Pharmaceutical combination of opioid and prostaglandin compound

Abstract

Provided is a method for treating a condition or disease which is one of the indications for opioid use, which comprises administering a combination of: (a) a pharmaceutically effective amount of an opioid, and (b) a pharmaceutically effective amount of a prostaglandin (PG) compound represented by the formula (I): to a patient in need thereof.

1 . A method for treating a condition or disease which is one of the indications for opioid use, which comprises administering a combination of:
 (a) a pharmaceutically effective amount of an opioid, and   (b) a pharmaceutically effective amount of a prostaglandin (PG) compound represented by the formula (I):   
     
       
         
         
             
             
         
       
       
         wherein L, M and N are hydrogen, hydroxy, halogen, lower alkyl, hydroxy(lower)alkyl, lower alkanoyloxy or oxo, wherein at least one of L and M is a group other than hydrogen, and the five-membered ring may have at least one double bond; 
         A is —CH 3 , or —CH 2 OH, —COCH 2 OH, —COOH or a functional derivative thereof; 
         B is single bond, —CH 2 —CH 2 —, —CH═CH—, —C≡C—, —CH 2 —CH 2 —CH 2 —, —CH═CH—CH 2 —, —CH 2 —CH═CH—, —C≡C—CH 2 — or —CH 2 —C≡C—; 
         Z is 
       
     
     
       
         
         
             
             
         
       
       
          or single bond 
         wherein R 4  and R 5  are hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or hydroxy(lower) alkyl, wherein R 4  and R 5  are not hydroxy and lower alkoxy at the same time; 
         R 1  is a saturated or unsaturated bivalent lower or medium aliphatic hydrocarbon residue, which is unsubstituted or substituted with halogen, alkyl, hydroxy, oxo, aryl or heterocyclic group, and at least one of carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen, nitrogen or sulfur; and 
         Ra is a saturated or unsaturated lower or medium aliphatic hydrocarbon residue, which is unsubstituted or substituted with halogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, cyclo(lower)alkyl, cyclo(lower)alkyloxy, aryl, aryloxy, heterocyclic group or hetrocyclic-oxy group; lower alkoxy; lower alkanoyloxy; cyclo(lower)alkyl; cyclo(lower)alkyloxy; aryl; aryloxy; heterocyclic group; heterocyclic-oxy group, provided that Ra is substituted by halogen or Z is C═O to a subject in need thereof. 
       
     
   
   
       2 . The method as described in  claim 1 , wherein said prostaglandin compound is 16-mono or dihalogen-prostaglandin compound. 
   
   
       3 . The method as described in  claim 1 , wherein said prostaglandin compound is 15-keto-prostaglandin compound. 
   
   
       4 . The method as described in  claim 1 , wherein said prostaglandin compound is 13,14-dihydro-16-mono or dihalogen-prostaglandin compound. 
   
   
       5 . The method as described in  claim 1 , wherein said prostaglandin compound is 13,14-dihydro-15-keto-prostaglandin compound. 
   
   
       6 . The method as described in  claim 1 , wherein said prostaglandin compound is 13,14-dihydro-15-keto-16-mono or dihalogen-prostaglandin compound. 
   
   
       7 . The method as described in  claim 1 , wherein said prostaglandin compound is 13,14-dihydro-16-mono or difluoro-prostaglandin compound. 
   
   
       8 . The method as described in  claim 1 , wherein said prostaglandin compound is 15-keto-16-mono or difluoro-prostaglandin compound. 
   
   
       9 . The composition as described in  claim 1 , wherein said prostaglandin compound is 13,14-dihydro-15-keto-16-mono or difluoro-prostaglandin compound. 
   
   
       10 . The method as described in  claim 1 , wherein said prostaglandin compound is 13,14-dihydro-16-mono or dihalogen-prostaglandin E compound. 
   
   
       11 . The method as described in  claim 1 , wherein said prostaglandin compound is 15-keto-16-mono or dihalogen-prostaglandin E compound. 
   
   
       12 . The method as described in  claim 1 , wherein said prostaglandin compound is 13,14-dihydro-15-keto-16-mono or dihalogen-prostaglandin E compound. 
   
   
       13 . The method as described in  claim 1 , wherein said prostaglandin compound is 13,14-dihydro-16,16-difluoro-prostaglandin E 1  compound. 
   
   
       14 . The method as described in  claim 1 , wherein said prostaglandin compound is 13,14-dihydro-15-keto-prostaglandin E 1  compound. 
   
   
       15 . The method as described in  claim 1 , wherein said prostaglandin compound is 13,14-dihydro-15-keto-16,16-difluoro-prostaglandin E 1  compound or 13,14-dihydro-15-keto-16,16-difluoro-18-methyl-prostagland in E 1  compound. 
   
   
       16 . The method as described in  claim 1 , wherein said prostaglandin compound is 13,14-dihydro-15-keto-16,16-difluoro-prostaglandin E 1  or 13,14-dihydro-15-keto-16,16-difluoro-18-methyl-prostaglandin E 1 . 
   
   
       17 . The method as described in  claim 1 , wherein the compounds are administered orally. 
   
   
       18 . The method as described in  claim 1 , wherein the opioid is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetylbuturate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethideine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentonil, tilidine, tramadol, a pharmaceutically acceptable salt thereof, and a mixture thereof. 
   
   
       19 . The method as described in  claim 1 , wherein the opioid is oxycodone. 
   
   
       20 . The method as described in  claim 1  wherein the respective compounds are administered simultaneously, separately or sequentially. 
   
   
       21 . The method as described in  claim 1 , wherein the disease or condition is pain. 
   
   
       22 . The method as described in  claim 21 , wherein the pain is chronic pain.