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Details for Patent: 6,004,957

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Details for Patent: 6,004,957

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:Jul 22, 1998
Application Number:09/121,008
Claims:1. A compound of formula I:

wherein: ##STR610## A is selected from the group consisting of Ht.sub.A ; --R.sup.1 --Ht.sub.A ; --R.sup.1 -C.sub.1 -C.sub.6 alkyl, which is substituted with one or more groups selected from the group consisting of Ht.sub.A and --O--Ht.sub.A ; and --R.sup.1 -C.sub.2 -C.sub.6 alkenyl, which is substituted with one or more groups selected from the group consisting of Ht.sub.A and --O--Ht.sub.A ;

each Ht.sub.A 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 Ht.sub.4 may be optionally substituted with one or more 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 --R.sup.7, methylenedioxy, --N(R.sup.2)--S(O).sub.2 (R.sup.2), halo, --CF.sub.3, --NO.sub.2, R.sup.7 and --O--R.sup.7 ;

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 Ht is independently selected from the group consisting of C.sub.3 -C.sub.7 cycloalkyl; C.sub.5 -C.sub.7 cycloalkenyl; C.sub.6 -C.sub.10 aryl; and 5-7 membered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from N, N(R.sup.2), and optionally containing O as an additional heteroatom, wherein said heterocycle may optionally be benzofused; and wherein any member of said Ht may be optionally substituted with one or more 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 --R.sup.7, methylenedioxy, --N(R.sup.2)--S(O).sub.2 (R.sup.2), halo, --CF.sub.3, --NO.sub.2, R.sup.7 and --O--R.sup.7 ;

each R.sup.2 is independently selected from the group consisting of H and C.sub.1 -C.sub.3 alkyl optionally substituted with R.sup.7 ; with the proviso that when R.sup.2 is C.sub.1 -C.sub.3 alkyl substituted with R.sup.7, said R.sup.7 may not be substituted with an R.sup.7 -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, Ht, 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 or more 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), Ht, --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 R.sup.7 ; C.sub.1 -C.sub.4 alkyl, which may be optionally substituted with one or more groups selected from C.sub.3 -C.sub.6 cycloalkyl, --OR.sup.2, --R.sup.3, --O--R.sup.7 and R.sup.7 ; C.sub.2 -C.sub.4 alkenyl, which may be 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--R.sup.7 and R.sup.7 ; C.sub.3 -C.sub.6 cycloalkyl, which may be optionally substituted with or fused with R.sup.7 ; and C.sub.5 -C.sub.6 cycloalkenyl, which may be optionally substituted with or fused with R.sup.7 ;

each R.sup.7 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, N, S, S(O).sub.n and N(R.sup.2), wherein said carbocyclic or heterocyclic ring may be saturated or unsaturated and optionally substituted with one or more 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 R.sup.7, --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 Ht; O--Ht; Ht--Ht; --O--R.sup.3 ; --NR.sup.2 R.sup.3 ; C.sub.1 -C.sub.6 alkyl, which may be optionally substituted with one or more groups selected from the group consisting of R.sup.4 and Ht; C.sub.2 -C.sub.6 alkenyl, which may be optionally substituted with one or more groups selected from the group consisting of R.sup.4 and Ht; C.sub.3 -C.sub.6 saturated carbocycle, which may optionally be substituted with one or more groups selected from the group consisting of R.sup.4 and Ht; and C.sub.5 -C.sub.6 unsaturated carbocycle, which may optionally be substituted with one or more groups selected from the group consisting of R.sup.4 and Ht; and

each R.sup.4 is independently selected from the group consisting of --OR.sup.2, --C(O)--NHR.sup.2, --S(O).sub.2 --NHR.sup.2, halo, --NR.sup.2 --C(O)--R.sup.2 and --CN.

2. The compound according to claim 1, wherein said compound has the structure of formula XXII: ##STR611## and 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, Ht, R.sup.3, D' and E are defined as in claim 1.

4. The compound according to claim 1, wherein said compound has the structure of formula XXXI: ##STR613## and A, R.sup.3, D' and E are defined as in claim 1.

5. A compound of formula I, wherein:

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

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 Ht is independently selected from the group consisting of C.sub.3 -C.sub.7 cycloalkyl; C.sub.5 -C.sub.7 cycloalkenyl; C.sub.6 -C.sub.10 aryl; and 5-7 membered saturated or unsaturated heterocycle, containing one or more N heteroatom and optionally containing O as an additional heteroatom, which may optionally be benzofused; wherein any member of said Ht may be optionally substituted with one or more 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 or more 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, Ht and --CN;

n is 1 or 2;

D and D' are independently selected from the group consisting of R.sup.7 ; C.sub.1 -C.sub.4 alkyl, which may be optionally substituted with C.sub.3 -C.sub.6 cycloalkyl or R.sup.7 ; C.sub.2 -C.sub.4 alkenyl, which may be optionally substituted with C.sub.3 -C.sub.6 cycloalkyl or R.sup.7 ; C.sub.3 -C.sub.6 cycloalkyl, which may be optionally substituted or fused with R.sup.7 ; and C.sub.5 -C.sub.6 cycloalkenyl, which may be optionally substituted or fused with R.sup.7 ;

R.sup.7 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, N and S, wherein said carbocyclic or heterocyclic ring may be saturated or unsaturated and optionally substituted with one or more 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, --R.sup.2 --OH, --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 Ht; --O--R.sup.3 ; --NR.sup.2 R.sup.5 ; C.sub.1 -C.sub.6 alkyl, which may be optionally substituted with one or more R.sup.4 or Ht; C.sub.2 -C.sub.6 alkenyl, which may be optionally substituted with one or more R.sup.4 or Ht; C.sub.3 -C.sub.6 saturated carbocycle, which may optionally be substituted with one or more R.sup.4 or Ht; and C.sub.5 -C.sub.6 unsaturated carbocycle, which may optionally be substituted with one or more R.sup.4 or Ht;

each R.sup.4 is independently selected from the group consisting of --OR.sup.2, --C(O)--NHR.sup.2, --S(O).sub.2 --NHR.sup.2, halo and --CN; and

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

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

A is R.sup.1 --Ht.sub.A ; 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 or more groups selected from the group consisting of C.sub.3 -C.sub.6 cycloalkyl, --OR.sup.2, --O--R.sup.7 and R.sup.7.

7. 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 or more 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).sub.2 Ht, --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 or more groups selected from the group consisting of C.sub.3 -C.sub.6 cycloalkyl, --OR.sup.2, --O--R.sup.7 and R.sup.7.

8. The compound according to claim 4, wherein:

A is R.sup.1 --Ht.sub.A ;

each R.sup.3 is independently C.sub.1 -C.sub.6 alkyl, which may be optionally substituted with a substituent 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, --CO.sub.2 R.sup.2, --NR.sup.2 --C(O)--R.sup.2 ; and

D' is C.sub.1 -C.sub.4 alkyl, which may be optionally substituted with a group selected from the group consisting of C.sub.3 -C.sub.6 cycloalkyl, --OR.sup.2, --O--R.sup.7 and R.sup.7 ; and

E is selected from the group consisting of Ht, Ht--Ht and --NR.sup.2 R.sup.3.

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

10. A compound according to claim 9, wherein said compound has a molecular weight less than or equal to about 600 g/mol.

11. A pharmaceutical composition effective against viral infection comprising a pharmaceutically effective amount of a compound according to any one of claims 1-4 and a pharmaceutically acceptable carrier, adjuvant or vehicle.

12. The pharmaceutical composition according to claim 11, further comprising an additional anti-viral agent.

13. 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 claims 1-4.

14. The method according to claim 13, wherein said virus is HIV-1, HIV-2, or HTLV.

15. 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 1-4.

16. The method according to claim 15, wherein said aspartyl protease is HIV protease.

17. 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 11.

18. The method according to claim 1, wherein said step of administering comprises oral administration or administration by injection.

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 12.

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