WO1995034585A1 - Process for removing bile salts from a patient and alkylated compositions therefor - Google Patents
Process for removing bile salts from a patient and alkylated compositions therefor Download PDFInfo
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- WO1995034585A1 WO1995034585A1 PCT/US1995/007181 US9507181W WO9534585A1 WO 1995034585 A1 WO1995034585 A1 WO 1995034585A1 US 9507181 W US9507181 W US 9507181W WO 9534585 A1 WO9534585 A1 WO 9534585A1
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/52—Amides or imides
- C08F220/54—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide
- C08F220/60—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide containing nitrogen in addition to the carbonamido nitrogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/785—Polymers containing nitrogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/785—Polymers containing nitrogen
- A61K31/787—Polymers containing nitrogen containing heterocyclic rings having nitrogen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F26/00—Homopolymers and copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F8/00—Chemical modification by after-treatment
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F8/00—Chemical modification by after-treatment
- C08F8/02—Alkylation
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F8/00—Chemical modification by after-treatment
- C08F8/44—Preparation of metal salts or ammonium salts
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L39/00—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen; Compositions of derivatives of such polymers
- C08L39/02—Homopolymers or copolymers of vinylamine
Definitions
- This invention relates to removing bile salts from a patient.
- Salts of bile acids act as detergents to solubilize and consequently aid in digestion of dietary fats.
- Bile acids are precursors to bile salts, and are derived from cholesterol. Following digestion, bile acids can be passively absorbed in the jejunum, or, in the case of conjugated primary bile acids, reabsorbed by active transport i ⁇ the ileum. Bile acids which are not reabsorbed by active transport are deconjugated and dehydroxylated by bacterial action in the distal ileum and large intestine.
- One method of reducing the amount of bile acids that are reabsorbed is oral administration of compounds that sequester the bile acids and cannot themselves be absorbed. The sequestered bile acids consequently either decompose by bacterial action or are excreted. Many bile acid sequestrants, however, bind relatively hydrophobic bile acids more avidly than conjugated primary bile acids, such as conjugated cholic and chenodeoxycholic acids.
- bile salts e.g., cholate, glycocholate, glycochenocholate, taurocholate, and deoxycholate salts
- the biological precursor to bile salt is cholesterol
- the metabolism of cholesterol to make bile salts is accompanied by a simultaneous reduction in the cholesterol in the patient.
- Cholestyramine a polystyrene/divinylbenzene ammonium ion exchange resin, when ingested, removes bile salts via the digestive tract. This resin, however, is unpalatable, gritty and constipating. Resins which avoid (totally or partially) these disadvantages and/or possess improved bile salt sequestration properties are needed.
- the invention relates to the discovery that a new class of ion exchange resins have improved bile salt sequestration properties and little to no grittiness, thereby improving the palatability of the composition.
- the resins comprise cross-linked polyamines which are characterized by one or more hydrophobic substituents and, optionally, one or more quaternary ammonium containing substituents.
- the invention features resins and their use in removing bile salts from a patient that includes administering to the patient a therapeutically effective amount of the reaction product of: (a) one or more crosslinked polymers characterized by a repeat unit selected from the group consisting essentially of:
- n is an integer and each R, independently, is H or a substituted or unsubstituted alkyl group (e.g., C 1 -C 8 alkyl) ;
- the reaction product is characterized in that: (i) at least some of the nitrogen atoms in the repeat units are unreacted with the alkylating agent; (ii) less than 10 mol% of the nitrogen atoms in the repeat units that react with the alkylating agent form quaternary ammonium units; and (iii) the reaction product is preferably non-toxic and stable once ingested.
- Suitable substituents include quaternary ammonium, amine, alkylamine, dialkylamine, hydroxy, alkoxy, halogen, carboxamide, sulfonamide and carboxylic acid ester, for example. ,
- the polyamine of compound (a) of the reaction product is crosslinked by means of a multifunctional crosslinking agent, the agent being present in an amount from about 0.5-25% (more preferably about 2.5- 20% (most preferably 1-10%) ) by weight-, based upon total weight or monomer plus crosslinking agent.
- a preferred crosslinking agent is epichlorohydrin because of its high availability and low cost. Epichlorohydrin is also advantageous because of it's low molecular weight and hydrophilic nature, increasing the water-swellability and gel properties of the polyamine.
- the invention also features compositions based upon the above-described reaction products.
- the invention provides an effective treatment for removing bile salts from a patient (and thereby reducing the patient's cholesterol level).
- the compositions are non-toxic and stable when ingested in therapeutically effective amounts.
- Preferred reaction products include the products of one or more crosslinked polymers having the formulae set forth in the Summary of the Invention, above, and one or more alkylating agents.
- the polymers are crosslinked.
- the level of crosslinking makes the polymers completely insoluble and thus limits the activity of the alkylated reaction product to the gastrointestinal tract only.
- the compositions are non-systemic in their activity and will lead to reduced side-effects in the patient.
- non-toxic it is meant that when ingested in therapeutically effective amounts neither the reaction products nor any ions released into the body upon ion exchange are harmful.
- Cross-linking the polymer renders the polymer substantially resistant to absorption.
- the cationic counterions are preferably selected to.minimize adverse effects on the patient, as is more particularly described below.
- stable it is meant that when ingested in therapeutically effective amounts the reaction products do not dissolve or otherwise decompose in vivo to form potentially harmful by-products, and remain substantially intact so that they can transport material out of the body.
- salt it is meant that the nitrogen group in the repeat unit is protonated to create a positively charged nitrogen atom associated with a negatively charged counterion.
- alkylating agent it is meant a reactant which, when reacted with the crosslinked polymer, causes an alkyl group or derivative thereof (e.g., a substituted alkyl, such as an aralkyl, hydroxyalkyl, alkylammonium salt, alkylamide, or combination thereof) to be covalently bound to one or more of the nitrogen atoms of the polymer.
- alkyl group or derivative thereof e.g., a substituted alkyl, such as an aralkyl, hydroxyalkyl, alkylammonium salt, alkylamide, or combination thereof.
- a second example of a preferred polymer is characterized by a repeat unit having the formula
- a third example of a preferred polymer is characterized by a repeat unit having the formula
- the polymers are preferably crosslinked prior to alkylation.
- suitable crosslinking agents include acryloyl chloride, epichlorohydrin, butanedioldiglycidyl ether, ethanedioldiglycidyl ether, and dimethyl succinate.
- the amount of crosslinking agent is typically between 0.5 and 25 weight %, based upon combined weight of crosslinking agent and monomer, with 2.5-20%, or 1-10%, being preferred.
- the amount of crosslinking agent that is reacted with the amine polymer is sufficient to cause between about 0.5 and twenty percent of the amines. In a preferred embodiment, between about 0.5 and six percent of the amine groups react with the crosslinking agent.
- Crosslinking of the polymer can be achieved by reacting the polymer with a suitable crosslinking agent in an aqueous caustic solution at about 25°C for a period of time of about eighteen hours to thereby form a gel. The gel is then combined with water and blended to form a particulate solid. The particulate solid can then be washed with water and dried under suitable conditions, such as a temperature of about 50°C for a period of time of about eighteen hours.
- Alkylation involves reaction between the nitrogen atoms of the polymer and the alkylating agent (which may contain additional nitrogen atoms, e.g., in the form of amido or ammonium groups) .
- the nitrogen atoms which do react with the alkylating agent(s) resist multiple alkylation to form quaternary ammonium ions such that less than 10 mol % of the nitrogen atoms form quaternary ammonium ions at the conclusion of alkylation.
- Preferred alkylating agents have the formula RX where R is a alkyl (preferably C 4 -C 20 ) , C 1 -C 20 hydroxy- alkyl (preferably C 4 -C 20 hydroxyalkyl) , C 7 -C 20 aralkyl, C ⁇ C 20 alkylammonium (preferably C 4 -C 20 alkyl ammonium) , or c ⁇ " C 20 alkylamido (preferably C 4 -C 20 alkyl amido) group and X includes one or more electrophilic leaving groups.
- electrophilic leaving group it is meant a group which is displaced by a nitrogen atom in the crosslinked polymer during the alkylation reaction. Examples of preferred leaving groups include halide, epoxy, tosylate, and mesylate group. In the case of, e.g., epoxy groups, the alkylation reaction causes opening of the three-membered epoxy ring.
- alkylating agents include a C ⁇ C 20 alkyl halide (e.g., an n-butyl halide, n-hexyl halide, n-octyl halide, n-decyl halide, n-dodecyl halide, n- tetradecyl halide, n-octadecyl halide, and combinations thereof); a C - ⁇ o dihaloalkane (e.g., a 1,10- dihalodecane) ; a C ⁇ ⁇ hydroxyalkyl halide (e.g., an 11- halo-1-undecanol) ; a C 1 -C 20 aralkyl halide (e.g., a benzyl halide); a C 1 -C 20 alkyl halide ammonium salt (e.g., a (4- halobutyl) tri
- one of the alkylating agents has the formula RX where R is a c i" c 20 a lkyl 9 rou P and ⁇ includes one or more electrophilic leaving groups (e.g., an alkyl halide), and the other alkylating agent has the formula R'X where R' is a C 1 -C 20 alkyl ammonium group and X includes one or more electrophilic leaving groups (e.g., an alkyl halide ammonium salt) .
- one of the alkylating agents has the formula RX where R is a C 1 -C 20 alkyl group and X includes one or more electrophilic leaving groups
- the other alkylating agent has the formula R'X where R' is a C ⁇ C ⁇ hydroxyalkyl group and X includes one or more electrophilic leaving groups (e.g., a hydroxy alkyl halide) .
- R' is a C ⁇ C ⁇ dihaloalkane
- the other alkylating agent is a C- ⁇ C ⁇ alkylammonium salt.
- the reaction products may have fixed positive charges, or may have the capability of becoming charged upon ingestion at physiological pH. In the latter case, the charged ions also pick up negatively charged counterions upon ingestion that can be exchanged with bile salts. In the case of reaction products having fixed positive charges, however, the reaction product may be provided with one or more exchangeable counterions.
- suitable counterions include Cl “ , Br “ , CH 3 OS0 3 " , HS0 4 " , S0 4 2" , HC0 3 “ , C0 3 " , acetate, lactate, succinate, propionate, butyrate, ascorbate, citrate, maleate, folate, an amino acid derivative, a nucleotide, a lipid, or a phospholipid.
- the counterions may be the same as, or different from, each other.
- the reaction product may contain two different types of counterions, both of which are exchanged for the bile salts being removed. More than one reaction product, each having different counterions associated with the fixed charges,may be administered as well.
- the alkylating agent can be added to the cross-linked polymer at a molar ratio between about- 0.05:1 to 4:1, for example, the alkylating agents can be preferably selected to provide hydrophobic regions and hydrophilic regions.
- the amine polymer is typically alkylated by combining the polymer with the alkylating agents in an organic solvent.
- the amount of first alkylating agent combined with the amine polymer is generally sufficient to cause reaction of the first alkylating agent with between about 5 and 75 of the percent of amine groups on the amine polymer that are available for reaction.
- the amount of second alkylating agent combined with the amine polymer and solution is generally sufficient to cause reaction of the second alkylating agent with between about 5 and about 75 of the amine groups available for reaction on the amine polymer.
- suitable organic solvents include methanol, ethanal, isopropanol, acetonitrile, DMF and DMSO.
- a preferred organic solvent is methanol.
- the reaction mixture is heated over a period of about forty minutes to a temperature of about 65°C, with stirring.
- an aqueous sodium hydroxide solution is continuously added during the reaction period.
- the reaction period at 65°C is about eighteen hours, followed by gradual cooling to a room temperature of about 25°C over a period of about four hours.
- the resulting reaction product is then filtered, resuspended in methanol, filtered again, and then washed with a suitable aqueous solution, such as two molar sodium chloride,and then with deionized water.
- the resultant solid product is then dried under suitable conditions, such as at a temperature of about 60°C in an air-drying oven. The dried solid can then be subsequently processed.
- the solid is ground and passed through an 80 mesh sieve.
- the amine polymer is a crosslinked poly(allylamine) , wherein the first substituent includes a hydrophobic decyl moiety, and the second amine substituent includes a hexyltrimethylammonium.
- the particularly preferred crosslinked poly(allylamine) is crosslinked by epichlorohydrin that is present in a range of between about two and six percent of the amines available for reaction with the epichlorohydrin.
- the first step involved the preparation of ethylidenebisacetamide.
- Acetamide (118 g) , acetaldehyde (44.06 g) , copper acetate (0.2 g) , and water (300 mL) were placed in a 1 L three neck flask fitted with condenser, thermometer, and mechanical stirred.
- Concentrated HCl (34 mL) was added and the mixture was heated to 45-50°C with stirring for 24 hours.
- the water was then removed in vacuo to leave a thick sludge which formed crystals on cooling to 5°C.
- Acetone (200 mL) was added and stirred for a few minutes, after which the solid was filtered off and discarded.
- the acetone was cooled to 0°c and solid was filtered off. This solid was rinsed in 500 mL acetone and air dried 18 hours to yield 31.5 g of ethylidenebis ⁇ acetamide.
- the next step involved the preparation of vinylacetamide from ethylidenebisacetamide.
- Ethylidenebisacetamide (31.05 g) , calcium carbonate (2 g) and celite 541 (2 g) were placed in a 500 mL three neck flask fitted with a thermometer, a mechanical stirred, and a distilling heat atop a Vigroux column.
- the mixture was vacuum distilled at 24 mm Hg by heating the pot to 180-
- Poly(vinylacetamide) (0.79 g) was placed in a 100 mL one neck flask containing water (25 mL) and cone. HCl (25 mL) . The mixture was refluxed for 5 days, after which the solid was filtered off, rinsed once in water, twice in isopropanol, and dried in a vacuum oven to yield 0.77 g of product. Infrared spectroscopy indicated that a significant amount of the amide (1656 cm “1 ) remained and that not much amine 91606 cm “1 ) was formed. The product of this reaction (-0.84 g) was suspended in NaOh (46 g) and water (46 g) and heated to boiling ( ⁇ 140°C) . Due to foaming the temperature was reduced and maintained at
- the crosslinking reaction was allowed to proceed for an additional 18 hours at room temperature, after which the polymer gel was removed and dried in a vacuum oven at 75°C for 24 hours.
- the dry solid was then ground and sieved to -30 mesh, after which it was suspended in 6 gallons of water and stirred for 1 hour.
- the solid was then filtered off and the rinse process repeated two more times.
- the resulting solid was then air dried for 48 hours, followed by drying in a vacuum oven at 50°C for 24 hours to yield about 415 g of the crosslinked polymer as a white solid.
- poly(allylamine) hydrochloride prepared as described in Example 3 (10 g) and water (40 mL) .
- the mixture was stirred to dissolve the hydrochloride and the pH was adjusted to 10 by adding solid NaOH.
- the resulting solution was cooled to room temperature in the beaker, after which 1,2- ethanedioldiglycidyl ether crosslinking agent (2.0 mL) was added all at once with stirring.
- the resulting mixture was stirred gently until it gelled (about 4 minutes) .
- the crosslinking reaction was allowed to proceed for an additional 18 hours at room temperature, after which the polymer gel was removed and blended in 500 mL of methanol.
- the solid was then filtered off and suspended in water (500 mL) . After stirring for 1 hour, the solid was filtered off and the rinse process repeated. The resulting solid was rinsed twice in isopropanol (400 mL) and then dried in a vacuum oven at 50°C for 24 hours to yield 8.7 g of the crosslinked polymer as a white solid.
- poly(allylamine) hydrochloride prepared as described in Example 3 (10 g) , methanol (100 mL) , and triethylamine (10 mL) .
- the mixture was stirred and dimethylsuccinate crosslinking agent (1 mL) was added.
- the solution was heated to reflux and the stirring discontinued after 30 minutes. After 18 hours, the solution was cooled to room temperature, and the solid filtered off and blended in
- poly(ethyleneimine) 510 g of a 50% aqueous solution, equivalent to 255 g of dry polymer
- isopropanol 2.5 L
- Acryloyl chloride crosslinking agent 50 g was added dropwise through the addition funnel over a 35 minute period while maintaining the temperature below 29°C.
- the solution was then heated to 60°C with stirring for 18 hours, after which the solution was cooled and the solid immediately filtered off.
- the solid was then washed three times by suspending it in water (2 gallons) , stirring for 1 hour, and filtering to recover the solid.
- the solid was rinsed once by suspending it in methanol (2 gallons) , stirring for 30 minutes, and filtering to recover the solid. Finally, the solid was rinsed in isopropanol as in Example 7 and dried in a vacuum oven at 50°C for 18 hours to yield 206 g of the crosslinked polymer as a light orange granular solid.
- Poly(allylamine) crosslinked with butanedioldiglycidyl ether prepared as described in Example 5 was alkylated according to the procedure described in Example 11 except that 2.47 mL of 1-iodododecane was used. The procedure yielded 4.7 g of alkylated product. 13. Alkylation of Poly(allylamine) crosslinked with butanedioldiglycidyl ether with benzyl bromide alkylating agent
- Poly(allylamine) crosslinked with butanedioldiglycidyl ether prepared as described in Example 5 was alkylated according to the procedure described in Example 11 except that 2.42 mL of benzyl bromide was used. The procedure yielded 6.4 g of alkylated product.
- Poly(allylamine) crosslinked with epichlorohydrin prepared as described in Example 4 (5 g) was alkylated according to the procedure described in Example 11 except that 2.1 mL of 1-iodotetradecane was used. The procedure yielded 5.2 g of alkylated product.
- Dialkylated products were prepared in an analogous manner by replacing 1-iodododecane with 1-iododecane and 1- iodooctadecane, respectively, followed by alkylation with glycidylpropyltrimethylammonium chloride.
- Alkylated products were prepared in an analogous manner using 50%, 200%, and 300% mole equiv of 90% glycidylpropyltrimethylammonium chloride.
- the first step is the preparation of (10-bromodecyl) trimethylammonium bromide as follows. 1,10-dibromodecane (200 g) was dissolved in methanol (3 D in a 5 liter three neck round bottom flask fitted with a cold condenser (-5°C) . To this mixture was added aqueous trimethylamine (176 mL of a 24% aqueous solution, w/w) . The mixture was stirred at room temperature for 4 hours, after which is was heated to reflux for an additional 18 hours. At the conclusion of the heating period, the flask was cooled to 50°C and the solvent removed under vacuum to leave a solid mass. Acetone
- 1,10-dibromodecane 200 g was dissolved in methanol (3 L) in a 5 liter round bottom flask fitted with a cold condenser (-5°C) . To this mixture was added aqueous trimethylamine (220 mL of a 24% aqueous solution, w/w) . The mixture was stirred at room temperature for 4 hours, after which it was heated to reflux for an additional 24 hours. The flask was then cooled to room temperature and found to contain 3350 mL of clear liquid.
- Dialkylated products were also prepared in analogous fashion using different amounts of 1-bromodecane as follows: (a) 3.19 g 1-bromodecane and 4.14 g sodium hydroxide to yield 11.8 g of dialkylated product; (b) 38.4 g 1-bromodecane and 6.96 g sodium hydroxide to yield 19.1 g of dialkylated product.
- Dialkylated products were also prepared in analogous fashion using the following combinations of alkylating agents: 1-bromodecane and (4-bromobutyl)trimethylammonium bromide; 1-bromodecane and (6-bromohexyl)trimethylammonium bromide; 1-bromodecane and (8-bromooctyl)trimethylammonium bromide; 1-bromodecane and (2-bromoethyl)trimethylammonium bromide; 1-bromodecane and (3-bromopropyl)trimethylammonium bromide; 1-bromohexane and (6-bromohexyl)trimethylammonium bromide; 1-bromododecane and (12-bromododecyl)trimethyl ⁇ ammonium bromide; and 1-bromooctane and (6-bromohexyl) trimethylammonium bromide.
- reaction was also performed using 1.05 g sodium hydroxide and 10 g 11-bromo-l-undecanol to yield 8.86 g of alkylated product.
- the first step is the preparation of N-allyl butyramide as follows. Butyroyl chloride (194.7 g, 1.83 mol) in 1 L of tetrahydrofuran was added to a three neck round bottom flask equipped with a thermometer, stir bar, and dropping funnel. The contents of the flask were then cooled to 15°C in an ice bath while stirring. Allylamine (208.7 g, 3.65 mol) in 50 mL of tetrahydrofuran was then added slowly through the dropping funnel while maintaining stirring. Throughout the addition, the temperature was maintained at 15°C. After addition was complete, stirring continued for an additional 15 minutes, after which the solid allylamine chloride precipitate was filtered off. The filtrate was concentrated under vacuum to yield 236.4 g of N-allyl butyramide as a colorless viscous liquid.
- N-ally ⁇ butyramide (12.7 g, 0.1 mol) was taken into a 1 L round bottom flask equipped with a stir bar and air condenser. Methylene chloride (200 mL) was added to the flask, followed by 3-chloroperoxybenzoic acid (50-60% strength, 200 g) in five portions over the course of 30 minutes and the reaction allowed to proceed. After 16 hours, TLC analysis (using 5% methanol in dichloromethane) showed complete formation of product. The reaction mixture was then cooled and filtered to remove solid benzoic acid precipitate.
- Alkylated products based upon 10 mol%, 20 mol%, and 30 mol% N- (2,3-epoxypropane) butyramide were prepared in analogous fashion except that 9a) in the 10 mol% case, 1.93 g (0.013 mol) N- (2,3-epoxypropane) butyramide and 1.1 g (0.0275 mol) sodium hydroxide pellets were used to yield 8.3 g of alkylated product, (b) in the 20 mol% case, 3.86 g (0.026 mol) N- (2,3-epoxypropane) butyramide and 2.1 g (0.053 mol) sodium hydroxide pellets were used to yield 8.2 g of alkylated product, and (c) in the 30 mol% case, 5.72 g (0.04 mol) N- (2,3-epoxypropane) butyramide and 2.1 g (0.053 mol) sodium hydroxide pellets were used to yield 8.32 g of al
- the first step is the preparation of N-allyl hexanamide as follows.
- Hexanoyl chloride (33 g, 0.25 mol) in 250 mL of tetrahydrofuran was added to a three neck round bottom flask equipped with a thermometer, stir bar, and dropping funnel. The contents of the flask were then cooled to 15°C in an ice bath while stirring. Allylamine (28.6 g, 0.5 mol) in 200 mL of tetrahydrofuran was then added slowly through the dropping funnel while maintaining stirring. Throughout the addition, the temperature was maintained at 15°C. After addition was complete, stirring continued for an additional 15 minutes, after which the solid allylamine chloride precipitate was filtered off. The filtration was concentrated under vacuum to yield 37 g of N-allyl hexanamide as a colorless viscous liquid.
- N-allyl hexanamide (16 g, 0.1 mol) was taken into a 1 L round bottom flask equipped with a stir bar and air condenser. Methylene chloride (200 mL) was added to the flask, followed by 3-chloroperoxybenzoic acid (50-60% strength, 200 g) in five portions over the course of 30 minutes and the reaction allowed to proceed. After 16 hours, TLC analysis (using 5% methanol in dichloromethane) showed complete formation of product. The reaction mixture was then cooled and filtered to remove solid enzoic acid precipitate.
- Solution 1 Tris-HCl buffer, containing 0.133 M Tris, 0.666 mM EDTA at pH 9.5.
- Solution 2 Hydrazine hydrate solution, containing 1 M hydrazine hydrate at pH 9.5.
- Solution 3 NAD solution, 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 EDTA) at pH 7.2.
- the polymers according to the invention may be administered orally to a patient in a dosage of about 1 mg/kg/day to about 10 g/kg/day; the particular dosage will depend on the individual patient (e.g., the patient's weight and the extent of bile salt removal required) .
- the polymer may be administrated either in hydrated or dehydrated form, and may be flavored or added to a food or drink, if desired to enhance patient acceptability. Additional ingredients such as other bile acid sequestrants, drugs for treating hypercholesterolemia, atherosclerosis or other related indications, or inert ingredients, such as artificial coloring agents may be added as well.
- suitable forms for administration include pills, tablets, capsules, and powders (e.g., for sprinkling on food) .
- the pill, tablet, capsule, or powder can be coated with a substance capable of protecting the composition from the gastric acid in the patient's stomach for a period of time sufficient to allow the composition to pass undisintegrated into the patient's small intestine.
- the polymer may be administered alone or in combination with a pharmaceutically acceptable carrier substance, e.g., magnesium carbonate, lactose, or a phospholipid with which the polymer can form a micelle.
Abstract
Description
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Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP95922232A EP0764174B1 (en) | 1994-06-10 | 1995-06-05 | Process for removing bile salts from a patient and alkylated compositions therefor |
CA002191478A CA2191478C (en) | 1994-06-10 | 1995-06-05 | Process for removing bile salts from a patient and alkylated compositions therefor |
DE69511861T DE69511861T2 (en) | 1994-06-10 | 1995-06-05 | METHOD FOR REMOVING GALLIC ACID FROM A PATIENT, AND THE ALKYLATED COMPOSITIONS THEREFOR |
DE200412000034 DE122004000034I1 (en) | 1994-06-10 | 1995-06-05 | A method of removing gallbladder from a patient and the alkylated compositions therefor. |
DK95922232T DK0764174T3 (en) | 1994-06-10 | 1995-06-05 | Method of removing bile salts from a patient and alkylated compositions thereto |
AU26990/95A AU698752C (en) | 1994-06-10 | 1995-06-05 | Process for removing bile salts from a patient and alkylated compositions therefor |
NZ288076A NZ288076A (en) | 1994-06-10 | 1995-06-05 | Process for removing bile salts from a patient and alkylated compositions therefor |
KR1019960707054A KR100271693B1 (en) | 1994-06-10 | 1995-06-05 | Process for removing bile salts from a patient and alkylated composition used for the process |
JP50230696A JP3931217B2 (en) | 1994-06-10 | 1995-06-05 | Method for removing bile salts from patients and alkylating compositions therefor |
GR990402794T GR3031702T3 (en) | 1994-06-10 | 1999-11-03 | Process for removing bile salts from a patient and alkylated compositions therefor |
NL300159C NL300159I2 (en) | 1994-06-10 | 2004-09-06 | Method for removing bile acids from a patient. |
LU91100C LU91100I2 (en) | 1994-06-10 | 2004-09-08 | Method for removing bile salts from a patient and alkylated compositions therefor. |
FR04C0021C FR04C0021I2 (en) | 1994-06-10 | 2004-09-08 | METHOD FOR ELIMINATING BILE SALTS IN A PATIENT AND ALKYLATED COMPOSITIONS FOR THIS PURPOSE |
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Cited By (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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WO1998057652A1 (en) * | 1997-06-18 | 1998-12-23 | Geltex Pharmaceuticals, Inc. | Polyallylamine polymers for treating hypercholesterolemia |
WO1999033452A2 (en) * | 1997-12-29 | 1999-07-08 | Geltex Pharmaceuticals, Inc. | Amine-containing copolymers as bile acid sequestrants |
US5925379A (en) * | 1997-03-27 | 1999-07-20 | Geltex Pharmaceuticals, Inc. | Interpenetrating polymer networks for sequestration of bile acids |
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WO2000032656A2 (en) * | 1998-12-01 | 2000-06-08 | Geltex Pharmaceuticals, Inc. | Polymers containing spirobicyclic ammonium moieties and use thereof |
US6129910A (en) * | 1993-06-02 | 2000-10-10 | Geltex Pharmaceuticals, Inc. | Water-insoluble noncrosslinked bile acid sequestrants |
WO2000064428A2 (en) * | 1999-04-23 | 2000-11-02 | Geltex Pharmaceuticals, Inc. | Polyether-based bile acid sequestrants |
US6203785B1 (en) | 1996-12-30 | 2001-03-20 | Geltex Pharmaceuticals, Inc. | Poly(diallylamine)-based bile acid sequestrants |
WO2002048209A1 (en) * | 2000-12-13 | 2002-06-20 | Dsm Fine Chemicals Austria Nfg Gmbh & Co. Kg | Alkylation of cross-linked polymers containing n- or amino- or ammonium groups |
WO2002085382A1 (en) * | 2001-04-18 | 2002-10-31 | Genzyme Corporation | Methods of treating syndrome x with aliphatic polyamines |
US6525113B2 (en) | 1999-04-16 | 2003-02-25 | Abbott Laboratories | Process for producing cross-linked polyallylamine hydrochloride |
EP1396517A2 (en) | 2002-09-03 | 2004-03-10 | DSM Fine Chemicals Austria Nfg GmbH & Co KG | Preparation of alkylated N or amino or ammonium or spirobicyclic ammonium groups containing cross-linked polymers |
US6726905B1 (en) | 1997-11-05 | 2004-04-27 | Genzyme Corporation | Poly (diallylamines)-based phosphate binders |
WO2006015594A1 (en) * | 2004-08-12 | 2006-02-16 | Versamatrix A/S | Beaded and cross-linked poly(aminoalkylene) matrix and uses thereof |
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WO2012027331A1 (en) | 2010-08-27 | 2012-03-01 | Ironwood Pharmaceuticals, Inc. | Compositions and methods for treating or preventing metabolic syndrome and related diseases and disorders |
WO2014096485A1 (en) | 2012-12-21 | 2014-06-26 | Laboratorios Rubio, S.A. | Oral pharmaceutical composition for drugs with a high-dosage regimen |
Families Citing this family (111)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5607669A (en) * | 1994-06-10 | 1997-03-04 | Geltex Pharmaceuticals, Inc. | Amine polymer sequestrant and method of cholesterol depletion |
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US6566407B2 (en) | 1997-11-05 | 2003-05-20 | Geltex Pharmaceuticals, Inc. | Method for reducing oxalate |
US5985938A (en) | 1997-11-05 | 1999-11-16 | Geltex Pharmaceuticals, Inc. | Method for reducing oxalate |
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US6299868B1 (en) | 1999-07-14 | 2001-10-09 | Geltex Pharmaceuticals, Inc. | Fat-binding polymers |
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US6362266B1 (en) | 1999-09-03 | 2002-03-26 | The Dow Chemical Company | Process for reducing cohesiveness of polyallylamine polymer gels during drying |
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EP2324861A1 (en) | 2000-11-20 | 2011-05-25 | Sorbent Therapeutics, Inc. | In vivo use of water absorbent polymers |
US8263112B2 (en) * | 2000-11-20 | 2012-09-11 | Sorbent Therapeutics, Inc. | In vivo use of water absorbent polymers |
DE60142527D1 (en) | 2000-11-28 | 2010-08-19 | Mitsubishi Tanabe Pharma Corp | EXTRACTION ACCELERATOR FOR AN ACCUMULATIVE CHLORINE CONNECTION |
WO2002066543A1 (en) * | 2001-02-16 | 2002-08-29 | Genzyme Corporation | Method of drying a material having a cohesive phase |
EP1923064B1 (en) | 2001-04-18 | 2017-06-28 | Genzyme Corporation | Use of amine polymer for lowering serum glucose |
WO2002085380A1 (en) * | 2001-04-18 | 2002-10-31 | Geltex Pharmaceuticals, Inc. | Method for treating gout and reducing serum uric acid |
WO2002085379A1 (en) * | 2001-04-18 | 2002-10-31 | Geltex Pharmaceuticals, Inc. | Method for improving vascular access in patients with vascular shunts |
JP5170932B2 (en) * | 2001-04-18 | 2013-03-27 | ジェンザイム コーポレーション | Polyallylamine in low salt form |
DE60225908T2 (en) * | 2001-04-18 | 2009-05-14 | Genzyme Corp., Cambridge | USE OF COLESEVELAM OR SEVELAMERHYDROGENCHLORIDE TO REDUCE SERUM GLUCOSE CONTENT |
US7049345B2 (en) * | 2001-06-29 | 2006-05-23 | Genzyme Corporation | Fat-binding polymers |
US7041280B2 (en) * | 2001-06-29 | 2006-05-09 | Genzyme Corporation | Aryl boronate functionalized polymers for treating obesity |
US6600011B2 (en) | 2001-10-09 | 2003-07-29 | Genzyme Corporation | Process for purification and drying of polymer hydrogels |
AU2003282867A1 (en) * | 2002-10-22 | 2004-05-13 | Genzyme Corporation | Amine polymers for promoting bone formation |
EP1658283A2 (en) | 2003-05-30 | 2006-05-24 | Ranbaxy Laboratories, Ltd. | Substituted pyrrole derivatives and their use as hmg-co inhibitors |
US7335795B2 (en) * | 2004-03-22 | 2008-02-26 | Ilypsa, Inc. | Crosslinked amine polymers |
US7608674B2 (en) * | 2003-11-03 | 2009-10-27 | Ilypsa, Inc. | Pharmaceutical compositions comprising cross-linked small molecule amine polymers |
US7767768B2 (en) * | 2003-11-03 | 2010-08-03 | Ilypsa, Inc. | Crosslinked amine polymers |
US7449605B2 (en) * | 2003-11-03 | 2008-11-11 | Ilypsa, Inc. | Crosslinked amine polymers |
US7459502B2 (en) * | 2003-11-03 | 2008-12-02 | Ilypsa, Inc. | Pharmaceutical compositions comprising crosslinked polyamine polymers |
US7385012B2 (en) * | 2003-11-03 | 2008-06-10 | Ilypsa, Inc. | Polyamine polymers |
CA2560927C (en) | 2004-03-26 | 2013-05-14 | Mitsubishi Pharma Corporation | Insulin resistance-improving agent |
US7854924B2 (en) | 2004-03-30 | 2010-12-21 | Relypsa, Inc. | Methods and compositions for treatment of ion imbalances |
GB2430367B (en) | 2004-03-30 | 2009-08-05 | Ilypsa Inc | Ion binding polymers and uses thereof |
US8282960B2 (en) * | 2004-03-30 | 2012-10-09 | Relypsa, Inc. | Ion binding compositions |
US8192758B2 (en) * | 2004-03-30 | 2012-06-05 | Relypsa, Inc. | Ion binding compositions |
US7556799B2 (en) * | 2004-03-30 | 2009-07-07 | Relypsa, Inc. | Ion binding polymers and uses thereof |
US7429394B2 (en) * | 2004-03-30 | 2008-09-30 | Relypsa, Inc. | Ion binding compositions |
DE602005026819D1 (en) * | 2004-08-27 | 2011-04-21 | Novo Nordisk As | FUNCTIONAL RESIN HIGH LOAD |
JP2008510861A (en) * | 2004-08-27 | 2008-04-10 | ヴァーサマトリックス・アクティーゼルスカブ | Polyether polymer matrix |
US20060177415A1 (en) * | 2004-11-01 | 2006-08-10 | Burke Steven K | Once a day formulation for phosphate binders |
US7985418B2 (en) | 2004-11-01 | 2011-07-26 | Genzyme Corporation | Aliphatic amine polymer salts for tableting |
JP4547620B2 (en) * | 2004-12-02 | 2010-09-22 | 日東紡績株式会社 | Method for producing crosslinked allylamine polymers |
MY144940A (en) * | 2005-01-25 | 2011-11-30 | Avantor Performance Mat Inc | Chromatographic media |
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US8986669B2 (en) | 2005-09-02 | 2015-03-24 | Genzyme Corporation | Method for removing phosphate and polymer used therefore |
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BRPI0618379A2 (en) | 2005-11-08 | 2011-08-30 | Ranbaxy Lab Ltd | (3r, 5r) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4 - [(4-hydroxymethylphenylamino) carbonyl] -pyrroleic acid 1-yl] -3,5-dihydroxy heptanoic |
WO2007130463A2 (en) * | 2006-05-05 | 2007-11-15 | Genzyme Corporation | Amine condensation polymers as phosphate sequestrants |
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US8425887B2 (en) | 2006-09-29 | 2013-04-23 | Genzyme Corporation | Amide dendrimer compositions |
JP2010513271A (en) | 2006-12-14 | 2010-04-30 | ゲンズイメ コーポレーション | Amide-amine polymer composition |
US8362217B2 (en) | 2006-12-21 | 2013-01-29 | Emd Millipore Corporation | Purification of proteins |
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US20100129309A1 (en) * | 2007-02-23 | 2010-05-27 | Dhal Pradeep K | Amine polymer compositions |
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WO2009151514A1 (en) | 2008-06-11 | 2009-12-17 | Millipore Corporation | Stirred tank bioreactor |
US20110142952A1 (en) * | 2008-06-20 | 2011-06-16 | Harris David J | Pharmaceutical Compositions |
DE102008030046A1 (en) | 2008-06-25 | 2009-12-31 | Ratiopharm Gmbh | Preparation of tablets comprising polyallylamine polymer, useful for treating e.g. hyperphosphatemia, comprises mixing polyallylamine polymer and additives, compacting to slug, granulating the slug and compressing the granules into tablets |
US8337824B2 (en) | 2008-08-22 | 2012-12-25 | Relypsa, Inc. | Linear polyol stabilized polyfluoroacrylate compositions |
EP2365988B2 (en) * | 2008-08-22 | 2019-07-03 | Vifor (International) Ltd. | Crosslinked cation exchange polymers, compositions and use in treating hyperkalemia |
US20100104527A1 (en) * | 2008-08-22 | 2010-04-29 | Relypsa, Inc. | Treating hyperkalemia with crosslinked cation exchange polymers of improved physical properties |
CA2735962A1 (en) * | 2008-09-02 | 2010-04-15 | Usv Limited | Crosslinked polymers |
WO2010062734A1 (en) * | 2008-11-03 | 2010-06-03 | University Of Maryland, Baltimore | Blood coagulation inducing polymer hydrogel |
US8404784B2 (en) * | 2008-12-03 | 2013-03-26 | Navinta Llc | Manufacturing process of making polymeric amine salts |
WO2010074953A1 (en) | 2008-12-16 | 2010-07-01 | Millipore Corporation | Stirred tank reactor and method |
US8673272B2 (en) * | 2009-07-27 | 2014-03-18 | Isp Investments Inc. | Ultraviolet-absorbing compounds |
GB0915449D0 (en) * | 2009-09-04 | 2009-10-07 | Univ Robert Gordon | Composition |
CA2790901C (en) * | 2010-02-24 | 2018-05-01 | Relypsa, Inc. | Amine polymers for use as bile acid sequestrants |
CN102858817B (en) | 2010-02-24 | 2015-09-02 | 瑞立普萨公司 | As the cross-linked polyvinylamine of bile acid chelating agent, polyallylamine and ethyleneimine |
US8691918B2 (en) * | 2010-05-17 | 2014-04-08 | Emd Millipore Corporation | Stimulus responsive polymers for the purification of biomolecules |
TR201005327A2 (en) | 2010-06-30 | 2012-01-23 | Bi̇lgi̇ç Mahmut | Synergistic pharmaceutical formulations. |
DK2637646T3 (en) | 2010-11-08 | 2016-08-29 | Albireo Ab | PHARMACEUTICAL COMBINATION CONTAINING AN IBAT inhibitor and a bile acid binder |
ME02554B (en) | 2010-11-08 | 2017-02-20 | Albireo Ab | Ibat inhibitors for the treatment of liver diseases |
ES2633766T3 (en) | 2011-10-28 | 2017-09-25 | Lumena Pharmaceuticals Llc | Bile acid recycling inhibitors for the treatment of pediatric cholestatic liver diseases |
US20130123433A1 (en) | 2011-11-14 | 2013-05-16 | Formosa Laboratories, Inc. | Method for preparing poly(allylamine) hydrochloride and derivatives therefrom |
AU2013329451B2 (en) | 2012-10-08 | 2018-08-09 | Vifor (International) Ltd. | Potassium-binding agents for treating hypertension and hyperkalemia |
US20160083343A1 (en) * | 2013-03-15 | 2016-03-24 | Global Blood Therapeutics, Inc | Compounds and uses thereof for the modulation of hemoglobin |
CN103446179B (en) * | 2013-05-14 | 2017-03-15 | 厦门绿洲安源投资管理有限公司 | The application of the tree-shaped crosslinking polycation gel of the poly- fullerene of parents of binding chelating agent as phosphate, aliphatic acid and bile acid |
ES2834485T3 (en) | 2013-06-05 | 2021-06-17 | Tricida Inc | Proton-binding polymers for oral administration |
US9475891B2 (en) | 2013-09-19 | 2016-10-25 | Navinta, Llc | Process for the preparation of colesevelam hydrochloride |
EP2875807B1 (en) | 2013-11-20 | 2021-03-24 | Sanovel Ilac Sanayi ve Ticaret A.S. | Tablet formulation of colesevelam |
ITMI20132132A1 (en) | 2013-12-19 | 2015-06-20 | Chemi Spa | PROCESS FOR THE PREPARATION OF COLESEVELAM |
CA2952223C (en) | 2014-06-13 | 2023-08-01 | United Therapeutics Corporation | Treprostinil formulations |
CA3205149A1 (en) | 2014-12-10 | 2016-06-16 | Tricida, Inc. | Proton-binding polymers for oral administration |
WO2016135065A1 (en) | 2015-02-23 | 2016-09-01 | Amneal Pharmaceuticals Company Gmbh | Process for granulating sevelamer carbonate |
EP3689925B1 (en) | 2015-10-21 | 2022-11-30 | Saudi Arabian Oil Company | Method for producing a mesoporous zeolite |
CN116211887A (en) | 2016-05-06 | 2023-06-06 | 特里赛达公司 | Composition for treating acid-base imbalance |
CN106008813B (en) * | 2016-06-15 | 2017-11-14 | 新发药业有限公司 | The method that polymerisation in solution prepares colesevelam hydrocholoride |
JP7418211B2 (en) | 2016-12-14 | 2024-01-19 | エコラブ ユーエスエイ インク | Quaternary cationic polymer |
CN107232191B (en) * | 2017-06-22 | 2021-05-18 | 华中师范大学 | Perfluorobutyl modified polyethyleneimine macromolecular fluorine-containing surfactant, preparation thereof and application thereof in pesticide slow release |
CA3080651A1 (en) | 2017-11-03 | 2019-05-09 | Tricida, Inc. | Compositions for and method of treating acid-base disorders |
WO2019241056A1 (en) | 2018-06-12 | 2019-12-19 | Ecolab Usa Inc. | Quaternary cationic surfactants and polymers for use as release and coating modifying agents in creping and tissue papers |
CN112047854B (en) * | 2020-10-20 | 2021-07-02 | 中国科学院长春应用化学研究所 | Preparation method of N-vinyl alkyl amide |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2036048A (en) * | 1978-11-14 | 1980-06-25 | Mitsubishi Chem Ind | Polymer compounds, process for their preparation and arteriosclerosis treating agents containing them |
WO1992010522A1 (en) * | 1990-12-07 | 1992-06-25 | Imperial Chemical Industries Plc | Quaternary crosslinked allylammoniumpolymers, preparation and use thereof |
EP0580078A1 (en) * | 1992-07-22 | 1994-01-26 | Hoechst Aktiengesellschaft | Hydrophilic groups containing poly(vinylamine) derivatives, process for their manufacture and use thereof as pharmaceutical compounds, substrates for active substances and foodstuff ingredients |
Family Cites Families (46)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BE580490A (en) * | 1958-07-15 | 1960-01-08 | Merck & Co Inc | Compositions and methods for lowering the cholesterol content of the blood |
US3383281A (en) * | 1961-09-22 | 1968-05-14 | Merck & Co Inc | Method for binding bile acids in vivo |
US3308020A (en) * | 1961-09-22 | 1967-03-07 | Merck & Co Inc | Compositions and method for binding bile acids in vivo including hypocholesteremics |
US3288770A (en) * | 1962-12-14 | 1966-11-29 | Peninsular Chem Res Inc | Water soluble quaternary ammonium polymers |
BE756035A (en) * | 1969-09-12 | 1971-03-11 | Inveresk Res Int | POLYMERS BRIDGES |
US3803237A (en) * | 1969-11-03 | 1974-04-09 | Upjohn Co | Reaction products of polyethylenepolyamines and chlorohydrins or epoxy containing compounds |
NL7017227A (en) * | 1969-12-27 | 1971-06-29 | ||
US3692895A (en) * | 1970-09-08 | 1972-09-19 | Norman A Nelson | Method of reducing hypercholesteremia in humans employing a copolymer of polyethylenepolyamine and a bifunctional substance, such as epichlorohydria |
US3980770A (en) * | 1971-06-04 | 1976-09-14 | Pharmacia Aktiebolag | Polymerization products containing amino groups useful in serum cholesterol level control |
AR206390A1 (en) * | 1973-02-05 | 1976-07-23 | Rohm & Haas | A MATRIX OF RETICULATED POLYMER RESIN AND PROCEDURE FOR ITS PREPARATION |
US4217429A (en) * | 1973-06-11 | 1980-08-12 | Merck & Co., Inc. | Poly-[(methylimino)trimethylene] |
US4027009A (en) * | 1973-06-11 | 1977-05-31 | Merck & Co., Inc. | Compositions and methods for depressing blood serum cholesterol |
US4205064A (en) * | 1973-06-11 | 1980-05-27 | Merck & Co., Inc. | Bile acid sequestering composition containing poly[{alkyl-(3-ammoniopropyl)imino}-trimethylenedihalides] |
CS187563B1 (en) * | 1974-02-08 | 1979-02-28 | Petr Strop | Method of preparation of the hydrophilic homogeneous or macroporous annexes |
CS173201B1 (en) * | 1974-02-13 | 1977-02-28 | ||
US4016209A (en) * | 1975-04-23 | 1977-04-05 | Merck & Co., Inc. | 3-[N'-(3-Halopropyl)-N-'-methylamino]-N,N,N-trimethyl-1-propanaminium halide and acid addition salts thereof |
US4101478A (en) * | 1976-04-12 | 1978-07-18 | Kostjuchenko Vladimir Mitrofan | Synthetic rubber mix |
US4071478A (en) * | 1976-06-07 | 1978-01-31 | Merck & Co., Inc. | Controlled partially cross-linked 3,3-ionenes |
FI67483C (en) * | 1977-02-17 | 1985-04-10 | Merck & Co Inc | PROCEDURE FOR THE FRAMEWORK OF ETHCYCLE ADMINISTRATION OF PHARMACOLOGICAL PRODUCT AGAINST GALLSYRAK COMPLEX BILDANDE ADSORBATE PREPARATION |
US4298715A (en) * | 1978-03-01 | 1981-11-03 | Monsanto Company | Polyamine/epihalohydrin reaction products |
IT1106718B (en) * | 1978-12-21 | 1985-11-18 | Alfa Farmaceutici Spa | PHARMACOLOGICALLY ACTIVE SALONIZED ANIONIC RESIN BASED COMPOSITIONS |
DE3272059D1 (en) * | 1982-01-18 | 1986-08-28 | Mitsubishi Petrochemical Co | Cholesterol lowering drug |
JPS6090243A (en) * | 1983-10-25 | 1985-05-21 | Nitto Boseki Co Ltd | Small spherical crosslinked monoallylamine polymer and its preparation |
AU551886B2 (en) * | 1983-11-14 | 1986-05-15 | Nitto Boseki Co. Ltd. | Poly(allylamine) derivatives |
JPS60106803A (en) * | 1983-11-14 | 1985-06-12 | Nitto Boseki Co Ltd | Production of allylurea polymer |
US4540760A (en) * | 1984-01-11 | 1985-09-10 | Nitto Boseki Co. Ltd. | Process for producing polymers of monoallylamine |
EP0162388B1 (en) * | 1984-05-11 | 1989-09-13 | Bristol-Myers Company | Novel bile sequestrant resin and uses |
US4759923A (en) * | 1987-06-25 | 1988-07-26 | Hercules Incorporated | Process for lowering serum cholesterol using poly(diallylmethylamine) derivatives |
US5300566A (en) * | 1988-04-15 | 1994-04-05 | Air Products And Chemicals, Inc. | Method for preparing poly(vinyl alcohol)-co-poly(vinylamine) via a two-phase process |
DE3901527A1 (en) | 1989-01-20 | 1990-07-26 | Hoechst Ag | ALKYLATED POLYETHYLENE IMIN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, THEIR USE AS MEDICINAL PRODUCTS AND PHARMACEUTICAL PREPARATIONS |
US5236701A (en) * | 1989-07-19 | 1993-08-17 | Lowchol Scientific Inc. | Ingestible hydrophilic polymeric amines useful for lowering blood cholesterol |
GB8928278D0 (en) * | 1989-12-14 | 1990-02-21 | Smith Kline French Lab | Compounds |
GB9011332D0 (en) * | 1990-05-21 | 1990-07-11 | Smith Kline French Lab | Compounds |
US5055197A (en) * | 1991-04-05 | 1991-10-08 | Rohm And Haas Company | Process for removing residual monomers and oligemers from amine-containing polymers |
US5142019A (en) * | 1991-10-03 | 1992-08-25 | Ppg Industries, Inc. | Oligomers formed from reaction of acrylamidoglycolate alkyl ethers with β-hydroxyalkylamines |
ATE146193T1 (en) * | 1992-07-22 | 1996-12-15 | Hoechst Ag | CROSS-LINKED, NITROGEN-CONTAINING VINYL COPOLYMERS, METHOD FOR THE PRODUCTION THEREOF AND THE USE OF THESE COMPOUNDS |
JP3412842B2 (en) * | 1992-07-28 | 2003-06-03 | ミヨシ油脂株式会社 | Metal collecting agent and method for producing the same |
ES2118254T3 (en) * | 1992-08-20 | 1998-09-16 | Du Pont | RETICULATED POLYMERIC AMMONIUM SALTS. |
US5451397A (en) * | 1992-12-21 | 1995-09-19 | Rohm And Haas Company | Bile acid sequestrant |
WO1994027620A1 (en) * | 1993-06-02 | 1994-12-08 | Geltex Pharmaceuticals, Inc. | Compositions and process for removing bile salts |
US5624963A (en) | 1993-06-02 | 1997-04-29 | Geltex Pharmaceuticals, Inc. | Process for removing bile salts from a patient and compositions therefor |
US5607669A (en) | 1994-06-10 | 1997-03-04 | Geltex Pharmaceuticals, Inc. | Amine polymer sequestrant and method of cholesterol depletion |
US5703188A (en) | 1993-06-02 | 1997-12-30 | Geltex Pharmaceuticals, Inc. | Process for removing bile salts from a patient and compositions therefor |
US5667775A (en) * | 1993-08-11 | 1997-09-16 | Geltex Pharmaceuticals, Inc. | Phosphate-binding polymers for oral administration |
US5414068A (en) * | 1994-01-24 | 1995-05-09 | Rohm And Haas Company | Crosslinked anion exchange particles and method for producing the particles |
TW474813B (en) * | 1994-06-10 | 2002-02-01 | Geltex Pharma Inc | Alkylated composition for removing bile salts from a patient |
-
1995
- 1995-05-22 TW TW084105201A patent/TW474813B/en not_active IP Right Cessation
- 1995-06-05 CA CA002191478A patent/CA2191478C/en not_active Expired - Lifetime
- 1995-06-05 KR KR1019960707054A patent/KR100271693B1/en not_active IP Right Cessation
- 1995-06-05 RU RU96124807/04A patent/RU2160742C2/en active
- 1995-06-05 US US08/460,980 patent/US5679717A/en not_active Expired - Lifetime
- 1995-06-05 DK DK95922232T patent/DK0764174T3/en active
- 1995-06-05 EP EP95922232A patent/EP0764174B1/en not_active Expired - Lifetime
- 1995-06-05 US US08/461,298 patent/US5693675A/en not_active Expired - Lifetime
- 1995-06-05 DE DE200412000034 patent/DE122004000034I1/en active Pending
- 1995-06-05 DE DE1995611861 patent/DE122004000034I2/en active Active
- 1995-06-05 AU AU26990/95A patent/AU698752C/en not_active Expired
- 1995-06-05 AT AT95922232T patent/ATE184027T1/en active
- 1995-06-05 DE DE69511861T patent/DE69511861T2/en not_active Expired - Lifetime
- 1995-06-05 CN CNB951935216A patent/CN1150217C/en not_active Expired - Lifetime
- 1995-06-05 ES ES95922232T patent/ES2135743T3/en not_active Expired - Lifetime
- 1995-06-05 EP EP98203744A patent/EP0909768A3/en not_active Withdrawn
- 1995-06-05 JP JP50230696A patent/JP3931217B2/en not_active Expired - Lifetime
- 1995-06-05 NZ NZ288076A patent/NZ288076A/en not_active IP Right Cessation
- 1995-06-05 WO PCT/US1995/007181 patent/WO1995034585A1/en active IP Right Grant
- 1995-06-08 IL IL11407395A patent/IL114073A/en not_active IP Right Cessation
-
1996
- 1996-12-06 MX MX9606171A patent/MX9606171A/en unknown
-
1998
- 1998-08-05 US US09/129,286 patent/US5917007A/en not_active Expired - Lifetime
-
1999
- 1999-04-08 US US09/288,357 patent/US5981693A/en not_active Expired - Lifetime
- 1999-09-02 US US09/388,876 patent/US6066678A/en not_active Expired - Lifetime
- 1999-11-03 GR GR990402794T patent/GR3031702T3/en unknown
-
2000
- 2000-03-22 US US09/532,984 patent/US6225355B1/en not_active Expired - Lifetime
-
2001
- 2001-03-09 US US09/803,647 patent/US6433026B2/en not_active Expired - Lifetime
- 2001-04-03 IL IL14241901A patent/IL142419A0/en unknown
-
2002
- 2002-01-30 US US10/060,556 patent/US20020095002A1/en not_active Abandoned
- 2002-10-03 US US10/264,350 patent/US6784254B2/en not_active Expired - Lifetime
-
2004
- 2004-07-07 US US10/886,016 patent/US7101960B2/en not_active Expired - Fee Related
- 2004-09-06 NL NL300159C patent/NL300159I2/en unknown
- 2004-09-08 FR FR04C0021C patent/FR04C0021I2/en active Active
- 2004-09-08 LU LU91100C patent/LU91100I2/en unknown
-
2006
- 2006-07-24 US US11/491,788 patent/US7399821B2/en not_active Expired - Lifetime
-
2008
- 2008-07-11 US US12/218,227 patent/US20090155201A1/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2036048A (en) * | 1978-11-14 | 1980-06-25 | Mitsubishi Chem Ind | Polymer compounds, process for their preparation and arteriosclerosis treating agents containing them |
WO1992010522A1 (en) * | 1990-12-07 | 1992-06-25 | Imperial Chemical Industries Plc | Quaternary crosslinked allylammoniumpolymers, preparation and use thereof |
EP0580078A1 (en) * | 1992-07-22 | 1994-01-26 | Hoechst Aktiengesellschaft | Hydrophilic groups containing poly(vinylamine) derivatives, process for their manufacture and use thereof as pharmaceutical compounds, substrates for active substances and foodstuff ingredients |
Cited By (38)
Publication number | Priority date | Publication date | Assignee | Title |
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US6605270B1 (en) | 1993-05-20 | 2003-08-12 | Genzyme Corporation | Iron-binding polymers for oral administration |
US5702696A (en) * | 1993-05-20 | 1997-12-30 | Geltex Pharmaceuticals | Iron-binding polymers for oral administration |
US5929184A (en) * | 1993-06-02 | 1999-07-27 | Geltex Pharmaceuticals, Inc. | Hydrophilic nonamine-containing and amine-containing copolymers and their use as bile acid sequestrants |
US6129910A (en) * | 1993-06-02 | 2000-10-10 | Geltex Pharmaceuticals, Inc. | Water-insoluble noncrosslinked bile acid sequestrants |
US6203785B1 (en) | 1996-12-30 | 2001-03-20 | Geltex Pharmaceuticals, Inc. | Poly(diallylamine)-based bile acid sequestrants |
US6610283B1 (en) | 1996-12-30 | 2003-08-26 | Genzyme Corporation | Poly(diallylamine)-based bile acid sequestrants |
US7125547B2 (en) | 1996-12-30 | 2006-10-24 | Genzyme Corporation | Poly(diallylamine)-based bile acid sequestrants |
US5925379A (en) * | 1997-03-27 | 1999-07-20 | Geltex Pharmaceuticals, Inc. | Interpenetrating polymer networks for sequestration of bile acids |
WO1998057652A1 (en) * | 1997-06-18 | 1998-12-23 | Geltex Pharmaceuticals, Inc. | Polyallylamine polymers for treating hypercholesterolemia |
US6423754B1 (en) | 1997-06-18 | 2002-07-23 | Geltex Pharmaceuticals, Inc. | Method for treating hypercholesterolemia with polyallylamine polymers |
US7638524B2 (en) | 1997-11-05 | 2009-12-29 | Genzyme Corporation | Combination therapy for treating hypercholesterolemia |
US6726905B1 (en) | 1997-11-05 | 2004-04-27 | Genzyme Corporation | Poly (diallylamines)-based phosphate binders |
WO1999033452A3 (en) * | 1997-12-29 | 1999-10-21 | Geltex Pharma Inc | Amine-containing copolymers as bile acid sequestrants |
WO1999033452A2 (en) * | 1997-12-29 | 1999-07-08 | Geltex Pharmaceuticals, Inc. | Amine-containing copolymers as bile acid sequestrants |
EP1153940A1 (en) | 1998-10-12 | 2001-11-14 | Chugai Seiyaku Kabushiki Kaisha | Polymer combining with phosphoric acid and preparation containing the same |
AU767239B2 (en) * | 1998-10-12 | 2003-11-06 | Chugai Seiyaku Kabushiki Kaisha | Phosphate-binding polymer and tablets using the same |
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US6271264B1 (en) | 1998-12-01 | 2001-08-07 | Geltex Pharmaceuticals, Inc. | Polymers containing spirobicyclic ammonium moieties as bile acid sequestrants |
WO2000032656A3 (en) * | 1998-12-01 | 2000-11-16 | Geltex Pharma Inc | Polymers containing spirobicyclic ammonium moieties and use thereof |
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US6525113B2 (en) | 1999-04-16 | 2003-02-25 | Abbott Laboratories | Process for producing cross-linked polyallylamine hydrochloride |
US6517825B1 (en) | 1999-04-23 | 2003-02-11 | Geltex Pharmaceuticals, Inc. | Polyether-based bile acid sequestrants |
WO2000064428A2 (en) * | 1999-04-23 | 2000-11-02 | Geltex Pharmaceuticals, Inc. | Polyether-based bile acid sequestrants |
WO2000064428A3 (en) * | 1999-04-23 | 2001-02-08 | Geltex Pharma Inc | Polyether-based bile acid sequestrants |
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WO2002048209A1 (en) * | 2000-12-13 | 2002-06-20 | Dsm Fine Chemicals Austria Nfg Gmbh & Co. Kg | Alkylation of cross-linked polymers containing n- or amino- or ammonium groups |
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US7148319B2 (en) | 2000-12-13 | 2006-12-12 | Dsm Fine Chemicals Austria Nfg Gmbh & Co Kg | Alkylation of crosslinked polymers containing N or amino or ammonium groups |
US7261880B2 (en) | 2001-04-18 | 2007-08-28 | Genzyme Corporation | Methods of treating Syndrome X with aliphatic polyamines |
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