MC1222A1 - NEW 2,4-DIAMINO-5-BENZYLPYRIMIDINES, THEIR PREPARATION AND THEIR APPLICATION AS MEDICINAL PRODUCTS - Google Patents

Description

*

The present invention relates to 2,4-diamino-5-benzylpyrimidines of general formula

10

15

20

25

30

35

a) R represents hydrogen or an alkyl group in

2 3

R represents hydrogen, R represents a mer- group

c -c 1 6 '

capto, alkylthio in carboxyalkylthio to alkyl remainder in

C^-Cg, alkoxyalkylthio with alkoxy and alkyl residues in C1~Cg dimethyl carbamoylthio, ~S(0)R' or -SO2R1 and R^ represents an alkylthio group in C1-C(-r) -S(0)R' or -SO9R', or

1 2 4

b) R represents hydrogen, R and R represent

3

each an alkylthio group in C^-Cg, -S(O)R' or -SO2R' and R represents an alkoxy group in C^-Cg, fiercapto, alkylthio in C^-

v-g, dimethylcarbamoyl-

Or

Cg, carboxyalkylthio with alkyl residue in thio, -S(O)R1, -SO2R' or -NR"R

>r ,3

1 " 2

c) R represents hydrogen, R represents a group

1 2

d) R represents hydrogen, R represents a halogen

alkoxy in C-Cg, R" represents a mercapto group, alkylthio in C-Cg, carboxyalkylthio with an alkyl residue in C-Cg/ alkoxyalkylthio with alkoxy and alkyl residues in C-Cg, dimethylcarbamoylthio, -S(0)R( or -SO2R' and R^ represents an alkylthio group in C-Cg, -S(0)R'

or -SO2R1, or 3

ne, R represents an alkylthio group in C1~Cg, -S(0)R' or -SO2R1 and R^ represents an alkylthio group in Cj-Cgr -S(0)R' or -SO2R', or

12

e) R represents hydrogen, R represents a halogen

3

ne or an alkoxy group in C^-Cg, R represents a mercapto group, alkylthio in C^-Cg, carboxyalkylthio with an alkyl residue in C^-Cg, carbalcoxyalkylthio with an alkyl residue in C^-Cg, cyanalkylthio with an alkyl residue in C^-Cg, alkoxyalkylthio with alkoxy and alkyl residues in C^-Cg, alkoxy-alkoxy-alkylthio with alkoxy and alkyl residues in C^-Cg

2

4

dimethylcarbamoylthio, -S(0)R' or -SC^R1 and R represents a halogen or a C^-Cg alkoxy group, whereas, in all cases a) to e) above, R' represents a C^-Cg alkyl remainder, R" and R'" represent, independently of each other, hydrogen or a C^-Cg alkyl group or, together, a C^-Cg alkylene group (possibly comprising 1 to 3 double bonds), and their physiologically acceptable salts, a process for their preparation, pharmaceutical compositions based on these compounds and their preparation.

The general formula (I) includes the groups of compounds with formulas 1-1 to 1-5 below.

3

10

1-4

1-5

15

20

25

35

2b

In these formulas 1-1 to 1-5, the symbols have the following meanings:

2a

R = hydrogen or alkyl group in C^-Cg,

= alkylthio group in C^-Cg, -S(O)R' or -SO2R',

= alkoxy group in ^"Cg,

= halogen,

= halogen or alkoxy group in C-j^Cg,

= mercapto group, alkylthio at C2-Cg1 carboxyalkylthio with alkyl residue at C1-Cg, alkoxyalkylthio with alkoxy and alky- residues

R

R'

2c 2d

R3a =

R R

R

3b the in C.-Cf-, dimethylcarbamoylthio,

-S(0)R' or -S02R!,

r3°

30„3d

R =

4a 4b

= alkoxy group in C^-Cg, mercapto, alkylthio in C^-Cg, carboxyalkylthio with alkyl residue in C^-Cg, dimethylcarbamoylthio, -S(O)R', -SO2R' or -KR'^1",

= alkylthio group in C^-Cg, -S(0)R' or -SO2R1,

mercapto group, alkylthio in carboxyalkylthio with alkyl residue in C^-Cg, carbalcoxyalkylthio with alkyl residue in C^-Cg, cyanalkylthio with alkyl residue in C^-Cg, alkoxyalkylthic with alkoxy and alkyl residue in C^-Cg, alkoxyalkoxyalkylthio with alkoxy and alkyl residue in C^-Cg, dimethylcarbamoylthio, -S(O)R' or -SO2R',

= alkylthio group in C^-Cg, -S(O)R* or -SO2R' and = halogen or alkoxy group in C^-Cg.

4

10

15

The substituents R', R" and R'" have the aforementioned meanings.

Examples of C2-Cg alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, and hexyl, with methyl and ethyl groups being preferred. Examples of C2-Cg alkylene groups include ethylene, trimethylene, tetramethylene, and pentamethylene. Examples of groups derived from these, with 1 to 3 double bonds, include vinylene, propylene, 2-butenylene, 1,3-butadienylene, 1,4-pentadienylene, and 1,3,5-hexatrienylene.

As halogens that can be used as substitutes, we can mention in particular chlorine, bromine and iodine, with chlorine and bromine being preferred.

The process for preparing the compounds according to the invention is characterized in that a) a compound of formula is condensed with guanidine or one of its salts

20

■25

30

35

in which RJ

2 3 4

R, R and R have the aforementioned meanings,

5

Z represents a group -C(CN)=CH-Y or -CH(CN)CH(0R)0. Y represents

5

a starting group and R represents an alkyl group at C2~C6r, a 2-alkoxyethyl group with an alkoxy residue at C2~C6', a 2-pheno- group

xyethyl or a 2-benzyloxyethyl group or both together 5

the R remains represent an alkylene group in or b) of a compound of formula

5

III

12 3 4

in which X represents a halogen and R, R, R and R have the aforementioned meanings, the substituent X is eliminated by reduction or c) with regard to the preparation of a compound of formula 1-1, a substituted benzylpyrimidine of formula (IV) is reacted

15

20

IV

25

30

35

in which R represents an alkoxy group in (preferably-

(reacts the methoxy group), the benzyloxy group, the hydroxy group or a halogen, with a compound of formula

V

1 *1*1 o ^ ^

in which R, R and R have the aforementioned meanings, or

2 3 4

d) we modify with respect to the substituents R, R and/or R,

within the framework of generally known processes, a compound of formula I and, if desired, the compound thus obtained is transformed into a physiologically acceptable salt.

6

According to variant (a) of the process according to the invention, a compound of formula II is reacted with guanidine or a guanidine salt. The reaction can be carried out in a manner known per se, for example in an organic solvent such as a 5-alkanol (methanol, ethanol), dimethylformamide, dimethyl sulfoxide, or N-methylpyrazolone, at a temperature between 25 and 200°C, preferably between 50 and 170°C. For example, the carbonate and hydrochloride guanidine salts can be used. Examples of starting groups represented by Y 10 in Formula II are alkoxy groups, such as methoxy, ethoxy, propoxy, etc., 2-alkoxyethoxy groups with alkoxy residues such as 2-methoxyethoxy and 2-ethoxyethoxy, 2-phenoxyethoxy, 2-benzyloxyethoxy groups, alkylthio groups, the amino group, and amino groups substituted by aliphatic, aromatic, or heterocyclic residues such as alkylamino, benzylamino, arylamino (e.g., possibly substituted anilino or naphthylamino), dialkylamino, 1-imidazolyl, pyrrolidino, piperidino, piperazino, or morpholino groups. The anilino remainder, whose phenyl ring can possibly be substituted one or more times by a halogen or an alkyl or alkoxy remainder, is particularly preferred as a starting group.

As shown in reaction diagram I, the preparation of starting compounds of formula II can be carried out from compounds of formula VIII, the different steps of the reaction taking place in a manner analogous to known reactions.

For example, an aldehyde of formula VIII can be transformed by reaction with a beta-alkoxypropionitrile of formula

5

NC-C^-CI^-OR, into a compound of formula VI and transform this, in the presence of an alkali metal alkoxide such as sodium methylate or potassium tert-butylate and an alkanol such as methanol, 11 ethanol or propanol, into a compound of formula II-a. The compound of formula VI, unsaturated in alpha, beta, is in equilibrium with the corresponding compound of formula II-e, unsaturated in beta, gamma, and which can be reacted with guanidine to form a compound of formula I.

If the initial reaction is induced with malonic dinitrile,

7

under the conditions of a Knoevenagel condensation (possible-

obtains a dinitrile of formula VII which can be transformed, by selective hydrogenation and for example with half a mole of sodium boro-5 hydride, into the compound II-b.

nique, an aldehyde of formula VIII can be transformed into a compound of formula II-c which can serve either directly as a raw material for the reaction according to the invention, or, and in fact, preferably, be transformed first, by exchange of the morpholino group for the anilino group, into a compound of formula II-d.

(with a basic catalyst), an aldehyde of formula VIII, we

By condensation with beta-morpholinopropio- nitrile

15

h2c h2c cn

^OR5

+ r oh selective hydrogenation

Island

He has

He-b

REDUCTION SCHEME I

morpholiho-propionitril R1

R.2

O

p-anilino-propionitril

II-c ii-a

9

The transformation of compound VIII into compound Il-d can also be carried out directly with beta-anilino-propionic nitrile, but the morpholino-anilino variant is the most suitable method for the preparation of benzylpyrimidi-5s of formula I because, due to milder conditions, better yields are obtained.

The methods for preparing benzylpyrimidines according to the invention and containing sulfur, from aldehydes of formula VIII, are therefore in principle analogous to those known 10 for the preparation of corresponding benzylpyrimidines and not containing sulfur.

With the exception of 3,4-bis-(methylthio)-benzaldehyde (that is-

1 ci *-.

i.e., the compound of formula VIII-1 in which R = hydrogen and R^a = R^a = methylthio), aldehydes of formula VIII are 15 new compounds and also form the subject of the present invention. By analogy with the subdivision of compounds of formula I, aldehydes of formula VIII can be classified into the subgroups "VIII-1 to VIII-5" below:

R 1 a

•25

20

VIII-2

30

35

VIII-3 In these

VIII-4

VIII-5

formulas VIII-1 to VIII-5, the substitutes have the aforementioned meanings.

10

w

Aldehydes of formula VIII can be prepared from known compounds and by any process known in itself, for example as described in detail in Examples 9 and 18 and as schematically represented in the following reaction tables II to V, or in a similar manner.

The thermolysis of a compound of formula XXIII to a compound of formula VIII-5d (see Reaction Scheme V) is a reaction for which nothing similar has yet been described in the technical literature and is therefore novel. This reaction is preferably carried out in dimethylformamide, at a temperature between approximately 50°C and the reflux temperature of the reaction mixture. The reaction is catalyzed by traces of an alkali metal xanthogenate, for example, potassium xanthogenate.

15. The elimination, by reduction, of the halogen atom X,

which is preferably a chlorine or bromine atom, of a compound of formula III according to variant b) of the process can be carried out in a manner known per se by treatment of a compound of formula III with suitable reducing agents, such as zinc in crystallizable acetic acid, zinc amalgam in sodium hydroxide, or by catalytic hydrogenation, for example in the presence of a noble metal, such as platinum, as a catalyst in an inert solvent such as ethanol.

25. The subject of the present invention. Their preparation may

to be carried out by analogy to known processes which are summarized in the reaction scheme II to VI below.

The compounds of formula III are new and form equally

30

35

.11

'REACTION SCHEME II'

11a r 1a

CHO

Br XV

cho i la

Alkyt—O—alky ( a

® S—Alkylt,

CHO

S—Alkyle. TIII-lc cho

O

TTT

S—Alkyl.

h3c-

I

CH3

R13

h3c—n'

ch3

"CHO ZI

S—Alkyle

'N

O

I 13

H3C—^S-ch3

îycLrciyse

H s'

Alkylation

Alkyl—S'

;ho 71

S—Alkyl«_ r 1a

,ho

VI

S—Alkyle t

R, a

CHO V

s—Alkyl,

.12

gggSMfr DE REAHTTokt xil

Br xvii

CHO

® S—Alkyle

Alkyl—S

cho

Alkyl—S

Alkyl-—o-

O

•CHO

S—Alkyl viii-2c h3c-

TrSi cooc h

Br

Alkyl—S s

CH3

CHO

xiii-2

S—Alkyl t_

Alkyl—S

Alkyl—S

1. ®S—Alkylfi.

2. Red u. cJtz

CHO

S—Alkylg.

viii-2b

Alkyl—S

HOOC-alkyl-S'

CHO

S—Alkyl^_ viii-2d

Alkyl—S

hs'

O

•CHO

viii-2a

S—Aikyie_

S—Alkyl e.

XX

S—Alky|<_

vtii-2;"

S—Alkyl xix

1.3

REACTION SCHEME IV

Alkyl—O

O

;ho

S r xu

®S-AIky,i. A'ky'-°

hit s—Alkyl -,

h3c—t-t ^cl

I

CH3

Alkyl—O

H->C

.A XIII-3

ch3

I

S—Alkyfç_

Alky.—0'

cho

Alky! O

■cho

:i-3o

7UI-3a

S—Alkyl.

