Bronchodilators for treating obstructive lung disease

Patent metadata

Field	Value
Publication number	US-2025268888-A1
Application number	US-202519069790-A
Country	US
Kind code	A1
Filing date	Mar 4, 2025
Priority date	Sep 1, 2020
Publication date	Aug 28, 2025
Grant date	—

Abstract

Disclosed herein are compounds useful for treating obstructive lung diseases. The compounds are TAS2Rs agonists and may further be used to treat disorders and conditions implicated by TAS2R. In some instances the disclosed compounds can be used to treat asthma.

First claim

What is claimed is:

1 . A method for treating an obstructive lung disease in a patient in need thereof, comprising administering to the patient a compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein
ring A represents a carbocyclic or heterocyclic ring system;
ring b represents a carbocyclic or heterocyclic ring system;
Z 1 is O, S, or NR a ; wherein R a is H, C 1-8 alkyl, or C 1-8 alkoxy; and
Z 2 is O, S, or NR b ; wherein R b is H, C 1-8 alkyl, or C 1-8 alkoxy.

2 . The method according to claim 1 , wherein ring A is a heterocyclic ring system having the formula:

wherein
X is N or CR 1 , wherein R 1 is selected from R a , OR a , N(R a ) 2 , F, Cl, Br, I, NO 2 , CN, wherein R a is in each case selected from H, C 1-8 alkyl, C 2-8 alkenyl; C 2-8 alkynyl;

3 . The method according to claim 2 , wherein ring A defines the group:

wherein wavy line “a” represent the point of attachment to the carbon ortho to the Z 1 bearing carbon, and wavy line “b” represents the point of attachment to the carbon para to the Z 2 bearing carbon;
X 1 is O, S, or NR 4
R 2 is selected from R b , OR b , N(R b ) 2 , F, Cl, Br, I, NO 2 , CN, wherein R b is in each case selected from H, C 1-8 alkyl, C 2-8 alkenyl; C 2-8 alkynyl;
R 3 is selected from R c , OR c , N(R c ) 2 , F, Cl, Br, I, NO 2 , CN, wherein R c is in each case selected from H, C 1-8 alkyl, C 2-8 alkenyl; C 2-8 alkynyl;
R 4 is H or C 1-8 alkyl, C 2-8 alkenyl; C 2-8 alkynyl;
wherein any two or more of R 1 , R 2 , R 3 , and R 4 may together form a ring; and
wherein either R 3 or R 4 may form a ring with R a .

4 . The method according to claim 2 , wherein the compound has the formula:

wherein X 1 is O, S, or NR 4
R 2 is selected from R b , OR b , N(R b ) 2 , F, Cl, Br, I, NO 2 , CN, wherein R b is in each case selected from H, C 1-8 alkyl, C 2-8 alkenyl; C 2-8 alkynyl;
R 3 is selected from R c , OR c , N(R c ) 2 , F, Cl, Br, I, NO 2 , CN, wherein R c is in each case selected from H, C 1-8 alkyl, C 2-8 alkenyl; C 2-8 alkynyl;
R 4 is H or C 1-8 alkyl, C 2-8 alkenyl; C 2-8 alkynyl;
wherein any two or more of R 1 , R 2 , R 3 , and R 4 may together form a ring; and
wherein either R 3 or R 4 may form a ring with R a .

5 . The method according to claim 1 , wherein ring B defines the group:

wherein wavy line “c” represent the point of attachment to the carbon ortho to the Z 2 bearing carbon, and wavy line “d” represents the point of attachment to the carbon para to the Z 1 bearing carbon;
X 2 is N or CR 5 ;
X 3 is N or CR 9 ;
R 5 is H or C 1-8 alkyl, C 2-8 alkenyl; C 2-8 alkynyl;
R 9 is H or C 1-8 alkyl, C 2-8 alkenyl; C 2-8 alkynyl;
R 6 is selected from R d , OR d , N(R d ) 2 , F, Cl, Br, I, NO 2 , CN, wherein R d is in each case selected from H, C 1-8 alkyl, C 2-8 alkenyl; C 2-8 alkynyl;
R 7 is selected from R e , OR e , N(R e ) 2 , F, Cl, Br, I, NO 2 , CN, wherein R e is in each case selected from H, C 1-8 alkyl, C 2-8 alkenyl; C 2-8 alkynyl;
R 8 is selected from R f , OR f , N(R f ) 2 , F, Cl, Br, I, NO 2 , CN, wherein R f is in each case selected from H, C 1-8 alkyl, C 2-8 alkenyl; C 2-8 alkynyl;
wherein any two or more of R 5 , R 6 , R 7 , and R 8 may together form a ring; and
wherein either R 8 or R 9 may form a ring with R b .

6 . The method according to claim 1 , wherein the compound has the formula:

Wherein R 1 is selected from R a , OR a , N(R a ) 2 , F, Cl, Br, I, NO 2 , CN, wherein R a is in each case selected from H, C 1-8 alkyl, C 2-8 alkenyl; C 2-8 alkynyl;
R 2 is selected from R b , OR b , N(R b ) 2 , F, Cl, Br, I, NO 2 , CN, wherein R b is in each case selected from H, C 1-8 alkyl, C 2-8 alkenyl; C 2-8 alkynyl;
R 3 is selected from R c , OR c , N(R c ) 2 , F, Cl, Br, I, NO 2 , CN, wherein R c is in each case selected from H, C 1-8 alkyl, C 2-8 alkenyl; C 2-8 alkynyl;
R 4 is H or C 1-8 alkyl, C 2-8 alkenyl; C 2-8 alkynyl;
wherein any two or more of R 1 , R 2 , R 3 , and R 4 may together form a ring; and
wherein R 3 may form a ring with R a ;
X 2 is N or CR 5 ;
R 5 is H or C 1-8 alkyl, C 2-8 alkenyl; C 2-8 alkynyl;
R 6 is selected from R d , OR d , N(R d ) 2 , F, Cl, Br, I, NO 2 , CN, wherein R d is in each case selected from H, C 1-8 alkyl, C 2-8 alkenyl; C 2-8 alkynyl;
R 7 is selected from R e , OR e , N(R e ) 2 , F, Cl, Br, I, NO 2 , CN, wherein R e is in each case selected from H, C 1-8 alkyl, C 2-8 alkenyl; C 2-8 alkynyl;
R 8 is selected from R f , OR f , N(R f ) 2 , F, Cl, Br, I, NO 2 , CN, wherein R f is in each case selected from H, C 1-8 alkyl, C 2-8 alkenyl; C 2-8 alkynyl;
wherein any two or more of R 5 , R 6 , R 7 , and R 8 may together form a ring; and
wherein R 8 may form a ring with R b .

7 . The method according to claim 1 , wherein Z 1 and Z 2 are both O.

8 . The method according to claim 1 , wherein the obstructive lung disease is asthma, chronic obstructive pulmonary disease, emphysema, bronchitis, cystic fibrosis, bronchiectasis, bronchiolitis, or allergic bronchopulmonary aspergillosis.

9 . The method according to claim 1 , wherein the compound is administered by nasal or buccal inhalation.

10 . A pharmaceutical composition, comprising at least one compound according to claim 1 , and a pharmaceutically acceptable excipient.

11 . The pharmaceutical composition according to claim 10 , comprising a fluorocarbon solvent.

12 . The pharmaceutical composition according to claim 10 , comprising a powdered matrix material.

Assignees

• Univ South Florida
• Univ Rutgers

Inventors

• Liggett Stephen
• Leahy James
• Kim Donghwa
• An Steven

Classifications

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• A61K31/122

  having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin · CPC title

• A61K31/4745 Primary

  condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48) · CPC title