Imidazole-Based Antimicrobial Agents

• US 20170368032A1
• Filed: 12/03/2015
• Published: 12/28/2017
• Est. Priority Date: 12/04/2014
• Status: Active Grant

• Current Assignee: Procomcure Biotech GmbH
• Original Assignee: Procomcure Biotech GmbH
• Inventors: nder, Kamil, Datema, Roelf, Mitchell, Dale, Kondratov, Ivan
• Granted Patent: US 10,322,110 B2
• Time in Patent Office: Days
• 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. A compound consisting of the structural moiety of formula (I) or a pharmaceutically-acceptable salt of said compound, for use as a medicament

2. A compound as defined in claim 1, wherein when R² is H in the structure of formula (I), A cannot be

3. A compound as defined in claim 1, wherein A is not

4. A compound as defined in claim 1, wherein B is selected from the group consisting of

5. A compound as defined in claim 1, wherein group A is selected from the formulae

6. A compound as defined in claim 1, wherein B is an unsubstituted phenyl ring or a substituted phenyl ring.

7. A compound 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_2to4alkyl, halogen, hydroxyl, —

OCH₃, —

OC_2to4alkyl, —

CF₃, —

OCF₃, —

NH₂, —

CH₂NH₂, —

N(CH₃)₂, —

NO₂, —

CH₂OH, —

CO₂CH₃, —

CO₂C_2to4alkyl, —

CO₂H, —

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

CH₃ or C_2to4alkyl, —

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

CH₃ or C_2to4alkyl, 4-morpholinyl, 1-piperidinyl, 4H-piperazinyl, 4-C_1to4alkyl-piperazinyl, and 4-C_3to6cycloalkyl-piperazinyl.

8. A compound as defined in claim 1, wherein B is a ring other than an unsubstituted or substituted phenyl ring and B is substituted or unsubstituted.

9. A compound as defined in claim 1, wherein B is a ring other than 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.

10. A compound as defined in claim 1, wherein R¹ is substituted or unsubstituted phenyl.

11. A compound as defined in claim 1, wherein R¹ is phenyl substituted with one or more substituents independently selected from the group consisting of —

CH₃, C_2to4alkyl, halogen, hydroxyl, —

OCH₃, —

OC_2to4alkyl, ethynyl, —

OCF₃, and —

CF₃.

12. A compound as defined in claim 1, wherein one of R¹ or R² is H, halogen, or —

CH₃.

13. A compound 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.

14. An antimicrobial composition comprising the compound as defined in claim 1, wherein the antimicrobial composition treats a microbial infection and/or a disorder, affliction or illness caused at least in part by the microbial infection.

15. An antibiotic comprising the compound as defined in claim 1, wherein the antibiotic treats a bacterial infection and/or a disorder, affliction or illness caused at least in part by the bacterial infection, said bacterial infection being selected from one or more infections and infectious diseases from the list of including respiratory tract infections, complicated skin and soft tissue infections, complicated intra-abdominal infections, community acquired pneumonia, hospital-acquired pneumonia, ventilator-associated pneumonia, urinary tract infections, bacterial meningitis, infective endocarditis, sepsis, osteomyelitis, septic arthritis, septicemia, anthrax, osteomyelitis, tuberculosis, leprosy, necrotizing fasciitis, scarlet fever, rheumatic fever, postpartum fever, and streptococcal toxic shock syndrome, and additional nosocomial infections.

16. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier.

17. A compound as defined in claim 1, wherein the compound treats a microbial infection and/or a disorder, affliction or illness caused by or at least in part by the microbial infection, said microbial infection being a bacterial infection caused by or at least in part by daptomycin-resistant methicillin-resistant Staphylococcus aureus.

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

19. A combination as defined in claim 18, wherein the combination is provided by combining the at least one compound as defined in claim 1 and the at least one inhibitor in a single formulation before dosing or by dosing the at least one compound as defined in claim 1 and the at least one inhibitor separately.

20. A compound as defined in claim 17, wherein the compound is selected from

21. A compound as defined in claim 20, wherein the compound is selected from compounds 2, 6, 19, 25, 26, 48, 50 or a combination thereof.

22. A composition comprising (i) at least one compound as defined in claim 20, and (ii) at least one inhibitor of bacterial lipid biosynthesis in staphylococci.