FR2576307A1 - New quinoxaline 1,4-di-N-oxide derivatives, process for their preparation and their use in human and veterinary therapeutics - Google Patents

Abstract

The derivatives correspond to the following formula: where R = H, CH3. R' represents a substituted aryl or alkyl residue or an optionally condensed and optionally substituted heterocyclic group. Application: use as antibacterial agents and growth-promoting agents.

Description

 The present invention relates to new quinoxaline derivatives di-N-1,4-oxide, their preparation process and their use in human and veterinary therapy.

 The antibacterial activity of certain quinoxaline di-N-oxide derivatives has already been known (see in particular US Pat. No. 2,626,259 concerning di-N-oxide-9 alkyl quinoxaline derivatives or US Pat. No. 3,371,090 relating to bases of Schiff derived from formyl-2-quinoxaline dioxide).

 The object of the present invention is to provide a new family of quinoxaline di-N-oxide derivatives having the advantage of giving easily administrable soluble salts (in contrast to all insoluble or very little prior art products). soluble), while maintaining antibacterial activity comparable to, or even greater than. that of previously known derivatives.

dans laquelle - R représente l'hydrogène ou le groupe méthyle - R' représente un groupe phényle éventuellement substitué par un ou plusieurs substituants choisis parmi les radicaux : méthyle, méthoxy, éthyle, éthoxy, chloro, fluoro, bromo, iodo, nitro, cyano, trifluorométhyle, hydroxycarboxamido, benzoyle, thiol, éthoxycarbonyle, méthylène dioxy-3,4, éthylène dioxy-3,4, hydroxyméthyle, méthylthio, phénoxy, benzyloxy, éthylthio, ahydroxyéthyle, isopropylthio, sulfamido, ou bien - R' représente un hétérocycle à un hétéroatome comprenant 5 à 7 chainons et dont l'hétéroatome est constitué par l'azote ou le soufre ou ltoxygène, cet hétérocycle pouvant être substitué par un ou plusieurs des radicaux substituants éventuellement le noyau phényle et cités ci-dessus, ou bien - R' représente un hétérocycle comprenant de 5 à 7 chainons comprenant deux hétéroatomes identiques ou différents choisis parmi l'azote, le soufre ou l'oxygène, cet hétérocycle pouvant être substitué par un ou plusieurs des radicaux substituants éventuellement le noyau phényle et cités ci-dessus, ou bien - R' représente un hétérocycle condensé polycyclique choisis parmi les hétérocycles suivants : indolizine, indole, isoindole, indazole, quinoléine, isoquinoléine, phtalazine, naphtyridine, quinoxaline, quinazoline, cinnoline, carbazole, sscarboline, phénanthridine, acridine, phénanthroline, phénazine, benzimidazole, benzothiazole, benzoxazole, benzoisothiazole, benzotriazole, benzotriazine, benzothiadiazole, ou bien - R' représente un radical alkyle de C1 à C12 linéaire ou ramifié éventuellement sustitué par des groupements OH ou des groupements dialkylamino, ces groupements dialkyle comprenant de 1 à 3 atomes de carbone, ou bien - Rl représente un radical cycloalkyle aliphatique comprenant de 5 à 7 chainons directement relié ou relié par l'intermédiaire d'un enchainement méthylène comprenant de 1 à 3 radicaux -CH2ainsi que leurs sels solubles obtenus à l'aide de bases minérales ou organiques pharmacologiquement compatibles.The subject of the present invention is the 1,4-dioxide-quinoxalinyl-2-aminomethanesulfonic acid derivatives of general formula I hereinafter:

