Certain chemical entities, compositions, and methods

Patent metadata

Field	Value
Publication number	US-10766920-B2
Application number	US-201916426442-A
Country	US
Kind code	B2
Filing date	May 30, 2019
Priority date	Feb 2, 2011
Publication date	Sep 8, 2020
Grant date	Sep 8, 2020

Abstract

Chemical entities that are novel compounds, pharmaceutical compositions and methods of treatment of cancer are described.

First claim

What is claimed is:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
R 1 , R 2 , R 3 , R 5 , R 6 , R 9 , R 10 , R 11 and R 12 are independently chosen from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; or
R 1 and R 2 , or R 5 and R 6 , or R 9 and R 10 , or R 11 and R 12 mutually independently, together in each case denote an oxo group (═O);
R 4 is hydroxy, or R 4 and R 5 may optionally be joined together with any intervening atoms to form an oxirane ring;
R 7 is chosen from hydrogen, hydroxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino;
R 8 is chosen from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; or
R 7 and R 8 together denote an oxo group (=O);
R 13 is chosen from hydrogen, optionally substituted alkyl, and formyl;
Z is OR 14 or NR 15 R 16 ;
R 14 is alkyl substituted with optionally substituted heterocycloalkyl;
R 15 is hydrogen;
R 16 is chosen from optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl;
W 1 is chosen from:

W 2 is chosen from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;
n is selected from 0 and 1; and
represents a single bond or a double bond;
provided that when R 4 is OH, R 13 is methyl, W 1 is

(2-oxo-2H-pyran-5-yl), and R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and W 2 are hydrogen then R 12 is not hydrogen; and
when Z is NR 15 R 16 , R 4 and R 5 are joined together with any intervening atoms to form an oxirane ring.

2. The compound of claim 1 , wherein R 1 , R 2 , R 3 , R 5 , R 6 , R 9 , R 10 , R 11 and R 12 are independently chosen from hydrogen, hydroxy, and methyl.

3. The compound of claim 1 , wherein R 4 is hydroxy.

4. The compound of claim 1 , wherein R 4 and R 5 are joined together with any intervening atoms to form an oxirane ring.

5. The compound of claim 1 , wherein R 7 is chosen from hydrogen and —OCOCH 3 .

6. The compound of claim 1 , wherein R 8 and W 2 are independently chosen from hydrogen and optionally substituted alkyl.

7. The compound of claim 1 , wherein R 13 is chosen from hydrogen, methyl, and hydroxymethyl.

8. The compound of claim 1 , wherein represents a single bond.

9. The compound of claim 1 , wherein represents a double bond.

10. The compound of claim 1 , wherein the compound is of Formula Ia:

11. The compound of claim 1 , wherein the compound is of Formula lb:

12. The compound of claim 1 , wherein the compound is of Formula Ic:

13. The compound of claim 1 , wherein the compound is of Formula Id:

14. The compound of claim 1 , wherein the compound is of Formula Ie:

15. The compound of claim 1 , wherein the compound is of Formula If:

16. The compound of claim 1 , wherein the compound is of Formula Ig:

17. The compound of claim 1 , wherein the compound is of Formula Ih:

18. The compound of claim 1 , wherein the compound is of Formula Ii:

19. The compound of claim 1 , wherein Z is OR 14 , and R 14 is chosen from 2-morpholinoethyl, 2-(pyrrolidin-1-yl)ethyl, and 2-(3-oxopiperazin-1-yl)ethyl.

20. The compound of claim 1 , wherein the compound is selected from:
(1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-7-yl (2-(pyrrolidin-1-yl)ethyl) carbonate,
(1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-7-yl (2-morpholinoethyl) carbonate,
(1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-2-yl acetate,
(1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(((2-morpholinoethoxy)carbonyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-2-yl acetate,
(1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-2-yl acetate,
(1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(((2-morpholinoethoxy)carbonyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-2-yl acetate,
(3 S,5R,8R,9 S,10 S,13R,14S,16 S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate,
(3 S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-morpholinoethoxy)carbonyl)oxy)-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate,
(3 S,5R,8R,9 S,10 S,13R,14S,16 S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(((2-(3-oxopiperazin-1-yl)ethoxy)carbonyl)oxy)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate,
(3 S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate,
(3 S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate,
(3 S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl (2-(3-oxopiperazin-1-yl)ethyl) carbonate,
(3 S, 8R

Assignees

• Neupharma Inc

Inventors

• Qian Xiangping

Classifications

• C07J41/0055

  the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives · CPC title

• C07J71/0021

  at position 14(15) · CPC title

• C07J19/00

  Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 by a lactone ring · CPC title

• C07J43/003 Primary

  not condensed · CPC title

• A61P35/00

  Antineoplastic agents · CPC title