MANNOSYL-1 PHOSPHATES, PREPARATION METHOD AND THERAPEUTIC USE, IN PARTICULAR AGAINST THE CDG-IA SYNDROME
First Claim
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1. A composition for use as a medicament, wherein it contains, in combination with a physiologically acceptable excipient, an active substance chosen from the combination consisting of:
- (a) the mono(α
-D-mannopyranosyl-1) phosphates of formula I;
in which R11, R12, R13 and R14, which are identical or different, each represent the hydrogen atom or an OH-protective group, R and R′
, which are identical or different, each representa C6-C10 aryloxy group capable of being substituted with one or more C1-C5 alkyl, C1-C5 alkoxy, halo, CF3 and/or nitro groups,an arylalkyleneoxy group, where the alkylene residue is C1-C5, and the aryl residue, which is C6-C10, is capable of being substituted with one or more C1-C5 alkyl, C1-C5 alkoxy, halo, CF3 and/or nitro groups,a group having a structure;
—
O—
CH(CH3)—
O—
CO-alkyl, or—
O—
CH(CH3)—
O—
CO—
O-alkylwhere the alkyl residue is C1-C5,a group —
O—
CH2—
CH(OH)—
CH2OH, where the OH groups may be protected,an OB residue, where B is an ethylenically unsaturated aliphatic C2-C21 residue containing a linear or branched hydrocarbon chain, or a C5-C21 cycloaliphatic residue, oran amino acid group having the structure VIIa;
where X is —
O—
, —
S—
or —
NZ1-, Y represents H or a C2-C5 alkyl group, A is an alkylene, phenylene or phenylalkylene group, (where each alkylene group is C1-C5), Z1 is H, a C1-C5 alkyl group or an N-protective group, Z2 and Z3, which are identical or different, each represent H, a C1-C5 alkyl group, or an N-protective group;
an amino acid group having the structure VIIb;
where Y represents H or a C2-C5 alkyl group, Z4 is an alkylene, phenylene or phenylalkylene group, (where each alkylene group is C1-C5), Z2 represents H, a C1-C5 alkyl group, or an N-protective group;
(β
) the di(α
-D-mannopyranosyl-1) phosphates of formula II;
in which R21, R22, R23 and R24, which are identical or different, each represent the hydrogen atom or an OH-protective group, and R representsan OH group,a C1-C20 alkoxy group,a C6-C10 aryloxy group capable of being substituted with one or more C1-C5 alkyl, C1-C5 alkoxy, halo, CF3 and/or nitro groups,an arylalkyleneoxy group, where the alkylene residue is C1-C5, and the aryl residue, which is C6-C10, is capable of being substituted with one or more C1-C5 alkyl, C1-C5 alkoxy, halo, CF3 and/or nitro groups,a group having the structure;
—
O—
CH(Q)-O—
CO-alkyl, or—
O—
CH(Q)-O—
CO—
O-alkylwhere Q is H or CH3, and the alkyl residue is C1-C5,a group —
O—
CH2—
CH(OH)—
CH2OH, where the OH groups may be protected,an OB residue, where B is an ethylenically unsaturated aliphatic C2-C21 residue containing a linear or branched hydrocarbon chain, or a cycloaliphatic C5-C21 residue, oran amino acid group having the structure VIIa;
where X is —
O—
, —
S—
or —
NZ1-, Y represents H or a C2-C5 alkyl group, A is an alkylene, phenylene or phenylalkylene group, (where each alkylene group is C1-C5), Z1 is H, a C1-C5 alkyl group or an N-protective group, and Z2 and Z3, which are identical or different, each represent H, a C1-C5 alkyl group, or an N-protective group;
an amino acid group having the structure VIIb;
where Y represents H or a C2-C5 alkyl group, Z4 is an alkylene, phenylene or phenylalkylene group, (where each alkylene group is C1-C5), Z2 represents H, a C1-C5 alkyl group, or an N-protective group;
(γ
) the tri(α
-D-mannopyranosyl-1) phosphates of formula III;
in which R31, R32, R33 and R34, which are identical or different, each represent a hydrogen atom or an OH-protective group; and
(δ
) mixtures thereof.
1 Assignment
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Accused Products
Abstract
The present invention relates, as medicaments, to the α-D-mannopyranosyl-1 phosphate derivatives of formulae I, II and III:
(where each group R11 to R14, R21 to R24, R31 to R34 is H or an OH-protective group, and R and R′ are defined as indicated in the description), which can be used as cellular sources of Man-1 P, against the CDG-I syndrome and in particular the CDG-Ia syndrome.
The invention also relates to these derivatives as industrial products and to their method of preparation.
2 Citations
17 Claims
-
1. A composition for use as a medicament, wherein it contains, in combination with a physiologically acceptable excipient, an active substance chosen from the combination consisting of:
-
(a) the mono(α
-D-mannopyranosyl-1) phosphates of formula I;in which R11, R12, R13 and R14, which are identical or different, each represent the hydrogen atom or an OH-protective group, R and R′
, which are identical or different, each representa C6-C10 aryloxy group capable of being substituted with one or more C1-C5 alkyl, C1-C5 alkoxy, halo, CF3 and/or nitro groups, an arylalkyleneoxy group, where the alkylene residue is C1-C5, and the aryl residue, which is C6-C10, is capable of being substituted with one or more C1-C5 alkyl, C1-C5 alkoxy, halo, CF3 and/or nitro groups, a group having a structure; —
O—
CH(CH3)—
O—
CO-alkyl, or—
O—
CH(CH3)—
O—
CO—
O-alkylwhere the alkyl residue is C1-C5, a group —
O—
CH2—
CH(OH)—
CH2OH, where the OH groups may be protected,an OB residue, where B is an ethylenically unsaturated aliphatic C2-C21 residue containing a linear or branched hydrocarbon chain, or a C5-C21 cycloaliphatic residue, or an amino acid group having the structure VIIa; where X is —
O—
, —
S—
or —
NZ1-,Y represents H or a C2-C5 alkyl group, A is an alkylene, phenylene or phenylalkylene group, (where each alkylene group is C1-C5), Z1 is H, a C1-C5 alkyl group or an N-protective group, Z2 and Z3, which are identical or different, each represent H, a C1-C5 alkyl group, or an N-protective group; an amino acid group having the structure VIIb; where Y represents H or a C2-C5 alkyl group, Z4 is an alkylene, phenylene or phenylalkylene group, (where each alkylene group is C1-C5), Z2 represents H, a C1-C5 alkyl group, or an N-protective group; (β
) the di(α
-D-mannopyranosyl-1) phosphates of formula II;in which R21, R22, R23 and R24, which are identical or different, each represent the hydrogen atom or an OH-protective group, and R represents an OH group, a C1-C20 alkoxy group, a C6-C10 aryloxy group capable of being substituted with one or more C1-C5 alkyl, C1-C5 alkoxy, halo, CF3 and/or nitro groups, an arylalkyleneoxy group, where the alkylene residue is C1-C5, and the aryl residue, which is C6-C10, is capable of being substituted with one or more C1-C5 alkyl, C1-C5 alkoxy, halo, CF3 and/or nitro groups, a group having the structure; —
O—
CH(Q)-O—
CO-alkyl, or—
O—
CH(Q)-O—
CO—
O-alkylwhere Q is H or CH3, and the alkyl residue is C1-C5, a group —
O—
CH2—
CH(OH)—
CH2OH, where the OH groups may be protected,an OB residue, where B is an ethylenically unsaturated aliphatic C2-C21 residue containing a linear or branched hydrocarbon chain, or a cycloaliphatic C5-C21 residue, or an amino acid group having the structure VIIa; where X is —
O—
, —
S—
or —
NZ1-,Y represents H or a C2-C5 alkyl group, A is an alkylene, phenylene or phenylalkylene group, (where each alkylene group is C1-C5), Z1 is H, a C1-C5 alkyl group or an N-protective group, and Z2 and Z3, which are identical or different, each represent H, a C1-C5 alkyl group, or an N-protective group; an amino acid group having the structure VIIb; where Y represents H or a C2-C5 alkyl group, Z4 is an alkylene, phenylene or phenylalkylene group, (where each alkylene group is C1-C5), Z2 represents H, a C1-C5 alkyl group, or an N-protective group; (γ
) the tri(α
-D-mannopyranosyl-1) phosphates of formula III;in which R31, R32, R33 and R34, which are identical or different, each represent a hydrogen atom or an OH-protective group; and (δ
) mixtures thereof.- View Dependent Claims (2, 3, 4, 5, 6)
(β
) di(α
-D-mannopyranosyl-1) phosphates of formula II,(γ
) tri(α
-D-mannopyranosyl-1) phosphates of formula III, and(δ
) mixtures thereof,as claimed in claim 1, for the preparation of a medicament intended for therapeutic use against the CDG-I syndrome, and in particular against the CDG-Ia syndrome.
-
-
7. A mannosyl-1 phosphate derivative, for use as a medicament, wherein it is chosen from the combination consisting of:
-
(α
) mono(α
-D-mannopyranosyl-1) phosphates of formula I;in which R11, R12, R13 and R14, which are identical or different, each represent the hydrogen atom or an OH-protective group, R and R′
, which are identical or different, each representa C6-C10 aryloxy group (in particular phenoxy, 1-naphthyloxy or 2-naphthyloxy) capable of being substituted with one or more C1-C5 alkyl, C1-C5 alkoxy, halo, CF3 and/or nitro groups, an arylalkyleneoxy group (in particular OCH2CH2C6H5, OCH2C6H5, 1-naphthylmethyloxy or 2-naphthylmethyloxy), where the alkylene residue is C1-C5, and the aryl residue, which is C6-C10, is capable of being substituted with one or more C1-C5 alkyl, C1-C5 alkoxy, halo, CF3 and/or nitro groups, a group having a structure; —
O—
CH(CH3)—
O—
CO-alkyl, or—
O—
CH(CH3)—
O—
CO—
O-alkylwhere the alkyl residue is C1-C5, a group —
O—
CH2—
CH(OH)—
CH2OH, where the OH groups may be protected,an OB residue, where B is an ethylenically unsaturated aliphatic C2-C21 residue containing a linear or branched hydrocarbon chain, or a C5-C21 cycloaliphatic residue, or an amino acid group having the structure VIIa; where X is —
O—
, —
S—
or —
NZ1-,Y represents H or a C2-C5 alkyl group, A is an alkylene, phenylene or phenylalkylene group, (where each alkylene group is C1-C5), Z1 is H, a C1-C5 alkyl group or an N-protective group, and Z2 and Z3, which are identical or different, each represent H, a C1-C5 alkyl group, or an N-protective group; an amino acid group having the structure VIIb; where Y represents H or a C2-C5 alkyl group, Z4 is an alkylene, phenylene or phenylalkylene group, (where each alkylene group is C1-C5), Z2 represents H, a C1-C5 alkyl group, or an N-protective group; (β
) the di(α
-D-mannopyranosyl-1) phosphates of formula II;in which R21, R22, R23 and R24, which are identical or different, each represent the hydrogen atom or an OH-protective group, and R represents an OH group, a C1-C20 (preferably C1-C5) alkoxy group, a C6-C10 aryloxy group capable of being substituted with one or more C1-C5 alkyl, C1-C5 alkoxy, halo, CF3 and/or nitro groups, an arylalkyleneoxy (in particular benzyloxy, phenylethyloxy, 1-naphthylmethyloxy or 2-naphthylmethyloxy) group, where the alkylene residue is C1-C5, and the aryl residue, which is C6-C10, is capable of being substituted with one or more C1-C5 alkyl, C1-C5 alkoxy, halo, CF3 and/or nitro groups, a group having the structure; —
O—
CH(Q)-O—
CO-alkyl, or—
O—
CH(Q)-O—
CO—
O-alkylwhere Q is H or CH3, and the alkyl residue is C1-C5, a group —
O—
CH2—
CH(OH)—
CH2OH, where the OH groups may be protected,an OB residue, where B is an ethylenically unsaturated aliphatic C2-C21 residue containing a linear or branched hydrocarbon chain, or a cycloaliphatic C5-C21 residue, or an amino acid group having the structure VIIa; where X is —
O—
, —
S—
or —
NZ1-,Y represents H or a C2-C5 alkyl group, A is an alkylene, phenylene or phenylalkylene group, (where each alkylene group is C1-C5), Z1 is H, a C1-C5 alkyl group or an N-protective group, and Z2 and Z3, which are identical or different, each represent H, a C1-C5 alkyl group, or an N-protective group; an amino acid group having the structure VIIb; where Y represents H or a C2-C5 alkyl group, Z4 is an alkylene, phenylene or phenylalkylene group, (where each alkylene group is C1-C5), Z2 represents H, a C1-C5 alkyl group, or an N-protective group; (γ
) the tri(α
-D-mannopyranosyl-1) phosphates of formula III′
;in which R31, R32, R33 and R34, which are identical or different, each represent an OH-protective group having at least three carbon atoms; and (δ
) mixtures thereof.- View Dependent Claims (8, 9, 10, 11, 12, 13, 14, 15, 16, 17)
where R11, R12, R13 and R14 are defined as indicated above, with a monosilver phosphate of formula (Va); where R and R′
are defined as indicated above,in order to obtain a mono(α
-D-mannopyranosyl-1) phosphate compound of formula I;(b) the reaction of a 1-bromomannopyranose of formula (IVb); where R21, R22, R23 and R24 are defined as indicated above, with a disilver phosphate of formula (Vb); where R is defined as indicated above, in order to obtain a di(α
-D-mannopyranosyl-1) phosphate compound of formula II;
or(c) the reaction of a 1-bromomannopyranose of formula (IVc); where R31, R32, R33 and R34, which are identical or different, each represent an OH-protective group which is a C3-C6 acyl group, with a trisilver phosphate of formula (Vc); in order to obtain a tri(α
-D-mannopyranosyl-1) phosphate compound of formula III′
.
-
-
16. The method as claimed in claim 15, wherein the reaction of IVa with Va, the reaction of IVb with Vb or the reaction of IVc with Vc is carried out at a temperature of 15 to 40°
- C., preferably at room temperature (15-25°
C.), advantageously in an appropriate inert solvent, preferably toluene, in the presence of a molecular sieve.
- C., preferably at room temperature (15-25°
-
17. The method as claimed in claim 15, wherein the silver phosphate of formula Va, Vb or, respectively, Vc may be replaced by a phosphate of formula VIa, VIb or, respectively, VIc:
-
in which R and R′
are defined as indicated above, and A is H or R″
4N, R″
being H or an N-alkyl, cycloalkyl or aromatic group.
-
Specification
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Current AssigneeCentre National De La Recherche Scientifique, Oe Operations, Universite Rene Descartes
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Original AssigneeCentre National De La Recherche Scientifique, Oe Operations, Universite Rene Descartes
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InventorsGravier-Pelletier, Christine, Hardre, Renaud, Khaled, Amira, Le Merrer, Yves
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Application NumberUS12/279,876Publication NumberTime in Patent OfficeDaysField of SearchUS Class Current514/25CPC Class CodesA61K 31/7024 Esters of saccharidesA61P 25/00 Drugs for disorders of the ...A61P 3/00 Drugs for disorders of the ...A61P 43/00 Drugs for specific purposes...C07H 11/04 Phosphates; Phosphites; Pol...Y02P 20/55 Design of synthesis routes,...
