MXPA99001725A - Polymer bile acid resorption inhibitors with simultaneous bile acid adsorbing effect - Google Patents

Abstract

Polymer bile acid resorption inhibitors with simultaneous bile acid adsorbing effect are disclosed, as well as a process for preparing the same, medicaments which contain these compounds and their use. Vinyl copolymers are disclosed which contain units of formula (I), in which R1 to R5, d, e, f, H, L, A, Y, Z and B have the meanings indicated in the description. Also disclosed is a process for preparing the same. These compounds are suitable for treating lipid metabolism disturbances.

Description

POLYMERIC INHIBITORS OF BILIARY ACID RESORPTION WITH SIMULTANEOUS EFFECT OF BILIARY ACID ADSORPTION DESCRIPTIVE MEMORY The invention relates to polymers having an action inhibiting the absorption of bile acid and simultaneously adsorbing action of bile acid, a process for their preparation and the use of these polymers as active pharmaceutical ingredients. Bile acids and their salts are natural detergents and have an important physiological function in the digestion of fats and in their absorption. As final products of cholesterol metabolism, they are synthesized in the liver, stored in the gall bladder and released from there as a constituent of bile to the intestine, where they show their physiological action. The largest part (approximately 85 to 90%) of the secreted bile acids (approximately 16g / day) is again absorbed from the intestinal wall via the enterohepatic circulation, mainly in the terminal ileum and transported back to the liver, ie recycle Only 10 to 15% of bile acids are excreted with feces. In the liver, a reduction in the amount of bile acid can be compensated to some degree via a closed control system of new bile acid synthesis from cholesterol. A reduction in the level of cholesterol in the liver leads to an increase in the absorption of cholesterol from the blood serum and thus decreases the level of cholesterol in the blood serum. Finally, by suppressing the reabsorption of bile acid by means of suitable inhibitors or adsorbers of bile acid, the enterohepatic circulation can, in this way, be interrupted in the intestine and as a result the level of cholesterol in the blood decreases. A very high level of cholesterol in the serum is recognized in medicine as serious, since it leads to atherosclerosis and in this way the risk of cardiac infarction increases. There are therefore many therapeutic proposals for the treatment of hypercholesterolemia One of these proposals is the interruption of the enterohepatic circulation.Using this route, it is also possible to treat all the diseases in which an inhibition of the reabsorption of bile acid in The small intestine appears to be desirable The following has been described in the prior art: a) Polymer bile acid adsorbers: Therapeutically non-absorbable polymers have been used for some time for binding bile acids. Particular insoluble, usually entangled polymers which contain quaternized nitrogen centers and act as anion exchangers These polymers bind some of the anions of bile acid that are present in the small intestine through mainly ionic interactions and transport them from the intestine. Such agents include, for example, the active compounds cholestyramine and colestipol. They are employed, for example, for hypercholesterolemia therapy. b) Inhibitors of the absorption of bile acid (receptor blockers): The proposed inhibition of active bile acid absorption has also been pursued in addition to polymeric bile acid adsorbers. Bile acid receptors located in the terminal ileum are blocked by molecules which, analogous to bile acids, can interact with the receptors, but unlike bile acids, they are not absorbed. As a result of this receptor block, the bile acids can no longer be absorbed and are then excreted with the feces. Examples of polymeric bile acid receptor blockers are found in EP 0 549 967. Bile acid polymers and oligomers are described herein in which the bile acid molecules are linked laterally to a polymer support. The compounds described in the prior art have the following disadvantages. a) polymeric bile acid adsorbers: 1.- The disadvantage of all polymer adsorbers of bile acid to date tin tin the market is the high dose (10-30 g / day; recommended dose in the case of cholestyramine, for example, 12 g / day). In the case of the polymers known to date, the high daily dose must be attributed to a low binding speed or a partial re-release of the bile acids adsorbed in the intestinal isotonic medium. 2.- Low acceptance in patients, in addition to the unpleasant consistency and sandy taste and the fishy odor of the adsorber powder (e.g. cholestyramine). The present administration form is problematic, since the powder adsorber does not dissolve in water but can only be suspended. To improve acceptance, in some cases more than 50% of flavor and odor enhancing additives must be added in such a way that as a result the daily dose of the adsorber medication is even increased. 3. The adsorbers known to date do not act sufficiently selectively and also bind to the vitamins (eg Vitamin K) and other physiologically important substances, so deficiency symptoms (eg, vitamin A deficiency) can occur. 4. - There is no extinguishing action of cholesterol metabolism of the intestinal bacteria. b) bile acid absorption inhibitors: 1.- With all known low molecular weight absorption inhibitors to date, there is a danger of cytotoxic side effects due to absorption in the intestine. In this way, pinocytosis and other transport mechanisms for the absorption of these low molecular weight inhibitors can not be excluded. Nor can a non-systematic action be guaranteed. 2. - An unpleasant side effect which can occur with the inhibitors of bile acid absorption known to date, due to the increase in the concentration of bile acid in the intestine caused by receptor blockage, is diarrhea.

Objective of the present invention: It was the objective of the present invention to prepare an active polymeric compound of non-systematic action that interrupts the enterohepatic circulation which no longer has the aforementioned disadvantages. The objective is achieved by linking the bile acid molecules or the low molecular weight bile acid absorption inhibitor molecules firmly to a polymer molecule covalently or through a spacer group, so that they can no longer be absorbable, but that still retain their inhibitory action of absorption. In this way, the systemic cytotoxic side effects of the low molecular weight absorption inhibitors which occur in some cases and may be caused by their absorption, are avoided. The polymer, on the other hand, is too large to be absorbed. Additionally the polymer contains bile acid adsorbing centers, e. g. centers of quaternized nitrogen, in the molecule. This reduces the concentration of bile acid in the intestine, which is increased by receptor blockage, by binding and adsorption of bile acid anions. Therefore polymers of this type have a dual action. On the one hand they act as polymeric inhibitors of the absorption of bile acid due to the receptor blocking units firmly united by covalence and, on the other hand, as bile acid adsorbers. The invention further relates to vinyl co-polymers consisting of units of the formula I and their physiologically tolerable salts wherein: R1, R2, R3 are hydrogen or CH3; R, R are hydrogen, alkyl- (C ^ -Cg), acyl- (C ^ -Cg); d is 0.01 to 1.00; e is 0 to 0.99; f is O at 0.99; where d + e + f must be equal to 1; L is a bond, -NH-, -N (CH3) -, - + NH2Cl ~ -, - NH (CH3) Cl " - + N (C? 3) 2C1 ~ -, -NH-CO-, -NH- (CH2) n-, -NH- [(CH2) n-0-] m- (CH2) p-, -NH- (CH2) n-CO-, -NH-CO- (CH2) p-, -NH- (CH2) n -CO-NH (CH2) m-N- (CH3) 2 + C1 ~ _ (CH2)? RT ' -NH- [CH2-CH (CH3) -0-] m -CH2-CH (CH3) -, -NH- (CH2) mN (CH3) 2 + Cl "- (CH2) n-, -0- (CH2 ) n- / -O- (CH2) n -CO-, -CO-, -CO-NH-, -CO-N (CH3) -, -CO-NH-CO-, -CO-NH- (CH2) n-, -CO-NH- [(CH2) n-0-] m- (CH2) p-, -CO-NH- (CH2) n-CO-, -CO-NH-CO- (CH2) n- , -CO-NH- [CH2-CH (CH3) -O-] m -CH2 -CH (CH3) -, -CO-NH- (CH2) m- + N (CH3) 2 Cl ~ - (CH2) n- , -CO- (CH2) n-0- (CH2) p-CO-, -Ar-, -Ar-CO-, -Ar-CH2-, -Ar-CH2- + N (CH3) 2C1"- (CH2) ) n ~ -CO-Ar- CO-, -alkylene- (C] _- C12) / -NH-Ar-CO-, -NH-CH2-Ar-CH2-, -NH-CO-Ar-CO-; H is a bond, -CH2-, -Ar-, -Ar-CH2-, where Ar is phenylene, naphthylene; m is 1 to 18; n is 1 to 18; P is 1 a l A is -O-, -NH-, a bond; B is -OH, -ONa, -OK, -NH2, -NH-CH3, -N (CH3) 2, -NH-CH2-CH2-S03Na, -NH-CH2-COONa, -NH-CH2-CH2- + N (CH3) 3C1-, -O-alkyl- (Cj_-C18), -NH-alkyl- (C ^ Cg), NH-alkylene- (C1-Cg) -OMe, R is -OH, -O-alkyl- (C! -Cg), -NH2; is -NH2, - + NH3C1"-NH-R- - + NH2R9C1" -NR9R10 - + NR9R10R1: LC1", -alkylene- (C -Cß) -NH2-, -alkylene- (C -Cg) - + NH3C1 -, -alkylene- (Cx-C s) NHR9, -alkylene- ( C! -C18) -NR9R10 (-alkylene- (Ci-C s) - + NR9R10R1: LC1 ~, -NH-CO- (C1-C18) -alkyl, NH-CO-alkylene- (C! -C1) -NR9R10, -NH-CO-alkylene- (C1-C12) -hNR, 99RR1 1R0RR? 1: 1LC1, -CORr, -CO-OR ^, -CO-NH-alkylene- (Ci-C ^) + NR9R10R1: LC1 -, • phenyl, -phenylene-alkylene- (CQ-CQ) -NH2, phenylene-alkylene- (C0-Cg) -NH-R, • phenylene-alkylene- (Cg-Cg) NR9R10, -phenylene-alkylene- (C0-Cg) - + NRyRluR ?: LCl, -CO-NH R9, -NH-alkylene- (C1-C18) -NHR9, -NH-alkylene- (C1-C18) -NR9R10.

NH-alkylene- (C ± - C ± Q) - + NR9R10R1: LC1_, -COOH, -O-R9, -CONH2, -OC COO - RR99 ,, --CCOO - aallqquuiilloo-- ((CC1! - -CC1122)), -OO-CCOO-aalkylene- (Cx-C ^) -NR9R10, O-CO-alkylene- (C1-C12 > '- + NR9R10R11C1' ", or 11 -C-NH- (CH2) m -NR9R10 CO-alkylene- (C -CÍQ) - + N- (C1-C8 alkyl) 3C1"CO-alkylene- (C1-C1Q) -NR9R10, is -NH2, hNH3Cl ~ -, -NH-R9, - + NH2R9C1 ~ -, - + NR9R10R1: LC1 '-alkylene- (C ^ Cxg) -NH2- -alkylene- (C? -C? 8) - + NH3C1-, -alkylene- (C1-C18) -NHR9, -alkylene- (C? -C18) -NR9R10, -alkylene- (C1-C18) - + NR9R10R1: LC1_-, -NH-CO-alkyl- (C ^ C ^), NH-CO-alkylene- (C1-C12) - + NR9R10. -NH-CO-alkylene- (C! -C12) + NR9R10R1: LC1 ~, -COR9, -CO-ORy, -CO-NH-alkylene- (^ C ^) + NRyRlüR11Cl ~, -phenyl, -phenylene-alkylene- (Cn-Cg) -NH, phenylene-alkylene- (C0-Cg) -NH-R- • phenylene-alkylene- (Cn-Cg) NR9R10, • phenylene-alkylene- (C0-Cg) - + NR9R10R1: LC1"-CONH-alkyl- (d-C12), -NH-alkylene- (C -CIS) -NHR9, -NH-alkylene- (Cx-) C18) -NR3 9RD10 -NH-alkylene- (C! -C18) - + NR9R10R1: LCl ", -COOH-, -O-R9, -CONH2, -O-CO-R9, -CO-alkyl- (C! -C12), -O-CO-alkylene- (Cx-C12) -NR9R10, -O-CO-alkylene- (CL-C12) - + NR9R10R11C1 '"; O. -C-NH- (CH2; m - NR9R10 O li C-O-alkylene- (C1-C18) -N + - (C1-6 alkyl) 3 -CY or a cross-linker selected from the group consisting of: , -CO-X-alkylene- (C2-Cg) -X-CO-CRx-CH2- (O-alkylene- (C! -C3)) 1_18-0-CH-CH2- -NH-alkylene- (Cx-C12) -NH-CH-CH2- -NH-CH2-CH (OH) -CH2-NH-CH-CH2- -NH-CHOH-alkylene- (C? -C12) -CHOH-NH-CH-CH2 • X is O, -NH-R, R are (C 1 -C 18) -alkyl, -phenyl, -CH-phenyl; R is H, alkyl- (C] -C- g) -, -phenyl, -CH 2 -phenyl; where at least one of the radicals L, Y and Z must contain an ammonium center. Preferred compounds of the formula I and their physiologically tolerable salts are those in which: R1, R2, R3 are hydrogen or CH3; R and R5 are hydrogen; d is 0.01 to 1.00; e is 0 to 0.99; f is 0 to 0.99; where d + e + f must be equal to 1; L is -NH-, -NH-alkylene- (Cx-Cxs) -, -NH- (alkylene- (C! -C3) -O-) 1_18 -alkylene- (C1-C3) -, -CO-NH- , -CO-NH-alkylene- (CX-CIS) -, -CO-NH-alkylene- (C1-C18) -, O -CO-, -NH-alkylene- (Cx-Cg) -C-NH-; H is a bond, -CH2-; A is -O-, a bond, -NH-; B is -OH, -ONa, -OCH3, -NH-CH2 -CH2-OCH3, Y is -NH2, -NHR9, -NR9R10, - + NR9R10R1: LCl ~, -NH-alkylene- (C1-C18) - + NR9R10R11C1 ~, -CH2-NH2, -CH2-NH-R9, -CH2 -NH- alkylene- (C -C18) - + NR9R10, -CH2-NH-alkylene- (C1-C18) - + NR9R10R1: LC1 ~, -NH-CO-R9, -CO-NH-R9, -CO-NH-propylene - + NR9R10R1: LCl ~, -X -CO-0-alkylene- (C1-C18) ~ NR9R10, Z is NH2, -NHR-NR9R10 -NH-alkylene- (C! -C18) - + N- (CH3) 3C1 ~, -CH2-NH2, -CH2-NH-R "-CH2-NR9R10. -CH2-NH-alkylene- (C_-1Q) -NR R? R Cl, or a linker selected from the group consisting of: -NH-alkylene- (C1-C12) -NH-CH-CH2-, -CO-X-alkylene- (C2-C18) -X-C0-CR1-CH2- -NH-CH2-CH (0H) -CH2-NH-CH-CH2, X is -O-, -NH-; R9, R10, R11 are alkyl- (Cx-Cg) -, -phenyl, -CH2-phenyl, wherein at least one of the radicals L, Y and Z must contain an ammonium center. Particularly preferred compounds of formula I and their physiologically tolerable salts are those in which R, R, R are hydrogen; R4 and R5 are hydrogen; d is 0.01 to 1.00; e is 0 to 0.99; f is 0 to 0.99; where d + e + f must be equal to 1; L is -NH-CH2-CH2-0-CH2-CH2-0-CH2-CH2-, O -C-NH-alkylene- (Ci-C ^) -, -NH-alkylene- (C? -C18) - , -CO-, -NH-, C-NH-alkylene (Cx-C) (C1-C18 -, -alkylene (Cx-Cg) -NH-alkylene (C ^ -CQ) H is a bond, -CH2-; A is -O-, -NH-, a bond; B is -OH, _ONa, _NH-CH2 -CH2-OCH3; Y is -NH2, -NHR9, -NH-alkylene (C1-C18) - + N (CH3) 3CL ~, -CO-NH-alkylene (CX-CXQ) - + N (CH3) 3C1", -CO-NH -alkylene (C] _ -Cg) -N- (CH3), -CH2-NH2, -CH2-NHR9; z is -NH2, -NHR9, -CH2-NH2, -CH2NHR9, NH-alkylene (C? -C18) ) - + N- (CH3) 3C1 ~, -CH2-NH- (C1-C18) alkylene- + N- (CH3) 3Cl ~, -CO-NH-propylene- + N (CH3) 3 Cl "; where at least one of the radicals L, Y and Z must contain an ammonium center. They are understood as physiologically tolerable acid addition salts to those compounds easily soluble in water, soluble or slightly soluble according to the definition in "German Pharmacopeia" (9th Edition 1986, official edition, Deutscher Apotheker-Verlag Stuttgart), page 19. Hydrochlorides and sulfates of the compounds are preferred. It is understood as an ammonium center to that positively charged (quaternized) nitrogen atom. The invention also relates to a process for the preparation of the polymers consisting of units of the formula 1. General description of the process for the preparation of the polymers: The synthesis of the monomers containing cholate was carried out as described in the examples .

Method 1: Binding of a crosslinker to cholic acid and subsequent polymer-analogous reaction to a polymer containing amino groups. First the colic acid is mesylated with methanesulfonyl chloride in basic medium. The mesyl group is a good leaving group and makes it possible to add secondary chains, e.g. of a triethylene glycol unit, by nucleophilic substitution. The free hydroxyl group of triethylene glycol is then selectively activated by reaction with tosyl chloride. The tosyl leaving group thus formed enables the polymer-analogous reaction with polymers containing amino groups, e.g. polyallylamine and polyvinylamine (Id example). The degree of substitution can be adjusted by changing the proportion of polyamine: cholic acid derivative.

Method 2: Preparation of amidoethers of cholic acid and subsequent binding of a crosslinker and polymer-analogous reaction with polymers containing amino groups. First the cholic acid is converted into the active ester using p-nitrophenol. The amido ether is then obtained by reaction with 2-methoxyethylamine (example 3b). This is linked via a crosslinker to a polymer containing amino groups as described in Method 1.

Method 3: Copolymerization of free radicals of cholic acid derivatives substituted with acrylic with vinyl monomers. A derivative of acrylic substituted acrylic acid is reacted with a vinyl monomer (preferably acrylic) by copolymerization of free radicals (see example 5). The ester groups which may still possibly be present in the cholate radical can be selectively hydrolyzed under basic conditions.

Method 4: Polymer-analogous reaction of mesyl cholic acid substituted with polymers containing amino groups.

The cholic acid mesylate can be reacted directly with polymers containing amino groups, e.g. polyamines, in a polymer-analogous reaction at pH = 8-10. The substituted polyamines can also be used here (examples 6, 17).

Method 5: Introduction of a linker group by reaction of cholic acid with dibromoalkanes and subsequent polymer-analogous reaction with polymers containing amino groups. In this method, a direct reaction of colic acids with a dibromo alkane, e.g. dibromohexane, is obtained in THF in basic medium (examples 7a, 15). A large excess of dibromoalkane is important here. The obtained smega-bromoalcoxicolic acid is then converted into the polymer according to the invention in a polymer-analogous reaction with a polymer containing amino groups, e.g. a polyamine (examples 7b, 12, 13, 15).

Method 6 Synthesis of a cholic acid derivative with a cationic center in the linker group and subsequent homopolymerization or copolymerization of the monomer obtained. 3- (N, N-dimethylaminopropyl) methacrylamide is reacted with a substituted bromo or substituted mesyl cholic acid derivative in a Menschutkin reaction. The group 3 -amino is quaternized here and a derivative of the cholic acid substituted with acrylate highly soluble in water is produced (examples 8, 9a). This can be homopolymerized under the conditions of free radicals or copolymerized with other vinyl co-monomers (example 9).

Method 7 Copolymerization of free radicals of acrylic substituted acrylic acid with allylamine (hydrochloride) or other polymerizable vinyl amine. Allylamine (hydrochloride) and other vinyl amines which can be polymerized under the conditions of free radicals can be polymerized directly with substituted acrylic acid derivatives (examples 11, 16).

Method 8 Addition of Michael polymer-analogous acrylic-substituted cholates to polymers containing amino groups. In this reaction a derivative of the acrylic substituted acrylic acid is reacted with a polymer containing amino groups, e.g. a polyamine, in alcoholic solution at a pH = 9-10 in a Michael addition. The present invention also relates to pharmaceutical preparations which comprise one or more of the active compounds according to the invention and, if appropriate, subsequent hypolipidemic agents. The active compounds according to the invention are suitable for use as hypolipidemic medicaments. The active compounds according to the invention are used, for example as pharmaceutical preparations, additives for foodstuffs, auxiliaries in the formulation, detergents, medicaments for influencing the enterohepatic circulation of bile acids, drugs for influencing lipid absorption, drugs for influencing the serum cholesterol level, drugs for the inhibition of bile acid absorption dependent on the concentration in the gastrointestinal tract or as a medication for the prevention of arteriosclerosis symptoms.

Experimental section EXAMPLE 1 a) EXAMPLE the colic acid mesylate: 9.2 ml (117 mmol) of methanesulfonyl chloride were added dropwise at 0 ° C to 40.9 g (100 mmol) of cholic acid in 200 ml of pyridine in the course of 20 minutes. The mixture was first stirred at 0 ° C for 15 minutes and then at room temperature for 5 hours. After allowing it to stand overnight, the mixture was poured into a solution of 1000 ml of ice water / 200 ml of concentrated sulfuric acid and stirred for another 10 minutes. The resulting precipitate was filtered off with suction and washed with water. The precipitate was then dissolved in methylene chloride and the solution was extracted with water. The organic phase was dried using sodium sulfate and then evaporated. The product (example la) was obtained quantitatively and was used in the next step without further purification. 1 H NMR: (CDCl 3) delta = 0.69 ppm (s, 3H, CH 3); 0.91 (s, 3H, CH 3); 0.99 (d, J = 6.0 Hz, CH3CH), 0.9-2.6 (m, 24 H, CH aliphat.), 2.99 (s, 3H, CH3S03); 3.87 (br.s, 1H, CHOH); 4.01 (br.s, 1H, CHOH); 4.50 (m; 1H, CHOS02) EXAMPLE lb Adducts of triethylene glycol to cholic acid, 6.1 g (12.5 mmol) of the product obtained in Example 1 were suspended in 25 ml (150 mmol) of triethylene glycol and dissolved with brief heating at 100 ° C. 4.0 g (100 mmol) of magnesium oxide were added and the mixture was stirred at 100 ° C for five hours. After letting it stand overnight, 100 ml were added. of chloride and the resulting precipitate was filtered with suction and washed with methylene chloride. The organic phase was extracted with 200 ml. of 2N aqueous hydrochloric acid and then concentrated. The raw yield: 7.2g. The crude material was purified by chromatography on silica gel (ethyl acetate gradient ethyl acetate: methanol = 1: 1). The product fraction was precipitated with methylene chloride by shaking under ultrasound and the precipitate was filtered. The filtrate contains pure Example lb. Performance after concentration: 1.7g. (25%) of Example lb. _ H NMR: (CDC13) delta = 0.69 ppm (s, 3H, CH3), 0.91 (s, 3H, CH3), 0.99 (d, J = 6.0 Hz, CH3CH), 0.8-2.4 (m, 24 H, CH alifat.); 3.5-3.75 (m, 13H, 0-CH2-CH2-0 and CHR2OCH2); 3.85 (br.s, 1H, CHOH); 3.97 (br.s, 1H, CHOH).

EXAMPLE 248 mg were added in portions. (1.3 mmoles) of tosyl chloride, dissolved in 20 ml. of dichloromethane, at 0 ° C, over the course of 30 minutes, to 600 mg. (1.1 mmol) of Example lb and 140 mg. (2.5 mmol) of potassium hydroxide powder in 30 ml. of dichloromethane. As the analysis with CCF still did not show complete reaction, 100 mg were added. additional (1.8 mmol) of potassium hydroxide powder. The mixture was stirred at room temperature for an additional hour. The resulting precipitate was filtered. The filtrate was concentrated. The crude yield: l.3g. The crude product was dissolved in a little dichloromethane and purified by column chromatography on silica gel (ethyl acetate: methanol = 9: 1). Yield: 540mg (70%). 1 H NMR: (CDC13) delta = 0.68 ppm (s, 3H, CH 3); 0.90 (s, 3H, CH3); 0.98 (d, J = 6.0 Hz, CH3CH), 0.6-2.5 (m, 24 H, CH aliphatic); 2.44 (s, 3H, Ts-CH3); 3.5-3.75 (m, 12H, 0-CH2-CH2-O); 3.84 (br.s, 1H, CHOH); 3.97 (br.s, 1H, CH0H); 4.15 (m, 1H, CHR2OCH2); 7.34 (d, J = 9Hz, 2H, H aryl), 7.79 (J = 9Hz, 2H, H aryl).

EXAMPLE Id 200 mg polyvinylamine was dissolved in 20 ml. of water and the pH = 10_ was adjusted. 66 mg (2 mol%) of le was dissolved in 20 ml. of ethanol, were added and brought back to pH = 10. The mixture was stirred at 50 ° C for 6 hours, the pH changed to pH = 8. The pH was again adjusted to pH = 10 and the mixture was allowed to stand overnight at room temperature. The product Id was purified by ultrafiltration (membrane 5000A) using ethanol: water = 1: 1 and the retentate was separated by freeze drying. Yield: 18Omg. The H-NMR analysis showed a degree of substitution on polyvinylamine of n = 1%. 1 H NMR (D 20): delta = 0.57 PPM (s, 3H, CH 3 cholate); 0.79 (br.m, 6H, cholate-CH3 and CH3CH); 1.0-1.6 (m, CH aliphatic cholate); 1.6-2.5 (m, CH2-CHNH and CH aliphatic cholate); 3.3-3.5 (O-CH2-0); 3.5-4.0 (br.s, CHNH-CH2); 4.0-4.4 (m, CHOH and CHR2OCH2) EXAMPLE 2 1 C 0. 7 ml. of 2N sodium hydroxide solution were added to a 100 mg solution. of polyvinylamine in 20 ml. of ethanol and the mixture was heated to 40-50 ° C. 496 mg were added. of the example in portions over the course of 6 hours. The pH was maintained at pH = 9 and the mixture was allowed to stand at room temperature for 3 days. Product 2 was purified by ultrafiltration (membrane 5000A) using ethanol: water = 1: 1 and the retained material was separated by freeze drying. Yield: 170 mg., H-NMR analysis showed a degree of substitution on polyvinylamine of n = 5%. 1 H NMR: as in the example Id.

EXAMPLE 3 Example 3a g (49 mmoles) of cholic acid were dissolved in 300 ml of THF and 10.2 g (73 mmoles) of p-nitrophenol and a pinch of p-N, N-dimethylaminopyridine were added thereto. The mixture was cooled to 0 ° C and then 13.2 g (64 mmol) of dicycloxycarbodiimide, dissolved in 50 ml of THF, were added. The mixture was stirred at 0 ° C for 30 min. and then at room temperature for 4 hours, a precipitate formed. This was filtered. The filtrate was concentrated to half its volume and treated with pentane until it became cloudy. The mixture was stirred for an additional hour and the resulting precipitate was filtered. The combined precipitates were washed with toluene and then dried. Yield: 11.5 g. The combined filtrates were evaporated to dryness and the residue was dissolved in 100 ml of THF. The solution was then treated again with pentane until it became cloudy and stirred for an hour more. The resulting precipitate was again filtered. Performance: 4.5g. Total yield of example 3a: 16.0 g (62%). X H NMR: (CDC 13) delta = 0.70 ppm (s, 3 H, CH 3); 0.90 (s, 3 H, CH 3); 1.06 (d, J = 6.0 Hz, CH3CH), 0.9-2.8 (m, 24H, CH aliphatic); 3.47 (br.s, 1H, CHOH); 3.85 (br.s, 1H, CHOH); 3.99 (br.s, 1H, CHOH); 7.28 (d, J = 9 Hz, 2H, H aryl), 8.26 (d, J = 9Hz, 2H, H aryl).

EXAMPLE 3b 3a 3b 750 mg. (10 mmoles) of 2-methoxyethylamine were initially introduced into a 100 ml mixture. of ethanol and 100 ml. of water and they were added in portions 5.9 g. (11 mmol) of example 3a. The pH was maintained at 10-11 by the addition of sodium hydroxide solution. The cloudy mixture was stirred at 40-50 ° C for 4 hours and then allowed to stand at room temperature for 3 days. The mixture was filtered and the filtrate was concentrated to a volume of 50 ml. By addition of hydrochloric acid, the pH was adjusted to a pH = 1. The mixture was extracted twice with diethyl ether and then twice with dichloromethane. The ether extracts were discarded. The combined dichloromethane phases were evaporated after being dried over sodium sulfate. Yield: 4.4 g (94%) of example 3b. NMR: (CDC13) delta = 0.68 ppm. (s, 3H, CH3); 0.99 (s, 3H, CH3); 1.00 (d, J = 6.0 Hz, CH3CH), 0.9-2.4 (m, 24 H, CH aliphatic); 3.36 (s, 3H, CH30); 3.45 (m, 5H, CHOH and NH-CH2-CH2-0); 3.84 (br.s, 1H, CHOH); 3.96 (br.s, 1H CHOH); 6.20 (br.s, 1H, NH).

EXAMPLE 3c 4.1 g was dissolved. (9.9 mmoles) of example 3b in 20 ml. of pyridine. 0.92 ml was added. of methanesulfonyl chloride at 0 ° C and the mixture was stirred at 0 ° C for 30 minutes and at room temperature for 1 hour. The mixture was treated with ice. Then, 20 ml. of concentrated sulfuric acid were slowly added with stirring. The mixture was stirred for another five minutes. The resulting precipitate was filtered, washed with water and then taken to dichloromethane. This solution was extracted with water. The organic phase was evaporated after drying over sodium sulfate. Crude yield: 4.7 g. The crude product was purified by column chromatography on silica gel (ethyl acetate). Yield: 2.9 g (54%) of example 3c. X H NMR: (CDC13) delta = 0.69 ppm (s, 3H, CH 3); 0.91 (s, 3H, CH3); 1.00 (d, J = 6.0 Hz, CH3CH), 0.9-2.4 (m, 24 H, CH aliphatic); 2.99 (s, 3H, CH3SO3); 3.36 (s, 3H, CH30); 3.45 (m, 4H, NH-CH2-CH2-O); 3.86 (br.s, 1H, CHOH); 3.99 (br.s, 1H, CHOH); 4.50 (br.s, 1H, CHOS02); 6.05 (br.s, 1H, NH). 1 ml of triethylamine was added to a solution of 2.9 g (5.3 mmol) of example 3c and 12. Og (80 mmol) of triethylene glycol in 5 ml of dichloromethane. The methylene chloride was distilled and the mixture was then heated to 100 ° C. 2 ml of triethylamine were added and the mixture was stirred at 100 ° C for 5 hours. Then, an additional 1 ml of triethylamine was added and the mixture was stirred at 100 ° C for another 8 hours. The mixture was allowed to stand at room temperature for a week and was then dissolved in dichloromethane. The solution was poured into 50 ml of a mixture of ice water / concentrated sulfuric acid (1: 1). This mixture was extracted three times with dichloromethane. The organic phase was washed with water, dried over sodium sulphate and evaporated. Crude yield 2.5 g. The crude material was purified by silica gel chromatography (gradient ethyl acetate-ethyl acetate: methanol = 9: 1). Yield: 0.9 g (30%) of the 3d example. ^ • H NMR: (CD3OD) S = 0.70 ppm (s, 3H, CH3); 0.91 (s, 3H, CH 3); 1.02 (d, J = 6.0 Hz, CH3CH), 0.8-2.5 (m, 24 H, CH aliphat.); 3.25-3.35 (m, 2H, NH-CH2-CH2-0); 3.34 (s, 3H, CH3O); 3.41-3.46 (m, 2H, NH-CH2-CH2-0); 3.50-3.67 (m, 13H, O-CH2-CH2-0 and CHR2OCH2); 3.79 (br.s, 1H, CHOH); 3.95 (br.s, 1H, CHOH).

EXAMPLE 3e 3d 3e 900 mg (1.5 mmol) of Example Id were dissolved in 30 ml of dichloromethane. 343 mg were added to this solution (1.8 mmol) of p-toluenesulfonyl chloride and 140 mg (2.5 mmol) of potassium hydroxide powder, at 0 ° C. The mixture was heated to room temperature with stirring. After stirring at room temperature for 30 minutes, another 100 mg (1.8 mmol) of potassium hydroxide powder was added and the mixture was stirred for another 2 hours. The precipitate was filtered. The filtrate was evaporated. Crude yield.- 1.2 g. Pure example 3e was obtained by column chromatography on silica gel (gradient dichloromethane dichloromethane: methanol = 95: 5). Yield 870 mg (77%) of 3e. NMR: (CDC13) S = 0.69 ppm (s, 3H, CH3); 0.90 (s, 3H, CH3); 0.98 (d, J = 6.0 Hz, CH3CH), 1.0-2.4 (m, 24 H, CH aliphatic); 2.45 (s, 3H, Ts-CH3); 3.36 (s, 3H, CH30); 3.4-3.65 (m, 13H, 0-CH2-CH2-0, NH-CH2-CH2-0 and CHR2OCH2); 3.70 (t, J = 6 Hz, 2H, Ts-0-CH2-CH2); 3.84 (br.s, 1H, CHOH); 3.97 (br.s, 1H, CHOH); 4.16 (t, J = 6 Hz, 2H, O-CH2-CH2); [lacuna] (1H, CHR2OCH2); 7.35 (d, J = 9 Hz, 2H, H aryl), 7.80 (d, J = 9 Hz, 2H, H aryl).

EXAMPLE 3f 150 mg of polyvinylamine was dissolved in a mixture of 20 ml of water and 20 ml of ethanol. The pH was adjusted to 10. 131 mg (5 mol%) of example 3e were added in portions at 40-50 ° C. The solution was stirred at room temperature for 4 hours and then heated under reflux for 3 hours. After allowing it to remain for another three days, example 3e was still detectable. The mixture was adjusted to pH = 12 and then heated under reflux for another 7 hours. After cooling, the polymer product was separated by ultrafiltration (membrane 5000A, ethanol / water = 1: 1) and then freeze-dried. Yield: 180 mg of Example 3f. The H-NMR analysis showed a degree of substitution of about n = 1%. ^ -H NMR: (D20) S = 0.73 ppm (s, 3H, CH3 cholate); 0.96 (br.m, 6H, CH3 cholate); 0.99 (d, J = 6.0Hz, 3H, CH3CH); 1.0-2.4 (m, CH aliphatic of cholate); 1.3-1.8 (br.m, 2H, CHNH-CH2), 2.94-3.16 (br.m, 1H, CHNH-CH2); 3.38 (s, 3H, CH30); 3.4-3.9 (0-CH2, N-CH2, O-CH); 3.91 (br.s, 1H, CHOH); 4.08 (br.s, 1H, CHOH).

EXAMPLE 4 100 mg of polyvinylamine was dissolved in a mixture of 20 ml of water and 20 ml of ethanol. The pH was adjusted to 10. 350 mg (20 mol%) of example 3e were added in portions at 40-50 ° C. The solution was stirred at room temperature for 4 hours and then heated with reflux for 3 hours. After allowing it to remain for another 3 days, example 3e was still detectable. The mixture was adjusted to pH = 12 and then heated with reflux for another 7 hours. After cooling, the polymer product was isolated by ultrafiltration (membrane 5000A; ethanol / water = 1: 1) and subsequently freeze drying. Yield 170 mg of Example 3f. The H-NMR analysis showed a degree of substitution of about n = 5%. 1 H NMR: (D 20) d = 0.73 ppm (s, 3H, CH 3 cholate); 0.96 (br.m, 6H, CH3 cholate); 0.99 (d, J = 6.0 Hz, 3H, CH3CH), 1.0-2.4 (m, CH aliphatic cholate); 1.3-1.8 (br.m, 2H, CHNH-CH2); 2.94-3.16 (br.m, 1H, CHNH-CH2); 3.38 (s, 3H, CH30); 3.5-3.85 (O-CH2, N-CH2, O-CH); 3.89 (br.s, 1H, CHOH); 4.05 (br.s, 1H, CHOH).

EXAMPLE 5 132 mg of 3-methacryloylamidopropyltrimethylammonium chloride were added to a solution of 344 mg of co-monomer 1 (synthesis as described in Patent EP 548793) in 2 ml of ethanol. Nitrogen was passed into the mixture for 45 minutes. Then 662 μg of Trigonox 62 (t-butylperoxydiethyl acetate, AKZO Chemicals) or dibenzoyl peroxide were added under a nitrogen atmosphere. The mixture was stirred at 75 ° C for 27 hours excluding air. As the starting material was still detectable, 687 μg of VA-044 (2, 2'-azobis- [2- (2'-cyanovaleric acid)] was added under a nitrogen atmosphere; 75% strength solution in water; Wako Chemicals). The mixture was stirred at 45-50 ° C for 20 hours. Then 5 ml of 20% strength aqueous sodium hydroxide solution was added and the mixture was stirred at 45 ° C for 18 hours. Then 150 ml of water were added. The pH was adjusted to pH = 7 by the addition of dilute hydrochloric acid. Example 5 was then separated by ultrafiltration (membrane 5000A, methanol / water = 1: 2). ^ -H NMR: (D20) S = 0.73 ppm (s, 3H, CH3 cholate); 0.96 (br.m, 6H, CH3 cholate); 0.99 (d, J = 6.0 Hz, 3H, CH3CH), 1.0-2.4 (m, CH aliphatic cholate); 1.3-1.8 (br.m, 2H, CHNH-CH2); 3.38 (s, 3H, CH30); 3.5-3.85 (0-CH2, N-CH2, O-CH); 3.89 (br.s, 1H, CHOH); 4.05 (br.s, 1H, CHOH). Proportion: 57:43 EXAMPLE I: m: n = 0.84: 0.15: 0.01 600 mg of polyvinylamine substituted with trimethylammoniododecyl (degree of substitution 20%) were dissolved in a mixture of 10 ml of water and 10 ml of methanol. The mixture was heated to 45-50 ° C. Then 239 mg (10 mol%) of 3-mesylcholic acid was added (Example la) the pH was maintained at 8-10 by the addition of dilute sodium hydroxide solution. The clear solution was stirred at 45-50 ° C for 15 hours. The product was purified by ultrafiltration (membrane 5000A) in methanol / water = 1: 1 and separated by freeze drying.

Yield: 550 mg. 1 H NMR: (D 20) delta = 0.8-2.2 (m), 2.25-4.2 (m), 3.04 (s, N-CH 3). Degree of substitution as indicated above.

EXAMPLE 7 EXAMPLE 7a 12.3 g (30 mmol) of cholic acid were dissolved in 200 ml of THF. Then 73.2 g (300 mmol) of 1,6-dibromohexane were added and the mixture was heated with reflux. 10.2 g (180 mmol) of potassium hydroxide powder were then added in portions over the course of 6 hours. The mixture was then stirred for another hour. After cooling, the resulting precipitate was filtered off with suction and washed with THF. The filtrate was concentrated. The excess dibromohexane was distilled in vacuo. The viscous residue was purified by column chromatography (ethyl acetate-ethyl acetate: methanol = 9: 1). Yield 6 g. 1 H NMR: (CDCl 3) delta = 0.68 ppm (s, 3H, CH 3 cholate); 0. 89 (br.m, 6H, CH3 cholate); 0.99 (d, J = 6.0 Hz, 3H, CH3CH), 1. 0-2.4 (m, cholate alifat, CH); 1.3-1.8 (br.m, 2H, CHNH-CH2); 2. 6-2.9 (br.m, 3H); 3.42 (d, J = 6.0 Hz, 2H); 3.84 (br. S, 1H, CHOH); 3.96 (br.s, 1H, CHOH); 4.06 (d, J = 6.0 Hz, 2H). MS: Cl (ammonium): m / e [%] = 590 (M + NH 4 from isotope 81 Br, 95); 588 (M + NH 4 from the 79Br isotope, 100).

EXAMPLE 7b m: n = 0.98: 0.02 10 g of polyallylamine were dissolved in 100 ml of water and the pH was adjusted to pH = 10 using dilute sodium hydroxide solution. 3.1 g of example 7a were added at 50-60 ° C over the course of three hours, with a temporary turbidity occurring each time. The pH was maintained at pH = 9.5-10 by the addition of dilute sodium hydroxide solution. The mixture was stirred 60 ° C for 4 hours. The product was purified by ultrafiltration in methanol / water = 1: 1 and dried by subsequent freezing. Yield: 7.4 g. 1 H NMR: (D 20) delta = 0.72 ppm (br. S, 3H, CH 3 cholate); 0.92 (br.s, 3H, CH3 cholate); 0.95-2.2 (m, CH aliphat.), 2.72 (br.s, 2H, CH2-NH2); 2.9-4.2 (m, CHOH, CH20 inter alia). Degree of substitution of cholate: 2%.

EXAMPLE 8 233 mg (0.44 mmol) of 3- (2-mesyl) ethoxycholic acid were dissolved in 1 ml of methanol and 75 mg (0.44 mmol) of 3- (N, N-dimethylammonopropyl) -methacrylamide were then added. After 20 minutes, a precipitate formed. The mixture was stirred at 50 ° C for 14 days. The solvent was removed and the residue was chromatographed three times on silica gel (methanol / water / acetic acid = 10: 0.5: 0.05). 50 mg of the product were obtained. 1 H NMR: (CD30D) delta = 0.71 ppm (s, 3H, CH3 cholate); 0.94 (s, 3H, CH3 cholate); 1.01 (d, J = 7 Hz, 3H, CH3CH cholate), 1.0-2.5 (m, alifat, CH); 2.80 (s, 3H, mesylate anion), 3.0-4.0 (several m, CHOH, CH20 inter alia); 3.16 (s, 6H, N-CH3), 5.40 (br.s, 1H, vinyl-H); 5.74 (br.s, 1H, vinyl-H). MS: m / e [%] = 605 (M +).

EXAMPLE 9 251 mg (0.44 mmol) of 3- (6-bromohexyloxy) cholate were dissolved in 2 ml of methanol and 75 mg (0.44 mmol) of 3- (N, N-dimethylaminopropyl) -methacrylamide were then added. The mixture was heated under reflux for 6 hours and then allowed to settle overnight. The solvent was removed and the residue was chromatographed on silica gel (methanol / water / acetic acid = 99: 0.5: 0.5). 160 mg of crude product were obtained, which were subsequently purified by a weakly acidic ion exchanger. Yield: 80 mg. -'- H NMR: (CDC13) delta = 0.67 ppm (s, 3H, CH3 cholate); 0.87 (s, 3H, CH3 cholate); 0.99 (d, J = 7 Hz, 3H, CH3CH cholate), 1.0-2.4 (m, aliphat.CH); 3.1-4.1 (several, CHOH, CH20 inter alia); 3.15 (s, 6H, N-CH3); 3.86 (s), 5.35 (br.s, 1H, H-vinyl).

EXAMPLE 9b 0.52 mg of a free radical initiator VA 044 (Wako) was added to a solution of 55 mg (77 μmol) of example 9a and 17 mg (77 μmol) of trimethylammoniumpropyl methacrylate chloride in 3 ml of water. The mixture was deaerated and then stirred at 45 ° C for 70 hours. The mixture was evaporated and the residue was dissolved in 10 ml of water and purified by ultrafiltration (membrane 5000Á). After freeze drying, 66 mg of example 9b was obtained. 1 H NMR: (CDC13) delta = 0.67 ppm (s, 3H, CH 3 cholate); 0.87 (s, 3H, CH3 cholate); 0.99 (d, J = 7 Hz, 3H, CH3CH cholate), 1.0-2.4 (m, aliphat.CH); 3.1-4.1 (several m, CHOH, CH20 inter alia); 3.15 (s, 6H, N-CH3); 3.86 (s), 5.35 (br.s, 1H, H vinyl); 5.85 (br.s, 1H, H vinyl).

EXAMPLE 9c Nitrogen was passed through a solution of 741 mg 81. 0 mmoles) of example 9a in 3.5 ml of methanol for 30 minutes. The solution was then heated to 60 ° C. 10 ml of the free radical initiator VA 044 (Wako) was added. The mixture was then stirred at 60 ° C under a nitrogen atmosphere for 4 hours. It was then diluted with water and purified by ultrafiltration (membrane 5000Á). For the exchange of the Br ion "Br" Cl, it was then washed twice with diluted aqueous NaCl solution and then twice with water. After freeze drying, 456 mg was obtained. Elementary analysis: Calculated: C 66.4% H 10.4% N 14.3% Cl 5.3% Found: C 66.2% H 10.5% N 14.2% Cl 5.2% EXAMPLE 10 38 mg (0.35 mmoles) of N- (3-N, N-dimethylaminopropyl) methacrylamide and 200 mg (0.35 mmoles) of comonomer 1 were dissolved in 1.39 ml of ethanol. Nitrogen was passed through the mixture with stirring for 45 minutes. 0.66 mg of the initiator VA 044 was then added. The mixture was stirred at 45-50 ° C for 27 hours. After cooling, the resulting copolymer was separated by ultrafiltration in water (membrane 5000A) and dried by subsequent freezing. Yield: 196 mg. xHCl 181 mg (3.19 mmol) of allylamine was added at room temperature to a solution of 80 mg (0.17 mmol) of 1 in 3 ml of ethanol. Nitrogen was passed into the mixture for one hour. Then, 1.14 mg (1 mol%) of the initiator VA 044 was added. The mixture was stirred at 50 ° C for 15 hours. The mixture was concentrated and the residue was stirred at 70 ° C for 4 hours in 5 ml of aqueous sodium hydroxide solution with 20% strength. The pH of the solution was adjusted to pH = 7. The product was separated by ultrafiltration in water (membrane 5000Á) and subsequent freeze drying. Yield: 106 mg.

EXAMPLE 12 I: m: n = 0.79: 0.20: 0.01 1.74 g of powdered sodium hydroxide were added at room temperature to a solution of 5.00 g (43 mmol) of 1 in 100 ml of water. Then a solution of 1.98 g of II in 60 ml of methanol was added. The mixture was stirred at 60 ° C for 6 hours. The mixture was diluted to a volume of 2 liters with water. The pH was adjusted to pH = 7. The product was separated by ultrafiltration in water (membrane 5000Á) and subsequent freeze drying. Yield: 5.63 g. ^ -H NMR (D20): I: m: n = 0.79: 0.20: 0.01.

EXAMPLE 13 I: m: n = 0.79: 0.20: 0.01 2.22 g (55.6 mmol) of powdered sodium hydroxide were added at room temperature to a solution of 5.00 g (55.6 mmol) of 1 in 100 ml of water. A solution of 2.54 g of II in 75 ml of methanol was then added. The mixture was stirred at 60 ° C for 8 hours. The mixture was diluted to a volume of 2 liters with water. The pH was adjusted to pH = 7. The product was separated by ultrafiltration in water (membrane 5000Á) and subsequent freeze drying. Yield: 5.50 g. XH NMR (D20): I: m: n = 0.79: 0.20: 0.01, EXAMPLE 14 m: n = 0.99: 0.01 274 mg (0.50 mmol) of 1 was added at room temperature to a solution of 107 mg (2.5 mmol) of polyvinylamine in 5 ml of ethanol. The pH of the solution was adjusted to pH = 9-10 and the mixture was stirred at room temperature for one week. The mixture was concentrated to one quarter of its volume and treated with 10 ml of 10% strength aqueous sodium hydroxide solution. It was stirred at room temperature for 2 days and the pH was then adjusted to pH = 7. The product was separated by ultrafiltration in water (membrane 5000Á) and subsequent freeze drying Yield: 90 mg. XH NMR (D20): m: n = 0.99: 0.01 EXAMPLE 15 Example 15a 4.1 g (10 mmol) of cholic acid were dissolved in 100 ml of THF. Then 9.0 g (30 mmol) of 1,10-dibromodecane were added and the mixture was heated under reflux. Then 3.4 g (60 mmol) of powdered potassium hydroxide was added in portions over the course of 5 hours. The mixture was then stirred for another hour. After cooling, the resulting precipitate was filtered off with suction and washed with THF. The filtrate was concentrated. The excess dibromodecane was distilled in vacuo. The viscous residue was purified by column chromatography (ethyl acetate). Yield: 0.81 g- EXAMPLE 15b m: n = 0.99: 0.01 1.5 g of polyallylamine hydrochloride were dissolved in 15 ml of water and 10 ml of methanol and the pH was adjusted to pH = 10 using dilute hydroxide solution. 0.5 g (5 mmoles%) of example 15a were added at 50-60 ° C within 2 hours, with temporary clouding occurring. The pH was maintained at pH = 9.5-10 by the addition of dilute hydroxide solution. The mixture was stirred at 60 ° C for 5 hours. The product was purified by ultrafiltration (membrane 3000A) in ethanol / water = 1: 1 and then in water and subsequent drying by freezing. Yield: 0.95 g. NMR: (D20) degree of cholate substitution: 1%.

EXAMPLE 16"Nitrogen was passed through a solution of 63 mg (0.14 mmol) of methyl 3-acryloylcolate in 2 ml of ethanol for 30 minutes, then 250 mg (2.60 mmol) of N-vinylimidazole (Polisaens) and 8.9 mg ( 0.027 mmol) of the VA 044 inhibitor. The mixture was heated to 45-48 ° C under nitrogen and stirred at that temperature for 2 days, a viscous material was obtained which was dissolved in 10 ml of methanol. ml of aqueous sodium hydroxide solution with 20% strength and the mixture was stirred at 50 ° C for 12 hours.The pH was adjusted to pH = 7. The product was isolated by ultrafiltration (membrane 5000Á) in water and subsequent drying by freezing Yield: 200 mg NMR: (D20) degree of cholate substitution: 3%.

EXAMPLE 17 m: n = 0.99: 0.01 500 ml of polyvinylamine were dissolved in a mixture of 10 ml of water and 10 ml of ethanol. 57 mg of 3-mesylcolic acid at 40-50 ° C were added in portions. The pH was maintained between 9 and 10. The mixture was stirred at 40-50 ° C for 9 hours. 200 ml of ethanol: water = 1: 1 were then added. The product was isolated by ultrafiltration (membrane 5000Á) in water and subsequent freeze drying. Yield: 500 mg. • ^ -H NMR: (D20) degree of cholate substitution: 1%.

EXAMPLE 18 139 mg (0.63 mmoles) of 3-methacrylamidopropyltrimethylammonium chloride and 4.1 mg (0.013 mmoles) of the initiator VA 044 were added to a deaerated solution of 300 mg (0.63 mmoles) of methyl 3-acryloylcholate in 2.1 ml of ethanol. The mixture was stirred at 45-48 ° C for 2 days under nitrogen. Monomers were no longer detected by checking the mixture with TLC. The pH was adjusted to pH = 7 and 50 ml of water was added. The product was isolated by ultrafiltration (membrane 5000Á) in water and subsequent freeze drying. Yield: 370 ml. 10 ml of THF and 1 ml of sodium hydroxide solution with strength of 20% were added to this product. The mixture was heated to 50 ° C. Since there was no homogeneous solution, the THF was distilled empty. 100 ml of water were added and the mixture was stirred at room temperature overnight. The pH was adjusted to pH = 7. Example 18 was then isolated by ultrafiltration (membrane 5000Á); methanol / water = 1: 1) and subsequent freeze drying. 1H NMR: (D20): proportion: 70:30. In the bile adsorption test, the ability of the polymer to adsorb bile acids is measured. Test of the bile adsorption test: The samples were prepared as follows: An aqueous solution is first prepared which contains the following salts in the concentrations indicated below: NaCl 90 mmoles / 1 KCl 6 mmoles / 1 CaCl2 3 mmoles / 1 NaHC03 10 mmoles / 1 Taurocholate of sodium 1.38 g / 1 Sodium glycocholate 2.49 g / 1 The pH of the solution is adjusted to pH = 7.0 ± 0.2. 10 ml of the above solution are taken and added to a sample container. Then 20 mg of polymer are added (examples 1 to 18). The mixture is slowly stirred for 2 hours and then centrifuged (5000 rpm). A 30 μl sample of the supernatant is taken for analysis and analyzed as described below.

CLAR WITH FLUORESCENCE DETECTION Equipment: Kontron CLAR unit, consisting of three pumps and mixing chambers, autosampler, UV detector, and analysis unit with MT2 software. Fluorescence detector from Merck-Hitachi. As the samples are sensitive to light and temperature, the autosampler is cooled to about 5 ° C. Mobile phase: Eluent A: water Miliporo (from the unit itself) Eluent B: acetonitrile / methanol 60:30. Column: ^ LiChrospher 100 RP-18.25 mm, 5 μm Merck Precolumn: RLiChrospher 60 RP-select B, 4 mm, 5 μm Merck.

Flow rate: 1.3 ml / min Detection: Excitation: 340 nm Emission: 410 nm Gradient: 0.00 min 66 ^ B 7.50 min 66 B 8.00 min 76% B 12.50 min 76% B 13.00 min 83% B 25.00 min 83% B 25.50 min 91% B 40.00 min 91% B Enzymatic determination of total bile acid. 900 microliters of each of the following mixtures are added to Eppendorf containers: 6 ml of 0.1 M tetrasodium diphosphate buffer, pH 8.9, 2 ml of NAD solution (4 mg / ml of water), 20 mol of Millipor water. 30 microliters of the sample of (concentration: 2 mg of polymer for each milliliter of water) and 30 microliters of enzyme solution are pipetted. Enzyme solution: 3 -alpha-hydroxysteroid dehydrogenase 0.5 units / ml. The batches are mixed and incubated at room temperature for 2 hours. The subsequent transfer to 1 ml disposable cuvettes and its measurement in a photometer at 340 nm.

RESULTS OF THE ENZIMA TEST HPLC WITH UV DETECTION Equipment: Kontron HPLC unit, consisting of three pumps and mixing chamber, autosampler, UV detector and analysis unit with MT2 software. Mobile phase: Eluent A: 0.019 M ammonium carbamate buffer, adjusted to pH 4.0 with phosphoric acid. Eluent B: acetonitrile Column: RLiChrospher 100 RP-8.25 mm, 5 μm Merck Precolumn: RLiChrospher 60 RP-select B, 4 mm, 5 μm Merck. Flow rate: Gradient: 0.00 min 0.8 ml / min 20.00 min 0.8 ml / min 23.00 min 1.3 ml / min 51.00 min 1.3 ml / min Detection: 200 nm (additionally for preparations at 254 nm) Gradient: 0.00 min 32% B 8.00 min 35% B 17.00 min 38% B 20.00 min 40% B 24.00 min 40% B 30.00 min 50% B 45.00 min 60% B Biliary Acid Binding [%] Cholestyramine Example 6 Example 17 Taurocholate (TC) 52 57 57 Glycocholate (GC) 34 50 48 Taurodeoxycholate (TDC) 86 93 89 Glycodeoxycholate (GDC) 74 90 88 Taurokenedeoxycholate (TCDC 100 100 100 Glycokenedeoxycholate (GCDC) 77 89 84 The "in vivo perfused rat intestine" trial investigates the ability of polymers to block the reabsorption of bile acids in the ileum region.

INTESTINE RATA PREFUNDIDO IN VIVO The in vivo investigation was carried out as described in F.G.J. Poelma et al. (J: Pharm. Sci. 78 (4), 285-89, 1989) - the modifications of the test are indicated. Taurocholate and taurocholic acid, and cholate and cholic acid, respectively, are used synonymously in research.

CANNULATION OF THE BILIARY DUCT The bile duct is exposed and a catheter is attached (PE 50, Intramedic). An adapter for accepting disposable 100 microliter pipette tips (Brandt) is attached to its end. Bile is collected in these pipettes and placed in pre-weighed Eppendorf flasks or reaction vessels at specific time intervals. At the end of the experiments, the bile, as well as the samples of the medium, they are weighed and the aliquots are measured in a flash counter. For this purpose, 10 microliters of the sample are pipetted into a Sarstedt sample flask, 58 x 22 mm, with 10 ml of Quickszint 212 (Zinsser GmbH, Frankfurt am Main, Germany) and counting in a beta-Beckman 2800 counter after a decay time of 30 minutes. 1.- The compounds according to the invention, examples 1 to 18 were instilled in the intestinal segment together with 10 mM of taurocholate using taurocholate-H or taurocholate -14C as markers and the perfusion solution circulated for two hours with the help of a peristaltic pump. The decrease in the marker in the intestine (medium) or the appearance of the tracer in the bile fluids (bile) was determined with the help of flash and HPLC measurements. 10 mM of taurocholate with the tracer without compound according to the invention was instilled as control and the change in the intestine and in the bile was determined. 2.- In vivo perfused intestine The experimental animals used are Wistar rats reared at home (handling of Hoechst animals) with an average body weight of 230 to 290 g. The experimental animals are not fastened before anesthesia (urethane 1 g / kg i.p.). After the start of the anesthesia, the animals were tied to an operating table (Medax) with temperature control (constant at 37 ° C) (Medax), shaved on the ventral side and then the abdominal wall of the animals was opened using an incision of approximately 7 cm in length. Then a Luer adapter (Hoechst Precision Mechanics) was tied in the lower portion of the intestine about 8 cm from the ileocecal skirt and at this point the small intestine is ligated. The ligated and detached posterior small bowel is carried out 13 to 14 cm from the beginning of the small intestine. The contents of this intestinal segment are carefully rinsed with warm isotonic saline at 37 ° C. The experimental solution is then instilled within that segment, the final part of the jejunum / onset of ileus. The pump tube is filled first with 2 ml of the instillation solution (10 mM taurocholate, polymer (example 1 to 18) in concentration of 0.1 mM / 1 in 0.9% strength saline solution regulated with phosphates), marker: 3.5 μCi [3H (G)] -taurocholic acid, NET-322, lot 2533-081, (DuPont from Nemour GmbH, Dreieich, Germany), dissolved in an isotonic saline solution regulated with phosphates (silicone tube A, 0.5 mm Desaga, Heidelberg, Germany, order No. 132020). The pump tube is then attached to the intestinal segment using two Luer adapters and the residual solution is instilled via a three-way valve (Pharmaseal K 75a) and a 2 ml disposable syringe (Chirana). Immediately afterwards, the peristaltic pump (LKB Multiperpex 2115)) is turned on, and in the middle it is recirculated at a speed of 0.25 ml / min. A sample to measure the activity (decrease in the radioactivity in the intestine = absorption rate), is taken at regular intervals by means of a Hamilton syringe and a cannula (Thermo 0.4 x 20) from an infusion tube integrated in the circuit. To demonstrate the prolonged action of oligomeric or polymeric bile acids, in this special experimental design the outflow (intestine) and filling (bile) of the radioactive label is tested with the inhibitor during the first instillation (Inst. I) and without the inhibitor during the second instillation (Inst. II).

Cholestyramine: 25% inhibition of absorption Example 6: 36% inhibition of absorption Example 7b: 50% inhibition of absorption Example 15b: 60% inhibition of absorption EVALUATION OF THE TESTS The bovine bile absorption test demonstrates that the polymers according to the invention have a distinctly superior ability to absorb bile acids than that of the substance of Example 15 of EP 0 549 967. The ability of the polymers according to the invention to absorb bile acids is similar to that of cholestyramine. In the test system "rat intestine perfused in vivo", the polymers according to the invention demonstrate an absorption inhibiting action of 36% to 60%. In contrast, cholestyramine demonstrates a slightly smaller absorption inhibiting action of 25%. The polymers according to the invention are therefore superior in their action even to cholestyramine, as in addition to a great ability to absorb bile acids, they by themselves easily bind to bile acid receptors, and in this way they demonstrate an inhibitory action of absorption.

Claims (3)

NOVELTY OF THE INVENTION CLAIMS

1. - A vinyl copolymer consisting of units of the formula I -1 and its physiologically tolerable salts, in which: R, R, R are hydrogen or CH3; R and R are hydrogen, alkyl- (C-Cg), acyl- (Cx-Cg); d is 0.01 to 1.00; e is 0 to 0.99; f is 0 to 0.99; where d + e + f must be equal to l; L is a bond, -NH-, - N (CH3) -, - + NH2Cl ~ -, - + NH (CH3) Cl ~ -, - + N (CH3) 2C1"-, -.NH-CO-, - NH- (CH2) n-, -NH- [(CH2) n-0-] m- (CH2) p-, -NH- (CH2) _n-CO-, -NH-CO- (CH2) p-, -NH- (CH2) n -CO-NH (CH2) mN- (CH-3) 2 + Cl "- (CH2) m-, -NH- [CH2-CH (CH3) -0-] m-CH2- CH (CH3) -, -NH- (CH2) mN (CH3) 2 + Cl ~ - (CH2) n-, -0- (CH2) n-, -O- (CH2) n -CO-, -CO- , -CO-NH-, -CO-N (CH3) -, -CO-NH- CO- -CO-NH- (CH2; n -CO-NH- [(CH2) n-0-] m- (CH2 ) -CO-NH- (CH2) n-CO-, -CO-NH-CO- (CH2) n-, -CO-NH- [CH2-CH (CH3) -O-] m-CH2-CH (CH3) ) -, -CO-NH- (CH2) m- + N (CH3) 2 Cl ~ - (CH2) n-, -CO- (CH2) n-0- (CH2) p-CO- -Ar- -Ar- CO-, -Ar-CH-- -Ar-CH2- + N (CH3) 2C1 ' (CH2: n -CO-Ar-CO-, -alkylene- (C ^ C ^) -, CH3 I-NH-CH2-Ar-CH2-N + - (CH2) n-, CH3 Cl ~. -NH-Ar-CO-, -NH-CH2-Ar-CH2-, -NH-CO-Ar-CO-; H is a bond, CH2-, -Ar-, -Ar-CH-, where Ar is phenylene, naphthylene; m is 1 to 18; n is 1 to 18; p is 1 to 18; A is -O-, -NH-, in bond; B is -OH, -ONa, -OK, -NH2, -NH-CH3, -N (CH3) 2, -NH-CH2 -CH2 -S03Na, -NH-CH2-COONa, -NH-CH2-CH2- + N (CH3) 3C1-, -O-alkyl- (C ^ CÍS), -NH-alkyl- (C1-Cg), NH-alkylene- (C ^ C) -OMe, R / is -OH, -O-alkyl- (Ci-Cg), -NH2; Y is -NH2, - + NH3C1 'NH-R • + NH2R9C1' -NR9R101 • + NR9R10R1: LCr -alkylene- (C ^ _-C18) -NH_2-, -alkylene- (C? -C18) - + NH3C1 ' -alkylene- (C] _-C18) NHR "-alkylene- - + NR9R10R1: LC1- -NH-CO-alkyl-C ± -C c.) -, -NH-CO-alkylene- (Cx- C12) - >? 9RD10Ki, -NH-CO-alkylene- (C? -C12) - + NR, 93DR1-L0? DR1x1-L, Cl ~, -CO-NH-alkylene- (C? -C18) - + NR9R10R11C1" ', -phenyl, -phenylene-alkylene- (C0-Cg) -NH2, -phenylene-alkylene- (C0-Cg) -NH-R9, -phenylene-alkylene- (C0-Cg) -NR9R10, -phenylene- alkylene- (C0-Cg) - + NR9R10R1: LC1", -CO-NH-R9, -NH-alkylene (C! -C18) -NHR9, -NH-alkylene- ^ C ^ -NR9R10, -NH-alkylene- (Cx-Cxs) - + NR9R10R1: LC1", -CONH2, -CO-alkyl- -NR9R10, - O-CO-alkylene- (ClT ^ _- C9D c1T ^ 2.) - + NR9R10nll Cl" -CH2-OH -CO-alkylene- (C1-C18) - + N- (C1-C8 alkyl) 3C1"O -CO-alkylene- (C! -C18) -NR9R10; Z is -NH2, - + NH3C1 -, - NH-R9, - + NH2R9C1 ~ -, -NR9R10, - + NR9R10R1: LC1", -alkylene- (C18) -NH2-, -alkylene- (Ci-Cxs) - + NH3C1 ~ -, -alkylene- (C1 -C18) - NHR9, -alkylene- --C ^) -NR9R10, -alkylene- (C ^ -C-LS) - + NR9R10R1: LC1 -, -NH-CO-alkyl- (C! -C18) -NH -CO-alkylene- (C-C12) NR9R10, -NH-CO-alkylene- (C? -C12) - + NR9R10R1: LC1", -COR9, -CO-ORy, -CO-NH-alkylene- (C- C18) - + NR9R1ÜR11C1 ~, -phenyl, phenylene-alkylene- (C0-Cg) -NH2, -phenylene-alkylene- (C0-Cg) -NH-R9, • phenylene-alkylene- (C? -Cg) • phenylene-alkylene- (Crj-Cg) + NR9R10R1: LC1 ~, -CO-NH-alkyl- (C-C12), -NH-alkylene- (C-C18) -NHR9, -NH-alkylene- (C-C18) -NR9R10, -NH-alkylene- (C -C18) - + NR9R10R11C1", -COOH, -O-R9, -CONH2, -O-CO-R9, -CO-alkyl- (Cx- C12), -O-CO-alkylene- (C-12) ) -O-CO-alkylene- (C? -C12; + NR9R10R1: LC1"; O -C-NH- (CH2) m-NR9R10, O II -C-O-alkylene- (C? -C18) -N + - (alkyl- (C-C18) 3-Cl, or a cross-linker selected from the group consisting of: -CO-X-alkylene- (C2-Cg) -X-CO-CR1-CH2- - (O-alkylene- (C -C3))? _18-0-CH-CH2 -NH alkylene (C1-C12) -NH-CH-CH2 I -NH-CH2-CH (OH) -CH2-NH-CH-CH2-, -NH-COOH-alkylene- (C-C12) -CHOH-NH-CH-CH2-; X is O, -NH-; R9, R10 are alkyl- (C? -C18) -, -phenyl, -CH2-phenyl; R is H, alkyl- (C? -C? 8) -, -phenyl, -CH-phenyl; where at least one of the radicals L, Y and Z must contain an ammonium center.

2. A compound according to claim 1, further characterized in that, in formula 1, R, R, R ° are hydrogen or CH3; R and R are hydrogen; d is 0.01 to 1.00; e is 0 to 0.99; f is 0 to 0.99; where d + e + f must be equal to 1; L is -NH-, -NH-alkylene- (C? -C18) -, -NH- (alkylene- (C? -C3) -0-) _18-alkylene- (C -C3) -, -CO- NH-, -CO-NH-alkylene- (C? -C18) -, -CO-NH-alkylene- (C? -C18) (C? -C18) -, 0 II -CO-, -NH-alkylene- (C? -C6) -C-NH-; H is a bond, -CH2-; A is -O-, a bond, -NH-; B is -OH, ONa, -OCH3, -NHCH2-CH2-OCH3, Y is -NH2, -NHR9, -NR9R10, - + NR9R10R11Cl ", -NH-alkylene- (C? ~ C18) - + NR9R10R1: LC1", -CH2-NH2, -CH2-NH-R9, - (CH2) -NH-alkylene- (l-Cl8) -NR9R10, -CH2-NH-alkylene- (C? -C18) - + NR9R10R1: LC1 ~, -NH- CO-R9, -CO-NH-propylene- + NR9R10R11Cl " , TO. -CO-O-alkylene- (C -C18) is -NH2, -NHR9, -NR9R10, CH2-NH2, -CH2-NH-R9, -CH2-NR9R10, -CH2-NH-alkylene- (C? -C18) ) - NR R UR1XC1", or a crosslinker selected from the group consisting of: -NH-alkylene- (C -C12) -NH-CH-CH2-, -CO-X-alkylene- (C2-C6) -X-CO-CR1-CH2- -NH-CH2-CH (0H) -CH2-NH-CH-CH2-; X is -O-, -NH-; R9, R10, R11 are alkyl- (C? -Cg) -, -phenyl, CH2-phenyl, wherein at least one of the radicals L, Y and Z must contain an ammonium center.

3. A compound according to claim 1 or 2, further characterized in that, in formula I, R, R, R3 are hydrogen; R4 and R are hydrogen; d is 0.01 to 0.5; e is 0 to 0.99; f is 0 to 0.99; where d + e + f must be equal to l; L is -N? -CH2-CH2-0-CH2-CH2-0-CH-2-CH2-, O n -C-NH-alkylene- (C? -C18) -, -NH-alkylene- (C? -C18) -, -CO-, -NH-, (C? -C18) -, -alkylene- (C? -Cg) -NH-alkylene- (C? -Cg) -, - H is a bond, -CH-; A is -O-, -NH-, a bond; B is -OH, -ONa, -NH-CH2-CH2-OCH3; Y is -NH2, -NHR9, -NH-alkylene- (C -C18) - + N (CH3) 3C1", -CO-NH-alkylene- (C? -C10) - + N (CH3) 3C1 ~, - CO-NH-alkylene- (C? -Cg) -N (CH3), -CH2-NH2, -CH2-NHR9; Z is -NH2, -NHR9, -CH2-NH2, -CH2-NHR9, -NH-alkylene - (C? -C18) - + N (CH3) 3C1", CH2-NH-alkylene- (C -C18) - + N (CH3) 3C1", -CO-NH-propylene- + N (CH3) 3C1 ~ where at least one of the radicals L, Y and Z must contain an ammonium center.