Compounds, formulations, and methods of protein kinase C inhibition

1. A method of inhibiting or reducing vascular permeability comprising:

administering to a subject in need thereof a composition comprising a compound in an amount effective to inhibit or reduce vascular permeability, the compound having a structure selected from the group consisting of structural formula (I) to (VIII):

structural formula (I):

structural formula (II):

structural formula (III):

structural formula (IV):

structural formula (V):

structural formula (VI):

structural formula (VII):

and structural formula (VIII):

wherein X 1 is selected from the group consisting of O, S, NH, and NMe;

wherein n has a value of zero (0), one (1), or two (2);

wherein R 1 is selected from the group consisting of CH 2 , CH(CH 3 ), C(CH 3 ) 2 , C 2 H 4 , and C 2 H 2 ;

wherein R 2 is selected from the group consisting of H, CH 3 , CH 2 OH, C 2 H 5 , C 2 H 5 O, CH(CH 3 ) 2 , C(CH 3 ), CH 2 CH(CH 3 ) 2 , and CH 2 C(CH 3 ) 3 ;

wherein X 2 is selected from the group consisting of O, S, NH and N; when X 2 is O, S, or NH, R 3 is selected from the group consisting of an aryl residue, an alkyl residue having 1 to 10 carbon atoms, an alkoxy residue having 1 to 10 carbon atoms, and a polyglycol residue having two to twelve carbon atoms; when X 2 is N, R 3 is either two independently selected residues each selected from the group consisting of an aryl residue, an alkyl residue having 1 to 10 carbon atoms, an alkoxy residue having 1 to 10 carbon atoms, and a polyglycol residue having two to twelve carbon atoms; or X 2 and R 3 are a cyclic group (X 2 —R 3 ) having five or six members and optionally one or more additional heteroatoms;

wherein R 4 and R 8 are individually selected from the group consisting of H, F, Cl, OH, and OCH 3 ;

wherein R 5 and R 7 are individually selected from the group consisting of H, F, Cl, Br, CH 3 , C 2 H 5 , OH, OCH 3 , OCH 2 CH 3 , OCH 2 OCH 3 , S(CH 3 ) 2 + , and N(alkyl) 3 + ;

wherein R 6 is selected from the group consisting of H; F; Cl; Br; CH 3 ; C 2 H 5 ; NO 2 ; OH; OCH 3 ; OCH 2 CH 3 ; OCH 2 OCH 3 ; OCH 2 CH 2 OH; OCH 2 CH 2 OCH 3 ; OCH 2 CH 2 OCH 2 CH 3 ; polyglycol residue selected from the group consisting of methylene glycols, ethylene glycols, propylene glycols and mixtures thereof; and an aryl group;

wherein Ar is selected from the group consisting of phenyl, napthyl, pyridyl, pyrrolidyl, furanyl, pyranyl, azepinyl, oxepinyl, imidizolyl, oxazolyl, pyrimidinyl, purinyl, dimethoxyphenyl, chlorophenyl, dichlorophenyl, bromophenyl, hydroxyphenyl, trimethylphenyl, fluorophenyl, nitrophenyl, methoxyphenyl, dihydrobenzopyran, pyridine, dimethyl aminophenyl, aminophenyl, piperonyl, fluoromethoxyphenyl, acetamidophenyl, and carbomoylphenyl;

wherein R 9 is selected from the group consisting of H, CH 3 , CH 2 N(CH 3 ) 2 , and phenyl;

wherein when either R 5 or R 7 is Cl and the other is H, R 6 is not Cl; and

wherein the compound is not isopropyl 2-amino-4-(3,4-dichlorophenyl)thiophene-3-carboxylate.

2. A method of inhibiting or reducing vascular permeability comprising:

administering to a subject in need thereof a composition comprising a compound in an amount effective to inhibit or reduce vascular permeability, the compound having structural formula (IX):

wherein X 1 is selected from the group consisting of O, S, NH, and NMe;

wherein R 10 is selected from the group consisting of H, CH 3 , COCH 3 , and C 5 H 10 N;

wherein R 11 is selected from the group consisting of phenyl, chlorophenyl, dichlorophenyl, dimethylaminophenyl, aminophenyl, piperonyl, dimethoxyphenyl, methoxyphenyl, acetamidophenyl, carbomoylphenyl, fluoromethoxyphenyl, napthyl, pyridyl, pyrrolidyl, furanyl, pyranyl, azepinyl, oxepinyl, imidizolyl, oxazolyl, pyrimidinyl, purinyl, and substituted groups thereof;

wherein R 12 is selected from the group consisting of an aryl ester carboxylate, an alkyl ester carboxylate, an alkoxy ester carboxylate, an aryl carboxamide, an alkyl carboxamide, an alkoxy carboxamide, C 2 H 4 NO, and nitrile;

wherein R 13 is selected from the group consisting of NH 2 , C 2 H 3 O, C 7 H 4 N 2 O 3 Cl, C 7 H 4 NOClF, C 6 H 4 N 2 O 3 Cl, and C 2 H 4 NO;

wherein when R 10 is CH 3 , R 13 is not C 2 H 4 NO; and

wherein when R 12 is isopropyl carboxylate, R 11 is not 3,4-dichlorophenyl.

3. The method of claim 1 , wherein the vascular permeability is associated with a disease or disorder characterized by abnormal vascular permeability selected from the group consisting of macular edema, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, uveitis, branch retinal vein occlusion, central retinal vein occlusion, ischemia-reperfusion injury, neoplasic disease, and brain edema.

4. The method of claim 1 , wherein X 1 is S; X 2 is O; n has a value of zero (0); and R 2 is H.

5. The method of claim 1 , wherein R 3 is an aryl residue or an alkyl residue having 1 to 10 carbons; and R 4 and R 8 are H.

6. The method of claim 1 , wherein R 7 is H; and R 5 is selected from the group consisting of H, F, Cl, Br, CH 3 , C 2 H 5 , OH, OCH 3 , OCH 2 CH 3 , OCH 2 OCH 3 , S(CH 3 ) + , and N(alkyl) 3 + .

7. The method of claim 1 , wherein R 6 is selected from the group consisting of H, F, Cl, Br, CH 3 , C 2 H 5 , NO 2 , OH, OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 OH, OCH 2 CH 2 OCH 3 , and OCH 2 CH 2 OCH 2 CH 3 .

8. The method of claim 1 , wherein R 5 is selected from the group consisting of H, OCH 3 , and OCH 2 CH 3 ; R 6 is selected from the group consisting of OH, OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 OH, OCH 2 CH 2 OCH 3 , and OCH 2 CH 2 OCH 2 CH 3 ; and R 7 is H.

9. The method of claim 1 , wherein R 5 is OCH 3 ; R 6 is OCH 3 ; and R 7 is H.

10. The method of claim 1 , wherein R 9 is selected from the group consisting of H, CH 3 , and CH 2 N(CH 3 ) 2 .

11. The method of claim 1 , wherein Ar is selected from the group consisting of phenyl, dimethoxyphenyl, chlorophenyl, dichlorophenyl, bromophenyl, hydroxyphenyl, trimethylphenyl, fluorophenyl, nitrophenyl, methoxyphenyl, dihydrobenzopyran, or pyridine.

12. The method of claim 11 , wherein X 1 is S; X 2 is O; n has a value of zero (0), R 2 is H, R 3 is CH(CH 3 ) 2 , R 9 is H, and Ar is a dimethoxyphenyl group.

13. The method of claim 1 , wherein the compound has a structure of structural formula (I).

14. The method of claim 13 , wherein Ar is selected from the group consisting of dimethoxyphenyl, chlorophenyl, dichlorophenyl, bromophenyl, hydroxyphenyl, trimethylphenyl, fluorophenyl, nitrophenyl, methoxyphenyl, dihydrobenzopyran, and pyridine.

15. The method of claim 14 , wherein Ar is dimethoxyphenyl.

16. The method of claim 1 , wherein the compound has a structure of structural formula (II).