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Treatment of ocular neovascular disorders such as macular degeneration, angiod streaks, uveitis and macular edema

A technology for neovascularization and macular edema, applied in cardiovascular system diseases, sensory diseases, organic active ingredients, etc., can solve problems such as progressive vision loss

Inactive Publication Date: 2009-02-18
SMITHKLINE BECKMAN CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These vascular abnormalities cause fluid leakage in the macula, which can lead to progressive vision loss

Method used

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  • Treatment of ocular neovascular disorders such as macular degeneration, angiod streaks, uveitis and macular edema
  • Treatment of ocular neovascular disorders such as macular degeneration, angiod streaks, uveitis and macular edema
  • Treatment of ocular neovascular disorders such as macular degeneration, angiod streaks, uveitis and macular edema

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0089] As used herein, the symbols and conventions used in these Procedures, Schemes and Examples are consistent with those used in contemporary scientific literature, eg, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Amino acid residues are generally designated using standard one-letter or three-letter abbreviations, and unless otherwise stated, these amino acids are assumed to be in the L-configuration. All starting materials were obtained from commercial suppliers and used without purification unless otherwise stated. Specifically, the following abbreviations are used in the examples and throughout the specification:

[0090] g (gram); mg (mg);

[0091] L (liter); mL (milliliter);

[0092]μl (microliter); psi (pounds per square inch);

[0093] M (mole); mM (millimole);

[0094] N (standard) Kg (kilogram)

[0095] i.v. (intravenous); Hz (hertz);

[0096] MHz (megahertz); mol (number of moles);

[0097] mmol (mmol); RT (room tempe...

Embodiment 2

[0133] Preparation of 2,3-dimethyl-6-amino-2H-indazole:

[0134]

[0135] method 1:

[0136] To a stirred solution of 2,3-dimethyl-6-nitro-2H-indazole (1.13 g) in 2-methoxyethyl ether (12 ml) was added dropwise over 5 minutes at 0°C A solution of 4.48 g of tin(II) chloride in 8.9 ml of concentrated hydrochloric acid. After the addition was complete, the ice bath was removed and the solution was stirred for an additional 30 minutes. About 40ml of diethyl ether was added to the reaction, resulting in a precipitate. The resulting precipitate was isolated by filtration and washed with diethyl ether to give a yellow solid (1.1 g, 95%) as the hydrochloride salt of 2,3-dimethyl-2H-indazol-6-amine.

[0137] 1 H NMR (300MHz, DMSO-d 6 )δ 7.77(d, J=8.9Hz, 1H), 7.18(s, 1H), 7.88(m, 1H), 4.04(s, 3H), 2.61(s, 3H).MS(ES+, m / z) 162 (M+H).

[0138] Method 2:

[0139] A 2L, 3-neck round bottom flask was equipped with a nitrogen inlet and outlet and mechanical stirring. A moderate ni...

Embodiment 3

[0142] Preparation of N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine:

[0143]

[0144] method 1:

[0145] To the stirred intermediate Example 2 product (2.97 g, .015 mol) and NaHCO at room temperature 3 (5.05 g, .06 mol) in THF (15 mL) and ethanol (60 mL) was added 2,4-dichloropyrimidine (6.70 g, .045 mol). After the reaction was stirred at 85°C for 4 hours, the suspension was cooled to room temperature, filtered and washed well with ethyl acetate. The filtrate was concentrated under reduced pressure and the resulting solid was triturated with ethyl acetate to give N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine (89%, 3.84g).

[0146] 1 H NMR (400MHz, DMSO-d 6 )δ 7.28(d, J=9.0Hz, 1H), 6.42(d, J=8.8Hz, 1H), 6.37(s, 1H), 5.18(br s, 1H), 3.84(s, 3H), 2.43( s, 3H). MS (ES+, m / z) 274 (M+H)

[0147] Method 2:

[0148] To a 1 L 3-necked flask equipped with a pneumatic mechanical stirrer, thermometer and nitrogen inlet / outlet was added the product of...

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Abstract

The present invention is directed to methods of treating an ocular neovascular disorder in a mammal by administration of pyrimidine derivatives, benzodiazepinyl derivatives and pharmaceutical compositions containing the same. The invention encompasses methods of treating an ocular neovascular disorder by administration of 5-[[4-[(2,3-Dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide, (S)-3-oxo-8-[3-(pyridin-2-ylamino)-1-propyloxy]-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid or salts or solvates thereof. Combination therapies for the treatment of ocular neovascular disorders are also encompassed.

Description

technical field [0001] The present invention relates to methods of treating neovascular eye diseases in mammals. The method involves administering pyrimidine derivatives, benzodiazepines derivatives, and pharmaceutical compositions containing them. Background technique [0002] Neovascularization, also known as angiogenesis, is the process of forming new blood vessels. Neovascularization occurs during normal development and also plays an important role in wound healing after tissue injury. However, neovascularization has also been implicated as an important etiology of many pathological conditions including, for example, cancer, rheumatoid arthritis, atherosclerosis, psoriasis, and eye diseases. [0003] Eye diseases associated with vascular leakage and / or neovascularization are responsible for the majority of ocular morbidity and vision loss in developed countries (Campochiaro (2004) Expert Opin. Biol. Ther. 4: 1395-402). An example of such a disease is diabetic retino...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/506A61P27/02A61K31/55
CPCA61K39/395A61K31/506A61K31/7052A61K31/55Y02P20/582A61P27/00A61P27/02A61P27/06A61P27/10A61P9/00A61K2300/00A61K31/64A61K31/505A61K31/416
Inventor R·A·布里甘迪M·莱维克W·H·米勒
Owner SMITHKLINE BECKMAN CORP
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