RU99101123A - CHELATING MATERIALS AND THEIR METALWORK FOR THE TREATMENT OF CONDITIONS CAUSED BY FREE RADICALS - Google Patents

Claims (18)

1. The use of the compounds of formula 1

or its metal chelate or its salt in the manufacture of a therapeutic agent for use in the treatment or prevention of conditions caused by the presence of free radicals in the human or animal body, where
each R ^{1 is} independently hydrogen or —CH ₂ COR ⁵ ;
R ⁵ is hydroxy, optionally hydroxylated alkoxy, amino or alkylamido;
each R ² independently represents a group XYR ⁶ ;
X represents a bond or a C _1-3 alkylene or oxoalkylene group optionally substituted with an R ⁷ group;
Y represents a bond, an oxygen atom or a group NR ⁶ ;
R ⁶ represents a hydrogen atom, a COOR ⁸ group, an alkyl, alkenyl, cycloalkyl, aryl or aralkyl group, optionally substituted with one or more groups selected from COOR ⁸ , CONR ₂ ⁸ , NR ₂ ⁸ , OR ⁸ , = NR ⁸ , = O, OP (O) (OR ⁸ ) R ⁷ and OSO ₃ M;
R ⁷ is hydroxy, optionally hydroxylated, optionally alkoxylated alkyl, or aminoalkyl group;
R ⁸ represents a hydrogen atom or an optionally hydroxylated, optionally alkoxylated alkyl group;
M represents a hydrogen atom or one equivalent of a physiologically acceptable cation;
R ³ is C _1-8 alkylene, 1,2-cycloalkylene or 1,2-arylene; and
each R ^{4 is} independently hydrogen or C _1-3 -alkyl. 2. The application of paragraph 1, where
R ⁵ is hydroxy, C _1-8 -alkoxy, ethylene glycol, glycerin, amino or C _1-8 -alkylamido;
X represents a bond or a group selected from CH ₂ , (CH ₂ ) ₂ , CO, CH ₂ CO, CH ₂ CH ₂ CO or CH ₂ COCH ₂ ;
Y represents a bond;
R ⁶ represents a mono - or poly (hydroxy - or alkoxylated) alkyl group or a group of the formula OP (O) (OR ⁸ ) R ⁷ and
R ⁷ represents a hydroxy or unsubstituted alkyl or aminoalkyl group. 3. The use according to claim 1 or 2, wherein R ³ is ethylene, and each R ¹ group is -CH ₂ COR ⁵ , where R ⁵ is hydroxy.  4. The use according to any one of paragraphs. 1-3, where the compound of formula 1 is a N, N'-bis- (pyridoxal-5-phosphate) -ethylene diamine-N, N'-diacetic acid.  5. The use according to any one of the preceding claims, wherein the metal chelate includes a metal ion selected from alkali and alkaline earth metals and metals having an atomic number of 22-31, 42, 44 and 58-70. 6. The use according to claim 5, wherein the metal chelate has a K _a from 10 ⁹ to 10 ²⁵ . 7. The use according to claim 5, wherein the metal chelate has a K _a from 10 ¹² to 10 ²² . 8. The use according to claim 5, wherein the metal chelate has a K _a value of at least 10 ³ times less than the K _a value of the corresponding iron chelate (Fe ³⁺ ). 9. The use according to any one of paragraphs. 5 to 8, where the metal ion is selected from Na ⁺ , Mn ²⁺ , Ca ²⁺ , Cu ⁺ , Cu ²⁺ , Mg ²⁺ , Gd ^3+, and Zn ²⁺ .  10. The use according to any one of the preceding claims, wherein the compound is a manganese chelate of (11) N, N'-bis (pyridoxal-5-phosphate) ethylene diamine-N, N'-diacetic acid.  11. The use according to any one of the preceding claims, wherein the therapeutic agent is intended for use in the treatment or prophylaxis of a lesion caused by reperfusion.  12. The use according to claim 11, wherein the lesion is the result of reperfusion in the myocardium.  13. The use according to claim 11, wherein the lesion is associated with thrombolytic therapy, cardiopulmonary bypass surgery, transcutaneous intravascular coronary angioplasty, or is the result of cardiac surgery or a transplant operation.  14. The use according to any one of paragraphs. 1 - 10, where a therapeutic agent is intended for use in the treatment or prevention of disorders caused by radiation.  15. A pharmaceutical composition comprising a compound of formula 1 or its metal chelate or its salt as defined in any one of claims. 1 to 10, together with a thrombolytic agent and at least one pharmaceutically acceptable carrier or excipient.  16. A package containing a compound of formula 1 or its metal chelate or its salt as defined in any one of claims. 1 -10, and a separate thrombolytic agent for simultaneous, separate or sequential use during thrombolytic therapy.  17. The use of the compounds of formula 1 or its metal chelate or its salt, defined according to any one of paragraphs. 1 - 10, together with a thrombolytic agent in the manufacture of a medicine for use during thrombolytic therapy.  18. A method of treating a human or animal to combat conditions associated with the presence of free radicals in the body or their prevention, including the introduction into the body of an effective amount of the compounds of formula 1 or its metal chelate or its salt, defined in any one of paragraphs. 1 - 10.