[4-(1,3,3-trimethyl-2-oxo-3,4-dihydro-1H-quinoxalin-7-yl)phenoxy]ethyloxy compound or salt thereof

Patent metadata

Field	Value
Publication number	US-10189796-B2
Application number	US-201615753410-A
Country	US
Kind code	B2
Filing date	Aug 25, 2016
Priority date	Aug 25, 2015
Publication date	Jan 29, 2019
Grant date	Jan 29, 2019

Abstract

The present invention relates to a novel [4-(1,3,3-trimethyl-2-oxo-3,4-dihydro-1H-quinoxalin-7-yl)phenoxy]ethyloxy compound or a salt thereof. The compound or a salt thereof of the present invention has a glucocorticoid receptor agonist activity, and is useful as a medicine, in particular as a prophylactic or therapeutic agent for the glucocorticoid receptor related disease.

First claim

The invention claimed is:

1. A compound of general formula (1):

wherein R 1 represents a hydrogen atom, a lower alkyl group which may have a substituent(s), a carboxyl group, an ester of a carboxyl group, an amide of a carboxyl group or a cyano group; and
R 2 represents a hydrogen atom, a lower alkylcarbonyl group which may have a substituent(s), a lower cycloalkylcarbonyl group which may have a substituent(s), an arylcarbonyl group which may have a substituent(s), a heterocyclic carbonyl group which may have a substituent(s), an ester of a carboxyl group, an amide of a carboxyl group, a phosphate group or an ester of a phosphate group,
or a salt thereof.

2. The compound or a salt thereof according to claim 1 , wherein,
in the general formula (1),
R 1 represents a hydrogen atom, a lower alkyl group, a carboxyl group, an ester of a carboxyl group, an amide of a carboxyl group or a cyano group;
in the case where R 1 is a lower alkyl group, the lower alkyl group may have one or a plurality of groups selected from a halogen atom, a lower cycloalkyl group, an aryl group, a heterocyclic group, a hydroxyl group, an ester of a hydroxyl group, a lower alkoxyl group, a lower alkoxyl group substituted by a halogen atom(s), a lower cycloalkyloxy group, an aryloxy group, a heterocyclicoxy group, an amino group, a lower alkylamino group, a lower cycloalkylamino group, an arylamino group, a heterocyclic amino group, an amide of an amino group, an amide of a lower alkylamino group, an amide of a lower cycloalkylamino group, an amide of an arylamino group, an amide of a heterocyclic amino group, a lower alkylcarbonyl group, a lower cycloalkyl-carbonyl group, an arylcarbonyl group, a heterocyclic carbonyl group, a carboxyl group, an ester of a carboxyl group, an amide of a carboxyl group and a cyano group as a substituent(s);
R 2 represents a hydrogen atom, a lower alkylcarbonyl group, a lower cycloalkylcarbonyl group, an arylcarbonyl group, a heterocyclic carbonyl group, a carboxyl group, an ester of a carboxyl group, an amide of a carboxyl group, a phosphate group or an ester of a phosphate group; and
in the case where R 2 is a lower alkylcarbonyl group, a lower cycloalkyl-carbonyl group, an arylcarbonyl group or a heterocyclic carbonyl group, the lower alkylcarbonyl group, the lower cycloalkylcarbonyl group, the arylcarbonyl group or the heterocyclic carbonyl group may have one or a plurality of groups selected from a halogen atom, a lower cycloalkyl group, an aryl group, a heterocyclic group, a hydroxyl group, an ester of a hydroxyl group, a lower alkoxyl group, a lower alkoxyl group substituted by a halogen atom(s), a lower cycloalkyloxy group, an aryloxy group, a heterocyclicoxy group, an amino group, a lower alkylamino group, a lower cycloalkyl-amino group, an arylamino group, a heterocyclic amino group, an amide of an amino group, an amide of a lower alkylamino group, an amide of a lower cycloalkylamino group, an amide of an arylamino group, an amide of a heterocyclic amino group, a lower alkylcarbonyl group, a lower cycloalkylcarbonyl group, an arylcarbonyl group, a heterocyclic carbonyl group, a carboxyl group, an ester of a carboxyl group, an amide of a carboxyl group and a cyano group as a substituent(s).

