JPH0459765A - New quinolone-3-carbaldehyde derivative and salt thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [X1 is halogen; X2 is H or halogen; R1 is lower alkyl, lower alkenyl, phenyl, etc.; R2 and R3 are H, lower alkyl, acyl, etc.; A is halogen, formula II (Y is 0, S, etc.; R4 and R5 are H, lower alkyl, etc.) or formula II (R6 is H, halogen, etc.; R7 to R9 are H, lower alkyl, acyl, etc.; m is 0 or 1; n is 3-5)]. EXAMPLE:5-Amino-1-cyclopropyl-6,8-difluoro-7-(cis-3,5-dimethyl-1 -piperazinyl)-1,4- dihydro-4-oxoquinoline-3-carbaldehyde. USE:An antimicrobial agent having excellent phylactic effects. PREPARATION:A compound expressed by formula IV is reacted with an N,N- disubstituted formamide and phosphorus oxychloride or phosphorus trichloride in a solvent such as dichlorobenzene at 10-150 deg.C to afford the objective compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to novel quinolone-3-carbaldehyde derivatives and salts thereof having excellent antibacterial activity.

Conventional technology Japanese Patent Publication No. 55-35392 and Japanese Patent Publication No. 56-20
No. 314 discloses 6-formylpyridopyrimidine derivatives.

Also, Journal φ of Medicinal φ Chemistry (J, Med, Chem), Volume 31, Page 221 (1
(988) describes the use of certain 3-formylquinolone derivatives as prodrugs.

However, a quinolone-3-pulp-human derivative having a substituent at the 5-position like the compound of the present invention is not yet known.

Problems to be Solved by the Invention The object of the present invention is to provide a novel chimeron-3-carbaldehyde derivative that exhibits excellent antibacterial activity.

Means for Solving the Problems The compound of the present invention has the following formula: alkenyl group.

It means a cycloalkyl group or a phenyl group which may have a substituent, and R2 and R3 are the same or different and are a hydrogen atom, a lower alkyl group, or an arylalkyl group.

means an alkyloxycarbonyl group, an arylalkyloxycarbonyl group or an acyl group, A means a halogen atom or a group represented by the following formula, where Y means an oxygen deuteron, a sulfur atom or Re N, R4 and R11 are the same or different and mean a hydrogen atom, a lower alkyl group or an arylalkyl group; RII is a hydrogen atom, a halogen atom, a lower alkyl group or a halogeno-lower alkyl group; R7, R11 and R8 are the same or different quinolo/-3-carbaldehyde derivatives and salts thereof represented by a) which means a hydrogen atom, a lower alkyl group or an acyl group, m means an integer 0 or 1, and n means an integer 3.4 or 5; It is.

In this specification, examples of the halogen atom include fluorine, chlorine, and bromine. Examples of lower alkyl groups include methyl, ethyl, propyl, butyl, inbutyl, t-butyl, pentyl, neopentyl, and the like. Examples of the lower alkenyl group include vinyl, allyl, 1-propenyl, impropenyl, and the like. Examples of the cycloalkyl group include cyclopropyl.

Examples include cyclobutyl, cyclobutyl, cyclohexyl and the like. In addition, examples of the substituent in the phenyl group which may have a substituent include halogen, lower alkyl,
Examples include lower alkyloxy, halogeno lower alkyl, hydroxy, nitro, and amine. Examples of the aryl group include phenyl, naphthyl, and the like. Examples of the acyl group include formyl, acetyl, and propionyl.

Examples include butyryl, imbutyryl, pivaloyl, trifluoroacetyl, and ri00acetyl.

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, lactic acid, oxalic acid, succinic acid, methanesulfonic acid, maleic acid, malonic acid, and gluconic acid; It is a salt with acidic amino acids such as aspartic acid and glutamic acid.

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 asymmetric carbon atoms, which 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 and may exist as different stereoisomers. These stereoisomers are also included in the compounds of the present invention.

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

(1) The compound of the present invention is a compound represented by the following formula (II) (wherein A, Xl, It can be produced by reacting phosphorus chloride or phosphorus trichloride.

This reaction is carried out at 10 to 150°C, preferably at 20°C, in a solvent such as 1,2-dichloroethane or dichlorobenzene.
This can be carried out by stirring the raw material compound (II), N,N-disubstituted formamide and phosphorus oxychloride or phosphorus trichloride at -60°C for 1 to 20 hours.

Examples of N, N-91m formamide include dimethylformamide, diethylformamide, and phenylmethylformamide. It is preferable to use N,N-diconverted formamide in a molar amount of at least twice the amount of the starting compound (If), but it is convenient to use it in excess so that it also serves as a solvent. It is preferable to use phosphorus oxychloride or phosphorus trichloride in an amount of 2 to 5 times the molar amount of starting compound (II).

If possible, the starting compound (II) used in this reaction may be used in a protected form with an amine group that does not participate in the reaction, and after the reaction, the protecting group may be removed by a conventional method. Any protecting group may be used as long as it can be removed without destroying the structure of the compound of the present invention formed by the reaction, and is used in the field of chemistry of peptides, amino acids, nucleic acids, or β-lactam compounds. As the protecting group, commonly used protecting groups are used. Preferred protecting groups include, for example, acetyl and trifluoroacetyl.

Examples include easily hydrolyzable groups such as ethoxycarbonyl, benzyloxycarbonyl, or be/zyl groups.

The starting compound (If) can be produced, for example, according to the scheme below.

↓ (■) (In the formula, X means a halogen atom, and A.

X-Kan, X2. R1, R2 and R3 are the same as above,
) According to this reaction formula, carboxylic acid (1) is reacted with malonic acid ester to form compound (2), which is then hydrolyzed to obtain acetyl compound (3). The starting compound (II) can be obtained by reacting the acetyl compound (3) with an amine (RINH2).

C) The compound of the present invention has the following - oxidation (wherein A, X+, X2. R1, RP and R
3 is the same as above. ) It can be produced by dehydrogenating the compound (I[I) represented by:

In this reaction, compound (I [I) is mixed with an inert solvent (e.g. benzene, toluene, xylene + vinegar
/ .

Dioxane, ethanol, t-butyl alcohol.

dimethylformamide, etc.), 2,3-dichloro,
6-dicyatwo 1,4-benzoquino:/(DDQ>.

Tetrachloro-1,4-benzoquinone (chloranil).

By adding a common dehydrogenating agent such as tetracyanoethylene, palladium on carbon, N-bromosuccinimide (N B S ), or manganese dioxide, and heating and stirring for a short time at room temperature or near the boiling point of the solvent used, or Direct heating of compound (Ill) above its melting point or benzene, toluene, dioxane, ethanol, n-hexane, carbon tetrachloride.

This can be carried out by heating in an inert solvent such as dimethylformamide or diphenyl ether.

The raw material compound (III) used in this reaction is used in a form in which the amino group that does not participate in the reaction is protected, if possible, as in the case of correction method (1), and after the reaction, the protecting group is removed by a conventional method. May be removed.

Starting compound (III) can be produced, for example, according to the scheme below.

(The following is a blank space) (3) The compound of the present invention has the following - killing effect (in the formula, A
, Xll X2. R1, R2 and R3 are the same as above. ) According to this reaction formula, for example, carvone@(4) is reduced with sodium borohydride in methanol, and then heat-deenoxidized in the presence of an acid to obtain compound (5). Compound (5
) is treated with ethyl formate in the presence of sodium methoxide to introduce a formyl group to obtain the starting compound (In).

(In the formula, R means an aryl group, A, X+.

X2. R1, R2 and R3 are the same as above. ) can be produced by thermally decomposing compound (IV).

In this reaction, starting compound (IV) is mixed with 100 to 20
This can be carried out by heating and stirring at 0°C, preferably 150 to 180°C, for 30 seconds to 10 minutes.

Examples of the base include inorganic bases such as sodium carbonate and potassium carbonate.

The raw material compound (IV) used in this reaction can be prepared by the method described above (
As in the case of 1), if possible, the amino group that does not participate in the reaction may be used in a protected form, and after the reaction, the protecting group may be removed by a conventional method.

The raw material compound (N) can be produced by the method described in Reference Examples below or a method analogous thereto.

(4) The compound of the present invention in which A is a group other than a halogen atom is represented by the following general formula (wherein, X means a halogen atom, and Xl.

X2. By reacting a compound represented by the following general formula (wherein A means a group other than a halogen atom in the definition of A above) with a compound represented by R1, R2 and R3 are the same as above. can be manufactured.

This reaction is carried out in an inert solvent at 10-180°C, preferably at 2
This can be carried out by stirring the starting compounds (V) and (Vl) at 0 to 130°C for 10 minutes to 24 hours, preferably 30 minutes to 3 hours.

Examples of the solvent include dimethyl amide ethanol, methanol, acetonitrile, and water.

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

This reaction is generally carried out in the presence of an acid acceptor using the starting compound (Vl) in an equivalent or excess amount relative to the starting compound (V); It may also be used to serve as an acid receptor.

Examples of acid acceptors include triethylamine.

Dimethylanili7. N,N-diinpropylethylamine, 1,8-diazabiscif Or54. Comber undecene (DBU), pyridine bases such as pyridine, hydroxides such as sodium hydroxide and potassium hydroxide, carbonates such as sodium carbonate and potassium carbonate, bicarbonates such as sodium bicarbonate and potassium bicarbonate. Examples include salt.

Starting compound (V) and/or (
As in the case of method (1), Vl) may be used in a protected form with the amine 7 group that does not participate in the reaction, if possible, and after the reaction is completed, the protecting group may be removed by a conventional method.

Raw material compound (V) can be produced, for example, by any of the methods (1) to (3) described above.

■ The compound of the present invention has the following general formula (■) (wherein, X means a halogen atom, and A.

Xl, X2 and R+ are the same as above. It can be produced by reacting a compound represented by ) with an amino compound represented by the following general formula % (wherein R2 and R3 are the same as above).

This reaction can be carried out under the same conditions as in method (4).

The raw material compound (■) used in this reaction, as in the case of the above method (dish), is used in a form with the amino group that does not participate in the reaction protected, if possible, and after the completion of reaction 2, it is protected by a conventional method. Groups may be removed.

The raw material compound (■) can be produced, for example, by a method according to any of the aforementioned methods (1) to (4).

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, the compound of the present invention 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 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, chromatographic separation, and the like. Note that 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.

Effects of the Invention The thus obtained compound (I) and its salts are both new compounds, and since they exhibit excellent infection-preventing effects, they are valuable as antibacterial agents.

Data regarding the infection-preventing effects of the compounds of the present invention are listed below.

EDso values were measured under experimental conditions of 1 or less, and the results are shown in the table above.

Animals used: 5td-ddY male mice (average weight 2
0g) Amount of infectious bacteria and infection method: 5 x 103 live bacteria/mouse were injected intraperitoneally.

Administration method: The compound was dissolved in 0.4% carboxymethyl cellulose and administered orally immediately after infection.

Method for determining results: EDso value was calculated from the survival rate 7 days after infection by the probit method.

As is clear from the table above, the compounds of the present invention exhibit excellent in ViVO infection protective effects.

Furthermore, the compounds of the present invention exhibit good safety in general toxicity tests in animals.

Furthermore, the solubility of the compound of the present invention in water is approximately 12°8 g/ml for the compound of Example 1■, and approximately 12°8 g/ml for the compound of Example 1■
of the compound is quite large at about 7.8-g/ml.

Therefore, the compounds of the present invention are useful not only as oral antibacterial agents, but also as injectable antibacterial agents.

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 g 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.

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 formulations are prepared according to conventional methods. Starch as a carrier for oral preparations.

mannitol, [& cellulose, CMCNa, water,
: A substance commonly used in the pharmaceutical field such as c-tanol and which does not react with the compound of the present invention is 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.

The above solutions and ointments are also used in otorhinolaryngology and ophthalmology treatments.

As mentioned above, the compound of the present invention is not only useful as an antibacterial agent itself (but also can be oxidized to form the following -killing agent (in the formulas A, XI, X2. R1, R2 and R
3L year old Same as above. ) It is a valuable compound as an intermediate for pharmaceutical production.

EXAMPLES Next, the method for producing the compound of the present invention will be specifically explained with reference to Examples and Reference Examples.

Reference example 1 5-benzyloxycarboxamide-1-cyclopropyl-a8-difluoro-7-(cis-5-dimethyl-
1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid: known compound 5-ami/-1-
Cyclopropyl-a8-difluoro-7-(cis-3,
5-dimethyl-1-piperazinyl)-1,4-dihydro-
2.36 g of 4-oxoquinoline-3-carboxylic acid and 0
．． A mixture of 24 parts of a 5N aqueous sodium hydroxide solution was cooled with water, and a 7-ton (2 parts) of base/zyloxycarbonyl chloride was added to the mixture.
4 Sodium 1) Add solution. The reaction solution was stirred for 30 minutes under water cooling and for 2 hours at room temperature, and then neutralized with acetic acid. The crystals were collected by filtration, washed with water, and then recrystallized from chloroform-methanol.
Obtain 2.10 g of the target product. m. p, 268-269°C.

Reference example 2 N'-benzenesulfonyl-N-[5-benzyloxycarboxamide-1-cyclopropyl-a8-difluoro-7-(cis-3.5-dimethyl-1-piperazinyl)-1.4-dihydro-4 -Oxoquinoline-3-carbocohydrazide: 5-benzyloxycarboxamide-1-cyclopropyl-a8-difluoro-7-(cis-a5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 5.3g+
) A mixture of 2.8 x 1 ethylamine and chloroform was cooled with water, and 1.15 x 1 of ethyl chlorocarbonate was added to it.
Add dropwise and stir. An ethanol solution of 2.58 g of benzenesulfonyl hydrazide was added to this reaction solution, and the mixture was stirred at room temperature for 1 hour. The product is recrystallized from chloroform-methanol to obtain 42 g of the desired product 8. m. 9.
225-226°C.

Example 1 5-Amino-1-cyclopropyl-6,8-difluoro-7-(cis-3,5-dimethyl-1-piperazinyl)
-1.4-dihydro-4-oxoquinoline-3-carbaldehyde: C11N'-benzenesulfonyl-N-[5-benzyloxycarboxamide-1-cyclopropyl-a8-difluoro-7-(cis-3.5- dimethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3
-carbo] hydrazide 7.6 g and ethylene glycol 7
The mixture of No. 61 is heated to 170° C., 2.37 g of anhydrous sodium carbonate is added thereto, and the mixture is heated at the same temperature. When the bubbling of the reaction solution subsides, add 20 parts to 1 part of water and cool with water. The reaction solution was extracted with 150 ml of chloroform, and the extract was dried and concentrated. The residue was purified by silica gel chromatography to give 5-benzyloxycarboxamide = 1-
Cyclopropyl-a8-difluoro-7-(cis-3.
3.4 g of 5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carbaldehyde are obtained. Recrystallize from chloroform-methanol. m.
p. 237-238°C.

(2) A mixture of 2.84 g of the above compound and 3o-1 of 20% hydrochloric acid is heated under reflux for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was diluted with 20 parts of water and cooled with water. The precipitated crystals are collected by filtration and recrystallized from methanol to obtain 1.8 g of the target hydrochloride.

m. P. 290-295°C (decomposition).

(3) Add water to the above compound, make it alkaline with a 20% aqueous solution of caustic soda, and extract with chloroform.

The extract is washed with water, dried, and then concentrated. The residue is recrystallized from ethanol to obtain the desired product.

m. P. 219~220℃.

Reference example 3 5-benzyloxycapoxamide-1-cyclopropyl-6-fluoro-7-(cis-3.5-dimethyl-1-
piperazinyl)-1,4-dihydro-4-okynequinoline-3-carbo7@: known compound 5-amino-1-cyclopropyl-6-fluoro-7-(cis-a5-dimethyl-1-piperazinyl)-1,4-dihydro- 2.25 g of 4-oxoquinoline-3-carbofic acid, benzyloxychloride 1,72 1 and 0. , 5
Using N hydroxide aqueous solution 24-1, reaction treatment is carried out in the same manner as in Reference Example 1 to obtain 2.10 g of the target product. Recrystallize from chloroform-methanol.

m. p. 267-268℃.

Reference example 4 N'-penze/sulfonyl-N-[5-benzyloxycarboxamide-1-cyclopropyl-6-fluoro-7-(cis-3,5-dimethyl-1-piperazinyl)
-1,4-dihydro-4-oxoquinoline-3-carbo]hydrazide: 5-benzyloxycapoxamide-1-cyclopropyl-6-fluoro-7-(cis-3,5-dimethyl-1-
3.4 g of 7m (piperazinyl)-1,4-dihydro-4-oxyquinoline-3-carbo was reacted in the same manner as in Reference Example 2 to obtain 3.83 g of the desired product. Recrystallize from chloroform-methanol.

m, p, 230-232°C.

Example 2 6-amino-1-cyclopropyl-6-fluoro-7-
(cis-3,5-dimethyl-1-piperazinyl)-1,
4-dihydro-4-oxoquinol/3-carbaldehyde: (INN'-benzenesulfonyl-N-[5-benzyloxycarboxamide-1-cyclopropyl-6-fluoro-7-(cis-5-dimethyl-1- piperazinyl)-1,4-dihydro+=+-4-okynequinoline-3-
3.2 g of carbo]hydrazide was reacted in the same manner as in Example 1 (1) to obtain 5-benzyloxycarboxamide-1.
-cyclopropyl-6 to fluoro-7-(cis-3,5
-dimethyl-1piperazinyl)-1,4-dihydro-4
-Oxoquinoline-3-carbaldehyde 1.53 g are obtained. Recrystallize from chloroform-methanol.

m, l), 237-238°C.

(2) The above compound is subjected to reaction treatment in the same manner as in Example 1 (2) to obtain the hydrochloride of the target product. Recrystallize from water.

m, p, 285-290°C (decomposition).

(3) The above compound is treated in the same manner as in Example 1 (3) to obtain the desired product. Recrystallize from ethyl acetate.

m, I), 223-224°C.

Reference example 5 5-ami/-1-cyclopropyl-8,8-difluoro-7-(cis-3,5-dimethyl-1-piperazinyl)
-1,4-dihydro-4-oxoquinoli7-3-carbo7! l: 5-amino-1-cyclopropyllumi-8-difluoro-
7-(cis-3,5-dimethyl-!-piperazinyl)-
A mixture of 1.9 g of 1,4-dihydro-4-oxoquinoline-3-carbaldehyde and an 80% aqueous acetic acid solution was cooled with water,
Add 1.5 g of chromium dioxide dissolved in 80% acetic acid aqueous solution to this. After stirring the reaction solution overnight at room temperature, the solvent was distilled off. Add water to the residue and neutralize with aqueous caustic soda solution. The crystals were collected by filtration, washed with water and dried to obtain the desired product 1.30
get g. m, p, 258-260°C.

Claims (1)

[Claims] General formula▲ Numerical formula, chemical formula, table, etc.▼ (In the formula, X_1 means a halogen atom, X_2 means a hydrogen atom or a halogen atom, R_1 is a lower alkyl group, a lower alkenyl group , a cycloalkyl group, or a phenyl group which may have a substituent, and R_2 and R_3 are the same or different and are a hydrogen atom, a lower alkyl group, an arylalkyl group, an alkyloxycarbonyl group, an arylalkyloxycarbonyl group. or acyl group, 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 Y is an oxygen atom, R_4 and R_5 are the same or different and represent a hydrogen atom, a lower alkyl group, or an arylalkyl group; R_6 represents a hydrogen atom, a halogen atom, a lower alkyl group, or a halogeno-lower alkyl group; R_7, R_8 and R_9 are the same or different and mean a hydrogen atom, a lower alkyl group or an acyl group, m means an integer 0 or 1, n means an integer 3, 4 or 5). Quinolone-3-carbaldehyde derivatives and salts thereof.