Antibody drug conjugates (ADCs) with kinesin spindel protein (KSP)

Patent metadata

Field	Value
Publication number	US-10022453-B2
Application number	US-201415105486-A
Country	US
Kind code	B2
Filing date	Dec 10, 2014
Priority date	Dec 23, 2013
Publication date	Jul 17, 2018
Grant date	Jul 17, 2018

Abstract

The present application relates to novel antibody drug conjugates (ADCs), to active metabolites of these ADCs, to processes for preparing these ADCs, to the use of these ADCs for the treatment and/or prophylaxis of diseases and to the use of these ADCs 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 conjugate of a binder or derivative thereof, wherein the derivative thereof comprises a cysteine residue or a lysine residue, with one or more active compound molecules, the active compound molecule being a kinesin spindle protein inhibitor attached to the binder via a linker L, where the kinesin spindle protein inhibitor has the formula (IIa) below:

where
X 1 represents N, X 2 represents N and X 3 represents C; or
X 1 represents CH or CF, X 2 represents C and X 3 represents N; or
X 1 represents NH, X 2 represents C and X 3 represents C; or
X 1 represents CH, X 2 represents N and X 3 represents C;
R 1 represents H, L-# 1 , MOD or —(CH 2 ) 0-3 Z, where Z represents —H, —NHY 3 , —OY 3 , —SY 3 , halogen, —CO—NY 1 Y 2 or —CO—OY 3 ,
where Y 1 and Y 2 independently of one another represent H, NH 2 , —(CH 2 CH 2 O) 0-3 —(CH 2 ) 0-3 Z′ or —CH(CH 2 W)Z′, and Y 3 represents H or —(CH 2 ) 0-3 Z′, where Z′ represents H, NH 2 , SO 2 H, COOH, —NH—CO—CH 2 —CH 2 —CH(NH 2 )COOH or —(CO—NH—CHY 4 ) 1-3 COOH, where W represents H or OH,
where Y 4 independently of one another represents straight-chain or branched C 1-6 -alkyl which is optionally substituted by —NHCONH 2 , or represents aryl or benzyl which are optionally substituted by —NH 2 ;
R 2 represents —L-# 1 , H, -MOD, —CO—CHY 4 —NHY 5 or —(CH 2 ) 0-3 Z, or R 2 and R 4 together (with formation of a pyrrolidine ring) represent —CH 2 —CHR 10 — or —CHR 10 —CH 2 —,
where R 10 represents L-# 1 , H, NH 2 , SO 3 H, COOH, SH, or OH;
where Z represents —H, halogen, —OY 3 , —SY 3 , NHY 3 , —CO—NY 1 Y 2 or —CO—OY 3 ,
where Y 1 and Y 2 independently of one another represent H, NH 2 or —(CH 2 ) 0-3 Z′, and Y 3 represents H or —(CH 2 ) 0-3 Z′, where Z′ represents H, SO 3 H, NH 2 or COOH;
where Y 4 independently of one another represents straight-chain or branched C 1-6 alkyl which is optionally substituted by —NHCONH 2 , or represents aryl or benzyl which are optionally substituted by —NH 2 , and Y 5 represents H or —CO—CHY 6 —NH 2 , where Y 6 represents straight-chain or branched C 1-6 -alkyl;
R 4 represents —L-# 1 , H, —CO—CHY 4 —NHY 5 or —(CH 2 ) 0-3 Z,
where Z represents —H, halogen, —OY 3 , —SY 3 , NHY 3 , —CO—NY 1 Y 2 or —CO—OY 3 ,
where Y 1 and Y 2 independently of one another represent H, NH 2 or —(CH 2 ) 0-3 Z′, and Y 3 represents H or —(CH 2 ) 0-3 Z′, where Z′ represents H, SO 3 H, NH 2 or COOH;
where Y 4 independently of one another represents straight-chain or branched C 1-6 alkyl which is optionally substituted by —NHCONH 2 , or represents aryl or benzyl which are optionally substituted by —NH 2 , and Y 5 represents H or —CO—CHY 6 —NH 2 , where Y 6 represents straight-chain or branched C 1-6 -alkyl;
or R 2 and R 4 together (with formation of a pyrrolidine ring) represent —CH 2 —CHR 10 — or —CHR 10 —CH 2 —, where R 10 represents L-# 1 , H, NH 2 , SO 3 H, COOH, SH or OH;
A represents CO, SO, SO 2 , SO 2 NH or CNNH;
R 3 represents —L-# 1 , MOD or an optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, heterocycloalkyl group;
R 5 represents —L-# 1 , H, NH 2 , NO 2 , halogen, —CN, CF 3 , —OCF 3 , —CH 2 F, —CH 2 F, SH or —(CH 2 ) 0-3 Z, where Z represents —H, —OY 3 , —SY 3 , halogen, NHY 3 , —CO—NY 1 Y 2 or —CO—OY 3 ,
where Y 1 and Y 2 independently of one another represent H, NH 2 or —(CH 2 ) 0-3 Z′, and Y 3 represents H or —(CH 2 ) 0-3 Z′, where Z′ represents H, SO 3 H, NH 2 or COOH;
R 6 and R 7 independently of one another represent H, cyano, (optionally fluorinated) C 1-10 -alkyl, (optionally fluorinated) C 2-10 -alkenyl, (optionally fluorinated) C 2-10 -alkynyl, hydroxy, NO 2 , NH 2 , COOH or halogen,
R 8 represents (optionally fluorinated) C 1-10 -alkyl, (optionally fluorinated) C 2-10 -alkenyl, (optionally fluorinated) C 2-10 -alkynyl, (optionally fluorinated) C 4-10 -cycloalkyl or —(CH 2 ) 0-2 -(HZ 2 ), where HZ 2 represents a 4- to 7-membered heterocycle having up to two heteroatoms selected from the group consisting of N, O and S, where each of these groups may be substituted by —OH, CO 2 H or NH 2 or —L-# 1 ;
where one or none of the substituents R 1 , R 2 , R 3 , R 4 R 5 , R 8 and R 10 represents or (in the case of R 8 ) contains —L-# 1 ,
L represents the linker and # 1 represents the bond to the binder or derivative thereof,
R 9 represents H, F, CH 3 , CF 3 CH 2 F or CHF 2 ;
where MOD represents —(NR 10 ) n -(G1) o -G2-H, where
R 10 represents H or C 1 -C 3 -alkyl;
G1 represents —NHCO—, —CONH— or

 (where, if G1 represents —NHCO— or

 R 10 does not represent NH 2 );
n is 0 or 1;
o is 0 or 1; and
G2 represents 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 by one or more of the groups —O—, —S—, —SO—, SO 2 , —NR y —, —NR y CO—, CONR y —, —NR y NR y —, —SO 2 NR y NR y —, —CONR y NR y — (where R y represents 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 —NHCONH 2 , —COOH, —OH, —NH 2 , NH—CNNH 2 , sulphonamide, sulphone, sulphoxide or sulphonic acid), —CO—, —CR x ═N—O— (where R x represents H, C 1 -C 3 -alkyl or phenyl), where the hydrocarbon chain including any side chains may be substituted by —NHCONH 2 , —COOH, —OH, —NH 2 , NH—CNNH 2 , sulphonamide, sulphone, sulphoxide or sulphonic acid;

and the salts, solvates and salts of the solvates thereof.

2. The conjugate according to claim 1 where the active compound molecule linker is represented by general formula (II):

where
X 1 represents N, X 2 represents N and X 3 represents C; or
X 1 represents CH, X 2 represents C and X 3 represents N; or
X 1 represents NH, X 2 represents C and X 3 represents C; or
X 1 represents CH, X 2 represents N and X 3 represents C
R 1 represents H, —L-# 1 or —(CH 2 ) 0-3 Z, where Z represents —H, —NHY 3 , —OY 3 , —SY 3 , halogen, —CO—NY 1 Y 2 or —CO—OY 3 ,
where Y 1 and Y 2 independently of one another represent H, NH 2 , —(CH 2 CH 2 O) 0-3 —(CH 2 ) 0-3 Z′ or —CH(CH 2 W)Z′, and Y 3 represents H or —(CH 2 ) 0-3 Z′, where Z′ represents H, NH 2 , SO 3 H, COOH, —NH—CO—CH 2 —CH 2 —CH(NH 2 )COOH or —(CO—NH—CHY 4 ) 1-3 COOH, where W represents H or OH, where Y 4 independently of one another represents straight-chain or branched C 1-6 -alkyl which is optionally substituted by —NHCONH 2 , or represents aryl or benzyl which are optionally substituted by —NH 2 ;
R 2 and R 4 independently of one another represent —L-# 1 , H, —CO—CHY 4 —NHY 5 or —(CH 2 ) 0-3 Z, or R 2 and R 4 together (with formation of a pyrrolidine ring) represent —CH 2 —CHR 10 — or —CHR 10 —CH 2 —, where R 10 represents L-# 1 , H, NH 2 , SO 3 H, COOH, SH or OH,
where Z represents —H, OY 3 , —SY 3 , halogen, NHY 3 , —CO—NY 1 Y 2 or —CO—OY 3 ,
where Y 1 and Y 2 independently of one another represent H, NH 2 or —(CH 2 ) 0-3 Z′, and Y 3 represents H or —(CH 2 ) 0-3 Z′, where Z′ represents H, SO 3 H, NH 2 or COOH;
where Y 4 independently of one another repres

Assignees

• Bayer Pharma AG

Inventors

• Lerchen Hans-Georg
• Wittrock Sven
• Griebenow Nils
• Stelte-Ludwig Beatrix
• Sommer Anette
• Berndt Sandra
• Mahlert Christoph
• Lobell Mario
• Terjung Carsten
• Greven Simone
• Cancho Grande Yolanda

Classifications

• C07D207/335

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

• A61K47/68

  the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment · CPC title

• C07D233/64

  with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine · CPC title

• C07K16/2875

  against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154 (against NGF C07K16/22, against TNF C07K16/241) · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title