Cyclohexylamine derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities

Patent metadata

Field	Value
Publication number	US-9315463-B2
Application number	US-201113697060-A
Country	US
Kind code	B2
Filing date	May 13, 2011
Priority date	May 13, 2010
Publication date	Apr 19, 2016
Grant date	Apr 19, 2016

Abstract

The present disclosure 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 (I), or pharmaceutically acceptable salts or solvates or deuterated derivatives thereof:

wherein:
X and Y are each independently a hydrogen atom, or X together with Y form the group —CH═CH—, —CH 2 —O— or —S—, wherein when X together with Y form —CH 2 —O—, the methylene group is bonded to the carbon atom in the amide substituent holding X and the oxygen atom is bonded to the carbon atom in the phenyl ring holding Y;
R 1 and R 2 are each independently chosen from a hydrogen atom or C 1-4 alkyl groups;
R 3 is chosen from a group of formula i) or ii):

wherein:
R a is chosen from a hydrogen atom, hydroxyl group, hydroxymethyl group, or C 1-4 alkyl groups,
R b and R c are each independently chosen from a thienyl group, phenyl group, benzyl group or C 4-6 cycloalkyl groups,
Z is chosen from a direct bond or an oxygen atom, and
* represents the point of attachment of R 3 to the remainder of the molecule of formula (I);
A 1 and A 2 are each independently C 1-6 alkylene groups unsubstituted or substituted with at least one C 1-4 alkyl group;
L is chosen from a direct bond, —O—, —NH(CO)—, —(CO)NH— or —NH(CO)O— group, wherein when L is —NH(CO)O—, the nitrogen atom is bonded to the W substituent and the oxygen atom is bonded to the A 2 substituent; and
W is chosen from a direct bond or phenylene group unsubstituted or substituted with at least one substituent each independently chosen from halogen atoms, C 1-4 alkyl groups, C 1-4 alkoxy groups, or cyano groups.

2. The compound according to claim 1 , wherein X together with Y form —CH═CH— or —CH 2 —O— group.

3. The compound according to claim 1 , wherein R 1 and R 2 are each independently chosen from a hydrogen atom or methyl group.

4. The compound according to claim 1 , wherein R 1 is a hydrogen atom and R 2 is a methyl group.

5. The compound according to claim 1 , wherein R 3 is a group of formula ii), wherein Z is an oxygen atom and R a is chosen from a hydrogen atom, hydroxyl group, or methyl group.

6. The compound according to claim 1 , wherein R 3 is a group of formula i) wherein:
R a is chosen from a hydrogen atom, hydroxyl group or methyl group, and
R b and R c are each independently chosen from a thienyl group, cyclopentyl group or phenyl group.

7. The compound according to claim 1 , wherein A 1 and A 2 are each independently C 1-6 alkylene groups unsubstituted or substituted with one or two methyl groups.

8. The compound according to claim 1 , wherein L is chosen from a —O—, —NH(CO)— or —NH(CO)O— group.

9. The compound according to claim 1 , wherein W is a phenylene group unsubstituted or substituted with one or two substituents each independently chosen from a chlorine atom, methyl group, methoxy group or cyano group.

10. The compound according to claim 1 , wherein
X together with Y form —CH═CH— or —CH 2 —O— group,
R 1 is chosen from a hydrogen atom or methyl group,
R 2 is chosen from a hydrogen atom or methyl group,
R 3 is a group of formula (i), wherein R a is a hydroxyl group and R b and R c are each independently chosen from a phenyl group, cyclopentyl group or thienyl group, or R 3 is a group of formula (ii), wherein R a is a methyl group and Z is an oxygen atom,
A 1 and A 2 are each independently C 1-6 alkylene groups unsubstituted or substituted with one or two methyl groups,
L is chosen from a direct bond, —O—, —NH(CO)— or —NH(CO)O— group, and W is chosen from a direct bond or phenylene group unsubstituted or substituted with one or two substituents each independently chosen from a chlorine atom, fluorine atom, methoxy group, or cyano group.

11. The compound according to claim 10 , wherein
X together with Y form —CH═CH— group,
R 1 is a hydrogen atom,
R 2 is chosen from a hydrogen atom or methyl group,
R 3 is a group of formula (I), wherein R a is a hydroxyl group and both R b and R c are thienyl groups,
A 1 and A 2 are each independently C 1-6 alkylene groups unsubstituted or substituted with one or two methyl groups,
L is chosen from a direct bond, —O—, —NH(CO)— or —NH(CO)O— groups, and
W is chosen from a direct bond or phenylene group unsubstituted, or substituted with one or two substituents each independently chosen from a chlorine atom, methoxy group, or cyano group.

12. The compound according to claim 11 , wherein R 2 is a hydrogen atom, L is chosen from a —O—, —NH(CO)— or —NH(CO)O— group, and W is a phenylene group substituted with two substituents each independently chosen from a chlorine atom, methyl group, methoxy group, or cyano group.

13. The compound according to claim 11 , wherein R 2 is a methyl group, L is chosen from a —O—, —NH(CO)— or —NH(CO)O— group, and W is a phenylene group substituted with two substituents each independently chosen from a chlorine atom, methyl group, methoxy group, or cyano group.

14. The compound according to claim 1 , wherein the compound is chosen from:
Formic acid-trans-4-[(9-{[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}nonyl)(methyl)amino]cyclohexyl hydroxy(di-2-thienyl)acetate (2:1);
Formic acid-trans-4-[{2-[4-(2-{[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}ethyl)phenoxy]ethyl}methyl)amino]cyclohexyl hydroxy(di-2-thienyl)acetate (1:1);
Formic acid-trans-4-[{3-[4-(2-{[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}ethyl)phenoxy]propyl}methyl)amino]cyclohexyl hydroxy(di-2-thienyl)acetate (1:1);
trans-4-[{2-[(6-{[(2R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)-ethyl]amino}hexyl)oxy]ethyl}(methyl)amino]cyclohexyl hydroxy(di-2-thienyl)-acetate hydrofluoride;
trans-4-[{3-[(6-{[(2R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)-ethyl]amino}hexyl)oxy]propyl}(methyl)amino]cyclohexyl hydroxy(di-2-thienyl)-acetate hydrofluoride;
Formic acid-trans-4-[{3-[4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)phenoxy]propyl}methyl)amino]cyclohexyl hydroxy(di-2-thienyl)acetate (1:1);
trans-4-[{2-[4-({[(2R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)-ethyl]amino}methyl)phenoxy]ethyl}(methyl)amino]cyclohexyl hydroxy(di-2-thienyl)acetate hydrofluoride;
trans-4-[{3-[4-(2-{[(2R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}propyl)phenoxy]propyl}(methyl)amino]cyclohexyl hydroxy(di-2-thienyl)acetate hydrofluoride;
trans-4-((3-(2-Chloro-4-(((2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino)methyl)-5-methoxyphenylamino)-3-oxopropyl)(methyl)amino)-cyclohexyl hydroxy(di-2-thienyl)acetate hydrofluoride;
trans-4-((3-(2-Chloro-4-(((2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino)methyl)phenylamino)-3-oxopropyl)(methyl)amino)cyclohexyl-hydroxy(di-2-thienyl)acetate hydrofluoride;
trans-4-[{3-[2-Chloro-4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-5-methoxyphenoxy]propyl}(methyl)amino]cyclohexyl-hydroxy(di-2-thienyl)acetate hydrofluoride;
trans-4-[{2-[({[2-Chloro-4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-5-methoxyphenyl]amino}carbonyl)oxy]ethyl}-(methyl)amino]-cyclohexylhydroxy(di-2-thienyl)acetate hydrofluoride;
trans-4-[(3-{[2-chloro-4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-5-methoxyphenyl]amino}-

Assignees

• Prat Quinones Maria
• Fonquerna Pou Silvia
• Puig Duran Carlos
• Lumeras Amador Wenceslao
• Aiguade Bosch Jose
• Caturla Jovaloyes Juan Francisco
• Almirall Sa

Inventors

• Prat Quinones Maria
• Fonquerna Pou Silvia
• Puig Duran Carlos
• Lumeras Amador Wenceslao
• Aiguade Bosch Jose
• Caturla Jovaloyes Juan Francisco

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P27/06

  Antiglaucoma agents or miotics · CPC title

• A61P29/00

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

• A61K31/4709

  Non-condensed quinolines and containing further heterocyclic rings · CPC title

• C07D215/26 Primary

  Alcohols; Ethers thereof · CPC title