Selective Opioid Compounds

Abstract

The present invention relates to compounds of Formula I or II, or pharmaceutically acceptable salts, esters, or prodrugs thereof: which relates to morphinan compounds useful as μ, δ and/or κ receptor opioid compounds and pharmaceuticals containing same that may be useful for mediating analgesia, combating drug addiction, alcohol addiction, drug overdose, mental illness, bladder dysfunctions, neurogenic bladder, interstitial cystitis, urinary incontinence, premature ejaculation, inflammatory pain, peripherally mediated and neuropathic pain, cough, lung edema, diarrhea, cardiac disorders, cardioprotection, depression, and cognitive, respiratory, diarrhea, irritable bowel syndrome and gastro-intestinal disorders, immunomodulation, and anti-tumor agents.

What is claimed: 
     
         1 . A method of preventing or treating a condition or disease associated with binding opioid receptors in a patient in need thereof, comprising the step of:
 administering to said patient a composition comprising an effective amount of a compound of Formula I or II:   
       
         
           
           
               
               
           
         
       
       or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein: 
       R 1  is selected from the group consisting of: hydrogen, halogen, OR a , SR a , S(O)R a , SO 2 R a , S(O)NR b R c , SO 2 NR b R c , NR b -Q-R c , CN, (C═W)NR b R c , C(O)OR a , CH 2 OR a , CH 2 NR b R c , heteroaryl, and substituted heteroaryl;
 R a , R b , R c  are each independently selected from: 
 (i) hydrogen; 
 (ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl; 
 (iii) heterocyclic or substituted heterocyclic; and 
 (iv) —C 1 -C 8  alkyl, —C 2 -C 8  alkenyl, or —C 2 -C 8  alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C 1 -C 8  alkyl, substituted —C 2 -C 8  alkenyl, or substituted —C 2 -C 8  alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C 3 -C 12  cycloalkyl, or substituted —C 3 -C 12  cycloalkyl; —C 3 -C 12  cycloalkenyl, or substituted —C 3 -C 12  cycloalkenyl; 
 alternatively, R b  and R c  are taken together to form a heterocyclic or substituted heterocyclic; 
 Q is absent or selected from (C═O), (SO 2 ), (C═NH), (C═S), or (CONR a ); 
 W is O, S, NOR a  or NR a ; 
 
       R 2  is independently selected from the group consisting of hydrogen, halogen, OR a , SR a , NR b R c ; 
       alternatively, R 1  and R 2  are taken together to form a heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocylic; 
       R 3  is independently selected from the group consisting of:
 (v) hydrogen; 
 (vi) aryl; substituted aryl; heteroaryl; substituted heteroaryl; 
 (vii) heterocyclic or substituted heterocyclic; and 
 (viii) —C 1 -C 8  alkyl, —C 2 -C 8  alkenyl, or —C 2 -C 8  alkynyl each containing 0, 1, 2, or 3 or more heteroatoms selected from O, S, or N; substituted —C 1 -C 8  alkyl, substituted —C 2 -C 8  alkenyl, or substituted —C 2 -C 8  alkynyl each containing 0, 1, 2, or 3 or more heteroatoms selected from O, S or N; —C 3 -C 12  cycloalkyl, or substituted —C 3 -C 12  cycloalkyl; —C 3 -C 12  cycloalkenyl, or substituted —C 3 -C 12  cycloalkenyl; 
 
       R 4  is hydrogen, OR a , or NR b -Q 1 -R c , where Q 1  is absent or selected from (C═O) or (SO 2 ); 
       R 5  is selected from the group consisting of: hydrogen, halogen, SR a , S(O)R a , SO 2 R a , S(O)NR b R c , SO 2 NR b R c , NR b -Q-R c , CN, (C═W)NR b R c , C(O)OR a , CH 2 OR a , CH 2 NR b R c , heteroaryl, and substituted heteroaryl; 
       Y is hydrogen, lower alkyl, or lower alkoxy; 
       V 1  is C═O, SO 2 , C 1 -C 6  alkylene, substituted alkylene, C 2 -C 6  alkenylene, C 2 -C 6  alkynylene; V 2  is absent, alkylene, substituted alkylene, C 2 -C 6  alkenylene, C 2 -C 6  alkynylene; heterocyclic, heteroaryl, aryl or C═O; V 3  is absent, alkylene, substituted alkylene, C 2 -C 6  alkenylene, C 2 -C 6  alkynylene; heterocyclic, heteroaryl, aryl or C═O; V 4  is absent, alkylene, substituted alkylene, C 2 -C 6  alkenylene, C 2 -C 6  alkynylene; heterocyclic, heteroaryl, aryl or C═O; 
       n is 1, 2, 3 or 4; wherein each repeating unit can be the same or different; 
       Z is hydrogen, NR b R c , (C═W)NR b R c , NR a (C═W)NR b R c , (C═W)OH, C(O)NHOH, heteroaryl, or substituted heteroaryl; 
       alternatively, 
       
         
           
           
               
               
           
         
       
       can be selected from the group consisting of natural or unnatural amino acids and peptidomimetics; and 
          denotes a carbon-carbon single or double bond. 
     
     
         2 . The method according to  claim 1 , wherein the binding antagonizes the activity of the opioid receptors. 
     
     
         3 . The method according to  claim 1 , wherein the condition or disease is pain, gastrointestinal dysfunction, or ileus. 
     
     
         4 . The method of  claim 3 , wherein the ileus is post-operative ileus. 
     
     
         5 . A method according to  claim 3 , wherein the condition is pain and the composition further comprises an effective amount of an opioid. 
     
     
         6 . The method according to  claim 2 , wherein the compound binds to the opioid receptors. 
     
     
         7 . The method according to  claim 6 , wherein the μ opioid receptors are located in the central nervous system. 
     
     
         8 . The method according to  claim 6 , wherein the μ opioid receptors are located peripherally to the central nervous system. 
     
     
         9 . The method according to  claim 2 , wherein the compound does not substantially cross the blood-brain barrier. 
     
     
         10 . The method of treating or preventing a side effect associated with an opioid, comprising the step of: administering to a patient in need thereof, a composition comprising an effective amount of a compound of Formula I or II: 
       
         
           
           
               
               
           
         
       
       or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein:
 R 1  is selected from the group consisting of: hydrogen, halogen, OR a , SR a , S(O)R a , SO 2 R a , S(O)NR b R c , SO 2 NR b R c , NR b -Q-R c , CN, (C═W)NR b R c , C(O)OR a , CH 2 OR a , CH 2 NR b R c , heteroaryl, and substituted heteroaryl;
 R a , R b , R c  are each independently selected from:
 (v) hydrogen; 
 (vi) aryl; substituted aryl; heteroaryl; substituted heteroaryl; 
 (vii) heterocyclic or substituted heterocyclic; and 
 (viii) —C 1 -C 8  alkyl, —C 2 -C 8  alkenyl, or —C 2 -C 8  alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C 1 -C 8  alkyl, substituted —C 2 -C 8  alkenyl, or substituted —C 2 -C 8  alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C 3 -C 12  cycloalkyl, or substituted —C 3 -C 12  cycloalkyl; —C 3 -C 12  cycloalkenyl, or substituted —C 3 -C 12  cycloalkenyl; 
 alternatively, R b  and R c  are taken together to form a heterocyclic or substituted heterocyclic; 
 
 Q is absent or selected from (C═O), (SO 2 ), (C═NH), (C═S), or (CONR a ); 
 W is O, S, NOR a  or NR a ; 
 
 R 2  is independently selected from the group consisting of hydrogen, halogen, OR a , SR a , NR b R c ; 
 alternatively, R 1  and R 2  are taken together to form a heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocylic; 
 R 3  is independently selected from the group consisting of:
 (ix) hydrogen; 
 (x) aryl; substituted aryl; heteroaryl; substituted heteroaryl; 
 (xi) heterocyclic or substituted heterocyclic; and 
 (xii) —C 1 -C 8  alkyl, —C 2 -C 8  alkenyl, or —C 2 -C 8  alkynyl each containing 0, 1, 2, or 3 or more heteroatoms selected from O, S, or N; substituted —C 1 -C 8  alkyl, substituted —C 2 -C 8  alkenyl, or substituted —C 2 -C 8  alkynyl each containing 0, 1, 2, or 3 or more heteroatoms selected from O, S or N; —C 3 -C 12  cycloalkyl, or substituted —C 3 -C 12  cycloalkyl; —C 3 -C 12  cycloalkenyl, or substituted —C 3 -C 12  cycloalkenyl; 
 
 R 4  is hydrogen, OR a , or NR b -Q 1 -R c , where Q 1  is absent or selected from (C═O) or (SO 2 ); 
 R 5  is selected from the group consisting of: hydrogen, halogen, SR a , S(O)R a , SO 2 R a , S(O)NR b R c , SO 2 NR b R c , NR b -Q-R c , CN, (C═W)NR b R c , C(O)OR a , CH 2 OR a , CH 2 NR b R c , heteroaryl, and substituted heteroaryl; 
 Y is hydrogen, lower alkyl, or lower alkoxy; 
 V 1  is C═O, SO 2 , C 1 -C 6  alkylene, substituted alkylene, C 2 -C 6  alkenylene, C 2 -C 6  alkynylene; V 2  is absent, alkylene, substituted alkylene, C 2 -C 6  alkenylene, C 2 -C 6  alkynylene; heterocyclic, heteroaryl, aryl or C═O; V 3  is absent, alkylene, substituted alkylene, C 2 -C 6  alkenylene, C 2 -C 6  alkynylene; heterocyclic, heteroaryl, aryl or C═O; V 4  is absent, alkylene, substituted alkylene, C 2 -C 6  alkenylene, C 2 -C 6  alkynylene; heterocyclic, heteroaryl, aryl or C═O; 
 n is 1, 2, 3 or 4; wherein each repeating unit can be the same or different; 
 Z is hydrogen, NR b R c , (C═W)NR b R c , NR a (C═W)NR b R c , (C═W)OH, C(O)NHOH, heteroaryl, or substituted heteroaryl; 
 alternatively, 
 
       
         
           
           
               
               
           
         
       
       can be selected from the group consisting of natural or unnatural amino acids and peptidomimetics; and
    denotes a carbon-carbon single or double bond. 
 
     
     
         11 . The method according to  claim 10 , wherein the opioid is endogenous. 
     
     
         12 . The method according to  claim 10 , wherein the opioid is exogenous. 
     
     
         13 . The method according to  claim 10 , wherein the composition further comprises an effective amount of at least one opioid. 
     
     
         14 . The method according to  claim 10 , wherein the side effect is selected from the group consisting of constipation, opioid-induced bowel dysfunction, nausea, vomiting, and combinations thereof. 
     
     
         15 . The method according to  claim 10 , wherein the administering step occurs before, during or after a step of administering at least one opioid. 
     
     
         16 . The method according to  claim 13 , wherein the opioid is alfentanil,
 buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine (pethidine), methadone, naloxone, naltrexone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, sufentanil, tramadol, or mixtures thereof.