[go: up one dir, main page]

WO2002053526A1 - Nouveaux composes destines a etre utilises comme produits intermediaires dans un polymere sequence lineaire et nouveau polymere sequence lineaire - Google Patents

Nouveaux composes destines a etre utilises comme produits intermediaires dans un polymere sequence lineaire et nouveau polymere sequence lineaire Download PDF

Info

Publication number
WO2002053526A1
WO2002053526A1 PCT/SE2001/002904 SE0102904W WO02053526A1 WO 2002053526 A1 WO2002053526 A1 WO 2002053526A1 SE 0102904 W SE0102904 W SE 0102904W WO 02053526 A1 WO02053526 A1 WO 02053526A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
amino
alkanoate
oxy
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/SE2001/002904
Other languages
English (en)
Inventor
Carl-Johan Aurell
Per Flodin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Artimplant AB
Original Assignee
Artimplant AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from SE0004925A external-priority patent/SE0004925L/xx
Application filed by Artimplant AB filed Critical Artimplant AB
Publication of WO2002053526A1 publication Critical patent/WO2002053526A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/42—Polycondensates having carboxylic or carbonic ester groups in the main chain
    • C08G18/4266—Polycondensates having carboxylic or carbonic ester groups in the main chain prepared from hydroxycarboxylic acids and/or lactones
    • C08G18/4269—Lactones
    • C08G18/4277—Caprolactone and/or substituted caprolactone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0019—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/507—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials for artificial blood vessels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/24—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/08—Processes
    • C08G18/10—Prepolymer processes involving reaction of isocyanates or isothiocyanates with compounds having active hydrogen in a first reaction step
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/30—Low-molecular-weight compounds
    • C08G18/38—Low-molecular-weight compounds having heteroatoms other than oxygen
    • C08G18/3819—Low-molecular-weight compounds having heteroatoms other than oxygen having nitrogen
    • C08G18/3823—Low-molecular-weight compounds having heteroatoms other than oxygen having nitrogen containing -N-C=O groups
    • C08G18/3829—Low-molecular-weight compounds having heteroatoms other than oxygen having nitrogen containing -N-C=O groups containing ureum groups
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/30—Low-molecular-weight compounds
    • C08G18/38—Low-molecular-weight compounds having heteroatoms other than oxygen
    • C08G18/3819—Low-molecular-weight compounds having heteroatoms other than oxygen having nitrogen
    • C08G18/3823—Low-molecular-weight compounds having heteroatoms other than oxygen having nitrogen containing -N-C=O groups
    • C08G18/3831—Low-molecular-weight compounds having heteroatoms other than oxygen having nitrogen containing -N-C=O groups containing urethane groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2230/00—Compositions for preparing biodegradable polymers

Definitions

  • New compounds for use as intermediates in linear block polymer and new linear block polymer are new linear block polymer.
  • the present invention relates to a new compound according to Formula (1), a method for preparing said compound, intermediates formed during preparation of said compound and use of said compound. Furthermore, the present invention relates to a method for preparing a linear block polymer, a new linear block polymer, use of said linear block polymer and new implants, pharmaceutical preparations, microencapsules, suspensions, emulsions and material for promoting wound healing.
  • SE, C2, 505703 describes a linear block polymer with a molecular weight of 10" Dalton, preferably 10 s Dalton, comprising urea and urethane groups and ester groups at such a distance from each other that after hydrolysis of the same, fragments are created that are so small that they can be excreted from a human body.
  • Said linear block polymer comprising urea and urethane groups is a suitable material for implants for humans and animals.
  • the present invention relates to a compound according to Formula (1)
  • A is [(2-4)-amino((C 2 -C 4 ) alkanoate)]((C 2 -C 5 )alkyl); or
  • Ri is amino((CrC5)alkyl) when R 2 is
  • each R p which R p can be the same or different, is hydroxy((C C 5 )alkyl) or [(2-4)-amino((C 2 -C 4 )aIkanoate)]((C 2 -C 5 )alkyl); or
  • R 2 is a substituent according to Formula (1A)
  • I is from 1 to 20, preferably 1 to 10 , and R-i is then
  • Each alkyl and each alkanoate in Formula (1) can, with exception for when the opposite is stated, independently of each other, be straight or branched, saturated or unsaturated, and/or substituted with, for example, methyl, phenyl, 4- hydroxyphenyl, 4-aminobutyl, 2-butyl, 2-hydroxymethy), 3-aminopropyl, 2- aminoethyl, 2-mercaptomethyl, or similar.
  • Salts of said compound of Formula (1) comprise, for example, its trifluoroacetic acid salt, acetic acid salt, p-toluenesulphonic acid salt, chloride salt, bromide salt or methanesulphonic acid salt.
  • Said compound according to Formula (1) has been shown to be useful during the preparation of new linear block polymers of the polyurea or polyurethaneurea type, wherein said linear block polymers comprise ester groups at such a distance from each other that after hydrolysis of the same, fragments are created that are so small, namely less than 2,000 Dalton, that they can be excreted from a human or animal body.
  • Said linear block polymers comprise blocks that contain urea groups, known as "hard" blocks, the size of which blocks is more than halved by hydrolysis of said ester groups, which ester groups are derived from said compound according to Formula 1, wherein the hydrolysis promotes excretion of residues in that it gives a smaller fragment size, less than 2,000 Dalton.
  • a further embodiment according to the present invention relates to the compound having Formula (1), wherein
  • Ri and R 2 which Ri and R 2 can be the same or different, are
  • A is [(2-4)-amino((C 2 -C 4 ) alkanoate)]((C 2 -C 5 )alkyl); or
  • R 2 is a substituent according to Formula (1 A)
  • R is (C 2 -C 4 )alkyl
  • I is from 1 to 20, preferably 1 to 10, and Ri is then
  • Still a further embodiment according to the present invention relates to a compound according to Formula (1), wherein
  • R-i is amino((C ⁇ -C 5 )alkyl) when R 2 is
  • each Rp which R p can be the same or different, is hydroxy((CrC 5 )alkyl) or [(2-4)-amino((C 2 -C 4 )alkanoate)]((C 2 -C 5 )alkyI).
  • a further embodiment according to the present invention relates to a compound having Formula (1), wherein
  • R-i is amino((C 3 -C 5 )alkyl), ((C ⁇ -C 4 )alkyl)[(2-4)-am ⁇ no((C 2 -C 4 ) alkanoate)], or [(2-4)-amino((C 2 -C ) alkanoate)]((C 2 -C 5 )alkyl); and
  • R 2 is amino((C 2 -C 5 )alkyl), ((C C 4 )alkyl)[(2-4)-amino((C 2 -C 4 ) alkanoate)], or [(2-4)-amino((C 2 -C 4 ) alkanoate)3((C 2 -C 5 )alkyl).
  • a further embodiment according to the present invention relates to a compound having Formula (1), wherein R 2 is A,
  • A is [(2-4)-amino((C 2 -C 4 ) alkanoate)]((C 3 -C 5 )alkyl).
  • a yet further embodiment according to the present invention relates to a compound having Formula (1), wherein
  • R 2 is a substituent according to Formula (1 A), as above, and
  • Ri is ((C C )alkyl)[(2-4)-amino((C 2 -C 4 ) alkanoate)], or [(2-4)-amino((C 2 -C ) alkanoate)]((C 3 -C 5 )alkyl).
  • a further embodiment according to the present invention relates to a compound according to Formula (1), wherein
  • R-i is amino((C C 5 )alkyl) when R 2 is
  • each R p which R p can be the same or different, is hydroxy((C ⁇ -C 3 )alkyl) or [(2-4)-amino((C 2 -C 4 )alkanoat)]((C 3 )alkyl).
  • the present invention relates to the compounds:
  • the present invention further relates to a method for preparing the compound described by Formula (1), which method comprises
  • Protective groups in method a) that protect said protected amines, and reaction conditions are well known from similar reactions.
  • the protecting groups can be tert- butyloxycarbonyl groups or benzyloxycarbonyl groups, wherein said deprotection can occur by acidic hydrolysis or by catalytic hydrolysis, or fluorenylmethyloxycarbonyl protecting groups (Fmoc-) and deprotection with piperidine or another suitable base, by base-catalysed B-elimination.
  • the conversion in methods b) and c) can be carried out by conventional methods, which are known per se, for example, reaction of the free base with an acid containing the desired anion, or by precipitation of the salt at basic pH.
  • the reaction is carried out in a suitable solvent such as N,N-dimethylformamide (DMF), N- methylpyrrolidone (NMP), N.N-dimethylacetamide (DMAC) or dimethylsulphoxide (DMSO).
