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Details for Patent: 6,838,474

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Details for Patent: 6,838,474

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, ND), Kaldor; Istvan (Durham, NC), Kazmierski; Wieslaw Mieczylaw (Raleigh, NC), Spaltenstein; Andrew (Raleigh, NC)
Assignee: Vertex Pharmaceuticals, Incorporated (Cambridge, MA)
Filing Date:Feb 19, 2003
Application Number:10/370,171
Claims:1. A compound of the formula: ##STR154##

wherein: R.sup.7 is selected from ##STR155## 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 --CR.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.sup.2, --N(R.sup.2).sub.2, N(R.sup.2).sub.3, --R.sup.2 OH, --CN, --CO.sub.2 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.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 ; 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 R.sup.7 is selected from: ##STR156## ##STR157##

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. A pharmaceutical composition, comprising a compound according to claim 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.

4. The pharmaceutical composition according to claim 3, wherein said virus is HIV.

5. The pharmaceutical composition according to claim 3, wherein said pharmaceutical composition is formulated for oral administration.

6. The pharmaceutical composition according to claim 3, further comprising one or more agents, selected from an anti-viral agent, an HIV protease inhibitor and an immunostimulator.

7. The pharmaceutical composition according to claim 6, 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).

8. A method for inhibiting aspartyl protease activity in a mammal in need thereof, comprising the step of contacting administering to said mammal a pharmaceutical composition according to claim 3.

9. 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 3.

10. The method according to claim 9, wherein said mammal is additionally administered one or more additional agents selected from an anti-viral agent, an HIV protease inhibitor, and an immunostimulator either as a part of a single dosage form with said pharmaceutical composition or as a separate dosage form.

11. The method according to claim 10, 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(phenylmethyl)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).

12. The method according to claim 9, wherein said step of administering comprises oral administration.
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