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English英语译成Chinese汉语: VISIBLE LIGHT ABSORBERS FOR OPHTHALMIC LENS MATERIALS General field: 法律/专利 Detailed field: 专利
原文文本 - English英语 Field of the Invention
This invention is directed to visible light absorbers. In particular, this invention relates to novel azo compound monomers especially suitable for use in implantable ophthalmic lens materials.
Background of the Invention
Both UV and visible light absorbers are known as ingredients for polymeric materials used to make ophthalmic lenses, and such absorbers may be used in combination with each other. These absorbers are preferably covalently bound to the polymeric network of the lens material instead of simply physically entrapped in the material to prevent them from migrating, phase separating or leaching out of the lens material. Such stability is particularly important for implantable ophthalmic lenses where the leaching of the absorber may present both toxicological issues and lead to the loss of visible light blocking activity in the implant.
Many absorbers contain conventional olefinic polymerizable groups, such as methacrylate, acrylate, methacrylamide, acrylamide or styrene groups. Copolymerization with other ingredients in the lens materials, typically with a radical initiator, incorporates the absorbers into the resulting polymer chain. Incorporation of additional functional groups on an absorber may influence one or more of the absorber's light-absorbing properties, solubility or reactivity. If the absorber does not have sufficient solubility in the remainder of the ophthalmic lens material ingredients or polymeric lens material, the absorber may coalesce into domains that could interact with light and result in decreased optical clarity of the lens.
Examples of visible light absorbers suitable for use in intraocular lenses can be found in U.S. Patent Nos. 5,470,932. What is needed are additional visible light absorbing compounds that are copolymerizable with other ingredients in implantable lens materials, relatively inexpensive to synthesize, and are efficient in absorbing light between approximately 380 -495 nm.
Summary of the Invention
The present invention provides novel azo compounds that satisfy the above objectives. These azo compounds are especially suitable for use as monomers that absorb a portion of visible light (approximately 380 - 495 nm). These absorbers are suitable for use in ophthalmic lenses, including contact lenses. They are particularly useful in implantable lenses, such as intraocular lenses (lOLs).
The azo compounds of the present invention contain reactive groups, which allow for covalent attachment of the absorbers to ocular lens materials. Additionally, the absorbers of the present invention can be synthesized in approximately 2-3 steps from readily available, inexpensive starting materials without the need for column chromatography.
The present invention also relates to ophthalmic device materials containing such azo compounds
Brief Description of the Drawings
Figure 1 shows the UV/Vis spectra of Compound A at 0.01 - 0.5 % (w/v) in CHCI3.
Figure 2 shows the UV/Vis spectra of Compound A at a concentration of 480 uM
Figure 3 shows the UVA/is spectra of Compound B at 150 - 2400 uM in
CHCI3.
Figure 4 shows the UV/Vis spectra of Compound B at a concentration of 300 uM.
Figure 5 shows the UV/Vis spectra of two formulations of Compound
B.
Detailed Description of the Invention
Unless indicated otherwise, all ingredient amounts expressed in percentage terms are presented as % w/w.
The azo compounds of the present invention have the following structure:
Formula I
wherein
R1 = C(0)CH=CH2, C(0)C(CH3)=CH2, C(0)NHCH2CH2OC(0)C(CH3)=CH2, or
C(0)NHC(CH3)2C6H4C(CH3)=CH2;
R2 = H, C1 - C4 alkyl, or Ci - C4 alkoxy;
R3 = H, C1 - C4 alkyl, F, CI, Br, CN, N02, COOR4; XOC(0)CH=CH2,
XOC(0)C(CH3)=CH2, XOC(0)NHCH2CH2OC(0)C(CH3)=CH2, or
XOC(0)NHC(CH3)2C6H4C(CH3)=CH2;
R4 = H or C1 - C4 alkyl; and
X = C1- C4 alkyl or C2- C4 alkenyl.
Docket 3709 US
Preferred compounds of Formula I are those wherein R1 = C(0)CH=CH2, C(0)C(CH3)=CH2l or C(0)NHCH2CH2OC(0)C(CH3)=CH2; R2 = H or C1 - C4 alkyl;
R3 = H, C1- C4 alkyl, F, CI, Br, CN, N02, COOR4; XOC(0)CH=CH2, XOC(0)C(CH3)=CH2, or XOC(0)NHCH2CH2OC(0)C(CH3)=CH2; R4 = C1 - C4 alkyl; and X = C1 - C4 alkyl.
Most preferred compounds of Formula I are those wherein R1 = C(0)C(CH3)=CH2 or C(0)NHCH2CH2OC(0)C(CH3)=CH2; R2 = H;
R3 = H, C1 - C4 alkyl, F, CI, Br, XOC(0)C(CH3)=CH2 or XOC(0)NHCH2CH2OC(0)C(CH3)=CH2; and X = C1 - C4 alkyl.
Especially preferred compounds of Formula I are (E)-4-((2-hydroxy-5-methylphenyl)diazenyl)phenethyl methacrylate ("Compound A") and (E)-4-hydroxy-3-((4-(2-(methacryloyloxy)ethyl)phenyl)diazenyl)phenethyl methacrylate ("Compound B").
Compound A Chemical Formula: C19H2oN2O3 Molecular Weight: 324.37
Compound B Chemical Formula: C24H26N2O5 Molecular Weight: 422.47
A representative synthesis of the azo compounds of Formula I is as follows. The compounds of Formula I are synthesized in 2 - 3 steps.
1. In steps 1-2, the diazonium salt of an aniline derivative is prepared and subsequently reacted with a desired phenol compound to form an azo dye.
Step1
Step 2
Azo dyes
2. In step 3, the free primary alcohol groups of the azo dyes are esterified to form a polymerizable azo dye containing at least one (meth)acrylate group. The (meth)acrylate group can then form covalent bonds when reacted with vinyl monomers, co-monomers, macromers, crosslinking agents, and other components typically used in the manufacturing of lOLs.
Azo dyes
Pyridine/
Polymerizable Azo Dyes
The azo compounds of the present invention are suitable for use in ophthalmic device materials, particularly lOLs. IOL materials will generally contain from 0.005 to 0.2% (w/w) of a compound of Formula I, Preferably, IOL materials will contain from 0.01 to 0.1 % (w/w) of a compound of the present invention. Most preferably, IOL materials will contain from 0.01 to 0.05 % (w/w) of a compound of the present invention. Such device materials are prepared by copolymerizing the compounds of Formula I with other ingredients, such as device-forming materials, cross-linking agents. The IOL or other ophthalmic device materials containing the compounds of Formula I optionally contain UV absorbers and other visible light absorbers.
Many device-forming monomers are known in the art and include both acrylic and silicone-containing monomers among others. See, for example, U.S. Nos. 7,101,949; 7,067,602; 7,037,954; 6,872,793 6,852,793; 6,846,897; 6,806,337; 6,528,602; and 5,693,095. In the case of lOLs, any known IOL device material is suitable for use in the compositions of the present invention. Preferably, the ophthalmic device materials comprise an acrylic or methacrylic device-forming monomer. More preferably, the device-forming monomers comprise a monomer of formula II:
where in formula II:
A is H, CH3, CH2CH3, or CH2OH; Bis (CH2)m or [0(CH2)2]z; C is (CH2)W; m is 2 -6; z is 1 - 10;
Y is nothing, O, S, or NR', provided that if Y is O, S, or NR', then B is (CH2)m;
R' is H, CH3, Cn'H2n' 1 (n'=1-10), iso-OC3H7, C6H5, or
CH2C6H5; w is 0 - 6, provided that m w CH2OH).
EXAMPLE 4
Synthesis of 4-hydroxy-3-((4-(2-(methacryloyloxy)ethyl)phenyl)diazenyl) phenethyl methacrylate. In a 250 ml 3-neck round bottom flask equipped with a magnetic stirrer and gas inlet was dissolved 4.97 g (17.4 mmol) 4-(2-hydroxyethyl)-2-((4-(2-hydroxyethyl)phenyl)diazenyl)phenol in 200 ml anhydrous THF. 4-Methoxyphenol (50 mg, Aldrich) was added followed by 94 g (1.2 mol) anhydrous pyridine. The reaction mixture was cooled to - 20 °C and 4.10 g (39.2 mmol) methacryloyl chloride was added dropwise. The reaction mixture was stirred for 1 hour at - 20 °C and 20 hours at ambient temperature. The solid was filtered and 200 ml diethyl ether was added to the filtrate. Ethyl acetate (100 ml) was also added to aid in the separation. The organic layer was washed with 0.5 N HCI, dried over magnesium sulfate, and then filtered. The solvent was removed under removed pressure and the crude product was recrystallized in ethanol to give an orange solid which was rinsed with cold ethanol and dried overnight under high vacuum at room temperature to afford 2.0 g (40%). 1H NMR (CD2CI2) delta: 12.67 (s, 1H, Ar-OH), 7.86 - 7.88 (m, 3H, Ar-H), 7.47 (m, 2H, Ar-H), 7.30 (m, 1H, Ar-H), 7.00 (m, 1H, Ar-H), 6.11 (s, 2H, vinyl-H), 5.59 (s, 2H, vinyl-H), 4.40-4.45 (m, 4H, 2 0=COCH2), 3.05 - 3.13 (m, 4H, 2 Ar-CH?CH9QC=0). 1.96 (bs, 6H, 2 0=CC(CH3_)=CH2).
EXAMPLE 5
Transmittance curves for Compound A at 0.01 - 0.5 % and Compound B at 0.005 - 0.1 % were generated by UV/Vis spectroscopy. Briefly, the tested compound (A or B) was dissolved in chloroform at the indicated concentration and evaluated in a PerkinElmer Lambda 35 UV/Vis spectrometer. The results are shown in Figures 1 through 4. These results show that Compounds A and B are effective dyes for the absorption of UV light between 300 - 400 nm and violet light between approximately 400 - 450 nm.
EXAMPLE 6
The molar absorptivities of Compound A and Compound B were measured to determine effectiveness in light absorption at lambda max values. The UVA/is absorption curves and molar absorptivity values are shown in Figure 2 and Figure 4 and in Table 1 below.
Table 1
Molar absorptivity values of Compound A and Compound B
Compound Wavelength s (L-mol"1-cm"1)
A Lambda Max 1 = 332 nm 23,200
A Lambda Max 2 = 396 nm 10,300
B Lambda Max 1 = 331 nm 20,600 '
B Lambda Max 2 = 391 nm 10,300
EXAMPLE 7
Acrylic IOL Formulations
Compounds of Formula I may be formulated in IOL materials as shown in Tables 2-5 below. All components are vortex mixed in a 30 ml glass vial, degassed with nitrogen, and then syringe filtered using a 0.2 micron Teflon filter into polypropylene molds. Samples are thermally cured at 70 °C for 1 hour and 110 °C for 2 hours or photo cured at ambient temperature for 30 minutes using a Philips TL 20W/03 T lamp at ambient temperature and then extracted in acetone at 50 °C for 6 hours with fresh solvent replacement every 90 minutes.
TABLE 2
Component EXAMPLE
7K (% w/w) 7L 7M
Compound B 0 0.030 0.029
UV-2 1.83 1.81 1.81
PEA 79.7 79.7 79.7
HEMA 15.2 15.2 15.2
BDDA 3.26 3.25 3.26
Irgacure 819 0 0.30 0
AIBN 0.50 0 0.51
UV-2 = 3-(2H-benzo[d][1,2,3]triazol-2-yl)-2-hydroxy-5-methoxybenzyl methacrylate
HEMA = 2-hydroxyethyl methacrylate
Irgacure 819 = phenylbis(2,4,6-trimethylbenzoyl)-phosphine oxide.
EXAMPLE 8 Photostability
Samples of Formulation 7J (containing Compound A) were subject to UV radiation from 300 to 800 nm using an Atlas Suntest CPS test chamber (Atlas Electric Devices Company, Chicago, Illinois) utilizing a xenon arc lamp with light intensity of approximately 8-10 mW/cm2 at the height of the test sample. The temperature of the PBS medium was 35 °C. UV/Vis spectra from 0.9 mm thick sample sections were collected using a PerkinElmer Lambda 35 UV/Vis spectrometer. No photo decomposition was observed as indicated by overlapping of spectra before and after irradiation.
Samples of Formulation 7L (containing Compound B) were polymerized using blue light radiation from 400 to 450 nm using a Philips TL 20W/03 T lamp with light intensity of approximately 1 -2 mW/cm2 at the height of the test sample. Samples were polymerized for 30 minutes, 90 minutes, and 18.5 hours at ambient temperature without additional external heat sources. The UV/Vis spectra of Formulation 7L was compared to that of 7M
which was thermally cured using AIBN. Minimal to no photobleaching of Formulation 7L was observed. The results are shown in Figure 5.
This invention has been described by reference to certain preferred embodiments; however, it should be understood that It may be embodied in other specific forms or variations thereof without departing from its special or essential characteristics. The embodiments described above are therefore considered to be illustrative in all respects and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description.
I claim:
1. An azo compound of the formula
wherein
R1 = C(0)CH=CH2, C(0)C(CH3)=CH2, C(0)NHCH2CH2OC(0)C(CH3)=CH2, or
C(0)NHC(CH3)2C6H4C(CH3)=CH2;
R2 = H, Ci - C4 alkyl, or Ci - C4 alkoxy;
R3 = H, Ci - C4 alkyl, F, CI, Br, CN, N02, COOR4; XOC(0)CH=CH2,
XOC(0)C(CH3)=CH2, XOC(0)NHCH2CH2OC(0)C(CH3)=CH2, or
XOC(0)NHC(CH3)2C6H4C(CH3)=CH2;
R4 = H or Ci - C4 alkyl; and
X = Ci - C4 alkyl or C2- C4 alkenyl.
2. An azo compound of Claim 1 wherein
R1 = C(0)CH=CH2, C(0)C(CH3)=CH2, C(0)NHCH2CH2OC(0)C(CH3)=CH2; R2 = H or Ci - C4 alkyl;
R3 = H, Ci - C4 alkyl, F, CI, Br, CN, N02, COOR4; XOC(0)CH=CH2, XOC(0)C(CH3)=CH2, or XOC(0)NHCH2CH2OC(0)C(CH3)=CH2; R4 = Ci - C4 alkyl; and X = Ci - C4 alkyl.
3. An azo compound of Claim 2 wherein
R1 = C(0)C(CH3)=CH2orC(0)NHCH2CH2OC(0)C(CH3)=CH2; R2 = H;
R3 = H, Ci - C4 alkyl, F, CI, Br, XOC(0)C(CH3)=CH2 or XOC(0)NHCH2CH2OC(0)C(CH3)=CH2; and X = Ci - C4 alkyl.
4. An azo compound of Claim 2 wherein the compound is selected from the group consisting of (£)-4-((2-hydroxy-5-methylphenyl)diazenyl)phenethyl methacrylate and (£)-4-hydroxy-3-((4-(2-(methacryloyloxy)ethyl)phenyl) diazenyl)phenethyl methacrylate.
5. An ophthalmic device material comprising an azo compound of Claim 1 and a device-forming monomer selected from the group consisting of acrylic monomers and silicone-containing monomers.
6. An ophthalmic device material of Claim 5 wherein the ophthalmic device material comprises from 0.005 to 0.2 % (w/w) of an azo compound of Claim 1.
7. An ophthalmic device material of Claim 6 wherein the ophthalmic device material comprises from 0.01 to 0.1 % (w/w) of an azo compound compound of Claim 1.
8. An ophthalmic device material of Claim 7 wherein the ophthalmic device material comprises from 0.01 to 0.05 % (w/w) of an azo compound compound of Claim 1.
9. An ophthalmic device material of Claim 5 wherein the ophthalmic device material comprises a device-forming monomer of formula [II]:
where in formula [II]:
A is H, CH3, CH2CH3, or CH2OH; Bis (CH2)m or[0(CH2)2]z; C is (CH2)W; m is 2 -6; z is 1 - 10;
Y is nothing, O, S, or NR', provided that if Y is O, S, or NR', then
B is (CH2)m;
R' is H, CH3, Cn'H2n' 1 (n'=1-10), iso-OC3H7, C6H5, or
CH2C6H5; w is 0 - 6, provided that m w
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