Homo- and heterodimeric SMAC mimetic compounds as apoptosis inducers

Patent metadata

Field	Value
Publication number	US-9730976-B2
Application number	US-201615071677-A
Country	US
Kind code	B2
Filing date	Mar 16, 2016
Priority date	Feb 20, 2012
Publication date	Aug 15, 2017
Grant date	Aug 15, 2017

Abstract

The present invention relates to conformationally constrained homo- and heterodimeric mimetics of Smac with function as inhibitors of Inhibitor of Apoptosis Proteins (IAPs), the invention also relates to the use of these compounds in therapy, wherein the induction of apoptotic cell death is beneficial, especially in the treatment of cancer, alone or in combination with other active ingredients.

First claim

The invention claimed is:

1. A method of treating cancer in a mammalian subject, wherein the cancer is breast cancer, ovarian cancer, acute myeloid leukemia (AML), or prostate cancer characterized by overexpression of an inhibitor of apoptosis protein (IAP) family member, said method comprising administering to the mammalian subject a compound of formula (I)

or pharmaceutically acceptable salt thereof, wherein
n is 1 or 2
m is an integer from 0 to 3
A is NR 1 R 2
R 1 and R 2 are, each independently,
hydrogen;
C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl;
optionally substituted aryl or alkylaryl;

R 4 are each independently
hydrogen;
optionally substituted C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl;
optionally substituted aryl or alkylaryl;

B is
C 1-4 alkyl; C 2-4 alkenyl; C 2-4 alkynyl;
aryl or alkylaryl;
all optionally substituted by one or more halogen;

Y is selected among OR 5 , NHR 5 , NR 5 R 6 , NH—S(O) 2 —R 5 , N + (R 5 ) 3 , SR 5 , N 3 , C(O)OR 5 , CN, C(S)OR 5 , C(S)NHR 5 , C(NH)NHR 5 , NH(CNH)NHR 5 , NH(CS)NHR 5 , NH(CO)NHR 5 or

R 5 is
hydrogen;
optionally substituted C 1-8 alkyl; C 2-8 alkenyl; C 2-8 alkynyl;
optionally substituted aryl or alkylaryl;

R 6 is
optionally substituted C 1-8 alkyl; C 2-8 alkenyl; or C 2-8 alkynyl;
optionally substituted aryl or alkylaryl;

L is a linker, wherein the linker is

L1

L2

L3

L4

L5

L6

L7

L8

L9

L10

L11

L12

L13

L14

L15

L16

L17

L18

L19

L20

L21

Assignees

• Seneci Pierfausto
• Belvisi Laura
• Cossu Federica
• Delia Domenico
• Drago Carmelo
• Lecis Daniele
• Maiorana Stefano
• Manzoni Leonardo Pierpaolo
• Mastrangelo Eloise
• Milani De Mayo De Mari Mario
• Perego Paola Maria Chiara
• Vasile Francesca
• Biontech Ag

Inventors

• Seneci Pierfausto
• Belvisi Laura
• Cossu Federica
• Delia Domenico
• Drago Carmelo
• Lecis Daniele
• Maiorana Stefano
• Manzoni Leonardo Pierpaolo
• Mastrangelo Eloise
• Milani De Mayo De Mari Mario
• Perego Paola Maria Chiara
• Vasile Francesca

Classifications

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• C07K5/1005

  and aliphatic · CPC title

• C07K5/0804

  and aliphatic · CPC title

• A61K38/07 Primary

  Tetrapeptides · CPC title

• C07K5/1008

  the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala · CPC title