Patent EA-001800-B1 (EA)
Title: Method of treatment and prevention of adverse effects of reactive oxygen species
Inventor: HORWITZ LAWRENCE D
IPC: A61K31/165
Filed: 1997-02-07
Abstract: 1. A method for the treatment of ischemic diseases or other conditions involving injury to mammalian tissue by reactive oxygen species which comprises administering an effective amount of a compound of the following general formula [I] or a pharmaceutically acceptable salt thereof together with pharmaceutically acceptable carriers:   wherein: R<1> and R<2>, independently of one another, are lower alkyl groups comprising from one to six carbon atoms; R<3> is a carboxyl group, an ester or amide; R<4> is selected from the group consisting of a hydrogen atom, a lower alkyl group comprising from one to six carbon atoms, a lower alkanoyl group comprising from one to six carbon atoms, a phenyl-lower alkyl group containing a linear or branched alkyl group comprising from one to six carbon atoms, or a phenylcarbonyl group; therewith phenyl in the phenyl-lower alkyl and phenylcarbonyl groups can be substituted by one of the substituents selected from the group consisting of galogen atoms, and a lower alkyl, hydroxy, lower alkoxy, lower alkylenedioxy, nitro, amino and lower alkylamino groups comprising from one to six carbon atoms; R<5> represents a hydrogen atom, the above mentioned lower alkyl group, lower alkanoyl group, phenyl-lower alkyl group or a phenylcarbonyl group; therewith phenyl in the phenyl-lower alkyl and phenylcarbonyl groups can be substituted by one of the substituents selected from the group consisting of halogen atoms, and the above mentioned lower alkyl, hydroxy, lower alkoxy, lower alkylenedioxy, nitro, amino and lower alkylamino groups; "n" is an integer that is 0 or 1; and "A" is a lower alkylene group comprising from one to six carbon atoms. 2. The method of Claim 1 wherein in the compound of formula I R<3> represents a carboxyl group, an ester containing alkyl comprising from one to six carbon atoms, an ester containing phenyl and alkyl comprising from one to six carbon atoms, an amide, alkylamino group comprising from one to six carbon atoms, or represents a group containing phenyl and alkylamino group comprising from one to six carbon atoms. 3. The method of Claim 2 wherein in the compound of formula I R<3> represents a carboxyl group and R<4> and R<5> are hydrogen atoms. 4. The method of Claim 3 wherein in the compound of formula I R<1> and R<2> are both methyl groups and A is a -CH2-group. 5. The method of Claim 1 wherein in the compound of formula I R<1> and R<2> are lower alkyl groups comprising from one to six carbon atoms; R<4> and R<5>, independently of one another, are hydrogen atoms or methyl groups and A is a -CH2-group. 6. The method of Claim 1 wherein the compound of formula I is N-(2-methyl-2-mercaptopropionyl)-L-cysteine. 7. The method of Claim 1 wherein the compound of formula I is N-(2,2-dimethyl-2-mercaptopropionyl)-L-cysteine. 8. A method of protecting live mammalian tissue from injury resulting from exposure to reactive oxygen species which comprises administering an effective amount of a compound of the following general formula [I] or a pharmaceutically acceptable salt thereof together with pharmaceutically acceptable carriers:   wherein: R<1> and R<2>, independently of one another, are lower alkyl groups comprising from one to six carbon atoms; R<3> is a carboxyl group, an ester or amide; R<4> is selected from the group consisting of a hydrogen atom, a lower alkyl group comprising from one to six carbon atoms, a lower alkanoyl group comprising from one to six carbon atoms, a phenyl-lower alkyl group containing a linear or branched alkyl group comprising from one to six carbon atoms, or a phenylcarbonyl group; therewith phenyl in the phenyl-lower alkyl and phenylcarbonyl groups can be substituted by one of the substituents selected from the group consisting of halogen atoms, and a lower alkyl, hydroxy, lower alkoxy, lower alkylenedioxy, nitro, amino and lower alkylamino groups comprising from one to six carbon atoms; R<5> represents a hydrogen atom, the above mentioned lower alkyl group, lower alkanoyl group, phenyl-lower alkyl group or a phenylcarbonyl group; therewith phenyl in the phenyl-lower alkyl and phenylcarbonyl groups can be substituted by one of the substituents selected from the group consisting of halogen atoms, and the above mentioned lower alkyl, hydroxy, lower alkoxy, lower alkylenedioxy, nitro, amino and lower alkylamino groups; "n" is an integer that is 0 or 1; and "A" is a lower alkylene group comprising from one to six carbon atoms. 9. The method of Claim 8 wherein the compound of formula I is N-(2-methyl-2-mercaptopropionyl)-L-cysteine or N-(2,2-dimethyl-2-mercaptopropionyl)-L-cysteine. 10. The method of Claim 9 wherein the method is used when the reactive oxygen species are formed after reestablishment of blood flow to a body organ after restriction of blood flow to that organ. 11. The method of Claim 8 wherein the live tissue is myocardium and the method is used for treatment of myocardial ischemia or infarction, heart failure or the effects of cardiopulmonary bypass. 12. The method of Claim 8 wherein the live tissue is brain and the method is used for treatment of cerebral ischemia or infarction. 13. The method of Claim 8 wherein the live tissue is coronary artery or other blood vessels and the method is used for treatment or prevention of atherosclerosis or vascular injury following reperfusion of obstructed arteries. 14. The method of Claim 8 wherein the live tissue is kidney and the method is used for treatment of renal infarction or acute tubular necrosis. 15. The method of Claim 8 wherein the live tissue is intestines and the method is used for treatment of intestinal ischemia or infarction. 16. The method of Claim 8 wherein the live tissue is coronary artery or other blood vessels and the method is used for treatment or prevention of tolerance to nitroglycerin and related nitrates.