  • a suitable solvent such as N,N-dimethylformamide (DMF), N- methylpyrrolidone (NMP), N.N-dimethylacetamide (DMAC) or dimethylsulphoxide (DMSO).
  • the present invention also relates to a method for preparing a linear block polymer, wherein the method comprises
  • prepolymers which prepolymers can be the same or different, and compounds according to Formula (1C), which compounds can be the same or different, and
  • Ri and R 2 which Ri and R 2 can be the same or different, are
  • A is [(2-4)-amino((C 2 -C ) alkanoate)]((C C 5 )alkyl);
  • A is [(2-4)-amino((C 2 -C ) alkanoate)]((C 3 -C 5 )alkyl); or wherein
  • R-i is diamino((C ⁇ -C 5 )alkyl)
  • R 2 is hydrogen, (C-*-C )alkyl or benzyl; or wherein R-i is amino((C ⁇ -C 5 )alkyl) when R 2 is
  • each R p which R p can be the same or different, is hydroxy((C C 5 )alkyl) or [(2-4)-amino((C 2 -C 4 )alkanoate)3((C 2 -C 5 )alkyl); or wherein
  • R 2 is a substituent according to Formula (1D)
  • R is (C 2 -C 4 )alkyl
  • I is from 1 to 20, preferably 1 to 10, and Ri is then
  • Each alkyl and each alkanoate in Formula (1C) can, independently of each other, be straight or branched, saturated or unsaturated, and/or substituted with, for example, methyl, phenyl, 4-hydroxyphenyl, 4-aminobuty!, 2-butyl, 2-hydroxymethyl, 3- aminopropyl, 2-aminoethyl, 2-mercaptomethyl, or similar.
  • Salts of said compound of Formula (1C) comprise, for example, its trifluoroacetic acid salt, acetic acid salt, p-toluenesulphonic acid salt, chloride salt, bromide salt or methanesulphonic acid salt.
  • the prepolymer can be prepared by, for example, the reaction of oligoesters and oligoethers, that have HO-terminations at both ends, with diisocyanate, with the molar ratio between diisocyanate and the OH-group being approximately 1:1 during the reaction.
  • a further embodiment according to the present invention relates to said method for preparing a linear block polymer, wherein the method comprises
  • prepolymers which prepolymers can be the same or different, and compounds according to Formula (1C), which compounds can be the same or different, and
  • R-* and R 2 which Ri and R 2 can be the same or different, are
  • A is [(2-4)-amino((C 2 -C 4 ) alkanoate)]((CrC 5 )alkyl);
  • A is [(2-4)-amino((C 2 -C 4 ) alkanoate)]((C 3 -C 5 )alkyl); or wherein R-i is diamino((C"i-C 5 )alkyl) and
  • R 2 is hydrogen, (C C )alkyl or benzyl; or wherein
  • R 2 is a substituent according to Fo ⁇ nula (1D)
  • R is (C 2 -C 4 )alkyl
  • I is from 1 to 20, preferably 1 to 10 , and Ri is then
  • a further embodiment according to the present invention relates to said method for preparing a linear block polymer, wherein A is
  • a yet further embodiment relates to a method for preparing linear block polymers according to the present invention, wherein said prepolymers are chain-extended with one or more of
  • a further embodiment relates to a method for preparing linear block polymers according to the present invention, wherein said prepolymers are chain- extended with one or more of
  • Another embodiment relates to said method for preparing a linear block polymer, wherein said prepolymer is chain-extended with one or more of
  • the present invention also relates to a linear block polymer with a molecular weight of at least 10 4 Dalton, which linear block polymer consists of internally and linearly linked sequences, which sequences can be described according to Formula (2)
  • each R 3 and each R 4 can be the same or different
  • R 3 can be described according to Formula (2A)
  • X and Y which X and Y can be the same or different, are (C-i-CsJalkyl, or are
  • A is [(2-4)-amino((C 2 -C 4 ) alkanoate)]((C C 5 )alkyl);
  • A is [(2-4)-amino((C 2 -C ) alkanoate)]((C 3 -C 5 )alkyl); or
  • X is derived from amino((CrC 5 )alkyl) when Y is derived from
  • each R p which R p can be the same or different, is hydroxy((C C 5 )alkyl) or [(2-4)-amino((C 2 -C 4 )alkanoate)]((C 2 -C 5 )alkyl); or
  • Y can be derived from a substituent according to Formula (3)
  • R is (C 2 -C 4 )alkyl
  • I is from 1 to 20, preferably 1 to 10, and X can then be derived from
  • R 3 can be described according to Formula (2B)
  • Y is hydrogen, (C .-C 4 )alkyl or benzyl
  • R can be derived from diisocyanate and comprises none, one or several ester groups
  • R 4 can be described according to Formula (2C)
  • each R 5 can be derived from diisocyanate
  • R 6 is (C 2 -C 4 )alkyl
  • m is from 1 to 20, preferably 1 to 10.
  • Each alkyl and each alkanoate in Formula (2) can, independently of each other, be straight or branched, saturated or unsaturated, and/or substituted with, for example, methyl, phenyl, 4-hydroxyphenyl, 4-aminobutyl, 2-butyl, 2-hydroxy methyl, 3- aminopropyl, 2-aminoethyl, 2-mercaptomethyl, or similar.
  • Said linear block polymer is of the polyurea or polyurethaneurea type when the polymer chain according to Formula (2) can contain urea groups as well as urethane and urea groups.
  • Both urethane and urea groups In the block polymer form intermolecular hydrogen bonds, which provides the cohesive forces that are required to hold the molecules together to a material. Particularly strong intermolecular forces are obtained by the urea groups, especially when several urea groups have the opportunity to cooperate.
  • Those blocks in a block polymers that contain urea groups are often known as "hard", since they are responsible for the cohesion of the material, wherein the cohesion is a function of the number and lengths of the blocks that contain urea groups.
  • the "hard” block is the block that is comprised in R 3 and the neighbouring urea groups.
  • the blocks in a block polymer that give the material its extensibility and elasticity are often known as "soft".
  • a "soft" block can be comprised within R , and, since R 4 can be described according to Formula (2C), the neighbouring urethane groups can also be comprised in a "soft" block.
  • Each R 3 which is the same or different, can be described according to Formula (2A) or (2B) and each R 4 , which is the same or different, comprises both one or several ester groups; wherein said linear block polymer comprises ester groups at such a distance from each other that after hydrolysis of said ester groups, fragments are created that are less than 2,000 Dalton, wherein the fragments can be excreted from a human or animal body.
  • the created fragments are preferably less than 1,000 Dalton.
  • the fragments can, according to the present invention, be of the order of 400-500 Dalton.
  • a linear block polymer comprising urea groups or urea and urethane groups, which linear block polymer is suitable for use as an implant, wherein said linear block polymer is biologically degradable in a human or animal body.
  • Said linear block polymer has degradation times when used as an implant, which degradation times can be varied from a few weeks to a couple of years through choice of said linear block polymer.
  • the present invention also relates to a linear block polymer with a molecular weight of at least 10 4 Dalton, which linear block polymer consists of internally and linearly linked sequences, which sequences can be described according to Formula (2)
  • each R 3 and each R 4 can be the same or different
  • R 3 can be described according to Formula (2A)
  • X and Y which X and Y can be the same or different, are (C ⁇ -C 5 )alkyl, or are
  • A is [(2-4)-amino((C 2 -C 4 ) alkanoate)]((C C 5 )alkyl);
  • A is [(2-4)-amino((C 2 -C ) alkanoate)]((C 3 -C 5 )alkyl); or Y can be derived from a substituent according to Formula (3)
  • R is (C 2 -C 4 )alkyl
  • I is from 1 to 20, preferably 1 to 10, and X can then be derived from
  • R 3 can be described according to Formula (2B)
  • Y is hydrogen, (d-C 4 )alkyl or benzyl
  • R 4 can be derived from diisocyanate and comprises none, one or several ester groups, or R 4 can be described according to Formula (2C)
  • each R 5 can be derived from diisocyanate
  • R 6 is (C 2 -C 4 )alkyl
  • m is from 1 to 20, preferably 1 to 10.
  • a further embodiment according to the present invention relates to said linear block polymers according to Formula (2), when Y can be derived from A, wherein A is
  • a further embodiment relates to a linear block polymer according to Formula (2), wherein each R 3 can be the same or different and can be derived from one or several of
  • each R 3 can be the same or different and can be derived from
  • each R 3 can be the same or different, may be derived from one or more of 3-[(aminoacetyl)oxy]-2,2-bis(hydroxymethyl)propyl aminoacetate or
  • a further embodiment according to the present invention relates to a linear block polymer wherein each R 4 , the same or different, or when R is according to Formula (2B), each R 5 , the same or different, can be derived from diphenylmethane diisocyanate, toluylene diisocyanate, hexamethylene diisocyanate, tetramethylene diisocyanate, naphthylene diisocyanate or ethyl-2,6-diisocyanatohexanoate (LDI).
  • each R 4 the same or different, or when R is according to Formula (2B)
  • each R 5 can be derived from diphenylmethane diisocyanate, toluylene diisocyanate, hexamethylene diisocyanate, tetramethylene diisocyanate, naphthylene diisocyanate or ethyl-2,6-diisocyanatohexanoate (LDI).
  • a further embodiment according to the present invention relates to a linear block polymer wherein each R 4 , the same or different, can be derived from one or several of polyesterdiol, polyetherdiol or monodiol and/or when R 4 can be described according to Formula (2C), each R 6 , the same or different, can be derived from one or several of polyesterdiol, polyetherdiol or monodiol.
  • a further embodiment of the present invention relates to a linear block polymer, wherein each R 4 , the same or different, can be derived from one or more of polytetramethylenoxidedio), polyethylenoxidediol, polycaprolactonediol, polyethyleneglycoladipatediol, polyldiethylenglycoladipatediol, toluylene diisocyanate, diphenylmethane, hexamethylene diisocyanate, tetramethylene diisocyanate, naphthylene diisocyanate, glycerin monoallylether, trimethylolpropane monallylether, glycerin monoglycidyl ether, ethyl-2,6-diisocyanatohexanoate (LDI), dimethylolpropionic acid methylester, dimethylolpropionic acid brombutylester, esters of monocarboxymethyl ethers, est
  • a further embodiment according to the present invention relates to a linear block polymer wherein said linear block polymer has a molecular weight of at least 2x10 4 Dalton. Further, the present invention relates to the use of a compound according to Formula (1) during preparation of linear block polymers.
  • the present invention also relates to the use of said linear block polymer, as has been described above, as material in implants for humans and animals.
  • linear block polymer according to the present invention also relates to, for example, pharmaceutical preparations, during microencapsulation, in suspensions, in emulsions or similar.
  • the present invention also relates to the use of said linear block polymer as material for promoting wound healing in humans and animals.
  • implants for humans and animals are concerned, wherein said implants comprise said linear block polymer.
  • the present invention also relates to pharmaceutical preparations, microencapsufes, suspensions or emulsions that comprise said linear block polymer.
  • the present invention also relates to material for promoting wound healing in humans and animals, which material comprises said linear block polymer.
  • the temperature in the reactor rose rapidly to 10°C, after which it sank to its original value.
  • the reaction was allowed to proceed for 3 hours at 0°C, after which it was warmed to approximately 30°C for one hour, and then left under stirring at room temperature until the next day.
  • Processing of the reaction mixture commenced with filtration through a 40-100 ⁇ m glass filter, wherein the filtration separates out precipitated dicyclohexylurea (DCU).
  • the dichloromethane that passed the filter was extracted with a 1M potassium hydrogen sulphate solution, followed by extraction with distilled water and with a saturated sodium hydrogen carbonate solution. The dichloromethane phase was then washed three times with distilled water.
  • the washed dichloromethane phase was dried over water-free magnesium sulphate and evaporated to give an oil that crystallised slowly. Yield 80-90%. If the oil contains contaminant in the form of dicyclohexylurea, the oil can be dissolved in ethyl acetate and the contaminant filtered out, in order to then evaporate off the ethyl acetate and regain the final product in a more pure condition. Yield: 16.4 g (approximately 80%).
  • DCM dichloromethane
  • the reaction mixture was processed by filtering out the DCU that had formed, after which the remaining solution was washed by extraction with a 1M potassium hydrogen sulphate solution, distilled water, a saturated solution of sodium hydrogen carbonate and, finally, three times with distilled water.
  • the thus purified organic phase was then dried over water-free magnesium sulphate, filtered and then evaporated to give a colourless oil that crystallised on reaching room temperature. Yield: 20 g (theoretical 23 g) 87%.
  • the reaction mixture was warmed for a short period to 30°C before processing. After cooling, the DCU was filtered out and the residue washed by extraction with potassium hydrogen sulphate (1 M), distilled water, sodium hydrogen carbonate (saturated) and three times with distilled water. The organic phase was then dried over water-free magnesium sulphate and evaporated to give an oil. The oil was dissolved in absolute ethanol and placed in the cold to crystallise. The crystals were filtered out and dried. Yield: approximately 8 g (theoretical 8.8 g) 90%.
  • the mixture was processed after being warmed to 30°C for approximately one hour. The residue was dissolved in ethyl acetate after filtering and evaporation, on which further DCU precipitated out. The product mixture was therefore allowed to stand for three days before being refiltered. The reaction mixture was washed by extraction with potassium hydrogen sulphate (1 M), distilled water, sodium hydrogen carbonate (saturated) and finally three times with distilled water. The organic phase was then dried over water-free magnesium sulphate, filtered and evaporated to dryness.
  • Pd/C 10% palladium on active carbon
  • TFA-salt of the above tetra-substituted pentaerythritol After evaporation of excess TFA, the TFA-salt of the tetra-substituted pentaerythritol may be used as a chain extender or a cross linking agent.
  • Mw 364.35 C13H24N4O8.
  • the molecular weight was estimated to be 33,000 Dalton by comparison with a polystyrene standard.
  • a prepolymer which is prepared from diphenylmethane diisocyanate that has reacted with polycaprolactonediol (PCL530) at a molar ratio of 2:1, were dissolved in 50 ml of dimethylformamide (DMF).
  • DMF dimethylformamide
  • the product from Example 5 dissolved readily in 25 ml DMF that was added to the prepolymer solution under vigorous stirring. The reaction was allowed to proceed until the next day, when it was precipitated with absolute ethanol. The polymer was washed in ethanol, dried and dissolved in DMF. A sample was removed for SEC analysis. The molecular weight was estimated to be approximately 21,000 Dalton by comparison with a polystyrene standard.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Polymers & Plastics (AREA)
  • General Health & Medical Sciences (AREA)
  • Vascular Medicine (AREA)
  • Dermatology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Materials Engineering (AREA)
  • Engineering & Computer Science (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Surgery (AREA)
  • Polyurethanes Or Polyureas (AREA)
  • Materials For Medical Uses (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un composé selon la formule (I) où R1 t R2 qui peuvent être identiques ou différents, représentent amino-(alkyle (C2-C5), (alkyle(C1-C4)((2-4)-amino(alkanoate(C2-C4)), ou A, A représentant ((2-4)-amino(alkanoate(C2-C4)) ((alkyle (C2-C5)) ; ou R1 représente amino (alkyle(C1-C5)) lorsque R2 représente ((2-4)-amino(alkanoate(C2-C4)))((2-4, 2-4)bis(Rp)(C2-C5)alkyle ; ou R2 est un substituant selon la formule (1A) Où R représente alkyle (C2-C4), et I vaut 1 à 20, de préférence, 1 à 10, R1 représentant alors (alkyle(C1-C4))((2-4)-amino(alkanoate(C2-C4))), ou ((2-4)-amino(alkanoate(C2-C4)))(alkyle(C2-C5)) ; et les nouveaux polymères séquencés linéaires.
PCT/SE2001/002904 2000-12-29 2001-12-27 Nouveaux composes destines a etre utilises comme produits intermediaires dans un polymere sequence lineaire et nouveau polymere sequence lineaire Ceased WO2002053526A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
SE0004925-4 2000-12-29
SE0004925A SE0004925L (sv) 2000-12-29 2000-12-29 Kemiska föreningar
SE0101523-9 2001-04-27
SE0101523A SE0101523L (sv) 2000-12-29 2001-04-27 Linjär polymer

Publications (1)

Publication Number Publication Date
WO2002053526A1 true WO2002053526A1 (fr) 2002-07-11

Family

ID=26655356

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/SE2001/002904 Ceased WO2002053526A1 (fr) 2000-12-29 2001-12-27 Nouveaux composes destines a etre utilises comme produits intermediaires dans un polymere sequence lineaire et nouveau polymere sequence lineaire
PCT/SE2001/002901 Ceased WO2002053616A1 (fr) 2000-12-29 2001-12-27 Nouveau polymere bloc lineaire

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/SE2001/002901 Ceased WO2002053616A1 (fr) 2000-12-29 2001-12-27 Nouveau polymere bloc lineaire

Country Status (3)

Country Link
AR (2) AR032053A1 (fr)
SE (1) SE0101523L (fr)
WO (2) WO2002053526A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7425559B2 (en) 2001-07-13 2008-09-16 Btg International Limited Medicine containing pyrimidine derivative
US20130108711A1 (en) * 2010-05-07 2013-05-02 Medicus Biosciences, Llc Methods for treating diseases of the lung
US8987339B2 (en) 2013-03-14 2015-03-24 Medicus Biosciences Llc Solid polyglycol-based biocompatible pre-formulation
US9072809B2 (en) 2012-05-11 2015-07-07 Medical Biosciences Llc Biocompatible hydrogel treatments for retinal detachment
US10111985B2 (en) 2011-08-10 2018-10-30 Medicus Biosciences, Llc Biocompatible hydrogel polymer formulations for the controlled delivery of biomolecules
US10294195B2 (en) 2014-01-31 2019-05-21 Seikagaku Corporation Diamine crosslinking agents, crosslinked acidic polysaccharides and medical materials
US11083821B2 (en) 2011-08-10 2021-08-10 C.P. Medical Corporation Biocompatible hydrogel polymer formulations for the controlled delivery of biomolecules
CN115433098A (zh) * 2022-09-19 2022-12-06 西南石油大学 一种环保性胺类抑制剂及其制备方法

