JPH0366688A - 1,4-dihydro-4-oxonaphthyridine compound - Google Patents

Abstract

NEW MATERIAL:The compound of formula l [R<1> is alkyl, cycloalkyl, haloalkyl, (substituted) phenyl, amino, etc.; R<2> is H, (substituted) alkyl, (substituted) cycloalkyl, acyl, etc.; R<3> is H, alkyl or aralkyl; R<2> and R<3> may together with adjacent N form a heterocyclic group; R<4> is H or alkyl; R<5> is H, alkyl, aralkyl or ester residue; m is 2 or 3; n is 1-3]. EXAMPLE:7-[2-(Aminomethyl)morpholino]-1-cyclopropyl-6-fluoro-1,4-dihyd ro-4- oxo-1,8-naphthyridine-3-carboxylic acid. USE:An antibacterial agent against Gram-negative and Gram-positive bacteria. It is free from side action and has low toxicity. PREPARATION:A compound of formula II (X<1> is halogen) is condensed with a compound of formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel 1,4-dihydro-4-oxonaphthyridine compound and its salt having excellent antibacterial activity.

[Conventional technology]

Since the introduction of nalidixic acid in 1962, various quinolone synthetic antibacterial agents have been studied. Among them, l-ethyl-6 to fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8
-naphthyridine-3-carboxylic acid 3/2 hydrate (enoxacin, JP-A-57-134482), D,
L-7-(3-amino-!-pyrrolidinyl)-1-(2
,4-difluorophenyl)-6-fluoro-1,4-
Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid tosylate l-hydrate (tosufloxacin,
Japanese Patent Publication No. 63-20828) is known.

[Problem to be solved by the invention]

These fluorine-substituted naphthyridine-based synthetic antibacterial agents and other pyridonecarboxylic acids have broad antibacterial activity against both Durum-positive and -resistant bacteria. However, the antibacterial effect against Durham-positive bacteria is not as effective as against Durham-negative bacteria. Currently, methicillin- and cephem-resistant Staphylococcus aureus and Staphylococcus epidermidis, which are highly resistant to β-lactam antibiotics, especially third-generation cephems, Staphylococcus epidermidis, Streptococcus pneumoniae and Enterococcus, and Streptococcus Streptococcus pyogenes, etc. A clinical problem has arisen in which infections caused by Durham-positive bacteria are difficult to treat with chemotherapy. However, there is a need for a type of antibacterial agent that does not cause bacterial replacement. Furthermore, as a treatment for infections in patients with weakened immune systems due to underlying diseases or other causes, it is desirable to develop antibacterial agents with even stronger antibacterial activity compared to the pyridone carboxylic acid compounds that have been used in the past. ing.

Efforts to improve and enhance the antibacterial spectrum are being undertaken under various intensive research and development efforts.

[Means to solve the problem]

The inventors described the above! As a result of extensive research to solve IIs, a new 1,4-dihydro-4-oxonaphthyridine compound has a strong antibacterial activity against Durham-negative bacteria, as well as the conventional 1,4-dihydro-4-oxonaphthyridine compound against Durham-positive bacteria. in vitro compared to dihydro-4-oxonaphthyridine compounds.
The present invention was completed based on the discovery that it has significantly enhanced ro and in vivo antibacterial activity, exhibits good absorption upon oral administration, exhibits almost no problematic side effects, and has low toxicity.

The present invention relates to phenyl, amine, mono or dialkyl having 1 to 3 of the following formula: R1 represents hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, acyl, alkoxycarbonyl, agono, mono- or dialkylamino; R3 represents hydrogen, alkyl or aralkyl, or Rt, Rs represents a group that combines with each other to form a heterocycle with adjacent nitrogen atoms; R4 represents hydrogen or alkyl; Rs represents hydrogen, alkyl, aralkyl, or an ester residue that can be hydrolyzed in vivo; m represents an integer of 2 or 3; n represents an integer of 1 to 3. >> It relates to a 1,4-dihydro-4-oxonaphthyridine compound represented by.

In this specification, halogen means chlorine, bromine, fluorine, iodine, and alkyl means methyl, ethyl, propyl, isopropyl,
Alkyl refers to alkyl having 1 to 18 carbon atoms such as butyl, isobutyl, tertiary butyl, pentyl, hexyl, heptyl, octyl, decyl, dodecyl, octadecyl, etc., and alkoxy refers to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, Alkoxy having 1 to 18 carbon atoms such as tertiary butoxy, pentyloxy, hexyloxy, octyloxy, decyloxy, dodecyloxy, octadecyloxy, etc., and alkenyl refers to carbon atoms such as vinyl, allyl, butenyl, pentenyl, hexenyl, octenyl, etc. Alkenyl having 2 to 8 carbon atoms, haloalkyl is an alkyl having 1 to 8 carbon atoms substituted with at least one halogen, and difluoromethyl, trifluoromethyl, fluoroethyl, trifluoroethyl, etc. are substituted with cycloalkyl. Alkyl means cyclopropyl, cyclobutyl,
Acyl refers to cycloalkyl having 3 to 7 carbon atoms such as cyclopentyl, cyclohexyl, cycloheptyl, formyl, acetyl, propionyl, butyryl, valeryl,
Acyl having 1 to 5 carbon atoms such as pivaloyl, and alkoxycarbonyl having an alkoxy moiety having 1 to 4 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxy Carbonyl, tertiary butoxycarbonyl, etc., as a substituent, halogen,
Alkyl, alkoxy, trifluoromethyl, hydroxyl group,
Phenyl having 1 to 3 of nitro and amino means 2-
13- or 4-fluorophenyl, 2-13- or 4-methylphenyl, 2-13- or 4-methoxyphenyl, 2-53- or 4-trifluoromethylphenyl, 2-13- or 4-hydroxyphenyl, 2-
13- or 4-nitrophenyl, 2.3- or 4-
Aminophenyl, 2.4-2.3- 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, 2.4-52.3-
or 3,4-dinitrophenyl, 2,4-12.3-
or 3,4-diaminophenyl, 2.4. Lotrifluorophenyl, etc., and aralkyl include benzyl, 2-, which may have 1 to 3 substituents selected from halogen, alkyl, alkoxy, trifluoromethyl, hydroxyl, nitro, and amino on the aromatic ring. 13- or 4-chlorobenzyl, 2-13- or 4-methylbenzyl, 2
−． 3- 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., substituted alkyl, substituted cycloalkyl, halogen, alkyl, alkoxy, hydroxyl, nitro, amino, etc. as a substituent, R1, R3 bonded to adjacent nitrogen A heterocycle formed with an atom is a 5- to 7-membered heterocycle containing at least one nitrogen atom, and is capable of hydrolyzing pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, 4-methylbiperazine, etc. in vivo. Ester residues that can be easily decomposed in vivo to form free carboxylic acids or salts thereof include acetoxymethyl, pivaloyloxymethyl,
Alkanoyloxyalkyl esters such as 1-acetoxyethyl and ■-pivaloyloxyethyl, alkoxycarbonyloxyalkyl esters such as ethoxycarbonyloxymethyl and 1-ethoxycarbonyloxyethyl, esters such as phthalidyl and dimethoxyphthalidyl, carbamoylmethyl, Carbamoyl alkyl esters such as carbamoylethyl, N-methylcarbamoylmethyl, N,N dimethylcarbamoylmethyl, N,N-diethylcarbamoylmethyl, alkoxyalkyl esters such as methoxymethyl, methoxyethyl, or 5-
Methyl-1,3-dioxolen-2-one-4-yl methyl ester can be mentioned.

Salts of the compound of general formula N) include acid addition salts, metal salts, etc. Acid addition salts include salts with inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, lactic acid, and acetic acid. Examples of the metal salts include alkali metal salts or alkaline earth metal salts (salts of sodium, potassium, calcium, magnesium, etc.).

The compounds of general formula (1) of the present invention may also exist as their corresponding hydrates or other solvates.

In the compound of general formula (1), there are 1 or 2 asymmetric carbon atoms on the morpholine ring of the 7-position substituent, so there are optical isomers and stereoisomers based on this,
All of these isomers and mixtures thereof are included in the present invention.

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

(Method 1) A compound represented by the general formula (in the formula, Xl represents a halogen, and the other symbols have the same meanings as above) and the general formula () (in the formula, each symbol has the same meanings as above). A method of condensing a compound represented by

In this condensation reaction, 1 compound (■) is added to compound (■).
~8 times the mole used, in the absence of a solvent or in the presence of an appropriate solvent, at 0 to 200°C, preferably 30 to 150°C, from 1 to 48
Take your time. Suitable solvents include water, alcohols (methanol, ethanol, propanol, etc.), acetonitrile, pyridine, dimethylformado, dimethyl sulfoxide, hexamethylphosphoric amide,
1-methyl-2-pyrrolidone and the like can be used. At this time, 1,8-diazabicyclo[5,4,0] was used as a deoxidizing agent.
Organic bases such as undec-7-ene, triethylamine or inorganic bases such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate may be used.

Compounds of general formula (II) are available from J, Med, Chem,
Volume 27, page 292, 1984; J, Med, C
hes+, No. 29@, p. 2363, 1986;
J, Heterocyclejc, Chea+, .

It can be synthesized by the method described in Vol. 24, p. 1333, 1987.

(Method 2) A compound represented by the general formula % formula % () (in the formula, X2 represents a halogen, and the other symbols have the same meanings as above) and the general formula (in the formula, each symbol has the same meanings as above) A method of condensation with a compound represented by

In this condensation reaction, 1 compound (V) is added to compound (IV).
~8 times the mole used, at 0 to 200°C, preferably 100 to 200°C, in the absence of a solvent or in the presence of an appropriate solvent.
Take your time. As suitable solvents, water, alcohols, dimethylformamide, dimethylsulfoxide, hexamethylphosphoricamide, etc. can be used. At this time, sodium iodide, potassium iodide, etc. may be used to accelerate the reaction.

Blank space below - (Method 3) Compounds in which R5 is alkyl or aralkyl among the compounds of general formula (1) can be deprotected according to a conventional method to form carboxylic acid compounds of general formula (I) in which R5 is hydrogen. can be converted into compounds.

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

Furthermore, in the compound of -Momonena (1), R2 is acyl, alkoxycarbonyl (ethoxycarbonyl, tertiary butoxycarbonyl, benzyloxycarbonyl, etc.) and R
3 is hydrogen, alkyl, or R2 is hydrogen and R1
is an aralkyl compound by deprotecting it according to a conventional method by hydrolysis or catalytic reduction using an acid or an alkali to obtain a compound of the general formula () (where Rt'', Ral is hydrogen, alkyl in the definition of R1, R3). and other symbols have the same meanings as above).

(Method 4) Cyclizing a compound represented by the general formula () (wherein R1 represents alkyl or aralkyl in the definition of R5, X3 represents halogen, and the other symbols have the same meanings as above), A method in which the resulting compound represented by the general formula () (in the formula, each symbol has the same meaning as above) is then subjected to a hydrolysis reaction.

This cyclization reaction is carried out by exposing the compound (■) to a suitable base catalyst in a suitable solvent (e.g., dioxane, alcohols (methanol, ethanol, propanol, butanol, etc.), polar solvents such as dimethylformamide, dimethyl sulfoxide, sulfolane, etc.). (sodium carbonate, potassium carbonate, 1,8-diazabicyclo(5,4,03undec-
0 to 200°C, preferably 5
It can be produced by cyclizing by heating at 0 to 150°C for 1 to several hours, followed by hydrolysis under acidic or basic conditions.

- When Mon'ena (1) is an ester that can easily undergo hydrolysis in vivo, - a compound in which R5 of Mon'ena (1) is hydrogen and the general formula % formula % () (wherein Rs” In the definition of RS, represents an ester residue that can be easily hydrolyzed in vivo, and X4 represents a halogen.

) can be obtained by reacting with a compound represented by:

Moreover, the carboxylic acid compound of -Momonena (1) can be exchanged into the corresponding salts such as acid addition salts or metal salts, hydrates, alkyl esters, and aralkyl esters exemplified above by a conventional method.

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 formulations include, for example, solid formulations such as tablets, granules, powders, and capsules, and suspensions, and liquid formulations such as syrups, emulsions, and lemonades. Furthermore, if necessary, adjuvants, stabilizers, wetting agents, lactose, magnesium stearate, terra alba, Sigli, etc. may be added to the above formulation.
, corn starch, talc, stearic acid, gelatin,
Agar, pectin, peanut oil, olive oil, cacao oil,
Commonly used additives such as ethylene glycol can be included.

Although the dosage varies depending on the age and symptoms of the patient, or the type of disease and the type of compound to be administered, an amount of 1 to about 4000 or more can be administered to the patient per day.

The average single dose of the compounds of the invention is approximately 50 μl, 10
O■, 251) g, 500■, 1000■, 2000■
It is.

[Action and effect of the invention]

Compounds of general formula (1) of the present invention and salts and hydrates thereof,
Through various pharmacological experiments, alkyl esters, aralkyl esters, and their in vivo hydrolyzable esters have been shown to maintain the strong antibacterial activity of conventional pyridonecarboxylic acid-based antibacterial agents against Durum-negative bacteria, while also inhibiting Durum-positive bacteria. In contrast, in vitr.

and has enhanced potency and broad antibacterial action in vivo. Furthermore, when administered orally to experimental animals, it exhibits better absorption, almost no problematic side effects, and low toxicity, so it is expected to have better clinical utility as an antibacterial agent.

〔Example〕

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

Example 1 (1) 2.37 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8 naphthyridine-3-carboxylic acid, 2-acetamidomethylmorpholino 2 .75 g is heated to reflux in acetonitrile 50TR1 for 3 hours. After cooling, the precipitated crystals are collected by filtration and washed with ethanol to give 7-
(2-(acetamidomethylmorpholino)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8 naphthyridine-3-carboxylic acid is obtained.

(21?-(2-(acetamidomethylmorpholino)-1
-cyclopropyl-6-fluoro-1,4-dihydro-
4-oxo-1,8-naphthyridine-3-carboxylic acid 1
．． 5g was mixed with 6ml of concentrated hydrochloric acid and 4.5ml of water. Dissolve in F+wl, 3.
Heat to reflux for 5 hours. After cooling, add 2°a + J of acetone,
The precipitated crystals are collected by filtration and washed with acetone. The obtained crystals are dissolved in water and adjusted to pH 7 with sodium hydroxide. When the precipitated crystals are collected by filtration, washed with water, and dried, the melting point is 2.
7-(2-(acdimethyl)morpholino-1-cyclopropyl-6-fluoro-1,4- at 10-212°C
Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is obtained.

Example 2 7-chloro-1-cyclopropyl-6-fluoro-1,
4-dihydro-4-oxo-1,8-naphthyridine-3
11.41 g of -carvone and 1.37 g of 2-methylaminomethylmorpholine are heated under reflux for 4 hours in 20 ml of acetonitrile. After cooling, the precipitated crystals are collected by filtration and washed with acetonitrile.

The crystals were dissolved in ethanol 5I, concentrated hydrochloric acid was added, and the precipitated white crystals were recrystallized with aqueous ethanol. Cyclopropyl-6-fluoro-1,4-dihydro-4oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride is obtained.

Example 3 (1) 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1
, 8-naphthyridine-3-carboxylic acid ethyl ester 0
．． 96g, 2-acemidomethylmorpholine 0.47g
, triethylamine 0.25g methylene chloride 2
The reaction mixture was washed with water, dried over anhydrous magnesium sulfate, and distilled off under reduced pressure to give 7-(2-(acetaξtomethyl〉morpholino)-1-( 2,4-difluorophenyl)-6
-Fluoro-1,4-dihydro-4-oxo-1,8-
Naphthyridine-3-carboxylic acid ethyl ester is obtained.

(2) Add 0.95 g of this oil to 6N hydrochloric acid 10+
+1 and heated under reflux for 4 hours. After cooling, the precipitated crystals are collected by filtration. The crystals were dissolved in 2N aqueous sodium hydroxide, and then adjusted to pH 6.5 with acetic acid. When the precipitated crystals are collected by filtration, washed with water, and dried, the melting point is 262-26.
7-(2-(aminomethyl)morpholino)-1 at 4°C
-(2,4-difluorophenyl)-6-fluoro-1
,4-dihydro-4oxo-1,8-naphthyridine-3
- A carboxylic acid is obtained.

Hereinafter, the following compounds are obtained in the same manner as in Examples 1 to 3.

(4) 1-cyclopropyl-7-(2-(ethylagodimethyl)morpholino]-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (5) 1-cyclopropyl -7-(2-(dimethylaminomethyl)morpholino-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (6) 1-cyclopropyl-7-(2 -(diethylaminomethyl)morpholino-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (7) 1-cyclopropyl-6-fluoro-1,4-dihydro-4 -oxo-7-[2-(1-pyrrolidinylmethyl)morpholino)-1,8-naphthyridine-3-carboxylic acid (8) 1-cyclopropyl-6-fluoro-1,4dihydro-4-oxo- 7-(2-(Piperidinomethyl)morpholino)-1,8-naphthyridine-3-carboxylic acid (9>1-cyclopropyl-6-fluoro-1,4-dihydro-7-(2-(morpholinomethyl)morpholino)
-4-oxo 1,8-naphthyridine-3-carboxylic acid (10) 1-cyclopropyl-6-fluoro-1,
4-dihydro-7-(2-(4-methyl-1-piperazinylmethyl)morpholino]-4-oxo1,8-naphthyridine-3-carboxylic acid (11) 1-cyclopropyl-6-fluoro-1 ,4-dihydro-4-oxo-7
-(2-(1-piperazinylmethyl)morpholino)-1
,8-naphthyridine-3-carboxylic acid (12) 1-cyclopropyl-6-fluoro-14
-dihydro-7-C2-(2-methylaminoethyl)morpholino-4-oxo-1,8-naphthyridine-3-
Carboxylic acid (13) 7- (2-(2-aminoethyl)morpholino)-1-cyclopropyl-6-fluoro-1,4-
Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (14)? -(2-(aminomethyl)morpholino-1-ethyl-6-fluoro-1,4-dihydro-4-
Oxo-1,8-naphthyridine-3-carboxylic acid (15) 1-ethyl-6-fluoro-1,4-dihydro-7-(2-(methylaminomethyl)morpholino-4-oxo-1,8-naphthyridine -3-Carboxylic acid (16) Mer[2-(dimethylaminomethyl)morpholino-1-ethyl-6-fluoro-14-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (17) 1- (2,4-difluorophenyl)-
6fluoro1,4-dihydro-7-(2-(methylaminomethyl)morpholino)-4-oxo1,8-naphthyridine-3-carboxylic acid (1B) 1- (2,4-
difluorophenyl)-7[2-(dimethylaminomethyl)morpholino]6-fluoro1,4-dihydro-4
-oxo-1,8-naphthyridine-3-carboxylic acid (1
9) 7-(2-(aminomethyl)morpholino-6-fluoro-1-(2-fluoroethyl)-1,4-
Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (20) 6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-7-(2-(methylaminomethyl)morpholino2 4-Oxo L 8-naphthyridine-3-carboxylic acid (21) ?-(2-(dimethylaminomethyl)morpholino-6-fluoro-1-(2-fluoroethyl)
-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 is alkyl, cycloalkyl, haloalkyl, alkenyl, phenyl, halogen as a substituent,
1 to alkyl, alkoxy, hydroxyl, nitro, amino
R^2 represents hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, acyl, alkoxycarbonyl, amino, mono- or dialkylamino; 3 represents hydrogen, alkyl or aralkyl, or represents a group in which R^2 and R^3 combine with each other to form a heterocycle with the adjacent nitrogen atom; R^4 represents hydrogen or alkyl; R^ 5 represents hydrogen, alkyl, aralkyl, or an ester residue that can be hydrolyzed in vivo; m represents an integer of 2 or 3; n represents an integer of 1 to 3. ) A 1,4-dihydro-4-oxonaphthyridine compound represented by: