Near-infrared chemiluminescent probes for in-vivo imaging

Patent metadata

Field	Value
Publication number	US-11241507-B2
Application number	US-201816616336-A
Country	US
Kind code	B2
Filing date	May 23, 2018
Priority date	May 24, 2017
Publication date	Feb 8, 2022
Grant date	Feb 8, 2022

Abstract

The present invention provides turn-ON dioxetane-based chemiluminescence probes based on the Schapp's adamantylidene-dioxetane probe, which emit light in the near-infrared (NIR) region and are therefore useful for in vivo imaging, as well as compositions and uses thereof.

First claim

What is claimed is:

1. A compound of the formula Ia or Ib:

wherein
R 1 is selected from the group consisting of a linear or branched (C 1 -C 18 )alkyl, and (C 3 -C 7 )cycloalkyl;
R 2 and R 3 each independently is selected from the group consisting of a branched (C 3 -C 18 )alkyl and (C 3 -C 7 )cycloalkyl, or R 2 and R 3 together with the carbon atom to which they are attached form a fused, spiro or bridged cyclic or polycyclic ring,
R 4 is H, or a caging group;
L is absent or is a linker of the formula L1, L2 or L3, optionally substituted at the aromatic ring with one or more substituents each independently selected from the group consisting of (C 1 -C 18 )alkyl and (C 3 -C 7 )cycloalkyl, wherein M is absent or is —O— or —NH—, and the asterisk represents the point of attachment to the group Y, provided that M is —O— or —NH— unless R 4 is 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl or —B(OH) 2 , and when R 4 is H, L is absent;

Y is absent or is —O—, provided that Y is —O— unless R 4 is 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl or —B(OH) 2 , and L is absent;
R 5 is H, or represents at least one electron acceptor group such as halogen, —NO 2 , —CN, —COOR 6 , —C(═O)R 6 and —SO 2 R 6 , each independently attached either ortho or para to the —Y-L-R 4 group;
R 6 each independently is H or —(C 1 -C 18 )alkyl; and
A represents one or two π* acceptor groups, each independently attached either ortho or para to the —Y-L-R 4 group and selected from the group consisting of —CN and —CH═CH-E, wherein E is (a) —CN, —COOH, or —COO(C 1 -C 18 )alkyl optionally interrupted in the alkylene chain with one or more —O— groups; (b) 4-pyridinyl, methylpyridinium-4-yl, 3,3-dimethyl-3H-indolyl, or 1,3,3-trimethyl-3H-indol-1-ium-2-yl, optionally substituted at one or more of the carbon atoms of the aromatic or heteroaromatic ring with a substituent each independently selected from the group consisting of halogen, —CN, —COOH, —COOR, and —C(O)R, wherein R is —(C 1 -C 18 )alkyl; (c) 4-(dicyanomethylene)-4H-chromen-2-yl, 4H-chromen-2-yl-4-one, 9-(dicyanomethylene)-9H-xanthen-3-yl, 9H-xanthen-3-yl-9-one, 2-dicyanomethylenemethyl-thieno[3,2-b]thiophene-5-yl, 3-methylbenzo[d]thiazol-2-yl-3-ium, tetrathiafulvalenyl, 1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-yl, benzo[d]oxazol-2-yl, benzo[d]thiazol-2-yl, 1H-benzo[d]imidazol-2-yl, 2,6-di-tert-butylpyrylium-4-yl, 1-methylquinolin-1-ium-4-yl, or 4-dicyanomethylene-2-methyl-4H-pyran-6-yl, optionally substituted at one or more of the carbon atoms of the aromatic or heteroaromatic ring with a substituent each independently selected from the group consisting of halogen, —CN, —COOH, —COOR, and —C(O)R, wherein R is —(C 1 -C 18 )alkyl; or (d) 5,5-dimethyl-3-cyano-2-dicyanomethylene-2,5-dihydrofuran-4-yl, or 5,5-dimethyl-3-cyano-2-oxo-2,5-dihydrofuran-4-yl, provided that at least one of said π* acceptor groups is —CH═CH-E, wherein E is selected from groups (c) and (d).

2. The compound of claim 1 , wherein:
(i) R 1 is a linear or branched (C 1 -C 8 )alkyl; or
(ii) R 2 and R 3 together with the carbon atom to which they are attached form a fused, spiro or bridged polycyclic ring; or
(iii) said caging group is selected from the group consisting of:

wherein Pep is a group comprising a peptide moiety consisting of at least two amino acid residues and linked to the aniline group via a carboxylic group of said peptide moiety; or

(iv) R 5 is H, or an electron acceptor group selected from the group consisting of halogen and —CN, attached either ortho or para to the —Y-L-R 4 group.

3. The compound of claim 2 , wherein R 2 and R 3 together with the carbon atom to which they are attached form adamantyl.

