[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-11053242-B2
Application number	US-202016748999-A
Country	US
Kind code	B2
Filing date	Jan 22, 2020
Priority date	Feb 6, 2015
Publication date	Jul 6, 2021
Grant date	Jul 6, 2021

Abstract

Compounds having a structure of formula (I), including stereoisomers and pharmaceutically acceptable salts and solvates thereof:wherein R1 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

We claim the following:

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

Assignees

• Neurocrine Biosciences Inc

Inventors

• Ashweek Neil
• Harriott Nicole

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · 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

• 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

• A61K31/4353

  ortho- or peri-condensed with heterocyclic ring systems · CPC title