Homo- and heterodimeric SMAC mimetic compounds as apoptosis inducers

Patent metadata

Field	Value
Publication number	US-9321808-B2
Application number	US-201214379675-A
Country	US
Kind code	B2
Filing date	Feb 20, 2012
Priority date	Feb 20, 2012
Publication date	Apr 26, 2016
Grant date	Apr 26, 2016

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 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

wherein each n is independently 1-6,

L2

wherein each n is independently 1-6,

L3

wherein each n is independently 1-6,

L4

wherein each n is independently 1-6,

L5

wherein each n is independently 1-6,

L6

wherein each n is independently 1-6,

L7

wherein each n is independently 1-10

L8

wherein each n is independently 1-10

L9

wherein each n is independently 1-3,

L10

wherein each n is independently 1-3,

L11

wherein each n is independently 1-3,

L12

wherein each n is independently 1-4

L13

wherein each n is independently 1-4,

L14

wherein each n is independently 1-4,

L15

wherein each n is independently 1-4,

L16

wherein each n is independently 1-4,

L17

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

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07K5/101

  the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu · CPC title

• C07K5/0806

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

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07K5/1008

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