NO783775L - 2,4-DIAMINO-5-BENZYLPYRIMIDINES AND PROCEDURES FOR THE PREPARATION OF THESE - Google Patents

Description

2, 4-amino-5-benzyl pyrimidines and method for their preparation.

The present invention relates to new 2,4-diamino-5-benzyl pyrimidines with the general formula

1 2

where R 3 is hydrogen or C, 1 -alkyl, R hydrogen,

R mercapto, C^_g-alkylthio, carboxy-C^_g-

alkylthio, C^_^-Alkoxy—C^_g-alkylthio, dimethylcarbamoylthio, -S(O)R' or -SO2R' and R4 c1_5_

alkylthio, -S(O)R' or -SO9R' or

1 2 4

R hydrogen, R and R C, .--alkylthio, -S^O)R'

3

or -SO2R<1>and R C₁₋-₆-Alkoxy, mercapto,

C1-6-alkylthio, carboxy-C1-6-alkylthio, dimethylcarbamoylthio, -S(O)R', -SO R" or —NR"R"<1>or

1 2 3

R hydrogen, R C 1-6 -alkylthio, R mercapto, C 1-6 -alkylthio, carboxy-C 1-6 -alkylthio, C 1-6-alkylthio, C 1-6 -alkylthio, dimethylcarbamoylthio, -S(O)R' or

-SO2R' and R<4>C1-6-alkylthio, -S(O)R' or -SO2R'

or R"<*>" hydrogen, R^ halogen, R^ C,^-alkylthio,

-S(0)R' or -SC^R' and R C 6 -alkylthio, -S(0)R'

or -S09R' or

R<1>hydrogen, R<2>halogen or C1-6-6-alkyloxy,

R^ mercapto, C^_g-alkylthio, carboxy-C^_^-alkylthio,

In car carboxy-C 1-6 -alkylthio, cyano-C 1-6-alkylthio,

C₁₋-Alkoxy-C₁₋-Alkylthio/C₁₋-Alkoxy-C₁₋-Alkoxy7-C,--alkylthio, dimethylcarbamoylthio, -S(O)R' or

1-0 ^

-SO 2 R' and R halogen or C 1-8 -alkyloxy,

R' C1-8-alkyl/R" and R"' independently of each other hydrogen or C1-8-alkyl or together C2-6~

alkylene (possibly with 1-3 double bonds),

and their physiologically tolerable salts, methods for their preparation, as well as pharmaceutical preparations based on these compounds and their preparation.

The general formula I comprises the compound groups of formula I-1 to 1-5:

In the formula I-l to 1-5 means:

R<1a>hydrogen or C18-alkyl,

R 2a C 1-6 alkylthio, -S(O)R' or -SC^R',

R2b C1_6-Alkoxy/

R2c halogen,

R halogen or C 1-3 - alkoxy,

R<3a>mercapto, C1-6-alkylthio, carboxy-C1-6-alkylthio, C1-6-alkyl-C1-6-alkylthio, dimethylcarbamoylthio,

-S(0)R' or -S09R',

R C 1-6 -Alkoxy, mercapto, C 1-6 -alkylthio, carboxy-C 1-6 -alkylthio, dimethylcarbamoylthio, -S(O)R', -SC^R' or —NR"R"•,.

R<3c>C, .-alkylthio, -S(O)R' or -SOoR',

R 3d mercapto, C 1-6 -alkylthio, carboxy-C 1-6 -alkylthio, caralkyloxy-C 1-6 -alkylthio, cyano-C 1-6 -alkylthio, C 1-6 -alkyl-C 1-6 -alkylthio, C 1-6 -alkyl-C 1-6 -alkylthio, C1-6-alkylthio, dimethylcarbamoylthio,

-S(O)R' or -SC^R',

R4a C1-6-alkylthio, -S(O)R' or -SO2<R>',

R 4 * 3 halogen or C 1-6 -alkyloxy.

The substituents R', R" and R"' have the meanings already mentioned above.

Examples of C 1-6 alkyl radicals are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl and hexyl, of which methyl and ethyl are preferred. Examples of C2-6~ alkylene residues are ethylene, trimethylene, tetramethylene and pentamethylene. Examples of residues derived from these with 1-3 double bonds are vinylene, propylene, 2-butenylene, 1,3-butadienylene, 1,4-pentadienylene or 1,3,5-hexatrienylene.

Chlorine, bromine and iodine in particular come as halogen substituents

in consideration, of which chlorine and bromine are preferred.

The method for producing compounds according to the present invention is characterized by (a) condensing a compound of formula

12 3 4

where R , R , R and R have the above meanings,

Z is a group -CtCN). = CH-Y or -CH(CN)CH(OR5)2',

Y a leaving group and R

ethyl, 2-phenoxy-ethyl or 2-benzyloxy-ethyl or

5

both residues R together C1-6-alkylene,

with guanidine or a guanidine salt or

! IN

(b) reductively eliminates the substituent X from a compound of formula

12 3 4

where X is halogen and R , R , R and R• have the aforementioned

meanings,

or

(c) for the preparation of a compound of formula I-1 reacts a substituted benzyl pyrimidine of formula

where R is C 1-6 -Alkoxy, (preferably methoxy), benzyloxy, hydroxy or halogen,

with a compound of formula

whereRla, R<3a>and R<4a>have the aforementioned meanings,

or that one

L I (d) modifies a compound of formula I within the framework of generally known methods on the substituents R 2 , R<3> and/or R 4 and, if desired, transfers the compound obtained in a physiologically tolerable salt.

According to variant (a) of the process according to the invention, a compound II is reacted with guanidine or a guanidine salt. The turnover can take place in a manner known per se, e.g. in an organic solvent such as an alkanol (methanol, ethanol), in dimethylformamide, dimethylsulfoxide or N-methylpyrazolone,

at a temperature between 25 and 200°C, preferably between 50 and 170°C. As guanidine salts, for example, the carbonate and the hydrochloride can be used. Representative examples of"

the leaving groups indicated by the symbol Y in formula II

is e.g. Alkoxy groups such as methoxy, ethoxy, propoxy etc, 2-(C^-g-Alkoxy)-ethoxy groups such as 2-methoxy-ethoxy and 2-ethoxy-ethoxy, 2-phenoxy-ethoxy, 2-benzyloxy-ethoxy, alkylthio groups, the amino group and amino groups substituted with aliphatic, aromatic or heterocyclic groups such as alkylamino, benzylamino, -arylamino (eg optionally substituted anilino or naphthylamino), dialkylamino, 1-imidazolyl, pyrrolidino, piperidino, piperazino or morpholino. Particularly preferred as a leaving group is the anilino residue, whose phenyl ring may optionally be substituted one or more times by halogen, alkyl or alkoxy.

The production of starting compounds II can, as shown in reaction core I, take place from compounds of formula VIII, as the individual reaction steps can take place analogously to known reactions.

In this way, e.g. an aldehyde of formula VIII is reacted with

a (3-Alkoxypropionitrile of formula NC-CH2-CH2-OR 5 to a compound of formula VI and in the presence of an alkali metal alkoxide such as sodium methoxide or potassium tert-butylate and an alkanol such as methanol, ethanol or propanol to a compound of formula II-a. The oe, (3-unsaturated compound VI stands in equilibrium with the corresponding (3,y-unsaturated compound II-e which can be reacted with guanidine to a compound I..!

If you react an aldehyde of formula VIII first with malodinitrile under conditions of a Knoevenagel condensation (possibly basic catalyst), you get a dinitrile of formula VII which can be transferred through selective hydrogenation, e.g. with half a mole of sodium borohydride, to compound II-b.

By condensation with (3-mofolinopropionitrile, an aldehyde of formula VIII can be transferred to a compound of formula II-c, which can either directly serve as starting material for the reaction according to the invention, or also, and preferably,

only then by exchange of the morpholino for the anilino group is transferred in a compound of formula II-d.

The conversion of VIII to II-d can also take place directly with (3-anilinopropionitrile, but still the morpholino-anilino-variant is the most suitable route for the production of the benzyl-pyrimidine I, as better yields are obtained under milder conditions.

The methods for producing the sulphur-containing benzyl pyrimidines according to the present invention from aldehydes of formula I are thus in principle analogous to those known for the preparation of corresponding non-sulphur-containing benzyl pyrimidines.

The aldehydes of formula VIII are, with the exception of 3,4-bis-(methylthio)-benzaldehyde (i.e. the compound VIII-1 with R = hydrogen and R 3a = R 4a = methylthio) new compounds, and likewise the subject of the present invention. Analogously to the division of the compounds I, the aldehydes VIII can be divided into the following subgroups VIII-1 to VIII-5:

In the formulas VIII-1 to VIII-5, the substituents have the meanings already indicated above.

The preparation of the aldehydes of formula VIII from known compounds can take place in ways known per se, e.g. as those described in detail in examples 9 - 18 and as schematically shown in the following reaction overviews II-V, respectively in analogy to these.

A reaction for which no parallel has been found in the literature so far and is therefore new is the thermal cleavage of a compound XXIII to a compound VIII-5d (compare reaction scheme V). The reaction is preferably carried out in dimethylformamide at a temperature from approx. 50°C to the reflux temperature of the reaction mixture. In case of traces of alkali metal xanthogenate, e.g. potassium xanthogenate, the reaction is catalysed.

The reductive elimination of the halogen atom X, which is preferably a chlorine or bromine atom, to a compound of formula III according to process variant (b), can take place in and for

known way when treating a compound III with suitable reducing agents such as zinc in glacial acetic acid, amalgamated zinc in caustic soda or by catalytic hydrogenation, e.g. in the presence of a noble metal catalyst such as palladium in an inert solvent such as ethanol.

The compounds of formula III are new and likewise subject to the present invention. The production of these can take place analogously to known methods which are summarized in the following reaction core VI.

The reaction of a compound IV with a compound V according to method variant (c) can take place in the presence of an inorganic acid, for example orthophosphoric acid, polyphosphoric acid, a hydrogen halide acid such as hydrogen chloride acid or hydrobromic acid or an organic acid, for example a trihaloacetic acid such as trifluoroacetic acid.

The reaction is preferably carried out in a temperature range from

about. 50 - 100°C. In general, the inorganic or organic acid used for the reaction can serve as solvent, however, if desired, an inert organic solvent can also be used. The obtained acid addition salt of a compound of formula I-1 is separated after the reaction in the usual way and purified by conventional purification methods such as crystallization or filtration. The free base can be obtained by neutralizing the acid addition salt, for example with an alkali metal hydroxide.

Although the starting compounds of formula IV are known, the compounds of formula V are partly new compounds. The new compounds can be prepared in a known manner from known compounds, e.g. 1,2-dimercaptobenzene, 2-methylmercaptobenzene, 3,4-dimercaptotoluene or 3,4-bis-(methylthio)toluene or analogously to the preparation of these known compounds, e.g. by alkylation of a mercapto group and/or oxidation of an alkylthio group to an alkylsulfinyl or alkylsulfonyl group. The production of a carboxyalkylthio compound can take place e.g. by reaction of a mercapto compound with a Cu-halocarboxylic acid derivative as an ester or amide and subsequent hydrolysis.

Within the framework of generally known methods, certain compounds according to the invention with formula I can also be modified on the substituents R 2 , R 3 and/or R 4 , i.e. transferred into each other (method variant d). Thus, e.g. a mercapto group is transferred in a compound I

with an alkylating agent to an alkylthio group, an alkoxyalkylthio group or a carboxyalkylthio group."Alkylthio-

groups can be oxidized to alkylsulfinyl and/or alkylsulfonyl groups, respectively these can be reduced in a manner known per se to alkylthio groups. The dimethylcarbamoylthio group can be converted into the mercapto group by hydrolysis.

Salts of the compound I include both salts with acids (so-called acid addition salts) as well as, depending on the substituent on the benzyl residue, salts with bases.

For the preparation of acid addition salts, especially of salts which are useful in pharmaceutical preparations, i.e. physiologically tolerable, considering the inorganic and organic acids commonly used for this purpose, such as hydrochloric/ sulfuric acid, phosphoric acid*, formic acid, acetic acid, oxalic acid, tartaric acid, maleic acid, benzoic acid, succinic acid, fumaric acid, levulinic acid, salicylic acid, citric acid, isocitric acid, adipic acid, lactic acid, oc-ketoglutaric acid, malic acid, malonic acid, glyceric acid, mevalonic acid, glucuronic acid, neuraminic acid, glutaric acid, glucaric acid, aspartic acid, gluconic acid, mandelic acid, ascorbic acid, lactobionic acid, glucoheptonic acid, gluta- minic acid, nicotinic acid, pantothenic acid, folic acid, adenylic acid, geranyl acid, cytidinic acid, inosic acid and methanesulfonic acid.

Examples of salts with bases are the sodium and potassium salts.

The compounds of formula I and their salts are antibacterially active. They inhibit the bacterial dihydrofolic acid reductase (DHFR) and further enhance the effect of sulfonamides and other dihydrofolic acid synthetase inhibitors. Examples of sulfonamides that are potentiated by the compounds according to the invention are those from the pyrimidine, isoxazole, oxazole and pyrazine series such as sulfadiazine, sulfadimethoxine, sulfadoxine, sulfamerazine, sulfameter, sulfamethazine, 6-methoxy-4-sulfanilamidopyrimidine, sulfamethoxazole, sulfisoxazole , 3-sulfanilamido-4,5-dimethyl-isoxazole, sulfamoxole and sulfalene. Quantitatively, the compounds according to the present invention excel compared to known compounds

at a lower 50%<1>ig inhibition concentration of bacterial

In DHFR, for example in E. coli, and in significantly higher levels

•

Q-values (50% inhibition of DHFR in rat/50% inhibition of DHFR in E. coli), which is a measure of the selectivity of inhibition of bacterial DHFR, as well as at low toxicity.

Data showing the antibacterial effect of some representative compounds according to the invention are summarized in table 1.

The benzylpyrimidines according to the invention can therefore be used as pharmaceutical preparations with direct or delayed release of the active ingredient in a mixture with a for oral,

rectal or parenteral application suitable organic or inorganic inert carrier material, e.g. water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, plant oils, polyalkylene glycols, petroleum jelly etc.. - The pharmaceutical preparations can be in solid form,

e.g. as tablets, dragées, suppositories, capsules, in semi-solid form, e.g. as ointments or in liquid form, e.g

as solutions, suspensions or emulsions. Optionally, they are sterilized and respectively or contain additional auxiliary substances such as preservatives, stabilisers, wetting or emulsifying agents, agents for flavor improvement, salts for changing osmotic pressure or buffer substances. The preparation of the pharmaceutical preparations can take place in any manner well known to a person skilled in the art.

In the preparations in which the compounds according to the invention are given in combination with sulphonamides, the weight ratio of the two components to each other can be varied within wide limits. It can be between 1:40 and 10:1 and is preferably 1:5 to 5:1. A tablet can, for example, contain 80 - 400 mg of a compound I and 400 - 80 mg of a sulfonamide. In preparations with a compound I as the only active component, a simple dosage of 100 - 1000 mg can be used as a guideline, which depending on the need can be given once or more times a day.

Example 1

A solution of 36 g of 3,5-dimethoxy-4-methylthiobenzaldehyde and

28 g (3-mor f olinopropionitrile in 300 ml of dimethyl sulfoxide was heated to 60°C and mixed with 3.9 g of solid sodium methylate. During a slight exothermic reaction, the solution immediately became dark colored. It was stirred for 1 hour in an oil bath (60 °C), cooled and poured into ice water. Extracted with acetic acid, washed with sodium chloride solution and dried over sodium sulfate. After removal of the solvent, 56 g (99%) of 3,5-dimethoxy-α-(morpho -linomethylene)-4-(methylthio)-hydrocinnamic acid nitrile in the form of a pale yellow oil (m.p. 110 - 113°C, from acetic ester/pentane) which was further processed in this form.

A mixture prepared under ice cooling of 18.6 g of aniline and 11.5 g of acetic acid was added to 56 g of 3,5-dimethoxy-α-(morpholinomethylene)-4-(methylthio)-hydrocinnamic acid nitrile dissolved in 250 ml of isopropanol. It was heated for 2 hours under reflux, 100 ml of isopropanol was distilled off towards the end of the reaction, cooled to 0°C, mixed with 300 ml of water and extracted with vinegar. The organic phase was washed with sodium chloride solution, dried over sodium sulfate and evaporated. From the residue, 50 g of crude oc-anilinomethylene-3,5-dimethoxy-4-(methylthio)-hydrocinnamic acid nitrile crystallized. Recrystallization from ethyl acetate/pentane gave 40 g (72%) of the compound with a melting point of 260-210°C.

A solution of 10.2 g of o-anilinomethylene-3,5-dimethoxy-4-(methylthio)-hydrocinnamic acid nitrile and 16.6 g of guanidine carbonate

in 200 ml of ethanol, containing 2.15 g of sodium, was heated for 20 hours under reflux. The solvent was removed, the residue slurried in ice water and the crystals filtered off,

washed exhaustively with ice water and recrystallized from hot ethanol. 7.1 g (77.5%) of 2,4-diamino-5-[3,5-dimethoxy-4-(methylthio)-benzyl]-pyrimidine were obtained, m.p. 231 - 232°C.

Example 2

Analogous to the method described in example 1, further aldehydes of formula VIII through compounds II-c and II-d were transferred into compounds of formula I. Results see table li

Example 3

A solution of 1.4 g of 3-bromo-4,5-bis-(methylthio)-benzaldehyde, 0.85 g of (3-methoxypropionitrile and 0.14 g of sodium methylate) in 15 ml of absolute methanol was heated at reflux for 18 hours. The solvent was removed, the residue taken up in 10 ml of methylene chloride and the solution washed with water, dried and evaporated.

The obtained crude 3-bromo-4,5-bis-(methylthio)-α-(methoxyethylene)-hydrocinnamic acid nitrile (1.5 g) was heated with 0.6 g of guanidine hydrochloride and 0.35 g of sodium methylate in 5:, .ml ethanol 18 hours at reflux. After evaporation of the solvent, the residue was purified by column chromatography on silica gel with ethyl acetate/methanol (3:1, v/v) as eluent and recrystallized from methanol. 2,4-diamino-5-[3-bromo-4,5-bis-(methylthio)-benzyl]pyrimidine was obtained, m.p. 240 - 243°C.

Example 4

A mixture of 10.6 g of 3,5-dimethoxy-4-methylthiobenzaldehyde,

6.2 g of cyanoacetic acid ethyl ester and 2 drops of piperidine were heated in an open flask with stirring for 90 min. at 120°C, then cooled and recrystallized from ether/n-heptane. The yield of oc-cyano-3, 5-dimethoxy-4-methylthio-cinnamic acid ethyl ester, m.p.

98 - 100°C (from ethanol) was 12.0 g (80%).

A suspension of 6.0 g of oc-cyano-3, 5-dimethoxy-4-methylthio-cinnamic acid ethyl ester in 130 ml of ethanol and 2 drops of 1N sodium

lye, 0.23 g of sodium borohydride was added with stirring, whereby a solution was formed. After 30 min. by water jet vacuum, the ethanol was evaporated at 40°C, the residue taken up in ether, the solution washed with water and filtered through silica gel.

5.0 g (79.1%) of oc-cyano-3,5-dimethoxy-4-methylthio-hydrocinnamic acid ethyl ester were obtained as a colorless oil.

In another experiment, a solution of 3 g of oc-cyano-3, 5-dimethoxy-4-methylthio-cinnamic acid ethyl ester in 250 ml of methanol and 500 mg of 5% Pd/C was hydrogenated for 24 hours under normal pressure and at room temperature. After the usual work-up, 3.0 g (~100%) of oc-cyano-3, 5-dimethoxy-4-methylthio-hydrocinnamic acid ester was isolated.

A solution of 0.7 g sodium in 60 ml abs. of ethanol was added 2.7 g of guanidine hydrochloride. After 30 min. the suspension was filtered and 4.5 g of oc-cyano-3,5-dimethoxy-4-methylthio-hydrocinnamic acid ethyl ester was added to the filtrate. The reaction mixture was refluxed for 18 hours, evaporated to dryness, the residue slurried with water and extracted three times with 200 ml of acetic acid. The extract was evaporated and the residue crystallized from methanol. 1.8 g (38.5%) of 2,6-diamino-5-(3,5-dimethoxy-4-methylthiobenzyl)-4-pyrimidinol were obtained, m.p. 213 - 215°C.

A suspension of 0.96 g of 2,6-diamino-5-(3,5-dimethoxy-4-methylthio-benzyl)-4-pyrimidinol in 7.6 g of phosphorus oxychloride was added dropwise with stirring to 0.73 g of dimethylaniline. The mixture was boiled for 4 hours with stirring and about half of the excess phosphorus oxychloride was distilled off under reduced pressure. The rest was added approx. 10 g of ice. The suspension was then allowed to stand for 36 hours at room temperature and pH adjusted to 10 with conc. ammonia solution. The resulting suspension was freed from dimethylaniline by steam distillation. After cooling the aqueous suspension, the solid crude product was filtered off, dissolved in benzene/methanol (4:1, v/v) and filtered through silica gel. After evaporation of the solvent, the 2,6-diamino-4-chloro-5-(3,5-dimethoxy-4-methylthiobenzyl)-pyrimidine obtained was recrystallized from methanol,

m.p. 218 - 221°C.

A solution of 167.7 mg of 2,6-diamino-4-chloro-5-(3,5-dimethoxy-4-methylthiobenzyl)-pyrimidine in 1.6 ml of glacial acetic acid and 10 mg of mercury(II) chloride in 0, 2 ml of water was added to 150 mg of zinc powder. The mixture was boiled overnight with stirring and reflux. The solution obtained was filtered hot, whereby unreacted zinc was washed with 0.5 ml of glacial acetic acid. The filtrate was diluted with 2 ml of water and made alkaline by quenching with conc. ammonia solution.• The suspension was extracted three times with 5 ml of acetic acid, the extract dried and evaporated and the residue -■" ; ' '.. t recrystallized from methanol. 148 mg of 2,4-diamino-5-(3,5-dimethoxy -4-methylthio-benzyl)-pyrimidine, m.p.

231-232°C. "

Example 5

A mixture of 3.03 g of 3,4-bis-(methylthio)-toluene, 2.8 g of 2,4-diamino-5-methoxymethylpyrimidine and 15 ml of orthophosphoric acid was stirred for 6 hours at 100°C. After cooling and diluting with 5 ml of water, 45 ml of a 50% potassium hydroxide solution was added dropwise at 0°C. The solid product was filtered,

stirred twice with water, dissolved in methanol and the solvent evaporated. The residue (2.5 g) was purified by column chromatography on silica gel with ethyl acetate/methanol (3:1, v/v) as eluent. The isolated 2,4-diamino-5-[2-methyl-4,5-bis-(methylthio)-benzyl]-pyrimidine was recrystallized from methanol, m.p. 217 - 222°C.

Example 6

3.9 g of 2,4-diamino-5-[3,5-dimethoxy-4-(methylthio)-benzyl]-pyrimidine was dissolved in 90 ml of acetic acid, mixed with 1.3 g of 30% hydrogen peroxide and stirred 3 hours at room temperature. The solution was then poured onto ice water and made alkaline with concentrated ammonia solution. The crystalline precipitate was filtered off and recrystallized from methanol/methylene chloride.

2.8 g (70%) of 2,4-diamino-5-[3,5-dimethoxy-4-(methyl-sulfinyl)-benzyl]-pyrimidine were obtained in the form of pale yellow crystals with a melting point of 288 - 289°C.

Example 7

610 mg of 2,4-diamino-5-[3,5-dimethoxy-4-(methylsulfinyl)-benzyl]-pyrimidine dissolved in 15 ml of glacial acetic acid and 1 ml of 30% hydrogen peroxide was stirred for 24 hours at room temperature.

It was then poured onto ice, made alkaline with concentrated ammonia solution, the crystalline precipitate filtered off, washed well with water and dried. Yield: 580 mg (85%) 2,4-diamino-5-[3,5-dimethoxy-4-(methylsulfonyl)-benzyl]-pyrimidine, m.p. 297 - 298°C (decomposition).

Example 8

9 g of 2,4-diamino-5-(3,5-dimethoxy-4-mercaptobenzyl)-pyrimidine hydrochloride, 4.1 g of potassium carbonate and 2.5 g of dimethyl sulfate were heated in 80 ml of acetone for 16 hours under reflux. It was then filtered, the solvent distilled off, the residue taken up in vinegar and washed with water. On evaporation of the dried solution, 2.7 g (88%) of colorless 2,4-diamino-5-[3,5-dimethoxy-4-(methylthio)-benzyl]-pyrimidine crystallized, m.p. 230 - 232°C, ext.

Example 9

A suspension maintained at 0-5°C of 63.3 g of 4-amino-3,5-dimethoxybenzoic acid methyl ester in 300 ml of water and 75 ml of concentrated hydrochloric acid was added dropwise to a solution of 23 g of sodium nitrite in 60 ml of water. The now clear orange-coloured solution was dropped into an ice-cold, vigorously stirred solution of 80 g of potassium methyl xanthogenate in 300 ml of water, whereby strong gas evolution was observed. After 4 hours of stirring at room temperature, the mixture was extracted with vinegar, the extract washed with sodium chloride solution and dried over sodium sulfate. From the residue remaining after evaporation, 54 g (60%) of crude S-[4-(methoxycarbonyl)-2,6-dimethoxyphenyl]-0-methyldithiocarbonate were obtained, m.p. 113 - 115°C.

A mixture of 29 g of S-[4-(methoxycarbonyl)-2,6-dimethoxy-phenyl]-O-methyldithiocarbonate and 2 g of potassium methyl xanthogenate was stirred in 450 ml of dimethylformamide for 1 hour at 100°C. so

the solvent was removed under reduced pressure and the residue taken up in vinegar. After washing with water and saturated sodium chloride solution, it was dried over sodium sulfate and the solvent was distilled off. The residue gave, after recrystallization from cyclohexane, 18.8 g (81%) of 3,5-dimethoxy-4-(methylthio)-benzoic acid methyl ester in the form of colorless crystals, m.p. 86 - 88°C.

To a solution cooled to 0°C of 150 g of sodium dimethoxy-ethoxyalanate (70% in toluene) in 150 ml of toluene was added dropwise

50 g morpholine in 200 ml toluene. The clear solution was

stirred further at 0°C and then added dropwise while stirring

a solution cooled to -20°C of 30 g of 3,5-dimethoxy-4-(methylthio)-benzoic acid methyl ester in 700 ml of toluene. One rowed

another 5 hours. Then 100 ml of water was slowly added dropwise, 100 ml of 3N hydrochloric acid was added and the phases were separated in a separatory funnel. The aqueous phase was extracted twice with ethyl acetate, while the organic phases were washed with sodium chloride solution and dried over sodium sulfate. Evaporation of the solution gave 26 g of a yellow oil which crystallized completely and after recrystallization from ethyl acetate/pentane gave 21 g (78%) of 3,5-dimethoxy-4-(methylthio)-benzaldehyde, m.p. 54 - 56°C.

Example 10;

In an analogous manner to example 9, 21.1 g of 4-amino-3,5-dimethoxy-benzoic acid methyl ester was transferred to 19 g (68%) of S-[4-methoxy-carbonyl)-2,6-dimethoxyphenyl]-0-ethyldithiocarbonate , m.p. 84 - 86°C, and this converted with 90% yield further to 3,5-dimethoxy-4-ethylthiobenzoic acid methyl ester, m.p. 50 - 52°C.

A solution stirred at 0°C of 10.8 g of 3,5-dimethoxy-4-(ethyl-thio)-benzoic acid methyl ester in 100 ml of absolute ether became in the course of 10 min. added dropwise 120 ml of a 20% diisobutylaluminum hydride solution in hexane. It was stirred for a further 2 hours at 0 - 5°C, mixed after slow addition of 100 ml of water with 150 ml of 3N hydrochloric acid, taken up in ether and washed neutrally. The solution was dried over sodium sulfate, the solvent distilled off, the remaining yellow oil (11.2 g) taken up in 100 ml of methylene chloride and the solution stirred in the presence of 15 g of manganese dioxide at room temperature. After 3 hours a further 15 g of manganese dioxide was added. It was then stirred for 3 hours, filtered through a filtration aid based on diatomaceous earth and the filtrate was evaporated. The residue gave, on recrystallization from ether/pentane, 9.2 g (96.5%) of 3,5-dimethoxy-4-(ethylthio)-benzaldehyde in the form of colorless crystals with m.p. 38 - 39°C.

Example 11

In an analogous manner to Example 9, 21.1 g of 4-amino-3,5-dimethoxybenzoic acid methyl ester was transferred into 23 g (66%) of S-[4-(methoxycarbonyl)-2,6-dimethoxyphenyl]-0-(2-methoxyethyl) )-dithiocarbonate, m.p. 86 - 88°C, this converted with 42% yield further to 3,5-dimethoxy-4-(2-methoxyethylthio)-benzoic acid methyl ester, m.p. 56 - 58°C and finally reduced to 3,5-dimethoxy-4-(2-methoxyethylthio)-benzaldehyde (yield 88%).

Example 12

A suspension of sodium mercaptide, prepared from 35.5 g of 55% sodium hydride dispersion in mineral oil and 270 ml of dimethylformamide and 39.6 g of methylmercaptan in 190 ml of dimethylformamide was under nitrogen purging, stirring and ice water cooling at 15 - 30°C in portions added 48 g of 3,5-di-bromo-4-nitrobenzoic acid ethyl ester. The mixture was stirred for 4 hours at room temperature, poured into 4 1 of water, the precipitated crystals were combined with the ether extracts of the filtrate and the solvent was distilled off. Recrystallization of the residue from ether/petroleum ether gave 10.2 g of 3,4,5-tris-(methylthio)-benzoic acid ethyl ester. The aqueous filtrate obtained during the work-up was cooled and adjusted to pH 2 with concentrated hydrochloric acid, the solid material filtered off and dried. After esterification with ethanol/HCl, 28 g of a mixture of 3-bromo-4,5-bis-(methylthio)-benzoic acid ethyl ester and 3,4,5-tris-(methylthio)-benzoic acid ethyl ester (weight ratio approx. lii) were obtained, which was separated by soil chromatography on silica gel with methylene chloride as eluent. 13.8 g (32%) of 3-bromo-4, 5-bis-(methylthio)-benzoic acid ethyl ester were obtained, m.p. 69 - 71°C and 12.8 g (total i.e. 23 g, 60%) 3, 4, 5-tris-(methylthio)-benzoic acid ethyl ester, m.p. 89 - 93°C.

Esterification of the mixture with methanol/HCl and analogous work-up gives 3-bromo-4,5-bis-(methylthio)-benzoic acid methyl ester, m.p. 105 - 106°C, and 3,4,5-tris-(methylthio)-benzoic acid methyl ester, m.p. 122 - 124°C.

In an analogous manner to example 10, 35.9 g of 3-bromo-4,5-bis-(methylthio)-benzoic acid methyl ester with a yield of 62% was then reduced to 3-bromo-4,5-bis-(methylthio)-benzaldehyde and 24.1 g of 3,4,5-tris-(methylthio)-benzoic acid methyl ester reduced in 58% yield to 3,4,5-tris-(methylthio)-benzaldehyde, m.p. 160 - 161°C.

In another embodiment, 3-bromo-4,5-bis-(methylthio)-benzoic acid methyl ester and 3,4,5-tris-(methylthio)-benzoic acid methyl ester were prepared in the following way:

(a) A suspension of sodium mercaptide prepared from 0.55 g of 55% sodium hydride dispersion (in mineral oil) in 10 ml of dimethylformamide and 1 ml of methyl mercaptan in 6 ml of dimethylformamide was added portionwise at 15 - 25°C under nitrogen purging, stirring and ice water cooling 1.76 g of 4-nitro-3,5-dibromo-benzoic acid ethyl ester. The reaction mixture was stirred for 20 min. at room temperature, evaporated under high vacuum at 45°C to dryness, the residue mixed with 30 ml of water and extracted with ether. The ether extract was dried, filtered and evaporated. From the residue, after recrystallization from hot n-heptane, 1.5 g (94%) of 3-bromo-4, 5-bis-(methylthio)-benzoic acid ethyl ester was obtained, m.p. 72 - 73°C.

(b) A suspension of sodium mercaptide prepared from 20.7 g of 55% sodium hydride dispersion (in mineral oil) in 160 ml of dimethylformamide and 27 ml of methyl mercaptan in 110 ml of dimethylformamide was at 15 - 25°C under nitrogen purging, stirring and ice water cooling in portions added 28 g of 4-nitro-3,5-dibromobenzoic acid ethyl ester. The reaction mixture was stirred for 4 hours at room temperature, evaporated under high vacuum at

45°C to dryness, the residue mixed with 750 ml of water and extracted 5 times with 150 ml of ether each time. The ether extract was dried, filtered and evaporated. From the residue, after recrystallization from hot n-heptane, 16.5 g (75%) of 3,4,5-tris-(methylthio)-benzoic acid ethyl ester were obtained, m.p. 90 - 92°C.

Example 13

To a suspension cooled to 0°C of 10.8 g of sodium methylate

20 ml of methyl mercaptan was added to 150 ml of methanol. The mixture was stirred for 30 min. at 0°C and mixed with 13.6 g of 3,5-dibromo-4-nitrobenzoic acid ethyl ester, whereby a thick suspension was formed. After 5 min. the reaction mixture was evaporated, the residue extracted with ether and the extract washed with water. After recrystallization from methanol, 13 g (92%) were obtained

3, 5-dibromo-4-(methylthio)-benzoic acid methyl ester, m.p. 101 -

102°C.

In an analogous manner to example 10, 14.7 g of 3,5-dibromo-4-(methylthio)-benzoic acid methyl ester was reduced with 83% yield to 3,5-dibromo-4-(methylthio)-benzaldehyde, m.p. 87-89°C.

Example 14

A mixture of 22 g of 4-amino-3,5-dibromobenzoic acid ethyl ester,

100 ml of acetic acid and 14.4 g of 2,5-diethoxytetrahydrofuran were kept for 1 hour at 100°C and then evaporated under reduced pressure. The dark residue was taken up in acetic acid, the solution first washed with sodium bicarbonate solution, then with sodium bicarbonate solution, dried over sodium sulfate and evaporated to dryness. From ether/petroleum ether, 20 g (60%) of 3, 5-dibromo-4-pyrrole-? ■ benzoic acid ethyl ester, m.p. 106 - 107°C. 18.5 g of this compound in 40 ml of hot dimethylformamide was added dropwise to a stirred solution at room temperature of methyl mercaptide (prepared from 6 g of sodium hydride and about 15 g of methyl mercaptan in dimethylformamide) in 100 ml of dimethyl formamide. It was stirred for 16 hours at room temperature, evaporated, taken up in vinegar, adjusted with hydrochloric acid to pH 2, washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated again. The residue was esterified in ethanol/HCl. The solution was evaporated. From the residue, dissolved in ether, after addition of hexane, 8.8 g (57%) of crystalline 3,5-bis-(methylthio)-4-pyrrole-benzoic acid ethyl ester were obtained, m.p. 108 - 109°C.

In an analogous manner to example 10, 21 g of 3,5-bis-(methylthio)-4-pyrrole-benzoic acid ethyl ester were then reduced with a 67% yield to 3,5-bis-(methylthio)-4-pyrrole-benzaldehyde, m.p. .

146 - 148°C.

Example 15

A stirred suspension at 0°C of 4.7 g of sodium hydride (50%)

which was freed from oil by washing twice with pentane,

6.2 ml (5.0 g) of methylmercaptan was added dropwise to 100 ml of dimethylformamide. After 15 min. 12.25 g of 3,5-dimethoxy-4-bromobenzaldehyde in 50 ml of dimethylformamide was added dropwise.

The brown solution, which gradually became lighter, was stirred for 1/2 hour at room temperature, poured into ice water and the mixture extracted with vinegar. The extract was washed with water,

cold IN hydrochloric acid and saturated sodium chloride solution, dried over sodium sulfate and the yellow oil that remained after distilling off the solvent crystallized from methanol. Yield 8.9 g (84%) 3,5-dimethoxy-4-(methylthio)-benzaldehyde, m.p. 55 - 56°C.

Example 16

A suspension of 16.5 g of sodium hydride (55%) in 200 ml of dimethylformamide was added dropwise to a solution of 18 g of methyl mercaptan in 70 ml of dimethylformamide under stirring and nitrogen blowing at 0 - 5°C. After 30 min. stirring at room temperature, 1.5 g of cupric (I) chloride and then 21 g of 3,5-dibromo-4-hydroxy-benzaldehyde were added. The reaction mixture was stirred for 68 hours at 120°C, then mixed with a further 1.5 g of cuprous (I) chloride and again stirred for 20 hours at 150°C. It was then evaporated under high vacuum, the residue taken up in a 10% NaCl solution and the solution filtered through diatomaceous earth. The aqueous phase was extracted with ether, acidified under reflux with concentrated hydrochloric acid and extracted with acetic acid. The acetic ester extracts which had been washed with water were dried and evaporated, 9 g of the mixture obtained (14 g in total) was dissolved in 90 ml of acetone and mixed with 10.7 g of potassium carbonate. To the resulting suspension was added 7.5 ml of dimethyl sulfate. The reaction mixture was stirred for 18 hours at 50°C, filtered, the inorganic salts were washed with acetone and the filtrate evaporated. The evaporation residue was dissolved in acetic acid, successively washed with concentrated ammonia and water and separated with heptane/acetone

(7:1, v/v). First, 3-bromo-5-methylthio-anisaldehyde, m.p.

54 - 56°C, yield 3.5 g and then 3,5-bis-(methylthio)-anisaldehyde, m.p. 84 - 86°C (from n-heptane), yield 2.6 g eluted.

Example 17

A solution of 23 g of 85% potassium hydroxide in 190 ml of ethanol

27.3 g of 1-methyl-3,4-dithiophenol (prepared from 4-methylanthranilic acid according to Synthesis 1976, 471) was added dropwise in 110 ml

ethanol over the course of 20 min..."After 45 min, the solution was mixed with 49.6 g of methyl iodide in 70 ml of ethanol, the precipitated KJ filtered off after 30 min of stirring, the ethanol evaporated and the 3,4-bis- (methylthio)-toluene distilled at 95 - 98°C/1 Torr Yield 30.0 g (93%), mp 38 - 39°C (heptane).

A solution of 27 g of 3,4-bis-(methylthio)-toluene in 20 g of N-methyl-formanilide was added dropwise to 21.6 g of phosphorus oxychloride at 15-20°C and the solution was stirred for 24 hours at 55°C. The reaction mixture was again mixed with a suspension of 9.6 g of N-methylformanilide and 10.8 g of phosphorus oxychloride and stirred for a further 24 hours at 55°C. The cooled mixture was mixed with water, extracted with ether, the combined extracts were dried, evaporated to dryness and the residue chromatographed on silica gel with benzene. 14.7 g of 3,4-bis-(methylthio)-6-methylbenzaldehyde was obtained, m.p. 51 - 52°C (heptane).

In an analogous way, from 1,2-dithiophenol, 1,2-bis-(methylthio)-benzene was obtained in 83% yield, which in 39% yield could be converted into 3,4-bis-(methylthio)-benzaldehyde , m.p. 50°C.

Example 18

To a slurry stirred at 0°C of 2.64 g of sodium hydride in 150 ml of dimethylformamide, 18 g of syringa aldehyde and then 15 g of dimethylthiocarbamoyl chloride were added in portions so that the internal temperature did not exceed 10°C. It was then stirred for 4 hours at room temperature, the reaction mixture was taken up in vinegar, washed in sequence with cold 3N hydrochloric acid, 1N caustic soda and saturated sodium chloride solution and dried. From the evaporated solution, after addition of hexane, 16.2 g crystallized

(60%) O-(4-formyl-2,6-dimethoxyphenyl)-N,N-dimethyl-thiocarbamate, m.p. 173 - 176°C.

14.5 g of O-(4-formyl-2,6-dimethoxyphenyl)-N,N-dimethyl-thiocarbamate were heated for 2 hours at 220°C, cooled and crystallized from acetic ester hexane. 12.1 g (83%) of S-(4-formyl-2,6-dimethoxyphenyl)-N,N-dimethyl-thiocarbamate were obtained,

m.p. 183 - 186°C.

l

This compound was converted into 3,5-dimethoxy-4-mercapto-benzaldehyde by basic hydrolysis.

In an analogous manner, 0-(4-formyl-2-methoxy-phenyl)-N,N-dimethyl-thiocarbamate, m.p. 114 - 115<0>C, prepared from vanillin, which could be converted with a yield of 83% into S-(4-formyl-2-methoxyphenyl)-N,N-dimethyl-thiocarbamate, m.p.

109 - 110°C and finally hydrolyzed to 4-mercapto-3-methoxybenzaldehyde.

Example 19

A suspension of 1.6 g of 2,4-diamino-5-[4-(N,N-dimethylcarbamoylthio)-3,5-dimethoxybenzyl]-pyrimidine in 25 ml of methanol and 25 ml of 3N caustic soda was heated for 16 hours under an argon atmosphere and reflux, whereby a clear solution occurred. The crystalline precipitate which falls out on cooling was filtered off and dissolved in 20 ml of water and 10 ml of methanol. The solution was mixed with 500 g of sodium borohydride, allowed to stand for 1 hour, then acidified with 3N hydrochloric acid to pH 3 and the crystals that formed were filtered off and dried under high vacuum. 0.8 g (62%) of 2,4-diamino-5-(4-mercapto-3,5-dimethoxybenzyl)pyrimidine hydrochloride was obtained, m.p. 275 - 277°C.

Example 20

A solution of 20.7 g of sodium in 250 ml of methanol was mixed

with 86 g of guanidine hydrochloride. After filtration, the solution was in the course of 30 min. dripped into a solution of 98 g of freshly prepared 3,5-dimethoxy-4-(methylthio)-α-(2-methoxy-ethoxymethylene)-hydrocinnamic acid nitrile in 250 ml of ethylene glycol monomethyl ether at 95°C, whereby the methanol was constantly distilled off. The temperature was increased for 1 hour to 120°C and during this time 200 ml of solvent were distilled off under reduced pressure. The reaction mixture was then

cooled to 0°C and mixed with 400..ml of water. The crystalline precipitate was filtered off and successively washed with water, ethanol and ether. Yield: 59 g of colorless 2,4-diamino-5-[3,5-dimethoxy-4-(methylthio)-benzyl]-pyrimidine, m.p.

219 - 223°C.

in

Starting material was easily prepared as follows:

A solution of 3.5 g of sodium in 500 ml of anhydrous ethylene glycol monomethyl ether was added dropwise to 71 g of (3-methoxy-ethoxypropionitrile. The solution was heated to 90°C and mixed portionwise with 106 g of 3,5-dimethoxy- 4-(methylthio)-benzaldehyde. The reaction mixture was heated to 125°C, whereby 50 ml of solvent distilled off. The remainder of the solvent was removed under reduced pressure at 65°C, the residue taken up in ethylene chloride and washed three times with each time 300 ml of water. The aqueous phases were again extracted twice with 300 ml of ethylene chloride, the combined organic phases were dried over sodium sulfate and evaporated to dryness. The dark oil obtained (155 g) was distilled under high vacuum at 200°C to give 98 g (60%) 3 ,5-dimethoxy-4-(methylthio)-α-(2-methoxy-ethoxymethylene)-hydrocinnamic acid nitrile in the form of a viscous yellow oil which was immediately reacted further.

Example 21

A solution of 5.3 g of 3,5-dimethoxy-4-(methylthio)-benzaldehyde and 3.1 g of (3-imidazolylpropionitrile in 50 ml of ethanol was mixed with 1.35 g of sodium methylate and then heated for 5 hours under reflux. The to the brown solution was added a suspension of 4.8 g of guanidine hydrochloride and 2.7 g of sodium methylate in 50 ml of ethanol. The ethanol was distilled off and the residue was further stirred for 90 min at 100° C. The reaction mixture was slurried in water and filtered, the filtrate evaporated and the residue recrystallized from ethanol/ether 3.6 g (48%) of 2,4-diamino-5-[3,5-dimethoxy-4-(methylthio)-benzyl]-pyrimidine were obtained, mp 224 - 227°C, in the form of pale yellow crystals.

Example 22

A solution of 1.6 g of 2,4-diamino-5-[4-(ethylthio)-3,5-dimethoxy-benzyl]-pyrimidine in 30 ml of acetic acid was mixed with 0.6 g of hydrogen peroxide (30%) and stirred 4 hours at room temperature.

The mixture was then poured onto ice, brought to pH 10 with conc.

In ammonia solution and the precipitated crystals were filtered off.

After recrystallization from methanol/ether, 1.45 g (86%) of 2,4-diamino-5-[4-(ethylsulfinyl)-3,5-dimethoxybenzyl]-pyrimidine were obtained in the form of colorless needles, m.p. 256 - 258°C (decomposition) .

Example 23

A solution of 5.82 g of 2,4-diamino-5-[3,5-dimethoxy-4-(methylthio)-benzyl]-pyrimidine in 130 ml of glacial acetic acid was mixed at room temperature with 2.1 ml of 30% hydrogen peroxide . The mixture was stirred for 7 hours at room temperature. 70 ml of this solution was poured in approx. 70 g of ice. It was made alkaline with conc. ammonia under dressing, filtered, the residue was dissolved in a little conc. ammonia, triturated with vinegar after decantation, filtered and dried. 1.25 g of crude 2,4-diamino-5-[4-methoxy-3-methylsulfinyl-5-methylthio-benzylj-pyrimidine were obtained, while extraction with acetic acid from the ammoniacal filtrate and evaporation to dryness yielded 0.4 g pure product, m.p. 215 - 217°C.

The second part of the reaction mixture was mixed with an additional 0.6 ml of 30% hydrogen peroxide and stirred overnight

above at room temperature. After analogous work-up and recrystallization from ethanol, 300 mg of 2,4-diamino-5-[4-methoxy-3, 5-bis-(methylsulfinyl)-benzyl]-pyrimidine was obtained, m.p.

178 - 180°C.

Example 2 4

A suspension of sodium mercaptide prepared from 10 g of a 55% sodium hydride dispersion (in mineral oil) in 200 ml of dimethylformamide and 11 g of methyl mercaptan in 50 ml of dimethylformamide was added at room temperature under nitrogen purging to 36 g of 2,4-diamino-5-[3, 5-dimethoxy-4-(dimethylcarbamoylthio)-benzyl]-pyrimidine. The mixture was stirred for 3 hours at 55°C. Bromoacetic ester (24.5 ml) was then added dropwise at 15 - 25°C and stirred for 1 hour further at room temperature. The solution was evaporated under high vacuum, the residue taken up with 1 N HCl, the solution washed with ether, made alkaline by the addition of 1 N NaOH under ice cooling to pH 8, filtered and the residue washed well with water and dried. Yield: 32 g (84.6%) of 2,4-diamino-5-[4-(carbethoxymethylthio)-3,5-dimethoxybenzyl]-pyrimidine,

m.p. 156 - 161°C.

Example 2 5

A mixture of 9.5 g of 2,4-diamino-5-[4-(carbethoxymethylthio)-3,5-dimethoxybenzyl]-pyrimidine, 75 ml of ethanol, 50 ml of water and 27.5 ml of 1 N NaOH was stirred for 2 hours . After filtration, the ethanol was distilled off under reduced pressure, the residue neutralized by adding 27.5 ml of 1 N HCl, filtered, washed with water and dried. 7 g of 2,4-diamino-5-[4-(carboxymethyl-thio)-3,5-dimethoxybenzyl]-pyrimidine were obtained, m.p. 280°C (decomposition).

Example 26

A solution of sodium mercaptide prepared from 1 g of 55% sodium hydride dispersion (in mineral oil) in 20 ml of dimethylformamide and 1.1 g of methyl mercaptan in 5 ml of dimethylformamide was added at room temperature under nitrogen purging to 3.6 g of 2,4-diamino-5 -[3,5-dimethoxy-4-(dimethylcarbamoylthio)-benzyl]-pyrimidine. The mixture was stirred for 2 hours at 55°C. Then, at 15 - 25°C, 5-bromovaleronitrile (2.5 ml) was added dropwise and the mixture was stirred for a further hour at room temperature. The solution was evaporated in high vacuum, the residue triturated with ether, filtered, slurried in water and filtered again. After recrystallization from methanol twice, one obtained

1.9 g of 2,4-diamino-5-[4-(4-cyanobutylthio)-3,5-dimethoxybenzyl]-pyrimidine, m.p. 186 - 188°C.

Example 2 7

A suspension of sodium mercaptide prepared from 1.44 g

55% sodium hydride dispersion (in mineral oil) in 30 ml of dimethylformamide and 1.94 ml (1.58 g) of methylmercaptan in 7.5 ml of dimethylformamide was added to 5.45 g of 2,4-diamino-5-[3, 5-dimethoxy-4-(dimethylcarbamoylthio)-benzyl]-pyrimidine. The mixture was stirred for 1 hour at 55°C and then mixed at 20°C with 4.57 g of 1-(2-chloroethoxy)-2-methoxyethane. After 10 min. at room temperature was worked up in the usual way and after recrystallization

lization from methanol gave a thin-layer chromatographic unit- |

lig 2,4-diamino-5-[3,5-dimethoxy-4-£2-(2-methoxyethoxy)-ethylthioj-benzylj-pyrimidine, m.p. 161 - 162°C.

Example 28

A mixture of 3.6 g of 2-(2-chloroethoxy)-2'-methoxydiethyl ether, 3.1 g of sodium 4-[(2,4-diamino-5-pyrimidinyl)-methyl]-2,6-dimethoxyphenylthiolate and 30 ml of dimethylformamide was stirred for 2 hours at 80°C, filtered and the filtrate evaporated to dryness. The residue was triturated with ether, filtered, washed with water and dried. The crude product obtained (3.5 g) was purified after column chromatography on silica gel with methanol/propanol/NH^OH (5:5:0.5, v/v/v) and gave 1.8 g of pure 2,4-diamino -5-{3,5-dimethoxy-4-[2-C2-(methoxyethoxy)-ethoxy3-ethylthio]-benzyl}-pyrimidine, m.p. 130 - 131°C.

Example 29

Tablets with the following composition were prepared:

The mixture was granulated wet with the addition of water and pressed into tablets.

Claims (1)

1. Procedure for the preparation of 2,4-diamino-5-benzyl pyrimidines with the general formula 1 2 in which R is hydrogen or C 1 -g-alkyl/ R is hydrogen, R <3> mercapto, C1 _6~ alkylthio, carboxy-C-^^ -alkylthio, C^ _g- alkoxy-C^ _g-alkylthio, dimethylcarbamoylthio, -S(0)R'' or -SC^ R' and R4 C1_4-alkylthio, -S(0)R' or -SO„R' or R 1 hydrogen, R 2 and R 4 C1_5 -alkylthio, -S (0)R' or -S02 R' and R <3> C1_g-Alkoxy, mercapto, C1-3-alkylthio, carboxy-C1_6-alkylthio, dimethylcarbamoylthio, -S(0)R' -S00 R' or -NR"R" <1> or .'R 1 hydrogen, R 2 C₁₆-alkyl-thio, R <₃> mercapto, C₁ _6~ alkylthio, carboxy-C₁₁ -alkylthio, C₁ _₂-alkyl-C₁₁-alkyl-thio, dimethylcarbamoylthio, -S( O)R' or -SOz-R' and R C 1 -6 -alkylthio, -S(O)R' or -SC^ R' or .'R1 hydrogen, R2 halogen, R <3> C1 _6 -alkylthio, -S(O)R' or -SO„R" and R4 C, .-alkylthio, -S(O)R' or -S 02 R' or R hydrogen, R halogen or C 1_ 6~ alkoxy, R 3 mercapto,^ -alkylthio, carboxy-C^ _6 -alkylthio, carbaloxy-C^ _g-alkylthio, cyano-C1 _g-alkylthio, C1 _6 -Alkoxy-C1 _g-alkylthio, C1 _6~ Alkoxy-C1 _g-Alkoxy-C1 _6~ Alkylthio, Dimethylcarbamoylthio, -S(0)R' or -SC^R <1> and R4 halogen or C1_Q-Alkoxy, R' C1_G-Alkyl, R" and R"' independently of each other hydrogen or C1_G-Alkyl or together I C2_g-alkylene (optionally with 1-3 double bonds) I and physiologically tolerable salts thereof, characterized in that one(a) condenses a compound of formula 12 3 4 where R , R , R and R have the meanings mentioned above, Z is a group -C(CN) = CH-Y or -CH(CN)CH(OR 5 ) 9 , 5 Y a leaving group and R C 1 -g -alkyl, 2-C 1 -g -alkyloxy-ethyl, 2-phenoxy-ethyl or 2-benzyloxy-ethyl or both residues R 5 together are C 1 -g-alkylene, with guanidine or a guanidine salt or (b) reductively eliminates the substituent X from a compound with formula 12 3 4 where X is halogen and R, R, R and R have the aforementioned meanings, or (c) in the preparation of a compound of formula I-1 reacts a substituted benzyl pyrimidine of formula where R is C 1 -C 6 -Alkoxy (preferably methoxy), benzyloxy, hydroxy or halogen, with a compound of formula let 3a 4a where R , R , and R have the aforementioned meanings, or that one (d) modifies a compound of formula I within the framework of commonly known methods on the substituents R 2 , R 3 and/or 4 R and, if desired, converts the resulting compound into a physiologically tolerable salt. 2. Procedure for the preparation of 2,4-diamino-5-benzyl pyrimidines with the general formula 1 2 3 where R is hydrogen or C 1 -g-alkyl, R hydrogen, R mercapto, C 1 -g -alkylthio, carboxy-C 1 -g -alkylthio, C 1 -g -alkyl-C 1 -g -alkylthio, dimethylcarbamoylthio, -S(0)R' or -SO 2 R' and R 4 C 1 -alkylthio, -S(0)R ' or -S00R' or R 1 hydrogen, R 2 and R C, 1-alkylthio, -S(O)R' or -S 02 R' and R 3 C^_g-Alkoxy, mercapto, C^_g- <a> alkylthio, carboxy-C^_g-alkylthio, dimethylcarbamoylthio, -S(0)R' -S09R' or -NR"R"' or 1 2 3 R hydrogen, R C 1 -C 6 -alkylthio, R mercapto, C 1 -C 6 -alkylthio, carboxy-C 6 -C 6 -alkylthio, C 6 -C 6 -C 6 -alkylthio, dimethylcarbamoylthio, -S(O)R' or -S00R ' and R C, .-alkylthio, -S(O)R' or -SO R' or R 1 hydrogen, R 2 halogen, R 3C, fi-alkylthio, -S(0)R' 4 or -S02 R' and R C1-6-alkylthio, -S(0)R' or -S02Rr or R hydrogen, R halogen or C1-6-alkylthio, R3 mercapto-C1-6-alkylthio, carboxy-C1-6-alkylthio , C 1 -C 4 -Alkoxy-C 4 -C 4 -Alkylthio, Dimethylcarbamoylthio, -S(0)R' or -SO2 R' and R4 halogen or C1_6~ alkoxy, R' C^_g-alkyl, R" and R"' independently of each other hydrogen or C^_g-alkyl or together C2_g-alkylene (optionally with 1-3 double bonds) and of their physiologically tolerable salts, characterized in that one(a) condenses a compound with the formula 12 3 4 where R , R , R and R have the meanings mentioned above, Z a group -C(CN) = CH-Y or -CH (CN) CH (OR5) 2 ' , Y a leaving group and R 5 C, C 1 -alkyl or both the radicals R 5 together are C 1 -g alkylene, j with guanidine or a guanidine salt or| (b) reductively eliminates the substituent X from a compound of the formula 12 3 4 where X is halogen and R, R, R and R have the aforementioned meanings, or (c) in the preparation of a compound of formula I-1 reacts a substituted benzyl pyrimidine with the formula where R is C 1 -6 -Alkoxy (preferably methoxy), benzyloxy, hydroxy or halogen, with a connection with the formula In which R la , R 3a and R 4a have the preceding meanings, l - or that one ..J (d) modifies a compound of formula I within the framework of widely known methods on the substituents R 2 , R 3 and/or R 4 and transfers, if desired, the resulting compound in a physiologically tolerable salt. 3. Method according to claim 1, characterized in that a compound with formula is prepared 'where R<la> means hydrogen or C1-6-alkyl, R<3a> mercapto, C1_g-alkylthio, carboxy-C-1_g-alkylthio, C1_g-alkoxy-C1_g-alkylthio, dimethylcarbamoylthio, -S(O)R' or -SC^ R' and R <4a> C1_6 -alkylthio, -S(O)R' or -SC^R", '... or a physiologically tolerable salt thereof. 4. Method according to claim 1, characterized in that a compound with the formula is prepared where R<2a> means C1_6 -alkylthio, -S(O)R' or -SC^R', R <2> mercapto, C₁₋₋-alkylthio, carboxy-C₋₋₋-alkylthio, C₋₋₋-alkylthio/dimethylcarbamoylthio, -S(O)R' or -SC^R' and R<4a> C1_6 -alkylthio, -S(O)R' or -SC^ R', or a physiologically tolerable salt thereof. 5. Method according to claim 1, characterized in that a compound with the formula is prepared 21) where, R means C1-6-Alkoxy, R<3a> mercapto, ^-alkylthio, carboxy-C-^ g-alkylthio, C1 _g- alkoxy-C^ _g-alkylthio, dimethylcarbamoylthio, -S(O)R' or -SC^ R' and R <4a> C1_6 -alkylthio, -S(O)R' or -SO2 R', or a physiologically tolerable salt thereof. 6. Method according to claim 1, characterized in that a compound with formula is prepared 2 Id where R means C 1 -C 6 - alkoxy R<3a> mercapto, C^_g-alkylthio, carboxy-C^__g-alkylthio, C^_g-alkoxy-C^_g-alkylthio/ dimethylcarbamoylthio, -S(0)R' or -S00 R' and 4b R halogen or C 1-6 alkoxy, or a physiologically tolerable salt thereof. 7. Method according to claim 1, characterized in that a compound with the formula is prepared 2d. where R means halogen or 3-alkyloxy, R <3d> mercapto, C1_g-alkylthio, carboxy-C1_g-alkylthio, caralkyloxy-C1_g-alkylthio, cyano-C1_g-alkylthio, C1_6-alkoxy-C1_g-alkylthio/ C1_g-alkylthio -C1-6-Alkoxy-C1-6-Alkylthio, Dimethylcarbamoylthio, -S(O)R' or -S09 R' and 4b R halogen or C^_^-Alkoxy, or a physiologically tolerable salt thereof. 8. Method according to claim 2, characterized in that a compound with the formula is prepared 2 cl where R means halogen or γ-alkyloxy, R<3a> mercapto, C₁ _g-alkylthio, carboxy-C₁₂ -alkylthio, C₁ _₂-alkoxy-C₁ _₂-alkylthio, dimethylcarbamoylthio, -S(0)R' or -S00 R' and 4b R halogen or C 1-6 -alkyloxy, or a physiologically tolerable salt thereof. 9. Process for the production of pharmaceutical preparations, characterized by mixing a 2,4-diamino-5-benzylpyrimidine with formula I 1 2 where R is hydrogen or C, 1-6 alkyl, R is hydrogen, R 3 mercapto, C 1 g -alkylthio, carboxy-C 1 -g -alkylthio, C 1 -g -alkylthio, C 1 -g -alkylthio, dimethylcarbamoylthio, -S(O)R' or -SC^ R" and R<4> C1_4 -alkylthio, -S(O)R' or -SO9 R' or 1 2 4 R hydrogen, R and R C 1 -6 -alkylthio, -S(O)R' or -SO2 R' and R<3> C-L_6 -Alkoxy, mercapto, C1_& -alkylthio, carboxy-C^_6 -alkylthio, dimethylcarbamoylthio, -S(0)R' -SO„R' or -NR"R"1 or 12 3 R hydrogen, R C^ _6~ alkoxy, R mercapto., c1 _5~ alkylthio, carboxy-C1 _g-alkylthio, C1 _g-alkoxy-C1 _g-alkylthio, dimethylcarbamoylthio, -S(0)R' or -S09 R' 4 z and R C, .-alkylthio, -S(O)R' or -SOo R' or 1 1-6 2 3 R hydrogen, R halogen, R C1_6 -alkylthio, -S(0)R' or -S0o R' and R<4> C, .-alkylthio, -S(O)R' or12 -SC^ R' or R hydrogen, R halogen or C2.-6~ alkoxy, R3 mercapto, C-^6-alkylthio, carboxy-C1_6 -alkylthio, carbolicoxy-C^_6-alkylthio, cyano-C1_6-1 alkylthio . ^_g-Alkoxy, R' C^_g-alkyl, R" and R"' independently of each other hydrogen or C^_g-alkyl or together are C2_g-alkylene (optionally with 1-3 double bonds), or a physiologically tolerable salt thereof, as active ingredient, with suitable for therapeutic administration, non-toxic, inert, per se usual in such preparations, solid or liquid carriers and brings the resulting mixture into a suitable galenic form. 10. Process for the production of pharmaceutical preparations, characterized by mixing a 2,4-diamino-5-benzylpyrimidine with formula I 1 2 where R is hydrogen or C1-6-alkyl, R hydrogen, R3 mercapto, C1-6-alkylthio, carboxy-C16-alkylthio, C16-6-alkylthio, dimethylcarbamoylthio, -S(0)R' or -SO2 R' and R <4> C1_4 -alkylthio, -S(0)R' or -SO9 R' or 12 4 R hydrogen, R and R C,_6 -alkylthio, -S(O)R' or 3 -LO -SO2 R' and R C₁₋₋-Alkoxy, mercapto, C₁₋₋-alkylthio, carboxy-C₋₋₋ -alkylthio, dimethylcarbamoylthio, -S(O)R', - S00R' or -NR"R" <1> or R <1> hydrogen, R <2> C1^ -Alkoxy, R <3> mercapto, C1 _g~ alkylthio, carboxy-C1 _g-alkylthio, C^g-Alkoxy-C^g-alkylthio, dimethylcarbamoylthio, -S( 0)R' or -SO2 R' and R4 ci_ q-alkylthio, -S(0)R' or -SO2 R' or 12 3 R hydrogen, R halogen, R C, .--alkylthio, -S(0)R ' or -SO 2 R' and R C 1 -6 -alkylthio, -S(0)R' or -SO 2 R' or R <1> hydrogen, R halogen or C 1 -6 -alkylthio, R <3> mercapto, C 1 -6 -alkylthio , carboxy-C1 _g-alkylthio, car- carboxy-C^ _g-alkylthio, cyano-C^_g-alkylthio, C2-6~ alkoxy-C^ _g-alkylthio, C^ _g- alkoxy-C^ _g-alkyl-C^ _g-alkyl4 thio, dimethylcarbamoylthio, -S(0)R' or -SO9 R' and R halogen or C1 _& -alkyl, R<1> C^ _g-alkyl, R" andR" <1> independently of each other hydrogen or C 1 -g-alkyl or is together C 2 -g-alkylene (optionally with 1-3 double bonds) or a physiologically tolerable salt thereof and an antibacterially active sulfonamide as active ingredients with suitable, non-toxic, inert, in and of themselves in such preparations, solid or liquid carriers suitable for therapeutic administration and brings the resulting mixture into a suitable galenic form. 11. Pharmaceutical preparations, characterized by a content of a 2,4-diamino-5-benzylpyrimidine of formula I 1 2 where R is hydrogen or ^-alkyl, R is hydrogen, R <3> mercapto, C-^^-alkylthio, carboxy-C-^g-alkylthio, C^ _g- alkoxy-C^ _g-alkylthio, dimethylcarbamoylthio, -S(0)R' or -SC^R' and R <4> C1_4 -alkylthio, -S(0)R' or -SO„R' or 1 2 4 R hydrogen, R and R C 1 -6 -alkylthio, -S(O)R' or -SO2 R' and R3 C1_g-Alkoxy, mercapto, C1_g-alkylthio, i carboxy-C1_g-alkylthio, dimethylcarbamoylthio, -S(0)R' -SO»R' or -NR"R"1 or 1 2 3 R hydrogen, R C₁₋₋-alkylthio, R mercapto, C₁₋₋-alkylthio, carboxy-C₁₋₋-alkylthio, C₋₋₋-alkylthio, C₁₋₋₋-alkylthio, dimethylcarbamoylthio, -S(O)R' or -SC ^ R' and R 4 c^_ q-alkylthio, -S(O)R' or -SO-R' or R 1 hydrogen, R 2 halogen, R 3 C-1 g-alkylthio, -S(O)R' or -S02 R' and R<4> C1_6 -alkylthio, -S(0)R' or -S02 R' or R"*" hydrogen, R2 halogen or C1_g- alkoxy, R <3> mercapto, C^ _g-alkylthio, carboxy-C^ _g-alkylthio, carbalkoxy-C^ _g-alkylthio, cyano-C^ _g-alkylthio,.C^ _Q -alkoxy-C^ _g-alkylthio, C ^_g-Alkoxy-C^_6 -Alkoxy-C.]L_g-Alkylthio, Dimethylcarbamoylthio, -S(O)R' or -S09 R' and R 4 Halogen or C1_6 -Alkoxy, R <1> C1_& -Alkyl , R" and R" 1 are independently hydrogen or C 1 -g-alkyl or together are C 2 -g-alkylene (optionally with 1-3 double bonds) or a physiologically tolerable salt thereof and a non-toxic, inert, solid or liquid carrier suitable for therapeutic administration. 12. Pharmaceutical preparations, characterized by a content of a 2,4-diamino-5-benzylpyrimidine with formula I 1 2 where R is hydrogen or C^_6~ alkyl, R is hydrogen, R <3> mercapto, C1_g-alkylthio, carboxy-C-^g-alkylthio, C1_g- alkoxy-C1g-alkylthio, dimethylcarbamoylthio, -S(O)R' or -SC^ R' and R 4 C 1 -alkylthio, -S(O)R' or -SO2R' or R 1 hydrogen, R 2 and R 4 C-^g-alkylthio, -S(O)R' or -SO2 R' and R <3> C1_6 -Alkoxy, mercapto, C1_6 -alkylthio, carboxy-C1_6 -alkylthio, dimethylcarbamoylthio, -S(0)R' -S09R' or -NR"R"1 or 1 2 3 R hydrogen, R C 1 -C 6 -alkylthio, R mercapto, C 1 -C 6 -alkylthio, carboxy-C 1 -C 6 -alkylthio, C-C 6 -C 6 -alkylthio, dimethylcarbamoylthio, -S(O)R' or -SC ^ R' and R4 c1 _6~ alkylthio, -S(O)R' or -SO9 R' or R 1 hydrogen, R halogen, R C 1 -6 -alkylthio, -S(O)R' or -SC^ R' and R <4> C^ _g -alkylthio, -S(O)R' or -SC^ R' or R <1> hydrogen, R halogen or C 1-6 alkoxy, R <3> mercapto, C -C -alkylthio, carboxy -C -C -alkylthio, carbolic -C -C -alkylthio, cyano -C -C -alkylthio, -C -C -alkylthio, C -C -alkylthio, C -C -alkyl C1_6 -Alkoxy-C1_6 -Alkylthio, Dimethylcarbamoylthio, -S(0)R' or -SO^ R <1> 4 and R halogen or C1_6 -Alkoxy, R' C1_6 -Alkyl, R" and R" 1 independently of each other is hydrogen or C] __g-alkyl or together is C2 __g-alkylene (possibly with 1-3 double bonds), or a physiologically tolerable salt thereof and an antibacterially active sulfonamide, as well as a non-toxic, inert, solid or liquid carrier suitable for therapeutic administration. 13. 2,4-diamino-5-benzylpyrimidines of the general formula characterized by that 1 2 R is hydrogen or C, >-alkyl, R is hydrogen, R 3 mercapto, C 1 -g -alkylthio, carboxy-C 1 -g -alkylthio, C 1 -g -alkyl-C 1 -g -alkylthio, dimethylcarbamoylthio, -S(0)R' or -SO2 R' and R4 C1-4-alkylthio, -S(0)R' or -SO„R' or R 1 hydrogen, R 2 and R 4 C, fi-alkylthio, -S(O)R' or -S02 R' and R 3 C₁₋₋-Alkoxy, mercapto, C₋₋₋-alkylthio, carboxy-C₋₋₋-alkylthio, dimethylcarbamoylthio, -S(O)R' -SO R' or -NR"R"1 or 1 2 3 R hydrogen, R C₁₋₋-alkylthio, R mercapto, C₁₋₋-alkylthio, carboxy-C₁₋₋-alkylthio, C₋₋₋-alkylthio, C₁₋₋-g-alkylthio, dimethylcarbamoylthio, -S(O)R' or -SO 2 R' and R 4 c±_ £-alkylthio, -S(O)R' or -SOo R' or R 1 hydrogen, R 2 halogen, R 3 C, .-alkylthio, -S(O)R' or -SO 2 R' and R C1_g-alkylthio, -S(0)R" or -SO^1 or R hydrogen, R halogen or C1_g-alkylthio, R <3> mercapto, c1_g-alkylthio, carboxy-C1_g- alkylthio, caralkyloxy-C 1 _g-alkylthio, cyano-C 1 _g-alkylthio, cj _g-alkoxy-C 1 _6 -alkylthio, C 1 _6 -alkyl-C 1 _6 -alkylthio, fi-alkylthio, dimethylcarbamoylthio, -S( 0)R' or i-o 4 -SO2 R' and R halogen or C-1 g-alkyl, R<1> c1-g-alkyl, R" and R"1 independently of each other hydrogen or g-alkyl or together C2-g-alkylene (optionally with 1-3 double bonds) and their physiologically tolerable salts. 14. 2,4-diamino-5-benzylpyrimidines of the general formula characterized by that 1 2 R is hydrogen or C, 1-alkyl, R hydrogen, R 3mercapto, C 1 -g-alkylthio, carboxy-C 1 -g-alkylthio,, C 1 -g-alkoxy-C 1 -g-alkylthio, dimethylcarbamoylthio, -S(0)R' or -SC^ R' and R<4> C]L_4 -alkylthio, -S(0)R' or -SO„R' or R 1 hydrogen, R 2 and R <4.> C 1 _& -alkylthio, -S(O)R' or -SC^ R <1> and R <3> C^_g-Alkoxy, mercapto, C^_g-alkylthio, carboxy-C^_g-alkylthio, dimethylcarbamoylthio, -S(0)R' -S09R' or -NR"R"' or 1 2 3 R hydrogen, R C 1 -6 -alkylthio, R mercapto, C 1 -6 -alkylthio, carboxy-C 1 -6 -alkylthio, C 1 -6 -alkoxy-C 1 -6 -alkylthio, dimethylcarbamoylthio, -S(O)R' or. -SC^R' and R4 alkylthio, -S(O)R' or -SO- R' or R 1 hydrogen, R 2 halogen, R 3 C 1 _6 -alkylthio, -S(0)R' or -SC^R 1 and R 4 C 3 -alkylthio, -S(0)R' or -SO 2 R' all R 1 hydrogen, R halogen or C 1 -C 6 -alkyl, R 3 mercapto, C 1 -C 6 -alkylthio, carboxy-C 6 -C 6 -alkylthio, C 6 -C 6 - alkoxy -C 6 -C 6 -alkylthio, dimethylcarbamoylthio, -S(O)R' or -SC^ R' and R 4 halogen or C 1 -g alkoxy, R' C1_6 -alkyl, R" and R"1 independently of each other hydrogen or C1_g-alkyl or together are C2_6 -alkylene (possibly with 1-3 double bonds), and their physiologically tolerable salts. 15. 2,4-diamino-5-benzylpyrimidines of the general formula characterized by that R"'"3 is hydrogen or C 1-6 alkyl, 3 3 R mercapto, C1 -g-alkylthio, carboxy-C1 -g-alkylthio, C 1 -C 6 -Alkoxy-C 1 -C 6 -Alkylthio, Dimethylcarbamoylthio, -S(0)R' or -SC^ R- and R 4a C 1 -6 -alkylthio, -S(O)R' or -SC^ R', and their physiologically tolerable salts. 16. 2,4-diamino-5-benzylpyrimidines of the general formula characterized by that R<2a> means C^-alkylthio, -S(0)R' or -SC^ R', R <3a> mercapto, C 1 -g-alkylthio, carboxy-C 1 -g-alkylthio, C1-6-Alkoxy-C1-6-Alkylthio, Dimethylcarbamoylthio, -S(O)R' or -SC^ R' and R 4a C 1 -6 -alkylthio, -S(O)R' or -SC^ R', and their physiologically tolerable salts. 17. 2,4-diamino-5-benzylpyrimidines of the general formula characterized by that R means C 1 -C 6 - alkoxy R <3a> mercapto, g-alkylthio, carboxy-C 3 -g-alkylthio, C1-6-Alkoxy-C1-6-Alkylthio, Dimethylcarbamoylthio, -S(0)R' or -S00R' and 4a R C 1 -C 6 -Alkoxy, and their physiologically tolerable salts. 18. 2,4-diamino-5-benzylpyrimidines of the general formula characterized by that 2c R stands for halogen, R3c C1-6-alkylthio, -S(0)R' or -SC^R' and R4a C1-6-alkylthio, -S(0)R' or -SC^R', and their physiologically tolerable salts. 19. 2,4-diamino-5-benzylpyrimidines of the general formula characterized by that R means halogen or C, C, C, C, C, R 3 clmercapto, C 1 -alkylthio, carboxy-C 1 -alkyl thio, carbalkoxy-C^_g-alkylthio, cyano-C^_g-alkylthio, C^_g-alkoxy-C^^^-alkylthio, C^_^-alkoxy-C^_g-alkyl-C^_g-alkylthio, dimethylcarbamoylthio , -S(0)R' or -SO„R' and 4b R halogen or C 1 -C 6 -alkyloxy, and their physiologically tolerable salts. 20. 2,4-diamino-5-benzylpyrimidines of the general formula characterized by that R 2ci means halogen or C 1 -C 6 -alkyloxy, R<3a> mercapto, C1-6-alkylthio, carboxy-C1-6-alkyl thio, C 1 -C 6 -Alkoxy-C 1 -C 6 -Alkylthio, dimethylcarbamoylthio, -S(O)R' or -S0„R' and 4b R halogen or C 1 -C 6 -alkyloxy, and their physiologically tolerable salts. 21. 2,4-diamino-5-[3,5-dimethoxy-4-(methylthio)-benzyl]-pyrimidine. 22. 2,4-Diamino-5-[4-(ethylthio)-3,5-dimethoxy-benzyl]-pyrimidine. 23. 2,4-diamino-5-[3,5-dimethoxy-4-(2-methoxy-ethylthio)-benzyl]-pyrimidine. 24. 2,4-diamino-5-(3,5-dimethoxy-4-pyrrolebenzyl)-pyrimidine. 25. 2,4-Diamino-5-[2-methyl-4,5-bis-(methylthio)-benzyl]-pyrimidine. 26. 2,4-Diamino-5-[4,5-bis-(methylthio)-benzyl]-pyrimidine. 27. 2,4-diamino-5-(5-bromo-4-methoxy-3-methylthiobenzyl]-.pyrimidine. 28. 2,4-Diamino-5-[4-methoxy-3,5-bis-(methylthio)-benzyl]-pyrimidine. 29. 2,4-diamino-5-(3-bromo-4-methylthio-benzyl)-pyrimidine. 30. 2,4-diamino-5-[3/4,5-tris-(methylthio)-benzyl]-pyrimidine. 31. 2,4-diamino-5-(4-methylthiobenzyl)-pyrimidine. 32. 2,4-diamino-5-[3-bromo-4/5-bis-(methylthio)-benzyl]-pyrimidine. 33. 2,4-diamino-5-[3,5-dimethoxy-4-(methylsulfinyl)-benzyl]-pyrimidine. 34. 2,4-diamino-5-[3,5-dimethoxy-4-(methylsulfonyl)-benzyl]-pyrimidine. 35. 2,4-Diamino-5-(4-mercapto-3,5-dimethoxybenzyl)-pyrimidine hydrochloride. 36. 2, 4-diamino-5-benzyl-6-halopyrimidine of the general formula characterized by that 1 2 R is hydrogen or C^_g-alkyl, R hydrogen, R3 mercapto, C^_g-alkylthio, carboxy-C^_g-alkylthio, g-alkoxy-C^_g-alkylthio, dimethylcarbamoylthio, -S(O)R' or -SC^ R' and R 4 C 1-4 -alkylthio, -S(O)R' or -SO 2 R' or R <1> hydrogen, R <2> and R <4> C,_& -alkylthio, -S(O)R' or 3 -Lo -SO2 R' and R C1_6 -Alkoxy, mercapto, C1_6-alkylthio, carboxy-C1_6 -alkylthio, dimethylcarbamoylthio, -S(0)R' -S09 R' or -NR"R"' or 12 3 R hydrogen, R C 1 -6 -alkylthio, R mercapto, C 1 -6 -alkylthio, carboxy-C 1 -6 -alkylthio, C 1 -6 -alkoxy-C. ^.-alkylthio, dimethylcarbamoylthio, -S(O)R' or -SO 2 R' and R C 1 -6 -alkylthio, -S(O)R' or -SC^ R' or R 1 hydrogen, R 2 halogen, R 3 C, .--alkylthio, -S(0)R' 4 1-13 or -SO^ R' and R C. fi-alkylthio, -S(0)R" or 1 2 -S02R' or R hydrogen, R halogen or C1-5~ alkoxy, R <3> mercapto, C^^-alkylthio, carboxy-C^_g-alkylthio, caralkyloxy-C^_g-alkylthio, cyano-C^_g-alkylthio , C₁ _g-Alkoxy-C₁ _g-alkylthio, C₁_₋-Alkoxy-C₁ _g-Alkoxy-C₁ _g-alkylthio, dimethylcarbamoylthio, -S(O)R' or -SO 2 R' and R 4 halogen or C1_g-Alkoxy, R' C^^ -alkyl, R" and R" <1> independently of each other hydrogen or C1_& -alkyl or together are C2_g-alkylene (optionally with 1-3 double bonds). 37. 2,4-diamino-5-benzyl-6-halopyrimidine with the general formula characterized by that 1 2 R is hydrogen or C^_g-alkyl, R hydrogen, R <3> mercapto, C1_6 -alkylthio, carboxy-C1_6 -alkylthio, C1_g- alkoxy-C1_6 -alkylthio, dimethylcarbamoylthio, -S(O)R' or -SC^ R' and R<4> C1_4 -alkylthio, -S(O)R' or -S00 R' or R hydrogen, R and R C 1 -6 -alkylthio, -S(O)R' or -SO2 R' and R <3> C1_6 -Alkoxy, mercapto, C1_6 -alkylthio, carboxy-C1_6 -alkylthio, dimethylcarbamoylthio, -S(0)R' -S0o R' or -NR"R" <1> or 1 2 3 R hydrogen, R C 1 _6~ alkoxy, R mercapto, c 1 _q-alkylthio, carboxy-C 1 _6~ alkylthio, C-^- alkoxy-C 1 _6 -alkylthio, dimethylcarbamoylthio, -S(0)R' or -S 02 R' and R<4> C1_6 -alkylthio, -S(O)R' or -S02 R' or R <1> hydrogen, R <2> halogen, R3 C1_6-alkylthio, -S(0)R' or -SC^ R' and R <4> C1_6 -alkylthio, -S(0)R' or -S0o R' or 12 3 R hydrogen, R halogen or C1_6~ alkoxy, R mercapto, C1_6 -alkylthio, carboxy-C1_6-ralkylthio, c^_ q- alkoxy-C^_6 -alkylthio, dimethylcarbamoylthio, -S(0)R' or -S02 R' and R<4> halogen or C1-6-alkyl, R' C1-6-alkyl, R" and R" <1> independently of each other hydrogen or C1-6-alkyl or together are C2-6~ alkylene (possibly with 1-3 double bonds) . 38. Aldehydes with the general formula characterized by that 1 2 R is hydrogen or C 1 -alkyl, R hydrogen, R 3mercapto, C 1 -alkylthio, carboxy-C 1 -alkylthio, C 1 -alkyl thio, dimethylcarbamoylthio, -S(0)R' or -SC^ R<1> and R4 C1-4-alkylthio, -S(0)R' or -SO„R' or R 1 hydrogen, R <2> and R 4 C 1_g -alkylthio, -S(O)R' or -SO2 R' and R <3> C-^_Q-Alkoxy, mercapto, C^_6 -alkylthio, carboxy-C^_6 -alkylthio, dimethylcarbamoylthio, -S(0)R' -SO„R' or —NR"R"1 or 1 2 3 R hydrogen, R 6 -alkyl, R mercapto, C 6 -alkylthio, carboxy-C 6 -alkylthio, C 6 -alkylthio, dimethylcarbamoylthio, -S(O)R' or -SO- R <1> and 4 R C, .-alkylthio, -S(0)R' or -SO9 R' or R hydrogen, R halogen, R C^g-alkylthio, -S(0)R' or -SC^R' and R <4> C ^ _6 -alkylthio, -S(0)R' or -SC^ R <1> or R^ hydrogen, R halogen or C^ _6 -alkylthio, R <3> mercapto, C-^^-alkylthio, carboxy- C₁ _g-alkylthio, caralkyloxy-C₁ _g-alkylthio, cyano-C₁ _g-alkylthio, c₁ _5~ alkoxy-C₁ _g-alkylthio, g-Alkoxy-C₁ _g-Alkoxy-C, .--alkylthio4o , dimethylcarbamoylthio, -S(O)R' or -S02 R' and R halogen or C1_g-alkyl, R' c±_q-alkyl, R" and R"' independently of each other hydrogen or C1_g-alkyl or together are C2_g-alkylene (optionally with 1- 3 double bonds), with the exception of 3,4-bis-(methylthio)-benzaldehyde. 39. Aldehydes with the general formula characterized by that 1 2 R is hydrogen or C 1 -alkyl, R hydrogen, 3 -LO R mercapto, C 1 -g -alkylthio, carboxy-C 1 -g -alkylthio, C 1 -6 -carboxy-C 1 -g -alkylthio, dimethylcarbamoylthio, -S(O)R- or -SC^ R' and R 4 C 1 -alkylthio, -S(O)R' or -SO 9 R' or R 1 hydrogen, R 2 and R 4 C-^g-alkylthio, -S(O)R' or -S02 R' and R <3> C1_g-Alkoxy, mercapto, C-^^-alkylthio, carboxy-C^_g-alkylthio, dimethylcarbamoylthio, -S(0)R' -S00 R' or -NR"R" <1> or R 1 hydrogen, R <2> C₁ _g-Alkoxy, R 3 mercapto, C₁ _g-Alkylthio, carboxy-C₁ _g-Alkylthio, C1 _g~ Alkoxy-C₁ _g-Alkylthio, dimethylcarbamoylthio, -S(0) R' or -SO2 R' and R<4> C..-alkylthio, -S(O)R' or -SO^ R' or 1 J--0 9 3 R hydrogen, R halogen, R C1_6 -alkylthio, -S(0)R' or -SC^ R' and R <4> C1_6 -alkylthio, -S(0)R' or -SO„R' or 12 3 R hydrogen, R halogen or C-1-6-alkylthio, R mercapto, 6-alkylthio, carboxy-C1-6-alkylthio, C-6-6-alkylthio, dimethylcarbamoylthio, -S(0)R' or -SC^ R<1> and R4 halogen or C1-6-6-alkyl, R' C-16-6-alkyl, R" and R"' independently of each other hydrogen or C-16-6-alkyl or is together c2 _6~ alkylene (possibly with 1-3 double bonds), with the exception of 3,4-bis-(methylthio)-benzaldehyde. 40. Aldehydes with the general formula characterized by that R"*"3 is hydrogen or C1-6-alkyl/ R<3a> mercapto, C-16-alkylthio, carboxy-C1-6-alkylthio, C1-6-Alkoxy-C1-8-alkylthio, dimethylcarbamoylthio, -S(O)R' or -SO2R' and R4a C1-6-alkylthio, -S(O)R' or -SO2R', with the exception of 3,4-bis-(methylthio)-benzaldehyde. 41. Aldehydes with the general formula characterized by that R<2a> is C1_6 -alkylthio, -S(O)R" or -SO2 R<*> , R3t) C1_g-Alkoxy, mercapto, C-^^-alkylthio, carboxy- C1_6 -alkylthio, dimethylcarbamoylthio, -S(0)R', -SO2R' or -NR"R"1 and R4a C1-6-alkylthio, -S(O)R' or -SO4'. 42. Aldehydes with the general formula characterized by that 2 Id R is C₁₋₆ alkoxy, R₃a mercapto, C₁₋₆ alkylthio, carboxy-C₁₋₆ alkylthio, C 1-6 -Alkoxy-C 1-6-Alkylthio, Dimethylcarbamoylthio, . ,-S(O)R' or -SO 2 R' and R 4a C 1-6 alkylthio, -S(O)R' or -SC^R'. 43. Aldehydes with the general formula characterized by that 2c R is halogen, R<3c> C1_5 -alkylthio, -S(O)R' or -SO2 R' and R<4a> C1_6 -alkylthio, -S(O)R' or -SC^R' . 44. Aldehydes with the general formula characterized by that 2 cl R is halogen or C 1 -C 6 -alkyloxy, 3 cl - Lo R mercapto, C1-6-alkylthio, carboxy-C1-6-alkyl thio, carbalkoxy-C 1 -g -alkylthio, C 1 -g -alkyl-C 1 -g -alkylthio, C 1 -g -alkylthio, C 1 -g -alkylthio, C 1 -g -alkylthio, dimethylcarbamoylthio, -S(O)R' or -S09R' and 4b R is halogen or C 1 -C 6 -alkyloxy. 45. Aldehydes with the general formula characterized by that 2 cl R is halogen or C 1 -C 6 -Alkoxy, R<3a> mercapto, C1-6-alkylthio, carboxy-C1-6-alkyl thio, C 1 -g -Alkoxy-C 1 -g -alkylthio, dimethylcarbamoylthio, -S(O)R' or -SO„R' and . 4b R halogen or g-alkoxy.