WO2001080839A2 - Use of naphthindazole-4,9-quinones as antiparasitic agents - Google Patents

Abstract

The invention relates to pharmaceutical compositions which are characterised in that they contain at least one of the compounds of general formula (I), to their pharmacologically suitable salts and to the use of compounds of general formula (I) or their pharmacologically suitable salts for prophylactic administration or for therapeutic treatment of a parasitic infection caused by Trypanosoma spp., Leishmania spp., Plasmodium spp., Cryptosporidium parvum, Eimeria spp., Toxoplasma gondii or Pneumocystis spp.

Description

 description

Use of naphthindazole-4,9-quinones as antiparasitic agents

The invention relates to pharmaceutical compositions, characterized by the content of at least one of the compounds of the general formula (I)

and their pharmacologically acceptable salts and the use of

Compounds of the general formula (I) or their pharmacologically acceptable salts for the prophylactic administration or therapeutic treatment of a parasitic infection caused by Trypanosoma spp., Lθishmania spp., Plasmodium spp., Cryptosporidium parvum, Eimeria spp., Toxoplasma gondii or Pneumocystis spp.

The invention thus relates to a group of chemically defined substances of the same basic structure, which have specific antiparasitic effects in vitro and in vivo (animal, human). The basic structures belong to the naphthoquinone and related anthraquinone and phenanthrenequinone types.

The human pharmacological use of previously investigated naphthoquinones is severely limited by the high toxicity, which made in vivo use in humans almost impossible.

Previously used naphthoquinones were experimentally investigated as cytostatics. Only the naphthoquinone "Atovaquone" (Wellvone ^® ) was used in monotherapy used to treat Pneumocystis carinii (PcP) infections and in combination therapy with Proguanil to treat Plasmodia infections. Atovaquone shows good effects in the monotherapy of Pneumocystis carinii (PcP) infections in HIV co-infections, but can only be used to a limited extent in longer therapies due to the rapid development of resistance of the pathogens. Monotherapy for malaria is not possible due to the rapid development of resistance of the pathogens. Another disadvantage is the very poor bioavailability and the high daily dose of 3 times 750 mg per day.

Other antiprotozoal compounds are pentamidine isethiate, melarsoprol and glucantime. Taken as a whole, they are highly toxic with little therapeutic benefit. According to current understanding and legal requirements, the approval of these drugs, which are more than 70 years old, would no longer be possible.

There is therefore an urgent need to provide new active ingredients and medications for the treatment or prophylaxis of parasitic infections. Above all, there is a lack of pharmaceutical compositions for the prophylactic administration or therapeutic treatment of a parasitic infection caused by Trypanosoma spp., Leishmania spp., Plasmodium spp., Cryptosporidium parvum, Eimeria spp., Toxoplasma gondii or Pneumocystis spp.

The present invention is therefore based on the object of compounds for the prophylactic administration or therapeutic treatment of a parasitic infection caused by Trypanosoma spp., Leishmania spp., Plasmodium spp., Cryptosporidium parvum, Eimeria spp., Toxoplasma gondii or Pneumocystis spp. to provide and to provide pharmaceutical compositions which contain at least one of the prophylactic administration or therapeutic treatment of a parasitic infection caused by Trypanosoma spp., Leishmania spp., Plasmodium spp., Cryptosporidium parvum, Eimeria spp., Toxoplasma gondii or Pneumocystis spp. used compounds included. According to the invention, this object is achieved by using the compounds of the general formula (I)

where R ^{1 is} hydrogen or a group

- (CH ₂ ) m-CH = CH— (CH ₂ ) ₈ - _m - H,

- (CH ₂ ) _m - C≡C (CH ₂ ) sm - H,

- (CH ₂ ) _n -R7

O

II

- (CH ₂ ) p— OC— R9

O

II

- (CH ₂ ) p— C-R11 _f

- C ₂ H ₄ -C≡C-R12 _?

- CH ₂ ~ C≡C-CH ₂ - R12 _f

- C≡CC ₂ H ₄ - R12

means and

r A c c

R, R, R, R and R independently of one another are hydrogen or the groups

-R ⁷ , -NO ₂ , -NH ₂ , -NHR ⁸ , -NR ⁸ R ⁸ ', -CN, -OH, - <CH ₂ ) ₀ -R14,

-O— (CH ₂ ) ₀ -R12

-S— (CH ₂ ) oR ¹²

O O O

II II II

C— R16. - OC— R16, - CO— R16,

OHO II I II OC— (CH ₂ ) ₀ -R ¹² - N- -C— R16 _?

O H O R16 '

II I II I

C— N— R16 - C— N— R16 J

R³ zusammen mit R und den beiden Kohlenstoffatomen C-5 und C-6 des

R ³ together with R and the two carbon atoms C-5 and C-6 des

Benzene ring forms a further condensed benzene or naphthalene ring which optionally carries further functional groups, these functional groups being fluorine, chlorine, bromine, iodine, nitro, cyano, amino, hydroxy, trifluoromethyl groups Alkyl groups with 1 to 5 carbon atoms, alkoxy or haloalkoxy groups with 1 to 5 carbon atoms or alkylthio or haloalkylthio groups with 1 to 5 carbon atoms,

R together with R and the two carbon atoms C-5 and C-6 of the benzene ring forms a further condensed five- or six-membered heterocycle, where R and / or R represent a carbon, oxygen or nitrogen atom and this further heterocycle optionally through Fluorine, chlorine, bromine, iodine or alkyl radicals having 1 to 4 carbon atoms is substituted,

R ⁴ together with R ⁵ and the two carbon atoms C-6 and C-7 des

Benzene ring forms a further condensed benzene or naphthalene ring which optionally carries further functional groups, these functional groups being fluorine, chlorine, bromine, iodine, nitro, cyano, amino, hydroxy, trifluoromethyl groups Alkyl groups with 1 to 5 carbon atoms, alkoxy or haloalkoxy groups with 1 to 5 carbon atoms or alkylthio or haloalkylthio groups with 1 to 5 carbon atoms,

R ⁴ together with R ⁵ and the two carbon atoms C-6 and C-7 des

Benzene ring forms a further condensed five- or six-membered heterocycle, where R ⁴ and R are each independently a carbon,

Represent oxygen or nitrogen atom and this further heterocycle is optionally substituted by fluorine, chlorine, bromine, iodine or alkyl radicals having 1 to 4 carbon atoms,

R ⁵ together with R ⁶ and the two carbon atoms C-7 and C-8 des

Benzene ring forms another condensed benzene or naphthalene ring, which optionally carries further functional groups, these functional groups being fluorine, chlorine, bromine, iodine, nitro, cyano, amino, hydroxyl, trifluoromethyl groups, alkyl groups having 1 to 5 carbon atoms, alkoxy groups or haloalkoxy groups with 1 to 5 carbon atoms or alkylthio or haloalkylthio groups with 1 to 5 carbon atoms,

5 6

R together with R and the two carbon atoms C-7 and C-8 des

Benzene ring forms a further condensed five- or six-membered heterocycle, where R and R each independently represent a carbon, oxygen or nitrogen atom and this further heterocycle optionally by fluorine, chlorine, bromine, iodine or alkyl radicals with 1 to 4 Carbon atoms is substituted,

