RU2795094C2 - Polymerizable condensed tricyclic compounds as uv and visible light absorbers - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to a contact lens, which is a polymerization reaction product of a reaction mixture containing a monomer suitable for the manufacture of a contact lens, and a condensed tricyclic compound selected from formulas III and V, where X represents O, S or NR⁶; Z is S; m and n are independently 0 or 1; R¹ and R² are independently at each occurrence H, C₁-C₆ alkoxy or -YP_g; R⁶ is H or YP_g; R⁷ is EWG or -C(=O)-TYP_g, and EWG is in each case independently -CN; P_g at each occurrence is independently -CH=CH₂, -C(CH₃)=CH₂; Y is independently at each occurrence a linking group selected from -O-(CH₂)₂-OC(O)-, -O-(CH₂)₃-OC(O)-, (CH₂)₃-OC(O)-CH(CH₃)-, -(CH₂)₃-OC(O)-CH(CH₃)-, -O-(CH₂)₃-OC(O)-CH(CH₃)-; and T is at each occurrence independently NR⁶, wherein the compound contains at least one P_g group.

EFFECT: obtained contact lens containing compounds that are effective for providing targeted absorption of high-energy radiation, such as UV radiation (UV-A and UV-B range), low-energy UV radiation (from 385 to 400 nm) or HEV radiation (for example, from 400 to 450 nm).

16 cl, 3 dwg, 1 tbl, 9 ex

Description

Related Applications

This application claims priority over U.S. Application No. 16/883,199, filed May 26, 2020, and U.S. Provisional Application No. 62/867,963, filed June 28, 2019, which is incorporated herein by reference in its entirety.

Scope of the invention

The present invention relates to UV and visible light absorbers. In particular, the present invention relates to compounds with polymerization functionality that absorb various wavelengths of UV radiation and/or visible light, such as high energy visible light, while remaining visually transparent when embedded in an article. Thus, these compounds can be used in polymer products, including biomedical devices such as ophthalmic devices.

Prerequisites for the creation of the invention

High-energy solar radiation, such as UV radiation or high-energy blue portion of visible light, is known to cause cell damage. While most of the radiation below 280 nm is absorbed by the Earth's atmosphere, photons in the wavelength range from 280 nm to 400 nm cause a number of eye diseases, including corneal degenerative changes, age-related cataracts, and macular degeneration. (See Statement on Ocular Ultraviolet Radiation Hazards in Sunlight, American Optometric Association, November 10, 1993). The human cornea absorbs some radiation up to 320 nm in wavelength (30% transmission) (Doutch, J.J., Quantock, A.J., Joyce, N.C., Meek, K.M,Biophys. J, 2012, 102, 1258-1264), but is inefficient in protecting the back of the eye from radiation ranging from 320 to 400 nm in wavelength.

Contact lens standards define an upper limit for the UV wavelength range of 380 nm. According to the American Optometric Association's current Class I UV absorption criteria, a contact lens must absorb > 99% of radiation in the 280 to 315 nm range (UV-B) and > 90% of radiation in the 316 to 380 nm range ( UV-A). While these criteria are effective for protecting the cornea (<1% UVB absorption), they do little to account for lower energy UV radiation (>380<400nm) that damages the retina (Ham, WT, Mueller, HA, Sliney, DH Nature 1976; 260 (5547): 153-5) or high-energy blue light in the visible spectrum.

High-energy visible blue (HEV) radiation can cause visual discomfort or circadian rhythm disturbances. For example, computer and electronic device screens, flat screen televisions, energy-saving lamps and LED lamps are known to emit HEV radiation. Prolonged exposure to such sources of blue light in the visible spectrum can cause eye strain. It is assumed that viewing devices that emit HEV radiation at night causes a disruption in the natural circadian rhythm, which leads, for example, to insufficient sleep.

Absorption of high-energy blue light in the visible spectrum before it reaches the eye remains a sought-after goal in ophthalmology. However, it is also important to what extent a certain range of wavelengths is absorbed. For example, in the UV-A and UV-B radiation ranges, it may be desirable to absorb as much of the radiation as possible. On the other hand, since HEV radiation forms part of the visible spectrum, complete absorption of HEV radiation may adversely affect vision. Thus, in the case of HEV radiation, partial absorption may be more desirable.

There is a need for materials that provide targeted absorption of unwanted wavelengths of high energy radiation and that are suitable for the production of functional products. Compounds that absorb or attenuate high energy radiation when used in ophthalmic devices can help protect the cornea, as well as the cells of the internal structures of the eye, from degradation, stress, and/or disruption of the circadian rhythm.

Statement of the Invention

The invention relates to high energy absorbing compounds that absorb UV and/or high energy visible blue (HEV) radiation while providing significant transmission (e.g., greater than 80% transmission) at wavelengths greater than about 450 nm. The compounds are thus effective in providing targeted absorption of high energy radiation such as UV (UV-A and UV-B), low energy UV (385 nm to 400 nm) or HEV radiation (e.g. from 400 nm up to 450 nm).

The compounds are also polymerizable and are generally compatible with other raw materials, as well as polymerization and processing conditions typically used for the manufacture of ophthalmic devices such as soft contact lenses. Thus, the compounds can be easily covalently incorporated into the finished product without the need for major modifications to existing manufacturing processes and equipment.

Accordingly, in one aspect of the present invention, a fused tricyclic compound of formula I is provided:

formula I

where m, n and t are independently 0, 1, 2, 3 or 4; R¹, R² and R³ independently each occurrence is H, an optional substituent, or -Y-P_g, or two adjacent groups R¹, R² or R³ together with the atoms to which they are attached are combined to form a cycloalkyl or aryl ring optionally substituted with -Y-P_g; B is a 5-, 6-, or 7-membered ring that is aromatic, saturated, or partially unsaturated, optionally containing up to three heteroatoms independently selected from O, S, N, and NR⁶, where R⁶ represents H, C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl or Y-P_g; one of C and D is a 5-, 6-, or 7-membered ring that is aromatic, saturated, or partially unsaturated, optionally containing up to three heteroatoms independently selected from O, S, N, and NR⁶, and the other of C and D is a 6-membered saturated or partially unsaturated heterocycloalkyl ring containing at least one carbon atom in the ring and at least one heterogroup independently selected from O, S, NR⁶, SO or SO₂, wherein the heterocycloalkyl ring is substituted on one carbon atom in the ring by a group of the formula =C(EWG)(R⁷), where R⁷ is EWG or -C(=O)-T-Y-P_g, and EWG is in each case independently an electron withdrawing group; P_g in each case independently represents a polymerizable group; Y is independently at each occurrence a linking group; and T is in each case independently a bond, O, or NR⁶, wherein the compound of formula I contains at least one group P_g.

In another aspect, the invention provides an ophthalmic device which is a free radical reaction product of a reaction mixture comprising: one or more monomers suitable for making an ophthalmic device; and a compound of formula I as described herein.

In a further aspect, the present invention provides an ophthalmic device comprising a polymer network and a non-reactive polymer containing repeating units derived from a compound of formula I as described herein.

Brief description of graphic materials

In FIG. 1 shows UV-visible transmission spectra of solutions of exemplary compounds (A), (C), (D), and (E) in methanol at a molar concentration of 0.2 mmol/l.

In FIG. 2 shows the UV-visible transmission spectra of solutions of exemplary compounds (E) and (F) in methanol at a molar concentration of 0.2 mmol/L.

In FIG. 3 shows the UV-visible transmission spectrum of exemplary silicone hydrogel contact lenses of Examples 7, 8 and 9.

Detailed description of the invention

It should be understood that the invention is not limited to the details of construction or method steps set forth in the following description. The invention is capable of other embodiments of the invention and may be or may be carried out in various ways using the teachings set forth herein.

As noted above, in one aspect, the invention provides compounds that absorb UV radiation and/or visible light (such as HEV radiation). The compounds contain polymerizable functional groups. It has been found that ophthalmic devices that absorb UV radiation and/or visible light (such as HEV radiation) can be easily manufactured as described herein.

The compounds of the present invention can successfully absorb UV radiation (UV-A, UV-B range) and/or visible light when transmitted in other regions of the visible spectrum. The compounds are suitable for incorporation into a variety of products, including biomedical devices and ophthalmic devices.

With regard to the terms used in the present description, the following definitions are provided.

Unless otherwise indicated, all technical and scientific terms used in this document have a generally accepted meaning, understandable to any person skilled in the field to which the invention pertains. Definitions for polymers are consistent with those described in the Compendium of Polymer Terminology and Nomenclature, IUPAC Recommendations 2008 edited by: Richard G. Jones, Jaroslav Kahovec, Robert Stepto, Edward S. Wilks, Michael Hess, Tatsuki Kitayama and W. Val Metanomski. All publications, patent applications, patents and other references mentioned in this document are incorporated herein by reference.

As used herein, the term "(meth)" refers to the possible presence of an optional methyl substituent. Thus, the term "(meth)acrylates" refers to both methacrylates and acrylates.

It should be appreciated that wherever chemical structures are given, variants presented as substituents in the structure may be combined in any combination. Thus, if the structure contains substituents R* and R**, each of which has three lists of potential groups, 9 combinations are possible. The same applies to the combination of properties.

When using a subscript, such as "n" in the standard formula [***] _n , to indicate the number of repeating units in the chemical formula of a polymer, such a formula should be understood as representing the number average molecular weight of the macromolecule.

As used herein, the term "subject" includes humans and vertebrates.

"Biomedical device" means any article capable of being used in or on mammalian tissues or body fluids, and preferably in or on human tissues or body fluids. Examples of such devices include, but are not limited to, wound dressings, bioadhesives, tissue fillers, drug delivery systems, coatings, adhesion barriers, catheters, implants, stents, and ophthalmic devices such as intraocular lenses and contact lenses. Biomedical devices can be ophthalmic devices, specifically contact lenses, more specifically contact lenses made from silicone hydrogels or conventional hydrogels.

"Surface of the eye" includes the superficial and glandular epithelium of the cornea, conjunctiva, lacrimal glands, accessory lacrimal glands, nasolacrimal duct, and meibomian glands, and their apical and basal matrices, punctures, and adjacent or associated structures, including the eyelids, connected as a functional system by continuity. epithelium, innervation and endocrine and immune systems.

The term "ophthalmic device" refers to any optical device relating to the eye and includes devices that are placed in or on the eye, or on any part of the eye, including the surface of the eye. Such devices may provide optical correction, cosmetic enhancement, vision enhancement, therapeutic effect (eg as a dressing), or delivery of active ingredients such as pharmaceutical and nutraceutical ingredients, or any combination of the above. Examples of ophthalmic devices include, but are not limited to, lenses and optic and ocular inserts, including but not limited to punctal obturators, and the like. The term "lenses" includes spectacle lenses, sun lenses, soft contact lenses, hard contact lenses, hybrid contact lenses, intraocular lenses and masking lenses. The ophthalmic device may include a contact lens.

The term "contact lens" means an ophthalmic device that can be placed on the cornea of a patient's eye. A contact lens may provide corrective, cosmetic, or therapeutic benefits, including wound healing, drug or nutraceutical delivery, diagnostic evaluation or monitoring, ultraviolet light absorption, visible or glare reduction, or any combination thereof. A contact lens may be made from any suitable material known in the art and may be a soft lens, a hard lens, or a hybrid lens containing at least two distinct parts with different physical, mechanical, or optical properties such as modulus, water content, light transmission, or combinations thereof.

The biomedical devices, ophthalmic devices and lenses of the present invention may be made from silicone hydrogels or conventional hydrogels. Silicone hydrogels typically contain at least one hydrophilic monomer and at least one silicone-containing component that are covalently bonded to each other in a polymerized device.

The term "target macromolecule" is a macromolecule synthesized from a reactive monomer mixture containing monomers, macromers, prepolymers, crosslinkers, initiators, additives, diluents, etc.

The term "polymerizable compound" means a compound containing one or more polymerizable groups. The term includes, for example, monomers, macromers, oligomers, prepolymers, crosslinkers, and the like.

"Polymerizable groups" are groups that can undergo chain growth polymerization, such as free radical and/or cationic polymerization, eg a carbon double bond group, that can polymerize when exposed to radical polymerization initiation conditions. Non-limiting examples of free radical polymerizable groups include (meth)acrylates, styrenes, vinyl ethers, (meth)acrylamides, N -vinyl lactams, N -vinyl amides, O-vinyl carbamates, O-vinyl carbonates, and other vinyl groups. Free radical polymerizable groups preferably contain (meth)acrylate, (meth)acrylamide, N-vinyl lactam, N-vinylamide, styryl functional groups, or mixtures of any of the above. Free radical polymerizable groups more preferably comprise (meth)acrylates, (meth)acrylamides and mixtures thereof. The polymerizable group may be substituted or unsubstituted. For example, the nitrogen atom in (meth)acrylamide may be bonded to a hydrogen, or the hydrogen may be substituted with alkyl or cycloalkyl (which may themselves be further substituted).

Any type of free radical polymerization may be used, including, but not limited to, mass, solution, suspension, and emulsion, as well as any controlled radical polymerization methods such as stable free radical initiated polymerization, nitroxide-mediated living polymerization, atom transfer radical polymerization, polymerization by reversible addition and fragmentation, organotellurium mediated living radical polymerization, etc.

A "monomer" is a monofunctional molecule that can undergo chain-growth polymerization, and in particular free radical polymerization, thus creating a repeating unit in the chemical structure of the target macromolecule. Some monomers have bifunctional impurities that can act as crosslinkers. "Hydrophilic monomer" is also a monomer that gives a clear, single-phase solution when mixed with deionized water at 25°C at a concentration of 5% by weight. A "hydrophilic component" is a monomer, macromer, prepolymer, initiator, crosslinker, additive, or polymer that gives a clear, single phase solution when mixed with deionized water at 25°C at a concentration of 5% by weight. A "hydrophobic component" is a monomer, macromer, prepolymer, initiator, crosslinker, additive, or polymer that is slightly soluble or insoluble in deionized water at 25°C.

A "macromolecule" is an organic compound having a number average molecular weight greater than 1500 and may or may not be reactive.

A "macromonomer" or "macromer" is a macromolecule that has a single group that can undergo chain propagation polymerization and, in particular, free radical polymerization, thereby creating a repeating unit in the chemical structure of the target macromolecule. As a rule, the chemical structure of the macromer differs from the chemical structure of the target macromolecule, that is, the repeating unit of the side group of the macromer differs from the repeating unit of the target macromolecule or its main chain. The difference between a monomer and a macromer is only in the chemical structure, molecular weight, and molecular weight distribution of the side group. As a result, and in the context of this document, monomers are sometimes defined in the patent literature as polymerizable compounds having a relatively low molecular weight of about 1500 daltons or less, which is known to include some macromers. In particular, monomers and macromers may include mono-n-butyl and monomethacryloxypropyl-terminated polydimethylsiloxane (molecular weight=500-1500 g/mol) (mPDMS) and mono-(2-hydroxy-3-methacryloxypropyl)-propylether-terminated polydimethylsiloxane group and mono-n-butyl (molecular weight=500-1500 g/mol) (OH-mPDMS). In addition, in the patent literature, macromers are sometimes defined as having one or more polymerizable groups, essentially extending the general definition of a macromer to include prepolymers. As a result, and as used herein, difunctional and multifunctional macromers, prepolymers, and crosslinkers can be used interchangeably.

