Hemi-synthetic trilobine analogs for use as a drug

Patent metadata

Field	Value
Publication number	US-10544156-B2
Application number	US-201615765048-A
Country	US
Kind code	B2
Filing date	Oct 3, 2016
Priority date	Oct 2, 2015
Publication date	Jan 28, 2020
Grant date	Jan 28, 2020

Abstract

The invention concerns a compound of the following formula (I) or a pharmaceutically acceptable salt or solvate thereof as well as a pharmaceutical composition containing such a compound, and the use of such a compound as a drug, notably as a DNMT inhibitor, in particular in the treatment of cancer.

First claim

The invention claimed is:

1. A compound of the following formula (I) or a pharmaceutically acceptable salt or solvate thereof:

wherein:
W is H,
X 1 and X 2 are, independently of each other, H, (C 1 -C 10 )-alkyl, (C 1 -C 10 )-alkyl-R 2 , (C 2 -C 10 )-alkenyl, (C 2 -C 10 )-alkenyl-R 2 , CONR 3 R 4 , CSNR 3 R 4 , COR 3 , COOR 6 , CN, SOOR 7 , C(NH)NHR 3 , (C 1 -C 10 )-alkyl-(C 5 -C 10 )-aryl or (C 1 -C 10 )-alkyl-(5-12)-membered-heterocycle, wherein:
at least one of X 1 and X 2 is CONR 3 R 4 or CSNR 3 R 4 ,
R 2 is OH, O—(C 1 -C 10 )-alkyl, O—(C 5 -C 10 )-aryl, NO 2 , CN, NR 4 R 5 , (5-12)-membered-heterocycle, (C 5 -C 10 )-aryl, O—((CH 2 ) 2 O) n —OH with n=1-3, CONR 3 R 4 , halogen, COOR 4 , CF 3 , or (C 3 -C 12 )-cycloalkyl, in which (C 5 -C 10 )-aryl and (5-12)-membered-heterocycle are optionally substituted by at least one group selected from NR 4 R 5 , OR 5 , (C 1 -C 10 )-alkyl, halogen and oxo (═O),
R 3 is H, or a group chosen among (C 1 -C 10 )-alkyl, (C 3 -C 12 )-cycloalkyl, (C 2 -C 10 )-alkenyl, (C 5 -C 10 )-aryl and a (5-12)-membered-heteroaryl, said group being optionally substituted by at least one group selected from halogen, CN, NR 4 R 5 , mono(C 1 -C 6 )alkyl-amino, di-(C 1 -C 6 )-alkyl-amino, NO 2 , CONR 4 R 5 , COOR 4 , CF 3 , OR 4 and (C 1 -C 10 )-alkyl-R 8 ,
R 4 is H or (C 1 -C 10 )-alkyl,
R 5 is H, (C 1 -C 10 )-alkyl, (C 5 -C 10 )-aryl or (5-12)-membered-heterocycle,
R 6 is H, (C 1 -C 10 )-alkyl, (C 5 -C 10 )-aryl or (C 1 -C 10 )-alkyl-R 2 ,
R 7 is (C 1 -C 10 )-alkyl, (C 2 -C 10 )-alkenyl, (C 5 -C 10 )-aryl or a (5-12)-membered-heterocycle, in which the fragments (C 5 -C 10 )-aryl and (5-12)-membered-heterocycle are optionally substituted by at least one group selected from halogen, CN, NR 4 R 5 , mono(C 1 -C 6 )alkyl-amino, di-(C 1 -C 6 )-alkyl-amino, NO 2 , CONR 3 R 4 , COOR 4 , CF 3 and OR 4 ,
R 8 is H, (C 1 -C 10 )-alkyl, (C 5 -C 10 )-aryl or (5-12)-membered-heterocycle, in which (C 5 -C 10 )-aryl and (5-12)-membered-heterocycle are optionally substituted by at least one group selected from NR 4 R 5 , OR 5 , (C 1 -C 10 )-alkyl, halogen and oxo,
R 1 is hydrogen, (C 1 -C 6 )-alkyl, COR 6 or SOOR 9 with R 9 being a (C 1 -C 6 )-alkyl group optionally substituted by at least one halogen,

with the proviso that at least one of X 1 and X 2 is not H or (C 1 -C 10 )-alkyl.

