Compounds

Patent metadata

Field	Value
Publication number	US-9487528-B2
Application number	US-201514731786-A
Country	US
Kind code	B2
Filing date	Jun 5, 2015
Priority date	Jun 9, 2014
Publication date	Nov 8, 2016
Grant date	Nov 8, 2016

Abstract

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

First claim

The invention claimed is:

1. A compound of formula (I):

wherein
A is CH or N;
B is CH or N;
D is CH or N;
E is CH or N;
R 1 is —CN or a group —C(O)—VR 2 ;
V is —O—, —(CH 2 )—, or —NH—;
R 2 is hydrogen or —(C 1 -C 6 )alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, OR 3 , and —NR 3 R 7 ;
R 3 is hydrogen or optionally substituted (C 1 -C 6 )alkyl;
R 4 is —CF 3 or —CHF 2 ,
R 5 is a group selected from the group consisting of:

j is 0 or an integer of from 1 to 4;
y is 0 or an integer of from 1 to 4;
L and T are independently a 4 to 8-membered heterocycloalkyl ring bringing an —X— group in any of the free positions;
X is —O—, —S—, —S(O 2 )—, or —NR 6 ;
W is —N(R 3 )—, —O—, —C(O)—, —OC(O)N(R 3 )—, —N(R 3 )C(O)N(R 3 )—, —C(O)N(R 3 )—, —NR 3 C(O)—, —SO 2 —, —SO 2 N(R 3 )—, —NR 3 S(O 2 )—, —S—, —C(O)O—, —OC(O)—, optionally substituted (C 1 -C 6 )alkylene, optionally substituted (C 3 -C 6 )cycloalkylene, or optionally substituted (C 4 -C 7 )heterocycloalkylene;
G is hydrogen, halogen, —CN, —N(R 3 )(R 7 ), —OR 3 , —OC(O)OR 3 , —OC(O)NR 3 R 7 , —N(R 3 )C(N)N(R 3 )(R 7 ), —N(R 3 )C(O)N(R 3 )(R 7 ), —C(O)N(R 3 )(R 7 ), —N(R 3 )C(O)R 7 , —S(O 2 )R 3 , —S(O 2 )N(R 3 )(R 7 ), —N(R 3 )S(O 2 )(R 7 ), —SR 3 , —C(O)OR 3 , —OC(O)R 3 , optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 6 )cycloalkyl, or optionally mono- or bi-substituted (C 4 -C 7 )heterocycloalkyl;
Ra is hydrogen, —OH, —NH 2 , or optionally substituted (C 1 -C 6 )alkyl;
R 6 is hydrogen, —S(O 2 )R 7 , —CO 2 R 7 , —CONR 3 R 7 , —SO 2 NR 3 R 7 , or optionally substituted (C 1 -C 6 )alkyl;
R 7 is hydrogen or optionally substituted (C 1 -C 6 )alkyl;
wherein, unless otherwise specified, optionally substituted means optionally substituted by one or more substituents selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )hydroxyalkyl, —OH, —NH 2 , halogen, —CF 3 , —OCF 3 , and —NR 3 R 7 ;
or a pharmaceutically acceptable salt thereof,
with the provisos that:
(1) when y is an integer ranging from 1 to 4, W is —O— and j is 0, then G is not hydrogen or (C 1 -C 6 )alkyl optionally substituted by one or more (C 1 -C 6 )alkoxy;
(2) when y is an integer ranging from 1 to 4, W is —N(R 3 )—, R 3 is hydrogen or (C 1 -C 6 )alkyl and j is 0, then G is not hydrogen or (C 1 -C 6 )alkyl;
(3) when y is 0, W is —C(O)N(R 3 )—, R 3 is hydrogen or (C 1 -C 6 )alkyl and j is 0, then G is not H or (C 1 -C 6 )alkyl optionally substituted with —NR 3 R 7 , wherein R 3 and R 7 are independently H or (C 1 -C 6 )alkyl;
(4) when y is 0, W is —S(O 2 )— and j is 0, then G is not (C 1 -C 6 )alkyl optionally substituted with —OH;
(5) when y is 0, W is —S(O 2 )N(R 3 )—, R 3 is H and j is 0, then G is not hydrogen; and
(6) when y is 0, W is —S(O 2 )N(R 3 )—, R 3 is H or (C 1 -C 4 )alkyl and j is 0, then G is not hydrogen or (C 1 -C 6 )alkyl.

2. A compound or pharmaceutically acceptable salt according to claim 1 , wherein R 5 is a group
* CH 2 y W CH 2 j G

wherein W is —C(O)—, —OC(O)N(R 3 )—, —N(R 3 )C(O)N(R 3 )—, —NR 3 C(O)—, —NR 3 S(O 2 )—, —S—, —C(O)O—, —OC(O)—, optionally substituted (C 1 -C 6 )alkylene, optionally substituted (C 3 -C 6 )cycloalkylene, or optionally substituted (C 4 -C 7 )heterocycloalkylene.

3. A compound or pharmaceutically acceptable salt according to claim 1 , wherein R 5 is a group
* CH 2 y W CH 2 j G

wherein y is 2, W is —NR 3 S(O 2 ), R 3 is hydrogen or optionally substituted (C 1 -C 6 )alkyl, j is 1, and G is hydrogen.

4. A compound or pharmaceutically acceptable salt according to claim 1 , wherein R 5 is a group
* CH 2 y W CH 2 j G

wherein y is 2 or 3, W is —S—, j is 0, and G is optionally substituted (C 1 -C 6 )alkyl.

5. A compound or pharmaceutically acceptable salt according to claim 1 , wherein R 5 is a group
* CH 2 y W CH 2 j G

wherein y is 2 or 3, W is —SO 2 —, j is 0, and G is optionally substituted (C 1 -C 6 )alkyl.

6. A compound or pharmaceutically acceptable salt according to claim 1 , wherein R 5 is a group
* CH 2 y W CH 2 j G

wherein y is 2 or 3, W is —NR 3 C(O)—, R 3 is hydrogen or optionally substituted (C 1 -C 6 )alkyl, j is 1, and G is hydrogen.

7. A compound or pharmaceutically acceptable salt according to claim 1 , wherein R 4 is —CF 3 .

8. A compound or pharmaceutically acceptable salt according to claim 1 , wherein R 4 is —CHF 2 .

9. A compound or pharmaceutically acceptable salt according to claim 1 , wherein R 1 is —CN or a group —C(O)—VR 2 ; V is —O—; R 2 is —(C 1 -C 6 )alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, OR 3 , and —NR 3 R 7 .

10. A compound or pharmaceutically acceptable salt according to claim 1 , wherein R 5 is a group selected from the group consisting of

wherein Ra is hydrogen, —OH, —NH 2 , or optionally substituted (C 1 -C 6 )alkyl; L and T are each independently a 4 to 8-membered heterocycloalkyl ring bringing an —X— group in any of the free positions; X is —O—, —S—, —S(O 2 )—, or —NR 6 —; R 6 is hydrogen, —SO 2 R 7 , —CO 2 R 7 , —CONR 3 R 7 , —SO 2 NR 3 R 7 , or optionally substituted (C 1 -C 6 )alkyl; R 3 and R 7 are each independently hydrogen or optionally substituted (C 1 -C 6 )alkyl.

11. A compound or pharmaceutically acceptable salt according to claim 1 , which is a compound of formula (I)′ and has the absolute configuration of carbon (1) shown below:

12. A compound or pharmaceutically acceptable salt according to claim 1 , which is in the form of a pharmaceutically acceptable salt.

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

14. A pharmaceutical composition according to claim 13 , which is in a form suitable for oral administration or administration by the pulmonary route.

15. A method of treating a disease or condition selected from the group consisting of chronic obstructive pulmonary disease, bronchiectasis, chronic bronchitis, lung fibrosis, pneumonia, acute respiratory distress syndrome, pulmonary emphysema, smoking-induced emphysema, cystic fibrosis, and asthma, comprising administering, to a subject in need thereof, an effective amount of a compound or pharmaceutically acceptable salt according to claim 1 .

16. A pressurized metered dose inhaler, which contains a compound or pharmaceutically acceptable salt according to claim 1 .

17. A dry powder inhaler, which contains a compound or pharmaceutically acceptable salt according to claim 1 .

18. A method according to claim 15 , wherein said disease or condition is chronic obstructive pulmonary disease.

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

20. A method according to claim 15 , wherein said disease or condition is chr

Assignees

• Chiesi Farm Spa

Inventors

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

Classifications

• A61P9/14

  Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P37/08

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

• A61P29/00

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

• A61P35/00

  Antineoplastic agents · CPC title