Sulphonamide derivatives as prodrugs of aspartyl protease inhibitors

Abstract

The present invention relates to prodrugs of a class of sulfonamides which are aspartyl protease inhibitors. In one embodiment, this invention relates to a novel class of prodrugs of HIV aspartyl protease inhibitors characterized by favorable aqueous solubility, high oral bioavailability and facile in vivo generation of the active ingredient. This invention also relates to pharmaceutical compositions comprising these prodrugs. The prodrugs and pharmaceutical compositions of this invention are particularly well suited for decreasing the pill burden and increasing patient compliance. This invention also relates to methods of treating mammals with these prodrugs and pharmaceutical compositions.

1 . A compound of formula I: 
     
       
         
         
             
             
         
       
       wherein: 
       A is selected from Ht; —R 1 —Ht; 
       each R 1  is independently selected from —C(O)—, —S(O) 2 —, —C(O)—C(O)—, —O—C(O)—, —O—S(O) 2 , —N(R 2 )—S(O) 2 —, —N(R 2 )—C(O)— or —N(R 2 )—C(O)—C(O)—; 
       each Ht is independently selected from C 3 -C 7  cycloalkyl; C 5 -C 7  cycloalkenyl; C 6 -C 10  aryl; or a 5-7 membered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from N, N(R 2 ), O, S and S(O) n ; wherein said aryl or said heterocycle is optionally fused to Q; and wherein any member of said Ht is optionally substituted with one or more substituents independently selected from oxo, —OR 2 , SR 2 , —R 2 , —N(R 2 ) 2 , —R 2 —OH, —CN, —C(O)O—R 2 , —C(O)—N(R 2 ) 2 , —S(O) 2 —N(R 2 ) 2 , —N(R 2 )—C(O)—R 2 , —C(O)—R 2 , —S(O) n —R 2 , —OCF 3 , —S(O) n -Q, methylenedioxy, —N(R 2 )—S(O) 2 —R 2 , halo, —CF 3 , —NO 2 , Q, —OQ, —OR 7 , —SR 7 , —R 7 , —N(R 2 )(R 7 ) or —N(R 7 ) 2 ; 
       each R 2  is independently selected from H, or (C 1 -C 4 )-alkyl optionally substituted with Q; 
       B, when present, is —N(R 2 )—C(R 3 ) 2 —C(O)—; 
       each x is independently 0 or 1; 
       each R 3  is independently selected from H, Ht, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 3 -C 6 )-cycloalkyl or (C 5 -C 6 )-cycloalkenyl; wherein any member of said R 3 , except H, is optionally substituted with one or more substituents selected from —OR 2 , —C(O)—NH—R 2 , —S(O) n —N(R 2 ) 2 , Ht, —CN, —SR 2 , —CO 2 R 2 , N(R 2 )—C(O)—R 2 ; 
       each n is independently 1 or 2; 
       G, when present, is selected from H, R 7  or (C 1 -C 4 )-alkyl, or, when G is (C 1 -C 4 )-alkyl, G and R 7  are bound to one another either directly or through a C 1 -C 3  linker to form a heterocyclic ring; or when G is absent, the atom to which G is attached is bound directly to the R 7  group in —OR 7  with the concomitant displacement of one -ZM group from R 7 ; 
       D and D′ are independently selected from Q; (C 1 -C 6 )-alkyl, which is optionally substituted with one or more groups selected from (C 3 -C 6 )-cycloalkyl, —OR 2 , —R 3 , —O-Q or Q; (C 2 -C 4 )-alkenyl, which is optionally substituted with one or more groups selected from (C 3 -C 6 )-cycloalkyl, —OR 2 , —R 3 , —O-Q or Q; (C 3 -C 6 )-cycloalkyl, which is optionally substituted with or fused to Q; or (C 5 -C 6 )-cycloalkenyl, which is optionally substituted with or fused to Q; 
       each Q is independently selected from a 3-7 membered saturated, partially saturated or unsaturated carbocyclic ring system; or a 5-7 membered saturated, partially saturated or unsaturated heterocyclic ring containing one or more heteroatoms selected from O, N, S, S(O) n  or N(R 2 ); wherein any ring in Q is optionally substituted with one or more groups selected from oxo, —OR 2 , —R 2 , —N(R 2 ) 2 , —N(R 2 )—C(O)—R 2 , —R 2 —OH, —CN, —C(O)OR 2 , —C(O)—N(R 2 ) 2 , halo or —CF 3 ; 
       E is selected from —O—R 3 ; —N(R 2 )(R 3 ); (C 1 -C 6 )-alkyl, which is optionally substituted with one or more groups selected from R 4  or Ht; (C 2 -C 6 )-alkenyl, which is optionally substituted with one or more groups selected from R 4  or Ht; 
       each R 4  is independently selected from —OR 2 , —SR 2 , —C(O)—NHR 2 , —S(O) 2 —NHR 2 , halo, —N(R 2 )—C(O)—R 2 , —N(R 2 ) 2  or —CN; 
       each R 7  is independently selected from 
     
