Saccharide conjugates
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.
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: