1. A compound represented by Formula I:
or a salt, ester or hydrate thereof, wherein:
X is halo, or X is O\u2014W-Z, wherein W is a bond, \u2014CH2\u2014, (O)\u2014 or (O)CH2\u2014;
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, \u2014S(O)0-2C1-10alkyl or \u2014NHC1-10alkyl, 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) \u2014NHR7, wherein R7 is independently H or C1-5alkyl,
(f) \u2014S(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 \u2014S(O)0-2phenyl,
(8) benzyloxy or \u2014S(O)0-2benzyl,
(9) benzoyl,
(10) phenyl or naphthyl,
(11) \u2014O-HET2 or \u2014HET2, 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) \u2014NHR7, wherein R7 is independently H or C1-5alkyl,
(f) \u2014S(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.
2. The compound according to claim 1 wherein X is halo.
3. The compound according to claim 1 wherein X is \u2014O\u2014W-Z.
4. The compound according to claim 3 wherein Z is selected from the group consisting of:
(1) C1-11alkyl,
(2) C3-11cycloalkyl or a benzofused analog thereof, and
(3) phenyl or naphthyl,
wherein groups (1)-(3) above are 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 and
(k) benzyloxy.
5. The compound according to claim 1 wherein R3 is methyl.
6. The compound according to claim 1 wherein R2 and each R4 are hydrogen.
7. The compound according to claim 1 wherein R5 is selected from the group consisting of: C1-6alkyl, phenyl and naphthyl.
8. The compound according to claim 1 wherein:
X is halo or \u2014O\u2014W-Z;
W is a bond, \u2014CH2\u2014, C(O)\u2014 or \u2014C(O)CH2\u2014;
Z is selected from the group consisting of:
(1) C1-6alkyl, optionally substituted with 1-3 halo groups,
(2) C3-11cycloalkyl or a benzofused analog thereof, and
(3) phenyl or naphthyl, optionally substituted with 1-3 groups independently selected from halo or C1-4alkyl,
R3 is methyl, ethyl or phenyl;
R2 and each R4 are hydrogen;
R5 is selected from the group consisting of: C1-6alkyl, C5-7cycloialkyl, phenyl and naphthyl; and
R6 is hydrogen.
9. 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, \u2014S(O)0-2C1-10alkyl or \u2014NHC1-10alkyl, 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) \u2014NHR7, wherein R7 is independently H or C1-5alkyl,
(f) \u2014S(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 \u2014S(O)0-2phenyl,
(8) benzyloxy or \u2014S(O)0-2benzyl,
(9) benzoyl,
(10) phenyl or naphthyl,
(11) \u2014O-HET2 or \u2014S-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) \u2014NHR7, wherein R7 is independently H or C1-5alkyl,
(f) \u2014S(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.
10. The compound according to claim 9 wherein:
R1 is selected from the group consisting of:
(1) halo,
(2) C1-4alkyl or C1-4alkoxy, each optionally substituted with oxo and 1-3 halo groups, and
(3) 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, and optionally substituted with 1-2 substituents independently selected from halo and C1-4alkyl, said C1-4alkyl being optionally substituted with 1-3 halo groups;
R2 and each R4 are hydrogen;
R5 is selected from the group consisting of: C1-6alkyl, phenyl and naphthyl; and
R6 is hydrogen.
11. The compound according to claim 10 wherein HET3 is 1,2,4-oxadiazole, optionally substituted with C1-4alkyl.
12. A method for detecting active caspase-3 in cells or tissues of a mammal comprising contacting said cells or tissues with a compound of claim 1 and detecting active caspase-3.
13. A method for detecting active caspase-3 in cells or tissues of a mammal comprising contacting said cells or tissues with a compound of claim 9 and detecting active caspase-3.
14. A method for determining the caspase-3 active site occupancy of a sample reversible caspase-3 inhibitor in an animal model of cellular injury comprising:
1) administering to said animal said sample reversible caspase-3 inhibitor;
2) euthanizing said animal and extracting said injured cells;
3) contacting said injured cells ex vivo with a compound according to claim 1;
4) detecting the amount of said compound to determine the number of caspase-3 free active sites; and
5) comparing said number of caspase-3 free active sites to the total measure of active caspases to determine the caspase-3 active site occupancy.
15. A method for determining the caspase-3 active site occupancy of a sample reversible caspase-3 inhibitor in a cell culture comprising:
1) contacting said cell culture with a sample reversible caspase-3 inhibitor;
2) contacting said cell culture with a compound according to claim 1;
3) detecting the amount of said compound to determine the number of caspase-3 free active sites; and
4) comparing said number of caspase-3 free active sites to the total measure of active caspases to determine the caspase-3 active site occupancy.
16. A kit for detecting active caspase-3 in cells or tissues of a mammal comprising a compound of claim 1.
17. A kit for detecting active caspase-3 in cells or tissues of a mammal comprising a compound of claim 9.
18. The compound according to claim 1 which is
or a salt, ester or hydrate thereof.
19. A compound according to claim 1 which is selected from the following table:
or a salt, ester or hydrate of any of the above.
20. A compound of any one of claims 1 to 11, 18 or 19 for use in detecting active caspase-3 in cells or tissues of a mammal.
21. 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.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A gas generating system comprising:
a baffle system for cooling a gas generated by the gas generating system, the baffle system including:
a first enclosure;
a second enclosure spaced apart from a wall of the first enclosure to define a first fluid flow passage between the second enclosure and the wall, the second enclosure defining a baffle chamber therein, the second enclosure including at least one first opening for enabling fluid communication between a gas source and the second enclosure baffle chamber, and at least one second opening for enabling fluid communication between the second enclosure baffle chamber and the first fluid flow passage; and
a third enclosure spaced apart from the wall of the first enclosure to define a second fluid flow passage between the third enclosure and the wall, the second fluid flow passage being in fluid communication with the first fluid flow passage, the third enclosure defining a baffle chamber therein, the third enclosure including at least one first opening for enabling fluid communication between the second fluid flow passage and the third enclosure baffle chamber, and at least one second opening for enabling fluid communication between the third enclosure baffle chamber and an exterior of the gas generating system,
wherein all generated gas flowing to the exterior of the gas generating system is directed through the third enclosure baffle chamber.
2. The gas generating system of claim 1 further comprising a rupturable, fluid-tight seal positioned to seal the at least one second enclosure first opening.
3. The gas generating system of claim 1 further comprising a rupturable, fluid-tight seal positioned to seal the at least one third enclosure second opening.
4. The gas generating system of claim 1 wherein the third enclosure is positioned adjacent the second enclosure.
5. The gas generating system of claim 1 wherein the second enclosure and the third enclosure from a single structure.
6. The gas generating system of claim 1 wherein the third enclosure abuts the second enclosure.
7. The gas generating system of claim 1 wherein the second fluid flow passage is contiguous with the first fluid flow passage.
8. The gas generating system of claim 1 wherein the gas source is a gas generant combustion chamber and the gas generating system further includes a barrier separating the second enclosure baffle chamber from the combustion chamber.
9. The gas generating system of claim 1 wherein the gas source is a gas generant combustion chamber and the gas generating system further includes a barrier separating the first fluid flow passage from the combustion chamber.
10. The gas generating system of claim 1 wherein the third enclosure is positioned adjacent the second enclosure along a longitudinal dimension of the gas generating system.
11. The gas generating system of claim 1 further comprising a gas generant composition and a barrier separating the first fluid flow passage from the gas generant composition.
12. The gas generating system of claim 11 wherein the gas generant composition is a smokeless gas generant composition.
13. The gas generating system of claim 1 further comprising a fourth enclosure spaced apart from a wall of the first enclosure to define a third fluid flow passage between the fourth enclosure and the wall, the fourth enclosure defining a baffle chamber therein, the fourth enclosure including at least one opening for enabling fluid communication between the third enclosure baffle chamber and the fourth enclosure baffle chamber; and
at least one opening for enabling fluid communication between the fourth enclosure baffle chamber and the third fluid flow passage,
wherein the third fluid flow passage is not in fluid communication with the second fluid flow passage, and the third fluid flow passage is in fluid communication with the exterior of the gas generating system.
14. The gas generating system of claim 13 further comprising a fifth enclosure spaced apart from a wall of the first enclosure to define a fourth fluid flow passage between the fifth enclosure and the wall, the fourth fluid flow passage being in fluid communication with the third fluid flow passage, the fifth enclosure defining a baffle chamber therein, the fifth enclosure including at least one opening for enabling fluid communication between the fourth fluid flow passage and the fifth enclosure baffle chamber, and
at least one opening for enabling fluid communication between the fifth enclosure baffle chamber and the exterior of the gas generating system.
15. The gas generating system of claim 14 wherein the fourth fluid flow passage is contiguous with the third fluid flow passage.
16. The gas generating system of claim 1 further comprising:
a gas generant composition;
an ignition source for igniting the gas generant composition upon activation of the gas generating system; and
a barrier positioned between the gas generant composition and the ignition source, the barrier including an orifice to enable fluid communication between the ignition source and the gas generant composition, the orifice defining a Venturi tube.