Pyrimidinone compounds which are HNE inhibitors

Patent metadata

Field	Value
Publication number	US-9868740-B2
Application number	US-201415317274-A
Country	US
Kind code	B2
Filing date	Jun 12, 2014
Priority date	Jun 12, 2014
Publication date	Jan 16, 2018
Grant date	Jan 16, 2018

Abstract

This invention relates to heterocyclic compounds, which are pyrimidinone derivatives having human neutrophil elastase inhibitory properties, and their use in therapy.

First claim

The invention claimed is:

1. A compound selected from the group consisting of:
1-(2-{5-Cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3a]pyrimidin-5-yl]-phenyl}-ethyl)-4-methoxy-pyridinium bromide;
1-(2-{5-Cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-3-hydroxy-pyridinium bromide;
1-(2-{5-Cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-2-methyl-pyridinium bromide;
1-(2-{5-Cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-4-hydroxymethyl-pyridinium bromide;
1-(2-{5-Cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-4-isopropyl-pyridinium bromide;
1-(2-{5-Cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-5-hydroxy-2-methyl-pyridinium bromide;
1-(2-{5-Cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-2,4-dimethyl-pyridinium bromide;
1-(2-{5-Cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-3,5-dimethyl-pyridinium bromide;
1-(2-{5-Cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-2-ethyl-pyridinium bromide;
1-(2-{5-Cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-2-(2-hydroxy-ethyl)-pyridinium bromide; and
1-(2-{5-Cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-4-ethyl-pyridinium bromide;
or a pharmaceutically acceptable salt of said compound.

2. A compound of formula (I)″ or a pharmaceutically acceptable salt thereof:

wherein the group R is selected from the group consisting of
4-methoxy-pyridinyl;
3-hydroxy-pyridinyl;
2-methyl-pyridinyl;
4-hydroxymethyl-pyridinyl;
4-isopropyl-pyridinyl;
5-hydroxy-2-methyl-pyridinyl;
2,4-dimethyl-pyridinyl;
3,5-dimethyl-pyridinyl;
2-ethyl-pyridinyl;
2-(2-hydroxy-ethyl)-pyridinyl; and
4-ethyl-pyridinyl.

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

4. A pharmaceutical composition of claim 3 , which is adapted for oral administration or administration by a pulmonary route.

5. A method of treating a disease or condition, comprising administering to a subject in need thereof an effective amount of a compound or salt according to claim 1 ,
wherein said disease or condition is chronic obstructive pulmonary disease, chronic bronchitis, lung fibrosis, pneumonia, acute respiratory distress syndrome, pulmonary emphysema, smoking-induced emphysema or asthma.

6. A method according to claim 5 , wherein said disease or condition is chronic obstructive pulmonary disease.

7. A method according to claim 5 , wherein said disease or condition is chronic bronchitis.

8. A method according to claim 5 , wherein said disease or condition is lung fibrosis.

9. A method according to claim 5 , wherein said disease or condition is pneumonia.

10. A method according to claim 5 , wherein said disease or condition is acute respiratory distress syndrome.

11. A method according to claim 5 , wherein said disease or condition is pulmonary emphysema.

12. A method according to claim 5 , wherein said disease or condition is smoking-induced emphysema.

13. A method according to claim 5 , wherein said disease or condition is asthma.

Assignees

• Chiesi Farm Spa

Inventors

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

Classifications

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61K9/007

  Pulmonary tract; Aromatherapy · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61P11/12

  Mucolytics · CPC title

• A61P11/06

  Antiasthmatics · CPC title