Antimicrobial compounds
View Patent ↗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.
1. A compound of the formula I below:
wherein:
X is O, S or SO 2 ,
Y is OH or C 1 to C 10 alkyl,
R 1 , R 2 and R 4 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 5 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;
and tautomers, salts, and solvates thereof.
2. The compound as claimed in claim 1 , which has the formula:
3. The compound as claimed in claim 1 , wherein n is 0 or 1 and L 2 is absent.
4. The compound as claimed in claim 1 , where R 6 is an alkyl that is a bridged ring system.
5. The compound 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 compound 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 compound 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.
8. The compound as claimed in claim 7 , where the aromatic heterocyclic ring is a pyrrole ring.
9. The compound 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.
10. The compound 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.
11. The compound as claimed in claim 1 , having the formula:
wherein R 5 is selected from 1-adamantyl and CH 2 —C 6 H 5 , or
wherein R 5 is CH 2 —C 6 H 5 .
12. The compound as claimed in claim 1 , selected from
and tautomers, salts, and solvates thereof.
13. The compound as claimed in claim 1 , where the salts are pharmaceutically acceptable salts.
14. A compound as claimed in claim 1 for use in a medicament for treating a topical microbial infection.
15. An antibacterial composition comprising a compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof.
16. The composition as claimed in claim 15 , which is a topical antimicrobial composition.
17. A method of using a compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof as an antimicrobial agent, the method comprising adding the compound or the pharmaceutically acceptable salt thereof to a composition or applying the compound or the pharmaceutically acceptable salt thereof to an object.
18. The method as claimed in claim 17 , wherein the composition or the object is paper, fabric, building materials, packaging materials, coating and paint compositions, disinfectants, detergents, household products, cosmetics or suncreams.
19. A method of inhibiting bacterial RNA polymerase and/or undecaprenyl pyrophosphate synthase, said method comprising contacting a cell with an effective amount of a compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof.
20. A method of synthesizing a compound of the Formula I according to claim 1 , wherein Y is a C 1 to C 10 alkyl, which comprises reacting a compound of Formula II with an amine of R 4 R 5 NH,
wherein:
X is O, S or SO 2 ,
Y is OH or C 1 to C 10 alkyl,
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.
21. A method of synthesizing a compound of the Formula Ia according to claim 2 , which comprises
a) reacting a compound of the formula III below
with a compound of the formula R 5 NCO, or
b) reacting a compound of the formula IV below
with an amine of the formula R 4 R 5 NH, where R 4 is H.
22. The method as claimed in claim 21 , wherein the compound of Formula IV is formed by acylating a compound of Formula III.