Quaternary ammonium salt compounds

Patent metadata

Field	Value
Publication number	US-9072734-B2
Application number	US-201013266651-A
Country	US
Kind code	B2
Filing date	Apr 27, 2010
Priority date	Apr 30, 2009
Publication date	Jul 7, 2015
Grant date	Jul 7, 2015

Abstract

[Problem]
The object of the present invention is to provide a novel compound having β2 adrenergic receptor agonist activity and muscarinic receptor antagonist activity.
[Means for Solving the Problem]
The present invention is a quaternary ammonium salt compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, with superior β2 adrenergic receptor agonist activity and muscarinic receptor antagonist activity.

First claim

The invention claimed is:

1. A quaternary ammonium salt compound represented by general formula (I):

wherein
R 1 represents a hydrogen atom or an unsubstituted C 1-8 alkyl group;
R 2 represents a single bond, unsubstituted C 1-8 alkylene or C 1-8 alkylene substituted on carbon atoms by 1 to 2 oxygen atoms, unsubstituted C 2-4 alkenylene, or unsubstituted —O—C 1-4 alkylene;
X represents a single bond, —O—, —CONR 3 —, —NR 3 CO—, or —NR 3 CO—CH 2 —O—; where R 3 represents a hydrogen atom or an unsubstituted C 1-8 alkyl group;
A 1 represents a single bond, unsubstituted C 6-10 arylene or C 6-10 arylene substituted with 1 to 4 substituents selected from the group consisting of halogen atom, hydroxyl group, cyano group, nitro group, carboxyl group, trifluoromethyl group, unsubstituted C 1-6 alkyl group, unsubstituted C 3-8 cycloalkyl group, unsubstituted C 1-6 alkoxy group, unsubstituted C 3-8 cycloalkyloxy group, mercapto group, unsubstituted C 1-6 alkylthio group, unsubstituted C 3-8 cycloalkylthio group, amino group, unsubstituted mono(C 1-6 alkyl)amino group and unsubstituted di(C 1-6 alkyl)amino group, unsubstituted 5- to 10-membered heteroarylene or 5- to 10-membered heteroarylene substituted with 1 to 4 substituents selected from the group consisting of halogen atom, hydroxyl group, cyano group, nitro group, carboxyl group, trifluoromethyl group, unsubstituted C 1-6 alkyl group, unsubstituted C 3-8 cycloalkyl group, unsubstituted C 1-6 alkoxy group, unsubstituted C 3-8 cycloalkyloxy group, mercapto group, unsubstituted C 1-6 alkylthio group, unsubstituted C 3-8 cycloalkylthio group, amino group, unsubstituted mono(C 1-6 alkyl)amino group and unsubstituted di(C 1-6 alkyl)amino group, unsubstituted C 1-4 alkylene-substituted or unsubstituted C 6-10 arylene where the substituents of C 6-10 arylene are 1 to 3 substituents selected from the group consisting of halogen atom, hydroxyl group, cyano group, nitro group, carboxyl group, trifluoromethyl group, unsubstituted C 1-6 alkyl group, unsubstituted C 3-8 cycloalkyl group, unsubstituted C 1-6 alkoxy group, unsubstituted C 3-8 cycloalkyloxy group, mercapto group, unsubstituted C 1-6 alkylthio group, unsubstituted C 3-8 cycloalkylthio group, amino group, unsubstituted mono(C 1-6 alkyl)amino group and unsubstituted di(C 1-6 alkyl)amino group, unsubstituted C 1-4 alkylene-substituted or unsubstituted 5- to 10-membered heteroarylene where the substituents of 5- to 10-membered heteroarylene are 1 to 3 substituents selected from the group consisting of halogen atom, hydroxyl group, cyano group, nitro group, carboxyl group, trifluoromethyl group, unsubstituted C 1-6 alkyl group, unsubstituted C 3-8 cycloalkyl group, unsubstituted C 1-6 alkoxy group, unsubstituted C 3-8 cycloalkyloxy group, mercapto group, unsubstituted C 1-6 alkylthio group, unsubstituted C 3-8 cycloalkylthio group, amino group, unsubstituted mono(C 1-6 alkyl)amino group and unsubstituted di(C 1-6 alkyl)amino group, or unsubstituted C 3-8 cycloalkylene or C 3-8 cycloalkylene substituted with 1 to 3 substituents selected from the group consisting of halogen and unsubstituted C 1-6 alkyl group;
R 4 represents unsubstituted C 1-10 alkylene;
R 8 and R 9 each independently represent a halogen atom, a cyano group, an unsubstituted C 1-6 alkyl group, a nitro group, —NR 10 R 11 where R 10 and R 11 each independently represent a hydrogen atom or an unsubstituted C 1-6 alkyl group, an unsubstituted C 1-6 alkoxy group, a carboxyl group, an unsubstituted C 1-6 alkoxycarbonyl group, a hydroxyl group, a trifluoromethyl group, a mercapto group, or an unsubstituted C 1-6 alkylthio group;
a and b each independently represent an integer of 0 to 3;
Y represents a group represented by formula (II):

Q represents formula (III):

wherein
R 6 and R 7 each independently represent an unsubstituted C 1-6 alkyl group or a C 1-6 alkyl group substituted with 1 to 4 substituents selected from the group consisting of halogen atom, hydroxyl group and unsubstituted C 1-6 alkoxy group, or an unsubstituted C 8-10 phenoxyalkyl group or a C 8-10 phenoxyalkyl group substituted with 1 to 4 substituents selected from the group consisting of halogen atom, hydroxyl group, unsubstituted C 1-6 alkyl group and unsubstituted C 1-6 alkoxy group;
R 5 represents an unsubstituted C 1-6 alkyl group or a C 1-6 alkyl group substituted with 1 to 4 substituents selected from the group consisting of halogen atom, hydroxyl group and unsubstituted C 1-6 alkoxy group;
n represents an integer of 1; and
m represents an integer of 0 to 3;
W − represents a negative ion;

or a pharmaceutically acceptable salt thereof.

2. The quaternary ammonium salt compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2 , X, and A 1 are any of the following (i) to (iv):
(i) R 2 represents a single bond, C 1-4 alkylene substituted on a carbon atom by an oxygen atom, unsubstituted C 1-8 alkylene, or unsubstituted —O—C 1-4 alkylene; X represents —O—; A 1 represents a single bond or unsubstituted phenylene,
(ii) R 2 represents unsubstituted C 1-4 alkylene, unsubstituted C 2-4 alkenylene, or unsubstituted —O—C 1-4 alkylene; X represents —CONR 3 —; A 1 represents a single bond, unsubstituted phenylene, unsubstituted C 1-4 alkylene-unsubstituted phenylene, or unsubstituted C 6-8 cycloalkylene,
(iii) R 2 represents unsubstituted C 1-4 alkylene; X represents —NR 3 CO— or —NR 3 CO—CH 2 —O; A 1 represents unsubstituted phenylene, and
(iv) R 2 , X, and A 1 represent a single bond.

3. The quaternary ammonium salt compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2 , X, A 1 , and R 4 are any of the following (v) to (xviii):
(v) R 2 represents a single bond; X represents —O—; A 1 represents a single bond; R 4 represents unsubstituted C 1-10 alkylene,
(vi) R 2 represents unsubstituted C 1-8 alkylene or C 1-8 alkylene substituted on a carbon atom by an oxygen atom; X represents —O—; A 1 represents a single bond; R 4 represents unsubstituted C 1-10 alkylene,
(vii) R 2 represents unsubstituted C 1-8 alkylene; X represents —O—; A 1 represents unsubstituted phenylene-; R 4 represents unsubstituted C 1-4 alkylene,
(viii) R 2 represents —O-unsubstituted C 1-4 alkylene; X represents —O—; A 1 represents unsubstituted phenylene; R 4 represents unsubstituted C 1-4 alkylene,
(ix) R 2 represents unsubstituted C 1-4 alkylene; X represents —CONR 3 —; A 1 represents a single bond; R 4 represents unsubstituted C 1-8 alkylene,
(x) R 2 represents unsubstituted C 1-4 alkylene; X represents —CONR 3 —; A 1 represents unsubstituted C 1-4 alkylene-unsubstituted phenylene; R 4 represents unsubstituted C 1-4 alkylene,
(xi) R 2 represents unsubstituted C 1-4 alkylene; X represents —CONR 3 —; A 1 represents unsubstituted C 6-8 cycloalkylene; R 4 represents unsubstituted C 1-4 alkylene,
(xii) R 2 represents unsubstituted C 1-4 alkylene; X represents —CONR 3 —; A 1 represents unsubstituted phenylene; R 4 represents unsubstituted C 1-4 alkylene,
(xiii) R 2 represents unsubstituted —O—C 1-4 alkylene; X represents —CONR 3 —; A 1 represents unsubstituted phenylene; R 4 represents unsubstituted C 1-4 alkylene,
(xiv) R 2 represents unsubstituted C 2-4 alkenylene; X represents —CONR 3 —; A 1 represents unsubstituted phenylene; R 4 represents unsubstituted C 1-4 alkylene,
(xv) R 2 represents unsubstituted C 2-4 al

Assignees

• Mitsuyama Etsuko
• Hara Takayuki
• Igarashi Junji
• Sugiyama Hiroyuki
• Yamamura Satoshi
• Nomura Johji
• Segawa Kei
• Teijin Pharma Ltd

Inventors

• Mitsuyama Etsuko
• Hara Takayuki
• Igarashi Junji
• Sugiyama Hiroyuki
• Yamamura Satoshi
• Nomura Johji
• Segawa Kei

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D401/12 Primary

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

• A61P11/06

  Antiasthmatics · CPC title

• C07D491/18

  Bridged systems · CPC title

• C07D413/12

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