Back to results
US 10,294,222 B2Granted
Benzomorpholine and benzomorpholine-substituted compounds as MGLUR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
AssigneeVanderbilt University
InventorsP. Jeffrey Conn, Craig W. Lindsley, Andrew Felts
Life of this patent
Estimating the term…
Abstract
Compounds which are useful as allosteric potentiators/positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4); synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of using the compounds, for example, in treating neurological and psychiatric disorders or other disease state associated with glutamate dysfunction.
Claims21
A compound having a structure of the following formula:
- wherein the variables are substituted or unsubstituted and:
- X is N, CH, CD, C-alkyl;
- Y is N, CH, CD, C-alkyl;
- R1 is H, alkyl, cycloalkyl (optionally substituted with one or more R), cycloheteroaryl (optionally substituted with one or more R), aryl (optionally substituted with one or more R), heteroaryl (optionally substituted with one or more R), CF3, alkoxy, CO, CH2F, CHF2, alkyl-aryl (optionally substituted with one or more R), alkyl-cycloalkyl (optionally substituted with one or more R), alkyl-heteroaryl (optionally substituted with one or more R);
- alkyl-cycloheteroaryl (optionally substituted with one or more R), CO-amino-cycloalkyl (optionally substituted with one or more R);
- R3 is H, alkyl, cycloalkyl, CF3, CH2F, CHF2, alkyl-aryl (optionally substituted with one or more R), alkyl-cycloalkyl (optionally substituted with one or more R), alkyl-heteroaryl (optionally substituted with one or more R);
- alkyl-cycloheteroaryl (optionally substituted with one or more R);
- R is independently H, alkyl, alkene, hydroxyl, alkoxy, CF3, O, O-Me, O-alkyl, O-cycloalkyl, CO—RA, SO2RA, hydroxyl, amino, aminoalkoxy, halogen, SO2, SO2-alkyl, SO2-Me, CONH2, CN, O, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl;
- RA is H, alkyl, alkene, hydroxyl, alkoxy, CF3, O, O-Me, O-alkyl, O-cycloalkyl, hydroxyl, amino, aminoalkoxy, halogen, SO2, SO2-alkyl, SO2-Me, CONH2, CN, O, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl;
- provided that at least one of X or Y is N;
- or a pharmaceutically acceptable salt thereof.
8 more elements
A method for the treatment of a neurotransmission dysfunction associated with Parkinson's disease in a mammal comprising the step of administering to the mammal a composition that comprises at least one compound of the following formula:
- wherein the variables are substituted or unsubstituted and:
- X is N, CH, CD, C-alkyl;
- Y is N, CH, CD, C-alkyl;
- R1 is H, alkyl, cycloalkyl (optionally substituted with one or more R), cycloheteroaryl (optionally substituted with one or more R), aryl (optionally substituted with one or more R), heteroaryl (optionally substituted with one or more R), CF3, alkoxy, CO, CH2F, CHF2, alkyl-aryl (optionally substituted with one or more R), alkyl-cycloalkyl (optionally substituted with one or more R), alkyl-heteroaryl (optionally substituted with one or more R);
- alkyl-cycloheteroaryl (optionally substituted with one or more R), CO-amino-cycloalkyl (optionally substituted with one or more R);
- R3 is H, alkyl, cycloalkyl, CF3, CH2F, CHF2, alkyl-aryl (optionally substituted with one or more R), alkyl-cycloalkyl (optionally substituted with one or more R), alkyl-heteroaryl (optionally substituted with one or more R);
- alkyl-cycloheteroaryl (optionally substituted with one or more R);
- R is independently H, alkyl, alkene, hydroxyl, alkoxy, CF3, O, O-Me, O-alkyl, O-cycloalkyl, CO—RA, SO2RA, hydroxyl, amino, aminoalkoxy, halogen, SO2, SO2-alkyl, SO2-Me, CONH2, CN, O, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl;
- RA is H, alkyl, alkene, hydroxyl, alkoxy, CF3, O, O-Me, O-alkyl, O-cycloalkyl, hydroxyl, amino, aminoalkoxy, halogen, SO2, SO2-alkyl, SO2-Me, CONH2, CN, O, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl;
- provided that at least one of X or Y is N;
- or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
8 more elements
A pharmaceutical composition comprising a compound having a structure represented by a compound of the following formula:
- wherein the variables are substituted or unsubstituted and:
- X is N, CH, CD, C-alkyl;
- Y is N, CH, CD, C-alkyl;
- R1 is H, alkyl, cycloalkyl (optionally substituted with one or more R), cycloheteroaryl (optionally substituted with one or more R), aryl (optionally substituted with one or more R), heteroaryl (optionally substituted with one or more R), CF3, alkoxy, CO, CH2F, CHF2, alkyl-aryl (optionally substituted with one or more R), alkyl-cycloalkyl (optionally substituted with one or more R), alkyl-heteroaryl (optionally substituted with one or more R);
- alkyl-cycloheteroaryl (optionally substituted with one or more R), CO-amino-cycloalkyl (optionally substituted with one or more R);
- R3 is H, alkyl, cycloalkyl, CF3, CH2F, CHF2, alkyl-aryl (optionally substituted with one or more R), alkyl-cycloalkyl (optionally substituted with one or more R), alkyl-heteroaryl (optionally substituted with one or more R);
- alkyl-cycloheteroaryl (optionally substituted with one or more R);
- R is independently H, alkyl, alkene, hydroxyl, alkoxy, CF3, O, O-Me, O-alkyl, O-cycloalkyl, CO—RA, SO2RA, hydroxyl, amino, aminoalkoxy, halogen, SO2, SO2-alkyl, SO2-Me, CONH2, CN, O, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl;
- RA is H, alkyl, alkene, hydroxyl, alkoxy, CF3, O, O-Me, O-alkyl, O-cycloalkyl, hydroxyl, amino, aminoalkoxy, halogen, SO2, SO2-alkyl, SO2-Me, CONH2, CN, O, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl;
- provided that at least one of X or Y is N;
- or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
8 more elements
A method for the treatment of a neurotransmission dysfunction associated with Parkinson's disease in a mammal comprising the step of co-administering to the mammal at least one compound of the following formula:
- wherein the variables are substituted or unsubstituted and:
- X is N, CH, CD, C-alkyl;
- Y is N, CH, CD, C-alkyl;
- R1 is H, alkyl, cycloalkyl (optionally substituted with one or more R), cycloheteroaryl (optionally substituted with one or more R), aryl (optionally substituted with one or more R), heteroaryl (optionally substituted with one or more R), CF3, alkoxy, CO, CH2F, CHF2, alkyl-aryl (optionally substituted with one or more R), alkyl-cycloalkyl (optionally substituted with one or more R), alkyl-heteroaryl (optionally substituted with one or more R);
- alkyl-cycloheteroaryl (optionally substituted with one or more R), CO-amino-cycloalkyl (optionally substituted with one or more R);
- R3 is H, alkyl, cycloalkyl, CF3, CH2F, CHF2, alkyl-aryl (optionally substituted with one or more R), alkyl-cycloalkyl (optionally substituted with one or more R), alkyl-heteroaryl (optionally substituted with one or more R);
- alkyl-cycloheteroaryl (optionally substituted with one or more R);
- R is independently H, alkyl, alkene, hydroxyl, alkoxy, CF3, O, O-Me, O-alkyl, O-cycloalkyl, CO—RA, SO2RA, hydroxyl, amino, aminoalkoxy, halogen, SO2, SO2-alkyl, SO2-Me, CONH2, CN, O, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl;
- RA is H, alkyl, alkene, hydroxyl, alkoxy, CF3, O, O-Me, O-alkyl, O-cycloalkyl, hydroxyl, amino, aminoalkoxy, halogen, SO2, SO2-alkyl, SO2-Me, CONH2, CN, O, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl;
- provided that at least one of X or Y is N;
- or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, with (i) a drug having a known side-effect of increasing metabotropic glutamate receptor activity, (ii) a drug known to treat a disorder associated with increasing metabotropic glutamate receptor activity, and/or (iii) a drug known to treat the neurotransmission dysfunction or other disease state associated with potentiation of mGluR4.
8 more elements
Dependencies are inferred from the claim text.