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US 10,744,127 B2Granted
MDR-reversing 8-hydroxy-quinoline derivatives
AssigneeMagyar Tudományos Akadémia Természettudományi Kutatóközpont
InventorsGergely Szakács, Tibor Soós, Roberta Ferenczi-Palkó, András Füredi, Szilárd Tóth, Dóra Türk, Veronika Pape, Ferenc Fülöp, István Szatmári, György Dormán
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Abstract
The present invention is related to 8-hydroxy-quinoline derivatives having multidrug-resistance reversing activity with improved selectivity and increased cytotoxicity towards multidrug-resistant cancer cells, preparation thereof and use of the same in the treatment of cancer, especially multidrug-resistant variants thereof.
Claims15
A compound of Formula I,
- wherein
- R1 is selected from the group consisting of hydrogen, methyl, 1-(2-hydroxyphenyl)-ethylidene]-hydrazin-1-yl, 1-(pyridin-2-yl)-ethylidene]-hydrazin-1-yl, 2-[(E/Z)-2-[1-(pyridin-2-yl)-ethylidene]hydrazin-1-yl, 2-[(pyridin-2-yl)-methylidene]-hydrazin-1-yl, ((benzothiazol-2-yl)-hydrazin-1-ylidene)-methyl, 2-(8-hydroxyquinolin-2-yl)-hydrazin-1-ylidene)methyl, thiosemicarbamoyl-1-(4-methoxyphenyl) and pyridine-2-yl, imidazole-2-yl;
- R2 is selected from the group consisting of hydrogen, nitro, (C1-C6)alkylsulfonyl, pyridinyl, imidazolyl and halogen,
- R3 is selected from the group consisting of (piperidin-1-yl)methyl, cyclohexylaminomethyl, (4-methoxybenzyl)-amino-methyl, (2-methoxybenzyl)-amino-methyl, (2,4-dimethoxybenzyl)-amino-methyl, 3,4-dimethoxybenzyl-amino-methyl, (2-fluorobenzyl)-aminomethyl, ethyl-2-{[(2-fluorophenyl)methyl]amino}acetate, {1H,2H,3H,4H,9H-pyrido[3,4-b]indol-1-yl}, {4H,5H,6H,7H-tetrahydrothieno[3,2-c]pyridin-4-yl}, 1,2,3,4-tetrahydroisoquinolin-1-yl, 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl, (pyridin-3-yl)[(1,3-thiazol-2-yl)amino]methyl, benzyl-amino-methyl and octahydroquinoxalin-2(1H)-one;
- with the provisos that
- when R1 and R2 are hydrogen, R3 is different from (piperidine-1-yl)-methyl, 1,2,3,4-tetrahydro-isoquionoline-1-yl and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquionoline-1-yl;
- when R1 is hydrogen, R2 is nitro, R3 is different from benzylamino-methyl, (piperidine-1-yl)-methyl;
- when R1 is methyl and R2 is hydrogen, R3 is different from (piperidine-1-yl)-methyl, 1,2,3,4-tetrahydro-isoquionoline-1-yl and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquionoline-1-yl;
- and
- when R1 is hydrogen and R2 is halogen, R3 is different from benzylamino-methyl and (piperidine-1-yl)-methyl;
- or a stereoisomer, pharmaceutically acceptable salt, solvate or metal complex thereof.
8 more elements
A compound of Formula I,
- wherein
- R1 is selected from the group consisting of hydrogen, methyl, 1-(2-hydroxyphenyl)-ethylidene]-hydrazin-1-yl, 1-(pyridin-2-yl)-ethylidene]-hydrazin-1-yl, 2-[(E/Z)-2-[1-(pyridin-2-yl)-ethylidene]hydrazin-1-yl, 2-[(pyridin-2-yl)-methylidene]-hydrazin-1-yl, ((benzothiazol-2-yl)-hydrazin-1-ylidene)-methyl, 2-(8-hydroxyquinolin-2-yl)-hydrazin-1-ylidene)methyl, thiosemicarbamoyl-1-(4-methoxyphenyl) and pyridine-2-yl, imidazole-2-yl;
- R2 is selected from the group consisting of hydrogen, nitro, (C1-C6)alkylsulfonyl, pyridinyl, imidazolyl and halogen,
- R3 is selected from the group consisting of (piperidin-1-yl)methyl, cyclohexylaminomethyl, (4-methoxybenzyl)-amino-methyl, (2-methoxybenzyl)-amino-methyl, (2,4-dimethoxybenzyl)-amino-methyl, 3,4-dimethoxybenzyl-amino-methyl, (2-fluorobenzyl)-aminomethyl, ethyl-2-{[(2-fluorophenyl)methyl]amino}acetate, {1H,2H,3H,4H,9H-pyrido[3,4-b]indol-1-yl}, {4H,5H,6H,7H-tetrahydrothieno[3,2-c]pyridin-4-yl}, 1,2,3,4-tetrahydroisoquinolin-1-yl, 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl, (pyridin-3-yl)[(1,3-thiazol-2-yl)amino]methyl, benzyl-amino-methyl and octahydroquinoxalin-2(1H)-one;
- wherein said compound is selected from the group consisting of
- 7-(((2,4-dimethoxybenzyl)amino)methyl)-5-(methylsulfonyl)quinolin-8-ol;
- 7-(((3,4-dimethoxybenzyl)amino)methyl)-5-nitroquinolin-8-ol;
- 7-(((2-methoxybenzyl)amino)methyl)-5-nitroquinolin-8-ol;
- 7-(((2,4-dimethoxybenzyl)amino)methyl)-5-nitroquinolin-8-ol;
- 7-(((4-methoxybenzyl)amino)methyl)-5-nitroquinolin-8-ol;
- (3R,4aS,8aS)-3-(5-chloro-8-hydroxyquinolin-7-yl)octahydroquinoxalin-2(1H)-one;
- (3S,4aS,8aS)-3-(5-chloro-8-hydroxyquinolin-7-yl)octahydroquinoxalin-2(1H)-one;
- 5-bromo-7-(((3,4-dimethoxybenzyl)amino)methyl)quinolin-8-ol;
- 5-chloro-7-(((2,4-dimethoxybenzyl)amino)methyl)quinolin-8-ol;
- (E/Z)-7-(piperidin-1 ylmethyl)-2-(2-(1-(pyridin-2-yl)ethylidene)hydrazinyl)quinolin-8-ol;
- (E/Z)-2-(2-(1-(2-hydroxyphenyl)ethylidene)hydrazinyl)-7-(piperidin-1-ylmethyl)quinolin-8-ol;
- (E/Z)-7-(piperidin-1-ylmethyl)-2-(2-(pyridine-2-ylmethylene)hydrazinyl)quinolin-8-ol;
- 5-chloro-7-((cyclohexylamino)methyl)quinolin-8-ol;
- 5-chloro-7-(((4-methoxybenzyl)amino)methyl)quinolin-8-ol;
- 5-bromo-7-(((2-methoxybenzyl)amino)methyl)quinolin-8-ol;
- 5-bromo-7-(((2,4-dimethoxybenzyl)amino)methyl)quinolin-8-ol;
- 5-bromo-7-(((4-methoxybenzyl)amino)methyl)quinolin-8-ol;
- 5-chloro-7-({[(2-fluorophenyl)methyl]amino}methyl)quinolin-8-ol;
- 5-chloro-7-(1,2,3,4-tetrahydroisoquinolin-1-yl)quinolin-8-ol;
- 5-bromo-7-(1,2,3,4-tetrahydroisoquinolin-1-yl)quinolin-8-ol;
- 5-nitro-7-(1,2,3,4-tetrahydroisoquinolin-1-yl)quinolin-8-ol;
- 5-chloro-7-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)quinolin-8-ol;
- 5-chloro-7-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-4-yl)quinolin-8-ol;
- 7-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-4-yl)quinolin-8-ol;
- 5-nitro-7-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-4-yl)quinolin-8-ol and
- 2-(2-methyl-7-{4,5,6,7-tetrahydrothieno[3,2-c]pyridin-4-yl}quinolin-8-ol
- or a stereoisomer, pharmaceutically acceptable salt, solvate or metal complex thereof.
29 more elements
A compound of Formula I,
- wherein
- R1 is selected from the group consisting of hydrogen, methyl, 1-(2-hydroxyphenyl)-ethylidene]-hydrazin-1-yl, 1-(pyridin-2-yl)-ethylidene]-hydrazin-1-yl, 2-[(E/Z)-2-[1-(pyridin-2-yl)-ethylidene]hydrazin-1-yl, 2-[(pyridin-2-yl)-methylidene]-hydrazin-1-yl, (benzothiazol-2-yl)-hydrazin-1-ylidene)-methyl, 2-(8-hydroxyquinolin-2-yl)-hydrazin-1-ylidene)methyl, thiosemicarbamoyl-1-(4-methoxyphenyl) and pyridine-2-yl, imidazole-2-yl;
- R2 is selected from the group consisting of hydrogen, nitro, (C1-C6)alkylsulfonyl, pyridinyl, and imidazolyl,
- R3 is selected from the group consisting of (piperidin-1-yl)methyl, cyclohexylamino-methyl, (4-methoxybenzyl)-amino-methyl, (2-methoxybenzyl)-amino-methyl, (2,4-dimethoxybenzyl)-amino-methyl, 3,4-dimethoxybenzyl-amino-methyl, (2-fluorobenzyl)-aminomethyl, ethyl-2-{[(2-fluorophenyl)methyl]amino}acetate, {1H,2H,3H,4H,9H-pyrido[3,4-b]indol-1-yl}, {4H,5H,6H,7H-tetrahydrothieno[3,2-c]pyridin-4-yl}, 1,2,3,4-tetrahydroisoquinolin-1-yl, 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl, (pyridin-3-yl)[(1,3-thiazol-2-yl)amino]methyl and benzyl-amino-methyl;
- with the proviso that
- when R1 and R2 are hydrogen, R3 is different from (piperidine-1-yl)-methyl, 1,2,3,4-tetrahydro-isoquionoline-1-yl and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquionoline-1-yl;
- when R1 is hydrogen and R2 is nitro, R3 is different from benzylamino-methyl and (piperidine-1-yl)-methyl;
- when R1 is methyl and R2 is hydrogen, R3 is different from (piperidine-1-yl)-methyl, 1,2,3,4-tetrahydro-isoquionoline-1-yl and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquionoline-1-yl;
- or a stereoisomer, pharmaceutically acceptable salt, solvate or metal complex thereof.
6 more elements
Dependencies are inferred from the claim text.