[go: up one dir, main page]

WO1998036002A1 - Polymeres de vinyle reticules a effet adsorbant d'acide biliaire - Google Patents

Polymeres de vinyle reticules a effet adsorbant d'acide biliaire

Info

Publication number
WO1998036002A1
WO1998036002A1 PCT/EP1998/000898 EP9800898W WO9836002A1 WO 1998036002 A1 WO1998036002 A1 WO 1998036002A1 EP 9800898 W EP9800898 W EP 9800898W WO 9836002 A1 WO9836002 A1 WO 9836002A1
Authority
WO
WIPO (PCT)
Prior art keywords
independently
mmol
mixture
compounds
alkyl
Prior art date
Application number
PCT/EP1998/000898
Other languages
German (de)
English (en)
Inventor
Heinke Von Seggern
Axel Hoffmann
Eugen Falk
Brigitte Hörsch
Adolf Heinz Linkies
Heiner Glombik
Original Assignee
Aventis Research & Technologies Gmbh & Co Kg
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Aventis Research & Technologies Gmbh & Co Kg filed Critical Aventis Research & Technologies Gmbh & Co Kg
Priority to BR9807408-3A priority Critical patent/BR9807408A/pt
Priority to EP98910693A priority patent/EP0960141A1/fr
Priority to JP53537598A priority patent/JP2002515930A/ja
Priority to CA002281602A priority patent/CA2281602A1/fr
Priority to AU64983/98A priority patent/AU728985B2/en
Priority to HU0001012A priority patent/HUP0001012A3/hu
Publication of WO1998036002A1 publication Critical patent/WO1998036002A1/fr

Links

Classifications

    • 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
    • C08F8/44—Preparation of metal salts or ammonium salts
    • 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
    • C08F271/00—Macromolecular compounds obtained by polymerising monomers on to polymers of nitrogen-containing monomers as defined in group C08F26/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C08F20/00—Homopolymers and copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride, ester, amide, imide or nitrile thereof
    • C08F20/02—Monocarboxylic acids having less than ten carbon atoms, Derivatives thereof
    • C08F20/10—Esters
    • C08F20/34—Esters containing nitrogen, e.g. N,N-dimethylaminoethyl (meth)acrylate
    • C08F20/36—Esters containing nitrogen, e.g. N,N-dimethylaminoethyl (meth)acrylate containing oxygen in addition to the carboxy oxygen, e.g. 2-N-morpholinoethyl (meth)acrylate or 2-isocyanatoethyl (meth)acrylate
    • 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
    • C08F22/00—Homopolymers and copolymers 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 a carboxyl radical and containing at least one other carboxyl radical in the molecule; Salts, anhydrides, esters, amides, imides or nitriles thereof
    • C08F22/10—Esters
    • C08F22/1006—Esters of polyhydric alcohols or polyhydric phenols, e.g. ethylene glycol dimethacrylate
    • 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
    • C08F22/00—Homopolymers and copolymers 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 a carboxyl radical and containing at least one other carboxyl radical in the molecule; Salts, anhydrides, esters, amides, imides or nitriles thereof
    • C08F22/36—Amides or imides
    • C08F22/38—Amides
    • C08F22/385—Monomers containing two or more (meth)acrylamide groups, e.g. N,N'-methylenebisacrylamide

Definitions

  • the invention relates to quaternary ammonium salts crosslinked vinyl polymers with bile acid adsorber activity, monomers thereof, a process for their preparation and the use of the polymers as medicaments for reducing the bile acid reabsorption in the intestine with the aim of lowering the serum cholesterol level in the blood (therapy of Hypercholesterolemia).
  • Bile acids and their salts are natural detergents and have an important physiological function in fat digestion and fat absorption. As end products of the cholesterol metabolism, they are synthesized in the liver, stored in the gallbladder and released from there into the intestine as part of the bile, where they develop their physiological effect. The major part (approx. 85-90%) of the secreted bile acids (approx. 16 g / day) is resorbed from the intestinal wall via the enterohepatic circulation, preferably in the terminal ileum, and transported back to the liver, i.e. recycled. Only 10-15% of the bile acids are excreted in the faeces.
  • a reduction in the amount of bile acid by post-synthesis of bile acids from cholesterol can be compensated to a certain extent via a control loop system.
  • a decrease in the liver cholesterol level leads to an increase in the absorption of cholesterol from the blood serum and thus lowers the
  • the enterohepatic circulation can be interrupted and the serum cholesterol level in the blood can be reduced by suppressing the bile acid reabsorption by means of suitable inhibitors or bile acid adsorbers in the intestine. Too high a serum cholesterol level is considered to be of concern in medicine because it leads to atherosclerosis and thus the risk of heart attack increases. Therefore, there are many therapeutic approaches for the treatment of hypercholesterolemia.
  • One of these approaches is to interrupt the enterohepatic cycle. This approach can also be used to treat all diseases in which inhibition of bile acid reabsorption in the small intestine appears desirable.
  • Non-absorbable bile acid adsorbers have been used therapeutically for some time to bind bile acids.
  • insoluble, mostly crosslinked polymers are used for this purpose, which contain quaternized nitrogen centers and act in a similar way to anion exchangers.
  • polymers are described in US Pat. No. 5,607,669. These polymers bind part of the bile acid anions present in the intestine via predominantly ionic interactions and transport them out of the intestine.
  • Commercial products of this type contain, for example, the active ingredients cholestyramine and colestipol. For example, they are used to treat hypercholesterolemia.
  • bile acid absorption inhibition In addition to the polymeric bile acid adsorbers, the mode of action of bile acid absorption inhibition (receptor blockers) was also pursued. Here, the bile acid receptor sites in the terminal ileum are blocked by molecules which can interact with the receptors analogously to the bile acids, but, unlike the bile acids, are not absorbed. Through this
  • Receptor blockade the bile acids can no longer be absorbed and are then excreted with the faeces.
  • polymeric bile acid receptor blockers can be found in EP-A-0 549 967. Bile acid polymers and oligomers are described therein, in which bile acid molecules are laterally linked to a polymer backbone.
  • the known compounds have the following disadvantages.
  • adsorbers also do not have a selective effect and also bind vitamins (e.g. vitamin K) and other physiologically important substances, so that deficiency symptoms (e.g. avitaminoses) can occur.
  • vitamins e.g. vitamin K
  • other physiologically important substances e.g. avitaminoses
  • diarrhea can occur in the previously known bile acid absorption inhibitors because of the increase in the bile acid concentration in the intestine caused by the receptor blockade.
  • Polymers which contain quaternary ammonium ions and are suitable as ion exchangers or fluoride ion donors are known, for example, from US Pat. No. 5,118,717 and WO 96/22761.
  • bile acid molecules and / or low-molecular bile acid absorption inhibitor molecules are covalently or firmly bound to a polymer molecule via a spacer group, so that they are no longer resorbable themselves but still retain their absorption-inhibiting effect.
  • the partially occurring systemic cytotoxic side effects of the low-molecular absorption inhibitors which can be caused by their own absorption, can be avoided.
  • the polymer is too large to be absorbed.
  • the polymer also contains bile acid adsorbent centers, e.g. B. quaternized nitrogen centers in the molecule. These reduce the increased bile acid concentration in the intestine due to the receptor blockade by binding and adsorbing bile acid anions.
  • Polymers of this type therefore have a dual effect. On the one hand, they act as polymeric bile acid absorption inhibitors due to the covalently firmly bound receptor blocker units and, on the other hand, as bile acid adsorbers.
  • A is hydrogen or alkyl C 1 -9
  • G and E independently represent O or NH, and preferably both NH, d and a independently represent an integer from 2 to 10, preferably both the same in number, R 1 and R 2 are independently C ⁇ g-alkyl, preferably identical, TC 2-200 -Alkylene by phenylene
  • N + R 3 R 4 - with R 3 and R 4 independently of one another C 1-6 -alkyl, preferably of the same type, can be interrupted, where T in the individual polymerized monomer units of the formula II are not constant within the molecule h must, but can fluctuate within the specified range.
  • the polymer can thus consist of one or more different monomers
  • the polymer can be of one or more different types of
  • Monomers can be constructed so that, for example, d and a in the polymer represent mean values and the number of groups -N + R 3 R 4 - in the remainder T can represent an average value. For example, there may be 0 to 10 interruptions in the radical T in the individual monomers, so that the polymer has an average value.
  • the preferred values below relate to the monomers. As a rule, there are no integers for the monomer mixtures and polymers thereof.
  • A is hydrogen or C 1 - alkyl, preferably hydrogen or C 1 -3 alkyl, particularly preferably hydrogen or methyl, d and e are integers from 2 to 5, preferably 2 or 3
  • R 1 and R 2 are C ⁇ alkyl, preferably C 1 -3 alkyl, particularly preferred
  • X is halide, preferably chloride or bromide.
  • T is preferably selected from
  • linear or branched C. 50 alkylene preferably C 6 . 30 alkylene, linear or branched C 2 . 22 alkylene, which is substituted by phenylene,
  • the interruption is preferably approximately in the
  • Linear or branched C 4-16 alkylene which is interrupted by 1 to 7 not immediately adjacent oxygen atoms and preferably has units -CH 2 -CH 2 -O-, linear or branched C 20 - 140 alkylene which is separated by 2 to 8 not immediately adjacent groups -N + R 3 R 4 - with R 3 and R 4 C 1-4 alkyl, preferably C 1 -3 alkyl, in particular methyl or ethyl, is interrupted.
  • T is selected from
  • n1 and n2 independently of one another integers from 4 to
  • n1 and n2 independently of one another integers from 6 to 12, especially 7 to 9,
  • R 3 and R 4 are C 1-3 alkyl, especially methyl or ethyl, X halide, especially chloride or bromide, n1 and n2 independently of one another whole numbers from 6 to 16, especially 8 to 2, and n3 whole numbers from 2 to 6 , especially 3 to 5,
  • C s -kyl especially methyl or ethyl
  • X ' halide especially chloride or bromide
  • n1 number from 8 to 16, preferably 12 to 16, especially 12 to 14 and n4 average value from 1 to 10, preferably 2 to 7, particularly preferred 2 to 5, especially 3 to 4, with n4 average value of 1 to 6, preferably 2 to 5, especially 3 to 4.
  • the compounds of general formula II and / or are preferably prepared by reacting compounds of general formula IV
  • the crosslinked polymers according to the invention are composed of the monomers
  • a1 0.5 to 100% by weight of difunctional basic building blocks of the general formulas II and / or III, as described above, or mixtures thereof, as component A1, a2: 0 to 99.5% by weight of monomers from compounds of the formulas / l
  • R "have a meaning for R 2 , R 3 have a meaning given for R 3 and R 5 is selected from
  • Hydrogen C 1-9 alkyl, preferably C 1-3 alkyl, especially methyl and ethyl and
  • the invention also relates to crosslinked vinyl polymers of the formula I.
  • A, B, and D independently of one another H, CH 3 (CH 2 ) f ;
  • E and G are independently O or NH;
  • Q is a bond, -CH-CH - K-
  • R 1 and R 2 are independent of each other R 3 and R 4 independently of one another NH 2 , NHR 5 , NR 5 R 6 , + NH 3 Cr, + NH 2 R 5 cr,
  • a and d are independently 2 to 10; b 0 to 3; x - 2 to 22;
  • Hai- Cr, Br, J-; k and q are independently 0.005 to 1; m and n are independently 0 to 0.995.
  • Preferred compounds of the formula I are those in which A, B and D independently of one another are: H, CH 3 (CH 2 ) fl in which f is a number from 0 to 8; particularly preferred: H, CH 3 .
  • g is a number from 8 to 24 and r is a number from 0 to 18; particularly preferred (CH ⁇ g , where g is a number from 8 to 22.
  • Preferred compounds of the formula I are those in which Q denotes: a bond or —CH— CH— NH -; a bond is particularly preferred.
  • R 1 and R 2 are CH 3 or -CH 2 -CH 3 are preferred, particularly preferably CH 3 .
  • Preferred compounds of the formula I are those in which n is 0 to 0.8; particularly preferably denotes 0.
  • A, B, and D independently of one another H, CH 3 (CH 2 ) f ; f 0 to 8;
  • Q is a bond, - CH— O ⁇ - NH -;
  • R 3 and R 4 independently of one another NH 2 , + NH 3 CI ⁇ , CH 2 -NH 2 , CH 2 - + NH 3 cr, CONHR 8
  • R 8 (CH 2 ) w + N (CH 3 ) 3 Cr; w 1 to 8; a and d each 3; b 1;
  • A, B, and D independently of one another H, CH 3 ;
  • Q is a bond;
  • the invention further relates to a process for the preparation of the polymers according to the invention, in which a corresponding bis (meth) acrylate monomer or bis (meth) acrylamide monomer, which contains at least one quaternary ammonium center, in an aqueous medium in the presence of a water-soluble radical initiator radicalized either homopolymerized or copolymerized with other vinylic monomers such as allylamine hydrochloride or the other specified monomers.
  • the invention also relates to a process for the preparation of the polymers according to the invention, in which a corresponding bis (meth) acrylate monomer or bis (meth) acrylamide monomer which contains at least one quaternary ammonium center, in a Michael addition with an amino - Group-containing vinylic polymer such as polyvinylamine, polymer-analogous in a basic environment.
  • the monomers can also preferably be prepared as follows:
  • a dialkylamino terminated monomer e.g. a dimethylaminoalkyl ester or a dimethylaminoalkylamide of acrylic acid is reacted with an I. omega-dihalide to form quaternary ammonium centers.
  • Monomers with steroid groups can be prepared analogously to Hoe96 / F223 or EP-A-0 549 967.
  • the polymerization is carried out by the customary methods, as described, for example, in Houben-Weyl. It can be initiated thermally, by radical initiators, cationically or anionically or by Michael addition. The polymerization is preferably carried out by free radicals.
  • the solvents customary for polymerizations can be used as solvents. Water can also be used as a solvent if the starting materials are water-soluble.
  • the polymerization itself takes place at room temperature or at higher temperatures.
  • the polymers obtained can be worked up by filtration or, in the case of water-swellable or water-soluble polymers, by ultrafiltration. Drying is carried out using suitable methods such as freeze drying.
  • l, omega-bis (meth) acrylate u ⁇ i / or amide monomers which carry one or more quaternary ammonium centers in the chain, in an aqueous or alcoholic medium at low temperatures (for example 45 ° C.) with suitable water - Homopolymerize or alcohol-soluble radical starters (eg NA-044 from Wako) or copolymerize with comonomers, giving gels which can be worked up by customary methods.
  • the anions can be exchanged by stirring with suitable salt solutions.
  • the invention further relates to medicaments containing at least one polymer according to the invention and optionally one or more further lipid-lowering active ingredients, customary carriers, auxiliaries and / or additives.
  • the invention further relates to a method for producing such a medicament by mixing the components.
  • the invention further relates to the use of the polymers according to the invention as medicaments; especially as an anti-hyperlipidemic.
  • the invention further relates to the use of the polymers according to the invention for the manufacture of a medicament or pharmaceutical compositions for the treatment of lipid metabolism disorders, as well as hyperlipidemia, for the concentration-dependent reduction of bile acid sorption in the gastrointestinal tract, for the non-systemic lowering of elevated serum cholesterol and blood fat values for the prevention of arteriosclerotic symptoms .
  • the invention further relates to mixtures of the above polymers with other polymers and / or biologically active substances.
  • Example 1a
  • Example 1b 45 mg of ammonium peroxodisulfate and a tiny amount of iron (II) chloride were added to a solution of 3.0 g of Example 1a in 12 ml of water under a nitrogen atmosphere and the mixture was stirred for 2 hours. Then another 45 mg of ammonium peroxodisulfate was added and the mixture was heated to 65 ° C. for 2 hours. A colorless gel was obtained. This was suctioned off and pressed through a sieve with a mesh size of 200 ⁇ m. Then it was stirred with 150 ml of water for 30 minutes. The polymer was filtered off in vacuo and washed first with saturated aqueous sodium chloride solution and then with water. It was dried in a drying cabinet at 40 ° C. for 18 hours. Yield: 2.1 g Example 1b.
  • VA-044 initiator 60 ° C; in water
  • Example 2a To a solution of 49.4 g (77.27 mmol) of Example 2a in 200 ml of water, 490 mg (1.0% by weight) of radical initiator VA-044 (2,2'-azobis [2- (2 ' -imidazolin-2-yl) propane] - dihydrochloride, from Wako). The mixture was left in the oven for 1 hour
  • VA-044 initiator 50 ° C; in water
  • VA-044 initiator 60 ⁇ C; in water
  • Example 4b 25 mg of radical initiator VA-044 (from Wako) were added to a solution of 300 mg of Example 4a in 5.0 ml of water saturated with nitrogen at 60 ° C. under a nitrogen atmosphere. The mixture was stirred at 60 ° C for 2.5 hours. The resulting white gel was homogenized with an Ultraturrax (IKA) and then transferred to an ultrafiltration cell ( ⁇ kDalton membrane). The polymer was ultrafiltered to ionic jsch (bromide - chloride) 2x in saturated aqueous NaCl solution and then in water. The polymer was freeze-dried to constant weight. Yield: 282 mg Example 4b.
  • IKA Ultraturrax
  • ionic jsch bromide - chloride
  • VA-044 initiator 60 ° C, in water
  • Example 5b 0.86 g (15 mmol) of allylamine (from Riedel-de Haen) was added to a mixture of 1, 42 ml of concentrated hydrochloric acid and 20 ml of water. Then 9.13 g (15 mmol) of Example 5a and 160 mg of radical initiator VA-044 (from Wako) were added. The mixture was degassed and then stirred at 60 ° C for 7 hours under a nitrogen atmosphere. A gel was obtained. This was homogenized, filtered off in vacuo and washed first with saturated aqueous sodium chloride solution and then with water. The polymer was dried to constant weight at 50 ° C. in a vacuum drying cabinet. Yield: 6.7 g. Example 5b.
  • VA-044 initiator 60 ° C; in water
  • VA-044 initiator 60 ° C; in water
  • Example 7b 25 mg of radical initiator VA-044 (from Wako) were added to a solution of 300 mg of Example 7a in 5.0 ml of water saturated with nitrogen at 60 ° C. under a nitrogen atmosphere. The mixture was stirred at 60 ° C for 2.5 hours. The resulting gel was transferred to an ultrafiltration cell (membrane 5000 A). The polymer was washed twice for ion exchange (bromide - * chloride) with saturated aqueous NaCl solution and once with water. The retentate was freeze-dried. Yield: 282 mg Example 7b.
  • Example 8 A solution of 6.2 g (11 mmol) of Example 1a in 50 ml of methanol was added to a solution of 1.0 g (23 mmol) of polyvinylamine in 15 ml of methanol. The mixture was stirred at 30 ° C for 18 hours. The mixture was diluted with 50 ml of water and then stirred for 30 minutes. The resulting polymer was filtered off in vacuo, washed with water and then freeze-dried. Yield: 4.3 g Example 8.
  • Example 8 A solution of 3.84 g (5.8 mmol) of Example 3a in 20 ml of methanol was added to a solution of 0.50 g (11.5 mmol) of polyvinylamine in 7.5 ml of methanol. The mixture was stirred for 18 hours. The methanol was distilled off on a rotary evaporator. Then 200 ml of water was added. The polymer was purified by twice ultrafiltration (membrane 5000 A) in saturated aqueous sodium chloride solution and water and then freeze-dried. Ausbe jte: 2.76 g Example 8.
  • Example 10 A solution of 1.54 g (2.3 mmol) of Example 3a in 10 ml of methanol was added to a solution of 1.00 g (23.0 mmol) of polyvinylamine in 15 ml of methanol. The mixture was at room temp. touched. The methanol was distilled off on a rotary evaporator. The residue was stirred with 200 ml of water and transferred to an ultrafiltration cell. The polymer was purified by two ultrafiltration (membrane 5000 A) in saturated aqueous saline and in water and then freeze-dried. Yield: 2.21 g Example 10.
  • Example 7a 342 mg (469 ⁇ ol) of Example 7a and 107 mg (1870 ⁇ mol) of allylamine were dissolved in 7.5 ml of 1N aqueous hydrochloric acid. The solution was saturated with nitrogen. The mixture was heated to 60 ° C. under a nitrogen atmosphere. Then 22 mg of radical initiator VA-044 was added. The mixture was stirred at 60 ° C for 18 hours. The mixture obtained was homogenized. The polymer was purified by ultrafiltration twice (membrane 5000 A) in saturated aqueous saline and in water and then freeze-dried. Yield: 319 mg Example 11.
  • VA-044 initiator 60 ° C; 1 h
  • Example 12c 100 mg (150 mmol) of Example 12b and 903 mg (1350 mmol) of Example 3a were dissolved in a mixture of 7.5 ml of water and 7.5 ml of methanol. The solution was saturated with nitrogen and then warmed to 60 ° C. Then 40 mg of radical initiator VA-044 were added under a nitrogen atmosphere and the mixture was stirred at this temperature for 1 hour. The resulting gel was transferred to an ultrafiltration cell (membrane 5000 A). The polymer was washed twice for ion exchange (bromide - chloride) with saturated aqueous NaCl solution and once with water. The retentate was freeze-dried. Yield: 912 mg Example 12c.
  • Example 12b 100 mg (150 mmol) of Example 12b and 816 mg (1350 mmol) of Example 5a were dissolved in 15 ml of a mixture of methanol and water (ratio 1: 1). Then 40 mg of radical initiator VA-044 (from Wako) were added. The mixture was degassed and then stirred under nitrogen atmosphere at 60 ° C for 2 hours. The resulting gel was transferred to an ultrafiltration cell (membrane 5000 A). The polymer was washed twice for ion exchange (bromide - chloride) with saturated aqueous NaCl solution and once with water. The retentate was freeze-dried. Yield: 849 mg Example 13.
  • Example 1 a 8 mmol of Example 1 a were dissolved in 70 ml of isopropanol at 60 ° C. A mixture of 7.0 g (32 mmol; 16.7 ml) of a 50% strength aqueous solution of [3- (methacryloylamino) propyl] trimethylammonium chloride (from Aldrich) in 70 ml of ethyl acetate was added to this solution. The solution was degassed. Then 35 mg of azobisisobutyronitrile (AIBN) were added under a nitrogen atmosphere. The solution was stirred at 65 ° C for 3 hours.
  • AIBN azobisisobutyronitrile
  • the resulting gel was mixed with 500 ml of water and the mixture was left to cool for 2 hours at room temperature. Then 1500 ml of isopropanol was added and the mixture was stirred for 4 hours, during which the polymer precipitated. After standing overnight, the supernatant was decanted off. The precipitated polymer was stirred first with saturated aqueous sodium chloride solution and then with 100 ml of water and 800 ml of isopropanol for 2 hours. The supernatant was then decanted off. 1500 ml of isopropanol were added to the polymer and the mixture was stirred for a further 2 hours. The polymer was then filtered off in vacuo and dried. Yield: 11.2 g Example 14.
  • Example 16 490 mg (732 mmol) of Example 3a and 100 mg (183 mmol) of the cholate-containing comonomer I (synthesis as described in EP 548793) were dissolved in 2 ml of ethanol. Then 4.4 mg of radical initiator VA-044 (from Wako) were added. The mixture was degassed and then stirred under nitrogen atmosphere at 50 ° C for 36 hours. A gel was formed which was homogenized with an Ultraturrax. A further 1.1 mg of VA 044 were added, the mixture was degassed again and the mixture was stirred at 50 ° C. for a further 10 hours under a nitrogen atmosphere. The gel was then transferred to an ultrafiltration cell (membrane 5000 A). The polymer was washed twice for ion exchange (bromide - chloride) with saturated aqueous NaCl solution and once with water. The retentate was freeze-dried. Yield: 530 mg Example 16.
  • Example 17 using 1, 18-dibromoctane.
  • Example 24 1, 24-Di [N, N-dimethyl, N- (3-methacrylamidopropyl) ammonium] tetraeicosane dibromide
  • VA-044 initiator 60 ° C; in water
  • Example 28 The product is insoluble in water.
  • VA-044 initiator 60 ° C; in water
  • VA-044 initiator 60 ° C; in water
  • the product is insoluble in water.
  • the polymer is then washed free of chloride by ultrafiltration (membrane: 5,000 ⁇ ).
  • the product is insoluble in water.
  • Example 34 The product is insoluble in water.
  • the product is insoluble in water.
  • the product is insoluble in water.
  • the product is heated in water under nitrogen to 50 ° C, whereby it goes into solution.
  • the polymerization is initiated by adding 2,2'-azobis [2 (2-imidazolin-2-yl) propane] dihydrochloride and is carried out by the customary method. Then saturated NaCl solution is stirred in. The precipitate is filtered off, washed free of NaCl and ultrafiltered. The residue is then freeze-dried. Yield: 10.6 g
  • the product is dissolved in water under nitrogen at 50 ° C.
  • 2,2'-azobis [2 (2-imidazolin-2-yl) propane] dihydrochloride the polymerization is initiated and carried out by the customary method. In the end, a jelly-like mass is created. Then saturated NaCl solution is stirred in. The gel-like mass is washed free of NaCl by ultrafiltration. The residue is freeze-dried. Yield: 3.0 g
  • the product is heated in water under nitrogen to 50 ° C., whereby it goes into solution.
  • the polymerization is initiated by adding 2,2 , -azobis [2 (2-imidazolin-2-yl) propane] dihydrochloride and is carried out by the customary method. A granular product is formed. Then saturated NaCl solution is stirred in. The product is washed free of NaCl by ultrafiltration. The residue is freeze-dried. Yield: 2.84 g
  • the ratio of the protons to each other results in an average value of 2 for n.
  • the ratio of the protons results in an average value of 2 for n.
  • the cloudy supernatant is decanted from the viscous precipitate.
  • the precipitate is gelled in 100 ml of water and precipitated again with acetone. After falling four times, the gel-like residue is freeze-dried. Yield: 5.8 g
  • Acetone slowly stirred in. After a stirring time of 15 minutes, 200 ml of hexane are added and the mixture is stirred for a further 10 minutes. The clear supernatant is decanted off (discarded) and the residue is dried on an oil pump.
  • Example 54a 7 g of product from Example 54a are dissolved in 40 ml of water and polymerized with the addition of 150 mg of initiator as in Example 53b. At the end, the filter is washed free of chloride on the suction filter and dried in a desiccator. After grinding, 3.9 g of brown powder are obtained.
  • the plasma cholesterol content was determined using the
  • Plasma cholesterol assays from Sigma (order no. 352-100, catalog from 1996) with the cholesterol calibrator (order no. C7921, catalog from 1996).
  • Table 1 shows the results of the determination.
  • Plasma cholesterol reduction caused a 41% reduction with the same dose of the compound from Example 3b (Group 6) and a 27% reduction with the same dose of the compound from Example 2b (Group 9).
  • microsome samples twice through a 1 ml syringe with cannula No. 18 (26 G).
  • HPLC mobile phase 70% acetonitrile / 30% methanol (possibly 80% acetonitrile / 20%
  • Running length 40 minutes, 240nm, 0.01 AUFS.
  • Buffer 1 (to be stored at 4 ° C)
  • Buffer 2 (to be stored at 4 ° C)
  • Cholesterol - cyclodextrin solution (to be stored at 4 ° C) 1 mg / ml cholesterol in 45% hydroxypropyl cyclodextrin (stir 4.5g cyclodextrin with approx soluble), then fill up to 10ml).
  • Regeneration buffer (always fresh!) 10 mM Na isocitrate (25.8 mg / 2 ml) 10 mM magnesium chloride (20.3 mg / 2 ml)
  • Table 2 shows the results of the 7- ⁇ -hydroxylase activity determination.
  • Hydroxylase activity increased by 19%, with the same dose of the compound from Example 3b (Group 6) a 207% and with the compound from Example 2b (Group 9) a 280% increase in activity was achieved.
  • the adsorption activity of the polymers according to the invention in relation to bile acid can be measured in an in vitro model.
  • the substance is stirred or shaken in an aqueous saline solution, which approximates the conditions in the small intestine, with glyco- and taurocholic acid, and after filtration or centrifugation, the amounts of bile acids remaining in the solution are determined by HPLC.
  • the strength of the adsorption is determined by stirring the residue with aqueous salt solution and determining the bile acids released in the salt solution by means of HPLC.
  • the polymer sample is weighed and the standard solution is added so that a concentration of 5 mg sample / ml standard solution is requested. (50 mg / lOml).
  • the stock solution is diluted 1:20 with water and the
  • Bile acid salts are added.
  • Bile acid salts 8 mmol / 1
  • the polymer sample is weighed and the standard solution is added so that mqn has a concentration of 5 mg polymer / ml standard.
  • GCA Glycocholic Acid
  • TCA Taurocholic Acid

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Polymers & Plastics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Epidemiology (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne des composés de formule générale (II), dans laquelle A désigne hydrogène ou alkyle C1-9, G et E représentent indépendamment O ou NH; d et a représentent indépendamment un nombre entier de 2 à 10; R1 et R2 représentent indépendamment alkyle C¿1-9?; T désigne alkylène C2-200, le cas échéant interrompu par phénylène, un des groupes (a), (b), (c), (d), ou (e), 1 à 10 atomes d'oxygène non adjacents ou des groupes -N?+R3R4¿-, dans lesquels R3 et R4 représentent indépendamment alkyle C¿1-9?, et X?-¿ désigne un anion acide. L'invention concerne également des polymères produits avec ces composés et leur utilisation comme agents hypolipidémiants.
PCT/EP1998/000898 1997-02-17 1998-02-17 Polymeres de vinyle reticules a effet adsorbant d'acide biliaire WO1998036002A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
BR9807408-3A BR9807408A (pt) 1997-02-17 1998-02-17 Polìmeros de vinila reticulados tendo ação de absorvente do ácido biliar
EP98910693A EP0960141A1 (fr) 1997-02-17 1998-02-17 Polymeres de vinyle reticules a effet adsorbant d'acide biliaire
JP53537598A JP2002515930A (ja) 1997-02-17 1998-02-17 胆汁酸吸着作用を有する架橋結合性ビニルポリマー
CA002281602A CA2281602A1 (fr) 1997-02-17 1998-02-17 Polymeres de vinyle reticules a effet adsorbant d'acide biliaire
AU64983/98A AU728985B2 (en) 1997-02-17 1998-02-17 Crosslinked vinyl polymers having bile acid adsorber action
HU0001012A HUP0001012A3 (en) 1997-02-17 1998-02-17 Cross-linked vinyl polymers with bile acid adsorbing effect

