Inhibitors of creatine transport and uses thereof
This invention relates to compounds that inhibit creatine transport and/or creatine kinase, pharmaceutical compositions including such compounds, and methods of utilizing such compounds and compositions for the treatment of cancer.
1. A method for treating gastrointestinal cancer, comprising administering to a subject in need thereof, a compound having the structure:
wherein Q 1 is optionally substituted amidino;
m is 1 or 2;
R 7 is hydrogen, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl;
R 8 and R 9 are independently hydrogen, deuterium, halo, hydroxyl, NH 2 , optionally substituted C 1 -C 3 alkyl, or R 8 and R 9 combine with the atoms to which they are attached to form an optionally substituted C 3 -C 6 cycloalkyl ring; or R 8 or R 9 combine with R 10 or R 11 with the atoms to which they are attached to form an optionally substituted C 3 -C 4 cycloalkyl ring; or R 8 or R 9 combine with R 12 with the atoms to which they are attached to form an optionally substituted C 3 -C 5 heterocycle;
R 10 and R 11 are independently hydrogen, deuterium, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl or R 10 and R 11 combine with the atoms to which they are attached to form an optionally substituted C 3 -C 6 cycloalkyl ring; or R 10 or R 11 combine with R 8 or R 9 with the atoms to which they are attached to form an optionally substituted C 3 -C 4 cycloalkyl ring; or R 10 or R 11 combine with R 12 with the atoms to which they are attached to form an optionally substituted C 3 -C 4 heterocycle;
R 12 is hydrogen, C 1 -C 6 alkyl, or R 12 combines with R 8 or R 9 with the atoms to which they are attached to form an optionally substituted C 3 -C 5 heterocycle, or R 12 combines with R 10 or R 11 with the atoms to which they are attached to form an optionally substituted C 3 -C 4 heterocycle;
or a pharmaceutically acceptable salt thereof,
in an amount sufficient to treat said gastrointestinal cancer.
2. A method of slowing the spread of gastrointestinal cancer, comprising administering to a subject in need thereof, a compound having the structure:
wherein Q 1 is optionally substituted amidino;
m is 1 or 2;
R 7 is hydrogen, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 5 -C 10 aryl C 1 -C 6 alkyl;
R 8 and R 9 are independently hydrogen, deuterium, halo, hydroxyl, NH 2 , optionally substituted C 1 -C 3 alkyl, or R 8 and R 9 combine with the atoms to which they are attached to form an optionally substituted C 3 -C 6 cycloalkyl ring; or R 8 or R 9 combine with R 10 or R 11 with the atoms to which they are attached to form an optionally substituted C 3 -C 4 cycloalkyl ring; or R 8 or R 9 combine with R 12 with the atoms to which they are attached to form an optionally substituted C 3 -C 5 heterocycle;
R 10 and R 11 are independently hydrogen, deuterium, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl or R 10 and R 11 combine with the atoms to which they are attached to form an optionally substituted C 3 -C 6 cycloalkyl ring; or R 10 or R 11 combine with R 8 or R 9 with the atoms to which they are attached to form an optionally substituted C 3 -C 4 cycloalkyl ring; or R 10 or R 11 combine with R 12 with the atoms to which they are attached to form an optionally substituted C 3 -C 4 heterocycle;
R 12 is hydrogen, C 1 -C 5 alkyl, or R 12 combines with R 8 or R 9 with the atoms to which they are attached to form an optionally substituted C 3 -C 5 heterocycle, or R 12 combines with R 10 or R 11 with the atoms to which they are attached to form an optionally substituted C 3 -C 4 heterocycle;
or a pharmaceutically acceptable salt thereof,
in an amount sufficient to slow the spread of said gastrointestinal cancer.
3. The method of claim 2 , wherein said method comprises the suppression of metastatic colonization of said gastrointestinal cancer in the liver.
4. The method of claim 2 , wherein said gastrointestinal cancer is metastatic gastrointestinal cancer.
5. The method of claim 4 , wherein the metastatic gastrointestinal cancer comprises cells exhibiting migration and/or invasion of migrating cells.
6. The method of claim 4 , wherein said metastatic gastrointestinal cancer comprises cells exhibiting endothelial recruitment and/or angiogenesis.
7. The method of claim 2 , wherein said gastrointestinal cancer spreads via seeding the surface of the peritoneal, pleural, pericardial, or subarachnoid spaces.