R ^{7 stands} for -R ¹² , -OR ⁸ or -SR ⁸ ,

R and R independently of one another represent an alkyl group having 1 to 4 carbon atoms, R ^{9 represents} an alkyl group having 1 to 4 carbon atoms or a group of the structure

represents,

R ^{10 stands} for -R ¹² , -R ⁸ or -OR ⁸ ,

R ^{11 stands} for -R ⁸ , -NH ₂ , -NHR ⁸ , -NR ⁸ R ^{8 '} , -OH, -OR ⁸ ,

R ¹² , -R ^{12 '} , -R ^{12 "} , -R ¹² , -R ¹² independently of one another represent -H, -F, -Cl, -Br or -I, R ^{13 represents} -R ⁸ , -R ¹² or is a group of the following structure

- C ₂ H ₄ -C≡≡C-R12 _f - CH ₂ -C≡C-CH ₂ - R1 _} - C≡≡CC ₂ H ₄ - R12

R ^{14 stands} for -CH ₃ , -R ⁷ , -SH,

R ¹⁵ , -R ^{15 '} , -R ^{15 "} , -R ^15"' , -R ^{15 "'} independently of each other for -R ⁷ , -R ⁸ , -NO ₂ , -NH ₂ , -NHR ⁸ , -NR ⁸ R ^{8 '} , -CN or

- O— (CH ₂ ) ₀ -R ¹² , - S— (CH ₂ ) ₀ -R12, - (CH ₂ ) ₀ -R12,

1 R Λ fi * ö

R and R independently of one another denote -H or -R,

R ^{17 represents} -R ⁷ , -CF ₃ , -NO _2l -CN, -SH, -OH or -NH ₂ ,

m stands for 0 to 8, n for 1 to 10, o for 1 to 5 and p for 0 to 4,

and their pharmacologically acceptable salts and dimers or trimers of the compounds of the general formula (I) or the pharmaceutical compositions which contain at least one compound of the general formula (I) or their pharmacologically acceptable salts or dimers or trimers of the compounds of the general formula (I) , for the prophylactic administration or therapeutic treatment of a parasitic infection caused by Trypanosoma spp., Leishmania spp., Plasmodium spp., Cryptosporidium parvum, Eimeria spp., Toxoplasma gondii or Pneumocystis spp. solved.

Preferred for use in the prophylactic administration or therapeutic treatment of a parasitic infection caused by Trypanosoma spp., Leishmania spp., Plasmodium spp., Cryptosporidium parvum, Eimeria spp., Toxoplasma gondii or Pneumocystis spp. are the compounds of general formula (I), wherein

R ^{1 represents} hydrogen or a group - (CH ₂ ) _m -CH = CH— (CH ₂ ) ₂ . _m - H,

- (CH ₂ ) _m -C≡C— (CH ₂ ) ₂ . _m - H,

- (CH ₂ ) _n -R7 _

stands,

R ^{7 stands} for -R ¹² , -OR ⁸ or -SR ⁸ ,

R and R independently of one another represent an alkyl group with 1 to 4 carbon atoms,

R ¹² , -R ^{12 '} , -R ^{12 "} , -R ^12" , -R ¹² "^" independently of one another represent -H, -F, -Cl, -Br or -I, R ¹⁵ , -R ^15' , -R ^{15 "} , -R ^15"' , -R ^{15 ""} independently of each other for

-R ⁷ , -R ⁸ , -NO ₂ , -NH ₂ , -NHR ⁸ , -NR ⁸ R ^{8 '} or -CN and m stands for 0 to 2 and n stands for 1 to 4.

Particularly preferred for use in the prophylactic administration or therapeutic treatment of a parasitic infection caused by Trypanosoma spp., Leishmania spp., Plasmodium spp., Cryptosporidium parvum, Eimeria spp., Toxoplasma gondii or Pneumocystis spp. are the compounds of general formula (I), wherein R ¹ for hydrogen, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert-butyl, n-pentyl, tert.-amyl, n-hexyl, pent-3-yl, 1, 2 -Dimethylpropy1 1,3-dimethylbutyl, 1-ethyl-2-methylpropyl, 1,2,2-trimethylpropyl, 2-methylhept-5-yl, allyl, methallyl crotyl, 2-ethyl-2-hexenyl, 5-hexenyl, 2 -Methyl-2-butenyl, 2-methyl-3-butenyl, 1-buten-3-yl, 2-methyl-1-buten-4-yl, 2-methyl-2-buten-4-yl, 3-

Methyl-1-buten-3-yl, propargyl, 1-butyn-3-yl, 2-butynyl, 2-chloroethyl 2-chloropropyl, 3-chloropropyl, 2-chlorobut-2-yl, 2-chloro-2-methylpropyl , 2-fluorobut-2-yl, 2-fluoro-2-methylpropyl, 1-fluoroprop-2-yl, 1-chloro-2-methylprop-2-yl, 2,2,2-trifluoroethyl, hydroxymethyl, 2-hydroxyethyl , 3-hydroxypropyl, 1-hydroxyprop-2-yl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-2-methylpropyl, 2-

Methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, 1-methoxyprop-2-yl, 3-methoxybutyl, 1-methoxybut-2-yl, 1-methoxy-2-methylprop-2-yl, 1-ethoxy-2-methylprop- 2-yl, 2-methoxybutyl, 4-methoxybutyl, cyclopropyl, cyclopentyl, cyclohexyl, 2-methylmercaptoethyl, 2-ethylmercaptoethyl, 3-methylmercaptopropyl, 3-methylmercaptobutyl, 1-methylmercaptobut-2-yl, 1-

MethyImercapto-2-methylprop-2-yl, 2-methyl mercaptobutyl, phenyl, 4-chlorophenyl, 3,4-dichlorophenyl, o-tert-butylphenyl, m-tert-butylphenyl, p-tert-butylphenyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, o-methylphenyl, m-methylphenyl, p-methylphenyl, 4-methoxy-3-chlorophenyl, 2-methyl-4-chlorophenyl, benzyl, 2,6-dichlorobenzyl, 2-chloro-6- fluorobenzyl, 2,6-

Difluorobenzyl, o-chlorobenzyl, m-chlorobenzyl or p-chlorobenzyl.

The naphthindazole-4,9-quinones were synthesized by H. Laatsch and structurally elucidated (Laatsch, H. Liebigs Ann. Chem. 1985, 251-274). The synthesis of the

Naphthindazole-4,9-quinones is carried out according to the synthesis scheme described in German patent DE 38 31 332. All compounds were structurally characterized using spectroscopic methods (H / C-NMR, mass spectroscopy, UV, IR spectroscopy). In the above-mentioned publication, as in the following communications, the author or authors did not report that the described naphthindazole-4,9-quinones show anti-parasitic effects. It is known that naphthoquinones form a structural class with a biological effect. A disadvantage of the naphthoquinones investigated was their high toxicity to cells and mammals. The high toxicity has been demonstrated in animal experiments on rats and mice (Sepύvelda-Boza, S., Cassels, BK Plant metabolites active against Trypanosoma cruzi. Planta Med 1996, 62, 98-105). Neither antiparasitic nor toxicological effects have been described for the compounds of the general formula (I), the naphthindazole-4,9-quinones. Only herbicidal effects against phytopathogenic fungi have been described by H. Laatsch (published application DE-A 21 07 053).

