NAPHTHYRIDIN-2 (1 H)-ONE COMPOUNDS USEFUL AS ANTIBACTERIALS

• US 20120115899A1
• Filed: 01/15/2010
• Published: 05/10/2012
• Est. Priority Date: 01/15/2009
• Status: Active Grant

• Current Assignee: Glaxo Group Limited (Glaxosmithkline Holdings Ltd.)
• Original Assignee: Glaxo Group Limited (Glaxosmithkline Holdings Ltd.)
• Inventors: Alemparte-Gallardo, Carlos, Barros-Aguirre, David, Cacho-Izquierdo, Monica, Fiandor Roman, Jose Maria, Lavandera Diaz, Jose Luis, Remuiñan-Blanco, Modesto Jesús
• Granted Patent: US 8,318,940 B2
• Time in Patent Office: Days
• US Class Current: 514/300
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/06 for tuberculosis
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

Compounds of Formula (I),

wherein substituents R¹, R² and R⁵ are as defined, and Ar represents substituted phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, furanyl, imidazolyl and thiophenyl substituted by a hydroxyalkyl substituent and an optional other substituent; compositions containing them, their use in therapy, including their use as antibacterials, for example in the treatment of tuberculosis, and methods for the preparation of such compounds, are provided.

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:

2. A compound of Formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein Ar represents a group selected from:

phenyl, pyridazinyl, pyridiminyl, pyrazinyl, thiazolyl, furanyl and thiophenyl.

3. A compound of Formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein Ar is pyridinyl.

4. A compound of Formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 3 wherein Ar is a 3-pyridinyl substituent and the C_1-5 hydroxyalkyl substituent R³ is in the 6-position relative to the ring nitrogen.

5. A compound of Formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein the C_1-5 hydroxyalkyl substituent R³ is hydroxymethyl.

6. A compound of Formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein the substituent R⁴ is present and is halo.

7. A compound of Formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 6 wherein R⁴ is present and is chloro.

8. A compound of Formula (I) or a pharmaceutically acceptable salt thereof according to claim 5, wherein Ar is 5-chloro-6-(hydroxymethyl)-3-pyridinyl.

9. A compound of Formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein R² represents hydroxy, and the absolute stereochemistry of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is:

10. A compound of Formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 selected from:

1-{2-[4-({[5-chloro-6-(hydroxymethyl)-3-pyridinyl]methyl}amino)-1-piperidinyl]ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one;

1-{2-[4-({[5-chloro-6-(hydroxymethyl)-3-pyridinyl]methyl}amino)-1-piperidinyl]ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one hydrochloride;

1-{2-[(3R,4S)-4-({[5-chloro-6-(hydroxymethyl)-3-pyridinyl]methyl}amino)-3-hydroxy-1-piperidinyl]ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one;

1-{2-[(3R,4S)-4-({[5-chloro-6-(hydroxymethyl)-3-pyridinyl]methyl}amino)-3-hydroxy-1-piperidinyl]ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one hydrochloride;

1-{2-[4-({[5-chloro-6-(hydroxymethyl)-3-pyridinyl]methyl}amino)-1-piperidinyl]ethyl}-7-(methyloxy)-1,5-naphthyridin-2(1H)-one;

1-{2-[4-({[5-bromo-6-(hydroxymethyl)-3-pyridinyl]methyl}amino)-1-piperidinyl]ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one;

1-{2-[(3R,4S)-4-({[5-chloro-6-(hydroxymethyl)-3-pyridinyl]methyl}amino)-3-hydroxy-1-piperidinyl]ethyl}-7-(methyloxy)-1,5-naphthyridin-2(1H)-one;

and

1-{2-[(3R,4S)-4-({[5-chloro-6-(hydroxymethyl)-3-pyridinyl]methyl}amino)-3-hydroxy-1-piperidinyl]ethyl}-7-(methyloxy)-1,5-naphthyridin-2(1H)-one hydrochloride.

11. A pharmaceutical composition comprising a) a compound of Formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, and b) one or more pharmaceutically acceptable carriers, excipients or diluents.

12. A method of treatment of tuberculosis in a mammal, which method comprises the administration to a mammal in need of such treatment an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1.

13. A method of treatment of bacterial infections in a mammal, which method comprises the administration to a mammal in need of such treatment an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof as claimed in claims 1.

21. A process for the preparation of a compound of Formula (I) according to claim 1, by a reaction between a compound of Formula (II), wherein R¹, R² and R⁵ are as defined for Formula (I), or an acid salt of a compound of Formula (II) such as a hydrochloride salt, and an aldehyde of Formula (III), wherein Ar is as defined for Formula (I), according to the scheme below:

23. A combination comprising a) a compound of Formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, and b) one or more additional therapeutic agents.

24. The method of claim 12 wherein said mammal is a human.

25. The method of claim 13 wherein said mammal is a human.

14-20. -20. (canceled)

22. A process for the preparation of a compound of Formula (I) wherein R¹ and Ar are as defined for Formula (I) and R² is hydrogen, by a reaction between a compound of Formula (II), wherein R¹ is as defined for Formula (I) and R² is hydrogen, and an alkylating agent of Formula (IV), wherein hal is a halo substituent, according to the scheme below: