SUBSTITUTED PYRAZOLO[1,5-a] PYRIDINE COMPOUNDS AND THEIR METHODS OF USE

Abstract

The present invention is directed to substituted pyrazolo[1,5-a]pyridines and related methods for their synthesis and use.

1 . A method for preparing a 2-substituted, 3-alkanoyl pyrazolo[1,5-a]pyridine, said method comprising acylating a 2-substituted pyrazolo[1,5-a]pyridine under conditions effective to provide a pyrazolo[1,5-a]pyridine compound comprising an acyl group at the 3-ring position. 
   
   
       2 . The method of  claim 1 , wherein said 2-substituted pyrazolo[1,5-a]pyridine possesses a moiety at the 2-ring position selected from alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, hydroxy, sulfhydryl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, alkanoyl, carbamoyloxy, thioalkyl, substituted thioalkyl, carbamoylthio, thioaryl, substituted thioaryl, amino, halo, and carbamoylamino. 
   
   
       3 . The method of  claim 2 , wherein said substituent at the 2-ring position is selected from lower alkyl, substituted lower alkyl, aryl, substituted aryl, alkoxy, halo, and alkanoyl. 
   
   
       4 . The method of  claim 3 , wherein said substituent at the 2-ring position is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, sec-butyl, phenyl, halophenyl, and methoxyphenyl. 
   
   
       5 . The method of  claim 1 , wherein said acylating comprises a Friedel Crafts acylation. 
   
   
       6 . The method of  claim 1 , wherein said acylating comprises reacting a 2-substituted pyrazolo[1,5-a]pyridine with an α-halo alkanyol chloride in the presence of aluminum chloride to provide a 2-substituted, 3-(α-haloalkanoyl)pyrazolo[1,5-a]pyridine. 
   
   
       7 . The method of  claim 6 , further comprising reacting the 2-substituted, 3-(α-haloalkanoyl)pyrazolo[1,5-a]pyridine with a nucleophile to replace the α-halo group therewith. 
   
   
       8 . A method for treating a mammalian subject experiencing neuropathic pain by administering to the subject a therapeutically effective amount of a substituted pyrazolo[1,5-a]pyridine compound having the following structure: 
     
       
         
         
             
             
         
       
       where: 
       R 2  is independently H or an organic radical selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, hydroxy, sulfhydryl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, carbamoyloxy, thioalkyl, substituted thioalkyl, carbamoylthio, thioaryl, substituted thioaryl, amino, and carbamoylamino; 
       R 3  is independently H or an organic radical selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; and 
       R 6  is independently H or an organic radical selected from the group consisting of hydroxy, sulfhydryl, alkoxy, aryloxy, thioalkyl, thioaryl, amino, halogen, alkyl, alkenyl, alkynyl, aryl, cyano, carboxyl, and carboxamido, 
       where at least one of R 2 , R 3 , and R 6  is other than a hydrogen, and in the event that R 2  is isopropyl and R 3  is 2-methylpropan-1-one, then R 6  is an organic radical other than hydrogen, 
       whereby as a result of such administering, the subject experiences relief of the neuropathic pain. 
     
   
   
       9 . The method of  claim 8 , wherein said mammalian subject is suffering from a condition selected from postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy. 
   
   
       10 . The method of  claim 8 , wherein said mammalian subject is suffering from neuropathic pain associated with a condition selected from the group consisting of migraine, herpes, HIV, traumatic nerve injury, stroke, post-ischemia, fibromyalgia, reflex sympathetic dystrophy, complex regional pain syndrome, and cancer-chemotherapeutic-induced neuropathic pain. 
   
   
       11 . The method of  claim 8 , wherein the administering is over a duration of time effective to result in attenuation or elimination of the neuropathic pain. 
   
   
       12 . The method of  claim 8 , wherein R 6  of said substituted pyrazolo[1,5-a]pyridine compound is H and R 2  is isopropyl. 
   
   
       13 . The method of  claim 8 , wherein said substituted pyrazolo[1,5-a]pyridine compound possesses the structure: 
     
       
         
         
             
             
         
       
       where Z is O, N—OH, or N—O—C(O)NH 2 ; 
       W is lower alkyl or amino; and 
       V is lower alkyl or substituted phenyl. 
     
   
   
       14 . The method of  claim 8 , wherein said substituted pyrazolo[1,5-a]pyridine compound possesses the structure: 
     
       
         
         
             
             
         
       
       and R 3  is selected from: 
     
     
       
         
         
             
             
         
       
     
   
   
       15 . The method of  claim 8 , wherein said substituted pyrazolo[1,5-a]pyridine compound is selected from the group consisting of compound 1013 (2-amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one), 1014 (1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one O-carbamoyl oxime), 1019 (1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one oxime), 1103 (2-Isopropyl-3-pyridin-4-yl-pyrazolo[1,5-a]pyridine), and 1137 (isopropyl-[4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-yl]-amine. 
   
   
       16 . The method of  claim 8 , wherein said substituted pyrazolo[1,5-a]pyridine compound is administered in combination with at least one other agent effective for treating pain. 
   
   
       17 . A method for treating inflammation by administering to a subject suffering from an inflammatory condition a therapeutically effective amount of a substituted pyrazolo[1,5-a]pyridine compound having the structure: 
     
       
         
         
             
             
         
       
       where: 
       R 2  is independently H or an organic radical selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, hydroxy, sulfhydryl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, carbamoyloxy, thioalkyl, substituted thioalkyl, carbamoylthio, thioaryl, substituted thioaryl, amino, and carbamoylamino; 
       R 3  is independently H or an organic radical selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; and 
       R 6  is independently H or an organic radical selected from the group consisting of hydroxy, sulfhydryl, alkoxy, aryloxy, thioalkyl, thioaryl, amino, halogen, alkyl, alkenyl, alkynyl, aryl, cyano, carboxyl, and carboxamido, 
       where at least one of R 2 , R 3 , and R 6  is other than a hydrogen, and in the event that R 2  is isopropyl and R 3  is 2-methylpropan-1-one, then R 6  is an organic radical other than hydrogen. 
     
   
   
       18 . A method of treating opioid dependence or opioid withdrawal syndrome in a mammalian subject by administering a substituted pyrazolo[1,5-a]pyridine compound having the following structure: 
     
       
         
         
             
             
         
       
       where: 
       R 2  is independently H or an organic radical selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, hydroxy, sulfhydryl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, carbamoyloxy, thioalkyl, substituted thioalkyl, carbamoylthio, thioaryl, substituted thioaryl, amino, and carbamoylamino; 
       R 3  is independently H or an organic radical selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; and 
       R 6  is independently H or an organic radical selected from the group consisting of hydroxy, sulfhydryl, alkoxy, aryloxy, thioalkyl, thioaryl, amino, halogen, alkyl, alkenyl, alkynyl, aryl, cyano, carboxyl, and carboxamido, 
     
     where at least one of R 2 , R 3 , and R 6  is other than a hydrogen, and in the event that R 2  is isopropyl and R 3  is 2-methylpropan-1-one, then R 6  is an organic radical other than hydrogen.