It was unexpectedly found that the compounds of the general formula (I)

and their pharmacologically acceptable salts or dimers or trimers, in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 have} the meaning given above, have high antiparasitic activity with very low toxicity.

The high antiparasitic effect and the very low toxicity could be demonstrated in the animal using the mouse as an example.

The following table lists the compounds of the general formula (I) which were used in the pharmacological tests.

The naphthindazole-4,9-quinones of the general formula (I) are notable for excellent activity against a broad spectrum of veterinary and human-pathogenic parasites, in particular against Leishmania and Cryptosporidia. They show high tolerance in the in vivo mouse model and can be used in antiparasitics for therapeutic use.

According to the invention, the antiparasitic compounds of the general formula (I) are used therapeutically for the prophylaxis of infections and / or for the treatment of an existing infection.

The following table lists the microbial pathogens against which the compounds of the general formula (I) are used and clarifies which diseases are caused by these microbial pathogens. Disease Microbial pathogen a) African human trypanosomiasis Trypanosoma spp. b) South American Trypanosomiasis Trypanosoma spp. c) Visceral Leishmaniasis Leishmania spp. d) Cutaneous and mucocutaneous leishmaniasis Leishmania spp. e) Canine Leishmaniasis Leishmania spp. f) Malaria Plasmodium spp. g) Babesiosis Babesia spp. h) Neosporidosis Neospora caninum i) Sarcocystosis Sarcocystis spp. j) Cryptosporidiosis Cryptosporidium spp. k) Coccidiosis Eimeria spp., Isospora spp.

I) Human toxoplasmosis Toxoplasma gondii m) Feline toxoplasmosis Toxoplasma spp. n) Pneumocystosis Pneumocystis carinii

The present invention furthermore provides pharmaceutical compositions which comprise at least one of the compounds of the general formula (I)

Λ * _. Λ C_ p. wherein R, R, R, R, R and R have the meanings given above.

The compounds of general formula (I) can be administered by themselves or in the form of a pharmacologically acceptable salt. Suitable examples these salts of the compounds of the general formula (I) include acid addition salts with organic or inorganic acids. The following acids can be mentioned as acids which form an acid addition salt of the compounds of the general formula (I): sulfuric acid, sulfonic acid, phosphoric acid, nitric acid, perchloric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, propionic acid, butyric acid, succinic acid, oxalic acid, glucolic acid, Lactic acid, malic acid, tartaric acid, fumaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, salicylic acid, p-aminosalicylic acid, ambonic acid, methanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid, Sulfanilic acid, camphorsulfonic acid, quinic acid, o-methylmandelic acid, hydrogenbenzenesulfonic acid, methionine, tryptophan, lysine, arginine, picric acid, adipic acid or do-tolyltartaric acid.

The compounds of the general formula (I) and their pharmacologically acceptable salts can be applied alone or in a known manner by stretching at least one of the compounds of the general formula (I) with solvents, carriers and / or animal feed, optionally using emulsifiers and / or dispersants , are converted into the usual formulations. The pharmaceutical compositions can be used in the form of solutions, suspensions, dispersions, emulsions, creams, ointments, pastes, powders, granules, tablets, suppositories, capsules or dragees.

The application depends on the parasite to be treated and is intended to kill or at least limit the multiplication or growth of the parasite.

For example, corresponding formulations are obtained by mixing at least one compound of the general formula (I) with solvents, carriers and / or animal feed, optionally using emulsifiers and / or dispersants, where in the case of water as Diluents other organic solvents can be used.

Aromatics, chlorinated aromatics, paraffins, alcohols, water, ketones, amines, ethanolamine, dimethylformamide and / or dimethyl sulfoxide are used as solvents for the formulations according to the invention. Natural rock powders, such as kaolin, clays, talc, chalk or synthetic rock powders, such as highly disperse silica or silicates, are used as carriers. Nonionic and ionogenic emulsifiers, such as polyoxyethylene fatty alcohol ethers, alkyl sulfonates or aryl sulfonates, are used as emulsifiers. Lignin, sulfite waste liquors, methyl cellulose and, as capsule bases for tablets, ethyl cellulose, starch, lactose, alkaline earth fatty acids or magnesium stearate are suitable as dispersants.

The anti-parasitic pharmaceutical compositions according to the invention contain at least one of the compounds of the general formula (I) in an amount between 0.1 and 99% by weight.

The antiparasitic pharmaceutical compositions according to the invention preferably contain at least one of the compounds of the general formula (I) in an amount between 50 and 99% by weight.

Depending on the clinical picture and its physical stature, the patient is administered a daily dose of between 0.5 and 1500 mg, based on the compounds of the general formula (I), of the pharmaceutical compositions according to the invention.

The compounds of the general formula (I) are applied by being administered systemically or locally to the organism. According to Forth, W. Henschler, D., Rummel, W., Starke, R. (1996) General and Special Pharmacology and Toxicology, Spektrum Verlag, oral, cutaneous, nasal, parenteral, buccal or anal administration and cutaneous application means application to the skin and / or mucous membranes without achieving systemic effects. Of particular interest are pharmaceutical compositions according to the invention in which the compounds of the general formula (I) are processed for systemic and local application to give particular pharmaceutical forms.

In addition to the usual formulations, processing into nanosuspensions should be mentioned separately, which optimizes the systemic and local application of the active ingredients.

Nanosuspensions, Solid Liquid Nanoparticies (SLN) or liposomes with an average particle diameter of 0.1 to 3 μm are pharmaceutical compositions which are referred to as particulate drug forms. The pharmaceutical compositions according to the invention are used for therapeutic treatment or prophylactic administration in the case of parasitic infections.

These are parasitic infections caused by the opportunistic pathogens Trypanosoma spp., Leishmania spp., Plasmodium spp., Cryptosporidium parvum, Eimeria spp., Toxoplasma gondii or Pneumocystis spp. to be triggered.

The pharmaceutical compositions according to the invention or the compounds of the general formula (I) can furthermore be used for the prophylaxis of infections of blood and blood products.

The compounds of the general formula (I) and their pharmaceutical compositions according to the invention are particularly important for combating the gastrointestinal infection of HIV-immunosuppressed patients. There is currently no effective drug for this indication area. The use in veterinary terms should also be emphasized, since there is a great need for effective and non-toxic drugs in the treatment of coccodose in poultry farming and trypanosomiasis in breeding cattle. Synthesis of the N ¹ -substituted naphthindazole-4,9-quinones

The compounds of the general formula (I) are synthesized according to the synthesis scheme described in German patent DE 38 31 332. Accordingly, the naphthindazole-4,9-quinones of the general formula (I) are obtained by the 5-arylmethylpyrazoI-4-ylcarboxylic acid halides of the general formula (II),

A Λ C ß in which R, R, R, R, R and R have the meanings given above and Hai represents halogen, in an inert solubilizer in the presence of a Friedel-Crafts catalyst, and the compounds of general obtained Formula (III),

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 have} the meanings given above, in the presence of a diluent with oxidizing agents in the naphthindazole-4,9-quinones of the general formula (I). The following Examples 1 to 6 describe the investigation of the leishmanicidal and trypanozidic activity, the anti-malaria activity, the cryptosporidicidal activity and the cytotoxic activity in vitro and in vivo.

Example 7 describes the provision of nanosuspensions to improve the in vivo bioavailability of the compounds of the general formula (I).

Example 8 deals with the improvement of the in vivo bioavailability by incorporation of the compounds of the general formula (!) In Solid Lipid Nanoparticies (SLN).

example 1

Studies of leishmanicidal activity

ΕXTRACELLULAR CYTOTOXICITY AGAINST LEISHMANIA spec.

In their vector (butterfly mosquitoes; Phlebotomidae) and in cell culture media, Leishmania parasites live in their promastigote (elongated-flagellated) form. Living cells metabolize the yellow dye MTT [3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide] to blue formazan crystals, which are colorimetrically quantified. Compared to untreated samples (controls), lower MTT sales indicate directly effective antiparasitic effects.

This test allows screening of substances. However, since Leishmania parasites are almost exclusively intracellular and in their amastigotic form after infection, its informative value is less than an intracellular cytotoxicity test (see there).

execution

1. Leishmania promastigote (L donovani, L. major, L. enriettii) ä be 1 x 10 ^4/100 ul medium in 96-well microtiter plates seeded.

2. Test and reference substances are added in dilution series.

3. The parasites are incubated at 25 ° C for 96 h. 4. MTT solution is added during the last 6 hours. 5. Formazan formed is dissolved in sodium (sodium) dodecyl sulfate (SDS) and quantified in an automatic ELISA device by absorbance measurement at 570 nm.

6. Leishmanicidal effects are calculated as EC ₅₀ (active ingredient concentration with 50% reduced MTT conversion compared to the untreated control).

INTRACELLULAR CYTOTOXICITY AGAINST LEISHMANIA spec.

Leishmania parasites are taken up by their obligatory host cells (macrophages, monocytes) by phagocytosis. Some succeed in establishing themselves in the parasitophoric vacuoles by converting them into the physiologically adapted amastigote form, which increases intracellularly and is causally related to the disease process. AnW-Leishmania agents must also enter the parasitophore vacuole and act as specifically as possible against amastigote Leishmania parasites under the conditions there. Macrophages already parasitized with Leishmania become active substances and

Reference self-dancing suspended. The host cells are dissolved after 96 hours. Surviving Leishmanias revert to Promastigote and multiply. Living cells metabolize the yellow dye MTT [3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide] to blue formazan crystals, which are colorimetrically quantified. Compared to untreated controls, lower MTT sales indicate intracellularly effective antiparasitic effects.

execution

1. Murine bone marrow culture macrophages (MΦ) are incubated with promastigote Leishmania (L. donovani, L. major, L enriettii). 2. After 1 h, extracellular Leishmania are removed by centrifugation, the parasitized MΦ are sown in microtiter plates and incubated at 37 ° C.

3. After 24 hours, test and reference substances are added in dilution series.

4. After 96 h, MΦ are selectively lysed using SDS. 5. The lysate is incubated for 72 hours in Leishmania growth medium at 25 ° C.

6. MTT solution is present for the last 6 hours.

7. Formazan formed is dissolved in SDS and quantified in the automatic ELISA device by absorbance measurement at 570 nm.

8. Leishmanicidal effects are calculated as EC ₅₀ (active substance concentration with 50% reduced MTT conversion compared to the untreated control).

Results

Tab. 1: Leishmanicidal activity of exemplary naphthindazole-4,9-quinones against different Leishmania species, specification of the EC ₅₀ in μg / ml

* ED ₅₀ in μg / kg body weight nd: not determined Example 2

Studies of the trypanozid effect

The trypanozidic effectiveness is determined according to WHO recommendations, which were described by Croft and Kaminsky (Croft, S.L., Kaminsky, R. (1997a), Standardization of Drug Screening, Communication on COST ACTION 815 Acrival, Louvain).

Durchfühung

In vitro determination of the activity against Trypanosoma h. brucei

Standard Parasitic Trypanosoma b. brucei STIB 920 (clone of STIB 348) lines Trypanosoma b. brucei STIB 900 (clone of STIB 754)

References Melarsoprol (Mel B®), Suramin (Germanin®)

Culture conditions Baltz-MEM with 10% fetal calf serum incubation: 37 ° C, 5% C0 ₂

Sample preparation Active ingredients with a known molecular weight are dissolved in a uniform stock solution of 20 mg / ml in 100% DMSO, in exceptional cases in 96% ethanol. The stock solution is kept at -20 ° C for a maximum of 2 weeks. Each batch is freshly made from the stock solution.

1. The effect is determined in the in vitro test model with 2 different trypanosoma strains. The substances were dissolved as indicated above.

2. The test is based on the LILI test (Low Inoculum Long Incubation Test) described by Brun and Lun (Brun R, Lun (1994), Vet. Parasitol. 52, 37-46)).

3. Starting from 30 mg / ml, test substances are linearly titrated 1: 2 in medium in a 96-microtiter plate (250 μl).

4. T. brucei (4x10 ³ / ml) 50 ul courtship medium / hole are added, the plates are incubated at 37 ° C for 72 h.

5. MTT solution is added for the last 5 hours. The relative parasite growth is determined after visual monitoring of the MTT conversion by surviving trypanosomes. In vitro determination of the activity against Trypanosoma cruzi

The trypanozidic effectiveness is determined according to WHO recommendations, which were described by Croft and Kaminsky, 1997, (Croft, S. L, Kaminsky, R. (1997a), Standardization of Drug Screening, Communication on COST ACTION 815 Acrival, Louvain).

execution

1. BALB7c mice are used as host cells after induction with 2% starch solution, i.p. 24 h before lavage, peritoneal macrophages obtained. 2. The infection is caused by Trypomastigote, obtained from the overiay of infected WI-38, Vero cells or L6 myoblasts. The infection ratio host: parasite is 1: 5.

3. The infected cells in a 24 microtiter plate are exposed to an active ingredient concentration of 30 μmol, which are diluted in a three-fold dilution series.

4. The incubation takes 3 to 6 days.

5. The determination of trypanozid effects is carried out visually with the aid of an inverted microscope. Results

Tab. 2: Trypanozide effect of exemplary naphthindazole-4,9-quinones against Trypanosoma b. brucei, specification of the EC ₅₀ in μg / ml

Example 3

Studies on the anti-malaria effect

Freshly transferred Plasmodium spec. go through a short intra- hepatocytic stage and then continuous intra-erythrocytic cycles. The erythrocytic cycle of human pathogenic P. falciparum can be fully understood in vitro.

The developmental stages within the erythrocytes can be followed and quantified using colored, microscopic specimens. The proportion of parasitized erythrocytes in comparison to the untreated control suggests the inhibition of intracellular proliferation, while the relative proportions of the individual development stages allow first conclusions to be drawn about the mode of action of a substance. execution

1. 7 day old P. falciparum blood cultures are added to fresh donor blood and sown in microtiter plates.

