Cyclohexylamine derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities
AssigneeAlmirall, S.A.
InventorsJose Aiguade Bosch, Silvia Gual Roig, Maria Prat Quinones, Carlos Puig Duran
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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.
Claims24
A compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or deuterated derivative thereof:
- wherein
- is a double bond or a single bond,
- wherein:
- when is a single bond, V is independently chosen from —O—, —NH—, and —S—, and W is —C(O)—, or
- when is a double bond, V and W are independently chosen from —N—and —CH—,
- R3 is formula:
- wherein:
- R4 is chosen from a hydrogen atom, a hydroxy group, a hydroxymethyl group, and a linear or branched C1-4 alkyl group,
- R5 and R6 are independently chosen from a thienyl group, a phenyl group, a benzyl group, and a C4-6 cycloalkyl group,
- Q is chosen from a direct bond or an oxygen atom,
- * is a point of attachment of R3 to the remainder of Formula (IV),
- R8 and R10 are independently chosen from a hydrogen atom and a linear or branched C1-4 alkyl group,
- n is 0, 1 or 2, and
- m is 2, 3 or 4.
A process for the preparation of trans-4-[[3-(5-formyl-1 H-1,2,3-benzotriazol-1-yl)propyl](methyl)amino]cyclohexyl hydroxy(di-2-thienyl)acetate, Intermediate 21, comprising the step of
- reacting trans-4-(methylamino)cyclohexyl hydroxy(di-2-thienyl)acetate, Intermediate 5, with a compound of formula (XIV),
- wherein
- is a double bond,
- V and W are nitrogen,
- m is 3,
- n is 0,
- R8 is hydrogen, and
- X1 is chosen from a bromine atom, a —O-methanesulfonyl group and a —O—p-toluenesulfonyl group.
A compound which is Intermediate 20:
- 1-(3-bromopropyl)-1H-1,2,3-benzotriazole-5-carbaldehyde or a pharmaceutically acceptable salt, solvate, or deuterated derivative thereof.
A compound which is Intermediate 99:
- 3-(5-formyl-1H-1,2,3-benzotriazol-1-yl)propyl methanesulfonate or a pharmaceutically acceptable salt, solvate, or deuterated derivative thereof.
A process for the preparation of a compound of formula (ID) or a pharmaceutically acceptable salt, solvate, or deuterated derivative thereof:
- wherein
- R9 is hydrogen,
- X and Y are independently chosen from a hydrogen atom or X together with Y forms —CH═CH—, —CH2—CH2—, —CH2—O—, or —S—, wherein in the case of —CH2—O—the methylene group is bound to the carbon atom in the amido substituent containing X and the oxygen atom is bound to the carbon atom in the phenyl ring containing Y,
- comprising the step of reacting a compound of formula (IV) or a pharmaceutically acceptable salt, solvate, or deuterated derivative thereof:
- wherein
- is a double bond or a single bond,
- wherein:
- when is a single bond, V is independently chosen from —O—, —NH—, and —S—, and W is —C(O)—, or
- when is a double bond, V and W are independently chosen from —N— and —CH—,
- R3 is formula:
- wherein:
- R4 is chosen from a hydrogen atom, a hydroxy group, a hydroxymethyl group, and a linear or branched C1-4 alkyl group,
- R5 and R6 are independently chosen from a thienyl group, a phenyl group, a benzyl group, and a C4-6 cycloalkyl group,
- Q is chosen from a direct bond and an oxygen atom,
- * is a point of attachment of R3 to the remainder of Formula (IV),
- R8 and R10 are independently chosen from a hydrogen atom and a linear or branched C1-4 alkyl group,
- n is 0, 1 or 2, and
- m is 2, 3 or 4,
- with a compound of formula (III),
- wherein P1 and P3 are independently chosen from a hydrogen atom or an oxygen-protecting group, and
- P2 is chosen from a hydrogen atom or a nitrogen-protecting group.
Dependencies are inferred from the claim text.