Sulphonamide derivatives as prodrugs of aspartyl protease inhibitors

1. A compound of formula I:

wherein

A is selected from —R 1 —(C 1 -C 6 )-alkyl, which is optionally substituted with one or more groups independently selected from hydroxy, C 1 -C 4 alkoxy, Ht, —O-Ht, —NR 2 —CO—N(R 2 ) 2 or —CO—N(R 2 ) 2 ; —R 1 —(C 2 -C 6 )-alkenyl, which is optionally substituted with one or more groups independently selected from hydroxy, C 1 -C 4 alkoxy, Ht, —O-Ht, —N(R 2 )—C(O)—N(R 2 ) 2 or —CO—N(R 2 ) 2 ; or R 7 ;

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; (C 2 -C 4 )-alkenyl; (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 Ht; O-Ht; Ht-Ht; —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; (C 3 -C 6 )-saturated carbocycle, which is optionally substituted with one or more groups selected from R 4 or Ht; or (C 5 -C 6 )-unsaturated carbocycle, 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:

PO 3 K 2 , PO 3 Ca, PO 3 -spermine, PO 3 -(spermidine) 2 or PO 3 -(meglamine) 2 .

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. The compound according to claim 3 , wherein:

E is a 5-membered heterocyclic ring containing one S and optionally containing N as an additional heteroatom, wherein said heterocyclic ring is optionally substituted with one to two groups independently selected from —CH 3 , R 4 , or Ht.

5. The compound according to claim 3 , wherein:

E is Ht substituted with N(R 7 ) 2 ;

R 7 in the —OR 7 group shown in formula XXII is —PO(OM) 2 or C(O)CH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 3 and both R 7 in the —N(R 7 ) 2 substituent of Ht are H; or R 7 in —OR 7 group shown in formula XXII is C(O)CH 2 OCH 2 CH 2 OCH 3 , one R 7 in the —N(R 7 ) 2 substituent of Ht is C(O)CH 2 OCH 2 CH 2 OCH 3 and the other R 7 in the —N(R 7 ) 2 substituent of Ht is H; and

wherein M is H, Li, Na, K or C 1 -C 4 alkyl.

6. The compound according to claim 2 , wherein said compound has formula XXIII:

7. The compound according to claim 6 , wherein:

R 3 is (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 5 -C 6 )-cycloalkyl, (C 5 -C 6 )-cycloalkenyl, or a 5-6 membered saturated or unsaturated heterocycle; wherein any member of R 3 is optionally substituted with one or more substituents selected from the group consisting of —OR 2 , —C(O)—NH—R 2 , —S(O) n N(R 2 ) 2 , -Ht, —CN, —SR 2 , —C(O)O—R 2 and N(R 2 )—C(O)—R 2 ; and

D′ is (C 1 -C 3 )-alkyl or C 3 alkenyl.

8. The compound according to claim 7 , wherein R 7 in the —OR 7 group depicted in formula XXIII is —PO(OM) 2 or —C(O)-M′.

9. The compound according to claim 2 , wherein said compound has formula XXXI:

10. The compound according to claim 9 , wherein R 7 in the —OR 7 group depicted in formula XXXI is —PO(OM) 2 or —C(O)-M′.

11. A pharmaceutical composition, comprising a compound according to any one of claims 1 - 3 , 4 - 5 , 6 - 9 , or 10 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.

12. The pharmaceutical composition according to claim 11 , wherein said virus is HIV.

13. The pharmaceutical composition according to claim 11 , wherein said pharmaceutical composition is formulated for oral administration.

14. The pharmaceutical composition according to claim 11 , 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.

15. The pharmaceutical composition according to claim 14 , further comprising one or more agents selected from zidovudine (AZT), zalcitabine (ddC), didanosine (ddI), stavudine (d4T), lamivudine (3TC), abacavir (1592U89), saquinavir (Ro 31-8959), indinavir (MK-639, L-735,524), ritonavir (ABT 538, A84538) nelfinavir (AG 1343), N,N′-di-m-aminobenzyl-4,7-dibenzyl-5,6-dihydroxy-1,3-diaza-cyclohept-2-one (XM 450), [(1S,2S,4R)-2-hydroxy-5-[[(1S)-2-methyl-1-[[[(1S)-2-(4-morpholinyl)-2-oxo-1-(phenylmethyl)ethyl]amino]carbonyl]propyl]amino]-5-oxo-1,4-bis(phenylmethyl)pentyl]-carbamic acid 1,1-dimethylethyl ester (CGP 53,437), polysulfated polysaccharides, ganciclovir, dideoxycytidine, ribavirin, acyclovir, TIBO, nevirapine, IL-2, GM-CSF, interferon alpha, or erythropoietin (EPO).

16. A method for inhibiting aspartyl protease activity in a mammal, comprising the step of administering to said mammal a pharmaceutical composition according to claim 11 .

17. A method for treating HIV infection in a mammal comprising the step of administering to said mammal a pharmaceutical composition according to any one of claim 11 .

18. The method according to claim 17 , 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.

19. The method according to claim 18 , wherein said additional agent is selected from zdovudine (AZT), zalcitabine (ddC), didanosine (ddI), stavudine (d4T), lamivudine (3TC), abacavir (1592U89), saquinavir (Ro 31-8959), indinavir (MK-639, L-735,524), ritonavir (ABT 538, A84538), nelfinavir (AG 1343), N,N′-di-m-aminobenzyl-4,7-dibenzyl-5,6-dihydroxy-1,3-diaza-cyclohept-2-one (XM 450), [(1S,2S,4R)-2-hydroxy-5-[[(1S)-2-methyl-1-[[[(1S)-2-(4-morpholinyl)-2-oxo-1-(phenylmethyl)ethyl]amino]carbonyl]propyl]amino]-5-oxo-1,4-bis(phenylmethyl)pentyl]-carbamic acid 1,1-dimethylethyl ester (CGP 53,437), polysulfated polysaccharides, ganciclovir, dideoxycytidine, ribavirin, acyclovir, TIBO, nevirapine, IL-2, GM-CSF, interferon alpha, or erythropoietin (EPO).

20. The method according to claim 17 , wherein said step of administering comprises oral administration.