Ionic liquid supported organotin reagents for the manufacturing of radiopharmaceuticals compounds

Patent metadata

Field	Value
Publication number	US-9714261-B2
Application number	US-201515109856-A
Country	US
Kind code	B2
Filing date	Jan 7, 2015
Priority date	Jan 7, 2014
Publication date	Jul 25, 2017
Grant date	Jul 25, 2017

Abstract

An ionic liquid supported organotin reagent of formula (I)

A process for manufacturing the ionic liquid supported organotin reagent of formula (I), a process for manufacturing an halogenated or radio-halogenated compound using compound of formula (I), a device for implementing the halogenating process and a kit including the compound of formula (I) are also described.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein:
X − represents an anion;
n represents an integer ranging from 3 to 10;
R 1 represents an alkyl group or a PEG chain;
R 2 and R 3 each independently represent an alkyl group;
R 5 represents H, alkyl or aryl;
R 4 represents:
an aryl vector; or
a group selected from aryl and heteroaryl, substituted by one or more substituents -L-M wherein:

L represents a single bound or a linker selected from aryl, heteroaryl, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl or a combination thereof;
said groups being optionally substituted by at least one group selected from oxo, thioxo, hydroxyl, ether, carboxylic acid, ester, alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocyclyl, alkynyl, cycloalkynyl, amine, amide, guanidine, imino, nitro, nitrile, azide, sulfhydryl, sulfide, thioester, thioether, sulfite, sulfate, phosphine, phosphite and phosphate, halogen;
said groups being optionally interrupted or terminated by —O—, —S—, —NR 6 — wherein R 6 is H or alkyl, or a combination thereof; and
optionally L additionally comprises a residue of a reactive group through which L is bounded to M;
M represents:
a reactive function selected from carboxylic acid, nitrile, ester, activated ester, aldehyde, acetal, ketone, ketal, alkyne, azide, alkene, diene, maleimide, protected maleimide, hydroxyl, phenol, 2-aminophenol, thiol, thioester, thioether, thiosulfonate, primary amine, secondary amine, tertiary amine, alkoxyamine, aniline, amide, phosphine, alkyl phosphate, isocyanates, isothiocyanates, hydrazide, hydrazine, tosylate ester, vinyl sulfone, carbamate, carbonate ester, 4-phenyl-1,2,4-triazole-3,5-dione, sulphide, azidoalkyl and azidoaryl; or
a bioactive group selected from amino acid, biogenic amine, peptide, heteropeptide, protein, antibody or fragment thereof, monobody, affibody, antibody construct, saccharide, polysaccharide, benzylguanine, biotin, avidin, nucleotide, oligonucleotide, microRNA, hapten, aptamer, ligand, enzyme, enzyme substrate, steroid, hormone, porphyrin, neurotransmitters, sympatomimetic drug, vitamin, phosphonate, nanocarrier, liposome, dendrimer, carbon nanotube and combinations thereof;
said aryl or heteroaryl being optionally further substituted by one or more substituents selected from hydroxyl; linear, cyclic or branched alkyl comprising 1, 2, 3, 4, 5 or 6 carbon atoms; aryl; heteroaryl; heterocyclyl; arylheterocyclyl; alkoxy; halogen; nitro; cyano; azido; aldehyde; boronato; phenyl; CF 3 ; —CH(OH) (CF 3 ); —CH(OCH 2 OCH 3 ) (CF 3 ); methylenedioxy; ethylenedioxy; SO 2 NRR′, NRR′, COOR, CONRR′, NRCOR′ wherein R and R′ are each independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl and aryl;
wherein the aryl vector is selected from the group consisting of:

2. The compound according to claim 1 , of formula (I′)

wherein
X − , n, R 1 , R 2 , R 3 and R 5 are as previously defined,
-L 1 -M 1 and -L 2 -M 2 represent each independently -L-M, wherein -L-M is previously defined; and
R 9 , R 10 and R 11 represent each independently a group selected from hydroxyl; linear, cyclic or branched alkyl comprising 1, 2, 3, 4, 5 or 6 carbon atoms; aryl; heteroaryl; heterocyclyl; arylheterocyclyl; alkoxy; halogen; nitro; cyano; azido; aldehyde; boronato; phenyl; CF 3 ; —CH(OH) (CF 3 ); —CH(OCH 2 OCH 3 ) (CF 3 ); methylenedioxy; ethylenedioxy; SO 2 NRR′, NRR′, COOR, CONRR′, NRCOR′ wherein R and R′ are each independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl and aryl.

3. The compound according to claim 1 , of formula (I″)

wherein
X − , n, R 1 , R 2 , R 3 , R 5 and -L-M are as previously defined; and
R 9 , R 10 , R 11 and R 12 represent each independently a group selected from hydroxyl; linear, cyclic or branched alkyl comprising 1, 2, 3, 4, 5 or 6 carbon atoms; aryl; heteroaryl; heterocyclyl; arylheterocyclyl; alkoxy; halogen; nitro; cyano; azido; aldehyde; boronato; phenyl; CF 3 ; —CH(OH) (CF 3 ); —CH(OCH 2 OCH 3 ) (CF 3 ); methylenedioxy; ethylenedioxy; SO 2 NRR′, NRR′, COOR, CONRR′, NRCOR′ wherein R and R′ are each independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl and aryl.

4. The compound according to claim 1 , of formula (I′″)

wherein
X − , n, R 1 , R 2 , R 3 R 5 and L are as previously defined;
R 9 , R 10 , R 11 and R 12 represent each independently a group selected from hydroxyl; linear, cyclic or branched alkyl comprising 1, 2, 3, 4, 5 or 6 carbon atoms; aryl; heteroaryl; heterocyclyl; arylheterocyclyl; alkoxy; halogen; nitro; cyano; azido; aldehyde; boronato; phenyl; CF 3 ; —CH(OH) (CF 3 ); —CH(OCH 2 OCH 3 ) (CF 3 ); methylenedioxy; ethylenedioxy; SO 2 NRR′, NRR′, COOR, CONRR′, NRCOR′ wherein R and R′ are each independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl and aryl; and
A represents a reactive function selected from carboxylic acid, nitrile, ester, activated ester, aldehyde, acetal, ketone, ketal, alkyne, azide, alkene, diene, maleimide, protected maleimide, hydroxyl, phenol, 2-aminophenol, thiol, thioester, thioether, thiosulfonate, primary amine, secondary amine, tertiary amine, alkoxyamine, aniline, amide, phosphine, alkyl phosphate, isocyanates, isothiocyanates, hydrazide, hydrazine, tosylate ester, vinyl sulfone, carbamate, carbonate ester, 4-phenyl-1,2,4-triazole-3,5-dione, sulphide, azidoalkyl and azidoaryl.

5. A process for manufacturing a compound of formula (I) according to claim 1 ,
comprising:
1) reacting an activated mixture of zinc and CoBr2 with a compound of formula (IV)
R 4 —Br  (IV)

wherein R 4 is as previously defined;
in presence of dibromoethane,
to afford the corresponding zinc derivative;
2) reacting the zinc derivative prepared in step 1) with ionic liquid (V) (Br − ),

wherein n, R 1 , R 2 , R 3 and R 5 are as previously defined;
to form compound of formula (I) (Br − )

Assignees

• Centre Nat De La Rech Scient (Cnrs)
• Univ Nantes
• Univ D'Angers
• Univ Maine
• Inserm (Institut Nat De La Sante Et De La Rech Medicale)
• Ct Hospitalier Universitaire Nantes
• Univ D' Angers

Inventors

• Legoupy Stephanie
• Faye Djibril
• Gestin Jean-Francois
• Rajerison Holisoa
• Faivre-Chauvet Alain
• Boeda Fabien

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• B01J2219/24

  Stationary reactors without moving elements inside · CPC title

• C07D207/46

  with hetero atoms directly attached to the ring nitrogen atom · CPC title

• C07B59/008

  Peptides; Proteins · CPC title

• C07K16/40

  against enzymes · CPC title