DE102005018642A1 - Use of ester compounds and/or compounds that are converted to ester compounds in organisms, in preparation of medicament for inhibition of cell proliferation by inhibiting reaction of glyoxalase I and/or II - Google Patents

Abstract

Use of ester compounds (A) and/or compounds (B1) that are converted to (A) in an organism, is claimed in the preparation of a medicament for the inhibition of cell proliferation by inhibiting the reaction of glyoxalase I and/or II. Use of ester compounds of formula R 1-O-C(=O)-C(=O)-CH 2-R 2 (A) and/or compounds (B1) that are converted to (A) in the organism, are claimed in the preparation of a medicament for the inhibition of cell proliferation by reaction of glyoxalase I and/or II inhibitor. R 1 = alkyl, alkenyl, alkynyl or cycloalkyl, and R 2 = H, alkyl, alkenyl or alkynyl. An independent claim is also included for a composition comprising (A) and/or (B1) for the inhibition of the increase and/or the growth of parasites. ACTIVITY : Cytostatic; Antiparasitic; Fungicide; Antihelmintic; Antimicrobial; Protozoacide; Antimalarial. Tests are described, but no relevant results are given. MECHANISM OF ACTION : Glyoxalase I inhibitor; Glyoxalase II inhibitor.

Description

The The invention relates to the use of compounds of the general Formula (I), in particular ethylpyruvate or butylpyruvate, and / or Substances that in the organism, on the skin or mucous membrane to compounds of the general formula (I) to inhibit the reactions glyoxalases I and / or II. The invention further relates the use of compounds of general formula (I), in particular Ethyl pyruvate or butyl pyruvate, and / or substances contained in the organism, on the skin or mucosa to compounds of the general formula (I) can be converted for the manufacture of a medicament for inhibiting proliferation of cells, especially for prevention and / or treatment of parasitic Diseases. The invention also relates to a pharmaceutical Composition containing a therapeutically effective amount of compounds of the general formula (I) and / or compounds resulting in compounds of the general formula (I) contains, which as a food additive and / or as a chemopreventive and / or for the treatment of parasitic diseases in the human and / or veterinary medicine can be used.

survivors Need cells considerable Amounts of energy to drain their cell division. The Energy is gained through the breakdown of various nutrients and especially as chemical energy in high-energy compounds saved in the form of ATP. These high-energy compounds are subject a significant turnover in coupling with anabolic and catabolic Processes by e.g. in the synthesis of cellular substances (e.g., proteins, nucleic acids, Sugar, lipids, etc.), the transport of substances against concentration gradients and regulatory processes consumed and in certain metabolic pathways again be formed. As energy-supplying substances comes a variety of compounds, as the most important such substances serve sugar and fatty acids. The breakdown of sugars takes place after the different monosaccharides and their di-, oligo- and polymers extra- or intracellular into corresponding Derivatives have been metabolized, taking place in glycolysis. Glycolysis allows both anaerobic and in conjunction with oxidative phosphorylation an aerobic energy production.

Some Protozoa and Mehrzeller are in terms of their energy production used metabolic pathways specialists by being ecological Colonize niches and there only use glucose. To such Specialists count e.g. living on or in the human body or on or Parasites settling in animals.

animal and human organisms regulate in their organs and in theirs body fluids the glucose concentration in a narrow concentration range. So is e.g. the glucose concentration in human blood is always about 5 mM. Animal organisms have a similar glucose homeostasis. Therefore most parasites have been found to affect glucose utilization in the blood, in body cavities and specialized on the skin and have a high glycolysis rate. Glycolysis, however, always involves the formation of glyoxal compounds, in particular methylglyoxal. These connections are highly toxic, as they readily form adducts with cellular proteins and nucleic acids, which lead to their inactivation. All glycosylating cells therefore use detoxification systems, which mostly exist in the two enzymes glyoxalase I and II.

By means of fungal diseases, the problems associated with parasites are to be described in more detail:
On and partly in the body of all humans and animals live a multiplicity of mushrooms, which cause no problems. Among the more than 100,000 types of fungi described so far, about 100 species are known that can cause disease in humans and animals. In general, a fungal infection (mycosis) is the result of an opportunistic infection based on a weakened immune system. The weakening of the immune system is often the result of chemotherapy, organ transplantation with concomitant immunosuppression or HIV infection. Mucosal fungi that live on the mucous membrane can enter the blood and vessels and become extremely dangerous for the patient (systemic mycosis). The most commonly encountered human pathogenic fungi are Candida and Aspergillus species. In Germany alone, about 40,000 people are affected each year by an invasive Candida infection. In terms of hospital infections, this yeast is now number 4 on the list of the most dangerous pathogens and requires a high financial therapy effort. Antifungal therapy is also of great importance for controlling candidiasis and aspergillosis in transplants (Higashiyama and Kohno, 2004). After bone marrow transplantation, fungal infections are the most common cause of death of the transplant recipient. About half of all transplant recipients suffer from systemic fungal infections and one-third die from uncontrollable infection (Epstein et al., 2003)

Candida fungi belong to the yeasts. The transfer of yeasts is due to contaminated foods as well through direct contact with other people and animals, especially Pets, possible. In addition to the infestation of mucous membranes in the mouth, esophagus or vagina, infection with candida can also spread in the liver, kidney, spleen and other organs. The preferred ones Germs are Candida albicans, but increasingly you can also find Candida glabrata and Candida krusei in the isolates, which are common Resistance to usual Have mushroom agents.

Next Candida infections can Aspergillus spp. (Molds), in particular Aspergillus fumigatus, the life-threatening clinical picture of invasive aspergillosis cause. The mushroom grows from the lungs, the place of first colonization as a result of inhalation of fungal spores into the tissue and can then affect all organs of the body. For one Treatment of invasive A. fumigatus infection is modest options to disposal, so that the disease affects more than 70 percent of the cases Death of the patient leads. But even if the infection only spreads to body surfaces, there are fungal infections not only unpleasant, but also dangerous there. Take with their root filaments The fungi absorb glucose from the blood and sometimes excrete poisonous substances Metabolism products, so-called mycotoxins that damage the liver. fungal infections have to therefore be treated.

fungal infections also make a big one Problem with animals (e.g., farm animals, birds, fish, small and zoo animals as well as invertebrates such as bees) where they have analogous diseases trigger can and treated or combated Need to become.

mushrooms like the organisms that colonize them are eukaryotic organisms and therefore much more difficult to fight than bacteria, without the harm human or animal organism. In particular, the fight against Candida infections is made more difficult by the fact that it is a particularly flexible microorganism that is constantly growing Shape changes. He changes from a small, spherical cell shape, the yeast type, too long, multicellular threads, the hyphae form. This form of hyphae is especially dangerous because it can penetrate tissue.

The Treating fungal diseases is often tedious. The duration The treatment depends on the type of fungus that causes the infection has caused. A therapy therefore goes with an identification of the mushroom and the description of its characteristics, above all its resistance to fungicides, in laboratory experiments.

fungal (Antifungals) in principle have two different effects. They can inhibit fungal propagation to lead and thus act fungistatic. But they can also act fungicidal and thus a killing Exercise on the fungi. A big part the common ones Disrupt fungi remedies the synthesis of the substance ergosterol, which is an important Component of cell membranes of mushrooms. Ergosterol synthesis takes place in several steps, using the different fungicides can intervene at different points in the synthesis. The disorder Ergosterol synthesis can inhibit the growth of fungi and even to a kill lead the mushrooms.

Azole inhibit the biosynthesis of ergosterol, an important component The cell membrane of fungi, by inserting into the cytochrome P454 system intervention. The effect of most azole derivatives is fungistatic, some also have fungicidal properties. Azole are mainly applied locally, but are also suitable for systemic Treatment. It should be noted that the active ingredients are not in the bone tissue and not enter the central nervous system allowed to.

Local applied agents are e.g. Clotrimazole, bifonazole and econazole. All three substances are effective against yeasts, molds and dermatophytes.

The systemic administration is oral or in the form of injections or Infusions. Indications are, for example, systemic mycoses, Fungal nail infections and severe mucocutaneous candidiasis especially in AIDS and immunodeficiencies. This includes medications such as fluconazole, Ketoconazole and others available. Fluconazole is considered by experts today as a first-choice drug once Candida has been detected in the blood culture, even if the Species not yet identified and the resistance test yet pending.

Squalene inhibitor also engage in ergosterol synthesis. Their effect is fungistatic. In dermatophytes, the substances also act fungicide. These medications include terbinafine and naftifine.

drugs from the group of morpholin derivatives (Amorolfin) preferably used for the treatment of dermatophytic diseases.

The Polyene derivatives form complexes (compounds) with the sterols of the fungal membranes and disturb hence the functions of the membranes. In a systemic application the polyene derivatives It is problematic that the sterols of the fungi attack the human sterols Strongly resemble cell membranes. Therefore, you can for one systemic treatment only those polyene derivatives are used, to the human skeletal substances, Like cholesterol, it does not have a low binding ability to harm them. The most common The agents used are amphotericin B and nystatin.

Amphotericin B is a broad-spectrum antifungal drug whose action and function are well-known in the patent US2908611 is explained. However, its use is limited by its strong kidney, liver and myelotoxicity. Due to its poor solubility it may be given in the form of colloids or as a liposome formulation ( US4663167 ; EP0421733 ).

Known is also the prophylactic and therapeutic treatment of Candida infections by administration of probiotic agents. These probiotics contain lactate-producing Bacteria, or their metabolites responsible for the healing effect to draw (WO9917788, Perdigon et al., 1990). Especially an immunostimulatory effect is believed to be desirable for defense reactions in fungal diseases is (De Simone et al, 1993). Such an antifungal Therapy is indicated after administration of antibiotics against bacterial infections, as Candida pathogens damage the mucosa and suppress the immune system.

Other, so-called non-classical antimycotics have different mechanisms of action. A patent ( US6414035 ) describes the use of polyols such as mannitol, sorbitol or xylitol for the treatment and prophylaxis of mucous fungal diseases.

The Patent WO9707802 describes the use of an inhibitor of the Chitin synthesis (Nikkomycin Z) against Candida pathogen.

Another patent recommends the use of complexing substances for combating fungi ( GB2033220 ). Mushrooms need zinc ions for their metabolism, which are extracted by complexing agents.

New approaches The antifungal therapy is based on the activation of the body's own Defense. By activation of human dendritic cells by Proteins or nucleic acids of fungi is said to be a cellular Immune response triggered become. However, this method has the disadvantage that it is species-specific (Bozza et al., 2004) and has no broad antifungal response.

One general problem with the use of antimycotics is the development of resistance (Sanglard and Odds, 2002). Resistance is closely related with the number of AIDS diseases, bone marrow transplants and chemotherapies (Randhawa, 2000). So is Candida glabrata and C. Krusei often resistant to Fluconazole (Marr, 2004). The resistance development is on an increased Attributed expression of ABC transporters containing the drug fluconazole out of the fungal cell (Bennett et al., 2004).

to Determination of fungal resistance are different tests available. For this will be et al the standardized platelet test according to Kirby-Bauer (Qin et al., 2004) or the determination of the minimum inhibitory concentration (MIC) with the VITEK2 (bioMerieux, Marcy l'Etoile, France). Of the platelet test Kirby-Bauer is based on the impregnation of filter discs and the measurement of Hemmhöfen after application of the filters on inoculated agar plates. At the MIC test be dilution series the test substance in nutrient medium introduced the fungus to be tested in defined concentrations contain. Measured is the minimum concentration of the inhibitor which inhibits the growth of microorganisms. The tests should be are based on the NCCLS guidelines (NCCLS, 1997)

Some antifungals have serious side effects, especially with prolonged or high dose use (Schwarze et al., 1998). Especially when Amphotericin B is administered, angioedema, allergies, chills, loss of appetite, nausea, vomiting, some severe anemia, kidney and liver can occur dysfunction, anaphylactic shock, hearing loss or tinnitus. The administration of antifungals with cisplatin, pentamidine, aminoglycosides can cause severe kidney damage.

New Therapy options are therefore more than desirable, especially among the Candida species C. glabrata and C. krusei proliferate primarily against strains Fluconazole are resistant (13th European Congress of Clinical Microbiology and Infectious Diseases, Glasgow, June 2003). A possibility for that can in the influence of glycolysis, since, as shown, many fungi and generally parasite glucose for energy degrade glycolytically.

Out The inhibition of glycolysis was therefore hoped for the derivation of a another group of compounds that are used to treat parasitic infections (Brady and Cameron, 2004; Kavanagh et al., 2004; Lakhdar-Ghazal et al., 2002). Such inhibitors are also especially for fighting of cancers has been developed and studied.

So describes US2004167079 Method for the treatment of cancer by the use of 2-deoxy-glucose (2-DG), an inhibitor of glycolysis.

US2003181393 discloses the glycolysis inhibitors 2-deoxyglucose, oxamate and iodine acetate. In this case, iodine acetate inhibits glyceraldehyde-3-phosphate dehydrogenase and oxamate inhibits lactate dehydrogenase.

Of the primary However, the shortcoming of the glycolysis inhibition strategy is that uses glycolysis in almost all cells for energy will, so that also body cells can be damaged by the inhibition of glycolysis. Especially the brain impact is dramatic as the brain is considered more obligatory Glucose consumer is heavily dependent on glycolysis.

One newer approach for a therapeutic intervention with the aim of changing and increased Therefore, it is no longer possible to influence glycolysis as a target the inhibition of glycolysis, but in the inhibition of glyoxalases (Thornalley et al., 1994; Vander et al., 1990; Pemberton and Barrett, 1989; Creighton et al., 2003; Hamilton and Batist, 2004).

Becomes by glyoxalase inhibitor the degradation of the glycolysis formed in Methylglyoxals is prevented in the cells by increased glycolysis increasingly form methylglyoxal such as parasite cells, however, the cytotoxin accumulated. this leads to to die off the parasite cells.

On the base of the substrate of glyoxalase I, the half thioacetal Methylglyoxal and glutathione, have already been peptidic glyoxalase inhibitors synthesized (Johansson et al., 2000; Thornalley et al., 1996; Kalsi et al., 2000; Sharkey et al., 2000).

US4898870 describes pyrroloquinoline quinone compounds in conjunction with the inhibition of glyoxalase I. WO99 / 35128 also describes compounds for inhibiting glyoxalase I. WO2004101506 describes another class of non-peptidic glyoxalase I inhibitors.

The However, previously known glyoxalase inhibitors have a relative high or very high toxicity and are metabolized in metabolism to compounds that again diverse have pharmacological effects and develop partly strong side effects.

The In addition, glyoxalase inhibitors known to inhibit either only Glyoxalase I or only glyoxalase II. Compared with inhibitors that are only against a single protein target, however, becomes very fast developed a resistance by, for example, in the corresponding protein, e.g. Mutations occur that make the inhibitor ineffective.

The The object of the invention is non-toxic and non-mutagenic Compounds for inhibiting cellular methylglyoxal toxification, in particular for the inhibition of the reactions of glyoxalases I and II indicate that inhibit cell proliferation and thus for treatment of parasitic Diseases and disorders associated with parasitic infections, can be used.

wobei R1 einen verzweigten oder unverzweigten Alkyl-, Alkenyl-, Alkinyl- oder Cycloalkyl-Rest vorzugsweise mit einer Kettenlänge von C1 bis C8 bedeutet und
wobei R2 H- oder einen verzweigten oder unverzweigten Alkyl-, Alkenyl- oder Alkinyl-Rest vorzugsweise mit einer Kettenlänge von C1 bis C8 bedeutet
und/oder von Verbindungen, die im Organismus, auf der Haut oder Schleimhaut zu Verbindungen der allgemeinen Formel (I) umgewandelt werden, zur Herstellung eines Arzneimittels zur Hemmung der Proliferation von Zellen durch Inhibition der Reaktionen der Glyoxalasen I und/oder II.According to the invention the object is achieved by the use of compounds of general formula (I),

where R1 is a branched or unbranched alkyl, alkenyl, alkynyl or cycloalkyl radical, preferably with a chain length of C1 to C8, and
where R2 is H or a branched or unbranched alkyl, alkenyl or alkynyl radical, preferably having a chain length of C1 to C8
and / or compounds which are converted in the organism, on the skin or mucous membrane to compounds of the general formula (I), for the preparation of a medicament for inhibiting the proliferation of cells by inhibiting the reactions of the glyoxalases I and / or II.

at the compounds of the invention the general formula (I) is, for example, ethyl pyruvate, Ethyl 2-oxobutyrate, butyl pyruvate, butyl 2-oxobutyrate, isobutyl pyruvate, Isopropyl pyruvate and cyclohexylmethylpyruvate. Especially preferred are the compounds methylpyruvate, ethylpyruvate, butylpyruvate, Isobutylpyruvate and ethyl 2-oxobutyrate.

Surprised has been found that compounds of general formula (I) as e.g. Ethyl pyruvate are capable of both the reaction of glyoxalase I as well as to inhibit the reaction of glyoxalase II. The inhibition the reactions of glyoxalases by compounds of the general Formula (I) prevents according to the invention the cellular detoxification of methylglyoxal and carries over different Mechanisms to inhibit cell proliferation and cell death.

Advantageous become by connections of the general formula (I) several enzymes - in the present case the reactions of glyoxalases I and II - inhibits what the probability Resistance training within the therapeutic period drastically reduced.

Advantageous become by compounds of the general formula (I) such cells inhibited, which increased significantly Have glycolysis rate while the metabolism in cells with normal glycolysis rate not or only slightly impaired becomes.

According to the invention it is the cells whose proliferation is inhibited, in particular human or animal pathogenic parasites. Under parasites understands organisms that live in whole or in part at the expense of a host. These include Mushrooms, protozoa and helminths. Such parasites cause infectious diseases such as various fungal diseases, malaria, sleeping sickness, Leishmaniasis, schistosomiasis, toxoplasmosis, Chagas' disease and many more diseases.

Of the Degradation of glucose over Glycolysis and the formation of glyoxal compounds are ubiquitous metabolic pathways, which are phylogenetically highly conserved (Heymans and Singh, 2003; Clugston et al., 1997). Human or animal pathogenic parasites that with availability especially about glucose glycolysis, for example, cover its energy consumption Fungi (e.g., Candida spp., Aspergillus spp., Cryptococcus spp., Zygomyces spp., dermatophytes, Blastomyces spp., Histoplasma spp., Coccidides spp., Sporothrix spp.), the cells of multicellular organisms such as Trypanosomes (such as Trypanosoma cruzi), Leishmania, Plasmodia (such as the malaria parasite Plasmodium falciparum), helminths (e.g. Schistosoma) as well as Toxoplasma. These provide other energy-supplying Processes by glucose and use glycolysis (catabolite repression) or grow under hypoxic conditions. It is therefore not surprising that such a variety of cells and organisms through compounds of the general formula (I) are inhibited in their growth and killed can.

The toxicity of compounds of general formula (I) and their derivatives is also extremely low (Clary et al., 1998). After saponification by esterases they also in the metabolism in not or only slightly toxic Alcohols and also carboxylic acids formed in normal cell metabolism (e.g. Pyruvate and lactate). This also explains the low or missing ecotoxicity of these Compounds (Bowmer et al., 1998) in tests with Selenastrum capricornutum, Daphnia magna, Pimephales promelas and Brachydanio rerio. As well lack of these compounds a mutagenic potential in normal cells, as demonstrated in an established test system (Andersen and Jensen, 1984).

The Use of compounds of general formula (I) for inhibition The reactions of glyoxalases have not been known so far.

In several patents ( US5580902 . US4234599 . US4105783 ) have described compounds of the general formula (I) such as ethyl pyruvate as an agent to improve the texture of the skin and to smooth wrinkles or to remove warts and similar skin symptoms.

