Water-soluble salts of dna binding agents

Patent metadata

Field	Value
Publication number	US-2025009727-A1
Application number	US-202218710267-A
Country	US
Kind code	A1
Filing date	Nov 17, 2022
Priority date	Nov 17, 2021
Publication date	Jan 9, 2025
Grant date	—

Abstract

Provided herein are salts which intercalate into the DNA of a cell and are capable of crossing the blood brain barrier of the formula (I) wherein the variables are as defined herein. These salts may be show improved water solubility and/or aqueous stability than free base or other salts of these compounds. Pharmaceutical compositions of the compounds and methods of treating cancer, for example brain, lung, or pancreatic cancer, are also provided herein.

First claim

What is claimed is:

1 . A salt comprising a cation of the formula:

wherein:
X 1 , X 2 , X 3 , X 6 , and X 7 are each independently hydrogen, halo, hydroxy, carboxy, ester (C≤12) , substituted ester (C≤12) , alkoxy (C≤12) , or substituted alkoxy (C≤12) ;
X 4 is acyl (C≤18) or substituted acyl (C≤18) ;
X 5 is hydrogen, hydroxy, alkoxy (C≤12) , or substituted alkoxy (C≤12) ;
Y 1 , Y 2 , and Y 3 are each independently O, S, or NH;
A is O or S;
R 1 , R 1 ′, R 2 , R 2 ′, R 3 , and R 3 ′ are each independently hydrogen, amino, halo, hydroxy, mercapto, or
alkyl (C≤8) , alkoxy (C≤8) , alkylthio (C≤8) , alkylamino (C≤8) , dialkylamino (C≤8) , or a substituted version of any of these groups;

Y 4 is arenediyl (C≤12) or a substituted version thereof;
each X 8 is independently —X 9 -heteroarenediyl (C≤12) or substituted —X 9 -heteroarenediyl (C≤12) , wherein:
X 9 is —NHC(O)— or —C(O)NH—;

R 4 is —X 10 -heteroaryl (C≤12) or substituted —X 10 -heteroaryl (C≤12) , wherein:
X 10 is —NHC(O)— or —C(O)NH—;

m is 0, 1, 2, or 3; and
n is 1, 2, or 3,

or an anion, wherein the anion is not a chloride, provided that the anion can be one or more anions such that the total charge of the anion balances the charge of the cation, x.

2 . The salt of claim 1 , wherein the anion is selected from a halide except chloride, hydroxide, phosphate, sulfate, a thiolate containing compound, a sulfinate containing compound, a sulfate containing compound, or a carboxylate containing compound.

3 . The salt of either claim 1 or claim 2 , wherein the anion is a compound of the formula:
− OS(O) a R 5   (II)
wherein:
a is 0, 1, or 2; and
R 5 is alkyl (C≤8) , cycloalkyl (C≤8) , aryl (C≤8) , heteroaryl (C≤8) , heterocycloalkyl (C≤8) , or a substituted version of any of these groups.

4 . The salt according to any one of claims 1-3 , wherein the anion is a compound of the formula:
− OC(O)R 6   (III)
wherein:
R 6 is alkyl (C≤30) , cycloalkyl (C≤8) , alkenyl (C≤30) , aryl (C≤8) , heteroaryl (C≤8) , heterocycloalkyl (C≤8) , or a substituted version of any of these groups.

5 . The salt according to any one of claims 1-4 , wherein the anion is citrate, tartrate, hippurate, lactate, camsylate, acetate, phosphate, fumarate, maleate, sulfate, succinate, mesylate, tosylate, gluconate, glucuronate, malate, benzoate, besylate, isethionate, lauryl sulfate, napsylate, oleate, pamoate, bromide, iodide, or nitrate.

6 . The salt according to any one of claims 1-5 further defined by the formula:

wherein:
X 1 , X 2 , X 3 , X 6 , and X 7 are each independently hydrogen, halo, hydroxy, carboxy, ester (C≤12) , substituted ester (C≤12) , alkoxy (C≤12) , or substituted alkoxy (C≤12) ;
X 4 is acyl (C≤18) or substituted acyl (C≤12) ;
X 5 is hydrogen, hydroxy, alkoxy (C≤12) , or substituted alkoxy (C≤12) ;
Y 1 , Y 2 , and Y 3 are each independently O, S, or NH;
A is O or S;
R 1 , R 1 ′, R 2 , R 2 ′, R 3 , and R 3 ′ are each independently hydrogen, amino, halo, hydroxy, mercapto, or
alkyl (C≤8) , alkoxy (C≤8) , alkylthio (C≤8) , alkylamino (C≤8) , dialkylamino (C≤8) , or a substituted version of any of these groups;

Y 4 is arenediyl (C≤12) or a substituted version thereof,
each X 8 is independently —X 9 -heteroarenediyl (C≤12) or substituted —X 9 -heteroarenediyl (C≤12) , wherein:
X 9 is —NHC(O)— or —C(O)NH—;

R 4 is —X 10 -heteroaryl (C≤12) or substituted —X 10 -heteroaryl (C≤12) , wherein:
X 10 is —NHC(O)— or C(O)NH—;

R 5 is alkyl (C≤12) , aryl (C≤12) , or a substituted version of either group;
m is 0, 1, 2, or 3; and
n is 1, 2, or 3.

7 . The salt according to any one of claims 1-6 further defined as:

wherein:
X 4 is acyl (C≤18) or substituted acyl (C≤18) ;
X 5 is hydrogen, hydroxy, alkoxy (C≤12) , or substituted alkoxy (C≤12) ;
Y 3 is O, S, or NH;
A is O or S;
R 1 , R 1 ′, R 2 , R 2 ′, R 3 , and R 3 ′ are each independently hydrogen, amino, halo, hydroxy, mercapto, or
alkyl (C≤8) , alkoxy (C≤8) , alkylthio (C≤8) , alkylamino (C≤8) , dialkylamino (C≤8) , or a substituted version of any of these groups;

Y 4 is arenediyl (C≤12) , heteroarenediyl (C≤12) , or a substituted version of either of these groups;
each X 8 is independently —X 9 -heteroarenediyl (C≤12) or substituted —X 9 -heteroarenediyl (C≤12) , wherein:
X 9 is —NHC(O)— or —C(O)NH—;

R 4 is —X 10 -heteroaryl (C≤12) or substituted —X 10 -heteroaryl (C≤12) , wherein:
X 10 is —NHC(O)— or —C(O)NH—;

R 5 is alkyl (C≤12) , aryl (C≤12) , or a substituted version of either group;
m is 0, 1, 2, or 3; and
n is 1, 2, or 3;

or a pharmaceutically acceptable salt thereof.

8 . The salt according to any one of claims 1-7 further defined as:

wherein:
R 1 , R 1 ′, R 2 , R 2 ′, R 3 , and R 3 ′ are each independently hydrogen, amino, halo, hydroxy, mercapto, or
alkyl (C≤8) , alkoxy (C≤8) , alkylthio (C≤8) , alkylamino (C≤8) , dialkylamino (C≤8) , or a substituted version of any of these groups;

Y 4 is a covalent bond, arenediyl (C≤12) , heteroarenediyl (C≤12) , or a substituted version of either of these groups;
each X 8 is independently —X 9 -heteroarenediyl (C≤12) or substituted —X 9 -heteroarenediyl (C≤12) , wherein:
X 9 is —NHC(O)— or —C(O)NH—;

R 4 is —X 10 -heteroaryl (C≤12) or substituted —X 10 -heteroaryl (C≤12) , wherein:
X 10 is —NHC(O)— or —C(O)NH—;

R 5 is alkyl (C≤12) , aryl (C≤12) , or a substituted version of either group;
m is 0, 1, 2, or 3; and
n is 1, 2, or 3.

9 . The salt according to any one of claims 1-8 further defined as:

wherein:
Y 4 is a covalent bond, arenediyl (C≤12) , heteroarenediyl (C≤12) , or a substituted version of either of these groups;
each X 8 is independently —X 9 -heteroarenediyl (C≤12) or substituted —X 9 -heteroarenediyl (C≤12) , wherein:
X 9 is —NHC(O)— or —C(O)NH—;

R 4 is —X 10 -heteroaryl (C≤12) or substituted —X 10 -heteroaryl (C≤12) , wherein:
X 10 is —NHC(O)— or —C(O)NH—;

R 5 is alkyl (C≤12) , aryl (C≤12) , or a substituted version of either group;
m is 0, 1, 2, or 3; and
n is 1, 2, or 3.

10 . The salt according to any one of claims 1-6 , wherein X 7 is alkoxy (C≤12) or substituted alkoxy (C≤12) .

11 . The salt of claim 10 , wherein X 7 is methoxy.

12 . The salt according to any one of claims 1-6 , wherein X 7 is halo.

13 . The salt of claim 12 , wherein X 7 is fluoro.

14 . The salt according to any one of claims 1-7 , wherein X 4 is acyl (C≤18) or substituted acyl (C≤18) .

15 . The salt of claim 14 , wherein X 4 is acyl (C≤8) .

16 . The salt of claim 15 , wherein X 4 is —C(O)CH 3 .

17 . The salt of claim 14 , wherein X 4 is substituted acyl (C≤8) .

18 . The salt of claim 17 , wherein X 4 is —C(O)CH 2 OH.

19 . The salt according to any one of claims 1-8 and 10-18 , wherein R 1 is alkyl (C≤8) .

20 . The salt of claim 19 , wherein R 1 is methyl.

21 . The salt according

Assignees

• Univ Texas

Inventors

• Priebe Waldemar
• Skora Stanislaw
• Fokt Izabela
• Zielinski Rafal

Classifications

• C07D405/14

  containing three or more hetero rings · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/351

  not condensed with another ring · CPC title

• A61K31/4439 Primary

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title