DE2736064A1 - Synergistic antimalarial compsn. contg. heterocyclic guanyl-hydrazone - and folic acid antagonist or glucose transport inhibitor - Google Patents

Abstract

Antimalarial agent comprises a mixt. of (a) a guanylhydrazone of formula (I) and (b) a folic acid antagonist or a glucose-transport inhibitor. In the formula, R, R1 and R2 =H, 1-6C alkoxy or NO2. X = O or S. N.B. In the disclosure R,R1 and R2 can also be 1-6C alkyl. (I) is esp. 6-methoxythioflavoneguanylhydrazone (Ia) and the second component is 2,6-diamino-4-ethyl-5-(4-chlorophenyl)pyrimidine (II) or 2,6-dihydroxy-2-(beta-D-glucosido)-beta-(4-hydroxyphenyl)-propiop- henone dihydrate (III). Synergistic enhancement of activity. The compsns, are effective against specieis of Plasmodium parasitic on humans (all 4 species) and other animals, including strains resistant to commercial antimalarials.

Description

Antimalarial agents

The present invention relates to new synergistic combinations of active ingredients with a strongly pronounced antimalarial effect from partly known guanylhydrazones with folic acid antagonists or glucose transport inhibitors known per se.

Malaria is still one of the most widespread infectious diseases today of the human. According to estimates by the World Health Organization, they fall ill annually more than 200 million people from malaria. About 1 million people die from malaria every year (see e.g. WHO Chronicle, 30, 486-493 (1976)). Human pathogen Malaria are four species of protozoa in the genus Plasmodium. The greatest importance belongs to the species P.falciparum and P.vivax. Available for treatment and prophylaxis While effective resources are available, they have been increasing over the past 15 years Measures and strains of the pathogen occurred in different parts of the world, which are no longer respond to the commercially available proven means. The appearance of such pyrimethamine, Chloroquine and multiple therapy resistant strains, especially P. falciparum is has already become a serious problem in different parts of the world. It It must be expected that the therapy-resistant strains will spread even further spread (WHO Technicle Reports No. 296 (1965), WHO Technicle Reports No. 529 (1973) WHO Chronicle 30, 492 (1976)). The development of new active ingredients for treatment and prevention of malaria is therefore an urgent problem today. Seems essential in the process that active ingredients from chemical body classes are found that have not been used until now not used to manufacture antimalarials to reduce the risk of cross-resistance to be kept as low as possible against existing funds. One more way, Countering the resistance problem is the combination of new active ingredients with already known anti-malarial drugs, especially if the result is a potentiation of the Effectiveness can be achieved.

It has now been found that new active ingredient combinations of (1) guanylhydrazones of the formula in which the substituents R, R1 and R2 can be identical or different and represent hydrogen, alkoxy (C1-C6), halogen, alkyl (C1-C6) or nitro and X represents an oxygen or a sulfur atom and (2) folic acid -Antagonists or glucose transport inhibitors have a particularly high antimalarial effect.

Surprisingly, the antimalarial effect is that of the invention Combinations of active ingredients are much higher than the sum of the effects of the individual ones Ingredients.

So there is a real synergistic effect. The invention Guanylhydrazones of the formula (I) show on their own and to a greater extent in Form of the active ingredient combinations according to the invention with folic acid antagonists or Glucose transport inhibitors have a very pronounced effectiveness against parasitic Protozoa in particular malaria pathogens, even if these are resistant to commercially available Active ingredients are. The active ingredient combinations represent a real enrichment of the Pharmacy.

The guanylhydrazone components of the drug combinations are made by the general formula (I) is clearly defined: Alkoxy (C1-C6) is preferably used herein for alkoxy with 1 to 4 carbon atoms and in particular for methoxy and ethoxy.

Alkyl (C1-C6) here preferably stands for alkyl having 1 to 4 carbon atoms, examples are: Methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, tert-butyl.

Halogen herein preferably represents fluorine, chlorine and bromine, in particular for chlorine.

The folic acid antagonists contained in the active ingredient combinations according to the invention are antimetabolites that cause the conversion of peroylglutamic acid (folic acid in the narrower sense) into the Citrovorum factor and thus those necessary for transformylation Inhibit coenzymes and thereby disrupt purine synthesis.

As folic acid antagonists to be considered for the new active ingredient combinations the following compounds are exemplified: 1) N 1 - (p-chlorophenyl) -N5-isopropyl diguanide; 2) N1- (3,4-dichlorophenyl) -N5-isopropyl diguanide; 3) Mixture of 4,6-diamino-1- (p-chlorophenyl) -1,2-dthydro-2,2-dimethyl-s-triazine with 4,4'-methylenebis (3-hydroxy-2-naphthoic acid (2: 1); 4) 2,4-diamino-5-p-chlorophenyl-6-ethylpyrimidine; 5) 2,4-diamino-5- (3 ', 4', 5'-trimethyloxybenzyl) pyrimidine; 6) 4,4'-diaminodiphenyl sulfone; 7) 4,9'-diacetyldiaminodiphenyl sulfone; 8) N'-2-pyrimidinylsulfanilamide; 9) N'- (3,4-Dimethyl-5-isoxazolyl) -sulfanilamide 10) N1- (2,6-Dimethoxy-4-pyrimidinyl) -sulfanilamide 11) N '- (6-Methoxy-3-pyridazinyl) -sulfanilamide 12) N '- (5,6-Dimethoxy-4-pyrimidinyl) sulfanilamide 13) N' - (3-Methoxy-2-pyrazinyl) sulfanilamide 14) 1- (4-Chlorophenyl) -2,2-dimethyl-4,6-diamino-dihydro-1,3,5-triazine As for the Glucose transport inhibitors are considered new combinations of active ingredients mentioned by way of example: 2,6-dihydroxy-2- (ß-D-glucosido) -ß- (4-hydroxyphenyl) -propiophenone and its dihydrate. (F. Alvarado and R.K. Crane Bichemica et Biophysica Acta 56, 170-172 (1962).

Individual active ingredients of group (1) are new, but they can be produced in a simple manner by known processes. They are obtained, for example, when using ketones of the general formula in which X, R, R1 and R2 have the meaning given above in the presence of diluents, preferably in the presence of catalytic amounts of acid at temperatures between 0 and 150 ° C., preferably between 40 and 120 ° C. with aminoguanidine of the formula preferably in the form of an acid addition salt.

The reaction products generally precipitate and are filtered off with suction and washed with lower alcohols, preferably with ethanol.

When reacting compounds of the formula (II) with aminoguanidine of the formula (III), preferably in the form of their salts, are preferably inert, polar, organic solvents in which components II and III dissolve well and the reaction product precipitates in poorly soluble form. As for implementation Examples of suitable solvents are: lower alkanols such as methanol, Ethanol and i-propanol, especially ethanol. Ketones such as acetone, methyl ethyl ketone. Acid nitriles such as acetonitrile and propionitrile. Ethers such as dioxane, tetrahyrofuran.

The new synergistic combinations of guanylhydrazones of formula (I) and folic acid antagonists or glucose transport inhibitors - and their salts - have a very strong effectiveness against malaria pathogens. As the most important human phatogenic plasmodia, which are synergistic with the invention Combinations that can be combated include: Plasmodium vivax Plasmodium ovale Plasmodium malariae Plasmodium falciparum In animal experiments the synergistic combinations according to the invention are highly effective against Plasmodium berghei (mouse, rat, golden hamster), Plasmodium cathemerium, Plasmodium praecox (canary), Plasmocium gallinaceum (chicken).

Due to the active ingredients of the formula (I) used, the Folic acid antagonists and the glucose transport inhibitors occurring individually Dosage ranges can determine the weight ratios of the active ingredient groups in the active ingredient combinations fluctuate in relatively large areas. The determination of the required Weight ratios of the active ingredients in the active ingredient combinations can be used by everyone Skilled in the art based on the individual dosage ranges.

The present invention also includes the use of the invention Combinations of active ingredients and pharmaceutical preparations which contain the combinations of active ingredients contained in human and veterinary medicine for prophylaxis, amelioration and / or Cure Malaria.

The active ingredient combinations according to the invention or the pharmaceutical ones Preparations can be oral, parenteral, intraperitoneal and / or rectal, preferably oral, rectal and administered parenterally.

In general, it has been used in both human and veterinary medicine Proven to be advantageous, the active ingredient (s) in amounts of about 5 to 50, preferably 10 to 30 mg / kg body weight per 24 hours, if necessary in the form of several single doses to be administered to achieve the desired results.

However, it may be necessary to deviate from the stated dosages depending on the type and body weight of the object to be treated the type and severity of the disease, the type of preparation and application of the drug and the period or interval within which the administration he follows. So in some cases it may be sufficient with less than the above Amount of active ingredient get along, while in other cases the amount of active ingredient listed above must be exceeded.

The determination of the necessary optimal dosage and The type of application of the active ingredients can be carried out by any person skilled in the art on the basis of his or her specialist knowledge easily done.

The therapeutically effective combinations of active ingredients should be in the above listed pharmaceutical preparations preferably in one concentration from about 0.1 to 99.5, in particular from about 0.5 to 95 percent by weight of the total mixture to be available.

The manufacture of the pharmaceutical preparations listed above takes place in the usual way according to known Methods, e.g. by mixing of the active ingredient combinations according to the invention with the carrier (s).

The present invention includes pharmaceutical preparations, the, in addition to non-toxic, inert pharmaceutically suitable carriers, those according to the invention Contain active ingredient combinations or those from the active ingredient combinations according to the invention exist as well as processes for the production of these preparations.

The present invention also includes pharmaceutical preparations in dosage units. This means that the preparations in the form of individual parts, e.g.

Tablets, coated tablets, capsules, pills, suppositories and ampoules are present, whose active ingredient content corresponds to a fraction or a multiple of a single dose. The dosage units can be, for example, 1, 2, 3 or 4 single doses or 1/2, 1/3 or Contain 1/4 of a single dose. A single dose preferably contains the amount Active ingredient that is administered in one application and that usually corresponds to a whole, corresponds to half a day or a third or a quarter of a daily dose.

Among non-toxic, inert pharmaceutically acceptable carriers are solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of any kind to understand.

Preferred pharmaceutical preparations are tablets, coated tablets, Capsules, pills, granules, suppositories, solutions, suspensions and emulsions called.

Tablets, coated tablets, capsules, pills and granules can be the or the active ingredients contain in addition to the usual carriers such as (a) fillers and extenders, e.g.

Starch, lactose, cane sugar, glucose, mannitol and silica, (b) binders, e.g. carboxymethyl cellulose, alginates, gelatine, polyvinylpyrrolidone, (c) humectants, e.g., glycerin, (d) disintegrants, e.g.

Agar-agar, calcium carbonate and sodium bicarbonate, (e) dissolution retarder, e.g. paraffin and (f) absorption accelerators, e.g. quaternary ammonium compounds, (g) wetting agents, e.g., cetyl alcohol, glycerol monostearate, (h) adsorbents, e.g. Kaolin and bentonite and (i) lubricants such as talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed and (a) - (i).

The tablets, coated tablets, capsules, pills and granules can be used with the customary coatings and casings, optionally containing opacifying agents be and also be composed so that they only or the active ingredient or preferably in a certain part of the intestinal tract, possibly delayed using e.g. polymer substances and waxes as embedding compounds can be.

The active ingredient combinations according to the invention can optionally with one or more of the above Carriers too are in microencapsulated form.

In addition to the active ingredient (s), suppositories can contain the usual water-soluble ones or water-insoluble carrier substances, e.g. polyethylene glycols, fats e.g. Cocoa fat and higher esters (e.g. C14 alcohol with C16 fatty acid) or mixtures of these Fabrics.

Solutions and emulsions can, in addition to the active ingredient or ingredients, the customary carriers, such as solvents, solubilizers and emulsifiers, e.g. Water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, Benzyl benzoate, proprene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular Cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerine, Glycerin formal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.

The solutions and emulsions can also be used for parenteral administration are in sterile and blood isotonic form.

In addition to the active ingredient (s), suspensions can include the usual carriers, such as liquid diluents, e.g. water, ethyl alcohol, propylene glycol, suspending agents, e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline Cellulose, aluminum ethahydroxide, bentonite, agar-agar and Tragacanth or mixtures of these substances.

The formulation forms mentioned can also contain colorants and preservatives as well as additives that improve smell and taste, e.g. peppermint oil and eucalyptus oil and sweeteners e.g. contain saccharine.

The malaria activity of some compounds of the invention is exemplarily shown in Tables 1, 2 and 3. As examples of effectiveness the animal models P. berghei (mouse), P.cathemerium and P.praecox (canary) are used.

Description of the test model (animal model) If e.g. 18-20 g heavy NMRI mice intraperitoneally with about 107 p.berghei infected erythrocytes inoculated, from the 3rd day after infection between 2% and 80% of the red ones are Affected blood cells. Untreated animals die between the 7th and 11th day after infection. The substances according to the invention are used to test for effectiveness dissolved in water or - optionally using an emulsifier - suspended and the test animals subcutaneously or orally with the help of the gullet on 4 consecutive Administered days; the 1st treatment takes place 2 hours after infection. The preparations are dissolved or suspended in water in such a way that 0.5 ml of solution or Suspension are to be applied; from the 3rd day after infection, the tail vein becomes 1 drop of blood is taken, a smear is made and this is stained according to Giemsa. At 950 times Magnification will be 25 if the infestation is very weak 50 fields of view checked. The number of parasitized erythrocytes per visual field is determined. The blood sample is taken 5 days a week. Permit microscopically no parasites are found in the blood for up to 4 weeks after infection, so the animals are reinfected. A normal approach to reinfection indicates this point out that there is no premunity, so the animals can be considered cured. Leads the reinfection lead to a delayed course of the infection or be treated with Animals fewer parasites than in the untreated controls or the parasites found only at a later point in time, then there is a suppressive effect before. In these cases, survival time is usually longer.

In further experiments it could be shown that the claimed Guanylhydrazones alone as well as in combination e.g. with folic acid antagonists high are effective against Plasmodium berghei strains that against conventional Antimalarials are resistant. This is exemplified by Table 3.

Table 1 Effectiveness of guanylhydrazones according to the invention malaria pathogens: Plasmodium cathemerium (canary), Plasmodium berghei (mouse) compounds of the general formula (I) Therapeutic index XR R1 R P.cathemerium P.berghei SH 1 6-OCH3 H 100 20 SH 6-CH3 H 10 10 O 6-C1 6-OCH 3 H 10 10 OH 6-OCH3 H 40 2 for comparison: Quinine 20 2 The therapeutic index is given here, ie

the ratio of dose tolerata maxima to dose effectiva minima.

Table 2 Potentiation of the effectiveness by combining the guanylhydrazones (I) with folic acid antagonists and glucose transport inhibitors. Plasmodium berghei / mouse; normally sensitive trunk. Average duration in days to Reaching a min- infection-related mg / kg at least 2% of the erythes death capture throcytes the parasitemia the mouse after the in- fection untreated Control - 3 10.5 A 5 3.0 11.5 25 5.5 10.5 50 7.0 14.5 B 0.05 8.0 15 0.1 9.75 15 0.25 13.75 15 C 1000 3 7 + 25+ BU, 1 15.8 20.5 + 5+ B 0.25 14 21 A + 50, + B 0.25> 28 (healing) 28 50+ B 0.1 17 21 A + 50+ B 0.05 13 22.5 25+ 18.75->28> 28 0.25 (50% of animal healing) A + 25+ 7 17 C 1000 A = 6-methoxythioflavine-guanylhydrazone hydrochloride B = pyrimethamine (2,6-diamino-4-ethyl-5- (4-chlorophenyl) -pyrimidine) as a folic acid antagonist C = phlorizine dihydrate (2,4,6-trihydroxy -2- (ß-D-glucosido) -ß- (4 hydroxyphenyl) -propionphenone dihydrate as a glucose transport inhibitor Table 3 Efficacy against therapy-resistant P.berghei strains P.berghei strain treatment survival finding resistant to treatment in days both the salt untreated 11.5 of cycloguanil with Embonsäure D 25 mg / kg 11.5 ineffective as well as against about chloroquine E 25 mg / kg 11.5 ineffective B 0.25 mg / kg 12 ineffective A 50 mg / kg 15 effect A 50 mg / kg + 28 cures B 0.25 mg / kg A 50 mg / kg + 23.5 effect D 25 mg / kg A = 6-methoxythioflavone-guanylhydrazone hydrochloride B = pyrimethamine D = salt of cycloguanil with emboxylic acid E = chloroquine diphosphate In Tables 1 and 2, ineffective means that after infection there is a normal course of infection as in the untreated control, effect that at least 7 days after infection no parasites can be found in the blood and healing that no parasites can be found in the blood up to 28 days after infection and a reinfection leads to a normal course of the infection.

A) Examples of the production of tablets containing the tablets according to the invention Combination of active ingredients.

a) Active ingredient combination consisting of 9.5 parts of 6-methoxythioflavone-guanylhydrazone, 10 mg hydrochloride and 0.5 parts pyrimethamine lactose 119 mg corn starch 60 mg (of which 15 mg as paste) talc 10 mg magnesium stearate 1 mg 200 mg mixture of active ingredients, Mix the milk sugar and half the amount of cornstarch with a paste of one quarter Knead the corn starch, through a sieve with 3 - 5 Press mm mesh size and dry in a suitable dryer at 60 - 800C.

Beat the dry granulate through a sieve with 0.8 mm mesh size, Mix in the remaining quarter of cornstarch, talc and magnesium stearate and use a conventional tablet press to round tablets with a diameter of 8 mm and a Compress a total weight of 200 mg.

b) Active ingredient combination consisting of 2 parts of 6-methoxythioflavone-guanylhydrazone hydrochloride 10 mg and 80 parts of phlorizin dihydrate calcium phosphate (secondary) 117 mg gelatin 2 mg wheat starch 20 mg magnesium stearate 150 mg mixture of active ingredients and secondary Mix calcium phosphate, knead with an aqueous gelatin solution, sieve (3 - 5 mm) and dry (60 - 800C). Sieve the dry granules (0.8 mm), then Mix in wheat starch and magnesium stearate and tablet in the known manner, (round tablets, diameter 7 mm, gross tablet weight 150 mg).

B) Examples of the production of capsules containing those according to the invention Active ingredient combination a) Active ingredient combination of 8 parts of 6-methoxythioflavone-guanylhydrazone 10 mg hydrochloride and 0.75 parts pyrimethamine calcium phosphate sec. 136 mg magnesium stearate 3 mg silica colloidal 1 mg 150 mg The ingredients are mixed and with filled into hard gelatine capsules using a suitable capsule filling and sealing machine.

b) Active ingredient combination of 1 part of 6-methoxythioflavonguanylhydrazone hydrochloride 10 mg and 35 parts of phlorizin dihydrate lactose 85 mg polyvinylpyrrolidone 3 mg Stearic acid 1 mg colloidal silica 1 mg talc 5 mg 100 mg combination of active ingredients and mix milk sugar with a solution of polyvinylpyrrolidone and stearic acid Knead in methylene chloride, sieve (3 - 5 mm) and dry (50 - 600C).

The dry granulate through a sieve with 0.5-0.6 mm mesh size Beat, add colloidal silica and talc and use a suitable apparatus Fill in hard gelatine capsules.

Preparation examples Preparation of the guanylhydrazones Example 1 6-methoxythioflavone-guanylhydrazone hydrochloride 26 g of 6-methoxyfhioflavone and 14 mg of aminoguanidine hydrochloride are heated in 500 ml of ethanol after adding a few drops of conc. Hydrochloric acid under reflux for 4-5 hours, the reaction product is filtered off with suction while hot and, after recrystallization, the reaction product is obtained in crystals with a melting point of> 2700 ° C. Yield: 90% of theory. Th.

In analogy to Example 1, the following guanylhydrazone compounds obtained: Example 2 7-methoxythioflavone guanylhydrazone hydrochloride from 13 g of 7-methoxythioflavone and 7 g of aminoguanidine hydrochloride in 400 ml of ethanol yellow crystals, melting point 200-2020C Yield: 80% of theory Th.

Example 3 6-Methoxy-4'-nitrothioflavone guanylhydra from 15 mg of 6-methoxy-4'-nitrothioflavone and 6 g of aminoguanidine in 350 ml of ethanol, brown crystals, melting point 285 ° C., yield: 80 % d. Th.

Example 4 6-chlorothioflavone-guanylhydrazone hydrochloride from 10 g 6-chlorothioflavone and 5 g aminoguanidine hydrochloride in 250 ml ethanol crystals of melting point 295 ° C. Yield: 90% of theory Th.

Example 5 6-methoxyflavone guanylhydrazone hydrochloride from 12 g of 6-methoxyflavone and 6 g of guanylhydrazone hydrochloride in 300 ml of ethanol, yellow crystals with a melting point of 2850C Yield: 95% of theory Th.

Example 6 6-methoxy-4'-chloroflavone guanylhydrazone hydrochloride 14 g of 6-methoxy-4'-chloroflavone and 6 g of aminoguanidine hydrochloride in 400 ml of ethanol orange crystals m.p. 3000C Yield: 90%. d. Th.

