WO2013079055A1 - Polymerisable dyes and compositions thereof for ophthalmological applications - Google Patents

Abstract

The invention relates to the preparation of polymerisable dyes for ophthalmological application, to an ophthalmological composition that includes said dye, and to an eye implant, in particular an intraocular lens, that is produced with said ophthalmological composition.

Description

 Polymerizable dyes and their compositions for

 ophthalmological applications.

Technical area

The present invention claims the priority of the German patent application DE102011119729.3 (filing date: 30.11.2011 in and claims

ophthalmic compositions containing polymerizable dyes based on the anthraquinone skeleton shown below,

independently of one another hydrogen, hydroxyl or methacrylic acid, independently of one another hydrogen,

 4- (methylamino) phenethyl methacrylate,

 2- (4- (methylamino) phenoxy) ethyl methacrylate or

 3-methoxy-2-methyl-2- (methylamino) -propyl methacrylate ring-closed to X,

Hydrogen, chloro, 4- (methylamino) phenethyl methacrylate, 2- (4- (methylamino) phenoxy) ethyl methacrylate, 2-methyl-2- (methylamino) propyl methacrylate, or 2-methyl-2- (methylamino) propane-1, 3-diyl bis (2-methyl acrylate)

Bestätigungskopiel means

 and

X is to be regarded as CH in all non-ring-closed cases.

Background of the Invention In order to regulate the amount of light incident, the eye has a natural iris which protects the retina from glare and melanin dyes. Irises usually show a multi-colored pattern, which develops through random development processes in the first months of life and represents a personal and unique character trait. The partial or complete absence of the iris always results in significant vision loss and increased photosensitivity. In addition to traumatic causes, various diseases and genetic changes such as aniridia, coloboma, iris atrophy and albinism may be responsible. To the eyesight of

In the first place, photosensitivity must be reduced in order to restore patients with these or other iris-related diseases.

It is known to replace the missing areas of the iris with an opaque implant, using different materials. These are usually colored by pigments monochrome, which gives the patient's eye an unnatural appearance. Since the dyes are not covalently attached to the

Material are bound, they can diffuse out of the implant.

State of the art

To the eyesight of patients with the said or other, the iris

diseases, and at least partially restore them, various methods and The company Morcher (Stuttgart) offers an individually made, artificial iris made of black colored polymethyl methacrylate (PMMA), which is clamped in the eye and complements the possibly existing part of the iris. The company Ophtec (Groningen, NL, Boca Raton, USA) distributes similar products of PMMA in the colors blue, green and brown, the more natural one

Provide color impression. In addition, black implants made of polycarbonate (PC) are available. A major disadvantage of Morcher and Ophtec iris implants is the large incision needed to implant the hard, non-swellable material into the eye. This must be sutured, leaving scars that patients often find uncomfortable. In addition, the dyes used are not covalently bound to the material

(especially with swellable materials), but in the form of insoluble

 Pigments are added. They can not possibly diffuse out of the eye. In addition, the monochrome surface of the implant can not adequately reflect the true nature of the iris, giving the patient's eye an unnatural appearance. Silicone-based iris implants are sold by Human-Optics AG (Erlangen, Germany). The foldable material can be implanted into the patient's eye via a 3 mm incision. In contrast to other prostheses, an individual color and pattern adaptation to the still existing iris of a patient can take place via a photograph. The implants are made individually by hand. The material is matted on the back and has a median pupil diameter.

Kahn Medical Devices (Marbella-Paitilla, Panama) sells green, blue and brown iris implants designed to cover the natural iris. These silicone-based foldable prostheses are mainly used in patients with albinism. However, the brilliant, monochrome surface does not give a completely natural impression.

Providers of common products generally do not provide ideal materials for making iris prostheses that give the eye a perfectly natural look. Object of the invention

The object of the invention is therefore to provide polymerizable dyes which ensure a high degree of biocompatibility with simultaneous UV resistance. In order to produce materials with individual colors from it are

Essentially a blue, a green and a red dye needed, from which an RGB color space can be built by mixing. The object of the invention was also to provide dyes which are particularly suitable for the production of ophthalmological implants. This object is achieved by the features of claim 1. Further embodiments of the invention are the subject of the dependent claims and the independent

Claims.

Description of the invention

The invention includes blue, red and green anthraquinone-based dyes which are characterized by at least one methacrylate end group and thereby can be used as a comonomer.

dyes

Suitable dyes of the ophthalmic composition according to the invention are, for example, the following compounds (all stereoisomers or racemic mixtures being included):

example 1

(Structure 2)

Example 2

(Structure 9)

Example 3

(Structure 8)

Beispiel 7

Example 7

(Structure 10)

Example 8

(Structure 7)

Example 9

(Structure 5)

Example 10

 (Structure 6)

The structures number 1, 2 and 4-6 offer the advantage that they allow a quantitative incorporation into the implant material due to the presence of several polymerizable end groups and also possess crosslinking properties.

Preferred dyes of the polymerizable dyes for ophthalmic use according to the invention are 1, 2 and 4.

Polymerizable blue dyes

Suitable blue polymerizable anthraquinone dyes of the ophthalmic composition according to the invention are compounds of the following structures, in which an anthraquinone base body is connected via various spacers to one or more acrylic or methacrylic radicals:

wobei

in which

R ⁵ : oxygen, acrylate or methacrylate radical R ⁶ : acrylate or methacrylate radical

Z ¹ / Z ² : organic branched and unbranched alkyl and aryl substituents of up to 30 atoms selected from C, H, Si, O, N, P, S, F, Cl, Br

X: either CH, or C connected to a chain which, when combined with Z ^1, gives a closed fused six-membered ring,

 selected from

-CH ₂ -O-, -CH ₂ -CH ₂ -, -O-CH ₂ -, -CH ₂ -N (H) -, - N (H) -CH ₂ -.

The acrylic and methacrylic radicals are used for covalent incorporation of the dye in a carrier material, in particular lens material based on acrylate or methacrylate. Due to the bifunctionality, the incorporation proceeds quantitatively and thus much more effectively than with available monofunctional dyes. Exemplary Embodiments of Blue Polymerizable Anthraquinone Dyes: Example 1

Z ¹ / Z ² = C ₈ H ₈ O, X = CH, R ⁵ / R ⁶ = acrylic bwz. methacryloyl

In this example, first 1,4-dichloroanthraquinone is built up, reacted with the previously synthesized 2- (4-nitrophenoxy) ethanol and then methacrylated with methacrylic chloride (see Figure 1).

Example 2:

ZVZ ² = C ₄ H ₈ O, X = CH, R ⁵ / R ⁶ = Acrylic bwz. methacryloyl

Struktur 9

Molekulargewicht 518 g/mol

Structure 9

Molecular weight 518 g / mol

In this example, 1, 4-dichloroanthraquinone with 2-amino-2-methylpropanol is added under protective gas, and then reacted with methacrylic acid chloride (see Figure 2). The resulting blue dye, in contrast to the previous blue dye has a reduced aromatic system, but still two polymerizable ends. Example 3:

Z ¹ = C ₄ H ₈ , X = C-O-CH ₂ -, Z ² = C (CH ₃ ) ₂ , R ⁶ = acrylic bwz. methacryloyl

Molekulargewicht 448 g/mol Structure 8

Molecular weight 448 g / mol

The preparation of this compound is carried out according to Example 2 in two steps, not working under a protective gas atmosphere. This can lead to an oxidative ring closure if there are two carbon units between hydroxy and amino functionality of the aminoalcohol and thus a new 6-membered ring can be formed (FIG. 3). The methacrylation is carried out analogously to Example 2. Polymerizable green dyes

Suitable green polymerizable anthraquinone dyes of the ophthalmic composition of the invention are compounds of the following

structures:

wobei

in which

R ¹ / R ² OH, O-acrylic or O-methacrylic radical R ⁵ / R ^{6 is} acrylic or methacrylic radical

Z ¹ / Z ^{2 are} organic branched and unbranched alkyl and aryl substituents having up to 30 atoms selected from C, H, Si, O, N, P, S, F, Cl, Br.

