1. Pharmaceutical composition characterized in that it comprises, as active principle a compound of formula I. (I) in which: - R0 represents a group chosen from: (i): in which: Z1 represents a chlorine, bromine, iodine or fluorine atom or a (C1-C4) alkyl, (C1-C4) alkoxy or trifluoromethyl group; Z2 represents a hydrogen, chlorine, bromine, iodine or. fluorine atom or a (C1-C4) alkyl, (C3-C5) cycloalkyl, (C1-C4) alkoxy, (C3-Cs) cycloalkoxy or (C1-C4)polyfluoroalkyl group; - - R5 represents T1W in which Ti represents -(CH2)m, it being possible for m to be equal to 0 or 1, and W 162 represents a hydrogen atom or a hydroxycarbonyl (or carboxyl), (C1-C4)alkoxycarbonyl, 1, 3-dioxolan-2-yl or 1,3-dioxan-2-yl group, or else W represents an -NR6R7 group in which 5 R6 and R7 represent, independently of one another, a hydrogen atom, a (C1-C4)alkyl group, a (C1-C4) alkylsulphonyl group or a phenylsulphonyl group in which the phenyl group can be mono-, di- or trisubstituted by Z5; or else R6 and R-7 form, with the nitrogen atom to which they are bonded, a morpholinyl group optionally substituted by a (C1-C4)alkyl group or an oxo; or else R6 and R7 form, with the nitrogen atom to which they are bonded, a piperazinyl group optionally substituted in the 15 4-position by a Z3 substituent; or else R6 and R7 form, with the nitrogen atom to which they are bonded, a pyrrolidinyl or piperidyl group, the said pyrrolidinyl and piperidyl groups optionally being substituted by Z4; or else W represents an -NR8COR9 group in which R8 represents a hydrogen atom or a (C1-C4)alkyl group and R9 represents a hydrogen atom or a (C1-C4)alkyl, benzyl, pyridyl or phenyl group, it being possible for the said phenyl group to be mono-, di- or trisubstituted by Z5; or else R9 represents an -NRi0Rn group in which R10 and R11 represent, independently of one another, a hydrogen 163 163 atom or a (C1-C4)alkyl [lacuna] or else R10 and R11 form, with the nitrogen atom to which they are bonded, a pyrrolidinyl, piperidyl or morpholinyl group optionally substituted by a (C1-C4)alkyl group; 5 or else R9 represents a pyrrolidin-2-yl or -3-yl or piperid-2-yl, -3-yl or -4-yl group, the said pyrrolidinyl and piperidyl groups optionally being substituted by Z7; or else R9 represents a -T2-R12 or -T2-COR12 group in which T2 represents -(CH2)n~, it- 10 being possible for n to be equal to 1, 2, 3 and 4, and R12 represents a (C1-C4) alkoxy or -NR10Rn group, R10 and R11 being as defined above; or else W represents a -CONR13R14 group in which R13 represents a hydrogen atom or a 15 (C1-C4) alkyl, (C3-C7) cycloalkyl, monofluoro (C1-C4) alkyl or polyfluoro (C1-C4) alkyl group and R14 represents 'a hydrogen atom, a (C1-C4)alkyl group, a phenyl group optionally substituted by Z5, a -T4-R15 group in which T4 20 represents -(CH2)q, with q equal to 1, 2, 3 or 4, . and R15 represents a hydroxyl group, a (C1-C4) alkoxy group, a (C1-C4) alkoxycarbonyl group, a (C1-C4)alkoxycarbonylamino group, a phenyl group, optionally mono- or disubstituted by Z5, a pyrid- 25 2-yl, -3-yl or -4-yl, or an –NR16R17 group in which RIG and R17 represent, independently of one another, a hydrogen atom or a ' (C1-C4) alkyl [lacuna] or else- 164 164 Ri6 and RX7 form, with the nitrogen atom to which they are bonded, a morpholinyl group optionally mono- or disubstituted by a (C1-C4) alkyl group or else RX6 and Ri7 form, with the nitrogen atom to 5 which they are bonded, a piperazinyl group optionally substituted in the 4-position by a Z3 substituent or else Ri6 and- R3.7 form, with the nitrogen atom to which they are bonded, a pyrrolidinyl or piperidyl group, the said 10 pyrrolidinyl and piperidyl groups optionally being substituted by Z5, it being understood that, when q = 1, R15 is other than hydroxyl, (C3-C4) alkoxy, (C1-C4) alkoxycarbonylamino or -NRi6Ri7; or else R13 and R14 form, with the nitrogen atom to which they are 15 . bonded, a morpholinyl group optionally mono- or• disubstituted by a (C1-C4) alkyl group or a piperazinyl group optionally substituted in the 4-position by a Z3 substituent; or else R13 and R14 form, with the nitrogen atom to which they are 20 bonded, an azetidinyl, pyrrolidinyl, piperidyl or hexahydroazepinyl group, the said pyrrolidinyl, piperidyl and hexahydroazepinyl groups optionally being mono- or disubstituted by Z8; or else W represents an OR3.8 group in which 25 R18 represents a hydrogen atom or a (C1-C4) alkyl, (C1-C4) alkoxy (C1-C4)alkyl or -T3-Rlg group in which T3 represents -(CH2)P-, it being possible for p to be 165 equal to 2 or 3, and R19 is chosen from the hydroxyl, triphenylmethoxy or -NR20R21 groups in which R2o represents a hydrogen atom or a (C1-C4) alkyl group and R21 represents a hydrogen atom or a (C1.-C4) alkyl, 5 tetrahydrofuranylmethyl or tetrahydropyranylmethyl group, or else R20 and R2i form, with the nitrogen atom to which they are bonded, a morpholinyl group optionally mono- or disubstituted by a (C1-C4) alkyl group or a piperazinyl group optionally substituted 10 in the 4-position by a Z3 substituent, or else R2o and R21 form, with the nitrogen atom to which they are bonded,, a pyrrolidinyl or piperidyl group, the said pyrrolidinyl and piperidyl groups optionally being substituted by Z5; 15 Z3 represents a (C1-C4) alkyl, pyridyl, phenyl, (C3-C4) alkylcarbonyl or (C1-C4) alkoxycarbonyl group; Z4 represents an oxo, a fluorine atom,, a hydroxyl, a (C1-C4) alkyl, a benzyl, an amino, a (C1-C4) alkylamino, a di (C1-C4) alkylamino, a 20 (C1-G4) alkoxy, a (G1-G4) alkoxycarbonyl or a (C1-C4) alkoxycarbonylamino; Z5 represents a chlorine, bromine, iodine or fluorine atom, a hydroxyl group, a (C1-C4) alkyl' group or - a (C1-C4) alkoxy group; 25 Z7 represents a fluorine atom, a hydroxyl group, a hydroxy (C1-C4) alkyl group, a (C1-C4) alkyl [lacuna], a (C1-C4) alkoxy [lacuna] or a (C1-C4) alkylcarbonyl 166 [lacuna]; Z8 represents a fluorine atom or a hydroxyl, (C1-C4) alkyl, (C3-C6) cycloalkyl, benzyl, amino, (C1-C4) alkylamino, di (C1-C4) alkylamino, 5 (C1-C4) alkoxycarbonyl, (C1-C4) alkoxycarbonylamino, (C3^-C6) cycloalkoxy, hydroxycarbonyl, hydroxy (C1-C4) alkyl, (C1-C4) alkoxy (C1-C4) alkyl, (C1-C4) alkoxy or -CONR23R24 group in which R23 and R24 represent, independently of one another, a hydrogen 10 ' atom, a (C1-C4) alkyl, a monofluoro (C1-C4) alkyl or a polyfluoro (C1-C4) alkyl, or else R23 and R24 form, with the nitrogen atom to which they are bonded, a pyrrolidinyl or piperidyl group, the said pyrrolidinyl or piperidyl groups optionally being 15 substituted by. Z3 or a difluoromethylidene; z6 represents a chlorine atom or a (C1-C4) alkyl or (C1-C4) alkoxy group; 20 R1 represents a (C1-C4) alkyl group optionally comprising a double or a triple bond, a (C1-C4)alkoxycarbonyl group, a phenyloxycarbonyl group or a T1-R22 group in which Ti is as defined above and R22 represents a hydroxyl or (C1-C4) alkoxy 25' group; R2 and R4 represent, independently of one another, a 167 167 hydrogen, chlorine or fluorine atom or a (C1-C4)alky. or. (C1-C4) alkoxy group; R3 represents a chlorine or fluorine atom or a (C1-C4) alkyl, (C1-C4) alkoxy, hydroxy!,

5. (C1-C4) carbamoyl, (C1-C4) alkylcarbonylamino, nitro, cyano, trifluoromethyl, amino, (C3-C6) cycloalkylamino, (C1-C4) alkylamino, di (C1-C4) alkylamino, tri (C1-C4) alkylammonium A", A- being an anion, pyrrolidin-1-yl, piperid-1-yl, piperazin-1-yl, 10 morpholin-4-yl or hexah'ydroazepin-1-yl group; X and Y represent, independently of one another," a hydrogen, chlorine, bromine, iodine or fluorine atom or a (C1-C4) alkoxy or trifluoromethoxy group; and their pharmaceutically acceptable salts, their. 15 solvates and their hydrates. -168- (2. Pharmaceutical composition as claimed in claim 1 comprising an antagonist of oxytocin receptors in combination with an antagonist of vasopressin Via receptors.

3. Product comprising an antagonist of oxytocin receptors and an antagonist of vasopressin Via receptors for simultaneous or separate use or use spread out over time in the treatment of dysmenorrhoea or endometriosis or the control of premature labour and for controlling preparatory labour for the purpose of a caesarean delivery. Dated this 7th day of March,

2006. -169-

FORM 2
THE PATENTS ACT 1970
[39 OF 1970]
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See Section 10; rule 13]
"INDOLIN-2-ONE DERIVATIVES, PREPARATION AND THEIR USE AS OCYTOCIN RECEPTOR LIGANDS"
We, SANOFI-SYNTHELABO, of 174, Avenue de France, F-75013 Paris, France,
The following specification particularly describes the invention and the manner in which it is to be performed:

WO 01/74775 1
INDOLIN-2-ONE DERIVATIVES AND THEIR USE AS OXYTOCIN RECEPTOR LIGANDS
A subject-matter of the present invention is novel indolin-2-one derivatives, a process for their
5 preparation and the pharmaceutical compositions
comprising them. These novel derivatives are powerful
and selective ligands of the oxytocin receptors and can
thus be used as an active principle in pharmaceutical
compositions, in particular in the obstetric or

10 gynaecological field.. Oxytocin (OT) is a hormone
excreted by the neurohypophysis with a cyclic
nonapeptide structure similar to that of arginine
vasopressin (AVP). The oxytocin receptors are
essentially found on the smooth muscle of the uterus

15 and on the myoepithelial cells of the mammary glands.
Thus, oxytocin plays an important role in parturition
since it is involved in the contraction of the uterine
muscle and in lactation. Furthermore, oxytocin
receptors are also located in other peripheral tissues

20 and in the central nervous system; oxytocin can thus
have effects in the cardiovascular, renal, endocrinal
or behavioural fields. ,
Indolin-2-one derivatives have been disclosed in some patent applications as ligands of the
25 vasopressin receptors and possibly of the oxytocin
receptors; mention may be made of Patent Applications WO 93/15051, EP 636 608, EP 636 609, WO 95/18105,

2
WO 97/15556 and WO 98/25901. To date, no indolin-2-one derivative has been disclosed as a powerful and selective ligand of oxytocin receptors.
It has now been found that certain indolin-
5 2-one derivatives are powerful and selective ligands of oxytocin receptors.
Thus, according to one of its aspects, the present invention relates to novel indolin-2-one derivatives in the form of a pure enantiomer or a
10 mixture of enantiomers of formula:


(I)

in which:
- R0 represents a group chosen from:
15


—R5
(i):

in which:

3
Z1 represents a chlorine, bromine, iodine or fluorine atom or a (C1-C4) alkyl, (C1-C4) alkoxy or trifluoromethyl group;
Z2 represents a hydrogen, chlorine, bromine, iodine 5 or fluorine atom or a (C1-C4) alkyl,
(C3-C5) cycloalkyl, (C1-C4) alkoxy, (C3-C5) cycloalkoxy or (C1-C4)polyfluoroalkyl group; -'
R5 represents T1W in which T1 represents -(CH2)m, it being possible for m to be equal to 0 or 1, and W
10 represents a hydrogen atom or a hydroxycarbonyl (or carboxyl), (C1-C4) alkoxycarbonyl, 1,3-dioxolan-2-yl or 1, 3-dioxan-2-yl group,
or else W represents an -NR6R7 group in which R6 and R7 represent, independently of one another, a
15 hydrogen atom, a (C1-C4) alkyl group, a
(C1-C4)alkylsulphonyl group or a phenylsulphonyl group in which the phenyl group can be mono-, di- or trisubstituted by Z5; or else R6 and R7 form, with the nitrogen atom to which they are bonded, a
20 morpholinyl group optionally substituted by a
(C1-C4) alkyl group or an oxo; or else R6 and R7 form, with the nitrogen atom to which they are bonded, a piperazinyl group optionally substituted in the 4-position by a Z3 substituent; or else R6 and R7
25 form, with the nitrogen atom to which they are
bonded, a pyrrolidinyl or piperidyl group, the said pyrrolidinyl and piperidyl groups optionally being

4
substituted by Z4;
or else W represents an –NR8COR9 group in which R8 represents a hydrogen atom or a (C1-C4) alkyl group and R9 represents a hydrogen atom or a
5 (C1-C4) alkyl, benzyl, pyridyl or phenyl group, it being possible for the said phenyl group to be mono-, di- or trisubstituted by Z5; or else R9 represents an -NRi0Ru group in which R10 and R11 represent, independently of one another, a hydrogen
10 atom or a (C1-C4) alkyl [lacuna] or else Rio and R10 form, with the nitrogen atom to which they are bonded, a pyrrolidinyl, piperidyl or morpholinyl group optionally substituted by a (C1-C4)alkyl group; or else R9 represents a pyrrolidin-2-yl or -3-yl or
15 piperid-2-yl, -3-yl or -4-yl group, the said
pyrrolidinyl and piperidyl groups optionally being substituted by Z7; or else R9 represents a -T2-R12 or -T2-COR12 group in which T2 represents -(CH2)n-/' it being possible for n to be equal to 1, 2, 3 and 4,
20 and R12 represents a (C1-C4) alkoxy or -NR10R11 group, R10 and R10 being as defined above;
or else W represents a -CONR13R14 group in which R13 represents a hydrogen atom or a (C1-C4) alkyl, (C3-C7)cycloalkyl,
25 monofluoro (C1-C4) alkyl or polyfluoro (C1-C4) alkyl group and R14 represents a hydrogen atom, a (C1-C4) alkyl group, a phenyl group optionally

5
substituted by Z5, a -T4-R15 group in which T4 represents -(CH2)q, with q equal to 1, 2, 3 or 4, and R15 represents a hydroxyl group, a (C1-C4) alkoxy group, a (C1-C4) alkoxycarbonyl group, a
5 (C1-C4)alkoxycarbonylamino group, a phenyl group optionally mono- or trisubstituted by Z5, a pyrid-2-yl, -3-yl or -4-yl, or an –NR16R17 group in which R16 and R17 represent, independently of one another, a hydrogen atom or a (C1-C4)alkyl [lacuna] or else .
10 R16 and R17 form, with the nitrogen atom to which they are bonded, a morpholinyl group optionally mono- or disubstituted by a (C1-C4)alkyl group or ; else R16 and R17 form, with the nitrogen atom to which they are bonded, a piperazinyl group
15 optionally substituted in the 4-position by a Z3 substituent or else R16 and R17 form, with the nitrogen atom to which they are bonded, a pyrrolidinyl or piperidyl group, the said pyrrolidinyl and piperidyl groups optionally being
20 substituted by Z5, it being understood that, when q = 1, R15 is other than hydroxyl, (C1-C4) alkoxy, (C1-C4) alkoxycarbonylamino or -NR16R17; or else R13 and R14 form, with the nitrogen atom to which they are bonded, a morpholinyl group optionally mono- or
25 disubstituted by a (C1-C4) alkyl group or a
piperazinyl group optionally substituted in the 4-position by a Z3 substituent; or else R13 and R14

6
form, with the nitrogen atom to which they are bonded, an azetidinyl, pyrrolidinyl, piperidyl or hexahydroazepinyl group, the said pyrrolidinyl, piperidyl and hexahydroazepinyl groups optionally
5 being mono- or disubstituted by Zs;
or else W represents an OR18 group in which R18 represents a hydrogen atom or a (C1-C4) alkyl, (C1-C4) alkoxy (C1-C4) alkyl or -T3-R19 group in which T3 represents -(CH2)P-, it being possible for p to be
10 equal to 2 or 3, and Ri9 is chosen from the hydroxyl, triphenylmethoxy or -NR20R21 groups in which R2o represents a hydrogen atom or a (C1-C4)alkyl group and R21 represents a hydrogen atom or a (C1-C4) alkyl, tetrahydrofuranylmethyl or tetrahydropyranylmethyl
15 group, or else R20 and R21 form, with the nitrogen atom to which they are bonded, a morpholinyl group optionally mono- or disubstituted by a (C1-C4) alkyl group or a piperazinyl group optionally substituted in the 4-position by a Z3 substituent, or else R20
20 and R21 form, with the nitrogen atom to which they are bonded, a pyrrolidinyl or piperidyl group, the said pyrrolidinyl and piperidyl groups optionally being substituted by Z5;
Z3 represents a (C1-C4) alkyl, pyridyl, phenyl,
25 (C1-C4) alkylcarbonyl or (C1-C4) alkoxycarbonyl group; Z4 represents an oxo, a fluorine atom, a hydroxyl, a (C1-C4) alkyl, a benzyl, an amino, a

7
(C1-C4) alkylamino, a di (C1-C4) alkylamino, a (C1-C4) alkoxy, a (C1-C4) alkoxycarbonyl or a (C3.-C4) alkoxycarbonylamino;
Z5 represents a.chlorine, bromine, iodine or
5 fluorine atom,'a hydroxyl group, a (C1-C4)alkyl group or a {C1-C4) alkoxy group;
Z7 represents a fluorine atom, a hydroxyl group, a hydroxy (C1-C4) alkyl group, a (C1-C4) alkyl [lacuna], a (C1-C4) alkoxy [lacuna] or a (C1-C4) alkylcarbonyl
10 [lacuna];
Z8 represents a fluorine atom or a hydroxyl, (C1-C4) alkyl, (C3-C6) cycloalkyl, benzyl, amino, (C1-C4) alkylamino, di (C1-C4) alkylamino, (C1-C4) alkoxycarbonyl, (C1-C4) alkoxycarbonylamino,
15 (C3-C6)cycloalkoxy, hydroxycarbonyl, hydroxy (C1-C4)alkyl, (C1-C4)alkoxy (C1-C4)alkyl, (C1-C4)alkoxy or -CONR23R24 group in which R23 and R24 represent, independently of one another, a hydrogen atom, a (C1-C4) alkyl, a monofluoro (C1-C4) alkyl or a
20 polyfluoro (C1-C4) alkyl, or else R23 and R24 form, , with the nitrogen atom to which they are bonded, a pyrrolidinyl or piperidyl group, the said pyrrolidinyl or piperidyl groups optionally being substituted by Z3 or a difluoromethylidene;


(ii):

8
-Z6 represents a chlorine atom or a (C1-C4) alkyl or (C1-C4) alkoxy group;
R1 represents a (C1-C4) alkyl group optionally
comprising a double or a triple bond, a

5 (C1-C4) alkoxycarbonyl group, a phenyloxycarbonyl
group or a T1-R22 group in which T1 is as defined
above and R22 represents a hydroxyl or (C1-C4) alkoxy
group; .
R2 and R4 represent, independently of one another, a
10 hydrogen, chlorine or fluorine atom or a (C1-C4)alkyl or (C1-C4) alkoxy group;
R3 represents a chlorine or fluorine atom or a (C1-C4) alkyl, (C1-C4) alkoxy, hydroxyl, (C1-C4) carbamoyl, (C1-C4) alkylcarbonylamino, nitro,
15 cyano, trifluoromethyl, amino,
(C3-C6) cycloalkylamino, (C1-C4) alkylamino,
di (C1-C4) alkylamino, tri (C1-C4) alkylammonium A-, A- being an anion, pyrrolidin-1-yl, pip.erid-1-yl, piperazin-1-yl, morpholin-4-yl or hexahydroazepin-
20 1-yl group;
X and Y represent, independently of one another, a hydrogen, chlorine, bromine, iodine or fluorine atom or a (C1-C4) alkoxy or trifluoromethoxy group; and to their pharmaceutically acceptable salts, their
25 solvates and their hydrates.
The term "alkyl" is understood to mean a saturated, linear or branched, monovalent

9
hydrocarbonaceous radical.
The term " (C1-C4) alkyl" is understood to mean an alkyl radical comprising from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,
5 isobutyl, sec-butyl and tert-butyl.
The term "alkylene" is understood to mean a saturated, linear or branched, bivalent hydrocarbonaceous radical.
The term "alkoxy" is understood to mean an
10 O-alkyl radical.
The term "anion A~" is understood to mean, for example, a Cl, Br, I' or CH3S04-.
The term “di(C1-C4) alkylamino" is understood to mean an amino radical substituted by two alkyl
15 radicals which can be identical or different. In the same way, for tri (C1-C4) ammoniums, the alkyl radicals can be identical or different.
The salts of the compounds according to the invention are prepared according to techniques which
20 are well known to a person skilled in the art. The
salts of the compounds of formula (I) according to the present invention comprise those with inorganic or organic acids, which make possible suitable separation or crystallization of the compounds of formula (I), and
25 pharmaceutically acceptable salts. Mention may be made, as appropriate acid, of: picric acid, oxalic acid or an optically active acid, for example a tartaric acid, a

10
dibenzoyltartaric acid, a mandelic acid or a camphorsulphonic acid, and those which form physiologically acceptable salts, such as the hydrochloride, the hydrobromide, the sulphate, the
5 hydrogensulphate, the dihydrogenphosphate, the maleate, the fumarate, the 2-naphthalenesuiphonate or the para-toluenesulphonate, the hydrochloride being preferred.
When a compound according to the invention
10 exhibits one or more asymmetric carbons, the optical isomers of this compound form an integral part of the invention. When a compound according to the invention exhibits stereoisomerism, for example of axial-equatorial or Z-E type, the invention comprises
15 all the stereoisomers of this compound.
The present invention comprises the compounds of formula (I) in the form of pure isomers but also in the form of a mixture of isomers in any proportion.
The compounds (I) are isolated in the form of
20 pure isomers by conventional separating technique's: use may be made, for example, of fractional recrystallizations of a salt of the racemate with an optionally active acid or base, the principle of which is well known, or conventional chromatography
25 techniques on a chiral or nonchiral phase.
The compounds of formula (I) above also comprise those in which one or more.hydrogen, carbon or

11
halogen, in .particular iodine, chlorine or fluorine, atoms have been replaced by their radioactive isotope, for example tritium or carbon-14. Such labelled compounds are of use in research, metabolic or
5 pharmacokinetic studies or in biochemical assays as receptor ligand.
The functional groups possibly present in the molecule of the compounds of formula (I) and in the. reaction intermediates can be protected, either in
10 permanent form, or in temporary form, by protective groups which ensure unequivocal synthesis of the expected compounds. The protection and deprotection reactions are carried out according to techniques well known to persons skilled in the art. The term
15 "temporary protective group for amines or alcohols" is understood to mean protective groups such as those described in Protective Groups in Organic Synthesis, Greene T.W. and Wuts P.G.M., published by Wiley Intersciences, 1999, and in Protecting Groups,
20 Kocienski P.J., 1994, Georg Thieme Verlag.
Mention may be made, for example, of temporary protective groups for amines: benzyls, carbamates (such as tert-butyloxycarbonyl, which can be cleaved in acidic medium, or benzyloxycarbonyl, which
25 can be cleaved by hydrogenolysis); for carboxylic acids: alkyl esters (such as methyl, ethyl or tert-butyl esters, which can hydrolyse in basic or

12
acidic medium) and benzyl esters, which can be hydrogenolysed; for alcohols or for phenols, such as tetrahydropyranyl, methyloxymethyl, methylethoxymethyl, tert-butyl and benzyl ethers; or for carbonyl
5 derivatives, such as linear or cyclic acetals, like, for example, 1,3-dioxane-2-yl or 1,3-dioxolan-2-yl; and reference.may be made to the well known general methods described in the abovementioned Protective Groups.
A person skilled in the art will be in
10 position to choose the appropriate protective groups. The compounds of formula (I) can comprise precursor groups of other functional groups which are subsequently generated in one or more other stages.
One family of compounds according to the
15 invention is composed of indolin-2-one derivatives in the form of a pure enantiomer or of a mixture of enantiomers of formula:


(I)

P4l

-R,

R
in which:
R0 represents

(i)


Z1, Z2, R1, R2, R3, R4, R5, Y and X are as defined for (I), and their pharmaceutically acceptable salts, their
5 solvates and their hydrates.
According to another of its aspects, the invention relates to the compounds of formula:-

X
r^N

Ro

Ri

^^K.^
Y
.1
R.
cm
VS

R.
R.

(Ia)

in which R1 represents a methyl or hydroxyl group and R0, R2, R3, R4, X and Y are as defined for (I) ; in the form of a pure enantiomer or of a mixture of enantiomers, and their pharmaceutically acceptable
15 salts, their solvates and their hydrates.
A subfamily of the compounds according to the

14
invention is composed of the compounds of formula:


(lb)

in which R1 represents a methyl or hydroxyl group and
5 R0, R3, R4 and X are as defined for (I); in the form of a pure enantiomer or of a mixture of enantiomers, and their pharmaceutically acceptable salts, their solvates and their hydrates.
Another subfamily of the compounds according
10 to the invention is composed of the Compounds of formula: '


OCH,
(Ic)

in which R1 represents a methyl or hydroxyl group and R0

15
and R3 are as defined for (I); in the form of a pure enantiomer or of a mixture of enaritiomers, and their pharmaceutically acceptable salts, their solvates and their hydrates.
Another subfamily of the compounds according to the invention is composed of the compounds of formula:

H3CO
OCH3

(Id)

in which R1 represents a methyl or hydroxyl group and R0 is as defined for (I); in the form of a pure enantiomer or of a mixture of enantiomers, and their pharmaceutically acceptable•salts, their solvates and their hydrates.
Among these compounds of formula (I), (la), (lb) , (Ic) and (Id) , those in which R0 represents the group:

16
in particular the group:


5 in which R5 is as defined for (I), constitute another
aspect of the invention.
Among the latter compounds, those in which R1
represents a methyl group constitute another aspect of
the invention.
10 According to another of its aspects, the
invention relates to the compounds chosen from:
5-Chloro-3-(2-chlorophenyl)-1-(2,4-dimethoxybenzyl)-
3-methylindolin-2-one (Example 1);
5-Chloro-3-(2-chlorophenyl)-1-[4-(isopropylamino)-
15 2-methoxybenzyl]-3-methylindolin-2-one (Example 56);
N-{4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-
3-methyl-2-oxoindolin-3-yl]phenyl}acetamide
(Example 70);
N-{4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-
20 3-methyl-2-oxoindolin-3-yl]phenyl}-3-methylbutanamide

17
(Example 73);
N-{4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}benzamide
(Example 74)
5 N-{4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}nicotinamide
(Example 76);
N-{4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-2-methoxyacetamide
10 (Example 77);
Methyl 3-{4-chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl] anilino}-3-o-xopropanoate
(Example 78);
AT-{4-Chloro-3- [5-chloro-l- (2, 4-dimethoxybenzyl).-
15 3-methyl-2-oxoindolin-3-yl]phenyl}-3-methoxypropanamide (Example 81);
N-{4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)- 3-methyl-2-oxoindolin-3-yl]phenyl}-N-methylacetamide (Example 87) ;
20 N-{4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-
3-methyl-2-oxoindolin-3-yl]phenyl}-N-methylmethane-sulphonamide(Example 97);
4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-W,N-diethylbenzamide (Example 102);
25 4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N,N-dimethylbenzamide (Example 109);
5-Chloro-3-[2-chloro-5-(1-piperidylcarbonyl)phenyl]-

18
1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one (Example 112);
4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin~3-yl]-N-ethylbenzamide (Example 114);
5 5-Chloro-3-(2-chloro-5-{[2-(methoxymethyl)-
1-pyrrolidinyl]carbonyl}phenyl)-1-(2,4-dimethoxybenzyl) -3-methylindolin-2-one (Example 119); 5-Chloro-3-{2-chloro-5-[(2-methyl-l-piperidyl)-carbonyl]phenyl}-l-(2,4-dimethoxybenzyl)-3-methyl-
10 indolin-2-one (Example 122);
4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl] -N-ethy1-AT-methylbenzamide
(Example 124);
Methyl l-{4-chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-
15 3-methyl-2-oxoindolin-3-yl]benzoyl}-2-piperidine-carboxylate (Example 131);
5-Chloro-3-{2-chloro-5-[(4-hydroxy-l-piperidyl)-carbonyl] phenyl }-.l- (2, 4-dimethoxybenzyl) -3-methyl-indolin-2-one (Example 134);
20 5-Chloro-3-{2-chloro-5-[(2-methoxyethoxy)methyl]-
phenyl}-l-(2,4-dimethoxybenzyl)-3-methylindolin-2-one (Example 142);
5-Chloro-3-[2-chloro-5-(4-morpholinylmethyl)phenyl]-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one
25 (Example 148);
5-Chloro-3-(2-chloro-5-{[2-(4-morphdlinyl)ethoxy]-methyl}phenyl)-1-(2,4-dimethoxybenzyl)-3-methylindolin-

19
2-one (Example 152);
1-[4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-3-hydroxypiperidine
(Example 194) ;
5 1-[4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-3-hydroxypiperidine (Example 195) ;
1-[4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-4-methoxypiperidine
10 (Example 166);
1-[4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-4-ethoxypiperidine
(Example 167) ;
1-[4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-
15 3-methyl-2-o,xoindolin-3-yl]benzoyl] - (R, S) -2, 6-dimethyl-piperidine (Example 189);
1-[4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-2-ethoxy-carbonylpiperidine (Example 175) ;
20 1-[4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-
3-methyl-2-oxoindolin-3-yl]benzoyl] - (R) -2-N,N-dimethyl-aminocarbonylpiperidine (Example 169) ;l-[4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-2-(N-methyl-
25 N-2,2,2-trifluoroethylaminocarbonyl)piperidine (Example 170); 1-[4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-

20
3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-2-pyrrolidino-
carbonylpiperidine (Example 168);
1-[4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-
3-methyl-2-oxoindolin-3-yl]benzoyl]-(S)-2-methyl-
5 piperidine (Example 174) ;
4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-
2-oxoindolin-3-yl]-N-ethyl-N- (2-phenylethyl)benzamide
(Example 185) ;
4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methy1-
10 2-oxoindolin-3-yl]-N-ethyl-N-(4-pyridylmethyl)benzamide hydrochloride (Example 188) ;
4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(3-pyridylmethyl)benzamide
(Example 201);
15 4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl] -N-ethyl-N- (2-pyr.idylmethyl) benzamide
(Example 200) ;
4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-methoxyethyl)benzamide
20 (Example 184);
4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N- (2-dimethylaminoethyl)-benzamide hydrochloride (Example 177);
4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-
25 2-oxoindolin-3-yl]-N-ethyl-N-(2-morpholinoethyl)-benzamide (Example 178); 4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-

21
2-oxoindolin-3-yl]-N-ethyl-W-(2-pyrrolidinoethyl)-benzamide hydrochloride (Example 182);
4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N- (2-piperidinoethyl)-
5 benzamide hydrochloride (Example 183) ;
4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-
10 (2-hydroxyethyl)benzamide (Example 198) ;
4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-10 2-oxoindolin-3-yl]-N-ethyl-N-[2-(pyrid-4-yl)ethyl]-benzamide.hydrochloride (Example 179);
4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-W- (2,2,2-trifluoroethyl)-benzamide (Example 180);
15 4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-methyl-N- (2,2,2-trifluoroethyl)-benzamide (Example 171); .
4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-isopropylbenzamide
20 (Example 187);
4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-(2-dimethylaminoethyl)-. N-(2,2,2-trifluoroethyl)benzamide hydrochloride (Example 202);
25 4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-W-cyclohexylbenzamide (Example 192); 4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-

22
2-oxoindolin-3-yl]-N-ethyl-N- [3-(pyrid-4-yl)propyl]-benzamide (Example 204);
in the form of a pure enantiomer or of a mixture of enantiomers, and to their pharmaceutically acceptable
5 salts, their solvates and their hydrates.
The compound of formula (I) can be prepared according to the following Scheme 1:
SCHEME 1

^
R<
R.

Ro
I
9H2 (in)

(n)

Ro
A

•Ri

(D

t ^ (i)

R,=OH

(IV)

r^
V^
r

23
In this scheme, R0, R1, R2, R3,R4, X and Y are as defined for (I) and, for (Ip), R'o, R'1,'R'2/ R'3, R'4, X' and Y' respectively represent either Ro, R1,- R2, R3, R4, X and Y as defined for (I) or a precursor group
5 for Ro, R1, R2, R3/- R4, X and Y, it being understood that R' 1'is other than hydrogen.
Another subject-matter of the present invention is a preparation process for the compounds of formula (I), characterized in that:
10 a) a compound of formula:

^N

R,

Ri

(nj

Y N O
in which X, Y, Ro and R1 are as defined for (I)', is reacted in the presence of a base with a halide of
15 formula:


Hal-

(1)

in which Hal represents a halogen atom and R2, R3 and R4 are as defined for (I);
20 b) or else, when R1 represents an electrophilic

24
group, the compound of formula:


>e^


R,

c)

in which Ro, R2, R3, R4, X -and Y are as defined for (I), is converted by the action of a derivative R1-Z, in which Z represents a leaving, group, in the presence of a base; or else, when Rx = OH, an isatin derivative of
formula:

^
L^-N
R
Y

(IV)

25

d)

in which R2, R3, R4, X and Y are as defined for (I) , is reacted with an organometallic derivative
Ro-M or R0MgHal, R0 being as defined for (I) , M
being a metal atom and Hal being a bromine or
iodine atom;•
or else the compound of formula:

X*
r*T^>

R'

R',

r
■'^-^ N O


in which R'0, R’, R'2, R'3, R' 4, X' and Y'
10 respectively represent either Ro, R1, B.2r R3> R4> X and Y as defined for (I) or a precursor group for Ro, R1, R2, R3, R4, X and Y, is subjected to a • subsequent treatment to convert any one of the R'o, R’f R'2, R'3/ Rr4/ X' and Y' groups to
15 respectively R0, R1, R2, R3, R4, X or Y as defined for (I) , according to reactions well known to a . person skilled in the art.
The reaction described in a) is preferably carried out with a compound (1) in which Hal = CI or Br

26
using, as base, a metal hydride, such as sodium
hydride, or an alkali metal alkoxide, such as potassium
tert-butoxide, in an anhydrous solvent, such as
dimethylformamide or tetrahydrofuran.
5 In the reaction described in b), the term
"leaving group" is understood to mean, for example, a
halogen atom, such as chlorine, bromine or iodine, or
alternatively a sulphonic ester group, such as
para-toluenesulphonate. The compound (III) is
10 preferably reacted with a halide R1-Hal, R1 being as
defined for (I) arid Hal being a halogen atom,
preferably an iodine atom, in the presence of a base;'
the reaction will be carried out, for example, in the
presence of a base, such as an alkali metal alkoxide,
15 for instance potassium tert-butoxide, in an ethereal
solvent, such as tetrahydrofuran, or alternatively in
the presence of a carbonate, such as sodium, potassium
or caesium carbonate, in a solvent such as
dimethylformamide or acetonitrile.
20 Advantageously, in the reaction described in
c), the compound of formula (IV) is reacted with a magnesium derivative RoMg-Hal, Ro being as defined for (I) or (Ip) and Hal being a bromine or preferably iodine atom, or alternatively the compound (IV) is
25 reacted with a derivative RoM in which M is preferably a lithium atom. This derivative RoLi is obtained either by direct lithiation, for example by the action of

27
butyllithium or lithium diisopropylamide according to Heterocycles, 1993, 35(1), 151-169, or by a halogen-lithium exchange reaction according to Organolithium Methods, Peirgamon Press, New York, 1988 or J. Am. Chem.
5 Soc, 1956, 2217. These reactions are preferably
carried out in an anhydrous solvent, such as diethyl ether or tetrahydrofuran.
The conversion of the compound (Ip), the precursor of the compound (I), described in d) is
10 carried out according to conventional techniques. Furthermore, the compounds (I) can be obtained from another compound (I) by conversion of one of the Ro, R1, R2, R3, R4, X or Y substituents, in particular Ro, R1 or R3 substituents. For example:
15 - the compounds (I) in which R3 = -NH2 can be obtained by reduction of the corresponding compounds (I) in which R3 = -NO2, for example by the action of hydrochloric acid in the presence of tin in an alcohol, such as ethanol;
20 - the compounds (I) in which R3 represents a
(C1-C4) alkylamino or di (C1-C4) alkylamino group can be obtained from the corresponding compounds (I) in which R3 = -NH2 by a reductive amination reaction. Reference may be made to J. Org. Chem., 1996, 61,
25 3849-3862 and the reaction can be carried out by the action of a (C1-C4) alkyl aldehyde in the presence of sodium triacetoxyborohydride or alternatively

28
reference may be made to J. Am. Chem. Soc, 1974, 96(25), 7812 and the reaction can be carried out by the action of a (C1-C4)alkyl acid in the presence of sodium borohydride. Use may also be made of
5 conventional N-alkylation reactions, for example by reacting the amino group with a (C1-C4)alkyl halide in the presence of dimethylformamide and potassium carbonate;
the compounds (I) in which R3 represents a
10 (C1-C4), alkoxy can be obtained from the corresponding compounds (Ip) in which R’3 = OH by a conventional O-alkylation reaction, for example by the action of a (C1-C4)alkyl halide in the presence of dimethylformamide and of caesium or potassium
15 carbonate;
the compounds (I) in which R3 represents a (C1-C4)alkylcarbonylamino group can be obtained from the corresponding compounds (I) in which R3 = -NH2 by a conventional acylation, such as the action of a
20 (C1-C4)alkyl acid chloride in the presence of a base, such as triethylamine, in a solvent, such as dichloromethane; - the compounds (I) in which R3 represents a cyclic amine or a morpholin-4-yl can be obtained from the
25 corresponding compounds (I) in which R3 = -NH2
according to the method described in Tetrahedron, 1989, 45(3), 629-636.

29
the compounds of formula (I) in which R0 represents a group:

'. I
can be obtained from the corresponding compounds of

formula (I) by conversion of the R5 group according
to conventional reactions, for example alkylation,
acylation, oxidation, reduction or amination
reactions, well known to a person skilled in the
art.
10 The compounds (III) are prepared by
dehalogenation of the compounds of formula:

15 in which R0, R2, R3, R4 X and Y are as defined for (I) and Hal represents a chlorine, bromine or iodine atom, for example by the action of a hindered lithium

30
dialkylamide, such as lithium diisopropylamide (LDA), by analogy with the method described by N. Newcom et al. in J. Am. Chem. Soc, 1990, 5186-5193.
The compound (I') is, for example, obtained
5 by conversion of the corresponding compound (I) in which R1 = OH by the action of a halogenated derivative, for example of acid halide type. Mention may be made, as chlorinated derivative, of SOCI2.
The compound (IV) is generally obtained by
10 reaction of the compound (1) with the. isatin derivative of formula:
x ,0
(2)
W\, A
Y NO
in which X and Y are as defined for (I), under the same conditions as those described above for the preparation
15 of the compound (I) from the compound (II). The isatin derivatives (2) are commercially available compounds or are prepared according to the methods described in Tetrahedron Letters, 1998, 39, 7679-7682; Tetrahedron-Letters, 199.4, 35, 7303-7306; J. Org. Chem., 1977, 42,
20 1344-1348 and Advances in Heterocyclic Chemistry, A.R. Katritzky and A.J. Boulton, Academic Press, New York, 1975, 18, 2-58.
The compounds (II) can be synthesized according to various methods disclosed in particular in
25 Patent Applications EP 526 348 and WO 95/18105.

31
Some routes.for the production of the compounds (II) are illustrated in Scheme 2:
SCHEME, 2

5
The term "nucleophilic R1" is understood to mean a (C1-C4) alkoxy group.
The compounds (II) in which R1 represents an electrophilic group, for example a (Ci-C4)alkyl group,
10 can be prepared from the compounds of formula:

in which Ro, X and Y are as defined for (I) , by

32
reaction with a derivative R1-Z in which Z represents a
leaving group, under the same -conditions as those
described above for the transformation of the compound
(III) to the compound (I).

5 The compound (V) is generally synthesized:
• either by dehydroxylation of the corresponding
compound (II) in which R1 = OH by the action of tin
chloride in acidic medium, according to the method
described in Tetrahedron, 1996, 52(20), 7003-7012, or
10 by the action of triethylsilane, according to
Bioorganic and Medicinal Letters, 1997, 7(10), 1255-1260;
• or by a cyclization reaction in a strong acid medium,
such as, for example, sulphuric acid, of the compound
15 • of formula:
r^TN NCH" (VII) Y N o

in which R0, X and Y are as defined for (I), this
20 compound (VII) itself being obtained by a condensation reaction between an a-hydroxyacetic acid derivative of formula:

Ro being as defined for (I), with an aminobenzene of formula


in which X and Y are as defined for (I) .
The compounds (3) are commercially available or
10 are conventionally synthesized.
The compounds of formula (VIII) are commercially
available or are synthesized according to methods well
known to a person skilled in the art. Reference may in
particular be made to J. Med. Chem., 1987, 30(8), 1447.
15 Other reactions can also lead to the

20 - the cyclization reaction in the presence of formic
compounds (V). Mention may be made of: - the Brunner reaction described in Tetrahedron, 1986, 42(15), 4267-4272:

34
acid described in J. Chem. Soc. Perkin Trans., 1986, 1,
349-360: ' nu
?H
WCH_R' jcoo^ ^ U (V)
•&. Jk H2S04,98% WJk /^
/^^NH, 5-C,45min Y^^ N ^O
- the following cyclization reactions:
x ? ° x R°
(^Y° CH—H LDA/THF ^ f^^jl H (V)
kXA uv-25*c'3h J*AA>
5 Y H ° H
according to J. Am. Chem. Soc, 1985, 101(2), 435-443:
xf^TCH~CQQH EtoH/Hci> K^ii—h
Ux Ai15min kAMAn (V)
according to. Tetrahedron, 1996, 52(20), 7003-7012.
The compounds (II) in which R1 represents a
10 (C1-C4)alkoxy group are obtained from the compounds of formula:
Y7^ NH-COC(CH3)3 Y ^^ N ^O
O

in which Ro, X and Y are as defined for (I) and Hal represents a halogen atom, for example a chlorine atom,
15 by the action of the corresponding alcohol R1H. The compound (VI) is prepared from the

35
corresponding compound (II) in which R1 = OH by reaction with thionyl chloride in the presence of pyridine in dichloromethane.
The compounds (II) in which R1 = OH are
5 generally prepared from the corresponding isatin of formula:
Vs—f
(2)
in which X and Y are as defined for (I), according to the method described above for the preparation of the
10 compounds (I) in which R1 = OH from the compounds (IV) When R1 does not represent a hydroxyl group, the compounds (II) can also be prepared according to Scheme 3 below:


5 In this Scheme 3, R0, R1, X and Y are as
defined for (I), R1 does not represent a hydroxyl group and M represents, for example, a lithium atom or MgHal, Hal being a halogen atom.
The transformation of the compound (X) to the
10 compound (IX) to give the compound (II) is carried out in particular according to the method described in J. Chem. Soc, 1957, 1928.

37
The benzyl halides (1) are known or are prepared according to known methods. Mention may be made, for example, of J.V. Rajanbabu, J. Org. Chem., 1986, 51, 1704-1712 and the publications cited in .
5 EP 636 609.
Generally, the halomethylbenzene derivatives (1) can be prepared by the action of N-halosuccinimides on the corresponding methylbenzene derivatives and according to EP 229 566. The reaction is carried out in
10 a solvent, such as carbon tetrachloride, in the
presence of dibenzoyl peroxide. A halomethylbenzene derivative can also be prepared from a corresponding hydroxymethylbenzene derivative by reaction with phosphorus tribromide in diethyl ether or by reaction
15 with thionyl chloride.
At any stage in the process, an intermediate
compound of (Up) , (IIIp) or (IVp) type, in which at
least one of the substituents is replaced by one of its
precursor groups, can be formed intermediately. These'

20 compounds-(Up), (IIIp) and (IVp) will be converted by
conventional reactions into (II), (III) and (IV)
respectively. A person skilled in the art will be in a
position to adapt the abovementioned reactions to the
compounds (Up), (IIIp) and (IVp).
25 The compounds according to the invention have
formed the subject of biochemical and pharmacological studies. The affinity of the compounds according to the

38
invention for oxytocin receptors was determined in an in vitro binding test using the method described by J. Elands et al. in Eur. Pharmacol., 1987, 141, 192-207. This method consists in studying in vitro the
5 displacement of a radioiodinated oxytocin analogue at the oxytocin receptors in a membrane preparation of human uterine oxytocin receptors. The IC50 values (concentration which inhibits 50% of the binding of the radioiodinated oxytocin analogue to its receptors) are
10 low and vary from 10~10 to 10"6 M in the latter test.
The affinity of the compounds according to the invention for human vasopressin Vla receptors (method described by M. Thibonnier et al. in J. Biol. Chem., 1994, 269, 3304-3310), Vib receptors (method
15 described by T. Sugimoto et al. in J. Biol. Chem., 1994, 269, 27088-27092) and V2'receptors (method described by M. Birnbaumer et al. in Nature (Lond.), 1992, 357, 333-335) has also been studied. The compounds studied have little or no affinity for the
20 Vla,V1b and V2 receptors. By way of indication, the compound of Example 1 exhibits an IC50 of less than 50 nM, the IC50 values with respect to the Via, Vib and V2 receptors being greater than 1 µM.
The agonist or antagonist nature of the
25 compounds is determined in vitro in a test for the measurement of intracellular calcium with respect to cells expressing human oxytocin receptors according to

39
the general technique described in Am. J. Physiol., 268 (Heart Circ. Physiol., 37), 1995, H404-H410.
When the compounds according to the invention behave as antagonists, their IC50 is advantageously
5 between 0.5 µM and 0.5 nM. By way of example, the
dextrorotatory enantiomer of Example 1 is an antagonist with an IC50 of 3.2 ± 1.9 nM.
The compounds according to the invention, powerful and selective ligands of oxytocin receptors, .
10 are particularly advantageous in the prevention and/or treatment of oxytocin-dependent disorders. The compounds according to the present invention can either mimic or inhibit the effects of oxytocin.
They will be particularly advantageous in
15 cicatrization, in analgesia and anxiolysis (prevention of pain and anxiety), depression, schizophrenia, autism, obsessive compulsive syndrome, in maternal behaviour (facilitation of mother-child recognition and acceptance) and social behaviour, memory, regulation of
20 food and drink intake, dependence on drugs, weaning and sexual motivation. They can be advantageously used in disorders of the urogenital sphere, in particular in the obstetric and gynaecological fields, in particular as uterine relaxant or tocolytic agent or for
25 controlling contractions of the uterus before pregnancy has arrived at term, for controlling prenatal labour or for controlling preparatory labour for the purpose of a

40
caesarean delivery, for solving problems of sterility or fertility, controlling births (in particular veterinary use), controlling oestrus, the halting of breast feeding, weaning, or embryo transfer and
5 implantation; treating endometriosis, dysmenorrhoea and urinary stress or.urgency incontinence, benign prostate hypertrophy and erectile dysfunctions, hypertension, hyponatraemia, cardiac insufficiency, atherosclerosis or angiogenesis, and regulating the storage of fat by
10 the adipocyte.
Furthermore', given the role of oxytocin in
controlling luteinizing hormone (J.J. Evans,
J. Endocrin., 1996, 151, 169-174), the compounds of the
invention can be used to induce contraception.

15 Furthermore, the compounds according to the
invention can be used for their antitumour effects in oxytocin-secreting tumours, in particular breast and prostate cancers.
The use of the compounds according to
20 invention for the prevention and/or the treatment of the abovementioned conditions and for the preparation of medicaments intended to treat these conditions forms an integral part of the invention.
Another subject-matter of the present
25 invention is thus pharmaceutical compositions
comprising a compound according to the invention or a pharmaceutically acceptable salt, solvate or hydrate of

41
the latter and suitable excipients. The said excipients are chosen according to the pharmaceutical form and the method of administration desired: oral, sublingual, subcutaneous, intramuscular, intravenous, topical,
5 intratracheal,_ intranasal, transdermal, rectal or intraocular. The pharmaceutical compositions are prepared according to techniques known to a person skilled in the art.
In order to obtain the desired prophylactic
10 or therapeutic effect, each' unit dose can comprise from 0.5 to 1 000 mg, preferably from 1 to 500 mg, of active ingredients in combination with a pharmaceutical vehicle. This unit dose can be administered 1 to 5 times daily, so as to administer a daily dosage of 0.5
15 to 5 000 mg, preferably from 1 to 2 500 mg.
The compounds according to the invention can also be used for the preparation of compositions for veterinary use intended to regulate births.
The compounds according to the invention can
20 also be used for the preparation of cosmetic
compositions. These formulations can be provided in the form of a cream for topical use and will be intended to control lipolysis.
The compositions of the present invention can
25 comprise, in addition to the products of formula (I) above or their pharmaceutically salts., solvates and hydrates, [lacuna], and for example active principles

42
which may be of use in the treatment of the disorders or conditions indicated above. Thus, another subject-matter of the present invention is pharmaceutical compositions comprising several active principles in
5 combination, one of which is a compound according to the invention. In particular, the present invention relates to pharmaceutical compositions comprising a compound according to the invention, an antagonist of oxytocin receptors, with a Vla antagonist compound. This
10 type of composition will be of particular use in the treatment of dysmenorrhoea or endometriosis or the control of premature labour and for controlling preparatory labour for the purpose of a caesarean delivery.
Another subject-matter of the invention is products comprising an antagonist of oxytocin receptors as defined above and an antagonist of vasopressin Via receptors for simultaneous or separate use or use spread out over time in the treatment of dysmenorrhoea
20 or endometriosis or the control of premature labour and for controlling preparatory labour for the purpose of a caesarean delivery.
The following PREPARATIONS and EXAMPLES illustrate the invention without, however, limiting it.
The nuclear magnetic resonance spectra were recorded in deuterated chloroform, unless otherwise mentioned, at 200 MHz and the chemical shifts are

43
expressed in ppm. The abbreviations used below are as follows: s = singlet; m = multiplet; d = doublet, t = triplet; q = quintet.
All the compounds according to the invention
5 have formed the object of organic elemental analysis
carried out by combustion at 1 000°C in the presence.of oxygen using a balance of Supermicro S4 Sartorius type and an elemental analyser of EA 1108 type. The percentage analyses of the elements carbon, hydrogen,
10 nitrogen and sulphur obtained are in agreement with the theoretical results expected.
PREPARATIONS
PREPARATION 1
15 N- (4-Chlorophenyl)-2-oxopropionamide, compound XI. 1.
26.3 g of 4-chlorophenylamine in 150 ml of dichloromethane and 35 ml of triethylamine are added, at -60°C, to 22 g of 2-oxopropionyl chloride (prepared according to Synthesis, 1975, 163-164 from
20 2-oxopropionic acid and 1,1-dichlorodimethyl ether) in 350 ml of dichloromethane. The reaction mixture is stirred at -60°C for 2 hours and then 200 ml of a 0.15N aqueous hydrochloric acid solution and 500 ml of dichloromethane are added at -30°C. The organic phase
25 is extracted, washed with a 0.25N aqueous hydrochloric acid solution and dried over sodium sulphate. The solvents are evaporated under reduced pressure and the

44
residue obtained is crystallized from dichloromethane; M.p. = 151°C.
PREPARATION 2
5 2-(2-Chloro-4-fluorophenyl)-N- (4-chlorophenyl)-2-hydroxypropionamide, compound IX.1.
0.18 g of magnesium and 2.57 g of 2-chloro-4-fluoro-1-iodobenzene are stirred at reflux in 30 ml of diethyl ether. The mixture thus obtained is added at
10 -60°C to -0.99 g of compound XI. 1 in 9 ml of
tetrahydrofuran. The reaction mixture is stirred at 20°C for 2 hours and then a saturated aqueous NH4C1 solution is added. Extraction is carried out with ethyl acetate, the organic phase is dried over Na2So4 and the
15 solvents are evaporated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, elution being carried out with a 1/1 (v/v) cyclohexane/dichloromethane mixture and then a 99/1 (v/v) dichloromethane/methanol mixture. The
20 solid thus isolated is crystallized from diisopropyl ether; M.p. 167°C.
The following compounds are prepared in the same way:
N- (4-Chlorophenyl)-2-(2,5-dimethoxyphenyl)-2-
25 hydroxypropionamide, compound IX.2; M.p. 145CC. N- (4-Chlorophenyl)-2-(2-chloro-4-methylphenyl)-2-hydroxypropionamide, compound IX.3; M.p. 116 ° C.

45
N- (4-Chlorophenyl)-2-(2-chloro-5-methylphenyl)-2-hydroxypropionamide, compound IX.4; M.p. 147°C. N- (4-Chlorophenyl)-2-(2-chloro-5-fluorophenyl)-2-hydroxypropionamide, compound IX.5; M.p. 171CC.
PREPARATION 3
(2-Chlorophenyl)-N- (4-chlorophenyl)hydroxyacetamide, compound VII.1.
A mixture of 60 g of (2-chlorophenyl)hydroxy-
10 acetic acid and 41 g of 4-chlorophenylamine in 300 ml of 1,2-dichlbrobenzene is heated to 200°C. The setup comprises a Dean and Stark apparatus and thus the water formed is removed during the reaction. Approximately 150 ml of solvent are distilled off and the expected
15 compound is crystallized at 20°C. The solid obtained is rinsed with diisopropyl ether; M.p. = 120°C.
In the same way, (2-chlorophenyl)-N- (4-methoxyphenyl)hydroxyacetamide, compound VII.2, is prepared from 4-methoxyphenylamine; M.p. = 130°C.
In the same way, (2-chloro-4-fluorophenyl)-N-(4-chlorophenyl)hydroxyacetamide, compound VII.3, is prepared from '(2-chloro-4-fluorophenyl) hydroxyacetic acid (synthesized according to J. Med. Chem., 1987, 30 (8), 1447, from 2-chlpro-4-fluorobenzaldehyde and
25 bromoform); M.p. = 136°C.

46
PREPARATION 4
5-Chloro-3-(2-chlorophenyl)indolin-2-one, compound V.1


(V.1): R0= —(( >> ; X = 5-CI ; Y = H

5 A solution of 263 ml of 95% sulphuric acid
and 100 ml of 20% oleum is prepared at 10°C. This solution is stirred with 74 g of compound VII.1 for 2 hours at 40°C. The reaction mixture is subsequently-cooled and then poured onto ice-cold water. The
10 precipitate obtained is filtered off and then washed with 1 000 ml of water. The solid is dissolved in dichloromethane and the solution thus obtained is washed successively with a saturated aqueous sodium hydrogencarbonate solution and with water and then
15 dried over Na2So4. The solvents are evaporated under
reduced pressure and then the solid obtained is washed with diethyl ether; M.p. = 201°C.
Compound V.2 below is prepared in the same way:
20 5-Chloro-3- (,2-chloro-4-fluorophenyl) indolin-2-one, compound V.2.

(V.2): Ro= —(/ \) F ; X = 5-CI ; Y = H
M.p. = 221°C

47

PREPARATION 5
5-Methoxy-3-(2-chlorophenyl)indolin-2-one, compound
V.3.
20.1 g of 2-(2-chlorophenyl)-N-(4-methoxy-
5 phenyl)-2-hydroxyacetamide, compound VII.2, are added to a mixture of polyphosphoric acid, obtained from 65 ml of 85% phosphoric acid and 130 g of phosphorus pentoxide, at a temperature of 50°C and then the reaction mixture is maintained at this temperature for
10 6 hours. After cooling, treatment is carried out with an aqueous sodium hydrogencarbonate solution until a pH of 5 is obtained. Extraction is carried out with ethyl acetate. The organic phase is washed with water and then dried over anhydrous sodium sulphate. The solvent
15 is partially evaporated under reduced pressure and the expected product is filtered off; M.p. = 179°C.
PREPARATION 6
5-Chloro-3-(2-chlOrophenyl)-3-methylindolin-2-one,
(II.1): R0= — ; R^-OChij ; X = 5-CI ; Y = H
M.p. = 179°C.

55
5-Chloro-3-(2-chloro-4-fluorophenyl)-3-methoxyindolin-2-one, compound II.13.

(11.13): Ro= —(/ \) F ; R^-OC^ ; X = 5-CI ; Y = H
M.p. = 82°C.
PREPARATION 12
5-Chloro-l-(2,4-dimethoxybenzyl)indolin-2,3-dione,
compound IV.1.
10 (IV.1.) : R2 = H; R3 = 4-OCH3; R4 = 2-OCH3; X = "5-C1; Y = H a) 0.25 ml of phosphorus tribromide is added at -50°C to a suspension of 1.45 g of 2,4-dimethoxyphenyl-methanol in 25 ml of diethyl ether. The solution thus obtained is allowed to return to a
15 temperature of 0CC.
b) 2 g of potassium tert-butoxide are added at -60°C to a suspension of 1.3 g of 5-chloroindolin-2,3-dione in 50 ml of tetrahydrofuran. The reaction mixture is stirred at 0°C for 5 minutes and then
20 the solution prepared' in a) is added at -60°C. The reaction mixture is stirred at room temperature for 16 hours and then the solvents are evaporated under reduced pressure. The residue obtained is purified by chromatography on a column of silica
25 gel, elution being carried out with a cyclohexane/dichloromethane mixture varying from

56
8/2 to 2/8 (v/v). The solid obtained is crystallized from toluene; M-.p. = 175°C.
The following compounds are prepared in the
same way:
5 5-Chloro-l-(4-chloro-2-methoxybenzyl)indolin-2,3-dione,
Compound IV.2.
M.p. = 136°C
5,7-Dichloro-l- (2,4-dimethoxybenzyl) indolin-2,3-dione,
Compound IV.3.
10 M.p. = 171°C
5-Fluoro-l-(2,4-dimethoxybenzyl)indolin-2,3-dione,
Compound IV.4.
M.p. = 163°C . . •
1-(2,4-Dimethoxybenzyl)indolin-2,3-dione, Compound
15 IV. 5.
M.p. = 142°C.
EXAMPLE 1
5-Chloro-3- (2-chlorophenyl) -1- (2 ,4-dimethoxybenzyl) -3-
20 methylindolin-2-one.


(I): R0 =

R3 = 4-OCH3; R4 = 2-OCH3; X = 5-C1; Y = H
a) 0.4 8 ml of phosphorus tribromide is added at -50°C
25 to a suspension of 2.6 g of 2,4-

57

dimethoxyphenylmethanol in 45 ml of diethyl ether. The solution thus obtained is allowed to return to a temperature of 0°C.
b) 1.2 g of potassium tert-butoxide are added at
5 -40°C to ,3 g' of compound II.1 in solution in 90 ml of tetrahydrofuran and then the reaction mixture is stirred until the temperature has returned to 0°C. The reaction mixture is subsequently cooled to -60°C and the solution prepared in a) is added.
10 The reaction mixture is stirred at 20°C for
2 hours, 50 ml of water are added and extraction is carried out with ethyl acetate. The organic phases are dried over sodium sulphate and the solvents are evaporated under reduced pressure.
15 The solid obtained is crystallized from diisopropyl ether/ M.p. = 179°C.
This compound, in the racemic form, is then separated by chromatography on a Chiralpak® AD column from Daicel, elution being carried out with a 98/2
20 (v/v) 2-methylpentane/ethanol mixture.
α23-5
The dextrorotatory enantiomer: M.p. = 92 °C;
= + 39° (c = 1,CH3OH) f anci its antipode are thus isolated.
25 EXAMPLE 2
5-Methoxy-3-(2-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one.

58


(I): R0 = . — 3.83 (s, 3H) , 1.33 (d, 6H) .
5 [4-(1-Methylethoxy)-2-methoxyphenyl]methanol is prepared according to the method described above in Example 3 for the transformation of methyl [4-(1,1-dimethylethoxy)-2-methoxy]benzoate into [4-(1,1-dimethylethoxy)-2-methoxy]phenylmethanol.
10 b) The compound of Example 4 is prepared according to the procedure described for Example 1/ M.p. = 158°C.
Examples 5 to 17 below are prepared according to the procedure described for Example 1.

15

EXAMPLE 5
5-Chloro-3-(2-chlorophenyl)-1-(2-methoxy-4-
nitrobenzyl)-3-methylindolin-2-one.
(i): R0 = —v / ; R1= -CH3 ; R2= H :
CI.

R3 = 4 -N02 ; R4 = 2-OCH3 ; X = 5-CI ; Y = H
20 M.p. = 179°C.

62
EXAMPLE 6
5-Chloro-l-(2,4-dimethoxybenzyl)-3-(2,5-
dimethoxyphenyl)-3-methylindolin-2-one.

(I): Ro= -V V : Ri =-CH3 .' R2 = H. :
H3CO

OCH3
R3 = 4-OCH3; R4 = 2-OCH3; X = 5-C1; Y = H M.p. = 140°C (0.3 H20)

EXAMPLE 18
5-Chloro-3-(2-chloro-4-fluorophenyl)-1-(2,4-
dimethoxybenzyl)-3-hydroxyindolin-2-one.

66


(I): R0 = __(/ \)—F ; R1 = -OH ; R2 = H ;

R3 = 4-OCH3; R4 = 2-OCH3; X = 5-C1; Y = H
This compound can be prepared from compound 11.10 according to the same procedure as for Example 1
5 or else according to the method below:
0.87 ml of 2-chloro-4-fluoro-1-iodobenzene
and 0.09 g of magnesium in 15 ml of diethyl ether are
stirred at reflux for 1 hour. 0.75 g of compound IV.1,
in partial solution in 15 ml of tetrahydrofuran, is

10 added at -40°C. The reaction mixture is stirred for 2
hours at 20°C and then a saturated aqueous ammonium
chloride solution is added. Extraction is carried out
with ethyl acetate, the organic phase is dried over
anhydrous sodium sulphate and then the solvents are

15 evaporated under reduced pressure. The residue obtained
is purified by chromatography on a column of silica
gel, elution being carried out with a 1/1 (v/v)
cyclohexane/dichloromethane mixture. The solid obtained
is crystallized from cyclohexane; M.p. = 177°C.

20 This compound, in the racemic form, is
separated by chromatography on a Chiralpak® AD column from Daicel, elution being carried out with a 9/1 (v/v) 2-methylpentane/ethanol mixture.
The dextrorotatory enantiomer:
20.5
25 [°\l =+63° (c=1,CH3OH), and its antipode are thus

67
isolated.
EXAMPLE 19
5-Chloro-3-(2-chloro-5-methoxymethoxymethylphenyl)-1-
5 (2,4-dimethoxybenzyl)-3-hydroxyindolin-2-one.

(I): R0= : R1 = -0H i R2 = H ;
CH2OCH2OCH3
R3 = 4-OCH3; R4 = 2-OCH3; X = 5-C1; Y = H a) Preparation of 2-chloro-l-iodo-5-
hydroxymethylbenzene according to J. Org. Chem.,
10 1991, 56, 59.64-5965, from the corresponding commercial benzoic acid.
5.02 g of sodium borohydride are added portionwise and then 14.6 g of iodine, in solution in 50 ml of tetrahydrofuran, are added very slowly to 25 g of
15 4-chloro-3-iodobenzoic acid in solution in 200 ml of tetrahydrofuran at 0°C. The reaction mixture is stirred for 2 hours at room temperature and then at 35CC for 30 minutes. Hydrolysis is carried out at 10°C with a 0.5N hydrochloric acid solution and
20 extraction is carried out with ethyl acetate. The organic phase is separated by settling and then treated with an aqueous sodium bisulphite solution and then with water. The organic phase is dried over anhydrous sodium sulphate and the solvents

68
are evaporated under reduced pressure. The expected compound is obtained by distillation; B.p. = 109°C under 3 Pa. b) Preparation of 2-chloro-l-iodo-
5 methoxymethyleneoxymethylbenzene according to Synthesis, 1985, 74.
1.5 ml of para-toluenesulphonic acid monohydrate and 1.4 g of lithium bromide are added to 24.45 g of the preceding compound in 100 ml of
10 dimethoxymethane. The reaction mixture is stirred at 35°C for 4 hours and then for 2 hours at reflux. Hydrolysis is carried out at room temperature
15 with a dilute aqueous sodium bicarbonate solution and extraction is carried out with- diethyl ether. The organic phase is washed with water and dried over anhydrous sodium sulphate and the solvents are evaporated under reduced pressure. The expected product is obtained by distillation; B.p. = 108°C under 1.9 Pa.
20 c) The compound of Example 19 is prepared according to the procedure described for Example 18; M.p. = 142°C.

69
EXAMPLE 20
Methyl 4-chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-
hydroxy-2-oxoindolin-3-yl]benzoate
(I): R0= ~\/ ' R1 = "°H : R?=H
COOCH3
5 R3 = 4-OCH3; R4 = 2-OCH3; X =' 5-C1; Y = H
45.2 ml of a 1.6M solution of n-butyllithium in hexane, diluted in 200 ml of tetrahydrofuran and cooled to -90°C, are slowly added to 10.72 g of methyl 4-chloro-3-iodobenzoate (prepared by esterification of
10 the corresponding commercial acid; M.p. = 56°C) in 200 ml of tetrahydrofuran cooled to -100°C. The reaction mixture is stirred at -95°C for 20 minutes and then the solution, cooled to -70°C, of 10 g of compound IV. 1 in 600 ml of tetrahydrofuran is added. After
15 returning to room .temperature, hydrolysis is carried out with 200 ml of a saturated ammonium chloride solution, the solvents are partially evaporated under reduced pressure, extraction is carried out with ethyl acetate, the organic phase is dried over anhydrous
20 sodium sulphate and then the solvents are evaporated under reduced pressure. The residue obtained is washed with diethyl ether, filtered off and then dried at 50°C under reduced pressure; M.p. = 236°C.

70
EXAMPLE 21
3-(5-Amino-2-chlorophenyl)-5-chloro-l-(2,4-
dimethoxybenzyl)-3-hydroxyindolin-2-one
c(I): R0= -/ S • Ri =-°H ; R2 = H ;
NH2
5 R3 = 4-OCH3; R4 = 2-OCH3; X = 5-C1; Y = H
a) Preparation of 4-chloro-3-bromo-N,iV- (tetramethyl-ethylene)disilylaniline
A mixture composed of 3.3 g of 3-bromo-4-chloroaniline, 3.72 g of bis(dimethylaminodimethyl-
10 silyl)ethylene, obtained according to Tetrahedron
Letters, 1984, 25 (12)", 1253-1254, and 0.03 g of zinc iodide is heated at 140°C for 5 hours' under an argon stream. The expected product is distilled; B.p. = 105°C under 37 Pa.
15 b) The compound of Example 21 is prepared
according to the same procedure described for Example 20, purification being carried out by chromatography on a column of silica gel, elution being carried out with a 99/1 (v/v) dichloromethane/methanol mixture;
20 M.p. = 133°C.
The compounds of Examples 22 to 31 below are prepared in the same way as for Example 18:

73

a) Preparation of 2-(3-bromo-4-methoxyphenyl)-1,3-
10 dioxolane according to J. Med. Chem.,' 1990, 33{3), 972. A mixture composed of 5 g of 3-bromo-para-

74
anisaldehyde, 5 ml of ethylene glycol, 0.088 g of para-toluenesulphonic acid and 125 ml of toluene is heated at reflux for 1 hour 30 minutes in a reactor equipped with a Dean and Stark apparatus. The reaction mixture
5 is poured at room temperature onto 50 ml of water, extraction is carried out with diethyl ether and the organic phase is dried over anhydrous sodium sulphate. The solvents are evaporated under reduced pressure. The oil obtained is purified by chromatography on a column
10 of silica gel, elution being carried out with an 8/2 (v/v) cyclohexane/ethyl acetate mixture. The expected
product is obtained after distillation under reduced
pressure; B.p. = 128°C under 5 Pa.
b) The compound of Example 32 is prepared from
15 the preceding compound according to the procedure
described for Example 18; M.p. = 140°C.
EXAMPLE 33
5-Chloro-l-(2,4-dimethoxybenzyl)-3-{5-[(dimethylamino)-
20 methyl]-2-methoxyphenyl}-3-hydroxyindolin-2-one H3CO
(I): R0= —/ \ : R1 = -OH ; R2 = H
\ R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-CI ; Y = H
CH2N(CH3)2
a) 3-[5-Chloro-l-(2,4-dimethoxybenzyl)-3-hydroxy-2-oxoindolin-3-yl]-4-methoxybenzaldehyde, obtained by deprotection of the compound of Example 32 in acidic
25 medium according to J. Chem. Soc. Chem. Commun., 1987,

75
1351.
The mixture composed of 0.55 g of the compound of Example 32, 5 ml of acetone, 2.5 ml of water and 0.22 ml of IN hydrochloric acid is brought to
5 30°C for 2 hours with stirring. The reaction mixture is neutralized at room temperature with an aqueous sodium bicarbonate solution and extraction is carried out with ethyl acetate. The organic phase is dried over anhydrous sodium sulphate, the solvents are evaporated
10 under reduced pressure and the desired compound is
obtained by filtration of the evaporation residue taken up in diethyl ether; M.p. = 189°C.
b) Reductive amination according to J. Org. Chem.,
1996, 61(11), 3849-3862.

15 0.015 g of dimethylamine, in solution in 1 ml
of 1,2-dichloroethane, and then 0.072 g of sodium triacetoxyborohydride are added to 0.113 g of the preceding compound obtained in a) in suspension in 3 ml of 1,2-dichloroethane. After stirring for 15 hours at
20 room temperature, hydrolysis is carried out with 10 ml of water and extraction is carried out with ethyl acetate. The organic phase is dried over sodium sulphate, the solvents are evaporated under reduced pressure and the residue obtained is purified by
25 chromatography on a column of silica gel, elution being carried out -with a 95/5 (v/v) dichloromethane/methanol mixture. The expected product is obtained after

76
crystallization from isopropyl ether; M.p. = 162°C (0.4 H20)
EXAMPLE 34 5
5- Chloro-3-(3-chloropyridin-4-yl)-1-(2,4-dimethoxy-benzyl)-3-hydroxyindolin-2-one.

R

1N ; R, = -OH ; R2 = H ; R3 = 4 -OCH3 ; R4 = 2 ^OCH3
o
N ,.M - w, , ,>2 - ., , ^3 r T-w^. ,3 , r\4 - z:-vjon3 ; X = 5-CI ; Y=H
A solution of 0.414 ml of 3-chloropyridine in
10 5 ml of tetrahydrofuran is added dropwise to a
solution, diluted in 7 ml of tetrahydrofuran and cooled to -75°C, of 2.88 ml of 1.5 M lithium diisopropylamide in cyclohexane. After the addition, the reaction mixture is stirred at -75°C for 20 minutes and then
15 1.2 g of compound IV. 1 in 15 ml of tetrahydrofuran are added. The temperature of the reaction mixture is allowed to slowly rise to 0°C and then hydrolysis is carried out with 30 ml of an aqueous ammonium chloride solution. Extraction is carried out with ethyl acetate
20 and the organic phase is dried over sodium sulphate. The solvents are evaporated under reduced pressure and the residue obtained is purified by chromatography on a column of silica gel,, elution being carried out with a 75/25 (v/v) cyclohexane/ethyl acetate mixture. The
25 solid obtained is subsequently crystallized from ethyl

77
acetate; M.p. = 215°C.
The compounds of Examples 35 and 3 6 below are prepared in the same way:

10
PREPARATION 13
5-Chloro-3-(2-chlorophenyl)-1-(2,4-
dimethoxybenzyl)indolin-2-one, compound III.l.

78
(III.1): Ro= —P \ ; R^H ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OGH3 ;
X = 5-Ct ; Y = H
a) 3,5-Dichloro-3-(2-chlorophenyl)-1-(2,4-dimethoxybenzyl)indolin-2-one, compound I'.l.
0.98 ml of thionyl chloride is added at -20°C
5 to a solution of 2 g of the compound of Example 30 and 1.4 ml of pyridine in 24 ml of dichloromethane. The reaction mixture is stirred for 1 hour 30 min at room temperature and is cooled to 0°C and then 50 ml of water and 50 ml of dichloromethane are added.
10 Separation is carried out by settling, the organic phase is washed with an aqueous NaHC03 solution and dried over anhydrous sodium sulphate, and the solvent is evaporated under reduced pressure. The residue obtained is dried under reduced pressure for 2 hours
15 and compound I'.l is isolated in the form of a resin which is used directly in the following stage, b) Compound III.l
6.53 ml-of a 1.5M solution of lithium diisopropylamide in cyclohexane, rediluted with 15 ml
20 of tetrahydrofuran, are added at -68°C to the solution of compound I'.l obtained above in'24 ml of tetrahydrofuran. The reaction mixture is stirred for 45 minutes at -68°C and then 5 ml of methanol are slowly added. At approximately 0°C, water is added and
25 extraction is carried out with ethyl acetate. The

79
organic phase is washed with an aqueous sodium chloride solution and dried over 'sodium sulphate and the solvent is evaporated under reduced pressure. The residue obtained is purified by chromatography on a column of
5 silica gel, elution being carried out with an 85/15 (v/v) cyclohexane/ethyl acetate mixture. The expected product is isolated after crystallization from isopropyl ether; M.p. = 151°C. (0.2H2O).
Compounds III.2 to III.8 below are prepared
10 in the same way:

R3 = 4-UUH3; K4 = Z-OCH3; X = 5-Cl; I = H
0.34, g of potassium tert-butoxide is added at
10 -40°C to a solution of 1.14 g of compound III.4 in 20 ml of tetrahydrofuran. The reaction mixture is stirred at 0°C for 5 minutes and then 0.32 ml of methyl iodide is added at -40°C. The reaction mixture is stirred for 2 hours at room temperature, then 10 ml of
15 a saturated aqueous ammonium chloride solution are
added and extraction is carried out with ethyl acetate. The organic phase is dried over anhydrous sodium sulphate and then the solvents are evaporated under reduced pressure. The residue obtained is crystallized
20 from diisopropyl ether; M.p. = 166°C.

82
The compounds of Examples 38 to 44 below are prepared in the same way, optionally purified by silica chromatography:


83
TABLE 8 (continuation 1)

EXAMPLE

Ro

M.p.; °C; salt, (solvate)

43

165

H3C
44

145 0.2 H20

The racemic compound of Example 41 is
5 chromatographed on a chiral column under the conditions of Example 1, .elution being carried out with a 90/10 2-methylpentane/2-propanol mixture. The dextrorotatory enantiomer: 'M.p. = 120°C, [af°0 = +112° (c = 1, ethyl
acetate), and its antipode are obtained.
10

EXAMPLE 45
Ethyl ester of [5-chloro-3-(2-chlorophenyl)-1-(2,4-
(I)
Ro =
dimethoxybenzyl)-2-oxoindolin-3-yl]carboxylic acid. CI
R, = -COOCH2CH3 ; R2 = H ;

15

R3 = 4-OCH3; R4 = 2-OCH3; X = 5-C1; Y = H
0.082 g of potassium tert-butoxide is added to 0.2 6 g of compound III.l in 7 ml of tetrahydrofuran cooled to -40°C. The reaction mixture is stirred for

84

15 minutes at 0°C and then 0.086 ml of ethyl
chloroformate is added slowly at -65°C. After stirring
for 30 minutes at 20°C, the reaction is hydrolysed with
20 ml of a 5% ammonium chloride solution and extraction
5 is carried out with ethyl acetate. The organic phase is
dried over sodium sulphate and then the solvents are
evaporated under reduced pressure. The expected product
is isolated after crystallization from isopropanol;
M.p. = 112°C (0.3H2O) .
10
EXAMPLE 46
Phenyl ester of [5-chloro-3-(2-chlorophenyl)-1-(2,4-
dimethoxybenzyl)-2-oxoindolin~3-yl]carboxylic acid. CI

(I):
R3 = 4 -OCH3 ; R4 = 2 -OCH3 ; X = 5 -CI ; Y = H
15 The compound of Example 4 6 is obtained with
phenyl chloroformate according to the same procedure as Example 45; M.p. = 126°C.
EXAMPLE 47
20 5-Chloro-3-(2-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-
hydroxymethylindolin-2-one.
(]): R0= —v v : R = -CH2OH ; R2 = H ;
CI
R3 = 4 -OCH, ; R4 = 2 -OCH, ; X = 5 -CI ; Y = H

85

0.13 g of potassium tert-butoxide is added at -40°C to 0.3 g of compound III.l in 5 ml of tetrahydrofuran. 0.3 g of paraformaldehyde, which ,is slowly depolymerized by heating, is sparged into the
5 reaction mixture at 0°C. The reaction mixture is stirred for 1 hour at room temperature and then hydrolysed with a 5% aqueous NH4C1 solution. Extraction is carried out with ethyl acetate and the organic phase is dried over sodium sulphate. The solvents are
10 evaporated under reduced pressure and the residue
obtained is purified by chromatography on a column of silica gel, elution being carried, out with a 90/10 (v/v) cyclohexane/ethyl acetate mixture. The expected product is isolated after crystallization from an
15 n-pentane/ethyl acetate mixture; M.p. = 165°C.
EXAMPLE 48
1-(4-Amino-2-methoxybenzyl)-5-chloro-3-(2-
chlorophenyl)-3-methylindolin-2-one. CI

(I):
R, = -CH3 ; R2 = H ; R3 = 4 -NH2 ;
2Q R< =2-OCH3 ; X =5-CI ; Y = H
2.83 g of tin powder and then 5.6 ml of concentrated hydrochloric acid are added to 5.19 g of the compound of Example 5 in 64 ml of ethanol. The reaction mixture is heated at 50°C for 3 hours. The
25 reaction mixture is filtered at room temperature

86
through celite, the solvent is partially evaporated under reduced pressure, the residue is taken up in ethyl acetate and then the solution is treated with an aqueous sodium bicarbonate solution. The organic phase
5 is dried over anhydrous sodium sulphate and then the solvents are evaporated under reduced pressure. The residue obtained is taken up in diisopropyl ether, filtered off and dried under reduced pressure; M.p. = 232°C. ,
10
EXAMPLE 49
5-Chloro-3-(2-chlorophenyl)-1-(2-methoxy-4-pyrrolidin-
1-ylbenzyl)-3-methylindolin-2-one.
CI
(I) : Ro= —f J : R1 ="CH3 ! R2 = H V_
R4 = 2 -OCH3 ; X = 5 -CI ; Y = H
15 0.4 g of sodium bicarbonate powder and
0.14 ml of 1,4-dibromobutane are added to 0.5 g of the compound of Example 4 8 in 50 ml of hexamethyl-phosphoramide. The reaction mixture is heated at 115°C for 10 hours. The reaction mixture is. hydrolysed at
20 room temperature and extracted with ethyl acetate. The organic phase is washed several times with water and dried over anhydrous sodium sulphate and then the solvents are evaporated under reduced pressure. The residue obtained is purified by chromatography on a
25 column of silica gel, elution being carried out with a

87
95/5 (v/v) cyclohexane/ethyl acetate mixture. The oil obtained is treated with hydrochloric acid in diethyl ether; M.p. = 198°C (HC1•0.4H20) .
The compounds of Examples 50 to 52 below are 5 prepared in the same way:


88
EXAMPLE 53
5-Chloro-3-(2-chlorophenyl)-1-[4-dimethylamino-2-
methoxybenzyl]-3-methylindolin-2-one.
(I) : CI
Ro= —P \ ; R1 =-CH3 ; R2 = H ; R3 = 4-N(CH3)2
R4 =2-OCH3 ; X = 5-CI ; Y = H
5 150 ml of methyl iodide are added to 238 mg
of the compound of Example 48, in 4 ml of methanol and 1 ml of dimethylformamide, and 100 mg of potassium carbonate and then the reaction mixture is heated at 45°C for 24 hours. 10 ml of water are added at room
10 temperature and extraction is carried out with ethyl acetate. The organic phase is washed twice with water and dried over anhydrous sodium sulphate the solvents are evaporated under reduced pressure and the residue is purified by chromatography on a column of silica
15 gel, elution being carried out with a 90/10 (v/v)
cyclohexane/ethyl acetate mixture. The residue obtained is crystallized from /i-pentane, filtered off and dried under reduced pressure for 4 hours; M.p. = 135°C.
20 EXAMPLE 54
5-Chloro-3-(2-chlorophenyl)-1-(2-methoxy-4-methylaminobenzyl)-3-methylindolin-2-one.

89

V
CI. R3 = 4-NHCH3

(I) : Ro= —f 7 ; R1 =-CH3 ; R2 = H
R4 = 2 -OCH3 ; X = 5 -CI ;■ Y = H
The compound of Example 54 is prepared according' to the procedure described for Example 53; M.p. = 226°C (H20).
5
EXAMPLE 55
5-Chloro-3-(2-chlorophenyl)-1-(4-diisobutylamino-2-
methoxybenzyl) -3-methylindolin-2-one
CI
(I) : Ro = —^ J ; R1=-CH3 ; R2=H ; R3 = 4 -N[CH2CH(CH3)2]2 ;
R4 = 2.-OCH3 ; X = 5 -CI ; Y = H.
10 Obtained by reductive diamination according
to J. Org. Chem., 1996, 61(11), 3849-3862.
347 mg of sodium triacetoxyborohydride are added at 20°C to 0.25 g of the compound of Example 48 in 6 ml of 1,2-dichloroethane, 167 p.1 of acetic acid
15 and 106 µl of isobutyraldehyde. After stirring for. 1 hour at room temperature, the reaction mixture is hydrolysed with 20 ml of water and extraction is carried out with ethyl acetate. The organic phase is dried over anhydrous sodium sulphate and then the
20 solvents are evaporated under reduced pressure. The residue is chromatographed on a column of silica gel, elution being carried out with a 97/3 (v/v)

90

cyclohexane/ethyl acetate mixture. The oil obtained is taken up in solution of hydrochloric acid in diethyl ether, filtration is carried out and the solvents are evaporated under reduced pressure. The solid obtained
5 is dried at .45°C under reduced pressure for 5 hours. M.p. = 153°C (HCl-0.5H2O) .
EXAMPLE 56
5-Chloro-3-(2-chlorophenyl)-1-(4-isopropylamino-2-
10 methoxybenzyl)-3-methylindolin~2-one
(I) : . *o = ~\ \ ; R^-CHa ; R2 = H ; R3 = 4-NH[CH(CH3)2] ;
CI.
R4 = 2-OCH3 ; X = 5-CI ; Y = H.
Obtained by reductive amination according to J. Org. Chem., 1996, 61(11), 3849-3862.
0.26 ml of acetic acid, 0.14 ml of acetone
15 and then 0.56 g of sodium triacetoxyborohydride are
added to 0.40 g of the compound of Example 48 in 10 ml of 1,2-dichloroethane at room temperature. After stirring for 2 hours at room temperature, the reaction mixture is hydrolysed with an aqueous sodium
20 hydrogencarbonate solution and extracted with ethyl acetate. The organic phase is washed with water and dried over anhydrous sodium sulphate and the solvents are evaporated.under reduced pressure. The expected product is obtained by filtration of the crystallized 2525 evaporation residue taken up in n-pentane;

91

M.p. = 154°C. This compound, in the racemic form, is then separated by' chromatography on a chiral column under the same conditions as in Example 1/ the dextrorotatory enantiomer: M.p. = 137°C; [α]20D =+ 34.6°
5 (c = 1, CH3OH), and its antipode are thus isolated.
EXAMPLE 57
5-Chloro-3-(2-chlorophenyl)-1-[4-(isopropylmethylamino)-2-methoxybenzyl]-3-
10 methylindolin-2-one.
CI

R1 = -CH3 ; R2 = H R3 =4-N—CH3
CH(CH3)2 R4 = 2 -OCH3 ; X = 5 -CI ; Y = H
The compound of Example 56 is treated with
aqueous formaldehyde and sodium borohydride. The
compound obtained is salified with a solution of
15 hydrochloric acid in diethyl ether. The hydrochloride
is then isolated after filtration and drying at 45°C
under reduced pressure; M.p. = 156°C (HCl -1. 5H20) ..

92
EXAMPLE 58
{4- [5-Chloro-3- (2-chlorophenyl) -3-methyl-2-oxoindolin-i 1-ylmethyl]-3-methoxyphenyl}isopropyldimethylairanonium iodide.

(I) :
R4 = 2-OCH3 ; X=5-CI ; Y= Hl CH(CH3)2
5 0.56 g of caesium, carbonate and then 0.27 ml
of methyl iodide are added to 0.4 g of the compound of Example 56 in 10 ml of dimethylformamide. The reaction mixture is heated with stirring at 40°C for 48 hours. The reaction mixture is treated at room temperature
10 with 4 0 ml of water and extracted twice with diethyl ether and then 3 times with dichloromethane. The chlorinated solvent organic phases are dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue thus obtained is taken up in
15 diethyl ether, filtered off and dried at 50°C under reduced pressure; M.p. = 146°C (IH2O) .
EXAMPLE 59
5-Chloro-3-(2-chlorophenyl)-1-[4-(cyclopropylamino)-2-
20 methoxybenzyl]-3-methylindolin-2-one.
CI

R0 =
/ y I ' R, = -CH3 ; R2 = H ; R3 =4-NH-<]
(I) :
R4 = 2 -OCH3 ; X = 5 -CI ; Y = H

93
Obtained from the compound of Example 4 8 according to T.L., 1995, 36(41), 7399-7402.
0.54 ml of acetic acid, 0.4 g of 3 A molecular sieve and 0.207 ml of (1-
5 ethoxycyclopropyl)oxytrimethylsilane are added to 0.4 g of the compound of Example 4 8 in solution in 10 ml of methanol. After stirring for 30 minutes at room temperature, 0.265 g of sodium cyanobbrohydride is added and then the mixture is heated at reflux for 10
10 hours. After cooling, hydrolysis is carried out with 20 ml of 2N sodium hydroxide solution, filtration is carried out through celite and the celite is rinsed with ethyl acetate. The organic phase is washed with a 10% aqueous sodium chloride solution and dried over
15 sodium sulphate and the solvents are evaporated under reduced pressure.
The residue is purified by chromatography on a column of silica gel, elution being carried out with a 50/50 (v/v) cyclohexane/dichloromethane mixture and then with
20 pure dichloromethane. The expected product is isolated after crystallization of from n-pentane; M.p. = 185°C (0.5 H20).
EXAMPLE 60
5-Chloro-3-(2-chlorophenyl)-1-[4-diethylamino-25 2-methoxybenzyl]-3-methylindolin-2-one.

94

R = H
(I) : \===/ ' R3 =4-N(CH2CH3)2
R4 = 2 -OCH3 ; X = 5 -CI ; Y = H
According to Gordon W. Gribble et al., J. Am. Chem.
Soc. 1974, 95(25), 7812.
0.45 g of sodium borohydride is added to
0.5 g of the compound of Example 4 8 in 7 ml of acetic
5 acid. The reaction mixture is heated to 60°C with
stirring for 4 hours, the solvents are partially
evaporated, the reaction mixture is hydrolysed with an
aqueous sodium bicarbonate solution and extraction is
carried out with ethyl acetate. The organic phase is
10 dried over anhydrous sodium sulphate and concentrated
under reduced pressure. The oil obtained is treated
with a solution of hydrochloric acid in diethyl ether;
M.p. = 198°C (HC1)
EXAMPLE 61
15 5-Chloro-3-(2-chlorophenyl)-1-[4-ethylamino-
2-methoxybenzyl]-3-methylindolin-2-one.
C!^ ' R3 =4-NH(CH2CH3)

R4 =2-OCH3 ; x =5-CI ; Y = H
The compound of Example 61 is prepared according to the same procedure as for Example 60;
20 M.p. = 167°C.

95

EXAMPLE 62
(I) : Ro =' —\ y ; R, = -CH3 ; R2 = H ; R3 = 4 -NH(COCH3) ;
N-{4-[5~Chloro-3-(2-chlorophenyl)-3-methyl-2-oxoindolin-1-yl]-3-methoxyphenyl}acetamide. CI.

R4 = 2-OCH3 ; X = 5-Ci ; Y = H.
5 0.10 ml of acetyl chloride is slowly added at
0°C to 0.5 g of the compound of Example 4 8 in 10 ml of dichloromethane and 0.5 ml of triethylamine. The reaction mixture is hydrolysed at room temperature, 20 ml of dichloromethane are added, the organic phase
10 is dried over Na2SC>4 and the solvents are evaporated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, elution being carried out with a 50/50 (v/v) cyclo-hexane/ethyl acetate mixture; M.p. = 83°C.
15 EXAMPLE 63
5-Chloro-3-(2-chlorophenyl)-1-(4-ethoxy-2-methoxy-
benzyl)-3-methylindolin-2-one.
CI

(I)

R0 = —v / : R1 = -CH3 ; R2 = H ; R3 = 4 -NH(COCH3) ;

R4 = 2 -0CH3 ; X = 5 -CI ; Y = H. a) 5-Chloro-3-(2-chlorophenyl)-1-(4-hydroxy-2-methoxy-benzyl)-3-methylindolin-2-one.
20 3 ml of trifluoroacetic acid are added at 0°C to 1.14 g-of the compound of Example 3 in 20 ml of

96
dichloromethane and 1 ml of methyl phenyl sulphide. After stirring for 2 hours at room temperature, the reaction mixture is hydrolysed and extraction is carried out with ethyl acetate. The organic phase is
5 washed with an aqueous sodium bicarbonate solution and dried over anhydrous sodium sulphate and then the solvents are evaporated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, elution being carried out
10 by an 80/20 (v/v) cyclohexane/ethyl acetate mixture; M.p. = 200°C. b) 0.23 g of caesium carbonate and then, at 0°C,
0.112 ml of iodoethane are added to 0.2 g of the compound obtained in a) in 5 ml of dimethyl-
15 formamide. After stirring for 1 hour at 28°C, the reaction mixture is hydrolysed and extraction is carried out with ethyl acetate. The organic phase is-dried over anhydrous sodium sulphate and the solvents .are evaporated under reduced pressure. The
20 oil obtained is taken up in .n-pentane and the
precipitate obtained is filtered off and dried at 50°C under reduced pressure for 5 hours; M.p. = 124°C.
EXAMPLE 64
25 5-Chloro-3-(2-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-methoxymethylindolin-2-one.

97


(I) ■:
R4 = 2-OCH3 ; X = 5-CI ; Y = H.
0.1 ml of methyl trifluoromethanesulphonate and then 0.07 ml of 2,6-di(tert-butyl)pyridine are added at -20°C to a solution of 70 mg of the compound
5 obtained according to Example 47 in 1 ml of dichloro-methane and the reaction mixture is maintained at + 5°C for one week. The solvent is evaporated under reduced pressure, 5 ml of 0.IN hydrochloric acid are added and extraction is carried out with ethyl acetate. The
10 organic phase is dried over anhydrous sodium sulphate and the solvent is evaporated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, elution being carried out with a 95/5 (v/v) cyclohexane/ethyl acetate mixture. The resin
15 obtained is taken up in r?-pentane.
The solid obtained is filtered off and dried for 5 hours at 50°C; M.p. = 125°C (0.4 H20) .
EXAMPLE 65
5-Chloro-3-(2-chloro-5-hydroxymethylphenyl)-
20 1-(2,4-dimethoxybenzyl)-3-hydroxyindolin-2-one.

98

(I) : Ro = —V y ; R, = -OH i R2 = H ; R3 = 4-OCH3 ;
CH2OH
R4 = 2 -OCH3 ; X = 5 -CI ; Y = H
A mixture of 0.307 g of the compound of Example 19, 15 ml of methanol and 1 ml of ION hydrochloric acid is heated at 50°C for 2 hours. The
5 solvent is evaporated under reduced pressure and the residue obtained is taken up in dichloromethane and water. The organic phase is washed twice with water and then dried over anhydrous sodium sulphate. The solvents are evaporated under reduced pressure. The expected
10 product is isolated after solidifying in cyclohexane, filtering and drying at 30°C under reduced pressure for 6 hours; M.p. = 107°C.
EXAMPLE 66
5-Chloro-3-[2-chloro-5-(dimethylamino)phenyl]-
15 1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one.
(I) : Ro = —\ Y ; R,=-CH3 ; R2 = H ; R3 = 4-OCH3 ;" R4 = 2-OCH
N(CH3)2
X = 5-CI;Y=H
Prepared from the compound of Example 43 according to the procedure described for Example 53. The expected product is isolated after crystallization
20 from isopropyl ether; M.p. = 149°C (0.7 H20) .

99

EXAMPLE 67
4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-
2-oxoindolin-3-yl]phenylformamide.
According to T.L., 1982, 23(33), 3315. CI.
(I) : Ro = —\ y ; R, = -CH3 ; R2 = H ; R3 = 4 -OCH3 ; R4 = 2-OCH3
NHCHO
5 X = 5- CI;Y = H
0.216 ml of formic acid is added to 0.44 ml of acetic anhydride cooled to 0°C and then the reaction mixture is heated at 58°C for 1 hour-30 minutes. After cooling to 10°C, -0.8 ml of tetrahydrofuran is added,
10 followed by 0.80 g of the compound of Example 43 in
solution of'4 ml of tetrahydrofuran. After stirring for 2 hours at 20°C, the solvents are evaporated under reduced pressure. The residue obtained is taken up in n-pentane and the produce is filtered off; M.p. =
15 190°C.
EXAMPLE 68
5-Chloro-3-[2-chloro-5-(methylamino)phenyl]-
1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one.
(I) : Ro = -—(' V ; R, = -CH3 ; R2 = H ; R3 = 4 -OCH3 ; R4 = 2-OCH3
NHCH3
CI.
X = 5-CI;Y=H
20 Prepared according to T.L. 1982, 23(33), 3315

100
0.5 6 ml of a 2M solution of borane-dimethyl sulphide in tetrahydrofuran is added to a solution, cooled to 0°C, of 0.4 g of the compound of Example 67 in 1 ml of tetrahydrofuran. After 1 hour at 58°C and
5 then cooling to 0°C, 0.2 ml of ION hydrochloric acid and 1 ml of methanol are added to the reaction mixture. The mixture is heated at 60°C for 1 hour and cooled, and the solvents are evaporated under reduced pressure. The solid residue, is treated with 1 ml of a saturated
10 potassium carbonate solution and extraction is carried out several times with ethyl acetate'. The organic phases are dried over anhydrous sodium sulphate and the solvents are evaporated under reduced pressure. Purification is carried out by chromatography on a
15 column of silica gel, elution being carried out with an 85/15 (v/v) cyclohexane/ethyl acetate mixture. The expected product is isolated in the form of the hydrochloride by treating the residue obtained with diethyl ether comprising hydrogen chloride and then
20 filtration is carried out; M.p. = 121°C (0. 5H20-1HC1) . EXAMPLE 69
5-Chloro-3-(2-chloro-5-[ethyl(methyl)amino]phenyl}-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one.

