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US 8,461,117 B2Granted
Chemical linkers and cleavable substrates and conjugates thereof
AssigneeMedarex, Inc.
InventorsBilal Sufi, Vincent Guerlavais, Liang Chen, Sanjeev Gangwar, Qian Zhang, David B. Passmore
Life of this patent
Estimating the term…
Abstract
The present disclosure provides drug-ligand conjugates and drug-cleavable substrate conjugates that are potent cytotoxins. The disclosure is also directed to compositions containing the drug-ligand conjugates, and to methods of treatment using them.
Claims9
A compound of the formula
- wherein
- L1 is a self-immolative linker;
- m is an integer 0, 1, 2, 3, 4, 5, or 6;
- F is a linker comprising the structure:
- wherein
- AA1 is one or more members independently selected from the group consisting of natural amino acids and unnatural α-amino acids;
- c is an integer from 1 to 20;
- L2 is a self-immolative linker;
- o is 0 or 1;
- L4 is a linker member;
- p is 0 or 1;
- X4 is a member selected from the group consisting of protected reactive functional groups, unprotected reactive functional groups, detectable labels, and targeting agents;
- and
- D has the structure:
- wherein
- Z is a member selected from O, S and NR23
- wherein
- R23 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, and acyl;
- R1 is H, substituted or unsubstituted lower alkyl, C(O)R8, or CO2R8, wherein R8 is a member selected from group consisting of substituted alkyl, unsubstituted alkyl, NR9R10 , NR9NHR10, and OR9
- in which R9 and R10 are members independently selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl;
- and
- R2 is H, substituted alkyl or unsubstituted lower alkyl,
- X is a member selected from O, S and NR23;
- 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, monophosphates, diphosphates, triphosphates, sulfonates, acyl, C(O)R12R13, 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, R4′, R5 and R5′ are members independently selected from the group consisting of H, substituted alkyl, unsubstituted alkyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted heterocycloalkyl, unsubstituted heterocycloalkyl, halogen, NO2, NR15R16, NHC(O)R15, OC(O)NR15R16, OC(O)OR15, C(O)R15, SR15, OR15, CR15=NR16, and O(CH2)nN(CH3)2, or any adjacent pair of R4, R4′, R5 and R5′, together with the carbon atoms to which they are attached, are joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl ring system having from 4 to 6 members,
- wherein
- n is an integer from 1 to 20;
- 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, wherein R15 and R16 together with the nitrogen 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;
- wherein at least one of R4, R4′, R5 and R5′ links said drug to L1, if present, or to F, and comprises
- wherein v is an integer from 1 to 6;
- and
- each R27, R27′, R28, and R28′ is independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl;
- 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;
- or a pharmaceutically acceptable salt thereof.
36 more elements
A compound of the formula
- wherein
- L1 is a self-immolative linker;
- m is an integer 0, 1, 2, 3, 4, 5, or 6;
- F is a linker comprising the structure:
- wherein
- AA1 is one or more members independently selected from the group consisting of natural amino acids and unnatural α-amino acids;
- c is an integer from 1 to 20;
- L3 is a spacer group comprising a primary or secondary amine or a carboxyl functional group;
- wherein if L3 is present, m is 0 and either the amine of L3 forms an amide bond with a pendant carboxyl functional group of D or the carboxyl of L3 forms an amide bond with a pendant amine functional group of D;
- o is 0 or 1;
- L4 is a linker member, wherein L4 comprises
- directly attached to the N-terminus of (AA1)c, wherein
- R20 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, and acyl,
- each R25, R25′, R26, and R26 ′ is independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl;
- and s and t are independently integers from 1 to 6;
- p is 1;
- X4 is a member selected from the group consisting of protected reactive functional groups, unprotected reactive functional groups, detectable labels, and targeting agents;
- and
- D comprises a structure:
- wherein the ring system A is a member selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl groups;
- E and G are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, a heteroatom, a single bond, or E and G are joined to form a ring system selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl;
- X is a member selected from O, S and NR23;
- R23 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, and acyl;
- R 3is 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, monophosphates, diphosphates, triphosphates, sulfonates, acyl, C(O)R12R13,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, R4′, R5 and R5′ are members independently selected from the group consisting of H, substituted alkyl, unsubstituted alkyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted heterocycloalkyl, unsubstituted heterocycloalkyl, halogen, NO2, NR15R16, NHC(O)R15, OC(O)NR15R16, OC(O)OR15, C(O)R15, SR15, OR15, CR15=NR16, and O(CH2)nN(CH3)2, or any adjacent pair of R4, R4′, R5 and R5′, together with the carbon atoms to which they are attached, are joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl ring system having from 4 to 6 members,
- wherein
- n is an integer from 1 to 20;
- 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, wherein R15 and R16 together with the nitrogen 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;
- 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 at least one of R4, R4′, R5, R5′, R15, R16 links said drug to L1, if present, or to F;
- or a pharmaceutically acceptable salt thereof.
35 more elements
Dependencies are inferred from the claim text.