DE10205864A1 - Combination preparations, useful for the treatment of protozoal infections, especially malaria, comprise a lincosamide antibiotic such as clindamycin and a dispiro-tetraoxane compound, e.g. TetA - Google Patents

Abstract

Pharmaceutical combination preparations (A), useful for treating parasitic protozoal infections, comprise a lincosamide antibiotic (I) and a dispiro-1,2,4,5-tetraoxane compound (II), for simultaneous, separate or successive administration. Pharmaceutical combination preparations (A), useful for treating parasitic protozoal infections, comprise a lincosamide antibiotic (I) and a tetraoxane compound of formula (II), for simultaneous, separate or successive administration. R1-R24 = H, OH or halo; or 1-26C alkyl, 1-26C alkoxy, 1-26C alkoxyalkyl, 1-26C hydroxyalkyl, aryl, acyl, aralkyl, 2-26C alkenyl, 2-26C alkynyl, cycloalkyl, heterocyclyl or silyl; and i, j, k, l, m, n = 0 or 1; One or more double or triple bonds may be present (in which case two or more of R1-R24 are absent).

Description

The present invention relates to pharmaceutical preparations which, as active ingredients, contain Contain antibiotics in combination with a tetraoxane-containing compound for therapy and prophylaxis of malaria and other infectious diseases caused by parasitic Protozoa are caused.

About a third of the world's population lives in areas threatened by malaria. According to estimates The World Health Organization (WHO) infects up to 500 million a year People with malaria; about 3 million of them die from the disease. The Most fatal cases are caused by P. falciparum, the causative agent of malaria tropica, caused. The majority of the fatalities are children.

There is a dramatic increase in malaria cases worldwide. This is in essentially due to the fact that the malaria pathogen increasingly resistant to common antimalarial drugs. In the area of malaria control At first, chloroquine proved to be particularly valuable. At the beginning of the sixties tried by mass application of chloroquine, for example with the table salt, the Eradicate malaria. Soon after, the first cases of chloroquine resistance were reported. Since then, chloroquine-resistant malaria pathogens have spread across most endemic areas spread. Resistance is also encountered in a large part of these areas Pyrimethamine, cycloguanil and sulfonamides. Resistance has also been emerging recently against quinine, mefloquine and halofantrine, especially in Southeast Asia Become a problem. Due to the occurrence of DDT, vector control is also more resistant Anopheles strains limited.

The use of common antimalarial drugs continues due to their side effects limited. Chloroquine has a very narrow therapeutic index; already a triple Overdose is potentially lethal. Quinine therapy is often associated with fever, confusion, Shortness of breath and arrhythmias linked; more serious, potentially lethal side effects such as Hypoglycemia and hypotension occur if the intravenous application is too rapid Standard therapy for complicated malaria. Sulfadoxin pyrimethamine (fansidar) is because of its photosensitizing effect and the risk of toxic epidermolysis No longer registered in Germany in 1992. Doxycycline and other tetraxycline derivatives have a damaging effect on the growth of bones and teeth and can therefore not be used in small children and pregnant women. Halofantrine is due its arrhythmogenic effect is used only to a limited extent. Mefloquine, the most important Malaria drug in industrialized nations, caused & a. neuropsychatrische Side effects; Serious side effects occur with curative doses Probability of 1 in 250 on. Because of the neuropsychiatric effects For example, malaria prophylaxis with mefloquine is not possible for flight pilots. The Side effects of malaria medication are one of the reasons why therapy and Prophylaxis can often be stopped prematurely. This in turn creates favored by resistance.

Due to the problems presented, the global malaria situation has been worsening since continuously in the seventies. The spread of malaria continues through political conditional population movements and anthropogenic environmental and climate changes favored. Malaria is now returning to areas that were already considered malaria-free, recently even epidemic in the Mediterranean and in the south of North America. Also the number of tourists and business people traveling in. malaria areas is constantly increasing. A effective malaria prophylaxis and therapy is no longer guaranteed in all cases. An effective vaccination against malaria is currently not available.

