US2009069371A1PendingUtilityA1
Isoquinoline compounds
Est. expiryJul 11, 2025(expired)· nominal 20-yr term from priority
Inventors:Mitchell A. DelongMarcos SznaidmanRobert H. OakleyAllen E. EckhardtChristine HudsonJeffrey D. YinglingMichael PeelThomas E. RichardsonClare Louise MurrayByappanahally N. Narasinga RaoBrian H. HeasleyParesma R. Patel
A61P 9/10A61P 9/12A61P 9/00A61P 37/08A61P 27/06A61P 27/02A61P 3/04A61P 35/00A61P 13/00A61P 19/00A61P 19/08A61P 1/18A61P 17/00A61P 1/16A61P 1/00A61P 13/12A61P 11/02A61P 15/08C07D 217/02A61P 13/10
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Claims
Abstract
Isoquinoline compounds with G are provided that influence, inhibit or reduce the action of a G-protein receptor kinase. Pharmaceutical compositions including therapeutically effective amounts of the isoquinoline compounds and pharmaceutically acceptable carriers are also provided. Various methods using the compounds and/or compositions to affect disease states or conditions such as cancer, osteoporosis and glaucoma are also provided.
Claims
exact text as granted — not AI-modified1 . A compound according to Formula (I):
wherein A is a substituted or unsubstituted isoquinoline radical wherein the isoquinoline radical may be mono- or disubstituted with halogen, cyano, nitro or C 1 -C 4 alkyl;
R 1 , R 2 , R 3 , R 4 , and R 5 are, independently, hydrogen; halogen; C 1 -C 8 alkyl; alkoxy; phenoxy, —OR 7 ; amino; nitro; cyano; aryl; C 1 -C 4 alkylaryl; heteroaryl; C 1 -C 4 alkyl heteroaryl; carbonylamino; thioalkyl; sulfonyl; sulfonylamino; acyl; or carboxyl;
R 7 is C 1 -C 4 alkyl, aryl, heteroaryl, C 1 -C 4 alkyl aryl or C 1 -C 4 alkyl heteroaryl;
X is O, S, S(O), S(O)(O),
R 6 is CH 2 or CH(C 1 -C 4 alkyl).
2 . A compound according to claim 1 wherein X is
3 . A compound according to claim 2 wherein R 1 , R 2 , R 3 , R 4 , and R 5 are not phenoxy.
4 . A compound according to claim 3 wherein X is
5 . A compound according to claim 4 wherein A is an unsubstituted isoquinoline radical and R 1 , R 3 , and R 5 are hydrogen.
6 . A compound according to claim 4 wherein R 1 , R 2 , R 3 , and R 5 are hydrogen and R 4 is —O—R 7 .
7 . A compound according to claim 4 wherein R 4 is carbonylamino, sulfylamino, acyl or carboxyl.
8 . A compound according to claim 4 wherein R 1 , R 2 , and R 5 are H and one of R 3 and R 4 is carbonylamino, sulfylamino, acyl or carboxyl.
9 . A compound according to Formula II:
wherein R 1′ , R 2′ , R 3′ , R 4′ , and R 5′ are, independently, hydrogen; halogen; unsubstituted C 1 -C 4 alkyl; amino; nitro; cyano; carbonylamino; alkoxy; —O—R 7′ ; sulfonylamino; carboxyl; acyl; or thioalkyl;
R 7′ is C 1 -C 4 alkyl, aryl, heteroaryl, C 1 -C 4 alkyl aryl or C 1 -C 4 alkyl heteroaryl;
X′ is O, S, S(O), S(O)(O),
R 6′ is CH 2 or CH(C 1 -C 4 alkyl).
10 . A compound according to claim 9 wherein X′ is
11 . A compound according to claim 9 wherein X′ is
12 . A compound according to claim 9 wherein R 1′ , R 2′ , R 3′ , and R 5′ are hydrogen and R 4′ , is —O—R 7′ .
13 . A compound according to claim 9 wherein R 4′ is carbonylamino, sulfylamino, acyl or carboxyl.
14 . A compound according to claim 13 wherein R 4′ is carbonylamino, and the carbonylamino is C(O)NHphenyl, C(O)NH-m-pyridyl, C(O)NH-o-pyridyl, C(O)NH-p-pyridyl, C(O)NH 2 , or C(O)NHCH 3 .
15 . A compound according to claim 9 wherein R 1′ , R 2′ , and R 5′ are H and one of R 3′ and R 4′ is carbonylamino, sulfylamino, acyl or carboxyl.
16 . A compound according claim 11 wherein R 2′ or R 4′ is —O—R 7′ .
17 . A compound according to claim 16 wherein R 7′ is methyl, ethyl, phenyl, benzyl, propyl or isopropyl.
18 . A method for influencing the action of a G-protein-coupled receptor kinase in a cell comprising administering to or contacting with the cell at least one compound according to Formula (II), or reducing GPCR desensitization in a cell comprising administering to or contacting with the cell a therapeutically effective amount of a compound according to Formula (II), or inhibiting the action of a G-protein-coupled receptor kinase comprising applying to a medium or contacting with a cell an effective inhibitory amount of a compound according to Formula (II):
wherein R 1′ , R 2′ , R 3′ , R 4′ , and R 5′ are, independently, hydrogen; halogen; unsubstituted C 1 -C 4 alkyl; amino; nitro; cyano; carbonylamino; alkoxy; —O—R 7′ ; sulfonylamino; carboxyl; acyl; or thioalkyl;
R 7′ is C 1 -C 4 alkyl, aryl, heteroaryl, C 1 -C 4 alkyl aryl or C 1 -C 4 alkyl heteroaryl;
X′ is O, S, S(O), S(O)(O),
R 6′ is CH 2 or CH(C 1 -C 4 alkyl).
19 . The method according to claim 18 wherein X′ is
20 . The method according to claim 19 wherein R 1′ , R 3′ , and R 5′ are hydrogen.
21 . The method according claim 20 wherein R 2′ or R 4′ is —O—R 7′ .
22 . The method according to claim 21 wherein R 7′ is methyl, ethyl, phenyl, benzyl, propyl or isopropyl.
23 . The method according to claim 20 wherein R 2′ or R 4′ is carbonylamino.
24 . The method according to claim 23 wherein the carbonylamino moiety is selected from C(O)NHphenyl, C(O)NH-m-pyridyl, C(O)NH-o-pyridyl, C(O)NH-p-pyridyl, C(O)NH 2 , or C(O)NHCH 3 .
25 . The method according to claim 18 wherein the G-protein-coupled receptor kinase is GRK-2, GRK-3, GRK-5 or GRK-6.
26 . The method according to claim 18 wherein the G-protein-coupled receptor kinase is GRK-2.
27 . A compound according to Formula III:
wherein R 8 and R 9 are independently hydrogen; halogen; unsubstituted C 1 -C 4 alkyl; substituted C 1 -C 4 alkyl; amino; nitro; cyano; carbonylamino; alkoxy; phenoxy, benzyloxy, —O—R 10 ; sulfonylamino; carboxyl; acyl; or thioalkyl; and
R 10 is unsubstituted C 1 -C 4 alkyl; substituted C 1 -C 4 alkyl; substituted aryl, heteroaryl, substituted heteroaryl, C 1 -C 4 alkaryl or C 1 -C 4 alkheteroaryl.
28 . A compound according to claim 27 wherein R 8 is carbonylamino, a carboxyl, a sulfonyl amino, a cyano, or an acyl moiety, and R 9 is selected from H, methyl, cyano, or halogen.
29 . A compound according to claim 28 wherein R 8 is the carbonylamino, and the carbonylamino is C(O)NHphenyl, C(O)NH-m-pyridyl, C(O)NH-o-pyridyl, C(O)NH-p-pyridyl, C(O)NH 2 , and C(O)NHCH 3 .
30 . A compound according to claim 28 wherein R 8 is the carboxyl and the carboxyl is C(O)O phenyl, C(O)O-m-pyridyl, C(O)O-o-pyridyl, C(O)O-p-pyridyl, C(O)NH 2 , or C(O)OCH 3 .
31 . A compound according to claim 28 wherein R 8 is the sulfonyl amino, and the sulfonyl amino is S(O) 2 NHphenyl, S(O) 2 NH-m-pyridyl, S(O) 2 NH-o-pyridyl, S(O) 2 NH-p-pyridyl, S(O) 2 NH 2 , or S(O) 2 NHCH 3 .
32 . A compound according to claim 27 wherein R 9 is a carbonylamino, a carboxyl, a sulfonyl amino, a cyano, or an acyl moiety, and R 8 is H, methyl, cyano, or halogen.
33 . A compound according to claim 27 wherein R 8 is alkoxy, phenoxy, benzyloxy, or —O—R 10 and R 9 is H, methyl, cyano, or halogen.
34 . A compound according to claim 27 wherein R 8 and R 9 are not phenoxy.
35 . A pharmaceutical composition comprising:
a) an isoquinoline derivative having the structure
wherein R 8 and R 9 are independently hydrogen; halogen; unsubstituted C 1 -C 4 alkyl; substituted C 1 -C 4 alkyl; amino; nitro; cyano; carbonylamino; alkoxy; phenoxy, benzyloxy, —O—R 10 ; sulfonylamino; carboxyl; acyl; or thioalkyl; and
R 10 is unsubstituted C 1 -C 4 alkyl; substituted C 1 -C 4 alkyl; substituted aryl, heteroaryl, substituted heteroaryl, C 1 -C 4 alkaryl or C 1 -C 4 alkheteroaryl; and
b) a carrier.
36 . The composition of claim 35 , wherein the carrier is selected from the group consisting of systemic and topical carriers.
37 . The composition of claim 35 , wherein the composition comprises about 0.01% to 10% of the isoquinoline derivative and 90 to 99.99% of the systemic carrier.
38 . A method of treating a condition comprising administering to a subject in need of treatment a safe and effective amount of an isoquinoline derivative, wherein the condition is selected from the group consisting of eye disease, bone disorder, heart disease, hepatic disease, renal disease, pancreatitis, cancer, myocardial infarct, gastric disturbance, hypertension, fertility control, nasal congestion, neurogenic bladder disorder, gastrointestinal disorder, and dermatological disorder.
39 . The method of claim 38 , wherein the condition comprises eye disease.
40 . The method of claim 39 , wherein the condition comprises glaucoma.
41 . The method of claim 40 , wherein the isoquinoline derivative is of the Formula (I):
wherein A is a substituted or unsubstituted isoquinoline radical wherein the isoquinoline radical may be mono- or disubstituted with halogen, cyano, nitro or C 1 -C 4 alkyl;
R 1 , R 2 , R 3 , R 4 , and R 5 are, independently, hydrogen; halogen; C 1 -C 8 alkyl; alkoxy; phenoxy, —O—R 7 ; amino; nitro; cyano; aryl; C 1 -C 4 alkylaryl; heteroaryl; C 1 -C 4 alkyl heteroaryl; carbonylamino; thioalkyl; sulfonyl; sulfonylamino; acyl; or carboxyl;
R 7 is C 1 -C 4 alkyl, aryl, heteroaryl, C 1 -C 4 alkyl aryl or C 1 -C 4 alkyl heteroaryl;
X is O, S, S(O), S(O)(O),
R 6 is CH 2 or CH(C 1 -C 4 alkyl).
42 . The method of claim 41 wherein X is
43 . The method of claim 42 wherein R 1 , R 2 , R 3 , R 4 , and R 5 are not phenoxy.
44 . The method of claim 40 wherein the isoquinoline derivative is according to Formula II:
wherein R 1′ , R 2′ , R 3′ , R 4′ , and R 5′ are, independently, hydrogen; halogen; unsubstituted C 1 -C 4 alkyl; amino; nitro; cyano; carbonylamino; alkoxy; —O—R 7′ ; sulfonylamino; carboxyl; acyl; or thioalkyl;
R 7′ is C 1 -C 4 alkyl, aryl, heteroaryl, C 1 -C 4 alkyl aryl or C 1 -C 4 alkyl heteroaryl;
X′ is O, S, S(O), S(O)(O),
R 6′ is CH 2 or CH(C 1 -C 4 alkyl).
45 . A method according to claim 44 wherein X′ is
46 . A method according to claim 44 wherein X′ is
47 . A compound selected from the following:Join the waitlist — get patent alerts
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