VMAT2 inhibitor and preparation method therefor and application thereof
The present invention relates to a class of compounds that serve as VMAT2 inhibitors, and relates in particular to a compound represented by formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, and a preparation method therefor, as well as the use thereof in the preparation of a medicament for treating diseases related to VMAT2.
1 . A compound represented by formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein
“- - - ” represents a single bond or a double bond;
when “- - - ” is a single bond, R is selected from OH, H or
when “- - - ” is a double bond, R is O;
R 1 is selected from hydrogen, methyl or ethyl;
R 2 is unsubstituted C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl, or 3- to 6-membered heterocycloalkyl-C 1-3 alkyl, or
R 2 is C 3-6 cycloalkyl substituted with 1, 2 or 3 R 3 , C 3-6 cycloalkyl-C 1-6 alkyl substituted with 1, 2 or 3 R 3 , or 3- to 6-membered heterocycloalkyl-C 1-3 alkyl substituted with 1, 2 or 3 R 3 , or
R 2 is C 2-10 alkyl substituted with 2 or 3 R 3 ; and
R 3 is F, Cl, Br, SH or NH 2 .
2 . The compound, or the stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2 is selected from unsubstituted C 3-6 cycloalkyl-C 1-6 alkyl, or C 2-5 alkyl substituted with 2 or 3 R 3 ; wherein R 3 is F, Cl, or Br.
3 . The compound, or the stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 is methyl;
R 2 is trifluoroethyl, trifluoropropyl, trifluorobutyl, trifluoropentyl, bisfluoroethyl or cyclopropanemethylene;
“- - - ” is a single bond, R is selected from OH or
or “- - - ” is a double bond, and R is O.
4 . The compound, or the stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is selected from:
5 . The compound according to claim 1 , wherein the compound is a p-toluenesulfonate salt of Formula (I) selected from the group consisting of:
6 . The compound of claim 5 having the formula below:
7 . The compound according to claim 6 having a crystal form belonging to the orthorhombic system with a space group of P2 1 2 1 2 1 , and unit cell parameters of a=27.14408(13) Å, b=16.24056(7) Å, c=6.13775(3) Å, α=90°, β=90°, γ=90°, V=2705.74(2) Å3, Z=4.
8 . The compound according to claim 6 having a crystal form comprising characteristic peaks of 2θ diffraction angle at 6.33±0.2°, 10.87±0.2° and 18.89±0.2° as measured by the X-ray powder diffraction using Cu—Kα radiation.
9 . The compound according to claim 6 having crystal form B, said crystal form B comprising characteristic peaks of 2θ diffraction angle at 6.32±0.2°, 5.42±0.2° and 10.85±0.2° as measured by the X-ray powder diffraction using Cu—Kα radiation.
10 . The compound according to claim 6 having crystal form C, said crystal form C comprising characteristic peaks of 2θ diffraction angle at 5.81±0.2°, 6.33±0.2° and 12.86±0.2° as measured by the X-ray powder diffraction using Cu—Kα radiation.
11 . The compound according to claim 6 having crystal form D, said crystal form D comprising characteristic peaks of 2θ diffraction angle at 6.02±0.2° and 23.91±0.2° as measured by the X-ray powder diffraction using Cu—Kα radiation.
12 . The compound according to claim 5 having the formula below:
wherein the compound has a crystal form of the orthorhombic system with a space group of P2 1 2 1 2 1 , and unit cell parameters of a=6.28880(10) Å, b=15.7958(3) Å, c=27.9234(6) Å, α=90°, β=90°, γ=90°, V=2773.82(9) Å3, Z=4.
13 . The crystal form of the compound according to claim 6 having crystal form E, said crystal form E comprising characteristic peaks of 2θ diffraction angle at 6.06±0.2°, 18.32±0.2° and 30.79±0.2° as measured by the X-ray powder diffraction using Cu—Kα radiation.
14 . A pharmaceutical composition comprising the compound, or the stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 , and a pharmaceutically acceptable carrier.
15 . A method for preparing a compound of formula (II), comprising the following preparation steps:
wherein R 2 is selected from unsubstituted C 3-6 cycloalkyl-C 1-6 alkyl, or, C 2-10 alkyl substituted with 2 or 3 R 3 ,
R 3 is selected from F, Cl, Br or NH 2 ; and
X is a leaving group.
16 . The method according to claim 15 ,
wherein, R 2 is trifluoroethyl, trifluoropropyl, trifluorobutyl, trifluoropentyl, bisfluoroethyl or cyclopropanemethylene, and X is Cl, Br or I.
17 . A method of treating a subject having a VMAT2 related disease or disorder, the method comprising administering to the subject the compound of claim 1 or a polymorph, stereoisomer or pharmaceutically acceptable salt thereof.
18 . A method of treating a subject having a hyperkinesis disorder, the method comprising administering to the subject the compound of claim 1 or a polymorph, stereoisomer or pharmaceutically acceptable salt thereof.
19 . The method of claim 18 wherein the hyperkinesis disorder is Huntington's disease, tardive dyskinesia, Tourette syndrome or convulsion.