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US 7,517,903 B2Granted
Cytotoxic compounds and conjugates
AssigneeMedarex, Inc.
InventorsLiang Chen, Sanjeev Gangwar, Vincent Guerlavais, Zhi-Hong Li, Bilal Sufi
Life of this patent
Estimating the term…
Abstract
The present disclosure provides drug-cleavable substrate conjugates that are potent cytotoxins. The disclosure is also directed to compositions containing the drug-cleavable substrate conjugates, and to methods of treatment using them.
Claims19
A compound of the formula
- wherein X and Z are independently 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,
- R1′ is H, substituted or unsubstituted lower alkyl, or C(O)R8,
- each R8 is a member independently selected from NR9R10 and OR9 and R9 and R10 are members independently selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl;
- R2 is H, substituted or unsubstituted lower alkyl, unsubstituted heteroalkyl, cyano, or alkoxy;
- R2′ is H, substituted or unsubstituted lower alkyl, or unsubstituted heteroalkyl,
- R3 is a member selected from the group consisting of 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 or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and substituted or unsubstituted aryl, or R12 and R13 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;
- 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,
- 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)nNR24R25 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;
- and R24 and R25 are independently selected from unsubstituted alkyl, and
- wherein at least one of R4, R4′, R5 and R5′ is O(CH2)nNR24R25.
11 more elements
Dependencies are inferred from the claim text.