4. The compound of claim 2 , wherein R 5 is halogen or —CN, attached ortho to the —Y-L-R 4 group.

5. The compound of claim 1 , wherein A represents one or two π* acceptor groups, wherein:
(i) one of said π* acceptor groups is of the formula —CH═CH-E, wherein E is (a) 4-(dicyanomethylene)-4H-chromen-2-yl, 4H-chromen-2-yl-4-one, 9-(dicyanomethylene)-9H-xanthen-3-yl, 9H-xanthen-3-yl-9-one, 2-dicyanomethylenemethyl-thieno[3,2-b]thiophene-5-yl, 3-methylbenzo[d]thiazol-2-yl-3-ium, tetrathiafulvalenyl, 1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-yl, benzo[d]oxazol-2-yl, benzo[d]thiazol-2-yl, 1H-benzo[d]imidazol-2-yl, 2,6-di-tert-butylpyrylium-4-yl, 1-methylquinolin-1-ium-4-yl, or 4-dicyanomethylene-2-methyl-4H-pyran-6-yl, optionally substituted at one or more of the carbon atoms of the aromatic or heteroaromatic ring; or (b) 5,5-dimethyl-3-cyano-2-dicyanomethylene-2,5-dihydrofuran-4-yl, or 5,5-dimethyl-3-cyano-2-oxo-2,5-dihydrofuran-4-yl; and
(ii) the other one of said π* acceptor groups, when present, is of the formula —CH═CH-E, wherein E is —CN, —COOH, or —COO(C 1 -C 18 )alkyl optionally interrupted in the alkylene chain with one or more —O— groups.

6. The compound of claim 5 , wherein:
(i) one of said π* acceptor groups is of the formula —CH═CH-E, wherein E is 4-(dicyanomethylene)-4H-chromen-2-yl optionally substituted at one or more of the carbon atoms of the aromatic or heteroaromatic ring, or 5,5-dimethyl-3-cyano-2-dicyanomethylene-2,5-dihydrofuran-4-yl; and
(ii) the other one of said π* acceptor groups, when present, is of the formula —CH═CH-E, wherein E is —CN, —COOH, or —COO(C 1 -C 18 )alkyl optionally interrupted in the alkylene chain with one or more —O— groups.

7. The compound of claim 1 , wherein:
R 1 is a linear or branched (C 1 -C 8 )alkyl;
R 2 and R 3 together with the carbon atom to which they are attached form a fused, spiro or bridged polycyclic ring;
R 5 is H, or an electron acceptor group selected from the group consisting of halogen and —CN, attached either ortho or para to the —Y-L-R 4 group; and
A represents one or two π* acceptor groups, wherein
(i) one of said π* acceptor groups is of the formula —CH═CH-E, wherein E is (a) 4-(dicyanomethylene)-4H-chromen-2-yl, 4H-chromen-2-yl-4-one, 9-(dicyanomethylene)-9H-xanthen-3-yl, 9H-xanthen-3-yl-9-one, 2-dicyanomethylenemethyl-thieno[3,2-b]thiophene-5-yl, 3-methylbenzo[d]thiazol-2-yl-3-ium, tetrathiafulvalenyl, 1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-yl, benzo[d]oxazol-2-yl, benzo[d]thiazol-2-yl, 1H-benzo[d]imidazol-2-yl, 2,6-di-tert-butylpyrylium-4-yl, 1-methylquinolin-1-ium-4-yl, or 4-dicyanomethylene-2-methyl-4H-pyran-6-yl, optionally substituted at one or more of the carbon atoms of the aromatic or heteroaromatic ring; or (b) 5,5-dimethyl-3-cyano-2-dicyanomethylene-2,5-dihydrofuran-4-yl, or 5,5-dimethyl-3-cyano-2-oxo-2,5-dihydrofuran-4-yl; and
(ii) the other one of said π* acceptor groups, when present, is of the formula —CH═CH-E, wherein E is —CN, —COOH, or —COO(C 1 -C 18 )alkyl optionally interrupted in the alkylene chain with one or more —O— groups.

8. The compound of claim 7 , wherein:
R 1 is methyl, ethyl, or isopropyl;
R 2 and R 3 together with the carbon atom to which they are attached form adamantyl;
R 5 is H, or is an electron acceptor group selected from the group consisting of halogen and —CN, attached ortho to the —Y-L-R 4 group; and
A represents one or two π* acceptor groups, wherein one of said π* acceptor groups is of the formula —CH═CH-E, wherein E is 4-(dicyanomethylene)-4H-chromen-2-yl, or 5,5-dimethyl-3-cyano-2-dicyanomethylene-2,5-dihydrofuran-4-yl; and the other one of said π* acceptor groups, when p

Assignees

• Univ Ramot

Inventors

• Shabat Doron
• Green Ori

Classifications

• C09B23/145

  the ethylene chain carrying an heterocyclic residue, e.g. heterocycle-CH=CH-C6H5 · CPC title

• C07C59/74

  containing —CHO groups · CPC title

• C07D407/10

  linked by a carbon chain containing aromatic rings · CPC title

• C09K11/06

  containing organic luminescent materials · CPC title

• A61K49/0021 Primary

  the fluorescent group being a small organic molecule · CPC title