Cyclohexyl and quinuclidinyl carbamate derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activity

Patent metadata

Field	Value
Publication number	US-9518050-B2
Application number	US-201314653048-A
Country	US
Kind code	B2
Filing date	Dec 17, 2013
Priority date	Dec 18, 2012
Publication date	Dec 13, 2016
Grant date	Dec 13, 2016

Abstract

The present invention relates to novel compounds having β2 adrenergic agonist and M3 muscarinic antagonist dual activity, to pharmaceutical compositions containing them, to the process for their preparation and to their use in respiratory therapies.

First claim

The invention claimed is:

1. A compound of Formula (A), or a pharmaceutically acceptable salt or deuterated derivative thereof:

wherein:
R is chosen from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, a linear or branched C 1-4 alkyl group, a linear or branched C 1-4 hydroxyalkyl group, and a linear or branched C 1-4 alkoxy group,
n is lor 2,
R 1 is:

wherein:
R 2 and R 3 are independently chosen from a hydrogen atom, a linear or branched C 1-4 alkyl group, a (C 5-6 aryl)-(C 1-4 )alkyl group, and a linear or branched C 1-4 alkoxy group,
R′ is chosen from a hydrogen atom or a linear or branched C 1-4 alkyl group,
* is a point of attachment of R 1 to the remainder of the molecule of Formula (A),
L x is a suitable covalent linker, and
B represents a group of Formula (IB):

wherein:
R 4 is chosen from the group consisting of a hydrogen atom, a linear or branched C 1-4 alkyl group, and a linear or branched C 1-4 alkoxy group,
Ar is chosen from the group consisting of a C 3-10 saturated or unsaturated, mono- or bicyclic cycloalkyl group; a C 5 -C 14 mono- or bicyclic aryl group; a 3 to 14-membered saturated or unsaturated mono- or bicyclic heterocyclyl group having one or more heteroatoms chosen from N, S, and O; and a 5- to 14-membered mono- or bicyclic heteroaryl group having one or more heteroatoms chosen from N, S, and O; and wherein the cyclic groups independently are optionally substituted with one or more substituents chosen from a halogen atom, a cyano group, a nitro group, an oxo group, a carboxy group, a C 1-4 alkyl group, a C 1-4 alkoxy group, —CF 3 , —OCF 3 , —NR e R f , —(CH 2 ) p —OH, —NR e (CO)R f , —NR e —SO 2 —R g , —SO 2 NR e R f , —OC(O)R h , and —NR e (CH 2 ) (0-2) —R i , wherein p is 0, 1 or 2 and wherein:

R e and R f are independently chosen from a hydrogen atom and a linear or branched C 1-4 alkyl group,
R g is chosen from the group consisting of a linear or branched C 1-4 alkyl group, a C 5-6 aryl group, and a saturated or unsaturated C 3-8 cycloalkyl, wherein the cyclic groups independently are optionally substituted with one or more substituents chosen from a halogen atom, a C 1-4 alkyl group, and a C 1-4 alkoxy group, R h is chosen from a hydrogen atom, —NR e R f , and a C 5-6 aryl group, which is optionally substituted with one or more substituents chosen from a C 1-4 alkyl group and a C 1-4 alkoxy group,
R i is chosen from the group consisting of a C 5-6 aryl group, a C 3-8 cycloalkyl group, and a 3 to 8 membered saturated or unsaturated heterocyclyl group, which groups independently are optionally substituted with one or more substituents chosen from a halogen atom, a C 1-4 alkyl group, and a C 1-4 alkoxy group.

2. The compound according to claim 1 , wherein L x is Formula (La) or Formula (Lb):

wherein k1, k2, s1, s2, l2, t1, and t2 are independently 0 or 1;
A 1 , A 2 , A 3 , A 4 and A 5 are independently chosen from the group consisting of a direct bond, a C 1-10 alkylene group, a C 2-10 alkenylene group, and a C 2-10 alkynylene group, wherein said groups are optionally substituted with one or more substituents chosen from a halogen atom, a hydroxy group, a linear or branched C 1-4 alkyl group, a linear or branched C 1-4 alkoxy group, a C 5-6 aryl group, and a C 3-7 cycloalkyl group,
L, L 1 and L 2 are independently chosen from a direct bond, —O—, —NR c —, —S—, —S(O)—, —SO 2 —, —NR c (CO)—, —(CO)NR c —, —NR c (CO)(CH 2 ) q O—, —O(CH 2 ) q (CO)NR c —, —NR c (CO)(CH 2 ) q NR c (CO)—, —O(CH 2 ) q NR c —, —NR c (CH 2 ) q O—, —NR c (CO)NR d —, —C(O)—, —C(O)O—, —OC(O)—, —S(O) 2 NR c —, —NR c S(O) 2 —, —NR c S(O) 2 NR d —, —C(O)NR c S(O) 2 —, and —S(O) 2 NR c C(O)—, wherein R c and R d are independently chosen from a hydrogen atom and a linear or branched C 1-4 alkyl group and q is 0, 1, 2, 3 or 4,
G and G 2 are independently chosen from the group consisting of a direct bond; a C 3-10 mono- or bicyclic cycloalkyl group; a C 5 -C 14 mono- or bicyclic aryl group; a 3 to 14-membered saturated or unsaturated mono- or bicyclic heterocyclyl group having one or more heteroatoms chosen from N, S, and O; a 5- to 14-membered mono- or bicyclic heteroaryl group having one or more heteroatoms chosen from N, S, and O; and a bicyclic ring system comprising two monocyclic ring systems which are linked between each other by a covalent bond or by a —O— or —NH— group; wherein said monocyclic ring systems are independently chosen from a C cydcloalkyl group; a C 5-6 aryl group; a 3 to 8-membered saturated or unsaturated heterocyclyl group having one or more heteroatoms chosen from N, S, and O; and a 5- to 6-membered heteroaryl group having one or more heteroatoms chosen from N, S, and O; wherein the cyclic groups independently are optionally substituted with one or more substituents chosen from a halogen atom, a C 1-4 alkyl group, a C 1-4 alkoxy group, a carboxy group, a cyano group, a nitro group, a hydroxy group, an oxo group, a trifluoromethyl group, and a trifluoromethoxy group.

3. The compound according to claim 2 , wherein k1, k2, s1, s2, l2, t1 and t2 are 0.

4. The compound according to claim 3 , wherein Lx is Formula (Lb1):

5. The compound according to claim 1 , wherein Lx is -A 1 -G-L-A 2 -.

6. The compound according to claim 1 , wherein Ar is formula (a), (b), (c), or (d):

wherein
G a and G b are independently chosen from a nitrogen atom and a carbon atom,
r is 0, 1, 2 or 3 and
R a is chosen from the group consisting of a halogen atom, an amino group, a cyano group, a nitro group, an oxo group, a carboxy group, a C 1-4 alkyl group, a C 1-4 alkoxy group, —CF 3 , —OCF 3 , —(CH 2 ) p —OH, —NH(CO)H, —NH—SO 2 —R g , —SO 2 NH 2 , —OC(O)H, —O(CO)-(4-methyl)phenyl, —O(CO)—N(CH 3 ) 2 , —OC(O)NH 2 , or —NH(CH 2 ) (1-2) —R i , wherein p is as defined above and R g and R i are independently chosen from a phenyl group optionally substituted with a one substituent chosen from a methyl group and a methoxy group,
R j is a halogen atom,
T is chosen from the group consisting of —CH 2 — and —NH—,
Both X and Y are a hydrogen atom or X together with Y forms —CH 2 —CH 2 —, —CH═CH—, —CH 2 —O—, or —S—, wherein in the case of —CH 2 —O— the methylene group is bound to the carbonyl group holding X and the oxygen atom is bound to the carbon atom in the phenyl ring holding Y.

7. The compound according to claim 6 , wherein Ar is formula (a) or (b) wherein:

Both G a and G b are a carbon atom,
R a is chosen from the group consisting of halogen atom, amino group, cyano group, nitro group, —(CH 2 ) p —OH, —NH(CO)H, —NH—SO 2 —CH 3 , —SO 2 NH 2 , —OC(O)H, —O(CO)-(4-methyl)phenyl, —O(CO)—N(CH 3 ) 2 , —OC(O)NH 2 , or —CF 3 , wherein p is 0, 1 or 2,
T is —NH—,
Both X and Y are a hydrogen atom or X together with Y forms —CH═CH—, —CH 2 —CH 2 —, —CH 2 —O—, or —S—, wherein in the case of —CH 2 —O— the methylene group is bound to the carbon atom in the amido substituent holding X and the oxygen atom is

Assignees

• Almirall Sa

Inventors

• Sole Feu Laia
• Carranco Moruno Ines
• Aiguade Bosch Jose
• Puig Duran Carlos
• Fonquerna Pou Silvia

Classifications

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P43/00

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P27/06

  Antiglaucoma agents or miotics · CPC title