Heterocyclic self-immolative linkers and conjugates

• US 7,989,434 B2
• Filed: 04/21/2010
• Issued: 08/02/2011
• Est. Priority Date: 02/23/2004
• Status: Active Grant

• Current Assignee: Seagen Inc.
• Original Assignee: Seattle Genetics Incorporated
• Inventors: Feng, Bainian
• Primary Examiner(s): Bradley; Christina
• Application Number:
  US12/764,821
• Publication Number:
  US 20100273843A1
• Time in Patent Office: 468 Days
• Field of Search: None
• US Class Current: 514/79
• 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 the group consisting of Formulas IIa and IIIa:

2. A drug-ligand conjugate compound comprising a cell-specific ligand and a drug moiety conjugated by a linker wherein said linker comprises a heterocyclic self-immolative moiety selected from the group consisting of Formulas II and III

3. The drug-ligand conjugate compound of claim 2 having Formula IV:

L-[A_n-Z_m-X-D]_p 

 

IV

wherein

L is a cell-specific ligand;

A is a Spacer unit;

Z is an Amino Acid;

X is a heterocyclic self-immolative moiety selected from the group consisting of Formula II and III;

D is a drug moiety;

m is 1, 2, 3, 4, 5 or 6;

n is 0 or 1; and

p is 1, 2, 3, 4, 5, 6, 7 or 8.

4. The drug-ligand conjugate compound of claim 3, wherein X is Formula II.

5. The drug-ligand conjugate compound of claim 4, wherein Q is N;

V¹ is CH; and

V² is CH.

6. The drug-ligand conjugate compound of claim 4, wherein Q is CH;

V¹ is CH; and

V² is N.

7. The drug-ligand conjugate compound of claim 4, wherein Q is N;

V¹ is CH; and

V² is N.

8. The drug-ligand conjugate compound of claim 4, wherein Q is N;

and V¹ is N; and

V² is N.

9. The drug-ligand conjugate compound of claim 4, wherein Q is N;

V¹ is N; and

V² is CH.

10. The drug-ligand conjugate compound of claim 4, wherein T is N or NH.

11. The drug-ligand conjugate compound of claim 3, wherein X is Formula III.

12. The drug-ligand conjugate compound of claim 11, wherein Q is N;

and V¹, V² and V³ are each CH.

13. The drug-ligand conjugate compound of claim 11, wherein Q is CH;

and V¹, V² and V³ are each CH.

14. The drug-ligand conjugate compound of claim 11, wherein T is N or NH.

15. The drug-ligand conjugate compound of claim 3 wherein m is 1, and Z is selected from the group consisting of alanine, 2-amino-2-cyclohexylacetic acid, 2-amino-2-phenylacetic acid, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, γ

-aminobutyric acid, α

,α

-dimethyl γ

-aminobutyric acid, β

,β

-dimethyl γ

-aminobutyric acid, ornithine, citrulline; and

protected forms thereof.

16. The drug-ligand conjugate compound of claim 3, wherein m is 2, and Z_m is a dipeptide selected from the group consisting of glycine-glycine, alanine-phenylalanine, phenylalanine-lysine, valine-citrulline and valine-lysine.

17. The drug-ligand conjugate compound of claim 3, wherein n is 1, and A is attached to a Cys residue of L which is an antibody.

18. The drug-ligand conjugate compound of claim 3,

19. The drug-ligand conjugate compound of claim 3, wherein D is an auristatin drug moiety.