Thiophenoxime and furanoxime scaffolds
The present invention relates to a compound of formula (I). It also relates to a pharmaceutical composition comprising at least one compound of formula (I) and at least one pharmaceutically acceptable support. Finally, it relates to the use of such a compound as a medicine, preferably in the treatment of a nervous and/or respiratory failure due to intoxication with at least one organophosphorous nerve agent; in the treatment of neurological diseases such as Alzheimer's disease; and/or in the treatment of cancer.
1 . A compound, or a salt thereof, selected from the group consisting of:
(E/Z)-5-(pyridin-3-ylethynyl)thiophene-2-carbaldehyde oxime 4:
(E/Z)-5-(pyridin-3-ylethynyl)thiophene-2-carbaldehyde oxime hydrochloride NM-27:
(E/Z)-5-(2-(pyridin-3-yl)ethyl)thiophene-2-carbaldehyde oxime 5:
(E/Z)-5-(2-(pyridin-3-yl)ethyl)thiophene-2-carbaldehyde oxime hydrochloride NM-29:
(E/Z)-5-(pyridin-3-ylethynyl)furan-2-carbaldehyde oxime 8:
(E/Z)-5-(2-(pyridin-3-yl)ethyl)furan-2-carbaldehyde oxime 9:
(E/Z)-5-(2-(pyridin-3-yl)ethyl)furan-2-carbaldehyde oxime hydrochloride NM-34:
(E/Z)-5-(4-(quinolin-4-ylamino)but-1-yn-1-yl)furan-2-carbaldehyde oxime 11:
(E/Z)-5-(4-(quinolin-4-ylamino)but-1-yn-1-yl)furan-2-carbaldehyde oxime hydrochloride NM-53:
(E/Z)-5-(4-(quinolin-4-ylamino)butyl)furan-2-carbaldehyde oxime 14:
(E/Z)-5-(4-(quinolin-4-ylamino)butyl)furan-2-carbaldehyde oxime hydrochloride NM-80:
(Z/E)-5-(4-(1,3-dioxoisoindolin-2-yl)but-1-yn-1-yl)thiophene-2-carbaldehyde oxime CV-65:
(Z/E)-5-((1-methyl-1H-imidazol-5-yl)ethynyl)furan-2-carbaldehyde oxime 5:
(E/Z)-5-(2-(1-methyl-1H-imidazol-5-yl)ethyl)furan-2-carbaldehyde oxime 6:
(Z)-5-(2-(1-methyl-1H-imidazol-5-yl)ethyl)furan-2-carbaldehyde oxime hydrochloride FR-152:
(3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-N-(4-(5-((Z)-(hydroxyimino)methyl)furan-2-yl)but-3-yn-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide FR-151:
(Z/E)-5-((3-hydroxyoxetan-3-yl)ethynyl)furan-2-carbaldehyde oxime FR-99:
(Z/E)-5-(4-(1,3-dioxoisoindolin-2-yl)but-1-yn-1-yl)furan-2-carbaldehyde oxime CV-59:
(Z/E)-5-(4-(1,3-dioxoisoindolin-2-yl)butyl)furan-2-carbaldehyde oxime CV-60
(E/Z)-4-(pyridin-3-ylethynyl)furan-2-carbaldehyde oxime 3:
(E/Z)-4-(2-(pyridin-3-yl)ethyl)furan-2-carbaldehyde oxime FR-82:
(Z/E)-4-(5-phenylpent-1-yn-1-yl)furan-2-carbaldehyde oxime FR-66:
2 . The compound of claim 1 formed as a hydrochloride salt.
3 . A pharmaceutical composition comprising at least one compound according to claim 1 , and at least one pharmaceutically acceptable flavorant, colorant, stabilizer, thickener, excipient, disintegrant, binder, or lubricant.
4 . A process for preparing a compound according to claim 1 , which comprises the following steps:
a Sonogashira coupling reaction between a terminal alkyne
and an isomer of unprotected bromo-thiophenoxime or an isomer of unprotected bromo-furanoxime, optionally under palladium catalysis, to obtain the conjugate
of formula (I), wherein G is O or S;
optionally, said conjugate is then submitted to hydrogenation, optionally with Pd/C catalyst in heterogeneous conditions, to provide the corresponding alkene, and finally the hybrid reactivator
of formula (I), wherein G is O or S,
R being chosen from the following structures
in which
represents the point of attachment to the alkyne.
5 . A method for treating a nervous and/or respiratory failure due to intoxication with at least one organophosphorous nerve agent, by virtue of their reactivation potency of organophosphorous inhibited cholinesterases, including acetylcholinesterase and butyrylcholinesterase, in a subject in need thereof, comprising administering at least one compound according to claim 1 to said subject.