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(CH3)2Z, 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 a compound represented by formula (III) to the human subject suffering from cerebral thrombosis, wherein use of a thrombolytic drug is contraindicated in the human subject: 
       
         
           
           
               
               
           
         
       
       wherein X 2  and X 3  are each —CHY—C(CH 3 ) 2 Z; Y and Z jointly form a bond, and R 2  and the two nitrogens to which it is attached are derived from compounds having the formula H 2 N—CH(COOH)—(CH 2 ) n —NH 2  wherein n is 3. 
     
     
       6. A method for treating cerebral embolism in a human subject in need thereof, comprising administering: to a subject experiencing a cerebral embolism and having experienced at least one symptom of said cerebral embolism for three or more hours, a therapeutically effective amount of a compound represented by formula (III) to the human subject: 
       
         
           
           
               
               
           
         
       
       wherein X 2  and X 3  are each —CHY—C(CH 3 ) 2 Z; Y and Z jointly form a bond, and R 2  and the two nitrogens to which it is attached are derived from compounds having the formula H 2 N—CH(COOH)—(CH 2 ) n —NH 2  wherein n is 3. 
     
     
       7. A method for treating cerebral embolism in a human subject in need thereof, comprising administering: to a subject experiencing a cerebral embolism and having a contraindication for use of a thrombolytic drug, a therapeutically effective amount of a triprenyl phenol of formula (III) to the human subject: 
       
         
           
           
               
               
           
         
       
       wherein 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 2  and the two nitrogens to which it is attached are derived from compounds having the formula H 2 N—CH(COOH)—(CH 2 ) n —NH 2  wherein n is an integer from 0 to 9. 
     
     
       8. A method of reducing ischemia reperfusion damage in a human subject, wherein the human subject is suffering from cerebral thrombosis or cerebral embolism and having experienced at least one symptom of said cerebral thrombosis or cerebral embolism for three or more hours, said method comprising administering a therapeutically effective amount of a triprenyl phenol of formula (III) to the human subject: 
       
         
           
           
               
               
           
         
       
       wherein 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 2  and the two nitrogens to which it is attached are derived from compounds having the formula H 2 N—CH(COOH)—(CH 2 ) n —NH 2  wherein n is an integer from 0 to 9. 
     
     
       9. A method for treating cerebral thrombosis in a human subject in need thereof, comprising administering, to the subject suffering from cerebral thrombosis and having experienced at least one symptom of said cerebral thrombosis for three or more hours, a therapeutically effective amount of a triprenyl phenol of formula (III) to the human subject: 
       
         
           
           
               
               
           
         
       
       wherein 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 2  and the two nitrogens to which it is attached are derived from compounds having the formula H 2 N—CH(COOH)—(CH 2 ) n —NH 2  wherein n is an integer from 0 to 9. 
     
     
       10. The method of claim 9, wherein said administering is carried out within 12 hours of onset of at least one symptom of cerebral thrombosis. 
     
     
       11. The method of claim 9, wherein said subject has discontinued thrombolytic drug treatment for cerebral thrombosis. 
     
     
       12. The method of claim 9, wherein said administering is carried out after the administration of a thrombolytic drug. 
     
     
       13. The method of claim 9, wherein no additional thrombolytic drug is administered to the subject in combination with the compound of formula (III). 
     
     
       14. The method of claim 7, wherein said triprenyl phenol of formula (III) has Y and Z jointly forming a bond and n is 3. 
     
     
       15. The method of claim 8, wherein said triprenyl phenol of formula (III) has Y and Z jointly forming a bond and n is 3. 
     
     
       16. The method of claim 9, wherein said triprenyl phenol of formula (III) has Y and Z jointly forming a bond and n is 3.