Method of removing gallstones from the body of the patient (options) and alkilirovanny poperechnyy polymer for implementing the method (variants)

 

(57) Abstract:

Describes a method of removing gallstones from the body, including the use of therapeutically effective ion-exchange resin, characterized in that the ion exchange resin is used, the reaction product containing one or more Poperechnaya polymers comprising recurring structural unit selected from the group consisting of units of formula 1, 2, 3, and salts of a copolymer based on them, where n is an integer and each radical R is independently - H or C1- C8alkyl group, and at least one alkylating agent, while some of the nitrogen atoms in the structural units of the polymer does not interact with the alkylating agent and less than 10 mol.% the nitrogen atoms in the structural units that interact with the alkylating agent to form the Quaternary ammonium compounds. The technical result is to simplify the process of removing bile salts from a patient's body. 4 C. and 50 C.p. f-crystals, 3 PL.

< / BR>
(-NR-CH2CH2-)n< / BR>
(-NR-CH2CH2-NR-CH2CH2-NR-CHOH-CH2-)nThe technical field

The invention relates to salts of bile acids from the body of the patient.

The reabsorption of bile acids from the intestine retains urine cholesterol in the blood stream. Cholesterol can be lowered by reducing reabsorption of bile acids.

Art

One way of lowering the level of reabsorption of bile acids is to use compounds that sequestered bile acids, and they can't be absorbed. Sequestered bile acids disintegrate or displayed.

However, some of bile acid sequestrants bind relatively hydrophobic bile acids significantly stronger than conjugated primary bile acids such as cholic, chenodeoxycholic acid. Further active piechnik acids and free education for reabsorption of bile acids. In addition, the number of biologically safe for the body sequestrants limited. So is limited and the efficiency of the use of sequestrants for the purpose of reducing the level of cholesterol in the blood.

There is also known a method of excretion of bile acids by adsorption of various insoluble derivatives of allylamine (international application N WO 92/10522, 25.06.92) or derivatives polyvinylene (U.S. patent N 5430110, 04.07.95). However, as shown by the results of experimental verification of the presented later in this description, the known method has limited effectiveness.

To reduce the cholesterol level in the body of a patient can be used, the scenery and the excretion of bile salts (e.g. salts holeva, glycocholate, Glickenhaus, human beings need it and deoxycholic acids). Since cholesterol is the biological precursor of bile salts, their education in the process of metabolism is accompanied by a decrease in the level of cholesterol in the human body. Cholesterin, polystyrene/divinylbenzene ion-exchange resin in oral introduction removes salts of bile acids through Pishevari. is therefore necessary other ion-exchange resin, available (in whole or in part from such deficiencies and/or having the best requestrefuse properties.

The invention

The first task to be solved by the present invention is directed, is to create a new class of ion-exchange resins, which are suitable for introduction into the digestive tract of the patient and capable of reducing the content of bile acids in the body, acting as sequestrants bile salts.

These resins include Poperechnaya polyamine, which are characterized by one or more hydrophobic substituents, and optionally one or more Deputy containing Quaternary ammonium.

The present invention includes resins and their use as sequestrants bile salts for removing these salts from the body of the patient, which in turn includes assigning the patient a therapeutically effective amount of the reaction product containing:

(a) one or more Poperechnaya polymers comprising recurring structural unit selected from the group consisting of:

< / BR>
(NR2-CH2CH2)n(2)

(NR - Nova where n is an integer and each of the radicals R, independently is H or C1- C8alkyl group; and

(b) at least one alkylating agent

The reaction product is characterized by the fact that: (i) at least some of the nitrogen atoms in the repeating structural units do not interact with an alkylating agent; (ii) less than 10 mol% of the nitrogen atoms in the repeating structural units interact with an alkylating agent to form the Quaternary ammonium compounds; and (iii) the reaction product mainly non-toxic and stable when introduced into the digestive tract.

Suitable substituents are, for example, Quaternary ammonium, amine, alkylamine, dialkylamino, hydroxy group, alkoxy group, halogen, carboxamide, sulphonamide and an ester of carboxylic acid.

According to preferred variants of the polymer of the present invention as R can be chosen N.

In preferred embodiments, the polyamine compound (a) comprises the reaction product of cross stitched with the help of a multifunctional cross-linking agent which is taken in the amount of 0.5 - 25% (preferably 2.5 to 20%, most preferably 1 to 10%) by weight of the total weight of monomer and schimmenti. The epichlorohydrin is preferred also because it has a small molecular weight and hydrophilic in nature, which improves the properties of swelling and gelation polyamine.

The second task is to develop a method of deducing from an organism of the patient salts of bile acids, involving the use of new sequestrants according to the present invention.

While preferably using an alkylating agent of the formula RX, where R is a C1-C20alkyl, C1-C20hydroxyalkyl, C7-C20Uralkaliy, C1-C20alkylammonium or C1-C20alkylamino group and X includes one or more electrophilic leaving groups. In particular, X may be a halide, epoxy-, tosylate or methylsulfonyl group, in particular, C1-C20haloalkyl, preferably C4-C18haloalkyl.

Alternatives alkylating agent are:

C1-C20dihaloalkanes, particularly 1,10-dialogical;

C1-C20halohydrocarbon, in particular, an 11-halo - 1-undecanol;

C1-C20haloalkylthio salt, in particular C4-C12keloidal trimethylammonium salt;

C1-C20amoxilcillin, for example, selected from the group consisting of N-(2,3-epoxypropan)butyramide, N-(2,3-epoxypropan)hexanamide and combinations thereof.

According to one alternative implementation of the method according to the invention using a polymer that interacts with at least two alkylating agents, one of the alkylating agents has the formula RX where R is a C1- C20alkyl group and X includes one or more electrophilic groups, and the other alkylating agent has the formula R X wherein R' is C1-C20alkylammonium group and X includes one or more electrophilic leaving groups.

In this case, as one of the alkylating agents take, for example, haloalkyl (preferably C4- C18haloalkyl, in particular, C10haloalkyl), and as another alkylating agent take haloalkylthio salt (preferably C4-C18haloalkylthio salt, in particular C6haloalkylthio salt).

The present invention also includes compositions based on the above-described reaction products.

The present invention includes the effect is on the body). The compositions of the present invention are non-toxic and stable with the introduction of the digestive tract in therapeutically effective amounts.

Information confirming the possibility of carrying out the invention

Songs

Preferred reaction products include one or more Poperechnaya of polymers having the formula (3), and one or more alkylating agents. The polymers cross stitched. The level of cross-linking provides the insolubility of the polymers and limits thus the activity of the alkylated reaction product of the gastrointestinal tract. Because of this limitation in the scope of activity decrease undesirable for human body side effects.

The term "non-toxic" means that when introduced into the intestinal tract in therapeutically effective quantities of any products of reaction, nor any ions generated in the process of ion exchange, are not harmful. The presence of cross-links makes the polymer is highly resistant to absorption. When the polymer is introduced in the form of salts, cationic counterions are preferably chosen in such a way as to minimize adverse effects on the patient, as it will be more PV therapeutically effective amounts, do not dissolve or not dissolve in any other way in vivo with the formation of potentially harmful by-products, and remain essentially unchanged, so that they are able to remove substances from the body.

The term "salt" means that the nitrogen group in the repeating part forms a positively charged nitrogen atom, which binds to negatively charged counterion.

The term "alkylating agent" refers to some reactant, which, reacting with Poperechnaya polymer forms an alkyl group or its derivative (for example, substituted alkyl, such as aralkyl, hydroxyalkyl, alkylammonium salt, alkylamide or combinations thereof), covalently associated with one or more nitrogen atoms of the polymer.

One preferred polymer includes a repeating structural unit having the formula

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or a salt or copolymer based on it, where x is zero or an integer from 1 to 4.

A second example of a preferred polymer contains a repeating structural unit having the formula

(NH-CH2CH2)n(5)

or a salt or copolymer based on it.

The third example of a preferred polymer is H2CHOH-CH2)n(6)

or a salt or copolymer based on it.

