Bicyclic mglur5 positive allosteric modulators and methods of making and using same

Abstract

In one aspect, the invention relates to bicyclic mGluR5 positive allosteric modulators, for example 6-(phenylethynyl)-3,4-dihydroisoquinolin-1(2H)-one, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5); synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with glutamate dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

1 . A compound that exhibits potentiation of mGluR5 response to glutamate as an increase in response to non-maximal concentrations of glutamate in human embryonic kidney cells transfected with rat mGluR5 in the presence of the compound, compared to the response to glutamate in the absence of the compound, comprising:
 a 3,4-dihydroisoquinolin-1(2H)-one derivative having a structure:   
       
         
           
           
               
               
           
         
         wherein Y 1  is selected from N and C—R 4 ; 
         wherein Y 2  is selected from N and C—H; 
         wherein R 1  is hydrogen or an organic radical comprising 1 to 12 carbon atoms; 
         wherein each R 2a  and R 2b  is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; 
         wherein each R 3a  and R 3b  is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; 
         wherein R 4  is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms; 
         wherein R 5  is an organic radical comprising 4 to 14 carbon atoms; 
         wherein L is an organic divalent radical comprising 1 to 7 carbon atoms and is selected from: 
       
       
         
           
           
               
               
           
         
         wherein R 7a  and R 7b  together form an optionally substituted carbocyclic or heterocyclic ring having from two to five carbons or are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 5 carbon atoms selected from optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl; and 
         wherein R 8  is selected from hydrogen, and an organic radical comprising 1 to 6 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, 
         or a pharmaceutically acceptable salt or N-oxide thereof. 
       
     
     
         2 . The compound of  claim 1 ,
 wherein R 1  is an organic radical comprising 1 to 12 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, and —(CH 2 ) m -aryl or —(CH 2 ) m -heterocycle, wherein m is 1, 2, 3 or 4; and   wherein R 5  is an organic radical comprising 4 to 14 carbon atoms selected from optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl, optionally substituted aryl, and optionally substituted heteroaryl.   
     
     
         3 . The compound of  claim 1 , having a structure: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , having a structure: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1 , having a structure: 
       
         
           
           
               
               
           
         
       
     
     
         6 . A method for preparing a compound having a structure: 
       
         
           
           
               
               
           
         
         wherein Y 1  and Y 2  are independently selected from N and C—R 4 ; 
         wherein L is an organic divalent radical comprising 1 to 7 carbon atoms selected from optionally substituted C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C3-C6 cycloalkyl or C3-C6 cycloalkenyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted amido; 
         wherein R 1  is selected from hydrogen and an organic radical comprising 1 to 12 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, and —(CH 2 ) m -aryl or —(CH 2 ) m -heterocycle, wherein m is 1, 2, 3 or 4; 
         wherein each R 2a  and R 2b  is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; 
         wherein each R 3a  and R 3b  is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; 
         wherein R 4  is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms; and 
         wherein R 5  is an organic radical comprising 4 to 14 carbon atoms; 
         or a pharmaceutically acceptable salt or N-oxide thereof, 
         the method comprising the step of coupling a first reactant with a second reactant, thereby forming linking moiety L. 
       
     
     
         7 . The method of  claim 6 , wherein the has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The method of  claim 6 , wherein the has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The method of  claim 6 , wherein the has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         10 . The method of  claim 6 , wherein the method comprises the steps of:
 a) providing a first reactant having a structure represented by a formula:   
       
         
           
           
               
               
           
         
         wherein X 1  comprises a halide, a pseudohalide, a carboxylic acid, a carboxylic acid derivative, a terminal acetylene moiety, an activated vinyl moiety, a N′-hydroxybenzimidamide, or a primary or secondary amine; 
         or a pharmaceutically acceptable salt or N-oxide thereof, and 
         b) providing a second reactant having a structure represented by a formula: 
       
       
         
           
           
               
               
           
         
         wherein X 2  comprises a halide, a pseudohalide, a carboxylic acid, a carboxylic acid derivative, a terminal acetylene moiety, an activated vinyl moiety, a N′-hydroxybenzimidamide, or a primary or secondary amine; 
         c) coupling the first reactant with the second reactant, thereby forming linking moiety L, to provide a compound having a structure represented by a formula: 
       
       
         
           
           
               
               
           
         
         wherein L is an organic divalent radical comprising 1 to 7 carbon atoms selected from optionally substituted C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C3-C6 cycloalkyl or C3-C6 cycloalkenyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted amido; 
         wherein, when X 1  is halide or pseudohalide, X 2  is a terminal acetylene moiety, or an activated vinyl moiety; 
         wherein, when X 1  is a carboxylic acid or a carboxylic acid derivative, X 2  is a N′-hydroxybenzimidamide, or a primary or secondary amine; 
         wherein, when X 2  is halide or pseudohalide, X 1  is a terminal acetylene moiety, or an activated vinyl moiety; 
         wherein, when X 2  is a carboxylic acid or a carboxylic acid derivative, X 1  is a N′-hydroxybenzimidamide, or a primary or secondary amine; and 
         d) optionally, if R 1  is hydrogen, alkylating the lactam or imide moiety. 
       
     
     
         11 . A method for potentiation of metabotropic glutamate receptor activity in a mammal comprising the step of administering to the mammal at least one compound having a structure: 
       
         
           
           
               
               
           
         
         wherein Y 1  is selected from N and C—R 4 ; 
         wherein Y 2  is selected from N and C—H; 
         wherein R 1  is hydrogen or an organic radical comprising 1 to 12 carbon atoms; 
         wherein each R 2a  and R 2b  is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; 
         wherein each R 3a  and R 3b  is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; 
         wherein R 4  is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms; 
         wherein R 5  is an organic radical comprising 4 to 14 carbon atoms; 
         wherein L is an organic divalent radical comprising 1 to 7 carbon atoms and is selected from: 
       
       
         
           
           
               
               
           
         
         wherein R 7a  and R 7b  together form an optionally substituted carbocyclic or heterocyclic ring having from two to five carbons or are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 5 carbon atoms selected from optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl; and 
         wherein R 8  is selected from hydrogen, and an organic radical comprising 1 to 6 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, 
         or a pharmaceutically acceptable salt or N-oxide thereof, 
         in a dosage and amount effective to potentiate metabotropic glutamate receptor activity in the mammal. 
       
     
     
         12 . The method of  claim 11 , wherein the compound comprises: 
       
         
           
           
               
               
           
         
       
     
     
         13 . The method of  claim 11 , wherein the compound comprises: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The method of  claim 11 , wherein the compound comprises: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The method of  claim 11 , wherein the mammal is human. 
     
     
         16 . The method of  claim 11 , wherein the mammal has been diagnosed with a need for potentiation of metabotropic glutamate receptor activity prior to the administering step. 
     
     
         17 . A method for the treatment of a disorder in a mammal comprising the step of administering to the mammal at least one compound having a structure: 
       
         
           
           
               
               
           
         
         wherein Y 1  is selected from N and C—R 4 ; 
         wherein Y 2  is selected from N and C—H; 
         wherein R 1  is hydrogen or an organic radical comprising 1 to 12 carbon atoms; 
         wherein each R 2a  and R 2b  is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; 
         wherein each R 3a  and R 3b  is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; 
         wherein R 4  is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms; 
         wherein R 5  is an organic radical comprising 4 to 14 carbon atoms; 
         wherein L is an organic divalent radical comprising 1 to 7 carbon atoms and is selected from: 
       
       
         
           
           
               
               
           
         
         wherein R 7a  and R 7b  together form an optionally substituted carbocyclic or heterocyclic ring having from two to five carbons or are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 5 carbon atoms selected from optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl; and 
         wherein R 8  is selected from hydrogen, and an organic radical comprising 1 to 6 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, 
       
       or a pharmaceutically acceptable salt or N-oxide thereof, 
       in a dosage and amount effective to treat the disorder in the mammal. 
     
     
         18 . The method of  claim 17 , wherein the compound comprises: 
       
         
           
           
               
               
           
         
       
     
     
         19 . The method of  claim 17 , wherein the compound comprises: 
       
         
           
           
               
               
           
         
       
     
     
         20 . The method of  claim 17 , wherein the compound comprises: 
       
         
           
           
               
               
           
         
       
     
     
         21 . The method of  claim 17 , wherein the mammal is human. 
     
     
         22 . The method of  claim 17 , wherein the disorder is a neurological and/or psychiatric disorder associated with glutamate dysfunction. 
     
     
         23 . The method of  claim 17 , wherein the disorder is selected from dementia, delirium, amnestic disorders, age-related cognitive decline, schizophrenia, psychosis including schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, substance-related disorder, movement disorders, epilepsy, chorea, pain, migraine, diabetes, dystonia, obesity, eating disorders, brain edema, sleep disorder, narcolepsy, anxiety, affective disorder, panic attacks, unipolar depression, bipolar disorder, and psychotic depression. 
     
     
         24 . The method of  claim 17 , wherein the mammal has been diagnosed with a need for treatment of the disorder prior to the administering step.