IE912696A1 - N-sulfonylindoline derivatives, their preparation and the pharmaceutical compositions in which they are present - Google Patents

Abstract

Compounds of formula: <IMAGE> in which - R1 denotes a halogen atom, a C1-C4 alkyl or alkoxy, a hydroxyl or a benzyloxy, cyano, trifluoromethyl, nitro or amino group; - R2 denotes a C1-C6 alkyl, a C3-C7 cycloalkyl, a C5-C7 cycloalkene, a phenyl, unsubstituted or mono- or polysubstituted by a C1-C4 alkyl or alkoxy, a halogen or a trifluoromethyl, nitro or amino group; - R3 denotes a hydrogen atom or a C1-C4 alkyl; - R4 denotes a carboxyl group, a C1-C6 alkoxycarbonyl group, a benzyloxycarbonyl group or a carboxamide group of formula CONR6R7; - R5 denotes a C1-C4 alkyl, 1-naphthyl, 2-naphthyl, 5-dimethylamino-1-naphthyl, phenyl, unsubstituted or substituted by one or more substituents chosen from a halogen, a C1-C4 alkyl, a trifluoromethyl, nitro, amino group free or substituted by one or 2 C1-C4 alkyls, a hydroxyl, a C1-C4 alkoxy, a C1-C4 alkenoxy, a C1-C4 alkylthio or a trifluoromethoxy, benzyloxy, cyano, carboxyl, C1-C4 alkoxycarbonyl, carbamoyl or C1-C4 alkylamido group or, when m = 0, R5 may denote a group: <IMAGE> - each of R6 and R7 independently denotes hydrogen, a C1-C6 alkyl, a phenylalkyl in which the alkyl is C1-C4 or R6 and R7 together form a -(CH2)p- group; - n denotes 0, 1 or 2; - m denotes 0, 1 or 2; - p denotes 4, 5 or 6; and their optional salts. These compounds have an affinity for the vasopressin and ocytocin receptors.

Description

The present invention relates to N-sulfonylindoline derivatives, to their preparation and to the compositions in which they are present.

US patent 3 838 167 describes some N-sulfonyl05 indole derivatives of the formula in which - R\ is hydrogen, an alkyl or a substituted or unsubstituted phenyl; - R'2 is a halogen, an alkyl, an alkoxy, a nitro or trifluoromethyl; - R'3 is an alkyl, a phenyl or an alkylphenyl; - R\ is an alkyl, a substituted or unsubstituted phenyl, an alkoxy or a phenoxy; and - n' = 0, 1 or 2.

These compounds 1 are synthesis inter25 mediates for the preparation of indole derivatives active on the central nervous system, said derivatives having the formula (R’2)n N ι H - 2 in which R' is an alkyl, a substituted or unsubstituted phenyl or a hydroxyl.

The N-sulfonylindoline derivatives according to the present invention have an affinity for the vaso05 pressin and ocytocin receptors.

Vasopressin is a hormone known for its antidiuretic effect and its effect in the regulation of the arterial pressure. It stimulates several types of receptors - Vx, V2, VXw, Vxto - and thus exerts cardio10 vascular, central, hepatic, antidiuretic and aggregating effects. Vasopressin receptor antagonists can affect the regulation of the central and peripheral circulation, especially the coronary, renal and gastric circulation, as well as the metabolism of water and the release of adrenocorticotrophic hormone (ACTH). The vasopressin receptors, like the ocytocin receptors, are also found on the smooth muscle of the uterus. Ocytocin has a peptide structure similar to that of vasopressin. Its receptors are also found on the myoepithelial cells of the mammary gland and in the central nervous system (Presse Mddicale, 1987, 16(10). 481-485, J. Lab. Clin. Med., 1989, 111(6), 617-632, and Pharmacol. Rev., 1991, 11(1), 73-108).

Thus the compounds according to the invention are useful especially in the treatment of complaints of the central nervous system, the cardiovascular system and the gastric sphere in humans and animals.

The present invention relates to compounds of the formula -β- ίο in which - Rx is a halogen atom, a Cx-C4 alkyl, a hydroxyl, a CX-CA alkoxy, a benzyloxy group, a cyano group, a trifluoromethyl group, a nitro group or an amino group; - Ra is a Cx-Ce alkyl, a C3-C7 cycloalkyl, a Cs-C7 cycloalkene or a phenyl which is unsubstituted or monosubstituted or polysubstituted by a Cx-C4 alkyl, a Cx-C4 alkoxy, a halogen, a trifluoromethyl group, a nitro group or an amino group; - R, is a hydrogen atom or a Cx-C4 alkyl; - R4 is a carboxyl group, an alkoxycarbonyl group in which the alkyl group is Cx-Ce, a benzyloxycarbonyl group or a carboxamide group of the formula CONReRv; - Rs is a Cx-C4 alkyl, a 1-naphthyl, a 2-naphthyl, a δ2 5 dimethylamino-l-naphthyl or a phenyl which is unsubstituted or substituted by one or more substituents selected from a halogen atom, a Cx-C4 alkyl, a trifluoromethyl group, a nitro group, an amino group which is free or substituted by one or 2 CX-CA alkyls, a hydroxyl, a CX-CA alkoxy, a Cx-C\ alkenoxy, a Cx-C4 alkylthio, a trifluoromethoxy group, a benzyloxy group, a cyano group, a carboxyl group, a CxC4 alkoxycarbonyl group, a carbamoyl group or a Cx-C4 alkylamido group, or, when m = 0, Rs can be a group CHa - Re and Rv are each independently hydrogen, a Cx-C& alkyl or a phenylalkyl in which the alkyl is Cx-C^, or Re and Rv together form a group - n is 0, 1 or 2; - m is 0, 1 or 2; and - p is 4, 5 or 6; and their salts, where appropriate.

The compounds (I) exhibit cis-trans isomerism around the 2,3 bond of the indoline. The different isomers form an integral part of the invention.

By convention, the compounds (I) in which and R4 are on the same side of the ring are called the cis isomers • By convention, the compounds (I) in which r2 and R4 are on opposite sides of the ring are called the trans isomers.

I R5 cis isomer »5 trans isomer io Moreover, the compounds according to the invention have 2 asymmetric carbon atoms. The optical isomers of the compounds (I) form part of the invention.

In the present description and in the claims 15 which follow, halogen is understood as meaning a fluorine, chlorine, bromine or iodine atom; alkyl group is understood as meaning linear or branched hydrocarbon groups.

Preferred compounds (I) according to the inven20 tion are those in which at least one of the following conditions is satisfied: - Rx is a chlorine or bromine atom or a methoxy group and n = 0; - Ra is a chlorophenyl, a methoxyphenyl or a cyclo25 hexyl; - R3 is hydrogen; - R4 is an alkoxycarbonyl in which the alkyl group is Cx-Ce, or Ra is a carboxamide group NReR7 in which Re and R7 are Cx-Ce alkyls; - Rs is a phenyl substituted in the 3 and 4 positions or in the 2 and 4 positions by a methoxy group, or Rs is a phenyl substituted in the 4 position by a methyl group; and - m is 0.

The compounds (I) which are in the form of the - 6 cis isomers are particularly preferred.

The following abbreviations are used in the description and the Examples; DCM : dichloromethane AcOEt ; ethyl acetate MeOH ; methanol EtOH ; ethanol ether : ethyl ether DMF : dimethylformamide THF : tetrahydrofuran DMSO ; dimethyl sulfoxide DIPEA : diisopropylethylamine DBU : 1,8-diazabicyclo[5.4.0]undec-7-ene TBD : 1,5,7-triazabicyclo[4.4.0]dec-5-ene DBN : l,5-diazabicyclo[4.3.0]non-5-ene DMAP ; 4-dimethylaminopyridine DMPU ; 1,3-dimethyl-2-oxohexahydropyrimidinone TMEDA : tetramethylethylenediamine LDA ; lithium diisopropylamide HMPA : hexamethylphosphoramide HMDS : 1,1,1,3,3,3-hexamethyldisilazane BOP : benzotriazolyloxytrisdimethylarainophosphonium hexafluorophosphate M.p. : melting point saline solution : water saturated with sodium chloride dry ice : solid carbon dioxide TLC ; thin layer chromatography HPLC : high pressure liquid chromatography NMR : nuclear magnetic resonance s : singlet m : multiplet sb : broad singlet d : doublet hydrochloric water ; dilute hydrochloric acid, - 7 about 1 N 80% NaH : dispersion of sodium hydride in mineral oil (Janssen Chemica) Me : methyl Et : ethyl Ph : phenyl RT : room temperature The present invention further relates to the method of preparing the compounds (I).

This method comprises a) reacting a sulfonyl derivative of the formula Hal-SO2-(CHa)in-RB (III) in which Hal is a halogen, preferably chlorine or bromine, and RB is as defined above for (I), with a 2aminophenone derivative of the formula in which Rx, Ra and n are as defined above for (I); b) treating the resulting compound of the formula (Rl) (IV) - 8 with a halogenated derivative of the formula Hal' - CFi - R3 (V) in which Hal' is a halogen, preferably bromine, and R3 and R4 are as defined above for (I); c) cyclizing the resulting compound of the formula in a basic medium in order to prepare the compound (I) according to the invention; and d) separating the cis and trans isomers of the compound (I), if appropriate.

The 2-aminophenone derivatives (II) are known or prepared by known methods such as those described by A.K. Singh et al., Synth. Commun., 1986, 1£(4), 485, and G.N. Walker, J. Org. Chem., 1962, 22, 1929.

The halogenosulfonyl derivatives (III) are known or prepared by known methods. Thus, for example, 4-dimethylaminophenylsulfonyl chloride is prepared according to C.N. SUKENIK et al., J. Amer. Chem. Soc., 1977, 99. 851-858; p-benzyloxysulfonyl chloride is prepared according to European patent application 229 566.

An alkoxysulfonyl chloride is prepared from a sodium alkoxysulfonate, which is itself prepared by reacting an alkyl halide with sodium hydroxyphenylsul35 fonate. The 2-amino-2-trifluoromethylbenzophenones and the other trifluoromethylated derivatives are prepared according to US patent 3 341 592. 2,4—Dimethoxybenzylsulfonyl chloride is prepared according to J. Am. Chem. Soc., 1952, 74. 2008.

The halogenated derivatives (V) are known or prepared by known methods such as those described by A.I. Vogel: A Text Book of Practical Organic Chemistry: Longman, 3rd ed. 1956, p. 383, or G. Kirchner et al., J. Am. Chem. Soc., 1985, 107, 24 . 7072.

Step a) of the method is carried out in pyridine by heating at a temperature between room temperature and the boiling point of the solvent for a period of time of between a few hours and a few days. If appropriate, the reaction can be carried out in the presence of dimethylaminopyridine, which is used in a catalytic or stoichiometric amount.

Step b) of the method is carried out between the sulfonamide (IV) and an excess of the halogenated derivative in a solvent such as dimethylformamide or dimethyl sulfoxide, under an inert atmosphere, at a temperature of between 0’C and room temperature, for a time of between a few hours and 24 hours, in the presence of sodium hydride.

Step c) of the method is closely related to an aldolization reaction: The group CH-R3 in the a position of the ester or the amide is deprotonated and the carbonyl group of the phenone then acts like an internal electrophile, resulting in cyclization with the appearance of two asymmetric carbons (C*).

