# US 9,872,919 B2 · Prodrugs for selective anticancer therapy

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- Number: US 9,872,919 B2
- Document ID: US9872919B2
- Status: Granted
- Kind: B2
- Application number: 14/428,501
- Filed: 2013-09-18
- Published: 2015-08-13
- Granted: 2018-01-23
- Earliest claimed: 2012-09-19
- Assignees: The Research Foundation for The State University of New York
- Applicants: Nobuhide Ueki; Michael J. Hayman
- Inventors: Nobuhide Ueki; Michael J. Hayman
- Web page: https://patentgrep.com/patent/US9872919B2

## CPC

- A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65)
- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K 31/7076: containing purines, e.g. adenosine, adenylic acid
- A61K 47/54: the modifying agent being an organic compound
- A61K 47/542: {Carboxylic acids, e.g. a fatty acid or an amino acid}
- A61P 35/00: Antineoplastic agents
- C07H 19/06: Pyrimidine radicals
- C07H 19/067: with ribosyl as the saccharide radical
- C07H 19/073: with 2-deoxyribosyl as the saccharide radical
- C07H 19/09: with arabinosyl as the saccharide radical
- C07H 19/16: Purine radicals
- C07K 5/0215: {containing natural amino acids, forming a peptide bond via their side chain functional group, e.g. epsilon-Lys, gamma-Glu}
- C07K 5/06008: {with the first amino acid being neutral}
- C07K 5/06086: {with the first amino acid being basic}
- C07K 5/0817: {the first amino acid being Arg}
- C07K 5/1019: {with the first amino acid being basic}
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## 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 CH3 or CF3; R1 is —H, —NR2R3, —NH—C(═O)—R4, —NH—C(═O)—OR4, —CH2—C(═O)—NR5R6, —OR7, —CO2R7, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, or heteroaryl, wherein R2, R3, R4, R5, R6 and R7 are each, independently, —H, C1-6 alkyl, C2-6 alkenyl, C2-6 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.

## Claims

### Claim 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 CH3 or CF3;
R1 is —NR2R3, —NH—C(═O)—R4 or —NH—C(═O)—OR4,
wherein R2, R3 and R4, are each, independently, —H, C1-6 alkyl, C2-6 alkenyl, C2-6 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.

### Claim 2 (depends on 1)

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 CH3 or CF3;
R1 is —NR2R3, —NH—C(═O)—R4 or —NH—C(═O)—OR4,
wherein R2, R3 and R4, are each, independently, —H, C1-6 alkyl, C2-6 alkenyl, C2-6 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.

### Claim 3 (depends on 2)

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 CH3 or CF3;
R1 is —NR2R3, —NH—C(═O)—R4 or —NH—C(═O)—OR4,
wherein R2, R3 and R4, are each, independently, —H, C1-6 alkyl, C2-6 alkenyl, C2-6 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.

### Claim 4 (depends on 2)

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 CH3 or CF3;
R1 is —NR2R3, —NH—C(═O)—R4 or —NH—C(═O)—OR4,
wherein R2, R3 and R4 are each, independently, —H, C1-6 alkyl, C2-6 alkenyl, C2-6 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.

### Claim 5 (depends on 2)

The compound of claim 2,
wherein R1 is
wherein R10 is —H, —CH3, Ac, —C(O)-Ot-Bu, —C(O)—OCH2Ph, —CHO, phenyl, or benzyl,
or a diastereomer, enantiomer or pharmaceutically acceptable salt of compound.

### Claim 6 (depends on 2)

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.

### Claim 7 (depends on 2)

The compound of claim 2 having the structure:
or a diastereomer, enantiomer or pharmaceutically acceptable salt of the compound.

### Claim 8 (depends on 1)

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

### Claim 9 (depends on 2)

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.

### Claim 10 (depends on 1)

The compound of claim 1,
wherein R1 is
or a diastereomer, enantiomer or pharmaceutically acceptable salt of the compound.

### Claim 11 (depends on 1)

The compound of claim 1,
wherein
R1 is —NHBoc;
n is 4;
X is puromycin or 5-fluorocytidine; and
Z is CH3,
or a diastereomer, enantiomer or pharmaceutically acceptable salt of the compound.

### Claim 12 (depends on 1)

The compound of claim 1,
wherein Z is CF3,
or a diastereomer, enantiomer or pharmaceutically acceptable salt of the compound.

### Claim 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 CH3 or CF3;
R3 is —NR2R3,
wherein
R2 is —H; and
R3 is an amino acid or oligonucleotide,
wherein the amino acid is bonded to the nitrogen through an amide bond, or
R1 is
wherein R8 and R9 are each independently —H, —CH3, t-butyl, phenyl, or benzyl; and
n is 4,
or a diastereomer, enantiomer or pharmaceutically acceptable salt of the compound.

### Claim 14 (depends on 13)

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 CH3 or CF3;
R1 is —NR2R3,
wherein
R2 is —H; and
R3 is an amino acid or oligonucleotide,
wherein the amino acid is bonded to the nitrogen through an amide bond, or
R1 is
wherein R8 and R9 are each independently —H, —CH3, t-butyl, phenyl, or benzyl; and
n is 4,
or a diastereomer, enantiomer or pharmaceutically acceptable salt of the compound.

### Claim 15 (depends on 13)

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 CH3 or CF3;
R1 is —NR2R3,
wherein
R2 is —H; and
R3 is an amino acid or oligonucleotide,
wherein the amino acid is bonded to the nitrogen through an amide bond, or
R1 is
wherein R8 and R9 are each independently —H, —CH3, t-butyl, phenyl, or benzyl; and
n is 4,
or a diastereomer, enantiomer or pharmaceutically acceptable salt of the compound.

### Claim 16 (depends on 7)

A pharmaceutical composition comprising the compound of claim 7 and a pharmaceutically acceptable carrier.