Compounds

Patent metadata

Field	Value
Publication number	US-10023558-B2
Application number	US-201715712366-A
Country	US
Kind code	B2
Filing date	Sep 22, 2017
Priority date	May 31, 2016
Publication date	Jul 17, 2018
Grant date	Jul 17, 2018

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.

First claim

The invention claimed is:

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

Assignees

• Chiesi Farm Spa

Inventors

• Sutton Jonathan Mark
• Heald Robert Andrew
• Jennings Andrew Stephen Robert
• Capaldi Carmelida
• Armani Elisabetta

Classifications

• A61P43/00

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

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P17/06

  Antipsoriatics · CPC title

• A61P17/00

  Drugs for dermatological disorders · CPC title

• A61P11/08

  Bronchodilators · CPC title