Texaphyrin-Pt(IV) conjugates and compositions for use in overcoming platinum resistance

Patent metadata

Field	Value
Publication number	US-12472187-B2
Application number	US-202217807245-A
Country	US
Kind code	B2
Filing date	Jun 16, 2022
Priority date	Jun 11, 2014
Publication date	Nov 18, 2025
Grant date	Nov 18, 2025

Abstract

The present disclosure relates platinum(IV) and texaphyrin linked conjugates and compositions comprising a texaphyrin and a platinum(IV) agent. The present disclosure also provides pharmaceutical compositions of the conjugates and compositions. Also, provided herein are methods of using the instant compounds in the treatment of cancer such as a platinum resistant cancer.

First claim

What is claimed is:

1 . A compound of the formula:

wherein:
R 1 and R 2 are each independently selected from hydrogen, halo, hydroxy, amino, mercapto, alkoxy (C<12) , substituted alkoxy (C<12) , and

wherein n is 1-20 and R 3 is hydrogen, alkyl (C≤6) , substituted alkyl (C≤6) , or a platinum (IV) chelating group;
A 1 and A 2 are each independently selected from hydrogen, halo, hydroxy, alkyl (C≤12) , substituted alkyl (C≤12) , alkoxy (C<12) , substituted alkoxy (C<12) , and

wherein n is 1-20 and R 3 is hydrogen, alkyl (C≤6) , substituted alkyl (C≤6) , or a platinum (IV) chelating group;
Y 1 , Y 2 , Y 3 , and Y 4 are each independently selected from hydrogen, halo, alkyl (C≤12) , and substituted alkyl (C≤12) ;
X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are each independently selected from hydrogen, hydroxy, halo, amino, carboxy, nitro, cyano,
alkyl (C≤12) , alkenyl (C≤12) , aryl (C≤12) , and a substituted version of any of these groups, or
a platinum chelating group of the formula: -A 3 -X 7 -A 4 -R 4 , wherein A 3 and A 4 are each independently alkanediyl (C≤12) , alkoxydiyl (C≤12) , alkylaminodiyl (C≤12) , or a substituted version of any of these groups, X 7 is —NR 5 —, —C(O)NR 5 —, or —NR 5 C(O)—, wherein R 5 is hydrogen, alkyl (C≤12) , or substituted alkyl (C<12) , and R 4 is

wherein:
R 6 is amino, or carboxy;
L 3 , L 4 , and L 6 are each ligands independently selected from aqua, ammonia, halide, or hydroxide, or

L 3 and L 6 are taken together and are alkyldicarboxylate (C≤18) , aryldicarboxylate (C≤18) , or a substituted version of any either group;
L 5 is aqua, amino, nitrate, sulfate, halide, nitrate, sulfate, or hydroxide,
alkylamine (C≤12) , cycloalkylamine (C≤12) , dialkylamine (C≤18) , dicycloalkylamine (C≤18) , arylamine (C≤12) , diarylamine (C≤18) , heteroarene (C≤12) , alkylcarboxylate (C≤12) , arylcarboxylate (C≤12) , and a substituted version of any of these groups;
L 7 is amino or L 4 and L 7 are taken together and arc diaminocycloalkane (C≤12) , or substituted diaminocycloalkane (C≤12) ;

provided that at least one of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 is a platinum (IV) chelating group;
M is a trivalent lanthanide metal ion; and
L 1 and L 2 are each anionic ligands independently selected from fluoride, chloride, bromide, perchlorate, nitrate, sulfate, trifluoromethylsulfonate, acetate, and trifluoroacetate;
or a pharmaceutically acceptable salt thereof.

2 . The compound of claim 1 , wherein the formula is further defined as:

wherein:
R 1 and R 2 are each independently selected from hydroxy, alkoxy (C≤12) , substituted alkoxy (C≤12) , and

wherein n is 1-20 and R 3 is hydrogen, alkyl (C≤6) , or substituted alkyl (C≤6) ;
or a pharmaceutically acceptable salt thereof.

