Certain chemical entities, compositions, and methods

Abstract

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

Claims

1. A compound of Formula I: ##STR00023## or a pharmaceutically acceptable salt thereof, wherein: R.sub.1, R.sub.2, R.sub.3, R.sub.5, R.sub.6, R.sub.9, R.sub.10, R.sub.11 and R.sub.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.sub.1 and R.sub.2, or R.sub.5 and R.sub.6, or R.sub.7 and R.sub.8, or R.sub.9 and R.sub.10, or R.sub.11 and R.sub.12 mutually independently, together in each case denote an oxo group (O); R.sub.4 is hydroxy, or R.sub.4 and R.sub.5 may optionally be joined together with any intervening atoms to form an oxirane ring; R.sub.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.sub.8 is chosen from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R.sub.13 is chosen from hydrogen, optionally substituted alkyl, and formyl; Z is OR.sub.14; R.sub.14 is chosen from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; W.sub.1 is chosen from: ##STR00024## W.sub.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.sub.4 is OH, R.sub.13 is methyl, W.sub.1 is ##STR00025## and R.sub.1, R.sub.2, R.sub.3, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, and W.sub.2 are hydrogen then R.sub.12 is not hydrogen.

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

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

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

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

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

7. The compound of claim 1, wherein R.sub.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: ##STR00026##

11. The compound of claim 1, wherein the compound is of Formula Ib: ##STR00027##

12. The compound of claim 1, wherein the compound is of Formula Ic: ##STR00028##

13. The compound of claim 1, wherein the compound is of Formula Id: ##STR00029##

14. The compound of claim 1, wherein the compound is of Formula Ie: ##STR00030##

15. The compound of claim 1, wherein the compound is of Formula If: ##STR00031##

16. The compound of claim 1, wherein the compound is of Formula Ig: ##STR00032##

17. The compound of claim 1, wherein the compound is of Formula Ih: ##STR00033##

18. The compound of claim 1, wherein the compound is of Formula Ii: ##STR00034##

19. The compound of claim 1, wherein R.sub.14 is chosen from optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl.

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

21. The compound of claim 1, wherein the compound is selected from the group consisting of: (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,11 a-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,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethyl)carbanoyl)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-morpholinoethyl)carbonyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1,2:6,7]indeno[1,7a-b]oxiren-2-yl acetate, (3S,5R,8R,9S,10S,13R,14S,16S,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, (3S,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, (3S,5R,8R,9S,10S,13R,14S,16S,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, (3S,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, (3S,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, (3S,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, (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopentatal[a]phenanthren-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate, (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopentata[a]phenanthren-3-yl (2-morpholinoethyl) carbonate, (3S,8R,9S, 10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl (2-(3-oxopiperazin-1-yl)ethyl) carbonate, (3S,5R,8R,9S, 10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta [a]phenanthren-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate, (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate, (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl (2-(3-oxopiperazin-1-yl)ethyl) carbonate, (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopentata[a]phenanthren-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate, (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate, (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl (2-(3-oxopiperazin-1-yl)ethyl) carbonate, (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexadecahydro-1H-cyclopentata[a]phenanthren-16-yl acetate, (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13 -dimethyl-3- (((2-morpholinoethoxy)carbonyl)oxy)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate, and (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(((2-(3-oxopiperazin-1-yl)ethoxy)carbonyl)oxy)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate, or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 1.

23. The pharmaceutical composition of claim 22, wherein the composition is formulated in a form chosen from tablets, capsules, powders, liquids, suspensions, suppositories, and aerosols.

24. A packaged pharmaceutical composition comprising the pharmaceutical composition of claim 22 and instructions for using the composition to treat a subject suffering from colorectal cancer, liver cancer, lung cancer, breast cancer, oral cancer, pancreatic cancer, ovarian cancer or prostrate cancer.

25. A method of treating colorectal cancer, liver cancer, lung cancer, breast cancer, oral cancer, pancreatic cancer, ovarian cancer or prostate cancer in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1.

26. A compound of Formula I: ##STR00035## or a pharmaceutically acceptable salt thereof, wherein: R.sub.1, R.sub.2, R.sub.3, R.sub.6, R.sub.9, R.sub.10, R.sub.11 and R.sub.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.sub.1 and R.sub.2, or R.sub.7 and R.sub.8, or R.sub.9 and R.sub.10, or R.sub.11 and R.sub.12 mutually independently, together in each case denote an oxo group (O); R.sub.4 and R.sub.5 are joined together with any intervening atoms to form an epoxide ring; R.sub.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.sub.8 is chosen from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R.sub.13 is chosen from hydrogen, optionally substituted alkyl, and formyl; Z is NR.sub.15R.sub.16; R.sub.15 is hydrogen; R.sub.16 is chosen from substituted alkyl; optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; W.sub.1 is chosen from: ##STR00036## W.sub.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.

27. The compound of claim 26, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.6, R.sub.9, R.sub.10, R.sub.11 and R.sub.12 are independently chosen from hydrogen, hydroxy, and methyl.

28. The compound of claim 26, wherein R.sub.7 is chosen from hydrogen and OCOCH.sub.3.

29. The compound of claim 26, wherein R.sub.8 and W.sub.2 are independently chosen from hydrogen and optionally substituted alkyl.

30. The compound of claim 26, wherein R.sub.13 is chosen from hydrogen, methyl, and hydroxymethyl.

31. The compound of claim 26, wherein represents a single bond.

32. The compound of claim 26, wherein represents a double bond.

33. The compound of claim 26, wherein the compound is of Formula Id: ##STR00037##

34. The compound of claim 26, wherein the compound is of Formula Ie: ##STR00038##

35. The compound of claim 26, wherein the compound is of Formula If: ##STR00039##

36. The compound of claim 26, wherein the compound is selected from the group consisting of: (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-l-yl)ethyl)carbamate, (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)carbamate, (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-yl4-methylpiperazine-l-carboxylate, (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11.sup.a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1,2:6,7]indeno[1,7a-b]oxiren-7-yl (2-(4-methylpiperazin-1-yl)ethyl)carbamate, (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 morpholine-4-carboxylate, 4-(((((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)oxy)carbonyl)amino)butanoic acid, (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)ethyl)carbamoyl)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-morpholinoethyl)carbamoyl)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,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1,2:6,7]indeno[1,7a-b]oxiren-2-yl acetate, 4-(((((1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9b S,11aR)-2-acetoxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1,2:6,7]indeno[1,7a-b]oxiren-7-yl)oxy)carbonyl)amino)butanoic acid, (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, (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)ethyl)carbamoyl)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-morpholinoethyl)carbamoyl)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-7-(((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1,2:6,7]indeno[1,7a-b ]oxiren-2-yl acetate, and 4-(((((1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-2-acetoxy-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1,2:6,7]indeno[1,7a-b]oxiren-7-yl)oxy)carbonyl)amino)butanoic acid, or a pharmaceutically acceptable salt thereof.

37. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 26.

38. The pharmaceutical composition of claim 37, wherein the composition is formulated in a form chosen from tablets, capsules, powders, liquids, suspensions, suppositories, and aerosols.

Description

EXAMPLES

(1) The following examples serve to more fully describe the manner of using the invention. These examples are presented for illustrative purposes and should not serve to limit the true scope of the invention.

(2) In carrying out the procedures of the methods described herein, it is of course to be understood that reference to particular buffers, media, reagents, cells, culture conditions and the like are not intended to be limiting, but are to be read so as to include all related materials that one of ordinary skill in the art would recognize as being of interest or value in the particular context in which that discussion is presented. For example, it is often possible to substitute one buffer system or culture medium for another and still achieve similar, if not identical, results. Those of skill in the art will have sufficient knowledge of such systems and methodologies so as to be able, without undue experimentation, to make such substitutions as will optimally serve their purposes in using the methods and procedures disclosed herein.

Example I

Preparation of (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-5,10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate

(3) ##STR00017##

(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate

(4) ##STR00018##

(5) To a solution of (3S,5R,8R,9S,10S,13R,14S,16S,17R)-3,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl) hexadecahydro- 1H-cyclopental[a]phenanthren-16-yl acetate (200 mg, 0.45 mmol) and DMAP (55 mg, 0.45 mmol) in CHCl.sub.3 (30 mL) were added DIEA (230 mg, 4 mmol) and 4-nitrophenyl carbonochloridate (360 mg, 4 mmol). The mixture was stirred at 65 C. for 16 h. The mixture was evaporated and the residue was purified via preparative TLC (PE/EA=2:1) to afford (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((4-nitrophenoxy)carbonyl)oxy)-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate as a white solid (230 mg, 84%).

(6) ##STR00019##

(7) To a solution of (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((4-nitrophenoxy)carbonyl)oxy)-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate (100 mg, 0.16 mmol) in CH.sub.2Cl.sub.2 was added piperazine (141 mg, 1.6 mmol). The mixture was stirred at room temperature for 16 h. The mixture was concentrated and the resulting residue was purified via preparative TLC (CH.sub.2Cl.sub.2/MeOH=5:1) to afford (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate (40 mg, 44%) as a white solid. LRMS (M+H.sup.+) m/z 557.3. .sup.1H NMR (CD.sub.3OD, 400 MHz) 8.13-8.16 (dd, 1H), 7.33 (m, 1H), 6.10-6.12 (d, 1H), 5.39-5.43 (m, 1H), 4.91 (s, 1H), 3.52 (s, 4H), 2.94-2.97 (m, 4H), 2.86-2.88 (d, 1H), 2.58-2.64 (m, 1H), 1.11-1.95 (m, 23H), 0.89 (s, 3H), 0.68 (s, 3H).

Example II

Preparation of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate

(8) ##STR00020##

(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate

(9) ##STR00021##

(10) To a solution of 4-((3S,5R,8R,9S,10S,13R,14S,17R)-3,14-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)furan-2(5H)-one (17.21 mg, 0.046 mmol) and DMAP (5.6 mg, 0.046 mmol) in CHCl.sub.3 (5 mL) were added DIEA (23.87 mg, 0.185 mmol) and 4-nitrophenyl carbonochloridate (37.2 mg, 0.185 mmol). The mixture was stirred at 70 C. for 16 h. The solvent was evaporated and the resulting residue was purified via preparative TLC (PE/EA =2:1) to give the crude (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 4-nitrobenzoate.

(11) ##STR00022##

(12) To a solution of crude (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 4-nitrobenzoate (5 mg) in CH.sub.2Cl.sub.2 was added piperazine (4 mg, 0.045 mmol). The mixture was stirred at room temperature for 16 h. The mixture was concentrated and the resulting residue was purified via Prep-HPLC to afford (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate (1.1 mg). LRMS (M+H.sup.+) m/z 487.3. .sup.1H NMR (CDCl3, 400 MHz) 5.88 (s, 1H), 5.32 (m, 1H), 4.97-5.05 (m, 3H), 4.78-4.83 (m, 1H), 3,83 (s, 4H), 3,19-3.20 (m, 4H), 2.81 m, 1H). 1.90-2.03 (m, 3H), 1.60-1.89 (m, 14H), 1.28-1.57 (m, 31H), 0,86-0.96 (m, 12H).

Example III

Inhibition of Cell Growth in Tumor Cells

(13) Inhibition of cell growth by compounds was measured using MTT assay (Mosmann, T., Journal of Immunological Methods, 1983, 65, 55-63). Tumor cell lines were purchased from ATCC (American Type Culture Collection, Manassas, Va.). All cell lines were maintained in RPMI 1640 (Hyclone) supplemented with 10% fetal bovine serum (FBS, Hyclone), glutamine (2 mM, Hyclone), and antibiotics (penicillin 100 U/mL and streptomycin 50 g/mL) at 37 C. in a humidified atmosphere of 5% CO.sub.2 in air. Taxol (positive control, Sigma) and compounds were dissolved in DMSO (Sigma), and the final concentration of DMSO in the medium was 1%. Tumor cells were plated in 96-well plates at densities from 4000 cells/well of a 96-well plate and allowed to adhere/grow for 24 h. They were then treated with various concentrations of drug for 72 h. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT, Sigma) was used to determine the number of viable cells at the time of compound addition and the number of cells remaining after 72 h compound exposure. The number of cells remaining after 72 h was compared to the number of viable cells at the time of compound addition by measuring the absorbance at 570 nm, allowing for the calculation of growth inhibition.

(14) All concentrations of compounds were tested in triplicate and controls were averaged over 4 wells. IC.sub.50 was calculated by plotting the concentration of compound vs the percentage of inhibition in treated wells using GraphPad Prism 5. Each of the compounds described in Table I above exhibit an IC.sub.50 for A549 cells of less than 10 uM. In some embodiments, the compounds exhibit an IC.sub.50 for A549 cells of less than 1 uM. In some embodiments, the compounds exhibit an IC.sub.50 for A549 cells of less than 100 nM. Data for representative compounds are shown below.

(15) TABLE-US-00002 TABLE 2 Inhibitory activity of representative compounds in A549 cells. A549 cell Chemical Name IC.sub.50 (nM) (3S,5R,8R,9S,10R,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13- 5.6 dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- 39 dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate

(16) While some embodiments have been shown and described, various modifications and substitutions may be made thereto without departing from the spirit and scope of the invention. For example, for claim construction purposes, it is not intended that the claims set forth hereinafter be construed in any way narrower than the literal language thereof, and it is thus not intended that exemplary embodiments from the specification be read into the claims. Accordingly, it is to be understood that the present invention has been described by way of illustration and not limitations on the scope of the claims.