N-substituted 3,4-bis (catechol) pyrrole compounds, and the preparation and use thereof in the treatment of cancer

Patent metadata

Field	Value
Publication number	US-9546159-B2
Application number	US-201314435768-A
Country	US
Kind code	B2
Filing date	Oct 14, 2013
Priority date	Oct 16, 2012
Publication date	Jan 17, 2017
Grant date	Jan 17, 2017

Abstract

The present invention relates to a compound of formula (I) in which: -m is an integer from 0 to 3, preferably from 0 to 2; n is an integer from 0 to 3, preferably from 0 to 2; m+n≧1; EAG is an electro-attractive group chosen independently from among a halogen atom, an NO 2 , CF 3 , CCI 3 , CN, CO 2 H, (C═O)NR 2 , CH═NR, (C═S)OR, (C═O)SR, CS 2 R, SO 2 R, SO 2 NR 2 , SO 3 R, P(O)(OR) 2 , P(O)(R) 2 , B(OR) 2 group where R is a (C 1 -C 6 ) alkyl radical, a phenyl group or a hydrogen atom; A is a saturated or unsaturated, linear or branched hydrocarbon chain including 1 to 10 atoms of carbon; and R 1 and R 2 each represent independently from one another a hydrogen atom, a CO-(Ci-C6)-alkyl, (C 1 -C 6 ) alkyl, phenyl or phenyl-(C 1 -C 6 )-alkyl group, in which R 1 and R 2 form, together with the nitrogen atom they carry, a 5- to 15-member heterocycle, optionally substituted by a (C 1 -C 6 ) alkyl group; including its stereoisomers and the mixtures thereof, or a pharmaceutically acceptable salt of same.

First claim

The invention claimed is:

1. A compound having the following formula (I):

wherein:
m is an integer from 0 to 3;
n is an integer from 0 to 3;
m+n≧1
EAG is an electro-attractive group chosen independently from among a halogen atom, an NO 2 , CF 3 , CCI 3 , CN, CO 2 H, (C═O)NR 2 , CH═NR, (C═S)OR, (C═O)SR, CS 2 R, SO 2 R, SO 2 NR 2 , SO 3 R, P(O)(OR) 2 , P(O)(R) 2 , B(OR) 2 group, where R is an alkyl (C 1 -C 6 ) radical, a phenyl group or a hydrogen atom;
A is a saturated or unsaturated, linear or branched hydrocarbon chain including 1 to 10 atoms of carbon; and
R 1 and R 2 each represent, independently from one another, a hydrogen atom, a CO—(C 1 -C 6 )-alkyl, (C 1 -C 6 ) alkyl, phenyl or phenyl-(C 1 -C 6 )-alkyl group, or R 1 and R 2 form, together with the nitrogen atom bearing same, a 5- to 15-member heterocycle, optionally substituted by a (C 1 -C 6 ) alkyl group;
including the stereoisomers and the mixtures thereof, or a pharmaceutically acceptable acid salt thereof.

2. The compound according to claim 1 , having the following formula (Ia):

wherein the radicals R 1 and R 2 have the meanings given in claim 1 , including the stereoisomers and the mixtures thereof, or a pharmaceutically acceptable acid salt thereof.

3. The compound according to claim 1 , wherein the radicals R 1 and R 2 form, together with the nitrogen atom bearing same, a heterocycle which is saturated and does not comprise any other heteroatom than the nitrogen atom bearing R 1 and R 2 .

4. The compound according to claim 1 , wherein the radicals R 1 and R 2 form, together with the nitrogen atom bearing same, a 10- to 15-member heterocycle.

5. The compound according to claim 1 , wherein A is a saturated linear hydrocarbon chain comprising 3 to 6 carbon atoms.

6. The compound according to claim 1 , corresponding to the compound having the following formula (1):

or a pharmaceutically acceptable acid salt thereof.

7. The compound according to claim 1 , wherein the pharmaceutically acceptable acid salt is a hydrochloride.

8. A pharmaceutical composition comprising at least one compound according to claim 1 , and at least one pharmaceutically acceptable excipient.

9. A process for preparing a compound having formula (I) according to claim 1 , comprising:
a) reaction between an amine having the following formula (II), a halide having the following formula (III), and an aldehyde having the following formula (IV),

wherein n and m, EAG, R 1 , R 2 and A are as defined in claim 1 and X represents a halogen atom, to arrive at a compound having formula (I) according to claim 1 , and
b) optionally, formation of a pharmaceutically acceptable salt from the compound having formula (I) obtained in the previous step (a).

10. The process for preparing a compound having formula (I) according to claim 9 , wherein the halide (III) and the amine (II) are first allowed to react with one another before adding the aldehyde (IV).

11. The process for preparing a compound having formula (I) according to claim 9 , wherein X is a chlorine, bromine, or iodine atom.

12. A method for treating cancer, said method comprising administering to a patient suffering from cancer an effective amount of a compound according to claim 1 , wherein said cancer is lung, breast, colon, rectal, kidney, skin, or bone cancer, or haematopoietic cancers, or tumours of neuroectodermal origin.

13. The method according to claim 12 , wherein said haematopoietic cancer is leukaemia, myeloid leukaemia, lymphoma or bone marrow cancer.

14. The method according to claim 12 , wherein said tumour of neuroectodermal origin is glioblastoma.

15. The method according to claim 12 , wherein said compound is a compound having the following formula (Ia):

wherein:
A is a saturated or unsaturated, linear or branched hydrocarbon chain including 1 to 10 atoms of carbon; and
R 1 and R 2 each represent, independently from one another, a hydrogen atom, a CO—(C 1 -C 6 )-alkyl, (C 1 -C 6 ) alkyl, phenyl or phenyl-(C 1 -C 6 )-alkyl group, or R 1 and R 2 form, together with the nitrogen atom bearing same, a 5- to 15-member heterocycle, optionally substituted by a (C 1 -C 6 ) alkyl group;
including the stereoisomers and the mixtures thereof, or a pharmaceutically acceptable acid salt thereof.

16. The method according to claim 12 , wherein said compound is a compound having the following formula (1):

or a pharmaceutically acceptable acid salt thereof.

17. The compound according to claim 1 , wherein:
m is an integer from 0 to 2;
n is an integer from 0 to 2; and
m+n≧1.

18. The compound according to claim 4 , wherein the radicals R 1 and R 2 form, together with the nitrogen atom bearing same, a 13-member heterocycle.

19. The compound according to claim 5 , wherein A is a saturated linear hydrocarbon chain comprising 3 carbon atoms.

Assignees

• Centre Nat De La Rech Scient (Cnrs)

Inventors

• Collin Pascal
• Egorov Maxim
• Delpech Bernard
• Bakala Joanna
• Achab Maria
• Bignon Jérome
• Thoison Odile
• Benechie Michel

Classifications

• C07D207/333

  Radicals substituted by oxygen or sulfur atoms · CPC title

• C07D403/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title