MXPA98003847A - Prepared with in vivo increment compatibility - Google Patents

Abstract

The present invention relates to a preparation containing a gliscosil-Y [-C (= Y) -X-] pW (R) nXC (= Y) -principle active, sugar or sugar-alcohol, optionally bivalent ions and a support pharmaceutically compatible, presents a compatibilityin vivo improvement

Description

Prepared with increased in vivo compatibility The therapy of malignant tumors, infectious diseases or autoimmune diseases is linked, together with the insufficient activity of the therapeutic agents, with strong side effects. This lack can be explained fundamentally with the too little in vivo compatibility of the active principles used. The invention aims, by means of the modification of the preparation, to improve the compatibility of active principles in therapy and, possibly, to increase the efficacy. Therefore, the invention relates to a preparation, which contains 1) a compound of the formula I, Glycosyl-Y [-C (= Y) -X-] p-W (R) n -X-C (= Y) -principle active (I) wherein Glycosyl is a polysaccharide, oligosaccharide or monosaccharide separable by enzymatic route, is an aromatic compound or a heteroaromatic compound or an aliphatic compound with conjugated double bonds or a cyclising amino acid derivative after the separation of the glycosyl moiety, wherein the Substituent R is a hydrogen atom, methyl, methoxy, carboxy, CN, methylcarbonyl, hydroxy, nitro, fluorine, chlorine, bromine, sulfonyl, sulfonamide or sulfon-alkyl (C? -? -C4) amide, p is 0 or 1, n is an integer, X is an oxygen atom, NH, methyleneoxy, methyleneamino or methylene-alkyl (C.-C4) -amino, and Y is an oxygen atom or NH, and active principle means a compound with biological activity linked through a hydroxy, amino or imino group, and / or a physiologically compatible salt of the compound of the formula I, 2) sugar and / or sugar alcohol and 3) a pharmaceutically compatible carrier. By the term "active ingredient" are meant compounds such as anthracycline, preferably doxorubicin, 4'-epidoxypubicin, 4- or 4'-deoxidoxorubicin or A compound preferably of the etoposide group, N-bis (2-chloroethyl) -4-hydroxyaniline, 4-hydroxycyclophosphamide, V * vindesine, vinblastine, vincristine, terfenadine, terbutaline, fenoterol, salbutamol, muscarine, oxyphenbutazone, salicylic acid, p-aminosalicylic acid, 5-fluorouracil, methotrexate, diclofenac, flufenamine, 4-methylaminophenazone, theophylline, nifedipine, mitomycin C, mitoxantron, camptothecin and camptothecin derivatives, m-AMSA, taxol, other taxanes, nocodaxol, colchicine, fexofenadine, cyclophosphamide, rachelmycin, cisplatin, melphalan, bleomycin, nitrogen-gas mustard, phosphoramide-mustard gas, verrucarin A, neocarzinostatin, calicheamicin, dynemycin, esperamycin A, quercetin, genistein, erbstatin, tyrphostin, rohituquine derivative, retinolic acid, butyric acid, phorbol ester, dimethylsulfoxide, aclacinomycin, progesterone, buserelin, tamoxifen, mifepriston, onapriston, N- (4-aminobutyl) -5-chloro-2-naphthalene-sulfonamide, pridiniloxazol-2-one, quinolyl-, isoquinoliloxazol-2-one, staurosporine, ethanolamine, verapamil, forscholine, 1, 9-dideoxytrorscholine, quinine, quinidine, reserpine, 18-0- (3, 5-dimethoxy-4-hydroxy-benzoyl) -reserpate, lonidartray, butioninsulfoximine, diethyldithiocarbamate, cyclosporin A, rapamycin, azathioprine, chlorambucil, derivative-2 of hydroxycodone amide, leflunomide, 15-deoxyspergualin, FK 506, ibuprofen, indomethacin, aspirin, sulfasalazine, penicillamine, chloroquine, dexamethasone, prednisolone, mephonamide acid, paracetamol, mol, 4-aminophenazon, muscosine, orciprenaline, isoprenaline, amiloride, p-nitrophenyl-guanidinbenzoate