# US 2014/0155373 A1 · Novel compounds

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- Number: US 2014/0155373 A1
- Document ID: US20140155373A1
- Status: Published application
- Kind: A1
- Application number: 14/097,397
- Filed: 2013-12-05
- Published: 2014-06-05
- Earliest claimed: 2012-12-05
- Assignees: Chiesi Farmaceutici S.p.A.
- Applicants: CHIESI FARMACEUTICI S.p.A.
- Inventors: Elisabetta Armani; Gabriele Amari; Mauro Riccaboni; Charles Baker-Glenn
- Web page: https://patentgrep.com/patent/US20140155373A1

## CPC

- C07D 453/02: containing not further condensed quinuclidine ring systems
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- C07D 453/00: Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Compounds of formula (I) described herein are both inhibitors of the phosphodiesterase 4 (PDE4) enzyme and muscarinic M3 receptor antagonists, and are useful for the prevention and/or treatment of diseases of the respiratory tract characterized by airway obstruction.

## Claims

### Claim 1

A compound represented by formula (I):
wherein:
R1 and R2 are different or the same and are:
H;
(C3-C7) cycloalkylcarbonyl;
(C1-C6) alkyl, optionally substituted by one or more substituents selected from the group consisting of (C3-C7) cycloalkyl and (C5-C7) cycloalkenyl;
(C1-C6) haloalkyl;
(C3-C7) cycloalkyl;
(C5-C7) cycloalkenyl;
(C2-C6) alkenyl; or
(C2-C6) alkynyl;
or R1 and R2, together with the interconnecting atoms, form a 2,2-difluoro-1,3-dioxolane ring represented by formula (r) fused to the phenyl moiety which bears groups —OR1 and —OR2, wherein asterisks indicate carbon atoms shared with the phenyl ring:
each R3 is independently CN, NO2, CF3, or a halogen atom;
k is zero or an integer ranging from 1 to 3;
A is a saturated and monocyclic (C3-C7) heterocycloalkylene group;
W is:
[1]-(CH2)sC(O)-[2] wherein s is zero or 1;
[1]-C(O)(CH2)j[2], wherein j is 1 or 2;
[1]-SO2(CH2)t-[2] wherein t is zero, 1 or 2;
[1]-(CH2)ySO2-[2] wherein y is 1 or 2;
[1](CH2)f-[2] wherein f is 1 or 2; or
[1]C(O)(CH2)2SO2-[2];
wherein [1] and [2] indicate the points of attachment for group W with, respectively, ring A and the phenyl moiety;
each R4 is hydrogen, halogen, (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4)haloalkyl, hydroxy, —SO2NR5R6, —CN, or —NR7SO2R8, and wherein said (C1-C4) alkyl and said (C1-C4) alkoxy are optionally substituted by one (C3-C7) cycloalkyl group,
R5 is hydrogen or (C1-C6) alkyl;
R6 is hydrogen or (C1-C6) alkyl;
R7 is hydrogen or (C1-C6) alkyl;
R8 is hydrogen or (C1-C6) alkyl;
m is an integer ranging from 1 to 3;
B is selected from:
a group represented by formula (a) wherein the asterisk indicates the point of attachment for group B to the phenyl ring:
wherein
p is zero or 1;
q is zero or 1;
each R9 is independently halogen, (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4)haloalkyl, hydroxy, —SO2NR10R11, —CN, or —NR12SO2R13, and wherein said (C1-C4) alkyl and said (C1-C4) alkoxy are optionally substituted by one (C3-C7) cycloalkyl group,
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;
n is an integer ranging from 1 to 3;
E is a nitrogen containing group which is:
a group (c) which is —(CH2)g—NR14R15 wherein g is an integer ranging from 1 to 4 and R14 and R15 are independently hydrogen or (C1-C4) alkyl; or
a group (d) which is a saturated monocyclic or bicyclic or tricyclic heterocyclic ring system optionally substituted by one or two groups R16 which are at each occurrence are independently (C1-C4) alkyl or benzyl;
a group of formula (b) wherein the asterisk indicates the point of attachment for group B to the phenyl ring:
wherein
R17 is hydrogen, (C1-C4) alkyl, or —SO2(C1-C4)alkyl;
R18 is an aryl group or a 5 to 11 membered heteroaryl group, wherein said aryl group and said heteroaryl group are optionally substituted by 1 to 3 groups R19;
R19 is at each occurrence independently halogen, (C1-C4)haloalkyl, hydroxy, —SO2NR20R21, —CN, —NR22SO2R23, (C1-C4) alkyl, or (C1-C4) alkoxy wherein said (C1-C4) alkyl and said (C1-C4) alkoxy are optionally substituted by one (C3-C7) cycloalkyl group, and wherein
R20 is hydrogen or (C1-C6) alkyl;
R21 is hydrogen or (C1-C6) alkyl;
R22 is hydrogen or (C1-C6) alkyl;
R23 is hydrogen or (C1-C6) alkyl;
Z is a bond or a divalent radical which is —(CH2)—, —(CH2)2—, —S—, —S(O)—, —S(O2)—, —C(O)—, or a group [5]-(C1-C4)alkylOC(O)-[6], wherein [5] and [6] represent, respectively the point of attachment of group Z to the phenyl ring and to the nitrogen atom; and
E is a group as above defined
or an N-oxide on the pyridine ring, or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A compound, N-oxide, or pharmaceutically acceptable salt according to claim 1, which is represented by formula (IB):

### Claim 3 (depends on 1)

A compound, N-oxide, or pharmaceutically acceptable salt according to claim 1, which is represented by formula (IA):

### Claim 4 (depends on 1)

A compound, N-oxide, or pharmaceutically acceptable salt according to claim 1, which has the absolute configuration of carbon (1) shown in formula (I)′:

### Claim 5 (depends on 1)

A compound, N-oxide, or pharmaceutically acceptable salt according to claim 1, wherein:
A is one of the divalent radicals shown below:
wherein the symbols [3] and [4] indicate the points of connection for group A with, respectively, the carbonyl group and W; and
E is a group (d) represented by formula (i), (ii), (iii) or (iv):
wherein:
h=1, 2 or 3;
v=1, 2 or 3.

### Claim 6 (depends on 1)

A compound, N-oxide, or pharmaceutically acceptable salt according to claim 1, which is a compound selected from the group consisting of
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl](2S)-3-[3-[[2-oxo-1-phenyl-2-[(3R)-quinuclidin-3-yl]oxy-ethyl]carbamoyl]phenyl]sulfonylthiazolidine-2-carboxylate;
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl](2S)-3-[3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonyl anilino)methyl]benzoyl]thiazolidine-2-carboxylate;
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl](2S)-1-[3-[[2-oxo-1-phenyl-2-[(3R)-quinuclidin-3-yl]oxy-ethyl]amino]phenyl]sulfonylpyrrolidine-2-carboxylate;
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl](2R)-1-[3-[[1-(3-fluorophenyl)-2-oxo-2-[(3R)-quinuclidin-3-yl]oxy-ethyl]amino]phenyl]sulfonylpyrrolidine-2-carboxylate;
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl](2S)-3-[3-[[2-oxo-1-phenyl-2-[(3R)-quinuclidin-3-yl]oxy-ethyl]amino]phenyl]sulfonylthiazolidine-2-carboxylate;
[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl) ethyl](2S)-3-[3-[[2-oxo-1-phenyl-2-[(3R)-quinuclidin-3-yl]oxy-ethyl]carbamoyl]phenyl]sulfonylthiazolidine-2-carboxylate;
[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl](2S)-1-[3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoyl]piperidine-2-carboxylate;
[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl](4R)-3-[3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxy carbonyl-anilino)methyl]benzoyl]thiazolidine-4-carboxylate;
[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl](2S)-1-[3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoyl]pyrrolidine-2-carboxylate;
[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]1-[3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoyl]azetidine-3-carboxylate; and
[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl](2S)-1-[4-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]phenyl]sulfonylpyrrolidine-2-carboxylate
or a pharmaceutically acceptable salt of said compound.

### Claim 7 (depends on 1)

A pharmaceutical composition, comprising a compound, N-oxide, or pharmaceutically acceptable salt according to claim 1 and at least one pharmaceutically acceptable carrier.

### Claim 8 (depends on 7)

A pharmaceutical composition, according to claim 7, further comprising another active ingredient.

### Claim 9 (depends on 1)

A method for the prevention and/or treatment of a disease of the respiratory tract characterized by airway obstruction, comprising administering an effective amount of a compound, N-oxide, or pharmaceutically acceptable salt according to claim 1 to a subject in need thereof.

### Claim 10 (depends on 9)

A method according to claim 9, wherein said disease of the respiratory tract is asthma or COPD.

### Claim 11 (depends on 7)

An inhalation device, comprising a pharmaceutical composition according to claim 7.

### Claim 12 (depends on 7)

A kit, comprising a pharmaceutical composition according to claim 7 and a device which is a single- or multi-dose dry powder inhaler, a metered dose inhaler, or a nebulizer.