Prodrugs for selective anticancer therapy

Patent metadata

Field	Value
Publication number	US-9872919-B2
Application number	US-201314428501-A
Country	US
Kind code	B2
Filing date	Sep 18, 2013
Priority date	Sep 19, 2012
Publication date	Jan 23, 2018
Grant date	Jan 23, 2018

Abstract

The present invention provides a compound having the structure:

wherein
X is a therapeutic agent containing at least one amine nitrogen and the amine nitrogen on the therapeutic agent covalently bonds directly to carbon α;
Z is CH 3 or CF 3 ;
R 1 is —H, —NR 2 R 3 , —NH—C(═O)—R 4 , —NH—C(═O)—OR 4 , —CH 2 —C(═O)—NR 5 R 6 , —OR 7 , —CO 2 R 7 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, or heteroaryl,
wherein R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each, independently, —H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, an amino acid or an oligopeptide;
wherein an amine of the amino acid or oligopeptide is substituted or unsubstituted; and

n is an integer from 0 to 6;

or a diastereomer, enantiomer or pharmaceutically acceptable salt of the compound.

First claim

What is claimed is:

1. A compound having the structure:

wherein
X is a chemotherapeutic agent,
wherein the chemotherapeutic agent is a nucleoside or deoxynucleoside;

Y is a chemical linker,
wherein Y is absent;

Z is CH 3 or CF 3 ;
R 1 is —NR 2 R 3 , —NH—C(═O)—R 4 or —NH—C(═O)—OR 4 ,
wherein R 2 , R 3 and R 4 , are each, independently, —H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, an amino acid or an oligopeptide;
wherein the amine of the amino acid or oligopeptide is substituted or unsubstituted; and

n is 4,

or a diastereomer, enantiomer or pharmaceutically acceptable salt of the compound.

2. The compound of claim 1 having the structure:

wherein
X is a chemotherapeutic agent containing at least one amine nitrogen and the amine nitrogen on the chemotherapeutic agent covalently bonds directly to carbon α,
wherein the chemotherapeutic agent is a nucleoside or deoxynucleoside;

Z is CH 3 or CF 3 ;
R 1 is —NR 2 R 3 , —NH—C(═O)—R 4 or —NH—C(═O)—OR 4 ,
wherein R 2 , R 3 and R 4 , are each, independently, —H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, an amino acid or an oligopeptide;
wherein the amine of the amino acid or oligopeptide is substituted or unsubstituted; and

n is 4,

or a diastereomer, enantiomer or pharmaceutically acceptable salt of the compound.

3. The compound of claim 2 having the structure:

wherein
X is a chemotherapeutic agent containing at least one amine nitrogen and the amine nitrogen on the chemotherapeutic agent covalently bonds directly to carbon α,
wherein the chemotherapeutic agent is a nucleoside or deoxynucleoside;

Z is CH 3 or CF 3 ;
R 1 is —NR 2 R 3 , —NH—C(═O)—R 4 or —NH—C(═O)—OR 4 ,
wherein R 2 , R 3 and R 4 , are each, independently, —H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, an amino acid or an oligopeptide;
wherein the amine of the amino acid or oligopeptide is substituted or unsubstituted; and

n is 4,

or a diastereomer, enantiomer or pharmaceutically acceptable salt of the compound.

4. The compound of claim 2 having the structure:

wherein
X is a chemotherapeutic agent containing at least one amine nitrogen and the amine nitrogen on the chemotherapeutic agent covalently bonds directly to carbon α,
wherein the chemotherapeutic agent is a nucleoside or deoxynucleoside;

Z is CH 3 or CF 3 ;
R 1 is —NR 2 R 3 , —NH—C(═O)—R 4 or —NH—C(═O)—OR 4 ,
wherein R 2 , R 3 and R 4 are each, independently, —H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, an amino acid or an oligopeptide;
wherein the amine of the amino acid or oligopeptide is substituted or unsubstituted; and

n is 4,

or a diastereomer, enantiomer or pharmaceutically acceptable salt of the compound.

5. The compound of claim 2 ,
wherein R 1 is

wherein R 10 is —H, —CH 3 , Ac, —C(O)-Ot-Bu, —C(O)—OCH 2 Ph, —CHO, phenyl, or benzyl,

or a diastereomer, enantiomer or pharmaceutically acceptable salt of compound.

6. The compound of claim 2 ,
wherein X is puromycin, 5-fluorocytidine, 2′-deoxy-5-fluorocytidine, 5′-deoxy-5-fluorocytidine, gemcitabine, cytarabine, cladribine, troxacitabine, azacitidine, clofarabine, decitabine, fludarabine, fludarabine phosphate, gemcitabine hydrochloride, or nelarabine,

or a diastereomer, enantiomer or pharmaceutically acceptable salt of the compound.

7. The compound of claim 2 having the structure:

or a diastereomer, enantiomer or pharmaceutically acceptable salt of the compound.

8. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

9. The compound of claim 2 ,
wherein X is puromycin, 5-fluorocytidine, 2′-deoxy-5-fluorocytidine, 5′-deoxy-5-fluorocytidine, gemcitabine or cytarabine,

or a diastereomer, enantiomer or pharmaceutically acceptable salt of the compound.

10. The compound of claim 1 ,
wherein R 1 is

or a diastereomer, enantiomer or pharmaceutically acceptable salt of the compound.

11. The compound of claim 1 ,
wherein
R 1 is —NHBoc;
n is 4;
X is puromycin or 5-fluorocytidine; and
Z is CH 3 ,

or a diastereomer, enantiomer or pharmaceutically acceptable salt of the compound.

12. The compound of claim 1 ,
wherein Z is CF 3 ,

or a diastereomer, enantiomer or pharmaceutically acceptable salt of the compound.

13. A compound having the structure:

wherein
X is a chemotherapeutic agent,
wherein the chemotherapeutic agent is a nucleoside or deoxynucleoside;

Y is a chemical linker,
wherein Y is absent;

Z is CH 3 or CF 3 ;
R 3 is —NR 2 R 3 ,
wherein
R 2 is —H; and
R 3 is an amino acid or oligonucleotide,
wherein the amino acid is bonded to the nitrogen through an amide bond, or

R 1 is

wherein R 8 and R 9 are each independently —H, —CH 3 , t-butyl, phenyl, or benzyl; and

n is 4,

or a diastereomer, enantiomer or pharmaceutically acceptable salt of the compound.

14. The compound of claim 13 having the structure:

wherein
X is a chemotherapeutic agent,
wherein the chemotherapeutic agent is a nucleoside or deoxynucleoside;

Y is a chemical linker,
wherein Y is absent;

Z is CH 3 or CF 3 ;
R 1 is —NR 2 R 3 ,
wherein
R 2 is —H; and
R 3 is an amino acid or oligonucleotide,
wherein the amino acid is bonded to the nitrogen through an amide bond, or

R 1 is

Assignees

• Ueki Nobuhide
• Hayman Michael J
• Univ New York State Res Found

Inventors

• Ueki Nobuhide
• Hayman Michael J

Classifications

• C07H19/067

  with ribosyl as the saccharide radical · CPC title

• C07K5/0817

  the first amino acid being Arg · CPC title

• C07K5/1019

  with the first amino acid being basic · CPC title

• C07H19/16

  Purine radicals · CPC title

• A61K31/7076

  containing purines, e.g. adenosine, adenylic acid · CPC title