COMPOUNDS, COMPOSITIONS, AND METHODS FOR THE TREATMENT OF CANCERS
The present teachings relate to compounds and compositions for treatment of cancers. In some embodiments, the composition comprises a platinum (IV) complex having at least one carboxylate or carbamate ligand.
1 . A compound of Formula I,
or a pharmaceutically acceptable salt thereof,
wherein:
two of R 1 , R 2 , R 3 , and R 4 each is a halide;
the remaining two of R 1 , R 2 , R 3 , and R 4 each is independently ammonia or an amine; and
R 5 and R 6 each independently is hydrogen, R 7 , or
wherein:
X is absent, C(R 8 ) 2 , O, S, or NR 8 , and
R 7 and R 8 independently at each occurrence is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups optionally is substituted with one or more groups, each independently selected from halogen, cyano, nitro, hydroxyl, ester, ether, alkoxy, aryloxy, amino, amide, carbamate, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heterocyclyl, phosphono, phosphate, sulfide, sulfinyl, sulfino, sulfonyl, sulfo, and sulfonamide, wherein each of the ester, ether, alkoxy, aryloxy, amino, amide, carbamate, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heterocyclyl, phosphono, phosphate, sulfide, sulfinyl, sulfino, sulfonyl, sulfo, and sulfonamide is optionally substituted with one or more suitable substituents.
2 . The compound of claim 1 , wherein two of R 1 , R 2 , R 3 , and R 4 each is a halide.
3 . The compound of claim 1 , wherein two of R 1 , R 2 , R 3 , and R 4 each is Cl.
4 . The compound of claim 1 , wherein the remaining two of R 1 , R 2 , R 3 , and R 4 each is ammonia.
5 . The compound of claim 1 , wherein at least one of the remaining two of R 1 , R 2 , R 3 , and R 4 is an amine.
6 . The compound of claim 1 , wherein the remaining two of R 1 , R 2 , R 3 , and R 4 joined together form a diamine.
7 . The compound of claim 1 , wherein the remaining two of R 1 , R 2 , R 3 , and R 4 joined together form cyclohexane-1,2-diamine.
8 . The compound of claim 1 , wherein at least one of R 5 and R 6 is
and X is C(R 8 ) 2 .
9 . The compound of claim 1 , wherein R 5 and R 6 are different.
10 . The compound of claim 1 , wherein at least one of R 5 and R 6 is
and X is NR 8 .
11 . The compound of claim 1 , wherein R 7 is alkyl or cycloalkyl.
12 . The compound of claim 1 , wherein R 7 is alkyl optionally substituted with one or more groups each independently selected from halogen, hydroxyl, ester, alkoxy, aryloxy, amino, amide, aryl, arylalkyl, cycloalkyl, heteroaryl, and heterocyclyl, wherein each of ester, alkoxy, aryloxy, amino, amide, aryl, arylalkyl, cycloalkyl, heteroaryl, and heterocyclyl optionally is substituted with one or more suitable substituents.
13 . The compound of claim 12 , wherein R 7 is alkyl optionally substituted with one or more groups each independently selected from halogen, hydroxyl, alkoxy, aryloxy, arylalkoxy, amino, amide, and aryl, wherein each of alkoxy, aryloxy, arylalkoxy, amino, amide, and aryl optionally is substituted with one or more substituents, each independently selected from one or more suitable substituents.
14 . The compound of claim 13 , wherein R 7 is alkyl optionally substituted with one or more groups each independently selected from F, Cl, phenyl, benzyloxy, t-butylphenyl, amino, and bistrifluoromethylphenyl.
15 . The compound of claim 1 , wherein at least one of R 5 and R 6 is R 7 .
16 . The compound of claim 1 , wherein R 7 is a monocycloalkyl, a bicycloalkyl, or a tricycloalkyl.
17 . The compound of claim 16 , wherein R 7 is cycloheptyl, cyclooctyl, cyclopentyl, cyclodecanyl, cycloundecanyl, cyclododecanyl, or adamantyl.
18 . A compound selected from:
19 . A pharmaceutical composition comprising a compound according to claim 1 .
20 . The pharmaceutical composition of claim 19 comprising a particle.
21 . The pharmaceutical composition of claim 20 , wherein the particle comprises polyester.
22 . The pharmaceutical composition of claim 19 comprising a surfactant.
23 . The pharmaceutical composition of claim 19 comprising a lyoprotectant.
24 . The pharmaceutical composition of claim 19 , wherein less than 50% of the compound is released in the first hour.
25 . A method of treating cancer selected from lung cancer, breast cancer, colorectal cancer, ovarian cancer, bladder cancer, prostate cancer, cervical cancer, renal cancer, leukemia, central nervous system cancers, myeloma, and melanoma, comprising administering a therapeutically effective amount of a compound of claim 1 .
26 . A method of inhibiting proliferation of a cell comprising contacting the cell with an effective amount of a compound of claim 1 .
27 . The method of claim 26 , wherein the cell is a cancer cell.