LU81031A1 - BENZYLPYRIMIDINE AND METHOD FOR PRODUCING THE SAME - Google Patents

Description

D. 5o.464

-0 ï ArAND-DUCHÉ DE LUXEMBOURG

Brevet N · -------------------------------------------- du .1.2 .... rnars ..... 19.79 ............ (TOP Monsieur le Ministre 1¾¾¾ de l'Économie Nationale et des Classes Moyennes

Titre délivré: _____________________________________ -¾¾ gijJæs] Service de la Propriété Industrielle

“LUXEMBOURG

M ipW

// j7 k Demande de Brevet d'invention I. Requête ........ La société dite: ..... P ...... HOFFMANN-LA ROCHE ..... & CO .. .... AKTIENGESELL -............... {1) ........ shaft ...... â 4oo2 BALE ...... Suisse » ..... représentée par Monsieur Jacques .....

........ de..Muyser, ..................................... ......................................... (2) i l.er jour Ü ^ OVERVIEW ................................................ ....... (3) a ............ ib ........... heures, au Ministère de l'Économie Nationale et des Classes Moyennes, à Luxembourg: 1. la présente requête pour l'obtention d'un brevet d'invention concernant: ......... "Benzylpyrimidine ..... and process for its production” ........ ...................... (4) déclare, en assumant la responsabilité de cette déclaration, que l '(es) inventeur (s) est (sont): ......... 1.-..... I.van ... j; OHEIS.ji ..... L. ^ fefcfènh.0.fs.traL.SSa_.5_ «. ..... à.OBERWIL.j, ..... Suisse ........................... (5) ... ...... 2 ...-..... Alexander ..... Eduard ... WICK. »..... Mhlestieg.s.trasse ..... à RIEHEN, __________________ .. ......................... Suisse ........................ .................................................. .................................................. ...................................... .................................................. .............

2. la délégation de pouvoir, datée de ........ BÂLE ................................ .............. le 7 ..... ί5.§. ¥! .§ ...... 1? .. Ζ? ......... ..............

3. la description en langue ......... al.l ^ iiande .............................. .... de l'invention en deux exemplaires; 4 ........ LL .............. ... planches de dessin, en deux exemplaires; 5th la quittance des taxes versées au Bureau de l'Enregistrement à Luxembourg, le .......... 12jnars 1979 ..................... .................................................. .................................................. .................................................. .............................................

revendique pour la susdite demande de brevet la priorité d'une (des) demande (s) de (6) ........................... .fe.t.syst ......................................... déposée (see ) en (7) ............................................. .................................................. ............

le ........... lo mars ..... 19.78 ........... (Ho ...... 2650/78) ....... .................................................. .................................................. ................................ (8) au nom de ..... l. ^ .... déppsante ................................................. .................................................. .................................................. .................................... (9) élit domicile pour lui (elle) et, si désigné , pour son mandataire, à Luxembourg ------------------------------------- - ..... ... 3.5 .., ..... bld. Royal ................................................. .................................................. .................................................. .................................................. (io) sollicite la délivrance d'un brevet d'invention pour l'objet décrit et représenté dans les annexes sœi ^ en ^ nnée ^ - avec ajournement de cette délivrance à .............. ..k? ........................ mois.

II, Procès-verbal de Dépôt

La susdite demande de brevet d'invention a été déposée au Ministère de l'Économie Nationale et des Classes Moyennes, Service de la Propriété Industrielle à Luxembourg, en date du: 12 mars 1979 V \ Pr. Le Ministre à ..... ......... 15 ....... heures / / ^ \ ^ jfiSe l'économie Nationale et des Classes Moyennes, T / -λ ............. ........... ii rTPt i rV> v_, j il) \ \ $ \ iy *: -J (/

f j iS A 58007 (J S

D. 50,464

, PRIORITY CLAIM

«__________,« * · _ der Patent / (ffitft ./- application IN: DER SCHWEIZ_

Dated: MARCH 10, 1978 νλληΑΜΑ

PATENT APPLICATION

in

Luxembourg

Applicant: F. HOFFMANN-LA ROCHE & CO. STOCK COMPANY

Subject: "Benzylpyrimidines and process for their preparation".

Λ «· W *" f * »***** 4440 / 151-1 K \ τ..

F. Hoffmann-La Roche & Co. Aktiengesellschaft, Basel / Switzerland

Benzylpvriniidines and process for their preparation

The present invention relates to new benzylpyrimidines, namely substituted 2,4-diamino-5-benzylpyrimidines of the general formula 5 R10 R3 \) -V / -Nv / ^ λΡ / - ° Η2-λΟ / “ΝΗ2 1

r2q H2N

1 2 5 wherein R and R are a C, ^ - alkyl radical, 3 1-6 'R a C, _ ..- alkyl radical and

4 1 y

R represents methylene or a C2 _ ^ - alkylidene radical, and their physiologically tolerable acid addition salts, 10 and processes for their preparation.

- 2 - *.

«Ι

C, -alkyl radicals are understood to mean both straight and branched 1-6-chain radicals, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc. C2_4-alkylidene radicals Ethylidene, propylidene, isopropylidene, butylidene, 5 isobutylidene and sec-butylidene.

Preferred compounds of the formula I are on the one hand 1 2 those in which R and R represent a C 1-4 alkyl radical, in particular a methyl or ethyl radical, and on the other hand those in which R 3 is a C 1-4 alkyl radical and 10 R ^ methylene or ethylidene .

Examples of compounds of the formula I according to the invention

are: 15 2,4-diamino-5- (4-isopropenyl-3,5-dimethoxybenzyl) pyrimidine, 2.4-diamino-5- (3-ithoxy-4-isopropenyl-5-methoxybenzyl) pyrimidine, 2.4-diamino -5- (3, f'-diethoxy-4-isopropenylbenzyl) pyrimidine, 20 2.4- diamino-5- <3dimethoxy-4- [2- (2-butenyl)] benzyl> -25 pyrimidine, 2.4- diamino- 5- <3,; - diethoxy-4- [2- (2-butenyl)] benzyl> pyrimidine, 2.4-diamino-5- <3, ^ -dimethoxy-4- [3- (2-pentenyl) ] -benzyl> -pyrimidine and 30 2,4-diamino-5 - <, 3 ,: -diethoxy-4- [3- (2-pentenyl)] -benzyl> - pyrimidine.

h - 3 - «.

»

According to the invention, the benzylpyrimidines of the formula I and their salts can be prepared by a) a compound of the formula R10 R3 / - \ / \ HO -! - (0 / _ ^ CH2_H \ 0 / NHR6 "

R5 \ -f \ -N

r2 (j R6HN

I 12 3 I 5 wherein R, R and R are as defined above, R ^ represents a C, _.- alkyl radical and g R represents hydrogen or an amino protecting group | -, optionally with simultaneous removal of existing 10 amino protecting groups, dehydrated, or j: b) a compound of the formula | R10 and R3. ) -v i WoV2

! · · / W

I r2o / «! I i> 1 4

Ji in which the radicals R - R are as defined above and .. Z is a group of the formula; 15 represents -CH2-CH (CN) -CH (OR7) 2 or -CH_-C (= CHY) CN, where 7. z R is a C ^ _ ^ alkyl group or both

R7 together represent a C ^ _ ^ - alkylene group and Y is a leaving group,% i - 4 - ft with guanidine or a guanidine salt, or that c) the hydroxy group in a compound of the formula H ° \ R3 \ / - \ / - \

\ - / QY-CH2- (O / NH2 IV

R4 / Y N

r2o / h2n

2 3 4 p

wherein R, R and R are as defined above, 5 etherified to a C ^ _g alkoxy group or that d) from a compound of the formula

R10 X

^^ - CH2 —— NHs vi11 r20 H2N

12 3 4 wherein X represents chlorine or bromine and R, R, R and R have the meanings given above, 10 reductively removes the substituent X, and that, if desired, a compound of the formula I obtained is converted, if desired, into an acid addition salt.

According to variant (a) of the process according to the invention, a compound of the formula II is dehydrated. The dehydration- J *! 15 can be done in a manner known per se, i.e. to ;

Methods for water separation from secondary and! tertiary alcohols are known (see e.g. Fieser & Fieser,

Reagents for Organic Synthesis, Volumes 1-5, John Wiley & Sons,

U

% - 5 - »\

Inc., N.Y., 1967-1975). It is preferably carried out in the presence of acidic dehydrating agents, such as inorganic or organic acids (e.g. HCl, HBr, p-toluenesulfonic acid), suitably in aqueous / alcoholic solution, at pH 5 below 5 and at room temperature to the reflux temperature of

Reaction mixture. However, it can also be carried out in suspension using an organic solvent such as tetrahydrofuran, dioxane, dimethyl sulfoxide etc. The dehydration can also be purely thermal, i.e. by heating 10 in a suitable solvent to about 100 ° to the reflux temperature of the mixture.

Any amino protecting groups present in a compound of formula II, such as e.g. Acyl residues (e.g. formyl, acetyl,

Trifluoroacetyl), alkoxycarbonyl residues (e.g. tert.-butoxycar-15 bonyl) or aralkoxycarbonyl residues (e.g. benzyloxycarbony1), j are split off under the conditions of acidic dehydration 'to form amino groups.

According to variant (b) of the process according to the invention, a compound III is reacted with guanidine or a guanidine salt 20. The implementation can follow in a manner known per se, e.g. in an organic solvent, such as an alkanol (methanol, ethanol), in dimethylformamide, dimethyl sulfoxide or N-methylpyrazolone, at a temperature between 25 and 200 °, preferably between 50 and 170 °. For example, the carbonate and the hydrochloride can be used as guanidine salts. Representative examples of leaving groups represented by the symbol Y in formula III are e.g. Alkoxy groups, such as methoxy, ethoxy, propoxy etc., alkylthio groups, amino, amino substituted by aliphatic, aromatic or hetero-30 cyclic radicals, such as alkylamino, benzylaminino, arylamino (eg optionally substituted anilino or naphthylamino), dialkylamino, Pyrrolidino, Piperidino, * Piperazino or Morpholino. The is particularly preferred

Anilino radical, the phenyl ring of which may optionally be substituted one or more times by halogen, alkyl or alkoxv.

% - 6 - «♦

The starting compounds of formula III can be prepared according to the following reaction scheme; R10 R3 / - \

HO - \ C3 / -CH ° VI

R20 'R10 R3 \ -v | - (O) —cho v R4) - 'R20

1. NC — CH? —CH2OR7 / v CN

7 / \ + H2C

2. LIST7 / \ \ / \ ch2y r1o R1o

r3 \ -v ^ CN R3 \ -, CN

/) - (0 / cH2-c \ /, r7 /) - (0) -ch2-\ r /) -7 CXH J) -7 CHY

r2o 'or7 r2o' - 7 - «%

A compound of the formula VI (known, for example, from Belgian Patent No. 818 131) is dehydrated in analogy to the manner described above as variant (a) to give a compound of the formula V which then, in analogy | 5 to those in Belgian patent no. 818 131 be described methods, either by condensation with a jj ß-alkoxypropionitrile and subsequent addition of a 1 * η, 1 alkanol R OH in a compound of formula III-1 or by | base-catalyzed condensation with a ß-substituted I 10 propionitrile of the formula Y-C ^ -C ^ -CN in a polar apro-; table solvent in a compound of formula III-2 j; is transferred.

li f ’

The intermediates of formula V are new compounds; and also the subject of the present invention.

i, i 15 By reacting a substituted benzaldehyde V with

Malodinitrile gives a compound of formula i -! 3 R10 R \ / 7 ^ \ / cn; / WOV "<

i /) - / CN

R20 | by reduction with a complex metal hydride, e.g.

i with sodium borohydride, at room temperature can easily be converted into an i Î 20. compound III-2 with Y = amino.

According to process variant (c), the hydroxy group i is etherified in a compound IV. This happens in itself; known by reaction with an alkylating agent 1 1 R X, wherein R is as defined above and X is, for example, 25 chlorine, bromine or iodine. This process variant is particularly suitable for the preparation of compounds I, in which i 12 - 8 - * where R φ R. The starting compounds can be obtained in a manner known per se. For example, they can be produced very easily and with high yield by partial demethylation of 3,5-dimethoxybenzyl compounds of the formula I with 5 excess sodium ethyl mercaptide in dimethylformamide.

, The removal of a chlorine or bromine substituent from; A compound VIII according to process variant (d) can be treated by treatment and a reducing agent in a manner known per se. Suitable as a reducing agent is, for example, zinc, preferably in an amalgamated form, in acetic acid solution.

The starting compounds VIII can be prepared in a conventional manner, e.g. on the following 15 reaction schemes.

/ U

!.

9 v - 9 - «.

Reaction scheme R10 ^ CN R \! R \ U H2CX r \ V-Λ cn

! teteote ™ CO0C2Hs / ^ aO) -ch = cC

! p4 y- r4 y COOC2H

| r2o v r2o R10 i R10 R \ \ -v '\ \ / Vvv ^ / cn

r3) -, y) - \\ ^ J / —ch2 — CH

y) - (O) -CH2Cl r4 C00C2l j; r4 //) - 'r2 ° i: r2 ° \ i \ * te-, / i, \ \ te / + guanidine

|: X H2N

i: 'l' i! _ 1 R 0 ho j CH2 -NH2

i R4 J ^ j-N

R2o h2n j

VIII -► I

! f, # - 10 - For the production of acid addition salts, in particular those which can be used in pharmaceutical preparations, i.e. Physiologically acceptable salts, the inorganic and organic acids usually used for this purpose are considered, such as hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, oxalic acid, tartaric acid, maleic acid, benzoic acid, succinic acid, fumaric acid, levulinic acid, salicylic acid, citric acid , Isocitric acid, adipic acid, lactic acid, α-ketoglutaric acid, malic acid, malonic acid, glyceric acid, 10 mevalonic acid, glucuronic acid, neuraminic acid, glutaric acid, aspartic acid, glucoheptonic acid, glutamic acid, nicotinic acid, nicotinic acid, nicotinic acid, nicotinic acid, nicotinic acid, nicotinic acid, nicotinic acid, nicotinic acid, nicotinic acid, nicotinic acid, nicotinic acid, nicotinic acid, nicotinic acid, nicotinic acid, nicotinic acid, nicotinic acid, nicotinic acid, nicotinic acid, nicotinic acid, nicotinic acid, nicotinic acid, nicotinic acid, nicotinic acid, nicotinic acid, nicotinic acid, nicotinic acid, nicotinic acid, nicotinic acid, nicotinic acid, nicotinic acid, nicotinic acid, nicotinic acid, and Cytidic acid and inosic acid.

15 The compounds of formula I are antibacterial. They inhibit bacterial dihydrofolic acid reductase (DHFR) and also potentiate the action of sulfonamides and other dihydrofolic acid synthetase inhibitors. Examples of sulfonamides which are potentiated by the compounds 2o according to the invention are sulfadiazine, sulfadimethoxine, sulfadoxine,

Sulfamethoxazole, sulfisoxazole, sulfamoxol, 3-sulfanilamido-4,5-dimethyl-isoxazole, sulfals, sulfamerazine, sulfameters, sulfamethazine and 6-methoxy-4-sulfanilamido-pyrimidine. In terms of quality, they are comparable to structurally similar benzylpyrimidines 25, for example the 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine or the 2,4-diamino-5- (3,5-dimethoxv-) 4-methylbenzyl) pyrimidine. Quantitatively, however, the compounds according to the invention are distinguished from the known compounds by 30 lower 50% inhibitory concentrations of bacterial DHFR, for example in E. coli, and by significantly higher Q values (50% inhibition of DHFR in rats / 50% inhibition of DHFR in E. coli), which are a must for the selectivity of inhibiting the bacterial DHFR.

35 The following table shows three representative orf i 'Πί ^ πηΓΓ ^ ΓΤ pm ii.QCP Vpr-Vn riHi cHpkp Wp.rfp anrronnKûn · I - Il - I «m2

JoCidf 'R3 <

50% inhibition of DHFR

Compound R1 R2 r ^ (mol / 1) x 10 8 • _____ E. coli rat / E. coli CH3 1 OC2H5 -CC OC2H5 0.22 160 000: ch2

i OH

j 2 OCH3 -C ^ OCH 0.34 440 000! CH2 i / ch3 3 3 OCH -C 'OC_H 0.32> 100 000! 3 Vch. 2 5 i z i i 5 i

i "/ U

5 q i «- 12 -

The compounds according to the invention can be used as pharmaceutical preparations with direct or delayed release of the active ingredient in a mixture with an organic or inorganic organic carrier material suitable for oral, rectal or parenteral administration, such as e.g. Water, gelatin,

Gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc. can be used. The pharmaceutical preparations can be in solid form, e.g. as tablets, dragees, suppositories, capsules; in 10 semi-solid forms, e.g. as ointments; or in liquid form, e.g.

as solutions, suspensions or emulsions. If necessary, they are sterilized and / or contain further auxiliaries, such as preservatives, stabilizers,

Wetting or emulsifying agents, agents for improving taste, salts for changing the osmotic pressure or

Buffer substances. The pharmaceutical preparations can be produced in the manner familiar to any person skilled in the art.

In preparations in which the compounds according to the invention are administered in combination with sulfonamides, the weight ratio of the two components to one another can vary within wide limits. It can be between 1:40 and 10: 1 and is preferably 1: 5 to 5: 1. A tablet can contain, for example, 80 to 400 mg of a compound I and 400-80 mg of a sulfonamide. In the case of preparations with a 25 compound I as the only active component, the guideline value for a single dose can be 100-1000 mg, which can be administered one or more times a day, as required.

u r for i! - 13 - ι, Example 1 h A suspension of 31.8 g of 4 - [(2f4-diamino-5-pyrimidyl) - methyl] -2,6-dimethoxy-a, a-dimethylbenzyl alcohol in 600 ml of methanol and 60 ml conc. Hydrochloric acid was heated to reflux for 1 hour with stirring and then under reduced pressure Pressure evaporated to dryness. The residue was suspended in 300 ml of water and the suspension after adding 25%

; aqueous ammonia solution with ice cooling to a pH

: stirred from about 10 another hour. The solid residue was filtered off with suction, washed neutral with water, dried and gave 27.6 g (92%) of 2,4-diamino-5- (4-isopro-! Penyl) -3,5-dimethoxybenzyl) pyrimidine, F. 228-229 ° c (from

Methanol).

'Example 2 i l | 15 A solution of 5.0 mg of 4 - [(4-acetylamino-2-amino-5- * pyrimidyl) methyl] -2,6-dimethoxy-cc, a-dimethylbenzyl alcohol was concentrated in 1 ml of conc. Hydrochloric acid heated under reflux.

! After cooling the reaction mixture was concentrated with. brought aqueous 1 ammonia to pH 10 and three times with 2 ml of vinegar ΐ? 20 acid ethyl esters extracted. The extract was dried, evaporated and, after recrystallization, the residue yielded 3.2 mg of 2,4-diamino-5- (4-isopropenyl-3,5-dimethoxy- | benzyl) -pyrimidine, F from methanol . 228-229 ° c.

u i Example 3 | 25 A suspension of 280.7 mg guanidine carbonate, 162 mg sodium methoxide and 273 mg 4-isopropenyl-3,5-dimethoxy-a- Ϊ (methoxymethylene) dihydrocinnamic acid nitrile was exposed to for 18 hours! 'Stirring heated to reflux, then the solvent * was removed under reduced pressure, the residue was stirred for 30 minutes' with 20 ml of water and the solid crude product was removed sucks. After recrystallization from methanol, 180 mg of jI (60%) 2,4-diamino-5- (4-isopropenyl-3,5-dimethoxybenzyl) - - 14- 4 pyrimidine, mp 228-229 ° C.

The starting material was produced as follows:

To a solution of 22.4 g of 4- (2-hydroxy-2-propyl) -3,5-dimethoxybenzaldehyde in 150 ml of benzene were added 10 ml of methanol and 5 10 ml of 2N hydrochloric acid. The mixture was under for 2 hours

Nitrogen gassing heated to reflux, brought to dryness under reduced pressure and the residue recrystallized from n-heptane. 15 g of 4-isopropenyl-3,5-dimethoxy-benzaldehyde, mp 97-98 ° C., were obtained.

10 A solution of 1 g of 4-isopropenyl-3,5-dimethoxybenzaldeyd, 0.375 g of β-methoxy-propionitrile and 0.1 g of sodium methylate in 5 ml of methanol was heated under reflux for 24 hours. The solvent was stripped off, the residue was dissolved in 10 ml of benzene and 5 ml of water and the benzene phase was separated off, which, after being washed several times with water, was dried and concentrated. This gave 0.92 g of 4-isopropenyl-3,5-dimethoxy-a- (methoxymethylene) dihydrocinnamonitrile which, after chromatographic purification on silica gel with ether, had a melting point of about 40 ° C.

Example 4 - * 20

2.85 g of guanidine carbonate and 3.5 g of 4-isopropenyl-3,5-dimethoxy-a- (anilinomethylene) dihydrocinnamic acid nitrile were added to a solution of 0.73 g of metallic sodium in 25 ml of ethanol, and the suspension became 18 Heated to reflux for hours with stirring. The solvent was reduced

The pressure is removed, the residue is stirred with 50 ml of water and suction filtered. After recrystallization from methanol, 2.9 g (83%) of 2,4-diamino-5- (4-isopropenyl-3,5-dimethoxybenzyl) pyrimidine, mp 228-229 ° C., were obtained.

