Coumarin derivatives, processes for their preparation and uses thereof for the treatment of cancer

Patent metadata

Field	Value
Publication number	US-11111238-B2
Application number	US-201816648348-A
Country	US
Kind code	B2
Filing date	Sep 20, 2018
Priority date	Sep 20, 2017
Publication date	Sep 7, 2021
Grant date	Sep 7, 2021

Abstract

The invention provides novel coumarin derivatives as specific mitochondrial RNA polymerase inhibitors for the treatment of cancer.

First claim

The invention claimed is:

1. A compound of the general formula (I)

wherein
R is —C 1 -C 4 -alkyl;
R 1 is —H, or -methyl;
M is CH or N;
W is

wherein
R 2 is C 1 -C 4 -alkyl, -halogen, —CN;
X is -halogen, or —CN;
n=0, 1, or 2;

Y is —NR 3 R 4 wherein
R 3 is —H, or —C 1 -C 4 -alkyl, and
R 4 is —C 1 -C 4 -alkyl or —C 3 -C 6 -cycloalkyl; or
an unsubstituted or substituted pyridine residue; or
an unsubstituted or substituted phenyl residue; or

Y is —NR 3 R 4 with N, R 3 and R 4 forming an unsubstituted or substituted 5- or 6-membered saturated heterocycle; or
Y is —OR 11 , with R 11 is —H or —C 1 -C 4 -alkyl;
or a pharmaceutically or veterinary acceptable salt, hydrate or solvate thereof.

2. The compound of claim 1 , wherein
R is —C 1 -C 4 -alkyl;
R 1 is —H, or -methyl;
M is —CH;
W is

wherein
R 2 is methyl, -halogen, —CN;
X is -halogen, or —CN;
n=0, 1, or 2;

Y is —NR 3 R 4 wherein
R 3 is —H, or —C 1 -C 4 -alkyl, and
R 4 is —C 1 -C 4 -alkyl or —C 3 -C 6 -cycloalkyl; or
an unsubstituted or substituted pyridine residue; or
an unsubstituted or substituted phenyl residue;

Y is —NR 3 R 4 with N, R 3 and R 4 forming an unsubstituted or substituted 5- or 6-membered saturated heterocycle; or
Y is —OR 11 , with R 11 is —H or —C 1 -C 4 -alkyl;
or a pharmaceutically or veterinary acceptable salt, hydrate or solvate thereof.

3. The compound of claim 1 , wherein Y is —NR 3 R 4 , wherein
R 3 is —H, or —C 1 -C 4 -alkyl, and
R 4 is a pyridine residue; or a phenyl residue substituted with —(CH 2 ) p OH with p=1 or 2; or
—C 1 -C 4 -alkyl or —C 3 -C 6 -cycloalkyl.

4. The compound of claim 1 , wherein N, R 3 and R 4 together form an unsubstituted or substituted piperidine, piperazine or pyrrolidine residue, each optionally and independently substituted with one or more of the following residues:
—C 1 -C 4 -alkyl;
—(CH 2 ) m —COOR 5 with R 5 is —H, —C 1 -C 8 -alkyl, —C 2 -C 4 -alkyl-N-morpholine or the group

—(CH 2 ) m CONR 6 R 7 with R 6 and R 7 is independently —H, or —C 1 -C 4 -alkyl;
—CO—(C 2 -C 4 -alkenyl); —CO—CH 2 —Cl; —CO—CH 2 —CH 3 ;
NH—CO—(C 2 -C 4 -alkenyl); —NH—CO—CH 2 —Cl; —NH—CO—CH 2 —CH 3 ;
—F;
—CN;
—SO 3 H;
—SO 2 NR 8 R 9 with R 8 and R 9 independently are —H, or —C 1 -C 4 -alkyl;
—SONHR 10 with R 10 is —C 1 -C 4 -alkyl; or

and
m=0, 1, or 2.

5. The compound according to claim 1 , wherein N, R 3 and R 4 together form an unsubstituted or substituted piperidine or pyrrolidine residue, each optionally and independently substituted with one or more of the following residues:
—C 1 -C 4 -alkyl;
—(CH 2 ) m —COOR 5 with R 5 is —H, —C 1 -C 8 -alkyl, —C 2 -C 4 -alkyl-N-morpholine or the group

—(CH 2 ) m CONR 6 R 7 with R 6 and R 7 is independently —H, or —C 1 -C 4 -alkyl;
—F;
—CN;
—SO 3 H;
—SO 2 NR 8 R 9 with R 5 and R 9 independently are —H, or —C 1 -C 4 -alkyl;
—SONHR 10 with R 10 is —C 1 -C 4 -alkyl; or

and
m=0, 1, or 2.

