LV10721B - Poymers containing diester units - Google Patents

Poymers containing diester units Download PDF

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LV10721B
LV10721B LVP-93-173A LV930173A LV10721B LV 10721 B LV10721 B LV 10721B LV 930173 A LV930173 A LV 930173A LV 10721 B LV10721 B LV 10721B
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formula
water
solution
polymers
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LVP-93-173A
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LV10721A (en
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Klaveness Jo
Strande Per
Wiggen Unni Nordby
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Nycomed Imaging As
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Abstract

limēri, kas satur diesteru vienības ar formulu [-CO-O-C(R1R2)-O-CO-j (I) vai to modifikācijas, kur R1 un R2 katrs apzīmē ūdeņraža atomu vai ar oglekli saistītu vienvērtīgu organisku grupu, vai arī R1 un R2 kopā veido ar oglekli saistītu divvērtīgu organisku grupu, un, gadījumā ja tādas vienības saistītas abos galos pie oglekļa atomiem un polimēri ir poliolefīni, tad šie polimēri ir biodegradējami un/vai ūdeni uzbriestoši, un/vai ir saistīti ar bioloģiski aktīvu vai diagnostisku aģentu.limits containing diester units of formula [-CO-O-C (R1R2) -O-CO- (I) or modifications thereof, wherein R 1 and R 2 each represent a hydrogen atom or a carbon monovalent organic compound. or R 1 and R 2 together form a carbon-linked bivalent organic group, and, if any units are attached at both ends to carbon atoms and polymers are polyolefins, these polymers are biodegradable and / or water swellable and / or associated with a biologically active or diagnostic agent.

Description

1 LV 10721
P0LYMERS CONTAINING DIESTER UNITS
This invention concerns polymers containing optionally substituted methylene diester groupings. Such groupings are capable of being biodegradable since they are labile to common esterase enzymes although in many instances the polymer may remain at least partly intact.
Biodegradable polymers have long been used in the medical field, for example to provide biodegradable implant materiāls and delayed release drug delivery systems. They are now of wider interest in overcoming the problem of pollution by long-lived insert packaging materiāls, household articles, detergents and the like.
There is also a need for polymers which, when they wholly or partially break down by Chemical or biological means, give reliably non-toxic products.
In general, biodegradation commonly involves enzymic hydrolysis of particular Chemical bonds in the polymer, notably ester, urethane or amide groups which are otherwise stable in the absence of enzymes. Thus, for packaging materiāls, aliphatic polyesters such as polycaprolactone, polyethylene adipate and polyglycolic acid are candidate materiāls although polyethylene terephthalate, which is very widely used in textiles and fibres, is resistant to biodegradation.
In the medical field, resorbable polymers are of interest for sutures and in wound closure, resorbable implants in the treatment of osteomyelitis and other bone lesions, tissue stapling and mesh tamponades, anastomosis as well as drug delivery systems and diagnostics. In these fields, polylactic acid, polyglycolic acid, poly (L-lactide-co-glycolide), polydioxanone, poly (glycolide-co-trimethylene carbonate), poly (ethylene carbonate), poly (iminocarbonates), polyhydroxybutyrate, poly (amino acids), poly (ester-amides), poly (orthoesters) and poly 2 (anhydrides) have ali been proposed (T.H. Barrows, Clinical Materials ļ (1986), pp. 233-257) as well as natūrai products such as polysaccharides. US-A-4180646, in particular, describes novel poly (orthoesters) for use in a very wide range of products.
Hovever, the polymers hitherto proposed for either medical or nore general use have each had one or more disadvantages and there is a demand for alternative polymers, in particular polymers containing readily biodegradable groupings. The present invention is based in the concept that diester units of the formula (IJ f-CO-O-C (R1 R2)-0-C0} (I) (where R1 and R2 are as defined below) are particularly rapidly degraded by common esterase enzymes but are stable in the absence of enzymes. A number of polymers containing such units have been described in the prior art. Thus, for example, US-A-2341334 describes the copolymerisation of monomers such as methylidene or ethylidene dimethacrylate with ethylenic monomers such as vinyl acetate, methyl methacrylate or styrene. The resulting copolymers are said to exhibit higher softening points than unmodified homopolymers of the ethylenic monomer and to be useful in the preparation of cast articles. DD-A-95108 and DE-A-1104700 similarly describe the copolymerisation of various alkylidene diacrylate esters with acrylic monomers to yield copolymers with modified physical properties. A number of alkylidene dicrotonates are disclosed in US-A-2839572 as monomers which may be homopolymerised or copolymerised with materiāls such as vinyl chloride, to yield resins useful as protective coatings. Kimura H. in J. Osaka Univ. Dent. Sch.~, 20 (1980) , pp. 4 3-49 describes the use of propylidyne trimethacrylate as a crosslinking aģent in coating dental polymethylmethacrylate in order to improve its abrasion resistance. Homopolymers of ethylidene, allylidene and benzylidene dimethacrylate are described in 3 LV 10721 FR-A-2119697 and by Arbuzova A. et al. in Zh.Obshch.Khim. 26 (1956), pp. 1275-1277, and typically comprise hard, glassy materiāls. EP-A-005294 6 discloses the use of certain polyacrylates to stabilise polyhydroxybutyric acid. The only polyacrylate having inore than one acryloyloxy group attached to a single carbon atom is pentaerithrityl monohydroxypentaacrylate, which by virtue of its numerous ethylenically unsaturated sites would be expected to form a complex mixture of addition polymers with polyhydroxybutyric acid. US-A-3293220 describes use of aldehyde dicarboxylates to stabilise polyoxymethylene polyxners by acylating the termiņai hydroxyl groups. There is no suggestion of cross-linking or incorporation of the aldehyde dicarboxylate residues into the polymer chains.
In such prior art, the diester grouping of formula (I) is introduced into the polymers by polymerisation of an alkylidene diacrylate or dimethacrylate monomer by a free radical mechanism whereby the olefinic bonds polymerise to form polyolefinic chains to which the diester groups are attached in side chains or cross-linking groups. The diester grouping is always of the form in which, referring to formula (I) , both carbonyl groups are joined directly to carbon, that is neither of the ester groups is other than a simple carboxylic ester group.
None of this prior art suggests that the diester groupings disclosed therein may be biodegradable; indeed, the introduction of crosslinking groups of the type represented by formula (I) above is generally seen as conveying enhanced rigidity and/or stability.
According to the present invention we have found it possible to prepare novel diester polymers containing linkages of formula (I) above which exhibit high stability in the absence of enzymes, which linkages are degradable by esterases both in the natūrai environment, e.g. by 4 bacterial attack, and in the human or animal body, to form non-toxic products, even where structural elements of the polymer, e.g. polymer backbone chains, retain their integrity.
In contrast to the diester-containing polyolefinic polymers described in the prior art, which typically are rigidly crosslinked, polymer of the invention may exhibit the property, even when polyolefinic, of being water-sttellable. This can convey a number of advantages, for example assisting the ingress of water-borne enzymes into the polymer structure, thereby facilitating biodegraditive attack. Water-swellable polymers may also be treated with aqueous or hydrophilic Solutions of, for example, biologically active or diagnostic aģents, whereby such aģents are incorporated into the polymer. In further embodiments of the invention such aģents may also be physically incorporated into the diester polymers during polymerisation or may be covalently bonded either to appropriate monomers which are subsequently polymerised or to preformed polymers.
Thus according to one aspect of the invention we provide polymers containing diester units of the formula (I) where R1 and R2 each represents a hydrogen atom or a carbon-attached monovalent organic group or R1 and R2 together form a carbon-attached divalent organic group, with the proviso that where such units are attached at both ends to carbon atoms and the polymers . are polyolefinic, then the polymers are biodegradable and/or are water-swellable and/or are associated with a biologically active or diagnostic aģent.
In general, biodegradable polymers are preferred. Polyolefinic polymers have the potential disadvantage of possessing carbon-carbon backbone chains which are not readily degraded although this may not be disadvantageous where the polymers are water-swellable and/or contain biological or diagnostic aģents and/or where the polymer backbone chains are water-soluble or dispersible, e.g. 5 LV 10721 after degradation of diester crosslinking groups.
The term 'diester' as used herein refers to the presence of two -C0-0- groups in the units of formula (I). These may be attached not only to carbon-attached organic groups, as in simple carboxylic esters, but to -0- atoms as in carbonate esters.
Thus polymers of the invention may be represented as containing units of the formula (II) f· (o) n—co—o—c (r’r2) —O—CO— (O) (II) where R1 and R2 are as defined above and m and n, which may be the same or different, are each 0 or 1.
In general, the polymers of the invention will contain units of the formula (III) t (O) n-CO-0-C (R1R2) -O-CO- (0) m-R3t (III) where R1, R2, m and n have the above meanings and R3 is a carbon-attached divalent organic grouping.
The polymers of the invention may advantageously be of relatively low molecular weight, since this may aid both biodegradation and dispersal of the degradation Products. Accordingly the term "polymer" as used herein in relation to the invention should be understood to include low molecular weight materiāls such as oligomers.
Polymers according to the invention may comprise a plurality of units of formula (III) having different meanings for m, n, R1, R2 and R3, for example as in block or graft copolymers. The diester linkages may occur at intervāls throughout the polymer, e.g. as crosslinking groups or between copolymer sections, in which case R3 will represent a polymeric grouping. Alternatively the linkages may be present throughout substantially the whole of the polymer, in v/hich case R3 will preferably be a low-molecular grouping.
Particularly interesting units (III) are those in 6 which n is 0 and m is 0 or 1, i.e. dicarboxylate units of the formula (IV) t CO-O-CiR’R^-O-CO-R3} (IV) 5 or carboxylate-carbonate units of the formula (V) f CO-O-C (R1R2) -O-CO-O-R3} (V) 10 The latter are of particular interest and have not been described previously in polymers of any kind. . R1 and R2 may, for example, each be hydrogen or a carbon-attached hydrocarbyl or heterocyclic group, for example having 1-20 carbon atoms, e.g. an aliphatic group 15 such as an alkyl or alkenyl group (preferably having up to 10 carbon atoms), a cycloalkyl group (preferably having up to 10 carbon atoms) , an araliphatic group such as an aralkyl group (preferably having up to 20 carbon atoms), an aryl group (preferably having up to 20 carbon atoms) or 20 a heterocyclic group having up to 20 carbon atoms and one or more heteroatoms selected from 0,S and N. Such a hydrocarbyl or heterocyclic grouping may carry one or more functional groups such as halogen atoms or groups of the formulae -NR4R5,-CONR4R5,-OR6,-SR6 and -COOR7, where R4 and 25 R5, which may be the same or different, are hydrogen atoms, acyl groups or hydrocarbyl groups as defined for R1 and R2; R6 is a hydrogen atom or an acyl group or a group as defined for R1 or R2 and R7 is a hydrogen atom or a group as defined for R1 or R2. Where R1 and R2 represent a 30 divalent grouping this may be an alkylidene, alkenylidene, alkylene or alkenylene group (preferably having up to 10 carbon atoms), which may carry one or more functional groups as defined above.
As indicated above, the diester groupings of formula 35 (I) may be separated by a wide range of groupings. Where it is desired that the polymer should break down into relatively short sections to aid biodegradation, the group 7 LV 10721 R3 which separates the diester units of formula (II) may, for example, be an alkylene or alkenylene group (e.g. containing up to 20, more preferably up to 10 carbon atoms), a cycloalkylene group (preferably having up to 10 carbon atoms), an arylene group (containing one or more aromatic rings and preferably having up to 20 carbon atoms), an aralkylene group (preferably having up to 20 carbon atoms and which may be bonded via the aryl and/or alkyl moieties - such aralkyl groups include, for example, two aryl groups joined by an alkylene Chain) or a heterocyclic group having one or more hetero-atoms selected from 0, S and N (preferably having up to 20 carbon atoms). The group R3 may carry functional groups, e.g. as set out above for R1 and R2 and/or substituents such as oxo groups; the carbon chains of R3 groups may be interrupted by heteroatoms such as ο, N or S, e.g. in conjunction with oxo substituents to form linkages such as ester, thioester or amide groups.
Where the group R3 comprises a polymeric grouping, this may, for example, be a poly(amino acid) such as a polypeptide, or a polyamide, poly(hydroxy acid), polyester, polycarbonate, polysaccharide, polyoxyethylene, polyvinyl alcohol or polyvinyl ether/alcohol grouping.
The wide range of possible groups R1, R2 and R3 enables the hydrophobicity or hydrophilicity of the polymer to be adjusted to any required use. Thus, the polymers may be water-soluble or water-insoluble.
Aliphatic groups present as, for example, R1 and R2 may be straight or branched, saturated or unsaturated and include, for example, alkyl and alkenyl groups, e.g. methyl, ethyl, isopropyl, butyl or allyl groups. Araliphatic groups include (monocarbocyclic aryl)-alkyl groups, for example benzyl groups. Aryl groups include mono- or bi-cyclic aryl groups, for example phenyl, tolyl or naphthyl groups. Heterocyclic groups include 5- or 6-membered heterocyclic groups preferably having one heteroatom, for example furyl, thienyl or pyridyl groups. 8
Halogen atom substituents may, for example, be chlorine, bromine or iodine.
Polymers according to the invention carrying functional groups or double bonds may serve as substrates for subsequent covalent attachment of biologically active materiāls such as drugs (e.g. antibacterial or antineoplastic aģents), steroids and other hormones, and agrochemicals such as weedkillers and pesticides, or of materiāls such as diagnostic aģents (e.g. X-ray and MRI contrast aģents) and may be sold in this form to users who will attach their own active material. Hovever, the invention also extends to p6lymers containing units of formula (III) vherein R1, R2 and/or R3 carry covalently-attached biologically active or diagnostic materiāls. Suitable active materiāls are exhaustively listed in US-A-4 180 646 referred to above, the contents of which are incorporated herein by reference.
In general, any biodegradation of the diester groupings of formula (I) will take place by enzymic hydrolytic cleavage of the bonds linking the group -0-C(r’r2)-O- to the adjacent carbonyl groups, generally yielding an aldehyde or ketone of the formula R1-C0-R2. The intervening sections, typified by -C0-(0)m-R3-(0) n-co-in the polymers of formula (III) will form different Products according to whether m or n is 0 or 1. Where m or n is 0, hydrolytic cleavage will generally yield a carboxyl group; where m or n is 1, a hypothetical carbonic acid group -R3-0-C00H is formed which generally eliminates carbon dioxide to form a grouping -R3-OH. This can be of use where liberation of carbon dioxide is physiologically or functionally desirable.
Polymers used for medical purposes must form non-toxic, physiologically acceptable degradation products. Thus, the groups R1, R2 and R3 should be such that degradation products such as the compound R1-C0-R2 and the products H00C-R3-C00H, HO-R3-C00H or H0-R3-0H are physiologically acceptable and readily 9 LV 10721 dispersible, preferably being water-soluble. Carbon dioxide liberated by cleavage of the carbonate groupings will normally be physiologically acceptable.
As indicated above, the units of formula (III) may be 5 different within the same polymer, i.e. the polymers may be copolymers such as block or graft copolymers. The polymers may be copolymers formed with non-biodegradable monomers; the non-biodegradable sections remaining after enzymic or other cleavage are preferably of acceptable 10 size to ensure their water-solubility or water-dispersibility and thus permit ready dispersal or repoval; it is possible to consider such non-biodegradable sections as part of the groupings R3 in formula (III) which, in effect, link together the biodegradable groupings of 15 formula (II) .
The polymers may be linear, branched or crosslinked. Branched and crosslinked polymers will in general make use of functional groups or double bonds in the corresponding R1, R2 or R3 groups of their monomers. The resulting 20 crosslinked or branched polymers will thus contain some units of formula (III) vherein R1, R2 and/or R3 are substituted with the crosslinking or branched chains. It is particularly useful for the group R3 to be derived from an amino acid which will in general be non-toxic and 25 soluble on cleavage. Dicarboxylic acids such as glutamic or aspartic acid can be used to make polymers containing -CO-R3-CO- units while hydroxy-amino acids such as serine or threonine can be used to make polymers containing -C0-0-R3-C0- units. The a-amino group of the amino acid 30 will comprise a functional amino substituent on R3 or the point of attachment of a branching or crosslinking chain. Crosslinking aģents can for example include di- or polyfunctional --molecules such as diols (for linking carboxyl groups) or diacids or diisocyanates (for linking 35 hydroxyl or amino groups).
