Compounds for the treatment of ischemia

a technology of ischemia and compound, which is applied in the field of compound for the treatment of ischemia, can solve the problems of sudden death, myocardial infarction or congestive heart failure, ischemic/hypoxic damage,

Inactive Publication Date: 2004-10-07
DENINNO MICHAEL P +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Mycardial ischemic injury can occur in out-patient as well as in perioperative settings and can lead to the development of sudden death, myocardial infarctio...

Method used

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  • Compounds for the treatment of ischemia
  • Compounds for the treatment of ischemia
  • Compounds for the treatment of ischemia

Examples

Experimental program
Comparison scheme
Effect test

example 2

Acetonide Cleavage

[0698] (2S,3S,4R,5R)3-Amino-5-{6-[5-chloro-2-(3,4,5,6-tetrahydroxytetrahyd-ropyran-2-ylmethoxy)benzylamino]-purin-9-yl}-4-hydroxytetrahydrofuran-2-ca-rboxylic acid methyl amide.

[0699] To a solution of 3-amino-5-{-6-[5-chloro-2-(2,2,7,7-tetramethyltetr-ahydro-bis[1,3]dioxolo[4,5-b;4',5'-d]pyran-5-ylmethoxy) benzylamino]purin-9-yl}-4-hydroxytetrahydrofuran-2-carboxylic acid methylamide (59 mg, 0.09 mmol) in chloroform (7 mL) was added trifluoroacetic acid (0.7 mL). This reaction was stirred under anhydrous conditions at room temperature for 2 h. After this time period water was added (10 mL) and the reaction was stirred at room temperature for 5 days. The solvent was removed with a rotary evaporator and the resulting solid was then triturated with Et.sub.2O to afford the title compound as a beige powder

[0700] (60 mg). Mp 212.0-218.0.degree. C. C.sub.24H.sub.30ClN.sub.7O.sub.9-. MW 596.00. MS 596.1 (M+H).sup.+.

[0701] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.52-8....

example 3

Reduction of Azide

[0702] (2S,3S,4R,5R)3-Amino-5-[6-(2-benzyloxy-5-chloro-benzylamino)-purin--9-yl]-4-hydroxytetrahydrofuran-2-carboxylic acid methylamide.

[0703] (2S,3S,4R,5R)-3-Azido-5-[6-(2-benzyloxy-5-chloro-benzylamino)-purin--9-yl-4-hydroxy tetrahydrofuran-2-carboxylic acid methyl amide (456 mg, 0.83 mmol) was dissolved in anhydrous THF (50 mL) and the reaction cooled to 0.degree. C. After adding triphenylphosphine (304 mg, 1.2 mmol), the reaction was stirred for 30 minutes at 0.degree. C. At the end of this time period, concentrated ammonium hydroxide (0.4 mL) and water (0.5 mL) were added and the reaction was allowed to slowly come to room temperature and stirred at room temperature for 15 h. The solvent was then removed by rotary evaporation and the product was preadsorbed onto silica gel and purified by flash chromatography (SiO.sub.2, 5% then 18% methanol / CH.sub.2Cl.sub.2) to afford the title compound as a colorless solid.

[0704] Mp 114.2-115.2.degree. C.

[0705] [.alpha.].sub...

example 4

[0709] (2S,3S,4R,5R)3-Amino-5-{6-[5-chloro-2-(2-morpholin-4-yl-ethoxy)-ben-zylamino]-purin-9-yl}-4-hydroxytetrahydrofuran-2-carboxylic acid methylamide.

[0710] Mp 99.0-108.0.degree. C.

[0711] [.alpha.].sub.22=-29.64.degree. (c=0.280, MeOH)

[0712] C.sub.24H.sub.31ClN.sub.8O.sub.5. MW 547.02. MS 547.2 (M+H).sup.+.

[0713] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.57 (s, 1H); 8.45 (quart, 1H, J=4.6 Hz); 8.28 (bs, 1H); 8.21 (s, 1H); 7.22 (dd, 1H, J=8.7 Hz, J=2.4 Hz); 7.05 (bs, 1H); 7.01 (d, 1H, J=8.7 Hz); 6.02 (d, 1H, J=3.7 Hz), 6.05-5.80 (mult, 1H); 4.63 (bs, 2H); 4.40-4.30 (mult, 1H); 4.12 (t, 3H. J=5.5 Hz); 3.55-3.50 (mult, 5H); 2.70-2.60 (mult, 5H); 2.55-2.45 (mult, 4H); 2.25-1.95 (mult, 2H).

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Abstract

A3 agonists, methods of using such A3 agonists and pharmaceutical compositions containing such A3 agonists. The A3 agonists are useful for the reduction of tissue damage resulting from tissue ischemia or hypoxia.

Description

[0001] This application claims priority from provision application U.S. Ser. No. 60 / 156,828 filed Sep. 30, 1999, the benefit of which is hereby claimed under 37 C.F.R..sctn.1.78(a)(3).BACKGROUND OF INVENTION[0002] This invention relates to adenosine A-3 receptor agonists, pharmaceutical compositions containing such inhibitors and the use of such inhibitors to treat for example, ischemia particularly, perioperative myocardial ischemic injury in mammals, including humans.[0003] Mycardial ischemic injury can occur in out-patient as well as in perioperative settings and can lead to the development of sudden death, myocardial infarction or congestive heart failure. There is an unmet medical need to prevent or minimize myocardial ischemic injury, particularly perioperative myocardial infarction. Such a therapy is anticipated to be life-saving and reduce hospitalizations, enhance quality of life and reduce overall health care costs of high risk patients.[0004] Pharmacological cardioprotect...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D473/00C07D473/30C07H19/16
CPCC07D471/04C07D473/00C07D473/30C07H19/16
Inventor DENINNO, MICHAEL P.MASAMUNE, HIROKOSCOTT, ROBERT W.
Owner DENINNO MICHAEL P
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