Note: Descriptions are shown in the official language in which they were submitted.
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5-Naphthalene-1-yl-1,3-dioxane derivatives, their
preparation and their therapeutic application
The present invention relates to compounds of
R1 O
in which
V
I
N
W
O O
(I)
R1 represents an alkyl group,
V represents a hydrogen atom, a linear or branched
alkyl group, a cycloalkyl group, a cycloalkylmethyl
group, a phenylalkyl group which is optionally
substituted on the phenyl ring, a carboxymethyl group,
an alkoxycarbonylmethyl group or a carbamoylmethyl
group which is optionally monosubstituted or
disubstituted on the nitrogen,
W represents a carboxymethyl group, an
alkoxycarbonylmethyl group, a carbamoylmethyl group
which is optionally monosubstituted or disubstituted on
the nitrogen, a 4- to 7-membered cyclic group
general formula (I)
optionally containing an oxygen or sulphur atom, a
2-pyridylmethyl group, a 3-pyridylmethyl group, a
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2
4-pyridylmethyl group, a 1-methyl-2-pyrrolylmethyl
group, a 2-furylmethyl group, a 2-thienylmethyl group
or a 1,3-thiazol-2-yl-methyl group, or alternatively
V and W form, together with the nitrogen atom which
bears them, a pyrrolidinyl, piperidyl or 1,2,3,4-
tetrahydroisoquinolyl group.
The compounds of the invention correspond
more particularly to one of the general formulae (IA),
(IB) , (IC) and (ID)
In the general formula (IA)
R1 represents a hydrogen atom, a linear or branched
(C2-Cq)alkyl group, a cyclo(C3-C6)alkyl group, a
cyclo(C3-C6)alkylmethyl group or a phenyl(C1-C3)alkyl
group which is optionally substituted on the phenyl
ring,
R2 represents a hydrogen atom, a linear or branched
(C1-Cq)alkyl group, a cyclo(C3-C6)alkyl group, a
cyclo(C3-C6)alkylmethyl group or a phenyl(C1-C3)alkyl
group which is optionally substituted on the phenyl
ring,
R3 represents a hydroxyl group, a (C1-C4)alkoxy group or
a group of general formula NRqRS in which R4 and R5,
independently of each other, each represent a hydrogen
atom, a linear or branched (C1-Cq)alkyl group, a
cyclo(C3-C6)alkyl group or a cyclo(C3-C6)alkylmethyl
group.
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R' .~ O
N,
Ra
O O
(IA)
i i
Ri. w w
O
R
N ( _)
( CH )
Z n~
X
( IB)
~C~O
N~R~
( IC)
x'C~O
(ID)
The compounds of general formula (IA) can
exist in the form of cis or trans stereoisomers or
mixtures of such isomers; they can also exist in the
form of free bases or of addition salts with acids.
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4
The compounds of general formula (IA) can be
prepared by various processes described below.
According to a first variant, illustrated by
Scheme A which follows, the amide of formula (IIA) is
subjected to a dealkylation in the presence of sodium
sulphide, in a polar aprotic solvent, for example
N-methylpyrrolidone, at a temperature of 100 to 150°C,
in order to obtain the amide of formula (IIIA),
according to a method described in J. Am. Chem. Soc.
(1976) 98 3237.
This amide is then subjected to an alkylation
using a derivative of general formula R1-X, in which R1
is as defined above, but is other than a hydrogen atom,
and X represents a halogen atom or an equivalent group,
in the presence of a base such as potassium carbonate,
and in a polar aprotic solvent, for example
This amide is then hydrolysed in basic
medium, for example sodium hydroxide, in a protic
solvent, for example water or an aliphatic alcohol, at
a temperature of 25 to 100°C, in order to obtain the
N,N-dimethylformamide, in order to obtain an amide of
general formula (IVA).
corresponding primary amine, after which this amine is
treated either with an aldehyde of general formula
R6-CHO, in which R6 is the lower homologue of the group
R2, in the presence of a reducing agent such as sodium
borohyride or sodium cyanoborohydride, under reductive
amination conditions known to those skilled in the art,
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in order to obtain an amine of general formula (VA).
The amine of general formula (VA) is then
reacted with ethyl bromoacetate in order to obtain a
compound of general formula (IA) in which R1 and RZ
5 represent an alkyl, cycloalkyl, cycloalkylalkyl or
phenylalkyl group and R3 represents an ethoxy group. If
so desired, the compound thus obtained can then be
saponified in order to convert it into the
corresponding acid, or alternatively can be reacted
with an amine of general formula HNR9R5, in which R4 and
RS are as defined above, in order to convert it into an
amide. The conditions of these reactions are standard
and are well known to those skilled in the art.
According to an alternative variant, the
amides of general formula (IA), in which R1 and RZ
represent an alkyl or phenylalkyl group, can be
obtained by reacting the amine of general formula (VA)
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Scheme A
0 0
0 0
fIIA) ~ tIIIA)
Hy~~ HO w w
1
1
~~ ~s
0
0 0 0 0
wA) ' ' ~ c IvA)
Rl~o w w Rl~o w w
R, _ o
i
~N'
/~~ ''' R~
0 0
i i
tIAI
Ri~O
directly with an a-halo alkanamide of general formula
(VIA)
O
X~N~R~ f VIA)
i
R5
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in which X represents a chlorine or bromine atom and R4
and R5 are as defined above. The conditions of this
reaction are well known to those skilled in the art.
According to a third variant, the amines of
general formula (VA), in which R1 represents a
cyclopropylmethyl group and R2 represents an alkyl or
phenylalkyl group, can be prepared either by reduction
of the corresponding alkanamides, described in patent
application EP-461,958, or by hydrolysis of the said
alkanamides into primary amines, followed by treatment
of these amines under conditions of N-monoalkylation.
All of these reactions are carried out according to
methods that are well known to those skilled in the
art.
Lastly, according to a final variant, a
compound of general formula (IA), in which R1
represents a hydrogen atom, can be prepared by
demethylation, using sodium sulphide in N,N-dimethyl-
formamide, of the corresponding compound, in the
formula in which R1 represents a methyl group,
described in patent application FR-2,742,152.
The examples which follow illustrate the
preparation of a number of compounds of general formula
(IA). The elemental microanalyses and the IR and NMR
spectra confirm the structures of the compounds
obtained.
The numbers indicated in parentheses in the
example titles correspond to those in the 1st column of
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Table A given later.
In the compound names, the hyphen "-" forms
part of the name, and the underscore line " " serves
merely to indicate the presence of a line break; it
should be removed if a line break does not occur at
that point, and should not be replaced either with a
normal hyphen or with a space.
Example 1A (Compound No. 2A).
2-[(3-[5-[6-(Cyclopropylmethoxy)-1-naphthyl]-
1,3-dioxan-2-yl]propyl]ethylamino]-N-(cyclopropyl-
methyl)acetamide.
lA.l. 5-[6-(Cyclopropylmethoxy)-1-naphthyl]-N-ethyl-
1,3-dioxane-2-propanamine.
0.8 g of lithium aluminium hydride suspended
in 30 ml of tetrahydrofuran is introduced into a 250 ml
2-necked round-bottomed flask, the mixture is heated to
reflux, 4.0 g (10.43 mmol) of N-[3-[5-[6-(cyclopropyl-
methoxy)-1-naphthyl]-1,3-dioxan-2-yl]propyl]acetamide
dissolved in 200 ml of tetrahydrofuran are added and
refluxing is continued for 4 h.
The mixture is cooled, 3.5 ml (2 eq.) of
aqueous O.1M potassium sodium tartrate solution are
added slowly, the mixture is stirred and the solvents
are evaporated off under reduced pressure. 4.55 g of an
oily product are obtained, which product is used
without further purification in the following step.
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1A.2. 2-[[3-[5-[6-(Cyclopropylmethoxy)-1-naphthyl]-
1,3-dioxan-2-yl]propyl]ethylamino]-N-(cyclopropyl-
methyl)acetamide
0.23 ml (2.6 mmol) of cyclopropylmethanamine,
20 ml of dioxane and 0.36 ml of triethylamine are
introduced into a 250 ml round-bottomed flask, a
solution of 0.21 ml (2.6 mmol) of chloroacetyl chloride
in 5 ml of dioxane is added dropwise and the mixture is
stirred at room temperature for 8 h.
30 ml of water, 1 g of potassium carbonate
and 1.0 g (-2.7 mmol) of 5-[6-(cyclopropylmethoxy)-
1-naphthyl]-N-ethyl-1,3-dioxane-2-propanamine are added
and the mixture is heated at 80°C for 8 h and left to
stand at room temperature overnight.
Water and ethyl acetate are added, the
organic phase is separated out, washed with water and
then with brine, dried over magnesium sulphate and
filtered, the solvent is evaporated off under reduced
pressure and the residue is purified by chromatography
on a column of silica gel, eluting with a 98/2 mixture
of dichloromethane and methanol.
0.5 g of an oily product is obtained, which
is dissolved in 2-propanol, 8 ml of 0.1M hydrochloric
acid in 2-propanol are added, the solvents are
evaporated off and the residue is recrystallized from
diisopropyl ether.
0.2 g of hydrochloride is finally isolated.
Melting point: 74-76°C.
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Example 2A (Compound No. 3A).
N-Cyclopropyl-2-[[3-(5-[6-(cyclopropylmethoxy)-
1-naphthyl]-1,3-dioxan-2-yl]propyl]ethylamino]-
acetamide.
5 2A.1. Chloro-N-cyclopropylacetamide.
2 g (17.7 mmol) of chloroacetyl chloride
dissolved in 10 ml of dioxane are introduced into a
100 ml round-bottomed flask, 1 g (17.7 mmol) of cyclo-
propanamine is added dropwise and the mixture is
10 stirred at room temperature for 2 h.
Bicarbonate solution and ethyl acetate are
added, the organic phase is separated out, washed with
water, dried over magnesium sulphate and filtered and
the solvent is evaporated off under reduced pressure,
which gives 0.7 g of a white solid.
The aqueous phase is concentrated under
reduced pressure and the residue is taken up in
ethanol, which gives a further 1.22 g of a white solid,
i.e. a total of 1.92 g of compound, which is used
without further purification in the following step.
2A.2. N-Cyclopropyl-2-[[3-[5-[6-(cyclopropylmethoxy)-
1-naphthyl]-1,3-dioxan-2-yl]propyl]ethylamino]-
acetamide.
0.69 g (1.87 mmol) of 5-[6-(cyclopropyl-
methoxy)-1-naphthyl]-N-ethyl-1,3-dioxane-2-propanamine
dissolved in 20 ml of acetonitrile, 0.37 g (2.77 mmol)
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of 2-chloro-N-cyclopropylacetamide and 0.26 g of
potassium carbonate are introduced into a 100 ml round-
bottomed flask and the mixture is heated at 70°C for
4 h.
The mixture is cooled, water and ethyl
acetate are added, the organic phase is separated out,
washed with water and then with saturated sodium
chloride solution, dried over magnesium sulphate and
filtered and the solvent is evaporated off under
reduced pressure. The residue is purified by
chromatography on a column of silica gel, eluting with
a 98/2 mixture of dichloromethane and methanol. After
crystallization from diisopropyl ether, 0.2 g of a
white solid is isolated.
Melting point: 87-89°C.
Example 3A (Compound No. 17A).
2-[[3-[5-[6-(Cyclopropylmethoxy)-1-naphthyl]-
1,3-dioxan-2-yl]propyl]methylamino]-N-(cyclopropyl-
methyl)acetamide.
3A.1. 5-[6-(Cyclopropylmethoxy)-1-naphthyl]-
1,3-dioxane-2-propanamine.
30.0 g (78.23 mmol) of N-(3-[5-(6-(cyclo-
propylmethoxy)-1-naphthyl]-1,3-dioxan-2-yl]propyl]-
acetamide, 330 ml of ethanol and 300 ml of 30~ sodium
hydroxide are introduced into a 1000 ml round-bottomed
flask and the mixture is heated at 110°C for 24 h.
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The alcoholic phase is separated out after
settling of the phases has taken place and this phase
is concentrated, water is added and the mixture is
extracted with ethyl acetate. The organic phase is
dried over magnesium sulphate and the solvent is
evaporated off under reduced pressure. 30.44 g of an
oily product are obtained, which product is used
without further purification in the following step.
3A.2. 5-[6-(Cyclopropylmethoxy)-1-naphthyl]-N-methyl-
1,3-dioxane-2-propanamine.
2.4 ml (25.3 mmol) of acetic anhydride are
introduced into a 50 ml round-bottomed flask, 1 ml
(26.5 mmol) of formic acid is added dropwise and the
mixture is heated on an oil bath at 50°C for 2 h.
The heating is removed, 2.5 ml of anhydrous
tetrahydrofuran are added and, while stirring the
mixture, a solution of 6.0 g (17.5 mmol) of
5-[6-(cyclopropylmethoxy)-1-naphthyl]-1,3-dioxane-
2-propanamine in 7 ml of tetrahydrofuran is added
dropwise without the temperature exceeding 40°C, and
stirring is continued at room temperature overnight.
The solvent is evaporated off under reduced
pressure, the residue is taken up in toluene, this
solution is evaporated under reduced pressure and the
residue is dried.
5.84 g (15.8 mmol) of a white solid are
obtained. This solid is dissolved in 40 ml of
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tetrahydrofuran in a 250 ml round-bottomed flask, a
suspension of 1.2 g of lithium aluminium hydride in
43 ml of tetrahydrofuran is added, at the reflux
temperature and under an argon atmosphere, and
refluxing is continued for 4 h.
The mixture is cooled in a bath of ice-cold
water, 9 ml of sodium potassium tartrate are added
dropwise and stirring is continued overnight. The
mixture is filtered and the filtrate is concentrated
under reduced pressure to give 5.89 g of an oily
product.
0.23 g of this product is dissolved in
2-propanol and, after treatment with one equivalent of
hydrochloric acid in 2-propanol, 0.188 g of
hydrochloride is finally isolated.
Melting point: 144-148°C.
3A.3. 2-[[3-[5-[6-(Cyclopropylmethoxy)-1-naphthyl]-
1,3-dioxan-2-yl]propyl]methylamino]-N-(cyclopropyl-
methyl)acetamide.
0.24 ml (2.81 mmol) of cyclopropanemethan-
amine, 20 ml of dioxane and 0.4 ml of triethylamine are
introduced into a 250 ml round-bottomed flask, a
solution of 0.22 ml (2.81 mmol) of chloroacetyl
chloride in 10 ml of dioxane is added dropwise and the
mixture is stirred at room temperature for 9 h.
ml of water, 1 g of potassium carbonate
and 1 g (2.81 mmol) of 5-[6-(cyclopropylmethoxy)-
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1-naphthyl]-N-methyl-1,3-dioxane-2-propanamine are
added and the mixture is heated at 80°C for 3 h.
It is cooled, water and ethyl acetate are
added, the organic phase is separated out, washed with
water and with brine, dried over magnesium sulphate and
filtered, the solvent is evaporated off under reduced
pressure and the residue is purified by chromatography
on a column of silica gel, eluting with a 98/2 mixture
of dichloromethane and methanol. 0.62 g of product is
obtained, which is dissolved in ethanol. After
treatment with one equivalent of oxalic acid, 0.5 g of
a white solid is isolated.
Melting point: 156-158°C.
Example 4A (Compound No. 19A).
2-[[3-[5-(6-Ethoxy-1-naphthyl)-1,3-dioxan-
2-yl]propyl](phenylmethyl)amino]acetamide.
4A.1. N-[3-[5-(6-Hydroxy-1-naphthyl)-1,3-dioxan-
2-yl]propyl]acetamide.
3.4 g (9.9 mmol) of N-[3-[5-(6-methoxy-
1-naphthyl)-1,3-dioxan-2-yl]propyl]acetamide and 20 ml
of 1-methyl-2-pyrrolidinone are introduced into a 250
ml round-bottomed flask, under a nitrogen atmosphere,
the mixture is stirred, 3.86 g (49.5 mmol) of sodium
sulphide are added and the mixture is heated on an oil
bath at 150°C overnight.
The mixture is allowed to cool to 25°C, 50 ml
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of ethyl acetate and 50 ml of water are added, the
organic phase is separated out, 10~ hydrochloric acid
is added to the aqueous phase to pH = 4 and this phase
is extracted again with ethyl acetate. The organic
5 phases are combined, washed with water and then with
saturated sodium chloride solution and are dried over
magnesium sulphate. The solution is filtered, the
solvent is evaporated off under reduced pressure and
the residue is purified by chromatography on a column
10 of silica gel, eluting with a 98/2 mixture of
dichloromethane and methanol.
The purified fraction is treated with
pentane, with ultrasound, with ethyl acetate and with
diisopropyl ether. 1.87 g of solid are finally
15 isolated.
Melting point: 135-137°C.
4A.2. N-[3-[5-(6-Ethoxy-1-naphthyl)-1,3-dioxan-
2-yl]propyl]acetamide.
4.5 g of (13.7 mmol) of N-[3-[5-(6-hydroxy-
1-naphthyl)-1,3-dioxan-2-yl]propyl]acetamide dissolved
in 70 ml of N,N-dimethylformamide, 2.8 g of potassium
carbonate and 1.53 ml (20.5 mmol) of bromoethane are
introduced into a 250 ml round-bottomed flask and the
mixture is stirred at room temperature overnight.
The solvent is evaporated off under reduced
pressure, by entrainment with toluene, the residue is
taken up in water and ethyl acetate and a solid is
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separated out by filtration. After rinsing with water
and with ethyl acetate, and drying, 2.74 g of solid are
isolated.
After separation of the phases once settling
has taken place, washing of the organic phase, drying,
filtration and evaporation of the solvent, a further
1.7 g of solid are obtained, i.e. a total of 4.44 g of
compound.
0.3 g of this product is recrystallized from
a 6/4 mixture of ethanol and water and 0.2 g of
compound is finally isolated.
Melting point: 140-142°C.
4A.3. 5-(6-Ethoxy-1-naphthyl)-1,3-dioxane-
2-propanamine.
4.1 g (11.4 mmol) of N-[3-[5-(6-ethoxy-
1-naphthyl)-1,3-dioxan-2-yl]propyl]acetamide dissolved
in 49 ml of ethanol and 43.4 ml of 30~ sodium hydroxide
are introduced into a 250 ml round-bottomed flask and
the mixture is refluxed for 24 h.
It is allowed to cool, the alcoholic phase is
separated out after settling of the phases has taken
place, this phase is concentrated and the residue is
taken up in water and extracted with dichloromethane.
The organic phase is washed with saturated sodium
chloride solution and dried over magnesium sulphate.
This solution is filtered and the solvent is evaporated
off under reduced pressure. The residue is purified by
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chromatography on a column of silica gel, eluting with
a 90/10/1 mixture of dichloromethane, methanol and
aqueous ammonia .
1.87 g of a solid are obtained, which product
is used without further purification in the following
step.
The hydrochloride thereof is prepared from a
O.1N solution of hydrochloric acid in 2-propanol.
Melting point: 180-183°C.
4A.4. 5-(6-Ethoxy-1-naphthyl)-N-(phenylmethyl)-
1,3-dioxane-2-propanamine.
1.63 g (5.17 mmol) of 5-(6-ethoxy-
1-naphthyl)-1,3-dioxane-2-propanamine dissolved in
450 ml of methanol are introduced into a 1000 ml round-
bottomed flask fitted with Dean-Stark apparatus,
followed by introduction of 0.604 g (5.69 mmol) of
benzaldehyde and the mixture is refluxed until it has
reduced to one-third of the initial volume.
The mixture is allowed to cool, it is placed
in an ice bath, 1.56 g (41.3 mmol) of sodium
borohydride are added portionwise and the mixture is
stirred overnight.
The solvent is evaporated off under reduced
pressure, the white residue is taken up in water and
ethyl acetate, the organic phase is washed twice with
water and once with ethyl acetate, dried over magnesium
sulphate and filtered, the solvent is evaporated off
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under reduced pressure and the residual oil is purified
by chromatography on a column of silica gel, eluting
with a 95/5 mixture of dichloromethane and methanol.
1.15 g of base are obtained, 0.1 g of which
product is taken in order to prepare the hydrochloride,
by dissolution in hot 2-propanol, addition of 2.46 ml
of O.1N hydrochloric acid in 2-propanol, evaporation of
the solvent under reduced pressure, trituration of the
residue from diisopropyl ether, filtration and drying
under vacuum. 0.97 g of hydrochloride is isolated.
Melting point: 206-208°C.
4A.5. 2-[3-[5-(6-Ethoxy-1-naphthyl)-1,3-dioxan-2-yl]-
propyl](phenylmethyl)amino]acetamide.
0.5 g (1.23 mmol) of 5-(6-ethoxy-1-naphthyl)-
N-(phenylmethyl)-1,3-dioxane-2-propanamine dissolved in
7 ml of acetonitrile, 0.17 g (1.23 mmol) of potassium
carbonate, 0.055 g (0.369 mmol) of sodium iodide and
0.138 g (1.47 mmol) of 2-chloroacetamide are introduced
into a 50 ml round-bottomed flask and the mixture is
refluxed for 5 h. The mixture is allowed to cool, water
and ethyl acetate are added, the organic phase is
separated out, the aqueous phase is extracted once
more, the organic phase is washed twice with water and
once with saturated aqueous sodium chloride solution,
dried over magnesium sulphate and filtered, the solvent
is evaporated off under reduced pressure and the
residue is purified by chromatography on a column of
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19
silica gel, eluting with a 99/1 mixture of dichloro-
methane and methanol.
0.590 g of pure base is obtained in the form
of a yellow oil, which is dissolved in hot 2-propanol
and 12.3 ml of O.1N hydrochloric acid in 2-propanol are
added. After evaporation of the solvent under reduced
pressure, trituration of the residue from diisopropyl
ether, filtration and drying under vacuum, 0.54 g of
hydrochloride is isolated.
Melting point: 190-193°C.
Example 5A (Compound No. 20A).
2-[[3-[5-(6-Ethoxy-1-naphthyl)-1,3-dioxan-2-yl]-
propyl](phenylmethyl)amino]-N-methylacetamide.
5A.1. Ethyl 2-[[3-[5-(6-ethoxy-1-naphthyl)-1,3-dioxan-
2-yl]propyl](phenylmethyl)amino]acetate.
0.5 g (1.23 mmol) of 5-(6-ethoxy-1-naphthyl)-
N-(phenylmethyl)-1,3-dioxane-2-propanamine suspended in
15 ml of acetonitrile, 0.42 g (3.07 mmol) of potassium
carbonate and 0.2 ml (1.84 mmol) of ethyl 2-bromo-
acetate are added and the mixture is heated at 60°C for
2.5 h.
20 ml of water and 15 ml of ethyl acetate are
added, the organic phase is separated out, washed with
water, dried over magnesium sulphate and filtered, the
solvent is evaporated off under reduced pressure and
the residue is purified by chromatography on a column
CA 02290695 1999-11-16
of silica gel, eluting with a 98/2 mixture of dichloro-
methane and methanol. 0.58 g of an oily product is
obtained, which is used without further purification in
the following step.
5 5A.2. 2-[[3-[5-(6-Ethoxy-1-naphthyl)-1,3-dioxan-2-yl]-
propyl](phenylmethyl)amino]-N-methylacetamide.
0.58 g (1.18 mmol) of ethyl 2-[[3-[5-
(6-ethoxy-1-naphthyl)-1,3-dioxan-2-yl]propyl]-
(phenylmethyl)amino]acetate is dissolved in a few ml of
10 ethanol, 5 ml of 33~ methanamine in ethanol are added
and the mixture is placed in an oven at 50°C for
7 days.
The solvent is evaporated off under reduced
pressure and 0.8 g of an oily product is obtained,
15 which is purified by chromatography on a column of
silica gel, eluting with a 98/2 mixture of dichloro-
methane and methanol, to give 0.5 g of pure base in the
form of an oil.
After treatment with 10.5 ml of O.1N
20 hydrochloric acid in 2-propanol, evaporation of the
solvent, trituration from diisopropyl ether, filtration
and drying, 0.37 g of hydrochloride is finally
isolated.
Melting point: 88-90°C.
Example 6A (Compound No. 23A).
2-[[3-[5-[6-(Cyclopentyloxy)-1-naphthyl]-1,3-dioxan-
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21
2-yl]propyl](phenylmethyl)amino]acetamide.
6A.1. N-[3-(5-[6-(Cyclopentyloxy)-1-naphthyl)-
1,3-dioxan-2-yl]propyl]acetamide.
Starting with 4.5 g (13.6 mmol) of N-[3-[5-
(6-hydroxy-1-naphthyl)-1,3-dioxan-2-yl]propyl]acetamide
and 3.0 g (20.1 mmol) of bromocyclopentane, and working
under conditions similar to those described in Example
4A.2, but at 80°C, 4.88 g of crude compound are
obtained. 0.388 g of this compound is purified by
chromatography on a column of silica gel, eluting with
a 90/10 mixture of dichloromethane and methanol. After
recrystallization from a mixture of ethanol and water
and then drying in the presence of phosphorus
pentoxide, 0.22 g of compound is isolated.
Melting point: 136-137°C.
6A.2. 5-[6-(Cyclopentyloxy)-1-naphthyl]-1,3-dioxane-
2-propanamine.
Starting with 4.5 g (11.3 mmol) of N-[3-(5-
(6-cyclopentyloxy-1-naphthyl)-1,3-dioxan-2-yl]propyl]-
acetamide, and working under conditions similar to
those described in Example 4A.3, 1.52 g of base are
obtained, followed by 1.15 g of hydrochloride.
6A.3. 5-[6-(Cyclopentyloxy)-1-naphthyl]-N-(phenyl-
methyl)-1,3-dioxane-2-propanamine.
Starting with 0.59 g (1.66 mmol) of
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22
5-(6-cyclopentyloxy-1-naphthyl)-1,3-dioxane-2-propan-
amine and 0.194 g (1.82 mmol) of benzaldehyde, and
working under conditions similar to those described in
Example 4A.4, 0.48 g of base is obtained, from which
0.435 g of hydrochloride is prepared.
Melting point: 186-190°C.
6A.4. 2-[[3-[5-[6-(Cyclopentyloxy)-1-naphthyl]-
1,3-dioxan-2-yl]propyl](phenylmethyl)amino]acetamide.
Starting with 0.710 g (1.59 mmol) of
5-(6-cyclopentyloxy-1-naphthyl)-N-(phenylmethyl)-
1,3-dioxane-2-propanamine and 0.178 g (1.9 mmol) of
2-chloroacetamide, and working under conditions similar
to those described in Example 4A.5, 0.640 g of base is
obtained in the form of an oil, from which 0.628 g of
hydrochloride is prepared.
Melting point: 212-215°C.
Example 7A (Compound No. 26A).
2-[[3-[5-[(6-(Phenylmethoxy)-1-naphthyl]-1,3-dioxan-
2-yl]propyl](phenylmethyl)amino]acetamide.
7A.1. N-[3-[5-[(6-(Phenylmethoxy)-1-naphthyl]-
1,3-dioxan-2-yl]propyl]acetamide.
Starting with 4.2 g (12.75 mmol) of
N-[3-5-(6-hydroxy-1-naphthyl)-1,3-dioxan-2-yl]-
propyl]acetamide and 1.82 ml (15.3 mmol) of
(bromomethyl)benzene, and working under conditions
CA 02290695 1999-11-16
23
similar to those described in Example 4A.2, 4.67 g of
product are obtained, 0.3 g of which is recrystallized
from a 6/4 mixture of ethanol and water, to give 0.15 g
of a white solid.
Melting point: 138-140°C.
7A.2. 5-[6-(Phenylmethoxy)-1-naphthyl]-1,3-dioxane-
2-propanamine.
Starting with 4.06 g of N-[3-[5-[(6-(phenyl-
methoxy)-1-naphthyl]-1,3-dioxan-2-yl]propyl]acetamide,
and working under conditions similar to those described
in Example 4A.3, 3.2 g of an oily product are obtained,
which product is used without further purification in
the following step.
7A.3. 5-[6-(Phenylmethoxy)-1-naphthyl]-N-(phenyl-
methyl)-1,3-dioxane-2-propanamine.
Starting with 1.13 g (2.99 mmol) of
5-[6-(phenylmethoxy)-1-naphthyl]-1,3-dioxane-2-propan-
amine and 0.317 g (2.99 mmol) of benzaldehyde and then
0.904 g (23.9 mmol) of sodium borohydride, and working
under conditions similar to those described in
Example 4A.4, 0.41 g of base is obtained, 0.1 g of
which is taken in order to obtain 0.090 g of
hydrochloride.
Melting point: 185-189°C.
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.,
24
7A.4. 2-[[3-[5-[(6-(Phenylmethoxy)-1-naphthyl]-
1,3-dioxan-2-yl]propyl](phenylmethyl)amino]acetamide.
Starting with 0.30 g (0.64 mmol) of
5-[6-(phenylmethoxy)-1-naphthyl]-N-(phenylmethyl)
1,3-dioxane-2-propanamine and 0.072 g (0.768 mmol) of
2-chloroacetamide, and working under conditions similar
to those described in Example 4A.5, 0.310 g of base is
obtained in the form of an oil, from which 0.285 g of
hydrochloride is prepared.
Melting point: 170-175°C.
Table A which follows illustrates the
chemical structures and the physical properties of a
number of compounds of general formula (IA).
In the "R1", "R2" and "R3" columns, cC3H5
represents a cyclopropyl group, cCSHg represents a
cyclopentyl group and C6H5 represents a phenyl group.
In the "Salt" column, "-" denotes a compound
in the form of the base, "ox." denotes an oxalate (or
ethanedioate), "fum" denotes a fumarate (or
(E)-2-butenedioate) and "HC1" denotes a hydrochloride;
the acid/base molar ratio is indicated in parentheses.
In the "m.p.(°C)" column, "(d)" denotes a
melting point with decomposition.
All the compounds are traps stereoisomers (1H
2 5 NMR ) .
CA 02290695 1999-11-16
'1
Table A
~O
R= 0
N~,
Rs
O O
i i
(IA)
No. Rl R~ R3 Salt m.p.(~C)
lA -CHZCC3H5-CH=CH3 -NHCH3 - 90-92
2A -CHscC3H5-CH~CH3 -NHCH=cC3H5HC1 (1:1)74-~6
3A -CH~CC3H5-CHyCH3 -NHcC3Hs - 87-89
4A -CFI=cC3H5-CH~CC3Hg-NH= HCl (1:1)63 (d)
5A -CIiZCC3H5-CHZCC3H5-NHCHy HC1 (l:l)78-AO
6A -CH=cC3H5-CHZCC3H5-NFiCH=cC~HS- 92-96
7A -CHZCC3Hg-CH=cC3H5-NFicC3H5 HC1 ( 80 - 82
1:1 )
8A -CHyCC3H5-CHZC6H5 -OCFisCH3 HCl (1:1)66-6B
9A -C8=cC~HS-CH=C6H5 -NHz - 135-137
l0A -CHZCC3H5-CH~C6H5 -NHCH3 - / 115-117
11A -CHZCC3Hs-CHsC6H5 -NHCHicC3H5HC1 (1:1)84-A6
12A -CHZCC3Hs-CHZC6H5 -NHcC3H5 HC1 (1:1)90-92
13A -CHicC3Hs-CHI -OCHZCH3 HCl (1:1)128-130
14A -CHZCC3FIs-CH3 -NH= HCl (1:1)98-110
15A -CH=cC3Hs-CH3 -1JHCH3 - 94-96
CA 02290695 1999-11-16
26
No. R1 R= R3 Salt m.p.(C)
16A -CHZCC~HS-CH3 -NHcC3H5 HC1 (1:1)92-94
17A -CH=cC3H5-CH3 -NHCH=CC~HSox. (1:1)156-158
i8A -CHZCC3H5-CH~CH3 -NH= - 12~-129
19A -CHZCH3 -CHZC6H5 -NHS HC1 (1:1)190-193
20A -CH=CHy -CHZC6H5 -NHCH3 HC1 ll:l)88-90
21A -CH(CH3)Z-CHZCsHS -NHy HCl (1:1)174-176
22A -CH(CH3)=-CH~C6H5 -NHCH3 HCl (1:1)88-90
23A -cC5H9 -CHZCsHs -NHz HC1 (1:1)212-215
24A -(CHI);CH3-CHZCsHs -NFi~ HC1 (l:l)192-195
25A -(CH2)3CH;-CHZC6H5 -NHCH~ ox. (1:1)68-70
26A -CH=CsHS -CHZCsHs -NHz HC1 (1:1)170-175
27A -(CHZ)3CH3-CH3 -NHZ - 120-121
28A -CHZCSHS -CH3 -NHCH3 - 114-116
29A -CHZC6H5 -CHzCsHs -NHCH3 - 108-110
30A -CB~CiHS -CH3 -NH HC1 (1:1)75-85
31A H -CHZCsHS -NHy - 90 (d)
32A -cC5H9 -CHyC6H5 -NHCH~ - - 116-118
33A -cC5H9 -CH3 -NFi2 - 138- 140
34A -CHZCH3 CH3 -NHz fum (l:l)161-162
CA 02290695 1999-11-16
27
In the general formula (IB)
R represents either a hydrogen atom or a group of
general formula CHZCOY in which Y represents a hydroxyl
group or a (C1-C4)alkoxy group, or alternatively a group
of general formula CH2CONR1R2 in which R1 and R2,
independently of each other, each represent a hydrogen
atom or a (C1-C4)alkyl group,
X represents an oxygen or sulphur atom or a CHZ group,
m represents 0 or 1, and
n represents 0, 1 or 2.
The compounds of general formula (IB) can
exist in the form of cis or traps stereoisomers or
mixtures of such isomers; moreover, on account of the
chirality of the ring attached to the nitrogen atom,
certain compounds can exist in the form of
diastereoisomers and/or enantiomers. They can also
exist in the form of free bases or of addition salts
with acids.
The compounds of general formula (IB) can be
prepared by a process illustrated by Scheme B which
follows .
2-(6-Methoxy-1-naphthyl)propane-1,3-diol of
formula (IIB) is reacted with 4,4-diethoxybutanamine of
formula (IIIB) in a refluxing non-protic solvent such
as toluene and in the presence of dry hydrochloric acid
dissolved in diethyl ether as catalyst, in order to
CA 02290695 1999-11-16
28
Scheme B
08 oa
clza~
s~c.o ~ ~ I
~o
tzzzs~
/~o~rrz;~
0 0
(IVB)
i i
\ I
Q~).
IVB)
x
).
,x I ~ x
0
czsa) ~
8sc,o o~ ccx,)~'
x~
I
s, x.R,
~xsb~
0
) s c,
' o ,
lc~=),\
x
czHc)
obtain 5-(6-methoxy-1-naphthyl)-1,3-dioxane-2-
propanamine of formula (IVB), and this compound is then
reacted with a ketone of general formula (VB), in which
X, m and n are as defined above, in the presence of a
CA 02290695 1999-11-16
29
reducing agent such as sodium borohydride or any other
equivalent agent, in a neutral or acidic medium, under
reductive amination conditions that are well known to
those skilled in the art. A compound of general formula
(IBa) which corresponds to the general formula (IB)
when R represents a hydrogen atom is obtained.
The compound of general formula (IBa) can
then, if so desired, be alkylated with a (C1-C4)alkyl 2-
bromoacetate in a polar aprotic solvent, for example
acetonitrile, in the presence of a base, for example
potassium carbonate, in order to obtain a compound of
general formula (IBb) in which Y represents a (C1-
Cq ) alkoxy group .
If so desired, this compound can be
saponified under conditions that are well known to
those skilled in the art, in order to obtain a compound
of general formula (IBb) in which Y represents a
hydroxyl group. The general formula (IBb) corresponds
to the general formula (IB) when R1 represents a group
of general formula CH2COY.
If so desired, the compound of general
formula (IBb) can then be reacted with an amine of
general formula HNR1R2, in which R1 and R2 are as
defined above, in order to obtain an amide of general
formula (IBc). The conditions of this reaction are
standard and are well known to those skilled in the
art.
An amide of general formula (IBc) can also be
CA 02290695 1999-11-16
obtained directly from a compound of general formula
(IBa) by alkylation with a halide of general formula
Z-CH2-CO-NR1R2, in which Z represents a chlorine or
bromine atom and R1 and R2 are as defined above, in a
5 polar aprotic solvent, for example N,N-
dimethylformamide, in the presence of a base, for
example potassium carbonate.
2-(6-Methoxy-1-naphthyl)propane-1,3-diol of
formula (IIB) is described in patent application EP-
10 0,461,958. 4,4-Diethoxybutanamine is commercially
available, as are the ketones of general formula (VB).
The examples which follow illustrate in
greater detail the preparation of a number of compounds
of general formula (IB). The elemental microanalyses
15 and the IR and NMR spectra confirm the structures of
the compounds obtained. The compound numbers indicated
in parentheses in the titles correspond to those in
Table B given later.
Example 1B (Compound No. 1B).
20 Ethyl 2-[(2,3-dihydro-1H-inden-1-yl)[3-[5-(6-methoxy-1-
naphthyl)-1,3-dioxan-2-yl]aminoJacetate hydrochloride.
1B.1. 5-(6-Methoxy-1-naphthyl)-1,3-dioxane-2-
propanamine hydrochloride.
7.56 g (32.5 mmol) of 2-(6-methoxy-1-
25 naphthyl)propane-1,3-diol, 6.8 g (42.1 mmol) of 4,4-
diethoxybutanamine and then 70 ml of hydrochloric ether
CA 02290695 1999-11-16
31
are introduced into a 1 1 round-bottomed flask
containing 300 ml of toluene, and the mixture is
refluxed for 2 h.
The mixture is cooled and the precipitate is
collected by filtration and rinsed with diethyl ether.
12.2 g of crude hydrochloride are obtained in
the form of a beige-coloured solid.
Melting point: 224-226°C.
1B.2. N-(2,3-Dihydro-1H-inden-1-yl)-5-(6-methoxy-1-
naphthyl)-1,3-dioxane-2-propanamine.
3.0 g (9.95 mmol) of 5-(6-methoxy-1-
naphthyl)-1,3-dioxane-2-propanamine are dissolved in
250 ml of ethanol in a 500 ml round-bottomed flask,
1.32 g (9.95 mmol) of 2,3-dihydro-(1H)inden-1-one are
added and the mixture is refluxed overnight.
The mixture is allowed to cool, 2 g of
potassium borohydride are added and stirring is
continued for 2 h 30. 100 ml of water are added and the
mixture is extracted three times with 50 ml of ethyl
acetate. The solvent is evaporated from the organic
phase and the residue is purified by chromatography on
a column of silica gel, eluting with a 9/1 mixture of
dichloromethane and methanol.
2.79 g of an oily product are obtained.
1B.3. Ethyl 2-[(2,3-dihydro-1H-inden-1-yl)[3-[5-(6-
methoxy-1-naphthyl)-1,3-dioxan-2-yl]propyl]amino]-
CA 02290695 1999-11-16
32
acetate hydrochloride.
1.88 g (4.5 mmol) of N-(2,3-dihydro-1H-inden-
1-yl)-5-(6-methoxy-1-naphthyl)-1,3-dioxane-2-
propanamine, 0.8 g (5.8 mmol) of potassium carbonate,
0.96 g (5.8 mmol) of ethyl 2-bromoacetate, a catalytic
amount of sodium iodide and 35 ml of N,N-
dimethylformamide are introduced into a 250 ml round-
bottomed flask and the mixture is heated at 60°C for
3 h.
100 ml of water are added, the mixture is
extracted with three times 150 ml of ethyl acetate and
the organic phase is washed with aqueous sodium
chloride and then with aqueous sodium hydrogen
carbonate. After drying and evaporation of the solvent,
3.5 g of an oily product are obtained, which product is
purified by chromatography on a column of silica gel
with an elution gradient of from 5~ to 10~ ethyl
acetate in cyclohexane. 1.97 g of pure base are
obtained, 0.55 g (1 mmol) of which is taken in order to
prepare the hydrochloride using 11 ml of a O.1N
solution of hydrochloric acid in 2-propanol. After
washing in diethyl ether, 0.44 g of hydrochloride is
isolated.
Melting point: 88-90°C.
Example 2B (Compound No. 2B).
2-[(2,3-Dihydro-1H-inden-1-yl)[3-[5-(6-methoxy-1-
naphthyl)-1,3-dioxan-2-yl]propyl]amino]-N-
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33
methylacetamide hydrochloride.
1.42 g (2.8 mmol) of ethyl 2-[(2,3-dihydro-
1H-inden-1-yl)[3-[5-(6-methoxy-1-naphthyl)-1,3-dioxan-
2-yl]propyl]amino]acetate are introduced into a 250 ml
round-bottomed flask, 30 ml of a 33~ solution of
methylamine in ethanol are added and the mixture is
stirred at room temperature for 2 days. The solvent is
evaporated off under reduced pressure and the residue
is purified by chromatography on a column of silica
gel, eluting with a 98/2 mixture of dichloromethane and
methanol, to give 1.16 g of an oily product.
The hydrochloride thereof is prepared using
24 ml of a 0.1N solution of hydrochloric acid in
2-propanol. After washing in diethyl ether, 0.98 g of
hydrochloride is isolated.
Melting point: 112-114°C.
Example 3B (Compound No. 6B).
5-(6-Methoxy-1-naphthyl)-N-(1,2,3,4-tetrahydro-1-
naphthyl)-1,3-dixoane-2-propanamine fumarate.
3.0 g (9.95 mmol) of 5-(6-methoxy-1-
naphthyl)-1,3-dioxane-2-propanamine, 90 ml of ethanol
and 1.45 g (9.95 mmol) of 3,4-dihydrohydro-1-
naphthyl(2H)-one are introduced into a 250 ml round-
bottomed flask, and the mixture is refluxed for 48 h.
The mixture is allowed to cool, 3 g
(55.6 mmol) of potassium borohydride are added and the
mixture is stirred at room temperature for 2 days.
CA 02290695 1999-11-16
34
Water is added, the mixture is extracted with
ethyl acetate, the organic phase is washed with water
and dried, the solvent is evaporated off under reduced
pressure, the residue is taken up in dichloromethane
and the solvent is evaporated off under reduced
pressure.
4.86 g of an oily product are obtained, which
product is purified by chromatography on a column of
silica gel, eluting with a 9/1 mixture of
dichloromethane and methanol.
1.6 g of base are obtained, 0.4 g of which
are taken in order to prepare the fumarate in 6 ml of
ethanol with 0.11 g of fumaric acid. 0.27 g of salt is
isolated.
Melting point: 134-136°C.
Example 4B (Compound No. 9B).
2-[[3-[5-(6-Methoxy-1-naphthyl)-1,3-dioxan-2-
yl]propyl](1,2,3,4-tetrahydro-1-
naphthyl)amino]acetamide hydrochloride.
0.85 g (1.97 mmol) of 5-(6-methoxy-1-
naphthyl)--N-(1,2,3,4-tetrahydro-1-naphthyl)-1,3-
dioxane-2-propanamine, 20 ml of acetonitrile, 0.28 g
(2.99 mmol) of 2-chloroacetamide, 0.54 g (3.94 mmol) of
potassium carbonate and 0.29 g (1.9 mmol) of sodium
iodide are introduced into a 250 ml round-bottomed
flask and the mixture is refluxed for 4 h. 50 ml of
water and 25 ml of ethyl acetate are added, the organic
CA 02290695 1999-11-16
phase is separated out, the aqueous phase is extracted
twice more with 25 ml of ethyl acetate, the solvent is
evaporated off under reduced pressure and the residue
is purified by chromatography on a column of silica
5 gel, eluting with a 9/1 mixture of dichloromethane and
methanol.
0.6 g of base is obtained, which allows 0.25
g of hydrochloride to be prepared using a O.1N solution
of hydrochloric acid in 2-propanol.
10 Melting point: 142-143°C.
Example 5B (Compound No. 13B).
N-(3,4-Dihydro-2H-1-benzopyran-4-yl)-5-(6-methoxy-1-
naphthyl)-1,3-dioxane-2-propanamine hydrochloride.
2 g (6.6 mmol) of 5-(6-methoxy-1-naphthyl)-
15 1,3-dioxane-2-propanamine are introduced into a 250 ml
round-bottomed flask, 150 ml of ethanol and 0.983 g
(6.6 mmol) of 3,4-dihydro-2H-1-benzopyran-4-one are
added and the mixture is refluxed overnight.
The mixture is cooled, 2 g of sodium
20 borohydride are added, the mixture is stirred for 1 h,
100 ml of water are added, this mixture is extracted
four times with 75 ml of ethyl acetate, the solvent is
evaporated off under reduced pressure and the residue
is dried under reduced pressure.
25 2.98 g of solid are obtained, which solid is
purified by chromatography on a column of silica gel,
eluting with a 9/1 mixture of dichloromethane and
CA 02290695 1999-11-16
36
methanol to give 1.3 g of base in the form of a pale
yellow oil.
0.30 g of this base is taken and the
hydrochloride thereof is prepared using 5 ml of a O.1M
solution of hydrochloric acid in 2-propanol. After
washing with diisopropyl ether and drying, 0.08 g of
hydrochloride is obtained.
Melting point: 172-173°C.
Example 6B (Compound No. 14B).
2-[(3,4-Dihydro-2H-1-benzopyran-4-yl)[3-[5-(6-methoxy
1-naphthyl)-1,3-dioxan-2-yl]propyl]amino]acetamide
hydrochloride.
Starting with 0.5 g (1.15 mmol) of N-(3,4-
dihydro-2H-1-benzopyran-4-yl)-5-(6-methoxy-1-naphthyl)-
1,3-dioxane-2-propanamine and 0.16 g (1.72 mmol) of
2-chloroacetamide, and working under conditions similar
to those described in Example 4B, and after
chromatography, 0.37 g of compound is obtained in the
form of the base, from which 0.17 g of hydrochloride is
obtained.
Melting point: 165-166°C.
Table B which follows illustrates the
chemical structures and the physical properties of a
number of compounds of general formula (IB).
In the "salt" column, "-" denotes a compound
in the form of the base, "fum." denotes a fumarate (or
(E)-2-butenedioate), "ox." denotes an oxalate (or
CA 02290695 1999-11-16
37
ethanedioate) and "HC1" denotes a hydrochloride; the
acid/base molar ratio is indicated in parentheses.
CA 02290695 1999-11-16
38
Table B
x~C~O
R
(CH=).
( CH= ) a I
O O
/ i
I
(IB)
No. R 7C m n Salt m.p.(C)
18 -CH=CO=CHZCH3CH2 0 1 HC1 (l:l) 88-90
28 -CHZCONHCH3CHZ 0 1 HC1 (l:l) 112-114
3H H CHZ 1 0 HC1 (l:l) 220-221
4H -CH=C02C:FI=CH3CFh 1 0 HCl (l:l) 77-79
58 -CH=CONHCH3CH= 1 0 ox. (1:1) 84-86
6B H CH= 0 2 fum. (1:1)134-136
?8 -CHsCO=CHzC83CH= 0 2 HC1 (1:1) ??-79
8H -CHZC'ONHCH3CSZ 0 2 HCl (1:1) 98-110
9B -CH~CONH= CH= 0 2 HCl (1:1) 142-143
lOB -CHZCOZCHZCH3CH= 1 1 HCl (l:ly 74-76
118 -CH~CONH= CHZ 1 1 HC1 (l:l) 208-210
12B -CH=CONHCH3CHz 1 1 fwa. (1:1)82-122
138 H O 0 2 HCl (l:l) 172-173
148 -CH=CONHZ O 0 2 HC1 (1:1) 165-166
158 -CH=CONHCH;O 0 ~ HCl (1:1) II7-119
CA 02290695 1999-11-16
39
No. R X m n Salt m.p.(~C)
16H H S 0 2 HC1 (1:1) 192-193
17H -CH=COsCH=CH38 0 2 HCl (1:1) 66-68
18H -CHZCONHCH3 S 0 2 HC1 (l:l) 114-116
198 -CH=CONH= CH= 0 1 - 106-108
20H H CH= 1 1 HCl (1:1) 211-213
21B -CHZCOZH CH= 0 2 - 90-92
22H -CHZCOzH O 0 2 - lOB-112
23B H CH= 0 1 HC1 (1:1) 124-125
(*) The compounds in which the carbon atom attached to
the nitrogen atom is chiral are racemic.
In the "Salt" column, "-" denotes a compound in the
form of the base, "fum." denotes a fumarate (or (E)-2-
butenedioate) and "HC1" denotes a hydrochloride; the
acid/base molar ratio is indicated in parentheses.
The melting points m.p. (°C) are indicated in the final
column.
In the general formula (IC) ,
R1 represents either a hydrogen atom or a group of
general formula CH2COY in which Y represents a hydroxyl
group or a (C1-C4)alkoxy group, or alternatively a group
of general formula CH2CONR4R5 in which Rq and R5,
independently of each other, each represent a hydrogen
atom or a (C1-C4)alkyl group, and
R2 represents a 2-pyridyl group, a 3-pyridyl group, a
4-pyridyl group, a 1-methyl-2-pyrrolyl group, a 2-furyl
CA 02290695 1999-11-16
group, a 2-thienyl group or a 1,3-thiazol-2-yl group,
the respective formulae of which are as follows:
/ \ / \ / \
. N ~ N o
N i
The compounds of general formula (IC) can
exist in the form of cis or traps stereoisomers or
5 mixtures of such isomers; they can also exist in the
form of free bases or of addition salts with acids.
The compounds of general formula (IC) can be
prepared by a process illustrated by Scheme C which
follows.
10 2-(6-Methoxy--1-naphthyl)propane-1,3-diol of
formula (IIC) is reacted with 4,4-diethoxybutanamine of
formula (IIIC) in a refluxing non-protic solvent such
as toluene and in the presence of hydrochloric acid
dissolved in diethyl ether, as catalyst, in order to
15 obtain 5-(6-methoxy-1-naphthyl)-1,3-dioxane-2-
propanamine of formula (IVC), which is then reacted, in
a protic solvent such as methanol, at a temperature of
25 to 60°C end with removal of the water formed during
-the reaction, with an aldehyde of general formula (VC)
20 in which R2 is as defined above, then the imine formed
is reduced for example using a reducing agent such as
sodium borohydride or any other equivalent agent, in
neutral or acidic medium, under reductive amination
conditions that are well known to those skilled in the
25 art. A compound of general formula (ICa) is obtained,
CA 02290695 1999-11-16
41
Scheme C
off as
(IIC>
/ /
H~c.o \ \ I
~o
O~~ IIIIC)
O O
(IVC)
/ /
H~C.O \ \ I
(VCI
Y
'O
c Ica) ~'T~R,
Hoc- 0 0
R R
(ICb)
HIC~O \ \ I
(ICC)
H~C~~
which corresponds to the general formula (IC) when R1
represents a hydrogen atom.
If so desired, the compound of general
formula (ICa) can then be alkylated with a haloacetate
CA 02290695 1999-11-16
42
of general formula Z-CH2-C02(C1-C4)alkyl, in which Z
represents a chlorine or bromine atom, in a polar
aprotic solvent, for example acetonitrile, in the
presence of a base, for example potassium carbonate, in
order to obtain a compound of general formula (ICb) in
which Y represents a (C1-Cq)alkoxy group.
If so desired, this compound can be
saponified under conditions that are well known to
those skilled in the art, in order to obtain a compound
of general formula (ICb) in which Y represents a
hydroxyl group. The general formula (ICb) corresponds
to the general formula (IC) when R1 represents a group
of general formula CH2COY.
If so desired, the compound of general
formula (ICb) can then be reacted with an amine of
general formula HNR4R5, in which R4 and R5 are as
defined above, in order to obtain an amide of general
formula (ICc). The conditions of this reaction are
standard and are well known to those skilled in the
art.
An amide of general formula (ICc) can also be
obtained directly from a compound of general formula
(ICa) by alkylation using a halide of general formula
Z-CH2-CO-NR4R5, in which Z represents a chlorine or
bromine atom and R4 and R5 are as defined above, in a
polar aprotic solvent, for example N,N-
dimethylformamide, in the presence of a base, for
example potassium carbonate.
CA 02290695 1999-11-16
43
The general formula (ICc) corresponds to the
general formula (IC) when R1 represents a group of
general formula CH2CONRqRS.
2-(6-Methoxy-1-naphthyl)propane-1,3-diol of
formula (IIC) is described in patent application EP-
0,461,958. 4,4-Diethoxybutanamine is commercially
available, as are the aldehydes of general formula
(VC) .
The examples which follow illustrate in
detail the preparation of a number of compounds of
general formula (IC). The elemental microanalyses and
the IR and NMR spectra confirm the structures of the
compounds obtained.
The compound numbers indicated in parentheses
in the titles correspond to those in Table C given
later.
Examt~le 1C (Compound No. 1C).
5-(6-Methoxy-1-naphthyl)-N-(4-pyridylmethyl)-1,3-
dioxane-2-propanamine dihydrochloride.
1C.1. 5-(6-Methoxy-1-naphthyl)-1,3-dioxane-2-
propanamine hydrochloride.
7.56 g (32.5 mmol) of 2-(6-methoxy-1-
naphthyl)propane-1,3-diol, 6.8 g (42.1 mmol) of
4,4-diethoxybutanamine and then 70 ml of dry gaseous
hydrochloric acid dissolved in diethyl ether are
introduced into a 1 1 round-bottomed flask containing
CA 02290695 1999-11-16
44
300 ml of toluene, and the mixture is refluxed for 2 h.
The mixture is cooled and the precipitate is
collected by filtration and rinsed with diethyl ether.
12.2 g of crude hydrochloride are obtained in
the form of a beige-coloured solid.
Melting point: 224-226°C.
1C.2. 5-(6-Methoxy-1-naphthyl)-N-(4-pyridylmethyl)-1,3-
dioxane-2-propanamine dihydrochloride.
0.5 g (1.67 mmol) of 5-(6-methoxy-1-
naphthyl)-1,3-dioxane-2-propanamine and 200 ml of
methanol are introduced into a 250 ml round-bottomed
flask, 0.178 g (1.67 mmol) of pyridine-4-carboxaldehyde
is added and the mixture is heated at 100°C for 2 h.
The mixture is allowed to cool, 0.5 g of
potassium borohydride is added and the mixture is
stirred for 0.5 h.
Half of the methanol is evaporated off under
reduced pressure, 100 ml of water are added, the
mixture is extracted with three times 20 ml of ethyl
acetate, the organic phase is concentrated under
reduced pressure and the residue is purified by
chromatography on a column of silica gel, eluting with
a 9/1 mixture of dichloromethane and methanol.
0.57 g of base is obtained in the form of an
oil.
0.15 g of this product is taken and dissolved
in 5 ml of a 0.1N solution of hydrochloric acid in 2-
CA 02290695 1999-11-16
propanol. After washing with diisopropyl ether and
drying, 0.12 g of dihydrochloride is obtained.
Melting point: 207-208°C.
Example 2C (Compound No. 3C).
5 2-[[3-[5-(6-Methoxy-1-naphthyl)-1,3-dioxane-2-
yl]propyl](4-pyridylmethyl)amino]acetamide
dihydrochloride.
1.2 g (3 mmol) of 5-(6-methoxy-1-naphthyl)-N-
(4-pyridylmethyl)-1,3-dioxane-2-propanamine are
10 dissolved in 200 ml of acetonitrile, 0.138 g (0.9 mmol)
of sodium iodide, 0.828 g (6 mmol) of potassium
carbonate and 0.42 g (4.5 mmol) of 2-chloroacetamide
are added and the mixture is refluxed for 3 h.
Since the reaction is not complete, a further
15 0.2 g (1.5 mmol) of potassium carbonate, 0.06 g
(0.45 mmol) of sodium iodide and 0.14 g (1.5 mmol) of
2-chloroacetamide are added and the mixture is refluxed
for a further 1 h.
The mixture is left to cool, 140 ml of water
20 are added and this mixture is extracted with four times
ml of ethyl acetate. After evaporation of the
solvent under reduced pressure, the residue is purified
by chromatography on a column of silica gel, eluting
with a 9/1 mixture of dichloromethane and methanol, and
25 0.3 g of pure base is obtained.
The base is salified using 8 ml of a O.1N
solution of hydrochloric acid in 2-propanol. After
CA 02290695 1999-11-16
46
washing with ethyl acetate and drying, 0.17 g of
dihydrochloride is obtained.
Melting point: 169-170°C.
Example 3C (Compound No. 19C).
5-(6-Methoxy-1-naphthyl)-N-(2-thiazolylmethyl)-1,3-
dioxane-2-propanamine.
2.4 g (8 mmol) of 5-(6-methoxy-1-naphthyl)-
1,3-dioxane-2-propanamine, 700 ml of methanol and 1 g
(8.8 mmol) of 1,3-thiazole-2-carboxaldehyde are
introduced into a 1000 ml round-bottomed flask fitted
with Dean-Stark apparatus and the mixture is distilled
until the volume of the reaction medium .reaches about
200 ml.
The mixture is cooled, 2.4 g of sodium
borohydride are added portionwise and the mixture is
left stirring overnight.
The methanol is evaporated off under reduced
pressure, the residue is taken up in water and ethyl
acetate, the organic phase is separated out, washed and
dried over magnesium sulphate and the solvent is
evaporated off under reduced pressure. 3.17 g of base
are obtained, 0.5 g of which is taken in order to
prepare the hydrochloride under conditions similar to
those described above.
0.5 g of hydrochloride is obtained.
Melting point: 134-137°C.
CA 02290695 1999-11-16
47
Example 4C (Compound No. 21C).
2-[[3-[5-(6-Methoxy-1-naphthyl)-1,3-dioxan-2-
yl]propyl](2-thiazolylmethyl)amino]acetamide
hydrochloride.
Starting with 0.7 g (1.75 mmol) of 5-(6-
methoxy-1-naphthyl)-N-(2-thiazolylmethyl)-1,3-dioxane-
2-propanamine and 0.2 g (2.1 mmol) of 2-
chloroacetamide, and working under conditions similar
to those of Example 2C, 0.76 g of base is obtained,
from which 0.763 g of hydrochloride is prepared.
Melting point: 189-191°C.
Table C which follows illustrates the
chemical structures and the physical properties of a
number of compounds of general formula (IC).
In the "R2" column, C5H4N-2- represents a 2-
pyridyl group, C5H9N-3- represents a 3-pyridyl group,
C5H4N-4- represents a 4-pyridyl group, CH3-1-C4H3N-2-
represents a 1-methyl-2-pyrrolyl group, C4H30-2-
represents a 2-furyl group, C4H3S-2- represents a 2-
thienyl group and C3H2NS-2- represents a 1,3-
thiazol-2-yl group.
In the "Salt" column, "-" denotes a compound
in the form of the base, "fum." denotes a fumarate (or
(E)-2-butenedioate), "ox." denotes an oxalate (or
ethanedioate) and "HC1" denotes a hydrochloride; the
acid/base molar ratio is indicated in parentheses.
In the "m.p. (°C)" column, "(d)" denotes a
melting point with decomposition.
CA 02290695 1999-11-16
48
Table C
H3C~0
NvRz
o O
i i
( IC)
No. Rl R~ Salt m.p.(C)
1C H CSH~N-4- HC1 (2:1) 207-208
~C -CH=COzH CsFi~N-4- - 115-125
3C -CHZCONFI= CsH~N-4- HCl (2:1) 169-170
4C -CH=CO~IC83CSH~N-4- HCl (2:1) 80-90
5C 8 CSH4N-3- 80-81
6C -CH~CONH= CsH~N-3- HC1 (1:1) 199-200
7C -CH=CONHCIi3CsH4N-3- ox. (Z:1) 138-140
8C $ CSH~N-2- HC1 (1:1) 158-159
9C -CFI=CONF~~CSH~N-Z- HCl ~(1:I)I74-I75
lOC -CH=CONHCH~CSH~N-2- HCl (2:1) 93-96
11C 8 CH3-1-C~H~N-2-HC1 (l:l) 183-186
l~C -CH~CONH~ CH3-1-C~H~N-Z-HCl (1:1) 188 (d)
13C -CH=COt~iC,8~C83-1-C~H~N-Z-HCI (1:1) 89-95
14C H C~H30-~- HCl (1:1) I86-187
15C -CS=CO=CIIsCH3C~H30-2- HC1 (l:l) 6Z-65
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49
No. Rl R= Salt m.p.(C)
isc -cH=eo~~ c,H,o-2- sci ci:i) 2os-2os
i~c H c,H,s-2- ec~ (1:1) 174-17s
iec -cx=coNH, c,H,s-~2- Hc~ W :l) z2o-22s
19C H C3HZNS-2- HC1 (1:1) 134-137
20C -CHZCOZCH=CA3C3H~NS-2- HC1 (l:l) 58-62
21C -CH~CONH~ C38~NS-2 HCl (1:1) 189-191
22C -CH=COZH C,A3S-2- - 152-156
23C -CH=COZH C,H30-2- - 78-82
CA 02290695 1999-11-16
In the general formula (ID)
Y represents a hydroxyl group, a (C1-C4)alkoxy group or
a group of general formula NR4R5 in which R4 and R5,
independently of each other, each represent a hydrogen
5 atom or a (C1-C4)alkyl group, and
R1 and R2 form, with the nitrogen atom and the carbon
atom which connect them, a pyrrolidine ring, a
piperidine ring or a 1,2,3,4-tetrahydroisoquinoline
ring.
10 The compounds of general formula (ID) can
exist in the form of cis or trans stereoisomers or
mixtures of such isomers; moreover, and on account of
the asymmetric carbon atom a to the group -C(O)Y, they
can exist in the form of pure enantiomers or mixtures
15 of enantiomers. They can also exist in the form of free
bases or of addition salts with acids.
The compounds of general formula (ID) can be
prepared by a process illustrated by Scheme D which
follows.
20 2-(6-Methoxy-1-naphthyl)propane-1,3-diol of
formula (IID) is reacted with 2-(3-chloropropyl)-1,3-
dioxolane of formula (IIID), in acidic medium and in an
aprotic solvent, in order to obtain 2-(3-chloropropyl)-
5-(6-methoxy-1-naphthyl)-1,3-dioxolane of formula
25 (IVD), and finally this compound is reacted with an
amine of general formula (VD), in which Y, R1 and R2 are
as defined above, in the presence of an organic or
inorganic base, in an aprotic solvent, for example N,N-
CA 02290695 1999-11-16
r
51
Scheme D
(IID)
~C.O
Cl (IIID)
1
0 0
(IVD)
~,~,
0
cvD)
O Y
N R=
O~Y
(ID)
~C~0
dimethylformamide, at a temperature of 20 to 110°C.
CA 02290695 1999-11-16
52
2-(6-Methoxy-1-naphthyl)propane-1,3-diol of
formula (IID) is described in patent application EP-
0,461,958. 2-(3-Chloropropyl)-1,3-dioxolane is
commercially available. The amines of general formula
(VD) are commercially available or are described in the
literature.
The examples which follow illustrate the
preparation of a number of compounds of general formula
(ID). The elemental microanalyses and the IR and NMR
spectra confirm the structures of the compounds
obtained. The compound numbers indicated in parentheses
in the titles correspond to those in Table D given
later.
Example 1D (Compound No. 1D).
Ethyl 1-[3-[5-(6-methoxy-1-naphthyl)-1,3-dioxan-2-
yl]propyl]-L-prolinate oxalate.
1D.1. 2-(3-Chloropropyl)-5-(6-methoxy-1-naphthyl)-1,3-
dioxane.
5 g (21.5 mmol) of 2-(6-methoxy-1-
naphthyl).propane-1,3-diol, 3.7 ml (28.05 mmol) of 2-(3-
chloropropyl)-1,3-dioxolane and then 40 ml of
hydrochloric ether are introduced into a 500 ml round-
bottomed flask containing 150 ml of toluene, and the
mixture is refluxed for 6 h.
The mixture is allowed to cool, 100 ml of
aqueous 5~ sodium hydrogen carbonate solution are added
CA 02290695 1999-11-16
53
and this mixture is extracted with twice 100 ml of
ethyl acetate. The organic phase is washed with water,
dried over magnesium sulphate and filtered, the solvent
is evaporated off under reduced pressure and the
residue is purified by chromatography on a column of
silica gel, eluting with a 9/1 mixture of petroleum
ether and ethyl acetate. 3.2 g of a white solid are
obtained, which product is used without further
purification in the following step.
1D.2. Ethyl 1-[3-[5-(6-methoxy-1-naphthyl)-1,3-dioxan-
2-yl]propyl]-L-prolinate oxalate.
0.32 g (1 mmol) of 2-(3-chloropropyl)-5-(6-
methoxy-1-naphthyl)-1,3-dioxane, 0.22 g (1.2 mmol) of
ethyl L-prolinate, 0.3 g (2.2 mmol) of potassium
carbonate and then 0.29 g (2 mmol) of potassium iodide
are introduced into a 50 ml round-bottomed flask
containing 10 ml of N,N-dimethylformamide and the
mixture is heated at 100°C for 4 h.
The mixture is allowed to cool, 50 ml of
water are added and this mixture is extracted with
twice 70 ml of ethyl acetate, the organic phase is
washed with water, dried over magnesium sulphate and
filtered, the solvent is evaporated off under reduced
pressure and the residue is purified by chromatography
on a column of silica gel, eluting with a gradient of
dichloromethane and methanol of from 99.5/0.5 to 99/1.
0.22 g (0.5 mmol) of compound is obtained,
CA 02290695 1999-11-16
54
which is crystallized, in the form of the oxalate, from
ethyl acetate.
Melting point: 116-118°C.
Example 2D (Compound No. 2D).
1-[3-[5-(6-Methoxy-1-naphthyl)-1,3-dioxan-2-yl]propyl]-
L-prolinamide.
0.5 g (1.6 mmol) of 2-(3-chloropropyl)-5-(6-
methoxy-1-naphthyl)-1,3-dioxane, 0.2 g (1.9 mmol) of L-
prolinamide, 0.2 g (1.6 mmol) of potassium carbonate
and then 0.48 g (3.2 mmol) of potassium iodide are
introduced into a 50 ml round-bottomed flask containing
ml of N,N-dimethylformamide and the mixture is
heated at 110°C for 3 h 30.
