EP3573625A1 - Produit pharmaceutique pour la chélation du fer - Google Patents

Produit pharmaceutique pour la chélation du fer

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Publication number
EP3573625A1
EP3573625A1 EP18704880.6A EP18704880A EP3573625A1 EP 3573625 A1 EP3573625 A1 EP 3573625A1 EP 18704880 A EP18704880 A EP 18704880A EP 3573625 A1 EP3573625 A1 EP 3573625A1
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Prior art keywords
group
type
mol
pharmaceutical
initiator
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German (de)
English (en)
Inventor
Holger Frey
Tobias Johann
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Johannes Gutenberg Universitaet Mainz
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Johannes Gutenberg Universitaet Mainz
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    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A61K31/77—Polymers containing oxygen of oxiranes
    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A61K31/78—Polymers containing oxygen of acrylic acid or derivatives thereof
    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • A61K31/787—Polymers containing nitrogen containing heterocyclic rings having nitrogen as a ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F112/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an aromatic carbocyclic ring
    • C08F112/02—Monomers containing only one unsaturated aliphatic radical
    • C08F112/04—Monomers containing only one unsaturated aliphatic radical containing one ring
    • C08F112/14—Monomers containing only one unsaturated aliphatic radical containing one ring substituted by hetero atoms or groups containing heteroatoms
    • C08F112/22—Oxygen
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F112/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an aromatic carbocyclic ring
    • C08F112/02—Monomers containing only one unsaturated aliphatic radical
    • C08F112/04—Monomers containing only one unsaturated aliphatic radical containing one ring
    • C08F112/14—Monomers containing only one unsaturated aliphatic radical containing one ring substituted by hetero atoms or groups containing heteroatoms
    • C08F112/26—Nitrogen
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F112/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an aromatic carbocyclic ring
    • C08F112/02—Monomers containing only one unsaturated aliphatic radical
    • C08F112/32—Monomers containing only one unsaturated aliphatic radical containing two or more rings
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F8/00—Chemical modification by after-treatment
    • C08F8/30—Introducing nitrogen atoms or nitrogen-containing groups
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/04—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers only
    • C08G65/06—Cyclic ethers having no atoms other than carbon and hydrogen outside the ring
    • C08G65/14—Unsaturated oxiranes
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/04—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers only
    • C08G65/22—Cyclic ethers having at least one atom other than carbon and hydrogen outside the ring
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/26—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds
    • C08G65/2603—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds the other compounds containing oxygen
    • C08G65/2606—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds the other compounds containing oxygen containing hydroxyl groups
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/26—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds
    • C08G65/2618—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds the other compounds containing nitrogen
    • C08G65/2633—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds the other compounds containing nitrogen the other compounds containing amide groups
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
    • C08G65/33396—Polymers modified by chemical after-treatment with organic compounds containing nitrogen having oxygen in addition to nitrogen
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/34—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from hydroxy compounds or their metallic derivatives
    • C08G65/48—Polymers modified by chemical after-treatment
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G81/00—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers

Definitions

  • the present invention relates to a pharmaceutical for the physiological complexation of iron in pathological iron overload.
  • iron is an essential trace element.
  • the effect of iron in the organism is based on the participation of Fe 2+ and Fe 3+ ions in reduction and oxidation processes.
  • Fe 2+ ions are highly toxic and Fe 3+ ions are not water soluble at a physiological pH of 7.4.
  • Microorganisms use low molecular weight high affinity iron ligands or siderophores, such as enterobactins. Higher life forms, such as mammals use specialized storage and transport proteins.
  • the human body Under normal physiological conditions, the human body contains 3.5 to 5 g of iron, predominantly (-70%) in the form of hemoglobin in erythrocytes and erythroid progenitor cells. The remaining approximately 30% of iron is found in myoglobin and intracellular stores such as hepatocytes of liver, spleen and bone marrow macrophages, as well as proteins and enzymes involved in cellular respiration. In humans, iron metabolism is largely conservative, with efficient recycling of iron contained in hemoglobin making a significant contribution. In addition, digestion plays an important role in the homeostasis of iron in the human body, taking in about 1 to 2 mg of iron per day. About the same amount of iron is excreted daily through the secretion of epithelial cells, skin and intestinal secretions and small blood loss in the digestive tract.
  • Transferrin Under physiological conditions, iron is complexed by proteins such as transferrin (Tf) to ensure that it does not contribute to the formation of free radicals. Iron bound to transferrin is transported in the plasma and is not available for redox reactions. Transferrin has a high iron capacity and ensures that there is no free toxic so-called non-transferrin-bound iron (NTBI). Transferrin contains 2 to 3 mg of iron and is only about 70% saturated under normal physiological conditions. Transferrin transports iron to the hepatocytes and specific binding sites on the precursors of bone marrow red cells involved in the synthesis of hemoglobin. In addition, transferrin binds iron, that of intestinal erythrocytes or from cells that catabolize senescent red blood cells into the plasma.
  • NTBI non-transferrin-bound iron
  • ferritin is the main storage molecule for reusable iron, accounting for about 27% (lg) of the total amount of iron in the body.
  • Ferritin has a storage capacity of 4500 atoms of iron per ferritin molecule and ensures that iron is present within the cell in a redox-inactive form. Accordingly, ferritin reduces toxicity due to the formation of free radicals while retaining iron in mobile form for metabolic processes. In oxidative stress, ferritin removes iron ions and oxygen from the cytoplasm and aids in the return to normal redox conditions.
  • iron chelation In addition to this intrinsic iron alumeration, patients regularly receive blood transfusions, which typically contain about 250 mg of iron. In order to keep the iron content in the plasma within the physiologically normal range, the patients are treated concomitantly by means of iron chelation. Iron chelation is clinically indicated for patients suffering from ß-TM, MDS or SCD and receiving blood transfections. In the context of iron chelation, drug molecules are used that bind iron under physiological conditions and form a non-toxic complex or chelate, which is subsequently excreted renally or fecally. Iron chelation protects cells from oxidative damage by reducing the level of reactive iron in the plasma and the cytosolic labile iron pool.
  • DFO deferiprone
  • DFX deferasirox
  • DFO Deferoxamine
  • DFO can increase the life expectancy of patients with The incidence of cardiac damage, liver failure, and endocrinological disorders can be significantly reduced, but despite its beneficial effects, DFO has significant drawbacks due to its low lipophilicity and its high potency DFO is absorbed by gastrointestinal cells only very slowly and has a short physiological half-life of only about 5 to 20 minutes Accordingly, DFO must be administered subcutaneously with a dose of 40-60 mg per kg of body weight distributed over 8-12 h 5 -7 days a week. Due to the complicated administration form is the patients Compliance deficient. On the other hand, at higher doses of DFO, severe neurotoxic disorders such as neurological hearing loss, electroretininal abnormalities, reduced bone development, and growth disorders may occur.
  • DFP Deferiprone
  • DFP DFP-phosphatidylcholine
  • the 3-hydroxyl functional group of DFP which is essential for the chelation of iron, causes rapid metabolisation in liver cells by glucuronidation.
  • 85% of the administered DFP dose was found in the urine in the form of inactive 3-0-glucuronide conjugates.
  • DFP has side effects such as agranulocytosis and neutropenia.
  • DFX Deferasirox
  • the present invention aims to provide improved pharmaceuticals for iron chelation.
  • well-defined hydroxamic acid functionalized macromolecular structures are proposed. So far, only a few studies on hydroxamic acid-functionalized macromolecular structures are known. Almost all polymers with hydroxamic acid functional groups were prepared by polymer-analogous reactions. The spectrum of structures is limited to polymers with vinyl backbones, in particular polymethyl methacrylates, polyacrylamides or special NHS active ester polymers which have been prepared by free-radical polymerization. A complete functionalization is not known yet.
  • hydroxamic acids are excellent chelating agents for medical and engineering applications (Codd, R. Coord. Chem. Rev. 2008, 252, 1387-1408).
  • Polyethers especially polyethylene glycol and its derivatives, are well established in the medical field and are accessible by anionic ring-opening polymerization of defined structure. In particular, the low toxicity, the water solubility and the "stealth" effect represent a great benefit for therapeutic purposes.
  • epoxy derivatives such as ethylene oxide, propylene oxide, butylene oxide and glycidyl ether, the preparation of multifunctional polyethers is possible.
  • Kizhakkedatu et al. were able to demonstrate the potential of hydroxamic acid-functional polyethers in medical applications using DFO-hbPG conjugates.
  • Deferoxamine is on the World Health Organization's Essential Medicines list and is the major therapeutic approach to preventing lethal iron intoxication (Marmion, CJ, Griffith, D., Nolan, KBEur, J. Inorg Chem 2004, 2004, 3003-3016, World Health Organization, Model List of Essential Medicines, 2015). Due to the short plasma half-life of approximately 5 minutes, subcutaneous injections must be carried out over several hours for a successful therapy. Kizhakkedathu et al. showed that the conjugation of deferoxamine with hyperbranched polyglycerol increased the half-life to up to 44 hours.
  • hydroxamic acid functional polyethers represent an alternative to deferoxamine, deferiprone and deferasirox with increased plasma half-life and / or reduced toxicity. This would be a significant improvement in therapy for patients suffering from ß-TM, SCD or MDS who are dependent on lifelong treatment with DFO, DFP or DFX.
  • 1,4,2-Dioxazole-protected hydroxamic acid derivatives provide an approach for the systematic preparation of polymers, with which also multifunctional polymer architectures without polymer-analogous reactions are accessible.
  • a defined number of hydroxamic acid groups in the Polymer are introduced. This counteracts crosslinking of the polymer molecules by a plurality of functional groups per polymer molecule.
  • inventive concept direct anionic ring-opening polymerization starting from protected hydroxamic acid-functional initiators and protected hydroxamic acid-functional epoxy monomers is described for the first time.
  • the object of the present invention is to provide a method and a pharmaceutical prepared by the method for the physiological iron chelation and excretion, which has an increased physiological half-life and / or a reduced toxicity compared to known active compounds, such as DFO, DFP and DFX.
  • Alcohols such as HOCH 3 , HOCH 2 CH 3 , HO (CHCH 3 ) CH 3 ,
  • Lithiumorganyle and radical initiators such as n-butyl lithium, sec-butyl lithium, dibenzoyl peroxide, azoisobutyronitrile, potassium peroxide sulfate, ammonium peroxide sulfate;
  • the initiator and / or one of the monomers contains a protected hydroxamic acid group or the at least one monomer contains an epoxide including the epoxide
  • R 1 is selected
  • - alcoholate such as -OCH 2 -, -OCH 2 CH 2 -, -0 (CHCH 3) CH 2 -, -0 (CH 2) 3 -, -0 (CH 2) 4 -, -0 (CH 2 ) 5 -;
  • Aromatic groups such as phenol or naphthyl radicals
  • R 6 is selected from -H and -CH 3 ;
  • step (c) mixing one or more of the monomers provided in step (b) with the initiator in a predetermined molar ratio;
  • step (a) the initiator is provided as a salt of one of the foregoing protected hydroxamic acid group-containing compounds;
  • a monomer used in step (c) has the structure Has;
  • a monomer used in step (c) has the structure Has;
  • a monomer used in step (c) has the structure
  • step (c) the initiator and one or more of the monomers provided in step (b) are mixed in a molar ratio of initiator to monomer (s)
  • step (c) the initiator and one or more of the monomers provided in step (b) at a temperature of ⁇ 0 ° C, ⁇ -10 ° C, ⁇ -20 ° C, ⁇ -30 ° C or ⁇ -40 ° C to be mixed;
  • step (c) the initiator and one or more of the monomers provided in step (b) are mixed in one or more solvents;
  • step (c) the initiator and one or more of the monomers provided in step (b) are mixed in one or more organic solvents, such as hexane, benzene, toluene, tetrahydrofuran, dioxane, dimethyl sulfoxide;
  • organic solvents such as hexane, benzene, toluene, tetrahydrofuran, dioxane, dimethyl sulfoxide
  • step (d) the polymerization is initiated by raising the temperature of the in
  • step (e) adding to the reaction mixture another of the monomers provided in step (b) and continuing the polymerization;
  • step (e) is carried out a plurality of times
  • the polymerization is terminated by consumption of the at least one monomer or by adding a terminating agent
  • the polymerization is terminated by adding a terminating agent selected from the group comprising protic reagents such as H 2 O; Alcohols, such as methanol,
  • a deprotecting agent selected from the group comprising aqueous and nonaqueous solutions of inorganic acids such as hydrochloric acid and sulfuric acid; aqueous and nonaqueous solutions of organic acids, such as para-toluenesulfonic acid and camphor-10-sulfonic acid; or by using acidic ion exchangers.
  • a deprotecting agent selected from the group comprising aqueous and nonaqueous solutions of inorganic acids such as hydrochloric acid and sulfuric acid; aqueous and nonaqueous solutions of organic acids, such as para-toluenesulfonic acid and camphor-10-sulfonic acid; or by using acidic ion exchangers.
  • all process steps are carried out under normal conditions at room temperature, i. carried out in a range of 20 to 35 ° C and a pressure of 0.9 to 1.1 bar. In individual cases, however, it may be expedient to carry out some of the process steps at elevated or reduced temperature and / or elevated or reduced pressure.
  • step (d) occurs spontaneously, the polymerization time being long compared to the time required to produce a homogeneous mixture of the monomers and the initiator by conventional mechanical methods, such as stirring or panning in step (c). and possibly in step (e) is needed.
  • step (c) is carried out at reduced temperature to ensure a homogeneous mixture of the monomers and the initiator and then, in step (d), raises the temperature to initiate the polymerization.
  • step (d) is carried out at elevated temperature.
  • the invention includes pharmaceuticals preparable by a process comprising one or more of the steps described above.
  • - alcoholate such as -OCH 3, -OCH 2 CH 3, -0 (CHCH 3) CH 3,
  • Residues of a lithium organyl or radical initiator such as CH 3 (CH 2 ) 3 -,
  • the Pol mer consists of styrene units, which are selected from the group comprising
  • R 1 is selected
  • - alcoholate such as -OCH 2 -, -OCH 2 CH 2 -, -0 (CHCH 3) CH 2 -,
  • Aromatic groups such as phenol or naphthyl radicals
  • R 2 is selected from -H and -CH 3 ;
  • R 6 is selected from -H and -CH 3 ;
  • R 1 is a pentanol group -0 (CH 2 ) 5 -;
  • R 1 is a phenol group -0 (C 6 H 4 ) -;
  • R 2 is -CH 3 ;
  • R 6 is -H; R 6 is -CH 3 ;
  • R I has polymer R 7 , the polymer being a polyethylene glycol
  • R I has polymer R 7 wherein the polymer is a polypropylene glycol
  • R 1 has polymer R 7 , the polymer being a linear polyglycerol
  • R 1 has polymer R 7 wherein the polymer is a branched polyglycerin consisting of 3 to 100 units selected from the group comprising
  • the pharmaceutical has a polydispersity M w / M n ⁇ 2; the pharmaceutical has a polydispersity M w / M n ⁇ 1.6, preferably M w / M n ⁇ 1.2 and in particular M w / M n ⁇ 1.1; the pharmaceutical has a molar mass MW with 100 g-mol "1 ⁇ MW ⁇ 2000 g-mol "1 ; the pharmaceutical a molar mass MW with 100 g-mol "1 ⁇ MW ⁇ 600 g-mol " 1 , 100 g-mol "1 ⁇ MW ⁇ 400 g-mol " 1 or 100 g-mol "1 ⁇ MW ⁇ 300 g -mol "1 ;
  • the pharmaceutical agent has a molar mass MW of 600 g-mol "1 ⁇ MW ⁇ 40,000 g-mol "1 ; the pharmaceutical has a molar mass MW with 800 g-mol "1 ⁇ MW ⁇ 40 000 g-mol “ 1 , preferably 1000 g-mol "1 ⁇ MW ⁇ 40 000 g-mol "1 ; and or
  • the pharmaceutical a molar mass MW with 600 g-mol "1 ⁇ MW ⁇ 2000 g-mol " 1 , 800 g-mol "1 ⁇ MW ⁇ 2000 g-mol " 1 preferably 1000 g-mol "1 ⁇ MW ⁇ 2000 g -mol "1 ; Furthermore, the invention relates to the use of the above-described
  • the GPC measurements were carried out according to DIN 55672-3 2016-01 with dimethylformamide (DMF), mixed with 1 g / L lithium bromide, as eluent on an Agilent 1100 series instrument with a HEMA 300/100/40 column from MZ-Analysetechnik ,
  • the signals were detected by RI detector (Agilent G1362A) and UV (254 nm) detector (Agilent G1314A).
  • the signal of the RI detector and possibly the signal of the UV detector were used primarily.
  • the measurements were carried out at 50 ° C and a flow rate of 1.0 mL / min. Calibration was carried out with polyethylene glycol Standards 200, 1000, 2000, 6000, 20000 and 40000 and polystyrene standards from Polymer Standard Service.
  • reaction solution is taken up in 100 mL diethyl ether, the organic phase separated and washed twice with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacao. After purification by column chromatography using silica (petroleum ether: ethyl acetate 4: 1), 306 mg (1.3 mmol, 19% of th.) Of 5,5-dimethyl-3- (5- (oxiran-2-ylmethoxy) pentyl-1,4 , 2-dioxazole obtained.
  • the initiator 5- (5,5-dimethyl-l, 4,2-dioxazol-3-yl) -pentan-1-ol is placed in a dried flask and treated with 0.9 eq cesium hydroxide monohydrate and 5 mL benzene under static vacuum stirred for 60 minutes. Subsequently, the initiator salt is dried in a high vacuum overnight and dissolved the next day in 10 mL of dry THF. Subsequently, ethylene oxide is cryotransferred into the reaction vessel and the reaction solution for 24 to 48 hours at 40 - 60 ° C stirred.
  • the alpha-1,4,2-dioxazole-functional polyethylene glycol is mixed with the same amount of DOWES 50WX8 ion exchange resin in isopropanol and shaken for 20 h.
  • the solution is then filtered, the filtrate concentrated in vacuo and the hydroxamic acid-functional polyethylene glycol obtained by precipitation in ice-cold diethyl ether.
  • the colorless hydroxamic acids form highly colored complexes with metals. Trishydroxamatometall complexes are usually formed here.
  • FIG. 1 shows the absorbance as a function of the concentration ratio of Fe 3+ to the alpha-1,4,2-dioxazole-functional polyethylene glycol designated HA in the diagram of Figure 1 for hydroxamic acid.
  • Example 6 Protected hydroxamic acid initiator for anionic ring-opening polymerization 1st stage 4- (2-hydroxyethoxy) benzoic acid ethyl ester
  • the reaction is then terminated by addition of 850 ml of 2 molar aqueous NaOH solution and stirred for 48 h at room temperature.
  • the organic phase is separated off and the aqueous phase is extracted with 200 ml of dichloromethane.
  • the combined organic phases are washed twice with 150 ml of 2 molar aqueous NaOH solution and once with 200 ml of saturated NaCl solution, dried over MgS0 4 and the solvent is removed completely in vacuo.
  • the residue obtained was 2.45 g (10.33 mmol, 40% of theory) of 2- (4- (5,5-dimethyl-1,2,2-dioxazol-3-yl) phenoxy) ethanol as a colorless solid.
  • Example 7 Epoxymonomer with protected hydroxamic acid group 5,5-dimethyl-3- (4- (2- (oxiran-2-ylmethoxy) etoxy) phenyl) -1,2,2-dioxazole
  • Example 9 Epoxide monomer from benzyl alcohol initiator 5,5-dimethyl-3- (4 - ((oxiran-2-ylmethoxy) methyl) phenyl) -1,2,2-dioxazole
  • Example 10 Anionic polymerization of 5,5-dimethyl-3- (4-vinylphenyl) -1-A2-dioxazole
  • Example 11 Anionic polymerization of epoxide derivatives starting from protected hydroxamic acids as initiator
  • 0.043 mmol (1 eq) of initiator are initially introduced into a 100 mL Schlenk flask, and 0.035 mmol (0.8 eq) of potassium tert-butoxide and 0.070 mmol (1.6 eq) of 18-crown-6 are added. Then 1 mL THF and 4 mL benzene are added to deprotonate and the solution is stirred under static vacuum (about 500 mbar) for 30 minutes at 40 ° C.
  • the solvent is completely removed under high vacuum (10 -3 mbar) and the initiator is dried for 24 h, then the initiator is dissolved in 10 mL of dry THF (over sodium), provided with 23 mmol (40 eq) of dried monomer and dried for 24 h.
  • the reaction is terminated by addition of 1 ml of methanol, the solvents are removed in a high vacuum and the polymer is purified by partitioning between dichloromethane and water, the residue is dissolved in dichloromethane and precipitated against aqueous NaCl.
  • the organic phase is separated off and dried over Na 2 SO 4 and completely freed of solvent under reduced pressure Typical yields 80-95% of theory
  • Example 12 (4- (5,5-Dimethyl-L4,2-dioxazol-3-yl ' ) phenyl) methanol-initiated polypropylene oxide
  • Example 13 2- (4- ( ' 5,5-Dimethyl-L4,2-dioxazol-3-yl phenoxy ethanol initiated polypropylene oxide
  • Example 15 2- (4- (5.5-Dimethyl-L4,2-dioxazol-3-yl phenoxy) ethanol-initiated polyethylene glycol
  • Example 16 Anionic Copolymerization of Epoxy Derivatives with Epoxymonomers with Protected Hydroxamic Acid Group
  • Example 18 Propylene oxide random copolymer and 5,5-dimethyl-3-f4- (2-isoxiran-2-ylmethoxy) ethoxy) phenyl) -1,2,2-dioxazole
  • Example 19 Statistical copolymer of ethylene oxide and 5,5-dimethyl-3- (4-f (oxiran-2-ylmethoxy) methyl) phenyl) -1,2,2-dioxazole
  • Example 21 Preparation of Block Copolymers of mPEG and a Protected Hydroxamic Acid Bloc
  • the macroinitiator is dissolved in 5 ml of dry THF and treated with 200 mg (0.76 mmol, 4.6 eq) of 5,5-dimethyl -3- (4 - ((oxiran-2-ylmethoxy) methyl) phenyl) -1,2,2-dioxazole (azeotropically dried with benzene for 24 h under high vacuum) and stirred for 48 h at 60 ° C. Subsequently, the reaction After removal by centrifugation, the residue is taken up in dichloromethane, washed with saturated NaCl solution, the organic phase is separated off and dried over Na 2 SO 4 Removal of the solvent in vacuo gives the product in a yield of 95% of theory.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)

Abstract

L'invention concerne un produit pharmaceutique pour la complexation du fer, ledit produit pharmaceutique se compose d'un groupe initiateur, d'un polymère et d'un groupe terminal R7, présente la structure groupe initiateur-polymère R7 et comprend un ou plusieurs groupes acide hydroxamique fonctionnels du type -(C=0)NHOH ou -(C=0)NCH3OH.
EP18704880.6A 2017-01-26 2018-01-24 Produit pharmaceutique pour la chélation du fer Pending EP3573625A1 (fr)

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DE102017101548.5A DE102017101548B4 (de) 2017-01-26 2017-01-26 Pharmazeutikum für Eisenchelatisierung
PCT/EP2018/051709 WO2018138136A1 (fr) 2017-01-26 2018-01-24 Produit pharmaceutique pour la chélation du fer

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* Cited by examiner, † Cited by third party
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US4613616A (en) 1984-07-20 1986-09-23 Research Corporation Polymeric iron chelators
US5128420A (en) 1987-02-26 1992-07-07 Massachusetts Institute Of Technology Method of making hydroxamic acid polymers from primary amide polymers
EP0347424B1 (fr) 1987-02-26 1992-03-18 Massachusetts Institute Of Technology Polymeres d'acide hydroxamique formes de polymeres d'amide primaires
AU643899B2 (en) * 1991-07-24 1993-11-25 Nalco Chemical Company Hydroxamic acid containing polymers used as corrosion inhibitors
US5624901A (en) 1994-04-15 1997-04-29 The Regents Of The University Of California 3-hydroxy-2(1H)-pyridinone chelating agents
JP2002264556A (ja) * 2001-03-14 2002-09-18 Fuji Photo Film Co Ltd 画像形成材料及び平版印刷版用原版
US6979717B2 (en) * 2001-08-13 2005-12-27 Moore Eugene R Anionic process design for rapid polymerization of polystyrene without gel formation and product produced there from
US20070160655A1 (en) 2003-04-23 2007-07-12 Sefton Michael V Hydroxyamate-containing materials for the inhibition of matrix metalloproteinases
US9139456B2 (en) 2008-04-16 2015-09-22 The Curators Of The University Of Missouri Chelating compounds and immobilized tethered chelators

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WO2018138136A1 (fr) 2018-08-02
US20190359769A1 (en) 2019-11-28

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