Phenyl butyl nitrone compositions and methods for treatment of oxidative tissue damage

Abstract

Compositions for treating tissue damage from ischemia contain PBN, or active derivatives thereof, which are active during ischemia in preventing ATP depletion of the cells which predisposes them to subsequent injury during reperfusion, and which are active during reperfusion as oxygen radical scavengers, in a suitable pharmaceutical carrier for systemic or local administration, especially to the CNS, spinal column and eyes. Based on animal studies, the dosage for treating damage due to stroke is in the range of 10 to 300 mg/kg. Similar dosages are useful in treating damage resulting from free radical generation during inflammation, either as a product of infection or exposure to inflammatory agents or abusive agents, including drugs and alcohol.

We claim: 
     
       1. A method for in vivo treatment of oxidative CNS tissue damage .[.resulting from ischemia or inflammation.]. comprising: administering α-phenyl t-butyl nitrone .[.and derivatives.]. .Iadd.or a derivative .Iaddend.thereof .[.having spin trapping activity and preventing ATP depletion in vivo in tissue.]. having the formula: ##STR11## wherein: X is phenyl or ##STR12## wherein R is H, ##STR13## and n is a whole integer from 1 to 5; or ##STR14## Y is a tert-butyl group that can be hydroxylated or acetylated on one or more positions; phenyl; or ##STR15## Z is a C 1  to C 5  straight or branched alkyl group; .[.and.]. .Iadd.in .Iaddend.   a pharmaceutically acceptable carrier for delivery of the α-phenyl t-butyl nitrone .Iadd.or derivative thereof .Iaddend.to .[.the CNS of.]. a patient in need of such treatment in a dosage effective to prevent or reverse .Iadd.oxidative CNS .Iaddend.tissue damage .[.resulting from ischemia of inflammation.]. not associated with bacterial toxins.   
     
     
       2. The method of claim 1 wherein the phenyl butyl nitrone derivatives are selected from the group consisting of hydroxy PBNs, PBN esters, acetoxy PBNs, alkyl PBNs, alkoxyl PBNs, phenyl PBNs. 
     
     
       3. The method of claim 1 wherein the PBN derivative is functionalinzd to release in vivo a compound selected from the group consisting of 2-, 3-, and 4-hydroxyphenyl t-butyl nitrone; 2-, 3-, and 4-hydroxyphenyl t-butyl nitrone; 2-, 3-, and 4-carboxyphenyl t-butyl nitrone; and 2-, 3-, and 4-aminophenyl t-butyl nitrone. 
     
     
       4. The method of claim 1 comprising as the active ingredient α-phenyl t-butyl nitrone. 
     
     
       5. The method of claim 1 further comprising administering an agent selected from the group consisting of streptokinase, tissue plasminogen activator, mannitol, and lazaroids. 
     
     
       6. The method of claim 1 wherein the PBN and derivatives thereof is in a pharmaceutical carrier delivering an effective dosage to a patient to prevent reperfusion injury of CNS tissue. 
     
     
       7. The method of claim 1 wherein the PBN and derivatives thereof is in a pharmaceutical carrier delivering an effective dosage to a patient to prevent CNS tissue damage from inflammation. 
     
     
       8. The method of claim 1 wherein the PBN and derivatives thereof is provided in a dosage of 10 to 300 mg PBN/kg body weight. 
     
     
       9. The method of claim 1 wherein the composition administered during or immediately after a stroke. 
     
     
       10. The method of claim 1 wherein the composition is administered to a patient having a progressive neuronal disorder. 
     
     
       11. The method of claim 1 wherein the composition is administered to a patient exposed to high pressure oxygen or an oxygen enriched environment. 
     
     
       12. The method of claim 1 wherein the composition is administered to a patient to mitigate damage to cells from exposure to a chemical agent. 
     
     
       13. The method of claim 1 wherein the composition is administered to a patient suffering from meningitis. 
     
     
       14. A composition for in vivo treatment of .Iadd.oxidative CNS .Iaddend.tissue damage .[.resulting from ischemia or inflammation.]. not associated with bacterial toxins comprising: α-phenyl t-butyl nitrone .[.and derivatives.]. .Iadd.or a derivative .Iaddend.thereof .[.having spin trapping activity and preventing ATP depletion in vivo in tissue.]. of the formula: ##STR16## X is phenyl or ##STR17## wherein R is H, ##STR18## and n is a whole integer from 1 to 5; or ##STR19## Y is a tert-butyl group that can be hydroxylated or acetylated on one or more positions; phenyl; or ##STR20## Z is a C 1  to C 5  straight or branched alkyl group .[.further comprising a compound selected from the group consisting of streptokinase, tissue plasminogen activator, mannitol and lazaroides.].   a pharmaceutically acceptable carrier for .[.intravenous.]. administration to a patient,   wherein the α-phenyl nitrone is in an amount effective to prevent tissue damage .[.resulting from ischemia or inflammation.]. not associated with bacterial toxins wherein the nitrone .[.and further compound are.]. .Iadd.is .Iaddend.present in effective amounts.   
     
     
       15. The composition of claim 14 wherein the phenyl butyl nitrone derivatives are selected from the group consisting of hydroxy PBNs, PBN esters, acetoxy PBNs, alkyl PBNs, alkoxyl PBNs, phenyl PBNs. 
     
     
       16. The composition of claim 14 wherein the PBN derivative is functionalized to release in vivo a compound selected from the group consisting of 2-, 3-, and 4-hydroxyphenyl t-butyl nitrone; 2-, 3, and 4-hydroxyphenyl t-butyl nitrone; 2-, 3-, and 4-aminophenyl t-butyl nitrone. 
     
     
       17. The composition of claim 14 comprising as the active ingredient α-phenyl t-butyl nitrone. 
     
     
       18. The composition of claim 14 wherein the PBN and derivatives thereof is in a pharmaceutical carrier delivering an effective dosage to a patient to prevent reperfusion injury. .Iadd.19. The method of claim 1 wherein the oxidative CNS tissue damage is associated with ischemia and wherein the route of administering is intravenous. .Iaddend. .Iadd.20. The method of claim 19 wherein the ischemia is stroke and wherein the effective dose is from 10 to 300 mg of nitrone compound per kg of body weight. .Iaddend. .Iadd.21. The method of claim 10 wherein the progressive neuronal disorder is due to Parkinson's disease. .Iaddend. .Iadd.22. The method of claim 10 wherein the progressive neuronal disorder is due to senile dementia. 
     
     
        .Iaddend. .Iadd.23.  The method of claim 1 wherein the oxidative CNS damage is associated with inflammation. .Iaddend. .Iadd.24. The method of claim 1 wherein the oxidative CNS damage is associated with meningitis. .Iaddend. .Iadd.25. The method of claim 1 wherein X is ##STR21## 
     
     
        and R is H or Z. .Iaddend. .Iadd.26.  The method of claim 25 wherein Y is a tert-butyl group. .Iaddend. .Iadd.27. A composition comprising: nitrone compound of the formula: ##STR22## wherein: X is phenyl or ##STR23## wherein R is H, ##STR24## and n is a whole integer from 1 to 5; or ##STR25## Y is a tert-butyl group that can be hydroxylated or acetylated on one or more positions; phenyl; or ##STR26## wherein W is ##STR27## and Z is a C 1  to C 5  stright or branched alkyl group;   subject to the proviso that X is not phenyl when Y is tert-butyl, in a pharmaceutically-acceptable, orally-administrable carrier. .Iaddend.   
     
     
        .Iadd.8.  The composition of claim 27 wherein Y is tert-butyl, X is ##STR28## 
     
     
        and R is H. .Iaddend. .Iadd.29.  The composition of claim 27 wherein Y is tert-butyl, X is ##STR29## 
     
     
        and R is Z. .Iaddend. .Iadd.30.  A composition comprising: nitrone compound of the formula: ##STR30## wherein: X is phenyl or ##STR31## wherein R is H, ##STR32## and n is a whole integer from 1 to 5; or ##STR33## Y is a tert-butyl group that can be hydroxylated or acetylated on one or more positions; phenyl; or ##STR34## wherein W is ##STR35## and Z is a C 1  to C 5  straight or branched alkyl group; subject to the proviso that X is not phenyl when Y is tert-butyl in pharmaceutically-acceptable, intravenously-administrable carrier.   
     
     
        .Iaddend. .Iadd.31.  The composition of claim 30 wherein Y is tert-butyl, X is ##STR36## 
     
     
        and R is H. .Iaddend. .Iadd.32.  The composition of claim 30 wherein Y is tert-butyl, X is ##STR37## and R is Z. .Iaddend.