DE1957769C3 - 4,6-diamino-1,2-dihydro-2,2-dimethyl-133-triazine derivatives, processes for their preparation and medicinal preparations containing these compounds - Google Patents

Description

H ₃ C CH ₃

R ₁ NH-C-NH-C-NH ₂

(H)

NH

NH

in which Ri is the remainder of the general formula III Ar — X- (CH ₂ J _n -O- (III)

or a radical which can be converted into such a radical, where Ar, X and η have the meanings given in claim 1, in the presence of an acidic catalyst with acetone to give a compound of the general formula IV

H, N

NH,

R ₁ --N

H ₂ N

"YY

Y ₂ -N

N NH ₂

(VI)

H ₃ C

CH,

in which Y _{2 is} a reactive group, reacts with a compound of the general formula R] Yi, in which Ri has the meaning given above and Yi is a radical which

15th

20th

in which Ar is an optionally substituted aryl radical which can be partially hydrogenated; except in the ring bonded to X, X is an oxygen or sulfur atom and π is 2 to 10, and their salts and N-acyl derivatives are lower aliphatic Carboxylic acids.

2. 4,6-diamino-1,2-dihydro-2,2-dimethyl-1,2- [3- (2,4,5-trichlorophenoxy) propyioxy] -1,3,5-triazine and its salts and N-acyl derivatives of lower aliphatic carboxylic acids.

3. Process for the preparation of the compounds according to claim 1, characterized in that one in a manner known per se

(a) a substituted diguanide of the general formula II

(IV)

H ₃ C CH ₃

converts, in which Ri has the meaning given above, or
(b) a triazine of the general formula VI

enables the conversion to a compound of the general formula IV, and then into the compounds of the general formula IV obtained after (a) or (b), if appropriate the Rest Ri in the rest

Ar-X- (CH ₂ ) _n -O-

converts and / or the connections into a Salt or a corresponding acyl derivative transferred

4. Medicinal preparations, characterized in that they contain a compound according to Claim 1 or 2 and optionally customary carrier materials and / or diluents.

5. Medicinal preparations according to claim 4, characterized by a further content of the usual Additives and / or a sulfonamide,

An important feature of the 4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine derivatives according to the invention of the general formula I.

H, N

NH ₂

(I)

30th

Ar-X (CH ₂ J _n -ON N

H ₃ C CH ₃

is the presence of the radical X, which is either an oxygen atom or a sulfur atom. When a such a radical is present, the corresponding compounds of general formula I have valuable and interesting properties, with the optionally substituted aryl radicals Ar having a wide variety of structures can have.

Specific examples of suitable radicals Ar are phenyl, naphthyl, phenanthryl, pyrenyl, anthryl and the 5,6,7,8-tetrahydronaphthyl radical.

With a suitable structure, the radical Ar can be very diverse Have substituents. He can z. B. be substituted one or more times by alkyl radicals, such as Methyl or ethyl groups, cycloalkyl radicals with 3 to 8 carbon atoms, such as cyclohexyl, cyclopentyl and cycloheptyl groups, Halogen atoms, such as chlorine or bromine atoms, nitro groups, halogen (lower-alkyl) radicals, such as Mono-, di- or trichloro, fluorine or bromo (lower alkylJ radicals, lower alkoxy groups, such as methoxy, ethoxy or propyloxy groups, lower alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl and propyloxycarbonyl groups, aryl (lower-alkyl) radicals, such as benzyl or phenylethyl groups, carboxyl groups, oxy groups, mercapto groups, cyano groups, Lower-alkyl-thio radicals, such as methylthio or ethylthio groups, Lower-alkyl-sulfonyl radicals, lower oxyalkyl radicals, Lower-alkoxy-alkyl radicals, lower cyanoalkyl radicals, sulfonamido groups, amino groups or mono- or pi- (lower-alkyl) -amino radicals, such as methylamino or ethylamino groups. When Ar has more than one substituent has, these can be the same or different. Unless otherwise specified, the The aforementioned radicals generally have 1 to 6 carbon atoms when they are referred to as "lower" radicals, as well as

1 to 24 C atoms if the abovementioned designation is not used.

Specific examples of the radical - (CH ₂ ) _n -, where w is an integer from 1 to 10, are the propylene and tetramethylene groups.

Although the compounds of the invention are characterized herein by certain formulas, the Invention not tied to the exact theoretical correctness of these formulas. The compounds of the invention The terms and formulas used here do not indicate any specific tautomers Boundary structure and not set to any particular optical or geometric isomer

The general formula I relates e.g. B. also on the structures of the general formulas Ia and Ib

H ₂ NN NH

(Ia)

Ar-X- _(CH2) "- O-NN

20th

H ₃ C

CH,

H

HN N NH

Y γ (ib,

Ar-X- (CH ₂ J _n -ON NH

H ₃ C CH ₃

The compounds of the invention are expediently in the form of their addition salts with acids, since the free bases have a certain tendency to instability. The most varied of substances can be used to produce the salts Use acids. When the compounds according to the invention for the production of medicaments are used, the acids used should of course be pharmacologically acceptable, i. H. z. B. have a low toxicity.

The compounds according to the invention can thus be used in the form of the monohydrohalides, e.g. B. the Hydrobromide or Hydrochloride, produce. You can, however, by simply reacting the base with an acid also produce other salts, which are often used to adjust the properties of the product, such as the Toxicity, taste, physical appearance and dosage rate towards the body. You can use the compounds according to the invention of the general Formula I e.g. B. in the form of their picrates, saccharinates, acetates, acidic maleatates, acidic phthalates, succinates, Phosphates, p-nitrobenzoates, stearates, almond acid salts, N-acetylglycinates, pamoates, cyclohexylsulfamates, Make citrates, tartrates or gluconates.

Stable salts are generally made from equimolar amounts of triazine and monobasic acids (or below Use of more than 1 mole of triazine per mole more eo basic acids) produced as a result of any basic substituents of the radicals Ar In some cases, however, further acid components can combine with the triazine.

The presence of amino groups on the triazine ring of the compounds of general formula I is guaranteed the producibility of acyl derivatives by reacting the aforementioned compounds with Acylating agents, such as acid halides, acid anhydrides or acid azides. You can z. B. one to four Introduce acetyl groups into the compound of general formula I, although in some cases it is more difficult is to prepare derivatives with such a higher number of acetyl groups.

The invention thus also relates to compounds of the general formula I in the form of their acyl derivatives, where the acyl radicals are derived from lower aliphatic carboxylic acids, preferably from acetic acid.

The compounds of general formula I according to the invention are effective against bacteria, Protozoa, parasites, such as the plasmodia of malaria, fungi, such as dermatophytes or candida, and they are in also effective against coccidia in certain cases.

Such an activity of the compounds according to the invention was against Staph. aureus, Escherichia coli, Candida albicans, Proteus mirabilis, Pseudomonas pyocyanea and Streptococcus haemolyticus observed

4,6-diamino-1,2-dihydro-2,2-dimethyl-l- [3 '- (2,4,5-trichlorophenoxy) propyloxy] -1,3,5-triazine hydrobromide of formula A

H ₂ N

NH,

Cl ^ f VO- (CH ₂ J ₃ -ON N • HBr

X
H ₃ C CH ₃

(A)

z. B. is sensitive to cycloguanil and resistant to cycloguanil Plasmodium berghei strains effective in mice.

It has been found that some types of the compounds according to the invention are optimally effective when the radical X is an oxygen atom and / or the radical - (CH ₂ J _n - with the meaning of / 7 = 2 to 10 is.

The invention also relates to a process for the preparation of the compounds of the formula I, which thereby is characterized in that a substituted diguanide of the general formula II

R ₁ -NH-C-NH-C-NH ₂ (II)

NH NH

in which R _{1 is} the remainder of the general formula III

Ar-X- (CH ₂ ) ,, - O- (III)

or a radical which can be converted into such a radical, where Ar, X and η have the meanings given above, in the presence of an acidic catalyst with acetone to give a compound of the general formula IV

H, N

NH ₃

(IV)

R ₁ -N

H ₃ C

4 N

CH,

converts and optionally the remainder Ri in the rest of the general formula III converts, as well as given

IO

if the corresponding salt or acyl derivative produces the catalyst used in the process of the invention The acid used is preferably a strong acid, such as hydrochloric or formic acid. It w: rd at least 1 mole Acid used per mole of starting compounds. The reaction can in some cases without solvent or Diluent addition can be carried out, but preferably an inert solvent, such as a lower aliphatic alcohol, e.g. methanol, added

If R _{1 is} a radical of the general formula III, the diguanide of the general formula II corresponds to the more specific general formula Ha

Ar —X - (CH ₂ ) "- O —NH-C —NH-C — NH,

Il Il

NH NH

(Ha)

These precursors of the general formula Ha are z. B. by reacting a bromide of the general formula ArX (CH ₂ ) "Br with benzhydroxamic acid, conversion of the reaction product by treatment with acids to an oxyamine of the general formula

Ar-X- (CH ₂ ) "- O-NH ₂

30th

and further reaction of this oxamine with dicyandiamide manufactured.

According to the invention, diguanides of the general formula II can also be used as starting compounds, the radical Rj of which is a radical which can be converted into a radical of the general formula III. Ri can e.g. B. be a radical R ₂ O-, which can be converted into a hydroxyl group _{by replacing R 2 with a hydrogen atom.} A triazine which is substituted by a radical R ₂ O N can thus be prepared from an appropriately substituted diguanide and this can then be produced by exchanging R ₂ for a hydrogen atom into an oxytriazine of the formula V

H ₂ NN NH ₂

Il
N

(V)

HO —N

H ₃ C CH,

55

convict.

The radical R ₂ is e.g. B. an optionally substituted benzyl or naphthylmethyl group. The replacement of this radical by a hydrogen atom can be carried out with the aid of hydrogen in the presence of a palladium catalyst.

The oxytriazine of the formula V can be obtained by a wide variety of known processes substituted triazine of the general formula I are implemented.

It can also be seen that the side chain of general formula III either before or after Conversion of the substituted diguanide of the general formula II into the substituted triazine of the general formula Formula IV can also be built up or introduced in stages. In general, however, is used to achieve optimal yields and, for practical reasons, the smallest possible number of such stages applied

One can thus for the introduction of the side chain into the triazine known processes for ether production apply, with the oxygen atom previously either on the side chain or on the triazine can be. Specific examples of such procedures are

1) the reaction of a halide with a hydroxyl compound, optionally in the presence of alkalis, and

2) the reaction of a reactive ester, such as a sulfonic acid ester, with a hydroxyl compound.

Analogous reactions can be used to introduce the radical Ar into a partial side chain which contains the radical - (CH ₂ ) ,, -, the atom X being previously either the radical Ar or the radical - (CH ₂ ) ,, - may have heard.

You can the end products according to the invention in the form of addition salts with acids in the course of The aforementioned reaction is obtained without a separate process stage of salt formation, but if necessary such an additional process step, d. H. a reaction of the free base with an acid with formation of a salt, carried out From the salts, the free bases can in turn by treatment with alkalis, such as potassium hydroxide, released and then converted into other desired salts by known processes will.

Another general embodiment of the process for the preparation of the compounds according to the invention consists in that a triazine of the general formula VI

45 H ₂ NN NH ₂

YY

Y ₂ -NN

H ₃ C CH ₃

(VI)

50 in which Y _{2 is} a reactive group, reacts with a compound of the general formula R1Y1, where Ri has the meaning given above and Yi represents a radical which enables the conversion to a compound of the general formula IV, and optionally the radical Ri in the rest

Ar-X- (CH ₂ ) _n -O-

converts and / or converts the compound obtained into a salt or a corresponding acyl derivative

The radicals Yi and Y ₂ are preferably hydroxyl groups (cf. formula V) or their derivatives which are capable of reacting with one another to form an oxygen bridge. At least one of the radicals Yi and Y ₂ should therefore have an oxygen atom suitable for such a bridge formation. The remainder Y is ₂

preferably an OH group or an -OM radical, where M is a metal atom such as sodium, potassium or Lithium atom, means. The radical Yi is preferably a chlorine, bromine or iodine atom. examples for further reactive derivatives of hydroxyl groups are radicals derived from sulfonic acids.

In a preferred embodiment of the method of the invention, a compound of the general formula

Ar ₂ -X- (CH ₂ J _n -Z

in which Z is a chlorine or bromine atom, with the oxytriazine of the formula V in an inert solution or Diluent brought to implementation. Specific examples of suitable solvents are dimethyl sulfoxide, Dimethylformamide and ethanol.

The oxytriazine of the formula V is generally used in the form of its addition salts with acids, e.g. B. as hydrochloride, manufactured. From these salts the free base can be replaced by 1 equivalent of a base, such as an alkali hydroxide, z. B. potassium hydroxide, or of sodium methylate or ethylate can be set free. That Mixture can be evaporated and stored in a suitable solvent such as dimethylformamide or Dimethyl sulfoxide, are brought to the reaction. Preferably no further base is added because when using 2 equivalents of sodium alcoholate z. B. receives a less pure product.

In a modified procedure, which generally gives poorer yields, the hydrochloride is used of the oxytriazine of the formula V in dimethylformamide or dimethyl sulfoxide with 1 equivalent aqueous potassium hydroxide solution, which contains as little water as possible, brought to implementation. The received The mixture is reacted further to form a triazine hydrohalide.

The triazine of the general formula VI substituted by a radical Y ₂ N can, as described above, be prepared from an appropriately substituted diguanide or by another convenient process.

As mentioned, the side chain of the general formula III can be introduced in the most varied of ways will. It can be implemented either in a single implementation or in stages. It can e.g. B. a compound of the general formula VII

Ar Y (ΓΗ> r ^ H = r (^ T-l | VTT \

be made to react with the oxytriazine of the formula V.

In a further modified process, certain oxy-substituted compounds of the invention can be used be prepared by using an appropriately substituted ethylene oxide with the oxytriazine of Formula V according to equation 1

Ar-X-CH ₂ -CH CH ₂

(D

+ HOTr Ar-X-CH ₂ -CH-CH ₂ OTr

OH

converts, where Tr is the remainder of the formula] VIII

H, N

NH,

(VIII)

—N

Y N

H ₃ C • CH ₃

is.

You can z. B. a compound of the general formula IX

H ₂ NN NH,

(IX)

Y ₄ - (CH ₂ ) "- ON N

X
H ₃ C CH ₃

in which Y4 is a reactive radical, with a compound of the general formula ArY ₃ , in which Y _{3 is} a reactive radical ensuring the reaction of the compound ArY ₃ with Y4 to form a radical ArX, to form a compound of the general formula I. As a more specific product, one can use a compound of the general formula X

Ar- O- (CH ₂₎ ,, - O - Tr

prepare by a compound ArZ, where Z is a bromine or chlorine atom, with a compound of general formula XI

HO- (CH ₂ ) ,, - 0-Tr

PCI)

brings to implementation

Finally, the invention relates to medicinal preparations containing the compounds according to the invention, which are effective against malaria, and possibly the usual pharmacologically tolerable ones Carrier materials, diluents, additives and / or sulfonamides ^

You can use the compounds of the invention, for. B. as active ingredients for the treatment or prophylaxis of the Use malaria in human medicine.

The compounds of the invention can be administered orally, parenterally, or in the form of suppositories will; the oral route is preferred.

The water solubility of the hydrochlorides of the compounds of the invention and most of the others Salts is low. The hydrochlorides are not hygroscopic. Therefore, when solutions are needed, one must incorporate solubilizers into the water, use non-aqueous solvents, more soluble salts use or prepare very dilute solutions.

Specific examples of orally administrable preparations that are preferred are given in consideration of the above requirements for solutions tablets, coated tablets, capsules, sachets, granules, powders, chewing gum, Suspensions, emulsions and solutions. Particularly preferred oral preparations are tablets and capsules. If this is possible and necessary, the preparations can also use diluents, binders, dispersants, surface-active agents, Lubricants, coating agents, flavoring agents, coloring agents

Substances, solvents, thickeners, suspending agents, sweeteners or any other pharmacological agent compatible additives such as gelatine, milk sugar, starch, talc, magnesium stearate, hydrogenated oils, Contain polyglycols or syrups. In the case e.g. B. of tablets or capsules, the preparations can be specified as Single doses, in the case of z. B. granules, powders or suspensions either given as such Single doses or in packs with several units, from which the suitable single dose can be found on the market.

Injection preparations can be aqueous or non-aqueous solutions, suspensions or emulsions in pharmacologically acceptable liquids, such as sterile, pyrogen-free water or parenterally acceptable oils, or mixtures of several liquids, the bacteriostatics, antioxidants or other preservatives, buffers (preferably with the physiological pH range of 6.5 to 7.0), solutes to produce isotonicity of the solution with the blood, thickeners, suspending agents or may contain other pharmacologically acceptable additives. Such injections are used in Single doses, such as ampoules or disposable syringes, or in several units, such as bottling, from which the appropriate dose can be taken, or as solid preparations or concentrates. which injectables can be manufactured rapidly, put on the market all injectables are preferably sterilized suppositories containing the compounds of the invention also suitable carrier materials, e.g. B. cocoa butter or polyglycols.

The medicinal preparations which can be produced from the compounds according to the invention contain optionally other therapeutic agents in addition to the usual pharmaceutical additives, in particular Antimalarials, such as sulfa drugs.

The examples illustrate the invention.

Establishing the interconnection

4,6-diamino-1,2-dihydro-2,2-dimethyl-1-hydroxy-

1,3,5-triazine hydrochloride

a) A flask equipped with a stirrer, dropping funnel and condenser is filled with 137 g (1.0 mol) of benzhydroxamic acid and 1.4 liters of ethanol denatured with 5% methanol are charged and the resulting mixture is Stirred until completely dissolved. Then a solution of 40 g (1.0 mol) of sodium hydroxide in 100 ml Added water while stirring the mixture thoroughly. At this point, the sodium salt of the Benzhydroxamic acid precipitate.

170 g (120 ml) of benzyl bromide are now added dropwise over the course of 45 minutes, the Mixture gradually becomes clear and only a small amount of inorganic material is undissolved remains. The reaction mixture is preferably left to stand for 3 days at room temperature. By bo Boiling under reflux for 1 to 2 hours gives somewhat lower yields.

The solvent is then removed under reduced pressure and the oily residue is in Dissolved ethyl acetate and washed several times with water. The solvent extract is over magnesium sulfate dried, filtered and evaporated to dryness under reduced pressure

The solid residue is rubbed with ether and given the desired benzylbenzhydroxamate

(C ₆ H ₅ CONHOCH ₂ C ₆ H ₅ )

from melting point 100 to 102 ^° C. worked up.

b) 170 g of benzylbenzhydroxamate are dissolved in 500 ml of methanol and mixed with 165 ml of concentrated hydrochloric acid offset. The resulting mixture is refluxed for 3 hours, filtered hot and used for Brought crystallization. The solid substance obtained by filtration is thoroughly washed with ether washed until there is no longer any smell of methyl benzoate.

Yield of amino-oxymethylbenzol hydrochloride: 120 g first fraction, mp 227-230 ⁰ C (sealed tube melting). after concentration of the mother liquors and treatment with ether, a further fraction (20 g) with a melting point of 220 to 225 ° C. (closed melting tube) is obtained. The total yield is 140 g (about 90% of theory).

c) 97.5 g of amino-oxymethyl-benzene hydrochloride and 51.4g of dicyandiamide are stirred and heated dissolved in 300 ml of ethanol denatured with 5% methanol. The resulting mixture is left for 3 hours boiled under reflux, filtered if necessary and then evaporated under reduced pressure. The oily residue is dissolved in water and treated with about 6 η aqueous NaOH while stirring. the The diguanide base which separates out solidifies on cooling and is separated off and washed with water and dried.

The yield of benzyloxydiguanide base is 95 to 100 g (80% of theory); M.p. 98 to 100 ^° C.

d) 52 g of Benzyloxydiguanidbase are dissolved in 200 ml of denatured ethanol and successively with 43 ml concentrated hydrochloric acid and 200 ml of acetone are added. The reaction mixture is preferably left for 3 days stand at room temperature, but refluxing for 2 to 3 hours only gives slightly lower yields. In general, a certain amount of triazine separates out and is filtered off with it Water is washed and dried.

The mother liquors are evaporated to dryness and the residue is triturated with acetone, whereby a solid white substance is obtained. This substance is isolated, washed with water and dried.

The total yield of 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-benzyloxy-1,3,5-triazine hydrochloride is 61 g (80% of theory); Mp. 204 to 206 ⁰ C.

e) A solution of 41 parts by weight of 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-benzyloxy-1,3,5-triazine hydrochloride in 320 parts by weight of ethanol and 220 Parts by weight of water are shaken with hydrogen and 0.25 to 1.0 part by weight of a 10% palladium-containing charcoal catalyst at room temperature and under atmospheric pressure until no more hydrogen is absorbed. The aforementioned catalyst consists of 90 parts by weight of acid-washed active charcoal, which has 10 parts by weight of finely divided metallic palladium in adsorbed form. The catalyst is then filtered off and the filtrate is evaporated to dryness. 24.5 parts by weight of the desired compound having a melting point of 234 ° to 235 ° C. (decomposition) are obtained. After recrystallization of the compound from ethanol, needles with a melting point of 237 ^° C. (decomposition) are obtained. The reduction described in this example can be carried out using a platinum catalyst as follows.

A solution of 11 parts by weight of 4,6-diamino-l, 2-dihydro ^^ - dimethyl-l-benzyloxy-lAS-triazine hydrochloride in 200 parts by weight of methanol and 100 parts by weight of water at room temperature and atmospheric pressure Shaken with water vapor and platinum (IV) oxide until it absorbs 10% more hydrogen than has been calculated theoretically. The hydrogenation is then stopped, the catalyst is removed and the clear filtrate is evaporated to dryness under reduced pressure. The firm one The residue is triturated with acetone, and the desired compound is obtained with theoretical yield isolated; Mp 234 ° C (decomposition).

B e is ρ i el 1

4,6-diamino-1,2-dihydro-2,2-dimethyl-1- [3- (2,4,5-trichlorophenoxy) propyloxy] -1,3,5-triazine hydrobromide

A mixture of 18.98 g of 2,4,5-trichlorophenol, 3.85 g of sodium hydroxide, 15.5 ml of water and 39.3 g of 1,3-dibromopropane is refluxed for 60 to 90 minutes, then with 25 ml 14% aqueous sodium hydroxide solution is added and the mixture is then heated to 50 to 70 ° C. for another 30 minutes. After extraction with ether and evaporation of the dried ether layer, 16.4 g of 3- (2,4,5-trichlorophenoxy) propyl bromide with a boiling point of 150 to 154 ° C. at 0.93 mbar = 0.7 Torr (mainly 150 ⁰ C) and mp. 34-35 ° C, 2.4 g of higher boiling material (bp. 154-164 ⁰ C at 0.93 mbar = 0.7 torr) and a flow of 1.74 g of oil.

A solution of 5.5 g of potassium hydroxide in 100 ml of methanol is 10 to 30 minutes with 15.23 g

4,6-diamino-1,2-dihydro-2,2-dimethyl-1-oxy-1,3,5-triazine hydrochloride heated to reflux. The mixture is then evaporated and the remaining solid residue is mixed with 25 g of the bromide prepared above in 100 ml of dimethylformamide 3 to 24 Stirred for hours at room temperature. The mixture is then filtered and the filtrate obtained is evaporated and the remaining solid residue is stirred with acetone. 23.7 g of product are obtained from which after washing with water and ether, 19.12 g of the desired compound with a melting point of 178 ° to 181 ° C. were obtained will.

Example 2

4,6-diamino-1,2-dihydro-2,2-dimethyl-1 - [2- (p-chlorophenylthio) ethoxy] -1,3,5-triazine hydrobromide

A solution of 14.5 g (0.1 mol) of p-chlorothiophenol in methanolic sodium hydroxide solution (4 g NaOH in 2Ö0mi methanol) is treated with 37.6 g (2.0 mol) dibromoethane, and the resulting mixture is refluxed for 90 minutes with stirring and then cooled and then freed from a small amount of insoluble material by filtration Then the solvent is removed under reduced pressure and the oil obtained is inorganic The salts are separated off, washed with water, dried and distilled. 11.9 g of 1- (p-chlorophenyl) -2-bromoethyl sulfide are obtained of bp 116 ° C at 2.67 mbar (2 Torr).

3.87 g of ^ ö-diamino-l ^ -dihydro - ^ - dimethyl-l-oxy-1,3,5-triazine hydrochloride are now reacted in the form of a solution in methanol with 1.4 g of potassium hydroxide, the methanol is evaporated and the residue obtained is suspended in dimethylformamide and

50 cooled to - 10 ° C. Thereafter, 5.05 g of the above bromide is added and stirring the resulting mixture for several hours while allowing the temperature gradually to rise to 2O ⁰ C. As soon as a clear solution is obtained, the solvent is evaporated and the remaining gummy substance is rubbed with acetone. This gives 4.9 g of a white solid which, after thorough washing with water and drying, 2.52 g of a solid compound, mp. 193 returns to 195 ⁰ C. After recrystallization from ethanol, the pure compound melts at 202 ^° C .; it is the connection you want.

Example 3

4,6-diamino-1,2-dihydro-2,2-dimethyl-1 - [2- (2-naphthoxy) ethoxy] -1,3,5-triazine hydrobromide

In a manner similar to that indicated in Example 1, using 2-naphthol and 1,2-Dibromoethane as starting compounds 2- (2-naphthoxy) ethyl bromide manufactured. After recrystallization it has a melting point of 90 to 91.degree.

Then 3.67 g of 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-oxy-1,3,5-triazine hydrochloride are added reacted in the form of a solution in methanol with 1.4 g of potassium hydroxide, the methanol is then removed, and the The residue obtained is suspended in dimethylformamide and added for 2 hours at room temperature with 5.0 g 2- (2-Naphthoxy) ethyl bromide stirred. After working up in the conventional manner, 3.4 g of a are obtained white solid substance of m.p. 195 to 197 ° C after Recrystallization from ethanol melts the pure desired compound at 196 ° C.

Example 4

4,6-diamino-1 ^ -dihydro ^ -dimethyl-1 - [3- (p-nitrophenoxy) propyloxy] -1,3,5-triazine hydrobromide

It is carried out in a manner similar to that described in Example 1 using p-nitrophenol and 1,3-dibromopropane as starting compounds 3- (p-nitrophenoxy) propyl bromide, melting at 50 to 52 ° C manufactured.

The from 2.96 g of 4,6-diamino-1,2-dihydro-2,2-dimethyll-oxy-1,3,5-triazine hydrochloride The free base obtained is now suspended in dimethylformamide and at room temperature with 4.0 g of the aforementioned bromide treated. After working up in the conventional manner, 4.25 g of the desired compound are obtained from m.p. 216 to 217 ° C

Example 5

4,6-diamino-1 ^ -dihydro - ^ - dimethyl-1 - [3- (2,4,5-trichlorophenoxy) propyloxy] -1,3,5-triazine hydrobromide

a) 3- (2,4,5-Trichlorophenoxy) propyl bromide

A solution of 39.5 g (1 mol) of 2,4,5-trichlorophenol in 33 ml of 25% sodium hydroxide solution is mixed with 81 g (2 mol) 1,3-Dibromopropane is added and the resulting mixture is stirred and refluxed for 2 hours heated to a gentle boil. After the heating has ceased, 51 ml of 14% sodium hydroxide solution are added and the mixture is then heated to 50 to 70 ° C for 30 minutes. Then it is cooled, and the lower layer is separated and washed five times with water. The oil obtained is under pressure distilled from 1.33 mbar (1 Torr) and gives

A) Kp 30 to 6O ⁰ C: 25 g of first fraction (ng ¹ = 1.5230). dibromopropane and water are obtained.

. B) Kp 130 to 160 ⁰ C: 50 g of second fraction (η "= 1.5838); the desired bromide solidifies gradually, mp 34-35 ⁰ C..

b) 3- (2,4,5-trichlorophenoxy) propyl benzhydroxarnate

A solution of 22.5 g of benzhydroxamic acid in 300 ml of methanol is mixed with a solution of 4.8 g of NaOH in 15 ml of water while stirring. 37 g of 3- (2,4,5-trichlorophenoxy) propyl bromide are then added, the mixture is refluxed for 1 hour and then left to stand for several days. The solution is then evaporated under reduced ^r jerk, and the hinterbieibende gummy residue is dissolved in ether, a small amount of inorganic material is filtered off. The ether extract on evaporation, solidified, and the solid substance is recrystallized from a mixture of ligroin (bp. 40 to 6O ⁰ C) and ethyl acetate. A total of 30 g of benzhydroxamate of melting point 73 ° to 75 ° C. (in two partial fractions) is obtained. A sample recrystallized from the aforementioned solvent mixture melts at 76 to 77 ^° C.

c) 3- (2,4,5-trichlorophenoxy) propyloxyamine hydrochloride

32.7 g of the benzhydroxamate (b) are with a mixture of 18.5 ml of concentrated hydrochloric acid and Treated 300 ml of methanol and the resulting mixture is refluxed for 3 hours. That after The oil obtained by evaporation of the solvent is cooled and ether is added. The precipitated solid The substance is isolated, washed with ether and dried. 21 g of the desired compound are obtained (c) from m.p. 134 to 136 ° C.

d) 3- (2,4,5-trichlorophenoxy) propyloxy diguanide

61.4 g of compound (c) are dissolved in 1 liter of ethanol and the resulting solution is mixed with 25.2 g of dicyandiamide offset. The mixture is refluxed with stirring for 3 hours, after which the solvent is evaporated under reduced pressure.

The residue obtained is dissolved in about 300 ml of water and the solution obtained is made alkaline with strong aqueous sodium hydroxide solution. An oil separates out, which soon solidifies. The solid substance is filtered off, washed successively with water and petroleum ether and finally at 6O ⁰ C geiroL-kncL one erhäli 49.5 g of a pale pink gefärbien solid substance of mp. 107 to HO ⁰ C.

After recrystallization from ethyl acetate, the analysis sample melts at 125 to 126 ° C.

e) 4,6-diamino-1,2-dihydro-2,2-dimethyl-l- [3- (2,4,5-trichlorophenoxy) propyloxy] -1,3,5-triazine hydrobromide

A solution of 45 g of diguanide (d) in 200 ml of methanol is concentrated with a mixture of 25 ml Hydrochloric acid and 300 ml of acetone are added. The reaction mixture is left to stand at room temperature for 3 days. The solvent is then evaporated off under reduced pressure and the remaining gummy substance is rubbed with acetone. The desired triazine (23.5 g) with a melting point of 187 is obtained to 189 ° C, and a small amount of a second fraction (indeterminate weight) from mp. 181 to 186 ° C. The first product turns out to be without any further Recrystallization as analytically pure.

Example 6

4,6-diamino-1,2-dihydro-2,2-dimethyl-1- [2- (2-naphthoxy) ethyloxy] -1,3,5-triazine hydrochloride

a) 2- (2-Naphthoxy) ethyl benzhydroxamate

A solution of 21.4 g of 2- (2-naphthoxy) -äthylbromid (m.p. 90-91 ⁰ C;.., See Example 3) in 50 ml methanol is slowly added to a solution of 15.05 g Natriumbenzhydroxamat in 100 ml of methanol. The resulting mixture is refluxed at brisk boiling for 6 hours. Inorganic solid materia! is filtered off and the solvent is evaporated off under reduced pressure. The remaining gummy substance is dissolved in ethyl acetate and washed several times with water. The solvent layer is dried over magnesium sulfate, filtered and evaporated. The remaining gummy substance is rubbed with ligroin (boiling point 60 to 80 ° C.) and the required benzhydroxamate is caused to crystallize. 50.6 g of product with a melting point of 90 to 93 ° C. are obtained up to 101 ° C.

b) 2- (2-naphthoxy) ethyloxyamine hydrochloride

A solution of 7.5 g of 2- (2-naphthoxy) ethyl benzhydroxamate in 30 ml of methanol is mixed with 10 ml of concentrated hydrochloric acid and the resulting mixture is refluxed for 3 hours. After 2 hours a solid substance begins to separate out, after which the reaction mixture is cooled and filtered. This gives 4.6 g of the desired Oxyamins, mp 192-194 ° C. Recrystallization from methanol gave the analytical sample melts at 195 ⁰ C.

Evaporation of the mother liquors and treatment of the residue with ether gives a further 0.9 g a product that is only slightly less pure

c) 2- (2-naphthoxy) ethyloxydiguanide

A solution of 7.8 g of 2- (2-naphthoxy) ethyloxyamine hydrochloride in 100 ml of ethanol is mixed with 4.1 g of dicyandiamide and the resulting mixture is then refluxed for 3 hours, filtered and evaporated under reduced pressure gummy substance is dissolved in water while warming and the resulting solution is made alkaline with strong sodium hydroxide solution. An oil separates out, which slowly becomes crystalline. After washing the solid substance with water and ligroin (bp. 60 to 8O ⁰ C) 135 is obtained 8.1 g of a solid substance of mp. To 137 ° C. after recrystallization from ethyl acetate melts at the analytical sample (the desired biguanide) 139 to 140 ⁰ C.

d) 4,6-diamino-1,2-dihydro-2,2-dimethyl-1- [2- (2-naphthoxy) ethyloxy] -l, 3,5-triazine-hydroch] oride

^{8 ml of concentrated 1} × hydrochloric acid and 75 ml of acetone are added to a solution of 8.0 g of 2- (2-naphthoxy) ethyloxydiguanide in 50 ml of methanol, and the resulting mixture is left to stand for 3 days at room temperature. The solvent is then evaporated off under reduced pressure and the residue obtained is triturated with acetone. 5.4 g are obtained

of the desired triazine from Ι · ρ. 190 to 193 ° C. To Recrystallization from ethanol melts the sample to be analyzed at 195 to 196 ° L (see Example 3).

Example 7

4,6-diamino-1 ^ -dihydro ^ -dimethyl-1 - [3- (4-cyclohexylphenoxy) propyloxy] -1,3,5-triazine hydrobromide

10

Following a procedure similar to that described in Example 1, 4-cyclohexylphenoxypropyl bromide is obtained using 4-cyclohexylphenol and dibromopropane as starting compounds in the presence made of NaOH

The bromide (b.p. 150 to 160 ° C at 2.67 mbar = 2 Torr; n'S 1.5468) slowly solidifies to a white, waxy substance with a melting point of 45 ° C.

The free oxytriazine base is by reaction of

3.87 g of 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-oxy-1,3,5-triazine hydrochloride prepared with a solution of 1.4 g of KOH in methanol. The residue obtained after evaporation of the solvent is dissolved in dimethylformamide suspended and for 2 days at room temperature with 5.94 g of 4-cyclohexylphenoxypropyl bromide touched. The reaction mixture is then filtered and evaporated under reduced pressure. The received The residue is rubbed with acetone, and the solid substance is filtered off, washed with water and dried. The product (5.48 g) is the desired compound with a m.p. 204-207 ° C.

Example 8

4,6-diamino-1 ^ -dihydro ^ -dimethyl-1 - [3- (4-chloro-

2-cyclohexyl-phenoxy) -propyloxy] -1,3,5-triazine-

hydrobromide

In a manner similar to that described in Example 1, 4-chloro-2-cyclohexylphenoxypropyl bromide is prepared; Bp 165 to 175 ° C at 2.0 mbar (1.5 torr); λ O ⁰ 1.5530.

6.63 g of the abovementioned bromide are mixed according to Example 7 with that of 3.87 g of oxytriazine hydrochloride obtained, suspended in dimethylformamide implemented free base. The reaction mixture is 24 hours stirred for a long time at room temperature, filtered and evaporated to dryness.

The residue obtained is stirred with acetone, filtered, and the solid substance is washed with water and dried. The crude triazine has a melting point of 220 to 222 ° C. and is recrystallized from ethanol. This gives 5.35 g of the desired compound with a melting point of 225 ° C.

Example 9

Diacetyl derivative of 4,6-diamino-1,2-dihydro-

2,2-dimethyl-1- [3- (2,4,5-trichlorophenoxy) propyloxy] -

1,3,5-triazine (M)

5 g of the above free base (M) are heated for 5 minutes with 25 ml of multi-distilled acetic anhydride on a steam bath, and the reaction mixture is then evaporated to dryness under reduced pressure, then extracted with ethyl acetate, washed with water, crystallized and removed Recrystallized ethanol. The diacetyl derivative is obtained in the form of small white needles with a melting point of 171 to 172 ^° C.

Example 10

A mixture of 2 g of 4,6-diamino-1,2-dihydro-2,2-dimethyl-1 - (2,4-dichlorobenzyloxypropyloxy) -1,3,5-triazine base and 10 ml of multi-distilled acetic anhydride is heated for 5 minutes on a steam bath and then evaporated under reduced pressure. After recrystallization. tion of the solid residue from a A mixture of ethyl acetate and ligroin gives 1.7 g of a product with a melting point of 154 to 156.degree. Through more The desired diacetyl derivative of triazine, which has a melting point of 154.degree. To 155.degree. C., is obtained from recrystallization having.

Example 11

A mixture of the triazine base from Example 10, 10 ml of multi-distilled acetic anhydride and 5 ml of triethylamine is stirred for 72 hours at room temperature, poured onto ice, for a further 30 minutes stirred for a long time and finally extracted with ethyl acetate. After washing with water, the solution becomes dried, treated with charcoal, concentrated and then added with ligroin. 0.7 g of des is obtained desired tetraacetyl derivative. The melting point (124 to 125 ° C) changes with further recrystallization not.

Example 12

In a manner similar to that given in Example 11 4,6-diamino-1,2-dihydro-2,2-dirrethyl-1- [3- (2,4,5-trichlorophenoxy) propyloxy] -1,3,5-triazine base converted into their tetraacetyl derivative, which after recrystallization from a mixture of ethanol and Ligroin has a melting point of 117 to 118 ° C.

The compounds listed in Table I are prepared by procedures similar to that described in Example 1 manufactured.

Table I. example

Ar

salt

Mp ° C

13th 2 0 3,5-dimethyl-4-chlorophenyi HBr 14th 2 0 3-methyl-4-chlorophenyl HBr 15th 2 0 3-trifluoromethylphenyl HBr 16 2 0 2,4,5-trichlorophenyl HBr 17th 3 0 2,4,5-trichlorophenyl Saccharinate 18th 3 0 2,4,5-trichlorophenyl Citrate

185-186

183-184

210

223-225

208

186-188

030 235/44

π 3 17th 1957 769 Ar 18th ü
I.
I.
ι 3 2,4,5-trichlorophenyl 1 continuation 3 χ 2,4,5-trichlorophenyl salt example 3 0 2,4,5-trichlorophenyl Maleat M.p., ° C i 19th 3 0 2,4,5-trichlorophenyl acetate 186 1 20th 3 0 2,4,5-trichlorophenyl Embonate 180 I. 21 3 0 2,4,5-trichlorophenyl Gluconate 140 I. 22nd 4th 0 2,4,5-trichlorophenyl Cyclohexyl sulfamate about 85 § 23 3 0 2,4,5-trichlorophenyl 1/2 pamoat 178-179 1 24 5 0 2,4,5-trichlorophenyl HCl 150 1 25th 6th 0 2,4,5-trichlorophenyl ¹ HBr 201-204 I. 26th 7th 0 2,4,5-trichlorophenyl phosphate 190-193 I. 27 8th 0 2,4,5-trichlorophenyl HBr 191-192 i 23 9 0 2,4,5-trichlorophenyl HBr 128-132 I. 29 10 0 2,4,5-trichlorophenyl HBr 185-186 I. 30th 2 0 2,4,5-trichlorophenyl HBr 174-175 I. 31 2 0 4-nitrophenyl HBr 184-185 I. 32 3 0 2,4-dichlorophenyl HBr $ 149-150 33 4th 0 2,4-dichlorophenyl HBr 180-181 I. 34 2 0 2,4-dichlorophenyl HBr 207 Jf 35 3 0 3,4-dichlorophenyl HBr 200-202 I. 36 4th 0 3,4-dichlorophenyl HBr 209-210 1 37 3 0 3,4-dichlorophenyl HBr 196-197 I. 38 3 0 3,5-dimethylphenyl HBr 198-200 I. 39 2 0 2-naphthyl HBr 208-210 I. 40 3 0 4-benzylphenyl HBr 190-191 i
197-198 ₅ | 41. 3 0 4-chlorophenyl HBr 192-193 ¥} 42 3 0 4-chlorophenyl HBr ¹⁷¹ I. 43 2 S. 2-M ethoxycarbonylphenyl HCl i
149 I. 44 3 0 4-methoxyphenyl HBr 205 I. 45 2 0 4-terL-butylphenyl HBr 135 I. 46 4th 0 3,5-dimethylphenyl HBr 193 I.
180 i 47 2 0 3-trifluoromethylphenyl HBr 207 I. 48 3 0 4-chlorophenyl HBr 157 y 49 3 0 o-bromophenyl HBr ^19: 1 50 4th 0 p-bromophenyl HBr 180 1 51 2
6th 0 p-chlorophenyl HBr ¹⁸⁷ I. 52 3 0 p-chlorobenzyl
3,4-dichlorophenyl HBr 165 I. 53 4th 0 2,4,6-trichlorophenyl HBr ? <H-193 1 54 4th 0
0 2,4,6-trichlorophenyl • flowr
HBr 198 I. 55
56 4th 0 Phenyl HBr 168-170 I. 57 3 0 2,3-dimethylphenyl HBr 161-163 I. 58 4th 0 3,4-dimethylphenyl HBr 178-180 | 59 4th 0 3,4-dimethylphenyl HBr 206-210 I. 60 4th 0 3,5-dimethylphenyl HBr about 90 I. 61 4th 0 3-methyl-4-chlorophenyl HBf 183-185 I. 62 3 0 2-cyclohexyl-4-chlorophenyl HBr 182 ρ 63 3 0 Pentachlorophenyl HBr 180 I. 64 2 0 Pentachlorophenyl HBr 187 1 65 3 0 1-naphthyl HBr 193-196 1 66 4th S. 1-naphthyl HBr 218 M. 67 6th 0 1-naphthyl HBr 191 I. 68 4th 1-naphthyl HBr 170-172 Ά 69 6th 0 2-naphthyl HBr 180 I. 70 2 0 2-naphthyl HBr 187 fei 71 3 0 4-chloro-1-naphthyl HBr 165 I. 72 6th 0 4-chloro-1-naphthyl HBr 211 'I. 73 2 0 4-chloro-1-naphthyl HBr 191-193 I. 74 3 0 5,6,7,8-tetrahydro-2-naphthyl HBr 198 y 75 6th 0 5,6,7,8-tetrahydro-2-naphthyl HBr 168-170 I. 76 3 0 5,6,7,8-tetrahydro-2-naphthyl HBr 161-163 ρ 77 3 0 2-chloro-4,5-dimethylphenyl HBr 178-180 1 78 0 2-isopropyl-5-methylphenyl HBr 182 I. 79 0 HBr 180 § 80 0 HBr 81

Example 82

Tablets made from 4,6-diamino-1,2-dihydro-2,2-dimethyl-

1- [3- (2,4 ^ -trichlorophenoxy) -propyloxy] -l, 3,5-triazine-

hydrobromide

One tablet contains 10 mg of active ingredient.
Approach to the production of 100,000 tablets

(about 15 kg) 1000 g Active ingredient 1500 g Cornstarch (maximum 6 to 9% moisture) 500 g Gum arabic 8000 g Milk sugar 4500 g Icing sugar 200 g Talc 100 g Magnesium stearate 15g paraffinum Hquidum about 1 liter water 100,000 tablets Theoretical yield production method (1) granulation

1.) The starch is dried in a hot air oven at 40 ^° C. to a moisture content of 6 to 9% by weight.

2.) The individual powders are separated through a sieve with a mesh size of 0.317 mm (40 mesh) sieved.

3.) The active ingredient is placed in a planetary stirrer and gradually add the milk sugar while stirring continuously

4.) Add the icing sugar, the starch and the gum arabic, after each addition Mix for about 5 minutes and then mix again for 20 minutes.

5.) Sufficient water is added with constant stirring until a suitable granulation consistency is achieved is achieved (about 1 liter).

6.) The moist granulate is through a rotary granulator, which is equipped with a sieve with a clear Mesh size of 1.27 mm (10 mesh) is provided, happens.

7.) The granules are dried on screens at about 50 ⁰ C

(2) Compression _{mix 5Q}

1.) The dried granulate is passed through a sieve with a mesh size of 0.792 mm (16 mesh) happened

2.) A sieve with a mesh size of 0.317 mm (40 mesh) is sufficient for this Amount of dried granules sieved to obtain approximately 500 g of fines in Table II.

3.) The paraffinum liquidum example no. Is mixed with the fines, and the whole thing through a sieve with a clear mesh size of 0.635 mm (20 mesh) happened.

4.) The talc and magnesium stearate are through

passed a sieve with a mesh size of 0.635 mm (20 mesh).

5.) The majority of the granules in the planetary stirrer are those provided with the lubricant Fines added, followed by the talc and magnesium stearate. After every The addition is mixed thoroughly for at least 10 minutes. Finally, another 20 minutes mixed

(3) tabletting

The tablets are made on a rotary press using certain punches and in compliance the thickness limits pressed The weight of the tablets is checked (10 tablets = 1.5 g). The tablets can be spray coated with special coating varnishes.

Test report

Mice are immediately infected with a cycloguanil-resistant strain of Plasmodium berghei then and on the following 3 days, the mice are subcutaneously given the dosages given below administered to the compound of interest. On the fourth day after infection, each mouse is treated and a blood sample was also taken from the mice that received no treatment after infection. Then the number of infected red blood cells in the sample is determined visually under a microscope and the potency of each compound at the indicated dose, expressed as the degree of presence of parasites in the blood, determined. All compounds tested show an LD50 value in mice of over 1000 mg / kg.

The comparative tests are carried out in the same way using cycloguanil (LD 50 value:> 100 mg / kg) and the two benzyloxy-dihydro-triazines below, namely compounds No. I and No. II (LD ₅₀ values: 100 mg / kg).

Cl

H ₂ N

H 1

NH ₂

H ₃ C CH ₃

Compound No. IH ₂ NN NH ₂

CH ₂ ON

H ₃ C CH ₃

Compound no. II

Degree of the presence of parasites in the blood after 4 days at a daily dose of

1 mg / kg 10 mg / kg

0 0 28 4th 1 0 5 0 15th 0 30th 0

21

continuation

Example no.

14 20 23 24 25 26 27 28 29 36 37 40 42 44 45 53 57

Degree of Presence of ParasiteL. in the blood after 4 days at a daily dose of

1mg / kg 10 mg / kg

26th 14th 9 3 10 3 25th 0 1 0 2 0 2 0 24 0 Z, 0 7th 0 16 0 17th 0 9 0 7th 19th 0 25th 0 13th 0

Example no.

58 60 61 62 63 64 69 71 72

Cycloguanil Compound No. I Compound No. II

22nd

Degree of presence of 10 mg / kg Parasites in the blood after 4 days 0 at a daily dose of 0 1 mg / kg 0 1.5 S. 12th 0 25th 1 - 0 21 0 6th 0 26th 0 0 0.6 7.5 0 12th 0 - 100 18th 50.2 21 50.6 100 98.0 61.3

Claims (1)

Patent claims: 1. 4,6-Diamino-1 ^ -dihydro- ^ - dimethyl-1,3,5-triazine derivatives of the general formula I. H ₂ NN NH ₂ (D Ar-X- (CH ₂ J _n -O-NN