30 The starting material was obtained as follows:! - 15 - ♦

0.54 g of INSodium methylate was added to a solution of 10.3 g of 4-isopropenyl-3,5-dimethoxybenzaldehyde and 7.7 g of β-morpholino-propio-nitrile in 8 ml of anhydrous dimethyl sulfoxide, heated to 60 ° C. While the temperature rose to 70 ° C., stirring was continued for 15 minutes, then cooled to 15 ° C., diluted with 10 ml of isopropanol and with cooling with ice water added dropwise with a total of 40 ml of water. The ent- |; standing suspension was stirred for 2 hours at 05 ° C, filtered and the residue was washed with a cold mixture of isopropanol and * -jo water (1: 4, v / v). After drying, 13.3 g of 4-isopropenyl-3,5-dimethoxy-cc- (morpholinomethylene) dihydro-cinnamonitrile, mp 124-125 ° C. (from methanol) were obtained.

j A suspension of 2.4 g aniline, 2.2 ml conc. Hydrochloric acid! J and 8.5 g of 4-isopropeny 1-3,5-dimethoxy-a- (morpholinomethylene) - 1 15 dihydrocinnamonitrile in 30 ml of isopropanol was heated to reflux with stirring [I for 1 hour. After cooling, the] crystalline 4-isopropeny1-3,5-dimethoxy-a- (anilinomethylene) - '! dihydrocinnamonitrile, mp 188-191 ° C (from methanol), suction filtered and dried (yield 83%).

; Example 5: 20 i A suspension of 164 mg of 4-isopropeny1-3,5-dimethoxy-a-! (morpholinomethylene) dihydrocinnamonitrile and 0.17 g! Guanidine carbonate in 0.25 ml of dimethyl sulfoxide was heated to 160 ° C. for 3 hours with stirring. After cooling, the: 25 reaction mixture was mixed with 1.5 ml of ice water, 1 hour every day; stirs, the solid crude product is filtered off with a little water and

H

Washed acetone and dried. After recrystallization from methanol, pure 2,4-diamino-5- (4-isopropenyl-3,5-f <dimethoxybenzyl) pyrimidine, mp 228-229 ° C., was obtained.

ii 'ir \ I: - 16 - «

Example 6

5.5 g of 3,5-diethoxy-4-isopropenyl-α- (anilinomethylene) dihydrozinitrile and 5 8.1 g of guanidine carbonate were added to a sodium ethylate solution freshly prepared from 1 g of sodium and 50 ml of ethanol. The mixture was heated under reflux for 60 hours, the solvent was stripped off, the residue was slurried in ice water, filtered off with suction and the crystalline crude product was recrystallized from ethyl acetate / petroleum ether. 4.5 g of 2,4-diamino-5- (3,5-ciethoxy ~ 4-isopro-10 penylbenzyl) pyrimidine, mp 197-198 ° C., were obtained.

The starting material was obtained as follows:

A solution of 24 g of ethyl 2,6-diethoxy-4-formylbenzoate in 100 ml of ethanol, 13.2 g of ethyl orthoformate and 1 ml of conc. Hydrochloric acid was heated under reflux for 2 hours and then concentrated under reduced pressure.

The oily residue, dissolved in 500 ml of ether, was added dropwise to a Grignard solution, which had been prepared from 6.5 g of magnesium, 42.6 g of methyl iodide and 240 ml of ether. The reaction mixture was heated under reflux for 3 hours, cooled to 20 room temperature, mixed with 30 ml of water and with 30 ml of 3 N sodium hydroxide solution. The ethereal phase was separated off, washed with 30 ml of 3N sodium hydroxide solution and the aqueous phases were exhaustively extracted with ether. The combined organic phases were concentrated to 150 ml, mixed with 60 ml of 1N 25 hydrochloric acid and shaken for 15 minutes at room temperature. Working up the ethereal phase gave 21 g of 3,5-diethoxy-4-isopropenyl-beraaldehyde, mp 60 ° C.

A solution of 11 g of 3,5-piethoxy-4-isopropenyl-benzaldehyde and 7 g of β-morpholino-propionitrile in 100 ml of dimethylformamide 30 was heated to 60 ° C. After 1.1 g of sodium methylate had been stirred for 30 minutes, the solvent was distilled off, the residue was filtered off with suction and washed twice with 100 ml of ether each time. 12.5 g of 3,5-7-ethoxy-4-isopropenyl-a- (mor- / i i 5

Ipholinomethylene) -dihydrocinnamonitrile, F.75-80 ° C (from vinegar ester / petroether).

A solution of 12 g of 3,5-diethoxy-4-! Was added to an ice-cooled mixture of 3.6 ml of aniline and 2.25 ml of acetic acid. 5 isopropenyl-α- (morpholinomethylene) dihydrocinnamonitrile in) 20 ml of isopropanol. It was heated to 80 ° C for 90 minutes, mixed with 40 ml of water, cooled to 10 ° C and suction filtered. After washing with water and ether, the crystalline residue gave 9.5 g of 3,5-diethoxy-4-isopropenyl-a- (anilino-i 0 i 10 methylene) -dihydrocinnamonitrile, F. 176-178 C.

Example 7. i i |

A mixture of 9.4 g of 2,4-diamino-5- (3-hydroxy-4-isopropenyl-5-methoxybenzyl) pyrimidine, 65.6 ml of 1N sodium hydroxide solution, 130 ml of 50% aqueous ethanol and 11 , 12 g diethyl sulfate j; 15 was stirred at room temperature for 2 hours. Then the ‘j ethanol was evaporated off, the residue was diluted with 50 ml of water; j with conc. Ammonia made alkaline and the raw product sucked off. After recrystallization from methanol, 5.5 g of 2,4-diamino-5- (3-ethoxy-4 ~ isopropenyl-5-methoxybenzyl) - ji 20 pyrimidine, mp 197-199 ° C, were obtained.

i; j * j H The starting material was prepared as follows: i r1.] 'To a suspension of 10.4 g of sodium hydride (50%) in:] 130 ml of dimethylformamide was stirred and under nitrogen Gassing a solution of 16.1 ml of ethyl mercaptan in 130 ml

Ji 25 drops of dimethylformamide. After gas evolution ceased, 'j was stirred for a further 15 minutes at room temperature with a | Solution of 13 g of 2,4-diamino-5- (4-isopropenyl ~ 3,5-dimethoxy-j] - benzyl) pyrimidine in 260 ml of dimethylformamide, the j] reaction mixture was stirred for 6 hours at 120 ° C, the solvent

Lj ’· 30 removed under high vacuum, the solid residue dissolved in water, filtered and the filtrate adjusted to pH 4 with 1N HCl. The acidic solution was then adjusted to pH 8 with ammonia; Â - 18 - w - «and the solid crude product is isolated (yield 98%). Recrystallization from methanol gave pure 2,4-diamino-5- (3-hydroxy-4-isopropenyl-5-methoxybenzyl) pyrimidine, mp 218-219 ° C.