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19705963A DE19705963A1 (de) 1997-02-17 1997-02-17 Vernetzte Vinylpolymere mit Gallensäure-Adsorberwirkung
DE19705963.5 1997-02-17

Publications (1)

Publication Number Publication Date
WO1998036002A1 true WO1998036002A1 (fr) 1998-08-20

Family

ID=7820445

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1998/000898 WO1998036002A1 (fr) 1997-02-17 1998-02-17 Polymeres de vinyle reticules a effet adsorbant d'acide biliaire

Country Status (14)

Country Link
EP (1) EP0960141A1 (fr)
JP (1) JP2002515930A (fr)
KR (1) KR20000071167A (fr)
CN (1) CN1251112A (fr)
AU (1) AU728985B2 (fr)
BR (1) BR9807408A (fr)
CA (1) CA2281602A1 (fr)
CZ (1) CZ293299A3 (fr)
DE (1) DE19705963A1 (fr)
HU (1) HUP0001012A3 (fr)
PL (1) PL335106A1 (fr)
RU (1) RU99119911A (fr)
TR (1) TR199901978T2 (fr)
WO (1) WO1998036002A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7291673B2 (en) 2000-06-02 2007-11-06 Eidgenossiche Technische Hochschule Zurich Conjugate addition reactions for the controlled delivery of pharmaceutically active compounds

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU4369499A (en) * 1998-06-30 2000-01-17 Aventis Research & Technologies Gmbh & Co. Kg Novel method for producing cross-linked vinyl polymers based on quaternary ammonium groups exhibiting a bile acid adsorbent effect
US6958212B1 (en) 1999-02-01 2005-10-25 Eidgenossische Technische Hochschule Zurich Conjugate addition reactions for the controlled delivery of pharmaceutically active compounds
MXPA01007777A (es) 1999-02-01 2003-10-06 Eidgenoess Tech Hochschule Bio-materiales formadas por reaccion de adicion nucleofila a grupos insaturados conjugados.
US8282912B2 (en) 2002-03-22 2012-10-09 Kuros Biosurgery, AG Compositions for tissue augmentation
JP2005054145A (ja) * 2003-08-07 2005-03-03 Mitsubishi Gas Chem Co Inc ガスバリア性（メタ）アクリレート樹脂硬化物および塗料、接着剤、フィルム
EP2136850B1 (fr) 2007-04-13 2012-02-01 Kuros Biosurgery AG Agent de scellement tissulaire polymère
JP6126498B2 (ja) * 2013-02-15 2017-05-10 富士フイルム株式会社 高分子機能性膜及びその製造方法
JP6071957B2 (ja) 2014-03-07 2017-02-01 富士フイルム株式会社 イオン交換性ポリマーおよびその製造方法、電解質膜およびその製造方法ならびにイオン交換性ポリマー製造用組成物
WO2017038328A1 (fr) * 2015-08-31 2017-03-09 富士フイルム株式会社 Polymère échangeur d'ions, composition durcissable, matériau durci, élément et dispositif
EP3680289B1 (fr) * 2017-09-15 2022-06-15 LG Chem, Ltd. Composition polymère, capsule polymère et composition d'adoucissant textile la comprenant
CN110317588A (zh) * 2018-03-29 2019-10-11 中国石油化工股份有限公司 一种阳离子表面活性剂及其制备方法和起泡剂及其应用
IT201900020949A1 (it) * 2019-11-12 2021-05-12 Univ Degli Studi Di Trieste Monomero fotopolimerizzabile antibatterico

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2232563A1 (fr) * 1973-06-11 1975-01-03 Merck & Co Inc
EP0541490A1 (fr) * 1991-11-07 1993-05-12 Sandoz Ltd. Polymères cationiques
EP0580078A1 (fr) * 1992-07-22 1994-01-26 Hoechst Aktiengesellschaft Dérivés de polyvinylamine présentant des groupes hydrophiles, leur procédé de préparation et leur application comme médicaments, supports de matières actives et ingrédients pour produits alimentaires
EP0602254A1 (fr) * 1992-07-06 1994-06-22 Otsuka Kagaku Kabushiki Kaisha Monomere polymerisable et son polymere; procede de production associe
WO1995034588A1 (fr) * 1994-06-10 1995-12-21 Geltex Pharmaceuticals, Inc. Polymeres reticules utilises pour eliminer les sels biliaires d'un patient
WO1996039449A1 (fr) * 1995-06-06 1996-12-12 Geltex Pharmaceuticals, Inc. Agent sequestrant hydrophobe contenant des heteroatomes et permettant une depletion cholesterolique

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2232563A1 (fr) * 1973-06-11 1975-01-03 Merck & Co Inc
EP0541490A1 (fr) * 1991-11-07 1993-05-12 Sandoz Ltd. Polymères cationiques
EP0602254A1 (fr) * 1992-07-06 1994-06-22 Otsuka Kagaku Kabushiki Kaisha Monomere polymerisable et son polymere; procede de production associe
EP0580078A1 (fr) * 1992-07-22 1994-01-26 Hoechst Aktiengesellschaft Dérivés de polyvinylamine présentant des groupes hydrophiles, leur procédé de préparation et leur application comme médicaments, supports de matières actives et ingrédients pour produits alimentaires
WO1995034588A1 (fr) * 1994-06-10 1995-12-21 Geltex Pharmaceuticals, Inc. Polymeres reticules utilises pour eliminer les sels biliaires d'un patient
WO1996039449A1 (fr) * 1995-06-06 1996-12-12 Geltex Pharmaceuticals, Inc. Agent sequestrant hydrophobe contenant des heteroatomes et permettant une depletion cholesterolique

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7291673B2 (en) 2000-06-02 2007-11-06 Eidgenossiche Technische Hochschule Zurich Conjugate addition reactions for the controlled delivery of pharmaceutically active compounds

Also Published As

Publication number Publication date
AU6498398A (en) 1998-09-08
CN1251112A (zh) 2000-04-19
BR9807408A (pt) 2000-03-14
CA2281602A1 (fr) 1998-08-20
DE19705963A1 (de) 1998-08-20
AU728985B2 (en) 2001-01-25
CZ293299A3 (cs) 1999-12-15
HUP0001012A2 (hu) 2000-09-28
PL335106A1 (en) 2000-04-10
TR199901978T2 (xx) 2000-06-21
JP2002515930A (ja) 2002-05-28
HUP0001012A3 (en) 2001-11-28
RU99119911A (ru) 2001-06-27
KR20000071167A (ko) 2000-11-25
EP0960141A1 (fr) 1999-12-01

Similar Documents

Publication Publication Date Title
DE60017805T2 (de) Verwendung von poly(diallylamin) polymeren
DE68919061T2 (de) Verbindungen.
WO1998036002A1 (fr) Polymeres de vinyle reticules a effet adsorbant d'acide biliaire
DE69828067T2 (de) Kationische polymere zur bindung von toxinen
DE2835145A1 (de) Substanz zum behandeln von nierensteinen
DE69511861T2 (de) Verfahren zur entfernung von gallsaüre von einem patienten sowie die alkylierte zusammensetzungen dafür
EP0918544A2 (fr) Inhibiteurs polymeres de resorption d'acide biliaire a effet simultane d'adsorption de l'acide biliaire
AU658713B2 (en) Cholesterol level depressant
DE2617524A1 (de) 3-eckige klammer auf n'-(3-halogenpropyl)-n'-methylamino eckige klammer zu -n,n,n-trimethyl-1-propanaminiumhalogenid und neue polymere
EP0379161B1 (fr) Utilisation des dérivés alcoylés de polyéthylèneimine comme médicaments adsorbants d'acide biliaire et compositions pharmaceutiques
DE60214713T2 (de) Arylborsäuren für die behandlung von fettsucht
EP0580078A1 (fr) Dérivés de polyvinylamine présentant des groupes hydrophiles, leur procédé de préparation et leur application comme médicaments, supports de matières actives et ingrédients pour produits alimentaires
DE69228999T2 (de) Neue jodierte makromolekulare polyaminverbindungen, verfahren zur herstellung und verwendung als kontrastmittel
EP0548794A2 (fr) Dérivés de polyaspartamide adsorbant les acides biliaires, dérivés de polyaspartamide chargés d'acides biliaires et leur procédé de préparation et leur utilisation comme médicament
DE68910211T2 (de) Estramustin-ester.
EP0810989B1 (fr) Derives de dtpa a substitution nouvelle, leurs complexes metalliques, produits pharmaceutiques contenant ces complexes, leurs usages diagnostique et therapeutique, ainsi que procedes pour preparer ces complexes et produits pharmaceutiques
DE2333211C2 (fr)
DE3436863C2 (de) Verwendung von Estern der 3-(Adenin-9-yl)-2-hydroxypropionsäure zur Behandlung viraler Erkrankungen
DE3878431T2 (de) Zusammensetzungen.
DE3218822C2 (fr)
WO1999022745A1 (fr) Copolymeres reticules contenant des groupes aminophosphonium pour applications medicales
DE4136325A1 (de) Cyclodextrinderivate als adsorptionsmittel fuer gallensaeure, mit gallensaeuren beladene cyclodextrinderivate und verfahren zu deren herstellung sowie deren anwendung als arzneimittel
DE19748712A1 (de) Aminophosphoniumgruppen enthaltende Polymere
MXPA99007600A (en) Cross-linked vinyl polymers with bile acid adsorbing effect
AT291264B (de) Verfahren zur Herstellung von neuen Pyrazincarbonsäurederivaten

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 98803685.1

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): AU BR CA CN CZ HU JP KR MX PL RU TR US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1998910693

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 64983/98

Country of ref document: AU

ENP Entry into the national phase

Ref document number: 2281602

Country of ref document: CA

Ref document number: 2281602

Country of ref document: CA

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: PA/a/1999/007600

Country of ref document: MX

Ref document number: PV1999-2932

Country of ref document: CZ

Ref document number: 1019997007457

Country of ref document: KR

Ref document number: 1999/01978

Country of ref document: TR

WWE Wipo information: entry into national phase

Ref document number: 09367430

Country of ref document: US

WWP Wipo information: published in national office

Ref document number: 1998910693

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: PV1999-2932

Country of ref document: CZ

WWP Wipo information: published in national office

Ref document number: 1019997007457

Country of ref document: KR

WWW Wipo information: withdrawn in national office

Ref document number: 1998910693

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: 64983/98

Country of ref document: AU

WWR Wipo information: refused in national office

Ref document number: PV1999-2932

Country of ref document: CZ

WWW Wipo information: withdrawn in national office

Ref document number: 1019997007457

Country of ref document: KR