Chemical compounds

• US 8,217,034 B2
• Filed: 07/23/2009
• Issued: 07/10/2012
• Est. Priority Date: 07/25/2008
• Status: Active Grant

• Current Assignee: Smithkline Beecham Corporation (GSK plc), VIIV Healthcare Company (GSK plc), Shionogi & Co., Ltd.
• Original Assignee: GlaxoSmithKline LLC (GSK plc), Shionogi & Co., Ltd.
• Inventors: Johns, Brian Alvin, Weatherhead, Jason Gordon, Hakogi, Toshikazu, Aoyama, Yasunori
• Primary Examiner(s): HABTE, KAHSAY
• Application Number:
  US13/054,633
• Publication Number:
  US 20110190236A1
• Time in Patent Office: 1,083 Days
• Field of Search: 544/95, 514/230.2
• US Class Current: 514/230.2
• 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: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: C07D 498/14 Ortho-condensed systems

Abstract

The present invention features compounds that are prodrugs of HIIV integrase inhibitors and therefore are useful in the inhibition of HIV replication, the prevention and/or treatment of infection by HIV, and in the treatment of AIDS and/or ARC.

Claims

1. A compound of formula (I):

2. A compound of formula (I) according to claim 1 wherein R¹ is C_1-8alkyl.

3. A compound of formula (I) according to claim 1 wherein R¹ is LR² wherein L is C_1-8alkylene and R² is hydroxy or alkoxy.

4. A compound of formula (I) according to claim 1 wherein R¹ is LR² wherein L is C_1-8alkylene and R² and —

OP(O)(OH)₂ or a pharmaceutically acceptable salt thereof.

5. A compound of formula (I) according to claim 1 wherein R¹ is LR² wherein L is C_1-8alkylene and R² and heterocyclyl or a pharmaceutically acceptable salt thereof.

7. A compound according to any one of claims 1 to 6 wherein the pharmaceutically acceptable salt is a hydrochloride salt.

8. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 6 together with a pharmaceutically acceptable carrier.

9. A pharmaceutical composition according to claim 8 in the form of a tablet, capsule, liquid or suspension.

10. A pharmaceutical composition according to claim 8 wherein the pharmaceutically acceptable salt is a hydrochloride salt.

6. A compound selected from the group consisting of:

{[(4R,12aS)-9-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′

,2′

;

4,5]pyrazino[2,1-b][1,3]oxazin-7-yl]oxy}methyl methyl carbonate;

{[(4R,12aS)-9-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′

,2′

;

4,5]pyrazino[2,1-b][1,3]oxazin-7-yl]oxy}methyl 2-(methyloxy)ethyl carbonate;

{[(4R,12aS)-9-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′

,2′

;

4,5]pyrazino[2,1-b][1,3]oxazin-7-yl]oxy}methyl 2-hydroxyethyl carbonate;

{[(4R,12aS)-9-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′

,2′

;

4,5]pyrazino[2,1-b][1,3]oxazin-7-yl]oxy}methyl 2-(phosphonooxy)ethyl carbonate;

{[(4R,12aS)-9-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′

,2′

;

4,5]pyrazino[2,1-b][1,3]oxazin-7-yl]oxy}methyl 2-(4-morpholinyl)ethyl carbonate; and

pharmaceutically acceptable salts thereof.