The polymers preferably transversely fastened to alkylation. Suitable alkylating agents are, for example, akriloilkhlorida, epichlorohydrin, potentiallity ether, ethiological ether and dimethylsuccinic. The amount of crosslinking agent is usually from 0.5 to 25% (preferably 2.5 to 20% or 1 to 10%) of the total weight of a crosslinking agent and monomer.

Typically, such an amount of crosslinking agent that interacts with aminoven polymer is sufficient for the formation of from 0.5 to 20% amines. In the preferred embodiment, with the cross-linking agent communicates about 0.5 - 6% of amine groups.

Cross-linking of the polymer is produced by interaction of the polymer with a suitable cross-linking agent in a solution of caustic soda at 25oC during the period of time from eighteen hours prior to gel formation. Then, the obtained gel is combined with water and stirred until the formation of specific solids. This substance can then be washed and dried under suitable conditions, for example at a temperature of about 50oC for about eighteen hours.

Alkynylamino nitrogen atoms, for example, in the form of amido - or ammonium groups. In addition, the nitrogen atoms that can interact with alkylating agent (s), prevent the formation of Quaternary ammonium ions with multiple alkylation, so that at the end of the alkylation less than 10 mol. % of nitrogen atoms form a Quaternary ammonium ions.

Preferred alkylating agents have the formula RX where R is a C1- C20alkyl (preferably C4- C20alkyl), C4-C20hydroxyalkyl (preferably C4- C20hydroxyalkyl), C7- C20aralkyl, C1-C20alkylamine (preferably C4-C20alkylammonium) or C1-C20alkylamide (preferably C4-C20alkylamide) and X includes one or more electrophilic leaving groups. The term "electrophilic leaving group" denotes a group, which replaces the nitrogen atom in Poperechnaya the polymer in the reaction of alkylation. Examples of such groups include halide, epoxy-, tosylate and methylsulfonyl group. If, for example, epoxy groups, in the alkylation reaction rupture of a three-membered epoxy ring.

Examples before the KSIL, n-galidictis, n-keloidal, n-kaleidotile, n-galottery, n-kaleidoscopical and combinations thereof); C1-C20dihaloalkanes (for example, 1,10 - dialogical), C1-C20halohydrocarbon (for example, an 11-halo - 1-undecanol): C1-C20haloalkyl (for example, halogenic), C1-C20haloalkylthio salt (for example, (4-halobutyl)trimethylammonium salt, (6 - haloacyl)trimethylammonium salt, (8-galactal)trimethylammonium salt, (10-Galadari)trimethylammonium salt, (12-galottery) trimethylammonium salts and combinations based on them); C1-C20amoxicillina salt (for example, goldpreis)trimethylammonium salt); and (C1-C20amoxilcillin (for example, N-(2,3-epoxypropan)butyramide, N-(2,3 - epoxypropan)hexanamide and combinations thereof.

Most preferred is the interaction of the polymer with at least two alkylating agents, added to the polymer simultaneously or sequentially. In one such example, one of the alkylating agents has the formula RX where R is a C1- C20alkyl group and X includes one or more electrophilic leaving groups (e.g., haloalkyl), and other alkylating AG is traviling leaving groups (for example, X globalcommunity salt).

In another example, one of the alkylating agents has the formula RX where R is a C1-C20alkyl group and X includes one or more electrophilic leaving groups (e.g., haloalkyl), and the other alkylating agent has the formula R X wherein R' is C1-C20hydroxyalkyl group and X includes one or more electrophilic leaving groups (e.g., halohydrocarbon).

In the following preferred example, one of the alkylating agents is C1-C20dihaloalkanes, and the other is C1-C20alkylammonium salt.

The reaction products may be fixed positive charges, or may have the ability to become charged with the introduction of at physiological pH. In the latter case, the ions can also capture negatively charged counterions, which can then be exchanged with bile salts. When the reaction products have a positive charge, they can capture one or more exchange of counterions. Such counterions may be, for example, Cl-, Br-CH3OSO3-, HSO4-, SO42-, HCO3-, CO3

The alkylating agent may be added to Poperechnaya the polymer in a molar ratio of from 0.05:1 to 4:1, for example, alkylating agents may be selected so as to provide a hydrophobic and hydrophilic areas.

Amine polymer in a typical case, alkylate, combining the polymer with an alkylating agent in an organic solvent. The number of the first alkylating agent, combined with aminoven polymer, it is usually enough to ensure the interaction of this alkylating agent from about 5 to 75% of the amine groups in the amine polymer that can participate in the reaction. The number of the second alkylating agent, combined with aminoven polymer and solvent, it is usually enough to ensure vzaimodeistviyami. Examples of suitable organic solvents are methanol, ethanol, isopropanol, acetonitrile, DMF and DMSO. The preferred organic solvent is methanol.

In one embodiment, the reaction mixture is heated while stirring for about four minutes to a temperature of about 65oC. Usually continuously add a solution of sodium hydroxide. Preferably the reaction time at 65oC is eighteen hours, followed by gradual cooling to approximately 25oC for 4 h the resulting product is filtered, resuspended in methanol and again filtered, washed in a suitable aqueous solution, such as dvuhpolyarnyy sodium chloride solution and then with deionized water. The solid product is dried at a temperature of about 60oC in a stream of dry air. The resulting product is preferably milled and sieved through a sieve.

In a preferred embodiment of the present invention aminoven polymer is poperechnyy poly(allylamine). More in detail the invention is illustrated in the following examples.

Examples

A. Obtaining polymers

1. Obtaining poly(vinylamine)

On the ground floor is a flask with a volume of 1 l, equipped with condenser, thermometer and mechanical stirrer. Add concentrated HCl (34 ml) and the mixture is heated to 45-50oC with continuous stirring for 24 hours and Then water is removed under vacuum to leave a thick layer of pulp, which when cooled to 5oC crystals are formed. Then add acetone and stirred for several minutes, then the solid precipitate is filtered and removed. Acetone is cooled to 0oC and the solid phase is filtered. This solid is washed with 500 ml of acetone and dried with air to obtain 31.5 g of ethylidenebicyclo.

In the next phase of ethylidenebicyclo get vinylacetate. Ethylidenebicyclo (31,05 g), calcium carbonate (2 g) and celite (2 g) was placed in a three-neck flask of 500 ml equipped with a thermometer, mechanical stirrer and distilleries heater placed above the column Vigroux. The mixture distil under vacuum at 24 mm RT.art., heating to 180-225oC. Select only a fraction (10.8 g), which, along with the product contains a significant amount of ndimethylacetamide (which is set using the NMR method). This solid product was dissolved in isopropanol (30 ml) before the formation of the crude vinylacetylene rasol (1 g, technical, 55% purity, mixture of isomers) and azobisisobutyronitrile, AIBN (0.3 g) are mixed and heated under reflux in nitrogen atmosphere for 90 min, thus obtaining a solid residue. The solution is cooled, add isopropanol (50 ml) and the solid is collected by centrifugation. The solid is washed twice in isopropanol, once with water and dried in vacuum to obtain 0.8 g of poly(vinylacetate), which is used then for the preparation of poly(vinylamine) as follows.

Poly(vinylacetate) (0,79 g) is placed in a 100 ml flask with water (25 ml) and HCl (25 ml). The mixture is condensed for 5 days, after which the solid phase is filtered, washed once with water and twice in isopropanol, and dried in vacuum to obtain of 0.77 g of product. By the method of infrared spectroscopy reveals that the product remains a significant amount of amide (1656 cm-1) and a not a lot amine (1606 cm-1). The product of this reaction (~ 0.84 g) is suspended in NaOH (46 g) and water (46 g) and heated to boiling (~ 140oC). Due to the evaporation temperature is lowered and maintained at about 100oC for 2 hours Then add water (100 ml) and the solid filtered. After washing snova filter, washed with water, then with isopropanol and dried in vacuum to obtain 0.51 g of product. By the method of infrared spectroscopy reveals that the product is a significant amount of amine.

2. Obtaining poly(etilenimina)

Polyethylenimine (120 g 50% aqueous solution; Scietific Polymer Products) dissolved in water (250 ml). The epichlorohydrin (22,1 ml) is added dropwise. The solution is heated to 60oC for 4 h, after which a gel is formed. This gel extract, mixed with water (1.5 l) and the substance is filtered, washed three times with water (3 l) and twice with isopropanol (3 l) and the resulting gel is dried in a vacuum to obtain 81,2 g of the above polymer.

3. Obtaining poly(allylamine)hydrochloride

In the reactor tank with a volume of 2 liters with water jacket, equipped with a condenser (1) with a hole for nitrogen, a thermometer (2) and a mechanical stirrer (3), add concentrated hydrochloric acid (360 ml). The acid is cooled to 5oC water circulating in the water jacket (water temperature 0oC). Allylamine (328,5 ml, 250 g) is added dropwise with stirring until then, until the temperature of the reaction 5-10oC. thereafter, the mixture is extracted, placed in a flask with a volume of 3 l with a narrow neck and 206 g W the bone back into the reactor vessel. Then add azobis(amidinopropane) dihydrochloride (0.5 g), suspended in 11 ml of water. The resulting mixture was heated to 50oC in nitrogen atmosphere with stirring for 24 hours Then add additional azobis(amidinopropane)dihydrochloride (5 ml), suspended in 11 ml of water, then continue heating and stirring for an additional 44 hours

At the end of this period the reaction mixture was added distilled water (100 ml) and the liquid mixture is cooled with stirring. The mixture is then selected and placed in 2 - liter separating funnel, from which the mixture is added dropwise in a mixed solution of methanol (4 l), causing the formation of solid substances. This solid is recovered by filtration, resuspended in methanol (4 l), stirred for 1 h and collected by filtration. Then repeat the washing with methanol and the solid is dried in vacuum to obtain 215,1 g poly(allylamine)hydrochloride in the form of granular solids in white.

4. Obtaining poly(allylamine)hydrochloride, Poperechnaya the epichlorohydrin

In a 22-liter vessel type poly(allylamine)hydrochloride, obtained as described in example 3 (the th pH. The resulting solution was cooled to room temperature, then added with continuous mixing a crosslinking agent epichlorohydrin (50 ml). The resulting mixture was thoroughly stirred until the formation of gel (about 35 min). The cross-linkage reaction proceeds in the next 18 hours at room temperature, then remove the gel polymer and put it in the mixer with 10 l of water. Each part is thoroughly mixed for 3 min before the formation of coarse particles, which are then stirred for 1 h and collected by filtration. The solid is washed three times with suspendirovanie in water (10 l, 15 l, 20 l), stirred for each suspension for 1 h, collecting every substance by filtration. The target substance is washed once with suspendirovanie it in isopropanol (17 l), the mixture is stirred for 1 h and then collect the solid product by filtration, after which it is dried in vacuum at 50oC for 18 h to obtain 677 g Poperechnaya polymer in the form of fragile granules white.

5. Obtaining poly(allylamine)hydrochloride, Poperechnaya butanedioldiglycidylether ether

In a 22-liter plastic vessel type poly(allylamine)hydrochlorot solid NaOH (134,6 g) to obtain a pH of 10. The resulting solution was cooled to room temperature, then as a cross-linking agent added with continuous stirring 1,4 - potentiallity ether (65 ml). The resulting mixture was thoroughly stirred until the formation of gel (approximately 6 min). The cross-linkage reaction is continued at room temperature for additional 18 h, after which the gel polymer is removed and dried in vacuum at 75oC for 24 hours of Dry solid is then ground into powder and sieved through a sieve, after which he suspended in 6 gallons of water and stirred for 1 hour. Then the solid product was filtered and twice repeated washing. The resulting material is dried by air for 48 hours, then dried in vacuum at 50oC for 24 hours to obtain 415 g Poperechnaya polymer white.

6. Obtaining poly(allylamine)hydrochloride, Poperechnaya ethiological ether

In chemical beaker with a volume of 100 ml add poly(allylamine)hydrochloride, obtained as described in example 3 (10 g) and water (40 ml). The mixture is stirred to dissolve the hydrochloride and add solid NaOH to obtain a pH of 10. The resulting solution was cooled to room Champigny ether (2 ml). The resulting mixture was thoroughly stirred until the formation of gel (about 4 min). The cross-linkage reaction continued at room temperature for additional 18 h, after which the gel polymer is removed and stirred in 150 ml of methanol. The solid is then filtered off and suspended in water (500 ml). After stirring for 1 h, the solid is filtered and repeatedly washed. The resulting substance washed twice in isopropanol (400 ml) and then dried at 50oC for 24 h to obtain 8.7 g Poperechnaya polymer white.

7. Obtaining poly(allylamine)hydrochloride, Poperechnaya dimethylsuccinic

In a 500 ml flask add poly(allylamine)hydrochloride, obtained as described in example 3 (10 g), methanol (100 ml) and triethylamine (10 ml). The mixture is stirred and added as a crosslinking agent dimethylsuccinic. The solution is heated for condensation and mixing is stopped after 30 minutes After 18 h the solution is cooled to room temperature, the solid is filtered and mixed with 400 ml of isopropanol. The solid is filtered and suspended in water (1 l). After stirring for 1 h, it is filtered and twice washed again. Then the substance is washed in isopropanol color.

8. Obtaining poly(etilenimina), Poperechnaya akriloilkhlorida

In a three-neck flask with a volume of 5 liters, equipped with a mechanical stirrer, thermometer and an additional funnel, add poly(ethylenimine) (510 g of a 50% aqueous solution, equivalent to 255 g of dry polymer) and isopropanol (2.5 g). As a cross-linking agent via an additional funnel is added dropwise akriloilkhlorida (50 g) for 35 minutes, until the temperature is below 29oC. Then the solution is heated to 60oC under stirring for 18 h, after which the solution is cooled and the solid is immediately filtered. The substance is then washed three times, suspending it in water (9 l), stirred for 1 h and filtered to recover the solid. Then it is washed, suspending in methanol (9 l), stirred for 30 min and filtered to obtain a solid substance. In conclusion, the substance is washed in isopropanol as in example 7, and dried in vacuum at 50oC for 18 h to obtain 206 g Poperechnaya polymer in the form of a light orange granules.

9. Alkylation of poly(allylamine), Poperechnaya butanedioldiglycidylether ether, alkylating agent is 1-iodooctane

Poly(allylamine (100 ml) and add sodium hydroxide (0.2 g). After stirring for 15 min add 1-iodooctane (1,92 ml) and the mixture is stirred for about 60oC for 20 h and Then the mixture is cooled and the solid product filtered off. Then the solid substance is washed, suspending it in isopropanol (500 ml), again stirred for 1 h and collected by filtration. The washing procedure is repeated twice using an aqueous solution of sodium chloride (500 ml of 1 M solution), twice - water (500 ml) and once isopropanol (500 ml), and after vacuum-drying at 50oC for 24 h get the 4.65 g of alkylated product.

The procedure is repeated using 2,88 ml of 1-iodooctane, and obtain 4.68 g of alkylated product.

10. Alkylation of poly(allylamine), Poperechnaya the epichlorohydrin, the alkylating agent is 1-iodooctane

Poly(allylamine), Poperechnaya with epichlorohydrin, obtained as described in example 4 (5 g) alkylate in accordance with the procedure described in example 9, except that the use of 3.84 ml of 1-iodooctane. The result 5,94 g of alkylated product.

11. Alkylation of poly(allylamine), Poperechnaya the epichlorohydrin, the alkylating agent is 1-iodocholesterol

Poly(allylamine), Poperechnaya epichlorhydrine the Le stirring for 15 min add 1-iodooctane (8,1 g) and the mixture was stirred at 60oC for 20 h and Then the mixture is cooled and the solid product filtered off. Next, the solid is washed, suspending it in isopropanol (500 ml), then stirred for 1 h and collected by filtration. The washing procedure is repeated twice using an aqueous solution of sodium chloride (500 ml of 1 M solution), twice - water (500 ml) and once isopropanol (500 ml), and after vacuum-drying at 50oC for 24 h to obtain 9.6 g of alkylated product.

12. Alkylation of poly(allylamine), Poperechnaya butanedioldiglycidylether ether, alkylating agent is 1-iododecane

Poly(allylamine), Poperechnaya butanedioldiglycidylether ester, obtained as described in example 5 (5 g) alkylate in accordance with the procedure described in example 11, except that use 2,47 ml 1 iododecane. The result of 4.7 g of alkylated product.

13. Alkylation of poly(allylamine), Poperechnaya butanedioldiglycidylether ether, alkylating agent benzylbromide

Poly(allylamine), Poperechnaya butanedioldiglycidylether ester, obtained as described in example 5 (5 g) alkylate in accordance with the procedure described in example 11, except that ispolzuyuschihsya), Poperechnaya with epichlorohydrin, an alkylating agent benzylbromide

Poly(allylamine), Poperechnaya with epichlorohydrin, obtained as described in example 4 (20 g) alkylate in accordance with the procedure described in example 11, except that the use of 1.21 ml benzylbromide. The result of 6.6 g of alkylated product.

15. Alkylation of poly(allylamine), Poperechnaya the epichlorohydrin, the alkylating agent is 1-iododecane

Poly(allylamine), Poperechnaya with epichlorohydrin, obtained as described in example 4 (20 g) alkylate in accordance with the procedure described in example 11, except that they use to 7.15 g of 1-iododecane and 2.1 g of NaOH. The result 20,67 g of alkylated product.

16. Alkylation of poly(allylamine), Poperechnaya the epichlorohydrin, the alkylating agent is 1-iodobutane

Poly(allylamine), Poperechnaya with epichlorohydrin, obtained as described in example 4 (20 g) alkylate in accordance with the procedure described in example 11, except that use 22,03 g 1-iodobutane and 8.0 g of NaOH. The result of 24.0 g of alkylated product. In accordance with the same procedure obtain 17.0 g and 21.0 g of alkylated product is crosslinked with epichlorohydrin, alkylating agent is 1-interdecadal

Poly(allylamine), Poperechnaya with epichlorohydrin, obtained as described in example 4 (5 g) alkylate in accordance with the procedure described in example 11, except that the use of 2.1 ml of 1-iteration. The result of 5.2 g of alkylated product.

In accordance with the same procedure get 7,15 r alkylated product using 6,4 ml 1 iteration.

18. Alkylation of poly(allylamine), Poperechnaya the epichlorohydrin, the alkylating agent is 1-iodooctane

Poly(allylamine), Poperechnaya with epichlorohydrin, obtained as described in example 8, (5 g) alkylate in accordance with the procedure described in example 11, except that the use of 1.92 ml of 1-iodooctane. The result is 5.0 g of alkylated product.

19. Alkylation of a copolymer of Diethylenetriamine and epichlorohydrin alkylating agent is 1-iodooctane

The copolymer comprising ethylendiamin and epichlorohydrin (10 g), alkylate in accordance with the procedure described in example 11, except that the use of 1.92 ml of 1-iodooctane. The result of 5.3 g of alkylated product.

20. Alkylation of poly(allylamine), mania

Poly(allylamine), Poperechnaya with epichlorohydrin, obtained as described in example 4 (20 g) alkylate in accordance with the procedure described in example 11, except that use 23,66 g 1 iododecane, 6.4 g of sodium hydroxide and 500 ml of methanol. Then carry out the reaction of 24 g of alkylated product with 50 g of 90% of the chloride of glycidylmethacrylate in methanol (1 l). The mixture is stirred for 24 h, then cooled to room temperature and washed thoroughly with water (three times, using each time in 2.5 l of water). After vacuum-drying gain of 22.4 g dialkylamino product.

Dialkylamino products are obtained in a similar manner, substituting 1-iododecane 1-iododecane and 1-iodocholesterol, respectively, followed by alkylation with chloride of glycidylmethacrylate.

21. Alkylation of poly(allylamine), Poperechnaya with epichlorohydrin, of alkylating agent of chloride glycidylmethacrylate

Poly(allylamine), Poperechnaya with epichlorohydrin, obtained as described in example 4 (5 g) reacts with 11,63 g 90% of the chloride of glycidylmethacrylate (1 mol equivalent) in methanol (100 ml). The mixture was stirred at 60oC for 20 h, after which it Oh ml). After vacuum-drying receive 6,93 g of alkylated product.

Alkylated products are obtained similarly, using 50%, 200% and 300% mole equivalent of 90% of the chloride of glycidylmethacrylate.

22. Alkylation of poly(allylamine), Poperechnaya with epichlorohydrin, an alkylating agent bromide (10 - bromacil)trimethylammonium

At the first stage receive bromide (10-bromacil)trimethylammonium as follows.

1,10-dibromodecane (200 g) is dissolved in methanol (3 l) in a 5-liter three-neck flask equipped with a cooling condenser (-5oC). To this mixture was added aqueous trimethylamine (176 ml of 24% aqueous solution). The mixture is stirred at room temperature for 4 h, then heated to boiling under reflux for 18 hours By the end of the period of heating the flask was cooled to 50oC and the solvent is removed under vacuum, so that there is only a solid mass. In the product add acetone (300 ml), the mixture was stirred at 40oC for one hour. This is followed by filtering the suspension in additional portions of acetone (1 l) and stirring for 90 minutes

After a period of stirring, the solid is filtered off and remove; ACE for 1 h, then the solid precipitate was filtered and washed with fresh hexane. The obtained solid substance was dissolved in isopropanol (75 ml) at 40oC. Add ethyl acetate (1500 ml) and increase the temperature to approximately the 50oC until complete dissolution of all solid material. Then the flask teploizolirovat and place in the refrigerator for 24 hours; the result is the formation of solid crystals. These crystals are filtered, washed with cooled ethyl acetate, dried in vacuum at 75oC and get to 100.9 g of the bromide (10 - bromacil)trimethylammonium in the form of white crystals.

Poly(allylamine), Poperechnaya with epichlorohydrin, obtained as described in example 4 (10 g) is suspended in methanol (300 ml). Add sodium hydroxide (3.3 g), the mixture is stirred until it is completely dissolved, add the bromide (10-bromacil)trimethylammonium (20.7 g) and the mixture refluxed with stirring for 20 hours Then cooled to room temperature and washed thoroughly with methanol (twice in 1 l), sodium chloride (twice with 1 l of 1 M solution each time), water (three times for 1 l) and isopropanol (1 l). After vacuum-drying obtain 14.3 g of alkylated product.

23. Alkilirovanie poly(allylamine), Poperechnaya-dibromodecane (200 g) is dissolved in methanol (3 l) in a 5-liter flask, equipped with a cooling condenser (-5oC). To this mixture was added aqueous trimethylamine (220 ml of 24% aqueous solution, w/w). The mixture is stirred at room temperature for 4 h, then heated to boiling under reflux for 24 hours Then the flask was cooled to room temperature and receive 3350 ml of clear fluid.

Poly(allylamine), Poperechnaya with epichlorohydrin, obtained as described in example 4 (30 g) is suspended in pure water (2 l) and stirred for 10 minutes, add sodium hydroxide (20 g) and the mixture is stirred until complete dissolution. Further, it is refluxed under stirring for 24 hours, cooled to room temperature and the solid is filtered off. Then the substance is thoroughly washed with methanol (10 l), sodium chloride (twice, each time using 10 l of 1 M solution), water (three times, each time using 10 l) and isopropanol (5 l). After vacuum-drying receive 35,3 g dialkylamino product.

24. Obtaining poly(allylamine), Poperechnaya with epichlorohydrin, alkylating agents bromide (10 - bromacil)trimethylammonium and 1-bramdean

Poly(allylamine), Poperechnaya with epichlorohydrin, policiesat until its complete dissolution, add bromide (10-bromacil)trimethylammonium, obtained as described in example 22, (20.7 g) and 1-bramdean and the mixture is refluxed with stirring for 20 hours Then cooled to room temperature and washed thoroughly with methanol (twice in 1 l), sodium chloride (twice with 1 l of 1 M solution each time), water (three times for 1 l) and isopropanol (1 l). After vacuum-drying obtain 10.8 g dialkylamino product.

In addition, dialkylamino products are obtained in a similar way, using different numbers 1 bramdean: (a) 3,19 g 1 bramdean and to 4.14 g of sodium hydroxide to obtain 11.8 g dialkylamino product; (b) of 38.4 g of 1-bramdean and of 6.96 g of sodium hydroxide to obtain 19.1 g dialkylamino product

Dialkylamino products also receive a similar way using the following combinations of alkylating agents:

1-bramdean and bromide (4-bromobutyl)trimethylammonium;

1-bramdean and bromide (6-bromohexyl)trimethylammonium;

1-bramdean and bromide (8-brackel)trimethylammonium;

1-bramdean and bromide (2-bromacil)trimethylammonium;

1-bramdean and bromide (3-bromopropyl)trimethylammonium;

1 bromhexin and bromide (6-bromohexyl)trimethylammonium;

25. Alkylation of poly(allylamine), Poperechnaya with epichlorohydrin, an alkylating agent, 11-bromo-1-undecanol

Poly(allylamine), Poperechnaya with epichlorohydrin, obtained as described in example 4, (5.35 g) is suspended in methanol (300 ml). Add sodium hydroxide (1.10 g), the mixture is stirred until it is completely dissolved, add 11-bromo-1-undecanol (5.0 g) and the mixture refluxed with stirring for 20 hours Then cooled to room temperature and thoroughly washed with methanol (3 l), sodium chloride (twice, each time using 500 ml of 1 M solution) and water (three times for 1 liter). After vacuum-drying receive 6,47 g of alkylated product.

The reaction is performed in the same way, using of 1.05 g of sodium hydroxide and 10 g of 11-bromo-1-undecanol to get 8,86 g of alkylated product.

26. Alkylation of poly(allylamine), Poperechnaya with epichlorohydrin, an alkylating agent N-(2,3 - epoxypropan)butyramide

First get N-alkylbetaine as follows.

Butyrolactone (194,7 g and 1.83 mol) in 1 l of tetrahydrofuran is added in the three-neck flask with a thermometer, stirrer and addition funnel. The contents of the flask cooled to 15oC in the ice bath at peremeci the m stirring, maintaining the temperature of the 15oC. after this procedure, the stirring is continued for another 15 min, then the precipitate is filtered off. The filtrate was concentrated in vacuo to obtain 236,4 g of N-alkyl butyramide in the form of a colorless viscous liquid.

N-alkylbetaine (12.7 g, 0.1 mol) is placed in a liter flask equipped with a stirrer and an air condenser. To the flask was added methylene chloride (200 ml), then 3-chloroperoxybenzoic acid (50 - 60%, 200 g) in five portions over 30 minutes and continue the reaction. Analysis by thin layer chromatography (using 5% methanol in dichloromethane) shows that after 16 h the formation of the product is completed. The mixture is then cooled and filtered to remove the solid precipitate of benzoic acid. The filtrate was washed with a saturated solution of sodium sulfite (twice using 100 ml) and then with a saturated solution of bicarbonate (twice using 100 ml). The dichloromethane layer is dried with anhydrous sodium sulfate and concentrated in vacuo to obtain 10.0 g of N-(2,3-epoxypropan)butyramide in the form of a yellow viscous liquid.

In liter flask add poly(allylamine), Poperechnaya with epichlorohydrin, obtained as described in example 4 (10 g, sifted the IDA sodium (0.55 g, 0,01375 mol). The mixture is stirred over night at room temperature. After 16 h the mixture is filtered and the solid is thoroughly washed with methanol (three times using 300 ml), water (twice using 300 ml) and isopropanol (three times using 300 ml). After vacuum-drying at 54oC over night get 9.0 g of alkylated product as a light yellow powder.

Similarly receive alkylated products using 10 mol%, 20 mol% and 30 mol% N-(2,3-epoxypropan)butyramide, except that: (a) in the case of 10 mol% use of 1.93 g (0,013 mol) of N-(2,3 - epoxypropan)butyramide and 1.1 g (0,0275 mol) of pellets of sodium hydroxide to obtain of 8.3 g of alkylated product: (b) in the case of 20 mol% use 3,86 g (0,026 mol) of N-(2,3-epoxypropan)butyramide and 2.1 g (0,053 mol) of pellets of sodium hydroxide to obtain 8.2 g of alkylated product and (C) in the case of 30 mol% use 35,72 g (0.04 mol) of N-(2,3 - epoxypropan)butyramide and 2.1 g (0,053 mol) of pellets of sodium hydroxide to obtain 8,32 g of alkylated product

27. Alkylation of poly(allylamine), Poperechnaya with epichlorohydrin, an alkylating agent N-(2,3-epoxypropan)hexanamide

First get N-allelectronic as follows.

Hapenney funnel. The contents of the flask cooled to 15oC in an ice bath with stirring. Then slowly through the funnel to add allylamine (28.6 g, 0.5 mol) in 200 ml of tetrahydrofuran under continuous stirring, keeping the temperature 15oC. after this procedure, the stirring is continued for another 15 min, after which the precipitate of arelaminated filtered. The filtrate was concentrated in vacuo to obtain 37 g of N-allelectronic in the form of a colorless viscous liquid.

N-allelectronic (16 g, 0.1 mol) is placed in a liter flask equipped with a stirrer and an air condenser. To the flask was added methylene chloride (200 ml), then 3-chloroperoxybenzoic acid (50 - 60%, 200 g) in five portions over 30 minutes and continue the reaction. Analysis by thin layer chromatography (using 5% methanol in dichloromethane) shows that after 16 h the formation of the product is completed. The mixture is then cooled and filtered to remove the solid precipitate of benzoic acid. The filtrate was washed with a saturated solution of sodium sulfite (twice using 100 ml) and then with a saturated solution of bicarbonate (twice using 100 ml). The dichloromethane layer is dried with anhydrous sodium sulfate and concentrated in vacuo to receive the poly(allylamine), poperechnyy with epichlorohydrin, obtained as described in example 4 (10 g, sifted through a sieve) and methanol (250 ml), then add N-(2,3-epoxypropan)hexanamide (4,46, 0,026 mol, 20 mol%) and pellets of sodium hydroxide (2.1 g, 0,053 mol). The mixture is stirred over night at room temperature. After 16 h the mixture is filtered and the solid is thoroughly washed with methanol (three times using 300 ml), water (twice 300 ml) and isopropanol (three times 300 ml). After vacuum-drying at 54oC over night get 9,59 g of alkylated product as a light yellow powder.

Similarly receive alkylated products using 30 mol% of N-(2,3-epoxypropan)hexanamide, except that to obtain 9,83 g of alkylated product use at 6.84 g (0.04 mol) of N-(2,3 - epoxypropan)hexanamide.

28. Alkylation of poly(allylamine), Poperechnaya with epichlorohydrin, alkylating agents bromide (6-bromohexyl)trimethylammonium and 1-bramdean

In a flask with a volume of 12 liters, equipped with a mechanical stirrer, thermometer and condenser, was placed methanol (5 l) and sodium hydroxide (133,7 g). The mixture is stirred until complete dissolution of the solids and add poperechnyy poly(allylamine) (297 g, question the foreign Ministry (6-bromohexyl)trimethylammonium (522,1 g) and 1-bramdean (311,7 g) and the mixture is heated to 65oC under stirring. After 18 h the mixture is cooled to room temperature. The solid product is filtered and washed with suspendirovanie under stirring for 30 minutes Filtration: methanol, 12 l: methanol, 12 l; 2 M aqueous NaCI, 22 l; 2 M aqueous NaCl, 22 l; deionized water, 22 l; deionized water, 22 l; deionized water, 22 l, and isopropanol, 22 L. the Residue is dried in vacuum at 50oC and get 505,1 g of a colorless substance. This product is then passed through a sieve with a mesh size of 80.

Testing of polymers

Preparation of artificial intestinal fluid

Sodium carbonate (1.27 g) and sodium chloride (1,87 g) dissolved in 400 ml of distilled water. To this solution add or glycocholic acid (1,95 g, 4.0 mmol), or glyconanoparticles acid (1.89 g, 4.0 mmol) to obtain a 10 mm solution. the pH of the solution was adjusted to 6.8 with acetic acid. These solutions are used for testing of various polymers.

Testing of polymers carry out as follows.

In 14 ml centrifuge placed 10 mg of polymer and 10 ml of a solution of salts of bile acids with concentrations 01-10 mm, obtained from 10 mm raw solution (as described above) and buffer without bile salts, from which the mixture is Then filtered and the filtrate analyzed for the content of 3-hydroxysteroid by enzymatic quantitative analysis, using 3 - hydroxysteroiddehydrogenase, as described below.

Enzymatic quantitative content analysis of bile salts

Get four of a solution.

Solution 1. Tris - HCl buffer containing of 0.133 M Tris, 0,666 mm add (ethylenediaminetetraacetic acid) at a pH of 9.5.

Solution 2. A solution of hydrazine hydrate is added, containing 1 M hydrazine hydrate is added at a pH of 9.5.

Solution 3. The solution ABOVE (nicotinamide) containing 7 mm NAD+ at pH 7.0.

Solution 4. HSD solution containing 2 units/ml in Tris - HCl buffer (0.03 M Tris, 1 mm add at a pH of 7.2.

A 3 ml cuvette add 1.5 ml 3,0,1 ml solution of 1, 1 ml of solution 2, 0.3 ml of solution 3, 0.1 ml of solution 4 and 0.1 ml of the upper layer/filtrate tested polymer. This solution is placed in a UV-spectrophotometer and measure the optical density of the ABOVE-H at 350 nm. The concentration of bile salts is determined by a calibration curve obtained with solutions of artificial intestinal fluid, prepared as described above.

Each of the above polymers were tested on one or both of the considered tests and each of them proved to be effective in removing bile salts from artificial intestinal ilkkaracan

The plan of the experiment

Used 70 Golden Syrian hamsters line F1B. After receipt of animals randomly divided into separate cells. All animals were given food in the form of pellets and water ad libidum during one week and test diets during the second week. At the end of the second week they had not received food for 24 h, were selected blood samples and determined the full content of cholesterol in the plasma. After this was established, the degree of growth inhibition of cholesterol in the groups treated with the drugs of the present invention.

Materials and methods

A. Animals

1. Reception and quarantine 70 male Golden Syrian hamster lines F1B at the age of 8 weeks were purchased from the firm Biobreeders. Before use in the experiment the animals were allowed to acclimatize to the laboratory within one week.

2. Ambient conditions. At admission and during periods of acclimatization and study the animals were housed in individual hanging cages stainless steel, equipped with individual bottles of water. During acclimatization, the animals were fed with pellets Purina Rodent (# 5001, Farmer's Exchange) and carrying a mixture of lipids (as will be described later) with the addition of tested preparations or in their absence.

B. Experimental procedure

1. Preparation of rations. The tested drugs were injected in food as follows. Pre-prepared mixture of fats. The ingredients received from the company Bioserv and consisted of:

54.4% of coconut oil - catalogue N G5200

44,5% corn oil - catalogue N G5320

1% cholesterol - catalogue N G5180

Coconut little heated until complete dissolution (21oC), were shaken, poured into a liter of chemical beakers and heated on a hot plate with stirring to about 80oC. Crystalline cholesterol was added to the hot coke to the oil and stirred until complete dissolution (about an hour). Residual clots cholesterol was crushed manually in a glass pestle. The mixture of hot coconut oil/cholesterol was poured in a large chemical glass with corn oil to obtain a mixture containing 1 g of cholesterol per 100 g of oil.

The resulting mixture oils are well mixed before adding it to the diet in order to prevent stratification of different types of lipids. Listed in table a composition of the present invention (hereinafter referred to as drugs) was mixed with the feed in the amount determined in prezentarea, included:

20 g of the drug - 0,4%

500 g of a mixture of oils - 10%

4480 g powdered feed - 89,6:

The preparation was thoroughly mixed with a spoon with 1 kg of the powder feed was combined with 1 kg of the powder feed and thoroughly mixed again. Feed ration weighing 2 kg was combined with 2,48 kg feed and again stirred.

The mixture of food and preparation was put into the mixer and again stirred at low speed for 1 minute Then mix the dry food-the drug was added to the stirred mixture of oil (500 g) and stirred at a high speed about 4 - 5 minutes Then, in the mixing process, the diet was slowly added water to obtain a paste-like consistency (about 700 ml/kg of powdery feed); the mixture in this state was stirred for about 2 minutes

Then the diet is extruded in an appropriate container and cut into pellets weighing 100 - 150g, which was stored in an airtight Tupperware container at a temperature of about 20oC for the period of the research.

2. Sampling of blood

Before sampling the blood of animals was not given food within 24 hours

Anesthesia animals produced a mixture of O2:CO250: 50. The blood collection was made using Gaprindashvili her and repeatedly turned, to ensure a good mixing of blood with heparin. Then directs the plasma by microentrepreneurial for 8 min at a rotation speed 12400 rpm (13,600 x g).

3. Determination of cholesterol in plasma

Plasma was stored at 4oC and analyzed within 24 hours Full cholesterol in plasma were determined by enzymatic method for installing a Technicon RA-1000 System. The degree of inhibition, i.e., prevent the increase of cholesterol compared to control animals not treated with the drug, was calculated as follows:

< / BR>
*100 is the baseline for total cholesterol in accordance with the accepted measurement technique.

Compositions shown in table a, contain the main chain in the form of poly(allylamine), Poperechnaya epichlohydrin with two alternates, obtained by alkylation. The degree of schiesty was 6 mol.% for all compositions. One of the deputies was a Quaternary amine-containing group, R2with the structure (CH)3NC6H12. The other substituent R1was either aromatic (e.g., benzyl) group, or an aliphatic alkyl group, II of monomer units of the polymer, given in table a under "Equivalent" for each Deputy. Molar equivalents were determined in order to maintain comparable levels of hydrophobicity and the number of substituted carbon in the polymer. For example, the molar equalent for butyl (4 carbon atoms) to a value of 0.54, while Attila (8 carbons) it amounted to 0.27, which corresponds to the same total number of carbon. Is equivalent to another, aminecontaining Deputy R2that was equal to 0.40 for all compositions listed in table a, except tracks 1 and 7, for which it was 0.26. However, comparison of data obtained for compositions 7 and 8, shows that polymers with values equivalent to 0.40 and 0.26 give similar results. For all compositions of table a, except 1 and 7, first performed alkylation using an alkylating agent containing a Quaternary amine, and then the hydrophobic alkylating agent. For compositions 1 and 7, the alkylation was carried out at the same time. It appears, however, that the introduction of substituents or conducting alkylation at the same time not have a significant impact on the effectiveness of the obtained product. This is indicated as soposta salts of bile acids. The method of preparation of the polymers described above in example 6. More specifically, we used the following procedure.

In a liter flask equipped with condenser, thermometer, heating casing and a mechanical stirrer, enter polyamine with 6% cross-links (35,0 g, is equivalent to 0.33), bromide 6-bromohexyl-1-trimethylammonium (26,4 g, 0,087 mol equivalent of 0.26), benzylbromide (12.2 g, 0,071 mol, equivalent to 0.21) and methanol (667 ml). Alternatively, to prepare a composition 7 in the table And, instead of benzylbromide can be added to bramdean (15,74 g, 0, 071 mol, equivalent to 0.21).

The reaction mixture is heated to 64oC under stirring. When the specified temperature is reached, add 50% aqueous sodium hydroxide solution (3,76 g). Add another three portions of sodium hydroxide (3,76 g) with two-hour intervals. Heating and stirring is continued overnight. The total reaction time is approximately 24 hours, the Reaction mixture is cooled, filtered and washed with methanol, aqueous solution of sodium chloride and finally with water. Drying at 60oC get with 37.4 g of the product.

The procedure for preparation of sequestrants bile salts: step-by-step. Compositions 2 to 6 and 8 to 14.

Preparation of poly(allylamine), and the Ohm, a thermometer, a heating jacket and a mechanical stirrer, add allylamine with 6% cross-links (300 g, amine value equivalent 4,00), bromide 6-bromohexyl-1-trimethylammonium (480 g, 1.58 mol, equivalent 0,395) and methanol (8 l).

The reaction mixture is heated to 65oC. When this temperature is reached, add 50% aqueous sodium hydroxide solution (38,8 g). Add another three portions of sodium hydroxide (38,8 g) with two-hour intervals. Heating and stirring is continued at night, the Total reaction time is 24 hours

The reaction mixture is cooled, filtered and washed with methanol, aqueous solution of sodium chloride and finally with water. Drying at 60oC get 492,9 g of the product. This product is used for further alkylation with various hydrocarbon bromide, as described next.

Preparation of double-alkylated of allylamine

In a liter flask equipped with condenser, thermometer, heating casing and a mechanical stirrer, enter allylamine, alkilirovanny bromide 6-bromohexyl-1-trimethylammonium (41,08 g, equivalent to the full content of the allylamine 0,33), bramdean (15,74 r, 0,071 mol, equivalent to 0.21) and methanol (667 ml).

The reaction mixture is cooled, filtered and washed with methanol, aqueous solution of sodium chloride and finally with water. Drying at 60oC get 45.6 g of product.

This same method with the use of substances listed in table 1, prepared other products with double alkylation.

The results are shown in table A, characterized by the accumulation of data from multiple tests to reduce lipid content. In each test as a control was used the same polymer, representing the allylamine with 6% cross-links with the Deputy C10H21and (CH3)3NC6H12. In the table And the experimentally obtained values, the control values and normalized values reduce lipid content in each test. Normalized values were calculated as the ratio actually found the experimental values and the corresponding values for the control polymer.

The results given in table a indicate that aromatic group, R1no significant decrease in the content of thetsa activity in lowering lipid, which surpasses the activity of control and lies in the range 33-81%.

The use of aliphatic and not aromatic alkyl groups gives unexpected results, allowing prescribe a bile acid having higher properties. Thus the effect of reducing the lipid content provided by the polymer, generally increases with the length of the carbon chain alkylating agent.

In addition there were prepared two sequestrants bile acids in accordance with the method, the combination of examples 12 and 13 of U.S. patent N 5430110, according to which the first alkylate the main chain poly(vinylamine), and then carry her cross-stitching. More specifically, poly(vinylamine) (equivalent to 20 g of dry polymer) with M. C. 40000 (Air Product Catalog # 13379-80) was dissolved in water (800 ml) containing benzylchloride (11.8 g). The mixture was heated to 90oC under stirring for 8 hours the Solution was cooled to room temperature and added solid NaOH (6.0 g) and 1,6-dibromohexane (17,2 g). The mixture was stirred for 5 min and added the bromide 3-bromopropylamine (39,2 g). The mixture was heated to 90oC under stirring for 8 hours was Added solid NaOH (6.0 g) and 1,6-dibromohexane (17,2 g) and peroratory. Given the solid component of the opportunity to settle for 30 min, and then decantation transparent liquid. I added acetone (2.0 l) and stirred the mixture for 30 minutes Again decantation transparent liquid. Added a mixture of water and ethanol in a volume ratio of 1: 1 (500 ml) and stirred the mixture for 30 minutes was Added concentrated HCl (46,1 g) and continued stirring for 2 hours was Added acetone (3.0 l) to precipitate the polymer, and the mixture was stirred for 30 minutes Decantation transparent liquid. Added water (1 l) and a few drops of 50% aqueous sodium hydroxide solution, having obtained after stirring for 30 min, pH = 4. Added 3 l of acetone, gave solid matter settling and decantation of the liquid. The wet solid part was dried in the dryer with forced air purge at 60oC and received and 46.3 g of polymer. The above procedure was repeated using as alkylating agents 1-brometea (16.7 g) and bromide (6-bromohexyl)ammonium (42,3 g). The output was 86.4,

Substances prepared according to the above method according to the specified U.S. patent, was Poperechnaya the main chain poly(vinylamine), and one substance soda is), and a second connection had aliphatic substituents, bromide of hexyltrimethoxysilane (Deputy containing Quaternary amine) and heptylene group (hydrophobic Deputy).

Using radiometric bile acids was studied substances, described in the previous paragraph, in relation to their ability to sekvestrirovatj bile acids. This study determined the number of labeled bile acids in the faeces tested animal after introducing him of bile acids, equipped with radioactive labels, and substances prepared by the method described above. More specifically, animal peritonal was injectible solution of bile acids (holeva and chenodeoxycholic), marked C14. The ratio holeva and chenodeoxycholic acid was approximately the same as in the bile of the gallbladder (3:1). Marked bile acids enter into the gallbladder and combine with endogenous acids. After that the animals within 36 h were given feed containing the test drug, collecting excretion during the last 29 PM Samples excretion were treated and appreciated by their radioactivity.

The results of studies using radioactive labels for gamestoplay by stitching, followed by alkylation using only the aliphatic substituents (decile group and (CH3)3NH6H12associated with the main polymer chain, are shown in table B.

In table B the results, which are presented as the content of radioactive substances in excretion, in %, more than content to control (when the drug is not introduced), per gram of fecal matter. In table B they are marked as "total activity/g of fecal matter

Use

The polymers in accordance with the present invention can be administered to the patient orally at a dose of from 1 mg/kg/day to 10 mg/kg/day, the exact dose depends on the individuality of the patient (for example, from its weight and the amount of bile salts is subject to removal). The polymer can be assigned or hydrate or dihydrates forms, it can be flavored or added to food or drink. You can add additional ingredients such as passivator bile acids, drugs for the treatment of hypercholesterolemia, atherosclerosis or similar diseases, or inert ingredients, such as artificial dyes.

Examples of suitable forms of PRA powders can be covered with a protective sheath, preventing the composition from gastric acids in the stomach of the patient over a period of time sufficient so that the composition has reached the small intestine of the patient without damage. The polymer can be assigned alone or in combination with pharmacologically suitable substances, such as magnesium carbonate, lactose, or a phospholipid with which the polymer can form a micelle.

1. Method of removing gallstones from the body of a patient, comprising the administration to a patient a therapeutically effective amount of ion exchange resin, characterized in that the ion exchange resin is used, the reaction product of: (a) one or more Poperechnaya polymer characterized by a recurring structural units selected from the group consisting of:

< / BR>
(-NR-CH2CH2-)n(2)

(-NR-CH2CH2-NR-CH2CH2-NR-NON-CH2-)n(3)

or salts thereof, where n is an integer, and each of the radicals R, independently, N or C1- C8alkyl group; b) at least one alkylating agent of the formula RX, where R is a C1- C20alkyl, C1- C20hydroxyalkyl, C1- C20alkylammonium or1- Cand is characterized by that at least some of the nitrogen atoms in the above recurring structural units of the polymer does not interact with the specified alkylating agent and less than 10 mol.% the nitrogen atoms in the above repeating structural units that interact with the specified alkylating agent to form links with Quaternary ammonium groups.

2. The method according to p. 1, characterized in that use, the polymer is cross-stitched using a multifunctional crosslinking agent, which are taken in quantities of 1 to 25% of the total weight of monomer and crosslinking agent.

3. The method according to p. 2, characterized in that the crosslinking agent take in the amount of 2.5 - 20% of the total weight of monomer and crosslinking agent.

4. The method according to p. 2 or 3, characterized in that as the cross-linking agent used epichlorohydrin.

5. The method according to any of paragraphs.1 to 4, characterized in that R is selected N.

6. The method according to p. 1, characterized in that use an alkylating agent of the formula RX, where R is a C1- C20alkyl, C1- C20hydroxyalkyl, C1- C20alkylammonium or1- C20alkylamino group and X includes one or more electrophilic groups.

7. The CLASS="ptx2">

8. The method according to p. 7, characterized in that the alkylating agent is used in a1- C20haloalkyl.

9. The method according to p. 8, characterized in that as haloalkyl use WITH4- C18haloalkyl.

10. The method according to p. 7, characterized in that the use of an alkylating agent, including WITH1- C20dihaloalkanes.

11. The method according to p. 10, characterized in that as dihaloalkanes use 1,10-dialogical.

12. The method according to p. 7, characterized in that the alkylating agent is used in a1- C20halohydrocarbon.

13. The method according to p. 12, characterized in that as haloalkaline use 11-halo-1-undecanol.

14. The method according to p. 7, characterized in that the alkylating agent is used in a1- C20haloalkylthio salt.

15. The method according to p. 14, characterized in that as haloalkylthio salt use4- C12galoiduglyerodov salt.

16. The method according to p. 7, characterized in that the alkylating agent include1- C20epoxyalkanes salt.

17. The method according to p. 16, characterized in that as apoxie the same time, as the alkylating agent used WITH1- C20amoxilcillin.

19. The method according to p. 18, characterized in that use amoxilcillin selected from the group consisting of N-(2,3-epoxypropan)butyramide, N-(2,3-epoxypropan)hexanamide and combinations thereof.

20. The method according to p. 1, characterized in that the use of polymer that interacts with at least two alkylating agents, one of the alkylating agents has the formula RX where R is a C1- C20alkyl group and X includes one or more electrophilic groups, and the other alkylating agent has the formula R X wherein R' is a C1- C20alkylammonium group and X includes one or more electrophilic groups.

21. The method according to p. 20, characterized in that as one of the alkylating agents take haloalkyl, and as another alkylating agent take haloalkylthio salt.

22. The method according to p. 21, characterized in that as haloalkyl take4- C18haloalkyl, and as haloalkylthio salt take4- C18haloalkylthio salt.

23. The method according to p. 22, characterized in that, as has keloidal the new Sol.

24. The method according to p. 1, characterized in that the use of polymer that interacts with at least two alkylating agents, one of the alkylating agents has the formula RX where R is a C1- C20alkyl group and X includes one or more electrophilic groups, and the other alkylating agent has the formula R X wherein R' is a C1- C20hydroxyalkyl group and X includes one or more electrophilic groups.

25. The method according to p. 24, characterized in that as one of the alkylating agents take haloalkyl, and as another alkylating agent - halohydrocarbon.

26. The method according to p. 1, characterized in that the use of polymer that interacts with at least two alkylating agents, and as one of the alkylating agents take1- C20dihaloalkanes, and as another take WITH1- C20alkylammonium salt.

27. Method of removing gallstones from the body of a patient, comprising the administration to a patient a therapeutically effective amount of ion exchange resin, characterized in that the ion exchange resin is used, the reaction product of: (a) one or more Poperechnaya polie number and each radical R, independently, - H or C1- C8alkyl group; b) at least one alkylating agent of the formula RX, where R is a C1- C20alkyl, C1- C20hydroxyalkyl, C1- C20alkylammonium or1- C20alkylamino group, and X is one or more electrophilic group, whereby said product of reaction is characterized by the fact that at least some of the nitrogen atoms in the above recurring structural units of the polymer does not interact with the specified alkylating agent and less than 10 mol.% the nitrogen atoms in the above repeating structural units that interact with the specified alkylating agent to form links with Quaternary ammonium groups.

28. The method according to p. 27, characterized in that use polymer poperechnyy with a multifunctional crosslinking agent, which are taken in quantities of 1 to 25% of the total weight of monomer and crosslinking agent.

29. The method according to p. 28, characterized in that the crosslinking agent take in the amount of 2.5 - 20% of the total weight of monomer and crosslinking agent.

30. The method according to p. 28, characterized in that as the cross-linking agent used epichlorohydrin.

31. Way
alkyl, C1- C20hydroxyalkyl, C1- C20alkylammonium or1- C20alkylamino group and X includes one or more electrophilic groups.

32. The method according to p. 31, characterized in that the use of an alkylating agent, in which X is a halide, epoxy-, tosylate or methylsulfonyl group.

33. The method according to p. 27, characterized in that the use of polymer that interacts with at least two alkylating agents, one of the alkylating agents has the formula RX where R is a C1- C20alkyl group and X includes one or more electrophilic groups, and the other alkylating agent has the formula R X wherein R' is a C1- C20alkylammonium group and X includes one or more electrophilic groups.

34. The method according to p. 33, characterized in that as one of the alkylating agents take haloalkyl, and as another alkylating agent - haloalkylthio salt.

35. The method according to p. 34, characterized in that as haloalkyl take4- C20haloalkyl, and as haloalkylthio salt take4- C18haloalkylthio salt.

localcommunities salt take6haloalkylthio salt.

37. The method according to p. 27, characterized in that the use of polymer that interacts with at least two alkylating agents, one of the alkylating agents has the formula RX where R is a C1- C20alkyl group and X includes one or more electrophilic groups, and the other alkylating agent has the formula R X wherein R' is a C1- C20hydroxyalkyl group and X includes one or more electrophilic groups.

38. The method according to p. 37, characterized in that as one of the alkylating agents take haloalkyl, and as another alkylating agent - halohydrocarbon.

39. The method according to p. 27, characterized in that the use of polymer that interacts with at least two alkylating agents, at the same time as one of the alkylating agents used WITH1- C20dihaloalkanes, and as another alkylating agent - C1- C20alkylammonium salt.

40. Alkilirovanny poperechnyy the polymer is a reaction product of: (a) one or more Poperechnaya polymer characterized by a recurring structural units selected from the group
-NR-NON-CH2-)n(3)

where n is an integer and each of the radicals R, independently, is N or C1- C8alkyl group; b) at least one alkylating agent of the formula RX, where R is a C1- C20alkyl, C1- C20hydroxyalkoxy,1- C20alkylammonium or1- C20alkylamino group, and X is one or more electrophilic group, whereby said product of reaction is characterized by the fact that at least some of the nitrogen atoms in the above recurring structural units of the polymer does not interact with the specified alkylating agent and less than 10 mol.% the nitrogen atoms in the above repeating structural units that interact with the specified alkylating agent to form links with Quaternary ammonium groups.

41. The polymer according to p. 40, characterized in that it is cross stitched with the help of a multifunctional cross-linking agent contained in the amount of 1 - 25% of the total weight of monomer and crosslinking agent.

42. The polymer according to p. 40, characterized in that the content of the crosslinking agent is 2.5 - 20% of the total weight of monomer and crosslinking agent.

43. The polymer according to p. 40, characterized in that the crosslinking agent is. is OLIMAR under item 40, wherein the alkylating agent has the formula RX where R is a C1- C20alkyl, C1- C20hydroxyalkyl, C1- C20alkylammonium or1- C20alkylamino group and X includes one or more electrophilic groups.

46. The polymer p. 45, wherein X is halide, epoxy-, tosylate or methylsulfonyl group.

47. The polymer according to p. 40, characterized in that it is selected interacting with at least two alkylating agents, one of the alkylating agents has the formula RX where R is a C1- C20alkyl group and X includes one or more electrophilic groups, and the other alkylating agent has the formula R X wherein R' is a C1- C20alkylammonium group and X includes one or more electrophilic groups.

48. The polymer p. 47, characterized in that as one of the alkylating agents selected haloalkyl, and as another alkylating agent - haloalkylthio salt.

49. The polymer p. 48, characterized in that as haloalkyl selected WITH4- C20haloalkyl, and as haloalkylthio salt - haloalkyl selected WITH10haloalkyl, and as haloalkylthio salt selected WITH6haloalkylthio salt.

51. The polymer according to p. 40, characterized in that it is selected interacting with at least two alkylating agents, one of which has the formula RX where R is a C1- C20alkyl group and X includes one or more electrophilic groups, and the other alkylating agent has the formula R X wherein R' is a C1- C20hydroxyalkyl group and X includes one or more electrophilic groups.

52. The polymer p. 51, characterized in that as one of the alkylating agents selected haloalkyl, and as another halohydrocarbon.

53. The polymer according to p. 40, characterized in that it is selected interacting with at least two alkylating agents, one of which is1- C20dihaloalkanes and the other WITH1- C20alkylammonium salt.

54. Alkilirovanny poperechnyy the polymer is a reaction product, and one or more Poperechnaya polymer characterized by a recurring structural units of

< / BR>
and salts thereof, where n is an integer and each radical R is, independently, - H Ile R is a C1- C20alkyl, C1- C20hydroxyalkyl, C1- C20alkylammonium,1- C20alkylamino group, and X is one or more electrophilic group, whereby said product of reaction is characterized by the fact that at least some of the nitrogen atoms in the above recurring structural units of the polymer does not interact with the specified alkylating agent and less than 10 mol.% the nitrogen atoms in the above repeating structural units that interact with the specified alkylating agent to form links with Quaternary ammonium groups.

 

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