WO2009074305A1

WO2009074305A1 - Gold xanthogenates and medicaments comprising them

Info

Publication number: WO2009074305A1
Application number: PCT/EP2008/010476
Authority: WO
Inventors: Eberhard Amtmann
Original assignee: Biosphings Ag
Priority date: 2007-12-13
Filing date: 2008-12-10
Publication date: 2009-06-18

Abstract

The invention relates to xanthogenate-gold compounds and to pharmaceutical formulations of these complexes, and also to medicaments which comprise these formulations for treatment of tumour, virus and autoimmune disorders influenced by activated macrophages.

Description

GOLD-XANTHOGENATES AND MEDICAMENTS CONTAINING THEM

The invention relates to xanthate gold compounds and medicaments for the treatment of viral, tumor and autoimmune diseases containing these compounds.

Gold compounds such as auranofin have long been used for the treatment of autoimmune diseases, in particular for the treatment of rheumatism in use. However, all currently available gold compounds are associated with significant systemic side effects. See, for example, "Sulfasalazine has a better efficacy / toxicity profile than auranofin-evidence from a 5 year prospective, randomized trial" McEntegart A, Porter D, Capell HA, Thomson EA, Center for Rheumatic Diseases, Glasgow Royal Infirmary, UK in J Rheumatol 1996 Nov; 23 (11): 1887-90.

It is therefore of great importance to provide new active ingredients with an improved side effect profile. A fundamental problem of the gold compounds available today is due to the untargeted, systemic therapeutic strategy. First, it will hit the entire immune system and thus achieve unspecific suppression. As a result, patients suffer e.g. at an increased risk of infection. Secondly, the uniform distribution in the organism very often unspecific side effects, such as organ damage and allergies, triggered. There is therefore the task of developing new active ingredients with improved selectivity.

Xanthate gold complexes with ethyl, isopropyl and cyclohexyl xanthate ligands have already been prepared in Friebolin W, Schilling G, Zoller M, Amtmann E., Antitumoral activity of non-platinum xanthate complexes. J Med Chem. 2005 Dec 15; 48 (25): 7925-31. All derivatives were insoluble in water. Only the cyclohexylxanthogenate complex could be dissolved in acetone and cytotoxic Effect in cell culture are investigated. It has been found to have a low toxic effect on tumor cells (IC 50 of 50-70 μM). The same publication describes highly active palladium complexes with IC50 between 0.1 and 0.5 μM. From these data it follows that xanthate-gold complexes are not suitable for tumor therapy.

It has now surprisingly been found that in water insoluble xanthate gold compounds are selectively absorbed only by cells of the immune system. The compounds present in fine particles are phagocytosed by the macrophages. In macrophages treated with such gold xanthate particles, the mechanisms leading to endotoxin-induced macrophage activation are inhibited. As a result, factors that stimulate the immune system are no longer formed in the treated macrophages. It is therefore possible with such compounds successfully treat diseases that are triggered by activated macrophages.

Such diseases pose autoimmune diseases, e.g. Crohn's disease and ulcerative colitis dar. But also tumors of the immune system, such as chronic myeloid leukemia come z.T. of macrophage precursors and are therefore accessible to therapy with gold xanthogenates. In addition, some viruses, such as the AIDS virus HIV in macrophages multiply. The proliferation of HIV in macrophages is considered in the literature to be an important step in the manifestation of the infection, lgarshi T et al., Macrophages are the principal reservoir and sustain high virus loads in Rhesus macaques following the depletion of CD4 + T cells by a highly pathogenic SHIV: implications for HIV-1 infections of man. Proc Natl Acad Sci., 98: 658-63 (2001).

The compounds of the invention are particularly suitable for local therapy, such as in the intestine after oral administration. That's the way it is managed to treat inflammatory bowel disease in an animal model (dextran sulfate induced colitis) without any obvious side effects.

The present invention thus achieves the above object by providing drugs containing novel xanthate-gold compounds.

The invention relates to medicaments for the treatment of activated by macrophages diseases, containing compounds having a stoichiometry according to formula (I) ROCSSAu in the R is an optionally mono- or polysubstituted, aryl or alkyl radical.

Preferably, R is a Ci-C ₂ o-alkyl radical, a C ₃ -C ₂₀ - cycloalkyl radical or a C ₆ -C ₈ -aryl radical, where the Ci-C ₂ o-alkyl radical by one or more hydroxyl radicals, a or a plurality of C ₁ -C ₅ -alkyl groups, one or more C 1 -C ₄ -alkoxy groups, one or more halogen atoms and / or one or more amino groups may be substituted, the C ₃ -C ₂ o-cycloalkyl radical by one or more hydroxyl radicals , one or more C ₁ -C ₆ -alkyl groups, one or more C 1 -C ₄ -alkoxy groups, one or more halogen atoms and / or one or more amino groups may be substituted and / or polycyclic and the C ₆ -C ₆ -aryl radical by one or more hydroxyl radicals, one or more C ₁ -C ₆ -alkyl groups, one or more C ₁ -C ₄ -alkoxy groups, one or more halogen atoms and / or one or more amino groups substituted and / or polycyclic and / or one or more heteroatoms in the ring can have.

Preference is given to unsubstituted, straight-chain or C ₁ -C ₆ -alkyl-substituted alkyl radicals and mono- or polycyclic, unsubstituted or d-C ₆ -alkyl-substituted cycloalkyl radicals or aryl radicals, the aryl radicals having one or more heteroatoms in the ring or in the rings can. The alkyl radicals, cycloalkyl radicals or aryl radicals which are substituted by C ₁ -C ₆ -alkyl groups are preferably substituted by one or more methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl or tert-butyl groups. Particularly preferred for R are unsubstituted, straight-chain or C ₁ -C ₃ -alkyl-substituted alkyl radicals and unsubstituted, mono- or polycyclic cycloalkyl radicals or aryl radicals. Very particular preference is given to unsubstituted cycloalkyl radicals and alkyl radicals substituted by one or more methyl, ethyl, n-propyl or isopropyl groups, in particular having one, two or three methyl and / or ethyl groups. Xanthate gold compounds having cyclic or branched alkyl groups have been found to be more stable than straight chain alkyl groups.

Particularly advantageous R is a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, cyclopentyl, n Hexyl, cyclohexyl, n-heptyl, cycloheptyl, n-octyl, cyclooctyl, n-nonyl, n-decyl, cyclodecyl, n-undecyl, n-dodecyl, cyclododecyl, tricyclo [5,2,1, 0 ^2r6 ] decyl, bicyclo [2,2,1] -heptyl, adamantyl, norbornyl, benzyl, furyl, pyridyl, anthracyl, naphthyl, phenanthryl, Perinaphthyl, quinuclidinyl, toluyl, methylbutyl, methylpentyl, dimethylpropyl, dimethylbutyl, methylethylbutyl or methylethylpentyl. Very particularly advantageous are n-propyl, isobutyl and cyclobutyl radicals.

Studies on butyl and ethyl xanthate gold compounds (A. Mohamed, I. Kani, A. Ramirez, J. Fackler, Inorg. Chem. 2004, 43, 3833-3839) have shown that the above formula I only shows the stoichiometry, because in these complexes, according to X-ray structure analysis, two Au atoms are associated with each other, the structure thus corresponds to the following formula II:

In the context of the present invention, therefore, the formula I is to be understood such that the compounds are those having the stoichiometric formula I, while the structural formula may correspond to a monomer, dimer, trimer or any other combination.

The preparation of the gold xanthate according to the invention is preferably carried out by reacting a commercially available gold complex with a xanthate of the formula SH-C (S) -OR, wherein R has the above meaning, in a suitable solvent. The reaction is typically carried out at room temperature, but can be carried out to accelerate the reaction at elevated temperature, for example 30 to 50 ⁰ C. The solvent is especially water. The xanthate can also be used in the form of its salt, for example sodium or potassium salt, or an ester, for example as methyl or ethyl ester. Suitable gold complexes are, for example, NaAuCl ₄ or KAuCl ₄ . The yields are typically very high, in the range of more than 90 mol%.

The compounds are solid, generally in water and in other organic or inorganic solvents insoluble substances. In the preparation described above, by reacting soluble gold complexes with xanthates in solvents, they usually arise as fine crystals, which can be easily separated by filtration from the reaction solution. [00016] The compounds according to the invention have valuable pharmacological properties. They are particularly suitable for the prophylaxis and / or treatment of macrophage-related autoimmune diseases, such as rheumatism, Crohn's disease, ulcerative colitis, tumor diseases of the immune system such as chronic myeloid leukemia and viral infections in which at least one step of virus propagation takes place in macrophages, such as HIV. Accordingly, the present invention provides pharmaceutical compositions for the treatment of viral, tumor or autoimmune diseases containing the compounds. The agents may further contain customary carrier materials and / or customary auxiliaries. It may also contain other active ingredients, as far as they affect neither the effect nor the stability of the xanthates.

The compounds of the invention for the preparation of the medicaments according to the invention, if necessary, first appropriately purified and / or separated into their isomers and / or enantiomers. Suitable processes for purification, isomer and enantiomer separation are known per se to the person skilled in the art. Examples include chromatographic processes, distillation and crystallization. With regard to radicals R, which occur as isomers and / or enantiomers, it is alternatively possible to use already isomerically pure or enantiomerically pure starting materials. For the purposes of the present invention, purity in the context of the present invention is understood as meaning a content of at least 90% by weight, preferably at least 95% by weight and in particular at least 99% by weight. With respect to isomers and enantiomers, "neat" means a proportion of the desired isomer or enantiomer of at least 60% by weight, preferably at least 80% by weight, more preferably at least 95% by weight and most preferably at least 98% by weight. -%. A pharmaceutical preparation of one or more compounds of the formula I is obtained. The resulting pharmaceutical preparations of the compounds of the invention can either be used directly as a drug or processed with one or more conventional additives and / or carriers and optionally other drugs to drugs.

The pharmaceutical formulations of the invention and compositions containing them are useful in the treatment of viral, tumor and autoimmune diseases in which activated macrophages have a crucial influence.

An inventive drug preferably contains 0.1 to 10 wt .-% of the xanthate gold compounds and 99.9 to 90 wt .-% of one or more conventional carrier material or mixture of one or more carrier materials and one or more excipients (s). Preferably, 1 to 5 wt .-% xanthate gold compounds are included.

[00021] The pharmaceutical compositions according to the invention, compounds of formula I containing ₁ according to the invention can be administered enterally or parenterally in liquid or solid form. Here, the usual forms of administration come into question, such as tablets, capsules, lozenges, dragees, syrups, solutions, suspensions, ointments, creams, sprays and suppositories.

With regard to intestinal diseases such as Crohn's disease and Colitis ulcerosa, agents in the form of enteric-coated capsules are preferred.

For liquid, parenteral dosage forms such as injection solutions comes as a carrier material preferably water used, which contains the usual additives for injection solutions such as stabilizers, solubilizers and buffers. Such additives are z. B. tartrate and citrate buffer, ethanol, Complexing agents such as ethylenediaminetetraacetic acid and its non-toxic salts, high molecular weight polymers such as liquid polyethylene oxide for viscosity control. Liquid carriers for injection solutions must be sterile and are preferably filled into ampoules.

For solid oral dosage forms such as tablets, capsules, dragees, etc. are solid carriers such as starch, lactose, mannitol, methyl cellulose, talc, highly disperse silicic acids, higher molecular weight fatty acids, such as. Stearic acid, gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular weight polymers such as polyethylene glycols, etc. Liquid oral dosage forms typically contain, in addition to water, alcohols and / or suitable thickeners, e.g. Methylcellulose or polyethylene glycols. Preparations suitable for oral applications may, if desired, contain flavorings or sweeteners. As auxiliaries, for example: disintegrants, stabilizers, emulsifiers, preservatives, antioxidants such as fats or polymers, ion exchangers or polymers for retarding, dyes, etc.

Parenteral dosage forms such as ointments, creams, etc. usually contain as carrier material, a water-in-oil or oil-in-water emulsion or an oily spreadable base such as paraffin. In addition, additives such as stabilizers, emulsifiers, preservatives and / or fragrances can be included.

The dosage may depend on various factors, such as route of administration, species, age or individual condition. The compounds according to the invention are usually administered in doses of 0.1-100 mg per kg of body weight per day, preferably 0.2-80 mg per kg of body weight per day, and particularly preferably 10 to 50 mg per kg of body weight per day. It is preferred to distribute the daily dose to 1 to 5 applications, with 1 to 2 solid or liquid administration forms having an active ingredient content of 0.5 to 500 mg being administered for each application. The tablets, capsules, dragees, etc. may also be retarded, reducing the number of applications per day to 1 - 3. The active substance content of the delayed-release tablets can be 2 to 1000 mg. The active ingredient may also be administered by 1 to 3 parenteral applications or by continuous infusion, with amounts of 5 to 1000 mg per day normally sufficient.

In the combination of compounds of the formula I with one or more further active compounds, the active compounds can be used either in fixed combination in the same application form, e.g. Tablet or ampoule, or in one or more different forms of administration. The latter is necessary if the active ingredients to be combined e.g. are not compatible with each other, e.g. because it comes to reactions during storage. Of course, even with a combination of three or more active ingredients, these can all be prepared in fixed combination in one application form or else in two or more administration forms and applied in free combination.

The invention further relates to Xanthogent gold complexes having a stoichiometry according to formula I, in which R is an aryl or alkyl radical, optionally mono- or polysubstituted, with the exception of unsubstituted methyl, ethyl, propyl, butyl and Cyclohexyl stands.

Preferably, R is an unsubstituted C ₅ -C ₂ o-alkyl radical, an unsubstituted C ₃ , C ₄ , C ₅ , or C ₇ -C ₂ o-cycloalkyl radical or an unsubstituted C ₆ -C ₁₈ -aryl radical, or for a substituted _{Ci-C2o-alkyl,} _{C3-C2o-cycloalkyl} radical or C ₆ -C ₈ aryl, wherein said _Ci-C2o-alkyl radical by one or more hydroxyl radicals, one or more alkyl groups CRCI ₅ , one or more C 1 -C ₄ -alkoxy groups, one or more halogen atoms and / or one or more Amino groups may be substituted, the C ₃ -C ₂ o-cycloalkyl radical by one or more hydroxyl radicals, one or more Ci-C ₆ alkyl groups, one or more C _r C ₄ alkoxy groups, one or more halogen atoms and / or one or more Amino groups may be substituted and / or polycyclic and the C ₆ - Ci ₈ aryl group by one or more hydroxyl groups, one or more Ci-Cβ-alkyl groups, one or more CrC ₄ alkoxy groups, one or more halogen atoms and / or one or more Amino groups may be substituted and / or polycyclic and / or may have one or more heteroatoms in the ring.

Preferred for R are unsubstituted, straight-chain or substituted with C-ι-C ₆ alkyl groups alkyl radicals and mono- or polycyclic, unsubstituted or substituted with C-rCβ-alkyl cycloalkyl radicals or aryl radicals, wherein the aryl radicals one or more heteroatoms may have in the ring or in the rings. The alkyl radicals, cycloalkyl radicals or aryl radicals which are substituted by C ₁ -C ₆ -alkyl groups are preferably substituted by one or more methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl or tert-butyl groups. Particularly preferred radicals R are unsubstituted, straight-chain or C ₁ -C ₃ -alkyl-substituted alkyl radicals and unsubstituted, mono- or polycyclic cycloalkyl radicals or aryl radicals. Very particular preference is given to unsubstituted cycloalkyl radicals and alkyl radicals substituted by one or more methyl, ethyl, n-propyl or isopropyl groups, in particular having one, two or three methyl and / or ethyl groups. Xanthate gold compounds having cyclic or branched alkyl groups have been found to be more stable than straight chain alkyl groups.

Particularly advantageous R is a tert-butyl, cyclobutyl, n-pentyl, isopentyl, cyclopentyl, n-hexyl, n-heptyl, cycloheptyl, n-octyl, cyclooctyl, n- Nonyl, n-decyl, cyclodecyl, n-undecyl, n-dodecyl, cyclododecyl, tricyclo [5,2,1,0 ² ' ⁶ ] decyl, bicyclo [2,2,1] - Heptyl, adamantyl, norbornyl, benzyl, Furyl, pyridyl, anthracyl, naphthyl, phenanthryl, perinaphthyl, quinuclidinyl-toluyl, methylbutyl, methylpentyl, dimethylpropyl, dimethylbutyl, methylethylbutyl or methylethylpentyl. In particular, R is selected from 4-O-cyclohexyl, iso-butyl (would correspond to the formula AuX8), 2-methylbutyl, n-decyl, benzyl, cyclopentyl, cyclobutly, and 5-hydroxy-n-pentyl radicals.

The following examples further illustrate the invention without, however, limiting it. Unless otherwise stated, in the context of the present invention all percentages and parts are by weight, in case of doubt the total weight of the mixture.

Example 1:

To prepare gold propyl xanthogenate C ₃ H ₇ OCSSAu, 333 mg of KAuCU (0.87 mmol) were dissolved in 2 ml of water and added dropwise to a solution of 909 mg of propyl xanthogenate (5.22 mmol) in 5 ml of water. After stirring for 20 min at room temperature, the product was filtered off and dried in vacuo for 24 h. Yield: 310 mg = 93%. (MW 332,14)

Example 2

The inhibition of endotoxin-induced macrophage activation by gamma-methylxanthogenate was determined. For this J774 macrophage cells were seeded in 96 well plates (3 x 10 ⁶ cells / plate). After 24 h, the cells were fed with fresh cell culture medium containing 0.1 μg / ml lipopolysaccharide (LPS) from E. coli. Control cells received fresh medium without LPS. The cells in each case three culture holes were treated additionally with 100, 50, 25, 12.5, 6.3, 3.2, and / or 1.6 μg / ml Goldmethylxanthogenat or Platinmethylxanthogenat. After 24 h incubation at 37 ° C, the supernatants were removed and the NO content in the culture media by the Griess reaction, as in Amtmann E, Baader W, Zoller M. neutral sphingomyelinase inhibitor C11AG prevents lipopolysaccharide-induced macrophage activation. Drugs Exp Clin Res. 2003; 29 (1): 5-13 described, determined. The number of cells remaining in the culture holes was determined by crystal violet staining and OD measurement in the ELISA reader as described in Amtmann E, Baader W, Zoller M. Neutral sphingomyelinase inhibitor C11AG prevented lipopolysaccharide-induced macrophage activation. Drugs Exp Clin Res. 2003; 29 (1): 5-13 described. The mean values of the NO concentration and the cell density were plotted against the goldmethylxanthogenate concentration in dose-response curves, and the concentration each causing a 50% inhibition (IC50) was calculated. The results are shown in Table 1.

Table 1

The high specificity of the gold compound and the superiority to other heavy metal compounds such as the analogous platinum derivative can be seen in the therapeutic index. While the gold compound shows a therapeutic index greater than 16.1, the difference between the cytotoxic and NO inhibitory effects is less than 2 for the platinum compound.

Example 3

The suppression of dextran sulfate-induced mouse colitis by goldmethylxanthogenate was investigated. For this purpose, female mice (BaIb C, 8 weeks old) were purchased from Charles River and kept under SPF conditions (specific pathogen free). The animals were given Altromin standard diet and water ad libitum. Colitis was induced by the addition of 7.5% dextran sulfate (DSS) (MW 36,000 - 50,000, ICN ₁ Aurora, Ohio, lot 2387F) in drinking water. After 5 days, dextran sulfate-free water was again added. The treatment with gold methylxanthogenate was done with a nasogastric tube once a day. The active ingredient was suspended in water containing 1% methyl cellulose. 0.2 ml suspension was administered per 20 g body weight. Placebo animals were given drug-free methyl cellulose / water mixture.

Treatment groups:

5 animals placebo

5 animals 30 mg / kg goldmethylxanthogenate per day

The treatment started simultaneously with the dextran sulfate treatment. Experimentally induced dextran sulfate colitis is characterized by significant body weight loss. The weight course is generally used to measure the severity of the disease, cf. Aharoni R, Sonego H, Brenner O, Eilam R, Arnon R. The therapeutic effect of glatiramer acetate in a murine model of inflammatory bowel disease is mediated by anti-inflammatory T-cells. Immunol Lett. 2007, 112 (2): 110-9. The course of the body weights is shown in FIG. It can be clearly seen that treatment with gold methyl xanthate (referred to as MethAuX) caused a significant improvement. In placebotieren rapid body weight loss was observed. On day 4, the animals lost on average more than 3 grams. After completion of the dextran sulfate treatment, the animals recovered again. The animals treated with goldmethylxanthogenate according to the invention first gained weight. On days 4 and 5, a slight weight loss was observed. The weight loss compared to the initial weight was only a maximum of 1.2 g (day 5). After discontinuation of the dextran sulfate a continuous increase in weight was observed. Example 4

Gold furyl xanthate (AuX-2) was prepared as follows. 1.0 g (4.25 mmol) 1-5-

O-cyclopentyl-3-xanthogenate of the formula

C ₆ HQKO ₂ S ₂ 216.35 were dissolved in 4 ml of water. 330 mg of KAuCl ₄ (0.79 mmol) dissolved in 2 ml of water were added dropwise over 12 minutes. After 30 minutes, the precipitate was filtered off with suction and washed with 2 ml of water. It was first dried in the air for 20 minutes and then in a high vacuum for 2 hours. 475 mg of an ocher solid were obtained. The product could be dissolved in CDCI ₃ .

Example 5

Gold isobutylxanthogenate (AuX-8) was prepared as follows. 1, 0 mg of 2-methyl-butyl-xanthogenate of the formula

C ₅ H ₉ KOS ₂ 188.34 were dissolved in 4 ml of water, 328 mg of KAuCl ₄ dissolved in 2 ml of water were added dropwise over 10 minutes (orange / brown precipitate, which clumped together after a few minutes). After 30 minutes, the supernatant Solution decanted off. The residue was dried under high vacuum. After washing with ethanol, it was dried in vacuo. Yield: 0.270 g. The product could be dissolved in DMSO.

Example 6

Gold n-decylxanthogenate (AuX-7) was prepared as follows. 1, 0 g of n-decyl xanthogenate of the formula

C ₁ ] H ₂₁ KOS ₂

272.51 were dissolved in 15 ml of water, then 331 mg KAuCl ₄ dissolved in 2 ml of water were added dropwise within 12 minutes (light yellow, very fine precipitate). After aspirating and drying, 110 mg of light yellow solid were obtained. The product could be dissolved in acetone.

Example 7

Gold benzyl xanthogenate (AuX-5) was prepared as follows. 0.82 g of phenylmethyl xanthogenate of the formula

C ₈ H ₇ KOS ₂

222.36 were dissolved in 2 ml of water; 320 mg of KAuCl _{4 dissolved} in 2 ml of water were added dropwise within 8 minutes, first an orange-brown precipitate which rapidly became light yellow and clumped together. The supernatant solution was decanted off, the residue was suspended in dichloromethane and on Concentrated rotary evaporator and dried under high vacuum. It was then washed with ethanol and dried in vacuo. Yield: 0.250 g (light yellow, solid). The product could be dissolved in acetone.

Example 8

Gold cyclopentyl xanthate (AuX-6) was prepared as follows. 0.83 g (4.12 mmol)

Cyclopentyl xanthate of the formula

C ₆ H ₉ KOS ₂ 200.36 were dissolved in 4 ml of water; 0.33 g of KAuCl _{4 dissolved} in 2 ml of water were added dropwise within 15 minutes. It formed brown precipitate, which agglomerated at the end of the addition. The precipitate was suspended in 5 ml of dichloromethane, concentrated on a rotary evaporator and dried under high vacuum. It was then washed with ethanol and dried in vacuo. The product was poorly soluble in chloroform, methanol and acetone. Yield: 0.21 g of brown solid.

Example 9

Gold 5-hydroxy-n-pentyl xanthogenate (AuX-3) was prepared as follows. 1, 00 g 5-

Hydroxy-n-pentyl-1-xanthogenate of the formula

C ₆ H _{1 1} KO ₂ S ₂ 218.37 were dissolved in 4 ml of water, 300 mg of KAuCl ₄ dissolved in 2 ml of water were added dropwise over 10 minutes (very dark precipitate, which turned yellow). The precipitate was filtered off with suction and dried under high vacuum. Yield: 357 mg. The product could be dissolved in acetone.

Example 10

Goldcyclobutylxanthogenate (AuX-4) was prepared as follows. 1, 0 g cyclobutyl xanthogenate of the formula

C ₅ H ₇ KOS ₂ 186.33 was dissolved in 4 ml of water, 0.322 g of KAuCl 4 dissolved in 2 ml of water were added dropwise within 10 minutes (orange-red precipitate). After 30 minutes, the precipitate was filtered off, washed with 2 ml of water and dried under high vacuum. Yield: 375 mg.

Example 11

The inhibition of endotoxin-induced macrophage activation was determined as follows. J774 mouse macrophages were cultured on Eagef's basal medium with 10% fetal calf serum. 3 × 10 ⁶ cells were seeded in 96-well plates. After 24 h, the test substances were suspended (1 mg / ml stock suspended in water: AuX-2, AuX-7, AuX-3, suspended in 50% acetone: AuX-4, AuX-5, AuX-6, AuX-8 ) in various concentrations (in triplicate). One hour later, the cells were treated with 10 ng / ml E. coli lipopolysaccharide (LPS). After 24 h incubation at 37 ⁰ C, the supernatants were removed and nitrite concentration is determined by means of the Gries reaction. Nitrite production is a measure of NO synthase activity that allows quantitative determination of macrophage activation. The nitrite content was determined in the ELISA reader at OD 450 nm. The means of OD were plotted against the concentration and the concentration at which 50% inhibition was present (IC50) determined. The results are shown in Table 2.

Table 2

All substances inhibit LPS-induced NO production and are therefore inhibitors of LPS-induced macrophage activation. Particularly effective is gold 5-hydroxy-n-pentylxanthogenate (AuX-3).

Claims

claims

1. A medicament for the treatment of activated macrophages influenced viral, tumor or autoimmune diseases, characterized in that at least one xanthate gold compound of the general formula (I) ROCSSAu in the R for one, optionally mono- or polysubstituted, aryl or alkyl radical stands, is included.

2. Medicament according to claim 1, characterized in that R is a Ci-C ₂ o-alkyl radical, a C ₃ -C ₂ o-cycloalkyl radical or a C ₆ -C ₈ -aryl radical, where the Ci-C ₂ o- Alkyl radical by one or more hydroxyl radicals, one or more C ₁ -C ₄ alkoxy, one or more Ci-C _1S - alkyl groups, one or more halogen atoms and / or one or more amino groups may be substituted, the C ₃ -C ₂ o Cycloalkyl radical may be substituted by one or more hydroxyl radicals, one or more C 1 -C ₆ -alkyl groups, one or more C 1 -C ₄ -alkoxy groups, one or more halogen atoms and / or one or more amino groups and / or polycyclic and the C ₆ -Ci ₈ -aryl radical by one or more hydroxyl radicals, one or more C _r C ₆ alkyl groups, one or more dC ₄ alkoxy groups, one or more halogen atoms and / or one or more amino groups substituted and / or polycyclic be and / or or may have a plurality of heteroatoms in the ring.

3. A pharmaceutical composition according to claim 1, characterized in that R is an unsubstituted, straight-chain or substituted with Ci-C _δ alkyl groups alkyl radical, a mono- or polycyclic, unsubstituted or substituted with Ci-Cβ- alkyl groups cycloalkyl radical or aryl radical, wherein the Aryl radicals may have one or more heteroatoms in the ring or in the rings.

4. Medicament according to claim 1, 2 or 3, characterized in that the alkyl groups substituted with alkyl groups, cycloalkyl radicals or aryl radicals are substituted by one, two or three methyl, ethyl, n-propyl and / or isopropyl groups.

5. Medicament according to claim 1, characterized in that R is a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl , Cyclopentyl, n-hexyl, cyclohexyl, n-heptyl, cycloheptyl, n-octyl, cyclooctyl, n-nonyl, n-decyl, cyclodecyl, n-undecyl, n-dodecyl , Cyclododecyl, tricyclo [5,2,1, 0 ^{2 6} ] -decyl, bicyclo [2,2,1] -heptyl, adamantyl, norbornyl, benzyl, furyl, pyridyl, anthracyl, Naphthyl, phenanthryl, perinaphthyl, quinuclidinyl, toluyl, methylbutyl, methylpentyl, dimethylpropyl, dimethylbutyl, methylethylbutyl or methylethylpentyl.

6. A pharmaceutical composition according to any one of claims 1 to 5, characterized in that one or more carrier materials are contained.

7. A pharmaceutical composition according to any one of claims 1 to 6, characterized in that one or more auxiliaries are included.

8. A pharmaceutical composition according to any one of claims 1 to 7, characterized in that one or more further active ingredients are contained.

9. Medicament according to at least one of claims 1 to 8, characterized in that it is an ointment, cream, capsule, tablet, dragee, juice, solution, suspension or a solid for the preparation of solutions or suspensions.

10. A pharmaceutical composition according to any one of claims 1 to 9, characterized in that it is an injection solution or a capsule, in particular an enteric capsule.

11. A pharmaceutical composition according to any one of claims 1 to 10, characterized in that the xanthate gold compound is selected from gold methylxanthogenate, gold ethylxanthogenate, Goldpropylxanthogenat, Goldcyclobutylxanthogenat, Goldcyclopentylxanthogenat and mixtures thereof.

12. xanthate gold compounds having a stoichiometry according to formula (I) ROCSSAu in the R for one, optionally mono- or polysubstituted, aryl or alkyl radical with the exception of a methyl, ethyl, propyl, n-butyl, isobutyl and Cyclohexylrestes stands.

13. A compound according to claim 12, characterized in that R is a substituted Ci-C ₂ o-alkyl radical, an unsubstituted C ₅ -C ₂ o-alkyl radical, an unsubstituted C ₃ , C ₄ , C ₅ , or C ₇ -C ₂ o-cycloalkyl radical, a substituted C ₃ -C ₂ o-cycloalkyl radical or a substituted or unsubstituted C ₆ -C ₁₈ -aryl radical, and wherein the substituted C ₁ -C 2 ₀ - alkyl radical by one or more hydroxyl radicals, one or more more -C ₄ - alkoxy groups, one or more Ci-cis-alkyl groups, one or more halogen atoms and / or one or more amino groups may be substituted, the substituted C ₃ -C ₂ o-cycloalkyl by one or more hydroxyl radicals, one or more CrCβ Alkyl groups, one or more C 1 -C ₄ alkoxy groups, one or more halogen atoms and / or one or more amino groups may be substituted and / or polycyclic and the Cδ Ciβ aryl radical by one or more hydroxyl radicals, one or more Ci-C _6- alkyl groups, one or more C 1 -C ₄ -alkoxy groups, one or more halogen atoms and / or one or more amino groups substituted and / or polycyclic and / or may have one or more heteroatoms in the ring.

14. A compound according to claim 12, characterized in that R is tert-butyl, cyclobutyl, n-pentyl, isopentyl, cyclopentyl, n-hexyl, n-heptyl, cycloheptyl, n-octyl, cyclooctyl -, n-nonyl, n-decyl, cyclodecyl, n-undecyl, n-dodecyl, cyclododecyl, tricyclo [5,2,1, 0 ²ⁱ⁶ ] decyl, bicyclo [2,2,1 ] -Heptyl, adamantyl, norbomyl, benzyl, furyl, pyridyl, anthracyl, naphthyl, phenanthryl, perinaphthyl, quinuclidinyl, toluyl, methylbutyl, methylpentyl, dimethylpropyl, dimethylbutyl, Methylethylbutyl or methylethylpentyl stands.

15. A compound according to claim 12, characterized in that R is selected from 4-O-cyclohexyl, iso-butyl 2-methylbutyl, n-decyl, benzyl, cyclopentyl, cyclobutly, and 5-hydroxy-n- pentyl.

16. A compound according to claim 12, characterized in that it is gold-5-hydroxy-n-pentylxanthogenate.

17. A method of treating activated macrophage affected tumor, viral and autoimmune diseases comprising the steps of: identifying a patient in need of treatment and administering an effective dose of a drug according to any one of claims 1 to 11 for a time sufficient for treatment in a treatment effective Dosage.

18. The method according to claim 17, characterized in that the patient is a mammal or human.

19. The method according to claim 17 or 18, characterized in that the disease is rheumatism, Crohn's disease, ulcerative colitis, chronic myeloid leukemia or HIV.