101

(I): R0 = —(' ^> ; R1 = -CH3 ; R2 = H ; R3 = 4 -OCH3 ; R4 = 2-OCH3
N(CH3)(CH2CH3)
X = 5-CI; Y = H

Obtained from the compound of Example 68 according to the same procedure as for Example 60; M.p. = 145°C.
5 EXAMPLE 70
N-{4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenylJacetamide.


(I) : Ro = —<( 's> ; R, = -CH3 ; R2 = H ; R3 = 4 -OCH3 ; R4 = 2-OCH3
'3
NHCOCH,
X = 5-CI;Y = H
Obtained according to the same procedure as
10 the compound of Example 62 from the compound of Example 43; M.p. = 117°C.
The [lacuna] following Examples 71 to 80 are obtained in the same way:

104
EXAMPLE 81
N-{4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-
3-methyl-2-oxoindolin-3-yl]phenyl}-3-methoxy-
(I) : Ro =—\ y : R1 = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3
propanamide. CI.
NHCO(CH2)2OCH3 5 X = 5-CI;Y = H
0.068 ml of 3-methoxypropionic acid and 320 mg of benzotriazolyl-N-oxytrisdimethylamino-phosphonium hexafluorophosphate are added to 0.3 g of the compound of Example 43 in 10 ml of dimethyl-
10 formamide. After cooling to 0°C, 0.23 ml of
triethylamine is added. The reaction mixture is stirred at room temperature for 16 hours. 4 0 ml of water are added and extraction is carried out with 30 ml of ethyl acetate. The organic phase is treated with 20 ml of an
15 aqueous sodium bicarbonate solution, this phase is separated by settling and is dried over anhydrous sodium sulphate, and the solvents are evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being
20 carried out with dichloromethane. The expected product is obtained after crystallization from n-pentane; M.p. = 168°C (0.3 H20) .

105
The compounds of the following Examples 82 to 8 6 are obtained in the same way:


106

TABLE 11 (continuation)
EXAMPLES Ro M.p.; °C

86 143
1 H20

EXAMPLE 87
N-{4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-
/ W
(I): R0 =
3-methyl-2-oxoindolin-3-yl]phenyl}-N-methylacetamide. CI.
1^=-^ ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3
N-C-CH, I CH3
X = 5-CI;Y = H
Obtained from the compound of Example 68 according to the same procedure as in Example 62; M.p. = 84°C.
The compounds of the following Examples 88 to 90 are obtained in the same way:

108
EXAMPLE 91
N-{4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-2-(dimethylamino)-N-methylacetamide.
(I): R,, = —^ \) ; R^-C^ ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3
O
|| X = 5-CI;Y = H
N—C—CH2-N(CH3)2 CH,
5
According to the procedure of Synthesis 1980, 547.
0.14 g of N,N-dimethylglycine, 0.40 ml of triethylamine and 0.34 g of N,N-bis[2-oxo-3-oxo-zalidinyl]phosphorodiamide chloride are added at 0°C to
10 0.32 g of [lacuna] Example 68 in 5 ml of
dichloromethane. The reaction mixture is stirred for 24 hours at room temperature, 20 ml of an aqueous sodium bicarbonate solution are added and extraction is carried out with 30 ml of ethyl acetate. The organic
15 phase is again washed with 20 ml of an aqueous sodium bicarbonate solution and then dried over anhydrous sodium sulphate. The solvents are evaporated under reduced pressure. Purification is carried out by chromatography on a column of silica gel, elution being
20 carried out with a 97/3 (v/v) dichloromethane/methanol mixture. The expected product is isolated by crystallization from n-pentane; M.p. = 104°C.

109
EXAMPLE 92
l-Acetyl-N-{4-chloro-3-[5-chloro-l-(2,4-dimethoxy-
benzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-N-methyl-
2-pyrrolidinecarboxamide. CI.

(I): RQ = —// \) ; R1 = -CH3 ; R2 = H ; R3 = 4 -0CH3 ; R4 = 2-OCH3
^O
O
X = 5-CI; Y = H
N- "
CH3 COCH,
Prepared according to the same procedure as
in Example 91; M.p. = 74°C (2 H20) .
EXAMPLE 93
N-{4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-
3-methyl-2-oxoindolin-3-yl]phenyl}urea. CI.
(I) : Ro = —\ y ; R, = -CH3 ; R2 = H ; R3 = 4 -OCH3 "; R4 = 2-OCH3

NHCONH2

X = 5-CI; Y = H

a) Formation of phenyl 4-chloro-3-[5-chloro-1- (2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenylcarbamate.
0.30 ml of 30% sodium hydroxide solution is . added to 0.4 g of the compound of Example 43 in 20 ml of tetrahydrofuran. After cooling to -5°C, 0.33 ml of phenyl chlorocarbonate is added to the reaction mixture. After stirring for 4 hours at room
20 temperature, 30 ml of water are added and extraction is

110

carried out with 50 ml of ethyl acetate. The organic
phase is dried over anhydrous sodium sulphate and the
solvents are evaporated under reduced pressure. The oil
obtained is used in the following stage.
5 b) Production of the compound of Example 93.
The compound obtained in a) is taken up in
30 ml of dichloromethane in the presence of 1 ml of
liquid ammonia. After stirring for 4 8 hours at room
temperature, the solvent is partially evaporated and
10 the residue obtained is taken up in diethyl ether. The
product is filtered off and washed with diethyl ether;
M.p. = 254°C (1.5 H20) .
EXAMPLE 94
N-{4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-
15 3-methyl-2-oxoindolin-3-yl]phenyl}-N,N-dimethylurea. CI.
(I): R0 = —^ \) ; R1 = -CH3 ; R2 = H ; R3 = 4 -OCH3 ; R4 = 2-OCH3
NHCON(CH3)2 X = 5-CI;Y=H
Obtained according to the same procedure as for Example ,93; M.p. = 182°C (0.4 H20) .
EXAMPLE 95
20 N-{4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-
3-methyl-2-oxoindolin-3-yl]phenylJmethanesulphonamide.

Ill
(I) : Ro = —X V ; R1=-CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3
NHS02CH3 X = 5-CI;Y = H
0.23 ml of triethylamine are added to 0.3 g of the compound of Example 43 in 10 ml of dichloromethane and then, after cooling to -10°C, 56 ml
5 of methanesulphonyl chloride are added. After stirring for 24 hours at room.temperature, 10 ml of an aqueous sodium hydrogen carbonate solution and 30 ml of ethyl acetate are added. The organic phase is isolated and dried over anhydrous sodium sulphate, and the solvents
10 are evaporated under reduced pressure. The residue
obtained is purified by chromatography on a column of silica gel, elution being carried out with dichloromethane.. The expected product is obtained after crystallization from n-pentane; M.p. = 210°C (0.25 H2O) .
15 EXAMPLE 96
N-{4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-N-methyl-sulphonyl)methanesulphonamide.
<' ^ ; RT--CH3 ; R2=H-; -R3"-*= 4-OCH3 ; R4 = 2-OCH3
(I)
N(S02CH3)2 X ~ 5"CI; Y " H

112
Obtained according to the process of
Example 95 using two equivalents of methanesulphonyl
chloride; M.p. = 159°C.
EXAMPLE 97
5 N-{4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-
3-methyl-2-oxoindolin-3-yl]phenyl}-N-methylmethane-
sulphonami.de. CI.
(I) : Ro = —v / ; R1=-CH3 •" R2 = H : R3 = 4-OCH3 ; R4 = 2-OCH3

3
N—S02CH3 X = 5-CI;Y=H
CH3
Obtained according to the procedure of
10 Example 95 from [lacuna] Example 68; M.p. = 76°C (0.8
H20) .
EXAMPLE 98
N-{4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-
3-methyl-2-oxoindolin-3-yl]phenyl}-N-methylphenyl-
(I) : Ro = —V 7 ; R, = -CH3 ; R2 = H ; R3 =4 -OCH3 ; R4 = 2-OCK
N-so
X = 5-CI; Y = H
15 sulphonamide. CI.
CH3
Obtained according to the same procedure as for Example 97; M.p. = 73°C (0.8 H20) .

113

EXAMPLE 99
5-Chloro-3-[2-chloro-5-(4-morpholinyl)phenyl]-
1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one.
(I) : Ro = —■? y ; R,=-CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3

N ^j X = 5-CI;Y = H
0

Obtained according to the same procedure as for Example 52 from the compound of Example 43; M.p. = 168°C.
EXAMPLE 100
3-Chloro-3-[2-chloro-5-(4-methyl-l-piperazinyl)phenyl]-
1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one.
CI

(I) : Ro = — ; R1=-CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3
X = 5-CI; Y = H CH2OH
16.5 ml of a diisobutylaluminium hydride
(DIBAL) solution are added to 3.3 g of the racemic
compound of Example 41 in 130 ml of dichloromethane at
5 -68°C. The reaction mixture is treated at -30°C with
10 ml of methanol and then with an aqueous ammonium
chloride solution, and extracted with dichloromethane.
Filtration is carried out through celite, the organic
phase is washed with water and dried over anhydrous
10 sodium sulphate, and the solvents are evaporated under
reduced pressure. The expected product is obtained
after crystallization from a cyclohexane/heptane
mixture; M.p. = 97°C.
This product can also be obtained by
15 deprotection of the compound of Example 40 in an acidic
medium under the conditions of Example 65.
EXAMPLE 141
5-Chloro-3-[2-chloro-5-(methoxymethyl)phenyl]-
1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one. CI
(I) : Ro = —\ y ; R,=-CH3 ; R2 = H ; R3 = 4/-OCH3 ; R4=2-OCH3

20

CH2OCH3 X = 5-CI;Y = H
0.08 ml of- methyl iodide and then, at 0°C7 0.02 g of sodium hydride as a 60% suspension in oil are

122
added to 0.2 g of the compound of Example 140 in 2 ml of tetrahydrofuran. After stirring for 16 hours at room temperature, the reaction mixture is hydrolysed with a 5% aqueous ammonium chloride solution and extraction is carried out with ethyl acetate. The organic phase is washed with water and dried over anhydrous sodium sulphate. The solvents are evaporated under reduced pressure. The product is obtained after crystallization from n-pentane; M.p. = 122°C.
The compounds of the following Examples 142 to 14 4 are obtained in the same way:


5 EXAMPLE 145
5-Chloro-3-{2-chloro-5-[(dimethylamino)methyl]phenyl}-1- (2,4-dimethoxybenzyl)-3-methylindolin-2-one.


124
a) Preparation of 4-chloro-3-[5-chloro-l-(2,4-dimethoxy-benzyl)-3-methyl-2-oxoindolin-3-yl]benzaldehyde. 1 g of the compound of Example 140 is added to 0.69 g' of pyridinium chlorochromate in 10 ml of dichloro-
5 methane. After stirring for 1 hour at 10°C, the
mixture is filtered through celite, the solvents are
evaporated under reduced pressure and the residue is
purified by chromatography on a column of silica gel,
elution" being carried out with a 90/10 (v/v)

10 cyclohexane/ethyl acetate mixture. The expected
product crystallized from pentane; M.p. = 134°C.
b) The compound of Example 145 is obtained by reductive
amination of the compound obtained in a) according to
the procedure of Example 33; M.p. = 125°C (0.6 H20) .

15 The compounds of the following Examples 14 6
to 149 are obtained in the same way:


The racemic compound of Example 148 is chromatographed on a chiral column under conditions
5 analogous to those of Example 102. The dextrorotatory enantiomer, salified with hydrochloric acid in ethyl ether, and its antipode are obtained; M.p. = 139°C.

126
EXAMPLE 150
N-{4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-
3-methyl-2-oxoindolin-3-yl]benzyl}-N-methylacetamide. CI
(I) : Ro = —\ y : R^-CHs ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3
\ X = 5-C!;Y = H
CH2N(CH3)COCH3
5 Obtained according to the same procedure as
that of the compound of Example 62 from [lacuna] Example 146; M.p. = 81°C (0.6 H20) .
EXAMPLE 151
5-Chloro-3-{2-chloro-5-[(2-hydroxyethoxy)methyl]-
10 phenyl}-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one.
c(I) : Ro = —\ \ : R = "CH3 ; R2 = H ; R3 = 4 -OCH3 ; R4 = 2-OCH3
\ X = 5-CI;Y = H
CH20(CH2)2OH
a) Preparation of 5-chloro-3-[2-chloro-5-(1,3-dioxolan-2-yl)phenyl]-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one.
15 1 ml of ethylene glycol and 16 mg of
p-toluenesulphonic acid are added to 2.044 g of the compound prepared in a) of Example 145 in solution in 22 ml of toluene. The reaction mixture is heated to reflux for 16 hours in a reactor equipped with a Dean
20 and Stark apparatus in order to remove the water
originating from the reaction. After cooling to room temperature, 30 ml of water are added and.extraction is

127
carried out with ethyl acetate. The organic phase is dried over anhydrous sodium sulphate and the solvents are evaporated under reduced pressure to produce the expected product, used directly in the following stage.
5 b) A 0.29M solution of zinc borohydride in diethyl ether (prepared according to the method described in Chem. Pharm. Bull., 1984, 32(4), 1411-1415) and then 1.2 ml of trimethylsilyl chloride are added to 2.20 g of the compound prepared in a), in solution in 14 ml of
10 dichloromethane, at 6°C. After stirring for 2 hours 30 minutes at room temperature, the reaction mixture is hydrolysed with 30 ml of IN hydrochloric acid and extraction is carried out with ethyl acetate. The organic phase is washed with water and dried over
15 anhydrous sodium sulphate, and the solvents are
evaporated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, elution being carried out with a 99/1 (v/v) dichloromethane/methanol mixture. The final product is
20 obtained after crystallization from n-pentane; M.p. = 53°C.
This product can also be obtained by deprotection in acidic medium of the compound of Example 143 according to T.L., 1977, 3473, or any other
25 method described in Protective Groups in O.S. by.
T.W. Green et al. from Wiley-Interscience (3rd Edition, 1999).

128

EXAMPLE 152
5-Chloro-3-(2-chloro-5-{[2-(4-morpholinyl)ethoxy]-
methyl}phenyl)-1-(2,4-dimethoxybenzyl)-3-methylindolin-
R2 = H ; R3=4-OCH3 ; R4 = 2-OCH3
2-one.
X = 5-CI; Y = H
(I) :

a)

Preparation of the 5-chloro-3- (2-chloro-5-({2-[ (4-methylphenyl)sulphonyl]ethoxy}methyl)phenyl]-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one derivative.
0.39 ml of triethylamine and then 0.27 g of
10 p-toluenesulphony-1 chloride are added to 0.48 g of the. compound of Example 151 in. 1.5 ml of tetrahydrofuran at 0°C. After stirring for 16 hours at room temperature, the reaction mixture is hydrolysed with 10 ml of water and extraction is carried out with ethyl acetate. The
15 organic phase is washed with with an aqueous sodium hydrogen carbonate solution and then with water. The organic phase is dried over anhydrous sodium sulphate and the solvents are evaporated under reduced pressure to produce the expected product in the. form of a paste,
20 which product is used in the following stage.
b) 0.12 g of sodium carbonate and then 0-.20 ml of morpholine are added to 0.75 g of the compound obtained in a) in solution in 2 ml of acetonitrile. After 2 hours at 75°C, the reaction mixture is cooled to room

129
temperature, hydrolysis is carried out with 20 ml of water and extraction is carried out with ethyl acetate. The organic phase is washed a further time with water and dried over anhydrous sodium sulphate, the solvents are evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a 20/80 (v/v) cyclohexane/ethyl acetate mixture. The expected product is obtained- after hydrochlorination with a solution of
10 hydrochloric acid in diethyl ether, evaporation and crystallization of the residue from n-pentane; M.p. = 81°C (0.7H2O-lHCl).
The enantiomers of the compound of Example 152 are obtained in the same way as for Example 102, which enantiomers are salified with fumaric acid in acetone. The fumarates are isolated after evaporation of the acetone and crystallization in diethyl ether: the dextrorotatory enantiomer: M.p. = +112°C; ; [CX]20D = + 76.7 (c = 1, CH3OH) and its antipode.
The racemic compounds of the following Examples 153 to 157 are obtained in the same way:


The compounds of Example's 158 to 162 below 5 are prepared according .to the procedure described for Example 18:

132

EXAMPLE 164
5-Chloro-3-(2-chlorophenyl)-1-(4-hydroxy-2-
R0 =_ \) ; R, = -CH3 ; R2 = H ; R3 = 4-OH ; R4 = 2-OCH3 ; X = 5-CI
methoxybenzyl)-3-methylindolin-2-one. CL

5 This compound is already described in a) of
Example 63. M.p. = 200°C.
EXAMPLE 165
10 4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-hydroxy-2-oxoindolin-3-yl] -W^-diethylbenzamide
R0=—V \ ; R1=-OH ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-CI ; Y = H
CON(C2H5)2
a) 4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-
hydroxy-2-oxoindolin-3-yl]benzoic acid
15 From the compound of Example 20 and under the
conditions described in Example 101, a solid is
isolated which is used in the following stage;
M.p. = 200°C.
b) By treating the preceding acid under the
20 conditions of Example 102, the expected compound is
obtained; M.p. = 244°C.

133
EXAMPLE 166
1-[4-Chloro-3-[5-chloro-l-(2, 4-dimethoxybenzyl)-3-
methyl-2-oxoiridolin-3-yl]benzoyl]-4-methoxypiperidine
CI
R0 ^-^\ ; R^-CHa ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-CI ; Y=H
\=< r~CON )—OCH3
5 a) 4-Methoxypiperidine:
21.8 ml of methyl trifluoromethanesulphonate are slowly added, at approximately -20°C, to 11 g of 1-tert-butoxycarbonyl-4-hydroxypiperidine, prepared according to J. Med.. Chem. , 1998, 41, 25, 4983-4994,
10 diluted in 400 ml of dichloromethane and 22.2 ml of 2,6-di(tert-butyl)pyridine. After 16 hours at 20°C, hydrolysis is carried out with 0.5N hydrochloric acid and extraction is carried out with dichloromethane. The organic phase is isolated [lacuna] over sodium
15 sulphate, the solvent is evaporated under reduced pressure and the residue is purified on a column of silica, elution being carried out with a 60/40 dichloromethane/cyclohexane mixture. The oil obtained is used in the following deprotection stage in the
20 presence of 50 ml of a 2M solution of hydrogen chloride in ethyl acetate. After two hours at 20°C, evaporation is carried out under reduced pressure, the residue is triturated with ethyl ether, and the white solid is filtered off and dried under reduced pressure at

134
approximately 50°C for three hours. The hydrochloride of the expected compound is obtained; M.p. = 135°C. b) By treating the dextrorotatory enantiomer of the compound of Example 101 with the amine described in
5 a) under conditions analogous to those of Example 102, the expected product, crystallized from isopropyl ether, is isolated; M.p. = 92°C (1H20) ; [a]20D = + 93.3° (c = 1, ethyl acetate).
10 EXAMPLE 167
1-[4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-
methyl-2-oxoindolin-3-yl]benzoyl]-4-ethoxypiperidine
CI.
R0 = _^/\ ; R^-CHa ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-Ci ; Y = H
^=< r~CON )—OC2H5
a) 4-Ethoxypiperidine:
15 Under the conditions of Example 166 a), using
ethyl trifluoromethanesulphonate, the hydrochloride of the expected amine is isolated; M.p. = 148°C.
b) Example 167 is obtained as for Example 166 b)
by using the above amine; M.p. = 108°C (1H20) ;
20 [cc]20D = + 100.1° (c = 1, ethyl acetate).
EXAMPLE 168
1-[4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-2-
25 pyrrolidinocarbonylpiperidine

135


R, =-CH3 ; R2=H ; R3 = 4-OCH3 ; R4=2-OCH3 ; X=5-CI ; Y=H

a) (R)-2-(Pyrrolidinocarbonyl)-1-{tert-butoxycarbonyl)piperidine.
From 1-tert-butoxycarbonyl-(R)-2-
5 piperidinecarboxylic acid and pyrrolidine, under conditions analogous to those of Example 102, the expected product is obtained after purification on a column of silica, elution being carried out with a 98/2 dichloromethane/methanol mixture; M.p. = 105°C.
10 b) (R)-2-(Pyrrolidinocarbonyl)piperidine hydrochloride. Deprotection of the preceding compound under the conditions described in Example 166 a); M.p. = 258°C.
c) Example 168 is obtained with the preceding
15 amine and as for Example 166 b); the expected product, crystallized from isopropyl ether, is obtained; M.p. = 114°C (0.5H2O) .
EXAMPLE 169
20 1-[4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-2-N,N-dimethylaminocarbonylpiperidine

136 CI,
R0 = —1/ \ ; R, = -CH3 ; R2 = H ; R3 = 4-0CH3 ; R4 = 2-OCH3 ; X = 5-CI ; Y = H
/ CON
V
CON(CHJ2
a) N,N-Dimethyl-l-tert-butoxycarbonyl- (R)-2-piperidinecarboxamide:
Obtained as for Example 168 a); M.p. = 7 6CC.
5 b) N,N-Dimethyl-(R)-2-piperidinecarboxamide hydrochloride:
Obtained as for Example 168 b); M.p. = 194.4°C.
c) Example 169.is obtained with the preceding
10 amine and as for Example 166 b); the expected product, which crystallizes from isopropyl ether, is obtained; M.p. = 1'23°C (1H20) .
EXAMPLE 170
15 l-[4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-
methyl-2-oxoindolin-3-yl]benzoyl] - (R) -2- (N-methyl-N-
2,2,2-trifluoroethylaminocarbonyl)piperidine Clv
R0 =—// \ ; R^-CH, ; R2 = i+; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-CI ; Y = H

CON
\
CON,

CH2— CF3

a) - W-Methyl-W-2,2,2-trifluoroethyl-1-tert-20 butoxycarbonyl-(R)-2-piperidinecarboxamide:

137

Obtained as for Example" 169 a) with the hydrochloride of N-methyl-2,2,2-trifluoroethylamine (M.p. = 185°C) prepared according to J.O.C., 1959, 24, 1256; M.p. = 93°C.
5 b) Example 170 is obtained by deprotecting the amine as for Example 169 b) and the hygroscopic hydrochloride obtained is used with the dextrorotatory enantiomer of the compound of Example 101 under - conditions analogous to those of Example 102. The
10 expected product, crystallized from pentane, is
isolated; M.p. = 99°C; [a]20D = + 103.6° (c = 1, ethyl acetate).
EXAMPLE 171
15 4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-methyl-N-(2,2,2-trifluoroethyl)benzamide.
; R., = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-CI ; Y = H
/CH3
CON
XCH—CF3
Obtained according to Example 166 b) with the
20 hydrochloride of N-methyl-2,2, 2-trifluoroethylamine . mentioned in a) of Example 170; M.p. = 89°C; [α]20D = + 83.4° (c = 1, ethyl acetate).

138

EXAMPLE 172
l-[4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-
methyl-2-oxoindolin-3-yl]benzoyl]-4-
difluoromethylidenepiperidine. CI,
0 \R, = -CH3 ; R2=H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-CI ; Y=H
CF2
a) 4-(Difluoromethylidene)piperidine hydrochloride:
Obtained by demethylation of the corresponding N-methyl compound, described in" Tetrahedron, 1980, 36, 3241, by the action of a-
10 chloroethyl chloroformate according to J.O.C. 1984, 49, 2081-2082; M.p. = 211.5°C.
b) Example 172 is prepared according to Example 166 b) with the amine prepared in a). The expected product is isolated by crystallization from pentane;
15 M.p. = 119°C.
EXAMPLE 173
1-[4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-2-ethoxycarbonyl-.

139

o = —(' V ; R-, = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-CI ; Y :

R„

C02C2H5

Obtained according to b) of Example 166 with ethyl (R)-4-methyl-(R)-2-piperidinecarboxylate, described in J. Med. Chem., 37, 1994, 23, 3889-3901.
5 The expected product, crystallized from pentane, is isolated; M.p. = 106°C.
EXAMPLE 174
1-[4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl) -3-methyl-2-oxoindolin-3-yl]benzoyl]-(S)-2-
methylpiperidine.
R, = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-CI ; Y = H
CH3

Obtained according to b) of Example 166 with (S)-2-methylpiperidine, described in Tetrahedron Asymmetry, J3, 1997, 8, 1275-1278; M.p. = 102°C (0.5H2O).
EXAMPLE 175
1-[4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-
methyl-2-oxoindolin-3-yl]benzoyl]-(R)-2-
20 ethoxycarbonylpiperidine

140

,^rR
o V 7 ; R,=-CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-CI ; Y = H

C02C2Hs
Obtained according to b) of Example 166 with ethyl (R)-2-piperidinecarboxylate, described in J. Med. Chem., 42, 1999, 22, 4584-4603; M.p. = 113°C.
EXAMPLE 176
l-[4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl] -(R)-2-tert-
butyloxycarbonylpiperidine. CI.
; R, = -CH3 ; R2 = H ; R3 = 4-0CH3 ; R4 = 2-OCH3 ; X = 5-CI ; Y = H

10
C02C(CH3)3

a) tert-Butyl (R)-2-piperidinecarboxylate.
A mixture of 0.5 g of (R)-homoproline, 22 ml of dioxane, 2.2 ml of concentrated sulphuric acid and then approximately 20 ml of isobutylene, condensed at
15 low temperature, is placed in an autoclave. After
stirring at room temperature for twenty four hours, the medium, cooled to approximately -10°C, is poured onto 150 ml of an aqueous potassium carbonate solution and then extraction is carried out with ethyl acetate. The
20 combined organic phases are washed with water, dried over N02S04 and evaporated to dryness. The residue is

141

distilled under reduced pressure; B.p. = 46°C under 30 Pa.
b) Example 176 is obtained according to b) of Example 166 with the amine prepared in a). The expected
5 product is crystallized from pentane; M.p. = 202.2°C.
EXAMPLE 177
4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-
2-oxoindolin-3-yl]-N-ethyl-N- (2-
10 dimethylaminoethy1)benzamide hydrochloride. CI,
; R, = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R„ = 2-OCH3 ; X = 5-CI ; Y = H
CONK
^ (CH2)2-N(CH3)2
Obtained according to b) of Example 166 with N-ethyl-2-dimethylaminoethylamine, described in J.A.C.S.,. 1963, 2256-2266. The hydrochloride of the
15 expected compound is isolated from ethyl ether;
M.p. = 171.5°C (1H20); [a]20D = + 99° (c = 1, methanol).
EXAMPLE 178
4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-
20 2-oxoindolin-3-yl] -N-ethyl-N- (2-
morpholinoethyl) benzamide. ClN
R // \\ ; R, =-CH3 ; R2=H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-CI ; Y=H
^C,HS
CON-
^{CH2)2N O
./.'. /-^
*o

142
Obtained according to b) of Example 166 with N-ethyl-2-morpholinoethylamine, described in Chem. Pharm. Bull., 45, 1997, 6, 996-1007; M.p. = 143°C (0.5H2O).
EXAMPLE 179
4-Chloro-3-t5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-
2-oxoindolin-3-yl]-W-ethyl-W- [2-(pyrid-4-
yl)ethyl]benzamide.
Ro =—fl \ ; R,=-CH3 ; R2=H ; R3=4-OCH3 ; R„ = 2-OCH3 ; X = 5-CI ; Y=H

C,H
2' '5

C°^(CH2>H^

Obtained according to b) of Example 166 with N-ethyl-2-(pyrid-4-yl)ethylamine, described in J.A.C.S., 1956, 78, 4441. The hydrochloride of the expected product is isolated from ethyl ether;
15 M.p. = 185°C (1.5H20) .
EXAMPLE 180
4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-W-ethyl-W-(2,2,2-
20 trifluoroethyl) benzamide.
Civ
R0 = // \\ ; R,= -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-CI ; Y = H
/C2HS
^CH,-CF3
CON-

143
Obtained according to b) of Example 166 with iv-ethyl-2, 2, 2-trif luoroethylamine, described in J.A.C.S., 11_3, 19-91, 4, 1288-1294; M.p. = 80°C (0.5H2O).
5 EXAMPLE 181
4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-W-ethyl-W-[2-(pyrid-2-yl)ethyl]benzamide hydrochloride.
CL

/ R0 = —(/ ^ ; R, = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-CI ; Y = H
/C2H5
-(CH2)2
CON-

N
10 Obtained according to b) of Example 166 with
N-ethyl-2-(pyrid-2-yl)ethylamine, described in
J.A.C.S., 1955, 5434.
The hydrochloride of the expected product is
isolated from ethyl ether; M.p. = 202°C (1H20) .
15
EXAMPLE 182
4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-
2-oxoindolin-3-yl]-N-ethyl-N-(2-
pyrrolidinoethyl)benzamide hydrochloride. CL
R0 = —(/ \ ; R, = -CH3 ; Rz = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-CI ; Y = H

20

/ 2' 5 r-
CON-(CH2)2N
V
Obtained according to b) of Example 166 with N-ethyl-2-pyrrolidinoethylamine, described in J. Med.

144
Chem., 35, 1992, 1, 38-47. "The hydrochloride of the" product obtained is isolated from ethyl ether; M.p. = 109°C (1.5H20) .
EXAMPLE 183
4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-
2-oxoindolin-3-yl]-N-ethyl-N-(2-
piperidinoethyl)benzamide hydrochloride.
RO= // \ . ; R,=-CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-CI ; Y = H
^C2H5 '
Obtained according to b) of Example 166 with N-ethyl-2-piperidinoethylamine, described in Chem. Pharm. Bull., 1997, 45, 6, 996-1007.
EXAMPLES 184 to 198
The [lacuna] following Examples 184 to 198 are obtained under the conditions b) of Example 166 and with commercially available amines:

clsv^N
ci-^V^

145
TABLE 18

EXAMPLES R5 M.p.; °C [a]20D
184 ##STR(-CON \XOCH3 )## 86.3
185 ##STR()## 111.7
186 ##STR()## 80.5 0.5 H20
187 ##STR()## 102..8
188 ##STR( )## 193.70.5 H201 HC1 + 96,8(c = 1,methanol)
189 ##STR()## 119.5 H20
190 J . 112 0.5 H20

146
TABLE 18 (continuation 1)

EXAMPLES R5 M.p.; °C [a]20D
191 ##STR()## 130 1.5 H20
192 ##STR()## 129.8 + 114°(c = 1, ethylacetate)
193 ##str()## 131
194 ##STR()## 124 2H20
195 199.4 1.5 H20
196 109 0.5 H20
197 104 0.5 H20
198 101 0.5 H20
199 ' 188 1 HC1

147

The compound of Example 199 is obtained by treating the compound of Example 191 with a solution of hydrochloric acid in ethyl acetate; the hydrochloride is isolated after evaporating the solvent and taking
5 out the residue in pentane.
EXAMPLE 2Q0
4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methy1-2-oxoindolin-3-yl]-N-ethyl-N- (2-
10 pyridylmethyl)benzamide.
; R^-CHj ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-CI ; Y = H
'2
N:

a) N-Ethyl-2-pyridylmethylamine:
5 g of 2-pyridylcarboxaldehyde are added to the mixture of 3.8 g of ethylamine hydrochloride, 60 ml
15 of toluene, 110 ml of ethanol and 13.2 ml of
triethylamine. After stirring at 20°C for 30 seconds, 25 g of 4 A molecular sieve are added and stirring is maintained at 20°C. The insoluble material is filtered off, copious washing with dichloromethane is carried
20 out, evaporation to dryness is carried out and the residue is taken up in 50 ml of methanol. 1.8 g of. sodium borohydride are added to this solution at approximately 0°C. After sixteen hours at approximately 20°C, the solvent is evaporated under reduced pressure
25 and the residue is taken up in dichloromethane. The

148
organic phase is washed with IN sodium hydroxide solution and then with an aqueous sodium chloride solution and dried over sodium sulphate, the solvent is evaporated under reduced pressure and then the residue
5 is distilled; B.p. = 64°C under 180 Pa.
b) Example 200 is obtained according to b) of Example 166 with the amine prepared in a); M.p. = 89°C-(0.5H2O).
10 EXAMPLE 201
4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-W-ethyl-N- (3-
pyridylmethy1)benzamide.
c,Ro = —P y ;- R1 =-CH3 ; R2 = H ; R3 = 4-OCH3 ; R4-=2-OCH3 ; X = 5-CI ; Y=H
15 a) W-Ethyl-3-pyridylmethylamine:
Obtained in the same way as in Example 200 a)
from 3-pyridinecarboxaldehyde; B.p. = 77°C under
530 Pa.
b) Example 201 is obtained according to b) of
20 Example 166 with the amine prepared in a);
M.p. = 95.5°C (0'.5H2O).,
149

EXAMPLE 202
4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N- (2-dimethylaminoethyl)-N-(2,2,2-trifluoroethyl)benzamide hydrochloride.
R0 _ _// \) ; R, = -CH3 ; R1 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-CI ; Y = H
CON>
,(CH2)2-N(CH3)2
-CH2-CF3

a) N-(2-Dimethylaminoethyl)trifluoroacetamide:
11.5 ml of trifluoroacetic anhydride are
added at approximately 0°C to a solution of 6 g of 2-
dimethylaminoethylamine in 150 ml of dichloromethane

10 and 23.9 ml of triethylamine. 50 ml of a dilute sodium
bicarbonate solution are added at 20°C, separation is
carried out by settling, the organic phase is dried
over sodium sulphate, the solvent is evaporated and the
residue is distilled under reduced pressure;

15 B.p. = 94°C under 1975 Pa. . '
b) N-2,2,2-Trifluoroethyl-2-dimethylaminoethylamine:
A solution of 5 g of amide prepared in a) in 250 ml of ether is added to 2.78 g of lithium aluminium hydride in 50 ml of ethyl ether at approximately 0°C.
20 After stirring overnight at 22°C, 20 ml of a saturated aqueous sodium sulphate solution are added, filtration is carried out through celite, the celite is washed with 3 times 100 ml of ether, the combined filtrates are partially evaporated and then treatment is carried
25 out with a solution of hydrochloric acid in ethyl

150

acetate. The hydrochloride of the expected product is filtered off; M.p. = 232.6°C.
c) Example 202 is obtained according to b) of Example 166 with the amine prepared in b) and then
5 salification with a solution of hydrochloric acid in ethyl ether; M.p. = 201.5°C (2H20) .
EXAMPLE 203
4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methy1-
10 2-oxoindolin-3-yl]-N- (3-dimethylaminopropyl)-N-ethylbenzamide hydrochloride.
; R, = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-CI ; Y = H C2HS (CH2)3N(CH3)2
a) N- (3-Dimethylaminopropyl)acetamide:
Obtained in the same way as in a) of Example 15 202 with acetic anhydride and 3-
dimethylaminopropylamine; B.p. = 919C under 84 Pa.
b) N-Ethyl-3-dimethylaminopropylamine:
Obtained under conditions analogous to those of b) of Example 202 in tetrahydrofuran at reflux;
20 B.p. = 75°C under 45 Pa.
c) Example 203 is obtained according to b) of
Example 166 with the amine prepared in b). The
hydrochloride is isolated by treatment with
hydrochloric acid in ethyl ether; M.p."= 222°C.

151

EXAMPLE 204
4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-methyl-
2-oxoindolin-3-yl]-N-ethyl-N- [3-(pyrid-4-
yl)propyl]benzamide hydrochloride.

CL
R, = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-CI ; Y = H
/C2HS
rT5 ^=^
a) N-Ethyl-3-(pyrid-4-yl)propylamine:
From 3-(pyrid-4-yl)propionaldehyde, described in J. Organometallic Chem., 599, 2", 2000, 298-303, and ethylamine hydrochloride, an oil is' obtained
10 analogously to a) of Example 200 and after purification on a column of silica, elution being carried out with a 90/10 dichloromethane/methanol mixture, which oil is used in the following stage.
b) Example 204-is obtained according to b) of
15 Example 166 with the amine prepared in a). The expected product is isolated after purification on a column of silica, elution being carried out with a 97/3 dichloromethane/methanol mixture, and hydrochlorination with a solution of- hydrochloric acid in ether;
20 M.p. = 207°C.

