Benzisoxazoles and azabenzisoxazoles as MGLUR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
Benzisoxazole and azabenzisoxazole 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.
1. A method for the treatment of Parkinson's disease, parkinsonism, and disease states involving akinesia or bradykinesia in a mammal comprising the step of administering to the mammal at least one compound in a dosage and amount effective to treat the dysfunction in the mammal, the compound having a structure represented by a formula:
wherein:
A is aryl or heteroaryl or a 3-8 membered ring comprising C, O, S, and/or N;
R is selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, OC 1-10 alkyl (which may contain a C 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 4 ), NR 3 R 4 , CONR 3 R 4 , S(O) 0-2 NR 3 R 4 , CN or CF 3 ;
R 1 is independently selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, OC 1-10 alkyl (which may contain a C 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 4 ), NR 3 R 4 , CR 3 R 4 , CONR 3 R 4 , S(O) 0-2 NR 3 R 4 , CN; CF 3 , or S(O) 0-2 C 1-10 alkyl (which may contain a C 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 4 ), COC 1-10 alkyl;
R 2 is independently selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, OC 1-10 alkyl (which may contain a C 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 4 ), NR 3 R 4 , CR 3 R 4 , CONR 3 R 4 , S(O) 0-2 NR 3 R 4 , CN or CF 3 , or S(O) 0-2 C 1-10 alkyl (which may contain a C 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 4 ), COC 1-10 alkyl;
R 1 and R 2 can optionally cyclize to form a ring comprising C 3 -C 12 cycloalkyl or C 3 -C 12 cycloalkenyl or aryl or heteroaryl or C 3 -C 12 heterocycloalkyl or 3-8 membered ring comprising C, O, S, and/or N, optionally substituted with one or more R 4 ;
R 3 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF 3 ;
R 4 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF 3 ;
R 3 and R 4 can optionally cyclize to form a ring comprising C 3 -C 12 cycloalkyl or C 3 -C 12 cycloalkenyl or aryl or heteroaryl or C 3 -C 12 heterocycloalkyl or 3-8 membered ring comprising C, O, S, and/or N, optionally substituted with one or more R 5 ;
R 5 is selected from hydrogen, halogen, OC 1-10 alkyl (which may contain a C 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 4 ), CN, CF 3 ;
provided that R 1 cannot be CF 3 when R 2 is H and R 2 cannot be CF 3 when R 1 is H;
or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.
2. The method of claim 1 , wherein the mammal is a human.
3. A method for the treatment of Parkinson's disease, parkinsonism, and disease states involving akinesia or bradykinesia in a mammal comprising the step of co-administering to the mammal at least one compound in a dosage and amount effective to treat the dysfunction in the mammal, the compound having a structure represented by a formula:
wherein:
A is aryl or heteroaryl or a 3-8 membered ring comprising C, O, S, and/or N;
R is selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, OC 1-10 alkyl (which may contain a C 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 4 ), NR 3 R 4 , CONR 3 R 4 , S(O) 0-2 NR 3 R 4 , CN or CF 3 ;
R 1 is independently selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, OC 1-10 alkyl (which may contain a C 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 4 ), NR 3 R 4 , CR 3 R 4 , CONR 3 R 4 , S(O) 0-2 NR 3 R 4 , CN; CF 3 , or S(O) 0-2 C 1-10 alkyl (which may contain a C 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 4 ), COC 1-10 alkyl;
R 2 is independently selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, OC 1-10 alkyl (which may contain a C 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 4 ), NR 3 R 4 , CR 3 R 4 , CONR 3 R 4 , S(O) 0-2 NR 3 R 4 , CN or CF 3 , or S(O) 0-2 C 1-10 alkyl (which may contain a C 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 4 ), COC 1-10 alkyl;
R 1 and R 2 can optionally cyclize to form a ring comprising C 3 -C 12 cycloalkyl or C 3 -C 12 cycloalkenyl or aryl or heteroaryl or C 3 -C 12 heterocycloalkyl or 3-8 membered ring comprising C, O, S, and/or N, optionally substituted with one or more R 4 ;
R 3 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF 3 ;
R 4 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF;
R 3 and R 4 can optionally cyclize to form a ring comprising C 3 -C 12 cycloalkyl or C 3 -C 12 cycloalkenyl or aryl or heteroaryl or C 3 -C 12 heterocycloalkyl or 3-8 membered ring comprising C, O, S, and/or N, optionally substituted with one or more R 5 ;
R 5 is selected from hydrogen, halogen, OC 1-10 alkyl (which may contain a C 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 4 ), CN, CF 3 ;
provided that R 1 cannot be CF 3 when R 2 is H and R 2 cannot be CF 3 when R 1 is H;
or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof 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.
4. The method of claim 3 , wherein co-administration is substantially simultaneous.
5. The method of claim 3 , wherein co-administration is sequential.
6. The method of claim 3 , wherein the mammal is a human.
7. The method of claim 3 , wherein A is phenyl or pyrrole.
8. The method of claim 1 , wherein the compound has a structure of the following formula:
and A is phenyl or pyrrole.
9. The method of claim 3 , wherein the compound has a structure of the following formula:
and A is phenyl or pyrrole.
10. A compound having a structure represented by a formula:
wherein:
A is aryl or heteroaryl or a 3-8 membered ring comprising C, O, S, and/or N;
R is selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, OC 1-10 alkyl (which may contain a C 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 4 ), NR 3 R 4 , CONR 3 R 4 , S(O) 0-2 NR 3 R 4 , CN or CF 3 ;
R 1 is independently selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, OC 1-10 alkyl (which may contain a C 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 4 ), NR 3 R 4 , CR 3 R 4 , CONR 3 R 4 , S(O) 0-2 NR 3 R 4 , CN; CF 3 , or S(O) 0-2 C 1-10 alkyl (which may contain a C 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 4 , COC 1-10 alkyl;
R 2 is independently selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, OC 1-10 alkyl (which may contain a C 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 4 ), NR 3 R 4 , CR 3 R 4 , CONR 3 R 4 , S(O) 0-2 NR 3 R 4 , CN or CF 3 , or S(O) 0-2 C 1-10 alkyl (which may contain a C 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 4 , COC 1-10 alkyl;
R 1 and R 2 can optionally cyclize to form a ring comprising C 3 -C 12 cycloalkyl or C 3 -C 12 cycloalkenyl or aryl or heteroaryl or C 3 -C 12 heterocycloalkyl or 3-8 membered ring comprising C, O, S, and/or N, optionally substituted with one or more R 4 ;
R 3 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF 3 ;
R 4 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF 3 ;
R 3 and R 4 can optionally cyclize to form a ring comprising C 3 -C 12 cycloalkyl or C 3 -C 12 cycloalkenyl or aryl or heteroaryl or C 3 -C 12 heterocycloalkyl or 3-8 membered ring comprising C, O, S, and/or N, optionally substituted with one or more R 5 ;
R 5 is selected from hydrogen, halogen, OC 1-10 alkyl (which may contain a C 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 4 ), CN, CF 3 ;
provided that R 1 cannot be CF 3 when R 2 is H and R 2 cannot be CF 3 when R 1 is H;
or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.
11. The compound of claim 10 , of the following formula:
12. The compound of claim 10 , wherein R 5 is O-alkyl.
13. The compound of claim 10 , wherein R is hydrogen or halogen.
14. The compound of claim 10 , wherein A is phenyl or pyrrole.
15. The compound of claim 10 , wherein R 1 and R 2 are independently halogen, O-alkyl, CF 3 , OCF 3 , OCF 2 , OCF 2 CF 3 , CN, C 1-10 alkyl; COC 1-10 alkyl; OC 1-10 alkyl; or S(O) 0-2 C 1-10 alkyl (which may contain a C 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 4 ).
16. The compound of claim 10 , wherein A is pyrrole and R 1 is
17. The compound of claim 10 , wherein A is phenyl and together with R 1 and R 2 forms
18. The compound of claim 10 , wherein R 1 is halogen and R 2 is halogen; R 1 is O-alkyl and R 2 is halogen; or R 1 is O-alkyl and R 2 is O-alkyl.
19. The compound of claim 15 , wherein OC 1-10 alkyl is
20. The compound of claim 10 , of the following formula:
21. A compound of claim 10 , of the following formula:
22. A pharmaceutical composition comprising a compound having a structure represented by a formula:
wherein:
A is aryl or heteroaryl or a 3-8 membered ring comprising C, O, S, and/or N;
R is selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, OC 1-10 alkyl (which may contain a C 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 4 ), NR 3 R 4 , CONR 3 R 4 , S(O) 0-2 NR 3 R 4 , CN or CF 3 ;
R 1 is independently selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, OC 1-10 alkyl (which may contain a C 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 4 ), NR 3 R 4 , CR 3 R 4 , CONR 3 R 4 , S(O) 0-2 NR 3 R 4 , CN; CF 3 , or S(O) 0-2 C 1-10 alkyl (which may contain a C 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 4 ), COC 1-10 alkyl;
R 2 is independently selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, OC 1-10 alkyl (which may contain a C 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 4 ), NR 3 R 4 , CR 3 R 4 , CONR 3 R 4 , S(O) 0-2 NR 3 R 4 , CN or CF 3 , or S(O) 0-2 C 1-10 alkyl (which may contain a C 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 4 ), COC 1-10 alkyl;
R 1 and R 2 can optionally cyclize to form a ring comprising C 3 -C 12 cycloalkyl or C 3 -C 12 cycloalkenyl or aryl or heteroaryl or C 3 -C 12 heterocycloalkyl or 3-8 membered ring comprising C, O, S, and/or N, optionally substituted with one or more R 4 ;
R 3 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF 3 ;
R 4 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF 3 ;
R 3 and R 4 can optionally cyclize to form a ring comprising C 3 -C 12 cycloalkyl or C 3 -C 12 cycloalkenyl or aryl or heteroaryl or C 3 -C 12 heterocycloalkyl or 3-8 membered ring comprising C, O, S, and/or N, optionally substituted with one or more R 5 ;
R 5 is selected from hydrogen, halogen, OC 1-10 alkyl (which may contain a C 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 4 ), CN, CF 3 ;
provided that R 1 cannot be CF 3 when R 2 is H and R 2 cannot be CF 3 when R 1 is H;
or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof, and
a pharmaceutically acceptable carrier.
23. The composition of claim 22 , wherein the compound has the following formula:
24. The composition of claim 22 , wherein R 5 is O-alkyl.
25. The composition of claim 22 , wherein R is hydrogen or halogen.
26. The composition of claim 22 , wherein A is phenyl or pyrrole.
27. The composition of claim 22 , wherein R 1 and R 2 are independently halogen, O-alkyl, CF 3 , OCF 3 , OCF 2 , OCF 2 CF 3 , CN, C 1-10 alkyl; COC 1-10 alkyl; OC 1-10 alkyl; or S(O) 0-2 C 1-10 alkyl (which may contain a C 3-8 membered ring containing C, O, S or N, optionally substituted with one or more R 4 ).
28. The composition of claim 22 , wherein A is pyrrole and R 1 is
29. The composition of claim 27 , wherein A is phenyl and together with R 1 and R 2 form
30. The composition of claim 27 , wherein R 1 is halogen and R 2 is halogen; R 1 is O-alkyl and R 2 is halogen; or R 1 is O-alkyl and R 2 is O-alkyl.
31. The composition of claim 27 , wherein OC 1-10 alkyl is
32. The composition of claim 22 , wherein the compound is of the following formula:
33. The composition of claim 22 , wherein the compound is of the following formula:
34. The composition of claim 22 , wherein the compound is of the following formula: