Fucosidase inhibitors
View Patent ↗The present disclosure relates, in general, to compounds useful as inhibitors of fucosidase enzymes, and to methods and compositions for the treatment of tumors or cancers, such as liver disorders and liver tumors (e.g., hepatocellular carcinoma), with a compound as disclosed herein.
1. A compound of formula I:
wherein:
X 1 , X 2 , and X 3 are independently selected from the group consisting of OH, halo, and O(C)OCH 3 ;
R is selected from the group consisting of C 1-3 alkyl and C 1-3 haloalkyl;
R 1 is selected from the group consisting of H, C 1-3 alkyl, OH, —CO 2 C 1-3 alkyl;
R 2 is selected from the group consisting of —NR b C(O)R a , —NR b C(O)OR a , —NR b C(O)NR c R a , —NR b C(O)SR a , —C(O)R a , and —C(O)NR b R a ;
R a is —C 0-3 alkylene-G;
G is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; and
R b and R c are independently selected from the group consisting of H and C 1-3 alkyl.
2. The compound of claim 1 , wherein X 1 , X 2 , and X 3 are OH, R is methyl, and/or R 1 is H.
3. The compound of claim 1 , wherein R 2 is —NR b C(O)R a or —C(O)NR b R a .
4. The compound of claim 1 , wherein G is selected from the group consisting of optionally substituted indolyl, benzothiophenyl, fluorenyl, indenyl, dihydro indenyl, and phenyl.
5. The compound of claim 1 , wherein G is selected from the group consisting of optionally substituted phenyl and
wherein A is a 5-, 6-, 7-, 8-, 9-, or 10-membered carbocyclic or heterocyclic ring system.
6. The compound of claim 1 , wherein G is selected from the group consisting of
R d and R e are independently selected from the group consisting of H, OR f , NR f R g , C 1-3 alkyl, and C 1-5 cycloalkyl; or
R d and R e taken together with the carbon atom to which they are attached form C═O;
R f and R g are independently selected from the group consisting of H and C 1-3 alkyl; and
Y is selected from the group consisting of NH, N—C 1-3 alkyl, S, SO, SO 2 , and O.
7. The compound of claim 1 , wherein G is selected from the group consisting of
8. The compound of claim 1 , wherein R a is selected from the group consisting of
9. The compound of claim 1 , wherein the compound of formula I has the following structure:
10. The compound of claim 1 , wherein the compound is selected from the group consisting of:
11. A method for treating a tumor or cancer in a subject in need thereof comprising administering the compound of claim 1 , compound II, or compound III, in a therapeutically effective amount:
wherein the tumor or cancer is liver cancer, breast cancer, melanoma, lung cancer, leukemia, pancreatic cancer, gastric cancer, colorectal cancer, and head and neck cancer.
12. The method of claim 11 , wherein the compound reduces tumor metastasis in a subject, the treatment results in a decrease in tumor size in the subject, and/or the treatment results in a reduction of alpha-fetoprotein levels in blood of the subject compared to levels before treatment.
13. The method of claim 11 , wherein the tumor is a result of hepatocellular carcinoma, hepatitis virus infection, cirrhosis, toxic liver damage, and hereditary hemochromatosis.
14. The method of claim 11 , wherein the compound is administered intravenously.
15. The method of claim 11 , wherein the compound is administered in combination with a second agent.
16. The method of claim 15 , wherein the second agent is a chemotherapeutic agent selected from the group consisting of doxorubicin and 5-fluorouracil.
17. The method of claim 15 , wherein the second agent is a cytotoxic agent.
18. The method of claim 15 , wherein the second agent is a radioisotope.
19. The method of claim 15 , wherein the tumor is associated with hepatitis virus infection, and the second agent is an antiviral agent.
20. The method of claim 14 , wherein the compound is administered via the hepatic artery.
21. The method of claim 15 , wherein the second agent is selected from the group consisting of a chemotherapeutic agent, a cytotoxic agent, a radioisotope, an anti-viral agent, an anti-fungal agent, an anti-inflammatory agent and an antibody.
22. The method of claim 17 , wherein the cytotoxic agent is selected from the group consisting of mechlorethamine hydrochloride, cyclophosphamide, ifosfamide, chlorambucil, melphalan, busulfan, thiotepa, carmustine, lomustine, dacarbazine and streptozocin.
23. The method of claim 18 , wherein the radioisotope is selected from the group consisting of 131 I, 125 I, 111 In, 90 Y, 67 Cu, 127 Lu, 212 Bi, 213 Bi, 255 Fm, 149 Tb, 223 Rd, 213 Pb, 212 Pb, 211 At, 89 Sr, 153 Sm, 166 Ho, 225 Ac, 186 Re, 67 Ga, 68 Ga and 99m Tc.
24. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.