Temozolomide compounds, polymers prepared therefrom, and method of treating a disease

Patent metadata

Field	Value
Publication number	US-11912709-B2
Application number	US-202117188162-A
Country	US
Kind code	B2
Filing date	Mar 1, 2021
Priority date	Sep 22, 2016
Publication date	Feb 27, 2024
Grant date	Feb 27, 2024

Abstract

A temozolomide compound according to formula (I)

is described, wherein R 1 , L 1 , and X are defined herein. The temozolomide compound can be used to prepare polymers comprising temozolomide. Additionally, the polymers comprising temozolomide can be particularly useful in the treatment of certain diseases.

First claim

The invention claimed is:

1. A temozolomide compound of structure (I)

wherein
X is —O— or —NR a —, wherein R a is hydrogen or a C 1-6 alkyl group;
L 1 is a divalent C 1-12 alkylene group, di(C 2-12 alkylene) disulfide group, C 2-12 alkylene ester group, C 6-20 arylene group, C 1-20 alkylene oxide group, or C 1-12 alkylene sulfide group;
n is 0 or 1; and
R 1 is a pentafluorophenyl group, a pyridyl disulfide group, a zwitterionic group having the structure A-B—C— or A-B—C-L 2 -, a glutathione group, or a thiamine group;
provided that when R 1 is a pentafluorophenyl group, X is —O— and n is 0; and
wherein in the zwitterionic group structure A-B—C— or A-B—C-L 2 ,
A is a center of permanent positive charge or a center of permanent negative charge;
B is a divalent group comprising a C 1-12 alkylene group, a C 6-30 arylene or heteroarylene group, or an alkylene oxide group; and
C is a center of permanent positive charge comprising a divalent ammonium group or a center of permanent negative charge comprising a divalent phosphate group,
provided that the zwitterionic group has an overall net charge of zero;
L 2 is a divalent C 1-6 alkylene group is covalently bound to L 1 through a thioether bond or a disulfide bond; and
wherein the zwitterionic group is a phosphorylcholine zwitterionic group,
a sulfobetaine zwitterionic group, or a carboxybetaine zwitterionic group.

2. The temozolomide compound of claim 1 , wherein R 1 is of the formula

wherein in the above formulas,
A is a center of permanent positive charge comprising an ammonium group of the formula —N(R 7 ) 3 , wherein R 7 is a C 1-6 alkyl or a center of permanent negative charge comprising a sulfonate group or a carboxylate group;
B is the divalent group comprising a C 1-12 alkylene group, a C 6-30 arylene or heteroarylene group, or an alkylene oxide group;
C is a center of permanent positive charge comprising a divalent ammonium group or a center of permanent negative charge comprising a divalent phosphate group; and
L 2 is a divalent C 1-6 alkylene group and is covalently bound to L 1 through a thioether bond or a disulfide bond.

3. The temozolomide compound of claim 1 , wherein
X is —O—;
n is 0; and
R 1 is a pentafluorophenyl group.

4. The temozolomide compound of claim 1 , wherein
X is —O—;
n is 1;
L 1 is a divalent C 1-6 alkylene group; and
R 1 is a pyridyl disulfide group.

5. The temozolomide compound of claim 1 , wherein
X is —O—;
n is 1;
L 1 is a divalent C 1-12 alkylene sulfide group or a divalent C 1-6 alkylene group; and
R 1 is a glutathione group.

6. The temozolomide compound of claim 1 , wherein
X is —NH—;
n is 1;
L 1 is a divalent C 1-6 alkylene group; and
R 1 is a thiamine group.

7. The temozolomide compound of claim 1 , wherein
X is —O— or —NH—;
n is 1;
L 1 is a divalent di(C 2-12 alkylene) disulfide group, C 2-12 alkylene ester group, C 6-20 arylene group, C 1-20 alkylene oxide group, or C 1-12 alkylene sulfide group; and
R 1 is a phosphorylcholine zwitterionic group having the structure A-B—C—, wherein
A is an ammonium group of the formula —N(R 7 ) 3 , wherein R 7 is a C 1-6 alkyl group;
B is a divalent C 1-6 alkylene group; and
C is a divalent phosphate group.

8. The temozolomide compound of claim 1 , wherein
X is —O— or —NH—;
n is 1;
L 1 is a divalent C 1-6 alkylene group; and
R 1 is a sulfobetaine zwitterionic group having the structure A-B—C-L 2 -, wherein
A is a sulfonate group;
B is a divalent C 1-6 alkylene group;
C is a divalent ammonium group; and
L 2 is a divalent C 1-6 alkylene group;

wherein L 2 of the zwitterionic group is covalently bound to L 1 through a thioether bond or a disulfide bond.

9. The temozolomide compound of claim 1 , wherein
X is —O— or —NH—;
n is 1;
L 1 is a divalent C 1-6 alkylene group; and
R 1 is a carboxybetaine zwitterionic group having the structure A-B—C-L 2 -, wherein
A is a carboxylate group;
B is a divalent C 1-6 alkylene group;
C is a divalent ammonium group; and
L 2 is a divalent C 1-6 alkylene group;

wherein L 2 of the zwitterionic group is covalently bound to L 1 through a thioether bond or a disulfide bond.

10. The temozolomide compound of claim 1 , wherein R 1 is a pentafluorophenyl group or a pyridyl disulfide group.

11. The temozolomide compound of claim 1 , wherein
the phosphorylcholine zwitterionic group is of the formula A-B—C—, wherein A is an ammonium group of the formula —N(R 7 ) 3 , wherein R 7 is a C 1-6 alkyl group; B is a divalent C 1-6 alkylene group; and C is a divalent phosphate group;
the sulfobetaine zwitterionic group is of the formula A-B—C-L 2 -, wherein A is a sulfonate group; B is a divalent C 1-6 alkylene group; C is a divalent ammonium group; and L 2 is a divalent C 1-6 alkylene group; wherein L 2 of the zwitterionic group is covalently bound to L 1 through a thioether bond or a disulfide bond; and
the carboxybetaine zwitterionic group is of the formula A-B—C-L 2 -, wherein A is a carboxylate group; B is a divalent C 1-6 alkylene group; C is a divalent ammonium group; and L 2 is a divalent C 1-6 alkylene group; wherein L 2 of the zwitterionic group is covalently bound to L 1 through a thioether bond or a disulfide bond.

Assignees

• Univ Massachusetts

Inventors

• Emrick Todd
• Skinner Matthew
• Ward Sarah M
• Saha Banishree

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/787

  containing heterocyclic rings having nitrogen as a ring hetero atom · CPC title

• A61K47/545

  Heterocyclic compounds (A61K47/558 takes precedence) · CPC title

• A61K47/58

  obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin · CPC title

• A61K47/60

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title