The mixture is allowed to cool, 60 ml of
15 water are added and the resulting mixture is extracted
with twice 80 ml of ethyl acetate. The organic phase is
washed with water, dried over magnesium sulphate and
filtered, the solvent is evaporated off under reduced
pressure and the residue is purified by chromatography
on a column of silica gel, eluting with a gradient of
dichloromethane and methanol of from 99/1 to 97/3.
0.3 g of compound is obtained, which is crystallized in
the form of the base from 2-propanol.
Melting point: 164-166°C.
Example 3D (Compound No. 6D).
2-[3-[5-(6-methoxy-1-naphthyl)-1,3-dioxan-2-yl]propyl]-
CA 02290695 1999-11-16
N-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide
oxalate.
3D.1. N-Methyl-1,2,3,4-tetrahydroisoquinoline-3-
carboxamide.
5 1.75 g (8.5 mmol) of ethyl 1,2,3,4-
tetrahydroisoquinoline-3-carboxylate are introduced
into a 100 ml round-bottomed flask containing 25 ml of
a 33~ solution of methylamine in ethanol and the
mixture is left at 25°C for 20 h. It is concentrated to
10 dryness under reduced pressure and 1.7 g of compound
are obtained in the form of a colourless oil, which is
used without further purification in the following
step.
3D.2. 2-[3-[5-(6-Methoxy-1-naphthyl)-1,3-dioxan-2-
15 yl]propyl]-N-methyl-1,2,3,4-tetrahydroisoquinoline-3-
carboxamide oxalate.
0.5 g (1.6 mmol) of 2-(3-chloropropyl)-5-(6-
methoxy-1-naphthyl)-1,3-dioxane, 0.3 g (1.6 mmol) of N-
methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide,
20 0.2 g (1.6 mmol) of potassium carbonate and then 0.23 g
(1.5 mmol) of potassium iodide are introduced into a
100 ml round-bottomed flask containing 20 ml of
acetonitrile and the mixture is heated at 80°C for 8 h.
The mixture is allowed to cool, 20 m1 of
25 water are added and the resulting mixture is extracted
with twice 20 ml of ethyl acetate. The organic phase is
CA 02290695 1999-11-16
56
washed with water, dried over magnesium sulphate and
filtered, the solvent is evaporated off under reduced
pressure and the residue is purified by chromatography
on a column of silica gel, eluting with a 98/2 mixture
of dichloromethane and methanol. 0.12 g (0.25 mmol) of
compound,is obtained, which is crystallized, in the
form of the oxalate, from diisopropyl ether.
Melting point: 88-90°C.
Table D which follows illustrates the
chemical structures and the physical properties of a
number of compounds of general formula (ID).
In the "R1NCHRz" column, "pyrrol", "piper" and
"isoq" mean that R1 and R2 form, with the nitrogen atom
and the carbon atom which connect them, a pyrrolidine
ring, a piperidine ring or a 1,2,3,4-
tetrahydroisoquinoline ring, respectively.
In the "Salt" column, "-" denotes a compound
in the form of the base, "fum." denotes a fumarate (or
(E)-2-butenedioate), "ox." denotes an oxalate (or
ethanedioate) and "HC1" denotes a hydrochloride; the
acid/base molar ratio is indicated in parentheses.
In the "m.p. (°C)" column, "(d)" denotes a
melting point with decomposition.
CA 02290695 1999-11-16
57
Table D
HsC~O
N ' Ri
O O O ~ Y
i i
( ID)
No.Y R1NC8R= Cotlfig. salt m.p.(~C)
1D -OCHZCH3pyrrol S ox . ( 1 116 - 2
:1 ) -118 6
2D -NHZ pyrrol S 1 164-166n.
d.
3D -NHCFI;pyrrol S - 119 - 3
-121 0
4D -OCH=Cfi;piper RS ox. tl:l) 129-131-
SD -NHC8; pyrrol RS - 99-101
6D -NHt~; isoq RS ox. tl: 88-90
)
CA 02290695 1999-11-16
58
The compounds according to the invention
underwent pharmacological tests which revealed their
value as therapeutic substances.
Neuronal antisodium properties
The entry of calcium brought about by a
depolarizing stimulus in rat cortical synaptosomes can
be measured using a fluorescent probe, according to the
method described by A. Deffois et al. in Neurosciences
Letters (1996) 220 117-120.
The effects of a sodium-channel agonist such
as veratridine (10 ~1M) on the increase in the levels of
intracellular calcium in this model are inhibited by
the compounds of the invention at ICSO (concentrations
which inhibit the response by 50~) values of from 0.1
tolO~.lM.
Activity on tonic convulsions induced in mice by
supramaximal electric shock
The procedure of this test is described by
E.A. Swinyard and J.H. Woodhead in Antiepileptic Drugs,
Raven Press, New York, 111-126 (1982).
10 min after intravenous administration of
the test compound, a note is made of the number of mice
showing tonic convulsions (extension of the fore- and
hind limbs), immediately after application of an
electric current (0.4 s, 60 mA, 50 Hz) using an Apelex
ETC UNIT 7801TM machine. The results are expressed by
CA 02290695 1999-11-16
59
the ADSO, the dose which protects 50 of the animals,
which is calculated according to the method of
J.T. Lichtfield and F. Wilcoxon (J. Pharm. Exp. Ther.,
96, 99-113 (1949)), using the ProbitTM software,
starting with 3 or 4 doses each administered to a group
of 8 mice. The ADSo values of the most active compounds
range from 1 to 10 mg/kg.
Anti-ischaemic properties
The compounds were subjected to the global
cerebral ischaemia test in mice.
The ischaemia is caused by a cardiac arrest
induced by a rapid intravenous injection of magnesium
chloride. In this test, the "survival time", i.e. the
interval between the moment of injection of the
magnesium chloride and the last observable respiratory
movement of each mouse, is measured. This last movement
is considered as the final indicator of central nervous
system functioning. Breathing stops approximately 19
seconds after the injection of magnesium chloride.
Male mice (Charles River CD1) are studied in
groups of ten. They are fed and watered freely before
the tests. The survival time is measured 10 minutes
after the intraperitoneal administration of the
compounds of the invention. The results are given in
the form of the difference between the survival time
measured in a group of ten mice which received the
compound, and the survival time measured in a group of
CA 02290695 1999-11-16
ten mice which received the liquid vehicle. The
relationships between the changes in the survival time
and the dose of the compound are recorded in graph form
on a semilogarithmic curve.
5 This curve makes it possible to calculate the
"3-second effective dose" (ED3~~), i.e. the dose (in
mg/kg) which produces a 3-second increase in the
survival time relative to the control group of ten
untreated mice.
10 A 3-second increase in the survival time is
both statistically significant and reproducible.
The ED3~~ values of the most active compounds
of the invention are from about 0.05 to 0.2 mg/kg via
the intravenous route.
15 Antinociceptive activity
The antinociceptive activity is evaluated in
rats, during the second stage of a formalin test
adapted from the work by A. Tjolsen, O.-G. Berge,
S. Hunskaar, J.H. Rosland and K. Hole in Pain (1992) 51
20 5-17.
Formalin (5~) is injected subcutaneously (100
~,1) into the plantar arch of the left hind paw. The
nociception is quantified, after injection, by
measuring, for the injected paw, the total duration of
25 licking activity, between +20 and +35 min, and by the
number of shuddering actions, measured in 2-min
sequences, every 5 min, between +35 and +60 min.
CA 02290695 1999-11-16
' '.
61
The compounds are administered at doses of 30
and 60 mg/kg, as a suspension (water + Tween 80 at 1~),
orally (5 ml/kg), 30 min before the injection of
formalin.
A compound is considered active if, after
treatment, by comparison with the values measured in
animals which have received the vehicle, a
statistically significant reduction (p<=0.05) in the
total duration of the licking activity and/or in the
number of shuddering actions (calculated from the areas
under the curve) is observed.
The activity threshold for the compounds of
the invention corresponds to reductions of 35 to 40~.
The most active compounds result in a 50~ reduction at
a dose of 30 mg/kg via the oral route.
The results of the tests show that the
compounds according to the invention have
neuroprotective properties and that they can therefore
be used for the preparation of medicaments which are
useful in the treatment or prevention of
cerebrovascular disorders of ischaemic or~hypoxic
origin (cerebral infarction, cranial or medullary
trauma, cardiac or respiratory arrests, transient
ischaemic attack, perinatal asphyxia), glaucoma,
progressive neurodegenerative diseases (senile
demential such as Alzheimer's disease, vascular
dementia, Parkinson's disease, Huntingdon's disease,
olivopontocerebellar atrophy, amyotrophic lateral
CA 02290695 1999-11-16
"
' x
62
sclerosis, neurodegenerative diseases of viral origin,
etc.), and in the prevention of cerebral ischaemic
accidents associated with cardiac and vascular surgery
and endovascular therapy.
On account of their anticonvulsive
properties, they can also be used in the treatment of
epilepsy. The compounds of the invention also have
analgesic properties and can thus be used in the
treatment of any acute or chronic pain.
Lastly, the treatment of other complaints,
such as neuropathy, neurogenic pain (for example pain
associated with neuropathies or with migraine attacks),
neurological spasticity and dyskinesia, can also be
envisaged.
The compounds of the invention can be in any
pharmaceutical composition form which is suitable for
enteral or parenteral administration, such as tablets,
coated tablets, gelatin capsules, wafer capsules,
drinkable or injectable suspensions or solutions, such
as syrups, vials, etc., combined with suitable
excipients, and dosed to allow a daily administration
of from 1 to 1000 mg of active substance.
