Prodrugs of cytotoxic active agents having enzymatically cleavable groups

Patent metadata

Field	Value
Publication number	US-12059472-B2
Application number	US-201716472634-A
Country	US
Kind code	B2
Filing date	Dec 18, 2017
Priority date	Dec 21, 2016
Publication date	Aug 13, 2024
Grant date	Aug 13, 2024

Abstract

The invention relates to novel prodrugs or conjugates of the general formula (Ia)

in which La, n, R and D have the definitions given in the description and which have a structural motif reduced to an asparagine derivative as cleavage site for tumour-associated proteases such as legumain, in which cytotoxic drugs, for example kinesin spindle protein inhibitors, are released by legumain cleavage, and to the use of these prodrugs or conjugates for treatment and/or prevention of diseases, and to the use of these prodrugs or conjugates for production of medicaments for treatment and/or prevention of diseases, especially of hyperproliferative and/or angiogenic disorders, for example cancers. Reduction of the legumain-cleavable substrate peptide sequence to an asparagine derivative as structural motif, as a result of slowed legumain cleavage, achieves an increase in stability in the lysosomes of healthy organs while simultaneously maintaining the high anti-tumour effect.

First claim

The invention claimed is:

1. A compound, or a salt, a solvate, or a salt of a solvate thereof, wherein the compound has one of the following structures:

wherein
AK 1 and AK 2 is an antibody or an antigen-binding fragment thereof, and
n is a number from 1 to 50.

2. The compound according to claim 1 , or a salt, a solvate, or a salt of a solvate thereof, wherein the antibody or the antigen-binding fragment thereof binds to an extracellular cancer target molecule.

3. The compound according to claim 2 , or a salt, a solvate, or a salt of a solvate thereof, wherein the antibody or the antigen-binding fragment thereof, after binding to its extracellular target molecule on t-h a target cell, is internalized by the target cell through the binding.

4. The compound according to claim 1 , or a salt, a solvate, or a salt of a solvate thereof, wherein the antibody is an anti-HER2 antibody, an anti-EGFR antibody, an anti-B7H3 antibody, an anti-TWEAKR antibody, or an antigen-binding fragment thereof.

5. The compound according to claim 4 , or a salt, a solvate, or a salt of a solvate thereof, wherein the anti-HER2 antibody is trastuzumab.

6. The compound according to claim 1 , or a salt, a solvate, or a salt of a solvate thereof, wherein the antibody
(i) is an anti-EGFR antibody comprising a variable region of the heavy chain (VH) comprising the variable CDR1 sequence of the heavy chain (H-CDR1), as shown by SEQ ID NO: 2, the variable CDR2 sequence of the heavy chain (H-CDR2), as shown by SEQ ID NO: 3 and the variable CDR3 sequence of the heavy chain (H-CDR3), as shown by SEQ ID NO: 4, and a variable region of the light chain (VL) comprising the variable CDR1 sequence of the light chain (L-CDR1), as shown by SEQ ID NO: 6, the variable CDR2 sequence of the light chain (L-CDR2), as shown by SEQ ID NO: 7 and the variable CDR3 sequence of the light chain (L-CDR3), as shown by SEQ ID NO: 8,
(ii) is an anti-HER2 antibody comprising a variable region of the heavy chain (VH) comprising the variable CDR1 sequence of the heavy chain (H-CDR1), as shown by SEQ ID NO: 12, the variable CDR2 sequence of the heavy chain (H-CDR2), as shown by SEQ ID NO: 13 and the variable CDR3 sequence of the heavy chain (H-CDR3), as shown by SEQ ID NO: 14, and a variable region of the light chain (VL) comprising the variable CDR1 sequence of the light chain (L-CDR1), as shown by SEQ ID NO: 16, the variable CDR2 sequence of the light chain (L-CDR2), as shown by SEQ ID NO: 17 and the variable CDR3 sequence of the light chain (L-CDR3), as shown by SEQ ID NO: 18,
(iii) is an anti-TWEAKR antibody comprising a variable region of the heavy chain (VH) comprising the variable CDR1 sequence of the heavy chain (H-CDR1), as shown by SEQ ID NO: 22, the variable CDR2 sequence of the heavy chain (H-CDR2), as shown by SEQ ID NO: 23 and the variable CDR3 sequence of the heavy chain (H-CDR3), as shown by SEQ ID NO: 24, and a variable region of the light chain (VL) comprising the variable CDR1 sequence of the light chain (L-CDR1), as shown by SEQ ID NO: 26, the variable CDR2 sequence of the light chain (L-CDR2), as shown by SEQ ID NO: 27 and the variable CDR3 sequence of the light chain (L-CDR3), as shown by SEQ ID NO: 28,
(iv) is an anti-TWEAKR antibody comprising a variable region of the heavy chain (VH) comprising the variable CDR1 sequence of the heavy chain (H-CDR1), as shown by SEQ ID NO: 32, the variable CDR2 sequence of the heavy chain (H-CDR2), as shown by SEQ ID NO: 33 and the variable CDR3 sequence of the heavy chain (H-CDR3), as shown by SEQ ID NO: 34, and a variable region of the light chain (VL) comprising the variable CDR1 sequence of the light chain (L-CDR1), as shown by SEQ ID NO: 36, the variable CDR2 sequence of the light chain (L-CDR2), as shown by SEQ ID NO: 37 and the variable CDR3 sequence of the light chain (L-CDR3), as shown by SEQ ID NO: 38,
(v) is an anti-TWEAKR antibody comprising a variable region of the heavy chain (VH) comprising the variable CDR1 sequence of the heavy chain (H-CDR1), as shown by SEQ ID NO: 42, the variable CDR2 sequence of the heavy chain (H-CDR2), as shown by SEQ ID NO: 43 and the variable CDR3 sequence of the heavy chain (H-CDR3), as shown by SEQ ID NO: 44, and a variable region of the light chain (VL) comprising the variable CDR1 sequence of the light chain (L-CDR1), as shown by SEQ ID NO: 46, the variable CDR2 sequence of the light chain (L-CDR2), as shown by SEQ ID NO: 47 and the variable CDR3 sequence of the light chain (L-CDR3), as shown by SEQ ID NO: 48,
(vi) is an anti-TWEAKR antibody comprising a variable region of the heavy chain (VH) comprising the variable CDR1 sequence of the heavy chain (H-CDR1), as shown by SEQ ID NO: 52, the variable CDR2 sequence of the heavy chain (H-CDR2), as shown by SEQ ID NO: 53 and the variable CDR3 sequence of the heavy chain (H-CDR3), as shown by SEQ ID NO: 54, and a variable region of the light chain (VL) comprising the variable CDR1 sequence of the light chain (L-CDR1), as shown by SEQ ID NO: 56, the variable CDR2 sequence of the light chain (L-CDR2), as shown by SEQ ID NO: 57 and the variable CDR3 sequence of the light chain (L-CDR3), as shown by SEQ ID NO: 58,
(vii) is an anti-TWEAKR antibody comprising a variable region of the heavy chain (VH) comprising the variable CDR1 sequence of the heavy chain (H-CDR1), as shown by SEQ ID NO: 62, the variable CDR2 sequence of the heavy chain (H-CDR2), as shown by SEQ ID NO: 63 and the variable CDR3 sequence of the heavy chain (H-CDR3), as shown by SEQ ID NO: 64, and a variable region of the light chain (VL) comprising the variable CDR1 sequence of the light chain (L-CDR1), as shown by SEQ ID NO: 66, the variable CDR2 sequence of the light chain (L-CDR2), as shown by SEQ ID NO: 67 and the variable CDR3 sequence of the light chain (L-CDR3), as shown by SEQ ID NO: 68,
(viii) is an anti-HER2 antibody comprising a variable region of the heavy chain (VH) comprising the variable CDR1 sequence of the heavy chain (H-CDR1), as shown by SEQ ID NO: 72, the variable CDR2 sequence of the heavy chain (H-CDR2), as shown by SEQ ID NO: 73 and the variable CDR3 sequence of the heavy chain (H-CDR3), as shown by SEQ ID NO: 74, and a variable region of the light chain (VL) comprising the variable CDR I sequence of the light chain (L-CDR1), as shown by SEQ ID NO: 76, the variable CDR2 sequence of the light chain (L-CDR2), as shown by SEQ ID NO: 77 and the variable CDR3 sequence of the light chain (L-CDR3), as shown by SEQ ID NO: 78,
(ix) is an anti-HER2 antibody comprising a variable region of the heavy chain (VH) comprising the variable CDR1 sequence of the heavy chain (H-CDR1), as shown by SEQ ID NO: 82, the variable CDR2 sequence of the heavy chain (H-CDR2), as shown by SEQ ID NO: 83 and the variable CDR3 sequence of the heavy chain (H-CDR3), as shown by SEQ ID NO: 84, and a variable region of the light chain (VL) comprising the variable CDR1 sequence of the light chain (L-CDR1), as shown by SEQ ID NO: 86, the variable CDR2 sequence of the li

Assignees

• Bayer Ag
• Bayer Pharma AG

Inventors

• Lerchen Hans-Georg
• Rebstock Anne-Sophie
• Marx Leo
• Johannes Sarah Anna Liesa
• Stelte-Ludwig Beatrix
• Dietz Lisa
• Joerissen Hannah
• Mahlert Christoph
• Greven Simone
• Sommer Anette

Classifications

• C07D207/335

  Radicals substituted by nitrogen atoms not forming part of a nitro radical · CPC title

• A61K31/402

  1-aryl substituted, e.g. piretanide · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K47/6855

  the tumour determinant being from breast cancer cell · CPC title

• A61K47/6849

  the antibody targeting a receptor, a cell surface antigen or a cell surface determinant · CPC title