NEW CYCLOHEXYLAMINE DERIVATIVES HAVING ß2 ADRENERGIC AGONIST AND M3 MUSCARINIC ANTAGONIST ACTIVITIES

Patent metadata

Field	Value
Publication number	US-2016200718-A1
Application number	US-201514956767-A
Country	US
Kind code	A1
Filing date	Dec 2, 2015
Priority date	Nov 11, 2011
Publication date	Jul 14, 2016
Grant date	—

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

1 - 33 . (canceled)

34 . A compound of Formula (I), or a pharmaceutically acceptable salt, N-oxide, solvate, or deuterated derivative thereof:

wherein:
B has formula:

wherein
X and Y are independently chosen from a hydrogen atom or X together with Y forms —CH═CH—, —CH 2 —CH 2 CH 2 —O—, or —S—,
wherein when X together with Y forms —CH 2 —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 C 6 aryl group containing Y, and

* is a point of attachment of B to the remainder of Formula (I);
R 1 and R 2 are independently chosen from a hydrogen atom and a hydrogen atom and a linear or branched C1-4 alkyl group;
R 3 has formula:

wherein:
R 4 is chosen from a hydrogen atom, a hydroxy group, a hydroxymethyl group, and a linear or branched C 1-4 alkyl group;
R 5 and R 6 are independently chosen from a C 6 aryl group, a 5- to 6-membered heteroaryl group containing at least one heteroatom chosen from N, S, and O, a (C 1-4 alkyl)-(C 6 aryl) group, and a C 3-8 cycloalkyl group; and
* is a point of attachment of R 3 to the remainder of the Formula (I);

A 1 and A 2 are independently chosen from a C 1-6 alkylene group that is unsubstituted or substituted with at least one substituent chosen from a C 1-2 alkyl group, a C 1-2 alkoxy group, and a C 6 aryl group;
L 1 is chosen from a direct bond, —NH—, —SO 2 —, —NH(CO)NH—, and —O(CH 2 )(CO)NR c , wherein R c is chosen from a hydrogen atom and a linear or branched C 1-4 alkyl group;
G is chosen from:
a C 6 aryl group,
a 9- to 10-membered saturated or unsaturated bicyclic heterocyclyl group having at least one heteroatom chosen from N, S and O,
a 9 to 10-membered bicyclic heteroaryl group having at least one heteroatom chosen from N, S and O,
a C 6 aryl group linked to a ring system chosen from a C 6 aryl group and a 5- to 6-membered heteroaryl group having two or three heteroatoms chosen from N, S and O,
wherein the cyclic groups independently are unsubstituted or substituted with at least one substituent chosen from a halogen atom, a methyl group, a methoxy group, a cyano group, a hydroxy group, and an oxo group;

with the proviso that when G is a phenyl group, L 1 is not chosen from a direct bond, —O—, —NHC(O)—, —C(O)NH— and —NH(CO)O— group.

35 . The compound according to claim 34 , wherein -G-L 1 - has Formula (Iwa) or Formula (Iwb):

wherein:
V, W, and Z are independently chosen from —N—, —C—, —S—, —O— and —C(O)—;
Lx is a 5- to 6-membered heteroaryl group having at least one heteroatom chosen from N, S and O, or Lx is —O—CH 2 —CO—NR c —, wherein R c is a hydrogen atom or a methyl group;
* is a point of attachment with A 2 ; and
• is a point of attachment with A 1 .

36 . The compound according to claim 35 , wherein -G-L 1 - has Formula (Iwa):

37 . The compound according to claim 36 , wherein -G-L 1 has Formula (Iwaa);

38 . The compound according to claim 34 , having Formula (IC):

wherein
X and Y are independently chosen from a hydrogen atom or X together with Y forms —CH═CH—, —CH 2 —CH 2 —, —CH 2 —O—, or —S—,
wherein when X together with Y forms —CH 2 —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 C 6 aryl group ring containing Y;
R 3 has formula:

wherein:
R 4 is chosen from a hydrogen atom, a hydroxy group, a hydroxymethyl group, and a linear or branched C 1-4 alkyl group;
R 5 and R are independently chosen from a C 6 aryl group, a 5- to 6-membered heteroaryl group containing at least one heteroatom chosen from N, S, and O, a (C 1-4 alkyl)-(C 6 aryl) group, and a C 3-8 cycloalkyl group; and

* is a point of attachment of R 3 to the remainder of Formula (IC);
R 8 , R 9 , and R 10 are independently chosen from a hydrogen atom and a linear or branched C 1-4 alkyl group;
n is chosen from 0, 1 and 2;
m is chosen from 2, 3 or 4;
-G-L 1 - is chosen from Formula (Iwa) or Formula (Iwb):

wherein:
V, W, and Z are independently chosen from a —N—, —C—, —S—, —O—, or —C(O)—,
Lx is chosen from a 5- to 6-membered heteroaryl group having at least one heteroatom chosen from N, S, and O, or Lx is —O—CH 2 —CO—NR d —, wherein R d is chosen from a hydrogen atom and a methyl group,
* is a point of attachment with the moiety containing the —[CH 2 ] m — group, and
• is a point of attachment with the moiety containing the —[CH 2 ] n — group.

39 . The compound according to claim 38 , wherein -G-L 1 - has Formula (Iwa).

40 . The compound according to claim 39 , wherein V, W, and Z are nitrogen.

41 . The compound according to claim 38 , having Formula (ID):

wherein:
R 3 has formula:

wherein:
R 4 is chosen from a hydrogen atom, a hydroxy group, a hydroxymethyl group, and a linear or branched C 1-4 alkyl group, R 5 and R 6 are independently chosen from a thienyl group, a C 6 aryl group, a benzyl group, and a C 4-6 cycloalkyl group, and
* is a point of attachment of R 3 to the remainder of Formula (ID).

42 . The compound according to claim 38 , wherein X together with Y forms —CH═CH— or —CH 2 —O.

43 . The compound according claim 38 , wherein W is chosen from a nitrogen atom and a carbonyl group.

44 . The compound according to claim 38 , wherein V is chosen from a nitrogen atom, an oxygen atom, and a sulfur atom.

45 . The compound according to claim 38 , wherein V is chosen from a nitrogen atom and an oxygen atom, and W is a carbonyl group.

46 . The compound according to claim 38 , wherein V is a nitrogen atom and W is a nitrogen atom.

47 . The compound according to claim 38 , wherein n has a value of 0 and m has a value of 3.

48 . The compound according to claim 38 , wherein R 10 is chosen from a hydrogen atom and a methyl group or R 8 and R 9 are independently chosen from a hydrogen atom and a methyl group.

49 . The compound according to claim 38 , wherein R 3 has formula i) wherein:
R 4 is chosen from a hydrogen atom, a methyl group, and a hydroxy group; and R 5 and R 6 independently chosen from a C 6 aryl group, a

Assignees

• Almirall Sa

Inventors

• Aiguade Bosch Jose
• Gual Roig Silvia
• Prat Quinones Maria
• Puig Duran Carlos

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

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

• A61P11/06

  Antiasthmatics · CPC title