2. Add different concentrations of test and reference substances.

3. Incubation 24 h and 48 h at 37 ° C.

4. At both times. Production of microscopic specimens / sample; Giemsa staining.

5. Counting of 4 visual fields / preparation.

6. Evaluation according to:

% parasitized erythrocytes

- Percentage of ring stage, trophozoite, schizonts

Results

Tab. 3: Antiplamosdial effect of exemplary naphthindazole-4,9-quinones against Plasmodium falciparum, specification of the EC ₅₀ in μg / ml

Example 4

Investigation to inhibit cryptosporidiosis

In Vitro Activity Against Cryptosporidium parvum Cryptosporidium parvum (C. parvum) strains KSU-1 and Iowa were developed by Dr. MV Nesterenko (Kansas State University) provided. Oocysts were cleaned with CsCI solution or by centrifugation in a sucrose gradient, placed in Chlorox® solution for 5 min for sterilization and then with sterile Washed water. For in vivo excitation, purified oocysts were incubated at 37 ° C for 1 hour in PBS buffer with 0.25% trypsin and 0.75% taurodeoxycholate. Free sporozoites were isolated by centrifugation in the Percoll® gradient. The method is based on the regulation by Nesterenko, MV, Upton, SJ (1996) J. Microbiol. Meth., 25: 87-89. The anti-cryptosporidia activity is investigated according to the regulations of Woods, KM, Nesterenko, MV (1995) FEMS Microbiol. Lett., 128: 89-94. The compounds of the general formula (I), the naphthindazole-4,9-quinones, were tested as follows:

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1. oocysts are given microtiter plates ä 3.0 x 10 ^4/100 ul medium in 96-well in which 4,0x10 ⁸ HCT-8 cells (ATCC CCI 244) were sown.

2. Plates are incubated at 37 ° C for 90 min and washed twice.

3. New nutrient medium and test and reference substances are added in dilution series.

4. The parasites are incubated for 48 hours at 37 ° C, 5% CO ₂ , 95% humidity.

5. Detection is carried out by ELISA measurement with rat anti-cryptosporidial antiserum.

6. After adding 3,3 ', 5,5'-tetramethylbenzidine, the optical density at 630 nm is quantified in the automatic ELISA device.

7. Anti-Cryptosporidium effects are calculated as EC _S0 .

In vivo activity against Cryptosporidium parvum

C. parvum is a globally widespread and important causative agent of diarrhea in calves and the most serious diarrhea in immunocompromised people

People. CD4 ⁺ T line-defective (TCR-α-deficient) mice are unable to spontaneously eliminate the pathogen.

At least one of the compounds of the general formula (I) is administered orally. You have to withstand the conditions and duration of the gastric passage and develop their effectiveness on the intestinal epithelium. C. parvum sporozoite are counted on a defined area of the small intestine epithelium. The reduction in colonization (in%) compared to untreated control animals is given.

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1. C. para / m-sensitive TCR-α-deficient mice are orally infected with C. parvum oocysts.

2. Test and reference substances are administered orally.

3. Animals are killed; dissected out the small intestine epithelium. 4. C. parvum sporozoite are counted.

Results

Tab. 4: Effect of exemplary naphthindazole-4,9-quinones against Cryptosporidium parvum, specification of the EC ₅₀ in μg / ml

Cryptosporidium parvum Cryptosporidium parvum

No. IC ₅₀ (u / ml) infectivity score

1> 100 n.d.

2 17.6 n.d.

3 21.8 n.d.

4 40.6 0.45

6> 100.0 n.a.

7 14.0 0.60

8> 100.0 n.d.

10 31.2 n.d.

12 100 n.d.

13 11.3 0.65

14> 100.0 n.a.

15 50 n.d.

16> 100.0 n.d.

17 <12.5 n.d.

18 <12.5 n.d.

19 100 ndnd: not determined Example 5

Investigations of the cytotoxic effects in vitro and in vivo

In vitro investigations We are looking for active substances with the highest possible toxicity for individual - or groups of - pathogens and at the same time low toxicity for cells of the host organism.

Living cells metabolize the yellow dye MTT [3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide] to blue formazan crystals, which are colorimetrically quantified. Lower MTT sales compared to untreated controls indicate cytotoxic effects.

The following were examined:

Mouse bone marrow culture macrophages

Mouse monocyte line RAW human melanoma line SK-Mel

Human line Heia

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1. cells x 10 ⁵ / seeded to 1 100 ul medium / well in 96-well microtiter plates and incubated for 1 h at 37 ° C.

2. Test and reference substances are added as dilution series in 100 μl / well.

3. Incubation time 48 h or 72 h, of which the last 6 h in the presence of MTT solution. 4. Formazan formed is released by SDS and in an automatic

ELISA device quantified by determining the relative absorbance at 570 nm.

5. Cytotoxic effects are calculated as EC ₅₀ (drug concentration with 50% reduced MTT conversion compared to the untreated sample. In vivo studies

In parallel to the studies on the effectiveness of test substances against Cryptosporidium parvum (R. Waters) or L. donovani (S. Croft) in vivo, non-infected animals were treated in the same way (orally or intravenously) in order to get a first impression of possible ones To get side effects of the compounds of the general formula (I) on the whole organism.

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1. Mice are given oral test or reference substances.

2. Animals are observed for:

- mortality - attitude - behavior

- external appearance (condition of the fur; food intake)

Results

Table 5: In vitro cytotoxicity determination of naphthindazole-4,9-quinones, EC ₅₀ = μg / ml

n.d.: nicht bestimmt (not determined)

nd: not determined

Mouse 1: see in vivo test against Cryptosporidium parvum

Mouse 2: see in vivo testing against Leishmania donovani Example 6

Investigations of in-vivo activity against Leishmania donovani

Leishmania donovani are obligate intracellular parasites of the monocyte-macrophage system. They cause visceralizing infections involving all organs, including the bone marrow. As a rule, it is a zoonosis, with rodents serving as a reservoir. The infection of the mouse thus offers a common infection model with symptoms similar to those in humans (visceralization of the pathogen, hepatosplenomegaly, etc.) with genetically determined, i.e. Mouse strain-dependent tendency towards self-healing or chronicity.

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1. Leishmania donovani strain MHOM / ET / 67 / L82 (HU3 or LV9) or Leishmania donovani strain LRC-1233 (WHO Reference Center Jerusalem) mouse strain BALB / c, female, 18-20g

2. Therapy standards: sodium stibogluconate (Pentostamä, Glexo-Wellcome), meglumine antimonate (Glucantimeä, Rhone-Poulenc Rover)

3. Test substances are usually taken up in 100% DMSO or ethanol (10 mM stocks produced). Before use, fresh dilution series of these stocks (90 μM) are prepared in culture medium or PBS.

4. Mice are infected either with metacyclic promastigotes (from in vitro cultures) intraperitoneally (i.p.) or amastigotes (from infected hamsters) intravenously (i.v.) à 1 X 107 parasites / mouse. 5. Treatment with test substances or therapy standards begins 7-10 d p.i. with one dose per day for the next 4-5 days.

