Compositions and methods for treating ocular diseases

a technology for ocular diseases and compositions, applied in the field of compositions and methods for treating ocular diseases, can solve problems such as blindness in the elderly, impairment of normal structure or function, and visual impairment and blindness

Inactive Publication Date: 2015-02-19
EYEPOINT PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0022]FIG. 6 represents the results of a single patient. The eye having the greater Central Foveal Thickness is chosen as the Treated Eye (Study Eye). The patient from day one was given 5 mg of the disclosed compound subcutaneously twice daily. At week 3 (21 days, indicated by arrow) the fellow eye is rescued with 2 mg of aflibercept. After rescue, the Fellow eye has a CFT reduction of approximately 400 μm. At week 6 (42 days, indicated by arrow) the treated eye is rescued with 2 mg of aflibercept. After rescue, the Study eye has a CFT reduction of approximately 310 μm.

Problems solved by technology

Injuries and diseases that impair the normal structure or function of these vascular beds are among the leading causes of visual impairment and blindness.
The wet form of age-related macular degeneration (AMD) is the most common form of choroidal neovascularization and a leading cause of blindness in the elderly.
AMD affects millions of Americans over the age of 60, and is the leading cause of new blindness among the elderly.
These new vessels are very fragile and break easily, causing blood and fluid to pool within the layers of the retina.
Eventually, however, diabetic retinopathy can result in blindness.
However, they have thin, fragile walls and without timely treatment, these new blood vessels can leak blood (whole blood or some constituents thereof) which can result in severe vision loss and even blindness.
Also, fluid can leak into the center of the macula, the part of the eye where sharp, straight-ahead vision occurs.
Laser therapy has had limited success and selected choroidal neovascular membranes which initially respond to laser therapy have high disease recurrence rates.
There is also a potential loss of vision resulting from laser therapy.
Low dose radiation has been applied ineffectively to induce regression of choroidal neovascularization.

Method used

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  • Compositions and methods for treating ocular diseases
  • Compositions and methods for treating ocular diseases
  • Compositions and methods for treating ocular diseases

Examples

Experimental program
Comparison scheme
Effect test

example 1

4-{(S)-2-[(S)-2-(tert-Butoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic acid (5)

Preparation of [1-(S)-carbamoyl-2-(4-nitrophenyl)ethyl-carbamic acid tert-butyl ester (1)

[0337]To a 0° C. solution of 2-(S)-tert-butoxycarbonylamino-3-(4-nitrophenyl)-propionic acid and N-methylmorpholine (1.1 mL, 9.65 mmol) in DMF (10 mL) is added dropwise iso-butyl chloroformate (1.25 mL, 9.65 mmol). The mixture is stirred at 0° C. for 20 minutes after which NH3 (g) is passed through the reaction mixture for 30 minutes at 0° C. The reaction mixture is concentrated and the residue dissolved in EtOAc, washed successively with 5% citric acid, water, 5% NaHCO3, water and brine, dried (Na2SO4), filtered and concentrated in vacuo to a residue that is triturated with a mixture of EtOAc / petroleum ether to provide 2.2 g (74%) of the desired product as a white solid.

Preparation of [2-(4-nitrophenyl)-1-(S)-thiocarbamoylethyl]carbamic acid tert-butyl ester (2)

[0338]To a solution...

example 17

(2-Methylthiazol-4-yl)methanesulfonyl chloride (41)

Preparation of sodium (2-methylthiazol-4-yl)methanesulfonate (40)

[0520]4-Chloromethyl-2-methylthiazole (250 mg, 1.69 mmol) is dissolved in H2O (2 mL) and treated with sodium sulfite (224 mg, 1.78 mmol). The reaction mixture is subjected to microwave irradiation for 20 minutes at 200° C. The reaction mixture is diluted with H2O (30 mL) and washed with EtOAc (2×25 mL). The aqueous layer is concentrated to afford 0.368 g of the desired product as a yellow solid. LC / MS ESI+ 194 (M+1, free acid).

Preparation of (2-methylthiazol-4-yl)methanesulfonyl chloride (41)

[0521]Sodium (2-methylthiazol-4-yl)methanesulfonate, 40, (357 mg, 1.66 mmol) is dissolved in phosphorous oxychloride (6 mL) and is treated with phosphorous pentachloride (345 mg, 1.66 mmol). The reaction mixture is stirred at 50° C. for 3 hours, then allowed to cool to room temperature. The solvent is removed under reduced pressure and the residue is re-dissolved in CH2Cl2 (40 mL) ...

example 18

(S)-4-(2-(2-Phenylthiazol-4-yl)2-(4-(methoxycarbonyl)thiazole-5-ylamino)ethyl)phenylsulfamic acid (45)

Preparation of (S)-2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethanamine hydrobromide salt (42)

[0535]A mixture of (S)-tert-butyl 4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate, 7, (1.62 g, 4.17 mmol) and thiobenzamide (0.63 g, 4.60 mmol) in CH3CN (5 mL) is refluxed for 24 hours. The reaction mixture is cooled to room temperature and diethyl ether (50 mL) is added to the solution. The precipitate which forms is collected by filtration. The solid is dried under vacuum to afford 1.2 g (67% yield) of the desired product. LC / MS ESI+326 (M+1).

Preparation of (S)-4-(1-isothiocyanato-2-(4-nitrophenyl)ethyl)-2-phenylthiazole (43)

[0536]To a solution of (S)-2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethanamine hydrobromide salt, 42, (726 mg, 1.79 mmol) and CaCO3 (716 mg, 7.16 mmol) in H2O (2 mL) is added CCl4 (3 mL) followed by thiophosgene (0.28 mL, 3.58 mmol). The reaction is stirred at roo...

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Abstract

Disclosed herein are compositions and methods for treating ocular diseases, inter alia, diabetic macular edema, age-related macular degeneration (wet form), choroidal neovascularization, diabetic retinopathy, retinal vein occlusion (central or branch), ocular trauma, surgery induced edema, surgery induced neovascularization, cystoid macular edema, ocular ischemia, uveitis, and the like. These diseases or conditions are characterized by changes in the ocular vasculature whether progressive or non-progressive, whether a result of an acute disease or condition, or a chronic disease or condition.

Description

CROSS REFERENCE[0001]This application claims the benefit of U.S. Provisional Application No. 61 / 792,868, filed Mar. 15, 2013, the contents of which is incorporated by reference in its entirety.FIELD[0002]Disclosed herein are compositions and methods for treating ocular diseases, inter alia, diabetic macular edema, age-related macular degeneration (wet form), choroidal neovascularization, diabetic retinopathy, retinal vein occlusion (central or branch), ocular trauma, surgery induced edema, surgery induced neovascularization, cystoid macular edema, ocular ischemia, uveitis, and the like. These diseases or conditions are characterized by changes in the ocular vasculature whether progressive or non-progressive, whether a result of an acute disease or condition, or a chronic disease or condition.BACKGROUND[0003]The eye comprises several structurally and functionally distinct vascular beds, which supply ocular components critical to the maintenance of vision. These include the retinal an...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395A61K38/17A61K31/427A61K31/497A61K31/4439C07D277/64A61K31/496A61K31/513A61K31/538C07D277/52C07D417/04A61K31/426A61K31/428
CPCA61K39/3955A61K31/426A61K38/179A61K31/427A61K31/497A61K31/4439A61K31/428A61K31/496A61K31/513A61K31/538C07D277/52C07D417/04C07D277/64A61K9/0019A61K31/04A61K31/10A61K31/635A61K38/05A61K47/40A61K2039/505C07D263/32C07D277/22C07D277/28C07D413/04C07D417/12C07D417/14C07K16/22A61K2300/00
Inventor PETERS, KEVINSHALWITZ, ROBERT
Owner EYEPOINT PHARMA INC
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