Methods of treating ischemic related conditions

Abstract

The present invention relates to methods of treating ischemia-related conditions by administering to a patient in need of such methods certain thiosemicarbazone compounds. Preferred embodiments of the present invention relates to methods of treating specific ischemia-related conditions, including but not limited to Alzheimer's disease, Parkinson's disease, Coronary artery bypass graft surgery, Global cerebral ischemia due to cardiac arrest, focal cerebral infarction, cerebral hemorrhage, hemorrhage infarction, hypertensive hemorrhage. hemorrhage due to rupture of intracranial vascular abnormalities, subarachnoid hemorrhage due to rupture of intracranial arterial aneurysms, hypertensive encephalopathy, carotid stenosis or occlusion leading to cerebral ischemia, cardiogenic thromboembolism, spinal stroke and spinal cord injury, diseases of cerebral blood vessels: e.g., atherosclerosis, vasculitis, Macular degeneration, myocardial infarction, cardiac ischemia and superaventicular tachyarrhytmia.

1 . A method for the treatment of neuronal damage due to an ischemia-related condition in a patient in need thereof, comprising administering to said patient a compound of Formula I: 
     
       
         
         
             
             
         
       
     
     wherein
 E is oxygen, sulfur, NH or N—C 1-6  alkyl; 
 R 1 , R 2 , R 3 , and R 4  are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted haloalkyl, optionally substituted aryl, optionally substituted aminoalkyl, optionally substituted hydroxyalkyl, optionally substituted alkoxyalkyl, and optionally substituted alkanoyl, or 
 NR 1 R 2  taken in combination form a 3 to 7 member ring which may comprise 0, 1, or 2 additional ring heteroatoms selected from N, O, and S; and 
 HET is an optionally substituted 5- to 7-membered heteroaryl residue which comprises between 1 and 4 ring heteroatoms selected from N, O, or S. 
 
   
   
       2 . The method of  claim 1 , wherein E is sulfur. 
   
   
       3 . The method of  claim 1 , wherein HET is a residue of the formula: 
     
       
         
         
             
             
         
       
       wherein 
       m is 0 or 1; 
       Z 1 , Z 2 , and Z 3  are independently selected from N, O, S, or CR, when m is 0, or 
       Z 1 , Z 2 , and Z 3  are independently selected from N or CR, when m is 1; 
       R is independently selected at each occurrence from the group consisting of hydrogen, halide, hydroxy, thiol, amino, hydroxyamino, mono-C 1-8  alkylamino, di(C 1-8  alkyl)amino, C 1-8  alkoxy, C 1-8  alkyl, C 2-8  alkenyl, and C 2-8  alkynyl; and 
       x is an integer from 0 to 4. 
     
   
   
       4 . The method of  claim 3 , wherein zero or one of Z 1 , Z 2 , or Z 3  is N and the remaining Z 1 , Z 2 , and Z 3  is CR. 
   
   
       5 . The method of  claim 1 , wherein HET is a residue selected from the group consisting of optionally substituted pyridyl, optionally substituted pyrazinyl, pyrimidinyl, pyrrolyl, imidazolyl, triazolyl, oxazolyl and thioxazolyl. 
   
   
       6 . The method of  claim 1 , wherein HET is an optionally substituted pyridyl residue. 
   
   
       7 . The method of  claim 1 , wherein
 E is sulfur;   HET is a residue selected from the group consisting of optionally substituted pyridyl, optionally substituted pyrazinyl, pyrimidinyl, pyrrolyl, imidazolyl, triazolyl, oxazolyl, thioxazolyl; and   R 1 , R 2 , R 3 , and R 4  are independently selected from the group consisting of hydrogen, C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl; C 3-8  cycloalkyl, C 1-8  haloalkyl, C 6-10  aryl, amino-C 1-8  alkyl, hydroxy-C 1-8  alkyl, C 1-8  alkoxy-C 1-8  alkyl, and C 1-8  alkanoyl, or   NR 1 R 2  taken in combination form a 3 to 7 member ring which may comprise 0, 1, or 2 additional ring heteroatoms selected from N, O, and S.   
   
   
       8 . A method for the treatment of neuronal damage due to an ischemia-related condition, comprising administering to a patient a compound of Formula II: 
     
       
         
         
             
             
         
       
       wherein 
       R, R 1 , R 2 , R 3 , and R 4  are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted haloalkyl, optionally substituted aryl, optionally substituted aminoalkyl, optionally substituted hydroxyalkyl, optionally substituted alkoxyalkyl, and optionally substituted alkanoyl, or 
       NR 1 R 2  taken in combination form a 3 to 7 member ring which may comprise 0, 1, or 2 additional ring heteroatoms selected from N, O, and S; and 
       x is an integer of 0 to 5. 
     
   
   
       9 . The method of  claim 8 , wherein
 x is 0, 1, 2, or 3   R, R 1 , R 2 , R 3 , and R 4  are independently selected from the group consisting of hydrogen, C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-8  cycloalkyl, C 1-8  haloalkyl, C 6-10  aryl, amino-C 1-8  alkyl, hydroxy-C 1-8  alkyl, C 1-8  alkoxy-C 1-8  alkyl, and C 1-8  alkanoyl, or   NR 1 R 2  taken in combination form a 3 to 7 member ring which may comprise 0, 1, or 2 additional ring heteroatoms selected from N, O, and S.   
   
   
       10 . The method of  claim 9 , wherein
 R, R 1 , R 2 , and R 3  are independently selected from the group consisting of hydrogen, C 1-4  alkyl, C 1-2  haloalkyl, phenyl, amino-C 1-4  alkyl, hydroxy-C 1-4  alkyl, C 1-4  alkoxy-C 1-8  alkyl, and C 1-4  alkanoyl, or   NR 1 R 2  taken in combination form a 3 to 7 member ring which may comprise 0 or 1 additional ring heteroatoms selected from N, O, and S.   
   
   
       11 . The method of  claim 8 , wherein the compound to be administered is a compound according to Formula III 
     
       
         
         
             
             
         
       
     
     wherein
 R, R 1 , R 2 , R 3 , and R 4  are independently selected from the group consisting of hydrogen, C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-8  cycloalkyl, C 1-8  haloalkyl, C 6-10  aryl, amino-C 1-8  alkyl, hydroxy-C 1-8  alkyl, C 1-8  alkoxy-C 1-8  alkyl, and C 1-8  alkanoyl, or 
 NR 1 R 2  taken in combination form a 3 to 7 member ring which may comprise 0, 1, or 2 additional ring heteroatoms selected from N, O, and S; 
 R 6  is hydrogen, hydroxy, amino, or C 1-8  alkyl; 
 R 5  and R 7  are independently selected from the group consisting of hydrogen, halide, hydroxy, thiol, amino, hydroxyamino, mono-C 1-8  alkylamino, di(C 1-8  alkyl)amino, C 1-8  alkoxy, C 1-8  alkyl, C 2-8  alkenyl, and C 2-8  alkynyl. 
 
   
   
       12 . The method of  claim 8 , wherein R 4  is hydrogen or C 1-6  alkyl. 
   
   
       13 . The method of  claim 12 , wherein R 4  is hydrogen, methyl, ethyl, n-propyl, or isopropyl. 
   
   
       14 . The method of  claim 11 , wherein
 R 5  is selected from hydrogen or optionally substituted amino;   R 6  is hydrogen or C 1-4  alkyl; and   R 7  is hydrogen, optionally substituted amino, or hydroxy, wherein at least one of R 5  amino, N-hydroxylamino, mono- or di-(C 1-4  alkyl)amino, or N—(C 1-4  alkyl)-N-(hydroxy)amino, and   R 5  is selected from the group consisting of hydrogen, hydroxyamino, mono- and di-(C 1-8  alkyl)amino, hydroxy, and C 1-8  alkoxy;   R 6  is selected from the group consisting of hydrogen, hydroxyamino, and mono- and di-(C 1-8  alkyl)amino; and   R 5  is different from R 6  and one of R 5  and R 6  is hydrogen.   
   
   
       15 . The method of  claim 11 , wherein R 4  is hydrogen or C 1-6  alkyl; and
 R 1 , R 2 , and R 3  are independently selected from the group consisting of hydrogen, C 1-4  alkyl, C 1-2  haloalkyl, phenyl, amino-C 1-4  alkyl, hydroxy-C 1-4  alkyl, C 1-4  alkoxy-C 1-8  alkyl, and C 1-4  alkanoyl, or   NR 1 R 2  taken in combination form a 3 to 7 member ring which may comprise 0 or 1 additional ring heteroatoms selected from N, O, and S.   
   
   
       16 . The method of  claim 11 , wherein R 4  is hydrogen, methyl, ethyl, n-propyl, or isopropyl; and
 R 1 , R 2 , and R 3  are independently selected from the group consisting of hydrogen, methyl, ethyl, acetyl, formyl, or   NR 1 R 2  taken in combination form a piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, or piperazinyl.   
   
   
       17 . The method of  claim 11 , wherein R 4  is hydrogen, methyl, or ethyl; and
 R 1 , R 2 , and R 3  are independently selected from the group consisting of hydrogen, methyl, ethyl, and acetyl.   
   
   
       18 . A method of any one of  claims 1  thru  17 , wherein the ischemia-related condition is selected from the group consisting of: Alzheimer's disease, Parkinson's disease, coronary artery bypass graft surgery, global cerebral ischemia, focal cerebral infarction, cerebral hemorrhage, hemorrhage infarction, hypertensive hemorrhage, intracranial vascular hemorrhage, subarachnoid hemorrhage, hypertensive encephalopathy, carotid stenosis or occlusion, cardiogenic thromboembolism, spinal stroke, spinal cord injury, atherosclerosis, vasculitis, macular degeneration, myocardial infarction, cardiac ischemia and supraventricular tachyarrhythmia. 
   
   
       19 . A method of treatment of neuronal damage due to an ischemia-related condition comprising administering to a patient the compound of the following formula: 
     
       
         
         
             
             
         
       
     
   
   
       20 . A method of  claim 19 , wherein the ischemia-related disorder is Alzheimer's disease or Parkinson's disease.