Activatable fluorogenic compounds and uses thereof as near infrared probes

Patent metadata

Field	Value
Publication number	US-2016229840-A1
Application number	US-201615131129-A
Country	US
Kind code	A1
Filing date	Apr 18, 2016
Priority date	Mar 15, 2011
Publication date	Aug 11, 2016
Grant date	—

Abstract

Novel fluorogenic compounds designed such that upon a chemical event, compounds capable of emitting NIR light are generated, are disclosed. The compounds comprise two or more acceptor-containing moieties and a cleavable donor-containing moiety, being in complete pi-electrons conjugation and being such that no delocalization of pi-electrons is enabled. Also disclosed are fluorescent compounds generated upon subjecting the fluorogenic compounds to a chemical event (e.g., deprotonation). Also disclosed are uses of the fluorogenic compounds as NIR probed with a Turn-ON mechanism in monitoring presence and/or level of various analytes.

First claim

What is claimed is:

1 . A fluorogenic compound comprising three acceptor-containing moieties and a donor-containing moiety arranged such that:
(i) said three acceptor-containing moieties and said donor-containing moiety form a conjugated π-electron system devoid of resonating electrons, such that the compound is incapable of emitting NIR infrared light; and (ii) upon a chemical event, said donor-containing moiety rearranges so as to transfer π-electrons to one of said acceptor-containing moieties and, as a result, said acceptor-containing moiety becomes a donor-containing moiety to the other acceptor-containing moieties, to thereby enable emission of near infrared light, wherein each of said acceptor-containing moieties is independently selected from an ammonium form of an indolenine or an ammonium form of a pyridine, and wherein said donor containing moiety comprises an aryl substituted by at least one electron-donating group, and is such that upon said chemical event, it rearranges by undergoing a quinonemethidine-like rearrangement, said donor-containing moiety being independently linked to each of said three acceptor-containing moieties either directly or via a linking moiety, said linking moiety comprising a carbomethine-containing chain of at least one —CR′═CR″— moiety, wherein R′ and R″ are each independently hydrogen, alkyl or cycloalkyl, or, alternatively, R′ and R″ form together an aryl, and is such that said acceptor-containing moieties and said donor containing moiety form said conjugated π-electron system.

2 . The fluorogenic compound of claim 1 , wherein each of said acceptor-containing moieties is an ammonium form of an indolenine.

3 . The fluorogenic compound of claim 1 , wherein each of said acceptor-containing moieties is an ammonium form of a pyridine.

4 . The fluorogenic compound of claim 1 , wherein one of said acceptor-containing moieties is an ammonium form of an indolenine and another one of said acceptor-containing moieties is an ammonium form of a pyridine.

5 . The fluorogenic compound of claim 1 , wherein said donor-containing moiety comprises phenyl substituted by hydroxy.

6 . The fluorogenic compound of claim 1 , selected from:

7 . The fluorogenic compound of claim 1 , wherein said chemical event is generated by an analyte.

8 . The fluorogenic compound of claim 1 , wherein said chemical event comprises cleavage in said donor-containing moiety.

9 . The fluorogenic compound of claim 1 , wherein said donor-containing moiety comprises a trigger unit, and wherein said chemical event comprises cleavage of said trigger unit.

10 . The fluorogenic compound of claim 9 , wherein said cleavage of said trigger unit is effected in the presence of an analyte.

11 . The compound of claim 7 , wherein said analyte is associated with a medical condition.

12 . The compound of claim 11 , wherein said analyte is an enzyme overexpressed in organs or tissues afflicted by said medical condition.

13 . The compound of claim 11 , wherein said analyte is a substance that is produced in organs or tissues in response to said medical condition.

14 . The fluorogenic compound of claim 1 , further comprising a therapeutically active agent being attached to said donor-containing moiety.

15 . The fluorogenic compound of claim 14 , wherein said therapeutically active agent is attached to said donor-containing moiety such that upon said chemical event, said therapeutically active agent is released.

16 . A method of determining a presence and/or level of an analyte in a sample, the method comprising contacting the sample with the fluorogenic compound of claim 7 ; and collecting a light emitted from said sample, wherein a presence and/or level of said light is indicative of the presence and/or level of said analyte.

17 . The method of claim 16 , wherein said light has a wavelength within a near infrared range.

18 . The method of claim 16 , wherein said analyte is associated with a medical condition, and wherein determining a presence and/or level of said analyte is being for determining a presence or progression of said medical condition.

19 . The method of claim 18 , wherein said analyte is an enzyme overexpressed in organs or tissues afflicted by said medical condition.

20 . The method of claim 19 , wherein said analyte is produced in response to said medical condition.

21 . A method of imaging a sample, the method comprising contacting the sample with the fluorogenic compound of claim 1 , and collecting a light emitted from said sample.

22 . The method of claim 21 , wherein said light has a wavelength within a near infrared range.

23 . A pharmaceutical composition comprising the fluorogenic compound of claim 1 and a pharmaceutically acceptable carrier.

24 . The pharmaceutical composition of claim 23 , wherein said chemical event is generated by an analyte and wherein the composition is identified for use in determining a presence and/or level of said analyte in a sample.

25 . A fluorescent molecule having the general Formula IVA:

wherein:
R 1 and R 2 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl, heteroalicyclic, heteroaryl;
p and q are each independently an integer of from 0 to 4;
R 3 and R 4 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroalicyclic, heteroaryl, alkoxy, hydroxy, thiohydroxy, thioalkoxy, aryloxy, thioaryloxy, amino, nitro, halo, trihalomethyl, cyano, amide, carboxy, sulfonyl, sulfoxy, sulfinyl, sulfonamide, and a saccharide;
R′ and R″ are each independently hydrogen, alkyl or cycloalkyl, or, alternatively, R′ and R″ form together an aryl; and
W is a group that comprises an aromatic moiety, wherein the π-electrons of said aromatic moiety are conjugated to the π electrons of said —(CR′═CR″)p- and said —(CR′═CR″)q-, such that delocalization of π electrons is effected between the ammonium and the amine groups in the molecule,
or having the general Formula IVB:

wherein:
D 1 and D 2 are each independently an aromatic moiety;

X 1 and X 2 are each independently selected from the group consisting of CR′R″, NR′, O, S and SiR′R″, wherein R′ and R″ are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroalicyclic, heteroaryl, alkoxy, hydroxy, thiohydroxy, thioalkoxy, aryloxy, thioaryloxy, amino, nitro, halo, trihalomethyl, cyano, amide, carboxy, sulfonyl, sulfoxy, sulfinyl, sulfonamide, and a saccharide;
R 1 and R 2 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl, heteroalicyclic, heteroaryl;
p and q are each independently an integer of from 0 to 4;
R′ and R″ are each independently hydrogen, alkyl or cycloalkyl, or, alternatively, R′ and R″ form together an aryl; and
W is a group that comprises an aromatic moiety, wherein the π-electrons of said aromatic moiety are conjugated to the π electrons of said —(CR′═CR″)p- and said —(CR′═CR″)q-, such that d

Assignees

• Ramot At Tel-Aviv Univ Ltd

Inventors

• Shabat Doron
• Satchi-Fainaro Ronit

Classifications

• A61K47/558

  the modifying agent being a chemiluminescent acceptor · CPC title

• C07D209/08

  with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring · CPC title

• C07D213/71

  to which a second hetero atom is attached · CPC title

• C07D209/12

  Radicals substituted by oxygen atoms · CPC title

• C07D213/85

  in position 3 · CPC title