or its derivatives * additionally substituted with one or more hydroxy, amino or imino groups. n is an integer from 1 to 8, preferably 1 to 6. The term sugar is understood to mean aldoses with 3 to 7 carbon atoms which may also belong to the D or L series; they also belong to aminosugars or uronic acids. By way of example, glucose, mannose, fructose, galactose, ribose, erythrose, glyceryl aldehyde, sedoheptulose, glucosamine, galactosamine, glucuronic acid, galacturonic acid, gluconic acid, galactonic acid or manonic acid can be measured. Sugar-alcohols result, for example, from reduction of the aforementioned sugars; They include glucitol, 15 mannitol (mannitol), sorbitol, glycerol or inositol. Suitable salts of the compound of the formula I, physiologically compatible, are for example alkali metal, alkaline earth metal and ammonium salts, including those of organic ammonium bases and salts of the protonated amino acid residues. Alkali metal salts, such as sodium or potassium salts, are preferred. In particular, the preparations according to the invention additionally contain bivalent ions. By the term "bivalent ions" is meant, for example, bivalent metal ions of Ca, Mg, Fe, Cu or Ni. Preferably, compounds of the formula I are used, wherein it is a phenyl radical or a phenyl radical substituted several times, and wherein the substituent R is. a hydrogen atom, methyl, methoxy, carboxy, methyloxycarbonyl, CN, hydroxy, nitro, fluoro, chloro, bromo, sulfonyl, sulfonamide or sulfon-alkyl (CJ.-C.-amide and p is 0 or 1.35 n is 1 to 4, X is an oxygen atom, NH, methyleneoxy, methyleneamino, or * methylene-alkyl (C ^ C-amino, Y is an oxygen atom or NH, and active ingredient means a compound as described above. Particularly preferred are compounds of the formula I, wherein glycosyl is a polysaccharide, oligosaccharide or monosaccharide, in particular a D-glucuromethyl, D-glucopyranosyl, D-galactopyranosyl, N-acetyl-D-β-glucosaminyl radical. , N-acetyl-D-galactosaminil or, D-mannopyranosyl 10 or L-fucopyranosyl bonded in an alpha- or beta-O-glycosidic form, W is a phenyl radical or a substituted phenyl radical, wherein the substituent R is methoxy , methyloxycarbonyl, CN, hydroxy, nitro, fluorine, chlorine, bromine, sulfonyl or sulphonamide, and the remainder are hydrogen atoms , X is O, NH, methyleneoxy, methyleneamino or methylenemethylamino, and Y is O or NH, and active ingredient means a compound as described above. Preferably, compounds are used which are characterized in that the glycosyl radical can be separated by enzymatic hydrolysis, because the spacer can be spontaneously separated by chemical hydrolysis, because the active ingredient is a pharmaceutical agent or one of its derivatives obtained by the introduction of additional hydroxy, amino or imino group, because it is more hydrophilic than the active principle, because it leads in vivo to reactions less toxic- that the active principle as such, because the active substance is a pharmacologically active substance, because the active principle is additionally substituted with one or more hydroxy, amino or imino groups and slows down the development of the tumor, because the active principle is a agent cytostatic standard, because the active principle is an antimetabolite, because the active principle is 5-fluorocytidine, 5-fluororidine, cytosine arabinoside or methotrexate, because the active substance is a substance that is inserted into the ADJKT, because the active substance is doxorubicin, daunomycin, idarubicin, epirubicin or mitoxantron, because the active ingredient inhibits topoisomerase I + II, because the active ingredient is camptothecin and camptothecin derivatives, etoposide or M-AMSA, because the active principle is a tubulin inhibitor, because the active ingredient is vincristine, vinblastine, vindesine, taxol and taxane, nocodaxol, colchicine or etoposide, because the active principle is an alkylating agent, because the active substance is cyclophosphamide, mitomycin C, rachelmycin, cisplatin, phosphoramide-mustard gas, melphalan , bleomycin, nitrogen-gas mustard or N-bis (2-chloroethyl-4-hydroxyaniline), because the active ingredient is neocarzinostatin, calicheamicin, epot ilon AC, dinemicin or esperamycin A, because the active principle is a compound that inactivates ribosomes, because the active substance is verrucarin A, because the active principle is an inhibitor of tyrosine-phosphokinase, because the active ingredient is quercetin, genistein, erbstatin, tyrphostin or a derivative of rohituquine, because the active principle is an inducer of differentiation, because the active substance is retinolic acid, butyric acid, forbolic ester, DMSO or aclacinomycin, because the active substance is a hormone, a hormone agonist or a hormone antagonist, because the active ingredient is progesterone, buserelin, tamoxifen or onapriston, because the active substance is a substance that modifies pleiotropic resistance with respect to cytostatic agents, because the active substance is a calmodulin inhibitor, because the principle active is an inhibitor of protein kinase C, because the active substance is an inhibitor of p-glycoprotein a, because the active principle is a modulator of mitochondrially bound hexokinase, because the active principle is an inhibitor of β-glutamylcystein synthetase or glutathione-S-transferase, because the active substance is an inhibitor of superoxide dismutase , # because the active ingredient is an inhibitor of the protein associated with proliferation defined by the monoclonal antibody Mak Ki67 of cells that divide in the cell nucleus, because the active principle is a substance that exerts immunosuppressive effects, because the active principle It is a standard immunosuppressive agent, because the active substance is a macrolide, because the active substance is cyclosporine A, rapamycin, FK 506, because the active substance is azathioprine, methotrexate, cyclophosphamide or chloramine-10, because the active substance is a substance which has an anti-inflammatory effect, because the active principle is a non-steroidal anti-inflammatory substance, because the active principle is a a slow-acting antirheumatic drug, because the active ingredient represents a steroid, because the The active principle is a substance that has an antiphlogistic, analgesic or antipyretic effect, because the active principle represents a derivative of an organic acid, because the active principle represents an analgesic, non-acidic antiphlogistic, because the active principle is oxyphenbutazole, because the active principle is a local anesthetic, because the active principle is an antiarrhythmic agent, because the active principle is a Ca ++ antagonist, because the active principle is an antihistamine, because the active substance is a substance inhibiting phosphodiesterase, because the The active principle is a parasympathomimetic agent, because the active principle is a sympathomimetic agent or because the active principle is a substance with an inhibitory effect on human urokinase; and, in addition, compounds characterized in that the glycosyl radical is a D-30-glucuronyl, D-glucopyranosyl, D-galactopyranosyl, N- -acetyl-D-glucosaminyl, N-acetyl-D-galactosaminyl, D- -mannoranosyl or L-fucopyranosyl bonded alpha or beta-glycosidic form, because it is 4 '-0- [4- (alpha-D-glucopyranosyl-xi) -phenylaminocarbonyl] -etoposide, 35 N- [4- (0- (beta-) acid D-glucopyranosyluronic) -3-nitro-benzyl-xicarbonyl] -doxorubicin, sodium salt, (compound II), N- [4- (O- (beta-D-glucopyranosyluronic acid) -3-chloro-benzyl-xicarbonyl] - doxorubicin, sodium salt, N- [4- (O- (beta-D-glucopyranosyluronic acid) -3-fluoro-benzyloxycarbonyl] -doxorubicin, sodium salt, N- [4- (0- (beta-D-glucopyranosyluronic acid) -3-nitro-benzyl-xicarbonyl] -daunorubicin, sodium salt, N- [4- (O- (beta-D-glucopyranosyluronic acid) -3-chloro-benzyl-xicarbonyl] -daunorubicin, sodium salt, N- [4 - (O- (alpha-D-galactopyranosyl) -3-nitro-benzyloxycarbonyl] -daun orrubicin, N- [4- (0- (alpha-D-galactopyranosyl) -3-chloro-benzyloxycarbonyl] -daunorubicin, N- [4- (0- (alpha-D-galactopyranosyl) -3-fluoro-benzyloxycarbo-nil] ] -daunorubicin, N- [4- (O- (beta-D-glucopyranosyluronic acid) -3-nitro-benzyl-xicarbonyl] -doxorubicin, sodium salt, N- [2- (0- (beta D-glucopyranosyluronic acid) -5-chloro-benzyl-xicarbonyl] -doxorubicin, sodium salt, N- [2- (0- (beta D-glucopyranosyluronic acid) -5-fluoro-benzyl-oxycarbonyl] -doxorubicin, sodium salt, N- [2- (0- (beta D-glucopyranosyluronic acid) -5-nitro-benzyl-xicarbonyl] -daunorubicin, sodium salt, N- [2- (0- (beta D-glucopyranosyluronic acid) -5-chloro-benzyl-xicarbonyl] - daunorubicin, sodium salt, N- [2- (0- (alpha-D-galactopyranosyl) -5-nitro-benzyloxycarbonyl] - -daunorubicin, N- [2- (0- (alpha-D-galactopyranosyl) -5-chloro -benzyloxycarbonyl] - -daunorubicin, N- [2- (0- (alpha-D-galactopyranosyl) -5-fluoro-benzyloxycarbonyl] -daunorubicin, 4 '-O- [4- (beta -D-glucopyranosyloxy) -phenylaminocarbonyl] -etoposide, 4 '-0- [4- (alpha-D-glucopyranosyloxy) -phenylaminocarbonyl] -etoposide, 4' -0- [4- (beta-D-glucuronyloxy) -phenylaminocarbonyl] -etoposide, 4 '-0- [4- (beta-D-glucuronyloxy) -3-nitro-benzylaminocarbonyl] - < a (P- etoposide, 4 '-0- [4- (beta-D-glucuronyloxy) -3-chloro-benzylaminocarbonyl] -etoposide, 1-N- [4- (beta-D-glucuronyloxy) -benzyloxycarbonyl] -mitomycin 5 C, 14-0- [4- (beta-D-glucuronyloxy) -3-nitro-benzylaminocarbonyl] - - doxo r rub ic ina, 4-0- [4- (beta-D-glucuronyloxy) -benzylaminocarbonyl] - 4-hydroxy-1-N- (bis-2-chloroethyl) -aniline, 4-0-0- [4- (beta-D-glucuronyloxy) -benzylaminocarbonyl] -terfenadine, 3 '-0- [4- (beta -D-glucuronyloxy) -benzylaminocarbonyl] -terbutalin, 3 '-0- [4- (beta-D-glucuronyloxy) -benzylaminocarbonyl] -phenote-15-rol, l "-0- [4- (beta-D- glucuronyloxy) -benzylaminocarbonyl] -salbutamol, 3-0- [4- (beta-D-glucuronyloxy) -benzylaminocarbonyl] -muscarine, 4 '-0- [4- (beta-D-glucuronyloxy) -benzylaminocarbonyl] -oxofenbu-20-tazone, Acido2-0- [4- (beta-D-glucuronyloxy) -benzylaminocarbonyl] -salicylic acid, N- [4- ( beta-D-glucuronyloxy) -benzyloxycarbonyl] -diclofenac, N- [4- (beta-D-glucuronyloxy) -benzyloxycarbonyl] -flufenal acid, 4-N- [4- (beta-D-glucuronyloxy) -benzyloxycarbonyl] -4-methylamine-phenazone, 7-N- [4- (beta-D-glucuronyloxy) -benzyloxycarbonyl] -teophylline, lN- [4- (beta-D-glucuronyloxy) -benzyloxycarbonyl] -nifedipine, [4- (/ β-D-glucuronyloxy) -3-nifrobenzyl] ] -2- [1-cyano-l- (N-4-trifluoromethyl-phenyl) -carbamoyl] -propen-1-yl-carbonate, 3'-N- [4-N- (alpha-D-galactosyloxycarbonyl) -4-aminobenzyloxycarbonyl] -doxorubicin, 9-0- [4- (beta-D-glucuronyloxy) -3-chlorobenzyloxycarbonyl] -3-quinoline, or 18-0- [3,5-dimethoxy-4- [4 - (beta-D-glucuronyloxy) -3-chloro-benzyloxycarbonyl] benzoyl] -reserpate. In a particularly preferred manner, compound II is used as well as mannitol, sugar-alcohol and Ca2 + as bivalent ion.

The preparation of the compound of the formula I is carried out, for example, as described in document P 0 751 144. The compound II is used in an amount of 1 to 1000 mg / kg of live weight, preferably 5 to 500 mg / kg. If a soluble preparation is present, mannitol is used in an amount of 1 mg / ml to 150 mg / ml, preferably 10 to 100 mg / ml, in particular 50 mg / ml. Ca2 + ions are used in a soluble preparation, for example in the form of CaCl2, in an amount of 0.01 mg / ml to 10 mg / ml, preferably 0.05 to 2 mg / ml, in particular 0.4. mg / ml of CaCl2 x 2 H20. The solid preparation according to the invention is suitable, for example, for the treatment of acute immunological events, such as sepsis, allergy, graft reactions against host and host against graft autoimmune diseases, in particular rheumatoid arthritis, lupus erythematosus. systemic, multiple sclerosis 10 - psoriasis, atopic dermatitis, asthma, urticaria, rhinitis, uveitis hepatic fibrosis, cystic fibrosis, colitis carcinogenic diseases, such as lung cancer, leukemia, ovarian cancer, sarcoma, Kaposi's sarcoma, 15 meningioma, cancer of intestine, cancer of the lymph node, brain tumors, breast cancer, pancreatic cancer, prostate cancer or skin cancer. The solid preparation according to the invention can also comprise combination containers or compositions in which the components are arranged side by side and, therefore, can be applied simultaneously, separately or stepwise in time to one another. and the same human or animal body. According to the invention, the components * 1, 2 and possibly bivalent ions may also be present in separate drug forms, arranged side by side, in particular when the drug forms make application difficult depending on the spatial dimensions. This applies in particular to oral forms, since often in the case of elderly patients a rejection prevails against tablets or large capsules. It is mandatory that the drug forms, present separately and arranged next to each other, be arranged for the common chronological intake. In this case, different forms, for example tablets and 35 capsules, can also be presented side by side. The invention also relates to a process for the production of the preparation according to the invention, characterized in that the components 1), 2), optionally bivalent ions and a pharmaceutical support are prepared to give a form of administration pharmaceutical The solid preparation according to the invention can be presented as a dosage unit in the form of medicinal forms such as capsules (including microcapsules), tablets (including dragees and pills) or suppositories, wherein, in the case of using capsules, the material of the capsule assumes the function of the support and the content may be present, for example, in the form of powder, gel, emulsion, dispersion or solution. However, it is particularly advantageous and simple to prepare oral formulations (perora-ies) with the three components 1), 2) and optionally bivalent ions containing the calculated amounts of the active ingredients together with any desired pharmaceutical support. A corresponding formulation (suppositories) can also be used for rectal therapy. Also, transdermal application in the form of ointments, creams, or oral application of solutions containing the preparation according to the invention is possible. In addition, the compounds of the formula I can also be presented in the form of lyophilizate which is reconstituted before application with a solution containing 5% mannitol and 0.4 mg CaCl, x 2 H20 / ml (pH about 7). Ointments, pastes, creams and powders can contain, together with the active ingredients, the usual support substances, for example animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicone, bentonite, talc, zinc oxide, lactose, silicic acid, hydroxide of aluminum, calcium silicate and polyamide powder or mixture of these substances. The tablets, pills or granule bodies can be prepared according to customary procedures, such as pressing, dipping or fluid bed processes or grafting in boilers, and contain customary support agents and other adjuvants, such as gelatin, agarose, starch (for example potato starch, corn or wheat), cellulose, such as ethylcellulose, silicon dioxide, different sugars, such as lactose, magnesium carbonate and / or calcium phosphates. The dragee solution usually consists of sugar and / or starch syrup and contains, in most cases, gelatine, gum arabic, polyvinylpyrrolidone, synthetic cellulose esters, surfactants, plasticizers, pigments and similar additives corresponding to the known state of The technique. For production of the preparations, any usual flux, lubricant or gliding regulating agent, such as magnesium stearate, and separating agents can be used. The dosage to be used depends, of course, on different factors such as the being to be treated (for example man or animal), age, weight, general state of health, degree of severity of the symptoms, of the disease to be treated, of possible concomitant diseases, (if present) of the type of concomitant treatment with other medications, or of the periodicity of the treatment. The dosages are administered, for example, one to three times per week (intravenously, i.v.). The amount of the active components depends in nature on the number of individual dosages and also on the disease to be treated. The individual dosage may also consist of several dosage units administered at the same time.

Examples Pharmacological examination As test animals, mice deprived of the immune system carry tumors of the NMRI race with a body weight of 17 to 25 g. For each test group, 6 to 8 animals are used. The animals receive an i.v. of compound II in dissolved form with physiological sodium chloride solution (dose of compound II as described in Table 1 in 0.9% NaCl), mannitol (dose 5 of compound II as described in Table 2 in a solution of 5% mannitol in water, pH 7) and a preparation according to the invention containing compound II, 2 and mannitol (dose of compound II as described in Table 1 in a solution of mannitol at room temperature). % with 0.4 mg of , 10 x 2H20). The application takes place on days 1, 4 and 8. The weight of the animals as well as the development of the lovo-tumor is determined at intervals of 3 to 4 days throughout the experiment. * < ment. The survival rate is calculated daily. Table 1 shows the results. 15 Table 1 twenty n.a. not reached (T-C) 200% means: time of tumor duplication (tumor volume) under treatment with compound II in the corresponding preparation in days minus the time of tumor duplication under treatment with the corresponding prepared without compound II in days. (TC) 400% means: tumor quadrupling time (tumor volume) under treatment with compound II in the corresponding preparation in days minus the quadruplication time of the tumor under treatment with the corresponding one prepared without compound II in days.

Minimum T / C ratio (%) means: lowest% value of tumor development of the therapy group compared to the control group. Minimum T / C ratio (day) means: day on which the tumor development of the therapy group is at the lowest value compared to the control group. Using the i.v. of compound II in physiological sodium chloride solution at a dose of 3 x 225 mg / kg only a weak anti-tumor effect is achieved. (T-C) 200%: 3.9 days. The weight reduction (a measure of the side effects of compound II) is already, however, relatively strong (24% weight reduction and 33% dead animals). The i.v. of 3 x 350 mg / kg of compound II in physiological sodium chloride solution leads to rapid death of all test animals. The application of 3 x 350 mg / kg of compound II in mannitol leads to clear antitumor effects (T-C (200%): 17.3 days) and moderate compatibility (weight reduction, 28% and 17% of dead animals). The administration of 3 x 400 mg / kg of compound II in Ca / mannitol induces strong anti-tumor effects (TC- (200%): 19.6 days) and is well compatible for test animals (weight reduction 18 %, no dead animal). Similar advantageous observations are made in experiments on Ma fascicularis monkeys after i.v. of 3 x 120 mg / kg of compound II in Ca / mannitol solution. The animals survive at this extremely high dose without serious signs of side effects. In the case of a dissolution of compound II in 0.1 M phosphate buffer, pH 7.35, a maximum of 1 x 40 mg / kg is tolerated. These studies confirm that the compound II in the Ca / mannitol solution according to the invention is not only essentially better compatible, but also clearly more effective.

Claims (9)

1. - Preparation containing 5 1) a compound of the formula I, Glycosyl-Y [-C (= Y) -X-] p-W (R) n -X-C (= Y) -principle active (I) wherein 10 Glicosil is a polysaccharide, oligosaccharide or monosaccharide separable by enzymatic route, W is an aromatic compound or a heteroaro¬ % mático or an aliphatic compound with conjugated double bonds or a cieling 15 amino acid derivative after the separation of the glycosyl moiety, and wherein the R substituent is a hydrogen atom, methyl, methoxy, carboxy, CN, methylcarbonyl, hydroxy, nitro , fluorine, chlorine, bromine, sulfonyl, sulfonamide or sulfon-alkyl (Cx- 20 -CJ -amide, p is zero or 1, n is an integer, X is an oxygen atom, NH, methyleneoxy, methyleneamine or Methylene-alkyl (C-CJ-amino, and Y is an oxygen atom or NH, and active ingredient means a compound with biological activity linked through a hydroxy, amino or imino group, and / or a physiologically compatible salt of the compound 30 formula I, 2) sugar and / or sugar alcohol and 3) a pharmaceutically compatible carrier.

2. Preparation according to claim 1, characterized in that bivalent ions are additionally present.

3. Preparation according to claim 1 or 2, characterized in that an anthracycline, preferably doxorubicin, is used as an active principle, as well as active principles of the etoposide group, epothilone AC, N-bis (2-chloroethyl) - 4-hydroxyaniline, 4-hydroxycyclophosphamide, vindesine, vinblastine, vincristine, terfenadine, terbutaline, phenotequin, salbutamol, muscarine, oxyphenbutazone, salicylic acid, p-aminosalicylic acid, 5-fluorouracil, methotrexate, diclofenac, flufenamine, 4- methylaminophenazone, theophylline, nifedipine, mitomycin C, mitoxantron, camptothecin and camptothecin derivatives, m-AMSA, taxol and other taxanes, nocoda- 10 xol, colchicine, fexofenadine, cyclophosphamide, rachelmycin, cisplatin, melf lan, bleomycin, nitrogen-gas mustard , phosphoramide-mustard gas, verrucarin A, neocarzinostatin, * calicheamicin, dynemycin, esperamycin A, quercetin, genistein, erbstatin, tyrphostin, rohituquine derivative, 15 retinolic acid, butyric acid, phorbolic ester, dimethylsulfoxide, aclacinomycin, progesterone, buserelin, tamoxifen, mifepriston, onapriston, N- (4-aminobutyl) -5-chloro-2-naphthalene-sulfonamide, pridiniloxazol-2-one , quinolyl-, iso-quinoliloxazol-2-one, staurosporine, ethanolamine, verapamil, 20 forscolin, 1, 9-dideoxyfrorscholine, quinine, quinidine, reprine, 18-0- (3, 5-dimethoxy-4-hydroxybenzoyl) -reserpate, lonidamine, butioninsulfoximine, diethyl dithiocarbamate, cyclosporin A, rapamycin, azathioprine, chlorambucil, 2-derivative of hydroxycodone amide, leflunomide, 15-25-deoxyspergualin, FK 506, ibuprofen, indomethacin, aspirin, sulfasalazine, penicillamine, chloroquine, dexamethasone, prednisolone, mephonamide acid, paracetamol, muscosine, 4- -aminofenazon, orciprenaline, isoprenaline, amiloride, p-nitrophenyl-guanidinbenzoate or its derivatives additionally 30 substituted with one or more hydroxy, amino or imino groups. 4. - Prepared according to one or more of claims 1 to 3, characterized in that the compound of the formula I is used, wherein W is a phenyl radical or a substituted phenyl radical. Several times and wherein the substituent R is a hydrogen atom, methyl, methoxy, carboxy, methyloxycarbonyl, CN, hydroxy, nitro, fluoro, chloro, bromo, sulfonyl, sulfamide or sulfon-alkyl (CX-CJ-amide and p is 0 or 1, n is 1 to

4, X is an oxygen atom, NH, methyleneoxy, methyleneamino or methylene-alkyl (Ci-CJ-amino, Y is an oxygen atom or NH, and active ingredient means a compound according to claim 3.

5. - Prepared according to one or more of the claims 1 to 4, characterized in that glucose, mannose, fructose, galactose, ribose, erythrose, glycerin aldehyde, sedoheptulose, glucosamine, galactosamine, glucuronic acid, galacturonic acid, gluconic acid, galactonic acid, manonic acid are added as sugar and / or sugar alcohol. , glucitol, mannitol, sorbitol, glycerol or inositol.

6.- Prepared according to one or more of the claims 2 to 5, characterized in that ions of Ca, Mg, Fe, Cu or Ni metals are added as bivalent ions.

7. - Prepared according to one or more of claims 2 to 6, characterized in that the preparation is presented as a solution and contains Ca2 + ions, mannitol and compound II

8. - Prepared according to claim 7, characterized in that the preparation contains 50 mg / ml of mannitol, 0.4 mg / ml of CaCl2 x 2 H20 and 25 mg / ml of compound II according to claim 7. 9. - Procedure for production of the preparation according to one or more of claims 1 to 8, characterized in that the compound of the formula I, sugar and / or sugar-alcohol, optionally bivalent ions and a pharmaceutical support is prepared to give a pharmaceutical administration form.