6. The compound according to claim 1 , wherein
R is -methyl;
R 1 is —H;
m=0, or 1;
W is

wherein
R 2 is methyl, or —Cl;
X is —F with n=1;

Y is —NR 3 R 4
wherein
R 3 is —H, and
R 4 is a pyridine residue,
a phenyl residue substituted at the para position;
or with
N, R 3 and R 4 forming together a piperidine residue, or a pyrrolidine residue, each optionally and independently substituted with one of the following residues: —COOH, —COOCH 3 , —COOC 2 H 5 , —CH 2 COOH, —CH 2 COOCH 3 , —CH 2 COOCH 2 CH 3 , —CONH 2 , —CONHCH 3 , —CON(CH 3 ) 2 , —CH 2 CONHCH 3 , —SO 2 NH 2 , —SO 2 NHCH 3 , or —CN.

7. The compound according to claim 1 , wherein
R is (R)-methyl;
R 1 is —H;
W is

with
R 2 is methyl, or Cl;
X is —F with n=1;

Y is —NR 3 R 4
with
N, R 3 and R 4 forming a piperidine residue, or a pyrrolidine residue, each optionally and independently substituted with one of the following residues: —COOH, —CH 2 COOH, —CONHCH 3 , —CH 2 CONHCH 3 , —SO 2 NH 2 , —SO 2 NHCH 3 , or —CN.

8. The compound according to claim 4 , wherein the piperidine residue or the pyrrolidine residue is substituted at the 3-position.

9. The compound according to claim 1 , wherein X is at the para-position of the phenyl ring.

10. The compound of claim 1 , wherein
R is -methyl or -ethyl;
R 1 is —H;
M is CH or N;
W is

wherein
R 2 is -methyl, -ethyl, —Cl, or —Br;
X is —Cl, or —F;
n=0, 1 or 2;

Y is —NR 3 R 4 wherein
R 3 is —H or -methyl, and
R 4 is -methyl, -ethyl, -isopropyl, or -cyclopropyl; or
an unsubstituted or substituted pyridine residue; or
an unsubstituted or a phenyl residue substituted at the para position; or

Y is —NR 3 R 4 with N, R 3 and R 4 forming an unsubstituted or substituted 5- or 6-membered saturated heterocycle; or
Y is —OR 11 , wherein R 11 is -methyl, -ethyl, or -isopropyl.

11. The compound of claim 1 , wherein
R is -methyl;
R 1 is —H;
M is —CH:
W is

wherein
R 2 is -methyl, —Cl, or —Br;
X is —F;
n=1 or 2;

Y is —NR 3 R 4 , wherein
R 3 is —H or -methyl, and
R 4 is -methyl, -ethyl, -isopropyl, or -cyclopropyl; or
an unsubstituted or substituted pyridine residue; or
an unsubstituted or a substituted phenyl residue, substituted at the para position;

Y is —NR 3 R 4 with N, R 3 and R 4 forming an unsubstituted or substituted 5- or 6-membered saturated heterocycle; or
Y is —OR 11 , wherein R 11 is -methyl, -ethyl, or -isopropyl.

12. The compound of claim 4 , wherein
R 5 is —H, -methyl, -ethyl, -isopropyl, -tert-butyl, -n-heptyl, 2-morpholinoethyl or -isopropoxycarbonyloxymethyl;
R 10 is -methyl; and
m is 0 or 1.

13. The compound of formula (I) according to claim 1 , selected from
7-[1-methyl-2-oxo-2-(1-piperidyl)ethoxy]-4-(o-tolyl)chromen-2-one, 4-(2-chlorophenyl)-7-[1-methyl-2-oxo-2-(1-piperidyl)ethoxy]chromen-2-one,
(3S)-1-[2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxylic acid,
2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxy-N-(2-pyridyl)propanamide,
7-(1-methyl-2-oxo-2-pyrrolidin-1-yl-ethoxy)-4-(o-tolyl)chromen-2-one,
methyl -1-[2-[4-(o-tolyl)-2-oxo-chromen-7-yl]oxypropanoyl]piperidine-3-carboxylate,
methyl -1-[2-[4-(

Assignees

• Lead Discovery Center Gmbh
• Max Planck Gesellschaft
• Sotio As
• Max Planck Ges Zur Foerderung Der Wissenschften E V

Inventors

• Di Lucrezia Raffaella
• Bergbrede Tim
• Nussbaumer Peter
• Koch Uwe
• Klebl Bert
• Choidas Axel
• Unger Anke
• Larsson Nils-Göran
• Falkenberg-Gustafsson Maria
• Gustafsson Claes M

Classifications

• A61K45/06

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

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D311/18 Primary

  substituted otherwise than in position 3 or 7 · CPC title

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• C07D491/052

  the oxygen-containing ring being six-membered · CPC title