6. At different times, the animals are sacrificed, the spleen and liver weighed and swab preparations made from each organ, which are fixed in methanol (100%) and stained according to Giemsa (10%, 45 min). 7. The number of amastigotes per liver cells and the total number of parasites / organ are counted according to the formula:

Amastigotes / 500 cells X organ weight [mg] X 200,000 (constant)

Results

The corresponding test results are summarized in Table 1.

Example 7

Improvement of the in-vivo bioavailability by transfer to nanosuspensions

Since nanosuspensions aim at the spontaneous readiness of the cells described above to absorb foreign bodies, nanosuspensions, as a particulate form of administration, represent effective "drug targeting" against pathogens which persist within phagocytes (macrophages). In this way, high concentrations of active substances around the pathogen can be achieved selectively and the burden on the rest of the organism are minimized and they also have the great advantage of improving the low solubility of the compounds of the general formula (I), the naphthindazole-4,9-quinones, by particle size reduction and surface enlargement.

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Nanosuspensions of the compounds of the general formula (I) are produced with the aid of a high-pressure homogenizer LAB 40 under pressure between 200 to a maximum of 1500 bar and using different number of cycles (usually 4-8 cycles) [RH MÜLLER and K. PETERS. Int. J. Pharmaceutics 1998, 160, 229-237]. The average particle diameter is in the range of approximately 50 to 999 nm. Sterilization is carried out by autoclaving. Alternatively, aseptic production using laminar air flow (LAF) can also be carried out. The particle size is determined with the help of PCS photon correlation spectroscopy (Malvern Zetasizer), a LD laser diffractometer and a Coulter Counter with 30 μm capillary (Coulter Electronics). The particle size is given to characterize the Nanosuspension due to their diameter (D50%, D90% and D99%). To determine the saturation concentration in the supernatant, the separation is carried out in a high-speed centrifuge and then the measurement of the compound of the general formula (I), the naphthindazole-4,9-quinone, using UV spectroscopy.

To set the highest possible physical storage stability (absence of particle aggregation), it is advantageous to charge the particles in the same direction as possible (high zeta potential). Charging is carried out by selecting optimized, charged surfactants, the charge achieved is determined by means of electrophoresis measurements (use of laser Doppler anemometry - LDA). The low solubility in biological media of the compounds of the general formula (I), the naphthindazole-4,9-quinones, has proven to be an advantage for systemic application as a nanosuspension. The compounds of the general formula (I) are converted into a nanosuspension by high-pressure homogenization and thus made intravenous. A sufficient bioavailability and optimized release of the compound of the general formula (I) into infected macrophages can be achieved in animal models by converting poorly water-soluble compounds of the general formula (I) into nanosuspensions. Testing for physical stability, release of the compound of general formula (I) and review of the

Saturation solubility is achieved by repeated particle size determination and UV spectroscopic examinations (possibly HPLC) in a defined time interval.

Example 8

Improvement of in-vivo bioavailability through formulation as Solid Lipid Nanoparticies (SLN)

The compound of general formula (I) is dissolved or suspended in a fat base which, after cooling, is homogenized with the aid of high-pressure homogenization, as described in Example 7, to give particles with an average size of 100-900 nm. An advantage over pure nano suspensions is that defined particles are generated which, for example, have higher cell affinity, reduce the toxicity of active substances, allow active substance release according to defined kinetics and are suitable for gastrointestinal and cellular targeting.

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The naphthoquinone SLN is produced using the cold homogenization technique: the fat base (for example Compritol ATO 888, Poloxamer 188) is melted, the compound of the general formula (I), the naphthindazole-4,9-quinone, into the Given melt and stirred cold. The solidified melt, which contains the compound of general formula (I) dissolved or suspended, is comminuted with the addition of, for example, Tween 80 and Span with an Ultra-Thurax. This solution or presuspension is then homogenized directly with a LAB-40 homogenizer in order to obtain particles in the range 100-900 nm. These particles are called Solid Lipid Nanoparticle (SLN). The particle size is determined with the aid of PCS photon correlation spectroscopy (Malvern Zetasizer), an LD laser diffractometer and a Coulter Counter with 30 μm capillary (Coulter Electronics). The particle size for characterizing the nanosuspension is indicated by its diameter (D50%, D90% and D99%). To determine the saturation concentration in the supernatant, it is separated off in a high-speed centrifuge and the is measured

Compound of general formula (I), naphthindazole-4,9-quinone, with the help of UV spectroscopy.

Claims

claims 1. Pharmaceutical compositions, characterized by the content of at least one of the compounds of the general formula (I)

where R, 1 e _i • n hydrogen atom or a group - (CH2) m ^- H— CH - (CH ₂ ) ₈ -m H, "(H2) m ^- C = C - (CH2) ₈ -m - H - (CH ₂ ) _n -R7

O II - (CH ₂ ) p— OC— R9

O II - (CH ₂ ) _P - C-R11 _j

- C ₂ H ₄ -C≡C-R12 _t - CH ₂ -C≡C-CH ₂ - R ¹² , - C = C ~ C ₂ H ₄ - R12 means and "Δ. k R R, R, R, R and R independently of one another each represent a hydrogen atom or one of the radicals -R ⁷ , -NO ₂ , -NH ₂ , -NHR ⁸ , -NR ⁸ R ^{8 '} , -CN, -OH, - (CH ₂ ) oR 4, -O— (CH ₂ ) ₀ -R ¹² -S— (CH ₂ ) ₀ -R ¹² O O O II II II -C— R16 -OC— R16 - CO— R16 O H O II I II -OC— (CH ₂ ) ₀ -R ¹² - N— C— R16 O H O R16 "II I II I -C— N— R16 -C— N— R16

represent R ³ together with R ⁴ and the two carbon atoms C-5 and C-6 des Benzene ring forms a further condensed benzene or naphthalene ring which optionally carries further functional groups, these functional groups being fluorine, chlorine, bromine, iodine, nitro, cyano, amino, hydroxy, trifluoromethyl groups Alkyl groups with 1 to 5 carbon atoms, alkoxy or haloalkoxy groups with 1 to 5 carbon atoms or alkylthio or haloalkylthio groups with 1 to 5 carbon atoms, R together with R and the two carbon atoms C-5 and C-6 des Benzene ring another condensed five- or six-membered Heterocycle forms, where R and R each independently Represent carbon, oxygen or nitrogen atom and this further heterocycle is optionally substituted by fluorine, chlorine, bromine, iodine or alkyl radicals having 1 to 4 carbon atoms, R ⁴ together with R ⁵ and the two carbon atoms C-6 and C-7 des Benzene ring forms a further condensed benzene or naphthalene ring which optionally carries further functional groups, these functional groups being fluorine, chlorine, bromine, iodine, nitro, cyano, amino, hydroxy, trifluoromethyl groups Alkyl groups with 1 to 5 carbon atoms, alkoxy or haloalkoxy groups with 1 to 5 carbon atoms or alkylthio or haloalkylthio groups with 1 to 5 carbon atoms, R ⁴ together with R and the two carbon atoms C-6 and C-7 of the benzene ring forms a further condensed five- or six-membered heterocycle, where R ⁴ and R each independently represent a carbon, oxygen or nitrogen atom and this further Heterocycle is optionally substituted by fluorine, chlorine, bromine, iodine or alkyl radicals having 1 to 4 carbon atoms, 5 6 R together with R and the two carbon atoms C-7 and C-8 of the benzene ring forms a further condensed benzene or naphthalene ring which optionally carries further functional groups, these functional groups being fluorine, chlorine, bromine, iodine, nitro, cyano, amino, hydroxy, trifluoromethyl groups, alkyl groups with 1 to 5 carbon atoms, alkoxy or haloalkoxy groups with 1 to 5 carbon atoms or around alkylthio or haloalkylthio groups with 1 to 5 carbon atoms, R together with R and the two carbon atoms C-7 and C-8 of the benzene ring another condensed five or six-membered 5 6 forms heterocycle, where R and R are each independently Represent carbon, oxygen or nitrogen atom and this further heterocycle is optionally substituted by fluorine, chlorine, bromine, iodine or alkyl radicals having 1 to 4 carbon atoms, R ^{7 stands} for -R ¹² , -OR ⁸ or -SR ⁸ , R ⁸ and R ⁸ independently of one another represent an alkyl group with 1 to 4 carbon atoms, R ^{9 is} an alkyl group having 1 to 4 carbon atoms or a group of the structure represents,

R ^{10 stands} for -R ¹² , -R ⁸ or -OR ⁸ , R ^{11 stands} for -R ⁸ , -NH ₂ , -NHR ⁸ , -NR ⁸ R ⁸ ', -OH, -OR ⁸ , R ¹² , -R ^{12 '} , -R ¹² ', -R ¹² ", -R ^12" "independently of one another for -H, -F, -Cl, -Br or -I stand R ^{13 represents} -R ⁸ , -R ¹² or a group of the following structure - C ₂ H ₄ - C≡C- R12 _ - CH ₂ -C≡C-CH ₂ - R12, - C≡C ~ C ₂ H ₄ - R12 R ^{14 represents} -CH ₃ , -R ⁷ or -SH, R ¹⁵ , -R ¹⁵ ' _f -R ¹⁵ " _t _R ¹⁵ " ^* _t -R ^{15 "} " independently of each other for -R ⁷ , -R ⁸ , -NO ₂ , -NH ₂ , -NHR ⁸ , -NR ⁸ R ⁸ ', -CN or - O— (CH ₂ ) ₀ -R ¹² , S— (CH ₂ ) ₀ -R ¹² , (CH ₂ ) ₀ -R ¹² , 1ß 16 'R R and R independently of one another denote -H or -R, R ^{17 stands} for -R ⁷ , -CF ₃ , -NO ₂ , -CN, -SH, -OH or -NH ₂ , m for 0 to 8, n for 1 to 10, 0 stands for 1 to 5 and p stands for 0 to 4, as well as their pharmacologically acceptable salts and their dimers and trimers. 2. Pharmaceutical compositions according to claim 1, characterized in that they are applied alone or in a known manner Stretching the active ingredient with solvents, carriers and / or animal feed, optionally using emulsifiers and / or dispersants, are converted into the customary formulations and as solutions, suspensions, dispersions, emulsions, creams, ointments, pastes, powders, granules, tablets, Suppositories, capsules or coated tablets can be used. 3. Pharmaceutical compositions according to at least one of the claims 1 or 2, characterized in that aromatics, chlorinated aromatics, paraffins, alcohols, water, ketones, amines, ethanolamine, dimethylformamide, dimethyl sulfoxide as carriers, natural rock powder as a carrier, Kaolin, clays, talc, chalk or synthetic stone powder, highly disperse silica or silicates, non-ionic and ionic emulsifiers as emulsifiers, polyoxyethylene fatty alcohol ethers, alkyl sulfonates, aryl sulfonates, lignin as dispersants, sulfite liquors, methyl cellulose for starch, and as capsule base cellulose , Alkaline earth Fatty acids or magnesium stearate can be used. 4. Pharmaceutical compositions according to at least one of claims 1 to 3, characterized in that the anti-parasitic pharmaceutical compositions between 0.1 and 99% by weight of at least one of the Contain compounds of the general formula (I). 5. Pharmaceutical compositions according to claim 4, characterized in that the anti-parasitic pharmaceutical compositions between 50 and 99% by weight of at least one of the Contain compounds of the general formula (I). 6. Pharmaceutical compositions according to at least one of claims 1 to 5, characterized in that these pharmaceutical compositions to the patient depending on the clinical picture and the physical stature of the patient with a daily dose between 0.5 and 1500 mg based on the compounds of the general Formula (I) can be administered. 7. Pharmaceutical compositions according to at least one of claims 1 to 6, characterized in that the compounds of the general formula (I) are processed for the systemic and local application into particulate pharmaceutical forms. 8. Pharmaceutical compositions according to claim 7, characterized in that it is the particulate drug forms Nanosuspensions, Solid Liquid Nanoparticies (SLN) or liposomes with an average particle diameter of 0.1 to 3 μm. Use of the compounds of the general formula (I)

for the prophylactic administration or therapeutic treatment of a parasitic infection caused by Trypanosoma spp., Leishmania spp., Plasmodium spp., Cryptosporidium parvum, Eimeria spp., Toxoplasma gondii or Pneumocystis spp., where R .1 e -: in hydrogen atom or a group (H2) m ^{- "} CH- CH (CH2) 8-m H, (CH2) m " ^~ 'C≡C (H2) ₈ -m H, - (CH ₂ ) _n -R7

O - (CH ₂ ) p— OC— R9,

O II - (CH ₂ ) p— C-R11 _

- C ₂ H ₄ - C≡C— R 2 _> - CH ₂ ~ C≡C-CH ₂ - R1 ² . - C≡CC ₂ H ₄ - R1 ² _j means and R, 2, _n R3, _n R4, r R-, 5 u. nd. r R, 6 each independently represent a hydrogen atom or one of the radicals -R ⁷ , -NO ₂ , -NH ₂ , -NHR ⁸ , -NR ⁸ R ^{8 '} , -CN, -OH, - (CH ₂ ) ₀ -R ¹⁴ , - O— (CH ₂ ) ₀ -R ¹² - S— (CH ₂ ) ₀ -R ¹² O O O II H II C - R16, - OC - R 6, - CO - R16 O H O I II OC— (CH ₂ ) oR ¹² - NC— R16 _} OH 0 R16 'II I II IC— N— R16, - C— N— R16,

represent R together with R and the two carbon atoms C-5 and C-6 of the benzene ring forms a further condensed benzene or naphthalene ring which optionally carries further functional groups, these functional groups being fluorine, chlorine, bromine, iodine, nitro, cyano, amino, hydroxy, trifluoromethyl groups, alkyl groups with 1 to 5 carbon atoms, alkoxy or haloalkoxy groups with 1 to 5 carbon atoms or around alkylthio or haloalkylthio groups with 1 to 5 carbon atoms, R ³ together with R and the two carbon atoms C-5 and C-6 of the benzene ring forms a further condensed five- or six-membered heterocycle, where R and R each independently Represent carbon, oxygen or nitrogen atom and this other Heterocycle is optionally substituted by fluorine, chlorine, bromine, iodine or alkyl radicals having 1 to 4 carbon atoms, R ⁴ together with R and the two carbon atoms C-6 and C-7 of the benzene ring forms a further condensed benzene or naphthalene ring which optionally carries further functional groups, these functional groups being fluorine, chlorine or bromine , iodine, nitro, cyano, amino, hydroxy, trifluoromethyl groups, alkyl groups with 1 to 5 carbon atoms, alkoxy or haloalkoxy groups with 1 to 5 carbon atoms or around alkylthio or haloalkylthio groups with 1 to 5 carbon atoms, R ⁴ together with R and the two carbon atoms C-6 and C-7 des Benzene ring forms a further condensed five- or six-membered heterocycle, where R and R are each independently Represent carbon, oxygen or nitrogen atom and this further heterocycle is optionally substituted by fluorine, chlorine, bromine, iodine or alkyl radicals having 1 to 4 carbon atoms, 5 6 R together with R and the two carbon atoms C-7 and C-8 des Benzene ring forms a further condensed benzene or naphthalene ring which optionally carries further functional groups, these functional groups being fluorine, chlorine, bromine, iodine, nitro, cyano, amino, hydroxy, trifluoromethyl groups , Alkyl groups with 1 to 5 carbon atoms, alkoxy or haloalkoxy groups with 1 to 5 Carbon atoms or alkylthio or haloalkylthio groups with 1 to 5 carbon atoms, R together with R and the two carbon atoms C-7 and C-8 of the benzene ring another condensed five or six-membered Heterocycle forms, where R and R each independently Represent carbon, oxygen or nitrogen atom and this further heterocycle is optionally substituted by fluorine, chlorine, bromine, iodine or alkyl radicals having 1 to 4 carbon atoms, R ^{7 stands} for -R ¹² , -OR ⁸ or -SR ⁸ , R and R independently of one another represent an alkyl group with 1 to 4 carbon atoms, Q R is an alkyl group having 1 to 4 carbon atoms or a group of the structure represents,

R ^{10 represents} -R ¹ , -R ⁸ or -OR ⁸ , R ^{11 stands} for -R ⁸ , -NH ₂ , -NHR ⁸ , -NR ⁸ R ^{8 '} , -OH, -OR ⁸ , R ¹² , -R ^{12 '} , -R ¹² ", -R ¹² ", -R ¹² "" independently of one another for -H, -F, -Cl, -Br or -I stand R ^{13 represents} -R ⁸ , -R ¹² or a group of the following structure - C ₂ H ₄ -C≡C-R1 ² _f - CH ₂ -C≡C-CH ₂ - R ¹² , - C≡CC ₂ H ₄ - R12 R ^{14 represents} -CH ₃ , -R ⁷ or -SH, R ¹⁵ , -R ^{15 '} , -R ¹⁵ ", -R ^15"' , -R ^{15 ""} independently of each other for -R ⁷ , -R ⁸ , -NO ₂ , -NH ₂ , -NHR ⁸ , -NR ⁸ R ^{8 '} , -CN or - O— (CH ₂ ) ₀ -R ¹² , - S— (CH ₂ ) ₀ -R ¹² , - (CH ₂ ) o ^~ R ¹² , R ¹⁶ and R ¹⁶ independently of one another are -H or -R, R ^{17 stands} for -R ⁷ , -CF ₃ , -NO _2l -CN, -SH, -OH or -NH ₂ , m for 0 to 8, n for 1 to 10, o for 1 to 5 and p represents 0 to 4, as well as their pharmacologically acceptable salts and their dimers and trimers. 10. Use of the compounds of general formula (I) for the prophylactic administration or therapeutic treatment of a parasitic infection according to claim 9, characterized in that R represents hydrogen or a group - (CH ₂ ) m- ~ H— CH - (CH2) 2-m - H, - (CH ₂ ) mC≡C- (CH ₂ ) 2-mH, - (CH ₂ ) _n -R ⁷

stands, R ^{7 stands} for -R ¹² , -OR ⁸ or -SR ⁸ , R ⁸ and R independently of one another are an alkyl group having 1 to 4 Carbon atoms mean R ¹² -R ¹² ', -R ¹² ", -R ¹² "', -R ¹² "^" independently of one another represent -H, -F, -Cl, -Br or -I, R ¹⁵ , -R ^{15 '} , -R ¹⁵ ", -R ^15'" , -R ^{15 "} " independently of each other for -R ⁷ , -R ⁸ , -NO ₂ , -NH ₂ , -NHR ⁸ , -NR ⁸ R ⁸ 'or -CN and m stands for 0 to 2 and n stands for 1 to 4. 11. Use of the compounds of general formula (I) for the prophylactic administration or therapeutic treatment of a parasitic infection according to claim 9, characterized in that R ^{1 is} hydrogen, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert-butyl, n-pentyl, teit-amyl, n-hexyl, pent-3-yl, 1,2- Dimethylpropyl 1,3-dimethylbutyl, 1-ethyl-2-methylpropyl, 1,2,2-trimethylpropyl, 2-methylhept-5-yl, allyl, methallyl crotyl, 2-ethyl-2-hexenyl, 5-hexenyl, 2-methyl-2-butenyl, 2 - ethyl-3-butenyl, 1-buten-3-yl, 2-methyl-1-buten-4-yl, 2-methyl-2-buten-4-yl, 3-methyl-1-buten-3-yl , Propargyl, 1-butyn-3-yl, 2-butynyl, 2-chloroethyl 2-chloropropyl, 3-chloropropyl, 2-chlorobut-2-yl, 2-chloro-2-methylpropyl, 2-fluorobut-2-yl, 2-fluoro-2-methylpropyl, 1-fluoroprop-2-yl, 1-chloro-2-methylprop-2-yl, 2,2,2-trifluoroethyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 1-hydroxyprop- 2-yl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-2-methylpropyl, 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, 1-methoxyprop-2-yl, 3-methoxybutyl, 1- Methoxybut-2-yl, 1-methoxy-2-methylprop-2-yl, 1-ethoxy-2-methylprop-2-yl, 2-methoxybutyl, 4-methoxybutyl, cyclopropyl, cyclopentyl, cyclohexyl, 2- Methylmercaptoethyl, 2-ethylmercaptoethyl, 3-methylmercaptopropyl, 3-methylmercaptobutyl, 1-methylmercaptobut-2-yl, 1-methylmercapto-2-methylprop-2-yl, 2-methylmercaptobutyl, phenyl, 4-chlorophenyl, 3,4-dichlorophenyl, o-tert-butylphenyl, m-tert-butylphenyl, p-tert-butylphenyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, o-methylphenyl, m-ethylphenyl, p-methylphenyl, 4-methoxy-3 - Chlorophenyl, 2-methyl-4-chlorophenyl, benzyl, 2,6-dichlorobenzyl, 2-chloro-6-fluorobenzyl, 2,6-difluorobenzyl, o-chlorobenzyl, m-chlorobenzyl or p-chlorobenzyl. 12. Use of the compounds of general formula (I) according to one of claims 9 to 11 for the prophylaxis of infections of blood and blood products.