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US 9,315,463 B2Granted
Cyclohexylamine derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities
AssigneeAlmirall, S.A.
InventorsMaria Prat Quinones, Silvia Fonquerna Pou, Carlos Puig Duran, Wenceslao Lumeras Amador, Jose Aiguade Bosch, Juan Francisco Caturla Jovaloyes
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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.
Claims25
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—, —CH2—O— or —S—, wherein when X together with Y form —CH2—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;
- R1 and R2 are each independently chosen from a hydrogen atom or C1-4 alkyl groups;
- R3 is chosen from a group of formula i) or ii):
- wherein:
- Ra is chosen from a hydrogen atom, hydroxyl group, hydroxymethyl group, or C1-4 alkyl groups,
- Rb and Rc are each independently chosen from a thienyl group, phenyl group, benzyl group or C4-6 cycloalkyl groups,
- Z is chosen from a direct bond or an oxygen atom, and
- * represents the point of attachment of R3 to the remainder of the molecule of formula (I);
- A1 and A2 are each independently C1-6 alkylene groups unsubstituted or substituted with at least one C1-4 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 A2 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, C1-4 alkyl groups, C1-4 alkoxy groups, or cyano groups.
10 more elements
A method for treating a subject afflicted with asthma or chronic obstructive pulmonary disease, comprising administering to said subject an effective amount of a compound chosen from:
- 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 formiate (2:1);
- 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]cyclohexylhydroxy(di-2-thienyl)acetate formiate (1:1);
- 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)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)ethylamino)methyl)phenylamino)-3-oxopropyl)(methyl)amino)-cyclohexylhydroxy(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]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-methoxyphenyl]amino}-3-oxopropyl)(methyl)amino]-1-methylcyclohexyl hydroxy(di-2-thienyl)acetate;
- trans-4-[(4-{[2-chloro-4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-5-methoxyphenyl]amino}-4-oxobutyl)(methyl)amino]cyclohexyl hydroxy(di-2-thienyl)acetate;
- trans-4-[(3-{[2-fluoro-4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-5-methoxyphenyl]amino}-3-oxopropyl)(methyl)amino]cyclohexyl hydroxy(di-2-thienyl)acetate;
- trans-4-[(3-{[2,5-difluoro-4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)phenyl]amino}-3-oxopropyl)(methyl)amino]cyclohexyl hydroxy(di-2-thienyl)acetate hydrofluoride (1:2);
- trans-4-[(3-{[2-chloro-4-(2-{[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}ethyl)-5-methoxyphenyl]amino}-3-oxopropyl)(methyl)amino]cyclohexyl hydroxy(di-2-thienyl)acetate hydrofluoride (1:2);
- trans-4-[{2-[({[2-cyano-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]cyclohexyl hydroxy(di-2-thienyl)acetate hydrofluoride (1:2);
- trans-4-[{4-[2-chloro-4-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl}-5-methoxyphenoxy]butyl}(methyl)amino]cyclohexyl hydroxy(di-2-thienyl)acetate hydrofluoride (1:2);
- trans-4-[({[2-[({[2-chloro-4-({[(2R)-2-hydroxy-2-(5-hydroxy-3-ox-3,4-dihydro-2H-1,4-benzoxazin-8-yl)ethyl]amino}methyl)-5-methoxyphenyl]amino}carbonyl)-oxy]ethyl}(methyl)amino]cyclohexyl hydroxy(di-2-thienyl)acetate;
- 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]cyclohexyl (2R)-cyclopentyl (hydroxy)phenylacetate;
- or
- 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]cyclohexyl (2S)-cyclopentyl(hydroxy)2-thienylacetate.
13 more elements
Dependencies are inferred from the claim text.