Phosphoramidate derivatives of 5-fluoro-2′-deoxyuridine for use in the treatment of cancer

Patent metadata

Field	Value
Publication number	US-10022390-B2
Application number	US-201715489884-A
Country	US
Kind code	B2
Filing date	Apr 18, 2017
Priority date	Mar 1, 2011
Publication date	Jul 17, 2018
Grant date	Jul 17, 2018

Abstract

Phosphoramidate derivates of 5-fluoro-2′-deoxyuridine are disclosed for use in the treatment of cancer, especially in the treatment of cancer where the patient shows resistance, for example, in a patient with cells with a lowered level of nucleoside transporter proteins and/or with nucleoside kinase-deficient cells and/or with mycoplasma -infected cells and/or with cells with a raised level of thymidylate synthase.

First claim

The invention claimed is:

1. A pharmaceutical formulation suitable for intravenous administration, said formulation comprising a compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable excipient, carrier or diluent:

wherein
Ar is a fused bicyclic aryl moiety or a monocyclic aryl moiety, either of which aryl moieties is carbocyclic or heterocyclic and is optionally substituted;
R 3 is alkyl, which is optionally substituted;
R 4 is H or alkoyl;
R 1 and R 2 are independently selected from the group consisting of H and alkyl, or R 1 and R 2 together form an alkylene chain so as to provide, together with the C atom to which they are attached, a cyclic system, or one of R 1 and R 2 comprises an alkylene chain attached to N, the H atom attached to N is absent and one of R 1 and R 2 comprise H or alkyl, any of which said alkyl moieties or alkylene chains may be substituted;
wherein the compound is not a compound having, in combination, Ar as unsubstituted phenyl, R 3 as CH 3 , R 4 as H, one of R 1 and R 2 as H and one of R 1 and R 2 as CH 3 .

2. The formulation according to claim 1 wherein Ar is 1-naphthyl.

3. The formulation according to claim 1 wherein R 4 is H.

4. The formulation according to claim 1 wherein R 3 is selected from the group consisting of benzyl and members of the group comprising C 1 to C 10 alkyls.

5. The formulation according to claim 1 wherein R 1 and R 2 correspond to the moieties attached to the alpha C atom in L-alanine.

6. The formulation according to claim 1 wherein the compound of Formula (I) is selected from the group consisting of:
5-Fluoro-2′-deoxyuridine-5′-O-[phenyl(benzoxy- L -alaninyl)]phosphate (CPF 381);
5-Fluoro-2′-deoxyuridine-5′-O-[phenyl(ethoxy- L -alaninyl)]phosphate (CPF383);
5-Fluoro-2′deoxyuridine-5′-O-[phenyl(isopropoxy- L -alaninyl)]phosphate (CPF384);
5-Fluoro-2′deoxyuridine-5′-O-[phenyl(cyclohexoxy- L -alaninyl)]phosphate (CPF508);
5-Fluoro-2′deoxyuridine-5′-O-[p-nitro-phenyl(ethoxy- L -alaninyl)]phosphate (CPF430);
5-Fluoro-2′deoxyuridine-5′-O-[1-naphthyl(benzoxy- L -alaninyl)]phosphate (CPF373);
5-Fluoro-2′deoxyuridine-5′-O-[1-naphthyl(methoxy- L -alaninyl)]phosphate (CPF385);
5-Fluoro-2′deoxyuridine-5′-O-[1-naphthyl(ethoxy- L -alaninyl)]phosphate (CPF386);
5-Fluoro-2′deoxyuridine-5′-O-[1-naphthyl(isopropoxy- L -alaninyl)]phosphate (CPF387);
5-Fluoro-2′deoxyuridine-5′-O-[1-naphthyl(cyclohexoxy- L -alaninyl)]phosphate (CPF509);
5-Fluoro-2′deoxyuridine-5′-O-[phenyl(benzoxy-α,α-dimethylglycine)]phosphate (CPF393);
5-Fluoro-2′deoxyuridine-5′-O-[phenyl(ethoxy-α,α-dimethylglycine)]phosphate (CPF394);
5-Fluoro-2′deoxyuridine-5′-O-[1-naphthyl(benzoxy-α,α-dimethylglycine)]phosphate (CPF395);
5-Fluoro-2′deoxyuridine-5′-O-[1-naphthyl(ethoxy-α,α-dimethylglycine)]phosphate (CPF396);
5-Fluoro-2′-deoxyuridine-5′-O-[phenyl(benzoxy-L-prolinyl)]phosphate (CPF583);
5-Fluoro-2′-deoxyuridine-5′-O-[1-naphthyl(benzoxy-L-prolinyl)]phosphate (CPF577);
5-Fluoro-2′-deoxyuridine-5′-O-[1-naphthyl(3,3-dimethyl-1-butoxy-L-alaninyl)]phosphate (CPF585);
5-Fluoro-2′-deoxyuridine-5′-O-[1-naphthyl-(cyclobutoxy-L-alaninyl)]phosphate (CPF578);
5-Fluoro-2′-deoxyuridine-5′-O-[1-naphthyl-(cyclopropylmethanoxy-L-alaninyl)]phosphate (CPF579);
5-Fluoro-2′-deoxyuridine-5′-O-[1-naphthyl-(tetrahydropyroxy-L-alaninyl)]phosphate (CPF580);
5-Fluoro-2′-deoxyuridine-5′-O-[1-naphthyl-(pentoxy-L-alaninyl)]phosphate (CPF581);
5-Fluoro-2′-deoxyuridine-5′-O-[1-naphthyl-(cyclopentoxy-L-alaninyl)]phosphate (CPF582);
5-Fluoro-2′-deoxyuridine-5′-O-[1-naphthyl-(2-indanoxy-L-alaninyl)]phosphate (CPF597);
5-Fluoro-2′-deoxyuridine-5′-O-[phenyl-(benzoxy-L-methioninyl)]phosphate (CPF586);
5-Fluoro-2′-deoxyuridine-5′-O-[1-naphthyl-(benzoxy-L-phenylalaninyl)]phosphate (CPF587);
5-Fluoro-2′-deoxyuridine-5′-O-[1-naphthyl-(2,2-dimethylpropoxy-L-alaninyl)]phosphate (CPF588);
5-Fluoro-2′-deoxyuridine-5′-O-[1-naphthyl-(butoxy-L-alaninyl)]phosphate (CPF589);
5-Fluoro-2′-deoxyuridine-5′-O-[phenyl(ethoxy-L-valinyl)]phosphate;
5-Fluoro-2′-deoxyuridine-5′-O-[phenyl(benzoxy-L-leucinyl)]phosphate;
5-Fluoro-2′-deoxyuridine-5′-O-[phenyl(benzoxy-L-isoleucinyl)]phosphate;
5-Fluoro-2′-deoxyuridine-5′-O-[phenyl(benzoxy-L-phenylalaninyl)]phosphate;
5-Fluoro-2′-deoxyuridine-5′-O-[phenyl(pentoxy-L-methioninyl)]phosphate;
5-Fluoro-2′-deoxyuridine-5′-O-[1-naphthyl(hexoxy-L-alaninyl)]phosphate;
5-Fluoro-2′-deoxyuridine-5′-O-[1-naphthyl(cyclohexoxy-L-valinyl)]phosphate;
5-Fluoro-2′-deoxyuridine-5′-O-[1-naphthyl(pentoxy-L-leucinyl)]phosphate;
5-Fluoro-2′-deoxyuridine-5′-O-[1-naphthyl(benzoxy-L-leucinyl)]phosphate;
5-Fluoro-2′-deoxyuridine-5′-O-[1-naphthyl(pentoxy-L-isoleucinyl)]phosphate;
5-Fluoro-2′-deoxyuridine-5′-O-[1-naphthyl(pentoxy-L-phenylalaninyl)]phosphate;
5-Fluoro-2′-deoxyuridine-5′-O-[1-naphthyl(benzoxy-L-methioninyl)]phosphate; and
5-Fluoro-2′-deoxyuridine-5′-O-[1-naphthyl(pentoxy-α,α-dimethylglycine)]phosphate, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

