WO2012130850A1 - Ciblage de tissu avec des dérivés diphényliques pontés oncocides pour le traitement sélectif de tumeurs des organes sexuels - Google Patents

Ciblage de tissu avec des dérivés diphényliques pontés oncocides pour le traitement sélectif de tumeurs des organes sexuels Download PDF

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WO2012130850A1
WO2012130850A1 PCT/EP2012/055420 EP2012055420W WO2012130850A1 WO 2012130850 A1 WO2012130850 A1 WO 2012130850A1 EP 2012055420 W EP2012055420 W EP 2012055420W WO 2012130850 A1 WO2012130850 A1 WO 2012130850A1
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independently
hydrogen
salts
solvates
another represent
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PCT/EP2012/055420
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German (de)
English (en)
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Heinz Förster
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Bayer Pharma Aktiengesellschaft
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/655—Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
    • C07C245/22—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond containing chains of three or more nitrogen atoms with one or more nitrogen-to-nitrogen double bonds
    • C07C245/24—Chains of only three nitrogen atoms, e.g. diazoamines

Definitions

  • the present invention relates to substituted bridged diphenyl derivatives containing per molecule at least (i) a dialkyl triazenyl group and (ii) at least one selected oxycarboxylic acid group, their salts, solvates and the solvates of these salts.
  • the invention further relates to processes for the preparation of these derivatives, the use of these derivatives for the treatment and / or prevention of diseases and the use of these derivatives for the preparation of medicaments for the treatment and / or prevention of diseases, in particular of cancers such as cancer of the sexual organs. Such treatments may be monotherapy or in combination with other medicines or other therapeutic measures.
  • Cancers are the result of uncontrolled cell growth of various tissues. In many cases, the new cells invade existing tissues (invasive growth) or they metastasize to distant organs. Cancers occur in various organs and often have tissue-specific disease courses. Therefore, the term cancer as a generic term describes a large group of defined diseases of various organs, tissues and cell types.
  • early stage tumors may be removed by surgical and radiotherapeutic measures.
  • metastatic tumors can only be treated palliatively by chemotherapeutic agents.
  • the goal here is to achieve the optimal combination of improving the quality of life and extending the lifetime.
  • chemotherapeutic agents administered parenterally today are often not targeted to tumor tissue or tumor cells, but are nonspecifically distributed in the body by systemic administration, i. even in places where drug exposure is undesirable, such as in healthy cells, tissues and organs. This can lead to unwanted side effects and even serious general toxic effects, which then often severely limit the therapeutically useful dose range of the drug or require a complete discontinuation of the medication.
  • Triazene derivatives have been extensively studied for their cytostatic efficacy in recent decades. These conventional triazine cytostatics are among the alkylating agents and have never been widely used in the clinic because of their severe side effects and toxicity. An exception is dacarbazine (DTIC), which is a prodrug of monomethyl triazeno-imidazole carboxamide (MTIC) and is used primarily to combat Hodgkin's disease and soft tissue sarcomas (Cancer Treatment Reports 60, 205-211 (1976)).
  • DTIC dacarbazine
  • MTIC monomethyl triazeno-imidazole carboxamide
  • DE 17 93 1 15 A, DE 21 47 78 1 A I and WO 2004/106358 AI Attempts to overcome the unspecific cancer chemotherapy with cytostatics, for example in breast cancer, have been described in DE 17 93 1 15 A, DE 21 47 78 1 A I and WO 2004/106358 AI.
  • DE 17 93 1 15 A, DE 21 47 781 Al and WO 2004/106358 AI compounds have been described, which have pharmacophoric properties as a carrier for a Triazenylwirken and their structure is derived from synthetic estrogen Diethylstilbestrol derived.
  • the pharmacophoric properties of these drugs enable sexual organ tissue targeting because all cell types and tissues of the body (here the cells of the sex organ tissue), including diseased tissues, such as tumors, are specific cell surface proteins ("markers" or receptors) for the particular tissue. which are able to bind suitable molecules (ligands).
  • markers specific cell surface proteins
  • ligands suitable molecules
  • the active compounds from DE 17 93 1 15 A, DE 2 1 47 78 1 A1 and WO 2004/106358 A1 introduced the oxyacetic acid group as a solubilizing group so that the compounds (applied as water-soluble salts) can be excreted more easily.
  • neither leukemia and thrombocytopenia nor bone marrow suppression were observed.
  • the connections showed a very good and sustained effect on rat breast carcinoma.
  • a Phase I / II clinical trial demonstrated the effect of a test substance in advanced breast and ovarian cancer.
  • oxyacetic acid residue was converted to an amide derivative of amino acids, for example, glycine.
  • the object of the present invention was therefore to provide suitable oncocidal active substances (bridged diphenyl derivatives), in particular for a long-term therapy, without toxic side effects on the kidney.
  • the object is achieved by the compounds according to the invention in that no oxyacetic acid group, but instead other short-chain and branched oxycarboxylic acids are used.
  • the compounds of the invention retain their effectiveness and are suitable for long-term use in cancer therapy.
  • the masking of the oxycarboxylic acid with amino acid such as glycine is not necessary.
  • R 1 , R 4 independently of one another represent hydrogen, hydroxyl, (C 1 -C 6) -alkyl, (C 1 -C 4) -alkoxy, halogen, nitro or cyano,
  • R 3 , R 6 independently of one another represent hydrogen or -O- (CR n R 12 ) n -CO 2 R 13 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 independently of one another represent hydrogen or ( C 6 ) -alkyl, n is 1, 2, 3, 4 or 5,
  • R 13 is hydrogen or (C 1 -C 6 ) -alkyl
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.
  • the compounds according to the invention may exist in different stereoisomeric forms, i. in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including those in atropisomers).
  • the present invention therefore includes the enantiomers and diastereoisomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase.
  • salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention.
  • Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, benzenesulfonic, toluenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic and citric acid, Fumaric acid, maleic acid and benzoic acid.
  • mineral acids for example hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, benzenesulfonic, toluenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic and citric acid, Fumaric acid, maleic acid and benzoic acid.
  • Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as by way of example and preferably alkali metal salts (eg sodium and potassium salts), alkaline earth salts (eg calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms as exemplified and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylpiperidine, N-methylmorpholine, arginine, lysine and 1,2-ethylenediamine.
  • customary bases such as by way of example and preferably alkali metal salts (eg sodium and potassium salts), alkaline earth salts (eg calcium and magnesium salts) and ammonium salts derived from ammoni
  • solvates are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.
  • substituents have the following meanings: (C 1 -C 6) -alkyl and (C 1 -C 4 ) -alkyl in the context of the invention are a straight-chain or branched alkyl radical having 1 to 10 or 1 to 6 or 1 to 4 carbon atoms. Preference is given to a straight-chain or branched alkyl radical having 1 to 4 carbon atoms.
  • radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. Substitution with one or two identical or different substituents is preferred. Particularly preferred is the substitution with a substituent.
  • R 1 , R 4 independently of one another represent hydrogen, hydroxyl, (C 1 -C 4 -alkyl, (C 1 -C 4 -alkoxy,
  • R 3 , R 6 are independently hydrogen or -0- (CR n R 12 ) n -CO 2 R 13 and in 2- or
  • R 7 , R 8 independently of one another represent hydrogen or (C 1 -C 6) -alkyl
  • R 11 , R 12 independently of one another represent hydrogen or (C 1 -C 6) -alkyl n is 1, 2 or 3
  • R 1 is hydrogen or (C 1 -C 6) -alkyl
  • Particularly preferred stilbenes are compounds of the formula (II) in which
  • R 1 , R 4 independently of one another represent hydrogen, hydroxyl, methyl, ethyl, propyl, isopropyl,
  • R 3 , R 6 are independently hydrogen or -0- (CR n R 12 ) n -CO 2 R 13 and in 2- or
  • R 7 , R 8 independently of one another represent hydrogen, methyl or ethyl
  • R 11 , R 12 are each independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl,
  • n 1, 2 or 3
  • Selected stilbenes of formula (5) include the following compounds:
  • the stilbenes of the invention may be in the E or Z conformation.
  • the Z conformation is preferred.
  • R 1 , R 4 independently of one another represent hydrogen, hydroxyl, (C 1 -C 6) -alkyl, (C 1 -C 4 -alkoxy,
  • R 3 , R 6 independently of one another represent hydrogen or -0- (CR n R 12 ) n -CO 2 R 13 ,
  • R 11 , R 12 independently of one another represent hydrogen or (C 1 -C 6) -alkyl, is 1, 2, 3, 4 or 5,
  • R is hydrogen or (C 1 -C 6) -alkyl
  • R 14 is methyl or ethyl
  • X is -CH 2 -, carbonyl, SO or SO 2
  • R 1 , R 4 independently of one another represent hydrogen, hydroxyl, methyl, ethyl, propyl, isopropyl,
  • R 3 , R 6 independently of one another represent hydrogen or -0- (CR n R 12 ) n -CO 2 R 13 ,
  • R 11 , R 12 are each independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl,
  • R 13 is hydrogen or (C 1 -C 4 ) -alkyl
  • the radicals R 2 and R 5 are in the 3- or 4-position and the radicals R 3 and R 6 are in the 2- or 4-position, in each case based on X.
  • Selected compounds of formula (I) include the following compounds: and their salts, solvates and solvates of the salts.
  • the residue definitions given in detail in the respective combinations or preferred combinations of residues are also replaced by residue definitions of other combinations, regardless of the particular combinations of the residues indicated.
  • the invention further provides a process for the preparation of the compounds of the formula (I) according to the invention, which comprises reacting a compound of the formula (I) in which at least one of the radicals R 2 and R 5 is -NFL.
  • Suitable diluents in the diazotization reaction are all polar solvents which are inert under the reaction conditions, for example alcohols, such as methanol, ethanol, also dimethylformamide and dimethyl sulfoxide, and in particular water or mixtures of these solvents.
  • Hydrohalic acids preferably hydrochloric acid or sulfuric acid, can be used as the strong acid in the diazotization reaction.
  • Potassium nitrite and sodium nitrite are preferably mentioned as diazotizing agents.
  • acid acceptors in the coupling reaction all common acid binders can be used. These preferably include sodium and potassium carbonate.
  • the aromatic amines as compounds of the formula (II) in which at least one of the radicals R 2 and R 5 is -NH 2 and the other radicals have the abovementioned meaning can best be prepared from the corresponding nitro-oxycarboxylic acid or oxycarboxylic acids in in a manner known per se, for example by catalytic reduction with hydrogen on palladium / carbon in ethanol or on platinum oxide in ethanol (Chem. Berichte 72, 839, [(1939)]) or with Raney nickel in THF (Chem. 1905 (1958)).
  • reaction scheme II Reaction scheme II:
  • the compounds according to the invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.
  • the compounds according to the invention can be used to prepare medicaments, preferably for the treatment of cancers of the tissues which can be influenced by estrogens, in particular of estrogen receptor-negative and estrogen receptor-positive tumors of the sexual organs, melanoma and colon carcinoma.
  • the compounds according to the invention can be used, for example, for the treatment of the following types of tumors: breast cancer, uterine cancer (endometrial carcinoma, corpus carcinoma), cervical cancer, ovarian cancer (ovarian carcinoma), vaginal cancer, prostate cancer, skin cancer, melanoma (malignant melanoma) and colon carcinoma.
  • the compounds according to the invention are known from DE 17 93 115, DE 21 47 781, GB 01371969 and WO 2004/106358 a reduction in the side effects.
  • the therapeutic range of the compounds according to the invention can be decisively increased and thus an oncocidal long-term therapy can be made possible.
  • treatment or “treating” is used conventionally within the context of this invention and means the care, care and supervision of a patient with the aim of combating, reducing, alleviating or alleviating a disease or health deviation and improving living conditions that are affected by the disease, such as cancer.
  • Another object of the present invention is thus the use of the compounds of the invention for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is the use of the compounds of the invention in a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.
  • the compounds according to the invention can be used alone or as needed in combination with one or more other pharmacologically active substances, as long as this combination does not lead to undesired and unacceptable side effects.
  • Another object of the present invention are therefore pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prevention of the aforementioned diseases.
  • the compounds according to the invention can be used medically as a monotherapy as well as in combination with other carcinostatics.
  • the compounds of the present invention may be combined with known anti-hyperproliferative, cytostatic or cytotoxic agents for the treatment of cancers.
  • suitable combination active ingredients are: aldesleukin, alendronic acid, alfaferone, alitretinoin, allopurinol, aloprim, aloxi, altretamine, aminoglutethimide, amifostine, amrubicin, amsacrine, anastrozole, anzmet, aranesp, arglabin, Arsenic trioxide, aromasine, 5-azacytidine, azathioprine, BCG or tice-BCG, bestatin, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, broxuridine, bortezomib, busulfan, calcitonin, campath, capecitabine, carboplatin, casodex, cefeson, Cel
  • the compounds of the present invention may be combined with anti-hyperproliferative agents, which may be by way of example, but not exhaustive: aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine, bleomycin, busulfan, carboplatin, carmustine , Chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, 2 ', 2'-difluorodoxycytidine, docetaxel, doxorubicin (adriamycin), epirubicin, epothilone and its derivatives, erythro-hydroxynonyladenine, ethinylestradiol, etoposide, fludarabine Phosphate, 5-fluorodeoxyuridine, 5-fluoro
  • the compounds of the invention may also be combined with biological therapeutics such as antibodies (e.g., Avastin, Rituxan, Erbitux, Herceptin).
  • biological therapeutics such as antibodies (e.g., Avastin, Rituxan, Erbitux, Herceptin).
  • the compounds according to the invention can also achieve positive effects in combination with therapies directed against angiogenesis, for example with avastin, axitinib, recentin, regorafenib, sorafenib or sunitinib.
  • Combinations with proteasome and mTOR inhibitors as well as combinations with antihormones and steroidal metabolic enzyme inhibitors are also particularly suitable because of their favorable side effect profile.
  • the combination of compounds of the present invention with other cytostatic or cytotoxic agents may have the following aims: • improved efficacy in slowing down the growth of a tumor, reducing its size or even eliminating it completely compared to treatment with a single drug;
  • the compounds according to the invention can also be used in combination with radiotherapy and / or surgical intervention.
  • compositions containing at least one compound of the invention usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • the compounds according to the invention can act systemically and / or locally.
  • they may be applied in a suitable manner, such as, for example, orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such as tablets (uncoated or coated Tablets, for example with enteric or delayed-dissolving or insoluble coatings, which control the release of the compound of the invention), tablets or films / wafers rapidly breaking down in the oral cavity, films / lyophilisates, capsules (for example hard or soft). gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
  • a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
  • absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicines including powder inhalers, nebulizers
  • nasal drops solutions or sprays
  • lingual, sublingual or buccal tablets films / wafers or capsules
  • suppositories ear or ophthalmic preparations
  • vaginal capsules aqueous suspensions (lotions, shake mixtures)
  • lipophilic suspensions ointments
  • creams transdermal therapeutic systems (eg plasters)
  • milk pastes, foams, powdered powders, implants or stents.
  • the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • excipients e.g., microcrystalline cellulose, lactose, mannitol
  • solvents e.g, liquid polyethylene glycols
  • emulsifiers and dispersing or wetting agents e.g., sodium dodecyl sulfate, polyoxysorbitol oleate
  • binders e.g., polyvinylpyrrolidone
  • synthetic and natural polymers e.g.
  • Albumin e.g antioxidants such as ascorbic acid
  • dyes eg inorganic pigments such as iron oxides
  • flavor and / or odoriferous agents it has proven to be advantageous, when administered parenterally, to administer amounts of about 0.1 to 60 mg / kg, preferably about 0.1 to 30 mg / kg of body weight, in order to achieve effective results.
  • the dosage is about 0.1 to 400 mg / kg, preferably about 0.1 to 200 mg / kg and most preferably 0 to 1 to 40 mg / kg of body weight.
  • a solution of 16 g of ammonium chloride in 60 ml of water is allowed to drip at a maximum of 30 ° C with stirring slowly to a mixture of 65.4 g (0.2 mol) of nitro compound of Intermediate 1, 800 ml of acetone and 200 g of zinc dust. Then stirring is continued for 20 hours. The zinc is then filtered off with suction and washed with 1 liter of hot acetone. The acetone solutions are concentrated. The residue is concentrated in 800 ml of water and 25 ml of conc. Hydrochloric acid and immediately extracted twice with ethyl acetate. It is then made slightly alkaline with sodium hydroxide solution and immediately extracted again with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is distilled off. The isolated brown oil is further processed as a crude product.
  • the biological activity of the compounds according to the invention can be detected by in vitro and in vivo studies, as are known to the person skilled in the art.
  • the pharmacological and pharmacokinetic properties of the compounds of the invention can be determined by the assays described below:
  • Benzidine-treated Wistat rats 24 female Wistar rats were subcutaneously treated with benzidine.
  • the first benzidine dose was 150 mg / kg; thereafter the doses were reduced to 100 mg / kg weekly. This was followed by doses of 75 mg / kg every 14 days. After 190 days and a total dose of about 1.225 g / kg, a total of about 29 breast carcinomas formed.
  • the mean life expectancy of the benzidine-treated Wistat rats was 365 days. After the first tumor (about 0.5 g) had formed, benzidine was no longer added. Then the breast carcinomas grew rapidly.
  • the volume of the individual tumors was measured with microcalipers and the tumor volume according to the method of Tomayko and Reynolds with the formula
  • V (mm 3 ) 0.5234 * (length * width * height) calculated.
  • Tumor weight was estimated assuming a density of the fabric of lg / cm 3.
  • Animals with a tumor weights of 0.5-1, 1 g were divided into treatment and control groups (randomized). Typically, group sizes of 2-5 animals were used, based on the number of individual tumors per animal. On average, in each group, the growth and treatment outcomes were assessed in 2-5 animals. Occasionally, the therapy was also followed on individual animals.
  • test substances (carboxylic acids) were administered as slightly water-soluble sodium or triethanolammonium salts subcutaneously on 5 days to week. The dosages used are given in the table. The test results were documented once a week. The measuring method is described above. T / C values were calculated for therapy days 10-50 and are presented in Table 8.
  • the breast carcinoma generated by benzidine in the tumor model grows very fast, as can be seen from the T / C values.
  • l-phenyl-3,3-dimethyltriazene Proc. Soc., Exper.biol. Med., 90, 484 (1955), is a cytostatic agent
  • the compound here has anti-mammalian carcinoma of the Wistar or Sprague-Dawley rats at a maximum possible dose (with a single dose of 100 mg / kg sc) only a modest impact compared to the untreated control foudroyante tumor growth continues thereafter.
  • the body weight of the animals decreased on average by about 30%, the coat of the animals was shaggy and signs of toxic damage were visible.
  • the embodiments were tested as sodium salts or triethanolammonium salts.
  • Embodiment 10 is a diagrammatic representation of Embodiment 10:
  • Exemplary Embodiment 11 After an initially strong increase in the T / C value, tumor growth is stopped and the C / T value remains constant. Between the 30th and 50th day begins a necrosis / oncolysis of the tumor.
  • the claimed compounds have a pronounced oncocidal effect on breast cancer with a broad therapeutic window and are promising candidates for clinical application.
  • Exemplary embodiments of pharmaceutical compositions are provided.
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • Composition 100 mg of the compound according to the invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.
  • the mixture of compound of the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water.
  • the granules are mixed after drying with the magnesium stearate for 5 minutes.
  • This mixture is compressed with a conventional tablet press (for the tablet format see above).
  • a pressing force of 15 kN is used as a guideline for the compression.
  • the rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. While stirring, the addition of water. Stirring is continued for about 6 h until the swelling of the rhodule is complete.
  • the compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention.
  • i.v. solution The compound of the present invention is dissolved in a concentration below the saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline, glucose solution 5%, and / or PEG 400 solution 30%). The solution is sterile-filtered and placed in sterile and pyrogen-free injection troughs.
  • a physiologically acceptable solvent e.g., isotonic saline, glucose solution 5%, and / or PEG 400 solution 30%.

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Abstract

La présente invention concerne des dérivés diphényliques pontés substitués qui contiennent par molécule au moins (i) un groupe dialkyltriazényle et (ii) au moins un groupe acide oxycarboxylique sélectionné, leurs sels, solvates et les solvates de ces sels. L'invention concerne également un procédé de production de ces dérivés, l'utilisation de ces dérivés pour le traitement et/ou la prévention de maladies ainsi que l'utilisation de ces dérivés pour la production de médicaments pour le traitement et/ou la prévention de maladies, en particulier de maladies cancéreuses comme par exemple des maladies cancéreuses des organes sexuels. De tels traitements peuvent avoir lieu comme monothérapie ou également en combinaison avec d'autres médicaments ou d'autres mesures thérapeutiques.
PCT/EP2012/055420 2011-03-31 2012-03-27 Ciblage de tissu avec des dérivés diphényliques pontés oncocides pour le traitement sélectif de tumeurs des organes sexuels WO2012130850A1 (fr)

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EP11160710 2011-03-31
EP11160710.7 2011-03-31
EP11163104.0 2011-04-20
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Cited By (3)

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WO2019241663A1 (fr) * 2018-06-15 2019-12-19 Afecta Pharmaceuticals, Inc. Inhibiteurs de ccl5
WO2022063549A1 (fr) * 2020-09-25 2022-03-31 Creative Therapeutics Gmbh Principes actifs et médicaments pour la thérapie de maladies virales, en particulier d'infections à coronavirus, en particulier de la covid -19

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105566153A (zh) * 2014-10-14 2016-05-11 中国医学科学院药物研究所 偶氮苯衍生物及其制法和药物组合物与用途
CN105566153B (zh) * 2014-10-14 2019-05-31 中国医学科学院药物研究所 偶氮苯衍生物及其制法和药物组合物与用途
WO2019241663A1 (fr) * 2018-06-15 2019-12-19 Afecta Pharmaceuticals, Inc. Inhibiteurs de ccl5
US10940132B2 (en) 2018-06-15 2021-03-09 Afecta Pharmaceuticals, Inc. CCL5 inhibitors
US11318111B2 (en) 2018-06-15 2022-05-03 Lapko Inc CCL5 inhibitors
US11497724B2 (en) 2018-06-15 2022-11-15 Lapko Inc CCL5 inhibitors
US11628154B2 (en) 2018-06-15 2023-04-18 Lapko Inc CCL5 inhibitors
WO2022063549A1 (fr) * 2020-09-25 2022-03-31 Creative Therapeutics Gmbh Principes actifs et médicaments pour la thérapie de maladies virales, en particulier d'infections à coronavirus, en particulier de la covid -19

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