# US 11,298,432 B2 · Method for preparing a marked purine derivative, said derivative and uses thereof

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- Number: US 11,298,432 B2
- Document ID: US11298432B2
- Status: Granted
- Kind: B2
- Application number: 14/633,067
- Filed: 2015-02-26
- Published: 2015-08-27
- Granted: 2022-04-12
- Earliest claimed: 2008-01-03
- Assignees: Commissariat A L'energie Atomique Et Aux Energies Alternatives
- Applicants: Commissariat a l'energie atomique et aux energies alternatives
- Inventors: Louisa Barre; Patrice Marchand
- Web page: https://patentgrep.com/patent/US11298432B2

## CPC

- A61K 51/0491: {Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers}
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- C07B 59/005: {Sugars; Derivatives thereof; Nucleosides; Nucleotides; Nucleic acids}
- C07D 473/04: two oxygen atoms
- C07D 473/40: with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
- 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
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention relates to a method for preparing a 2-fluoropurine marked with the radioisotope 18F comprising a fluorination step for a 2-nitropurine derivative. The present invention comprises a 2-fluoropurine derivative marked with the radioisotope 18F which can be obtained by or during a method according to the invention and its various uses.

## Claims

### Claim 1

A method for performing PET imaging studies in a subject having chronic lymphoid leukemia or a related illness, comprising:
synthesizing a 18F-labeled fludarabine corresponding to the formula (B) from a protected 2-nitropurine derivative having the formula (1c)
in which
R and R′ are identical or different protecting groups;
R2 is hydrogen, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted furanose group, or an optionally substituted pyranose group;
R3 is hydrogen, an optionally substituted alkyl group, an optionally substituted aryl group, a halogen, a —OR8 group or a —SR8 group, with R8 being hydrogen, an optionally substituted alkyl group or an optionally substituted aryl group,
wherein said synthesizing includes the following successive steps of
(i) reacting the protected 2-nitropurine derivative having the formula (1c) with a source of [18F] labeled fluoride ions in a solvent of CH3CN at a temperature between 55° C. and 60° C. for a duration of between 1 min and 30 min to obtain a protected 2-[18F] fluoropurine derivative and optionally a partially unprotected 2-[18F] fluoropurine derivative, and
(ii) unprotecting said protected 2-[18F] fluoropurine derivative and said partially unprotective 2-[18F] fluoropurine derivative to obtain said 18F-labeled fludarabine corresponding to the formula (B) with a yield of 40-60%
administering to the subject the 18F-labeled fludarabine of the formula (B) or one of its salts; and
detecting said 18F-labeled fludarabine.

### Claim 2 (depends on 1)

The method of claim 1, wherein said 18F-labeled fludarabine is a PET probe.

### Claim 3 (depends on 1)

The method of claim 1, wherein the step (ii) consists of reacting said protected 2-[18F] fluoropurine derivative and said partially unprotected 2-[18F] fluropurine derivative with an alcohol, followed by aqueous ammonia and then by heating at a temperature between 50° C. to 90° C. for between 5 min to 45 min.

### Claim 4 (depends on 1)

The method of claim 1, wherein said protected 2-[18F] fluoropurine derivative and optionally the partially unprotected 2-[18F] fluoropurine derivative are obtained with a yield of 70-100%.

### Claim 5

A method for performing PET imaging studies on a subject comprising:
synthesizing a 18F-labeled fludarabine corresponding to the formula (B) from a protected 2-nitropurine derivative having the formula (1c)
in which
R and R′ are identical or different protecting groups;
R2 is hydrogen, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted furanose group, or an optionally substituted pyranose group;
R3 is hydrogen, an optionally substituted alkyl group, an optionally substituted aryl group, a halogen, a —OR8 group or a —SR8 group, with R8 being hydrogen, an optionally substituted alkyl group or an optionally substituted aryl group,
wherein said synthesizing includes the following successive steps of
(i) reacting the protected 2-nitropurine derivative having the formula (1c) with a source of [18F] labeled fluoride ions in a solvent of CH3CN at a temperature between 55° C. and 60° C. for a duration of between 1 min and 30 min to obtain a protected 2-[18F] fluoropurine derivative and optionally a partially unprotected 2-[18F] fluoropurine derivative, and
(ii) unprotecting said protected 2-[18F] fluoropurine derivative and said partially unprotective 2-[18F] fluoropurine derivative to obtain said 18F-labeled fludarabine corresponding to the formula (B) with a yield of 40-60%
administering to the subject the 18F-labeled fludarabine of the formula (B) or one of its salts; and
detecting said 18F-labeled fludarabine,
wherein said PET imaging studies are used for in vivo mapping of malignant hematopoietic cells.

### Claim 6 (depends on 5)

The method of claim 5, wherein the 18F-labeled fludarabine is a PET probe.