IP Library › Granted Patent US 9,120,774

Granted Patent B2

US 9,120,774 · App. 13/202,382 · Granted Sep 1, 2015

Novobiocin analogues having modified sugar moieties

Inventors: Brian S. J. Blagg (Lawrence, KS); Huiping Zhao (Lawrence, KS); Alison Catherine Donnelly (Grand Island, NY)

Assignee: University of Kansas

C07D407/12 C07D487/14 C07H19/00

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Quick Facts

Patent No.: US 9,120,774
App. No.: 13/202,382
Granted: Sep 1, 2015
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

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

Claims (117)

1. A compound according to Formula I; or a pharmaceutically acceptable salt thereof:

wherein:

R 1 is —NHCOR″, where R″ is:

an aryl substituted with one or more hydroxy, nitro, amino, alkyl, alkenyl, aryl, alkoxy or halo groups;

a heterocyclic group, wherein the heterocyclic group is aromatic, wherein the heterocyclic group is optionally substituted with one or more hydroxy, nitro, amino, alkyl, alkenyl, aryl, alkoxy or halo groups; or

wherein R 24 and R 25 are each independently H, C 1 -C 4 alkyl, hydroxy or alkoxy; and

R 33 is H, C 1 -C 4 alkyl, C 1 -C 4 alkylamino, —(CO)—C 1 -C 4 alkyl, or

piperidinyl, each optionally substituted with C 1 -C 4 alkyl; and

R 31 is H, halo, C 1 -C 4 alkyl, hydroxy or alkoxy; and R 32 is H or C 1 -C 4 alkyl;

X 9 is:

—O-alkyl, substituted with one or more amino, amido, alkyl, alkoxy, halo, pyrrolidinyl, or hydroxyl groups;

—O—alkylamino, —O—cycloalkyl, —O—(CO)—alkyl, —O—(CO)—cycloalkyl, —O—(CH 2 ) n —pyridinyl, —O—(CH 2 ) n -piperidinyl, —O—(CH 2 ) n —pyrrolino, or —O—(CH 2 ) n —pyrrolidinyl, each optionally substituted with one or more amino, amido alkyl, halo, alkoxy, or hydroxyl groups; and where n is 0, 1, 2 or 3;

—O—mono-hydroxylated furanose, —O—dihydroxylated furanose, —O—mono-hydroxylated pyranose, —O—dihydroxylated pyranose, —O—trihydroxylated pyranose, —O—mono-hydroxylatedoxepinose, —O—dihydroxylated oxepinose, —O-azasugar, —O—acyl; or

ester, amino, amido, carbamate, phosphate ester, tosylate or mesylate;

X is H, nitrile, halo, amino, amido, C 1 -C 4 alkyl or alkoxy; and

Y is H, amido, ester, amino, C 1 -C 4 alkyl or alkoxy.

2. The compound of claim 1 wherein X 9 is —O—alkyl, —O—alkylamino, —O—cycloalkyl, —O—(CO)—alkyl, —O—(CO)—cycloalkyl, —O—(CH 2 ) n -pyridinyl, —O—(CH 2 ) n -piperidinyl, —O—(CH 2 ) n -pyrrolino, or —O—(CH 2 ) n -pyrrolidinyl, each optionally substituted with one or more amino, amido, alkyl, halo, alkoxy, or hydroxyl groups.

3. The compound of claim 1 wherein R 1 —NHCOR″, where R″ is:

wherein:

R 24 and R 25 are independently H, C 1 -C 4 alkyl, hydroxy or alkoxy;

R 33 is H, C 1 -C 4 alkyl, C 1 -C 4 alkylamino, —(CO)—C 1 -C 4 alkyl, or piperidinyl, each optionally substituted with C 1 -C 4 alkyl;

R 31 is H, halo, C 1 -C 4 alkyl, hydroxy or alkoxy; and

R 32 is H or C 1 -C 4 alkyl.

4. The compound of claim 3 wherein R 1 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:

wherein

R 33 is H, —CH 3 , —COCH 3 , —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 CH 2 N(CH 3 ) 2 , or

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).

8. The compound of claim 6 further defined as:

9. The compound of claim 3 wherein R′ is a heterocyclic group according to:

wherein R 31 is H, halo, or alkoxy; and R 32 is H or alkyl.

10. The compound of claim 9 :

wherein

X is H or —OCH 3 ;

Y is —CH 3 or —OCH 3 ;

R 31 is H, Cl, or —OCH 3 ;

R 32 is H or —CH 3 ; and

R is selected from the group consisting of:

11. The compound of claim 10 further defined as:

12. The compound of claim 4 :

wherein

X is H or —OCH 3 ;

Y is —CH 3 or —OCH 3 ; and

R is selected from the group consisting of: —COCH 3 , mesylate, tosylate, —CONH 2 , —CONHCH 3 , —CON(CH 3 ) 2 , —PO(OCH 3 ) 2 , —COCH 3 ,

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 .

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