JPH037283A - Pyridonecarboxylic acid compound - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> represents (halo)alkyl, cycloalkyl, alkynyl or (substituted)phenyl; R<2> represents H, alkyl, cycloalkyl, acyl or alkoxycarbonyl; R<3> represents H, alkyl or aralkyl or R<2> and R<3> are linked with each other to form a hyteroring together with the adjacent N; R<4> represents H or alkyl; R<5> represents H, alkyl, aralkyl, etc.; R<6> represents alkyl; R<7> represents H or amino; m is 2 or 3; n is 1-3]. EXAMPLE:1-Cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-7-[2-(methylamino methyl) morpholino]-4-oxoquinoline-3-carboxylic acid. USE:An antibacterial agent against Gram-negative and Gram-positive bacteria. PREPARATION:One mol compound expressed by formula II (X<1> represents halogen) is reacted with 1-8mol compound expressed by formula III, as necessary, in the presence of a solvent at 30-150 deg.C for 1-48hr.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a novel pyridonecarboxylic acid compound and a salt thereof which are excellent as antibacterial agents.

[Conventional technology]

Norfloxacin, ofloxacin, ciprofloxacin, and the like are known as pyridonecarboxylic acid compounds substituted with fluorine. Also, JP-A-62-22
No. 8063 discloses a 6-fluoro-8-methoxy-4-oxoquinoline-3-carboxylic acid compound substituted with a methoxy group at the 8-position.

[Problem to be solved by the invention]

The present invention maintains a strong antibacterial effect against Gram-positive bacteria,
Another object of the present invention is to provide a novel pyridonecarboxylic acid compound and a salt thereof, which have a satisfactory antibacterial activity even against Gram-positive bacteria.

[Means to solve the problem]

The present invention maintains a strong antibacterial effect against Gram-positive bacteria,
and Gram-positive bacteria, especially staphylococci such as methicillin- and cephem-resistant Staphylococcus aureus and Staphylococcus epidermidis;
This invention relates to a novel pyridonecarboxylic acid compound that has extremely strong antibacterial activity against Gram-positive bacteria such as Streptococcus pneumoniae and S. enterica, and has clinically satisfactory antibacterial activity.

That is, the present invention is based on the general formula % (1) (where %R' is alkyl, cycloalkyl, haloalkyl, alkenyl, phenyl, or 1 to 3 substituents of halogen, alkyl, alkoxy, hydroxyl, nitro, and amino) R2 represents hydrogen, alkyl, cycloalkyl, acyl or alkoxycarbonyl group, R' represents hydrogen, alkyl or aralkyl group, or RZ and Rff are bonded to each other to form an adjacent nitrogen atom R4 represents hydrogen or an alkyl group, R5 represents hydrogen, alkyl,
It represents aralkyl or an ester residue that can be hydrolyzed in vivo, R6 represents alkyl, R7 represents hydrogen or amino, m represents an integer of 2 or 3, and n represents 1 to 3.
pyridonecarboxylic acid compounds and salts thereof, represented by ), representing an integer of .

In this specification, halogen refers to chlorine, bromine, fluorine, iodine, and alkyl refers to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl,
Alkyl refers to alkyl having 1 to 18 carbon atoms such as hexyl, heptyl, octyl, decyl, dodecyl, octadecyl, etc., and alkoxy refers to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, hexyloxy, Alkoxy with 1 to 18 carbon atoms such as octyloxy, decyloxy, dodecyloxy, and octadecyloxy; alkenyl with 2 to 8 carbon atoms such as vinyl, allyl, butenyl, pentenyl, hexenyl, and octenyl; haloalkyl with is an alkyl having 1 to 8 carbon atoms substituted with at least one halogen, difluoromethyl,
Trifluoromethyl, fluoroethyl, trifluoroethyl, etc.; cycloalkyl refers to cycloalkyl having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl; acyl refers to formyl, acetyl, propionyl, butyryl,
Acyl having 1 to 5 carbon atoms such as valeryl and pivaloyl, and alkoxycarbonyl having an alkoxy moiety having 1 to 4 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, Phenyl having one to three substituents of halogen, alkyl, alkoxy, trifluoromethyl, hydroxyl, nitro, or amino, such as isobutoxycarbonyl or tertiary butoxycarbonyl, refers to 2-13- or 4-fluoro ethyl, 2-13
- or 4-methylphenyl, 2-23- or 4-methoxyphenyl, 2-13- or 4-trifluoromethylphenyl, 2-13- or 4-hydroxyphenyl, 2-13- or 4-nitrophenyl, 2 -13-
or 4-aminophenyl, 2.4-12.3- or 3.4-difluorophenyl, 2,4-12,3- or 3,4-dimethylphenyl, 2.4-12.3- or 3.4 -dimethoxyphenyl, 2,4-12,3- or 3,4-ditrifluoromethylphenyl, 2,4.
2,3- or 3,4-dihydroxyphenyl, 2,4
-12.3- or 3,4-dinitrophenyl, 2,4
-22.3- or 3.4-diaminophenyl, 2,4
．． 64 fluorophenyl, etc., aralkyl refers to benzyl, which may have 1 to 3 substituents selected from halogen, alkyl, alkoxy, trifluoromethyl, hydroxyl, nitro, and amino on the aromatic ring; -13-Mak
Ha 4-chlorobenzyl, 2-13-4 or 4-methylbenzyl, 2-13- or 4-methoxybenzyl,
2-13- or 4-trifluoromethylbenzyl, 2
-13- or 4-hydroxybenzyl, 2-13- or 4-nitrobenzyl, 2-13- or 4-aminobenzyl, phenylethyl, phenylpropyl, phenylbutyl, naphthylmethyl, etc., bonded to RZ, R3 A heterocycle formed with an adjacent nitrogen atom is a 5- to 7-membered heterocycle containing at least one nitrogen atom, and includes pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, 4-methylpiperazine, etc. Ester residues that can be hydrolyzed in the body are those that easily decompose in the body to form free carboxylic acids or their salts, such as acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl, l- Alkanoyloxyalkyl esters such as pivaloyloxyethyl, alkoxycarbonyloxyalkyl esters such as ethoxycarbonyloxymethyl and 1-ethoxycarbonyloxyethyl, esters such as phthalidyl and dimethoxyphthalidyl, carbamoylmethyl, carbamoylethyl, N
- carbamoyl alkyl esters such as methylcarbamoylmethyl, N,N-dimethylcarbamoylmethyl, N,N-diethylcarbamoylmethyl, methoxymethyl,
Alkoxyalkyl esters such as methoxyethyl or 5-methyl-1,3-dioxolen-2-one-4-
yl methyl ester.

Salts of the compound of general formula (1) include acid addition salts, metal salts, etc.; examples of acid addition salts include salts with inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid; methanesulfonic acid, p-toluenesulfonic acid, lactic acid; Examples include salts with organic acids such as acetic acid, citric acid, and tartaric acid. Metal salts include alkali metal salts or alkaline earth metal salts (salts of sodium, potassium, calcium, magnesium, etc.), and heavy metal salts include copper, Zinc, iron, gold, silver 1. Examples include salts such as platinum and manganese.

The compound of general formula (1) of the present invention is a corresponding hydrate (
1 hydrate, hemihydrate, trihydrate, etc.) or other solvates.

In the compound of general formula (1), one or two asymmetric carbon atoms exist on the morpholine ring or hexahydro-1,4 oxazepine ring of the 7-position substituent, so optical isomers and stereoisomerism based on this exist. All such isomers and mixtures thereof are included in the present invention.

Margin below - According to the present invention, the compound of general formula (1) is produced by the following method.

A compound represented by the general formula (wherein, Xl represents a halogen, and the other symbols have the same meanings as above) (for example, JP-A No. 62-22
It is manufactured by the method described in No. 8063. )
and a compound represented by the general formula (in the formula, each symbol has the same meaning as above).

This condensation reaction is carried out using 1 to 8 moles of compound (■) to compound (I[), and at 0 to 200°C, preferably 30 to 150°C, in the absence of a solvent or in the presence of an appropriate solvent.
It will take 8 hours. Suitable solvents include water, alcohols (methanol, ethanol, propatool, etc.),
Acetonitrile, pyridine, dimethylformamide, dimethylsulfoxide, hexamethylphosphoricamide, 1-methyl-2-pyrrolidone, and the like can be used. At this time, 1,8-diazabicyclo[5,4,
Organic bases such as undec-7-ene, triethylamine or inorganic bases such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate may be used.

1 Toyomata General formula % formula % (In the formula, each symbol has the same meaning as above.) A compound represented by the general formula % formula % () (In the formula, M is an alkali metal such as sodium 1, potassium, lithium, etc. and R6 has the same meaning as above.) A method of reacting with a compound represented by:

In this reaction, compound (V) is added to compound (IV) from 2 to
Using 3 times the molar amount, the reaction is carried out at 0 to 200°C, preferably 50 to 150°C, for 1 to 48 hours in the presence of an appropriate solvent.
Suitable solvents include methanol, dimethylformamide, dimethylacetamide, dimethylsulfoxide, and the like.

1 Loss A compound of general formula (1) in which Rs is alkyl or aralkyl is converted into a carboxylic acid compound of general formula (1) in which Rs is hydrogen by deprotection according to a conventional method. be able to.

This reaction can be carried out using hydrolysis or catalytic reduction using an acid or alkali.

Furthermore, in the compound of general formula (4), R1 is acyl, alkoxycarbonyl (ethoxycarbonyl, tertiary butoxycarbonyl, benzyloxycarbonyl, etc.) and R
3 is hydrogen, alkyl, or R1 is hydrogen and R3
A compound in which is aralkyl can be deprotected according to a conventional method by hydrolysis or catalytic reduction using an acid or alkali to form a compound of the general formula % (wherein R2' is hydrogen, R1' is hydrogen or alkyl, Other symbols have the same meanings as above.) It can be converted into a carboxylic acid compound represented by:

Compounds whose general formula <1> is an ester that can easily undergo hydrolysis in vivo include compounds whose RS in general formula (1) is hydrogen and general formula % formula % () (wherein R5' is R8 In the definition, X2 represents an ester residue that can be easily hydrolyzed in vivo, and X2 represents a halogen.
) can be obtained by reacting a compound represented by:

Furthermore, acid addition salts and metal salts of compound (I) can also be produced by conventional methods. Furthermore, optical isomers can also be resolved by conventional methods or produced using optically active raw material compounds.

When the compounds of the invention are used as antibacterial agents, they may be administered orally in the form of conventional formulations containing a therapeutically effective amount of the compounds of the invention together with an organic or inorganic, solid or liquid, pharmacologically acceptable carrier. It can be administered parenterally or topically.

Such preparations include, for example, solid preparations such as tablets, granules, powders, and capsules, suspensions, and liquid preparations such as syrups, emulsions, and lemonades. Furthermore, the above formulation may contain auxiliary substances, stabilizers, wetting agents, and other ingredients such as lactose, magnesium stearate, clay, silica sugar, corn starch, talc, stearic acid, gelatin, agar, pectin, peanut oil, olive oil, and cacao. Commonly used additives such as oil, ethylene glycol, etc. can be included.

The dosage will vary depending on the age and condition of the patient, or the type of disease and the type of compound to be administered, but generally an amount of 1 to about 4000 μ or more can be administered to the patient per day.

The average single dose of the compounds of the invention is approximately 50,10
They are 0■, 250■, 500■, 1000■, and 2000■.

[For production]

Compounds of general formula (1) of the present invention and salts and hydrates thereof,
Alkyl esters, aralkyl esters, esters that can be hydrolyzed in vivo, or their optical isomers have been investigated through various pharmacological experiments, including the experimental examples shown below, to determine the effectiveness of conventional pyridone carboxylic acid-based anti-depression agents. While maintaining strong antibacterial activity against negative bacteria, it has enhanced efficacy and broad antibacterial activity against Durham positive bacteria in vitro and in vivo. Furthermore, when administered orally to experimental animals, it shows better absorption, almost no problematic side effects, and low toxicity.
It is expected to have better clinical utility as an antibacterial agent.

The compounds of the invention are particularly suitable for staphylococci, such as methicillin and cephem resistant Staphylococcus aureus, Staphylococcus epidermidis,
Since it has very strong antibacterial activity against Durham-positive bacteria such as Streptococcus pneumoniae and Enterococcus enterococcus, it can also be used to treat various infectious diseases caused by these pathogens.

〔Example〕

Next, the present invention will be specifically explained in detail with reference to Examples, but the present invention is not limited by these in any way.

Example 1 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-(3.9 g of 2-(methylaminomethyl)monopholino-4-oxoquinoline-3-carboxylic acid and sodium methylate) 1. A mixture of 2 g and dimethylformamide 39- is stirred at 80° C. for 9 hours. After the reaction is complete, the solvent is concentrated under reduced pressure, water is added to the residual aroma, and the mixture is purified with acetic acid.
Adjust to H6.5.

After purification by HP-20 column chromatography and recrystallization from ethanol, 1-cyclopropyl-1,4
-dihydro-6-fluoro-8-methoxy-7-(2-
(Methylaminomethyl)morpholino]-4-oxoquinoline-3-carboxylic acid is obtained. Melting point 208-210
℃ IR(ell-', KBr) 3400.164O
NMR (CDCh), δ (ppm): 0.9
~1.3 (m, 4H), 2.46 (s, 38), 2
．． 5-4.1 (m, 10H), 3.8 (s, 3) 1)
, 7.86 (d, IH, 12Hz), 8.76 (s
, IH) Example 2 2.95 g of 1-cyclopropyl-6,7-difluoro1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid, 1.59 g of 2-(dimethylaminomethyl)morpholine , and 1,8-diazabicyclo(5,
4,0) 2.77 g of undecan-7-nin was stirred under reflux in 30 d of acetonitrile for 8 hours. After completion of the 8 reactions, the solvent was concentrated under reduced pressure and the residue was purified by HP-20 column chromatography. Recrystallization from ethanol yields 1-cyclopropyl-1,4-dihydro-7-[2(dimethylaminomethyl)morpholino]-6-fluoro-8-methoxy-4-oxoquinoline-3-carboxylic acid. Melting point 162-163℃r R(am-', KBr
) 3400.1735.1.62ONMR(CDCI
s), δ (ppm): 0.9 to 1.3 (m, 4H)
, 2.2-4.1 (++, 10H), 2.32 (s
, 6H), 3.8 (s, 3H), 7.86 (d 1
B, 12 Hz), 8.8 (s, IH) The following compounds can be produced in the same manner as in Example 1 and Example 2.

+a+7-[2-(aminomethyl)morpholinocy 1-
cyclopropyl-1,4-dihydro-6-fluoro-8
-methoxy-4-oxoquinoline-3-carboxylic acid, melting point 174-177°C ('b) 1-cyclopropyl-1,4-dihydro-6-
Fluoro-8-methoxy-7-[2-methyl6-(methylaminomethyl)morpholino]-4-oxoquinoline-
3-Carboxylic acid (C) 1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-7-(2-(2-methylaminoethyl)morpholino)-4-oxoquinoline-3-carboxylic acid (d) 1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-7-(2-(methylaminomethyl)hexahydro-1,4-oxazepin-4-yl)
-4-oxyquinoline-3-carboxylic acid (e17-(2-(ethylaminomethyl)morpholino-1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-4-oxoquinoline-3-carboxylic acid ( f) 1-Cyclopropyl-7-(2-(diethylaminomethyl)morpholino)-1,4-dihydro-6-fluoro-8-methoxy-4-oxoquinoline-3-carboxylic acid (1-cyclopropyl-1 ,4-dihydro-6fluoro8-methoxy-4-oxo-7-(2-(1-pyrrolidinylmethyl)morpholino)quinoline-3-carboxylic acid (h) 1-cyclopropyl-1,4-dihydro-6 -Fluoro-8-methoxy-4-oxo-7-[2-(piperidinomethyl)morpholino]quinoline-3-carboxylic acid (1) 1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-7- (2-(morpholinomethyl)morpholino]-4-oxoquinoline-3-carboxylic acid ('') 1-cyclopropyl-1,4-dihydro-6-
Fluoro-8-methoxy-7-(2-(N-methyl-1
-piperazinylmethyl)morpholino]4-oxoquinoline-3-carboxylic acid (k17-(2-(aminomethyl)morpholino)
Cyclopropyl-1,4-dihydro-8-ethoxy-6
-Fluoro-4-oxoquinoline-3-carboxylic acid (1) 1-cyclopropyl-1,4-dihydro-8-ethoxy6-fluoro7- (2-(methylaminomethyl)morpholino2-4-oxoquinoline-3 -Carboxylic acid (m) 1-cyclopropyl-1,4-dihydro-7-(
2-(dimethylaminomethyl)morpholino]-8-ethoxy-6-fluoro-4-oxoquinoline-3-carboxylic acid (nl 7- (2-(aminomethyl)morpholino)
-1,4-dihydro-1-ethyl-6-fluoro-8
-Methoxy-4-oxoquinoline-3-carboxylic acid (0
11,4-dihydro-1-ethyl-6-fluoro-8-
Methoxy-7-C2-(methylaminomethyl)morpholino-4-oxoquinoline-3carboxylic acid (pH, 4-dihydro-7-C2-(dimethylaminomethyl)morpholino)-1-ethyl-6-fluoro-8-
Methoxy-4-oxoquinoline-3-carboxylic acid (ql?-(2-(aminomethyl)morpholino)-1-
(2,4-difluorophenyl)-1,4dihydro-6
-Fluoro-8-methoxy-4-oxoquinoline-3-
Carboxylic acid (rl 1- (2,4-difluorophenyl) -
1,4-dihydro-6-fluoro-8-methoxy-7-
[2-(Methylaminomethyl)morpholino-4-oxoquinoline-3-carboxylic acid (311-(2,4-difluorophenyl)-1,4dihydro-7-(2-(dimethylaminomethyl)morpholino-6- Fluoro-8-methoxy4-oxoquinoline-3-carboxylic acid (t)7-[2-(aminomethyl)morpholino]1.4
-dihydro-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxoquinoline-3-carboxylic acid full, 4-dihydro-6-fluoro-1-(2-fluoroethyl)-8- Methoxy-7-[2(methylaminomethyl)morpholino-4-oxoquinoline-3-carboxylic acid (ν) 1,4-dihydro-7-(2-(dimethylaminomethyl)morpholino-6-fluoro-1-( 2-Fluoroethyl)-8-methoxy-4-oxoquinoline-
3-Carboxylic acid (b) 1-ethoxycarbonyloxyethyl 1-cyclopropyl-1,4-dihydro-6-fluoro-8-
Methoxy-7-(2-(methylaminomethyl)morpholino-4-oxoquinoline-3-carboxylate (x) 1-allyl-1,4-dihydro-6-fluoro-
8-Methoxy-7-(2-(methylaminomethyl)morpholino-4-oxoquinoline-3-carboxylic acid [Effects of the invention] Experimental example The in vitro antibacterial activity of the compound of the present invention was determined using the standard method of the Japanese Society of Chemotherapy (Chemotherapy). , Volume 23,
No. 1126, 1974). The test compound is 1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-? -(2-(methylaminomethyl)morpholino-4-oxoquinoline-3-
Carboxylic acid (compound A) was converted into 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3dihydro-7H-pyrido(1,2,3 -de)(1,4)-benzoxazine-
6-carboxylic acid (ofloxacin) and 1-cyclopropyl-6=fluoro-1,4-dihydro-7-(1-piperazinyl)-4-oxoquinoline-3-carboxylic acid (ciprofloxacin) were used. The results are summarized in Table 1.

Margin below - As is clear from Table 1, the compound of the present invention had far superior antibacterial activity against Durham positive surfaces compared to ofloxacin and ciprofloxacin.

In particular, it had very strong antibacterial activity against staphylococci such as methicillin- and cephem-resistant Staphylococcus aureus and Staphylococcus epidermidis, as well as Durham-positive bacteria such as Streptococcus pneumoniae and Enterococcus.

Therefore, the compound of general formula (I) obtained in the present invention and its salts, hydrates, alkyl esters, aralkyl esters, their in vivo hydrolyzable esters, or their optical isomers can be Compared to pyridonecarboxylic acid, it has enhanced potency and broad antibacterial activity against Durham-positive bacteria in vitro and in vivo, exhibits better absorption upon oral administration to experimental animals, and has no problematic side effects. Since it exhibits low toxicity, it is expected to be more clinically useful.

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 is alkyl, cycloalkyl, haloalkyl, alkenyl, phenyl, or as a substituent, halogen, alkyl, alkoxy, hydroxyl, nitro, amino. Represents a phenyl group having ~3 atoms, R^2 is hydrogen,
An alkyl, cycloalkyl, acyl or alkoxycarbonyl group, R^3 represents hydrogen, an alkyl or aralkyl group, or a group in which R^2 and R^3 are bonded to each other to form a heterocycle with the adjacent nitrogen atom. , R^4 represents hydrogen or an alkyl group, R^5 represents hydrogen, alkyl, aralkyl, or an ester residue that can be hydrolyzed in vivo, R^6 represents alkyl, and R^
7 represents hydrogen or amino, m represents an integer of 2 or 3, and n represents an integer of 1 to 3. ) Pyridonecarboxylic acid compounds and salts thereof.