Antimicrobial compounds

Patent metadata

Field	Value
Publication number	US-9981986-B2
Application number	US-201615354453-A
Country	US
Kind code	B2
Filing date	Nov 17, 2016
Priority date	Jun 25, 2012
Publication date	May 29, 2018
Grant date	May 29, 2018

Abstract

The present invention relates to certain tetramic acid derivatives and, in particular, bicyclic tetramic acid derivatives that are suitable for use in the preparation and development of antimicrobial (e.g. antibacterial or antifungal) compositions. The present invention also relates to the use of such compounds as antimicrobial (e.g. antibacterial or antifungal agents) and, in particular, as topical antibacterial or antifungal agents.

First claim

The invention claimed is:

1. A method of treating a microbial infection in a subject in need thereof, the method comprises administering an antimicrobial composition to the subject, wherein the antimicrobial composition comprises a compound of the formula II below:

wherein:
X is O, S or SO 2 ,
R 1 and R 2 are each independently selected from H and C 1 to C 6 alkyl,
R 3 is selected from a functional group selected from H, C 1 to C 6 alkyl, and a carbonyl-containing group,
R 12 is H, alkenyl, aryl, trihaloalkyl and C 1 to C 6 alkyl,
R 7 is a group of the formula L 1 -L 2 -R 6 or L 2 -L 1 -R 6 ,
where L 1 is a linker of the formula —[CR 8 R 9 ] n —, where n is an integer of from 0 to 12, and R 8 and R 9 are each independently selected from H or C 1 to C 2 alkyl, and
where L 2 is absent or a linker that is selected from O, S, SO, SO 2 , N(R′), C(O), C(O)O, OC(O), [O(CR′ 2 ) r ] s , [(CR′ 2 ) r O] s CH(OR′), C(O)N(R′), N(R′)C(O), N(R)C(O)N(R′), SO 2 N(R′) or N(R′)SO 2 where R′ and R″ are each independently selected from hydrogen and a C 1 to C 2 alkyl, and where r is 1 or 2 and s is 1 to 4, and
where R 6 is selected from OR 13 , heterocyclic and C 1 to C 25 hydrocarbyl group, wherein R 13 is a C 1 to C 6 alkyl, and said heterocyclic and hydrocarbyl group is optionally substituted with at least one functional group selected from alkenyl, alkyl, aryl, halo, trihaloalkyl, alcohol, keto, S(O)R 13 , sulfonyl, thio-alcohol, ester, thioester, ether, thioether, amide, thioamide, urea, thiourea, ═O, ═S, amine and heterocyclic group;
or tautomer, salt, or solvate thereof.

2. The method as claimed in claim 1 , wherein n is 0 or 1 and L 2 is absent.

3. The method as claimed in claim 1 , wherein R 6 is a straight chain, branched or cyclic C 6 to C 19 alkyl.

4. The method as claimed in claim 1 , where R 6 is an alkyl that is a bridged ring system.

5. The method as claimed in claim 1 , wherein R 6 is an alkyl group selected from adamantyl, myrtanyl, cyclohexyl and a C 6 to C 19 non-cyclic aliphatic alkyl group.

6. The method as claimed in claim 1 , wherein R 6 is a phenyl group that is optionally substituted with at least one functional group selected from alkyl, aryl, halo, trihaloalkyl, alcohol, thio-alcohol, ester, thioester, ether, thioether, amide, thioamide, urea, thiourea and heterocyclic group.

7. The method as claimed in claim 6 , wherein the phenyl group is substituted with a group selected from cyclohexyl, C 1 to C 3 alkyl, halo, trihalo(C 1 to C 3 ) alkyl, OH, SH, heterocyclic and OR 10 or SR 10 , where R 10 is a C 1 to C 4 alkyl or phenyl group.

8. The method as claimed in claim 6 , wherein the phenyl group is substituted with a heterocyclic group selected from a piperidine and morpholine group, or where the phenyl group is fused to an aromatic heterocyclic ring.

9. The method as claimed in claim 8 , wherein said aromatic heterocyclic ring is a pyrrole ring.

10. The method as claimed in claim 1 , wherein R 3 is selected from H, methyl, C(O)R 11 , and C(O)O[CR 8 R 9 ] n OR 11 , where R 11 is a C 1 to C 4 alkyl group.

11. The method as claimed in claim 1 , wherein R 2 is H.

12. The method as claimed in claim 1 , wherein R 1 is selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl and t-butyl.

13. The method as claimed in claim 12 , wherein R 1 is t-butyl.

14. The method as claimed in claim 1 , wherein the compound has the formula:

15. The method as claimed in claim 1 , wherein the composition is a medicament, cosmetic, or suncream.

16. The method as claimed in claim 1 , wherein the microbial infection is a topical microbial infection.

17. The method as claimed in claim 1 , wherein the composition is a topical composition.

18. The method as claimed in claim 1 , wherein the subject is a human or animal.

19. A method of inhibiting bacterial RNA polymerase and/or undecaprenyl pyrophosphate synthase, said method comprises contacting a cell with an effective amount of a compound of the formula II below:

wherein:
X is O, S or SO 2 ,
R 1 and R 2 are each independently selected from H and C 1 to C 6 alkyl,
R 3 is selected from a functional group selected from H, C 1 to C 6 alkyl, and a carbonyl-containing group,
R 12 is H, alkenyl, aryl, trihaloalkyl and C 1 to C 6 alkyl,
R 7 is a group of the formula L 1 -L 2 -R 6 or L 2 -L 1 -R 6 ,
where L 1 is a linker of the formula —[CR 8 R 9 ] n —, where n is an integer of from 0 to 12, and R 8 and R 9 are each independently selected from H or C 1 to C 2 alkyl, and
where L 2 is absent or a linker that is selected from O, S, SO, SO 2 , N(R′), C(O), C(O)O, OC(O), [O(CR′ 2 ) r ] s , [(CR′ 2 ) r O] s CH(OR′), C(O)N(R′), N(R′)C(O), N(R′)C(O)N(R′), SO 2 N(R′) or N(R′)SO 2 where R′ and R″ are each independently selected from hydrogen and a C 1 to C 2 alkyl, and where r is 1 or 2 and s is 1 to 4, and
where R 6 is selected from OR 13 , heterocyclic and C 1 to C 25 hydrocarbyl group, wherein R 13 is a C 1 to C 6 alkyl, and said heterocyclic and hydrocarbyl group is optionally substituted with at least one functional group selected from alkenyl, alkyl, aryl, halo, trihaloalkyl, alcohol, keto, S(O)R 13 , sulfonyl, thio-alcohol, ester, thioester, ether, thioether, amide, thioamide, urea, thiourea, ═O, ═S, amine and heterocyclic group;
or tautomer, salt, or solvate thereof.

Assignees

• Univ Oxford Innovation Ltd

Inventors

• Moloney Mark
• Jeong Yong-Chu

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D277/06

  with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms · CPC title

• A01N43/78

  1,3-Thiazoles; Hydrogenated 1,3-thiazoles · CPC title