Modulators of central nervous system neurotransmitters

Abstract

Disclosed are agents having pharmacological activity against cellular receptors and intracellular signaling, particularly receptors and signaling pathways of central nervous system (CNS) neurotransmitters. Also disclosed are related methods and compositions for the treatment or prevention of diseases or disorders using the agents.

1 . A compound of Formula X: 
       
         
           
           
               
               
           
         
         wherein 
         D is a member selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl; 
         J is a direct bond or optionally combined with A and X to form a 5-6 membered heterocylic ring, substituted with an R 1  and an R 2  group each independently selected from the group consisting of hydrogen and optionally substituted aryl, or optionally combined with D to form an optionally substituted aryl; 
         X is a member selected from the group consisting of 0, N and S 
         A is a member selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl; 
         E is a member selected from the group consisting of a direct bond and optionally substituted heterocylcoalkyl; 
         G is a member selected from the group consisting of hydrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl; 
         R 3  is a member selected from the group consisting of hydrogen and C 1 -C 6  alkyl, or optionally combined with G to form an optionally substituted heterocycloalkyl; 
         each of subscript a, c and d is independently an integer from 0-6; and 
         subscript b is an integer from 1-6; 
         or a pharmaceutically acceptable salt, hydrote, solvate, stereoisomer, prodrug or polymorph thereof. 
       
     
     
         2 . A compound of  claim 1 , having Formula XI; 
       
         
           
           
               
               
           
         
       
     
     
         3 . A compound of  claim 2 , wherein G is hydrogen or combined with R 3  to form a 5-6 membered heterocylcoalkyl containing 1-2 heteroatoms each independently selected from the group consisting of N and 0; and subscript b is 1-3. 
     
     
         4 . A compound of  claim 3 , wherein D is a member selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl and optionally substituted bi-phenyl; and subscript a is 0-3. 
     
     
         5 . A compound of  claim 3 , selected from the group consisting of:
 2-(aminomethyl)-5-phenyltetrahydrofuran,   2-(aminomethyl)-5-(4′-chlorophenyl)tetrahydrofuran,   2-(aminomethyl)-5-(4-bromophenyl)tetrahydrofuran,   2-(aminomethyl)-5-(4-methoxyphenyl)tetrahydrofuran,   2-(aminomethyl)-5-(4′-t-butylphenyl)tetrahydrofuran,   trans-2-(aminomethyl)-5-(2′-methoxy-5′-fluorophenyl)tetrahydrofuran,   cis-2-(aminomethyl)-5-(2′-methoxy-5-fluorophenyl)tetrahydrofuran,   2-(aminomethyl)-5-(3′-fluoro-4′-methylphenyl)tetrahydrofuran,   2-(aminomethyl)-5-cyclohexyltetrahydrofuran,   2-(aminomethyl)-5-(1′-naphthyl)tetrahydrofuran,   2-(aminomethyl)-5-(2′-naphthyl)tetrahydrofuran,   2-(aminomethyl)-5-(2′-naphthyl)tetrahydrofuran,   2-(aminoethyl)-5-phenyltetrahydrofuran,   2-(aminoethyl)-5-(4′-fluorophenyl)tetrahydrofuran,   2-(aminoethyl)-5-(4′-bromophenyl)tetrahydrofuran,   2-(aminoethyl)-5-(4′-t-butylphenyl)tetrahydrofuran,   trans-7 aminoethyl)-5-(2′-methoxy-5′-fluorophenyl)tetrahydrofuran,   cis-2-(aminoethyl)-5-(2′-methoxy-5′-fluorophenyl)tetrahydrofuran,   2-(aminoethyl)-5-cyclohexyltetrahydrofuran,   2-(aminoethyl)-5-(2′-furyl)tetrahydrofuran,   2-(aminomethyl)-5-benzyltetrahydrofuran,   2-(aminoethyl)-5-benzyltetrahydrofuran,   trans-2-(aminomethyl)-5-(2′-methoxy-5′-fluorobenzyl)tetrahydrofuran,   cis-2-(aminomethyl)-5-(2′-methoxy-5′-fluorobenzyl)tetrahydrofuran,   trans-2-(aminoethyl)-5-(2′-methoxy-5′-fluorobenzyl)tetrahydrofuran,   cis-2-(aminoethyl)-5-(2′-methoxy-5′-fluorobenzyl)tetrahydrofuran,   2-(aminomethyl)-5-(phenethyl)tetrahydrofuran,   2-(aminomethyl)-5-(4′fluorophenethyl)tetrahydrofuran,   2-(aminomethyl)-5-(3′-pyridylethyl)tetrahydrofuran,   2-(aminomethyl)-5-(2′-chloro-5′-trifluoromethyl)phenethyl)tetrahydrofuran,   2-(aminomethyl)-5-(pentafluorophenethyl)tetrahydrofuran,   2-(aminomethyl)-5-(2′-methoxy-5′fluorophenyl)tetrahydrofuran,   2-(aminomethyl)-5-(3′,4′-dimethoxyphenethyl)tetrahydrofuran,   2-(aminomethyl)-5-(1′-naphthylethyl)tetrahydrofuran,   2-(aminomethyl)-5-(2′-methoxy-1′-naphthylethyl)tetrahydrofuran,   2-(aminomethyl)-5-(4′-methoxy-1′-naphthylethyl)tetrahydrofuran,   2-(aminomethyl)-5-(2′-tetrahydrofuryl-2′-ethyl)tetrahydrofuran,   2-(aminoethyl)-5-(phenethyl)tetrahydrofuran,   2-aminoethyl)-5-(4′fluorophenethyl)tetrahydrofuran,   2-(aminoethyl)-5-(4′-hydroxyphenethyl)tetrahydrofuran,   2-(aminoethyl)-5-(4′-methoxyphenethyl)tetrahydrofuran,   2-(aminoethyl)-5-(4′trifluoromethoxyphenethyl)tetrahydrofuran,   2-(aminoethyl)-5-(4′-methylphenethyl)tetrahydrofuran,   2-(aminoethyl)-5-(4′-phenylphenethyl)tetrahydrofuran,   2-(aminoethyl)-5-(4′-t-butylphenethyl)tetrahydrofuran,   2-(aminoethyl)-5-(5′-fluoro-2′-methoxyphenethyl)tetrahydrofuran,   2-(aminoethyl)-5-(4′-fluoro-3′-methylphenethyl)tetrahydrofuran,   2-(aminoethyl)-5-(3′-fluoro-4′-methylphenethyl)tetrahydrofuran,   2-(aminoethyl)-5-(cyclohexylethyl)tetrahydrofuran,   2-(aminoethyl)-5-(3′-pyridylethyl)tetrahydrofuran,   2-(aminoethyl)-5-(1′-naphthylethyl)tetrahydrofuran,   2-(aminoethyl)-5-(2′-methoxy-1′-naphthylethyl)tetrahydrofuran,   2-(aminoethyl)-5-(4′-methoxy-1′-naphthylethyl)tetrahydrofuran,   2-(aminoethyl)-5-(2′-naphthylethyl)tetrahydrofuran,   trans-2-piperidylmethyl-5-(2′-methoxy-5′-fluorophenethyl)tetrahydrofuran,   trans-2-(N,N-diethylaminomethyl)-5-(2′-methoxy-5′-fluorophenethyl)-tetrahydrofuran,   trans-2-(morpholinomethyl)-5-(2′-methoxy-5′-fluorophenethyl)tetrahydrofuran,   2-(aminomethyl)-5-(3′-phenylpropyl)tetrahydrofuran   2-(aminoethyl)-5-(3′-phenylpropyl)tetrahydrofuran,   trans-2-(aminoethyl)-5-(3′-(2″-methoxy-5″-fluorophenyl-3′-propyl)tetrahydrofuran,   trans-2-(aminoethyl)-5-(2″-methoxy-5″-fluorophenyl-3′-propyl)tetrahydrofuran,   cis-2-(aminoethyl)-5-(2″-methoxy-5″-fluorophenyl-3′-propyl)tetrahydrofuran, and   trans-2-(piperidinomethyl)-5-(2″-methoxy-5″-fluorophenyl-3′-propyl)tetrahydrofuran   
     
     
         6 - 8 . (canceled) 
     
     
         9 . A compound of  claim 1 , having Formula XII: 
       
         
           
           
               
               
           
         
         wherein 
         D and G are both the same; 
         subscripts a and d are both 0-3 and are the same; and 
         subscripts b and c are both 2. 
       
     
     
         10 . A compound of  claim 9 , selected from the group consisting of:
 N,N-bis(5′-phenyl-2′-tetrahydrofurylethyl)amine,   N,N-bis(5′-(p-fluorophenyl)-2′-tetrahydrofurylethyl)amine,   N,N-bis(5′-(p-bromophenyl)-2′-tetrahydrofurylethyl)amine,   N,N-bis(5′-(p-t-butylphenyl)-2′-tetrahydrofurylethyl)amine,   N,N-bis(5′-cyclohexyl-2′-tetrahydrofurylethyl)amine,   N,N-bis(trans-5′-(2″-methoxy-5″-fluorophenyl-2-tetrahydrofuryl)ethyl)amine,   N,N-bis(cis-5′-(2″-methoxy-5″-fluorophenyl-2′-tetrahydrofuryl)ethyl)amine,   N,N-bis(5-benzyl-2′-tetrahydrofurylethyl)amine,   N,N-bis(5′-phenethyl-2′-tetrahydrofurylethyl)amine,   N,N-bis(5′-phenethyl-2′-tetrahydrofurylethyl)methylamine,   N,N-bis(5′-(p-hydroxyphenethyl)-2′-tetrahydrofurylethyl)amine,   N,N-bis(5′-(m-fluoro-p-methylphenethyl)-2′-tetrahydrofurylethyl)amine,   N,N-bis(5-(p-fluoro-m-methylphenethyl)-2′-tetrahydrofurylethyl)amine,   N,N-bis(5 (5″-fluoro-2″-methoxyphenethyl)-2′-tetrahydrofurylethyl)amine,   N,N-bis(5′-(3″-pyridylethyl)-2′-tetrahydrofurylethyl)amine,   N,N-bis(5′-(1″-naphthethyl)-2′-tetrahydrofurylethyl)amine,   N,N-bis(5′-(2″-methoxy-1″-naphthethyl)-2′-tetrahydrofurylethyl)amine,   N,N-bis(5′-(4″-methoxy-1″-naphthethyl)′-2′-tetrahydrofurylethyl)amine,   N,N-bis(trans-5′-(2″-methoxy-5″-fluorobenzyl-2′-tetrahydrofuranyl)ethyl)amine,   N,N-bis(cis-5′-(2″-methoxy-5″-fluorobenzyl-2′-tetrahydrofuranyl)ethyl)amine, and   N,N-bis(trans-5-(2″-methoxy-5″-fluorophenyl-3′-propyl-2′-tetrahydrofuryl)ethyl)-amine.   
     
     
         11 . A compound of  claim 1 , having Formula XIII: 
       
         
           
           
               
               
           
         
         E is an optionally substituted heterocylcoalkyl having at least from 1-3 nitrogen atoms; 
         R 1  is hydrogen or optionally combined with D to form an optionally substituted aryl; and 
         R 2  is a member selected from the group consisting of hydrogen and optionally substituted phenyl. 
       
     
     
         12 . A compound of  claim 11 , selected from the group consisting of:
 4-(3,4-Dimethoxyphenyl)-2-[5-(2-{5-[2-(5-fluoro-2-methoxyphenyl)-ethyl]-tetrahydrofuran-2-yl}-ethylamino)-pentyl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,   4-(3,4-Dimethoxyphenyl)-2-[5-(2-{5-[2-(5-fluoro-2-methoxyphenyl)-propyl]-tetra-hydrofuran-2-yl}-ethylamino)-pentyl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,   4-(3-Cyclopentyloxy-4-methoxy-phenyl)-1-[5-(2-{5-[2-(5-fluoro-2-methoxy-phenyl)ethyl]-tetrahydro-furan-2-yl}-ethylamino)-pentyl]-pyrrolidin-2-one,   4-(3-Cyclopentyloxy-4-methoxy-phenyl)-1-[5-(2-{5-[3-(5-fluoro-2-methoxy-phenyl)-propyl]-tetrahydro-furan-2-yl}-ethylamino)-pentyl]-pyrrolidin-2-one,   2-(3-{5-[4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-pentylamino}-propyl)-2-(4-fluoro-phenyl)-2,3-dihydro-benzofuran-6-carbonitrile,   2-(3-{5-[4-(3-Cyclopentyloxy-4-methoxy-phenyl)-2-oxo-pyrrolidin-1-yl]-pentylamino}-propyl)-2-(4-fluoro-phenyl)-2,3-dihydro-benzofuran-6-carbonitrile,   4-(3,4-Dimethoxy-phenyl)-2-(5-{[5-(4-methoxy-phenyl)-tetrahydro-furan-2-ylmethyl]-amino}-pentyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,   4-(3-Cyclopentyl oxy-4-methoxy-phenyl)-1-(5-{[5-(4-methoxy-phenyl)-tetrahydro-furan-2-ylmethyl]-amino}-pentyl)-pyrrolidin-2-one,   2-{5-[(5-Cyclohexyl-tetrahydro-furan-2-ylmethyl)-amino]-pentyl}-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,   1-{5-[(5-Cyclohexyl-tetrahydro-furan-2-ylmethyl)-amino]-pentyl}-4-(3-cyclopentyl-oxy-4-methoxy-phenyl)-pyrrolidin-2-one,   4-(3,4-Dimethoxy-phenyl)-2-(5-{[5-(3-fluoro-4-methyl-phenyl)-tetrahydro-furan-2-ylmethyl]-amino}-pentyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one, and   4-(3-Cyclopentyloxy-4-methoxy-phenyl)-1-(5-{[5-(3-fluoro-4-methyl-phenyl)-tetrahydro-furan-2-ylmethyl]-amino}-pentyl)-pyrrolidin-2-one.   
     
     
         13 . A compound of  claim 1 , having Formula XIV: 
       
         
           
           
               
               
           
         
         wherein 
         D is an optionally substituted phenyl; 
         A is an optionally substituted phenyl; 
         E is an optionally substituted heterocylcoalkyl having from 1-3 nitrogen atoms; 
         G is an optionally substituted phenyl; 
         subscripts hand care each independently 1-6; and 
         subscript d is 0. 
       
     
     
         14 . A compound of  claim 13 , selected from the group consisting of:
 4-(3,4-Dimethoxy-phenyl)-2-{5-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-propylamino]-pentyl}-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one, and   4-(3-Cyclopentyloxy-4-methoxy-phenyl)-1-{5-[3-phenyl-3-(4-trifluoro-methyl-phenoxy)-propylamino]-pentyl}-pyrrolidin-2-one.   
     
     
         15 . A compound of  claim 1 , wherein said compound is a dual inhibitor of serotonin reuptake and phosphodiesterase 4 (PDE4) enzyme activity. 
     
     
         16 . A pharmaceutical composition comprising: a compound of  claim 1 ; and a pharmaceutically acceptable carrier. 
     
     
         17 . A method for treating or preventing a central nervous system (CNS) disease or disorder in a subject, the method comprising: administering to a subject an effective amount of a compound of  claim 1 , wherein said subject is suffering from a CNS disease or disorder amenable to treatment or prevention by inhibition of at least one of serotonin reuptake and phosphodiesterase 4 (PDE4) activity. 
     
     
         18 . The method of  claim 17 , wherein the compound is a dual inhibitor of serotonin reuptake and phosphodiesterase 4 (PDE4) enzyme activity. 
     
     
         19 . The method of  claim 17 , wherein the CNS disease or disorder is selected from the group consisting of depression, a drug addiction, anxiety, attention-deficit disorder, schizophrenia, and bipolar disorder. 
     
     
         20 . The method of  claim 17 , wherein the CNS disease or disorder is a neurodegenerative disease or disorder. 
     
     
         21 . The method of  claim 20 , wherein the neurodegenerative disease is Parkinson's Disease or Alzheimer's Disease. 
     
     
         22 . The method of  claim 17 , wherein the compound induces non-addicting CNS stimulation in the subject. 
     
     
         23 . The method of  claim 17 , wherein the subject has been diagnosed with the CNS disease or disorder. 
     
     
         24 . The method of  claim 17 , wherein the subject is not suffering from a second disease or disorder. 
     
     
         25 . The method of  claim 17 , further comprising monitoring the subject for one or more symptoms of the CNS disease or disorder.