Antimetastatic 2H-selenopheno[3,2-h]chromenes, synthesis thereof, and methods of using same agents

1. A compound of Formula I:

R 1 is OH or an OC 1 -C 16 hydrocarbon group, wherein the OC 1 -C 16 hydrocarbon group is linear, branched or cyclic and is optionally substituted;

R 2 represents a halogen; or

R 3 is hydroxy-C 1-4 alkyl, 1-hydroxy-cyclo-C 3-6 alkyl, cyclo-C 5-7 alkenyl, hydroxy-C 1-6 cycloalkyl, or C 1-4 alkyl-N-heterocyclyl;

or an optical isomer thereof or a pharmaceutically acceptable acid addition salt thereof.

2. The compound according to claim 1 , wherein the compound is selected from the group consisting of:

methyl 7-bromo-8-(2-hydroxypropan-2-yl)-2-oxo-2H-selenopheno[3,2-h]chromene-3-carboxylate,

methyl 7-bromo-8-(cyclopent-1-en-1-yl)-2-oxo-2H-selenopheno[3,2-h]chromene-3-carboxylate,

methyl 7-bromo-8-(1-hydroxycyclohexyl)-2-oxo-2H-selenopheno[3,2-h]chromene-3-carboxylate,

methyl 7-bromo-8-(1-methoxycyclohexyl)-2-oxo-2H-selenopheno[3,2-h]chromene-3-carboxylate,

butyl 7-bromo-8-(1-methoxycyclohexyl)-2-oxo-2H-selenopheno[3,2-h]chromene-3-carboxylate,

octyl 7-bromo-8-(1-methoxycyclohexyl)-2-oxo-2H-selenopheno[3,2-h]chromene-3-carboxylate,

decyl 7-bromo-8-(1-methoxycyclohexyl)-2-oxo-2H-selenopheno[3,2-h]chromene-3-carboxylate,

methyl 7-bromo-2-oxo-8-(piperidin-1-ylmethyl)-2H-selenopheno[3,2-h]chromene-3-carboxylate,

methyl 7-bromo-8-(morpholinomethyl)-2-oxo-2H-selenopheno[3,2-h]chromene-3-carboxylate,

methyl 7-bromo-8-((4-methylpiperazin-1-yl)methyl)-2-oxo-2H-selenopheno[3,2-h]chromene-3-carboxylate,

7-bromo-8-(1-hydroxycyclohexyl)-2-oxo-2H-selenopheno[3,2-h]chromene-3-carboxylic acid,

7-bromo-8-(1-methoxycyclohexyl)-2-oxo-2H-selenopheno[3,2-h]chromene-3-carboxylic acid,

7-bromo-2-oxo-8-(piperidin-1-ylmethyl)-2H-selenopheno[3,2-h]chromene-3-carboxylic acid hydrochloride,

7-bromo-2-oxo-8-(morpholin-1-ylmethyl)-2H-selenopheno[3,2-h]chromene-3-carboxylic acid hydrochloride,

7-bromo-8-/(4-methylpiperazin-1-yl)methyl/-2-oxo-2H-selenopheno[3,2-h]chromene-3-carboxylic acid hydrochloride,

Octyl 7-bromo-8-(cyclohex-1-en-1-yl)-2-oxo-2H-selenopheno[3,2-h]chromene-3-carboxylate,

(3S,8S,9S,10R,13R, 14S,17R)-10,13-Dimethyl-17-((R)-6-methylheptan-2-yl)-2,3,4,7, 8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl-7-bromo-8-(cyclohex-1-en-1-yl)-2-oxo-2H-selenopheno[3,2-h]chromene-3-carboxylate,

(3S,8S, 9S, 10R, 13R, 14S,17R)-10,13-Dimethyl-17-((R)-6-methylheptan-2-yl)-2,3,4,7, 8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl-7-bromo-8-(1-methoxycyclohexyl)-2-oxo-2H-selenopheno[3,2-h]chromene-3-carboxylate,

7-Bromo-8-(cyclohex-1-en-1-yl)-3-(piperidine-1-carbonyl)-2H-selenopheno[3,2-h]chromen-2-one,

7-Bromo-8-(cyclohex-1-en-1-yl)-3-(morpholine-1-carbonyl)-2H-selenopheno[3,2-h]chromen-2-one,

7-Bromo-8-(cyclohex-1-en-i-yl)-N,N-bis(2-methoxyethyl)-2-oxo-2H-selenopheno[3,2-h]chromene-3-carboxamide,

7-Bromo-8-(1-methoxycyclohexyl)-3-(morpholine-4-carbonyl)-2H-selenopheno[3,2-h]chromen-2-one,

and pharmaceutically acceptable enantiomers, diastereomers, racemates, and salts thereof.

3. The compound according to claim 2 , wherein the compound has the structure:

4. The compound according to claim 2 , wherein the compound has the structure:

5. The compound according to claim 2 , wherein the compound has the structure:

6. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier.

7. The pharmaceutical composition according to claim 6 , wherein the composition is a mono-phasic pharmaceutical composition suitable for parenteral or oral administration, and the composition consists essentially of a therapeutically effective amount of the compound of Formula I, and the pharmaceutically acceptable carrier.

8. A method for the synthesis of a compound of Formula I:

wherein

R 1 represents OH or a OC 1 -C 16 hydrocarbon group, wherein the OC 1 -C 16 hydrocarbon group is linear, branched or cyclic and is optionally substituted;

R 2 represents a halogen;

R 3 represents hydroxy-C 1-4 alkyl, 1-hydroxy-cyclo-C 3-6 alkyl, cyclo-C 5-7 alkenyl, hydroxy-C 1-6 cycloalkyl, or C 1-4 alkyl-N-heterocyclyl;

comprising reacting a compound of formula II with a selenium halide:

wherein

R represents C 1 -C 10 hydrocarbon group.

9. The method of claim 8 , wherein reacting the compound of formula II with a selenium halide forms a compound of formula III:

10. The method of claim 9 , further comprising subjecting the compound of formula III to hydrolyzation to form a compound of formula I, in which R 1 is OH.

11. The method of claim 10 , further comprising subjecting the compound of formula I in which R 1 is OH to esterification to form a compound of formula I in which R 1 is an OC 1 -C 16 hydrocarbon group.

12. The compound of claim 1 , wherein R 1 is an OC 1 -C 16 hydrocarbon group optionally substituted by a steroid moiety, N(alkyl) 2 , or N-heterocyclyl.

13. The compound of claim 1 , wherein R 1 is OH or OCH 3 .

14. The compound of claim 1 , wherein R 2 is Br.

15. The compound of claim 1 , wherein R 3 is 1-hydroxy-cyclo-C 3-6 alkyl, hydroxy-C 1-6 cycloalkyl, or C 1-4 alkyl-N-heterocyclyl.

16. A method for the treatment of cancer or metastasis of cancer, comprising administering to an individual in need thereof a therapeutically effective amount of the compound of claim 1 ;

wherein the cancer is melanoma, breast adenocarcinoma, sarcoma, fibrosarcoma, lung cancer, hepatocellular carcinoma, and neuroblastoma.

17. The method of claim 16 , wherein the compound is administered in conjunction with one or more chemotherapeutic agents, surgery, chemotherapy, radiation, immunotherapy, or combinations thereof.