3-aryl propiolonitrile compounds for thiol labeling

Patent metadata

Field	Value
Publication number	US-2016145199-A1
Application number	US-201414899883-A
Country	US
Kind code	A1
Filing date	Jul 4, 2014
Priority date	Jul 4, 2013
Publication date	May 26, 2016
Grant date	—

Abstract

The present invention relates to a process for labeling compounds comprising thiol moieties with 3-arylpropiolonitrile compounds, to 3-arylpropiolonitrile compounds substituted with tag moieties and to specific 3-arylpropiolonitrile linkers.

First claim

1 . Process for the preparation of a labeled compound comprising a thiol moiety, comprising contacting a compound comprising a thiol moiety with a compound of formula (I):

wherein each of R 1 to R 5 is independently selected in the group consisting of:
hydrogen atoms,
alkyl, alkene or alkyne groups, optionally interrupted by at least one heteroatom selected among O, N and S,
aryl groups,
alkoxy groups,
halogen atoms,
amino (—NRR') groups, wherein R and R′ are independently hydrogen atoms, alkyl, alkene, alkyne or aryl groups,
hydroxylamine (—ONH 2 ) group,
hydrazine (—NH—NH 2 ) group,
nitro (—NO 2 ) group,
azido (—N 3 ) group,
diazonium (—N 2 | ) group,
maleimide group,
alkyl- or aryl-carboxyl (—C(═O)OR) groups,
alkyl- or aryl-carbonyl (—C(═O)R) groups,
hydroxyl (—OH) group,
boronic acid —B(OR″) 2 group, wherein R″ is a hydrogen atom or an alkyl group,
phosphine or phosphonium groups,
isocyanate (—N═C═O) or isothiocyanate (—N═C═S) group,
chlorosulfonyl (—SO 2 Cl) group,
a —O—C(═O)—C(N 2 )—CF 3 group or a —C(═O)—C(N 2 )—CF 3 group,
activated esters, such as —C(═O)—NHS, perfluorinated esters and acylureas,
a —C≡C—C≡N group,
tags, and
alkyl groups substituted by at least one of the previously listed groups,
alternatively, two of R1 to R5 may form together and with the carbon atoms of the phenyl ring to which they are linked a mono or polycyclic ring, and

wherein at least one of R 1 to R 5 comprises a tag moiety, selected from the group consisting of chemical groups appropriate for allowing one or several of the following:
detection of the compound,
vectorization of an agent of interest by the compound,
solubilization of the compound,
stabilization of the compound,
improvement of the extraction and/or purification of the compound,
modification of at least one of the ADME (Administration Distribution Metabolisation Excretion) parameters of the compound;
addition of bioactivity to the compound; and
addition of an appropriate functionality for click-chemistry.

2 . Compound of the formula (I):

wherein R 1 to R 5 are as defined in claim 1 , and wherein at least one of R 1 to Rs comprises a tag moiety, selected from the group consisting of chemical groups appropriate for allowing one or several of the following:
detection of the compound,
vectorization of an agent of interest by the compound,
solubilization of the compound,
stabilization of the compound,
improvement of the extraction and/or purification of the compound,
modification of at least one of the ADME (Administration Distribution Metabolisation Excretion) parameters of the compound;
addition of bioactivity to the compound; and
addition of an appropriate functionality for click-chemistry.

3 . Compound according to claim 2 , wherein the compound is selected from the group consisting of:

4 . Compound of the formula (II):

wherein each of R 1 to R 5 is selected independently in the group consisting of:
hydrogen atoms,
alkyl, alkene or alkyne groups, optionally interrupted by at least one heteroatom selected among O, N and S,
aryl groups,
alkoxy groups,
halogen atoms,
amino (—NRR′) groups, wherein R and R′ are independently hydrogen atoms, alkyl, alkene, alkyne or aryl groups,
hydroxylamine (—ONH 2 ) group,
hydrazine (—NH—NH 2 ) group,
nitro (—NO 2 ) group,
azido (—N 3 ) group,
diazonium (—N 2 + ) group,
maleimide group,
alkyl- or aryl-carboxyl (—C(═O)OR) groups,
alkyl- or aryl-carbonyl (—C(═O)R) groups,
hydroxyl (—OH) group,
boronic —B(OR″) 2 group, wherein R″ is a hydrogen atom or an alkyl group,
phosphine or phosphonium groups,
isocyanate (N═C═O) or isothiocyanate (—N═C═S) group,
chlorosulfonyl (—SO 2 Cl) group,
a O—C(═O)—C(N 2 )—CF 3 group or a —C(═O)—C(N 2 )_CF 3 group,
activated esters, such as —C(═O)—NHS, perfluorinated esters and acylureas,
tags, and
alkyl groups substituted by at least one of the previously listed groups,
alternatively, two of R1 to R5 may form together and with the carbon atoms of the phenyl ring to which they are linked a mono or polycyclic ring, and
wherein at least one of R 1 to R 5 comprises a maleimide, NHS-ester, azide or alkyne moiety.

5 . Compound according to claim 4 , wherein the compound is selected from the group consisting of:

6 . Compound of formula (II):

wherein each of R 1 to R 5 is selected independently in the group consisting of:
hydrogen atoms,
alkyl, alkene or alkyne groups, optionally interrupted by at least one heteroatom selected among O, N and S,
aryl groups,
alkoxy groups,
halogen atoms,
amino (—NRR′) groups, wherein R and R′ are independently hydrogen atoms, alkyl, alkene, alkyne or aryl groups,
hydroxylamine (—ONH 2 ) group,
hydrazine (—NH—NH 2 ) group,
nitro (—NO 2 ) group,
azido (—N 3 ) group,
diazonium (—N 2 + ) group,
maleimide group,
alkyl- or aryl-carboxyl (—C(═O)OR) groups,
alkyl- or aryl-carbonyl (—C(═O)R) groups,
hydroxyl (—OH) group,
boronic —B(OR″) 2 group, wherein R″ is a hydrogen atom or an alkyl group,
phosphine or phosphonium groups,
isocyanate (N═C═O) or isothiocyanate (—N═C═S) group,
chlorosulfonyl (—SO 2 Cl) group,
a O—C(═O)—C(N 2 )—CF 3 group or a —C(═O)—C(N 2 )—CF 3 group,
activated esters, such as —C(═O)—NHS, perfluorinated esters and acylureas,
tags, and
alkyl groups substituted by at least one of the previously listed groups,
alternatively two of R1 to R5 may form together and with the carbon atoms of the phenyl ring to which they are linked a mono or polycyclic ring, and
wherein at least one of R1 to R5 is bonded to a compound of interest selected from the group consisting of a fluorophore, a group of atoms comprising at least one radioactive atom, a group of atoms of known mass, a ligand, a drug, a therapeutic agent, a biomolecule, a DNA fragment, a nanoobject, or a support.

7 . Compound according to claim 6 , wherein the compound of interest is a biomolecule, wherein the biomolecule is an antibody or a protein.

8 . Compound of formula (III):

wherein

Assignees

• Univ Strasbourg
• Centre Nat Rech Scient

Inventors

• Wagner Alain
• Koniev Oleksandr

Classifications

• C07C319/02

  of thiols · CPC title

• G01N33/58

  involving labelled substances (G01N33/53 takes precedence) · CPC title

• C12Y302/01017

  Lysozyme (3.2.1.17) · CPC title

• C07D311/82

  Xanthenes · CPC title

• C07K16/30

  from tumour cells · CPC title