In general, where the carbon atoms linking the groups R3 to the groupings of formula (II) are chiral, the 10 chirality is preferably that found in natūrai products since the degrading enzymes will generally act more efficiently on such structures. The L-configuration of amino-acid units is thus preferred. However D-isomers are 5 also cleavable and it may be more convenient in many instances to use isomer mixtures rather than material of only the optimal chirality. It is possible to make use of the different rātes of enzymic hydrolysis of D- and L-isomers to producē a controlled rāte of degradation. 10 It has been generally observed that in crosslinked biodegradable polymers the crosslinking sections are, often degraded first, thus exposing the rest of the network to enzymic hydrolysis. It is particularly useful, therefore, to have groupings of formula (II) in the crosslinking 15 chains of a polymer. One possibility is thus to convert a water-soluble long Chain natūrai or synthetic non-biodegradable or slowly biodegradable substance, e.g. a protein such as gelatin or albumin, a polysaccharide or oligosaccharide, or a short Chain polyacrylaroide, into a 20 water-insoluble form by crosslinking using crosslinking units containing groupings of formula (II). This may minimise the cost of the final product by reducing the amount of the relatively expensive biodegradable units of formula (II). 25 Block copolymers may, for example, have the structure
f (0) n-CO-0-C (R1R2) -O-CO- (0) m“R3^ f (O) n~C0-0-C (R1R2) -O-CO- (0) m~R3t B where the respective values of R1, R2, R3, m and n are such that the repeating units in blocks A and B are different and q and r are integers, e.g. 10-20. One or more further 30 blocks may be attached to those shown above.
The polymers of the invention may be prepared in any convenient way, for example by one of the methods set out below. 35 (A) Synthesis of a homopolymer comprising units of formula (III) in which n is 0 and m is 0 or 1 by 11 LV 10721 condensation polymerisation of a compound of the formula (VI) Χ-Ο^^2) -0-C0-(0)m-R3-C00R8 (VI) where R8 is a mētai ion such as silver, sodium, potassium or lithium, X is a leaving group, e.g. chlorine, bromine, iodine or a hydrocarbylsulphonyloxy group such as a'mesyloxy or tosyloxy group, m is 0 or 1 and R1,R2 and R3 have the above meanings.
The compound of formula (VI) may be prepared by reaction of the corresponding acid in which R8 is hydrogen with an appropriate base, vhereupon polymerisation will normally take place in situ.
The acid of formula (VI) in which R8 is hydrogen and m is 1 may be prepared by condensation of a compound of formula (VII) HO-R3-COOH (VII) with a compound of formula (VIII) X-C(R1R2)-O-CO-Χ1 (VIII) where X1 is a chlorine, bromine or iodine atom and R^R2, R3 and X have the above meanings. The reaction is preferably effected in the presence of a weakly nucleophilic base such as pyridine in a solvent for the reactants such as a halogenated hydrocarbon, e.g. chloroform.
The acid of formula (VI) in which R8 is hydrogen and m is O may be prepared by reaction of a compound of the formula (IX)
Phenyl-S-C(R1R2) -0-C0-R3-C00H (IX) (where R1, R2 and R3 have the above meanings) with a 12 halogenating aģent such as sulphonyl chloride, conveniently in a halogenated hydrocarbon solvent such as dichloromethane.
The compound of formula (IX) may be made by reaction of a compound of formula (X) CO-R3-CO (X) \ / 0 with a compound of the formula (XI)
Phenyl-S-C (R1R2) -X1 (XI) where R1, R2, R3 and X1 have the above meanings, conveniently in a polar solvent such as dimethylformamide. (B) Synthesis of a homopolymer comprising units of formula (III) in which m and n are O by condensation of a compound of the formula (XII) R80-CO-R3-CO-OR8 (XII) where R8 is a mētai ion as defined above and R3 has the above meaning, with a compound of the formula (XIII) X-C(R1RZ)-X (XIII) where the groups X, which may be the same or different have the meanings given above, preferably chlorine, bromine or iodine, and R1 and R2 have the above meanings. The compound of formula (XII) may be prepared from the corresponding acid in which R8 is hydrogen by reaction with an appropriate base, whereupon polymerisation will normally take place in situ.
The acid of formula (XII) wherein R8 is hydrogen and m is 0 may be prepared by deprotecting the corresponding 13 LV 10721 compound of formula (XII) in which R8 is a carboxyl protecting group, e.g. a readily hydrolysed group such as t-butyl. This may be removed by addition of base, e.g. sodium or potassium hydroxide to yield compound (XII) directly and hence initiate polymerisation. (C) Condensation polymerisation of a compound of the formula HR9-R3a- (O) n-C0-0-C (R1R2) -O-CO- (O) m-R3B-C00H where R1, R2, m and n have the above meanings, R3A and R3B are each groups as defined for R3 and R9 is O or NR4 (where R4 is a hydrogen atom, an acyl group or a hydrocarbyl group as defined for R1) , to give a polymer with repeating units (XIV) fR9-R3A- (O) n-CO-0-C (R1R2) -O-CO- ( O) m-R3B-COt (ΧΓV)
Such a polymer may be formed under the conditions conventional for polyester or polyamide condensations. It will be appreciated that such a repeating unit (XIV) corresponds to a unit of formula (III) in which R3 comprises the grouping -R3B-CO-R9-R3A-.
The starting material may be foirmed by deprotection of the corresponding compound having a protected carboxyl and/or -R9H group. The latter roay be synthesised by reacting a compound of the formula (XV) HO-C ( R1 R2) -O-CO- (O) m-R3B-COORA (XV) where R1, R2, R38 and m have the above meanings and RA is a protecting group , with a compound (XVI) RBR9-R3A-(0)n-C0-Cl (XVI) where R3a, R9 and n have the above meanings and R8 is a protecting group.
The compound (XV) may be prepared by coupling a compound (XVII) (XVII)
RcO-C(RnR2) -OH with a compound (XVIII)
Cl-C0-(0)m-R3e-C00RA (XVIII) where R1, R2, R3B, RA and m have the above meanings and Rc is a protecting group which is subseguently removed. The compound of formula (XVII) may be made by reaction of a compound R1-CO-R2 as defined above with an alcohol RcOH to form a hemiacetal. (D) Reaction of a compound R’-CO-R2, optionally together with a compound HO-R3-OH, with phosgene in the presence of a base such as pyridine to give a product containing units of the formula (XIX). fCO-O-C (R’r2) “O-CO-O—R3-*0'ļ· (XIX)
Some units will be formed of the formula (XX) f-CO-O-C (R1R2) -O-CO-O-C (R1R2) -0} (XX) but it should be noted that the definition of R3 given above includes -C (r’r2) -, so that the latter units are within the definition of formula (III) . Homopolymers containing such units may also be produced by reaction of the compound R’-CO-R2 with phosgene in the presence of a base such as pyridine. (E) Reaction of a compound of the formula (XXI) R10_R3A_ (0 j n_CO_0_C (R’R2) -0-CO- (0) ^R^-R11 (XXI) (where R1, R2, R3a, R3b, m and n have the above meanings and R10 and R11, which may be the same or different, optionally together with the groups R3a and R38 to which they are 15 LV 10721 attached, are reactive functional groupings) with a difunctional compound of the formula (XXII) r12_r3C_r13 (XXII) where R3c is a group as defined for R3 and R12 and R13, which may be the same or different, are reactive functional groups capable of reacting with R10 and R11 whereby a polymer according to the invention is formed, or R12 and R13 separately or together form a polymerisable group or groups capable of interaction with R10 and R11, for example so as to generate a polymerised version of compound (XXII) containing crosslinking groups derived from compound (XXI).
The functional groupings R10 and R11 may, for example, be leaving groups such as halogen atoms e.g. chlorine or bromine (as in haloalkyl groups; a-halomethyl ester groups; a-halomethyl keto groups; or halocarbonyl or halosulphonyl groups such as alkanoyl or sulphonvl halides) or sulphonate ester groups, e.g. alkyl sulphonate esters such as mesyloxy groups and aromatic sulphonate esters such as tosyloxy groups; or activated carboxyl groups, e.g. symmetrical or mixed anhydrides; or activated hydroxyl groups; or with R3a and/or R3B form activated alkenes, e.g. a,β-unsaturated ketones and esters; epoxy groups; or aldehyde and ketone groups and acetals and ketals thereof.
The compound (XXII) may, for example, be a relatively short divalent monomer or preformed polymer whereby a copolymer is formed, or a polyvalent natūrai or synthetic polymeric material such as a protein or carbohydrate which will be crosslinked by the reaģent of formula (XXI). In such cases the groups R12 and R13 may be nucleophilic groups such as hydroxyl or amino, which commonly occur in natūrai polymers such as carbohydrates and proteīns and which will react with the groupings R10 and R11 listed above. It will be appreciated that R10 and R11 may equally be groups such 16 as hydroxyl or amino, while R12 and R13 are groups reacting with these as listed for R10 and R11.
Polymerisable compounds of formula (XXII) include those in which R12 and R13 form an optionally substituted ethylenically unsaturated group, e.g. a vinyl group. Examples of such compounds thus include vinyl monomers such as vinyl acetate and styrene and acrylic and methacrylic monomers such as acrylic acid, methacrylic acid, methyl acrylate, methyl methacrylate, acrylamide, methacrylamide, acrylonitrile, methacrylonitrile, hydroxyethyl methacrylate and hydroxypropyl methacrylate. Compounds of this type may be copolymerised with compounds of formula (XXI) in which R10 and R11 comprise ethylenically unsaturated groups, e.g. under conditions appropriate for free radical polymerisation, to yield appropriately crosslinked polymers.
Reaģents of formula (XXI) are new and constitute a further feature of the invention.
Polymers in accordance with the invention may, for example, be produced in a single solution phase whereby a mass of insoluble polymeric material is formed; after solvent removal this material may be shaped for the required end use e.g. as sheets, fibres, pārticies or articles such as surgical implants. Un-crosslinked polymers according to the invention will in general be thermoplastic and so may be shaped (e.g. by calendering, drawing or moulding) at elevated temperature to form a particular desired product. Films of polymers according to the invention may, for example, be made by solvent casting.
The polymers may also be produced by emulsion polymerisation to give pārticies of the polymeric material? a solution of the monomer(s) in a water-immiscible organic solvent may be dispersed in an agueous phase and polymerisation then initiated. Thus, for example, in reactions (A) and (B) above, where formation of a salt initiates polymerisation, the acid (VI) in 17 LV 10721 reaction (A) or the protected acid (XII) in reaction (B) may be dissolved in an organic solvent such as a halogenated hydrocarbon and emulsified, for example by sonication. Addition of a base such as sodium hydroxide to the aqueous phase, optionally with a phase transfer aģent, then initiates polymerisation. Heating may be desirable to promote polymerisation. Methods of emulsion polymerisation to producē pārticies, especially monodisperse pārticies, are described in EP-A-0003905, EP-A-0091453, EP-A-0010986 and EP-A-0106873.
Polymers according to the invention, e.g. containing units of formula (III) as hereinbefore defined,' find utility in, for example, surgical implants such as sutures, soft tissue prostheses, sponges, films (e.g. artificial skin) or wound dressings (e.g. hydrogel sheets), flexible sheet materiāls and articles such as containers formed therefrom. Such polymers are advantageously biodegradable. Biodegradable polymers also find use in, for example, the manufacture of biodegradable delayed release formulations for drugs or agricultural Chemicals, and horticultural aids such as water-retaining "mulch" sheeting and plant containers. Such usages and the polymers shaped for use therein comprise further features of the invention. For use as prostheses, the shaped polymers may advantageously carry heparin, at least on the surface thereof.
Where a polymer of the invention is to be used as a biodegradable delayed release aģent, the active material may be contained within a shell of the biodegradable polymer, e.g. in a capsule or in microspheres, or it may be physically incorporated during polymerisation so that it is uniformly distributed within the polymer and is released during biodegradation. Alternatively, the active material may comprise ali or part of any of the groups R1, R2 or R3 and thus be released by the enzymatic cleavage. Typical drugs for incorporation in delayed release formulations include steroids, contraceptives, antibacterials, narcotics-antagonists and anti-tumour drugs. 18
The polymers of the invention, when of appropriately short chain length, may be used as plasticisers for other polymers. Where the polymers of the invention are biodegradable, degradation of the plasticiser thus either breaks up the integrity of the material or opens it up to attack by enzymes.
Biodegradable polymer pārticies according to the invention can also advantageously be used for diagnostic purposes. Thus an X-ray contrast aģent, which will normally be a poly-iodo aromatic compound, xnay form ali or part of the group R3 or -C^R2)- so that it is liberated and safely eliminated from the body on biodegradation. Such pārticies may be used for visualisation of the liver and spleen since they are trapped in the reticulo-endothelial systems of those orgāns. The X-ray contrast aģent may also be simply held physically in the polymers by being incorporated during polymerisation.
Polymer pārticies according to the invention may also contain paramagnetic, superparamagnetic or ferromagnetic substances which are of use in magnetic resonance imaging (MRI) diagnostics. Thus, submicron pārticies of iron or a magnetic iron oxide can be physically incorporated into the polymers during polymerisation to provide ferromagnetic or superparamagnetic pārticies. Paramagnetic MRI contrast aģents principally comprise paramagnetic mētai ions, such as gadolinium ions, held by a chelating aģent which prevents their release (and thus substantially eliminates their toxicity). Such chelating aģents with complexed mētai ions may be physically held in the polymers by being present during polymerisation or the groups R1, R2 and R3 may comprise suitable chelating groups. In general many such chelating aģents are poly-amino poly-carboxylic acids such as diethylene triamine pentaacetic acid (R.B. Lauffer, Chem. Rev. 82 (1987), pp. 901-927).
Polymer pārticies of the invention may also contain ultrasound contrast aģents such as heavy materiāls, e.g. barium sulphate or iodinated compounds such as the X-ray contrast aģents referred to above, to provide ultrasound contrast media. LV 10721 19
The following Examples are given by way of illustration only. 20 EXAMPLE 1 Ροΐγ (1.6-dioxa-2.5-dioxoheptvlene)
To a mixture of di-sodium succinate (1.0 equiv.) in an appropriate amount of dimethylformamide is added diiodomethane (1.0 equiv.). The reaction mixture is stirred at ambient temperature until the main amount of the reaģents are consumed, dialysed to remove low inolecular weight material, and evaporated to give the title double ester polymer having repeating units of formula f0-CO-CH2-CH2-CO-O-CH2} 1 2 3 4 5 6 7 i.e. units (II) in which R1=R2=H, R3= -CH2-CH2~ and m=n=0. EXAMPLE 2
Polv (2.6-dimethvl-4.7-dioxo-l.3.5-trioxaheptvlene^
To a mixture of l-chloroethyl chloroformate (1.1 equiv.) and (S)-2-hydroxypropionic acid (1.0 eguiv.) in an appropriate amount of dimethylformamide is added dropvise pyridine (1.0 equiv.) at a temperature below 12*C. The reaction mixture is stirred at ambient temperature until the majority of the reaģents are consumed, dialysed to remove low molecular weight material, and evaporated to give the title carbonate ester polymer having repeating units of formula fO-CH (CH3) -0-C0-0-CH(CH3) -CO^· 1 2 3 4 5 6 7 i.e. units (II) in which R1=H, R2=CH3, R3=CH(CH3), m=l and n=0. 21 LV 10721 EXAMPLE 3 a) Mono-qlvcovloxvmethvl succinate
To a mixture of sodium glycolate (1.0 equiv.) in an approriate amount of diinethylforinainide, is dropwise added benzyl chlorometyl succinate (1.0 eguiv. prepared in accordance with Benneche, Strande and Wiggen, Acta Chem. Scand. 43. (1988), pp. 74-77) in dimethylformamide at ambient temperature. The reaction mixture is stirred at 50*C until the majority of the reactants are consumed, concentrated, and extracted into chloroform/sodium carbonate solution. The organic phase is dried and evaporated to give the benzyl ester of the title product. Catalytic hydrogenation in conventional manner removes the benzyl group, and the title compound is thus obtained, having the formula ho-co-ch2-ch2-co-o-ch2-o-co-ch2-oh b) Polv f 5.7,10-trioxa-l.4.8-trioxodecvlene^ A mixture of mono-glycoyloxymethyl succinate and a catalytic amount of p-toluenesulphonic acid in dry toluene is refluxed under a nitrogen atmosphere until water ceases to form. The solvent is removed at 200*C and a pressure of 0.1 mm Hg, to give the title polymer having repeating units of the formula fC0-CH2-CH2-C0-0-CH2-0-C0-CH2-0} 12 3 456789 10 i.e. units (II) in which R1=R2=H, R3= -CH2-0-C0-CH2-CH2-and m=n=0. 22 EXAMPLE 4 a) Methvlene dimethacrvlate A solution of potassium hydroxide (1.00 M, 40.00 ml) is added to methacrylic acid (3.44 g, 40.00 mmol) at 0'C and the solution freeze dried for 16 hours. Dry dimethylfo.rmantide (230 ml) is added and the suspension heated to 60 *C under a dry nitrogen atmosphere. Diiodomethane (1.61 ml', 20.00 mmol) is added in two portions during 10 min. and the reaction mixture left for 4 days at 60*C. The solvent is removed under reduced pressure (0.05 mm Hg) , before diethyl ether (140 ml), saturated aqueous sodium hydrogen carbonate (50 ml) and water (50 ml) are added. The aqueous layer is extracted with diethyl ether (6 x 60 ml) and the combined ether extracts washed with water (4 x 50 ml), dried (MgSOA) , and evaporated to give 2.63 g (72%) of the title compound. 1H NMR (60 MHz, CDC13) : S 1.97 (2 x CH3, m), 5.63 (2 X H-C=, m), 5.88 (CH2, s), 6.18 (2 X H-C=, m) . IR (film, cm'1): 2987 (w) , 2962 (w) , 2930 (w) , 1732 (str), 1638 (w), 1454 (w), 1315 (w), 1295 (w), 1158 (w) , 1100 (str), 1012 (m) , 989 (m) . b) Methvlene diacrvlate A solution of potassium hydroxide (1.00 M, 40.00 ml) is added to acrylic acid (2.88 g, 40.00 mmol) at o*c and the solution freeze dried for 16 hours. Dry dimethylformamide (200 ml) is added and the suspension heated to 60 *C under a dry nitrogen atmosphere. Diiodomethane (1.61 ml, 20.00 mmol) is added in two portions during 10 min. and the reaction mixture left for 4 days at 60*C. The solvent is removed under reduced pressure (0.05 mm Hg) , before diethyl ether (140 ml) , saturated aqueous sodium hydrogen carbonate (50 ml) and water (50 ml) are 23 LV 10721 added. The aqueous layer is extracted with diethyl ether (6 x 60 ml) and the combined ether extracts washed with water (4 x 50 ml) , dried (MgSOJ , and evaporated to give 1.06 g (34%) of the title compound. 1H NMR (60 MHz, CDC13) : <5 5.81-6.61 (2 x CH2 = CH-, m) , 5.84 (CH2, s). c) Chloromethvl (2-methacrvlovloxv)ethvl carbonate
Pyridine (0.89 ml, 11.00 mmol) is added dropwise to a solution of chloromethyl chloroformate (0.89 ml, 11.00 mmol) and 2-hydrox'yethyl methacrylate (1.22 ml, 10.00 mmol) in dichloromethane (12 ml) at 0*C under a dry nitrogen atmosphere. After 21 hours at 20*C the reaction mixture is washed with hydrochloric acid (1.00 M, 10 ml), saturated aqueous sodium hydrogen carbonate (10 ml) and water (10 ml). The organic phase is dried (MgS04) and the solvent evaporated under reduced pressure (10 mm Hg) to give l.97g (88%) of the title compound. 1H NMR (60 MHz, CDC13) : 6 1.88 (CH3, d, J=2 HZ) , 4.35 (0-CH2-CH2-0, m) , 5.47 (H-C=, m), 5.63 (CH2-C1, s), 6.00 (H-C=, m). d) ( 2-Methacrvlovloxv) ethvl_methacrvlovloxvmethvl carbonate A solution of potassium hydroxide (1.00 M, 5.00 ml) is added to methacrylic acid (0.43 g, 5.00 mmol) at 0*C and the solution freeze dried during 16 hours. Dry dimethylformamide (50 ml) is added and to the resulting suspension is added chloromethyl (2-methacryloyloxy)ethyl carbonate (1.11 g, 5.00 mmol). 18-Crown-6. (0.066 g, 0.25 mmol) is added as a catalyst and the reaction left under a dry nitrogen atmosphere. After 24 hours at 20°C and 6 days at 4”C the solvent is removed under reduced pressure (0.05 mm Hg) and diethyl ether (30 ml) and water (20 ml) 24 added. The aqueous layer is extracted with diethyl ether (3 x 20 ml) and the combined ether extracts washed with water (20 ml), dried (MgSOJ and evaporated to give 1.26 g (93%) of the title compound. 1H NMR (60 MHz, CDC13) : <5 1.97 (2 x CH3, m) , 4.38 (0-CH2-CH2-0, m) , 5.53 (2 X H-C=, m) , 5.77 (CH2, s) , 6.07 (2 X H-C=, m) .
Ethvlene di(chloromethvl carbonate)
Pyridine (0.89 ml, 11.00 mmol) is added dropwise to a solution of chloromethyl chloroformate (1.32 ml, 14.83 mmol) and ethylene glycol (0.28 ml, 5.00 mmol) in dichloromethane (10 ml) at 7*C with good stirring under a dry N2 atmosphere. After 15 min. at 7*C and 6 hours at 20*C the reaction mixture is transferred to a separating funnel with the aid of dichloromethane (10 ml) . The reaction mixture is washed with hydrochloric acid (1.00 M, 10 ml), saturated aqueous sodium hydrogen carbonate (10 ml) and water (10 ml) . The organic phase is dried (MgS04) and the solvent evaporated under reduced pressure to give 1.12g (90%) of the title product. 1H NMR (300 MHz, CDClj) : 6 4.48 (s, 0-CH2CH2-0) , 5.75 (s, 2 x Cl-CH2-0) . 13C NMR (75 MHz, CDC13) : δ 65.8 (0-CH2CH2~0) , 72.2 (2 X Cl-CH2-0) , 153.0 (2 X C=0) .
Bis(2-chloromethoxvcarbonvloxvethvl)ether
Pyridine (0.89 ml, 11.00 mmol) is added dropvise to a solution of chloromethyl chloroformate (1.32 ml, 14.83 mmol) and diethylene glycol (0.47 ml, 5.00 mmol) in dichloromethane (10 ml) at 7*C with good stirring under a dry N2 atmosphere. After 10 min. at 7*C and 6 hours at 20*C the reaction mixture is transferred to a separating funnel with the aid of dichloromethane (10 ml). The reaction mixture is 25 LV 10721 vashed with hydrochloric acid (1.00 M, 10 ml), saturated aqueous sodium hydrogen carbonate (10 ml) and water (10 ml). The organic phase is dried (MgS04) and the solvent evaporated under reduced pressure (10 mm Hg) to give 1.26 g (86%) title product. ’h NMR (300 MHz, CDC13) : 6 3.72 (m, 2 X CHj-O) , 4.34 (m, 2 x CH2-0-C=0) , 5.71 (s, 2 X Cl-CH2-0) . 13C NMR (75 MHz, CDC13) : S 67.6 (2 X CH2-0) , 68.5 (2 x CH2~0-C=0) , 72.1 (2 X Cl-CH2-0) , 153.2 (2 X C=0) . 1-Chloroethvl 2-methacrvlovloxvethvl carbonate
Pyridine (0.89 ml, 11.00 mmol) is added dropwise to a solution of l-chloroethyl chloroformate (1.20 ml, 11.00 mmol) and 2-hydroxyethyl methacrylate (1.22 ml, 10.00 mmol) in dichloromethane (12 ml) at 3*C under a dry N2 atmosphere. After 15 min. at 3‘C and 17 hours at 20*C the reaction mixture is transferred to a separating funnel with the aid of dichloromethane (10 ml). The reaction mixture is washed with hydrochloric acid (1.00 M, 10 ml), saturated aqueous sodium hydrogen carbonate (10 ml) and water (2 x 10 ml) . The organic phase is dried (MgSOJ and the solvent evaporated under reduced pressure to give 1.76g (74%) of the title product. ’h NMR (60 MHz, CDClj) : S 1.85 (3 H, d, J=6 Hz, CH3-CH), 1.96 (3 H,d, J=2 HZ, CH3-C=) , 5.55 (1 H, m, CH=) , 6.10 (1 H, m, CH=) , 6.38 (1 H, k, J=6 Hz, CH-CHj) .
Chloromethvl 4-acrvlovloxvbutvl carbonate
Pyridine (0.89 ml, 11.00 mmol) is added dropwise to a solution. of chloromethyl chloroformate (0.98 ml, 11.00 mmol) and 4-hydroxybutyl acrylate (1.38 ml, 10.00 mmol) in dichloromethane (12 ml) at 3'C under a dry N2 atmosphere. After 15 min. at 3*C and 17 hours at 20"C the reaction mixture is transferred to 26 a separating funnel with the aid of dichloromethane (10 ml). The reaction mixture is washed with hydrochloric acid (1.00 M, 10 ml), saturated aqueous sodium hydrogen carbonate (10 ml) and water (2 x 10 ml) . The organic phase is dried (MgS04) and the solvent evaporated under reduced pressure to give I. 76g (74%) of the title product. ’H NMR (60 MHz, CDClj) : <5 1.82 (4 H, m, CH2-CH2) , 4.27 (4 H, m, 2 x CH2-0) , 5.77 (2 Η, s, Cl-CH2-0) , 5.8-6.7 (3 H, m, CH=CH2) . i) 1-Chloroethvl 4-acrvlovloxvbutvl carbonate
Pyridine (0.89 ml, 11.00 mmol) is added dropwise to a solution of l-chloroethyl chloroformate (1.20 ml, II. 00 mmol) and 4-hydroxybutyl acrylate (1.38 ml, 10.00 mmol) in dichloromethane (12 ml) at 3*C under a dry N2 atmosphere. After 15 min. at 3*C and 17 hours at 20*C the reaction mixture is transferred to a separating funnel with the aid of dichloromethane (10 ml). The reaction mixture is vashed with hydrochloric acid (1.00 M, 10 ml), saturated aqueous sodium hydrogen carbonate (10 ml) and water (2 x 10 ml) . The organic phase is dried (MgSOJ and the solvent evaporated under reduced pressure to give 2.26g (90%) of the title product. nH NMR (60 MHz, CDClj) : δ 1.80 (4 H, m, CH2-CH2) , 1.86 (3 H, d, J=5
Hz, CH3) , 4.24 (4 H, m, 2 x CH2~0) , 5.7-6.6 (4 H, m, CH=CH2 and CH). j. 1-Methacrvlovloxvethvl 2-methacrvlovloxvethvl carbonate l-Chloroethyl 2-methacryloyloxyethyl carbonate (1.183g, 5.00 mmol) is added to a suspension of freeze dried potassium methacrylate (0.683 g, 5.50 mmol) and 18-crown-6 (0.066 g, 0.25 mmol) in 27 LV 10721 dimethylformamide (50 ml) under a dry N2 atmosphere. After 5 days at 20*C the solvent is removed under reduced pressure and the residue dissolved by adding dichloromethane (60 ml) and water (30 ml) . After separating the phases the aqueous layer is extracted with dichloromethane (3 x 30 ml) and the combined organic phase washed with saturated aqueous sodium hydrogen carbonate (50 ml) . The organic phase is dried (MgS04) and the solvent removed under reduced pressure to give 1.10g (77%) of the title product. ’H NMR (60 MHz, CDClj) : <5 1.63 (3 H, d, J=5 Hz, CHj-CH) , 1.98 (6 H, s, 2 X CHj) , 4.42 (4 H, S, O-CHj-CH.,-O) , 5.62 (2 H, m, CH=) , 6.15 (2 H, m, CH=) , 6.84 (1 H, k, J=5 Hz, CH-CH3) . k) Acrvlovloxvmethvl 4-acrvlovloxvbutvl carbonate
Chloromethyl 4-acryloyloxybutyl carbonate (1.183g, 5.00 mmol) is added to a suspension of freeze dried potassium acrylate (0.606 g, 5.50 mmol) and 18-crown-6 (0.066 g, 0.25 mmol) in dimethylformamide (50 ml) under a dry N2 atmosphere. After 5 days at 20*C the solvent is removed under reduced pressure and the residue dissolved by adding dichloromethane (60 ml) and water (30 ml). After separating the phases the aqueous layer is extracted with dichloromethane (3 x 30 ml) and the combined organic phase washed with saturated agueous sodium hydrogen carbonate (50 ml). The organic phase is dried (MgSOJ and the solvent removed under reduced pressure to give 1.24g (91%) of the title product. ’h NMR (60 MHz, CDClj): 6 1.82 (4 H, m, CH2-CH2) , 4.23 (4 H, m, 2 X CH2-0) , 5.88 (2 H, s, 0-CH2-0) , 5.7-6.8 (6 H, 2 X CH=CH2) . l) l-Acrvlovloxvethvl 4-acrvlovloxvbutvl carbonate l-Chloroethyl 4-acryloyloxybutyl carbonate (1.253g, 28 5.00 mmol) is added to a suspension of freeze dried potassium acrylate (0.606 g, 5.50 mmol) and 18-crown-6 (0.066 g, 0.25 mmol) in dimethylformamide (50 ml) under a dry N2 atmosphere. After 5 days at 20’C the solvent is removed under reduced pressure and the residue dissolved by adding dichloromethane (60 ml) and water (30 ml). After separating the phases the aqueous layer is extracted with dichloromethane (3 x 30 ml) and the combined organic phase washed with saturated aqueous sodium hydrogen carbonate (50 ml) . The organic phase is dried (MgS04) and the solvent removed under reduced pressure to give 1.28g (89%) of the title product. ’H NMR (60 MHz, CDC13) : δ 1.58 (3 H, d, J=5 Hz, CHj-CH) , 1.80 (4 H, m, CH2-CH2) , 4.24 (4 H, m, 2 X CH2-0) f 5.7-6.7 (6 H, m, 2 X CH=CH2) , 6.87 (1 H, k, J=5 Hz, CH-CHj) . m) Methvlene di(o-vinvlbenzoateī
Diiodomethane (0.20 ml, 2.50 mmol) is added to a solution of freeze dried potassium p-vinylbenzoate (0.931 g, 5.00 mmol), 18-crown-6 (0.040 g, 0.25 mmol) and hydroquinone (0.011 g, 0.10 mmol) in dimethylformamide (35 ml) under a dry N2 atmosphere and the reaction mixture left for 2.5 days at 60*C. The solvent is removed under reduced pressure and the residue dissolved by adding diethyl ether (20 ml) , saturated aqueous sodium hydrogen carbonate (5 ml) and water (10 ml). After separating the phases the aqueous layer is extracted with diethyl ether (6 x 10 ml) and the combined organic phase vashed with water (5 x 10 ml). The organic phase is dried (MgSOJ and the solvent removed under reduced pressure to give 0.64g (83%) of the title product. 1H NMR (300 MHz, CDClj) : <5 5.39 (2 H, d, J=10 Hz, 2 x CH=) , 5.86 (2 H, d, J=17.6 HZ, 2 X CH=), 6.24 (2 H, s, 0-CH2-0), 6.73 (2 H, dd, J=11.0, 17.6, 2 X CH=), 7.45 (4 H, 2 x d, 29 LV 10721 J=6·8 Hz, Ar), 8.04 (2 H, d, J=6.6 Hz, Ar), 8.05 (2 H, d, J=6.6 Hz, Ar). 13C NMR (75 MHz, CDClj) : 6 79.8 (0-CH2-0) , 116.8 (2 X CH=) , 126.0, 130.2 (C2#C2',C3, C3'), 127.8, 142.5 (C,, C, ' , C4, C4 ' ) / 135.7 (2 x CH=) , 164.9 (2 X C=0). n) Methvlene di(p-bromobenzoate)
Diiodoroethane (0.60 ml, 7.50 mmol) is added to a solution of freeze dried potassium p-bromobenzoate (3.587 g, 15.00 mmol) and 18-crown-6 (0.198 g_, 0.75 mmol) in dimethylformamide (100 ml) under a dry N? atmosphere and the reaction mixture left for 4 days at 60*C. The solvent is removed under reduced pressure and the residue dissolved by adding dichloromethane (60 ml) and water (30 ml) . After separating the phases the aqueous layer is extracted with dichloromethane (3 x 30 ml) and the combined organic phase washed with saturated aqueous sodium hydrogen carbonate (50 ml) . The organic phase is dried (MgS04) and the solvent removed under reduced pressure to give 2.62g (84%) of the title product. 1H NMR (60 MHZ, CDClj) : 6 6.29 (2 H, s, 0-CH2~0) , 7.63 (4 H, d, J—9 HZ, Ar), 8.00 (4 H, d, J=9 Hz, Ar). o) Methvlene di(p-hvdroxvbenzoate^
Diiodomethane (0.40 ml, 5.00 mmol) is added to a solution of freeze dried potassium p-hydroxybenzoate (1.762 g, 10.00 mmol) in dimethylformamide (60 ml) under a dry N2 atmosphere and the reaction mixture left for 4 days at 60*C. The solvent is removed under reduced pressure and the residue dissolved by adding dichloromethane (60 ml) and water (30 ml) . After separating the phases the aqueous layer is extracted with dichloromethane (3 x 30 ml) and the combined organic phase washed with brine (50 ml). 30 30 10 15 20 25 q) 30
The organic phase is dried (MgS04) and the solvent removed under reduced pressure to give 0.94g (65%) of the title product. ’H NMR (60 MHz, CDCl3/CD3OD 1:2): <5 4 -92 (2 H, s, 2 X OH) , 6.18 (2 H, s, O-CHj-O) , 6.88 (4 H, d, J=9 HZ, Ar), 7.96 (4 H, d, J = 9 Hz, Ar). p) Methvlene bisΓp-(hvdroxvmethvlethvnvl)benzoate1
Bis (triphenylphosphine)palladium dichloride (17.0 mg, 0.02 mmol) and cuprous iodide (2.0 mg, O.Olmmol) are added to a suspension of methylene bis (p-bromobenzoate) prepared as described in Example 4 (n) (0.500 g, 1.21 mmol) and propargyl alcohol (0.16 ml, 2.66 mmol) in triethylamine (10 ml) with good stirring, at 20*C, under a dry N2 atmosphere. After 10 days at 20*C, the triethylamine is removed under reduced pressure, water (20 ml) is added and the mixture is extracted with dichloromethane (3 x 15 ml) . The dichloromethane phases are washed with hydrochloric acid (0.5 M, 10 ml), dried (MgS04) and the dichloromethane removed under reduced pressure to give 0.37 g (85%) of the crude product. 1H NMR (60 MHZ, CDClj) : S 3.67 (2 H, s, OH) , 4.47 (4 H, s, CH2-0) , 6.18 (2 H, S, 0-CH2-0) , 7.2-7.5 (4 H, Ar), 7.8-8.0 (4 H, Ar).
Adipic acid bis 1-chloroethvl ester
Anhydrous zinc chloride (10.0 mg, 0.07 mmol) is added to adipoyl chloride (2.92 ml, 20.00 mmol) at 20*C, under a dry N2 atmosphere. Acetaldehyde (2.26 g, 40.00 mmol) is added dropwise to the reaction mixture at -5*C. .The reaction temperature is ķept between -5*C and 0*C and dichloromethane (20 ml) is added. The zinc chloride catalyst is removed by passing the reaction mixture through a chromatography column containing aluminium oxide (Fluka 06290, type 5016 A 35 31 LV 10721 basie, 20 g) at 5*C using dichloromethane as the solvent. The solvent is removed under reduced pressure to give 3.64 g (67%) of the crude produet. 1H NMR (60 MHz, CDClj) : δ 1.5-1.9 (4 H, m, CH2"CH2) , 1.77 (6 H, d, J=6 Hz, 2 x CH3), 2.1-2.5 (4 H, m, 2 x CH2-0), 6.49 (2 H, k, J=6 Hz, 2 x Cl-CH-O). EXAMPLE 5 a) Acrvlamide polvmer povder crosslinked with 5% methvlene dimethacrvlate
Methylene dimethacrylate prepared as deseribed in Example 4(a) (0.50 g, 2.72 mmol) dissolved in dimethylformamide (2 ml) is added to a solution of acrylamide (10.00 g, 140.70 mmol) and azobisisobutyronitrile (AIBN, 0.02 g, 0.86 mmol) in dimethylformamide and the reaction mixture heated to 60*C under a dry nitrogen atmosphere. After approximately 50 min. the clear reaction mixture turns into a white suspension. The reaction mixture is ķept at 60 *C for a total of 2 hours to complete the reaction. After cooling to 20*C the reaction mixture is filtered, the solid washed several times with dimethylformamide and dried under vacuum to yield the title compound as a powder. The produet is insoluble in water in contrast to uncrosslinked polyacrylamide prepared by the same method. IR (KBr, cm'1) : 3379 (broad, str) , 3199 (str) , 2932 (w) , 1739 (m), 1662 (Str), 1616 (str), 1451 (m), 1415 (m), 1348 (w), 1320 (w), 1102 (w), 976 (w), 610 (broad, m). On subtracting the spectrum of polyacrylamide prepared using the same procedure as above from the crosslinked polyacrylaraide, the following peaks originating from the incorporated crosslinker appear: 1740 (str), 1471 (w), 1387 (w), 1152 (m), 1084 (str), 963 (Str). 32 b) Acrvlamide polvmer gel crosslinked with 5% methvlene dimethacrvlate AIBN (0.01 g, 0.43 mmol) is added to a solution of acrylamide (5.00 g, 70.34 mmol) and methylene dimethacrylate prepared as described in Example 4(a) (0.250 g, 1.36 mmol) in water/DMSO (90:10,20 ml) at 60’C under a dry nitrogen atmosphere, with good stirring. After approximately 25 min. the reaction mixture turns into a gel and is ķept at 60'C for a total of 2 hours to complete the reaction. The resulting gel is not soluble in water vhereas the corresponding acrylamide homopolymer is soluble. c) Acrvlamide polvmer crosslinked with 2.6% methvlene dimethacrvlate AIBN (0.01 g, 0.43 mmol) is added to a solution of acrylamide (5.00 g, 70.34 mmol) and methylene dimethacrylate prepared as described in Example 4(a) (0.131 g, 0.709 mmol) in water/DMSO (90:10,20 ml) at 60 °C under a dry nitrogen atmosphere, with good stirring. After approximately 25 min. the reaction mixture turns into a gel and is ķept at 60 *C for a total of 2 hours to complete the reaction. The resulting gel is not soluble in water whereas the corresponding acrylamide homopolymer is soluble. d) Acrvlamide polvmer crosslinked with 1.3% methvlene dimethacrvlate AIBN (0.01 g, 0.43 mmol) is added to a solution of acrylamide (5.00 g, 70.34 mmol) and methylene dimethacrylate prepared as described in Example 4(a) (0.065 g, 0.035 mmol) in water/DMSO (90:10, 20 ml) at 60 *c under a dry nitrogen atmosphere, with good stirring. After approximately 25 min. the reaction 33 LV 10721 mixture turns into a gel and is ķept at 60 *C for a total of 2 hours to complete the reaction. The resulting gel is not soluble in water whereas the corresponding acrylamide homopolymer is soluble.
The degree of swelling in water of acrylamide-methylene dimethacrylate copolymer gels prepared according to this Example is inversely proportional to the degree of crosslinking as determined by the percentage of methylene dimethacrylate employed. EXAMPLE 6
Methvl acrvlate polvmer crosslinked vith 2% methvlene diacrvlate AIBN (0.005 g, 0.03 mmol) is added to a solution of methyl acrylate (3.029 g, 35.20 mmol) and methylene diacrylate prepared as described in Example 4(b) (0.110 g, 0.70 mmol) in dimethylformamide (10 ml) at 60 *C under a dry N2 atmosphere. After approximately 50 min. the clear reaction mixture turns into a gel. The reaction mixture is ķept at 60*C for a total of 2 hours to complete the reaction. The resulting gel is insoluble in tetrahydrofuran, whereas poly methyl acrylate is soluble. This proves that the gel is crosslinked. EXAMPLE 7
Acrvlic acid polvmer crosslinked with 2¾ methvlene diacrvlate AIBN (0.005 g, 0.03 mmol) is added to a solution of acrylic acid (2.534 g, 35.20 mmol) and methylene diacrylate prepared as described in Example 4(b) (0.110 g, 0.7 0 mmol) in dimethylformamide (10 ml) at 60'C under a dry N2 atmosphere. After approximately 60 min. the clear reaction mixture turns into a gel. The reaction mixture is ķept at 60 *C for a total of 2 hours to complete the 34 reaction. The resulting gel is insoluble in dimethylformamide, whereas poly acrylic acid is soluble. This proves that the gel is crosslinked. EXAMPLE 8
Acrvlamide polvmer crosslinked with 0.5% methvlene diacrvlate AIBN (0.005 g, 0.03 mmol) dissolved in tetrahydrofuran (2 ml) is added to a solution of acrylamide (2.500 g, 35.17 mmol) and methylene diacrylate prepared as described in Example 4(b) (0.027 g, 0.18 mmol) in tetrahydrofuran (10 ml) at 60eC under a dry N2 atmosphere. After approximately 2 hours no visible change is observable in the reaction mixture. AIBN (0.005 g, 0.03 mmol) is therefore added. The polymer then starts to precipitate from the reaction mixture and after a total of 5 hours the reaction mixture is cooled and filtered. The polymer is vashed several times with tetrahydrofuran and dried under reduced pressure. The resulting polymer is insoluble in water, whereas polyacrylamide is soluble. This proves that a crosslinked polymer is formed. The IR-spectrum of the polymer confirms this structure. Subtracting the IR-spectrum of polyacrylamide prepared by the same procedure as above confirms the incorporation of the crosslinker. The concentration of the crosslinker (0.5%) is, hovever, too low to give an accurate "subtraction spectrum". EXAMPLE 9
Acrvlamide polvmer crosslinked with_0,5%_2- methacrvlovloxvethvl methacrvlovloxvmethvl carbonate AIBN (0.005 g, 0.03 mmol) is added to a solution of acrylamide (2.500 g, 35.20 mmol) and 2-methacryloyloxyethyl methacryloyloxymethyl carbonate prepared as described in Example 4(d) (0.048 g, 0.18 mmol) in tetrahydrofuran (10 ml) at 60' C under a dry N2 35 LV 10721 atmosphere. After 2 hours no visible change is observed in the reaction mixture. AIBN (0.005 g, 0.03 mmol) dissovled in tetrahydrofuran (2 ml) is therefore added. The polymer then starts to precipitate from the reaction mixture and after a total of 4 hours the reaction mixture is cooled and filtered. The polymer is washed several times with tetrahydrofuran and dried under reduced pressure. IR (KBr, cm'1) : 3350 (broad, m) , 3198 (m) , 2933 (w) , 1659 (str.), 1617 (m) , 1450 (w) , 1420 (w) . The polymer is soluble in water giving a viscous solution, suggesting little crosslinking. EXAMPLE 10 2-Hvdroxvethvl methacrvlate polvmer crosslinked with 0.5% 2-methacrvlovloxvethvl methacrvlovloxvmethvl carbonate AIBN (0.005 g, 0.03 mmol) is added to a solution of 2-hydroxyethyl methacrylate (4.578 g, 35.20 mmol) and 2-methacryloyloxyethyl methacryloyloxymethyl carbonate prepared as described in Example 4(d) (0.0479 g, 0.18 mmol) in tetrahydrofuran (10 ml) at 60*C under a dry N2 atmosphere. After one hour tetrahydrofuran (10 ml) is added and the reaction mixture turns into a gel. The reaction mixture is ķept at 60*C for a total of 2 hours to complete the reaction. The resulting gel is insoluble in dichloromethane, whereas poly 2-hydroxye.thyl methacrylate is soluble. This proves that the gel is crosslinked. EXAMPLE 11
Methvl methacrvlate polvmer crosslinked with 2% acrvlovloxvmethvl 4-acrvlovloxvbutvl carbonate AIBN (0.005 g, 0.03 mmol) is added to a solution of methyl acrylate (3.029 g, 35.20 mmol) and acryloyloxymethyl 4-acryloyloxybutyl carbonate prepared as described in Example 4(k) (0.192 g, 0.70 mmol) in dimethylformamide (10 ml) at 60*C under a dry N2 atmosphere. After 1 hour the 36 clear reaction mixture turns into a gel. The reaction mixture is ķept at 60*C for a total of 2 hours to complete the reaction. The resulting gel is insoluble in tetrahydrofuran, vhereas poly methyl methacrylate is soluble. This proves that the gel is crosslinked. EXAMPLE 12
Acrvlamide polvmer crosslinked with 2% acrvlovloxvmethvl 4-acrvlovloxvbutvl carbonate AIBN (0.005 g, 0.03 mmol) is added to a solution of acrylamide (2.502 g. 35.20 mmol) and acryloyloxymethyl 4-acryloyloxybutyl carbonate prepared as described in Example 4(k) (0.202 g, 0.74 mmol) in dimethylformamide (10 ml) at 60*C under a dry N2 atmosphere. After approximately 40 min. the reaction mixture turns white and the polymer starts to precipitate. The reaction mixture is cooled and filtered after a total of 2 hours at 60*C. The polymer is washed several times with dimethylformamide and dried under reduced pressure. IR (KBr, cm'1) : 3387 (broad, m) , 3195 (m), 2932 (w), 2360 (w) , 1661 (str.), 1611 (m), 1451 (w) , 1415 (w) . The polymer product is insoluble in water, whereas polyacrylamide is soluble. This proves that the polymer is crosslinked. EXAMPLE 13
Acrvlamide polvmer crosslinked with 2% l-acrvlovloxvethvl 4-acrvlovloxvbutvl carbonate AIBN (0.005 g, 0.03 mmol) is added to a solution of acrylamide (2.502 g. 35.20 mmol) and l-acryloyloxyethyl 4-acryloyloxybutyl carbonate prepared as described in Example 4 (1) (0.202 g, 0.70 mmol) in dimethylformamide (10 ml) at 60"C under a dry N2 atmosphere. After approximately 30 min. the polymer starts to precipitate from the reaction mixture. The reaction mixture is cooled and filtered after a total of 2 hours at 60°C. The polymer is 37 LV 10721 washed several times with dimethy1formamide and dried under reduced pressure. IR (KBr, cm'1) : 3390 (broad, m) , 3197 (m) , 2933 (w), 1661 (str.), 1611 (m), 1452 (w) , 1415 (w) . The polymer product is insoluble in water, vhereas polyacrylamide is soluble. This provides that the polymer is crosslinked.
Exaniple 14
Polv (methvlene terephthalate) A solution of potassium hydroxide (1.00 M, 10.00 ml) is added to terephthalic acid (0.83 g, 5.00 mmol) at 0*C and the solution freeze dried during 16 hours Dry dimethylformamide (50 ml) is added and the suspension heated to 70 *C under a dry nitrogen atmosphere. Diiodomethane (1.61 ml, 20.00 mmol) and 18-crown-6 (0.066 g, 0.25 mmol) are added and the reaction mixture ķept for 3 days at 70’C and 3 days at 100 *C. The solvent is removed under reduced pressure (0.05 mm Hg) , whereafter diethyl ether (30 ml) and water (30 ml) are added. The pH of the aqueous suspension is adjusted to 9 with sodium hydroxide (1.00 M) before washing with diethyl ether (3 x 3 0 ml) . The aqueous suspension is centrifuged, the liquid decanted off and the solid resuspended in absolute ethyl alcohol. Centrifugation and decantation are repeated and the solid dried under vacuum to give 0.29 g (32%) of the product as a powder. IR (KBr, cm"1): 3400 (w, broad)., 1732 (str), 1600 (w), 1558 (w), 1456 (w), 1400 (w), 1288 (m), 1256 (m) , 1244 (m) , 1158 (w) , 1118 (w) , 1053 (str), 1014 (m) , 978 (m) , 727 (m). The solubility properties of the product indicate that a polymer is formed. EXAMPLE 15
Polvmer from ethvlene di(chloromethvl carbonate) and terephthalic acid
Ethylene di(chloromethy1 carbonate) prepared as described in Exarople 4(e) (0.489 g, 1.98 mmol) is added to a suspension of freeze dried di-potassium terephthalate (0.480 g, 1.98 itunol) and 18-crown-6 (0.027 g, 0.10 mmol) in dimethylformamide (20 ml). After 2 days at 20'C the reaction mixture is heated to 60 "C and ķept there for 3 weeks. The solvent is removed under reduced pressure and the residue dissolved by adding dichloromethane (60 ml) and water (30 ml). After separating the phases the dichloromethane phase is washed with saturated aqueous sodium hydrogen carbonate (30 ml) and brine (30 ml). The organic phase is dried (MgSOJ and the solvent removed under reduced pressure to give 0.35 g (53%) of the title product. ’H NMR (60 MHz, CDC13) : δ 4.4 7 (4 H, S; 0-CH2CH2-O) , 6.02 (4 H, s, 2 x 0-CH2-0) , 8.12(4 H, s, Ar). High temperature gel filtration chromatography (GPC) indicates that fractions of the material have a molecular weight exceeding 20,000 with respect to poly(ethylene glycol) as Standard. EXAMPLE 16
Polvester from methvlene di(p-hvdroxvbenzoate) and adipovl chloride
Pyridine (0.560 ml, 6.94 mmol) is added dropwise to a solution of methylene di(p-hydroxybenzoate) prepared as described in Example 4(o) (1.00 g, 3.47 mmol) and adipoyl chloride (0.635 g, 3.47 mmol) in dry dichloromethane (30 ml) at 20*C under a dry N2 atmosphere. After 18 hours at 2 0°C water (10 ml) is added to the reaction mixture and the phases are separated. The aqueous layer is extracted with dichloromethane (3 x 10 ml) and the combined organic phases are washed with water (3 x 20 ml). The volume of the organic phase is increased to 250 ml by adding more dichloromethane. The resulting organic phase is dried (MgSOJ and the solvent evaporated under reduced pressure (0.1 mmHg) to give 0.93 g (67%) product. 1H NMR (300 MHz, CDC13) : δ 1.76 (4 H, m, CH2-CH2) , 2.59 (4 H, m, 2 x CH2- 39 LV 10721 C=0) , 6.20 (2 H, s, 0-CH2-0) , 7.16 (4 H, Ar), 8.06 (4 H,
Ar) . High temperature gel filtration chromatography (GPC) indicates that fractions of the material have a molecular weight exceeding 20,000 with respect to poly(ethylene glycol) as Standard. EXAMPLE 17
Polvmer from bis (,2-chloroxnethoxvcarbonvloxvethvl) ether and di-potassium fumarate
Bis(2-chloromethoxycarbonyloxyethyl) ether prepared as described in Example 4(f) (1.456 g, 5.00 mmol) is added to a suspension of di-potassium fumarate (0.961 g, 5.00 mmol) and 18-crown-6 (0.039 g, 0.15 mmol) in DMF (50 ml) and the reaction mixture is heated to 60*C, under a dry N2 atmosphere. After 11 days at 60*C the solvent is removed under reduced pressure. Chloroform (40 ml) is added to the residue and the organic layer vashed with water (3 x 3 0 ml) . The combined water washings are extracted with chloroform (3 x 20 ml). The combined organic phases are concentrated in vacuo to give 1.57g (94%) of a brown oil product. ’H NMR (300 MHz, DMSO-d6, 40*C): <5 3.78 (4 H, m, 2 X CH2-0), 4.38 (4 H, m, 2 X CH2~0-C=0), 5.94 (4 H, s, 2 x 0-CH2-0) , 6.98 (2 H, s, CH=CH) . High temperature gel filtration chromatography (GPC) indicates that fractions of the material have a molecular weight exceeding 20,000 with respect to poly(ethylene glycol) as Standard. EXAMPLE 18
Methvlene bis Γρ-(2,3-epoxv-l-propvloxv)benzoatel
Potassium tert.butoxide (1.347 g, 12.00 mmol) is added to a solution of methylene di(p-hydroxybenzoate) prepared as described in Example 4(o) (1.728 g, 6.00 mmol) in DMF (75 ml), under a dry N2 atmosphere. Epichlorohydrin (2.22 g, 24.00 mmol) is added and after 24 hours at 20*C the solvent is removed under reduced pressure. The residue is 40 dissolved by adding dichloromethane (75 ml) and water (30 ml) and adjusting the pH to neutral using hydrochloric acid (1 M) . After separating the phases the dichloromethane layer is washed with water (3 x 30 ml) . The organic phase is dried (MgSOJ and the solvent removed under reduced pressure to give 1.22 g (51%) product as a colourless oil. 1H NMR (60 MHz, CDC13) : <S 2.8 (4 H, m, 2 X epoxy-CH2) , 3.3 (2 H, m, 2 x epoxy-CH) , 4.05 (2 H, dd, J=^22, 11 Hz, 2 X 0-CH-H) , 4.12 (2 H, dd, J=22, 11 Hz, 2 X O-CH-H), 6.14 (2 H, s, 0-CH2~0) , 6.9 (4 H, m, 2 x Ar), 7.9 (4 H, m, 2 X Ar). EXAMPLE 19
Hexamethvlene di(chloromethvl carbonate)
Pyridine (1.77 ml, 22.00 mmol) is added dropwise to a solution of chloromethyl chloroformate (2.61 ml, 29.70 mmol) and 1,6-hexanediol (1.182 g, 10.00 mmol) in dichloromethane (40 ml) at 7*C with good stirring under a dry N2 atmosphere. After 15 min. at 7*C and 6 hours at 20*C the reaction mixture is transferred to a separating funnel with the aid of dichloromethane (2 x 10 ml) . The reaction mixture is washed with hydrochloric acid (ΐ.οο M, 20 ml) , saturated aqueous sodium hydrogen carbonate (20 ml) and water (20 ml) . Ethyl acetate is added to the organic phase to get a clear solution. This solution is dried (MgS04) and the solvent evaporated under reduced pressure to give 2.76 g (99%) product. 1H NMR (300 MHz, CDClj) : <5 1.2-2.0 [8 H, m, (CH2)J , 4.22 (4 H, t, J=6 Hz, 2 X (CH2-0)), 5.73 [4 H, s, 2 X Cl-CH2-0) ] . EXAMPLE 20
Polvmer from adioic acid bis 1-chloroethvl ester and di-potassium terephthalate
Potassium tert.butoxide (1.122 g, 10.00 mmol) is added to a solution of terephthalic acid (0.831 g, 5.00 mmol) in 41 LV 10721 DMF (50 ml) at 20 *C, under a dry N2 atmosphere. Adipic acid bis l-chloroethyl ester prepared as described in Example 4(q) (1.356 g, 5.00 mmol) is added to the resulting suspension and the reaction mixture heated to 60'C. After 1 hour at 60'C, 18-crown-6 (0.066 g, 0.25 mmol) is added. The solvent is removed under reduced pressure after 8 days at 60eC and the residue dissolved by adding chloroform (60 ml), ethyl acetate (30 ml) and aqueous sodium hydroxide (1 M, 50 ml). After separating the phases the aqueous phase is extracted with chloroform (3 x 25 ml). The combined organic layers are washed with water (2 x 50 ml) and dried (MgS04) . The solvent is removed under reduced pressure to give 0.238 g (13%) of crude product. EXAMPLE 21
Polvmer from adipic acid bis l-chloroethvl ester and di-potassium fumarate
Potassium tert.butoxide (1.122 g, 10.00 mmol) is added to a solution of fumaric acid (0.580 g, 5.00 mmol) in DMF (50 ml) at 20'C, under a dry N2 atmosphere. Adipic acid bis 1-chloroethyl ester prepared as described in Example 4(q) (1.356 g, 5.00 mmol) is added to the resulting suspension and the reaction mixture heated to 60'C. After 1 hour at 60’C, 18-crown-6 (0.066 g, 0.25 mmol) is added. The solvent is removed under reduced pressure after 8 days at 60 “C and the residue dissolved by adding chloroform (60 ml), ethyl acetate (30 ml) and aqueous sodium hydroxide (1 M, 50 ml). After separating the phases the agueous phase is extracted with chloroform (3 x 25 ml) . The combined organic layers are washed with water (2 x 50 ml) and dried (MgS04) . The solvent is removed under reduced pressure to give 0.276 g (18%) of crude product. 42 EXAMPLE 22
Polv(methvlene adipoate)
Potassium tert.butoxide (1.122 g, 10.00 mmol) is added to a solution of adipic acid (0.731 g, 5.00 mmol) in DMF (50 ml) at 20 *C, under a dry N2 atmosphere. Adipic acid bis chloromethyl ester (prepared according to Rosnati: Bovet. Rend. lst. super Sanita 15 (1951), 473, 486) (1.215 g, 5.00 mmol) is added to the resulting suspension and the reaction mixture heated to 60*C. After 1 hour at 60’C, 18-crown-6 (0.066 g, 0.25 mmol) is added. The solvent is removed under reduced pressure after 8 days at 60*C and the residue dissolved by adding chloroform (60 ml), ethyl acetate (30 ml) and aqueous sodium hydroxide (1 M, 50 ml) . After separating the phases the aqueous phase is extracted with chloroform (3 x 25 ml). The combined organic layers are washed with water (2 x 50 ml) and dried (MgS04) . The solvent is removed under reduced pressure to give 0.618 g (39%) of crude product. 1H NMR (60 MHz, CDC13) : <S 1.67 (4 H, m, broad, CH2-CH2) , 2.37 (4 H, m, broad, 2 x CH2-0) , 5.77 (2H, s, 0-CH2-0) . EXAMPLE 23
Polvmer from hexamethvlene di(chloromethvl carbonate) and di-potassium tereohthalate
Potassium tert.butoxide (0.804 g, 7.16 mmol) is added to a solution of terephthalic acid (0.595 g, 3.58 mmol) in DMF (40 ml) at 20 *C, under a dry N2 atmosphere. Hexamethylene di(chloromethyl carbonate) prepared as described in Example 19 (1.00 g, 3.58 mmol) and 18-crown-6 (0.047 g, 0.179 mmol) are added to the resulting suspension and -the reaction mixture heated to 60*C. The solvent is removed under reduced pressure after 6 days at 60*C. The residue is insoluble in dichloromethane and sodium hydroxide (1 M), indicating the formation of a polymer. 43 LV 10721 EXAMPLE 24
Methvlene di(3.3-dimethoxvpropionate)
Cesium 3,3-dimethoxypropionate (19.95 g, 75 mmol) is added to dry DMF (11). Diiodomethane (10.04 g, 37.5 mmol) is added to the suspension and the reaction mixture is stirred for 2 days at 60‘C under a dry N? atmosphere. DMF is removed under reduced pressure (0.01 mmHg). Diethyl ether (500 ml) is added to the residue, which is then washed with saturated aqueous sodium hydrogen carbonate (250 ml). The agueous layer is extracted with diethyl ether (5 x 7 5 ml) . The combined ether extracts are washed with water (2 x 100 ml), dried (MgSO^) and evaporated to give 7.1 g (72%) product. 1H NMR (300 MHz, CDC13) : 6 2.61 (CH2, d) , 3.26 (CH3, s) , 4.76 (CH,t), 5.70 (CH2, s) . 13C NMR (300 MHZ, CDCl3) : <5 38.52 (CH2) , 53.37 (CHjO) , 79.02 (0CH20) , 168.32 (C=0) . EXAMPLE 25 Εροχν resin based on methvlene bisΓρ-2.3-epoxv-l-propvloxv)benzoatel and an aliphatic polvamine A sample of methylene bis[p-(2,3-epoxy-l-propyloxy)benzoate] prepared as described in Example 18 is blended with an equal weight of a commercial aliphatic polyamine curing aģent. This mixture is used as an adhesive to adhere two glass plates together at rooro temperature. The resin is observed to have hardened and good bonding is obtained within 24 hours of mixing. EXAMPLE 26
Aaueous polvmer gel prepared bv crosslinking an agueous solution of polv(vinvl· alcohoH with methvlene di(3,3-dimethoxvpropionate) (a) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w% in water, 7.0 mmol with respect to monomer 44 units, average M.W. 126 000, 98% hydrolyzed) is adjusted to pH=0.8 by adding hydrochloric acid (18% solution). To this solution, 0.10 g (0.35 mmol) of methylene di(3,3-dimethoxypropionate) prepared as described in Example 24 is added, and the solution is well mixed. After 24 hours at room temperature the viscosity of the solution is higher than initially, and after 48 hours at room temperature the solution has formed a relatively strong gel. The gel is thoroughly washed with excess vater for one day and stored under water to avoid drying. The water content of this gel is measured as being 98.5% (by volume). (b) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w% in water, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98% hydrolyzed) is adjusted to pH=0.3 by adding hydrochloric acid (18% solution). To this solution, 0.10 g (0.35 mmol) of methylene di(3,3-dimethoxypropionate) prepared as described in Example 24 is added, and the solution is well mixed. After 6 hours the solution has formed a gel and after 48 hours syneresis is observed. The gel is thoroughly washed with excess water for one day and stored under vater to avoid drying. The water content for this gel is measured as being 95.5% (by volume). (c) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w% in water, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98% hydrolyzed) is adjusted to pH=0.8 by adding hydrochloric acid (18% solution). To this solution is added 19.6 mg (0.07 mmol) of methylene di(3,3-dimethoxypropionate) prepared as described in Example 24 in 1 ml of water, and the solution is well mixed. After 3 hours at 50 ° C the solution has formed a gel. The gel is 45 LV 10721 thoroughly washed with excess water for one day and stored under water to avoid drying. The water content for this gel is estimated to be 98% (by volume). (d) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w% in water, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98% hydrolyzed) is adjusted to pH=0.8 by adding hydrochloric acid (18% solution). To this solution 0.1 g (0.35 mmol) of methylene di(3,3-dimethoxypropionate) prepared as described in Example 24 is added, and the solution is well mixed. After 3 hours at 50“C the solution has formed a gel. The gel is thoroughly washed with excess water for one day and stored under water to avoid drying. The water content for this gel is estimated to be 95% (by volume). (e) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w% in water, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98% hydrolyzed) is adjusted to pH=0.8 by adding hydrochloric acid (18% solution). To this solution is added 19.6 mg (0.07 mmol) of methylene di(3,3-dimethoxypropionate) prepared as described in Example 24 in 1 ml of water, and the solution is well mixed. After 40 minūtes at 8 0 * C the solution has formed a gel. The gel is thoroughly washed with excess water for one day and stored under water to avoid drying. The water content for this gel is estimated to be 98% (by volume). (f) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w% in vater, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98% hydrolyzed) is adjusted to pH=0.8 by adding hydrochloric acid (18% solution). To this solution 0.1 g (0.35 mmol) of 46 methylene di (3,3-dimethoxypropionate) prepared as described in Example 24 is added, and the solution is well mixed. After 40 minūtes at 80'C the solution has formed a gel. The gel is thoroughly washed with excess water for one day and stored under water to avoid drying. The water content for this gel is estimated to be 95% (by volume). (g) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w% in water, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98% hydrolyzed) is adjusted to pH=0.4 by adding hydrochloric acid (18% solution). To this solution is added 19.6 mg (0.07 mmol) of methylene di(3,3-dimethoxypropionate) prepared as described in Example 2 4 in 1 ml of water, and the solution is well mixed. After 40 minūtes at 80’C the solution has formed a gel. The gel is thoroughly washed with excess water for one day and stored under water to avoid drying. The vater content for this gel is estimated to be 98% (by volume). (h) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w% in water, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98% hydrolyzed) is adjusted to pH=0.4 by adding hydrochloric acid (18% solution). To this solution 0.1 g (0.35 mmol) of methylene di(3,3-dimethoxypropionate) prepared as described in Example 24 is added, and the solution is well mixed. After 40 minūtes at 80’C the solution has formed a gel. The gel is thoroughly washed with excess water for one day and stored under water to avoid drying. The water content for this gel is estimated to be 95% (by volume). 47 LV 10721 EXAMPLE 27
Polvmer ael containina chloramphenicol. prepared bv radical polvmerization of a water/DMSO (90:10) solution of the drug. acrvlamide and methvlene dimethacrvlate AIBN (0.010 g, 0.061 mmol) is added to a solution of acrylamide (5.00 g, 70.34 mmol), methylene dimethacrylate prepared as described in Example 4(a) (0.250 g, 1.36 mmol) and chloramphenicol (0.051 g, 0.157 mmol) in water/DMSO(90:10, 20 ml) at 60*C under a dry N2 atmosphere, with good stirring. AIBN (0.010 g, 0.061 mmol) is. again added after 1.5 hours After a total of 3 hours the reaction mixture is cooled to 20*C. The reaction mixture then proves to be a soft gel. The gel does not dissolve in water, even after 7 days, vhereas the corresponding acrylamide homopolymer is water-soluble. EXAMPLE 28
Polvmer ael containina testosterone. prepared bv radical polvmerization of a water/DMSO (90:10) solution of the drug, acrvlamide and methvlene diacrvlate AIBN (0.010 g, 0.061 mmol) is added to a solution of acrylamide (5.00 g, 70.34 mmol), methylene diacrylate prepared as described in Example 4(b) (0.212 g, 1.36 mmol) and testosterone (0.050 g, 0.173 mmol) in water/DMSO (90:10, 20 ml) at 60*C under a dry N2 atmosphere, with good stirring. After 40 mins. the reaction mixture has turned into a gel. The reaction mixture is ķept at 60*C for a total of 2 hours to complete the reaction. Upon cooling to 20*C the testosterone crystallizes in the gel. The gel does not dissolve in water, whereas the corresponding acrylamide homopolymer is water-soluble. 48 EXAMPLE 29
Polvmer ael containina 5-fluorouracil. prepared bv radical polvmerization of a water/DMSO (14:1) solution of the druo, acrvlamide and inethvlene diacrvlate
An aqueous solution of 5-fluorouracil (5.00 ml, 250 mg/10 ml, 0.961 mmol) is added to a solution of acrylamide (5.00 g, 70.34 mmol) and methylene diacrylate prepared as described in Example 4(b) (0.212 g, 1.36 mmol) in water/DMSO (90:10, 10 ml) at 60*C under a dry N2 atmosphere, with good stirring. AIBN (0.010 g, . 0.061 mmol) is then added and after 35 mins. the reaction mixture has turned into a gel. The reaction mixture is ķept at 60 ”C for a total of 2 hours to complete the reaction. The gel does not dissolve in water, whereas the corresponding acrylamide homopolymer is water-soluble. EXAMPLE 30
Polvmer ael containing sulfadiazine. prepared bv suspendina the drua in an aoueous solution of polvfvinvl alcoholī subseguentlv crosslinked with methvlene di(3.3-dimethoxypropionate) (a) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w% in water, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98% hydrolyzed) is adjusted to pH=0.4 by adding hydrochloric acid (18% solution). To this solution are added 19.6 mg (0.07 mmol) of methylene di(3,3-dimethoxypropionate) prepared as described in Example 24 in 1 ml of water and 0.20 g (0.8 mmol) of sulfadiazine, and the dispersion is well mixed. After 40 minūtes at 80°C the solution has formed a gel with the powder suspended in it. The gel is thoroughly washed with excess water for one day and stored under water to avoid drying. The water content for this gel is estimated to be 98% (by volume). 49 LV 10721 (fc>) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w% in water, 7.0 mmol with respect to mononter units, average M.W. 126 000, 98% hydrolyzed) is adjusted to pH=0.4 by adding hydrochloric acid (18% solution). To this solution are added 0.1 g (0.35 mmol) of methylene di(3,3-dimethoxypropionate) prepared as described in Example 24 and 0.20 g (0.8 mmol) of sulfadiazine, and the suspension is well mixed. After 40 minūtes at 80*C the polymer has formed a gel with the powder suspended in it. The gel is thoroughly washed with excess water for one day and stored under water to avoid drying. The water content for this gel is estimated to be 95% (by volume). EXAMPLE 31
Polvmer crel containina proaesterone. prepared bv suspendina the drua in an acmeous solution of polvfvinvl alcohol) subsecmentlv crosslinked with methvlene di(3,3-dimethoxvpropionate) (a) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w% in water, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98% hydrolyzed) is adjusted to pH=0.4 by adding hydrochloric acid (18% solution). To this solution are added 19.6 mg (0.07 mmol) of methylene di(3,3-dimethoxypropionate) prepared as described in Example 24 in 1 ml of water and 0.07 g (0.2 mmol) of progesterone, and the dispersion is well mixed. After 40 minūtes at 80*C the polymer has formed a gel with the powder suspended in it. The gel is thoroughly washed with excess water for one day and stored under water to avoid drying. The water content for this gel is estimated to be 98% (by volume). (b) 5 g of an agueous solution of poly(vinyl alcohol) 50 (6.25 w% in water, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98% hydrolyzed) is adjusted to pH=0.4 by adding hydrochloric acid (18% solution) . To this solution are added 0.1 g (0.35 5 mmol) of methylene di(3,3-dimethoxypropionate) prepared as described in Example 24 and 0.07 g (0.2 mmol) of progesterone, and the suspension is well mixed. After 40 minūtes at 80'C the polymer has formed a gel with the powder suspended in it. The 10 gel is thoroughly vashed with excess water for one day and stored under water to avoid drying._ The water content for this gel is estimated to be 95% (by volume). 15 20 25 30 EXAMPLE 32
Polvmer oel containina 5-fluorouracil. prepared bv dissolvina the drug in an acrueous solution of polvfvinvl alcohol) subseauentlv crosslinked with methvlene di(3,3-dimethoxvpropionate) (a) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w% in water, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98% hydrolyzed) is adjusted to pH=0.4 by adding hydrochloric acid (18% solution). To this solution are added 19.6 mg (0.07 mmol) of methylene di(3,3-dimethoxypropionate) prepared as described in Example 24 in 1 ml of vater and 13 mg (0.1 mmol) of 5-fluorouracil dissolved in 0.5 ml water, and the solution is well mixed. After 40 minūtes at 80°C the solution has formed a gel. The gel is thoroughly washed with excess water for one day and stored under water to avoid drying. The water content for this gel is estimated to be 98% (by volume). (b) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w% in water, 7.0 mmol with respect to monomer 35 51 LV 10721 units, average M-W. 126 000, 98% hydrolyzed) is adjusted to pH=0.4 by adding hydrochloric acid (18% solution) . To this solution are added 0.1 g (0.35 mmol) of methylene di(3,3-dimethoxypropionate) prepared as described in Example 24 and 13 mg (0.1 mmol) of 5-fluorouracil dissolved in 0.5 ml water, and the solution is well mixed. After 40 minūtes at 80'C the solution has formed a gel. The gel is thoroughly washed with excess water for one day and stored under water to avoid drying. The water content for this gel is estimated to be 95% (by volume). EXAMPLE 33
Polvmer gel containing Omnipacrue™, prepared bv dissolving the diagnostic aid in an aorueous solution of polv(vinvl alcohol) subsecmentlv crosslinked with methvlene di(3,3-dimethoxvpropionateī (a) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w% in water, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98% hydrolyzed) is adjusted to pH=0.4 by adding hydrochloric acid (18% solution). To this solution are added 19.6 mg (0.07 mmol) of methylene di(3,3-dimethoxypropionate) prepared as described in Example 24 in 1 ml of water and 1 ml of Omnipaque™ (300 mgl/ml) , and the solution is well mixed. After 40 minūtes at 80*C the solution has formed a gel. The gel is thoroughly washed with excess water for one day and stored under water to avoid drying. The water content for this gel is estimated to be 98% (by volume). (b) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w% in water, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98% hydrolyzed) is adjusted to pH=0.4 by adding hydrochloric acid (18% 52 solution) . To this solution are added 0.1 g (0.35 mmol) of methylene di(3,3-dimethoxypropionate) prepared as described in Example 24 and 1 ml of Omnipaque,M (300 mgl/ml), and the solution is well mixed. After 40 minūtes at 80'C the solution has formed a gel. The gel is thoroughly washed with excess water for one day and stored under water to avoid drying. The water content for this gel is estimated to be 95% (by volume). EXAMPLE 34
Polvmer crel containina magnetic starch microspheres. prepared bv suspending the material in an aaueous solution of polv(vinvl alcohol) subseauentlv crosslinked with methvlene di(3.3-dimethoxvpropionate) (a) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w% in water, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98% hydrolyzed) is adjusted to pH=0.4 by adding hydrochloric acid (18% solution). To this solution are added 19.6 mg (0.07 mmol) of methylene di(3,3-dimethoxypropionate) prepared as described in Example 24 in 1 ml of water and 0.5 ml of a suspension containing magnetic starch microspheres prepared as described in W0 85/02772 (Schroder) (7.5 mg Fe/ml, 0.9% NaCl0.5% glycerol) , and the suspension is well mixed. After 40 minūtes at 80 *C the polymer has formed a gel with the magnetic material suspended in it. The gel is thoroughly washed with excess water for one day and stored under water to avoid drying. The water content for this gel is estimated to be 98% (by volume). (b) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w% in water, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98% hydrolyzed) is 53 LV 10721 adjusted to pH=0.4 by adding hydrochloric acid (18% solution). To this solution are added 0.1 g (0.35 mmol) of methylene di(3,3-dimethoxypropionate) prepared as described in Example 24 and 0.5 ml of a suspension containing magnetic starch microspheres prepared as described in WO 85/02772 (Schroder) (7.5 mg Fe/ml, 0.9% NaCl, 0.5% glycerol), and the suspension is well mixed. After 40 minūtes at 80*C the polymer has formed a gel with the magnetic material suspended in it. The gel is thoroughly washed with excess water for one day and stored, under water to avoid drying. The water content for this gel is estimated to be 97% (by volume). EXAMPLE 35
Homopolvmerisation of methvlene dimethacrvlate 0.5 g (2.7 mmol) of methylene dimethacrylate prepared as described in Example 4(a) is blended with 2.5 mg (15 Mmol) of AIBN. After 2 hours at 70*C the monomer has formed a hard solid. This polymer is insoluble, indicating that its structure is a tightly crosslinked netvork. EXAMPLE 36
Homopolvmerisation of (2-methacrvlovloxv)ethvl methacrvlovloxvmethvl carbonate 0.4340 g (1.6 mmol) of (2-methacryloyloxy)ethyl methacryloyloxymethyl carbonate prepared as described in Example 4(d) is blended with 22.0 mg (13.2 Mmol) of AIBN. After 2 hours at 70*C the monomer has formed a hard solid. This polymer is insoluble, indicating that its structure is a tightly crosslinked network. 54 EXAMPLE 37
Emulsion copolvmerisation of methvlene dimethacrvlate and methvl methacrvlate 50 ml of a 1% wt/vol solution of sodium dodecyl sulphate in water is pre-heated to 60’C under a nitrogen atmosphere. 0.20 g (1.09 mmol) of methylene dimethacrylate prepared as described in Example 4(a) and 9.80 g (0.098 mol) of methyl methacrylate monomer are added under vigorous stirring. The polymerisation is initiated with a metabisulphite/persulphate redox -system comprising 1.6mg (7.2μιηο1) potassium metabisulphite and 0.08mg (0.3μ mol) potassium persulphate. The polymerisation is permitted to proceed for 8 hours before cooling to room temperature. The resultant emulsion has a solīds content of 11.1% which corresponds to a degree of conversion of 66%. The recovered polymer is not soluble in THF, a good solvent for poly(raethyl methacrylate) , indicating that the polymer is crosslinked. EXAMPLE 38
Emulsion cooolvmerisation of methvlene dimethacrvlate and stvrene 50ml of a 1% wt/vol solution of sodium dodecyl sulphate in water is pre-heated to 60*C under a nitrogen atmosphere. 0.20g (1.09mmol) of methylene dimethacrylate prepared as described in Example 4(a) and 9.80g (0.094 mol) styrene monomer are added under vigorous stirring. The polymerisation is initiated with a metabisulphite/ persulphate redox systera comprising 1.6mg (7.2μιηο1) potassium metabisulphite and 0.08mg (0.3pmol) potassium persulphate. The polymerisation is permitted to proceed for 8 hours before cooling to room temperature. The resultant emulsion has a solīds content of 11.2% which corresponds to a degree of conversion of 68%. The recovered polymer is not soluble in THF, a good solvent 55 LV 10721 for polystyrene, indicating that the polymer is crosslinked. EXAMPLE 39
Emulsion copolvmerisation of acrvlovloxvmethyl 4-acrvlovloxvbutvl carbonate and methvl methacrvlate 50 ml of a 1% wt/vol solution of sodium dodecyl sulphate in water is pre-heated to 60 *C under a nitrogen atmosphere. 0.20g (0.74 mmol) of acryloyloxymethyl 4- acryloyloxybutyl carbonate prepared as described in Example 4(k) and 9.80g (0.098 mol) of methyl methacrylate monomer are added under vigorous stirring. The polymerisation is initiated with a metabisulphite/ persulphate redox system comprising 1.6mg (7.2μmol) potassium metabisulphite and 0.08mg (0.3μπιο1) potassium persulphate. The polymerisation is permitted to proceed for 8 hours before cooling to room temperature. The resultant emulsion has a solids content of 11.2% which corresponds to a degree of conversion of 67%. The recovered polymer is not soluble in THF, a good solvent for poly(methyl methacrylate), indicating that the polymer is crosslinked. EXAMPLE 40
Emulsion copolvmerisation of acrvlovloxvmethvl 4-acrvlovloxvbutvl· carbonate and stvrene 50ml of a 1% wt/vol solution of sodium dodecyl sulphate in water is pre-heated to 60 *C under a nitrogen atmosphere. 0.20g (0.74 mmol) of acryloyloxymethyl 4-acryloyloxybutyl carbonate prepared as described in Example 4(k) and 9.80g (0.094 mol) of styrene monomer are added under vigorous stirring. The polymerisation is initiated with a metabisulphite/persulphate redox svstem comprising l.6mg (7.2μπιο1) potassium metabisulphite and 0.08mg (0.3μιηο1) potassium persulphate. The polymerisation is permitted to 56 proceed for 8 hours before cooling to room temperature. The resultant emulsion has a solids content of 12% which corresponds to a degree of conversion of 72%. The recovered polymer is not soluble in THF, a good solvent for polystyrene, indicating that the polymer is crosslinked. EXAMPLE 41
Polvmer ael containina maanetic starch microspheres prepared bv radical polvmerization of a water/DMSO (90:10) suspension of maanetic starch microspheres acrvlamide and l-acrvlovloxvethvl 4-acrvlovloxvbutvl carbonate
An aqueous suspension of magnetic starch microspheres prepared as described in WO 85/02722 (Schroder) (0.50 ml from a solution containing 7.5 mg Fe/ml, 0.9% NaCl and 0.5% glycerol) is added to a solution of acrylamide (5.00 g, 7 0.34 mmol) and l-acryloyloxyethyl 4-acryloyloxybutyl carbonate prepared as described in Example 4(1) (0.359 g, 1.3 6 mmol) in water/DMS0 (90: 10, 10 ml) at 60'C under a dry N2 atmosphere, with good stirring. AIBN, (0.010 g, 0.061 mmol) is then added and after approximately 40 minūtes the reaction mixture has turned into a gel. The reaction mixture is ķept at 60 *C for a total of 2 hours to complete the reaction. The gel does not dissolve in water, whereas the corresponding acrylamide homopolymer is water-soluble. EXAMPLE 42
Polvmer from hexamethvlene di(chloromethvl carbonate) and 2.3.5.6-tetraiodoterephthalic acid A solution of--hexamethylene di(chloromethyl carbonate) prepared as described in Example 19 (0.61 g, 2 mmol) m dry DMF (2 ml) is added dropwise to a suspension of di-potassium 2,3,5,6-tetraiodoterephthalate (1.49 g, 2 mmol) and 18-crown-6 (0.03, 0.1 mmol) in dry dimethylformamide 57 LV 10721 (18 ml) under an N2 atmosphere. After 4 days at 60 *C the solvent is removed under reduced pressure (0.5 mm Hg). The residue is dissolved in chloroform (400 ml) and washed with saturated aqueous sodium hydrogen carbonate (3 x 200 ml) and water (2 x 200 ml). The organic phase is dried (MgS04) and evaporated to give 1.16 g of product. ’h NMR (300 MHz) : 6 1.38-1.45 (m, area = 0.24), 1.65-1.76 (m, area = 0.24), 4.18-4.25 (m, area = 0.23), 5.73 (s, area = 0.01), 5.99 (s, area = 0.21). The area ratio between the signal at δ 5.73 from the cr-chloromethylene group of the aliphatic monomer and the signal at <5 5.99 from the methylene diester groups confirms that a polymer is formed. EXAMPLE 43
Covalent attachment of MCPA to 2-hvdroxvethvl methacrvlate polvmer crosslinked with 0.5% 2-methacrvlovloxvethvl methacrvlovloxvinethvl carbonate
The gel described in Example 10 (2.0 g) is swelled in 20 ml dry DMSO. The gel suspension is added a solution of 2-methyl-4-chloro-phenoxy acetic acid (MCPA) (2.0 g, 10 mmol), N-ethyl-N'-(3-(N''-dimethylamino) propyl) carbodiimide and 4-pyrrolidinopyridine (160 mg, 1 mmol) in 3 0 ml dry DMSO, under a dry nitrogen atmosphere. The suspension is shaken for 24 hours at room temperature, and the gel is washed with DMSO and finally vater and dried in vacuo to yield the product. The resulting water suspensible gel contains the highly water soluble weed killer MCPA covalently attached to the gel and provides sustained release of the agrochemical. 58 EXAMPLE 44
Covalent_attachment_o_f_5-acetvlamino-3 - (N- methvlacetvlamino^-2.4.6-triiodobenzoic acid flsopague) to 2-hvdroxvethvl methacrvlate polvmer crosslinked vith 0.5% 2-methacrvlovloxvethvl methacrvlovloxvTnethvl carbonate (a) The Isopacrue amide of 6-alanine-O-benzvl ester
Potassium carbonate (0.69, 5 nunol) is added to a solution of H-/3-alanine-0-benzyl ester (1.76 g, 5 mmol) in dry diTnethylformamide (50 ml) at O'C. After 10 minūtes at ambient temperatūre, 5-acetylaroino-3-(N-methylacetylamino)-2,4,6-triiodobenzoyl chloride (Isopaque acid chloride) (3.23 g, 5 mmol) dissolved in dry dimethylformamide (20 ml) is added dropwise to the suspension at 0*C under a nitrogen atmosphere. The reaction mixture is heated to 50*C. After 24 hours the solvent is removed under reduced pressure and chloroform (500 ml) and water (200 ml) are added. The organic phase is washed with saturated aqueous sodium hydrogen carbonate (100 ml), 0.01 M HCl (100 ml) and water (2 x 100 ml) . After drying of the organic phase evaporation of the solvent gives 3.10 g product (79%). ’H NMR (300 MHz): 6 1.72-1.83 (m) , 2.15-2.23 (m), 2.72-2.81 (m), 3.0-3.09 (m), 3.67-3.78 (m), 5.05-5.20 (m) , 6.6-7.0 (m) , 7.31-7.35 (m), 8.5-8.9 (m). (b) Debenzvlation of the Isopaaue amide of g-alanine-O-benzvl ester
The Isopaque amide of /3-alanine-0-benzy1 ester prepared in (a) above (1.578 g, 2 mmol) is dissolved in dry methanol (50 ml). Palladium on charcoal (10%, 0.4 g) is added in one portion vith stirring of the reaction mixture. Hydrogen gas is bubbled into the solution for two hours, and then the reaction mixture 59 LV 10721 is stirred for a further 2 hours. Filtration and evaporation of the solvent yield a yellow residue, which is purified on a weakly cationic ion exchanger to yield the product'. (c) Attachment of 5-acetvlamino-3-(N-methvlacetvlamino)-2.4.6—triiodobenzoic acid (Isopaaue) to polvmer ael
The carboxylic acid from (b) above is attached to the gel described in Example 10 using the method described in Example 43. EXAMPLE 45
Methvlene di(3-methoxvpropenoate)
Methylene di(3,3-dimethoxypropionate) prepared as described in Example 24 (14.Olg, 50 mmol) and a catalytic amount of p-toluene sulfonic acid is added to toluene (250 ml) . The methanol is removed by warming the reaction under an N2 atmosphere. When the reaction is complete the toluene is distilled off under reduced pressure. Diethyl ether (250 ml) is added and the mixture is vashed with saturated aqueous sodium hydrogen carbonate (5x50 ml) and water (3x50 ml) . The organic layer is dried (MgS04) before evaporation to give 8.52g (79%) product. EXAMPLE 46
Aoueous polvmer ael prepared bv crosslinking an acrueous solution of polvfvinvl alcohol) with methvlene dif3-methoxvpropenoate) (a) 5g of an aqueous solution of poly(vinyl alcohol) (6.25 w% in water, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98% hydrolyzed) is adjusted to pH=0.4 by adding hydrochloric acid (18% solution). To this solution is added 55 mg (0.23 mmol) of methylene di(3-methoxypropenoate) prepared 60 as described in Example 45 in lml of 50:50 dioxane/water, and the solution is well mixed. After 40 minūtes at 80*C the solution has formed a gel. The gel is thoroughly washed with excess water for one day and stored under water to avoid drying. The water content for this gel is estimated to be 98% (by volume). (b) 5g of an aqueous solution of poly(vinyl alcohol) (6.25 w% in water, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98% hydrolyzed) is adjusted to pH=0.4 by adding hydrochloric acid (18%) solution. To this solution is added 110 mg (0.56 mmol) of methylene di(3-methoxypropenoate) prepared as described in Example 4 5 in 2ml of 50:50 dioxane/water, and the solution is well mixed. After 4 0 minūtes at 80*C the solution has formed a gel. The gel is thoroughly vashed with excess water for one day and stored under water to avoid drying. The water content for this gel is estimated to be 97% (by volume). EXAMPLE 47 (a) Methvlene bis(10-undecenoate) 10-Undecylenic acid (12.75 g, 75 mmol) is dissolved in 100 ml water. Cesium carbonate (13.04 g, 40 mmol) is added to the mixture. The water is removed under reduced pressure and the salt dried for 2 hours in vacuo. The cesium salt is mixed with 150 ml DMF and diiodomethane is added to the solution. The reaction is stirred for 3 days at 60 "C under an N2 atmosphere. DMF is then removed under reduced pressure. The residue is purified through silica gel with hexane/ ethyl acetate (8:2) as eluant. The solvent is evaporated to give 7.18 g (54%) product. ’h NMR (300 61 LV 10721
MHz ; , CDClj) : δ 1.2-1.4 (10 x CH2, m) , 1. . 6 (2 X ch2, m) , 2.0 (2 x CH2, m) , 2.19 (2 x CH2, t) , 4 . 9 (2 X H2 c=, m), 5.88 (0-CH2-0, s) , 5.9 (2 x HC=, m) - 13C NMR (300 MHz, CDClj) : δ 24.92-33.98 (8 x CH2) , 79.04 (0-CH2-0) , 114.18 (=CH2) , 139.11 (=CH) , 172.48 (C=0) . (b) Methvlene bis(10.ll-epoxvundecanoate)
Methylene bis (10-undecenoate) (8.8g, 25 irimol) is added under an N2 atmosphere to methylene chloride and cooled to 0 * C. Metachloroperbenzoic acid 55% (15.75g, 50 mmol) is added to methylene chloride (150 ml) and the organic layer is separated and dried (MgS04) . The metachloroperbenzoic acid is then added dropwise to the diester. After completed addition the temperature is increased to 25°C. After 5 hours the reaction is complete. The mixture is washed with saturated agueous sodium sulphite (75 ml) and saturated aqueous sodium hydrogen carbonate (2 x 75 ml). The organic layer is purified on neutral aluminium oxide. The solvent is removed under reduced pressure to yield 8.45g (82%) product. 1H NMR (300 MHz, CDC13) : & 1.2-1.7(14 X CH2, m) , 2.35(2 X CH2C0,t), 2.45 (2 X CH,q), 2.75 (2 X CH,q), 2.90 (2 X CH,m) , 5.75 (0-CH2-0). 13C NMR (300 MHz, CDClj): 6 24.58 (CH2) , 25.99 (CH?) , 28.94 (CH2) , 29.09 (CH2) , 29.32 (2 X CH2) , 32.45 (CH2) , 33.92 (CH2) , 47.06 (CH2~ 0), 52.36 (CH-0), 79.06 (0-CH2-0); 172.2 (C=0). EXAMPLE 48 (a) Methvlene dibenzvloxvacetate
Benzyloxyacetic acid (49.8 g, 300 mmol) is dissolved in a 500 ml mixture of water and MeOH (60:40), and cesium carbonate (48.9 g, 150 mmol) is added to the solution. The solvent is evaporated under reduced pressure. and residual water is removed azeotropically 62 with benzene. The salt is dissolved in 1500 ml DMF and diiodomethane (40.2 g, 150 mmol) is added to the solution. The reaction mixture is stirred for 3 days at 60 ’C under an N2 atmosphere. The DMF is removed under reduced pressure and the residue is dissolved in ether (250 ml) and washed with saturated aqueous sodium hydrogen carbonate (250 ml) and water (3 x 75 ml) before drying (MgS04) . The solvent is evaporated and the residue is purified through silica gel with hexane/ethyl acetate (7:3) as eluant to give 23.6 g (46%) product. 1H NMR (300 MHz, CDCl3) : <5 4.1 (2 X CH2, s) , 4.6 (2 X CH2, S) , 5.9 (O-CH.,-0, s) , 7.35 (2 x C6 H5, m) . (b) Methvlene dihvdroxvacetate
Methylene dibenzyloxyacetate (0.52 g, 1.5 mmol) and Pd/C (100 mg, 10%) are added to dry ethanol (100 ml). Hydrogen (1 atm) is introduced and the reaction is complete after 16 hours at room temperature, whereupon the reaction mixture is filtered and the solvent is evaporated under reduced pressure (0.01 mmHg) to yield 0.23 g (95%) product. 1H NMR (200 MHz, MeOH) : 6 4.2 (CH2, s) , 4.9 (OH) , 5.9 (OCH20, s) . The product may be used to form polyesters with di- or poly- acids and to form polyurethanes with isocyanates. EXAMPLE 49
Homopolvmerisation of methvlene diepoxvpropionate
Anhydrous tert.butylhydroperoxide (3.3 ml, 3M) and BuLi (6.7 ml, 1.5 M) are dissolved in 30 ml cold (~78*C) THF. The solution is stirred for 5 minūtes before adding methylene diacrylate (0.78 g, 5 mmol). The reaction is performed under N2 atmosphere for 1 hour. The cold mixture is filtered through neutral aluminium oxide and evaporated 63 LV 10721 to yield a transparent polymer. The solubility properties of the product indicate that it is a polymer. EXAMPLE 50
Homopolvmerisation of l-acrvlovloxvethvl 4-acrvovloxvbutvl carbonate 348.2 mg (1.22 mmol) of l-acryloyloxyethyl 4-acryoyloxybutyl carbonate prepared as described in Example 4(1) is blended with 1.7 mg (10.2 μχαοί) AIBN. After 2 hours at 70*C the monomer has formed a hard solid. This polymer is insoluble, indicating that its structure is a tightly crosslinked network. EXAMPLE 51 Εοοχν resin based on methvlene bis(10,ll-epoxvundecanoate) and an aliphatic polvamine A sample of methylene bis(10,ll-epoxyundecanoate) prepared as described in Example 47 is blended with an equal weight of a commercial aliphatic polyamine curing aģent. This mixture is cured on the surface of a glass plate at 70°C. The resin is observed to have hardened and good bonding is obtained within 2 hours of mixing. EXAMPLE 52
Polvmer from 1,6-diisocvanatohexane and methvlene difp-hvdroxvbenzoate^ 1,6-Diisocyanatohexane (0.927 g, 5.51 mmol) is added to a solution of methylene di(p-hydroxybenzoate) prepared as described in Example 4(o) (1.588 g, 5.51 mmol) in DMF (15 ml) under a dry N2 atmosphere. The reaction mixture is heated to 100"C for 3 days before the solvent is removed under reduced pressure at 50"C. Upon cooling to 20”C the product turns into a rubber-like material which is practically insoluble in a 1:1 mixture of chloroform and DMSO, indicating formation of a polymer. 64 EXAMPLE 53
Characterisation of the size of the polvmers made in Examples 37. 38. 39 and 40
The characterisations are performed on a Malvern PS/MW 4700 using Buccard celis. Each sample is diluted until an opaque solution forms and is attemperated to 25*C prior to analysis. Viscosity of water = 0.891 cP is used, and instrument settings are: Light Power = 70 mW, PM-aperture = 200 m, Scattering angle = 90', Mode = Manual, Serial Configuration, Sample time = 4 s, Experimental duration = 90 s, Calculus mode = modei independent, fit error minimized. To obtain results for the mass distribution a "Particle Refractive IndexM = 1.4 5 is used. Each sample is analysed in triplicate.
Mass mean particle hydrodynamic diameter (Dh) and distribution Standard deviation (SD-distribution) for each sample are shown on the following Table. Experimental SD is shown in brackets.
Example Dh SD-distribution 37 57.5 (± 1.5) nm 11.2 (± 1.7) nm 38 58.7 (± 0.9) nm 12.1 (± 1.3) nm 39 56.7 (± 0.7) nm 16.6 (± 1.2) nm 40 62.1 (± 1.6) nm 14.0 (± 2.6) nm EXAMPLE 54 (a) Enzvme-catalvzed hvdrolvsis of acrvlamide polvmer crosslinked_with_2%_acrvlovloxvmethvl_4- acrvlovloxybutvl carbonate 432 mg samples of the polymer described in Example 12 and 50 ml 0.9% NaCl (Sterile, Hydro Pharma) are added to each of two reaction vials. To one of the vials is also added 1000 μΐ esterase (Sigma, E-2138, 2530 65 LV 10721 U). The pH vithin each vial is ķept constant at 8.4 by adding 0.10 M NaOH. By recording the consumption of NaOH the rātes of hydrolysis are calculated. During 21 hours, hydrolysis of the polymer with esterase is found to be 8.5 times faster than the control vithout esterase. (b) Enzvine-catalvzed hvdrolvsis of acrvlamide polvmer crosslinked with 2% methvlene dimethacrvlate compared with control polvester
To one vial are added 500 mg acrylamide polymer crosslinked with 2% methylene dimethacrylate prepared according to the method of Example 5(a), 40 ml (0.16 M, pH 7.4) PBS (phosphate buffer) and 800 μΐ esterase (Sigma, E-2138, 2024 U) .
As a control 500 mg acrylamide polymer crosslinked with 2% ethylene dimethacrylate (prepared according to the method of Example 5(a) but using ethylene dimethacrylate instead of methylene dimethacrylate), 40 ml (0.16 M, pH 7.4) PBS (phosphate buffer) and 800 μΐ esterase (Sigma, E-2138, 2024 U) are added to a second vial.
For the control polyester, pH of the buffer decreases from 7.1 to 6.9 during 200 hours, while pH in the buffer solution containing acrylamide polymer crosslinked with methylene dimethacrylate decreases from 7.1 to 6.4 during 24 hours,. indicating that the acid metabolites are formed much faster for methylene dimethacrylate polymer than for the control polyester.. 66 EXAMPLE 55
Polvmer from starch crosslinked with methvlene bis(10.11-epoxvundecanoate)
Titanum (IV) isopropoxide (1.11 g, 3.9 mmol) is added to a solution of methylene bis (10,11-epoxyundecanoate) prepared as described in Example 47 (1.0 g, 2.6 mmol) and starch (1.0 g) in dry DMSO (50 ml). The reaction mixture is stirred for 4 hours at ambient temperature. Chloroform/ether (250 ml, 1:1) is added, the oily material is dissolved in water and extracted with chloroform (2 x 50 ml). The aqueous phase is subjected to dialysis or gel filtration to furnish the polymer. EXAMPLE 56
Polvmer from dextran 70000 crosslinked with methvlene bis (10.ll-epoxvundecanoate\
Titanum (IV) isoproxide (1.11 g, 3.9 mmol) is added to a solution of methylene bis (10, ll-epoxyundecanoate) prepared as described in Example 47 (1.0 g, 2.6 mmol) and dextran 70,000 in dry DMSO (50 ml). The reaction mixture is stirred for 4 hours at ambient temperature. Chloroform/ ether (250 ml, 1:1) is added, the oily material is dissolved in water and extracted with chloroform (2 x 50 ml) . The aqueous phase is subjected to dialysis or gel filtration to furnish the polymer EXAMPLE 57
Polvmer from protein crosslinked with methvlene bisdo.li-epoxvundecanoate )
Methylene bis(10,ll-epoxyundecanoate) prepared as described in Example 47 (1.0 g, 2.6 mmol) is added to a solution of human serum albumin (1.0 g) in buffer (50 ml). The reaction mixture is stirred at ambient temperature overnight and evaporated. The polymer is vashed several times with tetrahydrofuran and dried under reduced pressure. 67 LV 10721
Claims 1. Polymers containing diester units of the formula (I) fCO-O-C (R1 R2)-0-C0} (I) where R1 and R2 each represents a hydrogen atom or a carbon-attached monovalent organic group or R1 and R2 together form a carbon-attached divalent organic group, with the proviso that where such units are attached at both ends to carbon atoms and the polymers are polyolefinic, then the polymers are biodegradable and/or are water-swellable and/or are associated with a biologically active or diagnostic aģent. 2. Polymers as claimed in claim 1 containing diester units of the formula (II) f ( O) n-C0-0-C (R1 R2) -O-CO- ( O) mt (II) where R1 and R2 have the meanings given in claim 1 and m and n, which may be the same or different, are each O or 1. / 3. Polymers as claimed in claim 2 containing units of the formula (III) f (O) n-C0-0-C (r’r2) -O-CO- (O) m-R3t (III) where m, n, R1 and R2 have the meanings given in claim 2 and R3 is a carbon-attached divalent organic grouping. 4. Polymers as claimed in claim 2 or claim 3 wherein n is O and m is 0 or 1. 68 5. Polymers as claimed in any of the preceding claims in which R1 and R2 are each hydrogen or a carbon-attached hydrocarbyl or heterocyclic group. 5 6. Polymers as claimed in claim 5 in which R1 and R2 are each hydrogen or an aliphatic group having up to 10 carbon atoms, a cycloalkyl group having up to 10 carbon atoms, an araliphatic group having up to 20 carbon atoms, an aryl group having up to 20 carbon atoms or a heterocyclic group 10 having up to 20 carbon atoms and one or more heteroatoms selected from 0, S and N, which group may carry one or more functional substitutents. 7. Polymers as claimed in any of claims 3 to 6 in which 15 R3 is an alkylene or alkenylene group having up to 2 0 carbon atoms, a cycloalkylene group having up to 10 carbon atoms, an aralkylene group having up to 20 carbon atoms, an arylene group having up to 20 carbon atoms or a heterocyclic group having up to 20 carbon atoms and one or 20 more heteroatoms selected from O, S and N, which groups may carry functional substituents and/or may be interrupted in the carbon chain by one or more heteroatoms. 25 8. Polymers as claimed in any of claims 1 to 6 in which the diester units cross-link polymer chains. 9. Polymers as claimed in any of claims 1 to 7 which are block or graft copolymers. 30 10. Polymers as claimed in any of the preceding claims which are biodegradable. 11. Polymers as claimed in any of the preceding claims in the form of surgical implants, soft tissue prostheses, sponges, films, v/ound dressings, flexible sheets, containers and delayed release formulations for drugs and 35 69 LV 10721 agricultural Chemicals, particulate imaging aģents or plasticisers. 12. A process for the preparation of a polymer as claimed in claim 1 comprising one or more of the following steps: (A) Synthesis of a homopolymer comprising units of formula (III) as defined in claim 3 wherein n is O and m is 0 or 1 by condensation polymerisation of a compound of the formula (VI) X—C (R’r2) -O-CO-(O)m-R3-C00R8 (VI) where R8 is a mētai ion, X is a leaving group, m is 0 or 1 and R1, R2 and R3 have the meanings given in claim 3 ; (B) Synthesis of a homopolymer comprising units of formula (III) as defined in claim 3 where m and n are O by condensation of a compound of the formula (XII) r8o-co-r3-co-or8 (XII) where R8 is a mētai ion as defined in (A) above and R3 is as defined in claim 3, with a compound of the formula (XIII) X-C(R1R2)-X (XIII) where the groups X, which may be the same or different have the meanings given above in (A) and R1 and R2 have the meanings given in claim 3; (C) Condensation polymerisation of a compound of the formula HR9-R3A-(0)n-C0-0-C(R1R2)-0-C0-(0)m-R38-C00H where R1, R2, m and n have the meanings given in claim 3, R3A and R38 are each groups as defined for R3 in claim 3 and R9 is 0 or NR4 (where R'* represents a hydrogen atom, an acyl group or 70 a carbon-attached hydrocarbyl group), to give a polymer with repeating units (XIV) f-R9-R3A-(0)n-C0-0-C(R1R2)-0-CO-(O)m-R38-COt (XIV) ; (D) Reaction of a compound R^CO-R2 where R1 and R2 are as defined in claim 3, optionally together with a compound H0-R3-0H where R3 is as defined in claim 3, with phosgene in the presence of a base to give a product containing units of the formula (XIX) tC0-0-C(R1R2) -0-C0-0-R3—0} (XIX); or (E) Reaction of a compound of the formula (XXI) R10-R3a- (O) n-CO—0-C (R1R2) -O-CO- (O) m-R3B-R11 (XXI) (vhere R1, R2, R3A, R38, m and n have the meanings given in (C) above and R10 and R11, which may be the same or different, optionally together with the groups R3a and R38 to which they are attached, are reactive functional groupings) with a difunctional compound of the formula (XXII) R12-R3c-R13 (XXII) vhere R3c is a group as defined for R3 in claim 3 and R12 and R13, vhich may be the same or different, are reactive functional groups capable of reacting with R10 and Rn whereby a polymer according to the invention is formed, or R12 and R13 separately or together form a polymerisable group or groups capable of interaction with R10 and R11. 13. Compounds of formula (XXI) as defined in claim 12. LV 10721
Abstract POLYMERS CONTAINING DIESTER UNITS [-C0-0-C(R1R2)-O-CO-] (l)
Polymers containing diester units of formula (1), where R1 and R2 each represents a hydrogen atom or a carbon-attached monovalent organic group or R1 and R2 together form a carbon-attached divalent organic group, with the proviso that where such units are attached at both ends to carbon atoms and the polymers are polyolefinic, then the polymers are biodegradable and/or are water-swellable and/ or are associated with a biologically active or diagnostic aģent.

Claims (10)

LV 10721 MFSIFRA VIKNĪFIAS SA'TUROŠI POMMKR1 I/(JUDROJIJMA FORMULA 1. Diestera vienības pec formulas (!) [-(0-0-C'(R'R2)-0-C0-| (I) saturoši polimēri, kur R1 un R2 katrs attēlo ūdeņraža atomu vai ar oglckli saistītu vienvērtīgu organisku grupu vai kur R1 un R2 kopā veido ar oglckli saistītu divvērtīgu organisku grupu, un gadījumā, ja tādas vienības saistītas abos galos pie oglekļa atomiem un polimēri ir poliolefīni, tad polimēri ir biodegradējami un/vai uzbriestoši ūdenī, un/vai ir saistīti ar bioloģiski aktīvu vai diagnostisku aģentu.LV 10721 MFSIFRA VICYFIELD SA'S PROTECTIVE POMMKR1 I / (Polymeric Diester Units of Formula (!) [- (O-O-C '(R'R2) -O-C0- (I)) wherein R1 and R2 each represents a hydrogen atom or a carbon-linked monovalent organic group, or wherein R1 and R2 together form a carbon-linked bivalent organic group, and when such units are attached at both ends to the carbon atoms and the polymers are polyolefins, the polymers are biodegradable and / or or swellable in water and / or are associated with a biologically active or diagnostic agent. 2. Polimēri, kas aprakstīti I .punktā un satur diestera vienības pēc formulas (II), -f(0)n CO-0-C(R'R2)-0-C0-(0)mļ· (IT) kur R1 un R2 nozīme dota 1.punktā un kur m un n var būt vienādi vai atšķirīgi, katrs var būt 0 vai I.2. Polymers described in I and containing diester units of formula (II), -f (O) n CO-O-C (R'R2) -O-C0- (O) mole · (IT) wherein R1 is and the meaning of R2 is given in paragraph 1 and where m and n can be the same or different, each of 0 or I. 3. Polimēri, kas aprakstīti 2.punktā un satur vienības pēc formulas (III), 4(0)n-C 0-0-C’(R'R2)-0-C0-(0)m-R3-ļ- (III) kur m, n, R1 un R2 nozīme dota 2.punktā un kur R3 ir ar oglekli saistīts divvērtīgs organisks grupējums.3. Polymers described in paragraph 2 and containing units of formula (III), 4 (O) nC 0-0-C '(R'R 2) -O-C 0 - (O) m -R 3 - (III) ) wherein m, n, R 1 and R 2 are as defined in claim 2, and wherein R 3 is a carbon-linked bivalent organic group. 4. Polimēri, kas aprakstīti 2. vai 3.punktā un kur n ir() un m ir 0 vai 1. 5. Kādā no iepriekšējiem punktiem aprakstītie polimēri, kur R1 un R2 katrs ir ūdeņradis vai ar oglckli saistīta ogļūdeņraža vai heterocikliska grupa.4. Polymers described in paragraph 2 or 3 and wherein n is () and m is 0 or 1. Polymers as described in any one of the preceding claims, wherein R 1 and R 2 are each hydrogen or a carbon-linked hydrocarbon or heterocyclic group. 6. Polimēri, kas aprakstīti 5.punktā un kur R1 un R2 katrs ir ūdeņradis vai līdz. 10 oglekļa atomus saturoša alifātiskā grupa, līdz. 10 oglekļa atomus saturoša cikloalkilgrupa, līdz 20 oglekļa atomus saturoša aralifāliskā grupa, līdz 20 oglekļa atomus saturoša arilgrupa vai līdz 20 oglekļa atomus saturoša heterocikliska grupa un viens vai vairāki O, S un N heteroatomi, kuru grupa var nest vienu vai vairākus funkcionālus aizstājējus.6. Polymers described in paragraph 5 and wherein R 1 and R 2 are each hydrogen or up to. 10 carbon atoms containing aliphatic, up to. 10 carbon atoms containing cycloalkyl, araliphatic group containing up to 20 carbon atoms, aryl of up to 20 carbon atoms or heterocyclic group containing up to 20 carbon atoms and one or more heteroatoms O, S and N, which group may bear one or more functional substituents. 7. Polimēri, kas aprakstīti 3. vai 6.punktā un kur R3 ir līdz 20 oglekļa atomiem saturoša alkilēn- vai alkcnilēngrupa. līdz 10 oglekļa atomus saturoša ciklpalkilēngmpa, līdz. 20 oglekļa atomus saturoša aralkilēngrupa, līdz 20 oglekļa atomus saturoša arilēngrupa vai līdz 20 oglekļa atomus saturoša heterocikliska grupa un viens vai vairāki 0, S un N heteroatomi, kuru grupas var nest funkcionālus aizstājējus un/vai var pārtraukt oglekļa ķēdi ar vienu vai vairākiem hctcroatoniiem.Polymers as described in claim 3 or 6, wherein R 3 is alkylene or alkenylene having up to 20 carbon atoms. up to 10 carbon atoms in the cycloalkyl ring, up to. 20 carbon atoms containing aralkylene, arylene of up to 20 carbon atoms or heterocyclic group containing up to 20 carbon atoms and one or more of 0, S and N heteroatoms, which groups may carry functional substituents and / or may terminate the carbon chain with one or more hctcroatons. 8. Polimēri, kas aprakstīti I. vai 6.punktā un, kuros diestera vienības šķērsām sasaista polimēra ķēdes.8. Polymers described in I or 6, in which the diester units cross-link the polymer chains. 9. Polimēri, kas aprakstīti I. vai 7.punktā un, kuri ir blokkopolimēri vai picpotētic kopolimēri. 10. Kādā no iepriekšējiem punktiem aprakstītie polimēri, kas ir biodegradējami. - 2- 1 l.Kādā no iepriekšējiem punktiem aprakstītie polimēri, kas ir ķirurģisku fiksāžu, mīksto audu protēžu, sūkļu, plēvju, ievainojumu pārsienamo materiālu, elastīgo saišu, medikamentu un lauksaimniecības ķimikāliju konteineru un palēninātas atbrīvošanās receptūru, speciālu aģentu vai plastikātu forma.9. Polymers described in I or 7 and which are block copolymers or picotethic copolymers. 10. Polymers described in any of the preceding paragraphs which are biodegradable. - 2- 1 l.In the form of polymers described in the preceding paragraph, which are surgical fixings, soft tissue prostheses, sponges, films, wound dressings, elastic bands, medication and agricultural chemical containers and slow-release formulations, special agents or plastics. 12.Polimēru, kas aprakstīti 1.punktā sagatavošanas paņēmiens un, kurš ietver sevī vienu vai vairākus sekojošus etapus: (A) Tāda homopolimēra, kas satur (III) formulas vienības kā definēts 3.punktā, kur n ir 0 un m ir 0 vai I, sintēze ( VI) formulas X-C(R1R2)-0-C0-(O)m-R3-COOR8 (VI) savienojumu kondensācijas polimerizācijā, kur R ir metāla jons, X ir grupas atlikums, m ir 0 vai 1 un R1, R2 un R3 nozīme dota 3.punktā; (B) (III) formulas vienību kā definēts 3.punktā, kur m un n ir 0, saturoša homopolimēra sintēze kondensējot (XII) formulas R80-C0-R3-C0-0R8 (XII) savienojumu, kur R8 ir metāla jons kā definēts iepriekš (A) un R3 - kā definēts 3.punktā, ar formulas (XIII) X-C(R1R2)-X (ΧΙΠ) savienojumu, kur X grupas, kuru nozīme dota iepriekš (A), var būt vienādas vai atšķirīgas un kur R1 un R2 nozīme dota 3.punktā; (C) Kondensācijas polimerizācijā savienojumam ar formulu HR9 -R3A-(0)n-C0-0-C(R1R2)-0-C0-(0)m-R3B-C00H, kur R1, R2, m un n nozīme dota 3.punktā, R3A un R3B ir ikviena 3.punktā definētā R3 grupa un R9 ir 0 vai NR4 (kur R4 attēlo ūdeņraža atomu, acilgrupu vai ar oglekli saistītu ogļūdeņraža grupu), lai iegūtu polimēru, kurā atkārtojas vienības (XIV) [-R9-R3A-(0)n-C0-0-C(R1R2)-0-C0-(0)m-R3B-C0-] (XIV); (D) savienojuma R'-CO-R2, kur R1 un R2 definēti 3.punktā, reakcija ne obligāti kopā ar savienojumu HO-R3-OH, kur R3 ir definēts 3.punktā, ar fosgenu bāzes klātbūtnē, lai iegūtu produktu, kas satur vienības pēc formulas (XIX) l-CO-O-CfR^-O-CO-O-R^O-] (XIX); vai (E) savienojuma pēc formulas (XXI) Rlu-R3A-(0)n-C0-0-C(R1R2)-0-C0-(0)m-R3B-R11 (XXI) (kur Rl, R2, R3A, R3B, m un n nozīme dota iepriekš (C) un kur R10 un Rn var būt vienādi vai atšķirīgi, ne obligāti kopā ar grupām R3A un R3B, ar kurām tie saistīti, ir reaktīvi funkcionāli grupējumi) reakcija ar bifunkcionālu savienojumu pēc formulas (XXII), R12.R3C.R13 (XXII) kur R3C - 3.punktā definētā R3 grupa un R12 un R13, kas var but vienādi vai atšķirīgi, ir reaktīvi funkcionālās grupas, kas spēj reaģēt ar R10 un RM, kā rezultātā saskaņā ar izgudrojumu veidojas polimērs, vai R12 un R13 atsevišķi vai kopā veido polimcrizējošos grupu vai grupas, kas spēj mijiedarboties ar R10 un RM.12. A process for preparing polymers as described in claim 1 and comprising one or more of the following steps: (A) A homopolymer containing units of formula (III) as defined in claim 3 wherein n is 0 and m is 0 or I, Synthesis of Condensation Polymerization of Compounds of Formula XC (R1R2) -O-C0- (O) m-R3-COOR8 (VI), wherein R is a metal ion, X is a residue of the group, m is 0 or 1 and R1 is R2 and R3 are as defined in claim 3; Synthesis of a homopolymer containing (B) (III) as defined in claim 3, wherein m and n are 0, condensing the compound of formula (XII) R80-C0-R3-C0-0R8 (XII), wherein R8 is a metal ion as defined above (A) and R3, as defined in paragraph 3, with a compound of formula (XIII) XC (R1R2) -X (ΧΙΠ), wherein X groups having the meaning given above (A) may be the same or different and wherein R1 and R 2 is given in paragraph 3; (C) Condensation polymerization for the compound of formula HR9 -R3A- (O) n-C0-0-C (R1R2) -O-C0- (O) m-R3B-C00H where R1, R2, m and n are given 3 , R3A and R3B are each R3 groups defined in point 3 and R9 is O or NR4 (wherein R4 represents a hydrogen atom, an acyl group or a carbon-linked hydrocarbon group) to obtain a polymer (XIV) [-R9-] R3A- (O) n-C0-0-C (R1R2) -O-C0- (O) m-R3B-C0-] (XIV); (D) The reaction of the compound R'-CO-R2, wherein R1 and R2 are as defined in claim 3, is not necessarily combined with the compound HO-R3-OH, wherein R3 is as defined in paragraph 3, in the presence of a phosgene to form a product which: contains units of formula (XIX) 1-CO-O-CfR4 -O-CO-OR1O- (XIX); or (E) of formula (XXI) Rlu-R3A- (O) n-C0-0-C (R1R2) -O-C0- (O) m-R3B-R11 (XXI) (wherein R1, R2, R3A , R3B, m and n are given above (C) and wherein R10 and Rn may be the same or different, not necessarily together with the groups R3A and R3B to which they are attached are reactive functionalities) with a bifunctional compound of formula (XXII) ), R12.R3C.R13 (XXII) where R3C - R3 and R12 and R13, which may be the same or different, are defined as reactive functional groups capable of reacting with R10 and RM. a polymer, or R12 and R13, alone or in combination, form a polymerizing group or groups capable of interacting with R10 and RM. 13.Savienojumi pēc formulas (XXI), kā definēts 12.punktā.13. Compounds of formula (XXI) as defined in paragraph 12.
LVP-93-173A 1991-09-07 1993-03-07 Poymers containing diester units LV10721B (en)

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