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US 7,507,420 B2Granted
Peptidyl prodrugs and linkers and stabilizers useful therefor
AssigneeMedarex, Inc.
InventorsHoward P. Ng, Danny P. C. McGee, Guoxian Wu, Jimmie Moore, Zhi-Hong Li, Sanjeev Gangwar, Oliver L. Saunders, Irina Astafieva
Life of this patent
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Abstract
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.
Claims32
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, S and NR23;
- X is a member selected from O, S and NR23
- wherein
- each R23 is independently a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, and acyl;
- R3 is a member selected from the group consisting of (=O), SR11, NHR11 and OR11,
- wherein
- R11 is a member selected from the group consisting of H, substituted alkyl, unsubstituted alkyl, substituted heteroalkyl, unsubstituted heteroalkyl, diphosphates, triphosphates, acyl, C(O)R12, C(O)OR12, C(O)NR12R13, P(O)(OR12)2, C(O)CHR12R13, SR12 and SiR12R13R14,
- in which
- R12, R13, and R14 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and substituted or unsubstituted aryl, wherein R12 and R13 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;
- R4 and R5 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, halogen, NO2, NR15R16, NC(O)R15, OC(O)NR15R16, OC(O)OR15, C(O)R15, SR15, and OR15
- wherein
- R15 and R16 are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl and substituted or unsubstituted peptidyl;
- and
- R6 is a single bond which is either present or absent and when present R6 and R7 are joined to form a cyclopropyl ring;
- and
- R7 is CH2—X1 or —CH2— joined in said cyclopropyl ring with R6, wherein X1 is a leaving group;
- wherein the compound comprises at least one member selected from R15 or R16 having the structure:
- wherein
- X4 is member selected from protected or unprotected reactive functional groups, detectable labels and targeting agents;
- L3 is a linker selected from substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl groups;
- AA1, AAC and AAc+1 are members independently selected from natural and unnatural α-amino acids;
- L4 is a linker selected from substituted or unsubstituted alkyl, substituted or unsubstituted 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;
- or a pharmaceutically acceptable salt thereof.
25 more elements
A compound having the structure:
- wherein
- A is a member selected from substituted or unsubstituted phenyl, and substituted or unsubstituted pyrrole;
- X is a member selected from O, S and NR23
- wherein
- each R23 is independently a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, and acyl;
- R3 is a member selected from the group consisting of (=0), SR11, NHR11 and OR11;
- wherein
- R11 is a member selected from the group consisting of H, substituted alkyl, unsubstituted alkyl, substituted heteroalkyl, unsubstituted heteroalkyl, diphosphates, triphosphates, acyl, C(O)R12, C(O)OR12, C(O)NR12R13, P(O)(OR12)2, C(O)CHR12R13, SR12 and SiR12R13R14,
- in which
- R12, R13 , and R14 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and substituted or unsubstituted aryl, wherein R12 and R13 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;
- R4 and R5 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, halogen, NO2, NR15R16, NC(O)R15, OC(O)NR15R16, OC(O)OR5, C(O)R15, SR15,and OR15
- wherein
- R15 and R16 are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl and substituted or unsubstituted peptidyl;
- and
- R6 is a single bond which is either present or absent and when present R6 and R7 are joined to form a cyclopropyl ring;
- and
- R7 is CH2—X1 or CH2— joined in said cyclopropyl ring with R6, wherein
- X is a halogen;
- wherein the compound comprises at least one member selected from R15 or R16having the structure:
- wherein
- X4 is member selected from an antibody or
- where . . . is a single or double bond;
- L3 is a linker selected from substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl groups;
- AA1, AAC and AAC+1 are members independently selected from natural and unnatural α-amino acids;
- L4 is a linker selected from substituted or unsubstituted alkyl, substituted or unsubstituted 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;
- or a pharmaceutically acceptable salt thereof.
25 more elements
A compound having the structure:
- wherein
- X is a member selected from O, S and NR23
- wherein
- each R23 is independently a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, and acyl;
- R3 is a member selected from the group consisting of (=O), SR11, NHR11 and OR11
- wherein
- R11 is a member selected from the group consisting of H, substituted alkyl, unsubstituted alkyl, substituted heteroalkyl, unsubstituted heteroalkyl, diphosphates, triphosphates, acyl, C(O)R12, C(O)OR12, C(O)NR12R13,
- P(O)(OR12)2, C(O)CHR12R13, SR12 and SiR12R13R14,
- in which
- R12, R13, and R14 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and substituted or unsubstituted aryl, wherein R12 and R13 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;
- R4 and R5 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, halogen, NO2, NR15R16, NC(O)R15, OC(O)NR15R6, OC(O)OR15, C(O)R15, SR15, and OR15
- wherein
- R15 and R16 are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl and substituted or unsubstituted peptidyl;
- and
- R6 is a single bond which is either present or absent and when present R6 and R7 are joined to form a cyclopropyl ring;
- and
- R7 is CH2—X1 or CH2— joined in said cyclopropyl ring with R6, wherein X1 is a halogen;
- wherein the compound comprises at least one member selected from R15 or having the structure:
- wherein
- X4 is member selected from an antibody or
- where . . . is a single or double bond;
- L3 is a linker selected from substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl groups;
- AA1, AAC and AAC+1 are members independently selected from natural α-amino acids;
- L4 is a linker selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
- p and t are integers independently selected from 0 and 1;and
- c is 0 or 1;
- or a pharmaceutically acceptable salt thereof.
24 more elements
Dependencies are inferred from the claim text.