152
EXAMPLE 205
5-Chloro-3-[2-chloro-5-(2-oxopiperidinomethyl)phenyl]-
1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one.
c'R° =\ / '' R1="CH3 : Rz=H : R3 = 4-°CH3 I R4 = 2-OCH3 ; X = 5-CI ; Y = H
CH—N
V
o
5 250 mg of the aldehyde prepared in a) of
Example 145 are added to a solution of 90 mg of methyl 5-aminopentanoate hydrochloride in 3 ml of toluene, 2 ml of ethanol and 150 ml of triethylamine at approximately 0°C. Fifteen minutes later, 1.9 g of 4 A
10 molecular sieve are added. After 3 hours at
approximately 20°C, the insoluble material is filtered off and is washed copiously with dichloromethane, and the solvents of the filtrate are evaporated under reduced pressure. The oil obtained is taken up in
15 4.1 ml of methanol and 20.1 mg of sodium borohydride are added at 0°C. After stirring for 16 hours at approximately 20°C, the solvent is evaporated under reduced pressure, the residue- is taken up in dichloromethane and washing is carried out with a 0.5N
20 aqueous sodium hydroxide solution and then with a
"dilute aqueous sodium chloride solution. The organic phase is dried over sodium sulphate, the solvent is evaporated under reduced pressure and the residue is chromatographed on a column of silica, elution being

153

carried out with a 98/2 dichloromethane/methanol mixture. The expected product is crystallized from pentane; M.p. = 72 °C.
5 EXAMPLE 206
1-[4-Chloro-3-[5-chloro-l-(4-chloro-2-methoxybenzyl)-3-
methyl-2-oxoindolin-3-yl]benzoyl]piperidine. CI.
R, = -CH3 ; R2 = H ; R3 = 4-CI ; R4-OCHj ; X = 5-CI ; Y = H
ONvJ
a) Methyl 4-chloro-3-[5-chloro-l-(4-chloro-2-
10 methoxybenzyl)-3-hydroxy-2-oxoindolin-3-yl]benzoate: From compound IV. 2 and according to the procedure described in Example 20, the expected product is obtained after chromatography on a column of silica, elution being carried out with a 50/50
15 cyclohexane/dichloromethane mixture; M.p. = 205°C.
b) Methyl 4-chloro-3-[3,5-dichloro-l-(4-chloro-2-
methoxybenzyl)-2-oxoindolin-3-yl]benzoate:
Obtained according to a) of Preparation 13 from the compound described in a).
20 c) Methyl 4-chloro-3-[5-chloro-l-(4-chloro-l-(4-
chloro-2-methoxybenzyl)-3H-2-oxoindolin-3-yl]benzoate; compound III.9:
Obtained according to b) of Preparation 13 from the compound described in b); M.p. = 126°C. .

154

d) Methyl 4-chloro-3-[5-chloro-l-(4-chloro-2-
methoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoate:
Obtained according to the procedure described in Example 37 from compound III.9; M.p.=158°C.
e) 4-Chloro-3-[5-chloro-l-(4-chloro-2-methoxybenzyl)-
3-methyl-2-oxoindolin-3-yl]benzoic acid:
Obtained according to the operational mixture described in Example 101 from the compound obtained in d); M.p. = 199°C.
f) Example 206 is obtained in the same way as
for Example 112 from the acid obtained in e);
M.p'. = 86°C.
EXAMPLE 207
1-[4-Chloro-3-[5-chloro-l-(4-chloro-2-methoxybenzyl)-3-
methyl~2-oxoindolin-3-yl]benzoyl]-4-hydroxypiperidine
CI,
; R1 = -CH3 ; R2 = H ; R3 = 4-CI ; R4 = 2-OCH3 ; X = 5-C1 ; Y = H

Obtained in the same way as for Example 134 from the acid prepared in e) of Example 206;
20 M.p. = 129°C (1H20).
EXAMPLE 208
1-[4-Chloro-3-[5-chloro-l-(4-chloro-2-methoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-2-methoxycarbonylpiperidine.

155

; R, = -CH3 ; R2 = H ; R3 = 4-CI ; R4 = 2-OCH3 ; X = 5-CI ; Y = H
C02Me

Obtained in the same way as for Example 131 from the acid prepared in e) of Example 206; M.p. = 101°C.
EXAMPLE 209
Methyl 4-chloro~3-[5,7-dichloro-l-(2,4-
dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoate.
CL

o
R,

// W

; R, = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-CI ; Y = 7-CI

C02CH3
10 a) Methyl 4-chloro-3-[5,7-dichloro-l-(2,4-
dimethoxybenzyl)-3-hydroxy-2-oxoindolin-3-yl]benzoate:
From compound IV. 3 and according to the procedure described in Example 20, the product obtained is isolated; M.p. = 225°C.
15 b) Methyl 4-chloro-3-[1-(2,4-dimethoxybenzyl)-3,5,7-trichloro-2-oxoindolin-3-yl]benzoate:
Obtained according to a) of Preparation 13 from the product described in a). c) Methyl 4-chloro-3-[5,7-dichloro-l-(2, 4-
20 dimethoxybenzyl) -3H-2-oxoindolin-3-yl]benzoate; compound III.10:

156
Obtained according to b) of Preparation 13 from the product described in b); M.p. = 173°C. d) Example 209 is obtained according to the procedure described in Example 37 from the product compound
5 III.10; M.p. = 166°C.
EXAMPLE 210
3-(5-Amino-2-chlorophenyl)-5,7-dichloro-l- (2,4-
dimethoxybenzyl)-3-methylindolin-2-one.
; R, = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-CI ; Y = 7-CI
a) 3-(2-Chloro-5-aminophenyl)-5,7-dichloro-l-(2,4-dimethoxybenzyl)-3-hydroxyindolin-2-one:
Obtained from compound IV. 3 and according to the procedure described in Example 21; M.p. = 124°C.
15 b) 3-(2-Chloro-5-aminophenyl)-l-(2,4-
dimethoxybenzyl)-3,5,7-trichloroindolin-2-one:
Obtained according to a) of Preparation 13 from the product described in a).
c) 3-(2-Chloro-5-aminophenyl)-1-(2,4-
20 dimethoxybenzyl)^2,7-dichloro-3H-indolin-2-one; compound 111.111-
Obtained according to b) of Preparation 13 from the product described in b)/ M.p. = 118°C.
d) Example 210 is obtained according to the
25 procedure described in Example "37 from the product
compound III.11; M.p. = 112°C.

157
EXAMPLE 211
l-[4-Chloro-3-[5-chloro-l-(2,4-dimethoxybenzyl)-3-
methyl-2-oxoindolin-3-yl]benzoyl]-4,4-
difluoropiperidine. CL
R // \ ; R, = -CH3 ; R1 = H ; Rj = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-CI ; Y = H
Obtained according to b).of Example 166 with 4,4-difluoropiperidine, described in Chem. Pharm. Bull., 1993, 4JL, 11, 1971-1986; M.p. = 98.5°C (0.5H2O).
10 EXAMPLE 212
5-Chloro-3-(2-chlorophenyl)-1-[4-(2-butylamino)-2-
methoxybenzyl]-3-methylindolin-2-one. CI.
R = _// \ ; R, = CH3 ; R2 = H ; R3 = 4-NH[CH(CH3)(C2H5)] ; R4 = 2-OCH3 X = 5-CI : Y = H
Obtained under conditions analogous to those 15 of Example 56; M.p. = 158°C.
EXAMPLE 213
5-Chloro-3-(2-chlorophenyl)-1-(4-isobutylamino-2-

20

methoxybenzyl)-3-methylindolin-2-one. CI
B --J/ \ : R=CH3 ; R2 = H ; R3 = 4-NHCH2CH(CH3)2 ;R4 = 2-OCH3 ;
"o ~ \ /
X = 5-CI : Y=H

158

Obtained under conditions analogous to those of Example 55; M.p. = 136°C.
EXAMPLE 214
5 4-Chloro-3-[5-fluoro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl] -N, N-diethylbenzamide.

; R, = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-F ; Y = H CON(C2Hs)2
a) Methyl 4-chloro-3-[1-(2,4-dimethoxybenzyl)-5-
fluoro-3-hydroxy-2-oxoindolin-3-yl]benzoate:
10 From compound IV. 4 and according to the
procedure described in Example 20, the expected product is isolated; M.p. = 188°C.
b) Methyl 4-chloro-3-[3-chloro-l-(2,4-
dimethoxybenzyl)-5-fluoro-2-oxoindolin-3-yl]benzoate:
15 Obtained according to a) of Preparation 13
from the product described in a) .
c) Methyl 4-chloro-3-[1-(2,4-dimethoxybenzyl)-5-
fluoro-3H-2-oxoindolin-3-yl]benzoate; compound III.12:
Obtained according to b). of Preparation 13 20 from compound III.12; M.p. = 138°C.
d) 4-Chloro-3-[1-(2,4-dimethoxybenzyl)-3-methyl-5-
fluoro-2-oxoindolin-3-yl]benzoic acid:
From the product described in c) and according to the procedure of Example 37, the methyl
25 ester of the expected compound is obtained, which ester

159
is used directly in .the saponification reaction under
the conditions of Example 101; M.p. = 89°C.
e) The racemic compound of Example 214 is
obtained under the conditions of Example 102;
M.p. = 79°C.
EXAMPLE 215
4-Chloro-3-[1-(2,4-dimethoxybenzyl)-3-methyl-2-
oxoindolin-3-yl] -2tf,2V-diethylbenzamide.

\ ; R1 = -CH3" ; Rj = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = H ; Y = H
a) Methyl 4-chloro-3-[1-(2,4-dimethoxybenzyl)-3-
hydroxy-2-oxoindolin-3-yl]benzoate:
From compound IV.5 and according to the procedure described in Example
20 the expected product is isolated; M.p. = 172°C.
b) Methyl 4-chloro-3-[3-chloro-l-(2,4-
dimethoxybenzyl)-2-oxoindolin-3-yl]benzoate:
Obtained according to a) of Preparation 13 from the product described in a).
c) Methyl 4-chloro-3-[1-(2,4-dimethoxybenzyl)-3H-2-
oxoindolin-3-yl]benzoate; compound III.13:
Obtained according to b) of Preparation 13 from compound III.13; M.p. = 122°C.
d) 4-Chloro-3-[l-(2,4-dimethoxybenzyl)-3-methyl-2-
25 oxoindolin-3-yl]benzoic acid:

160
From the product described in c) and according to the procedure of Example 37, the methyl ester of the expected compound is obtained, which ester is used directly in the saponification reaction under
5 the conditions of Example 101; M.p. = 103°C.
e) The racemic compound of Example 215 is obtained under the conditions of Example 102; M.p. = 85°C.

WE CLAIM:
1. Pharmaceutical composition characterized in that it comprises, as active principle a compound of formula I.


(I)

in which:
- R0 represents a group chosen from:


(i):

in which:
Z1 represents a chlorine, bromine, iodine or fluorine atom or a (C1-C4) alkyl, (C1-C4) alkoxy or trifluoromethyl group;
Z2 represents a hydrogen, chlorine, bromine, iodine or. fluorine atom or a (C1-C4) alkyl,
(C3-C5) cycloalkyl, (C1-C4) alkoxy, (C3-Cs) cycloalkoxy
or (C1-C4)polyfluoroalkyl group; - -
R5 represents T1W in which Ti represents -(CH2)m, it being possible for m to be equal to 0 or 1, and W
162

represents a hydrogen atom or a hydroxycarbonyl (or carboxyl), (C1-C4)alkoxycarbonyl, 1, 3-dioxolan-2-yl or 1,3-dioxan-2-yl group,
or else W represents an -NR6R7 group in which
5 R6 and R7 represent, independently of one another, a hydrogen atom, a (C1-C4)alkyl group, a (C1-C4) alkylsulphonyl group or a phenylsulphonyl group in which the phenyl group can be mono-, di- or trisubstituted by Z5; or else R6 and R-7 form, with the nitrogen atom to which they are bonded, a morpholinyl group optionally substituted by a (C1-C4)alkyl group or an oxo; or else R6 and R7 form, with the nitrogen atom to which they are bonded, a piperazinyl group optionally substituted in the
15 4-position by a Z3 substituent; or else R6 and R7 form, with the nitrogen atom to which they are bonded, a pyrrolidinyl or piperidyl group, the said pyrrolidinyl and piperidyl groups optionally being substituted by Z4;
or else W represents an -NR8COR9 group in which R8 represents a hydrogen atom or a (C1-C4)alkyl group and R9 represents a hydrogen atom or a (C1-C4)alkyl, benzyl, pyridyl or phenyl group, it being possible for the said phenyl group to be mono-, di- or trisubstituted by Z5; or else R9 represents an -NRi0Rn group in which R10 and R11 represent, independently of one another, a hydrogen
163

163
atom or a (C1-C4)alkyl [lacuna] or else R10 and R11 form, with the nitrogen atom to which they are bonded, a pyrrolidinyl, piperidyl or morpholinyl group optionally substituted by a (C1-C4)alkyl group;
5 or else R9 represents a pyrrolidin-2-yl or -3-yl or piperid-2-yl, -3-yl or -4-yl group, the said pyrrolidinyl and piperidyl groups optionally being substituted by Z7; or else R9 represents a -T2-R12 or -T2-COR12 group in which T2 represents -(CH2)n~, it-
10 being possible for n to be equal to 1, 2, 3 and 4, and R12 represents a (C1-C4) alkoxy or -NR10Rn group, R10 and R11 being as defined above;
or else W represents a -CONR13R14 group in which R13 represents a hydrogen atom or a
15 (C1-C4) alkyl, (C3-C7) cycloalkyl,
monofluoro (C1-C4) alkyl or polyfluoro (C1-C4) alkyl group and R14 represents 'a hydrogen atom, a (C1-C4)alkyl group, a phenyl group optionally substituted by Z5, a -T4-R15 group in which T4
20 represents -(CH2)q, with q equal to 1, 2, 3 or 4, . and R15 represents a hydroxyl group, a (C1-C4) alkoxy group, a (C1-C4) alkoxycarbonyl group, a (C1-C4)alkoxycarbonylamino group, a phenyl group, optionally mono- or disubstituted by Z5, a pyrid-
25 2-yl, -3-yl or -4-yl, or an –NR16R17 group in which RIG and R17 represent, independently of one another, a hydrogen atom or a ' (C1-C4) alkyl [lacuna] or else-
164

164
Ri6 and RX7 form, with the nitrogen atom to which they are bonded, a morpholinyl group optionally mono- or disubstituted by a (C1-C4) alkyl group or else RX6 and Ri7 form, with the nitrogen atom to
5 which they are bonded, a piperazinyl group
optionally substituted in the 4-position by a Z3 substituent or else Ri6 and- R3.7 form, with the nitrogen atom to which they are bonded, a pyrrolidinyl or piperidyl group, the said
10 pyrrolidinyl and piperidyl groups optionally being substituted by Z5, it being understood that, when q = 1, R15 is other than hydroxyl, (C3-C4) alkoxy, (C1-C4) alkoxycarbonylamino or -NRi6Ri7; or else R13 and R14 form, with the nitrogen atom to which they are
15 . bonded, a morpholinyl group optionally mono- or• disubstituted by a (C1-C4) alkyl group or a piperazinyl group optionally substituted in the 4-position by a Z3 substituent; or else R13 and R14 form, with the nitrogen atom to which they are
20 bonded, an azetidinyl, pyrrolidinyl, piperidyl or hexahydroazepinyl group, the said pyrrolidinyl, piperidyl and hexahydroazepinyl groups optionally being mono- or disubstituted by Z8;
or else W represents an OR3.8 group in which
25 R18 represents a hydrogen atom or a (C1-C4) alkyl,
(C1-C4) alkoxy (C1-C4)alkyl or -T3-Rlg group in which T3 represents -(CH2)P-, it being possible for p to be
165

equal to 2 or 3, and R19 is chosen from the hydroxyl, triphenylmethoxy or -NR20R21 groups in which R2o represents a hydrogen atom or a (C1-C4) alkyl group and R21 represents a hydrogen atom or a (C1.-C4) alkyl,
5 tetrahydrofuranylmethyl or tetrahydropyranylmethyl group, or else R20 and R2i form, with the nitrogen atom to which they are bonded, a morpholinyl group optionally mono- or disubstituted by a (C1-C4) alkyl group or a piperazinyl group optionally substituted
10 in the 4-position by a Z3 substituent, or else R2o and R21 form, with the nitrogen atom to which they are bonded,, a pyrrolidinyl or piperidyl group, the said pyrrolidinyl and piperidyl groups optionally being substituted by Z5;
15 Z3 represents a (C1-C4) alkyl, pyridyl, phenyl,
(C3-C4) alkylcarbonyl or (C1-C4) alkoxycarbonyl group; Z4 represents an oxo, a fluorine atom,, a hydroxyl, a (C1-C4) alkyl, a benzyl, an amino, a (C1-C4) alkylamino, a di (C1-C4) alkylamino, a
20 (C1-G4) alkoxy, a (G1-G4) alkoxycarbonyl or a (C1-C4) alkoxycarbonylamino;
Z5 represents a chlorine, bromine, iodine or fluorine atom, a hydroxyl group, a (C1-C4) alkyl' group or - a (C1-C4) alkoxy group;
25 Z7 represents a fluorine atom, a hydroxyl group, a
hydroxy (C1-C4) alkyl group, a (C1-C4) alkyl [lacuna], a (C1-C4) alkoxy [lacuna] or a (C1-C4) alkylcarbonyl

166
[lacuna];
Z8 represents a fluorine atom or a hydroxyl, (C1-C4) alkyl, (C3-C6) cycloalkyl, benzyl, amino, (C1-C4) alkylamino, di (C1-C4) alkylamino,
5 (C1-C4) alkoxycarbonyl, (C1-C4) alkoxycarbonylamino, (C3^-C6) cycloalkoxy, hydroxycarbonyl, hydroxy (C1-C4) alkyl, (C1-C4) alkoxy (C1-C4) alkyl, (C1-C4) alkoxy or -CONR23R24 group in which R23 and R24 represent, independently of one another, a hydrogen 10 ' atom, a (C1-C4) alkyl, a monofluoro (C1-C4) alkyl or a
polyfluoro (C1-C4) alkyl, or else R23 and R24 form, with the nitrogen atom to which they are bonded, a pyrrolidinyl or piperidyl group, the said pyrrolidinyl or piperidyl groups optionally being
15 substituted by. Z3 or a difluoromethylidene;
z6 represents a chlorine atom or a (C1-C4) alkyl or (C1-C4) alkoxy group;

20 R1 represents a (C1-C4) alkyl group optionally comprising a double or a triple bond, a (C1-C4)alkoxycarbonyl group, a phenyloxycarbonyl group or a T1-R22 group in which Ti is as defined above and R22 represents a hydroxyl or (C1-C4) alkoxy 25' group;
R2 and R4 represent, independently of one another, a
167

167
hydrogen, chlorine or fluorine atom or a (C1-C4)alky. or. (C1-C4) alkoxy group;
R3 represents a chlorine or fluorine atom or a (C1-C4) alkyl, (C1-C4) alkoxy, hydroxy!,
5. (C1-C4) carbamoyl, (C1-C4) alkylcarbonylamino, nitro,
cyano, trifluoromethyl, amino, (C3-C6) cycloalkylamino, (C1-C4) alkylamino, di (C1-C4) alkylamino, tri (C1-C4) alkylammonium A", A- being an anion, pyrrolidin-1-yl, piperid-1-yl, piperazin-1-yl,
10 morpholin-4-yl or hexah'ydroazepin-1-yl group;
X and Y represent, independently of one another," a hydrogen, chlorine, bromine, iodine or fluorine atom or a (C1-C4) alkoxy or trifluoromethoxy group; and their pharmaceutically acceptable salts, their.
15 solvates and their hydrates.
-168-

(2. Pharmaceutical composition as claimed in claim 1 comprising an antagonist of oxytocin receptors in combination with an antagonist of vasopressin Via receptors.
3. Product comprising an antagonist of oxytocin receptors and an antagonist of vasopressin Via receptors for simultaneous or separate use or use spread out over time in the treatment of dysmenorrhoea or endometriosis or the control of premature labour and for controlling preparatory labour for the purpose of a caesarean delivery.

Dated

this 7th day of March,

2006.

-169-