Compounds having muscarinic receptor antagonist and BETA2 adrenergic receptor agonist activity

Patent metadata

Field	Value
Publication number	US-10004728-B2
Application number	US-201715404897-A
Country	US
Kind code	B2
Filing date	Jan 12, 2017
Priority date	Feb 12, 2015
Publication date	Jun 26, 2018
Grant date	Jun 26, 2018

Abstract

Compounds of formula I, defined herein, act both as muscarinic receptor antagonists and beta2 adrenergic receptor agonists and are useful for treating broncho-obstructive and inflammatory diseases.

First claim

The invention claimed is:

1. A method for the treatment of a broncho-obstructive disease, comprising administering to a subject in need thereof an effective amount of a compound of formula I

wherein:
Q is a group of formula

Y is Y2 or Y1 which are divalent groups of formula

wherein
A1 and A2 are independently absent or selected from the group consisting of (C 1 -C 12 )alkylene, (C 3 -C 8 )cycloalkylene, and (C 3 -C 8 )heterocycloalkylene, each of which are optionally substituted by one or more substituents selected from the group consisting of (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, and heteroaryl(C 1 -C 6 )alkyl;
B is absent or is selected from the group consisting of (C 3 -C 8 )cycloalkylene, (C 3 -C 8 )heterocycloalkylene, arylene, and heteroarylene, each of which is optionally substituted by one or more groups selected from the group consisting of —OH, halogen, —CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, and aryl(C 1 -C 6 )alkyl;
C is absent or is selected from the group consisting of —O—, —C(O)—, —OC(O)—, —(O)CO—, —S—, —S(O)—, —S(O) 2 —, and —N(R 7 )—, or is one of the following groups C1-C23

wherein R 7 is in each occurrence independently H or selected from the group consisting of linear or branched (C 1 -C 8 )alkyl, aryl(C 1 -C 6 )alkyl, arylsulfanyl, arylsulfinyl, arylsulfonyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )heterocycloalkyl, aryl, and heteroaryl;
D is absent or is selected from the group consisting of (C 1 -C 12 )alkylene, (C 2 -C 12 )alkenylene, (C 2 -C 6 )alkynylene, arylene, heteroarylene, (C 3 -C 8 )cycloalkylene, (C 3 -C 8 )heterocycloalkylene; wherein said arylene, heteroarylene, (C 3 -C 8 )cycloalkylene, and (C 3 -C 8 )heterocycloalkylene is optionally substituted by one or more groups selected from the group consisting of —OH, halogen, —CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, and aryl(C 1 -C 6 )alkyl;
n is at each occurrence independently 0 or an integer from 1 to 3;
m is at each occurrence independently an integer from 1 to 3;
E is absent or is selected from the group consisting of —O—, —NR 7 —, —NR 7 —C(O)—, —C(O)—NR 7 —, —OC(O)—, —C(O)—(CH 2 ) n —O—; —NR 7 —C(O)—(CH 2 ) n —O—, —NR 7 —C(O)—NR 7 —, and —S—;
G is arylene or heteroarylene, each of which is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, oxo (═O), —SH, —NO 2 , —CN, —CON(R 6 ) 2 , —NH 2 , —NHCOR 6 , —CO 2 R 6 , (C 1 -C 10 )alkylsulfanyl, (C 1 -C 10 )alkylsulfinyl, (C 1 -C 10 )alkylsulfonyl, (C 1 -C 10 )alkyl, aryl, haloaryl, heteroaryl, and (C 1 -C 10 )alkoxy;
R 1 is selected from the group consisting of (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )heterocycloalkyl, aryl, heteroaryl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, each of which is optionally substituted by one or more groups selected independently from the group consisting of halogen, (C 1 -C 8 )alkyl, and (C 1 -C 10 )alkoxy;
s is 0 or an integer from 1 to 3;
R 2 is a nitrogen containing group which is:
a group (a) which is —NR 3 R 4 wherein R 3 and R 4 are independently hydrogen or (C 1 -C 4 ) alkyl; or
a group (b) of formula J1, J2, J3, J4 or J5

R 5 is a group of formula K

wherein p is 0 or an integer from 1 to 4; q is 0 or an integer from 1 to 4;
P is absent or is a divalent moiety selected from the group consisting of O, S, SO, SO 2 , CO, NR 6 CH═CH, N(R 6 )SO 2 , N(R 6 )COO, N(R 6 )C(O), SO 2 N(R 6 ), OC(O)N(R 6 ), and C(O)N(R 6 );
W is H or is selected from the group consisting of (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, aryl, and heteroaryl, each of which is optionally substituted by one or more substituents selected independently from the group consisting of halogen, —OH, oxo (═O), —SH, —NO 2 , —CN, —CON(R 6 ) 2 , —NH 2 , —NHCOR 6 , —CO 2 R 6 , (C 1 -C 10 )alkylsulfanyl, (C 1 -C 10 )alkylsulfinyl, (C 1 -C 10 )alkylsulfonyl, (C 1 -C 10 )alkyl, and (C 1 -C 10 )alkoxy;
R 6 is at each occurrence independently H or selected from the group consisting of (C 1 -C 10 )alkyl, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )alkynyl, (C 2 -C 6 )alkenyl, (C 3 -C 8 )cycloalkyl, heteroaryl, and aryl, each of which is optionally substituted by one or more substituents selected from the group consisting of halogen, —OH, oxo (═O), —SH, —NO 2 , —CN, —CONH 2 , —COOH, (C 1 -C 10 )alkoxycarbonyl, (C 1 -C 10 )alkylsulfanyl, (C 1 -C 10 )alkylsulfinyl, (C 1 -C 10 )alkylsulfonyl, (C 1 -C 10 )alkyl, and (C 1 -C 10 )alkoxy;
or a pharmaceutically acceptable salt thereof.

2. A method according to claim 1 , wherein R 2 is a group of formula J3:

and R 5 is a group of formula K, wherein p is 0 or 1, P is absent or is CO, q is absent or is 1, and W is H, (C 1 -C 6 )alkyl, or aryl.

3. A method according to claim 2 , wherein R 5 is methyl or benzyl.

4. A method according to claim 1 , wherein G is arylene and R 1 is aryl, optionally substituted by one or more group independently selected from the group consisting of halogen, (C 1 -C 8 )alkyl, and (C 1 -C 10 )alkoxy.

5. A method according to claim 4 , wherein A1 and A2 are independently absent or selected from the group consisting of methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, and nonylene, G is phenylene, and R 1 is phenyl, optionally substituted by one or more group independently selected from the group consisting of halogen, (C 1 -C 8 )alkyl, and (C 1 -C 10 )alkoxy.

6. A method according to claim 1 , wherein E is —O—, —C(O)—(CH 2 ) n —O—, or —NR 7 —C(O)—(CH 2 ) n —O—; G is phenylene, wherein E is linked to the phenyl ring G in the meta position, and R 1 is phenyl, optionally substituted by one or more groups selected from the group consisting of halogen, (C 1 -C 8 )alkyl, and (C 1 -C 10 )alkoxy.

7. A method according to claim 1 , wherein R 2 is J1, J2, or J5

8. A method according to claim 2 , wherein the absolute configuration of carbon (1) is that shown hereinbelow:

9. A method according to claim 1 , wherein
Y is a divalent group of formula Y2:

A2 is absent and A1 is independently selected from the group consisting of methylene, ethylene, n-propylene, isopropylene, butylene, pentylene, hexylene, and octylene;
B is absent or is selected from the group consisting of piperidinylene, phenylene, pyridine-diyl, and pyrazole-diyl; wherein B is optionally substituted by one or more groups selected from the group consisting of —OH, fluorine, chlorine

Assignees

• Chiesi Farm Spa

Inventors

• Rancati Fabio
• Rizzi Andrea
• Carzaniga Laura
• Linney Ian
• Knight Chris
• Schmidt Wolfgang

Classifications

• A61P5/38

  of the suprarenal hormones · CPC title

• A61P43/00

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

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P11/08

  Bronchodilators · CPC title