Compounds

Patent metadata

Field	Value
Publication number	US-9199980-B2
Application number	US-201314097586-A
Country	US
Kind code	B2
Filing date	Dec 5, 2013
Priority date	Dec 5, 2012
Publication date	Dec 1, 2015
Grant date	Dec 1, 2015

Abstract

Compounds of formula (I) described herein are inhibitors of the phosphodiesterase 4 (PDE4) enzyme and muscarinic M3 receptor antagonists and are useful for the prevention and/or treatment of diseases of the respiratory tract characterized by airway obstruction.

First claim

The invention claimed is:

1. A compound represented by formula (I):

wherein
W is aryl or heteroaryl;
each R 1 is independently hydrogen, halogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, hydroxy, —SO 2 NR 6 R 7 , —CN, —NR 8 SO 2 R 9 , —NR 6 R 7 , —CONR 6 R 7 , or —NR 8 COR 9 , and wherein said (C 1 -C 4 ) alkyl is optionally substituted by one or more groups selected from the group consisting of (C 3 -C 7 ) cycloalkyl, hydroxyl, and —NR 6 R 7 and said (C 1 -C 4 ) alkoxy is optionally substituted by one or more halogen atoms or (C 3 -C 7 ) cycloalkyl groups, and
wherein,
R 6 is hydrogen or (C 1 -C 6 ) alkyl;
R 7 is hydrogen or (C 1 -C 6 ) alkyl;
R 8 is hydrogen or (C 1 -C 6 ) alkyl;
R 9 is hydrogen or (C 1 -C 6 ) alkyl;

n is an integer ranging from 1 to 3;
each R 2 is independently hydrogen, halogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 )haloalkyl, hydroxy, —SO 2 NR 10 R 11 , —CN, or —NR 12 SO 2 R 13 , and wherein said (C 1 -C 4 ) alkyl and (C 1 -C 4 ) alkoxy are optionally substituted by one (C 3 -C 7 ) cycloalkyl group,
R 10 is hydrogen or (C 1 -C 6 ) alkyl;
R 11 is hydrogen or (C 1 -C 6 ) alkyl;
R 12 is hydrogen or (C 1 -C 6 ) alkyl;
R 13 is hydrogen or (C 1 -C 6 ) alkyl;

m is an integer ranging from 1 to 3;
p is zero or 1;
L 1 is a group (CH 2 ) t wherein t is 0 or an integer ranging from 1 to 3;
L 2 is:
(CH 2 ) q wherein q is an integer ranging from 1 to 3,
divalent ortho-benzyl (o-C 6 H 4 —CH 2 —),
divalent meta-benzyl (m-C 6 H 4 —CH 2 —),
divalent para-benzyl (p-C 6 H 4 —CH 2 —),
divalent ortho-methyleneoxy-benzyl (o-CH 2 —O—C 6 H 4 —CH 2 —),
divalent meta-methyleneoxy-benzyl (m-CH 2 —O—C 6 H 4 —CH 2 —), or
divalent para-methylenoxy-benzyl (p-CH 2 —O—C 6 H 4 —CH 2 —), wherein the carbon chain atom of the benzyl group is linked to the nitrogen atom and the respective aromatic carbon atom or the methylene carbon atom of the methylene oxy group is linked to the phenyl group;
R 3 and R 4 are different or the same and are each independently:
H;
(C 3 -C 7 ) cycloalkylcarbonyl;
(C 1 -C 6 ) alkyl, optionally substituted by one or more substituents selected from (C 3 -C 7 ) cycloalkyl or (C 5 -C 7 ) cycloalkenyl;
(C 1 -C 6 ) haloalkyl;
(C 3 -C 7 ) cycloalkyl;
(C 5 -C 7 ) cycloalkenyl;
(C 2 -C 6 ) alkenyl; or
(C 2 -C 6 ) alkynyl;
or R 3 and R 4 , together with the interconnecting atoms, form a 2,2-difluoro-1,3-dioxolane ring of formula (r) fused to the phenyl moiety which bears groups —OR 3 and —OR 4 , wherein asterisks indicate carbon atoms shared with the phenyl ring:

each R 5 is independently CN, NO 2 , CF 3 or a halogen atom;
k is an integer ranging from 1 to 3; and
A is a nitrogen containing group which may be:
a group (a) which is —(CH 2 ) s —NR 14 R 15 wherein s is an integer ranging from 1 to 4 and R 14 and R 15 are independently hydrogen or (C 1 -C 4 ) alkyl; or
a group (b) which is a saturated monocyclic, bicyclic, or tricyclic heterocyclic ring system optionally substituted by one or two groups R 16 which are at each occurrence independently (C 1 -C 4 ) alkyl or benzyl;
an N-oxide on the pyridine ring, deuterated derivative, or a pharmaceutically acceptable salt thereof.

2. A compound, N-oxide, deuterated derivative, or a pharmaceutically acceptable salt according to claim 1 , which is represented by formula (IB):

3. A compound, N-oxide, deuterated derivative, or a pharmaceutically acceptable salt according to claim 1 , which is represented by the formula (ID):

4. A compound N-oxide, deuterated derivative, or a pharmaceutically acceptable salt according to claim 1 , which is represented by formula (IA):

5. A compound, N-oxide, deuterated derivative, or a pharmaceutically acceptable salt according to claim 1 , which is represented by formula (IE):

wherein L 2 and L 1 are located in the ortho, meta or para position on the phenyl ring they are linked to;
L 1 is selected from a group (CH 2 ) t wherein t is 0 or an integer ranging from 1 to 3; and
L 2 is:
(CH 2 ) q wherein q is an integer ranging from 1 to 3,
divalent meta-benzyl (m-C 6 H 4 —CH 2 —),
divalent para-benzyl (p-C 6 H 4 —CH 2 —),
divalent meta-methyleneoxy-benzyl (m-CH 2 —O—C 6 H 4 —CH 2 —), or
divalent para-methylenoxy-benzyl (p-CH 2 —O—C 6 H 4 —CH 2 —), wherein the carbon chain atom of the benzyl group is linked to the nitrogen atom and the respective aromatic carbon atom or the methylene carbon atom of the methylene oxy group is linked to the phenyl group.

6. A compound, N-oxide, deuterated derivative, or a pharmaceutically acceptable salt according to claim 1 , which has the absolute configuration of carbon (1) shown in formula (I)′:

7. A compound, N-oxide, deuterated derivative, or a pharmaceutically acceptable salt according to claim 1 which is a compound selected from the group consisting of:
(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]3-[(4-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]3-[(3-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]3-[(2-methoxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]3-[(3-methoxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]3-[(4-methoxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]4-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]benzoate;
[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]4-[(4-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]4-[(2-methoxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]4-[(3-methoxy-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]4-[(2-methyl-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate;
[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]benzoate;
[(1R)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]3-[(

Assignees

• Chiesi Farma Spa

Inventors

• Armani Elisabetta
• Amari Gabriele
• Riccaboni Mauro
• Rizzi Andrea
• Baker-Glenn Charles
• Blackaby Wesley
• Van De Poel Herve′
• Whittaker Ben

Classifications

• A61K31/439

  the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46) · CPC title

• C07D453/00

  Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids · CPC title

• C07D453/02 Primary

  containing not further condensed quinuclidine ring systems · CPC title

• A61K9/0075

  for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles · CPC title

• A61P11/06

  Antiasthmatics · CPC title