Selenophenochromene hydroxamic acids, preparation and use as angiogenesis inhibitors
The present invention relates to a novel selenophenochromene hydroxamic acids as angiogenesis inhibitors, as well as methods of their manufacturing and use in different pharmaceutical compositions for the treatment or prevention of various diseases and disorders by administration of such substances.
1. A compound selected from the group consisting of those of Formula I:
optical isomers thereof, polymorphs thereof, pharmaceutically acceptable acid addition salts thereof, and hydrates and solvates thereof,
wherein
R 1 represents a halogen atom; and
R 2 represents C 1-4 -alkyl N-containing heterocyclyl.
2. The compound according to claim 1 , wherein the compound is selected from the group consisting of:
7-Bromo-N-hydroxy-8-((4-methylpiperazin-1-yl)methyl)-2-oxo-2H-selenopheno[3,2-h]chromene-3-carboxamide;
7-Bromo-N-hydroxy-2-oxo-8-((piperazin-1-yl)methyl)-2H-selenopheno[3,2-h]chromene-3-carboxamide;
7-Bromo-N-hydroxy-2-oxo-8-(2-(piperazin-1-yl)ethyl)-2H-selenopheno[3,2-h]chromene-3-carboxamide;
8-((1,4-Diazepan-1-yl)methyl)-7-bromo-N-hydroxy-2-oxo-2H-selenopheno[3,2-h]chromene-3-carboxamide;
and pharmaceutically acceptable enantiomers, diastereomers, racemates, and salts thereof.
3. The compound according to claim 1 , wherein the compound has the structure:
4. A process for the synthesis of a compound of Formula I:
wherein:
R 1 represents Br;
R 2 represents C 1-4 -alkyl N-containing heterocyclyl;
comprising:
(1) reacting compound 1-4:
in which R is R 2 , with O-(tetrahydro-2H-pyran-2-yl)hydroxylamine, 1-hydroxybenzotriazole and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride to obtain intermediate 5-8:
and
(2) reacting intermediate 5-8 with hydrogen chloride to obtain the compound of Formula reaction of a compound of intermediate 5-8.
5. The compound of claim 1 , wherein R 1 is F, Cl, Br, or I.
6. The compound of claim 5 , wherein R 1 is Br.
7. The compound of claim 6 , wherein R 2 is C 1-4 -alkyl N-containing heterocyclyl, in which the N-heterocyclyl group comprises two nitrogen atoms and is optionally substituted by methyl.
8. The compound of claim 7 , wherein R 2 is C 1-4 -alkyl-piperazinyl or C 1-4 -alkyl-diazepanyl, in which the piperazinyl group is optionally substituted by methyl.
9. The compound of claim 8 , wherein R 2 is (methylpiperazinyl)methyl, piperazinylmethyl, piperazinylethyl, or diazepanylmethyl.
10. The process of claim 4 , wherein R 2 is C 1-4 -alkyl N-containing heterocyclyl, in which the N-heterocyclyl group comprises two nitrogen atoms and is optionally substituted by methyl.
11. The process of claim 10 , wherein R 2 is C 1-4 -alkyl-piperazinyl or C 1-4 -alkyl-diazepanyl, in which the piperazinyl group is optionally substituted by methyl.
12. The process of claim 11 , wherein R 2 is (methylpiperazinyl)methyl, piperazinylmethyl, piperazinylethyl, or diazepanylmethyl.
13. A method of treating a disease, comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1 , wherein the disease is atheroma, arthritis, cancer, or tissue ulceration.
14. The method of claim 13 , wherein R 1 is F, Cl, Br, or I.
15. The method of claim 14 , wherein R 1 is Br.
16. The method of claim 15 , wherein R 2 is C 1-4 -alkyl N-containing heterocyclyl, in which the N-heterocyclyl group comprises two nitrogen atoms and is optionally substituted by methyl.
17. The method of claim 16 , wherein R 2 is C 1-4 -alkyl-piperazinyl or C 1-4 -alkyl-diazepanyl, in which the piperazinyl group is optionally substituted by methyl.
18. The method of claim 17 , wherein R 2 is (methylpiperazinyl)methyl, piperazinylmethyl, piperazinylethyl, or diazepanylmethyl.
19. The method of claim 13 , wherein the compound is selected from the group consisting of:
7-Bromo-N-hydroxy-8-((4-methylpiperazin-1-yl)methyl)-2-oxo-2H-selenopheno[3,2-h]chromene-3-carboxamide;
7-Bromo-N-hydroxy-2-oxo-8-((piperazin-1-yl)methyl)-2H-selenopheno[3,2-h]chromene-3-carboxamide;
7-Bromo-N-hydroxy-2-oxo-8-(2-(piperazin-1-yl)ethyl)-2H-selenopheno[3,2-h]chromene-3-carboxamide;
8-((1,4-Diazepan-1-yl)methyl)-7-bromo-N-hydroxy-2-oxo-2H-selenopheno[3,2-h]chromene-3-carboxamide;
and pharmaceutically acceptable enantiomers, diastereomers, racemates, and salts thereof.
20. The method of claim 13 , wherein the compound has the structure:
21. A method of inhibiting angiogenesis, comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1 .
22. A method of inhibiting MMP in a cell, comprising contacting the cell with an effective amount of the compound of claim 1 .