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Details for Patent: 6,392,046

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Details for Patent: 6,392,046

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 Rao (Lexington, MA)
Assignee: Vertex Pharmaceuticals, Inc. (Cambridge, MA)
Filing Date:Sep 30, 1999
Application Number:09/409,808
Claims:1. A compound of formula ##STR655##

wherein:

A is selected from the group consisting of H; Ht.sub.A ; --R.sup.1 --Ht.sub.A ; --R.sup.1 --C.sub.1 -C.sub.6 alkyl, which is optionally substituted with one or more groups independently selected from the group consisting of hydroxy, C.sub.1 -C.sub.4 alkoxy, Ht.sub.A, --O--Ht.sub.A, --NR.sup.2 --CO--N(R.sup.2)(R.sup.2) and --CO--N(R.sup.2)(R.sup.2); and --R.sup.1 --C.sub.2 -C.sub.6 alkenyl, which is optionally substituted with one or more groups independently selected from the group consisting of hydroxy, C.sub.1 -C.sub.4 alkoxy, Ht.sub.A, --O--Ht.sub.A, --NR.sup.2 --CO--N(R.sup.2)(R.sup.2) and --CO--N(R.sup.2)(R.sup.2);

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.sub.A 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 or N(R.sup.2), and optionally containing O, wherein said heterocycle is optionally benzofused; and wherein any member of said Ht.sub.A is optionally substituted with one or more substituents independently 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 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), O, S and S(O).sub.n, wherein said heterocycle is optionally be benzofused; and wherein any member of said Ht is optionally substituted with one or more substituents independently 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 is not substituted with an R7-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, is optionally substituted with one or more substituents independently 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, substituted with one or more groups independently selected from --O--R.sup.7 and R.sup.7 ; C.sub.2 -C.sub.4 alkenyl, substituted with one or more groups independently selected from the group consisting of --O--R.sup.7 and R.sup.7 ; C.sub.3 -C.sub.6 cycloalkyl, substituted with or fused with R.sup.7 ; and C.sub.5 -C.sub.6 cycloalkenyl, substituted with or fused with R.sup.7 ;

each R.sup.7 is independently selected from 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 heterocyclic ring is saturated or unsaturated and optionally substituted with one or more groups independently 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 is optionally substituted with one or more groups independently selected from the group consisting of R.sup.4 and Ht; C.sub.2 -C.sub.6 alkenyl, which is optionally substituted with one or more groups independently selected from the group consisting of R.sup.4 and Ht; C.sub.3 -C.sub.6 saturated carbocycle, which is optionally substituted with one or more groups independently selected from the group consisting of R.sup.4 and Ht; and C.sub.5 -C.sub.6 unsaturated carbocycle, which is optionally substituted with one or more groups independently 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: ##STR656##

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: ##STR657##

wherein x, Ht.sub.A, 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: ##STR658##

wherein A, R.sup.3, D' and E are defined as in claim 1.

5. A compound according to claim 1, wherein:

A is selected from the group consisting of H; --R.sup.1 --Ht.sub.A ; --R.sup.1 --C.sub.1 -C.sub.6 alkyl, which is optionally substituted with one or more groups independently selected from the group consisting of hydroxy, C.sub.1 -C.sub.4 alkoxy, Ht.sub.A and --O--Ht.sub.A ; and --R.sup.1 --C.sub.2 -C.sub.6 alkenyl, which is optionally substituted with one or more groups independently selected from hydroxy, C.sub.1 -C.sub.4 alkoxy, 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.sub.A 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, wherein said heterocycle is optionally benzofused; and wherein any member of said Ht.sub.A is optionally substituted with one or more substituents independently 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 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, O and S, which is optionally benzofused; wherein any member of said Ht is optionally substituted with one or more substituents independently 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 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 is optionally substituted with one or more substituents independently 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, substituted with R.sup.7 ; C.sub.2 -C.sub.4 alkenyl, substituted with R.sup.7 ; C.sub.3 -C.sub.6 cycloalkyl, substituted or fused with R.sup.7 ; and C.sub.5 -C.sub.6 cycloalkenyl, substituted or fused with R.sup.7 ;

R.sup.7 is selected from the group consisting of 5-6 membered heterocyclic ring containing one or more heteroatoms selected from O, N and S, wherein said heterocyclic ring is saturated or unsaturated and optionally substituted with one or more groups independently 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 R.sup.7, --CN, --CO.sub.2 R.sup.2, --C(O)--N(R.sub.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 is optionally substituted with one or more R.sup.4 or Ht; C.sub.2 -C.sub.6 alkenyl, which is optionally substituted with one or more R.sup.4 or Ht; C.sub.3 -C.sub.6 saturated carbocycle, which is optionally substituted with one or more R.sup.4 or Ht; and C.sub.5 -C.sub.6 unsaturated carbocycle, which is optionally 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, with the proviso that at least one R.sup.5 is not H.

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

A is R.sup.1 --Ht; 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 is substituted with one or more groups independently selected from the group consisting of --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 is optionally substituted with one or more substituents independently 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, --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 is substituted with one or more groups independently selected from the group consisting of C.sub.3 -C.sub.6 cycloalkyl, --OR.sup.2, --O--Ar and Ar.

8. The compound according to claim 4, 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 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 is substituted with a group independently selected from the group consisting of --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. The compound according to claim 11, 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 using of a compound according to any one of claims 1-4 as a therapeutic agent against viral infection, said virus requiring an aspartyl protease for an obligatory life cycle event.

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

15. A method for inhibiting enzymatic activity of an aspartyl protease comprising the step of administering 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 preventing 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 or 12.

18. 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 or 12.

19. The method according to claim 17 or 18, wherein said step of administering comprises oral administration or administration by injection.
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