyl,
Examples include hydroxy, nitro, amino and the like.

Salts of the compound of the present invention include salts with inorganic acids such as hydrochloric acid and phosphoric acid;
salts with acidic amino acids such as aspartic acid and glutamic acid; or sodium, potassium, and calcium compounds of formula (1).

Metal salts of magnesium, zinc, silver, etc.; dimethylamine,
Salts with organic bases such as triethylamine, dicyclohexylamine, benzylamine; lysine.

It is a salt with basic amino acids such as arginine.

The ester of the compound of formula (I) refers to lower alkyl esters such as methyl ester and ethyl ester of compound (I), or compounds that are easily eliminated by hydrolysis or in vivo to become Known esters such as acetoxymethyl ester, pivaloyloxymethyl ester.

It means aminoethyl esters such as ethoxycarbonyloxyethyl ester, choline ester, dimethylaminoethyl ester-piperidinylethyl ester, 5-i/danyl ester, phthalidyl ester, and the like.

Compounds of the invention may 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 multiple asymmetric carbon atoms in their 7-position substituent, and they may exist as different stereoisomers. These stereoisomers are also included in the present invention. Included in the compounds of the invention.

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

(1) The compound of the present invention is a carboxylic acid or its ester (preferably Lower alkyl ester) is reacted with a compound represented by the following general formula (% formula %) (where RI is the same as above), and the product is converted to I by a conventional method.
It can be manufactured by T'-ff.

This reaction can be performed using alcohols such as ethanol, ethers such as dioxa-tetrahydrofura-1,2-dimethoxyethane, benzene, and toluene.

The raw material compound (II) or its ester and (Ill) are mixed together at 10 to 180°C in an aromatic hydrocarbon such as xylene, acetonitrile, dimebylformamide, dimethylsulfokind, pyridine, water, or other inert solvent.
This can be carried out by reacting for 0 minutes to 24 hours.

This reaction is generally carried out in the presence of an acid acceptor using the starting compound (m) in excess of the starting compound (■)* or its ester;
III) may be used in excess to serve as an acid acceptor.

As acid acceptors, hydroxides such as sodium hydroxide and potassium hydroxide, carbonates such as sodium carbonate and potassium carbonate, bicarbonates such as sodium bicarbonate and potassium bicarbonate;
Triethylamine, dimedylanis/, N,N-diisopropylethylamine, 1,8-diazabicyclo[! l
x 4.01 undecene-7 (DIIU).

If possible, the starting compound (II) and/or (III) used in the above reaction may be used in a protected form with its amine 7 group, and after the completion of the reaction, the protecting group may be removed by a conventional method. . The protecting group may be any group that does not destroy (removable) the structure of the compound of the present invention formed by the reaction, including peptides, amine sugars,
Formyl is a group commonly used as a protective W in the field of chemistry of nucleic acids or β-lactam compounds.

Substituted carbonyl groups such as acetyl, trifluoroacetyl, ethoxycarbonyl, be/zyloxycarbonyl, t-butoxycarbonyl; benzyl group, nitrityl group; tri-lower alkylsilyl group such as trimethylsilyl; p-
) Luenesulfonyl group: 0-nitrophenylsulfenyl group; diphenylphosphinyl group: or tetrahydropyranyl group are mentioned as specific examples. Preferred protecting groups include, for example, easily hydrolyzable groups such as acetyl, trifluoroacetyl, ethoxycarbonyl, or heptadyl group.

Raw material compound (II) is a new compound, and reference example 1 and 2
It can be manufactured by the method of ``Ki'' or a method similar thereto.

■ The compound of the present invention also has the following general formula (wherein, X means a halogen atom, XI, X2.R1° and R
A carboxylic acid or its ester (preferably a lower alkyl ester) represented by It can be produced by isolating it by a conventional method.

In this reaction, starting compound (IV) or its ester and (V) are mixed at 50 to 150°C in an inert solvent.
This can be carried out by reacting for 48 hours.

As the solvent, the same solvent as described in reaction (1) above is used.

This reaction is generally carried out in the presence of an acid acceptor using the starting compound (V) in an equivalent or more than one excess amount relative to the starting compound (IV) or its ester. may also be used in excess to serve as an acid acceptor. As the acid acceptor, the same one as described in reaction (1) above is used.

Note that when volatile amines are used as the raw material compound (V), it is common practice to carry out the reaction in a sealed tube. Furthermore, the compounds of the present invention in which R2 and R3 are hydrogen atoms can also be produced by reacting the surgical compound IIV) with a salt such as ammonium acetate instead of reacting with ammonia.

