Improvements in or relating to contrast agents.

CONTRASTING MATERIAL AND METHOD FOR PREPARING IT

The present invention relates to novel contrast media, more particularly, new gas-containing or gas-release contrast media for use in diagnostic imaging.

It is well known that ultrasound imaging is a valuable method of diagnosis used in, for example, cardiovascular studies, particularly cardiography and microvascular tissue studies. A variety of contrast media, including particle suspensions, emulsified liquid droplets, or gas bubbles, have been recommended for better acoustic imaging. It is generally known that easily compressible low density contrast agents, particularly in terms of the acoustic background scattering they produce, are particularly effective, and therefore considerable interest has been shown in the manufacture of gas containing and gas separating systems.

Initial studies in which free gas bubbles were generated in vivo by intracardiac injection of physiologically compatible substances have shown the potential efficacy of such bubbles as contrast agents in echocardiography. However, such methods are extremely limited in practice due to the short life span of free bubbles. Therefore, there is a known interest in methods for stabilizing gas emulsions for echocardiography and other ultrasound examinations using, for example, emulsifiers, oils, thickeners, or

0 sugars, or the absorption or encapsulation of gas, its agent, in various polymer systems, such as porous gas-containing polymeric microparticles or gas "microcapsules" encapsulated in polymeric coatings.

For example, WO 80/02365 describes the use of gelatin encapsulated gas microbubbles to enhance ultrasound imaging. However, no

5 such bubbles are sufficiently stable due to the ultra-thin capsule at the preferred size (1-10 µm) for echocardiography.

US-A-4774958 discloses the use of micro-bubble dispersions that are stabilized by encapsulation of a denatured protein, such as human blood serum albumin. Such systems allow such micro bubbles

0 systems, for example, in the size of 2-5 pm, but do not allow the left

6th -ον 1 co effective visualization of the heart and myocardium. In addition, the use of such proteinaceous substances can cause problems in the form of allergic reactions.

EP-A-0327490 discloses, inter alia, ultrasonic contrast agents consisting of microparticles (particles) of a synthetic biodegradable polymer containing a gas or a volatile liquid (boiling point below 60 ° C) in free or coupled form. Such synthetic biodegradable polymers include hydroxy carbonic acid (polyesters), polyalkyl cyanoacrylates, polyamino acids, polyamides, polyacrylic saccharides, and polyorthoesters.

Biodegradable microparticulate polymers based on polymerized aldehydes are described in EP-A0441468, while microparticulate systems based on poly (amino acid) - poly (cyclic imide) derivatives are described in EP-A-80.

EP-A-0458745 discloses air or gas filled microcapsules having a deformable and elastic interface preferably with a biodegradable polymer at the interface, such as polysaccharides, polyamino acids, polylactides, polyglycolide, lactide / lactide, , poly-fi-aminoketones, polyphosphazenes, polyanhydrides and poly (alkyl cyanoacrylates). Typically, microcapsules are prepared by emulsion technique whereby the polymer is disposed around a droplet of volatile liquid which is subsequently evaporated.

WO 91/12823 discloses ultrasonic contrast media containing microcapsules of a gas or vapor filled polymer, wherein preferred polymers include insoluble proteins such as denatured albumin. Microcapsules may be made by forming a solid or liquid contents around the protein shell (for example, using simple or complex coacervation, double emulsion or minimizing solubility at the isoelectric point), strengthening the shell (chemical or heat treatment) and removing the contents (e.g., sublimation or evaporation). The use of double emulsion technology allows the preparation

0 honeycomb microcapsules with multiple gas or vapor filled chambers.

Gas-containing contrast agents are also known to be effective in obtaining magnetic resonance imaging (MR) images, for example as relaxation contrast agents, which reduce the intensity of the MR signal. Oxygen-containing contrast media may also be potentially useful paramagnetic MR contrast media.

In addition, X-rays have shown that gases such as carbon dioxide can be used as negative oral contrast agents.

It is generally known that polymer based contrast agents should preferably be biodegradable to facilitate their complete removal or absorption from the test subject. However, little attention has been paid to the specific construction of polymers to maximize this goal. It is generally expected that polymers such as polyesters, polyanhydrides, polycarbonates, polyamides and polyurethanes, albeit with slow biodegradation, will in principle result from the sensitivity of their ester, amide or urethane groups to enzymatic hydrolysis.

One exception emerges from EP-A-0458745, where it is recommended, among other things, to use various types of esterified polypeptide derivatives as ultrasound contrast agents, which are said to be controllably biodegradable.

Those polymers described in EP-A-0130935 as slow

0 sustained release carriers containing compounds of the formula:

- (NH-CH-CO) x (CH₂)_y-COO-CR^aR^b-OOC-R^c (where R^a and R^b represents alkyl groups or hydrogen atoms and R^c is an aliphatic or aromatic group which may be substituted, or R^b is hydrogen or alkyl; and R^a and R^ctogether form a divalent group such as dimethylene, vinylene or phenylene, y is 1 or 2, and x is such that the polymer has a molecular weight of at least 5000), and copolymers of these compounds with other polyamino acids.

The first step in the biodegradation of such polymers is said to be the degradation of the side chain of the methylene ester group to yield polymers containing the compounds of the formula:

- (NH-CH-CO) 5 (CH₂)_y-COOH

Such polymers are then said to be further degraded by peptidases to the amino acid components that are absorbed by the patient's body receiving such a polymer / drug combination in a relatively slow process. In addition, peptide structures can cause allergic reactions.

Thus, there continues to be a need for polymer-based contrast media that combine good stability with retention, in vivo administration (at least for multiple circulation in intracardiac injections) and subsequent rapid biodegradation.

The present invention is based on the discovery of the present inventors that contrast agents based on polymers containing methylene ester groups of formula (I) may serve these purposes:

-E CO-OC (R^!R²) -O-CO f - (I) (wherein R¹ and R² represent a hydrogen atom or a carbon-linked monovalent organic group, or R¹ and R² together form a carbon-linked divalent organic group). Such linkages are severely degraded by conventional esterase enzymes

5 quickly, but in the absence of enzymes they are stable. They can be attached not only to carbon-linked organic groups such as simple carboxylate esters, but also to -O- atoms such as carbonate esters.

Polymers of this type and various methods for their preparation are described in International Patent Application WO 92/04392, filed on behalf of the applicant, the contents of which are incorporated herein by reference. In such polymers, the groups of formula (I) may be present, for example, in the polymer backbone, either as repeating units or as linking groups between polymer sections or in cross-linking groups of polymer chains.

A new class of polymers of this type and methods for their preparation are described in the application filed on the same date and include low or zero water soluble, crosslinked polymers having non-polypeptide polymers backbone linked to at least a portion of said side chains containing lipophilic moieties (I) so that these lipophilic moieties are released during biodegradation, providing a water-soluble polymer.

In one aspect of the present invention, contrast agents are provided which comprise gas-containing or gas-separating polymeric microparticles and / or microcapsules, characterized in that the polymer is biodegradable, comprising lysates of formula (II):

-COK-CO-O-CCR ^ -O-COXOl · (Π) (where R¹ and R² is as defined above, and m and n, which may be the same or different, are each 0 or 1).

Polymers containing the compounds of formula (II) wherein either n or m, or both are 1, i.e. containing alkyl carbonate groups, have not been previously described elsewhere than in WO 92/04392 and may in some cases be particularly readily biodegradable.

Polymers having a polypeptide backbone can cause unwanted allergic reactions and non-polypeptide polymers are generally preferred.

The polymers used in accordance with the present invention may contain the compounds of formula (III):

-f (O)_m-CO-OC (R¹R²) - () - CO- (O),_l-R³ f (III)

0 where R¹ and R², m and n have the meaning given above and R³ is a divalent organic group, such as a carbon-linked divalent organic group.

Such polymers may contain a plurality of rings of formula (III) wherein m, n, R¹, R² and R³ different, for example as in block or graft copolymers. The diester bridges can be located at certain intervals in the polymer, for example as crosslinking groups or between copolymer sections, in which case

R³ represents a polymeric group. Alternatively, the bonds may be substantially throughout the polymer, in which case R³ is preferably a low molecular weight group.

Particularly interesting links (III) are those in which m is 0 and n is 0 or 1, i.e. the dicarboxylate groups of formula (IV):

-tCO-OC (R¹R²) -O-CO-R³j- (IV) or carboxylate carbonate groups of formula (V):

-f CO-OC {R'R²) -O-CO-OR³ j- (V)

R¹ and R² both can be, for example, hydrogen or carbon bonded hydrocarbyl or heterocyclic groups including 1-20 carbon atoms, exemplified by an aliphatic group such as alkyl or alkenyl (preferably up to 10 carbon atoms), cycloalkyl (preferably up to 10 carbon atoms), arylaliphatic (e.g. preferably up to 20 carbon atoms), an aryl group (preferably up to 20 carbon atoms) or a heterocyclic group, containing up to 20 carbon atoms and one or more heteroatoms selected from O, S and N. Such a hydrocarbyl or heterocyclic group may have one or more functional substituents, which may be halogens or groups

5 of the formulas -NR⁴R⁵, -CONR⁴R⁵, -OR⁶, -SR⁶ and -COOR⁷, where R⁴ and R⁵which may be the same or different are hydrogen, acyl or hydrocarbyl as defined in R¹ and R² for; R⁶ is a hydrogen atom or an acyl group or a group defined as R¹ or R² and R⁷ is a hydrogen atom or a group defined as R¹ or R² case. If R¹ and R² representing a divalent group, may

0 for example, an alkylidene, alkenylidene, alkylene or alkenylene group (preferably up to 10 carbon atoms) to which one or more of the above functional groups may be attached.

As indicated above, the diester groups of formula (I) can be separated with many different groups. If it is desired to break the polymer into relatively short pieces to facilitate biodegradation, the diester groups of formula (II) may be³ for example, alkylene or alkenylene (e.g. containing up to 20, preferably up to 10 carbon atoms), cycloalkylene (preferably containing up to 10 carbon atoms), arylalkylene (preferably up to 20 carbon atoms), which can be linked via aryl and / or alkyl moieties (s); such an arylalkyl group may be formed, for example, by two aryl groups linked by an alkylene chain) or by a heterocyclic group containing one or more heteroatoms selected from O, S and N (preferably up to 20 carbon atoms). Group R³ may be substituted with functional groups such as R as defined above¹ and R² and / or oxo groups. For groups R³ the carbon chains may be interrupted and / or terminated with heteroatoms Ο, N or S, for example with oxo substituents to form bonds such as ester, thioester or amide groups. To increase the hydrophilicity of the polymers, R³ for example, one or more sets of oxyethylene or polyoxyethylene units and / or hydroxyl substituted carbon chains (e.g., hydroxyalkyl or sugar groups). Such sets of links can

0 may be bonded, for example, via oxycarbonyl groups such as short chain diacid groups such as oxalyl, malonyl, succinyl, glutaryl or adipoyl.

If the group R³ forms a polymeric group, for example, polyamide, poly (hydroxy acid), polyester, polycarbonate, polysaccharide,

5 polyoxyethylene, polyoxyethylene / polyoxypropylene block copolymer, polyvinyl alcohol or polyvinyl ether / alcohol.

Wide selection of possible R¹-, R²- and R³groups allow the hydrophobicity or hydrophilicity of the polymer to be adjusted as needed. Thus, it is convenient to synthesize water-insoluble polymers which, after enzymatic hydrolysis, become water-soluble

0 degradation products.

Aliphatic groups such as R¹ and R², may be linear or branched, saturated or unsaturated, and include, for example, alkyl and alkenyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, decyl or allyl. Aryl aliphatic groups include (monocarbocyclic aryl) alkyl groups such as benzyl groups. Aryl groups include mono- or bicyclic aryl groups such as phenyl, tolyl or naphthyl. Heterocyclic groups include 5 or 6 membered heterocyclic groups which preferably contain one heteroatom, such as furyl, thienyl or pyridyl. Halogen substituents may be, for example, chlorine, bromine or iodine atoms.

Biodegradation of the polymers containing the linkages of formula (III) is generally accomplished by enzymatic hydrolysis of the bonds linking the -O-C 1 -C 4 - O - adjacent carbonyl groups, usually yielding an aldehyde or ketone of the formula R 4 -CO-R². The spacers form different products according to whether m and n are

0 or 1. When m and n are 0, the hydrolysis generally yields carboxyl groups, but if m or n is 1, the hypothetical carbon dioxide-R³-O-COOH, which generally releases carbon dioxide to form -R³-OH. It can be utilized when release of carbon dioxide is physiologically or functionally desirable.

As shown above, the units of formula (ΙΠ) may be in the same polymer

0 different, i.e. the polymers may be block or graft copolymers. The polymers may be copolymers of non-biodegradable monomers. The biodegradable moieties remaining after enzymatic or otherwise degradation are preferably of a suitable size to insure their solubility or dispersion in water and thus can be well dispersed or removed. Thus, these non-biodegradable parts may be present

5 read group R³ is part of formula (III) which combines biodegradable groups in formula (II).

The polymers may be linear, branched, or cross-linked (spatial). Branched and cross-linked polymers generally utilize R of their respective monomer groups¹, R² or R³ functional groups or double bonds. The resulting cross-linked or branched polymers thus contain the compounds of formula (III) wherein R¹, R² and / or R³ are replaced by crossing or branching chains.

As a general rule, when groups R³ Since the carbon atoms connecting the linking compounds of formula (II) are chiral, the chirality should preferably be as in natural products, since hydrolytic enzymes generally have a more efficient effect on such structures.

It has been observed that crosslinked biodegradable polymers often break down first as the crosslinking moieties, thus exposing the rest of the network to enzymatic hydrolysis. Therefore, it is particularly advantageous to have the links of formula (II) in the cross-linked chains of the polymer. Thus, one possibility is to convert a water-soluble long-chain natural or synthetic non-biodegradable or slowly biodegradable substance, such as a polysaccharide or oligosaccharide, or a short-chain polyacrylamide into a water insoluble form using cross-linking units containing the compounds of formula (H). This can minimize the cost of the final product by reducing the amount of relatively expensive biodegradable linkages of formula (II).

For example, block copolymers may have a structure

A (O)_n-CO-OC (R'R²) -O-CO- (O)_m-R³ 4 q

B

0 -KO)_I1-CO-OC (R¹R²) -O-CO- (O)_m-R³4 r

where R¹, R², R³The values ​​of m, n and n are such that the repeating links in blocks A and B are different and q and r are integers, for example 10-20. The above may be attached

5 one or more of the following blocks attached.

The polymers used in the present invention containing the compounds of formula (III) may be prepared, for example, according to the aforementioned patent application WO 92/04392. Another class of compounds of formula (VI) containing the polymers used in this invention are:

-E-A +

I (VI) (L) i- (O)_m-CO-OC (R'R²) -O-CO- (O)_n-R^3a wherein A represents a repeat member of a non-polypeptide polymeric backbone; L is a linking group; 1 is 0 or 1; m, n, R¹ and R² are the same as above; and R^3a represents a lipophilic organic group such as R¹ and R² in the case of an organic group as defined above. Group A and Group L (if present) must be such that the polymeric degradation products normally obtained from the biodegradation of the methylene ester group containing the linkages of formulas (VII) and (VIII):

+ A] I (Vn) (L) i-COOH (where A, L and 1 are the same as above) when m is 0 in formula (VI)

-EA] 15 I (VIII) (L) i-OH (where A, L, and 1 are the same as above), when m is 1 in formula (VI), are water soluble.

0 Factors affecting the water solubility of these polymer degradation products include the type of each of the existing comonomer linkages A, the length of each linking group L and the total length of the polymer chain.

The repeating units A and all comonomer units should preferably be relatively short, e.g. containing up to 10, for example 1-6 carbon atoms, and may be optionally interrupted by one or more heteroatoms selected from oxygen, nitrogen and sulfur and / or substituted by one or more substituents containing such heteroatoms (e.g., oxo, hydroxy and amino). If hydrophilic groups are present in the repeating unit A and / or any comonomer unit, the size of these units is not limited and the possible units include:

0 polyoxyethylene (e.g., as in polyoxyethylene esters of methacrylic acid).

All linking groups L are preferably short and contain, for example, C 1-3 alkylene groups such as methylene, ethylene or propylene, which are optionally bonded to the backbone of the polymer and / or (if necessary) interrupted by, for example, oxy, carbonyl, oxycarbonyl, imino or with an iminocarbonyl group. In the presence of polar groups, such as oxygen atoms or imino groups, the linking groups may be longer without excessively impeding water solubility. Examples of suitable polymeric breakdown products are, for example, polyvinyl alcohol, polyacrylic acid, polymethacrylic acid, polyhydroxyalkyl acrylates and methacrylates such as poly (2-hydroxyethyl acrylate), polysaccharides such as starch and dextran, polyesters, polyesters, acrylamides and methacrylamides (such as poly-N- (2-hydroxypropyl) methacrylamide), polyamides, polyurethanes and epoxy polymers.

Polymeric degradation products of biodegradable polymers containing the compounds of formula (VI) do not generally need to be biodegradable themselves due to their water solubility, so they can be, for example, polyvinyl or polyacrylic. Therefore, the invention encompasses the use of polymers comprising the units of formula (VI) wherein A is a repeating unit of a polyolefin, such as ethylene or propylene. It is very good that these types of polymers can be prepared by free radical polymerization quite simply and economically, unlike, for example, the more sophisticated methods of synthesizing polypeptides which are required to prepare the compounds described in EP-A-0130935.

0 polymers.

R¹, R² and R^3a the type and size of the linkages of formula (VI) affect both the degree at which polymers containing such linkages become lipophilic and thus insoluble in water as well as the rate at which the side chain is biodegraded. Thus, large and / or bulky groups tend to reduce the rate of biodegradation due to steric hindrance, while increasing the lipophilicity of the polymer. In one favorable side chain category, both Rs¹ as R² selected from hydrogen and C 1-4 alkyl groups such as methyl; and R^3a represents a lower alkyl group containing, for example, at least 3 carbon atoms, for example propyl and butyl groups; such side chains significantly combine lipophilicity and biodegradability.

0 It is good that, for example, linear polymers containing the units of formula (VI) may have better processing parameters (e.g. solubility in organic solvents and processability in the molten state) than crosslinked polymers containing, for example, crosslinking groups of formula (II). In this sense, they differ from the polymers described in EP-A-0130935, which have the potential disadvantage that strong bonding to hydrogen bonded polypeptides tends to cause fairly high melting points, and thus may not be technologically fused without causing degradation of the polymer.

Polymers containing the compounds of formula (VI) may be prepared by any suitable means, such as: (A) - reacting a preformed water-soluble polymer with a reagent that adds the desired lipophilic methylene ester side chain, or (B) polymerizing a functional monomer having the desired lipophilic methylene ester side chain.

Process (A) may be carried out, for example, by reacting a polymer having (side chain) free alcoholic hydroxyl groups (e.g. polyvinyl alcohol, polyhydroxyalkyl acrylate or methacrylate or polysaccharide) with a compound of formula (IX):

X-CO-O-QR ^ jO-CCHOVR³³ (IX) (wherein R¹, R², R^3a and n is as defined above and X is a leaving group which may be

0 a halogen atom such as fluorine, chlorine, bromine or iodine). Reagents of formula (IX) may be prepared, for example, according to Folkmann and Lund, Synthesis, 1990, 1159. Such reactions, which yield polymers containing the rings of formula (VI) wherein m is 1, are readily carried out in solution, e.g. tetrahydrofuran; in the presence of a weak nucleophilic base such as pyridine. A catalytic amount of a tertiary amine such as 4-dimethylaminopyridine may also be used. The amount of polymeric hydroxyl groups involved in the reaction which form the desired lipophilic methylene ester groups can be adjusted by selecting suitable factors, such as the amount of reagents, reaction time and temperature, to influence the final hydrophilic-lipophilic balance of the lipophilized polymer. The product may

0 purified by standard techniques such as extraction and / or dissolution / reprecipitation and / or flash chromatography.

Alternatively, process (A) may be carried out by reacting a polymer having (side chain) free carboxyl groups (e.g., polyacrylic acid, polymethacrylic acid or water-soluble peptide) with a compound of formula (X):

X-CR * R²-O-CO- (O)_n-R^3a (X) (where R¹, R², R³, X and n are as defined above). Such reactions, which yield polymers of the compounds of formula (VI) in which m is 0, can be readily carried out in solution, e.g. A catalytic amount of a crown ether such as 18-crown-6 may also be used. Here, too, the hydrophilic-lipophilic balance of the polymeric product can be controlled by selecting appropriate reaction parameters to determine the amount of carboxyl groups to be reacted, and the product can be purified using standard techniques.

Reagents of formula (X) may be prepared, for example, of the aldehyde or ketone formula

RECO-R² by reaction with an acid halide or a haloformic ester of formula R^3a- (O) - CO-X, for example in the presence of a catalyst such as zinc chloride or pyridine.

Process (A) may also be carried out, for example, by reacting a polymer having a functional group such as epoxy with a reagent containing a desired lipophilic methylene ester group and having a terminal group reacting with such functional groups. Terminal groups which react with epoxy groups include amino, hydroxy and carboxyl groups. The latter groups may also be present in the starting polymer and the reagent may have a terminal epoxy group.

If the products are intended for intravenous use, generally

5 it is preferred that the polymer used in process (A) has a molecular weight of not more than about 40,000. If the products are intended for other applications, said molecular weight is not critical.

Process (B) can be carried out using any monomers that can be polymerized or copolymerized to form non-crosslinked polymers, and

0 containing one or more non-polymerizable substituents which can be derivatized prior to polymerization to introduce the desired lipophilic methylene ester group. Free radical, condensation and ion polymerization techniques may be used.

Free radical polymerization can be carried out using, for example, carboxyl-containing monomers such as acrylic acid or methacrylic acid derivatized with a compound of formula (X), or using hydroxyl-containing monomers such as 2-hydroxyethyl acrylate or N- (2-hydroxypropyl) ). Alternatively, the monomers containing hydroxyl groups may be reacted with a compound of formula (XI):

X-CO-OC (R * R²) -X (XI) (wherein R¹, R² and X is as defined above) and reacting the resulting product with carboxylic acid R^3a-COOH with a suitable salt.

Free radical polymerization can also be carried out using vinyl carbonate esters of formula (XII):

CH₂= CH-O-CO-OC (R¹R²) -O-CO- (O) "- R^3a (XII)

0 (where n, R¹, R² and R^3a is defined above). Monomers such as n-0 can be prepared by reaction of vinyl chloroformate with an aldehyde or ketone R¹R²C = O, in the presence of a catalytic amount such as pyridine or Lewis acid, to form an optionally substituted chloromethyl vinyl carbonate of formula (XIII):

ΟΉ, νΗ-Ο-ίΌ-Ο-ίχκ'κ'Ο-ί :! (XIII) (wherein R¹ and R² is as defined above) followed by reaction with, for example, carboxylic acid R^3a-COOH in the presence of a suitable salt, preferably in the presence of a catalytic amount of a suitable crown ether. It is clear that compounds of formula (XII) may be formally considered as "vinyl alcohol" derivatized with a compound of formula (IX). The corresponding polymers should therefore be enzymatically degradable to polyvinyl alcohol.

Conventional polymerization methods can be used: in mass, in solution, in emulsion and in suspension. The molecular weight of the polymer product to be used intravenously should preferably not exceed 40,000 and may be regulated by chain transfer agents such as mercaptans from which a growing polymer chain can secrete a proton which terminates the chain with the formation of a sulfur radical which initiates a new polymer chain. Thus, the molecular weight of the polymer is regulated by the type and concentration of the carrier.

Suitable vinyl monomers having, for example, a carbonyl group adjacent to a vinyl group, such as an acrylic or methacrylic ester prepared by the method described above, may also employ ionic polymerization, both anionic and cationic. Such methods are particularly well suited for the production of polymers of defined molecular weights, particularly at relatively low molecular weights.

A wide variety of suitably functionalized monomers can be used in the preparation of polymers by polycondensation, examples of which are represented by formulas (XIV) and (XV):

Y

I (CH₂) a |

CH- (O)_m-CO-OC (R'R²) -0-C0- (0)_n-R^3a (XIV)

I (CH₂)„

I

Y

YI (CH₂)_a

I

CH- (O)_tn-CO-OC (R¹R²) -O-CO- (O)_n-R^3a

I (CH₂)_b

I

CH- (O)_m-CO-OC (R¹R²) -O-CO- (O)_n-R^3a

I (CH₂)_c

I

Y (XV) (where R¹, R², R^3a, m and n are as defined above, Y is a reactive group which may be a carboxyl, hydroxy or epoxy group such as 2,3-epoxypropyloxy, and a, b and c may each be 0 or a small integer such as 1, 2 or 3) . In formula (XV), groups R¹, R², R³ and m and n are the same or different in the two side chains. Such monomers may be used together in conventional condensation reactions

0 with suitable reagents such as dicarboxylic acids, dialcohols, diamines, di (acid chlorides); diisocyanates and bisepoxy compounds to form polymers such as polyesters, polyamides, polyurethanes and epoxy polymers. The molecular weight of the polymer products may be controlled by the choice of suitable reaction times, temperatures, etc. and / or by the use of monofunctional chain terminators.

If appropriate, the polymers may be prepared by emulsion polymerization; this may be particularly suitable if it is desired to form the polymers, for example in the form of monodisperse particles. Emulsion polymerization methods for preparing particles, particularly monodisperse particles, are described in EP-A30 00003905, EP-A-0091453, EP-A-0010986 and EP-A-0106873.

According to the invention, the polymers used in the contrast media should preferably be of relatively low molecular weight, for example not more than 40,000, since this can promote both biodegradation and excretion of degradation products. Accordingly, the term "polymer" used in this invention is to be understood as including low

5 molecular weight materials such as oligomers.

It is clear that since these polymers are intended for medical use, they should form non-toxic, physiologically acceptable degradation products; therefore groups R¹, R², R³ and R^3a the compounds of formulas (III) and (IV) must be selected according to that requirement and bearing in mind that degradation products are readily excreted. The carbon dioxide released upon decomposition of the carbonate ester groups is usually physiologically acceptable.

The contrast agents of the present invention may be used in a variety of diagnostic imaging techniques, such as ultrasound, magnetic resonance and X-ray imaging. They are particularly suitable for use in diagnostic ultrasound and magnetic resonance imaging, for example as relaxation contrast agents.

Any biocompatible gas such as air, nitrogen, oxygen, hydrogen, nitric oxide, carbon dioxide, helium, argon, sulfur hexafluoride and low molecular weight hydrocarbons, which may also be fluorinated, such as methane, acetylene or carbon tetrafluoride, may be used in the contrast agent of the present invention. In a microbubble, the gas may be in free form or bound, contained in a particular substance. The term "gas" as used herein includes any substance which is in a gaseous state at 37 ° C.

Gasifying agents include carbonates and bicarbonates, such as sodium or ammonium bicarbonate and aminomalonate esters.

For ultrasound applications, such as echocardiography, to allow free passage through the pulmonary system and to achieve resonance at a preferred imaging frequency of about 0.1 to 15 MHz, micro bubbles having a mean size of 0.1 to 10 µm, such as 1 to 7 µm, are suitable. Significantly larger bubbles, for example, up to 500 µm in size, may find application elsewhere, such as gastric and intestinal imaging

5 or studies of the uterus or fallopian tubes.

If desired, the microbubbles may contain particle stabilizers, such as amphiphiles, and inorganic materials, such as silica gel or iron oxide, e.g. Colloidal silica gel particles having a particle size of 530 to 50 nm can be successfully used for this purpose.

The contrast agents of the present invention may be prepared by various methods, typically emulsion techniques used in polymer technology. Microencapsulation technology for the preparation of microcapsules having a wall or membrane of polymeric material is described, for example: PD Deasy, "Microcapsulation and Related Drug Process", Marcel Dekker Inc., New York (1984).

Suitable is the interfacial coating method described in the above-referenced patent application EP-A-045875, which comprises dissolving or suspending the polymeric film-forming material in a water-immiscible low-boiling organic solvent (e.g. aliphatic or cycloaliphatic hydrocarb ester or other lipophilic solvent), emulsifying the resulting solution or suspension (for example, by vigorous stirring) in an aqueous phase (preferably containing a surfactant to stabilize the resulting oil in aqueous emulsion), and subsequently removing the organic phase (e.g. by evaporation or lyophilisation, preferably in the gas medium to be encapsulated); at the interface between the aqueous and organic phases of the membrane.

The size of the microparticles / microcapsules thus formed can be controlled by adjusting the mixing rate during emulsification, whereby faster mixing generally results in smaller particles and is also affected by the type of surfactant.

0 Surfactants can be selected, for example, from fatty acids (e.g., linear or saturated or unsaturated acids containing from 10 to 20 carbon atoms) and their carbohydrate and triglyceride esters, phospholipids (e.g., lecithin), proteins (e.g., human serum albumin), polyoxyethylenes, and blockers. consisting of hydrophilic and hydrophobic blocks (e.g., a polyoxyethylene-polyoxypropylene block copolymer such as Pluronic). Such emulsifiers are typically used in an amount of 1-10% (w / v) relative to the aqueous phase. Ordinary additives may also be added to the polymer. For example, materials such as polyethylene glycols may be added to modify the elasticity and / or polarity of the membrane. Alternatively, the polymer particles may be coated with, for example, polyethylene glycol

0 compounds, proteins or polysaccharides to modify their aggregation and / or biological properties.

The porosity of the membrane and thus its permeability by solvents, solutes and gases, which is dependent on the difference in boiling point between the volatile organic phase and the surrounding aqueous phase, can also be controlled. Thus, the porosity of the membrane increases with the mentioned difference in boiling points.

Alternatively, the polymer may be dissolved in a suitable organic solution (e.g., dichloromethane, dimethylsulfoxide, tetrahydrofuran or dimethylformamide) and then dispersed (using, for example, an to form a microparticulate polymer of the invention. Such methods are described in the aforementioned EP-A-0458079.

One way of preparing the microparticles is by introducing the organic polymer solution, preferably with a physiologically acceptable stabilizer such as hydroxypropylcellulose, into liquid nitrogen.

Alternatively, the polymer may be dissolved in a suitable organic solvent (e.g., dichloromethane or tetrahydrofuran), followed by spray drying of the solution or of the organic polymer solution formed with the aqueous phase in an oil-in-water or water-in-oil emulsion.

The microparticles according to the invention may also be prepared by a coacervation or a double emulsion, for example as described in the aforementioned patent application WO 91/12823. Thus, the aqueous phase containing the water-soluble polymer (hereinafter referred to as the "prepolymer") may be emulsified with a volatile organic solvent (e.g., an aliphatic or cycloaliphatic hydrocarbon or perfluorocarbon having up to 10 carbon atoms) to form an oil25 water emulsion. Addition of a co-preservative (e.g., a dehydrating agent such as isopropanol or a salt such as sodium sulfate) causes the "prepolymer" to be concentrated around the oil droplets, after which it is desirable to add a surfactant to prevent microparticle agglomeration resulting from crosslinking the prepolymer Water-insoluble pores are formed

0 polymer microparticles that can be dried by lyophilization. Suitable methods and reagents for cross-linking water-soluble "prepolymers" such as polyacrylamides are described in detail in our abovementioned International Application WO 92/04392.

The contrast agents of the invention can be stored and transported dried. In this form, contrast agents are normally perfectly stable. Prior to administration, they are mixed with a suitable liquid carrier (e.g., sterile water for injection, saline or phosphate buffer). Thus, the concentration of the contrast medium to be injected or otherwise administered can be varied freely depending on the mode of distortion. They can also be stored as suspensions in said carriers, especially if the porosity of the polymeric membrane of the microcapsules is relatively low and therefore, in the absence of esterase enzymes, are practically completely stable in the aqueous medium.

The following non-limiting examples are provided to illustrate the invention.

General

Methacrylic acid was distilled under high vacuum to remove the stabilizer.

2,2'-Azobisisobutyronitrile (AIBN), the thermal initiator was purified by recrystallization from methanol.

All reactions were carried out under a nitrogen atmosphere.

Size Exclusion Chromatosraphy (SEK).

Pump: Knauer HPLC Pump 64

Detector: Knauer differential refractometer

Columns: Polymer Laboratories PL Rigid Gel Columns, Pore Size 10⁴, 500 and 100 Å, 5 μπι, 30, 30 and 60 cm in size, respectively.

Solvent:

Solvent. THF

Calibration: Polystyrene Standards (Polymer Laboratories) Flow Rate Marker: Toluene

Software: Polymer Laboratories GPC / SEC version 5.10

Mw:

Mn:

average weight (mass) molecular weight average number molecular weight

Mw / Mn:

Sec:

polydispersity at the maximum height of the molecular weight detector

List of abbreviations

<td>Tg:</td><td>glass transition temperature</td>

<td>TBA-OH</td><td>tetrabutylammonium hydroxide</td>

<td>TBA:</td><td>tetrabutylammonium</td>

<td>AJBN:</td><td>2,2'-azobisisobutyronitrile</td>

<td>SO₂C1₂:</td><td>sulfuryl chloride</td>

<td>EtSCl:</td><td>ethanesulfenyl chloride</td>

<td>DBL:</td><td>1,8-diazabicyclo [5.4.0] undec-7-ene (1,5-5)</td>

<td>MgSO₄:</td><td>magnesium sulfate</td>

<td>THF:</td><td>tetrahydrofuran</td>

<td>DMF:</td><td>N, N-dimethylformamide</td>

<td>HSA:</td><td>human blood serum albumin</td>

<td>Example 1.</td><td>Preparation of intermediates</td>

(a) Methylenedimethacrylate

To the methacrylic acid (3.44 g, 40.00 mmol) was added potassium hydroxide solution (1.00 M, 40.00 mL) at 0 ° C and the solution was lyophilized for 16 hours. 230 ml of dry dimethylformamide were added and the suspension was heated to 60 ° C under a dry nitrogen atmosphere. Diiodomethane (1.61 mL, 20.00 mmol) was added in two portions over 10 minutes and the mixture was allowed to react for 4 days at 60 ° C. The solvent was removed under reduced pressure (0.05 mm Hg) before adding diethyl ether (140 mL), saturated aqueous sodium bicarbonate (50 mL) and water (50 mL). The aqueous layer was extracted with diethyl ether (6 x 60 mL) and the combined ether extracts washed with water (4 x 50 mL), dried (MgSO₄) and evaporated to give 2.63 g (72%) of the title compound.

^!1 H NMR (60 MHz, CDCl 3)₃): δ 1.97 (2 x CH₃, m), 5.63 (2 χ HO, m), 5.88 (CH₂, s), 6.18 (2xH-C =, m).

IR (film, cm '¹): 2987 (w), 2962 (w), 2930 (w), 1732 (str), 1638 (w), 1454 (w), 1315 (w), 1295 (w), 1158 (w), 1100 (str) ), 1012 (m), 1012 (m), 989 (m).

b) Methylene bis (16-hydroxyhexadecanoate) (i) 16-Triphenylmethoxyhexadecanoic acid

16-hydroxyhexadecanoic acid (1.36 g, 5.00 mmol), triphenylmethyl chloride 10 (1.53 g, 5.50 mmol), triethylamine (1.25 mL) and 4-dimethylaminopyridine (10.03 g).

A solution of 0.25 mmol) in dry dimethylformamide was stirred overnight at ambient temperature under a nitrogen atmosphere. After stirring for 16 hours, the brown cloudy solution was poured into ice water and extracted with dichloromethane (5 x 50 mL). The organic phases were washed with saturated ammonium chloride solution (2 x 100 mL), water (2 x 100 mL) and dried (MgSO 4).₄). The solvent was removed under reduced pressure and the product was purified by flash column chromatography on silica gel with dichloromethane / methanol (20: 1) to afford 0.41 g of a yellow oil on the title compound.

¹³C NMR (75 MHz, CDCl 3)₃): δ 24.9; 25.7; 26.3; 29.2; 29.5; 29.6; 29.7; 30; 32.8; 34.1; 62.9; 63.7; 86.2; 144.5; 177.2. MS (CI): 515 (@ + H) (ii) 16-triphenylmethoxyhexadecanoic acid cesium salt

Aqueous cesium carbonate (1 M, 0.16 mL) was added dropwise to a solution of 16-triphenylmethoxyhexadecanoic acid (0.16 g, 0.31 mmol) obtained in Example 1b (i) in tetrahydrofuran (10 mL) until a pH of about 8 was reached. the solvent was removed

5 under reduced pressure and the residue was dried under vacuum for 2 hours. The oily semi-crystalline residue was dispersed in dry dimethylformamide (10 mL) and evaporated to dryness in vacuo.

(iii) Methylene bis (16-triphenylmethoxyhexadecanoate)

The 16-triphenylmethoxyhexadecanoic acid cesium salt obtained in Example 1b (ii)

0 To a suspension of (0.31 mmol) in dry dimethylformamide (10 mL) was added diiodomethane (0.04 g, 0.16 mmol). The reaction mixture was heated at 60 ° C for 2 days under nitrogen

6th -01- 1 »in the atmosphere. The solvent was removed in vacuo and the product was purified by flash chromatography on a 2 x 5 cm silica gel column eluting with chloroform to afford 0.10 g of a brown oil on the title compound.

¹³C NMR (75 MHz, CDCl 3)₃): δ 24.6; 26.3; 29.0; 29.2; 29.4; 29.5; 29.6; 29.7; 30.0; 34.0, 63.7; 79.0; 86.2; 126.7; 127.2; 127.6; 127.9; 128.7; 144.5; 172.5.

(iv) Methylene bis (16-hydroxyhexadecanoate)

Methylene bis (16-triphenylmethoxyhexadecanoate) from Example 1b (iii) (0.07 g, 0.07 mmol) was dissolved in glacial acetic acid (8 mL) and heated at 55 ° C.

The reaction was monitored by TLC. After 10 hours, the mixture was poured onto ice, the crude product filtered, washed with aqueous sodium bicarbonate and water, and dried under reduced pressure. The product was purified by flash column chromatography on silica gel eluting with chloroform / methanol (20: 1) to give the title compound as a white solid.

Ή NMR (300 MHz, CDCl3)₃): δ 1.2-1.4 (m, 44H), 1.5-1.6 (m, 8H) 2.35 (t,

4H), 3.64 (t, 4H), 5.75 (s, 2H).

c) Methylene bis (12-hydroxydodecanoate)

To a solution of 12-hydroxydodecanoic acid (2.0 mmol) in DMF (2 mL) was added DBU (2.0 mmol). The solution was stirred for 5 min before the addition of CH 2 Cl 2 (1.0 mmol) and the resulting solution was stirred at 60 ° C for 12 h. The DMF was then removed under reduced pressure and the residue dissolved in CHCl3₃-s (50 mL), washed (10% K₂CO₃; 3 x 20 mL), dried (MgSO 4) and evaporated. The crude product was purified by flash chromatography on silica gel using

5 for elution by CHCL₃/ MeOH 95: 5; the yield was 75%.

1 H NMR (CDCl 3₃): δ 1.20-1.40 (m, 28H), 1.50-1.68 (m, 1OH), 2.35 (t, J 7.5)

Hz, 4H), 3.63 (t, J 6.6 Hz, 4H), 5.74 (s, 2H).

¹³C NMR (CDCl 3): δ 24.62; 25.75; 28.98; 29.19; 29.40; 29.42; 29.48; 29.56;

32,80; 33,99; 63,01; 79,06; 172,53.

MS (EI): 445 (M + 1, 100).

d) Methylene bis (10-hydroxydecanoate)

To 10-hydroxydecanoic acid (5.0 g, 0.027 mol) in DMF (100 mL) was added DBU (4.24 g, 0.027 mol). After stirring for 5 min, diiodomethane (4.09 g, 0.014 mol) was added and the mixture was stirred at room temperature for 3 days. DMF was evaporated under reduced pressure and the residue was dissolved by adding chloroform (100 mL) and water (50 mL). After phase separation, the aqueous layer was extracted with chloroform (3 x 75 mL) and the combined organic phase was dried (MgSO 4). The solvent was removed under reduced pressure and flash chromatography gave 2.98 g (54.9%) of the title compound.

1 H NMR (60 MHz, CDCl 3)₃): δ 1.30-1.80 (m, 28H, CH)₂), 2.35 (m, 4H,

CH₂CO), 3.65 (m, 6H, 2 x CH)₂O + 2 x OH), 5.75 (s, 2H, -OCH)₂O-).

(e) Bis (chloro-carbonyloxymethyl) terephthalate (i) Bis (ethylthiocarbonyloxymethyl) terephthalate

To a solution of terephthalic acid (2.40 g, 0.014 mol) in DMF (100 mL) was added potassium tert -butoxide (3.24 g, 0.029 mol). To the resulting suspension was added O-chloromethyl-acetylthiocarbonate¹ (4.50 g, 0.028 mol). 18-Crown-6 (0.23 g, 0.87 mmol) was then added and the mixture was stirred at room temperature for 4 days. The resulting mixture was filtered and the solvent removed under reduced pressure. The residue was purified by flash chromatography (silica gel / chloroform) to give 3.38 g (62%) of the title compound.

1 H NMR (60 MHz, CDCl 3)₃): δ 1.30 (t, 6H, CfibCH2), 2.95 (q, 4H, CH2Cl2), 5.80 (s, 4H, OCH)₂O), 8.20 (s, 4H, Ph).

(ii) Bis (chlorocarbonyloxymethyl) terephthalate

To the bis (ethylthiocarbonyloxymethyl) terephthalate (1.02 g, 0.0054 mol) obtained in Example le (i) above, SO was added with stirring at 0-5 ° C for 15 min.₂C1₂ (0.73 g, 0.0054 mol) followed by stirring at room temperature for 45 min. Evaporation of EtSCl at room temperature and 0.1 mm Hg gave light yellow crystals. Yield: 0.80 g (90%).

¹ 1 H NMR (60 MHz, CDCl 3)₃). δ 5.76 (s, 4H, OCH₂O), 8.20 (s, 4H, Ph).

(f) Methylene bis (4-hydroxymethylbenzoate)

To 4-hydroxymethylbenzoic acid (9.89 g, 0.065 mol) in DMF (325 mL) was added DBU (9.90 g, 0.065 mol). After stirring for 5 min, diiodomethane (8.705 g, 0.035 mol) was added and the mixture was left stirring for 3 days at room temperature. DMF was evaporated under reduced pressure and the residue was dissolved by adding chloroform (100 mL) and water (50 mL). After phase separation, the aqueous layer was extracted with chloroform (3 x 75 mL) and the combined organic phase was dried (MgSO 4).₄). The solvent was removed under reduced pressure to give 3.0 g (27%) of the title product.

Ή NMR (60 MHz, CDCl3): δ 4.7 (s, 4H, HO-CH)₂-Ph), 6.2 (s, 2H, O-CH)₂O), 7.4-8.2 (m, 8H, Ph).

(gk) General procedure for chloromethyl carbonates

To a solution of chloromethyl chloroformate and alcohol in dichloromethane (200 mL) was added pyridine at 0 ° C. After 20 min at 0 ° C and 21 h at 25 ° C, the reaction mixture was washed with aqueous hydrochloric acid (1 M, 10 mL), saturated aqueous sodium bicarbonate (10 mL), and water (10 mL). After drying (MgSO 4₄), the solvent was removed under reduced pressure to give crude chloromethyl carbonate.

Table 1

<td>An example 1</td><td>Chloromethyl chloroformates g, mmol</td><td>Alcohol, ROH R, (g, mmol)</td><td>Pyridine g, mmol</td>

<td>g</td><td> 25,01; 194</td><td>CH₃, (5,64; 176)</td><td> 15,52; 194</td>

<td>h</td><td> 15,81; 124</td><td>CH₃CH₂, (5,20; 113)</td><td> 9,91; 124</td>

<td>i</td><td> 14,20, 111</td><td>CH₃(CH₂)₃, (8,10; 109)</td><td> 8,90; 113</td>

<td>j</td><td> 20,01; 155</td><td>CH₃(CH₂)₉, (22,25; 139)</td><td> 12,54; 157</td>

<td>k</td><td> 20,02; 155</td><td>PhCH₂, (15,23; 141)</td><td> 12,54; 157</td>

g) Methyl chloromethyl carbonate

This compound was obtained from chloromethyl chloroformate and methanol.

Ή NMR (60 MHz, CDCl3)₃): δ 3.98 (s, 3H, OCH)₃), 5.85 (s, 2H, CH)₂C1).

h) Ethyl chloromethyl carbonate

This compound was obtained from chloromethyl chloroformate and ethanol.

1 H NMR (60 MHz, CDCl 3)₃): δ 1.25 (t, 3H, CH₃), 4.25 (q, 2H, CH)₂), 5.70 (s,

2H, OCH₂C1).

i) Butyl chloromethyl carbonate

This compound was obtained from chloromethyl chloroformate and butanol.

¹1 H NMR (60 MHz, CDCl 3)₃): δ 0.86 (m, 3H, CH)₃CH₂), 1.40 (m, 4H, CH)₂CH₂),

4.15 (t, 2H, CH₂-O), 5.63 (s, 2H, OCH)₂C1).

j) Decyl chloromethyl carbonate

0 This compound was obtained from chloromethyl chloroformate and decyl alcohol.

1 H NMR (60 MHz, CDCl 3)?₃): δ 0.90-1.50 (m, 19H, CH)₃ and CH₂), 4.20 (m, 2H,

CH₂O), 5.75 (s, 2H, OCH)₂C1).

k) Benzyl chloromethyl carbonate

This compound was obtained from chloromethyl chloroformate and benzyl alcohol.

Ή NMR (60 MHz, CDCl3)₃): δ 5.20 (s, 2H, PhCH₂O), 5.70 (s, 2H, ClCH)₂O),

7.32 (s, 5H, Ph).

-Μ- 1998

1-p) General procedure for methacryloyloxymethyl carbonates

Potassium tert -butoxide was added to a solution of methacrylic acid in DMF (200 mL). To the resulting suspension was added chloromethyl carbonate obtained according to Example 1 gk above. 18-Crown-6 was then added and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered and the solvent removed under reduced pressure. The residue was dissolved in chloroform (30 mL) and washed with saturated aqueous sodium bicarbonate (10 mL) and water (20 mL). The organic phase was dried (MgSO 4)₄) and the solvent was removed under reduced pressure.

Table 2

<td>An example</td><td>Compound from Example 1 (g, mmol)</td><td>Potassium methacrylate (g, mmol)</td><td>18-crown-6 (g, mmol)</td><td>DMF (ml)</td>

<td> 1</td><td>g, (9.67, 78)</td><td> 8,71; 78</td><td> 1,01; 38</td><td> 350</td>

<td>m</td><td>h, (8.04; 60)</td><td> 6,73; 60</td><td> 0,6; 23</td><td> 300</td>

<td>n</td><td>i, (30.61; 122)</td><td> 13,67; 122</td><td> 2,5; 94</td><td> 600</td>

<td> 0</td><td>j, (30.61; 122)</td><td> 13,67; 122</td><td> 2,5; 94</td><td> 600</td>

<td>P</td><td>k, (22.01, 110)</td><td> 13,64;110</td><td> 1,5; 57</td><td> 550</td>

1) Methyl methacryloyloxymethyl carbonate

This compound was obtained from methyl chloromethyl carbonate and potassium methacrylate. IR (KBr): 1772 (C = O, str.), 1737 (C = O, str.), 1635 (C = C, str.) Cm-1.¹Ή NMR (300 MHz, CDCl3)₃): δ 1.91 (s, 3H, CH)₃O), 3.79 (s, 3H, CH)₃O),

5.64 (m, 1H, CH₂=), 5.80 (s, 2H, -OCH)₂O-), 6.16 (m, 1H, CH)₂=).

¹³C NMR (75 MHz, CDCl 3)₃): δ 17.95 (CH₃C =), 55.13 (CH₃O), 82.18 (-OCH₂O-), 127.52 (CH₂=), 135.02 (C =), 154.44 (C = O), 165.46 (C = O).

m) Ethyl methacryloyloxymethyl carbonate

This compound was obtained from ethyl chloromethyl carbonate and potassium methacrylate.

IR (KBr): 1772 (C = O, str.), 1736 (O = str.), 1635 (C = C, str.) Cm-1.¹5 1 H NMR (300 MHz, CDCl 3)?₃): δ 1.27 (t, 3H, CH₃), 1.92 (s, 3H, CH)₃O), 4.23 (q, 2H, CH)₂), 5.66 (m, 1H, CH)₂=), 5.80 (s, 2H, -OCH)₂O-), 6.20 (m, 1H, CH)₂=).

¹³C NMR (75 MHz, CDCl 3)₃): δ 15.70 (CH₃CH₂), 19.60 (CH₃=), 65.72 (CH₂O), 83.05 (-OCH₂O-), 127.76 (CH₂=), 135.40 (O), 153.82 (OO), 165.42 (OO).

n) Butyl methacryloyloxymethyl carbonate

This compound was obtained from butyl chloromethyl carbonate and potassium methacrylate.

IR (KBr): 1772 (OO, str.), 1736 (OO, str.), 1635 (OC, str.) Cm¹15th Ή NMR (300 MHz, CDCl3)₃): δ 0.99 (t, 3H, CH5 Cl2, 1.47 (m,

CH₂CH₂), 1.72 (m, 2H, CH)₂CH₂), 2.01 (s, 3H, CH)₃O), 4.25 (t, 2H, CH)₂-O), 5.74 (m, 1H, CH)₂=), 5.89 (s, 2H, -OCH)₂O), 6.27 (m, 1H, CH)₂=).

¹³C NMR (75 MHz, CDCl 3)₃): δ 13.47 (CH₃CH₂), 17.97 (CH₃CH₂), 18.71 (CH₃O), 30.36 (CH₂), 68.46 (CH₂O), 82.07 (-OCH₂O-), 127.46 (CH₂=), 135,05

0 (O), 153.89 (OO), 165.50 (OO).

o) Decyl methacryloyloxymethyl carbonate

This compound was obtained from decyl chloromethyl carbonate and potassium methacrylate.

5 IR (KBr): 1772 (OO, str.), 1763 (OO, str.), 1635 (OC, str.) Cm¹ 1 H NMR (300 MHz, CDCl 3)₃): δ 0.90 (t, 3H, CH₃), 1.28 (m, 14H, CH)₂), 1.72 (m, 2H, CH)₂), 1.99 (s, 3H, CH)₃C = 4.21 (t, 2H, CH)₂O), 5.70 (m, 1H, CH)₂=), 5.86 (s, 3H, -OCH)₂O-), 6.24 (m, 1H, CH)₂=).

¹³C NMR (75 MHz, CDCl 3)₃): δ 13.78 (CH₃), 17.76 (CH₃C =), 22.76-31.55 (CH₂), 68.60 (CH₂O), 81.90 (-OCH₂O-), 127.28 (CH₂=), 134.86 (O), 153.73 (OO), 165.33 (OO).

p) Benzyl methacryloyloxymethyl carbonate

This compound was obtained from benzyl chloromethyl carbonate and potassium methacrylate.

IR (KBr): 3077 (Ph), 1772 (C = O, str.), 1763 (C = O, str.), 1635 (CC, str.) Cm-1.¹ 1 H NMR (300 MHz, CDCl 3)₃): δ 1.96 (s, 3H, CH)₃C = 5.22 (s, 2H, CH)₂O), 5.70 (m, 1H, CH)₂=), 5.87 (s, 3H, -OCH)₂O-), 6.22 (m, 1H, CH)₂=), 7.39 (s, 5H, Ph).

¹³C NMR (75 MHz, CDCl 3)₃): δ 17.96 (CH₃C =), 69.91 (CH₂O), 82.03 (-OCH₂O-), 127.41 (CH₂=), 128.32 (Ph), 134.78 (C =), 153.58 (C = O), 165.28 (C = O).

q) Ethyl 1-methacryloyloxyethyl carbonate (i) Ethyl chloroethyl carbonate

To a solution of chloroethyl chloroformate (23.16 g, 0.162 mol) and ethanol (7.45 g, 0.162 mol) in dichloromethane (200 mL) was added pyridine (12.82 g, 0.162 mol) at 0 ° C. After 10 min at 0 ° C and 21 h at 25 ° C, the reaction mixture was washed with aqueous hydrochloric acid (100 mL), saturated aqueous sodium bicarbonate (100 mL), and water (100 mL). After drying (MgSO 4₄), the solvent was removed under reduced pressure to give 18.5 g (74%) of the ethyl chloroethyl carbonate crude.

1 H NMR (60 MHz, CDCl 3)₃): δ 1.30 (t, 3H, CH₃), 1.85 (d, 3H, CH5 CH), 4.25 (q, 2H, CH)₂), 6.45 (q, 1H, CH).

(ii) Ethyl 1-methacryloyloxyethyl carbonate

To a solution of methacrylic acid (2.84 g, 0.033 mol) in DMF (100 mL) was added potassium tert -butoxide (3.70 g, 0.033 mol). To the resulting suspension was added ethyl chloroethyl carbonate (5.08 g, 0.033 mol) from Example 1q (i) above. 18-Crown-6 (0.61 g, 2.3 mmol) was then added and the reaction mixture was kept under stirring at room temperature for 3 days. The reaction mixture was then filtered and the solvent removed under reduced pressure. The residue was dissolved in chloroform (100 mL) and washed with saturated aqueous sodium bicarbonate (50 mL) and water (50 mL). The organic phase was dried (MgSO 4)₄) and the solvent was removed under reduced pressure. Flash chromatography gave 2.50 g (38%) of the title product. (Considering the recovered starting material, the yield was 75%).

1 H NMR (60 MHz, CDCl 3)₃): δ 1.30 (t, 3H, CH₍CH₂), 1.60 (d, 3H, CH)₃CH), 2.00 (s, 3H, CH₃O), 4.20 (q, 2H, CH)₂), 5.70 (m, 1H, CH)₂=), 6.25 (q, 1H,

-OCH (CH₃(O), 6.90 (m, 1H, CH)₂=).

r) Methacryloyloxymethyl benzoate

To a solution of methacrylic acid (7.75 g, 0.090 mol) in DMF (300 mL) was added potassium tert-butoxide (10.0 g, 0.090 mol). Chloromethyl benzoate was added to the resulting suspension² (15.0 g, 0.088 mol). 18-Crown-6 (1.8 g, 6.9 mmol) was then added and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was filtered and the solvent removed under reduced pressure. The residue was dissolved in chloroform (100 mL) and washed with saturated aqueous sodium bicarbonate (50 mL) and water (50 mL).

The organic phase was dried (MgSO 4)₄) and the solvent was removed under reduced pressure. Flash chromatography gave 15.9 g (82%) of the title product.

1 H NMR (60 MHz, CDCl 3)₃): δ 2.00 (s, 3H, CH)₃C =), 5.65 (m, 1H, CH)₂=), 6.15 (s, 2H, -OCH)₂O-), 6.35 (m, 1H, CH)₂=), 7.50 (m, 3H, Ph), 8.05 (m, 2H, Ph).

s) N- (2-Acetoxymethoxycarbonyloxypropyl) methacrylamide (i) N- (2-Chloromethoxycarbonyloxypropyl) methacrylamide

N- (2-hydroxypropyl) methacrylamide³ To a solution of (2.86 g, 20 mmol) and pyridine (1.90 g, 24 mmol) in dichloromethane (100 mL) was added chloromethyl chloroformate (3.87 g, 30 mmol) in dichloromethane (120 mL) at 0 ° C. After 15 min at 0 ° C and 24 h at 25 ° C, the reaction mixture was washed with water (5 x 25 mL). After drying (MgSO 4₄), the solvent was removed under reduced pressure. Flash chromatography (silica gel, chloroform) gave 3.30 g (70%) of the title product.

1 H NMR (60 MHz, CDCl 3)₃). δ 1.42 (d, 3H, CH2-CH-O), 2.0 (m, 3H, CH)₃C =),

3.2-4.0 (m, 2H, NH-CH)₂-CH), 4.8-5.3 (m, 1H, CH)₃-CH-O), 5.3 (m, 1H, CH)₂=), 5.70 (m, 1H, CH₂=), 5.7 (s, 2H, CH₂C1), 6.1-6.7 (br s, 1H, NH).

(ii) N- (2-Acetoxymethoxycarbonyloxypropyl) methacrylamide

Method 1:

To a stirred solution of N- (2-chloromethoxycarbonyloxypropyl) methacrylamide (0.943 g, 4 mmol) obtained in Example 1s (i) above in THF (10 mL) was added a solution of TBA acetate (1.21 g, 4 mmol) in THF (30 mL) at room temperature. ml) prepared by lyophilization of equimolar TBA-OH and aqueous acetic acid. After stirring for 5 days, the solvent was removed under reduced pressure. The residue was dissolved in chloroform (50 mL) and washed with water (5 x 10 mL). The organic phase was dried (MgSO 4)₄) and the solvent was removed under reduced pressure. Flash chromatography (silica gel, hexane / ethyl acetate (3: 4)) gave 0.486 g (47%) of the title product.

Ή NMR (60 MHz, CDCl3)₃): δ 1.4 (d, 3H, ΟΗ, -ΟΗ-Ο), 2.0 (s, 3H, CH₃C =),

2.2 (s, 3H, CH 3 C = O), 3.2-4.0 (m, 2H, NH-Qh-CH), 4.8-5.3 (m, 1H, CH₃-CH-O),

5.3 (m, 1H, CH)₂=), 5.70 (m, 1H, CH₂=), 5.8 (s, OCH₂O), 6.1-6.7 (br s, 1H, NH).

Method 2:

N- (2-hydroxypropyl) methacrylamide³ To a solution of (0.430 g, 3.0 mmol) and pyridine (0.285 g, 3.6 mmol) in dichloromethane (30 mL) was added acetoxymethyl chloroformate (0.500 g, 3.3 mmol) in dichloromethane (6 mL) at 0 ° C. After 10 min at 0 ° C and 3 days at room temperature, the reaction mixture was washed with water (100 mL). After drying (MgSO 4₄), the solvent was removed under reduced pressure. Flash chromatography (silica gel, hexane / ethyl acetate (3: 4)) gave 0.40 g (51%) of the title product. NMR data were in good agreement with the above.

t) N, N-2- (1-Acetoxyethoxycarbonyloxy-propyl) -methacrylamide (i) N-N-2- (1-Chloro-ethoxycarbonyloxy-propyl) -methacrylamide

N- (2-hydroxypropyl) methacrylamide³ To a solution of (3.15 g, 22 mmol) and pyridine (2.088 g, 26.4 mmol) in dichloromethane (100 mL) was added 1-chloroethyl chloroformate (4.718 g, 33 mmol) in dichloromethane (20 mL) at 0 ° C. After 10 min at 0 ° C and 5.5 h at 25 ° C, the reaction mixture was washed with water (5 x 40 mL). After drying (MgSO 4₄), the solvent was removed under reduced pressure to give 4.84 g (88%) of the title product.

Ή NMR (60 MHz, CDCl3)₃). δ 1.37 (d, 3H, CH₂-CH (CH 3) O-), 1.83 (d, 3H,

CH 3 -CH-Cl), 1.97 (m, 3H, CH)₃C =), 3.3-3.6 (m, 2H, NH-CH 2 -CH), 4.7-5.3 (m, 1H, CH₂-CH (CH₃(-O), 5.3 (m, 1H, CH)₂=), 5.70 (m, 1H, CH₂=), 6.0-6.6 (m, 2H, NH + -C 1 -CH-CH)₃).

(ii) N- [2- (1-Acetoxyethoxycarbonyloxypropyl) methacrylamide

To a stirred solution of N- [2- (1-chloroethoxycarbonyloxy) propyl] methacrylamide (4.736 g, 19 mmol) in THF (100 mL) obtained in Example l (i) above, a solution of TBA acetate (6.93 g, 23 mmol) was added at room temperature. In THF (100 mL) prepared by lyophilization of equimolar TBA-OH and aqueous acetic acid.

After stirring for 4 days, the solvent was removed under reduced pressure. The residue was dissolved in chloroform (100 mL) and washed with water (5 x 20 mL). The organic phase was dried (MgSO 4)₄) and the solvent was removed under reduced pressure. Flash chromatography (silica gel, hexane / ethyl acetate (3: 4)) gave 1.29 g (25%) of the title product.

* HNMR (60 MHz, CDCl3)₃): δ 1.3 (d, 3H, CH)₂-CH (CH₃) O-, 1.5 (d, 3H,

5 O-CH (CH₃O), 2.0 (m, 3H, CH)₃C =), 2.1 (s, 3H, CH)₃C = O), 3.3-3.6 (m, 2H,

NH-CH2-CH), 4.7-5.3 (m, 1H, CH)₂-CH (CH₃(-O), 5.4 (m, 1H, CH)₂=), 5.7 (m, 1H, CH₂=), 6.1-6.6 (br s, 1H, NH), 6.6-6.9 (m, 1H, O-CH (CH₃) O).

'ο

6 &lt;· 1998

u) Methyl 1-methacryloyloxyethyl carbonate (i) Methyl 1-chloroethyl carbonate

To a solution of 1-chloroethyl chloroformate (35.74 g, 0.25 mol) and methanol (8.00 g, 0.25 mol) in dichloromethane (300 ml) was added pyridine (19.78 g, 0.25 mol) at 0 ° C. ). After 10 min at 0 ° C and 2 days at 25 ° C, the reaction mixture was washed with aqueous hydrochloric acid (100 mL), saturated aqueous sodium bicarbonate (100 mL), and water (100 mL). After drying (MgSO 4₄), the solvent was removed under reduced pressure to give 25.5 g (74%) of the crude methyl 1-chloroethyl carbonate.

Ή NMR (60 MHz, CDCl3)₃): δ 1.85 (d, 3H, CH)₃CH), 3.80 (s, 3H, CH₃O),

6.50 (q, 1H, CH).

(ii) Methyl 1-methacryloyloxyethyl carbonate

To a solution of methacrylic acid (2.84 g, 0.033 mol) in DMF (100 mL) was added potassium 15 tert -butoxide (3.70 g, 0.033 mol). To the resulting suspension was added methyl 1-chloroethyl carbonate (4.55 g, 0.033 mol) obtained in Example lu (i) above. 18-Crown-6 (0.61 g, 2.3 mmol) was then added and the reaction mixture was stirred for 3 days at room temperature. The reaction mixture was filtered and the solvent removed under reduced pressure. The residue was dissolved in chloroform (100 mL) and washed with saturated aqueous sodium bicarbonate (50 mL) and water (50 mL). The organic phase was dried (MgSO 4)₄) and the solvent was removed under reduced pressure. Flash chromatography gave 4.46 g (72%) of the title product.

Ή NMR (60 MHz, CDCl3)₃): δ 1.65 (d, 3H, CH)₃CII), 2.00 (s, 3H, CH)₃C =),

3.90 (s, 3H, CH)₃Δ), 5.65 (m, 1H, CH)₂=), 6.25 (m, 1H, CH)₂=), 6.90 (q, 1H, CHCH)₃).

(v) Ethylene di (chloromethyl carbonate)

To an ice-cooled (0 ° C) solution of ethylene glycol (2.8 mL, 50 mmol) in CH₂Cl₂Chloromethyl chloroformate (19.12 g, 148.5 mmol) was added (200 mL). Pyridine (8.70 g, 110 mmol) was then added and the reaction mixture was stirred for 15 minutes at 0 ° C and for 6 hours at room temperature. The reaction mixture was washed with HCl (1 M, 100 mL), NaHCO₃with

6th -01- 1998 (saturated aqueous solution, 100 mL) and water and dried (MgSO 4)₄). The solvent was evaporated to give 11.88 g (96.2%) of the title product.

1 H NMR (60 MHz, CDCl 3)?₃): δ 4.48 (m, 4H, OCH)₂CH₂O), 5.75 (s, 4H, OCH)₂C1).

w) Acetoxymethyl chloroformate (i) O-Acetoxymethyl-S-ethylthiocarbonate

To a solution of potassium acetate (2.74 g, 0.028 mol) in THF (100 mL) was added O10 chloromethyl-S-ethylthiocarbonate¹ (4.50 g, 0.028 mol) in DMF (20 mL). Then 18 crown-6 (0.22 g, 0.84 mmol) was added and the reaction mixture was stirred for 3 days at room temperature. The reaction mixture was filtered and the solvent removed under reduced pressure. The residue was purified by flash chromatography (silica gel, chloroform) to give 4.23 g (85%) of the title product.

T1 NMR (60 MHz, CDCl3)₃): δ 1.30 (t, 3H, CH5 CH2 O, 2.20 (s, 3H, CH)₃C = O),

2.95 (q, 2H, CH₂CH₃), 5.80 (s, 2H, OCH)₂O).

(ii) Acetoxymethyl chloroformate

To the O-acetoxymethyl-S-ethylthiocarbonate (3.15 g, 0.018 mole) obtained in Example 1w (i) was added SO at 0-5 ° C.₂C1₂ (2.43 g, 0.018 mol) and stirred for 15 minutes. Stirring was continued at room temperature for 45 minutes. Evaporation of EtSCl at room temperature and 11 mm Hg gave a colorless liquid. Yield: 2.44 g (89%).

1 H NMR (60 MHz, CDCl 3)₃): δ 2.20 (s, 3H, CH)₃C = O), 5.76 (s, 2H, OCH)₂O).

(x) Hexamethylene di (chloromethyl carbonate)

Ice-cooled (0 ° C) to a solution of 1,6-hexanediol (5.90 g, 50 mmol) in CH₂C1₂Chloromethyl chloroformate (19.12 g, 148.5 mmol) was added (200 mL). Pyridine (8.70 g, 110 mmol) was then added and the reaction mixture was stirred for 15 minutes at 0 ° C and for 5 hours at room temperature. The reaction mixture was washed with HCl (1 M, 100 mL), NaHCO₃with

6th -01- 1998 (saturated aqueous solution, 100 mL), water (100 mL) and dried (MgSO₄). The solvent was evaporated to give 13.25 g (95%) of the title product.

1 H NMR (60 MHz, CDCl 3)₃): δ 1.20 - 2.00 (m, 8H, (CH₂)₄), 4.22 (t, 4H, 2x (CH₂0), 5.73 (s, 4H, 2 * OCH)₂C1).

v) Methacryloyloxymethyl acetate

To a solution of methacrylic acid (3.87 g, 0.045 mol) in DMF (150 mL) was added potassium tert -butoxide (5.0 g, 0.045 mol). Chloromethyl acetate was added to the resulting suspension³ (4.86 g, 0.045 mol). 18-Crown-6 (0.9 g, 3.45 mmol) was then added and the reaction mixture was stirred at room temperature for 4 days. The reaction mixture was filtered and the solvent removed under reduced pressure. The residue was dissolved in chloroform (100 mL) and washed with saturated aqueous sodium bicarbonate (50 mL) and water (50 mL). The organic phase was dried (MgSO 4)₄) and the solvent was removed under reduced pressure.

Flash chromatography gave 5.19 g (75%) of the title product.

11 NMR (60 MHz, CDCl₃): δ 2.00 (s, 3H, CH)₃C =), 2.18 (s, 3H, CH)₃C = O),

5.70 (m, 1H, CH₂=), 5.85 (s, 2H, -OCH)₂O-), 6.25 (m, 1H, CH)₂=).

z) Butyl acryloyloxymethyl carbonate

To a solution of acrylic acid (4.47 g, 0.045 mol) in DMF (220 mL) was added potassium tertbutoxide (5.84 g, 0.052 mol). To the resulting suspension was added butyl chloromethyl carbonate (6.5 g, 0.052 mol) in DMF (150 mL) obtained in Example l. Then 18 crown-6 (0.6 g) was added and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was filtered and the solvent removed under reduced pressure. The residue was dissolved in chloroform (100 mL) and washed with saturated aqueous sodium bicarbonate (50 mL) and water (50 mL). The organic phase was dried (MgSO 4)₄) and the solvent was removed under reduced pressure. Flash chromatography gave 4.57 g of the title product.

1 H NMR (60 MHz, CDCl 3)?₃). δ 0.80 (t, 3H, CH₃CH₂), 1.28 (m, 2H, CH)₂), 1.60 (m, 2H, CH)₂), 4.15 (t, CH₂O), 5.78 (s, 2H, OCH)₂O), 5.88 (dd, 1H, CH₂=), 6.1 (dd,

1H, CH₂=), 6.45 (dd, 1H, CH₂= CH-).

aa) 3,6,9-trioxaundecanedioic acid dichloride

3,6,9-Trioxaundanoic acid (2.0 mmol) was boiled in thionyl chloride (1 mL) for 6 hours before evaporation of the excess thionyl chloride under reduced pressure.

The crude product was used in the next step without purification.

Ή NMR (CDCl₃): Δ 3.64-3.68 (m, 4H), 3.76-3.82 (m, 4H), 4.49-4.51 (m,

4H).

¹³C NMR (CDCl 3): δ 70.70; 71.29; 76.65; 172.03.

ab) 1- (7-Benzyloxycarbonyl-heptanoyloxy) -ethyl-decylcarbonate (i) A solution of nonanedioic acid (25.0 g, 0.13 mol) in benzene (550 mL) was added to p-toluenesulfonic acid (0.71 g, 3.72 mmol). and heated to 80 ° C. Benzyl alcohol (14.3 g, 0.13 mol) in benzene (50 mL) was added dropwise. The reaction mixture was refluxed overnight. Water was removed from the reaction mixture and collected on a Dean-Stark apparatus. After 24 hours, no benzyl alcohol was detected by TLC. The reaction mixture was cooled to room temperature and then in an ice bath. Precipitated unreacted nonanedioic acid was removed by filtration. The filtrate was dried. The residue was purified by chromatography on a column using dichloromethane / methanol (10: 1) as eluent. Yield: 28%.