A "silicone-containing component" is a monomer, macromer, prepolymer, crosslinker, initiator, additive, or polymer in a reactive composition with at least one silicon-oxygen bond, typically in the form of siloxy groups, siloxane groups, carbosiloxane groups, and mixtures thereof.

Examples of silicone-containing components that are used in the present invention can be found in U.S. Patent Nos. , 5.331.067, 5.371.147, 5.760.100, 5.849.811, 5.962.548 . . 8,420,711, 8,450,387, 8,487,058 . , 9,244,196, 9,244,197, 9,260,544, 9,297,928, 9,297,929;

"Polymer" is a target macromolecule consisting of repeating units of monomers used during polymerization.

"Homopolymer" is a polymer derived from a single monomer; "copolymer" is a polymer derived from two or more monomers; "terpolymer" is a polymer derived from three monomers. "Block copolymer" consists of blocks or segments of different composition. Diblock copolymers have two blocks. Triblock copolymers have three blocks. "Comb copolymers" or "graft copolymers" consist of at least one macromer.

A "repeating unit" is the smallest group of atoms in a polymer that corresponds to the polymerization of a particular monomer or macromer.

An "initiator" is a molecule that can decompose into radicals that can sequentially react with a monomer to initiate a free radical polymerization reaction. The thermal initiator decomposes at a certain rate depending on the temperature; typical examples are azo compounds such as 1,1'-azobisisobutyronitrile and 4,4'-azobis(4-cyanovaleric acid), peroxides such as benzoyl peroxide, t-butyl peroxide, t-butyl hydroperoxide, t-butyl peroxybenzoate, dicumyl peroxide and lauroyl peroxide, peroxyacids such as peracetic acid and potassium persulfate, as well as a variety of redox systems. The photoinitiator is degraded by a photochemical process; typical examples are derivatives of benzyl, benzoin, acetophenone, benzophenone, camphorquinone and mixtures thereof, as well as various monoacyl and bisacyl phosphine oxides and combinations thereof.

A "crosslinker" is a difunctional or multifunctional monomer or macromer that can participate in free radical polymerization at two or more sites in a molecule, thereby creating branch points and forming a polymer network. Common examples include ethylene glycol dimethacrylate, tetraethylene glycol dimethacrylate, trimethylol propane trimethacrylate, methylene bisacrylamide, triallyl cyanurate, and the like.

A "prepolymer" is a monomer reaction product that contains remaining polymerizable groups capable of further reaction to form a polymer.

"Polymer network" is a cross-linked macromolecule that can swell but cannot dissolve in solvents. "Hydrogels" are polymeric networks that swell in water or aqueous solutions, usually absorbing at least 10% of the mass. water. "Silicone hydrogels" are hydrogels that are made from at least one silicone-containing component with at least one hydrophilic component. Hydrophilic components may also include non-reactive polymers.

"Conventional hydrogels" refers to polymer networks made from monomers without any siloxy, siloxane, or carbosiloxane groups. Traditional hydrogels are obtained from reaction mixtures containing hydrophilic monomers. Examples include 2-hydroxyethyl methacrylate (HEMA), N-vinylpyrrolidone (NVP), N,N-dimethylacrylamide (DMA), or vinyl acetate. U.S. Patent Nos. 4,436,887, 4,495,313, 4,889,664, 5,006,622, 5,039,459, 5,236,969, 5,270,418, 5,298,533, 5,824,719, 6,420,453, 6,423 ,761, 6,767,979, 7,934,830, 8,138,290 and 8,389,597 describe the preparation of traditional hydrogels. Commercially available traditional hydrogels include, without limitation, etafilcon, genfilcon, gilafilcon, lenefilcon, nesofilcon, omafilcon, polymacon, and vifilcon, including all variants thereof.

The term "silicone hydrogels" refers to polymer networks made from at least one hydrophilic component and at least one silicone-containing component. Examples of commercially available silicone hydrogels include aquafilcon, asmofilcon, balafilcon, comfilcon, delefilcon, enfilcon, fanfilcon, formofilcon, halifilcon, lotrafilcon, narafilcon, riofilcon, samfilcon, senofilcon, somofilcon, and stenfilcon, including all variants thereof, as well as silicone hydrogels manufactured US Patent Nos. 4,659,782; 4,659,783; 5,244,981; 5,314,960; 5,331,067; 5,371,147; 89.461, 5.849.811, 5.965.631, 6.367.929, 6.822.016, 6.867.245 .185 . 9,125,808 .297.928, 9.297.929 , as well as WO 03/22321, WO 2008/061992 and US 2010/0048847. The contents of all of these patents are hereby incorporated by reference in their entirety.

An "interpenetrating polymer network" comprises two or more polymer networks that are at least partially intertwined at the molecular level, but are not covalently bonded to each other and cannot be separated without breaking chemical bonds. A "semi-interpenetrating polymer network" comprises one or more networks and one or more polymers characterized by some mixing at the molecular level between at least one network and at least one polymer. A mixture of different polymers is a "polymer blend". A semi-interpenetrating network is technically a polymer blend, but in some cases the polymers are so tightly intertwined that they cannot be easily removed.

"Reactive Components" are the polymerizable compounds (such as monomers, macromers, oligomers, prepolymers, and crosslinkers) in a reaction mixture (defined below), as well as any other reaction mixture components that are intended to substantially remain in the resulting polymer. mesh after completion of polymerization and all processing steps (such as extraction steps) and packaging. The reactive components may be retained in the polymer network by covalent bonding, hydrogen bonding, electrostatic interactions, formation of interpenetrating polymer networks, or any other means. Components intended to be released from the polymer network once it is used are still considered "reactive components". For example, pharmaceutical or nutraceutical components in a contact lens that are intended to be released during wear are considered "reactive components". Components that are intended to be removed from the polymer network during the manufacturing process (eg by extraction), such as diluents, are not "reactive components".

The terms “reaction mixture” and “reaction monomer mixture” refer to a mixture of components that are mixed together and, when subjected to polymerization conditions, result in the formation of a polymer network (such as conventional or silicone hydrogels) as well as biomedical devices, ophthalmic devices, and contact lenses made from them. The reaction mixture may contain reactive components such as monomers, macromers, prepolymers, crosslinkers and initiators, additives such as wetting agents, polymers, dyes, light absorbing compounds such as UV absorbers, pigments, photochromic compounds, pharmaceutical compounds and/or nutraceutical compounds, any of which may be polymerizable or non-polymerizable, but they are able to be retained in the resulting biomedical device (for example, a contact lens). The reaction mixture may also contain other components that are intended to be removed from the device prior to use, such as diluents. It should be understood that a wide range of additives may be added depending on the type of contact lens being manufactured and its intended use. The concentrations of the components of the reaction mixture are expressed as mass fractions of all reactive components in the reaction mixture, with the exception of diluents. When diluents are used, their concentrations are expressed as mass fractions of the total amount of all components in the reaction mixture (including the diluent).

The term "silicone hydrogel contact lens" refers to a hydrogel contact lens made from at least one silicone-containing compound. Silicone hydrogel contact lenses essentially have increased oxygen permeability compared to conventional hydrogels. To transfer oxygen to the eye, silicone hydrogel contact lenses use both their water and polymer components.

The term "multifunctional" refers to a component having two or more polymerizable groups. The term "monofunctional" refers to a component having a single polymerizable group.

The terms "halogen" or "halo" refer to fluorine, chlorine, bromine and iodine.

"Alkyl" refers to an optionally substituted straight or branched chain alkyl group containing the specified number of carbon atoms. If the number is not specified, then alkyl (optionally including any substituents on alkyl) may contain from 1 to 16 carbon atoms. The alkyl group preferably has 1 to 10 carbon atoms, alternatively 1 to 8 carbon atoms, alternatively 1 to 6 carbon atoms, or alternatively 1 to 4 carbon atoms. Examples of alkyl include methyl, ethyl, propyl, isopropyl, butyl, iso-, sec-, and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl, and the like. Examples of substituents on an alkyl group include 1, 2, or 3 groups independently selected from hydroxy, amino, amido, oxa, carboxy, alkylcarboxy, carbonyl, alkoxy, thioalkyl, carbamate, carbonate, halogen, phenyl, benzyl, and combinations thereof. "Alkylene" means a divalent alkyl group such as -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH(CH ₃ )CH ₂ - and -CH ₂ CH ₂ CH _{2 CH2-} .

The term "haloalkyl" refers to an alkyl group as defined above which is substituted by one or more halogen atoms, where each halogen is independently F, Cl, Br, or I. Preferred halogen is F. Preferred haloalkyl groups contain 1-6 carbon atoms , more preferably 1-4 carbon atoms and even more preferably 1-2 carbon atoms. The term "haloalkyl" includes perhaloalkyl groups such as -CF ₃ - or -CF ₂ CF ₃ -. The term "haloalkylene" means a divalent haloalkyl group such as -CH ₂ CF ₂ -.

"Cycloalkyl" refers to an optionally substituted cyclic hydrocarbon containing the specified number of carbon atoms in the ring. If the number is not specified, then cycloalkyl may contain from 3 to 12 carbon atoms in the ring. Preferred are C ₃ -C ₈ cycloalkyl groups, C ₃ -C ₇ cycloalkyl, more preferably C ₄ -C ₇ cycloalkyl and even more preferably C ₅ -C ₆ cycloalkyl. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of substituents on the cycloalkyl group include 1, 2 or 3 groups independently selected from alkyl, hydroxy, amino, amido, oxa, carbonyl, alkoxy, thioalkyl, amido, carbamate, carbonate, halogen, phenyl, benzyl, and combinations thereof. The term "cycloalkylene" means a divalent cycloalkyl group such as 1,2-cyclohexylene, 1,3-cyclohexylene or 1,4-cyclohexylene.

The term "heterocycloalkyl" refers to a cycloalkyl ring or ring system as defined above in which at least one carbon in the ring is replaced by a heteroatom selected from nitrogen, oxygen and sulfur. The heterocycloalkyl ring is optionally fused or otherwise connected to other heterocycloalkyl rings and/or non-aromatic hydrocarbon rings and/or phenyl rings. Preferred heterocycloalkyl groups have 5 to 7 members. More preferred heterocycloalkyl groups have 5 to 6 members. The term "heterocycloalkyl" means a divalent heterocycloalkyl group.

"Aryl" refers to an optionally substituted aromatic hydrocarbon ring system containing at least one aromatic ring. The aryl group contains the indicated number of carbon atoms in the ring. If the number is not specified, aryl may contain from 6 to 14 carbon atoms in the ring. The aromatic ring may optionally be fused or otherwise attached to other aromatic hydrocarbon rings or non-aromatic hydrocarbon rings. Examples of aryl groups include phenyl, naphthyl and biphenyl. Preferred examples of aryl groups include phenyl. Examples of substituents on the aryl group include 1, 2 or 3 groups independently selected from alkyl, hydroxy, amino, amido, oxa, carboxy, alkylcarboxy, carbonyl, alkoxy, thioalkyl, carbamate, carbonate, halogen, phenyl, benzyl, and combinations thereof. The term "arylene" means a divalent aryl group, such as 1,2-phenylene, 1,3-phenylene or 1,4-phenylene.

The term "heteroaryl" refers to an aryl ring or ring system as defined above in which at least one carbon atom in the ring is replaced by a heteroatom selected from nitrogen, oxygen and sulfur. The heteroaryl ring may be fused or otherwise attached to one or more heteroaryl rings, aromatic or non-aromatic hydrocarbon rings, or heterocycloalkyl rings. Examples of heteroaryl groups include pyridyl, furyl, and thienyl. The term "heteroarylene" means a divalent heteroaryl group.

The term "alkoxy" means an alkyl group attached to the original fragment of the molecule through an oxygen bridge. Examples of alkoxy groups include, for example, methoxy, ethoxy, propoxy and isopropoxy. "Thioalkyl" means an alkyl group attached to the parent molecule through a sulfur-containing bridge. Examples of thioalkyl groups include, for example, methylthio, ethylthio, n-propylthio and isopropylthio. The term "aryloxy" means an aryl group attached to the original fragment of the molecule through an oxygen bridge. Examples include phenoxy. The term "cyclic alkoxy group" means a cycloalkyl group attached to the original fragment through an oxygen bridge.

The term "alkylamine" refers to an alkyl group attached to the original fragment of the molecule through the bridge -NH. The term "alkyleneamine" means a divalent alkylamine group such as -CH ₂ CH ₂ NH-.

The term "siloxanil" refers to a structure having at least one Si-O-Si bond. Thus, for example, a siloxanyl group means a group having at least one Si-O-Si group (ie, a siloxane group), and a siloxanyl compound means a compound having at least one Si-O-Si group. The term "siloxanil" embraces monomeric (eg Si-O-Si) as well as oligomeric/polymeric structures (eg -[Si-O] _n - where n is 2 or more). Each silicon atom in the siloxanyl group is substituted with independently selected groups R ^A (where R ^A is defined as indicated in (b)-(i) of formula A) to fill the valency.

The term "silyl" refers to a structure of formula R ₃ Si- and "siloxy" refers to a structure of formula R ₃ Si-O-, where each R in silyl or siloxy is independently selected from trimethylsiloxy, C ₁ -C ₈ alkyl (preferably C ₁ -C ₃ alkyl, more preferably alkyl or methyl) and C ₃ -C ₈ cycloalkyl.

The term "alkyleneoxy" refers to groups of the general formula -(alkylene-O) _p - or -(O-alkylene) _p -, where alkylene is defined as above and p is from 1 to 200, or from 1 to 100, or 1 to 50, or 1 to 25, or 1 to 20, or 1 to 10, each alkylene being independently optionally substituted with one or more groups independently selected from hydroxyl, halogen (e.g. fluorine), amino, amido, ether, carbonyl, carboxyl, and combinations thereof. If p is greater than 1, then all alkylenes may be the same or different, and alkyleneoxy may have a block or random configuration. If the alkyleneoxy forms an end group in the molecule, the alkyleneoxy end may, for example, be hydroxy or alkoxy (eg HO-[CH ₂ CH ₂ O] _p - or CH ₃ O-[CH ₂ CH ₂ O] _p -). Examples of alkyleneoxy include polyethyleneoxy, polypropyleneoxy, polybutyleneoxy, and poly(ethyleneoxy-co-propyleneoxy).

The term "oxaalkylene" refers to an alkylene group, as defined above, in which one or more non-adjacent CH ₂ groups have been replaced by an oxygen atom, eg -CH ₂ CH ₂ OCH(CH ₃ )CH ₂ -. The term "thiaalkylene" refers to an alkylene group, as defined above, in which one or more non-adjacent CH ₂ groups have been replaced by a sulfur atom, eg -CH ₂ CH ₂ SCH(CH ₃ )CH ₂ -.

