Benzodiazepine derivatives for use in the treatment of Chlamydiales infections

Patent metadata

Field	Value
Publication number	US-11136299-B2
Application number	US-201615134369-A
Country	US
Kind code	B2
Filing date	Apr 20, 2016
Priority date	Apr 21, 2015
Publication date	Oct 5, 2021
Grant date	Oct 5, 2021

Abstract

The invention relates to a method for treating a Chlamidyales infection comprising the administration of a therapeutically effective amount of a compound of formula (I) to a subject in need thereof:Wherein R1, R2, R3 and Ar are as defined in claim 1.

First claim

The invention claimed is:

1. A pharmaceutical composition comprising a compound of formula (A):

wherein:
p is 1;
is a single bond C—N;
R 1 is selected from F, Cl, Br and I;
R 2 is C 3 -C 8 cycloalkyl or (5- to 10-membered)heteroaryl(C 1 -C 6 )alkyl, wherein said cycloalkyl group is optionally substituted by one to three R 4 ;
Ar is selected from C 6 -C 10 aryl, C 5 -C 10 heteroaryl and (5- to 10-membered)heteroaryl(C 1 -C 6 )alkyl, said aryl or heteroaryl groups being optionally substituted by one to three R 5 ;
R 4 is, at each occurrence, independently selected from Cl, Br, I, F and C 1 -C 6 alkyl; and
R 5 is C 1 -C 6 alkyl,
and the stereoisomeric forms, mixtures of stereoisomeric forms or pharmaceutically acceptable salts thereof,
in admixture with one or more pharmaceutically acceptable excipients.

2. The pharmaceutical composition of claim 1 , wherein Ar is unsubstituted.

3. The pharmaceutical composition of claim 1 , wherein R 1 is Br and/or is located at position 7.

4. The pharmaceutical composition of claim 1 , wherein the compound of formula (A) is selected from the group consisting of:
7-bromo-4-cyclopentyl-5-phenyl-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one (HA229);
7-bromo-4-(3-methylcyclopentyl)-5-phenyl-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one (HA280); and
4-((1H-imidazol-2-yl)methyl)-7-bromo-5-phenyl-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one (VP196).

5. A compound of formula (A) as defined in claim 1 , and the stereoisomeric forms, mixtures of stereoisomeric forms or pharmaceutically acceptable salts thereof.

6. The pharmaceutical composition of claim 1 , wherein R 2 is C 3 -C 8 cycloalkyl.

7. The pharmaceutical composition of claim 6 , wherein Ar is phenyl.

8. The pharmaceutical composition of claim 1 , wherein R 2 is (5- to 10-membered)heteroaryl(C 1 -C 6 )alkyl.

9. The pharmaceutical composition of claim 8 , wherein Ar is phenyl.

10. A compound of formula (A) as defined in claim 6 , and the stereoisomeric forms, mixtures of stereoisomeric forms or pharmaceutically acceptable salts thereof.

11. A compound of formula (A) as defined in claim 7 , and the stereoisomeric forms, mixtures of stereoisomeric forms or pharmaceutically acceptable salts thereof.

12. A compound of formula (A) as defined in claim 8 , and the stereoisomeric forms, mixtures of stereoisomeric forms or pharmaceutically acceptable salts thereof.

13. A compound of formula (A) as defined in claim 9 , and the stereoisomeric forms, mixtures of stereoisomeric forms or pharmaceutically acceptable salts thereof.

14. A method for treating a Chlamidyales infection comprising the administration of a therapeutically effective amount of a compound of formula (I) to a subject in need thereof,

wherein:
R 1 is selected from F, Cl, Br and I;
R 2 is C 3 -C 8 cycloalkyl or (5- to 10-membered)heteroaryl(C 1 -C 6 )alkyl, wherein said cycloalkyl group is optionally substituted by one to three R 4 ;
R 3 is H;
Ar is selected from C 6 -C 10 aryl, C 5 -C 10 heteroaryl and (5- to 10-membered)heteroaryl(C 1 -C 6 )alkyl, said aryl and heteroaryl groups being optionally substituted by one to three R 5 ;
R 4 is, at each occurrence, independently selected from Cl, Br, I, F and C 1 -C 6 alkyl;
R 5 is C 1 -C 6 alkyl;
is a single bond C—N; and
p is 1,
and the stereoisomeric forms, mixtures of stereoisomeric forms or pharmaceutically acceptable salts thereof.

15. The method of claim 14 , wherein the Chlamidyales infection is a Chlamidya or Simkania infection.

16. The method of claim 14 , wherein at least one of R 1 is Br or Cl, and/or is located at position 7.

17. The method of claim 14 , wherein Ar is phenyl or pyridyl.

18. The method of claim 14 , wherein R 3 is H.

19. The method of claim 14 , wherein the compound of formula (I) is selected from the group consisting of:
7-bromo-4-cyclopentyl-5-phenyl-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one (HA229);
7-bromo-4-(3-methylcyclopentyl)-5-phenyl-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one (HA 280); and
4-((1H-imidazol-2-yl)methyl)-7-bromo-5-phenyl-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one (VP 196).

Assignees

• Commissariat Energie Atomique

Inventors

• Gillet Daniel
• Barbier Julien
• Cintrat Jean-Christophe
• Abdelkafi Hajer
• Rudel Thomas
• Herweg Jo-Ana
• Fischer Annette

Classifications

• A61K31/5513

  1,4-Benzodiazepines, e.g. diazepam {or clozapine} · CPC title

• C07D243/24 Primary

  Oxygen atoms · CPC title

• A61P31/04

  Antibacterial agents · CPC title