Heterocyclic self-immolative linkers and conjugates

• US 7,754,681 B2
• Filed: 10/26/2007
• Issued: 07/13/2010
• Est. Priority Date: 02/23/2004
• Status: Active Grant

• Current Assignee: Seagen Inc.
• Original Assignee: Seattle Genetics Incorporated
• Inventors: Feng, Bainian
• Primary Examiner(s): Tsang; Cecilia
• Assistant Examiner(s): Bradley; Christina
• Application Number:
  US11/925,659
• Publication Number:
  US 20090041791A1
• Time in Patent Office: 991 Days
• Field of Search: None
• US Class Current: 514/1.3
• 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 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 of Formula I

2. The drug-ligand conjugate compound of claim 1 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 of Formula I;

D is a drug moiety;

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

n is 0 or 1; and

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

3. The drug-ligand conjugate compound of claim 2, wherein and Q is N;

and U is S.

4. The drug-ligand conjugate compound of claim 2, wherein Q is CH;

and U is O.

5. The drug-ligand conjugate compound of claim 2, wherein R¹ is CF₃.

6. The drug-ligand conjugate compound of claim 2, wherein R¹ is H.

7. The drug-ligand conjugate compound of claim 2, wherein T is N or NH.

8. The drug-ligand conjugate compound of claim 2 wherein m is 1, and Z is selected from 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.

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

10. The drug-ligand conjugate compound of claim 2, wherein m is 3, and Z_m is a tripeptide selected from glycine-glycine-glycine, glycine-alanine-phenylalanine, glycine-phenylalanine-lysine, glycine-valine-citrulline and glycine-valine-lysine.

11. The drug-ligand conjugate compound of claim 2, wherein n is 1, and A is attached to a Cys residue of L which is a protein, peptide or antibody.

12. The drug-ligand conjugate compound of claim 2, wherein n is 1, and A has the structure:

13. The drug-ligand conjugate compound of claim 12 wherein R¹⁷ is selected from (CH₂)₅, (CH₂)₂, (CH₂CH₂O)₂CH₂, and CH₂CH₂C(O)NH(CH₂CH₂O)₂CH₂.

14. The drug-ligand conjugate compound of claim 2, wherein n is 1, and A is selected from 4-(N-succinimidomethyl)cyclohexane-1-carbonyl, m-succinimidobenzoyl, 4-(p-succinimidophenyl)butyryl, 4-(2-acetamido)benzoyl, 3-thiopropionyl, 4-(1-thioethyl)-benzoyl, and 6-(3-thiopropionylamido)-hexanoyl.

15. The drug-ligand conjugate compound of claim 2, wherein D is an auristatin drug moiety.

16. The drug-ligand conjugate compound of claim 2, wherein D is a drug moiety selected from N8-acetyl spermidine, actinomycin, 9-amino camptothecin, aminopterin, anguidine, anthracycline, bleomycin, butyric acid, calicheamicin, camptothecin, camptothecin, 1-(2chloroethyl)-1,2-dimethanesulfonyl hydrazide, cis-platin, daunorubicin, diacetoxypentyldoxorubicin, 1,8-dihydroxy-bicyclo[7.3.1]trideca-4,9-diene-2,6-diyne-13-one, doxorubicin, esperamicin, etoposide, maytansine, maytansinol, 6-mercaptopurine, methotrexate, mitomycin-C, mitomycin-A, morpholino-doxorubicin, retinoic acid, tallysomycin, taxol, vinblastine, and vincristine;

and salt forms thereof.

17. The drug-ligand conjugate of claim 2 wherein L is an antibody which binds to one or more tumor-associated antigens or cell-surface receptors selected from the group consisting of BMPR1B, E16, STEAP1, 0772P, MPF, Napi3b, Sema 5b, PSCA hlg, ETBR, MSG783, STEAP2, TrpM4, CRIPTO, CD21, CD79b, FcRH2, HER2, NCA, MDP, IL20Rα

, Brevican, Ephb2R, ASLG659, PSCA, GEDA , BAFF-R, CD22, CD79a, CXCR5, HLA-DOB, P2X5, CD72, LY64, FCRH1, IRTA2.

18. The drug-ligand conjugate compound of claim 2, wherein L is a ligand selected from the group consisting of bombesin, EDG, transferrin, gastrin, gastrin-releasing peptide, platelet-derived growth factor, IL-2, IL-6, TFG-alpha, TFG-beta, VGF, insulin and insulin-like growth factors I and II.

19. The drug-ligand conjugate compound of claim 17, wherein said antigen is HER2.