Substituted 5-hydroxy-3,4,6,9,9a, 10-hexanhydro-2h-1-oxa04a,8a-diaza-anthracene-6,10-dioness

• US 8,129,385 B2
• Filed: 04/28/2006
• Issued: 03/06/2012
• Est. Priority Date: 04/28/2005
• 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, Kawasuji, Takashi, Taishi, Teruhiko, Taoda, Yoshiyuki
• Primary Examiner(s): Wilson, James O
• Assistant Examiner(s): Willis, Douglas M
• Application Number:
  US11/919,386
• Publication Number:
  US 20090318421A1
• Time in Patent Office: 2,139 Days
• Field of Search: 514/250, 544/346
• US Class Current: 514/250
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/5365 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/20 Pills, tablets, discs, rods A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095
• 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: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 471/14 Ortho-condensed systems
• CPC Class Codes: C07D 471/22 in which the condensed systems contains four or more hetero rings
• CPC Class Codes: C07D 498/04 Ortho-condensed systems
• CPC Class Codes: C07D 498/14 Ortho-condensed systems
• CPC Class Codes: C07D 498/20 Spiro-condensed systems
• CPC Class Codes: C07D 498/22 in which the condensed system contains four or more hetero rings

Abstract

The present invention is directed to a class of substituted 5-hydroxy-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-6,10-diones useful as anti-HIV agents. The compounds have the formula:

Z═O; R²⁰, R²¹, R²², R²³, R²⁴ and R²⁵ independently are hydrogen, C₁-C₈ alkyl, (C₆-C₁₄)aryl-(C₁-C₈)alkyl, C₆-C₁₄ aryl, or alkoxy; the stereochemistry of an asymmetric carbon represented by * shows R- or S-configuration, or a mixture thereof; R^X is hydrogen; R¹⁴ is hydrogen or optionally substituted lower alkyl; R³ is hydrogen; R¹ is hydrogen or lower alkyl; R is halogen; and m is 1, 2 or 3; or a pharmaceutically acceptable salt thereof.

Claims

1. A compound of the formula:

2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R^X is hydrogen;

R¹⁴ is hydrogen;

R³ is hydrogen;

m is 1, 2 or 3 and R is halogen.

3. A compound according to claim 1 wherein the pharmaceutically acceptable salt is a sodium salt.

11. A pharmaceutical composition comprising a compound according to any one of claims 1, 5, 6, 7, 8, 9 or 4, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent.

4. A compound of formula (1-7):

5. A compound selected from the group consisting of:

(3S,9aS)-5-Hydroxy-3-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide;

(3R,9aR)-5-Hydroxy-3-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide;

(4S,9aR)-5-Hydroxy-4-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide;

(2R,9aR)-5-Hydroxy-2-methoxymethyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide;

(2S,9aS)-5-Hydroxy-2-methoxymethyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide;

(2S,9aR)-2-Ethyl-5-hydroxy-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide;

(2R,9aS)-2-Ethyl-5-hydroxy-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide;

(2S,9aS)-5-Hydroxy-6,10-dioxo-2-phenyl-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide;

(2S,9aS)-5-Hydroxy-2-isopropyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide;

(2R,9aR)-5-Hydroxy-2-isopropyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide;

(3S,9aS)-5-Hydroxy-3-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 4-fluoro-benzylamide;

(3R,9aR)-5-Hydroxy-3-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 4-fluoro-benzylamide;

(2R,9aS)-5-Hydroxy-2-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide;

(2S,9aR)-5-Hydroxy-2-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide;

(2S,9aR)-5-Hydroxy-2-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 4-fluoro-benzylamide;

(2R,9aS)-5-Hydroxy-2-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 4-fluoro-benzylamide;

5-Hydroxy-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diazaanthracene-7-carboxylic acid 4-fluorobenzylamide;

5-Hydroxy-3,3-dimethyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 4-fluoro-benzylamide;

5-Hydroxy-2-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-dizazaanthracene-7-carboxylic acid 4-fluorobenzylamide;

5-Hydroxy-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide;

5-Hydroxy-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 3-chloro-2-fluoro-benzylamide;

enantiomers thereof;

diastereomers thereof;

mixtures of enantiomers thereof;

mixtures of diastereomers thereof;

mixtures of enantiomers and diastereomers thereof; and

pharmaceutically acceptable salts thereof.

6. A compound selected from the group consisting of (4R,9aS)-5-Hydroxy-4-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide;

an enantiomer thereof;

diastereomer thereof;

mixtures of enantiomers thereof;

mixtures of diastereomers thereof;

mixtures of enantiomers and diastereomers thereof;

or a pharmaceutically acceptable salt thereof.

7. A compound which is (4R,9aS)-5-hydroxy-4-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide or a pharmaceutically acceptable salt thereof.

8. A compound which is (4R,9aS)-5-hydroxy-4-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic ac id 2,4-difluoro-benzylamide sodium salt.

9. A compound which is (4R,9aS)-5-hydroxy-4-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide.

10. A pharmaceutical composition comprising (4R,9aS)-5-hydroxy-4-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent.