Title of Invention

"N-(1H-INDOLYL)-1H-INDOLE-2-CARBOXAMIDE DERIVATIVES AND THEIR PREPARATION"

Abstract The invention relates to compounds of general formula (I): in which Xl, X2, X3, X4, Z1, Z2, Z3, Z4 and Z5 represent, independently of one another, a hydrogen or halogen atom or a C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, cyano, C(O)NR1R2, nitro, NR1R2, C1-C6 thioalkyl, -S (O)- (C1-C6) alkyl, -S(O)2-(C1-C6)alkyl, SO2NR1R2, NR3COR4, NR3SO2R5 or aryl group; X5 represents a hydrogen or halogen atom or a C1-C6 alkyl or C1-C6 fluoroalkyl group; R represents an optionally substituted 4-, 5-, 6- or 7- indolyl group; Y represents a hydrogen atom or a C1-C6 alkyl group; n is equal to 0, 1, 2 or 3; R1 and R2 represent, independently of one another, a hydrogen atom or a C1-C6 alkyl, C3-C7 cycloalkyl, (C3-C7) cycloalkyl (C1-C3)alkyl or aryl group; or R1 and R2 form, together with the nitrogen atom which carries them, an azetidine, pyrrolidine, piperidine, azepine, morpholine, thiomorpholine, piperazine or homopiperazine group, this group optionally being substituted by a C1-C6 alkyl, C3-C7 cycloalkyl, (C3-C7) cycloalkyl (C1-C3) alkyl or aryl group; R3 and R4 represent, independently of one another, a hydrogen atom or a C1-C6 alkyl or aryl group; R5 represents a C1-C6 alkyl or aryl group; in the form of the base or of an addition salt with an acid, and in the hydrate or solvate form. Preparation process and application in therapeutics.
Full Text

A subject-matter of the invention is
compounds derived from N-(1H-indolyl)-1H-indole-2-
carboxamides which exhibit an in vitro and in vivo
antagonist activity for receptors of TRPV1 (or VR1)
type.
Compounds disclosed in the document WO-A-
03049702 of use in the treatment of diseases in which
receptors of VR1 type are involved are already known.
There still exists a need to find and develop
products exhibiting a good in vivo activity.
The invention meets this aim by providing
novel compounds which exhibit an in vitro and in vivo
antagonist activity for receptors of VR1 type.
A first subject-matter of the invention is
the compounds corresponding to the general formula (I)
below.
Another subject-matter of the invention is
processes for the preparation of the compounds of
general formula (I).
Another subject-matter of the invention is
the use of the compounds of general formula (I), in
particular in medicaments or in pharmaceutical
compositions.
The compounds of the invention correspond to

the general formula (I):

in which
X1, X2, X3, X4, Z1, Z2, Z3, Z4 and Z5 represent,
independently of one another, a hydrogen or halogen
atom or a C1-C6 alkyl, C3-C7 cycloalkyl,
C1-C6 fluoroalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy,
cyano, C(O)NRxR2, nitro, NR1R2, C1-C6 thioalkyl, -S(O)-
(C1-C6) alkyl, -S (O) 2- (C1-C6) alkyl, SO2NRxR2, NR3COR4,
NR3SO2R5 or aryl group;
X5 represents a hydrogen or halogen atom or a
C1-C6 alkyl or C1-C6 fluoroalkyl group;
R represents a 4-, 5-, 6- or 7-indolyl group,

R optionally being substituted in the 1, 2 and/or 3
position by one or more groups chosen from C1-C6 alkyl

and C1-C6 fluoroalkyl groups;
R optionally being substituted in the 4, 5, 6 and/or 7
position by one or more groups chosen from halogen
atoms or C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy or
C1-C6 fluoroalkoxy groups;
Y represents a hydrogen atom or a C1-C6 alkyl group;
n is equal to 0, 1, 2 or 3;
R1 and R2 represent, independently of one another, a
hydrogen atom or a C1-C6 alkyl, C3-C7 cycloalkyl, (C3-
C7) cycloalkyl (C1-C3) alkyl or aryl group; or R1 and R2
form, together with the nitrogen atom which carries
them, an azetidine, pyrrolidine, piperidine, azepine,
morpholine, thiomorpholine, piperazine or
homopiperazine group, this group optionally being
substituted by a C1-C6 alkyl, C3-C7 cycloalkyl,
(C3-C7) cycloalkyl (C1-C3) alkyl or aryl group;
R3 and R4 represent, independently of one another, a
hydrogen atom or a C1-C6 alkyl or aryl group;
R5 represents a C1-C6 alkyl or aryl group.
In the context of the present invention:
- Ct-Cz, where t and z can take the values from 1 to 6,
is understood to mean a carbon chain which can have
from t to z carbon atoms, for example C1-C3 is
understood to mean a carbon chain which can have from
1 to 3 carbon atoms;
- an alkyl is understood to mean a saturated, linear or
branched, aliphatic group. Mention may be made, by

way of examples, of the methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, tert-butyl or pentyl
groups, and the like;
- a cycloalkyl is undertood to mean a cyclic carbon
group. Mention may be made, by way of examples, of
the cyclopropyl, cyclobutyl, cyclopentyl or
cyclohexyl groups, and the like;
- a fluoroalkyl is understood to mean an alkyl group,
one or more hydrogen atoms of which have been
substituted by a fluorine atom;
- an alkoxy is understood to mean an -O-alkyl radical
where the alkyl group is as defined above;
- a fluoroalkoxy is understood to mean an alkoxy group,
one or more hydrogen atoms of which have been
substituted by a fluorine atom;
- a thioalkyl is understood to mean an -S-alkyl radical
where the alkyl group is as defined above;
- an aryl is understood to mean a cyclic aromatic group
comprising between 6 and 10 carbon atoms. Mention may
be made, by way of examples of aryl groups, of the
phenyl or naphthyl groups;
- a halogen atom is understood to mean a fluorine, a
chlorine, a bromine or an iodine.
The compounds of formula (I) can exist in the
form of bases or of addition salts with acids. Such
addition salts form part of the invention.
These salts are advantageously prepared with

pharmaceutically acceptable acids but the salts of
other acids, of use, for example, in the purification
or the isolation of the compounds of formula (I), also
form part of the invention.
The compounds of general formula (I) can
exist in the form of hydrates or of solvates, namely in
the form of combinations or associations with one or
more molecules of water or of a solvent. Such
hydrates and solvates also form part of the invention.
Among the compounds of formula (I) which are
subject-matters of the invention, a first subgroup of
compounds is composed of the compounds for which:
X1, X2, X3, X4, Zi, Z2, Z3, Z4 and Z5 represent,
independently of one another, a hydrogen or halogen
atom, more particularly a fluorine, a bromine or a
chlorine, a C1-C6 alkyl group, more particularly a
methyl, a propyl, an isopropyl, a sec-butyl, a tert-
butyl or a pentyl, a C3-C7 cycloalkyl group, more
particularly a cyclopentyl or a cyclohexyl, a
C1-C6 fluoroalkyl group, more particularly a CF3, a
C1-C6 alkoxy group, more particularly a methoxy or an
ethoxy, a C1-C6 fluoroalkoxy group, more particularly an
OCF3, a nitro group, an NR1R2 group, a C1-C6 thioalkyl
group, more particularly a thiomethyl, an -S(O)-
(C1-Cs)alkyl group, an -S (O) 2- (C1-C6) alkyl group, more
particularly an -S(O)2-CH3, or an aryl group, more
particularly phenyl; and/or

X5 represents a hydrogen atom or a C1-C6 alkyl group,
more particularly a methyl; and/or
R represents a 4-, 5-, 6- or 7-indolyl group,

R optionally being substituted in the 1, 2 and/or 3
position by one or more C1-C6 alkyl groups, more
particularly methyl or isopropyl groups; and/or
Y represents a hydrogen atom; and/or
n is equal to 0, 1, 2 or 3;
R1 and R2 represent, independently of one another, a
hydrogen atom.
Among the compounds of formula (I) which are
subject-matters of the invention, a second subgroup of
compounds is composed of the compounds for which:
X1, X2, X3, X4, Zl, Z2, Z3, Z4 and Z5 represent,
independently of one another, a hydrogen or halogen
atom, more particularly a fluorine, a bromine or a
chlorine, a C1-C6 alkyl group, more particularly a
methyl, a propyl, an isopropyl, a sec-butyl, a tert-
butyl or a pentyl, a C3-C7 cycloalkyl group, more
particularly a cyclopentyl or a cyclohexyl, a
C1-C6 fluoroalkyl group, more particularly a CF3, a
C1-C6 alkoxy group, more particularly a methoxy or an
ethoxy, a C1-C6 fluoroalkoxy group, more particularly an

OCF3, a nitro group, a C1-C6 thioalkyl group, more
particularly a thiomethyl, an -S (O) - (C1-C6) alkyl group,
an -S (O) 2- (C1-C6) alkyl group, more particularly
an -S(O)2-CH3, or an aryl group, more particularly
phenyl; and/or
X5 represents a hydrogen atom or a C1-C6 alkyl group,
more particularly a methyl; and/or
R represents a 4-, 5-, 6- or 7-indolyl group,

R optionally being substituted in the 1, 2 and/or 3
position by one or more C1-C6 alkyl groups, more
particularly methyl groups; and/or
Y represents a hydrogen atom; and/or
n is equal to 0, 1, 2 or 3.
Among the compounds of formula (I) which are
subject-matters of the invention, a third subgroup of
compounds is composed of the compounds for which:
X1, X2, X3, X4, Z1, Z2, Z3, Z4 and Z5 represent,
independently of one another, a hydrogen or halogen
atom or a C1-C6 alkyl, C3-C7 cycloalkyl,
C1-Ce fluoroalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy,
cyano, C(O)NRXR2, nitro, NRXR2, C1-C6 thioalkyl, -S (O)-
(C1-Cs) alkyl, -S (O) 2-(C1-C5) alkyl, SO2NRxR2, NR3COR4,
NR3SO2R5 or aryl group;

X5 represents a hydrogen or halogen atom or a
C1-C6 alkyl or C1-C6 fluoroalkyl group;
R represents a 4-, 5-, 6- or 7-indolyl group,

R optionally being substituted in the 1, 2 and/or 3
position by one or more groups chosen from C1-C6 alkyl
and C1-C6 fluoroalkyl groups;
R optionally being substituted in the 4, 5, 6 and/or 7
position by one or more groups chosen from halogen
atoms or C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy or
C1-C6 fluoroalkoxy groups;
Y represents a hydrogen atom or a C1-C6 alkyl group;
n is equal to 0, 1, 2 or 3;
Ri and R2 represent, independently of one another, a
hydrogen atom or a C1-C6 alkyl, C3-C7 cycloalkyl, (C3-
C7) cycloalkyl (C1-C3) alkyl or aryl group; or Rx and R2
form, together with the nitrogen atom which carries
them, an azetidine, pyrrolidine, piperidine, azepine,
morpholine, thiomorpholine, piperazine or
homopiperazine group, this group optionally being
substituted by a C1-C6 alkyl, C3-C7 cycloalkyl,
(C3-C7) cycloalkyl (C1-C3) alkyl or aryl group;
R3 and R4 represent, independently of one another, a
hydrogen atom or a C1-C6 alkyl or aryl group;

R5 represents a C1-C6 alkyl or aryl group;
with the condition that, when Z1, Z2, Z3, Z4 and Z5
simultaneously represent hydrogen atoms, then n is
equal to 2 or 3.
Among the compounds of formula (I) which are
subject-matters of the invention, a fourth subgroup of
compounds is composed of the compounds for which:
R represents an indol-5-yl group

R optionally being substituted in the 1, 2 and/or 3
position by one or more groups chosen from C1-C6 alkyl
and C1-Ce fluoroalkyl groups;
R optionally being substituted in the 4, 6 and/or 7
position by one or more groups chosen from halogen
atoms or C1-C6 alkyl, C1-C6 fluoroalkyl, C!-C6 alkoxy or
C1-C6 fluoroalkoxy groups;
X1, X2, X3, X4, X5, Z1, Z2, Z3, Z4, Z5, Y, n, R1, R2, R3, R4
and R5 being as defined in the general formula (I) above
or as defined in the first, the second or the third
subgroup above.
Among the compounds of formula (I) which are
subject-matters of the invention, a fifth subgroup of
compounds is composed of the compounds for which:
X2 and/or X3 are other than a hydrogen atom;

X1, X3, X4, X5, Z1, Z2, Z3, Z4, Z5, R, Y, n, Rlt R2, R3, R4
and R5 being as defined in the general formula (I) above
or as defined in the first, the second, the third or
the fourth subgroup above.
Among the compounds of formula (I) which are
subject-matters of the invention, a sixth subgroup of
compounds is composed of the compounds for which:
X5 represents the hydrogen atom:
Xi, X2, X3, X4, Zi, Z2, Z3, Z4, Z5, R, Y, n, Ri, R2, R3, R4
and R5 being as defined in the general formula (I) above
or as defined in the first, the second, the third, the
fourth or the fifth subgroup above.
Among the compounds of formula (I) which are
subject-matters of the invention, a seventh subgroup of
compounds is composed of the compounds for which:
Y represents a hydrogen atom;
Xi, X2, X3, X4, X5, Zi, Z2, Z3, Z4, Z5, R, n, Ri, R2, R3, R4
and R5 being as defined in the general formula (I) above
or as defined in the first, the second, the third, the
fourth, the fifth or the sixth subgroup above.
In accordance with the invention, the
compounds of general formula (I) can be prepared
according to the process illustrated by the following
Scheme 1.
According to Scheme 1, the compounds of
general formula (IV) can be obtained by reaction of a
compound of general formula (II), in which Xlr X2, X3, X4


and X5 are as defined in the general formula (I) above
and A represents a C1-C5 alkoxy or hydroxyl group, with
a compound of general formula (III), in which Zlf Z2,

Z3, Z4, Z5 and n are as defined in the general formula
(I) above and R' represents a bromine or iodine atom, a
tosylate group or any other equivalent group.
When n = 1, 2 or 3, the compound of general
formula (III) can be an alkyl halide, such as a benzyl
bromide (n = 1: Kolasa T., Bioorg. Med. Chem., 1997, 5,
(3) 507) or a phenethyl iodide (n = 2: Abramovitch R.,
Synth. Commun., 1995, 25 (1), 1), and the reaction can
be carried out in the presence of a base, such as
sodium hydride or potassium carbonate, in a polar
solvent, such as dimethylformamide, dimethyl sulphoxide
or acetone.
When n = 0, the compound of general formula
(III) is an aryl iodide or bromide and the reaction can
be carried out at a temperature of between 8 0°C and
250°C in the presence of a copper-based catalyst, such
as copper bromide or copper oxide, and of a base, such
as potassium carbonate (Murakami Y., Chem. Pharm.
Bull., 1995, 43 (8), 1281). It is also possible to use
milder conditions, described in S.L. Buchwald, J. Am.
Chem. Soc, 2002, 124, 11684.
Alternatively, the compounds of general
formula (IV) in which n = 0 can be obtained by reaction
of the compound of general formula (II) with a compound
of general formula (III) of boronic acid type (n = 0,
R' = B(0H)2) in the presence of a base, such as
triethylamine or pyridine, and of copper diacetate, by

