Siderophore cephalosporin conjugates and uses thereof
A compound of compound according to formula (I): wherein X is selected from the group consisting of CH, CCl and N, Z is selected from the group consisting of CH 2 COOH, CH(CH 3 )COOH, C(CH 3 ) 2 COOH and CH 2 F, D is a single bond connecting A and Ar or selected from the group consisting of CO, NHCO and N(C 0-6 )alkyl-CO, A is selected from the group consisting of a (C 1-6 )alkanediyl and a (C 3-6 )cycloalkanediyl or, if D is N(C 0 )alkyl-CO, A forms a 4- to 7-membered aliphatic heterocyclic ring with the nitrogen atom of N(C 0 )alkyl-CO in D, and Ar is a 6-membered aromatic ring with a first hydroxyl group in para-position to D, a second hydroxyl group in meta-position to D, and with at least one electron-withdrawing element and uses thereof.
1. A compound according to formula (I):
wherein
X is selected from the group consisting of CH, CCl and N,
Z is selected from the group consisting of CH 2 COOH, CH(CH 3 )COOH, C(CH 3 ) 2 COOH and CH 2 F,
D is a single bond connecting A and Ar or selected from the group consisting of CO, NHCO and N(C 0-6 )alkyl-CO,
A is selected from the group consisting of
a (C 1-6 )alkanediyl and
a (C 3-6 )cycloalkanediyl or,
if D is N(C 0 )alkyl-CO, A forms a 4- to 7-membered aliphatic heterocyclic ring with the nitrogen atom of N(C 0 )alkyl-CO in D, and
Ar is a 6-membered aromatic ring with a first hydroxyl group in para-position to D, a second hydroxyl group in meta-position to D, and with at least one electron-withdrawing element.
2. The compound according to claim 1 , wherein the electron-withdrawing element may be a heteroatom in the aromatic ring or an electron-withdrawing substituent at the aromatic ring.
3. The compound according to claim 1 , wherein the compound is a compound according to formula (II)
wherein X, Z, D, and A are defined as in claim 1 and
wherein
E is selected from the group consisting of CH, N, N + —CH 3 , and N + —O—, and
G is H or an electron-withdrawing substituent,
with the provision that if E is CH, D is selected from the group consisting of CO, NHCO and N(C 0-6 )alkyl-CO and G is an electron-withdrawing substituent.
4. The compound according to claim 3 , wherein G is an electron-withdrawing substituent selected from the group consisting of F, Cl and OCF 3 .
5. The compound according to claim 1 , wherein a shortest linking path in A is defined by the number of bonds extending between the O of the oxime group and D excluding the bond to the O of the oxime group and excluding the bond to D or the single bond of D, and
A is selected such that the shortest linking path in A is shorter than or equal to 3 covalent (C—C) single bonds.
6. The compound according to claim 5 , wherein the shortest linking path in A extends over no single (C—C) bond, one cyclic or acyclic (C—C) single bond, or two cyclic covalent (C—C) bonds.
7. The compound according to claim 1 , wherein A is selected from the group consisting of methanediyl, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, cyclobutane-1,3-diyl, cyclopentane-1,3-diyl, cyclohexane-1,3-diyl, azetidine-1,3-diyl, pyrrolidine-1,3-diyl and piperidine-1,3-diyl, wherein in azetidine-1,3-diyl, pyrrolidine-1,3-diyl and piperidine-1,3-diyl, D is N(C 0 )alkyl-CO and the nitrogen atom of N(C 0 )alkyl-CO in D is the nitrogen in the heterocyclic ring.
8. The compound according to claim 3 , wherein
D is NHCO or N(C 0-6 )alkyl-CO,
A is
a (C 1-6 )alkanediyl, preferably a (C 1-4 )alkanediyl,
a (C 3-6 )cycloalkanediyl, or
A forms a 4- to 7-membered aliphatic heterocyclic ring with the nitrogen atom of N(C 0 )alkyl-CO in D,
E is CH, and
G is Cl.
9. The compound according to- claim 3 , wherein
D is a single bond,
A is
a (C 1-6 )alkanediyl, or
a (C 3-6 )cycloalkanediyl, E is N + —O—, and G is H.
10. The compound according to claim 1 , wherein
-A-D-Ar
is selected from the group consisting of
11. The compound according to claim 1 , wherein X is CH or N.
12. The compound according to claim 1 , wherein Z is C(CH 3 ) 2 COOH or CH 2 F.
13. The compound according to claim 1 , selected from the group consisting of
(6R,7R)-7-[[(2Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-methyl-ethoxy)imino-acetyl]amino]-3-[(1,5-dihydroxy-4-oxo-2-pyridyl)methoxyiminomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid,
(6R,7R)-7-[[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methyl-ethoxy)imino-acetyl]amino]-3-[(1,5-dihydroxy-4-oxo-2-pyridyl)methoxyiminomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid,
(6R,7R)-7-[[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(fluoromethoxyimino)acetyl]amino]-3-[(1,5-dihydroxy-4-oxo-2-pyridyl)methoxyiminomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid,
7-[[(2Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-methyl-ethoxy)imino-acetyl]amino]-3-[2-[(2-chloro-3,4-dihydroxy-benzoyl)amino]ethoxyiminomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid,
7-[[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methyl-ethoxy)imino-acetyl]amino]-3-[2-[(2-chloro-3,4-dihydroxy-benzoyl)amino]ethoxyiminomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid,
7-[[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(fluoromethoxyimino)-acetyl]amino]-3-[2-[(2-chloro-3,4-dihydroxy-benzoyl)amino]ethoxyiminomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid,
7-[[(2Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-methyl-ethoxy)imino-acetyl]amino]-3-1[[3-[(2-chloro-3,4-dihydroxy-benzoyl)amino]-trans-cyclobutoxy]iminomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
and
7-[[(2Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-methyl-ethoxy)imino-acetyl]amino]-3-{[(3S)-1-(2-chloro-3,4-dihydroxy-benzoyl)pyrrolidine-3-yl]oxyiminomethyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
14. A composition comprising a compound of claim 1 in association with at least one pharmaceutical excipient, optionally comprising further at least one pharmaceutical active agent.
15. A method of treating a bacterial infection in a subject in need thereof, comprising administering an effective amount of a compound according to formula (I)
to the subject, wherein
X is selected from the group consisting of CH, CCl and N,
Z is selected from the group consisting of CH 2 COOH, CH(CH 3 )COOH, C(CH 3 ) 2 COOH and CH 2 F,
D is a single bond connecting A and Ar or selected from the group consisting of CO, NHCO and N(C 0-6 )alkyl-CO,
A is selected from the group consisting of
a (C 1-6 )alkanediyl and
a (C 3-6 )cycloalkanediyl or,
if D is N(C 0 )alkyl-CO, A forms a 4- to 7-membered aliphatic heterocyclic ring with the nitrogen atom of N(C 0 )alkyl-CO in D, and
Ar is a 6-membered aromatic ring with a first hydroxyl group in para-position to D, a second hydroxyl group in meta-position to D, and with at least one electron-withdrawing element, and wherein the subject has the bacterial infection.
16. The method according to claim 15 , wherein the bacterial infection is mediated by Gram-negative bacteria.
17. The method according to claim 15 , wherein the bacterial infection is selected from the group consisting of a respiratory tract infection of the lower and/or upper respiratory tract, an urinary tract infection, an intraabdominal infection, a systemic infection, a prosthetic joint infection, a gastrointestinal infection, and an infection of skin and/or soft tissue.
18. The method according to claim 15 , wherein the bacterial infection is mediated by a bacteria selected from the group consisting of Escherichia coli, Salmonella typhimurium, Citrobacter freundii, Klebsiella pneumoniae, Enterobacter cloacae, Enterobacter aerogenes, Moraxella catarrhalis, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Serratia marcescens, Acinetobacter baumannii, Acinetobacter lwoffi, Pseudomonas aeruginosa, Haemophilus influenzae, Burkholderia cepacia, Burkolderia cenocepatia, Burkholderia vietnamensis, Streptococcus spp., and Streptococcus pneumoniae.
19. The method according to claim 15 , wherein the effective amount of the compound according to formula (I) is administered in the form of a pharmaceutical composition.
20. The compound according to claim 5 , wherein
A is selected such that the shortest linking path in A is shorter than or equal to 2 covalent (C—C) single bonds.
21. The compound according to claim 5 , wherein
A is selected such that the shortest linking path in A is shorter than 2 acyclic covalent (C—C) single bonds.
22. The compound according to claim 7 , wherein A is selected from
from methanediyl, ethane-1,2-diyl, cyclobutane-1,3-diyl, and pyrrolidine-1,3-diyl with D being N(C 0 )alkyl-CO and the nitrogen atom of N(C 0 )alkyl-CO in D being the nitrogen in the pyrrolidine ring.
23. The compound according to claim 8 , wherein A is
a (C 2 )alkanediyl ethane-1,2-diyl, or
a (C 4-5 )cycloalkanediyl, or
A forms a 5-membered aliphatic heterocyclic ring.
24. The compound according to claim 23 , wherein A is
a (C 4 )cycloalkanediyl cyclobutane-1,3-diyl, or
A forms a 5-membered heterocyclic ring pyrrolidine-1,3-diyl with the nitrogen atom of N(C 0 )alkyl-CO in D being the nitrogen in the pyrrolidine.
25. The compound according to claim 9 , wherein A is
a (C 1-4 )alkanediyl.
26. The compound according to claim 25 , wherein
A is methanediyl.
27. The compound according to claim 10 , wherein
-A-D-Ar
is selected from the group consisting of
28. The compound according to claim 27 , wherein
-A-D-Ar
is selected from the group consisting of
29. The method according to claim 17 , wherein the subject having the upper and/or lower respiratory tract infection has cystic fibrosis and/or bronchiectasis.
30. The method according to claim 18 , wherein the bacteria selected from the group consisting of Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa , and Burkholderia cepacia.