Tannin derivative and pharmaceutical compositions comprising said tannin derivative

The present invention relates to a tannin derivative, in particular tannin derivative having antibiotic activity and pharmaceutical compositions comprising said tannin derivative.

Tannins are distributed in species throughout the plant kingdom. They are commonly found in both gymnosperms as well as angiosperms. A tannin (also known as vegetable tannin, natural organic tannins or sometimes tannoid, i.e. a type of biomolecule, as opposed to modern synthetic tannin) is an astringent, bitter plant polyphenolic compound that binds to and precipitates proteins and various other organic compounds including amino acids and alkaloids. The term tannin in the context of the present invention comprises any large polyphenolic compound containing sufficient hydroxyls and other suitable groups (such as carboxyls) to form strong complexes with proteins and other macromolecules.

The tannin compounds play a key role in protection of plants from predation by fungi, insects and other abiotic agents. Tannin compounds are also supposed to play a key role as pesticides, and in plant growth regulation. The astringency of tannins is what causes the dry and puckery feeling in the mouth following the consumption of unripened fruit or red wine. Likewise, the destruction or modification of tannins with time plays an important role in the ripening of fruit and the aging of wine.

Tannins have molecular weights ranging from 500 to over 3,000 (gallic acid esters) and up to 20,000 (proanthocyanidins). Tannins are incompatible with alkalis, gelatin, heavy metals, iron, limewater, metallic salts, strong oxidizing agents and zinc sulfate, since they form complexes and precipitate in aqueous solution.

It is known in the art that when incubated with substances having a high content of condensed tannins, the poliovirus, herpes simplex virus, and various enteric viruses are inactivated. Tannins have thus shown potential antiviral, antibacterial and antiparasitic effects. It was also confirmed that tannins isolated from the stem bark also have antiinflammatory and antiulcer activity in rodents, showing a strong antioxidant property with possible therapeutic applications.

Tannin derivative galloyi glucose is a chemical compound formed from gallic acid and β- D-glucose. It can be found in oaks species like the North American white oak (Quercus alba) and European red oak (Quercus robur) and may be synthesized artificially. Galloyi glucose is formed by a gallate 1 -beta-glucosyltransferase (UDP-glucose: gallate glucosyl transferase), an enzyme performing the esterification of two substrates, UDP- glucose and gallate to yield two products, UDP and 1 -galloyl-beta-D-glucose (glucogallin). This enzyme can be found i.a. in oak leaves preparations.

Galloyi glucose carbon acid esters are substances having various properties that are about to exhibit pharmacological interest. Synthesis currently used provide for a derivatisation of gallic acid and coupling said gallic acid with glucose to yield galloyi glucose directly employable as antibiotic agent. The present invention however provides for the derivatisation of the entire molecule of galloyi glucose wherein the hydroxy groups of galloyi glucose become chemically modified.

US 2002/151582 (Tea polyphenol esters and analogs thereof for cancer prevention and treatment) dicloses an ester of pentagalloyl-monogallic acid. Molecukes presented in this document are Epigallocatechines with no glucose molecule incorporated in the basic structure

US2008/0319185 discloses pentagalloyl glucose having hydroxy groups of gallic acid derivatized with benzen groups for mere stabilisation purposes.

Enzymatic esterification is the first step in the biosynthesis of galloyi glucose or gallotannins. The molecule is then used by enzymes in the gallotannins synthetis pathway like beta-glucogallin O-galloyl transferase or beta-glucogallin-tetra-cis-galloyl glucose O-galloyl transferase.

Prior art anti-infective drug substances such as classical antibiotics have the disadvantage of decreasing efficiency due to increasing host resistance. Further these substances are found only effective against bacterial infections. Due to increasing occurrence of e.g. bacterial and fungal co-infections there is an increasing need of drug substances with increased efficiency against multiple microbial agents.

The present invention provides for tannin derivatives and a pharmaceutical compositions comprising said tannin derivative, effective for the treatment of multiple infections by different microbial agents. Furthermore, the tannin of the inventions provides for a vehicle to co-administer antimicrobial and other drug substances to a subject in need thereof. The invention thus provides for a molecule that may be applied in the synthesis of various drug substances useful for the synthesis of pharmaceutical compositions useful for treating co-infective diseases.

The invention provides for tannin derivative, in particular tannin derivative having antibiotic activity, obtained by covalent coupling of at least one organic acid with at least one tannin. The main aspect of the present invention is, that the covalent coupling is formed as an ester or ether bond. The acid residue thus provides at least one functional group for covalently coupling at least one pharmaceutically active ingredient.

In one embodiment of the present invention there is provided a tannin derivative in which the at least one organic acid provides one or more aromatic groups.

In yet another embodiment of the present invention there is provided a tannin derivative wherein the at least one tannin provides one or more substitutable hydroxyl groups.

In a further embodiment of the present invention the at least one tannin is selected from the group consisting of 1 -galloyl glucose, 2-galloyl glucose, tri-galloyl glucose, 4-galloyl glucose, penta-galloyl glucose or mixtures thereof.

In a preferred embodiment of the present invention the aromatic acid is selected from the group consisting of aromatic carboxylic acids such as amines, halogens and/or hydroxyl-containing aromatic carboxylic acids, benzoic acid or derivatives and/or mixtures thereof.

Preferably the tannin derivative provides a coupling of two or more identical or different aromatic acids, in particular wherein the aromatic acid is a pharmaceutically acceptable acid. In a further embodiment of the invention the at least one pharmaceutically active ingredient covalently coupled to the at least one functional group is selected from the group consisting of antibiotics, antifungals, cytostatics, antivirals, fungistatics, analgesics or combinations thereof.

It is particularly preferred if the at least one pharmaceutically active ingredient is selected from the group consisting of HIV-, HCV-, HBV, HSV, HRSV, HRV and VZV- effective antivirals or combinations thereof. The tannin derivative of the invention thus provided antibiotic properties via the basic tannin structure or compound whereas this properties are completed by an antiviral property. The preferred embodiment ma ythus be empoyed in the treatment of multiple infections with various pathogens in general requiring different active agents. The invention composition thus enables treatment of different pathogens with a single multiactive compound.

In a further embodiment of the invention in the tannin derivative the at least one pharmaceutically active ingredient is selected from the group consisting of β-lactame antibiotics, gram-positive effective antibiotics, gram negative effective antivbiotics, polypeptide antibiotics, chinolone antibiotics, polyketide antibiotics, sulfionamiude antibiotics, amino glucoside antibiotics or combinations thereof. The pharmaceutically active ingredient thus increases the efficiency of the underlying tannin derivative and provides for a broader range of antibiotic activity of the compound. Treatment of bacteria with increased resistance can thus be achieved with a single coumpound by different ways of pharmaceutical activity.

In a further embodiment the at least one pharmaceutically active ingredient is selected from the group consisting of polyene antifungals, midazole, triazole, and thiazole antifungals, allylamines echinocandins or combinatons thereof. The tannin derivative thus combines antibiotic with antifungal activity. The invention tannin derivative thus provide for a pharmaceutical compositions useful for treating co-infective diseases.

In a particularly preferred embodiment the at least one pharmaceutically active ingredient is selected from the group consisting of 7-aminocephalosporanic acid, acetylsalicylic acid, alanine, benzoic acid, benzylpenicillic acid, benzylpenicilloic acid, biotine, caprylic acid, cinnamic acid, cystein, dihydrofolic acid, folic acid, folinic acid, glutaminic acid, glycine, histidine, hydroxybenzoic acid, leucine, linoleic acid, lysine, nicotinic acid, p-aminobenzoic acid, p-aminosalicylic acid, phenylacetic acid,

phenoxyacetic acid, phenylacrylic acid, serine, styrylacetic acid, (S)-2-{4-[(2-4- diaminopteridin-6-yl methyl) methylamino] benzoylamino} pentandi acid, threonine, tryptophane, tyrosine, valine, sorbic acid, 1 ,2,4-triazol-3-carboxylic acid, 3-(thienyl)- malonic acid, 4-morpholine carboxylic acid, amethopterine (methotrexate), 9-(2- carboxyethoxymethyl)-guanin, 4-thiazolidincarbon acid, imidazolacrylic acid, or derivatives and/or combinations thereof.

Preferably the tannin derivative, in particular tannin derivative having antibiotic activity, obtained by covalent coupling of at least one organic acid with at least one tannin provides for the covalent coupling being formed as an ester or ether bond. In a particular embodiment contemplated by the present invention the acid residue provides at least one functional group for covalently coupling two or more pharmaceutically active ingredients. The pharmaceutically active ingredients are preferably functionally and/or structurally identical or similar or functionally and/or structurally different. The invention tannin derivative provides for integration of pharmaceutically active ingredients within molecule, whereas the pharmaceutically active ingredients and thus the molecule are adapted to treatment of various infections or infective indications occuring in an individual simultaneously or consecutively. Preferably said two or more

pharmaceutically active ingredients, in particular functionally and/or structurally identical or functionally and/or structurally different pharmaceutically active ingredients are selected from the group consisting of antibiotics, preferably β-lactame antibiotics, gram- positive effective antibiotics, gram negative effective antivbiotics, polypeptide antibiotics, chinolone antibiotics, polyketide antibiotics, sulfionamiude antibiotics, amino glucoside antibiotics, antifungals, preferably polyene antifungals, midazole, triazole, and thiazole antifungals, allylamines or echinocandins, cytostatics, antivirals, preferably HIV-, HCV-, HBV, HSV, HRSV, HRV and VZV-effective antivirals and fungistatics, analgesics. It is a particular advantage of the present invention that combinations of the aforesaid active ingredients may be combined in a single molecule. The effect of co-administration may thus be achieved by a single adaptive molecule combining several in particular complementary pharmaceutically active ingredients.

In an embodiment of the latter tannin derivative the two or more pharmaceutically active ingredients, in particular functionally and/or structurally identical or similar or functionally and/or structurally different pharmaceutically active ingredients are selected from the group consisting of 7-aminocephalosporanic acid, acetylsalicylic acid, alanine, benzoic acid, benzylpenicillic acid, benzylpenicilloic acid, biotine, caprylic acid, cinnamic acid, cystein, dihydrofolic acid, folic acid, folinic acid, glutaminic acid, glycine, histidine, hydroxybenzoic acid, leucine, linoleic acid, lysine, nicotinic acid, p-aminobenzoic acid, p-aminosalicylic acid, phenylacetic acid, phenoxyacetic acid, phenylacrylic acid, serine, styrylacetic acid, (S)-2-{4-[(2-4-diaminopteridin-6-yl methyl) methylamino]

benzoylamino} pentandi acid, threonine, tryptophane, tyrosine, valine, sorbic acid, 1 ,2,4- triazol-3-carboxylic acid, 3-(thienyl)-malonic acid, 4-morpholine carboxylic acid, amethopterine (methotrexate), 9-(2-carboxyethoxymethyl)-guanin, 4-thiazolidincarbon acid, imidazolacrylic acid, or derivatives and/or combinations thereof.

In one embodiment of the tannin derivative according to the invention the tannin derivative is selected from a composition of formula (A),

wherein R independently represents at least one covalently coupled pharmaceutically active ingredient as defined above, in particular wherein R represents the same, similar or different pharmaceutically active ingredients.

In a further embodiment, the tannin derivative is selected from a composition of formula (B),

wherein R independently represents at least one covalently coupled pharmaceutically active ingredient as defined above, in particular wherein R represents the same, similar or different pharmaceutically active ingredients.

In a further embodiment the tannin derivative is selected from a composition of formula (C),

wherein R independently represents at least one covalently coupled pharmaceutically active ingredient as defined above, in particular wherein R represents the same, similar or different pharmaceutically active ingredients.

In all of the aformentioned embodiments the tannin derivative provides for a multitude of binding sites for pharmaceutically active ingredients. Thus a macromolecule may be synthesised comprising on or more pharmaceutically active ingredients. The antibiotic activity of the underlying tannin may thus be combined with further pharmaceutical activity and allow for co-administration of pharmaceutically active ingredients thus increasing efficiency of treatment and reducing potential negative side effects.

Formula A shows galloyi glucose derivatised with p-aminobenzic acid, p-aminobenzic acid can be replaced by other pharmaceutically active molecules such as other carbon acids. Coupling is effected by an ester group as shown in formula A. However ester group may be substituted by an ether group or any other chemical binding agent as shown e.g. in formula B. An extension of the pharmaceutically active band width can be achieved by chemically binding further pharmaceutically active molecules (e.g. as defined above) to galloyi glucose. In particular long chained carbon acids could improve membrane permeability of the molecule. Additionally coupling with e.g. vitamine molecules can be useful for infiltration of bacterial cells. A particularly preferred active variant is the additional or sole coupling of beta-lactame molecule. Formula C suggests how a terminal amino group of derivated galloyi glucose as shown in formula A can be coupled using Hantzsch reaction with a further pharmaceutically active group of molecules.

As the basic molecule of galloyi glucose is able to form complexes of iron ions and to unspecifically denature proteins, the derivatisation of galloyi glucose as described above further provides additional modes of action against pathogens.

As in for example pentagalloyl glucose there are 15 hydroxy groups ready for derivatisation, a wide range of variation exists. Pharmaceutically active ingredients are used to merely influence only a single enzymatically important mechanism. The derivatisation as described above provides the possibility of influencing or even block multiple or different biochemical activities using a single molecule. The invention particularly aims at pathogens that tend to form multiple resistances and provides several modes of action by selcting suitable pharmaceutically active ingredients such as a combination of antivirals and antibiotics or antibiotics and antifungals or antifungals, antibiotics and antivirals. This could be used in the treatment of multiple simultaneous or sequential infections with different or various pathogen (fungi, virus, bacteria etc.) related to diseases such as for example HIV infections.

The present invention also provides for a pharmaceutical composition comprising or consisting of at least one tannin derivative as defined above. In a preferred embodiment of the present invention said pharmaceutical composition has a solid, orally administrable form, a liquid, orally administrable form, an injectably administrable form or in form of an ointment, an emulsion or a suspension.

The dosage form comprises a mixture of pharmaceutical composition and excipients and may be pressed or compacted from a powder into a solid dose or mixed to form a liquid orally administrable form, an injectably administrable form or an ointment, an emulsion or a suspension. The excipients can include but are not limited to diluents, binders or granulating agents, flow aids and lubricants to ensure efficient tabletting; disintegrants to promote tablet break-up in the digestive tract; sweeteners or flavours to enhance taste; and pigments to make the tablets or other adminstrable forms visually attractive. The pharmaceutical composition may be provided in a form administrable orally, sublingually, buccally, rectally or intravaginally. Further contemplated administrable forms are syrups, elixirs, suspensions, and emulsions.

Derivatives, in particular of galloyi glucose and aromatic carbon acids as well as combinations of galloyi glucose and derivatives of the latter, preferably comprising amino, halogen or hydroxyl groups exhibit strong antimicrobial properties.

To ensure membrane permeability derivatives of the molecule preferably have a terminal carbon chain of suitable length.

The galloyi glucose derivative metabolized in a pathogen, i.e. a bacterial cell, denatures proteins which, in the case of bacteria may avoid formation of resistance.

Furthermore, galloyi glucose derivative is able to form a complex with iron ions. This process will result in a reduction of iron availability within the microbial cell.

Tannin derivatives of the present invention thus provide antibacterial, antifungal, antiviral activity. Due to free hydroxyl groups anticancerogen activity is encompassed as well.

The present invention contemplates a method for producing a tannin derivatives, comprising the steps of i) providing a tannin, and ii) covalently coupling at least one aromatic acid or an acid derivative with at least one hydroxyl group of the tannin and iii) covalently coupling at least one pharmaceutically active ingredient as specified above with at least one functional group defined by the aromatic acid residue of the tannin derivative as specified above. In an embodiment of the invention method ii) covalently coupling at least one aromatic acid or an acid derivative with at least one hydroxyl group of the tannin provides for an esterification or etherification of the aromatic acid or acid derivative in the presence of an alcohol and/or an acid.

In yet another embodiment of the invention method a selective coupling with individual hydroxyl groups is provided. In particular such selection is performed by binding of suitable protecting groups with the hydroxyl groups. By removing selected protecting groups in the process of manufacture coupling may be directed to predetermined hydroxyl groups to further specify binding ability and selectivity of the invention pharmaceutical compositions. Protection groups suitable for use with the invention method are readily available for the skilled person.

In a preferred embodiment of the invention method coupling is effected in a Hantzsch reaction. Even though Hantzsch reaction is the preferred reaction for effecting coupling of the tannin derivative with pharmaceutically active ingredients, the invention also contemplated the use of other reactions, such as e.g. Biginelli reactions, mannich reactions and passerine reactions, without restricting the invention to the aforementioned reactions. Persons skilled in the art are completely aware of possible modifications and further reactions that may be employed in the context of the invention method and are covered. These modifications are contemplated by the invention.

The invention also provides for a pharmaceutical or pharmaceutical composition comprising or consisting of the invention tannin derivative as specified above for use in medicine.

In one embodiment of the invention the pharmaceutical or pharmaceutical composition comprising or consisting of the invention tannin derivative as specified above is used as an antibiotic, antifungal, cytostatic, antiviral, analgesic and/or fungistatic or a combination of the aforesaid.

The invention pharmaceutical or pharmaceutical composition comprising or consisting of a tannin derivative as specified above is preferably employed for the therapy or prevention of infections, in particular bacterial diseases, virus diseases and/or mycoses.

The invention contemplates synthesis between galloyl glucose and substituted aromatic acids. The isolated reaction product was tested with a test from milk industry, wherein Lactobacillus reduces the dyes methylene blue and brilliant black to a colorless form. If the reaction product is present in the medium no growth of Lactobacillus is reported. The dyes stay blue or black thus proving the reaction product of galloyl glucose and substituted aromatic acids to be effective as antimicrobial agent.

Furthermore, the invention contemplates that each hydroxyl group in the molecule of various tannins, in particular galloyl glucose, can be used to make another substitution. Reaction may be directed by the use of specific protection groups. The invention encompasses the case that the linking molecule, e. g. a pharmaceutically and physiologically acceptable substituted aromatic acids provides for a residual amino group, this amino group is used for a reaction, in particular Hantzsch reaction or any other suitable reaction, to build a pyrimidine, e.g. di-hydro-di-acetyl-pyrimidine which may be used as a precursor for a functionalized molecule.

EXAMPLES

Example 1

Experimental Synthesis of molecule galloyl glucose-para-amino-benzoic acid ester Synthesis

1 ,7g tannin and 5,1 g p-amino benzoic acid are placed with 50g Ν,Ν-dimethyl formamid in a 250ml 3-neck vessel. On top of the vessel was placed a water separation funnel with a cooler. Warming yielded a clear, brown solution. A solution consisting of 1 ,3g p- toluene sulfonic acid in 13g Ν,Ν-Dimethyl formamid and 86, 5g dry toluene was added. After 60 minutes of boiling 0,46g water was separated in the graduated water measuring funnel. The heating was stopped. To avoid oxidization of tannin synthesis steps were performed inert gas atmospheric conditions.

Isolation

The reaction mixture was mixed with the same weight of n-hexane in a separating funnel. Following phase separation a heavy phase in the form of dark oil remained. The remaining n-hexane was removed by incubation in a 40°C bain-marie. Transition from free base into hydrochloride was performed using 1 -n hydrochloride acid under pH control. The weak acidic solution was mixed with 1 g of charcoal, filtered and incubated at 36°C in a crystallization glass for 24hrs. The resulting product was filtered and dried in a vacuum desiccator overnight. The synthesis yielded 1 ,49g of a brownish substance exhibiting perpendicularly, chromatic crystals in polarized light

Microbial growing test of Lactobacillus confirmed the antimicrobial activity of the yielded substance even if present in the growth medium at very low concentrations.

Example 2

Synthesis of Tri-galloyl-glucose-di-hydro-di-acetyl-pyrimidin

Tri-galloyl glucose (Corilagin) having the chemical formula C27H24O18 and a molecular weight of 636,47 is covalently coupled with physiologically acceptable p-Amino-benzoic acid by an ester bond thereby yielding p-Amino-benzoic acid-ester. In a subsequent Hantzsch reaction a pharmaceutically active ingredient Di-methyl-di-acetyl-pyrimidin- benzaldehyd is coupled to a functional group of p-Amino-benzoic acid-ester thus providing a functionalized molecule having on the one hand antibiotic characteristics provided by the tannin derivative on the other hand antianginal and antihypersensitive characteristics provided by the pharmaceutically active ingredient. As an alternative penta-galloyl glucose can be used, without restricting the invention to the aforesaid compounds.

Example 2

In 50g waterfree Ν,Ν-Dimethylformamide (DMF) 1 ,7g Tannine (Riedel de Haen Art. Nr. 16201 Lot. Nr. 30500) and 5,1 g p-aminobenzoic acid are resolved by heating. A solution consisting of 1 ,3g p-toluolsulon acid in 13g DMF are added. Further 86, 5g toluol are added as water binding agent. After 60 minutes of Reflux cooking at approx. 1 18°C 0,45g water are precipitated and reaction is terminated. Preparation of the reaction mixture (RGM) is effected by adding 30ml 1 -n HCI and repeated agitation in the presence of Ligroin for complete removal of toluol until ligroine phase weight shows no further increase. The heavy phase containing the product as hydrochloride is stirred in the presence of 1 g active carbon, filtered. The filtrate is set aside for cristallisation at +36°C. After approx. 24 hrs the cristals are aspired, dried and weighed.

Weight: 1 ,49g. In linear polarised light of the microscope coloured square-shaped cristals are detected. In HPLC the product could be verified as being free of educts. In example 2 experimentation was done under CO2-atmosphere.

Example 3

In 20g Ν,Ν-Dimethylformamid (DMF) 1 ,08g tannine (Riedel de Haen Art.Nr. 16201 Lot.Nr. 30500) and 1 ,2g p-aminobenzoic acid are resolved at 30°C. At T of 60°C 600μΙ_ H ₂ SO ₄ cone, were added and allowed top react at 95°C. After 130 min. of reaction product formation is widly terminated. Higher temperature and higher amounts of H ₂ SO ₄ can shorten reaction time required. This could be verified in example 4 (cf. below).

Example 4

In 50g Ν,Ν-Dimethylformamid (DMF) 6,0g tannine (Riedel de Haen Art.Nr. 16201 Lot.Nr. 30500) and 6,0g p-aminobenzic acid are resolved at 30°C. At T of 60°C 3ml H ₂ SO ₄ cone, are added allowed to react at T=103°C. bain-marie was set to 107°C. After 85 min. of reaction product formation is terminated. Higher temperature and higher amounts of H ₂ SO ₄ may shorten reaction time required.

Sample dilution for HPLC: 1 :2000 with mobile phase.

Chromatographic Conditions for HPLC:

Column: ODS 5μ 150x6,35x4,0 (LxODxID in mm), mobile phase A consists of 985g Wasser, 6,66g KH ₂ PO ₄ and 9,3g H ₃ PO ₄ . pH is 2,5. Mobile phase B is CH ₃ CN. A:B= 80:20 (v/v). Flux rate 1 ml/min. Detection 254nm. INJVOL=10 L. column pressure at RT approx. 100bar (+/- approx. 50bar). p-aminobenzic acid eluates at approx. 2,12 min, the product at approx. 2,45 min. Tannine eluates in close proximity to dead time. Dilution of sample for examples 2 and 3 is 1 :1000 with mobile phase. With different weight preparations dilution is adapted, accordingly. As internal test substances aromatic carbon acids may be used, such as e.g. benzoic acid.

The invention comprises the following items:

A tannin derivative, in particular tannin derivative having antibiotic activity, obtained by covalent coupling of at least one organic acid with at least one tannin wherein the covalent coupling is formed as an ester or ether bond, and wherein the acid residue provides at least one functional group for covalently coupling at least one pharmaceutically active ingredient.

A tannin derivative wherein the at least one organic acid provides one or more aromatic groups.

A tannin derivative wherein the at least one tannin provides one or more substitutable hydroxyl groups.

A tannin derivative wherein the at least one tannin is selected from the group consisting of 1 -galloyl glucose, 2- galloyl glucose, tri-galloyl glucose, 4- galloyl glucose, penta- galloyl glucose or mixtures thereof.

A tannin derivative wherein the aromatic acid is selected from the group consisting of aromatic carboxylic acids such as amines, halogens and/or hydroxyl-containing aromatic carboxylic acids, benzoic acid or derivatives and/or mixtures thereof.

A tannin derivative wherein coupling of two or more identical or different aromatic acids is provided, preferably wherein the aromatic acid is a pharmaceutically acceptable acid.

A tannin derivative wherein the at least one pharmaceutically active ingredient is selected from the group consisting of antibiotics, antifungals, cytostatics, antivirals, fungistatics, analgesics or combinations thereof.

A tannin derivative wherein the at least one pharmaceutically active ingredient is selected from the group consisting of HIV-, HCV-, HBV, HSV, HRSV, HRV and VZV- effective antivirals or combinations thereof.

A tannin derivative wherein the at least one pharmaceutically active ingredient is selected from the group consisting of β-lactame antibiotics, gram-positive effective antibiotics, gram negative effective antivbiotics, polypeptide antibiotics, chinolone antibiotics, polyketide antibiotics, sulfionamiude antibiotics, amino glucoside antibiotics or combinations thereof.

A tannin derivative wherein the at least one pharmaceutically active ingredient is selected from the group consisting of polyene antifungals, midazole, triazole, and thiazole antifungals, allylamines echinocandins or combinatons thereof.

At annin derivative wherein the at least one pharmaceutically active ingredient is selected from the group consisting of 7-aminocephalosporanic acid, acetylsalicylic acid, alanine, benzoic acid, benzylpenicillic acid, benzylpenicilloic acid, biotine, caprylic acid, cinnamic acid, cystein, dihydrofolic acid, folic acid, folinic acid, glutaminic acid, glycine, histidine, hydroxybenzoic acid, leucine, linoleic acid, lysine, nicotinic acid, p- aminobenzoic acid, p-aminosalicylic acid, phenylacetic acid, phenoxyacetic acid, phenylacrylic acid, serine, styrylacetic acid, (S)-2-{4-[(2-4-diaminopteridin-6-yl methyl) methylamino] benzoylamino} pentandi acid, threonine, tryptophane, tyrosine, valine, sorbic acid, 1 ,2,4-triazol-3-carboxylic acid, 3-(thienyl)-malonic acid, 4-morpholine carboxylic acid, amethopterine (methotrexate), 9-(2-carboxyethoxymethyl)-guanin, 4- thiazolidincarbon acid, imidazolacrylic acid, or derivatives and/or combinations thereof.

A tannin derivative, in particular tannin derivative having antibiotic activity, obtained by covalent coupling of at least one organic acid with at least one tannin wherein the covalent coupling is formed as an ester or ether bond, and wherein the acid residue provides at least one functional group for covalently coupling two or more

pharmaceutically active ingredients, in particular functionally identical or functionally different pharmaceutically active ingredients.

A tannin derivative wherein said two or more pharmaceutically active ingredients, in particular functionally identical or functionally different pharmaceutically active ingredients are selected from the group consisting of antibiotics, preferably β-lactame antibiotics, gram-positive effective antibiotics, gram negative effective antivbiotics, polypeptide antibiotics, chinolone antibiotics, polyketide antibiotics, sulfionamiude antibiotics, amino glucoside antibiotics, antifungals, preferably polyene antifungals, midazole, triazole, and thiazole antifungals, allylamines or echinocandins, cytostatics, antivirals, preferably HIV-, HCV-, HBV, HSV, HRSV, HRV and VZV-effective antivirals and fungistatics, analgesics or combinations thereof.

A tannin derivative wherein said two or more pharmaceutically active ingredients, in particular functionally identical or functionally different pharmaceutically active ingredients are selected from the group consisting of 7-aminocephalosporanic acid, acetylsalicylic acid, alanine, benzoic acid, benzylpenicillic acid, benzylpenicilloic acid, biotine, caprylic acid, cinnamic acid, cystein, dihydrofolic acid, folic acid, folinic acid, glutaminic acid, glycine, histidine, hydroxybenzoic acid, leucine, linoleic acid, lysine, nicotinic acid, p-aminobenzoic acid, p-aminosalicylic acid, phenylacetic acid,

phenoxyacetic acid, phenylacrylic acid, serine, styrylacetic acid, (S)-2-{4-[(2-4- diaminopteridin-6-yl methyl) methylamino] benzoylamino} pentandi acid, threonine, tryptophane, tyrosine, valine, sorbic acid, 1 ,2,4-triazol-3-carboxylic acid, 3-(thienyl)- malonic acid, 4-morpholine carboxylic acid, amethopterine (methotrexate), 9-(2- carboxyethoxymethyl)-guanin, 4-thiazolidincarbon acid, imidazolacrylic acid, or derivatives and/or combinations thereof.

A tannin derivative wherein the tannin derivative is selected from a composition of formula (A),

wherein R independently represents at least one covalently coupled pharmaceutically active ingredient as defined above, in particular wherein R represents the same or different pharmaceutically active ingredients.

A tannin derivative wherein the tannin derivative is selected from a composition of formula (B),

wherein R independently represents at least one covalently coupled pharmaceutically active ingredient as defined above, in particular wherein R represents the same or different pharmaceutically active ingredients

A tannin derivative, wherein the tannin derivative is selected from a composition of formula (C),

wherein R independently represents at least one covalently coupled pharmaceutically active ingredient as defined above, in particular wherein R represents the same or different pharmaceutically active ingredients.

A pharmaceutical composition comprising a tannin derivative as defined before in particular in a solid, orally administrable form, a liquid, orally administrable form, an injectably administrable form or in form of an ointment, an emulsion or a suspension.

A Method for producing a tannin derivatives as specified above, comprising the steps of: i) providing a tannin, and ii) covalently coupling at least one aromatic acid or an acid derivative with at least one hydroxyl group of the tannin and iii) covalently coupling at least one pharmaceutically active ingredient with at least one functional group defined by the aromatic acid residue of the tannin derivative as specified above . The aforementionned method wherein step ii) provides an esterification or etherification of the aromatic acid or acid derivative in the presence of an alcohol and/or an acid.

The aforementionned method wherein selective coupling with individual hydroxyl groups is provided, in particular wherein the selection is performed by binding of suitable protecting groups with the hydroxyl groups.

The aforementionned method wherein the coupling is effected in a Hantzsch reaction.

A pharmaceutical comprising or consisting of a tannin derivative as specified above or a pharmaceutical composition as defined above for use in medicine.

A pharmaceutical for use as an antibiotic, antifungal, cytostatic, antiviral and/or fungistatic.

A pharmaceutical for the therapy or prevention of infections, in particular bacterial diseases, virus diseases and/or mycoses.