analogy with protocols described in W.W.K.R. Mederski,
Tetrahedron, 1999, 55, 12151.
The compounds of general formula (II) are
commercially available or are prepared according to
numerous processes described in the literature
(D. Knittel, Synthesis, 1985, 2, 186, and
T.M. Williams, J. Med. Chem., 1993, 36 (9), 1291, for
example).
In the case of the indoles of general formula
(IV) in which A represents a C1-C6 alkoxy group, the
compound of general formula (I) is obtained by reaction
of a compound of general formula (IV) as obtained above
with an amide of the compound of general formula (V),
in which R and Y are as defined in the general formula
(I) above, at reflux of a solvent, such as toluene. The
amide of the compound of general formula (V) is
prepared by prior reaction of trimethylaluminium with
the aminoindoles of general formula (V).
In the case of the indoles of general formula
(IV) in which A represents a hydroxyl group, the
carboxylic acid functional group can be converted
beforehand to an acid halide, such as an acid chloride,
by the action of thionyl chloride at reflux of a
solvent, such as dichloromethane or dichloroethane. The
compound of general formula (I) is then obtained by
reaction of the compound of general formula (IV), in
which A represents a chlorine atom, with the amino-

indole of general formula (IV) in the presence of a
base, such as triethylamine.
Alternatively, the indole of general formula
(IV) in which A represents a hydroxy1 group can be
coupled to the aminoindole of general formula (V) in
the presence of a coupling agent, such as a
dialkylcarbodiimide, (benzotriazol-1-yloxy)tri-
pyrrolidinophosphonium hexafluorophosphate, diethyl
cyanophosphonate or any other coupling agent known to a
person skilled in the art, in the presence of a base,
such as triethylamine, in a solvent, such as
dimethylformamide.
The aminoindoles of general formula (V) are
prepared according to processes described in the
literature, such as in I.T. Forbes, J. Med. Chem.,
1993, 36 (8), 1104 (Y = H), I.T. Forbes, WO9205170 (Y =
alkyl).
In Scheme 1, the compounds of formulae (II),
(III) and (V) and the other reactants, when their
method of preparation is not described, are
commercially available or are described in the
literature or else can be prepared according to methods
which are described therein or which are known to a
person skilled in the art.
The compounds of general formulae (II), (IV)
and (I) in which X1, X2, X3, X4, X5, Z1, Z2, Z3, Z4 and/or
Z5 represent a cyano group or an aryl can be obtained by

a coupling reaction, catalysed by a metal such as
palladium, carried out on the corresponding compounds
of general formulae (II), (IV) or (I) in which Xlf X2,
X3, X4, X5, Zi, Z2, Z3, Z4 and/or Z5 represent a bromine
atom.
The compounds of general formulae (II), (IV)
and (I) in which X1, X2, X3, X4, X5, Zlt Z2, Z3, Z4 and/or
Z5 represent a C(O)NR1R2 group can be obtained from the
corresponding compounds of general formulae (II), (IV)
or (I) in which X1, X2, X3, X4, X5, Zlt Z2, Z3, Z4 and/or
Z5 represent a cyano group according to methods which
are described in the literature or which are known to a
person skilled in the art.
The compounds of general formulae (II), (IV)
and (I) in which X1, X2, X3, X4, X5, Zr, Z2, Z3, Z4 and/or
Z5 represent an S(O)-alkyl or S(O)2-alkyl group can be
obtained by oxidation of the corresponding compounds of
general formulae (II), (IV) or (I) in which X1, X2, X3,
X4, X5, Z1, Z2, Z3, Z4 and/or Z5 represent a Cr
C6 thioalkyl group according to methods which are
described in the literature or which are known to a
person skilled in the art.
The compounds of general formulae (II), (IV)
and (I) in which Xl, X2, X3, X4, X5, Zlt Z2, Z3, Z4 and/or
Z5 represent an NR1R2, NR3COR4 or NR3SO2R4 group can be
obtained from the corresponding compounds of general
formulae (II), (IV) or (I) in which Xl, X2, X3, X4, X5,

Z1, Z2, Z3, Z4 and/or Z5 represent a nitro group, for
example by reduction and then acylation or
sulphonylation, according to methods which are
described in the literature or which are known to a
person skilled in the art.
The compounds of general formulae (II) , (IV)
and (I) in which Xl, X2, X3, X4, X5, Zlr Z2, Z3, Z4 and/or
Z5 represent an SO2NR1R2 group can be obtained by a
method analogous to that described in Pharmazie, 1990,
45, 34 G, or according to methods which are described in
the literature or which are known to a person skilled
in the art.
The following examples describe the
preparation of some compounds in accordance with the
invention. These examples are not limiting and only
illustrate the present invention. The numbers of the
compounds exemplified refer to those given in Table 1.
The elemental microanalyses, the LC-MS (liquid
chromatography coupled to mass spectrometry) analyses
and the IR and NMR spectra confirm the structures of
the compounds obtained.
Unless otherwise indicated, the chemical
reactants used in the examples are all commercially
available.
Example 1 (Compound No. 1)
N- (1-Methyl-1H-indol-5-yl)-1-(3-trifluoromethylbenzyl)-
1H- indole-2 -carboxamide

1.1 Ethyl 1-(3-trifluoromethylbenzyl)-1H-indole-2-
carboxylate
A suspension of 0.492 g (2.6 mmol) of ethyl
lH-indole-2-carboxylate, of 0.683 g (2.86 mmol) of 3-
trifluoromethylbenzyl bromide and of 0.8 98 g (6.5 mmol)
of potassium carbonate in 50 ml of dimethylformamide is
stirred at 60°C for 24 hours. The reaction mixture is
cooled and is poured into a mixture of ice-cold water
and of ethyl acetate. After settling, the organic phase
is separated and is then washed with two times 50 ml of
water and then with 50 ml of a saturated sodium
chloride solution. The solution is dried over magnesium
sulphate and filtered, and then the filtrate is
concentrated under reduced pressure. 0.8 g of an oil is
obtained, which oil is used as is in the following
stage.
1.2 N- (1-Methyl-1H-indol-5-yl)-1-(3-trifluoromethyl-
benzyl) -1H-indole-2-carboxamide (Compound No. 1)
A solution of 0.231 g (1.58 mmol) of 1-
methyl-1H-5-aminoindole (I.T. Forbes, J". Med. Chem.,
1993, 36 (8), 1104) in 15 ml of toluene is added
dropwise at 0°C to a solution of 0.93 ml (1.87 mmol) of
trimethylaluminium (2M in toluene) in 6 ml of toluene.
After stirring for 15 minutes, 0.5 g (1.44 mmol) of
ethyl 1-(3-trifluoromethylbenzyl)-1H- indole-2-
carboxylate, obtained in Stage 1.1, is added. The
mixture is heated at 50°C for 4 hours. The reaction

mixture is subsequently hydrolysed by addition of 10 ml
of water and then it is taken up in 100 ml of ethyl
acetate. The organic phase is washed with 100 ml of IN
hydrochloric acid, with two times 50 ml of water and
then with 50 ml of a saturated sodium chloride
solution. The solution is dried over magnesium sulphate
and filtered, and then the filtrate is concentrated
under- reduced pressure. The residue is purified by
chromatography on a silica column, elution being
carried out with a mixture of cyclohexane and of
dichloromethane, and then it is recrystallized from
isopropanol. 0.3 3 g of product is thus obtained.
Melting point: 189-190°C
XH NMR (dg-DMSO) : S (ppm) : 3.75 (s, 3H) , 5.93 (s, 2H) ,
6.38 (d, 1H), 7.4 (m, 11H), 7.71 (d, 1H), 7.96 (s, 1H).
Example 2 (Compound No. 2)
N-(1-Methyl-1H-indol-5-yl)-5-methoxy-l-(3-trifluoro-
methylbenzyl)-IK- indole-2 -carboxamide
2.1 Ethyl 5-methoxy-1H-indole-2-carboxylate
1.91 ml (26.15 mmol) of thionyl chloride are
added dropwise with stirring at 0°C to a solution of
1 g (5.23 mmol) of 5-methoxy-1H-indole-2-carboxylic
acid in 52 ml of ethanol. The reaction mixture is
heated at reflux for 2 hours and then it is cooled and
concentrated under reduced pressure. The residue is
taken up in 100 ml of ethyl acetate and this solution
is washed with two times 50 ml of water and then with

