Pharmaceutically active compounds and methods of use

Abstract

The present invention relates to pharmaceutically acceptable compounds, including acylguanidine compounds, and methods of treatment and pharmaceutical compositions that utilize or comprise one or more such compounds. Compounds of the invention are particularly useful for the treatment or prophylaxis of neurological injury and neurodegenerative disorders.

1 - 6 . (canceled)  
     
     
         7 . A compound of the following Formula:  
       
         
           
           
               
               
           
         
         wherein R is an optionally substituted cyclic alkyl; an optionally substituted carbocyclic aryl; an optionally substituted alkylaryl; an optionally substituted heteroaromatic or heteroalicyclic group having from I to 3 rings, 3 to about 8 ring members in each ring and from 1 to about 3 hetero atoms; optionally substituted aralkyl; optionally substituted heteroaralkyl; or optionally substituted heteroalicyclicalkyl;  
         each R 1  is independently hydrogen, optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted alkoxy; optionally substituted alkylthio; optionally substituted alkylsulfinyl; optionally substituted alkylsulfonyl; optionally substituted or unsubstituted carbocyclic aryl; or an optionally substituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to about 8 ring members in each ring and 1 to about 3 hetero atoms;  
         each R 2  and each R 3  are independently hydrogen, halogen, hydroxyl, azido, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, optionally substituted aminoalkyl, optionally substituted carbocyclic aryl, or optionally substituted aralkyl;  
         W is optionally substituted methylene, —S—, —O—, optionally substituted —N—, —S(O)— or —S(O 2 )—;  
         m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.  
       
     
     
         8 . A compound of  claim 7  wherein W is optionally substituted methylene.  
     
     
         9 - 18 . (canceled)  
     
     
         19 . A compound of  claim 7  wherein R is an optionally substituted cyclic alkyl; optionally substituted carbocyclic aryl; optionally substituted alkylaryl; an optionally substituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to about 8 ring members in each ring and from 1 to about 3 hetero atoms  
     
     
         20 . A compound of  claim 19  wherein R is optionally substituted cyclic alkyl.  
     
     
         21 . A compound of  claim 19  wherein R is optionally substituted carbocyclic aryl.  
     
     
         22 . A compound of  claim 21  wherein R is optionally substituted phenyl or naphthyl.  
     
     
         23 . A compound of  claim 19  wherein R is optionally substituted heteroaromatic or heteroalicyclic.  
     
     
         24 . A compound of  claim 19  wherein R is optionally substituted aralkyl.  
     
     
         25 . (canceled)  
     
     
         26 . A compound of  claim 7  wherein at least one R 1  group is hydrogen.  
     
     
         27 . A compound of  claim 7  wherein both R 1  groups are hydrogen.  
     
     
         28 . A compound of  claim 7  wherein at least one R 1  group is optionally substituted alkyl.  
     
     
         29 . A compound of  claim 7  wherein at least one R 1  group is alkyl having 1 to 3 carbon atoms.  
     
     
         30 . A compound of  claim 7  wherein both R 1  groups are optionally substituted alkyl.  
     
     
         31 . A method of treating a nerve degeneration disease comprising administering to a mammal suffering from or susceptible to said disease a therapeutically effective amount of a compound of  claim 7 .  
     
     
         32 . A method of treating a neurodegenerative disease comprising administering to a mammal suffering from or susceptible to said disease a therapeutically effective amount of a compound of  claim 7 .  
     
     
         33 . A method of treating Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, Down's Syndrome or Korsakoff's disease, Cerebral Palsy, or epilepsy, comprising administering to a mammal suffering from or susceptible to said disease a therapeutically effective amount of a compound of  claim 7 .  
     
     
         34 . A method of treating or preventing nerve cell death or degeneration comprising administering to a mammal suffering from or susceptible to nerve cell death or degeneration a therapeutically effective amount of a compound of  claim 7 .  
     
     
         35 . The method of  claim 34  wherein the nerve cell death or degeneration is associated with hypoxia, hypoglycemia, brain or spinal cord ischemia, retinal ischemia or brain or spinal cord trauma.  
     
     
         36 . A method of treating a mammal suffering from or susceptible to stroke or heart attack comprising administering to the mammal a therapeutically effective amount of a compound of  claim 7 .  
     
     
         37 . A method of treating a mammal suffering from or susceptible to brain or spinal cord trauma comprising administering to the mammal a therapeutically effective amount of a compound of  claim 7 .  
     
     
         38 . A method of treating a mammal suffering from or susceptible to pain including chronic pain or neuropathic pain, peripheral necropathy, migraines, shingles, emesis, narcotic withdrawal symptoms or age-dependent dementia, comprising administering to the mammal a therapeutically effective amount of a compound of  claim 7 .  
     
     
         39 . A method of treating a mammal suffering from or susceptible decreased blood flow or nutrient supply to retinal tissue or optic nerve, or retinal ischemia or trauma, or optic nerve injury, or aglaucoma, comprising administering to the mammal a therapeutically effective amount of a compound of  claim 7 .  
     
     
         40 . A method of treating a mammal suffering from or susceptible to post-surgical neurological deficits or neurological deficits associated with cardiac arrest, comprising administering to the mammal a therapeutically effective amount of a compound of  claim 7 .  
     
     
         41 . A method for treating an infection in a mammal, comprising administering to a mammal suffering from or susceptible to an infection an effective amount of an aminoglycoside antibiotic and a compound of  claim 7 .  
     
     
         42 . The method of  claim 41  wherein the mammal is suffering from an infection of a Gram negative bacteria or a Gram positive bacteria.  
     
     
         43 . (canceled)  
     
     
         44 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 7  and a pharmaceutically acceptable carrier.  
     
     
         45 . A compound of  claim 7  that is radiolabelled.