# US 2010/0168052 A1 · Treatment of EBV and KHSV Infection and Associated Abnormal Cellular Proliferation

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- Number: US 2010/0168052 A1
- Document ID: US20100168052A1
- Status: Published application
- Kind: A1
- Application number: 12/647,959
- Filed: 2009-12-28
- Published: 2010-07-01
- Earliest claimed: 2001-12-20
- Assignees: Pharmasset, Inc.; Emory University; Beth Israel Deaconess Medical Center, Inc.
- Inventors: Raymond F. Schinazi; Junxing Shi; Erik Gustafson; Joyce D. Fingeroth
- Web page: https://patentgrep.com/patent/US20100168052A1

## CPC

- C07H 19/06: Pyrimidine radicals
- A61K 31/513: having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- A61K 31/7072: having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/12: Antivirals
- A61P 31/22: for herpes viruses
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 239/54: as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- 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)
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

A method and composition for the treatment, prevention and/or prophylaxis of a host, and in particular, a human, infected with Epstein-Barr virus (EBV), is provided that includes administering an effective amount of a 5-substituted uracil nucleoside or its pharmaceutically acceptable salt or prodrug, optionally in a pharmaceutically acceptable diluent or excipient.

## Claims

### Claim 1

A method for treating a host infected with Epstein-Barr virus or KHSV comprising administering an effective amount of a compound of the general formula (I), (II) or (III):
or a pharmaceutically acceptable salt or prodrug thereof, wherein
i) X is O, S, NR4, CH2, CHF or CF2;
ii) R1 is chosen from hydrogen, halogen (Cl, Br, I, F), alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, hal0 alkynyl , cycloalkyl, CN, CF3, N3, NO2, aryl, heteroaryl, heteroaryl, acyl or COR5 where R5 is chosen from one of H, OH, SH, alkyl, aminoalkyl, alkoxy, or thioalkyl;
iii) R2 and R2′ are independently H, carbonyl substituted with a alkyl, alkenyl, alkynyl, aryl; benzyl, wherein the phenyl group is optionally substituted with one or more substituents; phosphate, phosphate ester, sulfonate ester; a lipid including a phospholipid; amino acid; peptide; cholesterol, or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein one or both of R2 and R2′ is H;
iv) R3 is chosen from H, OH, halogen (F, Cl, Br, I), protected hydroxyl group or CH2OR4;
v) R4 is independently H, acyl, alkyl, alkenyl, alkynyl or cycloalkyl;
vi) Y is chosen from H, OH, halogen (F, Cl, Br, I), N3, CN, or OR2′; and
vii) Z is 0 or S.

### Claim at position 2

2-14. (canceled)

### Claim 15 (depends on 1)

The method of claim 1 wherein the compound administered is a β-L isomer and is at least 95% pure.

### Claim 16 (depends on 1)

The method of claim 1 wherein the compound administered is a β-D isomer and is at least 95% pure.

### Claim 17 (depends on 1)

The method of claim 1 wherein the host is a human.

### Claim 18

A method for treating a host with abnormal cellular proliferation or a cellular dysfunction, wherein the cell carries the Epstein-Barr virus or KHSV genome, comprising administering an effective amount of a compound of the general formula (I), (II) or (III):
or a pharmaceutically acceptable salt or prodrug thereof, wherein
(i) X is O, S, NR4, CH2, CHF or CF2;
ii) R1 is chosen from hydrogen, halogen (Cl, Br, I, F), alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, CN, CF3, N3, NO2, aryl, heteroaryl, heteroaryl, acyl or COR5 where R5 is chosen from one of H, OH, SH, alkyl, aminoalkyl, alkoxy, or thioalkyl;
iii) R2 and R2′ are independently H, carbonyl substituted with a alkyl, alkenyl, alkynyl, aryl; benzyl, wherein the phenyl group is optionally substituted with one or more substituents; phosphate, phosphate ester, sulfonate ester including alkyl or aryl alkyl sulfonyl including methanesulfonyl; a lipid including a phospholipid; amino acid; peptide; cholesterol, or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein one or both of R2 and R2′ is H;
iv) R3 is chosen from H, OH, halogen (F, Cl, Br, I), protected hydroxyl group or CH2OR4;
v) R4 is independently H, acyl, alkyl, alkenyl, alkynyl or cycloalkyl;
yl) Y is chosen from H, OH, halogen (F, Cl, Br, I), N3, CN, or OR2′; and
vii) Z is 0 or S.

### Claim at position 7

19-41. (canceled)

### Claim 42 (depends on 18)

The method of claim 18 wherein the compound administered is a β-L isomer and is at least 95% pure.

### Claim 43 (depends on 18)

The method of claim 18 wherein the compound administered is a β-D isomer and is at least 95% pure.

### Claim 44 (depends on 18)

The method of claim 18 wherein the host is a human.

### Claim 45

A method for treating a host with abnormal cellular proliferation or a cellular dysfunction, wherein the cell does not carry the EBV or KHSV genome, comprising
(i) administering the EBV-TK or KHSV-TK gene to the cell or surrounding cells in a manner that allows the enzyme to be expressed in the cell, and then
(ii) administering an effective amount of a compound of the general formula (I), (II) or (III):
or a pharmaceutically acceptable salt or prodrug thereof, wherein
i) X is O, S, NR4, CH2, CHF or CF2;
ii) R1 is chosen from hydrogen, halogen (Cl, Br, I, F), alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, CN, CF3, N3, NO2, aryl, heteroaryl, heteroaryl, acyl or COR5 where R5 is chosen from one of H, OH, SH, alkyl, aminoalkyl, alkoxy, or thioalkyl;
iii) R2 and R2′ are independently H, carbonyl substituted with a alkyl, alkenyl, alkynyl, aryl; benzyl, wherein the phenyl group is optionally substituted with one or more substituents; phosphate, phosphate ester, sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl; a lipid including a phospholipid; amino acid; peptide; cholesterol, or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein one or both of R2 and R2′ is H;
iv) R3 is chosen from H, OH, halogen (F, Cl, Br, I), protected hydroxyl group or CH2OR4;
v) R4 is independently H, acyl, alkyl, alkenyl, alkynyl or cycloalkyl;
yl) Y is chosen from H, OH, halogen (F, Cl, Br, I), N3, CN, or OR2; and
vii) Z is O or S.

### Claim at position 12

46-56. (canceled)

### Claim 57 (depends on 45)

The method of claim 45 wherein the compound administered is a β-L isomer and is at least 95% pure.

### Claim 58 (depends on 45)

The method of claim 45 wherein the compound administered is a β-D isomer and is at least 95% pure.

### Claim 59 (depends on 45)

The method of claim 45 wherein the host is a human.

### Claim 60

A pharmaceutical composition comprising an effective amount to treat a cell carrying the Epstein-Barr virus or KHSV of a compound of the formula:
or a pharmaceutically acceptable salt or prodrug thereof, wherein
i) X is O, S, NR4, CH2, CHF or CF2;
ii) R1 is chosen from hydrogen, halogen (Cl, Br, I, F), alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, CN, CF3, N3, NO2, aryl, heteroaryl, heteroaryl, acyl or COR5 where R5 is chosen from one of H, OH, SH, alkyl, aminoalkyl, alkoxy, or thioalkyl;
iii) R2 and R2′ are independently H, carbonyl substituted with a alkyl, alkenyl, alkynyl, aryl; benzyl, wherein the phenyl group is optionally substituted with one or more substituents; phosphate, phosphate ester, sulfonate ester including alkyl or aryl alkyl sulfonyl including methanesulfonyl; a lipid including a phospholipid; amino acid; peptide; cholesterol, or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein one or both of R2 and R2′ is H;
iv) R3 is chosen from H, OH, halogen (F, Cl, Br, I), protected hydroxyl group or CH2OR4;
v) R4 is independently H, acyl, alkyl, alkenyl, alkynyl or cycloalkyl;
vi) Y is chosen from H, OH, halogen (F, Cl, Br, I), N3, CN, or OR2′; and
vii) Z is 0 or S.

### Claim at position 17

61-72. (canceled)

### Claim 73 (depends on 1, 60)

The pharmaceutical composition of claim 60 of claim 1 wherein the compound administered is a β-L isomer and is at least 95% pure.

### Claim 74 (depends on 1, 60)

The pharmaceutical composition of claim 60 of claim 1 wherein the compound administered is a β-D isomer and is at least 95% pure.

### Claim 75

An immortalized human embryonic kidney cell transfected with the EBV-TK or KHSV-TK gene.

### Claim at position 21

76-78. (canceled)

### Claim 79

A method for treating a host with abnormal cellular proliferation or a cellular dysfunction, wherein the cell does not carry the EBV or KHSV genome, comprising (i) administering a cell that carries and expresses the EBV-TK or KHSV-TK gene to a location that will enable a bystander effect on the abnormal cell, and then
(ii) administering an effective amount of a compound of the general formula (I), (II) or (III).

### Claim 80

(canceled)

### Claim 81 (depends on 1)

The method of claim 1 wherein the compound is selected from the group consisting of 2′-deoxy-5-vinyluridine, 5-vinyluridine, 2′-deoxy-5-iodouridine, 2′-deoxy-5-(hydroxymethyl)uridine, 5-butyl-2′-deoxyuridine, 5-E-(2-carboxyvinyl)-2′-deoxyuridine, (2S,4S)-5-(2-furanyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil, (2S,4S)-5-(5-bromo-2-furanyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil, (2S,4S)-5-(2-thienyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil, (2S,4S)-5-(5-bromthien-2-yl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil, and (2S,4S)-5-(3-hydroxypropenyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil.

### Claim 82 (depends on 1)

The method of claim 1 wherein the host exhibits acute mononucleoisis or oral hairy leukoplakia.

### Claim 83 (depends on 18)

The method of claim 18 wherein the host exhibits nasopharyngeal carcinoma, a B-cell lymphoma, B-cell lymphoproliferative disorder, Hodgkins disease, a T-lymphoma, an NK/monocytoid/dendritic cell malignancy, a sporadic epithelial carcinoma, a leiomyosarcoma, a multicentric leiomyosarcoma, Kaposi's sarcoma, multicentric Castleman's Disease, or germanotrophic lymphoma.

### Claim 84 (depends on 18)

The method of claim 18 wherein the compound is selected from the group consisting of 2′-deoxy-5-vinyluridine, 5-vinyluridine, 2′-deoxy-5-iodouridine, 2′-deoxy-5-(hydroxymethyl)uridine, 5-butyl-2′-deoxyuridine, 5-E-(2-carboxyvinyl)-2′-deoxyuridine, (2S,4S)-5-(2-furanyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil, (2S,4S)-5-(5-bromo-2-furanyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil, (2S,4S)-5-(2-thienyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil, (2S,4S)-5-(5-bromthien-2-yl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil, and (2S,4S)-5-(3-hydroxypropenyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil.

### Claim 85 (depends on 45)

The method of claim 45 wherein the compound is selected from the group consisting of 2′-deoxy-5-vinyluridine, 5-vinyluridine, 2′-deoxy-5-iodouridine, 2′-deoxy-5-(hydroxymethyl)uridine, 5-butyl-2′-deoxyuridine, 5-E-(2-carboxyvinyl)-2′-deoxyuridine, (2S,4S)-5-(2-furanyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil, (2S,4S)-5-(5-bromo-2-furanyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil, (2S,4S)-5-(2-thienyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil, (2S,4S)-5-(5-bromthien-2-yl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil, and (2S,4S)-5-(3-hydroxypropenyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil.

### Claim 86 (depends on 60)

The pharmaceutical composition of claim 60 wherein the compound is selected from the group consisting of 2′-deoxy-5-vinyluridine, 5-vinyluridine, 2′-deoxy-5-iodouridine, 2′-deoxy-5-(hydroxymethyl)uridine, 5-butyl-2′-deoxyuridine, 5-E-(2-carboxyvinyl)-2′-deoxyuridine, (2S,4S)-5-(2-furanyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil, (2S,4S)-5-(5-bromo-2-furanyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil, (2S,4S)-5-(2-thienyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil, (2S,4S)-5-(5-bromthien-2-yl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil, and (2S,4S)-5-(3-hydroxypropenyl)-1-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]uracil.