Saccharide conjugates

Patent metadata

Field	Value
Publication number	US-10046068-B2
Application number	US-201414776578-A
Country	US
Kind code	B2
Filing date	Mar 14, 2014
Priority date	Mar 15, 2013
Publication date	Aug 14, 2018
Grant date	Aug 14, 2018

Abstract

This invention relates to compounds comprising a saccharide conjugated to an imaging agent or a reporter group, compositions comprising them and methods of using them. Specifically BLM-disaccharide and BLM-monosaccharide conjugates containing different linker groups and an imaging agent or a reporter group are provided for the targeting and imaging of tumors.

First claim

What is claimed is:

1. A compound of formula (I):
[A-R 6 n R 7 —R 8   (I)

or a pharmaceutically acceptable salt thereof,
wherein A is:

R 1 is selected from the group consisting of H, OH, SH, NH 2 , OR 4 , OC(O)R 4 , OC(O)NHR 4 , OC(O)NR 4 R 5 , OC(S)NHR 4 , OC(S)NR 4 R 5 , SC(O)NHR 4 , SC(O)NR 4 R 5 , NHC(O)NHR 4 , NHC(O)NR 4 R 5 , NHC(S)NHR 4 , NHC(S)NR 4 R 5 , NHC(N)NHR 4 , NHC(N)NR 4 R 5 , OCH 2 C(O)NHR 4 , OCH 2 C(O)NR 4 R 5 , OCH 2 C(S)NHR 4 , OCH 2 C(S)NR 4 R 5 , SCH 2 C(O)NHR 4 , SCH 2 C(O)NR 4 R 5 , NHCH 2 C(O)NHR 4 , NHCH 2 C(O)NR 4 R 5 , NHCH 2 C(S)NHR 4 and NHCH 2 C(S)NR 4 R 5 ;
each R 4 is selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl;
each R 5 is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl;

R 2 is selected from the group consisting of H, OH, SH, NH 2 , OR 4 , OC(O)R 4 , OC(O)NHR 4 , OC(O)NR 4 R 5 , OC(S)NHR 4 , OC(S)NR 4 R 5 , SC(O)NHR 4 , SC(O)NR 4 R 5 , NHC(O)NHR 4 , NHC(O)NR 4 R 5 , NHC(S)NHR 4 , NHC(S)NR 4 R 5 , NHC(N)NHR 4 , NHC(N)NR 4 R 5 , OCH 2 C(O)NHR 4 , OCH 2 C(O)NR 4 R 5 , OCH 2 C(S)NHR 4 , OCH 2 C(S)NR 4 R 5 , SCH 2 C(O)NHR 4 , SCH 2 C(O)NR 4 R 5 , NHCH 2 C(O)NHR 4 , NHCH 2 C(O)NR 4 R 5 , NHCH 2 C(S)NHR 4 and NHCH 2 C(S)NR 4 R 5 ;
R 3 is selected from the group consisting of H, OH, SH, NH 2 , OR 4 , OC(O)R 4 , OC(O)NHR 4 , OC(O)NR 4 R 5 , OC(S)NHR 4 , OC(S)NR 4 R 5 , SC(O)NHR 4 , SC(O)NR 4 R 5 , NHC(O)NHR 4 , NHC(O)NR 4 R 5 , NHC(S)NHR 4 , NHC(S)NR 4 R 5 , NHC(N)NHR 4 , NHC(N)NR 4 R 5 , OCH 2 C(O)NHR 4 , OCH 2 C(O)NR 4 R 5 , OCH 2 C(S)NHR 4 , OCH 2 C(S)NR 4 R 5 , SCH 2 C(O)NHR 4 , SCH 2 C(O)NR 4 R 5 , NHCH 2 C(O)NHR 4 , NHCH 2 C(O)NR 4 R 5 , NHCH 2 C(S)NHR 4 and NHCH 2 C(S)NR 4 R 5 ;
R′ is selected from the group consisting of H, OH and NHR 4 ;
R 6 is a first linker;
n is an integer selected from 1 to 3;
R 7 is absent or a second linker, provided that when n is 1, R 7 is absent; and
R 8 is Cy5**.

2. The compound according to claim 1 , wherein A is selected from the group consisting of:

3. The compound according to claim 1 , wherein the first linker is X-(L 1 -Y) m -L 2 -Z,
wherein X is CH 2 or O;
L 1 is C 2 -C 6 alkyl;
Y is O, S, or NR y , wherein R y is hydrogen or C 1 -C 6 alkyl;
m is an integer selected from 1 to 10;
L 2 is C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, aryl, heteroaryl, heterocyclyl, C 3 -C 5 cycloalkyl; and
Z is absent, O, NR x , S, C(O), S(O), S(O) 2 , OC(O), N(R x )C(O), N(R x )S(O), N(R x )S(O) 2 , C(O)O, C(O)N(R x ), S(O)N(R x ), S(O) 2 N(R x ), OC(O)O, OC(O)N(R x ), N(R x )C(O)O, N(R x )C(O)N(R x ), or N(R x )S(O) 2 N(R x ), wherein
each R x is independently hydrogen or C 1 -C 6 alkyl.

4. The compound of claim 3 , wherein the first linker is O—(CH 2 CH 2 —O) m —CH 2 CH 2 —Z, wherein Z is O, N(H), or S and m is an integer selected from 1 to 20 or the first linker is O—(CH 2 CH 2 —O) m —CH 2 CH 2 —Z, wherein Z is C(O) or S(O) 2 and m is an integer selected from 1 to 20.

5. The compound according to claim 1 , wherein the second linker is (B-L 3 ) p -D-E-L 4 -F,
wherein B is bond, O, NR x , S, C(O), S(O), S(O) 2 , OC(O), N(R x )C(O), N(R x )S(O), N(R x )S(O) 2 , C(O)O, C(O)N(R x ), S(O)N(R x ), S(O) 2 N(R x ), OC(O)O, OC(O)N(R x ), N(R x )C(O)O, N(R x )C(O)N(R x ), or N(R x )S(O) 2 N(R x );
L 3 is C 2 -C 6 alkyl;
p is 2 or 3;
D is CH when p is 2 and D is C when p is 3;
E is a bond, O, NR x , S, C(O), S(O), S(O) 2 , OC(O), N(R x )C(O), N(R x )S(O), N(R x )S(O) 2 , C(O)O, C(O)N(R x ), S(O)N(R x ), S(O) 2 N(R x ), OC(O)O, OC(O)N(R x ), N(R x )C(O)O, N(R x )C(O)N(R x ), or N(R x )S(O) 2 N(R x );
L 4 is C 2 -C 6 alkyl; and
F is a bond, O, NR x , S, C(O), S(O), S(O) 2 , OC(O), N(R x )C(O), N(R x )S(O), N(R x )S(O) 2 , C(O)O, C(O)N(R x ), S(O)N(R x ), S(O) 2 N(R x ), OC(O)O, OC(O)N(R X ), N(R X )C(O)O, N(R x )C(O)N(R x ), or N(R x )S(O) 2 N(R x ),
wherein each R x is independently hydrogen or C 1 -C 6 alkyl.

6. The compound according to claim 1 , wherein R 1 is selected from the group consisting of H, OH, OR 4 , OC(O)R 4 , NHC(N)NHR 4 , NHC(N)NR 4 R 5 , OCONHR 4 , and OCONR 4 R 5 .

7. The compound according to claim 1 , wherein R 2 is selected from the group consisting of H, OH, OR 4 , OC(O)R 4 , NHC(N)NHR 4 , NHC(N)NR 4 R 5 , OCONHR 4 , OCONR 4 R 5 , OCSNHR 4 , NHCONHR 4 , OCH 2 CONHR 4 , and OCH 2 CONR 4 R 5 .

8. The compound according to claim 1 , wherein R 3 is selected from the group consisting of OH, OR 4 , OC(O)R 4 , NHC(N)NHR 4 , NHC(N)NR 4 R 5 , and OCONHR 4 .

9. The compound according to claim 1 , wherein R′ is H or OH.

10. The compound according to claim 1 , wherein each R 4 is selected from the group consisting of H, methyl and ethyl.

11. The compound according to claim 1 , wherein each R 5 is selected from the group consisting of methyl, ethyl, and isobutyl.

12. A compound selected from the group consisting of:

Assignees

• Arizona Board Of Regents For And On Behalf Of Arizona State Univ
• Univ Arizona State

Inventors

• Hecht Sidney
• Madathil Manikandadas Mathilakathu
• Bhattacharya Chandrabali
• Bozeman Trevor
• Paul Rakesh
• Yu Zhiqiang
• Rishel Michael J

Classifications

• A61K49/223

  Microbubbles, hollow microspheres, free gas bubbles, gas microspheres · CPC title

• A61K47/545

  Heterocyclic compounds (A61K47/558 takes precedence) · CPC title

• A61K51/0497

  conjugates with a carrier being an organic compounds · CPC title

• A61K49/0002

  General or multifunctional contrast agents, e.g. chelated agents · CPC title

• A61K49/0052 Primary

  Small organic molecules (oligomers, polymers, dendrimers A61K49/0054) · CPC title