Class of Gamma Delta T Cells Activators and Use Thereof
AssigneeInnate Pharma
InventorsChristian Belmant, Patrice Nury
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Abstract
The present invention relates to a new class of compounds having γδ T cells activating properties of Formula (I), a composition comprising these compounds and methods for regulating an immune response in a subject comprising the step of administering these compounds.
Claims20
A composition of matter comprising:
- in which Cat+ represents one or several, identical or different organic cations(s), mineral cation(s) or proton(s), B is O or NH or a hydrolysable group, m is an integer from 1 to 3, and Y is O−Cat+, a nucleoside, a radical -A-R or a radical selected from the group consisting of a nucleoside, an oligonucleotide, a nucleic acid, an amino acid, a peptide, a protein, a monosaccharide, an oligosaccharide, a polysaccharide, a fatty acid, a simple lipid, a complex lipid, a folic acid, a tetrahydrofolic acid, a phosphoric acid, an inositol, a vitamin, a co-enzyme, a flavonoid, an aldehyde, an epoxyde and a halohydrin, wherein A is O, NH, CHF, CF2 or CH2, and R is selected from the group consisting of:
- wherein n is an integer from 2 to 20, R1 is a (C1-C3)alkyl group, and R2 is an halogenated (C1-C3)alkyl, a (C1-C3)alkoxy-(C1-C3)alkyl, an halogenated (C2-C3)acyl or a (C1-C3)alkoxy-(C2-C3)acyl;
- wherein n is an integer from 2 to 20, and R1 is a methyl or ethyl group;
- and
- wherein R3, R4 and R5, identical or different, are a hydrogen or (CI-C3)alkyl group, W is —CH— or —N—, and R6 is an (C2-C3)acyl, an aldehyde, an (C1-C3)alcohol, or an (C2-C3)ester.
A method for preparing a diphosphoramidate monoester compound comprising:
- (a) reacting an alkylhalide R-X in a coupling step with a diethylphosphoramidate or diethylchlorophosphate reagent;
- (b) reacting the compound prepared in step (a) in a saponification step thereby removing O-ethyl groups;
- and
- (c) reacting the compound prepared in step (b) in a phosphorylation step thereby preparing a diphosphoramidate monoester,
- wherein R is a linear, branched, or cyclic, aromatic or not, saturated or unsaturated, C1-C50 hydrocarbon group, optionally interrupted by at least one heteroatom, wherein said hydrocarbon group comprises an alkyl, an alkylenyl, or an alkynyl, preferably an alkyl or an alkylene, which can be substituted by one or several substituents selected from the group consisting of:
- an alkyl, an alkylenyl, an alkynyl, an epoxyalkyl, an aryl, an heterocycle, an alkoxy, an acyl, an alcohol, a carboxylic group (—COOH), an ester, an amine, an amino group (—NH2), an amide (—CONH2), an imine, a nitrile, an hydroxyl (—OH), a aldehyde group (—CHO), an halogen, an halogenoalkyl, a thiol (—SH), a thioalkyl, a sulfone, a sulfoxide, and a combination thereof, and
- wherein X is a moiety capable of being displaced by a diethylphosphoramidate group under suitable conditions.
A method of preparing a (E)-2-(4-azido-2-methylbut-2-enyloxy)tetrahydro-2H-pyran compound, comprising providing a (E)-2-(4-Chloro-2-methylbut-2-enyloxy)tetrahydro-2H-pyran compound and reacting said compound with a sodium azide in a water-pentane biphasic mixture in the presence of phase transfer catalyst.
A method of activation γδ T cell, the method comprising bringing a γδ T cell into contact with a composition comprising a γδ T cell activator selected from the group consisting of:
- in which Cat+ represents one or several, identical or different organic cation(s), mineral cation(s) or proton(s), B is O or NH or any group capable to be hydrolyzed, m is an integer from 1 to 3, and Y is O−Cat+, a nucleoside, or a radical -A-R, wherein A is O, NH, CHF, CF2 or CH2, and R is selected from the group consisting of:
- wherein n is an integer from 2 to 20, R1 is a (C1-C3)alkyl group, and R2 is an halogenated (C1-C3)alkyl, a (C1-C3)alkoxy-(C1-C3)alkyl, an halogenated (C2-C3)acyl or a (C1-C3)alkoxy-(C2-C3)acyl;
- wherein n is an integer from 2 to 20, and R1 is a methyl or ethyl group;
- and
- wherein R3, R4 and R5, identical or different, are a hydrogen or (C1-C3)alkyl group, W is —CH— or and R6 is an (C2-C3)acyl, an aldehyde, an (C1-C3)alcohol, or an (C2-C3)ester.
A method of immunotherapy or stimulation of an immune response comprising the administration of a composition comprising a γδ T cell activator selected from the group consisting of:
- in which Cat+ represents one or several, identical or different organic cation(s), mineral cation(s) or proton(s), B is O or NH or any group capable to be hydrolyzed, m is an integer from 1 to 3, and Y is O−Cat+, a nucleoside, or a radical -A-R, wherein A is O, NH, CHF, CF2 or CH2, and R is selected from the group consisting of:
- wherein n is an integer from 2 to 20, R1 is a (C1-C3)alkyl group, and R2 is an halogenated (C1-C3)alkyl, a (C1-C3)alkoxy-(C1-C3)alkyl, an halogenated (C2-C3)acyl or a (C1-C3)alkoxy-(C2-C3)acyl;
- wherein n is an integer from 2 to 20, and R1 is a methyl or ethyl group;
- and
- wherein R3, R4 and R5, identical or different, are a hydrogen or (Cl-C3)alkyl group, W is —CH— or —N—, and R6 is an (C2-C3)acyl, an aldehyde, an (C1-C3)alcohol, or an (C2-C3)ester.
A method of regulating the activity of γδ T cells in a mammalian subject, the method comprising administering to a subject in need thereof, an effective amount of a γδ T cell activator according to a treatment cycle in which the γδ T cell activity is allowed to return to substantially basal rate prior to a second administration of the compound.
Dependencies are inferred from the claim text.