Site specific homogeneous with KSP inhibitors

Patent metadata

Field	Value
Publication number	US-11806404-B2
Application number	US-202117166713-A
Country	US
Kind code	B2
Filing date	Feb 3, 2021
Priority date	Jun 23, 2015
Publication date	Nov 7, 2023
Grant date	Nov 7, 2023

Abstract

The invention relates to site specific homogeneous binder drug conjugates of kinesin spindle protein inhibitors, to active metabolites of these conjugates, to processes for preparing these conjugates, to the use of these conjugates for the treatment and/or prophylaxis of diseases and to the use of these conjugates for preparing medicaments for treatment and/or prevention of diseases, in particular hyperproliferative and/or angiogenic disorders such as, for example, cancer diseases. Such treatments can be carried out as monotherapy or else in combination with other medicaments or further therapeutic measures.

First claim

The invention claimed is:

1. A compound of one of the formulae below:

or a salt, solvate, salt of a solvate, or epimer thereof, wherein:
X 1 is N, X 2 is N and X 3 is C;
or X 1 is N, X 2 is C and X 3 is N;
or X 1 is CH or CF, X 2 is C and X 3 is N;
or X 1 is NH, X 2 is C and X 3 is C;
or X 1 is CH, X 2 is N and X 3 is C;

L 1 is an organic group not cleavable in vivo;
SG is an in vivo cleavable 2-8 oligopeptide group;
Ry is —H, —C(═O)—NH-alkyl, —NH—C(═O)-alkyl, —C(═O)—NH 2 , or —NH 2 ;
R 1 is —H, -MOD, or —(CH 2 ) 0-3 Z;
wherein:
-MOD is the group —(NR 10 )n-(G1)o-G2-G3;
wherein:
R 10 is —H or C 1 -C 3 alkyl;
G1 is —NH—C(═O)—, —C(═O)NH— or

G2 is a linear and/or branched hydrocarbon group which has 1 to 10 carbon atoms and which may be interrupted once or more than once by one or more of the groups —O—, —S—, —S(═O)—, —S(═O) 2 —, —NR y —, —NR y C(═O)—, —C(═O)—NR y —, —NR y NR y —, —S(═O) 2 —NR y NR y —, —C(═O)—NR y NR y —, —C(═O)—, —CR x ═N—O—, and where the hydrocarbon chain is optionally substituted with —NH—C(═O)—NH 2 , —COOH, —OH, —NH 2 , NH—CNNH 2 , sulphonamide, sulphone, sulphoxide or sulphonic acid;
wherein:
R y is —H, phenyl, C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl or C 2 -C 10 -alkynyl, each of which may be substituted by —NH—C(═O)—NH 2 , —COOH, —OH, —NH 2 , NH—CN—NH 2 , sulphonamide, sulphone, sulphoxide or sulphonic acid;
R x is —H, C 1 -C 3 -alkyl or phenyl;

G3 is —H or —COOH; wherein MOD has at least one —COOH group;
n is 0 or 1; and
o is 0 or 1;

Z is —H, halogen, —OY 3 , —SY 3 , —NHY 3 , —C(═O)—NY 1 Y 2 or —C(═O)—OY 3 ,
Y 1 is —H, —NH 2 , —(CH 2 CH 2 O) 0-3 —(CH 2 ) 0-3 Z′ or —CH(CH 2 W)Z′
Y 2 is —H, —NH 2 , —(CH 2 CH 2 O) 0-3 —(CH 2 ) 0-3 Z′ or —CH(CH 2 W)Z′,
Y 3 is —H or —(CH 2 ) 0-3 Z′,
wherein:
W is —H or —OH,
Z′ is —H, —NH 2 , —SO 3 H, —COOH, —NH—C(═O)—CH 2 —CH 2 —CH(NH 2 )COOH or —(C(═O)—NH—CHY 4 ) 1-3 COOH, and
 Y 4 is linear or branched C 1-6 -alkyl which is optionally substituted by —NH—C(═O)—NH 2 ,
 or Y 4 is an aryl or benzyl, which are each optionally substituted by —NH 2 .

2. The compound of claim 1 , or a salt, solvate, salt of a solvate, or epimer thereof; wherein:
L 1 is an organic group not cleavable in vivo, of the formula: —(NH) n -G-;
wherein:
G represents a bond or an optionally substituted linear or branched hydrocarbon chain having 1 to 100 carbon atoms, comprising arylene groups, or linear, branched, or cyclic alkylene groups, wherein the arylene or alkylene groups may be interrupted once or more than once by one or more of the groups —O—, —S—, —S(═O)—, —S(═O) 2 —, —NH—, —C(═O)—, —NMe-, —NHNH—, —S(═O) 2 —NHNH—, —NH—C(═O)—, —C(═O)—NH—, —C(═O)—NHNH— and a 5- to 10-membered aromatic or non-aromatic heterocycle having up to 4 heteroatoms selected from the group consisting of —N—, —O— and —S—, —S(═O)— or —S(═O) 2 —; and
n is 0 or 1.

3. The compound of claim 1 , or a salt, solvate, salt of a solvate, or epimer thereof; of one of the formulae below:

or a salt, solvate, salt of a solvate, or epimer thereof; wherein:
X 1 is CH,
X 2 is C,
X 3 is N;
L 1 is an organic group not cleavable in vivo; and
Ry is —H, —C(═O)—NH-alkyl, —NH—C(═O)-alkyl, —C(═O)—NH 2 , or —NH 2 .

4. The compound of claim 1 , or a salt, solvate, salt of a solvate, or epimer thereof; of the formula below:

or a salt, solvate, salt of a solvate, or epimer thereof; wherein:
X 1 is CH,
X 2 is C,
X 3 is N;
L 1 is an organic group not cleavable in vivo;
SG is an in vivo cleavable 2-4 oligopeptide group, which can be cleaved by legumain or cathepsin;
Ry is —H, —C(═O)—NH-alkyl, —NH—C(═O)-alkyl, —C(═O)—NH 2 , or —NH 2 ; and
R 1 is —H, —COOH, or -MOD;
wherein:
MOD is —(NR 10 ) n -(G1) o -G2-G3;
R 10 is —H or C 1 -C 3 -alkyl; and n is 0 or 1;
G1 is —NH—C(═O)— or —C(═O)NH—; and o is 0 or 1;
G2 is a straight-chain and/or branched hydrocarbon group which has 1 to 10 carbon atoms and which may be interrupted once or more than once identically or differently by the groups —O—, —S—, —S(═O)—, —S(═O) 2 , —NR y —, —NR y C(═O)—, —C(═O)NR y —, —NR y NR y —, —S(═O) 2 —NR y NR y —, —C(═O)—NR y NR y —C(═O)—, —CR x ═N—O—, wherein the hydrocarbon chain including any side chains may be substituted by —NH—C(═O)—NH 2 , —COOH, —OH, —NH 2 , NH—CN—NH 2 , sulphonamide, sulphone, sulphoxide or sulphonic acid; R x is —H, C 1 -C 3 -alkyl or phenyl; and R y is —H, phenyl, C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl or C 2 -C 10 -alkynyl, each of which may be substituted by —NH—C(═O)—NH 2 , —COOH, —OH, —NH 2 , NH—CN—NH 2 , sulphonamide, sulphone, sulphoxide or sulphonic acid;
G3 is —H or —COOH.

5. The compound of claim 4 , or a salt, solvate, salt of a solvate, or epimer thereof; wherein:
SG is an in vivo cleavable 2-4 oligopeptide group, which can be cleaved by legumain or cathepsin, having the formula:
—CH(CH 2 C(═O)—NH 2 )—NH—P2-,

—CH(CH 2 C(═O)NH 2 )—NH—P2-P3-, or

—CH(CH 2 C(═O)—NH 2 )—NH—P2-(P3) 2 -;

wherein
P2 is Ala, Gly, Val, Leu, Ile, Pro, Ser, Thr, citrulline or Asn;
P3 is His, Pro, Ala, Val, Leu, Ile, Gly, Ser, citrulline or Gln, or the corresponding N-methyl-amino acid;

Ry is —H, —C(═O)—NH-alkyl, —NH—C(═O)-alkyl, —C(═O)—NH 2 , or —NH 2 ;
R 1 is —H, —COOH, or -MOD;
wherein:
MOD is —(NR 10 ) n -(G1) o -G2-G3;
R 10 is —H or C 1 -C 3 -alkyl; and n is 0 or 1;
G1 is —NH—C(═O)— or —C(═O)NH—; and o is 0 or 1;
G2 is a straight-chain and/or branched hydrocarbon group which has 1 to 10 carbon atoms and which may be interrupted once or more than once identically or differently by the groups —O—, —S—, —S(═O)—, —S(═O) 2 , —NR y —, —NR y C(═O)—, —C(═O)NR y —, —NR y NR y —, —S(═O) 2 —NR y NR y —, —C(═O)—NR y NR y —C(═O)—, —CR′═N—O—, wherein the hydrocarbon chain including any side chains may be substituted by —NH—C(═O)—NH 2 , —COOH, —OH, —NH 2 , NH—CN—NH 2 , sulphonamide, sulphone, sulphoxide or sulphonic acid; R x is —H, C 1 -C 3 -alkyl or phenyl; and R y is —H, phenyl, C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl or C 2 -C 10 -alkynyl, each of which may be substituted by —NH—C(═O)—NH 2 , —COOH, —OH, —NH 2 , NH—CN—NH 2 , sulphonamide, sulphone, sulphoxide or sulphonic acid;
G3 is —H or —COOH.

6. The compound of claim 5 , or a salt, solvate, salt of a solvate, or epimer thereof; wherein:
R 1 is -MOD;
MOD is -G1-G2-G3;
G1 is —C(═O)—NH—;
G2 is a linear hydrocarbon group which has 1 to 10 carbon atoms and is optionally interrupted by —C(═O)—NH— or —NHC(═O)—; and wherein the hydrocarbon chain is optionally substituted by —COOH or —NH 2 ; and
G3 is —COOH.

7. The compound of claim 1 , or a salt, solvate, salt of a solvate, or epimer thereof; wherein L 1 contains 1-20 —CH 2 CH 2 O— groups.

8. The compound of claim 1 , or a salt, solvate, salt of a solvate, or epimer thereof; wherein L 1 is an organic group not cleavable in vivo selected from the group consisting of:

Assignees

• Bayer Pharma AG

Inventors

• Lerchen Hans-Georg
• Cancho Grande Yolanda
• Stelte-Ludwig Beatrix
• Sommer Anette
• Mahlert Christoph
• Rebstock Anne-Sophie
• Greven Simone
• Griebenow Nils
• Tebbe Jan
• Kensch Oliver

Classifications

• A61K47/6803 Primary

  Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates · CPC title

• A61K47/6865 Primary

  the tumour determinant being from skin, nerves or brain cancer cell · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• C07K16/30

  from tumour cells · CPC title