6,7-unsaturated-7-carbamoyl substituted morphinan derivative

Abstract

A novel compound which is useful as an agent for treating and/or preventing emesis, vomiting and/or constipation. A compound represented by the formula (I): wherein R 1 and R 2 are each independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted cycloalkyl, optionally substituted aryl etc., R 3 is hydrogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy etc., R 4 is hydrogen or lower alkyl, R 5 is hydrogen, lower alkyl, cycloalkyl lower alkyl or lower alkenyl, or a pharmaceutically acceptably salt, or a solvate thereof is provided.

The invention claimed is: 
     
       1. A compound represented by the formula (I): 
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are each independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkylsulfonyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, an optionally substituted heterocyclic group, optionally substituted arylsulfonyl, or R 1  and R 2  are taken together with the nitrogen atom to which they are attached to form optionally substituted heterocycle;
 R 3  is hydrogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy, mercapto, optionally substituted lower alkylthio, optionally substituted amino, optionally substituted carbamoyl, optionally substituted acyl, optionally substituted acyloxy, optionally substituted aryl, or an optionally substituted heterocyclic group; or  
 athe group represented by the formula: 
 
       
         
           
           
               
               
           
         
       
       may beis selected from:  
       
         
           
           
               
               
           
         
       
       wherein ring A and ring B are each independently optionally substituted nitrogen-containing heterocycle optionally containing additional nitrogen atom, oxygen atom, and/or sulfur atom in the ring;
 broken line indicates the presence or the absence of a bond; 
 when broken line indicates the presence of a bond, p is 0; 
 when a broken line indicates the absence of a bond, p is 1; R a  is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, or optionally substituted lower alkynyl; and 
 R b  is hydrogen or oxo; 
 R 4  is hydrogen or lower alkyl; and  
 R 5  is hydrogen, lower alkyl, cycloalkyl lower alkyl or lower alkenyl, or a pharmaceutically acceptable salt thereof. 
 
     
     
       2. The compound according to  claim 1 , wherein R 3  is hydroxy, or a pharmaceutically acceptable salt thereof. 
     
     
       3. The compound according to  claim 1 , wherein R 3  is optionally substituted amino, or a pharmaceutically acceptable salt thereof. 
     
     
       4. The compound in any one of  claims 1  to  3 , wherein R 1  is hydrogen or lower alkyl, R 2  is optionally substituted lower alkyl, optionally substituted phenyl, optionally substituted cycloalkyl, or an optionally substituted heterocyclic group, and R 5  is cyclopropylmethyl, or a pharmaceutically acceptable salt thereof. 
     
     
       5. A pharmaceutical composition containing a compound in any one of  claims 1  to  4  3, or a pharmaceutically acceptable salt thereof. 
     
     
       6. A composition having an opioid receptor antagonistic activity containing a compound in any one of  claims 1  to  4  3, or a pharmaceutically acceptable salt thereof. 
     
     
       7. A composition for treating and/or preventing emesis, vomiting and/or constipation containing a compound in any one of  claims 1  to  4  3, or a pharmaceutically acceptable salt thereof. 
     
     
       8. A composition for alleviating and/or preventing a side effect induced by a compound having opioid receptor agonistic activity containing a compound in any one of  claims 1  to  4  3, or a pharmaceutically acceptable salt thereof. 
     
     
       9. An agent for treating and/or preventing a side effect according to  claim 8 , wherein the side effect is emesis, vomiting and/or constipation. 
     
     
       10. A composition for treatment and/or prevention according to  claim 8  or  9 , wherein the compound having the opioid receptor agonistic activity is morphine, oxycodone, or a pharmaceutically acceptable salt thereof. 
     
     
       11. A composition for analgesic containing a compound having an opioid receptor agonistic activity, and an effective amount of compound according to any one of  claims 1  to  4  3, or a pharmaceutically acceptable salt thereof, for alleviating and/or preventing a side effect induced by administrating of the compound having an opioid receptor agonistic activity. 
     
     
       12. A compound represented by the formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is hydrogen; R 2  is selected from lower alkyl optionally substituted with lower alkoxy, lower alkoxycarbonyl, or a heterocyclic group optionally substituted with lower alkyl or phenyl; phenyl optionally substituted with lower alkyl, lower alkoxy, halogen, or cyano lower alkyl; cycloalkyl optionally substituted with lower alkoxycarbonyl or lower alkoxy lower alkyl; or a heterocyclic group optionally substituted with lower alkoxy or oxo; 
 R 3  is hydroxyl; 
 R 4  is hydrogen; and 
 R 5  is cyclopropylmethyl; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
       13. A compound represented by the formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is hydrogen; 
 R 2  is lower alkyl optionally substituted with lower alkoxy or with a heterocyclic group that is optionally substituted with aryl; phenyl optionally substituted with lower alkyl or with lower alkoxy; cycloalkyl substituted with lower alkylcarbonyl; or a heterocyclic group substituted with lower alkoxy or with aryl; 
 R 3  is hydroxyl; R 4  is hydrogen; and 
 R 5  is cyclopropylmethyl; or a pharmaceutically acceptable salt thereof. 
 
     
     
       14. A compound, wherein the compound is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       15. A compound, wherein the compound is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       16. A composition for analgesic containing:
 a compound having an opioid receptor agonistic activity, 
 and an effective amount of compound according to  claim 12  or a pharmaceutically acceptable salt thereof, for alleviating and/or preventing a side effect induced by administrating of the compound having an opioid receptor agonistic activity. 
 
     
     
       17. A composition for analgesic containing:
 a compound having an opioid receptor agonistic activity, 
 and an effective amount of compound according to  claim 13  or a pharmaceutically acceptable salt thereof, for alleviating and/or preventing a side effect induced by administrating of the compound having an opioid receptor agonistic activity. 
 
     
     
       18. A composition for analgesic containing:
 a compound having an opioid receptor agonistic activity, 
 and an effective amount of compound according to  claim 14  or a pharmaceutically acceptable salt thereof, for alleviating and/or preventing a side effect induced by administrating of the compound having an opioid receptor agonistic activity. 
 
     
     
       19. A composition for analgesic containing:
 a compound having an opioid receptor agonistic activity, 
 and an effective amount of compound according to  claim 15  or a pharmaceutically acceptable salt thereof, for alleviating and/or preventing a side effect induced by administrating of the compound having an opioid receptor agonistic activity. 
 
     
     
       20. A compound of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       21. The compound of claim 20 wherein the compound is 
       
         
           
           
               
               
           
         
       
       
        
       
     
     
       22. The compound of claim 20 wherein the compound is a pharmaceutically acceptable salt of 
       
         
           
           
               
               
           
         
       
       
        
       
     
     
       23. The compound of claim 22 wherein the pharmaceutically acceptable salt is the p-toluene sulfonic acid salt. 
     
     
       24. A pharmaceutical composition comprising the compound of claim 20 or a pharmaceutically acceptable salt thereof. 
     
     
       25. A pharmaceutical composition comprising the compound of claim 23. 
     
     
       26. A composition comprising a compound having an opioid receptor agonistic activity and an effective amount of the compound of claim 20 or a pharmaceutically acceptable salt thereof, for alleviating and/or preventing a side effect induced by administering of the compound having an opioid receptor agonistic activity. 
     
     
       27. A composition comprising a compound having an opioid receptor agonistic activity and an effective amount of the compound of claim 23, for alleviating and/or preventing a side effect induced by administering of the compound having an opioid receptor agonistic activity. 
     
     
       28. The composition of claim 27 wherein the compound having the opioid receptor agonistic activity is morphine, oxycodone, or a pharmaceutically acceptable salt thereof. 
     
     
       29. The composition according to claim 25 in the form of a tablet. 
     
     
       30. The composition according to claim 27 in the form of a tablet.