DERIVATIVES OF MORPHINE-6-GLUCURONIDE, PREPARATION
METHOD THEREOF AND USE OF SAME IN THERAPEUTICS
FIELD OF THE INVENTION
The present invention relates to morphine-6-glucuronide derivatives, to their
preparation and to their use for treating and preventing pain.
One subject of the present invention is compounds corresponding to
formula (I)

in which:
R1 is a 5-membered heteroaromatic group optionally substituted with one or
more substituents chosen from halogen atoms and groups (C1-C4)alkyl, halogen,
hydroxyl, oxo, halo(C1-C4)alkyl, halo(C1-C4)alkyloxy, (C1-C4)alkyloxy, aryl(C1-
C4)alkyl and aryl, the said aryl group being optionally substituted with one or more
groups chosen from the groups (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxyl and (C1-
C4)alkyloxy,
in the form of base or of an acid-addition salt, and also in the form of a
hydrate or a solvate.
The compounds of formula (I) may comprise one or more asymmetric
carbon atoms. They may thus exist in the form of enantiomers or
diastereoisomers. These enantiomers and diastereoisomers, and also mixtures
thereof, including racemic mixtures, form part of the invention.
The compounds of formula (I) comprise an anomeric carbon. They may
exist in the form of a or ß anomers. The a and ß anomers and the mixture thereof
form part of the invention.
The compounds of formula (II) may exist in the form of bases or of acid-
addition salts. Such addition salts form part of the invention.
These salts may be prepared with pharmaceutically acceptable acids, but
the salts of other acids that are useful, for example, for purifying or isolating the
compounds of formula (I), also form part of the invention.
The compounds of formula (I) may also exist in the form of hydrates or
solvates, i.e. in the form of associations or combinations with one or more water
molecules or with a solvent. Such hydrates and solvates also form part of the
invention.
In the context of the present invention, the following definitions apply:
- a halogen atom: a fluorine, chlorine, bromine or iodine atom;
- a (C1-C4)alkyl group: a substituted or unsubstituted, linear or branched,
saturated aliphatic group containing between 1 and 4 carbon atoms; examples that
may be mentioned include methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-
butyl groups;
- a halo(C1-C4)alkyl group: an alkyl group in which one or more hydrogen
atoms have been replaced with a halogen atom as defined above; examples of
halo(C1-C4)alkyl groups that may be mentioned in particular include fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,
fluoroethyl, difluoroethyl, trifluoroethyl, chloroethyl, dichloroethyl and trichloroethyl
groups;
a hydroxyl group: an -OH group;
- an oxo group: group = O
- a group (C1-C4)alkyloxy: a group -O-(C1-C4)alkyl in which the group (C1-
C4)alkyl is as defined previously; examples that may be mentioned include
methoxy, ethoxy, propoxy and butyloxy groups;
- a group halo(C1-C4)alkyloxy: a group (C1-C4)alkyloxy in which one or more
hydrogen atoms have been replaced with a halogen atom as defined above;
examples that may be mentioned include the groups -OCF3, -OCHF2 and -OCCI3;
- an aryl group: a substituted or unsubstituted cyclic aromatic group
containing between 5 and 14 carbon atoms; examples of unsubstituted aryl groups
that may be mentioned include phenyl and naphthyl groups; examples of
substituted aryl groups that may be mentioned include groups (C1-
C4)alkyloxyphenyl such as methoxyphenyl, ethoxyphenyl, propoxyphenyl and
butyloxyphenyl groups;
- a group aryl(C1-C4)alkyl: an alkyl group in which one or more hydrogen
atoms have been replaced with an aryl group; an example that may be mentioned
is the benzyl group;
- a 5-membered heteroaromatic heterocyclic group: a cyclic aromatic group
containing from 1 to 4 carbon atoms and comprising one or more heteroatoms,
such as nitrogen, oxygen or sulfur; examples of 5-membered heteroaromatic
heterocyclic groups that may be mentioned include pyrrolyl, furyl, thiophenyl,
pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,
isothiazolyl and thiadiazolyl groups.
Among the compounds of formula (I) that are subjects of the invention, a
first group of compounds has one or more of the following characteristics:
- the heteroaromatic heterocyclic group is chosen from pyrrole, furan,
thiophene, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, thiazole,
isothiazole and thiadiazole groups, and
- when the heteroaromatic heterocyclic group is substituted with one or
more groups, the said group is chosen from methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,
dichloromethyl, trichloromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, chloroethyl,
dichloroethyl, trichloroethyl, methoxyphenyl, ethoxyphenyl, propoxyphenyl and
butyloxyphenyl groups.
Among the compounds mentioned previously, mention may be made in
particular of the compounds of formula (I) for which:
- the heteroaromatic heterocyclic group is chosen from tetrazole, triazole, in
particular 1,2,4-triazole, and oxadiazole, in particular 1,3,4-oxadiazole groups, and
- when the heteroaromatic heterocyclic group is substituted with at least one
group, the said group is chosen from methyl, trifluoroethyl and p-methoxyphenyl
groups.
Among the compounds of formula (I) that are subjects of the invention,
mention may be made especially of the following compounds:
- morphin-6-yl 5-C-(tetrazol-5-yl)-a/(3-D-xylopyranoside (1/1)
- morphin-6-yl 5-C-(tetrazol-5-yl)-(3-D-xylopyranoside
- morphin-6-yl 5-C-(2-methyl-1,3,4-oxadiazol-5-yl)-a/p-D-xylopyranoside
(2/3)
- morphin-6-yl 5-C-(2-methyl-1,3,4-oxadiazol-5-yl)-a-D-xylopyranoside
- morphin-6-yl 5-C-(2-methyl-1,3,4-oxadiazol-5-yl)-(3-D-xylopyranoside and
-morphin-6-yl5-C-[5-(4-methoxyphenyl)-4-(2,2,2-trifluoroethyl)-4H-
1,2,4-triazol-3-yl]-(3-D-xylopyranoside.
PREPARATION PROCESS
In the text hereinbelow, the term "protecting group PG" means a group that
can, firstly, protect a reactive function such as a hydroxyl or an amine during a
synthesis, and that can, secondly, enable regeneration of the intact reactive
function at the end of the synthesis. Examples of protecting groups and of
protection and deprotection methods are given in "Protective Groups in Organic
Synthesis" Greene et a/., 2nd Edition (John Wiley & Sons, Inc., New York).
In the text hereinbelow, the term "leaving group LG" means a group that can
be readily cleaved from a molecule by breaking a heterolytic bond, with loss of an
electron pair. This group may thus be readily replaced with another group during a
substitution reaction, for example. Such leaving groups are, for example, halogens
or an activated hydroxyl group such as a methanesulfonate, benzenesulfonate, p-
toluenesulfonate, triflate, acetate, etc. Examples of leaving groups and references
for preparing them are given in "Advances in Organic Chemistry", J. March, 3rd
Edition, Wiley Interscience, pp. 310-316.
In accordance with the invention, the compounds of general formula (I) may
be prepared according to the following process illustrated by Scheme 1.

In a first step, a compound of general formula (II), in which PG1 represents
a protecting group such as a pivaloyl group and R represents a (C1-C4)alkyl group,
for example a methyl or an ethyl, may be coupled to a compound of general
formula (V), in which R1 is as defined in the general formula (I), PG2 is a protecting
group such as a benzoyl group and LG is an activating group such as a
trichloroacetimidate group -CNHCCI3, to obtain a compound of general formula
(VI).
The coupling reaction may be performed, for example, in the presence of a
Lewis acid, such as trimethylsilyl trifluoromethanesulfonate (TMSOTf), in a solvent
such as dichloromethane, at a temperature of between 0°C and 25°C.
In certain cases, the compound of general formula (V) may be protected
prior to the coupling reaction. For example, when R1 represents a tetrazolyl group,
it may be protected beforehand with a protecting group such as a 4-methoxybenzyl
group. After the coupling reaction, this protecting group may be cleaved off, for
example in the case of a tetrazolyl group bearing a 4-methoxybenzyl group, in the
presence of trifluoroacetic acid (TFA) at the reflux temperature.
The compound of general formula (II) may be prepared, for example,
according to the method described in Portoghese et al., J. Med. Chem. 1972, 15,
208-210.
The compound of general formula (V) may be obtained by activating the
hydroxyl function of the compound of general formula (IV), in which R1 and PG2
are as defined above. When the group LG is a leaving group such as a
trichloroacetimidate group -CNHCCl3, the reaction may be performed in the
presence of trichloroacetonitrile and a strong base such as 1,8-
diazabicyclo[5.4.0]undec-7-ene, in a solvent such as dichloromethane.
The compound of general formula (IV) may be obtained beforehand by
anomeric deprotection of the compound of general formula (III) in which R1 and
PG2 are as defined above. When PG2 represents a benzoyl group, deprotection of
the hydroxyl group may be performed in the presence of hydrazine hydrate
(NH2NH2, CH3COOH).
In a second step, the compound of general formula (VI) is reduced and
deprotected simultaneously, for example in the presence of lithium aluminium
hydride, in a solvent such as tetrahydrofuran, at the reflux temperature of the
reaction medium, and is then isolated in the presence of a mineral acid such as
hydrochloric acid. The compound of general formula (I) is thus obtained.
When R1 represents a 2-methyl-1,3,4-oxadiazol-5-yl group, the compound
of general formula (I) may be obtained from the corresponding compound of
general formula (I) for which R1 represents a tetrazolyl group, this group being
prepared according to the method illustrated in Scheme 2.

According to Scheme 2 and in a first step, morphin-6-yl 5-C-(tetrazol-5-yl)-ß-
D-xylopyranoside (1) can react with an acyl chloride or an acid anhydride, such as
acetic anhydride, according to a Huisgen thermal rearrangement, to give 3-O-
acetylmorphin-6-yl 2,3,4-tri-O-acetyl-5-C-(2-methyl-1,3,4-oxadiazol-5-yl)-ß-D-
xylopyranoside (2). In a second step, the hydroxyl groups are deprotected, for
example in the presence of sodium methoxide, to give morphin-6-yl 5-C-(2-methyl-
1,3,4-oxadiazol-5-yl)-ß-D-xylopyranoside (3).
In Schemes 1 and 2, the starting compounds and the reagents, when their
mode of preparation is not described, are commercially available or described in
the literature, or may be prepared according to methods that are described therein
or that are known to those skilled in the art.
Synthetic intermediates
According to another of its aspects, a subject of the invention is also the
compounds of general formulae (III), (IV) and (V). These compounds are useful as
intermediates for the synthesis of the compounds of general formula (I).
A subject of the invention is, more particularly, the compounds of formulae
(IlIa), (IIIb), (lllc), (IVb), (IVc), (Vb) and (Vc).
Compounds (lllb), (IVb) and (Vb) exist in the form of a mixture of the two
positional isomers of the para-methoxybenzyl (PMB) group.
The compounds of formulae (IIIa), (lllb), (IVb) and (Vb) may be obtained
according to the method described in Scheme 3.
In Scheme 3, the compound of formula (Ilia) protected, for example, with
benzoate groups may be obtained by protection, dehydration and then
tetrazolylation of D-glucuronamide. One tetrazolylation method consists in reacting
the nitrile function in refluxing toluene in the presence of trimethylsilyl azide
(TMSN3) and bis(tributyltin) oxide (Bu3Sn)2O. As regards the D-glucuronamide
protection reaction, an adaptation of the method described in Carbohydrate
Research 2006, 341, 1, 41-48 may be used.
The compound of formula (IIIb), consisting of a mixture of compounds (Illb1)
and (Illb2), may be obtained from the compound of formula (IIIa) via protection of
the amine, for example with a para-methoxybenzyl group.
Selective deprotection of the anomeric position of the compound of formula
(IIIb) makes it possible to obtain the compound of formula (IVb), consisting of a
mixture of compounds (IVb1) and (IVb2). In the case of a protecting group of
benzoate type, this deprotection may be performed in the presence of hydrazine
acetate.
The free hydroxyl function of the compound of formula (IVb) may be
converted into an imidate to generate the compound of formula (Vb), consisting of
a mixture of compounds (Vb1) and (Vb2). Transformation of the hydroxyl function
into an imidate function may be performed, for example, in the presence of
trichloroacetonitrile and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) according to an
adaptation of the method described in Tetrahedron 2000, 56, 7591-7594.
The compounds of formulae (lllc), (IVc) and (Vc) may be obtained
according to the method described in Scheme 4.

According to Scheme 4, the compound of formula (IIIa) described above
may undergo a Huisgen thermal rearrangement in the presence of an imidoyl
chloride, for example 2,2,2-trifluoro-N-(4-methoxybenzyl)acetimidoyl chloride, to
give the compound of formula (lllc).
Selective deprotection of the anomeric position of the compound of formula
(lllc) makes it possible to obtain the compound of formula (IVc). In the case of a
protecting group of benzoate type, this deprotection may be performed in the
presence of hydrazine hydrate.
The free hydroxyl function of the compound of formula (IVc) may be
converted into an imidate to generate the compound of formula (Vc). The
transformation of the hydroxyl function into an imidate function may be performed,
for example, in the presence of trichloroacetonitrile and DBU (1,8-
diazabicyclo[5.4.0]undec-7-ene) according to an adaptation of the method
described in Tetrahedron 2000, 56, 7591-7594.
The invention is illustrated in a non-limiting manner by the examples below.
The examples that follow describe the preparation of certain compounds in
accordance with the invention. These examples are not limiting, and serve merely
to illustrate the present invention. The numbers of the compounds presented as
examples refer to those given in the table hereinbelow, which illustrates the
chemical structures and the physical properties of a number of compounds
according to the invention.
EXAMPLES
Example 1: morphin-6-yl 5-C-(tetrazol-5-yI)-p-d-xylopyranoside
trifluoroacetate (compound 2)
1.1. 1,2,3,4-tetra-O-benzoyl-a/ß-D-glucurononitrile
To a suspension of D-glucuronamide (25.0 g, 0.129 mol) in pyridine (100
mL) at room temperature is added over 30 minutes a solution of benzoyl chloride
(102 mL, 0.878 mol) in dichloromethane (90 mL). The reaction medium is stirred
overnight at room temperature, and dichloromethane (200 mL) and water (200 mL)
are then added. The organic phase is washed with 1N hydrochloric acid solution
(200 mL), saturated sodium hydrogen carbonate solution (3 x 200 mL) and
saturated sodium chloride solution (200 ml_). The organic phase is dried over
sodium sulfate and the solvent is removed under reduced pressure. The residue
(yellow oil) is triturated in ethanol (200 ml_) to give a mixture of anomers (43.4 g,
57%) in the form of pale yellow crystals. The proton NMR spectrum in
deuteriochloroform, CDCI3, shows a ratio a:ßn of 2:1.
Melting point: 209-212°C.
1H NMR (400 MHz, CDCI3): ? 8.10-7.30 (m, 20Ha+20H(3, H-aro), 6.88 (d,
1Ha, J 3.5 Hz, H-1a), 6.57 (d, 1Hß, J 3.0 Hz, H-1a), 6.21 (t, 1 Ha, J 9.5 Hz, H-3a),
5.93 (t, 1Ha, J 9.5 Hz, H-4a), 5.84 (t, 1Hß, J 4.0 Hz, H-3ß), 5.71-5.65 (m,
1HaD1Hß, H-2aD H-4ß), 5.64 (m, 1Hß, H-2ß), 5.16 (d, 1Hß, J 4.0 Hz, H-5ß), 5.11
(d, 1Ha, J 9.5 Hz, H-5a).
13C NMR (100 MHz, CDCI3) D 165.5, 165.1, 164.8, 164.6, 164.3, 163.8
(C=O), 134.4-128.0 (C-aro), 115.3 (C-6ß), 114.1 (C-6a), 90.9 (C-1ß), 89.4 (C-1a),
69.3, 69.2, 69.0 (C-2a, C-3a, C-4a), 67.4 (C-4ß), 66.7, 66.5 (C-2ß, C-3ß), 61.9 (C-
5a), 60.8 (C-5ß).
Mass calculated for C34H25NO9Na [M+Na]+ 614.1427, found 614.1422.
1.2. 1,2,3,4-tetra-O-benzoyl-5-C-(tetrazol-5-yl)-a/ß-D-xylopyranose
To a solution of 1,2,3,4-tetra-O-benzoyl-a/ß-D-glucurononitrile prepared
beforehand (43.0 g, 72.8 mmol) in toluene (500 mL) are added bis(tributyltin) oxide
(3.70 mL, 7.26 mmol) and trimethylsilyl azide (28.7 mL, 216 mmol). The reaction
medium is stirred overnight at reflux. The solvent is removed under reduced
pressure and the residue is purified by chromatography on silica gel (1:1 to 0:1
cyclohexane/ethyl acetate) to give 1,2,3,4-tetra-O-benzoyl-5-C-(tetrazol-5-yl)-a/B-
D-xylopyranose (27.0 g, 59%) in the form of brown crystals. The proton NMR
spectrum in CDCI3 shows a ratio a:BDof 2:1.
Melting point 144-147°C.
1H NMR (400 MHz, CDCI3): D 8.19-7.28 (m, 20Ha+20Hß, H-aro), 7.06 (d,
1Ha, J 3.5 Hz, H-1a), 6.50-6.44 (m, 1Hß+1Ha, H-1ßDD H-3a), 6.21 (t, 1Hß, J 9.0
Hz, H-3B), 6.13-6.01 (m, 2HßD1Ha, H-4ß, H-4aD H-2ß), 5.90-5.85 (m, 2Ha, H-
2aDDH-5a), 5.66 (d, 1Hß, J 9.0 Hz, H-5ß).
13C NMR (100 MHz, CDCI3) ???????? 65.79, 165.2, 164.7 (C=O, C=N), 134.4-
128.1 (C-aro), 93.0 (C-1ß), 89.9 (C-1a), 72.0, 70.5, 70.Z, 70.3, 69.5 (C-2a, C-2B?
C-3a, C-3ß C-4a, C-4ß), 68.9 (C-5ß), 67.0 (C-5a).
Mass calculated for C34h26n4O9Na [M+Na]+ 657.1597, found 657.1595.
1.3. 1,2,3,4-tetra-O-benzoyl-5-C-[2-(4-methoxybenzyl)-2H-tetrazol-5-yl]-
a/ß-D-xylopyranose (Illb2) and 1,2,3,4-tetra-O-benzoyl-5-C-[1-(4-
methoxybenzyl)-1 H-tetrazol-5-yl]-a/ß -D-xylopyranose (lllb1)
To a solution of 1,2,3,4-tetra-O-benzoyl-5-C-(tetrazol-5-yl)-a/ß-D-
xylopyranose (21.0 g, 33.12 mmol) in tetrahydrofuran (210 mL) are added
triethylamine (5.5 mL, 39.46 mmol) and 4-methoxybenzyl chloride (5.0 mL, 36.71
mmol). The reaction medium is stirred overnight at reflux. The solvent is removed
under reduced pressure and the residue purified by chromatography on silica gel
(4:1 cyclohexane/ethyl acetate) to give a mixture of isomers (18.5 g, 73%) in the
form of pale yellow crystals. The proton NMR spectrum in CDCI3 shows a ratio
(Mlb1 ):(lllb2) of 2:1 with for (lllb1) a ratio a/ß of 2:1 and for (Illb2) a ratio a/B of 2:1.
1H NMR (400 MHz, CDCI3) for the two a anomers: ? 8.21-7.29 (m,
20Ha+20Hb, H-aro), 7.23 (d, 2Hb, J 8.5 Hz, H-aroPMeb), 7.17 (d, 2Ha, J 8.5 Hz,
H-aroPMBa), 6.98 (d, 1 Ha, J 3.5 Hz, H-1a), 6.96 (d, 1Hß, J 3.5 Hz, H-1b), 6.86 (d,
2Hb, J 8.5 Hz, H-aroPMeb), 6.75 (d, 2Ha, J 8.5 Hz, H-aroPMBa), 6.42 (t, 1Ha, J
10.0 Hz, H-3a), 6.33 (t, 1Hß, J 10.0 Hz, H-3b), 6.13 (t, 1Ha, J 10.0 Hz, H-4a), 5.84
(dd, 1Ha, J 3.5 Hz, J 10.0 Hz, H-2a), 5.76-5.63 (m, 3Ha+5Hb, CH2PhOCH3a,
CH2PhOCH3b, H-5a, H-2b, H-4b, H-5b), 3.79 (s, 3Hb, OCH3b), 3.75 (s, 3Ha,
OCH3a).
13C NMR (100 MHz, CDCI3) for the two a anomers: ? 165.8, 165.2, 164.5,
164.3, 164.2, 162.1 (C=O, C=N), 134.4-124.7 (C-aro), 114.5 (C-aroPMBa), 114.3
(C-aroPMBb), 90.0 (C-1a), 89.7 (C-1b), 71.1 (C-4a), 70.4, 70.2, (C-2a, C-3a), 69.9,
69.6, 69.5 (C-2b, C-3b, C-4b), 67.0 (C-5a), 66.0 (C-5b), 56.7 (CH2PhOCH3a), 55.3
(OCH3b), 55.2 (OCH3a), 52.1 (CH2PhOCH3b).
Mass calculated for C42H34N4O10Na [M+Na]+ 777.2173, found 777.2181.
1.4. 2,3,4-tri-O-benzoyl-5-C-[2-(4-(methoxybenzyl)-2H-tetrazol-5-yl]-a/ß-
D-xylopyranose (IVb2) and 2,3,4-tri-O-benzoyl-5-C-[1-(4-(methoxybenzyl)-1H-
tetrazol-5-yl]-a/ß-D-xylopyranose (IVb1))
To a solution of the mixture obtained in step 1.3 (13.4 g, 17.77 mmol) in
N,N-dimethylformamide (100 mL) at 0°C is added hydrazine acetate (2.45 g, 26.60
mmol) portionwise over 15 minutes. The reaction medium is stirred for 1 hour at
0°C and then for 4 hours at room temperature. The solvent is removed under
reduced pressure and the residue purified by chromatography on silica gel (7:3
cyclohexane/ethyl acetate) to give a mixture of isomers of the expected product
(8.0 g, 70%) in the form of yellow crystals. The proton NMR spectrum in CDCI3
shows a ratio (IVb2):(IVb1) of 2:1 with for (IVb2) a ratio a/0 of 5:1 and for (IVb1) a
ratio a/ß of 5:1.
1H NMR (400 MHz, CDCI3) for the two a anomers: ? 8.14-7.15 (m,
17Ha+17Hb, H-aro), 6.96 (d, 2Ha, J 9.0 Hz, H-aroPMBa), 6.71 (d, 2Hb, J 9.0 Hz,
H-aroPMBb), 6.36-6.26 (m, 1Ha+1Hb, H-3a, H-3b), 6.02 (t, 1Ha, J 10.0 Hz, H-4a),
5.88 (d, 1Ha, J 3.5 Hz, H-1a), 5.86 (d, 1Hß, J 3.5 Hz, H-1b), 5.85-5.74 (m,
1Ha+3Hb, H-5a, H-5b, CH2PhOCH3b), 5.63 (s, 2Ha, CH2PhOCH3a), 5.51-5.42 (m,
1Ha+1Hb, H-4b, H-2a), 5.31 (dd, 1Hß, J 3.5 Hz, J 10.0 Hz, H-2b), 3.82 (s, 3Hb,
OCH3b), 3.75 (s, 3Ha, OCH3a).
13C NMR (100 MHz, CDCI3) for the two a anomers: D165.8, 165.5, 164.7,
162.9, 150.5 (C=O, C=N), 133.7-124.8 (C-aro), 114.5 (C-aroPMBb), 114.2 (C-
aroPMBa), 90.9 (C-1a), 90.8 (C-1b), 72.1 (C-2a), 71.8 (C-2b or C-3b or C-4b),
71.2 (C-4a), 70.2 (C-2b or C-3b or C-4b), 70.0 (C-3a), 69.3 (C-2b or C-3b or C-4b),
64.1 (C-5a), 63.4 (C-5b), 56.7 (CH2PhOCH3a), 55.4 (OCH3b), 55.2 (OCH3a), 52.0
Mass calculated for C35H31N4O9 [M+H]+ 651.2091, found 651.2111.
1.5. 2,3,4-tri-O-benzoyl-5-C-[2-(4-(methoxybenzyl)-2H-tetrazol-5-yl]-a-D-
xylopyranosyl trichloroacetimidate (Vb2) and 2,3,4-tri-O-benzoyl-5-C-[1-(4-
methoxybenzyl)-1H-tetrazol-5-yl]-a-D-xylopyranosyl trichloroacetimidate
(Vb1)
To a solution of the mixture obtained in step 1.4 (6.0 g, 9.23 mmol) in
dichloromethane (170 mL) at room temperature are added 1,8-diazabicyclo[5.4.0]
undec-7-ene (278 µL, 1.86 mmol) and then trichloroacetonitrile (14.6 ml, 184
mmol). The reaction medium is stirred for 1 hour at room temperature. A solution
of acetic acid (105 uL, 1.83 mmol) in water (50 mL) is added. The phases are
separated, the organic phase is washed with water (50 mL) and then dried over
sodium sulfate. The solvent is removed under reduced pressure and the residue
purified by chromatography on silica gel (silica neutralized beforehand by washing
with a 5% solution of triethylamine in ethyl acetate (7:3 cyclohexane/ethyl acetate),
to give a mixture of isomers of the expected product (4.7 g, 65%) in the form of
yellow crystals. The proton NMR spectrum in CDCI3 shows a ratio (Vb2):(Vb1 )Dof
3:1.
1H NMR (400 MHz, CDCI3): ? 8.77 (s, 1H-b, NHb ), 8.69 (s, 1Ha, NHa),
8.20-7.29 (m, 15Ha+17Hb, H-aro), 7.18 (d, 2Ha, J 8.5 Hz, H-aroPMBa), 6.99 (d,
2Hb, J 8.5 Hz, H-aroPMBb), 6.94 (m, 1Ha+1Hb, H-1a, H-1b), 6.74 (d, 2Ha, J 8.5
Hz, H-aroPMBa), 6.36 (t, 1Ha, J 10.0 Hz, H-3a), 6.29 (t, 1Hß, J 10.0 Hz, H-3b),
6.10 (t, 1Ha, J 10.0 Hz, H-4a), 5.80-5.69 (m, 2Ha+3Hb, H-2a, CH2PhOCH3b, H-5a,
H-5b), 5.64 (s, 2Ha, CH2PhOCH3a), 5.62-5.55 (m, 2Hb, H-4b, H-2b), 3.84 (s, 3Hb,
OCH3b), 3.75 (s, 3Ha, OCH3a).
13C NMR (100 MHz, CDCI3): D 165.6, 165.4, 164.4, 162.0, 160.5, 159.9
(C=O, C=N), 134.0-124.8 (C-aro), 114.6 (C-aroPMBb), 114.3 (C-aroPMBa), 93.1
(C-1a), 92.8 (C-1b), 70.9 (C-2b or C-3b or C-4b), 70.7 (C-4a), 70.5 (C-2a), 70.0
(C-2b or C-3b or C-4b), 69.8 (C-3a), 69.3 (C-2b or C-3b or C-4b), 66.9 (C-5a), 66.0
(C-5b), 56.5 (CH2PhOCH3a), 55.3 (OCH3b), 55.1 (OCH3a), 51.8 (CH2PhOCH3b).
1.6. 3-O-pivaloyl-N-ethoxycarbonylnormorphin-6-yl 2,3,4-tri-O-
benzoyl-5-C-[2-(4-methoxybenzyl)-2H-tetrazol-5-yl]-ß-D-xylopyranoside
To a solution of the mixture obtained in step 1.5 (3.6 g, 4.54 mmol) and 3-O-
pivaloyl-N-ethoxycarbonylnormorphine (1.0 g, 2.34 mmol) in dichloromethane (50
mL) at 0°C under argon is added trimethylsilyl trifluoromethanesulfonate (1.7 mL,
9.38 mmol). The reaction medium is stirred for 30 minutes at 0°C and then for 30
minutes at room temperature. N-Diisopropylethylamine (1 mL) is added and the
mixture is stirred for 15 minutes and then concentrated to dryness under reduced
pressure. The residue is purified by chromatography on silica gel (3:2
cyclohexane/ethyl acetate) to give the expected compound (1.7 g, 69%) in the
form of white crystals.
Melting point 185-188°C.
1H NMR (400 MHz, CDCI3): ? 7.97-7.28 (m, 15H, H-aro), 7.17 (m, 2H, H-
aroPMB), 6.72 (m, 3H, H-aroPMB, H-1), 6.54 (d, 1H, J 8.5 Hz, H-2), 6.13 (t, 1H, J
10.0 Hz, H-4'), 5.90 (t, 1H, J 10.0 Hz, H-3'), 5.72 (m, 1H, H-8), 5.67 (m, 1H, H-2'),
5.61 (d, 2H, J 5.0 Hz, CH2PhOCH3), 5.43 (d, 1H, J 7.0 Hz, H-1'), 5.32 (d, 1H, J
10.0 Hz, H-5'), 5.25 (m, 1H, H-7), 5.00-4.80 (m, 2H, H-9, H-5), 4.40 (m, 1H, H-6),
4.20 (m, 2H, OCH2CH3), 4.00 (m, 1H, H-16a), 3.74 (s, 3H, OCH3), 3.00 (m, 1H, H-
16b), 2.84-2.74 (m, 2H, H-10), 2.48 (m, 1H, H-14), 1.89 (m, 2H, H-15), 1.30 (m,
12H, C(CH3)3, OCH2CH3).
13C NMR (100 MHz, CDCI3): ? 176.4, 165.7, 165.1, 164.5, 159.9 (C=O,
C=N), 155.0, 150.5, 133.1, (C-aro), 130.7 (C-8), 129.8, 129.7, 129.6, 128.3, 128.2,
128.1, (C-aro), 127.4 (C-7), 122.2 (C-1), 119.3 (C-2), 114.3 (C-aroPMB), 99.4 (C-
1'), 89.9 (C-5), 72.9 (C-3', C-6), 72.5 (C-2'), 71.5 (C-4'), 68.7 (C-5'), 61.6
(OCH2CH3), 56.6 (CH2PhOCH3), 55.2 (OCH3), 50.2 (C-9), 44.3 (C-13), 39.8 (C-
14), 37.2 (C-16), 35.3 (C-15), 35.0 (C(CH3)3), 30.2 (C-10), 29.8 (C(CH3)3), 14.7
(OCH2CH3).
Mass calculated for C59H57N5O14Na [M+Na]+ 1082.3800, found 1082.3802.
1.7. 3-O-pivaloyl-N-ethoxycarbonylnormorphin-6-yl 2,3,4-tri-O-
benzoyl-5-C-(tetrazol-5-yl)-ß-?-xylopyranoside
A solution of the compound obtained in step 1.6 (1.6 g, 1.51 mmol) in
trifluoroacetic acid (4.5 mL, 60.6 mmol) is refluxed for 15 minutes. The reaction
medium is concentrated to dryness, and the residue is taken up in toluene (2x10
mL) and reconcentrated. The residue is purified by chromatography on silica gel
(1:2 cyclohexane/ethyl acetate) to give the expected compound (850 mg, 60%) in
the form of pale yellow crystals.
Melting point 169-171 °C.
1H NMR (400 MHz, CDCI3): ? 7.98-7.24 (m, 15H, H-aro), 6.76 (d, 1H, J 8.0
Hz, H-1), 6.58 (d, 1H, J 8.0 Hz, H-2), 6.01 (t, 1H, J 10.0 Hz, H-3'), 5.98-5.95 (m,
1H, H-8), 5.72 (m, 1H, H-4'), 5.62 (m, 1H, H-2'), 5.41 (d, 1H, J10.0 Hz, H-5'), 5.34-
5.26 (m, 2H, H-f and H-7), 5.02-4.96 (m, 1H, H-9), 4.85 (m, 1H, H-5), 4.38-4.31
(m, 1H, H-6), 4.22-4.13 (m, 2H, OCH2CH3), 4.07-3.98 (m, 1H, H-16a), 3.10-2.83
(m, 2H, H-16b, H-10a), 2.82-2.72 (m, 1H, H-10b), 2.47 (m, 1H, H-14), 1.93-1.85
(m, 2H, H-15), 1.47 (s, 9H, C(CH3)3), 1.33-1.25 (m, 3H, OCH2CH3).
13C NMR (100 MHz, CDCI3): ? 165.6, 165.1, 165.0 (C=O, C=N), 133.5,
132.4, 130.0, 129.8, 128.5, 128.4, 128.3 (C-aro, C-8, C-7), 122.5 (C-1), 119.9 (C-
2), 90.9 (C-1'), 77.0 (C-6), 72.0 (C-2' or C-3'), 71.9 (C-2' or C-3'), 70.7 (C-4'), 68.3
(C-5'), 61.8 (OCH2CH3), 49.7 (C-9), 44.5 (C-13), 40.0 (C-14), 37.1 (C-16), 35.5 (C-
15), 29.7 (C-10), 27.2 (C(CH3)3), 14.7 (OCH2CH3).
Mass calculated for C51H49N5O13Na [M+Na]+ 962.3225, found 962.3211.
1.8. morphin-6-yl 5-C-(tetrazol-5-yl)-ß-D-xylopyranoside
trifluoroacetate (compound 2)
To a suspension of lithium aluminium hydride (300 mg, 7.91 mmol) in
tetrahydrofuran (12 mL) is added a solution of the compound obtained in step 1.7
(500 mg, 0.532 mmol) in tetrahydrofuran (12 mL). The reaction medium is stirred
for 1 hour at reflux. Ethyl acetate is added to destroy the excess lithium aluminium
hydride and the medium is brought to pH 1 by adding 1N hydrochloric acid
solution. The reaction medium is concentrated to dryness. The residue is purified a
first time on a reverse-phase chromatography column (pure H2O and then 80:20
(H2O + 0.1% trifluoroacetic acid)/acetonitrile) to remove the salts. A second
purification by reverse-phase preparative chromatography (95:5 to 20:80 gradient
of (H2O+0.1% trifluoroacetic acid)/acetonitrile) gives the expected compound in the
form of white crystals (42 mg, 16%).
Melting point 204-207°C.
1H NMR (400 MHz, D2O): ? 6.74 (d, 1H, J 8.0 Hz, H-1), 6.65 (d, 1H, J 8.0
Hz, H-2), 5.73 (m, 1H, H-8), 5.30 (m, 1H, H-7), 5.23 (d, 1H, J 5.5 Hz, H-5), 4.94-
4.88 (m, 2H, H-1', H-5'), 4.48 (m, 1H, H-6), 4.15 (m, 1H, H-9), 3.80 (t, 1H, J 9.5 Hz,
H-4'), 3.69 (t, 1H, J 9.5 Hz, H-3'), 3.54 (m, 1H, H-2'), 3.37 (m, 1H, H-16a), 3.24 (m,
1H, H-10a), 3.10 (m, 1H, H-16b), 2.95 (s, 3H, NCH3), 2.95-2.83 (m, 2H, H-10b, H-
14), 2.32-2.02 (m,2H, H-15).
13C NMR (100 MHz, D2O): ? 145.5 (C=N), 137.8, 134.0 (C-ipso), 131.1 (C-
8), 129.0 (C-ipso), 126.0 (C-7), 123.3 (C-ipso), 120.4 (C-2), 117.7 (C-1), 102.3 (C-
1'), 88.1 (C-5), 75.0 (C-3'), 73.3 (C-6), 73.0 (C-2'), 72.4 (C-4'), 69.3 (C-5'), 60.5 (C-
9), 47.1 (C-16), 41.5 (C-13), 40.9 (NCH3), 38.4 (C-14), 32.4 (C-15), 20.8 (C-10).
Mass calculated for C23H28N5O7 [M+H]+ 486.1989, found 486.1982.
Example 2: morphin-6-yl 5-C-(2-methyl-1,3,4-oxadiazol-5-yl)-ß-D-
xylopyranoside trifluoroacetate (compound 5)
2.1. 3-O-acetylmorphin-6-yl 2,3,4-tri-O-acetyl-5-C-(2-methyl-1,3,4-
oxadiazol-5-yl)-ß-D-xylopyranoside
A solution of morphin-6-yl 5-C-(tetrazol-5-yl)-ß-D-xylopyranoside
trifluoroacetate (134 mg, 0.28 mmol), obtained in step 1.8 of Example 1, in acetic
anhydride (3 mL) is refluxed overnight. The reaction medium is concentrated to
dryness and the residue is taken up in toluene (2x10 mL) and reconcentrated.
The product is purified by chromatography on silica gel (98:2 to 95:5
chloroform/methanol) to give the expected compound (102 mg, 55%) in the form of
pale yellow crystals.
Melting point 180-186°C.
1H NMR (400 MHz, CDCI3): ? 6.77 (d, 1H, J 8.0 Hz, H-1),6.59(d, 1H, J 8.0
Hz, H-2), 5.71 (m, 1H, H-8), 5.37 (m, 2H, H-4' and H-3'), 5.27 (m, 1H, H-7), 5.18
(m, 1H, H-2'), 4.99 (d, 1H, J 7.5 Hz, H-1'), 4.95 (d, 1H, J 5.5 Hz, H-5), 4.87 (m, 1H,
H-5'), 4.31 (m, 1H, H-6), 3.71 (m, 1H, H-9), 3.07 (m, 1H, H-10a), 2.97-2.89 (m, 2H,
H-16a, H-14), 2.62-2.52 (m, 8H, H-10b, CH3oxadiazole, NCH3, H-16b), 2.33 (s,
CH3CO), 2.28 (m, 1H, H-15a), 2.14 (s, 3H, CH3CO), 2.04 (s, 3H, CH3CO), 1.98 (m,
1H, H-15b), 1.93 (s, 3H, CH3CO).
13C NMR (100 MHz, CDCI3): ? 175.9, 170.0, 169.4, 169.3, 165.3, 161.2
(C=O, C=N), 150.3, 132.0 (C-ipso), 130.9 (C-8), 130.6, 130.4 (C-ipso), 127.5 (C-
7), 122.6 (C-1), 119.5 (C-2), 100.0 (C-1'), 89.1 (C-5), 73.6 (C-6), 71.8 (C-3' or C-
4'), 71.0 (C-2'), 69.6 (C-3' or C-4'), 67.9 (C-5'), 58.5 (C-9), 46.0 (C-16), 42.7 (C-
13), 41.7 (NCH3), 38.9 (C-14), 33.8 (C-15), 21.5 (C-10), 20.7, 20.6, 20.4 (CH3CO),
11.0(CH3oxadiazole).
Mass calculated for C33H38N3O12 [M+H]+ 668.2455, found 668.2560.
2.2. morphin-6-yl 5-C-(2-methyl-1,3,4-oxadiazol-5-yl)-p-D-
xylopyranoside trifluoroacetate (compound 5)
To a solution of 3-O-acetylmorphin-6-yl 2,3,4-tri-O-acetyl-5-C-(2-methyl-
1,3,4-oxadiazol-5-yl)-(3-D-xylopyranoside prepared beforehand (100 mg, 0.15
mmol) in methanol (2 mL) at room temperature is added sodium methoxide (32
mg, 0.59 mmol). The reaction medium is stirred for 3 hours at room temperature
and then neutralized by addition of resin sold under the name Amberlyte H+®
(Rohm & Haas). The solution is filtered and the filtrate concentrated under reduced
pressure. The residue is purified by reverse-phase preparative chromatography
(95:5 to 20:80 gradient of (H2O + 0.1% trifluoroacetic acid)/acetonitrile) to give the
expected product (34 mg, 46%) in the form of white crystals.
Melting point 215-218°C.
1H NMR (300 MHz, D2O): ? 6.83 (d, 1H, J 8.0 Hz, H-1), 6.74 (d, 1H, J 8.0
Hz, H-2), 5.84 (m, 1H, H-8), 5.46 (m, 1H, H-7), 5.32 (d, 1H, J 6.5 Hz, H-5), 5.00 (d,
1H, J 8.0 Hz, H-1'), 4.90 (m, 1H, H-5'), 4.59 (m, 1H, H-6), 4.26 (m, 1H, H-9), 3.92
(t, 1H, J 9.5 Hz, H-4'), 3.74 (t, 1H, J 9.5 Hz, H-3'), 3.59 (m, 1H, H-2'), 3.45-3.38 (m,
1H, H-16a), 3.29 (d, 1H, H-10a), 3.17 (m, 1H, H-16b), 3.03-2.92 (m, 5H, NCH3, H-
10b, H-14), 2.63 (s, 3H, CHsOxadiazole), 2.40-2.11 (m, 2H, H-15).
13C NMR (75 MHz, D2O): ? 131.2 (C-8), 126.3 (C-7), 120.6 (C-2), 118.2 (C-
1), 102.5 (C-1'), 88.2 (C-5), 75.0 (C-3'), 73.5 (C-6), 73.0 (C-2' or C-4'), 71.4 (C-2'
or C-4'), 69.3 (C-5'), 60.7 (C-9), 47.4 (C-6), 41.1 (HCH3), 38.7 (C-14), 32.6 (C-15),
21.1 (C-10), 10.2 (CH3oxadiazole).
Mass calculated for C25H30N3O8 [M+H]+ 500.2033, found 500.2021.
Example 3: morphin-6-yl 5-C-[5-(4-methoxyphenyl)-4-(2,2,2-trifluoro-
ethyl)-4H-1,2,4-triazol-3-yl]-ß-D-xylopyranoside trifluoroacetate (compound 6)
3.1. 1,2,3,4-tetra-O-benzoyl-5-C-[5-(4-methoxyphenyl)-4-(2,2,2-trifluoro-
ethyl)-4H-1,2,4-triazol-3-yl]-a/ß-D-xylopyranose
To a solution of 1,2,3,4-tetra-O-benzoyl-5-C-(tetrazol-5-yl)-a/ß-D-
xylopyranose (10.0 g, 15.77 mmol), obtained in step 1.2 of Example 1, in toluene
(119 mL) are added triethylamine (4.3 mL, 30.85 mmol) and 2,2,2-trifluoro-N-(4-
methoxybenzyl)acetimidoyl chloride (7.9 g, 31.47 mmol). The reaction medium is
stirred overnight at reflux. The solvent is removed under reduced pressure and the
residue purified by chromatography on silica gel (1:1 cyclohexane/ethyl acetate) to
give the expected product (7.3 g, 56%) in the form of pale yellow crystals. The
proton NMR spectrum in CDCI3 shows a ratio a:B of 5:2.
1H NMR (400 MHz, CDCI3): ? 8.28-7.29 (m, 22Ha+22Hß, H-aro), 7.00 (d,
2Ha, J 8.5 Hz, H-aroPMPa), 6.94 (d, 2Hß, J 8.5 Hz, H-aroPMPß), 6.84 (d, 1Ha, J
3.5 Hz, H-1a), 6.54 (t, 1Hß, J 8.5 Hz, H-4ß), 6.45 (m, 2Ha, H-3a, H-4a), 6.38 (d,
1Hß, J 7.0 Hz, H-1B), 6.18 (t, 1Hß, J 8.5 Hz, H-3ß), 5.94 (dd, 1Hß, J 7.0 Hz, J 8.5
Hz, H-2ß), 5.76-5.69 (m, 2Ha, H-2a, H-5a), 5.61 (d, 1Hß, J 8.5 Hz, H-5ß), 5.13 (m,
1Hß??CH2CF3ß?), 4.99 (m, 1Ha??CH2CF3a), 4.65-4.51 (m,
1Ha+1Hß??CH2CF3a, CH2CF3ß?), 3.84 (s, 3Ha, OCH3a), 3.83 (s, 3Hß, OCH3ß).
13C NMR: (100 MHz, CDCI3) ? 166.0, 165.4, 165.2, 164.7 (C=O), 161.5,
156.8, 149.5 (C=N, C-ipsoPMP), 134.4-128.2 (C-aro), 117.5 (C-ipsoPMP), 114.6
(C-aroPMPa), 114.5 (C-aroPMPß), 93.2 (C-1ß), 90.1 (C-1a), 71.9 (C-2ß or C-3ß or
C-4ß), 70.3 (C-2a or C-2a or C-4a), 70.2 (C-2a or C-2a or C-4a), 70.0 (C-2ß or C-
3ß or C-4ß), 69.2 (C-2a or C-2a or C-4a), 69.1 (C-2ß or C-3ß or C-4ß), 66.1 (C-
5a??, C-5ß), 55.4 (OCH3a, OCH3ß), 45.4 (CH2CF3ß), 45.0 (CH2CF3a).
Mass calculated for C44H35F3N3O10 [M+H]+ 822.2275, found 822.2291.
3.2. 2,3,4-tri-O-benzoyl-5-C-[5-(4-methoxyphenyl)-4-(2,2,2-
trifluoroethyl)-4H-1,2,4-triazol-3-yl]-a/ß-D-xylopyranose
To a solution of the compound prepared in step 3.1 (7.2 g, 8.77 mmol) in
N,N-dimethylformamide (50 mL), at 0°C, is added hydrazine acetate (1.2 g, 13.0
mmol) portionwise over 15 minutes. The reaction medium is stirred for 1 hour at
0°C and then for 2.5 hours at room temperature. Ethyl acetate (100 mL) and water
(50 mL) are added. The phases are separated. The aqueous phase is re-extracted
with ethyl acetate (1 x 50 mL). The combined organic phases are dried over
sodium sulfate. The solvent is removed under reduced pressure and the residue
purified by chromatography on silica gel (2:3 cyclohexane/ethyl acetate) to give the
expected product (3.1 g, 49%) in the form of white crystals. The proton NMR
spectrum in CDCI3 shows a ratio a/ß of 9:1.
1H NMR (400 MHz, CDCI3) for the a anomer???7.99-7.26 (m, 17H, H-aro),
6.76 (d, 2H, J 9.0 Hz, H-aroPMP), 6.24 (t, 1H, J 10.0 Hz, H-3), 6.14 (t, 1H, J 10.0
Hz, H-4), 5.80 (d, 1H, J 10.0 Hz, H-5), 5.45 (d, 1H, J 3.0 Hz, H-1), 5.31 (m, 1H,
CH2CF3), 5.07 (dd, 1H, J 3.0 Hz, J 10.0 Hz, H-2), 4.92 (m, 1H, CH2CF3), 3.72 (s,
3H, OCH3).
13C NMR (100 MHz, CDCI3) for the a anomer: D 165.8, 165.5, 165.1 (C=O)
161.3, 156.5, 151.3 (C=N, C-ipsoPMP), 133.2-128.2 (C-aro), 122.9 (C-ipso) 117.6
(C-ipsoPMP), 114.4 (C-aroPMP), 90.2 (C-1), 72.1 (C-2), 70.8 (C-3), 69.6 (C-4),
62.1 (C-5), 55.2 (OCH3), 45.3 (m, CH2CF3).
Mass calculated for C37H31F3N3O9 [M+H]+ 718.2012, found 718.2034.
3.3. 2,3,4-tri-O-benzoyl-5-C-[5-(4-methoxyphenyl)-4-(2,2,2-
trifluoroethyl)-4H-1,2,4-triazol-3-yl]-a/ß-D-xylopyranosyl trichloroacetimidate
To a solution of the product prepared in step 3.2 (2.8 g, 3.91 mmol) in
dichloromethane (65 mL) at room temperature are added 1,8-
diazabicyclo[5.4.0]undec-7-ene (115 µL, 0.770 mmol) and then trichloroacetonitrile
(7.8 ml, 77.8 mmol). The reaction medium is stirred for 1 hour at room
temperature. A solution of acetic acid (45 µL, 0.786 mmol) in water (25 mL) is
added. The phases are separated, the organic phase is washed with water (25
mL) and then dried over sodium sulfate. The solvent is removed under reduced
pressure and the residue purified by chromatography on silica gel (silica
neutralized beforehand by washing with a 5% solution of triethylamine in ethyl
acetate) (7:3 cyclohexane/ethyl acetate) to give the expected product (2.1 g, 63%)
in the form of white crystals. The proton NMR spectrum in CDCI3 shows a ratio a/(3
of 5:4.
1H NMR (400 MHz, CDCI3): ? 8.78 (s, 1Hß, NHß), 8.77 (s, 1Ha, NHa), 8.00-
7.31 (m, 17Ha+17Hß, H-aro), 7.00 (m, 2Ha+2Hß, H-aroPMPa, H-aroPMPß), 6.78
(d, 1Ha, J 3.5 Hz, H-1a), 6.51 (t, 1Ha, J 10.0 Hz, H-4a), 6.44-6.34 (m, 1Ha+1Hß,
H-3a, H-4ß), 6.21 (d, 1Hß, J 8.0 Hz, H-1ß), 6.13 (t, 1Hß, J 9.5 Hz, H-3ß), 5.92 (dd,
1HB, J 8.0 Hz, J 9.5 Hz, H-2B), 5.69 (d, 1Ha, J 10.0 Hz, H-5a), 5.62 (dd, 1Ha, J
3.5 Hz, J 10.0 Hz, H-2a), 5.52 (d, 1H0, J 9.5 Hz, H-5B), 5.27 (m, 1H(3, CH2CF3ß),
5.00 (m, 1Ha, CH2CF3??a), 4.58 (m, 1H???a+1H???ß, CH2CF3???a??CH2CF3ß), 3.87 (s,
3Ha+3Hß, OCH3a, OCH3ß).
13C NMR (100 MHz, CDCI3) ? 165.7, 165.4, 164.7, 164.4, (C=O) 161.4,
149.2 (C=N, C-ipsoPMP), 133.7-128.2 (C-aro), 117.7 (C-ipsoPMP), 114.5 (C-
aroPMP), 96.6 (C-1(3), 93.5 (C-1a), 72.5, 70.5, 70.2, 70.0, 69.3, 68.9 (C-2a, C-3B,
C-3a, C-3ß??C-4a, C-4ß)?? 66.2 (C-5a, C-5ß), 55.4 (OCH3a, OCH3ß), 45.1 (m,
CH2CF3a, CH2CF3ß).
3.4. 3-O-pivaloyl-N-ethoxycarbonylnormorphin-6-yl 2,3,4-tri-O-benzoyl-
5-C-[5-(4-methoxyphenyl)-4-(2,2,2-trifluoroethyl)-4H-1,2,4-triazol-3-yl]-ß-D-
xylopyranoside
To a solution of the product prepared in step 3.3 (1.20 g, 1.40 mmol) and 3-
O-pivaloyl-N-ethoxycarbonylnormorphine (410 mg, 0.96 mmol) in dichloromethane
(50 mL) at 0°C under argon is added trimethylsilyl trifluoromethanesulfonate (696
µL, 3.84 mmol). The reaction medium is stirred for 30 minutes at 0°C and then for
30 minutes at room temperature. N-Diisopropylethylamine (0.5 mL) is added and
the mixture is stirred for 15 minutes and then concentrated to dryness under
reduced pressure. The residue is purified by chromatography on silica gel (3:7
cyclohexane/ethyl acetate) to give the expected compound (680 mg, 63%) in the
form of orange crystals.
Melting point 194°C.
1H NMR (400 MHz, CDCI3) ? 7.98-7.29 (m, 17H, H-aro), 7.03 (d, 2H, J 9.0
Hz, H-aroPMP), 6.71 (d, 1H, J 8.0 Hz, H-1), 6.54 (d, 1H, J 8.0 Hz, H-2), 6.00 (m,
2H, H-3', H-4'), 5.73 (m, 1H, H-8), 5.66 (m, 1H, H-2'), 5.41 (m, 2H, H-1', H-5'), 5.30
(m, 1H, H-7), 4.98 (m, 2H, H-9, CH2CF3), 4.86-4.76 (m, 2H, H-5, CH2CF3), 4.30
(m, 1H, H-6), 4.17 (m, 2H, OCH2CH3), 4.01 (m, 1H, H-16a), 3.89 (s, 3H, OCH3),
3.07-2.84 (m, 2H, H-16b, H-10a), 2.75 (m, 1H, H-10b), 2.47 (m, 1H, H-14), 1.88
(m, 2H, H-15), 1.27 (m, 12H, C(CH3)3, OCH2CH3).
13C NMR (100 MHz, CDCI3) ? 165.6, 165.1, 165.0, (C=O) 161.4, 156.9,
149.6 (C=N, C-ipsoPMP), 133.4 (C-aro), 130.7 (C-8), 129.9-127.8 (C-aro, C-7),
122.5 (C-1), 118.0 (C-ipsoPMP), 119.4 (C-2), 114.6 (C-aroPMP), 100.6 (C-1'),
90.2 (C-5), 74.0 (C-6), 72.3 (C-2' or C-3' or C-4'), 71.8 (C-2' or C-3' or C-4'), 70.3
(C-2', C-3' or C-4'), 69.9 (C-5'), 61.7 (OCH2CH3), 55.4 (OCH3), 48.1 (C-9), 44.5
(CH2CF3 or C-13), 39.8 (C-14), 37.2 (C-16), 35.3 (C-15), 35.0 (C(CH3)3), 30.0 (C-
10), 27.1 (C(CH3)3), 14.7 (OCH2CH3).
Mass calculated for C61H58F3N4O14 [M+H]+ 1127.3902, found 1127.3889.
3.5. morphin-6-yl 5-C-[5-(4-methoxyphenyl)-4-(2,2,2-trifluoroethyl)-4H-
1,2,4-triazol-3-yl]-ß-D-xylopyranoside trifluoroacetate (compound 6)
To a suspension of lithium aluminium hydride (311 mg, 8.19 mmol) in
tetrahydrofuran (13 mL) is added a solution of the compound obtained in step 3.4
(622 mg, 0.55 mmol) in tetrahydrofuran (13 mL). The reaction medium is stirred for
1 hour at reflux. Ethyl acetate is added to destroy the excess UAIH4 and the
medium is brought to pH 1 by adding 1N hydrochloric acid solution. The reaction
medium is concentrated to dryness. The residue is purified by passing twice
successively through a reverse-phase chromatography column (pure H2O then
80:20 (H2O + 0.1% trifluoroacetic acid)/CH3CN) to remove the salts. A final
purification by preparative reverse-phase chromatography (95:5 to 20:80 gradient
(H2O + 0.1% trifluoroacetic acid)/acetonitrile) gives the expected compound in the
form of white crystals (35 mg, 10%).
Melting point 274-276°C.
1H NMR (400 MHz, D2O): ? 7.51 (d, 2H, J 8.5 Hz, H-aroPMP), 7.15 (d, 2H,
J 8.5 Hz, H-aroPMP), 6.72 (d, 1H, J 8.0 Hz, H-1), 6.64 (d, 1H, J 8.0 Hz, H-2), 5.67
(m, 1H, H-8), 5.29 (m, 1H, H-7), 5.22 (d, 1H, J 6.0 Hz, H-5), 5.09-4.90 (m, 3H,
CH2CF3, H-1'), 4.82 (d, 1H, J 9.5 Hz, H-5'), 4.41 (m, 1H, H-6), 4.18 (m, 1H, H-9),
4.12 (t, 1H, J 9.5 Hz, H-4'), 3.88 (s, 3H, OCH3), 3.71 (t, 1H, J 9.5 Hz, H-3'), 3.57
(dd, 1H, J 8.0 Hz, J 9.5 Hz, H-2'), 3.36 (m, 1H, H-16a) 3.26 (m, 1H, H-10a), 3.12-
3.03 (m, 1H, H-16b), 2.96 (s, 3H, N-CH3), 2.93-2.84 (m, 2H, H-10b, H-14), 2.31-
2.22 (m, 2H, H-15).
13C NMR (100 MHz, D2O): ??130.9 (C-aroPMP), 126.0 (C-7), 120.4 (C-2),
117.7 (C-1), 116.8 (C-ipsoPMP), 114.7 (C-aroPMP), 102.6 (C-1'), 88.1 (C-5), 75.0
(C-3'), 73.6 (C-6), 72.8 (C-2'), 72.0 (C-4'), 67.9 (C-5'), 60.5 (C-9), 55.4 (OCH3),
47.2 (C-16), 46.6 (CH2CF3), 40.9 (NCH3), 38.4 (C-14), 32.4 (C-15), 20.8 (C-10).
Mass calculated for C33H36F3N4O8 [M+H]+ 673.2485, found 673.2482.
Example 4: morphin-6-yl 5-C-(tetrazol-5-yl)-a?ß-D-xylopyranoside
trifluoroacetate (compound 1)
4.1 3-O-pivaloyl-N-ethoxycarbonylnormorphin-6-yl?2,3,4-tri-O-
benzoyl-5-C-(tetrazol-5-yl)-a/ß-D-xylopyranoside
A solution of 3-O-pivaloyl-N-ethoxycarbonylnormorphin-6-yl 2,3,4-tri-O-
benzoyl-5-C-[2-(4-methoxybenzyl)-2H-tetrazol-5-yl]-B-D-xylopyranoside (1.6 g,
1.51 mmol), obtained in step 1.6 of Example 1, in trifluoroacetic acid (4.5 mL, 60.6
mmol) is refluxed for 45 minutes. The reaction medium is concentrated to dryness
and the residue is taken up in toluene (2 x 10 mL) and concentrated again.
Filtration on silica gel (ethyl acetate) allows the apolar impurities to be removed.
The residue (1.3 g) is used in the reduction step without further purification.
4.2 morphin-6-yl 5-C-(tetrazol-5-yl)-aß-D-xylopyranoside
trifluoroacetate (compound 1)
Morphin-6-yl 5-C-(tetrazol-5-yl)-a/ß-D-xylopyranoside trifluoroacetate is
synthesized from 3-O-pivaloyl-N-ethoxycarbonylnormorphin-6-yl?2,3,4-tri-O-
benzoyl-5-C-(tetrazol-5-yl)-a/ß-D-xylopyranoside obtained previously (1.30 g, 1.38
mmol) according to the same procedure as that described in step 1.8 of Example
1.
The expected mixture of anomers is obtained in the form of pale yellow
crystals (215 mg, 32%). The proton NMR spectrum in D2O shows a ratio a:B of
1:1.
1H NMR (400 MHz, D2O): ? 6.83-6.79 (m, 1Ha+1Hß, H-1a, H-1ß), 6.70 (m,
1Ha+1Hß, H-2a, H-2B???), 5.91 ?(m, 1Ha??, H-8a), 5.82 (m, 1Hß, H-8ß), 5.60
(d, 1Ha, J 10.0Hz, H-5'a), 5.48 (m, 1Ha, H-7a???), 5.39 (m, 1Hß, H-7ß), 5.31 (d,
1Ha, J 4.0 Hz, H-1'a), 5.28 (d, 1Hß, J6.0 Hz, H-5ß), 5.13 (d, 1Ha, J6.0 Hz, H-5a),
5.01-4.96 (m, 2HB, H-5'ß, H-1'ß), 4.55 (m, 1Hß, H-6ß), 4.43 (m, 1Ha??H-6a),
4.26-4.17 (m, 1Ha+1Hß, H-9a, H-9ß), 3.99 (t, 1 Ha, J 9.5 Hz, H-3'a), 3.82 (dd, 1Ha,
J 4.0 Hz, J 9.5 Hz, H-2'a), 3.78-3.74 (m, 1Ha+2Hß, H-4', H-3'ß, DDH-4'ß), 3.59
(m, 1Hß, H-2'ß), 3.41-3.38 (m, 1Ha+1Hß, H-16aa, H-16aaß), 3.33-3.27 (m,
1Ha+1Hß, H-10aa, H-10aß), 3.17-3.08 (m, 1Ha+1Hß, H-16ba, H-16bß), 3.00 (s,
3Ha+3Hp, NCH3a, NCH3ß), 3.00-2.88 (m, 2Ha+2Hß, H-10ba, H-10bß, ??H-14a,
H-14ß), 2.37-2.07 (m, 2Ha+2Hß, H-15a, H-15ß).
13C NMR (100 MHz, D2O): ???136.5 (C-ipso), 131.2 (C-8a), 130.4 (C-8ß),
129.0 (C-ipso), 126.5 (C-7a), 126.1 (C-7ß), 123.3 (C-ipso), 120.5 (C-2a, C-2ß),
117.8 (C-1a, C-1ß), 102.5 (C-1'ß), 100.0 (C-1'a), 90.1 (C-5a), 88.2 (C-5ß), 74.9,
74.7, 73.6, 72.9, 72.5, 72.4, 72.3, 71.1 (C-2'a??, C-2'ß??, C-3'a,C-3'??, C-4'a,
C-4'ß, C-6a??, C-6ß), 68.9 (C-5'ß), 65.6 (C-5'a), 60.5 (C-9a, C-9ß), 47.2 (C-16a,
C-16ß), 41.5 (C-13a, C-13ß), 40.9 (NCH3a NCH3ß), 38.7 (C-14a), 38.4 (C-14ß),
32.4 (C-15a, C-15ß), 20.9 (C-10a, C-10ß ).
Mass calculated for C23H28N5O7 [M+H]+ 486.1989, found 486.1979.
Example 5: morphin-6-yl 5-C-(2-methyl-1,3,4-oxadiazol-5-yl)-a-D-
xylopyranoside trifluoroacetate (compound 4)
5.1 3-O-acetylmorphin-6-yl 2,3,4-tri-O-acetyl-5-C-(2-methyl-1,3,4-
oxadiazol-5-yl)-a-D-xylopyranoside trifluoroacetate and 3-O-acetylmorphin-6-
yl 2,3,4-tri-O-acetyl-5-C-(2-methyl-1,3,4-oxadiazol-5-yl)-a/ß -xylopyranoside
trifluoroacetate
A solution of morphin-6-yl 5-C-(tetrazol-5-yl)-a/ß-D-xylopyranoside
trifluoroacetate (300 mg, 0.62 mmol), obtained in step 4.2 of Example 4, in acetic
anhydride (7 mL) is refluxed overnight. The reaction medium is concentrated to
dryness and the residue is taken up in toluene (2 x 10 mL) and concentrated
again. The product is purified on a column of silica (from 98:2 to 95:5 CHCI3-
CH3OH) to give two fractions:
- one containing the pure a anomer (45 mg)
- the other containing a mixture of the a and p anomers (92 mg). The proton
NMR spectrum in CDCI3 shows a ratio a/p of 2:3 estimated by NMR and by HPLC.
The overall reaction yield is 33%.
1H NMR (400 MHz, CDCI3) for the a anomer: ? 6.82 (d, 1H, J 8.0 Hz, H-1),
6.61 (d, 1H, J 8.0 Hz, H-2), 5.74 (m, 1H, H-8), 5.69 (t, 1H, J10.0 Hz, H-3'), 5.63 (d,
1H, J 10.0 Hz, H-5'), 5.40 (d, 1H, J 4.0 Hz, H-1'), 5.37-5.30 (m, 2H, H-4', H-7),
5.01-4.96 (m, 2H, H-2', H-5), 4.14 (m, 1H, H-6), 3.60 (m, 1H, H-9), 3.10 (m, 1H, H-
10a), 2.80 (m, 1H, H-16a), 2.70-2.50 (m, 9H, CH3oxadiazole, NCH3, H-10b, H-14,
H-16b), 2.34 (s, 3H, CH3CO), 2.31-2.25 (m, 1H, H-15a), 2.08 (s, 3H, CH3CO), 2.05
(s, 3H, CH3CO), 2.00 (m, 1H, H-15b), 1.95 (s, 3H, CH3CO).
13C NMR (100 MHz, CDCI3) for the a anomer: ? 170.2, 169.2, 168.6, 164.9,
162.2 (C=O, C=N), 122.7 (C-1), 119.4 (C-2), 97.6 (C-1'), 91.4 (C-5), 76.7 (C-6),
70.6 (C-2'), 70.0 (C-4'), 69.2 (C-3'), 64.2 (C-5'), 59.2 (C-9), 46.4 (C-16), 42.5
(NCH3), 33.5 (C-15), 21.3 (C-10), 20.7, 20.6, 20.5 (CH3CO), 11.0 (CH3-
oxadiazole).
Mass calculated for C33H38N3O12 [M+H]+ 668.2455, found 668.2560.
5.2 morphin-6-yl 5-C-(2-methyl-1,3,4-oxadiazol-5-yl)-a-D-
xylopyranoside trifluoroacetate (compound 4)
To a solution of 3-O-acetylmorphin-6-yl 2,3,4-tri-O-acetyl-5-C-(2-methyl-
1,3,4-oxadiazol-5-yl)-a-D-xylopyranoside trifluoroacetate (45 mg, 0.07mmol) in
methanol (0.5 mL), at room temperature is added sodium methoxide (14 mg, 0.26
mmol). The reaction medium is stirred for 3 hours at room temperature and then
neutralized by adding Amberlyte H+® resin (Rohm & Haas). The solution is filtered
and the filtrate concentrated under reduced pressure to give morphin-6-yl 5-C-(2-
methyl-1,3,4-oxadiazol-5-yl)-a-D-xylopyranoside trifluoroacetate (31 mg, 92%) in
the form of pale yellow crystals.
1H NMR (400 MHz, CD3OD) for the a anomer: ? 8.54 (s, 1H, PhOH), 6.57
(d, 1H, J 8.0 Hz, H-1), 6.46 (d, 1H, J 8.0 Hz, H-2), 5.86 (m, 1H, H-8), 5.49 (d, 1H, J
10.0 Hz, H-5'), 5.39 (m, 1H, H-7), 5.13 (d, 1H, J 4.0 Hz, H-1'), 4.95 (d, 1H, J 6.0
Hz, H-5), 4.24 (m, 1H, H-6), 3.84 (t, 1H, J 9.5 Hz, H-3'), 3.75 (dd, 1H, J 9.5 Hz, J
10.0 Hz, H-4'), 3.60-3.55 (m, 2H, H-9, H-2'), 3.08 (m, 1H, H-10a), 2.76-2.70 (m,
2H, H-14, H-16a), 2.59 (s, 3H, NCH3), 2.56 (s, 3H, CH3oxadiazole), 2.55-2.45 (m,
2H, H-10b, H-16b), 2.12 (m, 1H, H-15a), 1.84 (m, 1H, H-15b).
13C NMR (100 MHz, CD3OD) for the a anomer: n 166.4, 166.3 (C=N),
147.6, 140.0 {C-ipso), 131.6 (C-8), 130.9 (C-ipso), 129.1 (C-7), 125.5 (C-ipso),
120.6 (C-2), 118.2 (C-1), 102.1 (C-1'), 92.1 (C-5), 78.0 (C-6), 74.7 (C-3'), 73.4 (C-
2'), 73.3 (C-4'), 67.6 (C-5'), 60.9 (C-9), 47.7 (C-13), 44.6 (C-16), 42.5 (NCH3), 40.7
(C-14), 35.4 (C-10), 22.3 (C-15), 10.8 (CH3oxadiazole).
Mass calculated for C25H30N3O8 [M+H]+ 500.2033, found: 500.2029 (a).
Example 6: morphin-6-yl 5-C-(2-methyl-1,3,4-oxadiazol-5-yl)-a/ß-D-
xylopyranoside trifluoroacetate (compound 3)
The same protocol as that described in step 5.2 of Example 5 is used
starting with the 3-O-acetylmorphin-6-yl 2,3,4-tri-O-acetyl-5-C-(2-methyl-1,3,4-
oxadiazol-5-yl)-a/B-D-xylopyranoside (2:3 a:B) mixture (92 mg, 0.14 mmol)
obtained in step 5.1 of Example 5. The expected mixture of anomers is obtained in
the form of pale yellow crystals (62 mg, 90%). The proton NMR spectrum in CDCI3
shows a ratio a/B of 2:3 estimated by NMR and by HPLC.
Mass calculated for C25H30N3O8 [M+H]+ 500.2033, found: 500.2585 (a:ß
2:3).
The table that follows illustrates the chemical structures and the physical
properties of a few examples of compounds according to the invention. In this
table:
- in the "anomer" column, "a" and "ß" represent, respectively, the pure a and
B anomers and "a/ß" represents a mixture thereof, the ratio in parentheses being
the ratio (a:ß);
- the "mass" column gives the result of the mass of the compound obtained
according to the chemical ionization method;
- the "melting point" column indicates the melting point value of the
compound in degrees Celsius;
- the "aD" column indicates the optical rotation of the compound in degrees;
the solvent and the measuring concentration are given in parentheses ; and
- in the "salt" column, "CF3COO-" represents a compound in trifluoroacetate
form.
Biological activity
The compounds according to the invention underwent pharmacological
trials to determine their analgesic effect.
Tests consisting in measuring the in vivo activity of the compounds of the
invention on a nociceptive reflex response were performed. In this approach, the
latency of the animal's nociceptive reflex response is measured as a pain
indicator.
"Tail-Flick" test
Procedure
The analgesic activity was determined by means of the "tail-flick" test in
male Swiss mice (Iffa Credo). This test is based on the spontaneous nociceptive
reflex of removal of the animal's tail caused by a painful heat stimulus (infrared
source). The "tail-flick" test (D'Amour-Smith test, 1941, Pharmacol. Exp. Ther.; 72:
74-79) consists, after administering a product, in placing a mouse's tail at the focal
point of the infrared source so as to produce a nociceptive heat stimulus (surface
temperature of about 55-60°C). The mouse's reaction time (RT) (latency between
the moment when the light beam is switched on and the moment when the mouse
removes its tail) was measured in duplicate at different times ranging from 20
minutes to 120 minutes after administration of the product. The heat intensity is
regulated such that this removal reflex is between 0.5 and 3.5 seconds in the
control animals, and arbitrarily represents the criterion for minimum analgesia
(0%). Two reaction time measurements were taken before administration of the
product for each mouse, to establish a baseline measurement time. A maximum
time of 8 seconds was chosen as the maximum reaction time so as not to induce
tissue damage by burning the animals, and arbitrarily represents the criterion for
maximum analgesia (100%). The reaction time is increased by the analgesics
relative to a control animal not receiving any treatment. The products were
administered subcutaneously and orally at doses of between 1.25 and 30 mg/kg
(expressed as salt).
Results
The results obtained for the compounds of the invention are given in Table
2, which presents the following data:
- the maximum percentage of analgesic activity (% MPE max index)
obtained for each compound (at a test dose),
- the ED50 (expressed in mg/kg) corresponding to the effective dose for
each compound for which 50% analgesia was obtained ; this is calculated at a
given time after administration of the compounds ; and
- the duration of the analgesic action at a given dose.
The percentage of analgesic activity (% MPE) is determined by the following
formula:
% MPE = (RTpost-administration - RTpre-administration)*100/(RTmax -
RTpre-administration)
The results indicate that the compounds according to the invention have
powerful analgesic activities (>50%) for doses of between 1.25 mg/kg and 10
mg/kg if they are administered subcutaneously (measured 60 minutes post-
administration) and for doses of between at least 2.5 and 30 mg/kg if they are
administered orally (measured 60 minutes post-administration).
These analgesic activities are persistent and long-lasting, for more than
120 minutes after their administration as a single dose.
Among the most active compounds whose activity was evaluated orally, by
way of example, compound 5 shows a percentage of maximum analgesic activity
(% MPE max index) of 78 for a dose of 10 mg/kg and an ED50 at 60 minutes of
less than 2.5 mg/kg.
It is thus seen that the compounds according to the invention have
analgesic activity.
The compounds according to the invention may thus be used for the
preparation of medicaments, in particular medicaments intended for treating or
preventing pain.
Thus, according to another of its aspects, a subject of the invention is
medicaments comprising a compound of formula (I), or an addition salt thereof
with a pharmaceutically acceptable acid, or alternatively a hydrate or a solvate.
These medicaments find their therapeutic use especially in the treatment
and prevention of acute or chronic pain, especially peripheral pain or pain
associated with inflammatory diseases such as arthritis, rheumatoid arthritis,
osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease and irritable bowel
syndrome, neuropathic, muscular, bone, post-operative or migraine-related pain,
lumbar pain, and cancer-related, diabetes-related or AIDS-related pain.
The compounds according to the invention also find their use in the
treatment of sexual dysfunctions and in particular in the treatment of male
premature ejaculation, for which the activity of a compound of antalgic type has
been shown.
According to another of its aspects, the present invention relates to
pharmaceutical compositions comprising, as active principle, a compound
according to the invention. These pharmaceutical compositions contain an
effective dose of at least one compound according to the invention, or a
pharmaceutically acceptable salt, a hydrate or a solvate of the said compound,
and also at least one pharmaceutically acceptable excipient.
The said excipients are chosen, according to the pharmaceutical form and
the desired mode of administration, from the usual excipients known to those
skilled in the art.
In the pharmaceutical compositions of the present invention for oral,
sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal,
intranasal, transdermal, rectal or intraocular administration, the active principle of
formula (I) above, or the possible salt, solvate or hydrate thereof, may be
administered in a unit administration form, as a mixture with standard
pharmaceutical excipients, to man and animals for the treatment of the above
disorders or diseases.
The appropriate unit forms of administration include oral forms such as
tablets, soft or hard gel capsules, powders, granules and oral solutions or
suspensions, sublingual, buccal, intratracheal, intraocular, intranasal and
inhalation administration forms, topical, transdermal, subcutaneous, intramuscular
or intravenous administration forms, rectal administration forms and implants. For
topical application, the compounds according to the invention may be used in
creams, gels, ointments or lotions.
By way of example, a unit administration form of a compound according to
the invention in tablet form may comprise the following components:
According to another of its aspects, the present invention also relates to a
method for treating the pathologies indicated above, which comprises the
administration to a patient of an effective dose of a compound according to the
invention, or a pharmaceutically acceptable salt or hydrate or solvate thereof.
CLAIMS
1. Compound of general formula (I)

in which:
R1 is a 5-membered aromatic heterocyclic group optionally substituted with
one or more substituents chosen from halogen atoms and groups (C1-C4)alkyl,
halogen, hydroxyl, oxo, halo(C1-C4)alkyl, halo(C1-C4)alkyloxy, (C1-C4)alkyloxy,
aryl(C1-C4)alkyl and aryl, the said aryl group being optionally substituted with one
or more groups chosen from the groups (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxyl
and (C1-C4)alkyloxy,
in the form of base or of an acid-addition salt, and also in the form of a
hydrate or a solvate.
2. Compound of general formula (I) according to Claim 1, characterized in
that the said compound has one or more of the following characteristics:
- the aromatic heterocyclic group is chosen from pyrrole, furan, thiophene,
imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, thiazole, isothiazole
and thiadiazole groups, and
- when the aromatic heterocyclic group is substituted with one or more
groups, the said group is chosen from methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,
dichloromethyl, trichloromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, chloroethyl,
dichloroethyl, trichloroethyl, methoxyphenyl, ethoxyphenyl, propoxyphenyl and
butyloxyphenyl groups.
3. Compound of general formula (I) according to Claim 1, characterized in
that:
- the said aromatic heterocyclic group is chosen from tetrazole, triazole and
oxadiazole groups, and
- when the said aromatic heterocyclic group is substituted with one or more
groups, the said group is chosen from methyl, trifluoroethyl and p-methoxyphenyl
groups.
4. Compound of general formula (I) according to any one of the preceding
claims, characterized in that it is chosen from:
- morphin-6-yl 5-C-(tetrazol-5-yl)-a/ß-D-xylopyranoside (1/1)
- morphin-6-yl 5-C-(tetrazol-5-yl)-ß-D-xylopyranoside
- morphin-6-yl 5-C-(2-methyl-1,3,4-oxadiazol-5-yl)- a/ß-D-xylopyranoside
(2/3)
- morphin-6-yl 5-C-(2-methyl-1,3,4-oxadiazol-5-yl)- a -D-xylopyranoside
- morphin-6-yl 5-C-(2-methyl-1,3,4-oxadiazol-5-yl)-ß-D-xylopyranoside and
- morphin-6-yl 5-C-[5-(4-methoxyphenyl)-4-(2,2,2-trifluoroethyl)-4H-1,2,4-
triazol-3-yl]-ß-D-xylopyranoside.
5. Medicament, characterized in that it comprises a compound of general
formula (I) according to any one of Claims 1 to 4, or an addition salt of this
compound with a pharmaceutically acceptable acid, or a hydrate or solvate of the
compound of formula (I).
6. Pharmaceutical composition, characterized in that it comprises a
compound of general formula (I) according to any one of Claims 1 to 4, or a
pharmaceutically acceptable solvent, hydrate or solvate of this compound, and
also at least one pharmaceutically acceptable excipient.
7. Use of a compound of general formula (I) according to any one of
Claims 1 to 4, for the preparation of a medicament for treating or preventing pain.
8. Compound of general formula (III)

in which:
- R1 is as defined in Claim 1, and
- PG2 represents a benzoyl group.
9. Compound of general formula (III) according to Claim 8, characterized
in that R1 is chosen from tetrazole, 1,2,3,4-tetra-O-benzoyl-5-C-2-(4-
methoxybenzyl)-2H-tetrazole, 1,2,3,4-tetra-O-benzoyl-5-C-1 -(4-methoxybenzyl)-
1 H-tetrazole and 5-(4-methoxyphenyl)-4-(2,2,2-trifluoroethyl)-1,2,4-triazole groups.
10. Compound of general formula (IV)

in which:
- R1 is as defined in Claim 1, and
- PG2 represents a benzoyl group.
11. Compound of general formula (IV) according to Claim 10, characterized
in that R1 is chosen from 1,2,3,4-tetra-O-benzoyl-5-C-2-(4-methoxybenzyl)-2H-
tetrazole, 1,2,3,4-tetra-O-benzoyl-5-C-1-(4-methoxybenzyl)-1 H-tetrazole and 5-(4-
methoxyphenyl)-4-(2,2,2-trifluoroethyl)-1,2,4-triazole groups.
12. Compound of general formula (V)
in which:
- R1 is as defined in Claim 1,
- PG2 represents a benzoyl group, and
- LG represents a trichloroacetamidate group.
13. Compound of general formula (V) according to Claim 12, characterizec
in that R1 is chosen from 1,2,3,4-tetra-O-benzoyi-5-C-2-(4-methoxybenzyl)-2H-
tetrazole, 1,2,3,4-tetra-O-benzoyl-5-C-1-(4-methoxybenzyl)-1H-tetrazole and 5-(4-
methoxyphenyl)-4-(2,2,2-trifluoroethyl)-1,2,4-triazole groups.

The invention relates to derivatives of morphine-6-glucuronide having formula (I) wherein R1 is a 5-membered
heteroaromatic group optionally substituted by one or more substituents selected from among halogen atoms and (C1-C4)alkyl,
halogen, hydroxyl, halo(C1-C4)a]kyl, halo(C1-C4)alkyloxy, (C1-C4)alkyloxy, aryl(C1-C4)alkyl and aryl groups, said aryl group being
optionally substituted by one or more groups selected from among (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxyl and (C1-C4)alkyloxy
groups, in the form of a base or acid addition salt, as well as in hydrate or solvate form. The invention also relates to the
preparation method thereof and to the use of same in therapeutics.