Peptidomimetic compounds and antibody-drug conjugates thereof

Patent metadata

Field	Value
Publication number	US-10533058-B2
Application number	US-201415104388-A
Country	US
Kind code	B2
Filing date	Dec 16, 2014
Priority date	Dec 16, 2013
Publication date	Jan 14, 2020
Grant date	Jan 14, 2020

Abstract

This invention relates to peptidomimetic linkers and anti-body drug conjugates thereof, pharmaceutical compositions containing them, and to their use in therapy for the prevention treatment of cancer.

First claim

The invention claimed is:

1. A non-peptide compound of Formula (IV) or Formula (V):

wherein
Str is a stretcher unit which can be covalently attached to an antibody;
Sp is a bond or a spacer unit covalently attached to a drug moiety;
Y is selected from:

R 1 is C 1 -C 10 alkyl, (C 1 -C 10 alkyl)NHC(NH)NH 2 or (C 1 -C 10 alkyl)NHC(O)NH 2 ;
R 3 and R 2 are each independently H, C 1 -C 10 alkyl, arylalkyl or heteroarylalkyl, or R 3 and R 2 together may form a C 3 -C 7 cycloalkyl;
R 4 and R 5 form a C 3 -C 7 cycloalkyl ring;
D is a drug moiety of formula A or of formula B:

or a pharmaceutically acceptable salt thereof, wherein:
the wavy line indicates the covalent attachment site to the linker;
the dotted lines indicate the optional presence of a double bond between C1 and C2 or C2 and C3;
R 22 is independently selected from H, OH, ═O, ═CH 2 , CN, R m , O R m , ═CH—R D , ═C(R D ) 2 ,
O—SO 2—R m , CO 2 R m and CO R m , and optionally further selected from halo or dihalo, wherein
R D is independently selected from R m , CO 2 R m , CO R m , CHO, CO 2 H, and halo;
R 66 and R 99 are independently selected from H, R m , OH, O R m , SH, S R m , NH 2 , NH R m , N R m R p , NO 2 , Me 3 Sn and halo;
R 77 is independently selected from H, R m , OH, O R m , SH, S R m , NH 2 , NH R m , N R m R p , NO 2 ,
Me 3 Sn and halo;
Q is independently selected from O, S and NH;
R 11 is either H, or R m or, where Q is O, SO 3 M, where M is a metal cation;
R m and R p are each independently selected from optionally substituted C 1-8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalyl, C 3-8 heterocyclyl, C 5-20 aryl and C 5-20 heteroaryl groups, and optionally in relation to the group N R m R P , R m and R p together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, 6- or 7-membered heterocyclic ring;
R 12 , R 16 , R 19 , R 21 andR 17 are as defined for R 22 , R 66 , R 99 , R 11 and R 77 respectively;
R″ is a C 3 -C 12 alkylene group, which chain may be interrupted by one or more heteroatoms selected from O, S, N(H), or NMe or aromatic rings, which rings are optionally substituted;
X and X′ are independently selected from O, S and N(H); and
R C is a capping group.

2. The compound of claim 1 represented by one of the following formulae:
(a)(i)

wherein R 6 is C 1 -C 10 alkylene;
(a)(ii)

wherein
R 6 is C 1 -C 10 alkylene;

3. The non-peptide compound of claim 1 wherein C 3 -C 7 cycloalkyl is cyclobutyl.

4. The non-peptide compound of claim 1 wherein R 1 of Formula (IV) or Formula (V) is CH 2 CH 2 CH 2 NHC(O)NH 2 .

5. The non-peptide compound of claim 1 wherein Str is:

where R 6 is C 1 -C 10 alkylene.

6. The non-peptide compound of claim 1 wherein Sp has the structure:

7. The non-peptide compound of claim 1 selected from:

Assignees

• Genentech Inc
• Medimmune Ltd

Inventors

• Flygare John
• Gunzner-Toste Janet
• Pillow Thomas
• Safina Brian
• Verma Vishal
• Wei Binqing
• Zhao Guiling
• Staben Leanna
• Howard Philip Wilson
• Masterson Luke

Classifications

• A61K47/6867

  the tumour determinant being from a cell of a blood cancer · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K47/6869

  the tumour determinant being from a cell of the reproductive system: ovaria, uterus, testes, prostate · CPC title

• A61K47/6889

  Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment · CPC title