NO180047B - Indoline derivatives with an amide group and pharmaceutical compositions containing them - Google Patents

Abstract

3-Hydroxy-1-indolinyl sulphones of formula (I) and their salts are new: In (I), R1 = halogen, 1-4C alkyl, OH, 1-4C alkoxy, benzyloxy, CN, CF3, NO2 or NH2; R2 = 1-6C alkyl; 3-7C cycloalkyl,; 5-7C cycloalkenyl; phenyl opt. substd. by 1-4C alkyl, 1-4C alkoxy, halogen, CF3 and/or NH2; or nitrophenyl opt. substd. by CF3, 1-4C alkyl or halogen; R5 = 1-4C alkyl; 1- or 2-naphthyl;5-dimethylamino-1-naphthyl; phenyl opt. substd. by halogen, CF3, NH2, mono- or di (1-4C alkyl) amino, OH, 1-4C alkoxy, 2-4C alkenyloxy, 1-4C alkylthio, CF3, benzyloxy, CN, COOH, 2-5C alkoxycarbonyl, CONH2, mono- or di (1-4C alkyl)carbamoyl or 1-4C alkanoylamino; or nitrophenyl opt. substd. by CF3, 2-4C alkenyloxy, halogen, 1-4C alkyl, 1-4C alkoxy, 1-4C alkylthio, OCF3 or benzyloxy; R6 = 1-6C alkyl or R7; R7 = 1-R-4-piperidinyl, 1-R-3-azetidinyl or (CH2)rR'; R = H, 1-4C alkyl, benzyloxycarbonyl or 2-5C alkoxycarbonyl; R1 = pyridyl, OH, NH2, mono- or di(1-4C alkyl)amino, COOH, 2-5C alkoxycarbonyl, benzylcarbonyl, CONH2 or mono- or di(1-4C alkyl)carbamoyl; or NR6R7 = morpholino; thiomorpholino; thiazolidinyl or 2,2-dimethylthiazolidinyl opt. substd. by R8; 1-piperazinyl opt. 4-substd. by R"8; and unsatd. 5-membered monoaza ring substd. by R8; or a satd. 3- to 7-membered monoaza ring substd. by R8 and R9; R8 = R'8 or (CH2)rA1, where A1 = OH, NH2 or mono- or di(1-4C alkyl)amino; R'8 = (CH2)qA2, where A2 = COOH, 2-5C alkoxycarbonyl, benzyloxycarbonyl, CONH2, CONHOH, mono- or di(1-4C alkyl)carbamoyl, CSNH2 or mono- or di(1-4C alkyl)thiocarbamoyl; R"8 = R8' or (CH2)A3, where A3 = NH2 or mono- or di(1-4C alkyl)amino; R9 = H, halogen, (CH2rOR10), (CH2)rNR11R12, (CH2)SCONR11R'11 or N3; R10 = H, 1-4C alkyl, mesyl or tosyl; R11, R'11 and R12 = H or 1-4C alkyl, or R11 = H, and R12 = benzyloxycarbonyl or 2-5C alkoxycarbonyl; n and m = 0-2; q = 0-3; r = 0-3, but not 0 when R8 or R9 is in a position alpha to the intracyclic amidic nitrogen (SiC); s = 0 or 1.

Description

The present invention relates to N-sulfonylindole derivatives having a functional amide group and the pharmaceutical compositions containing them.

US Patent 3,838,167 describes some N-sulfonylindole derivatives of the formula:

where

R' is hydrogen, alkyl or substituted or unsubstituted phenyl;

R'' 2 is halogen, alkyl, alkoxy, nitro or trifluoromethyl;

R'' 3 is alkyl, phenyl or alkylphenyl;

R''4 is alkyl, substituted or unsubstituted phenyl, alkoxy or phenoxy;

n' = 0, 1 or 2.

These compounds 1 are synthetic intermediates for the production of indole derivatives that are active in the central nervous system, with formula:

where R'' is alkyl, substituted or unsubstituted phenyl or hydroxyl.

The indole derivatives according to the present invention have

affinity for vasopressin and the oxytocin receptors.

Vasopressin is a hormone known for its antidiuretic action and its action in regulating arterial pressure. It stimulates several types of receptors: Vlf V2, Vla, Vlb and thus exerts cardiovascular, central, hepatic, antidiuretic, emetic and aggregation effects, as well as growth and mitotic effects, especially with regard to vascular and liver tissue. Vasopressin receptor antagonists may affect the regulation of the central or peripheral circulation, especially the coronary vessels, renal and gastric circulations, as well as the turnover of water and the release of adrenocorticotropic hormone (ACTH). Vasopressin receptors, like those for oxytocin, are also found on smooth muscle in the uterus. Ocytocin has a peptide structure similar to that of vasopressin. Its receptors are also found on myoepithelial cells in the mammary gland and in the central nervous system. (Presse Médicale, 1987, 16 (10), 481-485, J. Lab. Clin. Med., 1989, 114 (6), 617-632 and Pharmacol. Rev., 1991 (43 (1), 73-108 ).

Thus, the compounds according to the invention are particularly useful in the treatment of diseases of the central nervous system, the cardiovascular system and the stomach area in humans and animals.

The present invention is characterized by the formula:

where

- Rx is a halogen atom, C1.4-alkyl, C1-4-alkoxy,

- R2 is C3.7-cycloalkyl or phenyl which is unsubstituted or monosubstituted by halogen, - R3 is a hydrogen atom; - R4 is a carbamoyl group of formula CONR6R7; - R 5 is phenyl which is substituted by one or more substituents selected from a C 1 -alkyl, C 1 -alkyl or benzyloxy group; - R 6 is C 1-6 alkyl or R 6 is equal to R 7 ; - R 7 is a 4-piperidyl group or a 3-azetidinyl group, the said groups being substituted or unsubstituted on the nitrogen with C 1 -alkyl, with a benzyloxycarbonyl or with C 1 -alkoxycarbonyl; a group (CH 2 )r which is itself substituted with a 2-, 3- or 4-pyridyl group, with an amino group which is free or substituted with one or two C 1 -alkyls, a carboxyl group, C 1 -alkoxycarbonyl group, benzyloxycarbonyl group or carbamoyl group which is free or substituted with one or two C 1 -alkyls; - or R6 and R7 together, with the nitrogen atom to which they are attached, form a heterocyclic compound selected from:

morpholine,

thiomorpholine,

thiazolidine or 2,2-dimethylthiazolidine, unsubstituted

or substituted with R8,

piperazine, unsubstituted or substituted in the 4-position

with a group R''8,

piperidine, pyrrolidine, azetidine or aziridine which is

substituted with R8 and optionally R9;

- R 8 is R' 8 or a group (CH 2 ) r which is itself substituted with hydroxyl or with amino which is free or substituted with one or two C 1.4 alkyls; - R' 8 is a group (CH 2 ) q which is itself substituted with a carboxyl group, a C 1-4 alkoxycarbonyl group, a benzyloxy-carbonyl group, a carbamoyl group which is free or substituted with a hydroxyl or with one or two C 1-4 alkyls or a aminocarbothioyl group which is free or substituted with one or two C 1 -alkyls; - R'' 8 is R' 8 or a group (CH 2 ) 2 NH 2 which is free or substituted with one or two C 1 -alkyls; - R 9 is hydrogen, a group (CH 2 ) rNR 11 R 12 , or an azido group; - R 1X and R 12 are each hydrogen or C 1-4 alkyl or R 1X is hydrogen and R 12 is benzyloxycarbonyl or a C 1-4 -alkyloxycarbonyl; - m is 0, 1 or 2; - q is 0, 1, 2 or 3; - r is 0, 1, 2 or 3 with the restriction that r is not zero when R8 or R9 is in the alpha position to the amide ring nitrogen; - s is 0 or 1;

as well as its possible salts.

The salts in the compounds of formula (I) according to the present invention include those with inorganic or organic acids which make it possible to separate or crystallize the compounds of formula (I), such as picric acid, oxalic acid or an optically active acid, e.g. mandelic acid or camphorsulfonic acid, and those which form pharmaceutically acceptable salts such as hydrochloride, hydrogen sulfate, dihydrogen phosphate, methanesulfonate, maleate, fumarate or 2-naphthalenesulfonate.

The salts of the compounds of formula (I) also include the salts with organic or inorganic bases, e.g. the salts with alkali or alkaline earth metals such as the salts of sodium, potassium or calcium, the salts of sodium and potassium being preferred, or with an amine, such as trometamol, or even the salts of arginine or lysine or of any pharmaceutically acceptable amine.

The compounds (I) show cis-trans isomerism at the 2,3 bond in indoline. The different isomers form part of the invention.

By definition, the compounds (I) where R2 and R4 are on the same side of the ring are designated as the cis-isomers.

By definition, the compounds (I) where R 2 and R 4 are on opposite sides of the ring are called the trans isomers.

Furthermore, the compounds according to the invention have 2 asymmetric carbon atoms or more when R4 contains a 1- or 2-asymmetric carbon. The optical isomers of the compounds (I) form part of the invention.

In the present description and in the claims that follow, halogen means a fluorine, chlorine, bromine, or iodine atom; alkyl group means straight or branched hydrocarbon groups.

Preferred compounds (I) according to the invention are those in which at least one of the following conditions is satisfied: Ri is a chlorine or bromine atom and n = 1;

R 2 is chlorophenyl or cyclohexyl;

R4 is a group CONR6R7 where Rs and R7 or NR6R7 have one of the following definitions: - NR6R7 is a pyrrolidine group which is substituted in the 2-position with a group (CH2)q which is itself substituted with a carboxyl or carbamoyl group with q = 0 , 1, 2 or 3. - NR6R7 is a piperidine group which is substituted in the 4-position with an amino group, a C1.4-alkylamino or a C1.4-dialkylamino, - NR6R7 is a thiazolidine group which is substituted with a group (CH2)q which is itself substituted with a carboxyl or carbamoyl group with q = 0, 1, 2 or 3. - NR6R7 is a pyrrolidine group which is substituted in the 2-position with a group (CH2)q which is itself substituted with a carboxyl or carbamoyl group with q = 0, 1, 2 or 3 and which is substituted in the 4-position by an amino group, a C3-4-alkylamino or a C1-dialkylamino;

R 8 is a C 1 -alkyl and R 7 is a group (CH 2 ) r which is itself substituted with a carboxylic acid or a carbamoyl group with r = 1, 2 or 3;

R 5 is a phenyl substituted in the 3- and 4-position or in the 2- and 4-position with a methoxy group, or R 5 is a phenyl substituted in the 4-position with a methyl group;

m = 0.

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

The following abbreviations are used in the description and in the examples.

DCM: dichloromethane

AcOEt: ethyl acetate

MeOH: methanol

EtOH: ethanol

Ether: ethyl ether

DMF: dimethylformamide

THF: tetrahydrofuran

TEA: triethylamine

DMSO: dimethyl sulfoxide

DIPEA: diisopropylethylamine

DCC: N,N'-dicyclohexylcarbodiimide

DBU: 1, 8-diazabicyclo[5.4.0]undec-7-ene

TBD: 1,5,7-triazabicyclo[4.4.0]dec-5-ene

DBN: 1,5-diazabicyclo[4.3.0]non-5-ene

DMAP: 4-dimethylaminopyridine

DMPU: 1,3-dimethyl-2-oxohexahydropyrimidinone

TMEDA: tetramethylethylenediamine

LDA: lithium diisopropylamide

HMPA: hexamethylphosphoramide

HOBT: 1-hydroxybenzotriazole hydrate

BOP: benzotriazolyloxytrisdimethylaminophosphonium hexafluorophosphate

TFA: trifluoroacetic acid

Lawesson's reagent: 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide

mp: melting point

Salt solution: water saturated with sodium chloride

Dry ice: solid carbon dioxide

TLC: thin layer chromatography

HPLC: high resolution liquid chromatography

NMR: nuclear magnetic resonance

s: singlet

m: multiplet

bs: wide singlet

d: duplicate

Hydrochloride water: dilute hydrochloric acid, about IN 80% NaH: dispersion of sodium hydride in mineral oil (Janssen Chemica)

Me: methyl

One: ethyl

iPr: isopropyl, Pr: propyl

iPentyl: isopentyl

iBu: isobutyl

tBu: tert-butyl, Bu: butyl

Bz: benzyl

Ph: phenyl

RT: room temperature

The compounds (I) can be prepared by

a) reaction between a 2-aminophenone derivative of formula:

where Rx, R2 and n have the meanings shown above for I, and et

sulfonyl derivative with formula:

where

Hal is a halogen, preferably chlorine or bromine,

m and R 5 have the meanings mentioned above for (I);

b) treatment of the resulting compound of formula: with a halogen-substituted derivative of formula:

where

Hal' is a halogen, preferably bromine, and A represents either the group NR 6 R 7 or the group OR where R is a tert-butyl or a benzyl;

c) deblocking the resulting ester with the formula:

under appropriate conditions, where applicable, when A is OR; d) treating, where possible, the resulting acid from step c) of formula: or its acid chloride of formula: with a compound HNR6R7 according to appropriate amide coupling procedures; e) cyclization of the resulting compound from step b) or from step d) with formula: in a base medium to prepare the compound (I) according to the invention; f) separating, if appropriate, the cis and trans isomers of the compound (I), and, if appropriate, separating the enantiomers.

The 2-aminophenone derivatives (II) are known or prepared using known methods, such as those described by A.K. Singh et al., Synth. Commun. 1986, 16 (4), 485 and G.N. Walker, J. Org. Chem., 1962, 27, 1929. The 2-amino-2'-trifluoromethylbenzophenones and the other trifluoromethylated derivatives are prepared according to US Patent No. 3,341,592.

2,4-dimethoxybenzenesulfonyl chloride is prepared according to J. Am. Chem. Soc., 1952, 74, 2008.

The sulfonyl derivatives of formula (III) are known or are prepared using known methods. Thus, e.g. 4-dimethylaminobenzenesulfonyl chloride according to C.N. Sukenik et al., J. Am. Chem. Soc, 1977, 99, 851-858; p-benzyloxybenzenesulfonyl chloride is produced according to European patent application EP 229,566.

Alkoxybenzenesulfonyl chloride is produced from the sodium alkoxybenzenesulfonate which itself is produced by reacting an alkyl halide with sodium hydroxybenzenesulfonate.

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

Step a) of the preparation is carried out in pyridine with heating to a temperature between room temperature and the boiling point of the solution within a time period 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) in the preparation is carried out between sulfonamide of formula (IV) and an excess of the halogenated derivative of formula (V) in a solution such as dimethylformamide or dimethylsulfoxide, in an inert atmosphere, at a temperature between 0°C and room temperature, from a few hours to 24 hours, in the presence of sodium hydride.

When the group -NR6R7 contains a secondary amine group, i.e. when R6 and/or R7 are substituted with an amino group, it is possible to choose to use a halogenated derivative (V) with the formula Hal'-CH2-CO2R where R is a tert- butyl or a benzyl, to prepare the intermediates of formula (VI)' and then (VI)''. In this case, step c) for the formation of the acid of formula (VI) ' ' is carried out either through the action of hydrogen in the presence of a catalyst such as palladium or charcoal when R is benzyl, or in an acidic medium when R is tert-butyl, e.g. in the presence of TFA or in the presence of hydrobromic acid in acetic acid or even in the presence of ZnBr2 in DCM.

Step d) is carried out under usual conditions for amide coupling, e.g. in the presence of BOP or HOBT and DCC.

The compounds HNR6R7 are known or are prepared using known methods. As an example, the stereo-specific synthesis of (R)- and (S)-2-pyrrolidinyl acetic acids is carried out according to H. Rueger et al. in Heterocycles, 1982, 19 (9), 1677 from a proline derivative of suitable structure. The preparation of methyl N-Boc-3,4-dehydro-α-prolinate is carried out according to J.R. Dormoy, Synthesis, 1982, 753. The preparation of optically pure derivatives of pipecolic acid is described e.g. in Tetrahedron, 1992, 48 (3) 431-442 and Tetrahedron, 1991, 47 (24) 4039-4062.

The preparation of the derivatives of aziridine carboxylic acid is carried out according to K. Nakajima et al. in Bull. Chem. Soc. Jap., 1978, 51 (5), 1577.

Step e) in the preparation is closely related to an aldolization reaction: the methylene group in the a-position of the amide is deprotonated and the carbonyl group in the phenone acts as an internal electrophile, resulting in ring formation with the appearance of two asymmetric carbons (C<*>) .

The reaction can be illustrated using the following diagram:

The principles of the aldol addition reaction have been published by C.H. Heathcock in Asymmetric Synthesis, vol. 3: Stereo-differentiating addition reactions, part B, 111-112; Academic Press, 1984, published by J.D. Morrison.

It is known that the indole reaction of achiralamide anions gives rise to the formation of two racemic diastereoisomers of S-hydroxyamides in a ratio that depends largely on the experimental conditions used. The following can be mentioned from these conditions: type of inorganic or organic base used, type of cations or companion ions, the possible presence of additives in the reaction medium, the solvent, the reaction temperature and the structure of the compound undergoing this reaction.

When the groups R6 and R7 do not contain a group that can be hydrolyzed in an alkaline medium, it is possible to use sodium hydroxide in water, in the presence of an additional solvent, with or without the addition of a phase transfer catalyst; it is also possible to use a quaternary ammonium hydroxide, e.g. benzyltrimethylammonium hydroxide in methanol.

To carry out this aldolization reaction, it is also possible to use organic bases, for example: guanidines such as 1,5,7-triazabicyclo[4.4.0]dec-5-ene, amidines such as 1,8-diazabicyclo [5.4.0]undek-5-en

or 1,5-diazabicyclo[4.3.0]non-5-ene,

in a solvent or in a mixture of solvents chosen e.g. from benzene, THF, dichloromethane, methanol and dimethylformamide; the reaction is carried out under an inert (noble gas) atmosphere between -10°C and 110°C; 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 preferred that step e) in the preparation according to the invention is carried out in the presence of 1,8-diazabicyclo[5.4.0]undec-5-ene (DBU) in a solvent such as dichloromethane or methanol, at a temperature between -10°C and the reflux temperature of the solution.

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 anhydride solution, e.g. an alcohol (if appropriate in the presence of an additional solution such as THF), or else in a stoichiometric amount in THF, DMF or DMSO, if appropriate, in the presence of crown ethers, e.g. dicyclohexyl-18-crown-6; the reaction is carried out between -15°C and 80°C.

The use of an amide of the type RR'NLi or RR'NMgBr, where R and R' are monovalent radicals, such as a deprotination compound, is a method for preparing enolates of amides, which are intermediate steps in the aldolization reaction; this procedure has recently been reviewed by R.E. Ireland et al., J. Org. Chem., 1991, 56, 650. The reaction solution can be benzene, hexane or THF used in anhydride form under an inert atmosphere. Additive compounds such as LiF, LiCl, LiBr, Lii, LiBu, TMEDA, DMPU, HMPA or a crown ether can be added. (M. Murakate et al., J. Chem. Soc. Commun., 1990, 1657). As an example, mention may be made of the use of lithium diisopropylamide between -78°C and -30°C in anhydride THF under an inert atmosphere or in THF in the presence of additives such as e.g. tetramethylenediamine, DMPU or HMPA. Examples of other known amides that can be used are lithium cyclohexylamide and lithium 2,2,6,6-tetramethylcyclohexylamide. It is also possible to prepare other amides by reacting the required amount of butyllithium in hexane with linear or cyclic secondary amines, the reaction taking place in one of the solutions 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. Commun., 1990, 1657; M. Yamaguchi, Tetrahedron Lett., 1986, 27 (8), 959; P. J. Cox and N.S. Simpkins, Tetrahedron: Asymmetry, 1991, 2 (1), 1.

Silylamides of lithium, sodium or potassium constitute another group of bases that can be used, among which can be mentioned: (Me3Si)2NLi, (Me2PhSi)2NLi, (Et3Si)2NLi, (Me3Si)2NK, (Me3Si)2NNa.

It is also possible to use mixed amides as described by Y. Yamamoto, Tetrahedron, 1990, 46, 4563, e.g. the lithium salt of N-(trimethylsilyl)benzylamine or an analogue where benzylamine is replaced by a chiral primary amine such as (R)- or (S)-α-methylbenzylamine.

When the compound of formula (I) is to be prepared with two asymmetric carbon atoms, the use of chiral amides or alcoholates in step e) enables an enantiomeric enrichment of each of the cis- or trans-stereoisomers. The ratio between each of the enantiomers is then determined by measurement on a chiral high-resolution liquid chromatography column.

When the compound of formula (I) is to be prepared with 3 or 4 asymmetric carbon atoms, the cyclization step c) can be accompanied by a diastereoisomeric enrichment and the use of a suitable chiral base which makes it possible to change this diastereoisomeric enrichment.

In step f), the cis- and trans-geometric isomers of the compound (I) which are formed are extracted by conventional methods and separated by chromatography or fractional crystallization.

If appropriate, the optical isomers of each of the cis-

and the trans isomers separated, e.g. by preparative chromatography on a chiral column and followed, if possible, by a fractional crystallization or by the formation of an optically active salt in the presence of an appropriately chosen chiral acid or base.

Thus, when the compound according to the invention has two asymmetric carbon atoms, the enantiomers can be separated by chiral HPLC.

When the compound according to the invention has three or four asymmetric carbon atoms, the diastereoisomers can be separated using chromatographic methods and fractional crystallization methods.

Several methods can be used to differentiate and characterize the cis-isomer and the trans-isomer of compound (I). When R 3 is hydrogen, a comparative analysis is performed with high-field NMR (250 MHz) coupled e.g. together with the study of the Overhauser effect (N.O.E.) e.g. between the proton of the indoline (R3 = H) and the proton of the hydroxyl.

The IR spectra of the cis isomer and the trans isomer in solution in • DCM are different. The cis-isomer usually has a strong, fine and symmetrical absorption band around 3550-3520 cm"<1>, due to the hydroxyl vibration, while the trans-isomer has no vibrational band in this region.

Using data collected, it has been shown that the cis isomer is generally more stable in TLC on an alumina plate (60F254 neutral, type E, Merck), and elution with DCM containing various portions of AcOEt. Similarly, in chromatography on an aluminum column (alumina 90, particle size 0.063-0.200 mm), the cis isomer is usually eluted first, the eluate being DCM containing various portions of AcOEt or MeOH.

Thus, the cis- or trans-isomer of the compound (I) according to the invention can most often be determined by an analytical method. It is also possible to use the analogy between similar compounds or between compounds made from each other.

The absolute structure of some compounds of the invention was determined by X-ray analysis. After derivation, taking into account the value of the optical rotation, it is also possible to know the absolute structure of other compounds obtained in an analogous way.

A compound (I) where Rx is an amino group and/or a compound where R5 is a phenyl group substituted with an amino can be prepared by transferring a compound (VI) obtained in step b), where Rx is a nitro group and/or R 5 is a phenyl group which is substituted with a nitro, the other substituents have the meanings desired for (I), by catalytic hydrogenation, e.g. in the presence of palladium on charcoal, or rhodium or aluminum or Raney nickel.

The compounds (I) in which the substituents R 6 and/or R 7 or the group NR 6 R 7 contain a C 1-4 -alkyloxycarbonyl group make it possible to obtain, by hydrolysis of the ester, the compounds (I) in which R 6 and/or R 7 or the group NR 6 R 7 contain a

.carboxyl group, the other substituents of (I) remain unchanged. Furthermore, the compounds where R 6 and/or R 7 or NR 6 R 7 contain a carboxyl group make it possible to obtain, by means of conventional amide coupling reaction, the compounds (I) where R 6 and/or R 7 or the group NR 6 R 7 contain a car-

bamoyl group which is free or substituted with one or two C1. i - ■ alkyls, the other substituents are the same.

Finally, the compounds (I) in which R6 and/or R7 or the group NR6R7 contain a carbamoyl group make it possible to obtain, by means of Hofmann rearrangement, the compounds (I) in which R6 and/or R7 or the group NR6R7 contain an amino group, the other substituents are the same (J. Org. Chem., 1979, 44 (10) , 1746).

Thus, according to the present invention, the preparation method for the compounds (I) where R 6 and/or R 7 or the group NR 6 R 7 contains an amino group which is free or substituted with one or two C 1 -alkyls can have two variation possibilities: i) Step b) of the method is carried out by treating the compound (IV) obtained in step a) with a halogenated derivative (V) of the formula Hal'-CH2CONRsR7 where R6 and/or R7 or the group NR6R7 contains a precursor group of the amine, e.g.

a carboxy ester, a carboxyl or a carbamoyl; The crystallization step e) is then carried out and the precursor group of the amine | is transferred to the amine, e.g. the carboxyester group of the compound (I) thus obtained is hydrolyzed to a carboxyl group, which is then transferred to a carbamoyl group and then; to an amino group by means of the Hofmann rearrangement.

ii) Step b) is carried out by treating the compound (IV) obtained in step a) with a halogenated derivative (V) of formula Hal'-CH 2 COOR where R is benzyl or a tert-butyl; the ester of the compound (VI)' thus obtained is deblocked by means of a suitable treatment, according to step c); a coupling is then carried out with the compound HNR6R7 where the amino group of R6 and/or R7 is, if possible, protected; the compound (VI) thus obtained is then cyclized according to step e); and, if possible, the compound (I) in which amino groups are free is prepared by deblocking the amine.

The compounds (I) where the groups R6 and/or R7 or the group NR6R7 contain a benzyloxycarbonyl or alkoxycarbonyl group as a substituent of an amine group make it possible to obtain the compounds (I) where the amine group is free, the other substituents remaining the same.

The compounds of formula (VI) which can be used as intermediate steps for the preparation of the compounds (I) according to the invention are new and form part of the invention. In the same way, the compounds (VI)' and (VI)'' are new and form part of the invention.

The present invention thus also relates to the compounds of formula:

where

A' is a group selected from: NR 6 R 7 , OH, OtBu, OBz ; -R 1 , R 2 and R 5 are as defined for the compounds of formula (I), with the proviso that when A' is OtBu, R 5 is not unsubstituted phenyl.

The compounds of formula (I)'

where R17 R2, R3, R5, m and n have the meanings shown above for the compounds of formula (I)

RVI is a C 1-6 alkyl,

.RVII is a group (CH2)rCOOH with r = 1, 2 or 3,

or RVI and RVII together, with the nitrogen atom to which they are attached, form a heterocyclic compound selected from:

- thiazolidine or 2,2-dimethylthiazolidine, substituted with a (CH2)qCOOH group, - piperazine substituted in the 4-position with a (CH2)qCOOH group, - an unsaturated, 5-sided ring containing a single nitrogen atom and substituted with a (CH2) qCOOH group, - a saturated, 3-, 4-, 5-, 6- or 7-sided ring containing a single nitrogen atom and substituted with a (CH2) qCOOH group, with q = 0, 1, 2 or 3, can be decarboxylated to a compound of formula (I)'' which has the same structure around the 2,3 bond to the indoline as the starting compound

where

Rlf R2, R3, R5, m and n are defined as above,

R'VI is a C 1 -alkyl,

R'vii is a group (CH2)rH,

or R'VI and R'Vu together, with the nitrogen atom to which they are attached, form a heterocyclic compound selected from:

- thiazolidine or 2,2-dimethylthiazolidine, substituted with a (CH2/qH- group, - piperazine substituted in the 4-position with a (CH2)gH group, - an unsaturated, 5-sided ring containing a single nitrogen atom and substituted with a (CH 2 ) qH group, - a saturated, 3-, 4-, 5-, 6- or 7-sided ring containing a single nitrogen atom and substituted with a (CH 2 ) qH group.

The free-radical decarboxylation reaction is carried out according to D.H.R. Barton et al. in J. Chem. Society; Chem. Commun.; 1984, 1298.

The affinity of the compounds according to the invention to the vasopressin receptors was determined in vitro using the method described in J. Biol. Chem., 1985, 260 (5), 2844-2851. This procedure involves studying the replacement of tritiated vasopressin bound to Våsetene in rat liver membranes. The 50% inhibitory concentrations (IC50) of the compounds according to the invention for the binding of tritiated vasopressin are low, and vary up to 10"<9>M.

Furthermore, the inhibition of platelet aggregation induced by vasopressin was measured in human platelet-rich plasma (human PRP) using the method described in Thrombosis Res., 1987, 45, 7-16. The compounds according to the invention inhibit the aggregation triggered by 50-100 nM concentrations of vasopressin with low ID50 values (inhibitory doses) varying up to 10"<9>M. These results show the antagonistic activity of the compounds according to the invention towards the Vj. receptors.

The affinity of the compounds (I) according to the invention for the V2 receptors was measured with a method adapted from P. Crause et al., Molecular and Cellular Endocrinology, 1982, 28, 529-541.

The compounds according to the invention with cis-structure around the 2,3-bond of the indole have a marked selectivity towards the Vx receptors.

The affinity of the compounds (I) according to the invention for the oxytocin receptors was determined in vitro by the displacement of tritiated oxytocin bound to the receptors in a membrane preparation of pregnant female rat glands. The IC50 values of the compounds of the invention are low, between 10"<5>M and 10"<8>M.

The compounds according to the invention are active after administration via various routes, especially orally (via the mouth).

No signs of toxicity have been observed with these compounds in pharmacologically active amounts.

Thus, the compounds according to the invention can be used in the treatment or prevention of various vasopressin-dependent diseases, especially cardiovascular diseases such as high blood pressure, heart failure, thrombosis or coronary spasm, especially in smokers; diseases of the central nervous system, e.g. cerebral oedema, psychotic conditions, appetite disorders or memory disorders; diseases of the renal system, such as renal vasoconstriction or degeneration of the renal cortex; and diseases of the digestive system, e.g. peptic ulcer or the syndrome with pathological secretion of the antidiuretic hormone (SIADH).

The compounds according to the invention can also be used as antiemetics, especially for motion sickness and as anti-growth compounds, e.g. in cancer or atherosclerosis.

In women, the compounds according to the invention can be used for the treatment of dysmenorrhea (menstrual pain) or premature birth.

The present invention further relates to pharmaceutical mixtures containing an effective amount of a compound according to the invention, or of a pharmaceutically acceptable salt, and suitable mixing agents. Said mixing agents are selected according to the pharmaceutical form and the

in the desired way of supply.

The pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, surface, intratracheal, intranasal, transdermal or rectal administration, the active principles of formula I above, and their possible salts, can be administered to animals and humans in unit forms of administration, mixed with common pharmaceutical carriers, to prevent or treat the above-mentioned ailments or diseases. Suitable 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

in

supply. For surface application, the compounds according to the invention can be used in creams, ointments or solutions.

In order to achieve the desired prophylactic or therapeutic effect, the amount of the active principle can vary between 0.01 and 50 mg per kg body weight per day.

Each unit dose may 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 1-5 times per day to provide a daily dose of 0.5 to 5000 mg, preferably 1-2500 mg.

If a solid composition in the form of tablets is made, the main active ingredient is mixed with a pharmaceutical aid 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 suitable compounds, or they can also be treated so that they have a prolonged or delayed activity and so that they release a predetermined amount continuously of the active principle.

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 syrup or elixir or for administration in the form of drops may contain the active ingredient in combination with a sweetener, which is preferably calorie-free, and methylparaben and propylparaben as antiseptics, as well as with flavoring agents and a suitable colour.

Water-soluble granules or powders may contain the active ingredient mixed with dispersing or wetting compounds or with suspending compounds such as polyvinylpyrrolidone, as well as with sweetening agents or flavoring.

Rectal administration is carried out using suppositories which are made with binders that melt at the temperature of the rectum, e.g. cocoa butter or polyethylene glycols.

Parenteral administration is carried out using aqueous suspensions, isotonic saline solutions or sterile and injectable solutions containing pharmaceutically compatible dispersing compounds and/or wetting compounds,

e.g. propylene glycol or butylene glycol.

The active principle can also be formulated as micro-capsules, if suitable 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 may contain other active principles which may be useful in the treatment of ailments or diseases mentioned above.

Thus, the present invention relates to pharmaceutical mixtures containing a number of active principles in mixture, at least one of which is a compound according to the invention. The following examples illustrate the invention.

The compounds are characterized by their melting points (m.p.°C) (or their boiling point b.p.) and/or their NMR spectrum read at 200 MHz in DMSO, and/or their optical rotation (cÆ>) measured at 25°C (except when otherwise stated) .

The measured value of the optical rotation is dependent on the amount of residual solution present in the manufactured product.

Unless otherwise stated, the term "cis-isomer" or "trans-isomer" means that the isolated compound is a mixture of enantiomers, either with cis structure or with trans structure.

The optical purity of the compounds is studied using HPLC.

Example 1

N-methyl-N-methoxycarbonylmethyl-5-bromo-3-(2-fluorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide, cis isomer

A) Methyl N-bromoacetyl sarcosinate

This compound is prepared according to T.D. Harris et al. in J. Heterocyclic Chem., 1981, 18, 423.

B) 5-bromo-2-(3,4-dimethoxyphenylsulfonamido)-2'-fluorobenzo-phenone 20 g of 2-amino-5-bromo-2'-fluorobenzophenone are heated to 85°C for 48 hours in 120 ml of dry pyridine in the presence of 20 g of 3,4-dimethoxyphenylsulfonyl chloride. The mixture is cooled, poured into ice-cold water, the solid is filtered off, the solid is extracted with AcOEt, the organic phase is washed with water, a solution of hydrochloric acid (IN), water and then brine. After drying over magnesium sulfate and evaporation of the solvent under vacuum, a solid compound is obtained which is recrystallized from DCM/isopropyl ether.

m = 28 g

mp = 125-128°C. C) 5-bromo-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-(N'-methyl-N(methoxycarbonylmethyl)carbamylmethyl)]amino-2'-fluorobenzophenone 3.5 g of the compound prepared in step B dissolve in anhydride DMF at 0°C under argon and add 250 mg of 80% sodium hydride; after 15 min, 4.85 g of the compound prepared in step A is added and the mixture is left with stirring at room temperature for 12 hours. The reaction mixture is poured into water, the solid is filtered off and then the solid is dissolved in AcOEt, the organic phase is washed with water and then with salt water, and the solution is evaporated under vacuum. The oil obtained is filtered on silica by eluting with a DCM/AcOEt (85/15; v/v) mixture. It is recrystallized from a DCM/isopropyl ether/MeOH mixture.

m = 3.2 g

sm.p. = 136-137°C.

D) N-methyl-N-methoxycarbonylmethyl-5-bromo-3-(2-fluorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide, cis isomer

3.2 g of product obtained in the previous step is dissolved in DCM (3 ml), 750 mg of DBU is added and the mixture is allowed to stand with stirring

at room temperature for 24 hours. The reaction mixture is poured into a silica column; by elution with DCM/AcOEt (90/10;

v/v), a product is obtained which is the mixture of the two isomers (cis and trans) of the expected compound. This product is triturated in a hexane/isopropyl ether mixture and the solid obtained is filtered. The filtrates are chromatographed on an aluminum column which was previously equilibrated in a DCM/AcOEt (70/30; v/v) mixture. The least polar compound is eluted with a DCM/AcOEt (60/40; v/v) mixture and then recrystallized from a DCM/hexane/isopropyl ether mixture.

Sm.p = 95°C with evolution of gas.

Examples 2 and 3 2-[(4-benzyloxycarbonyl)-1-piperazinyl]carbonyl-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline, cis isomer and trans -isomer

A) 1-bromoacetyl-4-(benzyloxycarbonyl)piperazine

A mixture of 22 g of 4-benzyloxycarbonylpiperazine and 10.1 g of triethylamine in 200 ml of ether is cooled to 0°C. 20.2 g of bromoacetyl bromide in 100 ml of ether are added over 30 minutes and the mixture is left to reach room temperature. After 4 hours I, the reaction mixture is washed with water, dried, concentrated and then chromatographed on silica. The mixture DCM/AcOEt (95/5; v/v) elutes the expected compound which is recrystallized from DCM/isopropyl ether.

m = 9 g

mp = 100-101°C.

B) 2', 5-dichloro-2-(3,4-dimethoxyphenylsulfonamido)benzophenone

5.6 g of 2-amino-2',5-dichlorobenzophenone and 5 g of 3,4-dimethoxyphenylsulfonyl chloride are heated in pyridine to 100°C overnight. The pyridine is evaporated to dryness, water is added and extraction is carried out with ethyl acetate containing a small amount of DCM. After washing more than once with water and drying over sodium sulfate, the extract is evaporated under vacuum, and 7.7 g

of the expected product is recrystallized in a DCM/AcOEt mixture.

Sm.p. = 164°C.

C) 2',5-dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-(4-benzyloxycarbonyl-1-piperazinylcarbonylmethyl)]aminobenzophenone

2.3 g of benzophenone prepared in step B is placed in 10 ml of DMF and treated with 200 mg of 80% sodium hydride in oil. After 30 min, 5.3 g of the compound prepared in step A is added, and the mixture is stirred for 60 h at room temperature. The mixture is poured into water, the precipitate is filtered, taken up in DCM, dried and then concentrated and chromatographed on silica. The mixture DMC/AcOEt (90/10, v/v) elutes the expected product which is crystallized from a DCM/isopropyl ether mixture.

m = 2 g

Sm.p. = 173-175°C.

D) 2-[(4-benzyloxycarbonyl)-1-piperazinyl]carbonyl-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline, cis isomer and trans isomer 1 g of the compound obtained in the previous step

suspended in 20 ml of methanol and 20 ml of TMF and treated with 75 g of sodium methylate. After 2 hours, the mixture is neutralized by adding a small amount of dry ice, concentrated to dryness and then taken up in water; the mixture is then extracted with DCM,

the extract is dried and concentrated. The crude product is chromatographed on aluminium, and the DCM/AcOEt (80/20; v/v) mixture elutes the two isomers in turn.

The least polar isomer is recrystallized from the DCM/hexane mixture. This compound is the cis isomer.

m = 262 mg

Sm.p. = 169-179°C.

The most polar isomer is recrystallized from the DCM/isopropyl ether mixture.

m = 200 mg

Sm.p. = 209-211°C.

Example 4

5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-(1-piperazinylcarbonyl)indoline, cis isomer

200 mg of the cis-isomer prepared in the previous example are dissolved in 10 ml of ethanol and 5 ml of THF and hydrogenolysed at room temperature in the presence of 10% Pd/C. After 30 min, the mixture is filtered on celite, the filtrates are concentrated and then chromatographed on silica. The mixture MeOH/DCM (10/90; v/v) elutes the expected product which is recrystallized from a DCM/isopropyl ether mixture.

m = 110 mg

sm.p. 230-233°C.

Examples 5 and 6 5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-morpholinecarbonylindoline, cis-isomer and trans-isomer A) 2',5-dichloro- 2-[N-(3,4-dimethoxyphenylsulfonamido)benzophenone is treated with 350 mg of 80% sodium hydride in 30 ml of DMF at RT for 20 min. 4.5 g of morpholine bromoacetamide are added and the mixture is stirred at RT for 48 hours. The mixture is poured into water, the precipitate is filtered, dissolved in DCM, the solution is dried and concentrated. The product formed is recrystallized from a DCM/isopropyl ether mixture. 5.4 g is the result.

Sm.p. = 173-176°C.

B) 5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-morpholinecarbonylindoline, cis-isomer 1 g of the product obtained in the previous step is dissolved in methanol (10 ml) and THF (20 ml) the mixture and treated with 92 mg of sodium methylate at RT for 1 hour. The mixture is neutralized with dry ice, the solutions are partially evaporated, the mixture is taken up in <: >water, extracted with DCM and the extract is dried, concentrated and chromatographed on aluminium. The mixture DCM/AcOEt (70/30; v/v) elutes the least polar isomer which is recrystallized from a DCM/isopropyl ether mixture.

m = 215 mg: cis isomer

Sm.p. = 260-264°C.

C) 5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-morpholinecarbonylindoline, trans isomer

In the chromatography in the previous step, a more polar product is collected by eluting with the AcOEt/MeOH (90/10; v/v) mixture. After recrystallization from a DCM/isopropyl ether mixture, the result is:

m = 513 mg: trans isomer

Melting point = 240-241°C.

Example 7

N-methyl-N-carboxymethyl-5-bromo-3-(2-fluorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide, cis-isomer 200 mg of the compound which is prepared in example 1 is dissolved in 3 ml of MeOH and 1 ml of water containing 13 mg of sodium hydroxide. After stirring for 24 hours at RT, a drop of concentrated sodium hydroxide solution is added to terminate the reaction, and then, after 15 min, the mixture is acidified to pH 3 by addition of a potassium hydrogen sulfate solution. Water is added, the mixture is extracted with AcOEt and the extract is washed with water and dried over magnesium sulfate and the solution is evaporated under vacuum. The product obtained is recrystallized from DCM/isopropyl ether.

Melting point = 206-208°C.

Examples 8 and 9

5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-(4-ethylcarboxylatepiperidinocarbonyl)indoline, cis isomer, trans isomer

A) Ethyl N-bromoacetyl-4-piperidine carboxylate

This product is prepared from ethyl 4-piperidine carboxylate, which is commercially available.

B) 2', 5-dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl]-N-(4-ethyl carboxylatepiperidinecarbonylmethyl)]aminobenzophenone 8 g of 2',5-dichloro-2-(3,4- dimethoxyphenylsulfonamido)-benzophenone is dissolved in 100 ml of DMF and then 541 g of sodium hydride is added. After stirring for 30 min, 9.5 g of the compound from step A is added, and the mixture is stirred for 18 h at RT. The mixture is concentrated under vacuum, dissolved in water, extracted with ethyl acetate, and the extract dried and concentrated. The oil obtained is chromatographed on silica, eluting with AcOEt/DCM/hexane (40/10/50; v/v) mixture. The expected product is crystallized from ether.

m = 3.5 g

Sm.p. = 128°C.

C) 5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-(4-ethylcarboxylatepiperidinocarbonyl)indoline, cis isomer, trans isomer

A mixture containing 3.4 g of the compound made in the previous step and 869 mg of DBU in 10 ml of chloroform is heated to 60°C for 18 hours. The reaction mixture is then filtered on an aluminum column, eluted with a DCM/AcOEt mixture (90/10; v/v) to obtain the cis isomer.

m = 700 mg

Sm.p. = 110°C.

Pure ethyl acetate elutes the trans isomer.. m = 610 mg Sm.p. = 187°C.

Examples 10 and 11

N-methyl-N-2-pyridylethyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide, cis isomer, trans -isomer

A) N-[2-(2-chlorophenylcarbonyl)-5-chlorophenyl]-N-3,4-dimethoxyphenylsulfonyl)glycinic acid a) 2',5-dichloro-2-(3,4-dimethoxyphenylsulfonamido)benzophenone. This compound is prepared in example 2-3, step B. b) 2',5-dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-benzyl-oxycarbonylmethyl]aminobenzophenone.

172 g of the product prepared earlier are dissolved in 800 ml of DCM and cooled to 0°C. 11.7 g of 80% sodium hydride are subsequently added under nitrogen and then, after 30 minutes, 256 g of benzyl bromoacetate are added and the mixture is stirred for 24 hours at RT. DMF is evaporated, the residue is taken up in water, extracted with DCM and the extract is dried and concentrated. The expected product is crystallized from isopropyl ether and then recrystallized from a DCM/isopropyl ether mixture.

m = 136.5 g

Sm.p. = 102-104°C. c) N-[2-(2-chlorophenylcarbonyl)-5-chlorophenyl]-N-(3,4-dimethoxyphenylsulfonyl)glycinic acid. 50 g of benzyl ester obtained from earlier are dissolved in 500 ml of AcOEt, and 2.5 g of 5% Pd/C are added under nitrogen. The solution is stirred vigorously, and a stream of hydrogen is passed over it for 5 hours. At the end of the hydrogenation, the product crystallizes. The mixture is filtered on celite, the cake is washed well with hot DCM and the organic phase is concentrated. The expected product crystallizes and is then recrystallized from the DCM/isopropyl ether mixture.

m = 33.7 g

Sm.p. = 177-178°C. B) 2',5-dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-(N'-(2-(2-pyridyl)ethyl)-N'-methyl)carbamoylmethyl]aminobenzophenone. 2 g of the acid prepared in step A is placed in 30 ml of DCM and 1.13 g of 2-(2-methylaminoethyl)pyridine, then 844 mg of triethylamine and finally 1.92 g of BOP are added, and the mixture is stirred for 18 <; >hours at RT. The mixture is taken up with water, the organic phase is separated, washed with a sodium carbonate solution, dried and concentrated. After chromatography on silica, the expected product is collected by elution with the DCM/MeOH mixture (95/5; v/v).

m = 2 g

Sm.p. = 150°C.

C) N-methyl-N-(2-pyridylethyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide

A mixture containing 1.7 g of the product obtained from the previous step and 44 2 mg of DBU in DCM is heated to 55°C for 18 hours. The reaction mixture is chromatographed on aluminium. The mixture AcOEt/DCM (40/60; v/v) elutes the cis isomer.

m = 410 mg

Sm.p. = 191°C.

Pure AcOEt elutes the trans isomer.

m = 790 mg

Sm.p. = 154°C.

Example 12

2-(4-carboxypiperidinecarbonyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline, cis isomer

500 mg of the cis-isomer prepared in Example 9 is placed in 5 ml of methanol in the presence of 48 mg of sodium hydroxide in 1 ml of water. After stirring for 18 hours, the mixture is poured into water, acidified with dilute hydrochloric acid and extracted with DCM and the extract dried and concentrated. The solid is purified by chromatography on silica gel, eluted with the DCM/MeOH mixture (95/5; v/v) and the product obtained is then crystallized from a DCM/isopropyl ether mixture.

m = 250 mg

Sm.p. = 150°C.

Examples 13 and 14

N-methyl-N-(1-methyl-4-piperidyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide, cis isomer and trans-isomer A) 2',5-dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-(N'-methyl-N'-(methyl-4-piperidyl)carbamoylmethyl]aminobenzophenone. 2 g of the acid prepared in Example 10-11 step A in 50 ml of DCM is mixed with 650 mg of 4-methylamino-l-methylpiperidine in the presence of 1.90 g of BOP.After stirring for 2 hours at RT, the organic phase is washed with carbonated water, dried and concentrated. The residue is then chromatographed on silica, eluting with the DCM/MeOH mixture (90/10, v/v). 1.2 g of the expected product is obtained.

Sm.p. = 165-166°C. B) N-methyl-N-(methyl-4-piperidyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide, cis isomer and trans isomer.

650 mg of the product obtained in the previous step is treated overnight with 100 mg of sodium methylate in 5 ml of methanol. Dry ice is added, the solution is evaporated, the residue is taken up in carbonated water, extracted with DCM and the extract is dried and concentrated and then chromatographed on silica. The methanol/DCM mixture (5/95; v/v) elutes the two isomers alternately. Each is then recrystallized from a DCM/isopropyl ether mixture.

The trans isomer is the least polar under these conditions.

m = 205 mg

Sm.p. = 181°C.

Cis-isomer: m = 150 mg

Sm.p. = 97°C: contains 0.25 M isopropyl ether.

Examples 15 and 16.

5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-[4-methyl-1-piperazinylcarbonyl]indoline, cis isomer and trans isomer. A) 2',5-dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-((4-methyl-1-piperazinyl)carbamoylmethyl))aminobenzophenone.

This compound is obtained by the action of N-methyl-piperazine on the acid prepared in example 10-11 step A.

Sm.p. = 165-167°C. B) 5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-[4-methyl-1-piperazinylcarbonyl]indoline, cis isomer and trans isomer.

The compound from the previous step is cyclized

by proceeding as in example 12-13. The two isomers that are formed are separated using chromatography on aluminium. The mixture DCM/AcOEt (75/25; v/v) elutes the least polar product: the cis isomer, which is recrystallized from a DCM/isopropyl ether mixture.

Sm.p. = 120°C: contains 0.25 M isopropyl ether.

The DCM/MeOH mixture elutes the most polar compound, the trans isomer, which is then recrystallized from methanol.

Sm.p. = 189°C.

Examples 17 and 18 N-isopropyl-N-methoxycarbonylethyl-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide, cis isomer and trans isomer A ) N-isopropyl-N-(methoxycarbonylethyl)bromoacetamide. 90 g of isopropylamine is added dropwise to 130 g of a solution, which has been cooled to -10°C, consisting of methyl acrylate in 300 ml of methanol. After 72 hours at RT, the mixture is evaporated and the residue distilled. The oil obtained (168.3 g) is methyl 3-(N-isopropyl)aminopropionate.

Boiling point = 73-78°C at 15 mm Hg.

29 g of the compound obtained in 100 ml of DCM are mixed with

20.2 g bromoacetyl bromide in 100 ml DCM at 0°C. After 12 hours at RT, the solution is evaporated, the residue taken up in water, extracted with ethyl acetate and the extract dried and concentrated. The oil that is obtained is used as such in the following steps. B) 2',5-dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-(N'-isopropyl-N'-methoxycarbonylethyl)carbamoylmethyl]amino-benzophenone.

The compound is obtained by following the usual procedure, by reacting the product prepared in step A with 2',5-dichloro-2-(3,4-dimethoxyphenylsulfonamido)benzophenone in the presence of sodium hydride.

Sm.p. = 135-137°C (recrystallization: DCM/isopropyl ether). C) N-isopropyl-N-methoxycarbonylethyl-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide, cis isomer and trans isomer.

This product is obtained by cyclizing the compound prepared in step B, in the presence of DBU. The cis isomer is separated by chromatography on aluminum eluted with a DCM/AcOEt mixture (90/10; v/v). The product is then crystallized from an AcOEt/hexane mixture.

Sm.p. = 153-155°C.

The trans isomer is obtained by eluting the aluminum column with ethyl acetate. The product is then recrystallized from a methanol/isopropyl ether mixture.

Sm.p. = 182-185°C.

Examples 19 and 20

N-methyl-N-methoxycarbonylmethyl-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide, cis isomer and trans isomer

The two isomers in this connection are prepared according to the method described in example 1. They are separated by chromatography on aluminium. The mixture DCM/AcOEt (80/20; v/v) elutes the cis isomer. It is recrystallized from a DCM/isopropyl ether mixture as a white powder containing 0.25 mol of isopropyl ether. It is transferred in foam form by heating in a vacuum.

The NMR spectrum of the cis isomer (Example 19) is given in Fig. 1.

The trans isomer is eluted with pure AcOEt. It is recrystallized from DCM/isopropyl ether.

Sm.p. = 176-178°C.

The NMR spectrum of the trans isomer (Example 20) is given in Fig. 2.

Examples 21 and 22

N-methyl-N-carboxymethyl-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide, cis isomer and trans isomer

These compounds are prepared from the compounds described in examples 19 and 20 according to the method described in example 8.

Cis-isomer: M.p. = 220-222°C after recrystallization from a DCM/isopropyl ether/MeOH mixture.

Trans isomer: M.p. = 222-225°C after recrystallization from a DCM/isopropyl ether mixture.

Examples 23 and 24

N-Methyl-N-carbamoylmethyl-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide, cis isomer and trans isomer

Each isomer is obtained from the corresponding isomer of the acid prepared in Examples 21-22. 605 mg of the trans isomer of the acid obtained in the previous example is dissolved in 10 ml of DCM, and 435 mg of BOP and 260 mg of DIPEA are added. After 5 min at RT, 6 ml of 20% aqueous ammonia is added with vigorous stirring, and the mixture is further stirred for 4 hours. A sodium carbonate solution is added and the mixture is extracted with DCM. The organic phase is washed successively with water, a sodium hydrogen sulphate solution and water and is then dried over magnesium sulphate. After evaporation, the residue is chromatographed on silica gel and eluted with an AcOEt/MeOH mixture (95/5; v/v). The product obtained is crystallized twice from a DCM/EtOH mixture at 0°C.

Sm.p. = 236°C.

The NMR spectrum of the trans isomer (Example 23) is given in Fig. 3.

Using the same procedure, the cis isomer is prepared.

The expected product is crystallized from DCM/isopropyl ether. The finely divided compound, dried in vacuum at -70°C for 8 hours, contains 0.25 mol of isopropyl ether. NMR spectra of the cis isomer (Example 24) are given in Fig. 4.

Examples 25 and 2 6

5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-1-(4-hydroxy-1-piperidyl)carbonylindoline, trans isomer.

This compound is prepared from N-[2-(2-chlorophenyl-carbonyl)-5-chlorophenyl]-N-(3,4-dimethoxyphenylsulfonyl)glycine acid described in examples 11-12, step A.

The preparation is then carried out as in examples 11-12 for the addition of 4-hydroxypiperidine, in the presence of BOP and triethylamine. The product obtained is then cyclized according to the usual procedure in the presence of DBU. The two isomers are prepared by chromatography on aluminium. The mixture DCM/MeOH (99/1; v/v) elutes the cis isomer.

The product is crystallized from a DCM/hexane/MeOH mixture and the solid obtained is then triturated in DCM/hexane to give an amorphous powder.

The cis-isomer is characterized by its NMR spectrum at 388°K.

1-18 ppm:m:4H:CH2 in positions 3 and 5 of the piperidine

2.8-3.65 ppm:m:5H:CH2 in positions 2 and 6 of the piperidine and CH in position 4.

3.75 ppm:2s:6H:20CH

4.15 ppm:d:1H:OH on piperidine

5.45 ppm:S:lH:CH (indoline)

6.1 ppm:s:1H:0H indoline

6.8-7.6 ppm:m:10H:H aromatic

DMSO: 2.4 ppm

DOH: 2.76 ppm.

The DCM/MeOH mixture (97/3; v/v) elutes the trans isomer which is recrystallized from DCM/isopropyl ether.

Sm.p. = 232-234°C.

Synthesis in the (L)-proline series: Examples 27, 29 and 30.

The examples 2 7 o<q> 27a

5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-[(2S)-(2-methoxycarbonyl)pyrrolidinecarbonyl]-indoline, (cis-isomers: 2 compounds ).

A) Methyl-(L)-N-(bromoacetyl)prolinate.

20 g of triethylamine and 20 g of bromoacetyl bromide in 30 ml of DCM are added simultaneously to a solution of 16.7 g of methyl (L)-prolinate hydrochloride in 20 ml of DCM while the temperature is maintained at -5°C and the mixture is stirred at room temperature for 24 hours . Water is added and the mixture is washed with a solution of KHSO 4 with water, with a sodium bicarbonate solution and with water and then dried over magnesium sulfate. After evaporation, an oil is obtained which is dried under vacuum. This oil, purified by TLC, is used as is in the following step. B) 2',5-dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-((2S)-(2-methoxycarbonyl)pyrrolidinecarbonylmethyl)]aminobenzophenone.

4.66 g of 2',5-dichloro-2-(3,4-dimethoxyphenylsulfonamido)-benzophenone dissolved in 40 ml of anhydride DMF under argon, at 0°C, 340 mg of 80% sodium hydride is added, and then, after 30 min , 6.5 g of the compound obtained in step A. After 4 days at RT, the mixture is poured into water, extracted with AcOEt, the extract is washed with water, with brine and then dried over magnesium sulfate and evaporated under vacuum. A solid compound containing a small amount of starting brominated derivative is eluted with a DCM/AcOEt mixture (85/15; v/v) by chromato-

graphy on silica gel. A sample is recrystallized from DCM/isopropyl ether.

Analysis calculated C 54.81, H 4.44, N 4.41

found 54.40, H 4.54, N 4.55

C) 5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2- [ (2S)-(2-methoxycarbonyl)pyrrolidinecarbonyl]-indoline, (cis-isomerism) . 1.1 g of the compound obtained in the previous step is heated in 4 ml of methylene chloride for 24 hours with one equivalent of DBU. HPLC analysis of a sample shows the existence of the expected 4 isomers. After 24 hours, the reaction mixture is poured onto an aluminum column, pre-equilibrated in DCM/AcOEt mixture (90/10; v/v) and eluted with the DCM/AcOEt mixture (90/10; v/v to 70/30; v/ v). 510 mg of a mixture of at least two polar compounds is obtained in the ratio 4/1 (measured by HPLC). 1°) Two subsequent crystallizations from DCM/isopropyl ether while cooling give the title compound. 2°) The crystallization starting liquids for the preceding compound are chromatographed on aluminum eluting with DCM/AcOEt (85/15; v/v). The preceding compound is then separated from the second, the latter being dissolved in a minimum amount of DCM and then precipitated by adding a minimum amount of hexane. Example 28 2-((2S)-2-carboxypyrrolidinecarbonyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline, cis isomer 43 0 mg of the compound prepared in example 27 is dissolved in 6 ml of methanol, 41 mg of sodium hydroxide in 1 ml of water is added and the mixture is stirred for 24 hours at RT. The mixture is acidified to pH 3 with a few drops of a potassium hydrogen sulphate solution and extracted with ethyl acetate. The extract is washed with water and then dried over magnesium sulphate. Chromatography is performed on a silica column developed in a DCM/pentane mixture (80/20; v/v). The unreacted ester elutes the expected acid which is then recrystallized from DCM/isopropyl ether. Examples 2 9 and 29a 2-((2S)-2-carbamoylpyrrolidinecarbonyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indoline, (cis- isomers: compounds). 230 mg of the compound prepared in example 28 is dissolved in 5 ml of DCM, 50 mg of DIPEA and then 165 mg of BOP is added and the mixture stands for 5 min at RT. The mixture is cooled in an ice bath and a stream of ammonia gas is bubbled through for 1 minute, and after 15 min for a further 1 min. Water and then a large volume of ethyl acetate are added to obtain two phases. The organic solution is washed with a sodium carbonate solution, water, a potassium hydrogen sulfate solution, water and then brine. After drying, the residue is chromatographed on silica and eluting with a DCM/MeOH mixture (93/7; v/v). The product obtained is triturated in a DCM/isopropyl ether/hexane mixture. It contains 1/3 mole of isopropyl ether.

The compound from example 29 can be prepared according to another method. A) 2',5-dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-((2S-2-carbamoylpyrrolidinecarbonylmethyl)]aminobenzophenone.

33.9 g of the acid prepared in example 10-11, step A is dissolved in 300 ml of chloroform. 15 g of thionyl chloride are added and the mixture is refluxed for 1.5 hours. The mixture is evaporated to dryness and the residue is taken up in DCM and evaporated again. The mixture is dissolved in 300 ml of DCM, brought to 0°C and 10.5 g of (L)-prolinamide hydrochloride is added, and then 18 g of DIPEA in 20 ml of DCM is slowly added without allowing the temperature of the reaction mixture to exceed 3°C.

After one night at room temperature, the reaction mixture is washed with sodium bicarbonate (2 times) and then with potassium hydrogen sulfate (2 times); the reaction mixture is dried and concentrated. The crude product obtained is dissolved in a minimum amount of DCM and added dropwise to isopropyl ether (1.2 1) with stirring. After stirring for 2 hours, the precipitate obtained is filtered and dried under vacuum for 6 hours at 60°C. 42 g are collected.

B) 2-((2S)-2-carbamoylpyrrolidinecarbonyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline, (cis-isomers: 2 compounds). Dissolve 5 g of the product prepared in the previous step in 50 ml of methanol. The solution is cooled to -10°C; 1.35 g of DBU is added and the mixture stands for 60 hours at -10°C. A compound crystallizes; it is filtered (cis compound 1). The crystallization liquids are neutralized with KHSO 4 , and the mixture is evaporated to dryness. It is taken up in water, extracted twice with DCM, and the extracts dried and concentrated. The crude product obtained is chromatographed on silica and eluted with an AcOEt/DCM mixture (28/72; v/v). A mixture is collected which is dissolved in the minimum amount of methanol while hot; insoluble material is filtered off, the liquids are placed overnight at -4°C and the cis-compound 2 is crystallized.

The analysis of the NMR spectrum shows the presence of one mole of MeOH per moles of product. The recrystallization of the product from ethanol makes it possible to remove the solution in the crystals.

This compound is identical, the solution expected, to that produced by the first method in the present example.

The compound crystallized in step B) above, called cis compound 1, is recrystallized from methanol.

Example 30 5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-[(2S)-2-(hydroxymethyl)pyrrolidinecarbonyl]indoline, cis isomers. A) 2', 5-dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-(2-(hydroxymethyl)pyrrolidinecarbonylmethyl)]aminobenzophenone.

This compound is obtained by reacting (L)-prolinol with the acid prepared in Example 10-11, step A, following the usual procedure. B) 5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-[(2S)-2-(hydroxymethyl)pyrrolidinecarbonyl]indoline, cis isomer.

1.5 g of the compound from the previous step is cyclized in the presence of 380 mg of DBU in 2 ml of DCM. After 3 days at RT, 1 ml of DCM is added, and the mixture is then heated to 40°C overnight. The formation of three main compounds is observed by TLC on silica (eluent AcOEt).

The least polar fraction is eluted by chromatography on silica with DCM/AcOEt (60/40 to 80/20; v/v). Chromatography on aluminum is then carried out by eluting with DCM/MeOH (99/1; v/v). The fraction obtained is homogeneous by TLC. The product is recrystallized three times from DCM/isopropyl ether. The expected product is obtained with an HPLC purity greater than 99%.

Syntheses in the (D)- proline series: example 31.

Example 31

5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-[(2R)-2-(methoxycarbonyl)pyrrolidinecarbonyl]-indoline, cis-isomer A) 2' ,5-dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-((2R)-2-methoxycarbonyl)pyrrolidinecarbonylmethyl]aminobenzophenone.

This compound is obtained from the acid prepared in Example 10-11, step A (3 g), to which is added 1.2 g of methyl-(D)-prolinate and 2.8 g of BOP in 10 ml of DCM in the presence of 1.15 g triethylamine. The mixture is left for 1 hour at RT and then diluted with DCM, the organic phase is washed with sodium carbonate and with potassium hydrogen sulphate, dried and concentrated. The crude product is chromatographed on silica, eluted with a DCM/AcOEt mixture (95/5; v/v). The product obtained is then recrystallized from a DCM/isopropyl ether mixture. B) 5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-[(2R)-2-(methoxycarbonyl) )pyrrolidinecarbonyl]-indoline, cis isomer.

1.5 g of the preceding compound is refluxed overnight in 5 ml of DCM in the presence of 360 mg of DBU. The mixture chroma-

is engraved on aluminium. The mixture DCM/AcOEt (95/5; v/v) elutes the least polar fraction (m = 300 mg) which is recrystallized twice in a DCM/isopropyl ether mixture.

This compound is the enantiomer obtained from (D)-proline in that described in Example 27.

Example 32 and 32a

N-methyl-N-methoxycarbonylmethyl-5-chloro-3-(2-chlorophenyl)-1-(4-ethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide, trans isomer and cis isomer A) 2',5- dichloro-2-[N-(4-ethoxyphenylsulfonyl)-N-(N'-methyl-N'-(methoxycarbonylmethyl)carbamoylmethyl]aminobenzophenone.

5.7 g of 2',5-dichloro-2-(4-ethoxyphenylsulfonamido)-benzophenone are dissolved under argon in 40 ml of DMF, and 400 mg of 80% sodium hydride are added at 0°C; after 15 min, 4.3 g of methyl N-(bromoacetyl)sarcosinate are added. After 48 hours, the expected product is extracted in the usual way and purified by chromatography on silica eluting with DCM/AcOEt (90/10;

l v/v) and recrystallization in a DCM/isopropyl ether mixture.

Sm.p. = 158-160°C. B) N-methyl-N-methoxycarbonylmethyl-5-chloro-3-(2-chlorophenyl)-1-(4-ethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide, trans isomer. 1 g of the compound obtained in the previous step is dissolved in 4 ml of DCM and treated for 90 min at room temperature with 312 mg of TBD. A solution of potassium hydrogen sulfate is added, the DCM is evaporated under vacuum, the mixture is extracted with AcOEt and the extract is washed and dried over magnesium sulfate. The expected product is obtained by chromatography on silica gel and elution with DCM/AcOEt (90/10; v/v).

m = 590 mg

Sm.p. = 168-171°C after recrystallization from DCM/hexane. C) N-methyl-N-methoxycarbonylmethyl-5-chloro-3-(2-chlorophenyl)-1-(4-ethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide, cis-isomer.

2.96 g of the compound obtained in step A is suspended in 20 ml of methanol and 10 ml of THF; 100 mg of sodium methylate is added and the mixture is left for 7 hours in a refrigerator. Water is added, the mixture is neutralized with a potassium hydrogen sulphate solution and part of the methanol is evaporated under vacuum. After extraction with AcOEt, the precipitate is chromatographed on aluminum and then eluted with a DCM/AcOEt mixture (80/20; v/v). 850 mg of the expected product is obtained and recrystallized from a DCM/isopropyl ether mixture.

NMR spectrum is given in fig. 6.

Using methods similar to those described above, intermediate compounds (VI) for the synthesis of the compounds (I) according to the invention were prepared.

the compounds (VI) which were prepared are described in table 1 below.

The compounds (I) which were prepared are described in Table 2 below.

3) This compound is characterized by its optical rotation:

- Example 34

Analysis: calculated C 55.54 H 4.24 N 3.93

found 55.72 4.57 3.83 NMR spectra at 200 MHz (DMSO: 2.5 ppm)

- Example 34: Fig. 5

- Example 3 8

0.7-1.1 ppm:m:6H:2CH3 (Et)

5.2-5.7 ppm:3s:1H:H (indoline)

6.2-8.2 ppm:m:llH:OH + aromatics

- Example 3 9

0.3-1.2 ppm:m:3H:CH3 (Et)

1.5-4.3 ppm:m: 15H: CH2 - CO, CH2 (Et), CH2-N, 20CH3, CO2CH3 , 5.2-5.6 ppm:3s:1H:H (indoline)

6.2-8.2 ppm:m:llH:OH + aromatics

- Example 4 0

0.8-1.1 ppm:m:3H:CH3 (Et)

2.2- 3.9 ppm:m:15H:CH2CO, CH2 (Et), CH2N, C02CH3, 20CH3 5.3- 5.7 ppm:2s:lH:H (indoline)

6.6- 8.2 ppm:m:llH:OH + aromatics

- Example 63

0.4-1 ppm: Split t :3H:CH2-CH2-CH3

5 ppm:m:2H:CH2-CH2-CH3

2.5-4.4 ppm:m:13H:CH2-CH2-CH3, NCH2COOCH3, 20CH3

5.2-5.8 ppm; bs:lH:H (indoline)

6.5-8.3 ppm:m:llH:OH + aromatics

- Example 66

0-1.5 ppm:m: 3H:CH2-CH3

2.3- 5.8 ppm:m:14H:CH2-CH3, NCH2COOCH3, 20CH3, H (indoline) 6.1-8.3 ppm:m:llH:OH + aromatics

-Example 75

1.95 ppm:bs:2H:NH2

2.7- 5.3 ppm:m:12H:20CH3, 2NCH2, H (indoline) CHNHj,

6-8.3 ppm:m:llH:OH + aromatics

- Example 76a

25

Q!D = +102 (c = 0.35; chloroform)

- Example 76b

a^5= -158 (c = 0.2; chloroform)

Some compounds according to the invention described in Table 2 are useful in the preparation of other compounds according to the invention. E.g. compound 41 was obtained from compound 39 by treatment in basic solution in methanol MeOH/H 2 O. Compound 49 was prepared from compound 41 by treatment with aqueous ammonia in the presence of DIPEA and BOP.

Example 77

N-ethyl-N-(2-aminoethyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide, (cis-isomer )

500 mg of compound 49 is dissolved in 10 ml of acetonitrile and 10 ml of water and 252 mg of pyridine and 380 mg of bis(trifluoroacetoxy)-iodobenzene are added. After stirring for 2 hours, the mixture is taken up in a solution of hydrochloric acid, extracted with ether, made alkaline with dilute sodium hydroxide solution, extracted with

DCM and the extract dried and concentrated. An oil is obtained and the expected product is then crystallized from ether.

m = 150 mg

Sm.p. = 164°C

Example 78

N-ethyl-N-[(IS)-1-(ethoxycarbonyl)ethyl]-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide , (cis-isomer) A) N-[2-(2-chlorophenylcarbonyl)-5-chlorophenyl]-N-(3,4-dimethoxy-phenylsulfonyl) glycic acid chloride.

A mixture containing 11 g of the acid prepared in example 10-11, step A) and 5 g of thionyl chloride in 10 ml of chloroform heated for 1 hour at 60°C. The mixture is allowed to reach RT, concentrated under vacuum and the precipitate taken up in DCM (twice). A yellow oil is obtained which is used as is in the following step.

IR: 1800 cm'<1> (C=0) B) 2',5-dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-(N'-ethyl-N'-((IS) -1-(ethoxycarbonylethyl)ethoxycarbamoylmethyl)]-aminobenzophenone.

The preparation of this compound was carried out according to J. Org. Chem., 1985, 50, 945-950.

5.15 g of (L)-Boe(N-Et)AlaOEt is treated with 10 ml of TFA at 0°C to remove the Boe group. The mixture is concentrated under vacuum, taken up in 20 ml of DCM, cooled to -78°C and two equivalents of TEA and the acid chloride made in the previous step dissolved in DCM are added. After 18 hours at RT, the mixture is extracted with DCM, the extract is washed with water and then chromatographed on silica eluting with a DCM/AcOEt mixture (90/10; v/v). The expected product is crystallized from isopropyl ether.

Sm.p. = 112°C

m = 8 g

C) N-ethyl-N-[(IS)-1-(ethoxycarbonyl)ethyl]-5-chloro-3-(2-chloro-.phenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy- 2-indoline carboxamide, (cis-isomer).

The compound obtained in the previous step is stirred at RT

for 18 h in 10 ml THF and 20 ml ethanol, in the presence of 1.4 6 g DBU. The mixture is concentrated under vacuum, the precipitate is collected

in DCM, washed with water, concentrated and the product chromatographed on aluminum by elution with AcOEt/DCM (10/90; v/v).

NMR

0-0.9 ppm: split d:3H:CH-CH3

0.9-1.7 ppm:m:6H:2CH3 (ethyl)

2.6-5.8 ppm:m:12H:20CH3, NCHz, OCH^, NCH, COCH

6.1-8.3 ppm:m:llH:OH - 10 H aromatics

Examples 79 and 80 N,N-di[2-(methoxycarbonyl)ethyl]-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide, cis- isomer and trans-isomer

A) N,N-di[2-(methoxycarbonyl)ethyl]benzylamine.

Preparation according to J. Am. Chem. Soc, 1950, 72, 3298.

107 g of benzylamine in 200 ml of ethanol are cooled in an ice bath and 172.2 g of methyl acrylate in 250 ml of ethanol are added slowly. After 13 days at RT, the solvent is evaporated under vacuum and part of the oily precipitate is distilled.

Sm.p. = 135-140°C at 0.6 mm Hg

m = 30 g

IR: 1730 cm'<1>

B) N,N-(2-dimethoxycarbonyl)ethyl]amine.

27.9 g of the amine obtained in the preceding step, placed in 500 ml of methanol, is mixed with 3 g of 5% palladium on charcoal and treated under hydrogen pressure for 1 hour. The mixture is filtered on celite, purified with methanol, and the solution is evaporated under vacuum; the remaining oil is used as is in the following step.

C) N,N-di[2-(methoxycarbonyl)ethyl]bromoacetamide.

A mixture containing 14.3 g of the amine prepared in the previous step, 100 ml of DCM and 10.6 ml of TEA is cooled in an ice bath; 15.3 g of bromoacetyl bromide are added dropwise and the mixture is stirred for 48 hours at RT. The mixture is extracted with DCM, the extract is washed with water and then chromatographed on silica eluting with a DCM/MeOH mixture (97/3; v/v). The expected product is obtained in the form of an oil.

m = 15.9 g

IR: 1650 cm"1 and 1730 cm"<1>. D) 2',5-dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-[N',N-di(2-methoxycarbonyl)ethyl)carbamoylmethyl] ] aminobenzophenone.

14.3 g of 2',5-dichloro-2-(3,4-dimethoxyphenylsulfonamido)-benzophenone is placed in 180 ml of DMF, and 1.1 g of sodium hydroxide is added in portions. After stirring for 1 hour at RT, the mixture is cooled in an ice bath, and 14.3 g of the product prepared in the previous step is added, and the mixture is stirred for 72 hours at RT. The mixture is extracted with DCM, the extract is washed with water and then chromatographed on silica and eluted with a DCM/AcOEt mixture (93/7; v/v).

m = 28.4 g

Sm.p. = 130°C.

E) N,N-di[2-(methoxycarbonyl)ethyl]-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide, cis isomer. 12 g of the compound prepared in the previous step and 0.930 g of sodium methylate in 150 ml of methanol are mixed at 0°C, and the mixture is stirred overnight at RT. The reaction mixture is neutralized by adding 5% HKSO 4 , and the solvent is then evaporated under vacuum. The precipitate is chromatographed on aluminum and eluted with a DCM/AcOEt mixture (8/2; v/v). 2.4 g of the expected product is recovered and crystallized from methanol.

Sm.p. = 175°C

F) N,N-di[2-(methoxycarbonyl)ethyl]-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide, trans isomer.

Chromatography of the previous step is continued and elution is carried out with a DCM/MeOH mixture (9.5/0.5; v/v). 1.82 g of the trans isomer is obtained and crystallized from isopropyl ether.

Sm.p. = 85°C.

Examples 81, 82 and 83

2-((2R)-2-carbamoylthiazolidinecarbonyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline (cis isomer: 2 compounds and trans isomer)

A) (L)-4-thiazolidinecarboxamide.

This compound is prepared according to J. Med. Chem.,

1981, 24, 692. B) 2',5-dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-((2R)-2-carbamoylthiazolidinecarbonylmethyl)]aminobenzophenone.

This compound is obtained using the usual methods from the acid prepared in examples 10-11, step A).

Sm.p. = 125°C after crystallization from ether.

C) 2-((2R)-2-carbamoylthiazolidinecarbonyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline. 4.3 g of the product obtained in step B) is cyclized in 90 ml of MeOH at RT in the presence of 1 g of DBU. The mixture is concentrated, the precipitate is taken up in water and DCM, the layers are separated, the organic layer is washed with KHSO 4 and then dried and concentrated. The precipitate is chromatographed on aluminum and eluting with DCM/MeOH (97/3; v/v). The compound is obtained in the cis form (mixture of two diastereoisomers): 1.5 g, and then in the trans form (mixture of two diastereoisomers): m = 1 g. a) The cis fraction is crystallized from MeOH/DCM to obtain cis compound 1.

Sm.p. = 17°C after crystallization from isopropyl ether.

b) The crystallization liquids from the previous product are chromatographed on silica and eluting with AcOEt/DCM (3 0/70; v/v). The cis compound 2 that was obtained is recrystallized from ether. c) The trans fraction (mixture of two diastereoisomers) is recrystallized from isopropyl ether.

Sm.p. = 170°C.

Examples 84, 85, 86 and 86a

5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-[(2S)-2-(N,N-dimethylthiocarbamoyl)pyrrolidinecarbonyl] indoline, cis- isomerism (2 compounds), trans-isomerism: 2 compounds).

A) (L)-(N'-Boc)-N,N-dimethylprolinthioamide.

The compound is prepared according to J. Med. Chem., 1989, 2178 .

2.36 g of (N'-Boe)-N,N-dimethylprolinamide is heated in anhydride toluene under argon at 80°C for 4 hours in the presence of 2.3 g of Lawesson's reagent. After 24 hours, the solvent is evaporated and isopropanol is added. The precipitate that forms is separated, and the isopropanol is evaporated and the precipitate is chromatographed on silica and eluted with hexane/AcOEt (30/70; v/v). The product obtained is recrystallized while cold from DCM/isopropyl ether (30/70; v/v).

Sm.p. = 62°C.

B) 2',5-dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-((2S)-2-(N',N'-dimethylthiocarbamoyl)pyrrolidinecarbonylmethyl)]amino-benzophenone. 3 g of the product prepared in the previous step are dissolved in 10 ml of DCM and treated at 0°C for 2 hours with 10 ml of DFA.

The mixture is evaporated to dryness, then 20 ml of DCM and 6.1 g of the acid prepared in examples 10-11, step A) are added at 0°C, and the mixture is neutralized with 3 g of DIPEA. 5.15 g BOP is dissolved in 30 ml DCM, and this solution is added to the previous solution at 0°C over 30 min; neutral pH is maintained by adding DIPEA and the mixture is stirred for 3 hours at 0°C. After one night at RT, the mixture is extracted in the usual way and then chromatographed on silica and eluting with DCM/AcOEt (85/15; v/v). The product obtained is recrystallized from isopropyl ether.

C) 5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-[(2S)-2-(N,N-dimethylthiocarbamoyl)pyrrolidinecarbonyl]indoline ( cis-isomerism: 2 compounds, and trans-isomers: 2 compounds). 3.8 g of the compound obtained in the previous step is dissolved in 15 ml of DCM and the mixture is heated to reflux for 36 hours in the presence of 850 mg of DBU. The different isomers that are formed are separated by repeated chromatographic runs on silica. a) When using DCM/AcOEt (85/15; v/v) the expected compound is eluted in the form of a mixture of 2 cis diastereoisomers.

The least soluble diastereoisomer is crystallized twice from a DCM/isopropyl ether/methanol mixture and then recrystallized from the minimum amount of DMF at 60°C, and then two volumes of ethanol are added.

b) The crystallization liquids from the previous mixture are taken up and the second cis diastereoisomer is crystallized

from a DCM/isopropyl ether mixt.

c) The chromatography fractions that were eluted last, as well as the crystallization starting liquids from fractions a) and b) are combined and chromatographed again on silica and eluting with hexane/AcOEt (20/80; v/v). First isolated is a fraction that is crystallized three times from a DCM/isopropyl ether mixture and an insoluble compound is removed on paper between each recrystallization. The trans isomer 1 is thus obtained. d) The second fraction contains trans-isomer 2 which is recrystallized from a DCM/isopropyl ether mixture and crystallized with 1/3 mol of isopropyl ether. Examples 87, 88 and 89 2-((2S)-2-carbamoylpyrrolidinecarbonyl)-5-chloro-3-cyclohexyl-1-3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline, (cis-isomers: 2 compounds, trans-isomers) A ) 5-chloro-2-[N-(3,4-dimethoxyphenylsulfonyl)amino]-cyclohexylphenone.

A solution of 35.6 g of 2-amino-5-chlorocyclohexylphenone and 39.5 g of 3,4-dimethoxyphenylsulfonyl chloride in 340 ml of pyridine is stirred for 24 hours at RT. The solvent is evaporated under vacuum and the precipitate is then washed with water and an acid solution (0.5N HCl). The expected product is crystallized from ethanol.

Sm.p. = 135°C

m = 56.1 g. B) 2-[(N-benzyloxycarbonylmethyl-N-(3,4-dimethoxyphenyl-sulfonyl))amino]-5-chlorocyclohexylphenone.

3.2 g of sodium hydride is added in portions to 52.6 g of the compound prepared in the previous step in 520 ml of DMF, and the mixture is stirred for 1 hour at RT. After cooling in an ice bath, 21 ml of benzyloxycarbonylmethyl bromide are added dropwise and the mixture is stirred for 24 hours at RT. The solvent is evaporated under vacuum and the precipitate is taken up in water. It is extracted with

DCM, and the extract is washed with water; the product obtained is used as is in the following step. ! C) N-(5-chloro-2-(cyclohexylcarbonyl)phenyl)-N-(3,4-dimethoxy-phenylsulfonyl)glycine.

The compound obtained in the previous step is placed with 3.9 g of 5% palladium on charcoal in 700 ml of acetic acid under hydrogen

(1 atmosphere). Towards the end of the reaction, the palladium is filtered

on Celitt' and cleaned with hot acetic acid; the solution is evaporated under vacuum and the precipitate is taken up in water. It is extracted with DCM and the extract is washed with water and then with a concentrated NaHCO 3 solution. The precipitate obtained is chromatographed on silica and eluted with a DCM/MeOH solution (97/3; v/v). The expected product is crystallized from ethanol.

Sm.p. = 160°C

m = 22.4 g. D) 5-chloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-((2S)-2-carbamoylpyrrolidinecarbonylmethyl)]aminocyclohexylphenone.

A mixture containing 9.92 g of the acid prepared in the previous step, 3 g of (L)-prolinamide hydrochloride and 3.5 ml of DIPEA in 75 ml of DCM is cooled to 0°C. 8.84 g of BOP in solution in DCM are added, and the pH is maintained at 7 by the addition of DIPEA. The mixture is stirred for 24 hours at RT. The mixture is extracted with DCM, and the extract is washed with a saturated NaHCO 3 solution, a brine solution, a 5% KHSO 4 solution and again with a brine solution. The product is chromatographed on silica and eluted with a DCM/MeOH solution (96/4; v/v). The expected product solidifies in isopropyl ether.

E) 2-((2S)-2-carbamoylpyrrolidinecarbonyl)-5-chloro-3-cyclohexyl-1-(3,4-dimethoxy enylsulfonyl)-3-hydroxyindoline, cis isomer (2 compounds, trans isomer). 5.9 g of the compound prepared in the previous step and 1.67 g of DBU are placed in 60 ml of methanol with stirring at 0°C for 48 hours. The solvent is evaporated under vacuum, water is added, the mixture is extracted with DCM and the extract is then washed with a 5% KHSO 4 solution. The product is chromatographed on aluminum and eluted with DCM/MeOH (98/2; v/v).

a) The least polar fraction contains the 2 cis isomers. This fraction is recrystallized from methanol. The first compound thus obtained (cis 1) is purified using

HPLC.

Sm.p. = 185°C.

By recrystallization of the starting solutions from MeOH, another compound is obtained (cis 2). HPLC purity: 75% (it contains 25% cis 1).

Sm.p. = 132°C.

b) The most polar fraction contains the trans isomer in the form of an apparently simple compound obtained by

recrystallization from methanol.

Example 89a

2-((2S)-2-carbamoylpyrrolidinecarbonyl)-5-chloro-3-cyclohexyl-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline, cis isomer (2 compounds, trans isomer).

Using a method similar to that described for example 87, 88 and 89, an analogous compound in the (D)-proline series is prepared.

The compound obtained after crystallization from a DCM/MeOH mixture has the trans structure.

The NMR spectrum of this compound and that described in step E b) of the previous example are identical.

Example 90

5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-2-[(2S)-(N-methylaminocarbonyl)pyrrolidinecarbonyl]-3-hydroxyindoline, cis isomer

920 mg of the compound prepared in Example 28 is placed, with stirring, in 20 mL of DCM containing 371 mg of BOP for 15 min, a stream of monomethylamine is bubbled through for 10 min, and stirring is continued for an additional 30 min. The mixture is taken up in water, the layers are separated, the organic layer is washed with potassium hydrogen sulphate and with sodium carbonate, dried and concentrated. The precipitate is chromatographed on silica and eluted with DCM/methanol (97.5/2.5; v/v). The expected product is collected and crystallized from an isopropyl ether/DCM mixture.

m = 750 mg

Sm.p. = 158°C

25

aD = -216° (c = 0.3; chloroform)

Proceeding as in the previously described examples (Examples 27-31 and 90), and using derivatives of (L)-proline (except where otherwise stated), other intermediate compounds (VI) were used for the synthesis of the compounds (I) according to the invention produced.

The compounds (VI) that were prepared are described in Table 3 below.

The compounds (I) which were prepared are described in Table 4 below.

The compound from Example 107 is the enantiomer of that of Example 106.

The compound from example 108a is prepared from the compound in example 28 by reaction with hydroxylamine hydrochloride in DMF and by activation with the compound BOP in the presence of DIPEA.

Some of the compounds according to the invention, described in Table 4 above, can be used for the preparation of other compounds. Thus, the compound from Example 99 makes it possible to obtain the compound from Example 101, then that from Example 103, and finally that from Example 104.

Example 109

2-((2S,4S)-4-azido-2-(methoxycarbonyl)pyrrolidinecarbonyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline, cis isomer

A) 2',5-dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-((2S,4R)-4-hydroxy-2-(methoxycarbonyl)pyrrolidinecarbonylmethyl)]amino-benzophenone .-

15 g of the acid prepared in examples 10-11, step A) and 6.25 g of methyl-(2S,4R)-4-hydroxyprolinate hydrochloride are heated to 0°C in 150 ml of DCM in the presence of 7.4 g of DIPEA. A solution of 12.7 BOP in 30 ml DCM is added dropwise over 30 min and the amount of DIPEA necessary to neutralize the solution is added. After one night at RT, the mixture is extracted in the usual way and chromatographed on silica eluting with a DCM/AcOEt mixture (60/40; v/v). The expected product is crystallized from a DCM/ether/isopropyl ether mixture. B) 2',5-dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-((2S,4R)-4-mesyloxy-2 -(methoxycarbonyl)pyrrolidinecarbonylmethyl)]-aminobenzophenone. 2 g of the compound obtained in the previous step are dissolved at 0°C in 10 ml of DCM. 550 mg of triethylamine and then 550 mg of methanesulfonyl chloride are added, and the mixture stands at 0°C for 20 hours. Water is added and the organic layer is washed with 0.5 N hydrochloric acid water, with water and then with a sodium bicarbonate solution, dried over magnesium sulfate and evaporated. The oil obtained is used as is in the following step. C) 2-[N-((2S,4S)-4-azido-2-(methoxycarbonyl)pyrrolidinecarbonylmethyl)-N-(3,4-dimethoxyphenylsulfonyl)]amino-2', 5-dichlorobenzophenone. 11 g of the product prepared in the preceding step is heated in 60 ml of DMSO to 80-90°C in the presence of 2.7 g of sodium azide for 18 hours. The mixture is poured into water, extracted with ethyl acetate, the organic layer is washed with water, dried and chromatographed on silica and eluted with a pentane/AcOEt mixture (50/50; v/v). An oil (10 g) is obtained. D) 2-((2S,4S)-4-azido-2-(methoxycarbonyl)pyrrolidinecarbonyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenyl-sulfonyl)-3 -hydroxyindoline, cis isomer. 3.3 8 g of the product obtained in the previous step is cyclized under the usual conditions in the presence of DBU. The expected product obtained is recrystallized from DCM/isopropyl ether.

Example 110

2-[(2S,4S)-4-(N-benzyloxycarbonyl-N-methyl)amino-2-(methoxy-carbonyl)pyrrolidinecarbonyl]-5-chloro-3-(2-chlorophenyl)-1-(3,4 -dimethoxyphenylsulfonyl)-3-hydroxyindoline, cis-isomer A) Methyl ester of (N-Boc)-4-hydroxyproline.

The starting compound is the hydrochloride of the methyl ester of (2S,4R)-4-hydroxyproline. 19 g of this compound is suspended in 100 ml of THF, 22.9 g of (Boc) 20 is added and the mixture is cooled to 0°C. 21.2 g of triethylamine in 25 ml of THF are added dropwise, and the mixture is stirred for 12 hours at 0°C and 4 hours at 60°C. Water is added, the mixture is extracted with ethyl acetate, the organic layer is washed with water, with a potassium hydrogen sulfate solution (4 times), with water and then with brine. The solvent is evaporated and the oil (21.6 g) is isolated and it contains a small amount of (Boc)20.

B) Methyl ester of (2S,4R)-(N-Boc)-4-mesyloxyproline.

A solution of 22.9 g of the product prepared in the previous step in 250 ml of DCM is cooled to 0°C. 22.9 g of mesyl chloride in 10 ml of DCM is added dropwise, then 9.4 g of triethylamine in 100 ml of DCM is added dropwise and the mixture is left overnight to reach RT. The mixture is evaporated to dryness, water is added, the mixture is extracted with AcOEt, the organic layer is washed with water and brine and dried over magnesium sulphate. After another evaporation, an oil is obtained which is used as it is in the following step. C) Methyl ester of (2S,4S)-(N-Boc)-4-azidoproline.

The compound is prepared from that obtained in step B. 15.2 g of methyl ester of (N-Boc)-4-mesyloxyproline is dissolved in 70 ml of DMSO and the solution is heated at 90°C for 5 hours in the presence of 3.05 g of sodium azide. The mixture is cooled, water is added, the mixture is extracted with AcOEt, the organic layer is washed with water and brine and dried over MgSO 4 . The oil obtained is purified by chromatography on silica and eluted with the AcOEt/hexane mixture (40/60; v/v).

aD =-37.8° (c=3; chloroform)

lit. otj^ = -36.6° (c = 2.8; chloroform) D.J. Abraham et al. ,

J. Med. Chem., 1983, 549, 26.

D) Methyl ester of (2S,4S)-(N-Boc)-4-aminoproline.

8.45 g of the compound obtained in step C is dissolved in 100 ml of methanol, 500 mg of 10% Pd/C is added, and the mixture is hydrogenated at 40°C for 18 hours. The catalyst is filtered off, half of the methanol is evaporated, 100 ml of 0.5 N HCl is added, the remaining methanol is evaporated and the unreacted starting material is extracted with AcOEt. The aqueous phase is treated with sodium carbonate and the fraction containing the expected product (m = 4.35 g) is extracted with AcOEt. E) Methyl ester of (2S,4S)-(N-Boc)-4-(N'-benzyloxycarbonylamino)proline.

The crude product obtained in the previous step is dissolved in 15 ml of ether and 15 ml of DCM at 0°C. 2.3 g of DIPEA and then 3.03 g of benzyl chloroformate in 5 ml of DCM are added, over 70 min at 0°C. After 3 hours, the solvents are evaporated at RT under vacuum; water and ethyl acetate are added, and the organic phase is washed successively with a potassium hydrogen sulphate solution (3 times), with water (3 times), with a sodium carbonate solution (3 times), with water (3 times) and with salt water. The product is chromatographed on silica and eluted with a hexane/AcOEt mixture (40/60; v/v) to give the expected product.

aD = -16.4° (c = 0.3; chloroform)

F) Methyl ester of (2S,4S)-(N-Boc)-4-(N'-benzyloxycarbonyl-N'-methyl)aminoproline. 2 g of the compound obtained in the previous step is dissolved in 20 ml of DMF at 0°C under argon in the presence of 2.25 g of methyl iodide. 170 mg of 80% sodium hydride are added in portions, and the mixture is stirred at 0°C for 90 min. The mixture is extracted with water and ethyl acetate, the organic phase is washed with water and then brine. The product is chromatographed on silica and eluted with a hexane/AcOEt mixture (50/50; v/v). 1.55 g of the expected product is obtained.

aD = -38.8° c ( 0.38: chloroform)

G) 2',5-dichloro-2-[(2S,4S)-N-(3,4-dimethoxyphenylsulfonyl)-N-(4-(N'-benzyloxycarbonyl-N'-methyl)amino-2-(methoxycarbonyl )-pyrrolidinecarbonylmethyl)]aminobenzophenone.

This product is obtained using the usual methods.

aD = -22.4° (c = 0.37; chloroform)

H) 2-[(2S,4S)-4-(N-benzyloxycarbonyl)-N-methyl)-amino-2-(methoxycarbonyl)pyrrolidinecarbonyl]-5-chloro-3-(2-chlorophenyl)-1-(3 ,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline, cis isomer.

This product is obtained by cyclization in the presence of DBU according to the usual procedures. The crystals that form are crystallized from DCM/isopropyl ether.

Sm.p. = 129°C

Q!D = -129° (c = 0.321; chloroform)

The isomeric purity by HPLC is 99%.

The compounds prepared in examples 109 and 110 are used to prepare the compounds according to the invention described in Table 5 below.

The compound from example 112 makes it possible to prepare one after another the compounds in examples 115 and 116 described in table 6 below, and the compound from example 114 makes it possible to prepare the compound from example 116a.

The compound from example 116a can be prepared either by transfer of the compound from example 114 or from (2S,4S)-(N-Boc)-4-(dimethylamino)prolinamide, the preparation of which is carried out as follows: 1) Methyl-(2S,4S )-(N-Boc)-4-aminoprolinate is prepared from methyl-(2S,4S)-4-azidoprolinate according to T.R. Webl in J. Org. Chem., 1991, 56, 3009.

2) Methyl-(2S,4S)-(N-Boc)-4-(dimethylamino)prolinate.

4 g of the compound prepared in 1) are dissolved in 50 ml of acetonitrile, 12.8 ml of 30% formalin are added and then, during 5

min, 3 g of sodium cyanoborohydride are added. After the reactants have been in contact for 2 hours, acetic acid is added to bring the pH of the solution to 6. After 3 hours, acetonitrile is evaporated, water, potassium carbonate and solid sodium chloride are added and the mixture is extracted with 4 volumes of ethyl acetate. The organic phase is evaporated, the precipitate is dissolved in IN hydrochloric acid and extracted with AcOEt. Solid sodium carbonate and then solid sodium chloride are added to the aqueous phase and the extraction is carried out with AcOEt. After evaporation, the precipitate is chromatographed on silica and eluted with a DCM/MeOH mixture (95/5; v/v), and an oil which solidifies is isolated.

m = 2.1 g

IR (DCM) : 1755 cm"<1>, 1695 cm"<1>.

3) 534 mg of the ester prepared in 2) is dissolved in 4 ml of MeOH and treated with sodium hydroxide (116 mg) in 1 ml of water for 4 8 hours

at RT. The mixture is acidified with 0.5 N hydrochloric acid to a pH of 3.5 and evaporated to dryness. An acetotropic drying of the precipitate is carried out in the presence of benzene (5 times), and then the precipitate is dried under vacuum for 8 hours. 2 ml of DMF and 3 ml of DCM are then added and the mixture is cooled to 0°C. 865 mg of BOP, and DIPEA, are added to bring the reaction mixture to neutral. After 15 min, a stream of ammonia gas is bubbled through 2 times for 30 min. After 2 hours at RT, the DCM is evaporated, carbonated water and sodium chloride are added, and the mixture is extracted with 4 volumes of AcOEt. After evaporation, the precipitate is chromatographed on silica. The mixture (DCM/NH 4 OH; 84.5/15/0.5; v/v/v) eluted a solid compound (m = 185 mg) which was recrystallized from a DCM/isopropyl ether mixture.

Example 117

Decarboxylation of N-(2-carboxyethyl)-N-ethyl-3-(2-chlorophenyl)-5-chloro-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indoline-carboxamide, cis isomer

630 mg of the compound prepared in Example 41 is placed in solution in 20 ml of THF under an argon atmosphere, and then 101 mg of N-methylmorpholine at -15°C and 118 mg of isobutyl chloroformate are added. After stirring for 5 minutes, 127 mg of N-hydroxy-2-pyridinethione and 101 mg of THF are added, the mixture is kept at -15°C with stirring for 15 min, 900 mg of tert-butyl mercaptan is then added and the mixture is allowed to return to room temperature. The reaction mixture is irradiated for 1.30 hours with a tungsten slit lamp (150 watts). The mixture is concentrated, taken up in water, extracted with DCM and the extract dried and concentrated. The precipitate is chromatographed on silica and eluted with DCM/AcOEt (95/5; v/v). The expected product is achieved.

m = 300 mg

Sm.p. = 215°C.

This compound is similar to that from example 125 described in European patent application EP 469984. It has the cis structure around the 2,3 bond in indoline as in the starting compound.

Example 118

Decarboxylation of 2-((2R,)-2-carboxymethyl)pyrrolidinecarbonyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenyl-sulfonyl)-3-hydroxyindoline, cis isomer

The preparation is carried out as in the preceding example from the compound described in example 102.

The product obtained is recrystallized from a DCM/isopropyl ether mixture.

Sm.p. = 215-220°C

aD = -214.5° (c = 0.2; chloroform)

This compound is 2-((2S)-2-methylpyrrolidinecarbonyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline, cis isomer.

Example 119

Decarboxylation of 2-(2-carboxypyrrolidinecarbonyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline, cis isomer

The preparation is carried out as in the previous example using the compound made in example 28 as the starting compound. The product obtained is recrystallized from an isopropyl ether/DCM mixture.

Sm.p. = 263°C

aD = -201.5° (c = 0.2; chloroform)

This compound is 2-pyrrolidinecarbonyl-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline, cis isomer.

Claims (13)

1. Compound characterized by formula: where - R x is a halogen atom, C 1-4 alkyl, C 1-4 alkoxy, - R 2 is C 3-7 -cycloalkyl or phenyl which is unsubstituted or monosubstituted by halogen, - R 3 is a hydrogen atom; - R4 is a carbamoyl group of formula CONR6R7; - R 5 is phenyl which is substituted by one or more substituents selected from a C 1 -alkyl, C 1 -alkyl or benzyloxy group; - R6 is C±-6-alkyl or R6 is equal to R7; - R7 is a 4-piperidyl group or a 3-azetidinyl group, the said groups being substituted or unsubstituted on the nitrogen by C-1-alkyl, by a benzyloxycarbonyl or by C1. 1 -Alkoxycarbonyl; a group (CH 2 )r which is itself substituted with a 2-, 3- or 4-pyridyl group, with an amino group which is free or substituted with one or two C 1-4 alkyls, a carboxyl group, C 1-4 alkoxycarbonyl group, benzyloxy- carbonyl group or carbamoyl group which is free or substituted with one or two C1-4 alkyls; - or R6 and R7 together, with the nitrogen atom to which they are attached, form a heterocyclic compound selected from: morpholine, thiomorpholine, thiazolidine or 2,2-dimethylthiazolidine, unsubstituted or substituted with R8, piperazine, unsubstituted or substituted in the 4-position with a group R''8, piperidine, pyrrolidine, azetidine or aziridine which is substituted with R8 and optionally R9; - R 8 is R' 8 or a group (CH 2 ) r which is itself substituted with hydroxyl or with amino which is free or substituted with one or two C 1.4 alkyls; - R'8 is a group (CH2)q which is itself substituted with a carboxyl group, a C₁-alkoxycarbonyl group, a benzyloxycarbonyl group, a carbamoyl group that is free or substituted with a hydroxyl or with one or two C₁-alkyls or an aminocarbothioyl group which is free or substituted with one or two C1-4 alkyls; - R'' 8 is R' 8 or a group (CH 2 ) 2 NH 2 which is free or substituted with one or two C 1 -alkyls; - R9 is hydrogen, a group (CH2) rNRuRi2' or an azido group; - RX 1 and R 12 are each hydrogen or C 1-4 alkyl or R 1X is hydrogen and R 12 is benzyloxycarbonyl or a C 1-4 alkoxycarbonyl; - m is 0, 1 or 2; - q is 0, 1, 2 or 3; - r is 0, 1, 2 or 3 with the restriction that r is not zero when R8 or R9 is in the alpha position to the amide ring nitrogen; - s is 0 or 1; as well as its possible salts. 2. Connection according to claim 1, characterized by Rx being a chlorine or bromine atom and n = 1. • 3. Compound according to one of claims 1-2, characterized in that R2 is chlorophenyl or cyclohexyl. 4. Compound according to one of claims 1-3, characterized in that R5 is phenyl substituted in the 3- and 4-positions or in the 2- and 4-positions with a methoxy group, or that R5 is a phenyl substituted in the 4-position with methyl. 5. Compound according to one of claims 1-4, characterized in that m = 0. 6. Compound according to one of claims 1-5, characterized in that R4 is CONR6R7 and NR6R7 is a pyrrolidine group substituted in the 2-position with a group (CH2)q which is itself substituted with a carboxyl group, or a carbamoyl group with q = 0, 1, 2 or 3. 7. Compound according to one of claims 1-5, characterized in that R 4 is CONR 6 R 7 and NR 6 R 7 is a piperidine group substituted in the 4-position with an amino group, a G 1 -alkylamino or a C 1-4 -dialkylamino. 8. Compound according to one of claims 1-5, characterized in that R4 is CONR6R7 and NR6R7 is a thiazolidine group substituted with a group (CH2)q which is itself substituted with a carboxyl group or a carbamoyl group with Q = 0, 1, 2 or 3 . 9. Compound according to one of claims 1-5, characterized in that R4 is CONR6R7 and NR6R7 is a pyrrolidine group substituted in the 2-position with a group (CH2)q which is itself substituted with a carboxyl group or a carbamoyl group and substituted in the 4-position with an amino group, a C 1 -alkylamino or a C 1 -dialkylamino. 10. Compound according to one of claims 1-5, characterized in that R 4 is CONR 6 R 7 and NR 6 R 7 is a C-1 alkyl and R 7 is a group (CH 2 ) r which is itself substituted with a carboxyl group or a carbamoyl group with r = 1, 2 or 3. 11. Compound according to one of claims 1-10 in the form of a cis-isomer, characterized in that R2 and R4 are on the same side of the indoline ring. 12. Compound characterized by the formula: where A is a group selected from: NRSR7, OH, OtBu, OBz; -Ri, R2 and R5 are as stated in claim 1, provided that when A' is OtBu, R 5 is not unsubstituted phenyl. 1 13. Pharmaceutical mixture, in characterized in that a compound according to et of claims 1-10 is present as the active principle together with a pharmaceutically acceptable carrier or excipient.