Chroman-substituted, tetrahydroquinoline-substituted and thiochroman-substituted heteroarotinoids as anti-cancer agents

Patent metadata

Field	Value
Publication number	US-10947198-B2
Application number	US-201916549337-A
Country	US
Kind code	B2
Filing date	Aug 23, 2019
Priority date	Aug 24, 2018
Publication date	Mar 16, 2021
Grant date	Mar 16, 2021

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.

First claim

What is claimed is:

1. A compound having a formula:

wherein,
R 1 and R 2 are optionally C1-C5 substituted alkyl;
R 3 and R 4 are optionally C1-C5 substituted alkyl;
G is CH 2 , C═O or CHOH;
X is S, O, NR or N + (R) 2 where R is hydrogen or an optionally substituted C1-C5 alkyl;
R 5 and R 6 are hydrogen or optionally substituted C1-C5 alkyl;
Y is O or S;
n is 0, 1, 2, 3, or 4; and
R 7 to R 11 are independently selected from a group consisting of hydrogen, halogen, CN, NO 2 , OH, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted haloalkyl, optionally substituted haloalkoxy, ester or sulfonamide;

wherein
i) R 7 , R 8 , R 10 , R 11 are hydrogen and
R 9 is hydrogen, CF 3 , OCF 3 , CN, Cl, OCH 3 or OH,
or a salt, solvate, or hydrate thereof;

 or
ii) R 7 , R 9 , R 10 , R 11 are hydrogen and
R 8 is CF 3 , OCF 3 , CN, Cl, OCH 3 or OH,
or a salt, solvate, or hydrate thereof;

 or
iii) R 7 , R 9 , R 11 are hydrogen and
R 8 , R 10 are CF 3 , OCF 3 , CN, Cl, OCH 3 or OH,
or a salt, solvate, or hydrate thereof;

 or
iv) the compound has a formula
wherein,
R 1 and R 2 are hydrogen, CH 3 or C 2 H 5 ,
R 3 and R 4 are CH 3 or C 2 H 5 ,
Y is O or S, and
R 9 is CF 3 , OCF 3 , CN, Cl, OCH 3 or OH,
or a salt, solvate, or hydrate thereof;

 or
v) the compound has a formula:

wherein,
R 1 and R 2 are hydrogen, CH 3 or C 2 H 5 ,
R 3 and R 4 are CH 3 or C 2 H 5 ,
Y is O or S, and
R 9 is CF 3 , OCF 3 , CN, Cl, OCH 3 or OH,
or a salt, solvate, or hydrate thereof;

 or
vi) the compound has a formula:

wherein
R 1 and R 2 are hydrogen, CH 3 or C 2 H 5 ,
R 3 and R 4 are CH 3 or C 2 H 5 ,
Y is O or S,
R 9 is CF 3 , OCF 3 , CN, Cl, OCH 3 or OH, and
R 13 is H or CH 3
or a salt, solvate, or hydrate thereof;

 or
vii) the compound has a formula:

wherein,
R 1 and R 2 are hydrogen, CH 3 or C 2 H 5 ,
R 3 and R 4 are CH 3 or C 2 H 5 ,
Y is O or S, and
R 9 is CF 3 , OCF 3 , CN, Cl, OCH 3 or OH,
or a salt, solvate, or hydrate thereof;

with the caveat that the compound is not ShetA2 with the formula

2. A compound having a formula:

wherein,
R 1 and R 2 are optionally C1-C5 substituted alkyl;
R 3 and R 4 are optionally C1-C5 substituted alkyl;
G is CH 2 , C═O or CHOH;
X is S, O, NR or N + (R) 2 where R is hydrogen or an optionally substituted C1-C5 alkyl;
R 5 , R 6 and R 12 are hydrogen or optionally substituted C1-C5 alkyl;
Y is O or S; and
R 7 to R 11 are independently selected from a group consisting of hydrogen, halogen, CN, NO 2 , OH, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted haloalkyl, optionally substituted haloalkoxy, ester or sulfonamide;

or a salt, solvate, or hydrate thereof.

3. A compound having a formula:

wherein,
R 1 and R 2 are optionally C1-C5 substituted alkyl;
R 3 and R 4 are optionally C1-C5 substituted alkyl;
G is CH 2 , C═O or CHOH;
X is S, O, NR or N + (R) 2 where R is hydrogen or an optionally substituted C1-C5 alkyl;
R 5 , R 6 and R 12 are hydrogen or optionally substituted C1-C5 alkyl;
Y is O or S; and
R 7 to R 11 are independently selected from a group consisting of hydrogen, halogen, CN, NO 2 , OH, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted haloalkyl, optionally substituted haloalkoxy, ester or sulfonamide;

or a salt, solvate, or hydrate thereof.

4. A compound of claim 2 , wherein,
R 7 , R 8 , R 10 , R 11 are hydrogen and
R 9 is hydrogen, CF 3 , OCF 3 , CN, Cl, OCH 3 or OH.

5. A compound of claim 3 , wherein,
R 7 , R 8 , R 10 , R 11 are hydrogen and
R 9 is hydrogen, CF 3 , OCF 3 , CN, Cl, OCH 3 or OH.

6. A compound of claim 2 , wherein,
R 7 , R 9 , R 10 , R 11 are hydrogen and
R 8 is CF 3 , OCF 3 , CN, Cl, OCH 3 or OH.

7. A compound of claim 3 , wherein,
R 7 , R 9 , R 10 , R 11 are hydrogen and
R 8 is CF 3 , OCF 3 , CN, Cl, OCH 3 or OH.

8. A compound of claim 2 , wherein,
R 7 , R 9 , R 11 are hydrogen and
R 8 , R 10 are CF 3 , OCF 3 , CN, Cl, OCH 3 or OH.

9. A compound of claim 3 , wherein,
R 7 , R 9 , R 11 are hydrogen and
R 8 , R 10 are CF 3 , OCF 3 , CN, Cl, OCH 3 or OH.

10. A compound of claim 1 having a formula:

wherein,
R 1 and R 2 are hydrogen, CH 3 or C 2 H 5 ;
R 3 and R 4 are CH 3 or C 2 H 5 ;
Y is O or S;
R 9 is CF 3 , OCF 3 , CN, Cl, OCH 3 or OH,

or a salt, solvate, or hydrate thereof.

11. A compound of claim 2 having a formula:

wherein,
R 1 and R 2 are hydrogen, CH 3 or C 2 H 5 ;
Y is O or S; and
R 9 is CF 3 , OCF 3 , CN, Cl, OCH 3 or OH.

12. A compound of claim 3 having a formula:

wherein,
R 1 and R 2 are hydrogen, CH 3 or C 2 H 5 ;
Y is O or S; and
R 7 to R 11 are independently selected from a group consisting of hydrogen, CF 3 , OCF 3 , CN, Cl, OCH 3 or OH.

13. 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-Tetraethylch

Assignees

• Univ Oklahoma State

Inventors

• Berlin Kenneth Darrell
• Bunce Richard A
• Gnanasekaran Krishna Kumar
• Watts Jr Field M
• Zhou Donghua Howard

Classifications

• C07D215/06 Primary

  having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom · CPC title

• C07D311/70

  with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6 · CPC title

• C07D335/06

  Benzothiopyrans; Hydrogenated benzothiopyrans · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• A61K31/352

  condensed with carbocyclic rings, e.g. methantheline  {(cannabinoids A61K31/658)} · CPC title