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Pyruvate derivatives

a technology of pyruvate and derivatives, applied in the field of pyruvate derivatives, can solve the problems of not being able to distinguish between "preventing" and "suppressing" and being sterically impractical and/or synthetically non-feasibl

Inactive Publication Date: 2003-01-16
GALILEO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns (e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum) that are sterically impractical and / or synthetically non-feasible.
It will be understood by those skilled in the art that in human medicine, it is not always possible to distinguish between "preventing" and "suppressing" since the ultimate inductive event or events may be unknown, latent, or the patient is not ascertained until well after the occurrence of the event or events.

Method used

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Examples

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example 1

Formula Ia where A is 1H-Benzimidazole-2-yl, R is Ethyl, and X is S

[0592] A solution of 2-mercaptobenzimidazole (200 mg, 1.33 mmol) and ethyl 3-bromopyruvate (0.20 mL, 1.43 mmol) in methanol (2.5 mL) and acetone (2 mL) was shaken at 20.degree. C. for 4 hours. The solvents were removed under the reduced pressure on a rotary evaporator. The residue was triturated with ethyl acetate. Solvent was decanted and the residue was dissolved in methylene chloride. The solution was washed with diluted aqueous sodium bicarbonate solution and water, and then dried over magnesium sulfate. Removal of the solvent gave the expected product, 3-(1H-Benzoimidazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester (326 mg, 93%). .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. (ppm): 7.31 (br. s, 1H), 7.24 (br. s, 1H), 7.15-7.05 (m, 2H), 4.32 (q, J=7.1 Hz, 2H), 4.29 (br. s, 1H), 3.90 (br. s, 1H), 1.24 (t, J=7.1 Hz, 3H). MS (ESI): m / z 265 (M+1, 100).

example 2

Formula Ia where A is 5-Methoxy-1H-benzimidazole-2-yl, R is Ethyl, and X is S

[0593] A solution of 2-mercapto-5-methylbenzimidazole (200 mg, 1.22 mmol) and ethyl 3-bromopyruvate (0.20 mL, 1.43 mmol) in methanol (2 mL) and acetone (3 mL) was shaken at room temperature for 4 hours. The solvents were removed under the reduced pressure on a rotary evaporator. The residue was triturated with ethyl acetate. Solvent was decanted and the residue was dissolved in methylene chloride. The solution was washed with diluted aqueous sodium bicarbonate solution and water, and then dried over magnesium sulfate. Removal of the solvent gave the expected product, 3-(5-methoxy-1H-benzoimidazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester (300 mg, 88%). .sup.1H-NMR (D.sub.3COD, 300 MHz) .delta. (ppm): 7.19 (br. s, 1H), 7.10 and 7.04 (br. 2 s, 1H), 6.94 (d, J=8.2 Hz, 1H), 4.34 (q, J=7.1 Hz, 2H), 4.31 (br. s, 1H), 3.91 (br. s, 1H), 2.37 (br. s, 3H), 1.26 (t, J=7.1 Hz, 3H). MS (ESI): m / z 279 (M+1, 100).

example 3

Formula Ia where A is 5-Methyl-1H-benzimidazole-2-yl, R is Ethyl, and X is S

[0594] A solution of 5-methoxy-2-benzimidazolethiol (200 mg, 1.11 mmol) and ethyl 3-bromopyruvate (0.20 mL, 1.43 mmol) in methanol (5 mL) and acetone (2 mL) was shaken at room temperature for 4 hours. The solvents were removed under the reduced pressure on a rotary evaporator. The residue was triturated with ethyl acetate. Solvent was decanted and the residue was dissolved in methylene chloride. The solution was washed with diluted aqueous sodium bicarbonate solution and water, and then dried over magnesium sulfate. Removal of the solvent gave the expected product, 3-(5-Methyl-1H-benzoimidazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester (300 mg, 92%). .sup.1H-NMR (D.sub.3COD, 300 MHz) .delta. (ppm): 7.19 (br. s, 1H), 6.75 (br. s, 1H), 6.69 (dd, J=2.3 Hz, J=8.8 Hz, 1H), 4.30 (q, J=7.1 Hz, 2H), 4.29 (br. s, 1H), 3.93 (br. s, 1H), 3.69 (s, 3H), 1.24 (t, J=7.1 Hz, 3H). MS (ESI): m / z 295 (M+1, 100).

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Abstract

Certain known and novel pyruvate derivatives are particularly active in restoring or preserving metabolic integrity in oxidatively competent cells that have been subjected to oxygen deprivation. These pyruvate-derived compounds include, but are not limited to oximes, amides, pyruvate analogues, modified pyruvate analogues, esters of pyruvate (e.g., polyol-pyruvate esters, pyruvate thioesters, glycerol-pyruvate esters and dihydroxyacetone-pyruvate esters). Such pyruvate derivatives (including single tautomers, single stereoisomers and mixtures of tautomers and / or stereoisomers, and the pharmaceutically acceptable salts thereof) are useful in the manufacture of pharmaceutical compositions for treating a number of conditions characterized by oxidative stress.

Description

[0001] This application claims priority as a continuation-in-part of co-pending provisional applications: U.S. Serial No. 60 / 288,649, filed May 3, 2001; U.S. Serial No. 60 / 295,314, filed Jun. 1, 2001; and U.S. Serial No. 60 / 368,456, filed Mar. 27, 2002, each incorporated herein by reference in its entirety. This application is also related to co-pending application U.S. Serial No. ______, filed on even date herewith and entitled "PROCESS FOR SOLID SUPPORTED SYNTHESIS OF PYRUVATE-DERIVED COMPOUNDS", incorporated herein by reference in its entirety.[0002] The present invention relates to pyruvate derivatives, particularly to derivatives having cytoprotective activity, and specifically to a series of aromatic and peptidyl pyruvates. The invention is also directed to formulations and methods for treating stroke, myocardial infarction and chronic heart failure, as well as other oxidative stress and / or inflammation related conditions that are typically responsive to cellular enzyme modula...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/12A61K31/16A61K31/215A61K31/223A61K38/00A61P9/10C07C249/12C07C251/60C07C319/20C07C323/57C07C323/60C07D207/16C07D207/22C07D207/24C07D211/62C07D211/74C07D211/78C07D213/30C07D217/04C07D233/42C07D233/54C07D233/84C07D235/28C07D239/78C07D249/14C07D271/10C07D271/113C07D277/16C07D277/74C07D279/12C07D285/12C07D285/125C07D285/135C07D295/13C07D295/15C07D295/185C07D339/08C07D345/00C07D405/12C07D473/38C07K5/02C07K5/093
CPCA61K31/12A61K31/16A61K31/215A61K31/223A61K38/00C07C249/12C07C319/20C07C323/60C07D207/16C07D207/22C07D207/24C07D211/62C07D211/74C07D211/78C07D213/30C07D217/04C07D233/42C07D233/64C07D233/84C07D235/28C07D239/78C07D249/14C07D271/113C07D277/16C07D277/74C07D279/12C07D285/125C07D285/135C07D295/13C07D295/15C07D295/185C07D339/08C07D345/00C07D405/12C07D473/38C07K5/0215C07K5/0819C07C323/57C07C251/60A61P9/10
Inventor WANG, BINGMILLER, GUYFLAIM, STEPHEN F.DEL BALZO, UGHETTAZHANG, WEIJANAGANI, SATYANARAYANASONG, JIANGAO
Owner GALILEO PHARMA
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