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US 7,691,962 B2Granted
Chemical linkers and conjugates thereof
AssigneeMedarex, Inc.
InventorsSharon E. Boyd, Liang Chen, Sanjeev Gangwar, Vincent Guerlavais, Killian Horgan, Zhi-Hong Li, Bilal Sufi
Life of this patent
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Abstract
The present disclosure provides drug-ligand conjugates that are potent cytotoxins, wherein the drug is linked to the ligand through either a peptidyl, hydrazine, or disulfide linker. The disclosure is also directed to compositions containing the drug-ligand conjugates, and to methods of treatment using them.
Claims47
A compound of the formula
- wherein
- D is a drug moiety comprising a structure:
- wherein the ring system A is a member selected from substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, and substituted and unsubstituted heterocycloalkyl groups;
- E and G are members independently selected from H, substituted and unsubstituted alkyl, substituted and unsubstituted heteroalkyl, a heteroatom, a single bond, or E and G are joined to form a ring system selected from substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, and substitute and unsubstituted heterocycloalkyl;
- X is a member selected from O, S and NR23;
- R23 is a member selected from H, substituted and unsubstituted alkyl, substituted and 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)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 and unsubstituted alkyl, substituted and unsubstituted heteroalkyl and substituted and 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, NC(O)R15, OC(O)NR15R16, OC(O)OR15, C(O)R15, SR15, OR15, CR15═NR16, and O(CH2)nN(CH3)2
- wherein
- n is an integer from 1 to 20;
- R15 and R16 are independently selected from H, substituted and unsubstituted alkyl, substituted and unsubstituted heteroalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted heterocycloalkyl, and substituted and 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;
- R 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 R11 R12 R13 R15 or R16 links said drug moiety D to L3, if present, or to the —NH—;
- each AA1 is 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, 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 1 or 1;
- L4 is selected from substituted alkyl, unsubstituted alkyl, substituted aryl, unsubstituted aryl, substituted heteroalkyl, and unsubstituted heteroalkyl, any of which may be straight, branched, or cyclic;
- positively and negatively charged amino acid polymers;
- a polymer;
- and combinations thereof, wherein L4 does not comprise a carboxylic acyl group directly attached to the N-terminus of (AA1)c;
- p is 1;
- and
- X4 is a member selected from the group consisting of protected reactive functional groups, unprotected reactive functional groups, detectable labels, and targeting agents.
29 more elements
A compound of the formula
- wherein
- D comprises a structure:
- wherein the ring system A is a member selected from substituted and unsubstituted phenyl and substituted and unsubstituted pyrrole;
- Z is a member selected from O, S and NR23′,
- wherein R23′ is a member selected from H, substituted and unsubstituted alkyl, substituted and unsubstituted heteroalkyl, and acyl;
- X is a member selected from O, S and NR23;
- R23 is a member selected from H, substituted and unsubstituted alkyl, substituted and 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)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 and unsubstituted alkyl, substituted and unsubstituted heteroalkyl and substituted and 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, NC(O)R15, OC(O)NR15R16, OC(O)OR15, C(O)R15, SR15, OR15, CR15═NR16, and O(CH2)nN(CH3)2
- wherein
- n is an integer from 1 to 20;
- R15 and R16 are independently selected from H, substituted and unsubstituted alkyl, substituted and unsubstituted heteroalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted heterocycloalkyl, and substituted and 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 selected from halogen, azide, sulfonic ester, oxonium ions, alkyl perchlorates, ammonioalkanesulfonate esters, alkylfluorosulfonates, and fluorinated triflates, nonaflates, and tresylates;
- wherein at least one of R11, R12, R13 R15 or R16 links said drug moiety D to L1, if present, or to F;
- L1 is selected from substituted alkyl, unsubstituted alkyl, substituted heteroalkyl, unsubstituted heteroalkyl, unsubstituted heterocycloalkyl, and substituted heterocycloalkyl;
- m is an integer 0, 1, 2, 3, 2, 5, or 6;
- F is a linker having the structure:
- wherein
- each AA1 is independently selected from the group consisting of natural amino acids and unnatural α-amino acids;
- c is an integer from 1 to 20;
- the -L3—NH— moiety of F is selected from
- wherein Z is a member selected from O, S and NR23, and
- wherein R23 is a member selected from H, substituted and unsubstituted alkyl, substituted and unsubstituted heteroalkyl, and acyl;
- o is 0 or 1;
- L4 is selected from substituted alkyl, unsubstituted alkyl, substituted aryl, unsubstituted aryl, substituted heteroalkyl, and unsubstituted heteroalkyl, any of which may be straight, branched, or cyclic;
- positively and negatively charged amino acid polymers;
- a polymer;
- and combinations thereof, wherein L4 does not comprise a carboxylic acyl group directly attached to the N-terminus of (AA1)c;
- p is 1;
- and
- X4 is selected from targeting agents, R29, COOR29, C(O)NR29, and C(O)NNR29 wherein R29 is a member selected from substituted and unsubstituted alkyl, substituted and unsubstituted heteroalkyl, and substituted and unsubstituted heteroaryl or R29 is a member selected from substituted and unsubstituted alkyl, substituted and unsubstituted heteroalkyl, and substituted and unsubstituted heteroaryl that has been reacted with a targeting agent to couple the targeting agent to the compound,
- wherein the targeting agent is selected from antibodies, fragments of antibodies, lectins, saccharides, peptides, and nucleic acids.
36 more elements
Dependencies are inferred from the claim text.