IP Library › Granted Patent US 10,023,558
Granted Patent B2
US 10,023,558 · App. 15/712,366 · Granted Jul 17, 2018

Compounds

Inventors: Jonathan Mark Sutton (Harlow, GB); Robert Andrew Heald (Harlow, GB); Andrew Stephen Robert Jennings (Harlow, GB); Carmelida Capaldi (Parma, IT); Elisabetta Armani (Parma, IT)
Assignee: CHIESI FARMACEUTICI S.P.A.
C07D403/04C07C309/29C07D401/14C07D403/14C07D413/14C07D417/14C07D471/04
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 10,023,558
App. No.
15/712,366
Granted
Jul 17, 2018
Kind
B2
Abstract

Compounds of formula (I) defined herein exhibit human neutrophil elastase inhibitory properties and are useful for the treatment of disease or conditions in which HNE is implicated.

Claims (64)

1. A compound of formula (I):

wherein

A is:

X is:

R 1 is one of the following groups:

n is an integer from 1 to 4;

m is 0 or an integer from 1 to 4;

t is 0 or an integer from 1 to 4;

y is an integer from 1 to 4;

w is an integer from 1 to 4;

z is 0 or 1;

l is 0 or 1;

R 2 is —H or linear or branched —(C 1 -C 4 )alkyl;

R 3 is linear or branched —(C 1 -C 4 )alkyl or R 2 and R 3 may form together a cycloalkyl;

R 4 is -arylene-(C 1 -C 4 )alkylene-NR d R e , -arylene-(C 1 -C 4 )alkylene-N + R a R b R c , -heteroarylene-(C 1 -C 4 )alkylene-NR d R e , -heteroarylene-(C 1 -C 4 )alkylene-N + R a R b R c and heteroaryl, wherein any of such arylene-(C 1 -C 4 )alkylene-NR d R e , -arylene-(C 1 -C 4 )alkylene-N + R a R b R c , -heteroarylene-(C 1 -C 4 )alkylene-NR d R e , -heteroarylene-(C 1 -C 4 )alkylene-N + R a R b R c and heteroaryl may be optionally substituted by one or more —(C 1 -C 4 )alkyl or R 4 is one of the following groups;

R 5 is aryl-(C 1 -C 4 )alkylenoxy-, linear or branched (C 1 -C 4 )alkyl-OC(O)—NH—, —(CH 2 ) t —NR d R e , —(CH 2 ) t —N + R a R b R c , —C(O)—N(R 10 )C 1 -C 4 )alkylene-NR d R e , —C(O)N(R 10 )(C 1 -C 4 )alkylene-N + R a R b R c , —C(O)O(C 1 -C 4 )alkylene-NR d R e , —C(O)O(C 1 -C 4 )alkylene-N + R a R b R c , —(CH 2 ) t NHC(O)—(C 1 -C 4 )alkylene-NR d R e , —(CH 2 )NHC(O)—(C 1 -C 4 )alkylene-N + R a R b R c , or one of the following groups

R 6 is —H, —(C 1 -C 4 )alkyl, aryl-(C 1 -C 4 )alkylene-OCO—, CF 3 C(O)—, aryl-(C 1 -C 4 )alkylene, linear or branched (C 1 -C 4 )alkyl-OC(O)—, —C(O)—(C 1 -C 4 )alkylene-NR d R e , —C(O)—(C 1 -C 4 )alkylene-N + R a R b R c , —C(O)O—(C 1 -C 4 )alkylene-NR d R e , —C(O)O—(C 1 -C 4 )alkylene-N + R a R b R c —C(O)—N(R 10 )(C 1 -C 4 )alkylene-NR d R e , or —C(O)N(R 10 )(C 1 -C 4 )alkylene-N + R a R b R c ;

R a is —(C 1 -C 4 )alkyl;

R b is —(C 1 -C 4 )alkyl;

R c is —(C 1 -C 4 )alkyl, aryl-(C 1 -C 4 )alkylene or heteroaryl-(C 1 -C 4 )alkylene, wherein said heteroaryl-(C 1 -C 4 )alkylene may be optionally substituted by one or more —(C 1 -C 4 )alkyl groups;

R d is H or —(C 1 -C 4 )alkyl;

R e is H or —(C 1 -C 4 )alkyl;

R 7 is —H or —(C 1 -C 4 )alkyl;

R 8 is —H or —(C 1 -C 4 )alkyl;

R 9 is heterocycloalkyl, heterocycloalkyl-(C 1 -C 4 )alkylene-, (C 1 -C 4 )alkylene-NR d R e and (C 1 -C 4 )alkylene-N + R a R b R c ;

R 10 is —H or —(C 1 -C 4 )alkyl; and

* and #, indicate the points of attachment for the radical groups to the rest of the molecule,

wherein any of such heterocycloalkyl, aryl, heteroaryl and aryl-(C 1 -C 4 )alkylene may be optionally substituted by one or more groups independently selected from (C 1 -C 4 )alkyl and OR 7 and wherein the nitrogen atom in the heterocycloalkyl and heteroaryl groups may be quaternized,

or a pharmaceutically acceptable salt thereof.

2. A compound or salt according to claim 1 , wherein

X is

n is 2; m is 2; R 7 is —H; R 5 is aryl-(C 1 -C 4 )alkylenoxy-, linear or branched (C 1 -C 4 )alkyl-OC(O)—NH, C(O)O(C 1 -C 4 )alkylene-N + R a R b R c , —(CH 2 ) t NHC(O)—(C 1 -C 4 )alkylene-NR d R e , —(CH 2 ) t NHC(O)—(C 1 -C 4 )alkylene-N + R a R b R c , or —C(O)N(R 10 )(C 1 -C 4 )alkylene-N + R a R b R c — wherein t is 0 or 1, R a and R b are independently —(C 1 -C 4 )alkyl, R c is —(C 1 -C 4 )alkyl, heteroaryl-(C 1 -C 4 )alkylene or aryl-(C 1 -C 4 )alkylene, R d and R e are independently —(C 1 -C 4 )alkyl, R 10 is —H or —(C 1 -C 4 )alkyl.

3. A compound or salt according to claim 1 , wherein,

X is

n is 2; m is 2; R 7 is —H; R 5 is —(CH 2 ) t —NR d R e , or —(CH 2 ) t —N + R a R b R c , wherein t is 0 or 1, R a and R b are independently —(C 1 -C 4 )alkyl, R c is —(C 1 -C 4 )alkyl, heteroaryl-(C 1 -C 4 )alkylene or aryl-(C 1 -C 4 )alkylene.

4. A compound or salt according to claim 1 , wherein

X is

n is 2; m is 2; R 7 is —H; R 5 is

R a is —(C 1 -C 4 )alkyl; R b is —(C 1 -C 4 )alkyl; R 10 is —H.

5. A compound or salt according to claim 1 , wherein

X is

n is 2; m is 2; R 7 is —H; R 5 is

R a is —(C 1 -C 4 )alkyl; R b is —(C 1 -C 4 )alkyl.

6. A compound or salt according to claim 1 , wherein

X is

n is 2; m is 2; R 7 is —H or —(C 1 -C 4 )alkyl; R 6 is aryl-(C 1 -C 4 )alkylenoxy-, aryl-(C 1 -C 4 )alkylene-OCO—, CF 3 C(O)—, —C(O)—(C 1 -C 4 )alkylene-NR d R e , —C(O)O—(C 1 -C 4 )alkylene-N + R a R b R c , —C(O)N(R 10 )(C 1 -C 4 )alkylene-N + R a R b R c , or —C(O)—(C 1 -C 4 )alkylene-N + R a R b R c wherein R d is —H or —(C 1 -C 4 )alkyl; R e is —H or —(C 1 -C 4 )alkyl, R a is —(C 1 -C 4 )alkyl; R b is —(C 1 -C 4 )alkyl; R c is selected from —(C 1 -C 4 )alkyl; R 10 is —H.

7. A compound or salt according to claim 1 , wherein

X is

n is 2; m is 2; R 7 is —H or —(C 1 -C 4 )alkyl; R a and R b are each independently —(C 1 -C 4 )alkyl.

8. A compound or salt according to claim 1 , wherein

X is

n is 2; m is 2; R 7 is —H; R 5 is —(CH 2 ) t —N + R a R b R c , R a and R b are each independently —(C 1 -C 4 )alkyl, and R c is aryl-(C 1 -C 4 )alkylene.

9. A pharmaceutical composition, comprising a compound or salt according to claim 1 and a pharmaceutically acceptable carrier or excipient.

10. A pharmaceutical composition according to claim 9 which is adapted for oral administration or administration by the pulmonary route.

11. A method of treatment of a disease or condition in which HNE is implicated, comprising administering to a subject in need thereof an effective amount of a compound or salt according to claim 1 .

12. A method according to claim 11 , wherein said disease or condition is chronic obstructive pulmonary disease, bronchiectasis, chronic bronchitis, lung fibrosis, pneumonia, acute respiratory distress syndrome, pulmonary emphysema, smoking-induced emphysema, or cystic fibrosis.

13. A method according to claim 11 , wherein said disease or condition is asthma, rhinitis, psoriasis, atopic dermatitis, non-atopic dermatitis, Crohn's disease, ulcerative colitis, or irritable bowel disease.

14. A method according to claim 11 , wherein said disease or condition is chronic obstructive pulmonary disease.

15. A method according to claim 11 , wherein said disease or condition is bronchiectasis.

16. A method according to claim 11 , wherein said disease or condition is chronic bronchitis.

17. A method according to claim 11 , wherein said disease or condition is lung fibrosis.

18. A method according to claim 11 , wherein said disease or condition is pneumonia.

19. A method according to claim 11 , wherein said disease or condition is acute respiratory distress syndrome.

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

Priority Claims (1)
EP 16172196 · May 31, 2016 · regional
Continuity (2)
Continuation 15606313 · May 26, 2017
Related Publication 20180009787A1 · Jan 11, 2018
Cited By (1)
US 12,577,208