HU183174B - Process for producing 1,6-naphtirine derivatives - Google Patents

Abstract

1,6-Naphthyridine derivatives of the Formula <IMAGE> and salts and quaternary salts thereof (wherein R represents hydrogen, carboxy, C1-4 alkoxycarbonyl, carbamoyl, carbohydrazido or cyano, and either (1) X is oxygen, or sulfur and i/R<2> and R<3> together form a valence bond, and R<1> represents hydrogen, C1-6 alkyl, C3-4 alkenyl or C7-12 aralkyl or ii/R<1> and R<2> together form a valence bond, and R<3> represents hydrogen, C1-6 alkyl, C3-4 alkenyl or C7-12 aralkyl or (2) R<1> and R<2> together form a valence bond, and X-R<3> represents halogen), are of interest as antibacterial and antifungal agents and for various agrochemical uses. They can be made by reacting a dialkyl 2,6-dimethylpyridine-3,5- dicarboxylate with 1,3,5-triazine and if necessary further transforming the product.

Description

The present invention relates to novel 1,6-naphthyridine derivatives of formula (I) and their salts and to compositions containing them.

The production of 1,6-naphthyridines has so far been poorly studied and their biological and pharmacological activity has been investigated in only a few areas. [Advances in Heterocyclic Chemistry, Vol. 11, New York-London, 1970, 124, 175; Viadomosci Chemiczne 32, 92-13. (1978).

In formula (3), R is hydrogen, carboxyl, C2 -C5 alkoxycarbonyl or carbohydrazide,

X is oxygen, sulfur, or when R ¹ and R ² together form a bond, then -X-R ³ is halogen, i, if R ² and R ³ together form a bond, then R ¹ is hydrogen, C 1-4 alkyl- , C 3 -C 5 alkenyl, or phenyl or naphthyl (C 1 -C 4) alkyl; or ii, when R ¹ and R ² together form a bond, then R ³ is hydrogen or C 14 alkyl.

The compounds of formula (I) may be prepared by:

a) reacting a compound of Formula 11 wherein R ⁴ is a C 1-3 alkyl group, preferably an alkali alcohol, with 1,3,5-triazine, or

b) reacting a compound of formula IV wherein R ⁴ is as defined above, R ⁵ is C 1 -C 4 alkyl with ammonia or an ammonia-providing reagent, and optionally a compound of formula I: wherein

X is oxygen, R is C 2 -C 5 alkoxycarbonyl, R ¹ is hydrogen, and

R ² and R ³ together bond to form - preparing XR compounds of formula I containing a halogen atom ³ in place - which form ^R1 and ^R2 together a bond wherein R is as defined above - with a halogenating agent, or a compound (1) - wherein X is oxygen, R is C 2 -C 5 alkoxycarbonyl, R 'is hydrogen, R ² and R ³ together form a bond - R ¹ is C 14 alkyl, C 3-5 alkenyl, or phenyl or naphthyl (C 14). ) for the preparation of a compound of formula (I) containing an alkyl group, wherein R ² and R ³ together form a bond, X is oxygen and R is as defined above, with a C 1 -C 4 alkylating agent, C 3 -C 5 alkenyl, alkenylating agent or phenyl or naphthyl Aralkylating agent containing a (C 14) alkyl group! reacted or formula (I), a compound of formula - wherein X is oxygen, R is a carboxyl group, R 'is as defined above, R ² and R ³ together bond to form - preparation of (1) compounds having hydrogen atom as R - is wherein X represents an oxygen atom, R ¹ is of the form given above, R ² and R ³ bond together - decarboxylated, or formula (I), a compound of formula - wherein R and ^R! R ² and R ^{3 are taken} together to form a bond and X is oxygen to form a compound of formula (I) wherein X is sulfur, R and R ¹ are as defined above, R ² and R ³ together form a single bond - reacting difoszforpentaszulfiddal or formula (I) wherein R is vegyületet- formula 2-5 alkoxycarbonyl group, ^R1 is as defined above, X is an oxygen atom. R ² and R ^{3 are taken} together to form a direct bond, either to hydrolyze or to hydrolyze a compound of formula I wherein R 1 is as defined above, X is O, R ² and R ³ together form a bond; A compound of formula (I) wherein

R is carboxyl, R ¹ is as defined above, X is oxygen - for the preparation of compounds of formula (I) wherein R is C 2 -C 5 alkoxycarbonyl - wherein X is oxygen, R ¹ is as defined above, R ² and R ^{3 is taken} together to form a valence line with a C 14 alcohol or a compound of formula I wherein R is carboxyl or C 2 -C 5 alkoxycarbonyl, R ¹ is as defined above, X is oxygen or sulfur, R ² and R ^{3 is taken} together to form a direct bond - to form compounds of formula I wherein R is carbohydrazido, wherein X is oxygen or sulfur, R ¹ is as defined above, and R ² and R ^{3 are taken} together directly by hydrazine or I) a compound of formula - wherein R is as defined above, R ¹ and R ² together with bond lines lat is alkyl, -XR ³ is halogen - R ³ is C 14 alkyl. And reacting a compound of formula I wherein X is oxygen or sulfur, wherein R is as defined above and R ¹ and R ² together form a bond, by reaction with the corresponding C 14 alcohol or thiolate, or a compound of formula I compound - wherein R is as defined above, R ¹ is hydrogen, R ² and R ³ together form a bond and X is S - preparation of (1) compounds of formula R ³ at 14 alkyl group and X is S - where R is as defined above and R ¹ and R ² together form a bond - C 1-4 alkylating agent, if desired, converting the resulting compound of formula (I) to an acid addition salt or liberating it or converting it to another salt.

In process (a), the reaction is preferably carried out in the presence of alcohol (methanol, ethanol, propanol, faith) and is carried out at a temperature of from 20 to 120 ° C, preferably at the boiling point of the alcohol used. The reaction time depends on the reaction temperature and 2 hours 10

-2183 can be up to 174 hours. 0.5 mol to 5.0 mol of 1,3,5-triazine and 0.5 mol to 2.0 mol of alkali alcohol are used for 1 mol of compound (II). In a preferred embodiment of the process, the compound of formula (II), 1,3,5-triazine and alkali alcoholate is used in an equivalent molar ratio. Preferred alkali alcoholates are lithium alcoholates (lithium methylate, lithium ethylate), sodium alcoholates (sodium methylate, sodium ethylate, sodium builate), potassium alcoholates (potassium ethylate, potassium tert-butylate).

The resulting 1,6-naphthyridine derivative of formula (I) is readily recovered from the reaction mixture. For example, the alcohol may be distilled off and the residue crystallized from a suitable solvent, or the reaction mixture may be diluted with water, neutralized if desired, and the resulting 1,6-naphthyridine derivative removed by filtration, centrifugation, settling, or the like.

In process (b), the compound of formula (IV) is reacted with ammonia or an ammonia-providing reagent. The reaction is preferably carried out in alcohol or in an aqueous alcoholic solution. The alcohols used, the reaction temperature and the reaction time are the same as those described in process a). Ammonia as a gas may be introduced into the reaction mixture, but may also be previously absorbed in water or alcohol. Alternatively, the ammonia may be used in the form of various inorganic or organic salts. For example, ammonium chloride, aluminium carbonate, ammonium acetate, ammonium formate can be used.

0.5 to 10 moles of ammonia may be used per mole of compound (IV).

The resulting 1,6-naphthyridine of formula (I) is recovered as described in process (a).

1,6-níiftiricIín R, R ^l, R ^2, R ³ substituents of a given formula (I) may be converted into by known methods per se, in any order a different meaning of R, R ^1, R ^2, R ³ substituent.

For example, the R = C 2 -C 5 alkoxycarbonyl group of a given 1,6-naphthyridine of formula (1) may be hydrolyzed to acidic or basic hydrolysis to form a carbohydrazide group using hydrazine hydrate. The 1,6-naphthyridine of formula (I) wherein R is a carboxyl group can be optionally converted to the ester by acid catalysis, either in phosphoric acid or in pyridine or quinoline, tetralin, benzophenone, optionally heated in the presence of a catalyst, and so on. ), 1,6-naphthyridine having the general formula: wherein R is hydrogen.

The N-alkylation and N-aralkylation of 1,6-naphthyridines of formula (I) wherein X is oxygen, R ² and R ³ together form a bond and R ¹ is hydrogen with alkylating agents used in a 1.1 to 4-fold molar excess. . aralkylating agents to give compounds of formula (I) wherein X, R ² and R ³ are as defined above, R ¹ is C 1 -C 4 alkyl, C 3 -C 5 alkenyl, or phenyl or naphthyl (I). (C 4 -C 4) alkyl.

Alkylating agents include di-alkylsilyl radicals, alkyl-halogenyls, alkenyl halides. Irialkyl esters are used, aralkylating agents are aralkyl halides.

Suitable solvents include C1-C4 alcohols, halogenated hydrocarbons such as chloroform, d-chloromethane, 1,2-dichloroethane, aromatic hydrocarbons such as benzene, toluene, xylene, and trialkyl phosphate alkylating agents.

Alkali carbonates, alkali metal hydrogencarbonates, alkali alcoholates, various organic bases such as pyridine are used as acid binders. trialkylamines are used.

Alkylation and aralkization is carried out at temperatures of from 20 to 180 ° C for 10 minutes to 10 hours. In the case of trialkyl phosphate alkylating agents, the N-alkyl esters of formula (I) wherein R ¹ is C ¹ -C 4 acyl, R is C 2 -C 5 alkoxycarbonyl, are isolated directly by N-alkyl hydrolysis without basic hydrolysis. acids where R is carboxyl.

A particular 1,6-naphthyridine derivative of formula (I) wherein X is oxygen, R ² and R ³ together form a bond and R ^{1 is} hydrogen, treated with hyalogenating agents such as phosphoryl halides, phosphorus trihalides, phosphorus pentahalides. a compound (I) of formula are obtained, wherein R ¹ and R ² together form a bond and XR ³ represents halogen. Halogenation is optionally carried out in an inert solvent such as benzene, chloroform, dichloromethane, 1,2-dichloroethane at temperatures of from 20 to 140 ° C for 3 to 10 hours. The halogenation may also be carried out in the presence of a catalytic amount of triethylamine.

(I) from compounds of formula wherein R ¹ and R ² together form a bond, is XR ³ is halogen and R is C2-5 alkoxycarbonyl group, two moles afford the corresponding alkoxy derivatives 1-4 szénatoniszámú alcohols containing alkaline alcohol alot and also the hydrolysis of the ester group to give compounds of formula (1) wherein R = carboxyl and X-R ³ = C 1-4 alkoxy, R ¹ and R ² are as defined above .

In the compound of formula (I) may be converted halogénatoniot XR ³ = sodium hydrosulfide mercapto group to form can provide the derivative of formula (I) wherein XR ³ is a mercapto group. Sodium alkyl sulfide can be used to introduce an alkylthio group into the compound of formula I (XR ³ = alkylthio).

The present invention also provides compounds of formula I wherein X is oxygen. R ^{1 is} hydrogen, C 14 alkyl, C 3-5 alkenyl, or phenyl or naphthyl (C 14) alkyl, R ² and R ^{3 taken} together form a divalent phosphorus pentasulfide.

The sulphurization is preferably carried out in a 50% molar excess of diphosphorus pentasulphide for 1-2 hours at the boiling point of appropriate solvents. Solvents used are pyridine, toluene, quinoline, tetralin, chloroform, dioxane. In the general formula (I), the thioxo derivatives wherein X = sulfur, R ¹ , R ⁵ and R ³ are as defined above are isolated from the reaction mixture by filtration or by solvent extraction and evaporation and evaporation of the residue with water.

The general formula (I) (X atom, R ¹ hydrogen atom, R ² and R ^{3 taken} together form a bond) wherein the thiol thiol tautomeric equilibrium can be converted to S-alkyl derivatives. As alkylating agent dialkyl sulfates, alkyl3

-3183,174 halides, thioalkylphosphates, Ν, Ν-dinethylforman-dimethylacetal, diazomethane are used. Preferred solvents are C1-C4 alcohols, halogenated hydrocarbons, aromatic hydrocarbons, and trialkyl phosphate alkylating agents.

Alkali carbonates, alkaline bicarbonates, alkali alcoholates, various organic bases such as pyridine, trialkylamines are used as acid binders.

Alkylation is carried out at temperatures between 20 ° C and 180 ° C for 10 minutes to 10 hours. The resulting compounds of formula (I) wherein X = sulfur, R ³ = C 1-4 alkyl, R ¹ and R ^{2 taken} together are a single bond may be isolated from the reaction mixture by filtration or by evaporation after solvent extraction.

The 1,6-naphthyridines of formula (I) may be optionally reacted with non-toxic organic or inorganic acids, if desired. In this way, the hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, acetate, formate, citrate, salicylate salt can be advantageously prepared. 1,6-Naphthyridines of the formula (I) containing a carboxyl group may also be formed with organic or inorganic bases. Thus, alkali metals (sodium, potassium salts), alkaline earth metals (calcium, magnesium salts), amines can be formed. The base can be liberated from the salts and, if desired, converted to another salt.

The compounds of the invention may be used primarily as medicaments. The compounds of formula (I) have a significant antibacterial activity.

Some agents exhibit antibacterial activity against various poly-resistant Gram-negative and · Grarn-positive strains (e.g., Vibrio parahaemoliticus, Pseudomonas aeruginosa, Proteus vulgaris, Shigella sonnei, Salmonella typhium, Escherichia coli, Klebsiella pneumonie, Staphylococcus aureus); known antibacterial compounds (e.g. nalidixic acid, superseptyl, streptomycin).

The biological activity of the compounds of formula (I) is illustrated by the following assay results:

]. spreadsheet

Species ethyl-2-methyl- -5-thioxo -5,6-dihydro -1,6-naphthyridine -3-carboxylate l butiikarba- ynoyl-benziini- imidazole-2-Niet! - carbamate (Bcnomyl) Coryne- yeast- minimum yeast bacteriology summarized broth summarized michiganeiise broth broth MIC (mg / ml) MIC (mg / ml) MIC Staphylo- coccus 25 6 (Mg / ml) 50 aureus 12 1.5 50

ctil-2 · inethyl 1-bu t ijcarba- -5-thioxo carbamoyl benzimidazole -5.6-dihydro dazol-2-iné t il 1,6-naphthyridine carbamate -3-CHAR1> oxylate (Bcnomyl)

Bacillus cereus var.

mycoides

1.5 50

The above minimum inhibitory concentration values (MICs) were obtained as follows:

Compounds ranging from 200 mg / ml upper concentration to 0.03 mg / ml were diluted in half with dimethyl sulfoxide so that the solvent did not exceed 1% of the total medium.

? -θ The spore suspension of the microorganisms was inoculated onto the surface of glucose yeast extract and glucose minimal medium. The lowest concentration (MIC) that caused complete inhibition of the growth of microorganisms was determined.

For use in medicine, 1,6-naphthylindines of Formula (1) may be used in the form of compositions containing the active ingredient and an inert, non-toxic solid or liquid diluent or carrier. The compositions may be employed in solid (e.g., tablet, dragee, capsule, expeller) or liquid (e.g., solution, suspension, emulsion) form.

Suitable carrier materials are those used for purpose c (for example, magnesium stearate, talc, calcium 35 carbonate, water, polyethylene glycol glycerol formol).

The compositions may, if desired, also contain conventional additives (for example emulsifiers, disintegrants).

Pharmaceutical compositions having antibacterial activity may have a broad range of active ingredient contents ranging from 0.005% to 99%.

The daily dose of active ingredient may vary within wide limits and will depend on the severity, age, weight, form of preparation, and activity of the patient. In the case of oral administration, the daily dose is usually 0.05 to 20 mg / kg body weight in single or multiple daily doses. The above data is for information purposes only and may vary both upwards and downwards depending on the particular circumstances of the case and the prescriptions of the physician.

Among the starting compounds used in our processes, the compounds of the formulas II and III are commercially available, while the compounds of the formula IV can be obtained by methods known in the literature, for example from the compound of the formula II and a derivative of the formula III. for example, the reaction of one of the formulas ro < ⁿ⁾ and (III) is preferably carried out in a dipolar aprotic solvent (preferably Ν, Ν-dimethylformamide, hexamethylphosphoric triamide) under ² inert atmospheres (nitrogen shielding gas). The reaction may also be carried out in the absence of a solvent in a melt.

-4183 174

Further details of the process are set forth in the Examples without limiting the process to the Examples.

Carbonyl-6-diethyl-2-pyridyl) -ethenamine is obtained which, when mixed with the material prepared in Example 2, gives no melting point reduction.

Tekla

Example 1

Sodium 2.3 g (0.1 g) was reacted with ethanol (20 ml). To the sodium ethylate solution was added diethyl 2,6-dimethyl-3,5-pyridinedicarboxylate (25.12 g, 0.1 mol) and 1,3,5-triazilite (8.11 g, 0.1 mol) to form the orange solution was stirred at reflux for 2 hours. The dark brown solution was evaporated and the residue was dissolved in 150 ml of water and neutralized with 10% hydrochloric acid. The precipitated brown material is filtered off after one day and washed twice with 30 ml of water. 18.7 g (80.4%) of ethyl 2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate, m.p. 250-252 DEG C., are obtained in a yield of 25 cm. is purified by elution with a 2.5 cm diameter Kieselgel 60 column (Merck, 0.2-0.5 mm) eluting with 10: 1 chloroform: methanol. Yield: 12.9 g (55.5%) of light 2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate, m.p. 260 ° C.

Calcd for _{C! 2} H ₁₂ N ₂ O ₃ formula.

Calculated: C, 62.06; H, 5.21%; N, 12.06%;

Found: C, 62.30%; H, 5.43%; Ν 11.83%.

Example 2

25.12 g (0.1 mol) of diclyl-2,6-dimethyl-3,5-pyridinedicarboxylate, 14.72 g (0.1 mol) of N, N-dinethylformamide diethyl acetate and 100 ml of Ν, The mixture of Ν-dimethylformamide was heated under reflux for 16 hours. The dark reaction mixture was evaporated, the residual thick oil was poured into water (1 L), the aqueous solution was brewed with benzene (6 x 200 mL), the combined organic layers were washed with water (2 x 200 mL), dried over Na2SO4, filtered and evaporated in vacuo. The remaining orange semisolid was triturated with 20 mL of gasoline and the yellow crystals were filtered. 8.2 g (26.6%) of N, N-dimethyl-2- (3,5-his-ethoxycarbonyl-6-methyl-2-pyridyl) -ethenamine are obtained, m.p. 92-93 ° C by recrystallization from ethanol.

Calcd for _{C) 6} H ₂₂ N ₂ O 4 formula.

Calculated: C, 62.73; H, 7.24%; N, 9.14%;

Found: C, 62.40%; H, 7.38%; N, 8.92%.

Example 3

A mixture of 2.51 g (0.01 mol) of diethyl 2, 3-dimethyl-3,5-pyridinedicarboxylate and 7.35 g (0.05 mol) of Ν, Ν-dimethylformamide diethyl acellal! Stir at 140 ° C for 6 hours. To the orange-red thick solution was added 100 ml of gasoline and allowed to stand at 4 ° C for 2 days. The precipitated yellow crystals were filtered off and washed with 20 ml of gasoline. 1.55 g (50.7%) of N, N-dimethyl-2- (3,5-bis-ethoxy) m.p. 94 ° C.

A mixture of 6, Ν-dimethyl-2- (3,5-bis-ethoxycabonyl-6-methyl-2-pyridyl) -ethenamine (3.06 g, 0.01 mol) in 25 ml of 25% strength ammonium hydroxide and 30 ml of ethanol Stir for 36 hours at room temperature. The light yellow crystals from the reaction mixture were filtered and washed with water (20 mL). 1.50 g (64.3%) of ethyl 2-methyl-5-oxo-5,6-dibidro-1,6-naphthyridine-3-carboxylate, m.p. 260 DEG C., were obtained in the same manner as in Example 1. does not give melting point depression when mixed with a substance.

Example 5

Sodium (0.23 g, 0.01 g) in ethanol (50 mL) was reacted. To the ethyl acetate solution was added 2.32 g (0.01 mol) of ethyl 2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate. A cherry red solution was formed, to which, after 5 minutes, 1.89 g (0.015 mol) of dimethyl sulfate was poured. The solution turns yellow, slightly warms, and after a few minutes tiny needle crystals begin to precipitate. The reaction mixture was stirred at 25 ° C for 3 hours, diluted with water (80 mL), neutralized by the addition of 5% sodium hydroxide solution (pH 7), extracted with chloroform (3 x 50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Yield: 2.36 g (96.2%) of yellow crystalline ctyl-2,6-dimethyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate, which is crystallized from ethanol at 144-146 ° C. are good.

Analysis for C ₁₃ H ₄ N ₂ O ₃ .

Calculated: C, 63.40; H, 5.73%, N, 11.38%;

Found: C, 63.65%; H, 5.94%; Ν 11.46%.

Example 6

2.32 g (0.01 mol) of ethyl 2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate were 7.29 g (0.04 mol) of triethyl phosphate and 1, Anhydrous potassium carbonate (38 g, 0.01 mol) was stirred at 180 ° C for 30 minutes. The dark brown reaction mixture was cooled to room temperature, diluted with water (50 mL), extracted with chloroform (3 x 50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. After evaporation, the brown oil is dissolved in 10 ml of benzene and chromatographed on a column of 16 µm Kieselgel 60 (Merck, particle size 0.2-0.5 mm), 2 cin in diameter, eluting with benzene. Evaporation of the benzene solution afforded 2.27 g (87.1%) of ethyl 6-ethyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate as clear crystals, m.p. 143 ° C.

Calculated for C ₄ H ₁₆ N ₂ O ₃ wherein

Calculated: C, 64.60; H, 6.20%; N 10.76 7 ?;

Found: C 64.40%, H 6.51%, N 11.01%.

184,174

Example 7

6.96 g (0.03 mol) of ethyl 2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate, 21.85 g (0.12 mol) of triethyl phosphate and Anhydrous potassium carbonate (4.14 g, 0.03 mol) was stirred at 180 ° C for 30 minutes, then 180 ml of a 5% solution of potassium hydroxide at 80 ° C was added to the brown reaction mixture and at 100 ° C for 1 hour. The reaction mixture is hydrolyzed for 1 hour. It is clarified with hot charcoal, filtered and acidified to pH 4 with 10% hydrochloric acid. The pale yellow precipitate is filtered off after standing for one day and washed with 20 ml of water. 5.9 g (84.8%) of 6-ethyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid are obtained, which is recrystallized from ethanol, m.p. 284 ° C.

Analysis for C _{l2 H!} Basis NO ₂ O ₃

date; C, 62.06%; H, 5.21%; N, 12.06%;

Found: C, 62.30%; H, 5.24%; N, 12.16%.

Example 8

A mixture of 2.32 g (0.01 mol) of ethyl 2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate, 90 ml of phosphoryl chloride and 3 ml of triethylamine was added at 140 ° C. Stir at C for 3 hours. Excess phosphoryl chloride was removed from the dark solution by evaporation in vacuo and the oily residue was poured onto 400 g of ice and adjusted to pH 8 with potassium carbonate. The aqueous solution was extracted five times with 100 ml of diethyl ether, dried over anhydrous sodium sulfate and evaporated. 1.2 g (48%) of ethyl 5-chloro-2-methyl-1,6-naphthyridine-3-carboxylate, m.p. 136-138 [deg.] C, are obtained.

Calc'd _{C) 2} H, O ₂ 0 £ 11,512.

date; C, 57.50%; H, 4.42%; Ν 11.17%; Cl, 14.14%; Found; C, 57.77; H, 4.74; N, 10.99%, Cl, 13.92%.

Example 9

Sodium (0.23 g, 0.01 g) was treated with ethanol (50 mL). To the sodium ethylate solution was added ethyl 5-chloro-2-ethyl-1,6-naphthyridine-3-carboxylate (1.25 g, 0.005 mol) and the mixture was refluxed for 2 hours. The precipitated sodium chloride was filtered off from the red solution and the filtrate was concentrated in vacuo to give 1.1 g of a brick red powder. It is dissolved in 35 ml of water and acidified to pH 2 with 10% hydrochloric acid. The precipitate was filtered off and washed with water (10 ml). 0.63 g (54.1%) of 5-ethoxy-2-methyl-1,6-naphthyridine-3-carboxylic acid melting at 208-209 ° C are obtained.

Analysis based on the formula CjjHuNjOj.

date; C, 62.06%; H, 5.21%; N, 12.06%;

Found; C, 61.71%; H, 5.49%; N, 11.75%.

example

4.64 g (0.02 mol) of ethyl 2-methyl-5-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate, 6.66 g (0.03 mol) A mixture of 6 diphosphorus pentasulfide and 50 mL of pyridine was refluxed for 2 hours. The red reaction mixture was distilled under reduced pressure to give pyridine (50 mL of ethanol). The distillation residue was triturated with water (100 mL) to give a yellow solid which was filtered and washed with water (2 x 20 mL). 4.5 g (90.9%) of yellow ethyl 2-methyl-5-thioxo-5,6-dihydro-1,6-naphthyridine-2-carboxylate are obtained, which is recrystallized from Ν, Ν-dinethylphonuanide. 220 ° C.

'0

Analysis for Ci ₂ H | ₂ N ₂ O ₂ S

date; C, 58.05%; H, 4.87%; Ν 11.28%; S, 12.91%; Found: C, 57.89%; H, 4.79%; N, 11.09%; S, 13.30%.

Example 77

A mixture of 2.32 g (0.01 mol) of ethyl 2-methyl-5-oxo-5,6-dihydrol, 6-naphthyridine-3-carboxylate, 3.33 g (0.015 mol) of diphosphorus pentasulfide and 25 ml of dioxane Boil for 1 hour. The dioxane was distilled off in vacuo, water (120 ml) was added to the remaining red oil and basified to pH 8 with 10% sodium hydroxide solution, extracted five times with 100 ml of chloroform, dried over anhydrous sodium sulfate, and concentrated in vacuo. 2.0 g (80.7%) of ethyl 2-methyl-5-thioxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate are obtained, which is recrystallized from dioxane, m.p.

When mixed with the material prepared in Example 10, no melting point reduction is obtained.

Example 12

2.32 g (0.01 mol) of ethyl 2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate, 3.33 g (0.015 mol) of diphosphorus pentasulfide and 25 ml of toluene. Example 40 gave 1.0 g (40.3%) of ethyl 2-methylethyl-5-thioxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate, m.p. after recrystallization from ethyl acetate. 220-221 ° C and the material prepared according to Example 11 showed no decrease in melting point.

Example 13

2.48 g (0.01 mol) of ethyl 2-methyl-5-thioxo-5,6-dihydro-1,650-naphthyridine-3-carboxylate, 4.20 (0.03 mol) of trinethyl phosphate and anhydrous potassium carbonate (1.38 g, 0.01 mol) were stirred at 140 ° C for 15 minutes. The dark brown solution precipitates a light yellow color upon cooling. After addition of 75 ml of water, the crystals are filtered off and washed twice with 25 ml of water 55. 2.5 g (95.2%) of ethyl 2-methyl-5-methylthio-1,6-naphthyridine-3-carboxylate were obtained, which, after recrystallization from elanol, gave 110 L of ethyl acetate. At 1 ° C.

Analysis of C ₁ 3ll | ₄ according to the formula N ₂ O ₂ S

Calculated: (59.52%; II, 5.38%; N, 10.68%; S, 12.22%; Found: C, 59.30%; H, 5.24%; N, 10.34%; 42%.

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Example 14

2.48 g (0.01 mol) of ethyl 2-methyl-5-thioxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate, 1.56 g (0.011 mol) of inethyl iodide,

A mixture of anhydrous potassium carbonate (1.52 g, 0.011 mol) and chloroform (50 ml) was refluxed for 6 hours. After stirring for 50 minutes with water (50 ml), the two phases were separated, the aqueous phase was extracted with chloroform (3 x 0 ml), dried over anhydrous sodium sulfate and evaporated in vacuo. 1.05 g (95.5%) of yellow crystals are obtained, which are 15 cm long, 2.5 cm diameter Kieselgel 60! (Merck, 0.2-0.5 mm particle size) was purified on a packed column eluting with chloroform. 0.73 g (66.5%) of ethyl 2-methyl-5-methylthio-1,6-naphthyridine-3-carboxylate, m.p. 110-111 ° C. The material thus obtained was identical to that of Example 13 by thin layer chromatography.

Example 75

Ethyl 2-methyl-5-thioxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (0.5 g, 0.002 mol) was dissolved in hot acetone (25 mL). The solution was filtered through a pleated filter and 10 mL of absolute ethanol saturated with hydrogen chloride gas was added. The precipitated pepper red crystals were filtered off and washed with ethanol. 0.25 g (43.5%) of ethyl 2-methyl-5-thioxo-5,6-dihydro-1,6-n-pyridine-3-carboxylate hydrochloride are obtained, m.p. 257-258 ° C. .

Analysis for C C ^H HClClN ^O _: S.

Calculated: C, 50.61; 11 4.60%; Cl, 12.45%; N, 9.84%; S, 11.26%.

Found: C, 50.95%; H, 4.88%; Cl, 12.46%; N, 9.86%;

S, 11.14%.

Example 76

A mixture of 2.32 g (0.01 mol) of ethyl 2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate and 60 ml of 8% potassium hydroxide solution at 100 ° C is added. stir for 2 hours. It is clarified with hot charcoal, filtered and acidified to pH 2 with 10% hydrochloric acid. The light yellow precipitate was filtered off and washed with water (10 mL). 1.7 g (83.1%) of 2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylic acid are obtained, after recrystallization from N, N-dimethylformamide, above 300 ° C. melted.

Analysis aC [oH ₈ N ₂ 0 ₃ based formula.

Calculated: C 58.82%; II 3.95%; N, 13.72%;

Found: C, 58.43%; H, 4.03%; N, 13.65%.

7. pclda

2.32 g (0.01 mol) of ethyl 2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate, 1.88 g (0.011 mol) of benzyl bromide, A mixture of 52 g (0.011 mol) of anhydrous potassium carbonate and 50 ml of Ν, Ν-dimethylformamide was stirred at reflux for 1.5 hours. The mixture was lifted and poured into 150 ml of water. The resulting light beige fluffy precipitate was filtered off and washed with water (2 x 50 mL). 2.3 g (87.0%) of ethyl 6-benzyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate are obtained, which is recrystallized from ethanol, m.p. 151-152 ° C. are good.

Analysis for C ₁₉ H ₁₈ N ₂ O ₃

Calculated: C 70.79%, H 5.63%, N 8.69%.

Found: C, 70.78%; H, 5.53%; N, 8.63%.

Example 18

2.32 g (0.01 mol) of ethyl 2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate, 1.33 g (0.011 mol) of allyl bromide,

A mixture of anhydrous potassium carbonate (1.52 g, 0.01 L) and N, N-dinethylformamide (50 mL) was stirred at reflux for 30 min. After cooling, the mixture was poured into 250 ml of water. The light yellow precipitate was filtered off and washed with water (50 mL). 2.0 g (73.6%) of ethyl 6-allyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate are obtained, which is recrystallized from ethanol at 110-111 ° C. They are C's. Analyzes according to the formula C _{) S} H, ₆ N ₂ 0 ₃ .

Calculated: C, 66.16%; H, 5.92%; N, 10.29%; Found: C, 66.03%; H, 5.83%; N, 10.42%.

Example 19

4.08 g (0.015 mole) of ethyl 6-allyl-2-yl (5-oxo-5,6-yl) tidro-1,6-naphthyridine-3-carboxylate, 3.75 g (0.075 mole). a mixture of hydrazine hydrate and 20 ml of ethanol is refluxed for 8 hours, and the white crystals precipitated from the light yellow solution upon cooling are filtered, washed with ethanol,

3.08 g (79.7%) of 6-allyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carbohydrazide are obtained, m.p. 185-186 ° C by recrystallization from ethanol.

Analysis for C, _{3 I} | Based N4O ₂ O _4.

Calculated: C, 60.45; H, 5.46; N, 21.69%;

Found: C, 60.24%; H, 5.34%; N, 21.42%.

Example 20

2.04 g (0.01 mol) of 2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridyl'-3-carboxylic acid are stirred in 20 g of polyphosphoric acid at 200 ° C for 2 hours. The reaction mixture was cooled to room temperature, water (100 mL) was added and neutralized with 20% sodium hydroxide solution. The flavor solution was extracted with chloroform (3 x 50 mL), dried over anhydrous sodium sulfate and evaporated.

Yield: 0.36 g (22.5%) of 2-methyl-5,6-dihydro-1,6-naphthyridin-5-one, m.p. 215-216 ° C. Analysis for C ₉ H ₈ N ₂ O.

Calculated: C, 67.49; H, 5.03%; N, 17.49%;

Found: C, 67.25%; H, 5.11%; N, 17.53%.

183,174

Example 21

1000 mg of ethyl 2-methyl-5-thioxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate were homogenized with 800 g of crystalline cellulose and 100 g of amylopectin. The mixture was then granulated with 70 g of Eudragit lacquer solution, after drying and regranulation at 40 ° C, homogenized with 15 g of talc and 14 g of magnesium stearate powder and tabletted at 150 mg in a manner known per se.

EXAMPLE 22 Ethyl 2-methyl-oxy-5,6-dihydro-1,6-nalthyridine-3-carboxylate and 10 parts by weight of a calcium salt of dodecylbenzenesulfonic acid were ground to a homogeneous powder having a particle size of less than 20 μm. .

The resulting 90% active ingredient wettable powder is suitable for the preparation of a 0.1-10.0% spray.

EXAMPLE 23 Ethyl 2-methyl-5-thioxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (97 parts by weight) was thoroughly mixed with powdered kaolin to give a powder containing 3% active ingredient.

Claims (4)

Patent claims A process for the preparation of 1,6-naphthyridine derivatives of the formula I and their acid addition salts comprising: R is hydrogen, carboxyl, C2 -C5 alkoxycabonyl or carbohydrazide, X is oxygen or sulfur or when R ¹ and R ² together form a bond, then -XR ³ is halogen, i, if R ² and R ³ together form a bond, then R ¹ is hydrogen, C 1-4 alkyl, 3 -C 5 -alkenyl or phenyl or naphthyl (C 1 -C 4) -alkyl; or ii, when R ¹ and R ² together form a bond, then R ³ is hydrogen or C 1-4 alkyl; characterized in that a) reacting a compound of formula 11 wherein R ⁴ is C 1-3 alkyl, preferably in the presence of an alkaline alcoholate, with 1,3,5-triazine, or b) reacting a compound of formula IV wherein R ⁴ is as defined above, R ⁵ is C 1 -C 4 alkyl with ammonia or an ammonia-providing reagent, and optionally a compound of formula I, wherein X is oxygen, R is 2-5 alkoxycarbonyl group, R ¹ is hydrogen and R ² and R ³ together form a bond -X- preparing R compounds of formula 1, a halogen atom, ³ when R ¹ and R ² together form a bond which képiéiben and R is as defined above - is reacted with a halogenating agent or a (I) a compound of formula - wherein X is oxygen, or dialkylamino of 2-5 alkoxycarbonyl group, R ¹ is hydrogen, R ² and R ³ together bond to form - ^R! for the preparation of compounds of formula (I) wherein C 1 -C 4 alkyl, C 3 -C 5 alkenyl, or phenyl or naphthyl (C 1 -C 4) alkyl, wherein R ² and R ³ together form a bond, X is oxygen and R is as defined above with an alkylating agent having 1 to 4 carbon atoms, an alkenylating agent having 3 to 5 carbon atoms or an aralkylating agent having phenyl or naphthyl (C 1 -C 4) or a compound of formula I wherein X is oxygen, R is carboxyl, R 'is as defined above, R ² and R ^{3 are taken} together to form a compound of formula I wherein R is hydrogen, wherein X is R ¹ represents the above-defined R ² and R ^{3 taken} together to form the valence decarboxyl we; or a compound of formula I wherein R and R ¹ are as defined above, R ² and R ^{3 taken} together form a bond and X is oxygen, for the preparation of compounds of formula I wherein X is sulfur, wherein X is sulfur. R and R ¹ are as defined above, R ² and R ^{3 are taken} together to form a bond - diphosphorus pentasulfide; or a compound of formula (I) wherein R is a C 2 -C 5 alkoxycarbonyl group, R ¹ is as defined above, X is oxygen, R ² and R ^{3 are taken} together to form a single bond, wherein R is a carboxyl group. preparation of a compound of formula - wherein ^R! is as defined above, X is oxygen, R ² and R ^{3 are taken} together to form a bond, or a compound of formula (1) wherein R is carboxyl, R ¹ is as defined above, X is oxygen, R is 2 -5 for preparing a compound of formula (I) wherein carbon atoms, an alkoxycarbonyl group - where X is O, R ¹ represents a form as defined above, R ² and R ³ together a valence bond - is reacted or reacting a compound (1) of the formula C 1-4 alcohol - where R is carboxyl or C 1 -C 5 alkoxycarbonyl, R ¹ is as defined above, X is oxygen or sulfur, R ² and R ^{3 are taken} together to form a bond - to form compounds of formula I wherein R is carbohydrazido - where X is oxygen or sulfur, R ¹ is as defined above, R ² and R ^{3 are taken} together to form a bond - hydrazine, or a compound of formula I where R is as defined above, R ¹ and R ² forms a valence line. -XR ³ is a halogen atom - R ³ site C1-4 alkyl group, and for preparing compounds of formula (I) is oxygen or sulfur containing location X - wherein R is as defined above and R 'and R ² together form a bond - the with a corresponding C 1-4 alcohol or thiolate, or with a compound of general formula (I) wherein R is as defined above, R ¹ is hydrogen, R ² and R ³ together form a bond and X is sulfur - R ^{3 is C} 1 -C 4 alkyl and X is sulfur -8187 174 is reacted with a C 1-4 alkylating agent and optionally converted to the acid addition salt of a compound of formula I, wherein R is as defined above, and R ¹ and R ² together form a bond; they are either liberated from their salt or converted into their other salts. 2. A process according to claim 1, wherein the alkali alcoholate is sodium ethylate. 10 3. A process according to claim 1, wherein the reagent used to provide ammonia is ammonium hydroxide. 4. A process for the preparation of a pharmaceutical composition having antibacterial activity, characterized in that a compound of the formula I or an acid addition salt thereof according to claim ¹ , wherein X, R, R ¹ , R ² and R ³ are as defined in claim 1. A conventional pharmaceutically acceptable carrier and diluent as defined in claim 1, and optionally mixed with other excipients to form a pharmaceutical composition.