If possible, the raw material compound (IV) and/or (V) used in this reaction may have its amine 7 group converted to the above reaction (1).
It may be used in a protected form with a yI group as described above, and the protecting group may be removed by a conventional method after the reaction is completed.

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 (1) 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 (1).

In addition, the compounds of the present invention having a primary and/or secondary amino group as a substituent can be alkylated at the amino group by a conventional method (for example, by treatment with a lower alkyl aldehyde and formic acid). .

The compound of the present invention produced in this manner is isolated and purified according to conventional methods. Isolation, by 'l:1'R conditions,
Although it is obtained in the form of a salt or a free form, these can be mutually converted depending on the purpose to produce the compound of the present invention in the desired form.

Stereoisomers of the compounds of the invention can be separated from each other by conventional methods, such as fractional crystallization, chromatography, and the like. In addition, the compound of the present invention having a corresponding specific steric configuration can also be produced by each of the above methods using the starting compound (III) or (mV) having a specific steric configuration.

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

The compound (summer) obtained by oxidation, its ester, and its salt are all new compounds. In particular, compound (I) and its salts exhibit extremely excellent antibacterial activity and are therefore valuable as antibacterial agents.

Compound (1) or a salt thereof can be used not only as a medicine for humans and animals, but also as a preservative for fish medicine, Q medicine, food, and the like. Also, compound? 3. The ester form of (I) is of course valuable as a raw material for the synthesis of compound (1), but in addition, when this compound is easily converted into compound (1) in vivo, compound CI)
It is also a useful compound as an antibacterial agent, as it can exhibit similar effects.

Next, data regarding the antibacterial activity of the compounds of the present invention are listed below.

(Margins below) Antibacterial action in a test tube "1 Experimental conditions Minimum inhibitory concentration (MIC: μg/ml) is Chemo
Therapy, 29(1), 7B (1981) α
The results are shown in the table above.

1 means the compound of Example 1 (the same applies hereinafter).

The compound (1) of the present invention also exhibits excellent antibacterial activity in animal experiments. In addition, the compound (1) of the present invention has good absorption properties, and when it shows a high blood concentration, it also has excellent transferability to various h3S in the body.

When the compound of the present invention is used as an antibacterial agent in humans, the dosage varies depending on age, body weight, yield, route of administration, etc., but the dose is 5 to 5 g per day, administered once or divided into several doses. It is recommended that

The route of administration may be either oral or parenteral.

The compound of the present invention may be used as an Ω powder, but usually together with a pharmaceutical carrier: 11! Administered in 1-dose form. Specific examples include tablets, liquids, capsules, granules, fine granules,
Examples include powders, syrups, injections, and ointments. These formulations are prepared according to conventional methods. As a carrier for oral preparations, Dep/.

Substances that are commonly used in the pharmaceutical field and do not react with the compound of the present invention are used, such as mannitol, crystalline cellulose, CMCNa, water, and ethanol. Examples of carriers for injection include carriers commonly used in the field of injections such as water, physiological saline, glucose solutions, and infusion preparations.

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 Examples.

Reference example 1 5-amino-1-cyclopropyl-8,7,8-)lifluoro-1,4-dihydro-4-oxoquinoline-3-
Carvone Wt= (1) Known compound pentafluorobe7zoylacetate ethyl [J, Org, Chem, 35.930 (19
70) 125g, ethyl orthoformate 20g, anhydrous vinegar f
After heating 1123 g of the mixture under reflux for 2 hours, the reaction mixture was concentrated to dryness under reduced pressure. The residue is dissolved in diethyl ether and reacted with 5.1 g of cyclopropylamine at room temperature to obtain 28 g of ethyl 2-(pentafluorobenzoyl)-3-cyclopropylaminoacrylate.

m, p, 89°C.

(2) Dissolve 28 g of the above compound in anhydrous tetrahydrofuran and react with 3.85 g of 60% sodium hydride at room temperature. -18.4 g of carbo/ethyl acid are obtained.

m, p, 170-171°C.

(3) 28.2 g of the above compound, 9.0 g of benzylamine.
8 ml.

Anhydrous potassium carbonate 23.6g, acetonitrile 140■
The mixture of 1 was heated at 100-110°C for 1 hour to form 5-
benzylamino-1-cyclopropyl-8,7,8-)
Refluoro-1,4-dihydro-4-oxoquinoline-
21.4 g of ethyl 3-carboxylate are obtained. Recrystallize from ethanol. m, p, 134-135°C.

4) 20 g of the above compound was dissolved in 100 μl of acetic acid and 150 μl of ethanol, and hydrolyzed in the presence of 0.5 g of 5% palladium-carbon to give 5-amino-1-cyclopropyl-&7.8-)refluoro- 1,4-dihydro-4-
14.1 g of ethyl oxoquinoline-3-carboxylate. Recrystallize from chloroform-ethanol. m
, 9.238-237°C.

5) The above compound 12.8ff, acetic acid 801. water 50
■ Add a mixture of 1° concentrated sulfuric acid 9-1 to 40°C at 100-110°C.
11.1 g of the target product was obtained. Recrystallize from chloroform-ethanol.

m, 9.294-295°C.

Example 1 5-amino-1-fuclopropyl-6,8-difluor+
+-7-(a4-dimethyl-1-piperazinyl)-1,
・1-dihydro-4-okitsuki/su/-3-cal acid: 5-amino-1-cyclopropyl-a7.8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carvone M 400 g soda, 1,2-dimethylpiperazine 5
A mixture of 50-g and pyridine 611 is heated to reflux for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, ethanol was added to the residue, and the crystals were collected by filtration. Recrystallization from chloroform-ethanol yields 270 g of the desired product as yellow crystals. m
, p, 232-234°C.

In the same manner as in Example 1, the following compounds of Examples 2 and 3 are obtained.

Example 2 5-amino-1-cyclopropyl-6,8-difluoro-7-[(R)-3-methyl-1-piperazinyl]-1
, 11-dihydro-4-oxo+7phosphorus-3-carboxylic acid, m, 9.252-253°C, [α]30fu-3
0,0° (c = 0.2. Black” Ho/Lz
1. ) Example 3 5-amino-1-cyclopropyl-6,8-difluoro-7-[(S)-3-methyl-1-piperazinyl]-1
, 4-dihydro-4-oxomori/-3-carbo/acid, m, p, 239-240°C, [a] 30-+
32.5° (c = 0.2. Chloroform) Example 4 5-amino-1-cyclopropyl-8,8-difluoro-7-(r-3-amino-&t-4-dimedy-1-pyrrolidinyl)- 1,4-dihydro-4-oxoquinoline-3-carboxylic acid: 5-amino-1-cyclopropyl-G, 7.8-)lifluoro-1,4-dihydro-4-oxoquinoline-3-
Carboxylic acid 1.0g, r-3-amino-3°t-4-9
790 sg of methylpyrrolisif, ) A mixture of 21 ethylamine and 201 pyridine is heated to reflux for 1.5 hours. After cooling with water, the crystals precipitated were collected by filtration and washed with ethanol.
do. Recrystallization from chloroform-ethanol yields 1.08 g of the desired product.

m, 9.293-296℃ (decomposition) In the same manner as in Example 4, the following compound of Example 5 is obtained.

Example 5 5-amino-1-cyclopropyl-a8-difluoro-
7-(3-ami7-3-methyl-4-ethyl-1-pyrrolidinyl)-1,4-dihydro-4-oxoquinoline-
3-carbo/acid.

m, p, 254-256°C.

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, X_1 and X_2 are the same or different and mean a halogen atom, R_1 is a group represented by the following formula ▲ Numerical formula, chemical formula, table, etc. ▼, or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and R_2 and R_3 are the same or different hydrogen atoms, lower alkyl groups, cycloalkyl groups, or phenyl which may have a substituent. R_4 means a lower alkyl group, a lower alkenyl group, a cycloalkyl group, or a phenyl group which may have a substituent; Y is an oxygen atom, a sulfur atom, or R_1_0-N R_5, R_6 and R_1_0 are the same or different and mean a hydrogen atom or a lower alkyl group, and R_7 is a hydrogen atom, a hydroxyl group, an amino group, a mono- or di-lower alkylamino group, an amino-lower alkyl group, or a mono- or di-lower alkyl group. It means a lower alkylamino lower alkyl group, R_8 and R_9 are the same or different and mean a hydrogen atom or a lower alkyl group, and n means an integer 3, 4 or 5. However, R_2 and R_3 are hydrogen atoms, R_4 is an ethyl group, R_1 is not a 1-piperazinyl group or a 4-lower alkyl-1-piperazinyl group.) A quinoline derivative, an ester thereof, and a salt thereof.