BETA- AND GAMMA-AMINO-ISOQUINOLINE AMIDE COMPOUNDS AND SUBSTITUTED BENZAMIDE COMPOUNDS
Disclosed are beta and gamma-amino isoquinoline amide compounds and substituted benzamide compounds. In particular, the invention provides compounds that affect the function of kinases in a cell and that are useful as therapeutic agents or with therapeutic agents. The compounds of the invention are useful in the treatment of a variety of diseases and conditions including eye diseases such as glaucoma, cardiovascular diseases, and diseases characterized by abnormal growth, such as cancers. The invention further provides compositions containing the beta or gamma-amino isoquinoline amide compounds or substituted benzamide compounds.
1 . A method of treating glaucoma, comprising administration via ocular administration of a composition comprising a Rho kinase inhibitor and a pharmaceutically acceptable carrier to a subject in need thereof,
wherein the administration is daily administration, weekly administration, or monthly administration, and
wherein the Rho kinase inhibitor is a compound of formula (I):
or a pharmaceutically acceptable salt thereof;
wherein
R 1 and R 2 are, independently, hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 4 carbonyl, or C 1 -C 4 carboxyl; or R 1 and R 2 combine to form a heterocycloalkyl ring of at least 5 and at most 8 member atoms, or R 1 and R 3 combine to form a heterocycloalkyl ring of at least 5 and at most 8 member atoms;
one of R 3 and R 4 is an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, C 1 -C 8 alkenyl, and the other of R 3 and R 4 is hydrogen or C 1 -C 4 alkyl; and
X 1 and X 2 are, independently, hydrogen, hydroxyl, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, amino, nitro, or cyano.
2 . The method of claim 1 , wherein one of R 3 and R 4 is aryl or heteroaryl.
3 . The method of claim 1 , wherein the amount of the Rho kinase inhibitor administered is about 0.01 to about 1,000 μg/kg subject body weight.
4 . The method of claim 2 , wherein the amount of the Rho kinase inhibitor administered is about 0.01 to about 1,000 μg/kg subject body weight.
5 . The method of claim 1 , wherein the amount of the Rho kinase inhibitor administered is about 0.1 to about 100 μg/kg subject body weight.
6 . The method of claim 2 , wherein the amount of the Rho kinase inhibitor administered is about 0.1 to about 100 μg/kg subject body weight.
7 . The method of claim 1 , wherein the amount of the Rho kinase inhibitor administered is about 1 to about 50 μg/kg subject body weight.
8 . The method of claim 2 , wherein the amount of the Rho kinase inhibitor administered is about 1 to about 50 μg/kg subject body weight.
9 . The method of claim 1 , wherein the administration is daily administration once daily, twice per day, or 4 times per day.
10 . The method of claim 2 , wherein the administration is daily administration once daily, twice per day, or 4 times per day.
11 . The method of claim 3 , wherein the administration is daily administration once daily, twice per day, or 4 times per day.
12 . The method of claim 4 , wherein the administration is daily administration once daily, twice per day, or 4 times per day.
13 . The method of claim 5 , wherein the administration is daily administration once daily, twice per day, or 4 times per day.
14 . The method of claim 6 , wherein the administration is daily administration once daily, twice per day, or 4 times per day.
15 . The method of claim 7 , wherein the administration is daily administration once daily, twice per day, or 4 times per day.
16 . The method of claim 8 , wherein the administration is daily administration once daily, twice per day, or 4 times per day.
17 . The method of claim 1 , wherein the administration is weekly administration once weekly or twice weekly.
18 . The method of claim 2 , wherein the administration is weekly administration once weekly or twice weekly.
19 . The method of claim 3 , wherein the administration is weekly administration once weekly or twice weekly.
20 . The method of claim 4 , wherein the administration is weekly administration once weekly or twice weekly.
21 . The method of claim 5 , wherein the administration is weekly administration once weekly or twice weekly.
22 . The method of claim 6 , wherein the administration is weekly administration once weekly or twice weekly.
23 . The method of claim 7 , wherein the administration is weekly administration once weekly or twice weekly.
24 . The method of claim 8 , wherein the administration is weekly administration once weekly or twice weekly.
25 . The method of claim 1 , wherein the administration is monthly administration once a month.
26 . The method of claim 2 , wherein the administration is monthly administration once a month.
27 . The method of claim 3 , wherein the administration is monthly administration once a month.
28 . The method of claim 4 , wherein the administration is monthly administration once a month.
29 . The method of claim 5 , wherein the administration is monthly administration once a month.
30 . The method of claim 6 , wherein the administration is monthly administration once a month.
31 . The method of claim 7 , wherein the administration is monthly administration once a month.
32 . The method of claim 8 , wherein the administration is monthly administration once a month.
33 . A method of treating glaucoma, comprising administration via ocular administration of a composition comprising a Rho kinase inhibitor and a pharmaceutically acceptable carrier to a subject in need thereof,
wherein the administration is daily administration, weekly administration, or monthly administration.
34 . The method of claim 33 , wherein the amount of the Rho kinase inhibitor administered is about 0.01 to about 1,000 μg/kg subject body weight.
35 . The method of claim 33 , wherein the amount of the Rho kinase inhibitor administered is about 0.1 to about 100 μg/kg subject body weight.
36 . The method of claim 33 , wherein the amount of the Rho kinase inhibitor administered is about 1 to about 50 μg/kg subject body weight.
37 . The method of claim 33 , wherein the administration is daily administration once daily, twice per day, or 4 times per day.
38 . The method of claim 34 , wherein the administration is daily administration once daily, twice per day, or 4 times per day.
39 . The method of claim 35 , wherein the administration is daily administration once daily, twice per day, or 4 times per day.
40 . The method of claim 36 , wherein the administration is daily administration once daily, twice per day, or 4 times per day.
41 . The method of claim 33 , wherein the administration is weekly administration once weekly or twice weekly.
42 . The method of claim 34 , wherein the administration is weekly administration once weekly or twice weekly.
43 . The method of claim 35 , wherein the administration is weekly administration once weekly or twice weekly.
44 . The method of claim 36 , wherein the administration is weekly administration once weekly or twice weekly.
45 . The method of claim 33 , wherein the administration is monthly administration once a month.
46 . The method of claim 34 , wherein the administration is monthly administration once a
47 . The method of claim 35 , wherein the administration is monthly administration once a month.
48 . The method of claim 36 , wherein the administration is monthly administration once a month.