GB2080794A - 1,6-Naphthyridine 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

SPECIFICATION 1,6-Naphthyridine derivatives This invention concerns new 1,6-naphthyridine derivatives, a process for their prepration and pharmaceutical and agrochemical compositions comprising them.

In the literature there are but a few references dealing with the preparation of 1,6-naphthyridine derivatives and the biological effect of these compounds have only been partially tested [Advances in Heterocyclic Chemistry, Vol. 11., New York-London 1970, pages 124-175; Wiadomosci Chemiczne 32 92-113 (1978)].

One aspect of the present invention provides new 1,6-naphthyridine derivatatives of the general Formula I

and salts and quaternary salts thereof (wherein R represents hydrogen, carboxy, C14 alkoxycarbonyl, carbamoyl, carbohydrazide or cyano and either (1) Xis oxygen or sulfur; and il R2 and R3 together form a valence bond, and R1 represents hydrogen, C16 alkyl, C34 alkenyl or C7--12 aralkyl; or ii/ R1 and R2 together form a valence bond, and R3 represents hydrogen, C16 alkyl, C34 alkenyl or C7-12 aralkyl; or (2) R1 and R2 together form a valence bond, and X-R3 represents halogen).

The term "alkyl group" denotes straight or branched chained saturated aliphatic hydrocarbon groups (e.g.

methyl, ethyl, n-propyl etc). The term "alkenyl group" denotes to straight or branched chain aliphatic hydrocarbon groups having a double bond (e.g. allyl, propenyl, methylallyl etc). The term "aralkyl group" denotes alkyl groups substituted by an aryl radical (e.g. benzyl, -phenyl ethyl etc). The term "alkoxycarbonyl group" includes e.g. a methoxycarbonyl or ethoxycarbonyl group, etc.Preferred compounds of the general Formula I are the following derivatives: Ethyl-2-methyl-5-oxo-5,6-dihydrn-1 ,6-na phthyridi ne-3-carboxylate N, N-dimethyl-2-(3,5-bis-ethoxycarbonyl-6-methyl-2-pyridyl )-ethenamine Ethyl-2,6-dimethyl-5-oxo-5,6-dihydro-1 ,6-naphthyridine-3-carboxylate Ethyl-6-ethyl-2-methyl-5-oxo-5,6-dihydro-1 ,6-naphthyridine-3-carboxylate 6-ethyl-2-methyl-5-oxo-5,6-di hydro-1 ,6-naphthyridine-3-carboxyl ic acid Ethyl-5-chloro-2-methyl-1,6-naphthyridine-3-carboxylate 5-ethoxy-2-methyl-1 ,6-naphthyridine-3-carboxylic acid Ethyl-2-methyl-5-thioxo-5,6-dihydro-1 ,6-naphthyridine-3-carboxylate Ethyl-2-methyl-5-methyl-thio-1 ,6-naphthyridine-3-carboxylate The salts of the compounds of the general Formula I may be acid addition salts formed with inorganic or organic acids (e.g. hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid perchloric acid, acetic acid, formic acid, citric acid, salicylic acid etc), the acid being biologically acceptable under the conditions of intended use.

The compounds of the general Formula I in which R represents a carboxy group can form salts with inorganic or organic bases. These salts may be alkali metal salts (e.g. potassium or sodium), alkaline earth metal (e.g. calcium, magnesium) salts or salts formed with amines.

The quaternary salts of the compounds of the general Formula I may be formed with conventional quaternising agents (e.g. alkyl halides, such as methyl iodide, ethyl iodide etc; dialkyl sulfates e.g.

methosulfates, p-toluene sulfonates, benzene sulfonates etc).

According to a further aspect of the present invention there is provided a process for the preparation of compounds of the general Formula land salts and quaternary salts thereof which comprises a/ reacting a compound of the general Formula II

(wherein R4 is C14 alkyl) with 1,3,5-triazine, preferably in the presence of an alkali metal alcoholate; or b/ reacting a compound of the general Formula IV

(wherein R4 is as stated above and R5 represents C14 alkyl) with ammonia or a compound capable of liberating ammonia.

If desired, in the product of the general Formula (I) so obtained (wherein X represents oxygen, R represents C14 alkoxycarbonyl, Rq is hydrogen and R2 and R3 together form a valence bond) one or more of the substituents X, R, R', R2 and/or R3 may be converted into another substituent X, R, R', R2 and/or R3 within the definition of said substituents by methods known perse. One may also convert a product of the general Formula I into a salt e.g. an acid addition salt or quaternary salt thereof, or set free a compound of the general Formula I from its salt or converting one salt into another salt.

Variant a/ of the process of the present invention is carried out preferably in the presence of an alkanol (e.g.

methanol, ethanol, propanol, butanol etc) at a temperature between 20"C and 1200C, particularly atthe boiling point of the solvent used. The reaction time depends on the temperature and may vary between about 2 and 10 hours. It is preferred to use 0,5-5,0 moles of 1,3,5-triazine and 0,5-2,0 moles of alkali metal alcoholate base per mole of a compound of the general Formula II,

It is expedient to use the compound of the general Formula II, the 1 ,3,5-triazine and the alkali alcoholate in about equimolar amounts. As alkali metal alcoholate one may use preferably lithium alcoholates (egg.

lithium methoxide, lithium ethoxide), sodium alcoholates (e.g. sodium methoxide, sodium ethoxideor sodium butoxide, etc) or potassium alcoholates (e.g. potassium methoxida, potassium ethoxide, potassium tertiary butoxide, etc).

The compound of the general Formula I thus obtained can be isolated from the reaction mixture by simple methods. Thus one may proceed by distilling off the alkanol and crystallizing the residue from a suitable solvent, or diluting the reaction mixture with water, if desired neutralising the mixture and separating the precipitated 1 ,6-naphthyridine derivative by means of filtration, centrifuging, sedimentation or other methods.

According to variant b/ of the process of the present invention a compound of the general Formula IV is reacted with ammonia or a compound capable of the liberating ammonia. The reaction is carried out preferably in an alkanol or aqueous alkanol as medium. The solvent, temperature and reaction time used maybe as described under variant a/. Gaseous ammonia may be introduced into the reaction mixture or a solution of ammonia in water or an alkanol can be used. Ammonia may also be used in theform of its salts with inorganic or organic acids (e.g. ammonium chloride, ammonium carbonate, ammonium acetate, ammonium formate etc). It is preferred to use 0,5-10 moles of ammonia or an equivadent amount of an ammonium salt, per 1 mole of the compound of the general Formula IV.

The 1 ,6-naphthyridine derivatives thus obtained may be isolated using the methods described for variant a/.

In a compound of the general Formula I thus obtained one or more substituents X, R, R1, R2 and R3 can be converted into another substituent X, R, R', R2 and/or R3 respectively by methods known perse.

Thus an alkoxycarbonyl group (R) can be converted into a carboxy group by acidic or alkaline hydrolysis, or can be transformed into a carbamoyl group by reaction with ammonium hydroxide; or can be converted into a carbohydrazido group by reaction with hydrazine hydrate; or can be transformed into another alkoxycarbonyl group by means of transesterification with the corresponding alkanol in the presence of an acidic catalyst.

Compounds of the general Formula I, wherein R is carboxy, can be esterified with the corresponding aikanol optionally in the presence of an acidic catalyst; or can be reacted with organic or inorganic acid halides to yield the corresponding acid halide, which can be then converted into the corresponding acid amide or carbohydrazide by reacting it with ammonia or hydrazine respectively. Compounds of the general Formula I, in which R is carboxy, can be subjected to decarboxylation by heating in phosphoric acid, polyphosphoric acid, pyridine, quinoline, tetralin or benzophenone, optionally in the presence of a catalyst - thus compounds of the general Formula I are obtained in which R represents hydrogen.

Compounds of the general Formula I, in which R represents a carboxamido group, can be hydrolysis with strong acids or alkali hydroxide to yield the corresponding compound of the general Formula ly}nwhlch R is ca rboxy.

Compounds of the general Formula I, in which R is a carboxamido group, can be treated with a dehydrating agent (e.g. phosphorus pentoxide, phosphoryl chloride, N,N-dicyclohexyl carbodiimide) to yield compounds of the general Formula I, in which R is cyano.

Compounds of the general Formula I, in which R is cyano, can be subjected to acidic or alkaline hydrolysis to yield compounds of the general Formula I, in which R is carboxy. The hydrolysis can also be stopped at the acid amide stage (compounds of the general Formula I in which R is carbamoyl).

Compounds of the general formula I, in which Xis oxygen, R2 and R3 together form a valence bond and R is hydrogen can be subjected to N-alkylation, N-alkenylation or N-aralkylation by reacting with 1,1-4 molar amount of the corresponding alkylating, alkenylating or aralkylating agent. Thus compounds of the general Formula I are obtained, in which X, R2 and R3 are as stated above and R1 is C16 alkyl, C34 alkenyl or C7-12 aralkyl.

As alkylating, alkenylating or aralkylating agent e.g. dialkyl sulfates, alkyl halides, alkenyl halides, trialkyl phosphates and aralkyl halides can be used.

As solvent C14 alkanols, halogenated hydrocarbons (e.g. chloroform, dichloro methane, 1,2-dichloro ethane etc), aromatic hydrocarbons (e.g. benzene, toluene, xylene etc) or an excess of the trialkyl phosphate alkylating agent may be used.

As acid binding agent alkali metal carbonates, alkali metal hydrogen carbonates, alkali metal alcoholates or organic bases (e.g. pyridine, trialkylamines, etc) may be used.

The alkylation, alkenylation and aralkylation reaction can be carried out at 20-1 80 C for a reaction period of between 10 minutes and 10 hours. If trialkyl phosphates are used as alkylating agent the N-alkyl-carboxylic acids of the general Formula I (wherein R is carboxy and R1 is C16 alkyl, C34 alkenyl or C7-12 aralkyl) can be directly obtained by alkaline hydrolysis without the isolation of the N-alkyl esters (compounds of the general Formula I, in which R is C14 alkoxycarbonyl and R1 is as stated here above).

A compound of the general Formula I, in which Xis oxygen, R2 and R3 together form a valence bond and R is hydrogen, can be reacted with a halogenating agent (e.g. phosphoryl halides, phosphorous trihalides, phosphorous pentahalides) to give compounds of the general Formula I, in which X-R3 represents halogen and R1 and R2 together form a valence bond. Halogenation can be preferably carried out in an inert solvent (e.g. benzene, chloroform, dichloro methane 1,2-dichioro ethane) at a temperature between 20"C and 140"C for 3-10 hours. One may also add a catalytic amount of triethyl amine to the reaction mixture.

Compounds of the general Formula I, in which R' and R2 together form a valence bond and X-R3 represents a halogen atom, can be reacted with C14 alkanols containing 2 moles of alkali metal alcoholate to give the corresponding C1 -4 alkoxy derivatives. The hydrolysis of the ester group takes place simultaneously so that compounds of the general Formula I are obtained, in which R is carboxy, X-R3 represents C14 alkoxy and R1 and R2 are as stated above.

Compounds of the general Formula I, in which X-R3 represents halogen can be converted into the corresponding mercapto derivative by reacting with sodium hydrogen sulfide (i.e. compounds of the general Formula I, in which X-R3 represents mercapto). An alkylthio group can be introduced into the compounds of the general Formula I with the aid of sodium alkyl sulfides (X-R3 stands for alkylthio).

Compounds of the general Formula I, in which Xis oxygen, R1 is hydrogen, C15 alkyl, C34 alkenyl or C7-12 aralkyl and R2 and R3 together form a valance bond, can be reacted with diphosphorous pentasulfide or p-methoxy-phenyl-thio-phosphine-sulfide dimer. The reaction can be carried out preferably by using a 50 molar % excess of diphosphorous pentasulfide at the boiling point of the solvent. The reaction time may be 1-2 hours. As solvent e.g. pyridine, toluene, quinoline, tetralin, chloroform or dioxane may be applied.The reaction product (i.e. a compound of the general Formula I, in which Xis sulfur, while R1, R2 and R3 are as stated above in this passage) can be isolated by evaporation of the solvent, admixture of the residue with water and filtration, or by solvent extraction and evaporation.

Compounds of the general Formula I, in which X is sulfur, R1 represents hydrogen and R2 and R3 together form a valence bond and a thine thiol tautomeric equilibrum exists, can be treated with an alkylating or aralkylating agent to give the corresponding S-alkyl or S-aralkyl derivative. As alkylating agent e.g. dialkyl sulfates, alkyl halides, trialkyl phosphates, N,N-dimethyl formamide, dimethyl acetal, diazomethane, or as aralkylating agent, aralkyl halides can be used. As solvent C14 alcohols, halogenated hydrocarbons, aromatic hydrocarbons, or an excess ofthetrialkyl phosphate alkylating agent can be used.The acid binding agent may be an alkali metal carbonate or hydrogen carbonate, alkali metal alcoholate, or an organic base (e.g. pyridine ortrialkyl amines).

Alkylation and aralkylation can be carried out at a temperature of 20-180"C for a reaction time of between 10 minutes and 10 hours. The product thus obtained (i.e. compounds of the general Formula I, in which Xis sulfur, R3 is C14 alkyl, C34 alkenyl or C7-12 aralkyl and R1 together with R2 form a valence bond, can be isolated by filtration or extraction and evaporation.

The compounds of the general Formula I can be converted into their salts by reacting with biologically acceptable inorganic or organic acids, or into their quaternary salts by treating with a quaternising agent. For this purpose e.g. hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, formic acid, citric acid, salicylic acid, methyl iodide, ethyl iodide, dimethyl sulfate, p-toluene-sulfonic acid, benzenesulfonic acid or halides thereof, etc, can be used. Compounds of the general Formula I, in which R represents carboxy, can form salts with organic or inorganic bases (e.g. alkali metal salts such as sodium or potassium salts; alkaline earth metal salts e.g. calcium or magnesium salts; or salts formed with amines). The compound of the general Formula I can be set free from its salt or quaternary salt or a salt can be converted into another salt.

The starting materials of the general Formula II and Ill

are commercial products. The starting materials of the general Formula IV can be prepared by known methods e.g. by reacting a compound of the general Formula II with a compound of the general Formula lil The said reaction can be carried out preferably under inert gas (e.g nitrogen) in a dipolar aproticsoivent (e.g.

N,N-dimethylformamide, hexamthyl phosphoric acid triamide) under heating. One may also work without solvent, in the melt. The compounds of the general Formula I are primarily of interest as medicines. Some representatives of the compounds of the general Formula I possess significant antibacterial and antifungal properties, while others exhibit insecticidal, or diuretic effects.

The antibacterial effect of some compounds of the general Formula I against various polyresistant gram negative and gram positive strain (E.g. Vibrio parahaemoliticus, Pseudomonas aeruginosa, Proteus vulgaris, Shigella sonnei, Salmonella typhium, Escherichia coli, Klebsiella pneumonie, Staphylococcus aureus; Streptococcus faecalis; Bacillus subtilis strains) surpasses that of some known antibacterial compourlds (e.g.

Nalidixic acid, Superseptyl, Streptomycin).

The activity of the compounds of the general Formula I is shown by the following test: From the compounds, dilution series are prepared in the range of from 200 to 0,03 Fgfrnl - each solution is diluted to twice of its volume, i.e. to half of its concentration. As diluent dimethyl sulfoxide is used. The amount of the solvent does not exceed 1 % of the total weight of the nutrient medium. The surface of the nutrient medium (glucose yeast extract solidified with agar, or a glucose minimal nutrient medium) is inoculated with the spore suspension of the microorganism. The minimal inhibitory concentration (MIC) causing complete inhibition of the growth of the microorganism is determined.

The following test compounds are used: Compound A = ethyl-2-methyl-5-thioxo-5,6-dihydro-1 ,6-naphthyridine-3-carboxylate; Compound B = Benomyl* (reference compound).

The results are summarised in Table I.

TABLE I Bacterial Compound A Compound B strain Yeast extract minimal Yeast extract nutrient medium nutrient medium nutrient medium MIC (Lg/ml) MlC(ig/ml) MIC (pg/mll Corynebacterium michiganense 25 6 50 Staphylococcus aureus 12 1,5 50 Bacillus cereus var. mycoides 50 1,5 50 *1-butylcarbamoyl benzimidazolyl carbamate According to a further feature of the present invention there are provided pharmaceutical compositions comprising as active ingredient a compound of the general Formula I or a salt or quaternary salt thereof in admixture with pharmaceutically acceptable carriers or diluent. The compositions may be provided in solid (e.g. tablets, pills, coated pills, capsules, suppositories) or liquid (e.g. solution, emulsion, suspension etc) forms.

The pharmaceutical compositions according to the present invention comprise usual csrrIarse,g.

magnesium stearate, talc, calcium carbonate, water; polyethylene glycols, glyceroIfarrro fiwl; The compositions according to the present invention can also contain conventional adjuvants (e.g.

emulsifying and disintegrating agents etc).

The active ingredient content of the compositions of a pharmaceutical composition having antibacterial effect may vary over a wide range (0.005-99%).

The daily dosage of the active ingredient can vary over a wide range and depends on the condition, age and weight of the patient, the form of the composition, the activity of the active ingredient, etc. The daily oral dosage may be preferably 0.05-20 mg/kg body weight and can be administered in one or several dose(s). The above data are given for guidance only and the actual dose can be higher or lower, depending on the circumstances of the given case and the prescription of the physician.

The pharmaceutical compositions of the present invention can be prepared by conventional methods of pharmacy.

According to the present invention there are also provided agrochemical and veterinary compositions comprising as active ingredient a compound of the general Formula I or a salt or quaternary salt thereof in admixture with suitable carriers or diluents and optionally with surfactants and other adjuvants.

The agrochemical compositions of the present invention can be fungicidal, baceteriacidal and/or herbicidal agents and can be formulated as emulsifiable concentrates, granules, powder mixtures, wettable powders or in any suitable conventional forms by known methods.

The active ingredient content of the above compositions can vary over a wide range and may be between 0.01 and 95%.

The compositions of the present invention may contain conventional solid or liquid carriers or diluents.

The solid carriers may be of mineral origin (e.g. clay, kaolin, talc, mica, bentonite, diatomaceous earth, apatite, montmorrilonite, calcium carbonate etc) or of vegetable origin (e.g. powders wheatmeal, wood meal, soya meal, tobacco powder, starch, cellulose, etc). Other substances (e.g. aluminium oxide, waxes, polyvinyl chloride, petroleum resins, etc) may be used.

As liquid carrier conventional liquids, e.g. alcohols (such as methanol, ethanol, ethylene glycol, benzyl alcohol, etc), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc), haiogenated hydrocarbons (e.g.

chloroform, carbon tetrachloride, chlorobenzene, etc), ketones (e.g. acetone, methyl ethyl ketone, cyclohexanone), ethers (e.g. tetrahydrofuran, dioxan, etc), ester (e.g. methyl acetate, ethyl acetate, propyl acetate, butyl acetate, ethylene glycol acetate, etc), acid amides (e.g. dimethyl formamide), nitriles (e.g.

acetonitrile, etc), ether alcohols (e.g. ethylene glycol monoethyl ether etc), or water etc. can be used.

The compositions may also contain surfactants and other adjuvants in order to enhance dispersion, emulsification and desintegration.

The surfactants may be of cationic, anionic or non-ionic character or amphoteric substances, e.g.

polyoxyethylene alkyl aryl ethers, polyoxyethylene fatty acid esters, polyoxyethylene alkyl ethers, oxypropylene polymers, salts of fatty acids, alkyl phosphates, alkyl sulfonates, alkyl aryl sulfonates, quaternary ammonium salts, oxyalkyl gamines, etc.

As adjuvants e.g. gelatine, starch, agar, polyvinylalcohol, casein, sodium alginate, etc. can be used.

Further details of the present invention are to be found in the Examples, which are given by way of illustration only.

Example 1 2,3 g (0,1 g atom) of sodium are reacted with 20 ml of ethanol. To the sodium athoxide solution thus obtained 25,12 g (0,1 mole) of diethyl-2,6-dimethyl-3,5-pyridine-dicarboxylate and 8,11 g (0,1 mole) of 1,3,5-triazine are added. The orange coloured solution thus obtained is stirred at the boiling point of the reaction mixture for 2 hours. The dark brown solution is evaporated, the residue dissolved in 150 ml water and the solution neutralised with 10 w/v % hydrochloric acid. The mixture is allowed to stand overnight, the precipitated brown substance is filtered, washed twice, each time with 30 ml of water.Thus 18,7 g (80,4 %) of ethyl-2-methyl-5-oxo-5,6-dihydro-1 ,6-naphthyridine-3-carboxylate are obtained in the form of a brown substance melting at 250-252"C. This product is purified by chromatography on Kieselgel 60 (length of the column 25 cm, diameter 2,5 cm, particle size 0,2-0,5 mm) and elution with a 10:1 volume mixture of chloroform and methanol. Thus 12,9 g (55 %) of the pure product are obtained, m.p.: 260"C, in the form of a light yellow substance.

Analysis: for the Formula C12H12N203 calc: C% = 62,06; H% = 5,21; N% = 12,06; .

found: C% = 62,30; H% = 5,43; N% = 11,83.

Example 2 A mixture of 25,12 g (0,1 mole) of diethyl-2,6-dimethyl-3,5-pyridine-dicarboxylate, 14,72 g (0,1 mole) of N,N-dimethylformamide - diethylacetal and 100 ml of N,N-dimethyl-formamide is heated to boiling for 16 hours under the circulation of nitrogen. The dark reaction mixture is evaporated and the residual viscous oil is poured into 1 litre of water, the aqueous solution is extracted six times, each time with 200 ml of benzene, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The orange coloured semi-solid residue is treated with 20 ml of petrol, the precipitated yellow crystals are filtered off. Thus 8,2 g (26,6%) of N,N-dimethyl-2-(3,5-bis-ethoxycarbonyl-6-methyl-2-pyridyl)-ethenamine are obtained.Mp.: 92-93"C (after recrystallization from ethanol).

Analysis: for the Formula C16H22N204 calc: C% = 62,73; H% = 7,24; N% = 9,14; found: C% = 62,40; H% = 7,38; N% = 8,92.

Example3 A mixture of 2,51 g (0,01 mole) of diethyl-3,5-pyridine-dicarboxylate and 7,35 g (0,05 mole) of N,N-dimethylformamide - diethylacetal is stirred at 140"C for 6 hours. To the orange coloured viscous solution thus formed 100 ml of petrol are added and the mixture is allowed to stand at 4"C for 2 days. The precipitated yellow crystals are filtered off-and washed with 20 ml of patrol. Thus 1,55 g of N,Ntimethyl-2- (3,5-bis-ethoxycarbonyl-6-methyl-2-pyridyl)-ethenamine are obtained. Yield: 50,7%. Mp.: 94"C. The product gives no melting point depression when mixed with the compound prepared according to Example 2.

Example 4 A mixture of 3,06 g (0,01 mole) of N,N-dimethyl-2-(3,5-bis-ethoxycarbonyl-6-methyl-2-pyridyl)- ethenamine, 30 ml of 25 w/v % ammonium hydroxide and 30 ml of ethanol is stirred at room temperature for 36 hours. The precipitated light yellow crystals are filtered off and washed with 20 ml of water. Thus 1,50 g of ethyl-2-methyl-5-oxo-5,6-dihydro-1 ,6-naphthyridine-3-carboxylate are obtained. Yield: 64,3 %. Mp.: 260at.

The product gives no melting point depression with the compound prepared according to Example 1.

Example 5 0,23 g (0,01 g atom) of sodium are dissolved in 50 ml of ethanol. To the sodium ethoxide solution thus obtained 2,32 g (0,01 mole) of ethyl-2-methyl-5-oxo-5,6-dihydro-l ,6-naphthyiridine-3-carbaxylate are added.

1.89 g (0.015 mole) of dimethyl sulfate are poured into the red solution thus formed after 5 minutes. The colour of the solution turns yellow, it warms up slightly and after a few minutes the precipitation of small needle crystals begins. The reaction mixture is stirred at 25"C for 3 hours, whereupon it is diluted with 80 ml of water, neutralized by the addition of a 5 w/v% sodium hydroxide solution (pH 7) and extracted three times each time with 50 ml of chloroform. The extract is dried over anhydrous sodium sulfate and evaporated in vacuo. Thus 2,36 g of ethyl-2,6-dimethyl-5-oxo-5,6-dihydro-l ,6-naphthyridine-3carboxyla2e are obtained in the form of yellow crystals. Yield 96,2%. Mp.: 144-146'C (from ethanol).

Analysis: for the Formula C13H14N203 calc: C% = 63,40; H% = 5,73; N% = 11,38 found: C% = 63,65; H% = 5,94; N% = 11,46.

Example 6 A mixture of 2,32 g (0,01 mole) of ethyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine 3-carboxylate, 7,29 g (0,04 mole) of triethyl phosphate and 1,38 g (0,01 mole) of anhydrous potassium carbonate is stirred at 180"C for 30 minutes. The dark brown reaction mixture is cooled to room temperature, diluted with 50 ml of water, extracted three times with 50 ml of chloroform each time, dried over anhydrous sodium sulfate and evaporated in vacuo. The residual brown oil is dissolved in 10 ml of benzene and subjected to chromatography on Kieselgel 60 (length of the column 16 cm, diameter 2 cm; Merck, particle size 0,2-0,5 mm). The column is eluted with bezene.On evaporating the benzene solution 2,27 g of ethyl-6-ethyl-2- methyl-5-oxo-5,6-dihydro-1 ,6-naphthyridine-3-carboxylate are obtained in the form of light yellow crystals.

Mp.: 143 C. Yield 87,1 %.

Analysis: for the Formula C14H16N203 calc.: C% = 64,60; H% = 6,20; N% = 10,76; found: C% =64,40; H% = 6,51; N% = 11,01 Example 7 A mixture of 6,96 g (0,03 mole) of ethyl-2-methyl-5-oxo-5,6-dihydro-l ,6-naphthyridine-3-carboxylate, 21,85 g (0,12 mole) of triethyl phosphate and 4,14 g (0,03 mole) of anhydrous potassium carbonate is stirred at 180"C for 30 minutes. To the brown reaction mixture 180 ml of 5w/v% potassium hydroxide solution is added at 80"C and the mixture is hydrolised at 1000C for an hour, clarified with activated charcoal until hot, filtered and acidified with 10 w,/v % hydrochloric acid to pH 4.The precipitated faint yellow product is filtered next morning and washed with 20 ml of water. Thus 5,9 g of 6-ethyl-2-methyl-5-oxo-5,6-dihydro-l ,6- naphthyridine-3-carboxylic acid are obtained. Yield 84,8 %, Mp.: 284"C (from ethanol).

Analysis: for the Formula C12H12N203 calc.: 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 mole) of ethyl-2-methyl-5-oxo-5,6-dihydro-l ,6-naphthyridine-3-carboxylate, 90 ml of phosphoryl chloride and 3 mi of triethylamine is stirred at 140"C for 3 hours. From the dark solution formed the excess of phosphoryl chloride is distilled off in vacuo, the oily residue is poured onto 4009 of ice and the pH is adjusted to 8 by adding potassium carbonate. The aque solution is extracted five times with 100 ml of diethyl ether each time, dried over anhydrous sodium sulfate and evaporated. Thus 1,2 g of ethyl-5-chloro-2-methyl-l ,6-naphthyridine-3-carboxylate are obtained in the form of light yellow crystals.

Yield 48%. Mp.: 136-138"C.

Analysis: for the Formula C12H11CIN2O2 calc: C% = 57,50; H% = 4,42; N% = 11,17; Cl% = 14,14; found: C% = 57,77; H% = 4,74; N% = 10,99; Cl % = 13,92.

Example 9 0,23 g (0,01 g atom) of sodium are dissolved in 50 ml of ethanol. 1.25 g (0.005 mole) of ethyl-5-chloro-2-methyl-1 ,6-naphthyridine-3-carboxylate are added to the sodium ethoxide solution thus formed and the mixture is heated to boiling for 2 hours. The red solution is filtered in order to remove the precipitated sodium chloride and the filtrate is evaporated in vacuo. Thus 1,1 g of a brick red powder are obtained which are dissolved in 35 ml of water and acidified with 10 w/v % hydrochloric acid to pH 2. The precipitated product is filtered off and washed with 10 ml of water. Thus 0,63 g of 5-ethoxy-2-methyl-1,6naphthyridine-3-carboxylic acid are obtained. Yield 54,1 %. Mp.: 208-209"C.

Analysis: for the Formula C12H12N203 calc: C% = 62,06; H% = 5,21; N% = 12,06; found; C% = 61,71; H% = 5,49%; N% = 11,75.

Example 10 A mixture of 4,64 g (0,02 mole) of ethyl-2-methyl-5-oxo-5,6-dihydro-l ,6-naphthyridine-3-carboxylate, 6,66 g (0,03 mole) of diphosphorous pentasulfide and 50 ml of pyridine is heated to boiling for 2 hours. From the red reaction mixture the pyridine is distilled off in vacuo under the addition of 50 ml of ethanol. The residue is treated with 100 ml of water. The yellow solid product thus formed is filtered off and washed twice with 20 ml of water each time. The 4.5 g of yellow ethyI-2-methyl-5-thioxo-5,6-dihydrn-1,6-naphthyridine-3-carboxyIate are obtained. Yield 90.9% Mp.: 220 (after recrystallization from N,N-dimethylformamide).

Analysis: for the Formula C12H22H202S calc.: C% = 58,05; H% = 4,87; N% = 11,28; S% = 12,91; found: C%= 57,89; H% = 4,79; N% = 11,09; S% = 13,30.

Example 11 A mixture of 2,32 g (0,01 mole) ethyl-2-methyl-5-oxo-5,6-dihydro-1 ,6-naphthyridine-3-carboxylate, 3,33 g (0,015 mole) of diphosphorous pentasulfide and 25 ml of dioxan is heated to boiling for an hour. The dioxan is removed in vacuo. 120 ml of water are added to the residual red oil and the mixture is neutralized by adding 10 w/v% sodium hydroxide solution to pH 8. The mixture is extracted five times with 100 ml of chloroform each time. The combined chloroform extracts are dried over sodium sulfate and evaporated in vacuo. Thus 2.0 g of ethyl-2-methyl-5-thioxo-5,6-dihydro-l ,6-naphthyridine-3-carboxylate are obtained. Yield 80.7%. Mp.: 220"C (from dioxan). The product gives no melting point depression with the substance prepared according to Example 10.

Example 12 2,32 g (0,01 mole) of ethyl-2-methyl-5-oxo-5,6-di hydro-l ,6-naphthyridine-3-carboxylate and 3.33 g (0,015 mole) of diphosphorous pentasulfide are reacted in 25 ml toluene in an analogous manner to Example 11.

Thus 1,0 g of ethyl-2-methyl-5-thioxo-5,6-dihyd ro-1,6-na phthyridi ne3-ca rboxylate are obtained. Yield 40.3 %.

Mp.: 220-221"C (from ethyl acetate). The product gives no melting point depression with the compound of Example 11.

Example 13 A mixture of 2,48 g (0,01 mole) of ethyl-2-methyl-5-thioxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate, 4,20 g (0.03 mole) of trimethyl phosphate and 1,38 g (0,01 mole) of anhydrous potassium carbonate is stirred at 140"C for 5 minutes. On cooling the dark brown solution a light yellow substance precipitatessAfter the addition of 75 ml of water the crystals are filtered off and washed twice with 25 ml of water each. Thus 2,5 g of ethyl-2-methyl-5-methyl-thio-1 ,6-naphthyridine-3-carboxylate are obtained.

Yield 95,2 %. Mp.:110-11 (from ethanol).

Analysis: for the Formula C13H14N202S calc.: C% = 59,52; N% = 10,68; S% = 12,22; H% = 5,38; found: C%= 59,30; N% = 10,34; S% = 12,42; H% = 5,24.

Example 14 A mixture of 2,48 g (0,01 mole) of ethyl-2-methyl-5-thioxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate, 1,56 g (0,011 mole) of methyl iodide, 1,52 g (0,011 mole) ofanhydrous potassium carbonate and 50 ml of chloroform is heated to boiling for 6 hours. To the reaction mixture 50 ml of water are added; the mixture is stirred for 10 minutes, the two layers are separated, the aqueous phase is extracted three times wfth 50 ml of chloroform each time, the combined extracts are dried over anhydrous sodium sulfate and evaporated in vacuo.Thus 1.05 g (95.5%) of yellow crystals are obtained which are purified by means of chromatography on Kieselgel 60 (Merck, particle size 0,2-0,5 mm, length of the column 15cm, diameter 2,5 cm) and elution with chloroform. Thus 0,73 g of ethyl-2-methyl-5-methyl-thio-1 ,6-naphthyridine3-carboxylate are obtained, yield 66,5 %. Mp.:110-11 According to thin layer chromatography this product is identical will the compound prepared according to Example 13.

Example 15 0,5 g (0,002 mole) of ethyl-2-methyl-5-thioxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate are dissolved in 25 ml of hot acetone. The solution is filtered and 10 ml of anhydrous ethanol saturated with gaseous hydrogen chloride are added. The precipitated red crystals are filtered off and washed with ethar}ol. Thus 0,25 g of ethyl-2-methyl-5-thioxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate-hydrochloride dlaobtained.

Yield 43,5 %. Mp.: 257-258"C (decomposition).

Analysis: for the Formula C12H13ClN2O2S calc: C% = 50,61; H% = 4,60; CI% =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 16 A mixture of 2,32 g (0,01 mole) of ethyl-2-methyl-5-oXo-5,6-dihydro-1,6-naphthyridine-3-carboxylate and 60 ml of 8 w/v % potassium hydroxide solution is stirred at 100C for 2 hours. The reaction mixture is clarified with activated charcoal, filtered and acidified with 10 w/v % hydrochloric acid to pH 2. The precipitated yellow crystals are filtered off and washed with 10 ml of water. Thus 1,7 g of 2-methyl-5-oxo 5,6-dihydro-1,6- naphthyridine-3-carboxylic acid are obtained. Mp.: above 300 C (from N,N-dimethylformamicie), Yield 83,1 %.

Analysis: for the Formula C10H8N2O3 calc. C%= 58,82; H% = 3,95; N% =13,82; found: C%= 58,43; H% = 4,03; N% = 13,65.

Example 17 A mixture of 2,32 g (0,01 mole) of ethyl-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3 < rboxylate.

1,88 g (0,011 mole) of benzyl bromide, 1,52 g (0,011 mole) of anhydrous potassium carbonate and 50 ml of N,N-dimethyl formamide is stirred at boiling temperature for 1.5 hours. The reaction mixture is filtered off and poured into 150 ml of water. The precipitated lighttanflocky product is filtered off and washed twice with 50 ml of water each time. Thus 2,8 g of ethyl-6-benzyl-2-methyl-5-oxo-5,6-dihydrn-1,Snaphthyridine-3 carboxylate are obtained. Mp: 151-152"C (from ethanol). Yield 87,0 %.

Analysis: for the Formula C19H18N203 calc: C% = 70,79; H% = 5;63; N% = 8,69; found: C% = 70,78; H% = 5,53; N% = 8,63.

Example 18 A mixture of 2,32 g (0,01 mole) of ethyl-2-methyl-5-oxo-5,6-dihydro-1 ,6-naphthyridine-3-carboxylate.

1,33 g (0,011 mole) of allyl bromide, 1,52 g (0,011 mole) of anhydrous potassium carbonate and 50 ml of N,N-dimethyl formamide is stirred at a boiling temperature for 30 minutes. The reaction mixture is cooled, and poured into 250 ml of water. The precipitated light yellow product is filtered off and washed with 50 ml of water. Thus 2,0 g of ethyl-6-aIlyI-2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate are obtained.

Yield 73,5 %. Mp.: 110-111"C (from ethanol).

Analysis: for the Formula C15H16N203 calc: C% = 66,16; H% = 5,92; N% = 10,29; found: C% =66,03; H% = 5,83; N% = 10,42.

Example 19 A mixture of 4,08 (0,015 mole) of ethyl-6-allyl-2-methyl-5-oxo-5,6-dihydro-1 ,6-na phthyridine-3- carboxylate, 3,75 g (0,075 mole) of hydrazine hydrate and 20 ml of ethanol is heated to boiling for 8 hours.

The light yellow solution is cooled, the precipitated white crystals are filtered off and washed with ethanol.

Thus 3,08 g of 6-allyl-2-methyl-5-oxo-5,6-dihyd ro-1 ,6-na phthyridine-3-ca rbohydrazide are obtained.

Yield 79,7 %. Mp.: 185-186 C (from ethanol).

Analysis: for the Formula C13H14N402 calc: C% = 60,45; H% =5,46; N% = 21,69; found: C% = 50,24; H% = 5,34; N% = 21,42.

Example 20 A mixture of 2,04 g (0,01 mole) of 2-methyl-5-oxo-5,6-dihydro-1 ,6-naphthyridine-3-carboxylic acid and 20 g of polyphosphoric acid is stirred at 2000C for 2 hours. The reaction mixture is cooled to room temperature, 100 ml of water are added and the mixture is neutralised with 20 w/v % sodium hydroxide solution. The aqueous solution is extracted three times with 50 ml of chloroform each time, dried over anhydrous sodium sulfate, dried and evaporated. Thus 0,36 g of 2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine are obtained in the form of light yellow crystals. Yield 22,5%. Mp.: 215-21 6"C.

Analysis: for the Formula CsHsN2O calc: C% = 67,49; H% = 5,03; N% = 17,49; found C% =67,25; H% = 5,11; N% = 17,53.

Claims (35)

1. 1,6-Naphthyridine derivatives of the general Formula I

and salts and quaternary salts thereof (wherein R represents hydrogen, carboxy, C14 alkoxycarbonyl, carbamoyl, carbohydrazido or cyano; and either (1) X is oxygen or sulfur; and i) R2 and R3 together form a valence bond, and Rq represents hydrogen, C15 alkyl, C34 alkenyl or C7-12 aralkyl; or ii) R1 and R2 together form a valence bond, and R3 represents hydrogen, C15 alkyl, C34 alkenyl or C7-12 aralkyl; or (2) R1 and R2 together form a valence bond, and X-R3 represents halogen).

2. Ethyl-2-methyl-5-oxo-5,6-dihydro-1 ,6-naphthyridi ne-3-carboxylate.

3. N,N-Dimethyl-2-(3,5-bis-ethoxycarbonyl-6-methyl-2-pyridyl)-ethenamine.

4. Ethyl-2,6-dimethyl-5-oxo-5,6-dihyd ro-1 ,6-naphthyridine-3-carboxylate.

5. Ethyl-6-ethyl-2-methyl-5-oxo-5,6-dihydro-1 ,6-naphthyridine-3-carboxylate.

6. 6-Ethyl-2-methyl-5-oxo-5,6-dihydro-1 ,6-naphthyridine-3-carboxylic acid.

7. Ethyl-5-ch lo ro-2-methyl-1 ,6-na phthyridine-3-carboxylate.

8. 5-Ethoxy-2-methyl-1 ,6-naphthyridine-3-ca rboxyl ic acid.

9. Ethyl-2-methyl-5-thiono-5,6-dihydro-1 ,6-naphthyridi ne-3-carboxylate.

10. Ethyl-2-methyl-5-methylthio-1 ,6-naphthyridine-3-carboxylate.

11. Salts and quaternary salts of the compound of claims 2 to 10.

12. Compounds according to claim 1, substantially as described herein and as illustrated with reference to any one of the Examples.

13. A process for the preparation of a compound of claim 1 which comprises reacting a compound of the general Formula II

(wherein R4 is C14 alkyl) with 1,3,5-triazine.

14. A process according to claim 13 wherein said reaction is performed in the prescence of an alkali metal alcoholate.

15. A process according to claim 14 wherein said alkali metal alcoholate is selected from sodium methoxide, lithium methoxide, potassium methoxide, sodium ethoxide, lithium ethoxide or potassium ethoxide.

16. A process for the preparation of a compound of claim 1 which comprises reacting a compound of the general formula IV

(wherein R4 and R5 are independently C14 alkyl) with ammonia or a compound capable of liberating ammonia.

17. A process according to variant claim 16 wherein ammonium chloride, ammonium carbonate, ammonium acetate, ammonium formate or ammonium hydroxide is used as said compound capable of liberating ammonia.

18. A process according to any of claims 13 to 17 including the step of converting a product of the general formula I wherein Xis oxygen, R is (C1-4 alkoxy) carbonyl, R1 is hydrogen and R2 and R3 together form a valence bond, into another compound of general formula I by transforming one or more of thesubstituents X, R, R1, R2 and R3 into other values within their respective definitions by methods known per se.

19. A process according to claim 18 wherein a compound of the general Formula I, wherein R represents C14 alkoxycarbonyl, carbamoyl or cyano, is hydrolysed to the corresponding compound of the general Formula I in which R is carboxy.

20. A process according to claim 18 wherein a compound of the general Formula I in which R is carboxy or C14 alkoxycarbonyl is amidated, or wherein a compound of the general Formula I in which 9 is cyano is hydrolysed, in each case yielding a product wherein R is carbamoyl.

21. A process according to claim 18 wherein a compound of the general Formula I in which R is carboxy or C14 alkoxycarbonyl is converted to a compound wherein R is carbohydrazido by reaction with hydrazine.

22. A process according to claim 18 wherein a compound of the general Formula I, wherein R is carboxy is esterified with a C14 alkanol.

23. A process according to claim 18 wherein a compound of the general Formula I in which R is carbamoyl is dehydrated to form a compound wherein R is cyano.

24. A process according to claim 18 wherein a compound of the general Formula 1 in which R is carboxy is decarboxylated.

25. A process according to claim 18 for the preparation of compounds of the general Formula I, in which R' is C1-6 alkyl, C3-4 alkenyl or C7--12 aralkyl, X is oxygen, R2 and R3 together form a valence bond and R is as defined in claim 1 which comprises reacting a product of the general Formula I in which R1 is hydrogen, R2, R3 and Rare as defined in claim 1 and X is oxygen, with an agent capable of introducing a C15 alkyl, C3-4 alkenyl or C7-,2 aralkyl group.

26. A process according to claim 18 for the preparation of compounds of the general Formula I in which X-R3 represents halogen, R1 and R2 together form a valence bond and R is as defined in claim 1, which comprises reacting a product of the general Formula I in which X is oxygen, 91 is hydrogen, R2 and R3 together form a valence bond and R is as defined in claim 1, with a halogenating agent

27.A process according to claim 18 for the preparation of compounds of the general Formula I in which R3 is C1 -6 alkyl, C34 alkenyl or C7-12 aralkyl, R is oxygen or sulfur, 91 and R2 together from a valence bond and R is as defined in claim 1, which comprises reacting a product of the general Formula I in which -X-R3 is halogen, R' and R2 together form a valence bond and R is as defined in claim 1, with the corresponding alcoholate orthiolate.

28. A process according to claim 18 for the preparation of compounds of the general Formula I, In which X is sulfur, R2 and R3 together form a valence bond and R and 91 have the meanings stated in claim lrwhl comprises reacting a corresponding product of the general Formula I in which X is oxygen, with diphosphorus pentasulfide.

29. A process according to claim 18 for the preparation of compounds of the general Formula I, in which R3 is C15 alkyl, C34 alkenyl or C7-12 aralkyl, X is sulfur, R' and R2 together form a valence bond and R is as defined in claim 1, which comprises reacting a compound of the general Formula I in which X is sulfur, R1 is hydrogen, R2 and R3 together form a valence bond and R is as defined in claim 1 with an agent capable of introducing a C15 alkyl, C34 alkenyl or C7-12 aralkyl group.

30. A process according to any of claims 13 to 29, substantially as described herein.

31. A process according to any of claims 13 to 29, substantially as illustrated with reference to any one of the Examples.

32. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 or 12 and a pharmaceutically acceptable carrier or diluent.

33. A composition according to claim 32 comprising a compound of any of claims 2 to 11.

34. An agrochemical composition comprising an effective amount of a compound of any of claims 1 to 12 and a suitable carrier or diluent.

35. Compounds of general Formula IV as defined in claim 16.