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Details for Patent: 5,856,353

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Details for Patent: 5,856,353

Title: Sulfonamide inhibitors of aspartyl protease
Abstract:The present invention relates to a novel class of sulfonamides which are aspartyl protease inhibitors. In one embodiment, this invention relates to a novel class of HIV aspartyl protease inhibitors characterized by specific structural and physicochemical features. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting HIV-1 and HIV-2 protease activity and consequently, may be advantageously used as anti-viral agents against the HIV-1 and HIV-2 viruses. This invention also relates to methods for inhibiting the activity of HIV aspartyl protease using the compounds of this invention and methods for screening compounds for anti-HIV activity.
Inventor(s): Tung; Roger D. (Arlington, MA), Murcko; Mark A. (Holliston, MA), Bhisetti; Govinda R. (Lexington, MA)
Assignee: Vertex Pharmaceuticals, Incorporated (Cambridge, MA)
Filing Date:Jun 07, 1995
Application Number:08/477,937
Claims:1. A compound of formula I: ##STR610## wherein: A is selected from the group consisting of Het; --R.sup.1 --Het; --R.sup.1 --C.sub.1 -C.sub.6 alkyl, which is substituted with one to two groups selected from the group consisting of Het and --O--Het; and --R.sup.1 --C.sub.2 -C.sub.6 alkenyl, which is substituted with one to two groups selected from the group consisting of Het and --O--Het;

each R.sup.1 is independently selected from the group consisting of --C(O)--, --S(O).sub.2, --C(O)--C(O)--, --O--C(O)--, --O--S(O).sub.2, --NR.sup.2 --S(O).sub.2 --, --NR.sup.2 --C(O)-- and --NR.sup.2 --C(O)--C(O)--;

each Het is independently selected from the group consisting of 5-7 membered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from O, S and S(O).sub.n, wherein said heterocycle may optionally be benzofused; and wherein any member of said Het may be optionally substituted with one to two substituents selected from the group consisting of oxo, --OR.sup.2, --R.sup.2, --N(R.sup.2) (R.sup.2), --R.sup.2 --OH, --CN, --CO.sub.2 R.sup.2, --C(O) --N(R.sup.2) (R.sup.2), --S(O).sub.2 --N(R.sup.2) (R.sup.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 --Ar, methylenedioxy, --N(R.sup.2)--S(O).sub.2 (R.sup.2), halo, --CF.sub.3, --NO.sub.2, Ar and --O--Ar;

each R.sup.2 is independently selected from the group consisting of H and C.sub.1 -C.sub.3 alkyl optionally substituted with Ar; with the proviso that when R.sup.2 is C.sub.1 -C.sub.3 alkyl substituted with Ar, said Ar may not be substituted with an Ar-containing moiety;

B, when present, is --N(R.sup.2)--C(R.sup.3) (R.sup.3)--C(O)--;

x is 0 or 1;

each R.sup.3 is independently selected from the group consisting of H, Het, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.6 cycloalkyl and C.sub.5 -C.sub.6 cycloalkenyl, wherein any member of said R.sup.3, except H, may be optionally substituted with one to two substituents selected from the group consisting of --OR.sup.2, --C(O)--NH--R.sup.2, --S(O).sub.n --N(R.sup.2) (R.sup.2), Het, --CN, --SR.sup.2, --CO.sub.2 R.sup.2, NR.sup.2 --C(O) --R.sup.2 ;

each n is independently 1 or 2;

D and D' are independently selected from the group consisting of Ar; C.sub.1 -C.sub.4 alkyl, which may be optionally substituted with one to two groups selected from C.sub.3 -C.sub.6 cycloalkyl, --OR.sup.2, --R.sup.3, --O--Ar and Ar; C.sub.2 -C.sub.4 alkenyl, which may be optionally substituted with one to two groups selected from the group consisting of C.sub.3 -C.sub.6 cycloalkyl, --OR.sup.2, --R.sup.3, --O--Ar and Ar; C.sub.3 -C.sub.6 cycloalkyl, which may be optionally substituted with or fused with Ar; and C.sub.5 -C.sub.6 cycloalkenyl, which may be optionally substituted with or fused with Ar;

each Ar is independently selected from the group consisting of phenyl; 3-6 membered carbocyclic ring and 5-6 membered heterocyclic ring containing one or more heteroatoms selected from O, S, and S(O).sub.n, wherein said carbocyclic or heterocyclic ring may be saturated or unsaturated and optionally substituted with one to two groups selected from the group consisting of oxo, --OR.sup.2, --R.sup.2, --N(R.sup.2) (R.sup.2), --N(R.sup.2)--C(O)--R.sup.2, C.sub.1 -C.sub.3 alkyl substituted with --OH and optionally substituted with Ar, --CN, --CO.sub.2 R.sup.2, --C(O)--N(R.sup.2) (R.sup.2), halo and --CF.sub.3 ;

E is selected from the group consisting of Het; O--Het; Het--Het; C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.6 saturated carbocycle and C.sub.5 -C.sub.6 unsaturated carbocycle, each of which is substituted with one to two Het groups.

2. The compound according to claim 1, wherein said compound has the structure of formula XXII: ##STR611## wherein A, D' and E are defined as in claim 1.

3. The compound according to claim 1, wherein said compound has the structure of formula XXIII: ##STR612## and x, Het, R.sup.3, D' and E are defined as in claim 1.

4. The compound according to claim 1, wherein:

A is selected from the group consisting of --R.sup.1 --Het; --R.sup.1 --C.sub.1 -C.sub.6 alkyl, which is substituted with one to two groups selected from the group consisting of Het and --O--Het; and --R.sup.1 --C.sub.2 -C.sub.6 alkenyl, which is substituted with one to two groups selected from Het and --O--Het;

each R.sup.1 is independently selected from the group consisting of --C(O)--, --S(O).sub.2 --, --C(O)--C(O)--, --O--CO--, --O--S(O).sub.2 -- and --NR.sup.2 --S(O).sub.2 --;

each Het is independently selected from the group consisting of and 5-7 membered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from O and S, which may optionally be benzofused; wherein any member of said Het may be optionally substituted with one to two substituents selected from the group consisting of oxo, --OR.sup.2, --R.sup.2, --N(R.sup.2).sub.2, --R.sup.2 --OH, --CN, --CO.sub.2 R.sup.2, --C(O)--N(R.sup.2).sub.2 and --S(O).sub.2 --N(R.sup.2).sub.2 ;

each R.sup.2 is independently selected from the group consisting of H and C.sub.1 -C.sub.3 alkyl;

B, when present, is --NH--CH(R.sup.3)--C(O)--;

x is 0 or 1;

R.sup.3 is selected from the group consisting of Het, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.6 cycloalkyl and C.sub.5 -C.sub.6 cycloalkenyl, wherein any member of said R.sup.3 may be optionally substituted with one to two substituents 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, Het and--CN;

n is 1 or 2;

D and D' are independently selected from the group consisting of Ar; C.sub.1 -C.sub.4 alkyl, which may be optionally substituted with C.sub.3 -C.sub.6 cycloalkyl or Ar; C.sub.2 -C.sub.4 alkenyl, which may be optionally substituted with C.sub.3 -C.sub.6 cycloalkyl or Ar; C.sub.3 -C.sub.6 cycloalkyl, which may be optionally substituted or fused with Ar; and C.sub.5 -C.sub.6 cycloalkenyl, which may be optionally substituted or fused with Ar;

Ar is selected from the group consisting of phenyl; 3-6 membered carbocyclic ring and 5-6 membered heterocyclic ring containing one or more heteroatoms selected from O and S, wherein said carbocyclic or heterocyclic ring may be saturated or unsaturated and optionally substituted with one to two groups selected from the group consisting of 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.3 alkyl substituted with --OH and optionally substituted with Ar, --CN, --CO.sub.2 R.sup.2, --C(O)--N(R.sup.2).sub.2, halo and --CF.sub.3 ;

E is selected from the group consisting of Het; C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.6 saturated carbocycle and C.sub.5 -C.sub.6 unsaturated carbocycle, each of which is substituted with one to two Het groups; and

each R.sup.5 is independently selected from the group consisting of H and R.sup.3.

5. The compound according to claim 2 or 3, wherein:

A, when present, is R.sup.1 --Het; and

D' is selected from the group consisting of C.sub.1 -C.sub.3 alkyl and C.sub.3 alkenyl, wherein said alkyl or alkenyl may optionally be substituted with one to two groups selected from the group consisting of C.sub.3 -C.sub.6 cycloalkyl, --OR.sup.2, --O--Ar and Ar.

6. The compound according to claim 3, wherein:

R.sup.3 is selected from the group consisting of 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 and a 5-6 membered saturated or unsaturated heterocycle, wherein any member of said R.sup.3 may optionally be substituted with one to two substituents selected from the group consisting of --OR.sup.2, --C(O)--NH--R.sup.2, --S(O).sub.n N(R.sup.2)(R.sup.2), Het, --CN, --SR.sup.2, --C(O).sub.2 R.sup.2, NR.sup.2 --C(O)--R.sup.2 ; and

D' is selected from the group consisting of C.sub.1 -C.sub.3 alkyl and C.sub.3 alkenyl, wherein said alkyl or alkenyl may optionally be substituted with one to two groups selected from the group consisting of C.sub.3 -C.sub.6 cycloalkyl, --OR.sup.2, --O--Ar and Ar.

7. The compound according to claim 1, wherein said compound has a molecular weight less than or equal to about 700 g/mol.

8. A compound according to claim 7, wherein said compound has a molecular weight less than or equal to about 600 g/mol.

9. The compound according to claim 2, wherein A is R.sup.1 --Het and wherein R.sup.1 and Het are defined as in claim 1.

10. The compound according to claim 9, wherein D' is selected from the group consisting of C.sub.1 -C.sub.4 alkyl and C.sub.1 alkyl substituted with C.sub.3 -C.sub.6 cycloalkyl.

11. The compound according to claim 9, wherein:

R.sup.1 is --O--C(O)--;

each Het is independently selected from the group consisting of 5-7 membered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from O, S and S(O).sub.n, wherein said heterocycle may optionally be benzofused; and wherein any member of said Het may be optionally substituted with one to two substituents selected from the group consisting of oxo, --OR.sup.2, --R.sup.2, --N(R.sup.2) (R.sup.2), --R.sup.2 --OH, --CN, --CO.sub.2 R.sup.2, --C(O)--N(R.sup.2)(R.sup.2), --S(O).sub.2 --N(R.sup.2) (R.sup.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 --Ar, methylenedioxy, --N(R.sup.2)--S(O).sub.2 (R.sup.2), halo, --CF.sub.3, --NO.sub.2, Ar and --O--Ar;

each D' is independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl, which may be optionally substituted with one to two groups selected from C.sub.3 -C.sub.6 cycloalkyl, --OR.sub.2, --R.sup.3, --O--Ar and Ar; C.sub.2 -C.sub.4 alkenyl, which may be optionally substituted with one to two groups selected from the group consisting of C.sub.3 -C.sub.6 cycloalkyl, --OR.sup.2, --R.sup.3, --O--Ar and Ar; C.sub.3 -C.sub.6 cycloalkyl, which may be optionally substituted with or fused with Ar; and C.sub.5 -C.sub.6 cycloalkenyl, which may be optionally substituted with or fused with Ar;

E is Het; and

each Het is independently selected from the group consisting of 5-7 membered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from O, S and S(O).sub.n, wherein said heterocycle may optionally be benzofused; and wherein any member of said Het may be optionally substituted with one to two substituents selected from the group consisting of oxo, --OR.sup.2, --R.sup.2, --N(R.sup.2) (R.sup.2), --R.sup.2 --OH, --CN, --CO.sub.2 R.sup.2, --C(O)--N(R.sup.2) (R.sup.2) , --S(O).sub.2 --N (R.sup.2) (R.sup.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 --Ar, methylenedioxy, --N(R.sup.2)--S(O).sub.2 (R.sup.2), halo, --CF.sub.3, --NO.sub.2, Ar and --O--Ar.

12. The compound according to claim 9, wherein said compound is: ##STR613## N-Cyclopentylmethyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)tetrahydrofuran-3-yloxycarbonylamino)-but yl)-4-methoxy-benzenesulfonamide (compound 140).

13. A pharmaceutical composition effective against viral infection comprising a pharmaceutically effective amount of a compound according to any one of claims 1-3 and a pharmaceutically acceptable carrier, adjuvant or vehicle.

14. The pharmaceutical composition according to claim 13, wherein the viral infection is HIV 1 or HIV 2.

15. A method for treating a viral disease in a mammal caused by a virus that requires an aspartyl protease for replication, said method comprising the step of administering to said mammal a compound according to any one of claims 1-3.

16. The method according to claim 15, wherein said virus is HIV-1, HIV-2, or HTLV.

17. A method for inhibiting the enzymatic activity of an aspartyl protease comprising the step of causing the protease to come in contact with a compound according to any one of claims 1-3.

18. The method according to claim 17, wherein said aspartyl protease is a HIV protease.

19. A method for treating HIV infection in a mammal comprising the step of administering to said mammal a pharmaceutically effective amount of a pharmaceutical composition according to claim 13.

20. The method according to claim 19, wherein said step of administering comprises oral administration or administration by injection.
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