7. A method of treatment of cancer, the method comprising administering intravenously to a patient in need thereof, an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof:

wherein
Ar is a fused bicyclic aryl moiety or a monocyclic aryl moiety, either of which aryl moieties is carbocyclic or heterocyclic and is optionally substituted;
R 3 is alkyl, which is optionally substituted;
R 4 is H or alkoyl;
R 1 and R 2 are independently selected from the group consisting of H and alkyl, or R 1 and R 2 together form an alkylene chain so as to provide, together with the C atom to which they are attached, a cyclic system, or one of R 1 and R 2 comprises an alkylene chain attached to N, the H atom attached to N is absent and one of R 1 and R 2 comprise H or alkyl, any of which said alkyl moieties or alkylene chains may be substituted;
wherein the compound is not a compound having, in combination, Ar as unsubstituted phenyl, R 3 as CH 3 , R 4 as H, one of R 1 and R 2 as H and one of R 1 and R 2 as CH 3 ;
wherein said cancer is selected from gastrointestinal cancer, leukemia, lymphoma, pancreatic cancer, prostate cancer, lung cancer, breast cancer, cervical cancer, head and neck cancer and ovarian cancer.

8. The method of claim 7 , wherein the compound of Formula (I) is administered as an aqueous solution or suspension.

9. The method of claim 8 , wherein the aqueous solution or suspension comprises an aqueous vehicle selected from Ringers solution and isotonic sodium chloride.

10. A formulation suitable for intravenous administration, said formulation comprising 5-fluoro-2′-deoxyuridine-5′-O-[1-naphthyl(benzoxy- L -alaninyl)]phosphate (CPF373) and a pharmaceutically acceptable excipient, carrier or diluent.

11. The formulation of claim 10 , wherein the formulation is an aqueous solution or suspension.

12. The formulation of claim 11 , wherein the formulation comprises an aqueous vehicle selected from Ringers solution and isotonic sodium chloride.

13. A method of treatment of cancer, the method comprising administering intravenously to a patient in need thereof, an effective dose of 5-fluoro-2′deoxyuridine-5′-O-[1-naphthyl(benzoxy-L-alaninyl)]phosphate (CPF373); wherein said cancer is selected from gastrointestinal cancer, leukemia, lymphoma, pancreatic cancer, prostate cancer, lun

Assignees

• NuCana plc

Inventors

• Mcguigan Christopher
• Balzarini Jan
• Slusarczyk Magdalena
• Gonczy Blanka
• Murziani Paola

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61K31/7072 Primary

  having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine · CPC title

• C07F9/65844

  the phosphorus atom being part of a five-membered ring which may be condensed with another ring system · CPC title

• C07F9/65515

  the oxygen atom being part of a five-membered ring · CPC title