in which - R represents hydrogen or methyl group - R 'represents a phenyl group optionally substituted by one or more substituents chosen from the radicals: methyl, methoxy, ethyl, ethoxy, chloro, fluoro, bromo, iodo, nitro, cyano; trifluoromethyl, hydroxycarboxamido, benzoyl, thiol, ethoxycarbonyl, methylene 3,4-dioxy, ethylene 3,4-dioxy, hydroxymethyl, methylthio, phenoxy, benzyloxy, ethylthio, ahydroxyethyl, isopropylthio, sulfamido, or - R 'represents a heterocycle with a heteroatom comprising 5 to 7 members and whose heteroatom is constituted by nitrogen or sulfur or oxygen, this heterocycle may be substituted by one or more of the substituent radicals optionally the phenyl ring and cited above, or else - R represents a 5- to 7-membered heterocycle comprising two identical or different heteroatoms chosen from nitrogen, sulfur or oxygen, this heterocycle it may be substituted with one or more of the substituent radicals, optionally the phenyl nucleus and mentioned above, or R 'represents a polycyclic fused heterocycle chosen from the following heterocycles: indolizine, indole, isoindole, indazole, quinoline, isoquinoline, phthalazine , naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, sscarboline, phenanthridine, acridine, phenanthroline, phenazine, benzimidazole, benzothiazole, benzoxazole, benzoisothiazole, benzotriazole, benzotriazine, benzothiadiazole, or - R 'represents a linear C1 to C12 alkyl radical or branched optionally substituted with OH groups or dialkylamino groups, these dialkyl groups comprising from 1 to 3 carbon atoms, or - R1 represents an aliphatic cycloalkyl radical comprising from 5 to 7 members directly connected or connected via a methylene chain comprising from 1 to 3 radicals -CH 2 as well as soluble salts obtained using pharmacologically compatible inorganic or organic bases.

 The subject of the present invention is also a process for the preparation of the derivatives of general formula I, characterized in that 2-formyl-2-quinoxaline-1,4-dioxide is reacted in a suitable solvent such as pyridine or a methyl pyridine. a primary amine and sulfur dioxide followed by isolating the product from the reaction.

According to an advantageous embodiment of the process, the amounts of formyl-2-quinoxaline-1,4-dioxide and primary amine are used in a stoichiometric ratio, whereas sulfur dioxide is used in excess.
According to the process described, the reaction is preferably carried out starting at 0 ° C. and the reaction medium is left for a few hours at room temperature.

 The reaction medium is diluted in a non-aqueous organic solvent miscible with pyridine such as an ether or hydrocarbon. The product according to the invention crystallizes in the solvent mixture from which it is then isolated by filtration and washing.

 According to another advantageous embodiment of the process which is the subject of the present invention, the major part of the pyridine can be recovered by distillation under reduced pressure and the active ingredient precipitated by dilution of the residual reaction medium in slightly acidified water.

After adjusting the pH between 5 and 6.5, the derivative according to the invention is filtered, washed with water, then with alcohol and dried.

 The present invention further relates to medicaments containing at least one derivative according to the invention.

These derivatives may be employed in their insoluble acid forms, or salified with a pharmaceutically acceptable inorganic or organic base to provide water-soluble forms.

 The derivatives according to the invention exhibit an anti-infectious activity especially on the urinary system in both humans and animals. This antibacterial activity extends over a wide variety of microorganisms including gram-positive and gram-negative bacteria. It should be noted that the derivatives according to the invention are active in the treatment of urinary tract infections, chronic respiratory disorders, in several animal species, especially in poultry, they prove to be particularly interesting in the prophylaxis or the prevention of these affections.

 In addition, the addition of a low concentration of at least one derivative according to the invention to the diet of animals, ruminants or non-ruminants at average daily doses of 0.1 to 10 mg / kg causes an acceleration of the speed. growth and increased feed efficiency.

 The derivatives according to the invention can be administered alone or in combination with inert, non-toxic pharmaceutically acceptable, solid, pasty or liquid carriers. In these forms can be considered tablets, dragees, capsules, pills, granules, suppositories, suspensions and aqueous or nonaqueous solutions, creams, lotions, powders.

 Examples of solid or semi-solid and liquid carriers that may be mentioned include water, non-toxic organic solvents, vegetable oils, alcohols, glycols, natural or synthetic mineral powders, sugars, emulsifiers, dispersants and the like; polymers. Various modes of administration may be recommended depending on the type of infection and their severity: oral, parenteral, subcutaneous or intramuscular. In the case of acute infections, it is advantageous to administer amounts of 5 to about 200 mg per k9 of body weight per 24 hours to obtain effective results.

 However, depending on the species and the body weight of the receptor, the severity of the disease and especially the mode of administration, it is sometimes necessary to deviate from the indicated dose. Thus, sufficient results can be obtained with quantities below the minimum limit indicated above.

This same dosage range is applicable in human medicine and veterinary medicine.

 The compounds according to the present invention can be used to promote the growth of animals and in particular in the case of rearing young animals.

Their administration in combination with food or drinking water helps to prevent or treat infections from both gram-negative and positive bacteria and further contributes to improved food assimilation and accelerated growth. the growth of animals. In this type of administration, the doses incorporated in the food or the drinking water are between 1 and about 100 ppm.

 The invention will be better understood with the aid of the examples which follow, and it is understood, however, that these examples do not constitute a limitation of the invention.

EXAMPLE 1 - ACID (QUINOXALIN DIOXIDE-1,4-YL-2) (PHENYL
AMINO) SULFONIC METHANE
15 g (0.079 mole) of formyl-2-quinoxaline-1,4-dioxide are added to 200 ml of pyridine, the reaction medium is cooled to +5 ° C. and 7.2 ml (0.079 mole) of aniline are added. excess sulfur dioxide, between 5 and 8 times the stoichiometric amount, maintaining the temperature of the reaction medium between + 5 OC and 10 OC, the reaction medium is stirred a few hours until the temperature is raised to 25 OC . The suspension is then poured into 1 liter of ether and the precipitate of pyridinium salt of the title derivative is filtered off. After washing and drying, the solid is added to 150 ml of water and the pH is adjusted to 7/8 with dilute sodium hydroxide solution.

 The resulting solution is treated with decolourising charcoal and then acidified with stirring to pH 2 with dilute hydrochloric acid.

 The precipitate that appears is filtered and washed with water.

After drying, the title derivative is obtained in the form of monohydrate with a yield of 85%.

 The sodium salt of the title derivative can be obtained by suspending the acid form in water and adding dilute sodium hydroxide solution to pH 7.0 and completely dissolving.

 The solution is then evaporated at low temperature under reduced pressure to give a crystalline solid.

EXAMPLE 2 - ACID (METHYL-3 QUINOXALIN DIOXYDE-1,4-YL-2) (PHENYL AMINO) METHANE SULFONIC
20.4 g (0.1 mole) of 2-formyl-3-methyl-1,4-quinoxaline-1,4-dioxide are added to 250 ml of 3-methylpyridine, the reaction mixture is cooled to approximately +5 ° C. and then 9.5 ml are added ( 0.1 mole) of aniline.

 About 30 to 50 grams (5-8 times the theory) of sulfur dioxide are then added in about two hours while maintaining the temperature of the reaction medium at between 50 and 10 ° C.

It is then treated according to the conditions of Example 1 to obtain (3-methylquinoxaline-1,4-dioxide-1-yl) phenyl aminomethanesulfonic acid.

EXAMPLE 3
By repeating the procedure of the preceding examples but using the appropriate amines instead of aniline, the following compounds having a single TLC spot on silica gel are obtained in the system: butanol 8 / acetic acid 1 / water 1 and having the general formula I wherein R and R 'have the meanings indicated below.

RR 'Rf
H 2-Methylphenyl 0.40
H 3-methyl-phenyl 0.40
H 4-Methylphenyl 0.40
H 2-Methoxyphenyl 0.60
H 3-Methoxyphenyl 0.65
H 4-Methoxyphenyl 0.60
H Chloro-2 phenyl 0.55
H Chloro-3 phenyl 0.55
H Chloro-4 phenyl 0.50
CH3 Chloro-2 phenyl 0.60
CH3 Chloro-3 phenyl 0.60
CH3 Chloro-4 phenyl 0.60
CH3 2-methylphenyl 0.50
CH3 3-methyl-phenyl-0.55
CH3 4-Methylphenyl 0.55
H Cyano-3 phenyl 0.50
CH3 Cyano-3 phenyl 0.55
2,6-Dimethylphenyl CH3 0.60
H 2,6-Dimethylphenyl 0.50
B Cyclohexyl 0.25
H 2,4-Dichlorophenyl 0.35
CH3 2,4-Dichlorophenyl 0.40
EXAMPLE 4 - ACID (QUINOXALIN DIOXYDE-1,4-YL-2) (pYRIDYL-2 AMINO) SULFONIC METHANE
50 g (0.263 mol) of formyl-2-quinoxaline-1,4-dioxide are added to 500 ml of pyridine. The reaction mixture is cooled to + 5 ° C. and 9 g of sulfur dioxide are introduced over 30 minutes. 24.8 g (0.263 mol) of 2-amino-pyridine are then added, then the slow introduction of sulfur dioxide at a rate of approximately 15 grams per hour and maintaining the temperature of the medium at approximately + 50 ° C. The flow of sulfur dioxide is stopped after having introduced 80 grams and allows the temperature to return to ambient.

 Pyridine is then evaporated under reduced pressure at a temperature not exceeding 45 C. The residual mass is taken up in cold water and the pH of the solution is reduced to 7 by introduction of dilute sodium hydroxide to pH 8.

 The aqueous solution is extracted 4 times with 100 ml of benzene, treated with black and then acidified to + 5 ° C. with hydrochloric acid diluted to pH 4.5.

After stirring for a few hours at this temperature, the precipitate is filtered, washed with water and dried. The hydrated acid form of the title derivative is obtained in the form of a solid bank of pF = 178 oC having a single
Rf = 0.25 by TLC on silica gel in the system:
Butanol 8 / Acetic acid 1 / water 1.

Elemental analysis gives the following results

<tb><SEP> C <SEP> H <SEP> N <SEP> S
<tb> calculated <SEP> 43.75 <SEP> 4.16 <SEP> 14.58 <SEP> 8.33
<Tb>
The infrared spectrum has the following characteristic bands (lcBr) -1 -1 (massive); 1640, 1670-1 3500 cm-1 (massive); 1640, 1670 cm-1 (FF); 1380 cm -1 (FF); 1230, 1270 cm-1 (F).

 The NMR spectrum recorded in DMSOd6 gives the following chemical shifts with respect to TMS 9.3 ppm (1 H) (m); 9.0 (1H) (s); 8.8 (2H) (2d); 7.9 (2H) (3d); 7.2-6.5 (3H) m; 4.5 (m).

The sodium salt of the title derivative can be obtained by suspending the previous acid form in water and bringing the pH of the suspension to 7 with the theoretical amount of dilute sodium hydroxide.

 The solution is then evaporated at low pressure and low temperature to give the sodium salt of the title derivative as a beige crystalline powder.

EXAMPLE 5 - ACID (QUINOXALINE DIOXIDE-1,4-YL-2) [[(TRIME-
THOXY-3,4,5 BENZYL) -5 AMINO-4 PYRIMIDYL-2 AMINCI METHANE
SULPHONIC
25 g (0.13 mol) of formyl-2-quinoxaline dioxide are added to 250 ml of pyridine, the reaction mixture is cooled to + 5 ° C. and 5 g of sulfur dioxide are introduced in the course of 30 minutes.

 38 g (0.13 mole) of 3,4,5-trimethoxy-5-benzyl-2,4-diaminopyrimidine are then charged and then the slow introduction of SO 2 is repeated at + 5 ° C.

 After absorption of 80 g of sulfur dioxide or about 3 hours, the pyridine is evaporated under reduced pressure and the remaining mass is concentrated by 3 x 100 ml of water.

The insoluble residual mass gradually hardens to turn into beige crystalline powder which is filtered and dried.

 The acid form of the title derivative having a single TLC spot of Rf = 0.35 on silica gel is obtained in the system: Butanol 8 / Acetic acid 1 / water 1.

The results of the elemental analysis are consistent with the calculated percentages.

EXAMPLE 6
Using the procedure of Example 4 and selecting the appropriate amines instead of 2-amino pyridine, the compounds of the following general formula I are obtained wherein R and R 'have the meanings given below.

R R '
H -2 pyrimidine
H-methyl-3 pyridine
CH3 -2 pyridine
H -3 pyridine
H -4 pyridine
CH3 methyl-3 pyridyl
H phenethyl
H n butyl
H isopropyl
H thiazolyl-2
H diethylaminoethyl
EXAMPLE 7
Using the technique of Example 4 and precipitating the reaction medium in solution in pyridine on a large volume of ether instead of evaporating it and taking it back into an aqueous medium, the pyridinium salts of the following derivatives are obtained , having naturally added the corresponding amines instead of 2-amino-pyridine.

R R '
H 2-Bromo phenyl
H 3-Bromo phenyl
H 4-Bromo phenyl
CH3 Bromo-4 phenyl
H Iodo-3 phenyl
H Iodo-4 phenyl
2-Trifluoromethyl-phenyl
H Trifluoromethyl-3 phenyl
CH3 Trifluoromethyl-3 phenyl
H 4-Trifluoromethylphenyl
H 2-Aminocarbonylphenyl
H 4-Aminocarbonylphenyl
2-hydroxy-2-phenyl phenyl
H 3-Hydroxymethyl phenyl
H 4-Hydroxymethyl phenyl
H 2-hydroxy-phenyl H 4-hydroxy-phenyl
H Methylthio-4 phenyl
H-4-cyclohexylphenyl
H 2-Fluoro phenyl
CH3 Fluoro-2 phenyl
H Methoxycarbonyl-2 phenyl
H Ethoxycarbonyl-4 phenyl
H Benzoyl-4 phenyl
H 3,5-Bistrifluoromethylphenyl
H 2-Bromo-6-chloro-4-phenylphenyl
H 3-Bromo-2,4,6-trimethylphenyl 4-chloro-2,5-dimethoxyphenyl
H 4-Isopropylphenyl H 2,3-Dimethylphenyl
H 2,4-Dimethylphenyl H 2,5-Dimethylphenyl
H 3,4-Dimethylphenyl
2,4-Dibromo phenyl
H 2,6-Dibromo phenyl
2,6-Dichlorophenyl
2,4-Difluoro phenyl
H 2,5-Difluoro phenyl
R R '
3,4-Dimethoxyphenyl
CH3 3,4-Dimethoxyphenyl
CH3 4-Methyl-2-nitro phenyl
H 4-Methyl-2-nitro phenyl
H 4-Methyl-3-nitro phenyl
H 2-methyl-6-nitro phenyl
H 2-Methyl-3-nitro phenyl
H Naphtyl-1
H (methyl-4) pyridyl-2
H (methyl-5) pyridyl-2
H (methyl-6) pyridyl-2
H 2-hydroxyethyl
H Cyano-5 n pentyl
H 3,3-Dimethylbutyl
H (pyridyl-2) -2 ethyl
H n-hexyl
CH3 n-hexyl
2-methyl-butyl
Benzyl
CH3 benzyl
H 3-chlorobenzyl
H cycloheptyl
H n-decyl
CH3 n-dodecyl
H isopentyl
Isopentyl CH3
H (naphthyl-1) -methyl
H (naphthyl-1) -1 ethyl
CH3 (naphthyl-1) -1 ethyl
CH3 n-propyl -H n-propyl
H (benzodioxane-1,4) yl-6
R R '
H 3-chloro-2-cyano phenyl
H 3-Fluoro-2-cyano phenyl
CH3 methylthio-4 phenyl
H benzothiazolyl-2
CH3 benzothiazolyl-2
H benzimidazolyl-2
H (6-ethoxycarbonyl-2-hydroxy-pyrimidyl) -4
H (2-chloro-5-nitro pyrimidyl) -4
H (5-chloro-pyrimidyl) -2
H (4,6-dichloropyrimidyl) -2
H (4-ethoxycarbonyl-isoxazolyl) -5
H (3-methylisothiazolyl) -5
H (3-methyl-isoxazolyl) -5 h (nitra-5-pyrimidinyl) -2
H quinolyl-8
CH3 quinolyl-8
H tetrazolyl-5
H thiadiazol-1,3,4-yl-2
H triazolyl-1,2,4-yl-3
H thienylmethyl-2
H furfuryl-2
EXAMPLE 8
Minimum inhibitory concentrations are determined by the serial dilution test.

 A complete medium is used as nutrient medium.

The incubation temperature is 37 OC and the incubation time is 24 hours.

The analyzes performed with the compound produced according to Example 4 have the following results expressed in pg / ml:

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<tb> Coli <SEP> Wall. <SEP> Oerugin <SEP> Mir. <SEP> Aur. <SEP> Fec.
<tb><SEP> 10 <SEP> 10 <SEP> 50-10 <SEP> 20 <SEP> 5 <SEP> 10
<Tb>

 It follows from the foregoing description that whatever the methods of implementation, implementation and application adopted, one obtains antibacterials which have compared with previously known quinoxaline dioxide 1,4, significant advantages, some of which have already been mentioned in the foregoing, and in particular the advantage of being able to be administered in all liquid or solid forms. Similarly, all methods of preparing dietary supplements for animals are made possible.

 As is apparent from the above, the invention is not limited to those of its modes of implementation, implementation and application that have been described more explicitly; it encompasses all the variants that may come to the mind of the technician in the field, without departing from the scope or scope of the present invention.

Claims (10)

1) Compound of general formula I

 in which R represents hydrogen or a methyl group. R 'represents a 5- to 7-membered aliphatic cycloalkyl radical directly attached or linked via a methylene chain comprising from 1 to 3 -CH 2 groups and their pharmaceutically acceptable base addition salts. R 'represents a 5- to 7-membered heterocycle comprising two identical or different heteroatoms chosen from nitrogen, sulfur or oxygen, this heterocycle may be substituted by one or more of the optionally substituted phenyl radicals mentioned above, or R 'represents a polycyclic fused heterocycle chosen from the following heteracycles: indole, indole, isa-indole, indazole, quinoleine isoquisoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, sscarboline, phenanthridine, acridine, phenantroline, phenazine, benzimidazole, benzothiazole, benzoxazole, benzoisothiazole, benzotriazole, benzotriazine, benzothiadiazole, or represents a linear or branched C1 to C12 alkyl radical optionally substituted by OH groups or dialkylamino groups, these dialkyl groups comprising from 1 to 3 atoms; carbon, or R 'represents a phenyl group optionally substituted with one or more substituents chosen from the radicals: methyl, methoxy, ethyl, ethoxy, chlorine, fluoro, bromo, iodo, nitro, cyano, trifluoromethyl, hydroxycarboxamido, benzayl thiol, ethoxycarbonyl, methylene oxide; 314, ethylene 3,4-dioxy-hydroxymethyl, methylthio, phenoxy, benzyloxy, ethylthio, alpha-hydroxyethyl, isapropylthia, sulEamido, or R 'represents a heterocycle with a heteroatom having 5 to 7 members and whose heteroatom is consisting of nitrogen or sulfur with oxygen, this heterocycle may be substituted by one or more of the substituent radicals optionally the phenyl ring and cited above, or  2) Compounds of formula I according to claim 1 wherein R represents hydrogen and R 'represents a heterocycle comprising from 5 to 7 members and whose heteroatom is constituted by nitrogen, sulfur or oxygen.  3) Compounds of formula I according to claim 1 wherein R represents a methyl group and wherein R 'represents a 5- to 7-membered heterocyclic ring and the hetero ring of which consists of nitrogen, sulfur or oxygen.  4) A compound of formula I according to claim 1 wherein R 'represents the pyridyl radical.  5) Process for obtaining a (a compound of general formula I according to claim 1, characterized in that the one reacts the formyl-2 derivative of quinaxaline dioxide on an amine, these two reactants being employed in stoichiometric amount and the reaction being conducted in pyridine or methylpyridine in the presence of an excess of sulfur dioxide between 0 and 35 OC.  6) Process according to claim 5 characterized in that the derivative is isolated by treatment in aqueous medium after concentration.  7) Process according to claim 5 characterized in that the derivative is isolated by precipitation in an organic solvent miscible with pyridine or methyl-pyridine.  8) Medicaments having in particular antibacterial activity and containing at least one of the compounds according to claim t.  9) A pharmaceutical composition comprising at least one of the components according to any one of the claims and a pharmaceutically acceptable carrier or carrier.  10) An animal food or beverage containing a compound according to any one of claims 1 to 4.