The term "linking group" refers to a functional group that links the polymerizable group to the original molecule. The linking group can be any functional group that is compatible with the compound of which it is a part, that does not adversely affect the polymerization of the compound, is stable under polymerization conditions, and also under the conditions of processing and storage of the finished product. For example, the linking group may be a bond or may be one or more of alkylene, haloalkylene, amide, amine, alkyleneamine, carbamate, ester (-CO ₂ -), arylene, heteroarylene, cycloalkylene, heterocycloalkylene, alkyleneoxy, oxaalkylene, thiaalkylene , haloalkyleneoxy (alkyleneoxy substituted with one or more halogen groups, for example -OCF ₂ -, -OCF ₂ CF ₂ -, -OCF ₂ CH ₂ -), siloxanyl, alkylenesiloxanyl, or combinations thereof. The linking group may optionally be substituted with 1 or more groups. Acceptable substituents may include groups independently selected from alkyl, halogen (e.g., fluoro), hydroxyl, HO-alkyleneoxy, MeO-alkyleneoxy, siloxanyl, siloxy, siloxy-alkyleneoxy-, siloxy-alkylene-alkyleneoxy- (in which may be present more than one alkyleneoxy group, and in which each methylene in the alkylene or alkyleneoxy is independently optionally substituted with hydroxyl), an ether, an amine, a carbonyl, a carbamate, and combinations thereof. The linking group may also be substituted with a polymerizable group such as (meth)acrylate (in addition to the polymerizable group to which the linking group is attached).

Preferred linking groups include C ₁ -C ₈ alkylene (preferably C ₂ -C ₆ alkylene) and C ₁ -C ₈ oxaalkylene (preferably C ₂ -C ₆ oxaalkylene), each of which is optionally substituted with 1 or 2 groups, independently selected from hydroxyl and siloxy. Preferred linking groups also include carboxylate, amide, C ₁ -C ₈ alkylene carboxylate-C ₁ -C ₈ alkylene or C ₁ -C ₈ alkylene amide-C ₁ -C ₈ alkylene.

If the linking group consists of combinations of the functional groups described above (eg, alkylene and cycloalkylene), then these functional groups may be present in any order. For example, if in formula A below L is indicated as -alkylene-cycloalkylene-, then Rg-L can be either Rg-alkylene-cycloalkylene- or Rg-cycloalkylene-alkylene-. Despite this, the order of enumeration is the preferred order in which the functional groups appear in the compound, starting with the terminal polymerizable group (Rg or Pg) to which the linking group is attached. For example, if in formula A below L is indicated as -alkylene-cycloalkylene-, then Rg-L is preferably Rg-alkylene-cycloalkylene-.

The term "electron withdrawing group" (EWG) refers to a chemical group that draws electron density away from the atom or group of atoms to which the electron withdrawing group is attached. Examples of EWG include, but are not limited to, cyano, amide, ester, keto, or aldehyde. The preferred EWG is cyano (CN).

The term "light-absorbing compound" refers to a chemical material that absorbs light in the visible region of the spectrum (eg, in the range from 380 nm to 780 nm). The terms "high energy absorber", "UV/HEV absorber", or "high energy absorbent compound" refer to a chemical material that absorbs radiation at various wavelengths in the ultraviolet region, the high energy region of the visible spectrum, or both. areas. The ability of a material to absorb light of certain wavelengths can be determined by measuring its UV/Visible transmission spectrum. Compounds that show no absorption at a particular wavelength will show substantially 100% transmission at that wavelength. Conversely, compounds that completely absorb radiation at a particular wavelength will show substantially 0% transmission at that wavelength. If the amount of transmission of a material is given as a percentage for a particular wavelength range, it should be understood that the material exhibits a percentage of transmission at all wavelengths within that range.

If the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise indicated, these compounds are assumed to include the cis, trans, Z, and E configurations. Likewise, all tautomeric forms and salt forms are intended to be included.

The term "optional substituent" means that a hydrogen atom in the underlying functional group is optionally substituted with a substituent. Any substituent may be used in the substitution site which may be sterically desirable and synthetically achievable. The definition of a suitable optional substituent is well known to the person skilled in the art. Examples of "optional substituent" include, without limitation, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkyl, C ₃ -C ₇ cycloalkyl, aryl, halogen, hydroxy, amino, NR ⁴ R ⁵ , benzyl, SO ₃ H or SO ₃ Na, where R ⁴ and R ⁵ independently represent H or C ₁ -C ₆ alkyl. The above substituents may optionally be substituted with an optional substituent (which, unless otherwise indicated, is preferably no longer substituted). For example, alkyl may be substituted with halogen (which gives, for example, CF ₃ ).

Unless otherwise indicated, ratios, percentages, fractions, etc. are by weight.

Unless otherwise noted, numeric ranges, such as in "2 to 10", include the numbers that define the range (eg, 2 and 10).

As noted above, in one aspect of the present invention, a fused tricyclic compound of formula I is provided:

formula I

where m, n and t are independently 0, 1, 2, 3 or 4; R¹, R² and R³ independently each occurrence is H, an optional substituent, or -Y-P_g, or two adjacent groups R¹, R² or R³ together with the atoms to which they are attached are combined to form a cycloalkyl or aryl ring optionally substituted with -Y-P_g; B is a 5-, 6-, or 7-membered ring that is aromatic, saturated, or partially unsaturated, optionally containing up to three heteroatoms independently selected from O, S, N, and NR⁶, where R⁶ represents H, C₁-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl or Y-P_g; one of C and D is a 5-, 6-, or 7-membered ring that is aromatic, saturated, or partially unsaturated, optionally containing up to three heteroatoms independently selected from O, S, N, and NR⁶, and the other of C and D is a 6-membered saturated or partially unsaturated heterocycloalkyl ring containing at least one carbon atom in the ring and at least one heterogroup independently selected from O, S, NR⁶, SO or SO₂, wherein the heterocycloalkyl ring is substituted on one carbon atom in the ring by a group of the formula =C(EWG)(R⁷), where R⁷ is EWG or -C(=O)-T-Y-P_g, and EWG is in each case independently an electron withdrawing group; P_g in each case independently represents a polymerizable group; Y is independently at each occurrence a linking group; and T is in each case independently a bond, O, or NR⁶, wherein the compound of formula I contains at least one group P_g.

Formula I-1. Compounds of formula I may include compounds of formula I-1 which are compounds of formula I, wherein the heteroatom in the 6-membered saturated or partially unsaturated heterocycloalkyl ring C or D is S.

I-2. Compounds of formula I may include compounds of formula I-2 which are compounds of formula I wherein the heteroatom in the 6-membered saturated or partially unsaturated heterocycloalkyl ring C or D is O.

I-3. Compounds of formula I may include compounds of formula I-3 which are compounds of formula I, wherein the heteroatom in the 6-membered saturated or partially unsaturated heterocycloalkyl ring C or D is NR ⁶ , preferably NH or N-alkyl.

I-4. Compounds of formula I may include compounds of formula I-4 which are compounds of formula I, wherein the heteroatom in the 6-membered saturated or partially unsaturated heterocycloalkyl ring C or D is SO.

I-5. Compounds of formula I may include compounds of formula I-5 which are compounds of formula I, wherein the heteroatom in the 6-membered saturated or partially unsaturated heterocycloalkyl ring C or D is SO ₂ .

I-6. Compounds of formulas I, I-1, I-2, I-3, I-4 and I-5 may include compounds of formula I-6 which are compounds of formula I, I-1, I-2, I-3 , I-4, or I-5, where m, n, and t are independently 0 or 1, or alternatively, each is 0.

I-7.Compounds of formulas I, I-1, I-2, I-3, I-4 and I-5 may include compounds of formula I-7 which are compounds of formula I, I-1, I-2, I-3 , I-4 or I-5, where R¹ represents H, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkyl, C₃-C₇ cycloalkyl, aryl, halogen, hydroxy, amino, NR⁴R⁵, benzyl, SO₃H or SO₃Na, where R⁴ and R 5 independently represent H or C₁-C₆ alkyl.

I-8. Compounds of formulas I, I-1, I-2, I-3, I-4, I-5 and I-7 may include compounds of formula I-8 which are compounds of formula I, I-1, I-2 , I-3, I-4, I-5 and I-7, where R ² and R ³ independently represent H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkyl, C ₃ -C ₇ cycloalkyl, aryl, halogen, hydroxy, amino, NR ⁴ R ⁵ , benzyl, SO ₃ H or SO ₃ Na, where R ⁴ and R ⁵ are independently H or C ₁ -C ₆ alkyl.

I-9. Compounds of formulas I, I-1, I-2, I-3, I-4, I-5, I-6, I-7 and I-8 may include compounds of formula I-9 which are compounds of formula I , I-1, I-2, I-3, I-4, I-5, I-6, I-7 or I-8, where R ⁶ is H or C ₁ -C ₆ alkyl. R ⁶ in the group T is preferably H.

I-10. Compounds of formulas I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8 and I-9 may include compounds of formula I-10 which are compounds formulas I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8 or I-9, with P _g (polymerizable group) in each case independently contains styryl, vinyl carbonate, vinyl ether, vinyl carbamate, N-vinyl lactam, N-vinylamide, (meth)acrylate or (meth)acrylamide. The polymerizable group allows the compounds of the present invention to form covalent bonds when interacting with monomers, crosslinkers and other components that can be used to make polymeric devices. The compatibility of the compounds with the reaction mixture can be controlled by the choice of polymerizable group (and linking group). Preferred polymerizable groups include (meth)acrylate or (meth)acrylamide. A more preferred polymerizable group is methacrylate.

I-11. Compounds of formulas I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9 and I-10 may include compounds of formula I-11 , which are compounds of formula I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9 or I-10, while Y (linking group) is alkylene, cycloalkylene, heterocycloalkylene, arylene (eg phenylene), heteroarylene, oxaalkylene, alkylene-amide-alkylene, alkylene-amine-alkylene, or combinations of any of the groups mentioned above. Preferred linking groups include C ₁ -C ₈ alkylene (eg ethylene or propylene), C ₁ -C ₈ oxaalkylene, C ₁ -C ₈ alkylene amide-C ₁ -C ₈ alkylene and C ₁ -C ₈ alkylene amine -C ₁ -C ₈ alkylene. Particular preference is given to C ₁ -C ₈ alkylene, especially ethylene (-CH ₂ CH ₂ -).

I-12. Compounds of formulas I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10 and I-11 may include compounds of formula I-12, which are compounds of formula I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I -10 or I-11, where T is a bond or is NR ⁶ (eg, NH).

I-13. Compounds of formulas I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11 and I- 12 may include compounds of formula I-13 which are compounds of formula I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I -9, I-10, I-11, or I-12, where EWG is in each case cyano, amide, ester, keto, or aldehyde.

I-14. Compounds of formulas I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I- 12 and I-13 may include compounds of formula I-14 which are compounds of formula I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I -8, I-9, I-10, I-11, I-12 and I-13, where B is a 6-membered aromatic ring, optionally containing one heteroatom selected from O, S and N.

I-15. Compounds of formulas I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I- 12, I-13 and I-14 may include compounds of formula I-15 which are compounds of formula I-1, I-2, I-3, I-4, I-5, I-6, I-7 , I-8, I-9, I-10, I-11, I-12, I-13 or I-14, where D is a 6-membered aromatic ring, optionally containing one heteroatom selected from O, S and N.

I-16. Compounds of formulas I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I- 12, I-13, I-14 and I-15 may include compounds of formula I-16 which are compounds of formula I-1, I-2, I-3, I-4, I-5, I-6 , I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, or I-15, where ring C is a 6-membered saturated heterocycloalkyl ring, containing at least one carbon atom in the ring and one heterogroup selected from O, S, NR ⁶ , SO or SO ₂ , wherein the heterocycloalkyl ring is substituted on one carbon atom in the ring by a group of the formula ═C(EWG)(R ⁷ ).

I-17. Compounds of formulas I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I- 12, I-13, I-14, I-15 and I-16 may include compounds of formula I-17 which are compounds of formula I, I-1, I-2, I-3, I-4, I -5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15 or I-16, where R ⁷ is an EWG.

I-18. Compounds of formulas I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I- 12, I-13, I-14, I-15 and I-16 may include compounds of formula I-18 which are compounds of formula I, I-1, I-2, I-3, I-4, I -5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15 or I-16, where R ⁷ is -C(=O)-TYP _g .

I-19. Compounds of formulas I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I- 12, I-13, I-14, I-15, I-16, I-17 and I-18 may include compounds of formula I-19 which are compounds of formula I, I-1, I-2, I -3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15 , I-16, I-17 or I-18, where the compound contains two YP _g groups.

I-20. Compounds of formulas I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I- 12, I-13, I-14, I-15, I-16, I-17 and I-18 may include compounds of formula I-20 which are compounds of formula I, I-1, I-2, I -3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15 , I-16, I-17 or I-18, where the compound contains one YP _g group.

Compounds of formula I-z may be excluded from compounds of formula I:

formula I-z

where X represents O, S, NR ⁶ , SO or SO ₂ ; and where R ¹ , R ² , n, m, EWG, T, Y, P _g and R ⁶ are defined above for compounds of formula II.

Compounds of formula I and its subformulas (I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I -11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19 and I-20) may include the compounds shown in Table A, which are compounds of formula I or any of its subformulas, having the following structures:

Table A

;
II

;
II

;
III

;
IV

;
V

;
VI

;
VII

;
VIII

;
IX

;
X

;
XI

;
XII

; And
XIII

,
XIV

In the structures shown in Table A, X is independently O, S, NR ⁶ , SO or SO ₂ ; and Z is independently O, S or NR ⁶ .

Specific examples of compounds of formula I include, without limitation, those shown in Table B.

Table B

The compounds of formula I can be used in combination with other light absorbing compounds to provide the desired absorption characteristics. For example, preferred compositions may contain a compound of Formula I and a UV absorbing compound. The UV absorbing compound may, for example, also be a compound of formula I which absorbs UV radiation, or it may be another UV absorbing compound. Suitable UV absorbing compounds other than those of formula I are known in the art and fall into several classes including, but not limited to, benzophenones, benzotriazoles, triazines, substituted acrylonitriles, salicyclic acid derivatives, benzoic acid derivatives, cinnamic acid derivatives, acids, chalcone derivatives, dipnon derivatives, crotonic acid derivatives, or any mixture thereof. A preferred class of UV absorbing compounds are benzotriazoles such as Norbloc (2-(2'-hydroxy-5-methacrylyloxyethylphenyl)-2H-benzotriazole).

The compounds of formula I can be obtained by experts in this field using methods described in the literature. As an example, various compounds of formula I, where EWG is cyano, can be obtained as shown in scheme 1 and the corresponding description. Examples of reagents and procedures for these reactions are provided in the demos.

Scheme 1

Scheme 1 shows a method for preparing exemplary compounds of the present invention. Thus, the carbonyl functional group of the starting material is converted to a reactive dihalogen intermediate, which is further reacted with the active methylene compound without further purification or isolation. The reaction mixture is protected from exposure to air and moisture until the reaction with the cyanomethylamide derivative is completed. Other compounds of the present invention can be prepared by those skilled in the art using procedures similar to those described in Scheme 1, with proper substitution of the reagents.

Other compounds of formula I can be prepared by those skilled in the art using or adapting the general strategy shown in Scheme 2.

Scheme 2

Compounds of formula I can be included in reaction mixtures to form a variety of products, including biomedical devices and ophthalmic devices. In general, the compounds of formula I may be present in any amount up to their limit of solubility. For example, the concentration of these compounds may be in the range of at least 0.1 percent or at least 2 percent; and up to 10 percent or up to 5 percent, based on the mass fraction of all components in the reaction mixture, with the exception of the diluent. A typical concentration may be in the range of 1 to 5 percent. The upper limit is generally determined by the solubility of the compound with other comonomers and/or diluents in the reaction monomer mixture.

The compounds of formula I are preferably formulated into ophthalmic devices. A variety of ophthalmic devices can be made, including hard contact lenses, soft contact lenses, corneal patches, corneal implants, intraocular lenses, or masking lenses. The ophthalmic device is preferably an intraocular lens or a soft contact lens. A soft contact lens can be made from conventional (non-silicone) hydrogel or silicone hydrogel.

The ophthalmic devices of the present invention may comprise a free radical reaction product of a reaction mixture containing one or more monomers suitable for making the desired ophthalmic device (also referred to herein as device-forming monomers or hydrogel-forming monomers), and optional components. Upon polymerization, the reaction mixture results in the formation of a polymeric network that can be used to form an ophthalmic device. The polymeric network may be, for example, a hydrogel (eg a conventional hydrogel or a silicone hydrogel).

The compound of formula I may be copolymerized with other components of the reaction mixture, in which case the reaction mixture may, in addition to one or more monomers suitable for making the desired ophthalmic device (and any optional components), also contain one or more compounds of formula I.

Alternatively or additionally, the compound of formula I may be incorporated into the polymer network as a preformed non-reactive polymer. The non-reactive polymer may be included in the reaction mixture or may be included in the polymer network after the polymer network has already been formed from the reaction mixture (for example, as a coating or by heating the mixture of the polymer network with the non-reactive polymer).

The non-reactive polymer may contain repeat units derived from a compound of formula I. The non-reactive polymer may contain, in addition to repeat units derived from a compound of formula I, repeat units derived from other compounds such as an amide monomer or a monofunctional polyalkylene glycol, or a combination thereof. The non-reactive polymer may contain at least 0.1 mole percent, alternatively at least 1 mole percent, alternatively at least 10 mole percent, or alternatively at least 20 mole percent of repeating units derived from compounds of Formula I. The non-reactive polymer may contain 100 mole percent, alternatively up to 80 mole percent, alternatively up to 50 mole percent, alternatively up to 20 mole percent, or alternatively up to 5 mole percent of repeating units derived from compounds of formula I.

An exemplary monofunctional polyalkylene glycol that can be used to form a non-reactive polymer is a monofunctional polyethylene glycol having a weight average molecular weight of about 200 g/mol to about 10,000 g/mol, such as about 200 g/mol to about 2,000 g/mol . A monofunctional polyethylene glycol contains only one polymerizable group and may be a monoether and mono-(meth)acrylate or (meth)acrylamide-terminated polyethylene glycol. Examples of monoether end groups include, without limitation, C ₁ -C ₆ alkoxy groups such as methoxy groups and ethoxy groups or alkoxy groups containing up to 8 carbon atoms. Examples of such monoether and monomethacrylate terminated polyethylene glycols include, without limitation, mPEG 475 (polyethylene glycol monomethacrylate monomethyl ether (molecular weight 475)) manufactured by Sigma-Aldrich, St. Louis, Missouri, USA ("mPEG475" ).

Examples of amide monomers that can be used to form a non-reactive polymer include an acyclic amide of formula H1 or H2, a cyclic amide of formula H3, or combinations thereof:

where R ⁴⁵ represents H or methyl; V is a direct link, -(CO)- or -(CONHR ₄₄ )-; R ₄₄ is C ₁ -C ₃ alkyl; R ₄₀ is H or C ₁ -C ₄ alkyl; R ₄₁ represents H, C ₁ -C ₄ -alkyl, amino containing up to two carbon atoms, amide containing up to four carbon atoms, and alkoxy containing up to two carbon groups; R ₄₂ represents H, C ₁ -C ₄ alkyl groups; or methoxy, ethoxy, hydroxyethyl or hydroxymethyl; R ₄₃ is H, C ₁ -C ₄ alkyl; or methoxy, ethoxy, hydroxyethyl or hydroxymethyl; moreover, the number of carbon atoms in R ₄₀ and R ₄₁ taken together is 8 or less; and wherein the number of carbon atoms in R ₄₂ and R ₄₃ taken together is 8 or less; and f is a number from 1 to 10; Illustrative optional substituents of the above groups include amine, amide, ether, hydroxyl, carbonyl or carboxyl groups, or combinations thereof.

Non-limiting examples of polymeric networks in which a compound of formula I can be incorporated (e.g., as a monomer or non-reactive polymer in a reaction mixture or by subsequent addition) are described above and include, for example, etafilcon, genfilcon, gilafilcon, lenefilcon, nesofilcon, omafilcon, polymacon, vifilcon, aquafilcon, asmofilcon, balafilcon, comfilcon, delefilcon, enfilcon, fanfilcon, formofilcon, halifilcon, lotrafilcon, narafilcon, riofilcon, samfilcon, senofilcon, somofilcon and stenfilcon, including all variants thereof.

As a further example, a polymer network can be made from a reaction mixture containing one or more of: hydrophilic components, hydrophobic components, silicone-containing components, wetting agents such as polyamides, cross-linking agents, and additional components such as diluents and initiators. As described above, the reaction mixture may also contain one or more compounds of formula I and/or non-reactive polymer containing repeating units derived from one or more compounds of formula I, or non-reactive polymer may be added after the formation of the polymer network.

Hydrophilic components

Examples of suitable families of hydrophilic monomers that may be present in the reaction mixture include (meth)acrylates, styrenes, vinyl ethers, (meth)acrylamides, N-vinyl lactams, N-vinylamides, N-vinylimides, N-vinylureas, O-vinylcarbamates , O-vinyl carbonates, other hydrophilic vinyl compounds and mixtures thereof.

Non-limiting examples of hydrophilic (meth)acrylate and (meth)acrylamide monomers include: acrylamide, N-isopropylacrylamide, N,N-dimethylaminopropyl(meth)acrylamide, N,N-dimethylacrylamide (DMA), 2-hydroxyethyl methacrylate (HEMA), 2-hydroxypropyl(meth)acrylate, 3-hydroxypropyl(meth)acrylate, 2,3-dihydroxypropyl(meth)acrylate, 2-hydroxybutyl(meth)acrylate, 3-hydroxybutyl(meth)acrylate, 4-hydroxybutyl(meth)acrylate, N-(2-hydroxyethyl)(meth)acrylamide, N,N-bis(2-hydroxyethyl)(meth)acrylamide, N-(2-hydroxypropyl)(meth)acrylamide, N,N-bis(2-hydroxypropyl)( meth)acrylamide, N-(3-hydroxypropyl)(meth)acrylamide, N-(2-hydroxybutyl)(meth)acrylamide, N-(3-hydroxybutyl)(meth)acrylamide, N-(4-hydroxybutyl)(meth) acrylamide, 2-aminoethyl(meth)acrylate, 3-aminopropyl(meth)acrylate, 2-aminopropyl(meth)acrylate, N-2-aminoethyl(meth)acrylamides), N-3-aminopropyl(meth)acrylamide, N-2 -aminopropyl(meth)acrylamide, N,N-bis-2-aminoethyl(meth)acrylamides, N,N-bis-3-aminopropyl(meth)acrylamide), N,N-bis-2-aminopropyl(meth)acrylamide, glycerol methacrylate, polyethylene glycol monomethacrylate, (meth)acrylic acid, vinyl acetate, acrylonitrile, and mixtures thereof.

Hydrophilic monomers can also be ionic, including anionic, cationic, zwitterion, betaines, and mixtures thereof. Non-limiting examples of such charged monomers include (meth)acrylic acid, N-[(ethenyloxy)carbonyl]-β-alanine (VINAL), 3-acrylamidopropanoic acid (ACA1), 5-acrylamidopentanoic acid (ACA2), 3-acrylamido -3-methylbutanoic acid (AMBA), 2-(methacryloyloxy)ethyltrimethylammonium chloride (Q-salt or METAC), 2-acrylamido-2-methylpropanesulfonic acid (AMPS), 1-propanaminium, N-(2-carboxyethyl)-N, N -dimethyl-3-[(1-oxo-2-propen-1-yl)amino]-, internal salt (CBT), 1-propanaminium, N,N-dimethyl-N-[3-[(1-oxo- 2-propen-1-yl) amino]propyl]-3-sulfo-, internal salt (SBT), 3,5-dioxa-8-aza-4-phosphonoundec-10-ene-1-aminium, 4-hydroxy- N,N,N-trimethyl-9-oxo-, internal salt, 4-oxide (9CI) (PBT), 2-methacryloyloxyethylphosphorylcholine, 3-(dimethyl(4-vinylbenzyl)ammonio)propane-1-sulfonate (DMVBAPS), 3-((3-acrylamidopropyl)dimethylammonio)propane-1-sulfonate (AMPDAPS), 3-((3-methacrylamidopropyl)dimethylammonio)propane-1-sulfonate (MAPDAPS), 3-((3-(acryloyloxy)propyl)dimethylammonio )propane-1-sulfonate (APDAPS); and methacryloyloxy)propyl)dimethylammonio)propane-1-sulfonate (MAPDAPS).

Non-limiting examples of hydrophilic N-vinyl lactam and N-vinylamide monomers include: N-vinylpyrrolidone (NVP), N-vinyl-2-piperidone, N-vinyl-2-caprolactam, N-vinyl-3-methyl-2 -caprolactam, N-vinyl-3-methyl-2-piperidone, N-vinyl-4-methyl-2-piperidone, N-vinyl-4-methyl-2-caprolactam, N-vinyl-3-ethyl-2-pyrrolidone , N-vinyl-4,5-dimethyl-2-pyrrolidone, N-vinylacetamide (NVA), N-vinyl-N-methylacetamide (VMA), N-vinyl-N-ethylacetamide, N-vinyl-N-ethylformamide, N -vinylformamide, N-vinyl-N-methylpropionamide, N-vinyl-N-methyl-2-methylpropionamide, N-vinyl-2-methylpropionamide, N-vinyl-N, N'-dimethylurea, 1-methyl-3-methylene- 2-pyrrolidone, 1-methyl-5-methylene-2-pyrrolidone, 5-methyl-3-methylene-2-pyrrolidone; 1-ethyl-5-methylene-2-pyrrolidone, N-methyl-3-methylene-2-pyrrolidone, 5-ethyl-3-methylene-2-pyrrolidone, 1-N-propyl-3-methylene-2-pyrrolidone, 1-N-propyl-5-methylene-2-pyrrolidone, 1-isopropyl-3-methylene-2-pyrrolidone, 1-isopropyl-5-methylene-2-pyrrolidone, N-vinyl-N-ethylacetamide, N-vinyl- N-ethylformamide, N-vinylformamide, N-vinylisopropylamide, N-vinylcaprolactam, N-vinylimidazole and mixtures thereof.

Non-limiting examples of hydrophilic monomers of O-vinyl carbamates and O-vinyl carbonates include N-2-hydroxyethyl vinyl carbamate and N-carboxy-β-alanine N-vinyl ester. Additional examples of hydrophilic vinyl carbonate or vinyl carbamate monomers are described in US Pat. No. 5,070,215. Hydrophilic oxazolone monomers are described in US Pat. No. 4,910,277.

Other hydrophilic vinyl compounds include ethylene glycol vinyl ether (EGVE), di(ethylene glycol) vinyl ether (DEGVE), allyl alcohol, 2-ethyloxazoline.

The hydrophilic monomers may also be macromers or prepolymers of straight or branched poly(ethylene glycol), poly(propylene glycol), or random or block copolymers of ethylene oxide and propylene oxide having polymerizable moieties such as (meth)acrylates, styrenes, vinyl ethers, (meth)acrylamides, N-vinylamides, and the like. The macromer of such polyethers has one polymerizable group; prepolymers may have two or more polymerizable groups.

Preferred hydrophilic monomers of the present invention are DMA, NVP, HEMA, VMA, NVA and mixtures thereof. Preferred hydrophilic monomers include mixtures of DMA and HEMA. Other suitable hydrophilic monomers will be apparent to those skilled in the art.

In general, there are no particular restrictions on the amount of hydrophilic monomer present in the reaction mixture. The amount of hydrophilic monomer can be selected based on the desired characteristics of the resulting hydrogel, including water content, transparency, wettability, protein uptake, and the like. Wettability can be measured using the contact angle. Desirable contact angles are less than about 100˚, less than about 80˚, and less than about 60˚. The hydrophilic monomer may be present in an amount in the range, for example, from about 0.1 wt.% to about 100 wt.%, in another embodiment, in the range from about 1 to about 80 wt.%, in another embodiment, in the range from about 5 to about 65 wt.%, in another embodiment, in the range from about 40 wt.% to about 60 wt.%, or in another embodiment, in the range from about 55 wt.% to about 60 wt.% of the total weight of the reactive components in the reaction monomer mixture .

Silicone containing components

Silicone-containing components suitable for use in the invention comprise one or more polymerizable compounds, each compound independently containing at least one polymerizable group, at least one siloxane group, and one or more linking groups connecting the polymerizable group(s)(- s) with siloxane(s) group(s). Silicone-containing components may, for example, contain from 1 to 220 siloxane repeating units, such as the groups described below. The silicone-containing component may also contain at least one fluorine atom.

The silicone-containing component may contain: one or more polymerizable groups as defined above; one or more optionally repeating siloxane units; and one or more linking groups linking the polymerizable groups to the siloxane units. The silicone-containing component may contain: one or more polymerizable groups, which are independently (meth)acrylate, styryl, vinyl ether, (meth)acrylamide, N-vinyl lactam, N-vinylamide, O-vinyl carbamate, O-vinyl carbonate, vinyl group, or mixtures of the above; one or more optionally repeating siloxane units; and one or more linking groups linking the polymerizable groups to the siloxane units.

The silicone-containing component may contain: one or more polymerizable groups which are independently (meth)acrylate, (meth)acrylamide, N-vinyl lactam, N-vinylamide, styryl, or mixtures of the foregoing; one or more optionally repeating siloxane units; and one or more linking groups linking the polymerizable groups to the siloxane units.

The silicone-containing component may contain: one or more polymerizable groups, which are independently (meth)acrylate, (meth)acrylamide, or mixtures of the foregoing; one or more optionally repeating siloxane units; and one or more linking groups linking the polymerizable groups to the siloxane units.

The silicone-containing component may contain one or more polymerizable groups of formula A:

wherein:

at least one R ^A is a group of formula R _g -L-, where R _g is a polymerizable group and L is a linking group, and each of the remaining R ^A is independently:

(a) _Rg -L-,

(b) C ₁ -C ₁₆ alkyl optionally substituted with one or more of hydroxy, amino, amido, oxa, carboxy, alkylcarboxy, carbonyl, alkoxy, amido, carbamate, carbonate, halogen, phenyl, benzyl, or combinations thereof,

(c) C ₃ -C ₁₂ cycloalkyl optionally substituted with one or more of alkyl, hydroxy, amino, amido, oxa, carbonyl, alkoxy, amido, carbamate, carbonate, halogen, phenyl, benzyl, or combinations thereof,

(d) C ₆ -C ₁₄ aryl optionally substituted with one or more of alkyl, hydroxy, amino, amido, oxa, carboxy, alkylcarboxy, carbonyl, alkoxy, amido, carbamate, carbonate, halogen, phenyl, benzyl, or combinations thereof,

(e) halogen,

(f) alkoxy, cyclic alkoxy or aryloxy,

(g) siloxy,

(h) an alkyleneoxyalkyl or alkoxyalkyleneoxyalkyl such as polyethyleneoxyalkyl, polypropyleneoxyalkyl or poly(ethyleneoxysopropyleneoxyalkyl), or

(i) a monovalent siloxane chain containing from 1 to 100 siloxane repeating units optionally substituted with alkyl, alkoxy, hydroxy, amino, oxa, carboxy, alkylcarboxy, alkoxy, amido, carbamate, halogen, or combinations thereof; And

n is from 0 to 500, or from 0 to 200, or from 0 to 100, or from 0 to 20, and it is assumed that if n is different from 0, then n is a distribution having a mode equal to the declared value. If n is 2 or more, the SiO units may have the same or different R ^A substituents, and if different R ^A substituents are present, then the n groups may have a random or block configuration.

In Formula A, each of the three ^RAs may contain a polymerizable group, alternatively, each of the two ^RAs may contain a polymerizable group, or alternatively, one ^RA may contain a polymerizable group.

Examples of silicone-containing components suitable for use in the invention include, without limitation, the compounds listed in Table C. If the compounds in Table C contain polysiloxane groups, then the number of SiO repeating units in such compounds, unless otherwise indicated, is preferably from 3 to 100, more preferably 3 to 40, or even more preferably 3 to 20.

Table C

1 monomethacryloxypropyl and mono-n-butyl terminated polydimethylsiloxanes (mPDMS) (preferably containing 3 to 15 SiO repeating units) 2 polydimethylsiloxane with monoacryloxypropyl and mono-n-butyl end groups 3 polydimethylsiloxane with mono(meth)acryloxypropyl and mono-n-methyl end groups 4 polydiethylsiloxane with mono(meth)acryloxypropyl and mono-n-butyl end groups 5 polydiethylsiloxane with mono(meth)acryloxypropyl and mono-n-methyl end groups 6 mono(meth)acrylamidoalkylpolydialkylsiloxanes 7 monoalkylpolydiarylsiloxanes with mono(meth)acryloxyalkyl end groups 8 3-methacryloxypropyltris(trimethylsiloxy)silane (TRIS) 9 3-Methacryloxypropylbis(trimethylsiloxy)methylsilane 10 3-methacryloxypropylpentamethyldisiloxane eleven mono(meth)acrylamidoalkylpolydialkylsiloxanes 12 mono(meth)acrylamidoalkylpolydimethylsiloxanes 13 N-(2,3-dihydroxypropane)-N'-(propyltetra(dimethylsiloxy)dimethylbutylsilane)acrylamide 14 N-[3-tris(trimethylsiloxy)silyl]propylacrylamide (TRIS-Am) 15 2-hydroxy-3-[3-methyl-3,3-di(trimethylsiloxy)silylpropoxy]propyl methacrylate (SiMAA) 16 2-hydroxy-3-methacryloxypropyloxypropyltris(trimethylsiloxy)silane 17

полидиметилсилоксаны с моно(2-гидрокси-3-метакрилоксипропил)-пропилэфирными и моно-н-бутильными концевыми группами (OH-mPDMS) (содержащие от 4 до 30, или от 4 до 20, или от 4 до 15 повторяющихся звеньев SiO)

mono(2-hydroxy-3-methacryloxypropyl)-propylether and mono-n-butyl terminated polydimethylsiloxanes (OH-mPDMS) (containing 4 to 30, or 4 to 20, or 4 to 15 SiO repeating units) 18

19

20

21

22

23

24

Additional non-limiting examples of suitable silicone-containing components are listed in Table D. Unless otherwise indicated, j2, where applicable, is preferably 1 to 100, more preferably 3 to 40, or even more preferably 3 to 15. In compounds containing j1 and j2, the sum of j1 and j2 is preferably 2 to 100, more preferably 3 to 40, or even more preferably 3 to 15.

Table D

25

26

p is between 1 and 10 27

p is between 5 and 10 28

29

thirty 1,3-bis[4-(vinyloxycarbonyloxy)but-1-yl]tetramethyldisiloxane 31 3-(vinyloxycarbonylthio)propyl[tris(trimethylsiloxy)silane] 32 3-[tris(trimethylsiloxy)silyl]propylallyl carbamate 33 3-[tris(trimethylsiloxy)silyl]propylvinylcarbamate 34 tris(trimethylsiloxy)silylstyrene (Styryl-TRIS) 35

36

37

38

39

40

41

It is possible to use mixtures of silicone-containing components. By way of example, suitable mixtures may include, but are not limited to: a mixture of mono-(2-hydroxy-3-methacryloxypropyloxy)-propyl and mono-n-butyl terminated polydimethylsiloxane (OH mPDMS) of various molecular weights, such as a mixture of OH mPDMS, containing 4 and 15 repeating units of SiO; a mixture of OH mPDMS of various molecular weights (eg, containing 4 and 15 SiO repeating units) together with a silicone crosslinker such as bis-3-acryloxy-2-hydroxypropyloxypropyl polydimethylsiloxane (ac-PDMS); a mixture of 2-hydroxy-3-[3-methyl-3,3-di(trimethylsiloxy)silylpropoxy]-propyl methacrylate (SiMAA) and monomethacryloxypropyl and mono-n-butyl terminated polydimethylsiloxane (mPDMS), such as mPDMS 1000.

Silicone-containing components for use in the present invention may have an average molecular weight of from about 400 to about 4000 daltons.

The silicone-containing(s) component(s) may be included in the composition in an amount of up to about 95 wt.%, from about 10 wt.% to about 80 wt.%, from about 20 wt.% to about 70 wt.% from the total content of reactive components in the reaction mixture (excluding diluents).

Polyamides

The reaction mixture may include at least one polyamide. Used in this document, the term "polyamide" refers to polymers and copolymers containing repeating units, which include amide groups. The polyamide may contain cyclic amide groups, acyclic amide groups, and combinations thereof, and may be any polyamide known to those skilled in the art. Acyclic polyamides contain pendant amide groups and are capable of associating with hydroxyl groups. Cyclic polyamides contain cyclic amide groups and are capable of associating with hydroxyl groups.

Examples of suitable acyclic polyamides include polymers and copolymers containing repeating units of formulas G1 and G2:

Formula G1

Formula G2

where X represents a direct connection, -(CO)- or -(CONHR ₄₄ )-, and R ₄₄ represents a C ₁ -C ₃ alkyl group; R ₄₀ is selected from H, substituted or unsubstituted C ₁ -C ₄ straight or branched chain alkyl groups; R ₄₁ is selected from H, substituted or unsubstituted C ₁ -C ₄ straight or branched chain alkyl groups, amino groups containing no more than two carbon atoms, amide groups containing no more than four carbon atoms, and alkoxy groups containing no more than two atoms carbon; R ₄₂ is selected from H, substituted or unsubstituted C ₁ -C ₄ straight or branched chain alkyl groups; or methyl, ethoxy, hydroxyethyl and hydroxymethyl; R ₄₃ is selected from H, substituted or unsubstituted C ₁ -C ₄ straight or branched chain alkyl groups; or methyl, ethoxy, hydroxyethyl and hydroxymethyl; where the number of carbon atoms in R ₄₀ and R ₄₁ taken together is 8 or less, including 7, 6, 5, 4, 3 or less; and where the number of carbon atoms in R ₄₂ and R ₄₃ taken together is 8 or less, including 7, 6, 5, 4, 3 or less. The number of carbon atoms in R ₄₀ and R ₄₁ taken together may be 6 or less, or 4 or less. The number of carbon atoms in R ₄₂ and R ₄₃ taken together may be 6 or less. As used herein, substituted alkyl groups include alkyl groups substituted with amino, amide, ether, hydroxyl, carbonyl, carboxyl groups, or combinations thereof.

R ₄₀ and R ₄₁ may be independently selected from H, substituted or unsubstituted C ₁ -C ₂ alkyl groups. X may be a direct bond, and R ₄₀ and R ₄₁ may be independently selected from H, substituted or unsubstituted C ₁ -C ₂ alkyl groups. R ₄₂ and R ₄₃ may be independently selected from H, substituted or unsubstituted C ₁ -C ₂ alkyl groups, methyl, ethoxy, hydroxyethyl and hydroxymethyl.

The acyclic polyamides of the present invention may contain a majority of the Formula LV or Formula LVI repeating units, or the acyclic polyamides may contain at least 50 mole percent of the Formula G or Formula G1 repeating units, including at least about 70 mole percent and at least about 80 mole percent percent. Specific examples of repeating units of formula G and formula G1 include repeating units derived from N-vinyl-N-methylacetamide, N-vinylacetamide, N-vinyl-N-methylpropionamide, N-vinyl-N-methyl-2-methylpropionamide, N-vinyl -2-methylpropionamide, N-vinyl-N,N'-dimethylureas, N,N-dimethylacrylamide, methacrylamide and acyclic amides of formulas G2 and G3:

Formula G2

Formula G3

Examples of suitable cyclic amides that can be used to prepare the cyclic polyamides of the present invention include α-lactam, β-lactam, γ-lactam, δ-lactam and ε-lactam. Examples of suitable cyclic polyamides include polymers and copolymers containing repeating units of formula G4:

Formula G4

where R ₄₅ represents a hydrogen atom or a methyl group; where f is an integer from 1 to 10; where X represents a direct connection, -(CO)- or -(CONHR ₄₆ )-, where R ₄₆ represents a C ₁ -C ₃ alkyl group. In formula LIX, f may be 8 or less, including 7, 6, 5, 4, 3, 2, or 1. In formula G4, f may be 6 or less, including 5, 4, 3, 2, or 1. In formula G4 f may be 2 to 8, including 2, 3, 4, 5, 6, 7, or 8. In LIX formula, f may be 2 or 3. If X is a direct bond, f may be 2. In such cases, the cyclic polyamide may be polyvinylpyrrolidone (PVP).

The cyclic polyamides of the present invention may contain 50 mole percent or more of a repeating unit of formula G4, or the cyclic polyamides may include at least 50 mole percent of a repeating unit of formula G4, including at least 70 mole percent, and at least 80 mole percent.

Polyamides can also be copolymers containing repeating units of cyclic and acyclic amides. Additional repeating units may be formed from monomers selected from hydroxyalkyl(meth)acrylates, alkyl(meth)acrylates or other hydrophilic monomers, and siloxanes substituted with (meth)acrylates. Any of the monomers listed above as suitable hydrophilic monomers may be used as a comonomer to form further repeating units. Specific examples of additional monomers that can be used to form polyamides include 2-hydroxyethyl (meth)acrylate, vinyl acetate, acrylonitrile, hydroxypropyl (meth)acrylate, methyl (meth)acrylate and hydroxybutyl (meth)acrylate, dihydroxypropyl (meth)acrylate, polyethylene glycol mono (meth)acrylate, etc., and mixtures thereof. Ionic monomers may also be included. Examples of ionic monomers include (meth)acrylic acid, N-[(ethenyloxy)carbonyl]-β-alanine (VINAL, CAS number 148969-96-4), 3-acrylamidopropionic acid (ACA1), 5-acrylamidopentanoic acid (ACA2), 3-acrylamido-3-methylbutanoic acid (AMBA), 2-(methacryloyloxy)ethyltrimethylammonium chloride (Q salt or METAC), 2-acrylamido-2-methylpropanesulfonic acid (AMPS), 1-propanaminium, N-(2-carboxyethyl)- N,N-dimethyl-3-[(1-oxo-2-propen-1-yl)amino]-, internal salt (CBT, carboxybetaine; CAS 79704-35-1), 1-propanaminium, N,N-dimethyl -N-[3-[(1-oxo-2-propen-1-yl)amino]propyl]-3-sulfo-, internal salt (SBT, sulfobetaine, CAS 80293-60-3), 3,5-dioxa -8-aza-4-phosphoundec-10-en-1-aminium, 4-hydroxy-N,N,N-trimethyl-9-oxo-, internal salt, 4-oxide (9CI) (PBT, phosphobetaine, CAS 163674 -35-9), 2-methacryloyloxyethylphosphorylcholine, 3-(dimethyl(4-vinylbenzyl)ammonio)propane-1-sulfonate (DMVBAPS), 3-((3-acrylamidopropyl)dimethylammonio)propane-1-sulfonate (AMPDAPS), 3 -((3-methacrylamidopropyl)dimethylammonio)propane-1-sulfonate (MAMPDAPS), 3-((3-(acryloyloxy)propyl)dimethylammonio)propane-1-sulfonate (APDAPS), methacryloyloxy)propyl)dimethylammonio)propane-1- sulfonate (MAPDAPS).

The monomer reaction mixture may contain both acyclic polyamide and cyclic polyamide or their copolymers. The acyclic polyamide can be any of the acyclic polyamides described herein or their copolymers, and the cyclic polyamide can be any of the cyclic polyamides described herein or their copolymers. The polyamide may be selected from the group consisting of polyvinylpyrrolidone (PVP), polyvinylmethacetamide (PVMA), polydimethylacrylamide (PDMA), polyvinylacetamide (PNVA), poly(hydroxyethyl(meth)acrylamide), polyacrylamide, and copolymers and mixtures thereof. The polyamide may be a mixture of PVP (eg, PVP K90) and PVMA (eg, having an M _w of approximately 570 kDa).

The total amount of polyamides in the reaction mixture can be in the range from 1 wt.% to about 35 wt.%, including in the range from about 1 wt.% to about 15 wt.%, and in the range from about 5 wt.% to about 15 wt.% in all cases, based on the total weight of the reactive components in the reaction monomer mixture.

Without wishing to be bound by theory, when used with silicone hydrogel, the polyamide acts as an internal wetted agent. The polyamides of the present invention may be non-polymerizable, in which case they are incorporated into silicone hydrogels as semi-interpenetrating polymer networks. The polyamides are captured or physically held within the silicone hydrogels. Alternatively, the polyamides of the present invention may be polymerizable, eg polyamide macromers or prepolymers, and in this case, are covalently incorporated into silicone hydrogels. Mixtures of polymerizable and non-polymerizable polyamides can also be used.

When polyamides are incorporated into the reactive monomer mixture, they may have a number average molecular weight of at least 100,000 daltons; more than about 150,000; between about 150,000 daltons to about 2,000,000 daltons; between about 300,000 daltons to about 1,800,000 daltons; Higher molecular weight polyamides may be used if they are compatible with the reactive monomer mixture.

Crosslinkers

As such, it is desirable to add one or more crosslinking agents, also referred to as crosslinking monomers, multifunctional macromers, and prepolymers, to the reaction mixture. Crosslinkers can be selected from bifunctional crosslinkers, trifunctional crosslinkers, tetrafunctional crosslinkers, and mixtures thereof, including silicone and non-silicon crosslinkers. Non-silicone containing crosslinkers include ethylene glycol dimethacrylate (EGDMA), tetraethylene glycol dimethacrylate (TEGDMA), trimethylol propane trimethacrylate (TMPTMA), triallyl cyanurate (TAC), glycerol methacrylate, methacryloxyethyl vinyl carbonate (HEMAVc), allyl methacrylate, methylene bisacrylamide (MBA), and polyethylene glycol dimethacrylate, with polyethylene the glycol has a molecular weight of up to about 5000 daltons. Crosslinkers are used in conventional amounts, for example, from about 0.000415 to about 0.0156 moles per 100 grams of reactive formulas in the reaction mixture. In another embodiment, if the hydrophilic monomers and/or silicone-containing components are multifunctional due to the structure of the molecule or due to the presence of impurities, then additional introduction of a crosslinking agent into the reaction mixture is optional. Examples of hydrophilic monomers and macromers which can act as crosslinkers and which do not require additional crosslinkers to be added to the reaction mixture include (meth)acrylate and (meth)acrylamide terminated polyesters. Other crosslinkers are known to those skilled in the art that can be used to prepare the silicone hydrogels of the present invention.

It may be desirable to select crosslinkers with the same reactivity as one or more other reactive components in the formulation. In some cases, it may be desirable to select a mixture of crosslinkers with different reactivity to control some physical, mechanical, or biological property of the resulting silicone hydrogel. The structure and morphology of the silicone hydrogel can also be influenced by the diluent(s) and the polymerization conditions used.

Multifunctional silicone-containing components, including macromers, crosslinkers, prepolymers, can also be used to further increase the elastic modulus while maintaining tensile strength. Silicone-containing crosslinkers may be used alone or in combination with other crosslinkers. An example of a silicone-containing component that acts as a crosslinker, and which does not require the addition of additional crosslinkers to the reaction mixture, is α,ω-bismethacryloxypropyl polydimethylsiloxane. Another example is bis-3-acryloxy-2-hydroxypropyloxypropyl polydimethylsiloxane (ac PDMS).

Crosslinking agents that have rigid chemical structures and polymerizable groups involved in free radical polymerization can also be used. Non-limiting examples of suitable rigid structures include crosslinkers containing

and a benzyl ring such as 1,4-phenylene diacrylate, 1,4-phenylene dimethacrylate, 2,2-bis(4-methacryloxyphenyl)propane, 2,2-bis[4-(2-acryloxyethoxy)phenyl]propane, 2, 2-bis[4-(2-hydroxy-3-methacryloxypropoxy)phenyl]propane and 4-vinylbenzylmethacrylate and combinations thereof. Rigid cross-linking agents can be introduced in amounts between about 0.5 and about 15, or 2-10, 3-7, based on the total weight of all reaction components. The physical and mechanical properties of the silicone hydrogels of the present invention can be optimized for a particular application by adjusting the components of the reaction mixture.

Non-limiting examples of silicone crosslinkers also include the multifunctional silicone-containing components shown in Table D above.

Additional components

The reaction mixture may contain additional components such as, but not limited to, diluents, initiators, UV absorbers, visible light absorbers, photochromic compounds, drugs, nutraceuticals, antimicrobials, dyes, pigments, copolymerizable dyes and non-polymerizable dyes, release agents and their combinations.

Classes of suitable diluents for silicone hydrogel reactive mixtures include alcohols having 2 to 20 carbon atoms, amides having 10 to 20 carbon atoms derived from primary amines, and carboxylic acids having 8 to 20 carbon atoms. Diluents can be primary, secondary and tertiary alcohols.

Essentially, the reactive components are mixed with a diluent to form a reaction mixture. Acceptable diluents are known to those skilled in the art. Suitable diluents for silicone hydrogels are described in WO 03/022321 and US 6020445, the description of which is incorporated herein by reference.

Classes of acceptable diluents for silicone hydrogel reactive mixtures include alcohols having 2 to 20 carbon atoms, amides having 10 to 20 carbon atoms derived from primary amines, and carboxylic acids having 8 to 20 carbon atoms. Primary and tertiary alcohols may be used. Preferred classes include alcohols having 5 to 20 carbon atoms and carboxylic acids having 10 to 20 carbon atoms.

Specific diluents that may be used include 1-ethoxy-2-propanol, diisopropylaminoethanol, isopropanol, 3,7-dimethyl-3-octanol, 1-decanol, 1-dodecanol, 1-octanol, 1-pentanol, 2 -pentanol, 1-hexanol, 2-hexanol, 2-octanol, 3-methyl-3-pentanol, tert-amyl alcohol, tert-butanol, 2-butanol, 1-butanol, 2-methyl-2-pentanol, 2- propanol, 1-propanol, ethanol, 2-ethyl-1-butanol, (3-acetoxy-2-hydroxypropyloxy)propylbis(trimethylsiloxy)methylsilane, 1-tert-butoxy-2-propanol, 3,3-dimethyl-2-butanol , tert-butoxyethanol, 2-octyl-1-dodecanol, decanoic acid, octanoic acid, dodecanoic acid, 2-(diisopropylamino)ethanol, mixtures thereof, and the like. Examples of amide diluents include N,N dimethyl propionamide and dimethylacetamide.

Preferred diluents include 3,7-dimethyl-3-octanol, 1-dodecanol, 1-decanol, 1-octanol, 1-pentanol, 1-hexanol, 2-hexanol, 2-octanol, 3-methyl-3-pentanol , 2-pentanol, tert-amyl alcohol, tert-butanol, 2-butanol, 1-butanol, 2-methyl-2-pentanol, 2-ethyl-1-butanol, ethanol, 3,3-dimethyl-2-butanol, 2-octyl-1-dodecanol, decanoic acid, octanoic acid, dodecanoic acid, mixtures thereof, etc.

More preferred diluents include 3,7-dimethyl-3-octanol, 1-dodecanol, 1-decanol, 1-octanol, 1-pentanol, 1-hexanol, 2-hexanol, 2-octanol, 1-dodecanol, 3- methyl 3-pentanol, 1-pentanol, 2-pentanol, tert-amyl alcohol, tert-butanol, 2-butanol, 1-butanol, 2-methyl-2-pentanol, 2-ethyl-1-butanol, 3.3 -dimethyl-2-butanol, 2-octyl-1-dodecanol, mixtures thereof, etc.

As such, there is no particular limitation on the amount of diluent present, so long as the diluent is present. If a diluent is used, it may be present in an amount in the range from about 2 wt.% to about 70 wt.%, including in the range from about 5 wt.% to about 50 wt.%, and in the range from about 15 wt.% to about 40 wt.% of the total mass of the reaction mixtures (including reactive and non-reactive formula). Mixtures of diluents may be used.

A polymerization initiator may be used in the reaction mixture. Polymerization initiators may include at least one of lauroyl peroxide, benzoyl peroxide, isopropyl percarbonate, azobisisobutyronitrile, and the like, which generate free radicals at moderately elevated temperatures, and photosensitizing systems such as aromatic alpha-hydroxy ketones, alkoxyoxybenzoins, acetophenones, acrylphosphine oxides, bisacylphosphine oxides, and tertiary amine plus diketone, mixtures thereof, etc. Illustrative examples of photoinitiators are 1-hydroxycyclohexylphenyl ketone, 2-hydroxy-2-methyl-1-phenylpropan-1-one, bis(2,6-dimethoxybenzoyl)-2,4-4 -trimethylpentylphosphine oxide (DMBAPO), bis(2,4,6-trimethylbenzoyl)-phenylphosphine oxide (Irgacure 819), 2,4,6-trimethylbenzyldiphenylphosphine oxide and 2,4,6-trimethylbenzoyldiphenylphosphine oxide, benzoin methyl ether, and a combination of camphorquinone and ethyl-4-( N,N-dimethylamino)benzoate.

Marketed (by IGM Resins B.V., Netherlands) visible light sensitive initiator systems include Irgacure® 819, Irgacure® 1700, Irgacure® 1800, Irgacure® 819, Irgacure® 1850 and Lucrin® TPO initiator. Marketed (by IGM Resins B.V.) UV-sensitive photoinitiators include Darocur® 1173 and Darocur® 2959. These and other photoinitiators that may be used are described in Volume III Photoinitiators for Free Radical Cationic & Anionic Photopolymerization, Volume III, 2 th edition by J. V. Crivello and K. Dietliker; edited by G. Bradley; John Wiley and Sons; New York; 1998. The initiator is used in the reaction mixture in effective amounts to initiate photopolymerization of the reaction mixture, for example, from about 0.1 to about 2 parts by weight per 100 parts of the reaction monomer mixture. The polymerization of the reaction mixture can be initiated by properly selected heating, or by exposure to visible or ultraviolet light, or by other means, depending on the polymerization initiator used. Alternatively, the initiation can be carried out using an electron beam without a photoinitiator. However, if a photoinitiator is used, the preferred initiators are bisacylphosphine oxides such as bis(2,4,6-trimethylbenzoyl)-phenylphosphine oxide (Irgacure® 819) or a combination of 1-hydroxycyclohexylphenylketone and bis(2,6-dimethoxybenzoyl)-2,4-4 -trimethylphenylphosphine oxide (DMBAPO).

The reaction mixture for the manufacture of ophthalmic devices of the present invention, in addition to the compounds of formula I, may contain any of the polymerizable compounds and optional components described above.

The reaction mixture may contain: a compound of formula I and a hydrophilic component.

The reaction mixture may contain: a compound of formula I and a hydrophilic component selected from DMA, NVP, HEMA, VMA, NVA, methacrylic acid and mixtures thereof. Mixtures of HEMA and methacrylic acid are preferred.

The reaction mixture may contain: a compound of formula I, a hydrophilic component and a silicone-containing component.

The reaction mixture may contain: a compound of formula I, a hydrophilic component selected from DMA, HEMA, and mixtures thereof; a silicone-containing component selected from 2-hydroxy-3-[3-methyl-3,3-di(trimethylsiloxy)silylpropoxy]propyl methacrylate (SiMAA), monomethacryloxypropyl and mono-n-butyl-terminated polydimethylsiloxane (mPDMS), mono-terminated polydimethylsiloxane -(2-hydroxy-3-methacryloxypropyloxy)-propyl and mono-n-butyl groups (OH-mPDMS) and mixtures thereof; and a wetting agent (preferably PVP or PVMA). For the hydrophilic component, mixtures of DMA and HEMA are preferred. For the silicone-containing component, blends of SiMAA and mPDMS are preferred.

The reaction mixture may contain: a compound of formula I, a hydrophilic component containing a mixture of DMA and HEMA; a silicone-containing component containing an OH-mPDMS mixture having 2 to 20 repeat units (preferably a mixture having 4 to 15 repeat units). The reaction mixture preferably further contains a silicone-containing cross-linking agent such as ac-PDMS. It is also preferred that the reaction mixture contains a wetting agent (preferably DMA, PVP, PVMA or mixtures thereof).

The reaction mixture may contain: a compound of formula I; from about 1 wt.% to about 15 wt.% at least one polyamide (eg, acyclic polyamide, cyclic polyamide, or mixtures thereof); at least one first monofunctional hydroxyl-substituted poly(disubstituted siloxane) containing 4 to 8 siloxane repeating units (eg OH-mPDMS where n is 4 to 8, preferably n is 4); at least one second hydroxyl-substituted poly(disubstituted siloxane) which is a monofunctional hydroxyl-substituted poly(disubstituted siloxane) having 10 to 200 or 10-100 or 10-50 or 10-20 siloxane repeating units (e.g., OH-mPDMS, where n is from 10 to 200, or 10-100, or 10-50, or 10-20, or preferably n is 15); from about 5 wt.% to about 35 wt.% at least one hydrophilic monomer; and in some cases, a multifunctional hydroxyl-substituted poly(disubstituted siloxane) having 10 to 200 or 10 to 100 siloxane repeat units (eg, ac-PDMS). The first monofunctional hydroxyl-substituted poly(disubstituted siloxane) and the second hydroxyl-substituted poly(disubstituted siloxane) are preferably present in concentrations that provide the ratio of the mass fraction of the first monofunctional hydroxyl-substituted poly(disubstituted siloxane) to the mass fraction of the second hydroxyl-substituted poly(disubstituted siloxane) equal to 0.4-1 .3 or 0.4-1.0.

The above reaction mixtures may contain optional ingredients such as but not limited to one or more initiators, internal wetting agents, crosslinking agents, other UV/HEV absorbers and diluents.

If the monomer suitable for making the ophthalmic device described above is a combination of a hydrophilic component and a silicone-containing component, the reaction product preferably contains repeating units derived from a compound of formula I other than a compound of formula I-z:

formula I-z

It should be noted that the compound of formula I-z may still be present in the reaction product, but it is preferred that other compounds of formula I are also present.

Hydrogel curing and lens fabrication

The reaction mixtures can be formed by any method known in the art, such as agitation or agitation, and used to form polymer articles or devices by known methods. The reactive components are mixed with or without a diluent to form a reaction mixture.

For example, ophthalmic devices can be made by mixing reactive components and optionally diluent(s) with a polymerization initiator and curing under the proper conditions to form a product that can subsequently be shaped by turning, milling, or the like. Alternatively, the reaction mixture may be placed in a mold and subsequently polymerized into a suitable product.

A method for manufacturing a molded ophthalmic device such as a silicone hydrogel contact lens may include: preparing a reactive monomer mixture; transferring the reaction monomer mixture to the first mold; placing the second mold on top of the first mold filled with the reactive monomer mixture; and curing the reactive monomer mixture by free radical copolymerization to form a silicone hydrogel in the form of a contact lens.

The reaction mixture can be cured by any known method of molding the reaction mixture in the manufacture of contact lenses, including spin casting and static casting. Centrifugal casting methods are described in US Pat. Nos. 3,408,429 and 3,660,545, and static casting methods are described in US Pat. Using this method, the reaction mixture is placed in a mold having the shape of the finished silicone hydrogel, and the reaction mixture is subjected to conditions under which the monomers are polymerized, thereby obtaining a polymer whose shape approximately corresponds to the desired shape of the finished product.

After polymerization, the lens may be subjected to extraction to remove unreacted components, after which the lens is removed from the mold. The extraction may be carried out using conventional extractants such as organic solvents, for example alcohols, or may be carried out using aqueous solutions.

Aqueous solutions are solutions containing water. The aqueous solutions of the present invention may contain at least about 20 wt.% water, or at least about 50 wt.% water, or at least about 70 wt.% water, or at least about 95 wt.% water. Aqueous solutions may also include additional water-soluble formulas such as inorganic salts or release agents, wetting agents, anti-friction additives, drug and nutraceutical formulas, combinations thereof, and the like. Release agents are compounds or mixtures of compounds that, when combined with water, reduce the time required to remove the contact lens from the mold, compared with the time required to remove such a lens using an aqueous solution that does not contain a release agent. Aqueous solutions may not require special handling, such as cleaning, recycling, or special disposal procedures.

Extraction can be performed, for example, by immersing the lens in an aqueous solution or by exposing the lens to a stream of an aqueous solution. The extraction may also include, for example, one or more of: heating the aqueous solution; stirring the aqueous solution; increasing the level of the auxiliary release agent in the aqueous solution to a level sufficient to remove the lens; mechanical or ultrasonic agitation of the lens; and introducing into the aqueous solution at least one leaching or extraction aid to a level sufficient to facilitate adequate removal of unreacted components from the lens. The above processes can be carried out sequentially or continuously with or without additional exposure to heating, stirring, or both.

Physical agitation may be required to facilitate leaching and recovery. For example, the portion of the mold to which the finished lens is attached may be subjected to vibration or back and forth movement within an aqueous solution. Other methods may include passing ultrasonic waves through an aqueous solution.

The lenses may be sterilized by known methods such as, but not limited to, autoclaving.

As stated above, the preferred ophthalmic devices are contact lenses, more preferably soft hydrogel contact lenses. The wavelengths and percentage transmittances described herein can be measured at various lens thicknesses using, for example, the techniques described in the examples. By way of example, a preferred thickness of the central portion for measuring transmission spectra in a soft contact lens may be 80 to 100 microns, or 90 to 100 microns, or 90 to 95 microns. Typically, the measurement can be made at the center of the lens using, for example, an instrument with a 4 nm slot. Various concentrations of one or more polymerizable high energy absorbing compounds can be used to obtain the characteristics described above. For example, the concentration may be in the range of at least 1 percent or at least 2 percent; and up to 10 percent or up to 5 percent of the mass fraction of all components in the reaction mixture, with the exception of the diluent. A typical concentration may be in the range of 3 to 5 percent.

Silicone hydrogel ophthalmic devices (eg contact lenses) according to the invention preferably have the following properties. All listed values are preceded by the "approximately" modifier, and devices can have any combination of the listed properties. Properties can be determined by methods known to those skilled in the art, for example, as described in US patent application US20180037690, the contents of which are incorporated herein by reference.

Water concentration, %: at least 20% or at least 25%, and up to 80% or up to 70%

Haze: 30% or less or 10% or less

Dynamic weep angle (Wilhelmy plate method): 100° or less or 80° or less; or 50° or less

Tensile modulus (psi): 120 or less, or 80 to 120

Oxygen permeability (Dk, barrers): at least 80 or at least 100 or at least 150 or at least 200

Elongation at break: at least 100

For ionic silicone hydrogels, the following properties may also be preferred (in addition to those listed above):

Lysozyme uptake (µg/lens): at least 100 or at least 150 or at least 500 or at least 700

Polyquaternium 1 (PQ1) absorption (%): 15 or less, or 10 or less, or 5 or less

Some embodiments of the invention will be described in detail in the following examples.

EXAMPLES

Testing Methods

UV-visible spectra of compounds in solution were measured using a Perkin Elmer Lambda 45, Agilent Cary 6000i, or Ocean Optics QE65 PRO scanning spectrometer (DH-2000-BAL light source). Before use, the instrument was thermally equilibrated for at least thirty minutes. For the Perkin Elmer instrument, the scan range was 200-800 nm; the scanning speed was 960 nm per minute; the slot width was 4 nm; the mode was set to transmit or absorb; and baseline correction selected. For the Cary instrument, the scanning range was 200-800 nm; the scanning speed was 600 nm/min; the slot width was 2 nm; the mode was for transmission or absorption; and baseline correction selected. For the Ocean Optics instrument, the scanning range was 200–800 nm; the slot width was 10 μm; the mode was for transmission or absorption; and baseline correction selected. Before analyzing the samples using the auto-zero function, a baseline correction was performed.

Spectra of contact lenses formed in part from the claimed compositions in the UV and visible region were measured using a scanning spectrometer Perkin Elmer Lambda 45 UV/VIS, Agilent Cary 6000i UV/VIS or Ocean Optics UV/VIS. Before use, the instrument was thermally equilibrated for at least thirty minutes. Baseline correction was performed using cuvettes containing two-cavity plastic lens holders and identical solvents. These two two-socket contact lens holders were configured to hold the sample in the quartz cuvette at the location through which the incident light passes. The control cuvette also contained a two-slot holder. To ensure consistent specimen thickness, all lenses were manufactured using identical molds. The thickness of the center of the contact lens was measured using an electronic thickness gauge. The given thicknesses of the central part and the transmission spectra are obtained by averaging the data for three separate lenses.

It is important to ensure that the external surfaces of the cuvette are completely clean and dry and that there are no air bubbles in it. The reproducibility of measurement results is improved when the reference cuvette and its lens holder are not interchanged, and when the same test cell and its lens holder are used in all samples, making sure that both cuvettes are properly inserted into the instrument.

In the examples and figures, the following abbreviations will be used, the meanings of which are given below:

l: liter(s)

ml: milliliter(s)

Equiv. or equivalent: equivalent

kg: kilogram

g:gram

mg:milligram

mole: mole(s)

mmol: millimol(s)

Yes: dalton or g/mol

kDa: kilodalton or atomic mass unit equal to 1000 daltons

min: minute(s)

µm: micrometer(s)

nm: nanometer(s)

¹ N NMR: nuclear magnetic resonance spectroscopy

UV-VIS: spectroscopy in the visible and ultraviolet regions of the spectrum

TLC: thin layer chromatography

BC: back or main curve plastic mold

FC: front curve plastic mold

PP: polypropylene, which is a propylene homopolymer

TT: Tuftec which is a hydrogenated styrene-butadiene block copolymer (Asahi Kasei Chemicals)

Z: Zeonor which is a polycycloolefin thermoplastic polymer (Nippon Zeon Co Ltd)

DMA: N,N-dimethylacrylamide (Jarchem)

HEMA: 2-hydroxyethyl methacrylate (Bimax)

PVP K90: poly(N-vinylpyrrolidone) (ISP Ashland)

TEGDMA: tetraethylene glycol dimethacrylate (Esstech)

Irgacure or Omnirad 1870: mixture of bis(2,6-dimethoxybenzoyl)-2,4,4-trimethylpentylphosphine oxide and 1-hydroxycyclohexylphenylketone (IGM Resins or BASF or Ciba Specialty Chemicals)

mPDMS: mono-n-butyl and monomethacryloxypropyl terminated polydimethylsiloxane (M _n =800-1500 daltons) (Gelest)

SiMAA: 2-propenoic acid, 2-methyl-2-hydroxy-3-[3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]disiloxanyl]propoxy]propyl ester (Toray) or 3 -(3-(1,1,1,3,5,5,5-heptamethyltrisiloxan-3-yl)propoxy)-2-hydroxypropyl methacrylate

Norbloc: 2-(2'-hydroxy-5-methacryloxyethylphenyl)-2H-benzotriazole (Janssen)

RB247: 1,4-Bis[2-methacryloxyethylamino]-9,10-anthraquinone

TL03 light sources: Phillips TLK 40W/03 lamps

LED: LED

D3O: 3,7-dimethyl-3-octanol (Vigon)

DIW: deionized water

MeOH: methanol

IPA: isopropyl alcohol

DMF: N,N-dimethylformamide

DMSO: dimethyl sulfoxide

DCM or CH ₂ Cl ₂ : dichloromethane or methylene chloride

DCE: 1,2-dichloroethane

CDCl ₃ : deutrochloroform

PhOH: phenol

H ₂ SO ₄ : sulfuric acid

HCl: hydrochloric acid

pTsOH: p-toluenesulfonic acid

Ac ₂ O: acetic anhydride

Cs ₂ CO ₃ : cesium carbonate

SOCl ₂ : thionyl chloride

NaH: sodium hydride

CPTP: 2-(3-chloropropoxy)tetrahydro-2H-pyran

NaI: sodium iodide

borate buffered storage solution: 18.52 grams (300 mmol) boric acid, 3.7 grams (9.7 mmol) sodium borate decahydrate and 28 grams (197 mmol) sodium sulfate were dissolved in enough deionized water to fill 2- liter measuring flask.

Preparation 1. Synthesis of 2-(2-cyanoacetamido)ethyl methacrylate

Methyl cyanoacetate (40 g, 0.4037 mol) and 25 ml dichloromethane were stirred in a 500 ml three-necked round bottom flask under reflux under nitrogen atmosphere. 2-Aminoethanol (23.8 grams, 0.3897 mol, ~0.97 eq.) was added to the solution via an addition funnel, after which the temperature increased and the methylene chloride began to drain. After the termination of the exothermic reaction, external heating was carried out to continue the smooth flow back for a total of two hours, after which no ethanolamine was detected by thin layer chromatography.

The reaction can also be carried out at room temperature and run for several hours. The mixture was cooled to room temperature and all the methylene chloride was evaporated under reduced pressure. The residual oil was washed three times with 50 ml of ethyl acetate to remove unreacted starting material and non-polar impurities. The residual ethyl acetate was then removed under reduced pressure and the resulting oil was used for the acylation without any further purification.

The crude N-2-hydroxyethylacetamide derivative was dissolved in 150 ml of dichloromethane containing 40 g of pyridine (~0.5 mol) in a three-necked round bottom flask equipped with a reflux condenser, addition funnel and magnetic stirrer. The flask was immersed in an ice bath and allowed to cool to about 0°C. Methacryloyl chloride (45.76 g, ~0.44 mol) was added dropwise from an addition funnel, the resulting reaction mixture was left to warm to room temperature with constant stirring of the system. Methanol (20 ml) was added to the flask to stop the reaction of any unreacted methacryloyl chloride. Volatile components were removed by evaporation on a rotary evaporator under reduced pressure and the crude product was dissolved in 800 ml of dilute aqueous HCl. The resulting aqueous solution was extracted three times with 100 ml of hexane in a separating funnel to remove any non-polar impurities. The organic layers were discarded. Sodium chloride was added to the aqueous layer, which was then extracted three times with 300 ml of ethyl acetate. About 50 milligrams of BHT was added to the combined organic fractions as an inhibitor and the ethyl acetate was removed by rotary evaporation under reduced pressure. The resulting crude product was crystallized from solution during removal of the solvent. After about 100 ml of ethyl acetate remained in the flask, 250 ml of hexane was added and the crude product was separated by vacuum filtration using a fritted glass funnel. Analysis by thin layer chromatography revealed one compound. The filter cake was washed twice with 150 ml of hexane and then dried in vacuo at 40°C to give 53 g (about 70% yield) of 2-(2-cyanoacetamido)ethyl methacrylate. ¹ H NMR (500 MHz, CDCl ₃ ) δ 1.93 (3H, s, CH ₃ ), 3.36 (2H, s, CNCH ₂ ), 3.60 (2H, dd, CH ₂ NH), 4, 26 (2H, t, CH ₂ OC=O), 5.59 (1H, m, vinyl), 6.11 (1H, bs, vinyl), 6.52 (1H, bs, NH).

Example 1 Synthesis of isomers of a mixture of (E and Z)-2-(2-cyano-2-(9H-thieno[3,2-b]tichromen-9-ylidene)acetamido)ethyl methacrylate and (E and Z)-2- cyano-N-(2-((3-methylbuta-1,3-dien-2-yl)oxy)ethyl)-2-(4H-thieno[2,3-b]tichromen-4-ylidene)acetamide (compound A) as shown in diagram 1

Scheme 1

To a stirred suspension of 7.0 g of 9H-thieno[3,2-b]tichromen-9-one and 4H-thieno[2,3-b]tichromen-4-one (0.032 mol) in 40 ml of anhydrous 1, Oxalyl chloride (25 grams, ~3 eq.) was added dropwise to 2-dichloroethane under nitrogen atmosphere over five minutes. The mixture quickly darkened and a gradual exothermic reaction was observed. After the termination of the exothermic reaction, the mixture was heated for 6 hours at a temperature of 55°C. Thereafter, the system was cooled to room temperature and the volatiles were evaporated under reduced pressure to give a solid. Under nitrogen atmosphere, a solution of 7.0 g of 2-(2-cyanoacetamido)ethyl methacrylate (~0.036 mol) and 5.0 g of triethylamine (excess) in 50 ml of anhydrous dichloromethane was added to the solid. The mixture was stirred at room temperature for 20 minutes and then gently heated under reflux for 6 hours. The system was cooled to room temperature and the volatiles were evaporated under reduced pressure. The crude products were dissolved in warm ethyl acetate and filtered. The filtrate was concentrated. After purification in a silica gel column (the mixture is designated as compound A), a mixture of target molecules was isolated. Mixture of isomers: compound A (mixture of isomers) ¹ H NMR (CDCl ₃ ) 1.85-1.94 (3H, m, CH ₃ ), 3.51-3.69 (2H, multiple signals, CH ₂ ), 4 .10-4.29 (2 H, multiple signals, CH ₂ ), 5.54-5.58 (1 H, multiple signals, vinyl), 6.00-6.12 (1 H, multiple signals, vinyl), 6.10-6.49 (1H, multiple signals, NH), 6.89-8.54 (6H, multiple signals, ArH) δ

The UV-VIS transmission spectrum of a 0.2 mmol/L solution of Compound A in methanol is shown in FIG. 1.

Example 3 Synthesis of a mixture of isomers of (E)-2-(2-cyano-2-(2-propoxy-9H-thioxanthene-9-ylidene)acetamido)ethyl methacrylate and (Z)-2-(2-cyano-2-( 2-propoxy-9H-thioxanthene-9-ylidene)acetamido)ethyl methacrylate (Compound C) as shown in Scheme 3

Scheme 3

To a stirred suspension of 2.28 g of 2-hydroxythioxanthenone (0.01 mol) and 5.0 g of cesium carbonate in anhydrous DMSO under nitrogen atmosphere was added 1.5 g of 1-bromopropane (~1.25 eq.) and the resulting mixture heated overnight at 60°C. The reaction mixture was cooled and poured into 300 ml of ethyl acetate. The organic layers were extracted 3 times with 300 ml of 1% aqueous sodium chloride. The volatiles were removed under reduced pressure and the crude material was used as is in the next step.

Thionyl chloride (10 g, 0.085 mol) was added to the crude propyl ether under nitrogen atmosphere and the mixture was stirred for one hour at reflux. The mixture was cooled to room temperature and the volatiles were evaporated under reduced pressure. The system was placed back under nitrogen and a solution of 2-(2-cyanoacetamido)ethyl methacrylate (3.0 g, ~1.5 eq.) and 5.0 g pyridine (excess) in 30 ml anhydrous dichloromethane was added. The mixture was stirred under gentle reflux for an additional 3 hours. The system was cooled to room temperature and the volatiles were evaporated under reduced pressure. The crude products were redissolved in ethyl acetate and extracted with dilute aqueous HCl. The organic layer was concentrated and the mixture of products was isolated by chromatography on a silica gel plug (the mixture is designated compound C). Compound C (mixture of isomers) - ¹ H NMR (CDCl3) - δ0.99 (3H, m, CH ₃ ), 1.57-1.85 (2H, m, CH ₂ and 3H, m, CH ₃ ), 3 .48 (2H, m, CH ₂ ), 3.84 (1H, t, J=6 Hz), 3.98 (1H, t, J=6 Hz), 4.0 (2H, m, CH ₂ ) , 5.54 (1H, m, vinyl), 5.85 (1H, m, NH), 5.96 and 5.97 (1H, br. (2 signals), NH), 6.78-8.14 (6H, Ar).

The UV-VIS transmission spectrum of a 0.2 mmol/L solution of Compound C in methanol is shown in FIG. 1.

Example 4 Synthesis of 3-(9-(dicyanomethylene)acrypyridin-10(9H)-yl)propyl methacrylate (Compound D) as shown in Scheme 4

Scheme 4

Acridone (3.92 g, 0.02 mol) and 0.8 g of a 60 wt% suspension of sodium hydride in mineral oil (0.02 mol) were stirred in 20 ml of anhydrous N,N-dimethylformamide under nitrogen atmosphere. After the evolution of gaseous hydrogen ceased, 3.9 g of 2-(3-chloropropoxy)tetrahydro-2H-pyran (~1.1 equiv.) were added to the flask, followed by 250 mg of sodium iodide, and the mixture was heated in a mantle heater to 90 night. The system was cooled to room temperature, the mixture was poured into water and stirred for 15 minutes. The resulting solids were filtered and the filter cake was washed with dichloromethane to remove most of the unreacted acridone. The filtrate was concentrated under reduced pressure. The residue was dissolved in 200 ml of methanol, 200 mg of p -toluenesulfonic acid was added and the resulting mixture was stirred at room temperature. Deprotection was complete by TLC after stirring overnight. The mixture was then stirred at room temperature for 30 minutes after adding 2 g of sodium carbonate. The suspension was filtered and the volatiles were evaporated under reduced pressure. The resulting solids were stirred in 100 ml of cold methanol and filtered. The insoluble material was a mixture of unreacted acridone and the desired product, which was nevertheless used directly in the next step.

A mixture of 10-(3-hydroxypropyl)acridin-9(10H)-one and acridin-9(10H)-one (1.6 g, <6.28 mmol starting material) and 3 g triethylamine (~30 mmol) was stirred in 70 ml of chilled methylene chloride. Methacryloyl chloride (1.0 g, 9.6 mmol) was added to the mixture dropwise into the system, after which it was allowed to warm to room temperature. After apparent completion of the acylation, the volatiles were removed under reduced pressure and the product was isolated as a 6:1 mixture along with the N-acylated (methacrylamide) acridine derivative after filtration through a thin layer of silica gel.

Malononitrile (1 g, 0.015 mol) and 0.5 g of a mixture of 3-(9-oxoacridin-10(9 H)-yl) propyl methacrylate and 10-methacryloylacridin-9(10 H)-one (< 1.56 mmol) were heated at 130°C in ~10 ml of acetic anhydride and the reaction was monitored by TLC. The reaction appeared to be complete after 6 hours as a bright orange non-polar spot was observed as the main reaction product. The mixture was cooled to room temperature, and then water was added thereto with continuous stirring for another 30 minutes. The precipitate formed was isolated by filtration, and then the filter cake was washed several times with water using a fritted glass funnel. The organic layers were dissolved in dichloromethane, filtered and the product was purified after chromatography on silica gel with a mixture of ethyl acetate and dichloromethane (compound D). Compound D ¹ H NMR (CDCl3) - δ2.00 (3H, br. CH ₃ ), 2.34 (2H, m, CH ₂ ), 4.36 (2H, t, J=6 Hz), 4, 45 (2H, m), 5.66 (1H, m, vinyl), 6.17 (1H, m, vinyl), 7.31 (2H, ddd, J=8.5, 7.0, 1.5 Hz, ArH), 7.48 (2H, d, 8.5 Hz, ArH), 7.67 (2H, ddd, J=7.5, 7.0, 1.5 Hz, ArH), 8.51 (2H, dd, J=8.5, 1.5 Hz, ArH).

The UV-VIS transmission spectrum of a solution of compound D in methanol at a concentration of 0.2 mmol/l is shown in FIG. 1.

Example 5 Synthesis of 2-((9-(dicyanomethylene)-9H-xanthen-3-yl)oxy)ethyl methacrylate

(connection E) as shown in diagram 5

Scheme 5

A suspension of 3-hydroxy-9H-xanthen-9-one (4.24 g, 0.02 mol), 7.0 g Cs ₂ CO ₃ (0.07 mol) and 3.0 g 2-chloroethyl methacrylate (0.02 mol) in 40 ml of anhydrous DMSO was heated overnight at 60°C. TLC monitoring showed complete consumption of the hydroxyxanthenone along with the formation of a less polar derivative. The reaction mixture was cooled to room temperature and diluted with 500 ml of ethyl acetate. The organic layers were washed three times with 300 ml of 2 wt.% aqueous sodium chloride solution, and then concentrated under reduced pressure. The resulting solid was washed with hexanes using a fritted glass funnel to give a white powder of 3-((9-oxo-9H-xanthen-3-yl)oxy)propyl methacrylate.

3-((9-oxo-9H-xanthen-3-yl)oxy)propyl methacrylate (1.0 g, 3.08 mmol) and 10 g thionyl chloride were heated under reflux for four hours under nitrogen atmosphere. The system was cooled to room temperature and the excess thionyl chloride was evaporated under reduced pressure. A solution of 1 g of malonitrile (~15.15 mmol) in 20 ml of dichloromethane was added to the flask under nitrogen and the mixture was heated gently at reflux for another 2 hours. The mixture was cooled to room temperature and after purification on a silica gel column (Compound E), the desired product was isolated. The ¹ H NMR spectrum of compound E is shown in FIG. 8. Compound E ¹ H NMR (CDCl3) - δ1.93 (3H, t, J=0.75 Hz, CH ₃ ), 4.33 (2H, t, J=4.5 Hz, CH ₂ ), 4 .53 (2H, m, CH ₂ ), 5.59 (1H, m, vinyl), 6.12 (1H, br., vinyl), 6.90 (1H, d, J=3.0 Hz, ArH), 6.97 (1H, dd, J=9.5, 3.0 Hz, ArH), 7.37 (1H, ddd, J=8.5, 7.0, 1.5 Hz, ArH), 7, 42 (1H, dd, J=8.5, 1.5 Hz), 7.65 (1H, ddd, J=8.5, 7.0, 1.5 Hz, ArH), 8.47 (1H, d, J=9.5 Hz, ArH), 8.53 (1H, dd, J=8.5, 1.5 Hz, ArH).

The UV-VIS transmission spectrum of a solution of compound E in methanol at a concentration of 0.2 mmol/l is shown in FIG. 1 and FIG. 2.

Example 6 Synthesis of 2-(2-cyano-2-(9H-thioxanthene-9-ylidene)acetamido)ethyl methacrylate (Compound F) as shown in Scheme 6

Scheme 6

A mixture of 9 H -thioxanthen-9-one (2.12 grams, 0.01 mol) and thionyl chloride (5 ml, 8.2 grams, ~0.07 mol) was refluxed in a 50 ml round bottom flask under nitrogen atmosphere with constant stirring. After two hours, the red solution was evaporated to dryness, ensuring that all unreacted thionyl chloride was removed from the system. 2-(2-cyanoacetamido)ethyl methacrylate (A) (2.3 grams, 0.0117 mol, ~1.17 eq.) and 15 ml dichloromethane were added and the resulting reaction mixture was refluxed under nitrogen. The reaction was monitored by thin layer chromatography. After two hours, the chromatogram showed no change, so the reaction mixture was allowed to cool to room temperature. 2-(2-cyano-2-(9H-thioxanthene-9-ylidene)acetamido)ethyl methacrylate (B) was separated as yellow crystals (3.2 g, 82% yield) after passing through a short silica gel column (CH ₂ Cl ₂ then 8 wt% EtOAc in CH ₂ Cl ₂ ). ¹ H NMR (500 MHz, CDCl ₃ ) δ 1.84 (3H, s, CH ₃ ), 3.47 (2H, m, CH ₂ NH), 4.01 (2H, t, CH ₂ OC=O) , 5.55 (1H, m, vinyl), 5.91 (1H, bs, NH), 5.98 (1H, bs, vinyl), 7.24 (1H, t, Ar-H), 7.31 (1H, t, Ar-H), 7.39 (2H, m, Ar-H), 7.49 (1H, d, Ar-H), 7.55 (1H, m, Ar-H), 7 .61 (1H, d, Ar-H), 8.04 (1H, m, Ar-H). The UV-VIS transmission spectrum of a 0.2 mmol/L solution of Compound F in methanol is shown in FIG. 2.

Examples 7-9

Monomer reaction mixtures were prepared from 77 weight percent of the compositions listed in Table 1 and 23 weight percent of diluent D3O. The monomer reaction mixtures were individually filtered through a 3 μm filter using a pressurized stainless steel syringe.

Table 1

Component (wt%) original product Example 7 Example 8 Example 9 mPDMS: 31.79 31.01 31.61 30.91 SiMAA 28.46 27.75 28.29 27.67 DMA 24.48 23.88 24.35 23.81 HEMA 6.24 6.08 6.09 5.95 TEGDMA 1.56 1.52 1.5 1.5 PVP K90 7.09 6.92 6.8 6.8 Omnirad 1870 0.35 0.35 0.34 0.34 RB247 0.02 0.02 0.02 0.02 Compound E 0.00 0.50 1 1 Connection F 0.00 1.98 0 2 General 100 100 100 100

These monomer reaction mixtures were degassed at ambient temperature by applying a vacuum (40 Torr) for at least 20 minutes. In a nitrogen gas glovebox with approximately 0.1-0.2 percent oxygen gas, approximately 75 μl of the reaction mixture was pipetted with an Eppendorf pipette at room temperature into FC made from a 90:10 Zeonor/TT mixture (according to mass). Then BC, made from a mixture of Z:TT in a ratio of 90:10 (by weight) was placed in FC. The molds were kept in the glove box for at least twelve hours prior to application. The trays, each containing eight molds, were transferred to an adjacent glove box, which was kept at 65°C, and the lenses were polymerized top and bottom using LED lamps with a wavelength of 435 nm and an intensity of about 1.5 mW/ cm² for 3 minutes and then about 2.5 mW/cm² for 7 minutes.

The lenses were molded by hand, with most of the lenses sticking to the FC, and were removed by suspending the lenses in about one liter of 70% IPA for about one hour, followed by soaking twice in 70% IPA for 30 minutes; then twice in fresh DIW for 15 minutes; then twice in with the packaging solution for 30 minutes. The lenses were balanced and stored in a borate buffered packaging solution. One of ordinary skill in the art will appreciate that this lens extraction process can be modified depending on the lens composition and mold materials, taking into account the concentration of isopropanol aqueous solutions, the number of washes with each solvent, and the duration of each step. The goal of the lens retrieval process is to remove all lenses without causing damage and transition from swollen diluent meshes to swollen storage solution meshes. Measured the average thickness of the Central part of each set of lenses; example 7=88 microns, example 8=91 microns, example 9=90 microns.

In FIG. 3 shows the spectra of UV-visible lenses made according to examples 7-9, showing that mixtures of Compound E and Compound F provide almost complete absorption in the range from 300 nm to 400 nm with significant absorption in the high-energy region of the visible spectrum from 400 nm to 450 nm. Similar mixtures in combination with other UV-VIS inhibitors such as benzotriazoles (Norbloc) and/or at different concentrations can provide complete absorption in the 300 nm to 400 nm range with significant absorption of high-energy visible light from 400 nm up to 500 nm.

Claims (44)

1. Contact lens, which is a polymerization reaction product of the reaction mixture, containing: a monomer suitable for the manufacture of a contact lens; and (b) a fused tricyclic compound selected from formulas III and V:

where X represents O, S or NR ⁶ ; Z is S; m and n are independently 0 or 1; R ¹ and R ² are independently at each occurrence H, C ₁ -C ₆ alkoxy or -YP _g ; R ⁶ is H or YP _g ; R ⁷ is EWG or -C(=O)-TYP _g , and EWG is in each case independently -CN; P _g at each occurrence is independently —CH=CH ₂ , —C(CH ₃ )=CH ₂ ; Y is independently at each occurrence a linking group selected from -O-(CH ₂ ) ₂ -OC(O)-, -O-(CH ₂ ) ₃ -OC(O)-, (CH ₂ ) ₃ -OC( O)-CH(CH ₃ )-, -(CH ₂ ) ₃ -OC(O)-CH(CH ₃ )-, -O-(CH ₂ ) ₃ -OC(O)-CH(CH ₃ )-; And T is in each case independently NR ⁶ , wherein the compound contains at least one P _g group. 2. The contact lens of claim 1, wherein m and n are each independently 0 or 1. 3. A contact lens according to any of the preceding claims, wherein R ¹ is H, C ₁ -C ₆ alkoxy. 4. A contact lens according to any of the preceding claims, wherein R ² is independently H, C ₁ -C ₆ alkoxy. 5. A contact lens according to any one of the preceding claims, wherein R ⁶ is H. 6. A contact lens according to any one of the preceding claims, wherein T is NR ⁶ . 7. A contact lens according to any of the preceding claims, wherein the EWG is independently cyano in each case. 8. A contact lens according to any one of the preceding claims, wherein R ⁷ is EWG. 9. A contact lens according to any one of the preceding claims, wherein R ⁷ is -C(=O)-TYP _g . 10. A contact lens according to any one of the preceding claims, wherein the compound contains one YP _g group. 11. A contact lens according to any one of the preceding claims, wherein the compound has a structure selected from formulas III and V. 12. Contact lens according to claim 1, where the connection is: 2-((9-(dicyanomethylene)-9H-xanthen-3-yl)oxy)ethyl methacrylate; 3-(9-(dicyanomethylene)acridin-10(9H)-yl)propyl methacrylate; (E)-2-(2-cyano-2-(4H-thieno[2,3-b]thiochromen-4-ylidene)acetamido)ethyl methacrylate; (Z)-2-(2-cyano-2-(4H-thieno[2,3-b]thiochromen-4-ylidene)acetamido)ethyl methacrylate. 13. A contact lens according to any one of the preceding claims, wherein the monomer suitable for making the device is selected from a hydrophilic component, a hydrophobic component, a silicone-containing component, or a mixture of two or more of these. 14. Contact lens according to any one of the preceding paragraphs, which is a traditional (non-silicone) hydrogel or silicone hydrogel; optionally, where the contact lens is an intraocular lens or a soft contact lens. 15. A contact lens containing a polymer network and a non-reactive polymer containing repeating units obtained from a compound selected from formulas III and V:

where X represents O, S or NR ⁶ ; Z is S; m and n are independently 0 or 1; R ¹ and R ² are independently at each occurrence H, C ₁ -C ₆ alkoxy or -YP _g ; R ⁶ is H or YP _g ; R ⁷ is EWG or -C(=O)-TYP _g , and EWG is in each case independently -CN; P _g at each occurrence is independently —CH=CH ₂ , —C(CH ₃ )=CH ₂ ; Y is independently at each occurrence a linking group selected from -O-(CH ₂ ) ₂ -OC(O)-, -O-(CH ₂ ) ₃ -OC(O)-, (CH ₂ ) ₂ -OC( O)-CH(CH ₃ )-, -(CH ₂ ) ₃ -OC(O)-CH(CH ₃ )-, -O-(CH ₂ ) ₂ -OC(O)-CH(CH ₃ )-; And T is in each case independently NR ⁶ , wherein the compound contains at least one P _g group. 16. The contact lens of claim 15, wherein the non-reactive polymer further comprises repeating units derived from an amide monomer, a monofunctional polyalkylene glycol, or a combination thereof; optionally wherein the amide monomer is an acyclic amide of formula H1 or H2, a cyclic amide of formula H3, or combinations thereof:

where R ⁴⁵ represents H or methyl; V is a direct link, -(CO)- or -(CONHR ₄₄ )-; R ₄₄ is C ₁ -C ₃ alkyl; R ₄₀ represents H or C ₁ -C ₄ alkyl; R ₄₁ represents H, C ₁ -C ₄ -alkyl, amino containing up to two carbon atoms, amide containing up to four carbon atoms, and alkoxy containing up to two carbon atoms; R ₄₂ represents H, C ₁ -C ₄ alkyl groups; or methoxy, ethoxy, hydroxyethyl or hydroxymethyl; R ₄₃ represents H, C ₁ -C ₄ alkyl; or methoxy, ethoxy, hydroxyethyl or hydroxymethyl; moreover, the number of carbon atoms in R ₄₀ and R ₄₁ taken together is 8 or less; and wherein the number of carbon atoms in R ₄₂ and R ₄₃ taken together is B or less; and f is a number between 1 and 10.

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