5 Example 8

A suspension of 4 g of 4 - [(2,4-diamino-5-pyrimidyl) methyl] -2,6-dimethoxy-c, a-diethylbenzyl alcohol in 72 ml of ethanol and 7.2 ml of conc. Hydrochloric acid was heated to reflux with stirring for 3 hours and then evaporated to dryness under reduced pressure 10. The residue was suspended in 100 ml of water, the suspension made alkaline with aqueous ammonia (pH approx. 10) and stirred for a further 2 hours. The crystalline product was stirred again with 50 ml of water, suction filtered and recrystallized from ethanol. 3.1 g of 15 (78%) 2,4-diamino-5- {3,5-dimethoxy-4- [3- (2-pentenyl)] benzyl ^ - pyrimidine, mp 197-199 ° c , receive.

Example 9

A solution of 2 c 4- [(2,4-diamino-5-pyrimidyl) methyl] - 2,6-diethoxy-cc, a-dimethylbenzyl alcohol in 40 ml methanol and 20 4 ml conc. Hydrochloric acid was refluxed for 2 hours.

The solvent was distilled off, the residue was slurried in water and the suspension was stirred for about 1 hour after adding 25% ammonia solution to a pH of about 10. The crystalline residue was filtered off with suction, washed neutral with water and dried. After recrystallization

Acetic ester gave 1.9 g of colorless 2,4-diamino-5- (3,5-diethoxy-4-isopropenylbenzyl) pyrimidine, mp 196-198 ° C.

Example 10. To a solution of 0.9 g of 2,4-diamino-5- (4-isopropenyl-30 3,5-dimethoxybenzyl) pyrimidine in 100 ml of methanol was added 3.3 ml of 1N HCl. The solution was concentrated to 25 ml I - 19 - I! · 'Π Η; 1 and after cooling, the crystals were filtered off and I dried. The 2,4-diamino-5- (4-isopropenyl-3,5- :: dimethoxybenzyl) pyrimidine hydrochloride obtained melts above 300 ° C.

j 5 Example 11, | 4.5 g of 2,4-diamino-5- (4-isopropeny1-3,5-dimethoxybenzyl) pyrimidine and 1.9 g of 72.5% lactic acid were dissolved in 250 ml of water. The solution was filtered, concentrated in half and cooled and the crystalline 2,4-diamino-5- (4-; 10 isopropenyl-3,5-dimethoxybenzyl) pyrimidine lactate, mp 287-290 ° C; (Dec.), Was sucked off.

j ί Example 12

From a mixture of 0.8 g of a- (aminomethylene) -3,5-] dimethoxy-4-isopropenylhydrocinnamic acid nitrile, 0.56 g of guani- 15 dicarbonate, 170 g of potassium hydroxide, 1.5 ml of water and | 10 ml of isoamyl alcohol were distilled off under reduced pressure, about 2 ml of solvent. The rest of the mixture turned 24

Stirred at 135 ° C under reflux. After evaporation to dryness, the residue was stirred first with ether and then with water, the product was filtered off with suction: and recrystallized from methanol. 0.11 g of 2,4-diamino-5- (3,5-dimethoxy-4-isopropenylbenzyl) pyrimidine, melting point 226-229 ° C., was obtained.

The starting material was produced as follows:

A mixture of 10.3 g of 3,5-dimethoxy-4-isopropenyl-25-benzaldehyde, 6.7 g of malodinitrile and 2 drops of piperidine was heated to 120 ° C. for 90 minutes with gassing with nitrogen and with stirring, cooled and recrystallized from methanol. Yield 80% a-cyan-3,5-dimethoxy-4-isopropenylcinnamonitrile, F.

129-131 ° C.

- 20 -

To a suspension of 2.5 g of a-cyan-3,5-dimethoxy-4-isopropenylcinnamonitrile in 75 ml of ethanol and 2 drops of 1'N NaOH was added in portions with stirring at room temperature 200 mg of NaBH 4. After stirring for 4 hours, solution 5 was evaporated, the residue was suspended in water and extracted with ether. The ether extract was dried and evaporated to dryness. Column chromatography of the crude product (2.6 g) on silica gel with benzene / methanol (9: 1, v / v) gave a- (aminomethylene) -3,5-dimethoxy-4-isopropenylhydrocinnamic acid nitrile, with a melting point of 122- 125 ° C (from ether).

Example 13

A mixture of 167.7 mg of 2,6-diamino-4-chloro-5- (3,5-dimethoxy-4-isopropenylbenzyl) pyrimidine, 1.6 ml of glacial acetic acid, 10 mg of mercury (II) chloride, 0, 2 ml of water and 150 mg of zinc-15 powder were boiled overnight with stirring and reflux.

The solution was filtered hot, unreacted zinc washed with 0.5 ml of glacial acetic acid, the filtrate diluted with 2 ml of water, while cooling with conc. Ammonia solution made alkaline and extracted three times with 5 ml of ethyl acetate.

20 The extract was dried and concentrated, the residue from

Recrystallized methanol. 148 mg (73%) of 2,4-diamino-5- (3,5-dimethoxy-4-isopropenylbenzyl) pyrimidine, melting point 226-229 ° C., were obtained.

The starting material was obtained as follows:

A mixture of 10.3 g of 3,5-dimethoxv-4-isopropenylbenzal-25 dehyde, 6.7 g of ethyl cyanoacetate and 2 drops of piperidine was heated in an open flask to 120 ° C. with stirring for 90 minutes, cooled and recrystallized from n-heptane . 12.8 g (85%) of a-cyan-3,5-dimethoxy-4-isopropenyl- were obtained; ethyl cinnamate, mp 100-102 ° C.

30 To a suspension of 4.3 g of a-cyan-3,5-dimethoxy-4-isopropenylcinnamic acid ethyl ester in 80 ml of ethanol and 2 drops of 1 N NaOH were added 0.14 g of NaBH 2 with stirring, where: | - 21 -

A solution arises. After 30 minutes, the ethanol was stripped off under a Viasser jet vacuum at 40 ° C., the residue was taken up in ether, the solution was washed with water and filtered through silica gel. 3.4 g (79.1%) of a-cyano- (3,5- 5 dimethoxy-4-isopropenyl) -hydrocinnamic acid ethyl ester, melting point 55 ° C., | receive.

; To a solution of 0.55 g sodium in 40 ml absolute

Ethanol was added to 2.3 g of guanidine hydrochloride. After 30 minutes the suspension was filtered and the filtrate was treated with 10 3.5 g of ethyl α-cyano-3,5-dimethoxy-4-isopropenylcinnamate! added. The reaction mixture was refluxed for 18 hours; boiled river, evaporated to dryness, the residue several times - i maize with ether and then triturated with water and off! sucked. 1.6 g (44%) of 2,6-diamino-5- (3,5-dimethoxy-15 4-isopropenylbenzyl) -4-pyrimidinol, mp 256-258 ° C., were obtained.

i. To a suspension of 0.8 g of 2,6-diamino-5- (3,5-dimethoxy-4-isopropenylbenzyl) -4-pyrimidinol in 6.5 g of phosphorus oxy-jj chloride were added dropwise with stirring 0.65 g dimethylaniline | given. The mixture was boiled with stirring for 4 hours; j 20 then about half of the phosphorus oxychloride was mixed under ver. Λ 'l reduced pressure distilled off. About 10 g of ice were added to the residue. The suspension was left at room temperature for 2 days. Ammonia solution to pH 10 and; | drained the precipitate 2 hours later. This was freed from dimethylaniline by steam determination. After the aqueous suspension had cooled, the crude 1 2,6-diamino-4-chloro-5- (3,5-dimethoxy-4-isopropenylbenzyl) -jj pyrimidine obtained was treated with benzene / methanol (9: 1, v / v) chromatographed on silica gel] and recrystallized after evaporation of the solvent from methanol j · 30. Yield: 0.27 g (32%), mp 199-200 ° C.

ji 3] j / i / - "- 22 -

Example 14

Tablets each containing 2,4-diamino-5- (3,5-dimethoxy-4-isopropenylbenzy3) “pyrimidine 80.00 mg 5 starch pregelatinized 12.50 mg

Sodium carboxymethyl starch 12.50 mg

Lactose pulY. 131.25 mg

Corn starch 12.50 mg

Magnesium stpatat 1.25 mg 10 250.00 mg is produced by wet granulating, drying and pressing the mixture with the addition of water.

Example 15

Injection solution containing 15 ml 2,4-diamino-: i “(3,5-dimethoxy-4-isopropenylbenzy! * '“ Pyrimidine 20.0 mg per ml

Glycofurol 0.3 ml

Lactic acid pH 4.0 q.s.

Water a <^ 1/0 ml 20 The solution was sterilized at 120 ° C for 20 minutes.

/ 1 ^

Claims (17)

1. A process for the preparation of new benzylpyrimidines of the general formula R10 R \ / - \ / - \ Ολ ~ ΝΗ2 1 r2o h2n 12 5 where R and R are a C .. _g-alkyl radical / R a C, _ ^ - alkyl radical and 4 1-3 R represent methylene or a C2_4-alkylidene radical, and their physiologically tolerable acid addition salts, 10 characterized in that a) a compound of the formula R10 R3 \ -v J- HO - (O) -CH2- (0) -NHRß 11 'r5 \ _ / \ -N r2o' R1 2hn I 12 3 wherein R, R and R are as defined above, 2 R is a C ^ _ ^ alkyl radical and 15 R2 represent hydrogen or an amino protective group, optionally with simultaneous removal of existing amino protective groups, dehydrated, or that one - 24 - 9 b) a compound of the formula R10 R3} -V y ~ \ OY ~ z 1111 R4) '' R20 1 4 wherein the radicals R - R are as defined above and Z is a group of the formula 5 -CH2-CH (CN) -CH (OR7) 2 or -CH? “C (= CHY) CN, where 7 ^ R is a C1_4-alkyl group or both R ^ together form a C ^ _ ^ ~ alkylene group and 10. are a leaving group, reacted with guanidine or a guanidine salt, or that c) the hydroxyl group in a compound of the formula 'HO R \) - \ / ΤΛ ^ - (0 ^ cHz Hz r2q H2N 2 t 4. wherein R , R and R are as defined above, 15 etherified to a C, -alkoxv group or by J.- Ö d) from a compound of the formula R10 X ^ —CHs— (O) —NH2 VI11 r20 H2N - 25 - 9 Γ. i: î! wherein X represents chlorine or bromine and 12 3 4 R, R, R and R have the meanings given above,. the substituent X is removed reductively, and that, if desired, a compound of the formula I obtained is converted into a 5 acid addition salt. 2. Process for the preparation of new benzylpyrimidines of the general formula! R1o _ I ^ /) - (O) —cH2— \ C) ^ - nh2 * | R / '\ -f \ -N! R20 HoN j 12 j where R and R are C, _fi-alkyl, i 3 1 b 10. a C-. _ ·, -Alkylrest and: 4 x; R represents methylene or a ^ ". ^ Alkylidene residue, and characterized by their physiologically acceptable acid addition salts i characterized in that ji 15 a) a compound of the formula j R10 j R3 \ -v / Nv I HO - (O) -CH2- (O) -NHR6 11 | R5 / - / —N | d2q 'R6HN «I 12 3 * in which R, R and R are as defined above, j R5 is a C 1 -C 4 -alkyl radical and j Rd is hydrogen or an amino protecting group | '20, "i jj if necessary with simultaneous cleavage of existing T ί amino protective groups, or that 5 # - 26 - b) a compound of the formula R10 r3 \ / - \ MpV- 111 R4)' r2o 'wor-in Residues R "*" - R4 are as defined above and Z is a group of the formula 5 represents -CH2-CH (CN) -CH (OR7) 2 or -CH ^ -C (= CHY) CN, wherein | 7 ^ R is a C - ^^ - alkyl group or both R ^ together represent a C ^ _ ^ - alkylene * group and 10. a leaving group, with guanidine or a guanidine salt, or that c) the hydroxy group in one Compound of the formula HO R \ / - \ / “ΐΛ \ - (O / -CH2— (O) —NH2 IV R Jj \ - / \ -N R20 H2N 3 4 wherein r ', R and R are as defined above, 15. etherified to a: (alkoxy group) and that if desired a vc bond of the formula I obtained is converted into an acid additive salt. 3. Procedure according to claim I or claim 2, characterized in that 2,4-diamino-5- (3,5-dimethoxy-4-isoprop-20 enylbenzyl) - \ 'yrimidine or one of its acid addition salts is prepared. ix I - 27 - i I> I 4. Compounds of the general formula R10 r3 \ -V / - ^ jj— \ 0 / CH2— \ 0 / NHs 1 r2c> h2n 1 12 where R and R are a Cn - alkyl group, I ·! 'o 1-6 i | R represents a C1_3 alkyl radical and I 5 R ^ methylene or a C2_4 alkylidene radical, and their physiologically tolerable acid addition salts. 5. Compounds according to claim 4 ^ characterized in that 1 2 'j that R and R represent a C ^ _3 alkyl radical. 3: | ) 10 g. Compounds according to claim 4, characterized in that R ^ "and R ^ represent methyl. 8 Î 7. Compounds according to claim 4, characterized in that i 1 2 I that R and R represent ethyl. i i j; * 15 i 8. Compounds according to any one of claims 4-7, characterized 3, that R is methyl. 9. Compounds according to any one of claims 4 -7, characterized 3, that R is ethyl. 10. Compounds according to any one of claims 4-7, characterized 3, that R is propyl or isopropyl. 11. Compounds according to any one of claims 4 -10., Characterized 2 I, that R is methylene. * - 28 - • » 12. Compounds according to any one of claims 4 - io, characterized in that is ethylidene. 13. 2,4-diamino-5- (4-isopropeny1-3,5-dimethoxybenzyl) -5 pyrimidine. : 14. 2,4-Diamino-5- (3,5-diethoxy-4-isopropenylbenzyl) pyrimidine. 15. 2,4-diamino-5- (3-ethoxy-4-isopropenyl-5-methoxybenzyl) pyrimidine. 10 16. 2,4-Diamino-5- <3,5-dimethoxy “4- [3- (2-pentenyl)] benzyl) pyrimine. h - 29 - 17. A process for the preparation of pharmaceutical preparations, * characterized in that a benzylpyrimidine of the formula I from claim 1 or a physiologically tolerated acid addition salt thereof, as an active ingredient, with non-toxic, inert substances suitable for therapeutic administration, per se in such Preparations mixed usual solid or p liquid carriers and the mixture obtained in ij | brings a suitable galenic form. · - »1 ij j '13. Process for the manufacture of pharmaceutical preparations; i 10 characterized in that a benzylpyrimidine of the formula I from claim 1 or a physiologically compatible; Acid addition salt thereof and an antibacterially active sulfonamide as active constituents are mixed with non-toxic, inert, solid or liquid carriers which are suitable for therapeutic administration and which are customary in such preparations and the mixture obtained is converted into a suitable |! !: brings galenic form. Hi; ; j j i • j v -. j i i J j. i l * \ ·% - 30 - m Pharmaceutical preparations, characterized in that they contain a benzylpyrimidine of the formula I from claim 1 or a physiologically acceptable acid addition salt thereof and a non-toxic, inert, solid or liquid carrier suitable for therapeutic administration. 2o. Pharmaceutical preparations, characterized by a "content of a benzylpyrimidine of the formula I from claim 1 or a physiologically tolerable acid addition salt thereof and an antibacterially active sulfonamide, and] _0 a non-toxic, inert, solid or liquid carrier suitable for therapeutic administration. H I '' '- 31 -, * * 21. A compound of the formula R10 R \ / - \ /) - \ C3 / —cho v r4 y r2o 1 2! , where R and R are a Cn-alkyl radical, I 3! R represents a C - alkyl radical and - 4 i -3 R methylene or a C2 _ ^ - alkylidene radical. h i - - 32 - i '4 22. Use of a compound of formula I or a physiologically acceptable acid addition salt thereof, gg £. mixed with a sulfonamide, nls antibacterial. % i »