     
       
         
         
             
             
         
       
       wherein each M is independently selected 
       from H, Li, Na, K, Mg, Ca, Ba, —N(R 2 ) 4 , (C 1 -C 12 )-alkyl, (C 2 -C 12 )-alkenyl, or —R 6 ; wherein 1 to 4 —CH 2  radicals of the alkyl or alkenyl group, other than the —CH 2  that is bound to Z, is optionally replaced by a heteroatom group selected from O, S, S(O), S(O) 2 , or N(R 2 ); and wherein any hydrogen in said alkyl, alkenyl or R 6  is optionally replaced with a substituent selected from oxo, —OR 2 , —R 2 , N(R 2 ) 2 , N(R 2 ) 3 , R 2 OH, —CN, —C(O)OR 2 , —C(O)—N(R 2 ) 2 , S(O) 2 —N(R 2 ) 2 , N(R 2 )—C(O)—R 2 , C(O)R 2 , —S(O) n —R 2 , OCF 3 , —S(O) n —R 6 , N(R 2 )—S(O) 2 —R 2 , halo, —CF 3 , or —NO 2 ; 
       M′ is H, (C 1 -C 12 )-alkyl, (C 2 -C 12 )-alkenyl, or —R 6 ; wherein 1 to 4 —CH 2  radicals of the alkyl or alkenyl group is optionally replaced by a heteroatom group selected from O, S, S(O), S(O) 2 , or N(R 2 ); and wherein any hydrogen in said alkyl, alkenyl or R 6  is optionally replaced with a substituent selected from oxo, —OR 2 , —R 2 , —N(R 2 ) 2 , N(R 2 ) 3 , —R 2 OH, —CN, —CO 2 R 2 , —C(O)—N(R 2 ) 2 , —S(O) 2 —N(R 2 ) 2 , —N(R 2 )—C(O)—R 2 , —C(O)R 2 , —S(O) n —R 2 , —OCF 3 , —S(O) n —R 6 , —N(R 2 )—S(O) 2 —R 2 , halo, —CF 3 , or —NO 2 ; 
       Z is CH 3 , O, S, N(R 2 ) 2 , or, when M is not present, H. 
       Y is P or S; 
       X is O or S; and 
       R 9  is C(R 2 ) 2 , O or N(R 2 ); and wherein when Y is S, Z is not S; and 
       R 6  is a 5-6 membered saturated, partially saturated or unsaturated carbocyclic or heterocyclic ring system, or an 8-10 membered saturated, partially saturated or unsaturated bicyclic ring system; wherein any of said heterocyclic ring systems contains one or more heteroatoms selected from O, N, S, S(O) n  or N(R 2 ); and wherein any of said ring systems optionally contains 1 to 4 substituents independently selected from OH, C 1 -C 4  alkyl, O—(C 1 -C 4 )-alkyl or O—C(O)—(C 1 -C 4 )-alkyl. 
     
   
   
       2 . The compound according to  claim 1 , wherein at least one R 7  is selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       3 . The compound according to  claim 2 , wherein said compound has formula XXII: 
     
       
         
         
             
             
         
       
       wherein A, D′, R 7  and E are as defined in  claim 1 . 
     
