Translocator Protein Ligands

Abstract

The present invention relates to compounds and methods for imaging translocator protein (18 kDa) (TSPO) expression in a subject. This invention also relates to compounds and methods for the treatment of neurodegenerative disorders, inflammation or anxiety in a subject.

1 - 62 . (canceled) 
     
     
         63 . A method of treating or diagnosing a disorder in a subject comprising administering to the subject a compound of formula (III) 
       
         
           
           
               
               
           
         
         wherein 
         R 12  and R 13  are each independently selected from the group consisting of H, benzyl, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, aryl and heteroaryl, each of which may optionally be substituted with one or more of halo or C 1 -C 6  alkyl; 
         or R 12  and R 13 , together with the nitrogen to which they are attached, form an optionally substituted heterocyclic ring having between 3 and 7 ring members; 
         R 14 , R 15 , R 16 , R 17  and R 18  are each independently H, halo, OH, NO 2 , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted NHC 1-6  alkyl, optionally substituted SC 1-6  alkyl, COOR 22 , (CH 2 ) n OR 22  or an optionally substituted polyether; 
         R 19  and R 21  are each independently halo, OH, NO 2 , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted NHC 1-6  alkyl, optionally substituted SC 1-6  alkyl, COOR 22 , (CH 2 ) n OR 22  or an optionally substituted polyether; 
         R 20  is H, halo, OH, NO 2 , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted NHC 1-6  alkyl, optionally substituted SC 1-6  alkyl, COOR 22 , (CH 2 ) n OR 22  or an optionally substituted polyether; 
         R 22  is optionally substituted alkyl; and 
         n is an integer from 1 to 6; 
       
       or a salt or solvate thereof. 
     
     
         64 . The method according to  claim 63 , comprising imaging translocator protein (18 kDa) (TSPO) in the subject. 
     
     
         65 . The method according to  claim 64 , comprising obtaining an image indicating the location of the protein. 
     
     
         66 . The method according to  claim 63 , wherein when the compound of formula III is radiolabelled with a radioisotope selected from the group consisting of  18 F,  123 I,  76 Br,  124 I and  75 Br. 
     
     
         67 . The method according to  claim 66 , wherein the compound of formula III is radiolabelled with  18 F,  76 Br,  124 I or  75 Br and the image is obtained by positron emission tomography (PET) imaging. 
     
     
         68 . The method according to  claim 66 , wherein the compound is radiolabelled with  123 I and the image is obtained by SPECT imaging. 
     
     
         69 . The method according to  claim 65 , wherein said image is obtained to assess the extent of TSPO binding of the compound of formula III, or salt thereof, in the brain parenchyma of the subject. 
     
     
         70 . The method according to  claim 63 , wherein the disorder is a neurodegenerative disorder, inflammation, or anxiety. 
     
     
         71 . The method according to  claim 63 , wherein the disorder is selected from the group consisting of: Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, multiple system atrophy, epilepsy, encephalopathy, stroke, brain tumour, anxiety, stress, emotional disturbances or cognitive impairment, glioblastoma, ischemic stroke, herpes encephalitis, HIV, amyotrophic lateral sclerosis, corticobasal degeneration, cancer, depression, an auto-immune disease, and an infectious disease. 
     
     
         72 . The method according to  claim 63 , wherein the subject is a human. 
     
     
         73 . A compound of formula (IV) 
       
         
           
           
               
               
           
         
         wherein 
         R 23  and R 24  are each independently selected from the group consisting of H, benzyl, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, aryl and heteroaryl, each of which may optionally be substituted with one or more of halo or C 1 -C 6  alkyl; 
         or R 23  and R 24 , together with the nitrogen to which they are attached, form an optionally substituted heterocyclic ring having between 3 and 7 ring members; 
         R 25 , R 26 , R 27 , R 28  and R 29  are each independently H, halo, OH, NO 2 , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted NHC 1-6  alkyl, optionally substituted SC 1-6  alkyl, COOR 30 , (CH 2 ) n OR 30  or an optionally substituted polyether; 
         R 30  is optionally substituted alkyl; 
         n is an integer from 1 to 6; 
         X is selected from the group consisting of O, NH, and S; 
         I, J, K and L are each independently CR 31  or N; 
         R 31  is H, halo, OH, NO 2 , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted NHC 1-6  alkyl, optionally substituted SC 1-6  alkyl, COOR 30 , (CH 2 ) n OR 30  or an optionally substituted polyether; and 
         R 33 , R 34 , R 35  and R 36  are each independently H, halo, OH, NO 2 , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl or optionally substituted heteroaryl; 
         or a salt or solvate thereof. 
       
     
     
         74 . The compound according to  claim 73 , wherein
 X is O;   I is N;   J, K, L are each CR 31 ; wherein each R 31  is independently H, halo, or an optionally substituted alkyl;   R 25 , R 26 , R 28  and R 29  are each H;   R 33 , R 34 , R 35  and R 36  are each H;   R 27  is halo, OH, NO 2 , optionally substituted alkyl, optionally substituted alkoxy, or optionally substituted aryl; and   R 23  and R 24  are each independently C 1-6  alkyl.   
     
     
         75 . The compound according to  claim 73  selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a salt or solvate thereof. 
       
     
     
         76 . The compound according to  claim 73 , wherein said compound is the (R)-enantiomer. 
     
     
         77 . The compound according to  claim 73 , radiolabelled with a radioisotope. 
     
     
         78 . The compound according to  claim 77 , wherein said radioisotope is  18 F,  123 I,  76 Br,  124 I, or  75 Br. 
     
     
         79 . A pharmaceutical composition comprising a compound according to  claim 73 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         80 . A method of treating or diagnosing a disorder in a subject comprising administering to the subject a pharmaceutical composition according to  claim 79 . 
     
     
         81 . The method according to  claim 80 , wherein the method comprises imaging translocator protein (18 kDa) (TSPO) in the subject. 
     
     
         82 . The method according to  claim 81 , wherein the method comprises obtaining an image indicating the location of the protein. 
     
     
         83 . The method according to  claim 80 , wherein when the compound is radiolabelled with a radioisotope selected from the group consisting of  18 F,  123 I,  76 Br,  124 I, and  75 Br. 
     
     
         84 . The method according to  claim 83 , wherein the compound is radiolabelled with  18 F,  76 Br,  124 I, or  75 Br and the image is obtained by positron emission tomography (PET) imaging. 
     
     
         85 . The method according to  claim 83 , wherein the compound is radiolabelled with  123 I and the image is obtained by SPECT imaging. 
     
     
         86 . The method according to  claim 82 , wherein said image is obtained to assess the extent of TSPO binding of the compound or salt thereof in the brain parenchyma of the subject. 
     
     
         87 . The method according to  claim 80 , wherein the disorder is a neurodegenerative disorder, inflammation or anxiety. 
     
     
         88 . The method according to  claim 80 , wherein the disorder is selected from the group consisting of: Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, multiple system atrophy, epilepsy, encephalopathy, stroke, brain tumour, anxiety, stress, emotional disturbances or cognitive impairment, glioblastoma, ischemic stroke, herpes encephalitis, HIV, amyotrophic lateral sclerosis, corticobasal degeneration, cancer, depression, an auto-immune disease and an infectious disease. 
     
     
         89 . The method according to  claim 80 , wherein the subject is a human. 
     
     
         90 . A compound of formula (V) for use as an intermediate in the production of a compound of formula (IV) 
       
         
           
           
               
               
           
         
         wherein 
         R 25 , R 26 , R 27 , R 28  and R 29  are each independently H, halo, OH, NO 2 , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted NHC 1-6  alkyl, optionally substituted SC 1-6  alkyl, COOR 30 , (CH 2 ) n OR 30  or an optionally substituted polyether; 
         R 30  is optionally substituted alkyl; 
         n is an integer from 1 to 6; 
         X is selected from the group consisting of O, NH and S; 
         I, J, K and L are each independently CR 31  or N; 
         R 31  is H, halo, OH, NO 2 , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted NHC 1-6  alkyl, optionally substituted SC 1-6  alkyl, COOR 30 , (CH 2 ) n OR 30  or an optionally substituted polyether; and 
         R 33 , R 34 , R 35  and R 36  are each independently H, halo, OH, NO 2 , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl or optionally substituted heteroaryl; 
         or a salt or solvate thereof; 
         provided that when I is N, R 27  is not methyl. 
       
     
     
         91 . The compound according to  claim 90  selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a salt or solvate thereof. 
       
     
     
         92 . The compound according to  claim 90 , radiolabelled with a radioisotope. 
     
     
         93 . The compound according to  claim 90 , wherein said radioisotope is  18 F,  123 I,  76 Br,  124 I, or  75 Br. 
     
     
         94 . A process for preparing a compound of formula (III), or a salt or solvate thereof, said process comprising reacting a compound of formula (VII) with a compound of formula (VIII) 
       
         
           
           
               
               
           
         
         wherein R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20  and R 21  are defined according to  claim 73  and wherein Y is a leaving group that reacts with VII. 
       
     
     
         95 . A process for preparing a compound of formula (IV), or a salt or solvate thereof, said process comprising reacting a compound of formula (V) with a compound of formula (VI) 
       
         
           
           
               
               
           
         
         wherein I, J, K, L, X, R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 33 , R 34 , R 35  and R 36  are defined according to  claim 73 .