Apart from tafenoquine and fosmidomycin, there are currently no other new active substances against malaria in an advanced clinical development. So that's the effective one Use of existing active ingredients necessary to stop the spread of malaria to command. One strategy is to have known but little before to use the active substances used systematically. These include Lumefantrine, amodiaquine, pyronaridine and chlorproguanil. Besides, were different active ingredients combined to achieve greater efficiency and Avoid development of resistance.

Although recently the combination of Proguanil and Atovaquone has been approved as Malarone has not been generally assumed that a combination of known anti- Malaria drugs have therapeutic benefits. So is the applicability of everyone known drug combinations to combat malaria due to various Limited disadvantages. These restrictions result primarily from the described side effect profiles of the individual substances and the fact that already Resistance to one of the combination partners is widespread. Furthermore, an adequate one Dosage of active ingredients such as atovaquone, lumefantrine and pyronaridine difficult because at the absorption of these substances strongly depends on the patient's diet. The Malarone's parasite and fever clearance is compared to other common ones Malaria drugs relatively slow. Cotrifazide is a questionable combination different active ingredients with questionable safety profile for simultaneous treatment of tuberculosis and malaria. Therefore, there is still a great need for new ones Active substances or combinations of active substances to combat parasitic infections, especially malaria.

The present invention has therefore set itself the task of drug combinations against malaria, which are associated with minor side effects, are effective against multi-resistant malaria pathogens and rapid parasite and fever Effect clearance. The aim is to expand the therapeutic scope of this enlarge pharmaceuticals, especially on treatment problematic patient groups such as B. children, pregnant women, HIV patients and Expand patients with complicated malaria.

It has now surprisingly been found that combinations of a lincosamide antibiotic and an anti-malaria active ingredient which contains a tetraoxane function as a pharmacophoric group have a significantly higher effectiveness in the treatment of malaria than the individual active ingredients in a monothermic treatment. The lincosamide antibiotic is selected from the group consisting of clindamycin, lincomycin, pirlimycin, 1'-demethyl-4'-depropyl-4'-pentylclindamycin (U-24,729A) and other derivatives of the natural antibiotic lincomycin. The second pharmaceutical agent is a tetraoxane compound according to formula I.

wherein the radicals R ₁ to R _{24 are} independently selected from the group consisting of H, OH, substituted and unsubstituted alkyl having 1 to 26 carbon atoms, substituted and unsubstituted alkoxyl having 1 to 26 carbon atoms, substituted and unsubstituted alkoxyalkyl having 1 to 26 Carbon atoms, substituted and unsubstituted hydroxyalkyl having 1 to 26 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl having 1 to 26 carbon atoms, substituted and unsubstituted alkynyl having 1 to 26 carbon atoms, substituted and unsubstituted cyclo , substituted and unsubstituted heterocyclic radical, substituted and unsubstituted silyl and halogen,
and i, j, k, l, m, n = 0 or 1, the corresponding radicals R _{x being} eliminated as soon as i, j, k, l, m or n = 0.

It also contains compounds in which at least two or more of the radicals R ₁ to R _{24 are} eliminated and at the same time one or more double or triple bonds are formed.

Preferred compounds are those in which the radicals R ₃ , R ₅ , R ₇ , R ₉ , R ₁₅ , R ₁₇ , R ₁₉ and R ₂₁ are selected from the group consisting of H, OH, substituted and unsubstituted alkyl having 1 to 9 carbon atoms and substituted and unsubstituted alkoxyl having 1 to 9 carbon atoms, the radicals R ₁ , R ₂ , R ₄ , R ₆ , R ₈ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₁₆ , R ₁₈ , R ₂₀ , R ₂₂ , R ₂₃ and R ₂₄ are defined as described above.

Also preferred are compounds in which the radicals R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₅ , R ₁₆ , R ₁₇ , R ₁₈ , R ₁₉ , R ₂₀ R ₂₁ and R ₂₂ are H or a substituted or unsubstituted alkyl having 1 to 9 carbon atoms and the other radicals are as defined above.

R ₁ , R ₂ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₂₃ and R ₂₄ are preferably selected from the group consisting of H, OH, substituted and unsubstituted alkyl having 1 to 9 carbon atoms, substituted and unsubstituted alkoxyl with 1 to 9 carbon atoms, substituted and unsubstituted alkenyl with 1 to 9 carbon atoms, substituted and unsubstituted alkynyl with 1 to 9 carbon atoms, substituted and unsubstituted (C ₁ -C ₉ ) alkox (C ₁ -C ₉ ) alkyl and substituted and unsubstituted Silyl.

Compounds in which R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₅ , R ₁₆ , R ₁₇ , R ₁₈ , R ₁₉ , R ₂₀ R ₂₁ and R ₂₂ is H and R ₁ , R ₂ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₂₃ and R ₂₄ are selected from the group consisting of H, substituted and unsubstituted alkyl of 1 to 9 carbon atoms and unsubstituted alkenyl having 1 to 9 carbon atoms, substituted and unsubstituted alkynyl having 1 to 9 carbon atoms, substituted and unsubstituted (C ₁ -C ₉ ) alkoxy- (C ₁ -C ₉ ) alkyl and substituted and unsubstituted silyl.

Compounds in which R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , R ₁₈ , R ₁₉ , R ₂₀ R ₂₁ , R ₂₂ and R ₂₃ are H and R ₁₂ and R ₂₄ are selected from the group consisting of H, substituted and unsubstituted alkyl of 1 to 9 carbon atoms , substituted and unsubstituted alkenyl having 1 to 9 carbon atoms, substituted and unsubstituted alkynyl having 1 to 9 carbon atoms and substituted and unsubstituted (C ₁ -C ₉ ) alkoxy (C ₁ -C ₉ ) alkyl.
j, k, l and m are preferably equal to 1.

Special features of the above definitions and suitable examples are given below:
"Acyl" is a substituent derived from an acid, such as an organic carboxylic acid, carbonic acid, carbamic acid or the thioic acid or imidic acid corresponding to the individual acids above, or from an organic sulfonic acid, these acids each being aliphatic, aromatic and / or heterocyclic Include groups in the molecule as well as carbamoyl or carbamidoyl.

Suitable examples of these acyl groups are given below.

Aliphatic acyl groups are acyl radicals derived from an aliphatic acid, which include the following:
Alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl etc.);
Alkenoyl (e.g. acryloyl, methacryloyl, crotonoyl etc.);
Alkylthioalkanoyl (e.g. methylthioacetyl, ethylthioacetyl etc.)
Alkanesulfonyl (e.g. mesyl, ethanesulfonyl, propanesulfonyl, etc.);
Alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, etc.);
Alkyl carbamoyl (e.g. methyl carbamoyl etc.);
(N-alkyl) thiocarbamoyl (e.g. (N-methyl) thiocarbamoyl etc.);
Alkyl carbamimidoyl (e.g. methyl carbamimidoyl etc.);
oxalo;
Alkoxalyl (e.g. methoxalyl, ethoxalyl, propoxalyl, etc.).

In the above examples of aliphatic acyl groups, the aliphatic Hydrocarbon part, in particular the alkyl group or the alkane radical, optionally one or have several suitable substituents, such as amino, halogen (e.g. fluorine, chlorine, bromine etc.), hydroxy, hydroxyimino, carboxy, alkoxy (e.g. methoxy, ethoxy, propoxy etc.), Alkoxycarbonyl, acylamino (e.g. benzyloxycarbonylamino etc.), acyloxy (e.g. acetoxy, Benzoyloxy etc.) and the like; as preferred aliphatic acyl residues with such Substituents are e.g. B. with amino, carboxy, amino and carboxy, halogen, acylamino or to name such substituted alkanoyles.

Aromatic acyl radicals are those acyl radicals which originate from an acid having a substituted or unsubstituted aryl group, where the aryl group can include phenyl, tolyl, xylyl, naphthyl and the like; suitable examples are given below:
Aroyl (e.g. benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl etc.);
Aralkanoyl (e.g. phenylacetyl etc.);
Aralkenoyl (e.g. cinnamoyl etc.);
Aryloxyalkanoyl (e.g. phenoxyacetyl etc.);
Arylthioalkanoyl (e.g. phenylthioacetyl etc.);
Arylaminoalkanoyl (e.g. N-phenylglycyl, etc.);
Arenesulfonyl (e.g. benzenesulfonyl, tosyl or toluenesulfonyl, naphthalenesulfonyl etc.);
Aryloxycarbonyl (e.g. phenoxycarbonyl, naphthyloxycarbonyl etc.);
Aralkoxycarbonyl (e.g. benzyloxycarbonyl etc.);
Arylcarbamoyl (e.g. phenylcarbamoyl, naphthylcarbamoyl etc.);
Arylglyoxyloyl (e.g. phenylglyoxyloyl etc.).

In the above examples of aromatic acyl radicals, the aromatic hydrocarbon part (in particular the aryl radical) and / or the aliphatic hydrocarbon part (in particular the alkane radical) may optionally have one or more suitable substituents, such as those which are suitable substituents for the alkyl group or the alkane radical have already been specified. In particular, and as an example of preferred aromatic acyl radicals with special substituents, arylanoyl substituted with halogen and hydroxy or with halogen and acyloxy and aralkanoyl substituted with hydroxy, hydroxyimino, dihalogenalkanoyloxyimino are also given
Arylthiocarbamoyl (e.g. phenylthiocarbamoyl etc.);
Arylcarbamidoyl (e.g. phenylcarbamimidoyl etc.).

A heterocyclic acyl radical is understood to mean an acyl radical which comes from an acid with a heterocyclic group; this includes:
Heterocyclic carbonyl, in which the heterocyclic radical is an aromatic or aliphatic 5- to 6-membered heterocycle with at least one heteroatom from the group consisting of nitrogen, oxygen and sulfur (e.g. thiophene-yl, furoyl, pyrrole carbonyl, nicotinoyl etc.);
Heterocycle alkanoyl, in which the heterocyclic radical is 5- to 6-membered and has at least one heteroatom from the group consisting of nitrogen, oxygen and sulfur (e.g. thiophenylacetyl, furylacetyl, imidazolylpropionyl, tetrazolylacetyl, 2- (2-amino-4- thiazolyl) -2-methoxyiminoacetyl etc.) and the like.

In the above examples of heterocyclic acyl radicals, the heterocycle and / or the aliphatic hydrocarbon part optionally one or more suitable substituents have, such as the same ones indicated as suitable for alkyl and alkane groups were.

"Alkyl" is a straight or branched chain alkyl radical with up to 9 carbon atoms, unless otherwise defined, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.- Butyl, pentyl, hexyl and the like, which may be substituted; as possible Substituents are u. a. Alkyl, alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. fluorine, Chlorine, bromine etc.), trifluoromethyl, nitro, substituted or unsubstituted acyl radicals substituted or unsubstituted aryl residues (such as p-chlorophenyl, p-nitrophenyl etc.), Carboxyl residues, solfonic acid residues and the like are suitable.

"Alkenyl" includes straight or branched chain alkenyl groups with up to 9 Carbon atoms, unless otherwise defined, such as B. vinyl, propenyl (e.g. 1-propenyl, 2-propenyl), 1-methylpropenyl, 2-methylpropenyl, butenyl, 2-ethylpropenyl, pentenyl, Hexenyl, which may optionally be substituted as described for "alkyl radicals", the rest can also be substituted with one or more OH groups.

"Alkynyl" includes straight or branched chain alkynyl groups with up to 9 Unless otherwise defined, carbon atoms may be as described for "alkyl radicals" can be substituted, the rest also with one or more OH groups can be substituted.

Cycloalkyl is preferably an optionally substituted C ₃ -C ₇ cycloalkyl; Suitable substituents include alkyl, alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. fluorine, chlorine, bromine etc.), trifluoromethyl, nitro, acyl residues, carboxyl residues, sulfonic acid residues and the like.

Aryl is an aromatic hydrocarbon residue such as phenyl, naphthyl, etc., which may be one or can have several suitable substituents such as substituted or unsubstituted Alkyl, hydoxy, carboxy, acyloxy (e.g. acetoxy, benzoyloxy etc.), substituted or unsubstituted acyl, alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. fluorine, chlorine, bromine etc.), nitro, amino and the like.

"Aralkyl" includes mono-, di-, triphenylalkyls such as benzyl, phenethyl, benzhydryl, trityl and the like, the aromatic portion optionally having one or more suitable substituents may have such as hydroxy, alkoxy (e.g. methoxy, ethoxy etc.), acyloxy (e.g. acetoxy, Benzoyloxy etc.), carboxy, halogen (e.g. fluorine, chlorine, bromine etc.), nitro, amino and like.

"Hydroxyalkyl" can include straight-chain or branched-chain alkyl radicals, up to 9 Have carbon atoms, with one or more selected carbon atoms with is substituted by a hydroxy group and which may optionally be further substituted. As possible substituents are u. a. Alkyl, alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. Fluorine, chlorine, bromine etc.), trifluoromethyl, nitro, substituted or unsubstituted acyl radicals substituted or unsubstituted aryl residues (such as p-chlorophenyl, p-nitrophenyl etc.), Carboxyl residues, sulfonic acid residues and the like are suitable.

Suitable examples of such hydroxyalkyl groups include hydroxymethyl, Hydroxyethyl (e.g. 1-hydroxyethyl and 2-hydroxyethyl), hydroxytrimethyl (e.g. 1- Hydroxytrimethyl, 2-hydroxytrimethyl and 3-hydroxytrimethyl), hydroxytetramethyl (e.g. 2-Hydroxytetramethyl).

"Heterocyclic residues" are residues as described for "aryl" or "aralkyl residues" can be substituted and must have at least one heteroatom such as O, N or S in the ring. It can be both aromatic and aliphatic rings.

Unless otherwise defined, "alkoxy radical" is a straight-chain or branched-chain alkoxy radical with up to 26 carbon atoms, such as a methoxy, ethoxy radicals, etc. He can z. B. with Hydroxy, amino, halogen, oxo groups and alkoxy radicals, such as methoxy, ethoxy radicals, be substituted.

Unless otherwise defined, "alkoxyalkyl radical" is a straight-chain or branched-chain radical with up to 26 carbon atoms, such as. B. a methoxymethyl, ethoxymethyl, ethoxyethyl, etc. He can z. B. with hydroxy, amino, halogen, oxo groups and alkoxy, such as Methoxy, ethoxy, may be substituted.

"Amino residues" can, for example, be substituted or substituted with the alkyl residues as defined above his.

For example, "silyl groups" may be substituted with the alkyl groups as defined above.

Aralkyl esters (benzyl esters, phenethyl esters, benzhydryl esters, trityl esters, etc.);

Aryl esters (e.g. phenyl esters, tolyl esters, naphthyl esters, etc.); Aroyl alkyl esters (e.g. Phenacyl esters etc.); and silyl esters (e.g. from trialkylhalosilyl, dialkyldihalosilyl, Alkyltrihalosilyl, dialkylarylhalosilyl, trialkoxyhalosilyl, Dialkylaralkylhalosilyl, dialkoxydihalosilyl, trialkoxyhalosilyl etc.) and like.

In the above esters, the alkane and / or arene part can optionally have at least one have suitable substituents such as halogen, alkoxy, hydroxy, nitro or the like.

The compounds of the invention leave, for example, for double bonds containing or chiral groups or by the formation of cycles the occurrence spatial isomer too. The use of the compounds according to the invention includes all spatial isomers both as pure substances and in the form of their mixtures.

The active compound combinations according to the invention are also suitable for the treatment of other diseases caused by parasitic protozoa, in particular Infections with babesia, toxoplasma and coccidia (cryptosporidia, microsporidia, Isospora) in humans and animals, especially in immunosuppressed patients such. B. HIV patients.

The individual active ingredients can be used as free bases or acids or as different ones Salt forms are used. In addition, pharmaceutically acceptable prodrugs individual active ingredients, e.g. B. used in the form of organic and inorganic esters become.

The use of a combination therapy with the help of pharmaceutical preparations from The present invention offers the advantage of enhancing the anti-parasitic activity of the individual substances. This results in the possibility of reducing the doses and the Therapy duration and thus the toxicities of the individual substances while maintaining the anti-parasitic effectiveness. It also helps patients to be free of parasites achieved by the combination. Furthermore, the combination results in the possibility overcoming and avoiding the emergence of resistance.

When using combination therapy, it is possible to combine the active ingredients in a so-called fixed combination, d. H. in a single pharmaceutical formulation in which both Active ingredients are included, to be administered or to choose a so-called free combination, at of the active ingredients in the form of separate pharmaceutical formulations simultaneously but can also be applied sequentially. If the active substances are solids, so can they are processed into solid pharmaceutical preparations by customary methods by: z. B. both active ingredients mixed together and with conventional carriers or excipients for example compressed into tablets. But it is also possible to separate the active ingredients to provide each other in a packaging unit ready for sale, whereby the packaging unit the two active ingredients in separate pharmaceutical formulations contains.

The pharmaceutical preparations can be enteral or in liquid or solid form parenteral application. All the usual come from this Application forms in question, for example tablets, capsules, dragees, syrups, solutions, Suspensions. Water is preferably used as the injection medium, which the usual additives for injection solutions such as stabilizers, solubilizers and Contains buffer. Preparations suitable for oral administration can be provided on request Contain flavorings or sweeteners. Formulations for intravenous, intramuscular and rectal application are particularly suitable for the treatment of complicated malaria.

The following examples demonstrate the positive effects of some representative ones Combination preparations.

Examples example 1

The efficiency of a combination of active substances according to the invention consisting of clindamycin and the tetraoxane TetA was tested on P. vinckei-infected BALB / c mice. TetA was synthesized according to published protocols. (Vennerstrom JL, Fu HN, Ellis WY, Ager AL Jr, Wood JK, Andersen SL, Gerena L, Milhous WK. Dispiro-1,2,4,5-tetraoxanes: a new class of antimalarial peroxides. J Med Chem. 1992 Aug 7; 35 (16): 3023-7). The mice were infected on day 0 by ip injection of 5 × 10 ⁷ infected erythrocytes from a donor mouse. On day 1 the success of the infection on Giemsa-stained blood smears was checked. The parasitemia was about 1%. Treatment was carried out on days 1 and 2 with 5 mg / kg clindamycin and 50 mg / kg TetA and the combination of both substances by ip injection. Clindamycin hydrochloride was dissolved in distilled water, TetA suspended in a medium consisting of 3% ethanol and 7% Tween 80 in water. Another group was left untreated as a control. The effectiveness of the treatment was determined by monitoring the parasitemia on the following days. The mice were sacrificed when the parasitemia exceeded approximately 40%. The treatment regimen was deliberately chosen so that the parasites were not completely eliminated. As a result, the time for the reappearance of a microscopically detectable parasitemia can be used as a reliable measure of the efficiency of the various active substances and combinations of active substances.

The results are shown in Fig. 1.

Example 2

In a similar experiment as in Example 1, the mice were treated with 20 mg / kg clindamycin and 100 mg / kg TetA by po application. The results are shown in Fig. 2.

Claims (17)

1. Pharmaceutical combination preparation for the prophylaxis and treatment of parasitic infections, containing a lincosamide antibiotic and a tetraoxane according to formula I.


wherein the radicals R ₁ to R _{24 are} independently selected from the group consisting of H, OH, substituted and unsubstituted alkyl having 1 to 26 carbon atoms,
substituted and unsubstituted alkoxyl with 1 to 26 carbon atoms,
substituted and unsubstituted alkoxyalkyl with 1 to 26 carbon atoms,
substituted and unsubstituted hydroxyalkyl with 1 to 26 carbon atoms,
substituted and unsubstituted aryl, substituted and unsubstituted acyl,
substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl
with 1 to 26 carbon atoms, substituted and unsubstituted alkynyl with 1 to 26 carbon atoms, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, substituted and unsubstituted silyl and halogen,
and i, j, k, l, m, n = 0 or 1, the corresponding radicals R _{x being} eliminated as soon as i, j, k, l, m or n = 0, for simultaneous, separate or chronologically graded Application. 2. Pharmaceutical preparation according to claim 1, characterized in that two or more of the radicals R ₁ to R _{24 are} eliminated and at the same time one or more double or triple bonds are formed. 3. Pharmaceutical preparation according to claim 1, characterized in that the radicals R ₃ , R ₅ , R ₇ , R ₉ , R ₁₅ , R ₁₇ , R ₁₉ and R ₂₁ are selected from the group consisting of H, OH, substituted or unsubstituted alkyl of 1 to 9 carbon atoms and substituted or unsubstituted alkoxyl of 1 to 9 carbon atoms. 4. Pharmaceutical preparation according to claim 1, characterized in that R ₁ , R ₂ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₂₃ and R ₂₄ are selected from the group consisting of H, OH, substituted and unsubstituted Alkyl with 1 to 9 carbon atoms, substituted and unsubstituted alkoxyl with 1 to 9 carbon atoms, substituted and unsubstituted alkenyl with 1 to 9 carbon atoms, substituted and unsubstituted alkynyl with 1 to 9 carbon atoms, substituted and unsubstituted (C ₁ -C ₉ ) alkox- ( C ₁ -C ₉ ) alkyl and substituted and unsubstituted silyl. 5. Pharmaceutical preparation according to one of claims 3 or 4, characterized in that R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₅ , R ₁₆ , R ₁₇ , R ₁₈ , R ₁₉ , R ₂₀ R ₂₁ and R ₂₂ are H and R ₁ , R ₂ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₂₃ and R ₂₄ are selected from the group consisting of H, substituted and unsubstituted alkyl having 1 to 9 carbon atoms, substituted and unsubstituted alkenyl having 1 to 9 carbon atoms, substituted and unsubstituted alkynyl having 1 to 9 carbon atoms, substituted and unsubstituted (C ₁ -C ₉ ) alkoxy- (C ₁ -C ₉ ) alkyl and substituted and unsubstituted silyl 6. Pharmaceutical preparation according to claim 5, characterized in that R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₈ , R ₇ , R ₉ , R ₁₀ , R ₁₁ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , R ₁₈ , R ₁₉ , R ₂₀ R ₂₁ , R ₂₂ and R ₂₃ are H and R ₁₂ and R ₂₄ are selected from the group consisting of H, substituted and unsubstituted alkyl with 1 to 9 carbon atoms, substituted and unsubstituted alkenyl having 1 to 9 carbon atoms, substituted and unsubstituted alkynyl having 1 to 9 carbon atoms and substituted and unsubstituted (C ₁ -C ₉ ) alkoxy- (C ₁ -C ₉ ) alkyl. 7. Pharmaceutical preparation according to one of claims 1 to 6, characterized in that that the active pharmaceutical ingredients are independent of one another either as pure isomers or in the form of isomer mixtures. 8. Pharmaceutical preparation according to claim 7, characterized in that the Lincosamide antibiotic is selected from the group consisting of clindamycin, Lincomycin, Pirlimycin and 1'-demethyl-4'-depropyl-4'-pentylclindamycin. 9. Pharmaceutical preparation according to one of claims 1 to 8 for treatment and Prevention of diseases in humans and animals caused by parasitic protozoa caused. 10. Pharmaceutical preparation according to claim 9 for the treatment of diseases in humans and animal caused by infections with plasmodia, babesia, toxoplasma and coccidia caused. 11. Pharmaceutical preparation according to claim 9 or 10 for the treatment and prophylaxis of Malaria. 12. Pharmaceutical preparation according to claim 11 for the treatment of complicated malaria. 13. Pharmaceutical preparation according to one of claims 9 to 12 for use in immunosuppressed patients. 14. Pharmaceutical preparation according to claim 13 for use in patients with a HIV infection. 15. Pharmaceutical preparation according to one of the preceding claims, characterized in that that the active ingredients are in a single pharmaceutical formulation. 16. Pharmaceutical preparation according to one of claims 1 to 14, characterized in that the active ingredients are in separate pharmaceutical formulations. 17. Pharmaceutical preparation according to one of the preceding claims in liquid or solid Form for enteral or parenteral application.