   
   
       4 - 12 . (canceled) 
   
   
       13 . The compound according to  claim 2 , wherein said compound has formula XXXI: 
     
       
         
         
             
             
         
       
     
   
   
       14 . The compound according to  claim 13 , wherein:
 A is R 1 -Ht;   each R 3  is independently (C 1 -C 6 )-alkyl which is optionally substituted with —OR 2 , —C(O)—NH—R 2 , —S(O) n N(R 2 ) 2 , —Ht, —CN, —SR 2 , —CO 2 R 2  or —N(R 2 )—C(O)—R 2 ; and   D′ is (C 1 -C 4 )-alkyl, which is optionally substituted with (C 3 -C 6 )-cycloalkyl, —OR 2 , —O-Q; and E is —N(R 2 )(R 3 ).   
   
   
       15 . The compound according to  claim 14 , wherein R 7  in the —OR 7  group depicted in formula XXXI is —PO(OM) 2  or —C(O)-M′. 
   
   
       16 . (canceled) 
   
   
       17 . A compound selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       wherein 
       R 10  is selected from isopropoyl or cyclopentyl; 
       R 11  is selected from NHR 7  or OR 7 ; 
       in compound 1005, when R 7  is PO 3 M, (G) x  is not H; and x, R 7  and G are as defined in  claim 1 . 
     
   
   
       18 . A pharmaceutical composition, comprising a compound according to any one of  claims 1  in an amount effective to treat infection by a virus that is characterized by an aspartyl protease; and a pharmaceutically acceptable carrier, adjuvant or vehicle. 
   
   
       19 . The pharmaceutical composition according to  claim 18 , wherein said virus is HIV. 
   
   
       20 . The pharmaceutical composition according to  claim 18 , wherein said pharmaceutical composition is formulated for oral administration. 
   
   
       21 . The pharmaceutical composition according to  claim 18 , further comprising one or more agents selected from an anti-viral agent, an HIV protease inhibitor other than a compound according to  claim 1 , and an immunostimulator. 
   
   
       22 . The pharmaceutical composition according to  claim 21 , further comprising one or more agents selected from zidovudine (AZT), zalcitabine (ddC), didanosine (ddI), stavudine (d4T), 3TC, 935U83, 1592U89, 524W91, saquinavir (Ro 31-8959), L-735,524, SC-52151, ABT 538 (A84538), AG 1343, XM 412, XM 450, CGP 53,437, tucaresol, polysulfated polysaccharides, ganciclovir, dideoxycytidine, ribavirin, acyclovir, TIBO, nevirapine, IL-2, GM-CSF, interferon alpha, or erythropoietin (EPO). 
   
   
       23 . A method for inhibiting aspartyl protease activity in a mammal, comprising the step of administering to said mammal a pharmaceutical composition according to  claim 18 . 
   
   
       24 . A method for treating HIV infection in a mammal comprising the step of administering to said mammal a pharmaceutical composition according to  claim 18 . 
   
   
       25 . The method according to  claim 24 , wherein said mammal is additionally administered one or more additional agents selected from an anti-viral agent, an HIV protease inhibitor other than a compound according to  claim 1 , and an immunostimulator either as a part of a single dosage form with said pharmaceutical composition or as a separate dosage form. 
   
   
       26 . The method according to  claim 25 , wherein said additional agent is selected from zidovudine (AZT), zalcitabine (ddC), didanosine (ddI), stavudine (d4T), 3TC, 935U83, 1592U89, 524W91, saquinavir (Ro 31-8959), L-735,524, SC-52151, ABT 538 (A84538), AG 1343, XM 412, XM 450, CGP 53,437, tucaresol, polysulfated polysaccharides, ganciclovir, dideoxycytidine, ribavirin, acyclovir, TIBO, nevirapine, IL-2, GM-CSF, interferon alpha, or erythropoietin (EPO). 
   
   
       27 . The method according to  claim 24 , wherein said step of administering comprises oral administration.