Potent sialyltransferase inhibitors
The present invention relates to a new class of sialyltransferase inhibitors. The class features a carbamate or similar moiety on the amine of a neuraminic acid derivative. Such inhibitors are suitable for use as a medicament, for example for treating, preventing, or delaying bacterial infection, viral infection, cancer, a disorder of sialic acid metabolism, or an autoimmune disease.
1. A compound of general formula (I):
wherein
X is in each instance independently chosen from the group consisting of hydrogen and a linear, branched, or cyclic C 1-6 acyl moiety wherein each carbon atom is optionally substituted by a halogen, an alkoxy, or a haloalkoxy moiety, and wherein the acyl chain is optionally unsaturated;
Z is chosen from the group consisting of hydrogen and a linear, branched, or cyclic C 1-6 alkyl, alkenyl, or alkynyl moiety wherein each carbon atom is optionally substituted by a halogen, an alkoxy, or a haloalkoxy moiety;
Q and Q′ are each independently chosen from the group consisting of O, S, and NH;
c′ is C;
L is either —CH 2 — or is absent; and
R is a linear, branched, or cyclic C 1-6 alkyl, alkenyl, or alkynyl moiety, wherein each carbon atom is optionally substituted by a halogen, an alkoxy, a haloalkoxy, a hydroxyl, or an oxo moiety;
wherein the compound is not of general formula (I) wherein Z is methyl, Q is O, Q′ is O, L is absent, R is tert-butyl, X at the anomeric position is axial and is H, and each other X is acetyl.
2. The compound according to claim 1 , wherein it is of general formula (II-ax) or (II-eq):
wherein each of X, Z, Q, Q′, c′, L, and R are as defined in claim 1 .
3. The compound according to claim 1 , wherein it is of general formula (III):
wherein each of X, Z, Q, Q′, c′, and R are as defined in claim 1 .
4. The compound according to claim 1 , wherein
X is in each instance chosen from the group consisting of acetyl, propionyl, and butyryl; and/or
Z is chosen from the group consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, allyl, propargyl, n-butyl, tert-butyl, sec-butyl, isobutyl, and cyclobutyl; and/or
Q is chosen from the group consisting of O and S; and/or
Q′ is chosen from the group consisting of O, S, and NH; and/or
L is absent; and/or
R is a linear, branched, or cyclic C 1-6 alkyl, alkenyl, or alkynyl moiety, wherein each carbon atom is optionally substituted by a halogen, an alkoxy, a haloalkoxy, a hydroxyl, or an oxo moiety.
5. The compound according to claim 1 , wherein
X is acetyl; and/or
Z is methyl; and/or
Q is O; and/or
Q′ is O; and/or
L is absent; and/or
R is chosen from the group consisting of methyl, ethyl, isobutyl, tert-butyl, n-butyl, allyl, propargyl, acetyl, 2-methoxyethyl, 2,2,2-trichloroethyl, and 2-fluoroethyl.
6. A method of treating, preventing, or delaying a bacterial infection, viral infection, cancer, a disorder of sialic acid metabolism, or an autoimmune disease in a subject in need thereof, the method comprising administrating to the subject a compound of general formula (I):
wherein
X is in each instance independently chosen from the group consisting of hydrogen and a linear, branched, or cyclic C 1-6 acyl moiety wherein each carbon atom is optionally substituted by a halogen, an alkoxy, or a haloalkoxy moiety, and wherein the acyl chain is optionally unsaturated;
Z is chosen from the group consisting of hydrogen and a linear, branched, or cyclic C 1-6 alkyl, alkenyl, or alkynyl moiety wherein each carbon atom is optionally substituted by a halogen, an alkoxy, or a haloalkoxy moiety;
Q and Q′ are each independently chosen from the group consisting of O, S, and NH;
c′ is C;
L is either —CH 2 — or is absent; and
R is a linear, branched, or cyclic C 1-6 alkyl, alkenyl, or alkynyl moiety, wherein each carbon atom is optionally substituted by a halogen, an alkoxy, a haloalkoxy, a hydroxyl, or an oxo moiety.
7. A compound of general formula (I):
wherein
c′ is S(═O);
X is in each instance independently chosen from the group consisting of hydrogen and a linear, branched, or cyclic C 1-6 acyl moiety wherein each carbon atom is optionally substituted by a halogen, an alkoxy, or a haloalkoxy moiety, and wherein the acyl chain is optionally unsaturated;
Z is chosen from the group consisting of hydrogen and a linear, branched, or cyclic C 1-6 alkyl, alkenyl, or alkynyl moiety wherein each carbon atom is optionally substituted by a halogen, an alkoxy, or a haloalkoxy moiety;
Q is O and Q′ is absent or is chosen from the group consisting of O, S, and NH;
L is either —CH 2 — or is absent; and
R is a linear, branched, or cyclic C 1-6 hydrocarbon moiety, wherein each carbon atom is optionally substituted by a halogen, an alkoxy, a haloalkoxy, a hydroxyl, or an oxo moiety, or optionally R is H when L is absent and Q′ is not absent.
8. The compound according to claim 7 , wherein it is of general formula (II-ax) or (II-eq):
wherein each of X, Z, Q, Q′, c′, L, and R are as defined in claim 7 .
9. The compound according to claim 7 , wherein it is of general formula (III):
wherein each of X, Z, Q, Q′, c′, and R are as defined in claim 7 .
10. The compound according to claim 7 , wherein
X is in each instance chosen from the group consisting of acetyl, propionyl, and butyryl; and/or
Z is chosen from the group consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, allyl, propargyl, n-butyl, tert-butyl, sec-butyl, isobutyl, and cyclobutyl; and/or
Q is chosen from the group consisting of O and S; and/or
Q′ is chosen from the group consisting of O, S, and NH; and/or
L is absent; and/or
R is a linear, branched, or cyclic C 1-6 alkyl, alkenyl, or alkynyl moiety, wherein each carbon atom is optionally substituted by a halogen, an alkoxy, a haloalkoxy, a hydroxyl, or an oxo moiety.
11. The compound according to claim 7 , wherein
X is acetyl; and/or
Z is methyl; and/or
Q is O; and/or
Q′ is O; and/or
L is absent; and/or
R is chosen from the group consisting of methyl, ethyl, isobutyl, tert-butyl, n-butyl, allyl, propargyl, acetyl, 2-methoxyethyl, 2,2,2-trichloroethyl, and 2-fluoroethyl.
12. A method of treating or delaying a bacterial infection, viral infection, cancer, a disorder of sialic acid metabolism, or an autoimmune disease in a subject in need thereof, the method comprising administrating to the subject a compound of general formula (I):
wherein
c′ is S(═O);
X is in each instance independently chosen from the group consisting of hydrogen and a linear, branched, or cyclic C 1-6 acyl moiety wherein each carbon atom is optionally substituted by a halogen, an alkoxy, or a haloalkoxy moiety, and wherein the acyl chain is optionally unsaturated;
Z is chosen from the group consisting of hydrogen and a linear, branched, or cyclic C 1-6 alkyl, alkenyl, or alkynyl moiety wherein each carbon atom is optionally substituted by a halogen, an alkoxy, or a haloalkoxy moiety;
Q is O and Q′ is absent or is chosen from the group consisting of O, S, and NH;
L is either —CH 2 — or is absent; and
R is a linear, branched, or cyclic C 1-6 hydrocarbon moiety, wherein each carbon atom is optionally substituted by a halogen, an alkoxy, a haloalkoxy, a hydroxyl, or an oxo moiety, or optionally R is H when L is absent and Q′ is not absent.