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US 2006/0069038 A1Published application
Irreversible caspase-3 inhibitors as active site probes
OwnerJohn Colucci, Andre Giroux +6inventors
InventorsJohn Colucci, Andre Giroux, Yongxin Han, Nathalie Methot, Donald Nicholson, Sophie Roy, John Vaillancourt, Paul Tawa
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Abstract
The present invention encompasses a compound of Formula (I) useful as caspase active site probes. These probes can be used to determine whether a caspase has been activated, in cells or in tissues of animal models of various pathologies. Furthermore, through competition based assays, these caspase active site probes can be used to calculate the percentage of occupancy of active caspases by other, unlabeled inhibitors.
Claims21
A compound represented by Formula I:
- or a salt, ester or hydrate thereof, wherein:
- X is halo, or X is O—W-Z, wherein W is a bond, —CH2—, (O)— or (O)CH2—;
- Z is selected from the group consisting of:
- (1) H,
- (2) C1-11alkyl,
- (3) C3-11cycloalkyl or a benzofused analog thereof,
- (4) phenyl or naphthyl, and
- (5) HET1, wherein HET1 represents a 5- to 10-membered mono- or bicyclic, aromatic or non-aromatic ring, or a benzofused analog thereof, containing 1-3 heteroatoms selected from O, S and N,
- groups (2), (3) and (5) above are optionally substituted with 1-2 oxo groups,
- groups (2)-(5) above are further optionally substituted with 1-3 substituents independently selected from the group consisting of:
- (a) halo
- (b) nitro,
- (c) hydroxy,
- (d) C1-4alkyl,
- (e) C1-4alkoxy,
- (f) C1-4alkylthio,
- (g) C3-6cycloalkyl,
- (h) phenyl or naphthyl,
- (i) phenoxy,
- (j) benzyl,
- k) benzyloxy, and
- (l) a 5 or 6-membered aromatic or non-aromatic ring containing from 1-3 heteroatoms selected from O, S and N,
- groups (d)-(g) above are optionally substituted with oxo and 1-3 substituents independently selected from halo and C1-4alkoxy,
- groups (h)-(l) above are optionally substituted with 1-3 substituents independently selected from halo and C1-4alkyl, and
- group (4) is further optionally substituted up to its maximum with halo groups;
- R2 is selected from the group consisting of:
- (1) H,
- (2) halo,
- (3) hydroxy,
- (4) nitro,
- (5) cyano,
- (6) C1-10alkyl, C3-10cycloalkyl, C1-10alkoxy, —S(O)0-2C1-10alkyl or —NHC1-10alkyl, each optionally substituted with 1-2 oxo or carboxy groups and further optionally substituted with 1-3 substituents independently selected from the group consisting of:
- (a) halo,
- (b) hydroxy
- (c) cyano,
- (d) C1-4alkoxy,
- (e) —NHR7, wherein R7 is independently H or C1-5alkyl,
- (f) —S(O)0-2C1-4alkyl, and
- (g) HET2, wherein HET2 represents a 5- to 7-membered aromatic or non-aromatic ring containing 14 heteroatoms selected from O, S and NR8, wherein R8 is independently H or C1-5alkyl, said HET2 being optionally substituted with oxo and further optionally substituted with 1-2 substituents independently selected from halo and C1-4alkyl, said C1-4alkyl being optionally substituted with 1-3 halo groups,
- (7) phenoxy or —S(O)0-2phenyl,
- (8) benzyloxy or —S(O)0-2benzyl,
- (9) benzoyl,
- (10) phenyl or naphthyl,
- (11) —O-HET2 or —HET2, said HET2 being optionally substituted with oxo and further optionally substituted as defined below, and
- (12) HET3, wherein HET3 is a 5- or 6-membered aromatic or non-aromatic ring, or a benzofused analog thereof, containing from 1 to 4 heteroatoms selected from O, S and N, said HET3 being optionally substituted with oxo and further optionally substituted as defined below,
- groups (7)-(12) above are each optionally substituted with 1-2 substituents independently selected from the group consisting of:
- halo, cyano, C1-4alkyl and C1-4alkoxy, said C1-4alkyl and C1-4alkoxy being optionally substituted with 1-3 halo groups;
- R3 is phenyl or C1-10alkyl, said C1-10alkyl optionally substituted with 1-2 oxo or carboxy groups and further optionally substituted with 1-3 substituents independently selected from the group consisting of:
- (a) halo,
- (b) hydroxy
- (c) cyano,
- (d) C1-4alkoxy,
- (e) —NHR7, wherein R7 is independently H or C1-5alkyl,
- (f) —S(O)0-2C1-4alkyl, and
- (g) HET2, wherein HET2 represents a 5- to 7-membered aromatic or non-aromatic ring containing 1-4 heteroatoms selected from O, S and NR8, wherein R8 is independently H or C1-5alkyl, said HET2 being optionally substituted with oxo and further optionally substituted with 1-2 substituents independently selected from halo or C1-4alkyl, said C1-4alkyl being optionally substituted with 1-3 halo groups,
- each R4 is independently selected from the group consisting of:
- H, halo, hydroxy, C1-6alkyl and C1-4alkoxy, said C1-6alkyl and C1-4alkoxy being optionally substituted with oxo and further optionally substituted with 1-3 halo groups;
- and
- R5 is selected from the group consisting of:
- H, phenyl, naphthyl, C1-6alkyl optionally substituted with OR12 and 1-3 halo groups, and C5-7 cycloalkyl optionally containing one heteroatom selected from O, S and NR13,
- wherein R12 is selected from the group consisting of:
- H, C1-5alkyl optionally substituted with 1-3 halo groups, and benzyl optionally substituted with 1-3 substituents independently selected from halo, C1-4alkyl and C1-4alkoxy, and R13 is H or C1-4alkyl optionally substituted with 1-3 halo groups;
- and
- R6 represents H;
- or in the alternative, R5 and R6 are taken in combination and represent a ring of 4-7 members, said ring optionally containing one heteroatom selected from O, S and NR13.
