Fumarate-CO-releasing molecule hybrids, their use in the treatment of inflammatory or cardiovascular diseases and their process of preparation

Patent metadata

Field	Value
Publication number	US-9944669-B2
Application number	US-201515127674-A
Country	US
Kind code	B2
Filing date	Mar 20, 2015
Priority date	Mar 21, 2014
Publication date	Apr 17, 2018
Grant date	Apr 17, 2018

Abstract

The present invention relates to hybrid fumarate-CO-releasing molecules capable of increasing heme oxygenase-1 (HO-1) activity and HO-1 protein expression and simultaneously releasing CO, their synthesis and their use in therapeutic applications, in particular their use in the treatment of inflammatory or cardiovascular diseases.

First claim

The invention claimed is:

1. A hybrid fumarate-carbon monoxide releasing molecule of formula (I)

wherein:
A represents:
a single bond, or
—Z-Q-, where:
Q represents O, S or NR 2 , where R 2 represents H, (C 1 -C 6 )alkyl, aryl, heteroaryl, (C 1 -C 6 )alkyl-aryl, (C 1 -C 6 )alkyl-heteroaryl, (C 1 -C 6 )alkyl-(C 3 -C 8 )heterocyclyl, or —(C 3 -C 14 )cycloalkyl, or R 2 and Z are connected to form a (C 3 -C 8 )heterocyclyl,
Z represents —(C 1 -C 6 )alkyl-, —(C 2 -C 6 )alkenyl-, -aryl-, -heteroaryl-, —(C 2 -C 6 )alkynyl-, —(C 3 -C 8 )heterocyclyl-, —(C 3 -C 14 )cycloalkyl, —(C 1 -C 6 )alkyl-R 3 —(C 1 -C 6 )alkyl-, —(C 2 -C 6 )alkenyl-R 3 —(C 1 -C 6 )alkyl-, —(C 1 -C 6 )alkyl-R 3 —(C 2 -C 6 )alkenyl-, —(C 2 -C 6 )alkenyl-R 3 —(C 2 -C 6 )alkenyl-, —(C 1 -C 6 )alkyl-R 3 —(C 2 -C 6 )alkynyl-, —(C 2 -C 6 )alkenyl-R 3 —(C 2 -C 6 )alkynyl-, —(C 2 -C 6 )alkynyl-R 3 —(C 2 -C 6 )alkynyl-, —(C 2 -C 6 )alkynyl-R 3 —(C 1 -C 6 )alkyl-, or —(C 2 -C 6 )alkynyl-R 3 —(C 2 -C 6 )alkenyl-, where R 3 represents aryl, heteroaryl, (C 3 -C 8 )heterocyclyl, (C 3 -C 14 )cycloalkyl, —(C 1 -C 6 )alkyl-OCO—, or —CH 2 —(CHOR 3 )CH 2 O—(C 1 -C 6 )alkyl-,

CORM represents a carbonyl metal complex selected from the group consisting of:
Mn(CO) 5 ,

where W represents O or NR 4 , where R 4 represents —(C 1 -C 6 )alkyl-, L represents an ionic ligand, or a counter-ion, M represents Rh, Co, Ru, Mn, Mo, V or Fe, and n is an integer chosen so that the metal M has no free valency, Q′ represents O, S or NR 5 , where R 5 represents H, (C 1 -C 6 )alkyl, aryl, heteroaryl, (C 1 -C 6 )alkyl-aryl, (C 1 -C 6 )alkyl-heteroaryl, (C 1 -C 6 )alkyl-(C 3 -C 8 )heterocyclyl, or —(C 3 -C 14 )cycloalkyl, and Y represents H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, -aryl, -heteroaryl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )heterocyclyl, —(C 3 -C 14 )cycloalkyl, —(C 1 -C 6 )alkyl-R 6 —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl-R 6 —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-R 6 —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkenyl-R 6 —(C 2 -C 6 )alkenyl, —(C 1 -C 6 )alkyl-R 6 —(C 2 -C 6 )alkynyl, —(C 2 -C 6 )alkenyl-R 7 —(C 2 -C 6 )alkynyl, —(C 2 -C 6 )alkynyl-R 6 —(C 2 -C 6 )alkynyl, —(C 2 -C 6 )alkynyl-R 6 —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkynyl-R 6 —(C 2 -C 6 )alkenyl, (C 1 -C 6 )alkyl-R 6 , —(C 2 -C 6 )alkenyl-R 6 , —(C 2 -C 6 )alkynyl-R 6 , or —CH, where R 6 represents aryl, heteroaryl, (C 3 -C 8 )heterocyclyl, or (C 3 -C 14 )cycloalkyl, and where R 7 represents H, (C 1 -C 6 )alkyl, aryl, heteroaryl, (C 1 -C 6 )alkyl-aryl, (C 1 -C 6 )alkyl-heteroaryl, (C 1 -C 6 )alkyl-(C 3 -C 8 )heterocyclyl, or (C 1 -C 6 )alkyl-(C 3 -C 4 )cycloalkyl.

2. The molecule of claim 1 , wherein Q represents O, S or NR 2 , where R 2 represents H, or (C 1 -C 6 )alkyl, and Z represents —(C 1 -C 6 )alkyl-, —(C 2 -C 6 )alkenyl-, —(C 3 -C 8 )heterocyclyl-, —(C 1 -C 6 )alkyl-R 3 —(C 1 -C 6 )alkyl-, or —(C 2 -C 6 )alkenyl-R 3 —(C 1 -C 6 )alkyl-, where R 3 represents heteroaryl or (C 3 -C 8 )heterocyclyl.

3. The molecule of claim 2 wherein Z— represents —CH 2 —CH 2 —,

4. The molecule of claim 1 , wherein CORM is selected from the group consisting of:
Mn(CO) 5 ,

5. The molecule of claim 1 , wherein Y represents H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, -aryl, -heteroaryl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )heterocyclyl, —(C 3 -C 8 )cycloalkyl or —(C 1 -C 6 )alkyl-aryl.

6. The molecule of claim 1 , wherein Q′ is O.

7. The molecule of claim 1 , wherein it is of formula (Ia1):

with M representing Mn(CO) 4 or Ru(CO) 3 Cl.

8. The molecule of claim 7 , wherein Z—W represents: —CH 2 —CH 2 —NR 7 —,

where R 7 represents (C 1 -C 3 )alkyl, Q′ represents O and Y represents H, —(C 1 -C 6 )alkyl or —(C 2 -C 6 )alkenyl.

9. The molecule of claim 1 , where it is selected from the group consisting of:

10. A method of treating cardiovascular or inflammatory disease comprising administering to a patient in need thereof a therapeutically effective amount of a hybrid fumarate-carbon monoxide releasing molecule of formula (I)

wherein:
A represents:
a single bond, or
—Z-Q-, where:
Q represents O, S or NR 2 , where R 2 represents H, (C 1 -C 6 )alkyl, aryl, heteroaryl, (C 1 -C 6 )alkyl-aryl, (C 1 -C 6 )alkyl-heteroaryl, (C 1 -C 6 )alkyl-(C 3 -C 8 )heterocyclyl, or —(C 3 -C 14 )cycloalkyl, or R 2 and Z are connected to form a (C 3 -C 8 )heterocyclyl,
Z represents —(C 1 -C 6 )alkyl-, —(C 2 -C 6 )alkenyl-, -aryl-, -heteroaryl-, —(C 2 -C 6 )alkynyl-, —(C 3 -C 8 )heterocyclyl-, —(C 3 -C 14 )cycloalkyl, —(C 1 -C 6 )alkyl-R 3 —(C 1 -C 6 )alkyl-, —(C 2 -C 6 )alkenyl-R 3 —(C 1 -C 6 )alkyl-, —(C 1 -C 6 )alkyl-R 3 —(C 2 -C 6 )alkenyl-, —(C 2 -C 6 )alkenyl-R 3 —(C 2 -C 6 )alkenyl-, —(C 1 -C 6 )alkyl-R 3 —(C 2 -C 6 )alkynyl-, —(C 2 -C 6 )alkenyl-R 3 —(C 2 -C 6 )alkynyl-, —(C 2 -C 6 )alkynyl-R 3 —(C 2 -C 6 )alkynyl-, —(C 2 -C 6 )alkynyl-R 3 —(C 1 -C 6 )alkyl-, or —(C 2 -C 6 )alkynyl-R 3 —(C 2 -C 6 )alkenyl-, where R 3 represents aryl, heteroaryl, (C 3 -C 8 )heterocyclyl, or (C 3 -C 14 )cycloalkyl, —(C 1 -C 6 )alkyl-OCO—, or —CH 2 —(CHOR 3 )CH 2 O—(C 1 -C 6 )alkyl-,

CORM represents a carbonyl metal complex selected from the group consisting of:
Mn(CO) 5 ,

where W represents O or NR 4 , where R 4 represents —(C 1 -C 6 )alkyl-,
L represents an ionic ligand, or a counter-ion,
M represents Rh, Co, Ru, Mn, Mo, V or Fe, and
n is an integer chosen so that the metal M has no free valency,

and R 1 represents:
-Q′-Y, where
Q′ represents O, S or NR 5 , where R 5 represents H, (C 1 -C 6 )alkyl, aryl, heteroaryl, (C 1 -C 6 )alkyl-aryl, (C 1 -C 6 )alkyl-heteroaryl, (C 1 -C 6 )alkyl-(C 3 -C 8 )heterocyclyl, or —(C 3 -C 14 )cycloalkyl,
Y represents H, —(C 2 -C 6 )alkenyl, -aryl, -heteroaryl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )heterocyclyl, —(C 3 -C 14 )cycloalkyl, —(C 1 -C 6 )alkyl-R 6 —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl-R 6 —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-R 6 —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkenyl-R 6 —(C 2 -C 6 )alkenyl, —(C 1 -C 6 )alkyl-R 6 —(C 2 -C 6 )alkynyl, —(C 2 -C 6 )alkenyl-R 7 —(C 2 -C 6 )alkynyl, —(C 2 -C 6 )alkynyl-R 6 —(C 2 -C 6 )alkynyl, —(C 2 -C 6 )alkynyl-R 6 —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkynyl-R 6 —(C 2 -C 6 )alkenyl, (C 1 -C 6 )alkyl-R 6 , —(C 2 -C 6 )alkenyl-R 6 , —(C 2 -C 6 )alkynyl-R 6 , or —CH 2 (CHOR 6 )CH 2 —OR 7 , where R 6 represents aryl, heteroaryl, (C 3 -C 8 )heterocyclyl, or (C 3 -C 14 )cycloalkyl, and where R 7 represents H, (C 1 -C 6 )alkyl, aryl, heteroaryl, (C 1 -C 6 )alkyl-aryl, (C 1 -C 6 )alkyl-heteroaryl, (C 1 -C 6 )alkyl-(C 3 -C 8 )heterocyclyl, or (C 1 -C 6 )alkyl-(C 3 -C 14 )cycloalkyl, Or,

A′-CORM′ where A′ and CORM′ are as defined respectively for A and CORM.

11. A ph

Assignees

• Univ Paris Val De Marne
• Centre Nat Rech Scient
• Inst Nat Sante Rech Med

Inventors

• Motterlini Roberto
• Foresti Roberta
• Martens Thierry
• Rivard Michael

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• C07F15/02

  Iron compounds · CPC title

• C07F15/0046

  Ruthenium compounds · CPC title

• C07F15/06 Primary

  Cobalt compounds · CPC title