2. The compound according to claim 1 , having the following formula (Ia) or a pharmaceutically acceptable salt or solvate thereof:

3. The compound according to claim 1 , wherein X 2 is not H or (C 1 -C 10 )-alkyl.

4. The compound according to claim 1 , wherein X 2 is CONR 3 R 4 .

5. The compound according to claim 4 , wherein R 2 is CN, NR 4 R 5 or a (5-12)-membered-heterocycle optionally substituted by at least one group selected from NR 4 R 5 , OR 5 , (C 1 -C 10 )-alkyl, halogen and oxo (═O).

6. The compound according to claim 1 , wherein R 3 is H, or a group chosen among (C 1 -C 10 )-alkyl, (C 3 -C 12 )-cycloalkyl, (C 2 -C 10 )-alkenyl and (C 6 -C 10 )-aryl, said group being optionally substituted by at least one group selected from halogen, NR 4 R 5 , mono-(C 1 -C 6 )-alkyl-amino, di-(C 1 -C 6 )-alkyl-amino, OR 4 and (C 1 -C 10 )-alkyl-R 8 .

7. The compound according to claim 1 , wherein:
R 4 is H or (C 1 -C 6 )-alkyl,
R 5 is H or (C 1 -C 6 )-alkyl,
R 6 is (C 1 -C 6 )-alkyl-R 2 ,
R 7 is (C 1 -C 6 )-alkyl,
R 8 is a (5-12)-membered-heterocycle, optionally substituted by at least one group selected from NR 4 R 5 , OR 5 , (C 1 -C 10 )-alkyl, halogen and oxo.

8. The compound according to claim 1 , wherein the (5-12)-membered-heterocycle is:
in the definition of R 2 , a monocyclic or bicyclic heteroaryl containing 1 to 5 nitrogen atoms, each cycle comprising 5 or 6 members;
in the definition of R 8 , a saturated, unsaturated or aromatic hydrocarbon monocycle or bicycle, each cycle having 5 or 6 members and 1 to 4 carbon atoms which have been replaced with heteroatoms selected from nitrogen, oxygen and sulfur atoms.

9. The compound according to claim 8 , wherein the (5-12)-membered-heterocycle is:
in the definition of R 2 , a pyrrole, an imidazole, a pyrazole, a pyridine, a pyrimidine, a pyridazine, a pyrazine, an indole, a benzimidazole, a purine, a quinoline, an isoquinoline, a cinnoline, a quinazoline or a quinoxaline;
in the definition of R 8 , a pyrroline.

10. The compound according to claim 1 , selected from the group consisting of compounds of the following formulas:

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

12. The pharmaceutical composition according to claim 11 , further comprising at least one other active ingredient.

13. The pharmaceutical composition according to claim 12 , wherein the at least one other active ingredient is an other anticancer agent.

14. The pharmaceutical composition according to claim 13 , wherein said other anticancer agent is selected from the group consisting of cytotoxic agents, immunotherapies and other epigenetics drugs.

15. The pharmaceutical composition according to claim 14 , wherein:
cytotoxic agents are selected from doxorubicin, R-CHOP, PARP inhibitors, etoposide, cisplatin, vinerolbine, vinflunine, and bortezomib;
immunotherapies are selected from antiCTL4 and antiPD1; and
other epigenetics drugs are selected from HDACi, inhibitors of chromatin remodeler and inhibitors of histone modifiers.

16. The pharmaceutical composition according to claim 15 , wherein:
the HDACi is selected from HDAC 1 & 2;
the inhibitor of chromatin remodeler is CDH4; and
the inhibitor of histone modifiers is selected from demethylases JARDI1A/B and methylases EZH2.

17. A pharmaceutical product comprising:
i. at least one compound according to claim 1 , and
ii. at least one other active ingredient,
as a combination product for simultaneous, separate or sequential use in the treatment of cancer.

Assignees

• Pf Medicament
• Centre Nat Rech Scient

Inventors

• Halby Ludovic
• Menon Yoann
• Kaloun El Bachir
• Long Christophe
• Arimondo Paola B

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D491/22 Primary

  in which the condensed system contains four or more hetero rings · CPC title

• C07D491/12

  in which the condensed system contains three hetero rings · CPC title

• 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