Heterocyclic self-immolative linkers and conjugates

• US 7,375,078 B2
• Filed: 02/22/2005
• Issued: 05/20/2008
• Est. Priority Date: 02/23/2004
• Status: Active Grant

• Current Assignee: Seagen Inc. (Pfizer Inc.)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Feng, Bainian
• Primary Examiner(s): Tate; Christopher R.
• Assistant Examiner(s): Harle; Jennifer I
• Application Number:
  US11/064,785
• Publication Number:
  US 20050256030A1
• Time in Patent Office: 1,183 Days
• Field of Search: None
• US Class Current: 530/329
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 47/65 Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 277/46 by carboxylic acids, or sulfur or nitrogen analogues thereof
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07K 5/06052 Val-amino acid

Abstract

The present invention provides heterocyclic linker compounds useful for linking drug moieties to ligands. The compounds also include drug-ligand conjugates comprising a ligand capable of targeting a selected cell population, and a drug connected to the ligand by a heterocyclic linker moiety. The linker moiety comprises a peptide sequence that is a substrate for an intracellular enzyme, for example a cathepsin, that cleaves the peptide at an amide bond. The peptide further contains a self-immolating moiety which connects the drug and the protein peptide sequence. Upon cleavage of the peptide sequence by an intracellular enzyme the self-immolating moiety cleaves itself from the drug moiety such that the drug moiety is in an underivatized and active form.

Claims

1. A heterocyclic linker compound selected from Formula Ia:

2. The heterocyclic linker compound of claim 1 having the structure:

3. The heterocyclic linker compound of claim 1 having the structure: