WO2012010918A2 - Optical devices - Google Patents

Optical devices Download PDF

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Publication number
WO2012010918A2
WO2012010918A2 PCT/HU2011/000077 HU2011000077W WO2012010918A2 WO 2012010918 A2 WO2012010918 A2 WO 2012010918A2 HU 2011000077 W HU2011000077 W HU 2011000077W WO 2012010918 A2 WO2012010918 A2 WO 2012010918A2
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WIPO (PCT)
Prior art keywords
general formula
group
same
alkyl
benzoyloxy
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PCT/HU2011/000077
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French (fr)
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WO2012010918A3 (en
Inventor
József Nagy
Péter ÁGOSTON
Erika Pusztai
Nándor TURKEVI-NAGY
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Medicontur Orvostechnikai Kft.
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Application filed by Medicontur Orvostechnikai Kft. filed Critical Medicontur Orvostechnikai Kft.
Publication of WO2012010918A2 publication Critical patent/WO2012010918A2/en
Publication of WO2012010918A3 publication Critical patent/WO2012010918A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/14—Eye parts, e.g. lenses, corneal implants; Implanting instruments specially adapted therefor; Artificial eyes
    • A61F2/16—Intraocular lenses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/612—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/612—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety
    • C07C69/614—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety of phenylacetic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/78—Benzoic acid esters
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F120/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride, ester, amide, imide or nitrile thereof
    • C08F120/62—Monocarboxylic acids having ten or more carbon atoms; Derivatives thereof
    • C08F120/68—Esters
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
    • C08F220/62—Monocarboxylic acids having ten or more carbon atoms; Derivatives thereof
    • C08F220/68—Esters
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F228/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a bond to sulfur or by a heterocyclic ring containing sulfur
    • C08F228/06—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a bond to sulfur or by a heterocyclic ring containing sulfur by a heterocyclic ring containing sulfur
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
    • C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
    • C08F220/10—Esters
    • C08F220/12—Esters of monohydric alcohols or phenols
    • C08F220/16—Esters of monohydric alcohols or phenols of phenols or of alcohols containing two or more carbon atoms
    • C08F220/18—Esters of monohydric alcohols or phenols of phenols or of alcohols containing two or more carbon atoms with acrylic or methacrylic acids
    • C08F220/1804—C4-(meth)acrylate, e.g. butyl (meth)acrylate, isobutyl (meth)acrylate or tert-butyl (meth)acrylate

Definitions

  • the invention concerns optical devices; especially intraocular lens made from high refractive index polymers prepared from hydroxyalkyl acrylates and methacrylates containing aromatic groups and carbonyl groups.
  • the invention also relates to the starting monomers, the polymers prepared; the application of the same for the manufacture of optical devices and the products derived therefrom.
  • plastic lenses are implanted in the eye, wherein an incision is made and the plastic lens is inserted through the incision.
  • the rigid polymethyl methacrylate lenses previously used have been replaced with soft lenses, which are thin and flexible enough to be inserted into the eye through a smaller incision, in a folded state, where they unfold and take their place.
  • Intraocular lens types and their properties are described in several references. A good overview of the topic is provided by, for example, U.S. Patent No. 7,387,642 or U.S. Patent No. 6,635,732.
  • the refractive power of the lens depends on the shape and the material of which it is made, the higher the refractive index of a material is, the thinner lens can be used to provide the same refractive power. Therefore, said requirements are met by a polymer that is soft and has a high refractive index. However, it is important that the polymer lens material should be biocompatible.
  • U.S. Pat. No. 5,290,892 discloses a solution according to which acrylates and methacrylates containing aromatic groups, especially phenyl ethyl acrylate (PEA) and phenyl ethyl methacrylate (PEMA), were used as a copolymer material for the preparation of IOL lenses.
  • PPA phenyl ethyl acrylate
  • PEMA phenyl ethyl methacrylate
  • the phenyl group provides the high refractive index of about 1.5 to 1.6.
  • the soft IOL lens is always composed of a copolymer prepared from different monomers, especially PEA/PEMA system, i.e. it is a multi-phase system, the composition of which cannot be given with perfect accuracy, which affects the constancy of physical properties as well.
  • the starting acrylate or methacrylate monomer used to prepare the intraocular lens contains both aromatic and carbonyl groups.
  • the invention is based on this recognition.
  • the invention relates to a biocompatible, hydrophobic, soft, high refractive index intraocular lens, wherein an aikane diol derivative is used as a starting monomer, which contains an aryl or aralkyl carboxylic acid ester group on one end, and an acrylic or methacrylic acid ester group to ensure polymerization on the other end.
  • the invention relates to the above starting compounds, the process for the preparation of the same, the polymers prepared therefrom and the use of the compounds for the preparation of optical devices, particularly intraocular lenses.
  • the invention also covers the preparation of intraocular lenses.
  • the common abbreviation (IOL) is used herein to refer to an intraocular lens.
  • the hydrophobic, soft, biocompatible, high- refractive index intraocular lens according to the invention is prepared from aikane diol derivatives containing an aryl or aralkyl carboxylic acid ester on one end and an acrylic or methacrylic acid ester on the other end.
  • Ar represents a substituted aromatic group, preferably a phenyl, biphenylyl, naphthyl, thienyl, furyl, pyrrolyl group, the substituent is one or more hydroxyl, alkyl, alkoxy, alkoxycarbonyl, amino, nitro groups, a halogen atom, wherein the alkyl group may be straight or branched and has 1 to 6 carbon atoms;
  • n is an integer of 2, 3, 4, 5 10;
  • f is an integer of 0, 1 , 2, 3 10;
  • X represents a hydrogen atom or a methyl group
  • Ri , R2, R3, 4 are the same or different and independently represent a hydrogen or halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyl or a carboxyl group.
  • Ar preferably represents an unsubstituted phenyl, thienyl, furyl or pyrrolyl group, particularly preferably a phenyl group, f preferably represents 0, 1 or 2, particularly preferably 0, n is preferably 2, 3 or 4, particularly preferably 2, whereas Ri, R 2 , R3, R4 each preferably represent a hydrogen atom.
  • Preferred compounds are thus the co-(co-phenylalkanoyloxy)alkyl acrylates, the ⁇ -( ⁇ - phenylalkanoyloxy)alkyl methacrylates, the co-[co-(thiophene-2-yl)alkanoyloxy]alkyl acrylates, the (o-[o)-(thiophene-2-yl)alkanoyloxy]alkyl methacrylates, the o-[co-(furan-2-yl)- alkanoyloxy]alkyl acrylates, the (o-[eo-(furan-2-yl)alkanoyloxy]alkyl methacrylates.
  • Furyl derivatives included in the compounds of the general formula (I) are described in U.S. Pat. No. 4,663,41 1. The compounds are used as binders or in the manufacture of coatings.
  • Example 1 1 of WO03/018648 describes a thienyl derivative [2-(thiophene-2-ylcarbonyl)ethyl methacrylate] belonging to compounds of the general formula (I), as the precursor of electrically conductive block copolymers. The said document does not contain any indication as to whether the compounds would be suitable for the preparation of intraocular lenses.
  • WO02/077044 discloses hydrophilic monomers comprising polyether chains, which are different from the hydrophobic compounds according to our invention, for the preparation of contact lenses and IOL lenses.
  • this particular compound and the preparation of this very compound is not presented, since the document discloses a synthesis starting from a polyether (as a first step, oligoether is prepared from 1 ,2-propanediol with propylene oxide, which has about 6 members).
  • Ar' represents a mono- or polysubstituted phenyl, biphenylyl, naphthyl or pyrrolyl group, wherein the substituent is a hydroxyl, alkyl, alkoxy, alkoxycarbonyl, amino, nitro group, a halogen atom, such as chlorine, bromine, fluorine, the alkyl and alkoxy groups have 1 to 6 carbon atoms and may be straight or branched;
  • n' is an integer of 2, 3, 4, 5 10;
  • f is an integer of 0, 1 , 2, 3 10;
  • X' represents a hydrogen atom or a methyl group
  • R]', R 2 ⁇ R3 ' , R4 ' are the same or different and independently represent a hydrogen or halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyl or a carboxyl group.
  • a compound of the general formula Ar-((CRiR 2 ) f -C(0)-0- (CR 3 R4) n -OH, wherein Ar, Ri, R 2 , R 3 , R ⁇ f and n are the same as in the general formula (I), is reacted with a compound of the general formula CH 2 C(X)-C(0)-L; in this latter formula, X is the same as in the general formula (I), L represents a leaving group, for example, a halogen atom, such as chlorine, bromine, fluorine or iodine; the reaction is carried out in the presence of an acid- binding agent, such as triethylamine, in a solvent, for example, an organic solvent, such as diethyl ether, ethyl acetate, acetone or other suitable solvent.
  • an acid- binding agent such as triethylamine
  • the invention also relates to the process for the preparation of compounds of the general formula ( ⁇ ).
  • a further object of the invention is the use of the compounds of the general formula (I) as defined above for the preparation of optical devices such as contact lenses, IOL, especially in the preparation of IOL.
  • the invention also extends to the preparation of polymers from compounds of the general formula (I) as monomers, the prepared polymers and the use thereof for the preparation of optical devices.
  • Monomers of the general formula (I) are suitable on their own for the preparation of homopolymers appropriate for optical devices such as intraocular lenses, but they can also be copolymerized with other known acrylate and methacrylate type monomers in order to prepare two- or three-, possibly multi-component copolymers.
  • Such co-monomers include, but are not limited to the following: methyl acrylate, methyl methacrylate, ethyl acrylate, ethyl methacrylate, butyl acrylate, butyl methacrylate, 2-hydroxyethyl acrylate (HEA), 2-hydroxyethyl methacrylate (HEMA), acrylic acid, methacrylic acid, NN-dimethylacrylamide, N-vinylpyrrolidone, styrene, polyethylene glycol monoacrylate and methacrylate, etc.
  • the invention includes the joint use of compounds of the general formula (I) and such co-monomers for the preparation of optical devices, e.g., contact lenses, IOL, especially IOL.
  • copolymers are prepared from the above monomers with the use of known copolymerizable cross-linking agents. With these, the rheological properties of monomers can be changed.
  • cross-linking agents to be used include, but are not limited to the following: ethylene glycol dimethacrylate, diethylene glycol dimethacrylate, allyl methacrylate, 1 ,3- propanediol dimethacrylate, 1,6-hexanediol dimethacrylate, 1 ,4-butanediol diacrylate and dimethacrylate and the like.
  • cross-linking agents preferably ethylene glycol dimethacrylate (EGDMA), 1 ,4-butanediol diacrylate (BDDA) or dimethacrylate (BDDMA) are used.
  • Organic silicone diacrylate and dimethacrylate compounds may also be used as a cross- linking agent, including the following compounds of the general formulae (Ila, lib),
  • X represents a hydrogen atom or a methyl group
  • n is 1 , 2, 3, 4, 5 or 6 and m is 0 or an integer between 1 and 20, and
  • X represents a hydrogen atom or a methyl group and n is 1, 2, 3, 4, 5 or 6, m is 0 or an integer between 1 and 20.
  • Preferred compounds of the general formula (II) include, but are not limited to the following siloxane-based monomers: l ,3-bis(acryloyloxymethyl)- l , l,3,3-tetramethyldisiloxane, 1 ,3-bis(acryloyloxypropyl)- 1 , 1 ,3,3-tetramethyldisiloxane, ⁇ (Tetramethyldisiloxane- 1 ,3-diyl) bis[propane-3, l-diyloxy(2-hydroxypropane-3,l-diyl)] ⁇ diacrylate, etc.
  • auxiliary materials and additives can also be integrated in copolymers used for intraocular lenses. Examples include:
  • Ultraviolet absorbing compounds such as substituted benzophenones like 2- hyroxybenzophenone, 2-(2-hydroxyphenyl)-2H-benzotriazol, or the photostabilizers mentioned in U.S. Patent No. 4,304,895, or the 2-(2-hydroxy-5-acryloyloxyphenyl>2H-benzotriazol or 2-[3-(2- methylallyl>2-hydroxy-5-methylphenyl]-2H-benzotriazol included in U.S. Patent No. 4,528,3 1 1.
  • Colour filter dyes making the lens yellow by filtering the blue light can also be used as an additive.
  • Such dyes are disclosed, for example, in the following documents: U.S. 2003/0078359, U.S. 6,310,215, U.S. 5,662,707, U.S. 5,543,504, U.S. 5,528,322, and U.S. 5,470,932.
  • the said yellow dyes contain active vinyl groups, which are incorporated in the polymer matrix, so they do not dissolve from the lens, and influence the vision through the yellow colour thereof.
  • Examples of the compounds include, but are not limited to, the following: 4-[4-(allyloxycarbonyl)phenylazo]-l- phenyl-3-methylpyrazol-5-on, l-phenyl-3-methyl-4-(4-vinylphenylazo)pyrazol-5-on, l-phenyl-3- methyl-5-oxopyrazol-4-carbaldehyde (MPCA),NN-bis (methaciyloylethyl)-/?-aminoazobenzene.
  • the polymer or copolymer forming the raw material of the intraocular lens is prepared by a known polymerization process.
  • the invention also involves the process of preparing polymers from new monomers.
  • the invention applies in particular to a polymer preparation process, wherein a tetrafunctional disiloxane of the general formula (Ila) or (lib) is used as a cross-linking agent; substituents in the formulae are the same as above.
  • Polymerization can be carried out by using free radical initiators, such as thermally decomposing peroxides, azides, or it can be carried out with the use of photoinitiators, for example, UV light, inducing radical polymerization.
  • free radical initiators such as thermally decomposing peroxides, azides
  • photoinitiators for example, UV light, inducing radical polymerization.
  • free radical initiators benzophenone peroxide, peroxycarbonates, bis-(4-/err-butylcyclohexyl) peroxycarbonate, azonitriles, for example, azobisisobutyronitrile.
  • Photoinitiators are generally of benzophenone type.
  • the refractive index of the soft IOL polymers according to the invention is around 1.5, the glass transition temperature thereof corresponds to the given use.
  • the materials used are either prepared by us or purchased from commercial sources.
  • BEA 2-(benzoyloxy)ethyl acrylate or 2-(acryloyloxy)ethyl benzoate
  • EGDMA ethylene glycol dimethacrylate or ethane- l ,2-diyl-bis(2-methacrylate)
  • BDDMA butanediol dimethacrylate or butane- l,4-diyl-bis(2-methacr late)
  • FEA 2-(furan-2-ylcarbonyloxy)ethyl acrylate
  • HEM A hydroxyethyl methacrylate
  • SD A 1 ,3 -bis(acry loyloxymethy 1)- 1 , 1 ,3,3 -tetramethyldisiloxane
  • UV ultraviolet light-absorbing compound
  • a 500-ml four-necked flask equipped with a thermometer, a reflux condenser closed with a CaCl 2 tube, a stirrer and a dropping funnel is charged with 90.0 g (0.7965 mol) of potassium acrylate (which was previously prepared from acrylic acid and potassium carbonate), 2.0 g of hydroquinone and 200 ml of dimethylformamide.
  • the reaction mixture is heated until dissolution and then 77.0 g (0.3333 mol) of (ClCH 2 SiMe 2)2 0, i.e. 1.3-bis(chloromethyl)-l,l,3,3,-tetramethyldisiloxane is slowly added thereto.
  • the reaction mixture is boiled for 6 hours and then the KCl salt formed is filtered over a G3 glass filter. 80% of the solvent is distilled off, the residue is dissolved in 300 ml of diethyl ether, washed four times with distilled water and then dried overnight over CaCl 2. The mixture is filtered, the solvent is distilled off and the residue is distilled under vacuum.
  • a 1500-ml four-necked flask equipped with a thermometer, a reflux condenser closed with a CaCl 2 tube, a stirrer and a dropping funnel is charged with 1000 ml of ethyl acetate, 2.0 g of hydroquinone and 250 g (1 mol) of l ,3-bis(hydroxypropyl)-l,l,3,3-tetramethyldisiloxane.
  • the reaction mixture is cooled to 5 °C; 190 g (2.1 mol) of acryloyl chloride is slowly added thereto and then stirred for 6 hours.
  • the crude product obtained is deinhibited as described in reference example 1.
  • a 250-ml four-necked flask equipped with a thermometer, a reflux condenser closed with a CaCl 2 tube, a stirrer and a dropping funnel is charged with 65.2 g (0.2 mol) of allyl glycidyl ether, 0.4 g hydroquinone, 0.5 ml of concentrated sulphuric acid and 28.8 g (0.4 mol) acrylic acid.
  • the reaction mixture is stirred for 6 hours at a temperature between 70-80 °C and then allowed to cool to room temperature. It is deinhibited as described in reference example 1.
  • n d 25 1.464.
  • a 2-liter apparatus equipped with a stirrer, a dropping funnel, a thermometer, a reflux condenser and a calcium chloride tube is charged with 700 ml of ethyl acetate, 202 g (2 mol) of triethylamine, 62 g (1 mol) of ethylene glycol, under nitrogen stream and 285 g (2 mol) of benzoyl chloride is added dropwise thereto for about 1 hour.
  • the reaction mixture is stirred for 4 hours and allowed to stand overnight.
  • 250 ml of 1 N hydrochloric acid is added thereto, stirred for 10 minutes and the phases are separated.
  • the organic phase is washed twice with 1 N hydrochloric acid solution and then washed neutral with water.
  • the organic phase is then dried over anhydrous calcium chloride, filtered, and the solvent is distilled. 264.2 g of the title compound is obtained, yield 97.9%. After crystallization from methanol, a white, solid material is obtained.
  • a one-liter flask equipped with a magnetic stirrer, a calcium chloride tube and a reflux condenser is charged with 264.2 g (0.978 mol) of melted ethylene dibenzoate prepared according to the previous step, and then 270 g (4.35 mol) of ethylene glycol and 2.0 g of potassium hydroxide are added thereto.
  • the reaction mixture is stirred for 16 hours at 160-170 C in oil bath, thus a homogeneous solution is obtained, which is allowed to cool to room temperature, and then the potassium hydroxide is neutralized with carbon dioxide gas.
  • the desired compound is separated by vacuum distillation. 221.0 g of 2-hydroxyethyl benzoate is obtained, yield 66.6%.
  • a 2-liter flask equipped with a stirrer, a thermometer, a nitrogen inlet, a dropping funnel and a reflux condenser is charged with 107.0 g (1.06 mol) of triethylamine, 166.0 g (1 mol) of 2- hydroxyethyl benzoate prepared according to the previous step and 600 ml of ethyl acetate.
  • 95.0 g (1.05 mol) of acryloyl chloride is added dropwise to the reaction mixture while cooling in ice, in the meantime the temperature thereof rises to 10 °C, it is stirred for 5 hours at this temperature, then allowed to stand overnight.
  • n D 20 1.5150.
  • a 2-liter four-necked round-bottom flask equipped with a stirrer, a reflux condenser closed with a CaCl 2 tube, a thermometer and a dropping funnel is charged with 1 12.0 g (1.1 mol) of triethylamine, 1 16.0 g (1 mol) of HEA, 600 ml of ethyl acetate and 0.40 g of hydroquinone stabilizer washed in with ethyl acetate.
  • Moist air is displaced with anhydrous nitrogen stream, and the nitrogen stream is maintained until the end of the reaction. Internal space is cooled to +4 °C with outside cooling in ice.
  • the product is deinhibited as described in reference example 1.
  • the process is the same as described in example 2, with the difference that 51 g (0.5 mol) triethylamine, 65 g (0.5 mol) of 2-hydroxyethyl methacrylate, 0.4 g of hydroquinone, 70.3 g (0, 5 mol) of benzoyl chloride and 500 ml of ethyl acetate is used.
  • a 2-liter four-necked round-bottom flask equipped with a stirrer, a reflux condenser closed with a CaC tube, a thermometer and a dropping funnel is charged with 1 12.0 g ( 1.1 mol) of triethylamine, 116.0 g (1 mol) of HEA, 600 ml of ethyl acetate and 0.40 g of hydroquinone stabilizer washed in with ethyl acetate.
  • Moist air is displaced with anhydrous nitrogen stream, and the nitrogen stream is maintained until the end of the reaction. Internal space is cooled to +4 °C with outside cooling in ice.
  • the product is deinhibited as described above.
  • a 2-liter four-necked round-bottom flask equipped with a stirrer, a reflux condenser closed with a CaCl 2 tube, a thermometer and a dropping funnel is charged with 1 12.0 g ( 1.1 mol) of triethylamine, 144.0 g ( 1 mol) of 4-hydroxybutyl acrylate, 600 ml of ethyl acetate and 0.40 g of hydroquinone stabilizer washed in with ethyl acetate.
  • Moist air is displaced with anhydrous nitrogen stream, and the nitrogen stream is maintained until the end of the reaction. Internal space is cooled to +4 °C with outside cooling in ice.
  • the product is deinhibited as described above.
  • a flask is charged with 196 g of BEA and 3 g of EGDMA. 0.3 g of initiator is added thereto, and the mixture is stirred intensively at 25 °C under a stream of nitrogen gas for 30 minutes. The monomer mixture is filled in an apparatus, then polymerized at 60 °C for 12 hours, and post- polymerized at 90 °C for 24 hours.
  • Discs of 13 to 17 mm in diameter and 2 to 3.5 mm thick are formed from the finished polymer sheets.
  • the finished discs are post-treated at 90 °C for 168 hours, then machining the same, lenses and test specimens are made therefrom.
  • the process is the same as described in example 11 , with the difference that 189 g of BEA, 10 g of EGDMA, and 0.3 g of initiator are used.
  • the process is the same as described in example 11, with the difference that 191 g of BEA, 7.9 g of BDDMA-t and 0.6 g of initiator are used.
  • the process is the same as described in example 11, with the difference that 185.8 g of BEA, 14.2 g of SDA, and 0.14 g of initiator are used.
  • the process is the same as described in example 11, with the difference that 85 g of BEA, 106 g of fractionated BA, 1.4 g of UV and 7 g of EGDMA, as well as 0.28 g of initiator are used.
  • Copolymer preparation from BEA with 56% BA and 3.7% EGDMA The process is the same as described in example 1 1 , with the difference that 78 g of BEA, 1 12.7 g of fractionated BA, 1.4 g of UV-t and 7.4 g of EGDMA, as well as 0.3 g of initiator are used.
  • the process is the same as described in example 11, with the difference that 67.7 g of BEA, 122.2 g of fractionated BA, 1.6 g of UV and 8 g of EGDMA, as well as 0.32 g initiator are used.
  • the process is the same as described in example 11, with the difference that 71 g of BEMA, 1 18.8 g of fractionated BA, 1.56 g of UV and 7.8 g of EGDMA, as well as 0.31 g of initiator are used.
  • Discs of 14 to 16 mm in diameter and 3 mm thick were formed from the polymer materials thus prepared, which served as a raw material for the test specimens and the lenses made therefrom. Refractive index and transmittance were determined for the test specimens prepared. Injectability of lenses made with the same geometry from different materials was examined on the lenses prepared.
  • compositions 1 and 2 The composition, physical constants, workability and elasticity of some polymers according to the invention are provided in Tables 1 and 2 below.
  • Machining means turning under cooled conditions.
  • Elasticity is a characteristic feature of injectability in case of a small wound.
  • EGDMA ethane- 1,2-diyl bis(2-methacrylate) SDA l,3-bis(acryloyloxymethyl)-l , 1 ,3,3-tetramethyldisiloxane
  • BDDMA butane- 1,4-diyl bis(2-methacrylate)
  • INN Radical polymerization initiator
  • the BEA-type material itself is suitable as a raw material for IOL lenses.
  • the synthesized polymers were subjected to toxicological tests in accordance with USP 32 ⁇ 88> and it was found that the compounds were not toxic.

Abstract

The invention relates to optical devices; especially intraocular lens made from high refractive index polymers produced from hydroxyalkyl acrylates and methacrylates containing aromatic groups and carbonyl groups. The invention also relates to the starting monomers, the polymers produced; the application of the same for the manufacture of optical devices and the products derived therefrom.

Description

OPTICAL DEVICES
Field of the Invention
The invention concerns optical devices; especially intraocular lens made from high refractive index polymers prepared from hydroxyalkyl acrylates and methacrylates containing aromatic groups and carbonyl groups. The invention also relates to the starting monomers, the polymers prepared; the application of the same for the manufacture of optical devices and the products derived therefrom.
Background of the Invention
As the average age of mankind increases, more and more elderly people suffer from cataract.
In the course of a surgical procedure to solve the problem plastic lenses are implanted in the eye, wherein an incision is made and the plastic lens is inserted through the incision. To reduce the size of the incision, the rigid polymethyl methacrylate lenses previously used have been replaced with soft lenses, which are thin and flexible enough to be inserted into the eye through a smaller incision, in a folded state, where they unfold and take their place. Intraocular lens types and their properties are described in several references. A good overview of the topic is provided by, for example, U.S. Patent No. 7,387,642 or U.S. Patent No. 6,635,732.
Since the refractive power of the lens depends on the shape and the material of which it is made, the higher the refractive index of a material is, the thinner lens can be used to provide the same refractive power. Therefore, said requirements are met by a polymer that is soft and has a high refractive index. However, it is important that the polymer lens material should be biocompatible.
To meet the above requirements, U.S. Pat. No. 5,290,892 discloses a solution according to which acrylates and methacrylates containing aromatic groups, especially phenyl ethyl acrylate (PEA) and phenyl ethyl methacrylate (PEMA), were used as a copolymer material for the preparation of IOL lenses. In this solution, the phenyl group provides the high refractive index of about 1.5 to 1.6.
However, the use of these materials over a longer period may lead to the slight hydrolysis of PEA and PEMA, and as a result of decomposition, phenyl ethyl alcohol and acrylic polymer are formed. And phenyl ethyl alcohol is a major cytotoxin.
Another problem is that according to the document referred to (and also to other known solutions, e.g. U.S. Patent No. 6,635,732), the soft IOL lens is always composed of a copolymer prepared from different monomers, especially PEA/PEMA system, i.e. it is a multi-phase system, the composition of which cannot be given with perfect accuracy, which affects the constancy of physical properties as well.
There is thus a need for a raw material from which a soft, biocompatible, high refractive index intraocular lens free from the disadvantages of the known solutions can be prepared.
Summary of the Invention
It has been recognized that these problems can be eliminated if the starting acrylate or methacrylate monomer used to prepare the intraocular lens contains both aromatic and carbonyl groups. The invention is based on this recognition.
The invention relates to a biocompatible, hydrophobic, soft, high refractive index intraocular lens, wherein an aikane diol derivative is used as a starting monomer, which contains an aryl or aralkyl carboxylic acid ester group on one end, and an acrylic or methacrylic acid ester group to ensure polymerization on the other end.
The invention relates to the above starting compounds, the process for the preparation of the same, the polymers prepared therefrom and the use of the compounds for the preparation of optical devices, particularly intraocular lenses.
The invention also covers the preparation of intraocular lenses. The common abbreviation (IOL) is used herein to refer to an intraocular lens.
Detailed Description of the Invention
The hydrophobic, soft, biocompatible, high- refractive index intraocular lens according to the invention is prepared from aikane diol derivatives containing an aryl or aralkyl carboxylic acid ester on one end and an acrylic or methacrylic acid ester on the other end.
These monomer compounds are preferably represented by the formula (I),
Figure imgf000003_0001
wherein
Ar represents a substituted aromatic group, preferably a phenyl, biphenylyl, naphthyl, thienyl, furyl, pyrrolyl group, the substituent is one or more hydroxyl, alkyl, alkoxy, alkoxycarbonyl, amino, nitro groups, a halogen atom, wherein the alkyl group may be straight or branched and has 1 to 6 carbon atoms;
n is an integer of 2, 3, 4, 5 10;
f is an integer of 0, 1 , 2, 3 10;
with the proviso that n + f < 15
X represents a hydrogen atom or a methyl group,
Ri , R2, R3, 4 are the same or different and independently represent a hydrogen or halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyl or a carboxyl group.
Compounds of the general formula (I) are therefore oo-(o)-arylalkanoyloxy)alkyl acrylates and (O-(co-arylalkanoyloxy)alkyl methacrylates.
Ar preferably represents an unsubstituted phenyl, thienyl, furyl or pyrrolyl group, particularly preferably a phenyl group, f preferably represents 0, 1 or 2, particularly preferably 0, n is preferably 2, 3 or 4, particularly preferably 2, whereas Ri, R2, R3, R4 each preferably represent a hydrogen atom.
Preferred compounds are thus the co-(co-phenylalkanoyloxy)alkyl acrylates, the ω-(ω- phenylalkanoyloxy)alkyl methacrylates, the co-[co-(thiophene-2-yl)alkanoyloxy]alkyl acrylates, the (o-[o)-(thiophene-2-yl)alkanoyloxy]alkyl methacrylates, the o-[co-(furan-2-yl)- alkanoyloxy]alkyl acrylates, the (o-[eo-(furan-2-yl)alkanoyloxy]alkyl methacrylates.
Some preferred compounds of the general formula (I) are mentioned herein by name, too: 2-
(benzoyloxy)ethyl acrylate, 2-(benzoyloxy)ethyl methacrylate, 3-(benzoyloxy)propyl acrylate, 3- (benzoyloxy)propyl methacrylate, 4-(benzoyloxy)butyl acrylate, 4-(benzoyloxy)butyl methacrylate, 2-(phenylacetoxy)ethyl acrylate, 2-(phenylacetoxy)ethyl methacrylate, 2-(3- phenylpropanoyloxy)- ethyl acrylate, 2-(3-phenylpropanoyloxy)ethyl methacrylate, 2-(4-phenylbutanoyloxy)ethyl acrylate, 2-(4-phenylbutanoyloxy)ethyl methacrylate, 2-(thiophene-2-ylcarbonyloxy)elhyl acrylate, 2- (thiophene-2-ylcarbonyloxy)ethyl methacrylate, 2-(furan-2-ylcarbonyloxy)ethyl acrylate, 2-(furan- 2-ylcarbonyloxy)e1hyl methacrylate.
Furyl derivatives included in the compounds of the general formula (I) are described in U.S. Pat. No. 4,663,41 1. The compounds are used as binders or in the manufacture of coatings. Example 1 1 of WO03/018648 describes a thienyl derivative [2-(thiophene-2-ylcarbonyl)ethyl methacrylate] belonging to compounds of the general formula (I), as the precursor of electrically conductive block copolymers. The said document does not contain any indication as to whether the compounds would be suitable for the preparation of intraocular lenses.
Other compounds of the general formula (I) are new; the preparation and identification thereof has not been described, therefore the invention in one respect relates to these new compounds defined by the general formula (Γ). Note that the names of 2-(benzoyloxy)ethyl acrylate and 2-(benzoyloxy)ethyl methacrylate appear in several documents in the long list of starting compounds to be used for the preparation of polymers (see, for example, documents U.S. 20040260318A1 or WO2005051452A2), and the name of 2-(benzoyloxy)ethyl acrylate is listed among active diluents in U.S. Pat. No. 5,523,152, but the preparation thereof is not described, and data suitable for the identification thereof is not disclosed either. In addition, WO02/077044 discloses hydrophilic monomers comprising polyether chains, which are different from the hydrophobic compounds according to our invention, for the preparation of contact lenses and IOL lenses. In the said document, the end value of 1 for m in the general formula for monomers, in principle, would result in a compound that corresponds to the case of the above general formula (I) wherein n = 2,
Figure imgf000005_0001
f=0 and Ar=phenyl group. However, this particular compound and the preparation of this very compound is not presented, since the document discloses a synthesis starting from a polyether (as a first step, oligoether is prepared from 1 ,2-propanediol with propylene oxide, which has about 6 members).
In view of the above, the invention relates to compounds of the general formula (Γ) as new compounds:
Figure imgf000005_0003
Figure imgf000005_0004
Figure imgf000005_0002
where Ar' represents a mono- or polysubstituted phenyl, biphenylyl, naphthyl or pyrrolyl group, wherein the substituent is a hydroxyl, alkyl, alkoxy, alkoxycarbonyl, amino, nitro group, a halogen atom, such as chlorine, bromine, fluorine, the alkyl and alkoxy groups have 1 to 6 carbon atoms and may be straight or branched;
n' is an integer of 2, 3, 4, 5 10;
f is an integer of 0, 1 , 2, 3 10;
with the proviso that n+f <1 5
X' represents a hydrogen atom or a methyl group,
R]', R2\ R3 ' , R4 ' are the same or different and independently represent a hydrogen or halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyl or a carboxyl group.
Compounds of the general formula (I) can be prepared with the application of organic synthetic processes, from starting compounds, which are either commercially available or can be prepared by a method described in the literature or known to the person skilled in the art.
One process variant [process a)] is illustrated on the following reaction scheme 1 :
Reaction Scheme 1
acid-binding agent
Ar-(CR,R2)rC(0)-0-(CR3R4)n-OH + CH2=C(X)-C(0)-L - - ->
solvent
Ar-[(CRiR2)]rC(0)-0-[(CR3R4)]n-0-C(0)-C(X)=CH2 + HL
According to process variant a), a compound of the general formula Ar-((CRiR2)f-C(0)-0- (CR3R4)n-OH, wherein Ar, Ri, R2, R3, R^ f and n are the same as in the general formula (I), is reacted with a compound of the general formula CH2=C(X)-C(0)-L; in this latter formula, X is the same as in the general formula (I), L represents a leaving group, for example, a halogen atom, such as chlorine, bromine, fluorine or iodine; the reaction is carried out in the presence of an acid- binding agent, such as triethylamine, in a solvent, for example, an organic solvent, such as diethyl ether, ethyl acetate, acetone or other suitable solvent.
The other process variant [process b)] is shown in the following Reaction Scheme 2:
Reaction Scheme 2
acid-binding agent
Figure imgf000006_0001
solvent
Ar-[(CR1R2)f]rC(0)-0-[(CR3R4]n-0-C(0)-C(X)=CH2 + HL According to process variant b), a compound of the general formula Ar-(CRiR )rC(0)-L where Ar, Rj, R2 and f are the same as in the general formula (I), L represents a leaving group, for example, a halogen atom, such as chlorine, bromine, fluorine or iodine, is reacted with a compound of the general formula
Figure imgf000006_0002
wherein X, R3, R4 and n are the same as in the general formula (I). The reaction is carried out under the reaction conditions given for the above process a).
The invention also relates to the process for the preparation of compounds of the general formula (Γ). The processes are carried out as described above, starting from the appropriate compounds of the general formula Ar'-((CR R2')r-C(0)-0-(CR3' R4')n-OH and CH2=C(X')- C(0)-L, or compounds of the general formula Ar'-CCR^R^r-CCOyL and CH2=C(X')-C(0)-0- (CR3'R4')n-OH, respectively, wherein the substituents are the same as in the general formula (Γ).
A further object of the invention is the use of the compounds of the general formula (I) as defined above for the preparation of optical devices such as contact lenses, IOL, especially in the preparation of IOL.
The invention also extends to the preparation of polymers from compounds of the general formula (I) as monomers, the prepared polymers and the use thereof for the preparation of optical devices.
Monomers of the general formula (I) are suitable on their own for the preparation of homopolymers appropriate for optical devices such as intraocular lenses, but they can also be copolymerized with other known acrylate and methacrylate type monomers in order to prepare two- or three-, possibly multi-component copolymers. Such co-monomers include, but are not limited to the following: methyl acrylate, methyl methacrylate, ethyl acrylate, ethyl methacrylate, butyl acrylate, butyl methacrylate, 2-hydroxyethyl acrylate (HEA), 2-hydroxyethyl methacrylate (HEMA), acrylic acid, methacrylic acid, NN-dimethylacrylamide, N-vinylpyrrolidone, styrene, polyethylene glycol monoacrylate and methacrylate, etc. The invention includes the joint use of compounds of the general formula (I) and such co-monomers for the preparation of optical devices, e.g., contact lenses, IOL, especially IOL. To prepare optical devices, copolymers are prepared from the above monomers with the use of known copolymerizable cross-linking agents. With these, the rheological properties of monomers can be changed. Examples of cross-linking agents to be used include, but are not limited to the following: ethylene glycol dimethacrylate, diethylene glycol dimethacrylate, allyl methacrylate, 1 ,3- propanediol dimethacrylate, 1,6-hexanediol dimethacrylate, 1 ,4-butanediol diacrylate and dimethacrylate and the like. Of these cross-linking agents, preferably ethylene glycol dimethacrylate (EGDMA), 1 ,4-butanediol diacrylate (BDDA) or dimethacrylate (BDDMA) are used.
Organic silicone diacrylate and dimethacrylate compounds may also be used as a cross- linking agent, including the following compounds of the general formulae (Ila, lib),
Figure imgf000007_0001
(Ila)
wherein X represents a hydrogen atom or a methyl group, n is 1 , 2, 3, 4, 5 or 6 and m is 0 or an integer between 1 and 20, and
Figure imgf000007_0002
(lib)
wherein X represents a hydrogen atom or a methyl group and n is 1, 2, 3, 4, 5 or 6, m is 0 or an integer between 1 and 20.
Preferred compounds of the general formula (II) include, but are not limited to the following siloxane-based monomers: l ,3-bis(acryloyloxymethyl)- l , l,3,3-tetramethyldisiloxane, 1 ,3-bis(acryloyloxypropyl)- 1 , 1 ,3,3-tetramethyldisiloxane, {(Tetramethyldisiloxane- 1 ,3-diyl) bis[propane-3, l-diyloxy(2-hydroxypropane-3,l-diyl)]}diacrylate, etc.
Known auxiliary materials and additives can also be integrated in copolymers used for intraocular lenses. Examples include:
Ultraviolet absorbing compounds, such as substituted benzophenones like 2- hyroxybenzophenone, 2-(2-hydroxyphenyl)-2H-benzotriazol, or the photostabilizers mentioned in U.S. Patent No. 4,304,895, or the 2-(2-hydroxy-5-acryloyloxyphenyl>2H-benzotriazol or 2-[3-(2- methylallyl>2-hydroxy-5-methylphenyl]-2H-benzotriazol included in U.S. Patent No. 4,528,3 1 1.
However, since monomers used according to the invention contain an aromatic group such as a phenyl group, and the UV absorption thereof is at the same place as that of said photoabsorbents, this additive may as well be omitted. This property represents one of the advantages of the invention.
Colour filter dyes making the lens yellow by filtering the blue light can also be used as an additive. Such dyes are disclosed, for example, in the following documents: U.S. 2003/0078359, U.S. 6,310,215, U.S. 5,662,707, U.S. 5,543,504, U.S. 5,528,322, and U.S. 5,470,932. The said yellow dyes contain active vinyl groups, which are incorporated in the polymer matrix, so they do not dissolve from the lens, and influence the vision through the yellow colour thereof. Examples of the compounds include, but are not limited to, the following: 4-[4-(allyloxycarbonyl)phenylazo]-l- phenyl-3-methylpyrazol-5-on, l-phenyl-3-methyl-4-(4-vinylphenylazo)pyrazol-5-on, l-phenyl-3- methyl-5-oxopyrazol-4-carbaldehyde (MPCA),NN-bis (methaciyloylethyl)-/?-aminoazobenzene.
The polymer or copolymer forming the raw material of the intraocular lens is prepared by a known polymerization process. The invention also involves the process of preparing polymers from new monomers. The invention applies in particular to a polymer preparation process, wherein a tetrafunctional disiloxane of the general formula (Ila) or (lib) is used as a cross-linking agent; substituents in the formulae are the same as above.
Polymerization can be carried out by using free radical initiators, such as thermally decomposing peroxides, azides, or it can be carried out with the use of photoinitiators, for example, UV light, inducing radical polymerization.
The following can be mentioned as examples of free radical initiators: benzophenone peroxide, peroxycarbonates, bis-(4-/err-butylcyclohexyl) peroxycarbonate, azonitriles, for example, azobisisobutyronitrile.
Photoinitiators are generally of benzophenone type.
The refractive index of the soft IOL polymers according to the invention is around 1.5, the glass transition temperature thereof corresponds to the given use.
In what follows, the invention is illustrated by examples, which are, however, not intended to restrict the scope of this invention.
The materials used are either prepared by ourselves or purchased from commercial sources.
The following abbreviations are used in the examples:
DBG: ethylene dibenzoate
MB: 2-hydroxy ethyl benzoate
BEA: 2-(benzoyloxy)ethyl acrylate or 2-(acryloyloxy)ethyl benzoate
BEMA: 2-(benzoyloxy)ethyl methacrylate
BA: butyl acrylate
EGDMA: ethylene glycol dimethacrylate or ethane- l ,2-diyl-bis(2-methacrylate) BDDMA: butanediol dimethacrylate or butane- l,4-diyl-bis(2-methacr late) FEA: 2-(furan-2-ylcarbonyloxy)ethyl acrylate
HEA: hydroxyethyl acrylate
HEM A: hydroxyethyl methacrylate
DMF: dimethylformamide
TEA: 2-(thiophene-2-ylcarbonyloxy)ethyl acrylate
SD A: 1 ,3 -bis(acry loyloxymethy 1)- 1 , 1 ,3,3 -tetramethyldisiloxane
UV: ultraviolet light-absorbing compound
INN: radical polymerization initiator Reference example 1
Preparation of l,3-bis(acryIoyloxymethyl)-l,l53,3-tetramethyldisiloxane (SDA)
Compound of the general formula (Ila), wherein X = H, m = 0, n = 1
Figure imgf000009_0001
A 500-ml four-necked flask equipped with a thermometer, a reflux condenser closed with a CaCl2 tube, a stirrer and a dropping funnel is charged with 90.0 g (0.7965 mol) of potassium acrylate (which was previously prepared from acrylic acid and potassium carbonate), 2.0 g of hydroquinone and 200 ml of dimethylformamide. The reaction mixture is heated until dissolution and then 77.0 g (0.3333 mol) of (ClCH2SiMe2)20, i.e. 1.3-bis(chloromethyl)-l,l,3,3,-tetramethyldisiloxane is slowly added thereto. The reaction mixture is boiled for 6 hours and then the KCl salt formed is filtered over a G3 glass filter. 80% of the solvent is distilled off, the residue is dissolved in 300 ml of diethyl ether, washed four times with distilled water and then dried overnight over CaCl2. The mixture is filtered, the solvent is distilled off and the residue is distilled under vacuum.
Deinhibiting (hereinafter similarly): the crude product obtained is extracted using diethyl ether, washed with In aqueous NaOH solution and then washed neutral with water. It is dried over CaCl2i filtered, finally the solvent is distilled off.
m=39.9 g of desired compound is obtained. Yield: 40.0%
nd 20= 1.4400. Reference example 2
Preparation of l,3-bis(acryloy[oxypropyl)-1 ,3,3-tetramethyldisiloxane
Compound of the general formula(IIa), wherein X = H, m = 0, n = 3
Figure imgf000010_0001
Figure imgf000010_0002
A 1500-ml four-necked flask equipped with a thermometer, a reflux condenser closed with a CaCl2 tube, a stirrer and a dropping funnel is charged with 1000 ml of ethyl acetate, 2.0 g of hydroquinone and 250 g (1 mol) of l ,3-bis(hydroxypropyl)-l,l,3,3-tetramethyldisiloxane. The reaction mixture is cooled to 5 °C; 190 g (2.1 mol) of acryloyl chloride is slowly added thereto and then stirred for 6 hours. 500 ml of IN hydrochloric acid is added thereto, the phases are separated, and the organic phase is washed twice with 1 n hydrochloric acid, five times with distilled water, and then dried over calcium chloride overnight. Then the mixture is distilled under vacuum (0.6 mmHg). Bp: 148 °C/2 mmHg.
The crude product obtained is deinhibited as described in reference example 1.
It gives 25.0 g of the product, yield 65.0%.
nd 25=1.4455.
Reference example 3
{(Tetramethyldisiloxane-l,3-diyl)bis[propane-3,l-diyloxy(2-hydroxypropane-3,l-diyl)]} diacrylate
In formula (lib), X = H, m = 0, n = 3
Figure imgf000011_0001
Figure imgf000011_0002
A 250-ml four-necked flask equipped with a thermometer, a reflux condenser closed with a CaCl2 tube, a stirrer and a dropping funnel is charged with 65.2 g (0.2 mol) of allyl glycidyl ether, 0.4 g hydroquinone, 0.5 ml of concentrated sulphuric acid and 28.8 g (0.4 mol) acrylic acid. The reaction mixture is stirred for 6 hours at a temperature between 70-80 °C and then allowed to cool to room temperature. It is deinhibited as described in reference example 1.
Product: m = 38.6 g, yield 76.3%.
nd 25= 1.464.
Example 1: 2-Benzoyloxyethyl aery late (BEA)
1.1 Ethylene dibenzoate (DBG)
Reaction equatio
Figure imgf000011_0003
Figure imgf000011_0004
A 2-liter apparatus equipped with a stirrer, a dropping funnel, a thermometer, a reflux condenser and a calcium chloride tube is charged with 700 ml of ethyl acetate, 202 g (2 mol) of triethylamine, 62 g (1 mol) of ethylene glycol, under nitrogen stream and 285 g (2 mol) of benzoyl chloride is added dropwise thereto for about 1 hour. The reaction mixture is stirred for 4 hours and allowed to stand overnight. Then 250 ml of 1 N hydrochloric acid is added thereto, stirred for 10 minutes and the phases are separated. The organic phase is washed twice with 1 N hydrochloric acid solution and then washed neutral with water. The organic phase is then dried over anhydrous calcium chloride, filtered, and the solvent is distilled. 264.2 g of the title compound is obtained, yield 97.9%. After crystallization from methanol, a white, solid material is obtained.
Mp: 62 °C.
1.2. 2-Hydroxyethyl bcnzoate (MB)
Reaction equation:
Figure imgf000012_0001
Figure imgf000012_0002
A one-liter flask equipped with a magnetic stirrer, a calcium chloride tube and a reflux condenser is charged with 264.2 g (0.978 mol) of melted ethylene dibenzoate prepared according to the previous step, and then 270 g (4.35 mol) of ethylene glycol and 2.0 g of potassium hydroxide are added thereto. The reaction mixture is stirred for 16 hours at 160-170 C in oil bath, thus a homogeneous solution is obtained, which is allowed to cool to room temperature, and then the potassium hydroxide is neutralized with carbon dioxide gas. The desired compound is separated by vacuum distillation. 221.0 g of 2-hydroxyethyl benzoate is obtained, yield 66.6%.
Bp: 117 °C/0.4 mmHg.
1.3. 2-(Benzoyloxy)ethyl acrylate (BE A)
Reaction equation: process a):
Figure imgf000012_0003
Figure imgf000012_0004
A 2-liter flask equipped with a stirrer, a thermometer, a nitrogen inlet, a dropping funnel and a reflux condenser is charged with 107.0 g (1.06 mol) of triethylamine, 166.0 g (1 mol) of 2- hydroxyethyl benzoate prepared according to the previous step and 600 ml of ethyl acetate. 95.0 g (1.05 mol) of acryloyl chloride is added dropwise to the reaction mixture while cooling in ice, in the meantime the temperature thereof rises to 10 °C, it is stirred for 5 hours at this temperature, then allowed to stand overnight. Then 500 ml of In hydrochloric acid is added to the reaction mixture, the phases are separated, the organic phase is washed three times with In hydrochloric acid, and then four times with distilled water. The organic phase is dried over anhydrous calcium chloride, filtered, and the solvent is distilled off under vacuum. The residue is fractionated under vacuum. The boiling point of the desired product is 122 C / 0.4 mmHg. 190.0 g of title compound is obtained (yield: 80.5%), which is dissolved in 400 ml of diethyl ether, the solution is washed three times with 1 N sodium hydroxide and then three times with water. 0.04 g of hydroquinone is added thereto, and then it is dried over anhydrous calcium chloride, filtered, and the solvent is distilled off. 170.0 g of desired compound is obtained, yield 72.0%.
nD 20= 1.5150.
Example 2: 2-(Benzoyloxy)ethyl acrylate (BEA)
Reaction equation: process b):
Figure imgf000013_0001
Figure imgf000013_0002
A 2-liter four-necked round-bottom flask equipped with a stirrer, a reflux condenser closed with a CaCl2 tube, a thermometer and a dropping funnel is charged with 1 12.0 g (1.1 mol) of triethylamine, 1 16.0 g (1 mol) of HEA, 600 ml of ethyl acetate and 0.40 g of hydroquinone stabilizer washed in with ethyl acetate. Moist air is displaced with anhydrous nitrogen stream, and the nitrogen stream is maintained until the end of the reaction. Internal space is cooled to +4 °C with outside cooling in ice. Then 155.0 g (1.1 mol) of benzoyl chloride is slowly added dropwise thereto, while paying attention not to allow the temperature to rise above +8 °C. When addition is complete, the reaction mixture is stirred for 4 hours at room temperature. Then 500 ml of In HCl solution is poured thereto while stirring, wherein the resulting triethylammonium chloride precipitation dissolves. The phases are separated; the organic phase is washed twice with 500 ml of In HCl and then washed neutral four times with salt water. After separation, 1.0 g of hydroquinone is added to the organic phase, which is then dried overnight over calcium chloride. The ethyl acetate solution is filtered, and the solvent is distilled off under vacuum. The crude residue is distilled at a pressure of 0.4 mmHg. Bp: 125-130 ° C.
The product is deinhibited as described in reference example 1.
It gives 164.5 g of product. Yield: 75.0%.
Refractive index nD 20= 1.5150
Ή-NMR: τ 4.558-4.454 (CH2.CH2), 6.448-641, 6.173-6.117, 5.837-5.816 (CH2=CH), 7.55-7.38, 8.067-8.034 (C6H5) Example 3: 2-fBenzoyloxy)ethyl melhacrylate ΓΒΕΜΑ)
process b)
The process is the same as described in example 2, with the difference that 51 g (0.5 mol) triethylamine, 65 g (0.5 mol) of 2-hydroxyethyl methacrylate, 0.4 g of hydroquinone, 70.3 g (0, 5 mol) of benzoyl chloride and 500 ml of ethyl acetate is used.
It gives 77.3 g of product. Yield: 66.1%.
Bp: 1 18-123 °C/0.4 mmHg
nD 26= 1.5089.
Example 4: 2-(Thiophen-2-ylcarbonyloxy)ethyl acrylate (TEA")
The process is the same as described in example 2, with the difference that instead of benzoyl chloride, 160.7 g (1.1 mol) of thiophene-carbonyl chloride is used. Bp: 135 °C/0.8 mmHg.
It gives 33.5 g of desired product. Yield: 74.4%.
nD 20= 1.531
1 H-NMR: τ 4.498-4.241 (CH2.CH2), 6.406-6.371, 6.13-6.074, 5.81-5-792 (CH2=CH), 7.056-7.038, 7.534-7.524, 7.676-7.758 (C4H4S)
Example 5: 2-(Furan-2-ylcarbonyloxy)ethvI acrylate (FEA)
The process is the same as described in example 2, with the difference that instead of benzoyl chloride, 143.5 g (1.1 mol) of furoyl chloride is used. Bp: 127 0 C / 0.1 mmHg.
It gives 27.0 g of product. Yield: 64.3%.
Refractive index nD 20= 1.498
1 H-NMR: τ 4.484-4.388 (CH2.CH2), 6.448-6.334, 6.096-6.041 , 5.769-5.766 (CH2=CH), 7.532-6.33 (C4H4O)
Example 6: (2-Phenylacetoxy)ethyl acrylate (PAEA) Reaction equation: process b):
Figure imgf000015_0001
A 2-liter four-necked round-bottom flask equipped with a stirrer, a reflux condenser closed with a CaC tube, a thermometer and a dropping funnel is charged with 1 12.0 g ( 1.1 mol) of triethylamine, 116.0 g (1 mol) of HEA, 600 ml of ethyl acetate and 0.40 g of hydroquinone stabilizer washed in with ethyl acetate. Moist air is displaced with anhydrous nitrogen stream, and the nitrogen stream is maintained until the end of the reaction. Internal space is cooled to +4 °C with outside cooling in ice. Then 170.0 g (1.1 mol) of 2-phenylacetyl chloride is slowly added dropwise thereto, while paying attention not to allow the temperature to rise above +8 °C. When addition is complete, the reaction mixture is stirred for 4 hours at room temperature. Then 500 ml of In HCI solution is poured thereto while stirring, wherein the resulting triethylammonium chloride precipitation dissolves. The phases are separated; the organic phase is washed twice with 500 ml of In HCI and then washed neutral four times with salt water. After separation, 1.0 g of hydroquinone is added to the organic phase, which is then dried overnight over calcium chloride. The ethyl acetate solution is filtered, and the solvent is distilled off under vacuum. The crude residue is distilled at a pressure of 0.2 mmHg. Bp: 118-120 ° C.
The product is deinhibited as described above.
It gives 42.0 g of the product. Yield: 18.0%..
Refractive index nD2o= 1.507
Example 7: 2-(3-PhenylpropanoyloxY)ethyl acrylate (PPEA)
Reaction equation: process b):
Figure imgf000016_0001
Figure imgf000016_0002
The process is the same as described in example 6, with the difference that instead of 2- phenylacethyl chloride, 184.8 g (1.1 mol) of 3-phenylpropionyl chloride is used. Bp: 132-133 ° C / 0.2 mrriHg.
It gives 56.0 g of product. Yield: 22.6%.
Refractive index nD2o= 1.505
Example 8: 4-f Acryloyloxy)bu yl benzoate (BBA)
Reaction: process b):
Figure imgf000016_0003
Figure imgf000016_0004
A 2-liter four-necked round-bottom flask equipped with a stirrer, a reflux condenser closed with a CaCl2 tube, a thermometer and a dropping funnel is charged with 1 12.0 g ( 1.1 mol) of triethylamine, 144.0 g ( 1 mol) of 4-hydroxybutyl acrylate, 600 ml of ethyl acetate and 0.40 g of hydroquinone stabilizer washed in with ethyl acetate. Moist air is displaced with anhydrous nitrogen stream, and the nitrogen stream is maintained until the end of the reaction. Internal space is cooled to +4 °C with outside cooling in ice. Then 155.0 g (1.1 mol) of benzoyl chloride is slowly added dropwise thereto, while paying attention not to allow the temperature to rise above +8 °C. When addition is complete, the reaction mixture is stirred for 4 hours at room temperature. Then 500 ml of I n HCI solution is poured thereto while stirring, wherein the resulting triethylammonium chloride precipitation dissolves. The phases are separated; the organic phase is washed twice with 500 ml of In HCI and then washed neutral four times with salt water. After separation, 1.0 g of hydroquinone is added to the organic phase, which is then dried overnight over calcium chloride. The ethyl acetate solution is filtered, and the solvent is distilled off under vacuum. The crude residue is distilled at a pressure of 0.2 mmHg. Bp: 134-135 0 C.
The product is deinhibited as described above.
98.5 g of product obtained. Yield: 39.7%.
Refractive index nD2o= 1 -508
Example 9: 4-(2-Phenylacetoxy) buty acrylate ( ABA)
Re
Figure imgf000017_0001
Figure imgf000017_0002
The process is the same as described in example 8, with the difference that instead of benzoyl chloride, 170.0 g (1.1 mol) of 2-phenylacetyl chloride is used. Bp: 129 °C/0.4 mmHg.
It gives 49.3 g of product. Yield: 18.8%.
Refractive index nD2o= 1.500 Example 10: 4-(3-Phenylpropanoyloxy)butyl acrylate CPPBA)
Reaction equation: process b):
Figure imgf000017_0003
Figure imgf000017_0004
The process is the same as described in example 8, with the difference that instead of benzoyl chloride, 184.8 g (1.1 mol) of 3-phenylpropyonyl chloride is used. Bp: 146 °C/0.3 mmHg.
It gives 75.25 g of product. Yield: 27.26%.
Refractive index nD20= 1.500 Preparation of polymers:
Example 11
Copolymer preparation from BEA with 1.5% EGDMA
A flask is charged with 196 g of BEA and 3 g of EGDMA. 0.3 g of initiator is added thereto, and the mixture is stirred intensively at 25 °C under a stream of nitrogen gas for 30 minutes. The monomer mixture is filled in an apparatus, then polymerized at 60 °C for 12 hours, and post- polymerized at 90 °C for 24 hours.
approximately 200 g of polymer is obtained, the physical constants thereof: colourless, transparent, solid polymer Tg ~ -10 - 25 0 C
Discs of 13 to 17 mm in diameter and 2 to 3.5 mm thick are formed from the finished polymer sheets. The finished discs are post-treated at 90 °C for 168 hours, then machining the same, lenses and test specimens are made therefrom.
Example 12
Copolymer preparation from BEA with 5% EGDMA
The process is the same as described in example 11 , with the difference that 189 g of BEA, 10 g of EGDMA, and 0.3 g of initiator are used.
Example 13
The process is the same as described in example 11, with the difference that 191 g of BEA, 7.9 g of BDDMA-t and 0.6 g of initiator are used.
Example 14
Copolymer preparation from BEA with 7% SDA
The process is the same as described in example 11, with the difference that 185.8 g of BEA, 14.2 g of SDA, and 0.14 g of initiator are used.
Example 15
Copolymer preparation from BEA with 53% BA and 3.5% EGDMA
The process is the same as described in example 11, with the difference that 85 g of BEA, 106 g of fractionated BA, 1.4 g of UV and 7 g of EGDMA, as well as 0.28 g of initiator are used.
Example 16
Copolymer preparation from BEA with 56% BA and 3.7% EGDMA The process is the same as described in example 1 1 , with the difference that 78 g of BEA, 1 12.7 g of fractionated BA, 1.4 g of UV-t and 7.4 g of EGDMA, as well as 0.3 g of initiator are used.
Example 17
Copolymer preparation from BEA with 61% BA and 4% EGDMA
The process is the same as described in example 11, with the difference that 67.7 g of BEA, 122.2 g of fractionated BA, 1.6 g of UV and 8 g of EGDMA, as well as 0.32 g initiator are used.
Example 18
Copolymer preparation from BEA with 59% BA and 3.9% EGDMA
The process is the same as described in example 11, with the difference that 71 g of BEMA, 1 18.8 g of fractionated BA, 1.56 g of UV and 7.8 g of EGDMA, as well as 0.31 g of initiator are used.
Other polymers shown in Tables 1 and 2 are prepared in the same way.
Discs of 14 to 16 mm in diameter and 3 mm thick were formed from the polymer materials thus prepared, which served as a raw material for the test specimens and the lenses made therefrom. Refractive index and transmittance were determined for the test specimens prepared. Injectability of lenses made with the same geometry from different materials was examined on the lenses prepared.
The composition, physical constants, workability and elasticity of some polymers according to the invention are provided in Tables 1 and 2 below.
Machining means turning under cooled conditions. Elasticity is a characteristic feature of injectability in case of a small wound.
Table 1
Refractive Refractive
Example Index Index
BEA BEMA BA EGDMA BDDMA SDA UV INN Machinability Injectability
No. (hydrated) (hydrated)
25°C 35°C
1 1 98.35% 1.50% 0.15% Acceptable Good 1.5502 1.5486
12 94.85% 5.00% 0.15% Good Acceptable 1.5512 1.5494
13 95.75% 3.95% 0.30% Good Good 1.5515 1.5497
14 92.92% 7.01% 0.07% * Good 1.5462 1.5449
15 42.51% 53.14% 3.50% 0.70% 0.14% Acceptable Good 1.4946 1.4941
16 39.05% 56.35% 3.71% 0.74% 0.15% Good Good 1.4956 1.4699
17 33.89% 61.12% 4.03% 0.81% 0.16% Good Good 1.4902 1.4884
18 35.70% 59.44% 3.92% 0.78% 0.16% Good Acceptable 1.4961 1.4972
19 97.35% 2.50% 0.15% Acceptable Good 1.5516 1.5481
20 96.35% 3.50% 0.15% Good Good 1.5503 1.5475
21 92.35% 8% 0.15% Good ** 1.5517 1.5495
22 89.85% 10% 0.15% Good ** 1.5515 1.5498
23 92.69% 7% 0.30% Good Good 1.5512 1.5498
24 89.66% 10% 0.30% Good Good 1.5514 1.5496
25 37.85% 57.45% 3.79% 0.76% 0.15% Good Good 1.4943 1.4916
26 34.30% 60.74% 4.00% 0.80% 0.16% Good Good 1.4900 1.489
27 43.47% 52.26% 3.44% 0.69% 0.14% Acceptable Acceptable 1.5003 1.4972
28 33.89% 61.12% 4.03% 0.81% 0.16% * Acceptable - -
29 46.53% 49.43% 3.26% 0.65% 0.13% * Acceptable - -
30 40.97% 54.57% 3.60% 0.72% 0.14% Good Acceptable 1.4961 1.4972
31 31.63% 63.20% 4.17% 0.83% 0.17% Good ** 1.4961 1.4972
32 54.61% 41.96% 2.77% 0.55% 0.1 1 % Good ** 1.5105 1.5032
33 48.06% 48.01% 3.16% 0.63% 0.13% Good ** 1.5050 1.5026
34 39.31 % 56.10% 3.70% 0.74% 0.15% Good Acceptable 1.4960 1.497
35 51.56% 44.78% 2.95% 0.59% 0.12% Good Acceptable 1.5030 1.501
*: Requires a different machining technique than the other
BEA: 2-(acryloyloxy)ethyl benzoate
materials included in the table.
BA: butyl acrylate ** : Not suitable for small wound size
EGDMA: ethane- 1,2-diyl bis(2-methacrylate) SDA l,3-bis(acryloyloxymethyl)-l , 1 ,3,3-tetramethyldisiloxane BDDMA: butane- 1,4-diyl bis(2-methacrylate) INN: Radical polymerization initiator
Table 2
Figure imgf000021_0001
It is clear from the tables that for 100 mass parts of a BEA type monomer, with 0.1 to 15, preferably 1 to 10 mass parts of cross-linking agent, the BEA-type material itself is suitable as a raw material for IOL lenses.
The synthesized polymers were subjected to toxicological tests in accordance with USP 32 <88> and it was found that the compounds were not toxic.
Eye-irritating effect of the polymers according to the invention was also examined in accordance with MSZ EN ISO 10993-10:2003, and it was found that they did not irritate the eyes.

Claims

Clainis
1. Biocompatible, hydrophobic, soft, high refractive index intraocular lens, which can be prepared from an alkane diol derivative monomer that contains an aryl or aralkyl carboxylic acid ester on one end, and an acrylic or methacrylic acid ester on the other end.
2. Intraocular lens, which is made up of a polymer prepared from a monomer of the general formula (I),
Figure imgf000023_0001
in the formula
Ar represents a mono- or polysubstituted aromatic group, preferably a phenyl, biphenylyl, naphthyl, thienyl, furyl, pyrrolyl group, wherein the substituent is hydroxyl, alkyl, alkoxy, alkoxycarbonyl, amino, nitro groups, a halogen atom, such as chlorine, bromine, fluorine, the alkyl and alkoxy groups have 1 to 6 carbon atoms and may be straight or branched;
n is an integer of 2, 3, 4, 5 10;
f is an integer of 0, 1 , 2, 3 10;
with the proviso that n + f < 15
X represents a hydrogen atom or a methyl group;
Ri, R2, R3, R are the same or different and independently represent a hydrogen or halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyl or a carboxyl group.
3. The intraocular lens according to claim 2, wherein Ar in the general formula (I) represents a phenyl, thienyl, furyl or pyrrolyl group, preferably phenyl group, f represents 0, 1 or 2, preferably 0, n is 2, 3 or 4, preferably 2, X represents a hydrogen atom or a methyl group and Rb R2, R3 and R each represent a hydrogen atom.
4. The intraocular lens according to claim 2, wherein the starting monomer compound of the general formula (I) is 2-(benzoyloxy)ethyl acrylate and 2-(benzoyloxy)ethyl methacrylate.
5. Compounds of the general formula (Γ),
Figure imgf000024_0001
where Ar1 represents a mono- or polysubstituted phenyl, biphenylyl, naphthyl or pyrrolyl group, wherein the substituent is a hydroxyl, alkyl, alkoxy, alkoxycarbonyl, amino, nitro group, a halogen atom, such as chlorine, bromine, fluorine, the alkyl and alkoxy groups have 1 to 6 carbon atoms and may be straight or branched;
n' is an integer of 2, 3, 4, 5 10;
f is an integer of 0, 1 , 2, 3 10;
with the proviso that n + f <15
X' represents a hydrogen atom or a methyl group,
Rl ', R2', R3 ', R4' are the same or different and independently represent a hydrogen or halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyl or a carboxyl group.
6. Compounds according to claim 5, with the exception of 2-(benzoyloxy)ethyl aery late and 2- (benzoyloxy)ethyl methacrylate.
7. The following of the compounds according to claim 5: 2-(benzoyloxy)ethyl and 2-(benzoyloxy)ethyl methacrylate.
8. Process for the preparation of compounds of the general formula (Γ) according to claim 5,
Figure imgf000024_0003
Figure imgf000024_0004
Figure imgf000024_0002
where Ar' represents a mono- or polysubstituted phenyl, biphenylyl, naphthyl or pyrrolyl group, wherein the substituent is a hydroxyl, alkyl, alkoxy, alkoxycarbonyl, amino, nitro group, a halogen atom, such as chlorine, bromine, fluorine, the alkyl and alkoxy groups have 1 to 6 carbon atoms and may be straight or branched;
n' is an integer of 2, 3, 4, 5 10;
f is an integer of 0, 1 , 2, 3 10;
with the proviso that n + f <15
X' represents a hydrogen atom or a methyl group, R] ', R2', R3 ', R4' are the same or different and independently represent a hydrogen or halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyl or a carboxyl group
characterized in that
a) a compound of the general formula Ar'-((CR, )r-C(0)-0-(CR3'R4')n-OH wherein Ar' , Ri ', R2\ R3 ' , R4', f and n' are the same as in the general formula (Γ), is reacted with a compound of the general formula CH2=C(X')-C(0)-L - in this latter formula, X' is the same as in the general formula (P), L represents a leaving group, for example, a halogen atom, such as chlorine, bromine, fluorine or iodine; in the presence of an acid-binding agent, such as triethylamine, in a solvent, preferably in an organic solvent, such as diethyl ether, ethyl acetate, acetone or other similar solvent, or
b) a compound of the general formula Ar'-(CRi 'R2')r-C(0)-L wherein Ar' , K\ R2' and f are the same as in the general formula (Γ), L represents a leaving group, for example, a halogen atom, such as chlorine, bromine, fluorine or iodine, is reacted with a compound of the general formula CH2=C(X')-C(0)-0-(CR3'R4')n -OH under the reaction conditions provided for the above process a), wherein X', R3', R4' and n' are the same as in the general formula (Γ).
9. The use of a compound of the general formula (I) - substituents in the formula represent the same as provided in claim 2 - in the manufacture of intraocular lenses.
10. The use according to claim 9, wherein Ar in the general formula (I) represents a phenyl, thienyl, furyl or pyrrolyl group, preferably phenyl group, f represents 0, 1 or 2, preferably 0, n is 2, 3 or 4, particularly preferably 2, X represents a hydrogen atom or a methyl group and Ri , R2, R3 and 4 each represent a hydrogen atom.
1 1 . Process for the preparation of polymers suitable for intraocular lenses, characterized in that one or more monomer compounds of the general formula (I) are used as a starting compound, substituents in the formula represent the same as according to claim 2, with the use of customary cross-linking agents and other auxiliary materials.
12. The process according to claim 1 1 , characterized in that 2-(benzoyloxy)ethyl acrylate is used as a starting monomer and for 100 mass parts of monomer, 0.1 to 15 mass parts of ethylene glycol dimethacrylate or butanediol dimethacrylate is used as a cross-linking agent.
13. The process according to claim 1 1 , characterized in that an oligosiloxane of the general formula (Ila) or (lib) is used as a cross-linking agent
Figure imgf000026_0001
(Ha)
wherein X represents a hydrogen atom or a methyl group, n is 1 , 2, 3, 4, 5 or 6 and m is 0 or an integer between 1 and 20,
Figure imgf000026_0002
(lib)
wherein X represents a hydrogen atom or a methyl group, n is 1, 2, 3, 4, 5 or 6 and m is 0 or an integer between 1 and 20.
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