DECLARATION
We, SANOH-SYNTHELABO, of 174, Avenue de France, FR -75013 PARIS,
France, do hereby certify to the best of our knowledge, information and
belief that the annexed specification is a true and complete translation in
English of the specification as filed in connection with the International
Application No. PCT/FRO1/02656 dated August 23, 2001.



1
(AMINOALKENYLBENZOYL)BENZOFURANS OR BENZOTHIOPHENES,
THEIR PROCESS OF PREPARATION AND THE COMPOSITIONS
COMPRISING THEM
The present invention relates generally to
novel heterocyclic derivatives and to their process of
preparation.
More specifically, the invention relates to
novel benzofuran or benzothiopene derivatives which can
be represented by the general formula:

and to their pharmaceutically acceptable salts, in
whi ch:
C C represents the -CH -CH— group or the
—C:rzC— group,
A represents a linear or branched Ci-C3 alkylene group
or a C2-C3 alkenylene group,
T represents hydrogen or a Ci-C4 alkyl radical,
R represents:
• the cyano, hydroxymethyl, formyl or tetrazolyl
group,
• an ester group of general formula:
2

in which R4 represents a Ci-Ce alkyl or C3-Ce
cycloalkyl group,
a carboxyl group of general formula:

in which R5 represents hydrogen or an alkali metal
atom,
an amide group of general formula:

in which Re and R7, which are identical or
different, represent hydrogen or a linear or
branched Ci-C4 alkyl radical or R6 and R7, when they
are taken together, represent a C2~Ce alkylene
chain,
a group of general formula:

in which Rig, RI? and RIB, which are identical or
different, represent a linear or branched GI-CS
3
alkylene group,
RI represents hydrogen, a linear or branched Ci-Ce alkyl
group, a C^-Ce cycloalkyl group or a phenyl group,
R2 and RB , which are identical or different, represent
hydrogen, a linear or branched Ci-Cg alkyl group or a
Cs-Ce cycloalkyl group,
or R2 and R3, when they are taken together, represent a
linear or branched CS-CIQ alkylene group,
' these alternatives R2 and R3/ which are identical or
different, and R2 and R3, taken together, being
represented in the formula {1} by the symbol

situated between R2 and RS,

W, W.' and Z are such that:
- when W and W, which are identical, represent
CH, Z represents -O- or -S-
- when W represents CH and W represents C-Rs, Z
I
represents -CH=C-Rg, R& and R9 being identical or
different and representing hydrogen, a halogen
atom, for example chlorine or bromine, a Ci-C4
alkyl radical, such as methyl, or a Ci-C4 alkoxy
radical, such as methoxy,
X represents -0- or -S-,
these benzofuran or benzothiphene derivatives being.in
the form of individual isomers or of mixtures of the
latter.
In particular, the benzofuran or benzothiopene

4
derivatives according to the invention are
characterized in that
C C represents the -CH CH- group.
Classes of preferred compounds of the
invention can be represented by the compounds of
formula (1);
- in which R represents an isopropoxycarbonyl
group
- or in which RI and/or R2 and/or R3' represent the
n-butyl group
- or in which X represents -O-.
Another class of preferred compounds of
formula (1) is that in which

represents the benzoyl radical.
Likewise, a specific class of compounds of
formula (1) is that in which the entity:

represents a benzoyl radical substituted in the
4-position by a

group
5
Finally, the compounds of formula (1) in
which R! represents [lacuna] n-butyl [lacuna], A
represents the methylene group and R2 and R3/ which are
identical, represent the n-butyl group can be regarded
as preferred.
The compounds of formula (1) can be provided
in the form of E or Z geometrical isomers.
Consequently, the invention relates both to
the individual isomers of the compounds of formula (1)
and.to their mixtures.
In addition, the E isomers of the compounds
of formula (1) constitute preferred compounds.
The invention also relates to the
pharmaceutically acceptable salts of the compounds of
formula (1) formed from an organic or inorganic acid.
Mention may be made, as examples of organic
salts of this type, of the oxalate, maleate, fumarate,
methanesulfonate, benzoate, ascobate, pamoate,
succinate, hexamate, bismethylenesalicylate, ethane-
disulfonate, acetate, propionate, tartrate, salicylate,
citrate, gluconate, lactate, malate, cinnamate,
mandelate, citraconate, aspartate, palmitate, stearate,
itaconate, glycolate, p-aminobenzoate, glutamate,
benzenesulfonate, p-toluenesulfonate and theophylline-
acetate, and the salts formed from an amino acid, such
as the lysine or histidine salt.
Mention may be made, as inorganic salts of

6
this type, of the hydrochloride, hydrobromide, sulfate,
sulfamate, phosphate and nitrate.
Mention may in particular be made of
isopropyl 2-butyl-3-[4-[(E)-3-(dibutylamino)-1-
propenyljbenzoyl]-l-benzofuran-5-carboxylate
hydrochloride.
It has been found that the compounds of the
invention possess noteworthy pharmacological
properties, in particular antiarrhythmic properties,
since they have proved to be capable of suppressing or
preventing disorders of the ventricular and auricular
rhythm. Most of the compounds of the invention have
electrophysiological properties of classes 1, 2, 3 and
4 of the Vaughn-Williams classification, which confer
bradycardic, antihypertensive and anti-a-adrenergic and
anti-p-adrenergic properties which are noncompetitive.
Furthermore, the majority of the compounds have also
displayed antioxidizing properties, an affinity for
sigma receptors and an ability to enhance the synthesis
of NO.
Furthermore, these compounds of the invention
demonstrate inhibitory properties with respect to
various hormonal agents, such as, for example,
angiotensin II, arginine vasopressin, neuropeptide Y or
endothelin.
These properties are capable of rendering the
compounds in question very useful in the treatment of

7
certain pathological syndromes of the cardiovascular
system, in particular in the treatment of angina
pectoris, hypertension, arrhythmia, in particular
atrial, ventricular or supraventricular arrhythmia, or
cerebral circulatory insufficiency. Likewise, the
compounds of the invention can be used in the treatment
of cardiac insufficiency or myocardial infarction,
complicated or not complicated by cardiac
insufficiency, or for the prevention of post-infarction
mortality.
In the antitumor field, the compounds of the
invention may be of use as potentiators of
antineoplastics.
Consequently, the invention also relates to a
medicament, characterized in that it comprises a
compound derived from benzofuran or benzothiophene, or
a pharmaceutically acceptable salt of the latter,
according to the invention.
Consequently, the invention also relates to
pharmaceutical or veterinary compositions comprising,
as active principle, at least one compound of the
invention in combination with an appropriate excipient
or pharmaceutical vehicle.
Depending upon the administration route
chosen, the daily dosage for a human being weighing
60 kg will lie between 2 and 2 000 mg of active
principle, in particular between 50 and 500 mg of

8
active principle.
The compounds of formula (1) can be prepared
according to the following methods:
A. - In the case where R represents the cyano
group, the formyl group, a group (a) or a group (c) and
when the .-compound of formula (1) is in the form of an
isomer with the E configuration, by reacting a compound
of general formula:

(2)
in which R' represents the cyano group, the formyl
group, a group (a) or a group (c), RIO represents a
halogen atom, preferably bromine or iodine, or the
trifluoromethanesulfonyloxy group and Rit T, X, W, W
and Z have the same meaning as above, with an organotin
derivative with the E configuration corresponding to
the general formula:
in which A, R2 and R3 have the same meaning as above and
RH represents a Ci-C4 alkyl radical, in particular a
butyl radical, after protection of the amine functional
group when R2 and/or £3 represent hydrogen, this

9
reaction being carried out 'in the presence of lithium
chloride and of an organopalladium derivative, such as
tetrakis(triphenylphosphine)palladium, and then by
deprotecting, if necessary, the compound thus formed,
which gives the desired compounds of formula (1) in the
free base form.
Usually, the reaction takes place at the
reflux temperature of the solvent, which can, for
example, be an ether, such as dioxane.
In addition, the protection of the amine
functional group of the compound of formula (3), that
is to say the protection envisaged when R2 and/or RB
represent hydrogen, can be obtained, for example, by
treatment by means of a compound which makes possible
the attachment of a group which can be easily removed,
in particular by means of a t-butoxycarbonyl anhydride,
and the deprotection is carried out subsequently, in
this case, after treatment in an acidic medium.

in which A, R', Rif R2, R3, T, W, W, X and Z have the
B. - In the case where R represents the cyano
group, the formyl group, a group (a) or a group (c) and
when the compound of formula (1) is in the form of an
isomer with the 1 configuration, by hydrogenating an

9
same meaning as above, this reaction being carried out
in the presence.of an appropriate catalyst, such as
palladium-on-charcoal, which gives the desired
compounds of formula (1) in the free base form.
Usually, the reaction is carried out in a
solvent, such as an aromatic hydrocarbon, for example
toluene, and at ambient temperature.
C. - In the case where R represents a group
(b), by saponifying a-compound of formula (1) as above
in which R represents a group (a), that is to say a
compound of general formula:

in which A, RI, R2, RS, R4, T, W, W and Z have the same
meaning as above, in the presence of a basic agent,
namely an alkali metal hydroxide, for example sodium >
hydroxide, which gives, in the free base form, the
compounds of formula (1) in which R5 represents an
alkali metal atom, which compounds are treated, if
necessary, with a strong acid, for example hydrochloric
acid, which gives, in the free base form, the desired
compounds of formula (1) in which R5 represents
hydrogen.
D. - In the case where R represents the
hydroxymethyl group, by deprotecting a ketal of general

10

in which A, RI, R2, R3, T, X, W, W and Z have the same
meaning as above, this reaction being carried out by
. means of pyridine p-toluenesulfonate and preferably at
the reflux temperature, which gives the desired
compounds of formula (1) in the free base form.
The benzofuran or benzothiophene derivatives
of formula (1) which also correspond to the general
I formula:

in which A, RI, R2/ R3, T, W, W, X and Z have the same
meaning as above, are themselves synthetic
intermediates for the preparation of compounds of
formula (1).
E. - For example, the compounds of formula
(1).in which R represents a group (c) in which R6 and R7
are identical and each represent hydrogen can be
prepared alternatively by reacting a compound of
formula (7) in question by means of dicyclohexylcarbo-
diirnide in the presence of hydroxybenzotriazole and of

ammonia, which gives the desired compounds of formula
(1) in the free base form.
Other compounds of formula (1) can be used as
intermediates in the synthesis of compounds of the
invention, in particular the cyano derivatives which
also correspond to the general formula:

in which A, R!, R2, RS, T, W, W, X and Z have the "same
meaning as above.
Thus, use may be made of the following
methods, that is to say:
F. - In the case where R represents a group
(c) in which R6 and R? each represent hydrogen, a
compound of formula (8) is hydrolyzed in the presence
of, a strong acid, such as, for example, sulfuric acid,
and generally at ambient temperature, which gives the
desired compounds of formula (1) in the free base form.
G. - In the case where R represents the
tetrazolyl group, a compound of formula (8) is reacted,
preferably in an aprotic solvent, such as an aromatic
hydrocarbon, for example benzene or toluene, and
usually at the reflux temperature of the medium, with a
[tri(Ci-C4 alkyl)Jazidotin, for example tributyltin
azide, which gives the desired compounds of formula (1)
in the free base form.

13
The methods described above make it possible
to obtain the compounds of formula {1} in the form of
individual E or Z isomers or in the form of mixtures of
the latter, according to the process employed.
If necessary, these isomers can be produced
in the separate form from their mixtures by employing
known methods, such as, for example, .chromatography or
precipitation.
H. - The compounds of formula (1) obtained in the "free
base form according to one or other of the methods
described above can subsequently be converted, if
necessary, to pharmaceutically acceptable salts by
reaction with an appropriate organic or inorganic acid,
for example oxalic, maleic, fumaric, methanesulfonic,
benzoic, ascorbic, pamoic, succinic, hexamic,
bismethylenesalicylic, ethanedisulfonic, acetic,
propionic, tartaric, salicylic, citric, gluconic,
lactic, malic, cinnamic, mandelic, citrac.onic,
aspartic, palmitic, stearic, itaconic, glycolic,
p-aminobenzoic, glutamic, benzenesul(f onic, p-toluene-
sulfonic or theophyllineacetic acid, lysine or
histidine, .or hydrochloric, hydrobromic, sulfuric,
sulfamic, phosphoric or nitric acid.
The compounds of formula {2} can be obtained:
a) when RIO represents a halogen atom, by
reacting a compound of general formula:


in which R', R! and T have the same meaning as above,
with a halide of general formula:

in which W, W and Z have the same meaning as above and
Hal and Hal', which are identical or different,
represent a halogen atom, preferably bromine or iodine,
this reaction being carried out in the presence of a
Lewis acid, such as aluminum chloride, ferric chloride
or stannic chloride, to form the desired compounds of
formula (2) ;
b) when RIO represents a trifluoromethane-
sulfonyloxy group, by reacting a compound of general
formula:

in which R', Rj, T, W, W, X and Z have the same meaning
as above; this reaction being carried out with
trifluoromethanesulfonic anhydride in the presence of
an acid acceptor, such as pyridine, which gives the
desired compounds of formula (2).
As regards the tin compounds of formula (3),

15
they can be obtained by reacting an alkynylamine of
general formula:
/R2,
HC=C — A— N, )
^R3/ (12)
/R2,
HC=C —A—N, )
^R3/ (12)
in which A, R2 and RI have the same meaning as above,
after protection of the amine functional group when R2
and/or R3 represent.hydrogen, this reaction being
carried out with a hydride of general formula:
(RnhSn-H (13)
in which RH has the same meaning as above, which gives
the desired compounds of formula (3).
With regard to the compounds of formula (4),
they can be prepared by reacting a compound of formula
(2) with an alkyne derivative of formula (12), after
protection of the amine functional group when R2 and/or
Ra represent hydrogen, this reaction being carried out
in the presence of an organopalladium compound as
catalyst, essentially a salt of palladium(II)
preferably complexed with at least one organophosphorus
compound comprising trivalent phosphorus, for example
dichlorobis{triphenylphosphine)palladium, and then, if
necessary, the compound thus formed is deprotected,
which gives the desired compounds of formula (4).
The protection of the amine functional group
of the compound of formula (12), that is to say the
protection envisaged when R2 and/or R3 represent

16
hydrogen, can be obtained, for example, by treatment by
means of a compound which makes possible the attachment
of a group which can be easily removed in particular by
means of a t-butyoxycarbonyl anhydride, and the
deprotection is carried out subsequently, in this case,
by treatment in an acidic medium.
The compounds of formula (6) can be prepared
starting from an ester of formula (1) in which R
represents a group (a):
(a) by treating this ester of formula (1) at the
reflux temperature of the medium with glycol in the
presence of p-toluenesulfonic acid, to form a diether
of general formula:

in which A, RI, R2, R3, R4/ T, X, W, W and Z have the
same meaning as above,
(b) by reducing this compound of formula (14) by
means of an alkali metal hydride, such as lithium
aluminum hydride, and .in a solvent, such as an ether,
to produce the desired compounds.
The compounds of formula (9) in which R' is
situated in the 5-position and represents the cyano
group or a group (a) and Rj. is situated in the 2- -
position can be prepared according to the sequence of
stages below:


a) either, a cyano derivative of general formula:
in which T and X have the same meaning as above,
is treated with iodine in the presence of ammonia
to form an iodo derivative of general formula:

in which T and X have the same meaning as above,
or, a benzoic acid derivative of general formula:

in which T and X have the same meaning as above,
is treated first with an alkali metal iodide and
an oxidizing agent, such as an alkali metal
hypochlorite, for example sodium hypochlorite, and
subsequently with an alcohol of general formula:

in which R4 has the same meaning as above, which
gives an iodo derivative of general formula:


18
in which R^, T and X have the same meaning as
above,
b) the iodinated derivative of formula (16) or (19)
is reacted with an acetylenic derivative of general
formula:
in which RI has the same meaning as above, this reaction
being carried out in the presence of an appropriate
catalyst, such as a palladium derivative, for example
tetrakis(triphenylphosphine)palladium, and of cuprous
iodide, which gives the desired compounds of formula
(2) .
If necessary, the preparation of the ester of
formula (19) can be carried out according to the method
described above but starting from an acid of formula
(17) in the acyl halide form obtained after treatment
of the benzole acid derivative of formula (17) by means
of a halogenating agent, for example thionyl chloride,
phosgene or oxalyl chloride.
B. - The compounds of formula (9) in which R' is
situated in the 6-position and represents the cyano
group or a group (a) and Ra is situated in the 2-
position can be obtained as follows:


19
a) a compound of general formula
in which T and X have the same meaning as above and R'i
represents the cyano group or a group (a), is reacted
with trifluoromethanesulfonic anhydride in the presence
of pyridine, to produce a compound of general formula:

in which R'i, RI, T and X have the same meaning as
in which R'i, T and X have the same meaning as ar»ove,
b) the compound thus formed is reacted with an
acetylenic derivative of formula (20) , this reaction
being carried out in the presence of an appropriate
catalyst, for example a palladium derivative, such as
dichlorobis(triphenylphosphine)palladium, and of an
acid acceptor, such as triethylamine, to form the
compounds of general formula:


20
above,
c) this compound of formula (23) is then
cyclized in the presence of boron tribromide at a
temperature of less than -50°C/ which gives the
heterocyclic compounds of general formula:

in which RI, T and X have the same meaning as above and
R"i represents the cyano or carboxylic group, which
gives either desired compounds of formula (9) when R"i
represents the' cyano group or an acid when R"i
represents the carboxylic group,
d) this acid is esterified with an alcohol of
formula (18), which gives desired compounds of formula
(9) .
C. - The compounds of formula (9) in which R' is
situated in the 4-position and represents the cyano
group or a group (a) and RI is situated in the 2-
position can be obtained as follows: . .
a) a compound of general formula:

in which R'i, T and X have the same meaning as above, is
reacted with trifluoromethanesulfonic acid in the
presence of pyridine, to produce a compound of general

21
formula:
in which R'i, T and X have the same meaning as above,
b) the compound thus formed is reacted with an
acetylenic derivative of formula (20), this reaction
being carried out in the presence of an appropriate
catalyst, such as a palladium derivative, for example
dichlorobis(triphenylphosphine)palladium, and of an
acid acceptor, such as triethylamine, to form the
compounds of general formula:

in which R'i, RI and X have the same meaning as above,
c) this compound of formula (27) is then
cyclized in the presence of boron tribromide, which
gives the heterocyclic compounds of general formula:

in which R'i, RI, T and X have the same meaning as
above, which correspond to the desired compounds of
formula (9).
Alternatively, the compounds of formula (9)

22
in which R' is situated in the 5-position and
represents the cyano group or a group (a) and Ri is in
the 2-position can also be prepared as follows:
I. When R' represents a group (a):
a) a benzoate of general formula:

in which R4, T and X have the same meaning as above, is
first treated with methanesulfonic acid in the presence
of phosphorus pentoxide and hexamethylenetetraamine, tc
give a formyl derivative of general formula:

in which R4, T and X have the same meaning as above,
b) this compound of formula (30) is subsequently
reacted with an ester of general formula:

in which RI has the same meaning as above, which gives
the compounds of general formula:

23

in which Rlf R4, T and X have the same meaning as above,
c) this ester of formula (32) is treated with
formic acid or trifluoroacetic acid, which gives the
acids of general formula:

in which Rlt R4, T and X have the same meaning as above,
d) this compound (33) is cyclized in the
presence of benzenesulfonyl chloride or p-toluene-
sulfonyl chloride and of an acid acceptor, such as
triethylamine, which gives the desired compounds of
formula (9)'.
II. When R' represents the cyano group:
a) a formyl derivative of general formula:

24

in which Hal, T and X have the same meaning as above,
is first treated with zinc cyanide in the presence of
an appropriate catalyst, for example a palladium
derivative, such as tetrakis(triphenylphosphine)-
palladium, which gives the compounds of general
formula:
in which T and X have the same meaning as above,
b) this compound of formula (35) is subsequently
demethylated with lithium chloride, which gives the
compounds of general formula:

in which T and X have has the same meaning as above,
c) this compound of formula {36} is then" treated
with an ester of general formula:

25

in which RI and R4 have the same meaning as above, this
reaction being carried out in the presence of a basic
agent, such as an alkali metal carbonate, which gives
the compounds of general formula:

in which R1( R4/ T and X have the same meaning as above,
d) and e) this ester of formula (38) is saponified
in the presence of a basic agent, such as an alkali
metal hydroxide, and the acid thus obtained is cyclized
in the presence of benzenesulfonyl chloride or
p-toluenesulfonyl chloride and of an acid acceptor,
such as triethylamine, which gives the desired
compounds.
The compounds of formula (9) in which R' is
situated in the 7-position and represents the cyano
group or a group (a) and R! is situated in the 2-
position can be obtained according to the sequence of
stages below:
a) an alcohol of general formula:

26

in which R12 represents a cyano or formyl group and T
and X have the same meaning as above, -is treated, this
reaction being carried out with methyl iodide in the
• presence of an alkali metal hydride, to give a compound
of general formula:
in which R12, T and X have the same meaning as above,
b) the compound thus formed is reacted with
trifluoromethanesulfonic anhydride, to form a compound
of general formula:

in which R12, T and X have the same meaning as above,
c) the compound thus formed is treated with a
compound of formula (20) in the presence of an
'appropriate catalyst, such as a palladium derivative,
for example dichlorobis(triphenylphosphine)palladium
which produces the compound of general formula:

27

in which RI, Ri2, T and X have the same meaning as
above,
d) the compound of formula (42) thus formed is
subsequently reacted:
• when Ri2 represents, the cyano group, with lithium
chloride, to form the desired compounds of formula
(9) in which R' represents the cyano group,
• when Ri2 represents the formyl1 group, with an
alkali metal cyanide in the presence of manganous
oxide and acetic acid, to give a compound of
general formula:

in which RI, T and X have the same meaning as
above, which is cyclized with lithium chloride, to
give a mixture of ester and of acid of general
formula:

in which RI, X and T have the same meaning as above

2
O
O
and RIB represents the methoxycarbonyl or
carboxylic group, which mixture is treated with
methanol in the presence of a strong acid, such as
sulfuric acid, which gives the desired compounds
of formula (9) in which R' represents the
methoxycarbonyl group.
The other compounds of formula (9), that is to say
the compounds of formula (9) in which R', situated
in the 7-position, represents a group (a), with
the exception of the methoxycarbonyl group, can be
obtained by saponifying an ester of formula (9) in
which R', situated in the 7-position, represents
the methoxycarbonyl group, this reaction being
carried out in the presence of a basic agent, such
as an alkali metal hydroxide, to give a salt,
which is acidified with a strong acid, such as
hydrochloric acid, to give a 7-carboxybenzofuran
derivative, which is esterified with an alcohol of
general formula:
'R'4-OH (45)
in which R'4 represents a C2-Ce alkyl group or a
Cs-Ce cycloalkyl group, which gives the desired
compounds of formula (9).
The compounds of formula (9) in which R'
)
represents the formyl group can be prepared by
oxidizing, with oxalyl chloride, an alcohol of
general formula:

29

in which Rlf T and X have the same meaning as
above, to give the desired compounds.
Likewise, the compounds of formula (9) in
which R' represents a group (c) can be obtained by:
* saponifying an ester of formula (9) in which R'
represents a group (a), this reaction being carried out
by means of an alkali metal hydroxide, to produce an
alkali metal derivative,
* treating the alkali metal derivative in question
with a strong acid, such as hydrochloric acid, to form
an acid,
* halogenating this acid by means of an
appropriate halogenating agent, such as thionyl
cfcloride, to produce an acyl halide,
* by amidating the acyl halide thus obtained, this
reaction being carried out by means of a compound of
general formula:

in which. Re and R7 have the same meaning as above, to
form the desired compounds of formula (9).
The compounds of formula (10) can be obtained
with the sequence of stages below:
a) acylation of a compound of general formula:

30

in which Hal', W, W and Z have the same meaning as
above, with acetyl chloride, this reaction being
carried out in the presence of a Lewis acid, such as
aluminum chloride, to form a compound of general
formula:
in which Hal', W, W and Z have the same meaning as
above,
b) reaction of the compound thus formed, first
with bromine in the presence of an alkali metal
hydroxide and subsequently with a strong acid, such as
hydrochloric or sulfuric acid, to produce the acids of
general formula:

in which Hal', W, W and Z have the same meaning as
above,
c) halogenation of the acid thus formed by
treatment by means, for example, of thionyl chloride,
to produce the desired compounds of formula (10).
As regards the compounds of formula (11),
they can be obtained by reacting a benzofuran or
benzothiophene derivative of formula (9) [lacuna] .a

halide of general formula:

in which Hal represents a halogen atom, such as
chlorine or bromine, this reaction being carried out in
the presence of a Lewis acid as catalyst, for example -
ferric chloride, aluminum chloride or tin
tetrachloride, which gives the methoxy derivatives of
general formula:

in which R', R1( T, W, W, X and Z have the same meaning
as above, which methoxy derivatives are demethylated by
heating in the presence, for example, of aluminum
chloride, to form the desired compounds.
Alternatively, the compounds of formula (11)
or of formula (52) in which R' represents a group (a),
a group (b) or a group (c) can be obtained for
employing various methods, according to which:
* an ester of general formula:


32
in which Rly T, W, W , X and Z have the same meaning as
above, Ri4 represents a Ci-C4 alkyl radical, preferably
methyl or ethyl, and RIS represents hydrogen or the
methyl radical, is saponified, this reaction being
carried out with an alkali metal hydroxide, to produce
the compounds of formula (11) or of formula (52) in
which R' represents a group (b) in which R6 represents
an alkali metal atom,
* the alkali metal derivative thus formed is
treated with a strong acid, such as hydrochloric acid,
to produce an acid, that is to say the compounds of
formula (11) or of formula (52) in which'R' represents
a group (b) in which R6 represents hydrogen,
* the acid thus formed is treated:
either; a) with a halogenating agent, such as
thionyl chloride, to produce an acyl
chloride, which is esterified with an
alcohol of formula (18),
or
b) with an alcohol of formula (18) in
the presence of a strong acid as
catalyst, for example sulfuric acid, to
produce the compounds of formula (11) or
of formula (51) in which R' represents a
group (a),
or: with a halogenating agent, such as
thionyl chloride, to produce an acyl

33
chloride, which is amidated with a-
compound of formula (47), to produce the
compounds of formula (11) or of formula
(52) in which R' represents a group (c).
The other starting compounds or intermediates
involved in the various processes described above are
for the most part known compounds or compounds which
can be prepared by known methods.
Benzothiophene derivatives comprising a
1-alkenylbenzoyl chain and which are variously
substituted on the homocycle are already known. Such
compounds have been disclosed, for example, in patents
or patent applications US 5 827 876 or WO 97/01549,
where they are presented as possessing inhibiting
properties with respect to bone loss or properties for
the treatment of symptoms of the menopause or for the
treatment of restenosis.
In point of fact, it has now been discovered,
in the context of the invention, that benzofuran or
benzothiophene derivatives comprising an aminoalkenyl-
benzoyl chain and other groups attached to the
heterocycle via a carbon atom exhibit highly
advantageous pharmacological properties, in particular
antiarrhythmic properties, while offering very good
metabolic stability, highly acceptable solubility arid
very good bioavailability via the oral route.
The results of pharmacological tests carried

34
out for the purpose of determining properties of the
compounds of the invention with respect to the
cardiovascular system are listed below.
I. Ventricular arrhythmias
The aim of this test is to determine the ability
of the compounds of the invention to provide
protection against arrhythmias brought about by
reperfusion. To this end, use was made of the
method reported by Manning A.S. et al. in Circ.
Res., 1984, 55, 545-548, modified as follows:
Rats, divided into batches, are first
anaesthetized with sodium pentobarbital (60 mg/kg
via the intraperitoneal route) and then they are
intubated and maintained under assisted
respiration.
A cannula for intravenous administration is
subsequently inserted in their right jugular
veins, an intravenous dose of the compound to be
studied is administered and, 5 minutes later, a
ligature loop is placed around the left anterior
descending coronary artery in the immediate
proximity of its origin. This artery is then
occluded for 5 minutes by pulling on the ends of
the ligature, so as to induce reperfusion by
relaxing the tension.
The arrhythmias induced by this reperfusion are
then evaluated.

35
An analogous test was carried out by the oral
route. In this case, the compound to be studied is
administered 120 minutes before ligating the left
anterior descending coronary artery.
The results of these tests showed that the
compounds of the invention significantly protect
the treated animals, ranging up to 100% at doses
of between 0.3 and 10 mg/kg via the intravenous
route and 10 to 90 mg/kg via the oral route.
II. Antiadrenergic properties
The aim of this test is to determine the ability
of the compounds of the invention to reduce the
increase in blood pressure induced by
phenylephrine (anti-ex effect) and the acceleration
in heart rate induced by isoprenaline {'anti-p
effect) in dogs anaesthetized beforehand with
pentobarbital and chloralose.
For each dog, the dose of phenylephrine (5 or
10 /zg/kg) which leads to an increase in the
arterial pressure of between 25 and 40 mmHg and
the dose of isoprenaline {0.9 or 1 M