Aldose reductase inhibitors and uses thereof

A technology of alkyl and compound, applied in the field of aldose reductase inhibitors and its application, can solve the problems of excess sorbitol and difficult diffusion

Active Publication Date: 2013-04-17
THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This results in an excess of sorbitol in the cell, which does not readily diffuse through cell membranes

Method used

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  • Aldose reductase inhibitors and uses thereof
  • Aldose reductase inhibitors and uses thereof
  • Aldose reductase inhibitors and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0252] Example 1: Preparation of Compound A.

[0253] Compound A was prepared as illustrated schematically below.

[0254]

[0255] Preparation of (E) / (Z)-2-(7-oxofuro[3,4-b]pyrazine-5(7H)-ylidene) tert-butyl acetate (compound 1)

[0256] To stirred 5.05 g (33.63 mmol) of commercially available 2,3-pyrazine dicarboxylic anhydride in 300 mL CHCl 3 12.34 g (33.63 mmol) (tert-butoxycarbonylmethylene)-triphenylphosphorane were added to the solution. The resulting solution was heated to 62 °C for 2 days. The reaction mixture was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (monitored by thin layer chromatography) and eluted with 1:1 (v / v) hexane:ethyl acetate. Evaporation of the collected fractions yielded 2.99 g (36% yield) of (E) / (Z)-2-(7-oxofurano as a mixture (~1:1) of unresolved geometric isomers [3,4-b]pyrazine-5(7H)-ylidene) tert-butyl acetate (compound 1): 1 HNMR (CDCl 3 ,300MHz):δ ppm 9.03(d,J=2.4Hz,1H),8.96(d,J...

Embodiment 2

[0263] Example 2: Alternative Preparation of Compound A.

[0264]

[0265] Preparation of 2-(iodomethyl)-5-(trifluoromethyl)benzo[d]thiazole (Compound 5)

[0266] To a stirred solution of 10.79 g (42.97 mmol) of 2-(chloromethyl)-5-(trifluoromethyl)benzo[d]thiazole (compound 3) in 86 mL of acetone was added 7.40 g (49.42 mmol) of sodium iodide . The resulting reaction mixture was heated to 55 °C for 1 hour. The reaction mixture was cooled to ambient temperature and concentrated under vacuum. The residue was partitioned between EtOAc and water, the layers were separated, and the organic layer was washed with water (1x). The recovered organic layer was then washed with 1.0M Na 2 S 2 o 3 Process and stir vigorously for 15 minutes. The layers were then separated and the organic layer was washed sequentially with water (1x) and brine (1x). The organic layer was washed with Na 2 SO 4 Dried, filtered and concentrated under vacuum to yield 14.28 g (97% crude yield) of 2-(i...

Embodiment 3

[0278] Example 3: Preparation of Compound 8.

[0279] Compound 8 shown below was prepared as follows:

[0280]

[0281] Except that 5-chloro-2-(chloromethyl)-benzo[d]thiazole was the reagent used instead of 2-(chloromethyl)-5-(trifluoromethyl)benzo[d]thiazole, The preparation described for compound 4 was repeated using the same molar ratios as previously described. In this case, the final product obtained was 2-(7-((5-chlorobenzo[d]thiazol-2-yl)methyl)-8-oxo-7,8-di Hydropyrazino[2,3-d]pyridazin-5-yl) tert-butyl acetate (compound 8): 1 HNMR (CDCl 3 ,300MHz): δ ppm 9.08(s,1H),9.05(s,1H),8.00(s,1H),7.74(d,J=8.7Hz,1H),7.36(d,J=8.7Hz,1H),5.87(s,2H ), 4.04(s,2H), 1.41(s,9H).

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PUM

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Abstract

The present invention relates to novel compounds and pharmaceutical compositions thereof, and methods for promoting healthy aging of skin, the treatment of skin disorders, the treatment of cardiovascular disorders, the treatment of renal disorders, the treatment of angiogenesis disorders, such as cancer, treatment of tissue damage, such as non-cardiac tissue damage, the treatment of evolving myocardial infarction, and the treatment of various other disorders, such as complications arising from diabetes with the compounds and compositions of the invention. Other disorders can include, but are not limited to, atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, infections of the skin, peripheral vascular disease, stroke, and the like.

Description

[0001] This application claims the benefit of priority to US Provisional Patent Application No. 61 / 365,098, filed July 16, 2010, the entire disclosure of which is hereby incorporated by reference. [0002] All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety. The disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art as known to those skilled in these publications as of the date of the invention described and claimed herein. [0003] This patent disclosure contains material that is protected by copyright. The copyright owner has no objection to the reproduction by anyone of the patent document or patent disclosure as it appears in the US Patent and Trademark Office patent file or files, but otherwise reserves any and all copyright rights therein. field of invention [0004] The present invention relates to nove...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/00
CPCC07D487/04A61P3/10A61P17/00A61P35/00
Inventor A·沃斯穆特D·W·兰德瑞S·X·邓R·拉马萨米A·M·施米德B·L·米拉瑞
Owner THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK
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