Vasculostatic agents and methods of use thereof
Compositions and methods and are provided for treating disorders associated with compromised vasculostasis. Invention methods and compositions are useful for treating a variety of disorders including for example, stroke, myocardial infarction, cancer, ischemia/reperfusion injury, autoimmune diseases such as rheumatoid arthritis, eye diseases such as retinopathies or macular degeneration or other vitreoretinal diseases , inflammatory diseases, vascular leakage syndrome, edema, transplant rejection, adult/acute respiratory distress syndrome (ARDS), and the like.
1. A compound of structure (III):
wherein:
each of Z 2 and Z 4 is C, each of Z 1 , Z 3 , Z 5 , and Z 6 is N;
each X is NH 2 ;
each Y is independently selected from a group consisting of —OR d , —NR d 2 , —SR d , and —OPO 3 H 2 , wherein R d is selected from a group consisting of H, lower alkyl, aryl, and —(CH 2 ) 2 NH(CH 2 CH 3 ); or
each Y is independently selected from a group consisting of alkyl, substituted alkyl, aryl, substituted aryl, and halogen, wherein said substituents are selected from a group consisting of halogen, —OR e , —NR e 2 , —SR e , and —P(O)(OH) 2 , wherein R e is selected from a group consisting of —H, lower alkyl, and aryl; or
each Y is independently selected from a group consisting of CH 2 glycinyl, CH 2 NHethoxy, CH 2 NHCH 2 alkyl, CH 2 NHCH 2 t-Bu, CH 2 NHCH 2 aryl, and CH 2 NHCH 2 substituted aryl; or
when n is 2, each Y is taken together to form a fused aromatic ring system; and
m and n are each independently 1 to 4,
wherein when m=n=2, Y is not phenyl or 4-hydroxyphenyl, or tautomers thereof.
2. A pharmaceutical composition comprising a compound of claim 1 in a pharmaceutically acceptable carrier.
3. A compound of claim 1 having the structure:
or pharmaceutically acceptable salts thereof.
4. A compound of claim 1 having the structure:
or pharmaceutically acceptable salts thereof.
5. A compound of claim 1 having the structure:
or pharmaceutically acceptable salts thereof.
6. A compound of claim 1 having the structure:
or pharmaceutically acceptable salts thereof.
7. A compound of claim 1 having any one of the structures:
or pharmaceutically acceptable salts thereof.
8. A compound of claim 1 having the structure:
or pharmaceutically acceptable salts thereof.
9. A compound having the structure:
or pharmaceutically acceptable salts thereof.