Aminoester derivatives

Patent metadata

Field	Value
Publication number	US-2016346268-A1
Application number	US-201615168425-A
Country	US
Kind code	A1
Filing date	May 31, 2016
Priority date	Jun 1, 2015
Publication date	Dec 1, 2016
Grant date	—

Abstract

Compounds of formula (I) defined herein are both phosphodiesterase 4 (PDE4) enzyme inhibitors and muscarinic M3 receptor antagonists and are useful for treating diseases of the respiratrory tract.

First claim

1 . A compound of formula (I):

wherein
each R 1 is hydrogen, halogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, hydroxy, —SO 2 NR 6 R 7 , —CN, —NR 8 SO 2 R 9 , —NR 6 R 7 , —CONR 6 R 7 , or —NR 8 COR 9 , wherein said (C 1 -C 4 ) alkyl is optionally substituted by one or more groups selected from (C 3 -C 7 ) cycloalkyl, hydroxyl, and —NR 6 R 7 and wherein said (C 1 -C 4 ) alkoxy is optionally substituted by one or more halogens or (C 3 -C 7 ) cycloalkyl groups, wherein
R 6 is hydrogen or (C 1 -C 6 ) alkyl;
R 7 is hydrogen or (C 1 -C 6 ) alkyl;
R 8 is hydrogen or (C 1 -C 6 ) alkyl;
R 9 is hydrogen or (C 1 -C 6 ) alkyl;

n is an integer ranging from 1 to 3;
each R 2 is hydrogen, halogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 )haloalkyl, hydroxy, —SO 2 NR 10 R 11 , —CN, or —NR 12 SO 2 R 13 , wherein said (C 1 -C 4 ) alkyl and said (C 1 -C 4 ) alkoxy are optionally substituted by one or more (C 3 -C 7 ) cycloalkyl groups, wherein
R 10 is hydrogen or (C 1 -C 6 ) alkyl;
R 11 is hydrogen or (C 1 -C 6 ) alkyl;
R 12 is hydrogen or (C 1 -C 6 ) alkyl;
R 13 is hydrogen or (C 1 -C 6 ) alkyl;

m is an integer ranging from 1 to 3;
R 3 and R 4 are the same or different and are independently:
H;
(C 3 -C 7 ) cycloalkylcarbonyl;
(C 1 -C 6 ) alkyl optionally substituted by one or more substituents selected from the group consisting of (C 1 -C 4 ) alkoxy, (C 3 -C 7 ) cycloalkyl, and (C 5 -C 7 ) cycloalkenyl;
(C 1 -C 6 ) haloalkyl;
(C 3 -C 7 ) cycloalkyl;
(C 5 -C 7 ) cycloalkenyl;
(C 2 -C 6 ) alkenyl; or
(C 2 -C 6 ) alkynyl;
each R 5 , whenever present, is CN, NO 2 , CF 3 , or halogen;
k is 0 or an integer ranging from 1 to 3;
W 1 is a divalent heteroarylene group;
W 2 is an aryl group, a heteroaryl group, or (C 3 -C 7 ) cycloalkyl;
L is a bond or a —(CH 2 )— group;
L 1 is:
a bond,
—(CH 2 ) p —,
[3]-(CH 2 ) p —O-[4],
[3]-(CH 2 ) p —NR 10 —(CH 2 )-[4],
[3]-(CH 2 ) p —OC(O)-[4],
[3]-(CH 2 ) p —NR 10 C(O)-[4],
[3]-(CH 2 ) p —NR 10 S(O 2 )-[4], or
[3]-(CH 2 ) p —S(O 2 )—N(R 10 )-[4],
wherein [3] and [4] represent, respectively the point of attachment of group L 1 to the carbonyl group and to the ring W 1 and wherein
R 10 is as described above,
p is an integer ranging from 1 to 4 and
t is an integer ranging from 1 to 4;

L 2 is —(CH 2 ) q — wherein q is an integer ranging from 1 to 4;
L 3 is a (C 1 -C 4 ) alkylene;
X is a group X 1 , X 2 , or X 3 :

wherein [1] represents at each occurrence the point of attachment of the group X to L2, [2a] represents at each occurrence the point of attachment to L-W 2 and [2b] represents at each occurrence the point of attachment to the carbonyl group —CO 2 A;
and wherein
R 14 is H, OH, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or —CN, wherein said (C 1 -C 4 ) alkyl is optionally substituted by one or more groups selected from (C 3 -C 7 ) cycloalkyl and hydroxyl, or, in the alternative, when R 14 is (C 1 -C 4 ) alkyl, W 2 is a phenyl ring, one of R 1 is an alkyl in ortho position with respect to L, both R 1 and R 14 may be connected to form with W 2 a condensed ring radical selected from at least 1H-cyclopropabenzene-1,1-diyl, indane-1,1-diyl (also named as 2,3-dihydro-1H-indene-1,1-diyl), indane-2,2-diyl (also named as 2,3-dihydro-1H-indene-2,2-diyl), 1,2,3,4-tetrahydronaphthalene-1,1-diyl, and 1,2,3,4-tetrahydronaphthalene-2,2-diyl;
R 15 is hydrogen, (C 1 -C 6 ) alkyl, (C 3 -C 7 ) cycloalkyl, (C 3 -C 7 ) heterocycloalkyl or benzyl; wherein said (C 1 -C 6 ) alkyl is optionally substituted by hydroxyl or NR 18 R 19 ; said R 18 and R 19 being independently hydrogen or (C 1 -C 4 ) alkyl, or, taken together with the nitrogen atom to which they are attached, form a nitrogen containing, saturated heterocycloalkyl group, optionally containing an additional heteroatom selected from O, S and NH;
and wherein
i is 1 or 2;
i′ is 1 or 2;
i″ is an integer ranging from 0 to 3;

A is a group of formula (i) to (vi):

wherein R 16 is in each occurrence independently (C 1 -C 4 ) alkyl optionally substituted by one or more (C 1 -C 4 ) alkoxy groups; R 17 is hydrogen, halogen or (C 1 -C 4 ) alkyl; f=0, 1, 2 or 3; g=0, 1, 2 or 3; and the asterisk (*) represents the point of attachment to the group L 3 in formula (I),

an N-oxide on the pyridine ring, a deuterated derivative, or a pharmaceutically acceptable salt thereof.

2 . A compound, N-oxide, deuterated derivative, or a pharmaceutically acceptable salt according to claim 1 , of formula (I)′:

3 . A compound, N-oxide, deuterated derivative, or a pharmaceutically acceptable salt according to claim 1 , wherein A is represented by a group of formula (i), (ii) or (iv):

wherein f=0, 1, 2, 3; g=0, 1, 2; R 17 is hydrogen, methyl, or fluorine; R 16 is methyl or ethyl and the asterisk (*) represents the point of attachment to L 3 in formula (I).

4 . A compound, N-oxide, deuterated derivative, or a pharmaceutically acceptable salt according to claim 1 , wherein X is the group X 2 and i″ is 0, of formula (IA):

5 . A compound, N-oxide, deuterated derivative, or a pharmaceutically acceptable salt according to claim 4 , wherein k is 2 and R 5 are halogen atoms.

6 . A compound, N-oxide, deuterated derivative, or a pharmaceutically acceptable salt according to claim 5 , wherein R 5 are two chlorine atoms at positions 3 and 5 of the pyridine ring.

7 . A compound, N-oxide, deuterated derivative, or a pharmaceutically acceptable salt according to claim 4 , wherein R 4 is (C 1 -C 6 ) alkyl and R 3 is (C 3 -C 7 ) cycloalkyl or (C 1 -C 6 ) alkyl; wherein said (C 1 -C 6 ) alkyl is optionally substituted by one or more halogens or (C 3 -C 7 ) cycloalkyl groups.

8 . A compound, N-oxide, deuterated derivative, or a pharmaceutically acceptable salt according to claim 1 , of formula (IC):

9 . A compound, N-oxide, deuterated derivative, or a pharmaceutically acceptable salt according to claim 8 , of general (ID):

10 . A compound, N-oxide, deuterated derivative, or a pharmaceutically acceptable salt according to claim 8 , wherein:
each R 1 is hydrogen, fluorine, methoxy, or hydroxyl; each R 2 is hydrogen; R 4 is methyl or difluoromethyl and R 3 is methyl, ethyl, pentyl cyclopropylmethyl, or 2-methoxyethyl L 1 is a bond and L 2 and L 3 are both methylene; m is 0; W 1 is thienylene-2,5-diyl or thienylene-2,4-diyl; n is 0; W 2 is phenyl, thienyl, or cyclohexyl; X is a group of formula X 1 wherein both i and i′ are 1 or 2; or X is a group of formula X 2 wherein i″ is 0 or 1 and R 14 is H, methyl, hydroxyl, or hydroxymethyl; or R 1 and R 14 are connected to form with W 2 a condensed ring radical which is indane-1,1-diyl; or X is a group of formula X 3 wherein both i and i′ are 1; R 15 is H or o

Assignees

• Chiesi Farm Spa

Inventors

• Amari Gabriele
• Armani Elisabetta
• Blackaby Wesley
• VAN DE POEOL Herve
• Baker-Glenn Charles
• Trivedi Naimisha

Classifications

• A61P11/06

  Antiasthmatics · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• C07D451/02

  containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof · CPC title

• C07D453/02

  containing not further condensed quinuclidine ring systems · CPC title

• A61K31/46

  8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine · CPC title