Near-infrared fluorescent contrast bioimaging agents and methods of use thereof

Patent metadata

Field	Value
Publication number	US-2016263249-A1
Application number	US-201415033337-A
Country	US
Kind code	A1
Filing date	Oct 30, 2014
Priority date	Oct 31, 2013
Publication date	Sep 15, 2016
Grant date	—

Abstract

The instant invention provides near-infrared fluorescent biological contrast agents and methods of using them.

First claim

1 . A near-infrared fluorescent contrast agent according to Formula (I):

Wherein
Each R 1 is independently H, OR′, halogen, sulfonato, substituted or unsubstituted amino, C(O)NH—C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or phenyl;
Each R 2 is independently H, OR′, halogen, sulfonato, substituted or unsubstituted amino, C(O)NH—C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or phenyl;
Or R 1 and R 2 can be taken together with the carbon atoms to which they are attached to form a 5-6 membered aryl or heteroaryl ring, optionally substituted with halogen, alkyl, alkoxy, hydroxyl, —SO 2 OH, or —CO 2 H;
Each R 3 is independently H, OR′, halogen, sulfonato, substituted or unsubstituted amino, C(O)NH—C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or phenyl;
Q is H, alkyl optionally substituted with alkoxy, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —N + (alkyl) 3 , —OCO-alkyl, —SO 2 OH, phenyl, sulfonato, phosphates, KUE, GPI, or —NR 3 R 4 R 5 , wherein R 3 , R 4 and R 5 are each independently for each occurrence H or C 1 -C 4 alkyl, or R 4 and R 5 , taken together with the nitrogen atom to which they are attached, form a heterocyclic ring;
X and Y are each independently O, S, Se, C(R″) 2 , NR′″;
Z is H, halogen, CN, R 6 , OR 6 , SR 6 , NHR 6 or CH 2 R 6 , in which R 6 is optionally substituted C 1 -C 6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl, alkyl-N 3 , aryl-N 3 , aryl-halogen;
Each R′ is independently H, alkyl or aryl;
Each R″ is independently H or alkyl;
Each R′″ is independently H, akyl, akyl-SO 3 H, or akyl-COOH;
m and n are independently an integer from 0-3; and
L is an anion;
or a salt, solvate, hydrate, polymorph, prodrug, or stereoisomer thereof.

2 . A near-infrared fluorescent contrast agent according to Formula (II):

Wherein
Each R 1 is independently H, OR′, halogen, sulfonato, substituted or unsubstituted amino, C(O)NH—C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or phenyl;
Each R 2 is independently H, OR′, halogen, sulfonato, substituted or unsubstituted amino, C(O)NH—C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or phenyl;
Or R 1 and R 2 can be taken together with the carbon atoms to which they are attached to form a 5-6 membered aryl or heteroaryl ring, optionally substituted with halogen, alkyl, alkoxy, hydroxyl, —SO 2 OH, or —CO 2 H;
Each R 3 is independently H, OR′, halogen, sulfonato, substituted or unsubstituted amino, C(O)NH—C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or phenyl;
Q is H, alkyl optionally substituted with alkoxy, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —N + (alkyl) 3 , —OCO-alkyl, —SO 2 OH, phenyl, sulfonato, phosphates, KUE, GPI, or —NR 3 R 4 R 5 , wherein R 3 , R 4 and R 5 are each independently for each occurrence H or C 1 -C 4 alkyl, or R 4 and R 5 , taken together with the nitrogen atom to which they are attached, form a heterocyclic ring;
X and Y are each independently O, S, Se, C(R″) 2 , NR;
Z is H, halogen, CN, R 6 , OR 6 , SR 6 , NHR 6 or CH 2 R 6 , in which R 6 is optionally substituted C 1 -C 6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl, alkyl-N 3 , aryl-N 3 , aryl-halogen;
R is independently H, OR″″ (where R=H, akyl, or aryl, NH 2 , NHR, alkyl NH 2 , alkyl COOH),
L is an anion;
Each R′ is independently H, alkyl or aryl;
Each R″ is independently H or alkyl;
Each R′″ is independently H, akyl, akyl-SO 3 H, or akyl-COOH;
Each R″″ is independently H, akyl, or aryl, NH 2 , NHR, alkyl-NH 2 , or alkyl-COOH;
m and n are independently an integer from 0-3; and
L is an anion;
or a salt, solvate, hydrate, polymorph, prodrug, or stereoisomer thereof.

3 . A near-infrared fluorescent contrast agent according to Formula (III):

wherein
Each R 1 is independently H, OR′, halogen, sulfonato, substituted or unsubstituted amino, C(O)NH—C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or phenyl;
Each R 2 is independently H, OR′, halogen, sulfonato, substituted or unsubstituted amino, C(O)NH—C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or phenyl;
Or R 1 and R 2 can be taken together with the carbon atoms to which they are attached to form a 5-6 membered aryl or heteroaryl ring, optionally substituted with halogen, alkyl, alkoxy, hydroxyl, —SO 2 OH, or —CO 2 H;
Each R 3 is independently H, OR′, halogen, sulfonato, substituted or unsubstituted amino, C(O)NH—C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or phenyl;
Q is H, alkyl optionally substituted with alkoxy, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —N + (alkyl) 3 , —OCO-alkyl, —SO 2 OH, phenyl, sulfonato, phosphates, KUE, GPI, or —NR 3 R 4 R 5 , wherein R 3 , R 4 and R 5 are each independently for each occurrence H or C 1 -C 4 alkyl, or R 4 and R 5 , taken together with the nitrogen atom to which they are attached, form a heterocyclic ring;
X and Y are each independently O, S, Se, C(R″) 2 , NR′″; Z is H, halogen, CN, R 6 , OR 6 , SR 6 , NHR 6 or CH 2 R 6 , in which R 6 is optionally substituted C 1 -C 6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl, alkyl-N 3 (for click chemistry), aryl-N 3 (for click chemistry), aryl-halogen (only for palladium catalyzed reactions);
Each R′ is independently H, alkyl or aryl;
Each R″ is independently H or alkyl;
Each R′″ is independently H, akyl, akyl-SO 3 H, or akyl-COOH;
m and n are independently an integer from 0-3; and
L is an anion;
or a salt, solvate, hydrate, polymorph, prodrug, or stereoisomer thereof.

4 . A near-infrared fluorescent contrast agent according to Formula (IV):

wherein
R 1 , R 2 , R 3 , R 4 , R 6 and R 7 are each independently H or C 1 -C 6 alkyl;
R 5 , R 8 and R 9 are each independently H, CN, OH, or C 1 -C 6 alkyl;
or R 1 and R 3 , taken together with the atoms to which they are connected, form a 5- to 6-membered heterocylic ring;
or R 2 and R 4 , taken together with the atoms to which they are connected, form a 5- to 6-membered heterocylic ring;
or R 5 and R 6 , taken together with the atoms to which they are connected, form a 5- to 6-membered heterocylic ring;
or R 7 and R 8 , taken together with the atoms to which they are connected, form a 5- to 6-membered heterocylic ring;
or R 8 and R 9 , taken together with the atoms to which they are connected, form an aryl or heteroaryl ring;
X is O, S, Se, N—R; where R=H or C 1 -C 6 alkyl; and
M − is an anion
or a salt, solvate, hydrate, polymorph, prodrug, or stereoisomer thereof.

5 . A near-infrared fluorescent contrast agent according to Formula (V):

Wherein:
Q is —B(R 3 ) 2 —; Si(R 3 ) 2
Each R 1 is independently H, alkyl, aryl, or heteroaryl, wherein each alkyl, aryl, or heteroaryl is optionally substituted with alkoxy, alkoxy-N

Assignees

• Beth Israel Deaconess Medical Ct Inc
• Univ Georgia State Res Found Inc

Inventors

• Frangioni John V
• Choi Hak Soo
• Henary Maged M

Classifications

• C09B23/0033

  the substituent being bound through a sulfur atom · CPC title

• A61K49/0041

  Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal (in vivo G01N) · CPC title

• C09B19/00

  Oxazine dyes · CPC title

• C09B69/008

  Dyes containing a substituent, which contains a silicium atom · CPC title

• A61K49/0032

  Methine dyes, e.g. cyanine dyes · CPC title