# US 2013/0157971 A1 · 2'-fluoronucleosides

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- Number: US 2013/0157971 A1
- Document ID: US20130157971A1
- Status: Published application
- Kind: A1
- Application number: 13/437,676
- Filed: 2012-04-02
- Published: 2013-06-20
- Earliest claimed: 1998-02-25
- Assignees: University of Georgia Research Foundation, Inc.; Emory University
- Inventors: RAYMOND F. SCHINAZI; Dennis C. Liotta; Chung K. Chu; J. Jeffrey McAtee
- Web page: https://patentgrep.com/patent/US20130157971A1

## CPC

- A61K 31/7076: containing purines, e.g. adenosine, adenylic acid
- A61K 31/706: containing six-membered rings with nitrogen as a ring hetero atom
- A61K 31/7064: containing condensed or non-condensed pyrimidines
- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K 31/7072: having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
- A61K 31/708: having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 31/18: for HIV
- A61P 31/20: for DNA viruses
- A61P 35/00: Antineoplastic agents
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 473/00: Heterocyclic compounds containing purine ring systems
- C07H 19/06: Pyrimidine radicals
- C07H 19/10: with the saccharide radical esterified by phosphoric or polyphosphoric acids
- C07H 19/16: Purine radicals
- 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)
- 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)

## Abstract

2′-Fluoro-nucleoside compounds are disclosed which are useful in the treatment of hepatitis B infection, hepatitis C infection, HIV and abnormal cellular proliferation, including tumors and cancer. The compounds have the general formulae: wherein Base is a purine or pyrimidine base; R1 is OH, H, OR3, N3, CN, halogen, CF3, lower alkyl, amino, loweralkylamino, di(lower)alkylamino, or alkoxy; R2 is H, phosphate, or a stabilized phosphate prodrug; acyl, or other pharmaceutically acceptable leaving benzyl, a lipid, an amino acid, peptide, or cholesterol; and R3 is acyl, alkyl, phosphate, or other pharmaceutically acceptable leaving group; or a pharmaceutically acceptable salt thereof.

## Claims

### Claim at position 1

-47. (canceled)

### Claim 48

A method for the treatment of a HCV infection in a host in need thereof comprising administering an effective treatment amount of a β-D-2′-fluoronucleoside wherein the 2′-fluoro of the β-D-2′-fluoronucleoside is alpha (α), or a pharmaceutically acceptable salt or prodrug thereof, optionally in a pharmaceutically acceptable carrier or diluent.

### Claim 49 (depends on 48)

The method of claim 48, wherein the β-D-2′-fluoronucleoside has a pyrimidine base.

### Claim 50 (depends on 49)

The method of claim 49, wherein the pyrimidine base is selected from the group consisting of thymine, uracil, 5-halouracil, 5-fluorouracil, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-aza-pyrimidine, 6-azacytosine, 2- and/or 4-mercaptopyrmidine, C5-alkylpyrimidine, C5-benzylpyrimidine, C5-halopyrimidine, C5-vinylpyrimidine, C5-acetylenic pyrimidine, C5-acyl pyrimidine, C5-hydroxyalkyl purine, C5-amidopyrimidine, C5-cyanopyrimidine, C5-nitropyrimidine, and C5-aminopyrimidine.

### Claim 51 (depends on 49)

The method of claim 49, wherein the pyrimidine base is thymine.

### Claim 52 (depends on 49)

The method of claim 49, wherein the pyrimidine base is uracil.

### Claim 53 (depends on 49)

The method of claim 49, wherein the pyrimidine base is 5-halouracil.

### Claim 54 (depends on 49)

The method of claim 49, wherein the pyrimidine base is cytosine.

### Claim 55 (depends on 49)

The method of claim 49, wherein the pyrimidine base is 5-fluorocytosine.

### Claim 56 (depends on 48)

The method of claim 48, wherein the β-D-2′-fluoronucleoside has a purine base.

### Claim 57 (depends on 56)

The method of claim 56, wherein the purine base is selected from the group consisting of N6-alkylpurine, N6-acylpurine (wherein acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl), N6-benzylpurine, N6-halopurine, N6-vinylpurine, N6-acei ylenic purine, N6-acyl purine, N6-hydroxyalkyl purine, N6-thioalkyl purine, N2-alkylpurines, N2-alkyl-6-thiopurines, N2-alkylpurine, N2-alkyl-6-thiopurine, 5-azacytidinyl, guanine, adenine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine.

