Cytoprotective agent

Abstract

Disclosed is a cytoprotective agent for use with respect to ischemic damage, including as an active ingredient a triprenyl phenol compound represented by the following general formula (I), wherein X is —CHY—C(CH 3 ) 2 Z, Y and Z are each independently —H or —OH, or jointly form a single bond, and R represents a hydrogen atom or a substituent with a molecular weight of 1000 or less.

The invention claimed is: 
     
       1. A method of treatment of cerebral hemorrhagic infarction, comprising the step of administering a drug containing a triprenyl phenol of formula (II) or formula (III) to a patient affected by cerebral hemorrhagic infarction: 
       
         
           
           
               
               
           
         
         wherein X 1 , X 2  and X 3  are each independently —CHY—C(CH 3 ) 2 Z; Y and Z are each independently —H or —OH, or jointly form a bond, and R 1  is selected from among any one of the following (A) through (C):
 (A) a residue of an amino compound selected from the group consisting of a natural amino acid, a D-isomer of a natural amino acid, and a compound derived by replacing a carboxy group in a natural amino acid, or a D-isomer of a natural amino acid, with a hydrogen atom, a hydroxy group, or a hydroxymethyl group, from which one amino group has been removed, with the proviso that R 1  is not hydroxymethyl; 
 (B) an aromatic group having at least one selected from the group consisting of a carboxy group, a hydroxy group, a sulfonic group and a secondary amino group as a substituent or a part of a substituent, or an aromatic group that contains a secondary amino group and may contain a nitrogen atom; and 
 (C) an aromatic amino acid residue represented by the following formula (II-1) 
 
       
       
         
           
           
               
               
           
         
         wherein, in formula (II-1), n is 0 or 1, and R 3  is at least one substituent selected from the group consisting of a hydroxy group, a carboxy group, and a C1 to C5 alkyl group, wherein R 3  may be present or absent; and 
         wherein, in formula III, R 2  and the two nitrogens to which it is attached are derived from a diamine selected from the group consisting of: a natural amino acid with two amino groups; a D-isomer of a natural amino acid with two amino groups; a compound derived from a natural amino acid with two amino groups by replacing a carboxy group with a hydrogen atom, a hydroxy group, or a hydroxymethyl group; a compound derived from a D-isomer of a natural amino acid with two amino groups by replacing a carboxy group with a hydrogen atom, a hydroxy group, or a hydroxymethyl group; compounds having the formula H 2 N—CH(COOH)—(CH 2 ) n —NH 2  wherein n is an integer from 0 to 9; and compounds having the formula H 2 N—CH(COOH)—(CH 2 ) m —S p —(CH 2 ) q —CH(COOH)—NH 2  wherein m, p and q are each independently an integer from 0 to 9. 
       
     
     
       2. The method of treatment of cerebral hemorrhagic infarction according to  claim 1 , wherein the triprenyl phenol compound is SMTP-7. 
     
     
       3. The method of treatment of cerebral hemorrhagic infarction according to  claim 1 , wherein the patient is a patient with respect to whom treatment with a thrombolytic drug is contraindicated. 
     
     
       4. The method of treatment of cerebral hemorrhagic infarction according to  claim 3 , wherein the triprenyl phenol compound is SMTP-7. 
     
     
       5. A method for treating cerebral thrombosis in a human subject in need thereof, comprising administering a therapeutically effective amount of SMTP-7 to the human subject, wherein the human subject has experienced at least one symptom of cerebral thrombosis for more than three hours. 
     
     
       6. The method of claim 5, wherein the SMTP-7 is administered by intravenous injection. 
     
     
       7. The method of claim 6, wherein the SMTP-7 is administered by bolus or continuous infusion for less than 24 hours per day. 
     
     
       8. The method of claim 5, wherein no additional thrombolytic drug is administered at the same time with the SMTP-7. 
     
     
       9. The method of claim 5, wherein the SMTP-7 is administered in a dose of 0.01-100 mg/kg. 
     
     
       10. The method of claim 5, wherein the SMTP-7 is administered in a dose of 0.1-30 mg/kg. 
     
     
       11. The method of claim 5, wherein the SMTP-7 is administered beginning less than 12 hours after onset of the at least one symptom of cerebral thrombosis. 
     
     
       12. The method of claim 5, wherein use of a thrombolytic drug is contraindicated in the human subject. 
     
     
       13. The method of claim 12, wherein the human subject is further affected by a condition selected from the group consisting of hemorrhagic diathesis, hemorrhage, hypertension, impaired blood glucose, transient ischemic attack, disseminated intravascular coagulation syndrome, thrombotic microangiopathy, thrombosis phlebitis, deep vein thrombosis and idiopathic thrombosis. 
     
     
       14. The method of claim 5, wherein the patient is at risk of cerebral hemorrhage. 
     
     
       15. A method for treating an ischemic condition selected from the group consisting of transient ischemic attack, disseminated intravascular coagulation syndrome, thrombotic microangiopathy, thrombosis phlebitis, deep vein thrombosis, idiopathic thrombosis, myocardial infarction, and pulmonary thromboembolism in a human subject in need thereof, comprising administering a therapeutically effective amount of SMTP-7 to the human subject, wherein use of a thrombolytic drug is contraindicated in the human subject. 
     
     
       16. The method of claim 14, wherein no additional thrombolytic drug is administered at the same time with the SMTP-7. 
     
     
       17. The method of claim 15, wherein the SMTP-7 is administered in a dose of 0.01-100 mg/kg. 
     
     
       18. The method of claim 15, wherein the SMTP-7 is administered in a dose of 0.1-30 mg/kg. 
     
     
       19. The method of claim 15, wherein the SMTP-7 is administered beginning less than 12 hours after the onset of at least one symptom of the ischemic condition. 
     
     
       20. The method of claim 14, wherein the human subject is further affected by a condition selected from the group consisting of hemorrhagic diathesis, hemorrhage, hypertension and impaired blood glucose. 
     
     
       21. A method of treating ischemia reperfusion damage in a human subject, wherein the human subject is suffering from or predicted to suffer from ischemic reperfusion damage, comprising administering an effective amount of SMTP-7 to the human subject to treat ischemic reperfusion damage. 
     
     
       22. The method of claim 21, wherein the SMTP-7 is administered to the subject in a period in which the possibility of cell damage caused by ischemia is predicted to increase. 
     
     
       23. The method of claim 22, wherein the subject is suffering from cerebral infarction. 
     
     
       24. The method of claim 23, wherein the cerebral infarction is caused by a cerebral thrombosis. 
     
     
       25. The method of claim 23, wherein the cerebral infarction is caused by a cerebral embolism. 
     
     
       26. The method of claim 22, wherein the period in which the possibility of cell damage caused by ischemia is predicted to increase comprises a period after treatment of cerebral thrombosis utilizing an anticoagulant, antiplatelet or a thrombolytic drug. 
     
     
       27. The method of claim 21, wherein the human subject is affected by an ischemic condition for which use of a thrombolytic drug is contraindicated. 
     
     
       28. The method of claim 27, wherein the ischemic condition for which use of a thrombolytic drug is contraindicated is selected from the group consisting of transient ischemic attack, disseminated intravascular coagulation syndrome, thrombotic microangiopathy, thrombosis phlebitis, deep vein thrombosis, idiopathic thrombosis, myocardial infarction, and pulmonary thromboembolism. 
     
     
       29. The method of claim 21, wherein the SMTP-7 is administered by intravenous injection. 
     
     
       30. The method of claim 21, wherein the SMTP-7 is administered by bolus or continuous infusion for less than 24 hours per day. 
     
     
       31. The method of claim 21, wherein the SMTP-7 is administered in a dose that causes both thrombolysis and cytoprotection in the human subject. 
     
     
       32. The method of claim 21, wherein no additional thrombolytic drug is administered at the same time with the SMTP-7. 
     
     
       33. The method of claim 21, wherein the SMTP-7 is administered after the administration of a thrombolytic drug. 
     
     
       34. The method of claim 33, wherein the thrombolytic drug is alteplase. 
     
     
       35. The method of claim 21, wherein the subject has discontinued thrombolytic drug treatment for cerebral infarction. 
     
     
       36. The method of claim 21, wherein the SMTP-7 is administered in a dose of 0.01-100 mg/kg. 
     
     
       37. The method of claim 21, wherein the SMTP-7 is administered in a dose of 0.1-30 mg/kg. 
     
     
       38. The method of claim 21, wherein the SMTP-7 is administered to the subject more than three hours after the onset of at least one symptom of cerebral infarction. 
     
     
       39. The method of claim 21, wherein the SMTP-7 is administered beginning less than 12 hours after the onset of at least one symptom of cerebral infarction in the human subject. 
     
     
       40. The method of claim 21, wherein use of a thrombolytic drug is contraindicated in the human subject. 
     
     
       41. The method of claim 21, wherein the human subject is affected by a condition selected from the group consisting of hemorrhagic diathesis, hemorrhage, hypertension and impaired blood glucose. 
     
     
       42. A method for treating cerebral thrombosis in a human subject in need thereof, comprising intravenously administering a therapeutically effective dose of SMTP-7 to the human subject, wherein use of a thrombolytic drug is contraindicated in the human subject. 
     
     
       43. The method of claim 42, wherein the human subject is further affected by a condition selected from the group consisting of hemorrhagic diathesis, hemorrhage, hypertension, impaired blood glucose, transient ischemic attack, disseminated intravascular coagulation syndrome, thrombotic microangiopathy, thrombosis phlebitis, deep vein thrombosis and idiopathic thrombosis. 
     
     
       44. The method of claim 42, wherein the therapeutically effective dose of SMTP-7 is 0.1-30 mg/kg. 
     
     
       45. The method of claim 44, wherein no additional thrombolytic drug is administered at the same time with the SMTP-7. 
     
     
       46. A method of treating ischemic reperfusion damage resulting from cerebral thrombosis in a human, wherein the human subject is at risk of cerebral hemorrhage, comprising administering an effective amount of SMTP-7 to the human subject to treat ischemic reperfusion damage. 
     
     
       47. The method of claim 46, wherein the SMTP-7 is administered to the subject in a period in which the possibility of cell damage caused by ischemia is predicted to increase. 
     
     
       48. The method of claim 47, wherein the subject is suffering from cerebral infarction. 
     
     
       49. The method of claim 47, wherein the period in which the possibility of cell damage caused by ischemia is predicted to increase comprises a period after treatment of cerebral thrombosis utilizing an anticoagulant, antiplatelet or a thrombolytic drug. 
     
     
       50. The method of claim 49, wherein use of a thrombolytic drug is contraindicated in the human subject. 
     
     
       51. The method of claim 50, wherein the ischemic condition for which use of a thrombolytic drug is contraindicated is selected from the group consisting of transient ischemic attack, disseminated intravascular coagulation syndrome, thrombotic microangiopathy, thrombosis phlebitis, deep vein thrombosis, idiopathic thrombosis, myocardial infarction, and pulmonary thromboembolism. 
     
     
       52. The method of claim 46, wherein the SMTP-7 is administered by intravenous injection. 
     
     
       53. The method of claim 46, wherein the SMTP-7 is administered by bolus or continuous infusion for less than 24 hours per day. 
     
     
       54. The method of claim 46, wherein the SMTP-7 is administered in a dose that causes both thrombolysis and cytoprotection in the human subject. 
     
     
       55. The method of claim 46, wherein no additional thrombolytic drug is administered at the same time with the SMTP-7. 
     
     
       56. The method of claim 46, wherein the SMTP-7 is administered after the administration of a thrombolytic drug. 
     
     
       57. The method of claim 56, wherein the thrombolytic drug is alteplase. 
     
     
       58. The method of claim 46, wherein the subject has discontinued thrombolytic drug treatment for cerebral thrombosis. 
     
     
       59. The method of claim 46, wherein the SMTP-7 is administered in a dose of 0.01-100 mg/kg. 
     
     
       60. The method of claim 46, wherein the SMTP-7 is administered in a dose of 0.1-30 mg/kg. 
     
     
       61. The method of claim 46, wherein the SMTP-7 is administered to the subject more than three hours after the onset of at least one symptom of cerebral thrombosis. 
     
     
       62. The method of claim 46, wherein the SMTP-7 is administered beginning less than 12 hours after the onset of at least one symptom of cerebral thrombosis in the human subject. 
     
     
       63. The method of claim 46, wherein use of a thrombolytic drug is contraindicated in the human subject. 
     
     
       64. The method of claim 46, wherein the human subject is affected by a condition selected from the group consisting of hemorrhagic diathesis, hemorrhage, hypertension and impaired blood glucose. 
     
     
       65. A method for treating cerebral thrombosis in a human subject in need thereof, comprising administering a therapeutically effective amount of SMTP-7 to the human subject, wherein the human subject has experienced at least one symptom of cerebral thrombosis for more than three hours, wherein the SMTP-7 is administered in a dose that causes both thrombolysis and cytoprotection in the human subject. 
     
     
       66. A method for treating an ischemic condition selected from the group consisting of transient ischemic attack, disseminated intravascular coagulation syndrome, thrombotic microangiopathy, thrombosis phlebitis, deep vein thrombosis, idiopathic thrombosis, myocardial infarction, and pulmonary thromboembolism in a human subject in need thereof, comprising administering a therapeutically effective amount of SMTP-7 to the human subject, wherein the SMTP-7 is administered in a dose that causes both thrombolysis and cytoprotection in the human subject. 
     
     
       67. A method for treating cerebral thrombosis in a human subject in need thereof, comprising intravenously administering a therapeutically effective dose of SMTP-7 to the human subject, wherein use of a thrombolytic drug is contraindicated in the human subject, wherein the SMTP-7 is administered in a dose that causes both thrombolysis and cytoprotection in the human subject.