Compounds and methods for the prevention and treatment of tumor metastasis and tumorigenesis
The disclosure provides compounds for reducing the prevalence of the perinucleolar compartment in cells, for example, of formula (I), wherein R 1 , R 2 , R 3 , and R 4 are as defined herein, that are useful in treating a disease or disorder associated with increased prevalence of the perinucleolar compartment, such as cancer. Also disclosed is a composition containing a pharmaceutically acceptable carrier and at least one compound embodying the principles of the invention, and a method of treating or preventing cancer in a mammal.
1. A compound of formula (I):
wherein R 1 is selected from the group consisting thioalkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, hydroxycycloalkyl, hydroxycycloalkylalkyl, thiocycloalkyl, alkoxycycloalkyl, alkylthiocycloalkyl, dialkylaminoalkyl, heterocyclyl, heteroaryl, arylalkylpiperidin-4-yl, arylpiperazinylalkyl, (tetrahydrofuran-3-yl)methyl, and (tetrahydrofuran-2-yl)methyl and (tetrahydro-2H-pyran-4-yl)methyl,
R 2 is phenyl, optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, hydroxyalkyl, thioalkyl, alkoxy, alkylthioalkyl, alkoxycarbonyl, alkylthiocarbonyl, amino, alkylamino, dialkylamino, and alkylcarbonyl,
R 3 is phenyl, optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, hydroxyalkyl, thioalkyl, alkoxy, alkylthioalkyl, alkoxycarbonyl, alkylthiocarbonyl, amino, alkylamino, dialkylamino, and alkylcarbonyl,
R 4 is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, and arylalkyl,
or a pharmaceutically acceptable salt thereof,
wherein R 4 is optionally substituted on the aryl and/or alkyl portion with one or more substituents selected from the group consisting of halo, alkyl, hydroxyalkyl, thioalkyl, alkylthioalkyl, alkoxycarbonyl, alkylthiocarbonyl, amino, alkylamino, dialkylamino, aminosulfonyl, hydroxyl, perfluoroalkoxy, alkylenedioxy, and alkylcarbonyl.
2. The compound or salt of claim 1 , wherein R 4 is benzyl, wherein the phenyl ring is optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxyalkyl, thioalkyl, alkylthioalkyl, alkoxycarbonyl, alkylthiocarbonyl, amino, alkylamino, dialkylamino, aminosulfonyl, hydroxyl, perfluoroalkoxy, and alkylcarbonyl.
3. The compound or salt of claim 1 , wherein R 1 is a 5 or 6-membered heterocyclyl group having at least one hetero atom selected from the group consisting of O, N, and S; a hydroxy C 3 -C 7 cycloalkyl group; a N,N-di(C 1 -C 6 alkyl)amino C 1 -C 6 alkyl group; a C 1 -C 6 alkoxy C 1 -C 6 alkyl group; N-benzyl piperadinyl; N-phenyl piperazinylalkyl; a phenyl C 1 -C 6 alkyl group where the alkyl is substituted with a hydroxy group.
4. The compound or salt of claim 1 , wherein R 1 is selected from the group consisting of the following:
5. The compound or salt of claim 1 , wherein R 2 is phenyl, R 3 is phenyl, R 4 is benzyl, and R 1 is selected from the group consisting of the following:
6. The compound or salt of claim 1 , wherein R 4 is 4-methoxybenzyl, R 2 is phenyl, R 3 is phenyl, and R 1 is selected from the group consisting of the following:
7. The compound or salt of claim 1 , wherein R 4 is phenylethyl, R 2 is phenyl, R 3 is phenyl, and R 1 is selected from the group consisting of the following:
8. The compound or salt of claim 1 , wherein R 4 is selected from 4-aminosulfonylbenzyl, 4-trifluoromethoxybenzyl, 4-methoxybenzyl, and cyclopropylmethyl and wherein R 1 is selected from the following:
9. A pharmaceutical composition comprising a compound or salt of claim 1 and a pharmaceutically acceptable carrier.
10. A compound of formula (I):
wherein R 1 is selected from the group consisting of alkyl, hydroxyalkyl, thioalkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, hydroxycycloalkyl, hydroxycycloalkylalkyl, thiocycloalkyl, alkoxycycloalkyl, alkylthiocycloalkyl, dialkylaminoalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, arylalkyl, arylalkylpiperidin-4-yl, and arylpiperazinylalkyl,
R 2 is phenyl, optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, hydroxyalkyl, thioalkyl, alkoxy, alkylthioalkyl, alkoxycarbonyl, alkylthiocarbonyl, amino, alkylamino, dialkylamino, and alkylcarbonyl,
R 3 is phenyl, optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, hydroxyalkyl, thioalkyl, alkoxy, alkylthioalkyl, alkoxycarbonyl, alkylthiocarbonyl, amino, alkylamino, dialkylamino, and alkylcarbonyl,
R 4 is benzyl, wherein the phenyl ring is substituted with one or more substituents selected from ethyl, propyl, isopropyl, n-butyl, sec-isobutyl, tert-butyl, pentyl, isoamyl, hexyl, hydroxyalkyl, thioalkyl, alkoxy, alkylthioalkyl, alkoxycarbonyl, alkylthiocarbonyl, amino, alkylamino, dialkylamino, aminosulfonyl, hydroxyl, perfluoroalkoxy, and alkylcarbonyl,
or a pharmaceutically acceptable salt thereof,
wherein R 1 is optionally substituted on the aryl and/or alkyl portion with one or more substituents selected from the group consisting of halo, alkyl, hydroxyalkyl, thioalkyl, alkoxy, alkylthioalkyl, alkoxycarbonyl, alkylthiocarbonyl, amino, alkylamino, dialkylamino, aminosulfonyl, hydroxyl, perfluoroalkoxy, alkylenedioxy, and alkylcarbonyl.
11. The compound or salt of claim 1 , wherein R 4 is benzyl, wherein the phenyl ring is optionally substituted with one or more substituents selected from the group consisting of ethyl, propyl, isopropyl, n-butyl, sec-isobutyl, tert-butyl, pentyl, isoamyl, hexyl, hydroxyalkyl, thioalkyl, alkoxy, alkylthioalkyl, alkoxycarbonyl, alkylthiocarbonyl, amino, alkylamino, dialkylamino, aminosulfonyl, hydroxyl, perfluoroalkoxy, and alkylcarbonyl.
12. The compound or salt of claim 10 , wherein R 1 is a 5 or 6-membered heterocyclyl group having at least one hetero atom selected from the group consisting of O, N, and S; a hydroxy C 3 -C 7 cycloalkyl group; a hydroxy C 1 -C 6 alkyl group; a N,N-di(C 1 -C 6 alkyl)amino C 1 -C 6 alkyl group; a C 1 -C 6 alkoxy C 1 -C 6 alkyl group; a heterocyclyl C 1 -C 6 alkyl group; phenyl C 1 -C 6 alkyl group where the phenyl ring is substituted with one or more C 1 -C 6 alkoxy groups; N-benzyl piperadinyl; N-phenyl piperazinylalkyl; or a phenyl C 1 -C 6 alkyl group where the alkyl is substituted with a hydroxy group.
13. The compound or salt of claim 10 , wherein R 1 is selected from the group consisting of the following:
14. The compound or salt of claim 10 , wherein R 2 is phenyl, R 3 is phenyl, R 4 is substituted benzyl, and R 1 is selected from the group consisting of the following:
15. The compound or salt of claim 10 , wherein R 4 is 4-methoxybenzyl, R 2 is phenyl, R 3 is phenyl, and R 1 is selected from the group consisting of the following:
16. The compound or salt of claim 10 , wherein R 4 is selected from 4-aminosulfonylbenzyl, 4-trifluoromethoxybenzyl, and 4-methoxybenzyl and wherein R 1 is selected from the following:
17. A pharmaceutical composition comprising a compound or salt of claim 10 and a pharmaceutically acceptable carrier.
18. The compound or salt of claim 5 , wherein R 2 is phenyl, R 3 is phenyl, R 4 is benzyl, and R 1 is selected from the group consisting of the following:
19. The compound or salt of claim 18 , wherein R 2 is phenyl, R 3 is phenyl, R 4 is benzyl, and R 1 is: