Imidazole-based antimicrobial agents

• US 10,456,379 B2
• Filed: 12/03/2015
• Issued: 10/29/2019
• Est. Priority Date: 12/04/2014
• Status: Active Grant

• Current Assignee: Procomcure Biotech GmbH
• Original Assignee: Procomcure Biotech GmbH
• Inventors: Onder, Kamil, Datema, Roelf
• Primary Examiner(s): Coughlin, Matthew P
• Assistant Examiner(s): Patel, Sagar
• Application Number:
  US15/532,696
• Publication Number:
  US 20170334887A1
• Time in Patent Office: 1,426 Days
• Field of Search: 514397, 514396, 5483435, 5483461
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/352 condensed with carbocyclic rings, e.g. methantheline cannabinoids A61K31/658
• CPC Class Codes: A61K 31/4164 1,3-Diazoles
• CPC Class Codes: A61K 31/4178 not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• CPC Class Codes: A61K 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 31/4188 condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
• CPC Class Codes: A61K 31/4192 1,2,3-Triazoles
• CPC Class Codes: A61K 31/4196 1,2,4-Triazoles
• CPC Class Codes: A61K 31/422 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/427 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/06 for tuberculosis
• CPC Class Codes: A61P 31/08 for leprosy
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond

Abstract

The present invention relates to novel therapeutic agents suitable for use in the treatment of mammalian disease and in particular to novel therapeutic agents suitable for use in the treatment of microbial infection in mammals. The present invention further relates to the use of pharmaceutical compositions comprising said agents in the treatment of medical conditions in mammals, in particular in the treatment of microbial infection. The agents and pharmaceutical compositions of the invention are of particular relevance in the treatment of diseases associated with antibiotic-resistant microbes.

Claims

1. An antimicrobial composition comprising a compound consisting of the structural moiety of formula (I) or a pharmaceutically-acceptable salt of said compound, and a pharmaceutically acceptable carrier;

2. The antimicrobial composition as defined in claim 1, wherein B is selected from the group consisting of

3. The antimicrobial composition as defined in claim 1, wherein group A is selected from the formulae

4. The antimicrobial composition as defined in claim 1, wherein the aromatic ring of A is substituted by one or more substituents independently selected from —

CH₃, C_2to4alkyl, halogen, —

OCH₃, and —

OC_2to4 alkyl.

5. The antimicrobial composition as defined in claim 1, wherein B is an unsubstituted phenyl ring or a substituted phenyl ring.

6. The antimicrobial composition as defined in claim 1, wherein B is a phenyl ring optionally substituted with one or more substituents independently selected from the group consisting of —

CH₃, C_2-4alkyl, halogen, hydroxyl, —

OCH₃, —

OC_2-4alkyl, —

CF₃, OCF₃, —

NH₂, —

CH₂NH₂, —

N(CH₃)₂, —

NO₂, —

CH₂OH, —

CO₂CH₃, —

CO₂C_2-4alkyl, —

CO₂H, N(alkyl)₂ where the two alkyl groups are independently selected from —

CH₃ or C_2-4alkyl, —

NH(alkyl) where the alkyl group is selected from —

CH₃ or C_2-4 alkyl, 4-morpholinyl, 1-piperidinyl, 4H-piperazinyl, 4-C_1-4alkyl-piperazinyl, and 4-C_3-6cycloalkyl-piperazinyl.

7. The antimicrobial composition as defined in claim 1, wherein B is a ring other than an unsubstituted or substituted phenyl ring and B is substituted or unsubstituted.

8. The antimicrobial composition as defined in claim 1, wherein B is a ring other that an unsubstituted or substituted phenyl ring and is optionally substituted with one or more substituents independently selected from the group consisting of —

CH₃, C_2to4alkyl, halogen, hydroxyl, —

OCH₃, —

OC_2to4alkyl, —

CF₃;

—

OCF₃, —

CO₂CH₃, —

CO₂C_2to4alkyl, and —

CO₂H.

9. The antimicrobial composition as defined in claim 1, wherein one of R¹ or R² is substituted or unsubstituted phenyl.

10. The antimicrobial composition as defined in claim 1, wherein one of R¹ or R² is phenyl substituted with one or more substituents independently selected from the group consisting of —

CH₃, C_2-4alkyl, halogen, hydroxyl, —

OCH₃, —

OC_2-4alkyl, ethynyl, —

OCF₃, and —

CF₃.

11. The antimicrobial composition as defined in claim 1, wherein one of R¹ or R² is H, halogen, or —

CH₃.

12. The antimicrobial composition as defined in claim 1, wherein R¹ is aryl, heteroaryl, or benzyl or benzyl substituted on the phenyl ring, and R² is selected from, H, —

CH₃, —

CH₂N(CH₃)₂, and halogen.

13. The antimicrobial composition as defined in claim 1, wherein the antimicrobial composition is an antibiotic.

14. A combination of the antimicrobial composition as defined in claim 1 and at least one inhibitor of bacterial lipid biosynthesis, where the combination treats the microbial infection and/or the disorder, affliction or illness caused by or at least in part by the microbial infection, where said microbial infection is a bacterial infection.

15. The combination as defined in claim 14, wherein the combination is provided by combining the antimicrobial composition as defined in claim 1 and the at least one inhibitor in a single formulation before dosing or by dosing the antimicrobial composition as defined in claim 1 and the at least one inhibitor separately.

16. The antimicrobial composition as defined in claim 1, wherein the compound is selected from

17. The antimicrobial composition as defined in claim 16, wherein the compound is selected from compounds 2, 19, 25, 26, 48, 50 or a combination thereof.

18. A composition comprising (i) at least one compound as defined in claim 16, and (ii) at least one inhibitor of bacterial lipid biosynthesis.

19. A method of treating a microbial infection in a mammal in need thereof, the method comprising administering the antimicrobial composition of claim 1 to the mammal.

20. The method of claim 19, further comprising administering at least one inhibitor of bacterial lipid biosynthesis to the mammal.