Compounds

• US 7,498,326 B2
• Filed: 06/25/2003
• Issued: 03/03/2009
• Est. Priority Date: 06/26/2002
• Status: Expired due to Fees

• Current Assignee: Glaxo Group Limited (GSK plc)
• Original Assignee: Glaxo Group Limited (GSK plc)
• Inventors: Daines, Robert A, Gallagher, Timothy Francis, Axten, Jeffrey Michael, Miller, William Henry, Pendrak, Israil, Pearson, Neil David, Davies, David Thomas, Jones, Graham Elgin
• Primary Examiner(s): HABTE, KAHSAY
• Application Number:
  US10/518,655
• Publication Number:
  US 20060058287A1
• Time in Patent Office: 2,078 Days
• Field of Search: 514/224.2, 544/48
• US Class Current: 514/224.2
• CPC Class Codes: A61K 31/03 aromatic
• CPC Class Codes: A61K 31/535 having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
• CPC Class Codes: A61K 31/54 having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: C07D 491/04 Ortho-condensed systems
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

Piperidine derivatives and pharmaceutically acceptable derivatives thereof useful in methods of treatment of bacterial infections in mammals, particularly in man. The piperidine derivatives include compounds of formula (I):

wherein R^A, AB, n, R³, R² and R⁴ are defined herein. For example, R^A is an optionally substituted bicyclic carbocyclic or heterocyclic ring system, and R⁴ is a group U-R⁵ in which R⁵ is an optionally substituted bicyclic heterocyclic ring system as defined herein (e.g. optionally substituted pyrido [3,2, -b][1,4] thiazin-yl).

Claims

1. A compound of formula (I) or a pharmaceutically acceptable derivative thereof:

2. A compound according to claim 1 wherein R^A is optionally substituted isoquinolin-5-yl, quinolin-8-yl, thieno[3,2-b]pyridin-7-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl, quinoxalin-5-yl, isoquinolin-8-yl, [1,6]-naphthyridin-4-yl, 1,2,3,4-tetrahydroquinoxalin-5-yl or 1,2-dihydroisoquinoline-8-yl.

3. A compound according to claim 1 wherein R¹ is H, methoxy, methyl, cyano or halogen and R^1a is H.

4. A compound according to claim 1 wherein R³ is hydrogen;

optionally substituted hydroxy;

optionally substituted amino;

halogen;

(C_1-4)alkoxycarbonyl;

CONH₂;

1-hydroxyalkyl;

CH₂CO₂H;

CH₂CONH₂;

—

CONHCH₂ CONH₂;

1,2-dihydroxyalkyl;

CH₂CN;

2-oxo-oxazolidin-5-yl;

or 2-oxo-oxazolidin-5-yl(C_1-4alkyl).

5. A compound according to claim 1 wherein n is 0 and A and B are both CH₂, A is CHOH and B is CH₂ or A is NH and B is CO.

6. A compound according to claim 1 wherein —

U—

is —

CH₂—

.

7. A compound according to claim 1 wherein Y² has a group S bonded to X⁵ and a group NHCO bonded via N to to X³.

8. A compound according to claim 1 wherein R⁵ is 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl.

10. A method of treatment of bacterial infections in mammals, which method comprises the administration to a mammal in need of such treatment an effective amount of a compound according to claim 1.

11. A pharmaceutical composition comprising a compound according to claim 1, and a pharmaceutically acceptable carrier.

12. A compound according to claim 1 wherein R^A is unsubstituted quinolin-4-yl, or quinolin-4-yl substituted by a cyano in the 6-position.

13. A compound according to claim 1 wherein R^A is optionally substituted quinolin-8-yl.

14. A compound according to claim 1 wherein R^A is optionally substituted quinoxalin-5-yl.

9. A compound selected from:

6-({(3R,4S)-3-Fluoro-1-[(R)-2-hydroxy-2-(2-methoxy-quinolin-8-yl)-ethyl]-piperidin-4-ylamino }-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one;

6-({(3S,4R)-3-Fluoro-1-[(R)-2-hydroxy-2-(2-methoxy-quinolin-8-yl)-ethyl]-piperidin-4-ylamino }-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one;

6-({(3R,4R)-3-Hydroxy-1-[(R)-2-hydroxy-2-(2-methoxy-quinolin-8-yl)-ethyl]-piperidin-4-ylamino }-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one;

6-({(3S,4S)-3-Hydroxy-1-[(R)-2-hydroxy-2-(2-methoxy-quinolin-8-yl)-ethyl]-piperidin-4-ylamino }-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one;

6-{[(1-{(2R/S)-2-hydroxy-2-[3-(methyloxy)-5-quinoxalinyl]ethyl}-4-piperidinyl )amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one;

6-[({1-[2-(4-quinolinyl)ethyl]-4-piperidinyl}amino)methyl]-2H-pyrido[3,2-b][1,4]thiazin-3 (4H)-one; and

4-[2-(3-hydroxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl) methyl]amino}-1-piperidinyl)ethyl]-6-quinolinecarbonitrile;

or a pharmaceutically acceptable derivative thereof.

15. A method of treatment of bacterial infections in mammals, which method comprises the administration to a mammal in need of such treatment an effective amount of a compound according to claim 9.

16. A pharmaceutical composition comprising a compound according to claim 9, and a pharmaceutically acceptable carrier.