62 more elements
A compound of Formula II
- or a salt, ester or hydrate thereof, wherein:
- X is halo;
- R1 and R2 are each independently selected from the group consisting of:
- (1) H,
- (2) halo,
- (3) hydroxy,
- (4) nitro,
- (5) cyano,
- (6) C1-10alkyl, C3-10cycloalkyl, C1-10alkoxy, —S(O)0-2C1-10alkyl or —NHC1-10alkyl, each optionally substituted with 1-2 oxo or carboxy groups and further optionally substituted with 1-3 substituents independently selected from the group consisting of:
- (a) halo,
- (b) hydroxy
- (c) cyano,
- (d) C1-4alkoxy,
- (e) —NHR7, wherein R7 is independently H or C1-5alkyl,
- (f) —S(O)0-2C1-4alkyl, and
- (g) HET2, wherein HET2 represents a 5- to 7-membered aromatic or non-aromatic ring containing 14 heteroatoms selected from O, S and NR8, wherein R8 is independently H or C1-5alkyl, said HET2 being optionally substituted with oxo and further optionally substituted with 1-2 substituents independently selected from halo and C1-4alkyl, said C1-4alkyl being optionally substituted with 1-3 halo groups,
- (7) phenoxy or —S(O)0-2phenyl,
- (8) benzyloxy or —S(O)0-2benzyl,
- (9) benzoyl,
- (10) phenyl or naphthyl,
- (11) —O-HET2 or —S-HET2, said HET2 being optionally substituted with oxo and further optionally substituted as defined below, and
- (12) HET3, wherein HET3 is a 5- or 6-membered aromatic or non-aromatic ring, or a benzofused analog thereof, containing from 1 to 4 heteroatoms selected from O, S and N, said HET3 being optionally substituted with oxo and further optionally substituted as defined below,
- groups (7)-(12) above are each optionally substituted with 1-2 substituents independently selected from the group consisting of:
- halo, cyano, C1-4alkyl and C1-4alkoxy, said C1-4alkyl and C1-4alkoxy being optionally substituted with 1-3 halo groups;
- R3 is C1-10alkyl, optionally substituted with 1-2 oxo or carboxy groups and further optionally substituted with 1-3 substituents independently selected from the group consisting of:
- (a) halo,
- (b) hydroxy
- (c) cyano,
- (d) C1-4alkoxy,
- (e) —NHR7, wherein R7 is independently H or C1-5alkyl,
- (f) —S(O)0-2C1-4alkyl, and
- (g) HET2, wherein HET2 represents a 5- to 7-membered aromatic or non-aromatic ring containing 14 heteroatoms selected from O, S and NR8, wherein R8 is independently H or C1-5alkyl, said HET2 being optionally substituted with oxo and further optionally substituted with 1-2 substituents independently selected from halo or C1-4alkyl, said C1-4alkyl being optionally substituted with 1-3 halo groups,
- each R4 is independently selected from the group consisting of:
- H, halo, hydroxy, C1-6alkyl and C1-4alkoxy, said C1-6alkyl and C1-4alkoxy being optionally substituted with oxo and further optionally substituted with 1-3 halo groups;
- and
- R5 is selected from the group consisting of:
- H, phenyl, naphthyl, C1-6alkyl optionally substituted with OR12 and 1-3 halo groups, and C5-7 cycloalkyl optionally containing one heteroatom selected from O, S and NR13,
- wherein R12 is selected from the group consisting of:
- H, C1-5alkyl optionally substituted with 1-3 halo groups, and benzyl optionally substituted with 1-3 substituents independently selected from halo, C1-4alkyl and C1-4alkoxy, and
- R13 is H or C1-4alkyl optionally substituted with 1-3 halo groups;
- and
- R6 represents H;
- or in the alternative, R5 and R6 are taken in combination and represent a ring of 47 members, said ring optionally containing one heteroatom selected from O, S and NR13.
40 more elements
A compound of any one of clams 1 to 11, 18 or 19 for use in determining the caspase-3 active site occupancy of a sample reversible capase-3 inhibitor in an animal model of cellular injury.
Dependencies are inferred from the claim text.