Compounds and methods

Abstract

The subject matter generally relates to compounds and methods of treatment and/or prophylaxis of CNS diseases, disorders, and/or injuries. In one aspect, the subject matter relates to inhibitors of phosphodiesterase 1 (PDE1) as neuroprotective agents and/or neural regenerative agents. In a further aspect, the subject matter relates to individuals that are at risk for the development of CNS disease or disorder.

1 - 16 . (canceled) 
     
     
         17 . A method for the prophylaxis and/or treatment of a CNS disease, disorder, and/or injury, wherein the method comprises the administration of an effective amount of a PDE1 inhibitor to a subject, wherein the administration of the PDE1 inhibitor modulates the subject's level of intracellular cAMP, wherein the PDE 1 inhibitor is a compound according to Formula V 
       
         
           
           
               
               
           
         
         wherein
 (i) R 1  is C 1-4  alkyl (e.g., methyl); 
 (ii) R 4  is H and R 2  and R 3  are, independently, H or C 1-4  alkyl (e.g., R 2  and R 3  are both methyl, or R 2  is H and R 3  is isopropyl); 
 (iii) R 5  is attached to one of the nitrogens on the pyrazolo portion of Formula V and is a moiety of Formula A 
 
       
       
         
           
           
               
               
           
         
         
           wherein X, Y and Z are C, and R 8 , R 9 , R 11  and R 12  are H, and R 10  is halogen, or heteroaryl optionally substituted with halogen, alkyl, haloalkyl, hydroxy or carboxy (e.g., pyridyl or 2-halopyridyl, (for example, pyrid-2-yl, 5-fluoropyrid-2-yl or 6-fluoropyrid-2-yl)); and 
           (iv) R 6  is H, C 1-4 alkyl, arylamino optionally substituted with C 1-4 alkyl or halogen (e.g., phenylamino or 4-fluorophenylamino); and 
           (v) n=0; 
           in free or pharmaceutically acceptable salt form. 
         
       
     
     
         18 . A method according to  claim 17 , wherein the CNS disease, disorder, or injury is a spinal cord injury. 
     
     
         19 . The method according to  claim 17 , wherein the CNS disease, disorder, or injury relates to motor neuron trauma. 
     
     
         20 . The method according to  claim 17 , wherein the CNS disease, disorder, or injury is selected from the group consisting of: neurological traumas and injuries, surgery related trauma and/or injury, retinal injury and trauma, injury related to epilepsy, spinal cord injury, brain injury, brain surgery, trauma related brain injury, trauma related to spinal cord injury, brain injury related to cancer treatment, spinal cord injury related to cancer treatment, brain injury related to infection, brain injury related to inflammation, spinal cord injury related to infection, spinal cord injury related to inflammation, brain injury related to environmental toxins, and spinal cord injury related to environmental toxins. 
     
     
         21 . The method according to  claim 17 , wherein the CNS disease, disorder, or injury is a neurodegenerative disorder. 
     
     
         22 . The method according to  claim 21 , wherein the neurodegenerative disease, disorder, or injury is selected from the group consisting of: Alzheimer's disease, Multiple Sclerosis, Glaucoma, Frontotemporal dementia, Dementia with Lewy bodies, Corticobasal degeneration, Progressive supranuclear palsy, Prion disorders, Huntington's disease, Multiple system atrophy, Parkinson's disease, Amyotrophic lateral sclerosis, Hereditary spastic paraparesis, Spinocerebellar atrophies, Friedreich's ataxia, Amyloidoses, Metabolic (diabetes) related disorders, Toxin related disorders, chronic CNS inflammation, and Charcot Marie Tooth disease. 
     
     
         23 . (canceled) 
     
     
         24 . A method according to  claim 17 , wherein the PDE1 inhibitor is administered to a patient that is shown to have elevated intracellular calcium levels compared to a control subject (e.g., reference standard). 
     
     
         25 . A method of prophylaxis of the development of a CNS disease or disorder in a subject that is at risk for developing a CNS disease or disorder, wherein the method comprises:
 1.) Obtaining a CNS sample from the subject;   2.) Measuring the levels of intracellular calcium from the sample;   3.) Comparing the levels of intracellular calcium in the biological sample to a reference standard;   4.) Determining whether a patient is at risk for developing a CNS disease or disorder based upon the level of intracellular calcium compared to the reference standard;   5.) Administering a PDE1 inhibitor to a subject based upon the subject's levels of intracellular calcium put them at risk for the development of a CNS disease or disorder (e.g., administration of a PDE1 inhibitor to a subject because they have elevated intracellular calcium levels compared to the reference standard), wherein the PDE1 inhibitor is a compound according to  claim 17 .   
     
     
         26 . A method according to  claim 17 , wherein R 1  is methyl. 
     
     
         27 . A method according to  claim 17 , wherein R 2  and R 3  are C 1-4  alkyl. 
     
     
         28 . A method according to  claim 17 , wherein R 2  and R 3  are both methyl. 
     
     
         29 . A method according to  claim 17 , wherein R 10  is heteroaryl optionally substituted with halogen. 
     
     
         30 . A method according to  claim 17 , wherein R 10  is pyrid-2-yl. 
     
     
         31 . A method according to  claim 17 , wherein R 10  is 5-fluoro-pyrid-2-yl. 
     
     
         32 . A method according to  claim 17 , wherein R 10  is 6-fluoro-pyrid-2-yl. 
     
     
         33 . A method according to  claim 17 , wherein R 6  is C 1-4  alkyl. 
     
     
         34 . A method according to  claim 17 , wherein R 6  is ethyl. 
     
     
         35 . A method according to  claim 17 , wherein R 6  is propyl. 
     
     
         36 . A method according to  claim 17 , wherein R 6  is arylamino optionally substituted with C 1-4 alkyl or halogen. 
     
     
         37 . A method according to  claim 17 , wherein R 6  is 4-fluorophenylamino. 
     
     
         38 . A method according to  claim 17 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         in free or pharmaceutically acceptable salt form. 
       
     
     
         39 . A method according to  claim 17 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         in free or pharmaceutically acceptable salt form. 
       
     
     
         40 . A method according to  claim 17 , wherein R 10  is halogen and R 6  is arylamino substituted with C 1-4  alkyl or halogen. 
     
     
         41 . A method according to  claim 17 , wherein R10 is unsubstituted heteroaryl and R6 is arylamino substituted with C1-4 alkyl or halogen. 
     
     
         42 . A method according to  claim 17 , wherein R10 is heteroaryl substituted with halogen, alkyl, haloalkyl, hydroxy. 
     
     
         43 . A method according to  claim 42 , wherein R 6  is C 1-4  alkyl.