CH596191A5 - Anti-bacterial benzyl-pyrimidines - Google Patents

Abstract

Anti-bacterial benzyl-pyrimidines esp powerful in combination with sulphonamides

Description

  

  
 



  The present invention relates to a process for the preparation of new benzylpyrimidines of the general formula
EMI1.1
 where R1 and R2 are C1-alkyl or r-alkenyl,
Z represents an oxygen atom bonded to one of the ring nitrogen atoms and n = 0 or 1 and of acid addition salts of such compounds.



   Examples of C4-alkyl radicals, which can be straight-chain or branched, are methyl, ethyl and propyl. An example of a C2¯3 alkenyl group is allyl.



   A subgroup of compounds of the formula I which is particularly preferred in the context of the present invention are those in which R1 and R2 are alkyl, in particular methyl or ethyl.



   The benzylpyrimidines of the formula I and their salts are obtained according to the invention by adding a compound of the formula
EMI1.2
 in which R3 represents an alkyl group and Rt, R2, Z and n have the meanings given above, the alkoxycarbonyl group reduces to the hydroxymethyl group and, if appropriate, converts a base obtained into an acid addition salt.



   The reduction of an alkoxycarbonyl group to the hydroxymethyl group can be carried out with diisobutylaluminum hydride in dioxane.



   Unless they are known or are not described below, the starting materials can be prepared in analogy to the methods given below.



   For the production of acid addition salts, in particular salts which can be used in pharmaceutical preparations, the inorganic acids usually used for this purpose, such as hydrochloric acid, sulfuric acid, phosphoric acid, etc. or organic acids, such as formic acid, acetic acid, succinic acid, lactic acid, citric acid, maleic acid, fumaric acid, are used , Tartaric acid, methanesulfonic acid, p-toluenesulfonic acid, etc. into consideration.



   The compounds of the formula I and their salts have an antibacterial effect. They inhibit the bacterial dihydrofolate reductase and potentiate the antibacterial effect of sulfonamides, such as B. sulfisoxazole, sulfadimethoxine, sulfamethoxazole, 4-sulfanilamido-5,6-dimethoxy-pyrimidine, 2 sulfanilamido-4,5-dimethyl-pyrimidine or sulfachinoxaline, sulfadiazine, sulfamonomethoxine, isosulfisoxazole and other inhibitors of enzymes involved in folic acid synthesis such as B. pteridine derivatives.



   For such combinations of one or more of the compounds I according to the invention with sulfonamides, oral, rectal and parenteral administration is possible in human medicine. The ratio of compound I to sulfonamide can vary within a wide range; it is z. B. between 1:40 (parts by weight) and 5: 1 (parts by weight); preferred ratios are 1: 1 to 1: 5.



   So z. B. a tablet 80 mg of a compound I according to the invention and 400 mg sulfamethoxazole, a children's tablet 20 mg of a compound I according to the invention and 100 mg sulfamethoxazole; Syrup (per 5 ml) contain 40 mg of compound I and 200 mg of sulfamethoxazole.



   example
To a solution of 4.45 g of a- (2,4-diamino-5-pyrimidinyl) 2,6-dimethoxy-p-toluic acid methyl ester in 400 ml of abs. Dioxane was added dropwise to 135 ml of approx. 15% diisobutylaluminum hydride solution in dioxane under nitrogen and with exclusion of moisture over the course of 30 minutes. The resulting suspension was stirred at 50 ° C. for 1 hour. After cooling to 30 ° C., a mixture of 25 ml of methanol, 5 ml of water and 50 ml of dioxane was added as the reaction mixture, and the mixture was stirred at 50 ° C. for a further 2 hours. The solid material was separated and discarded. The filtrate was evaporated to dryness.

  After recrystallization from approx. 20 ml of methanol, the residue gave 4 - [(2,4-diamino-5-pyrimidinyl) methyl] -2,6-dimethoxybenzyl alcohol of melting point.



     227-228 "C.



   The raw material was produced as follows:
A mixture of 271 g of 2,6-dimethoxyterephthalic acid 1-mono-methyl ester, 1.2 l abs. Benzene, 100 ml of thionyl chloride and 30 ml of dimethylformamide were refluxed for 2 hours with exclusion of moisture. The solution was evaporated to dryness in vacuo and the residue was dissolved twice in approx. 100 ml abs. Benzene dissolved and the solvent removed again in vacuo. After recrystallization from 7 l of hot n-heptane, the residue gave 260 g of acid chloride with a melting point of 100-101 C. After concentrating the mother liquors, a further 20 g of acid chloride (melting point 90-95 ° C.) were obtained.



