HK1050004B - Indolin-2-one derivatives, preparation and their use as ocytocin receptor ligands - Google Patents

Description

The present invention relates to novel derivatives of indolin-2-one, a process for their preparation and pharmaceutical formulations including them, which are potent and selective ligands of oxytocin receptors and can therefore be used as an active ingredient in pharmaceutical formulations, particularly in obstetrics and gynecology.

Oxytocin (OT) is a neurohypophyse hormone with a cyclic nonapeptide structure similar to arginine vasopressin (AVP).Oxytocin receptors are mainly found in the smooth muscle of the uterus and on the myoepithelial cells of the mammary glands.Oxytocin plays an important role in childbirth as it is involved in uterine muscle contraction and lactation.Oxytocin receptors are also located in other peripheral tissues and in the central nervous system; therefore, oxytocin can have effects in the cardiovascular, renal, endocrine or behavioral domains.

Indolin-2-one derivatives have been described in some patent applications as ligands of vasopressin receptors and possibly oxytocin receptors, including patent applications WO 93/15051, EP 636608, EP 636609, WO 95/18105, WO 97/15556 and WO 98/25901.

It has now been found that some indolin-2-one derivatives are potent and selective ligands of oxytocin receptors.

Thus, in one aspect, the present invention relates to new derivatives of indolin-2-one in the form of a pure enantiomer or a mixture of enantiomers of formula: where:R0 represents a group selected from: (i) The following: in which: Z1 represents a chlorine, bromine, iodine or fluorine atom, a (C1-C4) alkyl, (C1-C4) alcoxy or trifluoromethyl group; Z2 represents a hydrogen, chlorine, bromine, iodine or fluorine atom, a (C1-C4) alkyl, a (C3-C5) cycloalkyl, (C1-C4) alcoxy, a (C3-C5) cycloalkyl, or (C1-C4) group; polyfluoroalkyleR5 represents T1W in which T1 represents -CH2) m, m may be equal to 0 or 1, W represents a hydrogen atom, a hydroxycarbonyl (or carboxyl) group,(C1-C4) alcoxycarbonyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, or W represents a -NR6R7 group in which R6 and R7 independently represent each other a hydrogen atom, a (C1-C4) alkyl group, a (C1-C4) alkyl sulphonyl or a phenyl sulphonyl group in which the phenyl group may be mono, di or trisubstituted by Z5 or R6 and R7 form with the nitrogen atom to which they are bound a morpholinyl group possibly substituted by a (C1-C4) alkynyl group or an oxo group, or R6 and R7 are bound with the nitrogen atom possibly by a piperyl or a pyrrozinyl group; or R6 and R7 are bound by a piperyl or a pyrrozinyl group possibly substituted by R3 and R7the pyrrolidinyl and piperidinyl groups , where appropriate replaced by Z4; W is either a -NR8COR9 group in which R8 represents a hydrogen atom or a (C1-C4) alkyl group and R9 represents a hydrogen atom, a (C1-C4) alkyl group, a benzyl, pyridyl, phenyl, the said phenyl group may be mono, di or trisubstituted by Z5; or R9 is a -NR10R11 group in which R10 and R11 independently represent a hydrogen atom or a (C1-C4) alkyl, or R10 and R11 form with the nitrogen atom to which they are bound a pyrrolidine, piperidinyl, morphinyl or possibly a substitute (C1-C4) group,either R9 represents a pyrrolidine-2-yl or 3-yl, piperidin-2-yl, 3-yl or 4-yl group, the pyrrolidinyl and piperidinyl groups being possibly replaced by Z7; or R9 represents a -T2-R12 or -T2-COR12 group in which T2 represents -CH2-n-, where n may be equal to 1, 2, 3 and 4, and R12 represents a (C1-C4) alcoxy or -NR10R11, R10 and R11 being as defined above; or W is a -CONR13R14 group in which R13 is a hydrogen atom, a (C1-C4) alkyl group, a (C3-C7) cycloalkyl group, a mono- or polyfluoro ((C1-C4) alkyl, and R14 is a hydrogen atom, a (C1-C4) alkyl group, phenyl, possibly replaced by Z5,-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, (C1-C4) alkoxycarbonyl group, (C1-C4) alkoxycarbonylamino, phenyl possibly mono-, displaced by Z5, a pyrid-2-yl, 3-yl or 4-yl, a -NR16R17 group in which R16 and R17 independently represent one hydrogen atom, or a (C1-C4) alkyl, or R16 and R17 form with the nitrogen atom to which they are bound a morpholinyl group or possibly displaced by a (C1-C1-alkyl) group, or R16 and R17 possibly with a substituent nitrogen group in a substituent position, or R16 and R17 are bound to a substituent nitrogen by a substituent of a 43,either R16 and R17 form with the nitrogen atom to which they are bound a pyrrolidinyl or piperidinyl group, the said pyrrolidinyl and piperidinyl groups being possibly substituted by Z5 whereas, when q = 1, R15 is different from hydroxyl, (C1-C4) alcoxy, (C1-C4) alcoxycarbonylamino, -NR16R17; or R13 and R14 form with the nitrogen atom to which they are bound a morpholinyl group possibly mono- or dissubstituted by a (C1-C4) alkyl group, piperidinyl possibly substituted at position 4 by a substituent; orpiperidinyl and hexahydroazépinyl , possibly mono or dissubstituted by Z8; or W is an OR18 group in which R18 is a hydrogen atom, a (C1-C4) alkyl group, (C1-C4) alkyl group, (C1-C4) alkoxy group or -T3-R19 in which T3 is -(CH2)p-, p may be equal to 2, 3 and R19 is chosen from the hydroxyl groups, triphenylmethoxy, -NR20R21 in which R20 is a hydrogen atom or a (C1-C4) alkyl group and R21 is a hydrogen atom, a (C1-C4) alkyl group, tetrahydrofurethinyl or tetrahydropinylmethan, or R2021 and R21 are either forcibly bound to the nitrogen atom or forcibly dissociated with a morphol group or forcially dissociated with a piperyl group, or R2021 and R21 are either forcibly bound to the nitrogen atom or forcibly dissociated with a monopeptide group, or forcibly substituted with a piperyl group, or R2021 and R21 are forcially bound to the piperyl group, or forcially dissociated with a piperyl group, or forcially substituted with a piperyl group, or R2021 and R3 are forcially bound to the piperyl group, or R20 and R21 are forcially bound to a monopepid or forcially dissociated with a piperyl group, or R3 and R21 are forcially bound to a piperyl group, or R20 and R21 are forcially substituted with a piperyl group, or R3 and R21 are forcially substituted with a piperyl group, or R20 and R21 are forcially dissociated with a piperyl group, or R21 and R3 are forcially bound to a piperyl group, or R20 and R21 or R21 are forcially substituted with a piperyl group, or R21 and R3 are forcially substituted with a piperyl group, or R21 and R21 are forcially substituted with a piper, or R21 and R21 or R21 are forcially substituted with a piperthe pyrrolidinyl and piperidinyl groups , where appropriate replaced by Z5; 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 (C1-C4) alcohol, a (C1-C4) alkylocarbonyl, a (C1-C4) alkylocarbonyl; Z5 represents a chlorine atom, bromine, iodine or fluorine, a hydroxyl group, a (C1-C4) alkylocarbonyl, or (C1-C4) alkylocarbonyl; Z7 represents a fluorine group, a di-C1-C1-C4-alkylocarbonyl, a hydroxyl group, a hydroxyl group, a fluorine group, a hydroxyl group, a fluorine group, a hydroxyl group, a fluorine group, a hydroxyl group, a fluorine group, a hydroxyl group, a fluorine group, a hydroxyl group, a fluorine group, a hydroxyl group, a hydroxyl group, a fluorine group, a hydroxyl group, a hydroxyl group, a fluorine group, a (C1-C1-C4-C1-C1-C4-C1-C1-C1-C4-C1-C1-C4-C1-C1-C1-C4-C1-C1-C1-C4-C1-C1-C1-C4-C1-C1-C1-C4-C1-C1-C4-C1-C1-C4-C1-C1-C4-C1-C4-C1-C1-C4-C1-C4-C1-C1-C4-C1-C4-C1-C4-C4-C1-C1-C4-C4-C4-C4-C4-C4-C4-C1-C1-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-(C1-C4) alcoxycarbonylamino, (C3-C6) cycloalcoxy, hydroxycarbonyl, hydroxy ((C1-C4) alkyl or (C1-C4) alcoxy ((C1-C4) alkyl, (C1-C4) alcoxy,CONR23R24 in which R23 and R24 are independently of each other, a hydrogen atom, a (C1-C4) alkyl, a mono- or polyfluoro ((C1-C4) alkyl or R23 and R24 form with the nitrogen atom to which they are bound a pyrrolidinyl group or piperinyl groups, the said pyrrolidinyl or piperinyl groups being possibly replaced by a difluoropyrrodiene; (ii) the following: Z6 represents a chlorine atom or a (C1-C4) alkyl or (C1-C4) alcoxy group; R1 represents a (C1-C4) alkyl group with possibly a double or triple bond; (C1-C4) alcoxycarbonyl; phenyloxycarbonyl or a T1-R22 group in which T1 is as defined above and R22 represents a hydroxyl or (C1-C4) alcoxy group; R2 and R4 represent independently of each other,Hydrogen, chlorine or fluorine atom, a (C1-C4) alkyl or (C1-C4) alcoxy group;R3 represents a chlorine or fluorine atom, a (C1-C4) alkyl group; (C1-C4) alcoxy; hydroxyl; a (C1-C4) carbamoyl group; a (C1-C4) alkylcarbonylamino; nitro; cyano; trifluoromethyl amino (C3-C6); cycloalkylamino; (C1-C4) alkylamino; diC1-C4) alkylamino; (C1-C4) trialkylammonium, A- being an anion; (C1-C1-C4) pyrrolidin-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-1-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-

An alkyl is a saturated, linear or branched monovalent hydrocarbon radical.

(C1-C4) alkyl means an alkyl radical containing 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, dry-butyl and tert-butyl.

Alkylene is a saturated, linear or branched bivalent hydrocarbon radical.

By alcoxy, we mean an O-alkyl radical.

For example, an anion A′ is a Cl-, Br-, I- or CH3SO4- anion.

DiC1-C4 alkylamino refers to an amino radical substituted by two alkyl radicals, which may be identical or different.

The salts of the compounds of the invention are prepared according to techniques well known to the art. The salts of the compounds of formula (I) of the present invention include those with mineral or organic acids which allow a suitable separation or crystallization of the compounds of formula (I), as well as pharmaceutically acceptable salts. As appropriate acids may be cited: picric acid, oxalic acid or an optically active acid, e.g. a picric acid, a dibenzoyltartaric acid, a mandolulic acid or a camphosulfonic acid, and those which form physiologically acceptable salts, such as chlorhydrate, bromohydrate, sulphate, sulphate and sulphate, and preferably 2-hydrogen sulphate, fumarate, sulphate, sulphate, camphosulfonate.

When a compound of the invention has one or more asymmetrical carbons, the optical isomers of that compound are an integral part of the invention. When a compound of the invention has a stereoisomer, e.g. axial-equatorial or Z-E, the invention includes all stereoisomers of that compound.

The present invention includes compounds of formula (I) as pure isomers but also as mixtures of isomers in any proportion.

The compounds (I) are isolated as pure isomers by conventional separation techniques: recrystallizations fractionated from a racemic salt with an acid or an optically active base, the principle of which is well known, or conventional techniques of chiral or nonchiral phase chromatography may be used.

The compounds of formula (I) above also include those in which one or more hydrogen, carbon or halogen atoms, in particular iodine, chlorine or fluorine, have been replaced by their radioactive isotope e.g. tritium or carbon-14. Such labelled compounds are useful in research, metabolism or pharmacokinetics, in biochemical assays as receptor ligands.

The functional groups possibly present in the molecule of formula (I) compounds and in the reaction intermediates can be protected either permanently or temporarily by protective groups that ensure a univocal synthesis of the expected compounds. The protective and deprotective reactions are performed according to techniques well known to man of the art. By temporary protective group of amines or alcohols are meant protective groups such as those described in Protective Groups in Organic Synthesis, Greene T.W. and Wuts P.G.M., Ed. Wiley Intersciences 1999 and in Protecting Groups, Kocienski P.J., 1994, Georgeme Thi Verlag.

Examples of temporary protective groups of amines include: benzyls, carbamates (such as tert-butyloxycarbonyl cleasable in acidic media, benzyloxycarbonyl cleasable by hydrogenolysis); carboxylic acids: alkyl esters (such as methyl or ethyl, tert-butyl hydrolysable in basic media or acids) and hydrogenolysable benzylic groups; alcohols or phenols such as tetrahydropyranyl, methyloxymethyl or methyl ether, tert-butyl and benzyl; carbonyl derivatives such as linear acetals or cyclic groups described as 1,3-dioxylan or 1,3-dioxylan; and the well-known protective groups referred to above, the 2-cylindric groups.

The man of art will be able to choose the appropriate protective groups.The compounds of formula (I) may contain precursor groups of other functions which are generated later in one or more other steps.

A family of compounds according to the invention consists of indolin-2-one derivatives in the form of a pure enantiomer or a mixture of enantiomers of formula: R0 is (i) The following: Z1, Z2, R1, R2, R3, R4, R5. Y, X are as defined for (I) and their pharmaceutically acceptable salts, solvates and hydrates.

In another aspect, the invention relates to compounds with formula: where 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 a mixture of enantiomers, and their pharmaceutically acceptable solvates and hydrates.

A subfamily of compounds according to the invention consists of compounds with formula: wherein R1 represents a methyl or hydroxyl group and R0, R3, R4 and X are as defined for (I) in the form of a pure enantiomer or a mixture of enantiomers, and their pharmaceutically acceptable solvates and hydrates.

Another subfamily of compounds according to the invention consists of compounds with the formula: where R1 represents a methyl or hydroxyl group and R0 and R3 are as defined for (I) ; in the form of a pure enantiomer or a mixture of enantiomers, and their pharmaceutically acceptable solvates and hydrates.

Another subfamily of compounds according to the invention consists of compounds with the formula: where R1 is a methyl or hydroxyl group and R0 is as defined for (I) ; in the form of a pure enantiomer or a mixture of enantiomers, and their pharmaceutically acceptable solvates and hydrates.

Of these compounds of formulae (I), (Ia), (Ib), (Ic) and (Id), those in which R0 represents the group: in particular the group: where R5 is as defined for (I) constitute another aspect of the invention.

Of these latter compounds, those in which R1 represents a methyl group constitute another aspect of the invention.

In another aspect, the invention relates to compounds selected from: 5-D-methyl-1-methyl-1-methyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzyl-2-benzy

The compounds of formula (I) may be prepared in accordance with the following SCHEME 1:

In this diagram, R0, R1, R2, R3, R4, X and Y are as defined for (I), and for (Ip), R'0, R'1, R'2, R'3, R'4, X' and Y' respectively represent either R0, R1, R2, R3, R4, X and Y as defined for (I), or a precursor group of R0, R1, R2, R3, R4, X and Y, it being understood that R1 is different from hydrogen.

The present invention also relates to a preparation process for compounds of formula (I) characterized by: (a) a compound of formula: where X, Y, R0 and R1 are as defined for (I) is reacted in the presence of a base with a halogen of formula: where Hal is a halogen atom and R2, R3, R4 are as defined for (I) ; (b) or, where R1 is an electrophilic group, the compound is transformed to: wherein R0, R2, R3, R4, X and Y are as defined for (I), by the action of a derivative R1-Z,where Z is a starting group in the presence of a base; or, where R1 = OH, a derivative of isatin of the formula: wherein R2, R3, R4, X and Y are as defined for (I), with an organometallic derivative R0-M or R0MgHal, R0 being as defined for (I), M being a metal atom and Hal a bromine or iodine atom; oror a precursor group of R0, R1, R2, R3, R4, X and Y, to a further treatment to transform any of the groups R'0, R'1, R'2, R'3, R'4, X' or Y' respectively, R0, R1, R2, R3, R4, X or Y as defined for (I), according to reactions well known to the art.

The reaction described in (a) is preferably performed with a compound (I) in which Hal = Cl or Br, using as a base a metal hydride such as sodium hydride or an alkaline alcohol such as potassium tert-butylate in an anhydrous solvent such as dimethylformamide or tetrahydrofuran.

In the reaction described in (b) by leaving group, one means, for example, a halogen atom such as chlorine, bromine or iodine or an estersulfonic group such as para-toluene sulfonate. Preferably, a halogenide R1-Hal is reacted on the compound (III), with R1 as defined for (I) and Hal being a halogen atom preferably iodine in the presence of a base; one will operate, for example, in the presence of a base such as an alkaline alcohol such as potassium tert-butylate, in an etheric solvent such as tetrahydrofuran or in the presence of a carbonate such as sodium, potassium or potassium carbonate in a solvent such as ethylformethyl or dimethylformethyl acetate.

The reaction described in c) is either a reaction of magnesium R0Mg-Hal with R0 as defined for (I) or (Ip) and Hal as a bromine or preferably iodine atom, or a reaction of a derivative R0M with M as a lithium atom with the compound (IV) as the preferred solution. This derivative R0Li is obtained either by direct lithiation e.g. by lithium butyl or lithium diisopropylamidide according to Heterocycles 1993, 351), 151-169, or by a lithium halogen exchange reaction according to Organogamum Methods, Pergamon, New York, 1988 J. Chem. or 2217. These reactions are performed in either amethylated or diethyl anhydride or in a solvent.

The transformation of the compound (Ip), precursor to the compound (I) described in (d), is carried out by conventional techniques.

Furthermore, compounds (I) may be obtained from another compound (I) by transformation of one of the substituents R0, R1, R2, R3, R4, X or Y, in particular R0, R1 or R3. compounds (I) in which R3 = -NH2 can be obtained by reduction of the corresponding compounds (I) in which R3 = -NO2, e.g. by action of hydrochloric acid in the presence of tin in an alcohol such as ethanol; compounds (I) in which R3 represents a (C1-C4) alkylamine or di(C1-C4) alkylamine group can be obtained from the corresponding compounds (I) in which R3 = -NH2 by a reducing amining reaction.Reference can be made to J. Org. Chem., 1996, 61, 3849-3862 and to the action of an aldehyde in (C1-C4) alkyl in the presence of sodium triacetatoxyborohydride or to J. Am. Chem. Soc., 1974, 96(25), 7812 and to the action of an acid in (C1-C4) alkyl in the presence of sodium borohydride. The classical N-alkylation reactions can also be used, for example by acting on the amino group making a halogen of (C1-C4) alkyl in the presence of dimethylformamide and potassium carbonate compounds (I) in which R3 represents a (C1-C4) calcoxy to be obtained from the corresponding compounds (Ip) in which R3 = O-alkylation,for example by action of a (C1-C4) alkyl halogenide in the presence of dimethylformamide and caesium or potassium carbonate; compounds (I) in which R3 represents a (C1-C4) alkylcarbonylamine group may be obtained from the corresponding (I) compounds in which R3= -NH2 by a classical acylation such as the action of an acid chloride in (C1-C4) alkyl, in the presence of a base such as triethylamine, in a solvent such as dichloromethane; compounds (I) in which R3 represents a cyclic amine or a morpholine-4 may be obtained from the corresponding (I) compounds in which R3= -NH3 -NH2 as described in the method Tetrahedron,1989, 45 (c), 629-636. compounds of formula (I), in which R0 represents a group: The compounds (III) are prepared by dehalogenation of the compounds of formula: where R0, R2, R3, R4, X and Y are as defined for (I) and Hal represents a chlorine, bromine or iodine atom, e.g. by the action of a bulky lithium dialkylamidide such as lithium diisopropylamidide (LDA) by analogy with the method described by N.The results of the study were published in the journal Chemical Chemistry, Newcom et al. in J. Am. Chem. Soc. 1990, 5186-5193.

The compound (I') is obtained, for example, by transformation of the corresponding compound (I) in which R1 = OH by action of a halogen derivative, e.g. of the acid halogenide type.

The compound (IV) is generally obtained by the action of the compound (1) on the isatin derivative of formula: wherein X and Y are as defined for (I) under the same conditions as described above for the preparation of compound (I) from compound (II). Isatin derivatives (2) are commercial compounds or are prepared by the methods described in Tetrahedron Letters 1998, 39, 7679-7682; Tetrahedron Letters 1994, 35, 7303-7306; J. Org. Chem 1977, 42, 1344-1348 and Advances in Heterocyclic Chemistry, A.R. Katritzky and A.J. Boulton, Academic Press, New York, 1975, 18, 2-58.

The (II) compounds can be synthesised by various methods described in particular in patent applications EP 526348 and WO 95/18105.

SCHEME 2 shows some of the routes of production of the compounds (II): R1 nucleophile means a (C1-C4) alkoxy group.

Compounds (II) in which R1 represents an electrophilic group, e.g. a (C1-C4) alkyl group, may be prepared from compounds of formula: where R0, X and Y are as defined for (I), by action of a derivative R1-Z in which Z represents a starting group, under the same conditions as described above for the transition from compound (III) to compound (I).

The compound (V) is generally synthesized: either by dehydroxylation of the corresponding compound (II) in which R1 = OH by action of tin chloride in an acid medium according to the method described in Tetrahedron 1996, 52(20), 7003-7012 or by action of triethylsilane according to Bioorganic and Medicinal Letters, 1997, 7(10), 1255-1260; or by a cyclic reaction in a strong acid medium such as sulphuric acid, of the compound with the formula: where R0, X and Y are as defined for (I) and this compound (VII) is itself obtained by condensation reaction between a derivative of α-hydroxyacetic acid of the formula: - What?

R0 being as defined for (I) with an amino benzene of formula: wherein X and Y are as defined for (I).

The compounds (3) are commercially available or synthesized in a conventional manner.

The compounds of formula (VIII) are commercially available or synthesized by methods well known to the art.

Other reactions can also lead to compounds (V). The Brunner reaction described in Tetrahedron 1986, 42(15), 4267-4272: the cycling reaction in the presence of formic acid described in J. Chem. Soc. Perkin Trans., 1986, 1, 349-360: The following cycling reactions: according to J. Am. Chem. Soc., 1985, 107 (2), 435-443: The following is a list of the active substances in the active substance, as defined in Annex I to Regulation (EC) No 1907/2006 of the European Parliament and of the Council:

The compounds (II) in which R1 represents a (C1-C4) alcoxy group are obtained from the compounds of formula: where R0, X and Y are as defined for (I) and Hal represents a halogen atom e.g. of chlorine by action of the corresponding alcohol R1H.

The compound (VI) is prepared from the corresponding compound (II) in which R1 = OH by action of thionyl chloride in the presence of pyridine in dichloromethane.

The compounds (II) in which R1 = OH are generally prepared from the corresponding isatin of formula: where X and Y are as defined for (I), according to the method described above for the preparation of compounds (I) in which R1 = OH from compounds (IV).

When R1 does not represent a hydroxy group, the (II) compounds may also be prepared according to the following SCHEME 3:

In this SCHEME 3, R0, R1, X and Y are as defined for (I) and R1 does not represent a hydroxy group and M represents e.g. a lithium or MgHal atom, Hal being a halogen atom.

The conversion of the compound (X) to the compound (IX) to give the compound (II) is carried out in particular according to the method described in J. Chem. Soc. 1957, 1928.

Benzyl halides (1) are known or prepared by known methods, e.g. J.V. Rajanbabu, J. Org. Chem., 1986, 51, 1704-1712, and the publications cited in EP 636609.

Generally speaking, halogen methylbenzene derivatives (1) can be prepared by the action of N-halogenosuccinimides on the corresponding methylbenzene derivatives and according to EP 229566.The reaction is carried out in a solvent such as carbon tetrachloride in the presence of dibenzoyl peroxide.A halogen methylbenzene derivative can also be prepared from a corresponding hydroxymethylbenzene derivative by the action of phosphorus tribromide in diethyl ether or by the action of thionyl chloride.

At all stages of the process, an intermediate compound of type (IIp), (IIIp), (IVp) can be formed in which at least one of the substituents is replaced by one of its precursor groups. These compounds (IIp), (IIIp), (IVp) will be transformed by classical reactions into (II), (III), (IV) respectively.

The compounds of the invention have been studied biochemically and pharmacologically. The affinity of the compounds of the invention for oxytocin receptors was determined in an in vitro binding assay using the method described by J. Elands et al. in Eur. J. Pharmacol. 1987, 147, 197-207. This method consists of in vitro studying the movement of a radioiodine analogue of oxytocin to oxytocin receptors in a membrane preparation of human uterine oxytocin receptors. CI50 (inhibitory concentration of 50% of the binding of the radioiodine analogue of oxytocin to its receptors) and M10-10-6 in the latter assay are low.

The affinity of the compounds of the invention for human vasopressin receptors V1a (method described by Thibonnier et al. in J. Biol. Chem. 1994, 269, 3304-3310) V1b (method described by T. Sugimoto et al. in J. Biol. Chem. 1994, 269, 27088-27092) and V2 (method described by Bimbaumer et al. in Nature (London), 1992, 357, 333-335) was also studied. The compounds studied are not very or very closely related to V1a receptors V1b and V2.

The agonist or antagonist character of the compounds is determined in vitro in an intracellular calcium measurement assay on cells expressing human ocytocyte receptors using the general technique described in (Am. J. Physiol. 268 (Heart Circ. Physiol. 37), 1995, H404-H410.

When the compounds of the invention behave as antagonists, their CI50 is preferably between 0,5 μM and 0,5 nM. For example, the dextrogyre enantiomer of EXAMPLE 1 is antagonistic with a CI50 of 3,2 ± 1,9 nM.

The compounds of the invention, which are potent and selective ligands of oxytocin receptors, are of particular interest in the prevention and/or treatment of oxytocin-dependent disorders.

They will be of particular interest in healing, analgesia and anxiolytic (prevention of pain and anxiety), depression, schizophrenia, autism, obsessive compulsive disorder, maternal behaviour (facilitation of recognition and acceptance of mother-child) and social behaviour, memory, regulation of food and drink intake, drug addiction, withdrawal and sexual motivation. They will be of particular benefit for use in urogenital disorders, in the obstetric and gynaecological fields, in particular as a tofonic or relaxing dysfunctional agent or to control the severity of uterine contractions before the onset of pregnancy; to control the severity of urine or urethral contractions, to control the urine flow or urethral pressure, to control the endometriosis, to control the blood pressure, to control the urine flow, to control the urine flow, to control the urine flow, to control the flow of urine, to control the flow of urine, to control the flow of urine, to control the flow of urine, to control the flow of urine, to control the flow of urine, to control the flow of urine, to control the flow of urine, to control the flow of urine, to control the flow of urine, to control the urine, to control the flow of urine, to control the urine, to control the flow of urine, to control the urine, to control the urine, to control the flow of urine, to control the urine, to control the urine, to control the urine, to control the urine, to control the urine, to control the urine, to control the urine, to control the urine, to control the urine, to control the urine, to control the urine, to control the urine, to control the urine, to control the urine, to control the urine, to control the urine, to control the urine, to control the urine, to control the urine, to control the urine, to control the urine, to control the urine, to control the urine, to control the urine, to control the urine, to control the urine, to control the urine, to

Furthermore, given the role of oxytocin in the control of luteinizing hormone (J.J. Evans, J. Endocrin. 1996, 151, 169-174) the compounds of the invention may be used to induce contraception.

In addition, the compounds of the invention may be used for their anti-tumor effects in oxytocin-secreting tumours, particularly breast and prostate cancers.

The use of the compounds of the invention for the prevention and/or treatment of the diseases mentioned above and for the preparation of medicinal products for the treatment of these diseases is an integral part of the invention.

The present invention therefore also concerns pharmaceutical compositions containing a compound of the invention or a salt, solvate or hydrate thereof, pharmaceutically acceptable, and suitable excipients.

These excipients are selected according to the pharmaceutical form and the desired route of administration: oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transclerical, rectal or intraocular.

In order to achieve the desired prophylactic or therapeutic effect, each unit dose may contain 0.5 to 1000 mg, preferably 1 to 500 mg, of active ingredients in combination with a pharmaceutical carrier.

The compounds of the invention may also be used in the preparation of compositions for veterinary use for birth control.

The compounds of the invention may also be used for the preparation of cosmetic formulations, which may be in the form of topical cream and are intended to control lipolysis.

The compositions of the present invention may contain, in addition to the products of formula (I) above or their salts, pharmaceutically acceptable solvents and hydrates and, for example, active substances which may be useful in the treatment of the disorders or diseases indicated above. Thus, the present invention also concerns pharmaceutical compositions containing several active substances in combination, one of which is a compound of the invention. In particular, the present invention concerns pharmaceutical compositions containing a compound of the invention, an antagonist of the receptor for oxine with an antagonist V1a compound. This type of composition will be particularly useful in the treatment of dysmenorrhea, endometriosis, control of premature labor and control of labor prepared for c-section.

The invention also relates to products containing an oxytocin receptor antagonist as defined above and a vasopressin V1a receptor antagonist for simultaneous, separate or time-spaced use in the treatment of dysmenorrhoea, endometriosis, control of preterm labour and to control labour in preparation for cesarean delivery.

The following EXAMPLES and PREPARATIONS illustrate the invention without limiting it.

Nuclear magnetic resonance spectra were performed in deuterium chloroform unless otherwise stated at 200 MHz and chemical displacements are expressed in ppm. The abbreviations used below are: s = singlet; m = multiple; d = double; t = triple; q = quintuple.

All the compounds of the invention were subjected to organic elemental analysis by combustion at 1000°C in the presence of oxygen, using a Supermicro S4 Sartorius scale and an EA 1108 elemental analyzer. The percentages of carbon, hydrogen, nitrogen and sulphur obtained are in accordance with the expected theoretical results.

The Commission shall adopt implementing acts laying down the rules for the application of this Regulation. Preparation 1 N- ((4-Chlorophenyl)-2-oxopropionamide, compound XI.1.

At -60°C, add 26,3 g of 4-chlorophenylamine to 150 ml of dichloromethane and 35 ml of triethylamine to 22 g of 2-oxopropionyl chloride (prepared according to Synthesis 1975, 163-164 from 2-oxopropionic acid and 1,1-dichlorodimethyl ether) in 350 ml of dichloromethane. Stir the reaction mixture at -60°C for 2 hours and then add 200 ml of an aqueous solution of chloric acid at 0,15 N and 500 ml of dichloromethane to -30°C. Extract the organic phase, wash with an aqueous solution of hydrochloric acid 0,25 N and dry on sodium sulphate. Evaporate the residues; reduce the pressure in the crystal to 151°C.

Preparation 2 2-Chloro-4-fluorophenyl) N-Chloro-4-chlorophenyl)-2-hydroxypropionamide, compound IX.1.

The resulting mixture is added at -60°C to 0.99g of the compound XI.1 in 9 ml of tetrahydrofuran. The reaction mixture is stirred at 20°C for 2 hours and then an aqueous solution saturated with NH4Cl is added. The ethyl acetate is extracted, the organic phase is dried on Na2SO4 and the solvents are vaporized under reduced pressure. The resulting residue is purified by chromatography on a silica column by evaporation with a cycloxane/dichromethane gel (dichloromethane 1/1/vloromethane) /dichloromethane (1/vloromethane/dichloropropane) in a crystalline solution; the resulting isopropyl is thus F = 167°.

In the same way, the following compounds are prepared: N- ((4-Chlorophenyl)-2-(2,5-dimethoxyphenyl)-2-hydroxypropionamide, compound IX.2 ; F = 145°C.N- ((4-Chlorophenyl)-2-(2-chloro-4-methylphenyl)-2-hydroxypropionamide, compound IX.3 ; F = 116°C.N- ((4-Chlorophenyl)-2-(2-chloro-5-methylphenyl)-2-hydroxypropionamide, compound IX.4 ; F = 147°C.N- ((4-Chlorophenyl)-2-(chloro-5-fluoro-methylphenyl)-2-hydroxypropionamide, compound IX.5 F = 171°C.

Preparation 3 (2-Chlorophenyl) -N- ((4-Chlorophenyl) -hydroxyacetamide, with the compound VII.1.

A mixture of 60 g (2-chlorophenyl) hydroxyacetic acid and 41 g 4-chlorophenylamine in 300 ml of 1,2-dichlorobenzene is heated to 200 °C. The mounting includes a Dean-Stark, so the water formed is eliminated during the reaction.

The resulting solid is rinsed with diisopropyl ether; F = 120°C.

In the same way, (2-chlorophenyl) N- ((4-methoxyphenyl) hydroxyacetamide , compound VII.2 is prepared from 4-methoxyphenyllamine; F = 130°C.

In the same way, (2-chloro-4-fluorophenyl) -N-(4-chlorophenyl) -hydroxyacetamide, compound VII.3 is prepared from hydroxyacetic acid (2-chloro-4-fluorophenyl) (synthesized from J. Med. Chem., 1987, 30(8), 1447 from 2-chloro-4-fluorobenzaldehyde and bromoform);

Preparation 4 5-Chloro-3-(2-chlorophenyl) indole-2-one, compound V.1. (V.1):

X = 5-Cl; Y = H

A solution of 263 ml of 95 per cent sulphuric acid and 100 ml of 20 per cent oleum is prepared at 10 °C. This solution is stirred with 74 g of the compound VII.1 for 2 hours at 40 °C. The reaction mixture is then cooled and poured over ice water. The precipitate is filtered and washed with 1000 ml of water. The solid is dissolved in dichloromethane and the resulting solution is successively washed with an aqueous solution saturated in sodium hydrocarbonate and with water drained on Na2SO4. The solvents are evaporated at reduced pressure and the solid obtained is washed under diethyl ether F = 201 °C.

In the same way, the compound V.2 is prepared as follows:

5-Chloro-3-(2-chloro-4-fluorophenyl) indole-2-one, compound V.2. (V.2):

X = 5-Cl; Y = H F = 221°C

Preparation 5 5-Methoxy-3- ((2-chlorophenyl) indole-2-one, compound V.3

In a mixture of polyphosphoric acid obtained from 65 ml of 85% phosphoric acid and 130 g phosphoric anhydride, at 50°C, add 20.1 g of 2-(2-chlorophenyl) -N-(4-methoxyphenyl)-2-hydroxyacetamide, compound VII.2 and maintain the reaction mixture at this temperature for 6 hours. After cooling, treat with an aqueous solution of sodium hydrocarbonate until a pH of 5 is obtained. Extract from ethyl acetate. Wash the organic phase with water, dry on sodium anhydride sulphate. Evaporate partially under the filter and reduce the product to the desired temperature; F = 179°C.

Preparation 6 5-Chloro-3-(2-chlorophenyl)-3-methylindolin-2-one, compound II.1. is a substance which is used in the manufacture of chemicals for the treatment of the skin. (II. 1) is as follows:

R1 = -CH3 , X = 5-Cl , Y = H

To a solution of 15 g of V.1 in 240 ml of tetrahydrofuran, add 18.2 g of potassium tert-butylate at - 40 °C. Shake the reaction mixture for 5 minutes at 0 °C and then add 3.7 ml of methyl iodide solution in 80 ml of tetrahydrofuran at - 60 °C. Once the temperature of the reaction mixture has returned to 0 °C, add 100 ml of an aqueous solution saturated with ammonium chloride and extract with ethyl acetate. The organic phase is washed in water dried on anhydrous sodium sulphate. The solvents are evaporated under pressure. The solid is purified by chromatography on a gel of acetone with a crystalline solution of n-ethyl acetone (F = 185/9°C).

In the same way, the compounds II.2 to II.6 below are prepared.

The same procedure is followed for the preparation of 5-methoxy-3- (((2-chlorophenyl) -3-methyl indolin-2-one, composed II.7 from 5-methoxy-3- (((2-chlorophenyl) indolin-2-one; F = 176°C.

Preparation 7 5-Chloro-3-(2-chloro-4-fluorophenyl)-3-methylindolin-2-one, compounded with II.6. (II.6):

R1 = -CH3 , X = 5-Cl , Y = H

The compound II.6 described above may also be prepared as follows: 0,3 g of compound IX.1 and a pre-prepared solution of 5,3 g phosphorus anhydride are heated at 150 °C for 5 hours in 3 ml of an 85% aqueous solution of phosphoric acid. The reaction mixture is poured over ice, a saturated aqueous solution of potassium carbonate is added and extracted with ethyl acetate. The organic phase thus obtained is dried on anhydrous sodium sulphate. The solvents are evaporated at reduced pressure. The resulting solid is crystallized in n-pentane; = F 189°C.

In the same way, the compound 5-Chloro-3- ((2,5-dimethoxyphenyle) -3-methylindolin-2-one, compound II.8, is prepared;

(II.8):

R1 = -CH3 , X = 5-Cl , Y = H F = 163°C

Preparation for the 8th 5-Chloro-3-[2-chloro-5-(4-methyl-1-pipérazinyl) phenyle]-3-methylindol-2-one, Composed of II.9 (II.9):

R1 = -CH3 X = 5-Cl Y = H

The mixture of 0.5 g of compound II.6, 2.5 ml of dimethyl sulfoxide, 3.6 ml of N-methyl piperazine, 1 g of sodium carbonate and 0.1 g of copper iodide is heated at 120 °C for 24 hours. After returning to room temperature, the salts are filtered on talc, the precipitate is rinsed with dimethyl sulfoxide and then with 60 ml of ethyl acetate. The filtrate is washed with 40 ml of water and the organic matter is dried on anhydrous sodium sulfate. The solvents are evaporated under reduced pressure and the residue is chromatographed on a solid silicone gel with dichloromethane. The remainder is then isolated; the product is then re-filtered with the diopropyl chloride diolysis process.

Preparation 9 5-Chloro-3-(2-chloro-4-fluorophenyl)-3-hydroxyindolin-2-one, a compound specified in II.10. (II. 10):

R1 = -OH; X = 5-Cl; Y = H

A 2 g 5-chloroindolin-2,3-dione suspension in 60 ml of tetrahydrofuran is cooled, 0.44 g of a 60% sodium hydride dispersion is added to the oil at -40°C and the reaction mixture is agitated for 15 minutes at 0°C. 0.45 g of magnesium and 4.23 g of 2-chloro-4-fluoro-1-iodobenzene are agitated at low pressure for 3 hours in 18 ml of diethyl ether. The resulting solution is then slowly added to the aqueous reaction mixture at -60°C. The reaction mixture is agitated for 30 minutes at 20°C and a solid solution saturated with ammonium chloride is added.

In the same way, 5-Chloro-3- ((2,5-dimethoxyphenyl) -3-hydroxyindolin-2-one, compound II.11 is prepared from 1-bromo-2,5-dimethoxybenzene

(II.11):

R1 = -OH; X = 5-Cl; Y = H F = 221°C

Preparation for the 10th 3,5-Dichloro-3- ((2,5-Dimethoxyphenyl) indole-2-one, compound VI.1. (VI.1):

X = 5-Cl; Y = H

At a temperature below 20°C, 0.8 ml of thionyl chloride is added to 3 g of compound II.11 in the presence of 1.2 ml of pyridine in 50 ml of dichloromethane and the reaction mixture is stirred for one hour. The reaction mixture is washed with water, dried on anhydrous sodium sulphate. The solvents are evaporated under reduced pressure and the residue is chromatographed on a silica gel column by eluting to dichloromethane.

In the same way, the following compounds are prepared:

3,5-Dichloro-3- ((2-Chlorophenyl) indole-2-one, compound VI.2. (VI.2):

X = 5-Cl; Y = H F = 190°C

3,5-Dichloro-3-(2-chloro-4-fluorophenyl) indole-2-one, compound VI.3. (VI.3):

X = 5-Cl; Y = H F = 87°C

Preparation 11 5-Chloro-3-(2,5-dimethoxyphenyle) -3-methoxyindolin-2-one, a compound specified in II.11. (II. 11):

R1 = -OCH3 , X = 5-Cl , Y = H

Keep 0,4 g of VI.1 in the presence of 25 ml methanol in 50 ml of tetrahydrofuran at reflux for 3 hours.

In the same way, the following compounds are prepared:

5-Chloro-3-(2-chlorophenyl)-3-methoxylndolin-2-one, compounded with II.12. (II.12):

R1 = -OCH3 , X = 5-Cl , Y = H F = 179°C

5-Chloro-3-(2-chloro-4-fluorophenyl)-3-methoxyindolin-2-one, with a compound content of II.13. (II. 13):

R1 = -OCH3 , X = 5-Cl , Y = H F = 82°C

Preparation for the 12th 5-Chloro-1- ((2,4-dimethoxybenzyl) indole-2,3-dione, compound IV.1. (IV.1): R2 = H; R3 = 4-OCH3; R4 = 2-OCH3; X = 5-Cl; Y = H

(a) To a suspension of 1.45 g of 2,4-dimethoxyphenylmethanol in 25 ml diethyl ether, add 0.25 ml phosphorus tribromide at -50°C. The resulting solution is allowed to return at 0°C. (b) To a suspension of 1.3 g of 5-chloroindolin-2,3-dione in 50 ml tetrahydrofuran, add 2 g of potassium tert-butylate at -60°C. Stir the reaction mixture for 5 minutes at 0°C and then add the solution prepared at -60°C. Stir the solution at room temperature for 16 hours and evaporate the solvents under pressure. The remainder is purified by chromatography on a colour gel; the solution is obtained by a crystalline solution of toluene (F/2/C) at a temperature of 175°C.

The following compounds are prepared in the same way: The active substance is a compound with a specific chemical activity of approximately 10 ppm. F = 136°C5,7-Dichloro-1- ((2,4-dimethoxybenzyl) indole-2,3-dione, Compound IV.3. F = 171°C5-Fluoro-1- ((2,4-dimethoxybenzyl) indole-2,3-dione, Compound IV.4. F = 163°C1- ((2,4-Dimethoxybenzyl) indole-2,3-dione, Compound IV.5. F = 142°C

The following paragraphs are added: The substance is classified in the additive category 'Chemical products'. (I)

R1 = -CH3; R2 = H; R3 = 4 -OCH3 ; R4 = 2 -OCH3 ; X = 5-Cl ; Y = H (a) To a suspension of 2,4-dimethoxyphenylmethanol of 2.6 g in 45 ml diethyl ether, add 0,48 ml phosphorus tribromide at -50°C. The resulting solution is allowed to return to 0°C. (b) To 3 g of compound II.1 in solution in 90 ml tetrahydrofuran, add 1,2 g potassium tert-butylate at -40°C. Then shake the reaction mixture until the temperature has returned to 0°C. Cool the reaction mixture to -60°C and further reduce the prepared solution to a. Mix under the reaction at 20°C for 2 hours, add 50 ml of water and dry the diethyl acetate. Then dissolve the organic solvents in sodium phyllophilisate and diethyl sulphate at 179°C.

This racemic compound is then chromatographically separated on a Chiralpak® AD column of Daïcel by electrolysis with a 2-methylpentane/ethanol 98/2 mixture (v/v).

Thus the dextrogyre enantiomer is isolated: F = 92°C; and its antipodes [α] $\frac{\text{23,5}}{\text{D}}$ The following formulae are used:

The following paragraphs shall apply: The substance is classified in Annex I to Regulation (EC) No 396/2005 as a substance of very high concern. (I) The following:

R1 = -CH3 , R2 = H; R3 = 4 -OCH3 ; R4 = 2 -OCH3 ; X = 5-OCH3 ; Y = H

Following the same procedure, the compound in EXAMPLE 2 is prepared from 5-methoxy-3- ((2-chlorophenyl) indole-2-one, compound II.7; F = 133°C.

The Commission has The substance is classified as a substance with a specific epithet. (I)

R1 = -CH3; R2 = H; R3 = 4 -OC(CH3 ) 3; R4 = 2 -OCH3 ; X = 5-Cl ; Y = H (a) Preparation of [4-[1,1-dimethylethoxy) 2-methoxy]phenylmethanol Preparation of [4-[1,1-dimethylethoxy) 2-methoxy]methyl benzoate according to J. Org. Chem. 1986, 51, 111-113. 6.2 g of 4-hydroxy-2-methoxybenzoate of methyl (according to J. Med. Chem. 1985, 28, 717-727 from 2,4-dihydroxybenzoate of methyl commercial) in 60 ml of dichloromethane, 0,25 ml of trifluoromethane sulphonic acid added at -70°C and then 25 ml of 2-methylpropene pre-condensed at -20°C and natural heating degassed by means of a plunger tube.0,5 ml of triethylamine is added to the reaction mixture. The solvents are evaporated at reduced pressure, the residue is taken up with ethyl acetate and washed with a dilute sodium bicarbonate solution. The separate organic phase is dried on anhydrous sodium sulphate and the solvents are evaporated at reduced pressure. The expected product is isolated by chromatographic purification on a silica gel column by eluting with cyclohexane. The number of samples of the test chemical is calculated by multiplying the total number of samples by the number of samples of the test chemical. A 2,5 g of the above compound obtained by (a) in 25 ml of toluene,add 15.90 ml of a 2M solution of LiBH4 to tetrahydrofuran. Heat the reaction mixture to 100°C for 45 minutes. Pour the reaction mixture over a water/ice mixture at about 20°C and extract the aqueous phase to ethyl acetate. After settling, extract the aqueous phase to ethyl acetate. The organic phases are collected and dried on anhydrous sodium sulfate and then evaporate the solvents at reduced pressure. The number of hours worked in the reporting period is calculated as follows:

The Commission shall adopt implementing acts. The substance is classified as a substance with a specific epithet. (I)

R1 = -CH3; R2 = H; R3 = 4 -OCH(CH3) 2 , R4 = 2-OCH3 , X = 5-Cl , Y = H (a) Preparation of [4-[1-methylethoxy]-2-methyl]phenylmethanol. Preparation of [4-[1-methylethoxy]-2-methylethoxy]benzoate from methyl according to Synthesis 1988,712. 0.8 g of 4-hydroxy-2-methoxybenzoate methyl in 20 ml of dimethylformamide, 2.86 g of caesium carbonate and 1.28 ml of 2-iodopropane are added at 0 °C. The reaction mixture is stirred at 20 °C for 2 hours, then 50 ml of water is added and extracted to ethyl acetate. The organic phase is washed with water and then dried on anhydrous sodium sulfate. The solvents are evaporated at reduced pressure. 1HRMN: 7,81 ((d,1H) ; 6,47-6,42 ((m,2H) ; 4,69-4,51 ((m,1H) ; 3,85 ((s,3H) ; 3,83 ((s,3H) ; 1,33 ((d,6H).The [4-(1-methylethoxy)-2-methoxyphenyle]methanol is prepared by the method described above in EXAMPLE 3 for the conversion of [4-(1,1-dimethylethoxy)-2-methoxy]methyl benzoate to [4-(1,1-dimethylethoxy)-2-methoxy]phenyle-methanol. (b) The compound in EXAMPLE 4 is prepared by the method described for EXAMPLE 1 F = 158°C.

EXAMPLES 5 to 17 below are prepared in the manner described for EXAMPLES 1.

The Commission shall adopt implementing acts. The substance is classified in the additive category 'Chemical products'. (I) The following:

R1 = -CH3; R2 = H; R3 = 4 -NO2 ; R4 = 2-OCH3 ; X = 5-Cl ; Y = H F is 179 degrees.

