[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

Patent metadata

Field	Value
Publication number	US-2016289226-A1
Application number	US-201615017480-A
Country	US
Kind code	A1
Filing date	Feb 5, 2016
Priority date	Feb 6, 2015
Publication date	Oct 6, 2016
Grant date	—

Abstract

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.

First claim

1 . A compound having structure (I):

or a stereoisomer or pharmaceutically acceptable salt or solvate thereof,
wherein:
R 1 is a) hydrogen;
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 3 , —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 hydrogen and the compound is [(2R,3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido-[2,1-a]isoquinolin-2-yl]methanol, or a pharmaceutically acceptable salt or solvate thereof.

3 . The compound of claim 2 , wherein the compound is [(2R,3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methanol HCl.

4 . The compound of claim 1 , wherein R 1 is —P(═O)(OR 3 ) 2 .

5 . 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 .

6 . The compound of claim 5 , 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

Assignees

• Neurocrine Biosciences Inc

Inventors

• Ashweek Neil
• Harriott Nicole

Classifications

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D455/04 Primary

  containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine · CPC title

• A61K31/4745

  condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48) · CPC title