Hydroxyamino- and amino-substituted pyridine analogs for treating rho kinase-mediated diseases and conditions

1. An ophthalmic pharmaceutical composition useful in the treatment of glaucoma and control of intraocular pressure, comprising an effective amount of a compound according to Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt thereof:

wherein

R═H, R′, NH 2 , NHOH, NHCOR′, NHOR′, or NR′OH;

R′=alkyl or aryl;

Y═N, CH or CMe;

L=CO, CR′R′, SO, or SO 2 ; and

Ar (Alk)=an aromatic aryl, heteroaryl, or alkyl group substituted with one or more amines; and

a pharmaceutically acceptable vehicle therefore.

2. The composition of claim 1 , further comprising a compound selected from the group consisting of:

opthalmologically acceptable preservatives, surfactants, viscosity enhancers, penetration enhancers, gelling agents, hydrophobic bases, vehicles, buffers, sodium chloride, and water.

3. The composition of claim 1 , wherein said composition comprises from about 0.01 percent weight/volume to about 5 percent weight/volume of said compound.

4. The composition of claim 1 , wherein said composition comprises from about 0.25 percent weight/volume to about 2 percent weight/volume of said compound.

5. A method of controlling intraocular pressure comprising:

applying a therapeutically effective amount of an ophthalmic pharmaceutical composition useful in the treatment of glaucoma and control of intraocular pressure to the affected eye of a human or other mammal, the composition comprising an effective amount of a compound according to Formula (I), Formula (II), Formula (III), or Formula (IV):

wherein

R═H, R′, NH 2 , NHOH, NHCOR′, NHOR′, or NR′OH;

R′=alkyl or aryl;

Y═N, CH or CMe;

L=CO, CR′R′, SO, or SO 2 ; and

Ar (Alk)=an aromatic aryl, heteroaryl, or alkyl group substituted with one or more amines; and

a pharmaceutically acceptable vehicle thereof.

6. The method of claim 5 , wherein said applying comprises applying 1 to 2 drops of a composition comprising from about 0.01 percent weight/volume to about 5 percent weight/volume of a compound according to Formula (I), Formula (II), Formula (III), or Formula (IV) 1 to 4 times daily.

7. The method of claim 5 , wherein said composition further comprises a glaucoma treatment agent in addition to a compound of Formula (I), (II), (III), or (IV).

8. The method of claim 7 wherein at least one glaucoma treatment agent is selected from the group consisting of:

β-blockers, prostaglandin analog, carbonic anhydrase inhibitors, α 2 agonists, miotics, neuroprotectants, and combinations thereof.

9. A method of treating rho kinase-mediated diseases or rho kinase-mediated conditions, which comprises administering to a human or other mammal a therapeutically effective amount of a compound according to Formula (I), Formula (II), Formula (III), or Formula (IV):

wherein

R═H, R′, NH 2 , NHOH, NHCOR′, NHOR′, or NR′OH;

R′=alkyl or aryl;

Y═N, CH or CMe;

L=CO, CR′R′, SO, or SO 2 ; and

Ar (Alk)=an aromatic aryl, heteroaryl, or alkyl group substituted with one or more amines; and

a pharmaceutically acceptable vehicle therefore.

10. The method of claim 9 wherein said administering comprises applying 1 to 2 drops of a composition comprising from about 0.01 percent weight/volume to about 5 percent weight/volume of compound according to Formula (I), Formula (II), Formula (III), or Formula (IV), 1 to 4 times daily.

11. The method of claim 9 wherein said composition further comprises a glaucoma treatment agent in addition to a compound of Formula (I), (II), (III), or (IV).

12. The method of claim 11 wherein the glaucoma treatment agent is selected from the group consisting of:

β-blockers, prostaglandin analogs, carbonic anhydrase inhibitors, α 2 agonists, miotics, neuroprotectants, and combinations thereof.

13. A compound represented by Formula (I), or a pharmaceutically acceptable salt thereof:

wherein

R═H, R′, NH 2 , NHOH, NHCOR′, NHOR′, or NR′OH;

R′=alkyl or aryl;

L=CO, CR′R′, SO, or SO 2 ; and

Ar (Alk)=an aromatic aryl, heteroaryl, or alkyl group substituted with one or more amines.

14. A compound represented by Formula (II), or a pharmaceutically acceptable salt thereof:

wherein

R═H, R′, NH 2 , NHOH, NHCOR′, NHOR′, or NR′OH;

R′=alkyl or aryl;

Y═N, CH or CMe; and

Ar (Alk)=an aromatic aryl, heteroaryl, or alkyl group substituted with one or more amines.

15. A compound represented by Formula (III), or a pharmaceutically acceptable salt thereof:

wherein

R═H, R′, NHOH, NHCOR′, NHOR′, or NR′OH;

R′=alkyl or aryl;

Y═N, CH or CMe;

L=CO, CR′R′, SO, or SO 2 ; and

Ar (Alk)=an aromatic aryl, heteroaryl, or alkyl group substituted with one or more amines.

16. A compound represented by Formula (IV), or a pharmaceutically acceptable salt thereof:

wherein

R═H, R′, NH 2 , NHOH, NHCOR′, NHOR′, or NR′OH;

R′=alkyl or aryl;

Y═N, CH or CMe;

L=CO, CR′R′, SO, or SO 2 ; and

Ar (Alk)=an aromatic aryl, heteroaryl, or alkyl group substituted with one or more amines.