3 . The compound of claim 1 , wherein the formula is further defined as:

wherein:
o and p are each independently 1, 2, 3, 4, 5, or 6 or any range derivable therein;
X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are each independently selected from hydrogen, hydroxy, halo,
alkyl (C≤12) , substituted alkyl (C≤12) , and
a platinum chelating group of the formula: -A 3 -X 7 -A 4 -R 4 , wherein A 3 and A 4 are each independently alkanediyl (C≤12), alkoxydiyl (C≤12), or a substituted version of any of these groups, X 7 is —C(O)NR 5 —, or —NRSC(O)—, wherein R 5 is hydrogen, alkyl (C≤12) , or substituted alkyl (C≤12) , and R 4 is

wherein:
R 6 is
L 3 , L 4 , and L 6 are each ligands independently selected from ammonia, halide, or
L 3 and L 6 are taken together and are alkyldicarboxylate (C≤18) , aryldicarboxylate (C≤18) , or a substituted version of any either group;
L 5 is aqua, amino, nitrate, sulfate, halide, nitrate, sulfate, or hydroxide,
alkylamine (C≤12) , cycloalkylamine (C≤12) , dialkylamine (C≤18) , dicycloalkylamine (C≤18) , arylamine (C≤12) , diarylamine (C≤18) , heteroarene (C≤12) , alkylcarboxylate (C≤12) , arylcarboxylate (C≤12) , and a substituted version of any of these groups;
L 7 is amino or L 4 and Ly are taken together and are diaminocycloalkane (C≤12) , or substituted diaminocycloalkane (C≤12) ;

provided that at least one of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 is a platinum (IV) chelating group;
M is a trivalent lanthanide metal ion; and
L 1 and L 2 are each anionic ligands independently selected from nitrate, acetate, and trifluoroacetate;
or a pharmaceutically acceptable salt thereof.

4 . The compound of claim 1 , wherein R 2 is a platinum (IV) chelating group of the formula:

wherein: R 4 is as defined above.

5 . The compound of claim 1 , wherein R 4 is

6 . The compound of claim 5 , wherein R 6 is carboxy.

7 . The compound of claim 5 , wherein L 3 is halide.

8 . The compound of claim 5 , wherein L 6 is halide.

9 . The compound of claim 5 , wherein L 3 and L 6 are taken together and are alkyldicarboxylate (C≤18) .

10 . The compound of claim 5 , wherein L 7 is amino.

11 . The compound of claim 5 , wherein L 4 and L 7 are taken together and are diaminocycloalkane (C≤12) .

12 . The compound of claim 1 , wherein X 3 and X 4 are alkyl (C<12) or substituted alkyl (C<12) .

13 . The compound of claim 1 , wherein X 5 is a platinum (IV) chelating group or alkyl (C≤12) or substituted alkyl (C≤12) .

14 . The compound of claim 1 , wherein X 1 and X 6 is alkyl (C≤12) or substituted alkyl (C≤12) .

15 . The compound of claim 1 , wherein M is gadolinium.

16 . The compound of claim 1 , wherein L 1 or L 2 is acetate or nitrate.

17 . The compound of claim 1 further defined as:

or a pharmaceutically acceptable salt thereof.

18 . A pharmaceutical composition comprising:
(A) a pharmaceutically acceptable carrier; and (B) a compound of claim 1 .

19 . A method of treating a platinum resistant cancer in a patient comprising administering to the patient in need thereof a therapeutically effective amount of claim 1 .

20 . The method of claim 19 , wherein the cancer is colon cancer or colorectal cancer.

21 . The method of claim 19 , wherein

Assignees

• Univ Texas

Inventors

• Sessler Jonathan L
• Arambula Jonathan
• Siddik Zahid H
• Thiabaud Gregory

Classifications

• C07F15/0093

  without a metal-carbon linkage · CPC title

• C07D487/22 Primary

  in which the condensed system contains four or more hetero rings · CPC title

• A61K49/106

  the complex-forming compound being cyclic, e.g. DOTA · CPC title

• A61K49/10

  Organic compounds · CPC title

• A61K49/085

  conjugated systems · CPC title