8. The method of claim 2 , wherein said gastrointestinal cancer spreads via the lymphatic system.
9. The method of claim 2 , wherein said gastrointestinal cancer spreads hematogenously.
10. The method of claim 1 , wherein said gastrointestinal cancer is a drug resistant gastrointestinal cancer.
11. The method of claim 1 further comprising administering an additional antiproliferative agent.
12. The method of claim 11 , wherein said additional antiproliferative agent is capecitabine, gemcitabine, fluorouracil, FOLFOX (5-FU, leucovorin, and Eloxatin), FOLFIRI (5-FU, leucovorin, and Camptosar), EOX (Epirubicin, Oxaliplatinum, and Xeloda), Taxotere, Erbitux, Zaltrap, Vectibix, Ramucirumab, Tivozanib, Stivarga, CRS-207, or a PD-1 or PDL-1 antibody.
13. A method of treating metastatic gastrointestinal cancer in a subject in need thereof comprising:
(a) providing a subject identified as expressing CKB and/or SLC6a8; and
(b) administering to said subject an effective amount of a compound having the structure:
wherein Q 1 is optionally substituted amidino;
m is 1 or 2;
R 7 is hydrogen, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl;
R 8 and R 9 are independently hydrogen, deuterium, halo, hydroxyl, NH 2 , optionally substituted C 1 -C 3 alkyl, or R 8 and R 9 combine with the atoms to which they are attached to form an optionally substituted C 3 -C 6 cycloalkyl ring; or R 8 or R 9 combine with R 10 or R 11 with the atoms to which they are attached to form an optionally substituted C 3 -C 4 cycloalkyl ring; or R 8 or R 9 combine with R 12 with the atoms to which they are attached to form an optionally substituted C 3 -C 5 heterocycle;
R 10 and R 11 are independently hydrogen, deuterium, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl or R 10 and R 11 combine with the atoms to which they are attached to form an optionally substituted C 3 -C 6 cycloalkyl ring; or R 10 or R 11 combine with R 8 or R 9 with the atoms to which they are attached to form an optionally substituted C 3 -C 4 cycloalkyl ring; or R 10 or R 11 combine with R 12 with the atoms to which they are attached to form an optionally substituted C 3 -C 4 heterocycle;
R 12 is hydrogen, C 1 -C 6 alkyl, or R 12 combines with R 8 or R 9 with the atoms to which they are attached to form an optionally substituted C 3 -C 5 heterocycle, or R 12 combines with R 10 or R 11 with the atoms to which they are attached to form an optionally substituted C 3 -C 4 heterocycle;
or a pharmaceutically acceptable salt thereof.
14. A method for treating metastatic gastrointestinal cancer in a subject in need thereof, comprising contacting creatine transport channel SLC6a8 with a compound having the structure:
wherein Q 1 is optionally substituted amidino;
m is 1 or 2;
R 7 is hydrogen, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl;
R 8 and R 9 are independently hydrogen, deuterium, halo, hydroxyl, NH 2 , optionally substituted C 1 -C 3 alkyl, or R 8 and R 9 combine with the atoms to which they are attached to form an optionally substituted C 3 -C 6 cycloalkyl ring; or R 8 or R 9 combine with R 10 or R 11 with the atoms to which they are attached to form an optionally substituted C 3 -C 4 cycloalkyl ring; or R 8 or R 9 combine with R 12 with the atoms to which they are attached to form an optionally substituted C 3 -C 5 heterocycle;
R 10 and R 11 are independently hydrogen, deuterium, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl or R 10 and R 11 combine with the atoms to which they are attached to form an optionally substituted C 3 -C 6 cycloalkyl ring; or R 10 or R 11 combine with R 8 or R 9 with the atoms to which they are attached to form an optionally substituted C 3 -C 4 cycloalkyl ring; or R 10 or R 11 combine with R 12 with the atoms to which they are attached to form an optionally substituted C 3 -C 4 heterocycle;
R 12 is hydrogen, C 1 -C 6 alkyl, or R 12 combines with R 8 or R 9 with the atoms to which they are attached to form an optionally substituted C 3 -C 5 heterocycle, or R 12 combines with R 10 or R 11 with the atoms to which they are attached to form an optionally substituted C 3 -C 4 heterocycle;
or a pharmaceutically acceptable salt thereof,
in an amount effective to suppress metastatic colonization of said gastrointestinal cancer.