Novel compositions useful in treating brain-related diseases or disorders and methods using same

Abstract

The present invention provides compounds useful for treating or preventing a brain-related disease or disorder. The present invention further provides a method of treating or preventing a brain-related disease or disorder in a patient, comprising administering to the patient a pharmaceutical composition comprising at least one compound of the invention. The present invention further provides a method of modulating the activity of a monoamine transporter.

What is claimed is: 
     
         1 . A compound of Formula (II): 
       
         
           
           
               
               
           
         
       
       wherein:
 ring A is a monocyclic or bicyclic aryl or a monocyclic or bicyclic heteroaryl ring, and wherein the aryl or heteroaryl ring is optionally substituted with 1-4 R 1  groups; 
 ring B is a monocyclic or bicyclic arenediyl or a monocyclic or bicyclic heteroarenediyl ring, and wherein the arenediyl or heteroarenediyl ring is optionally substituted with 1-4 R 2  groups; 
 each occurrence of R 1  and R 2  is independently selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  fluoroalkyl, C 1 -C 6  heteroalkyl, F, Cl, Br, I, —CN, —NO 2 , —OR 5 , —SR 5 , —S(═O)R 5 , —S(═O) 2 R 5 , —(CH 2 ) 0-2 NHS(═O) 2 R 5 , —(CH 2 ) 0-2 C(═O)R 5 , —OC(═O)R 5 , —(CH 2 ) 0-2 CO 2 R 5 , —OCO 2 R 5 , —CH(R 5 ) 2 , —(CH 2 ) 0-2 N(R 5 ) 2 , —(CH 2 ) 0-2 C(═O)N(R 5 ) 2 , —OC(═O)N(R 5 ) 2 , —(CH 2 ) 0-2 NHC(═O)NH(R 5 ), —(CH 2 ) 0-2 NHC(═O)R 5 , —(CH 2 ) 0-2 NHC(═O)OR 5 , —C(OH)(R 5 ) 2 , and —C(NH 2 )(R 5 ) 2 ; 
 R 3  is selected from the group consisting of H, C 1 -C 6  alkyl, —OR 5 , —S(═O)R 5 , —S(═O) 2 R 5 , —C(═O)R 5 , —CO 2 R 5 , —CH(R 5 ) 2 , and —C(═O)N(R 5 ) 2 ; 
 R 4  is selected from the group consisting of —OR 5 , —SR 5 , —S(═O)R 5 , —S(═O) 2 R 5 , —NHS(═O) 2 R 5 , —C(═O)R 5 , —OC(═O)R 5 , —CO 2 R 5 , —OCO 2 R 5 , —CH(R 5 ) 2 , —N(R 5 ) 2 , —C(═O)N(R 5 ) 2 , —OC(═O)N(R 5 ) 2 , —NHC(═O)NH(R 5 ), —NHC(═O)R 5 , —NHC(═O)OR 5 , —C(OH)(R 5 ) 2 , —C(NH 2 )(R 5 ) 2 , C 1 -C 6  alkyl, C 3 -C 10  cycloalkyl, (C 4 -C 10 )heterocycle, (C 6 -C 10 )aryl, and (C 5 -C 10 )heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocycle, aryl and heteroaryl groups are independently optionally substituted; 
 each occurrence of R 5  is independently selected from the group consisting of H, C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, C 3 -C 10  cycloalkyl, —C 1 -C 3  alkyl-(C 3 -C 6  cycloalkyl), (C 4 -C 10 )heterocycle, —C 1 -C 3  alkyl-(C 4 -C 10 heterocycle), (C 6 -C 10 )aryl, —C 1 -C 3  alkyl-(C 6 -C 10 aryl), (C 5 -C 10 )heteroaryl, and —C 1 -C 3  alkyl-(C 5 -C 10  heteroaryl), wherein the alkyl, heteroalkyl, cycloalkyl, heterocycle, aryl and heteroaryl groups are independently optionally substituted; and 
 x and y are independently an integer from 0-4; 
 
       a salt or solvate thereof, and any combinations thereof. 
     
     
         2 . The compound of  claim 1 , wherein ring A is benzediyl (phenylene), pyridinediyl, pyrazinediyl, triazenediyl, imidazoldiyl, oxazolediyl, or pyrrolediyl. 
     
     
         3 . The compound of  claim 1 , wherein ring B is benzoimidazolyl, pyridinyl, or phenyl. 
     
     
         4 . The compound of  claim 1 , wherein each occurrence of R 1  and R 2  is independently selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  fluoroalkyl, C 1 -C 6  heteroalkyl, F, Cl, Br, I, —CN, —NO 2 , —OR 5 , —(CH 2 ) 0-2 NHS(═O) 2 R 5 , —(CH 2 ) 0-2 CO 2 R 5 , —(CH 2 ) 0-2 N(R 5 ) 2 , —(CH 2 ) 0-2 C(═O)N(R 5 ) 2 , —OC(═O)N(R 5 ) 2 , —(CH 2 ) 0-2 NHC(═O)R 5 , and —(CH 2 ) 0-2 NHC(═O)OR 5 . 
     
     
         5 . The compound of  claim 1 , wherein R 3  is H or C 1 -C 6  alkyl. 
     
     
         6 . The compound of  claim 1 , wherein R 4  is selected from the group consisting of —OR 5 , —NHS(═O) 2 R 5 , —NHC(═O)R 5 , C 1 -C 6  alkyl, C 3 -C 10  cycloalkyl, C 4 -C 10  heterocycle, C 6 -C 10  aryl, and C 5 -C 10  heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocycle, aryl and heteroaryl groups are independently optionally substituted. 
     
     
         7 . The compound of  claim 1 , which is selected from the group consisting of N-[4-(cyclopropylsulfamoyl)phenyl]-2-{[5-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-pyridinyl]sulfanyl}acetamide, 3-hydroxy-N′-({[4-(3-methoxypropyl)-5-(4-pyridinyl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetyl) benzohydrazide; N-(4-fluorophenyl)-2-((4-(2-((3-methoxyphenyl)amino)-2-oxoethyl)-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)thio)acetamide, a salt thereof, a solvate thereof, and any combinations thereof. 
     
     
         8 . A pharmaceutical composition comprising at least one compound of  claim 1  and at least one pharmaceutically acceptable carrier. 
     
     
         9 . A method of treating or preventing a brain-related disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of at least one compound of  claim 1 , a salt thereof, a solvate thereof, and any combinations thereof. 
     
     
         10 . The method of  claim 9 , wherein the at least one compound is selected from the group consisting of N-[4-(cyclopropylsulfamoyl)phenyl]-2-{[5-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-pyridinyl]sulfanyl}) acetamide, 3-hydroxy-N′-({[4-(3-methoxypropyl)-5-(4-pyridinyl)-4H-1,2,4-triazol-3-yl]sulfanyl)}acetyl) benzohydrazide; N-(4-fluorophenyl)-2-((4-(2-((3-methoxyphenyl)amino)-2-oxoethyl)-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)thio)acetamide, a salt thereof, a solvate thereof, and any combinations thereof. 
     
     
         11 . The method of  claim 9 , wherein the brain-related disease or disorder is at least one selected from the group consisting of attention deficit hyperactivity disorder (ADHD), schizophrenia, drug addiction, smoking addiction, eating disorders, obsessive-compulsive disorder, depression, an anxiety disorder, an affective disorder, traumatic brain injury, stroke, cognitive disorders and narcolepsy. 
     
     
         12 . The method of  claim 9 , wherein the compound enhances uptake or efflux of at least one neurotransmitter in the subject. 
     
     
         13 . The method of  claim 12 , wherein the neurotransmitter comprises at least one selected from the group consisting of serotonin, norepinephrine, and dopamine. 
     
     
         14 . The method of  claim 9 , wherein the compound inhibits the binding of at least one additional agent to a monoamine transmitter, wherein the additional agent comprises a psychostimulant or antidepressant. 
     
     
         15 . A method of modulating the activity of a mammalian monoamine transporter, the method comprising contacting the mammalian monoamine transporter with an effective amount of at least one compound of  claim 1 , a salt thereof, a solvate thereof, and any combinations thereof, whereby the activity of the mammalian monoamine transporter is modulated. 
     
     
         16 . The method of  claim 15 , wherein the at least one compound is selected from the group consisting of N-[4-(cyclopropylsulfamoyl)phenyl]-2-{[5-(5,6-dimethyl-1H-benzimidazol-2-yl)-2-pyridinyl]sulfanyl}acetamide, 3-hydroxy-N′-({[4-(3-methoxypropyl)-5-(4-pyridinyl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetyl) benzohydrazide; N-(4-fluorophenyl)-2-((4-(2-((3-methoxyphenyl)amino)-2-oxoethyl)-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)thio)acetamide, a salt thereof, a solvate thereof, and any combinations thereof. 
     
     
         17 . The method of  claim 15 , wherein the monoamine transporter is selected from the group consisting of a serotonin transporter, a norepinephrine transporter, a dopamine transporter, and any combinations thereof. 
     
     
         18 . The method of  claim 15 , wherein the monoamine transporter is in vivo. 
     
     
         19 . A method of inducing a conformational change in a monoamine transporter, the method comprising contacting the monoamine transporter with an effective amount of at least one compound of  claim 1 , whereby a conformational change is induced in the monoamine transporter. 
     
     
         20 . The method of  claim 19 , wherein the monoamine transporter is selected from the group consisting of a serotonin transporter, a norepinephrine transporter, a dopamine transporter, and any combinations thereof.