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1. WO2016177849 - AMINOESTER DERIVATIVES

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

CLAIMS

1. A compound of general formula (I)


wherein:

each R1 is hydrogen or is independently selected in the group consisting of: halogen, (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, hydroxy, -SO2NR6R7, -CN, -NR8SO2R9, -NR5R7, -CONR6R7 and -NR8COR9 and wherein said (C1-C4) alkyl is optionally substituted by one or more groups selected from (C3-C7) cycloalkyl, hydroxy and -NR5R7 and wherein said (C1-C4) alkoxy is optionally substituted by one or more halogens or groups (C3-C7) cycloalkyl wherein,

R6 is hydrogen or (C1-C6) alkyl;

R7 is hydrogen or (C1-C6) alkyl;

R8 is hydrogen or (C1-C6) alkyl;

R9 is hydrogen or (C1-C6) alkyl;

n is an integer ranging from 1 to 3;

each R2 is hydrogen or is selected in the group consisting of: halogen, (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4)haloalkyl, hydroxy, -SO2NR10R11, -CN and -NR12SO2R13 and wherein said (C1-C4) alkyl and said (C1-C4) alkoxy are optionally substituted by one or more group (C3-C7) cycloalkyl wherein

R10 is hydrogen or (C1-C6) alkyl;

R11 is hydrogen or (C1-C6) alkyl;

R12 is hydrogen or (C1-C6) alkyl;

R13 is hydrogen or (C1-C6) alkyl;

m is an integer ranging from 1 to 3;

R3 and R4 are different or the same and are independently selected from the group consisting of: H, (C3-C7) cycloalkylcarbonyl, (C1-C6) alkyl, optionally substituted by one or more substituents selected from (C1-C4 alkoxy), (C3-C7) cycloalkyl or (C5-C7) cycloalkenyl, (C1-C6) haloalkyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl, (C2-C6) alkenyl, and (C2-C6) alkynyl;

each R5, whenever present, is independently selected from the group consisting of: CN, NO2, CF3 and halogen atoms;

k is 0 or an integer ranging from 1 to 3;

L1 is a bond

W1 is selected from a divalent arylene and a heteroarylene group;

W2 is selected from an aryl and a heteroaryl;

L2 is a group selected from -(CH2)q- wherein q is an integer ranging from lto 4;

L3 is a bond or a group selected from -(CH2)S- wherein s is 1 or 2;

X is a group selected from X1 , X2 and X3:


wherein

R20 is selected in the group consisting of H, OH, wherein said (C1-C4) alkyl is optionally substituted by one or more hydroxyl,

R21 is selected from hydrogen, (C1-C6) alkyl optionally substituted by hydroxyl and wherein

i is 1 or 2;

i' is 1 or 2;

i" is an integer ranging from 1 to 4;

A is selected from:

- a group -(CH2)s-NR16R17 wherein s is an integer ranging from 1 to 4 and R16 and R17 are independently selected from hydrogen or (C1-C4) alkyl; and

- a saturated monocyclic, bicyclic or tricyclic heterocyclic ring system containing one N heteroatom or NR18 group wherein Ris is selected from (C1-C4) alkyl and benzyl;

their N-oxides on the pyridine ring, deuterated derivatives;

and pharmaceutically acceptable salts, or solvates thereof.

2. A compound according to claim 1 of general formula (I)'


wherein R1, R2, R3, R4, R5, L1, W1, L2, W2, X, L3, A, m, n, and k are as defined in claim 1; deuterated derivatives and pharmaceutically acceptable salts and solvates thereof.

3. A compound according to claim 1 wherein

W1 is heteroarylene;

W2 is selected from an aryl and a heteroaryl;

L2 is a group selected from -(CH2)q- wherein q is an integer ranging from 1 to 4; their N-oxides on the pyridine ring, deuterated derivatives;

and pharmaceutically acceptable salts, or solvates thereof.

4. A compound according to claim 1 or 2 wherein A is represented by a group of formula (i), (ii), (iii) or (iv):


wherein

f = 1, 2 or 3;

g =1, 2 or 3.

5. A compound according to claim 1 wherein L3 is a bond, and X is a group X2 and i" is 1, of formula (IA):


wherein R1, R2, R3, R4, R5, R20, R21, L1, W1, L2, W2, A, , m, n, and k are as defined in claim 1, deuterated derivatives and pharmaceutically acceptable salts and solvates thereof.

6. A compound according to claim 1 wherein L3 is a bond and X is the group X1, of formula (IB):


wherein R1, R2, R3, R4, R5, L1, W1, L2, W2, A, i, i', m, n, and k are as defined in claim 1; deuterated derivatives and pharmaceutically acceptable salts and solvates thereof.

7. A compound according to claim 1 wherein L3 is a bond, X is the group X3, deuterated derivatives and pharmaceutically acceptable salts and solvates thereof:


wherein R1, R2, R3, R4, R5, L1, W1, L2, W2, A, i, i', m, n, and k are as described for formula (I).

8. A compound according to claim 5, 6 or 7 wherein k is 2 and R5 are halogen atoms

9. A compound according to claim 8 wherein R5 are two chlorine atoms at positions 3 and 5 of the pyridine ring.

10. A compound according to claim 5, 6 or 7 wherein R4 is selected from a (C1-C6) alkyl and R3 is selected from (C3-C7) cycloalkyl or (C1-C6) alkyl which is optionally substituted by (C3-C7) cycloalkyl..

11. A compound according to claim 1 of general formula (IC)


wherein R1, R2, R3, R4, A, L1, W1, L2, W2, X, L3, m and n are as defined in claim 1; and the corresponding N-oxide on the pyridine ring, deuterated derivatives and pharmaceutically acceptable salts and solvates thereof.

12. A compound according to claim 11 of general formula (ID):


wherein R1, R2, A, L1, W1, L2, W2, X, L3, m and n are as defined in claim 11, the corresponding N-oxide on the pyridine ring, deuterated derivatives and pharmaceutically acceptable salts and solvates thereof

13. A compounds according to claim 12 wherein:

both L1 and L3 are a bond;

m is 0;

W1 is phenylene-1,4-diyl, phenylene-1,3-diyl, or thienylene-2,5-diyl;

n is 0;

W2 is phenyl;

X is a group of formula X1 wherein both i and i' are 1 or 2, or a group of formula X2 wherein i" is 1 and R20 and R21 are independently selected form H or methyl, or X is a group of formula X3 wherein both i and i' are 1 and R21 is H;

A is a group of formula (i) or (ii):


wherein f is 1 and g is 1 or f is 1 and g is 2 and the asterisk (*) represents the point of attachment to the oxygen atom of Formula (I); or A is the group -CH2CH2N(CH3). 14. A compound according to claims 1 or 2, represented by formula (I)" wherein the absolute configuration of carbon (1) is that shown herebelow


wherein R1, R2, R3, R4, R5, L1, W1, L2, W2, X, L3, A, m, n, and k are as defined in claim 1; deuterated derivatives and pharmaceutically acceptable salts and solvates thereof.

15. A compound according to claim 1 which is selected in the list consisting of:

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[3-oxo-2-phenyl-3-[(3R)-quinuclidin-3-yl]oxy-propyl]amino]methyl]thiophene-2-carboxylate;

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]

4-[[[3-oxo-2-phenyl-3-[(3R)-quinuclidin-3-yl]oxy-propyl]amino]methyl]benzoate;

[(3R)-quinuclidin-3-yl] 1-[[5-[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-l-(3,4-dimethoxyphenyl)ethoxy]carbonyl-2-thienyl]methyl]-4-phenyl-piperidine-4-carboxylate;

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]-5-[[[3-[(3R)-1-methylpyrrolidin-3-yl]oxy-3-oxo-2-phenyl-propyl]amino]methyl]thiophene-2-carboxylate;

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]

5-[[[3-[(1-methyl-4-piperidyl)oxy]-3-oxo-2-phenyl-propyl]amino]methyl]thiophene-2-carboxylate;

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[3-(2-dimethylaminoethyloxy)-3-oxo-2-phenyl-propyl]amino]methyl]thiophene-2-carboxylate;

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[2-methyl-3-oxo-2-phenyl-3-[(3R)-quinuclidin-3-yl]oxy-propyl]amino]methyl]thiophene-2-carboxylate;

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[2-methyl-3-[(1-methyl-4-piperidyl)oxy]-3-oxo-2-phenyl-propyl]amino]methyl]thiophene-2-carboxylate;

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[3-(2-dimethylaminoethyloxy)-2-methyl-3-oxo-2-phenyl-

propyl]amino]methyl]thiophene-2-carboxylate;

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]-5-[[methyl-[2-methyl-3-oxo-2-phenyl-3-[(3R)-quinuclidin-3-yl]oxy-propyl]amino]methyl]thiophene-2-carboxylate;

[(3R)-quinuclidin-3-yl]-1-[[4-[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)- 1-(3,4-dimethoxyphenyl)ethoxy]-carbonylphenyljmethyl]-4-phenyl-piperidine-4-carboxylate;

[(3R)-quinuclidin-3-yl]-1-[2-[4-[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethoxy]carbonylphenyl]ethyl]-4-phenyl-piperidine-4-carboxylate;

[(3R)-quinuclidin-3-yl] 1-[2-[3-[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethoxy]carbonylphenyl]ethyl]-4-phenyl-piperidine-4-carboxylate;

[(3R)-quinuclidin-3-yl]-1-[[3-[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethoxy]carbonylphenyl]methyl]-4-phenyl-piperidine-4-carboxylate;

[(3R)-quinuclidin-3-yl]-1-[[5-[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethoxy]carbonyl-2-thienyl]methyl]-3-phenyl-azetidine-3-carboxylate;

[(3R)-1-methylpyrrolidin-3-yl] 1-[[5-[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium- 4-yl)-1-(3,4-dimethoxyphenyl)ethoxy]carbonyl-2-thienyl]methyl]-3-phenyl-azetidine-3-carboxylate;

Single diastereoisomer of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[2-hydroxy-3-oxo-3-[(3R)-quinuclidin-3-yl]oxy-2-(2-thienyl)propyl]amino]methyl]thiophene-2-carboxylate;

Single diastereoisomer 1 of [(1S)-2-(3,5-dichloro-l-oxido-pyridin-l-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]-5-[[[3-oxo-2-phenyl-3-[(3R)-quinuclidin-3-yl]oxypropyl]amino]-methyl]thiophene-2-carboxylate (diastereoisomer 1);

Single diastereoisomer2 of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]-5-[[[3-oxo-2-phenyl-3-[(3R)-quinuclidin-3-yl]oxypropyl]amino]-methyl]thiophene-2-carboxylate(diastereoisomer2);

Single diastereoisomer 1 of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[2-hydroxy-3-oxo-2-phenyl-3-[(3R)-quinuclidin-3-yl]oxy-propyl]amino]methyl]thiophene-2-carboxylate;

Single diastereoisomer2 of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[2-hydroxy-3-oxo-2-phenyl-3-[(3R)-quinuclidin-3-yl]oxy-propyl]amino]methyl]thiophene-2-carboxylate;

Single diastereoisomer 1 of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1- (3,4-dimethoxyphenyl)ethyl] 5-[[[3-(2-dimethylaminoethyloxy)-3-oxo-2-phenyl-propyl]amino]methyl]thiophene-2-carboxylate;

Single diastereoisomer2 of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[3-(2-dimethylaminoethyloxy)-3-oxo-2-phenyl-propyl]amino]methyl]thiophene-2-carboxylate;

Single diastereoisomer 1 of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[2-methyl-3-[(1-methyl-4-piperidyl)oxy]-3-oxo-2-phenyl-propyl]amino]methyl]thiophene-2-carboxylate;

Single diastereoisomer2 of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[2-methyl-3-[(1-methyl-4-piperidyl)oxy]-3-oxo-2-phenyl-propyl]amino]methyl]thiophene-2-carboxylate;

Single diastereoisomer 1 of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[methyl-[2-methyl-3-oxo-2-phenyl-3-[(3R)-quinuclidin-3-yl]oxy-propyl]amino]methyl]thiophene-2-carboxylate;

Single diastereoisomer2 of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1- (3,4-dimethoxyphenyl)ethyl] 5-[[methyl-[2-methyl-3-oxo-2-phenyl-3-[(3R)-quinuclidin-3-yl]oxy-propyl]amino]methyl]thiophene-2-carboxylate;

Single diastereoisomer 1 of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1- (3,4-dimethoxyphenyl)ethyl] 5-[[[3-(2-dimethylaminoethyloxy)-2-methyl-3-oxo-2-phenyl-propyl]amino]methyl]thiophene-2-carboxylate;

Single diastereoisomer 2 of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[3-(2-dimethylaminoethyloxy)-2-methyl-3-oxo-2-phenyl-propyl]amino]methyl]thiophene-2-carboxylate;

Single diastereoisomer 1 of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[2-methyl-3-oxo-2-phenyl-3-[(3R)-quinuclidin-3-yl]oxy-propyl]amino]methyl]thiophene-2-carboxylate;

Single diastereoisomer 2 of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[2-methyl-3-oxo-2-phenyl-3-[(3R)-quinuclidin-3-yl]oxy-propyl]amino]methyl]thiophene-2-carboxylate;

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[3-[(1-methyl-4-piperidyl)oxycarbonyl]-3-phenyl-cyclobutyl]amino]methyl]-thiophene-2-carboxylate;

Single diastereoisomer 1 of [(1S)-2-(3,5-dichloro-l-oxido-pyridin-l-ium-4-yl)-1- (3,4-dimethoxyphenyl)ethyl] 5-[[[3-[(1-methyl-4-piperidyl)oxycarbonyl]-3-phenyl-cyclobutyl]amino]methyl]-thiophene-2-carboxylate;

Single diastereoisomer 2 of [(1S)-2-(3,5-dichloro-l-oxido-pyridin-l-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[3-[(1-methyl-4-piperidyl)oxycarbonyl]-3-phenyl-cyclobutyl]amino]methyl]-thiophene-2-carboxylate;

[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[3-phenyl-3-[(3R)-quinuclidin-3-yl]oxycarbonyl-cyclobutyl]amino]methyl]thiophene-2-carboxylate;

Single diastereoisomer 1 of [(1S)-2-(3,5-dichloro-l-oxido-pyridin-l-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[3-phenyl-3-[(3R)-quinuclidin-3-yljoxycarbonyl-cyclobutyl]amino]methyl]thiophene-2-carboxylate;

Single diastereoisomer 2 of [(1S)-2-(3,5-dichloro-l-oxido-pyridin-l-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 5-[[[3-phenyl-3-[(3R)-quinuclidin-3-yljoxycarbonyl- cyclobutyl]amino]methyl]thiophene-2-carboxylate.

16. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 15, in admixture with one or more pharmaceutically acceptable carrier.

17. A pharmaceutical composition according to claim 16 further comprising another active ingredient.

18. A compound according to any one of claims 1 to 15, for use as a medicament.

19. A compound according to any one of claims 1 to 15, for use in the prevention and/or treatment of a disease of the respiratory tract characterized by airway obstruction.

20. A compound for use as defined in claim 19 wherein the disease of the respiratory tract is selected from asthma and COPD.