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3567763A (en) * 1966-01-06 1971-03-02 Rohm & Haas Ester polyisocyanates
GB1251718A (fr) * 1968-03-15 1971-10-27
US3939200A (en) * 1966-01-06 1976-02-17 Rohm And Haas Company Aliphatic acyl-containing amine hydrochlorides
US4049632A (en) * 1976-07-14 1977-09-20 Armstrong Cork Company Chain extending polyurethanes with a large excess of water
EP0129396A2 (fr) * 1983-06-16 1984-12-27 Pfizer Hospital Products Group, Inc. Poly(éther-uréthane-urée) biocompatible et procédé pour sa fabrication
US4689353A (en) * 1986-02-21 1987-08-25 The Dow Chemical Company Hydroxy and amino-functional polyahls containing carbonate, urethane and/or urea moieties
US5236966A (en) * 1989-08-15 1993-08-17 British Technology Group Limited Polymeric materials
WO1997022643A1 (fr) * 1995-12-15 1997-06-26 Artimplant Development Artdev Ab Polymere bloc lineaire comprenant des groupes uree et urethane, procede pour le produire et son utilisation sous forme d'implants
WO2000045869A1 (fr) * 1999-02-02 2000-08-10 Artimplant Ab Film a usage medical, compose de polymeres blocs lineaires de polyurethane, et procede de production de ce film
US6221997B1 (en) * 1997-04-28 2001-04-24 Kimberly Ann Woodhouse Biodegradable polyurethanes

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3567763A (en) * 1966-01-06 1971-03-02 Rohm & Haas Ester polyisocyanates
US3939200A (en) * 1966-01-06 1976-02-17 Rohm And Haas Company Aliphatic acyl-containing amine hydrochlorides
GB1251718A (fr) * 1968-03-15 1971-10-27
US4049632A (en) * 1976-07-14 1977-09-20 Armstrong Cork Company Chain extending polyurethanes with a large excess of water
EP0129396A2 (fr) * 1983-06-16 1984-12-27 Pfizer Hospital Products Group, Inc. Poly(éther-uréthane-urée) biocompatible et procédé pour sa fabrication
US4689353A (en) * 1986-02-21 1987-08-25 The Dow Chemical Company Hydroxy and amino-functional polyahls containing carbonate, urethane and/or urea moieties
US5236966A (en) * 1989-08-15 1993-08-17 British Technology Group Limited Polymeric materials
WO1997022643A1 (fr) * 1995-12-15 1997-06-26 Artimplant Development Artdev Ab Polymere bloc lineaire comprenant des groupes uree et urethane, procede pour le produire et son utilisation sous forme d'implants
US6221997B1 (en) * 1997-04-28 2001-04-24 Kimberly Ann Woodhouse Biodegradable polyurethanes
WO2000045869A1 (fr) * 1999-02-02 2000-08-10 Artimplant Ab Film a usage medical, compose de polymeres blocs lineaires de polyurethane, et procede de production de ce film

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8288399B2 (en) 2001-07-13 2012-10-16 Btg International Limited Medicine containing pyrimidine derivative
US7425559B2 (en) 2001-07-13 2008-09-16 Btg International Limited Medicine containing pyrimidine derivative
US20160075635A1 (en) * 2010-05-07 2016-03-17 Medicus Biosciences Llc Vivo gelling pharmaceutical pre-formulation
US20130108711A1 (en) * 2010-05-07 2013-05-02 Medicus Biosciences, Llc Methods for treating diseases of the lung
US20130116341A1 (en) * 2010-05-07 2013-05-09 Medicus Biosciences, Llc In-vivo gelling pharmaceutical pre-formulation
US10227289B2 (en) 2010-05-07 2019-03-12 Medicus Biosciences, Llc Methods for treating diseases of the lung
US10189773B2 (en) * 2010-05-07 2019-01-29 Medicus Biosciences, Llc In-vivo gelling pharmaceutical pre-formulation
US10111985B2 (en) 2011-08-10 2018-10-30 Medicus Biosciences, Llc Biocompatible hydrogel polymer formulations for the controlled delivery of biomolecules
US11083821B2 (en) 2011-08-10 2021-08-10 C.P. Medical Corporation Biocompatible hydrogel polymer formulations for the controlled delivery of biomolecules
US9623144B2 (en) 2012-05-11 2017-04-18 Medicus Biosciences Llc Biocompatible hydrogel treatments for retinal detachment
US10507262B2 (en) 2012-05-11 2019-12-17 C.P. Medical Corporation Biocompatible hydrogel treatments for retinal detachment
US11596710B2 (en) 2012-05-11 2023-03-07 C.P. Medical Corporation Biocompatible hydrogel treatments for retinal detachment
US9072809B2 (en) 2012-05-11 2015-07-07 Medical Biosciences Llc Biocompatible hydrogel treatments for retinal detachment
US8987339B2 (en) 2013-03-14 2015-03-24 Medicus Biosciences Llc Solid polyglycol-based biocompatible pre-formulation
US9149560B2 (en) 2013-03-14 2015-10-06 Medicus Biosciences Llc Solid polyglycol-based biocompatible pre-formulation
EP3101064B1 (fr) * 2014-01-31 2020-07-15 Seikagaku Corporation Agent de réticulation diamine, corps réticulé de polysaccharide acide, et matériau médical
US10919840B2 (en) 2014-01-31 2021-02-16 Seikagaku Corporation Diamine crosslinking agents, crosslinked acidic polysaccharides and medical materials
US10294195B2 (en) 2014-01-31 2019-05-21 Seikagaku Corporation Diamine crosslinking agents, crosslinked acidic polysaccharides and medical materials
CN115433098A (zh) * 2022-09-19 2022-12-06 西南石油大学 一种环保性胺类抑制剂及其制备方法