### Claim 58 (depends on 48)

The method of claim 48, wherein the β-D-2′-fluoronucleoside has a triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, or pyrazolopyrimidinyl base.

### Claim 59 (depends on 48)

The method of claim 48, wherein the β-D-2′-fluoronucleoside is in substantially pure form.

### Claim 60 (depends on 48)

The method of claim 48, wherein the β-D-2′-fluoronucleoside is administered in the form of a dosage unit.

### Claim 61 (depends on 60)

The method of claim 60, wherein the dosage unit contains 50-1000 mg of the β-D-2′-fluoronucleoside.

### Claim 62 (depends on 60)

The method of claim 60, wherein the dosage unit is in the form of a tablet or capsule.

### Claim 63 (depends on 48)

The method of claim 48, wherein the pharmaceutically acceptable carrier is suitable for oral delivery.

### Claim 64 (depends on 52)

The method of claim 52, wherein the β-D-2′-fluoronucleoside is in substantially pure form.

### Claim 65 (depends on 52)

The method of claim 52, wherein the β-D-2′-fluoronucleoside is administered in the form of a dosage unit.

### Claim 66 (depends on 65)

The method of claim 65, wherein the dosage unit contains 50-1000 mg of the β-D-2′-fluoronucleoside.

### Claim 67 (depends on 65)

The method of claim 65, wherein the dosage unit is in the form of a tablet or capsule.

### Claim 68 (depends on 52)

The method of claim 52, wherein the pharmaceutically acceptable carrier is suitable for oral delivery.

### Claim 69 (depends on 54)

The method of claim 54, wherein the β-D-2′-fluoronucleoside is in substantially pure form.

### Claim 70 (depends on 54)

The method of claim 54, wherein the β-D-2′-fluoronucleoside is administered in the form of a dosage unit.

### Claim 71 (depends on 70)

The method of claim 70, wherein the dosage unit contains 50-1000 mg of the β-D-2′-fluoronucleoside.

### Claim 72 (depends on 70)

The method of claim 70, wherein the dosage unit is in the form of a tablet or capsule.

### Claim 73 (depends on 54)

The method of claim 54, wherein the pharmaceutically acceptable carrier is suitable for oral delivery.

### Claim 74 (depends on 56)

The method of claim 56, wherein the β-D-2′-fluoronucleoside is in substantially pure form.

### Claim 75 (depends on 56)

The method of claim 56, wherein the β-D-2′-fluoronucleoside is administered in the form of a dosage unit.

### Claim 76 (depends on 75)

The method of claim 75, wherein the dosage unit contains 50-1000 mg of the β-D-2′-fluoronucleoside.

### Claim 77 (depends on 75)

The method of claim 75, wherein the dosage unit is in the form of a tablet or capsule.

### Claim 78 (depends on 56)

The method of claim 56, wherein the pharmaceutically acceptable carrier is suitable for oral delivery.

### Claim 79

A method for the treatment of a HCV infection in a host in need thereof comprising administering an effective treatment amount of a β-D-2′-α-fluoronucleoside, or a pharmaceutically acceptable salt or prodrug thereof, optionally in a pharmaceutically acceptable carrier or diluent.

### Claim 80 (depends on 79)

The method of claim 79, wherein the β-D-2′-α-fluoronucleosi de has a pyrimidine base.

### Claim 81 (depends on 80)

The method of claim 80, wherein the pyrimidine base is selected from the group consisting of thymine, uracil, 5-halouracil, 5-fluorouracil, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-aza-pyrimidine, 6-azacytosine, 2- and/or 4-mercaptopyrmidine, C5-alkylpyrimidine, C5-benzylpyrimidine, C5-halopyrimidine, C5-vinylpyrimidine, C5-acetylenic pyrimidine, C5-acyl pyrimidine, C5-hydroxyalkyl purine, C5-amidopyrimidine, C5-cyanopyrimidine, C5-nitropyrimidine, and C5-aminopyrimidine.

### Claim 82 (depends on 80)

The method of claim 80, wherein the pyrimidine base is thymine.

### Claim 83 (depends on 80)

The method of claim 80, wherein the pyrimidine base is uracil.

### Claim 84 (depends on 80)

The method of claim 80, wherein the pyrimidine base is 5-halouracil.

### Claim 85 (depends on 80)

The method of claim 80, wherein the pyrimidine base is cytosine.

### Claim 86 (depends on 80)

The method of claim 80, wherein the pyrimidine base is 5-fluorocytosine.

### Claim 87 (depends on 79)

The method of claim 79, wherein the β-D-2′-α-fluoronucleoside has a purine base.

### Claim 88 (depends on 87)

The method of claim 87, wherein the purine base is selected from the group consisting of N6-alkylpurine, N6-acylpurine (wherein acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl), N6-benzylpurine, N6-halopurine, N6-vinylpurine, N6-acetylenic purine, N6-acyl purine, N6-hydroxyalkyl purine, N6-thioalkyl purine, N2-alkylpurines, N2-alkyl-6-thiopurines, N2-alkylpurine, N2-alkyl-6-thiopurine, 5-azacytidinyl, guanine, adenine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine.

### Claim 89 (depends on 79)

The method of claim 79, wherein the β-D-2′-α-fluoronucleoside has a triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, or pyrazolopyrimidinyl base.

### Claim 90 (depends on 79)

The method of claim 79, wherein the β-D-2′-α-fluoronucleoside is in substantially pure form.

### Claim 91 (depends on 79)

The method of claim 79, wherein the β-D-2′-α-fluoronucleoside is administered in the form of a dosage unit.

### Claim 92 (depends on 91)

The method of claim 91, wherein the dosage unit contains 50-1000 mg of the β-D-2′-α-fluoronucleoside.

### Claim 93 (depends on 91)

The method of claim 91, wherein the dosage unit is in the form of a tablet or capsule.

### Claim 94 (depends on 79)

The method of claim 79, wherein the pharmaceutically acceptable carrier is suitable for oral delivery.

### Claim 95 (depends on 83)

The method of claim 83, wherein the β-D-2′-α-fluoronucleoside is in substantially pure form.

### Claim 96 (depends on 83)

The method of claim 83, wherein the β-D-2′-α-fluoronucleoside is administered in the form of a dosage unit.

### Claim 97 (depends on 96)

The method of claim 96, wherein the dosage unit contains 50-1000 mg of the β-D-2′-α-fluoronucleoside.

### Claim 98 (depends on 96)

The method of claim 96, wherein the dosage unit is in the form of a tablet or capsule.

### Claim 99 (depends on 83)

The method of claim 83, wherein the pharmaceutically acceptable carrier is suitable for oral delivery.

### Claim 100 (depends on 85)

The method of claim 85, wherein the β-D-2′-α-fluoronucleoside is in substantially pure form.

### Claim 101 (depends on 85)

The method of claim 85, wherein the β-D-2′-α-fluoronucleoside is administered in the form of a dosage unit.

### Claim 102 (depends on 101)

The method of claim 101, wherein the dosage unit contains 50-1000 mg of the β-D-2′-α-fluoronucleoside.

### Claim 103 (depends on 101)

The method of claim 101, wherein the dosage unit is in the form of a tablet or capsule.

### Claim 104 (depends on 85)

The method of claim 85, wherein the pharmaceutically acceptable carrier is suitable for oral delivery.

### Claim 105 (depends on 87)

The method of claim 87, wherein the β-D-2′-α-fluoronucleoside is in substantially pure form.

### Claim 106 (depends on 87)

The method of claim 87, wherein the β-D-2′-α-fluoronucleoside is administered in the form of a dosage unit.

### Claim 107 (depends on 106)

The method of claim 106, wherein the dosage unit contains 50-1000 mg of the β-D-2′-α-fluoronucleoside.

### Claim 108 (depends on 106)

The method of claim 106, wherein the dosage unit is in the form of a tablet or capsule.

### Claim 109 (depends on 87)

The method of claim 87, wherein the pharmaceutically acceptable carrier is suitable for oral delivery.