Peptidomimetic compounds and antibody-drug conjugates thereof

Patent metadata

Field	Value
Publication number	US-10632210-B2
Application number	US-201816150623-A
Country	US
Kind code	B2
Filing date	Oct 3, 2018
Priority date	Dec 16, 2013
Publication date	Apr 28, 2020
Grant date	Apr 28, 2020

Abstract

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

First claim

The invention claimed is:

1. A compound of Formula:

wherein
Str is a stretcher unit which can be covalently attached to an antibody, having the structure:

where R 6 is C 1 -C 10 alkylene;
Sp is an optional spacer unit covalently attached to a drug moiety selected from —C 1 -C 6 alkylene-C(O)NH— or —Ar—R b —, wherein Ar is aryl or heteroaryl, and R b is (C 1 -C 10 alkylene)O—;
Y is a moiety selected from the group consisting of

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; and
D is a drug moiety having the formula:

wherein
R 11 is selected from H, P(O) 3 H 2 , C(O)NR aa R bb , or a bond to Sp;
R 22 is selected from H, P(O) 3 H 2 , C(O)NR aa R bb , or a bond to Sp;
R aa and R bb are independently selected from H and C 1 -C 6 alkyl optionally substituted with one or more F,
or R aa and R bb form a five or six membered heterocycloalkyl group;
T is a tether group selected from C 3 -C 12 alkylene, Y 1 , (C 1 -C 6 alkylene)-Y 1 —(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-Y 1 —(C 1 -C 6 alkylene)-Y 1 —(C 1 -C 6 alkylene), (C 2 -C 6 alkenylene)-Y 1 —(C 2 -C 6 alkenylene), or (C 2 -C 6 alkynylene)-Y 1 —(C 2 -C 6 alkynylene);
where Y 1 is independently selected from O, S, NR 11 , aryl, or heteroaryl;
where alkylene, alkenylene, aryl, and heteroaryl are independently and optionally substituted with F, OH, O(C 1 -C 6 alkyl), NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC(O)(C 1 -C 6 alkylene) m , OP(O) 3 H 2 , or C 1 -C 6 alkyl, where alkyl is optionally substituted with one or more F, m is 0 or 1;
or alkylene, alkenylene, aryl, and heteroaryl are independently and optionally substituted with a bond to Sp, wherein the bond to Sp may connect through one of the optional substituents;
D′ is a drug moiety selected from:

where the wavy line indicates the site of attachment to T;
X 1 and X 2 are independently selected from O or NR 33 , where R 33 is selected from H, C(O), or C 1 -C 6 alkyl, optionally substituted with one or more F, or X 1 and X 2 are each independently absent;
R 44 is H, CO 2 R, C(O), or a bond to Sp, where R is C 1 -C 6 alkyl or benzyl; and
R 55 is H or C 1 -C 6 alkyl.

2. The compound of claim 1 represented by the following formula:

3. The compound of claim 2 , which is represented by the following formula:

4. The compound of claim 1 wherein R 2 and R 3 are each independently selected from H and C 1 -C 10 alkyl.

5. The compound of claim 1 wherein D′ is:

X 1 and X 2 are O; and each R 11 is independently selected from H and P(O) 3 H 2 .

6. The compound of claim 5 wherein T is (C 2 -C 6 alkenylene)-Y 1 —(C 2 -C 6 alkenylene); and Y 1 is aryl substituted with a bond to Sp.

7. The compound of claim 1 wherein the drug moiety is selected from:

where the wavy line indicates the point of attachment to Sp.

Assignees

• Genentech Inc

Inventors

• Lee Ho Huat
• Tercel Moana
• Flygare John A
• Gunzner-Toste Janet
• Pillow Thomas H
• Safina Brian
• Staben Leanna
• Verma Vishal
• Wei Binqing
• Zhao Guiling

Classifications

• C07K16/28

  against receptors, cell surface antigens or cell surface determinants · CPC title

• A61K47/6889 Primary

  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

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title

• A61K47/6851

  the antibody targeting a determinant of a tumour cell · CPC title

• C07K2317/24

  containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered · CPC title