Also Published As

Publication number Publication date
AR032053A1 (es) 2003-10-22
AR032222A1 (es) 2003-10-29
SE0101523D0 (sv) 2001-04-27
WO2002053616A1 (fr) 2002-07-11
SE0101523L (sv) 2002-06-30

Similar Documents

Publication Publication Date Title
US6319984B1 (en) Biodegradable and thermosensitive polyphosphazenes and their preparation method
WO2002053526A1 (fr) Nouveaux composes destines a etre utilises comme produits intermediaires dans un polymere sequence lineaire et nouveau polymere sequence lineaire
EP0713859B1 (fr) Dérivés d'acide cinnamique, dérivés polymères photoréticulables d'acide cinnamique et dérivés polymères réticulés d'acide cinnamique
EP0312502B1 (fr) Dipeptides utilisables comme régulateurs de croissance de plantes
EP2088140B1 (fr) Composés dihydrazide, leur préparation et leurs utilisations
CA2672620A1 (fr) Procede de preparation du (1r,2s,5s)-n-[(1s)-3-amino-1-(cyclobutylmethyl)-2,3-dioxopropryl]-3-[(2s)-2-[[[(1,1-dimethylethyl)amino]-carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
WO2003062298A1 (fr) Co-poly(ester amide) et co-poly(ester urethane) compositions presentant une biodegradabilite, procedes de production et utilisation associes
CN106749159B (zh) 5-炔丙氧基-三亚甲基碳酸酯及其制备方法和应用
Ruddick et al. A new method for the polymer-supported synthesis of cyclic oligoesters for potential applications in macrocyclic lactone synthesis and combinatorial chemistry
JP5158716B2 (ja) 乳酸残基を含有するデプシペプチド
CN113200919A (zh) 一种n-乙酰-肌肽的合成方法
JPH023415A (ja) 新規アルファーオキシ酸ポリマー
CN106543136A (zh) 苄氧羰基乙二胺三亚甲基碳酸酯及其制备方法和用途
Ueda et al. 3, 3'-(Phenylphosphinylidene) bis (2 (3H)-benzoxazolone) and 3, 3'-(phenylphosphinylidene) bis (2 (3H)-benzothiazolone). New activating agents.
CN106565771B (zh) 一种含有双氨基的磷酰胆碱化合物Lys-PC及其制备方法
US5248761A (en) Amino acid terminated polyesters having predetermined monomeric sequence
SU602114A3 (ru) Способ получени -/аминоациламинофенил/-ацетамидинов
DE602004011235T2 (de) Verfahren zur gewinnung von urethangeschützten n-carboxyanhydriden von alpha-aminosäuren
CN106543153A (zh) 2‑咪唑羰基‑2‑甲基三亚甲基碳酸酯及其制备方法和用途
CA2099999A1 (fr) Polyesters a sequence monomerique predeterminee
JP4219709B2 (ja) デプシペプチドの製造方法
JPS6372670A (ja) タウリン誘導体
CN101157748A (zh) 一种新型可降解网状结构聚氨酯/脲及其制备方法
CN111675666B (zh) (四唑-1-基)-n,n,n′,n′-四甲基脲六氟磷酸盐及制备方法
DE19513398C1 (de) Verfahren zur Darstellung von optisch aktiven oder optisch nicht aktiven N-(alpha-Hydroxyacyl)-alpha-aminosäuren

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

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

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP