Quaternary opioid carboxamides

Abstract

Compounds of formulas: are disclosed. The compounds are useful for ameliorating the side effects of therapeutic opiates.

What is claimed is: 
     
         1 . A compound of formula: 
       
         
           
           
               
               
           
         
         wherein: 
         G is a polar, neutral residue; 
         Y is a pharmaceutically acceptable counterion; 
         Q is a substituted or unsubstituted, saturated or unsaturated aliphatic or aromatic group; 
         R 2  and R 2a  are independently hydrogen, alkyl, aryl, arylalkyl, heteroaryl, hydroxy, amino, or alkoxy or taken together R 2  and R 2a  are ═O; 
         R is chosen from hydrogen or a substituted or unsubstituted, saturated or unsaturated aliphatic or aromatic group; 
         R 4  is chosen from hydrogen, hydroxy, amino, lower alkoxy, or a substituted or unsubstituted, saturated or unsaturated aliphatic or aromatic group; 
         R 5  is a hydrogen or a substituted or unsubstituted alkyl; 
         R 6  is a substituted or unsubstituted alkyl; 
         R 7  is chosen from hydrogen, hydroxy, amino, lower alkoxy, or a substituted or unsubstituted, saturated or unsaturated aliphatic or aromatic group; or 
         together G, R 4 , R 5 , R 6  and/or R 7  may form from one or more rings, said rings having optional additional substitution, and/or 
         together Q and R may form from one to three rings or more, said rings having optional additional substitution, and/or 
         together Q and R 2  may form from one to three rings or more, said rings having optional additional substitution. 
       
     
     
         2 . The compound of  claim 1  wherein G is selected from the group consisting of carboxamide, thiocarboxamide, acylamine, formamide, amine; amidine, and alkyls substituted by polar neutral residues. 
     
     
         3 . The compound of  claim 1  wherein G is —CH 2 Z, where Z is a polar neutral residue, —CN, —NR b SO 2 —R c , —C(═W)R a , —NR a COR b , —NR a CSR b , —SO 2 NR b R c , —(C═W)NR b R c , —C(O)OR a , heterocycle, substituted heterocycle, 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) substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl each containing 0, 1, 2, or 3 or more heteroatoms selected from O, S, or N; 
 alternatively, R a , R b  and R c  are taken together with the attached atom form a heterocyclic or substituted heterocyclic. 
 
 Q a  is absent or selected from (C═O), (SO 2 ), (C═NH), (C═S), or (CONR a ); and 
 W is O, S, NOR a  or NR a ; 
 
     
     
         4 . The compound of  claim 1  wherein G is CONH 2  or CSNH 2 . 
     
     
         5 . The compound of  claim 1  wherein Q is a substituted or unsubstituted, saturated or unsaturated alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, arylalkenyl, arylalkynyl or heteroarylalkyl. 
     
     
         6 . The compound of  claim 4  wherein Q is an alkyl or benzyl. 
     
     
         7 . A compound of formula: 
       
         
           
           
               
               
           
         
         wherein 
         G is chosen from CONH 2  and CSNH 2 ; 
         Y is a pharmaceutically acceptable counterion; 
         Q is chosen from alkyl and benzyl; 
         R 2  and R 2a  are both hydrogen or taken together R 2  and R 2a  are ═O; 
         R 3  is chosen from hydrogen, lower alkyl, alkenyl, aryl, heterocyclyl, benzyl and hydroxyalkyl; 
         R 4  is chosen from hydrogen, hydroxy, amino, lower alkoxy, C 1 -C 20  alkyl and C 1 -C 20  alkyl substituted with hydroxy or carbonyl; 
         Y is a pharmaceutically acceptable counterion; 
         R 5  is lower alkyl; 
         R 6  is lower alkyl; 
         R 7  is chosen from hydrogen and hydroxy; or 
         together R 4 , R 5 , R 6  and R 7  may form from one to three rings, said rings having optional additional substitution. 
       
     
     
         8 . A compound according to  claim 7  wherein:
 R 4  is chosen from hydrogen, hydroxy, lower alkoxy, C 1 -C 20  alkyl and C 1 -C 20  alkyl substituted with hydroxy or carbonyl; 
 R 5  is lower alkyl; 
 R 6  is lower alkyl; and 
 R 7  is hydrogen or hydroxy. 
 
     
     
         9 . A compound according to  claim 8  wherein:
 R 3  is chosen from hydrogen, cyclopropyl, cyclobutyl, phenyl, vinyl, dimethylvinyl, hydroxycyclopropyl, furanyl, and tetrahydrofuranyl; 
 R 4  is chosen from hydrogen and 3-oxo-5-cyclopentyl-1-pentanyl; 
 R 5  is methyl; and 
 R 6  is methyl or ethyl. 
 
     
     
         10 . A compound according to  claim 1  wherein R 5  and R 6  form a ring and R 7  is hydrogen or hydroxy. 
     
     
         11 . A compound according to  claim 10  having the formula: 
       
         
           
           
               
               
           
         
         wherein G, Q, Y, R 2 , R 2a , R 3 , and R 4  are as defined in  claim 1  and R 19 , R 20 , R 21 , R 22 , and R 23  are hydrogen or a substituted or unsubstituted aliphatic or aromatic group or R 4 , R 19 , R 20 , R 21 , R 22 , and/or R 23  can be taken together to form a heterocyclic or carbocyclic ring. 
       
     
     
         12 . A compound according to  claim 11  wherein R 19  is hydrogen or lower alkyl;
 R 20  is chosen from hydrogen, lower alkyl and hydroxy(lower alkyl); 
 R 21  is hydrogen; 
 R 22  is chosen from hydrogen, hydroxy, lower alkoxy and —NR 13 R 14 ; or 
 together, R 21  and R 22  form a carbonyl or a vinyl substituent; 
 R 13  and R 14  are chosen independently from hydrogen, C 1 -C 6  alkyl and C 1 -C 6  acyl; and 
 R 23  is hydrogen, methyl, or together R 19  and R 23  from a second bond. 
 
     
     
         13 . A compound according to  claim 10  having the formula: 
       
         
           
           
               
               
           
         
         wherein G, Q, Y, R 2 , R 2a , R 3 , and R 4  are defined as in  claim 1  and R 19 , R 20 , R 21 , R 22 , and R 23  are hydrogen or a substituted or unsubstituted aliphatic or aromatic group or R 4 , R 19 , R 20 , R 21 , R 22 , and/or R 23  can be taken together to form a heterocyclic or carbocyclic ring. 
       
     
     
         14 . A compound according to  claim 13  wherein R 19  is hydrogen or lower alkyl;
 R 20  is chosen from hydrogen, lower alkyl and hydroxy(lower alkyl); 
 R 21  is hydrogen; 
 R 22  is chosen from hydrogen, hydroxy, lower alkoxy and —NR 13 R 14 ; or 
 together, R 21  and R 22  form a carbonyl or a vinyl substituent; 
 R 13  and R 14  are chosen independently from hydrogen, C 1 -C 6  alkyl and C 1 -C 6  acyl; and 
 R 23  is hydrogen, methyl, or together R 19  and R 23  form a second bond. 
 
     
     
         15 . A compound according to  claim 1  of formula 
       
         
           
           
               
               
           
         
         wherein Y is a counterion. 
       
     
     
         16 . A compound according to  claim 1  selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         17 . A compound according to  claim 1  having the structure: 
       
         
           
           
               
               
           
         
         wherein G, Q, Y, R 2 , R 2a , R 3 , and R 4  are as defined in  claim 1  and R 19 , R 20 , R 21 , R 22 , and R23 are hydrogen or a substituted or unsubstituted aliphatic or aromatic group or R 4 , R 19 , R 20 , R 21 , R 22 , and/or R 23  can be taken together to form a heterocyclic or carbocyclic ring. 
       
     
     
         18 . A compound according to  claim 17  wherein R 19  is hydrogen or lower alkyl;
 R 20  is chosen from hydrogen, lower alkyl and hydroxy(lower alkyl); 
 R 21  is hydrogen, or together, R 4  and R 21  form a sixth ring; 
 R 22  is chosen from hydrogen, hydroxy, lower alkoxy and —NR 13 R 14 ; or 
 together, R 21  and R 22  form a carbonyl or a vinyl substituent; 
 R 13  and R 14  are chosen independently from hydrogen, C 1 -C 6  alkyl and C 1 -C 6  acyl; and 
 R 23  is hydrogen, methyl, or together R 19  and R 23  from a second bond. 
 
     
     
         19 . A compound according to  claim 1  of formula 
       
         
           
           
               
               
           
         
         wherein Y is a counterion. 
       
     
     
         20 . A compound according to  claim 1  selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         21 . A compound according to  claim 1  having the formula 
       
         
           
           
               
               
           
         
         wherein 
       
       
         
           
           
               
               
           
         
       
       is an aryl or heteroaryl residue of one to three rings;
 A is a bond or a linker; 
 R 10  is one or two substituents; 
 R 11  is H or 
 
       
         
           
           
               
               
           
         
       
       is an aryl or heteroaryl residue of one to three rings;
 A′ is a direct bond or a linker; 
 R 12  is chosen from hydrogen and lower alkyl; 
 R 15  is one or two residues chosen independently from hydrogen, hydroxyl, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl and halo(C 1 -C 6 )alkoxy and (C 1 -C 6 )alkylthio. 
 
     
     
         22 . A compound according to  claim 21  wherein
 A is (CH 2 ) n , wherein one or more CH 2  may be replaced by —O—, cycloalkyl or —CR 1a R 1b ; 
 R 1a  and R 1b  are chosen independently from hydrogen, halogen, lower alkyl, lower alkoxy and lower alkylthio; 
 R 10  is one or two residues chosen independently from hydrogen, hydroxyl, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy and (C 1 -C 6 )alkylthio; 
 R 11  is 
 
       
         
           
           
               
               
           
         
         A′ is (CH 2 ) m , wherein one or more CH 2  may be replaced by —O—, cycloalkyl, —CR 1a R 1b , —C(═O)— or —NH—; 
         R 15  is one or two residues chosen independently from hydrogen, hydroxyl, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy and (C 1 -C 6 )alkylthio; 
         m is zero or an integer from 1 to 6; and 
         n is an integer from 1 to 6. 
       
     
     
         23 . A compound according to  claim 21  wherein
 R 11  is phenyl, R 12  is hydrogen and A is —CH 2 CH 2 —. 
 
     
     
         24 . A compound according to  claim 21  wherein
 A is (CH 2 ), wherein one or more CH 2  may be replaced by —O—, cycloalkyl or —CR 1a R 1b ; 
 R 1a  and R 1b  are chosen independently from hydrogen, halogen, lower alkyl, lower alkoxy and lower alkylthio; 
 R 10  is one or two residues chosen independently from hydrogen, hydroxyl, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy and (C 1 -C 6 )alkylthio; 
 R 11  is hydrogen; and 
 
       
         
           
           
               
               
           
         
       
       is chosen from phenyl, indolyl and benzofuranyl. 
     
     
         25 . A compound according to  claim 1  wherein Q is CH 3 . 
     
     
         26 . A method of ameliorating a side-effect of an opiate in a patient who has been given an opiate, comprising administering a compound of  claim 1  to said patient. 
     
     
         27 . A method according to  claim 26  wherein said side effect is chosen from constipation, nausea/vomiting, cough suppression, pruritis, dysphoria and urinary retention. 
     
     
         28 . A method of improving post-operative bowel function in a patient who has undergone surgery, comprising administering a compound of  claim 1  to said patient.