Antimicrobial compounds

Patent metadata

Field	Value
Publication number	US-9765069-B2
Application number	US-201314410538-A
Country	US
Kind code	B2
Filing date	Jun 24, 2013
Priority date	Jun 25, 2012
Publication date	Sep 19, 2017
Grant date	Sep 19, 2017

Abstract

The present invention relates to certain 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. An antibacterial composition comprising a compound or a pharmaceutically acceptable salt thereof, said composition optionally being a topical antibacterial composition; wherein the compound is of the Formula I or II below:

wherein
x is 0 or 1,
Y is OH or C 1 to C 15 alkyl,
R 4 is H or C 1 to C 6 alkyl,
either
R 1 is a C 1 to C 15 hydrocarbyl optionally substituted with a heterocyclic group or an ether group, and
R 2 is H, ether, thioether or C 1 to C 8 alkyl, or
R 1 and R 2 together form part of a 5-membered or 6-membered ring fused to the pyrrolidine/piperidine ring,
R 3 and R 5 are each independently selected from 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 in each instance 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, [O(CH 2 ) r ] s , [(CH 2 ) r O] s , OC(O), 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,
where R 6 is selected from OR 11 , a heterocyclic and C 1 to C 25 hydrocarbyl group, wherein R 11 is a C 1 to C 6 alkyl, and wherein said heterocyclic and hydrocarbyl group is optionally substituted with at least one functional group selected from alkyl, alkenyl, aryl, halo, trihaloalkyl, alcohol, thio-alcohol, keto, S(O)R 11 , ester, thioester, ═O, ═S, alkanoyl, ether, thioether, amide, thioamide, urea, thiourea, amine and heterocyclic group,

with the proviso that the compound is not a compound of the formula III or IV below:

wherein p is 2 or 4.

2. The composition as claimed in claim 1 , wherein R 1 is selected from a C 1 to C 10 straight chain or branched alkyl or alkenyl group, or a phenyl group that is optionally substituted with a C 1 to C 6 alkyl.

3. The composition as claimed in claim 1 , wherein R 2 is selected from hydrogen, a C 1 to C 6 alkyl or a thioether group of the formula (CH 2 ) q SR′, where q is 1 to 4 and R′ is a C 1 to C 4 alkyl group.

4. The composition as claimed in claim 1 , wherein L 1 is absent or selected from (CH 2 ) n where n is 1 to 5, or CH 2 C(CH 3 ) 2 CH 2 .

5. The composition as claimed in claim 1 , wherein L 2 is selected from C(O)O, O(O)C, C(O)NH, HNC(O), NH, O and O(C 2 H 4 ) 2 .

6. The composition as claimed in claim 1 , with the proviso that, when the compound is of Formula I and x=0, the following condition is not met: a) R 3 is methyl.

7. A method of using a compound or a pharmaceutically acceptable salt thereof as an antibacterial agent, wherein the compound is of the Formula I or II below:

wherein
x is 0 or 1,
Y is OH or C 1 to C 15 alkyl,
R 4 is H or C 1 to C 6 alkyl,
either
R 1 is a C 1 to C 15 hydrocarbyl optionally substituted with a heterocyclic group or an ether group, and
R 2 is H, ether, thioether or C 1 to C 8 alkyl, or
R 1 and R 2 together form part of a 5-membered or 6-membered ring fused to the pyrrolidine/piperidine ring,
R 3 and R 5 are each independently selected from 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 in each instance 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, [O(CH 2 ) r ] s , [(CH 2 ) r O] s , OC(O), 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,
where R 6 is selected from OR 11 , a heterocyclic and C 1 to C 25 hydrocarbyl group, wherein R 11 is a C 1 to C 6 alkyl, and wherein said heterocyclic and hydrocarbyl group is optionally substituted with at least one functional group selected from alkyl, alkenyl, aryl, halo, trihaloalkyl, alcohol, thio-alcohol, keto, S(O)R 11 , ester, thioester, ═O, ═S, alkanoyl, ether, thioether, amide, thioamide, urea, thiourea, amine and heterocyclic group,

with the proviso that the compound is not a compound of the formula III or IV below:

wherein p is 2 or 4.

8. The method as claimed in claim 7 , wherein the compound is used as a preservative.

9. The method as claimed in claim 7 , wherein the compound is used in a non-edible composition.

10. The method as claimed in claim 9 , wherein the compound is used in paper, fabric, building materials, packaging materials, coating and paint compositions, disinfectants, detergents, household products, cosmetics and suncreams.

11. A method of synthesising a compound of the Formula II,

wherein
x is 0 or 1,
Y is OH or C 1 to C 15 alkyl,
R 4 is H or C 1 to C 6 alkyl,
either
R 1 is a C 1 to C 15 hydrocarbyl optionally substituted with a heterocyclic group or an ether group, and
R 2 is H, ether, thioether or C 1 to C 8 alkyl, or
R 1 and R 2 together form part of a 5-membered or 6-membered ring fused to the pyrrolidine/piperidine ring,
R 5 is selected from 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 in each instance 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, [O(CH 2 ) r ] s , [(CH 2 ) r O] s , OC(O), 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,
where R 6 is selected from OR 11 , a heterocyclic and C 1 to C 25 hydrocarbyl group, wherein R 11 is a C 1 to C 6 alkyl, and wherein said heterocyclic and hydrocarbyl group is optionally substituted with at least one functional group selected from alkyl, alkenyl, aryl, halo, trihaloalkyl, alcohol, thio-alcohol, keto, S(O)R 11 , ester, thioester, ═O, ═S, alkanoyl, ether, thioether, amide, thioamide, urea, thiourea, amine and heterocyclic group, the method comprises

reacting a compound of the formula V below

with a compound of the formula R 5 NCO, or
reacting a compound of the formula VI below

with an amine of the formula R 4 R 5 NH, with the proviso that, where compound of the Formula V is reacted with R 5 NCO, R 4 is H.

12. The method as claimed in claim 7 , wherein R 1 is selected from a C 1 to C 10 straight chain or branched alkyl or alkenyl group, or a phenyl group that is optionally substituted with a C 1 to C 6 alkyl.

13. The method as claimed in claim 7 , wherein R 2 is selected from hydrogen, a

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

• A61P31/10

  Antimycotics · CPC title

• A61P43/00

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

• C07D409/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title