3. The compound or a salt thereof according to claim 1 , wherein,
in the general formula (1),
R 1 represents a hydrogen atom, a lower alkyl group, a carboxyl group or an ester of a carboxyl group;
in the case where R 1 is a lower alkyl group, the lower alkyl group may have one or a plurality of groups selected from a halogen atom, a hydroxyl group, a lower alkoxyl group, a lower alkylcarbonyl group, a carboxyl group, an ester of a carboxyl group, an amide of a carboxyl group and a cyano group as a substituent(s);
R 2 represents a hydrogen atom, a lower alkylcarbonyl group, a heterocyclic carbonyl group, a phosphate group or an ester of a phosphate group; and
in the case where R 2 is a lower alkylcarbonyl group, the lower alkylcarbonyl group may have one or a plurality of groups selected from a halogen atom, a hydroxyl group, an ester of a hydroxyl group, a lower alkoxyl group, a lower alkoxyl group substituted by a halogen atom(s), an amino group, a lower alkylamino group, a lower alkylcarbonyl group, a carboxyl group, an ester of a carboxyl group, an amide of a carboxyl group and a cyano group as a substituent(s).

4. The compound or a salt thereof according to claim 1 , wherein
in the general formula (1),
R 1 represents a hydrogen atom, a lower alkyl group or an ester of a carboxyl group;
in the case where R 1 is a lower alkyl group, the lower alkyl group may have one or a plurality of groups selected from a halogen atom, a hydroxyl group, a carboxyl group, an ester of a carboxyl group, an amide of a carboxyl group and a cyano group as a substituent(s);
R 2 represents a hydrogen atom, a lower alkylcarbonyl group, heterocyclic carbonyl group or a phosphate group; and
in the case where R 2 is a lower alkylcarbonyl group, the lower alkylcarbonyl group may have one or a plurality of groups selected from a hydroxyl group, an amino group, a lower alkylamino group and a carboxyl group as a substituent(s).

5. The compound or a salt thereof according to claim 1 , wherein
in the general formula (1),
R 1 represents a lower alkyl group;
the lower alkyl group may have one or a plurality of hydroxyl groups as a substituent(s);
R 2 represents a hydrogen atom or a lower alkylcarbonyl group; and
in the case where R 2 is a lower alkylcarbonyl group, the lower alkylcarbonyl group may have one or a plurality of lower alkylamino groups as a substituent(s).

6. The compound or a salt thereof according to claim 1 , wherein
in the general formula (1),
R 1 represents methyl or 1-hydroxyethyl; and
R 2 represents a hydrogen atom or dimethylaminomethylcarbonyl.

7. A compound selected from the group consisting of
(S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxypropyl)oxy-2-methoxy-phenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxy-3,3,3-trifluoropropyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
(R)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxypropyl)oxy-2-methoxy-phenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
(R)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxybutyl)oxy-2-methoxy-phenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
(S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxybutyl)oxy-2-methoxy-phenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
(R)-7-[4-(2-ethoxycarbonyl-2-hydroxyethyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
(S)-7-[4-(2,4-dihydroxybutyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxy-methyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
(R)-7-[4-(2,4-dihydroxybutyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxy-methyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
(S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxyacetoxypropyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxyethyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7-[4-(2,3-dihydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxy-methyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
(S)-7-[4-(2,3-dihydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methyl-phenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
(R)-7-[4-(2,3-dihydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methyl-phenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quino

Assignees

• Santen Pharmaceutical Co Ltd

Inventors

• Kawashima Kenji
• Yamazaki Yusuke
• Takaoka Shinji
• Shii Daisuke
• Oda Tomoko
• Matsuyama Takahiro

Classifications

• C07D241/44 Primary

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/498

  Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine · CPC title

• A61K31/675

  having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate · CPC title