CH589067A5 - Anti-bacterial benzyl-pyrimidines - esp powerful in combination with sulphonamides - Google Patents

Abstract

Benzylpyrimidines of formula (I) and their acid addition salts are new: (where R1 and R2 are alkyl or alkenyl; Z is O linked to one of the N atoms; n = O or 1; A1 is CF3, -C=R6 R7 or -C R8 R9 R10 either (i) R6 is oxo and R7 is H, alkyl or alkoxy, (ii) R6 is NOH and R7 is alkyl or (III) -C=R6 R7 is -CN, R8 and R9 are H or alkyl; R10 is OH, alkoxy or NR3R4; alternatively R9 and R10 are alkoxy or alkylthio, or R9 and R10 is alkylene-dioxy or alkylene-dithio; R3 and R4 are H, alkyl or alkanoyl).

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 C1-6-alkyl or C2 are 6-alkenyl, and A1 is trifluoromethyl or one of the groups
EMI1.2
 is in which R6 is oxo and R7 is hydrogen, C1¯6-alkyl, or -c alkoxy; or R6 is hydroxyimino and R7 is Cl¯6-alkyl; or R6 together with R7 nitrilo; R8 and Rg are hydrogen or C1- alkyl and R10 is hydroxy, Cl s-alkoxy, or -N (R3, R4);

   or R9 and R10 Cl 6-alkoxy or C1 6-alkylthio; or R9 together with R10 C2 3-alkylenedioxy or C2 3-alkylenedithio; and R3 and R4 represent hydrogen, C1-6-alkyl or C1-6-alkanoyl: and acid addition salts of such compounds.



   The term C1-6-alkyl denotes straight-chain or branched saturated aliphatic hydrocarbon groups such as methyl, ethyl and propyl. The expression C2-6-alkenyl relates to straight-chain or branched, olefinically unsaturated hydrocarbon radicals such as allyl.



   The term C1-6-alkanoyl refers to straight-chain or branched alkanecarboxylic acid residues such as formyl and acetyl.



   The expression C2-3-alkylenedioxy or C2 3-alkylenedithio refers to groups with 2 or 3 carbon atoms.



   Group (a) includes in particular the radicals cyano, C1-6-alkoxycarbonyl, N-hydroxyimino-C1-6-alkyl, formyl and Cl 6-alkylcarbonyl.



   Group (b) includes in particular the radicals C1-6-alkyl-di-C1-6-alkoxymethyl, C1-6-alkyl-C2-3-alkylenedioxymethyl, C1-6-alkyl-di-C1-6-alkylthiomethyl , C1-6-alkyl-C2-3-alky lendithiomethyl, optionally C-mono- or -di-1-6-alkylated hydroxymethyl, optionally C-mono- or -di-1-6 -alkylated Cl 6 -alkoxymethyl , optionally C-mono- or di-C10-alkylated aminomethyl, optionally C-mono- or -di-C1-6-alkylated C1-6-alkylaminomethyl, optionally C-mono- or -di-C1-6-alkylated di-C1- 6-alkylaminomethyl.



   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 represent Cl s-alkyl, in particular methyl or ethyl. Also preferred are those compounds of the formula I in which A1 is C-mono- or di-C1-6-alkylated hydroxymethyl; or optionally C-mono- or -di-C1-6-alkylated Cl s -alkoxymethyl; or C1- -alkylcarbonyl.



   The benzylpyrimidines of the formula I and their salts are obtained according to the invention by the amino protective groups in a compound of the formula
EMI1.3
 wherein X represents H or an amino protective group and at least one X represents a protective group, and R1, R2 and A have the above meaning, cleaved off hydrolytically or hydrogenolytically, and optionally converting a base obtained into an acid addition salt.



   In the compound of the formula II, the symbol X represents an amino protective group which can be converted into a free amino group by hydrolysis or hydrogenolysis.



  Representative examples of the former category of protecting groups are acyl groups such as alkanoyl groups. such as formyl, acetyl, propionyl, etc., or aroyl groups such as benzoyl, or tert. Butyloxycarbonyl. A group which can be converted into a free amino group by hydrogenolysis is, for example, the carbobenzoxy group. The preferred amino protecting groups are acyl groups, especially the acetyl group.



   The hydrogenolysis of an amino protecting group X can for example be catalytic, e.g. by means of palladium on carbon and in a solvent e.g. an alcohol such as methanol at 10-50, preferably at room temperature.



   The hydrolysis of a compound II can be alkaline, e.g.



  with aqueous or aqueous alkanolic (methanolic) alkali; or acidic, e.g. be carried out with aqueous or aqueous alcoholic mineral acids (e.g. hydrochloric acid).



   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 that 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, tartaric acid, methanol sulfonic 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 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 that are involved in folic acid synthesis, such as 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 e.g. between 1: 40 (parts by weight) and 5: 1 (parts by weight); preferred ratios are 1: 1 to 1: 5.



   E.g. 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
A suspension of 11.3 g of N- [2-amino-5- <4- (1-hydroxy- -1-methylethyl) -3,5-dimethoxybenzyl> -4-pyrimidinyl] acetamide in 40 ml of 10% methanolic KOH Was refluxed for 1 hour, then cooled to about 10. The crystals were suction filtered and washed with a little methanol.



  Crystallization from methanol gave 4 - [(2,4-di-amino-5-pyrimidinyl) methyl] -2,6-dimethoxy-α, α-dimethylbenzyl alcohol of m.p. 248-2500.



   The starting material was prepared as follows:
5 g of methyl a- (2,4-diamino-5-pyrimidinyl) -2,6-dimethoxy-p-toluic acid were added in portions to hot acetic anhydride (10 ml). The resulting solution was stirred for a further 30 minutes at this temperature and then treated with 30 ml of toluene and cooled. The a- (2,4-diacetamido-5-pyrimidinyl) -2,6-dimethoxy-p-toluic acid methyl ester which had been filtered off with suction was recrystallized from methanol.



  183-185.



   A solution of 2.5 g of α- (2,4-diacetamido-5-pyrimidinyl) -2 was added to a methylmagnesium iodide solution prepared from 2.4 g of magnesium and 14.5 g of methyl iodide in 100 ml of ether 6-dimethoxy-p-toluic acid methyl ester in 200 ml of abs tetrahydrofuran was added dropwise over the course of 30 minutes and the resulting suspension was stirred for 24 hours. The reaction mixture was admixed with 20 ml of water, the organic phase was separated off and washed with a little 4H NaOH and water, dried (MgSO4) and evaporated. The crude product thus obtained (yellowish oil) was used directly in the next stage.

 

   After chromatographic purification (silica gel, CHCl3: n-propanol: conc. Ammonia / 80: 20: 1), a sample yielded N- [2-amino-5- <4- (1-hydroxy-1-methylethyl) -3.5 -dimethoxy-benzyl> -4-pyrimidinyl] acetamide of melting point 214-2160 (from methanol).

 

Claims (1)

PATENT CLAIM Process for the preparation of compounds of the general formula EMI2.1 where R 'and R2 are C1-6-alkyl or C2-6-alkenyl, and A is trifluoromethyl or one of the groups EMI2.2 represents in which R6 is oxo and R7 is hydrogen, C1-6-alkyl, or C1-6-alkoxy; or R6 is hydroxyimino and R7 is C1-alkyl; or R6 together with R7 nitrilo; R8 and R9 are hydrogen or C1G-alkyl and R10 is hydroxy, C1-6-alkoxy, or -N (R3, R4); or R9 and R10 C1-6-alkoxy or C1-6-alkylthio; or R9 together with R10 C-2 3-alkylenedioxy or C2 3-alkylenedithio; and R3 and R4 represent hydrogen, C1-6-alkyl or C10-aikanoyl, and acid addition salts of such compounds, characterized in that the amino protective groups are in a compound of the formula EMI2.3 wherein X represents H or an amino protective group and at least one X represents a protective group, and R1, R2 and A have the above meaning, cleaved off hydrolytically or hydrogenolytically, and optionally converting a base obtained into an acid addition salt. SUBClaim Process according to claim, characterized in that one starts from compounds in which R1 and R2 are C1-6-alkyl and A is C-mono- or di-C1-6-alkylated hydroxymethyl; or optionally C-mono- or di-C1-6-alkylated Cl G -alkoxymethyl; or C16 .Alkylcarbonyl.