Moreover Ethyllactate shampoos can be added to make an acidification, which is achieved with the hydrolysis of the ester, the effect antibacterial Means to improve (de Jaham, 2003).

ethyl pyruvate has been used to improve cataractic conditions (Devamanoharan et al., 1999). This was a lowering of dulcitol and glycated Proteins found by Ethylpvruvat, based on the action of pyruvate is due which is formed by hydrolysis from ethyl pyruvate. The advantage of Use of ethyl pyruvate is in its easier membrane permeability to search.

Furthermore, it has been described that the use of ethyl pyruvate can improve inflammatory conditions and sepsis. In the patent US2004110833 Ethyl pyruvate is used to influence cytokine-mediated diseases. This was attributed to the elimination of the effect of NFκB (Han et al., 2005, Yang et al., 2004, Fink et al., 2004, Miyaji et al, 2003, Ulloa et al., 2002). However, there are also conflicting observations on this finding (Mulier et al., 2005). In no case, however, can this mechanism be used to explain the inhibition of the growth of cells in their diversity shown here, since, as shown, yeast cells are also inhibited in their growth by ethyl pyruvate, which has neither NFκB nor cytokines nor any other inflammatory Proteins have. In particular, this mechanism can not be used to explain the antiproliferative effect of ethylpyruvate, since the effect of ethylpyruvate on the cytokine secretion can also be detected if the animal cells examined do not proliferate.

The proliferation inhibiting and killing Effect of ethylpyruvate mediated by the inhibition of the reactions of glyoxalases, is even more surprising as ethylpyruvate, due to its described action as a "scavenger" (scavenger) of reactive oxygen radicals rather a growth-promoting Should have effect. (Varma et al., 1998). This is indeed too for humane T lymphocytes have been described (Dong et al., 2005). In this work was also described that the formation of the cytokine interleukin-2 in the T lymphocytes was increased. This is an important indication that normal body cells through Not only are ethyl pyruvate not harmed, but even that a positive effect is exerted on the cell-mediated immune defense. This has a synergistic effect in the treatment of a parasitic disease with a compound of the invention. Become parasites damaged by compounds of general formula (I) and inhibited in their growth, at the same time there is a strengthening of the Immune system, especially the cellular defense by the effect on cytokines, increasing the proliferation of T lymphocytes and by the removal of oxygen radicals.

From particular advantage is the use of compounds of the general Formula (I) and its Derivatives for the Treatment of Tumor Patients, which often suffer from fungal infections due to their high susceptibility to infection. It is known that most tumors also have a high glycolysis (Gatenby RA and Gillies RJ., 2004). This can be tumor cells and fungi are simultaneously inhibited in their growth.

Also from the known insulinotropic effect of methyl pyruvate was the Influence of glyoxalases unpredictable. methyl pyruvate has been extensively studied for years as an insulinotropic compound (Dufer et al., 2002, Valverde et al., 2001, Lembert et al. 2001). This effect is over the influence of potassium channels and mediates mitochondrial effects.

Another example of the surprising finding that compounds of the general formula (I) inhibit the proliferation of cells is disclosed in the patent JP8208422 clear. Normal human cells, such as keratinocytes, become weaker JP8208422 even stimulated by compounds of the general formula (I) in their proliferation, which finds application for improving the appearance of the skin.

wobei R1 einen verzweigten oder unverzweigten Alkyl-, Alkenyl-, Alkinyl- oder Cycloalkyl Rest vorzugsweise mit einer Kettenlänge von C 1 bis C8 bedeutet und
wobei R2 H- oder einen verzweigten oder unverzweigten Alkyl-, Alkenyl- oder Alkinyl-Rest vorzugsweise mit einer Kettenlänge von C1 bis C8 bedeutet,
beispielsweise die reduzierten Derivate Butyllaktat bzw. Ethyllaktat, die im Organismus durch die in den Zellen vorkommenden Dehydrogenasen (insbesondere durch die Laktatdehydrogenase) zu den entsprechenden Verbindungen der allgemeinen Formel (I) z.B. Butylpyruvat bzw. Ethylpyruvat umgesetzt werden (Lluis et al., 1976).According to the invention, the inhibition of the growth of cells not only by the use of compounds of general formula (I) itself, but also by compounds which are converted in the organism, on the skin or mucosa to compounds of general formula (I). These are, for example, compounds of the general formulas (II) and / or (III),

where R 1 denotes a branched or unbranched alkyl, alkenyl, alkynyl or cycloalkyl radical, preferably with a chain length of C 1 to C 8, and
wherein R 2 signifies H or a branched or unbranched alkyl, alkenyl or alkynyl radical, preferably with a chain length of C 1 to C 8,
For example, the reduced derivatives butyl lactate or ethyl lactate, which are implemented in the organism by the occurring in the cells dehydrogenases (especially by lactate dehydrogenase) to the corresponding compounds of general formula (I), for example butylpyruvate or ethylpyruvate (Lluis et al., 1976) ,

According to the invention the inhibition of cell growth continues not only through the Use of compounds of general formula (I) itself, but also through connections that during their application chemically to compounds of the general formula (I) to be converted. These are, for example, compounds of general formulas (II) and / or (III), such as the reduced derivatives Butyl lactate or ethyl lactate, for example, during their use by an oxidizing agent such as potassium permanganate to butyl pyruvate or ethyl pyruvate are converted. Other oxidants are for example, hydrogen peroxide, iodine, iodobenzoic acid and other.

These it concerns with the connections, in the organism to connections of the general formula (I) are converted to compounds with one or more chiral centers, for example, ethyl lactate or butyl lactate, so can both the corresponding D and L compounds as well as racemic mixtures are used, for example D-ethyl lactate (DEL), L-ethyl lactate (LEL) or racemic mixtures of DEL and LEL or D-butyl lactate (DBL), L-butyl lactate (LBL) or racemic mixtures from DBL and LBL.

Becomes Ethyl lactate used are both L-ethyl lactate (LEL) as well D-ethyl lactate (DEL) effective. The effect of D-lactate esters is surprising there D-lactate as in mammalian cells not metabolizable applies (Murray et al., 1993) and the same also for Had to accept D-lactate ester. Some microorganisms, in contrast, can D-forms of 2-hydroxycarboxylic acids and their esters oxidize.

own Confirm measurements the interconversion of ethyl lactate and ethylpyruvate by NAD-dependent lactate dehydrogenases. Butyl lactate can also be converted by NAD-dependent lactate dehydrogenase but worse than ethyl lactate. Becomes butyl lactate used according to the invention, Only cells with particularly high lactate dehydrogenase activity become therapeutic achieve effective concentrations of butyl pyruvate.

lactate is present in human blood in a concentration of 2-20 mM. Lactate is contained in many foods, arises even in the Metabolism or can be implemented in the metabolism. It can be breathed or converted into derivatives. It is therefore not toxic.

About one Lactate shuttle (monocarboxylate transporters (MCT's) (Garcia et al., 1994; by Grumbckow et al, 1999) are lactate and alkyl lactate via cell membranes in conjunction with transported an H-ion transporter. For transport in mitochondria Mitochondrial MCTs are available. The addition of lactate or its alkyl ester leads to blood to a slight alkalization due to the H-coupled lactate transport, while the addition of pyruvate or its alkyl esters an acidosis in the blood caused by the enzymatic cleavage of the esters comes. Compared to pyruvate and alkylpyruvate, lactate and Alkyl lactate stereoselective and better transported through membranes (Roth and Brooks, 1990). Alkylpyruvate, which is applied to the blood Need to become first converted into alkyl lactates before they enter cells can.

Therefore it is advantageous therapeutic, physiologically compatible alkyl lactates to use.

Moreover is also the rate of hydrolysis of the compounds of the general formulas (II) and (III) compared with the compounds of the general formula (I) lower, indicating the stability of pharmaceutical preparations with compounds of the general Improved formulas (II) and (III) as an active ingredient.

The Inhibition of cell proliferation can also be achieved by a combined application of compounds of general formula (I), e.g. ethyl pyruvate, and compounds found in the organism in compounds of general Formula (I) are converted, such as compounds of the general Formulas (II) and (III), e.g. Ethyl lactate (D and / or L-ethyl lactate) take place.

The Compounds of the general formula (I) and / or compounds which to compounds of general formula (I) are converted preferably as a food additive and / or as a chemopreventive and / or as an adjuvant for the treatment of parasitic diseases or infections used in human and / or veterinary medicine.

The Compounds of the general formula (I) and / or compounds which in the organism, on the skin or mucous membrane to compounds of the general formula (I) are converted to treatment of mucosal (topical) and / or systemic diseases. The mucosal diseases can be caused by oral or vaginal infections. The oral or vaginal infections are e.g. the result of AIDS, one Chemotherapy or an immunosuppressive therapy or immunosuppressive States.

The Compounds of the general formula (I) and / or compounds which can be converted to compounds of general formula (I) can thereby can be applied topically or systemically, in particular, the Application intravenously, subcutaneous, intramuscular, intraperitoneal, oral, rectal, nasal, percutaneous, transdermal, as Aerosol, as rinsing solution, via minipumps, as a mouthwash, as a cream as a paste, as a lotion, as a bath, as a gel, as a plaster, as an ointment, and / or by means of pulmonary administration.

ester are naturally limited only stable, there is a need for a systemic application higher Use doses of the compounds. The latter can be bypassed by a local application takes place.

Around to achieve a therapeutic effect, the compounds of the invention in general for several days or weeks with the respective therapeutically effective Dose applied. The application takes place systemically, for example, e.g. by repeated oral or parenteral administration, or also locally, e.g. while Stereotactic operations that bring the drug to the desired location is brought by locally placed probes in connection with pumps, by creams or by procedures in which the drug is in one inert vehicle is systemically introduced into the body and only at the desired Place is released by appropriate manipulation.

Also according to the invention a combination of compounds of general formula (I) and / or compounds, in the organism, on the skin or mucous membrane to compounds of general formula (I), and at least one another pharmaceutically active compound can be used. As further pharmaceutically active compound are preferred Chemotherapeutics, immunosuppressants, known worm and fungus agents, Glykolysehemmstoffe or glycolysis substrates used.

in the In general, a parasitic disease, such as a fungal infection an opportunistic infection based on a weakened immune system. The weakening the immune system is often the one Consequence of chemotherapy in a cancer, organ transplantation with concomitant immunosuppression or HIV infection.

A Inhibition of the reaction of glyoxalases by compounds of the general Formula (I) and in particular by ethyl pyruvate and related substances is in combination with chemotherapy for cancer treatment of particular advantage since the reactions of the glyoxalases both inhibited in cancer cells as well as in parasitizing cells and the Killed cancer cells and parasites become.

The known effect of the compound according to the invention ethylpyruvate as a scavenger of reactive oxygen radicals also represents a desirable side effect for cells which do not have a high glycolysis rate (body cells), since such cells are additionally protected Combination therapy with a chemotherapeutic agent or immunosuppressant is an additional advantage since normal cells are also subjected to stress that is attenuated by compounds of general formula (I).

A preferred combination consists of compounds of the general Formula (I) and / or compounds resulting in compounds of general Formula (I) are converted, and a glycolysis inhibitor the glycolysis inhibitor below the triosephosphate isomerase reaction engages in glycolysis. The meaning of such a combination exists in it, the concentration of triose phosphates making up methylglyoxal parametabolic or paracatalytic arises, increase and thus the effectiveness to improve the therapy.

Especially preferred is the combination of compounds of the general Formula (I), especially ethyl pyruvate, and the lactate dehydrogenase inhibitor Oxamat. Also particularly preferred is the combination of compounds of the general formula (I) and / or compounds present in the organism be converted to compounds of general formula (I), with the glyceraldehyde-phosphate-dehydrogenase inhibitor iodoacetate.

When other pharmaceutically active compounds are preferably substances that promote the growth of parasites, such as glycolysis substrates, especially glucose, or by acting as a decoupler of the respiratory chain act, for example 2,4-dinitrophenol.

to present invention also pharmaceutical preparations, in addition to non-toxic, inert pharmaceutically suitable excipients, the compounds according to the invention of the general formulas (I), (II) and / or (III), as well as Process for the preparation of these preparations.

The Production of the above listed Pharmaceutical preparations are carried out in the usual manner according to known Methods, e.g. by mixing the one or more active ingredients with the or the carriers.

A pharmaceutical preparation can also be prepared by the ester components of the compounds of the general formula (I) or the compounds which in the organism become compounds of the general formula (I), under conditions with each other are mixed, among which the compounds of general formula (I) and the compounds which in the organism become compounds of the general formula (I) are converted arise.

The pharmaceutical preparation can also be prepared by the ester components of the compounds of the general formula (I) or the compounds which are in the organism to compounds of the general Formula (I) to be converted so that in the organism, for example, in the acidic environment of the stomach Compounds of the general formula (I) or of the compounds which to give compounds of general formula (I).

at The ester components are, for example, an alkanol such as ethanol and the organic acid such as lactic acid.

Based the following nd embodiments the invention will be closer explained.

there demonstrate

1 : Influence of Ethylpyruvate (EP), Butylpyruvate (BP) and Butylactate (BL) on the Enzymatic Reaction of Glyoxalase I from Yeast.

2 Influence of Ethylpyruvate (EP) on the Enzymatic Reaction of Glyoxalase II from Yeast.

3 : Effect of D-ethyl lactate (DEL), L-ethyl lactate (LEL) and ethyl pyruvate (EP) on the vitality of primary human fibroblasts

table 1: inhibition of the growth of yeast cells (Saccharomyces cerevisiae) by ethyl pyruvate (EP) and butyl pyruvate (BP).

table 2: inhibition of the growth of a fluconazole-resistant strain of Candida albicans by ethyl pyruvate (EP), butyl pyruvate (BP) and Ethyl 2-oxo-butyrate (EOB).

table 3: inhibition of the growth of a fluconazole-sensitive strain of Candida albicans by ethyl pyruvate (EP) and butyl pyruvate (BP).

Exemplary embodiment 1

Influence of ethyl pyruvate (EP), butyl pyruvate (BP) and butyl lactate (BL) on the enzymatic reaction of glyoxalase I made of yeast.

The determination of yeast glyoxalase I (EC4.4.1.5, lactoyl-glutathione lyase Sigma, G-4252) was carried out according to a protocol of McLellan and Thornalley (1989). The principle is based on the measurement of the initial rate of formation of SD-lactoylglutathione from methylglyoxal (Sigma, MO252, 40%) and reduced L-glutathione (Aldrich, G4251,> 99%). The formation of the product is monitored using the extinction coefficient of ε = 2.86 mM ^-1 cm ^-1 at 240 nm. The determination was carried out in 50 mM sodium phosphate buffer pH 7.0. For this purpose, 2 mM methylglyoxal and 2 mM reduced glutathione were incubated for 2 minutes at 30 ° C. to form the hemithioacetate. Then 20 μl of a 1: 1000 dilution of the glyoxalase I were pipetted into the measurement batch of 1 ml to start the reaction.

The glyoxalase activity (IE) corresponds to the amount of enzyme which forms 1 μmol of SD-lactoylglutathione / min. The effect of effectors on the enzymatic reaction was determined by adding increasing concentrations (0-30 mM) of EP (Sigma, No. E4,780-8, Lot S18972-513) (triangular symbol), BP (prepared as described in patent JP11080089 ; 98%) (circle symbol) and BL (Fluka, 69819; Lot 443090/1 21503090) (cross symbol) are examined for the measurement approach (s. 1 ).

The Experiments show that both EP and BP are the reaction of Glyoxalase I concentration-dependent inhibit the effect of BP is stronger than the effect of EP. BL does not affect the glyoxalase response if it does not has been converted to BP.

Embodiment 2

Influence of Ethylpyruvate (EP) on the enzymatic reaction of glyoxalase II from yeast.

A colony of strain HD65-5a (Saccharomyces cerevisiae) was added overnight in 5 ml of YPD medium [(2% glucose (Fluka), 1% Yeast Extract (BD, Sparks), 2% Peptone (BD, Sparks)] An aliquot (10 ml) was pipetted into 200 ml of nutrient medium in a 500 ml glass bottle and incubated on a shaker (250 rpm) at 30 ° C. The yeast cells were removed from the stationary growth ^phase (OD ^{1 cm /} min). ^600nm = ^2-4 ) were harvested by centrifugation (15 min, 3000 x g) The cells were diluted with 0.1 M MES buffer, pH 6.5, to an OD of 4, followed by cell disruption in a glass mill (Schwock et al. Cell disruption was then centrifuged for 30 min at 23,000 x g, 4 ° C. The protein concentration of the cell-free extract was determined by the Bradford method (Bradford, 1976) Determining the activity of glyoxalase II (hydroxyacylglutathione hydrolase, EC 3.1.2.6.) Was carried out according to a protocol of Martins et al. (1999) i n 0.1 M MES buffer, pH 6.5, 1.5 mM SD-lactoylglutathione (L7140, Sigma-Aldrich Chemie GmbH) and 0.75 mM DTNB (Sigma, D8130). After addition of suitable amounts of the cell extract and an incubation time of 15 min at 25 ° C, the formation of glutathione at 412 nm (ε = 13.6 mM ^-1 cm ^-1 ) was measured. Glyoxalase II activity (IE) is the amount of enzyme that hydrolyzes 1 μmol of SD-lactoylglutathione / min.

Of the Influence of Ethyl pyruvate on the enzyme activity was increased by the addition of Concentrations of EP (Sigma, No. E4,780-8; Lot 518972-513) (0-20 mM) examined for the measurement approach.

The relative activities of glyoxylase II in the absence and presence of EP are in 3 shown. The experiments show that EP inhibits the reaction of glyoxalase II in a concentration-dependent manner.

Embodiment 3

Inhibition of growth of yeast cells (Saccharomyces cerevisiae) by ethyl pyruvate (EP) Butyl pyruvate (BP) and oxidized L-ethyl lactate (LEL).

A colony of strain HD65-5a (Saccharomyces cerevisiae) was resuspended in 5 ml YPD medium [(2% Glucose (Fluka), 1% Yeast Extract (BD, Sparks), 2% Peptone (BD, Sparks)] in 20 ml glass tubes and incubated overnight at 30 ° C while rotating. At an OD of 12.9 (580 nm), an initial density of OD 0.19 was adjusted by dilution with nutrient medium. The batch was aliquoted to 10 ml (in 20 ml glass vials), added with increasing concentrations of EP and BP and incubated at 30 ° C with continuous rotation (200 rpm). Another cell batch was treated with LEL previously oxidized with potassium permanganate (KMnO4). After 8 hours, samples of 1 ml each were taken and the OD was measured at 600 nm.

The Experiment (Table 1) shows that EP and BP increase the growth of yeast cells concentration-dependent manner inhibit.

Table 1:

Exemplary embodiment 4

Inhibition of a fluconazole-resistant Strain of Candida albicans by Ethyl Pyruvate (EP) Butyl Pyruvate (BP) and ethyl 2-oxo-butyrate (EOB)

A Colony of fluconazole-resistant Candida albicans strain A435 was dissolved in 5 ml of YPD medium [(2% glucose (Fluka), 1% Yeast Extract (BD, Sparks), 2% peptones (BD, Sparks)] in 20 ml glass tubes and over Night at 30 ° C incubated while rotating. At an O.D. of 14.4 (600 nm) was through Dilute with nutrient medium an initial density of O.D. 0.20 set. The approach became too 10 ml aliquoted (in 20 ml glass vial), with increasing concentrations of EP, BP and EOB and at 30 ° C with continuous rotation (200 U / min) incubated. After 5 hours, 1 ml samples were taken taken and the O.D. determined at 600 nm as a measure of the cell count. The Determination of resistance Fluconazole followed the guidelines of the NCCLS (1997). As resistant applies a growth at a dose of ≥ 64 μg / ml for fluconazole.

The Experiment (Table 2) shows that EP, BP and EOB increase the growth of Fluconazole-resistant Candida albicans cells inhibits.

Table 2

Exemplary embodiment 5

Inhibition of growth of a fluconazole-sensitive strain of Candida albicans by ethyl pyruvate (EP) and butyl pyruvate (BP)

A colony of the fluconazole-sensitive Candida albicans strain R / HO13 was dissolved in 5 ml of YPD medium [(2% glucose (Fluka), 1% Yeast Extract (BD, Sparks), 2% Peptone (BD, Sparks)] in 20 ml The tubes were seeded and incubated overnight at 30 ° C. At an OD of 14.4 (600 nm), an initial density of OD 0.20 was set by dilution with nutrient medium The batch was aliquoted to 10 ml (in 20 ml glass vials) with ascending tubes Concentrations of EP and BP added and at 30 ° C under konti with a slow turn (200 rpm). After 9 hours, samples of 1 ml each were taken and the OD was measured at 600 nm. Sensitivity to fluconazole was at a dose of ≤ 0.13 μg / ml.

The Experiment (Table 3) shows that EP and BP increase the growth of fluconazole-sensitive Candida albicans cells inhibits.

Table 3

Exemplary embodiment 6

Effect of D-ethyl lactate (DEL), L-ethyl lactate (LEL) and ethyl pyruvate (EP) on the vitality of primary human fibroblasts

An identical number (10 ⁴ cells per well) of primary human dermal fibroblasts were seeded in 24-well plates (Greiner, # 662160) and in DMEM (Gibco, # 41966-092) in the presence of 10% calf serum (Biochrom, S0113 / 5), 2mM L-glutamine (Gibco, # 25030-024), penicillin / streptomycin (100 units penicillin / ml, 100μg streptomycin / ml) (Gibco, # 15140/122), 5mg% ascorbic acid ( Serva, No. 14030.02) at 37 ° C, 5% CO ₂ and 95% humidity. The production of primary human fibroblasts was carried out according to a protocol of Birkenmeier et al (1998). After reaching 50% confluency, the medium was replaced with fresh serum-free medium.

• Ansatz 1: Serumfreies Medium-Volumenäquivalent
• Ansatz 2: 1 mM DEL oder 1 mM LEL oder 1 mM EP
• Ansatz 3: 5 mM DEL oder 5 mM LEL oder 5 mM EP
• Ansatz 4: 10 mM DEL oder 10 mM LEL oder 10 mM EP
• Ansatz 5: 20 mM DEL oder 20 mM LEL oder 20 mM EP
• Ansatz 6: 50 mM DEL oder 50 mM LEL oder 50 mM EP.

Subsequently, the following additives were added to the cells:

• Approach 1: serum-free medium volume equivalent
• Batch 2: 1 mM DEL or 1 mM LEL or 1 mM EP
• Batch 3: 5 mM DEL or 5 mM LEL or 5 mM EP
• Approach 4: 10 mM DEL or 10 mM LEL or 10 mM EP
• Batch 5: 20 mM DEL or 20 mM LEL or 20 mM EP
• Batch 6: 50 mM DEL or 50 mM LEL or 50 mM EP.

The cultivation was continued at 37 ° C, 5% CO ₂ and 95% humidity for 24 hours. Subsequently, the supernatants were removed and 100 .mu.l of a 50% Thymolblaulösung pipetted into the wells. After washing with medium, the unstained and stained cells were counted under the light microscope with coordinate system. Blue-stained cells were referred to as avital, unstained cells as vital. The percentage of unstained cells in total cell number corresponds to the vitality of the cells.

The experiment (see 3 ) shows that DEL, LEL and EP are non-toxic over the concentration range studied and do not significantly affect the vitality of primary human fibroblasts.

Embodiment 7

One 54 years old male Patient with diagnosed diabetes mellitus (fasting blood sugar level at the presentation 6.88 mM) complained about feeling of dryness in the mouth, chapped lips and white-spotty changes on the oral mucosa. An oral swab revealed an infection with Candida albicans pathogens. The determination of the germ count in one Oral Rinse (10 ml physiological saline, 30 seconds) gave a value of> 100 CFU / ml rinse solution.

Of the Patient led three times a day a mouthwash with 10 ml of ethylpyruvate solution (75 mM ethyl pyruvate, 1% glycose in physiological saline). The mouthwashes were over a period of 4 days. The renewed germ count after flushing with 10 ml saline resulted in a reduction of the germ count to <5%.

The Results show that the application of ethyl pyruvate to oral Candidiasis is helpful.

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List of abbreviations

• BP

  Butylpyruvat

  BL

  butyl lactate

  DEL

  D-ethyl lactate

  DMEM

  Dulbecco's modified Eagle medium

  DTNB

  5,5'-dithiobis (2-nitrobenzoic acid)

  E.C.

  Enzymes commission

  EDTA

  ethylenediaminetetraacetate

  EP

  ethyl pyruvate

  IE

  International unity

  LEL

  L-ethyl lactate

  MCT

  monocarboxylate

  MES

  4-Morpholineethanesulfonic acid

  NF

  κB nuclear factor Kappa B

  O.D.

  Optical density

  PBS

  Phosphate buffered salt

  e

  OB ethyl 2-oxo-butyrate

  SF

  Serum-free

  YPD

  Yeast Peptone Dextrose medium

Claims (27)

Use of compounds of general formula (I),

wherein R 1 is a branched or unbranched alkyl, alkenyl, alkynyl or cycloalkyl radical and wherein R 2 is H or a branched or unbranched alkyl, alkenyl or alkynyl radical and / or of compounds which are in the organism, on of the skin or mucosa are converted to compounds of general formula (I) for the preparation of a medicament for inhibiting the proliferation of cells by inhibiting the reactions of glyoxalases I and / or II. Use according to claim 1, characterized in that the compounds which are converted in the organism, on the skin or mucosa to compounds of the general formula (I) are compounds of the general formulas (II) and / or (III),

where R 1 is a branched or unbranched alkyl, alkenyl, alkynyl or cycloalkyl radical and where R 2 is H or a branched or unbranched alkyl, alkenyl or alkynyl radical. Use according to claim 1, characterized the compounds of general formula (I) are methylpyruvate, Ethyl pyruvate, butyl pyruvate, isobutyl pyruvate or ethyl 2-oxo butyrate are. Use according to claim 1, characterized that the compounds in the organism, on the skin or mucous membrane to compounds of general formula (I), L-methyl lactate or D-methyl lactate or a racemic mixture of L-methyl lactate and D-methyl lactate or L-butyl lactate or D-butyl lactate or a racemic mixture of L-butyl lactate and D-butyl lactate or L-ethyl lactate or D-ethyl lactate or a racemic mixture of L-ethyl lactate and D-ethyl lactate or D-isobutyl lactate or L-isobutyl lactate or a racemic mixture of D-isobutyl lactate and L-isobutyl lactate. Use according to one of Claims 1 to 4, characterized that compounds of the general formula (I) and / or compounds in the organism, on the skin or mucous membrane to compounds of the general formula (I), as a food additive and / or for prevention and / or for the treatment of parasitic Diseases in human and / or veterinary medicine are used. Use according to claim 5, characterized that the parasitic Diseases caused by human or animal pathogenic parasites are. Use according to claim 6, characterized that the human or animal pathogenic parasites fungi, helminths or representatives of the genera Trypanosoma, Leishmania, Plasmodium or Toxoplasma. Use according to claim 7, characterized that the fungi are yeasts (e.g., Candida spp., Cryptococcus spp.), molds (e.g., Aspergillus spp., Zygomyces spp.) or filamentous fungi (dermatophytes) represent. Use according to claim 1, characterized that compounds of the general formula (I) and / or compounds in the organism, on the skin or mucous membrane to compounds of general formula (I) for the treatment of mucosal (topical) and / or systemic diseases become. Use according to claim 9, characterized that the mucosal diseases are caused by oral or vaginal infections are caused. Use according to claim 10, characterized that the oral or vaginal infections are the result of AIDS, a Chemotherapy or immunosuppressive therapy or immunosuppressive conditions. Use according to one of claims 1 to 11, characterized that compounds of the general formula (I) and / or compounds in the organism, on the skin or mucous membrane to compounds of the general formula (I), topically or systemically be applied. Use according to claim 12, characterized that for topical and systemic use compounds of the general Formula (I) and / or compounds in the organism, on the skin or Mucosa converted to compounds of general formula (I) be, intravenously, subcutaneous, intramuscular, intraperitoneal, oral, rectal, nasal, percutaneous, transdermal, as Aerosol, as rinsing solution, via minipumps, as a mouthwash, as a cream, as a paste, as a lotion, as a bath, as a gel, as a plaster, administered as an ointment and / or by pulmonary administration become. Use according to claim 1, characterized that a combination of compounds of general formula (I) and / or compounds in the organism, on the skin or mucous membrane be converted to compounds of general formula (I), and used at least one other pharmaceutically active compound becomes. Use according to claim 13, characterized as another pharmaceutically active compound, chemotherapeutics, known worm and fungus agents, immunosuppressants, glycolysis inhibitors or Substances that promote the metabolism of parasites are used. Use according to claim 15, characterized that as substances that promote the metabolism of parasites, glucose or 2,4-dinitrophenol is used. Pharmaceutical composition for inhibiting the proliferation and / or growth of Parasites by inhibiting the reactions of the glyoxalases I and / or II, comprising a therapeutically effective amount of at least one of the compounds of the general formula (I) and / or at least one of the compounds which are converted in the organism to compounds of the general formula (I) .

where R 1 is a branched or unbranched alkyl, alkenyl, alkynyl or cycloalkyl radical and where R 2 is H or a branched or unbranched alkyl, alkenyl or alkynyl radical. Pharmaceutical composition according to claim 17, characterized in that the compounds which are converted in the organism to compounds of general formula (I) are compounds of general formulas (II) and / or (III),

where R 1 is a branched or unbranched alkyl, alkenyl, alkynyl or cycloalkyl radical and where R 2 is H or a branched or unbranched alkyl, alkenyl or alkynyl radical. Pharmaceutical composition according to claim 17, characterized in that the compounds of the general formula (I) methyl pyruvate, ethyl pyruvate, butyl pyruvate, isobutyl pyruvate or ethyl 2-oxo-butyrate are. A pharmaceutical composition according to claim 18, characterized in that the compounds in the organism be converted to compounds of general formula (I), L-methyl lactate or D-methyl lactate or a racemic mixture of L-methyl lactate and D-methyl lactate or L-butyl lactate or D-butyl lactate or a racemic mixture from L-butyl lactate and D-butyl lactate or L-ethyl lactate or D-ethyl lactate or a racemic mixture of L-ethyl lactate and D-ethyl lactate or D-isobutyl lactate or L-isobutyl lactate or a racemic one Mixture of D-isobutyl lactate and L-isobutyl lactate are. Pharmaceutical composition according to claim 17, characterized in that at least one further pharmaceutically effective compound is included. Pharmaceutical composition according to claim 21, characterized in that as further pharmaceutically effective Combination chemotherapeutic agents, known worm and fungus agents, immunosuppressants, Glycolysis inhibitors or substances that increase the metabolism of parasites promote, are included. A pharmaceutical composition according to claim 22, characterized in that as substances affecting the metabolism promote the parasite, Glucose or 2,4-dinitrophenol be used Inhibitor of the reaction of the glyoxalases I and / or II, containing at least one of the compounds of general formula (I) and / or at least one of the compounds which are converted in the organism to compounds of general formula (I),

where R 1 is a branched or unbranched alkyl, alkenyl, alkynyl or cycloalkyl radical and where R 2 is H or a branched or unbranched alkyl, alkenyl or alkynyl radical. Inhibitor of the reaction of the glyoxalases I and / or II according to claim 24, characterized in that the compounds which are converted in the organism to compounds of the general formula (I) are compounds of the general formulas (II) and / or (III),

where R 1 is a branched or unbranched alkyl, alkenyl, alkynyl or cycloalkyl radical and where R 2 is H or a branched or unbranched alkyl, alkenyl or alkynyl radical. Inhibitor of the reaction of glyoxalases I and / or II according to claim 24, characterized in that the compounds of the general formula (I) methylpyruvate, ethylpyruvate, butylpyruvate, Isobutylpyruvate or ethyl 2-oxo-butyrate. Inhibitor of the reaction of glyoxalases I and / or II according to claim 25, characterized in that the compounds, in the organism converted to compounds of general formula (I) be, L-methyl lactate or D-methyl lactate or a racemic Mixture of L-methyl lactate and D-methyl lactate or L-butyl lactate or D-butyl lactate or a racemic mixture of L-butyl lactate and D-butyl lactate, or L-ethyl lactate or D-ethyl lactate or a racemic Mixture of L-ethyl lactate and D-ethyl lactate or D-isobutyl lactate or L-isobutyl lactate or a racemic mixture of D-isobutyl lactate and L-isobutyl lactate