50 ml of a saturated sodium chloride solution. The
solution is dried over magnesium sulphate and filtered,
and then the filtrate is concentrated under reduced
pressure. 1.2 g of product are obtained, which product
is used as is in the following stage.
2.2 Ethyl 5-methoxy-1-(3 -1rifluoromethylbenzyl)-1H-
indole-2-carboxylate
A solution of 1.2 g (5.47 mmol) of ethyl 5-
methoxy-l.H-indole-2-carboxylate, obtained in Stage 2.1,
in 50 ml of dimethylformamide is added dropwise to a
suspension of 0.306 g of sodium hydride in 10 ml of
dimethylformamide. The mixture is stirred at ambient
temperature for 1 hour, then 1.01 ml (6.57 mmol) of 3-
trifluoromethylbenzyl bromide are added and stirring is
maintained for an additional 4 hours. The reaction
mixture is poured onto 2 00 ml of ice-cold water and
100 ml of ethyl acetate. After settling, the organic
phase is separated and then it is washed with three
times 50 ml of water and then with 50 ml of a saturated
sodium chloride solution. The solution is dried over
magnesium sulphate and filtered, and then the filtrate
is concentrated under reduced pressure. 2 g of product
are obtained, which product is used as is in the
following stage.
2.3 N- (1-Methyl-1H-indol-5-yl)-5-methoxy-l-(3-
trifluoromethylbenzyl)-1H- indole-2-carboxamide
(Compound No. 2)

A solution of 0.278 g (1.91 mmol) of 1-
methyl-1H-5-aminoindole (I.T. Forbes, J". Med. Chem. ,
1993, 36 (8), 1104) in 15 ml of toluene is added
dropwise at 0°C to a solution of 1.59 ml (3.18 mmol) of
trimethylaluminium (2M in toluene) in 10 ml of toluene.
After stirring for 15 minutes, 0.6 g (1.59 mmol) of
ethyl 5-methoxy-l-(3-trifluoromethylbenzyl)-1H-indole-
2-carboxylate, obtained in Stage 2.2, is added. The
mixture is heated at 50°C for 4 hours. The reaction
mixture is hydrolysed by addition of 10 ml of water and
then it is taken up in 100 ml of ethyl acetate. The
organic phase is washed with 100 ml of IN hydrochloric
acid, with two times 50 ml of water and then with 50 ml
of a saturated sodium chloride solution. The solution
is dried over magnesium sulphate and filtered, and then
the filtrate is concentrated under reduced pressure.
The resulting product is purified by chromatography on
a silica column, elution being carried out with a
mixture of cyclohexane and of ethyl acetate, and then
it is recrystallized from isopropanol. 0.55 g of
product is obtained.
Melting point: 176-177°C
XH NMR (de-DMSO) : 5 (ppm) : 3.8 (s, 3H) , 3.89 (s, 3H) ,
5.9 (s, 2H), 6.49 (d, 1H), 7.2 (m, 8H), 7.48 (m, 2H),
7.9 (m, 2H).
Example 3 (Compound No. 3)
N-(1-Methyl-1H-indol-5-yl)-5-fluoro-l-(3-fluorobenzyl)-

1H- indole-2 -carboxamide
3.1 Ethyl 5-fluoro-l-(3-fluorobenzyl)-1H-indole-2-
carboxylate
A suspension of 0.207 g (1 mmol) of ethyl 5-
fluoro-1H-indole-2-carboxylate, 0.173 g (1.2 mmol) of
3-fluorobenzyl chloride and 0.276 g (2 mmol) of
potassium carbonate in 10 ml of dimethylformamide is
stirred at 60°C for 24 hours. The reaction mixture is
subsequently cooled and is poured into a mixture of
ice-cold water and of ethyl acetate. After settling,
the organic phase is separated and then it is washed
with two times 50 ml of water and then with 50 ml of a
saturated sodium chloride solution. The solution is
dried over magnesium sulphate and is filtered, and then
the filtrate is concentrated under reduced pressure.
0.195 g of an oil is obtained, which oil is used as is
in the following stage.
3.2 N- (1-Methyl-1H-indol-5-yl)-5-fluoro-l-(3-fluoro-
benzyl) -1H-indole-2-carboxamide (Compound No. 3)
A solution of 0.146 g (0.7 mmol) of 1-methyl-
lH-5-aminoindole (I.T. Forbes, J. Med. Chem., 1993, 36
(8), 1104) in 15 ml of toluene is added dropwise at 0°C
to a solution of 0.7 ml (1.4 mmol) of
trimethylaluminium (2M in toluene) in 3 ml of toluene.
After stirring for 15 minutes, 0.195 g (0.62 mol) of
ethyl 5-fluoro-l-(3-fluorobenzyl)-1H-indole-2-
carboxylate, obtained in Stage 3.1, is added. The

mixture is heated at 50°C for 4 hours. The reaction
mixture is hydrolysed by addition of 10 ml of water and
then it is taken up in 100 ml of ethyl acetate. The
organic phase is washed with 100 ml of IN hydrochloric
acid, with two times 50 ml of water and then with 50 ml
of a saturated sodium chloride solution. The solution
is dried over magnesium sulphate and filtered, and then
the filtrate is concentrated under reduced pressure.
The residue is purified by chromatography on a silica
column, elution being carried out with a mixture of
cyclohexane and of dichloromethane. 0.152 g of product
is obtained.
Melting point = 187-189°C
XH NMR (d6-DMSO) : 5 (ppm) : 3.77 (s, 3H) , 5.37 (s, 2H) ,
6.38 (d, 1H), 7 (m, 4H), 7.32 (m, 7H), 7.98 (s, 1H).
Example 4 (Compound No. 30)
N- (1-Methyl-1H-indol-5-yl)-1-(4-isopropylphenyl)-1H-
indole-2-carboxamide
4.1 1-(4-Isopropylphenyl)-1H-indole-2-carboxylic acid
A suspension of 12 8.8 g (0.8 mol) of 1H-
indole-2-carboxylic acid, of 159.2 g (0.8 mol) of 4-
bromocumene, of 111.6 g (0.808 mol) of potassium
carbonate and of 8 g (0.1 mol) of copper oxide in
200 ml of dimethylformamide is stirred at reflux for
24 hours. After cooling, 6 1 of water are added to the
beige suspension obtained. The suspension is filtered
and then the insoluble material is taken up in 1 1 of a

