# US 10,117,860 B2 · Aminoester derivatives

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- Number: US 10,117,860 B2
- Document ID: US10117860B2
- Status: Granted
- Kind: B2
- Application number: 15/673,710
- Filed: 2017-08-10
- Published: 2017-11-30
- Granted: 2018-11-06
- Earliest claimed: 2014-06-05
- Assignees: Chiesi Farmaceutici S.p.A.
- Applicants: Chiesi Farmaceutici S.P.A.
- Inventors: Elisabetta Armani; Gabriele Amari; Carmelida Capaldi; Wesley Blackaby; Ian Linney; Hervé Van De Poël; Charles Baker-Glenn; Naimisha Trivedi
- Web page: https://patentgrep.com/patent/US10117860B2

## CPC

- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/4436: containing a heterocyclic ring having sulfur as a ring hetero atom
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/04: for throat disorders
- A61P 11/06: Antiasthmatics
- A61P 11/08: Bronchodilators
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 409/14: containing three or more hetero rings
- C07D 453/02: containing not further condensed quinuclidine ring systems
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Compounds of formula (I), defined herein, are both phosphodiesterase 4 (PDE4) enzyme inhibitors and muscarinic M3 receptor antagonists and are useful for the prevention and/or treatment of a disease of the respiratory tract.

## Claims

### Claim 1

A compound of formula (I):
wherein
each R1 is the same or different and is independently hydrogen, halogen, (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, hydroxy, —SO2NRIRII, —CN, —NRISO2RIII, —NRIRII, —(CO)NRIRI, or —NRI(CO)RIII, and wherein each said (C1-C4) alkyl is optionally substituted by one or more groups selected from the group consisting of (C3-C7) cycloalkyl, hydroxyl, and —NRIRII and wherein each said (C1-C4) alkoxy is optionally substituted by one or more halogen atoms or (C3-C7) cycloalkyl groups, wherein:
RI is hydrogen or (C1-C6) alkyl;
RII is hydrogen or (C1-C6) alkyl;
RIII is hydrogen or (C1-C6) alkyl;
n is an integer ranging from 1 to 3;
each R2 is the same or different and is independently hydrogen, halogen, (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4)haloalkyl, hydroxy, —SO2NRIRII, —CN, —NRISO2RIII, —NRIRII, —(CO)NRIRII, or —NRI(CO)RIII and wherein eachsaid (C1-C4) alkyl is optionally substituted by one or more groups selected from the group consisting of (C3-C7) cycloalkyl, hydroxyl, and —NRIRII and wherein each said (C1-C4) alkoxy is optionally substituted by one or more halogen atoms or (C3-C7) cycloalkyl groups, wherein:
RI, RII, and RIII are as defined above;
m is an integer ranging from 1 to 3;
each R3 and each R4 are the same or different and is independently 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, and (C2-C6) alkynyl;
or R3 and R4, together with the interconnecting atoms, form a 2,2-difluoro-1,3-dioxolane ring of formula (r) fused to the phenyl moiety which bears groups —OR3 and —OR4, wherein asterisks indicate carbon atoms shared with such phenyl ring:
each R5 is the same or different and is independently CN, NO2, CF3, or halogen;
k is 0 or an integer ranging from 1 to 3;
x′ is 0 or 1;
L1 is a bond or —(CH2)p— wherein p is an integer ranging from 1 to 4;
W1 is a divalent arylene, heteroarylene, or saturated monocyclic heterocycloalkylene group;
L2 is a bond, —(CH2)q— wherein q is 1 or 2, [1]-(CO)—[X]—(CH2)t-[2], or [1]-(SO2)—[X]—(CH2)t-[2], wherein [1] and [2] represent, respectively the point of attachment of group L2 to the ring W1 and to the chain nitrogen atom, and wherein
[X] is a bond or a substituted or unsubstituted arylene group;
t is an integer ranging from 1 to 4;
R7 is hydrogen or (C1-C4) alkyl optionally substituted by hydroxy or —NR11R12, wherein R11 and R12 are independently hydrogen or (C1-C4) alkyl, or, together with the nitrogen atom to which they are linked, R11 and R12 form a saturated heterocycloalkyl group having an additional heteroatom selected from the group consisting of O, S, and NH; and
A is a nitrogen containing group which is:
a group (a) which is —(CH2)s—NR8R9 wherein s is an integer ranging from 1 to 4 and R8 and R9 are independently hydrogen or (C1-C4) alkyl; or
a group (b) which is a saturated monocyclic, bicyclic or tricyclic heterocyclic ring system optionally substituted by one or two groups R10 which are at each occurrence independently (C1-C4) alkyl or benzyl; and
wherein W2 is a phenyl ring, L is a bond, and one of R1, which is in the ortho position with respect to L, and R6 are connected to form a ring radical, represented by formula (IB):
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A compound, or pharmaceutically acceptable salt according to claim 1, wherein A is a group of formula (i), (ii), (iii), or (iv):
wherein
f=1, 2 or 3;
g=1, 2 or 3;
and the asterisk (*) represents the point of attachment to the oxygen atom of formula (I).

### Claim 3 (depends on 1)

A compound, or pharmaceutically acceptable salt according to claim 1, wherein x′ is 1.

### Claim 4 (depends on 1)

A compound or pharmaceutically acceptable salt according to claim 1, wherein L1 is a bond, W1 is thiophene-2,5-diyl, thiophene-2,4-diyl, phenylene-1,4-diyl, phenylene-1,3-diyl, or phenylene-1,2-diyl, L2 is —(CH2)—, and R7 is H.

### Claim 5 (depends on 1)

A compound, or pharmaceutically acceptable salt according to claim 1, wherein R7 is H or methyl.

### Claim 6 (depends on 1)

A compound, or pharmaceutically acceptable salt according to claim 1, wherein L1 is a bond and W1 is a divalent saturated monocyclic heterocycloalkylene group.

### Claim 7 (depends on 1)

A compound or pharmaceutically acceptable salt according claim 1, represented by formula (I)′ which has the absolute configuration of carbon (1) which is shown below:

### Claim 8

A compound, which is selected from the group consisting of:
[(3R)-quinuclidin-3-yl]-1-[[4-[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethoxy]carbonylphenyl]methylamino]indane-1-carboxylate;
[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)-ethyl]-5-[[[1-[(3R)-quinuclidin-3-yl]oxycarbonylindan-1-yl]amino]methyl]thiophene-2-carboxylate;
[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)-ethyl]-5-[[[1-(2-dimethylaminoethyloxycarbonyl)indan-1-yl]amino]methyl]thiophene-2-carboxylate;
[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)-ethyl]-5-[[[1-[(1-methyl-4-piperidyl)oxycarbonyl]indan-1-yl]amino]methyl]thiophene-2-carboxylate;
or a pharmaceutically acceptable salt of said compound.

### Claim 9 (depends on 1)

A pharmaceutical composition, comprising a compound or pharmaceutically acceptable salt according to claim 1 in admixture with one or more pharmaceutically acceptable carriers.

### Claim 10 (depends on 9)

A pharmaceutical composition according to claim 9, further comprising another active ingredient.

### Claim 11 (depends on 1)

A method for the treatment of a disease selected from the group consisting of asthma and COPD, said method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt according to claim 1.

### Claim 12 (depends on 11)

A method according to claim 11, wherein said disease is asthma.

### Claim 13 (depends on 11)

A method according to claim 11, wherein said disease is COPD.

### Claim 14 (depends on 9)

An inhalation device, which contains a pharmaceutical composition according to claim 9.

### Claim 15 (depends on 10)

An inhalation device, which contains a pharmaceutical composition according to claim 10.

### Claim 16 (depends on 9)

A kit, comprising a pharmaceutical composition according to claim 9 and a device which is a single- or multi-dose dry powder inhaler, a metered dose inhaler or a nebulizer.

### Claim 17 (depends on 10)

A kit, comprising a pharmaceutical composition according to claim 10 and a device which is a single- or multi-dose dry powder inhaler, a metered dose inhaler or a nebulizer.