1,4-di-(4-methylthiophenyl)-3-phtaloylazetidine-2-one and the derivatives thereof

Patent metadata

Field	Value
Publication number	US-10457665-B2
Application number	US-201615762878-A
Country	US
Kind code	B2
Filing date	Sep 23, 2016
Priority date	Sep 25, 2015
Publication date	Oct 29, 2019
Grant date	Oct 29, 2019

Abstract

The present invention relates to a compound with formula (I) or a salt and/or a pharmaceutically acceptable solvate thereof, the method for preparing same as well as the uses thereof, in particular the therapeutic use thereof, mainly in the treatment of diseases associated with a hyperactivity of the endocannabinoid system.

First claim

The invention claimed is:

1. A compound of following formula (I):

wherein:
R 1 and R 2 , which can be identical or different, represent a hydrogen atom or a COR 3 , SO 2 R 4 or CONR 5 R 6 group; or form together with the nitrogen atom that bears them a 5- or 6-member heterocycle comprising at least one additional heteroatom, C═O group, aryl group or heteroaryl group;
R 3 , R 4 , R 5 and R 6 independently represent a hydrogen atom, or an aryl or heteroaryl group, said group being optionally substituted by one or more groups selected from a halogen atom, OR 7 , NR 8 R 9 , SR 10 , S(O)R 11 , SO 2 R 12 , SO 2 NR 13 R 14 , OCOR 15 , NR 16 COR 17 , NR 18 C(O)OR 19 , CO 2 R 20 , CONR 21 R 22 , OCO 2 R 23 , OCONR 24 R 25 , COR 26 , nitro (NO 2 ), cyano (CN), oxo (═O) and CF 3 ; and
R 7 to R 26 independently represent a hydrogen atom or a (C 1 -C 6 )alkyl, aryl or aryl-(C 1 - 6 )alkyl group,

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein R 1 and R 2 form together with the nitrogen atom that bears them a heterocycle of following formula (II) or (III):

wherein R 27 represents a hydrogen atom or a COR 3 or SO 2 R 4 group, R 3 and R 4 being as defined in claim 1 , in particular R 27 represents a hydrogen atom.

3. The compound according to claim 1 , wherein:
R 1 and R 2 , which can be identical or different, represent a hydrogen atom or a COR 3 , SO 2 R 4 or CONR 5 R 6 group;
R 3 , R 4 and R 5 independently represent an aryl group, optionally substituted by a group selected from a halogen atom, CF 3 and SO 2 R 12 , with R 12 representing a (C 1 C 6 )alkyl group, preferably a methyl; and
R 6 represents a hydrogen atom.

4. The compound according to claim 1 , wherein R 1 is a hydrogen atom and R 2 represents a COR 3 , SO 2 R 4 or CONR 5 R 6 group, with R 3 , R 4 , R 5 and R 6 being as defined in claim 1 .

5. The compound according to claim 1 , wherein it is selected from the following compounds:

or a pharmaceutically acceptable salt thereof,
wherein X represents a hydrogen atom, a halogen or CF 3 .

6. A process for preparing a compound of formula (I) as defined according to claim 1 , comprising the following steps:
(i) condensation of 4-methylthiobenzaldehyde with 4-methylthioaniline to obtain the composition of following formula (IV):

(ii) Staudinger cycloaddition between the composition of formula (IV) obtained and a ketene of following formula (V):

to obtain the composition of following formula (IA):

(iii) optionally, deprotection of the phthaloylated amine function of the compound of formula (IA), preferably by action of methylhydrazine, to obtain the composition of following formula (IF):

then, optionally, coupling of the compound of formula (IF) thus obtained with a compound of formula R 1 —X and/or R 2 —X′, wherein R 1 —X and R 2 —X′ are activated forms, such as acyl chlorides, sulphonyl chlorides and aryl isocyanates, of groups R 1 and R 2 as defined in claim 1 ; and
(iv) collection of the compound obtained in step (ii) or in step (iii).

7. A method comprising the in vitro use of at least one compound of formula (I) as defined in claim 1 , as inverse agonist of the peripheral endocannabinoid CB1 receptors, said method comprising the step of contacting in vitro said peripheral endocannabinoid CB1 receptor with at least one compound of formula (I).

8. A pharmaceutical composition comprising as active ingredient at least one compound of formula (I) as defined in claim 1 , and at least one pharmaceutically acceptable excipient.

9. A nontherapeutic composition, comprising at least one compound of formula (I) as defined in claim 1 , and at least one acceptable excipient.

10. A method for treating diseases associated with hyperactivity of the endocannabinoid system comprising the administration of an effective amount of a compound as defined by the following formula (I):

wherein:
R 1 and R 2 , which can be identical or different, represent a hydrogen atom or a COR 3 , SO 2 R 4 or CONR 5 R 6 group; or form together with the nitrogen atom that bears them a 5- or 6-member heterocycle comprising at least one additional heteroatom, C═O group, aryl group or heteroaryl group;
R 3 , R 4 , R 5 and R 6 independently represent a hydrogen atom, or an aryl or heteroaryl group, said group being optionally substituted by one or more groups selected from a halogen atom, OR 7 , NR 8 R 9 , SR 10 , S(O)R 11 , SO 2 R 12 , SO 2 NR 13 R 14 , OCOR 15 , NR 16 COR 17 , NR 18 C(O)OR 19 , CO 2 R 20 , CONR 21 R 22 , OCO 2 R 23 , OCONR 24 R 25 , COR 26 , nitro (NO 2 ), cyano (CN), oxo (═O) and CF 3 ; and
R7 to R26 independently represent a hydrogen atom or a (C1-C6)alkyl, aryl or aryl-(C1-C 6 )alkyl group,

or a pharmaceutically acceptable salt and/or solvate thereof,
or the pharmaceutical composition as defined in claim 8 , in a subject in need thereof.

11. The method according to claim 10 , wherein said diseases are selected from obesity and obesity—related metabolic disorders, insulin resistance, diabetes and associated complications, hepatic steatosis, liver fibrosis, cirrhosis, renal fibrosis, nephropathy, cardiomyopathies, gastroparesis, bone and/or cartilage loss, muscle loss, and fertility problems.

12. The method according to claim 10 , wherein subject is put on a balanced normocaloric diet.

13. The method according to claim 10 , wherein compound or said composition is administered to said subject before and/or during the subject's meal(s).

14. A method for treating a disease associated with hyperactivity of the endocannabinoid system comprising the administration of an effective amount of the compound of formula (I) as defined in claim 1 , and therapeutic agent, as combined preparation for simultaneous, separate, or sequential administration, in a subject in need thereof.

15. A nontherapeutic method for promoting and/or accelerating weight gain or for slowing and/or reducing weight gain in a subject, comprising administering an effective amount of a compound of formula (I) as defined by the following formula (I):

wherein:
R1 and R2, which can be identical or different, represent a hydrogen atom or a COR3, SO2R4 or CONR5R6 group; or form together with the nitrogen atom that bears them a 5- or 6-member heterocycle comprising at least one additional heteroatom, C═O group, aryl group or heteroaryl group;
R3, R4, R5 and R6 independently represent a hydrogen atom, or an aryl or heteroaryl group, said group being optionally substituted by one or

Assignees

• Univ Nantes
• Univ Bourgogne
• Inst Nat Sante Rech Med

Inventors

• Robert Jean-Michel
• Troy-Fioramonti Stéphanie
• Demizieux Laurent
• Degrace Pascal

Classifications

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• C07D205/085

  with a nitrogen atom directly attached in position 3 · CPC title

• C07D403/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title