Vasculostatic agents and methods of use thereof

Abstract

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 method for treating a subject having, or at risk of developing, a disorder or a disease, comprising administering to a subject in need thereof an effective amount of at least one compound having the general structure III, or any combination thereof, or tautomers, pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers thereof:  
     
       
         
         
             
             
         
       
       wherein:  
       each of Z 1 —Z 6  is independently selected from a group consisting of C, —C═O, N, and NR a , wherein R a  is selected from a group consisting of —H, an alkyl, or a substituted alkyl, wherein said substituent is selected from a group consisting of a halogen, hydroxy, oxo, and amino, each X is independently selected from a group consisting of a halogen, —OR b , —NR b   2 , and —SR b , wherein R b  is selected from a group consisting of —H, a lower alkyl, —(CH 2 ) 2 NH(CH 2 CH 3 ), —(CH 2 ) 3  morpholyn-1-yl, —(CH 2 ) 3 (N-methylpiperazinyn-1-yl), an aryl, a heteroaryl, —(NH—NH—R c ), and —(N═N—NH—R c ), wherein R c  is H or a lower alkyl,  
       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, a lower alkyl, an aryl, a heteroaryl, —(CH 2 ) 2 NH(CH 2 CH 3 ), —(CH 2 ) 3  morpholyn-1-yl, and —(CH 2 ) 3 (N-methylpiperazinyl-1-yl); or  
       each Y is independently selected from a group consisting of an alkyl, a substituted alkyl, an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl, and a halogen, wherein said substituent is selected from a group consisting of a halogen, —OR e , —NR e   2 , —SR e , and —P(O)(OH) 2 , wherein R e  is selected from a group consisting of —H, a lower alkyl, an aryl, and a heteroaryl; 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, CH 2 NHCH 2 substituted aryl, CH 2 NHCH 2 heteroaryl, and CH 2 NHCH 2 -substituted heteroaryl; or  
       when n is 2, each Y is taken together to form a fused aromatic or heteroaromatic ring system; and  
       each of m and n is independently an integer having the value between 1 and 4,  
       wherein when each of Z 1 , Z 3 , Z 5 , and Z 6  is N, X is NH 2 , and m=n=2, Y is not phenyl or 4-hydroxyphenyl,  
       thereby treating the disorder.  
     
   
   
       2 . The method of  claim 1 , wherein the compound III has the structure:  
     
       
         
         
             
             
         
       
       wherein:  
       each of m and n is independently an integer having the value between 1 and 4,  
       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, a lower alkyl, an aryl, and —(CH 2 ) 2 NH(CH 2 CH 3 ), or  
       each Y is independently selected from a group consisting of an alkyl, a substituted alkyl, an aryl, a substituted aryl, and a halogen, wherein said substituent is selected from a group consisting of a halogen, —OR e , —NR e   2 , —SR e , and —P(O)(OH) 2 , wherein R e  is selected from a group consisting of —H, a lower alkyl, and an 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  
       wherein when m=n=2, Y is not phenyl or 4-hydrokyphenyl.  
     
   
   
       3 . The method of  claim 2 , wherein the compound III has the structure selected from a group consisting of:  
     
       
         
         
             
             
         
       
     
   
   
       4 . The method of  claim 2 , wherein the compound III has the structure:  
     
       
         
         
             
             
         
       
     
   
   
       5 . The method of  claim 2 , wherein the compound III has the structure:  
     
       
         
         
             
             
         
       
     
   
   
       6 . The method of  claim 2 , wherein the compound III has the structure:  
     
       
         
         
             
             
         
       
     
   
   
       7 . The method of  claim 2 , wherein the compound III has the structure:  
     
       
         
         
             
             
         
       
     
   
   
       8 . The method of  claim 2 , wherein the compound III has the structure:  
     
       
         
         
             
             
         
       
     
   
   
       9 . The method of  claim 2 , wherein the compound III has the structure:  
     
       
         
         
             
             
         
       
     
   
   
       10 . The method of  claim 2 , wherein the compound III has the structure:  
     
       
         
         
             
             
         
       
     
   
   
       11 . The method of  claim 1 , wherein the disorder or disease is selected from a group consisting of any disorder or disease associated with compromised vasculostasis, myocardial infarction, stroke, congestive heart failure, an ischemia or reperfusion injury, cancer, arthritis or other arthropathy, retinopathy or vitreoretinal disease, macular degeneration, autoimmune disease, vascular leakage syndrome, an inflammatory disease, edema, transplant rejection, burn, or acute or adult respiratory distress syndrome (ARDS).  
   
   
       12 . The method of  claim 11 , wherein the disorder or disease is vascular leakage syndrome (VLS).  
   
   
       13 . The method of  claim 11 , wherein the disorder or disease is cancer or tumor.  
   
   
       14 . The method of  claim 13 , wherein the compound III is administered in combination with an effective amount of a compound selected from a group consisting of a therapeutic antibody, a chemotherapeutic agent, and an immunotoxic agents, or any combination thereof.  
   
   
       15 . The method of  claim 13 , wherein the cancer is selected from a group consisting of an alimentary/gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer, breast cancer, ovarian cancer, prostate cancer, lymphoma, leukemia, kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer, and brain cancer.  
   
   
       16 . The method of  claim 15 , wherein the cancer is colon cancer or lung cancer.  
   
   
       17 . The method of  claim 14 , wherein the therapeutic agent is selected from a group consisting of an antimetabolite; a DNA cross-linking agent; an alkylating agent; a topoisomerase I inhibitor; a microtubule inhibitor, a vinca alkaloid, a mitomycin-type antibiotic, and a bleomycin-type antibiotic.  
   
   
       18 . The method of  claim 14 , wherein the chemotherapeutic agent is selected from a group consisting of methotrexate, cisplatin/carboplatin; canbusil; dactinomicin; taxol (paclitaxol), antifolate, colchicine, demecoline, etoposide, taxane/taxol, docetaxel, doxorubicin, anthracycline antibiotic, doxorubicin, daunorubicin, carminomycin, epirubicin, idarubicin, mithoxanthrone, 4-demethoxy-daunomycin, 11-deoxydaunorubicin, 13-deoxydaunorubicin, adriamycin-14-benzoate, adriamycin-14-octanoate, and adriamycin-14-naphthaleneacetate.  
   
   
       19 . The method of  claim 18 , wherein the therapeutic agent is selected from a group consisting of doxorubicin, docetaxol, and taxol.  
   
   
       20 . The method of  claim 14 , wherein the therapeutic agent is selected from a group consisting of an antibody that binds to HER2 protein, a growth factor, a growth factor receptor, and an integrin receptor.  
   
   
       21 . The method of  claim 14 , wherein the therapeutic agent is selected from a group consisting of trastuzumab; bevacizumab, OSI-774, and Vitaxin.  
   
   
       22 . The method of  claim 11 , wherein the disorder or disease is retinopathy or a vitreoretinal disease.  
   
   
       23 . The method of  claim 11 , wherein the disorder or disease is ARDS.  
   
   
       24 . The method of  claim 11 , wherein the disorder or disease is autoimmune disease.  
   
   
       25 . The method of  claim 11 , wherein the disorder or disease is burn.  
   
   
       26 . The method of  claim 11 , wherein the disorder or disease is stroke.  
   
   
       27 . The method of  claim 11 , wherein the disorder or disease is myocardial infarction.  
   
   
       28 . The method of  claim 11 , wherein the disorder or disease is ischemia or reperfusion injury.  
   
   
       29 . The method of  claim 11 , wherein the disorder or disease is arthritis.  
   
   
       30 . The method of  claim 11 , wherein the disorder or disease is edema.  
   
   
       31 . The method of  claim 11 , wherein the disorder or disease is transplant rejection.  
   
   
       32 . The method of  claim 11 , wherein the disorder or disease is the inflammatory disease.  
   
   
       33 . The method of  claim 11 , wherein the disorder or disease is congestive heart failure.  
   
   
       34 . The method of  claim 11 , wherein the disorder or disease is associated with a kinase.  
   
   
       35 . The method of  claim 34 , wherein the kinase is a tyrosine kinase.  
   
   
       36 . The method of  claim 34 , wherein the kinase is a serine kinase or a threonine kinase.  
   
   
       37 . The method of  claim 34 , wherein the kinase is a Src family kinase.  
   
   
       38 . The method of  claim 11 , wherein the disorder or disease is asthma.  
   
   
       39 . The method of  claim 11 , wherein the disorder or disease is rhinitis.  
   
   
       40 . The method of  claim 1 , wherein the compound III is administered in combination with an effective amount of an agent selected from a group consisting of an anti-inflammatory agent, a chemotherapeutic agent, an immunomodulatory agent, a therapeutic antibody and a protein kinase inhibitor.