N-benzyl substituted pyridyl porphyrin compounds and methods of use thereof

Abstract

The present invention relates to N-Benzyl-Substituted Pyridyl Porphyrin Compounds, compositions comprising an effective amount of an N-Benzyl-Substituted Pyridyl Porphyrin Compound and methods for treating or preventing injury due to exposure to a reactive species, erectile dysfunction, urinary incontinence, lung disease, hyperoxia, neurodegenerative disease, liver disease, myocardial damage during cardioplegia, an inflammatory condition, a reperfusion injury, an ischemic condition, a cardiovascular disease, diabetes, a diabetic complication, cancer, a side effect of cancer chemotherapy, or a radiation-induced injury, and methods for prolonging the half-life of an oxidation-prone compound, comprising administering to a subject in need thereof an effective amount of an N-Benzyl-Substituted Pyridyl Porphyrin Compound.

1 . A method of treating a disease associated with exposure to a reactive species, comprising administering to a subject in need thereof an effective amount of a compound having the Formula (A): 
     
       
         
         
             
             
         
       
     
     wherein:
 M is Fe or Mn; 
 f is 0 or 1; 
 each R is independently —C(O)(amino acid residue) or —SO 2  (amino acid residue); and 
 n is the number of counterions sufficient to balance the charges of the compound of formula (A). 
 
   
   
       2 - 23 . (canceled) 
   
   
       24 . The method of  claim 66 , wherein the inflammatory condition is an inflammatory condition of a joint, a Chronic inflammatory condition of the gum, an inflammatory bowel disease, an inflammatory lung disease, an inflammatory condition of the central nervous system, an inflammatory condition of the eye, gram-positive shock, gram negative shock, hemorrhagic shock, anaphylactic shock, traumatic shock, chemotherapeutic shock, or shock induced in response to administration of a pro-inflammatory cytokine. 
   
   
       25 . (canceled) 
   
   
       26 . The method of  claim 66 , wherein the reperfusion injury is stroke, myocardial infarction, or a reoxygenation injury resulting from organ transplantation. 
   
   
       27 . The method of  claim 26 , wherein the organ transplantation is cardiac transplantation or kidney transplantation. 
   
   
       28 . (canceled) 
   
   
       29 . The method of  claim 66 , wherein the ischemic condition is myocardial ischemia, stable angina, unstable angina, stroke, ischemic heart disease or cerebral ischemia. 
   
   
       30 . (canceled) 
   
   
       31 . The method of  claim 66 , wherein the radiation-induced injury is acute radiation sickness. 
   
   
       32 . (canceled) 
   
   
       33 . The method of  claim 66 , wherein the diabetes is diabetes mellitus. 
   
   
       34 . The method of  claim 66 , wherein the diabetes is Type I diabetes or Type II diabetes. 
   
   
       35 . (canceled) 
   
   
       36 . The method of  claim 66 , wherein the diabetic complication is diabetic neuropathy, retinopathy, neuropathy, angiopathy, cardiomyopathy, or erectile dysfunction. 
   
   
       37 . (canceled) 
   
   
       38 . The method of  claim 66 , wherein the cardiovascular disease is acute heart failure, chronic heart failure, ischemic heart failure, drug-induced heart failure, idiopathic heart failure, alcoholic heart failure, or a cardiac arrhythmia. 
   
   
       39 . The method of  claim 66 , wherein the cardiovascular disease is balloon-induced vascular injury, coronary stenting, atherosclerosis, or restenosis. 
   
   
       40 . (canceled) 
   
   
       41 . The method of  claim 66 , wherein the cancer is colorectal cancer, lung cancer, pancreatic cancer, esophageal cancer, stomach cancer, skin cancer, leukemia, lymphoma, testicular cancer, bladder cancer, breast cancer, prostate cancer, head and neck cancer or ovarian cancer. 
   
   
       42 . (canceled) 
   
   
       43 . The method of  claim 66 , wherein the cancer chemotherapy comprises administering a platinum-based chemotherapy agent to the subject. 
   
   
       44 . The method of  claim 43 , wherein the platinum-based chemotherapy agent is cisplatin. 
   
   
       45 . The method of  claim 66 , wherein the radiation-induced injury is caused by radiation therapy administered to a subject for the treatment of cancer. 
   
   
       46 . (canceled) 
   
   
       47 . A method for increasing a subject's survival time following exposure to radiation, comprising administering to a subject in need thereof an effective amount of a compound having the formula (A): 
     
       
         
         
             
             
         
       
     
     wherein:
 M is Fe or Mn; 
 f is 0 or 1; 
 each R is independently —C(O)(amino acid residue) or —SO 2  (amino acid residue); and 
 n is the number of counterions sufficient to balance the charges of the compound of formula (A). 
 
   
   
       48 - 49 . (canceled) 
   
   
       50 . The method of  claim 66 , wherein the inflammatory skin disease is contact dermatitis, erythema, or psoriasis. 
   
   
       51 . (canceled) 
   
   
       52 . (canceled) 
   
   
       53 . The method of  claim 66 , wherein the erectile dysfunction is due to surgery of the prostate or the colon. 
   
   
       54 . (canceled) 
   
   
       55 . (canceled) 
   
   
       56 . The method of  claim 66 , wherein the lung disease is cystic fibrosis, hyperoxic lung injury, emphysema, or adult respiratory distress syndrome. 
   
   
       57 . (canceled) 
   
   
       58 . The method of  claim 66 , wherein the injury due to hyperoxia is hyperoxia-induced eye injury or hyperoxia-induced lung injury. 
   
   
       59 . (canceled) 
   
   
       60 . The method of  claim 66 , wherein the neurodegenerative disease is Parkinson's disease, Alzheimer's disease, Huntington's disease, or amyotrophic lateral sclerosis. 
   
   
       61 . (canceled) 
   
   
       62 . The method of  claim 66 , wherein the liver disease is hepatitis, liver failure, or drug-induced liver injury. 
   
   
       63 . A method for inducing cardioplegia, comprising administering to a subject in need thereof an effective amount of a cardioplegia-inducing agent and the compound of  claim 1 . 
   
   
       64 . A method for prolonging the half-life of hyaluronic acid in vivo, comprising administering to a subject in need thereof an effective amount of hyaluronic acid and the compound of  claim 1 . 
   
   
       65 . A method for treating osteoarthritis, comprising administering to a subject in need thereof an effective amount of hyaluronic acid and the compound of  claim 1 . 
   
   
       66 . The method of  claim 1 , wherein the disease associated with exposure to a reactive species is selected from the group consisting of
 (a) an inflammatory condition,   (b) a reperfusion injury,   (c) an ischemic injury,   (d) a radiation-induced injury,   (e) diabetes,   (f) a diabetic complication,   (g) cardiovascular disease,   (h) cancer,   (i) a side effect of cancer chemotherapy,   (j) radiation-induced death,   (k) inflammatory skin disease,   (l) skin wrinkling, skin aging, sunburn erythema, UV induced skin injury, or UV-induced skin disease,   (m) erectile dysfunction,   (n) urinary incontinence,   (o) a lung disease,   (p) injury due to hyperoxia,   (q) neurodegenerative disease, and   (r) liver disease.