Bis-trifluoromethyl honokiol analogs and their use in treating cancers
View Patent ↗Compounds, pharmaceutical compositions including the compounds, and methods of preparation and use thereof are disclosed. The compounds are hexafluoro-honokiol analogs. The compounds and compositions can be used to treat and/or prevent a wide variety of cancers, including drug resistant cancers. Representative hexafluoro-honokiol analogs include hexafluoro-honokiol, analogs in which one or both hydroxy groups are replaced with dichloroacetate esters, and analogs with increased fluorination. The compounds are believed to function, at least, by inhibiting angiogenesis and/or inducing apoptosis. Thus, the compounds are novel therapeutic agents for a variety of cancers.
1. A pharmaceutical composition composition a therapeutically-effective amount of a compound of the following formula:
wherein
R 1 is H, alkyl phosphate, dichloroacetate, trifluoromethyl, or valproate,
R 2 is H, alkyl, aryl, arylalkyl, or alkylaryl, and when bonded to carbon, halo, such as fluoro,
Y is N or C bonded to a substituent, G,
G is a substituent selected from the group consisting of C 1-6 alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, halo, —OR′, —NR 3 R 4 , —CF 3 , —CN, —NO 2 , —C 2 R 3 , —S R 3 , —N 3 , —C(═O)NR 3 R 4 , —NR 3 C(═O)R 3 , —C(═O)R 3 , —C(═O)OR 3 , —OC(═O)R 3 , —OC(═O)NR 3 R 4 , —NR 3 C(═O)OR 3 , —SO 2 R 3 , —SO 2 NR 3 R 4 , and —NR 3 SO 2 R 3 , where R 3 and R 4 are individually hydrogen, C 1-6 alkyl, cycloalkyl, heterocyclyl, aryl, or arylalkyl, and
z is an integer of from 0-3, but in any case cannot exceed the number of carbon atoms in the ring, and
a pharmaceutically-acceptable carrier or excipient,
wherein the therapeutic amount of the compound is that which provides a dosage of between about 1 and about 500 micrograms (μg) per patient per day.
2. A pharmaceutical composition of claim 1 , wherein the compound has the formula:
wherein
R 1 is H, alkyl phosphate, dichloroacetate, trifluoromethyl, or valproate,
R 2 is H, alkyl, aryl, arylalkyl, or alkylaryl, and when bonded to carbon, halo, such as fluoro,
G is a substituent selected from the group consisting of C 1-6 alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, halo, —OR′, —NR 3 R 4 , —CF 3 , —CN, —NO 2 , —C 2 R 3 , —S R 3 , —N 3 , —C(═O)NR 3 R 4 , —NR 3 C(═O)R 3 , —C(═O)R 3 , —C(═O)OR 3 , —OC(═O)R 3 , —OC(═O)NR 3 R 4 , —NR 3 C(═O)OR 3 , —SO 2 R 3 , —SO 2 NR 3 R 4 , and —NR 3 SO 2 R 3 , where R 3 and R 4 are individually hydrogen, C 1-6 alkyl, cycloalkyl, heterocyclyl, aryl, or arylalkyl, and
z is an integer of from 0-3, but in any case cannot exceed the number of carbon atoms in the ring.
3. A pharmaceutical composition of claim 1 , wherein the compound has one of the formulas:
, and analogs thereof with between one and six additional fluorine atoms.
4. A pharmaceutical composition of claim 1 , wherein both of X are O.
5. A pharmaceutical composition of claim 1 , wherein one of X is O, and the other represents a bond between the two carbons to which it is attached.
6. A pharmaceutical composition of claim 1 , wherein all Y are C bonded to H or a substituent, G.
7. A pharmaceutical composition of claim 1 , wherein one of Y is N.
8. A pharmaceutical composition of claim 1 , wherein two of Y are N.
9. A pharmaceutical composition of claim 1 , wherein each R 2 is H.
10. A pharmaceutical composition of claim 1 , wherein each W is CH 2 .
11. A pharmaceutical composition of claim 1 , wherein one or two of R 1 represent an alkyl phosphate ester, or a dichloroacetate.
12. A pharmaceutical composition of claim 1 , wherein the compound has the formula:
13. A pharmaceutical composition of claim 1 , wherein the compound is selected from the group consisting of valproate mono and diesters of hexafluoro-honokiol, dichloroacetate mono and diesters of hexafluoro-honokiol, and C 1-6 alkyl phosphate mono and di-esters of hexafluoro-honokiol.