   40 g of acid chloride were dissolved in 400 ml of xylene dried over sodium. While gassing with N2, 4 g of 5% Pd / BaSO4 and 0.4 ml of quinoline-sulfur regulator were added, the suspension was blown out with N2 for a further 10 minutes and then hydrogen was passed through at 110 ° C. with stirring. The course of the reaction was followed by titrating the HCl formed. After about 2 hours (90% of the theoretical amount of HCl released) the reaction was terminated, the suspension was cooled under N2 and the catalyst was suction filtered. The filtrate was concentrated to dryness in vacuo, the residue was taken up in 150 ml of benzene and shaken with 500 ml of about 37% sodium bisulfite solution for 2 hours. The benzene phase was separated off and the aqueous phase was washed with 100 ml of benzene.



   The remaining aqueous solution was cooled to 5 "C and then with approx. 20% NaOH solution to approx.



  pH 10 set. The precipitated aldehyde (and inorganic salts) was filtered off with suction. The solid material was taken up in 400 ml of benzene and 700 ml of water, the benzene solution was separated off and the aqueous phase was extracted twice with 100 ml of benzene each time. The combined benzene extracts were washed with 2 × 50 ml of water, dried over MgSO4 and evaporated to dryness in vacuo; 2,6-Dimethoxy-4-formylbenzoic acid methyl ester, m.p. 113-114 "C.



   From a solution of 0.9 g of sodium metal in 15 ml of abs.



  MeOH, the solvent was evaporated off under N2 and with exclusion of moisture. The remaining sodium methylate was suspended in a solution of 25.2 g of β-morpholinopropionitrile in 28 ml of dimethyl sulfoxide dried over molecular sieves and heated to 70.degree. C. At this temperature, a solution of 30 g of methyl 2,6-dimethoxy-4formylbenzoate in 45 ml of anhydrous dimethyl sulfoxide was added dropwise over the course of 30 minutes and the mixture was then stirred at 75 ° C. for a further 30 minutes. After this time, practically no more aldehyde could be detected. The solution was cooled to + 5 ° C., about 30-40 ml of water were added dropwise, the mixture was seeded and stirring was continued for about 3 hours.

  The crystalline product was filtered off with suction, washed with about 15 ml of methanol cooled to 0 C and recrystallized from methanol.



   The 4- (2-cyano-3-morpholinoallyl) -2,6-dimethoxybenzoic acid methyl ester has a melting point of 137-138 C.



   8.6 g of aniline were concentrated with 7.6 ml with cooling. HC1 offset. 32 g of methyl 4- (2-cyano-3-morpholino allyl) -2,6-dimethoxybenzoate and 100 ml of isopropanol were then added. The suspension was heated to reflux with stirring for 30 minutes. About 1/3 to half of the solvent was evaporated, 20 ml of water were added, the crystalline product filtered off with suction, washed with a little cold methanol and dried. Recrystallization from methanol gave 4- (3-anilino-2-cyanoallyl) -2,6-dimethoxybenzoic acid methyl ester of melting point 193-194 C.



   In a 2 l flask with magnetic stirrer and reflux condenser, 8 g of Na metal in 200 ml of abs. Dissolved methanol.

 

   24.7 g of guanidine HCl were added to this solution and the suspension was stirred at room temperature for 30 minutes. The sodium chloride was sucked off and mixed with approx.



  10 ml cold abs. Methanol washed. The filtrate was admixed with 46 g of 4- (3-anilino-2-cyanoallyl) -2,6-dimethoxybenzoic acid methyl ester and 1000 ml of isopropanol and the suspension was refluxed for 50 hours while stirring. The reaction mixture was concentrated and cooled, and the precipitated crystals were suction filtered.



   After crystallization from about 4 liters of methanol with the addition of about 1 g of charcoal, methyl a- (2,4-diamino-5-pyrimidinyl) -2,6-dimethoxy-p-toluic acid with a melting point of 250-251 ° C. was obtained.

 

Claims (1)

PATENT CLAIM Process for the preparation of compounds of the general formula EMI2.1 where Rl and R2 are C1 4-alkyl or C23-alkenyl, Z represents an oxygen atom bonded to one of the ring nitrogen atoms and n = 0 or 1. and of acid addition salts of such compounds, characterized in that in a compound of the formula EMI2.2 in which R3 represents an alkyl group, the alkoxycarbonyl group is reduced to a hydroxymethyl group, and a base obtained is optionally converted into an acid addition salt. SUBClaim Process according to claim, characterized in that one starts from compounds in which R1 and R2 represent methyl.