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Thiazole derivatives

a technology of thiazole and derivatives, applied in the field of thiazole derivatives, can solve the problems of high physical and economic burden on patients, difficult irradiation of lasers on the macular area, and unnecessary laser treatments that may produce side effects

Inactive Publication Date: 2006-06-15
ASTELLAS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, irradiation of laser on the macular area is not easy and unnecessary laser treatments may produce side effects (e.g., possible encouragement of edema by causing inflammation).
The vitreous surgery is considered to provide effect in 70 percent of macular edema, but physical and economical burden on patients is high, and the incidence of recurrence is also high.
These treatment methods are not usually employed in the initial stage of macular edema, particularly so in the stages when the decrease of vision is comparatively small.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

production example 1

[0170] Step 1

[0171] A mixture of 3-chloro-2-oxopropyl acetate (5 g) and thiourea (2.5 g) in ethanol (25 ml) was refluxed for 4 hours. The reaction mixture was cooled to ambient temperature and the resulting crystalline precipitate was collected by filtration and washed with ethanol (20 ml) to give (2-amino-1,3-thiazol-4-yl)methyl acetate hydrochloride (3.5 g) as white crystals.

[0172]1H-NMR (DMSO-d6), δ (ppm): 2.07(3H, s), 4.92(2H, s), 6.87(1H, s).

[0173] MS: 173(M+H)+

Step 2

[0174] To a mixture of (2-amino-1,3-thiazol-4-yl)methyl acetate hydrochloride (56 g) and pyridine (45 g) in dichloromethane (560 ml) was added acetyl chloride (23 g) over a period of 30 minutes at 5° C., and the reaction mixture was stirred for 10 minutes at the same temperature. The reaction mixture was poured into water (500 ml) and extracted with chloroform (1 L). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residual solid was collected by filtration with isopropyl ether to...

production example 2

Synthesis of N-(4-(2-(4-(4,5-dihydro-1,3-thiazol-2-ylamino)phenyl)ethyl)-1,3-thiazol-2-yl)acetamide

[0194] N-(4-(2-(4-Aminophenyl)ethyl)-1,3-thiazol-2-yl)acetamide (1.8 g) prepared in a similar manner according to Step 6 of Production Example 1,2-(methylsulfanyl)-4,5-dihydro-1,3-thiazole (918 mg), hydrochloric acid concentrate (0.57 ml) and 2-methoxyethanol (28 ml) were combined under nitrogen atmosphere, and stirred at 120° C. for 10 hours. After cooled to room temperature, the reaction mixture was concentrated in vacuo. The residue was dissolved in tetrahydrofuran / water, and made basic with aqueous potassium carbonate. The mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash column chromatography over silica gel with chloroform / methanol (30:1→20:1) as an eluent, and triturated with ethyl acetate to give N-(4-(2-(4-(4,5-dihydro-1,3-thiazol-2-ylamino)phenyl)ethyl)-1,3-thiazol-2-yl)ace...

production example 3

Synthesis of N-(4-{(E)-2-[4-(4,5-dihydro-1,3-thiazol-2-ylamino)phenyl]ethenyl}-1,3-thiazol-2-yl)acetamide

Step 1

[0198] A mixture of 4-nitrobenzyl bromide (6.35 g), triphenylphosphine (7.71 g) and N,N-dimethylformamide (50 ml) was stirred for 5 hours at room temperature. To the mixture were added potassium butoxide (3.96 g), and then N-(4-formyl-1,3-thiazol-2-yl)acetamide (5.0 g) prepared in a similar manner according to Step 4 of Production Example 1, and the mixture was stirred for 13 hours at the same temperature. The reaction mixture was poured into ethyl acetate (200 ml) and water (200 ml). The organic layer was washed with water (20 ml), dried over sodium sulfate and concentrated in vacuo. The crystalline residue was collected and washed with 30% ethyl acetate / diisopropyl ether to give N-{4-[(E)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide (7.8 g).

[0199]1H-NMR (DMSO-d6), δ (ppm): 2.16(3H, s), 7.29(1H, d, J=16 Hz) 7.48(1H, d, J=16 Hz), 7.88(2H, d, J=7 Hz), 8.22(2H, d,...

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Abstract

A compound of the formula (I): R1—NH—X—Y-Z (I) wherein each symbol is as defined in the specification, or a pharmaceutically acceptable salt thereof useful as a vascular adhesion protein-1 (VAP-1) inhibitor, a pharmaceutical composition, a method for preventing or treating a VAP-1 associated disease, especially macular edema, which method includes administering an effective amount of the compound or a pharmaceutically acceptable salt thereof to a mammal, and the like.

Description

TECHNICAL FIELD [0001] The present invention relates to a compound or a pharmaceutically acceptable salt thereof useful as a vascular adhesion protein-1 inhibitor, a pharmaceutical composition comprising the compound or salt thereof as an active ingredient, a method for preventing or treating a vascular adhesion protein-1 associated disease, especially macular edema, use of the compound, salt thereof or composition, and the like. BACKGROUND ART [0002] Vascular adhesion protein-1 (hereinafter to be abbreviated as VAP-1) is an amine oxidase (semicarbazide sensitive amine oxidase, SSAO) which is abundant in human plasma, and shows remarkably increased expression in vascular endothelium and vascular smooth muscle of the inflammatory region. While the physiological role of VAP-1 has not been clarified until recently, VAP-1 gene was cloned in 1998, and VAP-1 has been reported to be a membrane protein that regulates rolling and migration of lymphocyte and NK cell as an adhesion molecule un...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/427A61K31/426C07D417/02A61P27/02C07D277/46C07D277/48C07D277/56C07D417/06C07D417/12
CPCC07D277/46C07D277/48C07D417/12C07D417/06C07D277/56A61P1/02A61P1/04A61P1/16A61P11/00A61P11/06A61P17/02A61P19/02A61P19/06A61P21/00A61P25/00A61P25/28A61P27/02A61P29/00A61P3/00A61P3/04A61P37/00A61P37/08A61P43/00A61P7/10A61P9/00A61P9/10A61P9/12A61P3/10A61K31/427
Inventor INOUE, TAKAYUKITOJO, TAKASHIMORITA, MASATAKAOHKUBO, MITSURUYOSHIHARA, KOUSEINAGASHIMA, AKIRA
Owner ASTELLAS PHARMA INC
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