5N hydrochloric acid solution. This mixture is
extracted with 500 ml of dichloromethane. The organic
phase is washed with water, dried over sodium sulphate
and then concentrated under reduced pressure. After
drying under reduced pressure, 204.4 g of a white solid
are obtained, which solid is used as is in the
following stage.
Melting point = 203-204°C
4.2 1-(4-Isopropylphenyl)-lff-indole-2-carbonyl
chloride
A solution of 111 mg (0.4 mmol) of 1-(4-
isopropylphenyl)-1H-indole-2-carboxylic acid, obtained
in Stage 4.1, and of 90 microlitres (1.2 mmol) of
thionyl chloride in 2 ml of dichloroethane is stirred
at reflux for 3 hours. The reaction medium is
concentrated under reduced pressure. A residue is
obtained, which residue is used as is in the following
stage.
4.3 N-(1-Methyl-1H-indoi-5-yl)-1-(4-isopropylphenyl)-
1H-indole-2-carboxamide (Compound No. 3 0)
A solution of 119 mg (0.4 mmol) of 1-(4-
isopropylphenyl)-lff-indole-2-carbonyl chloride,
obtained in Stage 4.2, 70 mg (0.48 mmol) of 1-methyl-
lH-5-aminoindole and 110 microlitres (0.8 mmol) of
triethylamine in 2 ml of tetrahydrofuran is stirred at
ambient temperature for 18 hours. The reaction mixture
is concentrated under reduced pressure and is taken up

in 2 0 ml of water and 5 0 ml of dichloromethane. The
organic phase is separated, washed with 50 ml of IN
hydrochloric acid, dried over magnesium sulphate and
then concentrated under reduced pressure. The residue
is purified by chromatography on a silica column,
elution being carried out with a mixture of cyclohexane
and of ethyl acetate. 0.133 g of product is obtained.
Melting point: 178-179°C
XH NMR (CDC13) : 5 (ppm) : 1.39 (d, 6H) , 3.05 (sept., 1H) ,
3.8 (s, 3H) , 6.4 (d, 1H) , 7.29 (m, 11H) , 7.78 (m, 3H) .
Example 5 (Compound No. 4)
N- (1 -Methyl-1H-indol-5-y.l) -1- (3-trifluoromethylphenyl) -
lH-indole-2-carboxamide
5.1 1-(3-Trifluoromethylphenyl)-1H-indole-2-carboxylic
acid
The compound can be prepared according to a
method analogous to that described in Stage 4.1 of
Example 4, the 4-bromocumene being replaced with 3-
bromo-a,a,a-trifluorotoluene.
5.2 N- (1-Methyl-Iff-indol-5-yl)-1-(3-trifluoromethyl-
phenyl) -lK-indole-2-carboxamide
A solution of 2 g (6.55 mmol) of l-(3-
trifluoromethylphenyl)-1H-indole-2-carboxylic acid
(prepared by analogy with the method described in Stage
4.1 of Example 4), 1.14 g (7.86 mmol) of 1-methyl-Iff-5-
aminoindole (I.T. Forbes, J. Med. Chem. , 1993, 36 (8),
1104), 1.2 ml (7.86 mmol) of diethyl cyanophosphonate

and 2.03 ml (14.41 mmol) of triethylamine in 2 0 ml of
dimethylformamide is stirred at ambient temperature for
18 hours. The reaction mixtures is concentrated under
reduced pressure and then it is taken up in 50 ml of
water. This solution is extracted with two times 50 ml
of dichloromethane. The organic phases are combined,
dried over sodium sulphate and then concentrated under
reduced pressure. The residue obtained is purified by
chromatography on a silica column, elution being
carried out with a mixture of cyclohexane and of ethyl
acetate.
1.97 g of product are isolated.
Melting point: 225-226°C
^ NMR (d6-DMSO) : 5 (ppm) : 3.79 (s, 3H) , 6.41 (d, 1H) ,
7.05 (d, 1H), 7.28 (m, 3H), 7.77 (m, 7H).
Example 6 (Compound No. 41)
N-(1-Methyl-lfl-indol-5-yl)-1-(3-isopropylphenyl)-5-
trif luoromethyloxy-lJf- indole- 2 -carboxamide
6.1 Ethyl 1-(3-isopropyiphenyl)-5-trifluoromethyloxy-
lH-indole-2-carboxylate
A mixture of 0.2 g (0.73 mmol) of ethyl 5-
trifluoromethyloxy-lff-indole-2-carboxylate, of 0.24 g
(1.46 mmol) of 3-isopropylphenylboronic acid, of 0.2 g
(1.1 mmol) of copper diacetate and of 0.12 ml
(1.46 mmol) of pyridine in 5 ml of dichloromethane is
stirred in the presence of 4 A molecular sieve at
ambient temperature for 4 days. The mixture is poured

onto 100 ml of water and 50 ml of dichloromethane. The
organic phase is separated, washed with IN hydrochloric
acid, dried over magnesium sulphate and then
concentrated under reduced pressure. The residue is
purified by chromatography on a silica column, elution
being carried out with a mixture of cyclohexane and of
ethyl acetate. 0.1 g of product is obtained, which
product is used as is in the following stage.
6.2 N-(1-Methyl-1H-indol-5-yl)-1-(3-isopropylphenyl)-
5-trifluoromethyloxy-1H-indole-2-carboxamide
(Compound No. 41)
A solution of 0.0493 g (0.34 mmol) of 1-
methyl-5-amino-1H-indole (I.T. Forbes, J. Med. Chem.,
1993, 36 (8), 1104) in 5 ml of toluene is added
dropwise at 0°C to a solution of 0.28 ml (0.56 mmol) of
trimethylaluminium (2M in toluene) in 2 ml of toluene.
After stirring for 15 minutes, 0.1 g (0.28 mmol) of
ethyl 1-(3-isopropylphenyl)-5-trifluoromethyloxy-1H-
indole-2-carboxylate, obtained in Stage 6.1, is added.
The mixture is heated at 50°C for 4 hours. The reaction
mixture is hydrolysed by addition of 10 ml of water and
then it is taken up in 100 ml of ethyl acetate. The
organic phase is washed with 100 ml of IN hydrochloric
acid, with two times 50 ml of water and then with 50 ml
of a saturated sodium chloride solution. The solution
is dried over magnesium sulphate and filtered, and then
the filtrate is concentrated under reduced pressure.

The residue is purified by chromatography on a silica
column, elution being carried out with a mixture of
cyclohexane and of ethyl acetate, and then it is
recrystallized from isopropanol. 0.136 g of product is
obtained.
Melting point: 164-165°C
XH NMR (ds-DMSO) : § (ppm) : 1.22 (dxs, 6H) , 2.98 (m, 1H) ,
3.79 (s, 3H), 6.38 (d, 1H), 7.4 (m, 11H), 7.9 (m, 2H).
Example 7 (Compound No. 7 0)
N- (ltf-Indol-5-yl)-5-fluoro-l-(3-fluorobenzyl)-1H-
indole-2-carboxamide
A solution of 0.46 g (3.49 mmol) of 5-amino-
1H-indole in 50 ml of toluene is added dropwise at 0°C
to a solution of 4.76 ml (9.51 mmol) of
trimethylaluminium (2M in toluene) in 10 ml of toluene.
After stirring for 15 minutes, 1 g (3.17 mmol) of ethyl
5-fluoro-l-(3-fluorobenzyl)-1H-indole-2-carboxylate,
obtained in Stage 3.1 of Example 3, is added. The
mixture is heated at 5 0°C for 4 hours. The reaction
mixture is hydrolysed by addition of 10 ml of water and
then it is taken up in 100 ml of ethyl acetate. The
organic phase is washed with 100 ml of IN hydrochloric
acid, with two times 50 ml of water and then with 50 ml
of a saturated sodium chloride solution. The solution
is dried over magnesium sulphate and filtered, and then
the filtrate is concentrated under reduced pressure.
The residue is purified by chromatography on a silica

column, elution being carried out with a mixture of
cyclohexane and of dichloromethane. 0.7 g of product is
obtained.
Melting point = 158-163°C
XH NMR (d6-DMSO) : 5 (ppm) : 5.87 (s, 2H) , 6.38 (m, 1H) ,
6.9 (m, 2H) , 7.1 (m, 2H), 7.31 (m, 5H) , 7.51 (m, 2H),
7.92 (s, 1H) , 10.26 (s, 1H) , 10.98 (s, 1H) .
The chemical structures and the physical
properties of a few compounds of general formula (I)
according to the invention are illustrated in the
following Table 1. In this table:
the column "M.p." gives the melting points of the
products in degrees Celsius (°C). When the
products have been isolated in the form of an
amorphous solid or oil, they are characterized in
this column by their mass ( [MH]+) ;
Me, MeO, EtO, n-Pr, i-Pr, s-Bu and t-Bu
respectively represent methyl, methoxy, ethoxy,
propyl, isopropyl, sec-butyl and tert-butyl
groups.








The compounds of the invention have been
subjected to in vitro and in vivo pharmacological
trials which have demonstrated their advantage as
substances possessing therapeutic activities.
Test of the inhibition of the current induced by
capsaicin with regard to rat DRGs
- Primary culture of rat dorsal route ganglion (DRG)
cells:
The neurons of the DRG naturally express the
TRPV1 receptor.
Primary cultures of DRGs of newborn rats are
prepared from 1-day-old rats. Briefly, after
dissection, the ganglions are trypsinized and their
cells dissociated mechanically by gentle trituration.
The cells are resuspended in an Eagle's basal culture
medium comprising 10% of foetal calf serum, 25 mM KCl,
2 mM glutamine, 100 /ig/ml of gentamicin and 50 ng/ml of
NGF and then deposited on glass cover slips covered
with laminin (0.25 x 106 cells per cover slip) which
are subsequently placed in 12-well Corning dishes. The

cells are incubated at 3 7°C in a humidified atmosphere
comprising 5% of C02 and 95% of air. Cytosine (3-D-
arabinoside (1 JXM) is added 48 h after culturing, in
order to prevent the growth of non-neuronal cells.
After culturing for 7-10 days, the cover slips are
transferred into experimental chambers for the patch
clamp studies.
- Electrophysiology:
The measurement chambers (volume 8 00 ul)
comprising the cell preparation are placed on the stage
of an inverted microscope (Olympus IMT2) equipped with
Hoffman optics (Modulation Contrast, New York) and are
observed at a magnification of 400x. The chambers are
continuously perfused by gravity (2.5 ml/min) using a
distributor of solutions which has 8 inlets, the single
outlet of which, composed of a polyethylene tube
(opening 500 /im) , is placed at least 3 mm from the cell
studied. The "whole cell" configuration of the patch
clamp technique was used. Borosilicate glass pipettes
(resistance 5-10 Mohms) are brought close to the cell
using a 3D piezoelectric micromanipulator (Burleigh,
PC1000). The overall currents (membrane potential set
at -60 mV) are recorded with an Axopatch ID amplifier
(7Axon Instruments, Foster City, California) connected
to a PC controlled by Pclamp8 software (Axon
Instruments). The current plots are recorded on paper
and simultaneously recorded digitally (sampling

frequency 15 to 25 Hz) and acquired on the hard disk of
the PC.
The application of a 300 nM capsaicin
solution produces an incoming cationic current with
regard to the DRG cells (voltage set at -70 mV). In
order to minimize the desensitization of the receptors,
a minimum interval of one minute between two
applications of capsaicin is observed. After a control
period (stabilization of the capsaicin alone response),
the test compounds are applied alone at a concentration
of 10 nM for a period of time of 4 to 5 minutes, during
which several capsaicin + compound tests are carried
out (obtaining the maximum inhibition). The results are
expressed as % of inhibition of the control capsaicin
response.
The percentages of inhibition of the
capsaicin (300 nM) response are between 20% and 100%
for the most active compounds of the invention tested
at a concentration of 10 nM (see some examples in
Table 2).
The compounds cf the invention are thus
effective in vitro antagonists of receptors of TRPV1
type.


Mouse corneal irritation test
The irritating nature of capsaicin is easily
assessed on the cornea since this organ is one of the
most innervated by C fibres. In this context, according
to preliminary experiments, the application of a very
small amount of capsaicin (2 /xl at a concentration of
160 nM) at the surface of the cornea of an animal
results in a number of kinds of stereotyped behaviour
related to irritation which are easy to record. These
include: blinking of the eye, rubbing of the instilled
eye by the ipsilateral front paw, rubbing of the face
with the two front paws and scratching of the
ipsilateral face by the hind paw. The duration of these
kinds of behaviour does not exceed 2 minutes of
observation and the animal then resumes its normal
activity. Its appearance is furthermore also normal.
The mouse does not hide in a corner with the hairs
standing on end and does not develop any observable
signs of suffering. It may be concluded therefrom that
the duration of action of capsaicin at these doses is
less than 2 minutes.

Summary of the methodology:
The principle of the series of experiments is
to determine whether the compounds of the invention can
influence the behavioural response induced by a given
amount of capsaicin. Capsaicin is initially diluted to
25 mM in DMSO and is diluted, for its final use, in 10%
Tween 80 in physiological saline. It appears, from
control studies, that the solvent has no effect under
these conditions.
In practice, the test product is administered
orally and, with a delay (pretreatment time: t) which
depends on the pharmacokinetic data, the animal
receives the ocular instillation of 2 p.1 of a 160 JJ,M
capsaicin solution prepared as indicated above. During
observation for 2 minutes following the instillation,
the number of rubbing actions on the instilled eye by
the ipsilateral front paw is recorded.
For a given animal, the percentage of
protection is calculated as follows:
P = 100 - ((number of scratching actions observed/mean
number of scratching actions of the group treated with
the solvent) x 100).
This percentage of protection is converted to
a mean for each group of animals (n = number of animals
tested with the compound of the invention).
The percentages of protection evaluated in
this model for the most active compounds of the

invention, used at a doss of 60 mg/kg (p.o.), are
between 8% and 10 0% (see some examples in Table 3):

The results of these trials show that the
most active compounds of the invention block the
effects induced by the stimulation of the TRPV1
receptors.
The compounds of the invention can thus be
used for the preparation of medicaments, in particular
for the preparation of a medicament intended to prevent
or to treat pathologies in which receptors of TRPV1
type are involved.
Thus, according to another of its aspects, a
subject-matter of the invention is medicaments which
comprise a compound of formula (I) or a
pharmaceutically acceptable salt or also a hydrate or a
solvate of the said compound.
These medicaments are employed in
therapeutics, in particular in the prevention and/or
the treatment of pain and inflammation, chronic,
neuropathic (traumatic, diabetic, metabolic,
infectious, toxic, induced by an anticancer treatment
or iatrogenic), (osteo)arthritic or rheumatic pain,
fibromyalgia, bone pain, cancer-related pain,

trigeminal neuralgia, cephalgia, migraine, dental pain,
burns, sunburn, bites or stings, post-herpetic
neuralgia, muscle pain, nerve compression (central
and/or peripheral), marrow and/or brain trauma,
ischaemia (of the marrow and/or brain),
neurodegeneration, haemorrhagic vascular accidents (of
the marrow and/or brain) or post-stroke pain.
The compounds of the invention can be used
for the preparation of a medicament intended to prevent
and/or to treat urological disorders, such as bladder
hyperactivity, bladder hyperreflexia, bladder
instability, incontinence, urgent urination, urinary
incontinence, cystitis, renal colic, pelvic
hypersensitivity and pelvic pain.
The compounds of the invention can be used
for the preparation of a medicament intended to prevent
and/or to treat gynaecological disorders, such as
vulvodynia, salpingitis-related pain or dysmenorrhoea.
These products can also be used for the
preparation of a medicament intended to prevent and/or
to treat gastrointestinal disorders, such as gastro-
oesophagal reflux disorder, stomach ulcers, duodenal
ulcers, functional dyspepsia, colitis, IBS, Crohn's
disease, pancreatitis, oesophagitis or biliary colic.
Likewise, the products of the present
invention may be of use in the prevention and/or the
treatment of respiratory disorders, such as asthma,

coughs, COPD, bronchoconstriction and inflammatory
disorders. These products can also be used to prevent
and/or to treat psoriasis, pruritus, irritation of the
skin, eyes or mucous membranes, herpes or shingles.
The compounds of the invention can also be
used for the preparation of a medicament intended to
treat depression.
According to another of its aspects, the
present invention relates to pharmaceutical
compositions comprising, as active principle, a
compound according to the invention. These
pharmaceutical compositions comprise an effective dose
of at least one compound according to the invention, or
a pharmaceutically acceptable salt, a hydrate or a
solvate of the said compound, and at least one
pharmaceutically acceptable excipient.
The said excipients are chosen, according to
the pharmaceutical form and the method of
administration desired, from the usual excipients known
to a person skilled in the art.
In the pharmaceutical compositions of the
present invention for oral, sublingual, subcutaneous,
intramuscular, intravenous, topical, local,
intratracheal, intranasal, transdermal or rectal
administration, the active principle of formula (I)
above, or its optional salt, solvate or hydrate, can be
administered in unit administration form, as a mixture

with conventional pharmaceutical excipients, to animals
and human beings for the prophylaxis or the treatment
of the disorders or diseases mentioned above.
The appropriate unit administration forms
comprise oral forms, such as tablets, soft or hard
gelatin capsules, powders, granules and oral solutions
or suspensions, sublingual, buccal, intratracheal,
intraocular and intranasal administration forms, forms
for administration by inhalation, topical, transdermal,
subcutaneous, intramuscular or intravenous
administration forms, rectal administration forms and
implants. The compounds according to the invention can
be used, for topical application, in creams, gels,
ointments or lotions.
By way of example, a unit administration form
of a compound according to the invention in the tablet
form can comprise the following components:
Compound according to the invention 50.0 mg
Mannitol 223.75 mg
Croscarmellose sodium 6.0 mg
Maize starch 15.0 mg
Hydroxypropylmethylcellulose 2.25 mg
Magnesium stearate 3.0 mg
The said unit forms comprise doses in order
to make possible daily administration of 0.001 to 30 mg
of active principle per kg of body weight, depending on
the pharmaceutical dosage form.
There may be specific cases where higher or

lower dosages are appropriate; such dosages do not
depart from the scope of the invention. According to
the usual practice, the dosage appropriate to each
patient is determined by the physician according to the
method of administration and the weight and response of
the said patient.
The present invention, according to another
of its aspects, also relates to a method for the
treatment of the pathologies indicated above which
comprises the administration, to a patient, of an
effective dose of a compound according to the
invention, or one of its pharmaceutically acceptable
salts or hydrates or solvates.

WE CLAIM :
1. Compound corresponding to the formula
(I)

in which
X1, X2, X3, X4, Z1, Z2, Z3, Z4 and Z5 represent,
independently of one another, a hydrogen or halogen
atom or a C1-C6 alkyl, C3-C7 cycloalkyl,
C1-C6 fluoroalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy,
cyano, C(O)NR1R2, nitro, NR1R2, C1-C6 thioalkyl, -S (O)-
(C1-C6) alkyl, -S(O)2-(C1-C6)alkyl, SO2NR1R2, NR3COR4,
NR3SO2R5 or aryl group;
X5 represents a hydrogen or halogen atom or a
C1-C6 alkyl or C1-C6 fluoroalkyl group;
R represents a 4-, 5-, 6- or 7-indolyl group,

R optionally being substituted in the 1, 2 and/or 3

position by one or more groups chosen from the
C1-C6 alkyl and C1-C6 fluoroalkyl groups;
R optionally being substituted in the 4, 5, 6 and/or 7
position by one or more groups chosen from halogen
atoms or C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy or
C1-C6 fluoroalkoxy groups;
Y represents a hydrogen atom or a C1-C6 alkyl group;
n is equal to 0, 1, 2 or 3;
R1 and R2 represent, independently of one another, a
hydrogen atom or a C1-C6 alkyl, C3-C7 cycloalkyl, (C3-
C7) cycloalkyl (C1-C3) alkyl or aryl group; or R1 and R2
form, together with the nitrogen atom which carries
them, an azetidine, pyrrolidine, piperidine, azepine,
morpholine, thiomorpholine, piperazine or
homopiperazine group, this group optionally being
substituted by a C1-C6 alkyl, C3-C7 cycloalkyl,
(C3-C7) cycloalkyl (C1-C3) alkyl or aryl group;
R3 and R4 represent, independently of one another, a
hydrogen atom or a C1-C6 alkyl or aryl group;
R5 represents a C1-C6 alkyl or aryl group;
or a salt thereof.
2. Compound of formula (I) as claimed in
Claim 1, wherein
X1, X2, X3, X4, Z1, Z2, Z3, Z4 and Z5 represent,
independently of one another, a hydrogen or halogen
atom or a C1-C6 alkyl, C3-C7 cycloalkyl,

C1-C6 fluoroalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy,
nitro, NR1R2, C1-C6 thioalkyl, -S (O) - (C1-C6) alkyl, -S(O)2-
(C1-C6)alkyl or aryl group;
X5 represents a hydrogen atom or a C1-C6 alkyl group;
R represents a 4-, 5-, 6- or 7-indolyl group,

R optionally being substituted in the 1, 2 and/or 3
position by one or more C1-C6 alkyl groups;
Y represents a hydrogen atom;
n is equal to 0, 1, 2 or 3;
R1 and R2 represent, independently of one another, a
hydrogen atom;
or a salt thereof.
3. Compound of formula (I) as claimed in
Claim 1, wherein
R represents an indol-5-yl group

R optionally being substituted in the 1, 2 and/or 3
position by one or more groups chosen from C1-C6 alkyl

and C1-C6 fluoroalkyl groups; and
R optionally being substituted in the 4, 6 or 7 position
by one or more groups chosen from halogen atoms or C1-C6
alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy or C1-C6 fluoroalkoxy
groups; or a salt thereof.
4. Compound of formula (I) as claimed in claim 1,
wherein X2 or X3 is other than a hydrogen atom;
or a salt thereof.
5. Compound of formula (I) as claimed in claim 1,
wherein X5 represents a hydrogen atom;
or a salt thereof.
6. Compound of formula (I) as claimed in claim 1,
wherein Y represents a hydrogen atom;
or a salt thereof.
7. Process for the preparation of a compound of formula
(I) as claimed in claim 1, comprising the steps of:
a) reacting a compound of formula (V)

in which R and Y are as defined in the formula (I) as
claimed in claim 1, with trimethylaluminum in a solvent;
b) adding a solution of a compound of formula (IV)


in which Xl, X2, X3, X4, X5, Z1, Z2, Z3, Z4, Z5 and n are as
defined in the formula (I) as claimed in claim 1 and A
represents a C1-C4 alkoxy group, to reaction mixture
obtained in step a); and
c) refluxing said reaction mixture to obtain the compound
of formula (I).
8. Process for the preparation of a compound of formula
(I) as claimed in claim 1, comprising the steps of:
a) reacting a compound of general formula (IV)

in which X1, X2, X3, X4, X5, Z1, Z2, Z3, Z4, Z5 and n are as

defined in the formula (I) as claimed in claim 1 and A
represents a hydroxyl group, with thionyl chloride at
reflux of a solvent to form an acid chloride;
b) reacting so obtained acid chloride of formula (IV), in
the presence of a base, with the amino-indole of formula
(V),

in which R and Y are as defined in the formula (I) as
claimed in claim 1 to form the compound of formula (I).
9. Process for the preparation of a compound of formula
(I) as claimed in claim 1, comprising the step of:
subjecting a compound of formula (IV),

in which X1, X2, X3, X4, X5, Z1, Z2, Z3, Z4, Z5 and n are as
defined in the formula (I) as claimed in claim 1 and A
represents a hydroxyl group, and the aminoindole of
formula (V),


in which R and Y are as defined in the general formula
(I) as claimed in claim 1, to a coupling reaction in the
presence of a coupling agent and a base in a solvent.
10. Pharmaceutical composition comprising a compound of
formula (I) as claimed in claim 1, or a pharmaceutically
acceptable salt thereof, in combination with at least one
pharmaceutically acceptable excipient.
11. Pharmaceutical composition comprising a compound of
formula (I) as claimed in claim 2, or a pharmaceutically
acceptable salt thereof, in combination with at least one
pharmaceutically acceptable excipient.
12. Pharmaceutical composition comprising a compound of
formula (I) as claimed in claim 3, or a pharmaceutically
acceptable salt thereof, in combination with at least one
pharmaceutically acceptable excipient.
13. Pharmaceutical composition comprising a compound of
formula (I) as claimed in claim 4, or a pharmaceutically
acceptable salt thereof, in combination with at least one
pharmaceutically acceptable excipient.
14. Pharmaceutical composition comprising a compound of
formula (I) as claimed in claim 5, or a pharmaceutically

acceptable salt thereof, in combination with at least one
pharmaceutically acceptable excipient.
15. Pharmaceutical composition comprising a compound of
formula (I) as claimed in claim 6, or a pharmaceutically
acceptable salt thereof, in combination with at least one
pharmaceutically acceptable excipient.


The invention relates to compounds of general
formula (I):

in which Xl, X2, X3, X4, Z1, Z2, Z3, Z4 and Z5 represent,
independently of one another, a hydrogen or halogen
atom or a C1-C6 alkyl, C3-C7 cycloalkyl,
C1-C6 fluoroalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy,
cyano, C(O)NR1R2, nitro, NR1R2, C1-C6 thioalkyl, -S (O)-
(C1-C6) alkyl, -S(O)2-(C1-C6)alkyl, SO2NR1R2, NR3COR4,
NR3SO2R5 or aryl group; X5 represents a hydrogen or
halogen atom or a C1-C6 alkyl or C1-C6 fluoroalkyl group;
R represents an optionally substituted 4-, 5-, 6- or 7-
indolyl group; Y represents a hydrogen atom or a C1-C6
alkyl group; n is equal to 0, 1, 2 or 3; R1 and R2
represent, independently of one another, a hydrogen
atom or a C1-C6 alkyl, C3-C7 cycloalkyl,

(C3-C7) cycloalkyl (C1-C3)alkyl or aryl group; or R1 and R2
form, together with the nitrogen atom which carries
them, an azetidine, pyrrolidine, piperidine, azepine,
morpholine, thiomorpholine, piperazine or
homopiperazine group, this group optionally being
substituted by a C1-C6 alkyl, C3-C7 cycloalkyl,
(C3-C7) cycloalkyl (C1-C3) alkyl or aryl group; R3 and R4
represent, independently of one another, a hydrogen
atom or a C1-C6 alkyl or aryl group; R5 represents a
C1-C6 alkyl or aryl group; in the form of the base or of
an addition salt with an acid, and in the hydrate or
solvate form.
Preparation process and application in therapeutics.

Documents:

00194-kolnp-2007 assignment-1.1.pdf

00194-kolnp-2007 correspondence-1.1.pdf

0194-kolnp-2007-abstract.pdf

0194-kolnp-2007-assignment.pdf

0194-kolnp-2007-claims.pdf

0194-kolnp-2007-correspondence others.pdf

0194-kolnp-2007-description(complete).pdf

0194-kolnp-2007-form-1.pdf

0194-kolnp-2007-form-2.pdf

0194-kolnp-2007-form-3.pdf

0194-kolnp-2007-form-5.pdf

0194-kolnp-2007-international publication.pdf

194-KOLNP-2007-ABSTRACT-1.1.pdf

194-KOLNP-2007-ABSTRACT.pdf

194-KOLNP-2007-AMANDED CLAIMS.pdf

194-KOLNP-2007-ASSIGNMENT.pdf

194-KOLNP-2007-CORRESPONDENCE OTHERS 1.2.pdf

194-KOLNP-2007-CORRESPONDENCE-1.3.pdf

194-KOLNP-2007-CORRESPONDENCE.pdf

194-KOLNP-2007-DESCRIPTION (COMPLETE).pdf

194-kolnp-2007-english translation.pdf

194-KOLNP-2007-EXAMINATION REPORT REPLY RECIEVED.pdf

194-KOLNP-2007-EXAMINATION REPORT.pdf

194-KOLNP-2007-FORM 1-1.1.pdf

194-KOLNP-2007-FORM 1.pdf

194-KOLNP-2007-FORM 13-1.1.pdf

194-KOLNP-2007-FORM 13.2.pdf

194-kolnp-2007-form 13.pdf

194-KOLNP-2007-FORM 18.1.pdf

194-kolnp-2007-form 18.pdf

194-KOLNP-2007-FORM 2.pdf

194-KOLNP-2007-FORM 3.1.pdf

194-KOLNP-2007-FORM 3.pdf

194-KOLNP-2007-FORM 5.pdf

194-KOLNP-2007-FORM-27.pdf

194-KOLNP-2007-GPA.pdf

194-KOLNP-2007-GRANTED-ABSTRACT.pdf

194-KOLNP-2007-GRANTED-CLAIMS.pdf

194-KOLNP-2007-GRANTED-DESCRIPTION (COMPLETE).pdf

194-KOLNP-2007-GRANTED-FORM 1.pdf

194-KOLNP-2007-GRANTED-FORM 2.pdf

194-KOLNP-2007-GRANTED-SPECIFICATION.pdf

194-KOLNP-2007-MISCLLENIOUS.pdf

194-KOLNP-2007-OTHER PCT FORM.pdf

194-KOLNP-2007-OTHERS.pdf

194-KOLNP-2007-OTHERS1.1.pdf

194-KOLNP-2007-PETITION UNDER RULE 137.pdf

194-KOLNP-2007-REPLY TO EXAMINATION REPORT.pdf

194-KOLNP-2007-TRANSLATED COPY OF PRIORITY DOCUMENT.pdf

abstract-00194-kolnp-2007.jpg


Patent Number 249822
Indian Patent Application Number 194/KOLNP/2007
PG Journal Number 46/2011
Publication Date 18-Nov-2011
Grant Date 15-Nov-2011
Date of Filing 16-Jan-2007
Name of Patentee SANOFI-AVENTIS
Applicant Address 174, AVENUE DE FRANCE, PARIS, F-75013
Inventors:
# Inventor's Name Inventor's Address
1 DUBOIS, LAURENT 132, AVENUE DE LA RESISTANCE, F-92350, LE PLESSIS-ROBINSON
2 EVEN, LUC 77 RUE LECOURBE, F-75015, PARIS
3 EVANNO, YANNICK 12 RUE DE COURANCE, F-91490 DANNEMOIS
PCT International Classification Number C07D209/42
PCT International Application Number PCT/FR2005/002014
PCT International Filing date 2005-08-02
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 04/08,652 2004-08-05 France