Ή NMR (300 MHz, CDCl3)₃). δ 7.35-7.31 (m, Ar); 5.10 (s, ArClFb); 2.33 (t, CH₂CO); 1.62 (m, CH 2 Cl 2 O); 1.29 [m, (CH₂)₃], (ii) cesium salt of 1-benzylnonandiic acid

The 1-benzyl nonanoic acid (6.3 g, 21.6 mmol) obtained in Example lab (i) was suspended in distilled water (100 mL) and heated to 50 ° C. Cesium carbonate (3.5 g, 10.8 mmol) in water (20 mL) was added dropwise to pH 7. Water was removed by lyophilization for 2 days. Yield: 95%.

f iii) 1-Chloroethyl decyl carbonate

To a stirred solution of decanol (6.0 g, 7.23 mmol) in dichloromethane (150 mL) was added dry pyridine (3.66 mL, 45.6 mmol). The solution was cooled in an ice bath. To the resulting solution was added dropwise 1-chloroethyl chloroformate (6.5 g, 45.6 mmol). The reaction mixture was left overnight, diluted with dichloromethane and washed with 0.5 N HCl solution, twice with saturated sodium bicarbonate solution and finally with distilled water. The solvent was dried over magnesium sulfate, filtered through silica gel and dried. Yield: 93%.

^!1 H NMR (300 MHz, CDCl 3)₃): δ 6.43 (q, CHCl 1); 4.19 (t, CH₂O); 1.83 (d, 10 CHsCH); 1.69 (C 1 -C 4 O); 1.40-1.22 [m, (CH₂)₈]; 0.88 (t, CH₃CH₂).

(iv) 1- (7-Benzyloxycarbonylheptanoyloxy) ethyl decyl carbonate

The 1-benzyl-nonanedioic acid cesium salt (from Example lab (ii), 5.0 g, 12.2 mmol) was dissolved in DMF (150 mL). To this was added 1-chloroethyl decyl carbonate (from Lab 15 (iii), 3.25 g, 12.2 mmol) followed by potassium iodide (125 mg, 0.75 mmol).

The reaction was allowed to proceed at 50 ° C for 3 days. The solvent was removed under reduced pressure. The residue was suspended in dichloromethane, washed three times with saturated sodium bicarbonate solution and finally twice with water. After drying over magnesium sulfate, the solution was evaporated to dryness. The product was purified by chromatography on a column using petroleum ether / ethyl acetate (12: 1) as eluent. Yield: 65%.

1 H NMR (300 MHz, CDCl 3)₃): δ 7.35-7.31 (m, Ar); 6.78 (q, OCHCH₃O); 5.10 (s, ArCB); 4.19 (t, CH₂O); 2.33 (t, CH₂CO).

(v) A catalytic amount of palladium on activated carbon (150 mg) was added to a solution of 1- (7-carboxy-heptanoyloxy) ethyl-decyl carbonate 1- (7-benzyloxycarbonyl-heptanoyloxy) -ethyl-decyl carbonate (from lab (iv), 4.0 g, 7.9 mmol) in acetic acid (15 mL). ). The mixture was hydrogenated with hydrogen at ambient temperature for 5 hours. The acetic acid was removed under reduced pressure. The residue was purified by chromatography on a column using heptane / ethyl acetate (4: 1) as eluent. Yield: 52%.

-01- 1998 'Η NMR (300 MHz, CDCl₃): δ 6.76 (q, OCHCH₃O); 4.19 (t, CH₂O); 2.32 (t, CH₂CO).

¹³C NMR (300 MHz, DMSO-d6)₆) δ 174.67 (COOH), 171.30 (CH₂COO); 152.68 (OCOO); 91.09 (OCHCH₃).

ac) Nonylcarbonyloxymethyl chloroformate (i) Potassium decanoate

To a suspension of decanoic acid (8.0 g, 46.4 mmol) in water (300 mL) was added a solution of KOH (2.6 g, 46.4 mmol) in water (50 mL) dropwise at 60 ° C to pH 7. Water was removed by lyophilization. Yield: 9.28 g (95%).

(ii) O-Nonylcarbonyloxymethyl-S-ethylthiocarbonate

To a suspension of potassium decanoate (Example lae (i), 6.5 g, 0.031 mol) in DMA (500 mL) was added O-chloromethyl-S-ethylthiocarbonate¹ (4.79 g, 0.031 mol) in DMA (20 mL). 18-Crown-6 (0.25 g, 0.93 mmol) was then added and the reaction mixture was stirred at ambient temperature for 22 hours. The reaction mixture was filtered and the solvent removed under reduced pressure. The residue was purified by flash chromatography (silica gel, hexane / ethyl acetate (30: 1)). Yield: 5.96 g (67%).

0 1 H NMR (300 MHz, CDCl 3)₃): δ 0.88 (t, 3H, CH 3 (CH₂)_g), 1.27 (m, 12H, (CH₂)₆), 1.33 (t, 3H, CH₃CH₂S). 1.63 (m, 2H, CH)₂CH₂= O), 2.37 (t, 2H, CH)₂C = O), 2.89 (q, 2H, CH)₂S), 5.81 (s, 2H, OCH)₂O).

¹³C NMR (300 MHz, CDCl3)₃): δ 14.1; 14.8; 22.7; 24.6; 25.4; 29.0; 29.2; 29.3, 29.4; 31.9; 33.9; 80.2 (OCH₂O), 170.7 (C = O), 172.2 (C = O).

(iii) Nonylcarbonyloxymethyl chloroformate

O-nonylcarbonyloxymethyl-S-ethylthiocarbonate (from example lae (ii), 2.10 g, 7.22 mmol) in CH₂Cl₂SO (5 mL) was added at 0 ° C₂C1₂ (1.17 g, 8.65 mmol) with stirring for 15 minutes, followed by stirring at ambient temperature for 17 hours.

Evaporation of EtSCl at 30 ° C and 20 mm Hg gave a yellow liquid. Yield: 1.62 g (85%).

1 H NMR (300 MHz, CDCl 3)₃): δ 0.88 (t, 3H, CH₃), 1.27 (m, 12H, (CH₂)₆), 1.66 (m, 2H, CH)₂CH₂C = O), 2.41 (t, 2H, CH)₂C = 0), 5.82 (s, 2H, 0CH)₂0).

¹³C NMR (300 MHz, CDCl3)₃): Δ 14.1; 22.7; 24.5; 29.0, 29.19; 29.24; 29.4; 31.9; 33.8; 83.3 (0CH₂O), 150.1 (Cl = O), 171.7 (C = 0).

ad) 1-Acetoxy-1-phenylmethyl-vinyl carbonate (i) 1-Chloro-1-phenyl-methyl-vinyl carbonate

Vinyl chloroformate (3.0 g, 0.028 mol) and benzaldehyde (4.14 g, 0.039 mol) were dissolved in 1,2-dichloroethane (30 ml) and pyridine (0.1 g, 1.28 mol) was added dropwise to the stirred solution. The solution was stirred for 1 day at 80 ° C, washed with water (25 mL) and the aqueous phase was extracted with dichloromethane (25 mL). The combined organic phases were dried (MgSO 4) and concentrated to give 3.0 g (50%) of the title product.

1 H NMR (60 MHz, CDCl 3)?₃): δ 4.55 (dd, 1H, CH)₂=), 4.95 (dd, 1H, CH₂=),

7.05 (dd, 1H, CH₂= CH-), 7.25 (s, 1H, CH-Ph), 7.40 (m, 5H, Ph).

(ii) 1-Acetoxy-1-phenylmethyl-vinyl carbonate

To a solution of 1-chloro-1-phenylmethyl-vinyl carbonate (2.50 g, 0.012 mol) in DMF (60 mL) was added silver acetate (2.0 g, 0.012 mol). The reaction mixture was stirred at room temperature

12th hours. The reaction mixture was filtered and the solvent removed under reduced pressure. The residue was purified by flash chromatography (silica gel, dichloromethane) to give 0.56 g (20%) of the title product.

1 H NMR (60 MHz, CDCl 3)?₃): δ 2.24 (s, 3H, CH)₃C = O), 4.60 (dd, 1H, CH)₂=), 4.95 (dd, 1H, CH₂=), 7.00 (dd, 1H, CH =), 7.50 (m, 5H, Ph), 8.00 (s, 1H, -CH-Ph).

ae) Benzoyloxymethyl chloroformate (i) O-Benzoyloxymethyl-S-ethylthiocarbonate

To a solution of potassium benzoate (5.94 g, 0.037 mol) was added O-chloromethyl-S30 ethylthiocarbonate¹ (5.73 g, 0.037 mol) in DMF (20 mL) and then 18-crown-6 (0.485 g, 1.85 mmol) in DMF (130 mL) was added and the reaction mixture was stirred at room temperature

01 -01- «98 hours. The solvent was removed under reduced pressure. The residue was dissolved in chloroform (150 mL), washed with water (5 x 20 mL) and dried (MgSO₄). The solvent was removed under reduced pressure and purified by flash chromatography (silica gel, chloroform) to give 7.16 g (81%) of the title product.

Ή NMR (60 MHz, CDCl3)₃): δ 1.3 (t, 3H, CH₃), 2.9 (q, 2H, CH 2 Cl 2), 6.1 (s,

2H, OCH₂O), 7.3-7.7 (m, 3H, Ph), 8.0-8.2 (m, 2H, Ph).

(ii) Benzoyloxymethyl chloroformate

To 0-benzoyloxymethyl-S-ethylthiocarbonate (7.16 g, 0.030 mol) was added SO at 0-5 ° C.₂C1₂ (4.03 g, 0.030 mol) with stirring for 15 minutes. Stirring was continued at room temperature for 2 hours. Evaporation of EtSCl at room temperature and 11 mm Hg gave a yellow liquid. Yield: 5.30 g (83%).

Ή NMR (60 MHz, CDCl3)₃): δ 6.1 (s, 2H, OCH)₂O), 7.3-7.7 (m, 3H, Ph), 8.08.2 (m, 2H, Ph).

Example 2. Preparation of Polymers

(a) Emulsion copolymerization of methylenedimethacrylate and styrene

50 ml of a 1% (w / v) aqueous solution of sodium dodecyl sulfate was preheated to 60 ° C under a nitrogen atmosphere. Under vigorous stirring, 0.20 g (1.09 mmol) of methylenedimethacrylate from Example 1a above and 9.80 g (0.094 mol) of styrene monomer were added. The polymerization was initiated with a metabisulfite / persulfate redox system containing 1.6 mg (7.2 mmol) of potassium metabisulfite and 0.08 mg (0.3 mmol) of potassium persulfate. The polymerization was allowed to proceed for 8 hours before cooling to room temperature. The resulting emulsion had a solids content of 11.2%, corresponding to a conversion rate of 68%. The resulting polymer was not soluble in THF (good polystyrene solvent), which shows the cross-linking of the polymer.

6th -tn- w

(b) Polymer of methylene bis (16-hydroxyhexadecanoate) and adipoyl chloride

To a solution of methylene bis (16-hydroxyhexadecanoate) (2.000 g, 3.59 mmol) in xylene / trichlorethylene (80:20 v / v, 160 mL) from Example 1b (iv) above was added dropwise at 60 ° C a solution of adipoyl chloride (0.657 g, 3 mL). , 59 mmol) in xylene / trichloroethylene (80:20 by weight, 5 mL). After 44 hours at 60 ° C under reduced pressure, the reaction mixture was cooled to 20 ° C and the solvent was evaporated under reduced pressure to give 0.227 g of a white solid.

IR (undiluted), cm¹: 2915 (s), 1759, 1732 (s), 1466, 1417 (w), 1380, 10 1263, 1175 (w), 1105 (w), 991 (w), 798 (w), 726.

Ή NMR (300 MHz, CDCl3)₃): δ 1.58 (m, 44H, CH)₂), 1.63 (m, 12H, CH)₂),

2.29 (m, 8H, CH)₂CO), 4.04 (m, 4H, 2 x CH)₂O), 5.73 (m, 2H, -OCH)₂O-).

Exclusive Chromatography (SEC): Mw = 11100, Mn = 6500,

Mp = 14100, Mw / Mn = 1.7.

(c) Polymer of methylene bis (12-hydroxydodecanoate) and adipoyl chloride

Methylene bis (12-hydroxydodecanoate) obtained in Example 1c above (3.00 g,

To a solution of 6.7 mmol) in xylene / trichlorethylene (80:20 by volume, 100 mL) was added dropwise a solution of adipoyl chloride (1.22 g, 6.7 mmol) in xylene / trichlorethylene (80:20 by weight, 50 mL) at 60 ° C. ). After 4 days at 60 ° C under reduced pressure, the reaction mixture was cooled to 20 ° C and the solvent was evaporated under reduced pressure to give a yellow solid. The compound was purified by flash chromatography (silica gel / step chromatography from chloroform to ethyl acetate).

Exclusive Chromatography (SEC): Mw = 18276, Mn = 12840,

Mw / Mn = 1.423.

(d) Polymer of methylene bis (10-hydroxydecanoate) and succinyl chloride

Methylene bis (10-hydroxydecanoate) obtained in Example 1d above (0.500 g,

To a solution of 1.29 mmol) in toluene (60 mL) at 70 ° C was added succinyl chloride (0.200 g,

6 -01- 1938

1.29 mmol). After 100 hours at 70 ° C under reduced pressure, the reaction mixture was cooled to 20 ° C and the solvent was evaporated under reduced pressure to give 0.436 g of a yellow solid.

IR (undiluted): 2933 (s), 1787, 1738 (s), 1650, 1465 (w), 1413 (w), 1357 (w), 1262 (w), 1164, 1099 (w), 1049 (w) , 988, 906, 802 cm '¹.

1 H NMR (300 MHz, CDCl 3)₃): δ 1.25 (m, 20H, CH)₂), 1.57 (m, 8H, CH)₂), 2.32 (m, 4H, CH)₂CO), 2.61 (m, 4H, CH)₂CO), 4.04 (m, 4H, 2 x CH)₂O), 5.70 (s, 2H, -OCH)₂O-).

Exclusive Chromatography (SEC): Mw = 1870, Mn = T580, Mp = 1310, 10 Mw / Mn = 1.18.

e) Oligomer of methylene bis (10-hydroxydecanoate) and succinic acid

To a solution of methylene bis (10-hydroxydecanoate) (0.500 g, 1.29 mmol) and p-toluenesulfonic acid (0.007 g, 0.004 mmol) obtained in Example 1d above in toluene (12 mL) was added succinic acid (0.152 g, 1 mL) at 130 ° C. , 29 mmol). After 84 hours at 140 ° C with continuous removal of water formed by distillation, the reaction mixture was cooled to 20 ° C. The solvent was evaporated under reduced pressure to give 0.425 g of a yellow solid.

IR (undiluted): 2933 (s), 1739 (s), 1650, 1467 (w), 1415, 1360 (w), 1261,

1168, 1100, 995, 803, 724 cm '¹.

Ή NMR (300 MHz, CDCl3)₃): δ 1.27 (m, 20H, CH)₂), 1.59 (m, 8H, CH)₂), 2.33 (m, 4H, CH)₂CO), 2.64 (m, 4H, CH)₂CO), 4.05 (m, 4H, 2 x CH)₂O), 5.72 (s, 2H, -OCH)₂O-), 10.00 (bs, 2H).

Exclusive Chromatography Data (SEC): No polymer formation was observed (oligomers only).

(f) Polymer of methylene bis (10-hydroxydecanoate) and adipoyl chloride

Methylene bis (10-hydroxydecanoate) obtained in Example 1d above (2,000 g,

A solution of adipoyl chloride (0.943 g, 5.15 mmol) in xylene / trichlorethylene (80:20 by weight, 7 mL) was added dropwise to a solution of 5.15 mmol) in xylene / trichloroethylene (80.20 by volume, 120 mL) at 60 ° C. After 48 hours at 60 ° C under reduced pressure, the reaction mixture was cooled to 20 ° C and the solvent was evaporated under reduced pressure to give a white solid. Flash chromatography (silica gel, ethyl acetate) gave 0.44 g of a polymer fraction.

1 H NMR (300 MHz, CDCl 3)?₃): δ 1.32 (m, 20H, CH)₂), 1.57 (m, 12H, CH)₂), 2.34 (m, 8H, CH)₂CO), 4.03 (m, 4H, 2 x CH)₂O), 5.71 (s, 2H, --CH)₂O-).

Exclusive Chromatography (SEC): Mw = 20964, Mn = 12382,

Mp = 22843, Mw / Mn = 1.693.

(g) Polymer of bis (chlorocarbonyloxymethyl) terephthalate and 1,6-diaminohexane

To a solution of bis (chlorocarbonyloxymethyl) terephthalate (0.70 g, 0.002 mol) in THF (20 mL) obtained in Example le (ii) above was added 1,6-diaminohexane (0.23 g, 0.002 mol) and triethylamine (0.40 g). g (0.004 mol) in THF (5 mL). The reaction mixture was stirred for 6 days at room temperature. The reaction mixture was filtered and the solvent removed under reduced pressure to give a polymer which was insoluble in chloroform.

1 H NMR (60 MHz, CDCl 3)₃): δ 1.20 (m, 8H, 4 x CH)₂), 2.85-3.20 (m, 6H, 2 x NH and 2 x CH)₂N, 5.85 (s, 2H, OCH)₂O), 8.00 (s, 4H, Ar).

(h) Polymer of methylene bis (4-hydroxymethylbenzoate) and adipoyl chloride

To a solution of methylene bis (4-hydroxymethylbenzoate) (2.18 g, 6.89 mmol) obtained in Example 1f above in 1,1,2,2-tetrachloroethane / trichloroethylene (80:20 by weight, 90 mL) was added at 60 ° C. a solution of adipoyl chloride (1.26 g, 6.89 mmol) in 1,1,2,2,2-tetrachloroethane / trichloroethylene (80:20 by weight, 5 mL) was added dropwise. After 4 days at 60 ° C under reduced pressure, the reaction mixture was cooled to 20 ° C and the solvent was evaporated under reduced pressure to give 2.82 g of a brown viscous oil. Precipitation in methanol gave 0.80 g of a yellow compound. Exclusive Chromatography Data (SEC): Mw = 3793,

Mn = 2715, Mp = 2845, Mw / Mn = 1.724.

-01- 199S 1 H NMR (200 MHz, CD₃COCD₃): δ 1.65 (s br, 4H, CH)₂), 2.40 (s br, 4H, CH)₂CO), 5.18 (s, 4H, O-CH)₂-Ph), 6.25 (s, 2H, OCH)₂O), 7.4-7.6 (m, 4H, Ph), 7.9-8.1 (m, 4H, Ph).

(im) General procedure for the polymerization of methacryloyloxymethyl carbonates

A solution of methacryloyloxymethyl carbonate (1.0 g) obtained in Example 1-p above in DMF (8.0 g) was heated to 60 ° C and AIBN (0.005 g, 0.03 mmol) was added. After 24 hours, the reaction mixture was cooled and the polymer solution was added dropwise to the stirring excess methanol (non-solvent). The polymer was filtered, washed with methanol and water and dried under reduced pressure.

(i) Polymer of methyl methacryloyloxymethyl carbonate

ER (KBr): 1763 (C = O, str.) Cm-1¹.

1 H NMR (300 MHz, CDCl 3)₃): δ 1.00 (m, 2H, CH)₂), 1.90 (m, 3H), 3.85 (s, 3H, CH)₃O), 5.70 (s, 2H, OCH)₂O).

¹³C NMR (75 MHz, CDCl 3)₃): δ 46.35 (C-CH₃), 56.55 (CH₃O), 83.59 (-OCH₂O-), 154.41 (C = O), 175.50 (C = O).

Differential scanning calorimetry (DSC) showed a Tg = 59.8 ° C and an initial degradation temperature of 242.2 ° C. Thermo-mechanical analysis showed that the transition to the glassy structure took place at 59.9 ° C.

Exclusive Chromatography (SEC): Mw = 100000, Mn = 59000,

Mw / Mn = 1.7.

(i) Polymer of ethyl methacryloyloxymethyl carbonate

IR (KBr): 1763 (C = O, str.) Cm -1¹.

Ή NMR (300 MHz, CDCl3)₃): δ 1.00 (m, 2H, CH)₂), 1.32 (t, 3H, CH₃), 1,90

0 (m, 3H, CH₃), 4.25 (m, 2H, CH)₂O), 5.70 (s, 2H, OCH)₂O).

¹³C NMR (75 MHz, CDCl 3)₃): δ 15.77 (-OCH₂O-), 46.35 (C-CH)₃), 65.90 (CH₂O), 83.50 (-OCH₂O-), 153.69 (C = O), 175.80 (OO).

Differential scanning calorimetry (DSC) showed a Tg = 35.9 ° C and an initial degradation temperature of 260.9 ° C. Thermo-mechanical analysis showed that the transition to the glassy structure took place at 31.2 ° C.

Exclusive Chromatography Data (SEC): Mw = 34000, Mn = 20000,

Mw / Mn = 1.7.

(k) Polymer of butyl methacryloyloxymethyl carbonate

IR (KBr): 1763 (O)¹.

Ή NMR (300 MHz, CDCl3)₃): δ 0.90 (t, 3H, CH₃), 1.00 (m, 2H, CH)₂), 1.39 (m, 2H, CH)₂), 1.70 (m, 2H, CH)₂), 1.90 (m, 3H, CH)₃), 4.20 (t, 2H, CH₂O), 5.68 (s, 2H, OCH)₂O).

¹³C NMR (75 MHz, CDCl 3)₃): δ 13.54 (CH₃CH₂), 18.73 (CH₂), 30.39 (CH₂),

46.26 (C-CH₃), 69.72 (CH₂O), 83.67 (-OCH₂O-), 153.86 (OO), 175.80 (OO).

Differential scanning calorimetry (DSC) showed an initial degradation temperature of 239.9 ° C. (Tg was not monitored). Thermo-mechanical analysis showed that the transition to the glassy structure occurred at a temperature of 24.7 ° C.

0 Exclusive Chromatography Data (SEC): Mw = 60000, Mn = 29000, Mw / Mn = 2.1.

l) Polymer of decyl methacryloyloxymethyl carbonate

IR (KBr): 1763 (10 °, str.) Cm-1¹.

Ή NMR (300 MHz, CDCl3)₃): δ 0.90 (t, 3H, CH₃), 0.90 (m, 3H, CH)₂), 1.30 (m, 14H, CH)₂), 1.70 (m, 2H, CH)₂), 1.90 (m, 2H), 4.19 (t, 2H, CH)₂O), 5.66 (s, 2H, OCH)₂O).

¹³C NMR (75 MHz, CDCl 3)₃): δ 13.78 (CH₃), 22.34-31.57 (CH₂),

46.26 (C-CH₃), 68.70 (CH₂O), 83.67 (-OCH₂O-), 153.55 (OO), 175.80 (OO).

Differential scanning calorimetry (DSC) showed that the initial temperature of degradation was 232.9 ° C. (Tg was not monitored). Thermo-mechanical analysis showed that the transition to the glassy structure took place at -3.3 ° C.

Exclusive Chromatography Data (SEC): Mw = 160000, Mn = 90000,

Mw / Mn = 1.7.

m) Benzyl methacryloyloxymethyl carbonate polymer

IR (KBr): 3077 (Ph), 1763 (C = O, str.) Cm -1¹.

1 H NMR (300 MHz, CDCl 3)₃): δ 0.95 (m, 3H, CH)₃), 1.90 (m, 2H), 5.25 (s, 2H,

CH₂O), 5.75 (s, 2H, OCH)₂O), 6.70 (s, 5H, Ph).

¹³C NMR (75 MHz, CDCl 3)₃): δ 46.26 (-C-CH₃), 68.03 (-OCH₂Ph), 82.02 (-OCH₂O-), 129.45 (Ph), 153.67 (C = O), 175.80 (C = O).

Differential scanning calorimetry (DSC) showed a Tg = 31.6 ° C and an initial decomposition temperature of 197.1 ° C. Thermo-mechanical analysis indicated that the transition to the glassy structure took place at 32.8 ° C.

Exclusive Chromatography (SEC): Mw = 92000, Mn = 44000,

Mw / Mn = 2.1.

(n) Free radical polymerization of benzyl methacryloyloxymethyl carbonate in solution.

which yields a low molecular weight polymer

A solution of the benzyl methacryloyloxymethyl carbonate (0.5 g, 2.0 mmol) in DMF (7.5 g) obtained in Example 1p above was heated to 60 ° C and allyl mercaptan (0.0015 g, 0.02 mmol) was added along with AIBN. (0.0025 g, 0.015 mmol). After 24 hours, the reaction mixture was cooled and the polymer solution was added dropwise to the stirring excess methanol (non-solvent). The polymer was filtered, washed with methanol and water and dried under reduced pressure.

Exclusive Chromatography (SEC): Mw = 22000, Mn = 14000.

(o) Free radical polymerization of methyl 1-methacryloyloxyethyl carbonate

To a solution of the methyl 1-methacryloyloxyethyl carbonate (1.0 g, 5.0 mmol) obtained in Example lu (ii) above in dry THF (8 g) was added AJÜBN (0.005 g, 0.03 mmol) at 60 ° C under a dry nitrogen atmosphere. . After 24 hours, the reaction mixture was cooled to 20 ° C and the solvent removed under reduced pressure. The resulting polymer was dissolved in CH 2 Cl 2 and reprecipitated in methanol. The methanol was isolated from the polymer by filtration to give a white powder.

1 H NMR (200 MHz, CDCl 3)₃): δ 0.90 (m, 3H, CH)₃), 1.45 (s, 3H, CH 2 CH), 1.87 (m, 2H, CH)₂), 3.80 (s, 3H, CH)₃O), 6.65 (bs, 1H, CHCH)₃).

Exclusive Chromatography (SEC): Mw = 16033, Mn = 6641,

Mp = 16192, Mw / Mn = 2.41. Differential scanning calorimetry (DSC) showed Tg = 57.65 ° C.

(p) Free radical polymerization of ethyl 1-methacryloyloxyethyl carbonate

To a solution of ethyl 1-methacryloyloxyethyl carbonate (0.504 g, 2.49 mmol) obtained in Example 1q (ii) above in dry THF (8 mL) was added AIBN (0.033 g, 0.02 mmol) at 50 ° C under a dry nitrogen atmosphere. After 7 hours it was cooled

0 reaction mixture to 20 ° C, the polymer was precipitated in methanol (50 mL) and the solution was filtered. The resulting polymer was dissolved in THF, reprecipitated in methanol (70 mL) and filtered to give 0.138 g of a white powder.

1 H NMR (300 MHz, CDCl 3)₃): δ 0.90 (m, 3H, CH)₃), 1.25 (s, 3H, CH)₃), 1.45 (s, 3H, CH)₃), 1.87 (m, 2H, CH)₂), 4.15 (bs, 2H, CH₂O), 6.62 (bs, 1H, -CHCH)₃).

Exclusive Chromatography (SEC): Mw = 26500, Mn = 18600,

Mp = 22000, Mw / Mn = 1.43.

q) Ethyl methacryloyloxymethyl carbonate polymer, emulsion polymerization

A solution of sodium dodecyl sulfate (0.056 g, 0.19 mmol) in water (20.5 mL) was heated to 60 ° C under a nitrogen atmosphere before the product of Example 1m above.

-01 "1998 ethyl methacryloyloxymethyl carbonate (5.266 g, 28.00 mmol) was added.

The polymerization was initiated by the redox system of potassium metabisulfite (53.4 mg, 0.24 mmol) and potassium persulfate (4.38 mg, 0.02 mmol). After 16 hours at 60 ° C, potassium persulfate (4.38 mg, 0.02 mmol) was added and the polymerization was allowed to continue for 3 hours at 60 ° C under nitrogen before cooling to 20 ° C.

r) Polymer of methacryloyloxymethyl benzoate

To a solution of the methacryloyloxymethylbenzoate (1.00 g, 4.55 mmol) obtained in Example 1r above in dry THF (8 g) was added AIBN (0.005 g, 0.03 mmol) at 60 ° C under a dry nitrogen atmosphere. After 24 hours, the reaction mixture was cooled to 20 ° C and the solvent removed under reduced pressure. The resulting polymer was dissolved in dichloromethane and reprecipitated in methanol. The methanol was isolated from the polymer by filtration to give a white powder.

1 H NMR (200 MHz, CDCl 3)₃): δ 0.85 (m, 3H, CH)₃), 1.87 (m, 2H, CH)₂), 5.70 (m, 2H, -OCH)₂O-), 7.45 (m, 3H, Ph), 8.05 (m, 2H, Ph).

Exclusive Chromatography (SEC): Mw = 30281, Mn = 11580,

Mp = 32286, Mw / Mn = 2.615.

Differential scanning calorimetry (DSC) showed Tg = 60.98 ° C.

(s) Free radical polymerization of N- (2-acetoxymethoxycarbonyloxypropyl) methacrylamide

To a solution of N- (2-acetoxymethoxy-25-carbonyloxypropyl) -methacrylamide (0.519 g, 2 mmol) in dry THF (8 mL) obtained in Example ls (ii) above was added AIBN (0.0138 g, 0.084 mmol) at 50 ° C under a dry nitrogen atmosphere. . After 3 days, the solvent was removed under reduced pressure to give 0.439 g of a white powder.

Ή NMR (200 MHz, CDCl3)₃): δ 0.8-1.2 (m, 3H, CH)₃), 1.2-1.4 (m, 3H, CH)₂-CH (CH₃(O), 1.6-2.0 (m, 2H, CH)₂), 2.1 (s, 3H, CH)₃CO), 2.9-3.9 (m, 2H,

NH-CH₂), 4.7-5.0 (m, 1H, CH₂CH (CH₃) -O), 5.8 (s, 2H, O-CH)₂-O), 6.2-7.0 (m, 1H, NH).

Exclusive Chromatography (SEC): Mw = 5411, Mn = 2857,

Mw / Mn = 1.894.

Differential scanning calorimetry (DSC) showed Tg = 52.91 ° ​​C.

t) Free radical polymerization of N- [2- (1-acetoxyethoxycarbonyloxypropyl] methacrylamide

To a solution of N- [2- (1-acetoxyethoxycarbonyloxy) propyl] methacrylamide (1.23 g, 4.5 mmol) obtained in Example l (ii) above in dry THF (18 mL) was added AIBN (50 mL) under a dry nitrogen atmosphere. 0.0031 g, 0.189 mmol). After 3 days, the solvent was removed under reduced pressure.

Flash chromatography (step gradient from hexane / ethyl acetate (3: 4) to methanol) gave 0.96 g of a white powder.

Ή NMR (200 MHz, CDCl3)₃): δ 0.8-1.2 (m, 3H, CH)₃), 1.2-1.4 (m, 3H,

CH₂-CH (CH₃O), 1.5 (d, 3H, O-CH (CH 3) -O), 1.6-2.0 (m, 2H, CH₂), 2.0-2.2 (s, 3H,

CH₃CO), 2.9-3.9 (m, 2H, NH-CH)₂), 4.7-5.0 (m, 1H, CH₂CH (CH₃) -O), 6.2-7.0 (m, 2H, NH + O-CH (CH)₃) -O).

Exclusion Chromatography (SEC): Mw = 1991, Mn = 1268, Mp = 2105,

Mw / Mn = 1. 548.

0 Differential scanning calorimetry (DSC) showed Tg = 51.53 ° C.

u) Oligomer of ethylene di (chloromethyl carbonate) and dipotassium terephthalate

To a solution of terephthalic acid (1.20 g, 0.0072 mol) in DMF (40 mL) was added potassium tert-butoxide (1.62 g, 0.014 mol). To the resulting suspension was added ethylene di (chloromethyl carbonate) (1.78 g, 0.0072 mol) from the above example. Then 18 crown-6 (0.056 g, 0.21 mmol) was added and the resulting mixture was left in the mixer at room temperature for 2 days and then at 60 ° C for 11 days. The reaction mixture was filtered and the solvent removed under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate (30 mL) and water (30 mL).

6th -01- W

The organic phase was dried (MgSO 4)₄) and the solvent was removed under reduced pressure to give the title product.

1 H NMR (60 MHz, CDCl 3)₃): δ 4.48 (m, 4H, OCH)₂CH₂O), 6.02 (s, 4H,

OCH₂O), 8.12 (s, 4H, Ar).

Exclusion Chromatography (SEC): Mw = 1938, Mn = 1511, Mp = 2137,

Mw / Mn = 1.283.

(v) Homopolymerization of free radical emulsion of benzyl methacryloyloxymethyl carbonate

To a 50 mL two-necked round bottom flask equipped with a magnetic stirrer and a condenser was added sodium dodecyl sulfate (1.6 x 10² g, 5.5 x 10 '² solution) in deoxidized water (6.0 mL). Potassium metabisulfite (0.015 g, 6.7 x 10 ') dissolved in deoxidized water (1.0 mL) was added to the solution.² mmol) and the benzyl methacryloyloxymethyl carbonate obtained in Example 1p above (2.0 g, 8.0 mmol). The reaction mixture was heated to 60 ° C. Potassium persulfate (1.25 x 10 ') was added to the heated mixture.³ g, 4.6 x 10 '³ mmol) and the reaction was allowed to proceed. After about 5 hours, the polymerization was stopped and the polymer emulsion was added dropwise to a large excess of methanol (insoluble). The polymer was then filtered and washed with methanol and water. The procedure was repeated three times to purify the polymer. The polymer was then collected and dried under vacuum to remove solvent impurities. Part of the stable emulsion was not isolated as above, but was stored under a light microscope for particle size analysis. The particle size of the emulsion was determined by light microscopy and was found to be slightly less than 1pm in diameter.

wz) Free radical copolymerization of ethyl methacryloxyloxymethyl carbonate and methacrylic acid in solution

Example 1m from ethyl methacryloyloxymethyl carbonate and

0 A monomer mixture of methacrylic acid in DMF (8.0 g) was heated to 60 ° C and AIBN (0.005 g, 0.03 mol) was added. After 24 hours, the polymer solution was added dropwise to the stirring excess chloroform (insoluble), filtered and washed with additional chloroform and dried under reduced pressure.

Table 3

<td>An example 2</td><td>Methacrylic acid (g, mmol)</td><td>Ethyl methacryloyl oxymethyl carbonate (g, mmol)</td><td>The molar ratio methacrylic acid: lm</td>

<td>w</td><td> 0,73; 8,48</td><td> 0,25; 1,33</td><td> 86 : 14</td>

<td>X</td><td> 0,73; 8,48</td><td> 0,17; 0,90</td><td> 90 : 10</td>

<td>y</td><td> 0,73; 8,48</td><td> 0,14; 0,74</td><td> 92 : 8</td>

<td>z</td><td> 0,92; 10,7</td><td> 0,08, 0,43</td><td> 96 : 4</td>

1 H NMR (200 MHz, CDCl 3)₃): δ (s, 6H, 2xCH₃), 1.27 (t, 3H, CH₃CH₂), 1.90 (s, 4H, 2xCH)₂), 3.52 (bs, 1H, OH), 4.2 (m, 2H, CH)₃CH 2), 5.72 (s, -OCH)₂O-)

Table 4: Solubility of copolymers in cold and hot water

<td>An example</td><td>Solubility</td><td>Solubility</td>

<td> 2</td><td>(cold water)</td><td>(hot water)</td>

<td>w</td><td>no</td><td>no</td>

<td>X</td><td>no</td><td>no</td>

<td>y</td><td>no</td><td>no</td>

<td>z</td><td>complete *</td><td>complete</td>

* Complete dissolution occurs only after a relatively long time.

(aa) Oligomer of hexamethylene di (chloromethyl carbonate) and dipotassium terephthalate

To a solution of terephthalic acid (5.66 g, 0.034 mol) in DMF (200 ml) was added potassium tert -butoxide (7.87 g, 0.068 mol). To the resulting suspension was added hexamethylene (chloromethyl carbonate) (Example 1x, 9.50 g, 0.034 mol). 18-Crown-6 (0.24 g, 0.82 mmol) was then added and the mixture was stirred at room temperature for 5 hours and at 60 ° C for 14 days. The resulting mixture was filtered and the solvent removed under reduced pressure. The residue was dissolved in chloroform (100 mL), washed with saturated aqueous sodium bicarbonate (50 mL) and water (50 mL). The organic phase was dried (MgSO 4)₄) and the solvent was removed under reduced pressure to give a yellow product.

Ή NMR (60 MHz, CDCl3)₃): δ 1.25-1.90 (m, 8H, 4xCH)₂), 4.20 (t, 4H,

-OCH₂CH₂-), 6.00 (s, 4H, OCH₂O), 8.10 (s, 4H, Ar).

Exclusion Chromatography (SEC): Mw = 2987, Mn = 1754, Mp = 3014,

Mw / Mn = 1.703.

Differential scanning calorimetry (DSC) showed a Tg of less than 20 ° C.

ab) Polymer of methacryloyloxymethyl acetate

To a solution of methacryloyloxymethyl acetate (example ly, 1.00 g, 4.55 mmol) in dry THF (8 g) was added 60 (0.005 g, 0.03 mmol) at 60 ° C under a dry nitrogen atmosphere. After 24 hours, the mixture was cooled to 20 ° C and the solvent removed under reduced pressure. The resulting polymer was dissolved in CH₂C1₂and precipitated in methanol. The methanol was isolated from the polymer by filtration to give a white powder.

Differential scanning calorimetry (DSC) showed Tg = 54.99 ° C.

0 Exclusion Chromatography (SEC): Mw = 184678, Mn = 2446, Mp = 54732,

Mw / Mn = 7.56.

ac) Oligomer of methylene bis (10-hydroxydecanoate) and malonyl chloride

To a solution of methylene bis (10-hydroxydecanoate) (Example 1d, 0.70 g, 1.80 mmol) in xylene / trichlorethylene (80:20 by volume, 50 mL) was added malonyl chloride (0.254 g, 1.80 mmol) at 60 ° C. ). After 77 hours at 60 ° C under reduced pressure, the mixture was cooled to 20 ° C and the solvent was evaporated, yielding 0.665 g of a brown viscous liquid.

Exclusive Chromatography (SEC): Mw = 2700, Mn = 2100, Mp = 1600,

Mw / Mn = 1.28.

6th -01-199 (ad) Ethyl 1-methacryloyloxyethyl carbonate polymer, emulsion polymerization

A mixture of sodium dodecyl sulfate (6.5 mg, 0.023 mmol) in water (2.40 mL) and potassium metabisulfite (6.3 mg, 0.028 mmol) in water (0.82 mL) was heated to 60 ° C under nitrogen before ethyl 1-methacryloxyethyl carbonate (Example 1q (ii), 0.617 g, 3.10 mmol). The polymerization was initiated by the addition of potassium persulfate (0.54 mg, 0.002 mmol) in water (0.25 mL). The polymerization was allowed to proceed for 20 hours at 60 ° C under nitrogen before cooling to 20 ° C.

ae) Polymer of methylene bis (12-hydroxydodecanoate) and triphosgene

A solution of methylene bis (12-hydroxydodecanoate) (Example 1c, 2.0 mmol) and triphosgene (0.67 mmol) in xylene / trichlorethylene 95: 5 (2 mL) was heated at 60 ° C for 36 hours at 50 mm Hg and then evaporated. , yielding a polymeric substance.

af) Polymer of methylene bis (12-hydroxydodecanoate) and 3.6.9-trioxaundecanedioic acid dichloride

A solution of methylene bis (12-hydroxydodecanoate) (Example 1c, 2.0 mmol) and 3,6,920 trioxaundecanedioic acid dichloride (Example 1aa, 2.0 mmol) in xylene / trichlorethylene 95: 5 (2 mL) was heated at 60 ° C for 36 h. 50mm

Hg was then evaporated to give a polymeric material.

ag) Dextran 10-1- (7-carboxy-heptanoyloxy) ethyl-decyl carbonate

To a solution of dextran 10 (0.65 g) in dry DMSO (40 mL) was added 1- (7-carboxyheptanoyloxy) ethyl decyl carbonate (Example 1 ab, 1.5 g, 36 mmol), N-N '- (3-dimethylaminopropyl) carbodiimide ( 0.83 g, 4.3 mmol) and 4-pyrrolidinopyridine (42 mg, 0.28 mmol) dissolved in dry DMSO (30 mL). After

0 after stirring at ambient temperature for 2 days, the mixture was diluted with water (250 mL) and dialyzed from water for 30 hours. Lyophilization of the solution gave 1.3 g of a light yellow powder.¹³In the C NMR spectrum, a new carbonyl signal appeared at 171.28 ppm. This corresponded to the expected region of the ester carbonyl signal of the product. The remaining signals were consistent with the product structure.

ah) Pluronic® F68 and a benzoyloxymethyl chloroformate polymer

Pluronic® F68 (9.889 g, 1.191 mmol) was dissolved in toluene (dry, 30 mL). After heating to 45 ° C, triethylamine (0.70 mL) was added with constant stirring. Benzyloxymethyl chloroformate dissolved in toluene (4 mL) was added dropwise (Example lae (ii), 1.072 g,

5.00 mmol) followed by addition of triethylamine (0.25 mL) in a mixture of toluene (dry,

2.5 ml). The reaction mixture was kept at 45 ° C for 8 hours, then at 55 ° C for 16 hours, then cooled and filtered. The solvent was removed under reduced pressure, the resulting compound was dissolved in toluene and reprecipitated from n-heptane (500 mL) with stirring to give a white powder (8.45 g). IR (KBr): 1722 (C = O)¹.

(ai) Free radical polymerization of 1-acetoxy-1-phenylmethylvinyl carbonate

To a solution of 1-acetoxy-1-phenylmethyl-vinyl carbonate (example lad (ii), 1.0 g) in dry THF (8 mL) was added AIBN (0.005 g at 60 ° C under a dry nitrogen atmosphere).

0 0.03 mol). After 12 hours, the solvent was removed under reduced pressure. The resulting polymer was dissolved in CH 2 Cl 2 and reprecipitated in a suitable solvent. The solvent was removed by filtration to give a white powder.

aj) Free radical copolymerization of N- (2-hydroxypropyl) methacrylamide in solution with N- (2-acetoxymethoxycarbonyloxypropyl) methacrylamide

N- (2-hydroxypropyl) methacrylamide³ (0.430 g, 3.0 mmol) and N- (2-acetoxymethoxycarbonyloxypropyl) methacrylamide (Example 1s, 0.778 g, 3.0 mmol) were dissolved in tetrahydrofuran (10 mL) and heated to 55 ° C. AIBN (0.0207 g, 0.126 mmol) was added and the mixture was stirred at 55 ° C for 3 days to give a clear gel. It was dissolved in tetrahydrofuran and the solvent was evaporated under reduced pressure to give 1.33 g of a white powder.

Exclusive chromatography (SEC) showed the formation of a polymer.

Example 3. Preparation of polymer particles

(a) Polymer particles of methylene dimethacrylate and styrene

A sample of the polymer emulsion (13 mL) from Example 2a above was mixed with heptane (13 mL) at room temperature. After 40 minutes, the sample was lyophilized to give a white powder.

(b) Polymer particles of methylene bis (16-hydroxyhexadecanoate) and adipoyl chloride

6.204 g of a 4.1% (w / w) polymer solution of Example 2b above in xylene / trichlorethylene (90:10) were added to 25 ml of 0.5% (w / v) aqueous Pluronic® F68. The mixture was shaken vigorously (by hand) for one minute and lyophilized for 16 hours. Light microscopy showed the formation of microparticles.

(c) Polymer particles of methylene bis (16-hydroxyhexadecanoate) and adipoyl chloride

6.204 g of a 4.1% (w / w) polymer solution of Example 2b above in xylene / trichlorethylene (90:10) were added to 25 ml of 0.5% (w / v) aqueous Pluronic® F68. The mixture was mixed with an Ultra Turax T25 mixer at 20500 rpm for 40 seconds and lyophilized for 16 hours. Light microscopy showed the formation of microparticles.

(d) Polymers of methylene bis (16-hydroxyhexadecanoate) and adipoyl chloride

12.408 g of a 4.1% (w / w) solution of the polymer in Example 5 2b above in xylene / trichlorethylene (90:10) was added to 50 ml of 0.5% (w / v) aqueous Pluronic® F68. The mixture was blended in an Ultra Turax® T25 blender at 24000 rpm for 40 seconds and lyophilized for 16 hours. Light microscopy showed the formation of microparticles.

(e) Polymer particles of methylene bis (12-hydroxydodecanoate) and adipoyl chloride

Methylene bis (12-hydroxydodecanoate) polymer from Example 2c above and adipoyl chloride (0.40 g) in xylene / trichlorethylene ((10: 1), 4 mL) were added to 20 mL.

0.5% (w / v) Pluronic® F68 aqueous solution. The mixture was mixed with Ultra

The Turax® T25 was agitated at 20500 rpm for 30 seconds and lyophilized (0.5 mm Hg) for 16 hours. Light microscopy showed the formation of microparticles.

(f) Prepared from ethylene di (chloromethyl carbonate) and dipotassium terephthalate

0 oligomeric particles

Oligomeric solution of ethylene di (chloromethyl carbonate) and dipotassium terephthalate in 2u chloroform (22.5 ml of a 4% (w / v) solution prepared by dissolving the polymer by gentle heating) from the above example was added to 30 ml of 0.5% (w / v) Pluronic® F68 aqueous solution. The mixture was blended in an Ultra Turax® T25 blender at 24000 rpm for 40 seconds and lyophilized for 16 hours. Light microscopy showed the formation of microparticles.

(g) Polymer particles of ethyl methacryloxyoxymethyl carbonate

A polymer solution of ethyl methacrylooyloxymethyl carbonate from Example 2j above in chloroform (9 mL of a 10% (w / v) solution) was added to 30 mL of a 0.5% (w / v) aqueous solution of Pluronic® F68. The mixture was mixed with an Ultra Turax® T25 mixer at 24000 rpm for 40 seconds and lyophilized for 16 hours. Light microscopy showed the formation of microparticles.

h) Polymeric particles made from methyl 1-methacryloyloxyethyl carbonate

Methyl 1-methacryloyloxyethyl carbonate polymer (0.462 g) from the above example in 20 ° toluene (5 ml) was added to 20 ml of 1.0% (w / v) aqueous Pluronic® F68. The mixture was mixed with an Ultra Turax® T25 mixer at 20500 rpm for 30 seconds and lyophilized (0.05 mm Hg) for 16 hours. Light microscopy showed the formation of microparticles.

(i) Polymer particles of methacryloxyoxymethyl benzoate

Polymer of methacryloyloxymethyl benzoate (0.45 g) from Example 2r above

0 in a mixture of toluene / trichlorethylene ((10: 1), 2 mL) was added to 20 mL of 1.0% (w / v) aqueous Pluronic® F68. The mixture was stirred at 20500 rpm for 30 seconds on an Ultra Turax® T25 and lyophilized (0.05 mm Hg) for 4 hours. Light microscopy showed the formation of microparticles.

(j) Polymer particles made of ethyl methacryloyloxymethyl carbonate

The polymer emulsion was prepared according to Example 2q above. 14.783 g of the emulsion was added to 47.305 g of toluene. The mixture was stirred vigorously for 20 hours and lyophilized for 16 hours to give 1.813 g of a white powder. Light microscopy and scanning

0 electron microscopy showed the formation of microparticles.

(k) Polymer particles of ethyl methacryloxyoxymethyl carbonate

The polymer emulsion was prepared according to Example 2q above. 12.7612 g of the emulsion was added to 40.836 g of chloroform. The mixture was stirred vigorously for 20 hours and lyophilized for 16 hours to give 1.496 g of a white powder. Light microscopy and scanning electron microscopy showed the formation of microparticles.

(l) Oligomeric particles of ethylene (chloromethyl carbonate) and dipotassium terephthalate

The oligomer (1.0 g) from ethylene (chloromethyl carbonate) and dipotassium terephthalate from Example 2u above was dissolved in 19.0 g of liquid naphthalene at 100 ° C. The naphthalene solution was emulsified at 90 ° C in 200 mL of aqueous polyvinyl alcohol (8.0 g, Mw = 13000-23000) containing Pluronic® F68 (0.2 g). The emulsifier was Ultra Turax® T25. The emulsion was then diluted by stirring with 500 ml of the same aqueous phase at 15 ° C and stirring for 8 minutes. The naphthalene droplets solidified into beads, which were filtered through a 50 µm filter to remove larger portions than 50 µm. The suspension was centrifuged at 1000 xg, the beads were washed with water and centrifuged

0 again. This was repeated twice. The beads were resuspended in 100 ml water with 0.8 g lactose and the suspension was frozen at -40 ° C. The block was then lyophilized for 16 hours. Light microscopy showed the formation of microparticles.

m) Polymer particles of methylene bis (16-hydroxyhexadecanoate) and adipoyl chloride in ml of 3.37% (w / v) polymer solution (Example 2b) in xylene / trichlorethylene (90:10) were added to 10 ml of 0.5% w / w Tween® 80 aqueous solution. The mixture was blended with an Ultra Turax® T25 mixer at 20500 rpm for 1 minute and

30th seconds and lyophilized for 18 hours to give a white powder. Light microscopy showed the formation of microparticles.

ί »

η) Polymer particles of methylene bis (16-hydroxyhexadecanoate and adipoyl chloride)

3 ml of a 3.37% (w / v) polymer solution (Example 2b) in xylene / trichloroethylene (90:10) was added to 10 ml of a 0.5% (w / w) Brij® 99 aqueous solution. The mixture was blended with an Ultra Turax® T25 mixer at 20500 rpm for 1 minute and 30 seconds and then lyophilized for 17 hours to give a white powder. Light microscopy showed the formation of microparticles.

(o) Polymer particles of methylene bis (16-hydroxyhexadecanoate) and adipoyl chloride

5.5 ml of a 1.84% (w / v) polymer solution (Example 2b) in xylene / trichlorethylene (90:10) were added to 10 ml of a 0.5% (w / w) aqueous solution of Cremophor® RH40. The mixture was mixed with an Ultra Turax® T25 mixer at 20500 rpm for 1 minute and 30 seconds and lyophilized for 16 hours to give a white powder.

Light microscopy showed the formation of microparticles.

0 (p) Polymer particles of methylene bis (16-hydroxyhexadecanoate) and adipoyl chloride

5.5 ml of a 1.84% (w / v) polymer solution (Example 2b) in xylene / trichlorethylene (90:10) were added to 10 ml of 0.5% (w / w) Kollidon® 30

5 aqueous solution. The mixture was blended with an Ultra Turax® T25 mixer at 20500 rpm for 1 minute and 30 seconds and lyophilized for 16 hours to give a white powder. Light microscopy showed the formation of microparticles.

q) Polymer particles of methylene bis (10-hydroxydecanoate) and adipoyl chloride in ml of 2.52% (w / v) polymer solution (Example 2f) in 5 xylene / trichlorethylene (90:10) were added to 10 ml of 0.5% ( by weight) for Pluronic® F68 aqueous solution. The mixture was mixed with an Ultra Turax® T25 blender at 20500 rpm for 1 minute and 30 seconds and lyophilized for 15 hours to give a white powder. Light microscopy showed the formation of microparticles.

(r) Oligomeric particles of hexamethylene di (chloromethyl carbonate) and dipotassium terephthalate

22.5 ml of a 4% (w / v) polymer solution (Example 2aa) in chloroform was added to 30 ml of 0.5% (w / w) Pluronic® F68 aqueous solution. The mixture was mixed with Ultra

Turax® T 25 was blended at 24000 rpm for 40 seconds and lyophilized for 16 hours to give a yellow gummy solid. Light microscopy showed the formation of microparticles.

s) Polymer particles of N- [2- (1-acetoxyethoxycarbonyloxy] propyl] methacrylamide in ml of 2.55% (w / v) polymer solution (Example 2t) in xylene / trichlorethylene (90:10) were added to 20 ml of 0.5% w / w Pluronic® F68 aqueous solution The mixture was blended with an Ultra Turax® T25 mixer at 20500 rpm for 1 minute and

30th seconds and lyophilized for 16 hours to give a white powder. Light microscopy showed the formation of microparticles.

(t) Polymer particles made of methacryloyloxymethyl acetate

0 8 ml of a 2.48% (w / v) polymer solution (Example 2ab) in xylene / trichloroethylene (90:10) were added to 20 ml of a 0.5% w / w Pluronic® F68 aqueous solution. The mixture was mixed with an Ultra Turax® T25 mixer at 20500 rpm for 1 minute and 30 seconds and lyophilized for 16 hours to give a white powder. Light microscopy showed the formation of microparticles.

u) Polymer particles of N- (2-acetyloxymethoxycarbonyloxypropyl) methacrylamide in ml of 2.54% (w / v) polymer solution (Example 2s) in chloroform were added to 10 ml of 0.5% (w / w) aqueous Pluronic® F68. The mixture was mixed with Ultra

Turax® T25 at 24000 rpm for 50 seconds and lyophilized for 16 hours to give a white powder. Light microscopy showed the formation of microparticles.

v) Polymeric particles made from ethyl 1-methacryloyloxyethyl carbonate

The polymer emulsion was prepared from ethyl 1-methacryloyloxyethyl carbonate, respectively, by polymer emulsion polymerization (Example 2ad). 2.00 g of the emulsion was added to 7.41 g of toluene. The mixture was stirred vigorously for 20 hours and lyophilized for 16 hours to give 0.250 g of a white powder. Light microscopy showed the formation of microparticles.

w) Polymeric particles made of ethyl 1-methacryloyloxyethyl carbonate

The polymer emulsion was prepared from ethyl 1-methacryloxyethyl carbonate, respectively, by polymer emulsion polymerization (Example 2ad). 2.00 g of the emulsion was added to 6.40 g of chloroform. The mixture was stirred vigorously for 20 hours and lyophilized for 16 hours to give 0.250 g of a white powder. Light microscopy showed the formation of microparticles.

(x) Polymer particles of butyl methacryloxyoxymethyl carbonate

The butyl methacrylooyloxymethyl carbonate polymer (Example 2k, 0.45 g) was dissolved in toluene (9 mL). Water (30 mL) containing 0.3 g Pluronic® F68 was added and an emulsion was prepared using a Ystral® homogenizer at 2000 rpm for 30 seconds. This emulsion was lyophilized for 19 hours and light microscopy showed microparticle formation.

(v) HSA coated particles of polymer made from methacryloyloxymethyl benzoate

A polymer prepared from methacryloyloxymethyl benzoate (Example 2r, 0.9 g) was dissolved in toluene (9 mL). A 5% aqueous solution of human blood serum albumin (HSA30 mL) was added and the mixture was homogenized using a Ystral® homogenizer at 20,000 rpm for 30 seconds. The resulting emulsion was lyophilized for 16 hours. Light microscopy showed the formation of microparticles.

(z) Polyoxyethylene coated particles of a polymer made from methacryloyloxymethyl benzoate

The double block copolymer, one block of polymethyl methacrylate (Ma 1000) and the other block of polyoxyethylene (POE, Ma2000) (0.4 g), was dissolved in toluene (9 mL). The polymer prepared from methacryloyloxymethyl benzoate (Example 2r, 0.9 g) was then dissolved in the toluene solution. 30 ml of water and mixture were added

5 was homogenized using a Ystral® homogenizer at 20,000 rpm for 30 seconds. The resulting emulsion was lyophilized for 16 hours to give POE-coated microparticles.

(aa) Polymer particles of methyl methacryloxyoxymethyl carbonate

A polymer made from methyl methacryloyloxymethyl carbonate (Example 20, 0.9 g) was dissolved in toluene (9 mL). A mixture of sodium dodecyl sulfate (0.3 g) and

Pluronic® F68 (0.025 g) in water (35 mL) and the solution was homogenized using a Ystral® homogenizer at 20,000 rpm for 30 seconds. The emulsion was lyophilized for 16 hours and light microscopy showed microparticle formation.

(ab) Polymeric particles of methylene bis (12-hydroxydodecanoate) and 3.6.9-trioxaundecanedioic acid dichloride

The polymer prepared from methylene bis (12-hydroxydodecanoate) and 3,6,9-trioxaundecanedioic acid dichloride (Example 2f, 9.9 g) was dissolved in toluene (9 mL). Water (30 mL) containing Pluronic® F68 (0.3 g) was added and the mixture was homogenized for 30 seconds using a Ystral® homogenizer at 20,000 rpm. The emulsion was lyophilized for 48 hours. Light microscopy showed the formation of microparticles.

(ac) Particles obtained by spray drying the polymer of methacryloyloxymethyl benzoate

0.72 g of the polymer from Example 2r above was dissolved in 60 g of dichloromethane. The solution was dried on a Büchi 190 mini spray dryer. The inlet temperature was 54 ° C, the outlet temperature was measured 40 ° C. Light microscopy showed the formation of microparticles.

ad) Particles obtained by spray drying a polymer made of Pluronic® F68 coated methylene bis (16-hydroxyhexadecanoate) and adipoyl chloride

A mixture of 1.71 g of the polymer from Example 2b above and Pluronic® F68 (50:50) was dissolved in 100 mL of dichloromethane. The solution was dried in a Büchi 190 mini spray dryer.

The inlet temperature was 50 ° C and the outlet temperature was measured at 42 ° C. Light microscopy showed the formation of microparticles.

ae) Coating of particles made of polymer of methylene bis (16-hydroxyhexadecanoate) and adipoyl chloride

The particles prepared according to Example 3c above were redispersed in different aqueous solutions of different coatings and at different concentrations according to Table 5. Light microscopy showed an improved dispersion with a reduced tendency for aggregation.

Table 5

<td>On the cover</td><td>Concentration (% -% by weight)</td>

<td>Tween® 60</td><td> 0,1; 0,5</td>

<td>Sodium hexadecanoate</td><td> 0,1; 0,5</td>

<td>T cetyltrimethylammonium chloride</td><td>o, i; 0.5</td>

<td>Kollidon® 30 (polyvinylpyrrolidone)</td><td> 0,2; 1,0</td>

<td>Cremophor® RH40</td><td> 0,2; 1,0</td>

<td>Pluronic® F68</td><td> 1,0</td>

af) Pluronic® F68-Coated Methyl Methacryloyloxymethyl Carbonate Polymer Particles

The methyl methacrylooyloxymethyl carbonate polymer (Example 2i, 0.9 g) was dissolved in toluene (9 mL). Water (30 mL) containing cetyltrimethylammonium chloride (0.4 g) was added and the mixture was homogenized using

0 Ystral® homogenizers. The emulsion was lyophilized for 24 hours. The resulting particles were washed several times with distilled water to remove the surfactant. After the final wash, the particles were lyophilized for 24 hours.

Example 4. Acoustic Characterization

General procedure

The dry powder of polymer particles prepared according to Example 3 above was redispersed in aqueous solution by shaking on a laboratory shaker for 12-16 hours. Light microscopy showed the formation of particle suspensions. The particles floated easily, as would have been expected for gas containing particles.

The acoustic effect of the above suspensions was found by measuring ultrasonic transmission of aqueous carrier solutions through suspensions of various concentrations (mg / ml) using a 3.5 MHz wide-band transducer. Pure vehicle fluid was used for control and measurements were made in the dilution series, whereby the initial suspension was gradually diluted with the vehicle.

Measurements were taken until the signal had decreased to about 3-5 db / cm. The resulting acoustic performance was at such a level that these products could find application as ultrasonic contrast agents. According to theoretical calculations, solid particles (as opposed to gas ones) of the same size should give acoustic attenuation less than 0.1 db / cm at the same dilution ratio.

(a) Characterization of polymeric particles produced by copolymerization of methylenedimethacrylate and styrene

The particles were made of methylene dimethacrylate and styrene

5 by copolymerization. These particles had a strong effect on acoustic transmission, which decreased with increasing dilution rate, as can be seen in FIG. 1.

(bi) Characterization of different polymer particles

0 The results are summarized in Table 6 and FIGS. 2-9.

Table 6

The acoustic measurements of the particles of Example 3 above. The acoustic results are presented in column 3 as the concentration at which the contrast effect was measured at 8 db / cm, i.e. half the value of the saturated signal. At higher concentrations, the signal intensity increased until saturation was observed.

<td>An example 4</td><td>Particles, Example 3, aqueous solution</td><td>Particle concentration (mg / ml) At 8 db / cm</td><td>Corresponding drawing number</td>

<td>b</td><td>b, 0.9% (w / w in weight) NaCl (aqueous)</td><td> 0,9</td><td> 2</td>

<td>c</td><td>c, 0.9% (w / w in weight) NaCl (aqueous)</td><td> 0,2</td><td> 3</td>

<td>d</td><td>d, 0.9% (w / w in weight) NaCl (aqueous)</td><td> 0,5</td><td> 4</td>

<td>e</td><td>h, water</td><td> 1,0</td><td> 5</td>

<td>f</td><td>i, water</td><td> 0,9</td><td> 6</td>

<td>g</td><td>y, water</td><td> 0,1</td><td> 7</td>

<td>h</td><td>z, water</td><td> 0,5</td><td> 8</td>

<td>i</td><td>ac, HSA / water</td><td> 2,5</td><td> 9</td>

Example 5. In vivo characterization

General procedure

The dry powder of polymer particles described in Example 3 was redispersed in sterile 0.9% (w / w) aqueous NaCl by shaking in a laboratory shaker

12-16 hours. The dispersions were injected into chinchillas and measured by doppler, with the ultrasound probe placed directly on the carotid artery and inferior hollow vein. Particle dispersions were injected into the ear vein. Signal amplitude and duration were recorded. Obtained

The LO signal amplitudes were significant, indicating a strong ultrasound contrast effect of the dispersions in vivo. The long duration of the signal indicates good in vivo stability.

Table 7

Characterization of polymer particles in vivo. Doses are in Rg of particles per kg of body weight. The signal intensity is measured in doppler units [DU].

<td rowspan="2">An example 5</td><td rowspan="2">Particles from Example 3</td><td rowspan="2">Account. (mg / ml)</td><td rowspan="2">Doos (Pg / kg)</td><td colspan="2">Arter</td><td colspan="2">The vein</td>

<td>Hint (DU)</td><td>Duration (s)</td><td>Hint (DU)</td><td>Duration (s)</td>

<td>a</td><td>b</td><td> 4,8</td><td> 320</td><td> 0,5</td><td></td><td></td><td></td>

<td>b (i)</td><td>c</td><td> 4,6</td><td> 307</td><td> 1,9</td><td> 6</td><td> 0,8</td><td></td>

<td>b (ii)</td><td>c</td><td> 4,6</td><td> 767</td><td> 5,6</td><td> 39</td><td> 2,8</td><td></td>

<td>c</td><td>d</td><td> 3,7</td><td> 247</td><td> 0,6</td><td></td><td></td><td></td>

<td>d (i)</td><td>i</td><td> 2,1</td><td> 139</td><td> 1,7</td><td> 5</td><td></td><td></td>

<td>d (ii)</td><td>i</td><td> 2,1</td><td> 347</td><td> 3,2</td><td> 13</td><td> 1,2</td><td> 70</td>

<td>d (iii)</td><td>i</td><td> 2,1</td><td> 693</td><td> 3,1</td><td> 10</td><td> 2,1</td><td> 120</td>

<td>e (i)</td><td>h</td><td> 2,0</td><td> 136</td><td> 0,5</td><td></td><td></td><td></td>

<td>e (ii)</td><td>h</td><td> 2,0</td><td> 340</td><td> 1,0</td><td> 5</td><td></td><td></td>

<td>e (iii)</td><td>h</td><td> 2,0</td><td> 680</td><td> 1,4</td><td> 5</td><td> 0,7</td><td></td>

<td>f (i)</td><td>y</td><td> 2,1</td><td> 140</td><td> 2,8</td><td> 8</td><td> 0,5</td><td></td>

<td>f (ii)</td><td>y</td><td> 2,1</td><td> 350</td><td> 3,7</td><td> 11</td><td> 0,8</td><td> 44</td>

<td>f (iii)</td><td>y</td><td> 2,1</td><td> 700</td><td> 5,3</td><td> 33</td><td> 0,8</td><td> 74</td>

<td>g (i)</td><td>z</td><td> 2,0</td><td> 133</td><td> 1,6</td><td> 7</td><td> 0</td><td></td>

<td>g (ii)</td><td>z</td><td> 2,0</td><td> 333</td><td> 3,6</td><td> 32</td><td> 0,7</td><td> 74</td>

<td>g (y)</td><td>z</td><td> 2,0</td><td> 666</td><td> 5,3</td><td> 79</td><td> 1,6</td><td> 99</td>

<img file="EE03079B1_D0001.tif" />

Example 6. Biodegradation studies

(a) Enzymatic catalytic hydrolysis of methacryloyloxymethyl benzoate polymer

50 mg of the polymer sample of Example 2r as a fine powder and 20 ml of 0.9% aqueous NaCl were added to each of three tubes. 0.1 ml of pig liver esterase 3.2 M (NH4) was also added to one tube.₂SO₄(Sigma E-3128, 250). In a second tube, 0.1 ml of 3.2 M (NEÜESCU) was maintained at pH 8.0 constant in each tube using 0.1 M NaOH using a pH stat (Radiometer). Hydrolysis rates were calculated by recording NaOH consumption. hourly at 37 ° C, hydrolysis of the polymer with esterase was found to be 11 times faster than that used for control (NH4)₂SO₄-s air esterase. In a control experiment with 0.9% NaCl in the polymer, no hydrolysis was observed (see Figure 10).

Table 8

Consumption of 0.1 M NaOH in a tube containing 0.1 mL of polymer and esterase

3.2 M (NH4)₂SO₄with 20 ml of 0.9% NaCl solution

<td>Time (min)</td><td>PH</td><td>0.1 M added Amount of NaOH (ml)</td>

<td> 0</td><td> 8,00</td><td> 0,000</td>

<td> 100</td><td> 8,00</td><td> 0,080</td>

<td> 220</td><td> 8,00</td><td> 0,142</td>

<td> 355</td><td> 8,00</td><td> 0,239</td>

<td> 2670</td><td> 8,00</td><td> 1,101</td>

<td> 2710</td><td> 8,00</td><td> 1,105</td>

Table 9

Consumption of 0.1 M NaOH in control containing 0.1 mL of 3.2 M (NH4)₂SO₄ 20 ml of 0.9% NaCl solution

<td>Time (min)</td><td>pH</td><td>0.1 M added Amount of NaOH (ml)</td>

<td> 0</td><td> 8,00</td><td> 0,000</td>

<td> 120</td><td> 8,00</td><td> 0,012</td>

<td> 240</td><td> 8,00</td><td> 0,012</td>

<td> 4316</td><td> 8,00</td><td> 0,130</td>

Table 10

Consumption of 0.1 M NaOH in control sample containing polymer in 20 ml 0.9% NaCl solution

<td>Time (min)</td><td>pH</td><td>0.1 M added Amount of NaOH (ml)</td>

<td> 0</td><td> 8,4</td><td> 0</td>

<td> 115</td><td> 8,0</td><td> 0,002</td>

<td> 250</td><td> 8,0</td><td> 0,002</td>

<td> 300</td><td> 8,0</td><td> 0,002</td>

<td> 1600</td><td> 8,0</td><td> 0,002</td>

b) Catalytic hydrolysis of the polymer of methylene bis (16-hydroxyhexadecanoate) and adipoyl chloride 10 mg mg of the polymer sample of Example 2b as a fine powder and 20 ml of 0.9% aqueous NaCl solution were added to each of three tubes. 0.1 mL of pig liver esterase 3.2 M (NH 4) was also added to one tube₄)₂SO₄(Sigma E-3128, 250). In another tube 0.1 ml of 3.2 M (NH 4) was added₄)₂SO₄. Using a pH statist (Radiometer), the pH of each tube was kept constant at 8.0 by the addition of 0.1 M NaOH. By recording NaOH consumption, hydrolysis rates were calculated. The hydrolysis of the polymer with esterase was found to be 10 times faster in the assay over 44 hours at 37 [deg.] C. than in the control (NHthSO4 without esterase). In the control experiment with 0.9% NaCl, no hydrolysis was observed (see Figure 11).

Table 11

Consumption of 0.1 M NaOH in a tube containing 0.1 mL of polymer and esterase

3.2 M (NH4)₂SO4 in 20 mL of 0.9% NaCl

<td>Time (min)</td><td>PH</td><td>0.1 M added Amount of NaOH (ml)</td>

<td> 0</td><td> 8,00</td><td> 0,000</td>

<td> 135</td><td> 8,00</td><td> 0,058</td>

<td> 255</td><td> 8,00</td><td> 0,134</td>

<td> 1240</td><td> 8,00</td><td> 0,431</td>

<td> 1705</td><td> 8,00</td><td> 0,602</td>

<td> 2635</td><td> 8,00</td><td> 1,026</td>

<td> 2665</td><td> 8,00</td><td> 1,034</td>

Table 12

Consumption of 0.1 M NaOH in control containing 0.1 mL of 3.2 M (NHt)₂SO4 in 20 ml of 0.9% NaCl solution

<td>Time (min)</td><td>PH</td><td>0.1 M added Amount of NaOH (ml)</td>

<td> 0</td><td> 8,00</td><td> 0,000</td>

<td> 120</td><td> 8,00</td><td> 0,012</td>

<td> 240</td><td> 8,00</td><td> 0,030</td>

<td> 4316</td><td> 8,00</td><td> 0,130</td>

Table 13

Consumption of 0.1 M NaOH in control sample containing polymer in 20 ml 0.9% NaCl solution

<td>Time (min)</td><td>pH</td><td>0.1 M added Amount of NaOH (ml)</td>

<td> 0</td><td> 8,4</td><td> 0,002</td>

<td> 50</td><td> 7,9</td><td> 0,002</td>

<td> 145</td><td> 7,9</td><td> 0,002</td>

<td> 235</td><td> 7,9</td><td> 0,002</td>

References:

1. Folkmann M., Lund FJ, Synthesis 1990, 1159

2. Benneche T., Strande P., Wiggen U., Aeta Chem, Scand. 43, 1988, 74

3. Stroholm J., Kopecek J., Angew. Macromol, Chemie 70, 1978, 109