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US 10,947,198 B2Granted
Chroman-substituted, tetrahydroquinoline-substituted and thiochroman-substituted heteroarotinoids as anti-cancer agents
AssigneeThe Board of Regents for Oklahoma State University
InventorsKenneth Darrell Berlin, Richard A. Bunce, Krishna Kumar Gnanasekaran, Field M. Watts, Jr., Donghua Howard Zhou
Life of this patent
Estimating the term…
Abstract
Chemical compounds that inhibit cancer cell growth are provided. The compounds are heteroarotinoids and derivatives thereof with oxygen, nitrogen or sulfur in chroman systems, tetrahydroquinoline systems, and tetrahydrothiochroman systems.
Claims15
A compound having a formula:
- wherein,
- R1 and R2 are optionally C1-C5 substituted alkyl;
- R3 and R4 are optionally C1-C5 substituted alkyl;
- G is CH2, C═O or CHOH;
- X is S, O, NR or N+(R)2 where R is hydrogen or an optionally substituted C1-C5 alkyl;
- R5 and R6 are hydrogen or optionally substituted C1-C5 alkyl;
- Y is O or S;
- n is 0, 1, 2, 3, or 4;
- and
- R7 to R11 are independently selected from a group consisting of hydrogen, halogen, CN, NO2, OH, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted haloalkyl, optionally substituted haloalkoxy, ester or sulfonamide;
- wherein
- i) R7, R8, R10, R11 are hydrogen and
- R9 is hydrogen, CF3, OCF3, CN, Cl, OCH3 or OH,
- or a salt, solvate, or hydrate thereof;
- or
- ii) R7, R9, R10, R11 are hydrogen and
- R8 is CF3, OCF3, CN, Cl, OCH3 or OH,
- or a salt, solvate, or hydrate thereof;
- or
- iii) R7, R9, R11 are hydrogen and
- R8, R10 are CF3, OCF3, CN, Cl, OCH3 or OH,
- or a salt, solvate, or hydrate thereof;
- or
- iv) the compound has a formula
- wherein,
- R1 and R2 are hydrogen, CH3 or C2H5,
- R3 and R4 are CH3 or C2H5,
- Y is O or S, and
- R9 is CF3, OCF3, CN, Cl, OCH3 or OH,
- or a salt, solvate, or hydrate thereof;
- or
- v) the compound has a formula:
- wherein,
- R1 and R2 are hydrogen, CH3 or C2H5,
- R3 and R4 are CH3 or C2H5,
- Y is O or S, and
- R9 is CF3, OCF3, CN, Cl, OCH3 or OH,
- or a salt, solvate, or hydrate thereof;
- or
- vi) the compound has a formula:
- wherein
- R1 and R2 are hydrogen, CH3 or C2H5,
- R3 and R4 are CH3 or C2H5,
- Y is O or S,
- R9 is CF3, OCF3, CN, Cl, OCH3 or OH, and
- R13 is H or CH3
- or a salt, solvate, or hydrate thereof;
- or
- vii) the compound has a formula:
- wherein,
- R1 and R2 are hydrogen, CH3 or C2H5,
- R3 and R4 are CH3 or C2H5,
- Y is O or S, and
- R9 is CF3, OCF3, CN, Cl, OCH3 or OH,
- or a salt, solvate, or hydrate thereof;
- with the caveat that the compound is not ShetA2 with the formula
53 more elements
A compound having a formula:
- wherein,
- R1 and R2 are optionally C1-C5 substituted alkyl;
- R3 and R4 are optionally C1-C5 substituted alkyl;
- G is CH2, C═O or CHOH;
- X is S, O, NR or N+(R)2 where R is hydrogen or an optionally substituted C1-C5 alkyl;
- R5, R6 and R12 are hydrogen or optionally substituted C1-C5 alkyl;
- Y is O or S;
- and
- R7 to R11 are independently selected from a group consisting of hydrogen, halogen, CN, NO2, OH, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted haloalkyl, optionally substituted haloalkoxy, ester or sulfonamide;
- or a salt, solvate, or hydrate thereof.
7 more elements
A compound having a formula:
- wherein,
- R1 and R2 are optionally C1-C5 substituted alkyl;
- R3 and R4 are optionally C1-C5 substituted alkyl;
- G is CH2, C═O or CHOH;
- X is S, O, NR or N+(R)2 where R is hydrogen or an optionally substituted C1-C5 alkyl;
- R5, R6 and R12 are hydrogen or optionally substituted C1-C5 alkyl;
- Y is O or S;
- and
- R7 to R11 are independently selected from a group consisting of hydrogen, halogen, CN, NO2, OH, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted haloalkyl, optionally substituted haloalkoxy, ester or sulfonamide;
- or a salt, solvate, or hydrate thereof.
7 more elements
A compound which is:
- Ethyl 4-(3-(2,2,4,4-Tetramethylchroman-6-yl)thioureido)benzoate;
- 1-(2,2,4,4-Tetramethylchroman-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea;
- 4-(3-(2,2,4,4-Tetramethylchroman-6-yl)thioureido)benzenesulfonamide;
- 1-(2,2,4,4-Tetramethylchroman-6-yl)-3-(4-(trifluoromethyl)phenyl)urea;
- 1-(4-Cyanophenyl)-3-(2,2,4,4-tetramethylchroman-6-yl)urea;
- 1-(2,2,4,4-Tetramethylchroman-6-yl)-3-(4-(trifluoromethoxy)phenyl)urea;
- 1-(4-Nitrophenyl)-3-(4,4-dimethylchroman-6-yl)thiourea;
- 1-(4,4-Dimethylchroman-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea;
- 1-(4,4-Dimethylchroman-6-yl)-3-(4-(trifluoromethoxy)phenyl)thiourea;
- 1-(4-Nitrophenyl)-3-(4,4-dimethylchroman-6-yl)urea;
- (4,4-Dimethylchroman-6-yl)-3-[4-trifluoromethyl)phenyl]urea;
- 1-(4,4-Dimethylchroman-6-yl)-3-(4-(trifluoromethoxy)phenyl)urea;
- 1-(2,2-Diethyl-4,4-dimethylchroman-6-yl)-3-(4-nitrophenyl)thiourea;
- 1-(2,2-Diethyl-4,4-dimethylchroman-6-yl)-3-(4-nitrophenyl)urea;
- 1-(2,2-Diethyl-4,4-dimethylchroman-6-yl)-3-(4-(trifluoromethyl)phenyl)urea;
- 1-(4,4-Diethyl-2,2-dimethylchroman-6-yl)-3-(4-nitrophenyl)thiourea;
- 1-(4,4-Diethyl-2,2-dimethylchroman-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea;
- 1-(4,4-Diethyl-2,2-dimethylchroman-6-yl)-3-(4-nitrophenyl)urea;
- 1-(4,4-Diethyl-2,2-dimethylchroman-6-yl)-3-(4-(trifluoromethyl)phenyl)urea;
- 1-(4-Nitrophenyl)-3-(2,2,4,4-tetraethylchroman-6-yl)thiourea;
- 1-(4-Nitrophenyl)-3-(2,2,4,4-tetraethylchroman-6-yl)urea;
- 1-(2,2,4,4-Tetraethylchroman-6-yl)-3-(4-(trifluoromethyl)phenyl)urea;
- 1-(2,2,4,4-Tetraethylchroman-6-yl)-3-(4-(trifluoromethoxy)phenyl)urea;
- 1-(4,4-Dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-nitrophenyl)urea;
- 1-(4,4-Dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-nitrophenyl)thiourea;
- 1-(4,4-Dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea;
- 1-(4,4-Dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-(trifluoromethoxy)phenyl)-thiourea;
- 1,1,4,4-Tetramethyl-6-(3-(4-nitrophenyl)ureido)-1,2,3,4-tetrahydroquinolin-1-ium iodide;
- 1-(4-Nitrophenyl)-3-(1,2,2,4,4-pentamethyl-3-oxo-1,2,3,4-tetrahydroquinolin-6-yl)urea;
- 1-(4-Nitrophenyl)-3-(1,2,2,4,4-pentamethyl-3-oxo-1,2,3,4-tetrahydroquinolin-6-yl)thiourea;
- 1-(1,2,2,4,4-Pentamethyl-3-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-(trifluoromethyl)-phenyl)urea;
- 1-(1,2,2,4,4-Pentamethyl-3-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-trifluoromethyl)-phenyl)thiourea;
- 1-(1,2,2,4,4-Pentamethyl-3-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-(trifluoromethoxy)-phenyl)urea;
- 1-(1,2,2,4,4-Pentamethyl-3-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-(trifluoromethoxy)-phenyl)thiourea;
- 1-(4-Aminophenyl)-3-(1,2,2,4,4-pentamethyl-3-oxo-1,2,3,4-tetrahydroquinolin-6-yl)urea;
- 3-(1,2,2,4,4-Pentamethyl-1,2,3,4-tetrahydroquinolin-6-yl)-1-(4-nitrophenyl)thiourea;
- 1-(3-Hydroxy-1,2,2,4,4-pentamethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-nitrophenyl)-urea;
- 1-(3-Hydroxy-1,2,2,4,4-pentamethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-nitrophenyl)-thiourea;
- 1-(3-Hydroxy-1,2,2,4,4-pentamethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-(trifluoro-methyl)phenyl)urea;
- 1-(3-Hydroxy-1,2,2,4,4-pentamethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-(trifluoro-methyl)phenyl)thiourea;
- 1-(3-Hydroxy-1,2,2,4,4-pentamethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-(trifluoro-methoxy)phenyl)urea;
- 1-(3-Hydroxy-1,2,2,4,4-pentamethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-(trifluoro-methoxy)phenyl)thiourea;
- 1-(4-Acetylphenyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)urea;
- 1-(2,2,4,4-Tetramethylthiochroman-6-yl)-3-(4-(trifluoromethyl)phenyl)urea;
- 1-(2,2,4,4-Tetramethylthiochroman-6-yl)-3-(4-(trifluoromethoxy)phenyl)urea;
- 1-(4-Cyanophenyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)urea;
- 1-(2-Methoxy-4-nitrophenyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)urea;
- 1-Phenyl-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;
- 1-(4-Methylphenyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;
- 1-(5,6,7,8-Tetrahydronaphthalen-2-yl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;
- 1-(4-Chlorophenyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;
- 1-(2,2,4,4-Tetramethylthiochroman-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea;
- 1-(2,2,4,4-Tetramethylthiochroman-6-yl)-3-(4-(trifluoromethoxy)phenyl)thiourea;
- 1-(3-Nitrophenyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;
- 1-(2,2,4,4-Tetramethylthiochroman-6-yl)-3-(2-(trifluoromethyl)phenyl)thiourea;
- 4-(3-(2,2,4,4-Tetramethylthiochroman-6-yl)thioureido)benzamide;
- 1-(4-Methoxyphenyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;
- 1-(3-Methoxyphenyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;
- 1-(4-Hydroxyphenyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;
- 1-(3-Hydroxy-4-methoxyphenyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;
- 1,3-Bis(2,2,4,4-Tetramethylthiochroman-6-yl)thiourea;
- 1-(2,2,4,4-Tetramethylthiochroman-6-yl)-3-(4-(trifluoromethyl)phenyl)urea;
- 1-(2,2,4,4-Tetramethylthiochroman-6-yl)-3-(4-(trifluoromethoxy)phenyl)urea;
- 1-(4-Cyanophenyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)urea;
- 1-(4-Chlorophenyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;
- 1-(2,2,4,4-Tetramethylthiochroman-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea;
- 1-(2,2,4,4-Tetramethylthiochroman-6-yl)-3-(4-(trifluoromethoxy)phenyl)thiourea;
- 4-(3-(2,2,4,4-Tetramethylthiochroman-6-yl)thioureido)benzamide;
- 1-(4-Methoxyphenyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;
- 1-(3-Methoxyphenyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;
- 1-Benzyl-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;
- 1-Phenethyl-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;
- 1-(4-Chlorobenzyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;
- 1-(4-Nitrobenzyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;
- 1-(2,2,4,4-Tetramethylthiochroman-6-yl)-3-(4-(trifluoromethyl)benzyl)thiourea;
- 1-(4-Methoxybenzyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;
- 1-(4-Hydroxybenzyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;
- 2-Phenyl-N-(2,2,4,4-tetramethylthiochroman-6-yl)hydrazine-1-carbothioamide;
- 2-Benzoyl-N-(2,2,4,4-tetramethylthiochroman-6-yl)hydrazine-1-carbothioamide;
- 2-(4-Nitrobenzoyl)-N-(2,2,4,4-tetramethylthiochroman-6-yl)hydrazine-1-carbothioamide;
- N-(2,2,4,4-Tetramethylthiochroman-6-yl)-2-(4-(trifluoromethoxy)benzoyl)hydrazine-1-carbothioamide;
- 2-(3,5-Bis(trifluoromethyl)benzoyl)-N-(2,2,4,4-tetramethylthiochroman-6-yl)hydrazine-1-carbothioamide;
- or,
- 4,4-Dimethylthiochroman-6-amine hydrochloride;
- or a salt, solvate, or hydrate thereof.
82 more elements
A compound which is:
- or a salt, solvate, or hydrate thereof.
A compound having a formula:
- wherein,
- R1 and R2 are optionally C1-C5 substituted alkyl;
- R3 and R4 are optionally C1-C5 substituted alkyl;
- G is CH2, C═O or CHOH;
- X is S, O, NR or N+(R)2 where R is hydrogen or an optionally substituted C1-C5 alkyl;
- R5 and R6 are hydrogen or optionally substituted C1-C5 alkyl;
- Y is O or S;
- n is 1, 2, 3, or 4;
- and
- R7 to R11 are independently selected from a group consisting of hydrogen, halogen, CN, NO2, OH, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted haloalkyl, optionally substituted haloalkoxy, ester or sulfonamide;
- or a salt, solvate, or hydrate thereof.
8 more elements
Dependencies are inferred from the claim text.