Aromatic prodrugs of propofol, compositions and uses thereof

Abstract

Prodrugs of propofol, methods of making prodrugs of propofol, pharmaceutical compositions of prodrugs of propofol and methods of using prodrugs of propofol and pharmaceutical compositions thereof to treat or prevent diseases or disorders such as migraine headache pain and post-chemotherapy or post-operative surgery nausea and vomiting are disclosed herein.

1 . (canceled) 
     
     
         2 . A method of treating nausea and vomiting in a patient comprising administering to the patient in need of such treatment a therapeutically effective amount of the compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable N-oxide of any of the foregoing, wherein: 
         n is 0 or 1; 
         Y is selected from the group consisting of a bond, CR 1 R 2 , NR 3 , O and S; 
         A is CR 4  or N; 
         B is CR 5  or N; 
         D is CR 6  or N; 
         E is CR 7  or N; 
         G is CR 8  or N; 
         R 18  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, heteroaryl, substituted heteroaryl and heteroarylalkyl; 
         R 1  and R 2  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, heteroaryl, substituted heteroaryl and heteroarylalkyl; 
         R 3  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl; 
         R 4  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carboxy, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, halo, heteroaryl, substituted heteroaryl, heteroarylalkyl, hydroxy and —W[C(O)] k Z(CR 9 R 10 ) r CO 2 R 11 ; 
         R 5  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carboxy, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, halo, heteroaryl, substituted heteroaryl, heteroarylalkyl, hydroxy and —W[C(O)] k Z(CR 9 R 10 ) r CO 2 R 11 ; 
         R 6  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carboxy, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, halo, heteroaryl, substituted heteroaryl, heteroarylalkyl, hydroxy and —W[C(O)] k Z(CR 9 R 10 ) r CO 2 R 11 ; 
         R 7  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carboxy, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, halo, heteroaryl, substituted heteroaryl, heteroarylalkyl, hydroxy and —W[C(O)] k Z(CR 9 R 10 ) r CO 2 R 11 ; 
         R 8  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carboxy, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, halo, heteroaryl, substituted heteroaryl, heteroarylalkyl, hydroxy and —W[C(O)] k Z(CR 9 R 10 ) r CO 2 R 11 ; 
         W is selected from the group consisting of a bond, CR 12 R 13 , NR 14 , O and S; 
         Z is selected from the group consisting of CR 15 R 16 , NR 17 , O and S; 
         k is 0 or 1; 
         r is 1, 2 or 3; 
         each of R 9 , R 10 , R 11 , R 12 , R 13 , R 15  and R 16  is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, heteroaryl, substituted heteroaryl and heteroarylalkyl; and 
         R 14  and R 17  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl; 
         with the provisos that:
 at least one of A, B, D, E and G is not N; 
 one and only one of R 4 , R 5 , R 6 , R 7  or R 8  is —W[C(O)] k Z(CR 9 R 10 ) r CO 2 R 11 ; 
 and if k is 0 then W is a bond. 
 
       
     
     
         3 . The method of  claim 2 , wherein:
 n is 0;   Y is selected from the group consisting of a bond and O;   A is CR 4 ;   B is CR 5 ;   D is CR 6 ;   E is CR 7 ;   G is CR 5 ;   R 4  is selected from the group consisting of hydrogen and —W[C(O)] k Z(CR 9 R 10 ) r CO 2 R 11 ;   R 5  is selected from the group consisting of hydrogen and —W[C(O)] k Z(CR 9 R 10 ) r CO 2 R 11 ;   R 6  is selected from the group consisting of hydrogen and —W[C(O)] k Z(CR 9 R 10 ) r CO 2 R 11 ;   R 7  is selected from the group consisting of hydrogen and —W[C(O)] k Z(CR 9 R 10 ) r CO 2 R 11 ;   R 8  is selected from the group consisting of hydrogen and —W[C(O)] k Z(CR 9 R 10 ) r CO 2 R 11 ;   W is a bond;   Z is NR 7 ;   k is 1;   r is 1, 2 or 3;   each of R 9 , R 10 , and R 11  is hydrogen;   R 17  is hydrogen; and   R 18  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, heteroaryl, substituted heteroaryl and heteroarylalkyl;   with the proviso that:
 one and only one of R 4 , R 5 , R 6 , R 7  or R 8  is —W[C(O)] k Z(CR 9 R 10 ) r CO 2 R 11 . 
   
     
     
         4 . The method of  claim 3 , wherein Y is a bond. 
     
     
         5 . The method of  claim 4 , wherein the compound is 3-{[2-[2,6-bis(isopropyl)phenoxycarbonyl]-benzoyl]amino}-propanoic acid or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The method of  claim 3 , wherein Y is O. 
     
     
         7 . The method of  claim 6 , wherein the compound is 3-{[2-[2,6-bis(isopropyl)phenoxycarbonyloxy]-benzoyl]amino}-propanoic acid or a pharmaceutically acceptable salt thereof. 
     
     
         8 . A method of treating nausea and vomiting in a patient comprising administering to the patient in need of such treatment a pharmaceutical composition comprising a compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable N-oxide of any of the foregoing, and a pharmaceutically acceptable vehicle, wherein: 
         n is 0 or 1; 
         Y is selected from the group consisting of a bond, CR 1 R 2 , NR 3 , O and S; 
         A is CR 4  or N; 
         B is CR 5  or N; 
         D is CR 60 r N; 
         E is CR 7  or N; 
         G is CR 8  or N; 
         R 18  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, heteroaryl, substituted heteroaryl and heteroarylalkyl; 
         R 1  and R 2  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, heteroaryl, substituted heteroaryl and heteroarylalkyl; 
         R 3  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl; 
         R 4  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carboxy, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, halo, heteroaryl, substituted heteroaryl, heteroarylalkyl, hydroxy and —W[C(O)] k Z(CR 9 R 10 ) r CO 2 R 11 ; 
         R 5  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carboxy, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, halo, heteroaryl, substituted heteroaryl, heteroarylalkyl, hydroxy and —W[C(O)] k Z(CR 9 R 10 ) r CO 2 R 11 ; 
         R 6  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carboxy, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, halo, heteroaryl, substituted heteroaryl, heteroarylalkyl, hydroxy and —W[C(O)] k Z(CR 9 R 10 ) r CO 2 R 11 ; 
         R 7  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carboxy, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, halo, heteroaryl, substituted heteroaryl, heteroarylalkyl, hydroxy and —W[C(O)] k Z(CR 9 R 10 ) r CO 2 R 11 ; 
         R 8  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carboxy, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, halo, heteroaryl, substituted heteroaryl, heteroarylalkyl, hydroxy and —W[C(O)] k Z(CR 9 R 10 ) r CO 2 R 11 ; 
         W is selected from the group consisting of a bond, CR 12 R 13 , NR 14 , O and S; 
         Z is selected from the group consisting of CR 15 R 16 , NR 17 , 0 and S; 
         k is 0 or 1; 
         r is 1, 2 or 3; 
         each of R 9 , R 10 , R 11 , R 12 , R 13 , R 15  and R 16  is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, heteroaryl, substituted heteroaryl and heteroarylalkyl; and 
         R 14  and R 17  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl; 
         with the provisos that:
 at least one of A, B, D, E and G is not N; 
 one and only one of R 4 , R 5 , R 6 , R 7  or R 8  is —W[C(O)] k Z(CR 9 R 10 ) r CO 2 R 11 ; 
 and if k is 0 then W is a bond. 
 
       
     
     
         9 . The method of  claim 8 , wherein:
 n is 0;   Y is selected from the group consisting of a bond and O;   A is CR 4 ;   B is CR 5 ;   D is CR 6 ;   E is CR 7 ;   G is CR 8 ;   R 4  is selected from the group consisting of hydrogen and —W[C(O)] k Z(CR 9 R 10 ) r CO 2 R 11 ;   R 5  is selected from the group consisting of hydrogen and —W[C(O)] k Z(CR 9 R 10 ) r CO 2 R 11 ;   R 6  is selected from the group consisting of hydrogen and —W[C(O)] k Z(CR 9 R 10 ) r CO 2 R 11 ;   R 7  is selected from the group consisting of hydrogen and —W[C(O)] k Z(CR 9 R 10 ) r CO 2 R 11 ;   R 8  is selected from the group consisting of hydrogen and —W[C(O)] k Z(CR 9 R 10 ) r CO 2 R 11 ;   W is a bond;   Z is NR 17 ;   k is 1;   r is 1, 2 or 3;   each of R 9 , R 10 , and R 11  is hydrogen;   R 17  is hydrogen; and   R 18  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, heteroaryl, substituted heteroaryl and heteroarylalkyl;   with the proviso that:
 one and only one of R 4 , R 5 , R 6 , R 7  or R 8  is —W[C(O)] k Z(CR 9 R 10 ) r CO 2 R 11 . 
   
     
     
         10 . The method of  claim 9 , wherein Y is a bond. 
     
     
         11 . The method of  claim 10 , wherein the compound is 3-{[2-[2,6-bis(isopropyl)phenoxycarbonyl]-benzoyl]amino}-propanoic acid or a pharmaceutically acceptable salt thereof. 
     
     
         12 . The method of  claim 9 , wherein Y is O. 
     
     
         13 . The method of  claim 12 , wherein the compound is 3-{[2-[2,6-bis(isopropyl)phenoxycarbonyloxy]-benzoyl]amino}-propanoic acid or a pharmaceutically acceptable salt thereof. 
     
     
         14 . The method of  claim 9 , wherein the pharmaceutical composition is an oral formulation. 
     
     
         15 . The method of  claim 14 , wherein the oral formulation is a sustained release oral formulation. 
     
     
         16 . The method of  claim 8 , wherein the pharmaceutical composition is an oral formulation. 
     
     
         17 . The method of  claim 16 , wherein the oral formulation is a sustained release oral formulation.