Exemplary Embodiments of Green Polymerizable Anthraquinone Dyes: Example 4

Z ¹ / Z ² = C ₈ H ₈ , X = CH, R ¹ / R ² = OH, R ⁵ / R ⁶ = acrylic bwz. methacryloyl

This compound was synthesized by the reaction of 5,8-dichloro-1,4-dihydroxyanthraquinone with 2- (4-aminophenyl) ethanol and then methacrylated with methacrylic anhydride.

Polymerizable red dyes

Suitable red polymerizable dyes of the invention

ophthalmic compositions are compounds of the following structure:

wobei

in which

R ⁵ : an acrylic or methacrylic radical

Z ¹ organic branched and unbranched Alky substituents of up to 30 atoms selected from C, H, Si, O, N, P, S, F, Cl, Br

X is either CH, or C connected to a chain which, when joined to Z ^1, gives a closed fused six-membered ring selected from

-CH ₂ -O-, -CH ₂ -CH ₂ -, -O-CH ₂ -, -CH ₂ -N (H) -, - N (H) -CH ₂ - R ⁴ denotes H or CI. Exemplary Embodiments of Red Polymerizable Anthraquinone Dyes:

Z ¹ = CH ₈ O, X = CH, R ⁵ = H, R ⁵ = acrylic bwz. methacryloyl

Molekulargewicht 363 g/mol Structure 3

Molecular weight 363 g / mol

The preparation of the compound 3 1- (methacryloxy-2-methylpropyl-2-amino) - anthraquinone takes place in two steps, all educts used being commercially available, and the first synthesis step under protective gas (FIG. 4). Example 6:

Z ¹ = C 8 H 11 O 2, X = CH, R ⁵ = H, R ⁵ = Acrylic bwz. methacryloyl

Structure 4

Molecular weight 447 g / mol

A further exemplary embodiment of a red polymerizable dye in the context of the inventive composition of polymerizable anthraquinone dyes is (1- (1,3-dimethacryloxy-2-methylpropan-2-yl-amino) anthraquinone). This too can be prepared in a 2-step synthesis in a simple synthetic manner analogously to Example 1. (The starting materials required for this are likewise commercially available.) In this way a compound can be prepared in which an additional acrylate / methacrylate anchor group has been introduced Attachment of this second anchor group allows this compound to act as a crosslinker in the preparation of the lens material. Example 7:

Z ¹ = CH ₈ 0 ₂ , X = CH, R ⁴ = H, R ⁵ = acrylic bwz. methacryloyl

Structure 10

C22H21NO5

Molecular weight 379 g / mol

The preparation of the compound (1- (1-dimethacryloxy-2-methyl-3-hydroxypropan-2-ylamino) anthraquinone) is carried out analogously to the preparation of Example 2. The degree of methacrylation can be controlled by the reaction time and the ratio of the starting materials to one another.

Example 8:

Z ¹ = C ₄ H ₇ 0 ^' X, X = C-O-CH ₂ -Z1, R ⁴ = H, R ⁵ = acrylic bwz. methacryloyl

Structure 7 C22H19NO5 Molecular weight 377 g / mol

A special case is the synthesis of compound 7. Here, an oxidative ring closure can be observed without a protective gas atmosphere and using educts with two carbon units between amine and hydroxyl functionality (FIG. 6). The introduction of an additional ring in the preferred dyes described above changes the spectral properties of the chromophore only to a small extent. comonomers:

As biocompatible carrier material are acrylates and methacrylates, in particular with a water content of 1% to 30%, for the ophthalmic

Composition suitable. In this carrier material are the respective

Dyes covalently bound, and preferably in one

Concentration range of 0.0001% to 0.1% included. The danger of washing out of the dyes from the carrier matrix does not exist, since the dyes according to the invention are both water-insoluble and also carry one to two polymerizable end groups, and are thereby incorporated quantitatively into the lens material.

Suitable biocompatible carrier materials for the ophthalmological

Composition are, for example, hydroxyethyl methacrylate (HEMA), methyl methacrylate (MMA), ethoxyethyl methacrylate, tetrahydrofurfuryl methacrylate,

Tetrahydrofurfuryl acrylate, 2-hydroxypropyl methacrylate, 2-hydroxypropyl acrylate, 2-hydroxyethyl acrylamide, 2-hydroxyethyl methacrylamide, methoxyethyl methacrylate, methoxyethyl methacrylate, 2-hydroxymethylacrylic acid ethyl ester,

Oxybismethylacrylsäureethylester, 2-hydroxymethylacrylic acid tetrahydrofurfurylester and Oxybismethylacrylsäuretetrahydrofurfurylester. Also

Copolymers of these materials, possibly using a cross-linker, can be used as acrylate / methacrylate support material. The

Support materials may be hydrophilic with a water content of, for example, 1% to 30%.

Embodiments of the ophthalmic composition are as follows with quantitative compositions in weight%.

Example of the copolymerization of the dyes with hydrophilic materials

2-Hydroxyethyl methacrylate (70%) is mixed with tetrahydrofurfuryl methacrylate (30%), ethylene glycol dimethacrylate (0.3%) and polymerizable dye (0.8%), purged with nitrogen, added with an azo initiator (0.07%) and copolymerized in a specific form.

The polymerizable dyes for ophthalmic application are suitable for intraocular lenses, in particular for iris implants. It has been found to be a particular advantage that the various dyes are not only physically compatible with each other, but also in terms of your

Biocompatibility and in particular with regard to their optical properties to harmonize perfectly with each other. By mixing at least two, but usually at least three different dyes, can be in

outstanding way to span an RGB color space, which ensures the best possible suitability of the resulting lens - and in particular the lens implants - for the purpose of the invention. By an appropriate manufacturing process, in which the dye distribution in the lens is inhomogeneous can be made ophthalmic lenses - especially implants that have a pattern, for example, correspond to a natural iris. As a further advantage, the excellent UV absorption of the dyes according to the invention has been found to give us dye mixtures.

Interestingly, it has also turned out that the

Dyes according to the invention are also suitable for cosmetic treatments as described in EP 1399111 B1. One or more dyes are made with a biocompatible material (vector) in a gel-like consistency and applied subcutaneously, intradermally or subdermally. The acrylate or methacrylate radical of the dyes according to the invention is preferably used for

Copolymerization with corresponding groups of the vector used. Suitable materials for this purpose correspond to those for the production of ophthalmological preparations. But also modified silicones can be used as vectors. Due to the simple miscibility of the dyes can be a hue

Adjustment to the appropriate skin color can be guaranteed.

Items of registration

Objects of the application are therefore:

I. Polymerizable dyes for ophthalmic use, which are based exclusively on acrylate and / or methacrylate and which have a Anthrachinongerüst in which one or more acrylic acid or methacrylic acid units bonded via an alkyl or aryl spacer to a substituted or unsubstituted anthraquinone structure are. Polymerizable dyes for ophthalmic use according to item I, wherein the dye is a stereoisomer or

 racemic mixture of the formula I.

wobei R1 / R2 Wasserstoff, ein Hydroxy-, Acryl- bzw. Methacryl-Rest ist R3 / R4: organische verzweigte und unverzweigte Alkyl- oder Aryl- Substituenten (oder Kombinationen von beiden) mit bis zu 30 Atomen ausgewählt aus C, H, Si, O, N, P, S, F, Cl, Br sowohl mit und ohne Acryl- bzw. Methacryl-Rest

wherein R1 / R2 is hydrogen, hydroxy, acrylic or methacrylic R3 / R4: organic branched and unbranched alkyl or aryl substituents (or combinations of both) having up to 30 atoms selected from C, H, Si , O, N, P, S, F, Cl, Br both with and without acrylic or methacrylic radical

X: either CH, as well as atoms connected to R3 and / or

R4 give a closed six-membered ring selected from C, H, O.

III. Polymerizable blue dyes for ophthalmic application according to item II, in which the dye is a stereoisomer or

 racemic mixture of the formula II

wobei

in which

R ⁵ : oxygen, acrylate or methacrylate radical R ⁶ : acrylate or methacrylate radical

Z ¹ / Z ² : organic branched and unbranched alkyl and aryl

Substituents of up to 30 atoms selected from C, H, Si, O, N, P, S, F, Cl, Br

X: either CH, or C connected to a chain which, when linked to Z ^1, gives a closed, fused six-membered ring selected from

-CH ₂ -O-, -CH ₂ -CH ₂ -, -O-CH ₂ -, -CH ₂ -N (H) -, - N (H) -CH ₂ -. IV. Polymerizable blue dyes for ophthalmological use according to

or

Polymerizable green dye for ophthalmological application according to item II, characterized by the structure:

wobei

in which

R ¹ / R ² OH, O-acrylic or O-methacrylic radical

R ⁵ / R ⁶ acrylic or methacrylic radical

Z ¹ / Z ² organic branched and unbranched alkyl and aryl

Substituents having up to 30 atoms selected from C, H, Si, O, N, P, S, F, Cl, Br means. VI. Polymerizable green dye for ophthalmic use according to item V, characterized by the structure:

Polymerizable red dye for ophthalmic use according to item II, in which the dye is a stereoisomer or racemic mixture of the following structure:

wobei

in which

R ⁵ : an acrylic or methacrylic radical

Z ¹ organic branched and unbranched Alky substituents of up to 30 atoms selected from C, H, Si, O, N, P, S, F, Cl, Br X: either CH, or C connected to a chain which, when linked to Z ^1, gives a closed fused six-membered ring selected from

-CH ₂ -O-, -CH ₂ -CH ₂ -, -O-CH ₂ -, -CH ₂ -N (H) -, - N (H) -CH ₂ -.

R ^{4 is} H or Cl.

Polymerizable red dye for ophthalmological application according to item VII, characterized by the structures

 or

IX. Ophthalmic composition containing at least one

 Dye according to one of the items I to VIII, characterized by a biocompatible carrier in which the dye is provided.

X. Ophthalmic composition according to item IX, characterized

 in that the dye is covalently bound in the acrylate methacrylate material.

XI. A copolymer comprising at least one dye according to at least one of the items I to VIII and at least one for the

 ophthalmic composition suitable monomer,

 such as hydroxyethyl methacrylate (HEMA), methyl methacrylate (MMA), ethoxyethyl methacrylate, tetrahydrofurfuryl methacrylate,

Tetrahydrofurfuryl acrylate, 2-hydroxypropyl methacrylate, 2-hydroxy propyl acrylate, 2-hydroxyethyl acrylamide, 2-hydroxyethyl methacrylamide, methoxyethyl methacrylate, methoxyethyl methacrylate, 2-hydroxy-methylacrylic acid ethyl ester, oxybismethylacrylic acid ethyl ester, 2-hydroxy-methylacrylic acid tetrahydrofurfuryl ester and oxybismethylacrylic acid tetrahydrofurfuryl ester.

XII. Use of an ophthalmic composition according to any one of items IX to XI for the preparation of an ophthalmic lens, an ophthalmic implant or an intraocular lens.

XIII. Eye implant, whose implant material is an ophthalmic

 Having composition according to one of the items IX to XI.

XIV. Eye implant according to item XIII, which is an intraocular lens

 is trained.

XV. Use of at least one dyestuff according to at least one of the items I to VIII together with a biocompatible vector for the cosmetic treatment of the skin.

Further objects of the application are apparent to the person skilled in the art from the description and the examples without inventive step.

Claims

claims 1. Use of an ophthalmic composition,  containing  at least one dye of the formula I as a stereoisomer or as a racemic mixture

in which R1 / R2: is hydrogen, a hydroxy, acrylic or methacrylic radical R3 / R4: organic branched and unbranched alkyl or aryl Substituents (or combinations of both) having up to 30 atoms selected from C, H, Si, O, N, P, S, F, Cl, Br both with and without acrylic or methacrylic radical X: either CH, as well as atoms which, when linked to R 3 and / or R 4, give a closed six-membered ring selected from C, H, O,  together with at least one for the ophthalmic  Composition of suitable monomer,  selected from hydroxyethyl methacrylate (HEMA), methyl methacrylate (MMA), ethoxyethyl methacrylate, tetrahydrofurfuryl methacrylate, Tetrahydrofurfuryl acrylate, 2-hydroxypropyl methacrylate, 2-hydroxypropyl acrylate, 2-hydroxyethylacrylamide, 2-hydroxyethylmethacrylamide, methoxyethyl methacrylate, methoxyethyl methacrylate, 2-hydroxymethyl-acrylic acid ethyl ester, oxybismethylacrylic acid ethyl ester, 2-hydroxy- methylacrylic acid tetrahydrofurfuryl ester and oxybismethylacrylic acid tetrahydrofurfuryl ester. for the preparation of an ophthalmic lens, an ophthalmic implant or an intraocular lens, wherein the dye of the formula I is covalently bonded. , 2. Use of an ophthalmic composition according to  Claim 1, characterized in that the composition contains at least two dyes of the formula I. 3. Use of an ophthalmic composition according to  Claim 1, characterized in that the composition comprises at least three dyes of the formula I. 4. Use of an ophthalmic composition according to  Claim 1, characterized in that at least one dye is characterized by the structure

in which R ⁵ : oxygen, acrylate or methacrylate radical R ⁶ : acrylate or methacrylate radical Z ¹ / Z ² : organic branched and unbranched alkyl and aryl Substituents of up to 30 atoms selected from C, H, Si, O, N, P, S, F, Cl, Br X: either CH, or C connected to a chain which, when linked to Z ^1, gives a closed, fused six-membered ring selected from -CH ₂ -O-, -CH ₂ -CH ₂ -, -O-CH ₂ -, -CH ₂ -N (H) -, - N (H) -CH ₂ -. 5. Use of an ophthalmic composition according to  Claim 1, characterized by at least one dye as  Stereoisomer or racemic mixture selected from:

6. Use of an ophthalmic composition according to claim 1, characterized in that at least one dye is characterized by the structure:

in which R ¹ / R ² OH, O-acrylic or O-methacrylic radical R ⁵ / R ⁶ acrylic or methacrylic radical Z ¹ / Z ² organic branched and unbranched alkyl and aryl Substituents having up to 30 atoms selected from C, H, Si, O, N, P, S, F, Cl, Br means. 7. Use of an ophthalmic composition according to  Claim 1, characterized by a dye as stereoisomer or racemic mixture of the following structure:

8. Use of an ophthalmic composition according to Claim 1, characterized in that at least one dye is characterized by the structure:

an acrylic or methacrylic radical organic branched and unbranched Alky substituents of up to 30 atoms selected from C, H, Si, O, N, P, S, F, Cl, Br either CH, or C connected to a chain which, when connected to Z ^1, gives a closed annealed six-membered ring,  selected from -CH ₂ -O-, -CH ₂ -CH ₂ -, -O-CH ₂ -, -CH ₂ -N (H) -, - N (H) -CH ₂ -. H or Cl means. 9. Use of an ophthalmic composition according to claim 1, characterized by at least one dye as stereoisomer or racemic mixture selected from:

or

10. Use of an ophthalmic composition according to claim 1-9 for the preparation of an eye implant.