[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 compound having structure (I):
or a stereoisomer or pharmaceutically acceptable salt or solvate thereof,
wherein:
R 1 is
b) —P(═O)(OR 3 ) 2 ;
c) —C(═O)alkyl, wherein alkyl is optionally substituted with R 10 and/or R 20 ;
d) —C(═O)heterocyclyl, wherein heterocyclyl is optionally substituted with R 10 and/or R 20 ;
e) —C(═O)carbocyclyl, wherein carbocyclyl is optionally substituted with R 10 and/or R 20 ;
f) —C(═O)N(R 3 )alkyl, wherein alkyl is optionally substituted with R 10 and/or R 20 ;
g) —C(═O)N(R 3 )carbocyclyl, wherein carbocyclyl is optionally substituted with R 10 and/or R 20 ;
h) —C(═O)Oalkyl, wherein alkyl is optionally substituted with R 10 and/or R 20 ; or
i) alkyl, wherein alkyl is optionally substituted with R 10 and/or R 20 ;
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) t 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 compound of claim 1 , wherein R 1 is —P(═O)(OR 3 ) 2 .
3. The compound 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 compound of claim 3 , wherein the compound is selected from one of the following:
Cpd.
O—R 1
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
4-30
4-31
4-33
4-34
4-36
4-37
4-38
5. The compound 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 compound of claim 5 , wherein the compound is selected from one of the following:
Cpd.
O—R 1
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
7. The compound 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 compound of claim 7 , wherein the compound is selected from one of the following:
Cpd.
O—R 1
2-20
2-38
3-4
3-5
3-6
4-18
4-25
9. The compound 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 compound of claim 9 , wherein the compound is selected from one of the following:
Cpd.
O—R 1
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
11. The compound 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 compound of claim 11 , wherein the compound is selected from one of the following:
Cpd.
O—R 1
5-9
E
5-35
E
5-40
E
5-41
E.
13. The compound of claim 1 , wherein R 1 —C(═O)Oalkyl, and wherein alkyl is optionally substituted with R 10 and/or R 20 .
14. The compound of claim 13 , wherein the compound is:
Cpd
O—R 1
8-1
15. The compound of claim 1 , wherein —R 1 is alkyl, and wherein alkyl is optionally substituted with R 10 and/or R 20 .
16. The compound of claim 15 , wherein the compound is:
Cpd.
O—R 1
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
17. The compound of claim 1 having the following stereochemistry:
18. A pharmaceutical composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable excipient and/or diluent.
19. 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 compound of claim 1 .
20. The method of claim 19 , wherein the hyperkinetic disorder is Huntington's disease, tardive dyskinesia, Tourette's syndrome or tics.