Example 7 8-methoxythioflavone guanylhydrazone hydrochloride 13th g of 8-methoxythioflavone and 7 g of aminoguanidine hydrochloride in 400 ml of green-yellow ethanol Crystals yield 80 8 d. Th. Mp.> 2500C Example 8 5-Chloro-8-methoxy-4'-methoxythioflavone-guanylhydrazone hydrochloride from 11 g of 5-chloro-8-methoxy-4'-methoxythioflavone and 5 g of aminoguanidine hydrochloride in 350 ml of ethanol green-brown crystals yield 85% of theory. Th. Mp.> 275 ° C Example 9 7-Methoxy-4'-chloroflavone guanylhydrazone hydrochloride from 12 g of 7-methoxy-4'-chloroflavone and 5 g of aminoguanidine hydrochloride in 250 ml of ethanol canary yellow crystals yield 85% d. Th. Mp.> 2500C Example 10 6-Methylthioflavone-guanylhydrazone hydrochloride from 10 g of 6-methylthioflavone and 5 g of aminoguanidine hydrochloride in 250 ml of ethanol yellow-yellow crystals yield 90% of theory Th. M.p. 5250C Example 11 3'-nitrothioflavone guanylhydrazone hydrochloride from 28 g 3'-nitrothioflavone and 12 g of aminoguanidine hydrochloride in 1.2 l of ethanol yellow crystals yield 80% of theory. Th. Mp.> 260 ° C. Example 12 4'-nitrothioflavone-guanylhydrazone hydrochloride from 14 g of 4'-nitrothioflavone and 6 g of aminoguanidine hydrochloride in 400 ml of orange ethanol Crystals yield 85% of theory Th. Mp.> 260 ° C. Example 13 6-Chloro-4'-methoxythioflavone-guanylhydrazone hydrochloride from 15 g of 6-chloro-4'-methoxythioflavone and 6 g of aminoguanidine hydrochloride in 400 ml of ethanol gray-green crystals yield 90% of theory. Th. Mp.> 260 ° C. Example 14 6 <chloro-4'-nitrothioflavone-guanylhydrazone hydrochloride from 16 g of 6-chloro-4'-nitrothioflavone and 7 g of aminoguahidine hydrochloride in 400 ml Ethanol red crystals yield 90% of theory. Th. Mp.> 260 ° C example 15 6-Äthoxythioflavon-guanylhydrazone hydrochloride from 10 g 6-Äthoxythioflavon and 4 g of aminoguanidine hydrochloride in 150 ml of ethanol green-yellow crystals, yield 95 % d. Th. Mp. 7 27 50C Example 16 6-Methoxy-3'-chloroflavone-guanylhydrazone hydrochloride from 14 g of 6-methoxy-3'-chloroflavone and 6 g of aminoguanidine hydrochloride in 400 ml of ethanol green-yellow crystals 0 yield 90% of theory Th. Mp. 273 ° Example 17 6,4'-dimethoxyflavone guanylhydrazone hydrochloride from 14 g of 6,4'-dimethoxyflavone and 6 g of aminoguanidine hydrochloride in 500 ml of ethanol green-yellow crystals with a melting point of 2750C, yield 90% of theory. Th.

Claims (9)

Claims 1. Antimalarial agents, characterized by a content of an active ingredient combination consisting of (1) guanylhydrazones of the formula in which the substituents R, R1 and R2 can be identical or different and are hydrogen, alkoxy (C1-C6) or nitro and X is an oxygen or sulfur atom and (2) a compound from the group of folic acid antagonists or Glucose transport inhibitors. 2. Antimalarial agent according to claim 1, characterized in that it is the active ingredient combination consisting of a guanylhydrazone of the formula (I) and contains a folic acid antagonist. 3. Antimalarial agent according to claim 1, characterized in that it is the active ingredient combination consisting of a guanylhydrazone of the formula (I) and contains a glucose transport inhibitor. 4. Antimalarial agent according to claim 2, characterized in that it is an active ingredient combination consisting of 6-methoxythioflavonguanylhydrazone and Contains 2,6-diamino-4-ethyl-5- (4-chlorophenyl) pyrimidine. 5. Antimalarial agent according to claim 3, characterized in that it is an active ingredient combination consisting of 6-methoxythioflavonguanylhydrazone and 2,6-Dihydroxy-2- (ß-D-glucosido) -ß- (4-hydroxyphenyl) propiophenone dihydrate contains. 6. Process for the production of antimalarial agents, characterized in that that one guanylhydrazones of the formula (I) according to claim 1, folic acid antagonists or Glucose transport inhibitors according to claim 1 and inert, non-toxic, pharmaceutical suitable carriers mixed together. 7. A process for the production of antimalarial agents according to claim 6), characterized in that guanylhydrazones of the formula (I) according to claim 1, folic acid antagonists and inert, non-toxic, pharmaceutically acceptable carriers mixed together. 8. A method for the production of antimalarial agents according to claim 6), characterized in that guanylhydrazones of the formula (I) according to claim 1, glucose transport inhibitors and inert, non-toxic, pharmaceutically acceptable Carriers mixed together. 9. A method for the treatment of malaria, characterized in that active ingredient combinations according to claim 1 are administered to humans or animals, the have malaria.