Methods for treating chronic pain and opioid dependence using adenylyl cyclase inhibitors

Abstract

This present application disclosed a method for the treatment of treating pain, opioid dependence, alcohol use disorder or autism comprising the step of administering to a mammal in need thereof a therapeutically effective amount of one or more compounds of formula (I), or a pharmaceutically acceptable salt thereof, and one or more carriers, diluents, or excipients. Those compounds are selective adenylyl cyclase 1 (AC1) inhibitors, which may provide an effective method of treatment for chronic/inflammatory pain, and prevent opioid dependence and/or reduce opioid dependence.

What is claimed is: 
     
         1 . A method for treating pain, opioid dependence, alcohol use disorder or autism comprising the step of administering to a mammal in need thereof a therapeutically effective amount of one or more compounds of formula (I) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and one or more carriers, diluents, or excipients, wherein 
         R 1  is an alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyloalkyl, cycloalkenyl, heterocycloakenyl, heterocyclyl, or an optionally substituted aryl, arylalkyl, or arylalkenyl; and 
         R 2  represents five substituents independently selected from the group consisting of hydrogen, halo, hydroxy, amino, nitro, cyano, thio, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyloalkyl, cycloalkenyl, heterocycloakenyl, heterocyclyl, alkoxyl, alkylamino, alkylthio, haloalkyl, alkylsulfide, sulphonyl, sulfonamide, alkylsulfonamide, or an optionally substituted aryl, arylalkyl, or arylalkenyl; or any two adjacent substituents that are taken together with the attached carbons to form an optionally substituted cycle or heterocycle and each of other substituents is defined as above. 
       
     
     
         2 . The method of  claim 1 , wherein the pain is chronic pain. 
     
     
         3 . The method of  claim 1 , wherein the treatment is for reducing pain and opioid dependence. 
     
     
         4 . The method of  claim 1 , wherein R 1  is a C 1 -C 24  alkyl, cycloalkyl, or an optionally substituted C 4 -C 24  aryl or heteroaryl. 
     
     
         5 . The method of  claim 1 , wherein one of the five R 2  substituents is an alkylsulfide, sulfonamide, or alkylsulfonamide, and other four substituents are hydrogen. 
     
     
         6 . The method of  claim 1 , wherein one of the five R 2  substituents is a halo or haloalkyl, and other four substituents are hydrogen. 
     
     
         7 . The method of  claim 1 , wherein treating pain or opioid dependence further comprises a step of administering a compound of formula (I) in combination with an opioid drug, wherein the compound of formula (I) enhances μ-opioid receptor inhibition of adenylyl cyclase 1. 
     
     
         8 . The method of  claim 7 , wherein the opioid drug is selected from codeine, morphine, thebaine, oripavine, diacetylmorphine, nicomorphine, dipropanoylmorphine, diacetyldihydromorphine, acetylpropionylmorphine, desomorphine, methyldesorphine, dibenzoylmorphine, dihydrocodeine, ethylmorphine, heterocodeine, buprenorphine, etorphine, hydrocodone, hydromorphone, oxycodone, oxymorphone, fentanyl, alphamethylfentanyl, alfentanil, sufentanil, remifentanil, carfentanyl, ohmefentanyl, pethidine (meperidine), ketobemidone, desmethylprodine (MPPP), allylprodine, prodine, phenethylphenylacetoxypiperidine (PEPAP), promedol, propoxyphene, dextropropoxyphene, dextromoramide, bezitramide, piritramide, methadone, dipipanone, levomethadyl acetate (LAAM), difenoxin, diphenoxylate, loperamide, dezocine, pentazocine, phenazocine, buprenorphine, dihydroetorphine, etorphine, butorphanol, nalbuphine, levorphanol, levomethorphan, lefetamine, menthol, meptazinol, mitragynine, tilidine, tramadol, tapentadol, eluxadoline, nalmefene, naloxone, and naltrexone. 
     
     
         9 . A method for treating pain, opioid dependence, alcohol use disorder or autism comprising the step of administering to a mammal in need thereof a therapeutically effective amount of one or more compounds of formula (I), 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, and one or more carriers, diluents, or excipients, in combination with one or more other compounds by the same or different mode of action, and one or more carriers, diluents, or excipients, to a patient in need of relief from said disorder. 
     
     
         10 . The method according to  claim 1 , wherein said compounds are selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         11 . A pharmaceutical composition comprising one or more compounds of formula (I) according to  claim 1 , or a pharmaceutically acceptable salt thereof, together with one or more diluents, excipients or carriers. 
     
     
         12 . A pharmaceutical composition comprising one or more compounds of formula (I) according to  claim 1 , or a pharmaceutically acceptable salt thereof, in combination with one or more other compounds by the same or different mode of action, together with one or more diluents, excipients or carriers.