[9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11BH-pyrido-[2,1-a]isoquinolin-2-yl]methanol and compounds, compositions and methods relating thereto
Compounds having a structure of formula (I), including stereoisomers and pharmaceutically acceptable salts and solvates thereof: wherein R 1 is as defined herein. Such compounds are inhibitors of the vesicular monoamine transporter 2 (VMAT2) and have utility for treating, for example, hyperkinetic disorders. Also disclosed are compositions containing these compounds in combination with a pharmaceutically acceptable carrier or diluent, as well as methods relating to the use in a subject in need thereof.
1. A pharmaceutical composition comprising a compound having the following structure:
or a pharmaceutically acceptable salt or solvate thereof, in combination with a pharmaceutically acceptable excipient and/or diluent,
wherein:
R 1
a) —P(═O)(OR 3 ) 2 ;
b) —C(═O)alkyl, wherein alkyl is optionally substituted with R 10 and/or R 20 ;
c) —C(═O)heterocyclyl, wherein heterocyclyl is optionally substituted with R 10 and/or R 20 ;
d) —C(═O)carbocyclyl, wherein carbocyclyl is optionally substituted with R 10 and/or R 20 ;
e) —C(═O)N(R 3 )alkyl, wherein alkyl is optionally substituted with R 10 and/or R 20 ;
f) —C(═O)N(R 3 )carbocyclyl, wherein carbocyclyl is optionally substituted with R 10 and/or R 20 ;
g) —C(═O)Oalkyl, wherein alkyl is optionally substituted with R 10 and/or R 20 ; or
h) alkyl, wherein alkyl is optionally substituted with R 10 and/or and wherein,
each R 3 is independently hydrogen or alkyl;
each R 10 is independently halo, haloalkyl, cyano, nitro, trimethylsilanyl, —OR 30 , —SR 30 , —OC(O)—R 30 , —N(R 30 ) 2 , —C(O)R 30 , —C(O)OR 30 , —C(O)N(R 30 ) 2 , —N(R 30 )C(O)OR 31 , —N(R 30 )C(O)R 31 , —N(R 30 )C(═NR 31 )N(R 32 ) 2 , —N(R 30 )S(O)R 31 (where t is 1 to 2), —S(O) t OR 30 (where t is 1 to 2), —S(O) p R 30 (where p is 0 to 2) or —S(O) t N(R 30 ) 2 (where t is 1 to 2), —OP(═O)(OR 30 ) 2 , or when a single atom bears two R 10 groups such two R 10 groups may be taken together to form oxo;
each R 20 is independently alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclalkyl, heteroaryl or heteroarylalkyl, or when a single atom bears two R 20 groups such two R 20 groups may be taken together to form cycloalkyl, wherein each of said alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclalkyl, heteroaryl and heteroarylalkyl groups is optionally substituted with R 10 and/or R 22 ;
each R 22 is independently alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclalkyl, heteroaryl or heteroarylalkyl, wherein each of said alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclalkyl, heteroaryl and heteroarylalkyl groups is optionally substituted with R 10 ; and
each R 30 , R 31 and R 32 is independently hydrogen or alkyl.
2. The pharmaceutical composition of claim 1 , wherein R 1 is —P(═O)(OR 3 ) 2 .
3. The pharmaceutical composition of claim 1 , wherein R 1 is —C(═O)alkyl, and wherein alkyl is optionally substituted with R 10 and/or R 20 .
4. The pharmaceutical composition of claim 1 , wherein the compound is selected from one of the following:
2-1
2-2
2-3
2-4
2-5
2-7
2-8
2-9
2-10
2-13
2-14
2-15
2-16
2-17
2-19
2-23
2-24
2-28
2-29
2-30
2-32
2-33
2-34
2-35
2-36
2-39
3-1
3-2
3-3
3-7
3-8
3-9
3-10
3-11
3-12
3-13
4-2
4-9
4-10
4-12
4-14
4-16
4-17
4-19
4-23
4-24
4-28
4-29
4-30
4-31
4-33
4-34
4-36
4-37
4-38
or a pharmaceutically acceptable salt or solvate thereof.
5. The pharmaceutical composition of claim 1 , wherein R 1 is —C(═O)heterocyclyl, and wherein heterocyclyl is optionally substituted with R 10 and/or R 20 .
6. The pharmaceutical composition of claim 1 , wherein the compound is selected from one of the following:
2-6
2-11
2-12
2-18
2-21
2-22
2-25
2-26
2-27
2-31
2-37
4-1
4-3
4-4
4-5
4-6
4-7
4-8
4-11
4-13
4-15
4-20
4-21
4-22
4-26
4-27
4-29
4-32
4-35
5-4
5-6
5-7
5-8
5-12
5-13
5-14
5-15
5-18
5-21
5-24
5-27
5-31
5-37
5-43
5-44
5-48
5-49
5-50
5-52
5-53
5-54
6-1
6-2
6-3
6-4
6-5
6-6
6-7
6-8
6-9
6-10
6-11
6-12
6-13
6-14
or a pharmaceutically acceptable salt or solvate thereof.
7. The pharmaceutical composition of claim 1 , wherein R 1 is —C(═O)carbocyclyl, and wherein carbocyclyl is optionally substituted with R 10 and/or R 20 .
8. The pharmaceutical composition of claim 1 , wherein the compound is selected from one of the following:
2-20
2-38
3-4
3-5
3-6
4-18
4-25
or a pharmaceutically acceptable salt or solvate thereof.
9. The pharmaceutical composition of claim 1 , wherein R 1 —C(═O)N(R 3 )alkyl, and wherein alkyl is optionally substituted with R 10 and/or R 20 .
10. The pharmaceutical composition of claim 1 , wherein the compound is selected from one of the following:
5-1
5-2
5-3
5-5
5-10
5-11
5-16
5-17
5-19
5-20
5-22
5-23
5-25
5-26
5-28
5-29
5-30
5-32
5-33
5-34
5-36
5-38
5-39
5-42
5-45
5-46
5-47
5-51
5-55
5-56
5-57
or a pharmaceutically acceptable salt or solvate thereof.
11. The pharmaceutical composition of claim 1 , wherein R 1 is —C(═O)N(R 3 )carbocycle, and wherein carbocycle is optionally substituted with R 10 and/or R 20 .
12. The pharmaceutical composition of claim 1 , wherein the compound is selected from one of the following:
5-9
5-35
5-40
5-41
or a pharmaceutically acceptable salt or solvate thereof.
13. The pharmaceutical composition of claim 1 , wherein R 1 —C(═O)Oalkyl, and wherein alkyl is optionally substituted with R 10 and/or R 20 .
14. The pharmaceutical composition of claim 1 , wherein the compound is:
8-1
or a pharmaceutically acceptable salt or solvate thereof.
15. The pharmaceutical composition of claim 1 , wherein —R 1 is alkyl, and wherein alkyl is optionally substituted with R 10 and/or R 20 .
16. The pharmaceutical composition of claim 1 , wherein the compound is:
9-1
9-2
9-3
9-4
9-5
9-6
9-7
9-8
9-9
10-1
10-2
10-3
10-4
10-5
10-6
10-7
or a pharmaceutically acceptable salt or solvate thereof.
17. A method of treating a hyperkinetic disorder that benefits from inhibiting vesicular monoamine transporter 2 (VMAT2) comprising administering to a subject having said disorder a pharmaceutically effective amount of a pharmaceutical composition of claim 1 .
18. The method of claim 17 , wherein the hyperkinetic disorder is Huntington's disease, tardive dyskinesia, Tourette's syndrome or tics.
19. The pharmaceutical composition of claim 4 , wherein the compound is selected from one of the following:
2-10
4-16
4-23
4-28
4-34
4-36
4-38
or a pharmaceutically acceptable salt thereof.
20. The pharmaceutical composition of claim 4 , wherein the compound is:
2-10
or a pharmaceutically acceptable salt thereof.