Substituted triazolophthalazine derivatives

Abstract

This invention relates to novel substituted triazolophthalazines and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering selective α5 receptor partial or full inverse agonists.

1 .- 25 . (canceled) 
     
     
         26 . A method of treating a disease or condition selected from anxiety, convulsions, skeletal muscle spasm, spasticity, athetosis, epilepsy, stiff-person syndrome, other disorders of the central nervous system, and pain, in a subject, the method comprising the step of administering to the subject an effective amount of a compound of formula Ia, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 R 5  is selected from CD 3  and CH 4 ; 
 R 8  is CD 3 ; 
 W is —CY 1 Y 2 —, wherein Y 1  and Y 2  are the same and are selected from hydrogen and deuterium; and 
 Y 3  is hydrogen or deuterium; 
 wherein there is at least 50.1% incorporation of deuterium at any atom designated as D or deuterium, and wherein any atom not designated as deuterium is present at its natural isotopic abundance. 
 
       
     
     
         27 . The method of  claim 26 , wherein the disease or condition is selected from anxiety and convulsions. 
     
     
         28 . The method of  claim 26 , comprising the additional step of co-administering to the subject a second therapeutic agent useful in the treatment of skeletal muscle spasm, spasticity, athetosis, stiff-person syndrome, other disorders of the central nervous system, and pain. 
     
     
         29 . The method of  claim 26 , wherein the pain is selected from the group consisting of acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head pain, neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, and cancer pain. 
     
     
         30 . The method of  claim 29 , wherein the pain is selected from the group consisting of femur cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, including abdominal, pancreatic, and IBS pain; chronic and acute headache pain; migraine; tension headache, including cluster headaches; chronic and acute neuropathic pain, including post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie Tooth neuropathy; hereditary sensory neuropathies; peripheral nerve injury; painful neuromas; ectopic proximal and distal discharges; radiculopathy; chemotherapy induced neuropathic pain; radiotherapy-induced neuropathic pain; post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; complex regional pain syndrome; phantom pain; intractable pain; acute pain, acute post-operative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendonitis; injury/exercise pain; acute visceral pain, including abdominal pain, pyelonephritis, appendicitis, cholecystitis, intestinal obstruction, and hernias; chest pain, including cardiac pain; pelvic pain; renal colic pain; acute obstetric pain, including labor pain; cesarean section pain; acute inflammatory, burn and trauma pain; acute intermittent pain, including endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain including sinusitis pain and dental pain; multiple sclerosis (MS) pain; pain in depression; leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painful legs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry's disease pain; painful bladder syndrome; interstitial cystitis (IC); prostatitis; complex regional pain syndrome (CRPS), type I and type II; and angina-induced pain. 
     
     
         31 . The method of  claim 30 , wherein the pain is selected from the group consisting of fibromyalgia, acute herpes zoster pain, HIV-associated neuropathy, neuropathic low back pain, chemotherapy induced neuropathic pain, radiotherapy-induced neuropathic pain, peripheral nerve injury, spinal cord injury pain, and multiple sclerosis (MS) pain. 
     
     
         32 . The method of  claim 26 , wherein the compound of Formula Ia is a compound selected from the table below: 
       
         
           
                 
                 
                 
                 
                 
                 
               
                     
                     
                 
                     
                   Compound 
                   Y 3   
                   W 
                   R 5   
                   R 8   
                 
                     
                     
                 
                     
                   102 
                   H 
                   CD 2   
                   CH 3   
                   CD 3   
                 
                     
                   103 
                   H 
                   CH 2   
                   CH 3   
                   CD 3   
                 
                     
                   104 
                   H 
                   CH 2   
                   CD 3   
                   CD 3   
                 
                     
                   105 
                   H 
                   CD 2   
                   CD 3   
                   CD 3   
                 
                     
                   112 
                   D 
                   CD 2   
                   CH 3   
                   CD 3   
                 
                     
                   113 
                   D 
                   CH 2   
                   CH 3   
                   CD 3   
                 
                     
                   114 
                   D 
                   CH 2   
                   CD 3   
                   CD 3   
                 
                     
                   115 
                   D 
                   CD 2   
                   CD 3   
                   CD 3   
                 
                     
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
               
            
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         33 . A pyrogen-free pharmaceutical composition comprising a compound of formula Ia, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 R 5  is selected from CD 3  and CH 3 ; 
 R 8  is CD 3 ; 
 W is —CY 1 Y 2 —, wherein Y 1  and Y 2  are the same and are selected from hydrogen and deuterium; and 
 Y 3  is hydrogen or deuterium; 
 wherein there is at least 50.1% incorporation of deuterium at any atom designated as D or deuterium, and wherein any atom not designated as deuterium is present at its natural isotopic abundance; and 
 
         a pharmaceutically acceptable carrier; 
         the composition additionally comprising a second therapeutic agent useful in the treatment or prevention of a disease or condition selected from anxiety, convulsions, skeletal muscle spasm, spasticity, athetosis, epilepsy, stiff person syndrome, other disorders of the central nervous system, and pain. 
       
     
     
         34 . The pyrogen-free pharmaceutical composition of  claim 33 , wherein the compound of Formula Ia is a compound selected from the table below: 
       
         
           
                 
                 
                 
                 
                 
                 
               
                     
                     
                 
                     
                   Compound 
                   Y 3   
                   W 
                   R 5   
                   R 8   
                 
                     
                     
                 
                     
                   102 
                   H 
                   CD 2   
                   CH 3   
                   CD 3   
                 
                     
                   103 
                   H 
                   CH 2   
                   CH 3   
                   CD 3   
                 
                     
                   104 
                   H 
                   CH 2   
                   CD 3   
                   CD 3   
                 
                     
                   105 
                   H 
                   CD 2   
                   CD 3   
                   CD 3   
                 
                     
                   112 
                   D 
                   CD 2   
                   CH 3   
                   CD 3   
                 
                     
                   113 
                   D 
                   CH 2   
                   CH 3   
                   CD 3   
                 
                     
                   114 
                   D 
                   CH 2   
                   CD 3   
                   CD 3   
                 
                     
                   115 
                   D 
                   CD 2   
                   CD 3   
                   CD 3   
                 
                     
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
               
            
           
         
         or a pharmaceutically acceptable salt thereof.