Alkylation

Afkyl——O

N

O

CHO

Alkyl TIII-3c

$—A(kyf,_

uni o2n

\

COOEl ^ ^ ©su 1

In t

2. Ed.

21st

Wrong

-, 0

1. S—Alkyl

2. Red.

h s

REACTION SCHEME V

CHO

VIII-5a

Alkyl—S

Wrong

SH-Subs t j. tution

United

CHO

n'02s

VIII-5C

"ft?

liai

..^36

■*0„ Uni n'os

Cl IO

VIII-5f

Cl IO

VIII-5th

Alkyl—S

CHO

Alkyl—Ov O

S—Alkyl

VIII-4

For hydroxylated compounds:

+ (It c) 2N-CS-Cl

Alkyl—O A.lkyl—S

cho

( Wrong )

Alkyl—O

Cl 10 Hydrolysis

Alkyl—O

CHO

O—Alkyl VI IJ> 5g

US'

(liai) 6—Alkyl-VTII-5b

HAS

S—Alkyl.

(for amino compounds (Mal) C"° first diar

(M2N)

+ Xonthoqennht-

Alkyl—O

q— Alkyl XXTI

CHO

X M

DMF

(Hat) Alkyl—O

n'o2s

(Uni) Alkyl—0

n o

(Hal) Alkyl-O

Alkyl—S

Cl IO

VIIT-5.1 q—Alkyl

Oxidation io

V[IJ-5h

" I)—Alkyl Ç.

Oxidation

Cl io

O—Alkylf xxiii

()_ AtUyln.

VI TI-5d

15 •

REACTION SCHEME VI

R1

K

16

The reaction of a compound of formula IV with a compound of formula V according to variant c) of the process can be carried out in the presence of a mineral acid, for example orthophosphoric acid, polyphosphoric acid, a hydrohalic acid such as hydrochloric acid or hydrobromic acid, or an organic acid, for example a trihaloacetic acid such as trifluoracetic acid.

The reaction is advantageously carried out within a temperature range of approximately 50° to approximately 100°C. Generally, the mineral or organic acid used in the reaction can serve as the solvent. However, if desired, an inert organic solvent may also be used. The acid addition salt thus obtained of a compound of formula 1-1 is usually separated after the reaction has concluded and purified using conventional methods, for example, by recrystallization or filtration. The free base can be obtained by neutralizing the acid addition salt, for example, with an alkali metal hydroxide.

While the starting compounds of formula IV are known compounds, the compounds of formula V are, in part, new compounds. The latter can be prepared in a manner known per se from known compounds, for example, 1,2-di-mercaptobenzene, 2-methylmercaptobenzene, 3,4-dimercapto-toluene, or 3,4-bis-(methylthio)-toluene, or by analogy to the preparation of these known compounds, for example, by alkylation of a mercapto group and/or oxidation of an alkylthio group to an alkylsulfonyl or alkylsulfonyl group. A carboxyalkylthio compound can be prepared, for example, by reacting a mercapto compound with a derivative of an omega-halocarboxylic acid, such as an ester or an amide, and subsequent hydrolysis.

30 Within the framework of generally known methods,

We can also modify certain compounds of formula I as follows

2 3 4

the invention with respect to the substituents R, R and/or R, that is to say, transforming one into another (variant d) of the process). For example, in a compound of formula I and by means of an alkylating agent, a .mercapto group can be transformed into an alkylthio, alkoxyalkylthio or carboxyalkylthio group. Alkylthio groups can be oxidized to alkylsulfinyl and/or alkylsulfonyl groups or, conversely, reduced, in a manner known per se,

17

into alkylthio groups. The α-methylcarbamoylthio group can be transformed by hydrolysis into the mercapto group.

As salts of compounds of formula I, we can consider both salts formed with acids (called acid addition salts) and, depending on the substituent on the benzyl rest, salts formed by reaction with bases.

For the preparation of acid addition salts, in particular salts usable in pharmaceutical compositions, i.e. physiologically acceptable salts, one can use the mineral and organic acids usually employed for this purpose, such as hydrochloric, sulfuric, phosphoric, formic, acetic, oxalic, tartaric, maleic, benzoic, succinic, fumaric, levulic, salicylic, citric, isocitric, adipic, lactic, alpha-ketoglutaric, malic, malonic, glyceric, mevalonic, glucuronic, neuraminic acids,

glutaric, glucaric (saccharic), aspartic, gluconic, mandelic, ascorbic, lactobionic, glucoheptonic, glutamic, nicotinic, pantothenic, folic, adenyl, geranic, cyti-dylic, inosic and methanesulfonic.

20 Examples of salts formed with bases are sodium salt and potassium salt.

The compounds of formula I and their salts possess antibacterial activity. They inhibit bacterial dihydrofolic acid reductase (DHFR) and further enhance the action of 25-sulfonamides and other inhibitors of dihydrofolic acid synthase. Examples of sulfonamides whose efficacy is enhanced by the compounds according to the invention are those of the pyrimidine, isoxazole, oxazole, and pyrazine series, such as sulfadiazine, sulfadimethoxine, sulfadoxine, sul-famerazine, sulfa-5-methoxypyrimidine, sulfamethazine, 6-methoxy-4-sulfanilaminopyrimidine, sulfamethoxazole, suifisoxazole, 3-sulfanilamido-4,5-dimethylisoxazole, sul-famoxole, and suifalene. Quantitatively, the compounds according to the invention are distinguished from known compounds by lower 50% inhibition concentrations of bacterial DHFR.

for example in Escherichia coli, and by significantly higher Q values (Q = 50% inhibition of DHFR in rats/

V

50% inhibition of DHFR on E. coli) which constitute a measure of the selectivity of bacterial DHFR inhibition, as well as low toxicity.

Data proving the antibacterial efficacy of 5 representative compounds according to the invention are recorded in the following Table I.

Table I

10

compound i activity in vitro (mic)

50% inhibition of dhfr (M x 10)

r1

r2

r3

r4

e. coli 1346

S. aureus Schoch.

e. coli

h och,

sch3

0ch3

0.02

0.4

0.35

15

h och3

sc2H5

0ch3

0.04

0.4

0.18

h och3

sc2h4och3

och3

1.0

9.7

h sch3

n<^j sch3

> 1

4.0

0.52

h sch,

och3

Br

0.2

1.0

1.1

h sch,

och3

och3

0.1

0.78

0.5

20

h sch3

0ch3

sch3

0.7

0.2

0.72

h sch3

sch3

sch3

0.2

0.2

0.45

h h

sch3

sch3

0.7

1.6

ch3

h sch3

sch3

0.7

0.7

1.5

The benzylpyrimidines according to the invention can therefore be used in the form of pharmaceutical compositions, with direct or delayed release of the active substance, mixed with an inert organic or mineral carrier suitable for oral, rectal, or parenteral administration, for example, with water, gelatin, acacia gum, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petrolatum, etc. These pharmaceutical compositions can be presented in solid form, for example, as tablets, coated tablets, suppositories, capsules, in semi-solid form, for example, as ointments, or in liquid form, for example, as solutions, suspensions, or emulsions. Optionally, they are sterilized and/or contain other excipients, such as preservatives, stabilizers, wetting agents, or emulsifiers.

19

I

Enzymatic agents, flavor enhancers, salts for modifying osmotic pressure, or buffers. The preparation of pharmaceutical compositions can be carried out in a manner familiar to any technician.

5. In compositions in which the compounds according to the invention are administered in combination with sulfonamides, the weight ratio of the two constituents may vary within wide limits. It may be between 1:40 and 10:1 and is preferably between 1:5 and 5:1. A tablet may contain, for example, 80 to 400 mg of a compound of formula I and 400 to 80 mg of a sulfonamide. In the case of compositions in which the only active constituent is a compound of formula I, a unit dose of 100 to 1000 mg may be considered, this dose being able to be administered once or several times a day as needed.

15 Example 1

A solution of 36 g of 3,5-dimethoxy-4-methylthiobenzaldehyde and 2.8 g of beta-morpholinopropionitrile is heated to 60°C in 300 mL of dimethyl sulfoxide, and 3.9 g of solid sodium methoxide is added. The reaction is slightly exothermic, and the solution immediately turns dark. It is stirred for one hour in an oil bath (60°C), cooled, and poured into ice-cold water. It is then extracted with ethyl acetate, washed with sodium chloride solution, and dried over sodium sulfate. After removing 25 g of the solvent, 56 g (99%) of 3,5-dimethoxy-alpha-(morpholinomethylene)-4-(methylthio)-hydrocinnamic nitrile is obtained as a light yellow oil (F = 110-113°C after recrystallization in an ethyl acetate/pentane mixture). This oil is then directly subjected to further processing.

30. In a mixture of 18.6 g of aniline and 11.5 g of acetic acid, prepared by cooling with ice, 56 g of 3,5-dimethoxy-alpha-(morpholinomethylene)-4-(methylthio)-hydrocinnamic nitrile in solution in 250 mL of isopropanol is introduced. The mixture is then heated for two hours under reflux, 35 100 mL of isopropanol is removed by distillation towards the end of the reaction, the mixture is cooled to 0°C, 300 mL of water is added, and the mixture is extracted with ethyl acetate. The organic phase is washed with a sodium chloride solution, dried over sodium sulfate, and concentrated. From the remaining product, crystallization occurs.

V

20

I

50 g of crude alpha-anilinomethylene-3,5-dimethoxy-4-(methylthio)-hydrocinnamic nitrile. By recrystallization in a mixture of ethyl acetate and pentane, 40 g (72%) of the compound is obtained, melting at 206-210°C.

5. A solution of

10.2 g of alpha-anilinomethylene-3,5-dimethoxy-4-(methylthio)-hydrocinnamic nitrile and 16.6 g of guanidine carbonate in 200 ml of ethanol with the addition of 2.15 g of sodium. The solvent is then evaporated, and the remaining product is suspended in water.

10. After freezing, the crystals are drained, exhausted by washing with ice water, and recrystallized in ethanol. 7.1 g (77.5%) of 2,4-diamino-5-/3,5-dimethoxy-4-(methylthio)-benzyl/-pyrimidine, melting at 231-232°C, is obtained.

Example 2

15. In a manner analogous to the method described in the example

1. We transform ep compounds of formula I into other aldehydes of formula VIII by way of intermediate compounds of formulas II-c and II-d. The results are recorded in Table II.

"25

30

35

y io ro ui o un o

TABLE II

ui en

R1

R2

R3

R4

COMP.

III /g/

COMPOUND

II-c

COMP.

II-c /g/

COMPOSE Il-d

COMP.

COMPOUND

I

Remarks

Yield /g/ /%/

f

/°c/

Yield /g/ /%/

f r c/

he—a /g/

Yield /g/ /%/

f r c/

h h

OUU3 OCH3

SC2H5

OCH3

och3 och3

5.3

4.6

5.3 6.2

57,941)

125-130 146-149

5 = 6.2

4.3 6.0

86 97

117-119 135-138

8; 3 6.5

4.7 3.0

62

50.4

201-203 180-182

1) processed without purification

H

sch3

n<3

sch3

19.6

22

77

152-153

8.5

8.0

94

167-169

8.3

4.5

59.5

189-191

ch3

H

H H H H

H

H h sch3

SCH3 Br sch3 h

SCH3

sch3 och3

OCH3

sch3 sch3

,sch3

0

S-^N/

0 1

SCH3

sch3

Br SCH

H3' sch3

h

7.73 2.2

3.4 2.6 10 2.4

13.5

10.3 3.56

4.5 3.9 3.5 3.1

15

84 71

92^ 90^ 31

85

62

94-96 86-88

Oel Oel 108-111 143

0.3

3.6

4.5 3.9 1.75

4.7

4.5

9.0 3.72>

3.1

2.9 1.5

3.4

3.5

87 90

68 73 84 71

76

136-140

170-172 135-139 148-150

171-173

98-100

9.0 7.2

6.0

5.4 1.4 4.9

4.7

5.1 3.75

2.8

2.6 0.75 2.1

2.7

63 55

51 50 72 54

64

224-225 163-164

202-204 192-193 205-207 222-224

212-213

2) gross product

3) in the compound

VIII 4

R » Br

H

och3

H

12

14

75

167-169

3.5

1.6

46

173-175

0.8

0.4

55

205-207

H

OCH3

S

\

och3

13

11

57

168-172

9.5

5.5

68.5

198-202

6.5

4.85

81

272-273

22

Example 3

A solution of 1.4 g of 3-bromo-4,5-bis-(methylthio)benzaldehyde, 0.85 g of beta-methoxypropionitrile, and 0.14 g of sodium methoxide is heated under reflux for 18 hours in 5 mL of absolute methanol. The solvent is then removed, the remaining product is reconstituted with 10 mL of methylene chloride, the solution is washed with water, dried, and evaporated. The crude nitrile of 3-bromo-4,5-bis-(methylthio)-alpha-(methoxymethlene)-hydrocinnamic acid (1.5 g) is obtained by heating it under reflux for 18 hours with 0.6 g of guanidine hydrochloride and 0.35 g of sodium methoxide in 5 mL of ethanol. After evaporation of the solvent, the remaining product is purified by chromatography on a silica gel-packed column using a mixture of ethyl acetate and methanol (3:1, 15 volumes) as the eluent, and then recrystallized in methanol. The yield is 2,4-diamino-5-/3-bromo-4,5-bis-(methylthio)-benzyl/-pyrimidine, which melts at 240-243°C.

Example 4

In an open-flask with stirring, a mixture of 10.6 g of 3,5-dimethoxy-4-methylthiobenzaldehyde, 6.2 g of ethyl cyanacetate, and 2 drops of piperidine is heated to 120°C for 90 minutes. It is then cooled and recrystallized in a mixture of ether and n-heptane. The yield of ethyl alpha-cyano-3,5-dimethoxy-4-methylthiocinnamate, a compound melting at 98-100°C after recrystallization in ethanol, is 12.0 g (80%).

In a suspension of 6.0 g of ethyl alpha-cyano-3,5-dimethoxy-4-methylthio-cinnamate in 130 mL of ethanol and 2 drops of normal sodium hydroxide solution, 0.23 g of sodium borohydride is introduced while stirring, and a solution is formed. After 30 minutes, the ethanol is removed by evaporation at 40°C under vacuum in a water aspirator. The remaining product is recovered with ether, the solution is washed with water, and filtered through silica gel. The result is 5.0 g (79.1%) of ethyl alpha-cyano-3,5-dimethoxy-4-methylthio-hydrocinnamate as a colorless oil.

In another test, a hydrogen solution was used under atmospheric pressure and at room temperature, in 250 ml of

23

methanol and, in the presence of 500 mg of 5% Pd palladium charcoal, 3 g of ethyl alpha-cyano-3,5-dimethoxy-4-methylthio-cinnamate. After usual processing, 3.0 g (approximately 100%) of ethyl alpha-cyano-3,5-dimethoxy-4-methylthio-hydrocinnamate is isolated.

In a solution of 0.7 g of sodium in 60 mL of absolute ethanol, 2.7 g of guanidine hydrochloride is introduced. After 30 minutes, the suspension is filtered, and 4.5 g of ethyl alpha-cyano-3,5-dimethoxy-4-methylthiohydrocinnamate 10 are added to the filtrate. The reaction mixture is boiled under reflux for 18 hours, evaporated to dryness, the remaining product is suspended in water, and extracted three times with 200 mL of ethyl acetate. The extract is evaporated to dryness, and the remaining product is recrystallized in methanol. 1.8 g 15 (38.5%) of 2,6-diamino-5-(3,5-dimethoxy-4-methylthiobenzyl)-4-py-rimidinol, melting at 213–215°C, is obtained.

In a suspension of 0.96 g of 2,6-diamino-5-(3,5-di-methoxy-4-methylthiobenzyl)-4-pyrimidinol in 7.6 g of phosphorus oxychloride, 0.73 < 20 of dimethylaniline is added dropwise, while stirring. The mixture is boiled for 4 hours with stirring, and approximately half of the excess phosphorus oxychloride is then removed by distillation under reduced pressure. About 10 g of ice is added to the remaining product. The suspension is then left to stand at room temperature for 25–36 hours, and then adjusted to pH 10 with concentrated ammonia. The dimethylaniline is removed from the resulting suspension by steam distillation. After cooling the aqueous suspension, the crude, solid product is drained, dissolved in a 4:1 (by volume) mixture of benzene and methanol, and filtered through silica gel. After removal of the solvent by evaporation, the resulting 2,6-diamino-4-chloro-5-(3,5-dimethoxy-4-methylthiobenzyl)-pyrimidine is recrystallized in methanol.

It melts at 218-221°C.

To a solution of 167.7 mg of 2,6-diamino-4-chloro-5-(3,355-dimethoxy-4-methylthiobenzyl)pyrimidine in 1.6 ml of crystallizable acetic acid and 10 mg of mercuric chloride in 0.2 ml of water, 150 mg of zinc powder is added. The mixture is then boiled.

24

The mixture is refluxed, with stirring, until the following day. The resulting solution is filtered while still warm, removing any unreacted zinc by washing with 0.5 mL of crystallizable acetic acid. The filtrate is diluted with 2 mL of water and, upon cooling, alkalized with concentrated ammonia. The suspension is extracted three times, each time with 5 mL of ethyl acetate. The combined extracts are dried, the remaining product is concentrated, and it is recrystallized from methanol. 148 mg of 2,4-diamino-5-(3,5-dimethoxy-4-methylthiobenzyl)-pyrimidine, melting at 231–232°C, is obtained.

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 is stirred for six hours at 100°C. After cooling and dilution with 5 mL of water, 45 mL of a 50% potassium hydroxide solution is added dropwise at 0°C. The solid product is drained, diluted twice with water, dissolved in methanol, and the solvent evaporated. The remaining product (2.5 g) is purified by silica gel column chromatography with a mixture of ethyl acetate and methanol (3:1 by volume) as the eluent. The isolated 2,4-diamino-5-/2-methyl-4,5-bis-(methylthio)-benzyl/-pyrimidine is recrystallized in methanol. Melting point: 217-222°C. Example 6

25. 3.9 g of 2,4-diamino-5-/3,5-dimethoxy-4-(me) are dissolved

thylthio)-benzyl/-pyrimidine is dissolved in 90 mL of acetic acid, 1.3 g of 30% hydrogen peroxide is added, and the mixture is stirred for three hours at room temperature. The solution is then poured into ice water and alkalized with concentrated ammonia. The crystalline precipitate is drained and recrystallized in a mixture of methanol and methylene chloride. 2.8 g (70%) of 2,4-diamino-5-/3,5-dimethoxy-4-methylsulfinyl)-benzyl/-pyrimidine is obtained as pale yellow crystals melting at 288-289°C.

35 Example 7

A solution of 610 mg of 2,4-diamino-5-/3,5-dimethoxy-4-(methyl-

2b suifinyl)-benzyl/-pyrimidine is dissolved in 15 mL of crystallizable acetic acid and 1 mL of 30% hydrogen peroxide. The mixture is then poured onto ice, alkalized with concentrated ammonia, the crystalline precipitate is drained, thoroughly washed with water, and dried. This yields 580 mg (85% yield) of 2,4-diami-no-5-/3,5-dimethoxy-4-(methylsulfonyl)-benzyl/-pyrimidine, which melts at 297-298°C and decomposes.

Example 8

In 80 mL of acetone, 9 g of 2,4-diamino-5-(3,5-dim-thoxy-4-mer-captobenzyl)-pyrimidine hydrochloride, 4.1 g of potassium carbonate, and 2.5 g of methyl sulfate are heated under reflux for 16 hours. The solution is filtered, the solvent is removed, the remaining product is resuspended with ethyl acetate, and the mixture is washed with water. By concentrating the dried solution, 2.7 g (88%) of 2,4-diamino-5-/3,5-dimethoxy-4-(methylthio)-benzyl/-pyrimidine crystals are crystallized into colorless crystals that melt at 230–232°C.

Example 9

In a suspension, maintained at 0-5°C, of 63.3 g of methyl 20-4-amino-3,5-dimethoxybenzoate in 300 mL of water and 75 mL of concentrated hydrochloric acid, a solution of 23 g of sodium nitrite in 60 mL of water is introduced dropwise. A clear, orange solution is formed, which is then introduced dropwise into a vigorously stirred, ice-cold solution of 80 g of potassium 25-methylxanthogenate in 300 mL of water, and a strong gas evolution is observed. After four hours of stirring at room temperature, the extract is extracted with ethyl acetate, washed with a sodium chloride solution, and dried over sodium sulfate. From the product remaining after 30 concentration, we obtain in crude state 54 g (60%) of dithiocarbonate of 5-/4-(methoxycarbonyl)-2,6-dimethoxyphenyl/-0-methyl melting at 113-115°C.

A mixture of 29 g of S-/4-(me-35thoxycarbonyl)-2,6-dimethoxyphenyl/-0-methyl dithiocarbonate and 2 g of potassium methylxanthogenate is stirred for one hour at 100°C in 450 ml of dimethylformamide. The solvent is then removed by evaporation under reduced pressure, and the remaining product is recovered with ethyl acetate. After washing with water and then with

#

26

a saturated solution of sodium chloride is dried over sodium sulfate and the solvent is removed. Recrystallization in cyclohexane of the remaining product yields 18.8 g (81%) of methyl 3,5-dimethoxy-4-(methylthio)-benzoate in the form of colorless crystals melting at 86-88°C.

Sodium xyethoxyalanate (70% in toluene) is dissolved in 150 mL of toluene. A solution of 50 g of morpholine in 200 mL of toluene is then added dropwise. The clear solution is stirred continuously at 0°C and then added dropwise, while stirring, to a solution of 30 g of methyl 3,5-dimethyl-4-(methylthio)benzoate in 700 mL of toluene, cooled to -20°C. The mixture is then stirred for another five hours. Finally, 100 mL of water is added dropwise, followed by 100 mL of 3N hydrochloric acid, and the phases are separated in a separatory funnel. The aqueous phase is extracted twice with ethyl acetate, while the combined organic phases are washed with a sodium chloride solution and dried with sodium sulfate. The concentrated solution yields 26 g of a yellow oil that solidifies and, after recrystallization in a mixture of ethyl acetate and pentane, provides 21 g (78%) of 3,5-dimethoxy-4-(methylthio)-benzaldehyde, melting at 54-56°C. Example 10

'25 we transform 21.1 g of methyl 4-amino-3,5-dimethoxybenzoate into 19 g (68%) of S-/4-(methoxycarbonyl)-2,6-dimethoxyphenyl/-0-ethyl dithiocarbonate (F = 84-86°C) and we then transform this, in a yield of 90%, into methyl 3,5-dimethoxy-4-ethylthiobenzoate, melting at 50-52°C.

30. In a stirred solution maintained at 0°C, containing 10.8 g of methyl 3,5-dimethoxy-4-(ethylthio)benzoate in 100 mL of absolute ether, 120 mL of a 20% diisobutylaluminum hydride solution in hexane is introduced dropwise over 10 minutes. The mixture is stirred continuously for two hours at 0°-5°C. After the slow, dropwise addition of 100 mL of water, 150 mL of 3N hydrochloric acid is added, followed by the addition of ether, and the mixture is washed to neutrality. The solution is then dried over sulfate.

In a solution, cooled to 0°C, of 150 g of dimetho-

By proceeding in a manner similar to that of example 9

M

27

of sodium, "the solvent is removed, the remaining yellow oil (11.2 g) is added to 100 ml of methylene chloride, and the solution is stirred at room temperature in the presence of 15 g of manganese dioxide. After three hours, 15 g of manganese dioxide is added. The mixture is then stirred for three hours, filtered through a diatomaceous earth filter aid, and the filtrate is concentrated. By recrystallization in a mixture of ether and pentane, 9.2 g (96.5%) of 3,5-dimethoxy-4-(ethylthio)-benzaldehyde is obtained as 10 colorless crystals melting at 38-39°C.

Example 11

Similar to Example 9, 21.1 g of methyl 4-amino-3,5-dimethoxybenzoate is transformed into 23 g (66%) of S-/4-(methoxycarbonyl)-2,6-dimethoxyphenyl/-15 O-(2-methoxyethyl) dithiocarbonate melting at 86-88°C, then this, in a yield of 42%, into methyl 3,5-dimethoxy-4-(2-methoxyethylthio)-benzoate, melting at 56-58°C, and finally this is reduced, in a yield of 88%, to 3,5-dimethoxy-4-(2-methoxyethylthio)-benzaldehyde.

Example 12

To a sodium mercaptide suspension prepared from 35.5 g of a 55% sodium hydride dispersion in mineral oil and 270 ml of dimethylformamide and 39.6 g of methyl mercaptan in 190 ml of dimethylformamide, 48 g of ethyl 3,5-dibromo-4-nitrobenzoate is added in 25 successive portions, under a nitrogen atmosphere, with stirring and cooling to 15°–30°C with ice water. The mixture is stirred for four hours at room temperature, poured into 4 L of water, the precipitated crystals are combined with the ethereal extracts of the filtrate, and the solvent is removed. Recrystallization of the remaining product in a mixture of ether and petroleum ether yields 10.2 g of ethyl 3,4,5-tris-(methylthio)-benzoate. The aqueous filtrate obtained during the treatment is cooled, adjusted to pH 2 with concentrated hydrochloric acid, the solid product is drained, and dried. After esterification with a mixture of ethanol and HCl, 28 g of a mixture of ethyl 3-bromo-4,5-bis-(methylthio)-benzoate and ethyl 3,4,5-tris-(methylthio)-benzoate are obtained (ratio

28

9

in weight of approximately 1:1), which is split by silica gel column chromatography using methylene chloride as the eluting agent. 13.8 g (32%) of ethyl 3-bromo-4,5-bis-(methylthio)-benzoate melting at 69-71°C and 12.8 g (therefore 5 g in total, 23 g, i.e., a yield of 60%) of ethyl 3,4,5-tris-(methylthio)-benzoate melting at 89-93°C are obtained.

By esterification of the mixture with methanol saturated with HC1 and treatment similar to the previous one, we obtain 3-bromo-4,5-bis(methylthio)-methyl benzoate, melting at 105-106°C, and 10 3,4,5-tris-(methylthio)-methyl benzoate, melting at 122-124°C.

In a manner analogous to that of example 10, 35.9 g of 3-bromo~4,5-bis-(methylthio)-methyl benzoate is then reduced in a yield of 62% to 3-bromo-4,5-bis-(methylthio)-benzal-15 dehyde and, in a yield of 58%, 24.1 g of 3,4,5-tris-(methylthio)-methyl benzoate to 3,4,5-tris-(methylthio)-benzaldehyde, melting at 160-161°C.

According to another embodiment, 3-bromo-4,5-bis-(methylthio)-ethyl-20 benzoate and 3,4,5-tris-(methylthio)-ethyl benzoate are prepared in the following manner.

a) To a suspension of sodium mercaptide, prepared from 0.55 g of a 55% sodium hydride dispersion (in mineral oil) in 10 ml of dimethylformamide and 1 ml of methyl mercaptan in 6 ml of dimethylformamide, is added by por-

25 successive ions, at 15–25°C, under a nitrogen atmosphere, with stirring and cooling through ice water, yielded 1.76 g of ethyl 4-nitro-3,5-dibromobenzoate. The reaction mixture was stirred for 20 minutes at room temperature, evaporated to dryness at 4–5°C, and under high vacuum, 30 mL of water was added to the remaining product and extracted with ether. The extract was dried, filtered, and evaporated to dryness. From the remaining product, recrystallization in n-heptane yielded 1.5 g (94%) of ethyl 3-bromo-4,5-bis-(methylthio)benzoate, melting at 72–73°C.

b) In a sodium mercaptide suspension, prepared from 20.7 g of a 55% sodium hydride dispersion

(in mineral oil) in 160 ml of dimethylformamide and -21 ml of methyl mercaptan in 110 ml of dimethylformamide, on in

29

Introduced in successive portions at 15–25°C under a nitrogen atmosphere, with stirring and cooling in ice, 28 g of ethyl 4-nitro-3,5-dibromobenzoate was stirred for four hours at room temperature. It was then evaporated to dryness under high vacuum at 45°C. 750 mL of water was added to the remaining product, and the mixture was extracted five times, each time with 150 mL of ether. The ether extract was dried, filtered, and evaporated to dryness. Recrystallization of the remaining product in n-heptane yielded 16.5 g (75%) of ethyl 3,4,5-tris-(methylthio)benzoate, melting at 90–92°C.

Example 13

To a suspension, cooled to 0°C, of 10.8 g of sodium methoxide in 150 mL of methanol, 20 mL of methyl mercaptan is added. The mixture is stirred for 30 minutes at 0°C, and 13.6 g of ethyl 3,5-dibromo-4-nitrobenzoate is added. A thick suspension is formed. After 5 minutes, the reaction mixture is concentrated, the remaining product is extracted with ether, and the extract is washed with water. After recrystallization in methanol, 13 g (92%) of methyl 3,5-dibromo-4-20(methylthio)benzoate, melting at 101–102°C, is obtained.

Similar to example 10, 14.7 g of methyl 3,5-dibromo-4-(methylthio)-benzoate is reduced, in a yield of 83%, to 3,5-dibromo-4-(methylthio)-benzaldehyde, melting at 87-89°C.

'25 Example 14

A mixture of 22 g of ethyl 4-amino-3,5-dibromobenzoate, 100 mL of acetic acid, and 14.4 g of 2,5-diethoxytetrahydrofuran is maintained at 100°C for one hour and then concentrated under reduced pressure. The remaining dark-colored product is resuspended with ethyl acetate, washed first with sodium bicarbonate solution and then with sodium chloride solution, dried over sodium sulfate, and evaporated to dryness. Recrystallization in a mixture of ether and petroleum ether yields 20 g (60%) of 3,5-dibromo-

C

35/ ethyl 4-pyrrolobenzoate, melting at 10–107°C. 18.5 g of this compound, dissolved in 40 ml of hot dimethylformamide, is introduced dropwise into a stirred solution at temperature

30

»

At room temperature, methyl mercaptide (prepared from 6 g of sodium hydride and approximately 15 g of methyl mercaptan in dimethylformamide) is mixed in 100 mL of dimethylformamide. The mixture is stirred for 16 hours at room temperature, then concentrated, resuspended with ethyl acetate, adjusted to pH with hydrochloric acid, washed with a saturated sodium chloride solution, dried over sodium sulfate, and evaporated again to dryness. The remaining product is esterified with ethanol saturated with HCl. The solution is evaporated to dryness. From the remaining 10 product, dissolved in ether, after the addition of hexane, 8.8 g (57%) of ethyl 3,5-bis-(methylthio)-4-pyrrolo-benzoate crystals are obtained, melting at 108-109°C.

In a manner analogous to that of example 10, 21 g of 3,5-bis-(methylthio)-4-pyrrolo-benzoate of 15-ethyl is then reduced, in a yield of 67%, to 3,5-bis-(methylthio)-4-pyrrolo-benzaldehyde, melting at 146-148°C,

Example 15

In a suspension, stirred at 0°C, of 4.7 g of sodium hydride (50%, from which the oil has been removed by washing twice with pentane) in 300 mL of dimethylformamide, 6.2 mL (5.0 g) of methyl mercaptan is added dropwise. After 15 minutes, 12.25 g of 3,5-dimethoxy-4-bromobenzaldehyde is added dropwise to 50 mL of dimethylformamide. The brown solution is stirred for half an hour at room temperature until it clears, then it is poured into ice water and extracted with ethyl acetate. The extract is washed successively with water, with a normal, cold hydrochloric acid solution, and with a saturated sodium chloride solution. It is then dried over sodium sulfate, and the yellow oil remaining after solvent removal is crystallized in 30% methanol. 8.9 g (yield: 84%) of 3,5-dimethoxy-4-(methyl-thio)benzaldehyde, melting at 55-56°C, is collected.

Example 16

To a suspension of 16.5 g of sodium hydride (55%) in 200 ml of dimethylformamide, a solution of 18 g of methyl mercaptan in 70 ml of dimethylformamide is added dropwise, while stirring, at 0°-5°C and under a nitrogen atmosphere. After 30 minutes

31

After stirring at room temperature, 1.5 g of cuprous chloride is added, followed by 21 g of 3,5-dibromo-4-hydroxybenzaldehyde. The reaction mixture is stirred for 68 hours at 120°C, then another 1.5 g of cuprous chloride is added and the mixture is stirred for a further 5 to 20 hours at 150°C. The mixture is then concentrated by evaporation under high vacuum, the remaining product is reconstituted with a 10% sodium chloride solution, and the solution is filtered through diatomaceous earth. The aqueous phase is extracted with ether, acidified, while cooling, with concentrated hydrochloric acid, and extracted with ethyl acetate. The extract is dried after being washed with water, then evaporated to dryness. Nine grams of the resulting mixture (14 g total) are dissolved in 90 mL of acetone, and 10.7 g of potassium carbonate is added. 7.5 mL of methyl sulfate is added to the resulting suspension. The reaction mixture is stirred at 15-50°C for 18 hours, then drained, the mineral salts are washed with acetone, and the filtrate is evaporated to dryness. The remaining product is dissolved in ethyl acetate, and this solution is washed successively with concentrated ammonia and then with water if the solution is to be separated by chromatography with elution using a 7:1 heptane/acetone mixture (by volume). First, there is elution of 3-bromo~5-methylthioanisaldehyde, melting at 54-56°C (yield; 3.5 g), then of 3,5-bis-(methylthio)anisaldehyde, melting at 84-86°C after recrystallization in n-heptane (yield: 2.6 g).

25 Example 17

In 190 ml of ethanol, 27.3 g of 1-methyl-3,4-dithiophenol (prepared from 4-methyl-30 anthranilic acid according to Synthesis, 1976, p. 471) is introduced dropwise over 20 minutes in solution in 110 ml of ethanol. After 45 minutes, 49.6 g of methyl iodide in 70 ml of ethanol is added to the solution, and after 30 minutes of stirring, the precipitated potassium iodide is separated by filtration. The ethanol is removed by evaporation, and the resulting 3,4-bis-35(methylthio)-toluene is distilled at 95-98°C/1 mmHg. 30.0 g is collected (yield: 93%). After recrystallization in heptane, it melts at

In a solution of 23 g of 85% potassium hydroxide

38-32°C9

o n

To a solution of 27 g of 3,4-bis-(methylthio)-toluene in 20 g of N-methylformanilide, 21.6 g of phosphorus oxychloride is added dropwise at 15°-20°C and the solution is stirred for 24 hours at 55°C. To the reaction mixture, a suspension obtained from 9.6 g of N-methylformanilide and 10.8 g of phosphorus oxychloride is added, and the mixture is stirred for another 24 hours at 55°C. Water is added to the cooled mixture, extracted with ether, the combined extracts are dried, evaporated to dryness, and the remaining product is chromatographed on silica gel with benzene. 14.7 g of 3,4-bis-(methylthio)-6-methylbenzaldehyde is obtained, melting at 51-52°C after recrystallization in heptane.

Similarly, from 1,2-dithio-phenol, 1,2-bis-(methylthio)-benzene is obtained in a yield of 83%, which can be transformed, in a yield of 39%, into 3,4-bis-(methylthio)-benzaldehyde, melting at 50°C.

Example 18

To a suspension, stirred at 0°C, of 2.64 g of sodium hydride in 150 ml of dimethylformamide, 20 successive portions are added, first 18 g of syringic aldehyde, then 15 g of dimethylthiocarbamoyl chloride, so that the temperature within the mixture does not exceed 10°C. The mixture is then stirred for four hours at room temperature, the reaction mixture is resuspended with ethyl acetate, washed successively with 25 ml of cold hydrochloric acid, with sodium hydroxide solution, and with a saturated sodium chloride solution, and dried. The solution is concentrated and, after the addition of hexane, 16.2 g (60%) of H,N-dimethyl-thiocarbamate of O-(4-formyl-2,6-dimethoxyphenyl) crystallizes, melting at 173-176°C. 14.5 g of N,N-

O-(4-formyl-2,6-dimethoxyphenyl) dimethylthiocarbamate is then cooled and recrystallized in a mixture of ethyl acetate and hexane. This yields 12.1 g (83%) of H₂N-dimethylthiocarbamate of S-(4-formyl-2,6-dimethoxyphenyl), which melts at 183-35-186°C.

By basic hydrolysis, this compound is transformed into 3,5-dimethoxy-4-mercaptobenzaldehyde.

33

Similarly, from vanillin, N,N-dimethylthiocarbamate of O-(4-formyl-2-methoxyphenyl), melting at 114-115°C, is prepared in a yield of 78.5%. This is then transformed, in a yield of 83%, into N,N-dimethylthiocarbamate of 5'-(4-formyl-2-methoxyphenyl), melting at 109-110°C, which can finally be hydrolyzed to 4-mercapto-3-methoxybenzaldehyde. Example 19

A suspension of 1.6 g of 2,4-diamino-5/4-(H,N-dimethyl-10 carbamoylthio)-3,5-dimethoxybenzyl/-pyrimidine is heated under reflux for 16 hours in an argon atmosphere in 25 mL of methanol and 25 mL of 3N sodium hydroxide solution. A clear solution is formed. The crystalline precipitate that forms upon cooling is drained off and dissolved in 20 mL of water and 10 mL of methanol. 500 mg of sodium 15 dihydrogen borohydride is added to the solution, it is allowed to stand for one hour, and then acidified.

pH 3 with 3N hydrochloric acid, the crystals that form are drained and dried under high vacuum. 0.8 g (62%) of 2,4-diamino-5-(4-mercapto-3,5-dimethoxybenzyl)-pyrimidine hydrochloride is obtained, melting at 275-277°C.

Example 20

To a solution of 20.7 g of sodium in 250 mL of methanol, 86 g of guanidine hydrochloride are added. After filtration, the solution is introduced dropwise over 30 minutes into a freshly prepared solution at 95°C of 98 g of 3,5-dimethyl-25-thoxy-4-(methylthio)-alpha-(2-methoxyethoxymethylene)-hydrocinnamic nitrile in 250 mL of ethylene glycol monomethyl ether, with the methanol being continuously removed by distillation. The temperature is raised to 120°C for one hour, and during this time, 200 mL of solvent is removed by distillation under reduced pressure. The reaction mixture is then cooled to 0°C, and 400 mL of water is added. The crystalline precipitate is squeezed out and washed successively with water, ethanol and ether. 59 g of 2,4-diamino-5-/3,5-dimethoxy-4-(methylthio)-benzyl/-pyrimidine, a colorless compound melting at 35,219-223°C, is collected.

The raw material is prepared in the following way:

A solution of 3.5 g of sodium in 500 ml of ether

34

■i

5

10

15

20

25

30

To anhydrous monomethyl ethylene glycol, 71 g of beta-methoxy-ethoxypropionitrile are added dropwise. The solution is heated to 90°C and, while stirring, 106 g of 3,5-dimethoxy-4-(methylthio)-benzaldehyde are introduced in successive portions. The reaction mixture is heated to 125°C, removing 50 mL of solvent by distillation. The remaining solvent is removed by evaporation at 65°C under reduced pressure, the remaining product is resuspended with ethylene chloride, and the mixture is washed three times with, each time,

300 ml of water. The aqueous phases are combined, and the mixture is extracted twice more with 300 ml of ethylene chloride. The combined organic phases are dried over sodium sulfate and evaporated to dryness. The resulting dark-colored oil (155 g) is distilled at 200°C under high vacuum, yielding 98 g (60%) of 3,5-dimethoxy-4-(methylthio)-alpha-(2-methoxyethoxymethylene)-hydrocinnamic nitrile as a viscous yellow oil, which is then subjected as is to further processing.

Example 21

One 1.35 g of sodium methylate is added to a solution of 5.3 g of 3,5-dimethoxy-4-(methylthio)benzaldehyde and 3.1 g of bota-imidazoylpropionitrile in 50 mL of ethanol, and the mixture is heated under reflux for five hours. To the brown solution, a suspension of 4.8 g of guanidine hydrochloride and 2.7 g of sodium methylate in 50 mL of ethanol is added. The ethanol is then removed by distillation, and the remaining product is stirred for 90 minutes at 100°C. The reaction mixture is then suspended in water, filtered, the filtrate is evaporated to dryness, and the remaining product is recrystallized from a mixture of ethanol and ether. 3.6 g (48%) of 2,4-diamino-5/3,5-dimethoxy-4-(methylthio)-benzyl/-pyrimidine is obtained as pale yellow crystals melting at 224–227°C. Example 22

To a solution of 1.6 g of 2,4-diamino-5-/4-(ethylthio)-3,5-dimethoxybenzyl/-pyrimidine in 30 ml of acetic acid, 0.6 g of 30% hydrogen peroxide is added, and the mixture is stirred for four hours at room temperature. The mixture is then poured onto ice, adjusted to pH 10 with concentrated ammonia, and the precipitated crystals are drained off. After recrystallization

35

In a mixture of methanol and ether, 1.45 g (86%) of 2,4-diamino-5/4-(ethylsulfinyl)-3,5-dimethoxybenzyl/-pyrimidine is obtained as colorless needles melting at 256-258°C with decomposition, Example 23

5 A solution of 5.82 g of 2,4-diamino-5-/3,5-dimetho-

xy-4-(methylthio)-benzyl/-pyrimidine is added to 130 ml of crystallizable acetic acid, and 2.1 ml of 30% hydrogen peroxide is added at room temperature. The mixture is stirred for seven hours at room temperature.

10. Pour 70 ml of this solution onto approximately 70 g of ice. While cooling, alkalize with concentrated ammonia, drain, suspend the remaining product in a little concentrated ammonia, decant, triturate with ethyl acetate, drain, and dry. 1.25 g of crude 152,4-diamino-5-/4-methoxy-3-methylsulfinyl-5-methylthiobenzyl/-pyrimidine is obtained, while from the ammonia filtrate, by extraction with ethyl acetate and evaporation to dryness, 0.4 g of pure product is obtained, melting at 215-217°C.

To the other part of the reaction mixture, 0.6 20 ml of 30% hydrogen peroxide is added and the mixture is stirred overnight at room temperature. After treatment similar to the previous one and recrystallization in ethanol, 300 mg of 2,4-dia-mino-5-/4-methoxy-3,5-bis(methylsulfinyl)-benzyl/-pyrimidine, melting at 178-180°C, is obtained.

25 Example 24

In a sodium mercaptide suspension, prepared from 10 g of a 55% dispersion (in mineral oil) of sodium hydride in 200 ml of dimethylformamide and 11 g of methyl mercaptan in 50 ml of dimethylformamide, 36 g of

2,4-diamino-5-/3,5-dimethoxy-4-(dimethylcarbamoylthio)-benzyl/-pyrimidine. The mixture is stirred for three hours at 55°C. Then, at 15-25°C, 24.5 mL of ethyl bromacate is added dropwise, and the mixture is stirred for another hour at room temperature (35°C). The solution is evaporated to dryness under high vacuum, the remaining product is reconstituted with normal hydrochloric acid, the solution is washed with ether, and the pH is adjusted to 8.

36

By adding a normal NaOH solution while cooling in ice, the mixture is squeezed out, the remaining product is thoroughly washed with water, and it is dried. This yields 32 g (84.6%) of 2,4-di-amino-5-/4-(carbethoxymethylthio)-3,5-dimethoxybenzyl/-pyrimidine, 5, which melts at 156-161°C.

Example 25

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 normal NaOH solution is shaken for two hours. After filtration, the ethanol is removed by evaporation under reduced pressure, the remaining product is neutralized by the addition of 27.5 mL of normal hydrochloric acid solution, the mixture is drained, washed with water, and dried. This yields 7 g of 2,4-diamino-5-/4-(carboxymethylthio)-3,5-dimethoxybenzyl/-pyrimidine, which melts at 280°C and decomposes.

Example 26

In a sodium mercaptide solution prepared from 1 g of a 55% dispersion (in mineral oil) of sodium hydride in 20 mL of dimethylformamide and 1.1 g of 20-methylmercaptan in 5 mL of dimethylformamide, 3.6 g of 2,4-di-amino-5-/3,5-dimethoxy-4-(dimethylcarbamoylthio)-benzyl/-pyrimi-dine are introduced at room temperature under a nitrogen atmosphere. The mixture is stirred for two hours at 55°C. Then, at 15–25°C, 2.5 mL of 5-bromovaleron-itrile 25 is added dropwise, and the mixture is stirred for another hour at room temperature. The solution is evaporated under high vacuum, the remaining product is triturated with ether, drained, suspended in water, and drained again. After recrystallization twice in methanol, 1.9 g of 2,4-di-30 amino-5-/4-(4-cyanobutylthio)-3,5-dimethoxybenzyl/-pyrimidine, melting at 186-188°C, is obtained.

Example 27

In a sodium mercaptide suspension, prepared from 1.44 g of a 55% dispersion (in mineral oil) of sodium hydride in 30 ml of dimethylformamide and 1.94 ml (1.58 g) of methyl mercaptan in 7.5 ml of dimethylformamide, 5.45 g of 2,4-diamino-5-/3,5-dimethoxy-4-(dimethylcar-

37

bamoylthio)-benzyl/-pyrimidine. The mixture is stirred for one hour at 55°C, then, after cooling to 20°C, 4.57 g of (2-chlorethoxy)-2-methoxyethane is added. After 10 minutes at room temperature, the treatment is continued in the usual manner, and after recrystallization in methanol, 2,4-diamino-5-3,5-dimethoxy-4-/2-(2-methoxyethoxy)-ethylthio-benzyl-pyrimidine is obtained, melting at 161-162°C. Thin-layer chromatography proves that it is a single compound.

Example 23

10. A mixture consisting of 3.6 g of 2-(2-chloroethoxy)-2'-methoxydiethyl ether, 3.1 g of sodium 4-(2,4-diamino-5-pyrimidinyl)-methyl7-2,6-dimethoxyphenylthiolate, and 30 mL of dimethylformamide is stirred at 80°C for two hours. The filtrate is then strained and evaporated to dryness. The remaining product is triturated with ether, strained, washed with water, and dried. The resulting product (3.5 g) is purified by silica gel column chromatography with a mixture of methanol, propanol, and HH^OH (volume proportions: 5:5:0.5), yielding 1.8 g of pure 2 ,4-diamino-5-^3 ,5-dimethoxy-4-/2-^72-( 2-20 methoxy-ethoxy ) -ethoxy/^ethylthio/-benzylj-pyrimidine, melting at 130-131°C.

Example 29

Tablets are prepared with the following composition (mg per tablet):

25 2,4-diamino-5-/3,5-dimethoxy-4-(methylthio)-

benzyl 17-pyrimidine 50.00

cold-swelling starch 12.50'

sodium salt of carboxymethyl starch... 12.50

powdered lactose 143.75

30 magnesium stearate 1.25

220.00

This mixture is granulated after being moistened with a little water and then molded into tablets.

38

Claims (2)

CLAIMS 1. A process for the preparation of 2,4-diamino-5-benzylpyrimidines of general formula 10 in which 15 20 25 35 W a) R represents hydrogen or an alkyl group in 2 r 3 R represents hydrogen, R represents a mercapto group, alkylthio in carboxyalkylthio with alkyl residue in C1-C(-), alkoxyalkylthio with alkoxy and alkyl residues in dimethylcarbamoylthio, -S(0)R' or -SO2R' and R^ represents an alkylthio group in "C, -Cr, -S(0)R' or -SO2R', or T 2 4* b) R represents hydrogen, R and R represent 3 each an alkylthio group in C-^-Cg, -S(O)R' or -SO2R' and R represents an alkoxy group in c2_~cq# mercapto, alkylthio in carboxyalkylthio to alkyl remainder in dimethylcarbamoylthio, -S(0)R1 , -S0„R’ or- -NR,,R,t • f or 1 2 c) R represents hydrogen, R represents a group 3 alkoxy at C2.~C6' ^ represents a mercapto group, ali;ylthio at C^-Cg, carboxyalkylthio with an alkyl residue at C^-C^, alkoxyalkylthio with alkoxy and alkyl residues at C^*"C6" dimethylcarbamoylthio, -S(0)R' or -SO2R* and R^ represents an alkylthio group at C2.~C6' -S(0)R' or -SO9R*, or 1 2 d) R represents hydrogen, R represents a halo- O gene, R represents an alkylthio group at C3-Cg, -S(0)R' or -SO2R' and R^ represents an alkylthio group at -S(0)R' or —S0oR', or even 1 2 e) R represents hydrogen, R represents a hcilo- 3 ✓ gene or an alkoxy group in R represents a mercap group, alkylthio in C2.~C6' car^02cyan^cy-'-t^1i0 a 2-"este alkyl in c^~cg/ carbalcoxyalkylthio with alkyl residue in C-^-Cg, cyanalkylthio with alkyl residue in C^-C^, alkoxyalkylthio with alkoxy and alkyl residues in jy C-Cg, alkoxy-alkoxy-alkylthio with alkoxy and alkyl residues in C-Cg, dimethylcarbamoylthio, -S(O)R' or -SO2R' and R represents a halogen or an alkoxy group in C-Cg, whereas, in all cases a) to e) mentioned above, R' represents an alkyl residue in C-Cg/ R' and R'' represent, independently of each other, hydrogen or an alkyl group in C-Cg or » together, an alkylene group in C-Cg (possibly comprising 1 to 3 double bonds)f and its physiologically acceptable salts, characterized by the fact that a) a compound of formula R1 is condensed with guanidine or one of its salts 15 20 25 30 35 in which R"*", R2, R^ and R^ have the aforementioned meanings, Z represents a group -C(CN)=CH-Y or -CH(CN) CII(0R^) ~,Y represents 5 a starting group and R represents a C-Cg alkyl group, a 2-alkoxyethyl group with an alkoxy residue in group 2- phenoxyethyl or a 2-benzyloxyethyl group or, together, all 5 two R residues represent an alkylene group in c) or b) of a compound of formula in which X represents a halogen and R, R, R and R have the aforementioned meanings, the substituent X is eliminated by reduction or c) with regard to the preparation of a compound of formula 1-1, a substituted benzylpyrimidine is reacted with * 40 formula (IV) 10 15 IV in which R represents a C-Cg alkoxy group (preferably the methoxy group), the benzyloxy group, the hydroxy group, or a halogen, with a compound of formula R 1 a V in which R" R4a R and R have the aforementioned meanings, or 2 3 4 d) a compound of formula I is modified with respect to the substituents R,' R and/or R"*, 20 in the context of generally known processes and, if desired, the compound thus obtained is transformed into a physiologically acceptable salt. 2. Process for the preparation of 2,4-diamino-5-benzylpyrimidines of general formula 25 R1 NHn 30 in which a) R"*" represents hydrogen or an alkyl group in 2 3 C^-Cg, R represents hydrogen, R represents a mer- group 35 capto, alkylthio in C-^-Cg, carboxyalkylthio with alkyl remainder in C-Cg, alkoxyalkylthio with alkoxy and alkyl residues in dime thylcarbamoylthio, -S(O)R' or -5O2R' and R^ represents a group 41 alkylthio in C^-Cg, -S(0)R' or -SC^R' 1 2 4 b) R represents hydrogen, R and R' represent O each an alkylthio group in C^-Cg, -S(0)R' or -SC^R' and R represents an alkoxy group in C^-Cg, mercapto, alkylthio in C^-Cg, 5 carboxyalkylthio with alkyl residue in C^-Cg, dimethylcarbamoylthio, -S(0)R', -SO?R' -HR"R"', OR 1 * 2 c) R represents hydrogen, R represents a group- 3 pe alkoxy in C^-Cg, R represents a mercapto, alkylthio group in C^-Cg, carboxyalkylthio with alkyl residue in C^-Cg, alkoxyalkylthio 10 to alkoxy and alkyl residues in C, -C,., dimethylcarbamoylthio, -S(0)R' HAS or -SO2R* and R* represents an alkylthio group in -S(0)R' or -S0«R1, or 1 2 d) R represents hydrogen, R represents a halo- 3 gene, R represents an alkylthio group in -S(0)R' or 30 35 15 ^SO2R' and R^ represents an alkylthio group at C1-C6' ~s^0^ -S0„R', or even 1 2 e) R represents hydrogen, R represents a halo- 3 gene or "an alkoxy group in C-Cg, R represents a mercapto group, alkylthio in C-Cg, carboxyalkylthio with an alkyl residue in C-Cg/ 20 alkoxyalicylthio with alkyl and alkyl residues in C-Cg, dimethylcarbamoylthio, -S(O)R' or -SO2R' and R represents a halogen or an alkoxy group in C-Cg, whereas, in all cases a) to e) mentioned above, R' represents an alkyl residue in C-Cg, R" and R'" represent, independently of each other, hydrogen or an alkyl group in C-Cg or, together, a C2-C6 alkylene group (possibly comprising 1 to 3 double bonds), and their physiologically acceptable salts, characterized by the fact that a) on condenses, with guanidine or one of its salts, a compound of formula T> I Or <1 42 in which R"*", R2, R^ and R^ have the aforementioned meanings, 5 Z represents a group -C(CN)=CH-Y or -CH(CH)CH{OR ) 9 Y represents 5 (xm starting group) and R represents a C-Cg allcyl group, or, together, the two Rs represent a 5-alkylene group, or b) of a compound of formula 10 iii R 15 in which X represents a halogen and R"*", R2, R^ and R^ have the aforementioned meanings, the substituent X is eliminated by reduction or c) with regard to the preparation of a compound of formula 1-1, a substituted benzylpyrimidine of formula 20 is reacted NH, 25 IV in which R represents a C-Cg alkoxy group (preferably the methoxy group), the benzyloxy group, the hydroxyl group, or a halogen, with a compound of formula Rla 35 V 43 10 15 20 25 30 35 in which R' JL 3 cX ^ R and R have the aforementioned meanings, 2 **> ^ d) we modify with respect to the substituents R, R° and/or R", or within the framework of generally known processes, a compound of formula I and, if desired, the compound thus obtained is transformed into a physiologically acceptable salt. 3. A process according to claim 1, characterized in that a compound of formula is prepared R 1 a 1-1 in which R .3a represents hydrogen or an alkyl group and represents a mercapto, alkylthio group at C3.~C6' carboxyalkylthio with alkyl residue in C-^-Cg, alkoxyalkylthio with residue; alkoxy and alkyl in C,-C,, dimethylcarbamoylthio, -S(0)R' or 4a. -SO2I-V1 and R represents an alkylthio group in c]_~cg; -S(0)R' or -SO2R', or one of their physiologically acceptable salts. 4. A process according to claim 1, characterized in that a compound of formula is prepared 1-2 in which R represents an alkylthio group in -S(0)R' or -SO2R', R^ represents an alkoxy group in C-^-Cg, mercapto, alkylthio in C^-Cg, carboxyalkylthio with alkyl residue in C^-Cg, dimethylcarbamoylthio, -S(0)R', -SO2R' or -NR"R'" and R4a represents an alkylthio group in -S(0)R' or -SO2R', or one of their physiologically acceptable salts. 5th Method according to claim 1, characterized by 9 44 the fact that we are preparing a compound formula NH, 1-3 10 in which R^*3 represents an alkoxy group in £"ePïé- sente a mercapto group, alkylthio in C^-C^, carboxyalkylthio with alkyl residue in C-j_~C6' alkoxyalkylthio with alkoxy and alkyl residues in C^-Cg, dimethylcarbamoylthio, -S(0)R' or -SO^R' and R^a represents an alkylthio group in cj_~cg/ -S(0)R' or -SO2&', or one of their physiologically acceptable salts. G. A process according to claim 1, characterized in that a compound of formula is prepared 20 25 1-4 30 2C - 3C r in which R represents a halogen, R represents a group 4-3. alkylthio in C^-Cg, -S(O)R' or -SO2R' and R represents an alkylthio group in C^-Cg, -S(O)R' or -SO2R', or one of their physiologically acceptable salts, 7. A process according to claim 1, characterized in that a compound of formula is prepared 1-5 45 10 15 20 25 30 35 2 J in which R represents a halogen or an alkoxy group in 3cL C^-Cg, R represents a mercapto-alkylthio group in C^-Cg. carboxyalkylthio with an alkyl residue at C^-Cg, carbalcoxyalkylthio with alkyl group remains at C^-Cg, cyanalkylthio with alkyl group remains at C^-Cg, alkoxyalkylthio with alkoxy and alkyl residues in C-Cg, alkoxyalkoxy- alkylthio with alkoxy and alkyl residues in C,-C,-, dimethylcarbamoyl- 4b thio, -S(O)R* or -SO2R' and R represents a halogen or an alkoxy group in C^-Cg, or one of their physiologically acceptable salts. 8. A process according to claim 2, characterized in that a compound of formula is prepared. I-5J in which R, 3a 2d represents a halogen or an alkoxy group in C,-C, R' represents a mercapto, alkylthio group in C^-Cg, carboxyalkylthio with alkyl residues at C1-Cg, alkoxyalkylthio with alkoxy and alkyl residues at C1-CK/ dimethylcarbamoylthio, -S(0)R' or 4b -SO2R' and R represents a halogen or an alkoxy group in C^-Cg, and their physiologically acceptable seis. 9. A process for preparing pharmaceutical compositions, characterized in that a 2,4-diamino-5-benzylpyrimidine of formula is mixed as the active constituent. R1 46 a) R represents hydrogen or an alkyl group in 2 3 C^-Cg, R represents hydrogen, R represents a mercapto group, alkylthio in carboxyalkylthio with alkyl residue in C^-Cg, alkoxyalkylthio with alkoxy and alkyl residues in C^-Cg, 5-dimethyl carbamoylthio, -S(0)R- or -SC^R1 and R4 represents an alkylthio group in C,-C,-, -S (0) R' or -S0~R', or 1 2 4 b) R represents hydrogen, R and R represent 3 each an alkylthio group in C^-Cg, -S(0)R' or -SC^R' and R represents an alkoxy group in C-^-Cg, mercapto, alkylthio in C^-Cg, 10 carboxyalkylthio with alkyl remainder in dimethylcarbamoylthio, -S(0)R', -S09R' or -NR"R"', or 1 2 c) R represents hydrogen, R represents a group 3 alkoxy in C^-Cg, R represents a mercapto group, alkylthio in C-Cg, carboxyalkylthio with alkyl residue at c1~cg/ alkoxyalkylthio 15 to alkoxy and alkyl residues in C^-C,-, dimethylcarbamoylthio, -S(0)R' 4 or -SO2R' and R represents an alkylthio group in C^-Cg, -S(O)R' or -SO~R', or 1 2 d) R represents hydrogen, R represents a halo- 3 gene, R represents an alkylthio group in C -C,., -S(0)R' or 4 20 -SO2R' and R represents an alkylthio group in / ~S(0)R' or -S0~R', or even 1 2 e) R represents hydrogen, R represents a halo- 3 gene or an alkoxy group in C-Cg, R represents a mercapto group, alkylthio in carboxyalkylthio with an alkyl residue in C-Cg, 25 carbalcoxyalkylthio with an alkyl residue in C-Cg, cyanalkylthio with an alkyl residue in Cg, alkoxyalkylthio with alkoxy residues in C-Cg, alkoxy-alkoxy-alkylthio with alkoxy and alkyl residues in C-Cg, dimethylcarbamoylthio, -S(0)R' or -SO2R1 and R4 represents a halogen or an alkoxy group in C-Cg/ however, in all 30 cases a) to e) mentioned above, R' represents an alkyl residue in C-Cg/ R" and R'" represent, independently of each other, hydrogen or an alkyl group in C-Cg or, together, a group alkylene in C2~Cg (possibly comprising 1 to 3 double bonds), or one of its physiologically acceptable salts, with 35 non-toxic and inert solid or liquid supports suitable for therapeutic administration and customary in such compositions, and that the mixture thus obtained is put into an appropriate galenic form. 47 10. A process for preparing pharmaceutical compositions, characterized in that the active constituents are mixed with a) a 2,4-diamino-5-benzylpyrimidine of formula in which a) R* represents hydrogen or an alkyl group 2 3 C1~Cg, R represents hydrogen, R represents a mercapto group, alkylthio in C^-Cg, carboxyalkylthio with an alkyl residue in C^-Cg, alkoxyalkylthio with alkoxy and alkyl residues in C^-Cg, dimethyl carbamoylthio, -S(O)R* or -SO2R' and R4 represents an alkylthio group in C,-C,-, -S(O)R' or -SO-R', or 1 2 4 b) R represents hydrogen, R and R represent 3 each an alkylthio group in C^-Cg,• -S(O)R" or -SO2R' and R represents an alkoxy group in Cj-Cg/ mercapto, alkylthio in C^-Cg, carboxyalkylthio a remains alkyl in dimethylcarbamoylthio, -S(0)R', ~S0,R' or -NR"R"«, or 1 2 c) R represents hydrogen, R represents a group 3 alkoxy in C-Cg, R represents a mercapto group, alkylthio in C-Cg, carboxyalkylthio with an alkyl residue in C-Cg, alkoxyalkylthio with alkoxy and alkyl residues in C-Cg, dimethylcarbamoylthio, -S(0)R' or -SO2R' and R4 represents an alkylthio group in C-Cg, -S(0)R' or -SO0R', or 1 2 d) R represents hydrogen, R represents a halo- 3 gene, R represents an alkylthio group at C -C,-, -S(0)R' or 4. 1 b -SO2R1 and R represents an alkylthio group in C^-Cg, -S(0)R' or -S09R', or even 1 2 e) R represents hydrogen, R represents a halo- 3 gene or an alkoxy group in c1~c6» R represents a mercap- group b 48 10 15 20 25 to, alkylthio in C-^-Cg,. carboxyalkylthio with alkyl residue in Cj-Cg/ carbalcoxyalkylthio with alkyl residue in C^-Cg/ cyanalkylthio with alkyl residue in alkoxyalkylthio with alkoxy and alkyl residues in (c) C-Cg, alkoxy-alkoxy-alkylthio with alkoxy and alkyl residues in C-Cg, dimethylcarbamoylthio, -S(O)R' or -SO2R', and R represents a halogen or an alkoxy group in C-Cg, whereas, in all cases a) to e) above, R' represents an alkyl residue in C1-Cg, R" and R'" represent, independently of each other, hydrogen or an alkyl group in C-Cg or, together, an alkylene group in C2-C6 (possibly 1 to 3 double bonds), or one of its physiologically acceptable salts, and (b) a sulfonamide with antibacterial activity, with non-toxic and inert solid or liquid supports suitable for therapeutic administration and customary in such compositions, and the mixture thus obtained is placed in a form appropriate dosage form. 11. Pharmaceutical compositions, characterized in that they contain a 2,4-diamino-5-benzylpyrimidine of formula 30 in which C1~C6' a) R represents hydrogen or an alkyl group in 2 3 R represents hydrogen, R represents a mercapto group, alkylthio in G→Cg, carboxyalkylthio with an alkyl residue in C→Cg, alkoxyalkylthio with alkoxy and alkyl residues in C→Cg#' dimethyl carbamoylthio, -S(O)R' or -SO2R' and R4 represents an alkyl- group 35 thio in C1-C(-, -S(0)R' or -S09R', or 1 2 4 b) R represents hydrogen, R and R each represent an alkylthio group in C^-Cg, -(O)R' or -SO2R' and R" D- 49 10 15 20 25 30 35 presents an alkoxy group at C]-Cg, mercapto, alkylthio at C-Cg, carboxyalkylthio remains alkyl at C]-Cg# dimethylcarbamoylthio, -S(O)R1, -SO-R' or -NR"R"1, or 1 2 c) R represents hydrogen, R represents a group 3 alkoxy in R represents a mercapto, alkylthio group in C-Cg, carboxyalkylthio with an alkyl group at C2.~C6' alCOXYa^cylt^iO with alkoxy and alkyl groups at C-Cg, dimethylcarbamoylthio, -S(O)R' or -SO2R1 and R4 represents an alkylthio group at C2.~C6' or ~S0~R', or 1 2 d) R represents hydrogen, R represents a halo- 3 gene, R represents an alkylthio group in -S(0)R' or -SO2R1 and R4 represent an alkylthio group in C^-Cg, -S(0)R! or -SO-R', or even 1 2 e) R represents hydrogen, R represents a halo- 3 R represents a gene or an alkoxy group at C2-Cg/ R represents a mercapto group, an alkylthio group, a carboxyalkylthio group with an alkyl residue at C2-Cg/ carbalcoxyalkylthio group with an alkyl residue at C2-Cg/ cYanalkylth:i-0 has an alkyl residue at C2-C6', alCOXyal^y^-tlli0 has alkoxy and alkyl residues at C2-Cg, alkoxy-alkoxy-alkylthio group with alkoxy and alkyl residues at C2-Cg, dimethylcarbamoylthio, -S(0)R' or -SO2R' and R4 represents a halogen or an alkoxy group at C2-Cg, while, in all cases a) to e) mentioned above, R* represents an alkyl residue at C2-C6'. R" and R'" represent, independently of each other, hydrogen or an alkyl group at Cj-Cg together, an alkylene group at C2~C6 (possibly taking 1 to 3 double bonds), or one of its physiologically acceptable salts, and a solid or liquid, non-toxic and inert support suitable for therapeutic administration. 12. Pharmaceutical compositions, characterized in that they contain (a) a 2,4-diamino-5-benzylpyrimidine of formula _ NH0 50 10 in which a) R"*" represents hydrogen or an alkyl group in 2 3 C^-Cg, R represents hydrogen, R represents a mercapto group, alkylthio in C2-CQ, carboxyalkylthio with an alkyl residue in C^-Cg, alkoxyalkylthio with alkoxy and alkyl residues in C^-Cg, dimethyl carbamoylthio, -S(0)R' or -SO2R' and R4 represents an alkylthio group in C,-Cr, -S(0)R1 or -SO2R', or 1 2 4 b) R represents hydrogen, R and R represent 3 each an alkylthio group at C^-Cg, -S(O)R' or -SO2R' and R represents an alkoxy group at C2-Cg » mercapto, alkylthio at C^-Cg/ carboxyalkylthio with alkyl residue at C^-Cg, dimethylcarbamoylthio, -S(0)R', -S0„R' or -NR"R"', or 1 2 c) R represents hydrogen, R represents a group 3 alkoxy in C-Cg, R represents a mercapto group, alkylthio in 15 carboxyalkylthio with alkyl remainder in cj[_~cg» alkoxyalkylthio to alkoxy and alkyl residues in > dimethylcarbamoylthio, -s(0)R' or -SO2R' and R4 represents an alkylthio group in C]-Cg, -S(0)R' or -SO«R', or 1 > ^ d) R represents hydrogen, R represents a halo- 3 20 gene, R represents an alkylthio group in c^~cg, -S(0)R' or -SO2R' and R4 represents an alkylthio group in C^-Cg, -S(0)R' or ~S0„R', or even 1 2 e).R represents hydrogen, R represents a halo- 3 gene or an alkoxy group at C-Cg, R represents a mercap-25 group, alkylthio at C2-C6' carkoxyalkylthio with an alkyl residue at C-Cg, carbalcoxyalkylthio with an alkyl residue at C-Cg, cyanalkylthio with an alkyl residue at C-Cg, alkoxyalkylthio with alkoxy and alkyl residues at C-Cg, alkoxy-alkoxy-alkylthio with alkoxy and alkyl residues at C-Cg, dimethylcarbamoylthio, -S(0)R' or ~S02R' and R4 represents a halo-30 gene or an alkoxy group at C-C6. However, in all cases a) to e) mentioned above, R' represents an alkyl residue at C-Cg, R" and R1" represent, independently, one of the other, hydrogen or a C-Cg alkyl group or, together, a C-Cq alkylene group (possibly comprising 1 to 3 double bonds), or 35 one of its physiologically acceptable salts and (b) a sulfonamide with antibacterial activity, and a suitable, non-toxic, inert solid or liquid carrier for administration 51 therapeutic. 13. 2,4-Diamino-5-benzylpyrimidines of general formula 10 in which 15 20 C1"C6' a) R represents hydrogen or an alkyl group in 2 3 R represents hydrogen, R represents a mer- group thio en ^-Cg, capto, alkylthio at C2.~^6' carboxyalkylthio with alkyl residue at C^-Cg, alkoxyalkylthio with alkoxy and alkyl residues at C^~C6' dimethyl carbamoylthio, ~S{O)R' or ~SO2R' and R4 represents an alkyl- group S(0)R' or -S0„R', or 2.4 b) R represents hydrogen, R and R represent 3 each an alkylthio group in cj_-cg, -s(0)r* or -sO2r' and r represents an alkoxy group in C^-Cg/ mercapto, alkylthio in C^-Cg, carboxyalkylthio with alkyl residue in C^-Cg, dimethylcarbamoylthio, ~s(o)r1 , -so2r! or -: NR"R' Or 3 2 c) R' represents hydrogen, R represents a group 3 ■25 alkoxy in C^-Cg, R represents a mercapto group, alkylthio in C^-Cg, carboxyalkylthio with alkyl residue in C^-Cg, alkoxyalkylthio with alkoxy and alkyl residues in C^-Cg, dimethylcarbamoylthio, -S(0)R' where -SO2R' and R4 represents an alkylthio group in C3-Cg, -S(0)R' or -SO^R', or 1 2 30 d) R represents hydrogen, R represents a halo- 3 gene, R represents an alkylthio group in c^_cg/ -S(0)R' or -SO2R' and R4 represents an alkylthio group in C-^-Cg, -S(0)R' or -SO-R1, or even 1 2 e) R represents hydrogen, R represents a halo- 3 35 gene or an alkoxy group in c^-cg/ R represents a mercapto group, alkylthio in C]-Cg, carboxyalkylthio with an alkyl residue in c1~cg# carboxyalkylthio with an alkyl residue in C^-Cg, cyanalkylthio with a residue 52 10 alkyl in c^~cq, alkoxyalkylthio with alkoxy and alkyl residues in C^-Cg, alkoxy-alkoxy-alkylthio with alkoxy and alkyl residues in C1-Cr, A J» O dimethylcarbamoylthio, -S(O)R' or -SO2R' and R represents a halogen or a C-Cg alkoxy group, whereas, in all cases a) to e) above, R' represents a C-Cg alkyl residue, R" and R'R' represent, independently of each other, hydrogen or a C-Cg alkyl group or, together, a C2-Cg alkylene group (possibly comprising 1 to 3 double bonds), or one of its physiologically acceptable salts. 14. 2,4-Diamino-5-benzylpyrimidine with general formula 15 20 in which C1"C6' a) R represents hydrogen or an alkyl group in 2 3 R represents hydrogen, R represents a mercapto group, alkylthio in C^-Cg, carboxyalkylthio with an alkyl residue in C^-Cg, alkoxyalkylthio with alkoxy and alkyl residues in C^-Cg, dimethyl .25 carbamoylthio, -S(0)R' or -SO2R' and R4 represents an alkylthio group in C,-Cc. -S(0)R' or -SO2R', or 1 1 94, b) R represents hydrogen, R and R represent 3 each an alkylthio group at C^~C6# -S(O)R' or -SO2R' and R represents an alkoxy group at C^-Cg, mercapto, alkylthio at C^~C6' 30 carboxyalkylthio with alkyl remainder at C2~C6' ^^ethylcarbamoylthio, -S(0)R', -50-R' or ~NR"R"1, or 1 2 c) R represents hydrogen, R represents a group 3 alkoxy at C2.~C6' ^ represents a mercapto group, alkylthio at C^-Cg, carboxyalkylthio with an alkyl residue at C-^-Cg, alkoxyalkylthio 35 with alkoxy and alkyl residues at dimethylcarbamoylthio, -S(0)r' or -SO2R' and R4 represents an alkylthio group in -S(0)R' or -SO^R', or 1'^ 2 d) R represents hydrogen, R" represents a halo- 3 gene, R represents an alkylthio group in C^-C5/ -S(0)R' or 53 10 -SO2R' and'R represent an allcylthio group in C^-Cg, -S(O)R' or -so2R', or 1 2 e) R represents hydrogen, R represents a halo- 3 R represents a gene or an alkoxy group in C6, R represents a mercapto group, an alkylthio group in carboxyalkylthio with an alkyl residue in C6, an alkoxyalkylthio group with alkoxy and alkyl residues in C6, dimethylcarbamoylthio, -SO2R, or -SO2R, and R4 represents a halogen or an alkoxy group in C6, whereas, in all cases a) to e) mentioned above, R' represents an alkyl residue in C6. R1 and R2 represent, independently of each other, hydrogen or an alkyl group in C6 or, together, an alkylene group in C2-C6 (possibly comprising 1 to 3 double bonds), and their physiologically acceptable salts. 15. 2,4-Diamino-5-benzylpyrimidines of general formula 15 20 25 30 in which R' ,3a the R1a 1-1 represents hydrogen or an alkyl group at R"" represents a mercapto, alkylthio group at C]_-Cg, carboxyalkylthio with alkyl residue at C2~C6' a^oxyal^ylthio with residue; alkoxy and alkyl at C]_-Cg/ dimethylcarbamoylthio, -S(O)R' or -SO2R' and R^a represents an alkylthio group at C2~C6' or -SO2R', or one of their physiologically acceptable salts. 16. 2,4-Diamino-5-benzylpyrimidines of general formula 35 1-2 54 ,2a in which R represents an alkylthio group in C,-C,, -S(0)R' 3b or -SC^R', R represents an alkoxy group in c1_cqi mercapto, alkylthio in c-j__cg, carboxyalkylthio with alkyl remainder in C^~Cg, dimethylcarbamoylthio, -S(0)R', -SC^R' or -NR"R'" and R^a represents an alkylthio group in C^-C^, -S(0)R' or -SC^R*, or one of their physiologically acceptable salts. 17. 2,4-Diamino-5-benzylpyrimidines of general formula 10 20 1-3 in which R2'° represents an alkoxy group in C-^-Cg, R^a represents a mercapto group, alkylthio in » carboxyalkylthio to alkyl residue in C,-C,., alkoxyalkylthio with alkoxy and alkyl residues 4a. in i dimethylcarbamoylthio, -S(O)R' or -SO2R' and R represent sent an alkylthio group in C^-Cg, -S(O)R* or -SO2R', or one of their physiologically acceptable salts. 18. 2,4-Diamino-5-benzylpyrimidines of general formula 25 30 1-4 in which R2c represents a halogen, R^C represents a group ^■a alkylthio in C^-Cg, -S(0)R* or -SO2R' and R * represents a 35 alkylthio group in C^~Cg, -S(0)R' or -SO2R', or one of their physiologically acceptable salts. 55 10 15 20 25 19. 2,4-Diamino-5-benzylpyrimidines with general formula NH, Rgd *N 1-5 in which represents a halogen or an alkoxy group 3d C^-Cg, R represents a mercapto group, alkylthio in carboxyalkylthio with an alkyl remainder in c±~cç, carbalcoxyalkylthio alkyl group remains at C-Cg, cyanalkylthio group remains at C-Cg, alkoxyalkylthio with alkoxy and alkyl residues at C2.~C6' alkoxyalcoxY- alkythio with alkoxy and alkyl residues in C,-C,. , dimethylcarbamoyl- 4b, thio, -S(O)R' or -SO2R' and R* represents a halogen or an alkoxy group in C^-Cg, or one of their physiologically acceptable salts. 20. 2,4-Diamino-5-betzylpyrimidines of general formula 1-5 I- 30 35 in which R, 3a 2d represents a halogen or an alkoxy group in C^-Cg, R"" represents a mercapto, alkylthio group in cj_"C6' carboxyalkylthio with alkyl residue in alkoxyalkylthio with alkoxy and alkyl residues in C-, -C-, dimethylcarbamoylthio, -S(0)R' or X O -SO2R* and R" represents a halogen or an alkoxy group in C2.-C6' and their physiologically acceptable salts. 21. General formula compound I chosen from: 56 2,4-diamino-5-/3,5-dimethoxy-4-(methylthio)-benzyl/-pyrimidine. 2,4-diamino-5-/4-(ethylthio)-3,5-dimethoxy-benzyl)-pyrimidine. 2,4-diamino-5-/3,5-dimethoxy-4-(2-methoxy-ethylthio)-benzyl-17-pyrimidine. 5 the 2,4-diamino-5-(3,5-dimethoxy-4-pyrrolobenzyl)-pyrimidine. 2,4-Diamino-5-/3-methyl-4,5-bis-(methylthio)-benzyl-17-pyrimidine. 2,4-Diamino-5-/%,5-bis-(methylthio)-benzyl/-pyrimidine. 2,4-Diamino-5-(5-bromo-4-methoxy-3-methylthiobenzyl-7-pyrimidine. 2,4-Diamino-5-/4-methoxy-3,5-bis-(methylthio)-benzyl-17-pyrimidine. 2,4-Diamino-5-(3-Bromo-4-Methylthiobenzyl)-pyrimidine. 2,4-Diamino-5-Z3,4,5-Tris-(Methylthio)benzyl-pyrimidine. 2,4-Diamino-5-(4-Methylthiobenzyl)-pyrimidine 2,4-Diamino-5-/3-bromo-4,5-bis-(methylthio)-benzyl1/-pyrimidine. 15 2,4-diamino-5-/3,5-dimethoxy-4-(mdethylsulfinyl)-benzyl17-pyrimidine. 2,4-di-amino-5-/^3,5-dimethoxy-4-(methylsulfonyl)-benzy 17-pyrimidine. 2,4-diamino-5-(4-mercapto-3,5-dimsthoxybenzyl)-20 pyrimidine hydrochloride 22. 2,4-Diamino-5-benzyi-6-halogenopyriraidines of general formula .25 30 III R in which ajR"1" represents hydrogen or an alkyl group 2 3 C^-Cg, R represents hydrogen, R represents a mer- group 35 capto, alkylthio in C2-Cg/ carboxyalkylthio with alkyl residue in C^-Cg, alkoxyalkylthio with alkoxy and "alkyl" residues in c3_~cg/ dimethyl carbamoylthio, -S(O)R' or -SO2R' and R4 represents an alkyl- group o 57 thio en c, -Ce, -S(0)R' iu -S0oR', ou 1 2 4 b) R represents hydrogen, R and R represent 3 each an alkylthio group in cj_-cg, -S(0)R' or -SC^R' and R represents an alkoxy group in mercapto, alkylthio in C^-Cg# 5 carboxyalkylthio with alkyl remainder in cj_~cg/ dimethylcarbamoylthio, -S(0)R', -S07R' or -NR"R"', or 1 2 c) R represents hydrogen, R represents a group 3 alkoxy in C-Cg, R represents a mercapto group, alkylthio in C-Cg, carboxyalkylthio with an alkyl residue in C-Cg, alCOXYal₂Y; i-t: i0 10 with alkoxy and alkyl residues in C-Cg, dimethylcarbamoylthio, -S(0)R' or -SO₂R1 and R4 represents an alkylthio group in C-Cg, -S(0)R' or -SO₂R', or 1 2 d) R represents hydrogen, R represents a halo- 3 gene, R represents an alkylthio group in C^-Cg, -S(0)R* or 15 -SO2R1 and R4 represents an alkylthio group in c^~cg/ -S(0)R' or -S0„R', or even 1 2 e) R represents hydrogen, R represents a halo- 3 gene or an alkoxy group in C-Cg, R represents a mercapto group, alkylthio in C-Cg, carboxyalkylthio with an alkyl residue in C-Cg/ 20 carb alkoxy alkyl thio with an al'.cyl residue in -Cg, cyanalkylthio with an alkyl residue in C-Cg, alkoxyalkylthio with alkoxy and alkyl residues in C-Cg, alkoxy-alkoxy-alkylthio with an alkoxy and alkyl residue in C-Cg/ dimethylcarbamoylthio, -S(0)R' or -SO2R1 and R4 represents a halogen or an alkoxy group in C-Cg, whereas, in all 25 cases a) to e) mentioned above, R' represents an alkyl residue in C-Cg, R" and R'" represent, independently of each other, hydrogen or an alkyl group in C^-C^ or, together, an alkylene group in C2~cg (possibly including 1 to 3 double bonds), 23rd 2,4-diamino-5-benzyl-6-halogenopyrimidines of general form-30 S 58 in which a) R"*" represents hydrogen or an alkyl group in 2 3 C-L-Cg, R represents hydrogen, R represents a raercapto group, alkylthio in c^-cg, carboxyalkylthio with alkyl residue in C^-Cg, alkoxyalkylthio with alkoxy and alkyl residues in C2~C6' dimethyl 5 carbamoylthio, -S(0)R'" or -SO2R' and R4 represents an alkylthio group in C.,-Cr, -s(0)R' or -SO„R', or 1 6 1 , » 2 ' 4 b) R represents hydrogen, R and R represent 3. each an alkylthio group in c]_~cg/ -S(0)R' or -SC^R' and R represents an alkoxy group in C^-Cg, mercapto, alkylthio in C-^-Cg, 10 carboxyalkylthio with alkyl remainder in C]_-Cg, dimethylcarbamoylthio, -S(0)R', -SO-R' or -NR"R'", or 1 2 c) R represents hydrogen, R represents a group 3 alkoxy in C-Cg, R represents a mercapto group, alkylthio on C-Cg, carboxyalkylthio with an alkyl residue in C-Cg# alkoxyalkylthio 15 with alkoxy and alkyl residues in C2-Cg» dimethylcarbamoylthio, -S(0)R' or -SO2R' and R"J represents an alkylthio group in C;j_~cg, -S(0)R' or -SO2R', or 1 - 2 d) R represents hydrogen, R represents a halo- 3 gene, R represents an alkylthio group in C]-Cg, -S(0)R' or 20 -SO2R' and R4 represents an alkylthio group in C^-Cg/ -S(0)R' or -SO^R', or even 1 >2 e) R represents hydrogen, R represents a halo- ^ 3 gene or an alkoxy group in C^-Cg, R represents a mercapto, alkylthio group in C6' cark0XYal^yl't:ki0 a remains alkyl in C^-Cg, 25 alkoxyalkylthio with alkoxy and alkyl residues in C1-Cf, dimethylearba- 4 - moylthio, -S(0)R' or -SO2R1 and R represents a halogen or an alkoxy group in c]_""cg" whereas, in all cases a) to e) above, R' represents an alkyl remainder in C^-Cg > R" and R'" represent, independently of each other, hydrogen or an alkyl group in C^-Cg or, together, an alkylene group in C2-Cg (possibly comprising 1 to 3 double bonds) 24. General forrojule aldehydes R£ A >*CH0 h 35 VIII R 59 t clans in which a) R represents hydrogen or an alkyl group in 2 3 C-Cg, R represents hydrogen, R represents a mercapto group, alkylthio in C-Cg, carboxyalkylthio with an alkyl residue in C-Cg, alkoxyalkylthio with alkoxy and alkyl residues in C-Cg, dimethyl carbamoylthio, -S(0)R' or -SC^R' and R4 represents an alkylthio group in C,-Cc, -S(0)R' or -S0oR', or 1 2 . 2 4 b) R represents hydrogen, R and R represent 3 each an alkylthio group in C^-Cg, -S(0)R' or -SC^R1 and R represents an alkoxy group in C^-Cg, mercapto, alkylthio in c^~cg/ carboxyalkylthio with alkyl remainder in c3_~cgi dimethylcarbamoylthio, —S(0)R', -SO-R' or -NR"R"', or 1 2 c) R represents hydrogen, R represents a group 3 alkoxy in C-Cg, R represents a mercapto group, alkylthio in C-Cg, alkylthio with alkyl residue in C-Cg, alkoxyalkylthio with alkoxy and alkyl residues in C-Cg, dimethylcarbamoylthio, -S(0)R' or -S(0)R', and R4 represents an alkylthio group in C-Cg, -S(0)R' or -S(0)R', or 1 2 v d) R represents hydrogen, R represents a halo- 3 gene, R represents an alkylthio group in C-Cg, -S(0)R' or -SO2R' and R4 represents an alkylthio group in C-Cg, -S(0)R' or -SO-R', or even 1 2 - e) R represents hydrogen, R represents a halo- 3 gene or an alkoxy group at C2.~C6' R represents a mercap-25 group, alkylthio at C2~cg» car^0xya^cyltîi;i-0 a alkyl residue at C^-Cg, carbalcoxyalkylthio with an alkyl residue at C^-Cg, cyanalkylthio with an alkyl residue at cj_-cgt alkoxyalkylthio with alkoxy and alkyl residues at C^-Cg, alkoxy-alkoxy-alkylthio with alkoxy and alkyl residues at C^-Cg, dimethylcarbamoylthio, -S(0)R' or -SO2R* and R4 represents a halo-30 gene or an alkoxy group at C^-Cg# However, in all cases a) to e) mentioned above, R' represents an alkyl residue at c~cgf and R1" represent, independently one from the other, hydrogen or an alkyl group in C^-Cg °u, together, an alkylene group in C^-Cg (possibly including 1 to 3 double bonds), with the exception of 3,4-bis-(methylthio)-benzaldehyde. 25. Aldehydes of general formula 10 15 20 60 CHO VIII 10 in which a) B?" represents hydrogen from an alkyl group 2 3 C-Cg, R represents hydrogen, R represents a mercapto group, alkylthio at C-Cg, carboxyalkylthio with an alkyl residue at C-Cg, alkoxyalkylthio with alkoxy and alkyl residues at C-Cg, dimethyl 15 carbamoylthio, -S(O)R' or -SO2R' and R4 represents an alkylthio group at C-Cr, -S(O)R' or -SO-R', or 1 2 4 b) R represents hydrogen, R and R' represent 3 each an alkylthio group at C]-Cg/ -S(O)R' or -SO2R' and R represents an alkoxy group at C]-Cg/ mercapto, alkylthio at C2-C6' 20 carbc-cyalkylthio with alkyl remainder at C1-Cg/ dimethylcarbamoylthio, -S(0)R', -S09R' or -NR"R"', or 1 2 c) R- represents hydrogen, R represents a group 3 alkoxy in C-Cg, R represents a mercapto group, alkylthio in C-Cg, carboxyalkylthio with alkyl residue at C2.~C6' a-C0XYa-!-^yl't:^1-0 25 with alkoxy and alkyl residues at C-Cg, dimethylcarbamoylthio, -S(0)R' r or -SO2R' and R' represents an alkylthio group in -S(0)R' or -S0~R1, or 1 2 d) R represents hydrogen, R represents a halo- 3 gene, R represents a C^-Cg alkylthio group, -S(0)R' or 30 -SO2R' and R4 represents a C^-C^ alkylthio group, -S(0)R' or -S09R', or even 1 2 e) R represents hydrogen, R represents a halo- 3 gene or an alkoxy group in C^-Cg,'R represents a mercapto group, alkylthio in C^-Cg, carboxyalkylthio with alkyl residue in C^-Cg, 35 alkoxyalkylthio with alkoxy and alkyl residues in C]__C5, dimethylcarbamoylthio, -S(0)R' or -SOpR' and R4 represents a halogen or an alkoxy group in C^~Cg/ however, in all cases a) to e) 61 As mentioned above, R"*" represents an alkyl group in C;j_~Cg, R" and R1" represent, independently of each other, hydrogen or an alkyl group in C^-Cg or, together, an alkylene group in ^2~C6 (possibly including 1 to 3 double bonds), with the exception " ,1' , 5 of 3,4-bis-(methylthio)-benzaldehyde. 26. Aldehydes of general formula R 1 8 CHO VIII-1 R4a 15 3- a r N in which R represents hydrogen or an alkyl group 3 3, R represents a mercapto-alkylthio group in C]-Cg, carboxyalkylthio with alkyl residue at C]-C5, alkoxyalkylthio with alkoxy and alkyl residues at C^-Cg, dimethylcarbamoylthio, -S(0)R' or 20 -SO2R* and R4a represents an alkylthio group at -S(0)R' or -SO2R', with the exception of 3,4-bis-(methylthio)-benzaldehyde. 27. Aldehydes of general formula 10 2a in which R represents an alkylthio group at C,-C-, -S(0)R' 3 b pu -SO2R', R represents an alkoxy group at C]_~C5/ mercapto, alkylthio in carboxyalkylthio with alkyl remainder at C-^-Cg , 35 dimethylcarbamoylthio, -S(0)R', -SO2R' or -NR"R'" and R4a represents an alkylthio group in C-^-Cg, -S(0)R' or -SO2R11. 62 28. Aldehydes of general formula CHO viii-3 10 2b 3 a. in which R represents an alkoxy group in R constituting a mercapto group, alkylthip at C2-~Cg, carboxyalkylthio with an alkyl residue at C1-~C9, alkoxyalkylthio with alkoxy and alkyl residues at dimethylcarbamoylthio, -S(O)R' or -SO2R' and R4a 15 sends an alkylthio group in C^-Cg, -S(O)R' or -SO2R'. 29.0 Aldehydes of general formula represent- 20 CHO VIII-4 25 30 35 2c 0 x 3 o - in which R represents a halogen, R represents a group 4 a. alkylthio in C-^-Cg, ~S(0)R' or -SO2R' and R represents an alkylthio group in , -S(0)R' or -SO2R'. 30» Aldehydes of general formula CHO viii-5 63 10 15 in which R represents a halogen or an alkoxy group in 3d C-Cg, R represents a mercapto group, alkylthio in C-Cg, carboxyalkylthio with an alkyl residue in C-Cg, carbalcoxyalkylthio with an alkyl residue in C2-Cg, cyanalkylthio with an alkyl residue in C-Cg, alkoxyalkylthio with alkoxy and alkyl residues in C-Cg, alkoxyalkoxy-alkylthio with alkoxy and alkyl residues in C-Cg, dimethylcarbamoylthio, -S(0)R' or -SO2R1 and R4''3 represents a halogen or an alkoxy group in C-Cg 31. Aldehydes of general formula CHO VIII-5' in which R" represents a halogen or an alkoxy group 3a 20+ C^-Cg, R represents a mercapto, alkylthio group in the C11~C6' configuration. carboxaylkylthio with alkyl residue in alkoxyalkylthio with alkoxy and alkyl residues in C, dimethylcarbamoylthio, -S(0)R' or -SO2R' and Rx represent a halogen or an alkoxy group in C^-Cg. 32. As new medicinal products, the compounds of 25 general formula I according to any one of claims 13 to ORIGINAL in JB» P*9®s containing References . word added mol W* José CURAU Industrial Property Consulting Firm 26th Princess Charlotte Blvd. MONTE-CARLO By proxy of T. - <L&