Novobiocin analogues having modified sugar moieties

• US 9,120,774 B2
• Filed: 02/19/2010
• Issued: 09/01/2015
• Est. Priority Date: 11/03/2004
• Status: Active Grant

• Current Assignee: University of Kansas
• Original Assignee: University of Kansas
• Inventors: Blagg, Brian S. J., Zhao, Huiping, Donnelly, Alison Catherine
• Primary Examiner(s): LEWIS, PATRICK T
• Application Number:
  US13/202,382
• Publication Number:
  US 20120252745A1
• Time in Patent Office: 2,020 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 407/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 487/14 Ortho-condensed systems
• CPC Class Codes: C07H 19/00 Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof

Abstract

The disclosure provides novobiocin analogues with noviose replacements which are useful as Hsp90 inhibitors in the treatment of cancer.

Claims

1. A compound according to Formula I;

or a pharmaceutically acceptable salt thereof;

2. The compound of claim 1 wherein X₉ is —

O—

alkyl, —

O—

alkylamino, —

O—

cycloalkyl, —

O—

(CO)—

alkyl, —

O—

(CO)—

cycloalkyl, —

O—

(CH₂)_n-pyridinyl, —

O—

(CH₂)_n-piperidinyl, —

O—

(CH₂)_n-pyrrolino, or —

O—

(CH₂)_n-pyrrolidinyl, each optionally substituted with one or more amino, amido, alkyl, halo, alkoxy, or hydroxyl groups.

3. The compound of claim 1 wherein R¹—

NHCOR″

, where R″

is;

4. The compound of claim 3 wherein R¹ is —

NHCOR″ and

R″

is

5. The compound of claim 4 in which the compound is selected from the group consisting of:

6. The compound of claim 3 wherein R′

is aryl according to;

8. The compound of claim 6 further defined as:

9. The compound of claim 3 wherein R′

is a heterocyclic group according to;

10. The compound of claim 9:

11. The compound of claim 10 further defined as:

12. The compound of claim 4:

13. The compound of claim 12 further defined as:

14. A pharmaceutical composition for the treatment of cancer in a patient in need thereof, the composition comprising a therapeutically effective amount of a compound of claim 1, and a pharmaceutically acceptable carrier.

15. A method of treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of claim 1.

17. The compound of claim 12, further defined by the formula:

20. The compound of claim 1, wherein the formula is further defined as:

21. The compound of claim 1, wherein the formula is further defined as:

22. The compound of claim 1 wherein X₉ is

7. A compound selected from the group consisting of:

4-(8-Methyl-7-(1-methylpiperidin-4-yloxy)-2-oxo-2H-chromen-3-ylcarbamoyl)-2-(3-methylbut-2-enyl)phenyl acetate (29a, KU-397);

4-(8-Methyl-7-(1-methylpiperidin-3-yloxy)-2-oxo-2H-chromen-3-ylcarbamoyl)-2-(3-methylbut-2-enyl)phenyl acetate (29c, KU-417);

4-(7-(2-(Dimethylamino)ethoxy)-8-methyl-2-oxo-2H-chromen-3-ylcarbamoyl)-2-(3-methylbut-2-enyl)phenyl acetate (29e, KU-421);

4-(7-(3-(Dimethylamino)propoxy)-8-methyl-2-oxo-2H-chromen-3-ylcarbamoyl)-2-(3-methylbut-2-enyl)phenyl acetate (29f, KU-406);

4-(8-methyl-2-oxo-7-(piperidin-4-yloxy)-2H-chromen-3-ylcarbamoyl)-2-(3-methylbut-2-enyl)phenyl acetate (30b, KU-415);

4-(8-methyl-2-oxo-7-(piperidin-3-yloxy)-2H-chromen-3-ylcarbamoyl)-2-(3-methylbut-2-enyl)phenyl acetate (30d, KU-419);

4-(8-methyl-7-(2-(methylamino)ethoxy)-2-oxo-2H-chromen-3-ylcarbamoyl)-2-(3-methylbut-2-enyl)phenyl acetate (30g, KU-423);

4-Hydroxy-N-(8-methyl-7-(1-methylpiperidin-4-yloxy)-2-oxo-2H-chromen-3-yl)-3-(3-methylbut-2-enyl)benzamide (31a, KU-398);

4-Hydroxy-N-(8-methyl-2-oxo-7-(piperidin-4-yloxy)-2H-chromen-3-yl)-3-(3-methylbut-2-enyl)benzamide (31b, KU-416);

4-Hydroxy-N-(8-methyl-7-(1-methylpiperidin-3-yloxy)-2-oxo-2H-chromen-3-yl)-3-(3-methylbut-2-enyl)benzamide (31c, KU-418);

4-Hydroxy-N-(8-methyl-2-oxo-7-(piperidin-3-yloxy)-2H-chromen-3-yl)-3-(3-methylbut-2-enyl)benzamide (31d, KU-420);

N-(7-(2-(Dimethylamino)ethoxy)-8-methyl-2-oxo-2H-chromen-3-yl)-4-hydroxy-3-(3-methylbut-2-enyl)benzamide (31e, KU-422);

N-(7-(3-(Dimethylamino)propoxy)-8-methyl-2-oxo-2H-chromen-3-yl)-4-hydroxy-3-(3-methylbut-2-enyl)benzamide (31f, KU-407);

4-Hydroxy-N-(8-methyl-7-(2-(methylamino)ethoxy)-2-oxo-2H-chromen-3-yl)-3-(3-methylbut-2-enyl)benzamide (31g, KU-424);

N-(7-((2R,3R,4R)-3,4-dihydroxytetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-4-hydroxy-3-(3-methylbut-2-enyl)benzamide (16a, KU-425);

N-(7-((2S,3R,4R)-3,4-dihydroxytetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-4-hydroxy-3-(3-methylbut-2-enyl)benzamide (16b, KU-426);

4-Hydroxy-N-(7-((2R,3R)-3-hydroxytetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-3-(3-methylbut-2-enyl)benzamide (17a, KU-247);

4-Hydroxy-N-(7-((2S,3R)-3-hydroxytetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-3-(3-methylbut-2-enyl)benzamide (17b, KU-428);

4-Hydroxy-N-(7-((2S,4R)-4-hydroxytetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-3-(3-methylbut-2-enyl)benzamide (18a, KU-429);

4-Hydroxy-N-(7-((2R,4R)-4-hydroxytetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-3-(3-methylbut-2-enyl)benzamide (18b, KU-430);

4-(7-((2S,3S,4S)-3,4-Dihydroxytetrahydrofuran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-ylcarbamoyl)-2-(3-methylbut-2-enyl)phenyl acetate (19, KU-431);

4-(7-((2S,4R)-4-Hydroxytetrahydrofuran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-ylcarbamoyl)-2-(3-methylbut-2-enyl)phenyl acetate (20a, KU-432); and

4-(7-((2R,4R)-4-Hydroxytetrahydrofuran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-ylcarbamoyl)-2-(3-methylbut-2-enyl)phenyl acetate (20b, KU-433).

16. The compound of claim 7 selected from the group consisting of

4-(8-Methyl-7-(1-methylpiperidin-4-yloxy)-2-oxo-2H-chromen-3-ylcarbamoyl)-2-(3-methylbut-2-enyl)phenyl acetate (29a, KU-397);

4-(8-Methyl-7-(1-methylpiperidin-3-yloxy)-2-oxo-2H-chromen-3-ylcarbamoyl)-2-(3-methylbut-2-enyl)phenyl acetate (29c, KU-417);

4-(7-(2-(Dimethylamino)ethoxy)-8-methyl-2-oxo-2H-chromen-3-ylcarbamoyl)-2-(3-methylbut-2-enyl)phenyl acetate (29e, KU-421);

4-(7-(3-(Dimethylamino)propoxy)-8-methyl-2-oxo-2H-chromen-3-ylcarbamoyl)-2-(3-methylbut-2-enyl)phenyl acetate (29f, KU-406);

4-(8-methyl-2-oxo-7-(piperidin-4-yloxy)-2H-chromen-3-ylcarbamoyl)-2-(3-methylbut-2-enyl)phenyl acetate (30b, KU-415);

4-(8-methyl-2-oxo-7-(piperidin-3-yloxy)-2H-chromen-3-ylcarbamoyl)-2-(3-methylbut-2-enyl)phenyl acetate (30d, KU-419);

4-(8-methyl-7-(2-(methylamino)ethoxy)-2-oxo-2H-chromen-3-ylcarbamoyl)-2-(3-methylbut-2-enyl)phenyl acetate (30g, KU-423);

4-Hydroxy-N-(8-methyl-7-(1-methylpiperidin-4-yloxy)-2-oxo-2H-chromen-3-yl)-3-(3-methylbut-2-enyl)benzamide (31a, KU-398);

4-Hydroxy-N-(8-methyl-2-oxo-7-(piperidin-4-yloxy)-2H-chromen-3-yl)-3-(3-methylbut-2-enyl)benzamide (31b, KU-416);

4-Hydroxy-N-(8-methyl-7-(1-methylpiperidin-3-yloxy)-2-oxo-2H-chromen-3-yl)-3-(3-methylbut-2-enyl)benzamide (31c, KU-418);

4-Hydroxy-N-(8-methyl-2-oxo-7-(piperidin-3-yloxy)-2H-chromen-3-yl)-3-(3-methylbut-2-enyl)benzamide (31d, KU-420);

N-(7-(2-(Dimethylamino)ethoxy)-8-methyl-2-oxo-2H-chromen-3-yl)-4-hydroxy-3-(3-methylbut-2-enyl)benzamide (31e, KU-422);

N-(7-(3-(Dimethylamino)propoxy)-8-methyl-2-oxo-2H-chromen-3-yl)-4-hydroxy-3-(3-methylbut-2-enyl)benzamide (31f, KU-407); and

4-Hydroxy-N-(8-methyl-7-(2-(methylamino)ethoxy)-2-oxo-2H-chromen-3-yl)-3-(3-methylbut-2-enyl)benzamide (31g, KU-424).

18. A pharmaceutical composition for the treatment of cancer in a patient in need thereof, the composition comprising a therapeutically effective amount of a compound of claim 7, and a pharmaceutically acceptable carrier.

19. A method of treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of claim 7.