Polymers containing diester units

The present invention relates to polymers having optionally substituted methylene diester groups. Such groups may be biodegradable because they are degraded by simple enzymes esterases, although in most cases the polymer may survive, at least in part.

Biodegradable polymers have long been used in medicine, such as biodegradable implant materials or delayed-release drug systems. Recently, they have received more attention to reduce environmental pollution by stable packaging materials, household items, detergents, etc.

In addition, polymers are required which are completely non-toxic products of chemical or biodegradation in whole or in part

In general, biodegradation is the enzymatic hydrolysis of certain polymeric bonds, such as ester, urethane or amide groups. In the absence of enzymes, these bonds are stable. Therefore, aliphatic polyesters, such as polycaprolactam, polyethylene adipate and polyglycolic acid, are the most suitable bleaching agents, although polyethylene terephthalate, widely used in textiles and fiber production, is biodegradable.

-2EN 3665 B

Medical resorbable polymers are needed for sutures and wound dressings, resorbable implants, treatment of osteomyelitis and other bone diseases, tissue fusion and reticulation, anastomoses and drug delivery systems, diagnostics. Poly-lactic acid, polyglycolic acid, poly (L-lactide-co-glycolide), polydioxanone, poly (glycolide-co-trimethylene carbonate), poly (ethylene carbonate), poly (imine carbonates), polyhydroxybutyrate, poly (amino) are suggested for use in these applications. acids), poly (ester amides), poly (ortho esters) and poly (anhydrides) (TH Barrows, Clinical Materials 1 (1986), pp. 233-257), and natural products such as polysaccharides. Specifically, US-A4180646 describes novel poly (orthoesters) that can be used in many products.

However, all polymers used to date in medicine or other fields have at least one or more disadvantages, and new polymers are needed, especially those with readily biodegradable groups. The present invention is based on the concept that simple enzymes esterases very rapidly degrade diester units of the formula [CO-O-CfRiR ^ -O-CO} (I).

(wherein R 1 and R 4 will be defined later), but are stable in the absence of enzymes.

Many of the polymers containing such blocks are described previously. Yes, for example, in a patent

US-A-2341334 describes copolymerization of monomers such as methylidene or ethylidene dimethacrylate with ethylene monomers such as vinyl acetate, methyl methacrylate or styrene. The resulting polymers are said to have a higher softening point than unmodified ethylene monomer homopolymers and can be used for molding products DD-A-95108 and DE-A-1104700 also describe copolymerization of various alkylidene diacrylate esters with acrylic monomers. modified physical properties. US-A-2839572 discloses that many alkylidene dicrotonate monomers may be homopolymerized or copolymerized with materials such as vinyl chloride. The resulting resins can be used for protective coatings. In the journal Osaka Univ. Dent. Sch. 20 (1980), p. 43-49.

-3EN 3665 B

Kiniura H. describes the use of propylidene trimethacrylate as a cross-linking agent in the manufacture of post-methyl methacrylate coatings for teeth to enhance their abrasion resistance. FR-A-2119697 and A. Arbuzova (See Obshi Chim. 26 (1956), pp. 1275-1277) disclose homopolymers of ethylidene, allylidene and benzylidene dimethacrylate, which are mostly solid materials in the glass state.

EP-A-0052946 describes the use of some polyacrylates to stabilize polyhydroxybutyric acid. The only polyacrylate containing more than one acryloxy group attached to one carbon atom is pentaerythrityl monohydroxypentaacrylate, which, having a large number of unsaturated ethylene bonds, should form a complex mixture of added polymers and polyhydroxybutyric acid.

US-A-3293220 describes the use of aldehyde dicarboxylates to stabilize polyoxymethylene polymers by acylation of terminal hydroxyl groups. The patent does not mention cross-linking or incorporation of aldehyde dicarboxylate residues into polymer chains.

In the prior art, diester groups of formula (I) are incorporated into polymers by polymerization of alkylidene diacrylate or dimethacrylate monomers according to free radical mechanism, and olefinic bonds are polymerized to form polyolefinic chains to which diester groups are attached. The diester groups are always in such a form that, compared to formula (I), both carbonyl groups are directly attached to carbon, that is, all ester groups are nothing more than a simple carboxylic ester group.

No report mentions that the diester groups described may be biodegradable, as it is generally believed that cross-linking groups of formula (I) provide increased hardness and / or stability.

According to the present invention, we have been able to obtain novel diester polymers having cross-linking groups of formula (I) which are very stable in the absence of enzymes but

-4LT 3665 B esterases break down bonding groups very easily, both in the natural environment such as bacteria and in the human or animal body, producing non-toxic products, even though the polymer's structural elements, such as basic polymer chains, remain.

In contrast to the polyesterefined polyesterefinic polymers described above, which have very rigid cross-links, the polymers of the present invention, even the polyolefinic ones, may even exhibit water swelling properties. This can provide various benefits, such as facilitating the entry of aqueous enzymes into the polymer structure and thereby promoting biodegradation. In addition, water-swellable polymers can be treated with aqueous or hydrophilic solutions, such as biologically active or diagnostic agents, to introduce them into the polymer. Another feature of the present invention is that such agents can be physically introduced into the diester polymers during the polymerization, or they can be covalently attached to the corresponding monomers which are subsequently polymerized, or to the partially prepared polymers.

Thus, one aspect of the present invention is the preparation of polymers having diester units of formula (I) wherein each is a hydrogen atom or a carbon-attached monovalent organic group or together forms a carbon-attached divalent organic group. provided that when these units are attached at both ends to carbon atoms and the polymers are olefins, the polymers are biodegradable and / or swell in water, and / or bound to a biologically active or diagnostic agent.

In general, biodegradable polymers are always more desirable. The potential disadvantage of polyolefinic polymers is that they have carbon-carbon backbone chains which are not readily degradable, although this is not a disadvantage when the polymer swells in water and / or contains biological or diagnostic agents and / or when the polymer backbone chains are swollen or dispersed in water, for example by disruption of diester crosslinking groups.

The term diester as used herein means that the block of formula (I) contains two CO-O- groups. They can be attached not only to organic groups at carbon atoms but also to -O- atoms as carbonate esters.

-5EN 3665 B

Thus, the polymers of the present invention can be defined as polymers having blocks represented by the formula (Π),

KO)_a-CO-OC (R1R2) -O-CO- (O)_m] (Π), wherein R 1 and R 4 are as previously defined, om and n, which may be the same or different, each being 0 or 1.

In general, the polymers of the present invention have blocks represented by Formula (III),

KO)_n-CO-OC (R1R2) -O-CO- (O)_m-R3} (ΠΙ) in which R1, R6, n and m are as previously defined and R6 is a divalent organic group attached to carbon.

The polymers of the present invention may have relatively low molecular weights, which is desirable because they are then more readily degraded and the degradation products more readily dispersed.

Thus, it should be understood that the term polymer as used in this invention includes low molecular weight materials, e.g., oligomers.

According to the present invention, the polymers may have a plurality of blocks represented by the formula (ΠΙ), wherein m, n, R 1, R 4, and R 4 may have different meanings, for example, as block or graft copolymers. The diester linkages may be spaced, for example, as crosslinking groups, or may be in the polymer sections, in which case R 3 is a polymeric group. Alternatively, the bonds may be present practically throughout the polymer, and in this case R ^ will generally be a low molecular weight group.

Of particular interest are blocks having the formula (UI) wherein n is 0, om is 0 or 1, i.e..

dicarboxylate units of formula (IV),

-6EN 3665 B

-ECO-O-CCRiR ^ -O-CO-R³} (IV) or carboxylate-carbonate units of formula (V) [CO-OC (R²) -O-CO-OR³] (V)

Of particular interest are the latter, which have not hitherto been described in any type of polymer.

R 1 and R 2² each may be, for example, hydrogen or a carbon-attached hydrocarbyl or heterocyclic group having, for example, 1 to 20 carbon atoms, being conciliated by an aliphatic group such as an alkyl or alkenyl group (preferably having up to 10 carbon atoms), a cycloalkyl group (preferably containing 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 a heterocyclic group, having up to 20 carbon atoms and one or more heteroatoms which may be O, S and N. Such hydrocarbyl or heterocyclic group may have one or more functional groups, e.g., halogen atoms or groups having the formulas -NR ^ R ^, CONR ^ rS , -OR6, -SR ^ and -COOR²wherein R 4 and R 6, which may be the same or different, are hydrogen, acyl or hydrocarbyl as defined for R² case; R 6 is a hydrogen atom or an acyl group or a group such as R 6 or R 6², and R² is a hydrogen atom or a group such as R ^ or R². When R¹ and R² are bivalent groups and may be alkylidene, alkenylidene, alkylene or alkenylene groups (preferably having up to 10 carbon atoms) which may have one or more previously defined functional groups.

As stated above, the diester groups of formula (I) may be separated by various other groups. If it is desired that the polymer break down into relatively short sections to promote biodegradation, R³ a group which distinguishes diester units having the formula (H) may be, for example, an alkylene or alkenylene group (e.g. having up to 20, preferably up to 10 carbon atoms), a cycloalkylene group (preferably having up to 10 carbon atoms), an arylene

-7 (having one or more aromatic rings and preferably up to 20 carbon atoms), an aralkylene group (preferably having up to 20 carbon atoms, and may be attached via aryl and / or alkyl groups and these aralkyl groups may contain e.g. , two aryl groups linked by an alkylene chain), or a heterocyclic group containing one or more heteroatoms which may be O, S and N (preferably having up to 20 carbon atoms). R³ the group may have functional groups, say the same as lU and R², and / or substituents, e.g., oxo groups; R² the carbon chains of the groups may be interrupted by beteroatoms, such as O, N or S, which together with the oxo substituents may form linkages such as ester, thioester or amide groups.

If the group contains a polymeric block, it may be, for example, a polyphamic acid, for example a polypeptide, or a polyamide, a poly (hydroxylic acid), a polyester, a polycarbonate, a polysaccharide, a polyoxyethylene, a polyvinyl alcohol or a polyvinyl ether / alcohol block. Rl, R² and R² the variety of groups allows the hydrophobicity or hydrophilicity of the polymer to be customized as desired. Therefore, polymers can be both bulk and water insoluble. Aliphatic groups such as R², may be linear or branched, saturated or unsaturated, and may be, for example, alkyl and alkenyl groups, e.g. methyl, ethyl, isopropyl, butyl or allyl. The araliphatic groups may be (monocarbo-acyl aryl) -alkyl groups, for example benzyl groups. Aryl groups may be mono- or di-cyclic aryl groups such as phenyl, toluyl or naphthyl. Heterocyclic groups may be 5 or 6 atom heterocyclic groups preferably having one heteroatom, for example furyl, thienyl or pyridyl. Halogen substituents may be, for example, chlorine, bromine or iodine.

Polymers of the present invention having functional groups or double bonds may serve as substrates for covalent bioactive agents, e.g. drugs (e.g. antibacterial or antmeoplastic agents), steroids and other hormones, agrochemicals such as herbicides and pesticides, or agents such as diagnostic agents (e.g. X-ray and MRI contrast agents) for attachment, and can be sold to users in a form that allows them to attach the active agent themselves. However, the present invention includes

-8EN 3665 B and polymers having blocks represented by the formula (ΙΠ) in which R 1, R 2 and / or groups are covalently bonded! biologically active or diagnostic materials. Suitable active ingredients are listed in full in the aforementioned US-A-4 180 646, the disclosure of which is incorporated herein by reference.

In general, the degradation of any diester block of formula (I) will take the form of an enzymatic hydrolytic cleavage of the bonds that bind the -OC (R 1 R 2) -O- group to adjacent carbonyl groups, usually leading to an aldehyde or ketone of formula R * CO-R . The intermediates, which are defined in the (ΠΙ) polymer by the formula -CO (0) m '^' (0) nC0-, will produce various products, depending on whether m and n are 0 or 1. If m and n are 0, the hydrolytic cleavage usually results in the formation of a carboxyl group, and if m and n are 1, the hypothetical carbonic acid group -R ^ -O-COOH, from which carbon dioxide is usually formed and -R ^ -OH group. This can be useful when the release of carbon dioxide is desirable from a physiological or functional point of view.

Polymers used in medicine must form non-toxic, physiologically acceptable degradation products. Therefore, the groups R 1, R 2 and R 3 must be such that the cleavage products, say R 1 -CO-R 2 and HOOC-R 4 -COOH, HO-R 4 -COOH or HO-R 4 -OH are physiologically acceptable and rapidly dispersible, preferably soluble in water. The carbon dioxide formed during the decomposition of the carbonate group is generally physiologically acceptable.

As already stated, blocks of the formula (ΠΙ) in the same polymer may be different, Ly. the polymers may be copolymers, say block or graft copolymers. They may also be copolymers formed with non-biodegradable monomers. The non-biodegradable moieties remaining after enzymatic or other degradation should be of an acceptable size to accommodate or disperse in water and thus to rapidly disperse or expel. Such non-biodegradable groups can be considered as part of the R 3 block of formula (UI), which actually contains the bio-degradable blocks of formula (().

-9EN 3665 B

The polymers may be in contact, branching or crosslinking. Branched or crosslinked polymers will be utilized in their respective monomers RL R-ii 'R³ functional groups in groups and double bonds. Therefore, crosslinked and branched polymers will have a reasonable number of blocks of formula (III) in which RL in'or R³ are replaced by transverse or branched chains.

It is particularly desirable that Rs³ the group would be an amino acid derivative because the amino acids are non-toxic ii 'soluble Dicarboxylic acids, such as glutamic or aspartic acids, and -CO-OR polymers can be used to produce polymers having -CO-R-'-CO- blocks³-CO- blocks, suitable hydroxy-amino acids, say serine or threonic acid, will have an R in the α-amino group of uric acid³ a functional amino substituent on a block or an attachment point on a branching or crosslinking chain. The crosslinking agents may be di- or polyfunctional molecules, for example diols (for linking carboxyl groups) or acids or diisocyanates (for linking hydroxyl or amino groups).

In general, if R³ groups and the compounds of formula (II) are linked by chiral carbon atoms, preferably the same chirality as natural products in e, since such structures are much more efficiently affected by degrading enzymes. Therefore, it is desirable that the amino acid blocks have an L-configuration. However, the D-isomers are also cleaved and in many cases it is more convenient to use not only optimum chiral materials but mixtures of isomers. Different rates of D- and Lysomeric enzymatic hydrolysis can be used to obtain a controlled rate of degradation.

It has been observed that crosslinked biodegradable polymers usually first break down the crosslinking blocks and then open the remainder of the network for enzymatic hydrolysis. Therefore, it is very useful that the blocks of formula (II) are present in the polymer cross-linking chains. Thus, a water-soluble natural or synthetic non-biodegradable or slowly biodegradable substance having a long chain, such as a protein such as gelatin or albumin, a polysaccharide or oligosaccharide, or a short-chain polyacrylamide,

- 10LT 3665 B. I should be converted to a water-insoluble form by cross-linking joints having blocks of formula (II). In this way, reducing the amount of relatively expensive biodegradable blocks of formula (II) can significantly reduce the cost of the final product.

The block copolymers may, for example, have the following structure:

{<O)_andCC) -OC (R 1 R 2) -O-CO- (O)_m-R³jq^A f (O) n-CO-O-C (R1R²-O-CO- (O) mR³] ^B, in which iU, R², r3_> j_rn respectively, such that the repeating blocks in A and B are distinct, oq and r being integers, e.g. 10-20. One or more other units may be connected to the units shown here.

The polymers of the present invention may be obtained in any convenient manner, for example, by one of the methods described below.

(A) The T ox method is the synthesis of homopolymers of blocks of formula (III) wherein n is 0, om is 0 or 1 by condensation polymerization of a compound of formula (VI)

XC (R¹R²) -O-CO- (O)_nl-R³-COOR⁸, (VI) wherein R 8 is an ion of a metal such as silver, sodium, potassium or lithium, X is a leaving group such as chlorine, bromine, iodine or hydrocarbylsulfonyloxy, for example mesyloxy or tosyloxy, m is 0 or 1 and R 1, R² and R³ define earlier.

The compound of formula (VI) may be prepared by reacting the corresponding acid, wherein r8 is hydrogen, with a suitable base, and the polymerization is usually carried out in situ.

The acid of formula (VI) containing hydrogen with an om of 1 can be obtained by condensation of a compound of formula (VII)³-cooh (VU)

- 11LT 3665 B with a compound of formula (VIII), kc ^ f-o-co-k¹ (viii) wherein χΐ is a chlorine, iodine or bromine atom and R 1, R², R² and X defined earlier. The reaction is preferably carried out in the presence of a weak nucleophilic base targeting pyridine in a reactive solvent such as a halogen hydrocarbon, e.g. chloroform.

The acid of formula (VI) containing hydrogen, om being 0 may be obtained by reaction of a compound of formula (IX),

Phenyl-SC (R1R²) -O-CO-R²-COOH (IX) ₍ (wherein R 1, R 4 are as defined above) with a halogenating agent, e.g. sulfonyl chloride, in a solvent in a halogenated hydrocarbon such as dichloromethane.

The compound of formula (IX) can be obtained by reacting a compound of formula (X),

CO-R³-CO

<img file="LT3665B_D0001.tif" />

(X) with a compound of formula (XI),

Phenyl-SC (R¹R²) -X¹, (XI) wherein R 1, R², R² and defined above, preferably in a polar solvent, say dimethylformamide.

_I2 EN 3665 B (B) This method involves the synthesis of homopolymers of blocks of formula (IH) wherein m and n are 0, by condensing a compound of formula (,),

R⁸O-CO-R³-CO-OR⁸ (ΧΠ) in which R⁸ is a metal ion as defined previously and R³ also as previously defined, with a compound of formula (ΧΠΙ),

XC (R! R²) -X (XHI \ wherein X, which may be the same or different, are as previously defined (preferably chlorine, bromine or iodine) and R ^ and R² meaning the same as before. The compound of formula (ΧΠ) can be obtained by reacting the corresponding acid wherein R⁸ is hydrogen, with a suitable base, and polymerization usually occurs in warm.

An acid of formula (XII) wherein R⁸ is hydrogen, om is 0, can be obtained by deprotection of the corresponding compound of formula (ΧΠ) wherein R⁸ is a carboxyl protecting group, say a readily hydro-hydrating group such as t-butyl. This can be done by adding a base, say sodium or potassium hydroxide, to directly form the (XH) compound and begin the polymerization.

(C) Compound of Formula HR⁹-R^3A- (O) n-CO-OC (pjR²-O-CO- (O) mR^3BCOOH, in which R ^, R², m and n defined above, R^3A and R^3B are in the same group as R³, and R⁹ is O or NR ^ (where hydrogen is present, an acyl group or a hydrocarbyl group as defined at R¹), condensation polymerization to form a polymer with repeating units (XIV) fR⁹-R^3A- (O) n-CO-OC (R¹R²-O-CO- (O) mR^3B-CO17 (XIV)

-13 LT 3665 B

This polymer can be obtained under conventional polyester or polyamide condensation conditions. Preferably, the repetitive block (XIV) corresponds to a block having the formula (UI) in which R³ would be -R^3B-CO-R⁹-R^3A- the group.

The starting material can be obtained by removal of the protective carboxyl and / or -R⁹H group. It is formed by the reaction of a compound of formula (XV)

HO-C (R¹R²) -O-CO- (O)_m-R^3B-COOR^A (XV) in which R¹, R², R^3B and m are defined earlier and R^A is a protecting group with a compound of formula (XVI),

R^BR⁹-R^3A- (O) n-CO-Cl (XVI), wherein R^3a, R⁹ and n are defined earlier and R^B is a protecting group.

Compound (XV) can be obtained by coupling compound (XVH) with rQ) -C (r1r²) -OH (XVII) with (XVHI) compound

Cl-CO- (O)_m-R^3B-COOR^A (xvm)₍ wherein R 1, R 5², R^3B, R^a and m are defined above, and RC is a protecting group which is removable. A compound of formula (XVH) can be obtained by reacting R as defined above¹CO-R² for a compound with an alcohol R ^ OII. Hemiacetal is formed during the reaction.

(D) Compound R ^-CO-R², optionally in combination with HO-R³-OH, reaction with phosgene in the presence of a base, say pyridine, to give blocks of formula (XIX).

-14EN 3665 B

-fCO-OC (R¹R²) -O-CO-OR³-Of (XIX)

Blocks of formula (XX) will also be formed

- [- co-oC {R¹R²) -o-co-oC (r1r²) -O4 (XX) but it should be noted that the above R³ the definition includes -C {R ^ R²) -, so these blocks fall within the definition of formula (ΙΠ). In addition, homopolymers containing such blocks can be obtained by reacting R 1 -CO-R² with phosgene in the presence of a base, say pyridine.

(E) Compound of Formula (XXI)

R10-R³A- (O) n-CO-OC (R1R²-O-CO- (O) mR^3B-R ^ (XXI) / {wherein Rl, R², R^3y\ R^3B, m and n are defined above, and R ^ and R ^, which may be the same or different, together with R³and R3B to which they are attached form active functional groups) by reaction with a difunctional compound of formula (XXII) r12._R3C.r13 (ΧΧΠ) in which R³⁽² defined in the same way as R³, and R ^² and R ^³, which may be the same or different, are active functional groups capable of reacting with R 1 and R 2¹¹, thus forming the polymer of the present invention, or R6² and R ^³ alone or in combination, may form a polishing agent

or a group which may react with R @ 1 and RH, for example to form a polymerized variant of compound (ΧΧΠ) with cross-linking groups derived from compound (XXI).

Functional groups R ^ and R¹* may be, for example, a leaving group, say a halogen atom, e.g. chlorine or bromine (as in haloalkyl groups; α-halomethyl ester

-14-tCO-O-CCRIP-O-CO-OR ^ -O} (XIX)

Blocks of formula (XX) will also be formed

4-C0-OC (R1r²) -O-CO-OC (R1r²) -O -} - (XX) but it should be noted that the above definition of R ^ also includes -C (R ^ R).²) -, so these blocks fall within the definition of the (UI) formula. In addition, homopolymers containing such blocks can be obtained by reacting R 4 -CO-R² with phosgene in the presence of a base, say pyridine.

(E) Compound of Formula (XXI)

R10-_R3A (_O)_a-CO-OC (R¹R²) -O-CO- (O)_m-R^3B-R¹¹ (XXI), {in which Rl, R², R ^ A r3B ni and n are as previously defined, and also ROO, which may be the same or different, together with the R ^ A-R3B groups to which they are attached form active functional groups) with a difunctional compound having (ΧΧΠ) has the formula r12.r3C.r13 (ΧΧΠ) where R ^ C is defined as R ^ and R ^² and R ^, which may be the same or different, are active functional groups capable of reacting with R ^ and R¹¹, thus forming the polymer of the present invention, or R 1² and R 13, alone or in combination, forms a polymerizable group or groups which can react with R 6 and R 6, for example, to form a polymerized variant of compound (XXU) with cross-linking groups derived from compound (XXI).

Functional groups R 6 and may be, for example, leaving groups, for example halogen atoms, e.g. chlorine or bromine (as in haloalkyl groups; α-halomethyl ester

- 15LT 3665 in Group B; α-halomethyl in keto groups; or halocarbonyl or halosulfonyl groups such as alkanoyl or sulfonyl halides) or sulfonate ester groups e.g. alkylsulfonate esters, e.g. mesyloxy groups, and aromatic sulfonate esters, e.g. tosyloxy groups; or activated carboxyl groups, e.g. symmetric or mixed anhydrides; or activated hydroxyl groups; or activated alkenes formed with R ^ A π / or R ^ B, e.g. αβ-unsaturated ketones and esters; epoxy groups; or groups of aldehydes and ketones and their acetals and ketahns.

The (ΧΧ3ΧΧ) compound may be, for example, a relatively short divalent monomer or either a prepared polymer and then a copolymer or a polyvalent natural or synthetic substance, say a protein or a hydrocarbon, which is crosslinked by a reagent of formula (XXI). In such cases, R ^² and the RH groups may be nucleophilic, e.g., hydroxyl or amino groups, which are typically present in natural polymers, e.g., tumors and proteins, and which react with the above and RH groups. Preferably, h rU also represents groups such as hydroxyl or amine, since R12 and Rg react with them as defined by RiO and R¹¹ in group definitions.

The polymerizable compounds of formula (ΧΧΠ) may be those wherein R¹² h R13 forms optionally substituted unsaturated ethylene groups, e.g. vinyl group. Thus, examples of such compounds include vinyl monomers, e.g. vinyl acetate, styrene, acrylic and methacrylic monomers, e.g. Compounds of this type may be copolymerized with compounds of formula (XXI) wherein R¹⁰ and R¹¹ may be ethylenically unsaturated groups, under certain conditions, suitable for radical polymerization, and the corresponding polymers having cross-links may be obtained.

The reagents of formula (XXI) are novel and are another aspect of the present invention.

The polymers of the present invention, for example, can be obtained in a single solution phase which forms an insoluble polymeric material; after solvent removal, depending on the end use

This material can be used to form, for example, sheets, particles or details such as surgical implants. The non-crosslinked polymers of the present invention will generally be thermoplastic, so that at higher temperatures they can be formed (e.g., by calendering, stretching or molding) into the desired articles. The polymers of the present invention, for example, can be used to produce films by solvent molding.

Polymers can also be produced by emulsion polymerization to produce particles of polymeric material; monomer (s) solution Dispersible in water-miscible in an organic solvent, causing polymerization. Thus, for example, in the above reactions (A) and (B), where the polymerization is caused by the formation of a salt, the (VI) acid in the (A) reaction or the protected (XII) acid in the (B) reaction can be dissolved and emulsified in an organic solvent, e.g. such as sound. When added to the water phase. polymerization by a base, say sodium hydroxide, optionally with a phase transition agent. Warming may be desirable to promote polymerization. Emulsion polymerization methods, particularly for obtaining monodisperse particles, are described in EP-A-0003905, EP-A-0091453, EP-A-0010986 and EP-A-0106873.

The polymers of the present invention, e.g. blocks having the formula (IU) defined above may be used, for example, for surgical implants, e.g. sutures, soft tissue prostheses, sponges, films (eg, artificial skin) or wound dressings (eg, hydrogel sheets), flexible sheeting and parts, suppose to make containers. These polymers are biodegradable. In addition, biodegradable polymers can be used, for example, for the production of biodegradable delayed-release pharmaceuticals , agrochemicals, horticultural excipients, such as mulch mixtures or plant containers. Such use and polymers therefor form another aspect of the present invention. It is desirable that the formed polymers used as prostheses contain heparin, at least on the surface.

If the polymer of the present invention is used as a biodegradable delaying agent, the active agent may be contained within the shell of the biodegradable polymer, e.g. in a capsule

- 17LT 3665 B or microspheres, or it may be introduced during polymerization, evenly distributed throughout the polymer, and released during biodegradation. Alternatively, the active ingredient may contain all or some of R ^, R- or R³ groups, and this material can be released during decomposition. Most delayed-release drugs include steroids, contraceptives, antibacterials, antagonists and anticancer agents.

If the polymers of the present invention have a sufficiently short chain, they can be used as plasticizers for other polymers. When the polymers of the present invention are biodegradable, plasticizing degradation either destroys the integrity of the material or opens it to the action of enzymes.

Biodegradable polymer particles of the present invention can be used successfully for diagnostic purposes. Suppose an X-ray contrast agent, which is usually a polyiodine aromatic compound, can be wholly or partially R³ or -Cf R ^ R ^) - groups, and it is safely eliminated and eliminated from the body by biodegradation. Such particles can be used for examination of the liver and spleen as they are trapped in the reticuloendothelial systems of these organs. The X-ray contrast agent can be incorporated into the polymer simply by physical polymerization.

The polymeric particles of the present invention may contain paramagnetic, superparamagnetic or. ferromagnetic materials used in magnetic resonance imaging (MRI) diagnostics. During polymerization, submicron particles of iron or magnetic iron oxide can be introduced into the polymers to produce ferromagnetic or superparamagnetic particles. Paramagnetic MRI contrast agents usually contain a paramagnetic metal, say a gadolinium ion. who are prevented from relaxing (thereby significantly reducing their toxicity) by their chelating agents retaining them. Such chelating agents, together with the complex metal ions, may be physically mixed with the polymers, or suitable chelating groups may have I, R 2 and R³ groups. In general, most chelating agents are polyamine polycarboxylic acids such as diethylene triamine pentaacetic acid (RB Lauffer, Chem. Rev. 87 (1987), pp. 901-927).

- 18LT 3665 B

The polymer particles of the present invention may also contain ultrasound contrast agents, e.g., heavy materials, e.g. barium sulfate or iodinated compounds, such as the above-mentioned X-ray contrast agents, which give a contrasting ultrasound environment.

The following examples are til; illustration.

-19EN 3665 B

EXAMPLE

Poly- (1,6-dioxa-2,5-dioxoheptylene)

To the mixture of disodium succinate (1.0 eq.) And the required amount of dimethylformamide is added diiodomctane (1.0 eq.). The reaction mixture is stirred at ambient temperature until the bulk of the reagents are consumed, then dialyzed to be; low molecular weight materials are removed and evaporated. Returns the title of the double ester with the repeating groups of the formula iO-CO-CH2-CH2-CO-0-CH2k 1 2 3 4 5 6 7

Ly. (Π) in groups where r1 = r2 = H, R ^ = -CH2-CH2-, om = n = 0.

EXAMPLE

Poly (2_&gt;6-Dimethyl-4,7-dioxo-13β-trioxaheptylene)

To a mixture of 1-chloroethyl chloroformate (1.1 eq) and (S) -2-hydroxypropionic acid (1.0 eq) in a suitable amount of dimethylformamide is less than ⁰ Adds pyridine (1.0 equiv.) At C. The reaction mixture is stirred at ambient temperature until the bulk of the reagents are consumed, then dialyzed to remove low molecular weight materials and evaporated. Gets the title carbonate ester polymer with the repeating groups of the formula

-O-CH (CH₃) -O-CO-O-CII (CII₃) -CO-) j?

2 3 4 5 6 7 ty. (Π) in groups where R ^ = H, R ^ = CH₃, r3 = Cl1 (CH₃), m = 1, is = 0.

-20LT 3665 B

EXAMPLE

(a) Mono-glycoyloxymethyl succinate

To a solution of sodium glycolate (1.0 equiv.) In dimethylformamide in an appropriate amount is added dropwise benzylchlonetyl succinate (1.0 equiv., Made by Benneche, Strande and Wiggen, Acta Chem. Scand. 43, (1988), pp. 74-77). ) Dinethylfomiamide. The reaction mixture is stirred at 50 ° C until most of the reactants are reacted, concentrated and extracted with chlorophyll-sodium carbonate solution. The organic phase is dried and evaporated. Gives the benzyl ester of the title compound. Catalytic hydrogen removal removes the benzyl group by conventional means to give the title compound of formula

HO-CO-CH₂-CH₂-CO-O-CH₂-O-CO-CH₂-OH.

b) Poly- (5,7,10-tricxy) -1,4,8- (rioxocarboxylic acid)

A mixture of mono-glycoyloxymethyl succinate and a catalytic amount of p-toluenesulfonic acid in dry toluene is refluxed under nitrogen until the formation of water is complete. The solvent is removed at 200 ° C and 0.1 mm Hg. Returns the polymer of the name with repeating groups having the formula

-fCO-CH₂-CH₂-CO-O-CH₂-O-CO-CH₂-Oj;

2 3 456789 10 t y. (Π) Blocks where R * = r2 = H, R³= -CH₂-O-CO-CH₂-CH₂-, if = n = 0. ⁴

EXAMPLE

(a) Methylene dimethacrylate

A solution of potassium hydroxide (1.00 M, 40.00 mL) was added to methacrylic acid (3.44 g, 40.00 mmol) at 0 ° C and the solution was freeze-dried for 16 hours. Once added

Dry dimethylformamide (230 ml) was heated at 60 ° C under a dry nitrogen atmosphere. Adds within 10 minutes two portions of diiodornetan (1.61 mL, 20.00 mmol), leave the reaction mixture at 60 ° C for four days. The solvent was distilled off under reduced pressure (0.05 mm lg) and then diethyl ether (140 ml), saturated aqueous sodium bicarbonate solution (50 ml) and water (50 ml) were added. The aqueous layer was extracted with diethyl ether (6 x 60 mL), the combined ether extract washed with water (4 x 50 mL), dried (MgSO 4) and evaporated. Obtain 2.63 g (72%) of the title compound. 1 H NMR (60 MHz, CDCl 3): δ 1.9 97 (2xCH y, m), 5.63 (2 x HC =, m), 5.88 (CH₂, s), 6.18 (2 x HC =, 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) Diacrylate of methylene

A solution of potassium hydroxide (1.00 M, 40.00 mmol) was added to acrylic acid (2.88 g, 40.00 mL) at 0 ° C and the solution was freeze-dried for 16 hours. After addition of dry dimethylformamide (200 ml), the suspension is heated to 60 ° C under a dry nitrogen atmosphere. Adds within 10 minutes two portions of diiodornetan (1.61 mL, 20.00 mmol), leave the reaction mixture at 60 ° C for four days. The solvent was distilled off under reduced pressure (0.05 mm Hg) and then diethyl ether (140 ml), saturated aqueous sodium bicarbonate solution (50 ml) and water (50 ml) were added. The aqueous layer was extracted with diethyl ether (6 x 60 mL), the combined ether extract washed with water (4 x 50 mL), dried (MgSO 4) and evaporated. Obtain 1.06 g (34%) of the title compound. NMR (60 MHz, CDCl 3): δ 5.81-6.61 (2 x CH₂ = CH-, m), 5.84 (CH₂, s).

22LT 3665 B

c) Chloromethyl- (2 → n 5 -ethacryloxy-oxy) -ethio carbonate

Pyridine (0.89 ml) was added dropwise to a solution of clonnethyl chloroformate (0.89 ml, 11.00 mmol) and 2-hydroxyethyl methacrylate (1.22 ml, 10.00 mmol) in dichloromethane (12 ml) at 0 ° C under a dry nitrogen atmosphere. , 11.00 mrnol). After 21 hours at 20 ° C, the reaction mixture was washed with hydrochloric acid (1.00 M, 10 mL), saturated aqueous sodium bicarbonate solution (10 mL), and water (10 mL). The organic phase is dried (MgSO 4) and the solvent is evaporated off under reduced pressure (10 mm Hg). 1.97 g (88%) of the title compound are obtained. NMR (60 MHz, CDCl 3): δ 1.88 (CH 3, d, J = 2 Hz), 4.35 (O-CH₂-CH₂-O, m), 5.47 (HC =, m), 5.63 (CK)₂-C1, s), 6.00 (H-, C =, m).

(

d) (2-Methacryloxy)&gt; ethyl-methacryloxy-oxyethyl carbonate

A solution of potassium hydroxide (1.00 M, 5.00 mmol) was added to methacrylic acid (0.43 g, 5.00 mL) at 0 ° C and the solution was freeze-dried for 16 hours. Dry dimethylformamide (50 mL) was then added and chloromethyl- (2-methacryloxy) -ethyl carbonate (1.11 g, 5.00 mmol) was added to the resulting suspension. 18-Crown-6 (0.066 g, 0.25 mmol) is then added as a catalyst and the mixture is left under an atmosphere of dry nitrogen. After 24 hours at 20 ° C and 6 days at 4 ° C, the solvent is distilled off under reduced pressure (0.05 mm Hg) and then diethyl ether (30 ml) and water (20 ml) are added. The aqueous layer was extracted with diethyl ether (3 x 20 mL), the combined ether extract washed with water (20 mL), dried (MgSO 4) and evaporated. 1.26 g (93%) of the title compound are obtained. NMR (60 MHz, CDCl 3); δ 1.97 (2 x CH₃, m), 4.38 (O-CH₂-CH₂-O, m), 5.53 (2 x HC =, m), 5.77 (CH₂, s), 6.07 (2 x HC =, m).

-23EN 3665 B

(c) Non-fly (carbonate of clonnet)

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 under dry nitrogen dropwise add pyridine (0.89 mL) , 11.00 mmol). After 15 minutes At 7 ° C and 6 hours at 20 ° C, transfer the reaction mixture into a separatory funnel and add dichloromethane (10 mL). The reaction mixture was washed with hydrochloric acid (1.00 M, 10 mL), saturated aqueous sodium bicarbonate solution (10 mL) and water (&lt;10 mL). The organic phase is dried (MgSO 4) and the solvent is evaporated off under reduced pressure. 1.12 g (90%) of the title compound are obtained. NMR (300 MHz, CDCl 3): δ 4.48 (s, O-CH)₂-CH₂-O), 5.75 (s, 2 x Cl-CH 2 -O). ¹³C NMR (75 MHz, CDCl 3): δ 65.8 (O-CH₂-CH₂-O), 72.2 (2 x C1-CH₂-O), 153.0 (2 x C = O).

f) Bis (2-chloromethoxycarbonyloxy) ether

To a solution of chloromethyl chloroformate (1.32 mL, 14.83 mmol) and diethylene glycol (0.47 mL, 5.90 mmol) in dichloromethane (10 mL) at 7 ° C under dry nitrogen, is added dropwise pyridine (0.89 mL) , 11.00 mmol). After 10 minutes. At 7 ° C and 6 hours at 20 ° C, transfer the reaction mixture into a separatory funnel and add dichloromethane (10 mL). The reaction mixture was washed with hydrochloric acid (1.00 M, 10 mL), saturated aqueous sodium bicarbonate solution (10 mL), and water (10 mL). The organic phase is dried (MgSO 4) and the solvent is evaporated off under reduced pressure (10 mm Hg). 1.26 g (86%) of the title compound are obtained. NMR (300 MHz, CDCl 3): δ 3.72 (m, 2 x CH)₂-O), 4.3-1 (m, 2 x CH)₂-OC = O), 5.71 (s, 2 x Cl-CH)₂O). ¹³C NMR (75 MHz, CDCl 3): δ 67.6 (2 x CH₂-O), 68.5 (2 x CH₂-OC = O), 72.1 (2 x Cl-CH)₂-O), 153.2 (2 x C = O).

-24EN 3665 B

g) 1-Chloroethyl-2-methylcryloxyloxycarbonyl carbonate

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 is added dropwise pyridine (0, 89 mL, 11.00 mmol). After 15 minutes At 3 ° C and for 17 hours at 20 ° C, the reaction mixture was transferred to a separatory funnel and dichloromethane (10 mL) was added. The reaction mixture was washed with hydrochloric acid (1.00 M, 10 mL), saturated aqueous sodium bicarbonate solution (10 mL), and water (2 x 10 mL). The organic phase is dried (MgSO 4) and the solvent is evaporated off under reduced pressure. Gets

1.76 g (74%) of the title compound. 1 H NMR (60 MHz, CDCl 3): δ 1.85 (3H, d, J = 6Hz, CH 3 -CH, 1.96 (3H, d, J = 2Hz, CH₃-C =), 5.55 (1H, m, CH =), 6.10 (1H, m, CH =), 6.38 (1H, k, J = 6Hz, CH-CH3).

h) Chloromethyl-4-acryloyloxybutyl carbonate

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 is added dropwise pyridine (0.89 mL) , 11.00 mmol). After 15 minutes At 3 ° C and for 17 hours at 20 ° C, the reaction mixture was transferred to a separatory funnel and dichloromethane (10 mL) was added. The reaction mixture was washed with hydrochloric acid (1.00 M, 10 mL), saturated aqueous sodium bicarbonate solution (10 mL), and water (2 x 10 mL). The organic phase is dried (MgSO 4) and the solvent is evaporated off under reduced pressure. Yield: 76 g (74%) of the title compound. 1 H NMR (60 MHz, CDCl 3): δ 1.82 (4H, m, CH 2 -CH 2), 4.27 (4H, m, 2 x CH₂-O), 5.77 (2H, s, C1-CH)₂-O), 5.8-6.7 (3H, m, CH = CH 2).

-25LT 3665 B

j) Chloroethyl 4-acryloyl oxybutyl carbonate

To a solution of l-chloroethyl chloroformate (1.20 mL, 11.00 mmol) and 4-hydroxybutyl acrylate (1.38 mL, 10.00 mmol) in dichloromethane (12 mL) at 3 ° C was added dropwise pyridine (0 , 89 mL, 11.00 mmol). After 15 minutes At 3 ° C and for 17 hours at 20 ° C, the reaction mixture was transferred to a separatory funnel and dichloromethane (10 mL) was added. The reaction mixture was washed with hydrochloric acid (1.00 M, 10 mL), saturated aqueous sodium bicarbonate solution (10 mL), and water (2 x 10 mL). The organic phase is dried (MgSO 4) and the solvent is evaporated off under reduced pressure. 2.26 g (90%) of the title compound are obtained. 1 H NMR (60 MHz, CDCl 3): δ 1.80 (4H, m, CH)₂-CH₂), 1.86 (3H, d, J = 5Hz, CH)₃), 4.24 (4H, m, 2 x CH)₂-O), 5.7-6.6 (4H, m, CH = CH)₂ and CH).

j) 1-Methacryloyloxyethyl-N-methacryloxy-oxylyl carbonate

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 dimethylformamide (50 mL) was added 1-chloroethyl-2-methacryloxyethyl carbonate (1.183 g, 5 mL). , 00 mmol). After 5 days at 20 ° C, the solvent was distilled off under reduced pressure and the residue was dissolved by the addition of dichloromethane (60 ml) and water (30 ml). After separation of the phases, the organic layer is extracted with dichloromethane (3 x 30 mL) and the combined organic phase is washed with saturated aqueous sodium bicarbonate (50 mL). The organic phase is dried (MgSO4) and the solvent is distilled off under reduced pressure. 1.10 g (77%) of the title compound are obtained. 1 H NMR (60 MHz, CDCl 3)?₃): δ 1.63 (3H, d, J = 5Hz, CH 3 -CIJ), 1.98 (6H, s, 2 x CH₃), 4.24 (4H, s, O-CH)₂-CH₂-O), 5.62 (2H, m, CH =), 6.15 (2H, m, CH =), 6.84 (1H, k, J = 5Hz, CH-CH).₃).

-26EN 3665 B

k) 1-Acryloxyloxymethyl-4-acryloxyloxybutyl carbonate

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) was added 1-clonnethyl-4-acryloyloxybutyl carbonate (1.183 g, 5 mL). , 00 mmol). After 5 days at 20 ° C, the solvent was distilled off under reduced pressure and the residue was dissolved by the addition of dichloromethane (60 ml) and water (30 ml). After separation of the phases, the aqueous layer is extracted with dichloromethane (3 x 30 mL) and the combined organic phase is washed with saturated aqueous sodium bicarbonate (50 mL). The organic phase is dried (MgSO4) and the solvent is distilled off under reduced pressure. 1.24 g (91%) of the title compound are obtained. IR NMR (60 MHz, CDCl3)₃): δ 1.82 (4H, m, CH)₂-CH₂), 4.23 (4H, m, 2 x CH)₂-O), 5.88 (2H, s, O-CH)₂-O), 5.7-6.8 (6H, 2 x CH = CH 2).

l) 1-Acryloxyoxyethyl 4-acryloxyloxybutyl carbonate

To a suspension of freeze-dried potassium acrylate (0.606 g, 5.50 mmol) ii-crown-6 (0.066 g, 0.25 mmol) in dimethylformamide (50 mL) was added 1-chloroethyl 4-acryloxy-oxybutyl carbonate (1.253 g, 5 mL) under dry nitrogen. , 00 mmol). After 5 days at 20 ° C, the solvent was distilled off under reduced pressure and the residue was dissolved by the addition of dichloromethane (60 ml) and water (30 ml). After separation of the phases, the aqueous layer is extracted with dichloromethane (3 x 30 mL) and the combined organic phase is washed with saturated aqueous sodium bicarbonate (50 mL). The organic phase is dried (MgSO4) and the solvent is distilled off under reduced pressure. 1.28 g (89%) of the title compound are obtained. 1 H NMR (60 MHz, CDCl 3)?₃): δ 1.58 (3H, d, J = 5Hz, CH)₃-CH), 1.80 (4H, m, CH)₂-CH₂), 4.24 (4H, m, 2 x CH)₂-O), 5.7-6.7 (6H, m, 2 x CH = CH)₂), 6.87 (1H, k, J = 5Hz, CH-CH)₃).

-27 LT 3665 B

m) Meile-di (p-viii-benzoate)

To a solution of freeze-dried potassium p-vinibenzoate (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) was added dry nitrogen. add diiodomethane (0.20 mmol, 2.50 mmol) in the atmoafer and leave the reaction mixture at 60 ° C for 2.5 days. The solvents were distilled off under reduced pressure and the residue was dissolved by addition of diethyl ether (20 ml), saturated aqueous sodium bicarbonate (5 ml) and water (10 ml). After separation of the phases, the aqueous layer is extracted with diethyl ether (6 x 10 mL) and the combined organic phase is washed with water (5 x 10 mL). The organic phase is dried (MgSO₄) and the solvent is distilled off under reduced pressure. 0.64 g (83%) of the title product is obtained in hi NMR (300 MHz, CDCl3)₃): Δ 5.39 (2 H, d, J = 10 Hz, 2 x CH =), 5.86 (2 H, d, J = 17.6 Hz, 2 x Cl =), 6.24 (2 H, s, O-CH 2 -O), 6.73 (2H, dd, J = 11.0, 17.6, 2 x CH =), 7.45 (4H, 2 xd, J = 6, 8Hz, Ar), 8.04 (2H, d, J = 6.6Hz, Ar), 8.05 (2H, d, J = 6.6Hz, Ar), ¹³C NMR (75 MHz, CDCl 3): δ 79.8 (O-CH₂-O), 116.8 (2x PM =), 126.0, 130.2 (C₂, C₂', C₃, C₃), 127.8, 142.5 (Cf, cf, C₄, C₄'), 135.7 (2 x Cl =), 164.9 (2 x C = O).

(n) Methylene di (p-bromobeazoate)

To a solution of freeze-dried potassium p-bromobenzoate (3.587 g, 15.00 mmol), 18-crown-6 (0.198 g, 0.75 mmol) in dimethylformamide (100 mL) in dry nitrogen atmaphera is added • diiodomethane (0.60 mmol, 7.50 mmol) and leave the reaction mixture at 60 ° C for 4 days. The solvent was distilled off under reduced pressure and the residue was dissolved by the addition of dichloromethane (60 ml) and water (30 ml). After separation of the phases, the aqueous layer is extracted with dichloromethane (3 x 30 mL) and the combined organic phase is washed with saturated sodium bicarbonate (50 mL). The organic phase is dried (MgSO₄), O

-28EN 3665 B solvent is distilled off under reduced pressure. Obtain 2.62 g (84%) of the title product. 1 H NMR (60 MHz, CDCl 3)?₃): δ 6.29 (2H, s, O-CH)₂-O), 7.63 (4H, d, J = 9H2, Ar), 8.00 (4H, d, J = 9Hz, Ar).

o) Metileu-di (p-hydroxybeuzoate)

To a solution of freeze-dried potassium p-hydroxybenzoate (1.762 g, 10.00 mmol) in dimethylformamide (60 mL) under dry nitrogen was added diiodomethane (0.40 mmol, 5.00 mmol) and left for 4 days at 60 ° C. The solvent was distilled off under reduced pressure and the residue was dissolved by the addition of dichloromethane (60 ml) and water (30 ml). After separation of the phases, the aqueous layer is extracted with dichloromethane (3 x 30 mL) and the combined organic phase is washed with brine (50 mL). The organic phase is dried (MgSO4) and the solvent is distilled off under reduced pressure. 0.94 g (65%) of the title product is obtained in hl NMR (60 MHz, CDCl3 / CD3OD 1: 2): δ 4.92 (2H, s, 2 x OH), 6.18 (2H, s) , O-CH₂-O), 6.88 (4H, d, J = 9Hz, Ar), 7.96 (4H, d, J = 9Hz, Ar).

p) Methylene bis [p- (hydroxymethylenyl) benzoate3

Add bis (triphenylphosphine) palladium dichloride (17.0 mg, 0.02 mmol) copper iodide (2.0 mg, 0.01 mmol) at 20 ° C under nitrogen, to a suspension of methylenebis (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). After 10 days at 20 ° C, triethylamine is distilled off under reduced pressure, water (20 ml) is added and the mixture is extracted with dichloromethane (3 x 15 ml). The dichloromethane phase was washed with hydrochloric acid (0.5 M, 10 mL), dried (MgSO 4), and dichloromethane

-29LT 3665 B is distilled under reduced pressure. Yield 0.37 g (85%) of crude product. NMR (60 Hz, CDCl 3): δ 3.67 (2H, s, OH), 4.47 (4H, s, Cl₂-O), 6.18 (2H, s, O-CH)₂-O), 7.2-7.5 (4H, Ar), 7.8-8.0 (4H, AR).

q) Bis-l-chiorethio ester of adipic acid

To the adipoyl chloride (2.92 mL, 20.00 mmol) at 20 ° C is added anhydrous zinc chloride (10.0 mg, 0.07 min!) Under dry nitrogen, and the reaction mixture is added dropwise at -5 ° C ( 2.26 g, 40.00 mmol). Maintain the reaction temperature between -5 ° C and 0 ° C with dichloromethane (20 ml). The zinc chloride catalyst is removed by passing the reaction mixture at 5 ° C through a alumina column (Fluka 06290, type 5016 A, basic, 20 g) using dichloromethane as solvent. Removes solvent under reduced pressure. 3.64 g (67%) of crude product are obtained. 1 H NMR (60 MHz, CDCl 3): δ 1.5-1.9 (4 H, m, CH)₂-CH₂), 1.77 (6H, d, J = 6Hz, 2 x CH 3), 2.1-2.5 (4H, m, 2 x CH)₂-O), 6.49 (2H, k, 2 x Cl-CII-O).

EXAMPLE

(a) Powders of acrylamide polymer cross-linked with 5% methylenedimethacrylate

Methylenedimethacrylate, prepared as described in Example 4 (a) (0.50 g, 2.72 mmol) and dissolved in dimethylformamide (2 mL), is added to acrylamide (10.00 g, 140.70 mmol) and azobisisobutyronitrile (AJBN). , 0.02 g, 0.86 mmol) in dimethylformamide. The reaction mixture was heated at 60 ° C under a dry nitrogen atmosphere. After about 50 min. the clear reaction mixture turns into a white suspension. The reaction mixture is maintained at 60 ° C for 2 hours to complete the reaction

-30LT at 3665 B temperature. After cooling to 20 ° C, the reaction mixture is filtered, the solid residue is washed several times with dimethylformamide and dried in vacuo. Gives powder of the product named. In contrast to the polyacrylamide produced in the same manner but not cross-linked, the product obtained is insoluble in water. 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 (iv), 976 (w), 610 (wide, m). In the spectrum of the polyacrylamide with cross-links prepared as described herein, the peaks appearing as a result of the incorporated cross-linking compound are: 1740 (str), 1471 (v /), 1387 (iv), 11 $ 2 (m), 1084 (str), 963 (str. ).

(b) Acrylamide polymer cross-linked 5% methylenedimethacrylate gel

To a solution of acrylamide (5.00 g, 70.34 mmol) and methylenedimethacrylate prepared as described in Example 4 (a) (0.250 g, 1.36 mmol) in water / DMSO (90:10, 20 mL) at 20 ° At C, under dry nitrogen, AIBN (0.01 g, 0.43 mmol) was added with good stirring. After about 25 minutes. the reaction mixture becomes a gel and is maintained at 60 ° C for a total of 2 hours to complete the reaction. The resulting gel is insoluble in water, although the corresponding acrylamide homopolymer is soluble.

(c) Acrylamide polymer cross-linked with 2,6% methylenedimethacrylate

To a solution of acrylamide (5.00 g, 70.34 mmol) and methylenedimethacrylate 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, add AIBN (0.01 g, 0.43 mmol) with good stirring. After about 25 minutes. the reaction mixture becomes a gel and is maintained at 60 ° C for a total of 2 hours to complete the reaction. The resulting gel is insoluble in water, although the corresponding acrylamide homopolymer is soluble.

-31 LT 3665 B

(d) Acrylamide polymer cross-linked with 1,3% methylenedimethacrylate

To a solution of acrylamide (5.00 g, 70.34 mmol) and methylenedimethacrylate 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, add AIBN (0.01 g, 0.43 mmol) with good stirring. After about 25 minutes. the reaction mixture becomes a gel and is maintained at 60 ° C for a total of 2 hours to complete the reaction. The resulting gel is insoluble in water, although the corresponding homopolymer of acrylamide is present.

Acrylamide-methylenedimethacrylate gels, made! as described in this example, the swelling in water is inversely proportional to the degree of cross-linking as determined by the amount of methylene dimethacrylate consumed.

EXAMPLE

Polymer of methyl acrylate, crosslinked with 2% methylenediacrylate

To a solution of methyl acrylate (3.029 g, 35.20 mmol) and methylenediacrylate prepared as described in Example 4 (b) (0.110 g, 0.70 mmol ).dimethylOrmamide (10 mL) at 60 ° C was added AIBN. (0.005 g, 0.03 mmol). After about 50 minutes. the clear reaction mixture turns into a gel. The reaction mixture is maintained at 60 ° C for a total of 2 hours to complete the reaction. The resulting gel is insoluble in tetrahydrofuran, although polymethyl acrylate is soluble. This means that the gel has cross-links.

EXAMPLE

Acrylic acid polymer cross-linked with 2% methylenediacrylate _;

To a solution of acrylic acid (2.534 g, 35.20 mmol) and methylenediacrylate prepared as described in Example 4 (b) (0.110 g, 0.70 mmol) in dimethylformamide (10 mL) was added. ^!At C, under dry nitrogen, AIBN (0.005 g, 0.03 mmol) was added. About 60

-32LT 3665 B min. the clear reaction mixture turns into a gel. The reaction mixture is maintained at 60 ° C for a total of 2 hours to complete the reaction. The resulting gel is insoluble in dimethylformamide, although polyacrylic acid is soluble. This means that the gel has cross-links.

EXAMPLE

Acrylamide polymer crosslinked with 0.5% methylenediacrylate

To a solution of acrylamide (2.500 g, 35.17 mmol) and methylend 'acrylate prepared as described in Example 4 (b) (0.027 g, 0.18 mmol) in tetrahydrofuran (10 mL) at 60 ° C under a dry nitrogen atmosphere add AIBN (0.005 g, 0.03 mmol) dissolved in tetrahydrofuran (2 mL). After about 2 hours the reaction mixture shows no noticeable change. Therefore, AIBN (0.005 g, 0.03 mmol) was added. The polymer then begins to precipitate in the reaction mixture, ii 'after a total of about 5 hours, the reaction mixture is cooled and filtered. The polymer is washed several times with tetrahydrofuran and dried under reduced pressure. The resulting polymer is insoluble in water, -. although polyacrylamide is soluble. This means that a polymer with crosslinks is formed.

The IR spectrum of the polymer confirms this structure. The IR spectrum of the polyacrylamide produced by this method incorporates the incorporation of a crosslinking compound. However, the concentration of the crosslinking compound (0.5%) is too low to obtain a detachable spectrum.

\ 3 · EXAMPLE 9

Acrylamide polymer cross-linked with 0.5% 2-methacryloxyloxyethyl methacryloxyloxymethyl carbonate

To a solution of acrylamide (2.500 g, 35.20 mmol) and 2-methacryloxyethyl-methacryloyloxymethyl carbonate prepared as described in Example 4 (d) (0.048 g, 0.18 nunol) in tetrahydrofuran (10 mL) at 60 ° C, dry AIBN (0.005 g, 0.03 mmol) was added under nitrogen. After about 2 hours the reaction mixture shows no noticeable change; Therefore

Add AIBN (0.005 g, 0.03 mmol) dissolved in tetrahydrofuran (2 mL). The polymer then begins to precipitate in the reaction mixture and, after a total of about 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 and forms a viscous solution. This should indicate a low degree of cross-linking.

EXAMPLE

2-Hydroxyethyl methacrylate polymer, cross-linked 0.5%

2-methacryloxy-ethyl-1-methacryloxy-oxymethyl carbonate

To a solution of 2-hydroxyethyl methacrylate (4.578 g, 35.20 mmol) and 2-methacryloxyethyl methacryloyl oxymethyl carbonate prepared as described in Example 4 (d) (0.0479 g, 0.18 mmol) in tetrahydrofuran (10 mL) at 60 ° C. at ambient temperature, AIBN (0.005 g, 0.03 mmol) was added under a dry nitrogen atmosphere. After about 1 hour, tetrahydrofuran is added and the reaction mixture becomes a gel. The reaction mixture is maintained for a total of about 2 hours at 60 ° C to complete the reaction. The resulting gel is insoluble in dichloromethane, although pob-2-hydroxyethyl methacrylate is soluble. This means that the gel has cross-links.

EXAMPLE

Polymer of methyl methacrylate cross-linked with 2% acryloxyloxymethyl 4-acryloxyloxybutyl carbonate

Of a solution of methyl acrylate (3.029 g, 35.20 mmol) and acryloyloxymethyl 4-acryloxyloxybutyl carbonate prepared as described in Example 4 (k) (0.192 g, 0.70 mmol) in dimethylformamide (10 mL) at 60 ° C, AIBN (0.005 g, 0.03 mmol) was added under dry nitrogen. After about 1 hour, the clear reaction mixture becomes a gel.

-34EN 3665 B

The reaction mixture is maintained for a total of about 2 hours at 60 ° C to complete the reaction. The resulting gel is insoluble in tetrahydrofuran, although the polymethylmethacrylate is soluble. This means that the gel has cross-links.

EXAMPLE

Acrylamide polymer cross-linked with 2% acryloyl oxymethyl 4-acryloyl oxybutyl carbonate

To a solution of acrylamide (2.502 g, 35.20 mmol) and acryloxyloxymethyl 4-acryloxyloxybutyl carbonate obtained as described in Example 4 (k) (0.202 g, 0.74 mmol) in dimethylformamide (10 mL) at 60 ° C was added AIBN (0.005 g, 0.03 mmol) was added under nitrogen. After about 40 minutes, the reaction mixture turns white and the polymer begins to precipitate. After 2 hours at 60 ° C, the reaction mixture is cooled and filtered. The polymer is washed several times with dimethylformamide and dried under reduced pressure. IR (KBr, cm -1): 3387 (broad, m), 3195 (m), 2932 (w), 1661 (str), 1611 (m), 1451 (w), 1415 (w). The resulting polymer is insoluble in water, although polyacrylamide is soluble. This means that the polymer has cross-links.

EXAMPLE

Acrylamide polymer cross-linked with 2% 1-acryloxyloxyethyl 4-acryloxyoxybutyl carbonate

To a solution of acrylamide (2.502 g, 35.20 mmol) and l-acryloxyethyl-4-acryloyloxybutyl carbonate prepared as described in Example 4 (1) (0.202 g, 0.70 mmol) in dimethylformamide (10 mL) at 60 ° C , AIBN (0.005 g, 0.03 mmol) was added under dry nitrogen. After about 30 minutes of reaction in the mixture, the polymer begins to precipitate. After maintaining for a total of 2 hours at 60 ° C, the reaction mixture was cooled and

-35LT 3665 B filters out. The polymer is washed several times with dimethylformamide and dried under reduced pressure. IR (KBr, cm ')¹): 3390 (wide, m), 3197 (m), 2933 (w), 1661 (w), 1611 (m), 1452 (w), 1415 (\ v). The resulting polymer is insoluble in water and is not soluble in polyacrylamide. This means that the polymer has cross-links.

EXAMPLE

PoH- (methylene terephthalaph)

Potassium hydroxide solution is added to terephthalic acid (0.83 g, 5.00 mmol) at 0 ° C and the resulting solution is freeze-dried within 16 hours. Dimethylformamide is added and the resulting suspension is 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 then added and the resulting reaction mixture is kept for 3 days at 70 ° C and for 3 days at 100 ° C. The solvent is removed under reduced pressure (0.05 mm Hg) and then diethyl ether (30 mL) and water (30 mL) are added. Prior to washing with diethyl ether (3 x 30 ml), the aqueous suspension is adjusted to pH 9. The aqueous suspension is centrifuged, the liquid is decanted and the solid substance is resuspended in absolute ethyl alcohol. Repeat the centrifugation and decanting and dry the solid in vacuo. 0.29 g (32%) of product are obtained in the form of a powder. IR (KBr, cm -1): 3400 (w, broad), 1732 (str), 1600 (w), 1558 (w), 1456 (\ v), 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 the formation of a polymer.

EXAMPLE

Polymer of ethylene-dichloromethyl carbonate) and tetraphalic acid

To freeze-dried dipotassium terephthalate (0.480 g, 1.98 mmol) and 18-crown-6 (0.027 g,

0.10 mmol) in dimethylformamide (20 mL) add ethylene-dichloromethyl carbonate)

-36EN 3665 B prepared as described in Example 4 (e). After 2 days at 20 ° C, the reaction mixture is heated to 60 ° C and maintained for 3 weeks. The solvent is removed under reduced pressure and the residue is dissolved by the addition of dichloromethane (60 ml)^- water (30 mL). After separation of the phases, the dichloromethane phase is washed with saturated aqueous sodium bicarbonate (30 ml) and brine (30 ml). The organic phase is dried (MgSO 4) and the solvent removed under reduced pressure. Yield: 0.35 g (53%) of the title product, hi NMR (60 MHz, CDCl3)₃): δ 4.47 (4H, s, O-CH₂-CH₂-O), 6.02 (4H, s, 2 x O-CH)₂-O), 8.12 (4H, s. Ar). Gel filtration chromatography at high temperature indicates that the material fractions have a molecular weight greater than 20,000 relative to poly (ethylene glycol) as a standard.

EXAMPLE

Polyester of methylenedi- (p-hydroxybenzoate) and adipoyl chloride

To a solution of methylenedi- (p-hydroxybenzoate) prepared as in Example 4 (o) (1.00 g, 3.47 mmol) and adipoyl chloride (0.635 g, 3.47 mmol) in dry dichloromethane (30 mL) was added. Add pyridine (0.560 mL, 6.94 mmol) dropwise at 0 ° C under a dry nitrogen atmosphere. After 18 hours, water (10 mL) was added at 20 ° C and the phases were 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 with the addition of more dichloromethane. The resulting organic phase was dried (MgSO 4) and the solvent evaporated under reduced pressure (0.1 mm Hg). 0.93 g (67%) of product is obtained. 1 H NMR (300 MHz, CDCl 3)₃): δ 1.76 (4H, m, CH)₂-CH₂), 2.59 (4H, m, 2 x CH)₂-C = O, 6.20 (2H, s, O-CH₂-O), 7.16 (4H, Ar), 8.06 (4H, Ar). Gel filtration chromatography at high temperature indicates that the material fractions have a molecular weight greater than 20,000 relative to poly (ethylene glycol) as a standard.

- 37 LT 3665 B

EXAMPLE

Polymer of bis- (2-chloromethoxycarbonyloxyethyl) ether and dicalcium fumarate

To a suspension of dipotassium fumarate (0.961 g, 5.00 mmol) and 18-crown-6 in DMI⁷ (50 mL) was added bis- (2-chloromethoxycarbonyloxyethyl) ether prepared as in Example 4 (f) (1.456 g, 5.00 mmol) and heated to 60 ° C under a dry nitrogen atmosphere. After 11 days at 60 ° C, the solvent is removed under reduced pressure. Chloroform (40 mL) was added to the residue and the organic layer was washed with water (3 x 30 mL). The combined wash water is extracted with chloroform (3 x 20 mL). The combined organic phases are concentrated in vacuo. 1.57 g (94%) of a brown oil are obtained. NMR (300 MHz, DMSO-d6, 40): δ 3.78 (4H, m, 2 x CH₂-O), 4.38 (4, m, 2 x CH)₂-OC = O), 5.94 (4H, s, 2 x OCHp-O), 6.98 (2H, s, CH = CH). Gel filtration chromatography at high temperature indicates that the fractions of the material have a molecular weight greater than 20,000 relative to the standard for poly (ethylene glycol) k.

EXAMPLE

Methylene-S- [p- (2,3-epoxy] -1-propyl, ksi) -bun7-one]

To a solution of methylenedi- (p'hydroxybenzoate) prepared as in Example 4 (o) (1.728 g, 6.00 mmol) in DMF (75 mL) under an atmosphere of dry nitrogen was added potassium tert-butoxide (1.347 g, 12.00 mmol). . Epichlorohydrin (2.22 g, 24.00 mmol) was then added and the solvent removed under reduced pressure after 24 hours at 20 ° C. Dissolve the residue in dichloromethane (75 ml) and water (30 ml) and adjust the pH to neutral with hydrochloric acid (1 M). After separation of the phases, the dichloromethane layer was washed with water (3 x 30 mL). The organic phase is dried (MgSO 4) and the solvent removed under reduced pressure. 1.22 g (51%) of product are obtained as a colorless oil. NMR (60 MHz, CDCl 3): δ 2.8 (4H, m, 2x)

-38LT 3665 B Epoxy-CH₂), 3.3 (2H, m, 2 x epoxy-CH), 4.05 (2H, dd, J = 22, 11Hz, 2 x O-CH-H), 4.12 (2H, dd, J = 22, 11Hz, 2 x O-CH-H), 6.14 (2H, s, O-CH₂-O), 6.9 (4H, m, 2 x Ar), 7.9 (4H, m, 2 x Ar).

EXAMPLE

Hexamethylene di (chloromethyl carbonates)

To a solution of chlonylneyl chloroformate (2.61 mL, 29.70 mmol) and 1,6-hexanediol (1.182 g, 10.00 mmol) in dichloromethane (40 mL) at 7 ° C is added dropwise pyridine (1, 77 mL, 22.00 mmol). After 15 minutes 7 hours at 6 ° C. At 20 ° C, the reaction mixture was transferred to a separatory funnel, rinsing with dichloromethane (2 x 10 mL). The reaction mixture was washed with hydrochloric acid (1.00 M, 20 mL), saturated aqueous sodium bicarbonate (20 mL), and water (20 mL). Ethyl acetate is added to the organic phase to make the solution clear. This solution is dried (MgSO 4) and the solvent is evaporated under reduced pressure. 2.76 g (99%) of product are obtained. 1 H NMR (300 MHz, CDCl 3): δ 1.22.0 [8 H, m, (CH₂) 4j, 4.22 [4II, t, J = 6Hz, 2 x (CH₂-O&gt; j, 5.73 [4H, s, 2 x Cl-CH 0 -O)].

EXAMPLE

Polymer of bis-l-chloroethyl ester of adipic acid and dicalcium terephthalate

To a solution of terephthalic acid (1.122 g, 10.00 mmol) in DMF (75 mL) at 20 ° C under dry nitrogen is added potassium tert-butoxide (1.122 g, 10.00 mmol). To the resulting suspension is added the bis-1-chloroethyl ester of adipic acid, obtained as described in Example 4 (q) (1.356 g, 5.00 mmol), and the reaction mixture is heated to 60 ° C. After 1 h at 60 ° C, 18-crown-6 (0.066 g, 0.25 mmol) was added. After 8 days at 60 ° C, the solvent is removed under reduced pressure and the residue is dissolved in

-39LT 3665 B chloroform (60 mL), ethyl acetate (30 mL), and aqueous sodium hydroxide (1 M, 50 mL). After separation of the phases, the aqueous phase is extracted with chloroform (3 x 25 ml). The combined organic layers were washed with water (2 x 50 mL) and dried (MgSO 4). Removes solvent under reduced pressure. 0.238 g (13%) of crude product are obtained.

EXAMPLE

Polymer of adipic acid

Ms-l-chlordHo ester and dipotassium fumarate

To a solution of fumaric acid (0.580 g, 5.00 mmol) in DMF (50 mL) at 20 ° C was added potassium tert. butoxide (1.122 g, 10.00 mmol). To the resulting suspension is added the bis-l-chloroethyl ester of adipic acid, obtained as described in Example 4 (q) (1.356 g, 5.00 mmol), and the reaction mixture is heated to 60 ° C. After 1 hour at 60 ° C, 18-crown-6 (0.066 g, 0.25 mmol) was added. After 8 days at 60 ° C, the solvent is removed under reduced pressure and the residue is dissolved in chloroform (60 ml), ethyl acetate (30 ml) and aqueous sodium hydroxide (1 M, 50 ml). After phase separation, the water phase. extraction with chloroform (3 x 25 mL). The combined organic layers were washed with water (2 x 50 mL) and dried (MgSO 4). Removes solvent under reduced pressure. Yield: 0.276 g (18%) of crude product.

EXAMPLE

Poly (n-dipoate of ethylene)

To a solution of adipic acid (0.731 g, 5.00 mmol) in DMF (50 mL) at 20 ° C under dry nitrogen is added potassium tert-butoxide (1.122 g, 10.00 mmol). To the resulting slurry is added the bischloromethyl ester of adipic acid (obtained from Rosnati: BoveL, Rend. Super Sanila 15 (1951), 473, 486) (1.215 g, 5.00 mmol), and the reaction mixture is heated to 60 ° C. After 1 hour at 60 ° C, 18-crown-6 (0.066 g, 0.25 mmol) was added.

-40LT 3665 B

After 8 days at 60 ° C, the solvent is removed under reduced pressure and the residue is dissolved in chloroform (60 ml), ethyl acetate (30 ml) and aqueous sodium hydroxide (1 M, 50 ml). After separation of the phases, the aqueous phase is extracted with chloroform (3 x 25 ml). The combined organic layers were washed with water (2 x 50 mL) and dried (MgSO 4). Removes solvent under reduced pressure. 0.618 g (39%) of crude product are obtained. NMR (60 MHz, CDCl 3): δ 1.67 (4H, m, broad, CH)₂-CH₂), 2.37 (4H, m, broad, 2 x CH)₂-O), 5.77 (2H, s, O-CH)₂-0).

EXAMPLE

Polymer of hexamethylene di (chlonylmethyl carbonate) and dicall terephthalate

To a solution of terephthalic acid (0.595 g, 3.58 mmol) in DMF (40 mL) at 20 ° C under dry nitrogen is added potassium tert-butoxide (0.804 g, 7.16 mmol). To the resulting suspension is added hexamethylene di (chloromethyl carbonate) obtained as described in Example 19 (1.00 g, 3.58 mmol) and 18-crown-6 (0.047 g, 0.179 mmol), and the reaction mixture is heated to 60 ° C. After 6 days at 60 ° C, the solvent is removed under reduced pressure. The residue is insoluble in dichloromethane and caustic soda (1 M). This indicates the formation of a polymer.

EXAMPLE

Methylene (3,3-dimethoxypropionate)

To dry DMF (1 L) was added cesium 3,3-dimethoxypropionate (19.95 g, 75 mmol). Diiodomethane (10.04 g, 37.5 mmol) is added to the suspension and the reaction mixture is stirred for two days at 60 ° C under a dry nitrogen atmosphere. DMF is removed under reduced pressure (0.01 mm Hg). Diethyl ether (500 mL) was added to the residue and then washed with saturated aqueous sodium bicarbonate (250 mL). The aqueous layer was extracted with diethyl ether (5 x 75 mL). The combined ether extracts are washed with water (2 x 100 mL), dried (MgSO 4) and evaporated. Gets

-41 LT 3665 B

7.1 g (72%) of product. 1 H NMR (300 MHz, CDCl 3)₃): δ 2.61 (CH₂, d), 3.26 (CII₃), s),

4.76 (CH, t), 5.70 (CH₂, s). ¹³C NMR (300 MHz, CDCl 3): δ 38.52 (CH₂), 53.37 (CH₃O), 79.02 (AND₂O), 168.32 (C = O).

EXAMPLE

Epoxy resin based on methylenebis [p&gt; (2,3-epoxy-1-propyloxy) benzoate] and aliphatic polyamine

The methylenebis [p, - (2,3-epoxy-1-propyloxy) benzoate] sample obtained as described in Example 18 is mixed with an equal amount of a commercial aliphatic polyamide curing agent. This mixture is used as a glue to glue two cyclic plates together at room temperature.

The resin has been found to harden well and has good adhesion within 24 hours of mixing.

EXAMPLE

Aqueous polymer gel obtained by cross-linking an aqueous solution of poly (vinyl alcohol) in methylenedi (3,3-dhr.yloxypropionate) (a) Aqueous 5 g of poly (vinyl alcohol) solution (6.25% by weight, 7.0 mmol monomer units, average molecular weight 126000, 98% hydrolyzed), after addition of hydrochloric acid (18% solution), pH = 0.8. To this solution is added 0.10 g (0.35 mmol) of methylenedioxy (3,3-dimethoxypropionate) obtained as described in Example 24 and the solution is thoroughly mixed. After 24 hours at room temperature, the solution has a higher viscosity than initially obtained, and after 48 hours at room temperature the solution turns into a relatively strong gel. Wash the gel well one day with excess water and leave under water to dry. The measured water content of this gel is 98.5% (vol.).

-42EN 3665 B (b) Aqueous 5 g poly (vinyl alcohol) solution (6.25% w / w, 7.0mmol monomer units, average molecular weight 126000, 98% hydrolyzed) with the addition of hydrochloric acid (18% solution), sets the pH to 0.3. To this solution is added 0.10 g (0.35 mmol) of methylenedioxy (3,3-dimethoxypropionate) obtained as described in Example 24 and the solution is thoroughly mixed. After 6 hours, the solution turns into a gel and after 48 hours, syneresis is observed. Wash the gel well one day with excess water ii 'leave under water to dry. The measured water content of this gel is 95.5% (v / v).

(c) Adjust the pH to 0 with 5 g of an aqueous solution of poly (vmyl alcohol) (6.25% w / w, 7.0mmol monomer units, average molecular weight 126000, 98% hydrolyzed) with hydrochloric acid (18% solution). , 8. To this solution was added 19.6 mg (0.07 mmol) of methylenedioxy (3,3-dimethoxypropionate) obtained as described in Example 24 in one liter of water and the solution was stirred well. After 3 hours at 50 ° C, the solution turns into a gel. Wash the gel well one day with excess water and leave under water to dry. The estimated water content of this gel is 98% (v / v).

(d) Determine pH = 0 in aqueous 5 g poly (vinyl alcohol) solution (6.25% w / w, 7.0 mmol monomer units, average molecular weight 126000, 98% hydrolyzed) with hydrochloric acid (18% solution). , 8. To this solution is added 0.1 g (0.35 mmol) of methylenedioxy (3,3-dimethoxypropionate) obtained as described in Example 24 and the solution is thoroughly mixed. After 3 hours at 50 ° C, the solution turns into a gel. Wash the gel well one day with excess water and leave under water to dry. The estimated water content of this gel is 95% (vol).

(E) In an aqueous solution of 5 g of polyvinyl alcohol (6.25% w / w, 7.0mmol monomer units, average molecular weight 126000, 98% hydrolyzed), with hydrochloric acid (18% solution). ), sets the pH = 0.8. To this solution is added 19.6 mg (0.07 mmol) of methylenedioxy (3,3-dimethoxypropionate) obtained as described in Example 24 in one ml of water and the solution is stirred well. After 40 minutes At 80 ° C, the solution turns into a gel. Wash the gel well one day with excess water and leave under water to dry. The estimated water content of this gel is 98% (v / v).

(f) In aqueous 5 g poly (vinyl alcohol) solution (6.25% w / w, 7.0 mmol per monomer unit, average molecular weight 126000, 98% hydrolyzed), add hydrochloric acid (18% solution) to pH = 0. , 8. To this solution is added 0.1 g (0.35 mmol) of methylenedioxy (3,3-dimethoxypropionate) obtained as described in Example 24 in one ml of water and the solution is thoroughly mixed. After 40 minutes At 80 ° C, the solution turns into a gel. Wash the gel well one day with excess water and leave under water to dry. The estimated water content of this gel is 95% (vol).

(g) In aqueous 5 g poly (vinyl alcohol) solution (6.25% w / w, 7.0 mmol per monomer unit, average molecular weight 126000, 98% hydrolyzed), add hydrochloric acid (18% solution) to pH = 0 , 4. To this solution is added 19.6 mg (0.07 mmol) of methylenedioxy (3,3-dimethoxypropionate) obtained as described in Example 24 in one ml of water and the solution is stirred well. After 40 minutes At 80 ° C, the solution turns into a gel. Wash the gel well one day with excess water and leave under water to dry. The estimated water content of this gel is 98% (v / v).

-44EN 3665 B (h) In aqueous solution of 5 g of poly (vinyl alcohol) (6.25% w / w, 7.0 mmol monomer units, average molecular weight 126000, 98% hydrolyzed) with the addition of hydrochloric acid (18% solution), sets the pH = 0.4. To this solution is added 0.1 mg (0.35 mmol) of methylenedioxy (3,3-dimethoxypropionate) obtained as described in Example 24 in one ml of water and the solution is thoroughly mixed. After 40 minutes At 80 ° C, the solution turns into a gel. Wash the gel well one day with excess water and leave under water to dry. The estimated water content of this gel is 95% (vol).

EXAMPLE

Polymer gel with chloramphenicol obtained by radical polymerization from a drug solution in water / DMSO (90:10), acrylamide and methylene dimethacrylate

To a solution of acrylamide (5.00 g, 70.34 mmol), methylenedimethacrylate obtained as 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 dry nitrogen, add AIBN (0.010 g, 0.061 mmol) with good stirring. After 1.5 or. again add AIBN (0.010 g, 0.061 mmol). After a total of 3 hours, the reaction mixture was cooled to 20 ° C. The reaction mixture then turns into a soft gel. The gel does not dissolve in water even after 7 days, when the economically acrylamide homopolymer is water soluble.

EXAMPLE

Polymer gel with testosterone obtained by radical polymerization from a drug solution in water / DMSO (90:10), acrylamide and methylene diacrylate

To a solution of acrylamide (5.00 g, 70.34 mmol), methylene diacrylate obtained as described in Example 4 (b) (0.212 g, 1.36 mmol) and testosterone (0.050 g, 0.173 mmol)

-45LT 3665 B in water / DMSO (90:10, 20 mL) at 60 ° C under dry nitrogen, added AIBN (0.010 g, 0.061 mmol) with good stirring. After 40 min, the mixture becomes a gel. The reaction mixture is maintained for a total of 2 hours. At 60 ° C to terminate the reaction. When cooled to 20 ° C, testosterone crystallizes on the gel. The gel is insoluble in water while the acrylamide homopolymer is water soluble.

EXAMPLE

Polymer gel with 5-fluorouracil obtained by radical polymerization of a drug solution in water / DMSO (14: 1), acrylamide and methylene diacrylate

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 ° Aqueous 5-fluorouracil solution (5.00 mL, 250 mg / 10 mL, 0.961 mmol) was added at C under a dry nitrogen atmosphere with good stirring. After 35 min. adds AIBN (0.010 g, 0.061 mol). The reaction mixture turns into a gel. The reaction mixture is maintained for a total of 2 hours. At 60 ° C to terminate the reaction. The gel is insoluble in water, thus rendering the acrylamide homopolymer water-soluble.

EXAMPLE

Polymer gel with sulfadiazine, obtained by suspension of the drug in aqueous poly (vinyl alcohol) solution followed by cross-linking with methylene (33dimethoxypropionate) (a) In aqueous 5 g poly (vinyl alcohol) solution (6.25% w / w, 7.0 mmol per monomer unit) , average molecular weight 126000, 98% hydrolyzed), after addition of hydrochloric acid (18% solution) to pH = 0.4. To this solution is added 19.6 mg (0.07 mmol) of methylenedioxy (3,3-dimethoxypropionate) obtained as described in

-46LT 3665 in Example B, one mL of water and 0.20 g (0.8 mmol) of sulfadiazine, and mix well. After 40 minutes At 80 ° C, the polymer turns into a gel with a powder suspended therein. Wash the gel well one day with excess water and leave under water to dry. The estimated water content of this gel is 98% (v / v).

(b) In aqueous 5 g poly (vinyl alcohol) solution (6.25% w / w, 7.0 mmol per monomer unit, average molecular weight 126000, 98% hydrolyzed), add hydrochloric acid (18% solution) to pH = 0 , 4. To this solution is added 0.1 g (0.35 mmol) of methylenedioxy (3,3-dimethoxypropionate) obtained as described in Example 24 and 0.20 g (0.8 mmol) of sulfadiazine and the dispersion is thoroughly mixed. After 40 minutes At 80 ° C, the polymer turns into a gel with a powder suspended therein. Wash the gel well one day with excess water and leave under water to dry. Estimated water content This gel contains 95% (v / v).

EXAMPLE

Progesterone polymer gel obtained by suspending the drug in aqueous poly (vinyl alcohol) solution followed by cross-linking with methylene (3,3-dimethoxypropionate) (a) In aqueous 5 g poly (vinyl alcohol) solution (6.25% w / w, 7.0 mmol) based on monomer units, average molecular weight 126,000, 98% hydrolyzed), with the addition of hydrochloric acid (18% solution), pH = 0.4. To this solution is added 19.6 mg (0.07 mmol) of methylenedioxy (3,3-dimethoxypropionate) obtained as described in Example 24 in one ml of water and 0.07 g (0.2 mmol) of progesterone and the dispersion mix. After 40 minutes At 80 ° C, the polymer turns into a gel with

-47LT 3665 B in powdered suspension. Wash the gel well one day with excess water and leave under water to dry. The estimated water content of this gel is 98% (v / v).

(b) In aqueous 5 g poly (vinyl alcohol) solution (6.25% w / w, 7.0 mmol per monomer unit, average molecular weight 126000, 98% hydrolyzed), add hydrochloric acid (18% solution) to pH = 0 , 4. To this solution is added 0.1 g (0.35 mmol) of methylenedioxy (3,3-dimethoxypropionate) obtained as described in Example 24 and 0.07 g (0.2 mmol) of progesterone and the dispersion is thoroughly mixed. After 40 minutes At 80 ° C, the polymer turns into a gel with a powder suspended therein. Wash the gel well one day with excess water and leave under water to dry. The estimated water content of this gel is 95% (vol).

EXAMPLE

Polymer gel with 5-fluorouradium obtained by dissolving the drug in aqueous poly (vinyl alcohol) solution followed by cross-linking with methylene (33 'dimethoxypropionate) (a) In aqueous 5 g poly (vinyl alcohol) solution (6.25% by weight, 7.0) mmol per monomer unit, average molecular weight 126,000, 98% hydrolyzed), with the addition of hydrochloric acid (18% solution), adjusts the pH to ~ 0.4. To this solution is added 19.6 mg (0.07 mmol) of methylenedioxy (3,3-dimethoxypropionate) obtained as described in Example 24 in one ml of water and 13 mg (0.1 mmol) of 5-fluorouracil dissolved in 0, 5 ml of water and mix well. After 40 minutes At 80 ° C, the solution turns into a gel. Wash the gel well one day with excess water and leave under water to dry. The estimated water content of this gel is 98% (v / v).

-48EN 3665 B (b) In aqueous 5 g poly (vinyl alcohol) solution (6.25% w / w, 7.0mmol monomer units, average molecular weight 126000, 98% hydrolyzed) with the addition of hydrochloric acid (18% solution), sets the pH = 0.4. To this solution is added 0.1 g (0.35 mmol) of methylenedioxy (3,3-dimethoxypropionate) obtained as described in Example 24 and 13 mg (0.1 mmol) of 5-fluorouracil dissolved in 0.5 ml of water. , and mix well. After 40 minutes 80 At the temperature of ° C, the polymer turns into a gel. Wash the gel well one day with excess water and leave under hydrogen to dry. The estimated water content of this gel is 95% (vol).

EXAMPLE

Polymer gel with Omnipaate ™, obtained by dissolving diagnostic preparations in aqueous poly (virilyl alcohol) solution followed by cross-linking with ethylene (3,3-dimethoxypropionate) (a) in aqueous 5 g polyvinyl alcohol (6.25 wt. 0 mmol by monomer units, average molecular weight -426000, 98% hydrolyzed) to pH = 0.4 with hydrochloric acid (18% solution). To this solution, 19.6 mg (0.07 mmol) of methylenediene (3,3-dimethoxypropionate) obtained as described in Example 24 in one ml of water and Imi Omnipaueue ™ (300 mg / ml) are added and the dispersion is thoroughly mixed. After 40 minutes At 80 ° C, the solution turns into a gel. Wash the gel well one day with excess water and leave under water to dry. The estimated water content of this gel is 98% (v / v).

(b) In aqueous 5 g poly (vinyl alcohol) solution (6.25% w / w, 7.0mmol monomer units, average molecular weight 126000, 98% hydrolyzed), add hydrochloric acid (18% solution) to pH = 0 , 4. To this solution is added 0.1 g (0.35 mmol) of methylenedioxy (3,3-dimethoxypropionate) obtained as described in

-49LT 3665 in Example B and Imi Omnipaque ™ (300 mgJ / ml) and mix well. After 40 minutes At 80 ° C, the polymer turns into a gel with a powder suspended therein. Wash the gel well one day with excess water and leave under water to dry. The estimated water content of this gel is 95% (vol).

EXAMPLE

Polymer gel with magnetic starch microspheres, obtained by dissolving the diagnosis preparation in aqueous poly (vinyl alcohol) solution followed by cross-linking with ethylene (3,3-dimethoxypropionate) (a) In aqueous 5 g poly (vinyl alcohol) solution (6.25% by weight) , 7.0 mmol, based on monomer units, average molecular weight 126,000, 98% hydrolyzed), after addition of hydrochloric acid (18% solution) to pH = 0.4. To this solution is added 19.6 mg (0.07 mmol) of methylenedioxy (3,3-dimethoxypropionate) obtained as described in Example 24 in one ml of water and 0.5 ml of a suspension of the magnetic starch microspheres obtained as described in WO 85/02772 (Schroder) (7.5 mg Fe / ml, 0.9% NaCl, 0.5% glycerol) and mix well. After 40 minutes At 80 ° C, the solution turns into a gel with magnetic material suspended therein. Wash the gel well one day with excess water and leave under water to dry. The estimated water content of this gel is 98% (v / v).

(b) In aqueous 5 g poly (vinyl alcohol) solution (6.25% w / w, 7.0 mmol per monomer unit, average molecular weight 126000, 98% hydrolyzed), add hydrochloric acid (18% solution) to pH = 0 , 4. To this solution is added 19.6 mg (0.07 mmol) of methylenedioxy (3,3-dimethoxypropionate) obtained as described in Example 24 and 0.5 ml of a suspension of the magnetic starch microspheres obtained as

-50LT 3665 B is 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 minutes At 80 ° C, the solution turns into a gel with magnetic material suspended therein. Wash the gel well one day with excess water and leave under water to dry. The estimated water content of this gel is 97% (v / v).

EXAMPLE

Homopolymerization of Methylene Dimethacrylate

0.5 g (2.7 mmol) of methylene dimethacrylate obtained as described in Example 4 (a) was mixed with 2.5 g (15 µmol) of AIBN. After 2 hours At 70 ° C, the monomer solidifies into a solid. This polymer is insoluble, indicating that its structure is a network of solid cross-links.

EXAMPLE Homopolymerization of (2-Methacryloxyoxy) Ethyl-Mephacryloxyoxyethyl Carbonate

0.4340 g (1.6 mmol) of (2-methacryloxy) ethyl-methacryloyloxymethyl carbonate obtained as described in Example 4 (d) was mixed with 22 mg (13.2 µmol) of AIBN. After 2 hours At 70 ° C, the monomer solidifies into a solid. This polymer is insoluble, indicating that its structure is a network of solid cross-links.

-51EN 3665 B

EXAMPLE

The emulsion copolymerization of methylenedimethacrylate and methylethyl acrylate in ml of a 1% (w / v) solution of sodium dodecyl bisulfate in water warms to 60 ° C under a nitrogen atmosphere. Then, with vigorous stirring, 0.20 g (1.09 mmol) of methylenedimethacrylate obtained as described in Example 4 (a) and 9.80 g (0.098 mmol) of methyl methacrylate monomer are added. Polymerization is initiated by a methabisulfite / persulfate oxidative redox system of 1.6 mg (7.2 pmol) of potassium metabisulfite and 0.08 mg (0.3 μηιοί) of potassium persulfate. Allow the polymerization to proceed for 8 hours and then cool to room temperature. The resulting emulsion contains 11.1% solids, which corresponds to 66% conversion. The resulting polymer is insoluble in THF, which is a good solvent for poly (methyl methacrylate), indicating that the polymer is cross-linked.

EXAMPLE

Emulsion copolymerization of methylenedimethacrylate and styrene in ml of a 1% (w / v) solution of sodium dodecyl sulphate in water warms up to 60 ° C under a nitrogen atmosphere. Then, with vigorous stirring, 0.20 g (1.09 mmol) of methylenedimethacrylate obtained as described in Example 4 (a) and 9.80 g (0.094 mmol) of styrene monomer are added. The polymerization is initiated by an oxidative-reduction system of metabisulfite / persulfate from 1.6 mg (7.2 μηιοί) of potassium metabisulfite and 0.08 mg (0.3 µmol) of potassium persulfate. Allow the polymerization to proceed for 8 hours and then cool to room temperature. The resulting emulsion contains 11.2% solids, which corresponds to 68% conversion. The resulting polymer is insoluble in THF, which is a good solvent for poly (methyl methacrylate), indicating that the polymer is cross-linked.

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EXAMPLE

Emulsion copolymerization of acryloyl oxymethyl 4-acryloyl oxybutyl carbonate and methylethacrylate in ml of a 1% (w / v) solution of sodium dodecyl sulfate in water warms up to 60 ° C under a nitrogen atmosphere. Then, with vigorous stirring, 0.20 g (0.74 mmol) of acryloxyoxymethyl-4-acryloyloxybutyl carbonate obtained as described in Example 4 (k) and 9.80 g (0.098 nunol) of methyl methacrylate monomer are added. Polymerization is initiated by a methabisulfite / persulfate oxidative redox system of 1.6 mg (7.2 pmol) potassium metabisulfite and 0.08 mg (0.3 pmol) potassium persulfate. Allow the polymerization to proceed for 8 hours and then cool to room temperature. The resulting emulsion contains 11.2% solids, which corresponds to 67% conversion. The resulting polymer is insoluble in THF, which is a good solvent for poly (methyl methacrylate), indicating that the polymer is cross-linked.

EXAMPLE

Emulsion copolymerization of acryloxymethyl 4-acrylic oxybutyl carbonate and styrene in ml of 1% (w / v) sodium dodecyl sulfate in tepal water warms to 60 ° C under nitrogen. Then, with vigorous stirring, 0.20 g (0.74 mmol) of acryloxy-methyl-4-acryloxy-oxybutyl carbonate obtained as described in Example 4 (k) and 9.80 g (0.094 mmol) of styrene monomer are added. The polymerization is initiated by the oxidative-reduction system of the metabisulphite / persulphate from 1.6 mg (7.2 pmol) of potassium metabisulphite and 0.08 mg (0.3 μηιοί) of potassium persulphate. The polymerization is allowed to proceed for 8 hours and then cooled to room temperature. The resulting emulsion contains 12% solids, which corresponds to 72% conversion. The resulting polymer is insoluble in THF, which is a good solvent for poly (methyl methacrylate), indicating that the polymer is cross-linked.

-53LT 3665 B

EXAMPLE

Polymer gel with magnetic starch microspheres, obtained by radical polymerization of an acrylamide suspension of magnetic starch microspheres and l-acryloxyoxyethylmacryloyloxybutyl carbonate

To a suspension of acrylamide (5.00 g, 70.34 mmol) and 1-acryloxyloxyethyl-4-acryloxyloxybutyl carbonate obtained as described in Example 4 (1) (0.359 g, 1.36 mmol) in water / DMSO (90:10, 10 ml) at 60 ° C under a gentle stirring of nitrogen, add a suspension of the microspheres of magnetic starch in water obtained as described in WO 85/02722 (Scliroder) (0.50 ml of a solution containing 7.5 mg Fe / ml, 0.9). % NaCl and 0.5% glycerol). AIBN (0.010 g, 0.061 mmol) was then added, and after about 10 min. the reaction mixture turns into a gel. The reaction mixture was maintained at 60 ° C for a total of 2 hours to complete the reaction. The gel is insoluble in water and the corresponding acrylamide homopolymer is water soluble.

EXAMPLE

Polymer of hexamerylene di (chloromethyl carbonate) and 2,3,5,6-tetraiodoterephthalic acid

To a suspension of dipotassium 2,3,5,6-tetraiodododereephthalate (1.49 g, 2 mmol) and 18-crown-6 (0.03 g, 0.1 mmol) in dry dimethylformamide (18 mL) under nitrogen was added hexamethylene di (chloromethyl carbonate) obtained as described in Example 19 (0.61 g, 2 mmol) in dry DMF (2 mL). After 4 days at 60 ° C, the solvent is removed under reduced pressure (0.5 mm Hg). The residue was dissolved in chloroform (400 mL) and washed with saturated aqueous sodium bicarbonate (3 x 200 mL) and water (2 x 200 mL). The organic phase is dried (MgSO4) and evaporated. 1.16 g of product are obtained. 1 H NMR (300 MHz): δ 1.381.45 (m, area = 0.24), 1.65-1.76 (m, area = 0.24), 4.18-4.25 (m, area = 0.23),

-54LT 3665 B

5.73 (s, area = 0.01), 5.99 (s, area = 0.21). The area ratio of the aliphatic monomer σ.-chloromethylene group signal at δ 5.73 and the methylene diester group signal at δ 5.99 confirms the formation of a polymer.

EXAMPLE

Covalent Attachment of MCPA to 2-Hydroxyyl Meacrylate Polymer Crosslinked with 0.5% 2-Meacryloyloxyethyl Methacryloyl Oxymethyl Carbonate

The gel described in Example 10 (2.0 g) is swollen with 20 ml of dry DMSO. The gel suspension is made up in dry nitrogen atmosphere with 2-methyl-4-chlorophenoxyacetic acid (MCPA) (2.0 g, 10 mmol), N-ethyl-N '- (3- (N-dimethylamino) propyl) carbodiimide and 4-pyrrolidinopyridine. (160 mg. 1 mmol) in 30 mL of dry DMSO. The suspension was shaken for 24 hours. at room temperature, then the gel was washed with DMSO followed by water and dried in vacuo. Gets product. The resulting gel, which can be suspended in water, contains a very water-soluble herbicide, MCPA, which is covalently bound to the gel and can gradually relax during use.

EXAMPLE

Covalent Attachment of 5-Acetylamino-3- (N-Methylacetylaniline) -2,4,6-iodo-benzoic acid (isopak) to a 2-Hydroxy Phenyl Methacrylate Polymer Crosslinked with 0.5% 2-Methacryloxyethyl-Methacryloxymethyl Carbonate (a) β-Alanine; O-benzyl ester isopac amide

To a solution of 11-β-alanine-O-benzyl ester (1.76 g, 5 mmol) in dry dimethylformamide (50 mL) was added potassium carbonate (0.69, 5 mmol) at 0 ° C. After passing 10 rnin.

at ambient temperature, dropwise at 0 ° C under nitrogen atmosphere

-55LT 3665 B

5-Acetylamino-3- (N-methylacetylamino) -2,4,6-triiodobenzoyl chloride (isopoic acid chloride) (3.23 g, 5 mmol) dissolved in dry dimethylformamide (20 mL). The reaction mixture is heated to 50 ° C. After 24 or. the solvent is removed under reduced pressure and chloroform (500 ml) and water (200 ml) are added. The organic phase was washed with saturated aqueous sodium bicarbonate (100 mL), 0.01 M HCl (100 mL) and water (2 x 100 mL). After drying the organic phase and evaporating the solvent, 3.10 g of product (79%) are obtained. δ 1.72-1.83 (m), 2.15-2.23 (m), 2.72-2.81 (m), 3.03-3.09 (m), 3.67-3 , 78 (m), 5.05-5.20 (m), 6.7-7.0 (m), 7.31-7.35 (m), 8.5-8.9 (m).

(b) Debenzylation of the isopac amide of β-alanine-O-benzyl ester The isopac amide of β-alanine-O-benzyl ester obtained in the previous example (a) (1.578 g, 2 mmol) was dissolved in dry methanol (50 mL). The reaction mixture was added palladium on carbon (10%, 0.4 g) in one portion. Add hydrogen to the solution by bubbling for two hours and then stir the reaction mixture for two more hours. Filtration and distillation of the solvent gives a yellow residue which is purified by a weak cationic resin to give the product.

(c) Coupling of 5-acetylamino-3- (N-methylacetylamino) -2,4,6-triiodobenzoic acid (isopak) to a polymer gel

The carboxylic acid obtained in Example (b) is coupled to the gel obtained in Example 10 by the method described in Example 43.

-56LT 3665 B

EXAMPLE

Methylene (3-Method Cipropenoate)

To toluene (250 mL) was added methylenedioxy (3,3-dimethoxypropionate) obtained as described in Example 24 (14.01 g, 50 mmol) and a catalytic amount of p-toluenesulfonic acid. Methanol is removed by heating the reaction mixture under nitrogen. At the end of the reaction, toluene is distilled off under reduced pressure. Add diethyl ether (250 mL) and wash the reaction mixture with saturated aqueous sodium bicarbonate (5 x 50 mL) and water (3 x 50 mL). The organic layer is dried (MgSO4). Evaporation gives 8.52 g (79%) of product.

EXAMPLE

Aqueous polymer gel obtained by cross-linking aqueous polyvinyl alcohol aqueous solution of methylene (3-methoxypropenoate) (a) Aqueous 5 g poly (vinyl alcohol) solution (6.25% w / w, 7.0 mmol monomer units, average molecular weight 126000, 98% hydrolyzed) to pH = 0.4 with hydrochloric acid (18% solution). To this solution is added 55 mg (0.23 mmol) of methylenedioxy (3,3-dimethoxypropenate) obtained as described in Example 45 in one ml of dioxane / water (50:50) and the solution is thoroughly mixed. After 40 minutes at 80 ° C, the solution turns into a gel with magnetic material suspended therein. Wash the gel well one day with excess water and leave under water to dry. The estimated water content of this gel is 98% (v / v).

(b) Adjust the pH to 0 with 5 g of an aqueous solution of poly (vinyl alcohol) (6.25% w / w, 7.0 mmol monomer units, average molecular weight 126000, 98% hydrolyzed) with hydrochloric acid (18% solution). 4. To this solution is added 110 mg (0.56 mmol) of methylenedioxy (3,3-dimethoxypropenate) obtained as described in

-Example 3665 in Example B, two mL of dioxane / water (50:50), and mix well. After 40 minutes At 80 ° C, the solution turns into a gel. Wash the gel well one day with excess water and leave under water to dry. The estimated water content of this gel is 97% (v / v).

EXAMPLE (a) Melylenbis (10-undecenoate)

10-Undecylene acid (12.75 g, 75 mmol) was dissolved in 100 mL of water. Cesium carbonate (13.04 g, 40 mmol) is added to the mixture. Water is removed under reduced pressure and salt for 2 hours. dries in vacuo. The cesium salt is mixed with 150 ml of DMF and diiodomethane is added to the solution. The reaction mixture was stirred for 3 days at 60 ° C under nitrogen. DMF is then removed under reduced pressure. The residue is purified by passing through silica gel using hexane / ethyl acetate (8: 2) as eluant. Evaporation of the solvent gave 7.18 g (54%) of product. 1 NMR (300 MHz, CDCl 3): δ 1.2-1.4 (10 x CH 2, m), 1.6 (2 x CH 2, m), 2.0 (2 x CH 2, m), 2.19 ( 2 x CH 2, t), 4.9 (2 x H 2 C =, m), 5.88 (O-CH 2 -O, s), 5.9 (2 x HC =, m). 13 C NMR (300 MHz, CDCl 3): δ 24.92-33.98 (8 x CH 2), 79.04 (O-CH 2 O), 114.18 (= CH 2), 139.11 (= CH), 172, 48 (C = O).

(b) Methylenebis (10,11-epoxyundecanoate)

Methylene bis (10-undecenoate) (8.8 g, 25 mmol) was added to methylene chloride under nitrogen and cooled to 0 ° C. To methylene chloride (150 mL) was added 55% methachlorperbenzoic acid (15.75 g, 50 mL), the organic layer was separated and dried (MgSO 4). Methachlorperbenzoic acid is then added dropwise to the diester. After instillation, the temperature is raised to 25 ° C. After 5 or. the reaction ends. The mixture was washed with concentrated aqueous sodium sulfite (75 mL) and concentrated aqueous sodium

-58LT 3665 B hydrocarbonate (2 x 75 mL). The organic layer is cleaned with neutral alumina. Removes solvent under reduced pressure. 8.45 g (82%) of product are obtained. nmr (300 MHz, CDCl3)₃): δ 1.2-1.7 (14 x CH₂, m), 2.35 (2 x CH₂CO, t), 2.45 (2 x CH, q), 2.75 (2 x CH, q), 2.90 (2 x CH, m), 5.75 (O-CH).₂-O). ^13C 1 H (300 MHz, CDCl 3) δ 24.58 (CH₂), 25.99 (CH₂), 28.94 (CH₂), 29.09 (CH₂), 29.32 (2 x CIi₂), 32.45 (CH₂), 33.92 (CH₂), 47.06 (CH₂qq), 52.36 (CH-O), 79.06 (O-CH₂-O), 172.2 (C = O).

EXAMPLE (a) Methylene dibenzyloxyacetate

Benzyloxyacetic acid (49.8 g, 300 mmol) was dissolved in 500 mL of water and MeOH (60:40) and cesium carbonate (48.9 g, 150 mmol) was added. The solvent is evaporated under reduced pressure and the water is removed azeotropically with benzene. The salt was dissolved in 1500 mL of DMF and diiodomethane (40.2 g, 150 mmol) was added. The reaction mixture was stirred for 3 days at 60 ° C under a dry nitrogen atmosphere. DMF is removed under reduced pressure and the residue is dissolved in ether (250 mL), washed with saturated aqueous sodium bicarbonate (250 mL) and water (3 x 75 mL), and^- dries (MgSO 4). The solvent was evaporated and the residue was purified by passing through silica gel with hexane / ethyl acetate (7: 3) as eluent. 23.6 g (46%) of product are obtained. 1 H NMR (300 MHz, CDCl 3): δ 4.1 (2 x CH)₂, s), 4.6 (2 x CH₂, s), 5.9 (O-CH₂-O, s), 7.35 (2 x C ^, m).

(b) Methylene dihydroxyacetate

Methylene dibenzyloxyacetate (0.52 g, 1.5 mmol) was added to dry ethanol (100 mmol) and

Pd / C (100 mg, 10%). Hydrogen is introduced and the reaction is complete after 16 hours. room

-59LT at 3665 B temperature. The reaction mixture is then filtered and the solvent evaporated under reduced pressure (0.01 mm Hg). 0.23 g (95%) of product are obtained. 1 H NMR (200 MHz, MeOH): δ 4.2 (CH 2, s), 4.9 (OH), 5.9 (OCH 2 O, s). The product can be used with di- or polyglycerides to obtain polyesters or with isocyanates to obtain polyurethanes.

EXAMPLE

Homopolymerization of methylene diepoxypropionate

Anhydrous tert-butyl hydroperoxide (3.3 mL, 3 M) and BuLi (6.7 mL, 1.5 M) were dissolved in 30 mL of cold (-78 ° C) THF. The solution was stirred for 5 min and then methyl diacrylate (0.78 g, 5 mmol) was added dropwise. The reaction lasts for 1 hour. in a nitrogen atmosphere. The cold mixture is filtered through neutral alumina and evaporated. Gets a transparent} polymer. The solubility properties of the product indicate that it is a polymer.

EXAMPLE Bomopolymerization of 1-Acryloyloxyethyl-4-acryloyloxybutyl carbonate

348.2 g (1.22 mmol) of 1-acryloxyloxyethyl-4-acryloxyloxybutyl carbonate obtained as described in Example 4 (1) were mixed with 1.7 mg (10.2 µmol) of AIBN. After 2 or. At 70 ° C, the monomer solidifies into a solid. This polymer is insoluble, indicating that its structure has elastic cross-links.

EXAMPLE

Epoxy resin based on methylene bis (10,11-epoxyundecanoate) and aliphatic polyamine

A sample of methylene bis (10,11-epoxyundecanoate) obtained as described in Example 47 was mixed with the same amount of commercial aliphatic amine hardener. This mixture

-60LT 3665 B hardens on a glass plate at 70 ° C. This mixture was found to harden within 2 hours of mixing and to obtain good adhesion.

EXAMPLE

Polymer of 1,6-diisocyanatohexane and methylidene (p-hydroxybenzoate)

To a solution of the methylenedi (p-hydroxybenzoate) obtained in Example 4 (o) (1.588 g, 5.51 mmol) in DMF (15 mL) under dry nitrogen was added 1,6-diisocyanatohexane (0.927 g, 5.51). The reaction mixture is heated at 100 ° C for 3 days, then the solvent is removed under reduced pressure at 50 ° C. The product, when cooled to 20 ° C, becomes a gum-like substance which is insoluble in a mixture of chloroform and DMSO (1: 1). This indicates the formation of a polymer.

EXAMPLE

The size characteristics of the polymers obtained in Examples 37,38,39 and 40

The characteristic is assessed by a Malvem PS / MW instrument using Buccardo cuvettes. Dilute each sample until an opaque solution is obtained and adjust the temperature to 25 ° C before analysis. The viscosity value of water is assumed to be 0.891 cP, the device is set as follows: luminous power = 70 mW, PM slit = 200m, spreading angle = 90 °, manual method, sequential configuration, sample duration = 4 s, test duration = 90 s, calculation method independent model , the matching error is minimized. Assumes a particle refractive index = 1.45 for the mass distribution results. Repeat the analysis for each sample 3 times.

The mean particle mass hydrodynamic diameter (Dh) and standard deviation of the distribution (SN distribution) for each sample are given in the table. Experiment $ N is given in brackets.

<td>An example</td><td>ie</td><td>The distribution of SN</td>

<td> 37</td><td>57.5 (± 1.5) nm</td><td>11.2 (± 1.7) nm</td>

<td> 38</td><td>58.7 (± 0.9) nm</td><td>12.1 (± 1.3) nm</td>

<td> 39</td><td>56.7 (+ 0.7) nm</td><td>16.6 (+ 1.2) nm</td>

<td> 40</td><td>62.1 (± 1.6) nm</td><td>14.0 (± 2.6) nm</td>

EXAMPLE (a) Enzyme-Catalyzed Hydrolysis of an Acrylic Polymer Cross-linked with 2% Acryloxyoxymethyl-4-Acryloxy Oxybudlo Carbonate

To each flask were added 432 mg of the polymer of Example 12 and 50 mL of 0.9% NaCl (sterile, Hydro Pharma). In addition, 1000 μΐ of esterase (Sigma, E2138, 2530 U) is added to one flask. Maintain a constant pH in each flask by adding 0.10 M NaOH. The rate of hydrolysis is calculated from the amount of NaOH consumed. The hydrolysis of the esterase polymer is 8.5 times faster in 21 hours than in the esterase-free control.

(b) Enzyme-catalyzed hydrolysis of an acrylamide polymer cross-linked with 2% methylenedimethacrylate as compared to control polyester

Add to each flask 500 mg of acrylamide polymer cross-linked with 2% ethylenedimethacrylate obtained by the method described in Example 5 (a), 40 ml (0.16 M, pH 7.4) of PBS (phosphate buffer) and 800 μΐ of esterase (Sigma, E). -2138, 2024 U).

To the control flask add 500 mg of acrylamide polymer cross-linked with 2% methylenedimethacrylate (obtained by the method described in Example 5 (a) but using ethylenedimethacrylate instead of methylenedimethacrylate) in 40 ml (0.16 M, pH 7.4) of PBS (phosphate).

-62LT 3665 B buffer) and 800 μΐ esterase (Sigma, E-2138, 2024 U).

In a flask containing the control polyester pH over 200 hours. decreases from 7.1 to 6.9, and the pH of the buffer solution with acrylamide polymer crosslinked with methylenedimethacrylate

7.1 to 6.4 in 24 hours This indicates that the acidic metabolites are formed from the methylene dimethacrylate polymer, much faster than the control polyester.

EXAMPLE

Polymer of starch cross-linked with methylene-bis (10,11-epoxyundecanoic)

To a solution of methylene bis (10,11-epoxyundecanoate) obtained as in Example 47 (1.0 g, 2.6 mmol) and starch (1.0 g) in dry DMSO (50 mL) was added titanium (IV). ) isopropoxide (1.11 g, 3.9 mmol). The reaction mixture was stirred for 4 hours. at ambient temperature. Chloroform / ether (250 mL, 1: 1) is then added, the oily substance is dissolved in water and extracted with chloroform (2 x 50 mL). The aqueous phase is treated with dialysis or gel filtration to obtain the polymer.

..56 EXAMPLE

Polymer of dextran 70000, cross-linked with methylene bis (10, lloxy-oxide decanoate)

To a solution of methylenebis (10,11-epoxyundecanoate) obtained as described in Example 47 (1.0 g, 2.6 mmol) and dextran 70,000 in dry DMSO (50 mL) was added titanium (IV) isopropoxide (1). 11 g, 3.9 mmol). The reaction mixture was stirred for 4 hours. at ambient temperature. Chloroform / ether (250 mL, 1: 1) is then added, the oil form is dissolved in water and extracted with chloroform (2 x 50 mL). The aqueous phase is treated with dialysis or gel filtration to obtain the polymer.

-6357 EXAMPLE

Polymer of protein cross-linked with methylene-bis (10,11-epoxyundecanoate)

To a solution of human serum albumin (1.0 g) in buffer (50 mL) was added methylenebis (10, lloxyoxadecanoate) obtained as described in Example 47 (1.0 g, 2.6 mmol). The reaction mixture was stirred overnight at ambient temperature then evaporated. The polymer is rinsed several times with tetralridrofuyan and dried under reduced pressure.