Arsenoplatin anti-cancer agents

Patent metadata

Field	Value
Publication number	US-9725475-B2
Application number	US-201615291274-A
Country	US
Kind code	B2
Filing date	Oct 12, 2016
Priority date	Aug 14, 2012
Publication date	Aug 8, 2017
Grant date	Aug 8, 2017

Abstract

Disclosed herein are conjugates that include a ligand, and a compound having the structure of formula (I)

M is Pt, Pd or Ni; Q is As, Sb or Bi; Z 1 is N; Z 2 is O or S; L 1 and L 2 are independently C(O), C—R 1 or C—R 2 ; X is a Lewis base; Y 1 and Y 2 are independently selected from —OR 3 , —OR 4 , —SR 3 and —SR 4 , wherein R 1 and R 2 are independently selected from hydrogen, halogen, cyano, keto, ester, ether, thiol, thioether, thioester, imino, C 1 -C 10 alkyl, C 1 -C 10 alkenyl, alkynyl, alkoxyl, amino, amidyl, immino, sulfonyl, sulfoxyl, phosphoryl, phosphoryl ester, glycosyl, aryl, C 3 -C 15 cycloalkyl, heteroaryl, and C 3 -C 15 heterocycloalkyl; and R 3 and R 4 are independently selected from hydrogen, C 1 -C 10 alkyl, C 1 -C 10 alkenyl, alkynyl, alkoxyl, amino, amidyl, immino, sulfonyl, sulfoxyl, phosphoryl, phosphoryl ester, glycosyl, aryl, C 3 -C 15 cycloalkyl, heteroaryl, and C 3 -C 15 heterocycloalkyl.

First claim

What is claimed is:

1. A conjugate comprising:
a ligand, and
a compound having the structure of formula (I)

wherein M is Pt, Pd or Ni; Q is As, Sb or Bi; Z 1 is N; Z 2 is O or S; L 1 and L 2 are independently C(O), C—R′ or C—R 2 ; X is a Lewis base; Y 1 and Y 2 are independently selected from —OR 3 , —SR 3 and —SR 4 , wherein R 1 and R 2 are independently selected from hydrogen, halogen, cyano, keto, ester, ether, thiol, thioether, thioester, imino, C 1 -C 10 alkyl, C 1 -C 10 alkenyl, alkynyl, alkoxyl, amino, amidyl, immino, sulfonyl, sulfoxyl, phosphoryl, phosphoryl ester, glycosyl, aryl, C 3 -C 15 cycloalkyl, heteroaryl, and C 3 -C 15 heterocycloalkyl;
wherein R 3 and R 4 are independently selected from hydrogen, C 1 -C 10 alkyl, C 1 -C 10 alkenyl, alkynyl, alkoxyl, amino, amidyl, immino, sulfonyl, sulfoxyl, phosphoryl, phosphoryl ester, glycosyl, aryl, C 3 -C 15 cycloalkyl, heteroaryl, and C 3 -C 15 heterocycloalkyl;
wherein the Lewis base can be halogen, N-bonded cyano, nitroso, nitroxyl, N-bonded C 1 -C 10 alkyl, alkenyl, N-bonded C 3 -C 10 cycloalkyl, N-bonded heteroalkyl, N-bonded C 1 -C 10 heteroalkenyl, N-bonded aryl, N-bonded heteroaryl, N-bonded C 3 -C 15 heterocycloalkyl, —NR 5 R 6 , N-bonded ligand, S-bonded cyano, sulfonyl, sulfoxyl, thiol, S-bonded thioether, S-bonded thioester, S-bonded C 1 -C 10 alkyl, C 1 -C 10 alkenyl, S-bonded C 3 -C 10 cycloalkyl, S-bonded C 1 -C 10 heteroalkyl, S-bonded C 1 -C 10 heteroalkenyl, S-bonded aryl, S-bonded heteroaryl, S-bonded C 3 -C 15 heterocycloalkyl, —SR 5 , S-bonded ligand, O-bonded C 3 -C 10 cycloalkyl, O-bonded C 1 -C 10 heteroalkyl, O-bonded C 1 -C 10 heteroalkenyl, O-bonded aryl, O-bonded heteroaryl, O-bonded C 3 -C 15 heterocycloalkyl, —OR 5 , O-bonded carboxylato, O-bonded polycarboxylato, O-bonded ligand, or P-bonded phosphine having formula P(R 7 ) 3-x (R 8 ) x , where x is 0, 1, 2 or 3;
wherein R 5 and R 6 are independently selected from hydrogen, O, —CO 2 R 9 , —COR 9 , C 1 -C 10 alkyl, C 1 -C 10 alkenyl, aryl, heteroaryl, C 3 -C 15 cycloalkyl and C 3 -C 15 heterocycloalkyl;
wherein R 7 and R 8 are independently selected from C 1 -C 10 alkyl, C 1 -C 10 alkenyl, aryl, heteroaryl, C 3 -C 15 cycloalkyl and C 3 -C 15 heterocycloalkyl; and
wherein R 9 is selected from hydrogen, hydroxyl, halogen, amine, thiol, ether, C 1 -C 10 alkyl, C 1 -C 10 alkenyl, aryl, heteroaryl, C 3 -C 15 cycloalkyl and C 3 -C 15 heterocycloalkyl.

2. The conjugate of claim 1 , wherein the ligand is selected from the group consisting of an amino acid, a peptide, a protein, a glycan, a peptidoglycan, a polysaccharide, a biologically-compatible polymer and an oligonucleotide.

3. The conjugate of claim 1 , wherein the ligand is specific for a cancer cell type.

4. The conjugate of claim 1 , wherein the ligand is selected from the group consisting of an N-bonded ligand, an S-bonded ligand, O-bonded ligand and a P-bonded ligand.

5. The conjugate of claim 1 , wherein the compound has the structure of formula (II):

wherein M is Pt, Pd or Ni; Q is As, Sb or Bi; X is a Lewis base;
wherein R 1 and R 2 are independently selected from hydrogen, halogen, cyano, keto, ester, ether, thiol, thioether, thioester, imino, C 1 -C 10 alkyl, C 1 -C 10 alkenyl, alkynyl, alkoxyl, amino, amidyl, immino, sulfonyl, sulfoxyl, phosphoryl, phosphoryl ester, glycosyl, aryl, C 3 -C 15 cycloalkyl, heteroaryl, and C 3 -C 15 heterocycloalkyl;
wherein R 3 and R 4 are independently selected from hydrogen, C 1 -C 10 alkyl, C 1 -C 10 alkenyl, alkynyl, alkoxyl, amino, amidyl, immino, sulfonyl, sulfoxyl, phosphoryl, phosphoryl ester, glycosyl, aryl, C 3 -C 15 cycloalkyl, heteroaryl and C 3 -C 15 heterocycloalkyl;
wherein the Lewis base can be halogen, N-bonded cyano, nitroso, nitroxyl, N-bonded C 1 -C 10 alkyl, C 1 -C 10 alkenyl, N-bonded C 3 -C 10 cycloalkyl, N-bonded heteroalkyl, N-bonded C 1 -C 10 heteroalkenyl, N-bonded aryl, N-bonded heteroaryl, N-bonded C 3 -C 15 heterocycloalkyl, —NR 5 R 6 , N-bonded ligand, S-bonded cyano, sulfonyl, sulfoxyl, thiol, S-bonded thioether, S-bonded thioester, S-bonded C 1 -C 10 alkyl, C 1 -C 10 alkenyl, S-bonded C 3 -C 10 cycloalkyl, S-bonded C 1 -C 10 heteroalkyl, S-bonded C 1 -C 10 heteroalkenyl, S-bonded aryl, S-bonded heteroaryl, S-bonded C 3 -C 15 heterocycloalkyl, —SR 5 , S-bonded ligand, O-bonded C 3 -C 10 cycloalkyl, O-bonded C 1 -C 10 heteroalkyl, O-bonded C 1 -C 10 heteroalkenyl, O-bonded aryl, O-bonded heteroaryl, O-bonded C 3 -C 15 heterocycloalkyl, —OR 5 , O-bonded carboxylato, O-bonded polycarboxylato, O-bonded ligand, or P-bonded phosphine having formula P(R 7 ) 3-x (R 8 ) x , where x is 0, 1, 2 or 3;
wherein R 5 and R 6 are independently selected from hydrogen, O, —CO 2 R 9 , C 1 -C 10 alkyl, C 1 -C 10 alkenyl, aryl, heteroaryl, C 3 -C 15 cycloalkyl and C 3 -C 15 heterocycloalkyl;
wherein R 7 and R 8 are independently selected from C 1 -C 10 alkyl, C 1 -C 10 alkenyl, aryl, heteroaryl, C 3 -C 15 cycloalkyl and C 3 -C 15 heterocycloalkyl; and
wherein R 9 is selected from hydrogen, hydroxyl, halogen, amine, thiol, ether, C 1 -C 10 alkyl, C 1 -C 10 alkenyl, aryl, heteroaryl, C 3 -C 15 cycloalkyl and C 3 -C 15 heterocycloalkyl.

6. The conjugate of claim 1 , wherein the compound has the structure of formula (VI):

wherein M is Pt, Pd or Ni; Q is As or Sb; X is a Lewis base;
wherein R 1 and R 2 are independently selected from hydrogen, halogen, cyano, keto, ester, ether, thiol, thioether, thioester, imino, C 1 -C 10 alkyl, C 1 -C 10 alkenyl, alkynyl, alkoxyl, amino, amidyl, immino, sulfonyl, sulfoxyl, phosphoryl, phosphoryl ester, glycosyl, aryl, C 3 -C 15 cycloalkyl, heteroaryl, and C 3 -C 15 heterocycloalkyl; and
wherein the Lewis base can be halogen, N-bonded cyano, nitroso, nitroxyl, N-bonded C 1 -C 10 alkyl, C 1 -C 10 alkenyl, N-bonded C 3 -C 10 cycloalkyl, N-bonded heteroalkyl, N-bonded C 1 -C 10 heteroalkenyl, N-bonded aryl, N-bonded heteroaryl, N-bonded C 3 -C 15 heterocycloalkyl, —NR 5 R 6 , N-bonded ligand, S-bonded cyano, sulfonyl, sulfoxyl, thiol, S-bonded thioether, S-bonded thioester, S-bonded C 1 -C 10 alkyl, C 1 -C 10 alkenyl, S-bonded C 3 -C 10 cycloalkyl, S-bonded C 1 -C 10 heteroalkyl, S-bonded C 1 -C 10 heteroalkenyl, S-bonded aryl, S-bonded heteroaryl, S-bonded C 3 -C 15 heterocycloalkyl, —SR 5 , S-bonded ligand, O-bonded C 3 -C 10 cycloalkyl, O-bonded C 1 -C 10 heteroalkyl, O-bonded C 1 -C 10 heteroalkenyl, O-bonded aryl, O-bonded heteroaryl, O-bonded C 3 -C 15 heterocycloalkyl, —OR 5 , O-bonded carboxylato, O-bonded polycarboxylato, O-bonded ligand, or P-bonded phosphine having formula P(R 7 ) 3-x (R 8 ) x , where x is 0, 1, 2 or 3;
wherein R 5 and R 6 are independently selected from hydrogen, O, —CO 2 R 9 , C 1 -C 10 alkyl, C 1 -C 10 alkenyl, aryl, heteroaryl, C 3 -C 15 cycloalkyl and C 3 -C 15 heterocycloalkyl;
wherein R 7 and R 8 are independently selected from C 1 -C 10 alkyl, C 1 -C 10 alkenyl, aryl, heteroaryl, C 3 -C 15 cycloalkyl and C 3 -C 15 heterocycloalkyl; and
wherein R 9 is selected from hydrogen, hydroxyl, halogen, amine, thiol, ether, C 1 -C 10 alkyl, C 1 -C 10 alkenyl, aryl, heteroaryl, C 3 -C 15 cycloalkyl and C 3 -C 15 heterocycloalkyl.

7. The conjugate of claim 6 , wherein the compound is selected from the group cons

Assignees

• Univ Northwestern

Inventors

• Miodragovic Denana U
• O'Halloran Thomas V

Classifications

• C07F15/0066

  without a metal-carbon linkage · CPC title

• C07F15/045

  without a metal-carbon linkage · CPC title

• C07F15/0013 Primary

  without a metal-carbon linkage · CPC title

• C07F15/0093

  without a metal-carbon linkage · CPC title

• A61K31/285

  Arsenic compounds · CPC title