PLATINUM COMPOUNDS, COMPOSITIONS AND METHODS FOR THE TREATMENT OF CANCER
The present disclosure relates to novel pharmaceutical compositions comprising a nanoparticle associated with, tether to, or encapsulating a platinum-based active pharmaceutical agent. The platinum-based drug is released from the nanoparticles in a controlled fashion. Also contemplated are methods of making the nanoparticles, as well as methods for using them in the treatment or prevention of diseases or conditions. One embodiment relates to phenanthriplatin nanoparticles and methods of using and making the same.
1 . A compound of Formula I:
wherein:
X is a halide, sulfonate, sulfate, phosphate, or carboxylate such as stearate;
L each is independently ammonia or an amine;
Y is selected from N, P, and S;
A together with Y form a heteroaromatic optionally substituted with one or more substituents 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; and
Z is a pharmaceutically acceptable counter ion.
2 . The compound of claim 1 , wherein X is a halogen.
3 . The compound of claim 1 or claim 2 , wherein X is Cl.
4 . The compound of claim 1 , wherein X is —O(C═O)R a and R a is hydrogen, alkyl, aryl, arylalkyl, or cycloalkyl, wherein each of the alkyl, aryl, arylalkyl, and cycloalkyl is optionally substituted with one or more suitable substituents.
5 . The compound of claim 1 , wherein X is formyl, acetate, propionate, butyrate, benzoate, or tosylate.
6 . The compound of any one of claims 1 to 5 , wherein L each is ammonia.
7 . The compound of any one of claims 1 to 5 , wherein at least one L is an amine.
8 . The compound of any one of claims 1 to 7 , wherein Y is N.
9 . The compound of any one of claims 1 to 8 , wherein the heteroaromatic is a monocyclic heteroaromatic, a bicyclic heteroaromatic, or a tricyclic heteroaromatic.
10 . The compound of any one of claims 1 to 9 having Formula III or Formula IV:
wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 each is independently selected from a group consisting of hydrogen, 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; or optionally, two adjacent substituents selected from R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are connected to form an optionally substituted 5 or 6-membered ring.
11 . The compound of claim 10 , wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 each is independently selected from a group consisting of hydrogen, halogen, and aryl.
12 . The compound of any one of claims 1 to 11 has Formula Ma:
wherein R 4 is selected from a group consisting of hydrogen, 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.
13 . The compound of claim 12 , wherein R 4 is halogen or aryl.
14 . The compound of any one of claims 1 to 11 having Formula Mb:
wherein R 2 is selected from a group consisting of hydrogen, 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.
15 . The compound of claim 14 , wherein R 2 is halogen or aryl.
16 . The compound of any one of claims 1 to 11 having Formula IIIc:
wherein R 7 is selected from a group consisting of hydrogen, 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.
17 . The compound of claim 16 , wherein R 7 is halogen or aryl.
18 . The compound of any one of claims 1 to 11 having Formula IIId:
wherein R 2 and R 7 are connected to form an optionally substituted 5 or 6-membered ring selected from a group consisting of cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of the cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more suitable substituents.
19 . The compound of claim 18 , wherein R 2 and R 7 are connected to form an optionally substituted cycloalkyl.
20 . The compound of any one of claims 1 to 11 having Formula IVa:
wherein R 2 is selected from a group consisting of hydrogen, 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.
21 . The compound of claim 20 , wherein R 2 is halogen or aryl.
22 . The compound of any one of claims 1 to 11 having Formula IVb:
wherein R 1 and R 2 are connected to form an optionally substituted 5 or 6-membered ring selected from a group consisting of cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of the cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more suitable substituents.
23 . The compound of claim 22 , wherein R 1 and R 2 are connected to form an optionally substituted cycloalkyl.
24 . The compound of any one of claims 1 to 9 having Formula V:
wherein R 1 , R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , R 10 , and R 11 each is independently selected from a group consisting of hydrogen, 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; or optionally, two adjacent substituents selected from R 1 , R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , R 10 , and R 11 are connected to form an optionally substituted 5 or 6-membered ring.
25 . A compound of Formula II,
or a salt thereof,
X is a halide, sulfonate, sulfate, phosphate, or carboxylate such as stearate;
L each is independently ammonia or an amine;
Y is selected from N, P, and S;
A together with Y form a heteroaromatic optionally substituted with one or more substituents 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;
Z is a pharmaceutically acceptable counter ion;
and R 1 and R 2 individually is a hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroalkyl, carbamoyl, and carbonyl, each optionally substituted, or are absent.
26 . A compound selected from a group consisting of:
27 . A pharmaceutical composition comprising a compound from any one of claims 1 to 26 .
28 . A method of treating cancer selected from a group consisting of lung cancer, breast cancer, colorectal cancer, ovarian cancer, bladder cancer, prostate cancer, cervical cancer, renal cancer, leukemia, central nerve system cancers, myeloma, and melanoma, comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 26 .
29 . A nanoparticle and/or microparticle comprising a compound of any one of claims 1 to 26 .
30 . The nanoparticle and/or microparticle of claim 29 , wherein the compound is phenanthriplatin.