Compounds for the Treatment of Neurological Disorders

Abstract

Provided are compounds, pharmaceutical compositions and methods of treatment or prophylaxis of certain neurologic disorders, including disorders related to NMDA receptor activation, including neuropsychiatric disorders, neurodegenerative diorders and other neurologic diseases, disorders and conditions including stroke, brain injury, epilepsy, neuropsychiatric disorders, mood disorders, chronic pain and related conditions. The compounds are of the general Formula I, or a pharmaceutically acceptable salt, ester, prodrug or derivative thereof are provided: wherein Ar 1 and Ar 2 are independently substituted or unsubstituted aryl, heteroaryl or heterocycle; m, n, p and q are each independently 0, 1 or 2; A is a bond, CH 2 , CH═CH, C≡C, NR, O or S; Each R 3 is independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, OH, O-alkyl, O-aryl, SH, S-alkyl, fluoro, chloro, bromo, iodo, nitro, or cyano; Q is selected from CH 2 , CHR, CR 2 , NH, NR, O and S; Each Y is independently CR 2 or CR 2 CR 2 ; each R is independently selected from H, OH or alkyl, in particular C 1-4 alkyl; X is O, S, or CH 2 ; and Z is OH, NR 6 R 7 , NR 8 SO 2 (C 1 -C 6 alkyl), NR 8 C(O)NR 6 R 7 , NR 8 C(S)NR 6 R 7 , NR 8 CHO, NR 8 C(O)(C 1 -C 6 alkyl), NR 8 C(O)O(C 1 -C 6 alkyl), NR 8 -dihydrothiazole, or NR 8 -dihydroimidazole wherein each R 6 , R 7 and R 8 is independently H, C 1 -C 6 alkyl or C 6 -C 12 aralkyl; or Z comes together with Ar 2 together to form a substituted or unsubstituted heterocyclic ring system with Ar 2 .

1 . (canceled) 
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . A method of treatment or prophylaxis of neurologic disorders comprising administering to a host in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or ester thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 Ar 1  and Ar 2  are independently substituted or unsubstituted aryl; 
 m, n, p and q are each independently 0, 1 or 2; 
 A is a bond, CH 2 , CH═CH, C≡C, NR, O or S; 
 Each R 3  is independently selected from C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 1 -C 6  haloalkyl, —OH, O-alkyl, O-aryl, —SH, —S-alkyl, fluoro, chloro, bromo, iodo, nitro, or cyano; 
 Q is selected from CH 2 , CHR, CR 2 , NH, NR, O and S; 
 Each Y is independently CR 2  or CR 2 CR 7 ; 
 each R is independently selected from H, OH or alkyl, in particular C 1-4  alkyl; 
 X is O or S; and 
 Z is OH, NR 6 R 7 , NR 8 SO 2 (C 1 -C 6  alkyl), NR 8 C(O)NR 6 R 7 , NR 8 C(S)NR 6 R 7 , NR 8 CHO, NR 8 C(O)(C 1 -C 6  alkyl), NR 8 C(O)O(C 1 -C 6  alkyl), NR 8 -dihydrothiazole, or NR 8 -dihydroimidazole wherein each R 6 , R 7  and R 8  is independently H, C 1 -C 6  alkyl or C 6 -C 12  aralkyl or 
 Z comes together with Ar 2  to form a heterocyclic ring 
 
       
         
           
           
               
               
           
         
         wherein X 2  is —O—, —S—, —N(H)—, —N(R)—, —NH—CH 2 —, —N═CH—, —NR—CH 2 —, —CH 2 —N(H)—, —CH 2 —N(R)—, —CH 2 — —CH 2 —CH 2 —, —CH═CH—, —CR—CH 2 —, or —CR═CH—; or 
         Z comes together with Ar 2  to form a heterocyclic ring selected from: 
       
       
         
           
           
               
               
           
         
         wherein R 9  and R 10  are each independently H, C 1 -C 6  alkyl or aralkyl, optionally in a pharmaceutically acceptable carrier. 
       
     
     
         9 . The method of  claim 8 , wherein the disorder is a neurodegenerative disorder. 
     
     
         10 . The method of  claim 8 , wherein the neurologic disorder is neuropathic pain, stroke, traumatic brain injury, epilepsy, or other neurologic events. 
     
     
         11 . The method of  claim 8 , wherein the administration is for treatment of a host suffering from neuropathic pain. 
     
     
         12 . The method of  claim 8 , wherein the administration is for reducing neuronal injury in a host suffering from stroke or traumatic brain injury. 
     
     
         13 . The method of  claim 8 , wherein the neurological disorder is an event resulting from NMDA receptor activation. 
     
     
         14 . The method of  claim 8 , wherein the neurologic disorder is a neuropsychiatric disorder. 
     
     
         15 . The method of  claim 14 , wherein the disorder is depression. 
     
     
         16 . The method of  claim 14 , wherein the host has been diagnosed with major depression. 
     
     
         17 . The method of  claim 14 , wherein the compound is administered to a host at risk of suffering a major depressive episode. 
     
     
         18 . The method of  claim 8 , wherein the compound is administered in combination with a pharmaceutically acceptable carrier. 
     
     
         19 . The method of  claim 8 , wherein the compound is administered in combination or alternation with a second active agent. 
     
     
         20 . A method of treatment or prophylaxis of neurologic disorders comprising administering to a host in need thereof an effective amount of a compound of compound of Formula I-a, or a pharmaceutically acceptable salt or ester thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 each R 1  is independently selected from C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 1 -C 6  haloalkyl, —OH, O-alkyl, O-aryl, —SH, —S-alkyl, fluoro, chloro, bromo, iodo, nitro, or cyano; or two R 1  may be taken together with Ar 1  to form a bicyclic ring system; 
 each R 2  and R 3  is independently selected from C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 1 -C 6  haloalkyl, —OH, O-alkyl, O-aryl, —SH, —S-alkyl, fluoro, chloro, bromo, iodo, nitro, or cyano; 
 r is independently selected from 0, 1, 2, 3, 4 or 5; and 
 s is independently selected from 0, 1, 2, 3, 4 or 5; 
 
       Ar 1  and Ar 2  are independently substituted or unsubstituted aryl; 
       m, n, p and q are each independently 0, 1 or 2; 
       A is a bond, CH 2 , CH═CH, C≡C, NR, O or S; 
       Q is selected from CH 2 , CHR, CR 2 , NH, NR, O and S; 
       each Y is independently CR 2  or CR 2 CR 2 ; 
       each R is independently selected from H, OH or alkyl, in particular C 1-4  alkyl; 
       X is O or S; and 
       Z is OH, NR 6 R 7 , NR 8 SO 2 (C 1 -C 6  alkyl), NR 8 C(O)NR 6 R 7 , NR 8 C(S)NR 6 R 7 , NR 8 CHO, NR 8 C(O)(C 1 -C 6  alkyl), NR 8 C(O)O(C 1 -C 6  alkyl), NR 8 -dihydrothiazole, or NR 8 -dihydroimidazole wherein each R 6 , R 7  and R 8  is independently H, C 1 -C 6  alkyl or C 6 -C 12  aralkyl or Z comes together with Ar 2  to form a heterocyclic ring 
       
         
           
           
               
               
           
         
       
       wherein X 2  is —O—, —S—, —N(H)—, —N(R)—, —NH—CH 2 —, —N═CH—, —NR—CH 2 —, —CH 2 —N(H)—, —CH 2 —N(R)—, —CH 2 —, —CH 2 —CH 2 —, —CH═CH—, —CR—CH 2 —, or —CR═CH—; or 
       Z comes together with Ar 2  to form a heterocyclic ring selected from: 
       
         
           
           
               
               
           
         
       
       wherein R 9  and R 19  are each independently H, C 1 -C 6  alkyl or aralkyl,
 optionally in a pharmaceutically acceptable carrier. 
 
     
     
         21 . A method of treatment or prophylaxis of neurologic disorders comprising administering to a host in need thereof an effective amount of a compound of compound of Formula I-b, or a pharmaceutically acceptable salt or ester thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 m, n, p and q are each independently 0, 1 or 2; 
 A is a bond, CH 2 , CH═CH, C≡C, NR, O or S; 
 each R 3  is independently selected from C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 1 -C 6  haloalkyl, —OH, O-alkyl, O-aryl, —SH, —S-alkyl, fluoro, chloro, bromo, iodo, nitro, or cyano; 
 each Y is independently CR 2  or CR 2 CR 2 ; 
 each R is independently selected from H, OH or alkyl, in particular C 1-4  alkyl; 
 X is O or S; and 
 Z is OH, NR 6 R 7 , NR 8 SO 2 (C 1 -C 6  alkyl), NR 8 C(O)NR 6 R 7 , NR 8 C(S)NR 6 R 7 , NR 8 CHO, NR 8 C(O)(C 1 -C 6  alkyl), NR 8 C(O)O(C 1 -C 6  alkyl), NR 8 -dihydrothiazole, or NR 8 -dihydroimidazole wherein each R 6 , R 7  and R 8  is independently H, C 1 -C 6  alkyl or C 6 -C 12  aralkyl or Z comes together with the phenyl moiety to which it is attached to form heterocyclic ring 
 
       
         
           
           
               
               
           
         
         wherein X 2  is —O—, —S—, —N(H)—, —N(R)—, —NH—CH 2 —, —N═CH—, —NR—CH 2 —, —CH 2 —N(H)—, —CH 2 —N(R)—, —CH 2 —, —CH 2 —CH 2 —, —CH═CH—, —CR—CH 2 —, or —CR═CH—; or the heterocyclic ring selected from: 
       
       
         
           
           
               
               
           
         
         wherein R 9  and R 10  are each independently H, C 1 -C 6  alkyl or aralkyl,
 optionally in a pharmaceutically acceptable carrier. 
 
       
     
     
         22 . The method of  claim 21 , wherein Z comes together with the phenyl moiety to which it is attached to form the heterocyclic ring 
       
         
           
           
               
               
           
         
       
       wherein X 2  is —O—, —S—, —N(H)—, —N(R)—, —NH—CH 2 —, —N═CH—, —NR—CH 2 —, —CH 2 —N(H)—, —CH 2 —N(R)—, —CH 2 —, —CH 2 —CH 2 —, —CH═CH—, —CR—CH 2 —, or —CR═CH—. 
     
     
         23 . The method of  claim 21 , wherein Z comes together with the phenyl moiety to which it is attached to form a heterocyclic ring selected from: 
       
         
           
           
               
               
           
         
       
       wherein R 9  and R 10  are each independently H, C 1 -C 6  alkyl or aralkyl. 
     
     
         24 . The method of  claim 8 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         25 . The method of  claim 20 , wherein the administration is for reducing neuronal injury in a host suffering from stroke or traumatic brain injury. 
     
     
         26 . The method of  claim 21 , wherein the administration is for reducing neuronal injury in a host suffering from stroke or traumatic brain injury. 
     
     
         27 . The method of  claim 20 , wherein the disorder is depression. 
     
     
         28 . The method of  claim 21 , wherein the disorder is depression.