BICYCLIC DERIVATIVES OF MORPHINE-6-GLUCURONIDE,
PREPARATION METHOD THEREOF AND USE OF SAME IN
THERAPEUTICS
FIELD OF THE INVENTION
The present invention relates to bicyclic morphine-6-giucuronide
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 represents a hydrogen atom or a group (C1-C4)alkyl,
R2 represents a hydroxyl group, a thiol group, a group (C1-C4)alkyloxy or a
group thio(C1-C4)alkyl, and
n is an integer equal to 1 or 2,
in the form of base or of acid-addition salt, and also in the form of hydrate
or solvate.
The compounds of formula (I) may comprise an asymmetric carbon.
They may thus exist in the form of two enantiomers. These enantiomers,
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 also a
mixture thereof, form part of the invention.
The compounds of formula (I) 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 group (C1-C4)alkyl: 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 hydroxyl group: a group -OH;
- a thiol group: a group -SH;
- 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; and
- a group thio(C1-C4)alkyl: a group -S-(C1-C4)alkyl in which the
group (C1-C4)alkyl is as defined previously; examples that may be
mentioned include thiomethyl, thioethyl, thiopropyl and thiobutyl groups.
Among the compounds of formula (I) according to the invention, a
first group of compounds has one or more of the following characteristics:
- R1 is a hydrogen atom,
- R2 is a hydroxyl group, and
- n is equal to 2.
Among the compounds of formula (I) according to the invention,
mention may be made in particular of the following compound:
- morphin-6-yl 5-C-(5-hydroxy-4,5,6,7-tetrahydro[1,2,4]triazolo[1,5-
a]pyrimidin-2-yl)-ß-D-xylopyranoside.
PREPARATION PROCESS
In the text hereinbelow, the term "leaving group" means a group that
can, firstly, protect a reactive function such as a hydroxyl or an amine
during a synthesis and, secondly, regenerate 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 al., 2nd Edition (John Wiley & Sons, Inc., New York).
In the text hereinbelow, the term "leaving group" means a group that
may 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, 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.
Reaction Scheme 1 below illustrates the reaction for the particular
example of morphin-6-yl 5-C-(5-hydroxy-4,5,6,7-
tetrahydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-ß-D-xylopyranoside.
Reaction scheme 1
In a first step, compound (7), bearing a protecting group in position 3
of the morphine ring, for example a pivaloyl group, and bearing an ethyl
carboxylate group in position 17, may be coupled with compound (6)
protected beforehand, for example with a benzoyl group, and whose
hydroxyl function on the anomeric carbon is activated, for example with a
trichioroacetimidate group -CNHCCI3, to give compound (8).
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 and 25°C.
Compound (7) may be prepared, for example, according to the
method described in Portoghese et al., J. Med. Chem. 1972, 15, 208-210.
Compound (6) may be obtained via activation of the hydroxyl
function of compound (5). When the activating group is a
trichioroacetimidate group -CNHCCI3, 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.
Compound (5) may be obtained beforehand via anomeric
deprotection of compound (4). For example, when the protecting group is a
benzoyl group, deprotection of the hydroxyl group may be performed in the
presence of hydrazine acetate (NH2NH2CH3COOH).
In a second step, compound (8) is reduced and simultaneously
deprotected, for example in the presence of lithium aluminium hydride, in a
solvent such as tetrahydrofuran, at the reflux temperature of the reaction
medium, and then isolated in the presence of a mineral acid such as
hydrochloric acid. Compound (9) is thus obtained, which is an example of a
compound of general formula (I).
The invention is illustrated in a non-limiting manner by the examples
below.
EXAMPLE
1.1. 1,2,3,4-tetra-O-benzoyl-a/p-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 then
dichloromethane (200 mL) and water (200 mL) are 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, CDCl3, shows an a/B ratio of 2/1.
Melting point: 209-212°C.
1H NMR (400 MHz, CDCI3): d 8.10-7.30 (m, 20Ha+20H ß, H-aro), 6.88 (d,
1Ha, J 3.5 Hz, H-1a), 6.57 (d, 1H ß, J 3.0 Hz, H-1 ß), 6.21 (t, 1Ha, J 9.5
Hz, H-3a), 5.93 (t, 1Ha, J 9.5 Hz, H-4a), 5.84 (t, 1H ß, J 4.0 Hz, H-3 ß),
5.71-5.65 (m, 1Ha+1H ß, H-2a , H-4 ß), 5.64 (m, 1H ß, H-2 ß), 5.16 (d, 1H
ß, J 4.0 Hz, H-5 ß), 5.11 (d, 1 Ha, J 9.5 Hz, H-5).
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-6 ß), 114.1 (C-6a), 90.9 (C-1 ß), 89.4
(C-1a), 69.3, 69.2, 69.0 (C-2 a, C-3 a, C-4 a), 67.4 (C-4 B), 66.7, 66.5 (C-2
ß, C-3 ß), 61.9 (C-5 a), 60.8 (C-5 ß).
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/B-D-xylopyranose

To a solution of 1,2,3,4-tetra-O-benzoyl-a/ß-D-glucurononitrile prepared
previously (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/ß-D-xylopyranose (27.0 g, 59%) in the form of
brown crystals. The proton NMR spectrum in CDCI3 shows an a/B ratio of
2/1.
Melting point 144-147°C.
1H NMR (400 MHz, CDCI3): d 8.19-7.28 (m, 20Ha+20H ß, H-aro), 7.06 (d,
1 Ha, J 3.5 Hz, H-1a), 6.50-6.44 (m, 1H ß +1Ha, H-1 ß. H-3a), 6.21 (t, 1H ß,
J 9.0 Hz, H-3 ß), 6.13-6.01 (m, 2H ß +1Ha, H-4 ß, H-4a H-2 ß), 5.90-5.85
(m, 2Ha, H-2a, H-5a), 5.66 (d, 1H ß, J 9.0 Hz, H-5 ß).
13C NMR (100 MHz, CDCI3): d 165.79, 165.2, 164.7 (C=O, C=N), 134.4-
128.1 (C-aro), 93.0 (C-1 ß), 89.9 (C-1a), 72.0, 70.5, 70.4, 70.3, 69.5 (C-2a,
C-2 ß, C-3a, C-3 ß, C-4a, C-4 ß), 68.9 (C-5 ß), 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-([1,2,4]triazolo[4,3-a]pyrimidin-3-yl)-
a/ß-D-xylopyranose (4a)
1,2,3,4-tetra-O-benzoyl-5-C-([1,2,4]triazolo[1,5-a]pyrimidin-3-yl)-a/ß-D-
xylopyranose (4b)

A solution of 1,2,3,4-tetra-O-benzoyl-5-C-(tetrazol-5-yl)-a/ß-D-xylopyranose
(2) (3.0 g, 4.73 mmol) and 2-chloropyrimidine (813 mg, 7.10 mmol) in
pyridine (38 mL) is maintained at reflux with stirring overnight.
The solvent is removed under reduced pressure and the residue is purified
by chromatography on silica gel (3/7 cyclohexane/ethyl acetate) to give a
mixture of the isomers 1,2,3,4-tetra-O-benzoyl-5-C-([1,2,4]triazolo[4,3-
a]pyrimidin-3-yl)-a/ß-D-xylopyranose (4a) (1.8 g) and 1,2,3,4-tetra-O-
benzoyl-5-C-([1,2,4]triazolo[4,3-a]pyrimidin-3-yl)-a/ß-D-xylopyranose (4b)
(0.6 g) in the form of pale yellow crystals. The proton NMR spectrum in
CDCI3 shows an a:ß ratio of 2/1 for the isomer 1,2,3,4-tetra-O-benzoyl-5-C-
([1,2,4]triazolo[4,3-a]pyrimidin-3-yl)-a/ß-D-xylopyranose (4a) and 7/3 for
1,2,3,4-tetra-O-benzoyl-5-C-([1,2,4]triazolo[1,5-a]pyrimidin-3-yl)-a/ß-D-
xylopyranose (4b).
The overall reaction yield is 74%.
Analyses for 1,2,3,4-tetra-O-benzovl-5-C-([1,2,4]triazolo[4,3-a]pyrimidin-3-
yl)-a/ß-D-xylopyranose 4a
Rf = 0.55 (1/4 cyclohexane/ethyl acetate)
Melting point: 175-179°C
1H NMR (400 MHz, CDCI3): d 8.93 (m, 1Ha, H-5'a or H-7'a), 8.87 (m, 1Hß,
H-5'ß or H-7'ß), 8.73 (m, 1Ha, H-5'a or H-7'a), 8.64 (m, 1Hß, H-5'ß or H-
7'ß), 8.22-7.25 (m, 20Ha+20Hß, H-aro), 7.04 (d, 1Ha, J 3.5 Hz, H-1a), 7.00
(dd, 1Ha, J 4.0 Hz, J 7.0 Hz, H-6'a), 6.93 (dd, 1Hß, J 3.5 Hz, J 6.5 Hz, H-
6'ß), 6.57 (t, 1Ha, J 9.5 Hz, H-3a), 6.52 (d, 1Hß, J 7.5 Hz, H-1ß), 6.29 (m,
2Hß, H-3ß, H-4ß), 6.11-6.01 (m, 2Ha+1Hß, H-4a, H-5a, H-2ß), 5.93 (dd,
1 Ha, J 3.5 Hz, J 10.0 Hz, H-2a), 5.90-5.86 (m, 1Hß, H-5ß).
13C NMR (100 MHz, CDCI3): d 165.5, 165.2, 165.1, (C=O), 164.6 (C-3'ß),
164.4 (C-3'a), 155.1 (C-8a'a, C-8a'ß), 154.2 (C-5'a or C-7'a), 154.0 (C-5'ß
or C-7'ß), 140.3 (C-5'ß or C-7'ß), 140.1 (C-5'a or C-7'a), 134.4, 134.2,
133.8, 133.7, 133.5, 132.5, 132.4, 130.2-128.3 (C-aro), 110.4 (C-6'a, C-
6'ß), 93.0 (C-1ß), 89.7 (C-1a), 71.5 (C-2ß or C-3ß or C-4ß or C-5ß), 70.6
(C-2ß or C-3ß or C-4ß or C-5ß), 70.4 (C-2a), 70.0 (C-2ß or C-3ß or C-4ß or
C-5ß), 69.5 (C-3a or C-4a), 69.1 (C-3a or C-4a), 68.7 (C-5ß).
Mass calculated for C38H29N4O9 [M+H]+: 685.1935, found 685.1953
Analyses for 1,2,3,4-tetra-O-benzoyl-5-C-([1,2,4]triazolo[1,5-a]pyrimidin-3-
yl)-a/ß-D-xylopyranose 4b
Rf = 0.65 (1/4 cyclohexane/ethyl acetate)
Melting point: 188-190°C
1H NMR (400 MHz, CDCI3): d 8.80-8.71 (m, 2Ha + 2Hß, H-5'a, H-7'a, H-
5'ß, H-7'ß), 8.22-7.30 (m, 20Ha + 20Hß, H-aro), 7.10 (dd, 1Ha, J 6.5 Hz, J
4.5 Hz, H-6'a), 7.07-7.02 (m, 1Ha + 1Hß, H-6'ß, H-1a), 6.47 (m, 1Ha +
1Hß, H-1ß + H-3a), 6.27-6.16 (m, 1Ha + 2Hß, H-4a, H-3ß, H-4ß), 6.06 (m,
1Hß, H-2ß), 5.89 (dd, 1Ha, J 3.5 Hz, J 10.0 Hz, H-2a), 5.73 (d, 1Ha, J 10.0
Hz, H-5a), 5.53 (d, 1Hß, J 9.0 Hz, H-5ß).
13C NMR (100 MHz, CDCI3): d 165.8, 165.6, 165.3, 165.0, 164.8, 164.5,
164.2 (C=O), 164.0 (C-2'a), 163.8 (C-2'ß), 155.3 (C-3a'a, C-3a'ß), 155.1
(C-7'a), 155.0 (C-7'ß), 136.0 (C-5'a, C-5'ß), 134.0, 133.7, 133.4-133.2,
130.2-128.2 (C-aro), 110.7 (C-6'a), 110.6 (C-6'ß), 92.9 (C-1ß), 90.0 (C-1a),
72.5 (C-3ß or C-4ß or C-5ß), 72.0 (C-3ß or C-4ß or C-5ß), 71.3 (C-4a), 70.6
(C-3a), 70.3 (C-2a), 69.4 (C-5a).
Mass calculated for C38H29N4O9 [M+H]+: 685.2524, found: 685.1953
1.4. 2,3,4-tri-O-benzoyl-5-C-([1,2,4]triazoIo[1,5-a]pyrimidin-2-yl)-a/ß-
D-xylopyranose (5b)

To a solution of the compound 1,2,3,4-tetra-O-benzoyl-5-C-
([1,2,4]triazolo[4,3-a]pyrimidin-3-yl)-a/ß-D-xylopyranose (4a) or 1,2,3,4-
tetra-O-benzoyl-5-C-([1,2,4]triazolo[1,5-a]pyrimidin-3-yl)-a/ß-D-
xylopyranose (4b) (500 mg, 0.73 mmol) in N,N-dimethylformamide (19 mL)
at 0°C is added hydrazine acetate (101 mg, 1.10 mmol) portionwise over
10 minutes. The reaction medium is stirred for 1 hour at 0°C and then for 2
hours at room temperature.
The solvent is removed under reduced pressure and the residue is purified
by chromatography on silica gel (1/4 cyclohexane/ethyl acetate) to give
2,3,4-tri-O-benzoyl-5-C-([1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-a/ß-D-
xylopyranose 5 (284 mg, 67%) in the form of white crystals. The proton
NMR spectrum in CDCI3 shows an a:ß ratio of 4/1.
Rf = 0.30 (1/4 cyclohexane/ethyl acetate)
Melting point: 133-135°C
1H NMR (400 MHz, CDCI3) for the a anomer: d 8.77 (dd, 1H, J 2.0 Hz, J
7.0 Hz, H-5' or H-7'), 8.69 (m, 1H, H-5' or H-7'), 8.02-7.27 (m, 15H, H-aro),
7.04 (m, 1H, H-6'), 6.43 (t, 1H, J10.0 Hz, H-3), 6.11 (t, 1H, J10.0 Hz, H-4),
5.95 (d, 1H, J 3.5 Hz, H-1), 5.88 (d, 1H, J10.0 Hz, H-5), 5.49 (dd, 1H, J 3.5
Hz, J 10.0 Hz, H-2).
13C NMR (100 MHz, CDCI3) for the a anomer: d 165.8, 165.7, 165.0 (C=O),
164.9 (C-2'), 155.2 (C-3a'), 155.1 (C-7'), 136.1 (C-5'), 133.2-132.9, 129:3-
128.2 (C-aro), 110.8 (C-6'), 90.8 (C-1), 72.2 (C-2), 71.7 (C-4), 70.5 (C-3),
66.3 (C-5).
Mass calculated for C31H25N4O8 [M+H]+: 581.1672; found 581.1661
1.5. 2,3,4-tri-O-benzoyl-5-C-([1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-a-D-
xylopyranosyl trichloroacetimidate (6)

To a solution of 2,3,4-tri-O-benzoyl-5-C-([1,2,4]triazolo[1,5-a]pyrimidin-2-
yl)-a/ß-D-xylopyranose 5 (650 mg, 1.12 mmol) in dichloromethane (15 mL)
at room temperature are added 1,8-diazobicyclo[5.4.0]undec-7-ene
(186 uL, 1.24 mmol) and then trichloroacetonitrile (2.2 ml, 21.94 mmol).
The reaction medium is stirred for 1.5 hours at room temperature. A
solution of acetic acid (70 uL, 1.22 mmol) in water (7 mL) is added. The
phases are separated, and the organic phase is washed with water (7 mL)
and then dried over sodium sulfate.
The solvent is removed under reduced pressure and the residue is purified
by chromatography on silica gel (silica neutralized beforehand by washing
with a 5% solution of triethylamine in ethyl acetate) (1/1 cyclohexane/ethyl
acetate) to give 2,3,4-tri-O-benzoyl-5-C-([1,2,4]triazolo[1,5-a]pyrimidin-2-
yl)-a-D-xylopyranosyl trichloroacetimidate (6) (565 mg, 70%) in the form of
yellow crystals.
Rf = 0.35 (2/3 cyclohexane/ethyl acetate)
Melting point: 72-73°C
[a]25D= 117.2 (c = 0.1, CDCl3)
1H NMR (400 MHz, CDCI3): d 8.81-8.76 (m, 2H, H-5', H-7'), 8.69 (s, 1H,
NH), 8.00-7.29 (m, 15H, H-aro), 7.11 (dd, 1H, J 4.0 Hz, J 7.0 Hz, H-6'),
7.00 (d, 1H, J 3.5 Hz, H-1), 6.43 (t, 1H, J 10.0 Hz, H-3), 6.20 (t, 1H, J
10.0 Hz, H-4), 5.81 (dd, 1H, J 3.5 Hz, J 10.0 Hz, H-2), 5.71 (d, 1H, J 10.0
Hz, H-5).
13C NMR (100 MHz, CDCI3): d 165.6, 165.3, 164.7 (C=O), 164.0 (C-2'),
160.4 (C=N), 155.4 (C-3a'), 155.1 (C-7'), 135.9 (C-5'), 133.5-133.2, 129.9-
128.2 (C-aro), 110.7 (C-6'), 93.3 (C-1), 71.1 (C-4), 70.6 (C-2), 70.1 (C-3),
69.4 (C-5).
1.6. 3-O-pivaloyl-N-ethoxycarbonylnormorphin-6-yl 2,3,4-tri-O-
benzoyl-5-C-([1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-ß-D-xylopyranoside
(8)

To a solution of 2,3,4-tri-O-benzoyl-5-C-([1,2,4]triazolo[1,5-a]pyrimidin-2-
yl)-D-D-xylopyranosyl trichloroacetimidate (6) (1.5 g, 2.07 mmol) and 3-O-
pivaloyl-N-ethoxycarbonylnormorphine (7) (738 mg, 1.73 mmol) in
dichloromethane (24 mL) cooled to 0°C is added trimethylsilyl
trifluoromethanesulfonate (1.2 mL, 6.61 mmol).
The reaction medium is stirred for 30 minutes at 0°C and then for 1 hour at
room temperature.
Hunig's base (1.1 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 (1/4 cyclohexane/ethyl acetate) to
give the compound 3-O-pivaloyl-N-ethoxycarbonylnormorphin-6-yl 2,3,4-tri-
O-benzoyl-5-C-([1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-ß-D-xylopyranoside (8)
(470 mg, 31%) in the form of yellow crystals.
Rf = 0.45 (1/4 cyclohexane/ethyl acetate)
Melting point: 171.5°C
[a]25D = -65.3 (c = 0.5, CDCI3)
1H NMR (400 MHz, CDCI3): d 8.80 (dd, 1H, J 2.0 Hz, 4.0 Hz, H-5" or H-7"),
8.75 (dd, 1H, J 2.0 Hz, 7.0 Hz, H-5" or H-7"), 8.02-7.29 (m, 15H, H-aro),
7.10 (dd, 1H, J 4.0 Hz, J 7.0 Hz, H-6"), 6.71 (d, 1H, J 8.0 Hz, H-1), 6.52 (d,
1H, J 8.0 Hz, H-2), 6.21 (m, 1H, H-4'), 5.95 (t, 1H, J 9.0 Hz, H-3'), 5.75-
5.69 (m, 2H, H-2', H-8), 5.47 (d, 1H, J 7.0 Hz, H-1'), 5.34 (d, 1H, J 9.5 Hz,
H-5'), 5.23 (m, 1H, H-7), 4.98 (d, 1H, J 5.5 Hz, H-5), 4.93 (m, 1H, H-9),
4.46 (m, 1H, H-6), 4.20-4.05 (m, 2H, OCH2CH3), 3.99 (m, 1H, H-16a), 3.00
(m, 1H, H-16b), 2.90-2.70 (m, 2H, H-10), 2.48 (m, 1H, H-14), 1.88 (m, 2H,
H-15), 1.31 -1.25 (m, 12H, C(CH3)3, OCH2CH3).
13C NMR (100 MHz, CDCI3): d 165.7, 165.2, 164.7 (C=O), 155.4 (C-3a"),
154.9 (C-7"), 136.0 (C-5"), 133.1-128.2 (C-aro), 122.2 (C-1), 119.2 (C-2),
110.6 (C-6"), 99.4 (C-1'), 89.9 (C-5), 73.0 (C-6), 72.7 (C-3'), 72.2 (C-2'),
71.3 (C-4\ C-5'), 61.5 (OCH2CH3), 49.8 (C-9), 44.3 (C-13), 39.8 (C-14),
37.2 (C-16), 35.3 (C-15), 30.0 (C-10), 27.2 (C(CH3)3), 14.7 (OCH2CH3).
Mass calculated for C55H52N5O13 [M+H]+: 990.356, found: 990.3596
1.7. morphin-6-yl 5-C-(5-hydroxy-4,5,6,7-
tetrahydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-ß-D-xylopyranoside (9)
To a suspension of lithium aluminium hydride (140 mg, 3.69 mmol) in
tetrahydrofuran (6 mL) is added a solution of the compound 3-O-pivaloyl-N-
ethoxycarbonylnormorphin-6-yl 2,3,4-tri-O-benzoyl-5-C-([1,2,4]triazolo[1,5-
a]pyrimidin-2-yl)-p-D-xylopyranoside (8) (250 mg, 0.28 mmol) in
tetrahydrofuran (6 mL).
The reaction medium is stirred at reflux for 1 hour. 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 + 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) affords
morphin-6-yl 5-C-(5-hydroxy-4,5,6,7-tetrahydro[1,2,4]triazolo[1,5-
a]pyrimidin-2-yl)-ß-D-xylopyranoside (9) in the form of white crystals (61
mg, 40%).
Melting point: 201 °C
[a]23D = -118.4 (c = 0.5, methanol)
1H NMR (300 MHz, D2O): 6.80 (d, 1H, J 8.0 Hz, H-1), 6.72 (d, 1H, J 8.0 Hz,
H-2), 5.83 (m, 1H, H-8), 5.43 (m, 1H, H-7), 5.36 (m, 1H, H-5"), 5.29 (d, 1H,
J 5.5 Hz, H-5), 4.91 (d, 1H, J 8.0 Hz, H-1'), 4.52 (m, 1H, H-6), 4.51 (d, 1H,
J 9.5 Hz, H-5'), 4.32-4.20 (m, 2H, H-9, H-6"a), 4.10 (m, 1H, H-6"b), 3.78 (t,
1H, J 9.5 Hz, H-4'), 3.68 (t, 1H, J 9.5 Hz, H-3'), 3.53 (dd, 1H, J 8.0 Hz, J
9.5 Hz, H-2'), 3.40 (m, 1H, H-16a), 3.25 (m, 1H, H-10a), 3.12 (m, 1H, H-
16b), 3.05-2.89 (m, 5H, H-10b, H-14, NCH3), 2.35-2.11 (m, 4H, H-15, H-
7").
13C NMR (75 MHz, D2O): 131.2 (C-8), 126.1 (C-7), 120.5 (C-2), 117.8 (C-
1), 102.5 (C-1'), 88.3 (C-5), 74.9 (C-3'), 73.7 (C-6), 72.9 (C-2'), 71.7 (C-4'),
71.1 (C-5"), 70.4 (C-5'), 60.6 (C-9), 47.2 (C-16), 40.9 (NCH3), 40.1 (C-6")(
38.5 (C-14), 32.4 (C-15), 26.2 (C-7"), 20.9 (C-10).
Mass calculated for C27H34N5O8 [M+H]+: 556.2407, found: 556.3278.
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. Then; 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.
Results
The results obtained for the compounds of the invention are
represented by 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).
Among the most active compounds whose activity was evaluated
subcutaneously, by way of example, morphin-6-yl 5-C-(5-hydroxy-4,5,6,7-
tetrahydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-p-D-xylopyranoside has a
maximum percentage of analgesic activity (% MPE max index) of 80% for
dose of 1.25 mg/kg and an ED50 of less than 1.25 mg/kg determined 60
minutes after administration. The analgesic effects are persistent and last
for more than 120 minutes via this administration route.
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, as
analgesics, in the treatment of sexual dysfunctions and in particular in the
treatment of male premature ejaculation.
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 represents a hydrogen atom or a group (C1-C4)alkyl,
R2 represents a hydroxyl group, a thiol group, a group (C1-C4)alkyloxy or a
group thio(C1-C4)alkyl, and
n is an integer equal to 1 or 2,
in the form of base or of acid-addition salt, and also in the form of hydrate
or 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:
- R1 is a hydrogen atom,
- R2 is a hydroxyl group; and
- n is equal to 2.
3. Compound of general formula (I) according to Claim 1 or 2,
characterized in that the said compound is morphin-6-yl 5-C-(5-hydroxy-
4,5,6,7-tetrahydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-(3-D-xylopyranoside.
4. Medicament, characterized in that it comprises a compound of general
formula (I) according to any one of Claims 1 to 3, or an addition salt of this
compound with a pharmaceutically acceptable acid, or alternatively a
hydrate or a solvate of the compound of formula (I).
5. Pharmaceutical composition, characterized in that it comprises a
compound of general formula (I) according to any one of Claims 1 to 3, or a
pharmaceutically acceptable salt, a hydrate or a solvate of this compound,
and also at least one pharmaceutically acceptable excipient.
6. Use of a compound of general formula (I) according to any one of Claims
1 to 3, for the preparation of a medicament for treating or preventing pain.

The invention relates to compounds having formula (I) wherein: R1 represents a hydrogen atom or a (C1-C4)alkyl
group; R2 represents a hydroxyl group, a thiol group, a (C1-C4)alkyloxy group or a thio(C1-C4)alkyl group; and n is an integer
equal to 1 or 2, 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.