The reaction can be illustrated by the following scheme: - 10 05 π base -> (solvent) I RS The principles of the aldol addition reaction have been reviewed by C.H. Heathcock in Asymmetric Synthesis, vol. 3: Stereodifferentiating addition reac20 tions, part B, 111-212, Academic Press, 1984, edited by J.D. Morrison.

It is known that the aldol addition of achiral ester anions (or amide anions) on to achiral bases gives rise to the formation of 2 racemic diastereoiso25 mers of 0-hydroxyesters (or 0-hydroxyamides) in a ratio which depends largely on the experimental conditions used. The following may be mentioned among these conditions: the nature of the inorganic or organic base used, the nature of the cations or counterions, the possible presence of additives in the reaction medium, the solvent, the reaction temperature and the structure of the compound undergoing this reaction.

If R4 is a carboxamide group C0NReR_,, in which r6 and R7 are as defined above for (I), it is possible to use sodium hydroxide in water, in the presence of a - 11 cosolvent, with or without the addition of a phase transfer catalyst.

This reaction can be carried out using organic bases, for example: - tertiary organic bases such as triethylamine, - guanidines such as l,5,7-triazabicyclo[4.4.0]dec-5ene, or - amidines such as l,8-diazabicyclo[5.4.0]undec-5-ene or 1,5-diazabicyclo[4.3.0 Jnon-5-ene, in a solvent or a mixture of solvents selected for example from benzene, THF, dichloromethane, methanol and dimethylformamide; the reaction is carried out under an inert atmosphere at between 25 and 110 °C; the amount of base used is at least stoichiometric; the reaction can also be carried out without a solvent, at the temperature of the bath.

It is also possible to use an alcoholate of a primary, secondary or tertiary alcohol with lithium, sodium, potassium, calcium or magnesium.

The alcoholate is used in a catalytic or stoichiometric amount in an anhydrous solvent, for example an alcohol (if appropriate in the presence of a cosolvent such as THF), or else in a stoichiometric amount in THF, DMF or DMSO, if appropriate in the presence of crown ethers, for example dicyclohexyl-18 crown-6; the reaction is carried out at between 0‘ and 80 *C. It is also possible to use a base such as sodium hydride, lithium hydride or potassium hydride, in a solvent such as, for example, ethyl ether, THF, benzene or DMF, or else alkali metal amides in a solvent such as aqueous ammonia, ether or toluene, at a temperature of between -30°C and 110*C.

The use of an amide of the type RR'NLi or RR'NMgBr, in which R and R' are monovalent radicals, as a deprotonating agent is a method of forming enolates - 12 of esters or amides, which are intermediates in the aldolization reaction? this method has recently been reviewed by R.E. Ireland et al., J. Org. Chem., 1991, 56, 650. The reaction solvent can be benzene, hexane or THF used in anhydrous form under an inert atmosphere. Adjuvants such as LiF, LiCl, LiBr, Lil, LiBu, TMEDA, DMPU, HMPA or a crown ether can be added (M. Murakate et al., J. Chem. Soc. Chem. Commun., 1990, 1657). The influence of the reaction conditions on the proportion of each of the isomers formed has been studied. By way of example, there may be mentioned the use of lithium diisopropylamide at -78°C in anhydrous THF under an inert atmosphere, or in THF in the presence of additives such as, for example, tetramethy15 lenediamine, DMPU or HMPA. Examples of other known amides which can be used are lithium cyclohexylamide and lithium 2,2,6,6-tetramethylcyclohexylamide. It is also possible to prepare other amides by reacting the requisite amount of butyllithium in hexane with linear or cyclic secondary amines, the reaction taking place in one of the solvents mentioned above. Finally, various publications describe amides of optically active secondary amines: L. Duhamel et al., Bull. Soc. Chim. France, 1984, II, 421; J.K. Whitesell et al., J.

Org. Chem., 1980, 45, 755; M. Murakata et al., J. Chem. Soc. Chem. Comm., 1990, 1657; M. Yamaguchi, Tetrahedron Lett., 1986, 22(8), 959; P.J. Cox and N.S. Simpkins, Tetrahedron: Asymmetry, 1991, 2(1)/ 1.

The silylamides of lithium, sodium or potassium constitute another group of bases which can be used, among which there may be mentioned (Me3Si)2NLi, (Me2PhSi)2NLi, (Et3Li)2NLi, (Me3Si)2NK and (Me3Si)2NNa.

It is also possible to use mixed amides such as those described by Y. Yamamoto, Tetrahedron, 1990, 46, 4563, for example the lithium salt of N-(trimethylIE 912696 - 13 silyl)benzylamine or an analog in which the benzylamine is replaced with a chiral primary amine such as (R)- or (S)-β-methylbenzylamine.

When chiral amides are used, the 2 diastereo05 isomers, cis and trans, can together or independently of one another exhibit an optical activity created by asymmetric induction and enantiomeric enrichment. The proportion of each of the enantiomers is then determined on a chiral HPLC column.

In step d), the 2 isomers of the compound (I) formed are extracted by the conventional methods and separated by chromatography or fractional crystallization.

If appropriate, the optical isomers of each of the cis and trans isomers are separated, for example by preparative chromatography on a chiral column.

If the 2 isomers of the compounds (I) are difficult to separate by the customary methods, it is also possible to prepare a compound of the formula in which Rx, Ra, R3, R4, Re, ra and n are as defined 30 above for (I), by reacting hexamethyldisilazane with the corresponding compound (I). The reaction is carried out in the presence of a catalytic amount of imidazole by heating to 60-120*C under an inert atmosphere. The silyl ester is obtained by crystallization from the medium or after chromatography. The 2 isomers - 14 of (VII) are separated by chromatography on silica and each isomer of (VII) is then hydrolyzed in an alkaline medium to give each isomer of (I).

Several methods can be used to differentiate and characterize the cis isomer and the trans isomer of a compound (I). If R3 is hydrogen, a comparative analysis is performed by high field NMR (at 250 MHz) coupled for example with a study of the Overhauser effect (NOE) between, for example, the proton of the indoline (R3 = H) and the proton of the hydroxyl.

If R4 is a carboxamide group, the IR spectra of the cis isomer and the trans isomer in solution in DCM are different. The cis isomer most commonly has a strong, fine and symmetrical absorption band at around 3550-3520 cm-1, due to the hydroxyl vibration, whereas the trans isomer has no resolved vibration band in this region.

By means of the data collected, it has been found that the cis isomer is generally the more mobile in TLC on an aluminum oxide plate (60F254 neutral, type E, Merck), the eluent being DCM containing variable proportions of AcOEt. Similarly, in chromatography on an alumina column (aluminum oxide 90, particle size 0.063-0.200 mm), the cis isomer is most commonly eluted first, the eluent being DCM containing variable proportions of AcOEt or MeOH.

If Ra is an ester group, it is possible to carry out the TLC on a silica plate (Kieselgel 60F250, Merck) using DCM as the eluent; when the TLC is carried out on a mixture of the isomers, the cis isomer is generally the more mobile.

Thus the cis or trans isomerism of a compound (I) according to the invention can most often be determined by an analytical method. It is also posIE 912696 - 15 sible to utilize the analogy between similar compounds or between compounds prepared from one another.

The compounds (I) in which R4 is a carboxyl group are prepared by debenzylation of the compounds (I) in which R4 is a benzyloxycarbonyl group by means of catalytic hydrogenation, for example in the presence of palladium-on-charcoal.

The compounds (I) in which Rd is a carboxamide group, CONHa, can be prepared from the corresponding compounds (I) in which RA is a carboxyl group, for example by a conventional coupling method used in peptide synthesis, for example in the presence of BOP and DIPEA.

A compound (I) in which Rx is an amino group and/or a compound in which Rs is a phenyl group which is substituted by an amino can be prepared by the conversion of a compound (VI), obtained in step b), in which Rx is a nitro group and/or Rs is a phenyl group substituted by a nitro, the other substi20 tuents having the meanings desired for (I), by means of catalytic hydrogenation, for example in the presence of palladium-on-charcoal or rhodium-on-alumina.

The compounds of formula (VI) obtained at the end of step b) are novel and form part of the invention.

The affinity of the compounds according to the invention for the vasopressin receptors was determined in vitro using the method described in J. Biol. Chem., 1985, 260(5). 2844-2851. This method consists in studying the displacement of tritiated vasopressin bound to the Vx sites of rat liver membranes. The 50% inhibitory concentrations (ICSO) of the compounds according to the invention for the binding of tritiated vasopressin are low and range up to nanomolar.

Likewise, the affinity of the compounds (I) according to the invention for the ocytocin receptors - 16 was determined in vitro by the displacement of tritiated ocytocin bound to the receptors of a membrane preparation of gestating rat glands. The ICSO values of the compounds according to the invention are low and range up to io-7 M.

Furthermore, the inhibition of the platelet aggregation induced by vasopressin was measured on a human platelet rich plasma (human PRP) using the method described in Thrombosis Res., 1987, 45. 7-16. The com10 pounds according to the invention inhibit the aggregation induced by 50 to 100 nM vasopressin with low IDSO values (inhibitory doses) which range up to 10-® M. These results show the antagonistic activity of the compounds according to the invention towards the Vx receptors.

The affinity of the compounds (I) according to the invention for the Va receptors was measured by a method adapted from P. Crause et al., Molecular and Cellular Endocrinology, 1982, 28. 529-541.

The compounds according to the invention are active after administration by various routes, especially orally.

No sign of toxicity is observed with these compounds at the pharmacologically active doses.

Thus the compounds according to the invention can be used in the treatment or prevention of various vasopressin-dependent complaints, especially cardiovascular complaints such as hypertension, cardiac insufficiency or coronary vasospasm, in particular in smokers; complaints of the central nervous system, for example cerebral edemas, psychotic states or memory disorders; complaints of the renal system, such as renal vasospasm or necrosis of the renal cortex; and complaints of the gastric system, for example ulcers or the syndrome of inappropriate secretion of antidiuretic - 17 05 hormone (SIADH). In women, the compounds according to the invention can also be used for the treatment of dysmenorrhea or premature labor.

The present invention further relates to pharmaceutical compositions containing an effective dose of a compound according to the invention, or of a pharmaceutically acceptable salt, and suitable excipients. Said excipients are chosen according to the pharmaceutical form and the desired mode of administration.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration, the active principles of formula (I) above, or their salts if appropriate, can be administered to animals and humans in unit forms of administration, mixed with conventional pharmaceutical carriers, for the prophylaxis or treatment of the above disorders or diseases. Appropriate unit forms of administration include forms for oral administration, such as tablets, gelatin capsules, powders, granules and solutions or suspensions to be taken orally, forms for sublingual, buccal, intratracheal or intranasal administration, forms for subcutaneous, intramuscular or intravenous administration and forms for rectal administration. For topical application, the compounds according to the invention can be used in creams, ointments or lotions.

To obtain the desired prophylactic or therapeutic effect, the dose of active principle can vary between 0.01 and 50 mg per kg of body weight and per day.

Each unit dose can contain from 0.5 to 1000 mg, preferably from 1 to 500 mg, of active ingredients in combination with a pharmaceutical carrier. This unit dose can be administered 1 to 5 times a day so as to - 18 administer a daily dosage of 0.5 to 5000 mg, preferably 1 to 2500 mg.

If a solid composition in the form of tablets is prepared, the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose, a cellulose derivative or other appropriate substances or they can be treated so as to have a prolonged or delayed acti10 vity and so as to release a predetermined amount of active principle continuously.

A preparation in the form of gelatin capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.

A preparation in the form of a syrup or elixir or for administration in the form of drops can contain the active ingredient in combination with a sweetener, which is preferably calorie-free, and methylparaben and propylparaben as antiseptics, as well as with a flavoring and an appropriate color.

Water-dispersible granules or powders can contain the active ingredient mixed with dispersants or wetting agents or with suspending agents such as polyvinylpyrrolidone, as well as with sweeteners or taste correctors.

Rectal administration is effected using suppositories which are prepared with binders melting at the rectal temperature, for example cacao butter or poly30 ethylene glycols.

Parenteral administration is effected using aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersants and/or wetting agents, for example propylene glycol or butylene - 19 ~ glycol.

The active principle can also be formulated as microcapsules, if appropriate with one or more carriers or additives.

Apart from the products of formula (I) above or one of the pharmaceutically acceptable salts, the compositions of the present invention can contain other active principles which may be useful in the treatment of the disorders or diseases indicated above.

Thus the present invention relates to pharmaceutical compositions containing several active principles in association, one of which is a compound according to the invention.

EXAMPLES 1 AND 2 Methyl 5-chloro-3-cyclohexy1-3-hydroxy-1(naphthyl-l-sulfonyl)indoline-2-carboxylate, cis isomer, trans isomer A) 5-Chloro-2-[(naphthyl-l-sulfony1)amino]cyclohexyl20 phenone A mixture containing 3 g of 2-amino-5-chlorocyclohexylphenone and 3.2 g of naphthyl-l-sulfonyl chloride is heated in pyridine at 100'c for 8 hours. The pyridine is evaporated off, water is added, the mixture is extracted with ethyl acetate and the extract is then filtered on silica using dichloromethane as the eluent to give 4.27 g of the expected product.

After recrystallization from a DCM/isopropyl ether mixture, m.p. = 140-142’C.

B) 5-Chloro-2-[N-(methoxycarbonylmethyl)-N-(naphthyl-lsulf onyl ) amino]cyclohexylphenone 4.27 g of the product obtained in the previous step are dissolved in 20 ml of anhydrous DMF under argon. 320 mg of 80% sodium hydride are added at O’C, after 20 minutes 6.1 g of ethyl bromoacetate are then - 20 added over 30 minutes and the mixture is stirred for 3 hours at room temperature. After extraction, the crude product obtained is recrystallized from a DCM/isopropyl ether mixture to give 2.45 g of the expected compound.

M.p. = 130-132’C C) Methyl 5-chloro-3-cyclohexyl-3-hydroxy-l-(naphthyl1-sulfonyl)indoline-2-carboxylate 2.4 g of the compound obtained in the previous step are suspended in 30 ml of methanol under a nitro10 gen atmosphere, 26 mg of sodium methylate are added at O’C, after 10 minutes at room temperature a further 26 mg of sodium methylate are added and, finally, after 45 min, 1 ml of THF is added in order to achieve total dissolution. Then, after 1 hour, a precipitate is formed by the addition of dry ice and water. The precipitate is filtered off, taken up with ethyl acetate, washed with water and an aqueous solution of sodium chloride and dried. The oil obtained is chromatographed on silica, the eluents being DCM and then DCM containing up to 10% of AcOEt; the 2 isomers are separated in this way.

The compounds contained in each of the fractions are then recrystallized from a DCM/isopropyl ether mixture.

M.p. = 155-157eC: cis isomer M.p. = 141-142°C: trans isomer EXAMPLES 3 AND 4 Methyl 5-chloro-3-(2-fluorophenyl)-3-hydroxy-l30 (4-nitrophenylsulfonyl)indoline-2-carboxylate, cis isomer, trans isomer A) 5-Chloro-2'-fluoro-2-[ (4-nitrophenylsulfonyl)amino]benzophenone A mixture containing 24.9 g of 2-amino-535 chloro-2'-fluorobenzophenone and 22.1 g of 4-nitroIE 912696 - 21 phenylsulfonyl chloride is refluxed for 10 hours in pyridine. It is evaporated to dryness, water and ethyl acetate are then added and the ethyl acetate phase is washed with water and an aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated under vacuum. The expected product precipitates on evaporation; it is filtered off and recrystallized from a DCM/isopropyl ether mixture to give 20 g.

M.p. = 155°C B) 5-Chloro-2'-fluoro-2-[N-(methoxycarbonylmethyl )-N(4-nitrophenylsulfonyl)amino]benzophenone g of the compound obtained in the previous step are dissolved in 20 ml of DMF at 0°C under argon, 367 mg of 80% sodium hydride are added, 3.5 g of methyl bromoacetate are added after 5 minutes and a further 3.5 g of methyl bromoacetate are added after 1 hour. After 5 hours at room temperature, the reaction mixture is poured into iced water and then extracted 3 times with ethyl acetate and the extract is washed 3 times with water and an aqueous solution of sodium chloride and then dried over magnesium sulfate. The product is chromatographed on silica gel using DCM as the eluent to give 6.1 g of the expected compound, which solidifies in methanol.

C) 3 g of the compound obtained in the previous step are suspended in 50 ml of methanol and cooled in an ice bath. 330 mg (0.1 equivalent) of sodium methylate are added and the mixture is stirred for 60 minutes, the temperature being allowed to rise to 10°C. Dry ice and then water are added, the mixture is extracted 3 times with ethyl acetate and the extract is then washed with water and an aqueous solution of sodium chloride, dried and evaporated under vacuum. The crude reaction product (6.1 g) is chromatographed on a silica column prepared in DCM. - 22 The 2 isomers are eluted successively with DCM.

The less polar isomer is the cis isomer.

After recrystallization from a DCM/isopropyl ether mixture, m.p. = 219-220eC.

The more polar isomer is the trans isomer.

After recrystallization from a DCM/methanol mixture, m.p. = 203-204°C.

EXAMPLES 5 AND 6 Methyl l-(4-aminophenylsulfonyl)-5-chloro-3-(2fluorophenyl)-3-hydroxyindoline-2-carboxylate, trans isomer, cis isomer A) 5-Chloro-2'-f luoro-2-[N-(methoxycarbony Imethyl )-N(4-aminophenylsulfonyl)amino]benzophenone The 5-chloro-2'-fluoro-2-[N- (methoxycarbony 1methyl)-N-(4-nitrophenylsulfonyl)amino]benzophenone prepared in Example 2, step b, is dissolved in 100 ml of ethyl acetate and 5 ml of methanol and hydrogenated at ordinary pressure for 2 hours in the presence of 620 mg of 10% palladium-on-charcoal; the existence of 3 compounds (starting material, intermediate and expected product) is observed in TLC. The catalyst is filtered off, the solvent is evaporated off and the residue is chromatographed on silica gel. The expected compound is eluted with DCM containing 1% of methanol. After recrystallization from DCM/isopropyl ether, m.p. = 168170’C.

B) Trans isomer 3.4 g of the compound obtained in the previous step are dissolved in 20 ml of methanol and 20 ml of THF at o’c under nitrogen and 190 mg of sodium methylate are added. After 60 minutes at 5*C, with stirring, the reaction medium is poured into water and extracted with ethyl acetate. A compound crystallizes and is recrystallized from DCM containing a small - 23 amount of methanol.

M.p. = 215-216°C.

This is the trans compound according to a study of the NMR spectrum with NOE.

C) Cis isomer 200 mg of the compound prepared in Example 3 are dissolved in 10 ml of ethyl acetate and 2 ml of methanol and hydrogenated at ordinary pressure for 3 hours in the presence of 50 mg of 10% palladium-on10 charcoal. The catalyst is filtered off, the filtrate is evaporated to dryness and the residue is chromatographed on silica gel, the eluent being DCM containing 1% of methanol. The product obtained is recrystallized from MeOH/isopropyl ether to give 105 mg.

M.p. = 186-190’C.

EXAMPLES 7 AND 8 Methyl 3-(2-fluorophenyl)-3-hydroxy-5-nitro-ltosylindoline-2-carboxylate, cis isomer, trans isomer A) 2'-Fluoro-5-nitro-2-tosylaminobenzophenone A mixture containing 10 g of 2-amino-5-nitro2'-fluorobenzophenone and 7.5 g of tosyl chloride is refluxed in 50 ml of pyridine for 24 hours. The solvent is evaporated off to dryness, water and ethyl acetate are added, an insoluble material is filtered off and the organic phase is washed with a dilute solution of hydrochloric acid, water and an aqueous solution of sodium chloride and then dried over magnesium sulfate and evaporated. The residue is chromatographed on silica and the expected product is eluted with DCM.

B) 2 '-Fluoro-2-[N-(methoxycarbonylmethyl)-N-(tosyl)amino]-5-nitrobenzophenone g of the compound obtained in the previous step are placed in 40 ml of anhydrous DMF and treated at 0°C with 320 mg of 80% sodium hydride and, after 10 - 24 minutes, with 6 g of methyl bromoacetate. The mixture is allowed to return to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The residue obtained after evaporation of the solvent is purified by chromatography on silica gel. The oil obtained by elution with DCM and then DCM containing up to 2% of AcOEt solidifies completely.

Elemental analysis: C33HieFN2O7S calculated % C : 56.79 H : 3.94 N : 5.76 found % C : 56.54 H : 3.88 N : 5.54 C) A suspension containing 1.70 g of the product obtained in the previous step in 30 ml of methanol is cooled to 10°C under argon and then treated with 100 mg of sodium methylate for 45 minutes. A large volume of water is added, the mixture is extracted with ethyl acetate and the organic phase is washed with water until the washings are neutral, washed with a saline solution, dried over magnesium sulfate and evaporated under vacuum. The residue is chromatographed on silica gel. The less polar compound is eluted with pure DCM to give 700 mg: cis isomer.

M.p. = 191-192’c after recrystallization (DCM/ isopropyl ether) The more polar compound is eluted with a DCM/ ethyl acetate mixture (95/5, v/v). 650 mg are obtained after recrystallization from DCM/isopropyl ether.

M.p. = 206-207’C: trans isomer EXAMPLE 9 Methyl 5-amino-3-(2-fluorophenyl)-3-hydroxy-ltosylindoline-2-carboxylate, cis isomer 450 mg of the cis compound obtained in Example are solubilized in 13 ml of an ethyl acetate/methanol mixture (10/3, v/v) and hydrogenated at ordinary tem35 perature and pressure for 2 hours in the presence of - 25 100 mg of 10% palladium-on-charcoal. The catalyst is filtered off, the solvent is evaporated off and the residue is chromatographed on silica gel using a DCM/ ethyl acetate mixture (1/1, v/v) as the eluent.

A white powder is obtained after trituration in a DCM/isopropyl ether mixture.

M.p. = 203°C (cis isomer) EXAMPLES 10 AND 11 Methyl 5-chloro-3-cyclohexyl-3-hydroxy-l-(4methoxyphenylsulfonyl)indoline-2-carboxylate, cis isomer, trans isomer A) 5-Chloro-l-[(4-methoxyphenylsulfonyl)aminoJcyclohexylphenone A mixture containing 20 g of 2-amino-5-chlorophenyl cyclohexyl ketone and 18 g of 4-methoxyphenylsulf onyl chloride is heated in pyridine at 100 °C overnight, the solvent is concentrated, the residue is taken up with hydrochloric water and extracted with DCM and the extract is dried and concentrated. The residue is recrystallized from an isopropyl ether/cyclohexane mixture to give 27 g of the expected compound, which crystallizes.

M.p. = 78-80’C B) 5-Chloro-l-[N-(methoxycarbonylmethyl)-N-(4-methoxyphenylsulfonyl)aminoJphenyl cyclohexyl ketone The compound obtained in the previous step (27 g) is treated with 2.2 g of sodium hydride in 150 ml of DMF at room temperature under argon for 30 minutes. 50 g of methyl bromoacetate are added and the mixture is left to stand overnight, with stirring. The DMF is evaporated off, the residue is taken up with water and extracted with DCM and the extract is dried and concentrated. The residue is chromatographed on silica using DCM as the eluent to give 19.5 g of the - 26 expected compound, which crystallizes from methanol. M.p. = 115-116’C C) The product obtained in the previous step (10 g) is solubilized in 350 ml of methanol, and 0.6 g of sodium methylate in 50 ml of methanol is added. After a contact time of 5 minutes, TLC shows that the reaction is complete. The methanol is evaporated off after dry ice has been added to the medium. The residue is taken up with water and extracted with methylene chloride and the extract is chromatographed on silica using methylene chloride as the eluent.

The first fractions contain the less polar isomer, which is recrystallized from isopropyl ether.

M.p. = 100°C (cis isomer) This is followed by the more polar isomer.

M.p. = 145°C (trans isomer) EXAMPLES 12 AND 13 Methyl 5-chloro-3-hydroxy-3-pentyl-1-tosylindo20 line-2-carboxylate, cis isomer, trans isomer A) 4-Chloro-2-hexanoy1-N-tosylani1ine A mixture containing 15 g of 4-chloro-2-hexanoylaniline and 10.5 g of tosyl chloride is heated in 100 ml of pyridine at 100‘c overnight. The solvent is evaporated off, the residue is taken up with hydrochloric water and extracted with methylene chloride and the extract is dried and concentrated. The crude reaction product crystallizes from isopropyl ether to give 14.5 g.

M.p. = 78-80’C B) 4-Chloro-2-hexanoyl-N-methoxycarbonylraethyl-N-tosylaniline g of the compound obtained in the previous step are treated at O’C under argon with 1 g of sodium hydride in DMF. After stirring for 15 minutes, 22.5 g - 27 of methyl bromoacetate are added and the mixture is stirred overnight at room temperature. After evaporation of the solvent and the excess brominated derivative with a vacuum pump, the residue is taken up with water and extracted with methylene chloride, the extract is dried and concentrated and the crude reaction product is then chromatographed on silica using a DCM/pentane mixture (50/50, v/v) as the eluent to give 12.1 g of the expected product.

M.p. = 68-70‘C C) 5 g of the compound obtained in the previous step are dissolved at 0°C in 100 ml of methanol and treated with 600 mg of sodium methylate. After 10 minutes, TLC shows that the starting material has disappeared. Dry ice is added, the solvent is partially evaporated off, the residue is taken up with water and extracted with methylene chloride and the extract is dried and concentrated. The crude reaction product is chromatographed on silica using DCM as the eluent, which separates the 2 isomers. The less polar isomer is recrystallized in the cold from an ether/cyclohexane mixture to give 0.85 g.

M.p. = 95-96°C: cis isomer The more polar isomer is recrystallized from isopropyl ether to give 2 g of product.

M.p. = 102-104‘C; trans isomer EXAMPLES 14 AND 15 Methyl l-butylsulfonyl-5-chloro-3-(2-chloro30 phenyl)-3-hydroxyindoline-2-carboxylate, cis isomer, trans isomer A) 2-Butylsulfonamido-2', 5-dichlorobenzophenone g of 2',5-dichloroaminobenzophenone and 8.2 g of n-butanesulfonyl chloride in 40 ml of pyridine are stirred for 9 days at room temperature. The pyriIE 912696 - 28 dine is evaporated off under vacuum, water is added, the mixture is extracted with 3 volumes of ethyl acetate and the organic phase is washed with hydrochloric water and an aqueous solution of sodium chloride and dried over magnesium sulfate. After evaporation of the solvent, the residue is chromatographed on silica gel, the expected product being eluted with a pentane/ethyl acetate mixture (90/10, v/v) to give 4.4 g.

B) 2-[N-(Butylsulfonyl)-N-(methoxycarbonylmethyl)10 amino ] -2', 5-dichlorobenzophenone g of the compound obtained in the previous step are dissolved in 40 ml of anhydrous DMF at O’C under argon, the solution is treated with 320 mg of 80% sodium hydride for 15 minutes, 6.5 g of ethyl bromo15 acetate are then added over 2 hours and the mixture is left to stand for 6 hours at room temperature. Water is added, the reaction product is then extracted and the extract is filtered on silica gel using DCM as the eluent to give the expected product in the form of a thick oil.

C) 4.3 g of the compound obtained in the previous step are placed in 50 ml of methanol at 0’c and treated with 54 mg of sodium methylate for 3 hours. After the starting material has disappeared (as shown by TLC), the mixture is poured into a large volume of water and extracted with 3 volumes of ethyl acetate, the organic phase is washed with water and an agueous solution of sodium chloride and dried over magnesium sulfate and the solvent is then evaporated off under vacuum. The residue is chromatographed on silica gel.

The first isomer is eluted with DCM.

M.p. = 140-143’C: cis isomer (recrystallization from DCM/isopropyl ether) The second isomer (trans isomer) is eluted with a DCM/isopropyl ether mixture. - 29 M.p. = 161-163’C: trans isomer (recrystallization from DCM/isopropyl ether) EXAMPLES 16 AND 17 Methyl 5-chloro-3-(2-chlorophenyl)-l-(2,5-dimethoxyphenylsulfonyl)-3-hydroxyindoline-2-carboxylate, cis isomer, trans isomer A) 2',5-Dichloro-2-(2,5-dimethoxyphenylsulfonamido)benzophenone This compound is prepared by the procedure described in the previous Examples.

B) 2',5-Dichloro-2-[N-(2,5-dimethoxyphenylsulfonyl)-N(methoxycarbonylmethyl)amino]benzophenone 8.2 g of the compound prepared in the previous step are dissolved in 60 ml of anhydrous DMF at 0’C under argon, 550 mg of 80% sodium hydride are added, after 15 minutes 8 g of methyl bromoacetate are then added and the mixture is stirred for 10 hours at room temperature. The reaction medium is poured into water and the solid formed is filtered off and then dissolved in ethyl acetate. The organic phase is washed with water and an aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated under vacuum. The solid is recrystallized from a DCM/isopropyl ether mixture.

M.p. = 129-131’C C) Methyl 5-chloro-3-(2-chlorophenyl)-2-(2,5-dimethoxypheny1sulfonyl)-3-hydroxyindo1ine-2-carboxy1ate The cyclization step can be carried out in the presence of various reagents. a) 1 g of the compound obtained in the previous step is dissolved in 10 ml of DCM at 0’C, 145 mg of DBU are added and the reaction medium is kept for 24 hours at +5°C. It is poured directly on to a silica column and eluted with DCM. - 30 The first compound eluted (231 mg) is recrystallized from DCM/isopropyl ether.

M.p. = 168-169°C (cis isomer) The trans isomer is eluted next.

M.p. = 193-195°C (recrystallization from DCM/ isopropyl ether) b) 800 mg of the compound obtained in step B are dissolved in 5 ml of anhydrous THF, 0.8 ml of HMPA is added and the mixture is cooled to -78°C under an argon atmosphere. 1 ml of a solution of the complex LDA.TFA (1.5 M) in cyclohexane is added by syringe; after 45 minutes, a further 0.3 ml of LDA is added, water is then added at -78°C and the mixture is extracted with ethyl acetate.

NMR analysis of the product obtained shows the existence of the cis isomer (39%) and the trans isomer (61%). c) 400 mg of the compound obtained in step B are dissolved in 3 ml of anhydrous THF under argon, the solution is cooled to -78 °C and 0.9 ml of a molar solution of LiHMDS in THF is then added, followed by 0.4 ml of HMPA in 2 ml of THF. After stirring for 60 minutes at -78°C, a further 0.3 ml of LiHMDS is added, after 10 minutes water is added at -78°C and the mixture is then extracted with ethyl acetate.

NMR analysis of the product obtained shows the existence of the cis isomer (60%) and the trans isomer (40%). d) 400 mg of the compound obtained in step B are dissolved in 3 ml of anhydrous THF, the solution is cooled to -78°C under argon and 1.8 ml of a solution of KHMDS (0.5 M) in 1 ml of toluene and 0.4 ml of HMPA in 1 ml of THF are then added. The solution obtained is kept at -78°C for 20 minutes, water is then added and the mixture is extracted with ethyl acetate. - 31 NMR analysis of the product obtained shows the existence of the cis isomer (32%) and the trans isomer (68%). e) 2 ml of THF and 0.4 ml of HMPA are cooled to -70°C under argon and a molar solution of LiHMDS in 0.9 ml of THF is added; 400 mg of the compound prepared in step B in 3 ml of THF are then added dropwise.

After one hour at -70°C, water is added and the mixture is then extracted with ethyl acetate. NMR analysis of the product obtained shows the existence of the cis isomer (63%) and the trans isomer (37%). f) 1 g of l,3-diphenyl-l,l,3,3-tetramethyldisilazane is dissolved in 4 ml of anhydrous THF, and 2.2 ml of a 1.6 M solution of butyllithium in hexane and 1.8 ml of THF are added at -10°C under argon.

In a parallel procedure, 400 mg of the compound prepared in step B are dissolved in 3 ml of anhydrous THF at -78°C under argon and 2.2 ml of the solution prepared above are added over 5 minutes, followed by 0.4 ml of HMPA. After 1 hour, a further 0.5 ml of the solution prepared above is added, the mixture is then left to stand for 1 hour at -78°C and, finally, water is added and the mixture is extracted with ether.

NMR analysis of the product obtained shows the existence of the cis isomer (57%) and the trans isomer (43%).

EXAMPLES 18, 19 AND 20 Isopentyl 5-chloro-3-cyclohexyl-3-hydroxy-l30 tosylindoline-2-carboxylate, trans isomer, cis isomer, and isopentyl 5-chloro-3-cyclohexyl-3-trimethylsilyloxy-l-tosylindoline-2-carboxylate, cis isomer A) 5-Chloro-2-tosylaminophenyl cyclohexyl ketone This compound is prepared by the procedure described in the previous Examples. - 32 Β) 2-[N—(Tosyl)-N-(isopentoxycarbonylmethyl)amino]-5chlorophenyl cyclohexyl ketone .7 g of the compound prepared in the previous step are dissolved in 50 ml of anhydrous DMF, 420 mg of 80% sodium hydride are added, 12 g of isopentyl bromoacetate are then added after 15 minutes and the mixture is stirred for 8 hours at room temperature. After extraction, the extract is chromatographed on silica gel and an oil is eluted with mixtures from pentane/DCM (20/80, v/v) to pure DCM.

C) Isopentyl 5-chloro-3-cyclohexyl-3-hydroxy-l-tosylindoline-2-carboxylate, trans isomer 1.6 g of the compound obtained in the previous step are dissolved in 10 ml of anhydrous 3-methyl15 butanol. The solution is cooled to O’C, 7 mg of sodium methylate are added and the mixture is then brought back to ordinary temperature over 150 minutes. Dry ice and water are added, the mixture is extracted by decantation and the extract is washed with water and an aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent is evaporated off under vacuum and the residue is then chromatographed on silica gel. A mixture of 2 isomers (1.6 g) is eluted with DCM and recrystallized from a DCM/isopropyl ether mixture: SR 47275 (trans isomer).

D) Isopentyl 5-chloro-3-cyclohexyl-3-trimethylsilyloxy-l-tosylindoline-2-carboxylate, cis isomer The mother liquors from crystallization of the trans isomer (980 mg) are dissolved under argon in 8 ml of hexamethyldisilazane in the presence of 100 mg of imidazole and the mixture is heated at 120 °C. The reaction is followed by TLC on silica gel using DCM as the eluent.

A product of low polarity appears after 1 hour and a second compound, which is slightly more polar - 33 than the previous one, appears after one night. The solvent is evaporated off to dryness under vacuum and the residue is chromatographed on silica gel. The less polar compound is eluted with a DCM/pentane mixture (50/50, v/v) to give 304 mg, which are recrystallized from a DCM/isopropyl ether mixture.

M.p. = 118-121*C E) Isopentyl 5-chloro-3-cyclohexyl-3-hydroxy-l-tosylindoline-2-carboxylate, cis isomer 2.4 mg of solid sodium hydroxide are added to a suspension of the mother liquors of the cis isomer isolated above (220 mg) in 1 ml of water and 3 ml of THF. After 3 hours, water is added, the THF is partially evaporated off and the mixture is extracted under vacuum at room temperature by the customary methods. The residue is chromatographed on silica using a DCM/pentane mixture (95/5, v/v) as the eluent. According to the NMR spectrum, 87% of the compound obtained is in the cis form.

EXAMPLE 21 Butyl 5-chloro-3-cyclohexyl-3-hydroxy-l-tosylindoline-2-carboxylate This compound is prepared by the reaction of butyl bromoacetate with 5-chloro-2-tosylaminophenyl cyclohexyl ketone, followed by cyclization in the presence of sodium methylate in butanol.

The compound formed is the trans isomer.

M.p. = 115C EXAMPLES 22 AND 23 Methyl 5-chloro-3-(2-chlorophenyl)-3-hydroxy-2methyl-l-tosylindoline-2-carboxylate, cis isomer, trans isomer A mixture containing 0.5 g of 2',5-dichloroIE 912696 - 34 2-[N-(1-methoxycarbonylethyl)-N-(tosyl)amino]benzophenone, 0.1 g of sodium methylate and 2 ml of DMF is stirred for 20 hours at room temperature under nitrogen. It is concentrated under vacuum, the residue is taken up with water and the precipitate is filtered off and washed with water. The residue is chromatographed on silica using DCM as the eluent to give 60 mg of the cis isomer and 250 mg of the trans isomer.

EXAMPLE 24 Methyl 5-chloro-3-(2-chlorophenyl)-1-(4-cyanophenylsulfonyl)-3-hydroxyindoline-2-carboxylate, cis isomer A) 2-[N-(4-Cyanophenylsulfonyl)amino]—2',5-dichloro15 benzophenone g of 2-amino-2', 5-dichlorobenzophenone and 7.7 g of 4-cyanophenylsulfonyl chloride are heated in pyridine at 100°C for 48 hours in the presence of 4.6 g of DMAP, the mixture is evaporated to dryness, water and ethyl acetate are added, the organic phase is washed with dilute hydrochloric water, water and an aqueous solution of sodium chloride and dried over magnesium sulfate and the solvent is evaporated off under vacuum. The precipitate formed is filtered off and then recrystallized twice from a DCM/isopropyl ether mixture to give the expected product.

M.p. = 172—173*C B) 2-[N-(4-Cyanophenylsulfonyl)-N-(methoxycarbonylmethyl ) amino ] -2', 5-dichlorobenzophenone g of the compound obtained in the previous step are dissolved in 70 ml of DMF at 0’C under argon, 740 mg of 80% sodium hydride are then added and 14 g of methyl bromoacetate are added after 15 minutes. After hours, water is added, the aqueous phase is decan35 ted, the solid obtained is extracted with AcOEt and the - 35 organic phase is washed with water and an aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated under vacuum to give the expected product, which is recrystallized from DCM/isopropyl ether.

M.p. = 186-188’C C) 2 g of the previous compound are suspended at 0°C in 40 ml of an MeOH/THF mixture (1/1, v/v) and treated with 100 mg of sodium methylate. After 3 hours at ordinary temperature, total dissolution is observed.

The solvents are partially evaporated off under vacuum, a large amount of water is added and the mixture is extracted with ethyl acetate. The extract is washed with water and an aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated under vacuum. The residue is chromatographed on silica gel. The 2 isomers are successively eluted with methylene chloride.

The less polar isomer is recrystallized from DCM/isopropyl ether.

M.p. = 222-223’c (cis isomer) EXAMPLES 25 AND 26 Methyl 5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulf onyl )-3-hydroxyindoline-2-carboxylate, trans isomer, cis isomer A) 2',5-Dichloro-2-(3,4-dimethoxyphenylsulfonamido)benzophenone .6 g of 2-amino-2',5-dichlorobenzophenone and 5 g of 3,4-dimethoxyphenylsulfonyl chloride are heated in pyridine overnight at 100C. The pyridine is evaporated off to dryness, water and ethyl acetate containing a small amount of DCM are added and the mixture is extracted. After washing several times with water and drying over sodium sulfate, the extract is evaporated under vacuum and 7.7 g of the expected product are - 36 recrystallized from a DCM/AcOEt mixture.

M.p. = 164°C B) 2',5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-M(methoxycarbonylmethyl)amino]benzophenone 7.2 g of the compound obtained in the previous step are dissolved in anhydrous DMF at 0°C under nitrogen. 500 mg of sodium hydride are added, followed after 10 minutes by 9.5 g of ethyl bromoacetate. After 1 night, excess water is added and the precipitate obtained is filtered off. It is dissolved in DCM, the solution is dried over magnesium sulfate and the solvent is evaporated off. 7.7 g of the expected product are recrystallized from a DCM/isopropyl ether mixture.

M.p. = 164‘C C) Trans isomer A suspension of 7 g of the product obtained in the previous step in 90 ml of methanol containing 2 ml of THF is cooled to 0°C under nitrogen and treated with 720 mg of sodium methylate. After 2 hours at ordinary temperature, the unreacted starting material is filtered off, a large volume of water and dry ice are added and the mixture is extracted with ethyl acetate. 4 products appear in TLC. The most abundant product is recrystallized twice from a DCM/isopropyl ether mix2 5 ture.

M.p. = 184-185’C: trans isomer D) Cis isomer 1.3 g of the compound obtained in step B are dissolved at o’C in 13 ml of DCM in the presence of 180 mg of DBU. After stirring overnight, the reaction medium is poured directly on to a silica column prepared in DCM and the mixture of compounds resulting from cyclization is thus separated by elution with DCM. Chromatography is then carried out on alumina using a DCM/isopropyl ether mixture (70/30, v/v) as the eluent. - 37 The cis isomer is thus isolated.

NMR spectrum at 200 MHz in DMSO at T = 370°K: Delta Appearance Integration Assignment 2.50 DMSO 3.15 s 3 H CO_CH3 3.80 s 3 H och3 3.85 s 3 H OCH_ 5.10 s 1 H CH 6.50 s 1 H OH 7.00 to 7.80 m 10 H aromatic protons EXAMPLES 27, 28, 29 AND 30 Benzyl 5-chloro-3-(2-chlorophenyl)-3-hydroxy-l15 p-tosylindoline-2-carboxylate, trans isomer, cis isomer, and 5-chloro-3-(2-chlorophenyl)-3-hydroxy-l-ptosylindoline-2-carboxylic acid, trans isomer, cis isomer A) 2',5-Dichloro-2-[N-(tosyl)-N-(benzyloxycarbonyl20 methyl)amino]benzophenone g of 2',5-dichloro-2-N-tosylaminobenzophenone (prepared by the customary method) and 1.6 g of sodium hydride are reacted in 100 ml of DMF. After stirring for 15 minutes, 34 g of benzyl bromoacetate are added and the mixture is left to stand overnight at room temperature. The DMF is evaporated off, the residue is taken up with water and extracted with methylene chloride , and then dried and concentrated. The crude product obtained is chromato30 graphed on silica gel using DCM as the eluent. The 14.39 g of product obtained are recrystallized from isopropyl ether.

M.p. = 99-lOl’C - 38 B) Benzyl 5-chloro-3-(2-chlorophenyl)-3-hydroxy-l-ptosylindoline-2-carboxylate, trans isomer g of the compound obtained in the previous step is treated at -78’c with 1.2 ml of concentrated LDA (1.5 M) in cyclohexane. After 3 hours, the mixture is taken up with water and extracted with DCM and the extract is dried and concentrated. The crude reaction product is chromatographed on silica gel using DCM as the eluent and the mixture of 2 isomers is separated.

The more polar isomer is recrystallized twice from a DCM/isopropyl ether mixture to give 600 mg of trans isomer.

M.p. = 168-169*C (recrystallization from DCM/ isopropyl ether) C) Benzyl 5-chloro-3-(2-chlorophenyl)-3-hydroxy-l-ptosylindoline-2-carboxylate, cis isomer g of the compound prepared in step A are dissolved in DCM at 0eC and 540 mg of DBU are added. After 20 minutes at 0’C, a potassium sulfate solution and water are added, the mixture is then extracted and the extract is dried and concentrated. Chromatography on silica using DCM as the eluent gives 450 mg of the less polar product (cis isomer) and 700 mg of the more polar product (trans isomer).

The cis isomer is obtained in the form of a foam.

Elemental analysis: calculated % C : 61.27 H : 4.05 N : 2.46 found % 61.29 4.20 2.48 D) 5-Chloro-3-(2-chlorophenyl)-3-hydroxy-l-p-tosylindoline-2-carboxylic acid, trans isomer 500 mg of the trans isomer of the compound prepared in step B are dissolved in 300 ml of ethyl acetate in the presence of 100 mg of palladium-on35 charcoal. The product crystallizes after 10 min of - 39 hydrogenolysis. The palladium is filtered off and the crystals are then solubilized with hot DMF. The DMF is concentrated and the residue is taken up with a large volume of THF. The mixture is concentrated, methanol is added and the product crystallizes to give 175 mg of the expected product (trans isomer).

NMR: Delta Appearance Integration Assignment 2.44 s 3 H CH3 (tosyl) 4.87 s 1 H H6 (2-chlorophenyl) 6.74 d 1 H H4 (indole) 6.98 s 1 H OH 7.28-7.53 m 7 H aromatic protons 7.88 d OH 15 (J - 8.6 Hz) 2 H H2, H6 (tosyl) In the same way, the cis isomer of the acid is prepared by hydrogenolysis of the benzyl ester obtained in step C.

M.p. = 209-212‘C EXAMPLE 31 -Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline-2-carboxylic acid, cis isomer This acid is prepared by the procedure described in the previous Example via the benzyl ester of said acid.

M.p. = 130-132’C Methyl esters of formula (I) were prepared by analogous procedures. They are described in Table 1 below.

For each compound of formula (I) having the substituents Rx, R2 and Rb in the Table below, the cis isomer is indicated and then the trans isomer, unless stated otherwise.

Example Ri r2 Rb M.p. °C Solvent 32 H phenyl p-tolyl 154 15 33 170 34 5-C1 cyclopentyl p-tolyl 187-190 DCM/MeOH 35 153-157 DCM/isopropyl ether 20 36 5-C1 cyclohexyl p-tolyl 180 e the r/cyc1ohexane 37 144 e the r/cyc1ohexane 25 38 5-C1 cyclohexyl 2-naphthyl 177 MeOH 39 150 e the r/cy cl ohexane 40 5-C1 isopropyl p-tolyl 158 DCM/isopropyl ether 30 41 172 DCM/isopropyl ether 42 5-C1 2-F-phenyl p-tolyl 165-166 DCM/isopropyl ether 35 43 212-213 DCM/isopropyl ether 44 (*) 5-C1 phenyl p-tolyl 206 DCM/isopropyl MeOH ether/ 45 193-194 AcOEt/MeOH 46 5-C1 cycloheptyl p-tolyl 170-172 isopropyl ether 47 154-155 48 5-C1 2-Cl-phenyl p-tolyl 174 49 255 50 5-C1 cyclohexyl 4-dimethylaminophenyl 184-185 51 198-200 DCM/isopropyl ether 52 5-C1 cyclohexyl 2,4,6-tri- methylphenyl 139-142 DCM/isopropyl ether 53 200-203 DCM/isopropyl ether 54 5-C1 cyclohexyl n-butyl 150-153 MeOH/isopropyl ether 55 5-C1 2-Cl-phenyl 2-CF3-phenyl 216 56 2-CF3-phenyl 242 57 5-C1 2-Cl-phenyl 4-benzyloxyphenyl 166 DCM/isopropyl ether 58 195 DCM/isopropyl ether 59 5-Cl 2-Cl-phenyl 4-Cl-phenyl 174 60 230 61 5-C1 4-Cl-phenyl p-tolyl 224 62 186 EtOH 63 5-Cl 2-CH3- phenyl p-tolyl 168 64 65 5-C1 2-Cl-phenyl 4-OH-phenyl 238 AcOEt NMR (**) 66 163 MeOH/isopropyl ether 67 5-C1 2-Cl-phenyl 3-Cl-phenyl 175 68 186 69 5-C1 2-Cl-phenyl m-tolyl 173 70 229 71 5-C1 2-methoxy- p-tolyl 165 phenyl 72 240 73 5-C1 3-Cl-phenyl p-tolyl 137 74 210 75 5-Cl 2-methyl- 3,4-diCl- 196 phenyl phenyl 76 175 77 5-C1 2-Cl-phenyl 3-methoxy- 132 cis phenyl 78 5-Cl 2-Cl-phenyl 2,3,4-tri- 207 me thoxyphenyl 79 183 80 5-Cl 2-Cl-phenyl 4-butoxy- 124-125 phenyl hexane 81 190-192 MeOH/isopropyl ether 82 5-Cl 2-Cl-phenyl 4-trifluoro- 170 me thoxyphenyl 83 166 84 5-Br 2-F-phenyl 3,4-di- 162-164 methoxyphenyl 85 86 5-C1 2-Cl-phenyl phenyl 162-165 DCM/isopropyl ether 148 isopropyl ether 87 230 DCM/isopropyl ether 88 5-C1 2-Cl-phenyl 4-methoxyphenyl 173 hexane/isopropyl ether 89 217 hexane/isopropyl ether 90 5-Br 2-Cl-phenyl 3,4-dime thoxyphenyl 160-162 91 199 92 5-C1 2-Cl-phenyl 4-ethoxy- phenyl 174 hexane/isopropyl ether 93 186 hexane/isopropyl ether 94 trans 2-CH30 2-C1 p-tolyl 215 95 5-CH3 2-Cl-phenyl p-tolyl 165 96 216 EtOH 97 5-CF3 2-CF3- phenyl p-tolyl 189 98 202 99 5-C1 2-CF3- phenyl p-tolyl 166 100 205 101 trans 5-C1 2-Cl-phenyl 3-methoxyphenyl 206.5 102 5-Cl 2-Cl-phenyl 4-CF3-phenyl 191 103 180 - 44 (*) For this compound, the silylated derivative (VII) was prepared cis isomer, m.p. = 176-178°C.

(**) Example 65: NMR spectrum at 200 MHz in DMSO at T = 380°K: Delta Appearance Integration Assignment 2.45 DMSO 3.10 s 3 H co2ch3 5.00 s 1 H CH 6.30 s 1 H OH 6.80-7.80 ra 11 H aromatic protons EXAMPLES 104 AND 105 N,N-Dimethyl-5-chloro-3-cyclohexyl-3-hydroxy-ltosylindoline-2-carboxamide, trans isomer, cis isomer A) 5-Chloro-2-tosylarainophenyl cyclohexyl ketone This compound is the one prepared in Example 18, step A.

B) Dimethylbromoacetamide A solution containing 56 g of bromoacetyl bromide in 100 ml of DCM is cooled to 0'c and gaseous dimethylamine is bubbled into the medium until it becomes basic. The mixture is filtered and dried and the crude amide is concentrated to give an oil (22 g).

C) 2-[N-(Tosyl)-N-(dimethylcarbamoylmethy1)amino] -5chlorophenyl cyclohexyl ketone 4.3 g of 5-chloro-2-tosylarainophenyl cyclohexyl ketone are placed in 20 ml of DMF in the presence of 360 mg of 80% sodium hydride, after 15 minutes at RT .4 g of the compound prepared in step B are added and the mixture is stirred overnight at RT. The reaction medium is poured into water and the precipitate is filtered off and then taken up with DCM, dried and concentrated. The expected product crystallizes from isopropyl ether. m = 3.9 g M.p. = 184-187‘C - 45 D) N,N-Dimethyl-5-chloro-3-cyclohexyl-3-hydroxy-ltosylindoline-2-carboxamide, trans isomer 1.5 g of the compound obtained in the previous step are cooled to -78 *C in 20 ml of anhydrous THF, 2.3 ml of a 1.5 M solution of LDA in cyclohexane are added and the mixture is stirred for 2 hours at -78°C. It is poured into water and extracted with DCM and the extract is dried and concentrated. The crude product obtained is chromatographed on silica; an AcOEt/DCM mixture (10/90, v/v) elutes a compound which is shown by NMR to be the trans isomer. It is recrystallized from an isopropyl ether/DCM mixture.

M.p. = 179-182‘C E) N,N-Dimethyl-5-chloro-3-cyclohexyl-3-hydroxy-l15 tosylindoline-2-carboxamide, cis isomer 1.5 g of the product obtained in step C are treated with 950 mg of DBU in 10 ml of DCM for 24 hours at RT. The reaction medium is then chromatographed on silica using a DCM/AcOEt mixture (95/5, v/v) as the eluent to give the other isomer (cis isomer). It is recrystallized from isopropyl ether. m = 120 mg M. p. = 152-155’C EXAMPLES 106 AND 107 N, N-Dimethyl-5-chloro-3-(2-chlorophenyl)-3hydroxy-l-tosylindoline-2-carboxamide, trans isomer, cis isomer.

A) 5,2'-Dichloro-2-tosylarainobenzophenone This compound is prepared by the customary method.

B) 2-[N-(Tosyl)-N-(dimethylcarbamoylmethyl)amino]-5,2 'dichlorobenzophenone 8.4 g of 5,2'-dichloro-2-tosylaminobenzophenone 35 are dissolved in 40 ml of DMF and treated with 0.7 g of - 46 80% sodium hydride; after 15 minutes, 10 g of dimethylbromoacetamide, prepared in Example 1, are added and the mixture is stirred overnight at RT. The reaction medium is poured into water, the precipitate formed is filtered off and taken up with DCM and the solution is dried and concentrated. 9.2 g of the expected product are obtained after crystallization from isopropyl ether.

M.p. = 154-157‘c C) N,N-Dimethyl-5-chloro-3-(2-chlorophenyl)-3-hydroxyl-tosylindoline-2-carboxamide, trans isomer 1.5 g of the compound obtained in the previous step are treated at -78°C, in 100 ml of anhydrous THF, with 2.6 ml of a 1.5 M solution of LDA in cyclohexane for 3 hours. The mixture is poured into water and extracted with DCM and the extract is dried and concentrated. The residue is chromatographed on silica using a DCM/AcOEt mixture (94/6, v/v) as the eluent. A small amount of the less polar compound is collected and the more polar compound is then eluted: trans isomer.

It is recrystallized from a DCM/isopropyl ether mixture.

M.p. = 232-233*C D) N,N-Dimethyl-5-chloro-3-(2-chlorophenyl)-3-hydroxyl-tosylindoline-2-carboxamide, cis isomer 1.5 g of the compound prepared in step B are refluxed in DCM for 24 hours in the presence of 900 mg of DBU. The mixture is chromatographed on a silica column using a DCM/AcOEt mixture (95/5, v/v) as the eluent. 190 mg of the expected product are obtained after recrystallization from isopropyl ether.

M.p. = 220-221°C E) The compound of step B (1.0 g) is dissolved in acetonitrile (25 ml), and 109 mg of sodium hydroxide in - 47 2 ml of water are added. The medium is heterogeneous; it is stirred violently at 45’C for 1 hour, using a turbine and compressed air, either in the presence of 110 mg of benzyltriethylammonium chloride or without the addition of this reagent.

After extraction, the product obtained in the form of a mixture of the 2 isomers, cis and trans, is determined. The ratio of the 2 isomers observed by NMR at 360 °K in DMSO is 1/1.

EXAMPLE 108 N,N-Dimethyl-1-(4-allyloxyphenylsulfonyl)-5chloro-3-(2-chlorophenyl)-3-hydroxyindoline-2-carboxamide, cis isomer A) Sodium 4-allyloxyphenylsulfonate g of sodium phenylsulfonate are dissolved in 60 ml of ethanol and 50 ml of 15% sodium hydroxide, 20 g of allyl bromide are added and the mixture is refluxed for 48 hours. The ethanol is concentrated and the precipitate obtained is filtered off and then dried under vacuum in the presence of phosphorus pentoxide to give 23.3 g of the expected product.

B) 4-Allyloxyphenylsulfonyl chloride The product obtained in the previous step (23.3 g) is treated overnight with 24 g of phosphorus pentachloride under reflux in 300 ml of DCM. The medium is filtered and concentrated to give an oil (16.5 g).

C) 2- [ N- (4-Allyloxyphenylsulfonyl) amino ]-2', 5-dichloro30 benzophenone The sulfonyl chloride obtained in the previous step is added to 19 g of 2', 5-dichloro-2-aminobenzophenone in 200 ml of pyridine. After one night at room temperature, the pyridine is concentrated, the residue is taken up with hydrochloric water and extracted with - 48 DCM and the extract is dried and concentrated. The crude product is chromatographed on silica and a DCM/ pentane mixture (50/50, v/v) elutes the expected product, which is crystallized from a DCM/isopropyl ether mixture to give 8.5 g of the expected product.

M.p. = 96-97’C D) 2-[N-(4-Allyloxyphenylsulfonyl)-Ν-(Ν',N'-dimethy1carbamoy lmethyl) amino ] -2', 5-dichlorobenzophenone g of the product obtained in the previous 10 step are dissolved in 20 ml of DMF under nitrogen, 310 mg of 80% sodium hydride are added, the mixture is stirred for 15 minutes at RT and 3.1 g of bromo-N,Ndiraethylacetamide are then added. After one night at RT, the medium is poured into water, the product is filtered off and taken up with DCM, the solution is dried and concentrated and the residue is then crystallized from a DCM/isopropyl ether mixture to give 4 g of the expected product, which is finally recrystallized from the same solvent mixture.

M.p. = 133-135’C E) N,N-Dimethyl-l-(4-allyloxyphenylsulfonyl)-5-chloro3-(2-chlorophenyl)-3-hydroxyindoline-2-carboxamide, cis isomer 3.8 g of the product obtained in the previous 25 step are treated at 30’C with 1.8 g of DBU in 20 ml of DCM for 3 days. The medium is chromatographed on alumina and DCM elutes the less polar compound, which is recrystallized from a DCM/isopropyl ether mixture to give m = 840 mg.

M.p. = 181-182*C - 49 EXAMPLE 109 N-Benzyl-N-methyl-5-chloro-3-(2-chlorophenyl)3-hydroxy-l-(3,4-dimethoxyphenylsulfonyl)indoline-2carboxamide, cis isomer A) N-Methyl-N-benzylbromoacetamide At 0°C, a solution of 10 g of bromoacetyl bromide in 20 ml of DCM is added to a solution of 6 g of methylbenzylamine and 5g of triethylamine in 50 ml of DCM. After one night at RT, ether is added, the precipitate formed is filtered off and the filtrate is concentrated to give 12 g of the expected product in crude form.

B) 2',5-Dichloro-2-(3,4-dimethoxyphenylsulfonamido)benzophenone This compound was prepared in Example 25, step A.

C) 2',5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N(Ν'-methy l-N'-benzylcarbamoy lmethy 1) amino] benzophenone .5 g of the compound described in step B are 20 dissolved in 30 ml of DMF and treated with 400 mg of sodium hydride. After 15 minutes, 12 g of the brominated derivative prepared in step A are added and the mixture is stirred at RT for 24 hours. The DMF is evaporated off, the residue is taken up with water and extracted with DCM and the extract is dried and concentrated. The crude product is chromatographed on silica and the expected product is eluted with DCM. m = 2.1 g M.p. = 148-150*C D) N-Benzyl-N-methyl-5-chloro-3-(2-chlorophenyl)-3hydroxy-l-(3,4-dimethoxyphenylsulfonyl)indoline-2carboxamide, cis isomer The 2.1 g of product obtained in the previous step are treated with 1 g of DBU in 20 ml of DCM for 3 days. The reaction medium is poured on to an alumina - 50 column and DCM elutes the less polar isomer (870 mg) in the form of an oil. After drying, a foam is obtained which is characterized by NMR: 2.81 ppm : s : 3H • N-CH3 05 3.60 ppm : m : 8H • • 20CH3 + N-CH2-CeHB 5.35 ppm : s : IH • • CH (2- indoline) 6.20 - 7.80 ppm : m : 16H : aromatic protons + OH EXAMPLES 110 AND 111 -Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulf onyl )-3-hydroxy-2-pyrrolidinocarbonylindoline, cis isomer, trans isomer This compound is prepared by the customary pro15 cedure by the reaction of pyrrolidine bromoacetamide with 2-(3,4-dimethoxyphenylsulf onamido) -5,2'-dichlorobenzophenone and then cyclization of the resulting product with DBU in chloroform. A product is eluted on an alumina column with DCM/AcOEt (90/10, v/v); it is the cis isomer.

M.p. = 237’C AcOEt elutes the trans isomer, which is then recrystallized from AcOEt.

M.p. = 230’C 25 EXAMPLE 112 -Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulf onyl )-3-hydroxyindoline-2-carboxamide, trans isomer A) 2',5-Dichloro-2-(3,4-dimethoxyphenylsulfonamido)benzophenone 114 g of 2-amino-5,2'-dichlorobenzophenone and 100 g of 3,4-dimethoxyphenylsulfonyl chloride are mixed in 300 ml of pyridine. After 4 days at RT, the excess pyridine is evaporated off, the residue is taken up - 51 with hydrochloric water and extracted with DCM and the extract is dried and concentrated. The expected product then crystallizes from a DCM/isopropyl ether mixture. m = 181 g M.p. = 159-16l’C B) 2’,5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)N-(benzyloxycarbonylmethyl)amino]benzophenone 172 g of the product prepared above are dis10 solved in 800 ml of DCM and cooled to 0eC. 11.7 g of 80% sodium hydride are added gradually under nitrogen, 256 g of benzyl bromoacetate are then added after 30 minutes and the mixture is stirred for 24 hours at RT. The DMF is evaporated off, the residue is taken up with water and extracted with DCM and the extract is dried and concentrated. The expected product crystallizes from isopropyl ether and is then recrystallized from a DCM/isopropyl ether mixture. m = 136.5 g M.p. = 102-104°C C) Benzyl 5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline-2-carboxylate, trans isomer g of the product obtained in the previous 25 step are treated with 740 mg of TBD in 20 ml of DCM at RT for 1 hour. The reaction medium is chromatographed on silica and DCM elutes the expected compound in the form of the trans isomer, which is the only isomer formed by the cyclization reaction.

The compound obtained is recrystallized from a DCM/isopropyl ether mixture, m = 2 g M.p. = 190-192*C D) 5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline-2-carboxylic acid, trans isomer The benzyl ester obtained in the previous step, 05 in 50 ml of AcOEt, is treated with hydrogen for 30 minutes in the presence of 100 mg of 10% Pd/C. The reaction medium is filtered on C61ite·, the material on the filter is washed with hot methanol and the filtrate is concentrated. The expected product crystallizes from a DCM/isopropyl ether mixture, m = 1.5 g M.p. = 218-221’C E) 5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline-2-carboxamide, trans isomer 180 mg of the compound obtained in the previous step, in 15 ml of DCM, are treated with 140 mg of BOP in the presence of a sufficient amount of DIPEA to solubilize the acid. After 15 minutes, gaseous ammonia is introduced for 10 minutes. The medium is poured into a saturated solution of sodium hydrogencarbonate and extracted and the extract is dried and then concentrated. The crude product is chromatographed on silica using a DCM/AcOEt mixture (80/20, v/v) as the eluent to give the expected compound, which is then recrystallized from a DCM/isopropyl ether mixture. m = 63 mg M.p. = 183-185’C EXAMPLES 113 AND 114 N-Isopenty1-5-chloro-3-cyclohexyl-3-hydroxy-1tosylindoline-2-carboxamide, cis isomer, trans isomer A) 2-(N-tosylamino)-5-chlorophenyl cyclohexyl ketone is prepared by the customary method. - 53 Β) 2- [ Ν- (N'-Isopentylcarbamoylmethy 1) -Ν- (tosyl) amino ] 5-chlorophenyl cyclohexyl ketone 7.2 g of the compound obtained above in 130 ml of DMF are cooled to 0°C and placed under argon, 1.1 equivalents of sodium hydride are added and the mixture is allowed to return to RT. 15.2 g of N-isopentyl-2bromoacetamide are then added and the mixture is stirred overnight at RT. The DMF is evaporated off, the residue is taken up with water and extracted with DCM and the extract is dried and concentrated. The crude product is chromatographed on silica using an ether/ pentane mixture (70/30, v/v) as the eluent.

C) N-Isopentyl-5-chloro-3-cyclohexyl-3-hydroxy-l-tosylindoline-2-carboxamide, mixture of isomers 2.1 equivalents of LDA are added to 3 g of the above product in 50 ml of anhydrous THF at -20°C and the temperature is then kept at +4°C for 30 minutes. The medium is poured into a saturated solution of ammonium chloride and extracted and the extract is dried and concentrated. Chromatography on silica using methylene chloride as the eluent gives the expected product in the form of a mixture of 2 isomers. m = 2 g D) N-Isopentyl-5-chloro-3-cyclohexyl-3-trimethylsilyl25 oxy-l-tosyli ndo1ine-2-carboxamide g of the product obtained above is heated at 100°C in 5 g of HMDS for 12 hours under argon in the presence of 0.1 g of imidazole. The medium is evaporated, the residue is taken up with DCM and the solution is chromatographed on silica. DCM successively elutes the less polar isomer, which is recrystallized from isopropyl ether: m = 345 mg M.p. = 137-138*C and then the more polar isomer, which is recrystallized - 54 from isopropyl ether: m = 165 mg M.p. = 175-176’C E) N-Isopentyl-5-chloro-3-cyclohexyl-3-hydroxy-l-tosyl05 indoline-2-carboxamide, cis isomer 150 mg of the less polar isomer obtained above are treated with 10 mg of sodium hydroxide at 0"C in 5 ml of THF and 2 ml of water for 3 hours. The mixture is taken up with water and extracted with DCM and the extract is dried and concentrated. The crude product is recrystallized from a DCM/isopropyl ether mixture. m = 120 mg M.p. = 189-19l’C F) N-Isopentyl-5-chloro-3-cyclohexyl-3-hydroxy-l-tosyl15 indoline-2-carboxamide, trans isomer 150 mg of the more polar isomer obtained in step D are treated with 10 mg of sodium hydroxide in 5 ml of THF and 2 ml of water for 2 hours at RT. The mixture is taken up with water and extracted with DCM and the extract is dried and concentrated. The expected product is recrystallized from a DCM/isopropyl ether mixture. m = 65 mg M.p. = 195-196’C The compounds according to the invention which are described in Table 2 below were prepared by following the procedure given in the Examples described above: - 55 TABLE 2 For each compound of formula (I) having the substituents Rj, R2, (R'5)p, and NR6R7 in the Table below, the cis isomer is indicated and then the trans isomer, unless stated otherwise.

Ex. Ri R2 (R'bV ^Re -N M.p. °C crystallization solvent 115 5-Cl 2 -Cl-phenyl 3,4-dime thoxy N(CH3)2 201 DCM/isopropyl ether 20 116 222 DCM/isopropyl ether 117 5-Cl cyclohexyl 4-CH3 nhch3 224-225 DCM/isopropyl ether 25 118 141-148 DCM/isopropyl ether 119 5-Cl 2-Cl-phenyl 3,4-dimethoxy nhch3 148 trans DCM/isopropyl 30 ether 120 5-Br 2-F-phenyl 3,4-dimethoxy N(CH3)2 165 DCM/isopropyl ether 121 214 DCM/isopropyl 35 ether | -C1 2-Cl-phenyl 2,5-dimethoxy N(CH3)2 140-142 DCM/isopropyl ether 5-C1 2-Cl-phenyl 4-methoxy N(CH3)z 240 DCM/hexane 187 DCM/hexane 5-C1 2-Cl-phenyl 3,4-dimethoxy N(CHzCH3)2 213 hexane/isopropyl ether 200 hexane/isopropyl ether 5-C1 2-Cl-phenyl 3,4-dimethoxy N(CH3)-CHz- CH2-C6Hs 125-130 hexane/isopropyl ether 140-142 DCM/isopropyl ether 5-C1 2-Cl-phenyl 2,4-dimethoxy N(CH3)2 213 206 5-C1 2-methoxyphenyl 3,4-dimethoxy N(CH3)z 205 hexane/isopropyl ether 206 hexane/isopropyl ether 5-CH3 2-Cl-phenyl 3,4-dimethoxy N(CH2CH3)z 189 isopropyl ether 191 isopropyl ether 5-CH3 2 -Cl -phenyl 2,4-dimethoxy N(CH2CH3)2 208-209 isopropyl ether 214-215 isopropyl ether 5-C1 2-Cl-phenyl 2,4-dimethoxy N(CHzCH3)2 225 138 139 5-Cl 2-Cl-phenyl 4-cyano N(CH3)2 200 242-243 THF/EtOH 140 228-231 DCM/isopropyl ether 141 cis 5-Cl 2-Cl-phenyl 3,4-dimethoxy N(C4Hg)2 203 DCM/isopropyl ether 142 5-Cl cyclohexyl 3,4-dimethoxy N(CH2CH3)2 117-120 143 NMR 144 cis 5-Cl 2-F-phenyl 4-nitro N(CH3)z 230 NMR spectrum Example 143: trans isomer 0.2 - 1.8 ppm : m : 17H : 2CH3 (ethyl), 11H cyclohexyl 2.8 - 3.5 ppm : m : 4H : N-(CH2)2- 3.7 ppm : s : 3H : 0CH3 3.75 ppm : : s : : 3H : OCH3 4.7 ppm : s : 1H : H (indoline) 5.65 ppm : : s : : 1H : OH (indoline) 6.8 - 7.6 ppm : m : 6H : aromatic protons EXAMPLES 145 AND 146 Methyl 5-chloro-3-(2-chlorophenyl)-3-hydroxy-ltosylindoline-2-carboxylate, dextrorotatory cis isomer, 25 levorotatory cis isomer The optical isomers of methyl 5-chloro-3-(2chlorophenyl)-3-hydroxy-l-tosylindoline-2-carboxylate, described in Example 48 of Table 1, were separated by preparative chromatography on a chiral column.

Supercritical phase analytical chromatography is first carried out on the product of Example 48.

The column used is a Chiralcel OD* column marketed by DAICEL. This column consists of silica gel coated with cellulose carbamate.

The eluent is a carbon dioxide/propan-2-ol/diIE 912696 - 58 ethylamine mixture (75/25/0.3, v/v/v) used at a flow rate of 2 ml/minute. The exit pressure is 160 atmospheres, the temperature is 32’c and UV detection is carried out at 226 nm.

The chromatogram shows 2 peaks of equal areas and with retention times of about 4 minutes and 5.4 minutes.

A Chiralcel· column is also used for preparative chromatography.

The sample of product to be chromatographed is dissolved in methanol (30 mg/ml) and 1 ml is injected into the column. The eluent is a hexane/propan-2-ol mixture (80/20, v/v) used at a flow rate of 1.5 ml/ minute. UV detection is carried out at 226 nm. The analysis time is 45 minutes. Twelve fractions were collected and analyzed in the supercritical phase.

Under the same conditions, 13 injections of 30 mg are then carried out. The fractions corresponding to the first peak, collected between 16 and 24 minutes, are pooled; the fractions corresponding to the second peak, collected between 29 and 42 minutes, are pooled. After passage under a stream of nitrogen, each batch is recrystallized from a DCM/isopropyl ether/hexane mixture.

The first peak gives a product with a chromatographic purity of more than 99.9%; this is the dextrorotatory cis isomer. oDae = +236 (chloroform) M.p. = 174-177’c (after recrystallization from DCM/hexane/isopropyl ether) m = 130 mg The second peak gives a product with a chromatographic purity of more than 99.5%; this is the levorotatory cis isomer.

Claims (21)

CLAIMS:

1. A compound of the formula (CH 2 ) ra R 5 in which - R x is a halogen atom, a C^^-C^ alkyl, a hydroxyl, a alkoxy, a benzyloxy group, a cyano group, a trifluoromethyl group, a nitro group or an amino group; - R 2 is a C 1 -C 6 alkyl, a C 3 -C v cycloalkyl, a C s -C 7 cycloalkene or a phenyl which is unsubstituted or monosubstituted or polysubstituted by a C 1 -C 4 alkyl, a C 1 -C 4 alkoxy, a halogen, a trifluoromethyl group, a nitro group or an amino group; - R 3 is a hydrogen atom or a C^-C^ alkyl; - R 4 is a carboxyl group, an alkoxycarbonyl group in which the alkyl group is C x -C e , a benzyloxycarbonyl group or a carboxamide group of the formula CONR e R 7 ; - R s is a C x -C 4 alkyl, a 1-naphthyl, a 2-naphthyl, a 5dimethylamino-l-naphthyl or a phenyl which is unsubstituted or substituted by one or more substituents selected from a halogen atom, a C x -C 4 alkyl, a trifluoromethyl group, a nitro group, an amino group which is free or substituted by one or 2 C x -C 4 alkyls, a hydroxyl, a C X -C A alkoxy, a C x -C 4 alkenoxy, a C x -C 4 alkylthio, a trifluoromethoxy group, a benzyloxy group, a cyano group, a carboxyl group, a C x IE 912696 - 61 C A alkoxycarbonyl group, a carbamoyl group or a C x -C 4 alkylamido group, or, when m = 0, R s can be a group - R 6 and R_, are each independently hydrogen, a C x -C e alkyl or a phenylalkyl in which the alkyl is C x -C 4 , or R e and R v together form a group -(CH 2 ) p -; - n is 0, 1 or 2; - m is 0, 1 or 2; and - p is 4, 5 or 6; and its salts, where appropriate.

2. A compound according to claim 1 in which R x is a chlorine or bromine atom or a methoxy group, n = 0 and the other substituents are as defined for (I) in claim 1.

3. A compound according to claim 1 in which R 2 is a methoxyphenyl, a chlorophenyl or a cyclohexyl and the other substituents are as defined for (I) in claim 1.

4. A compound according to claim 1 in which R 3 is hydrogen and the other substituents are as defined for (I) in claim 1.

5. A compound according to claim 1 in which R 4 is an alkoxycarbonyl in which the alkyl group is C x -C e , and the other substituents are as defined for (I) in claim 1.

6. A compound according to claim 1 in which R 4 is a carboxamide group CONR e R„ in which R e and R_, are C x -C e alkyls, and the other substituents are as defined for (I) in claim 1.

7. A compound according to claim 1 in which R e is a phenyl substituted in the 3 and 4 positions or in the 2 - 62 and 4 positions by a methoxy group, or else R s is a phenyl substituted in the 4 position by a methyl group, and the other substituents are as defined for (I) in claim 1.

8. A compound according to claim 1 in which m is 0 and the other substituents are as defined for (I) in claim l.

9. A compound according to claim 1 in the form of the cis isomer in which R a and R 4 are on the same side of the indoline ring.

10. A method of preparing a compound according to claim 1, which comprises a) reacting a sulfonyl derivative of the formula Hal-SO a -(CH a ) ra -R s (III) in which Hal is a halogen, preferably chlorine or bromine, and R s is as defined for (I) in claim 1, with a 2-aminophenone derivative of the formula (II) in which R x , R a and n are as defined above for b) treating the resulting compound of (Di the formula (IV) with a halogenated derivative of the formula Hal (V) in which Hal' is a halogen, preferably bromine, and R a and R 4 are as defined for (I) in claim l? c) cyclizing the resulting compound of the formula in a basic medium in order to prepare the compound (I) according to claim 1; and d) separating the cis and trans isomers of the compound (I), if appropriate.

11. A compound of the formula rf ( R1) ή ΙςΖ fi COR 2 -CH S0 2 (CH 2 )m r 5 . r 3 (VI) - 64 in which - R x is a halogen atom, a C x -C 4 alkyl, a hydroxyl, a C x -C 4 alkoxy, a benzyloxy group, a cyano group, a trifluoromethyl group, a nitro group or an amino group; - R 2 is a C x -C e alkyl, a C 3 -C 7 cycloalkyi, a C 5 -C 7 cycloalkene or a phenyl which is unsubstituted or monosubstituted or polysubstituted by a C^-C^ alkyl, a C ± -C 4 alkoxy, a halogen, a trifluoromethyl group, a nitro group or an amino group; - R 3 is a hydrogen atom or a C x -C 4 alkyl; - R 4 is a carboxyl group, an alkoxycarbonyl group in which the alkyl group is C x -C e , a benzyloxycarbonyl group or a carboxamide group of the formula CONR e R_,; - R s is a C X -C A alkyl, a 1-naphthyl, a 2-naphthyl, a 5dimethylamino-l-naphthyl or a phenyl which is unsubstituted or substituted by one or more substituents selected from a halogen atom, a C X -C A alkyl, a trifluoromethyl group, a nitro group, an amino group which is free or substituted by one or 2 C x -C 4 alkyls, a hydroxyl, a C x -C 4 alkoxy, a C x -C 4 alkenoxy, a C x -C 4 alkylthio, a trifluoromethoxy group, a benzyloxy group, a cyano group, a carboxyl group, a C x C 4 alkoxycarbonyl group, a carbamoyl group or a C x -C 4 alkylamido group, or, when m =» 0, R e can be a group - R e and R, are each independently hydrogen, a C x -C e alkyl or a phenylalkyl in which the alkyl is C x -C 4 , or R e and R 7 together form a group -(CH 2 ) p -; - n is 0, 1 or 2; - 65 - is Ο, 1 or 2; and - p is 4, 5 or 6.

12. A pharmaceutical composition in which a compound according to any one of claims 1 to 9 is present as the active principle.

13. A pharmaceutical composition in which a compound according to any one of claims 1 to 9 is present in association with another active principle. - 66

14. A compound of the formula (I) as herein defined, substantially as herein described in the Examples.

15. A compound of the formula (VI) as herein defined, 5 substantially as herein described in the Examples.

16. A method of preparing a compound of the formula (I) as herein defined, substantially as herein described in the Examples . 1 0

17. A compound of the formula (I) as herein defined whenever prepared by a method according to Claim 10 or Claim 16. 15

18. A method of preparing a compound of the formula (VI) as herein defined, substantially as herein described in the Examples .

19. A compound of the formula (VI) as herein defined 20. Whenever prepared by a method according to Claim 18.

20. A pharmaceutical composition according to Claim 12 or Claim 13, substantially as herein described.

21. 25 21. The features described in the foregoing specification, or any obvious equivalent thereof, in any novel selection.