The Commission has It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.] (I) The following:

R1 = -CH3; R2 = H; R3 = 4 -OCH3 ; R4 = 2-OCH3; X = 5-Cl; Y = H The temperature of the water is measured at a temperature of approximately 140 °C (0.3 H2O). - What?

The Commission has not yet adopted a decision. The following substances are to be classified in the same category as the active substance: (I) The following:

R1 = -OH; R2 = H; R3 = 4 -OCH3 ; R4 = 2 -OCH3 ; X = 5 -Cl ; Y = H

This compound may be prepared from compound II.10 by the same method as in EXAMPLE 1 or by the following method:

The reaction mixture is agitated for 1 hour at 20°C and then an aqueous solution saturated with ammonium chloride is added. The organic phase is extracted from ethyl acetate, dried on anhydrous sodium sulfate and then evaporated at reduced pressure. The resulting residue is chromatographically obtained on a silica gel column by blending with a solid cyclohexane/chlorhexane 1/1v (hexane/hexane) in the crystal; the resulting cyclohexane is obtained at 177°C.

This racemic compound is chromatographically separated on a Chiralpak® AD column of Daïcel by electrolysis with a 2-methylpentane/ethanol 9/1 mixture (v/v).

Thus the dextrogyre enantiomer is isolated: and its antipodes [α] $\frac{\text{20,5}}{\text{D}}$ The following formulae are used:

The first is the The substance is classified in the additive category 'Chemical products'. (I) The following:

R1 = -OH; R2 = H; R3 = 4 -OCH3 ; R4 = 2-OCH3 ; X = 5-Cl ; Y = H (a) preparation of 2-chloro-1-iodo-5-hydroxymethylbenzene according to J. Org. Chem. 1991, 56, 5964-5965, from the corresponding commercial benzoic acid. To 25 g of 4-chloro-3-iodobenzoic acid in solution in 200 ml of tetrahydrofuran at 0 °C, add 5,02 g of sodium borohydride in portions and then 14,6 g of iodine in solution in 50 ml of tetrahydrofuran very slowly. Stir the reaction mixture for 2 hours at room temperature and then at 35 °C for 30 minutes. Hydrolyses at 10 °C with a solution of hydrochloric acid 0,The organic phase is separated by settling and then treated with an aqueous solution of sodium bisulfite and then with water. The organic phase is dried on anhydrous sodium sulfate and the solvents are evaporated at reduced pressure. The desired compound is obtained by distillation; (b) Preparation of 2-chloro-1-iodo-5-methoxymethyleneoxymethylbenzene according to Synthesis, 1985, 74. To 24.45 g of the above compound in 100 ml of dimethoxymethane, add 1.5 ml of para-toluenesulfonic acid monohydrate and 1.4 g of lithium bromide.At room temperature hydrolysis with a dilute aqueous solution of sodium bicarbonate and extraction with diethyl ether. Wash the organic phase with water, dry on anhydrous sodium sulphate, and evaporate the solvents under reduced pressure. The desired product is obtained by distillation; Eb = 108°C at 1.9 Pa.c.

The Commission has 4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-hydroxy-2-oxo-indolin-3-yl]methyl benzoate (I) The following:

R1 = -OH; R2 = H R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-Cl ; Y = H

At - 100°C, add slowly to 200 ml of tetrahydrofuran 10,72 g of 4-chloro-3-iodobenzoate of methyl (prepared by esterification of the corresponding commercial acid; F = 56°C) 45,2 ml of a 1.6M n-butyllithium solution in hexane diluted in 200 ml of tetrahydrofuran and refoam at - 90°C. Stir the reaction mixture for 20 minutes at - 95°C, then add the 10 g solution of IV.1 compound in 600 mi tetrahydrofuran cooled to - 70°C. After return to room temperature, hydrolyze with 200 ml of saturated solution in dry solvent chloronium, partially evaporate the residual solvents; reduce the sodium diethyl acetate to the desired pH, then reduce the sodium diethyl sulphate to the desired pH, and then reduce the sodium diethyl anhydride to the desired pH.

The Commission shall adopt the implementing acts referred to in Article 21 (2). 3- ((Amino-2-chlorophenyl) -5-chloro-1- ((2,4-dimethoxybenzyl) -3-hydroxyindolin-2-one) is a substance which is used in the manufacture of foodstuffs for human consumption. (I) The following:

R1 = -OH; R2 = H; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-Cl ; Y = H (a) Preparation of 4-chloro-3-bromo-N,N-tetramethylethylene disyllaniline Heat at 140°C for 5 hours under argon current a mixture consisting of 3.3 g of 3-bromo-4-chloroaniline, 3.72 g of bis (dimethylaminodimethylsilyl) ethylene obtained according to Tetrahedron letters 1984, 25 (12), 1253-1254 and 0.03 g of zinc iodide. The product to be distilled is; Eb = 105°C at 37 Pa. (b) the compound of EXAMPLE 21 is prepared in the same manner as described for EXAMPLE 20 by chromatographic purification on a silica gel column by eluting with a dichloromethane/ethanol mixture: 99/1 (v/v) F = 133°C.

As in EXAMPLE 18, the following are the preparations of EXAMPLE 22 to 31:

The Commission has not yet adopted a decision. It consists of a mixture of hydrocarbons having carbon numbers predominantly in the range of C1 through C5 and boiling in the range of approximately -15oC to -15oC (-75oF to -15oF).] (I) The following:

R1 = -OH; R2 = H; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-Cl ; Y = H (a) Preparation of 2- (bromo-4-methoxyphenyl) -1,3-dioxolan according to J. Med. Chem. 1990, 33), 972. In a reactor equipped with a Dean-Stark apparatus, a mixture of 5 g of 3-bromo-para-anisaldehyde, 5 ml of ethylene glycol, 0.088 g of para-toluenesulfonic acid and 125 ml of toluene is reflux heated for 1 hour 30 minutes. At room temperature, the reaction mixture is poured over 50 ml of water, extracted with diethyl ether and the organic phase is dried on anhydrous sodium sulphate. The solvents are evaporated under reduced pressure. The reduced oil is obtained by chromatography on a silicone column by operation with a mixture of 8/2th (v/v) para-toluene/acetate. The product is then reduced to the desired level by means of a decantation method; after the previous decantation, the product is removed from the palette at a temperature of 128°C. The pre-treatment is performed at the prescribed temperature of 180°C.

The first is the It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.] (I) The following:

R1 = -OH; R2 = H R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-Cl ; Y = H (a) 3-[5-Chloro-1-(2,4-dimethoxybenzyl) 3-hydroxy-2-oxoindolin-3-yl]-4-methoxybenzaldehydes obtained by deprotection of the compound of EXAMPLE 32 in an acid medium according to J. Chem. Soc. Chem. Common 1987, 1351. The mixture of 0.55 g of the compound of EXAMPLE 32, 5 ml of acetone, 2.5 ml of water and 0.22 ml of 1N hydrochloric acid is brought to 30 °C for 2 hours under stirring. At room temperature, the reaction mixture is neutralized with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate.evaporates the solvents at reduced pressure and obtains the desired compound by filtration of the evaporation residue taken up in diethyl ether; F = 189°C.b) Reductive amination according to J. Org. Chem. 1996, 61(11), 3849-3862. Add 0.113 g of the above compound obtained as a) suspension in 3 ml of 1,2-dichloroethane, 0,015 g of dimethylamine in solution in 1 ml of 1,2-dichloroethane and 0,072 g of sodium triacetatoxyborohydride. After 15 hours agitation at room temperature, hydrolyze with 10 ml of water and extract to ethyl acetate. Dry the organic phase on sodium sulphate, evaporate the solvents under reduced pressure,purifies the residuum obtained by chromatography on a silica gel column by eluting with a dichloromethane/methanol 95/5 (v/v) mixture. The expected product is obtained after crystallization in isopropyl ether; F = 162°C (0.4 H2O).

The Commission has The substance is classified as a substance of very high concern in the Union for the purposes of the definition of the term 'chemical' in Annex I to Regulation (EC) No 1907/2006 of the European Parliament and of the Council.

R1 = -OH; R2 = H; R3 = 4 -OCH3; R4 = 2 -OCH3 The following table shows the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calculation of the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the calc the the the the the calc the calc the the the calc the calc

Add a solution of 0.414 ml of 3-chloropyridine to 5 ml of tetrahydrofuran to a 2.88 ml solution of 1.5M lithium diisopropylamidide in cyclohexane, diluted in 7 ml of tetrahydrofuran and cooled to -75°C, and add a solution of 0.414 ml of 3-chloropyridine to 5 ml of tetrahydrofuran by drip. After addition, stir the reaction mixture at -75°C for 20 minutes and then add 1.2 g of IV.1 to 15 ml of tetrahydrofuran. Slowly raise the temperature of the reaction mixture to 0°C and then hydrolyze with 30 ml of solid solution of chloronium chloride. Extract the mixture from the organic solution of ethyl acetate and sodium sulphate. Then reduce the residual acid to 215°C and use a crystalline solution of cycloacetyl acetate (C/25/C) to obtain a solution of sulphate of chromethyl acetate on a dry crystalline gel.

In the same way the following EXAMPLES 35 and 36 are prepared:

Preparation for the 13th 5-Chloro-3- ((2-chlorophenyl)-1- ((2,4-dimethoxybenzyl) indole-2-one, compound III.1. (iii.1):

R1 = H; R2 = H; R3 = 4-OCH3; R4 = 2-OCH3; X = 5-Cl; Y = H (a) 3,5-Dichloro-3- (dichlorophenyl)-1- (dichlorophenyl)-2--2-one, containing by weight: To a solution of 2 g of the compound in EXAMPLE 30 and 1.4 ml of pyridine in 24 ml of dichloromethane, add 0.98 ml of thionyl chloride at -20 °C. Stir the reaction mixture for 1 hour 30 min at room temperature, cool to 0 °C and then add 50 ml of water and 50 ml of dichloromethane.The resulting residue is dried at reduced pressure for 2 hours and the compound I.'1 is isolated as a resin which is directly used in the next step. (b) Compound III.1A the solution of the previously obtained compound I.'1 in 24 ml of tetrahydrofuran is added at -68°C 6.53 ml of a 1.5 M lithium diisopropylamidide solution in cyclohexane redulsed with 15 ml of tetrahydrofuran. The reaction mixture is agitated for 45 minutes at -68°C, then 5 ml of methanol is added slowly.The resulting residue is purified by chromatography on a silica gel column by eluting with a mixture of cyclohexane/ethyl acetate 85/15 (v/v). The desired product is isolated after crystallization in isopropyl ether; F = 151°C (0,

In the same way, the following compounds III.2 to III.8 are prepared:

The Commission has not yet adopted a decision. The substance is classified as a substance of very high concern for the protection of human health and the environment. (I) The following:

R1 = -CH3; R2 = H; R3 = 4 -OCH3 ; R4 = 2 -OCH3 ; X = 5 -Cl ; Y = H

Add 0,34 g of potassium tert-butylate to a solution of 1,14 g of III.4 in 20 ml of tetrahydrofuran at -40 °C. Shake the reaction mixture at 0 °C for 5 minutes and then add 0,32 ml of methyl iodide at -40 °C. Shake the reaction mixture for 2 hours at room temperature and then add 10 ml of an aqueous solution saturated with ammonium chloride and extracted with ethyl acetate. Dry the organic phase on anhydrous sodium sulphate and evaporate the solvents at reduced pressure. The resulting residue is then crystallised in the diethyl dipropyl ether = 166 °C;

In the same way, the following EXAMPLES 38 to 44 are prepared, possibly by silica chromatography:

The racemic compound in EXAMPLE 41 is chromatographed on a chiral column under the conditions of EXAMPLE 1 by electrolysis with a mixture of 2-methylpentane/2-propano1/90110. [α]20D = +112°(c = 1, ethyl acetate) and its antipodes.

The Commission has not yet adopted a decision. The ethyl ester of the carboxylic acid [5-chloro-3-(2-chlorophenyl)-1-(2,4-dimethoxybenzyl)-2-oxo-indolin-3-yl]. (I)

R1 = -COOCH2CH3 , R2 = H , R3 = 4 -OCH3 ; R4 = 2 -OCH3 ; X = 5 -Cl ; Y = H

At -40°C, 0.26 g of III.1 in 7 ml of tetrahydrofuran is cooled, 0.082 g of potassium tert-butylate is added. The reaction mixture is agitated for 15 minutes at 0°C and then 0.086 ml of ethyl chloroformate is added slowly at -65°C. After 30 minutes of agitation at 20°C, the reaction mixture is hydrolysed with 20 ml of a 5% ammonium chloride solution and extracted to ethyl acetate. The organic phase is dried on sodium sulphate and the evaporated solvents are reduced to air. The product is isolated under low pressure after crystallization in isopropanol F = 112°C (0,3O2Hole).

The Commission has not yet adopted a decision. The phenylic ester of the [5-chloro-3-(2-chlorophenyl)-1-(2,4-dimethoxybenzyl)-2-oxo-indolin-3-yl]carboxylic acid. (I)

R2 = H; R3 = 4 -OCH3 ; R4 = 2 -OCH3 ; X = 5 -Cl ; Y = H

The compound in EXAMPLE 46 is obtained with phenyl chloroformate in the same manner as in EXAMPLE 45; F = 126°C.

The Commission has not yet adopted a decision. The substance is classified in the additive category 'Chemical products'. (I) The following:

R1 = -CH2OH; R2 = H; R3 = 4 -OCH3 ; R4 = 2 -OCH3 ; X = 5 -Cl ; Y = H

At 0°C, 0.3 g of paraformaldehyde is stirred in the reaction mixture and slowly depolymerized by heating. The reaction mixture is stirred for 1 hour at room temperature and then hydrolysed with a 5% aqueous solution of NH4Cl. The organic phase is extracted from ethyl acetate and dried on sodium sulphate. The solvents are evaporated and the remainder is reduced by chromatography under low pressure on a glue of silica by evaporation with a mixture of cyclohexane/acetyl acetate (F/C10/C10 is expected to be obtained in a crystal mixture).

The Commission has not yet adopted a decision. a width of not more than 30 mm, (I) The following:

R1 = -CH3 , R2 = H , R3 = 4 -NH2 , R4 = 2 -OCH3 , X = 5 -Cl , Y = H

At room temperature, filter the reaction mixture on cellite, partially evaporate the solvent at reduced pressure, re-use with ethyl acetate, then treat with an aqueous solution of sodium bicarbonate. Dry the organic phase on anhydrous sodium sulphate, then evaporate the solvents at reduced pressure. Re-use the resulting residue with diisopropyl ether, filter and dry at reduced pressure = 23°C.

The Commission shall adopt the implementing acts referred to in Article 4 (2). The substance is classified in Annex I to Regulation (EC) No 396/2005 as a substance of very high concern. (I) The following:

R1 = -CH3; R2 = H R4 = 2 -OCH3 , X = 5 -Cl , Y = H

At room temperature, the reaction mixture is hydrolysed and extracted to ethyl acetate. The organic phase is washed several times with water, dried on anhydrous sodium sulphate, and then evaporated under reduced pressure. The resulting residue is purified by chromatography on a silica column by treatment with a 95/5v/v cycloxane/ethyl acetate mixture. The chloride is obtained in the diethyl chloride solution (HCl, HCl, HCl) (H2O) = 0.4 °C 198 °C.

In the same way, the following EXAMPLES 50 to 52 are prepared:

The Commission has not yet adopted a decision. The substance is classified as a substance with a specific chemical activity as defined in point 1 of Annex I to Regulation (EC) No 1907/2006 of the European Parliament and of the Council. (I) The following:

R1 = -CH3 ; R2 = H ; R3 = 4 -N(CH3) 2 R4 = 2 -OCH3 , X = 5 -Cl , Y = H

At 238 mg of the compound in EXAMPLE 48 in 4 ml of methanol and 1 ml of dimethylformamide and 100 mg of potassium carbonate, add 150 ml of methyl iodide and then heat the reaction mixture to 45°C for 24 hours. At room temperature, add 10 ml of water and extract with ethyl acetate. Wash the organic phase twice with water, dry on anhydrous sodium sulphate and purify the solvents under reduced pressure and chromatograph the residue on a silica gel column by eluting with a cyclohexane/ethyl acetate mixture for 90/10 (v/v). The resulting residue is obtained in a crystalline solution, filtered for 135 hours and reduced to F = 4°C.

The Commission has not yet adopted a decision. The substance is classified in Annex I to Regulation (EC) No 396/2005 as a substance of very high concern. (I) The following:

R1 = -CH3 , R2 = H R3 = 4-NHCH3 R4 = 2 -OCH3 , X = 5 -Cl , Y = H

The compound in EXAMPLE 54 is prepared in the manner described in EXAMPLE 53; F = 226°C (H2O)

The Commission has not yet adopted a decision. 5-Chloro-3-(2-chlorophenyl)-1- ((4-diisobutylamino-2-methoxybenzyl) 3-methyl indolin-2-one) and its salts (I) The following:

R1 = -CH3 ; R2 = H ; R3 = 4 -N[CH2CH(CH3)2]2 ; R4 = 2 -OCH3 , X = 5 -Cl , Y = H. The solution is then added to the solution.

The reaction mixture is then hydrolysed with 20 ml of water and extracted to ethyl acetate. The organic phase is reduced to dry sodium sulphate anhydrous by steaming the solvents under chromite pressure. The residue is then reduced to a solid solution of chlorite for a few hours by evaporating the solution with a cycloacetate diethyl acetate. The solution is then reduced to a solution of chlorite anhydrous (H3O) at a pressure of 5 °C.

The Commission has not yet adopted a decision. It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.] (I) The following:

R1 = -CH3 ; R2 = H ; R3 = 4 -NH[CH(CH3)2]; R4 = 2-OCH3 , X = 5-Cl , Y = H.

Produced by reducing amination according to J. Org. Chem. 1996, 61(11), 3849-3862. At 0.40 g of the compound of EXAMPLE 48 in 10 ml of 1,2-dichloroethane at room temperature, 0.26 ml of acetic acid, 0.14 ml of acetone and then 0.56 g of sodium triacetetoxyborohydride are added. After 2 hours agitation at room temperature, the reaction mixture is hydrolysed with an aqueous solution of sodium dihydrogen carbonate and extracted with ethyl acetate. The organic phase is washed with water, dried on anhydrous sodium sulphate and evaporated by solvents under pressure. The resulting product is obtained by reducing the residual filtered in the crystalline phase of F = 154 °C.

This racemic compound is then separated by chromatography on a chiral column under the same conditions as in EXAMPLE 1, thus isolating the dextrogyre enantiomer: F = 137°C; [α]20D=+34.6° (c = 1, CH3OH) and its antipod.

The Commission has not yet adopted a decision. The substance is classified as a substance with a specific epithet 'Chloro-3- ((2-chlorophenyl)-1-[4- ((isopropylmethylamino)-2-methoxybenzyl]-3-methylindolin-2-one). (I) The following:

R1 = -CH3; R2 = H R4 = 2 -OCH3 , X = 5 -Cl , Y = H

The compound of EXAMPLE 56 is treated with aqueous formaldehyde and sodium borohydride. The resulting compound is salivated by a solution of hydrochloric acid in diethyl ether. The hydrochloride is thus isolated after filtration and drying at 45°C under reduced pressure; F = 156°C (HCl; 1.5 H2O)

The Commission has not yet adopted a decision. The substance is a mixture of hydrocarbons obtained from the distillation of hydrocarbons. (I) The following:

R1 = -CH3; R2 = H R4 = 2 -OCH3 , X = 5 -Cl , Y = H

0.56 g of caesium carbonate is added to 0.4 g of the compound in EXAMPLE 56 in 10 ml of dimethylformamide and then 0.27 ml of methyl iodide. The reaction mixture is heated by stirring at 40 °C for 48 hours. At room temperature the reaction mixture is treated with 40 ml of water, extracted twice with diethyl ether and then three times with dichloromethane. The organic phases of the chlorinated solvent are dried on sodium anhydrate sulphate and evaporated under reduced pressure. The resulting residue is then filtered with diethyl ether, filtered under reduced pressure and dried at 50 °C;

The Commission has not yet adopted a decision. The following substances are to be classified in the same heading as the active substance: (I) The following:

R1 = -CH3; R2 = H; R4 = 2 -OCH3 , X = 5 -Cl , Y = H

After 30 minutes agitation at room temperature, add 0.265 g of sodium cyanoborohydride and then reflux heat for 10 hours. After cooling, hydrolyze with 20 ml of 2N solder, filter on cellulose and under the solvent with ethyl acetate. After washing with a 10% sodium chloride solution, wash the remaining solution with a solution of sodium chloride and eventually with a solution of dichlorophane on a crystal of chlorophane (H2O/C) and dilute it with a solution of chlorophane chloride (H2O/C) for 50 °C.

The Commission has The following substances are to be classified in the same category as the active substance: (I) The following:

R1 = -CH3 ; R2 = H R3 = 4-N(CH2CH3) 2 R4 = 2 -OCH3 , X = 5 -Cl , Y = H

According to Gordon W. Gribble et al., J. Am. Chem. Soc. 1974, 96(25), 7812.

At 0.5 g of the compound of EXAMPLE 48 in 7 ml of acetic acid, add 0.45 g of sodium borohydride. Heat the reaction mixture to 60°C under stirring for 4 hours, partially evaporate the solvents, hydrolyze the reaction mixture with an aqueous solution of sodium bicarbonate and extract to ethyl acetate. Dry the organic phase on anhydrous sodium sulphate and concentrate under reduced pressure. The oil obtained is treated with a solution of hydrochlorothiric acid in diethyl ether FCl = 198°C (H)

The Commission shall adopt the implementing acts referred to in Article 61. The following substances are to be classified in the same category as the active substance: (I) The following:

R1 = -CH3 ; R2 = H R3 = 4-NH(CH2CH3) R4 = 2 -OCH3 , X = 5 -Cl , Y = H

The compound in EXAMPLE 61 is prepared in the same manner as in EXAMPLE 60; F = 167°C

The Commission has N-{4-[5-Chloro-3-(2-chlorophenyl)-3-methyl-2-oxoindolin-1-yl]-3-methoxyphenyl} acetamide, whether or not chemically defined (I) The following:

R1 = -CH3 ; R2 = H ; R3 = 4 -NH(COCH3); R4 = 2 -OCH3 , X = 5 -Cl , Y = H. The solution is then added to the solution.

At 0.5 g of the compound of EXAMPLE 48 in 10 ml of dichloromethane and 0.5 ml of triethylamine, 0.10 ml of acetyl chloride is added slowly at 0 °C. The reaction mixture is hydrolysed at room temperature, 20 ml of dichloromethane is added, the organic phase is dried on Na2SO4 and the solvents are evaporated under reduced pressure. The resulting residue is purified by chromatography on a silica gel column by eluting with a cyclohexane/ethyl acetate mixture, 50/50 (v/v) F = 83°C.

The Commission has The substance is classified in Annex I to Regulation (EC) No 1907/2006 as a substance of very high concern. (I) The following:

R1 = -CH3 , R2 = H R3 = 4-OCH2CH3 R4 = 2 -OCH3 , X = 5 -Cl , Y = H (a) 5-Chloro-3-(2-chlorophenyl)-1-(4-hydroxy-2-methoxybenzyl)-3-methylindolin-2-one. At 1,14 g of the compound in EXAMPLE 3 in 20 ml of dichloromethane and 1 ml of methylphenyl sulphide, add 3 ml of trifluoroacetic acid at 0°C. After stirring for 2 hours at room temperature, hydrolyze the reaction mixture and extract it to ethyl acetate. Wash the organic phase with an aqueous solution of sodium bicarbonate, dry on sodium anhydrous sulphate and then evaporate the solvents under pressure. The resulting solution is chromatographically evaporated by reducing the gel with a cycloacetate solution; F/ethyl acetate = 200°C.(b) Add 0.23 g of caesium carbonate to 0.2 g of the compound obtained by (a) in 5 ml of dimethylformamide, then 0.112 ml of iodothane at 0 °C. After 1 hour agitation at 28 °C, hydrolyze the reaction mixture and extract to ethyl acetate. Dry the organic phase on anhydrous sodium sulphate and evaporate the solvents at reduced pressure. Take the oil obtained with n-pentane filter and dry the precipitate obtained at 50 °C at reduced pressure for 5 hours; F = 124 °C.

The Commission has The substance is classified in Annex I to Regulation (EC) No 1907/2006 as a substance with a specific epithet. (I) The following:

R1 = -CH2OCH3 , R2 = H , R3 = 4 -OCH3 , and R4 = 2 -OCH3 , X = 5 -Cl , Y = H. The solution is then added to the solution.

To a 70 mg solution of the compound obtained in EXAMPLE 47, in 1 ml of dichloromethane, add at -20 °C 0.1 ml of methyl trifluoromethane sulfonate and then 0.07 ml of 2.6-di-tert-butyl) pyridine, maintain the reaction mixture for one week at + 5 °C. Evaporate the solvent at reduced pressure, add 5 ml of hydrochloric acid 0.1 N and extract to ethyl acetate. Dry the organic phase on anhydrous sodium sulfate and purify the solvent at reduced pressure. The resulting residue is obtained by chromatography on a silica gel by eluting with a cyclohexane/acetate mixture (ethyl acetate 95/5/v) The residue is re-absorbed from the solvent.

Filter and dry the resulting solid for 5 hours at 50°C; F = 125°C (0.4H2O)

The Commission has not yet adopted a decision. 5-Chloro-3-(2-chloro-5-hydroxymethylphenyle)-1-(2,4-dimethoxybenzyl)-3-hydroxyindolin-2-one (I) The following:

R1 = -OH; R2 = H; R3 = 4-OCH3; R4 = 2 -OCH3 , X = 5 -Cl , Y = H

Heat a mixture of 0.307 g of the compound of EXAMPLE 19, 15 ml of methanol and 1 ml of hydrochloric acid 10N at 50 °C for 2 hours. Evaporate the solvent at reduced pressure and take up the residue obtained with dichloromethane and water. Wash the organic phase twice with water and then dry on anhydrous sodium sulphate. Evaporate the solvents at reduced pressure. Isolate the product to be obtained after concreting in cyclohexane, filter and dry at 30 °C at reduced pressure for 6 hours; F = 107 °C.

The number of people who are The following substances are to be classified in the same heading as the active substance: (I) The following:

The following equation is used: X = 5 -Cl; Y = H

Prepared from the compound in EXAMPLE 43 and following the procedure described for EXAMPLE 53, the product to be obtained is isolated after crystallization in isopropyl ether; F = 149°C (0.7 H2O).

The Commission has not yet adopted a decision. 4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl formamide

According to T.L. 1982, 23 (((33), 3315.

(I) The following:

R1 = -CH3 ; R2 = H ; R3 = 4 -OCH3 ; R4 = 2-OCH3 X = 5-Cl; Y = H

At 0,44 ml of acetic anhydride cooled to 0°C, add 0,216 ml of formic acid and then heat the reaction mixture for 1 hour 30 minutes at 58°C. After cooling to 10°C, add 0,8 ml of tetrahydrofuran and then 0,80 g of the EXAMPLE 43 compound in solution in 4 ml of tetrahydrofuran. After 2 hours agitation at 20°C, evaporate the solvents at reduced pressure. Take the residue obtained by n-pentane and filter the product; F = 190°C.

The first is the It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.] (I) The following:

R1 = -CH3 ; R2 = H ; R3 = 4 -OCH3 ; R4 = 2-OCH3 X = 5-Cl; Y = H

Prepared according to T. L. 1982, 23 (((33), 3315.

After 1 hour at 58°C and then cooling to 0°C, add to the reaction mixture 0,2 ml of 10N hydrochloric acid and 1 ml of methanol. Heat at 60°C for 1 hour, cool and evaporate the solvents. Treat the solid residue under reduced pressure with 1 ml of a saturated solution of potassium carbonate extracted from Oxychlorochloroquine acetate. Dry the organic phases on sodium anhydride and evaporate the residues in the form of sodium chloride dioxide (0.5 °C); reduce the colour of the chloride in the form of a chloride chloride gel (HCl) by purifying the solution with a chloride chloride diethyl chloride (1/15 °C).

The first is the 5-Chloro-3-(2-chloro-5-[ethyl(methyl) amino]phenyl}-1-(2,4-dimethoxybenzyl) 3-methylindolin-2-one (I) The following:

R1 = -CH3 ; R2 = H ; R3 = 4 -OCH3 ; R4 = 2-OCH3 X = 5-Cl; Y = H

Produced from the compound in EXAMPLE 68 and in the same operating mode as in EXAMPLE 60; F = 145°C.

The Commission has N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl} acetamide (I) The following:

R1 = -CH3 ; R2 = H ; R3 = 4 -OCH3 ; R4 = 2-OCH3 X = 5-Cl; Y = H

Produced by the same method as the compound in EXAMPLE 62 from the compound in EXAMPLE 43.

In the same way, the following EXAMPLES 71 to 80 are obtained:

The Commission has not yet adopted a decision. N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-3-methoxypropanamide (I) The following:

R1 = -CH3 ; R2 = H ; R3 = 4 -OCH3 ; R4 = 2-OCH3 X = 5-Cl; Y = H

After cooling to 0°C, add 0.23 ml of triethylamine. Stir the reaction mixture at room temperature for 16 hours. Add 40 ml of water and extract with 30 ml of ethyl acetate. Treat the organic phase with 20 ml of an aqueous solution of sodium bicarbonate, under this treatment phase, dry it on sodium anhydrate and decorating the solvents. Reduce the residual chloride in a chromatograph with a crystal cleaning gel of dichlorinated silicon (0,2 H2O).

In the same way the following compounds of EXAMPLES 82 to 86 are obtained:

The Commission has not yet adopted a decision. N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-N-methylacetamide (I)

R1 = -CH3 ; R2 = H ; R3 = 4 -OCH3 ; R4 = 2-OCH3 X = 5-Cl; Y = H

Produced from the compound in EXAMPLE 68 by the same method as in EXAMPLE 62; F = 84°C.

In the same way, the following EXAMPLES 88 to 90 are obtained:

The Commission has not yet adopted a decision. N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl} -2-dimethylamino) -N-methylacetamide (I) The following:

R1 = -CH3 ; R2 = H ; R3 = 4 -OCH3 ; R4 = 2-OCH3 X = 5-Cl; Y = H

According to the Synthesis 1980 method of operation, 547

At 0°C, 0.14 g N,N-dimethylglycine, 0.40 ml triethylamine and 0.34 g N,N-bis[2-oxo-3-oxozalidinyl]phosphorodiamide chloride are added to 0.32 g EXAMPLE 68 in 5 ml dichloromethane. The reaction mixture is stirred for 24 hours at room temperature, 20 ml of an aqueous solution of sodium bicarbonate is added, extracted with 30 ml of ethyl acetate. The organic phase is again washed with 20 ml of an aqueous solution of sodium bicarbonate, then dried on anhydrous sodium sulphate. The evaporated solvents are reduced by chromatography on a gel of chloride; the product is then purified with a crystal of dichloromethane (F/Col = 97°/F).

The Commission has a width of not more than 30 mm, (I) The following:

R1 = -CH3 ; R2 = H ; R3 = 4 -OCH3 ; R4 = 2-OCH3 X = 5-Cl; Y = H

Prepared in the same manner as in EXAMPLE 91 .

The Commission has not yet adopted a decision. N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl) -3-methyl-2-oxoindolin-3-yl]phenyl} urea (I) The following:

R1 = -CH3 ; R2 = H ; R3 = 4 -OCH3 ; R4 = 2-OCH3 X = 5-Cl; Y = Ha) formation of 4-chloro-3-[5-chloro-1-[2,4-dimethoxybenzyl]-3-methyl-2-oxoindolin-3-yl] phenylcarbamate of phenyl After cooling to -5°C, add 0.33 ml of phenyl chlorcarbonate to the reaction mixture. After stirring for 4 hours at room temperature, add 30 ml of water and extract by 50 ml of ethyl acetate. Dry the organic phase on anhydrous sodium sulphate, evaporate the solvents at reduced pressure. The resulting oil is used in the next step. The compound obtained by (a) is taken up by 30 ml of dichloromethane in the presence of 1 ml of liquid ammonia. After 48 hours of stirring at room temperature, the solvent is partially evaporated and the resulting residue is taken up by diethyl ether.

The Commission has N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl) -3-methyl-2-oxoindolin-3-yl]phenyl}-N,N-dimethyl (I) The following:

R1 = -CH3 ; R2 = H ; R3 = 4 -OCH3 ; R4 = 2-OCH3 X = 5-Cl; Y = H

Obtained by the same method of operation as for EXAMPLE 93; F = 182°C (0.4 H2O)

The Commission has not yet adopted a decision. N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl} methanesulfonamide (I) The following:

R1 = -CH3 ; R2 = H ; R3 = 4 -OCH3 ; R4 = 2-OCH3 X = 5-Cl; Y = H

0.3 g of the compound of EXAMPLE 43 in 10 ml of dichloromethane is added to 0.23 ml of triethylamine and then, after cooling to -10°C, 56 μl of methanesulfonyl chloride is added. After 24 hours of stirring at room temperature, 10 ml of an aqueous solution of sodium hydrocarbonate and 30 ml of ethyl acetate is added. The organic phase is isolated, dried on anhydrous sodium sulphate and the solvents are evaporated under reduced pressure. The resulting residue is purified by chromatography on a silicon column by ejecting dichloromethane. The product is obtained after crystallization in n-pentane; F = 210 °C (0,25 O2 H).

The number of employees N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl) -3-methyl-2-oxoindolin-3-yl]phenyl}-N-methylsulfonyl) methanesulfonamide (I) The following:

R1 = -CH3 ; R2 = H ; R3 = 4 -OCH3 ; R4 = 2-OCH3 X = 5-CI: Y = H

Obtained by the process in EXAMPLE 95 using two methanesulfonyl chloride equivalents; F = 159°C

I'm not going to do it. N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-N-methylmethanesulfonamide (I) The following:

R1 = -CH3 ; R2 = H ; R3 = 4 -OCH3 ; R4 = 2-OCH3 X = 5-Cl; Y = H

Obtained by the operation of EXAMPLE 95 from EXAMPLE 68; F = 76°C (0.8 H2O).

The Commission has not yet adopted a decision. N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-N-methylphenylsulfonamide (I) The following:

R1 = -CH3 ; R2 = H ; R3 = 4 -OCH3 ; R4 = 2-OCH3 X = 5-Cl; Y = H

Obtained by the same operation as for EXAMPLE 97; F = 73°C (0.8 H2O).

The Commission has 5-Chloro-3-[2-chloro-5-(4-morpholinyl) phenyle]-1-(2,4-dimethoxybenryl) 3-methyl indolin-2-one (I) The following:

R1 = -CH3 ; R2 = H ; R3 = 4 -OCH3 ; R4 = 2-OCH3 X = 5-Cl; Y = H

Produced by the same method as for EXAMPLE 52 from the compound of EXAMPLE 43; F = 168°C.

The number of employees 3-Chloro-3-[2-chloro-5-(4-methyl-1-piperazinyl) phenyle]1-(2,4-dimethoxybenzyl) 3-methylindolin-2-one (I) The following:

R1 = -CH3 ; R2 = H ; R3 = 4 -OCH3 ; R4 = 2-OCH3 X = 5-Cl; Y = H

Produced by the same method as for EXAMPLE 1 from compound II.9; F = 140°C (2HCl, 0,3H2O)

The Commission has not yet adopted a decision. It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.] (I) The following:

R1 = -CH3 ; R2 = H ; R3 = 4 -OCH3 ; R4 = 2-OCH3 X = 5-Cl; Y = H

At 3,46 g of the racemic compound of EXAMPLE 41 in 300 ml of a solution containing methanol/dioxane (v/v), add 11 ml of a 2N aqueous solution of sodium and let the reaction mixture agitate for 5 hours at 65°C. After cooling to room temperature, partially evaporate the solvents at reduced pressure and extract with ethyl acetate. Acidify the aqueous phase at 10°C with a 1N hydrochloric acid solution and extract the acid with dichloromethane. Dry this last organic phase on anhydrous sodium sulphate and evaporate the solvents at reduced pressure. The desired product is obtained by crystallization of FH isopropyl isopropyl at 186°C.

By chiral chromatography, under the conditions of EXAMPLE 1, by electrolysis with a mixture of 2-methylpentane/2-propanol 90/10 and 0.1% trifluoroacetic acid, the dextrogyre enantiomer [α]20D = +101.8 (C=1, CH3OH) F = 114°C and its antipodes are isolated.

The Commission has not yet adopted a decision. The following substances are to be classified in the same group as the active substance: (I) The following:

R1 = -CH3 ; R2 = H ; R3 = 4 -OCH3 ; R4 = 2-OCH3 X = 5-Cl; Y = H

At 0°C, 0.48 g of the compound of EXAMPLE 101 is added to 10 ml of dimethylformamide, 0.46 g of benzotriazolyl-N-oxytrisdimethylaminophospho nium hexafluorophosphate, 0.20 ml of diethylamine and 0.28 ml of triethylamine. After 15 hours of agitation at 20°C, the reaction mixture is hydrolysed with 70 ml of hydrochloric acid 0,1 N, and extracted with ethyl acetate. The organic phase is treated with 70 ml of an aqueous solution of sodium senohydrogencarbonate and sodium sulphate anhydrous. The solvents are evaporated under pressure. The desired product is obtained by reduction in the crystal; F = 88°C.

The compound of EXAMPLE 102 in racemic form is chromatographically purified on a Daicel ChiralPack® AD column by elution with a 2-methylpentane/propanol-2 90/10 (v/v) mixture, thus isolating the dextrogyre enantiomer F = 86°C; [α]20D = + 100,3° (c = 1 , CH3CO2C2H5), and its antipodes.

In the same way as for the racemic mixture, the amides of TABLE 13 are obtained:

The racemic compound in EXAMPLE 119 is chromatographed on a chiral column under the conditions of EXAMPLE 102 to obtain the dextrogyre enantiomer and its antipod; F = 86°C; [α]20D = + 129° (c = 1, ethyl acetate). The enantiomer dextrogyre and its antipode are obtained from the compound in EXAMPLE 134. F = 174°C (H2O) ; [α]20D = + 107° (c = 1, ethyl acetate).idem from the compound in EXAMPLE 131.

The Commission has not yet adopted a decision. 5-Chloro-3-[2-chloro-5- ((hydroxymethyl) phenyle]-1- ((2,4-dimethoxybenzyl) 3-methylindolin-2-one) (I) The following:

R1 = -CH3 ; R2 = H ; R3 = 4 -OCH3 ; R4 = 2-OCH3 X = 5-Cl; Y = H

At 68°C, add 16.5 ml of disobutylaluminium hydride (DIBAL) solution to 3.3 g of the racemic compound of EXAMPLE 41 in 130 ml of dichloromethane. At 30°C, treat the reaction mixture with 10 ml of methanol and then with an aqueous solution of ammonium chloride and extract with dichloromethane. Filter on cellite, wash the organic phase with water, dry on anhydrous sodium sulphate and evaporate the solvents at reduced pressure. The desired product is obtained after crystallization in a cyclohexane/heptane mixture. F = 97°C.

This product can also be obtained by acidic deprotection of the compound of EXAMPLE 40 under the conditions of EXAMPLE 65.

The Commission has not yet adopted a decision. 5-Chloro-3-[2-chloro-5- ((methoxymethyl) phenyle]-1- ((2,4-dimethoxybenzyl) 3-methylindolin-2-one) (I) The following:

R1 = -CH3 ; R2 = H ; R3 = 4 -OCH3 ; R4 = 2-OCH3 X = 5-Cl; Y = H

At 0.2 g of the compound in EXAMPLE 140 in 2 ml of tetrahydrofuran, 0.08 ml of methyl iodide is added and then at 0 °C 0.02 g of sodium hydride in 60% oil suspension. After 16 hours of stirring at room temperature, the reaction mixture is hydrolysed with 5% aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed with water and dried on anhydrous sodium sulphate. The solvents are evaporated at reduced pressure. The product is obtained after crystallization in n-pentane; F = 122 °C.

In the same way, the following compounds from EXAMPLES 142 to 144 are obtained: - What?

The Commission has not yet adopted a decision. 5-Chloro-3-{2-chloro-5-[[[dimethylamino]methyl]phenyl}-1-[[2,4-dimethoxybenzyl) -3-methylindolin-2-one]] is a substance which is used in the manufacture of foodstuffs for human consumption. (I) The following:

R1 = -CH3 ; R2 = H ; R3 = 4 -OCH3 ; R4 = 2-OCH3 X = 5-Cl; Y = Ha) Preparation of 4-chloro-3-[5-chloro-1-[2,4-dimethoxybenzyl]-3-methyl-2-oxoindolin-3-yl]benzaldehyde After 1 hour of agitation at 10°C, filter on cellite, evaporate the solvents at reduced pressure and purify the residue by chromatography on a silica gel column by eluting with a cyclohexane/ethyl acetate mixture 90/10 (v/v). The product to be obtained crystallizes in pentane; F = 134°C. (b) The compound in EXAMPLE 145 is obtained by reductive amining of the compound obtained by (a) using the operation method in EXAMPLE 33; F = 125°C (0.6H2O).

In the same way the following EXAMPLES 146 to 149 are obtained: - What?

The racemic compound in EXAMPLE 148 is chromatographed on a chiral column under conditions analogous to EXAMPLE 102 to obtain the dextrogyre enantiomer salicylated by hydrochloric acid in ethyl ether and its antipodes; F = 139°C.

The Commission has not yet adopted a decision. N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzyl}-N-methylacetamide (I) The following:

R1 = -CH3 ; R2 = H ; R3 = 4 -OCH3 ; R4 = 2-OCH3 X = 5-Cl; Y = H

Produced by the same operation as the compound in EXAMPLE 62 from EXAMPLE 146; F = 81 °C (0,6 H2O).

The Commission has not yet adopted a decision. 5-Chloro-3-{2-chloro-5-[(2-hydroxyethyoxy)methyl]phenyl}-1-(2,4 dimethoxybenzyl) 3-methylindolin-2-one (I) The following:

R1 = -CH3 ; R2 = H ; R3 = 4 -OCH3 ; R4 = 2-OCH3 X = 5-Cl; Y = H (a) Preparation of 5-chloro-3-[2-chloro-5-[1,3-dioxolan-2-yl]phenyl]-1-[2,4-dimethoxybenzyl]-3-methylindolin-2-one At 2,044 g of the compound prepared in (a) of EXAMPLE 145 in solution in 22 ml of toluene, 1 ml of ethylene glycol and 16 mg of p-toluenesulfonic acid are added. The reaction mixture is heated at reflux for 16 hours in a reactor equipped with a Dean Stark system to remove water from the reaction. After cooling to room temperature, 30 ml of water is added and extracted with ethyl acetate. The organic phase is dried on anhydrous sodium sulphate and the solvents are evaporated under reduced pressure to obtain the product to be used directly in the next step.(b) A 0.29M zinc borohydride solution in diethyl ether (prepared according to the method described in Chem. Pharm. Bull. 1984, 32(4), 1411-1415), and then 1.2 ml trimethylsilane chloride, is added to 2.20 g of the compound prepared in a) in solution in 14 ml of dichloromethane at 6°C. After stirring for 2 hours and 30 minutes at room temperature, the reaction mixture is hydrolyzed with 30 ml of hydrochloric acid 1N and extracted with ethyl acetate. The organic phase is washed with water, sequestered on anhydrous sodium sulphate and the evaporated solvents are reduced under pressure. The remainder is chromatographically purified on a gel of dichloromethane (ethanol/silicon) using a chloride chromatograph.The final product is obtained after crystallization in n-pentane; F = 53°C.

This product can also be obtained by acidic deprotection of the compound of EXAMPLE 143 according to T. L. 1977, 3473 or any other method described in Protective Groups in O. S. by T. W. Green et al. in WILEY-INTERSCIENCE (3rd Edition, 1999).

The Commission has not yet adopted a decision. 5-Chloro-3-(2-chloro-5-{[2-(4-morpholinyl) ethoxy]methyl}phenyl)-1-(2,4-dimethoxy benzyl) 3-methylindolin-2-one (I) The following:

R1 = -CH3 ; R2 = H ; R3 = 4 -OCH3 ; R4 = 2-OCH3 X = 5-Cl; Y = H (a) Preparation of the derivative 5-chloro-3- ((2-chloro-5- ((({2-[4-methylphenyle) sulphonyl) ethoxy} methylphenyle)-1- ((2,4-dimethoxybenzyl) 3-methylindolin-2-one At 0.48 g of the compound of EXAMPLE 151 in 1.5 ml of tetrahydrofuran at 0 °C, add 0.39 ml of triethylamine and then 0.27 g of p-toluenesulfonyl chloride. After 16 hours of stirring at room temperature, hydrolyze the reaction mixture with 10 ml of water and extract with ethyl acetate. Wash the organic phase with an aqueous solution of sodium hydrocarbonate, then with water. Dry the organic phase on anhydrous sodium sulphate and evaporate the solvents at reduced pressure to obtain the desired product in the form of a paste to be used in the next step.(b) 0.75 g of the compound obtained as (a) in solution in 2 ml of acetonitrile, add 0.12 g of sodium carbonate and then 0.20 ml of morpholine. After 2 hours, cool the reaction mixture at room temperature at 75°C, hydrolyze with 20 ml of water and extract with ethyl acetate. Wash the organic phase once more with water, dry on anhydrous sodium sulphate and evaporate the solvents under reduced pressure. Purify the residue by chromatography on a silica gel column by eluting with a 20/80 (v/v) cyclohexane/acetyl acetate mixture. Obtain the desired product after hydrolyzation with diethyl chloride solution in diethyl chloride,evaporation and crystallization of the residue in n-pentane; F = 81°C (0,7 H2O, 1 HCl). As in EXAMPLE 102, the enantiomers of the compound in EXAMPLE 152 are obtained by salivation with fumaric acid in acetone. The fumarates are isolated after evaporation of the acetone and crystallization in diethyl ether: the dextrogyre enantiomer : F = + 112°C; [α]20D = + 76.7 (c = 1 , CH3OH) and its antipodes.

In the manner described for EXAMPLE 18, the following EXAMPLE 158 to 162 compounds are prepared: - What?

The first is the 5-Chloro-3- ((2-chlorophenyl)-1- ((4-hydroxy-2-methoxybenzyl) 3-methylindolin-2-one) and its salts

R1 = -CH3 ; R2 = H ; R3 = 4-OH ; R4 = 2-OCH3 ; X = 5-Cl This compound is already described in (a) of EXAMPLE 63. F is 200 degrees.

The Commission has not yet adopted a decision. The following substances are to be classified in the same group as the active substance:

R1 = -OH ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-Cl ; Y = H (a) 4-chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl) 3-hydroxy-2-oxoindolin-3-yl] benzoic acid, whether or not containing by weight more than 10% of sulphur dioxide or of other alkyl ethers of mercury From the compound in EXAMPLE 20 and under the conditions described in EXAMPLE 101 a solid is isolated and the next step is taken; F = 200°Cb) Treatment of the preceding acid under the conditions of EXAMPLE 102 gives the expected compound; F = 244°C.

The Commission has not yet adopted a decision. 1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl) -3-methyl-2-oxoindolin-3-yl]benzoyl]-4-methoxypipperidine

R1 = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-CI ; Y = H (a) 4-methoxypipperidine: 11 g of 1-tert-butoxycarbonyl-4-hydroxypipperidine prepared according to J. Med. Chem., 1998, 41, 25, 4983-4994, diluted in 400 ml of dichloromethane and 22.2 ml of 2.6-diterbutylpyridine, at -20°C, slowly added 21.8 ml of methyl trifluoromethane sulfonate. After 16 hours at 20°C hydrolyzed with 0.5 N hydrochloric acid and extracted to dichloromethane. The organic phase is isolated on sodium sulfate, evaporated at reduced pressure and purified on a silica column by mixing with a dichloromethane 60/40 ethanol mixture.The resulting oil is then introduced into the next step of de-protection in the presence of 50 ml of a 2M hydrogen chloride solution in ethyl acetate. After two hours at 20°C, evaporate under reduced pressure, crush the residue with ethyl ether, filter the white solid and dry under reduced pressure at about 50°C for three hours. The hydrochloride of the expected compound is obtained; F = 135°C. (b) By treating the dextromer of the compound of EXAMPLE 101 with the anti-dextrogyl described in (a) under conditions analogous to EXAMPLE 102, the expected crystalline product is isolated in the isopropyl ether; F = 92°C; O = 92°C. [α]20D = + 933° (c = 1, ethyl acetate).

The Commission has not yet adopted a decision. 1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl] 4-ethoxypipperidine

R1 = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-CI ; Y = H (a) 4-ethoxypipperidine: In the conditions of EXAMPLE 166 (a), using ethyl trifluoromethane sulphonate, the chlorohydrate of the expected amine is isolated; F = 148°Cb) EXAMPLE 167 is obtained as in EXAMPLE 166 (b), using the above amine; F = 108°C (1 H2O) The test chemical is a chemical that is used to produce a specific chemical.

The Commission has not yet adopted a decision. The following substances are to be classified in the same category as the active substance:

R1 = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-Cl ; Y = H (a) (R)-2- (pyrrolidinocarbonyl)-1- (terbutoxycarbonyl) piperidine From 1-terbutoxycarbonyl- ((R)-2-carboxylic acid piperidine and pyrrolidine, under conditions analogous to EXAMPLE 102, the product to be obtained after purification on a silica column is obtained by eluting with a dichloromethane/methanol 98/2 mixture; F = 105°C.b) (R)-2-pyrrolidinocarbonyl) piperidine, hydrochloride (c) EXAMPLE 168 is obtained with the previous amine and as with EXAMPLE 166 (b) the expected product is obtained crystallized in isopropyl ether; F = 114°C (0.5H2O).

The Commission has not yet adopted a decision. The substance is to be classified in the additive as a substance of heading 2913 or 2913 and in the additive as a substance of heading 2913 or 2913

R1 = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-Cl ; Y = H (a) N,N-dimethyl-1-terbutoxycarbonyl-R)-2-pipéridine carboxamide: Obtained as in EXAMPLE 168 (a); F = 76°Cb) N,N-dimethyl- ((R)-2-pipperidine carboxamide/chrohydrate: (c) EXAMPLE 169 is obtained with the previous amine and as with EXAMPLE 166 (b) the expected product is obtained which crystallizes in the isopropyl ether; F = 123°C (1H2O).

The Commission has not yet adopted a decision. 1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl) -3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-2-(N-methyl-N-2,2,2-trifluoroethylaminocarbonyl) piperidine

R1 = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-Cl ; Y = H (a) N-methyl-N-2,2,2-trifluoroethyl-1-terbutoxycarbonyl-R)-2-pipéridinecarboxamide: (b) EXAMPLE 170 is obtained by deprotecting the amine as in EXAMPLE 169 (b), the hygroscopic hydrochloride obtained is bound with the dextrogyre enantiomer of the compound in EXAMPLE 101 under conditions analogous to EXAMPLE 102. The expected crystallised penta-ane is isolated; The test chemical is a chemical that is used to produce a specific chemical.

The Commission has not yet adopted a decision. 4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-methyl-N-(2,2,2-trifluoroethyl) benzamide

R1 = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-Cl ; Y = H

Obtained by EXAMPLE 166 (b) with the hydrochloride of N-methyl-2,2,2-trifluoroethylamine referred to in EXAMPLE 170 (a); F = 89°C [α]20D = + 83,4° (c = 1, ethyl acetate)

The Commission has not yet adopted a decision. 1-[4-Chloro-3-[5-Chloro-1-(2,4-dimethoxybenzyl) 3-methyl-2-oxoindolin-3-yl]benzoyl]-4-difluoromethylidenepipperidine

R1 = -CH3 R2 = H R3 = 4-OCH3 R4 = 2-OCH3 X = 5-Cl Y = H (a) 4-difluoromethylidene piperidine, chlorhydrate: Obtained by demethylation of the corresponding N-methyl compound, described in Tetrahedron, 1980, 36, 3241, by action of α-chloroethylchloroformate according to J.O.C. 1984, 49, 2081-2082; F = 211,5°C. (b) EXAMPLE 172 is prepared according to EXAMPLE 166 (b) with the amine prepared in (a). The desired product is isolated by crystallization in pentane.

The Commission has not yet adopted a decision. The substance is to be classified in the additive as a substance of heading 2913 or as a substance of heading 2913 or 2913

R1 = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-Cl ; Y = H

Obtained by EXAMPLE 166 (b) with the ethyl (R) -4-methyl- ((R) -2-pipperidine carboxylate described in J. Med. Chem. 37, 1994, 23, 3889-3901. The expected product is isolated crystallized in pentane; F = 106°C.

The Commission has not yet adopted a decision. It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

R1 = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-Cl ; Y = H

Obtained by EXAMPLE 166 (b) with (S)-2-methylpipperidine as described in Tetrahedron Asymetry 8, 1997, 8, 1275-1278.

The Commission has not yet adopted a decision. The substance is to be classified in the additive as a substance of heading 2913 or 2913 and in the additive as a substance of heading 2913 or 2913

R1 = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-Cl ; Y = H

Obtained by EXAMPLE 166 (b) with the ethyl (R)-2-pipéridine carboxylate described in J. Med. Chem. 42, 1999, 22, 4584-4603.

The Commission has not yet adopted a decision. The following substances are to be classified in the same category as the active substance:

R1 = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-Cl ; Y = H (a) (R)-2-pipperidine-carboxylate of tert-butyl: After twenty-four hours of stirring at room temperature, the medium is cooled to -10°C over 150 ml of an aqueous solution of potassium carbonate and then extracted with ethyl acetate. The organic phases are washed with water, distilled on NO2SO4, evaporated to dry. The residue is distilled under reduced pressure. Eb = 46°C at 30 Pa. (b) EXP 176 is obtained from the EXP 166 with a solution of pentamine prepared at 20°C. (c) EXP 166 is prepared in the pentacrystalline.

The Commission has not yet adopted a decision. 4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]N-ethyl-N-(2-dimethylaminoethyl)benzamide, chloride of a strength by weight of less than 0,5%

R1 = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-Cl ; Y = H

Obtained by EXAMPLE 166 (b) with N-ethyl-2-dimethylaminoethylamine described in J.A.C.S., 1963, 2256-2266. The test chemical is a chemical that is used to produce a specific chemical.

The Commission has not yet adopted a decision. 4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-morpholinoethyl) benzamide, whether or not chemically defined

R1 = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-Cl ; Y = H

Obtained according to EXAMPLE 166 (b) with N-ethyl-2-morpholino-ethylamine as described in Chem. Pharm. Bull. 45, 1997, 6, 996-1007.

The Commission has not yet adopted a decision. 4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-[2-(pyridine-4-yl) ethyl]benzamide

R1 = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-Cl ; Y = H

Obtained by EXAMPLE 166 (b) with N-ethyl-2- ((pyridine-4-yl) -ethylamine described in J.A.C.S., 1956, 78, 4441. The hydrochloride of the expected product is isolated in ethyl ether.

The Commission shall adopt the implementing acts referred to in Article 180. 4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2,2,2-trifluoroethyl) benzamide

R1 = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-Cl ; Y = H

Obtained by EXAMPLE 166 (b) with N-ethyl-2,2,2-trifluoroethylamine as described in J.A.C.S. 113, 1991, 4, 1288-1294.

The Commission shall adopt the implementing acts referred to in Article 181. 4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl) -3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-[2-(pyridin-2-yl) ethyl]benzamide, chlorohydrate

R1 = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-Cl ; Y = H

Obtained by EXAMPLE 166 (b) with N-ethyl-2- ((pyridin-2-yl) ethylene described in J.A.C.S., 1955, 5434.

Isolate the hydrochloride of the expected product in ethyl ether.

The Commission shall adopt the implementing acts referred to in Article 182. 4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-pyrrolidinoethyl)benzamide, chloride, whether or not chemically defined

R1 = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-Cl ; Y = H

Obtained by EXAMPLE 166 (b) with N-ethyl-2-pyrrolidinoethylamine described in J. Med. Chem., 35, 1992, 1, 38-47.

The Commission shall adopt the implementing acts referred to in Article 183. 4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-pipéridinoethyl)benzamide, chloride of a strength by weight of less than 0,5%

R1 = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-Cl ; Y = H

Obtained according to EXAMPLE 166 (b) with N-ethyl-2-pipperidinoethylamine as described in Chem. Pharm. Bull., 1997, 45, 6, 996-1007.

Examples 184 to 198

In conditions (b) of EXAMPLE 166 and with commercial amines the following EXAMPLES 184 to 198 are obtained:

The compound of EXAMPLE 199 is obtained by treating the compound of EXAMPLE 191 with a solution of hydrochloric acid in ethyl acetate, isolating the hydrochloride after evaporation of the solvent and taking up the residue by pentane.

The number of employees 4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-pyridylmethyl) benzamide

R1 = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-Cl ; Y = H (a) N-ethyl-2-pyridylmethylamine: After 30 seconds of stirring at 20°C, 25 g of molecular sieve 4 Å is added and kept stirring at 20°C. The insoluble is filtered, then washed thoroughly with dichloromethane, evaporated dry and the residue is re-administered with 50 ml of methanol. To this solution, at 0°C, 1.8 g of sodium borohydride is added. After 16 hours at about 20°C, evaporating under pressure, the residue is re-administered with dichloromethane. The solvent phase is washed with a solution of sodium chloride at about 180°C (0.64oP) and the sodium chloride residue is evaporated at about 180°C (0.80oP) (see Figure 1).

The Commission shall adopt the implementing acts referred to in Article 21 (2). 4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(3-pyridylmethyl) benzamide

R1 = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-Cl ; Y = H (a) N-ethyl-3-pyridylmethylamine: Obtained in the same manner as in EXAMPLE 200 (a) from 3-pyridine carboxaldehyde. Eb. = 77°C at 530 Pab. EXAMPLE 201 is obtained by using EXAMPLE 166 (b) with the amine prepared in a). F = 95.5°C (0.5 H2O).

The Commission shall adopt implementing acts laying down the rules for the application of this Regulation. 4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl) -3-methyl-2-oxoindolin-3-yl]-N-(2-dimethylaminoethyl) -N-(2,2,2-trifluoroethyl) benzamide, chloride

R1 = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-Cl ; Y = H (a) N-dimethylaminoethyl) trifluoroacetamide: At 20°C, add 50 ml of a dilute sodium bicarbonate solution, decant, dry the organic phase on sodium sulphate, evaporate the solvent and distill the residue at reduced pressure. Eb. = 94°C at 1975 Pa.b) N-2,2,2-trifluoroethyl-2-dimethylaminoethylamine: To 2,78 g of lithium aluminium hydride in 50 ml of ethyl ether at 0 °C, the solution of 5 g of amide prepared in (a) is added in 250 ml of ether.After a night of agitation at 22°C, add 20 ml of a saturated aqueous solution of sodium sulphate, filter on the cellulite, wash the cellulite with 100 ml of ether three times, evaporate the collected filtrates partially and then treat with a solution of hydrochloric acid in ethyl acetate. Filter the hydrochloride of the product to be obtained. F = 232.6°C.

The Commission shall adopt implementing acts laying down the rules for the application of this Regulation. 4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl) -3-methyl-2-oxoindolin-3-yl]-N-(3-dimethylaminopropyl) -N-ethylbenzamide, chloride

R1 = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-Cl ; Y = H (a) N-dimethylaminopropyl) acetamide: Obtained in the same manner as in (a) of EXAMPLE 202 with acetic anhydride and 3-dimethylaminopropylamine. Obtained under conditions analogous to (b) of EXAMPLE 202, in tetrahydrofuran at reflux. Eb. = 75°C at 45 Pa.c) EXAMPLE 203 is obtained according to (b) of EXAMPLE 166 with the amine prepared in b) Isolate the hydrochloride by treatment with hydrochloric acid in ethyl ether.

The Commission shall adopt the implementing acts referred to in Article 204. 4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl) -N-ethyl-N-[3-(pyridin-4-yl)propyl]benzamide, chloride of sodium or of potassium chloride, whether or not chemically defined

R1 = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-CI ; Y = H (a) N-ethyl-3- ((pyridine-4-yl) propylamine: From 3- ((pyridin-4-yl) propionaldehyde described in J. Organometallic Chem. 599 2000 298-303 and ethylene hydrochloride, obtained in a manner analogous to (a) of EXAMPLE 200, and after purification on a silica column by eluting with a dichloromethane/methanol 90/10 mixture an oil which is used in the next step. (b) EXAMPLE 204 is obtained according to (b) of EXAMPLE 166 with the amine prepared in (a). The desired product is isolated after purification on a silica column by eluting a dichloromethane/methanol, 97/3, and chlorine hydrochloride in a solution of acetic acid at 207°C.

The Commission shall adopt the implementing acts referred to in Article 205. It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

R1 = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-Cl ; Y = H

After 15 minutes, add 1.9 g of molecular sieve 4 Å. After three hours at 20 °C, filter the insoluble which is washed thoroughly with dichloromethane, evaporate the solvents from the wire under reduced pressure. The resulting oil is re-treated with 4.1 ml of methanol, at 0 °C add 20.1 mg of sodium borohydride. After six hours of agitation at 20 °C, evaporate the residual solvent, reduce the residual solvent to the dichloromethane phase, wash the remaining solvent with a solution of dichloromethane at a temperature of 72 °C, then dilute the solvent with sodium chloride, dilute the solution with a solution of dichloromethane, and wait for the product to be washed in water at 0.5 °C.

The Commission shall adopt the implementing acts referred to in Article 206. It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

R1 = -CH3 ; R2 = H ; R3 = 4-Cl ; R4 = 2-OCH3 ; X = 5-Cl ; Y = H (a) 4-Chloro-3-[5-chloro-1-(4-chforo-2-methoxybenzyl) 3-hydroxy-2-oxo-indolin-3-yl]methyl benzoate: From compound IV.2 and following the procedure described in EXAMPLE 20, the expected product is obtained by chromatography on a silica column by eluting with a mixture of cyclohexane/dichloromethane, 50/50 F = 205°Cb) 4-Chloro-3-[3,5-dichloro-1-(4-chloro-2-methoxybenzyl)-2-oxo-indolin-3-yl]methyl benzoate: Manufactured from a compound described in (a) (c) of Preparation 13 as 4-Chloro-3-[5-chloro-1-(4-chloro-1-(4-chloro-2-methoxybenzyl)-3-H-2-oxo-indolin-3-yl]methyl benzoate;Compound III.9 Obtained by means of (b) of PREPARATION 13 from the compound described in (b); F = 126°C.d) 4-Chloro-3-[5-chloro-1- ((4-chloro-2-methoxybenzyl) -3-methyl-2-oxo-indolin-3-yl]methyl benzoate : Obtained by the method described in EXAMPLE 37 from the compound III.9 ; F = 158°C.e) 4-chloro-3-[5-chloro-1- ((4-chloro-2-methoxybenzyl) -3-methyl-2-oxo-indolin-3-yl]benzoic acid: Produced by the operational mixture described in EXAMPLE 101 from the compound obtained at (d): F = 199°Cf. EXAMPLE 206 is obtained in the same way as for EXAMPLE 112 from the acid obtained at (e); F = 86°C.

The Commission shall adopt the implementing acts referred to in Article 207. It consists predominantly of hydroxybenzene and hydroxybenzoylbenzene

R1 = -CH3 ; R2 = H ; R3 = 4-Cl ; R4 = 2-OCH3 ; X = 5-Cl ; Y = H

Obtained in the same manner as in EXAMPLE 134 from the acid prepared in E) of EXAMPLE 206.

The Commission shall adopt the implementing acts referred to in Article 208. The substance is to be classified in the additive as a substance of heading 2913 or as a substance of heading 2913 or 2913

R1 = -CH3 ; R2 = H ; R3 = 4-Cl ; R4 = 2-OCH3 ; X = 5-Cl ; Y = H

Obtained in the same manner as for EXAMPLE 131 from the acid prepared in E) of EXAMPLE 206.

The Commission shall adopt the implementing acts referred to in Article 209. 4-Chloro-3[5,7-dichloro-1-(2,4-dimethoxybenzyl) -3-methyl-2-oxoindolin-3-yl]methyl benzoate

R1 = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-Cl ; Y = 7-Cl (a) 4-Chloro-3-[5,7-dichloro-1-(2,4-dimethoxybenzyl) 3-hydroxy-2-oxoindolin-3-yl]methyl benzoate: From the compound IV.3 and following the procedure described in EXAMPLE 20, the product obtained is isolated; F = 225°C.b) 4-Chloro-3-[1-(2,4-dimethoxybenzyl)-3,5,7-trichloro-2-oxoindolin-3-yl]methyl benzoate: Preparation of a kind used as a base for the manufacture of foodstuffs of heading 2911 or 2913 Obtained from the product described in (b) of Preparation 13; F = 173°C.

The Commission shall adopt the implementing acts referred to in Article 210. The following substances are to be classified in the same heading as the active substance:

R1 = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-Cl ; Y = 7-Cl (a) 3-Chloro-5-amino-phenylenedichlor-1-5,7-dichlor-1-2,4-dimethoxybenzyl-3-hydroxyindolin-2-one: Prepared from compound IV.3 and by the method described in EXAMPLE 21. F = 124°C.b) 3-(2-Chloro-5-aminophenyl)-1-(2,4-dimethoxybenzyl)-3,5,7-trichloroindolin-2-one: Prepared by a) from the product described in a) 3- (c) 2-Chloro-5-aminophenyl)-1- (d) 2,4-dimethoxybenzyl)-2,7-dichloro-3-H-indolin-2-one; compound III.11: (d) EXAMPLE 210 is obtained by the method described in EXAMPLE 37 from the product; compound III.11: F = 112°C.

The Commission shall adopt the implementing acts referred to in Article 214. It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

R1 = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-Cl ; Y = H

Obtained according to EXAMPLE 166 (b) with 4,4-difluoropiperidine described in Chem. Pharm. Bull., 1993, 41, 11, 1971-1986. The temperature of the water is calculated as follows:

The Commission shall adopt the implementing acts referred to in Article 21 (2). The following substances are to be classified in the same heading as the active substance:

R1 = CH3 ; R2 = H ; R3 = 4-NH[CH(CH3) ((C2H5) ]; R4 = 2-OCH3 ; X = 5-Cl ; Y = H

Produced under conditions similar to EXAMPLE 56.

The Commission shall adopt the implementing acts referred to in Article 213. It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

R1 = CH3 ; R2 = H ; R3 = 4-NHCH2CH(CH3) 2 ; R4 = 2-OCH3 ; X = 5-Cl : Y = H

Produced under conditions similar to EXAMPLE 55.

The Commission shall adopt the implementing acts referred to in Article 214. The following substances are to be classified in the same group as the active substance:

R1 = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = 5-F ; Y = Ha) 4-Chloro-3-[1-(2,4-dimethoxybenzyl) -5-fluoro-3-hydroxy-2-oxoindolin-3-yl]methyl benzoate: From the compound IV.4 and following the procedure described in EXAMPLE 20, the product to be isolated is obtained; F = 188°C.b) 4-Chloro-3-[3-chloro-1-(2,4-dimethoxybenzyl) -5-fluoro-2-oxoindolin-3-yl]methyl benzoate: Obtained by (a) from preparation 13 of the product described in (a) (c) 4-Chloro-3-[1-(2,4-dimethoxybenzyl)-5-fluoro-3-H-2-oxoindolin-3-yl]methyl benzoate; compound III.12: Obtained by (b) from preparation 13 of the compound III.12; F = 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 method of operation in EXAMPLE 37, the methyl ester of the compound is obtained when it is expected to be directly involved in the saponification reaction under the conditions of EXAMPLE 101; F = 89°C:e) The racemic compound of EXAMPLE 214 is obtained under the conditions of EXAMPLE 102; F = 79°C:

The Commission shall adopt the implementing acts referred to in Article 215. It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

R1 = -CH3 ; R2 = H ; R3 = 4-OCH3 ; R4 = 2-OCH3 ; X = H ; Y = H (a) 4-Chloro-3-[1-(2,4-dimethoxybenzyl)-3-hydroxy-2-oxoindolin-3-yl]methyl benzoate: From the compound IV.5 and following the procedure described in EXAMPLE 20, the product to be isolated is obtained; F = 172°C.b) 4-Chloro-3-[3-chloro-1-(2,4-dimethoxybenzyl)-2-oxoindolin-3-yl]methyl benzoate: Manufacture from a) Preparation 13 from the product described in (a) (c) 4-Chloro-3-[1-(2,4-dimethoxybenzyl)-3-H-2-oxoindolin-3-yl]methyl benzoate;Compound III.13: Obtained by (b) preparation 13 from compound III.13; F = 122°C:d) 4-chloro-3-[1-(2,4-dimethoxybenzyl) -3-methyl-2-oxoindolin-3-yl]benzoic acid:From the product described in (c) and according to the method of EXAMPLE 37, the methyl ester of the compound is obtained by directly entering the saponification reaction under the conditions of EXAMPLE 101; F = 103°C.e) The racemic compound of EXAMPLE is obtained under the conditions of EXAMPLE 102; F = 215°C.

Claims (18)

1. Compound in the form of a pure enantiomer or of a mixture of enantiomers of formula: 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-C₅)cycloalkoxy or polyfluoro(C₁-C₄)alkyl group;

   - R₅ represents T₁W in which T₁ represents -(CH₂)_m-, it being possible for m to be equal to 0 or 1, and W 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 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 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 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 -NR₁₀R₁₁ group in which R₁₀ and R₁₁ represent, independently of one another, a hydrogen atom or a (C₁-C₄)alkyl 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; 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 being possible for n to be equal to 1, 2, 3 and 4, and R₁₂ represents a (C₁-C₄)alkoxy or -NR₁₀R₁₁ group, R₁₀ and R₁₁ 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, 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 represerts -(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-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 or else 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 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 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 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 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 OR₁₈ group in which R₁₆ 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 equal to 2 or 3, and R₁₉ is chosen from the hydroxyl, triphenylmethoxy or -NR₂₀R₂₁ groups in which R₂₀ represents a hydrogen atom or a (C₁-C₄)alkyl group and R₂₁ represents a hydrogen atom or a (C₁-C₄)alkyl, tetrahydrofuranylmethyl or tetrahydropyranylmethyl 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 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, (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 (C₁-C₄)alkylamino, a di (C₁-C₄) alkyl amino, a (C₁-C₄)alkoxy, a (C₁-C₄)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;

   - Z₇ represents a fluorine atom, a hydroxyl group, a hydroxy (C₁-C₄) alkyl group, a (C₁-C₄) alkyl, a (C₁-C₄)alkoxy or a (C₁-C₄)alkylcarbonyl;

   - 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, (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 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) :

   - 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 (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 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, 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, morpholin-4-yl or hexahydroazepin-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 solvates and their hydrates.
2. Compounds according to Claim 1 in the form of a pure enantiomer or of a mixture of enantiomers of formula: in which:

   R₀ represents    (i) :

   Z₁, Z₂, R₁, R₂, R₃, R₄, R₅, Y and X being as defined for (I), and their pharmaceutically acceptable salts, their solvates and their hydrates.
3. Compounds according to Claim 2 of formula: 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 salts, their solvates and their hydrates.
4. Compounds according to Claim 3 of formula: in which R₁ represents a methyl or hydroxyl group and 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.
5. Compounds according to Claim 4 of formula: in which R₁ represents a methyl or hydroxyl group and R₀ and R₃ 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.
6. Compounds according to Claim 5 of formula: 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.
7. Compounds according to any one of Claims 1 to 6 in which R₀ represents the group: Z₁, Z₂ and R₅ being as defined for (I).
8. Compound according to Claim 7 in which R₀ represents the group: R₅ being as defined for (I).
9. Compounds according to any one of Claims 1 to 8 in which R₁ represents a methyl group.
10. Compounds according to Claim 1 chosen from:

    5-Chloro-3-(2-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one;

    5-Chloro-3-(2-chlorophenyl)-1-[4-(isopropylamino)-2-methoxybenzyl]-3-methylindolin-2-one;

    N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl)phenyl}acetamide;

    N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-3-methylbutanamide;

    N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}benzamide;

    N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}nicotinamide;

    N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-2-methoxyacetamide;

    Methyl 3-{4-chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl)anilino}-3-oxopropanoate;

    N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-3-methoxypropanamide;

    N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-N-methylacetamide;

    N-(4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-N-methylmethanesulphonamide;

    4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N,N-diethylbenzamide;

    4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N,N-dimethylbenzamide;

    5-Chloro-3-[2-chloro-5-(1-piperidylcarbonyl)phenyl]-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one;

    4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethylbenzamide;

    5-Chloro-3-(2-chloro-5-{[2-(methoxymethyl)-1-pyrrolidinyl]carbonyl}phenyl)-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one;

    5-Chloro-3-{2-chloro-5-[(2-methyl-1-piperidyl)-carbonyl]phenyl}-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one;

    4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-methylbenzamide;

    Methyl 1-{4-chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl)-2-piperidinecarboxylate;

    5-Chloro-3-{2-chloro-5-[(4-hydroxy-1-piperidyl)-carbonyl)phenyl}-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one;

    5-Chloro-3-{2-chloro-5-[(2-methoxyethoxy)methyl]-phenyl}-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one;

    5-Chloro-3-[2-chloro-5-(4-morpholinylmethyl)phenyl]-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one;

    5-Chloro-3-(2-chloro-5-{[2-(4-morpholinyl)ethoxy]-methyl}phenyl)-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one;

    1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-3-hydroxypiperidine;

    1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-3-hydroxypiperidine;

    1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-4-methoxypiperidine;

    1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-4-ethoxypiperidine;

    1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxcindolin-3-yl]benzoyl]-(R,S)-2,6-dimethylpiperidine;

    1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-2-ethoxycarbonylpiperidine;

    1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-2-N,N-dimethylaminocarbonylpiperidine;

    1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-2-(N-methyl-N-2,2,2-trifluoroethylaminocarbonyl)piperidine;

    1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-2-pyrrolidinocarbonylpiperidine;

    1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(S)-2-methylpiperidine;

    4-chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-phenylethyl)benzamide;

    4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(4-pyridylmethyl)-benzamide hydrochloride;

    4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(3-pyridylmethyl)-benzamide;

    4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-pyridylmethyl)-benzamide;

    4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-methoxyethyl)benzamide;

    4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-dimethylaminoethyl)-benzamide hydrochloride;

    4-Chloro-3-(5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-morpholinoethyl)-benzamide;

    4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-pyrrolidinoethyl)-benzamide hydrochloride;

    4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-piperidinoethyl)-benzamide hydrochloride;

    4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-hydroxyethyl)benzamide;

    4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-[2-(pyrid-4-yl)ethyl]-benzamide hydrochloride;

    4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2,2,2-trifluoroethyl)-benzamide;

    4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-methyl-N-(2,2,2-trifluoroethyl)-benzamide;

    4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-isopropylbenzamide;

    4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-(2-dimethylaminoethyl)-N-(2,2,2-trifluoroethyl)benzamide hydrochloride;

    4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-cyclohexylbenzamide;

    4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-[3-(pyrid-4-yl)propyl]-benzamide;

    in the form of a pure enantiomer or of a mixture of enantiomers, and their pharmaceutically acceptable salts, their solvates and their hydrates.
11. Process for the preparation of the compounds of formula (I) according to Claim 1, characterized in that:

    a) a compound of formula:    in which X, Y, R₀ and R₁ are as defined for (I), is reacted in the presence of a base with a halide of formula:    in which Hal represents a halogen atom and R₂, R₃ and R₄ are as defined for (I);

    b) or else, when R₁ represents an electrophilic group, the compound of formula:    in which R₀, 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;

    c) or else, when R₁ = OH, an isatin derivative of formula:    in which R₂, R₃, R₄, X and Y are as defined for (I), is reacted with an organometallic derivative R₀-M or R₀MgHal, R₀ being as defined for (I), M being a metal atom and Hal being a bromine or iodine atom;

    d) or else the compound of formula:

       in which R'₀, R'₁, R'₂, R'₃, R'₄, X' and Y' respectively represent either R₀, R₁, R₂, R₃, R₄, X and Y as defined for (I) or a precursor group for R₀, R₁, R₂, R₃, R₄, X and Y, is subjected to a subsequent treatment to convert any one of the R'₀, R'₁, R'₂, R'₃, R'₄, X' and Y' groups to respectively R₀, R₁, R₂, R₃, R₄, X or Y as defined for (I).
12. Pharmaceutical composition, characterized in that it comprises, as active principle, a compound according to any one of Claims 1 to 10.
13. Pharmaceutical composition according to Claim 12, characterized in that it comprises an antagonist of oxytocin receptors according to any one of Claims 1 to 10 in combination with an antagonist of vasopressin V_1a receptors.
14. Product comprising an antagonist of oxytocin receptors according to any one of Claims 1 to 10 and an antagonist of vasopressin V_1a 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.
15. Use of a compound according to any one of Claims 1 to 10 in the preparation of a medicament intended for the treatment of oxytocin-dependent disorders.
16. Use of a compound according to any one of Claims 1 to 10 in the preparation of a uterine relaxant or tocolytic medicament.
17. Use of a compound according to any one of Claims 1 to 10 in the preparation of medicaments intended to promote cicatrization, to treat analgesia, anxiolysis, depression, schizophrenia, autism or obsessive compulsive syndrome, to improve maternal and social behaviour, to facilitate recognition and acceptance of the mother by the child, to treat memory disorders, to regulate food and drink intake, dependence on drugs, weaning and sexual motivation, to treat disorders of the urogenital sphere in the obstetric and gynaecological fields, to control contractions of the uterus before pregnancy has arrived at term, to control prenatal labour, to treat dysmenorrhoea, to control preparatory labour for the purpose of a caesarean delivery, to solve problems of sterility or fertility, to control births, to control oestrus, the halting of breast feeding, weaning, or the transfer and implantation of embryos, to treat endometriosis, urinary stress or urgency incontinence, benign prostate hypertrophy, erectile dysfunctions, hypertension, hyponatraemia, cardiac insufficiency, atherosclerosis or angiogenesis, to regulate the storage of fat by the adipocyte and to treat breast or prostate cancers.
18. Medicament, characterized in that it comprises a compound according to any one of Claims 1 to 10.