IP Library › Granted Patent US 8,927,717

Granted Patent B1

US 8,927,717 · App. 14/180,707 · Granted Jan 6, 2015

Thiochromeno[2,3-

Inventors: Hsu-Shan Huang (Taipei, TW); Dah-Shyong Yu (Taipei, TW); Tsung-Chih Chen (Nantou County, TW)

Assignee: National Defense Medical Center

C07D495/04

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Quick Facts

Patent No.: US 8,927,717
App. No.: 14/180,707
Granted: Jan 6, 2015
Kind: B1

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Abstract

The invention provides a series of novel thiochromeno[2,3-c]quinolin-12-one derivatives. Further, the invention also provides the preparation method and application of said derivatives, said application comprises: said derivatives with treating effective amount are prepared into pharmaceutical compositions for inhibition of topoisomerase type I and II, inhibition of cancer cell growth, further treating cancer.

Claims (128)

1. A compound as shown in formulation (I):

wherein the R is selected from the groups consisting of:

i) halo, amino, hydroxyl and thiol groups;

ii) linear alkyl chains of N(CH 2 ) n H, alkyl groups with substituted side chains, alkyl side chains with a substituted amino group and alkyl side chains with a substituted hydroxyl group, wherein 1≦n≦10;

iii) O(CH 2 ) n H, N(CH 3 ) 2 , NH(CH 2 ) n NH(CH 2 ) n OH, wherein 1≦n≦10;

iv) nitrogen-containing cycloalkyl groups and heterocyclic compounds of C 3-12 which contain 1 to 3 heteroatoms selected from O, S and N, wherein the ortho-, para- and meta-position can be further selected independently from one of the groups consisting of: hydrogen group, (CH 2 ) n alkyl groups, (CH 2 ) n hydroxyl groups, (CH 2 ) n C 3-12 cycloalkyl groups, (CH 2 ) n C 3-12 nitrogen-containing cycloalkyl groups, (CH 2 ) n benzene rings, formyl group and (CH 2 ) n COC 3-12 nitrogen-containing cycloalkyl groups, wherein 0≦n≦10;

v) NH(CH 2 ) n R 1 , 0≦n≦10, wherein R 1 is selected from the groups consisting of: N(CH 3 ) 2 , C(NH 2 ) 2 , linear alkyl chains of NH(CH 2 ) n H, alkyl groups with substituted side chains, alkyl side chains with a substituted amino group and alkyl side chains with a substituted hydroxyl group;

vi) NH(CH 2 ) n R 2 , 0≦n≦10, wherein R 2 is selected from the groups consisting of: benzene rings, C 3-12 cycloalkyl groups and heterocyclic groups of which contain 1 to 3 heteroatoms selected from O, S and N, wherein the ortho-, para- and meta-position can be further selected independently from one of the groups consisting of: Methoxyl group, amino group, benzene rings, alkyl, amino, nitro, hydroxyl groups with substituted C1-C3 side chains and C 3-12 heterocyclic groups; wherein the C 3-12 heterocyclic groups which contain 1 to 3 heteroatoms selected from O, S and N;

and their pharmaceutically acceptable salts, stereoisomers and enantimoers.

2. The compound according to claim 1 , where the R group consisting of i)˜iv) are selected from the group consisting of chlorine, hydroxyl, methoxyl, dimethylamino, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-Benzylpiperazin-1-yl, 4-phenylpiperazin-1-yl, morpholino, thiomorpholino, piperidin-1-yl, 4-hydroxypiperidin-1-yl, 4-Benzylpiperidin-1-yl, (1,4′-Bipiperidin)-1′-yl, 4-(3-(piperidin-4-yl)propyl)piperidin-1-yl, pyrrolidin-1-yl, 2-oxopiperidin-1-yl, methylamino, ethylamino, propylamino, butylamino, isobutylamino, pentan-3-ylamino, (2-(dimethylamino)ethyl)amino, (2-(diethylamino)ethyl)amino, 2-ethanolamino, 3-propanolamino, 5-pentanolamino, (1-hydroxybutan-2-yl)amino, (4-methylpentan-2-yl)amino, (2-Aminoethyl)amino, (2-((2-hydroxyethyl)amino)ethyl)amino, (2-morpholinoethyl)amino, (3-(dimethylamino)propyl)amino, (3-(diethylamino)propyl)amino, (3-((2-hydroxyethyl)amino)propyl)amino, (2,3-dihydro-1H-inden-2-yl)amino, cyclohexylamino, (1-Benzylpiperidin-4-yl)amino, (thiophen-2-ylmethyl)amino, (cyclohexylmethyl)amino, benzylamino, (pyridin-2-ylmethyl)amino, (Benzo[d][1,3]dioxol-5-ylmethyl)amino, (2-methoxybenzyl)amino, (3,4-dimethoxybenzyl)amino, phenethylamino, (4-methoxyphenethyl)amino, (4-aminophenethyl)amino, guanidine and piperidin-1-ylamino.

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

3-((4-Chlorophenyl)thio)-2-hydroxyquinoline-4-carboxylic acid,

6,9-Dichloro-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-hydroxy-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-methoxy-12H-thiochromeno[2,3-c]quinolin-12-one

10-Chloro-6-dimethylamino-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-(piperazin-1-yl)-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-(4-methylpiperazin-1-yl)-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-(4-ethylpiperazin-1-yl)-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-(4-(2-hydroxyethyl)piperazin-1-yl)-12H-thiochromeno[2,3-c]quinolin-12one,

6-(4-Benzylpiperazin-1-yl)-10-chloro-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-(4-phenylpiperazin-1-yl)-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-morpholino-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-thiomorpholino-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-(piperidin-1-yl)-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-(4-hydroxypiperidin-1-yl)-12H-thiochromeno[2,3-c]quinolin-12-one,

6-(4-Benzylpiperidin-1-yl)-10-chloro-12H-thiochromeno[2,3-c]quinolin-12-one,

6-([1,4′-Bipiperidin]-1′-yl)-10-chloro-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-(4-(3-(piperidin-4-yl)propyl)piperidin-1-yl)-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-(pyrrolidin-1-yl)-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-(2-oxopiperidin-1-yl)-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-methylamino-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-ethylamino-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-propylamino-12H-thiochromeno[2,3-c]quinolin-12-one,

6-(Butylamino)-10-chloro-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-isobutylamino-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-(pentan-3-ylamino)-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-((2-(dimethylamino)ethyl)amino)-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-((2-(diethylamino)ethyl)amino)-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-(2-ethanolamino)-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-(3-propanolamino)-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-(5-pentanolamino)-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-((1-hydroxybutan-2-yl)amino)-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-((4-methylpentan-2-yl)amino)-12H-thiochromeno[2,3-c]quinolin-12-one,

6-((2-Aminoethyl)amino)-10-chloro-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-((2-((2-hydroxyethyl)amino)ethyl)amino)-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-((2-morpholinoethyl)amino)-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-((3-(dimethylamino)propyl)amino)-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-((3-(diethylamino)propyl)amino)-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-((3-((2-hydroxyethyl)amino)propyl)amino)-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-((2,3-dihydro-1H-inden-2-yl)amino)-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-(cyclohexylamino)-12H-thiochromeno[2,3-c]quinolin-12-one,

6-((1-Benzylpiperidin-4-yl)amino)-10-chloro-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-((thiophen-2-ylmethyl)amino)-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-((cyclohexylmethyl)amino)-12H-thiochromeno[2,3-c]quinolin-12-one,

6-(Benzylamino)-10-chloro-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-((pyridin-2-ylmethyl)amino)-12H-thiochromeno[2,3-c]quinolin-12-one,

6-((Benzo[d][1,3]dioxol-5-ylmethyl)amino)-10-chloro-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-((2-methoxybenzyl)amino)-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-((3,4-dimethoxybenzyl)amino)-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-(phenethylamino)-12H-thiochromeno[2,3-c]quinolin-12-one,

10-Chloro-6-((4-methoxyphenethyl)amino)-12H-thiochromeno[2,3-c]quinolin-12-one,

6-((4-Aminophenethyl)amino)-10-chloro-12H-thiochromeno[2,3-c]quinolin-12-one,

2-(10-Chloro-12-oxo-12H-thiochromeno[2,3-c]quinolin-6-yl)guanidine,

10-Chloro-6-(piperidin-1-ylamino)-12H-thiochromeno[2,3-c]quinolin-12-one,

and their salts.

4. A pharmaceutical composition comprising the effective dosage compound according to claim 1 and at least one pharmaceutically acceptable vehicle, diluent or excipient.

5. A method for inhibiting Topoisomerase I activity which comprises administrating a effective amount of the compound according to claim 1 .

6. A method for inhibiting Topoisomerase II activity which comprises administrating an effective amount of the compound according to claim 1 .

7. A method for the treatment of cancer which comprises administrating an effective amount of the compound according to claim 1 .

8. The method according to claim 7 , wherein the cancer is selected from the groups consisting of leukemia, non-small cell lung cancer, colorectal cancer, central nervous system (CNS) cancer, melanoma, ovarian cancer, renal cancer, prostate cancer and breast cancer.

9. A method for preparation of thiochromeno[2,3-c]quinolin-12-one derivatives, wherein the method comprising:

(1) mix isatin, 2-((4-chlorophenyl)thio)acetic acid and sodium acetate was heated at 150° C. for 1 h, after cooling the mixture was added acetic acid, the precipitate was collected, washed with acetic acid, water and n-hexane, and obtained compound 2 (3-((4-Chlorophenyl)thio)-2-hydroxyquinoline-4-carboxylic acid);

(2) a solution of compound 2 (3-((4-Chlorophenyl)thio)-2-hydroxyquinoline-4-carboxylic acid) in phosphoryl trichloride was heated at 150° C. for 48 h, after cooling the mixture was poured into water 0° C., the precipitate was collected by filtration, then added into 10% NaHCO 3 with vigorous stirring for 1 h, the resulting precipitate was collected and washed with H 2 O, the crude solid was recrystallized by dichloromethane to give compound 3 (6,9-Dichloro-12H-thiochromeno[2,3-c]quinolin-12-one);

(3) a solution of compound 3 (6,9-Dichloro-12H-thiochromeno[2,3-c]quinolin-12-one) in DMF was added conc. HCl and refluxed, after 6 hours, the conc. HCl was added dropwise and refluxed for another 12 hours, the mixture was evaporated in vacuo and treated with H 2 O, after filtered the crude solid was washed with EtOH to give compound 4 (10-Chloro-6-hydroxy-12H-thiochromeno[2,3-c]quinolin-12-one);

(4) a suspension of compound 3 (6,9-Dichloro-12H-thiochromeno[2,3-c]quinolin-12-one) and sodium methoxide in methanol was refluxed for 16 h, after cooled the solvent was removed, filtrated and washed with ethanol and n-hexane to collect compound 5 (10-Chloro-6-methoxy-12H-thiochromeno[2,3-c]quinolin-12-one);

(5) a solution of compound 3 (6,9-Dichloro-12H-thiochromeno[2,3-c]quinolin-12-one), appropriate secondary amines and sodium carbonate in DMSO was refluxed for 10 hours, then the reaction was added ice-water, the precipitate was filtered, washed with water/methanol and collected to get compound 6-21: