Peptidyl prodrugs and linkers and stabilizers useful therefor
View Patent ↗The present invention provides analogues of duocarmycins that are potent cytotoxins. Also provided are peptidyl and disulfide linkers that are cleaved in vivo. The linkers are of use in forming prodrugs and conjugates of the cytotoxins of the invention as well as other diagnostic and therapeutic moieties. The invention provides prodrugs and conjugates of the duocarmycin analogues with the linker arms of the invention.
1. A compound having the structure:
wherein
Z is NH;
X is O;
R 3 is a member selected from the group consisting of (═O) and OR 11 ,
wherein
R 11 is a member selected from the group consisting of C(O)R 12 , C(O)OR 12 , and C(O)NR 12 R 13 ,
in which
R 12 and R 13 are H or R 12 and R 13 together with the nitrogen or carbon atom to which they are attached are joined to form a substituted or unsubstituted heterocycloalkyl ring system having from 4 to 6 members, optionally containing two or more heteroatoms;
R 5 is H;
R 4 is NHR 16 ,
wherein
R 16 is
wherein
X 4 is an antibody or a reactive functional group having the structure:
wherein
is a single or double bond;
L 3 is a linker selected from substituted or unsubstituted C 1-10 alkyl and substituted or unsubstituted C 1-10 heteroalkyl groups;
AA 1 , AA c and AA c+1 are members independently selected from natural and unnatural α-amino acids;
L 4 is a linker selected from substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 1-10 heteroalkyl groups, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted cycloalkyl;
p and t are integers independently selected from 0 and 1; and
c is an integer from 0 to 5; and
R 6 is a single bond which is either present or absent and when present R 6 and R 7 are joined to form a cyclopropyl ring; and
R 7 is CH 2 —X 1 or —CH 2 — joined in said cyclopropyl ring with R 6 , wherein
X 1 is a leaving group,
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein R 6 is absent, R 7 is CH 2 —X 1 , R 3 is OR 11 , and R 11 is C(O)NR 12 R 13 , in which R 12 and R 13 together with the nitrogen atom to which they are attached are joined to form a substituted or unsubstituted heterocycloalkyl ring system having from 4 to 6 members, optionally containing two or more heteroatoms.
3. The compound of claim 1 , wherein L 3 is a substituted or unsubstituted C 1-10 heteroalkyl group and L 4 is substituted or unsubstituted aryl or heteroaryl.
4. The compound of claim 1 , wherein p is 1, t is 1, and c is 0 or 1.
5. The compound of claim 1 , wherein AA 1 is valine.
6. The compound of claim 1 , wherein X 4 is an antibody.
7. The compound of claim 1 , wherein R 6 is absent, R 7 is CH 2 —X 1 , R 3 is OR 11 , and R 11 is C(O)NR 12 R 13 , in which R 12 and R 13 together with the nitrogen atom to which they are attached are joined to form a substituted or unsubstituted heterocycloalkyl ring system having from 4 to 6 members, containing two or more heteroatoms;
p is 1 and L 3 is a substituted or unsubstituted C 1-10 heteroalkyl; and
t is 1 and L 4 is substituted or unsubstituted aryl or heteroaryl.
8. The compound of claim 7 , wherein c is 0 or 1 and AA 1 is valine.
9. The compound of claim 7 , wherein X 4 is an antibody.
10. The compound of claim 1 , wherein R 6 is absent, R 7 is CH 2 —X 1 , R 3 is OR 11 , and X 1 is halogen.
11. A compound having the structure:
wherein
A is a member selected from substituted or unsubstituted phenyl and substituted or unsubstituted pyrrole;
Z is a member selected from O and NR 23 ;
X is a member selected from O and NR 23 ;
wherein
each R 23 is independently a member selected from H, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 1-10 heteroalkyl, and acyl;
R 3 is a member selected from the group consisting of (═O) and OR 11 ,
wherein
R 11 is a member selected from the group consisting of diphosphates, triphosphates, acyl, C(O)R 12 , C(O)OR 12 , C(O)NR 12 R 13 , P(O)(OR 12 ) 2 , C(O)CHR 12 R 13 , SR 12 and SiR 12 R 13 R 14 ,
in which
R 12 , R 13 , and R 14 are members independently selected from H, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 1-10 heteroalkyl and substituted or unsubstituted aryl, wherein R 12 and R 13 together with the nitrogen or carbon atom to which they are attached are optionally joined to form a substituted or unsubstituted heterocycloalkyl ring system having from 4 to 6 members, optionally containing two or more heteroatoms;
R 5 is H, substituted or unsubstituted C 1-10 alkyl, halogen, or NO 2 ;
R 4 is NR 15 R 16,
wherein
R 15 is H, substituted or unsubstituted C 1-10 alkyl, or substituted or unsubstituted C 1-10 heteroalkyl;
R 16 is
wherein
X 4 is member selected from protected or unprotected reactive functional groups, detectable labels and targeting agents;
L 3 is a linker selected from substituted or unsubstituted C 1-24 alkyl and substituted or unsubstituted C 1-24 heteroalkyl groups;
AA 1 , AA c and AA c+1 are members independently selected from natural and unnatural α-amino acids;
L 4 is a linker selected from substituted or unsubstituted C 1-24 alkyl, substituted or unsubstituted C 1-24 heteroalkyl groups, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted cycloalkyl;
p and t are integers independently selected from 0 and 1; and
c is an integer from 0 to 20; and
R 6 is a single bond which is either present or absent and when present R 6 and R 7 are joined to form a cyclopropyl ring; and
R 7 is CH 2 —X 1 or —CH 2 — joined in said cyclopropyl ring with R 6 , wherein
X 1 is a leaving group;
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 11 wherein
Z is a member selected from O and NH;
X is O;
R 6 is absent; and
R 7 is CH 2 -halogen.
13. The compound of claim 11 wherein R 6 is absent, R 7 is CH 2 —X 1 , R 3 is OR 11 , and
R 11 is a member selected from the group consisting of H, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 heteroalkyl, C(O)R 12 , C(O)OR 12 , C(O)NR 12 R 13 , in which
R 12 and R 13 are H or R 12 and R 13 together with the nitrogen or carbon atom to which they are attached are joined to form a substituted or unsubstituted heterocycloalkyl ring system having from 4 to 6 members, optionally containing two or more heteroatoms.
14. The compound of claim 13 wherein R 6 is absent, R 7 is CH 2 —X 1 , R 3 is OR 11 , and R 11 is a substituted or unsubstituted C 1-10 heteroalkyl or C(O)NR 12 R 13 .
15. The compound of claim 14 wherein R 6 is absent, R 7 is CH 2 —X 1 , R 3 is OR 11 , and
R 11 is C(O)NR 12 R 13 and wherein
R 12 and R 13 together with the nitrogen or carbon atom to which they are attached are joined to form a substituted or unsubstituted heterocycloalkyl ring system having from 4 to 6 members, optionally containing two or more heteroatoms.
16. The compound of claim 11 , wherein X 4 is an antibody or a reactive functional group having the structure:
where
is a single or double bond.
17. The compound of claim 11 , wherein
L 3 is a linker selected from substituted or unsubstituted C 1-10 alkyl and substituted or unsubstituted C 1-10 heteroalkyl groups;
AA 1 , AA c and AA c+1 are members independently selected from natural and unnatural α-amino acids;
L 4 is a linker selected from substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 1-10 heteroalkyl groups, and substituted or unsubstituted aryl,
p and t are both 1; and
c is an integer from 0 to 5.
18. The compound of claim 11 , wherein L 3 is a substituted or unsubstituted C 1-10 heteroalkyl group and L 4 is substituted or unsubstituted aryl or heteroaryl.
19. The compound of claim 11 , wherein p is 1, t is 1, and c is 0 or 1.
20. The compound of claim 11 , wherein AA 1 is valine.
21. The compound of claim 20 , wherein X 4 is an antibody.