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Details for Patent: 6,559,137

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Details for Patent: 6,559,137

Title: 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.
Inventor(s): Tung; Roger Dennis (Beverly, MA), Hale; Michael Robin (Bedford, MA), Baker; Christopher Todd (Waltham, MA), Furfine; Eric Steven (Durham, NC), Kaldor; Istvan (Durham, NC), Kazmierski; Wieslaw Mieczylaw (Raleigh, NC), Spaltenstein; Andrew (Raleigh, NC)
Assignee: Vertex Pharmaceuticals Incorporated (Cambridge, MA)
Filing Date:Jun 23, 2000
Application Number:09/602,494
Claims:1. A compound of formula I: ##STR163##

wherein: A is selected from Ht; --R'--Ht; each R' is independently selected from --C(O)--, --S(O).sub.2 --, --C(O)--C(O)--, --O--C(O)--, --O--S(O).sub.2, --N(R.sup.2)--S(O).sub.2 --, --N(R.sup.2)--(O)-- or --N(R.sup.2)--C(O)--C(O)--; each Ht is independently selected from C.sub.3 -C.sub.7 cycloalkyl; C.sub.5 -C.sub.7 cycloalkenyl; C.sub.6 -C.sub.10 aryl; or a 5-7 membered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from N, N(R.sup.2), O, S and S(O).sub.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.sup.2, SR.sup.2, --R.sup.2, --N(R.sup.2).sub.2, --(C.sub.1 -C.sub.4)-alkyl substituted with OH and optionally substituted with Q, --CN, --C(O)O--R.sup.2, --C(O)--N(R.sup.2).sub.2, --S(O).sub.2 --N(R.sup.2).sub.2, --N(R.sup.2)--C(O)--R.sup.2, --C(O)--R.sup.2, --S(O).sub.n --R.sup.2, --OCF.sub.3, --S(O).sub.n --Q, methylenedioxy, --N(R.sup.2)--S(O).sub.2 --R.sup.2, halo, --CF.sub.3, --NO.sub.2, Q, --OQ, --OR.sup.7, --SR.sup.7, --R.sup.7, --N(R.sup.2)(R.sup.7) or --N(R.sup.7).sub.2 ; each R.sup.2 is independently selected from H, or (C.sub.1 -C.sub.4)-alkyl optionally substituted with Q; B, when present, is --N(R.sup.2)--C(R.sup.3).sub.2 --C(O)--; each x is independently 0 or 1; each R.sup.3 is independently selected from H, Ht, (C.sub.1 -C.sub.6)-alkyl, (C.sub.2 -C.sub.6)-alkenyl, (C.sub.3 -C.sub.6)-cycloalkyl or (C.sub.5 -C.sub.6)-cycloalkenyl; wherein any member of said R.sup.3, except H, is optionally substituted with one or more substituents selected from --OR.sup.2, --C(O)--NH--R.sup.2, --S(O).sub.n --N(R.sup.2).sub.2, Ht, --CN, --SR.sup.2, --CO.sub.2 R.sup.2, N(R.sup.2)--C(O)--R.sup.2 ; each n is independently 1 or 2; G, when present, is selected from H, R.sup.7 or (C.sub.1 -C.sub.4)-alkyl; D and D' are independently selected from Q; (C.sub.1 -C.sub.6)-alkyl, which is optionally substituted with one or more groups selected from (C.sub.3 -C.sub.6)-cycloalkyl, --OR.sup.2, --R.sup.3, --O--Q or Q; (C.sub.2 -C.sub.4)-alkenyl, which is optionally substituted with one or more groups selected from (C.sub.3 -C.sub.6)-cycloalkyl, --OR.sup.2, --R.sup.3, --O--Q or Q; (C.sub.3 -C.sub.6)-cycloalkyl, which is optionally substituted with or fused to Q; or (C.sub.5 -C.sub.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).sub.n or N(R.sup.2); wherein any ring in Q is optionally substituted with one or more groups selected from oxo, --OR.sup.2, --R.sup.2, --N(R.sup.2).sub.2, --N(R.sup.2)--C(O)--R.sup.2, --(C.sub.1 -C.sub.4)-alkyl substituted with OH and optionally substituted with Q, --CN, --C(O)OR.sup.2, --C(O)--N(R.sup.2).sub.2, halo or --CF.sub.3 ; E is selected from Ht; O--Ht; Ht--Ht; (C.sub.3 -C.sub.6)-saturated carbocycle, which is optionally substituted with one or more groups selected from R.sup.4 or Ht; or (C.sub.5 -C.sub.6)-unsaturated carbocycle, which is optionally substituted with one or more groups selected from R.sup.4 or Ht; each R.sup.4 is independently selected from --OR.sup.2, --SR.sup.2, --C(O)--NHR.sup.2, --S(O).sub.2 --NHR.sup.2, halo, --N(R.sup.2)--C(O)--R.sup.2, --N(R.sup.2).sub.2 or --CN; each R.sup.7 is independently selected from ##STR164## wherein each M is independently selected from H, Li, Na, K, Mg, Ca, Ba, N(R.sup.2).sub.4, (C.sub.1 -C.sub.12)-alkyl, (C.sub.2 -C.sub.12)-alkenyl, or --R.sup.6 ; wherein 1 to 4 --CH.sub.2 radicals of the alkyl or alkenyl group, other than the --CH.sub.2 that is bound to Z, is optionally replaced by a heteroatom group selected from O, S, S(O), S(O).sub.2, or N(R.sup.2); and wherein any hydrogen in said alkyl, alkenyl or R.sup.6 is optionally replaced with a substituent selected from oxo, --OR.sup.2, --R.sup.2, N(R.sup.2).sub.2, N(R.sup.2).sub.3, R.sup.2 OH, --CN, --C(O)OR.sup.2, --C(O)--N(R.sup.2).sub.2, S(O).sub.2 --N(R.sup.2).sub.2, N(R.sup.2)--C(O)--R.sub.2, C(O)R.sup.2, --S(O).sub.n --R.sup.2, OCF.sub.3, --S(O).sub.n --R.sup.6, N(R.sup.2)--S(O).sub.2 --R.sup.2, halo, --CF.sub.3, or --NO.sub.2 ; M' is H, (C.sub.1 -C.sub.12)-alkyl, (C.sub.2 -C.sub.12)-alkenyl, or --R.sup.6 ; wherein 1 to 4 --CH.sub.2 radicals of the alkyl or alkenyl group is optionally replaced by a heteroatom group selected from O, S, S(O), S(O).sub.2, or N(R.sup.2); and wherein any hydrogen in said alkyl, alkenyl or R.sup.6 is optionally replaced with a substituent selected from oxo, --OR.sup.2, --R.sub.2, --N(R.sup.2).sub.2, N(R.sup.2).sub.3, --R.sup.2 OH, --CN, --CO.sub.2 R.sub.2, --C(O)--N(R.sup.2).sub.2, --S(O).sub.2 --N(R.sup.2).sub.2, --N(R.sup.2)--C(O)--R.sub.2, --C(O)R.sup.2, --S(O).sub.n --R.sub.2, --OCF.sub.3, --S(O).sub.n --R.sup.6, --N(R.sup.2)--S(O).sub.2 --R.sup.2, halo, --CF.sub.3, or --NO.sub.2 ; Z is --CH.sub.2 --, O, S, --N(R.sup.2)--, or, when M is not present, H, CH.sub.3, or --N(R.sup.2).sub.2 ; Y is P or S; X is O or S; R.sup.9 is C(R.sup.2).sub.2, O or N(R.sup.2); and wherein when Y is S, Z is not S; and R.sup.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).sub.n or N(R.sup.2); and wherein any of said ring systems optionally contains 1 to 4 substituents independently selected from OH, C.sub.1 -C.sub.4 alkyl, O--(C.sub.1 -C.sub.4)-alkyl or O--C(O)--(C.sub.1 -C.sub.4)-alkyl.

2. The compound according to claim 1, wherein at least one R.sup.7 is selected from: ##STR165##

-(L)-lysine, --PO.sub.3 Na.sub.2, ##STR166##

-(L)-tyrosine, ##STR167##

--PO.sub.3 Mg, --PO.sub.3 (NH.sub.4).sub.2, --CH.sub.2 --OPO.sub.3 Na.sub.2, ##STR168##

-(L)-serine, --SO.sub.3 Na.sub.2, ##STR169##

--SO.sub.3 Mg, --SO.sub.3 (NH.sub.4).sub.2, --CH.sub.2 --OSO.sub.3 Na.sub.2, --CH.sub.2 --OSO.sub.3 (NH.sub.4).sub.2, ##STR170##

acetyl, ##STR171##

-(L)-valine, -(L)-glutamic acid, -(L)-aspartic acid, -(L)-.gamma.-t-butyl-aspartic acid, ##STR172##

-(L)-(L)-3-pyridylalanine, -(L)-histidine, --CHO, ##STR173## ##STR174##

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

3. The compound according to claim 2, wherein said compound has formula XXII: ##STR175##

wherein A, D', R.sup.7 and E are as defined in claim 1.

4. The compound according to claim 3, wherein A is selected from 3-tetrahydrofuryl-O--C(O)--, 3-(1,5-dioxane)-O--C(O)--, or 3-hydroxy-hexahydrofura[2,3-b]-furanyl-O--C(O)--; D' is (C.sub.1 -C.sub.4)-alkyl which is optionally substituted with one or more groups selected from the group consisting of (C.sub.3 -C.sub.6)-cycloalkyl, --OR.sup.2, --R.sup.3, --O--Q and Q; E is (C.sub.6 -C.sub.10)-aryl optionally substituted with one or more substituents selected from oxo, --OR.sup.2, SR.sup.2, --R.sup.2, --N(R.sup.2).sub.2, --(C.sub.1 -C.sub.4)-alkyl substituted with OH and optionally substituted with Q, --CN, --C(O)O--R.sup.2, --C(O)--N(R.sup.2).sub.2, --S(O).sub.2 --N(R.sup.2).sub.2, --N(R.sup.2) --C(O)--R.sup.2, --C(O)--R.sup.2, --S(O).sub.n --R.sup.2, --OCF.sub.3, --S(O).sub.n --Q, methylenedioxy, --N(R.sup.2)--S(O).sub.2 --R.sup.2, halo, --CF.sub.3, --NO.sub.2, Q, --OQ, --OR.sup.7, --SR.sup.7, --R.sup.7, --N(R.sup.2)(R.sup.7) or --N(R.sup.7).sub.2 ; or 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.sub.3, R.sup.4, or Ht; and Ht, insofar as it is defined as part of R.sup.3, is defined as in claim 1 except for the exclusion of heterocycles.

5. The compound according to claim 4, wherein: A is 3-tetrahydrofuryl-O--C(O)--; G is hydrogen; D' is isobutyl; E is phenyl substituted with N(R.sup.7).sub.2 ; each M is independently selected from H, Li, Na, K, Mg, Ca, Ba, C.sub.1 -C.sub.4 alkyl or N(R.sup.2).sub.4 ; and each M' is H or C.sub.1 -C.sub.4 alkyl.

6. 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.sub.3, R.sup.4 or Ht.

7. The compound according to claim 3, wherein: E is Ht substituted with N(R.sup.7).sub.2 ; R.sup.7 in the --OR.sup.7 group shown in formula XXII is --PO(OM).sub.2 or C(O)CH.sub.2 OCH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 OCH.sub.3 and both R.sup.7 in the --N(R.sup.7).sub.2 substituent of Ht are H; or R.sup.7 in --OR.sup.7 group shown in formula XXII is C(O)CH.sub.2 OCH.sub.2 CH.sub.2 OCH.sub.3, one R.sup.7 in the --N(R.sup.7).sub.2 substituent of Ht is C(O)CH.sub.2 OCH.sub.2 CH.sub.2 OCH.sub.3 and the other R.sup.7 in the --N(R.sup.7).sub.2 substituent of Ht is H; and wherein M is H, Li, Na, K or C.sub.1 -C.sub.4 alkyl.

8. The compound according to claim 2, wherein said compound has formula XXIII: ##STR176##

9. The compound according to claim 8, wherein: R.sup.3 is (C.sub.1 -C.sub.6)-alkyl, (C.sub.2 -C.sub.6)-alkenyl, (C.sub.5 -C.sub.6)-cycloalkyl, (C.sub.5 -C.sub.6)-cycloalkenyl, or a 5-6 membered saturated or unsaturated heterocycle; wherein any member of R.sup.3 is optionally substituted with one or more substltuents selected from the group consisting of --OR.sup.2, --C(O)--NH--R.sup.2, --S(O).sub.n N(R.sup.2).sub.2, --Ht, --CN, --SR.sup.2, --C(O)O--R.sup.2 and N(R.sup.2)--C(O)--R.sup.2 ; and D' is (C.sub.1 -C.sub.3)-alkyl or C.sub.3 alkenyl; wherein D' is optionally substituted with one or more groups selected from (C.sub.3 -C.sub.6)-cycloalkyl, --OR.sup.2, --O--Q or Q.

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

11. The compound according to claim 2, wherein said compound has formula XXXI: ##STR177##

12. The compound according to claim 11, wherein: A is R.sup.1 --Ht; each R.sup.3 is independently (C.sub.1 -C.sub.6)-alkyl which is optionally substituted with --OR.sup.2, --C(O)--NH--R.sup.2, --S(O).sub.n N(R.sup.2).sub.2, --Ht, --CN, --SR.sup.2, --CO.sub.2 R.sup.2 or --N(R.sup.2)--C(O)--R.sup.2 ; and D' is (C.sub.1 -C.sub.4)-alkyl, which is optionally substituted with (C.sub.3 -C.sub.6)-cycloalkyl, --OR.sup.2, --O--Q; and E is Ht, Ht--Ht and --N(R.sup.2)(R.sup.3).

13. The compound according to claim 12, wherein R.sup.7 in the --OR.sup.7 group depicted in formula XXXI is --PO(OM).sub.2 or --C(O)--M'.

14. The compound according to claim 1, wherein said compound is selected from any one of compound numbers 198 to 217, 225-229, 231, 237 to 242, 245 to 254, 261 to 267, 308 or 243 to 244 as depicted below:

15. The compound according to claim 3, wherein: A is 3-hexahydrofura[2,3-b]-furanyl-O--C(O)--; D' is (C.sub.1 -C.sub.4)-alkyl which is optionally substituted with one or more groups selected from the group consisting of (C.sub.3 -C.sub.6 ) -cycloalkyl, --OR.sup.2, --R.sup.3, --O--Q and Q; E is (C.sub.6 -C.sub.10)-aryl optionally substituted with one or more substituents selected from oxo, --OR.sup.2, SR.sup.2, --R.sup.2.sub.1, --N(R.sup.2).sub.2, --(C.sub.1 -C.sub.4)-alkyl substituted with OH and optionally substituted with Q, --CN, --C(O)O--R.sup.2, --C(O)--N(R.sup.2).sub.2, --S(O).sub.2 --N(R.sup.2).sub.2, --N(R.sup.2)--C(O)--R.sup.2, --C(O)--R.sup.2, --S(O).sub.n --R.sup.2, --OCF.sub.3, --S(O).sub.n --Q, methylenedioxy, --N(R.sup.2)--S(O).sub.2 --R.sup.2, halo, --CF.sub.3, --NO.sub.2, Q, --OQ, --OR.sup.7, --SR.sup.7, --R.sup.7, --N(R.sup.2)(R.sup.7) or --N(R.sup.7).sub.2 ; or 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.sub.3, R.sup.4, or Ht; and Ht, insofar as it is defined as part of R.sup.3, is defined as in claim 1 except for the exclusion of heterocycles.

16. The compound according to claim 15, wherein: D' is isobutyl; and E is phenyl substituted with --N(R.sup.2).sub.2.

17. The compound according to claim 3 having the structure: ##STR232##

18. The compound according to claim 16, wherein: each M is independently selected from H, Li, Na, K, Mg, Ca, Ba, C.sub.1 -C.sub.4 alkyl or --N(R.sup.2).sub.4 ; and each M' is H or C.sub.1 -C.sub.4 alkyl.

19. The compound according to claim 17, wherein: each M is independently selected from H, Li, Na, K, Mg, Ca, Ba, C.sub.1 -C.sub.4 alkyl or --N(R.sup.2).sub.4 ; and each M' is H or C.sub.1 -C.sub.4 alkyl.

20. The compound according to claim 3, having the structure: ##STR233##

wherein each M is Na or K.

21. A compound having the structure: ##STR234##

22. A pharmaceutical composition, comprising a compound according to any one of claims 1-7 or 8-14 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.

23. The pharmaceutical composition according to claim 22 wherein said virus is HIV.

24. The pharmaceutical composition according to claim 22, wherein said pharmaceutical composition is formulated for oral administration.

25. The pharmaceutical composition according to claim 22, 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.

26. The pharmaceutical composition according to claim 25, 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(phenylmeth yl)pentyl]-carbamic acid 1,1-dimethylethyl ester (CGP 53,437), polysulfated polysaccharides, ganciclovir, ribavirin, acyclovir, TIBO, nevirapine, IL-2, GM-CSF, interferon alpha, or erythropoietin (EPO).

27. A pharmaceutical composition, comprising a compound according to any one of claims 15 to 21 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.

28. The pharmaceutical composition according to claim 27, wherein said virus is HIV.

29. The pharmaceutical composition according to claim 27, wherein said pharmaceutical composition is formulated for oral administration.

30. The pharmaceutical composition according to claim 27, 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.

31. The pharmaceutical composition according to claim 30, 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(phenylmeth yl)pentyl]-carbamic acid 1,1-dimethylethyl ester (CGP 53,437), polysulfated polysaccharides, ganciclovir, ribavirin, acyclovir, TIBO, nevirapine, IL-2, GM-CSF, interferon alpha, or erythropoietin (EPO).

32. A method for inhibiting aspartyl protease activity in a mammal, comprising the step of administering to said mammal a pharmaceutical composition according to claim 22.

33. A method for treating HIV infection in a mammal comprising the step of administering to said mammal a pharmaceutical composition according to claim 22.

34. The method according to claim 33, 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.

35. The method according to claim 34, wherein said additional agent is 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(phenylmeth yl)pentyl]-carbamic acid 1,1-dimethylethyl ester (CGP 53,437), polysulfated polysaccharides, ganciclovir, ribavirin, acyclovir, TIBO, nevirapine, IL-2, GM-CSF, interferon alpha, or erythropoietin (EPO).

36. The method according to claim 33, wherein said step of administering comprises oral administration.

37. A method for inhibiting aspartyl protease activity in a mammal, comprising the step of administering to said mammal a pharmaceutical composition according to claim 27.

38. A method for treating HIV infection in a mammal comprising the step of administering to said mammal a pharmaceutical composition according to claim 27.

39. The method according to claim 38, 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.

40. The method according to claim 39, wherein said additional agent is 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(phenylmeth yl)pentyl]-carbamic acid 1,1-dimethylethyl ester (CGP 53,437), polysulfated polysaccharides, ganciclovir, ribavirin, acyclovir, TIBO, nevirapine, IL-2, GM-CSF, interferon alpha, or erythropoietin (EPO).

41. The method according to claim 38, wherein said step of administering comprises oral administration.
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