US2004063785A1PendingUtilityA1
Symmetrically disubstituted aromatic compounds and pharmaceutical compositions for inhibiting poly (ADP-ribose) glycohydrolase, and methods for their use
Est. expiryJan 16, 2021(expired)· nominal 20-yr term from priority
A61P 3/10A61P 9/10A61P 37/04A61P 9/00A61P 43/00A61P 7/00A61P 27/02A61P 29/00A61P 25/02A61P 3/00A61P 31/04A61P 25/00A61P 19/02C07C 2603/40C07C 2601/14A61P 17/02C07C 225/16C07D 207/325A61P 19/00C07D 327/08A61P 1/00A61P 21/00C07D 311/86C07D 295/192C07C 2603/18C07C 233/73C07C 69/76C07C 233/69A61P 19/10C07D 311/82C07C 311/46A61P 17/00A61P 21/04C07C 255/46A61P 13/00C07C 233/65C07D 213/40A61P 1/04C07D 213/30C07D 411/12C07D 295/13A61P 13/12C07C 233/66
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Claims
Abstract
Symmetrically disubstituted aromatic compounds and pharmaceutical compositions containing such compounds that inhibit and/or modulate the activity of poly(ADP-ribose) glycohydrolase, also known as PARG, are described. The invention is also directed to the therapeutic or prophylactic use of such compounds and compositions, and to methods of treating diseases and disorders described herein, by administering effective amounts of such compounds.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of the Formula I:
wherein:
A is CH 2 , O, or S;
n is 0 to 4; and
Y is hydrogen, or a substituted or unsubstituted cycloalkyl, aryl, or heteroaryl, or N(R 1 )(R 2 ), wherein R 1 and R 2 are independently hydrogen, a substituted or unsubstituted lower alkyl, lower alkenyl, heterocycloalkyl, alkoxy, aryloxy, alkylamino, arylamino, or R 1 and R 2 are taken together to form a substituted or unsubstituted five to seven membered heterocyclic ring that contains 1-3 heteroatoms of O, N, or S;
or a pharmaceutically acceptable prodrug of said compound, pharmaceutically active metabolite of said compound, or pharmaceutically acceptable salt of said compound or metabolite.
2 . A compound, prodrug, metabolite, or salt according to claim 1 , wherein:
A is 0; n is 0-4; and Y is a substituted or unsubstituted aryl.
3 . A compound, prodrug, metabolite, or salt according to claim 2 selected from:
4 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula I:
wherein:
A is CH 2 , O, or S;
n is 0 to 4; and
Y is hydrogen, or a substituted or unsubstituted cycloalkyl, aryl, or heteroaryl, or N(R 1 )(R 2 ), wherein R 1 and R 2 are independently hydrogen, a substituted or unsubstituted lower alkyl, lower alkenyl, heterocycloalkyl, alkoxy, aryloxy, alkylamino, arylamino, or R 1 and R 2 are taken together to form a substituted or unsubstituted five to seven membered heterocyclic ring that contains 1-3 heteroatoms of O, N, or S;
or a pharmaceutically acceptable prodrug of said compound, pharmaceutically active metabolite of said compound, or pharmaceutically acceptable salt of said compound or metabolite.
5 . The pharmaceutical composition according to claim 4 , wherein: A is 0; n is 0-4; and Y is a substituted or unsubstituted aryl.
6 . The pharmaceutical composition according to claim 5 , wherein the compound is selected from:
7 . The composition according to claim 4 , wherein said composition is administered as a sterile solution, suspension or emulsion, in a single or divided dose.
8 . The composition according to claim 4 , wherein said composition is administered as a capsule or tablet containing a single or divided dose of said compound.
9 . The composition according to claim 4 , wherein the composition is a solid implant.
10 . The composition according to claim 4 , wherein the carrier comprises a biodegradable polymer.
11 . The composition according to claim 10 , wherein the biodegradable polymer releases the compound of formula I over a prolonged time.
12 . A method of modulating or inhibiting PARG by administering a compound of Formula I according to claim 1 , or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt of such compound or metabolite thereof, to treat diseases and disorders selected from acute pain, arthritis, atherosclerosis, cachexia, cardiovascular disorders, chronic pain, degenerative diseases, diabetes, head trauma, hyperglycemia, immune senescence, inflammatory bowel disorders, ischemia, macular degeneration, muscular dystrophy, tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases, neuronal tissue damage or disease, neuropathic pain, nervous insult, osteoarthritis, osteoporosis, peripheral nerve injury, renal failure, resuscitated hemorrhagic shock, retinal ischemia, septic shock, skin aging, vascular stroke, diseases or disorders relating to lifespan or proliferative capacity of cells, and diseases or disease conditions induced or exacerbated by cellular senescence.
13 . The method according to claim 12 wherein the diseases or conditions are selected from diabetes, head trauma, inflammatory bowel disorders, ischemia, tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases, neuronal tissue damage disease, neuropathic pain, nervous insult, peripheral nerve injury, retinal ischemia, vascular stroke, and diseases or disorders relating to lifespan or proliferative capacity of cells.
14 . The method according to claim 13 wherein the disease or condition is tissue damage resulting from ischemia and reperfusion injury.
15 . A compound of Formula II
wherein:
x is C═O, CH 2 , or C(Cl) 2 ;
n is 0 to 4; and
Y is hydrogen, or a substituted or unsubstituted cycloalkyl, aryl, or heteroaryl, or N(R 1 )(R 2 ), wherein R 1 and R 2 are independently hydrogen, a substituted or unsubstituted lower alkyl, lower alkenyl, heterocycloalkyl, alkoxy, aryloxy, alkylamino, arylamino, or R 1 and R 2 are taken together to form a substituted or unsubstituted five to seven membered heterocyclic ring that contains 1-3 heteroatoms of O, N, or S;
or a pharmaceutically acceptable prodrug of said compound, pharmaceutically active metabolite of said compound, or pharmaceutically acceptable salt of said compound or metabolite.
16 . A compound, prodrug, metabolite, or salt according to claim 15 , wherein:
x is C═O or C(Cl) 2 ; n is 0 to 4; and Y is a substituted or unsubstituted aryl.
17 . A compound, prodrug, metabolite, or salt according to claim 16 selected from:
18 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula II:
wherein:
x is C═O, CH 2 , or C(Cl) 2 ;
n is 0 to 4; and
Y is hydrogen, or a substituted or unsubstituted cycloalkyl, aryl, or heteroaryl, or N(R 1 )(R 2 ), wherein R 1 and R 2 are independently hydrogen, a substituted or unsubstituted lower alkyl, lower alkenyl, heterocycloalkyl, alkoxy, aryloxy, alkylamino, arylamino, or R 1 and R 2 are taken together to form a substituted or unsubstituted five to seven membered heterocyclic ring that contains 1-3 heteroatoms of O, N, or S;
or a pharmaceutically acceptable prodrug of said compound, pharmaceutically active metabolite of said compound, or pharmaceutically acceptable salt of said compound or metabolite.
19 . The pharmaceutical composition according to claim 18 , wherein: x is C═O or C(Cl) 2 ; n is 0 to 4; and Y is a substituted or unsubstituted aryl.
20 . The pharmaceutical composition according to claim 19 selected from:
21 . The composition according to claim 18 , wherein said composition is administered as a sterile solution, suspension or emulsion, in a single or divided dose.
22 . The composition according to claim 18 , wherein said composition is administered as a capsule or tablet containing a single or divided dose of said compound.
23 . The composition according to claim 18 , wherein the composition is a solid implant.
24 . The composition according to claim 18 , wherein the carrier comprises a biodegradable polymer.
25 . The composition according to claim 24 , wherein the biodegradable polymer releases the compound of formula II over a prolonged time.
26 . A method of modulating or inhibiting PARG by administering a compound of Formula II according to claim 15 , or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt of such compound or metabolite thereof, to treat diseases and disorders selected from acute pain, arthritis, atherosclerosis, cachexia, cardiovascular disorders, chronic pain, degenerative diseases, diabetes, head trauma, hyperglycemia, immune senescence, inflammatory bowel disorders, ischemia, macular degeneration, muscular dystrophy, tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases, neuronal tissue damage or disease, neuropathic pain, nervous insult, osteoarthritis, osteoporosis, peripheral nerve injury, renal failure, resuscitated hemorrhagic shock, retinal ischemia, septic shock, skin aging, vascular stroke, diseases or disorders relating to lifespan or proliferative capacity of cells, and diseases or disease conditions induced or exacerbated by cellular senescence.
27 . The method according to claim 26 wherein the diseases or conditions are selected from diabetes, head trauma, inflammatory bowel disorders, ischemia, tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases, neuronal tissue damage disease, neuropathic pain, nervous insult, peripheral nerve injury, retinal ischemia, vascular stroke, and diseases or disorders relating to lifespan or proliferative capacity of cells.
28 . The method according to claim 27 wherein the disease or condition is tissue damage resulting from ischemia and reperfusion injury.
29 . A method of treating or preventing diseases or conditions resulting from cell damage or death comprising administering to an animal a therapeutically effective amount of a compound of Formula II according to claim 15 , or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt thereof.
30 . The method according to claim 29 wherein the diseases or conditions are selected from acute pain, arthritis, atherosclerosis, cachexia, cardiovascular disorders, chronic pain, degenerative diseases, diabetes, head trauma, hyperglycemia, immune senescence, inflammatory bowel disorders, ischemia, macular degeneration, muscular dystrophy, tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases, neuronal tissue damage or disease, neuropathic pain, nervous insult, osteoarthritis, osteoporosis, peripheral nerve injury, renal failure, resuscitated hemorrhagic shock, retinal ischemia, septic shock, skin aging, vascular stroke, diseases or disorders relating to lifespan or proliferative capacity of cells, and diseases or disease conditions induced or exacerbated by cellular senescence.
31 . The method according to claim 30 wherein the diseases or conditions are selected from diabetes, head trauma, inflammatory bowel disorders, ischemia, tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases, neuronal tissue damage disease, neuropathic pain, nervous insult, peripheral nerve injury, retinal ischemia, vascular stroke, and diseases or disorders relating to lifespan or proliferative capacity of cells.
32 . The method according to claim 31 wherein the disease or condition is tissue damage resulting from ischemia and reperfusion injury.
33 . A compound of the Formula III:
wherein:
n is 0 to 4; and
Y is hydrogen, or a substituted or unsubstituted cycloalkyl, aryl, or heteroaryl, or N(R 1 )(R 2 ), wherein R 1 and R 2 are independently hydrogen, a substituted or unsubstituted lower alkyl, lower alkenyl, heterocycloalkyl, alkoxy, aryloxy, alkylamino, arylamino, or R 1 and R 2 are taken together to form a substituted or unsubtituted five to seven membered heterocyclic ring that contains 1-3 heteroatoms of O, N, or S;
or a pharmaceutically acceptable prodrug of said compound, pharmaceutically active metabolite of said compound, or pharmaceutically acceptable salt of said compound or metabolite.
34 . A compound, prodrug, metabolite, or salt according to claim 33 , wherein:
n is 0 to 4; and Y is a substituted or unsubstituted cycloalkyl, aryl, or heteroaryl, or N(R 1 )(R 2 ), wherein R 1 and R 2 are taken together to form a substituted or unsubstituted five or six membered heterocyclic ring that contains 1-3 heteroatoms of O, N, or S.
35 . A compound, prodrug, metabolite, or salt according to claim 34 selected from:
36 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula III:
wherein:
n is 0 to 4; and Y is hydrogen, or a substituted or unsubstituted cycloalkyl, aryl, or heteroaryl, or N(R 1 )(R 2 ), wherein R 1 and R 2 are independently hydrogen, a substituted or unsubstituted lower alkyl, lower alkenyl, heterocycloalkyl, alkoxy, aryloxy, alkylamino, arylamino, or R 1 and R 2 are taken together to form a substituted or unsubtituted five to seven membered heterocyclic ring that contains 1-3 heteroatoms of O, N, or S;
or a pharmaceutically acceptable prodrug of said compound, pharmaceutically active metabolite of said compound, or pharmaceutically acceptable salt of said compound or metabolite.
37 . The pharmaceutical composition according to claim 36 , wherein: n is 0 to 4;
and Y is a substituted or unsubstituted cycloalkyl, aryl, or heteroaryl, or N(R 1 )(R 2 ), wherein R 1 and R 2 are taken together to form a substituted or unsubstituted five or six membered heterocyclic ring that contains 1-3 heteroatoms of O, N, or S.
38 . The pharmaceutical composition according to claim 37 selected from:
39 . The composition according to claim 36 , wherein said composition is administered as a sterile solution, suspension or emulsion, in a single or divided dose.
40 . The composition according to claim 36 , wherein said composition is administered as a capsule or tablet containing a single or divided dose of said compound.
41 . The composition according to claim 36 , wherein the composition is a solid implant.
42 . The composition according to claim 36 , wherein the carrier comprises a biodegradable polymer.
43 . The composition according to claim 42 , wherein the biodegradable polymer releases the compound of formula III over a prolonged time.
44 . A method of modulating or inhibiting PARG by administering a compound of Formula III according to claim 33 , or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt of such compound or metabolite thereof, to treat diseases and disorders selected from acute pain, arthritis, atherosclerosis, cachexia, cardiovascular disorders, chronic pain, degenerative diseases, diabetes, head trauma, hyperglycemia, immune senescence, inflammatory bowel disorders, ischemia, macular degeneration, muscular dystrophy, tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases, neuronal tissue damage or disease, neuropathic pain, nervous insult, osteoarthritis, osteoporosis, peripheral nerve injury, renal failure, resuscitated hemorrhagic shock, retinal ischemia, septic shock, skin aging, vascular stroke, diseases or disorders relating to lifespan or proliferative capacity of cells, and diseases or disease conditions induced or exacerbated by cellular senescence.
45 . The method according to claim 44 wherein the diseases or conditions are selected from diabetes, head trauma, inflammatory bowel disorders, ischemia, tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases, neuronal tissue damage disease, neuropathic pain, nervous insult, peripheral nerve injury, retinal ischemia, vascular stroke, and diseases or disorders relating to lifespan or proliferative capacity of cells.
46 . The method according to claim 45 wherein the disease or condition is tissue damage resulting from ischemia and reperfusion injury.
47 . A compound of the Formula IV:
wherein:
n is 0 to 4;
A is CH 2 , O, or S; and
Z is a substituted or unsubstituted aryl or heteroaryl, or N(R 3 )(R 4 ), wherein R 3 is a substituted or unsubstituted aryl or heteroaryl, and R 4 is hydrogen, a substituted or unsubstituted lower alkyl, lower alkenyl, heterocycloalkyl, alkoxy, aryloxy, alkylamino, arylamino, or R 3 and R 4 are taken together to form a substituted or unsubstituted five to six membered aromatic ring;
or a pharmaceutically acceptable prodrug of said compound, pharmaceutically active metabolite of said compound, or pharmaceutically acceptable salt of said compound or metabolite.
48 . A compound, prodrug, metabolite, or salt according to claim 47 , wherein:
n is 1 to 3; A is CH 2 or 0; and Z is a substituted or unsubstituted aryl or heteroaryl, or N(R 3 )(R 4 ), wherein R 3 is a substituted or unsubstituted aryl or heteroaryl, and R 4 is a substituted or unsubstituted lower alkyl, or R 3 and R 4 are taken together to form a substituted or unsubstituted five to six membered aromatic ring.
49 . A compound, prodrug, metabolite, or salt according to claim 48 selected from:
50 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula IV:
wherein:
n is 0 to 4;
A is CH 2 , O, or S; and
Z is a substituted or unsubstituted aryl or heteroaryl, or N(R 3 )(R 4 ), wherein R 3 is a substituted or unsubstituted aryl or heteroaryl, and R 4 is hydrogen, a substituted or unsubstituted lower alkyl, lower alkenyl, heterocycloalkyl, alkoxy, aryloxy, alkylamino, arylamino, or R 3 and R 4 are taken together to form a substituted or unsubstituted five to six membered aromatic ring;
or a pharmaceutically acceptable prodrug of said compound, pharmaceutically active metabolite of said compound, or pharmaceutically acceptable salt of said compound or metabolite.
51 . The pharmaceutical composition according to claim 50 , wherein: n is 1 to 3; A is CH 2 or 0; and Z is a substituted or unsubstituted aryl or heteroaryl, or N(R 3 )(R 4 ), wherein R 3 is a substituted or unsubstituted aryl or heteroaryl, and R 4 is a substituted or unsubstituted lower alkyl, or R 3 and R 4 are taken together to form a substituted or unsubstituted five to six membered aromatic ring.
52 . The pharmaceutical composition according to claim 51 , wherein the compound is selected from:
53 . The composition according to claim 50 , wherein said composition is administered as a sterile solution, suspension or emulsion, in a single or divided dose.
54 . The composition according to claim 50 , wherein said composition is administered as a capsule or tablet containing a single or divided dose of said compound.
55 . The composition according to claim 50 , wherein the composition is a solid implant.
56 . The composition according to claim 50 , wherein the carrier comprises a biodegradable polymer.
57 . The composition according to claim 56 , wherein the biodegradable polymer releases the compound of formula IV over a prolonged time.
58 . A method of modulating or inhibiting PARG by administering a compound of Formula IV according to claim 47 , or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt of such compound or metabolite thereof, to treat diseases and disorders selected from acute pain, arthritis, atherosclerosis, cachexia, cardiovascular disorders, chronic pain, degenerative diseases, diabetes, head trauma, hyperglycemia, immune senescence, inflammatory bowel disorders, ischemia, macular degeneration, muscular dystrophy, tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases, neuronal tissue damage or disease, neuropathic pain, nervous insult, osteoarthritis, osteoporosis, peripheral nerve injury, renal failure, resuscitated hemorrhagic shock, retinal ischemia, septic shock, skin aging, vascular stroke, diseases or disorders relating to lifespan or proliferative capacity of cells, and diseases or disease conditions induced or exacerbated by cellular senescence.
59 . The method according to claim 58 wherein the diseases or conditions are selected from diabetes, head trauma, inflammatory bowel disorders, ischemia, tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases, neuronal tissue damage disease, neuropathic pain, nervous insult, peripheral nerve injury, retinal ischemia, vascular stroke, and diseases or disorders relating to lifespan or proliferative capacity of cells.
60 . The method according to claim 59 wherein the disease or condition is tissue damage resulting from ischemia and reperfusion injury.
61 . A compound of the Formula V:
wherein:
x is C═O, CH 2 , or C(Cl) 2 ;
n is 0 to 4; and
Q is a substituted or unsubstituted aryl or heteroaryl;
or a pharmaceutically acceptable prodrug of said compound, pharmaceutically active metabolite of said compound, or pharmaceutically acceptable salt of said compound or metabolite.
62 . A compound, prodrug, metabolite, or salt according to claim 61 , wherein: n is 2; x is C═O or CH 2 ; and Q is a substituted or unsubstituted aryl.
63 . A compound, prodrug, metabolite, or salt according to claim 62 selected from:
64 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula V:
wherein:
x is C═O, CH 2 , or C(Cl) 2 ;
n is 0 to 4; and
Q is a substituted or unsubstituted aryl or heteroaryl;
or a pharmaceutically acceptable prodrug of said compound, pharmaceutically active metabolite of said compound, or pharmaceutically acceptable salt of said compound or metabolite.
65 . The pharmaceutical composition according to claim 64 wherein: n is 2; x is C═O or CH 2 ; and Q is a substituted or unsubstituted aryl.
66 . The pharmaceutical composition according to claim 65 selected from:
67 . The composition according to claim 64 , wherein said composition is administered as a sterile solution, suspension or emulsion, in a single or divided dose.
68 . The composition according to claim 64 , wherein said composition is administered as a capsule or tablet containing a single or divided dose of said compound.
69 . The composition according to claim 64 , wherein the composition is a solid implant.
70 . The composition according to claim 64 , wherein the carrier comprises a biodegradable polymer.
71 . The composition according to claim 70 , wherein the biodegradable polymer releases the compound of formula V over a prolonged time.
72 . A method of modulating or inhibiting PARG by administering a compound of Formula V according to claim 61 , or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt of such compound or metabolite thereof, to treat diseases and disorders selected from acute pain, arthritis, atherosclerosis, cachexia, cardiovascular disorders, chronic pain, degenerative diseases, diabetes, head trauma, hyperglycemia, immune senescence, inflammatory bowel disorders, ischemia, macular degeneration, muscular dystrophy, tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases, neuronal tissue damage or disease, neuropathic pain, nervous insult, osteoarthritis, osteoporosis, peripheral nerve injury, renal failure, resuscitated hemorrhagic shock, retinal ischemia, septic shock, skin aging, vascular stroke, diseases or disorders relating to lifespan or proliferative capacity of cells, and diseases or disease conditions induced or exacerbated by cellular senescence.
73 . The method according to claim 72 wherein the diseases or conditions are selected from diabetes, head trauma, inflammatory bowel disorders, ischemia, tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases, neuronal tissue damage disease, neuropathic pain, nervous insult, peripheral nerve injury, retinal ischemia, vascular stroke, and diseases or disorders relating to lifespan or proliferative capacity of cells.
74 . The method according to claim 73 wherein the disease or condition is tissue damage resulting from ischemia and reperfusion injury.
75 . A method of treating or preventing diseases or conditions resulting from cell damage or death comprising administering to an animal a therapeutically effective amount of a compound of Formula V according to claim 61 , or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt thereof.
76 . The method according to claim 75 wherein the diseases or conditions are selected from acute pain, arthritis, atherosclerosis, cachexia, cardiovascular disorders, chronic pain, degenerative diseases, diabetes, head trauma, hyperglycemia, immune senescence, inflammatory bowel disorders, ischemia, macular degeneration, muscular dystrophy, tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases, neuronal tissue damage or disease, neuropathic pain, nervous insult, osteoarthritis, osteoporosis, peripheral nerve injury, renal failure, resuscitated hemorrhagic shock, retinal ischemia, septic shock, skin aging, vascular stroke, diseases or disorders relating to lifespan or proliferative capacity of cells, and diseases or disease conditions induced or exacerbated by cellular senescence.
77 . The method according to claim 76 wherein the diseases or conditions are selected from diabetes, head trauma, inflammatory bowel disorders, ischemia, tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases, neuronal tissue damage disease, neuropathic pain, nervous insult, peripheral nerve injury, retinal ischemia, vascular stroke, and diseases or disorders relating to lifespan or proliferative capacity of cells.
78 . The method according to claim 77 wherein the disease or condition is tissue damage resulting from ischemia and reperfusion injury.
79 . A compound of the Formula VI:
wherein:
R 1 and R 2 are independently hydrogen, a substituted or unsubstituted lower alkyl, lower alkenyl, heterocycloalkyl, alkoxy, aryloxy, alkylamino, arylamino, or R 1 and R 2 are taken together to form a substituted or unsubstituted five to seven membered heterocyclic ring that contains 1-3 heteroatoms of O, N, or S;
or a pharmaceutically acceptable prodrug of said compound, pharmaceutically active metabolite of said compound, or pharmaceutically acceptable salt of said compound or metabolite.
80 . A compound, prodrug, metabolite, or salt according to claim 79 , wherein:
R 1 and R 2 are independently hydrogen, a substituted or unsubstituted lower alkyl, or R 1 and R 2 are taken together to form a substituted or unsubstituted six membered heterocyclic ring that contains 1-3 heteroatoms of O, N, or S.
81 . A compound, prodrug, metabolite, or salt according to claim 80 selected from:
82 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula VI:
wherein:
R 1 and R 2 are independently hydrogen, a substituted or unsubstituted lower alkyl, lower alkenyl, heterocycloalkyl, alkoxy, aryloxy, alkylamino, arylamino, or R 1 and R 2 are taken together to form a substituted or unsubstituted five to seven membered heterocyclic ring that contains 1-3 heteroatoms of O, N, or S;
or a pharmaceutically acceptable prodrug of said compound, pharmaceutically active metabolite of said compound, or pharmaceutically acceptable salt of said compound or metabolite.
83 . The pharmaceutical composition according to claim 82 , wherein:
R 1 and R 2 are independently hydrogen, a substituted or unsubstituted lower alkyl, or R 1 and R 2 are taken together to form a substituted or unsubstituted six membered heterocyclic ring that contains 1-3 heteroatoms of O, N, or S.
84 . The pharmaceutical composition according to claim 83 selected from:
85 . The composition according to claim 82 , wherein said composition is administered as a sterile solution, suspension or emulsion, in a single or divided dose.
86 . The composition according to claim 82 , wherein said composition is administered as a capsule or tablet containing a single or divided dose of said compound.
87 . The composition according to claim 82 , wherein the composition is a solid implant.
88 . The composition according to claim 82 , wherein the carrier comprises a biodegradable polymer.
89 . The composition according to claim 88 , wherein the biodegradable polymer releases the compound of formula VI over a prolonged time.
90 . A method of modulating or inhibiting PARG by administering a compound of Formula VI according to claim 79 , or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt of such compound or metabolite thereof, to treat diseases and disorders selected from acute pain, arthritis, atherosclerosis, cachexia, cardiovascular disorders, chronic pain, degenerative diseases, diabetes, head trauma, hyperglycemia, immune senescence, inflammatory bowel disorders, ischemia, macular degeneration, muscular dystrophy, tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases, neuronal tissue damage or disease, neuropathic pain, nervous insult, osteoarthritis, osteoporosis, peripheral nerve injury, renal failure, resuscitated hemorrhagic shock, retinal ischemia, septic shock, skin aging, vascular stroke, diseases or disorders relating to lifespan or proliferative capacity of cells, and diseases or disease conditions induced or exacerbated by cellular senescence.
91 . The method according to claim 90 wherein the diseases or conditions are selected from diabetes, head trauma, inflammatory bowel disorders, ischemia, tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases, neuronal tissue damage disease, neuropathic pain, nervous insult, peripheral nerve injury, retinal ischemia, vascular stroke, and diseases or disorders relating to lifespan or proliferative capacity of cells.
92 . The method according to claim 91 wherein the disease or condition is tissue damage resulting from ischemia and reperfusion injury.
93 . A compound of the Formula VII:
wherein:
n is 1 to 3; and
Q is a substituted or unsubstituted aryl or heteroaryl;
or a pharmaceutically acceptable prodrug of said compound, pharmaceutically active metabolite of said compound, or pharmaceutically acceptable salt of said compound or metabolite.
94 . A compound, prodrug, metabolite, or salt according to claim 93 selected from:
95 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula VII:
wherein:
n is 1 to 3; and
Q is a substituted or unsubstituted aryl or heteroaryl;
or a pharmaceutically acceptable prodrug of said compound, pharmaceutically active metabolite of said compound, or pharmaceutically acceptable salt of said compound or metabolite.
96 . The pharmaceutical composition according to claim 95 selected from:
97 . The composition according to claim 95 , wherein said composition is administered as a sterile solution, suspension or emulsion, in a single or divided dose.
98 . The composition according to claim 95 , wherein said composition is administered as a capsule or tablet containing a single or divided dose of said compound.
99 . The composition according to claim 95 , wherein the composition is a solid implant.
100 . The composition according to claim 95 , wherein the carrier comprises a biodegradable polymer.
101 . The composition according to claim 100 , wherein the biodegradable polymer releases the compound of formula VII over a prolonged time.
102 . A method of modulating or inhibiting PARG by administering a compound of Formula VII according to claim 93 , or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt of such compound or metabolite thereof, to treat diseases and disorders selected from acute pain, arthritis, atherosclerosis, cachexia, cardiovascular disorders, chronic pain, degenerative diseases, diabetes, head trauma, hyperglycemia, immune senescence, inflammatory bowel disorders, ischemia, macular degeneration, muscular dystrophy, tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases, neuronal tissue damage or disease, neuropathic pain, nervous insult, osteoarthritis, osteoporosis, peripheral nerve injury, renal failure, resuscitated hemorrhagic shock, retinal ischemia, septic neurodegenerative diseases, neuronal tissue damage or disease, neuropathic pain, nervous insult, osteoarthritis, osteoporosis, peripheral nerve injury, renal failure, resuscitated hemorrhagic shock, retinal ischemia, septic shock, skin aging, vascular stroke, diseases or disorders relating to lifespan or proliferative capacity of cells, and diseases or disease conditions induced or exacerbated by cellular senescence.
103 . The method according to claim 102 wherein the diseases or conditions are selected from diabetes, head trauma, inflammatory bowel disorders, ischemia, tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases, neuronal tissue damage disease, neuropathic pain, nervous insult, peripheral nerve injury, retinal ischemia, vascular stroke, and diseases or disorders relating to lifespan or proliferative capacity of cells.
104 . The method according to claim 103 wherein the disease or condition is tissue damage resulting from ischemia and reperfusion injury.
105 . A compound of the Formula VIII:
wherein:
R 5 is hydrogen, and R 6 is a substituted or unsubstituted lower alkyl, lower alkenyl, heterocycloalkyl, alkoxy, aryloxy, alkylamino, arylamino, or R 5 and R 6 are taken together to form a substituted or unsubstituted five to seven membered heterocyclic ring that contains 1-3 heteroatoms of O, N, or S;
or a pharmaceutically acceptable prodrug of said compound, pharmaceutically active metabolite of said compound, or pharmaceutically acceptable salt of said compound or metabolite.
106 . A compound, prodrug, metabolite, or salt according to claim 105 , wherein:
R 5 is hydrogen, and R 6 is a substituted or unsubstituted lower alkyl, or R 5 and R 6 are taken together to form a substituted or unsubstituted six membered heterocyclic ring that contains 1-2 heteroatoms of N.
107 . A compound, prodrug, metabolite, or salt according to claim 106 selected from:
108 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula VIII:
wherein:
R 5 is hydrogen, and R 6 is a substituted or unsubstituted lower alkyl, lower alkenyl, heterocycloalkyl, alkoxy, aryloxy, alkylamino, arylamino, or R 5 and R 6 are taken together to form a substituted or unsubstituted five to seven membered heterocyclic ring that contains 1-3 heteroatoms of O, N, or S;
or a pharmaceutically acceptable prodrug of said compound, pharmaceutically active metabolite of said compound, or pharmaceutically acceptable salt of said compound or metabolite.
109 . The pharmaceutical composition according to claim 108 , wherein:
R 5 is hydrogen, and R 6 is a substituted or unsubstituted lower alkyl, or R 1 and R 6 are taken together to form a substituted or unsubstituted six membered heterocyclic ring that contains 1-2 heteroatoms of N.
110 . The pharmaceutical composition according to claim 109 selected from:
111 . The composition according to claim 108 , wherein said composition is administered as a sterile solution, suspension or emulsion, in a single or divided dose.
112 . The composition according to claim 108 , wherein said composition is administered as a capsule or tablet containing a single or divided dose of said compound.
113 . The composition according to claim 108 , wherein the composition is a solid implant.
114 . The composition according to claim 108 , wherein the carrier comprises a biodegradable polymer.
115 . The composition according to claim 114 , wherein the biodegradable polymer releases the compound of formula VIII over a prolonged time.
116 . A method of modulating or inhibiting PARG by administering a compound of Formula VIII according to claim 105 , or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt of such compound or metabolite thereof, to treat diseases and disorders selected from acute pain, arthritis, atherosclerosis, cachexia, cardiovascular disorders, chronic pain, degenerative diseases, diabetes, head trauma, hyperglycemia, immune senescence, inflammatory bowel disorders, ischemia, macular degeneration, muscular dystrophy, tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases, neuronal tissue damage or disease, neuropathic pain, nervous insult, osteoarthritis, osteoporosis, peripheral nerve injury, renal failure, resuscitated hemorrhagic shock, retinal ischemia, septic shock, skin aging, vascular stroke, diseases or disorders relating to lifespan or proliferative capacity of cells, and diseases or disease conditions induced or exacerbated by cellular senescence.
117 . The method according to claim 116 wherein the diseases or conditions are selected from diabetes, head trauma, inflammatory bowel disorders, ischemia, tissue damage resulting from ischemia and reperfusion injury, neurological disorders and neurodegenerative diseases, neuronal tissue damage disease, neuropathic pain, nervous insult, peripheral nerve injury, retinal ischemia, vascular stroke, and diseases or disorders relating to lifespan or proliferative capacity of cells.
118 . The method according to claim 117 wherein the disease or condition is tissue damage resulting from ischemia and reperfusion injury.Join the waitlist — get patent alerts
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