Fused cyclooctyne compounds and their use in metal-free click reactions

Patent metadata

Field	Value
Publication number	US-2025084022-A1
Application number	US-202418955142-A
Country	US
Kind code	A1
Filing date	Nov 21, 2024
Priority date	Apr 27, 2010
Publication date	Mar 13, 2025
Grant date	—

Abstract

The invention relates to fused cyclooctyne compounds, and to a method for their preparation. The invention also relates to a conjugate wherein a fused cyclooctyne compound according to the invention is conjugated to a label, and to the use of these conjugates in bioorthogonal labeling, imaging and/or modification, such as for example surface modification, of a target molecule. The invention further relates to a method for the modification of a target molecule, wherein a conjugate according to the invention is reacted with a compound comprising a 1,3-dipole or a 1,3-(hetero)diene.

First claim

1 . A modified target molecule of Formula (VIIIa), (VIIIb1), (VIIIb2), (VIIIc1), (VIIIc2), (IXa), (IXb1), (IXb2), (IXc1) or (IXc2):

wherein:
n is 0 to 8;
p is 0 or 1;
R 3 is selected from the group consisting of [(L) p —Q], hydrogen, halogen, C 1 -C 24 alkyl groups, C 6 -C 24 (hetero)aryl groups, C 7 -C 24 alkyl(hetero)aryl groups, and C 7 -C 24 (hetero)arylalkyl groups, the alkyl groups optionally being interrupted by one of more hetero-atoms selected from the group consisting of O, N, and S, wherein the alkyl groups, (hetero)aryl groups, alkyl(hetero)aryl groups, and (hetero)arylalkyl groups are independently optionally substituted with one or more substituents independently selected from the group consisting of C 1 -C 12 alkyl groups, C 2 -C 12 alkenyl groups, C 2 -C 12 alkynyl groups, C 3 -C 12 cycloalkyl groups, C 1 -C 12 alkoxy groups, C 2 -C 12 alkenyloxy groups, C 2 -C 12 alkynyloxy groups, C 3 -C 12 cycloalkyloxy groups, halogens, amino groups, oxo groups, and silyl groups, wherein the alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, alkoxy groups, alkenyloxy groups, alkynyloxy groups, and cycloalkyloxy groups are optionally substituted, the alkyl groups, the alkoxy groups, the cycloalkyl groups, and the cycloalkoxy groups being optionally interrupted by one of more hetero-atoms selected from the group consisting of O, N, and S, wherein the silyl groups are represented by the formula (R 4 ) 3 Si—, wherein R 4 is independently selected from the group consisting of C 1 -C 12 alkyl groups, C 2 -C 12 alkenyl groups, C 2 -C 12 alkynyl groups, C 3 -C 12 cycloalkyl groups, C 1 -C 12 alkoxy groups, C 2 -C 12 alkenyloxy groups, C 2 -C 12 alkynyloxy groups, and C 3 -C 12 cycloalkyloxy groups, wherein the alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, alkoxy groups, alkenyloxy groups, alkynyloxy groups, and cycloalkyloxy groups are optionally substituted, the alkyl groups, the alkoxy groups, the cycloalkyl groups, and the cycloalkoxy groups being optionally interrupted by one of more hetero-atoms selected from the group consisting of O, N, and S;
L is a linking group selected from linear or branched C 1 -C 24 alkylene groups, C 2 -C 24 alkenylene groups, C 2 -C 24 alkynylene groups, C 3 -C 24 cycloalkylene groups, C 5 -C 24 cycloalkenylene groups, C 8 -C 24 cycloalkynylene groups, C 7 -C 24 alkyl(hetero)arylene groups, C 7 -C 24 (hetero)arylalkylene groups, C 8 -C 24 (hetero)arylalkenylene groups, and C 9 -C 24 (hetero)arylalkynylene groups, the alkylene groups, alkenylene groups, alkynylene groups, cycloalkylene groups, cycloalkenylene groups, cycloalkynylene groups, alkyl(hetero)arylene groups, (hetero)arylalkylene groups, (hetero)arylalkenylene groups, and (hetero)arylalkynylene groups optionally being substituted with one or more substituents independently selected from the group consisting of C 1 -C 12 alkyl groups, C 2 -C 12 alkenyl groups, C 2 -C 12 alkynyl groups, C 3 -C 12 cycloalkyl groups, C 5 -C 12 cycloalkenyl groups, C 8 -C 12 cycloalkynyl groups, C 1 -C 12 alkoxy groups, C 2 -C 12 alkenyloxy groups, C 2 -C 12 alkynyloxy groups, C 3 -C 12 cycloalkyloxy groups, halogens, amino groups, oxo groups, and silyl groups, wherein the silyl groups are represented by the formula (R 4 ) 3 Si—, wherein R 4 is defined as above;
Q is bonded to a label or is a functional group selected from the group consisting of hydrogen, halogen, R 6 , —CH═C(R 6 ) 2 , —C≡CR 6 , —[C(R 6 ) 2 C(R 6 ) 2 O] q —R 6 , wherein q is in the range of 1 to 200, —CN, —N 3 , —NCX, —XCN, —XR 6 , —N(R 6 ) 2 , — + N(R 6 ) 3 , —C(X)N(R 6 ) 2 , —C(R 6 ) 2 XR 6 , —C(X)R 6 , —C(X)XR 6 , —S(O)R 6 , —S(O) 2 R 6 , —S(O)OR 6 , —S(O) 2 OR 6 , —S(O)N(R 6 ) 2 , —S(O) 2 N(R 6 ) 2 , —OS(O)R 6 , —OS(O) 2 R 6 , —OS(O)OR 6 , —OS(O) 2 OR 6 , —P(O)(R 6 )(OR 6 ), —P(O)(OR 6 ) 2 , —OP(O)(OR 6 ) 2 , —Si(R 6 ) 3 , —XC(X)R 6 , —XC(X)XR 6 , —XC(X)N(R 6 ) 2 , —N(R 6 )C(X)R 6 , —N(R 6 )C(X)XR 6 , and —N(R 6 )C(X)N(R 6 ) 2 , wherein X is oxygen or sulphur, and wherein R 6 is independently selected from the group consisting of hydrogen, halogen, C 1 -C 24 alkyl groups, C 6 -C 24 (hetero)aryl groups, C 7 -C 24 alkyl(hetero)aryl groups, and C 7 -C 24 (hetero)arylalkyl groups;
R 1 is independently selected from the group consisting of hydrogen, C 1 -C 24 alkyl groups, C 6 -C 24 (hetero)aryl groups, C 7 -C 24 alkyl(hetero)aryl groups, and C 7 -C 24 (hetero)arylalkyl groups;
R 2 is independently selected from the group consisting of halogen, —OR 6 , —NO 2 , —CN, —S(O) 2 R 6 , C 1 -C 12 alkyl groups, C 1 -C 12 aryl groups, C 1 -C 12 alkylaryl groups, and C 1 -C 12 arylalkyl groups, wherein R 6 is as defined above, and wherein the alkyl groups, aryl groups, alkylaryl groups, and arylalkyl groups are optionally substituted; and
wherein:
the label is selected from the group consisting of fluorophores, biotin, polyethylene glycol chains, polypropylene glycol chains, mixed polyethylene/polypropylene glycol chains, radioactive isotopes, steroids, pharmaceutical compounds, lipids, peptides, glycans, nucleotides, and peptide tags; and
“target” refers to a target molecule selected from the group consisting of biomolecules.

2 . The modified target molecule according to claim 1 , wherein the target molecule is selected from peptides, proteins, glycans, lipids, nucleic acids, enzymes, and hormones.

3 . The modified target molecule according to claim 2 , wherein the target molecule is selected from peptides, proteins, glycans, lipids, and nucleic acids.

4 . The modified target molecule according to claim 1 , wherein Q is bonded to a label selected from the group consisting of pharmaceutical compounds, lipids, peptides, glycans, and nucleotides.

5 . The modified target molecule according to claim 4 , wherein the label is selected from the group consisting of pharmaceutical compounds and peptides.

6 . The modified target molecule according to claim 1 , wherein the target molecule is selected from peptides, proteins, glycans, lipids and nucleic acids and the label selected from the group consisting of pharmaceutical compounds, lipids, peptides, glycans, and nucleotides.

7 . The modified target molecule according to claim 1 , which is of Formula (VIIIa), (VIIIb1), (VIIIb2), (VIIIc1), or (VIIIc2).

8 . The modified target molecule according to claim 1 , which is of Formula (VIIIa) or (IXa).

9 . The modified target molecule according to claim 1 , which is of Formula (VIIIa).

10 . The modified target molecule according to claim 1 , wherein p is 1 and L is CH 2 .

11 . The modified target molecule according to claim 1 , wherein R 1 is hydrogen.

12 . The modified target molecule according to claim 1 , wherein n is 0.

13 . The modified target molecule according to claim 1 , wherein Q is bonded to a label, p is 1, L is CH 2 , R 1 is hydrogen, and n is 0.

14 . A composition comprising the modified target molecule according to claim 1 and a pharmaceutically acceptable carrier.

Assignees

• Synaffix Bv

Inventors

• Van Delft Floris Louis
• Rutjes Floris Petrus Johannes Theodorus
• Dommerholt Frederik Jan

Classifications

• G01N2021/6439

  with indicators, stains, dyes, tags, labels, marks · CPC title

• G01N21/6428

  Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" (in vivo A61B5/00; immunoassay G01N33/53) · CPC title

• G01N33/582

  with fluorescent label · CPC title

• C07K14/47

  from mammals · CPC title

• C07D495/04

  Ortho-condensed systems · CPC title