CA2101011A1 - Polyvinylamine derivatives having hydrophilic centers, processes for their preparation and the use of the compounds as a medicament, active compound carrier and foodstuff auxiliary - Google Patents
Polyvinylamine derivatives having hydrophilic centers, processes for their preparation and the use of the compounds as a medicament, active compound carrier and foodstuff auxiliaryInfo
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- CA2101011A1 CA2101011A1 CA002101011A CA2101011A CA2101011A1 CA 2101011 A1 CA2101011 A1 CA 2101011A1 CA 002101011 A CA002101011 A CA 002101011A CA 2101011 A CA2101011 A CA 2101011A CA 2101011 A1 CA2101011 A1 CA 2101011A1
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- Prior art keywords
- compound
- formula
- polyvinylamine
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Classifications
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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
- C08F126/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen
- C08F126/02—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen by a single or double bond to 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
- C08F8/12—Hydrolysis
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/12—Powdering or granulating
Abstract
Abstract of the Disclosure:
Polyvinylamine derivatives having hydrophilic centers, processes for their preparation and the use of the compounds as a medicament, active compound carrier and foodstuff auxiliary Polyvinylamine derivatives containing hydrophilic cen-ters, of the formula I
(I) in which R1, R2, R3, X, w, x, y and z have the meanings given, and a process for their preparation, and the use of these compounds as medicaments, active compound carriers and foodstuff auxiliaries are described. Highly pure polyvinylamines having the recurring unit of the formula Ia
Polyvinylamine derivatives having hydrophilic centers, processes for their preparation and the use of the compounds as a medicament, active compound carrier and foodstuff auxiliary Polyvinylamine derivatives containing hydrophilic cen-ters, of the formula I
(I) in which R1, R2, R3, X, w, x, y and z have the meanings given, and a process for their preparation, and the use of these compounds as medicaments, active compound carriers and foodstuff auxiliaries are described. Highly pure polyvinylamines having the recurring unit of the formula Ia
Description
21Q~
HOECHST AXTIENGESELLSCHAFT HOE 92/F 215 Dr.D/rh Description Polyvinylamine derivatives having hydrophilic centers, processes for their preparation and the use of the compounds as a medicament, active compound carrier and foodstuff auxiliary The invention relates to soluble and insoluble nitrogen-containing vinyl polymers containing hydrophilic center~, their use as bile ~cid adsorber with the aim of reducing the blood chole~terol level, their use as an active compound carrier and as a foodstuff auxiliary and addi-tive, and furthermore a process for the preparation of these compounds.
9ile acids have an important phyæiological ~unction in fat digestion. As end products of cholesterol metabolism, they are synthesized in the liver, stored in the gall-bladder and released into the intestine, where they display their physiological action. The major proportion of bile acids secreted is recovered via the enterohepatic circulation (about 20-50 g/day). Suppression of this resorption reduces the bile acid pool in the liver and in this way causes an increased absorption of cholesterol from the blood circulation, a~ well a~ a stimulation in endogenous cholestarol 6ynthesi~. For this purpose, the number of hepatic LDL receptors on the membrane~ of the liver cells is increased, 80 that cataboli~m of the cholesterol-containing LDL particles is accelerated and the cholesterol content in the blood i8 reduced.
It is known that bile acids can be bonded to insoluble, basic, cros~linked polymer~ such as polyethyleneimines (~f., for exzmple EP-A-O 379 161) or polyvinylimidazoles (cf. EP-B-O 162 388), and are therefore regarded as being suitable for treatment of diseases in which inhibition of the absorption of bile acid in the intestine, especially in the ~mall intestine, appezrs to be desirable. For example, chologenic diarrhea following ileum re~ection or increased cholssterol blood level~ are treated in this manner.
A very high daily dose is to be maintained, in particu-lar, for the ion exchanger resins used as lipid-lowering agents, such as colestipol and colestyramine. For example, it is 12-24 g for colestyramine, 32 g in the highest instance, and 15-30 g for cole~tipol.
Thi~ high dosage and the unpleasant smell, taste and consistency makes patient compliance difficult.
Side effects of these ion exchanger re~ins are also to be attributed to the lack of selectivity (for example avitaminoses). For both preparations, a therapeutic importance has been reported in combination with other drugs which have a hypolipidemic action, such as fibrates, HMG-CoA reductase inhibitors and probucol (cf., for example, M.N. Cayen, Pharmac, Ther. 29, 187 (1985) and 8th International Symposium on Atherosclero6is, Rome, Oct. 9-13, 1988, Abstracts pages 544, 608, 710), the effects achieved also allowing treatment of severe cases of hyperlipidemia. It therefore ceem~ Lmportant to discover substances which are suitable for the given action principle without having the disadvantages of the preparations currently used.
The following features of the preparations mentioned and in particular of colestipol are to be regarded as being worthy of improvement: -1. The high daily doses, which are due to a low bonding rate in isotonic solution and to partial re-release of the bile acid adsorbed.
0 2. The qualitative shift in the bile acid composition of bile with a decreasing trend for chenodeoxycholic acid and the associated increa~ing ri~k of cholelithia~is.
2~0~011 3. The absence of a suppressant action on the cholesterol metabolism of the intestinal bacteria.
HOECHST AXTIENGESELLSCHAFT HOE 92/F 215 Dr.D/rh Description Polyvinylamine derivatives having hydrophilic centers, processes for their preparation and the use of the compounds as a medicament, active compound carrier and foodstuff auxiliary The invention relates to soluble and insoluble nitrogen-containing vinyl polymers containing hydrophilic center~, their use as bile ~cid adsorber with the aim of reducing the blood chole~terol level, their use as an active compound carrier and as a foodstuff auxiliary and addi-tive, and furthermore a process for the preparation of these compounds.
9ile acids have an important phyæiological ~unction in fat digestion. As end products of cholesterol metabolism, they are synthesized in the liver, stored in the gall-bladder and released into the intestine, where they display their physiological action. The major proportion of bile acids secreted is recovered via the enterohepatic circulation (about 20-50 g/day). Suppression of this resorption reduces the bile acid pool in the liver and in this way causes an increased absorption of cholesterol from the blood circulation, a~ well a~ a stimulation in endogenous cholestarol 6ynthesi~. For this purpose, the number of hepatic LDL receptors on the membrane~ of the liver cells is increased, 80 that cataboli~m of the cholesterol-containing LDL particles is accelerated and the cholesterol content in the blood i8 reduced.
It is known that bile acids can be bonded to insoluble, basic, cros~linked polymer~ such as polyethyleneimines (~f., for exzmple EP-A-O 379 161) or polyvinylimidazoles (cf. EP-B-O 162 388), and are therefore regarded as being suitable for treatment of diseases in which inhibition of the absorption of bile acid in the intestine, especially in the ~mall intestine, appezrs to be desirable. For example, chologenic diarrhea following ileum re~ection or increased cholssterol blood level~ are treated in this manner.
A very high daily dose is to be maintained, in particu-lar, for the ion exchanger resins used as lipid-lowering agents, such as colestipol and colestyramine. For example, it is 12-24 g for colestyramine, 32 g in the highest instance, and 15-30 g for cole~tipol.
Thi~ high dosage and the unpleasant smell, taste and consistency makes patient compliance difficult.
Side effects of these ion exchanger re~ins are also to be attributed to the lack of selectivity (for example avitaminoses). For both preparations, a therapeutic importance has been reported in combination with other drugs which have a hypolipidemic action, such as fibrates, HMG-CoA reductase inhibitors and probucol (cf., for example, M.N. Cayen, Pharmac, Ther. 29, 187 (1985) and 8th International Symposium on Atherosclero6is, Rome, Oct. 9-13, 1988, Abstracts pages 544, 608, 710), the effects achieved also allowing treatment of severe cases of hyperlipidemia. It therefore ceem~ Lmportant to discover substances which are suitable for the given action principle without having the disadvantages of the preparations currently used.
The following features of the preparations mentioned and in particular of colestipol are to be regarded as being worthy of improvement: -1. The high daily doses, which are due to a low bonding rate in isotonic solution and to partial re-release of the bile acid adsorbed.
0 2. The qualitative shift in the bile acid composition of bile with a decreasing trend for chenodeoxycholic acid and the associated increa~ing ri~k of cholelithia~is.
2~0~011 3. The absence of a suppressant action on the cholesterol metabolism of the intestinal bacteria.
4. The excessively high bonding rate of vitamin~ and drugs, which may necessitate a substitution require-ment for these substances and blood level checks.
5. An inadequate purity and stability of the polymers (risk of 6plitting of ammonium groups from colestyramine).
6. Inadequate patient compliance because of a) the "sandy'~ consistency (colestyramine - hard gel polymer) and b) the unpleasant smell and taste.
Variations in the preparations used to date, such as, for example, introduction of spacer~ between ammonium groups and the polymer main chain in the case of colestyramine (EP-A-0 404 062), do not leat to a decisive reduction in the disadvantages described.
The object of the present invention was to provide compounds having a different polymer ~tructure which bond bile acids to a high degree as a function of the concen-tration. The6e compounds moreover ~hould not have the existing di6advantages of the exchanger resins used to date or ~hould not have them to the same known extent.
The object i5 achieved and the deficiencies described are overcome with the highly water-absorbing polymers of the formula I and the highly pure polyvinylamines having the recurring unit of the formula Ia.
The invention therefore relates to polyvinylamines of the formula I.
_ 4 _ 2 1 ~ ~ o 1 1 ( CH2--IH--)~-(--CH2--IH--)X-(--CH2--CH~ CH2--f H--)z--~H2 NH NH NH
X R 2 1, ( I ) in which Rl is a substituent chosen ~rom the group compri~ing:
1. -(CH2)n-CH3, in which n is an integer from 3 to 21, ~ranched alkyl having 3 to 21 carbon atoms or straight-chain or branched alkenyl having up to 21 carbon atoms, 2. cycloalkyl or cycloalkenyl having in each ca~e 5-12 carbon atoms, or mono , di- or trisub6titu-ted cycloalkyl or cycloalkenyl having in each case 5-12 ring carbon atoms and 3. aryl, arylalkyl or arylalkenyl, in which the aryl radicals are mono- or polynsclear, can be mono-to trisubstituted and can contain heteroatoms, X is a single bond, a bridge group or a hydrophilic spacer for linking the radical Rl, R2 is RA-Y~ RB or F~, in which Y is a bri.d~e group or a spacer which allows RA to be linked to the polymer, R~ is a hydrophilic or amphiphilic substituent chosen from the group comprising:
~ (CH2)b-cH3 1. ~(CH2)a~N
\ ~CH2)b-CH3 - 5 ~
2.
(CH2)b CH3 (CH2)o N \ (CH2)b CH3 A~
(CH2)~- CH3 3.
(C~2)"--CH3 ---- ( C ~12 ) I --( C H
A ( C~2 ) ~-- CH~ ~ 5 4. -(CBz)c-~, in which B i8 a pyrrolidinyl, piperi-dinyl or morpholinyl radical bonded via N, 5. -(CH2),-D-Ae, in which D- i8 pyridinium, pyri~i dinium or imidazolinium, (CH2)b CH3 (CH2)c N~--(ÇH2)d CH3 ~H2'~ CH3 in which, for the substituents described under 1.
to 6., a is an inte~er from 2 to 1~, b is zero, 1, 2 or 3, c is an integer from 2 to 6, d is an integer from 6 to 17 and A is a physiologically tolerated anion, R~ 1. is a cholic acid bonded via the 3-a-O~ or 24-COOH group dir~ctly or via a spacer, or 2. is a tauro- or glycocholic acid whi~h i~
bonded via the 3~-OH or tauro or glycofunction directly or via a spacer, F~ is a hydrophilic cyclic radical cr a slu~opyran-uronic ~cid radical, R3 is a crosslinking group chosen from the group - 6 - 21Q101~
comprlslng:
1. -(cH2)~
- CH2 - !H R4 2 (c~2 cH2)t - 2 - C- CH - CH2 -in which Z is oxygen or NH, 3.
I
O = C--O-- (CH2 --CH2-- )9-- C =~
4 . - ( CH2-CH2-O ) h-CH2-CH2- ~
O O O
5. W-(CH2)~-W, in which W is a -C-, -C-NH- or -C-O-group, O O
Il D
6. -C-O-(CH2-CH2-O)g-C- and OH OH
Variations in the preparations used to date, such as, for example, introduction of spacer~ between ammonium groups and the polymer main chain in the case of colestyramine (EP-A-0 404 062), do not leat to a decisive reduction in the disadvantages described.
The object of the present invention was to provide compounds having a different polymer ~tructure which bond bile acids to a high degree as a function of the concen-tration. The6e compounds moreover ~hould not have the existing di6advantages of the exchanger resins used to date or ~hould not have them to the same known extent.
The object i5 achieved and the deficiencies described are overcome with the highly water-absorbing polymers of the formula I and the highly pure polyvinylamines having the recurring unit of the formula Ia.
The invention therefore relates to polyvinylamines of the formula I.
_ 4 _ 2 1 ~ ~ o 1 1 ( CH2--IH--)~-(--CH2--IH--)X-(--CH2--CH~ CH2--f H--)z--~H2 NH NH NH
X R 2 1, ( I ) in which Rl is a substituent chosen ~rom the group compri~ing:
1. -(CH2)n-CH3, in which n is an integer from 3 to 21, ~ranched alkyl having 3 to 21 carbon atoms or straight-chain or branched alkenyl having up to 21 carbon atoms, 2. cycloalkyl or cycloalkenyl having in each ca~e 5-12 carbon atoms, or mono , di- or trisub6titu-ted cycloalkyl or cycloalkenyl having in each case 5-12 ring carbon atoms and 3. aryl, arylalkyl or arylalkenyl, in which the aryl radicals are mono- or polynsclear, can be mono-to trisubstituted and can contain heteroatoms, X is a single bond, a bridge group or a hydrophilic spacer for linking the radical Rl, R2 is RA-Y~ RB or F~, in which Y is a bri.d~e group or a spacer which allows RA to be linked to the polymer, R~ is a hydrophilic or amphiphilic substituent chosen from the group comprising:
~ (CH2)b-cH3 1. ~(CH2)a~N
\ ~CH2)b-CH3 - 5 ~
2.
(CH2)b CH3 (CH2)o N \ (CH2)b CH3 A~
(CH2)~- CH3 3.
(C~2)"--CH3 ---- ( C ~12 ) I --( C H
A ( C~2 ) ~-- CH~ ~ 5 4. -(CBz)c-~, in which B i8 a pyrrolidinyl, piperi-dinyl or morpholinyl radical bonded via N, 5. -(CH2),-D-Ae, in which D- i8 pyridinium, pyri~i dinium or imidazolinium, (CH2)b CH3 (CH2)c N~--(ÇH2)d CH3 ~H2'~ CH3 in which, for the substituents described under 1.
to 6., a is an inte~er from 2 to 1~, b is zero, 1, 2 or 3, c is an integer from 2 to 6, d is an integer from 6 to 17 and A is a physiologically tolerated anion, R~ 1. is a cholic acid bonded via the 3-a-O~ or 24-COOH group dir~ctly or via a spacer, or 2. is a tauro- or glycocholic acid whi~h i~
bonded via the 3~-OH or tauro or glycofunction directly or via a spacer, F~ is a hydrophilic cyclic radical cr a slu~opyran-uronic ~cid radical, R3 is a crosslinking group chosen from the group - 6 - 21Q101~
comprlslng:
1. -(cH2)~
- CH2 - !H R4 2 (c~2 cH2)t - 2 - C- CH - CH2 -in which Z is oxygen or NH, 3.
I
O = C--O-- (CH2 --CH2-- )9-- C =~
4 . - ( CH2-CH2-O ) h-CH2-CH2- ~
O O O
5. W-(CH2)~-W, in which W is a -C-, -C-NH- or -C-O-group, O O
Il D
6. -C-O-(CH2-CH2-O)g-C- and OH OH
7. -CH2-CH-(CH2)~-cH-cH2-in which, in the groups described undPr 1. to 7., e is an integer from 3 to 12, f is an integer from 1 to 6, g is an integer from 1 to 8, h is an integer from 1 to 7, k is an integer from 4 to 8 and - 7 - ~ ~0 1 0 R' is hydrogen or CH3, and in which w is 0.1 - 0.995, x is 0.0 - 0.8, y is 0.01 - 0.8 and Z i8 zero or 0.005 - 0.3, and w+x+y+z = 1, and physiologically tolerated salt6 thereof.
The invention furthermore relates to highly pure poly-vinylamines having the recurring unit of the formula la. ~
-(CH;~-CH)- Ia and physiologically tolerated salts thereof, obtainable by free radical polymerization of vinylformamide to give polyvinylformamide and subsequent hydrolysis.
Compounds of the formula I where n is zero are non-crosslinked and soluble, while the compounds where z is 0.005 to 0.3 are crosslinked and insoluble.
In the statements above and below:
aryl is a mono- or polynuclear aromatic hydrocarbon radical having 6 to 14 carbon atoms, the aryl groups in the case of polynuclear radicals being fu~ed with one another or bonded to on~ another via C-C bonds or via bridge members, such as -O-, -COO- or -CON~-.
The term aryl furthermore also includeæ 5- to 14-membered heteroaryl having 1 heteroatom or 2 non-adjacent, identi-cal or different heteroatoms chosen from the groupcomprising oxygen and nitrogen.
Aryl i6, in particular, phenyl, arylalkyl i~ benzyl or phenylethyl and aralalkenyl is CH- CH ~
Examples of aromatic radicals having 1 or 2 heteroatoms 2~ olall are radicals of quinolinecarboxylic, benzimidazole-carboxylic, furancarboxylic, nicotinic and coumarilic acid.
~ he cycloalkyl and cycloalkenyl radicals are optionally mono-, di- or trisubstituted by hydroxyl, (C,-C6)-alkyl and/or (Cl-C6)-alkoxy radicals, and in the case of poly-substitution, the 6ubstituents are identical or dif-ferent. Corresponding ~tatements also apply to the substituents on aryl; a possible radical is, for example, a triethylbenzoic acid radical~
O O O
Il ~ 11 The bridge member X is -C-, -C-NH- or -C-0-.
The hydrophilic 6pacer X i8 a radical of the formula O O
Il 11 Z--C ( CH2 ) ~ --C
where Z is oxygen or NH, and in which, in the case of 3-8 methylene groups, a central CH2 group can b~ replaced by oxygen, and in which the alkylene chain can be sub~ti-tuted by 1 to 4 hydroxyl groups, or a radical of the formula O O
Il 11 -- C CH CH --C
or o NH ~CH2)2-S C
Rl-X is, for example, a radical of the formula O O
C /\ O /\ C N H
o o o The bridge member Y i~ -C-, -C-NH- or -C-O-. The ~pacer Y is a radical of the formula O O
Il 11 C ( CH2 ), _,-- C
in which, in the case of 3-4 methylene group~, a central CH2 group can be replaced by oxygen.
An example of R2 as RB is the radical of the formula C (CH2)5--NH - C ~
HO OH
A hydrophilic cyclic radical RC is a cyclodextrin radical or a functionalized 7- to 18-membered carbon-containing azamacrocyclic radical having 2 to 4 nitrogen atoms and optionally 2, 3 or 4 oxygen atoms, which are 6eparated by ethylene group~, such as, for example, 1,4,7-triazacyclo-nonane, a cyclene or cyclam radical or 1,4-diaza-18 crown 6.
The polyvinylamines of the formula I where z i8 zero ~nd the highly pure polyvinylamines having the recurring unit of the formula Ia are linearO
As is customary in polymer chemistry, the molecular portions occurring w, x, y and z times shown in the formula I are randomly di6tributed over the entire polymer or can be concentrated in blocks on the basi~ of adjacent group effects, especially in the ca~e of hydro-phobic substituents.
The radical Rl is preferably hydrophobic.
If b occur6 more than once in a structure, b is identical or different. c, R4 and W are always identical in a structure. Highly pure polyvinylamine (PVAm) or PVAm salt is understood as meaning polymer3 having a molecular weight of 10,000 to 1,000,000 D which contain no residual monomers, no free initiator constituent6 and no cocompo-nents detectably in the polymer.
Vinylamine polymers and their preparation have already been described.
Crosslinked PVAm prepared from isopropyl N-vinylcarbamate have been described as an anion exchanger (Storck, W. and Manecke G., Makromol. Chem. 110, 207 (1967)).
.S. Patent 4,018,826 describes the preparation of polyvinylamine(PVAm) from polyvinylacetonitrile, and U.S.
Patent 4,943,676 describes partial thermolysis of poly-vinylformamide to give polyvinylamine. Copolymers ofvinylformamide and vinylamine prepared by polymerization of vinylformamide and subsequent partial hydrolysis are described in EP-B-0 071 050 and DE-A-40 07 310.
EP-A-0 262 577 describes a homopolymer of at least 10'6 D
MW (molecular weight), which "chiefly" compri~es poly-vinylamine units and was prepared by inverse emulsion polymerization.
EP-A-0 374 646 relates to the preparation of water-in-oil emulsions from polyvinylamine.
In accordance with the information in the abovementioned publications, polyvinylamines are suitable for industrial uses in the non-medical field, for example as flocculat-ing agent6 in papermaking, thickeners in tertiary ~rl~de oil production, additives for engine oils and as filter membranes.
- 11 210101~
Spanish Patent No. 2 006 782 describes the preparation of a specific ion exchanger from vinylamine, epichlorohydrin and chloroammonium-glycidine. This ion exchanger iB ~aid to have cholesterol-lowering properties. ~here is no information on its pharmacological action. With knowledge of the publications by ~.A~ Augurt in Encyclopedia of Polymer Science and Technology, Vol. 14; Wiley & Sons, NY, 1971, page 251; P. Ferruti et al., Adv. Polym. Sci, 58, 55 - 92 (1984) and Bayer E. et al. Makromol. Chem.
181, 585 (1980), however, the synthesis could not be reconstructed.
The dissertation by Thomas Fischer (Marburg 1992) relates to bile acid adsorbers ba ed on aliphatic polyamines. The polyvinylamines described are ~ree from additional hydrophilic centers.
Finally, U.S. Patent 4,362,711 describes vesicles of a polymer matrix filled with a solution, which can contain polyvinylamine hydrochloride as a constituent, as a bile acid sequestrant without mentioning the activity.
It has now been found that the introduction of additional hydrophilic centers in particular leads to compounds having a good action.
On the basis of the known prior art, PVAm is obtained by polymerization of vinylformamide with subsequent hydroly-sis to give polyvinylamine, and if appropriate a polymer-analogous reaction. To avoid intolerances on the basis of possibly toxic, low molecular weight constituents, ~uch as residues of initiator and monomers, antioxidants, regulators and by-products, it is necessary for u~e in the medicaments sector for these to be removed from the polymer without trace, which under certain circumstances is very expensive or cannot be carried out at all in practice.
A route has now been found for preparing the base polymer - 12 ~ 2 1 0 1 0 1 1 having the recurring unit of the formula Ia in a highly pure form. An essential prerequisite for the use of the compounds in the pharmaceuticals sector is therefore met.
The invention therefore also relates to a process for the preparation of highly pure polyvinylamines having the recurring unit of the formula Ia, which comprises prepar-ing polyvinylformamide (homopolymer) by free radical polymerization of vinylformamide and sub~equently hydrolyzing the product, highly pure polyvinylamine being formed. The polyvinylformamide intermediately formed is expediently subjected to purification by ultrafiltration and freeze drying before the hydrolysis.
The invention furthermore relates to a process for the preparation of polyvinylamines of the formula I, which comprises introducing the functional groups Rl-X, R2 and/or R3 into polyvinylamines having the recurring unit of the formula I by methods customary in polymer chemistry.
The highly pure PVAm having the recurring unit of the formula Ia prepared by the process according to the invention is preferably employed in the above process.
Compounds of the formula I comprise, individually or in combination, the following structural elements: polymer main chain, hydrophilic, cationic, amphiphilic and hydrophobic substituents and croæslinking group. The compounds are synthesized by polymer-analogous reactions, preferably on PVAm of the formula Ia prepared according to the invention. For this, the hydrochloride salt or the free base form of the polymer iB alkylated, acylated, substituted by addition of the Michael type or on i~ocy-anates or reacted with epoxide~.
PVAm is partly alkylated by customary methods using agents of the formula R-M, in which ~ iB chlorine, bromine, iodine, CH3-SO2-O or tosyl and R is such that polymer~ as described in formula I are formed, in water 21~1011 or in a mixture with a water-miscible orqanic solvent, such as dioxane, DMF, formamide and the like, in a homogeneous phase or as a phase boundary reaction with phase transfer agents, such as sodium dodecyl sulfate or cetyltrimethylammonium bromide, with or without addition of auxiliary ba~e~, such as NaO~, ROH, triethylamine or pyridine. Analogously, PVAm can be reacted by acylation with the corresponding acid chlorides, bromide~ or anhydrides. Acylation with active ester~ ~uch as para-nitrophenyl-carboxylic acid ester~ i8 particularly succes~ful in methanolO
Compounds containing suitable functional groups, such as, for example, benzyl chloride, bromomethylbenzene, cinnamic and hydroxycinnamic acid, naphthylacetic acid, N-(~-bromohexyl)carbazole, furancarboxylic acid and nicotinic acid, can be used to prepare polyvinylamine derivatives having aromatic substituents.
Medium- to long-chain n-alkyl and branched and cyclic alkyl and alkenyl halides, mesylates and tosylate6 are employed, for example, for introduction of ~ubstituent~
Rl, which preferably have a hydrophobic character, by alkylation. Butyl, hexyl, dodecyl and hexadecyl bromides are preferred. Hexanoyl, decanoyl, lauroyl, stearoyl chloride are u~ed for the acylation. The hydrophobic radical R' can be detached from the polymer main chain by hydrophilic spacer~ X - preferably by u3ing Buccinic or diglycolic anhydride.
Halides of alkyl- or hydroxyalkylamines and corresponding ammonium salts, such as, for example, the hydrochlorides of dimethylaminoethyl chloride, dimethylaminopropyl chloride, diethylamino-ethyl, -propyl and -hexyl chloride and bromopropylpyridinium chloride, are preferably used for introduction of hydrophilic substituent~ R2.
If an anion Ae occurs in R2, thi6 is a physiologically tolerated anion, such as Cl-, 8r~, ~C03~ malonate, citrate, ascorbate and the like, preferably Cl-.
2l~lall ~-Bromododecyltriethylammonium chloride and ~-mesylethyl-dimethyldodecylammonium chloride are preferably used for introduction of amphiphilic substituents R2, B0 that optionally either the ammonium center or the hydrophobic alkyl part i9 linked directly to the polymer main chain.
To utilize a template effect, bile acids are linked to PVAm derivatives directly or via a spacer.
Substitution for the derivatives prepared in a polymer-analogous manner is effected with up to 80~, preferably 5-40%, per radical R' or R'X, and for R2 with 1-80%, preferably 5-40%, but not more than 90% in total, 80 that at least 10% of the amino groups of the PVAm are present in the free form or partly as the physiologically tole-rated salt.
~oth hydrophilic and hydrophobic linking agents are employed as crosslinking agents, ~uch a , for example, dibromohexane, dibromopropane, diepoxypropyl ether, epichlorohydrin, adipic acid dichloride, triethylene glycol ditosylate and ethyldiacrylamide.
The degree of crosslinking varies from 0.5 to 30%, preferably from 3 to 15%. The degree of ~welling in water can be adjusted from 2 ml/g to 1 l/g by the extent of crosslinking. A degree of cros~linking of 10-300 ml/g, in particular 50-200 ml/g, is particularly preferred.
The soft gel polymers are worked up by direct and inver6e precipitation with a precipitating agent~ preferably acetone, and by ultrafiltration and freeze drying.
The base polymer PVAm is used as the starting material for preparation of the functional polymers of the formula I, it being necessary for this base polymer to meet the prerequisites for medical use. PVAm i8 therefore prepared by the process according to the invention, which allows a homopolyvinylamine, which contains no further cocompo-nents in polymer and i8 free from low molecular weight 2 1. ~
impurities, to be obtained.
For this, for example, vinylformA~;de is polymerized in 14% strength aqueous solution with 0.5 mol% of the free radical initiator 4,4'-azocyanopentanoic acid (ACPA) at 70C for 8 hours. A polyvinylformamide having a viscosity of 1.74 dl/g is obtained with a conversion of 99.8%. Thi~
polymer is purified by ultrafiltration (10,000 D mem-brane) such that residual monomer or free initiator constituents are no lonqer detectable (less than 1 ppb in 1~ strength solution).
Conditions: membrane cassettes with exclusion limit of 10,000 D MM, Minisette from Filtron, for example once with 3xlOl of H20/100 g of polymer and once with 3xlOl of H20/20 g of polymer.
The amounts of water required can be purified, if neces-sary by active charcoal, and used several times.
Determination of vinylformamide by means of ~PLC:
Column: ~LiChrosorb Si 60 (5 ~m) Flow rate: 0.55 ml/minute 20 Pressure: 360 psi Detector: W, 225 nm Retention time: 7.2 minutes.
Before the determination of vinylformamide in the poly-vinylformamide, the polymer solution is pas~ed over a purified preliminary column (silica gel 60)~ Calibration solutions are treated in an identical manner to the polymer solution.
For the HPLC elution diagram see Figure 1 (PVAm according to Example 1).
For the calibration for the HPLC determination of vinyl-formamide, see Figure 2.
A polymer of viscosity 2.48 dl/g is obtained with 0.25 mol% of ACPA, while a viscosity of 0.31 dl/g is 2~ 01011 reached by precipitation polymerization in isopropanol.
The molecular weight can be adjusted by the customary method (choice of the parameters of initiator and monomer concentration and temperature).
Polyvinylformamide of very high molecular weight (~1,000,000 D) was prepared and hydrolyzed to PVAm, but this has a weaker action in respect of bile acid adsorp-tion than derivatives of low molecular weight (for example 75,000 D). It has been found that in the case of pure PVAm, PV~m derivatives and crosslinked secondary products thereof, in each case the preparations having a lower MW of the starting polymer have better bile acid adsorption values than those of high molecular weight.
The compounds prepared from a btarting polymer with a molecular weight which is not too high (less than 1,000,000, for example 10,000 to 500,000 D) are therefore preferred.
To prepare PVAm which is free from ~ocomponents, 1/3 the volume (v/v) of a strong acid, for example concentrated HCl, is added to the aqueouæ polyvinylformamide solution and the mixture is heated under reflux for 2 hours.
Thereafter, about 2/3 the volume (v/v) of acid are added over a period of 6 hours, while heating, such that the polymer remains dissolved. Only after the hydrolysis does PVAm precipitate on cooling, BO that it can be separated off from the reaction solution. Formic acid and the excess hydrochloride are removed by ultrafiltration.
Another possibility for the preparation of insoluble PVAm formulations is ionic complexing of the amino-containing polymers with di-, tri- and tetraacids and oligo- and polyacids to give polyelectrolyte complexes (PEC). For this, a dilute solution of the acid is usually initially introduced into the reaction vessel and the solution of the polybase is added dropwise such that fine gel drop-lets which can be eeparated are formed.
The invention furthermore relates to bile acid ad~orbents of the formula I and bile acid adsorbents having the recurring unit of the formula Ia, which, if appropriate in the form of salts, are particularly ~uitable for treatment of ca6es of hyperlipidemia, and to the preparation of 6uch medicaments.
To prepare highly active bile acid ad~orbents, compounds of the general formula I and highly pure PVAm having the recurring unit of the formula Ia which, compared with the adsorbents used at preæent, have a higher bonding capa-city were synthesized using a) polymers having recurring units of low molecular weight, b) more effective ion exchanger groups and c) formulations having a large active surface area.
An improved selectivity can be achieved by utilizing either electrostatic or hydrophobic interactions as well as specific network structures.
The usual dosage of the bile acid adsorbers used to date for treatment of hypercholesterolemia can be reduced considerably by using the vinyl polymers. The problem of dosage and compliance thereby arise to a lesser extent.
In addition, compliance is also improved by the fact that the compounds have a soft gel character and are of neutral taste and Bmell ~ BO that no taste and smell compensators are required.
The effectiveness of the active compounds descri~ed can be increased by specific microformulations. For this, the compounds are converted into microparticles by means of various techniques. In the ca~e of soluble compounds, this is possible by ~pray drying, freeze drying and emulsion processes. Soluble and insoluble compounds can also be micronized mechanically. The microparticles are distinguished by the fact that the active compound i6 substituted over a very large adsorptive surface area.
21~1011 Crosslinked microparticles can thus be prepared from the compounds of the formula I inter alia, by spraying a 4%
strength aqueous solution of basic PVAm or non-cross-linked derivatives thereof at 170C. The nano- and microparticles obtained are ~uspended in isopropanol or dichloroethane with 0.3 - 0.5% of dibromohexane and the suspension îs incubated at 70 - 80C for 8 hours. The particles are insoluble in water, but swell, their diameter increasing 1%- to 5-fold.
One advantage of the compounds of the formula I and the PVAm having the recurring unit of the formula Ia is that film-coated tablets can be prepared very easily from these compounds. In vitro, these exhibit the same acti-vity as the compounds in powder form. Per 250 mg of active compound, for example, they comprise only 40 mg of pharmaceutically customary auxiliaries.
The reduction in serum cholesterol level to be achieved with the compounds can be improved further by ~imulta-neous use of other lipid-lowering agents which do not have a systemic action or have a systemic action (for example HMG-CoA reductase inhibitors) in the context of a combination therapy.
Since the compounds acccrding to the invention interrupt the enterohepatic circulation, they are suitable as an antidote in the event of oral toxification.
The compounds of the formula I where z e 0.005 to 0.3 furthermore can be employed as ~atiation promoters because of their water uptake capacity.
Since the compounds of the formula I according to the invention and PVAm having the recurring unit la are readily swellable and bond acids, they can be employed as antacids for the treatment of excessive production of gastric acid, and can therefore be u ed as agents against gastritis and ulcus ventriculi or duodeni.
;
- 19 - 21Ql~ll On the basis of their interaction with cholesterol, the compounds are capable of adsorbing the chole~terol consumed with food. The content of cholesterol in food i8 therefore bonded immediately and i6 not adsorbed by the body.
The compounds of the formula I are furthermore also suitable as foodstuff auxiliaries. Thus, for example, cholesterol is adsorbed from milk or egg constituents.
The resulting foodstuffs are distinguished by a reduced cholesterol content.
Compounds of the formula I or highly pure PVAm having the recurring unit of the formula Ia are suitable as muco-adhesive transportation systems for active compounds.
They form highly hydratable polymer matricee which have groups which form hydrogen bridges and cationic group~, display a high flexibility of the polymer chain and can be additionally substituted by hydrophobic unit~. The compounds are therefore capable of increasing the resi-dence time of a bonded or adsorbed active compound in the stomach or small intestine. They are adsorbed as active compound carriers onto the mucosal layer of the gastro-intestinal wall, the positively charged groups of the polymers interacting with the negatively charged groups of the terminal sialic acid of the mucin molecules in order thus to cause delayed transportation of the active compounds through the gastrointestinal tract. At the same time, the absorption of the active compound i8 improved by the nature of the interaction.
In vitro test The bonding capacity and selectivity are tested in an in vitro test. A bovine bile assay is used here. For this, 5 mg of polymer sample are dissolved in 2 ml of test solution and the solution i8 incubated at 37C for 24 hours. The test solution comprises bovine bile, diluted 1:10 with PBS buffer, p~ 6.5. Evaluation is ~y - 20 - ~ 1 0 10 means of thin-layer chromatography and HPLC. Cuemid i~
used as the reference. The results are ~ummarized in Table l.
Table 1: ~ile acid adsorption in vitro (bovine bile assay) ~xample Bile aoid adsorption (%) Taurocholate Glycocholate _ 69 - - 68- ~ -15 r , T~
I .
I .
Cole6tyramine 38 24 . I
In vivo test The action of four preparations in respect of a reduction in serum cholesterol level was tested on rabbit~ fed with cholesterol.
For this, after a preliminary feeding period (to raise the cholesterol level) the cholesterol level was 2~010~ 1 determined (initial value). 2~ strength cholesterol-containing food and the preparations in concentrations of 12.5 - 50 mg/kg (or 100 - 500 mg for cole6tyramine~ were fed to randomized test groups of 5 animals each for 4 weeks. The change in serum cholePterol compared with the initial value i8 shown for each preparation and for colestyramine as the compari~on substance in Table 2.
Table 2: Change in the total cholesterol of rabbits fed with 0.2% of cholesterol Preparations Dosage Change in serum choleRterol com-pared with the initial value .
Control ~Tylose 1% ~ 4 mmol/l . .
Example 5 50 mg/kg -2.5 mmol/l . . _ .
Example 6 50 mg/kg -1 mmol/l Example 7 50 mg/kg +0.5 mmol/l l . I
Example 8 50 mg/kg -0.4 mmol/l . , . .
Colestyramine 500 mg/kg -0.3 mmol/l Example 1 Vinylamine homopolymer for pharmaceutical quality MW: - 380,000 D
1.8 1 of deionized water are heated to 60C, degassed and fluæhed with N2. 300 g of vinylformamide, 3 ml of concen-trated NH~OH and 6 g of ACPA are added, and the entire mixture i6 stirred at 70C for 8 hours. The monomer conversion is monitored by I2 titration, and is 99.8%
after 8 hours.
The 601ution i6 diluted 4 tLme6 with water to in each ca~e 20 1 and concentrated in each ca~e 4 times to 2.5 1 21010~ 1 by means of ultrafiltration (5xlO X Minisette from Filtron), and then freeze dried. A purely white product having a residual monomer content of 1.4 ppm is obtained.
50 g of the polymer are dissolved in water again, the ~olution i6 diluted to 10 1 and ultrafiltered 4 tLmes and the product iB then freeze dried.
The residual monomer conten~ ic below the detection limit of the ~PLC method (< 0.1 ppm) and GC-MS.
Viscosity [~] in 0.5% ~trength NaCl: 1.74 dl/g.
100 g of polyvinylformamide are dissolved in 800 ml of H20, 270 ml of concentrated ~Cl are added and the mixture is heated under reflux for 2 hour~. 270 ml of concentra-ted HCl are added. The mixture i5 heated under reflux for 4 hours and, after addition of a further 270 ml of concentrated ~Cl, i5 heated at 60C for 2 hours. The hydrochloric acid i8 decanted off at room temperature, the polymer i~ dissQlved in H20 and the pH is brought to 4 with NaO~. The product i8 ultrafiltered 4 times with in each case 20 1 and then freeze dried. According to 1~_300 MHz-NMR, the polymer no longer contains formamide groups (no peak between 8 and 8.5 ppm), i.e. the content is below the detection 1- it (c0.05%).
The free base form of the PVAm can be obtained from the above polymer using alkali metal hydroxide solution and 6ubsequent dialysis and freeze drying by using ion exchanger resins.
Example 2 Vinylamine homopolymer for pharmaceutical quality MW: - 75,000 D
100 g of vinylformamide, 0.5 ml of concentrated N~3 and 1.5 g of ACPA are added to 500 ml isopropanol. The mixture is 6tirred at Ç5C for 6 hours. The polymer is filtered off with suction, dried in vacuo, dissolved in 2101 0~1 water and ultrafiltered as described in Example 1.
50 g of polyvinylformamide are dissolved in 400 ml of H2O, and concentrated NaO~ ~olution (83 g) are added at 50C such that the polymer does not precipitate. The mixture is stirred at 70C for 7 hours. The polymer i8 precipitated in acetone, dissolved in water and further purified by ultrafiltration and freeze drying as described in Example 1.
Example 3 0.165 g of PVAm (75,000 D from Example 2) are dissolved in 3 ml of methanol, and 0.4 g of cholic acid ~-~;doca-proic acid p-nitrophenyl ester in 10 ml of dimethyl sulfoxide is added. Three drop~ of triethylamine are added and the mixture iB stirred at room temper~ture for 1 hour. The product i8 precipitated in ethyl acetate and dissolved in methanol/H2O, the pH is ~rought to 4 and the product is precipitated again in ethyl acetate. The polymer is filtered off with suction and dried in vacuo.
Yield: 310 mg Degree of substitution; 12%
Example 4 2 g of PVAm (Example 1, basic form) are dissolved in 80 ml of H20, 4.5 g of 6-bromohexylpyrimidinium bromide and 560-mg of NaOH are added, and the mixture iB ~tirred at 90C for 9 hours.
For working up, the batch iB acidified with lN HCl (p~ 1) and precipitated inversely with acetone. The product is dissolved in H2O, the ~olution i~ titrated with NaO~ to pH 4 and the product i8 precipitated again with acetone.
After a further precipitation in acetone, the resulting product is freeze dried from H2O.
Yield: 4 g - 24 - 2~Q1011 Example 5 360 g of PVAm x HCl (24% of Cl) are dissolved in 5 1 of H20. After the pH has been brought to 10, 323 g of 6-bromohexylpyridinium bromide and 72 g of NaO~ are added. The mixture is ~tirred under N2 at 90C for 10 hours. Thereafter, it i~ neutralized with hydrochloric acid and ultrafiltered with 30 1 of R20 (cut off:
10,000 D).
Degree of substitution according to NMR: 15.7%.
The batch (4 1) is brought to pH 10 with NaO~, and 69 g of 1,6-dibromohexane and 22 g of NaOH are added. The mixture is heated to 90C under N2, with very rapid stirring. After about 1~ hours, gel formation ~tarts. The mixture is stirred at 90C for a further 4~2 hours. For working up, the batch is acidified with 2 1 of 2 N
hydrochloric acid and the product i8 precipitated in-versely with 10 1 of acetone. The bromide/chloride exchange is carried out by swelling the polymer in 2 N
hydrochloric acid. Thereafter, the product is again precipitated inversely with acetone and taken up in 8 1 of H20, and the pH is brought to 5 with dilute sodium hydroxide solution. After precipitation in acetone, the product i6 dried in vacuo at 50C.
Yield: 460 g.
Example 6 140 g of PVAm x HCl are dissolved in 4 1 of H20 and the pH is brought to 11 with NaOH. After addition of 3~ g of dimethylaminoethyl chloride hydrochloride and 18 g of NaOH, the mixture is stirred under N2 at 35C for 9 hours.
The pH is brought to 1 with hydrochloric acid and the batch is precipitated with acetone. The product is dissolved in H20, the p~ is brought to 5 and the product is ultrafiltered and freeze dried.
Degree of substitution: 6%
Yield: 150 g.
Example 7 110 g of PVAm from Example 1 are dissolved in 4 1 Of ~2~
and 36.8 g of dimethylaminoethyl chloride hydrochloride and 25.6 g of NaOH (in 200 ml of H20) are added. The mixture is heated at 90C for 9 hours. 80 g of dibromo-hexans are added, while stirring rapidly. ~ter 2 hours, the solution changes into a gel. The temperature i8 kept at 85-90C for 9 hours. The batch i8 diluted with 3 parts of acetone (v/v) and the gel is extracted. The ~olution is decanted off and the residue i~ extracted by stirring in further acetone. The product iB ~wollen in water/ethanol, the p~ i8 initially brought to 1, and the polymer is precipitated with acetone and 3wollen again in water at pH 4. After a ~urther precipitation with acetone, the product is finally dried in vacuo at 50C.
Example 8 100 g of PVAm x HCl are dissolved in 2.5 1 of H20 and the pH is brought to 11 with NaO~. After addition of 87 g of (3-bromopropyl)-trimethylammonium chloride and 27 g of NaOH, the mixture ic boiled under reflux under N2 for 17 hours. Working up is carried out analogously to Exampl~
6 by acidification, precipitation in acetone and ultrafiltration.
Degree of substitution: 20%.
Yield: 99 g.
Example 9 a, b, c, d, e, f 2 g of PVAm x HCl (33 mmol) are initially introduced into 70 ml of H20 and the pH is brought to 10 with 10 ml of sodium hydroxide solution. In 6 batches (a - f), 0.2~ g;
0.64 g; 1.28 g; 1.92 g; 2.56 g and 3.19 g of 12-bromodo-decyltrimethylaDmonium bromide are dissolved in 10 ml of - 26 - 2 1 0 1 ~ ~ 1 H20 with 1.1 times the particular molar amount of NaOH, and the solution~ are added dropwi~e. The batches are stirred at 80C for 7 hours. Batches a, b and c are worked up analogously to Example 4; for working up batches d, e and f, these are freeze dried. The product is taken up in methanol/H20 and precipitated in acetone/diisopropyl ether 3:2. The precipitation is repeated at pH 1 and pH 4. The batche~ are freeze dried from H20.
10 9a~ Degree of sub6titution:2~
Yield: 58%
b) Degree of 6ubstitution: 5%
Yield: 54%
c) Degree of substitution: 8%
Yield: 40%
d) Degree of substitution: 12%
Yield: 88%
e) Degree of substitution: 19%
Yield: 85%
f) Degree of substitution: 25%
Yield: 91%
Example 10 10 ml of an aqueous solution of polyacrylic acid (Polyscience, 450 kD) are initially introduced into the reaction vessel in a concentration of 1 mg/ml. 10 ml of the compound from Example 1 are added dropwi~e in a concentration of 1 mg/ml by means of a cannula (diameter O.6 mm). A gel is formed, which is freeze dried; accord-ing to analysis, the gel comprises 50% of the polybase of Example 1.
Example 11 1 g of PVAm (Example 1, ~alt-free form) i8 di~solved in 40 ml of H20, 588 mg of benzyl chloride are added and the mixture is stirred at 90C for 8 hours. After addition of - 27 - 2101~11 2.25 ~ of 6-bromohexylpyridinium bromide and 470 mg of NaOH, the mixture is stirred at 90C for 8 hours. Working Up i8 carried out analogously to Example 4.
Degree of substitution: 18% benzyl, 28% hexylpyridinium Yield: 0.76 g Example 12 1 g of PVAm (Example 1, salt-free form) is dissolved in 40 ml Of ~2~ 588 mg of benzyl chloride are added and the mixture is stirred at 90C for 8 hours. After addition of 1.96 g of 3-bromopropylpyridinium bromide and 470 mg of NaOH, the mixture is 3tirred at 90C for B hours. For working up, 23 ml of the solution are treated as described in Example 4.
Substitution: 18~ benzyl, 8% propylpyridinium 1/2 yield: 0.66 g Example 13 430 mg of dibromohexane and 150 mg of NaOH are added to 23 ml of the reaction solution from Example 12 and the mixture is stirred at 90C for 8 hour~. Working up is ~arried out analogously to Example 7.
Yield: 0.96 g Example 14 1.35 g of trimethyldodecylammonium chloride-substituted PVAm - 0.25 (obtained a~ the free amine from Example 9f by means of the ion exchanger Amberlite 400) are di~-solved in 60 ml of ethanol/~20 1:1, and 1.8 g of p-nitro-phenyl caproate in 20 ml of ethanol are added. The mixture is stirred at room temperature for 2 hour~ and at 40C for ~ hour. The p~ i8 brought to 6 with hydrochloric acid, the ethanol is evaporated off in a rotary evapora-tor and the aqueous phase is freeze dried. The polymer is precipitated in ether from ethanol/isopropanol 1:1, dissolved in B20~ dialyzed (cutoff: 15,000) and freeze ~ 28 - 2 ~ ~ 1 0 :L ~
dried .
Yield: 1 . 5 g.
The invention furthermore relates to highly pure poly-vinylamines having the recurring unit of the formula la. ~
-(CH;~-CH)- Ia and physiologically tolerated salts thereof, obtainable by free radical polymerization of vinylformamide to give polyvinylformamide and subsequent hydrolysis.
Compounds of the formula I where n is zero are non-crosslinked and soluble, while the compounds where z is 0.005 to 0.3 are crosslinked and insoluble.
In the statements above and below:
aryl is a mono- or polynuclear aromatic hydrocarbon radical having 6 to 14 carbon atoms, the aryl groups in the case of polynuclear radicals being fu~ed with one another or bonded to on~ another via C-C bonds or via bridge members, such as -O-, -COO- or -CON~-.
The term aryl furthermore also includeæ 5- to 14-membered heteroaryl having 1 heteroatom or 2 non-adjacent, identi-cal or different heteroatoms chosen from the groupcomprising oxygen and nitrogen.
Aryl i6, in particular, phenyl, arylalkyl i~ benzyl or phenylethyl and aralalkenyl is CH- CH ~
Examples of aromatic radicals having 1 or 2 heteroatoms 2~ olall are radicals of quinolinecarboxylic, benzimidazole-carboxylic, furancarboxylic, nicotinic and coumarilic acid.
~ he cycloalkyl and cycloalkenyl radicals are optionally mono-, di- or trisubstituted by hydroxyl, (C,-C6)-alkyl and/or (Cl-C6)-alkoxy radicals, and in the case of poly-substitution, the 6ubstituents are identical or dif-ferent. Corresponding ~tatements also apply to the substituents on aryl; a possible radical is, for example, a triethylbenzoic acid radical~
O O O
Il ~ 11 The bridge member X is -C-, -C-NH- or -C-0-.
The hydrophilic 6pacer X i8 a radical of the formula O O
Il 11 Z--C ( CH2 ) ~ --C
where Z is oxygen or NH, and in which, in the case of 3-8 methylene groups, a central CH2 group can b~ replaced by oxygen, and in which the alkylene chain can be sub~ti-tuted by 1 to 4 hydroxyl groups, or a radical of the formula O O
Il 11 -- C CH CH --C
or o NH ~CH2)2-S C
Rl-X is, for example, a radical of the formula O O
C /\ O /\ C N H
o o o The bridge member Y i~ -C-, -C-NH- or -C-O-. The ~pacer Y is a radical of the formula O O
Il 11 C ( CH2 ), _,-- C
in which, in the case of 3-4 methylene group~, a central CH2 group can be replaced by oxygen.
An example of R2 as RB is the radical of the formula C (CH2)5--NH - C ~
HO OH
A hydrophilic cyclic radical RC is a cyclodextrin radical or a functionalized 7- to 18-membered carbon-containing azamacrocyclic radical having 2 to 4 nitrogen atoms and optionally 2, 3 or 4 oxygen atoms, which are 6eparated by ethylene group~, such as, for example, 1,4,7-triazacyclo-nonane, a cyclene or cyclam radical or 1,4-diaza-18 crown 6.
The polyvinylamines of the formula I where z i8 zero ~nd the highly pure polyvinylamines having the recurring unit of the formula Ia are linearO
As is customary in polymer chemistry, the molecular portions occurring w, x, y and z times shown in the formula I are randomly di6tributed over the entire polymer or can be concentrated in blocks on the basi~ of adjacent group effects, especially in the ca~e of hydro-phobic substituents.
The radical Rl is preferably hydrophobic.
If b occur6 more than once in a structure, b is identical or different. c, R4 and W are always identical in a structure. Highly pure polyvinylamine (PVAm) or PVAm salt is understood as meaning polymer3 having a molecular weight of 10,000 to 1,000,000 D which contain no residual monomers, no free initiator constituent6 and no cocompo-nents detectably in the polymer.
Vinylamine polymers and their preparation have already been described.
Crosslinked PVAm prepared from isopropyl N-vinylcarbamate have been described as an anion exchanger (Storck, W. and Manecke G., Makromol. Chem. 110, 207 (1967)).
.S. Patent 4,018,826 describes the preparation of polyvinylamine(PVAm) from polyvinylacetonitrile, and U.S.
Patent 4,943,676 describes partial thermolysis of poly-vinylformamide to give polyvinylamine. Copolymers ofvinylformamide and vinylamine prepared by polymerization of vinylformamide and subsequent partial hydrolysis are described in EP-B-0 071 050 and DE-A-40 07 310.
EP-A-0 262 577 describes a homopolymer of at least 10'6 D
MW (molecular weight), which "chiefly" compri~es poly-vinylamine units and was prepared by inverse emulsion polymerization.
EP-A-0 374 646 relates to the preparation of water-in-oil emulsions from polyvinylamine.
In accordance with the information in the abovementioned publications, polyvinylamines are suitable for industrial uses in the non-medical field, for example as flocculat-ing agent6 in papermaking, thickeners in tertiary ~rl~de oil production, additives for engine oils and as filter membranes.
- 11 210101~
Spanish Patent No. 2 006 782 describes the preparation of a specific ion exchanger from vinylamine, epichlorohydrin and chloroammonium-glycidine. This ion exchanger iB ~aid to have cholesterol-lowering properties. ~here is no information on its pharmacological action. With knowledge of the publications by ~.A~ Augurt in Encyclopedia of Polymer Science and Technology, Vol. 14; Wiley & Sons, NY, 1971, page 251; P. Ferruti et al., Adv. Polym. Sci, 58, 55 - 92 (1984) and Bayer E. et al. Makromol. Chem.
181, 585 (1980), however, the synthesis could not be reconstructed.
The dissertation by Thomas Fischer (Marburg 1992) relates to bile acid adsorbers ba ed on aliphatic polyamines. The polyvinylamines described are ~ree from additional hydrophilic centers.
Finally, U.S. Patent 4,362,711 describes vesicles of a polymer matrix filled with a solution, which can contain polyvinylamine hydrochloride as a constituent, as a bile acid sequestrant without mentioning the activity.
It has now been found that the introduction of additional hydrophilic centers in particular leads to compounds having a good action.
On the basis of the known prior art, PVAm is obtained by polymerization of vinylformamide with subsequent hydroly-sis to give polyvinylamine, and if appropriate a polymer-analogous reaction. To avoid intolerances on the basis of possibly toxic, low molecular weight constituents, ~uch as residues of initiator and monomers, antioxidants, regulators and by-products, it is necessary for u~e in the medicaments sector for these to be removed from the polymer without trace, which under certain circumstances is very expensive or cannot be carried out at all in practice.
A route has now been found for preparing the base polymer - 12 ~ 2 1 0 1 0 1 1 having the recurring unit of the formula Ia in a highly pure form. An essential prerequisite for the use of the compounds in the pharmaceuticals sector is therefore met.
The invention therefore also relates to a process for the preparation of highly pure polyvinylamines having the recurring unit of the formula Ia, which comprises prepar-ing polyvinylformamide (homopolymer) by free radical polymerization of vinylformamide and sub~equently hydrolyzing the product, highly pure polyvinylamine being formed. The polyvinylformamide intermediately formed is expediently subjected to purification by ultrafiltration and freeze drying before the hydrolysis.
The invention furthermore relates to a process for the preparation of polyvinylamines of the formula I, which comprises introducing the functional groups Rl-X, R2 and/or R3 into polyvinylamines having the recurring unit of the formula I by methods customary in polymer chemistry.
The highly pure PVAm having the recurring unit of the formula Ia prepared by the process according to the invention is preferably employed in the above process.
Compounds of the formula I comprise, individually or in combination, the following structural elements: polymer main chain, hydrophilic, cationic, amphiphilic and hydrophobic substituents and croæslinking group. The compounds are synthesized by polymer-analogous reactions, preferably on PVAm of the formula Ia prepared according to the invention. For this, the hydrochloride salt or the free base form of the polymer iB alkylated, acylated, substituted by addition of the Michael type or on i~ocy-anates or reacted with epoxide~.
PVAm is partly alkylated by customary methods using agents of the formula R-M, in which ~ iB chlorine, bromine, iodine, CH3-SO2-O or tosyl and R is such that polymer~ as described in formula I are formed, in water 21~1011 or in a mixture with a water-miscible orqanic solvent, such as dioxane, DMF, formamide and the like, in a homogeneous phase or as a phase boundary reaction with phase transfer agents, such as sodium dodecyl sulfate or cetyltrimethylammonium bromide, with or without addition of auxiliary ba~e~, such as NaO~, ROH, triethylamine or pyridine. Analogously, PVAm can be reacted by acylation with the corresponding acid chlorides, bromide~ or anhydrides. Acylation with active ester~ ~uch as para-nitrophenyl-carboxylic acid ester~ i8 particularly succes~ful in methanolO
Compounds containing suitable functional groups, such as, for example, benzyl chloride, bromomethylbenzene, cinnamic and hydroxycinnamic acid, naphthylacetic acid, N-(~-bromohexyl)carbazole, furancarboxylic acid and nicotinic acid, can be used to prepare polyvinylamine derivatives having aromatic substituents.
Medium- to long-chain n-alkyl and branched and cyclic alkyl and alkenyl halides, mesylates and tosylate6 are employed, for example, for introduction of ~ubstituent~
Rl, which preferably have a hydrophobic character, by alkylation. Butyl, hexyl, dodecyl and hexadecyl bromides are preferred. Hexanoyl, decanoyl, lauroyl, stearoyl chloride are u~ed for the acylation. The hydrophobic radical R' can be detached from the polymer main chain by hydrophilic spacer~ X - preferably by u3ing Buccinic or diglycolic anhydride.
Halides of alkyl- or hydroxyalkylamines and corresponding ammonium salts, such as, for example, the hydrochlorides of dimethylaminoethyl chloride, dimethylaminopropyl chloride, diethylamino-ethyl, -propyl and -hexyl chloride and bromopropylpyridinium chloride, are preferably used for introduction of hydrophilic substituent~ R2.
If an anion Ae occurs in R2, thi6 is a physiologically tolerated anion, such as Cl-, 8r~, ~C03~ malonate, citrate, ascorbate and the like, preferably Cl-.
2l~lall ~-Bromododecyltriethylammonium chloride and ~-mesylethyl-dimethyldodecylammonium chloride are preferably used for introduction of amphiphilic substituents R2, B0 that optionally either the ammonium center or the hydrophobic alkyl part i9 linked directly to the polymer main chain.
To utilize a template effect, bile acids are linked to PVAm derivatives directly or via a spacer.
Substitution for the derivatives prepared in a polymer-analogous manner is effected with up to 80~, preferably 5-40%, per radical R' or R'X, and for R2 with 1-80%, preferably 5-40%, but not more than 90% in total, 80 that at least 10% of the amino groups of the PVAm are present in the free form or partly as the physiologically tole-rated salt.
~oth hydrophilic and hydrophobic linking agents are employed as crosslinking agents, ~uch a , for example, dibromohexane, dibromopropane, diepoxypropyl ether, epichlorohydrin, adipic acid dichloride, triethylene glycol ditosylate and ethyldiacrylamide.
The degree of crosslinking varies from 0.5 to 30%, preferably from 3 to 15%. The degree of ~welling in water can be adjusted from 2 ml/g to 1 l/g by the extent of crosslinking. A degree of cros~linking of 10-300 ml/g, in particular 50-200 ml/g, is particularly preferred.
The soft gel polymers are worked up by direct and inver6e precipitation with a precipitating agent~ preferably acetone, and by ultrafiltration and freeze drying.
The base polymer PVAm is used as the starting material for preparation of the functional polymers of the formula I, it being necessary for this base polymer to meet the prerequisites for medical use. PVAm i8 therefore prepared by the process according to the invention, which allows a homopolyvinylamine, which contains no further cocompo-nents in polymer and i8 free from low molecular weight 2 1. ~
impurities, to be obtained.
For this, for example, vinylformA~;de is polymerized in 14% strength aqueous solution with 0.5 mol% of the free radical initiator 4,4'-azocyanopentanoic acid (ACPA) at 70C for 8 hours. A polyvinylformamide having a viscosity of 1.74 dl/g is obtained with a conversion of 99.8%. Thi~
polymer is purified by ultrafiltration (10,000 D mem-brane) such that residual monomer or free initiator constituents are no lonqer detectable (less than 1 ppb in 1~ strength solution).
Conditions: membrane cassettes with exclusion limit of 10,000 D MM, Minisette from Filtron, for example once with 3xlOl of H20/100 g of polymer and once with 3xlOl of H20/20 g of polymer.
The amounts of water required can be purified, if neces-sary by active charcoal, and used several times.
Determination of vinylformamide by means of ~PLC:
Column: ~LiChrosorb Si 60 (5 ~m) Flow rate: 0.55 ml/minute 20 Pressure: 360 psi Detector: W, 225 nm Retention time: 7.2 minutes.
Before the determination of vinylformamide in the poly-vinylformamide, the polymer solution is pas~ed over a purified preliminary column (silica gel 60)~ Calibration solutions are treated in an identical manner to the polymer solution.
For the HPLC elution diagram see Figure 1 (PVAm according to Example 1).
For the calibration for the HPLC determination of vinyl-formamide, see Figure 2.
A polymer of viscosity 2.48 dl/g is obtained with 0.25 mol% of ACPA, while a viscosity of 0.31 dl/g is 2~ 01011 reached by precipitation polymerization in isopropanol.
The molecular weight can be adjusted by the customary method (choice of the parameters of initiator and monomer concentration and temperature).
Polyvinylformamide of very high molecular weight (~1,000,000 D) was prepared and hydrolyzed to PVAm, but this has a weaker action in respect of bile acid adsorp-tion than derivatives of low molecular weight (for example 75,000 D). It has been found that in the case of pure PVAm, PV~m derivatives and crosslinked secondary products thereof, in each case the preparations having a lower MW of the starting polymer have better bile acid adsorption values than those of high molecular weight.
The compounds prepared from a btarting polymer with a molecular weight which is not too high (less than 1,000,000, for example 10,000 to 500,000 D) are therefore preferred.
To prepare PVAm which is free from ~ocomponents, 1/3 the volume (v/v) of a strong acid, for example concentrated HCl, is added to the aqueouæ polyvinylformamide solution and the mixture is heated under reflux for 2 hours.
Thereafter, about 2/3 the volume (v/v) of acid are added over a period of 6 hours, while heating, such that the polymer remains dissolved. Only after the hydrolysis does PVAm precipitate on cooling, BO that it can be separated off from the reaction solution. Formic acid and the excess hydrochloride are removed by ultrafiltration.
Another possibility for the preparation of insoluble PVAm formulations is ionic complexing of the amino-containing polymers with di-, tri- and tetraacids and oligo- and polyacids to give polyelectrolyte complexes (PEC). For this, a dilute solution of the acid is usually initially introduced into the reaction vessel and the solution of the polybase is added dropwise such that fine gel drop-lets which can be eeparated are formed.
The invention furthermore relates to bile acid ad~orbents of the formula I and bile acid adsorbents having the recurring unit of the formula Ia, which, if appropriate in the form of salts, are particularly ~uitable for treatment of ca6es of hyperlipidemia, and to the preparation of 6uch medicaments.
To prepare highly active bile acid ad~orbents, compounds of the general formula I and highly pure PVAm having the recurring unit of the formula Ia which, compared with the adsorbents used at preæent, have a higher bonding capa-city were synthesized using a) polymers having recurring units of low molecular weight, b) more effective ion exchanger groups and c) formulations having a large active surface area.
An improved selectivity can be achieved by utilizing either electrostatic or hydrophobic interactions as well as specific network structures.
The usual dosage of the bile acid adsorbers used to date for treatment of hypercholesterolemia can be reduced considerably by using the vinyl polymers. The problem of dosage and compliance thereby arise to a lesser extent.
In addition, compliance is also improved by the fact that the compounds have a soft gel character and are of neutral taste and Bmell ~ BO that no taste and smell compensators are required.
The effectiveness of the active compounds descri~ed can be increased by specific microformulations. For this, the compounds are converted into microparticles by means of various techniques. In the ca~e of soluble compounds, this is possible by ~pray drying, freeze drying and emulsion processes. Soluble and insoluble compounds can also be micronized mechanically. The microparticles are distinguished by the fact that the active compound i6 substituted over a very large adsorptive surface area.
21~1011 Crosslinked microparticles can thus be prepared from the compounds of the formula I inter alia, by spraying a 4%
strength aqueous solution of basic PVAm or non-cross-linked derivatives thereof at 170C. The nano- and microparticles obtained are ~uspended in isopropanol or dichloroethane with 0.3 - 0.5% of dibromohexane and the suspension îs incubated at 70 - 80C for 8 hours. The particles are insoluble in water, but swell, their diameter increasing 1%- to 5-fold.
One advantage of the compounds of the formula I and the PVAm having the recurring unit of the formula Ia is that film-coated tablets can be prepared very easily from these compounds. In vitro, these exhibit the same acti-vity as the compounds in powder form. Per 250 mg of active compound, for example, they comprise only 40 mg of pharmaceutically customary auxiliaries.
The reduction in serum cholesterol level to be achieved with the compounds can be improved further by ~imulta-neous use of other lipid-lowering agents which do not have a systemic action or have a systemic action (for example HMG-CoA reductase inhibitors) in the context of a combination therapy.
Since the compounds acccrding to the invention interrupt the enterohepatic circulation, they are suitable as an antidote in the event of oral toxification.
The compounds of the formula I where z e 0.005 to 0.3 furthermore can be employed as ~atiation promoters because of their water uptake capacity.
Since the compounds of the formula I according to the invention and PVAm having the recurring unit la are readily swellable and bond acids, they can be employed as antacids for the treatment of excessive production of gastric acid, and can therefore be u ed as agents against gastritis and ulcus ventriculi or duodeni.
;
- 19 - 21Ql~ll On the basis of their interaction with cholesterol, the compounds are capable of adsorbing the chole~terol consumed with food. The content of cholesterol in food i8 therefore bonded immediately and i6 not adsorbed by the body.
The compounds of the formula I are furthermore also suitable as foodstuff auxiliaries. Thus, for example, cholesterol is adsorbed from milk or egg constituents.
The resulting foodstuffs are distinguished by a reduced cholesterol content.
Compounds of the formula I or highly pure PVAm having the recurring unit of the formula Ia are suitable as muco-adhesive transportation systems for active compounds.
They form highly hydratable polymer matricee which have groups which form hydrogen bridges and cationic group~, display a high flexibility of the polymer chain and can be additionally substituted by hydrophobic unit~. The compounds are therefore capable of increasing the resi-dence time of a bonded or adsorbed active compound in the stomach or small intestine. They are adsorbed as active compound carriers onto the mucosal layer of the gastro-intestinal wall, the positively charged groups of the polymers interacting with the negatively charged groups of the terminal sialic acid of the mucin molecules in order thus to cause delayed transportation of the active compounds through the gastrointestinal tract. At the same time, the absorption of the active compound i8 improved by the nature of the interaction.
In vitro test The bonding capacity and selectivity are tested in an in vitro test. A bovine bile assay is used here. For this, 5 mg of polymer sample are dissolved in 2 ml of test solution and the solution i8 incubated at 37C for 24 hours. The test solution comprises bovine bile, diluted 1:10 with PBS buffer, p~ 6.5. Evaluation is ~y - 20 - ~ 1 0 10 means of thin-layer chromatography and HPLC. Cuemid i~
used as the reference. The results are ~ummarized in Table l.
Table 1: ~ile acid adsorption in vitro (bovine bile assay) ~xample Bile aoid adsorption (%) Taurocholate Glycocholate _ 69 - - 68- ~ -15 r , T~
I .
I .
Cole6tyramine 38 24 . I
In vivo test The action of four preparations in respect of a reduction in serum cholesterol level was tested on rabbit~ fed with cholesterol.
For this, after a preliminary feeding period (to raise the cholesterol level) the cholesterol level was 2~010~ 1 determined (initial value). 2~ strength cholesterol-containing food and the preparations in concentrations of 12.5 - 50 mg/kg (or 100 - 500 mg for cole6tyramine~ were fed to randomized test groups of 5 animals each for 4 weeks. The change in serum cholePterol compared with the initial value i8 shown for each preparation and for colestyramine as the compari~on substance in Table 2.
Table 2: Change in the total cholesterol of rabbits fed with 0.2% of cholesterol Preparations Dosage Change in serum choleRterol com-pared with the initial value .
Control ~Tylose 1% ~ 4 mmol/l . .
Example 5 50 mg/kg -2.5 mmol/l . . _ .
Example 6 50 mg/kg -1 mmol/l Example 7 50 mg/kg +0.5 mmol/l l . I
Example 8 50 mg/kg -0.4 mmol/l . , . .
Colestyramine 500 mg/kg -0.3 mmol/l Example 1 Vinylamine homopolymer for pharmaceutical quality MW: - 380,000 D
1.8 1 of deionized water are heated to 60C, degassed and fluæhed with N2. 300 g of vinylformamide, 3 ml of concen-trated NH~OH and 6 g of ACPA are added, and the entire mixture i6 stirred at 70C for 8 hours. The monomer conversion is monitored by I2 titration, and is 99.8%
after 8 hours.
The 601ution i6 diluted 4 tLme6 with water to in each ca~e 20 1 and concentrated in each ca~e 4 times to 2.5 1 21010~ 1 by means of ultrafiltration (5xlO X Minisette from Filtron), and then freeze dried. A purely white product having a residual monomer content of 1.4 ppm is obtained.
50 g of the polymer are dissolved in water again, the ~olution i6 diluted to 10 1 and ultrafiltered 4 tLmes and the product iB then freeze dried.
The residual monomer conten~ ic below the detection limit of the ~PLC method (< 0.1 ppm) and GC-MS.
Viscosity [~] in 0.5% ~trength NaCl: 1.74 dl/g.
100 g of polyvinylformamide are dissolved in 800 ml of H20, 270 ml of concentrated ~Cl are added and the mixture is heated under reflux for 2 hour~. 270 ml of concentra-ted HCl are added. The mixture i5 heated under reflux for 4 hours and, after addition of a further 270 ml of concentrated ~Cl, i5 heated at 60C for 2 hours. The hydrochloric acid i8 decanted off at room temperature, the polymer i~ dissQlved in H20 and the pH is brought to 4 with NaO~. The product i8 ultrafiltered 4 times with in each case 20 1 and then freeze dried. According to 1~_300 MHz-NMR, the polymer no longer contains formamide groups (no peak between 8 and 8.5 ppm), i.e. the content is below the detection 1- it (c0.05%).
The free base form of the PVAm can be obtained from the above polymer using alkali metal hydroxide solution and 6ubsequent dialysis and freeze drying by using ion exchanger resins.
Example 2 Vinylamine homopolymer for pharmaceutical quality MW: - 75,000 D
100 g of vinylformamide, 0.5 ml of concentrated N~3 and 1.5 g of ACPA are added to 500 ml isopropanol. The mixture is 6tirred at Ç5C for 6 hours. The polymer is filtered off with suction, dried in vacuo, dissolved in 2101 0~1 water and ultrafiltered as described in Example 1.
50 g of polyvinylformamide are dissolved in 400 ml of H2O, and concentrated NaO~ ~olution (83 g) are added at 50C such that the polymer does not precipitate. The mixture is stirred at 70C for 7 hours. The polymer i8 precipitated in acetone, dissolved in water and further purified by ultrafiltration and freeze drying as described in Example 1.
Example 3 0.165 g of PVAm (75,000 D from Example 2) are dissolved in 3 ml of methanol, and 0.4 g of cholic acid ~-~;doca-proic acid p-nitrophenyl ester in 10 ml of dimethyl sulfoxide is added. Three drop~ of triethylamine are added and the mixture iB stirred at room temper~ture for 1 hour. The product i8 precipitated in ethyl acetate and dissolved in methanol/H2O, the pH is ~rought to 4 and the product is precipitated again in ethyl acetate. The polymer is filtered off with suction and dried in vacuo.
Yield: 310 mg Degree of substitution; 12%
Example 4 2 g of PVAm (Example 1, basic form) are dissolved in 80 ml of H20, 4.5 g of 6-bromohexylpyrimidinium bromide and 560-mg of NaOH are added, and the mixture iB ~tirred at 90C for 9 hours.
For working up, the batch iB acidified with lN HCl (p~ 1) and precipitated inversely with acetone. The product is dissolved in H2O, the ~olution i~ titrated with NaO~ to pH 4 and the product i8 precipitated again with acetone.
After a further precipitation in acetone, the resulting product is freeze dried from H2O.
Yield: 4 g - 24 - 2~Q1011 Example 5 360 g of PVAm x HCl (24% of Cl) are dissolved in 5 1 of H20. After the pH has been brought to 10, 323 g of 6-bromohexylpyridinium bromide and 72 g of NaO~ are added. The mixture is ~tirred under N2 at 90C for 10 hours. Thereafter, it i~ neutralized with hydrochloric acid and ultrafiltered with 30 1 of R20 (cut off:
10,000 D).
Degree of substitution according to NMR: 15.7%.
The batch (4 1) is brought to pH 10 with NaO~, and 69 g of 1,6-dibromohexane and 22 g of NaOH are added. The mixture is heated to 90C under N2, with very rapid stirring. After about 1~ hours, gel formation ~tarts. The mixture is stirred at 90C for a further 4~2 hours. For working up, the batch is acidified with 2 1 of 2 N
hydrochloric acid and the product i8 precipitated in-versely with 10 1 of acetone. The bromide/chloride exchange is carried out by swelling the polymer in 2 N
hydrochloric acid. Thereafter, the product is again precipitated inversely with acetone and taken up in 8 1 of H20, and the pH is brought to 5 with dilute sodium hydroxide solution. After precipitation in acetone, the product i6 dried in vacuo at 50C.
Yield: 460 g.
Example 6 140 g of PVAm x HCl are dissolved in 4 1 of H20 and the pH is brought to 11 with NaOH. After addition of 3~ g of dimethylaminoethyl chloride hydrochloride and 18 g of NaOH, the mixture is stirred under N2 at 35C for 9 hours.
The pH is brought to 1 with hydrochloric acid and the batch is precipitated with acetone. The product is dissolved in H20, the p~ is brought to 5 and the product is ultrafiltered and freeze dried.
Degree of substitution: 6%
Yield: 150 g.
Example 7 110 g of PVAm from Example 1 are dissolved in 4 1 Of ~2~
and 36.8 g of dimethylaminoethyl chloride hydrochloride and 25.6 g of NaOH (in 200 ml of H20) are added. The mixture is heated at 90C for 9 hours. 80 g of dibromo-hexans are added, while stirring rapidly. ~ter 2 hours, the solution changes into a gel. The temperature i8 kept at 85-90C for 9 hours. The batch i8 diluted with 3 parts of acetone (v/v) and the gel is extracted. The ~olution is decanted off and the residue i~ extracted by stirring in further acetone. The product iB ~wollen in water/ethanol, the p~ i8 initially brought to 1, and the polymer is precipitated with acetone and 3wollen again in water at pH 4. After a ~urther precipitation with acetone, the product is finally dried in vacuo at 50C.
Example 8 100 g of PVAm x HCl are dissolved in 2.5 1 of H20 and the pH is brought to 11 with NaO~. After addition of 87 g of (3-bromopropyl)-trimethylammonium chloride and 27 g of NaOH, the mixture ic boiled under reflux under N2 for 17 hours. Working up is carried out analogously to Exampl~
6 by acidification, precipitation in acetone and ultrafiltration.
Degree of substitution: 20%.
Yield: 99 g.
Example 9 a, b, c, d, e, f 2 g of PVAm x HCl (33 mmol) are initially introduced into 70 ml of H20 and the pH is brought to 10 with 10 ml of sodium hydroxide solution. In 6 batches (a - f), 0.2~ g;
0.64 g; 1.28 g; 1.92 g; 2.56 g and 3.19 g of 12-bromodo-decyltrimethylaDmonium bromide are dissolved in 10 ml of - 26 - 2 1 0 1 ~ ~ 1 H20 with 1.1 times the particular molar amount of NaOH, and the solution~ are added dropwi~e. The batches are stirred at 80C for 7 hours. Batches a, b and c are worked up analogously to Example 4; for working up batches d, e and f, these are freeze dried. The product is taken up in methanol/H20 and precipitated in acetone/diisopropyl ether 3:2. The precipitation is repeated at pH 1 and pH 4. The batche~ are freeze dried from H20.
10 9a~ Degree of sub6titution:2~
Yield: 58%
b) Degree of 6ubstitution: 5%
Yield: 54%
c) Degree of substitution: 8%
Yield: 40%
d) Degree of substitution: 12%
Yield: 88%
e) Degree of substitution: 19%
Yield: 85%
f) Degree of substitution: 25%
Yield: 91%
Example 10 10 ml of an aqueous solution of polyacrylic acid (Polyscience, 450 kD) are initially introduced into the reaction vessel in a concentration of 1 mg/ml. 10 ml of the compound from Example 1 are added dropwi~e in a concentration of 1 mg/ml by means of a cannula (diameter O.6 mm). A gel is formed, which is freeze dried; accord-ing to analysis, the gel comprises 50% of the polybase of Example 1.
Example 11 1 g of PVAm (Example 1, ~alt-free form) i8 di~solved in 40 ml of H20, 588 mg of benzyl chloride are added and the mixture is stirred at 90C for 8 hours. After addition of - 27 - 2101~11 2.25 ~ of 6-bromohexylpyridinium bromide and 470 mg of NaOH, the mixture is stirred at 90C for 8 hours. Working Up i8 carried out analogously to Example 4.
Degree of substitution: 18% benzyl, 28% hexylpyridinium Yield: 0.76 g Example 12 1 g of PVAm (Example 1, salt-free form) is dissolved in 40 ml Of ~2~ 588 mg of benzyl chloride are added and the mixture is stirred at 90C for 8 hours. After addition of 1.96 g of 3-bromopropylpyridinium bromide and 470 mg of NaOH, the mixture is 3tirred at 90C for B hours. For working up, 23 ml of the solution are treated as described in Example 4.
Substitution: 18~ benzyl, 8% propylpyridinium 1/2 yield: 0.66 g Example 13 430 mg of dibromohexane and 150 mg of NaOH are added to 23 ml of the reaction solution from Example 12 and the mixture is stirred at 90C for 8 hour~. Working up is ~arried out analogously to Example 7.
Yield: 0.96 g Example 14 1.35 g of trimethyldodecylammonium chloride-substituted PVAm - 0.25 (obtained a~ the free amine from Example 9f by means of the ion exchanger Amberlite 400) are di~-solved in 60 ml of ethanol/~20 1:1, and 1.8 g of p-nitro-phenyl caproate in 20 ml of ethanol are added. The mixture is stirred at room temperature for 2 hour~ and at 40C for ~ hour. The p~ i8 brought to 6 with hydrochloric acid, the ethanol is evaporated off in a rotary evapora-tor and the aqueous phase is freeze dried. The polymer is precipitated in ether from ethanol/isopropanol 1:1, dissolved in B20~ dialyzed (cutoff: 15,000) and freeze ~ 28 - 2 ~ ~ 1 0 :L ~
dried .
Yield: 1 . 5 g.
Claims (18)
1. A polyvinylamine derivative containing hydrophilic centers, of the formula I
(I) in which R1 is a substituent chosen from the group compris-ing:
1. -(CH2)n-CH3, in which n is an integer from 3 to 21, branched alkyl having 3 to 21 carbon atoms or straight-chain or branched alkenyl having up to 21 carbon atoms,
(I) in which R1 is a substituent chosen from the group compris-ing:
1. -(CH2)n-CH3, in which n is an integer from 3 to 21, branched alkyl having 3 to 21 carbon atoms or straight-chain or branched alkenyl having up to 21 carbon atoms,
2. cycloalkyl or cycloalkenyl having in each case 5-12 carbon atoms, or mono-, di- or trisubstituted cycloalkyl or cycloalkenyl having in each case 5-12 ring carbon atoms and
3. aryl, arylalkyl or arylalkenyl, in which the aryl radicals are mono- or polynuclear, can be mono- to trisubstituted and can contain heteroatoms, X is a single bond, a bridge group or a hydrophilic spacer for linking the hydrophobic radical R1, R2 is RA-Y, RB or RC, in which Y is a bridge group or a spacer which allows RA
to be linked to the polymer, RA is a hydrophilic or amphiphilic substituent chosen from the group comprising:
1. 2.
3.
to be linked to the polymer, RA is a hydrophilic or amphiphilic substituent chosen from the group comprising:
1. 2.
3.
4. -(CH2)C-B, in which B is a pyrrolidinyl, piperidinyl or morpholinyl radical bonded via N,
5. -(CH2)?-D°A°, in which D° is pyridinium, pyrimidinium or imidazolinium,
6.
in which, for the substituents described under 1. to 6., a is an integer from 2 to 16, b is zero, 1, 2 or 3, C is an integer from 2 to 6, d is an integer from 6 to 17 and A is a physiologically tolerated anion, RB 1. is a cholic acid bonded via the 3-.alpha.-OH or 24-COOH group directly or via a spacer, or 2. is a tauro- or glycocholic acid which is bonded via the 3.alpha.-OH or tauro or glyco function directly or via a spacer, Rc is a hydrophilic cyclic radical or a gluco-pyranuronic acid radical, R3 is a crosslinking group chosen from the group comprising:
1. -(CH2).-, 2.
in which Z is oxygen or NH, 3.
4. -(CH2-CH2-O)R-CH2-CH2-, 5. , in which W is a , or 6. and
in which, for the substituents described under 1. to 6., a is an integer from 2 to 16, b is zero, 1, 2 or 3, C is an integer from 2 to 6, d is an integer from 6 to 17 and A is a physiologically tolerated anion, RB 1. is a cholic acid bonded via the 3-.alpha.-OH or 24-COOH group directly or via a spacer, or 2. is a tauro- or glycocholic acid which is bonded via the 3.alpha.-OH or tauro or glyco function directly or via a spacer, Rc is a hydrophilic cyclic radical or a gluco-pyranuronic acid radical, R3 is a crosslinking group chosen from the group comprising:
1. -(CH2).-, 2.
in which Z is oxygen or NH, 3.
4. -(CH2-CH2-O)R-CH2-CH2-, 5. , in which W is a , or 6. and
7. in which, in the groups described under 1. to 7., e is an integer from 3 to 12, f is an integer from 1 to 6, g is an integer from 1 to 8, h is an integer from 1 to 7, k is an integer from 4 to B and R4 is hydrogen or CH3, and in which w is 0.1 - 0.995, x is 0.0 - 0.8, y is 0.01 - 0.8 and z is zero or 0.005 - 0.3, and w+x+y+z = 1, or a physiologically tolerated salt thereof.
2. A polyvinylamine derivative as claimed in claim 1, in which z is zero.
3. A polyvinylamine derivative as claimed in claim 1, in which z is 0.005 to 0.3.
4. A process for the preparation of a highly pure polyvinylamine having the recurring unit of the formula Ia (Ia) and a molecular weight of 10,000 to 1,000,000 D or a physiologically tolerated salt thereof, which comprises preparing polyvinylformamide (homopolymer) by free radical polymerization of vinylformamide and subsequently hydrolyzing the product to give a polyvinylamine having the recurring unit of the formula Ia or a physiologically tolerated PVAm salt.
5. A highly pure polyvinylamine having the recurring unit of the formula Ia, obtainable by the process as claimed in claim 4.
6. A process for the preparation of a polyvinylamine of the formula I or a physiologically tolerated salt as claimed in claim 1, which comprises introducing the functional groups R1-X, R2 and/or R3 into polyvinyl-amines, in particular those having the recurring unit of the formula Ia obtainable by the process as claimed in claim 4, by the methods customary in polymer chemistry.
7. A process for the preparation of a compound as claimed in claim 2, which comprises introducing the functional groups of R'-X, R2 and/or R3 into PVAm having a molecular weight of 10,000 to 1,000,000 D
by the customary methods.
2. A polyvinylamine derivative as claimed in claim 1, in which z is zero.
3. A polyvinylamine derivative as claimed in claim 1, in which z is 0.005 to 0.3.
4. A process for the preparation of a highly pure polyvinylamine having the recurring unit of the formula Ia (Ia) and a molecular weight of 10,000 to 1,000,000 D or a physiologically tolerated salt thereof, which comprises preparing polyvinylformamide (homopolymer) by free radical polymerization of vinylformamide and subsequently hydrolyzing the product to give a polyvinylamine having the recurring unit of the formula Ia or a physiologically tolerated PVAm salt.
5. A highly pure polyvinylamine having the recurring unit of the formula Ia, obtainable by the process as claimed in claim 4.
6. A process for the preparation of a polyvinylamine of the formula I or a physiologically tolerated salt as claimed in claim 1, which comprises introducing the functional groups R1-X, R2 and/or R3 into polyvinyl-amines, in particular those having the recurring unit of the formula Ia obtainable by the process as claimed in claim 4, by the methods customary in polymer chemistry.
7. A process for the preparation of a compound as claimed in claim 2, which comprises introducing the functional groups of R'-X, R2 and/or R3 into PVAm having a molecular weight of 10,000 to 1,000,000 D
by the customary methods.
8. A highly pure PVAm or a physiologically tolerated salt thereof as claimed in claim 5 for use as a medicament, foodstuff auxiliary or foodstuff additive.
9. Microparticles obtained by spray drying, freeze drying or micronization of a polyvinylamine as claimed in claim 1 or 5.
10. A polyelectrolyte complex obtained from a compound as claimed in claim 2 or from a compound as claimed in claim 5 and a customary polyacid.
11. A medicament comprising a compound as claimed in claim 1 or comprising a compound as claimed in claim 5.
12. The use of a compound as claimed in claim 1 or of a compound as claimed in claim 5 for the preparation of a hypolipidemic agent.
13. The use of a compound as claimed in claim 1 or as claimed in claim 5 for adsorption of cholesterol.
14. The use of a compound as claimed in claim 1 as a foodstuff additive or foodstuff auxiliary.
15. The use of a compound as claimed in claim 1 or claim 5 as an antidote or antacid.
16. The use of a compound as claimed in claim 1 or claim 5 in combination with a systemically or non-systemi-cally acting hypolipidemic agent.
17. The use of a compound as claimed in claim 3 as a satiation promoter.
18. The use of a compound as claimed in claim 2 or 3 as an active compound carrier.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4224108.1 | 1992-07-22 | ||
| DE4224108 | 1992-07-22 |
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|---|---|
| CA2101011A1 true CA2101011A1 (en) | 1994-01-23 |
Family
ID=6463788
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002101011A Abandoned CA2101011A1 (en) | 1992-07-22 | 1993-07-21 | Polyvinylamine derivatives having hydrophilic centers, processes for their preparation and the use of the compounds as a medicament, active compound carrier and foodstuff auxiliary |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US5430110A (en) |
| EP (1) | EP0580078B1 (en) |
| JP (1) | JPH06166728A (en) |
| KR (1) | KR940005681A (en) |
| AT (1) | ATE159262T1 (en) |
| AU (2) | AU659746B2 (en) |
| CA (1) | CA2101011A1 (en) |
| DE (1) | DE59307535D1 (en) |
| DK (1) | DK0580078T3 (en) |
| ES (1) | ES2110543T3 (en) |
| FI (1) | FI933273A (en) |
| GR (1) | GR3025321T3 (en) |
| IL (1) | IL106420A (en) |
| NO (1) | NO301427B1 (en) |
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| ZA (1) | ZA935266B (en) |
Families Citing this family (65)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US5703188A (en) * | 1993-06-02 | 1997-12-30 | Geltex Pharmaceuticals, Inc. | Process for removing bile salts from a patient and compositions therefor |
| US5624963A (en) * | 1993-06-02 | 1997-04-29 | Geltex Pharmaceuticals, Inc. | Process for removing bile salts from a patient and compositions therefor |
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-
1993
- 1993-07-15 DK DK93111375.7T patent/DK0580078T3/en active
- 1993-07-15 EP EP93111375A patent/EP0580078B1/en not_active Expired - Lifetime
- 1993-07-15 DE DE59307535T patent/DE59307535D1/en not_active Expired - Fee Related
- 1993-07-15 AT AT93111375T patent/ATE159262T1/en not_active IP Right Cessation
- 1993-07-15 ES ES93111375T patent/ES2110543T3/en not_active Expired - Lifetime
- 1993-07-20 NZ NZ248192A patent/NZ248192A/en unknown
- 1993-07-20 FI FI933273A patent/FI933273A/en unknown
- 1993-07-20 IL IL10642093A patent/IL106420A/en not_active IP Right Cessation
- 1993-07-21 CA CA002101011A patent/CA2101011A1/en not_active Abandoned
- 1993-07-21 JP JP5180215A patent/JPH06166728A/en active Pending
- 1993-07-21 ZA ZA935266A patent/ZA935266B/en unknown
- 1993-07-21 US US08/095,623 patent/US5430110A/en not_active Expired - Lifetime
- 1993-07-21 AU AU42090/93A patent/AU659746B2/en not_active Ceased
- 1993-07-21 NO NO932634A patent/NO301427B1/en not_active IP Right Cessation
- 1993-07-21 KR KR1019930013755A patent/KR940005681A/en not_active Application Discontinuation
-
1995
- 1995-02-28 AU AU13531/95A patent/AU673479B2/en not_active Ceased
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1997
- 1997-11-07 GR GR970402963T patent/GR3025321T3/en unknown
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|---|---|
| NO932634L (en) | 1994-01-24 |
| AU673479B2 (en) | 1996-11-07 |
| AU1353195A (en) | 1995-05-25 |
| EP0580078B1 (en) | 1997-10-15 |
| IL106420A (en) | 1997-01-10 |
| EP0580078A1 (en) | 1994-01-26 |
| NO301427B1 (en) | 1997-10-27 |
| US5430110A (en) | 1995-07-04 |
| JPH06166728A (en) | 1994-06-14 |
| AU4209093A (en) | 1994-01-27 |
| ES2110543T3 (en) | 1998-02-16 |
| IL106420A0 (en) | 1993-11-15 |
| FI933273A0 (en) | 1993-07-20 |
| ATE159262T1 (en) | 1997-11-15 |
| ZA935266B (en) | 1994-02-10 |
| NO932634D0 (en) | 1993-07-21 |
| FI933273A (en) | 1994-01-23 |
| KR940005681A (en) | 1994-03-22 |
| AU659746B2 (en) | 1995-05-25 |
| DK0580078T3 (en) | 1998-05-25 |
| DE59307535D1 (en) | 1997-11-20 |
| GR3025321T3 (en) | 1998-02-27 |
| NZ248192A (en) | 1995-05-26 |
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